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Volume 31

July/September

Number 3

Official Journal of the Brazilan Society of Coloproctology FOUNDER Klaus Rebel - RJ EDITOR Eduardo de Paula Vieira - RJ Coeditors Afonso Henrique da Silva e Souza Junior - SP Olival de Oliveira Junior - PR Editorial board José Hypolito da Silva -  SP José Reinan Ramos - RJ José Ribamar Baldez - MA Julio César M. dos Santos Junior - SP Karen Delacoste Pires Mallmann - RS Klaus Rebel - RJ Lusmar Veras Rodrigues - CE Maria Cristina Sartor - PR Mauro de Souza Leite Pinho - SC Paulo Gonçalves de Oliveira - DF Paulo Roberto Arruda Alves - SP Raul Cutait - SP Renato Araújo Bonardi - PR Robert William de Azevedo Bringel - SP Roberto Misici - CE Rogerio Saad Hossne - SP Rubens Valarini - PR Sergio Carlos Nahas - SP Sidney Nadal - SP Sinara Monica de Oliveira Leite - MG

Angelita Habr-Gama - SP Antonio Booz Senna Silva Ferreira - PE Boris Barone  - SP Cláudio Saddy Rodrigues Coy - SP Elísio Meirelles De Miranda - MG Fang Chia Bin - SP Fernando Zaroni Swaybricker - RJ Flávio Antonio Quilici - SP Flávio Ferreira Diniz - RS Francisco Lopes Paulo - RJ Francisco Sergio Pinheiro Regadas - CE Galdino José Sitonio Formiga - SP Geraldo Magela Gomes da Cruz - MG Hélio Moreira - GO Henrique Sarubbi Fillmann - RS João Francsico Xavier Mussnichi - RS João Gomes  Netinho - SP Joaquim José Ferreira - RJ José Alfredo dos Reis Junior - SP José Alfrredo Reis Neto - SP

Foreign correspondents

Ezio Ganio ‑ Ivreia ‑ Itália Fidel Ruiz Healy ‑ México D.F. ‑ México Mario Trompetto ‑ Ivreia ‑ Itália Michael R.B. Keighley ‑ Birmingham - Inglaterra Brazilian Society of Coloproctology Av. Marechal Câmara, 160 ‑ Conj. 916 / 917 Edifício Orly CEP 20020‑080 ‑ Rio de Janeiro ‑ RJ Fax (21) 2220‑5803 * Telefone: (21) 2240‑8927 Home page: http://www.sbcp.org.br * E-mail: sbcp@sbcp.org.br

Pedro Morgado Nieves ‑ Caracas ‑ Venezuela Saúl Sokol ‑ Dallas ‑ EUA Steven D. Wexner ‑ Fort Lauderdale ‑ EUA Study Center Pitanga Santos Av. Marechal Câmara, 160 ‑ sala 1202 Edifício Orly CEP 20020‑080 ‑ Rio de Janeiro ‑ RJ Fax: (21) 2220-5803

Impressão e Acabamento: Prensa


Brazilian Society of Coloproctology – Board 2010/2011 PRESIDENT Francisco Sergio Pinheiro Regadas (CE) Elected president Luciana Maria Pyramo Costa (MG) Vice-president Carlos Walter Sobrado Junior (SP) General secretary Ronaldo Coelho Salles (RJ) First secretary Francisco Jean Crispim Ribeiro ((CE) Second secretary Alice Capobiango (MG) First treasurer Diógenes Guilherme Castro Alvarenga (RJ) Second treasurer David de Lanna (MG)

Consulting council

Committee of the expert title

Raul Cutait (SP) Arminda Caetano de Almeida Leite (GO) João de Aguiar Pupo Neto (RJ) Renato Valmassoni Pinho (PR) Karen Delacoste Pires Mallmann (RS) Sergio Carlos Nahas (SP) Francisco Lopes Paulo (RJ)

Roberto Misici (CE) – Relator Sergio Eduardo Alonso Araújo (SP) Paulo César de Castro Junior (RJ) Dasio Lopes Simões (RJ) Antonio Sergio Brenner (PR) Henrique Sarubbi Fillmann (RS) Magda Maria Profeta da Luz (MG) Ilson Geraldo da Silva (MG) Claudia Rosali Esmeraldo Justo (PE) Mauro de Souza Leite Pinho (SC) Sthela Maria Murad Regadas (CE) Odorino Hideyoshi Kagohara (SP) Eduardo Cortez Vassallo (RJ) Carlos Frederico Sparapan Marques(SP) Mario Jorge Jucá (AL)

Scientific committee Paulo Gonçalves de Oliveira (DF) José Reinan Ramos (RJ) José Vinícius Cruz (RS)

Teaching and medical residency committee Journal committee Eduardo de Paula Vieira (RJ) Hélio Moreira Junior (GO) Olival de Oliveira Junior (PR)

Class defense committee Luiz Alberto Mendonça de Freitas (DF) Marcelo Rodrigues Borba (SP) Sidney Roberto Nadal (SP)

Carlos Walter Sobrado Junior (SP) João Batista de Sousa (DF) Erico Ernesto Pretzel Fillmann (RS) Paulo Gustavo kotze (PR) Manoel alvaro de Freitas lins Neto (AL) Fernando Zaroni Sewaybricker (RJ) Marlise Mello Cerato (RS) Antonio Lacerda Filho (MG) Francisco Luis Altenburg (SC) Mauricio José de Matos e Silva (PE) Cláudio Saddy Rodrigues Coy (SP) Juvenal da Rocha Torres Neto (SE) Sarhan Sydney Saad (SP) Lusmar Veras Rodrigues (CE) Rubens Valarini (PR)

SBCP delegates at SBCP Titular Sergio Carlos Nahas (SP) Afonso Henrique da Silva e Souza Junior (SP) Alternates Paulo Fernando de Carvalho (RJ) Flavia Rachel Starling Schwanz (ES)


VOLUME

Number

31

3

Contents

Original Article Immunohistochemical expression of the epidermal growth factor receptor (EGFR) in colorectal carcinoma: relation with clinicopathological parameters Maurício Andrade Azevedo, Bianca Doimo Souza, Ana Maria Amaral Antonio Mader, Lourdes Conceição Martins, Jaques Waisberg������������������������������������������������������������� 225 Adalimumab in the induction of Crohn’s disease remission: results of a Brazilian multicenter case series Paulo Gustavo Kotze, Andrea Vieira, Carlos Walter Sobrado Junior, Juliana Barreto Salem, Lorete Maria Da Silva Kotze����������������������������������������� 233 Correlation between location, size and histologic type of colorectal polyps at the presence of dysplasia and adenocarcinoma Sandra Beatriz Marion Valarini, Vinícius Tomadon Bortoli, Noelle Suemi Wassano, Maiara Fontes Pukanski, Dariana Carla Maggi, Lucas Amadeu Bertollo�������������� 241

July / September 2011

Analysis of direct costs of anesthesia-related materials between spinal and venous anesthesia with propofol associated with local perianal block in hemorrhoidectomy Paulo Gustavo Kotze, Ilario Froehner Junior, Cristiano Denoni Freitas, Fábio Diniz, Álvaro Steckert-Filho����������������������������������������������������� 268 Mucocele of the appendix - appendectomy or colectomy? Janduí Gomes de Abreu Filho, Erivaldo Fernandes De Lira��������������������������������������������������������������������������� 276 Anus neoplasm: study of a case series Igor Lima Fernandes, Larice Oliveira Santana, José Batista da Silva Júnior, Marcel Machado da Motta, Alex Rodrigues Moura, Ana Carolina Lisbôa Prudente, Juvenal da Rocha Torres Neto��������������������������������������� 285 CASE REPORT

Fecal incontinence as consequence of anorectal surgeries and the physiotherapeutic approach Kelly Cristina Duque Cortez, Sarah De Souza Mendonça, Marina de Souza Figueiroa�������������������������������������������� 248

Temporary ileostomy for the preservation of colon fistula in patients with postoperative complications: case report Solaine Chiminácio de Oliveira Patrício, Alcides José Branco Filho, Ana Carlabroetto Biazon������������������������� 291

What is the value of proctography for diagnostic of outlet obstruction? Maria Auxiliadora Prolungatti Cesar, Wilmar Artur Klug, Jorge Alberto Ortiz, Chia Bin Fang, Peretz Capelhuchmik����������������������������������������������������� 257

Sigmoidoanal intussusception with exteriorization of sigmoid adenocarcinoma Pedro Roberto de Paula, Maria Auxiliadora Prolungatti César, Eduardo Fortes de Albuquerque, Fernanda Perez Adorno da Silva������������������������������������ 294

Evaluation of the effectiveness of 4% formalin in the treatment of hemorrhagic actinic proctitis Juvenal Rocha Torres Neto, Alex Rodrigues Moura, Fábio Ramos Teixeira, Ana Paula Andrade Menezes, Dam Rodrigues Mariano������������������������������������������������ 262

Giant schistosomal granuloma mimicking rectum neoplasia – case report Luiz Eduardo Correia Miranda, Eduardo Carvalho, Diego Laurentino Lima�������������������������������������������������� 299


Pyoderma gangrenosum as a initial manifestation of ulcerative proctocolitis Carla Bortolin Fonseca, Guilherme Lang Motta, Alexandre Rampazzo, João Carlos Cantarelli Junior, Renato Borges Fagundes������������������������������������������������ 301

Special Sessions�������������������������������������������������� 306 Services accredited���������������������������������������� 308


Information for Authors 1. OBJECTIVE The JOURNAL OF COLOPROCTOLOGY is published under the coordination of the Editorial Board, and the authors are responsible for the concepts presented in the studies. The purpose of the JOURNAL is to present studies about Human Medicine and Surgery, conducted by national or international experts, provided that they follow the *Study Guideline*. 2. OVERVIEW The JOURNAL OF COLOPROCTOLOGY is published quarterly, in one annual indexed issue in December. It is sent exclusively to subscribers, collaborators, libraries, hospitals, medical communities, study centers and national and international journals with which it exchanges materials. The JOURNAL OF COLOPROCTOLOGY follows the concepts of a guideline published in 1997 by the Committee on Publication Ethics (COPE) and suggests and recommends that the authors read the instructions provided in such guideline before they submit their studies for approval. 3. REGULATION OF STUDIES 3.1. General Instructions The studies should not have been published in any other journal and should be exclusively submitted to the JOURNAL OF COLOPROCTOLOGY. Review articles will be inserted at the Editorial Board’s discretion. In exceptional cases of republishing national or international studies, these should contain the formal authorization of the author and the periodical that owns the copyright. *Study Protocols* Preliminary Elements-a) *Title* - article title, in Portuguese, and the full names of the authors. b) *Scientific affiliation and corresponding author’s address.*Text: Whenever possible, the text should be in accordance with the conventional scheme of a scientific article-a) *Introduction* - It should explain clearly the purpose of the study, relating it with others from the same field and providing a brief presentation of the current situation of the investigated problem. Long literature reviews should be replaced for references to more recent studies, in which such reviews have already been presented. b) *Patients and Methods* - The Methods description should present only the necessary to allow the reader’s perfect understanding and repetition; the techniques already described in other studies will be referred to only by quoting, unless they have been considerably modified. c) *Results* - They should be clearly presented, and, as required, bring tables and proper illustrative material. d) *Discussion* - It should be limited to presenting the obtained data and results, correlating the new contributions with prior knowledge. Avoid hypotheses or generalizations that are not based on the study results. e) *Conclusion* - They should be based on the manuscript. The regulations below are based on the concept proposed by the International Committee of Medical Journal Editors and published in the article: “Uniform requirements for manuscripts submitted to biomedical journals”, which was updated in October 2004 and can be accessed at http://www.icmje.org/. For randomized clinical trials, the CONSORT guidelines (Begg C, Cho N, Eastwood S et al. Improving the quality of reporting of randomized clinical trials: the CONSORT statement. JAMA 1996;276:637-9) are recommended as reference. A checklist is presented in the JAMA website: htt://jama.ama-assn.org. ARTICLE JUDGEMENT PROCESS The manuscripts submitted to the JOURNAL that meet the “Instructions to Study Authors” and these editorial guidelines are sent to 4 members of the Editorial Board, who will consider the scientific merit of the contribution. The manuscripts are previously sent to committee members and randomly selected by the Editors. Anonymity is ensured during the whole judgement process. The decision of approving the manuscript is made by the Editors, after an evaluation by 4 members of the Editorial Board; also, the manuscript publication should be recommended by at least 3/4 of the members. Copies of the opinions can be sent to authors and committee members; the latter may use an exchange system with each other.

Refused manuscripts – Refused manuscripts will not be returned, unless requested by their respective authors. Refused manuscripts that can be reformulated may be resubmitted as a new study, thus starting a new judgement process. Approved manuscripts – Approved manuscripts or those which were accepted with certain conditions may be returned to their respective authors to approve alterations in the layout and normalization according to the style of the JOURNAL. Approval for Publication – All articles proposed for publication will be previously submitted to the evaluation of 4 members of the Editorial Board. If accepted, they will be submitted to minor corrections or changes that do not alter the author’s style. Alterations to the structure, style or interpretation will only be made after approval. If refused, the articles will be returned with the justification of the Editor in Chief. The Counselors’ comments in these cases may be sent by the Editor in Chief or requested by the author. PREPARATION OF THE manuscriPT • Identification page: There should be: a) Article title in English, which should be concise, but informative; b) full name of each author and their scientific affiliation; c) name of the department and institution with which the study should be associated; d) name, address, fax and e-mail of the corresponding author, e) funding sources of the investigation, f) potential conflicts of interest. • Abstract and keywords: The second page should contain the abstract, in Portuguese and in English, with no more than 200 words for original articles, review articles, brief communications and update articles. For original articles, review articles and brief communications, the abstract should be structured in a way to emphasize the study objectives, methods and main results, presenting significant data and conclusions. For update articles, the abstract does not have to be structured, but it should contain the important information for the recognition of the value of the study. Below the abstract, 5 keywords should be specified to define the study theme. The keywords should be based on DeCS (Health Sciences Descriptors), created by Bireme, which is translated from MeSH (Medical Subject Headings) of the National Library of Medicine, available in http://decs.bvs.br • Text: It should be in accordance with the structure requested for each article category. In all categories, the quotation of authors in the text should be numbered and sequential, using Arabic numerals in parentheses and superscript, avoiding the indication of the author’s name. Quotations in the text and references cited in legends of tables and figures should be consecutively numbered, in the same order that they appear in the text, using Arabic numerals (index numbers). Only the reference number should be included, without other information. • Tables: Each table should be sent on a single page and in an editable file (.doc or .exl), in text form, to enable font, shading and border standardization. All tables should be presented in consecutive numerical order, with Arabic numerals, in the order cited in the text, with a proper title above each table. They should be cited in the text without duplicated information. The tables, as well as their titles and legends, should be self-explanatory. Tables from other sources should present the original references in the footnote. • Figures e charts: The illustrations (pictures, charts, drawings, etc.) should be submitted individually. They should be presented in consecutive numerical order, using Arabic numerals, in the order cited in the text and be sufficiently clear to enable their reproduction. The legends of figures should be submitted on a single page. Photocopies will not be accepted. The authors should obtain written permission to reproduce figures extracted from previously published studies. This authorization should be submitted with the manuscripts for publication.

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• Statistical analysis: The authors should demonstrate that the statistical procedures were not only adequate to test the study hypotheses, but that they were also correctly interpreted. The levels of statistical significance (for instance, p<0.05; p<0.01; p<0.001) should be mentioned. • Abbreviations: The abbreviations should be indicated in the first time they are used in the text. After that, only the abbreviation should be used. • Names of medications: The generic name should be used. • Acknowledgements: They should include collaboration from people, groups or institutions that deserve recognition, but who did not participate as authors; acknowledgements for funding support, technical help, etc. • References: They should be presented in consecutive numerical order, in the order cited in the text and with Arabic numerals. They should be in accordance with the “Vancouver Style” format, according to the examples below, and the titles of periodicals should be abbreviated as the style presented by the List of Journal Indexed in Index Medicus, of the National Library of Medicine, available at ftp://nlmpubs.nlm.nih.gov/online/journals/ljiweb.pdf. The authors should be positive that the references mentioned in the text are also included in the list of references with exact dates and correctly spelled names. The authors are responsible for the correct presentation of references. Personal communications, pioneer studies or studies in progress may be mentioned when absolutely necessary, but they should not be included in the list of references; only mentioned in the text or in footnotes. The list of references should follow the examples below: For the references, mention all authors, if the total is max. six. More than six authors, mention the six first followed by the expression “et al.”. Articles from periodicals Ex.: Periodical: Regadas F S P - Tratamento cirúrgico do prolapso retal completo em adulto masculino jovem. Rev bras Coloproct 1998; 4(4): p 213-217 Articles without the author’s name Cancer in South Africa [editorial]. S. Afr Med J 1994; 84 (1):15. Books in general Ringsven MK, Bond D. Gerontoloy and leadership skills for nurses. 2nd ed. Albany (NY): Delmar Publishers; 1996. Chapters of a book Phillips SJ, Whisnant JP Hypertension and stroke. In: Laragh JH, Brenner BM, editors. Hypertension: pathophysiology, diagnosis, and management. 2nd ed. New York: Raven Press; 1995. p. 465-78.

Books in which the editors (organizers) are authors Norman IJ, Redfern SJ, editors. Mental health care for elderly people. New York: Churchill Livingstone; 1996. Theses Kaplan SJ. Post-hospital home health care: the elderly’s access and utilization [dissertation]. St Louis (MO): Washington Univ.; 1995 Studies presented in congresses Bengtsson S, Solheim BG. Enforcement of data protection, privacy and security in medical informatics. In: Lun KC Degoulet P, Piemme TE, Rienhoff O, editors. MEDINFO 92. Proceedings of the 7th World Congress on Medical Informatics; 1992 Sep 6-10; Geneva, Switzerland. Amsterdam: North-Holland; 1992. p. 1561-5. Article from a periodical in electronic format Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis [serial on the Internet] 1995 Jan-Marc [cited 1996 Jun 5]; 1(1): [about 24 screens]. Available from: URL: http://www.cdc.gov/ncidod/EID/eid.htm Other types of reference should follow the document of the International Committee of Medical Journal Editors (Vancouver Group), available at www. icmje.or, October 2004. 4. SUBMISSION OF ORIGINAL TEXTS The articles should be sent by e-mail (sbcp@sbcp.org.br). In this case, it is essential to have the permission for material reproduction with the approval of the Ethics Committee of the Institution where the study was conducted, when involving (diagnostic or therapeutic) interventions in human beings, and a letter signed by all authors stating the pioneer characteristic of the study, to be sent by fax to RBCP (fax number: 55 21 2220 5803). 5. THE JOURNAL OF COLOPROCTOLOGY Reserves all rights, including translation rights, in all countries that are signatories to the Pan-American Convention and the International Copyright Convention regarding the following: 6. The total or partial reproduction of the studies in other periodicals – with mandatory quotation of the source – will be at the JOURNAL’s discretion. 7. For commercial purposes, the translation and total or partial reproduction of the studies published in this JOURNAL is prohibited. 8. The JOURNAL OF COLOPROCTOLOGY does not accept a paid article in its editorial space, and it does not pay any amount, in kind or other currencies, to the authors of studies published in its pages. 9. The JOURNAL reserves the right to refuse original texts that are not considered to be adequate (presentation, items covered, etc.) and propose modifications, according to the evaluation of Consultants and the Editorial Board. 10. The JOURNAL, if required, will automatically adapt all studies approved for publication to these guidelines.


VOLUME

Number

31

3 July / September 2011 ORIGINALS ARTICLES

Immunohistochemical expression of the epidermal growth factor receptor (EGFR) in colorectal carcinoma: relation with clinicopathological parameters MAURÍCIO ANDRADE AZEVEDO1, BIANCA DOIMO SOUZA2, ANA MARIA AMARAL ANTONIO MADER3, LOURDES CONCEIÇÃO MARTINS4, JAQUES WAISBERG5 Doctor at the Surgical Gastroenterology Service of the Hospital Complex of Mandaqui – São Paulo (SP), Brazil. 2Student at Faculdade de Medicina do ABC – Santo André (SP), Brazil. 3Assistant Professor of Pathology at Faculdade de Medicina do ABC – Santo André (SP), Brazil. 4Assistant Professor of the Post-Graduation Program in collective health at Universidade Católica de Santos (UNISANTOS) – Santos (SP), Brazil. 5Head Professor of Surgery of the Digestive System at Faculdade de Medicina do ABC – Santo André (SP), Brazil; Head of nursing at the Surgical Gastroenterology Service at Hospital do Servidor Público Estadual (IAMSPE) – São Paulo (SP), Brazil; Titular of the Brazilian Society of Coloproctology.

1

AZEVEDO MA, SOUZA BD, MADER AMAA, MARTINS LC, WAISBERG J. Immunohistochemical expression of the epidermal growth factor receptor (EGFR) in colorectal carcinoma: relation with clinicopathological parameters. Rev bras Coloproct, 2011;31(3): 225-232. Abstract: Introduction: The study of tissue immunostaining of the epidermal growth factor receptor (EGFR) may contribute with the understanding of its role in the prognosis of colorectal carcinoma. Objective: To analyze the immunohistochemical expression of EGFR in colorectal carcinoma tissues and transitional tumor-mucosa and mucosa adjacent to neoplasia, and its relation with cancer. Method: The study was conducted with 40 patients with colorectal carcinoma who had surgery with curative intent in order to analyze the immunoexpression of EGFR with anti-EGFR. We used parametric and nonparametric tests. Results: The immunohistochemical expression of EGFR in tumor samples showed a significant difference as to the level of immunostaining in tissue specimens of transitional tumor-mucosa (p=0.01) and the level of immunoreactivity in tissues of the adjacent mucosa (p=0, 04). The immunoexpression of EGFR showed no significant relation with the size of the tumor, angiolymphatic invasion, neural invasion, cellular differentiation, level of carcinoma infiltration in the intestinal wall, lymph node metastases and liver metastases. Conclusions: The EGFR showed a more intense expression in the mucosa of colorectal carcinoma than in the transitional epithelium and adjacent non-neoplastic mucosa. The immunoexpression of EGFR did not correlate with pathological parameters of colorectal carcinoma and liver metastases. Keywords: genes, erbB-1; receptor, epidermal growth factor; immunohistochemistry; colorectal neoplasms; neoplasm metastasis.

Financing source: none. Conflict of interest: nothing to declare. Submitted on: 26/04/2011 Approved on:27/05/2011

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Journal of Coloproctology July/September, 2011

Immunohistochemical expression of the epidermal growth factor receptor (EGFR) in colorectal carcinoma: relation with clinicopathological parameters Maurício Andrade Azevedo et al.

INTRODUCTION

Vol. 31 Nº 3

explanations regarding this event, including tumor heterogeneity, low sensitivity to the method that detects EGFR and the lack of a standard methodology related to the studies33,37-38. It is important to define the factors that can be used to identify the patients who have favorable response to EGFR inhibitors, and so a treatment can be chosen39. The objectives of this study were to analyze EGFR expression by the immunohistochemical technique in the colorectal carcinoma tissue, in the transitional tumor-mucosa, and in the tissue of the mucosa adjacent to the neoplasm, and correlate it with clinicopathologial aspects, clinical staging and metastases in patients who had surgery for colorectal carcinoma.

The incidence of colorectal carcinoma is increasing in western countries and in Brazil, colorectal carcinoma is the third most frequent1,2. The colorectal neoplasm staging is still the most reliable prognostic factor; however, such information is not usually available at the preoperative period3. In order to decide whether or not to submit the patient who had surgery for colorectal carcinoma to postoperative chemotherapy, it is important to select the patients with unfavorable prognosis, especially those with advanced lesions; in such cases, the expression of tumor markers at the neoplastic tissue may be useful for this purpose4-6. Different tissue markers are described in literature, however, only a few are relevant in relation to the clinical treatment of the patient7-8. In colorectal neoplasms, ideally, tissue markers should be altered according to tumor staging, besides serving as prognosis and helping to define the need for complementary therapy7,9-12. Even for those patients submitted to primary disease resection with curative intent, postoperative recurrence is a common cause of death13-15. The protein family of the epidermal growth factor (EGF) includes groups of receptors and growth factors that are structurally related16-20. Many of these proteins, which are highly expressed in human colon cancer cell line, are connected to EGF receptors (EGFR), and have an important role in the growth of colorectal carcinoma17-18. EGFR tissue expression may be immunohistochemically determined by the connection of EGF with the tumor membrane17,21-25. As to the gastrointestinal tract, EGFR expression is usually more intense for tumors than for regular tissues26-29. EGFR tissue hyperexpression indicates an unclear clinical prognosis28-29, suggesting the evolution of the colorectal carcinoma and its metastatic potential28-31. EGFR hyperexpression was reported in 25 to 82% of the patients with colorectal cancer, and proved to be predictive of distance metastases for patients with advanced stating28-32. However, the impact of this finding in the prognosis is still controversial. Studies failed to show the relation between the EGFR expression and the clinical efficiency of the target therapy33-36. Such difference brought to life some

METHODS This study was approved by the Research Ethics Committee of Universidade Federal de São Paulo (UNIFESP), protocol n. 0344/09, and the committee of Instituto de Assistência Médica ao Servidor Público Estadual (IAMSPE), protocol n. 056/08. From October 2005 to March 2007, 40 patients presenting with colorectal carcinoma had surgery with curative intent at the Surgical Gastroenterology Service at Hospital do Servidor Público Estadual de São Paulo (IAMSPE). Out of these patients, 20 (50%) were males and 20 (50%) were females. Mean age was 68.7±11.6 years (44 to 90 years). In this study, inclusion criteria were: the presence of colorectal carcinoma confirmed by histopathological analysis and lesion with curative intent. Exclusion criteria were: patients aged less than 18 years, those with bowel inflammatory disease, neoplasm in other organs or lesion healing in a palliative way. Preoperative staging was performed by complete clinical and Physical exam, serum determination of carcinoembryogenic antigen (CEA), colonoscopy with biopsy and histopathological analysis of the lesion, thoracic and abdominal CTscan. The most common surgery was rectosigmoidectomy, performed in 24 patients (60%), followed by total colectomy, in 5 patients (12.5%), left colectomy, in 5 patients (12.5%), right colectomy in 5 patients (12.5%) and abdominoperineal rectal amputation in 1 patient (2.5%). 226


Journal of Coloproctology July/September, 2011

Immunohistochemical expression of the epidermal growth factor receptor (EGFR) in colorectal carcinoma: relation with clinicopathological parameters Maurício Andrade Azevedo et al.

For the histopathological study, three specimens were obtained: one in the central area of the tumor, in order to avoid ulcers or necrosis; another in the transitional region between the neoplasm and the macroscopically non-tumoral area with microscopic confirmation of this transitional area, and a third sample of the adjacent mucosa located 10 cm from the lesion. All surgical specimens were previously fixed in formalin 10% and included in paraffin blocks. Three 4 µm cuts were made in each block to obtain neoplastic areas, transitional area of mucosa neoplasm, macroscopically non-tumorous, and the area that is macroscopically neoplasm free. All specimens were stained with hematoxylin-eosin (HE) for the microscopic analysis and the verification of neoplastic compromise of resected lymph nodes and surgical margins. Paraffin blocks were cut with 3 µm of width, and the blades were submitted to ABC immunohistochemistry (Avidin-Biotin-Peroxidase Complex) with antiEGFR primary antibody in the dilution 1:30 (mouse monoclonal anti human epidermal growth factor receptor – EGFR, lot 3360, clone H11, Dako Cytomation, EUA). A positive reaction to the EGFR antibody was considered when the color brown appeared on the cytoplasmic membranous area of the cell. Positive controls were normal cuts of the tonsil germinal center. For the blades used as negative control, the primary antibody reaction was removed. An experienced pathologist analyzed the blades with a binocular microscope by Nikon, with planachromatic objectives. At first, the hot spots were selected with 100x zoom; afterwards, with 400x zoom, analyzing ten consecutive fields. EGFR immunoexpression represented by the color brown, both in the cytoplasm (Figure 1) and in the cytoplasmic membrane (Figure 2) of neoplastic cells, was analyzed in a semiquantitative way, according to the criteria proposed by Kountourakis et al.40. In the cytoplasm, immunoexpression was classified as 0: without staining, or <10% of the neoplastic  cells  with low intensity staining; +: >10% of the cells with  low  intensity staining; ++: >10% of the cells with medium intensity staining; +++: >10% of the cells with strong intensity staining. At the cytoplasmic membrane, the immunoexpression was classified as 0: without staining; +: <10% of neoplastic cells with

Vol. 31 Nº 3

Figure 1. Immunoexpression of the epidermal growth factor receptor in neoplastic cells with medium intensity cytoplasmic pattern (immunohistochemistry; 400x).

Figure 2. Immunoexpression of the epidermal growth factor receptor in neoplastic cells of membranous pattern and strong intensity (immunohistochemistry; 400x).

any rate of intensity, or <30% of the cells with weak intensity staining; ++: 10-30% of medium to strong intensity staining or 30-50% of cells with low to medium intensity staining; +++: >30% of the cells with strong intensity staining or >50% of neoplastic cells with any staining intensity. EGFR immunosuppression was analyzed in the tumor, in the transitional non-neoplastic tumor-mucosa and in the mucosa that is 10 cm adjacent to the neoplastic lesion. In order to analyze the results, patients were divided into two groups: group 0, which showed no EGFR immunoexpression, and group 1, with EGFR immunoexpression, regardless of its intensity. 227


Journal of Coloproctology July/September, 2011

Immunohistochemical expression of the epidermal growth factor receptor (EGFR) in colorectal carcinoma: relation with clinicopathological parameters Maurício Andrade Azevedo et al.

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According to cell differentiation, 31 (77.5%) patients had moderately differentiated adenocarcinoma, 2 (5.0%) had a little differentiated adenocarcinoma, and 7 (17.5%) had a well differentiated carcinoma. The lesion penetrated the serous (peritoneum) without the invasion of adjacent structures (spleen, stomach, liver, diaphragm, pancreas, abdominal wall, adrenal, kidney, small intestine and retroperitoneum) (T3) in 28 patients (70%); the lesion invaded the muscularis propria or subserosa (T2) in 10 patients (25%), and adjacent structures (T4) in 2 patients (5%). None of the patients presented only the invasion of lamina propria or submucosa (T1). Four patients (10%) had liver metastasis at the moment of surgery, while 36 (90%) patients did not present such condition. The samples of tumorous tissue showed that EGFR immunoexpression was absent in 22 patients (55%) and present in 18 of them (45%). In relation to the samples of non-neoplastic transitional tumor-mucosa, EGFR immunoexpression was present in 14 patients (35%), while 26 (65%) tissue samples did not present EGFR immunoexpression. As to EGFR in the adjacent mucosa, it was observed that 11 patients (27.5%) had tissue samples with immunoexpression, and 29 (72.5%) did not present immunoexpression (Table 1). The absence or presence of EGFR immunoexpression in neoplastic tissue samples, transitional tumor-mucosa and adjacent mucosa was not significantly different in relation to the location in the large intes-

Data referring to quantitative variables were presented by average. Categorical variables were analyzed by the Mann-Whitney test, and the correlation was observed by the Spearman test. The variance analysis of the samples of three or more groups was obtained by the Kruskal-Wallis test. Dicotomic variables were analyzed by the Fisher’s exact test. The statistical software used was Prism 4.0 (GraphPad Software Inc., USA), and the significance level was lower than 0.05 or 5%. RESULTS The mean size of colorectal neoplasm was 4.25±2.1 cm (1.0 to 9.0 cm). The lesions of 21 patients had ≤5.0 cm in diameter, while 19 patients (47.5%) presented neoplasm with >5.0 cm of diameter. Twelve (30%) patients presented neoplastic vascular invasion at clinicopathological examination, while 28 (70%) patients did not have vascular invasion. Fourteen (35%) patients presented lymphatic vascular invasion at clinicopathological examination, while 26 (65%) patients did not have lymphatic vascular invasion. Seven (17.5%) patients presented perineural invasion at clinicopathological examination, while 33 (82.5%) patients did not have neoplastic perineural invasion. Lymph nodes were affected by the colorectal carcinoma in 19 patients (47.5%). For other 21 patients (52.5%), the lymph nodes were negative.

Table 1. Presence or absence of immunoexpression of the epidermal growth factor receptor in the samples of tumorous tissue, transitional tumor-mucosa and adjacent mucosa in patients with colorectal carcinoma. Immunoexpression of the Immunoexpression of the absent EGFR Tissue n present EGFR n (%) n (%) Tumorous tissue 40 18 (45.0) 22 (55.0) Transitional tumor-mucosa 40 14 (35.0) 26 (65.0) Adjacent mucosa 40 11 (27.5) 29 (72.5) EGFR: epidermal growth factor receptor; n: number of patients

Table 2. Comparison between the presence of immunoexpression of the epidermal growth factor receptor in the tumorous tissue, transitional tumor-mucosa and the adjacent mucosa in patients with colorectal carcinoma. Tissue Tumorous tissue Transitional tumor-mucosa Adjacent mucosa p A) EGFR immunoexpression n= 8 (45.0%) n=14 (35.0%) – 0.01* B) EGFR immunoexpression n=18 (45.0%) – n=11 (27.5%) 0.04* C) EGFR immunoexpression – n=14 (35.0%) n=11 (27.5%) 0.01* EGFR: epidermal growth factor receptor; n: number of patients *Mann-Whitney’s test

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tine, diameter of the lesion, vascular invasion, lymphatic vascular invasion, perineural invasion, lymph node metastasis, cell differentiation, staging classification of malignant tumors and liver metastases (p>0.05). EGFR immunoexpression in the neoplastic tissue was significantly higher (p=0.01) than in the transitional tumor-mucosa. Likewise, EGFR immunoexpression was significantly more intense (p=0.04) in the neoplastic tissue when compared to the adjacent mucosa. Also, EGFR immunoexpression in the transitional tumor-mucosa was significantly higher (p=0.01) in relation to the adjacent mucosa (Table 2).

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find an association between the hyperexpression of EGFR and cell differentiation. Galizia et al.34 studied 49 speciments of colorectal neoplastic tissue and did not idenfity a relation between the intensity of EGFR expression and histological differentiation. The former authors also did not show a relation between the EGFR expression and histological differentiation; however, they identified the trend of association between EGFR hyperexpression in the deeper layers of carcinomas. On the other hand, in a study with 114 colorectal neoplastic tissue samples, McKay et al.26 identified the association between EGFR hyperexpression in well or moderately differentiated tumors in relation to little differentiated tumors. In our study, the degree of cell differentiation of the neoplasm was not related to immunoexpression, which indicates that, unlike CEA, less differentiated neoplasms have the same intensity regarding EGFR than the more differentiated ones. Thus, this event would not depend on the degree of cell differentiation of the colorectal carcinoma. In this study, EGFR expression was similar in tumors that presented or not the angiolymphatic and/ or perineural invasion. Spano et al.29 analyzed EGFR expression and its relation with angiolymphatic invasion, and did not observe a significant relation, as well as Baiocchi et al.42. On the other hand, Karameris et al.41 established an association between EGFR immunoexpression and angiolymphatic and neural compromise. As to morphological parameters, vascular invasion, lymphatic vascular invasion and neural invasion were not related to EGFR immunoexpression. It is possible to consider that vascular and lymphatic invasions are not the only mechanism to express the marker in other sites. In the present study, EGFR expression presented no significant differences in relation to the clinical staging of colorectal neoplasm. Goldstein and Armin28 analyzed EGFR expression in patients with stage IV colorectal carcinoma, according to the TNM classification of malignant tumors. Even though they found a more intense expression in tumors that were clinically more advanced, these authors did not find a significant difference between the hyperexpression of the marker and the most advanced stage of the disease. Spano et al.29 identified a relation between EGFR hyperexpression and the more advanced stages of the TNM classification. These authors observed that EGFR hyperexpres-

DISCUSSION The EGFR marker was chosen to identify relevant information regarding the carcinogenesis of colorectal neoplasm. When the expression of this marker is increased in the tissue, there is a relation with a worse prognosis and the presence of liver metastases. However, the meaning of the increased expression of this marker is controversial in the literature30,32,33,35,37,39. The expression of the EGFR marker in this study was significantly higher in the neoplastic tissue than in specimens of transitional carcinoma/mucosa and the adjacent mucosa. EGFR is a receptor tyrosine-kinase, and is necessary to activate the system related with cell differentiation and multiplication. Goldstein and Arrmin28 identified the hyperexpression of EGFR in the deeper layers of the tumor and its association with liver and lymph node metastases. These authors identified a higher expression of EGFR in the neoplastic tissue in relation to the non-neoplastic mucosa adjacent to the tumor. Also, this study observed that the measures of immunoexpression (positive index and intensity of expression) presented significant differences in the central region of the tumor, transitional tumor-mucosa and adjacent mucosa. Considering that the immunoexpression has a direct relation with the amount of EGFR in the sample tissue, this finding suggests that the content of EGFR is more intense in the neoplastic tissue when compared to the non-neoplastic transitional tumor-mucosa and to mucosa adjacent of the colorectal carcinoma Our study showed EGFR expression was similar to well, moderately and little differentiated colorectal carcinomas. Spano et al.29 analyzed sample tissues of 150 specimens of colorectal carcinomas and did not 229


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sion in stage T3 was higher than the stage T4. Galizia et al.34 identified a significantly higher EGFR expressions in stages C and D of the modified Duke’s staging system (Turnbull) in relation to stages A and B, which suggests that the more advanced the clinical stage, the more intense the hyperexpression of EGFR. However, Baiocchi et al.42 and McKay et al.26 did not find a relation between EGFR hyperexpression and the different stages of the Duke’s system. These authors suggested the increased expression of EGFR had no relation with the colorectal carcinoma aggressiveness. The depth degree of carcinoma invasion on the colorectal wall was not related to the indexes of EGFR immunoexpression adopted in this study. The hyperexpression of EGFR would be expected in lesions of more advanced stages, as well as in deeper lesions of the tumor. This study showed no significant difference to EGFR expression according to rectal location or carcinoma colic. The same finding was observed by Spano et al.29, Baiocchi et al.42, McKay et al.26 and Kountourakis et al.40. This result may indicate that the immunoexpression of EGFR does not depend on the morphological aspects of the different areas of the large intestine, when the colon and the rectum are compared. In this study, the analysis of EGFR expression did not identify a significantly higher number of lymph nodes that were compromised by neoplasm in the patients with EGFR hyperexpression. Likewise, McKay et al.26, Scartozzi et al.33, Bralet et al.32 and Spindler et al.38 demon-

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strated that EGFR hyperexpression was not significantly related to the presence of lymph node metastases. Doger et al.37 studied 60 specimens of colorectal carcinoma and did not observe a relation between EGFR hyperexpression and the presence of lymph node, liver and distance metastases. The immunoexpression was not related to the neoplastic lymph node infiltration. In the present study, no significant relation between EGFR expression and liver metastases was found. Likewise, Bralet et al.32 and Scartozi et al.33 analyzed the expression of EGFR in colorectal tumors, and could not find a relation between liver metastases and the expression of the marker. On the other hand, Italiano et al.30 identified a more intense expression of EGFR in patients with liver and distance metastases. Khalifa et al.31 assessed the expression of EGFR in the tissue of 33 colorectal carcinomas and found a relation between liver and distance metastases with neoplasm recurrence. CONCLUSIONS EGFR immunoexpression was more intense in the colorectal carcinoma mucosa than in the transitional tumor-mucosa epithelium and the non-neoplastic adjacent mucosa. Additional studies are important to analyze the relation between immunohistochemical expression of EGFR and the prognosis of colorectal carcinoma, and also if the immunohistochemical expression of EGFR can be used as a predictive marker so that the patient has positive results with chemotherapy.

Resumo: Introdução: O estudo da imunoexpressão tecidual do receptor do fator de crescimento epitelial (EGFR) pode contribuir para o entendimento de seu papel no prognóstico do carcinoma colorretal. Objetivo: Analisar a expressão imunohistoquímica do EGFR no carcinoma colorretal e nos tecidos da transição tumor-mucosa e da mucosa adjacente à neoplasia, e avaliar a relação com os aspectos anatomopatológicos da neoplasia. Método: Em 40 doentes com carcinoma colorretal operados com intenção curativa, estudou-se a imunoexpressão do EGFR com anticorpo anti-EGFR. Foram utilizados testes paramétricos e não paramétricos. Resultados: A imunoexpressão do EGFR nas amostras de tumores apresentou diferença significante, em relação ao nível de imunoexpressão em espécimes de tecido da transição tumor-mucosa (p=0,01), e ao nível de imunoexpressão em tecidos da mucosa adjacente (p=0,04). A imunoexpressão do EGFR não apresentou relação significante com o tamanho da neoplasia, invasão angiolinfática, invasão neural, grau de diferenciação celular, nível de infiltração do carcinoma na parede intestinal, acometimento linfonodal e metástase hepática. Conclusões: O EGFR apresentou maior imunoexpressão na mucosa do carcinoma colorretal do que no epitélio de transição e na mucosa adjacente não neoplásica. A imunoexpressão do EGFR não se relacionou com os parâmetros anatomopatológicos do carcinoma colorretal e com a presença de metástase hepática. Palavras-chave: genes, erbB-1; receptor do fator de crescimento epidérmico; imuno-histoquímica; neoplasias colorretais; metástase neoplásica.

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Cancer Res 2007;176:61-80. 16. Lee Jc, Wang ST, Chow NH, Yang HB. Investigation of the prognostic value of coexpressed erB family members for the survival of colorectal cancer patients after curative surgery. Eur J Cancer 2002;38(8):1065-71. 17. Yano S, Kondo K, Yamaguchi M, Richmond G, Hutchison M, Wakeling A, et al. Distribution and function of EGFR in human tissue and the effect of EGRF tyrosine Kinase inhibition. Anticancer Res 2003;23(5A):3639-50. 18. Thompson DM, Gill GN. The EGF receptor: structure, regulation and potential role in malignancy. Cancer Surv 1985;4(4):767-88. 19. Carpenter G, Cohen S. Epidermal growth factor. J Biol Chem 1990; 265(14):7709-12. 20. Yarden Y, Ullrich A. Growth factor receptor tyrosine kinases. Annu Rev Biochem 1988;57:443-78. 21. Grandis JR, Sok JC. Signaling through the epidermal growth factor receptor during the development of malignancy. Pharmacol Ther 2004;102(1):37-46. 22. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003;21(14):2787-99. 23. Roberts RB, Min L, Washington MK, Olsen SJ, Settle SH, Coffey RJ, et al. Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis. Proc Natl Acad Sci USA 2002;99(3):1521-6. 24. Alferez D, Wilkinson RW, Watkins J, Poulsom R, Mandir N, Wedge SP, et al. Dual inhibition of VEGFR and EGFR signaling reduces the incidence and size of intestinal adenomas in Apc(Min/+) mice. Mol Cancer Ther 2008;7(3):590-8. 25. Sergina NV, Moasser MM. The HER family and cancer: emerging molecular mechanisms and therapeutic targets. Trends Mol Med 2007;13(12):527-34. 26. McKay JA, Murray LJ, Curran S, Ross VG, Clark C, Murray GL, et al. Evaluation of the epidermal growth factor receptor (EGFR) in colorectal tumours and lymph node metastases. Eur J Cancer 2002;38(17):2258-64. 27. Ciardiello F, Tortora G. A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 2001;7(10):2958-70. 28. Goldstein NS, Armin M. Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: implications for a standardized scoring system. Cancer 2001;92(5):1331-46. 29. Spano JP, Lagorce C, Atlan D, Milano G, Domont J, Benamouzing R, et al. Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol 2005;16(1):102-8. 30. Italiano A, Saint-Paul MC, Caroli-Bosc FX, François E, Bourgeon A, Benchimol D, et al. Epidermal growth factor (EGFR) status in primary colorectal tumors correlates with EGFR expression in related metastatic sites: biological and

Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al. Cancer Statistics, 2006. CA Cancer J Clin 2006;56(2):106-30. Global Cancer Facts & Figures 2007 [texto na Internet]. Atlanta: American Câncer Society; 2007 [cited 2010 Nov 19]. Available from: http://www.cancer.org Louvet C, de Gramont A, Tournigand C, Artru P, MaindraultGoebel F, Krulik M. Correlation between progression free survival and response rate in patients with metastatic colorectal carcinoma. Cancer 2001;91(11):2033-8. Midgley RS, Kerr DJ. Adjuvant treatment of colorectal cancer. Cancer Treat Rev 1997;23(3):135-52. Sobrero A, Guglielmi A. Current controversies in the adjuvant therapy of colon cancer. Ann Oncol 2004;15(Suppl 4):iv39-41. Zaniboni A, Labianca R. Grupo Italiano per lo studio e la cura dei Tumori del Digerente. Adjuvant therapy for stage II colon câncer: an elephant in the living room? Ann Oncol 2004;15(9):1310-8. Bhatavdekar JM, Patel DD, Chikhlikar PR, Shah NG, Vora HH, Glosh N, et al. Molecular markers are predictors of recurrence and survival in patients with Dukes B and Dukes C colorectal adenocarcinoma. Dis Colon Rectum 2001;44(4):523-33. Waisberg J, Landman G, Cha ASH, Henriques AC, Gaspar HA, Speranzini MB. Padrão da distribuição tecidual do CEA no carcinoma colo-retal: relação com o nível sérico do CEA e classificação de Dukes. Rev bras Coloproctol 2002;22(1):20-6. Levy M, Visokai V, Lipska L, Topolcan O. Tumor markers in staging and prognosis of colorectal carcinoma. Neoplasma 2008;55(2):138-42. Lyall MS, Dundas SR, Curran S, Murray GI. Profiling markers of prognosis in colorectal cancer. Clin Cancer Res 2006;12(4):1184-91. Galizia G, Lieto E, Ferraracio F, Orditura M, De Vita F, Castellano P, et al. Determination of molecular marker expression can predict clinical outcome in colon carcinomas. Clin Cancer Res 2004;10(10):3490-9. Bukeirat FA, Ostrinsky Y, McFadden D. Use of GI tumor markers in clinical practice: a practical interpretation. W V Med J 2008;104(4):17-21. Duffy MJ, van Dalen A, Haglund C, Hansson L, Holinski-Feder E, Klapdor R, et al. Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use. Eur J Cancer 2007;43(9):1348-60. Daniels IR, Fisher SE, Heald RJ, Moran BJ. Accurate staging, selective preoperative therapy and optimal surgery improves outcome in rectal cancer: a review of the recent evidence. Colorectal Dis 2007;9(4):290-301. Stein U, Schlag PM. Clinical, biological, and molecular aspects of metastasis in colorectal cancer. Recent Results

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clinical implications. Ann Oncol 2005;16(9):1503-07. 31. Khalifa MA, Rowsell CH, Gladdy RA, Ko YJ, Hanna S, Smith A, et al. Expression of epidermal growth factor receptor in primary colorectal adenocarcinoma predicts expression in recurrent disease. Am J Clin Pathol 2006;125(2):229-33. 32. Bralet MP, Paule B, Falissard B, Adam R, Guettier C. Immunohistochemical variability of epidermal growth factor receptor (EGFR) in liver metastases from colonic carcinomas. Histopathology 2007;50(2):210-6. 33. Scartozzi M, Bearzi I, Bearzi R, Mandolesi A, Fabris G, Cascinu S. Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: implication for treatment with EGFR-targeted monoclonal antibodies. J Clin Oncol 2004;22(23):4772-8. 34. Galizia G, Lieto E, Ferraraccio F, De Vita F, Castellano P, Orditura M, et al. Prognostic significance of epidermal growth factor receptor expression in colon cancer patients undergoing curative surgery. Ann Surg Oncol 2006;13(6):823-35. 35. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecam in irinotecan-refractory metastatic colorectal câncer. N Engl J Med 2004;351(4):337-45. 36. Overman MJ, Hoff PM. EGFR-target therapies in colorectal cancer. Dis Colon Rectum 2007;50(8):1259-60. 37. Doger FK, Meteoglu I, Tuncyurek P, Okyay P, Cevikel H. Does the EGFR and VEGF expression predict the prognosis

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in colon cancer? Eur Surg Res 2006;38(6):540-4. 38. Spindler KL, Lindebjerg J, Nielsen JN, Olsen DA, Bisgard C, Brandslund I, et al. Epidermal growth factor receptor analyses in colorectal cancer: a comparison of methods. Int J Oncol 2006;29(5):1159-65. 39. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 2008;358(11):1160-74. 40. Kountourakis P, Pavlakis K, Psyrri A, Rontogianni D, Xiros N, Patsouris E, et al. Clinicopathologic significance of EGFR and Her-2/neu in colorectal adenocarcinomas. Cancer J 2006;12(3):229-36. 41. Karameris A, Kanavaros P, Aninos D, Gorgoulis V, Mikou G, Rokas T, et al. Expression of epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) in gastric and colorectal carcinomas. An immunohistological study of 63 cases. Pathol Res Pract 1993;189(2):133-7. 42. Baiocchi G, Lopes A, Couldry RA, Rossi BM, Soares FA, Aguiar S, et al. ErbB family immunohistochemical expression in colorectal cancer patients with higher risk of recurrence after radical surgery. Int J Colorectal Dis 2009;24(9):1059-68. Correspondence to: Maurício Andrade Azevedo Rua Itapeva, 202, cj. 37, Bela Vista CEP: 01332-000 – São Paulo (SP), Brazil E-mail: dr.mauricioazevedo@uol.com.br

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Original Article

Adalimumab in the induction of Crohn’s disease remission: results of a Brazilian multicenter case series PAULO GUSTAVO KOTZE1, ANDREA VIEIRA2, CARLOS WALTER SOBRADO JUNIOR3, JULIANA BARRETO SALEM4, LORETE MARIA DA SILVA KOTZE5 Coordinator of the Proctology Service at Hospital Universitário Cajuru (SeCoHUC), Pontifícia Universidade Católica do Paraná (PUC-PR) – Curitiba (PR), Brazil. 2Head of the Gastroenterology Clinic at Irmandade de Misericórdia Santa Casa de São Paulo – São Paulo (SP), Brazil. 3Doctor at the Coloproctology Service of Hospital da Polícia Militar do Estado de São Paulo – São Paulo (SP), Brazil. 4Doctor at the Surgery Service of Hospital Municipal de Urgência of Guarulhos – Guarulhos (SP), Brazil. 5Head Professor of the Gastroenterology Service at Hospital Universitário Cajuru, PUC-PR – Curitiba (PR), Brazil. 1

KOTZE PG, VIEIRA A, JUNIOR CWS, SALEM JB, KOTZE LMDS. Adalimumab in the induction of Crohn’s disease remission: results of a Brazilian multicenter case series. Rev bras Coloproct, 2011;31(3): 233-240. Abstract: Introduction: Adalimumab (ADA) is a subcutaneous fully-human anti-TNF antibody which has a significant role in the management of Crohn’s disease (CD). Its efficacy has been demonstrated in several clinical trials. The main objective of this study was to evaluate the role of ADA in the induction of clinical remission in a Brazilian series of CD cases. Method: A retrospective analysis of CD patients treated with ADA was performed in three Brazilian inflammatory bowel diseases (IBD) reference centers. The following characteristics were analyzed: gender, age, indication to ADA treatment, type of response, previous exposure to infliximab (IFX), concomitant use of immunomodulators and adverse events, among others. Results: 54 patients (29 females) were included in this series, with mean age of 36.72 years (ranging from 15 to 62 years). After induction regimen, 26 patients (48.14%) were in clinical remission, 26 (48.14%) had partial response, and 2 (3.72%) were primary non-responders. After a mean follow-up of 9.83 (2 to 28) months, 17 patients (31.48%) presented adverse events. The most common event was pain on the injection site (7 patients – 12.96%). Conclusions: ADA was effective to induce CD remission in this Brazilian case series. The remission and response rates were similar to the literature, as well as the safety profile of this drug. Keywords: Crohn’s disease; tumor necrosis factor-alpha; remission induction; antibodies, monoclonal.

INTRODUCTION

with limited efficacy and considerable adverse effects. Starting with derivatives of the 5-aminosalicylic acid (5-ASA) and steroids, then moving on to antibiotics and immunomodulators, it was not possible to change the natural history of CD; as a consequence, it was common to observe its evolution to more severe forms1.

Crohn’s disease (CD) has always been considered as challenging for patients and health professionals, because it is incurable and difficult to treat. In the past 60 years, different drugs have been used in the treatment

Study carried out at the Proctology and Gastroenterology services of Hospital Universitário Cajuru, Pontifícia Universidade Católica do Paraná, Curitiba (PR), and at Hospital da Polícia Militar do Estado de São Paulo and the Gastroenterology Service of Irmandade de Misericórdia da Santa Casa de São Paulo, São Paulo (SP), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 31/01/2011 Approved on: 02/03/2011

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METHOD

The tumor necrosis factor (TNF) therapy represents the ultimate advance regarding the treatment of CD, and is currently used in daily clinical practice2. The first biological drug commercially available for this purpose was Infliximab (IFX), an intravenous chimeric antibody. Randomized clinical trials on IFX published in the early 2000s represented a turning point to treat these patients, since they resulted in significant clinical remission and response rates in patients with moderate and severe CD3,4. In order to reduce immunological responses induced by chimeric fractions of IFX, there was the attempt to develop fully human monoclonal antibodies5. Recently, the use of Adalimumab (ADA) was permitted by regulatory bodies in many countries for the treatment of CD. In Brazil, this drug has been used for this purpose since 2007, and the experience with this medication has been increasing. ADA can also be indicated for the treatment of adult patients with moderate or severe active CD, who no longer respond or are intolerant to IFX6. However, better results have been demonstrated in patients who have never used anti-TNF agents7. It is a fully human recombinant IgG1 monoclonal antibody (with 100% of human peptide sequences), with subcutaneous self-administration5. ADA inhibits the tumor necrosis factor-alpha (TNF-α), leading to the apoptosis of inflammatory cells and the consequent reduction of tissue inflammation. ADA’s clinical efficiency and safety have been demonstrated in several phase III clinical trials, randomized and double-blind. Among these, the studies CLASSIC I, CLASSIC II, CHARM and GAIN stand out, and include a total of 1,754 patients5-8. Afterwards, many real life studies were published in literature, showing case series of many countries, such as Australia, Spain, among others9,10. There is no data in the literature regarding the efficacy of ADA in Brazilian patients as to CD management. Thus, it is necessary to conduct a more detailed assessment of Brazilian patients with CD, and this fact encouraged the authors to perform this study. The main objective of this paper was to assess the clinical efficacy of ADA to induce CD clinical remission in a series of Brazilian patients coming from three reference centers of inflammatory bowel diseases (IBD). The secondary objectives included the analysis of demographic data, drug’s safety (presence of adverse effects) and reasons to discontinue the treatment, among other variables.

This study was previously approved by the Research Ethics Committee of Pontifícia Universidade Católica do Paraná (CEP – PUC-PR), n. 5087/2009. It is an open, retrospective and analytical study concerning a case series. The studied sample consisted of patients with CD being treated with subcutaneous ADA. They came from three reference centers of inflammatory bowel diseases (IBD), one from the South and two from the Southeast region in Brazil. Data were collected from the patients’ medical records, and a specific protocol that had been previously established was filled. The analyzed variables were: - Age; - Gender; - Weight; - Corticoid dependency; - How the disease is presented (luminal, stenosing or penetrating); - Presence of anal and abdominal fistulae at the treatment; - Prior anal and abdominal surgeries; - Treatment strategy (step-up or top-down); - Use of immunosuppressors; - Type of response after the induction therapy (total, partial or absent); - Follow-up time to maintain the treatment; - Presence of adverse effects; - Reasons to discontinue the treatment. The study included all the patients who had been submitted to the subcutaneous ADA treatment (Humira®, Abbott Laboratórios do Brasil Ltda.) to handle CD in a period of two years (from October 2007 to September 2009). The patients came from the three aforementioned reference centers (one from Curitiba – PR, and two from the city of São Paulo – SP). The main inclusion criterion for this study was the performance of the doses of remission induction, which corresponds to 160 mg on week 0 and 80 mg on week 2. All patients received this dose (four subcutaneous syringes of 40 mg each on week 0, and two subcutaneous syringes of 40 mg on week 2). The patients could be on immunosuppressors or not, and could also have previously used another anti-TNF agent or not (IFX). 234


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Patients with a different induction dose were excluded from the study (80/40 mg or absent). All data were collected by the researchers, being compiled in tables for further analyses. The main idea to be analyzed as to efficacy was the way patients responded to the drug, after remission induction in the first two weeks; the analysis took place on week 4. Total response was defined as clinical remission (absence of symptoms after the period of induction). Partial response was subjectively defined as the improvement of symptoms, without their complete absence (residual symptoms, however, less intense than before the treatment). Absence of response was defined as the lack of clinical improvement due to the treatment (primary non-responders). This classification was in accordance with the one used in a similar methodology study, by Palacios et al., published in 20089. No quantitative methods were used to analyze the clinical response to the treatment, such as the Crohn’s disease activity index (CDAI) or the Harvey-Bradshaw index. All patients were submitted to the maintenance treatment, with 40 mg of ADA every two weeks, for a variable period of time. In order to analyze the adverse effects and the reasons to discontinue the treatment, not only the period of remission induction was calculated, but also the doses subsequent to the maintenance of the treatment. The information was compiled in a specific spreadsheet for the final data analysis. To evaluate the type of response after the induction, no specific statistical analysis was used, only frequency tables. To analyze the type of response in relation to the use of immunosuppressors and prior use of IFX, the Chi-squared test was performed to compare the three groups. Fischer’s exact test was only used to analyze the relation between the total and partial responses as to the prior use of IFX. Significance level for these analyses was 95% (p<0.05).

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28 presented the penetrating form (fistulizing). Out of the analyzed cases, 30 depended on corticoids for the treatment. These and other general characteristics of the patients, such as the presence of fistula, abdominal surgery, prior use of immunomodulators or IFX are demonstrated in Table 1. Out of the sample of 54 patients, 26 (48.14%) presented complete clinical remission (total response) on week 4, and 26 (48.14%) presented partial response; only 2 (3.72%) were primary non-responders. These findings are demonstrated in Figure 1. The relation between the type of response and the use of immunomodulators (in all cases, azathioprine 2 mg/kg) was also analyzed. Out of the 26 patients with total response after induction, only one used monotherapy with ADA. From the 26 patients who partially responded, five were not on immunomodulators and used monotherapy. The two primary non-responders used azathioprine. These findings are demonstrated in Figure 2. None of the patients in this Table 1. General characteristics of the patients (n=54). Mean age 36.72 years (15-62 years) Gender Male 25 (46.3%) Female 29 (53.7%) Mean weight 58.25 kg (36-102 kg) Corticoid dependency Yes 30 (55.5%) No 24 (44.5%) How the CN disease Luminal 19 (35.2%) is presented Stenosing 7 (13.0%) Penetrating 28 (51.8%) Anal fistulae Yes 27 (50.0%) No 27 (50.0%) Abdmonial fistulae Yes 6 (11.1%) No 48 (88.9%) Prior anal surgeries Yes 18 (33.3%) No 36 (66.7%) Yes 26 (48.1%) Prior abdominal surgeries No 28 (51.9%) Prior use of Yes 48 (88.9%) immunosuppressors No 6 (11.1%) Previous use of IFX Yes 30 (55.5%) No 24 (44.5%) Treatment strategy 48 (88.9%) Step-up 6 (11.1%) Top-down

RESULTS Fifty-four patients with CD and history of treatment with ADA were included in this study. Mean age of the patients was 36.72 (15-62) years, and mean weight was 58.25 (36-102) kg. In relation to gender, out of the 54 patients, 25 were males and 29 were females. As to the disease presentation, 19 patients had the luminal disease, 7 had the stenosing disease and 235


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series used methotrexate or another immunomodulator. There were no statistical differences between the groups as to the presence of immunomodulator in the type of response, according to the Chi-squared test. Another interesting fact in this sample was the type of response obtained after the remission induction in relation to the prior use of IFX. Out of the 25 patients who presented total response (remission), 16 had previously used IFX, as well as 14 out of the 26 patients with partial response to ADA. Both cases of primary non-responders in this study had not used IFX. These findings are demonstrated in Figure 3. There were no statistical differences among the three groups according to the Chi-squared test and Fischer’s exact test (used only to compare remission and partial response). In order to analyze secondary objectives, the maintenance of biological treatment with ADA in all patients was registered. Mean follow-up time was 9.83 months, ranging from 2 to 28 months. Out of the 54 patients analyzed in this study, nine had to discontinue the treatment with ADA. From these, six could not access the drug due to bureaucracy motives (difficulties with the health insurance or the public system). Out of the three patients who discontinued the treatment due to clinical reasons, one presented with diffuse urticariform eczema (Figure 4); the other presented bronchopneumonia, and the last one had hesper zoster. After the treatment of these adverse events, ADA injections were reestablished at the average maintenance dose (40 mg every 2 weeks), and the follow-up of these patients was not included in the rest of the analyses. From the whole sample, 17 (31,48%) patients had adverse effects. The total number of events was 21, which means that four patients presented two adverse events. The most common effect was pain in the site of subcutaneous injection in 12.96% of the patients (seven cases). Infection by herpes simplex occurred in three patients (5.55%). The other adverse effects are listed in Table 2.

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Type of response - induction (%) 60 50

48.14% (n=26)

48.14% (n=26)

40 Total (remission) Partial Absent

30 20 3.72% (n=2)

10 0

Figure 1. Total, partial or absent response rates, analyzed four weeks after remission induction in all included patients (n=54). The clinical remission was defined as the absence of symptoms, the partial response, as clinical improvement at the presence of residual symptoms, and absent in patients with no improvement.

Use of immunosuppressors vs. clinical response p=1.857

p=0.168

25

21

p=1.338

5

1 Total (remission)

2

Partial IS +

0 Absent

IS -

Figure 2. Type of response in relation to the use of immunosuppressors (azathioprine). Absence of statistical differences between the three groups (Chi-squared test).

Prior use of IFX vs. clinical response 16

p=0.575

p=0.349 14

12 p=0.481

10

0 Total (remission)

DIsCUssION

Partial IFX +

2 Absent

IFX -

IFX: Infliximab Figure 3. Type of response in relation to the prior use of IFX. Absence of statistical differences between the three groups according to the Chi-squared test and Fischer’s exact test (used only to compare partial response and remission).

The efficacy and the safety bprofile of ADA to manage CD are currently well established, after the performance of several randomized studies5-8. The requirements for a study with such great characteristics 236


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Table 2. Adverse effects ot the treatment with adalimumab in the case series (n=17 out of the 54 patients). Only four patients presented two adverse effects, accounting for 21 events. Mean follow-up of 9.83 months. Adverse effect n (%) Pain at the injection site 7 (12.96) Herpes simplex 3 (5.55) Urinary tract infection 2 (3.7) Ungual inflammation 2 (3.7) Headache 2 (3.7) Arthralgia 1 (1.85) Eczema 1 (1.85) Bronchopneumonia 1 (1.85) Amigdalitis 1 (1.85) Herpes Zoster 1 (1.85)

Reasons for treatment discontinuation (n=9) Difficulty to access

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Clinical reasons

3 (33%)

6 (67%)

Figure 4. Reasons that led nine patients to discontinue treatment with subcutaneous adalimumab.

are many, and there is a good chance for a strict analysis of primary and secondary outcomes of these studies. This means that, in outpatient clinics and offices, it is possible to succeed with the patients regarding the management of biological therapy for CD. After the publication of these renowned papers, literature started to present retrospective case series of patients with CD treated with ADA. These series came from different countries in the world, and showed clinical remission rates after the remission induction dose (160/80 mg), which was different from that found in controlled studies, especially in CLASSIC I5. The total response index (clinical remission) found in this study, of 48.13% of the cases, is higher than the 25% found in CLASSIC I, a study exclusively designed for the clinical remission outcome after induction. One of the factors that may explain these high levels was that 51.9% of the patients had the penetrating disease with active inflammation, and, in this case, response tends to be better. By adding the patients in remission and those with partial response, the result was impressive: 96.2% of improvement with ADA in the patients of this series. This number is probably due to the limitations of a retrospective methodology and to the non-definition of strict disease activity rates (such as CDAI), with a more subjective analysis. Palacios et al., a Spanish team, found 25% of remission and 56.3% of partial response after the

Figure 5. Diffuse urticariform eczema after two doses of adalimumab. Adverse effect that led to the temporary discontinuation of the drug.

Figure 6. Ungual inflammation in a patient on adalimubab. Simple adverse effect, which did not require the interruption of the treatment.

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same induction dose, for the luminal CD9, using the Harvey-Bradshaw index. For the fistulizing disease, observed in six patients, one case presented remission (16.7%), four patients had partial response (66.7%). This paper was conducted with a methodology similar to the one used in this study, and had a small sample of 22 patients. Trinder et al. published a study in 2009 representing a case series of Australian patients with CD, and found 54.5% of clinical remission and 27.3% of partial response10. It is important to emphasize that, in this study, the analysis as to the type of response was conducted in the eighth week, which may have increased these numbers, since cohort studies with long-term follow-up of patients demonstrated that remission rates and response to biological therapy can be optimized until week 20, in cases in which the treatment maintenance occurs11. Swaminath et al. analyzed the results of ADA in 48 patients. They reported remission in only 2% of the cases, with 43.8% of clinical improvement subjectively determined by the patientâ&#x20AC;&#x2122;s assistant12. Findings from the main studies of literature regarding remission and response to CD with ADA are demonstrated in Table 3. Two reasons may explain the higher success rates regarding therapy in retrospective studies. First, patients are less selected than the rigid inclusion criteria of randomized trials, as aforementioned. Second, cohort patients throughout the world usually present with active inflammation, and it is known that, in these patients, treatment tends to be more efficient, especially for those with high levels of C-reactive protein (CRP)13.

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In relation to the number of primary non-responders, the findings in this study (3.72%) are lower than the ones found in literature. In a study with a mean follow-up of 55 months with IFX, in the cohort of Leuven, Belgium, Schnitzler et al. identified that 10.9% of the 614 IFX users were primary non-responders14. In the aforementioned Australian study, 18.2% of the ADA users did not present any response10. A very similar number was found in the Spanish study, in which 4 out of the 22 patients did not respond to ADA induction, corresponding to 18.1% of the cases9. The exact proportion of nonresponders to induction with ADA in literature is unknown, since data from randomized studies are not clear. However, the low rates of patients with no response in this retrospective series can be explained by the subjectivity in the analysis of the used answer. Corticoid dependency was found in 30 out of the 54 cases in this study (55.5%). Besides, the strategy ascending from the treatment (step-up) was used in 48 patients (88.9% of the cases). With these numbers, it is possible to observe that, in relation to these patients, who represented the early experience of the three reference centers of this case series with ADA, there was the trend to use biological treatment in a significantly conservative way. More recently, criteria of CD worse prognosis have been defined in literature, which will certainly increase rates of more aggressive therapy in the future. In the reference centers mentioned in this study, there probably will be more cases of descending strategy (top-down). The use of immunosuppressors with the biological therapy may influence the efficacy of the antibodies in CD. However, literature shows controversies in relation to this topic. The study called SONIC, published in 2010, was exclusive designed with this purpose15. It was a randomized study with patients who had CD, and had never used anti-TNF agents or immunosuppressors. The results in that study demonstrated that the combined use of IFX and azathioprine had better clinical remission rates without corticoids and mucosal healing than the group with IFX as monotherapy. There are no studies with the same objective regarding ADA in literature. A subanalysis of the

Table 3. Main findings as to remission and clinical response to adalimumab found in literature, compared to this study. Author, year Remission (%) Response (%) Hanauer et al., 2006 36.0 59.0 (CLASSIC I)5 Palacios, 20089 22.7 59.1 10 Trinder et al., 2009 54.5 81.8 Kotze et al., 2011 48.13 48.13 (present study)

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study CHARM did not show any differences as to the efficacy of ADA in patients using azathioprine or not7. However, this study focused on therapy maintenance and lasted a year. In the present study, it was possible to analyze the role of azathioprine together with ADA, in relation to monotherapy with the biological agent, because almost all patients (48 out of the 54 in the sample) were treated with the combined therapy. The number of patients on monotherapy was small, which was partially negative for the analysis. Despite that, the statistical analysis showed no significance. However, the study was not designed for this purpose. Another controversy as to biological therapy for CD is the previous use of another TNF-agent in the treatment. Since IFX was approved seven years before ADA in Brazil, one of the reasons to use ADA is the lack of or the intolerance to the previously used IFX. Even though the authors in this study are experienced in relation to the use of IFX when ADA fails to work in a few cases, there is no randomized trial in literature with this purpose. Clearly, the concept that exists in literature is that patients who had never used IFX respond better to ADA subcutaneous injections than those who have previously tried another biological agent. This can be demonstrated in randomized trials and in a recent meta-analysis published by a Canadian group16. It is known that around 2/3 of the patients who had never used IFX respond better to ADA. However, for those patients who have been previously exposed, those rates are reduced. The study GAIN was exclusively designed with this purpose, and demonstrated that 21% of the patients were in complete clinical remission after induction, and that 50% of them responded to treatment6. On the other hand, the sample of this important study about ADA includes patients who have had adverse reactions to IFX and those with loss of response to the drug. This difference as to ADA may have influenced the results, since it is more efficient for intolerance due to adverse events than for loss of response. In this case series, there was no significantly statistical difference between patients who used IFX or not in remission and partial response levels, which is not in accordance with literature. Absolute numbers even show the opposite pattern. There is

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no justification for these results, however, it is believed that with more patients, there could be a better conclusion as to the effect of the previous use of IFX in patients treated with ADA. In relation to the adverse effects observed in this series, the findings are in accordance with literature. In a review of all controlled trials about ADA in CD, which included 3,160 patients, Colombel et al.17 demonstrated adverse events in up to 60% of the cases. These events ranged from simple situations, like hematomas and pain at the site of injection, to serious infections. The findings in this study showed adverse effects in 31.48% of the cases, which is a lower percentage in comparison to the information in randomized studies. The authors of this review regarding the safety of ADA found severe adverse effects in 34.4 patients/year, which led to the discontinuation of treatment in 16.3 patients/year. In this study, 3 out of the 54 patients (5.55% of the cases) needed to discontinue treatment due to clinical reasons. The low number may be explained by the short followup time. Infections were the most frequent and severe events, in accordance with literature. The estimated mortality with ADA was of 4 among 3,160 patients, which is lower than CD mortality17. The malignancy incidence in literature was present in 44 out of the 3,160 analyzed patients, with only two cases of lymphoma. There were no deaths or malignancy in the present series. CONCLUSIONS The use of ADA in this case series showed high rates of remission and clinical response, and also a low number of primary non-responders. These results can be compared with those of retrospective studies found in literature. There was a significant number of patients who needed to discontinue the treatment, especially for bureaucratic motives (difficulty to access the medication) rather than clinical reasons. Rates and types of adverse events were similar to those of literature. With this first case series about ADA in Brazilian patients who have CD, the conclusion is that the drug is efficient and safe, similar to the findings from other series in different countries of the world. 239


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Adalimumab in the induction of Crohn’s disease remission: results of a Brazilian multicenter case series Paulo Gustavo Kotze et al.

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Resumo: Introdução: O adalimumabe (ADA) é um anticorpo anti-fator de necrose tumoral alfa totalmente humano, de uso subcutâneo, com eficácia e perfil de segurança bem determinados na doença de Crohn (DC). O objetivo principal deste estudo foi determinar o papel do ADA na indução da remissão na DC, em uma série brasileira de casos. Método: Estudo retrospectivo, realizado em três centros de referência em doenças inflamatórias intestinais, com usuários do ADA para tratamento da DC. As variáveis analisadas foram: idade, sexo, indicação do tratamento, forma de apresentação da doença, tipo de resposta (total, parcial ou ausente), exposição prévia ao Infliximabe (IFX), entre outras. Resultados: 54 pacientes foram analisados (29 mulheres), com média de idade de 36,72 (15 a 62) anos. Após a dose de indução da remissão, 26 pacientes (48,14%) apresentaram resposta total (remissão clínica), 26 (48,14%) tiveram reposta parcial e 2 (3,72%) foram não-respondedores primários. Após seguimento médio de 9,83 (entre 2 e 28) meses, 17 pacientes (31,48%) apresentaram efeitos adversos (o mais comum foi dor no local da injeção em 7 pacientes – 12,96%). Conclusões: O ADA se mostrou efetivo na indução da remissão na DC em pacientes brasileiros, com taxas de remissão clínica e resposta compatíveis com as da literatura. Palavras-chave: doença de Crohn; fator de necrose tumoral alfa; indução de remissão; anticorpos monoclonais.

REFERÊNCIAS 1. Vermeire S, Van Assche G, Rutgeerts P. Review article: altering the natural history of Crohn’s disease – evidence for and against current therapies. Aliment Pharmacol Ther 2006;25:3-12. 2. Rutgeerts P, Van Assche G, Vermeire S. Review article: infliximab therapy for inflammatory bowel disease – seven years on. Aliment Pharmacol Ther 2006;23:451-63. 3. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541-9. 4. Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al. Infliximab maintenance therapy for fistulizing Crohn’s Disease. N Engl J Med 2004;350:876-85. 5. Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas N, Macintosh D, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006;130(2):323-33. 6. Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, et al. Adalimumab induction therapy for Crohn’s disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146:829-38. 7. Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132(10):52-65. 8. Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M, Macintosh D, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 2007;56:1232-9. 9. Palacios NL, Mendoza JL, Taxonera C, Lana R, Ferrer MF, Díaz-Rubio M. Adalimumab induction and maintenance therapy for Crohn’s disease. An open label study. Rev Esp Enferm Dig 2008;100(11):676-81. 10. Trinder MW, Lawrance IC. Efficacy of adalimumab for the

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management of inflammatory bowel disease in the clinical setting. J Gastroenterol Hepatol 2009;24:1252-7. Reinisch W, Louis E, Lofberg R, Kron M, Camez A, Robinson A, et al. Influence of disease duration on adalimumab efficacy in Crohn’s disease: Subanalysis of the CARE Trial. Presented at ECCO congress, Hamburg, Germany; 2009. Swaminath A, Ullman T, Rosen M, Mayer L, Lichtiger S, Abreu MT. Early clinical experience with adalimumab in treatment of inflammatory bowel disease with infliximabtreated and naïve patients. Aliment Pharmacol Ther 2009;29(3):273-8. Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomsen OØ, Hanauer SB, McColm J, et al. PRECISE 2 Study Investigators. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 2007;357(3):239-50. Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, Van Assche G, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort. Gut 2009;58(4):492-500. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362(15):1383-95. Ma C, Panaccione R, Heitman SJ, Devlin SM, Ghosh S, Kaplan GG. Systematic review: the short-term and longterm efficacy of adalimumab following discontinuation of infliximab. Aliment Pharmacol Ther 2009;30(10):977-86. Colombel JF, Sandborn WJ, Panaccione R, Robinson AM, Lau W, Li J, et al. Adalimumab safety in global clinical trials of patients with Crohn’s disease. Inflamm Bowel Dis 2009;15(9):1308-19.

Correspondence to: Paulo Gustavo Kotze Rua Mauá, 682, Juvevê CEP: 80030-200 – Curitiba (PR), Brazil E-mail: pgkotze@hotmail.com

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Original Article

Correlation between location, size and histologic type of colorectal polyps at the presence of dysplasia and adenocarcinoma SANDRA BEATRIZ MARION VALARINI1, VINÍCIUS TOMADON BORTOLI2, NOELLE SUEMI WASSANO2, MAIARA FONTES PUKANSKI2, DARIANA CARLA MAGGI2, LUCAS AMADEU BERTOLLO2 1

Master’s degree in Emergency Medicine at Pontifícia Universidade Católica of Paraná (PUC-PR); Professor of Gastroenterology at PUC-PR – Curitiba (PR), Brazil. 2Sixth-year medical students at PUC-PR – Curitiba (PR), Brazil.

VALARINI SBM, BORTOLI VT, WASSANO NS, PUKANSKI MF, MAGGI DC, BERTOLLO LA. Correlation between location, size and histologic type of colorectal polyps at the presence of dysplasia and adenocarcinoma. Rev bras Coloproct, 2011;31(3): 241-247. Abstract: Adenocarcinoma represents 96-98% of colorectal neoplasms, and neoplastic polyps (adenomas) are their precursors. The aim of this study is to correlate size, location and histologic type of colorectal polyps at the presence of dysplasia and adenocarcinoma. Methods: Colonoscopies from January/2007 to December/2008 were retrospectively studied, in order to evaluate the characteristics of the polyps. Results and Discussion: Out of the 2,401 analyzed colonoscopies, 583 (24.3%) presented polyps. Due to the lack of histopathologic data, 139 exams were excluded. Mean age of the patients was 58±12 years, and 60% were females. Polyps were prevalent in the left colon (38.5%) and rectum (32.5%). Out of the 850 polyps which were histologically examined, 55.17% were tubular adenomas; 21.88%, hyperplastic; 17.05%, serrated; 5.4%, tubulovillous; and 0.47%, villous. As to polyps ≤1.0 cm, dysplasia was observed in 16.0% and adenocarcinoma in 1.9%. Those >1.0 cm, 72.0% (p<0.001) presented dysplasia, and 25.3% (p<0.001) presented adenocarcinoma. Polyps in the right and transverse colon were strongly associated with dysplasia (17.8% and 16.7%). Adenocarcinomas were prevalent in the left colon (2.5%) and rectum (2.1%). Conclusion: Polyps were more frequent in the left colon and rectum. The right and transverse colons were strongly correlated with dysplasia. Those of the left colon and rectum were associated with adenocarcinoma. Lesions >1.0 cm were positively related to dysplasia and neoplasm. Keywords: intestinal polyps; colorectal neoplasms; colonoscopy.

Adenocarcinomas represent 96 to 98% of colorectal malignant tumors, and it is a known fact that neoplastic polyps (adenomas) are precursors to this type of cancer9. About 2/3 to 3/4 of colon polyps are adenomatous, with potential to become CRC – adenoma-carcinoma sequence5,7. Some high risk factors for cancer were identified from adenomas, such as the size of the polyp, histologic type and the presence of high grade dysplasia10. Since most patients with polyps are asymptomatic, tracking these lesions through fecal occult blood,

INTRODUCTION Colorectal câncer (CRC) is among the most prevalent diseases in western and eastern countries, and its incidence has been increasing in the past decades1-7. In the United States and England, it is the second most common condition among all malignant diseases8. In Brazil, it is the fourth most frequent malignant neoplasm among men, and the third in women7. The incidence of this disease increases after the age of 50, however there are other factors to explain such as changes in diet and smoking4,6,7. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 27/01/2011 Approved on: 12/02/2011

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Journal of Coloproctology Correlation between location, size and histologic type of colorectal polyps at the presence of dysplasia and adenocarcinoma July/September, 2011 Sandra Beatriz Marion Valarini et al.

rectosigmoidoscopy and colonoscopy enables the suspicion, detection and removal of the lesion1,2,5,11. Since 2000, colonoscopy has become the most important examination to track polyps and CRC. Nowadays, in the USA, one out of four colonoscopies aim to track polyps10. Besides detecting polyps, their removal through endoscopic polypectomy has proved to be effective to reduce the incidence of this tumor2,5,12. Anatomopathological analysis enables the histological classification of adenomas, and also allows checking for dysplasia or neoplasm, as well as vascular and/or lymphatic invasion13. This assessment determines if polypectomy and/or mucosectomy were effective to heal the patient who presented with polyp or CRC, or if therapeutics will be necessary14. The objective of this study was to correlate location, size and histologic type of colorectal polyps at the presence of high grade dysplasia and adenocarcinoma.

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ostium and/or the ileocecal valve until the shadow of the liver (hepatic flexure of the colon). Transverse colon was determined as the segment between the shadow of the liver and the spleen (splenic flexure of the colon). The left colon consisted of the segment between the splenic flexure and the rectosigmoid junction. Finally, the rectum was the segment distal to this junction. The approximate size of the polyp was assessed by an open biopsy forceps, with 0.8 cm of diameter. Afterwards, polypectomy and/or mucosectomy were performed. Mucosectomy was chosen for flat or broad-based lesions, and the elevation of the lesion was maintained with the submucosal saline or 10% mannitol injection. For polyp resection diathermic devices with different shapes were used (oval, elliptic or hexagonal), with diameters ranging from 16 to 35 mm; the shape choice depends on the size of the polyp and the presence or absence of pedicle. For polyps measuring up to 0.5 cm, a hot-biopsy was occasionally performed. Two electrocauteries were used in the polypectomy, one WEM, HF 120, and one Medicir MBJII. After being removed, the polyps were immerse in 10% formalin, separated by segment (right, transverse, left colon and rectum) and sent to the pathology department.. Adenoma was determined as a pre-malignant neoplasm with abnormal glandular epithelium and no stromal invasion. The identification of adenomas was based on structural and cytology modifications. They were classified as tubular, villous and tubulovillous adenomas, according to the presence of 0 to 25% of villous tissue for tubular adenoma ; 25 to 75% of villous lesions, as tubulovillous; and above 75%, as villous. Cellular atypia was defined as enlarged nucleus, chromatin dispersion and prominent nucleolus. The loss of polarity, stratification and atypical mitotic figures, coexisting with architecture changes, characterizes high grade dysplasia. Adenocarcinoma isan invasion of any degree in the stroma13. If the muscularis mucosae had been compromised, it was classified as submucousal adenocarcinoma; in this situation, vascular and/or lymphatic invasion was assessed. Statistica v.8.0. software was used to analyze data and significance was reached if p<0.05.

METHODS A retrospective study was conducted with patients who were submitted to colonoscopy from January 2007 to December 2008 and presented with colorectal polyps, regardless of being referred to examination. Colon preparation started 24 hours prior to the examination, and consisted of a free-fiber diet, ingestion of bisacodyl, 10% mannitol solution or polyethylene glycol and intestinal lavage with monobasic and dibasic sodium phosphate. All patients had a pre-anesthesia appointment and were submitted to general anesthesia with propofol 2–3 mg/kg. Two different scopes were used: Olympus CLV E, model CF, and the other was Fujinon 2200, model EC250HL. All procedures were performed by one member of the endoscopy team; all of three had broad experience in this type of procedure and were registered by the Brazilian Society of Digestive Endoscopy and/or the Brazilian Society of Coloproctology. When a colorectal polyp was found, the location of the lesion in the colon and/or rectum was identified by anatomical references. The right colon was defined as the segment between the appendicular 242


Journal of Coloproctology Correlation between location, size and histologic type of colorectal polyps at the presence of dysplasia and adenocarcinoma July/September, 2011 Sandra Beatriz Marion Valarini et al.

RESULTS

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bular adenoma was also prevalent (79.64%), followed by the serrated one (9.7%); the tubular adenoma was prevalent in the right colon (71.2%), followed by the tubulovillous one (11.36%). Polyps that were larger than 1.0 cm corresponded to 19.5% of the lesions in the left colon; 15.3% in the right colon; 8.2% in the rectum; and 6.0% in the transverse colon. Out of the four villous polyps found, one was in the right colon and three were in the rectum. The hyperplastic adenoma was frequently smaller than 1 cm (97.85%), followed by the serrated (91.72%) and tubular (85.07%) adenomas. Among the ones that were larger than 1.0 cm, villous and tubulovillous adenomas were prevalent (56.0%) (Table 1). The size of the polyp and the grade of dysplasia were highly related. The larger the polyp, the higher the chances of presenting high grade dysplasia or

From 2,401 videocolonoscopies, 583 (24.3%) had colorectal polyps. Out of these, 139 were excluded due to lack of histopathological data. The mean age of the 444 analyzed patients was 58±12 years (26 to 90 years old), and (nº patients) 60% were females. The mean number of polyps was 2:54.1% presented only one polyp; 23.2% had two polyps; and 22.5% presented three or more polyps. No statistical significance between the number of polyps and the age of the patient was found (p=0.350) (Figure 1). However, the chances of having more than one polyp are significantly higher for men than for women (p=0.020). 52.2% of the males had more than one polyp, compared to 42.0% of the females. Polyps were more frequently located in the left colon (38.5%), followed by the rectum (32.5%), right colon (15.5%) and transverse colon (13.3%). In relation to size, 60.7% measured less than 0.5 cm, 25.8% had 0.6 to 1.0 cm, and 13.4% measured more than 1.0 cm. Out of the 882 polyps that were found, 32 could not be recovered during colonoscopy or were removed from the study for not being related to the epithelial line. Among the 850 polyps that were histologically analyzed, 55.2% were tubular, 21.9% were hyperplastic, 17.1% were serrated, 5.4% were tubulovillous and 0.5 were villous adenomas. No dysplasia was observed in 87.5% of the polyps; 10.4% presented high grade dysplasia and 2.1% were adenocarcinomas. The prevalent histologic type in the rectum was the hyperplastic adenoma (35.01%), followed by the tubular adenoma (33.93%), which was also prevalent in the left colon (58.23%), followed by the hyperplastic adenoma (21.03%). In the transverse colon, the tu-

se: Standard Error; sd: Standard Deviation Figure 1. Relation between age and number of polyps.

Table 1. Relation between size and histologic type. Size (cm) ≤1 >1 Total

Hyperplastic 182 97.85% 4 2.15% 186

Histologic type Tubular Tubulovillous or Villous 399 22 85.07% 44.00% 70 28 14.93% 56.00% 469 50

243

Serrated 133 91.72% 12 8.28% 145 p<0.001


Journal of Coloproctology Correlation between location, size and histologic type of colorectal polyps at the presence of dysplasia and adenocarcinoma July/september, 2011 Sandra Beatriz Marion Valarini et al.

adenocarcinoma (Figure 2). Out of the serrated adenomas, 98.6% did not present dysplasia, as well as 86.6% of the tubular adenomas. However,, tubulovillous adenomas 69.6% presented high grade dysplasia. Out of the four villous polyps found, two had high grade dysplasia and one presented adenocarcinoma (Table 2). The polyps located in the right or transverse colon had higher chances of high grade

dysplasia than those located in the left colon or rectum; however, the chances of adenocarcinoma were lower (p=0.003) (Table 3). DIsCUssION Colorectal câncer is the third most common cause of cancer in the world, and the second cause in developed countries1,2,6, representing 9.4% of all cancers15. In Brazil, it is the fourth most common malignant neoplasm among men and the third in women15. The adenoma-carcinoma sequence was first analyzed by Morson and is considered as the main path for colorectal carcinogenesis16-18. Out of the colonoscopies analyzed in this study, 24.28% presented colorectal polyps. This information is in accordance with findings in literature, which show the prevalence of polyps of 16.4 to 29.96% in colonoscopies7,9. Median age of the patients with polyps was similar to other studies, in which the mean ranged from 57.5 and 62.5 years7,9,19. Thus, the prevalence of the disease is higher among individuals over 50 years old1,4,6,7,20.

100% 80% 60% 40% 20% 0%

Up to 0.5 0.6-1 1.1-2 Size of the polyp (cm) Absent

High grade

>2

Adenocarcinoma

Figure 2. Relation between size and grade of dysplasia.

Table 2. Relation between dysplasia and histologic type. Dysplasia Absent High grade Adenocarcinoma Total

Hyperplastic 186 100.00% 0 0.00% 0 0.00% 186

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tubular 406 86.57% 53 11.30% 10 2.13% 469

Histologic type tubulovillous 7 15.22% 32 69.57% 7 15.22% 46

Table 3. Relation between dysplasia and location. Dysplasia Right colon transverse colon Absent 106 92 80.30% 81.42% High grade 24 19 18.18% 16.81% Adenocarcinoma 2 2 1.52% 1.77% Total 132 113

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Left colon 295 89.12% 28 8.46% 8 2.42% 331

Villous 1 25.00% 2 50.00% 1 25.00% 4

serrated 143 98.62% 2 1.38% 0 0.00% 145 p<0.001 Rectum 256 91.43% 18 6.43% 6 2.14% 280 p=0.003


Journal of Coloproctology Correlation between location, size and histologic type of colorectal polyps at the presence of dysplasia and adenocarcinoma July/September, 2011 Sandra Beatriz Marion Valarini et al.

Most of the patients who had polyps were females. The relation between gender and the development of polyps is not clear yet, but some studies point to higher prevalence rates among men2,4,5,7,19. This difference in our findings in comparison to literature is possibly due to the higher number of colonoscopies performed in women than in men in the analyzed service. In this sample, it was more likely for men to have more than one polyp with a relation of 1.2:1 (p=0.202). Polyps were more frequently located in the left colon and the rectum, and these two locations accounted for 71.0% of the observed polyps, which is in accordance with other studies6,9,17. On the other hand, Santos et al. (2008) located a higher number of polyps in the right colon7. Polyps larger than 2.0 cm (3.08%) were more frequently correlated with high grade dysplasia, and were more likely to become adenocarcinoma. Polyps larger than 1.0 cm were more frequently found in the left colon, followed by the right colon and rectum. The size of the polyp is considered as the most important risk factor for in situ and invasive neoplasm, even though it is possible to observe high grade dysplasia in small lesions1,6,9,16,21. Some studies have demonstrated that adenomatous polyps tend to be larger than hyperplastic polyps2. In these cases, villous adenomas are the largest (mean of 1.56 cm), and tubular adenomas are the smallest (mean of 0.47 cm)6. In this study, hyperplastic polyps were the smallest, and tubulovillous or villous polyps were the largest. Almost all hyperplastic polyps had less than 1.0 cm (97.85%), and 56.0% of the tubulovillous or villous polyps had more than 1.0 cm. Histologically, tubular polyps were the most prevalent (54.3%), which is shown in different studies2,6,7,22. Other authors reported the prevalence of hyperplastic polyps7,9, which was the second most frequent in our study. Villous adenomas have more potential to be malignant6,7,16. Out of the four villous polyps analyzed, two presented high grade dysplasia, and one was classified as adenocarcinoma. This is in accordance with literature, however, it cannot be statistically assessed due to the restricted sample size.

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It has been increasingly accepted that colorectal cancer with microsatellite instability involves serrated polyps instead of adenomas22. Since it consists of adenomatous and hyperplastic tissues7, the serrated adenoma may be related with dysplasia. Out of the 143 serrated polyps, only two presented high grade dysplasia (1.38%), and there were no adenocarcinomas, but this information also represents limited value due to the sample size. High grade dysplasia was more prevalent in polyps located in the right and transverse colon. Polyps in the left colon and the rectum were strongly associated with adenocarcinoma. Studies regarding the genetic characteristics of colorectal tumors will provide great advances as to the understanding of this neoplasm, once genetics opens perspectives in order to substantially change prognosis and survival rates related to this disease16,23,24. Recent updates of the National Polyp Study and the U.S. Multi-Society Task Force recommend that patients be identified as low risk (one or two tubular adenomas smaller than 1.0 cm or low grade dysplasia) or high risk (three or more adenomas, one of them being larger than 1.0 cm, villous or tubulovillous histology or high grade dysplasia)10. Low risk patients should undergo another colonoscopy in five years or more, while high risk patients should be submitted to a new colonoscopy in three years, as long as all polyps are properly removed4,10,18. According to guidelines of the American Gastroenterology Association and the American College of Gastroenterology, low risk patients should be re-evaluated in five years10. The American Cancer Society informs that low risk patients should be followed-up for a period from three to six years10. Regardless of this disagreement as to time of follow-up, the conclusion is that periodic colonoscopies are necessary to detect polyps; besides, this examination enables their removal and reduces the prevalence of adenocarcinoma. It is common for gastroenterologists not to follow the guidelines as to endoscopic surveillance. They usually recommend a smaller interval because of the suboptimal quality of the colonoscopy or due to clinical factors associated with the patient; also, they might be afraid of not detecting an existing adenoma or of the incomplete resection of colorectal cancer10. 245


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FINAL COMMENTS

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sis and periodic monitoring of the patients are essential to reduce the incidence of CRC.

In this study, out of the analyzed colonoscopies, the presence of polyps in ¼ of them was observed, especially in the left colon and rectum, measuring less than 1.0 cm and being histologically classified as tubular adenomas. However, tubulovillous and villous adenomas, which are larger than 1.0 cm, were strongly correlated with high grade dysplasia and adenocarcinoma. These findings are in accordance with literature. Since it is a known fact that polyps are precursors of adenocarcinomas, referral to colonoscopy, recognition of the polyp and the establishment of adequate therapeutic measures, besides the determination of progno-

ACKNOWLEGDMENTS We thank Drs. Rubens Valarini, Antônio Sérgio Brenner and Jean Rodrigo Tafarel, who have performed the colonoscopies and polypectomies with Dr. Sandra Valarini; Dra. Danielle Giacometti Sakamoto, for the histological examination of almost all the polyps in this study; Prof. Márcia Olandoski, for the attention and data statistical analysis; Dr. Lorete Maria da Silva Kotze and Dr. Júlio César Pisani, for revising the text.

Resumo: O adenocarcinoma representa 96-98% do câncer colorretal, sendo os pólipos neoplásicos (adenomas) seus precursores. O objetivo desse estudo é correlacionar tamanho, localização e tipo histológico de pólipos colorretais com a presença de displasia e adenocarcinoma. Métodos: Estudou-se retrospectivamente colonoscopias realizadas entre janeiro/2007 e dezembro/2008, avaliandose as características dos pólipos. Resultados e Discussão: Das 2401 colonoscopias analisadas, 583 (24,3%) apresentaram pólipos. Por falta de dados histopatológicos, excluiu-se 139 exames. A média de idade foi 58±12 anos, sendo 60% mulheres. Houve predomínio no cólon esquerdo (38,5%) e reto (32,5%). Quanto ao tamanho, 86,58% eram ≤1 cm. Dos 850 pólipos analisados histologicamente, 55,17% eram adenomas tubulares, 21,88% hiperplásicos, 17,05% serrilhados, 5,4% tubulovilosos e 0,47% vilosos. Dos pólipos ≤1,0 cm, 16,0% apresentaram displasia e 1,9% adenocarcinoma; dos >1,0 cm houve displasia em 72,0% (p<0,001) e adenocarcinoma em 25,3% (p<0,001). Pólipos do cólon direito e transverso associaram-se mais à displasia (17,8% e 16,7%, respectivamente). Adenocarcinoma predominou no cólon esquerdo (2,5%) e reto (2,1%). Conclusão: Os pólipos predominaram em cólon esquerdo e reto. Os do cólon direito e transverso correlacionam-se fortemente à displasia, e os do reto e cólon esquerdo ao adenocarcinoma. Lesões maiores que 1,0 cm associaram-se positivamente com a presença de displasia e neoplasia. Palavras-chave: pólipos intestinais; neoplasias colorretais; colonoscopia.

REFERENCES 1.

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Manzione CR, Nadal SR, Nadal MA, Melo SVM. Análise morfológica e histológica de pólipos colorretais submetidos à ressecção endoscópica. Rev bras Coloproct 2004;24(2):119-25. 7. Santos JM, Felício F, Lyra Júnior HF, Martins MRC, Cardoso FB. Análise dos pólipos colorretais em 3491 videocolonoscopias. Rev bras Coloproct 2008;28(3):229-305. 8. Quilici FA, Cordeiro F, Quilici LCM. Neoplasias do intestino grosso benignas e malignas. In: Prado J. Tratado das enfermidades gastrintestinais e pancreáticas. 1ª ed. São Paulo: Editora Roca; 2008. p 1000-17. 9. Almeida MG, Baraviera AC, Malheiros APR, Bellandi DM, Cury RM, Milman MHSA, et al. Polipectomias endoscópicas - estudo histopatológico e complicações. Rev bras Coloproct 2003;23(2):100-4. 10. Saini SD, Nayak RS, Kuhn L, Schoenfeld P. Why don´t gastroenterologists follow colon polyp surveillance guidelines? Results of a national survey. J Clin Gastroenterol 2009;43(6):554-8. 11. Altenburg FL, Biondo-Simões MLP, Santiago A. Pesquisa

Bafandeh Y, Khoshbaten M, Sadat ATE, Farhang S. Clinical predictors of colorectal polyps and carcinoma in a low prevalence region: Results of a colonoscopy based study. World J Gastroenterol 2008;14(10):1534-8. Bokemeyer B, Bock H, Hüppe D, Düffelmeyer AR, Tacke W, Koop H. Screening colonoscopy for colorectal cancer prevention: results from a German online registry on 269000 cases. Eur J Gastroenterol Hepatol 2009;21:650-5. Cheung DY, Kim TH, Kim CW, Kim JI, Cho SH, Park SH, et al. The anatomical distribution of colorectal cancer in Korea: evaluation of the incidence of proximal and distal lesions and synchronous adenomas. Inter Med 2008,47:1649-54. Gupta S, Palmer BF. Colorectal polyps: the scope and management of the problem. Am J Med Sci 2008;336(5):407-17. Kim DH, Lee SY, Choi KS, Lee HJ, Park SC, Kim J, et al. The usefulness of colonoscopy as a screening test for detecting colorectal polyps. Hepatogastroenterol 2007;54(80):2240-2.

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de sangue oculto nas fezes e correlação com alterações nas colonoscopias. Rev bras Coloproct 2007;27(3):304-9. Leslie A, Carey FA, Pratt NR, Steele RJC. The colorectal adenoma-carcinoma sequence. BJS 2002;89(7):845-60. Kudo S, Lambert R, Allen JI, Fujii H, Fujii T, Kashida H, et al. Nonpolypoid neoplastic lesions of the colorectal mucosa. Gastrointest Endosc 2008;68(4):3-47. Hassan C, Zullo A, Risio M, Rossoni FP, Morini S. Histologic risk factors and clinical outcome in colorectal malignant polyp: a pooled-data analysis. Dis Colon Rectum 2005;48(8):1588-96. Instituto Nacional de Câncer. Estimativa 2010: incidência de câncer no Brasil. Rio de Janeiro: INCA, 2009. Cotti GCC, Santos FPS, Sebastianes FM, Habr-Gama A, Seid VE, Martino RB. Genética do câncer colorretal. Rev Med (São Paulo) 2000;79(2):45-64. Hossne RS, Maranhão MF, Carvalho FA, Mendes FG. Estudo retrospectivo do resultado anatomopatológico de 100 polipectomias colonoscópicas realizadas na FMB-UNESP. Rev bras Coloproct 2007;27(3):251-5. Rostirolla RA, Pereira-Lima JC, Teixeira CR, Schich AW, Perazzoli C, Saul C. Desenvolvimento de neoplasias/ adenomas avançados colorretais no seguimento a longo prazo de pacientes submetidos a colonoscopia com polipectomia. Arq Gastroenterol 2009;46(3):167-72. Parra-Blanco A, Gimeno-García AZ, Nicolás-Pérez D, Garcia C, Medina C, Díaz-Flores L, et al. Risk for high-grade dysplasia

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or invasive carcinoma in colorectal flat adenomas in a Spanish population. Gastroenterol Hepatol 2006;29(10):602-9. Lyra Júnior HF, Bonardi MA, Schiochet VJC, Baldin Júnior A, Carmes ER, Sartor MC, et al. Importância da colonoscopia no rastreamento de pólipos e câncer colorretal em pacientes portadores de pólipos retais. Rev bras Coloproct 2005;25(3):226-34. Rodrigues MAM. Adenoma: o marcador biológico de risco para câncer de cólon. GED 1996;15(2):59-61. Spring KJ, Zhao ZZ, Karamatic R, Walsh MD, Whitehall VLJ, Pike T, et al. High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy. Gastroenterol 2006;131(5):1400-7. Perez RO, Habr-Gama A, Jacob CE, Sousa Júnior AHS, Picolo MM, Pécora RA. A genética do câncer colorretal - princípios para o cirurgião. Rev bras Coloproct 1998;18(1):5-10. Roa-S JC, Roa-E I, Melo-A A, Araya-O JC, Villaseca-H MA, Flores-M M, et al. Mutación del gen p53 en el câncer de colon y recto. Rev Med Chile 2000;128(9):996-1004.

Correspondence to: Vinicius Tomadon Bortoli Av. Iguaçu, 1355, Apto. 13 – Água Verde CEP: 80250-190 – Curitiba (PR), Brazil. E-mail: viniciustbortoli@gmail.com.

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Original Article

Fecal incontinence as consequence of anorectal surgeries and the physiotherapeutic approach KELLY CRISTINA DUQUE CORTEZ1, SARAH DE SOUZA MENDONÇA2, MARINA DE SOUZA FIGUEIROA3 1

Physiotherapist graduated at Faculdade Integrada do Recife (FIR) – Recife (PE), Brazil. 2 Physiotherapist graduated at FIR – Recife (PE), Brazil. 3Ms Professor, Physiotherapy Program at FIR – Recife (PE), Brazil.

CORTEZ KCD; MENDONÇA SDS; FIGUEIROA MDS. Fecal incontinence as consequence of anorectal surgeries and the physiotherapeutic approach. Rev bras Coloproct, 2011;31(3): 248-256. Abstract: Caused by sphincter injuries in various anorectal procedures, fecal incontinence (FI) is a common complication in some patients undergoing coloproctology surgeries. Objective: Demonstrate the occurrence of FI as a result of anorectal surgeries, present the physiotherapy resources for the treatment of this disorder and, based on that, propose the inclusion of physiotherapy as a routine postoperative practice for these types of interventions. Materials and Methods: An integrative review of databases from the virtual health library (VHL) and the Physiotherapy Evidence Database (PEDro) published between 2000 and 2010, in English and Portuguese. Results: Thirteen articles (one cross-section cohort, two uncontrolled clinical trials and ten retrospective cohorts), with evidence level between 2C and 4C and published between 2001 and 2009, were selected; review articles were excluded. The review demonstrated that FI is an important complication of anorectal surgeries, causing major impacts on the patients’ quality of life and that physiotherapy provides effective resources to treat this disorder. Conclusion: Further studies are recommended, in the form of systematic reviews, using a higher number of articles and better scientific evidences. Keywords: colorectal surgery; postoperative complications; fecal incontinence; physiotherapy; prevention.

INTRODUCTION

tremely important for a successful treatment4. The fear of postoperative pain is the patients’ main reason to run away from the proctology surgery, postponing a procedure whose indication is almost always precise5. However, traditional surgical treatments may often promote fecal incontinence (FI), caused by sphincter injuries, constituting a complication in some patients4 that can become a permanent disorder6. FI is the inability to keep the physiological control of the bowels in a socially adequate place and time, with symptoms varying from occasional flatus to continuous and involuntary stool loss7,8, and the patients with fecal incontinence are more subject to health complications, such as skin injuries, urinary in-

It is estimated that around 5% of the adult population of the United States have anal disorders; in Brazil, they are more predominant in women between 30 and 50 years old1. In coloproctology routine, these disorders account for around 50 to 80% of total surgeries in this department1-3; and the most common operations are for hemorrhoid and anal fissure and fistula treatments, which can adopt conservative methods; however, the surgery is sometimes required4. The postoperative phase of most interventions usually involves intense discomfort, pain, secretion, bleeding, among other typical symptoms, and it is ex-

Study carried out at the Department of Physiotherapy, Faculdade Integrada do Recife, Recife (PE), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 29/03/2011 Approved on: 25/08/2011

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fection and nutritional alterations9. The losses develop high physical and psychological inability, leading to reduced self-esteem and gradual social withdrawal, with negative impact on the patients’ mental health and psychosocial aspects10. In hemorrhoidectomy and anal fissurectomy with internal sphincterotomy, the occurrence of FI can be considered a serious technical error. In anal fistulotomy, with internal or external sphincter incision, it may be an expected consequence; however, it should be prevented by the medical team4. The clinical selection of FI treatment method is dependent on the disorder etiology, and the options include dietary changes and medicine that reduces the intestinal motility11. The physiotherapy approach of perineal re-education is another conservative therapy that involves training for increased contractile ability and voluntary control of the external anal sphincter and the levator ani muscle, as well as analgesia, by incrementing the local blood circulation12. In a debate published by Revista Brasileira de Coloproctologia in 1999, five coloproctologists discussed about the ideal composition of a multidisciplinary team in this area, and only one of them had a physiotherapist in his team13. In view of that, the purpose of this study was to demonstrate the occurrence of FI as a consequence of anorectal surgeries, present the physiotherapy resources and their efficacy in the treatment of this disorder and, based on that, propose the inclusion of physiotherapy as a routine postoperative practice for these types of interventions to prevent FI and other complications.

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also screened for therapy methods used by physiotherapy to treat FI. Review articles were excluded. Thirteen articles were selected (one cross-section cohort, one study of a series of cases, two uncontrolled clinical trials and nine retrospective cohorts), with evidence level between 2C and 4C, three of them related to the treatment of anal fistula, six to anal fissure and five to hemorrhoid, all published between 2001 and 2009; one of the articles, with two types of orifice pathology, appears twice in this study – and in Table 1 –, and for this reason, this investigation analyzed 13, and not 14 articles. The evidence levels from the analyzed studies were classified according to the Oxford Centre for Evidence-based Medicine14. Theoretical reference The anal continence mechanism is complex and involves the integrated action of anal sphincter muscles and pelvic floor muscles, the presence of rectoanal inhibitory reflex, the rectal capacity, sensitivity and complacency, as well as the stool consistency15. The internal anal sphincter (IAS) is a smooth muscle in continuous condition of maximum contraction, creating a natural barrier to prevent stool loss16 and representing 55% of the pressure of the anal canal at rest17. The external anal sphincter (EAS) is a striated muscle and its deeper portion is close to the puborectalis muscle and it seems to be a single assembly, despite their distinct innervation16. It promotes 30% of the anal canal basal pressure and, with the puborectalis muscle, it produces the voluntary contraction pressure of the canal17. The EAS, the puborectalis muscle and the levator ani muscles are predominantly composed of type I fibers, characteristic of skeletal muscles with tone contractile activity18. When in liquid state, feces quickly reach the rectum, causing sphincter muscle overburden and, even in normal individuals, they may lead to urgent episodes and fecal incontinence16. The rectoanal inhibitory reflex enables the stool to be eliminated to be in contact with the proximal portion of the anal canal, a region with many free nervous terminations, and this way, it is felt by the individual19. The rectal capacity and complacency allow the defecation to be postponed, and the sensitivity accounts for rectal completeness16. Lastly, the hemorrhoid plexuses promote the remaining 15% of the pressure at rest for the anal canal closing17.

MATERIALS AND METHOD An integrative review was conducted in databases from the virtual health library (VHL) and the Physiotherapy Evidence Database (PEDro), using the following indicators: Fecal Incontinence, Postoperative Complications, Colorectal Surgery, Prevention and Physiotherapy, all obtained from DeCS/MeSH descriptors. The inclusion criteria were: studies that addressed fecal incontinence as a consequence of anorectal surgeries and that had been published between 2000 and 2010. Table 1 shows references of all articles. Databases were 249


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Fecal incontinence as a consequence of anorectal surgeries: literature review

Dilation resulting from the insertion of a speculum to expose the anal canal, which is involved in most anorectal surgical procedures, may affect continence, due to sphincter injuries, mostly temporary20. Speakman et al.21 reported fecal incontinence in 12 men after dilation, observed through anal manometry and ultrasound; all of them presented low pressure of the anal canal at rest and 11 had IAS injury, which significantly impacted continence. The same study also identified EAS injury in three of these patients.

Surgical correction of anal fistula: Fistulectomy/ Fistulotomy Anal fistula is granulation tissue connections between the anorectum and the perineum that are more predominant in men. They are mostly caused by idiopathic reasons and originate from the anal glands, but they may result from other causes, such as perianal alterations and injuries22. Anal fistula healing prevents

Table 1. References of articles included in the study. Author

Year

Prudente et al.1

2009

Pescatori et al.28

2003

Garcia-Armengol et al.29 Prudente et al.1

2001

Hasse et al.37

2004

Patti et al.38

2009

Arroyo et al.39

2001

Baldez40

2004

Cassillas et al.42

2005

Souza et al.48

2003

Altomare et al.49

2001

Cruz et al.46

2007

Marianelli et al.50

2008

Sobrado et al.51

2006

2009

Study design/ Evidence level Retrospective cohort/4C Retrospective cohort/4C Uncontrolled clinical trial/4C Retrospective cohort/4C Retrospective cohort/4C Uncontrolled clinical trial/4C Retrospective cohort/4C Cross-section cohort/2C Retrospective cohort/4C Retrospective cohort/4C

Hemorrhoidal 247 (580) disease

Uncontrolled clinical trial/4C Retrospective cohort/4C Retrospective cohort/4C Retrospective cohort/4C

Hemorrhoidal disease Hemorrhoidal disease Hemorrhoidal disease Hemorrhoidal disease

Incontinent patients (%) 36.0 (flatus) 10.0 (feces) 24.0 (feces)

Pathology

n

Surgical intervention

Anal fistula

58 (455)

Fistulectomy

Anal fistula

39

Fistulectomy

Anal fistula

31

Anal fissure

59 (455)

20.0 (soiling) 4.0 (flatus) 3.5 (flatus)

Anal fissure

209

Sphincteroplasty after fistulectomy Fissurectomy with LLS* Sphincterotomy

Anal fissure

16

Advancement flap

25.0 (feces)

Anal fissure

254

4.7 (feces)

Anal fissure

120

Anal fissure

184 (298)

Internal lateral sphincterotomy Sphincterotomy/ hemorrhoidectomy Sphincterotomy

20 2417 212 41 155

*Left Lateral Sphincterotomy

250

Hemorrhoidectomy - Milligan-Morganâ&#x20AC;&#x2122;s technique Stapled hemorrhoidectomy hemorrhoidectomy Conventional hemorrhoidectomy Procedure for Prolapse and Hemorrhoids (PPH) Hemorrhoideopexy using circular stapler

14.8 (feces)

30 (feces) 31 (flatus) 30 (feces) 3.9 (feces) 35 (feces) 0.2 (feces) 0.5 (feces) 2.4 (feces) 1.9 (flatus)


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recurrent septic processes that may lead to new anal sphincter injuries, which is a potentially threatening fact. Then, fistulas are a clear indication of surgical intervention20. Some authors suggest that alterations to continence in these procedures are due to anal deformation caused by healing and/or intraoperative sphincter injury23. The incidence of incontinence after fistulotomy ranges from 18 to 52%, with soiling in up to 35-45% of the patients24-27. In the retrospective study conducted by Prudente et al.1, all surgeries made by the Service of Coloproctology of a university hospital in Sergipe between 2005 and 2007 were analyzed, totaling 455 procedures. Fistulectomy was performed in 20% of the cases, and fecal incontinence after the surgery was observed in 36% of the patients. Among the 39 patients submitted to fistulectomy observed in the retrospective study conducted by Pescatori et al.28, nine (24%) complained of fecal incontinence. Garcia-Armengol et al.29, when analyzing the result of an immediate reconstruction of anal sphincter of a selected group of patients at risk of FI after fistulectomy, observed that, after the follow-up period, among the 25 continent patients before the surgery, five (20%) presented perianal soiling and one (4%) presented flatus incontinence.

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blood flow around the fissure is covered by a healthy and well vascularized flap34. The reduced pressure at rest of the anal canal after the surgery may be the cause of FI35. Lateral sphincterotomy is the most common technique for the surgical treatment of anal fissure36. In the study conducted by Prudente et al.1 mentioned above, the technique used by the hospital service was fissurectomy with left lateral sphincterotomy, presenting, as postoperative complications, pain in 62.5% and flatus incontinence in 3.5% of the cases. Hasse et al.37 analyzed long-term results after lateral sphincterotomy in 209 patients, and, despite the increase in the healing rate of fissures to 94.7%, they observed 14.8% of fecal incontinence three months after the surgery. Patti et al.38 reported in their study that, among the 16 individuals submitted to advancement flap for chronic anal fissure correction, 4 (25%) remained with fecal losses. Arroyo et al.39 reported 5.5% of incontinence from total 254 patients submitted to internal lateral sphincterotomy six weeks after the surgery. Baldez 200440 observed that 30% of the 120 patients with fecal incontinence analyzed in the study had sphincter injuries caused by complications of inadequate anorectal surgeries and Leite et al.41 reported in their study two individuals with FI resulting from surgical injuries among total 16 individuals. In the study conducted by Casillas et al.42, longterm results of patients submitted to sphincterotomy for chronic anal fissure correction were evaluated. The medical records were analyzed and a questionnaire to assess the patientsâ&#x20AC;&#x2122; current state was sent to them, as well as a questionnaire about the quality of life with FI and an investigation to quantify the severity of losses. From total 298 patients, 62% returned the questionnaires. Temporary incontinence occurred in 31% of the patients and persistent flatus incontinence occurred in 30% of the cases.

Surgical correction of anal fissure: Fissurectomy/Sphincterotomy Anal fissure is a linear injury in the anal canal skin, generally a single lesion, located in the posterior portion of the anus, usually resulting from the passing of hard stools. It produces spasming of the internal anal sphincter, which will make the injury remain, due to pain and difficult evacuation. It may heal naturally or require a surgical procedure30. A partial or full incision in the internal anal sphincter, made during sphincterotomy, is the most effective method to reduce the anal pressure of the anal canal at rest in individuals with anal fissure31. The risk of FI is higher in patients with more chances of presenting signs of fecal loss, just as elderly people, women (particularly multipara), individuals with prior anoperineal surgery, anal Crohnâ&#x20AC;&#x2122;s disease, chronic diarrhea or previous complaints of incontinence32,33. In these cases, the advancement V-Y flap is recommended, in which the granulation tissue with reduced

Surgeries for hemorrhoidal disease: hemorrhoidectomy The surgical treatment of hemorrhoidal disease should be selected to patients with persistent symptoms after a clinical or conservative treatment43. Continence disorders reported after hemorrhoidectomy range between 0 and 28%44,45. The fact of having the anal canal partially filled with hemorrhoid cushions, 251


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whose removal may lead to widening, according to the cushion size, may cause incontinence, but, after a while, when the sphincter contraction returns to normal, fecal and/or flatus incontinence may reduce46. Moreira Jr. et al.47, in a study comparing hemorrhoidectomy with and without sphincterotomy in the treatment of end-stage hemorrhoidal disease, showed that such association did not reduce the postoperative pain and it increased the risk of anal incontinence. In a hospital in the State of Bahia, 580 anorectal surgeries were performed in 5 years; 42.6% of them were hemorrhoidectomy procedures, and all cases of temporary fecal incontinence (3.9%) were submitted to the Milligan-Morgan technique48. Altomare et al.49, when analyzing the long-term effects of hemorrhoidectomy, reported that all patients (n=20) submitted to stapled hemorrhoidectomy had incontinence before the surgery and, in the postoperative period, seven patients (35%) still experienced some fecal incontinence, especially urgent episodes. Alterations to the anal canal sensitivity and postoperative complications, such as stenosis and anal incontinence, are due to muscle fiber injury, which may occur during the surgical procedure49. Some studies that also report FI after hemorrhoidectomy are: Cruz et al.46, who obtained 0.2% of fecal incontinence, Marianelli et al.50, with 0.5% of patients reporting fecal losses after the conventional hemorrhoidectomy technique and 2.4% after mechanical hemorrhoidopexy and Sobrado et al.51, with 1.9% of incontinence cases after the surgery.

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Late complications of hemorrhoidectomy include: urinary tract infection, secondary bleeding, injury infection, anal fissure and anal incontinence. Up to 50% of the patients complain of soiling in early postoperative period53,54. In their study, Altomare et al.49 observed that, six months after hemorrhoidectomy, anal continence was reestablished in all analyzed cases. Non-surgical treatments of FI, especially effective in symptomatic cases and in patients with accelerated colonic transit, appear to be very useful during the postoperative period of anorectal surgeries, as they help improve and keep the results obtained with the surgery and prevent postoperative complications. Physiotherapy can act on anorectal disorders and offers resources that will attempt to promote the evacuation control55. The basic objectives of perineal re-education can be considered as: prevention and treatment of pelvic floor dysfunctions and it actually constitutes the gold standard for the treatment of such disorders, as they increase tone and strain of pelvic floor fibers in the presence of variations in intra-abdominal pressure6,56. The progress of physiotherapeutic techniques has enabled the functional recovery of the pelvic floor and it may restore the anal continence functionality, thus improving the quality of life of individuals with FI6. The physiotherapeutic techniques for perineal reeducation include: perineal electrostimulation, biofeedback and perineal kinesiotherapy. The purpose of electrostimulation is to improve the power, speed and resistance of the voluntary contraction of the external sphincter or improve the perception of the external sphincter and, consequently, the ability to control or postpone evacuation in response to the evacuation desire57. The muscle function can be improved by changing faster-contracting, fatigable muscle fibers into slower-contracting less fatigable fibers and by increasing the capillary density in the region, promoting the efficient activity of these slow and oxidative fibers. This is a low-cost technique, usually well tolerated, with most patients that are submitted to it reporting benefits with the treatment58-60. According to a prospective study conducted by Pescatori et al.61, an improvement in clinical, psychological and manometric aspects was observed in two thirds of the investigated patients with fecal inconti-

DISCUSSION The analysis of selected studies showed that the surgery for anal fistula correction is the one presenting the highest risk for anal continence, an evidence confirmed by Sainio52 and Ommer et al.20, who reported in their studies that this procedure is one of the main causes of continence disorders. Although the articles analyzed presented different numbers of studied individuals, they demonstrated that surgeries for anal fissure correction are the second intervention that most affect continence. Lateral sphincterotomy, in most cases, leads to quick healing of chronic fissure and presents low recurrence rate, but it may be associated with long-term anal incontinence37. 252


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nence who received anorectal electrostimulation for 30 days, once a day. Biofeedback is a clinical treatment frequently indicated to fecal inconsistence in the colorectum and gastroenterology literature58. It is a very active re-education technique for the patient, which uses a device that records and amplifies the activity practiced by the patient, with no electrical stimulation. The purpose is to change an inadequate physiological response or enable the acquisition of a new physiological response, with the possibility of acting on rectal sensitivity, power and coordination58,62,63. In the long-term study conducted by Pager 64 et  al. , which interviewed 120 patients submitted to a four-month FI treatment program based on pelvic floor exercises and biofeedback, the purpose was to assess the volunteers’ clinical conditions and quality of life; 83% of them reported improved quality of life and 75% reported reduced symptoms. Perineal kinesiotherapy is founded on the principle of repetitive voluntary contractions to increase muscle power. This additional power is obtained by combining many motor units, small frequencies and gradually stronger contractions, with few daily repetitions and gradual increase of power intensity and contraction time. Kinesiotherapy is the only method that does not have contraindications65. According to Coffey et al.66, in their studies on the effect of a program that combined progressive physiotherapeutic exercises and electromyographic biofeedback on a woman with fecal incontinence, physiotherapy promoted intestinal continence, improved and increased the pelvic floor musculature control, resulting in enhanced confidence and

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comfort in social and work situations, as well as fewer restrictions in the patient’s physical relation with her partner. The questionnaires for to quantify fecal incontinence, such as the one proposed by Jorge and Wexner in 199367, and the quality of life of patients with FI, such as the Fecal Incontinence of Quality of Life (FIQL), validated into Portuguese by Yusuf et al.10, are also part of the physiotherapeutic practice and valuable instruments for the evaluation and re-evaluation of the clinical condition of such patients. CONCLUSION This review showed that deficient intestinal continence is, in reality, a relevant complication after anorectal surgeries, in which sphincter injuries are common, leading to anal continence disorders; and that physiotherapy can help improve the recovery process of patients submitted to such procedures, promoting sustainable results and effectively preventing or treating postoperative complications. It should be noted that many of these complications, besides increasing personal and hospital costs, could be prevented with an early intervention of physiotherapy, which would speed up the individual’s full recovery and improve the quality of life of such subjects. Thus, further studies are recommended, in the form of systematic reviews, using a higher number of articles, of better quality and evidence levels, for a real analysis of the impact of anorectal surgeries on the anal continence mechanism, therefore promoting discussions on the inclusion of physiotherapy in the postoperative routine of these procedures.

Resumo: Causada por lesões esfincterianas em variados procedimentos anorretais, a incontinência fecal (IF) representa uma complicação presente em alguns indivíduos submetidos a cirurgias coloproctológicas. Objetivo: Evidenciar a ocorrência de IF como consequência de cirurgias anorretais e expor os recursos fisioterapêuticos no tratamento desta desordem e, com isso, propor a inclusão da fisioterapia como prática rotineira nos pós-operatórios desses tipos de intervenções. Materiais e Métodos: Revisão integrativa realizada a partir de pesquisas nos bancos de dados da biblioteca virtual em saúde – BVS - e do Physiotherapy Evidence Database – PEDro - publicados no período de 2000 a 2010, nos idiomas inglês e português. Resultados: Foram selecionados 13 artigos publicados entre os anos de 2001 e 2009, sendo um corte transversal, dois ensaios clínicos não controlados e dez coortes retrospectivos, com nível de evidência entre 2C e 4C, artigos de revisão foram excluídos. Foi evidenciado que a IF representa uma complicação importante de cirurgias anorretais, causando grande impacto sobre a qualidade de vida dos portadores e que a fisioterapia dispõe de recursos eficazes para o tratamento dessa disfunção. Considerações Finais: Recomenda-se a continuação do presente estudo, no formato de revisão sistemática, com um maior número de artigos e de melhores evidências científicas. Palavras-chaves: cirurgia colorretal; complicações pós-operatórias; incontinência fecal; fisioterapia; prevenção.

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34. Ayantunde AA, Debrah SA. Current concepts in anal fissures. World J Surg 2006;30:2246-60. 35. César MAP, Uemura LA, Passos MPS. Retalhos de avanço no tratamento da fissura anal crônica - Experiência inicial. Rev Bras Coloproctol 2009;29(4):466-71. 36. Morgado NP, Barriola J, Morgado SP, Morgado SY. Fissura anal: esfincterotomia lateral exclusiva ou fissurectomia? Rev Bras Coloproctol 1989;9(3):111-2. 37. Hasse C, Brune M, Bachmann S, Lorenz W, Rothmund M, Sitter H. Laterale, partielle Sphinkteromyotomie zur Therapie der chronischen Analfissur - Langzeitergebnisse einer epidemiologischen Kohortenstudie. Chirurg 2004;75:160-7. 38. Patti R, Famà F, Barrera T, Migliore G, Di Vita G. Fissurectomy and anal advancement flap for anterior chronic anal fissure without hypertonia of the internal anal sphincter in females. Colorectal Dis 2010;12(11):1127-30. 39. Arroyo A, Costa D, Fernández A, Serrano P, Pérez F, Oliver I, et al. ¿Es la esfinterotomía lateral cerrada realizada ambulatoriamente con anestesia local la técnica ideal en el tratamiento de la fisura anal crónica? Cir Esp 2001;70:84-7. 40. Baldez JR. Relação entre os sintomas clínicos da incontinência anal e os resultados da manometria anoretal. Rev Bras Coloproctol 2004;24(2):140-3. 41. Leite JS, Monteiro A, Martins M, Manso A, Oliveira J, Sousa FC. A estimulação nervosa sagrada no tratamento da incontinência fecal e da obstipação severa. Rev Port Coloproctol 2008;5(2):24-37. 42. Casillas S, Hull TL, Zutshi M, Trzcinski R, Bast JF, Xu M. Incontinence after a lateral internal sphincterotomy: are we underestimating it? Dis Colon Rectum 2005;48:1193-9. 43. Madoff RD, Fleshman JW. Clinical Practice Committee, American Gastroenterological Association. American. Gastroenterological Association technical review on the diagnosis and treatment of hemorrhoids. Gastroenterology 2004;126:1463-73. 44. Athanasiadis S, Gandji D, Girona J. Langzeitergebnisse nach submuköser Hämorrhoidektomie unter besonderer Berücksichtigung der Kontinenz Phlebol u Proktol 1986;15:119–21. 45. Ebert KH, Meyer HJ. Die Klammernahtresektion bei Hämorrhoiden - eine Bestandsaufnahme nach zweijähriger Anwendung. Vergleich der Ergebnisse mit der Technik nach Milligan-Morgan. Zentralbl Chir 2002;127:9–14. 46. Cruz GMG, Santana SKAA, Santana JL, Ferreira RMRS, Neves PM, Faria MNZ. Complicações pós-operatórias de cirúrgicas de hemorroidectomia: revisão de 76 casos de complicações. Rev Bras Coloproctol 2007;27(1):42-57. 47. Moreira Junior H, Moreira JPT, Moreira H, Iguma CS, Almeida AC, Magalhães CN. Esfincterotomia lateral interna associada à hemorroidectomia no tratamento da doença hemorroidária. Vantagem ou desvantagem? Rev Bras

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Coloproctol 2007;27(3):293-303. 48. Souza JVS, Carvalho FR, Oliveira IAN, et al. Patologias orificiais: Experiência de 580 casos. Rev Bras Coloproctol 2003;23:34. 49. Altomare DF, Rinaldi M, Sallustio PL, Martino P, De Fazio M, Memeo V. Long-term effects of stapled haemorrhoidectomy on internal anal function and sensitivity. Br J Surg 2001;88:1487-91. 50. Marianelli R, Machado SPG, Almeida MG, Baraviera AC, Falleiros V, Lolli RJ, et al. Hemorroidectomia convencional versus hemorroidopexia mecânica (PPH): estudo retrospectivo de 253 casos. Rev Bras Coloproctol 2009;29(1):30-7. 51. Sobrado CW, Cotti GCC, Coelho FF, Rocha JRM. Initial experience with stapled hemorrhoidopexy for treatment of hemorrhoids. Arq Gastroenterol 2006;43(3):238-42. 52. Sainio P. A manometric study of anorectal functions after surgery for anal fistula, with special reference to incontinence. Acta Chir Scand 1985;151:695-700. 53. Roe A, Bartolo D, Vellacott K, Locke-Edmunds J, Mortensen NJ. Submucosal versus ligation excision haemorrhoidectomy: a comparison of anal sensation, anal sphincter manometry and post-operative pain function. Br J Surg 1987;74:948-95. 54. Isler JT. Hemorrhoidectomy. Part A: Open surgical hemorrhoidectomy. In: Bailey HR, Snyder MJ (eds.). Ambulatory anorectal surgery. Springer Publishing Company Heidelberg 1999; 81-88. 55. Sielezneff I, Pirro N, Ouaissi M. Traitement chirurgical de l’incontinence anale. Ann Chirurg 2002;127:670-9. 56. McIntoch LJ, Frahn JD, Mallet N, Richardson DA. Pelvic floor rehabilitation in the treatment of incontinence. J Report Med 1993;38:662-6. 57. Hosker G, Cody JD, Norton CC. Electrical stimulation for faecal incontinence in adults. Cochrane Database of Systematic Reviews 2007; Issue 3. 58. Norton CC, Cody JD, Hosker G. Biofeedback and/or sphincter exercises for the treatment of faecal incontinence in adults. Cochrane Database of Systematic Reviews 2006; Issue 3. 59. Hudlicka O, Dodd L, Renkin EM, Gray SD. Early changes in fiber profile and capillary density in longterm stimulated muscles. Am J Physiol Heart Circ Physiol 1982;243:528-35. 60. Salmons S, Vrbova G. The influence of activity on some contractile characteristics of mammalian fast and slow muscles. J Physiol 1969;201(3):535-49. 61. Pescatori M, Anastacio G, Bottini C, Mentasti A. New grading and scoring for anal incontinence. Dis Colon Rectum 1992;35(5):482-7. 62. Grosse D, Sengler J. Reeducação perineal. São Paulo: Manole; 2002. 63. Hanke TA. Usos terapêuticos do biofeedback. In: Nelson RM, Hayes KW, Currier DP. Eletroterapia Clínica. 3.ed. São Paulo: Manole; 2003.

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64. Pager CK, Solomon MJ, Rex J, Roberts RA. Long-term outcome of pelvic floor exercise and biofeedback treatment for patients with fecal incontinence. Dis Colon Rectum 2002;45(8):997-1003. 65. Moura RVA, Costa TPB. Avaliação do grau de força do assoalho pélvico em mulheres que apresentam anorgasmia secundária. Belém: Universidade da Amazônia [cited 2010 May 13]. [dissertation]. Available from: http://www.unama. br/graduacao/cursos/Fisioterapia/tcc/2006/avaliacao-dograu-de-forca-do-assoalho-pelvico-em-mulheres-queapresentam-anorgasmia-secundaria.pdf. 66. Coffey SW, Wilder E, Majsak MJ, Stolove R, Quinn L.

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The effects of a progressive exercise program with surface electromyographic biofeedback on an adult with fecal incontinence. Phys Ther 2002;82:798-811. 67. Jorge JM, Wexner SD. Etiology and management of fecal incontinence. Dis Colon Rectum 1993;36:77–97. Corresponding author: Kelly Cristina Duque Cortez Rua Coelho Neto, 85, Campo Grande CEP: 52040-310 – Recife (PE), Brazil. E-mail: kellycristinadc@hotmail.com.

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Original Article

What is the value of proctography for diagnostic of outlet obstruction? MARIA AUXILIADORA PROLUNGATTI CESAR1, WILMAR ARTUR KLUG2, JORGE ALBERTO ORTIZ3, CHIA BIN FANG5, PERETZ CAPELHUCHMIK6 Doctorate in Surgery at Faculdade de Ciências Médicas of Santa Casa de São Paulo – São Paulo (SP), Brazil; Assistant Professor and Doctor of the Department of Medicine at Universidade de Taubaté – Taubaté (SP), Brazil. 2Professor of the Department of Surgery at Faculdade de Ciências Médicas of Santa Casa de São Paulo – São Paulo (SP), Brazil. 3Master’s degree in Surgery at Faculdade de Ciências Médicas of Santa Casa de São Paulo; Head of the anal physiology sector of the coloproctology área at Faculdade de Ciências Médicas of Santa Casa de São Paulo – São Paulo (SP), Brazil. 5Master’s degree in Surgery at Faculdade de Ciências Médicas of Santa Casa de São Paulo; Adjunct Professor of the Department of Surgery at Faculdade de Ciências Médicas of Santa Casa de São Paulo – São Paulo (SP), Brazil. 6Professor of the Department of Surgery at Faculdade de Ciências Médicas of Santa Casa de São Paulo – São Paulo (SP), Brazil. 1

CESAR MAP, KLUG WA, ORTIZ JA, FANG CB, CAPELHUCHMIK P. What is the value of proctography for diagnostic of outlet obstruction? Rev bras Coloproct, 2011;31(3): 257-261. Abstract: The diagnosis of constipation is complicated due to the multiplicity and complexity of the causes. Regarding diagnostic tests, proctography is the best choice because it provides information on functions and visualization of abnormalities. Objective: To measure the isolated value of proctography in patients with obstructed defecation. Method: We evaluated 40 constipated patients at the Coloproctology Clinic of Santa Casa de Misericórdia de São Paulo. The test was performed by introducing 120 mL of barium contrast in the rectum and by analyzing the different stages of evacuation. Three x-rays were performed in the lateral position: rest, anal contraction and evacuation. Results: The diagnoses were: rectocele: 2 (5.0%); anismus: 8 (20.0%); perineal descent: 13 (32.5%); sigmoidocele: 6 (15.0%); internal invagination: 10 (25.0%); rectocele + sigmoidocele 9 (22.5%); rectocele + internal invagination 11 (27.5%); rectocele + anismus: 18 (45.0%). Several patients presented multiple disorders. Conclusion: Constipation by obstructed defecation depends on multiple factors and it is important to have an accurate diagnosis. Proctography is essential, but insufficient as a single procedure. The other tests contribute with the diagnosis, therefore, they should be included in the investigation. Keywords: constipation; defecation; defecography.

INTRODUCTION

evacuation disorder such as the inability to evacuate the rectal volume, the full rectum feeling, rectal pain, descent of the pelvic diaphragm and excessive effort 1-6. The most common disorder in obstructed defecation is the non-relaxation of the puborectal muscle or anismus1-6. Proctography is a dynamic and anatomic study that provides information on different abnormalities aspects1,3,4,7-10. It is common to find associated disorders in proctography, such as paradoxal contraction of

Constipation is a disorder characterized by twice or less bowel movements per week, having difficult evacuation, hard stool and the sensation of incomplete evacuation1-6. It is classified in two types: slow transit or colonic inertia and obstructed defecation. Inertia is the less common disorder, and it is caused by slower transit. The obstructed defecation is an

Study carried out at the discipline of Coloproctology, Department of Surgery at Faculdade de Ciências Médicas of Santa Casa de São Paulo. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 21/01/2011 Approved on: 30/06/2011

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a)

pubococcygeus: between the upper pubis and the coccyx; b) anal canal: from the anus to the anorectal junction; c) rectal axis: posterior rectum. Afterwards, the following measures were defined: a) position of pelvic diaphragm: between the upper extremity of the anal canal and the pubococcygeus muscles through a perpendicular line; b) perineal position: between the lower extremity of the anal canal and the pubococcygeus muscles through a perpendicular line; c) Length of the anal canal; d) Anorectal angle: between the rectum axis and the anal canal at the intersection of lines. Data were analyzed by the Student’s t test, with significance of 0.05%.

puborectalis, rectocele, invagination, prolapse, rectocele, hernia and perineal descen. It is also possible to measure perineal descent and anorectal angle at rest, contraction and evacuation1,3,4,7-10. The objective of this study was to assess the importance of proctography diagnosing constipation by obstructed defecation. PATIENTS AND METHOD In this study, 40 proctographies of patients presenting with constipation at the Coloproctology clinic of Santa Casa de Misericórdia de São Paulo were analyzed. They were refractory to the treatment and diagnosed with obstructed defecation. Their proctographies were compared to those of the asymptomatic control group, comprised of 20 patients. Proctography consisted of the introduction of 120 mL of barium contrast in the rectum by a rectal probe 14, with the patient in supine, left lateral position. Afterwards, the contrast marker was placed with the same barium contrast, fixated on the sacrum and pubis. After the introduction of the contrast, three x-rays in the lateral position were performed. The patient was sitting on the chair for the proctography: at rest, anal contraction and evacuation. The following guidelines were determined after the analysis of the x-rays:

RESULTS Forty proctographies of patients who were constipated due to obstructed defecation were compared with 20 proctographies of patients in the control group. The measurements of the proctographies in the positions at rest, contraction and evacuation are demonstrated in Tables 1 to 3, respectively. At rest, pelvic diaphragm was lower, as well as the anorectal angle

Table 1. Proctography measurements at rest in constipated patients, compared with the control group. Proctography measurements Constipated Control p Anorectal angle <0.05 105.60±15.83 120.38±14.17 Length of anal canal ns 3.49±1.31 3.76±1.04 Position of pelvic diaphragm <0.05 6.29±2.26 3.95±1.12 Perineal position <0.05 8.87±2.13 6.62±1.66 Anorectal angle at contraction <0.05 84.77±13.29 103.28±15.86 ns: not significant.

Table 2. Proctography measurements at contraction position in constipated patients, compared with the control group. Proctography measurements Constipated Control p Anorectal angle <0.05 84.77±13.29 103.28±15.86 Length of the anal canal ns 6.42±4.67 4.71±0.96 Position of pelvic diaphragm ns 4.13±1.62 3.05±1.12 Perineal position <0.05 7.46±1.51 6.19±1.63 ns: not significant.

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Table 3. Proctography measurements at evacuation position in constipated patients, compared with the control group. Proctography measurements Constipated Control p Anorectal angle <0.05 114.85±12.41 130.71±16.20 Length of anal canal ns 2.30±1.24 1.86±0.91 Position of pelvic diaphragm ns 6.75±2.44 5.90±1.90 Perineal position ns 8.33±2.09 6.90±2.00 ns: not significant.

and the perineal position; at contraction, the anorectal angle was lower, as well as the perineal position; at evacuation, anorectal angle was lower. The other measurements were not statistically different. The differences between proctographies of patients with different specific diagnoses were compared to those of the patients in the control group at rest, contraction and evacuations. These differences are demonstrated in Tables 4 to 6. There were many differences, marked with *, except as to the length of the anal canal, since there was no variation between the groups. In relation to diagnostics, many patients presented more than one diagnosis at proctography, with the following rates:

a) b) c) d e) f) g) h)

rectocele: 2 (5.0%); puborectal paradoxal contraction: 8 (20.0%); perineal descent: 13 (32.5%); sigmoidocele: 6 (15.0%); internal invagination: 10 (25.0%); rectocele + sigmoidocele: 9 (22.5%); rectocele + invagination: 11 (27.5%); rectocele + paradoxal contraction: 18 (45.0%). DISCUSSION

Constipation caused by inertia or obstructed defecation is complex and little understood. It is multifactorial and includes factors regarding diet, age, gender, general

Table 4. Proctography measurements at rest and diagnoses of causes for constipation. Puborectal Rectocele paradoxal Invagination Sigmoidocele Control contraction Anorectal angle 102.40±12.51* 100.70±1.08* 105.80±15.89* 100.20±9.64* 120.38±14.17 Length of anal 3.16±1.43 3.79±1.09 2.91±1.22 2.75±1.21 3.76±1.04 canal Position of 6.56±2.27* 6.22±2.31* 7.16±2.33* 5.93±2.04 3.95±1.12 pelvic diaphragm Perineal position 9.19±2.30* 8.96±2.32* 9.01±2.44* 7.85±2.25 6.62±1.66

p <0.05 ns <0.05 <0.05

ns: not significant.

Table 5. Proctography measurements at contraction and diagnoses of causes for constipation. Puborectal Rectocele paradoxal Invagination Sigmoidocele Control contraction Anorectal angle 79.83±11.24* 79.74±0.26* 86.90±9.62* 84.00±7.01* 103.28±15.86 Length of anal 6.63±6.48 5.59±2.22 5.42±2.18 5.05±1.99 4.71±0.96 canal Position of 4.36±1.59* 4.32±1.49* 4.97±1.45* 4.47±0.97 3.05±1.12 pelvic diaphragm Perineal position 7.82±1.30* 7.50±0.97* 8.00±1.89* 7.08±2.43 6.19±1.63 ns: not significant.

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Table 6. Proctography measurements at evacuation and diagnoses of causes for constipation. Puborectal Rectocele paradoxal Invagination Sigmoidocele Control contraction Anorectal angle 111.17±2.88* 111.74±9.70* 117.40±14.15* 114.33±16.47* 130.71±16.20 Length of anal 1.88±0.99 2.28±0.76 2.16±1.64 1.70±1.02 1.86±0.91 canal Position of 8.08±2.16* 6.41±2.39 7.84±2.74 7.58±3.36 5.90±1.90 pelvic diaphragm Perineal position 9.21±2.02* 7.81±1.92 9.31±2.51* 8.70±3.20 6.90±2.00

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p <0.05 ns <0.05 <0.05

ns: not significant.

conditions, hormones and intestinal polypeptides, parity, neurological lesions and physiology of pelvic organs1-6. Pelvic functional phenomena related to evacuation and analyzed by anal physiology tests are prevalent for obstructed defecation. Clinical diagnoses are based on history and markers, manometry, proctography, electromyography, and latency of the pudendal nerve1-6.  Rectocele is a common diagnosis, being present in almost all constipated patients. It varies as to dimension and is usually associated with other alterations. Proctography images are clear and a good way to diagnose1-4,7-12. In our sample, diagnoses were based on the association of clinical, manometric and radiological data, as well as electromyography in selected patients after the correction of eating and hygiene habits and the exclusion of associated diseases. The previous selection of patients excluded those who were constipated due to colonic inertia. Among the tests, we separated the results obtained by proctography with the objective to assess its diagnostic potential in an isolated way. It was clear that, because of the multiplicity and association of causes, the approach to these patients required the use of different physiological methods. We believe that proctography is useful to analyze constipation. The method should be investigated due to its importance, because it not only enables current diagnoses, but also a more detailed analysis of the pelvic diaphragm. In spite of that, when we perform this test on asymptomatic patients, normal findings may occur9. The possible alterations in young asymptomatic patients are perineal descent, invagination and rectocele, and their importance is not clear at the proctography9. In our sample, the measurements of anorectal angles in constipated patients were lower than the con-

trol group in all phases of the test, and the differences were significant. At rest, we observed that the values of the constipated patients were lower than the control group, as well as at contraction and evacuation. The length of the anal canal increases at the moment of contraction, and decreases at evacuation, with no statistical differences as to the control group. At rest, the position of the pelvic diaphragm presented significant higher values for the constipated patients, because they were located at a lower position; however, there were no differences during contraction and effort. For those who have rectocele, sigmoidocele and invagination, radiographic evidence is essential and confirms the diagnosis; however, at puborectal paradoxal contraction, we observed perineal descent and lower anorectal angle. This difference may be important, because the other possible way to diagnose this disorder is electromyography. For sigmoidocele, there were no significant differences in proctography measurements in comparison to those who do not have this condition, except for the radiographic evidence of the presence of colon loop, which presses the rectum. In relation to the position of the pelvic diaphragm and the perineal position, we observed perineal descent. This is in accordance with the usually accepted idea that the efforts made by constipated patients lead to alterations in the position of the pelvic diaphragm. Factors such as age, gender, parity, associated conditions and obstetric trauma certainly interfere in the results, but they were not considered for not being the objective of this study. On the other hand, when series of patients are investigated, the mean values positively contribute to the interpretation of the disorders. Proctography has demonstrated many findings and is important to assess constipation; however, it is 260


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important to remember that patients with refractory constipation at clinical treatment should be fully assessed, because only one examination may lead to a wrong diagnosis of the cause of constipation. A very important example is the presence of rectocele (frequent diagnosis at proctography), associated with puborectal paradoxal contraction. The former would be surgically treatable, but the outcomes could be negative in case there was associated puborectal paradoxal contraction. The latter is clinically treatable, and proctography is not gold standard for this diagnosis.

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Proctography usually finds signs of perineal descent, because this may suggest that the patient may present innervation compromise of the pelvic diaphragm; in this case, it is recommended to investigate fecal continence. CONCLUSION Proctography proved to be important to assess constipation through diagnoses and measurements, and it is useful as an examination associated with the full evaluation of the constipated patient.

Resumo: O diagnóstico da constipação é difícil pela multiplicidade e complexidade das causas. Dos exames diagnósticos, a proctografia é preferida, fornecendo informações da função e visualização de anormalidades. Objetivo: Medir o valor isolado da proctografia, em pacientes com diagnóstico de defecação obstruída. Método: Avaliamos 40 pacientes com constipação intestinal do Ambulatório de Coloproctologia da Santa Casa de Misericórdia de São Paulo. O exame foi feito introduzindo-se 120 mL de contraste no reto e analisando-se as diferentes fases da evacuação. Foram realizadas três radiografias na posição lateral: repouso, contração anal e evacuação. Resultados: Os diagnósticos foram: retocele: 2 (5,0%); contração paradoxal do puborretal: 8 (20,0%); descida perineal: 13 (32,5%); sigmoidocele: 6 (15,0%); invaginação interna: 10 (25,0%); retocele + sigmoidocele: 9 (22,5%); retocele + invaginação: 11 (27,5%); retocele + contração paradoxal: 18 (45,0%). Vários pacientes apresentaram distúrbios múltiplos. Conclusão: Constipação por defecação obstruída depende de múltiplos fatores e é importante o diagnóstico preciso. A proctografia é essencial, mas insuficiente como procedimento isolado. Os outros exames são importante contribuição para firmar o diagnóstico, devendo ser incluídos na investigação. Palavras-chave: constipação intestinal; defecação; defecografia.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8. Karasick S, Ehrlich SM. Is constipation a disorder of defecation or impaired motility? Distinction based on defecography and colonic transit studies. AJR 1996;166(1):63-6. 9. Fang CB, Peixoto VCS, Klug WK, Ortiz JA, Capelhuchnik P. Esvaziamento retal em voluntários assintomáticos através da proctografia. Rev bras Coloproct 1997;17(3):175-9. 10. Hiltunen KM, Kolehmainen H, Matikainen M. Does defecography help in diagnosis and clinical decision-making in defecation disorders? Abdom Imaging 1994;19(4):355-8. 11. Sobrado Jr. CV, Pires CEF, Araújo SEA, Amaro Jr. E, Habr-Gama A, Kiss DR. Avaliação computadorizada do esvaziamento retal em voluntários assintomáticos. Rev bras Coloproct 2003;23(1):5-8. 12. Sentovich SM, Rivela LJ, Thorson AG, Christensen MA, Blatchford GJ. Simultaneous dynamic proctography and peritoneography for pelvic floor disorders. Dis Colon Rectum 1995;38(9):912-5.

Cesar MAP, Klug WA, Aguida HAC, Ortiz JA, Bin FC, Kapelhuchnik P. A presença de retocele interfere nos resultados de exames de fisiologia anal? Rev bras Coloproct 2008;28(3):329-33. Cesar MAP, Klug WA, Aguida HAC, Ortiz JA, Fang CB, Capelhuchnik P. Alterações das pressões anais em pacientes constipados por defecação obstruída. Rev bras Coloproct 2008;28(4):402-8. Cesar MAP, Klug WA, Ortiz JA, BIN FC, Kapelhuchnik P. Diagnóstico do anismus através dos exames de fisiologia anal. Rev bras Coloproct 2009;29(2):192-6. Cesar MAP, Klug WA. Fisiologia Anorretal e cirurgia. Investigação dos distúrbios de evacuação (Constipação intestinal e incontinência fecal). In Speranzini MB, Deutsch CR, Yagi OK. Manual de diagnóstico e tratamento para o residente de cirurgia. 2009(2):1465-72. Cesar MAP, Oliveira CC. Existe importância na utilização da manometria anal no diagnóstico da síndrome do intestino irritável? Rev bras Coloproct 2009;29(3):358-62. Vieira EP, Pupo Neto J, Lacombe DLP. Contribuição da manometria ano retal na avaliação da constipação intestinal crônica. Rev bras Coloproct 2005;25(4):348-60. Mellgren A. Diagnosis and treatment of constipation Eur J Surg 1995;161(9):623-34.

Correspondence to: Maria Auxiliadora Prolungatti Cesar, Serviço de Clínica Cirúrgica do Hospital Universitário de Taubaté Avenida Granadeiro Guimarães, 270 CEP: 12100-000 – Taubaté (SP), Brazil. E mail: prolungatti@uol.com.br

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Original Article

Evaluation of the effectiveness of 4% formalin in the treatment of hemorrhagic actinic proctitis JUVENAL ROCHA TORRES NETO1, ALEX RODRIGUES MOURA2, FÁBIO RAMOS TEIXEIRA2, ANA PAULA ANDRADE MENEZES3, DAM RODRIGUES MARIANO4 Doctor Professor and Head of the Coloproctology Service at Universidade Federal de Sergipe (UFS) – Aracaju (SE), Brazil. 2 Resident doctors of proctology at UFS – Aracaju (SE), Brazil. 3Radiologist at UFS – Aracaju (SE), Brazil. 4 Coloproctologist at UFS – Aracaju (SE), Brazil.

1

NETO JRT, MOURA AR, TEIXEIRA FR, MENEZES APA, MARIANO DR. Evaluation of the effectiveness of 4% formalin in the treatment of hemorrhagic actinic proctitis. Rev bras Coloproct, 2011;31(3): 262-267. Abstract: Radiotherapy is an important discovery as to the treatment of pelvic tumors. Proctitis is frequently observed nowadays, and can be divided into acute and chronic. Treatment with 4% formalin solutions has been used with positive results in literature. Objective: To evaluate the effectiveness and morbidity rates related to the use of 4%formalin in hemorrhagic chronic actinic proctitis. Methods: We evaluated the sigmoidoscopy records and reports of 11 patients with chronic hemorrhagic actinic proctitis from February to December 2010, coming from the Serbian colorectal University Hospital of the State of Sergipe. Results: The study was comprised of 11 patients (36.36% were females and 63.63% were males). Mean age was 67.7 years. Mean time between the end of radiotherapy and the onset of symptoms was 6.6 months. The treatment was completely effective in 27.27% of the cases, and reduced rectal bleeding in 100% of patients. The following main complications were observed: chills (9%), tenesmus (18.18%) and mild stenosis (9%). Conclusions: The 4%formalin solution has fewer side effects, and its administration is very inexpensive. The treatment is effective and reduces bleeding in almost 100% of cases. Keywords: proctitis; formalin; radiotherapy.

complications are mainly caused by injuries of the radiation in the mucosa. This is due to the action of the radiation on the dividing cells, usually leading to self limited lesions. Chronically, the symptoms are owed to the progressive submucosal fibrosis and endoarterial obliteration, leading to the formation of neovascular telangiectasia, causing fragility and bleeding5. Since the rectum is more fixed and close to the pelvic organs, it is more prone to complications from the radiation3. Different clinical and surgical therapies may be performed. Derivatives of aminosalicylic acid, corticoid, sucralfate, argon plasma, bipolar electrocoagulation, retinol palmitate, rectal misoprostal, vitamin E,

INTRODUCTION Radiotherapy is part of the healing treatment for many malignant pathologies, such as neoplasm of the rectum, uterus, prostate, bladder, anal canal and margin1,2. Despite the benefits of this procedure, the lesions caused by radiation may cause early and late unwanted effects3, ranging from 5 and 20%. During the radiotherapy treatment of abdominal or pelvic tumors, the intestine is an important organ at-risk4. The toxicity of the radiation in the intestine is classified as acute and chronic, according to the onset of symptoms. In less than three months, it is considered as acute, and after this time, it is chronic4. The acute

Study carried out at the Service of Coloproctology at the University hospital of Sergipe – Aracaju (SE), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 25/01/2011 Approved on: 02/03/2011

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Statistical analysis The collected data will be inserted in a database system; afterwards, they will be submitted to statistical analysis. Simple frequency tables will be used to characterize the results, as well as the median, mean and standard deviation.

vitamin C, hyperbaric therapy and different concentrations of formalin are some of the methods used to treat this pathology5-6. The surgical treatment is used in complicated processes, such as obstruction, fistulization or uncontrollable hemorrhage, thus being restricted due to the increased morbimortality rates caused by actinic alterations, which makes the healing more difficult. Since the 4% formalin has shown positive outcomes, associated with the low cost, simple use and versatility, it can be used as the first treatment in refractory cases6. Despite the decreasing incidence of actinic proctitis with the use of more precise radiotherapy devices, there is still a significant number of patients who need outpatient follow-up. So, the objective was to assess the efficacy and the morbidity rates of the mentioned method, which is already used in the Service of Proctology of the University Hospital of Sergipe, Brazil.

Methodology The 4% formol solution was administrated via rectosigmoidoscopy. The highest amount of 4% formalin was 500 mL, administered for 30 s. After the administration, the content was aspirated and irrigated with a 0.9% physiological solution, 1,000 mL, until the complete withdrawal of the solution. All patients underwent at least two rectosigmoidoscopies. At first, before the use of formalin, the endoscopic classification was level I (less than 10 telangiectasias), II (more than 10 telangiectasias, with coalescence of 2 telangiectasias at most), III (multiple coalescent telangiectasias), or IV (ulcers) (Figure 1) at the first use of formalin. After one month, the second rectosigmoidoscopy was performed for endoscopic grading, and if the patient had no more complaints, the treatment would be suspended. If the complaints persist, new formalin solutions were used every month until the total remission of the hemorrhage.

OBJECTIVES •

• • •

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Main objective: To assess the efficacy and morbidity rates related to the use of 4% formalin for hemorrhagic chronic actinic proctitis. Secondary objectives: To assess the demographic profile of actinic proctitis; To analyze which pathologies led to the need for radiotherapy, causing actinic proctitis; Time between the end of radiotherapy and the onset of symptoms.

RESULTS The study consisted of 11 patients with hemorrhagic chronic actinic proctitis, and 36.36% of them were males and 63.63% were females. For males, the basal disease that led to radiotherapy was prostate cancer in 100% of the cases; for females, the radiotherapy was a result of uterine cervical neoplasm. Mean age was 67.7 years (ranging from 56 and 66 years), with median of 66.5 years. For males, the mean was 67.75 years, and for females, it was 67.71 years. Mean time between the end of radiotherapy and the onset of symptoms was 6.6 months, ranging from 1 month to 11 months. The dose and the type (teletherapy and/or brachytherapy) were not accounted for, since most patients did not have the radiotherapy report. Out of the common endoscopic findings observed among patients, there are: telangiectasis, fri-

MATERIALS AND METHODS Sample The medical records of patients coming from the Service of Coloproctology at the University Hospital of Sergipe who presented with hemorrhagic chronic actinic proctitis were analyzed. They were submitted to 4% formalin from February to December 2012. It was not necessary that the patient signed the informed consent form, since the paper consists only on data collection from medical records. The study was approved by the Research Ethics Committee of Universidade Federal de Sergipe. 263


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DISCUSSION

ability and small ulcers. Rectal bleeding and sphincter irritability were observed in 100% of the patients; tenesmus, in 80%; diarrhea and mucus in 60% of the cases, and essential hemorrhage in 9% of them. Mild stenosis and a small ulcer in the posterior anal canal were observed in one patient; after the biopsy, the anatomopathological was compatible with actinic proctitis. Response to treatment was classified as to the endoscopic classification of the rectosigmoid mucosa in: level I (less than 10 telangiectasias), II (more than 10 telangiectasias, with coalescence of 2 telangiectasias at most), III (multiple coalescent telangiectasias), or IV (ulcers). In the beginning of the treatment, the findings were 18.18% of level I; 27.27% of level II; 36.36% of level III and 18.18% of level IV. Complications such as perforations and fever were not observed. However, the chills were observed in 9% of the patients, tenesmus, in 18.18% of them, and mild stenosis, in 9%. Only one patient (9%) had to terminate the treatment, since he had aplastic anemia as a complication of radiotherapy. The treatment was completely effective in 27.27% of the cases. For all other patients, rectal bleeding was significantly reduced. After the beginning of the treatment, hemotransfusion was necessary for only three patients (27.27%). No ostomy was necessary for transit deviation due to uncontrolled bleeding. Table 1 shows data regarding the patients treated with 4% formalin. Table 1. Patients treated with 4% formalin. Initials Gender JCS F AAO F MR F MMS M RFL F MJM M JAS M JBS M MFS F MCJ F EBA F

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Radiotherapy was a major discovery to treat several diseases, leading to cure without the need for surgery. However, it is not a complication-free procedure. The hemorrhagic chronic actinic proctitis is one of these complications; this pathology leads to great morbidity rates, limiting activities and even mortality. There is a great range of substances that have been studied for the clinical treatment of this disease (derivatives of aminosalicylic acid, sucralfate, argon plasma, bipolar electrocoagulation, short-chain acids, hyperbaric oxygen and different concentrations of formalin)7. Due to the great possibility of technical complications, since local fibrosis is caused by the radiation and the adherence of pelvic organs, the surgical treatment is restrict to local complications (fistulae), persistence of symptoms and uncontrollable bleeding6. For patients without surgical roof, it is possible to use the derivation of intestinal transit8-9. The formalin has been used since the past century. At first, it was used for cases of hemorrhagic cystitis, by Brown, in 1968. It was first introduced by Rubinstein et al. to treat hemorrhagic chronic proctitis at a 3.6% concentration, showing good results. Thus, some papers have been showing the success and safety in using 4% formalin10-15. Mean age of the patients in our paper was 67.7 years (56 to 77 years), which is in accordance with literature. There is no difference between women and men as to mean ages (67.71 and 67.75 years, respectively).

Age 68 75 56 65 67 72 67 67 77 64 67

Neoplasm UCN* UCN* UCN* PN** UCN* PN** PN** PN** UCN* UCN* UCN*

*Uterine Cervical Neoplasm. **Prostate Neoplasm.

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Period of Time (months) 7 3 6 8 11 10 1 3 4 11 9


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Table 2. Pathologies that lead to radiotherapy treatment. Authors Mathai and SheowChoen11 * Biswal et al.13 Saclarides et al.14 HUWC Group HUSE Group

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N. of Patients

Mean Age (Years)

Prostate Neoplasm

Uterine Cervical Neoplasm

29

67 (38–94)

03

25

00

00

01

00

14

02

00

00

10

03

00

03

00

19

09

03

02

00

04

07

00

00

00

16 16 33 11

50 (40–60) 73.1 (50–83) 65.39 (36–77) 67.7 (56–77)

Endometrial Anal Canal Neoplasm Neoplasm

Rectal Neoplasm

* Including the initial sample by Seow-Choen et al. (1993). HUWC: Hospital Universitário Walter Cantídio – Universidade Federal do Ceará. HUSE: Hospital Universitário de Sergipe – Universidade Federal de Sergipe.

Table 3. Complications. Anal Fever/ Tenesmus/ Fissure/ N. of Incontinence Stenosis Diarrhea Authors pain Chills Proctalgia Ulcer patients Mathai and Sheow29 01 00 00 00 00 00 00 Choen11 Biswal et 16 00 00 00 00 00 00 00 al.13 Saclarides 16 00 00 04 00 01 00 00 et al.14 HUWC 33 01 03 00 00 04 01 03 Group HUSE 11 01 00 00 00 00 01 02 Group

Total 01 3.44% 00 05 31.25% 12 36.36% 04 36.36%

HUWC: Hospital Universitário Walter Cantídio – Universidade Federal do Ceará. HUSE: Hospital Universitário de Sergipe – Universidade Federal de Sergipe.

In literature, the pathology that is mainly responsible for pelvic radiation was uterine cervical neoplasm, which confirms our study, since it presented 63.63% of the patients with such neoplasm. Most patients with complications presented colorectal alterations, which appear from 12 to 18 months after radiotherapy. Mean time between the onset of hemorrhagic symptoms and the end of radiotherapy was 6.6 months, ranging from 1 to 11 months. Rectal bleeding, tenesmus, diarrhea, mucus stool, abdominal pain, and sphincter irritability are the more

common symptoms of hemorrhagic chronic actinic proctitis. The lower gastrointestinal bleeding caused by telangiectasias may cause severe anemia, leading to the need for multiple hemotransfusions. In our study, three patients (27.27%) needed a hemotransfusion after the administration of 4% formalin. The concentration of 4% formalin was obtained after observations; some studies showed that such dilution is efficient and presents no adverse effects16. The technique of intrarectal administration is safe when the time of contact with rectal mucosa is 265


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CONCLUSION

about 30 to 60 seconds, and the volume is 400 to 500 mL13. The complications described in literature range from 0 to 36.36%. In our study, one patient presented with chills, another one had mild stenosis, and two others had tenesmus, accounting for 36.36% of complications. Only one patient had to interrupt the participation in the study due to aplastic anemia as a complication from the radiotherapy. As to the general effectiveness of the treatment (improvement of symptoms, capacity to control hematocrit and hemoglobin levels, avoiding the need for hemotransfusion), it ranged from 93.1 to 100%; the results in our studies were compatible with literature (100%).

After the literature review and the results of the use of 4% formalin, it is possible to observe that: • The treatment of hemorrhagic chronic actinic proctitis is a challenge to the doctors; prevention is the most important step; • The 4% formalin solution has a few side effects, besides being low-cost. • The treatment is effective, and reduces the bleeding in almost 100% of the cases. With these results, we suggest the administration of 4% formalin as an effective treatment for hemorrhagic chronic actinic proctitis.

Resumo: A radioterapia foi uma importante descoberta, no que tange o tratamento das neoplasias de pelve. A proctite é uma das complicações bastante observadas atualmente, podendo ser dividida em aguda e crônica. O tratamento com solução de formalina a 4% vem sendo utilizado com resultados positivos na literatura. Objetivo: Avaliar a eficácia e morbidade do uso da formalina a 4% na retite actínica crônica hemorrágica. Métodos: Foram avaliados os prontuários e laudos das retossigmoidoscopias de 11 pacientes portadores de retite actínica crônica hemorrágica entre o período de fevereiro a dezembro de 2010, oriundos do Serviço de Coloproctologia do Hospital Universitário do Estado de Sergipe. Resultados: O estudo foi composto de 11 pacientes (36,36% feminino e 63,63% masculino). A média das idades foi de 67,7 anos. O tempo médio entre o término da radioterapia e o início dos sintomas foi de 6,6 meses. O tratamento foi completamente efetivo em 27,27%, sendo reduzido sangramento retal em 100% dos pacientes. Como principais complicações foram observadas: calafrio (9%), tenesmo (18,18%) e estenose leve (9%). Conclusão: A solução de formalina a 4% apresenta poucos efeitos colaterais, sendo muito barata a sua administração. O tratamento é efetivo, reduzindo, em praticamente 100% dos casos, o sangramento. Palavras-chave: retite; formalina; radioterapia.

REFERENCES 1.

2.

3. 4.

5.

6.

Khan MA, Birk JW, Anderson JC, Georgsson M, Park LT, Smith CJ, et al. A prospective randomized placebo-controlled double-blinded pilot study of misoprostol rectal suppositories in the prevention of acute and chronic radiation proctitis symptoms in prostate cancer patients. Am J Gastroenterol 2000;95(8):1961-6. 7. Sharma B, Pandey D, Chauhan V, Gupta D, Mokta J, Thakur SS. Radiation Proctitis. JIACM 2005;6(2):146-51. 8. Pikarsky AJ, Belin B, Efron J, Weiss EG, Nogueras JJ, Wexner SD. Complications following formalin installation in the treatment of radiation induced proctitis. Int J Colorectal Dis 2000;15(2):96–9. 9. Jao SW, Beart RWJ, Gunderson LL. Surgical treatment of radiation injuries of the colon and rectum. Am J Surg 1986;151(2):272-7. 10. Mathai V, Seow-Choen F. Endoluminal formalin therapy for haemorragic radiation proctitis. Br J Surg 1995;82(2):190. 11. Seow-Choen F, Goh H-S, Eu KW, Ho YH, Tay ST. A simple and effective treatment for hemorrhagic radiation proctitis using formalin. Dis Colon Rectum 1993;36(2):135-8.

Hauer-Jensena M, Wangb J, Boermac M, Fud Q, Denhame JW. Radiation damage to the gastrointestinal tract: mechanisms, diagnosis, and management. Curr Opin Support Palliat Care 2007;1(1):23-9. DeVita VT, Hellman S, Rosenberg SA. Cancer: principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins; 2005. Leiper K, Morris AI. Treatment of radiation proctitis. Clin Oncol 2007;19(9):724-29. Paredes V, Etienney I, Bauer PP, Bourguignon J, Meary N, Mory B, et al. Forrmalin application in the treatment of chronic radiation-induced hemorrhagic proctitis - an effective but not risk-free procedure: a prospective study of 33 patients. Dis Colon Rectum 2005;48(8):1535–41. Kennedy M, Bruninga K, Mutlu EA, Losurdo J, Choudhary S, Keshavarzian A. Successful and sustained treatment of chronic radiation proctitis with antioxidant vitamins E and C. Am J Gastroenterol 2001;96(4):1080-4.

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Evaluation of the effectiveness of 4% formalin in the treatment of hemorrhagic actinic proctitis Juvenal Rocha Torres Neto et al.

12. Biswal BM, Lal P, Rath GK, Shukla NK, Mohanti BK, Deo S. Intrarectal formalin application, an effective treatment for grade III haemorrhagic radiation proctitis. Radiother Oncol 1995;35(3):212-5. 13. Saclarides TJ, King DG, Franklin JL, Doolas A. Formalin instillation for refractory radiation-induced hemorrhagic proctitis: Report of 16 patients. Dis Colon Rectum 1996;39(2):196–9. 14. Myers JA, Hollinger EF, Mall JW, Jakate SM, Doolas A, Saclarides TJ. Mechanical, histologic, and biochemical effects of canine rectal formalin instillation. Dis Colon Rectum 1998;41(2):153–8. 15. Lima LAP, Rodrigues LV. O uso da solução de formalina no tratamento da retite actínica crônica hemorrágica Monografia

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apresentada ao Serviço de Coloproctologia do Hospital Universitário Walter Cantídio. Ceará: 2003. 16. Kochhar R, Patel F, Dhar A, Sharma SC, Ayyagari S, Aggarwal R, et al. Radiation-induced proctosigmoiditis. Prospective, randomized, double-blind controlled trial of oral sulfasalazine plus rectal steroids versus rectal sucralfate. Dig Dis Sci 1991;36(1):103-7.

Correspondence to: Alex Rodrigues Moura Rua Itabaiana, 820, Edf. Veleiro, ap. 603 – São José CEP: 49915-110 – Aracaju (SE), Brazil. E-mail: alexrmoura@ig.com.br

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Original Article

Analysis of direct costs of anesthesia-related materials between spinal and venous anesthesia with propofol associated with local perianal block in hemorrhoidectomy PAULO GUSTAVO KOTZE1, ILARIO FROEHNER JUNIOR2, CRISTIANO DENONI FREITAS3, FÁBIO DINIZ4, ÁLVARO STECKERT-FILHO4 Head of Coloproctology Service, Hospital Universitário Cajuru (SeCoHUC) at Pontifícia Universidade Católica do Paraná (PUCPR) – Curitiba (PR), Brazil. 2Intern physician, Coloproctology Service, SeCoHUC at PUCPR – Curitiba (PR), Brazil. 3Former intern physician, Coloproctology Service, SeCoHUC at PUCPR, Curitiba (PR), Brazil; physician, Coloproctology Service, Hospital Governador Celso Ramos – Florianópolis (SC), Brazil. 4Academicians, Medical School; former interns, Coloproctology Service, SeCoHUC at PUCPR – Curitiba (PR), Brazil. 1

KOTZE PG, JUNIOR IF, FREITAS CD, DINIZ F, STECKERT-FILHO A. Analysis of direct costs of anesthesia-related materials between spinal and venous anesthesia with propofol associated with local perianal block in hemorrhoidectomy. Rev bras Coloproct, 2011;31(3): 268-275. Abstract: Introduction: There is no consensus on the ideal anesthesia for hemorrhoidectomy in ambulatory facilities. Spinal anesthesia and venous propofol associated with local perianal block (combined anesthesia) are frequently used, and their direct costs may be crucial for the anesthesia type selection. The objective of this study was to compare the direct costs of anesthesia-related materials in hemorrhoidectomy between these two anesthetic techniques. Method: Retrospective and cross-section analysis, comparing the direct costs of the materials of spinal and venous anesthesia with propofol associated with local perianal block, in hemorrhoidectomy. Results: Twenty patients were included, ten submitted to each anesthesia type (five from each gender). The mean age in the spinal anesthesia group was 46.5 years and in the combined anesthesia group, 42.5 years (p=0.334). The mean cost of anesthesia-related materials was R$ 58.50 (R$ 36.48 – R$ 85.79) in the first group versus R$ 190.31 (R$ 98.16 – R$ 358.51) in the second – 69.27% difference between them (p<0.001). The mean costs according to gender analysis were R$ 50.32 and R$ 66.69 (p=0.263) in the spinal anesthesia group versus R$ 222.52 and R$ 158.10 (p=0.221) in the combined anesthesia group, respectively. Conclusions: The direct costs of anesthesia-related materials were significantly lower in patients submitted to hemorrhoidectomy using spinal anesthesia. No difference was observed between the genders in each group analyzed. Keywords: costs and cost analysis; hemorrhoids; anesthesia, spinal; anesthesia, intravenous; anesthesia, local.

INTRODUCTION

Following the global tendencies for small surgical procedures in patients with favorable anesthetic conditions, hemorrhoidectomy, just as most procedures in the anorectum, may be performed in ambulatory facilities4,5. In the context of anorectal surgeries in ambulatory facilities, the anesthetic technique is extremely important and should enable good surgery conditions, agility in the surgery room, possibility

Anorectal diseases are considerably more predominant in the Western population. Around 4.4% of the North-American adult population complains of hemorrhoids1,2. In this group, around 27% will have to be submitted to a surgical treatment, according to data in the Brazilian literature3.

Study carried out at the Coloproctology Service of Hospital Universitário Cajuru at Pontifícia Universidade Católica do Paraná, Curitiba (PR), Brazil. Financing Source: none. Conflict of interest: nothing to declare. Submitted on: 14/01/2011 Approved on: 02/03/2011

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optimize the anesthetic technique employed in these surgeries, without negative impacts to patients or health systems. The main purpose of this study was to evaluate and compare the direct costs of anesthetic materials used in hemorrhoidectomy, in patients submitted to spinal anesthesia or combined (venous with propofol associated with local perianal block) anesthesia.

of early discharge from hospital, reduced costs, few side effects, comfortable administration and fast recovery6. The main anesthetic techniques that have been used so far for anorectal procedures are: spinal anesthesia and combined (venous and local) anesthesia7 and, less frequently, general and epidural anesthesia810 . Local anesthesia alone, despite producing interesting results presented in the literature11-13, has been increasingly questioned, as it brings more benefits to selected patients. The combined use of venous anesthesia with local infiltrations offers comfort to both patient and surgeon and prevents several complications associated with general and spinal anesthesia14. Today, there is no consensus on the ideal anesthetic technique for anorectal surgeries10,15. The financial cost of health has increased at a fast pace at global level, a concern to users, governments and communities16,17. In the 1960’s, in the United States, the amount allocated to health was 5.2% of the Gross Domestic Product (GDP), and estimates for 2030 exceed 30%. In mid 1970’s, the term “pharmacoeconomy” was created to define the studies on health economy aiming at optimized efficiency of health costs18,19. The health economy studies direct costs (medications, materials, etc.) and indirect costs (occupation time of the operating room, working hours of professionals, among others). Indirect costs are usually higher, although involving more difficult measurement and quantification. Therefore, economic analyses in Medicine are significantly complex19. The international literature is still incipient regarding themes involving economic aspects associated with proctologic or anesthetic surgical procedures7,20. Few Brazilian articles on this subject have been published21,22. Given the significant prevalence of hemorrhoidal disease and the high proportion of patients that will require a surgical treatment, the anesthetic procedure costs have become an important factor in the selection of the best technique for these surgeries, as the surgical procedure per se is unvarying. Thus, an economic analysis may help making decisions as one of the important aspects in the multifactorial analysis of the disease, patients and health system. Considering this scenario, where clinical aspects are combined with economic factor, it is important to use previous experiences of reference services to

METHOD This study was approved by the Research Ethics Committee of Pontifícia Universidade Católica do Paraná (CEP – PUCPR), listed under 5088/2009. This retrospective study analyzed 20 patients from the Coloproctology Service of Hospital Universitário Cajuru (SeCoHUC) at PUCPR, submitted to a surgical procedure in the hospital-day sector of this institution, performed by the same surgical team and using standardized surgical and anesthetic techniques. The various anesthetic techniques described for anorectal procedures are employed in this Coloproctology Service. The most frequent technique is the combined (venous with propofol associated with local perianal block) anesthesia, as it may allow early discharge from hospital, among other advantages6. The patients included in this study were all adults, from the Coloproctology Ambulatory Service of Hospital Universitário Cajuru, with mixed symptomatic hemorrhoidal disease, three hemorrhoid cushions at the proctologic exam. All patients fulfilled the anesthetic criteria to be submitted to a surgical procedure provided in ambulatory facilities (healthy or with compensated comorbidities, without functional limitations – ASA I and ASA II, respectively)4,23. The patients were selected through simple random sampling from the database of the Coloproctology Service. Ten patients were included in the spinal anesthesia group and ten other patients to the combined anesthesia group. Each group was constituted of five men and five women (Figure 1). The surgeries in all patients were performed by the same surgical team and submitted to Milligan-Morgan hemorrhoidectomy (open technique), under rigorous technical standardization. The anesthesia process, regardless of the technique (spinal or combined anesthesia) or the anesthetist, followed equally rigorous 269


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steps, according to the practice of the Anesthesiology Service of Hospital Universitário Cajuru. The patients from the spinal anesthesia group were placed in the sitting position, with forward trunk flexion, to better expose the intervertebral spaces. The anesthetist, after performing his own antisepsis procedure, was getting ready and performing the patient’s antisepsis using 70% alcohol. The amount of 5 mL of lidocaine 1%, without vasoconstrictor, for skin and subcutaneous anesthesia, was inserted in the space between the second and third lumbar vertebras. Afterwards, this intervertebral space was punctured with a 27 g needle for spinal anesthesia into the subarachnoid space (confirmed by the cerebrospinal fluid backflow) for the administration of 2 mL of 0,5% isobaric bupivacaine (10 mg). Then, the patients were placed in the lithotomy position, with their lower limbs secured to their respective stirrups using 15-cm-wide crepon ties. Antisepsis of the perianal region was performed using 20 mL of topic iodopovidone and sterile surgical fields were established. After a perianal anesthesia test with thumb forceps (mouse-tooth forceps), the Milligan-Morgan hemorrhoidectomy started. The patients from the combined anesthesia group, after having their peripheral venous access and monitoring, were sedated by the anesthetist with 2 mg/kg of propofol (Propovan, Cristália®, Brazil). The sedation maintenance occurred with infusion of propofol as needed, at the anesthetist’s discretion24. The surgery preparation and antisepsis procedures were similar to those performed in the spinal anesthesia group. The surgeon administered the local anesthesia with a 25 g needle, injecting 10 mL of 0.75% ropivacaine using the Schneider’s technique25, which refers to the subcutaneous perianal administration of the anesthetic in a fan-like distribution, starting with an anterior median puncture and then a posterior median puncture in relation to the anus. Other 10 mL of the solution were divided for the pudendal nerve block through transperineal punctures medially to the ischial tuberosity26. With the perianal anesthesia confirmed as described above, the Milligan-Morgan hemorrhoidectomy started. When the surgical procedures were concluded, the patients were taken to the postoperative recovery room, where they remained under monitoring until day-hospital discharge by the anesthesiology team.

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n=20 patients

Spinal anesthesia

Combined anesthesia

(n=10)

(n=10)

Men

Women

Men

Women

(n=05)

(n=05)

(n=05)

(n=05)

Figure 1. Study design and sampling for subsequent cost analysis.

Then, the patients were taken to the recovery ambulatory service for subsequent discharge, at the physician’s discretion. Data collection was performed by reviewing the patients’ clinical records, starting with the analysis of the document describing the materials used in the surgery room during the procedure, i.e., the surgery report. All quantities of items used in the anesthetic technique were extracted from this report, such as anesthetic and sedative substances and disposable materials (needles, syringes, devices, gloves, among others). These quantities were multiplied by the individual cost of each item, as standardized by pharmaceutical magazine Kairos/Kairos Web Brasil27. Then, the final cost of the anesthetic materials was obtained for each patient. These costs were added up, and a mean cost was assigned to each group, for subsequent comparison. The data was submitted to a descriptive and statistical analysis of the Statistical Package for the Social Sciences - SPSS®, version 17.0. The analyses of mean age and mean costs used the Student’s t-test, with confidence interval of 95% (p<0.05). RESULTS The patients were equally distributed into each group in terms of gender (ten males and ten females). In the spinal anesthesia group, the mean age was 46.5 years, ranging between 33 and 65 years; in the combined anesthesia group, the mean age was 42.5 years, ranging between 26 and 55 years (p=0.334) (Table 1). The groups were comparable only when considering the mean age. The anesthetic procedure cost in the spinal anesthesia group ranged from R$ 36.48 to R$ 85.79, with mean cost of R$ 58.50 (standard deviation: R$ 22.04). 270


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female patients from the combined anesthesia group, it was not statistically significant after the Student’s t-test analysis. Other substances were used in association with the anesthetic techniques of each group, according to the anesthetist in charge of each case. In the spinal anesthesia group, opioid fentanyl citrate and benzodiazepine midazolam maleate were additionally used in four patients. In other four patients, anxiolytic alone was used, and no patient received the opioid alone. Five of these eight patients were females. For the maximum cost in this group, the spinal anesthesia per se (excluding the use of opioids and benzodiazepines) corresponded to 31.08% of the costs of all patients (kit of spinal anesthesia materials). Cost variability occurred due to the associated administered substances. In the combined anesthesia group, only three patients required three or more propofol ampoules (doses above 600 mg), two of them were male. In five patients, hemorrhoidectomy was performed with only one propofol ampoule (max. 200 mg). Midazolam maleate and fentanyl citrate were jointly used in three patients, midazolam alone in three and fentanyl alone in one. Five of these were female patients. In the patient whose cost was R$ 358.51, the use of propofol (seven ampoules) corresponded to 87.31% of the total cost of the anesthetic materials compiled in the analysis. In the patient with the lowest cost in this group (R$ 98.16), propofol corresponded to 45.55%. All patients from the combined anesthesia group were submitted to local anesthesia with only one ampoule of

In the combined anesthesia group, the mean cost was R$ 190.31 (standard deviation: R$ 80.06), ranging from R$ 98.16 to R$ 358.51. The Student’s t-test analysis result was p<0.001, which shows that the anesthetic material cost was lower in the spinal anesthesia group. The difference between the mean values of the two groups was R$ 131.80, with the spinal anesthesia group presenting 69.27% cost reduction. Figure 2 illustrates these findings. The study attempted to analyze if the costs between the groups presented any difference in terms of gender. In the spinal anesthesia group, the mean values of male and female patients were R$ 50.32 and R$ 66.69, respectively (p=0.263). In the combined anesthesia group, the mean costs of male and female patients were R$ 222.52 and R$ 158.10 (p=0.221), respectively. Figure 3 illustrates these findings. Although absolute numbers showed a lower mean cost for male patients from the spinal anesthesia group and for Table 1. Demographic data (gender patients from the two groups. Spinal anesthesia Male 5 Gender Female 5 Mean age 46.5 years* Minimum age 33.0 years Maximum age 65.0 years

and age) of Combined anesthesia 5 5 42.5 years* 26.0 years 55.0 years

*Statistical analysis using the Student’s t-test (p=0.334), without significant difference.

Costs (R$) versus gender

Costs of procedures (R$) 400

250

358.51

350

158.1

250

100

150

0

150

190.31 *

200

50

222.52

200

300

100

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98.16

85.79

58.5 *

36.84

50 0

Minimum

Maximum Spinal anesthesia

Mean

50.32

66.69

Spinal anesthesia

Anestesia combinada Male

Combined anesthesia

Figure 2. Minimum, maximum and mean costs of anesthetic materials used in the hemorrhoidectomy performed with spinal anesthesia and combined anesthesia. *Student’s t-test (p<0.001). Lower costs were observed with the spinal anesthesia (dark columns), which means 69.27% reduction.

Female

Figure 3. Costs in relation to gender in each analyzed group. Analysis made with the Student’s t-test: p=0.263 (spinal anesthesia) and p=0.221 (combined anesthesia), without significant different between men and women in each group.

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0.75% ropivacaine. In the patients with the highest and lowest values, the use of such anesthetic corresponded to 10.45% and 38.17% of the total direct cost, respectively.

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Anorectal Surgery”, by the American Society of Colon and Rectal Surgeons, described the effectiveness and cost-benefit ratio of local anesthesia in anorectal procedures4. The significant pain and discomfort associated with the use of local perianal anesthesia alone can be properly minimized, as mentioned above, by combining it with venous anesthesia, without adding morbidity to the procedure15,29. In more complex anorectal and perineal surgeries, or with broader surgical fields, such as colpoperineoplasty and sphincteroplasty, general anesthesia or spinal anesthesia is indicated32. The same is applicable to current procedures of broad local inflammatory processes, such as large perianal abscesses, in which the local anesthetist operates in unfavorable medium. Therefore, not all patients are eligible to combined anesthesia in ambulatory facilities. The population analyzed in this study was selected thorough simple sampling, considering patients that had already been submitted to the surgery, where the criteria for the anesthetic technique indication was jointly elaborated by the surgical team and the anesthetist. Assuming that the surgical technique adopted is unvarying and standardized, the variability of the anesthetic technique, with its respective materials, is a determining factor in the procedure costs. Patients submitted to surgeries using anesthetic techniques that allow early hospital discharge (in ambulatory facilities) usually incur lower costs15,33,34. Kushwaha et al. conducted a prospective study with analyzed 19 patients submitted to local anesthesia and 22 patients submitted to general anesthesia in hemorrhoidectomy. They observed significantly reduced hospitalization period and overall (direct + indirect) costs in the first group20. A prospective and randomized study that analyzed 93 patients submitted to anorectal surgeries, assigned to combined (propofol and local), general and spinal anesthesia groups, observed significantly reduced overall costs and hospitalization period, with higher patient satisfaction in the first group15. Kotze et al. demonstrated, in a similar study, reduced utilization time of the operating room in patients submitted to surgeries with combined anesthesia6. In the same study, published later, the overall costs were similar when comparing spinal and combined anesthesia21. However, in these four studies, the analysis was of direct and indirect costs. No analysis of direct costs alone has been performed, as in this study.

DISCUSSION The current scenario of cost reduction of hospital activities and optimization of hospital bed turnover rate requires a method that harmoniously combines clinical, ethical, managerial and economic aspects1619 . Anorectal procedures account for around 80% of all coloproctology surgeries28 and among these procedures, more than 90% may be performed in ambulatory facilities4,5,15. A series of cases published by Steckert et al. that analyzed 430 patients submitted to 453 anorectal surgeries, described hemorrhoidectomy as the most frequent procedure, corresponding to 50.3% of total surgeries28. Therefore, as hemorrhoidectomy is the most frequent anorectal surgery, it is important that the proctologist should be aware of the costs associated. Until the 1970’s, almost all anorectal surgeries used to be performed in the hospital environment, regardless of the procedure complexity5. Following the global economy tendencies towards optimization of financial resources, ambulatory surgeries have gained increasing and gradual acceptance from surgeons29,30. The ambulatory facilities require a strong association of these three elements: patient, surgery and anesthesia, aiming at an early and safe hospital discharge. Anesthesia is an essential item for the ambulatory service to achieve its purposes. It should enable the ideas conditions to perform the procedure, exposing the patient to minimum incidence of adverse effects. In addition, it should cause fast recovery after the anesthesia, for an early and safe hospital discharge, with consequent cost reduction. The local perianal anesthesia allows proper relaxation of anal sphincters and is not associated with the typical complications of spinal anesthesia, such as: cephalalgia, lumbar pain, arterial hypotension and urinary retention9,31. However, patient acceptance is low, and its association with venous anesthesia has enabled a more comfortable procedure. Place et al., in the publication of “Practice Parameters for Ambulatory 272


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The main finding of this study was that the spinal anesthesia group presented lower direct costs of anesthetic materials, when compared to the combined (propofol and local perineal block anesthesia group. Such reduction of almost 70% in direct costs was extremely important. The explanation found for these results was the high cost of propofol ampoules used in the combined anesthesia group (Propovan, Cristália®, Brazil). Each propofol ampoule cost R$  44.72, an amount that is nearly the mean value of the costs of materials used by the spinal anesthesia group27. The fact that three out of total ten patients in the propofol group used more than three ampoules each significantly increased the mean cost in this group. In the spinal anesthesia group, the mean cost was R$ 58,50. In this group, the anesthetic procedure consisted in the administration of 0.5% bupivacaine into the subarachnoid space, providing anesthesia for around 4 hours, without requiring anesthetic complementation in this period. The use of benzodiazepine and/or opioid agents, which corresponded to the highest costs of anesthetic materials in this group, occurred due to the personal preference of some anesthetics or the eventually required sedation and analgesia to enable the spinal anesthesia, a useful procedure for anxious patients in relation to the surgery. Then, cost variability occurred due to the associated substances, and not due to the spinal anesthesia per se. It should be mentioned that the cost of tray preparation and sterilization for the spinal anesthesia (including a bowl for the antiseptic substance, forceps, gauzes and field marking) was not calculated in this study due to the subjectivity involved in determining values related to material cleaning, tray assembly and oven time. In this group, direct costs were higher in women (in absolute numbers), which can be explained by the fact that they presented a lower degree of anxiety in the immediate preoperative period. We believe that a study with a higher number of patients may show statistical significance. In the combined anesthesia group, the mean direct cost of materials was R$ 190.31. The venous anesthesia, performed with propofol, occurred with initial bolus (2 mg/kg), enabling local anesthesia and maintenance dose as needed. Read et al., in a prospective study, analyzed 389 anorectal surgeries. Among them, 260 were performed using combined

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anesthesia, with additional propofol bolus, using no infusion pump for the continuous administration of the venous anesthetic24. This study used the same maintenance method of venous anesthesia. Propofol has always been associated with high costs. Along the time, new compositions have been offered, and the costs of this substance have decreased. Despite such reduction, propofol still accounts for the highest costs of anesthetic materials, according to the procedure duration. It is known that, despite the extensive metabolism in the liver, hepatopathies and nephropathies do not cause significant changes in the substance pharmacokinetics35. Its half-life is 2 to 4 minutes, requiring additional injections in longer procedures, according to the patient’s weight. In this study, only three patients required three or more propofol ampoules, corresponding to 70% of the procedures performed with relatively low doses of this substance. In general, men present higher body mass than women. In addition, hemorrhoids in male patients tend to be larger, involving arduous and longer surgical procedures, requiring more frequent doses of venous anesthetic (short halflife of propofol). For this reason, we believe that costs tend to be higher in male patients, which was not observed in this study, as sampling may have been insufficient and no statistical significance was observed. Today, the anorectal surgeries at SeCoHUC are performed, except with contraindications related to the method, with combed anesthesia. The experience acquired in some years with this anesthetic technique, combined with a good relationship with the anesthesiology service, shows that the selection of combined anesthesia is more suitable to most patients. In addition, the service study group on this theme showed equivalent overall costs of the procedures, not only regarding the anesthetic materials, when comparing the two techniques6,21. At the final decision on the technique selected for the service procedures, indirect costs were also taken into account (shorter time in the operating room and hospitalization, among others), as well as the additional clinical benefits to the patient from the significant reduction of complications (mainly urinary retention and cephalalgia). The investigation of direct costs fulfilled a simple curiosity of the study group regarding this theme. The study performed a retrospective analysis of the patients submitted to spinal anesthesia, as it is not 273


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part of the service routine, only indicated to selected cases. This factor limits the possibility to perform a prospective study with the same patients, as this technique is not habitually indicated.

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anesthesia using propofol associated with local perianal block. No influence of gender was observed on the direct costs of these materials in the two techniques. Further analyses should be performed using a higher number of patients to consolidate these conclusions. The decision on the best anesthetic technique in hemorrhoidectomy remains an open discussion, and the analysis of direct and indirect costs should be considered when selecting the type of anesthesia, in an agreement involving the surgical team, the anesthetist and the health system sponsors.

CONCLUSIONS The mean direct costs of anesthetic materials used in hemorrhoidectomy were significantly lower in patients submitted to surgeries with spinal anesthesia, when comparing to the patients submitted to surgeries with venous

Resumo: Introdução: Não há consenso sobre a técnica anestésica de escolha para hemorroidectomias em regime ambulatorial. A raquianestesia e a anestesia combinada (venosa com propofol + local) são frequentemente utilizadas, e os custos das mesmas podem ser determinantes na escolha do melhor tipo de anestesia. O objetivo deste trabalho foi avaliar e comparar os custos diretos dos materiais anestésicos utilizados em hemorroidectomias entre essas duas técnicas. Método: Foi feito um estudo retrospectivo e transversal, comparativo entre os custos diretos dos materiais anestésicos entre a raquianestesia e a anestesia venosa com poropofol associada ao bloqueio perianal local, em hemorroidectomias. Resultados: Foram analisados 20 pacientes, 10 operados com cada técnica anestésica (5 de cada gênero). A média de idade do grupo da raquianestesia foi de 46,5 anos e do grupo da anestesia combinada foi de 42,5 anos (p=0,334). O custo médio do procedimento anestésico no primeiro grupo foi de R$ 58,50 (R$ 36,48 – R$ 85,79), no segundo foi de R$ 190,31 (R$ 98,16 – R$ 358,51). A diferença das médias foi de 69,27%, com significância estatística (p<0,001). A média dos custos dos gêneros masculino e feminino no grupo da raquianestesia foi de R$ 50,32 e R$ 66,69 (p=0,263) e no grupo da anestesia combinada foi de R$ 222,52 e R$ 158,10 (p=0,221), respectivamente. Conclusões: Os custos diretos médios dos materiais anestésicos dos pacientes submetidos a hemorroidectomias foram significativamente menores no grupo da raquianestesia. Não houve significância estatística na diferença entre os gêneros em cada grupo. Palavras-chave: custos e análise de custo; hemorroidas; raquianestesia; anestesia endovenosa; anestesia local.

REFERENCES 1.

2. 3.

4.

5. 6.

7.

Anannamcharoen S, Cheeranont P, Boonya-Usadon C. Local perianal nerve block versus spinal block for closed hemorrhoidectomy: a randomized controlled trial. J Med Assoc Thai 2008;91(12):1862-7. 8. Kotze PG, Martins JF, Steckert JS, Rocha JG, Sartor MC, Miranda EF. Anopexia mecânica com anestesia combinada – experiência inicial. Rev Med Res 2009;11(2):54-61. 9. Sungurtekin H, Sungurtekin U, Erdem E. Local anesthesia and midazolam versus spinal anesthesia in ambulatory pilonidal surgery. J Clin Anesth 2003;15(3):201-5. 10. Gudaitytè J, Marchertiene I, Pavalkis D. Anesthesia for ambulatory anorectal surgery. Medicina 2004;40(2): 101-11. 11. Tepetes K, Symeonidis D, Christodoulis G, Spyridakis M, Hatzitheofilou K. Pudendal nerve block versus local anesthesia for harmonic scalpel hemorrhoidectomy: a prospective randomized study. Tech Coloproctol 2010;14(Suppl 1):S 1-3. 12. Clery AP. Local anesthesia containing hyaluronidase and adrenaline for anorectal surgery: experience with 576 operations. Proc R Soc Med 1973;66(7):680-1.

Johanson JF, Sonnenberg A. The prevelence of hemorrhoids and chronic constipation. An epidemiologic study. Gastroenterol 1990;98(2):380-6. Haas PA, Haas GP. The prevalence of hemorrhoids and chronic constipation. Gastroenterol 1990;99(6):1856-7. Cruz GMG, Ferreira RMRS, Neves PM. Doença hemorroidária – aspectos epidemiológicos e diagnósticos de 9289 pacientes portadores de doença hemorroidária. Rev Bras Coloproct 2006;26(1):6-23. Place R, Hyman N, Simmang C, Cataldo P, Church J, Cohen J, et al. Standards Task Force; American Society of Colon and Rectal Surgeons. Practice parameters for ambulatory anorectal surgery. Dis Colon Rectum 2003;46(5):573-6. Sobrado CW. Outpatient surgical proctology – past, present and future. Arq Gastroenterol 2005;42(3):133-5. Kotze PG, Tambara EM, Von Bahten LC, Silveira F, Wietzikoski E. Influência da técnica de anestesia no tempo de ocupação de sala cirúrgica nas operações anorretais. Rev Bras Coloproct 2008;28(2):227-33.

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Analysis of direct costs of anesthesia-related materials between spinal and venous anesthesia with propofol associated with local perianal block in hemorrhoidectomy Paulo Gustavo Kotze et al.

13. Riss S, Riss P. Re: Randomized clinical trial comparing day-care open haemorrhoidectomy under local versus general anaesthesia (Br J Surg 2008;95:555-63). Br J Surg 2008;95(8):1068-9. 14. Castellví J, Sueiras A, Espinosa J, Vallet J, Gil V, Pi F. LigasureTM versus diathermy hemorrhoidectomy under spinal anesthesia or pudendal block with ropivacaine: a randomized prospective clinical study with 1-year follow-up. Int J Colorectal Dis 2009;24(9):1011-8. 15. Li S, Coloma M, White PF, Watcha MF, Chiu JW, Li H, et al. Comparison of the costs and recovery profiles of three anesthetic techniques for ambulatory anorectal surgery. Anesthesiology 2000;93(5):1225-30. 16. Herrera MMC. Farmaeconomía. Eficiencia y uso racional de los medicamentos. Rev Bras Cienc Farm 2004;40(4): 445-53. 17. Verano RD, Masis DP. Pharmacoeconomy. Acta Med Colombiana 2006;31(2):53-5. 18. Secoli SR, Padilha KG, Litvoc J, Maeda ST. Farmacoeconomia: perspectiva emergente no processo de tomada de decisão. Ciênc Saúde Coletiva. 2005;10(Suppl):287-96. 19. Álvarez JS. Pharmacoeconomic studies: why, how, when and for what? Medifam 2001;11(3):147-55. 20. Kushwaha R, Hutchings W, Davies C, Rao NG. Randomized clinical trial comparing day-care open haemorrhoidectomy under local versus general anaesthesia. Br J Surg 2008;95(5):555-63. 21. Kotze PG, Freitas CD, Steckert JS, Martins JF, SobradoJunior CW, Von Bahten LC, et al. Análise de custos entre a raquianestesia e a anestesia venosa com propofol associada ao bloqueio perianal local em operações anorretais. Arq Bras Cir Dig 2009;22(3):137-42. 22. Lacerda-Filho A, Melo JRC. Hemorroidectomia em regime ambulatorial sob anestesia local – estudo prospectivo de 50 casos. Rev Bras Coloproct 1995;15(4):206-10. 23. American Society of Anesthesiologists [internet]. ASA Physical Status Classification System 2010 [cited 2010 Jun]. Available from: http://www.asahq.org/clinical/physicalstatus. htm. 24. Read TE, Henry SE, Hovis RM, Fleshman JW, Birnbaum EH, Caushaj PF, et al. Prospective evaluation of anesthetic technique for anorectal surgery. Dis Colon Rectum 2002;45(11):1553-8.

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25. Schneider HC. Hyaluronidase with local anesthesia in anorectal surgery. J Surg 1954;88(5):703-6. 26. Imbelloni LE, Beato L, Beato C, Cordeiro J, Souza DD. Analgesia pós-operatória com bloqueio bilateral do nervo pudendo com bupivacaína S75-R25 a 0,25%. Estudo piloto em hemorroidectomia sob regime ambulatorial. Rev Bras Anestesiol 2005;55(6):614-21. 27. Kairos Web Brasil [internet]. Revista Farmacêutica Kairos 2010 [cited 2010 Jun]. Available from: http://brasil.kairosweb.com/. 28. Steckert JS, Sartor MC, Miranda EF, Rocha JG, Martins JF, Kotze PG, et al. Análise das complicações tardias em operações anorretais: experiência de um serviço de referência em coloproctologia. Rev Bras Coloproct 2010;30(3):305-17. 29. Argov S, Levandosky O. Radical ambulatory hemorrhoidectomy under local anesthesia. Am J Surg 2001;182(1):69-72. 30. Nahas SC, Sobrado CW, Marques CF, Imperiale AR, Habr-Gama A, Rocha JPS, et al. Orifice diseases project – experience of the “Hospital das Clínicas” University of São Paulo medical center in day-hospital of anorectal disease. Rev Hosp Clin Fac Med S Paulo 1999;54(3):75-80. 31. Fleischer M, Marini CP, Statman R, Capella J, Shevde K. Local anesthesia is superior to spinal anesthesia for anorectal surgical procedures. Am Surg 1994;60(11):812-5. 32. Sun MY, Canete JJ, Friel JC, McDade J, Singla S, Paterson CA, et al. Combination propofol/ketamine is a safe and efficient anesthetic approach to anorectal surgery. Dis Colon Rectum 2006;49(7):1059-65. 33. Cariati A. Hospital costs of conventional and stapled 1-day hemorrhoidectomy. Arch Surg 2009;144(10):979-80. 34. McKenzie L, De Verteuil L, Cook J, Shanmugan V, Loudon M, Watson AJ, et al. Economic evaluation of the treatment of grade II haemorrhoids: a comparison of stapled haemorrhoidectopexy and rubber band ligation. Colorectal Dis 2010;12(6):587-93. 35. Magella HA, Cheibub ZB. Propofol: revisão bibliográfica. Rev Bras Anest 1990;40(4):289-94. Corresponding author: Paulo Gustavo Kotze Rua Mauá, 682, Alto da Glória CEP: 80030-200 – Curitiba (PR), Brasil E-mail: pgkotze@hotmail.com

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Original Article

Mucocele of the appendix - appendectomy or colectomy? JANDUÍ GOMES DE ABREU FILHO1, ERIVALDO FERNANDES DE LIRA1 1

Service of Coloproctology of Hospital de Base do Distrito Federal (HBDF), Secretariat of Health in Distrito Federal - Brasília (DF), Brazil.

FILHO JGDA; LIRA EFD. Mucocele of the appendix - appendectomy or colectomy? Rev bras Coloproct, 2011;31(3): 276-284. Abstract: Mucocele of the appendix is a rare disease. It can be triggered by benign or malignant diseases, which cause the obstruction of the appendix and the consequent accumulation of mucus secretion. The preoperative diagnosis is difficult due to non-specific clinical manifestations of the disease. Imaging tests can suggest the diagnosis. The treatment is always surgical and depends on the integrity and size of the appendix base and on the histological type of the original lesion. The prognosis is good in cases of integrity of the appendix. The perforation of the appendix and subsequent extravasation of its contents into the abdominal cavity may lead to pseudomyxoma peritonei, which has very poor prognosis if not treated properly. Keywords: mucocele; appendix; pseudomyxoma peritonei; treatment.

INTRODUCTION

first one defends the right colectomy as a treatment9, and the second one recommends only appendectomy10. Despite the different adopted conducts, in both reported cases a cystadenoma was diagnosed in the appendix; the choice was for elective surgery. The objective of this review is to analyze literature as to mucocele, especially regarding diagnosis and treatment, besides discussing follow-up and prognosis of the individuals who have this disease.

The mucocele of the appendix was first described in 1842 by Rokitansky1. This disease is considered as a rare lesion of the appendix, which is found in 0.2 to 0.3% of the appendectomies2. It is characterized by the dilation of the organ lumen with mucus accumulation, being more frequent among individuals aged 50 years or more3,4. Gender prevalence is controversial. Appendix mucocele may come as a consequence of obstructive or inflammatory processes, cystadenomas or cystadenocarcinomas7. Besides these causes, other tumor lesions in the appendix or cecum may present as mucocele8. Its main complication is pseudomyxoma peritonei. Treatment is always surgery and determined by the organ’s integrity, the dimensions of the base and histological type of the lesion. Revista Brasileira de Coloproctologia has recently published two articles about this disease. The

LITERATURE REVIEW The mucocele of the appendix is a descriptive and unspecific term to define the cystic dilation of the appendix caused by the accumulation of mucus secretion. This process is slow and gradual, with no signs of infection inside the organ. It results from the lumen obstruction in the appendix, which is secondary to the inflammatory or neoplastic proliferation of the appendix mucosa, or of lesions in the cecum, adjacent to the appendiceal ostium.

Study carried out at the Service of Coloproctology of HBDF, Brasília (DF), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 13/09/2010 Approved on: 31/01/2011

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While some articles confirm its prevalence among women3,4, others demonstrate a higher incidence among men5,6. Mucocele in the appendix may be classified according to the histological characteristics of lumen obstruction7. Simple mucocele (inflammatory, obstructive or retention cyst) is characterized by degenerative epithelial changes and results in the obstruction and the distension of the appendix. There is no evidence of hyperplasia or mucosal atypia. In hyperplastic mucocele, the appendix dilation occurs due to the hyperplastic growth of the appendix or cecal mucosa, just like hyperplastic polyps in the colon. Simple and hyperplastic mucoceles correspond to 5 to 25% of the cases, and mucus is usually acellular. The mucinous cystadenoma is an appendix neoplasm with dysplastic epithelium similar to colon adenomatous polyps, and corresponds to 63 to 84% of the cases. The mucinous cystadenocarcinoma presents high grade cellular dysplasia and stromal invasion, besides muscularis mucosae, and represents 11 to 20% of the cases. In both types described, the mucus material contains epithelial adenoma cells with low or high grade of dysplasia. The rupture of the appendix may lead to the dissemination of the epithelium that produces mucins in the abdominal cavity, causing mucinous ascites or pseudomyxoma peritonei. Stocchi et al.4 analyzed 135 patients with mucocele of the appendix. Out of these, 129 were submitted to surgery and histological analyses, and 37 presented pseudomyxoma peritonei. From the 37 cases of pseudomyxoma peridonei, 95% had malignant mucocele, and 83% of the perforated mucoceles were malignant. Ronnet et al.11 studied 109 cases of pseudomyxoma peritonei and classified it in two types: disseminated peritoneal adenomucinosis, which is a result of mucinous adenoma, with survival rate of 84%; and peritoneal mucinous carcinomatosis, which is secondary to mucinous adenocarcinoma, with survival rate of 6.7%. Thus, both the benign and the malignant mucocele may cause pseudomyxoma peritonei, however, this complication is more frequent and has worse prognosis for malignant cases, probably because in this situation the appendix ruptures more easily, and the celular seeding is more aggressive4,5,11.

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Mucocele of the appendix can also result from alterations in the cecum, such as fecal impaction, polyps or malignant neoplasms, which, in theory, can obstruct the appendiceal ostium. Another rare cause found in literature is endometriosis, which may be established on the wall of the appendix, causing lumen obstruction8. The classification based on histopathological standards is really important, once the progress of the disease and its prognosis are related to the subtypes. Simple and benign mucoceles have an insidious evolution and are rarely perforated; on the other hand malignant mucocele evolution is faster, like in acute appendicitis, usually presenting as an organ perforation4. The diameter of the non-neoplastic mucocele (simple and hyperplastic) is smaller than the neoplastic mucocele (cystadenoma and cystadenocarcinoma); however, there is no difference related to size among benign and malignant neoplastic mucoceles. Besides, no neoplastic mucocele has a diameter smaller than two centimeters4. The clinical presentation of mucocele in the appendix is usually unspecific, with difficult preoperative diagnosis. The most common complaint is pain in the right lower quadrant of the abdomen, which may last for months, being noticed in up to 50% of the cases, associated or not with a palpable tumor. About 25 to 50% of the subjects can be asymptomatic4,5. The carcinoembryonic antigen (CEA) level at preoperative may suggest malignity in the appendix or in the colon9,10. Imaging tests, such as ultrasound, computed tomography and enema, besides colonoscopy, may suggest the presence of mucocele of the appendix, which helps to define the treatment. The ultrasound shows an encapsulated cystic lesion in the lower quadrant of the abdomen with a liquid content of variable echogenicity, according to the density of the mucus12. Some tests present images of multiple echogenic layers in the dilated appendix, which may be considered as pathognomonic of appendix mucocele13. At computer tomography, the typical feature of mucocele of the appendix is a cystic mass with a thin wall and of low density, which communicates directly with the cecum (Figure 1). The presence of punctate or curvilinear calcification in this wall confirms the mucocele diagnosis and differs from the appendicular abscess, which does not have this characteristic6. 277


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At enema, the presence of mucocele can be characterized by a cecal filling defect, besides the lateral displacement of the cecum and terminal ileum14. Colonoscopy may show a soft erythematous mass, with a central crater due to the protrusion of appendiceal ostium, which can increase or decrease according to the respiratory movement15. This condition is known as “volcano sign”16 (Figure 2). This examination may still show the presence of synchronic neoplastic lesions in the colon, which occur in up to 20% of the cases17. The cytology of the mucus inside the mucocele obtained by puncture with a thin needle may distinguish benign and malignant forms, but it should not be

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used due to the risk of cell dissemination and evolution to pseudomyxoma peritonei18,19. The treatment of appendix mucocele is surgeryl and determined by some factors, such as the integrity of the wall of the organ, the dimensions of its base and histopathological examination of the cause of mucocele. For mucocele (Figure 3), appendectomy with lymphadenectomy, including all the fat from the mesoappendix in the resection, is indicated for cases of simple or benign mucocele, when the appendicular base is not compromised by the dilation and is smaller than 2.0 cm (Figure 4). The partial cecal resection with linear stapler cutter, including the site of implantation of the appendix, Mucocele of the appendix Free base (up to 2.0 cm)

Appendectomy + Lymphanedectomy

Compromised base (>2.0 cm) Lesion in the cecum (no biopsy) Typhlectomy

Frozen section Benign

Histopathological

Malignant Right colectomy

Figure 1. Computed tomography: cystic image adjacent to the cecum.

Follow-up Figure 3. Treatment protocol of mucocele.

Figure 2. Colonoscopy: Protrusion of the appendiceal ostium, volcano sign (file: Dr. José Juvenal de Araújo).

Figure 4. Mucocele of the appendix with a narrow base.

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is performed in cases of mucocele with dilated appendicular base (larger than 2.0 cm), or at the presence of some cecal tumor. This procedure prevents the dissemination of neoplastic cells to the abdominal cavity, besides ensuring a negative margin in the resection-line (Figures 5 and 6). The release and exteriorization of the cecum should occur in order to reduce the risk of contamination in the abdominal cavity in cases of unwanted rupture during the manipulation of the cecal appendix. In both surgical procedures, the cecal appendix is sent to frozen section. In case there is suspicion or detection of malignant neoplasm as the cause of mu-

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cocele, the resection is complemented with the right colectomy, with the objective of removing the whole lymphatic chain of the region. If the frozen section is not available at the time of the initial surgery, which is usually urgent, right colectomy should not be performed. This can prevent unnecessary abdominal incisions, since the malignant neoplasm is the cause of mucocele in only 10 to 20% of the cases7. If the lymph nodes are increased and the frozen section is positive for malignity, or even if the histopathological examination of the surgical piece confirms the malignant etiology, the patient is submitted to right colectomy. However, when the patient undergoes colonoscopy at the preoperative and a malignant neoplasm is diagnosed in the cecum, or if a cecal tumor is noticed, right colectomy is the first choice. A complete abdominal exploration during intraoperative is indicated due to the occurrence of mucocele in synchrony with other tumors, like colon and ovaries. This conduct is mainly indicated when the surgery is performed with urgency, and preoperative examinations are not made17. In cases of mucocele, lymphadenectomy in the mesoappendix is common to help the pathologist define the histology of the lesion. Besides, lymphadenectomy is important to define the conduct of other cecal appendix tumors, like carcinoid and adenocarcinoid tumors, which may eventually lead to mucocele19,20. If the mucocele is simple and benign, appendectomy with lymphadenectomy is the definite treatment, as well as it is for carcinoid and adenocarcinoid tumors with favorable histology (small, with negative and well differentiated lymph nodes) and endometriosis. If the histological diagnosis points to bowel or mucinous adenocarcinoma, carcinoid or adenocarcinoid tumors larger than 2.0 cm, with positive lymph nodes or high mitotic rate, the resection is complemented with right colectomy19,20. Even though lymphatic dissemination is not so frequent in this type of tumor, the mucinous adenocarcinoma of the non-perforated appendix has higher chances of healing with the right colectomy. This surgery has low mortality rates, especially when elective and performed in patients at a good general state21,22. The bowel adenocarcinoma is always submitted to right colectomy because the incidence of lymphatic dissemination is high in this type of tumor23.

Figure 5. Mucocele of the appendix with a wide base.

Figure 6. Partial resection of the cecum in mucocele with palpable tumor at the base.

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The performance of appendectomy by videolaparoscopy in cases of mucocele is not indicated due to the manipulation and risk of appendicular rupture and the dissemination of mucus with the possibility of peritoneal implants24. In case mucocele is diagnosed during laparoscopy, the surgery should be converted into a laparotomy. However, some authors disagree as to the recommendation to avoid laparoscopy for mucocele, by saying that laparoscopic appendectomy to handle appendix tumors has late results, similar to the open technique, in case there is a careful manipulation of the organ and the use of protective envelopes25,26. However, although it is technically possible to remove the intact appendix with free resection margins with laparoscopy, the advantage of open surgery is the release and exteriorization of the cecum, avoiding the contamination of the cavity in case of accidental rupture of the appendix. As to follow-up, a recent study suggests histological, clinical and genetic similarities in proliferative lesions of the appendix and colonic mucosa27.

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So, simple and hyperplastic mucoceles would not require follow-up, benign mucocele would be followed-up as an adenomatous polyp with colonoscopies, according to the follow-up of colonic adenomas28, and the malignant one would be followed-up as a colonic adenocarcinoma, with doses of CEA and serial colonoscopies29. In cases of perforated mucocele of the appendix (Figure 7), there is mucus extravasation to the abdominal cavity, the pseudomyxoma peritonei. This entity was first described in 1884 by Werth30, and is characterized by implants of mucinous epithelium and mucus accumulation in the peritoneal cavity. The treatment depends on the histology of the appendix, the cytology of the ascitic fluid and the presence of positive lymph nodes in the mesoappendix23,31. These patients may present an abrupt evolution, with symptoms that characterize acute appendicitis, or present chronic evolution, with an increased abdominal circumference, mucinous ascites, mucin within the hernia sac and ovarian tumor32.

Ruptured Mucocele of the Appendix

Appendectomy + lymphadenectomy + Mucus Collection Bowel adenocarcinoma

Mucinous adenocarcinoma

Right colectomy

Lymph node

Positive

Right colectomy

Negative

Definite

Mucus

Margin

Positive

Negative

Positive

Negative

Typhlectomy

Definite

QT + cytoreduction

QT

Figure 7. Treatment protocol of perforated mucocele.

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Computed tomography can show the ascitic fluid, changes in hepatic contour and presence of nodes in the splenic capsule, corresponding to peritoneal implants, calcification of serous implantations; besides, it can also show metastatic ovarian carcinoma. The initial surgery in cases of mucocele of the appendix is appendectomy, block resection of the appendicular fat and collection of mucinous ascitic fluid. In patients with free mucinous fluid in the abdominal cavity, the peritoneum would work as a defense against the dissemination of epithelial cells. Thus, the initial surgery should be as minimal as possible, in order to keep the peritoneum intact23,31. Patients with perforated mucocele who did not present positive lymph nodes or compromised margins, and who undergo right colectomy, present lower survival rates when compared to those who are only submitted to appendectomy at the time of the primary surgery23. Cases of deep invasion into paracaval retroperitoneal tissues at right colectomy have been reported, which is different from the minor superficial aggression, usually observed in patients with pseudomyxoma peritonei and an intact peritoneum33. This conduct is different from the primary colon cancer with peritoneal carcinomatosis, in which the results are better when the definite conduct is performed at the initial surgery34. However, if it is an adenocarcinoma of the intestine, or if the lymph nodes are positive as to malignity at the frozen section, right colectomy is performed at the initial surgery. If the histopathological examination diagnoses bowel adenocarcinoma, the indication is right colectomy. If it is mucinous, the colectomy is performed if the lymph nodes of the appendicular fat are positive, and typhlectomy is indicated if the margins are compromised31. The lymphatic dissemination of the mucinous adenocarcinoma is rare, and the survival of these patients does not change when the bowel resection is magnified in cases in which the peritoneum is compromised23. The prognosis of patients with adenocarcinoma of the appendix is controversial, depending on histological type. While some authors observe a better prognosis with bowel adenocarcinoma, others demonstrate more favorable results with the mucinous adenocarcinoma27,35,36.

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As previously reported, any patient with benign or malignant mucocele of the appendix may have pseudomycoma peritonei, however, this condition is more common for the malignant mucocele4,5. There is no such risk in simple mucocele, since there are no epithelial cells in the mucus. Mucus cytology should be immediately performed, because the result will define surgical therapy. If the cytology of the mucinous ascitic fluid is negative for adenomatous epithelial cells, the indication is hyperthermic intraoperative intraperitoneal chemotherapy. If it is positive, besides the operative chemotherapy, the cytoreductive surgery and postoperative intraperitoneal chemotherapy are performed31. The cytoreductive surgery and intraperitoneal chemotherapy are indicated for patients with the disease limited to the peritoneum, with curative intent. This procedure is not recommended at the presence of unresectable malignant liver or distant disease. The surgery consists of trying to resect all visible peritoneal implants or, if it is not possible, of leaving only implants smaller than 2.5 mm in diameter, maximum limit for the intraperitoneal chemotherapy to work with curative intent. This may include omentectomy, splenectomy, upper quadrant and pelvic peritonectomy, cholecystectomy, partial or total colectomy, partial or total gastrectomy, besides rectosigmoidectomy and hysterectomy37-39. After the cytoreductive surgert, the hyperthermic intraperitoneal chemotherapy is performed. Only after intraoperative chemotherapy, possible intestinal anastomoses can occur. At the end of surgery, abdominal drains are located in the cavity for postoperative chemotherapy37-39. The extensive removal of the peritoneal surface may lead to a diffuse and deep implantation of malignant cells in the abdomen and pelvis, which would involve important structures, such as the ureter and blood vessels, if intraoperative intraperitoneal and immediate postoperative chemotherapies were not performed. The hyperthermic intraperitoneal chemotherapy is performed with mitomycin or heated oxaliplatin (42°C, for 60 to 120 min). Hyperthermia intensifies the cytotoxic effects of chemotherapy and increases the effect of the drug in the tissues. 281


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The postoperative chemotherapy is performed with 5-fluorouracil in the first five postoperative days, which prevents free tumor cells to fixate on wound healing sites of peritonectomy, and also that adherences harm the uniform distribution of the drug in the abdominal cavity37-39. Even at the unsuccessful attempt of complete cytoreduction, a better evolution is observed in these patients when compared to those who have not been submitted to any procedure38. Only when surgical cytoreduction is minimal, there is no need for intraperitoneal chemotherapy. In this case, the option is systemic chemotherapy and palliative care39. In patients with perforated appendix and neoplastic or epithelial cells disseminated into the peritoneal cavity, prognosis will be determined by chemotherapy and cytoreduction, and not by indication of appendectomy or right colectomy; it is important to ensure free resection margins at the base of the appendix, resection of all lymph nodes in the mesoappendix and collection of all peritoneal fluid for cytology23,31,40. If the tumor is mucinous and the resection margin is posi-

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tive, the partial cecal resection is recommended, with a liner stapler cutter. The follow-up of subjects with perforated mucocele of the appendix is valid considering that mucinous tumors of the appendix are rarely disseminated through lymphatic or hematogenic pathways, and that the dissemination limited to the peritoneal cavity would be a localized disease, with healing chances. However, there is no consensus as to the follow-up model. Medical history, physical examination and CEA dose, all performed every three months, are the main follow-up measures in patients submitted to cytoreductive surgery and intraperitoneal chemotherapy. Abdominal computed tomographies are performed every 6 to 12 months, or only in cases of CEA elevation and changes observed at clinical evaluation41. The prognosis of patients with pseudomyxoma peritonei was very poor, with limited life expectancy and no chances of healing. The cytoreduction associated with hyperthermic intraperitoneal chemotherapy has reached survival rates in five years of 50% to 96%, in selected cases, when peritoneal cytoreduction is complete and there are no distant metastases41,42,43.

Resumo: A mucocele do apêndice cecal é uma doença rara. Pode ser causada por doenças benignas ou malignas que provocam a obstrução da luz do apêndice e, consequente, acúmulo de secreção mucoide. O diagnóstico pré-operatório é difícil devido ao quadro clínico inespecífico da doença. Exames de imagem sugerem o diagnóstico. O tratamento é sempre cirúrgico e é determinado pela integridade do órgão, dimensões da base e tipo histológico da lesão. O prognóstico é bom nos casos com integridade do apêndice cecal. A perfuração do apêndice e o consequente extravasamento do seu conteúdo para a cavidade abdominal pode ocasionar o pseudomixoma peritoneal, cujo prognóstico é bastante desfavorável se não tratado adequadamente. Palavras-chave: mucocele; apêndice cecal; pseudomixoma peritoneal; tratamento.

REFERENCES 1.

2. 3.

4. 5.

6.

Kim SH, Lim HK. Mucocele of the appendix: ultrassonographic and CT findings. Abdom Imaging 1998;23(3):292-6. 7. Higa E, Rosai J, Pizzimbono CA, Wise L. Mucosal hyperplasia, mucinous cystadenoma, and mucinous cystadenocarcinoma of the appendyx. A re-evalutation of appendiceal mucocele. Cancer 1973;32(6):1525-41. 8. Driman DK, Melega DE, Vilos GA, Plewes EA. Mucocele of the appendix secondary to endometriosis. Report of two cases, one with localized psedomyxoma peritonei. Am J Clin Pathol 2000;113(6):860-4. 9. Yamane YD, Yamane H, Castro Júnior PC, Marsilac A, Mesquita RB, Paulo FL. Mucolele da apêndice - relato de caso e revisão da literatura. Rev bras Coloproct 2005;25(3):256-60. 10. Fonseca LM, Sassine GCA, Luz MMP, Silva RG, Conceição SA, Lacerda-Filho A. Cistoadenoma de apêndice - relato

Rokitansky CF. A manual of pathological anatomy. Vol 2. English translation of the Vienna edition (1842). Philadelphia: Blancard and Lea, 1855:89. Woodruff R, McDonald J. Benign and malignant cystic tumors of the appendix. Surg Gynecol Obstet 1940;71:751-5. Misdraji J, Yantiss RK, Graeme-Cook FM, Balis UJ, Young RH. Appendiceal mucinous neoplasms. A clinicopathologic analysis of 107 cases. Am J Surg Pathol 2003;27(8):1089-103. Stocchi L, Wolff BG, Larson DR, Harrington JR. Surgical treatment of appendiceal mucocele. Arch Surg 2003;138:585-90. Ruiz-Tovar J, Teruel DG, Castineiras VM, Dehesa AS, Quindós PL, Molina EM. Mucocele of the appendix. World J Surg 2007;31(3):542-8.

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de caso e revisão da literatura sobre tumores mucinosos do apêndice vermiforme. Rev bras Coloproct 2008;28(1):89-94. Ronnett CM, Zahn CM, Kurman RJ, Kass ME, Sugarbaker PH, Shmookler BM. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinghishing pathologic features, site of origin, prognosis, and relationship to pseudomyxoma peritonei. Am J Surg Pathol 1995;19(12):1390-408. Sasaki K, Ishida H, Komatsuda T, Suzuki T, Konno K, Ohtaka M, et al. Appendiceal mucocele: sonographic findings. Abdom Imaging 2003;28(1):15-8. Caspi B, Cassif E, Auslender R, Herman R, Hagay Z, Appelman Z. The onion skin sign: a specific sonographic marker of appendiceal mucocele. J Ultrassound Med 2004; 23(1):117-21. Pickhardt PJ, Levy AD, Rohrmann CA Jr, Kende AI. Primary neoplasms of the appendix: radiologic spectrum of disease with pathologic correlation. Radiographics 2003;23(3):645-62. Zanati SA, Martin JA, Baker JP, Streutker CJ, Marcon NE. Colonoscopic diagnosis of mucocele of the appendix. Gastrointest Endosc 2005;62(3):452-6. Hamilton DL, Stormont JM. The volcano sign of appendiceal mucocele. Gastrointest Endosc 1989;35(5):453-6. Fujiwara T, Hizuta A, Iwagaki A, Matsuno T, Hamada M, Tanaka N, et al. Appendiceal mucocele with concomitant colonic cancer. Report of two cases. Dis Colon Rectum 1996;39(2):232-6. Zuzarte JC, Liu YC, Cohen AM. Fine needle aspiration cytology of appendiceal mucinous cystadenoma: a case report. Acta Cytol 1996;40(2) 327-30. Pahlavan PS, Kanthan R. Goblet cell carcinoid of the appendix. World J Surg Oncol 2005;3(36):1-11. Fornaro R, Frascio M, Sticchi C, De Salvo L, Stabilini C, Mandolfino F, et al. Appendectomy or right hemicolectomy in the treatment of appendiceal carcinoid tumors? Tumori 2007;93(6):587-90. Veyril N, Ata T, Muscari F, Couchard A, Msika S, Hay J, et al. Anastomotic leakage after elective right colectomy versus left colectomy for cancer: Prevalence and independent risk factors. J Am Coll Surg 2007;205(6):785-93. Gurevitch AJ, Davidovitch B, Kashtan H. Outcome of right colectomy for cancer in octogenarians. J Gastrointest Surg 2009;13(1):100-4. González Moreno S, Sugarbaker PH. Right hemicolectomy does not confer a survival advantage in patients with mucinous carcinoma of the appendix and peritoneal seeding. Br J Surg 2004;91(3):304-11. González Moreno S, Shmookler BM, Sugarbaker PH. Appendiceal mucocele. Contraindication to laparoscopic appendectomy. Surg Endosc 1998;12(9):1177-9. Navarra G, Asopa V, Basaglia E, Jones M, Jiao LR, Habib NA. Mucous cystadenoma of the appendix: is it safe to remove it by a laparoscopic approach? Surg Endosc 2003;17(5):833-4.

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26. Bucher P, Mathe Z, Demirag A, Morel P. Appendix tumors in the era of the laparoscopic appendectomy. Surg Endosc 2004;18(7):1063-6. 27. Kabbani W, Houlihan PS, Luthra R, Hamilton SR, Rashid A. Mucinous and non-mucinous appendiceal adenocarcinomas: different clinicopathological features but similar genetic alterations. Mod Pathol 2002;15(6):599-605. 28. Winawer SJ, Zauber AG, Fletcher RH, Stillman JS, O´Brien MJ, Levin B, et al. Guidelines for colonoscopy surveillance after polipectomy: a consensus update by the US MultiSociety Task Force on Colorectal Cancer and the American Cancer Society. J Clin Oncol 2006;56(3):143-59. 29. Desch CE, Benson III AB, Somerfield MR, Flynn PJ, Krause C, Loprinzi CL, et al. Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2005;23(33):8512-9. 30. Werth R. Kliniche and anastomische untersuchungen zur lehre von der bauchgeschwullsten und der laparotomy. Arch Gynecol Obstet 1884;24:100-18. 31. Dhage-Ivatury S, Sugarbaker PH. Update on the surgical approach to mucocele of the appendix. J Am Coll Surg 2002;202(4):680-4. 32. Esquivel J, Sugarbaker PH. Clinical presentation of the pseudomyxoma peritonei syndrome. Br J Surg 2000;87(10):1414-8. 33. Ortega-Perez G, Sugarbaker PH. Right psoas muscle/ aortoiliac groove recurrence: an unusual anatomic site for progression of epithelial tumors of the appendix. Int Surg 2002;87(4):212 -6. 34. Pestieau SR, Sugarbaker PH. Treatment of primary colon cancer with peritoneal carcinomatosis: comparison of concomitant vs. delayed management. Dis Colon Rectum 2000;43(10):1341-8. 35. Ito H, Osteen RT, Bleday R, Zinner MJ, Ashley SW, Whang EE. Appendiceal adenocarcinoma: long-term outcomes after surgical therapy. Dis Colon Rectum 2004;47(4):474-80. 36. Cortina R, McCormick J, Kolm P, Perry RR. Management and prognosis of adenocarcinoma of the appendix. Dis Colon Rectum 1995;38(8):848-52. 37. Stephens AD, Alderman R, Chang D, Edwards GD, Esquivel J, Sebbag G, et al. Morbidity and mortality analysis of 200 treatments with cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy using the coliseum technique. Ann Surg Oncol 1999;6(8):790-6. 38. Murphy EM, Sexton R, Moran BJ. Early results of surgery in 123 patients with pseudomyxoma peritonei from a perfurated appendiceal neoplasm. Dis Colon Rectum 2006;50(1):37-42. 39. Esquivel J, Sticca R, Sugarbaker P, Levine E, Yan TD, Alexander R, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: a consensus statement. Ann Surg Oncol 207;14(1):128-33. 40. González-Moreno S, Brun E, Sugarbaker PH. Lymph nodes metastasis in epithelial with peritoneal dissemination does

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not reduce survival in patients treated by cytoreductive surgery and perioperative intraperitoneal chemotherapy. Ann Surg Oncol 2005;12(1):72-80. 41. Verwaal VJ, Zoetmulder FAN. Follow-up of patients treated by cytoreduction and chemotherapy for peritoneal carcinomatosis of colorectal origin. Eur J Surg Oncol 2004;30(3):280-5. 42. Loungnarath R, Causeret S, Bossard N, Faheez M, SayagNeaujard AC, Brigand C, et al. Cytoreductive surgery with intraperitoneal chemohyperthermia for the treatment of pseudomyxoma peritonei: a prospective study. Dis Colon Rectum 2005;48(7):1372-9.

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Deraco M, Baratti D, Inglese MG, Allaria B, Andreola S, Gavazzi C, et al. Peritonectomy and intraperitoneal hyperthermic perfusion: a strategy that has confirmed its efficacy in patients with pseudomyxoma peritonei. Ann Surg Oncol 2004;11(4):393-8.

Correspondence to: Janduí Gomes de Abreu Filho Rua 35 Sul, Lote 9, Apto. 1204, Ed. Del Fiori CEP: 71931-180 – Águas Claras (DF), Brazil. E-mail: jgabreufilho@bol.com.br

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Original Article

Anus neoplasm: study of a case series IGOR LIMA FERNANDES1, LARICE OLIVEIRA SANTANA1, JOSÉ BATISTA DA SILVA JÚNIOR1, MARCEL MACHADO DA MOTTA1, Alex Rodrigues Moura2 Ana Carolina Lisbôa Prudente3, Juvenal da Rocha Torres Neto4 Medical Student at Universidade Federal de Sergipe (UFS) – Aracaju (SE), Brazil. 2Resident of Coloproctology at the University Hospital of UFS - Aracaju (SE), Brazil. 3Coloproctologist at the University Hospital of UFS – Aracaju (SE), Brazil. 4Professor and Head of the Coloproctology Service of UFS – Aracaju (SE), Brazil. 1

FERNANDES IL, SANTANA LO, JÚNIOR JBDS, MOTTA MMD, Moura AR, Prudente ACL, Torres Neto JR. Anus neoplasm: study of a case series. Rev bras Coloproct, 2011;31(3): 285-290. Abstract: Anus neoplasm accounts for 2 to 4% of colorectal tumors, being more prevalent around the seventh and the eighth decades. Females are mostly affected, and the ratio is 3:1. Its increased prevalence amongst the population in the past years is probably related to the higher number of people that are affected by sexually transmitted diseases, mainly human papillomavirus (types 16 and 18, mostly) and/or the human immunodeficiency virus. Diagnosis is based on clinical findings and anatomopathological tests. The treatment of choice is radiochemotherapy, and the rescue surgery with abdominoperineal resection is used for recurrence and persistence cases. A retrospective and prospective longitudinal observational study was performed with 11 patients diagnosed with anal neoplasm from 2004 to 2010. Six (54.5%) were females and five (45.5%) were males. The incidence was higher in the sixth decade, at the mean age of 54.45 years. The most frequent histological type observed was the epidermoid carcinoma, and the most frequent cell differentiation type was the moderately differentiated. Chemotharapy associated with radiotherapy was used in 81.9% of the patients, and abdominoperineal resection was necessary as a rescue surgery in 18.2% of the patients. Keywords: anus neoplasms; diagnosis; chemotherapy; radiotherapy; surgery.

INTRODUCTION

In a study conducted in Sergipe, which involved almost all databases of pathology laboratories in the State, the incidence rate ranged from 0.18 to 0.83 per 100,000 people, with mean age of 63.8 years; also, there is the proportion of 3.3 women for each man who have the anal carcinoma3. Even if some patients are asymptomatic, more than half of the anus neoplasm cases present with bleeding. Besides, other findings may be present, such as pruritus, mucus discharge, changes in bowel habit, anal pain and changes in stool diameter9,10. Since 1974, with the work conducted by Nigro, the treatment of choice for cases of anus neoplams has

The anus neoplasm is not prevalent in the population, and corresponds to 2 to 4% of the neoplasms that affect the large intestine1. It is more prevalent after the sixth decade of life, and some of the risk factors associated with the neoplasm are: infection by the human papillomavirus (HPV), subtypes 16 and 18, smoking and immunosuppression; it is also more prevalent among patients who have the human immunodeficiency virus (HIV) around the third and fourth decades of life, due to the immunologic depression2-8.

Study carried out at the Coloproctology Service of the University Hospital of Universidade Federal de Sergipe (HU-UFS), Aracaju (SE), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 05/04/2011 Approved on: 02/05/2011

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been radiotherapy associated with chemotherapy as the initial treatment, with the use of mitomycin and 5-fluorouracil; cisplatin was the alternative when mitomycim was being tested2,3,7,9,11-13. The surgical treatment with abdominoperineal resection can be used as rescue therapy2,9,11. This paper aims to study a case series of anus neoplasm with the objective to define the profile of patients who have this condition, focusing on the diagnosis and follow-up, and also showing determined tests and treatments.

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All patients were enlightened as to the objectives of the research and signed the informed consent form. This research offered no risks or extra expenses to the subject of study. The participants remained anonymous, and his right not to answer the questionnaire was assured. c. Statistical analysis: the collected data were inserted in a database system, thus being submitted to statistical analysis with the software Statistics Package of the Social Science (SPSS/PC+), version 9.0 (1998). In order to characterize the sample, simple frequency tables were used, as well the definition of median, mean and standard deviation.

SAMPLE AND METHOD Sample It is a retrospective and prospective longitudinal observational study of the case series based on two groups. Group A was comprised of all the patients who had been diagnosed with and treated for anus neoplasm from 2004 to 2008 at the Coloproctology Service of the University Hospital of Universidade Federal de Sergipe (HU/UFS); Group B was prospective and comprised of all the patients who had been diagnosed and followed-up from 2009 to 2010 in the same service. Exclusion criteria Patients who abandon the treatment/follow-up or those who could not be contacted were excluded from the study.

RESULTS Eleven patients diagnosed with anus neoplasm were analyzed. Six (54.5%) belonged to Group A, and were diagnosed before 2009; five (45.5%) belonged to Group B, and were diagnosed after 2009. Out of these, five (45.5%) were males, and six (54.5%) were females. The age of the patients ranged from 36 to 89 years, with mean age of 54.45 years median of 55 years and standard deviation ±14.45. Two (18.2%) patients were in the fourth decade of life, two (18.2%) were in the fifth decade, five (45.5%) were in the sixth decade, one (9.1%) were in the seventh decade, and one (9.1%) in the ninth decade. Mean age among females was 61 years, ranging from 48 to 89 years and standard deviation ±14.63. As to males, mean age was 50.6 years, ranging from 36 to 59 years, and standard deviation ±10.83. As to provenance, six (54.5%) patients lived in the capital, and five (45.5%) lived in the countryside. Eight patients (72.7%) had epidermoid carcinoma, 2 (18.2%) patients had cloacogenic tumor, and one (9.1%) of squamous verrucous carcinoma. Seven (63.6%) patients had anal canal neoplasm, and four (36.4%) had anal margin cancer. There were four (36.4%) cases of well differentiated carcinoma, six cases (54.5%) of moderately differentiated carcinoma and we could not obtain such information from one patient (9.1%). Bleeding was observed in seven (63.3%) patients, mucus in stool was seen in six patients (54.5%),

Method Patients in group A were analyzed by the medical records of patients who died. The living patients were contacted for a periodical review and evaluation of the studied variables. Patients in group B were prospectively analyzed with the same variables. a. Studied variables: demographic data: (age, gender, provenance); family history, data related to the tumor (histological type, topographic location, tumor differentiation, lymphatic, neural and vascular invasion, staging); data related to the treatment (type, efficacy, recurrence, complications, treating the complications); and mortality rates. b. Ethical considerations: the project was submitted to the Research Ethics Committee of UFS. 286


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NO GRテ:ICO: proctalgia was present in six patients (54.5%); dizziPrincipais Achados Clテュnicos: ness was observed in four patients (36.4%), pruritus, Sangramento: in three (27.3%), diarrhea, in three (27.3%), weight Muco nas fezes ou proctalgia: loss, in two (18.2%), and fever, in two (18.2%). Syncope, anal incontinence, purulent discharge, Tontura: anemia, Prurido ou diarreia: abdominal distention, anal mass sensation and constiPerda de Peso ou Febre: pation corresponded to one case each (9.1%). All patients (100%) presented with at least two symptoms each (Graphic 1). Anuscopy was used as the diagnostic method for all patients. Ulcerative lesion was present in four medical records (36.4%), and tumor was found in seven records (63.7%). Three patients (27.3%) had T1 tumors, four (36.3%) had T2 tumors (27.3%), one (9.1%) had T3 tumor, one (9.1%) had T4 tumor, and two (18.2%) patients had no data concerning the size of the tumor. Six patients had no lymph node compromise, one (9.1%) were in N2, one (9.1%) was in N1 and three (27.3%) had no data. One patient (9.1%) had lung metastasis. Thus, one (9.1%) was in stage I, three (27.3%) were in stage II, one (9.1%) was in stage IIIA, and one patient (9.1%) was in stage IV. Two patients (18.2%) still had not been submitted to imaging examinations, and one had T4NXMX. Two patients (18.2%) had no information concerning staging. Nine patients (81.9%) underwent radiochemotherapy. The other two patients (18.2%) are under oncologic analysis until the present time, thus not being treated. Four patients (36.4%) presented with tumor recurrence at follow-up biopsy; one of them (9.1%) had not initially adhered to the previously established treatment. Two (18.2%) underwent abdominoperineal resection for the rescue surgery, and one (9.1%) had another series of chemoradiotherapy sessions. Three patients (27.3%) with epidermoid carcinoma presented recurrence, and one (9.1%) died. There was one case of recurrence in a patient with squamous verrucous carcinoma, and recurrence was not observed in any patient with basaloid tumor (Table 1). One of the patients (9.1%) died and two patients (18.2%) were no longer followed-up.

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Main Clinical Findings 70,00% 60,00% 50,00% 40,00% 30,00% 20,00% 10,00% 0,00% Bleeding

Mucus in stool or proctalgia

Dizzinness

Pruritus or Diarrhea

Weight Loss or Fever

Graphic 1. Graphic showing the prevalence of clinical findings in patients with anus neoplams.

Table 1. Distribution as to number of recurrences per histological subtype. Staging Squamous cell carcinoma Basaloid carcinoma Squamous verrucous carcinoma Total

Follow-up Biopsy Recurrence No recurrence 3

5

0

2

1

0

4

7

intestine cancers, and 3 to 3.5% of anorectal tumors. In Sergipe, its incidence it 0.18 to 0.83 per 100,000 people/year3,10. In this study, this corresponded to 11 diagnosed patients who were followed-up at the coloproctology service of HU/UFS, which reinforces the idea that this is the least frequent tumor in the digestive tract. The low sample was a result of the low incidence and prevalence of the neoplasm, which made it difficult to effectively make the statistical analysis. The anal carcinoma is more prevalent among women, at a proportion of 1.6:1 to 5:1. In our study, data analysis confirmed the prevalence of anal carcinoma among females (54.5%), at a proportion of 1.2:12,3,14. The anal cancer is more frequent at the seventh and eighth decades of life, and the mean age reported is 63.8 years3. The most affected age group is comprised of people in the sixth decade of life. Mean age of female patients was 61 years, from 48 to 89, and stan-

DISCUSSION Anal canal neoplasm is not frequent in the gastrointestinal tract, corresponding to 1 to 2% of large 287


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that will define histological type and level of differentiation10. This routine was adopted to diagnose the lesions of all patients in the present series. Anuscopy not only defines if the lesion is anal canal or anal margin, but also describes the aspect of the lesion, which was ulcerous in four cases, and its size, which is important for staging. The size of the tumor is an important prognostic factor10. Despite the few patients in this series, the only one who had a T4 tumor was the same person who had the worst prognosis, developing recurrence after radiochemotherapy, thus being submitted to abdominoperineal resection to rescue, confirming this observation. About 50 to 60% of the patients have T1 and T2 tumors, with survival rates of 80 to 90%. In our study, 63.3% of the cases corresponded to these sizes4. The patient in stage IV (9.1%) with distant metastasis showed recurrence to radiochemotherapy, with posterior abdominoperineal resection, which shows the prognostic importance of staging10. Five of them (45.5%) presented incomplete data as to TNM grading, which is partly due to lack of information in medical records (27.3%), and also because (18.2%) these patients were still being clinically investigated. As to staging, the thoracic x-ray and the tomputed tomography of abdomen and pelvis were used. Recently, the importance of the endorectal ultrasound has been increasing, since it enables to define the level of invasion in the anal wall and to assess perirectal ganglion to define ganglion metastasis. At the moment, we still do not dispose of this examination for semiotic complement10. In spite of the liver being the most common location of distant metastasis, according to literature, the lung was the only location (9.1%) affected by dissemination in our study4. There are other important factors in prognosis, such as histological type, anemia, irradiation dose and gender. Epidermoid carcinomas have more chances of therapy failure and causes more obits than the cloacogenic subtype, which is confirmed in our study, in which three patients with squamous cell carcinoma had recurrence, and no cloacogenic presented therapy failure10. Since Nigro’s study from 1974, in which radiochemotherapy would at first be used as a neoadjuvant

dard deviation of ±14.63. As to males, mean age was 50.6 years, from 36 to 59 years, and standard deviation of ±10.83. The three patients (27.3%) aged less than 50 years were males. There are reports regarding the increased prevalence of anus neoplasm in homosexual male patients, maybe due to the association with HPV. This fact could be the cause for a higher prevalence of anus neoplasm among men than young women3,5. The increased incidence of anus neoplasm has been reported in urban centers, which was also found in our study, in which 54.5% of the patients lived in the capital10. The epidermoid carcinoma was the most common histopathological finding (72.7%), followed by two patients (18.2%) with cloacogenic tumor, and one (9.1%) with the rare variable of squamous verrucous carcinoma. This is in accordance with literature, in which the epidermoid type is more prevalent, followed by the cloacogenic tumor3,14. It is important to emphasize that we observed the squamous verrucous carcinoma in our series, which is a rare variable of the epidermoid carcinoma that can manifest as a mass that resembles a cauliflower, pale rose, at the anal margin or anal canal. Histopathological examination shows a well differentiated lesion that can invade subjacent tissues, despite being apparently benign9. The squamous verrucous carcinoma in the series was well differentiated, as demonstrated in literature. The anal canal is the most affected site, which is also in accordance with our study10. About 20% of the patients affected by the anal canal tumor are asymptomatic, and the most common clinical finding is bleeding2,10. The mass sensation and/or rectal pain correspond to 30% of the patients with neoplasm. Other findings include pruritus, anal incontinence, changes in bowel habit and mucus discharge4. No patient was asymptomatic at diagnosis. Thus, bleeding was present in 63.7% of the patients, proving to be the most common finding. Mass and/or anal pain were observed in 36.4% of the patients, as described in the review. Such symptoms and signs are also present in other conditions, such as fissure and hemorrhoid, which are important for the differential diagnosis of anal neoplasm9,10. The anus neoplasm diagnosis is based on anamnesis and physical examination. Anuscopy is essential for the diagnosis, to be confirmed by the lesion biopsy 288


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therapy for the abdominoperineal resection, until there was no residual lesion in the response, the treatment with 5-fluorouracil and mitomycim with radiotherapy became essential to resolve anal neoplasm, thus going through changes with time as to doses and number of radiochemotherapy sessions9,10,12,13. Such therapy was used for 9 (81.9%) patients, thus becoming the treatment of choice. The other two cases (18.2%) are still in oncologic evaluation. The role of the rescue surgery for a recurrent or persistent disease is still relevant, besides the palliative care for the anus neoplasm. Two (18.2%) out of the three patients who presented with recurrence underwent abdominoperineal resection2,11. Predisposing factors for anal tumor are usually infection by HPV subtypes 16 and 184,5,8. Thus, detecting and eliminating HPV clinical and subclinical lesions may provide better prognosis and prevent the tumor from becoming malignant15. Genetic studies may be used in the future to track patients who are more prone to anal canal and anal margin neoplasm. Studies have tried to establish the relation between genetic changes and anus neoplasm. Such studies showed the increased expression of 143-3σ, inhibitor regulator of p53 in its association with anus neoplasm. However, there is no relation between this protein and p53, or the association of the neoplasm with p1616,17. A significant part of the medical records had incomplete data as to staging, although the patients had been properly staged at diagnosis, undergoing radiochemotherapy. The need to computerize the information of medical records is urgent, so that important

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data concerning the patients’ follow-up cannot be lost. Since we are dealing with a university hospital, such fact makes it difficult to access the information and conduct scientific work. The American Joint Committee on Cancer (AJCC) observes that “the classification and the staging of cancer enable doctors and cancer registers to stratify the patients, which will lead to better decisions as to treatment and the development of a common language”; this organizes the assistance to patients and the therapy of choice, analyzing prognosis, enabling the professionals to change experiences and assess therapy results18. CONCLUSION • • • •

• •

Seven patients were diagnosed with anal canal câncer, and four were diagnosed with anal margin câncer; It was more prevalent among females in relation to males; The incidence peak was during the sixth decade of life; The most frequent histological type was epidermoid carcinoma, followed by the cloacogenic carcinoma. The rare squamous verrucous carcinoma was found; The moderately differentiated level was present in 54.5% of the cases, and the well differentiated level was found in 36.4% of the cases; Radiochemotherapy was the most used technique, and the abdominoperineal resection was necessary as a rescue therapy in 18.2% of the patients.

Resumo: Neoplasias do ânus correspondem de 2 a 4% dos tumores de intestino grosso, sendo predominante nas sétima e oitava décadas. A maior prevalência é em gênero feminino, com proporção de 3:1. O aumento da prevalência na população nos últimos anos provavelmente está relacionado ao número maior de pessoas com doenças sexualmente transmissíveis, principalmente o papilomavírus humano (tipos 16 e 18, mais comumente) e/ou o vírus da imunodeficiência humana. O diagnóstico é feito a partir de achados clínicos somados ao exame anatomopatológico. O tratamento de escolha baseia-se na radioquimioterapia, sendo a cirurgia de resgate com amputação abdominoperineal utilizada para casos de recidiva ou persistência. Foi feito um estudo observacional longitudinal retrospectivo e prospectivo, com 11 pacientes diagnosticados com neoplasia anal no período de 2004 a 2010. Seis (54,5%) eram do gênero feminino e 5 (45,5%) do masculino. O pico de incidência foi em sexta década, com média de idade de 54,45 anos. O tipo histológico mais encontrado foi o carcinoma epidermoide (72,7%), sendo o moderadamente diferenciado o mais frequente grau de diferenciação. A quimioterapia associada à radioterapia foi instituída em 81,9% dos pacientes, sendo necessária a cirurgia de amputação abdominoperineal como terapia de resgate em 18,2% dos pacientes. Palavras-chave: neoplasias do ânus; diagnóstico; quimioterapia; radioterapia; cirurgia.

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Anus neoplasm: study of a case series Igor Lima Fernandes et al.

REFERENCES 1.

Nadal SR, Calore EE, Cruz SHA, Horta SHC, Manzione CR, Bin FC, et al. Comparação das contagens das células de Langerhans de tecidos contendo carcinoma anal em doentes com e sem infecção pelo HIV. Rev Bras Coloproct 2006;26(3):269-74. 2. Santos Jr JCM. Câncer ano-retal-cólico - aspectos atuais: I câncer anal. Rev Bras Coloproct 2007;27(2):219-23. 3. Torres-Neto JR, Prudente ACL, Santos RL. Estudo demográfico do câncer de canal anal e ânus no estado de Sergipe. Rev Bras Coloproct 2007;27(2):190-5. 4. Uronis HE, Bendell CJ. Anal cancer: an overview. Oncologist 2007;12(5):524-34. 5. Frisch M, Glimelius B, Van den Brule AJ, Wohlfah J, Meijer CJ, Wallboomers JM, et al. Sexually transmitted infection as a cause of anal cancer. N Engl J Med 1997;337(19):1350-8. 6. Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med 2000;342(11):792-800. 7. Dallan LAP, Cruz SHA, da Rosa DL, Bin FC, Nadal SR, Capelhuchnik P, et al. Avaliação dos resultados do tratamento de 14 doentes de carcinoma espinocelular anal. Rev Bras Coloproct 2005;26(1):34-40. 8. Nakamura RA, Ferrigno R, Salvajoli JV, Nishimoto IN, David Filho WJ, Lopes A. Tratamento conservador do carcinoma do canal anal. Rev Col Bras Cir 2005;32:23-31. 9. Keighley M, Williams N. Cirurgia do ânus, reto e colo. 1st ed. São Paulo: Manole, 1998. 10. Soares WGP. Radioquimioterapia no câncer de canal anal: avaliação de 12 pacientes. Sergipe, 2002. 11. Rodrigues MRS, Magi JC, Corrêa RS, Guerra GMLSR, Souza

12.

13.

14.

15. 16.

17.

18.

HFS, Fonseca MFM, et al. Cirurgia de resgate no carcinoma de canal anal. Rev Bras Coloproct 2004;24(2):137-9. Nigro ND, Vaitkevicius VK, Considine BJR. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974;17(3):354-6. Charnley N, Chouldhury A, Chesser P, Cooper RA, SebagMontefiore D. Effective treatment of anal cancer in the elderly with low-dose chemoradiotherapy. Br J Cancer 2005;92(7):1221-5. Larangeira LLS, Andrade SKV. Incidência do carcinoma de canal anal na Regional de Saúde de Londrina (PR). Rev Bras Coloproct 2004;24(3):240–6. Nadal SR, Manzione CR. Papilomavirus humano e o câncer anal. Rev Bras Coloproct 2006;26(2):204-7. Roma AA, Goldblum JR, Fazio V, Yang B. Expression of 143-3σ, p16 and p53 proteins in anal squamous intraepithelial neoplasm and squamous cell carcinoma. Int J Clin Exp Pathol 2008;1(5):419-25. Contu SS, Agnes G, Damin AP, Contu PC, Rosito MA, Alexandre CO, et al. Lack of correlation between p53 codon 72 polymorphism and anal cancer risk. World J Gastroenterol 2009;15(36):4566-70. Greene FL. Cancer staging handbook from the AJCC cancer staging manual. 6th ed. Springer-Verlag (NY): Springer Science + Business Media; 2004.

Correspondence to: Juvenal da Rocha Torres Neto Rua Ananias Azevedo Nº 100, apto. 902, Praia 13 de Julho CEP: 49020-080 – Aracaju (SE), Brazil. E-mail: jtorres@infonet.com.br

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Case Report

Temporary ileostomy for the preservation of colon fistula in patients with postoperative complications: case report SOLAINE CHIMINÁCIO DE OLIVEIRA PATRÍCIO1, ALCIDES JOSÉ BRANCO FILHO2, ANA CARLA BROETTO BIAZON3 Pharmacist – Biochemist; Post-graduate student in Clinical Analysis of the Laboratory of Clinical Analyses at the Pharmacy Department of Faculdade Integrado de Campo Mourão – Campo Mourão (PR), Brazil. 2Specialist Doctor in General Surgery and Trauma at Universidade de São Paulo (USP) – São Paulo (SP), Brazil. 3Pharmacist – Biochemistry; Professor of the postgraduation course in Clinical Analysis of Faculdade Integrado de Campo Mourão – Campo Mourão (PR), Brazil. 1

PATRÍCIO SCDO, FILHO AJB, BIAZON ACB. Temporary ileostomy for the preservation of colon fistula in patients with postoperative complications: case report. Rev bras Coloproct, 2011;31(3): 291-293. Abstract: Among the postoperative complications in the digestive system, the fistulae are the most common ones. The changes resulting from these fistulae are very important, once they can determine the patient’s situation and the development of multiple organic failures. This paper reports the case of a patient who had relevant complications after having undergone temporary ileostomy to maintain the colon fistulized. About 90 to 95% of the digestive tract fistulae have spontaneous resolution. In some cases, the general state of the patient compromises the spontaneous closure. In this study, after one month of nutritional support and medicine treatment, the spontaneous closure of the colon fistula did not occur, thus, a surgical intervention was necessary to solve the case. Keywords: gastric fistula; ileostomy; gastroplasty.

INTRODUCTION

tulae, peritonitis; toxic megacolon, perforation or digestive fistula3. The postoperative fistula represents more than 90% of all intestinal fistulae, and is usually one of the main complications related to surgery of the digestive system4. Mortality rates resulting from the complications related to intestinal fistulae are still high, ranging from 6.5 to 48%, against the mean of 2% obtained from elective surgical procedures5. The fistulae that drain 500 mL or more of digestive secretions every 24 hours are considered as highdebt. Spoliation is determined by these great losses,

Ileostomy is defined as the opening of the ileal segment in the patient’s abdomen, under general anesthesia, aiming to deflect the stool to the external side. Ileostomies can be classified as temporary or loop, and also as definite or terminal. They are usually placed on the right lower abdominal quadrant1. Different situations may require ileostomy, such as deformities or bowel blockage, bleeding, infection or ulcers due to small bowel inflammation; cancer, pre-cancerous polyps2; extensive lesions, perianal fis-

Study carried out at the Laboratory of Clinical Analyses of the Pharmacy Department of Faculdade Integrado de Campo Mourão – Campo Mourão (PR), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 25/02/2010 Approved on: 24/05/2010

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and causes important hydroelectrolytic and nutritional impacts. These losses are easily compensated with low-debt fistulae5. The treatment of digestive fistula, especially high-debt fistulae, is a complex procedure which demands multi-professional work, besides specific and dynamic conducts. Clinical and surgical measurements add up in different stages of the treatment towards the final objective, that is, to obtain the closure of the fistula and achieve the patient’s full recovery5. Intra-abdominal infection is still the factor that is more likely to compromise the prognosis. In this situation, early surgical intervention is essential to decrease mortality rates. Studies show a 90% mortality rate in patients who presented with sepsis and malnutrition4. Parenteral nutrition can speed up the nonoperative closure of high-debt fistulae, and, in case the fistula has not healed after four to six weeks of parenteral nutrition, it is unlikely to heal without surgery6. In this context, the objective of this study is to discuss the case of a patient who presented with relevant complications after a temporary ileostomy to preserve the fistulized colon, and the intervention measurements that were used to resolve the case.

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1.14 mg/dL (normal: 0.0-0.7 mg/dL); aspartate aminotransferases (AST) 36.0 U/L (normal: 15-37 U/L); alanine aminotransferases (ALT) 168.0U/L (normal: 30-65 U/L); gamma glutaryl transferases (GGT) 341 U/L (normal: 15-85 U/L); glucose 98 mg/dL (normal: 70-110 mg/dL); negative hemoculture. After one month of parenteral nutrition and sepsis control with broad spectrum antibiotics and octreotide to decrease gastric secretion, the fistula did not close spontaneously. The case was surgically resolved after the ileostomy removal. After this intervention, the patient fully recovered in approximately 60 days. DISCUSSION The presence of the septic focus is always seen as an aggravating factor that needs to be rapidly identified, since it has a direct relation with the severity of the disease. In this case, the patient presented with sepsis due to the abdominal collection drained by the chronic gastric fistula. Despite the patient’s general state, the choice for laparotomy was based on data from the literature which describe that, in such situations, the risk of surgery is lower than not undergoing surgery, since it avoids the development of multiple organic failures5. Many complications may occur during the drainage of the abdominal abscess, such as the perforation of organs and the risk of infection. In the studied case, the abscess adhered to the colon, and the drainage caused its perforation. The colon fistula can close spontaneously or by surgical intervention. Thus, ileostomy was performed to deflect the bowel transit in order to prevent the aggravation of the abdominal contamination, aiming at the spontaneous closure of the fistula’s path. Generally, 90 to 95% of the digestive fistulae are spontaneously resolved, and the closure takes place four to five weeks after the infection is eradicated4. According to Torres et al., when the sepsis is controlled within one month, the rate of spontaneous closure is 48%, while the rate of spontaneous closure is 6%4 for those patients whose sepsis has never been controlled. In this case, besides sepsis, the patient’s general state also compromised the spontaneous closure of the fistula; after the picture improved, surgical intervention was necessary to resolve the case.

CASE REPORT A 33 year-old male patient with chronic gastric fistula post-gastroplasty, sleeve type, was submitted to drainage of the abdominal abscess, which resulted in colon fistula, diagnosed with the radiologic examination. In order to preserve the fistulized colon, a temporary ileostomy was performed. After seven days of hospital stay, the patient was discharged and received nutritional guidance. Five days later, the patient suddenly presented with severe dehydration, persistent diarrhea, jaundice and fever, being admitted to an emergency unit. The results of the laboratory examinations performed during hospital stay were: hematocrit 37% (normal: 36-52%); total leukocytes 20,190/mm3 with no deflection to the left (normal: 4,000-10,000/mm3); sodium 116 mmol/L (normal: 140-14 mmol/L); potassium 5.50  mmol/L (normal: 3.50-4.50 mmol/L); creatinine 3.86 mg/dL (normal: 0.6-1.3 mg/dL); total bilirubin 3.90 mg/dL (normal: 0.0-1.0 mg/dL); direct bilirubin 2.76 mg/dL (normal: 0.0-0.3 mg/dL); indirect bilirubin 292


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The use of different drugs to control the infection and to restore the organic functions of the patient resulted in hepatotoxicity, which was observed by changes in the liver function. Alterations in bilirubins, especially of the direct fraction, are compatible with the obstruction of the bile ducts, as well as changes in the GGT enzyme. Jaundice is also a consequence of sepsis5. ALT also presents altered values, which demonstrates hepatocyte injuries. Hundreds of drugs have been pointed out as possible causes of liver lesion, be it a result of direct or indirect toxicity, probably hepatocytic, cholestatic or mixed7,8. However, after the resolution of the case, such liver alterations were controlled, which demonstrates the absence of a pathology that would be directly related to the liver. The patient presented with hyponatremia, which could be explained by the massive liquid loss due to

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the diarrhea caused by ileostomy. In these situations, total body sodium low, and this characterizes hypotonic hypovolemia7. On the other hand, potassium levels were high, probably due to the changes in renal function, demonstrated by the serum creatinine exam test. Laboratory changes such as leukocytosis and the increased creatinine, followed by jaundice and fecer, are compatible with sepsis5. The negative hemoculture was considered a result of the continuous use of antimicrobials. The treatment of a complicated fistula is long and requires the work of a multidisciplinary team. Future studies should dedicate some attention to drugs and therapies that could improve the healing of such fistulae, thus, enabling an earlier hospital discharge and preventing the occurrence of hospital infections.

Resumo: Dentre as complicações pós-operatórias do aparelho digestório, as fístulas apresentam alta incidência. As alterações decorrentes dessas fístulas são muito importantes, pois podem determinar o agravamento do estado geral do paciente e o desenvolvimento de insuficiências orgânicas múltiplas. O presente trabalho relata o caso de um paciente com complicações relevantes após a realização de uma ileostomia temporária para preservação do cólon fistulizado. A maioria (90-95%) das fístulas do trato digestório tem resolução espontânea; entretanto, em alguns casos, o estado geral do paciente compromete o fechamento espontâneo. No caso em estudo, após um mês de suporte nutricional e tratamento medicamentoso, o fechamento espontâneo da fístula de cólon não ocorreu, sendo necessária a intervenção cirúrgica para resolução do caso. Palavras-chave: fístula gástrica; ileostomia; gastroplastia.

REFERÊNCIAS

5.

1. Araujo SEA, Seid VE. Definições e técnicas de estomas intestinais (acesso em 01 de setembro de 2009). Disponível em: http://www.colorretal.com.br/conteudocompleto. asp?cidconteudo=137. 2. Ressecção do intestino delgado (acesso em 15 de julho de 2009). Disponível em: http://adam.sertaoggi.com.br/ encyclopedia/ency/article/002943.htm. 3. Formiga GJS. Ileostomia continente com preservação da papila íleo-cecal. Acta Cir Bras [online]. 2000;15(Suppl 1):20-3. 4. Torres OJM, Salazar RM, Costa JVG, Corrêa FCF, Malafaia O. Fístulas enterocutâneas pós-operatórias: análise de 39 pacientes. Rev Col Bras Cir 2002;29(6):359-63.

6. 7. 8.

Jorge Filho I. O papel da UTI no tratamento das fístulas entéricas. Medicina, Ribeirão Preto. 1998;31(4):568-76. Towsend CM. Sabiston: Tratado de cirurgia. 17ª ed. Rio de Janeiro: Editora Elsevier, 2005. Prado FC. Atualização terapêutica. 22ª ed. São Paulo: Editora Artes Médicas, 2005. Henry JB. Diagnósticos clínicos e tratamentos por métodos laboratoriais. 2ª ed brasileira. São Paulo: Editora Manole, 1999.

Correspondence to: Ana Carla Broetto Biazon Rodovia BR 158, Km 207, Batel CEP: 87300-970 – Campo Mourão (PR), Brazil. Email: acbbiazon@uol.com.br

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Case Report

Sigmoidoanal intussusception with exteriorization of sigmoid adenocarcinoma PEDRO ROBERTO DE PAULA1, MARIA AUXILIADORA PROLUNGATTI CÉSAR2, EDUARDO FORTES DE ALBUQUERQUE3, FERNANDA PEREZ ADORNO DA SILVA4 Assistant Professor and Doctor of the Medicine Department of Universidade de Taubaté; Head of the Coloproctology Service of the University Hospital of Taubaté – Taubaté (SP), Brazil. 1Assistant Professor and Doctor of the Medicine Department of Universidade de Taubaté; Head of the Anal Physiology Service of the University Hospital of Taubaté – Taubaté (SP), Brazil. 3Ex-Resident of general surgery at the University Hospital of Taubaté – Taubaté (SP), Brazil. 4 Medical student at Universidade de Taubaté – Taubaté (SP), Brazil.

1

PAULA PR; CÉSAR MAP; ALBUQUERQUE EF; SILVA FPA. Intussuscepção sigmoidoanal com exteriorização de adenocarcinoma de sigmoide. Rev bras Coloproct, 2011;31(3): 294-298. Abstract: The intestinal intussusception is a rare disease in adults, and is mostly caused by malignant neoplasm. Symptoms are usually nonspecific and chronic, and in most cases suggesting intestinal obstruction. Treatment consists of removing the malignant tumor. This article reports the case of a patient with hematochezia and apparent mass in the anus who underwent anterior rectosigmoidectomy and had the diagnosis of adenocarcinoma of the sigmoid confirmed. Keywords: intestinal intussusception; colon adenocarcinoma; proctocolectomy.

INTRODUCTION

ma in 80% of the cases. Among adults, the disease is frequently secondary to the organic cause, which makes the preoperative diagnosis difficult; it is usually confirmed during laparotomy. The diagnosis is based on surgical findings. However, imaging tests and minimally invasive procedures can be useful, such as the simple abdominal x-ray, contrast examinations, colonoscopy, ultrasonography and computed tomography (CT)5. In 80 to 90% of the cases, neoplasm can be considered as the main organic cause for intussusceptions in adults, in which 68% of the large intestine is a result of the malignant disease, and, among these, 62% are adenocarcinomas. The opposite happens to the small intestine, since its main etiology consists of benign tumors1,4.

Intestinal intussusception is rare among adults, corresponding to 5% of all cases and 1% of intestinal obstructions; it is more common among infants. It occurs when the proximal bowel segment (intussuscepts) penetrates the distal segment lumen (intussuscepted)1,2. It was first described by Barbette de Amsterdam, in 1674, and Jonathan Hutchinson performed the first surgical reduction in 18713. The symptoms of intussusception in adults, unlike for children, are usually nonspecific and chronic, mostly suggesting intestinal obstruction4. Among infants, it is mostly primary and benign, and the treatment consists of the reduction with ene-

Financing source: none. Conflict of interest: nothing to declare. Submitted on: 01/02/2010 Approved on: 22/03/2010

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The treatment of choice for malignant colon neoplasm is the removal of the tumor and all tissues involved in the angiolymphatic drainage, which are the main dissemination paths for these tumors 6. We reported a rare case in which the â&#x20AC;&#x153;headâ&#x20AC;? of the invagination, which was formed by malignant sigmoid neoplasm, was exteriorized by the anus.

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We report the case of a 50-year-old black female patient that had been presenting with hematochezia for nine months, which was independent from evacuations; also, for six months she had been noticing the exteriorization of a mass in the anal region during the effort to evacuate, thus being necessary to digitally reduce it. She also presented with abdominal pain with moderate colic at the left flank and hypogastrium before evacuating. She had diarrhea intercalated with dry stool. She was regularly taking laxatives every three days. She lost 16 kg in the past eight months. Proctocological examination showed: (a) inspection: absence of skin tags, tumors, fistulous orifice and prolapse; (b) rectal touch: normotonic/hypotonic sphincter, identifying the presence of a tumor mass in the anterior wall, approximately 9 cm to the anal margin; (c) rectosigmoidoscopy: presence of vegetating friable lesion in the anterior wall, with 6 cm in diameter, approximately 9 cm from the anal margin

(after biopsy); it moved upwards with the movement of the device. An abdominal and pelvic CT scan showed a target image in the rectosigmoid region, which suggested a loop inside a loop (Figure 1). The colonoscopy confirmed the presence of a vegetating lesion of the sigmoid, hard with friable surface 20 cm from the anal border. The lesion was blocking 90% of the light and preventing the entrance of the device. A new biopsy was conducted and showed the presence of a tubular pattern adenocarcinoma with strong atypia. The patient was admitted for surgery and underwent a radical anterior upper rectosigmoidectomy, with primary manual termino-terminal anastomosis. At intraoperative, a vegetating sigmoid tumor of about 7.0x5.0 cm was observed, which was invaginated within the sigmoid and the rectum, thus allowing its exteriorization through the anus (Figure 2). The presence of a main ganglion was identified, with 2 cm in diameter, hard and located at the emergency of the inferior mesenteric artery. The anatomopathological examination of the resected piece showed that the lesion was microscopically infiltrated to the serous and, out of the 17 dissected lymph nodes in the pericolic adipose tissue, only one was compromised. It was close to the inferior mesenteric artery (main ganglion) (Figures 3 and 4). The patient evolved without intercurrences, and was discharged from the hospital on the third postoperative day.

Figure 1. Pelvic computed tomography showing lesion in the rectal region (target image).

Figure 2. Vegetating tumor of the sigmoid exteriorized through the anus.

CASE REPORT

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Figure 3. Surgical piece with tumor lesion and the main affected ganglion.

Figure 4. Histological bowel cut showing the invasion by neoplastic cells to the serous, affecting blood and lymphatic vessels.

DISCUSSION

plications, such as ischemia or intestinal perforation, they are contraindicated. Ultrasonography is the choice due to the accuracy to diagnose intussusceptions, both for adults and for children, showing the “target” image or the “onion skin” in the cross-sectional view, and the “pseudokidney sign” or “double kidney” in the longitudinal view, which may not be pathognomonic, but very suggestive5. Abdominal and pelvic CT have also been important for the preoperative diagnosis of this condition1,5. The density of the mass generated by the compromised segment, which is associated to the edema of the intestinal wall and the mesenteric, creates a characteristic signal in the CT, which is also called the “target sign”1. However, the tomography is not reliable concerning the differentiation between neoplasm and the nonspecific thickening of the intestinal wall. Besides, this examination is still limited since it is not available in all the emergency services and due to the need of contrast administration5. Colonoscopy may help in cases of colonic obstruction. The comparison between the different examinations in order to define the diagnosis, such as x-ray, ultrasound, barium studies, colonoscopy and CT, shows that CT is the test with the most diagnostic sensitivity, proving to be efficient and 88.6% more recommended to diagnose intussusceptions among adults12,13. Our patient was investigated with colonoscopy and tomography, which confirmed the intussusception and its

Intussusception can usually be classified according to the compromised intestinal segment; it can be called enteric (small intestine), ileocolic (penetration of the ileum in the ileocecal valve), ileocecal (when the ileocecal valve is the intussusception point), colocolic (colon) and colorectal4. In the studied case, the sigmoid was exteriorized through the anal orifice. The general clinical Picture is variable, but abdominal pain is the most common symptom, present in 100% of the studied cases2,5,7-9. Other symptoms are nausea, vomit, hematochezia, changes in intestinal habit, distension and palpable abdominal mass10,11. However, the abdominal mass is not a common finding related to intussusceptions among adults, occurring in 7 to 42% of the cases2,7. In the studied case, the patient presented with moderate abdominal pain before evacuating and at the moment of digital reduction of the mass that was exteriorized through the anus, hematochezia and changes in the intestinal habit. The certain diagnosis is based on surgical findings. However, imaging tests and minimally invasive procedures can be useful in cases like this, in which the diagnosis can be established before surgery. Simple contrast abdomen x-rays, ultrasonography, abdominal CT scan and colonoscopy can reveal the segment that is affected by the disease1. Barium studies like intestinal transit and enema may help the diagnosis; however, in cases of com296


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etiology. It was possible to perform the preoperative abdominal staging. The treatment for the intussusceptions in adults demands an individual and systematic approach. Laparotomy is mandatory, once it can identify an organic lesion that could be neoplastic. The theoretical possibility to implant malignant cells indicates the resection of the lesion. The need and the extension of this resection are controversial, since there is the risk of an unnecessary intestinal resection2,7. In cases of colocolonic intussusceptions, it is necessary to resect the segment with an oncologic purpose due to the high risk of malignity2,7,14, which could be observed in this study; we had already diagnosed the sigmoid adenocarcinoma, and the patient presented a sigmoido-anal insussusception. She was submitted to a radical rectosigmoidectomy, which was essencial, since the main lymphatic ganglion had metastatic compromise, in the root of the inferior mesenteric artery. As to the surgical approach, laparoscopy performed by a trained team can be used with several advantages; however, the conventional path is still more common15. In this case, the conventional approach was used, and the patient did not present with any postoperative complication, being discharged early. Nowadays, the patient has finished the chemotherapy cycles, and is asymptomatic The incidence of colorectal malignant neoplasm, which is the main organic cause of intussusception, has been increasing in Brazil and represents the fifth most common cause of death by cancer16. It is more frequent among white males, especially those aged more than 40 years, with mean age of 60 and 70 years17,18.

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In this case, the patient was female, black, at the fifth decade of life, and her age was within the prevalent age group. The malignant lesions of the colon are adenocarcinomas in 95% of the cases, more commonly located in the rectosigmoid segment, which can be observed in the present case, in which the patient had a tumor affecting the sigmoid, which was the “head” of the invagination, that presented as a mass that was exteriorized by the anal canal17,18. At the postoperative staging of the disease proposed by Dukes, which considers the tumor depth in the intestinal wall and the compromise of regional lymphatic ganglia, the case was classified as Dukes C for presenting a compromised regional lymphatic ganglion2,13. Imperfections in this classification system led to the creation of new classifications; TNM is the most appropriate and the most used one, even though its accuracy is around 65%, which leads to a flaw when estimating the evolution of patients11,13. The stage of our patient was T3 N1 M0, stage IIIa. The involvement of lymphatic nodules is considered to be the most important discriminating factor when related to the short survival of patients13,19,20. FINAL CONSIDERATIONS Intussusception is a rare condition, and, in this case, the “head” of the invagination was formed by a malignant sigmoid neoplasm, which was exteriorized through the anus. It was diagnosed at the preoperative period by anamnesis, and confirmed by colonoscopy with biopsy and CT. The treatment was a radical surgery.

Resumo: A intussuscepção intestinal é uma doença rara em adultos, sendo na maior parte dos casos causada por neoplasia maligna. Os sintomas são geralmente inespecíficos e crônicos, na maioria das vezes sugerindo obstrução intestinal. O tratamento consiste na remoção oncológica do tumor. Este artigo relata o caso de uma paciente com quadro de hematoquezia e exteriorização de massa através do ânus que foi submetido à retossigmoidectomia anterior alta em bloco e confirmado o diagnóstico de adenocarcinoma de sigmoide. Palavras-chave: intussuscepção intestinal; adenocarcinoma de cólon; protocolectomia.

REFERENCES 1.

2.

Wang N, Cui XY, Liu Y, Long J, Xu YH, Guo RX, et al. Adult intussusception: a retrospective review of 41 cases. World J Gastroenterol 2009;15(26):3303-8.

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Yakan S, Calıskan C, Makay O, Denecli AG, Korkut MA. Intussusception in adults: Clinical characteristics, diagnosis and operative strategies. World J Gastroenterol 2009;15(16):1985-9. Butte BJM, Iniguez CA, Torres MJ. Intususcepción de colon por lipoma. Rev Chi Cir 2006;58(2):151-4.


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4. Marinis A, Yiallourou A, Samanides L, Dafnios N, Anastasopoulos G, Vassiliou I, et al. Intussusception of the bowel in adults: a review. World J Gastroenterol 2009;15(4):407-11 5. Korkmaz O, Yilmaz HG, Taçyildiz HH, Akgün Y. Intussusception in adults. Ulus Travma Acil Cerrahi Derg 2009;15(2):154-8. 6. Gordon PH, Nivatvongs S. Principles and practice of surgery for the colon, rectum, and anus. 2nd ed. Missouri: Quality Medical Publishing; 1999. p. 900-1097. 7. Dell’abate P, Del Rio P, Sommaruga L, Arcuri MF, Sianesi M. Laparoscopic treatment of sigmoid colon intussusception by large malignant tumor. Case report. G Chir 2009;30(89):374-6. 8. Zissin R, Gayer G, Konen O, Shapiro-Feinberg M. Transient colocolic intussusception. J Clin Imaging 2000;24(1):8-9. 9. Chen CF, Chuang CH, Lu CY, Hu C, Kuo TL, Hsieh JS. Adult intussusception secondary to lymphangioma of the cecum: a case report. Kaohsiung J Med Sci 2009;25(6):347-52. 10. Martin-Lorenzo JG, Torralba-Martinez A, Liron-Ruiz R. Intestinal invagination in adults. Int J Colorectal Dis 2004;19(1):68-72. 11. Warshauer DM, Lee JKT. Adult intussusception detected at CT or MR imaging: clinical-imaging correlation. Radiology 1999;212(3):853–60. 12. Pisano G, Manca A, Farris S, Tatti A, Atzeni J, Calò PG. Adult idiopathic intussusception: a case report and review of the literature. Chir Ital 2009;61(2):223-9. 13. Chang CC, Chen YY, Chen YF, Lin CN, Yen HH, Lou HY. Adult intussusception in Asians: clinical presentations, diagnosis and treatment. J Gastroenterol Hepatol 2006;22(11):1767-71.

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14. Hanan B, Diniz TR, da Luz MM, da Conceição SA, da Silva RG, Lacerda-Filho A. Intussusception in adults. Colorectal Dis 2010;12(6):574-8. 15. Chuang CH, Hsieh CB, Lin CH, Yu JC. Laparoscopic management of sigmoid colon intussusception caused by a malignant tumor: case report. Rev Esp Enferm Dig 2007;99(10):615-6. 16. Priolli DG, Cardinalli IA, Piovesan H, Margarido NF, Martinez CAR. Proposta para estadiamento do câncer colorretal baseada em critérios morfofuncionais. Correlação com níveis séricos do antígeno carcinoembrionário. Rev Bras Coloproct 2007;27(4):374-83. 17. Cruz GMG, Santana JL, Santana SKAA, Constantino JRM, Chamone BC, Ferreira RMRS, et al. Câncer colônico epidemiologia, diagnóstico, estadiamento e gradação tumoral de 490 pacientes. Rev Bras Coloproct 2007;27(2):139-53. 18. Roediger WEW. Estadiamento TNM. Trad. Marcio Constantino Mimessi. 6a ed. São Paulo: Fundação Oncocentro de São Paulo; 2006. p. 347-59. 19. Mahmoud N, Rombeau J, Ross HM, Fry RD. Colon e reto. In: Sabiston DC. Tratado de Cirurgia: a base biológica da moderna prática cirúrgica. Rio de Janeiro: Elsevier; 2005. p. 1443-66 20. Araújo PHJ, Rangel MF, Batista TP. Intussuscepção íleocólica em adulto. Rev Bras Coloproct 2008;28(4):470-3. Correspondence to: Dr: pedro roberto de paula. Rua Santo Antonio nº 45, Centro CEP: 12080-440 – Taubaté (SP), Brazil. E-mail: pedrordepaula@hotmail.com

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Giant schistosomal granuloma mimicking rectum neoplasia – case report LUIZ EDUARDO CORREIA MIRANDA1, EDUARDO CARVALHO2, DIEGO LAURENTINO LIMA3 Adjunct Professor of Abdominal Surgert at Faculdade de Ciências Médicas of Universidade de Pernambuco (UPE) – Recife (PE), Brazil. 2Doctor of the Endoscopy Service at Hospital Geral Octávio de Freitas – Recife (PE), Brazil. 3Medical student at Faculdade de Ciências Médicas of UPE – Recife (PE), Brazil. 1

MIRANDA LEC, CARVALHO E, LIMA DL. Giant schistosomal granuloma mimicking rectum neoplasia – case report. Rev bras Coloproct, 2011;31(3): 299-300. Abstract: We report the case of a young man from an area where schistosomiasis is endemic, in the state of Pernambuco, who presented with hemorrhage. Initially diagnosed as rectum neoplasia, subsequent investigation demonstrated rectal giant schistosomal granuloma. The diagnoses and clinical aspects of the case are discussed in this study. Keywords: schistosomiasis; granuloma; neoplasm; rectum; general surgery.

INTRODUCTION

Phisical examination: abdomen was flat, not tender, no masses, no hepatomegalies or splenomegalies. No clinical findings were related to hepatic insufficiency or portal hypertension. His blood tests were normal, except for mild microcytic anemia and eosinophilia. Colonoscopy demonstrated a mass measuring from 3 to 4 cm, bleeding in the anterior rectal wall, 6 cm from the anal margin (Figure 1); Pathological report showed chronic rectal mucosa inflammation and granulomas consisting of epithelioid cells and some nucleus Langhans giant cells, involving eggs with long lateral spine, which suggested rectal schistosomal granuloma (Figure 2). Patient was treated with praziquantel and colonoscopy after 90 days showed the clinical resolution of the granuloma.

Schistosomiasis mansoni is a chronic infection caused by the direct contact with fresh water that contains cercaria, the larval form of the parasite. The disease is endemic in Brazil, being prevalent in the Northeast region and spread to the West and South; there are serious consequences to the people who are infected1. Hyperplastic manifestations of schistosomiasis are uncommon and may present in different clinical forms, including the pseudotumoral form. In this paper, we report the case of a rectal schistosomal pseudotumor. CASE REPORT A 24-year-old man presented symptoms of constipation for a long period and rectal bleeding for one month. He denied using any type of medication, as well as weight loss, anorexia, hematemesis, jaundice or fever. He comes from an endemic area of schistosomiasis, and did not present with acute suffering.

DISCUSSION The pseudotumoral form of schistosomiasis mansoni has hyperplastic manifestations in which the egg of the parasite (antigen) causes exaggerated response,

Study carried out at the University Hospital Oswaldo Cruz – Recife (PE), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 08/02/2010 Approved on: 19/09/2010

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Figure 2. Rectal giant schistosomal granuloma.

cal symptoms to schistosomal proctocolitis, abdominal pain, nausea, tenesmus, mucous-bloody diarrhea and transrectal bleeding2. Santana and Lima1 described a schistosomal granuloma of the colon in the descending sigmoid junction, simulating malignant neoplasm. Lantsberg et al.5 described the rectal pseudotumor of an Ethiopian man who presented with rectal bleeding and received praziquantel after the disease was diagnosed by a rectal biopsy. The conclusion is that the diagnosis of the pseudotumoral form of schistosomiasis should be considered for patients who come from endemic areas for schistosomiasis with rectal mass. Praziquantel heals 60 to 90% of these patients, and endoscopic findings may induce to a diagnostic error of rectal neoplasm.

Figure 1. Large and fragile lesion in the anterior rectal wall 6 cm from the anal margin.

with a granulomatous inflammatory reaction2. The schistosomal granuloma is the most uncommon type of hyperplastic manifestation3. The incidence in the intestinal form of schistosomiases are more frequent in the rectum, sigmoid and descending colon. Differential diagnosis of granuloma are adenocarcinoma, sarcoma, polyps, tuberculosis and lymphoma. The chronic disease is caused by a granulomatous inflammation that occurs in response to the deposit of eggs in the tissue4. The clinical presentation of the intestinal form of the schistosomal granuloma may vary from dyspepti-

Resumo: Nós relatamos o caso de um homem, jovem, proveniente de uma área endêmica para esquistomossomose, no Estado de Pernambuco, e que apresentou hematoquezia. Inicialmente diagnosticado como neoplasia do reto, a investigação subsequente demonstrou um granuloma esquistossomótico gigante do reto. O diagnóstico e os aspectos clínicos do caso são discutidos. Palavras-chave: esquistossomose; granuloma; neoplasia; reto; cirurgia geral.

REFERÊNCIAS 1. 2.

3. 4.

5.

Santana HJ, Lima CA. Pseudotumor esquistossomótico de cólon – Relato de um caso. Rev bras Coloproct 1985;5(1):17-21. Kalil M, Battisti Netto O, Vieira LCA, Cintra LC. Forma pseudotumoral intra-abdominal da esquistossomose mansônica. Ver Col Bras Cir [Internet] 2006 Mai-Jun; 33(3). Available from: http://www.scielo.br/rcbc Prata A. Esquistossomose mansoni. In: Doenças infecciosas e parasitárias. 6ª ed. Rio de Janeiro: Guanabara-Koogan; 1976. Neto JB. Manifestações hiperplásicas da esquistossomose

mansônica. J Bras Med 1983;45(5):37-40. Lantsberg L, Khodadadi J, Krugliak P. Schitosomal granuloma mimicking adenocarcinoma of the rectum. J Clin Gastroenterol 1987;9(4):489-90.

Correspondence to: Luiz Eduardo Correia Miranda Serviço de Cirurgia Geral e Transplante de Fígado Rua Arnóbio Marques, 310 CEP: 50100-130 – Recife (PE), Brazil. E-mail: lecmiranda@gmail.com

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Pyoderma gangrenosum as a initial manifestation of ulcerative proctocolitis CARLA BORTOLIN FONSECA1,2, GUILHERME LANG MOTTA1,2, ALEXANDRE RAMPAZZO1, JOÃO CARLOS CANTARELLI JUNIOR1,2, RENATO BORGES FAGUNDES2,3 University Hospital of Universidade Federal de Santa Maria (UFSM) – Santa Maria (RS), Brazil. 2Departament of Medical Clinic/Center of Health Sciences of UFSM – Santa Maria (RS), Brazil. 3Post Graduation Program: Gastroenterology Sciences of the Medical School at Universidade Federal do Rio Grande do Sul (UFRGS) – Porto Alegre (RS), Brazil.

1

FONSECA CB, MOTTA GL, RAMPAZZO A, JUNIOR JCC, FAGUNDES RB. Pyoderma gangrenosum as a initial manifestation of ulcerative proctocolitis. Rev bras Coloproct, 2011;31(3): 301-305. Abstract: pyoderma gangrenosum is a rare inflammatory skin condition characterized by progressive and recurrent skin ulceration of destructive course. It is usually associated with rheumatoid arthritis, paraproteinemia, myeloproliferative diseases and inflammatory bowel diseases, especially non-specific ulcerative proctocolitis. In these situations, skin lesions are described as concurrent with the intestinal condition. However, reports on pyoderma gangrenosum preceding intestinal findings are less frequent. The authors describe a case of a woman with febrile condition associated with skin lesions diagnosed by biopsy as pyoderma gangrenosum. Two weeks later, she developed diarrhea, arthralgia and sepsis, being diagnosed as ulcerative proctocolitis. After the administration of the treatment for ulcerative proctocolitis, she showed improvements in sepsis care, remission of diarrhea and regression of skin lesions. This case highlights the importance of considering pyoderma gangrenosum as a manifestation associated with inflammatory bowel disease, regardless of its timing in relation to intestinal symptoms. Keywords: pyoderma gangrenosum; proctocolitis; pyoderma; colitis.

INTRODUCTION

have inflammatory bowel disease (IBD), especially the severe forms of unspecified ulcerative proctocolitis (UUP)8,9. PG affects people at any age group, especially young women with proctocolitis and diffuse compromise of the entire colon10,11. It can appear in any part of the body, but is mostly described in the inferior limbs, especially the lower third of the legs. The skin lesion usually manifests during the two first years of inflammatory bowel disease, being more prevalent during the periods of UUP clinical exacerbation12. Skin lesions that precede the onset of the intestinal picture are a less frequent situation13. The authors report the case of a patient with severe UUP whose initial manifestation was the pyoderma gangrenosum, preceding diarrhea in two weeks.

Pyoderma gangrenosum (PG) is a type of inflammatory skin condition of unknown origin characterized by progressive and recurrent skin ulceration of destructive course1-3. Dermatosis is usually unpredictable, sudden and aggressive, but it can also be chronic, slow and insidious, presenting skin ulcers that expand centrifugally4. The aggressive form may cause painful ulcerative lesions, with necrotic and hemorrhagic base5. It is associated with systemic disease in about 50% of the cases, such as rheumatoid arthritis, inflammatory bowel disease, paraproteinemia and myeloproliferative disease6,7. It is described as one of the extraintestinal manifestations for the patients who

Study carried out at the University Hospital of Universidade Federal de Santa Maria, Santa Maria (RS), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 22/12/2010 Accepted on: 16/02/2011

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CLINICAL CASE

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days prior to the first visit. At the doctor’s appointment, the patient was given antithermic drugs; skin lesions were biopsied. The anatomopathological examination of the lesions showed superficial and deep diffuse dermatitis with the prevalence of neutrophils (Figure 3) and epidermal ulceration, which are compatible with pyoderma gangrenosum and evidence of deep abscesses in the subcutaneous tissue (Figure 4). Two weeks after, she started presenting liquid diarrhea without mucus, suppuration or blood, followed by vomit and persistent fever. She reported the ingestion of untreated water, but denied having contact with sick people, trips, previous medications, insect bi-

A white 46-year-old female patient, who was previously healthy, presented with a 38.5ºC fever and skin lesions in the face, limbs and vulva, characterized as deep and painful ulcers, with necrotic purulent center and small hemorrhagic blisters (Figures 1 and 2), five

Figure 1. Deep ulcer with necrotic purulent center and hemorrhagic blisters on the face.

Figure 3. Superficial diffuse dermatitis with an inflammatory process at base, and deep dermatitis with the prevalence of neutrophils, compatible with PG - hematoxylin-eosin (H&E) 5x.

Figure 4. Deep skin inflammation and presence of abscesses in the subcutaneous tissue – H&E 5x and H&E 3x.

Figure 2. Deep ulcer with necrotic purulent center on the right hand.

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Figure 5. Colonoscopy showing edema, hyperemia and erosions throughout the colons, which is compatible with the active inflammatory bowel disease.

Figure 6. Colonic mucosa with architectural distortion. Detail: gland bifurcation, criterion of a chronic inflammatory process (H&E 20x).

tes and similar cases in the family. She was admitted at the hospital and submitted to complementary examinations, with the following results: hemoglobin 7.4 g/dL, leukocytes 22500/mm3, band cells 7232/mm3, segmented 12,430/mm3; parasitological examination of stools without evidence of intestinal parasites or their evolutive forms. Fecal leukocytes test was positive (++). At coproculture, gram positive cocci were prevalente. The Widal reaction was negative. Right after admission, diarrhea had mucus and blood, and the patient started reporting arthralgia of the knees. On the seventh day after admission, she evolved to a septic picture and was transferred to the intensive care unit. Then, antibiotic therapy and support measurements were performed, including oxacilin and imipenem. The abdominal computed tomography showed a general distension of loops and thickening of the right colonic wall. Colonoscopy showed edema, hyperemia, erosions and pseudopolyps throughout the colon, compatible with inflammatory bowel disease (Figures 5 and 6). The treatment also consisted of prednisone, mesalamine and azathioprine, with the respective daily doses: 40 mg, 3 g and 100 mg. The patient showed improvements, reduction in the number of evacuations, no more blood and mucus in the stool and gradual regression of skin lesions. She was discharged from the hospital 30 days after the treatment for UUP started. Seven months after discharge, on mesalamine and azathioprine, the patient had regular intestinal habits and full remission of the skin lesions.

DISCUSSION Pyoderma gangrenosum is believed to be the skin manifestation of several systemic diseases. It is associated with: rheumatoid arthritis, myeloproliferative diseases, liver disease, monoclonal gammopathy, Wegener’s granulomatosis, diabetes mellitus and inflammatory bowel disease14. In approximately 50% of the cases, no associated disease can be identified, thus being called idiopathic pyoderma. Among the systemic diseases, IBD is the most frequently found, corresponding to 27% of the cases15. About 20% of the patients who present with skin lesions suggestive of PG can have IBD16. According to other data, the established relation is 0.5 to 5%8,9. The relation between between PG and the extension, length and severity of IBD is controversial. PG is a relatively rare extraintestinal presentation of ulcerative proctocolitis, and its incidence ranges from 2 and 12%17,18,19, affecting both genders and all age groups. It is also associated with Chron’s disease, however, the prevalence of such association is lower than the one observed for ulcerative proctocolitis20,21. It is believed that PG occurs due to a reaction against antigens of bowel disease. The presence of bacterial antigens in the bowel lumen and their absorption through the affected colonic mucosa could trigger and continue a local and systemic inflammatory reaction, which would be a result of the stimulation of cells in the immune system and 303


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of the production of proinflammatory cytokines22,23. The existence of an antigenic relation between bacterial antigens and the colonic mucosa, biliary tract, skin and/or joints would turn these organs into real “target antigens”, which would explain the different manifestations24,25. Deficiencies in immunoglobulin synthesis, the production of an inhibitory factor for mast cells, neutrophil dysfunction and skin allergies can also be involved8,5. In most cases described in literature, PG presents during the active bowel disease12. Bowel symptoms precede or are concomitant with PG, and exacerbations of the disease can be usually related with worse skin lesions26. However, PG can occur in any stage of the disease, at the absence of active inflammation, even after total colectomy24,27,28. In the described report, skin manifestations preceded the diagnosis of ulcerative proctocolitis in two weeks. PG preceded the intestinal picture in the described report, which reinforces how important it is to correlate both pathologies in order to conduct an early diagnosis.

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Clinically, PG may be presented in four types: classic, pustulous, bullous and vegetative29. The patient had the classic type, characterized by deep and painful ulcer, with violaceous border and necrotic purulent center. This type usually affects the legs, but it can also reach the head, neck and the genitalia13, which was the case for this patient. When PG is associated with IBD, the therapy should be directed to the bowel disease, whose remission is followed by the clinical improvement of the skin lesion30. It is also important to have extra local hygiene care to avoid the secondary infection15. CONCLUSION It is essential to consider the presence of IBD in patients with pyoderna gangrenosum, even at the absence of gastrointestinal symptoms, so that it is possible to have an early diagnosis. Thus, the treatment can be rapidly administered to avoid the development of the disease and further complications.

Resumo: Pioderma gangrenoso é uma forma de inflamação cutânea, caracterizada por ulceração progressiva e recorrente da pele, com curso destrutivo. Geralmente é associada à artrite reumatoide, paraproteinemia, doenças mieloproliferativas e doença inflamatória intestinal, em especial retocolite ulcerativa inespecífica. Em tais casos, as lesões cutâneas são descritas concomitantes ao quadro intestinal, porém, relatos com descrição de pioderma gangrenoso precedendo achados intestinais são menos frequentes. Os autores relatam caso de mulher com quadro febril associado a lesões cutâneas diagnosticadas por biópsia como pioderma gangrenoso. Duas semanas depois, apresentou diarreia, artralgia e sepse sendo diagnosticada retocolite ulcerativa. Com o tratamento para retocolite ulcerativa apresentou melhora do quadro séptico, remissão da diarreia e regressão das lesões cutâneas. Este caso enfatiza a importância em considerar o pioderma gangrenoso como manifestação associada à doença inflamatória intestinal, independente de sua temporalidade em relação aos sintomas intestinais. Palavras-chave: pioderma gangrenoso; proctocolite; pioderma; colite.

REFERENCES 1.

2.

3.

4.

5.

Schwaegerle SM, Bergfeld WF, Senitzer D, Tidrick RT. Pyoderma gangrenosum: a review. J Am Acad Dermatol 1988;18(3):559-68. Owell FC, Su WP, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol 1996;34(3):395-409. Tromm A, May D, Almus E, Voigt E, Greving I, Schwegler U,Griga T. Cutaneous manifestations in inflammatory bowel disease. Z Gastroenterol 2001;39(2):137-44. Brunsting LA, Goeckerman WH, O’Leary PA. Pyoderma (echtyma) gangrenosum. Clinical and experimental observations in five cases occurring in adults. Arch Derm Syphilol 1930;22:655-80.

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Houli J, Netto, Gumercindo M. Retocolite ulcerativa inespecífica. Bras Colo-Proct 1984;4(4):191-205. Powell FC, O’Kane M. Management of pyoderma gangrenosum. Dermatol Clin 2002;20(2):347-55. Su WP, Davis MD, Weenig RH, Powell FC, Perry HO. Pyoderma gangrenosum: clinico-pathologic correlation and proposed diagnostic criteria. Int J Dermatol 2004;43(11):790-800. Futami H, Kodaira M, Furuta T, Hanai H, Kaniko E. Pyoderma gangrenosum complicating ulcerative colitis: Successful treatment with methylprednisolone pulse therapy and cyclosporine. J Gastroenterol 1998;33(3):408-11. Mir-Madjlessi SH, Taylor JS, Farmer RG. Clinical course and evolution of erythema nodosum and pioderma gangrenosum in chronic ulcerative colitis: A study of 42 patients. Am J Gastroenterol 1985;80(8):615-20.


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10. Menachem Y, Gotsman I. Clinical manifestations of pyoderma gangrenosum associated with inflammatory bowel disease. Isr Med Assoc J 2004;6(2):88-90. 11. Tromm A, May D, Almus E, Voigt E, Greving I, Schwegler U, et al. Cutaneous manifestations in inflammatory bowel disease. Z Gastroenterol 2001;39(2):137-44. 12. Restrepo AJ, Farfán YQ, Angarita O, Cifuentes S, Hormaza N, Marulanda JC, et al. Ulcerative colitis associated with cutaneous manifestations. Rev Colomb Gastroenterol 2006;21(4):300-5. 13. Callen JP. Pyoderma gangrenosum. Lancet 1998;351(9102):581–5. 14. Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 1998;115(1):182-205. 15. Martinez CAR, Priolli DG, Ramos RFB, Nonose R, Schmidt KH. Complete remission of gangrenous pyoderma after total colectomy in patient with ulcerative colitis. Arq Méd ABC 2005;30(2):106-10. 16. Powell FC, Schroeter AL, Su WP, Perry HO. Pyoderma gangrenosum: a review of 86 patients. Q J Med 1985;55(217):173-86. 17. Bennett ML, Jackson JM, Jorizzo JL, Fleischer Jr AB, White WL, Callen JP. Pyoderma gangrenosum. A comparison of typical and atypical forms with an emphasis on time to remission. Case review of 86 patients from 2 institutions. Medicine (Baltimore) 2000;79(1):37-46. 18. Veloso FT, Carvalho J, Magro F. Immune-related systemic manifestations of inflammatory bowel disease. A prospective study of 792 patients. J Clin Gastroenterol 1996;23(1):29-34. 19. López San Román A, Bermejo F, Aldanondo I, Carrera E, Boixeda D, Muñoz Zato E. Pyoderma gangrenosum associated with ulcerative colitis: response to infliximab. Rev Esp Enferm Dig 2004;96(6):420-2; 422-4. 20. Weiner SR, Clarke J, Taggart NA, Utsinger PD. Rheumatic manifestations of inflammatory bowel disease. Semin Arth Rheum 1991;20:353–66. 21. Bernstein CN, Blanchard JF, Rawsthorne P, Yu N. The prevalence of extraintestinal diseases in inflammatory bowel

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disease: a population-based study. Am J Gastroenterol 2001;96(4):1116-22. Barbieri D. Inflammatory bowel disease. J Pediatr 2000;76(Supl.2):s173-s80. Veloso FT. Review article: skin complications associated with inflammatory bowel disease. Aliment Pharmacol Ther 2004;20(Suppl. 4):50–3. Cabral VLR, Miszputen SJ, Catapani WR. Antineutrophil cytoplasmic antibody (ANCA) in pyoderma gangrenosum, a serologic marker for associated systemic diseases: a study of eight cases. An Bras Dermatol 2004;79(1). Chowdhury SMZ, Broomhead V, Spickett GP, Wilkinson R. Pitfalls of formalin fixation for determination of antineutrophil cytoplasmic antibodies. J Clin Pathol 1999;52(6):475-7. Souza CS, Chiossi MPV, Takada MH, Foss NT, Roselino AMF. Pioderma gangrenoso: casuística e revisão de aspectos clínico-laboratoriais e terapêuticos. Ann Bras Dermatol 1999;74(5):465-72. Sheldon DG, Sawchuk LL, Kozarek RA, Thirlby RC. Twenty cases of peristomal pyoderma gangrenosum diagnostic implications and management. Arch Surg 2000;135(5):564-8. Levitt MD, Ritchie JK, Lennard-Jones JE, Phillips RKS. Pyoderma gangrenosum in inflammatory bowel disease. Br J Surg 1991;78(6):676-8. Ruocco E, Sangiuliano S, Gravina AG, Miranda A, Nicoletti G. Pyoderma gangrenosum: an updated review. JEADV 2009;23(9):1008–17. Souza CS, Chiossi MPV, Takada MH, Foss NT, Roselino AMF. Pioderma gangrenoso: casuística e revisão de aspectos clínico-laboratoriais e terapêuticos. An Bras Dermatol 1999;74(5):465-72.

Correspondence: Renato B. Fagundes, MD, PhD Avenida Grécia 1000, ap. 1002 B Passo d’areia – CEP: 91350-070 Porto Alegre (RS), Brazil. E-mail: fagundesrb@gmail.com

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PANDINI, LC. Summary Rev bras Coloproct, 2011;31(3):306-307.

Hjern F, Wolk A, Hakansson N. Smoking and the risk of diverticular disease in women. Br J Surg 2011;98(7):997-1002.

trothermal bipolar sealers (ligasureTM) and two types of ultrasonic shear devices (Harmônico ACE® and Harmônico LotusTM). The surgical specimens submitted to colorectal laparoscopic resection were selected for each of the devices. After the removal of surgical specimens, eight or more mesenteric vessels were “ex vivo” dissected and sealed with the studied devices. Vessel sealing was tested for the maximum rupture pressure, and the depth of the thermal lesion was assessed by the pathologist. A total of 93 vessels from 18 selected patients were analyzed (LotusTM n=33; harmônico ACE® n=30; ligasureTM n=30), with the average of 6 vessels (1 to 8) per surgical specimen, mean diameter of 1.06 (0.70) mm, and vascular wall thickness of 0.29 (0.19) mm. The mean pressure of vascular rupture was 1,170, 1,470 and 1,510, with LotusTM , harmônico ACE® and ligasureTM, respectively (p=0.058). The depth of the thermal lesion was significantly increased with ligasureTM (3.37) mm than with LotusTM (2.18) mm or harmônico ACE® (1.95) mm (p<0.001). The authors conclude that the three instruments are equally good to seal vessels with pressure of vascular rupture that is higher than physiological values of blood pressure.

This retrospective study was conducted to investigate the association between smoking and colonic diverticular disease. In this study, 35,809 Swedish female smokers who were born between 1914 and 1948 were analyzed, and followed-up from 1997 to 2008. Relative risks (RRs) of symptomatic diverticular disease (resulting in hospital admission or death) related to smoking were estimated by specific statistical models. Out of the 35,809 women in this study, 561 (1.6%) presented symptomatic diverticular disease. In a multivariable analysis, smokers have an increased risk for symptomatic diverticular disease (perforation and abscess) compared to those who do not smoke, after adjustment as to age, fiber diet, diabetes, arterial hypertension and use of aminosalicylate, nonhormonal anti-inflammatory, corticosteroids, alcohol consumption, body mass index, physical activity and schooling. Former smokers also presented increased risk. The authors conclude that smokers are at high risk of developing symptomatic diverticular disease in comparison to those who do not smoke.

Maurer CA, Renzulli P, Kull C, Käser SA, Mazzucchelli L, Ulrich A, Büchler MW. The impact of the introduction of total mesorectal excision on local recurrence rate and survival in rectal cancer: long-term results. Ann Surg Oncol 2011;18(7):1899-906.

Noble EJ, Smart NJ, Challand C, Sleigh K, Oriolowo A, Hosie KB. Experimental comparison of mesenteric vessel sealing and thermal damage between one bipolar and two ultrasonic shears devices. Br J Surg 2011;98(6):707-800.

The objective of this retrospective study was to investigate the influence of the introduction of total mesorectal excision on local recurrence and survival rates of patients submitted to rectal cancer surgery. This study analyzed 171 patients submitted to

This study compared the sealing ability of mesenteric vessels with three devices in colorectal surgical specimens. The sealing instruments adopted were the elec306


Journal of Coloproctology July/September, 2011

Special Sessions Luis Claudio Pandini

abdominoperineal amputation or anterior resection. Group 1 (1993-1995, n=53) consisted of patients who underwent conventional surgery, and group 2 (19952001, n=118) had patients who were submitted to total mesorectal excision. All surgeries were performed by the same team. All patients were followed-up for seven years or until death. Total local recurrence rate was 11 out of 53 (20.8%) in group 1, and 7 out of 118 (5.9%) in group 2. The isolated recurrence rates were 6 out of 53 (11.3%) in group 1, and 2 out of 118 (1.7%) in group 2. Both differences were statistically significant. The disease-free survival rates in groups 1 and 2 were 60.4 and 65.2% in 5 years, and 58.5 and 65.3% in 7 years, respectively. After the exclusion of patients with metachronous or synchronous distant metastasis, disease-free and cancer-specific survival rates were significantly higher in group 2. There were no significant differences in both groups as to global survival. The authors conclude that the introduction of total mesorectal excision resulted in the expressive reduction of local recurrence rates. Survival rates are mainly determined by the occurrence of distant metastasis, but total mesorectal excision has improved the survival of patients without the systemic disease.

Vol. 31 Nº 3

of both groups. The authors conclude that postoperative complications or long-term survival rates were not better after the preoperative bowel preparation.

Frasson M, Garcia-Granero E, Roda D, FlorLorente B, Roselló S, Esclapez P, et al. Preoperative chemoradiation may not always be needed for patients with T3 and T2N+rectal cancer. Cancer 2011;117(14):3118-25. The objective of this study was to assess the factors that influence the recurrence of patients with rectal cancer and clinical staging of T2 tumor and positive ganglia (cT2 N+) or (cT3NO/N+) who were submitted to radical surgery without preoperative chemoradiation. From 1997 to 2008, the authors staged 398 patients with rectal cancer in the preoperative period by using endorectal ultrasound and/or magnetic resonance. The analysis included 152 patients with cT2 NT, cT3 No or cT3 N+ rectal cancer who underwent radical surgery with total mesorectal excision and without preoperative chemoradiation. Macroscopic evaluation of total mesorectal excision and the resection of the lateral margin were determined. Factors that are potentially related to local recurrence (LR) were analyzed, such as diseasefree survival (DFS) and cancer-specific survival (CSS). The results showed that, after the mean follow-up of 39 months, LR, DFS and CSS rates were 9.5, 65.4 and 77.8%, respectively. Rectal fascia compromise at preoperative staging was the only independent factor that influenced the increased risk of LR (p=0.007), lower DFS (p=0.007) and lower CSS (p=0.05). Local recurrence rate in five years for patients with and without a compromised resection of the lateral margin was 19.4 and 5.4%, respectively. The authors conclude the results in this study suggest that patients with rectal cancer who are clinically staged as T3 N+ or T2 N+, with free distal edge >2 mm for the rectal fascia, may undergo radical surgery with total mesorectal excision, in order to avoid preoperative chemoradiation.

Nicholson GA, Finlay IG, Diament RH, Molloy RG, Horgan PG, Morrison DS. Mechanical bowel preparation does not influence outcomes following colonic cancer resection. Br J Surg 2001;98(6):866–71. The objective of this retrospective study was to compare long-term survival rates and surgical complications in patients who have or have not received mechanical bowel preparation for colon cancer surgery. This study analyzed 1,730 patients who underwent potentially healing colon cancer surgery. Out of the total, 1,460 patients (84.4%) had bowel preparation. The mean follow-up was 3.5 years (1-6,7). There was no statistical difference as to the complications in the postoperative period of 30 days and in survival rates

307


Services accredited by SBCP for the improvement in coloproctology Hospital Universitário C. Fraga Filho - UFRJ Reg. Mec. 124 Av. Brigadeiro Trompowsky - Ilha do Fundão 21941-590 - Rio de Janeiro - RJ Tel: (21) 2562-2010 - ramal 2719

Fundação Ensino Superior Vale do Sapucai Hospital das Clínicas Samuel Libânio Rua Comendador José Garcia, 777 36540-000 - Pouso Alegre - MG Tel: (35) 3422-2345

Hospital Universitário Pedro Ernesto - UERJ Reg. Mec 153 Av. 28 de Setembro, 77 20551-030 - Rio de Janeiro - RJ Tel: (21) 2587-6100

Hospital Ernesto Dornelles Av. Ipiranga, 1801 96160-093 - Porto Alegre - RS Tel: (51) 3217-2002 Hospital Nossa Senhora da Conceição Av. Francisco Trein, 596 91350-200 - Porto Alegre - RS Tel: (51) 3341-1300

Hospital de Ipanema Reg. Mec 156 Rua Antonio Parreiras, 69 - Ipanema 22411-020 - Rio de Janeiro - RJ Tel: (21) 3111-2379

Hospital Barão de Lucena Av. Caxangá, 3860 - Iputinga 50731-000 - Recife - PE Tel: (81) 3453-3566

Hospital dos Servidores do Estado Reg. Mec 160 Rua Sacadura Cabral, 178 - Saúde 22221-161 - Rio de Janeiro - RJ Tel: (21) 2291-3131

Hospital das Clínicas - UFCE Rua Capitão Francisco Pedro, 1290 60430-370 - Fortaleza - CE Tel: (85) 3243-9117

Hospital da Lagoa Reg. Mec 162 Rua Jardim Botânico, 501 22470-050 - Rio de Janeiro - RJ Tel.: (21) 3111-5100

Irmandade da Santa Casa da Misericórdia de São Paulo Departamento de Cirurgia Rua Cesário Mota Junior, 112 01221-020 - São Paulo - SP Tel.: (11)224-0122

Hospital Naval Marcílio Dias Reg. Mec 171 Rua César Zama, 185 - Lins de Vasconcelos 20725-090 - Rio de Janeiro - RJ Tel: (21) 2599-5599 - ramal 5648 / 5428

Pontifícia Universidade Católica de Campinas Rodovia D. Pedro I, Km 136 13020-904 - Campinas - SP Tel. (19)3252-0899 / 3729-8600

Hospital Heliópolis Reg. Mec 210 Rua Cônego Xavier, 276 Vila Heliópolis 04231-030 - São Paulo - SP Tel. (11) 2274-7600 (ramal 244)

Hospital Municipal Miguel Couto - Rio Rua Mário Ribeiro, 157 - Leblon 22430-160 - Rio de Janeiro - RJ Tel. (21) 2274-6050 Santa Casa de Belo Horizonte Grupo de Colo-Proctologia de Belo Horizonte Av. Francisco Sales, Praça Hugo Werneck, s/nº 30150-300 - Belo Horizonte - MG Tel. (31) 3238-8131

Hospital Universitário da Faculdade de Medicina PUC RS - Serviço de Coloproctologia Av. Ipiranga, 6690 90610-000 - Porto Alegre - RS Informações: COREME tel. 3339-1322 Ramal 2378 Tel: (51) 3320-3000 Hospital Clínicas da Universidade Federal do Paraná Rua Gal. Carneiro, s/n 80060-150 - Curitiba - PR Tel: (41) 3360-1800

Hospital das Clínicas Faculdade de Medicina da Universidade de São Paulo - SP Av. Dr. Eneas de Carvalho Aguiar, 255 Cerqueira Cesar 05403-000 - São Paulo - SP Tel. (11)3069-6000 308


Journal of Coloproctology July/September, 2011

Services accredited by SBCP for the improvement in coloproctology

Hospital do Andaraí Rua Leopoldo, 280 - 2º andar -Andaraí 20541-170 - Rio de Janeiro - RJ (21) 2562-2719

Hospital de Base do Distrito Federal S M H S , 101 BL. A Setor Hospitalar Sul 70335-900 - Brasília - DF Tel. (61) 3325-5050

Hospital Municipal São José Av. Getúlio Vargas, 233 89202-001 - Joinville - SC (47) 3441-6666

Real e Benemérita Sociedade Portuguesa de Beneficência Hospital São Joaquim Rua Maestro Cardim, 769 01323-001 - São Paulo - SP Tel: (11) 3253-5022

Hospital Geral de Goiânia Dr. Alberto Rassi Av. Anhanguera , 6379 - Setor Oeste 74043-011 - Goiânia - GO Tel: (62) 3221-6031

Hospital Universitário Evangélico de Curitiba Al. Augusto Stellfeld, 1908 80730-150 - Curitiba - PR Tel. (41) 3222-0727 / 3322-4141

Santa Casa de Misericórdia - Fortaleza - CE Serviço de Coloproctologia Rua Barão do Rio Branco, 1816 60025-061 - Fortaleza - CE Tel: (85) 3211-1911

Hospital do Servidor Público Estadual de São Paulo – “FMO” Serviço de Gastroenterologia Cirúrgica e Coloproctologia Rua Pedro de Toledo, 1800 - 11º andar - Ala Central 04029-000 - São Paulo - SP Tel. (11) 5088-8117 / 5088-8119

Hospital do Serviço Público Municipal - SP Serviço de Coloproctologia Rua Castro Alves nº 60 - Liberdade 01532 - São Paulo - SP Tel: (11) 3208-2211

Hospital Geral Roberto Santos MEC/CNRM - PARECER Nº 98/99 Est. do Saboeiro, S/N - Cabula 41180-780 - Salvador - BA Tel. (71) 3372-2849

Hospital Nossa Senhora das Graças Serviço de Coloproctologia Rua Alcides Munhoz, 433 - Mêrces 80810-040 Curitiba - PR Tel: (41) 3240-6706 Fax. (41) 3240-6500

Centro de Colo-Proctologia do Ceará Av. Pontes Vieira, 2551 (2º andar) 60130-241 - Fortaleza - CE Tel. (85) 3257-6588 - 257-7728

Serviço de Coloproctologia Hospital das Clínicas da Faculdade de Medicina Universidade Federal de Goiás 1ª Avenida, s/nº 74650-050 - Goiânia - GO Tel.: (62) 3202-1800 ramal 1094 - COREME Tel.: (62) 3202-4443

Hospital de Base da Faculdade de Medicina de São José do Rio Preto Av. Brigadeiro Faria Lima, 5416 15090-000 - São José do Rio Preto - SP Tel. (17) 3201-5000 Hospital Felício Rocho Av. Contorno, 9.530 30110-130 - Belo Horizonte - MG Tel. (31) 3339-7142

Hospital Universitário Prof. Alberto Antunes Av. Lourival Melo Mota, s/n Tabuleiro do Martins 57072-900 - Maceió - AL Tel.: (82) 3322-2494

Hospital de Jacarepaguá Av. Menezes Cortes, 3245 20715-190 - Rio de Janeiro - RJ Tel. (21) 2425-2255 - R. 200 Hospital Sírio Libanês CNRN / MEC Nº 23/2002 Rua Dona Adma Jafet, 91 01308-050 - São Paulo - SP Tel. (11) 3155-0200

Vol. 31 Nº 3

Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP Av. Bandeirantes, 3900 14048-900 - Ribeirão Preto - SP Tel. (16) 3602-1000 / 3602-2509 309


Journal of Coloproctology July/September, 2011

Services accredited by SBCP for the improvement in coloproctology

Hospital Universitário da Universidade Federal de Sergipe Rua Cláudio Batista s/nº Sanatório 49060-100 - Aracajú - SE Tel. (79) 3218-1738

Hospital São Rafael Serviço de Coloproctologia Av. São Rafael, 2152 - São Marcos 41256-900 - Salvador - BA Tel.: (71) 3281-6400

Hospital das Clínicas -UFMG Instituto Alfa de Gastroenterologia Av. Prof. Alfredo Balena, 110 , 2º andar Sta. Efigênia 30130-100, Belo Horizonte, MG Tel. (31) 3248-9403 / (31) 3248-9251

Vitória Apart Hospital Serviço de Coloproctologia Rod. BR 101 Norte Km 2 - Carapina 29101-900 - Serra - ES Tel.: (27) 3201-5555

Vol. 31 Nº 3

Hospital Municipal Dr. Mário Gatti Serviço de Coloproctologia Av. Prefeito Faria Lima, 340 - Parque Itália 13036-902 - Campinas - SP Tel.: (19) 3772-5700

Clínica Reis Neto Rua General Osório, 2273 12025-155 - Cambuí - Campinas - SP Tel.: (19) 3252-5611 Hospital Universitário Cajuru - Serviço de Coloproctologia Reg. Mec. Parecer 43/06 Av. São José, 300 80050-350 - Cristo Rei - Curitiba - PR Tel.: (41) 3271-3009

Serviço de Coloproctologia Hospital de Clínicas de Porto Alegre Universidade Federal do Rio Grande do Sul Rua Ramiro Barcelos, 2.350 / sala 600 CEP: 90035-903 - Porto Alegre - RS Tel.: (51) 3359-8232

We require the Coloproctology services that have medical residency or internships related to this specialty to send their program and schedule to the Society, so they can be publicized. This section will be available to publicize rules and dates of selection. Minimum program to be accredited by the Brazilian Society of Coloproctology Staff – Participation of at least two full members of SBCP. Surgeries – Monthly mean of at least three colorectal surgeries and six anoperineal surgeries. Ambulatory – Monthly mean of at least 50 appointments. Endoscopies – Monthly mean of at least 20 rectosigmoidoscopies and five colonoscopies. Available supporting units: Radiology, pathological anatomy, endoscopy, clinical analysis laboratory, ICU, Oncology, Radiotherapy, Statistical and Medical Files. Teaching – a) Weekly meetings of the service to discuss cases and also published articles; b) To estimulate the production of scientific papers to be presented at the annual congress of the Brazilian Society of Coloproctology and possible publication in the SBCP journal; c) To send at least one original article per year for possible publication in the SBCP journal. 310


Journal of Coloproctology, Vol 31 N 3  

Jul/Sep 2011

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