Autopsy & Case Reports by Editora Cubo

ISSN 2236-1960

v.3, n.1, jan./mar. 2013

Autopsy and Case Reports 2013; 3(1): 1-4

Editorial

Dr. Dorfman legacy to pathology: beyond Rosai-Dorfman disease Maria Claudia Nogueira Zerbinia Zerbini MCN. Dr. Dorfman legacy to pathology: beyond Rosai-Dorfman disease [editorial]. Autopsy Case Rep [Internet]. 2013;3(1): 1-4. http://dx.doi.org/10.4322/acr.2013.001

Credit to Stanford School of Medicine.

Ronald F. Dorfman (1923-2012), an Emeritus Professor of Pathology at the Stanford University School of Medicine, had significant input in advancing the study of diseases of hematopoietic cells and the lymph nodes, which included identifying a disease that has been named after him. Dr. Dorfman was one of the founders of the field of Hematopathology, and, with Dr. Costan Berard, founded the Society of Hematopathology in 1981, serving as its president from 1982 through 1984, and published a classification of non-Hodgkin lymphomas in 1974,1 which was a variant of the Rappaport classification.2 a

Dr. Dorfman was born in Johannesburg, South Africa, on March 14, 1923 and studied medicine at the University of the Witwatersrand. From 1944 to 1946 his medical studies were suspended due to his military service during World War II. In 1948, he received his medical degree and completed medical and surgical internships and residencies at the Johannesburg General Hospital. After that, he went to England, to obtain his MD in Internal Medicine at the Royal Postgraduate Medical School and Hammersmith Hospital. At one point, he concluded that clinical medicine was not his passion

Department of Pathology – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil.

Copyright © 2013 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution NonCommercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

Autopsy and Case Reports 2013; 3(1): 1-4

and switched to pathology, initially in London and subsequently at the South African Institute for Medical Research (SAIMR) in Johannesburg. During his nine years of working there, his interest in the lymphoreticular system was stimulated by Dr. George Oettlé, who was the head of the South African National Cancer Institute at that time. During the early 1960s at the SAIMR, Dr. Dorfman came across two very unusual cases. The patients were African boys, aged 9 and 19, presenting enlarged lymph nodes in the neck, producing a “bullneck” appearance. The oldest patient’s disease had started 10 years earlier, and the disease followed a stable course. The histological appearance was so uncommon that the slides were submitted to several consultants in England, including Dr. Alistair Robb-Smith at Oxford University and Professor Donald Harrison at the Postgraduate Medical School of London. Varied opinions included “an unusual reaction to an undetermined infectious agent,” a cholesterol-type lipidosis, and even a form of Letterer-Siwe disease. In a fascinating article published recently by Dr. Dorfman in a periodical of the Adler Museum of Medicine, University of the Witwatersrand, Johannesburg, he described in detail the identification of this rare and intriguing disease.3 In 1963, due to his opposition to a society that established the superiority of white races over the black people of South Africa, he immigrated with his family to St. Louis, Missouri, USA, as Assistant Professor in the Surgical Pathology Division of the Department of Pathology at the Washington University School of Medicine, invited by Dr. Lauren V. Ackerman. While working there, one day a surgical pathology fellow named Juan Rosai, born in Poppi, Italy, came to his office with slides of two peculiar cases, which he identified among a series of cases he had been studying, including lymph node biopsies with the diagnosis of “malignant reticuloendotheliosis” – a generic term embracing malignant disorders of the socalled reticuloendothelial system. The patients were a boy and a girl, both 7 months old presenting enlarged painless cervical lymph nodes. The two doctors studied the slides of these cases as well as those from Dr. Dorfman’s two patients from Johannesburg, and immediately agreed that they were dealing with the same disease. Reviewing the literature, Dr. Rosai found two more cases with great clinical and histological similarities to theirs.4,5 They prepared and submitted the first description of the entity they named “sinus histiocytosis with massive

Zerbini MCN.

lymphadenopathy (SHML): a newly recognized benign clinicopathologic entity”.6 The publication stimulated a great deal of interest and by the end of 1971 they had collected 30 new cases received in consultation, motivating their second paper with detailed analysis of their 34 cases, establishing the validity of SHML as a definitive clinicopathologic entity.7 They described the histological features in early and advanced phases of the disease, and called attention to the most conspicuous feature, seen in greater or lesser degree in every case: the presence of apparently viable hematopoietic cells (mostly lymphocytes) within extremely large cells, with abundant, clear, granular or finely vacuolated cytoplasm and large, round, vesicular nuclei containing distinct nucleoli. Later, histochemical and immunophenotypic studies were able to support these large cells as having the features of histiocytes and activated monocytes/ macrophages.8 They differed from reactive sinus histiocytes by virtue of their strong staining for S100 protein. In addition, they differed from Langerhans cell histiocytes in that they failed to express CD1a antigen, and they do not have Birbeck´s granules at the electron microscopy. The other peculiar finding was the presence of dozens of lymphocytes located within cytoplasmic vacuoles, which most probably represented the ability of these cells to enter and leave the histiocytic cytoplasm without undergoing degenerative changes, a phenomenon known as emperipolesis (from the Greek: em = inside, peri = around, polesis = going about). They further emphasized the essentially benign nature of the disease and the capacity of this disorder to clinically simulate a malignant process. It was in 1973 that a group of Spaniards published a paper using the eponym Rosai-Dorfman for the first time, and from that time this name was adopted by many others, particularly for those cases where the disease was exclusively extranodal.9 Dr. Rosai, who had been appointed Head of Anatomic Pathology at Yale University in New Haven, Connecticut, USA, created an archive of all the cases of SHML he was aware of, first at Minnesota and after at Yale. As an increasing number of cases were sent to Dr. Rosai and Dr. Dorfman in consultation over the ensuing years, they began to appreciate that SHML affected not only lymph nodes but also many different extranodal sites, at times without lymph node involvement. The most prominent extranodal manifestations were observed in the skin and soft tissues, upper

Dr. Dorfman legacy to pathology: beyond Rosai-Dorfman disease

respiratory tract, bone, genitourinary system, lower respiratory tract, and oral cavity, but nowadays the literature has shown that this disease can occur anywhere. In 1990, the editor of Seminars in Diagnostic Pathology decided to devote an entire issue of the journal to a review of the clinical and pathological features of 423 cases of extranodal SHML.10 Nowadays, the cause of Rosai-Dorfman disease is still unknown. It is suspected that it may be of viral etiology and that minor upper respiratory tract infections may stimulate the characteristic interaction between lymphocytes, the unique histiocytes and plasma cells, resulting in massive lymphadenopathy and the widespread extranodal lesions of this disorder. There is no specific treatment for Rosai-Dorfman disease and the lesions are not responsive to antibiotics. Treatment is not necessary in most cases and enlarged lymph nodes usually resolve spontaneously; however, some patients may require surgery, radiation therapy and/or chemotherapy because of severe disease manifestations. A month before his death, Dr. Dorfman went to the Stanford Department of Pathology to give his opinion on an unusually difficult example of RosaiDorfman disease. I wondered what comments he would make about the challenging case of SHML presented in this issue of Autopsy and Case Reports. As in this case, a series of 14 deaths occurring in the SHML registry were described, and it was noted that many of these patients had had immunologic and/or hematologic abnormalities.11,12 “Ron Dorfman was considered a gifted diagnostician, teacher, and researcher, but those who knew him well were equally impressed by his warmth. He was considered a consummate gentleman and scholar.” These were the words of Dr. Stacey E. Mills, Editor-in-Chief of The American Journal of Surgical Pathology at the time of Dr. Dorfman’s death last June. Beyond the enigmatic disease of RosaiDorfman, we hope that this brief overview of Dr. Dorfman’s life can inspire many young pathologists around the world to be good observers, to seek the answers to their questions, and to practice medicine with humanity and passion.

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ACKNOWLEDGEMENTS The author thanks to Prof. Juan Rosai for reviewing the text. REFERENCES 1.

Berard CW, Dorfman RF. Histopathology of malignant lymphomas. Clin Haematol. 1974;3(1):39-76. http://dx.doi. org/10.1016/S0308-2261(74)80005-6

Rappaport H. Tumors of the hematopoietic system. Washington: Armed Forces Institute of Pathology; 1966. (Atlas of Tumor Pathology).

Dorfman RF. The true story behind Rosai-Dorfman disease. Adler Mus Bull. 2008;34(1):13-8. PMid:20050417.

Azoury FJ, Reed RJ. Histiocytosi. Report of an anusual case. New Engl J Med. 1966;274(17):928-30. PMid:5908885. http://dx.doi.org/10.1056/NEJM196604282741702

Vincent TN, Miercort R, editor. Case 9. Eighteenth Seminar of the Penrose Cancer Hospital. 1967;3:246-50.

Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy - a Newly recognized benign clinicopathological entity. Arch Pathol. 1969;87(1):63-70. PMid:5782438.

Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a pseudolymphomatous benign disorder. Analysis of 34 cases. Cancer. 1972;30(5):1174-88. http:// dx.doi.org/10.1002/1097-0142(197211)30:5<1174::AIDCNCR2820300507>3.0.CO;2-S

Eisen RN, Buckley PJ, Rosai J. Immunophenotypic characterization of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Semin Diagn Pathol. 1990;7(1):74-82. PMid:2180014.

Vallé Jiménez AFGJ, Martinez Martinez A. Histiocitosis sinusal con linfadenopatia masiva de Rosai y Dorfman. Patologia. 1973;6:263-7.

10. Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol. 1990;7(1):19-73. PMid:2180012. 11. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. An analysis of 14 deaths occurring in a patient registry. Cancer. 1984;54(9):1834-40. http:// dx.doi.org/10.1002/1097-0142(19841101)54:9<1834::AIDCNCR2820540911>3.0.CO;2-F 12. F o u c a r E , R o s a i J , D o r f m a n R F, E y m a n J M . Immunologic abnormalities and their significance in sinus histiocytosis with massive lymphadenopathy. Am J Clin Pathol. 1984;82(5):515‑25. PMid:6496400.

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Correspondence: Maria Claudia Nogueira Zerbini Editor in Chief Autopsy and Case Reports Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil E-mail: czerbini@usp.br

Zerbini MCN.

Autopsy and Case Reports 2013; 3(1): 5-14

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Hepatoid adenocarcinoma of the lung Lívia Barreira Cavalcantea, Aloísio Felipe-Silvab, Fernando Peixoto Ferraz de Camposc, João Augusto dos Santos Martinesd Cavalcante LB, Felipe-Silva A, Campos FPF, Martines JAS. Hepatoid adenocarcinoma of the lung. Autopsy Case Rep [Internet]. 2013;3(1): 5-14. http://dx.doi.org/10.4322/acr.2013.002

ABSTRACT Lung adenocarcinomas with a mixture of tubular or papillary pattern, sheet-like or trabecular architecture, eosinophilic cytoplasm with centrally located nuclei and alpha-fetoprotein-producing cells have been described as hepatoid adenocarcinomas. Hepatoid adenocarcinomas are mainly found in the stomach but rare cases in other organs have been described. Immunostaining for alpha-fetoprotein (AFP), hepatocyte paraffin 1 (HepPar-1) and thyroid transcription factor-1 (TTF-1) helps in the diagnostic workup. Tumor behavior is still not entirely known but it seems to be associated with early metastases. We report on a 66-year-old, heavy-smoker male patient who had a 10-month history of respiratory complaints and weight loss. At the time he was hospitalized, respiratory failure was already established. The computed tomography corresponded to a collapsed right lung due to a poorly defined expanding mass. The bronchoscopy revealed narrowing of the inferior and medium lobar bronchi. The patient developed irreversible shock and died. At the right lung inferior lobe was extensively replaced by a grayish diffuse neoplasia in a “pneumonia-like” gross pattern. Metastatic disease was found in the right adrenal gland and thoracic and abdominal lymph nodes. Microscopic dissemination through lymphatics, pleura, and airways was detected. Histological examination revealed a poorly differentiated adenocarcinoma with hepatoid features. Immunohistochemmistry stains were positive for keratin 7, polyclonal carcinoembryonic antigen (CEA) in a diffuse pattern, AFP and HepPar-1 antibody. TTF-1 showed a diffuse granular cytoplasmic staining of the neoplastic cells, and only focal nuclear positivity. Multiple bilateral emboli originated from deep venous thrombosis were present in large and medium branches of the pulmonary artery and contributed to the cause of death. Keywords: Adenocarcinoma; Lung Neoplasms; Carcinoembryonic Antigen; Pulmonary Embolism; Autopsy.

Department of Pathology – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. c Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. d Diagnostic Imaging Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. a b

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CASE REPORT A 66-year-old, black, male patient sought medical attention because of a 10-day history of productive cough and dyspnea. He referred respiratory complaints, recurrent pneumonia and weight loss during the last 10 months, raising the suspicion of lung cancer by the primary care physician. His past medical history was uneventful, but he had been a heavy smoker for 40 years. Physical examination showed an ill-looking patient, emaciated, pale, showing mild respiratory distress. Blood pressure = 160/110 mmHg, pulse rate = 112 beats per minute, respiratory rate = 32 respiratory movements per minute, and room air pulse oximetry = 83%. Edema was present in lower limbs. Lung examination revealed decreased bronchial breath sounds in the right hemithorax and scattered crackles. Cardiac and abdominal examinations were normal. Initial treatment comprised supplementary O2 by nasal catheter and antibiotics. The patient was hospitalized for further investigation. The initial laboratory tests are in Table 1. Room air gasometry revealed: pH = 7.44; pO2 = 52 mmHg; pCO2 = 44 mmHg; HCO3 = 28 mEq/L; BE = 3.7, and oxygen saturation = 88%. Chest radiography showed diffuse and homogeneous opacity of the right hemithorax and right bronchus

Figure 1 – Complete opacification of the right hemithorax. Note obliteration of ipsilateral main bronchus and foci of perihilar alveolar opacity on the left lung.

Cavalcante LB, Felipe-Silva A, Campos FPF, Martines JAS.

obliteration without a significant deviation of the mediastinum, suggesting pulmonary atelectasis associated with pleural effusion. A perihilar alveolar opacification was seen on the left lung (Figure 1). The chest computed tomography showed volumetric reduction of the right lung parenchyma, which had totally collapsed, with bronchial and alveolar areas filled in by fluid content (Figure 2). The basal segments had heterogeneous attenuation with some parenchymal calcifications, which suggested the presence of a poorly delimited expanding mass (Figure 3). Right pleural enhancement by contrast medium and effusion was present. Ground-glass opacity areas associated with diffuse interstitial thickening displaying a mosaic pattern was present in the left lung (Figure 4). Poorly defined subpleural nodules were also depicted. Dilation of the trunk of the pulmonary artery was observed. Calcified mediastinal lymph nodes were seen without evidence of mediastinal lymph node enlargement. Thoracentesis resulted in serohemorrhagic exudate effusion drainage. Cytological examination failed to show malignancy. The lower limbs venous echo Doppler revealed thrombosis of right popliteal vein and thrombosis of the left femoral veins, which led to the addition of enoxaparin to his prescription. The bronchoscopy showed that the left bronchial tree, the right main bronchus, and the right upper lobe bronchus were free from lesions. The secondary carina was warped, and the intermediate bronchus showed converging grooves and granular mucosa. The distal bronchial ostia (to the inferior and medium lobes) showed reduced caliber that could not be surmounted. Bronchial biopsies were carried out on the tenth day of hospitalization.

Figure 2 – Axial computed tomography (CT) of the chest – mediastinal window – showing voluminous hypodense collection with discrete pleural thickening and enhancement associated with retraction of the apex of the right hemithorax.

Hepatoid adenocarcinoma of the lung

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Table 1 – Admission laboratory workup RV

Hemoglobin

12.3

12.3-15.3 g%

Creatinine

0.5

0.4-1.3 mg/dL

Hematocrit

37.6

36.0-45.0%

Potassium

4.5

3.5-5.0 mEq/L

Leucocytes

25.4

Bands

4.4-11.3 × 10 /mm

Sodium

135

136-146 mEq/L

1-5%

ALT

9-36 U/L

Segmented

45-70%

AST

10-31 U/L

Eosinophils

1-4%

Total bilirubin

0.39

0.3-1.2 mg/dL

Basophils

0-2.5%

Glucose (random)

109

70-140 mg/dL

Lymphocytes

18-40%

LDH

324

120-246

Monocytes

2-9%

Cai+

1.11

1.11-1.4 mmol/L

Platelets

453.103

150-400 × 103/mm3

Total protein

7.0

7-8 g/dL

CRP

158

<5 mg/L

Albumin

3.6

3-5 g/dL

BUN

5-25 mg/dL

PT (INR)

1.4

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; Cai+ = ionized calcium; CRP = C-reactive protein; LDH = lactic dehydrogenase, PT = prothrombin time; RV = reference value.

Figure 3 – Axial CT of the chest – mediastinal window. A - Hypodense liquid content in the right main bronchus (arrow) and heterogeneous enhancement of the lung parenchyma; B - Hypodense liquid content within the interlobar bronchus (arrow); C - Irregularity and thinning of the pulmonary veins close to the left atrium. Note pleural and pericardial effusion as well as bilateral gynecomastia.

Figure 4 – Axial CT of the chest – pulmonary window. A and B - Fissure thickening with micronodules. Septal thickening and ground glass opacities associated with septal thickening (“crazy paving”) in the left upper lobe. Clinical outcome was unfavorable accompanied by a worsening of the patient’s respiratory function and then shock, despite supportive therapy. The patient died after 12 days of hospitalization without a precise diagnosis of pulmonary pathology.

On the day of death, the biopsies performed during bronchoscopy were completed and disclosed a diagnosis of non-small cell lung carcinoma infiltrating the bronchial mucosa, accompanied by squamous metaplasia with moderate dysplasia of the respiratory epithelium. Immunohistochemical

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Cavalcante LB, Felipe-Silva A, Campos FPF, Martines JAS.

analyses were performed on the autopsy samples. Serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and beta-human chorionic gonadotrophin (beta-hCG) were tested in stored blood samples, after patient’s death. Serum AFP and beta-hCG determinations were normal, but CEA was 580 µg/L (reference value < 5 µg/L).

grayish diffuse neoplasia, which mimicked a lobar pneumonia (“pneumonia-like” gross pattern). A dense fibrous pleural thickening encased the right pulmonary lobes and the inferior airways were obstructed by tumor invasion. This pneumonia-like pattern also affected the superior lobe of the left lung. Microscopic dissemination through lymphatics, pleura, and airways was detected (Figure 5).

Autopsy

Histological examination revealed mucinproducing neoplastic cells arranged in solid sheets or dyscohesive clusters, which filled the alveolar spaces (Figure 5). Signet-ring-like cells and mucinpositive cytoplasmic vacuoles were present. Moderately differentiated areas with columnar cells and acini as well as foci of keratinization and necrosis were seen scattered through the tumor (Figure 6).

The external examination of the body showed an emaciated, cachectic man. Bilateral jugular stasis and gynecomastia were evident. A large volume serosanguineous pleural effusion with multiple adhesions between the lungs, pleura, diaphragm, and the rib cage were observed upon opening the thoracic cavity. These findings were more prominent in the right hemithorax. Invasion of the pericardium led to a fibrinous and hemorrhagic pericarditis. Examination of the right lung revealed extensive replacement of the inferior lobe by a

Other areas (about 20%) showed abundant eosinophilic or clear cytoplasm with distinct cell borders, cytoplasmic grumous (“Mallory bodylike”) and globoid PAS-positive hyalines. Nuclear pseudoinclusions were occasionally seen (Figure 7).

Figure 5 – A - Gross examination of right lung showing pleural thickening, adherence to diaphragm, and pneumonia-like pattern; B - Photomicrography of tumor cells filling alveolar spaces (air dissemination) (H&E 200×); C - Photomicrography of tumor lymphatic dissemination; note fluid edema in bronchiolar lumen (right bottom) (H&E 200×); D - Photomicrography of segmental bronchus invaded and obliterated by tumor (H&E original magnification 12.5×).

Hepatoid adenocarcinoma of the lung

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Figure 6 – Photomicrographs. A - Acinar pattern with columnar cells (H&E 400×); B - Solid pattern with mucin vacuoles (H&E 400×); C – Signet-ring cells (H&E 400×); D - Sheet-like pattern of poorly cohesive cells with eosinophilic cytoplasm (H&E 400×).

Figure 7 – Photomicrographs. A - Large eosinophilic cells in focal trabecular pattern (H&E 400×); B - Clear cells (H&E 400×); C - Eosinophilic globules (H&E 400×); D - Large nuclear pseudoinclusion (arrow) (H&E 400×).

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These features suggested a poorly differentiated adenocarcinoma with hepatoid features. Immunohistochemical stains were positive for keratin 7, polyclonal CEA in a diffuse pattern, AFP (multifocal) and hepatocyte paraffin 1 (HepPar-1) antibody. HepPar-1 staining was diffuse. Thyroid transcription factor-1 (TTF-1) showed a diffuse granular cytoplasmic staining of the neoplastic cells, and only focal nuclear positivity. Staining for keratins 5/6 was focally positive, especially in the foci of keratinization (Figures 8 and 9). The reactions were negative for keratin 20, chromogranin, synaptophysin, p63 protein, and beta-hCG. Multiple bilateral emboli that originated from deep venous thrombosis in the left popliteal and common iliac veins were present in large and medium caliber branches of the pulmonary artery. Additionally, histological examination revealed local arterial thrombosis entrapped in tumor areas and fibromuscular narrowing and thickening of small pulmonary arteries. These findings were suggestive of pulmonary hypertension attributed

Cavalcante LB, Felipe-Silva A, Campos FPF, Martines JAS.

to local thrombosis and to possible recurrent thromboembolism. Microscopic examination did not demonstrate thrombus in different stages of organization, however, previous thromboembolic events in a patient with advanced cancer could not be ruled out. Right cardiac chambers and main pulmonary arteries were preserved. Lung edema, alveolar hemorrhage and diffuse alveolar damage were present. The left ventricle wall had severe concentric hypertrophy, left atrium was mildly dilated and hyaline arteriolosclerosis was detected in the spleen. These findings were consistent with previous systemic arterial hypertension which might have contributed to the final events. Metastatic disease was found in the right adrenal gland and mediastinal, para-aortic and peripancreatic lymph nodes.

DISCUSSION In 1990, Ishikura et al.1 described hepatoid lung adenocarcinomas as tumors with a mixture

Figure 8 – Photomicrographs. A - Immunohistochemistry for keratin 7 (H&E 400×); B - Focal nuclear TTF-1 immunostaining (H&E 400×); C - Focal keratinization (H&E 400×); D - Focal immunostaining for keratin 5/6 (H&E 400×).

Hepatoid adenocarcinoma of the lung

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Figure 9 – Photomicrographs. A - Immunohistochemistry for CEA with diffuse staining (H&E 100×); B - Multifocal immunostaining for AFP (H&E 400×); C - Diffuse Hep-par (H&E 400×); D - Cytoplasmatic granular TTF-1 staining (H&E 400×). of tubular or papillary adenocarcinoma with sheetlike or trabecular proliferation of neoplastic cells with abundant eosinophilic cytoplasm and centrally located nuclei, resembling hepatocellular carcinoma cells. Accordingly, hepatoid lung adenocarcinoma is a major histological subtype in clinically AFPproducing lung adenocarcinomas. Other histological features include cuboidal or polygonal cells with clear cytoplasm, PAS-positive diastase-resistant hyaline globules and vascular lake-like cystic spaces lined by tumor cells.2 Lazaro et al.3 considered abundant eosinophilic cytoplasm and evidence of AFP production as the minimum histological criteria for a diagnosis of hepatoid carcinoma. In a recent review of 261 published cases of hepatoid adenocarcinomas, Metzgeroth et al.4 found that the most common primary site was the stomach (63%), followed by ovaries (10%), lung (5%), gallbladder, pancreas, and uterus (4% each). Immunohistochemical positivity for AFP (88%) and HepPar-1 (63%) were important diagnostic features. Other extrahepatic organs include ampulla of Vater, kidney, and urinary bladder.3,5 Fornasa6 reported

one case of metastatic hepatoid lung carcinoma to soft tissues of the shoulder. We report on a patient with a poorly differentiated, advanced lung adenocarcinoma that showed some morphological and immunohistochemical hepatoid features. Although sinusoid-like spaces or trabecular architecture with the typical round and centrally located nuclei of hepatocytes were not observed, some areas demonstrated sheets of cells with eosinophilic or clear cytoplasm, distinct cell borders, and hyaline PAS-positive cytoplasmic globules that were reminiscent of hepatocellular differentiation and set prompt immunohistochemical investigation. Immunohistochemistry revealed positivity for AFP, HepPar-1 and cytoplasmic granular staining of TTF-1. HepPar-1 is quite specific for hepatocellular differentiation, but other adenocarcinomas may be positive as well, mainly gastric poorly differentiated and signet-ring cell adenocarcinomas (about 50%).7 Lung adenocarcinomas are infrequently stained (4-8%).8 Maitra et al.9 demonstrated HepPar-1 expression in six of seven hepatoid

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adenocarcinomas of the gastrointestinal tract. In the report and review by Papatsimpas et al.,5 HepPar-1 was positive in two of four tested lung hepatoid adenocarcinomas. Although not specific, cytoplasmic granular staining for TTF-1 has been reported as a marker of hepatocellular differentiation. This pattern is rarely seen in other adenocarcinomas.10,11 Anti-TTF-1 antibodies seem to react with a different epitope of the hepatocellular mitochondrial urea cycle enzyme carbamoyl phosphate synthetase 1, which is the antigen for the HepPar-1 antibody,12,13 and not with a hypothetical alternative splicing product of the TTF-1 gene in hepatocytes.14 The serum AFP was normal in the present case; however, neither serum- nor tissue-expressed AFP are required for diagnosis since this is mostly based on histopathological criteria. Nagai et al.2 demonstrated that gastric carcinomas with hepatoid features have a worse prognosis than conventional carcinomas regardless of AFP detection by immunohistochemistry. Serum AFP levels have been shown to decrease after tumor resection and increase with recurrent disease, so it may be a useful tool for diagnosis and follow-up purposes.1,3,15,16 Lung hepatoid adenocarcinoma is diagnosed at an average age of 60 years (range 36–82), predominantly in males.5 There is not a consensus on the specific amount of hepatoid features for pathological diagnosis. The prognosis for hepatoid lung carcinoma and AFP-producing pulmonary carcinoma has not been fully elucidated because of the low number of reported cases. However, it seems to be associated with high proliferative indexes and early metastatic potential.1,16,17 For instance, hepatoid carcinomas of the stomach have been associated with a high incidence of vascular invasion and metastases.2 Although this feature has not been established for lung hepatoid adenocarcinomas, the present case showed many sites of vascular invasion with obliteration of pulmonary veins and adrenal metastasis. On the other hand, cases with early stage disease have been curatively resected.18,19 Three mechanisms of carcinogenesis are suggested for hepatoid adenocarcinomas. First, AFP-producing lung carcinoma may originate from respiratory epithelium capable of multipotential differentiation.16 Second, an adenocarcinoma acquires the hepatic phenotype in the process of tumor progression.20 Third, (the most unlikely) the

Cavalcante LB, Felipe-Silva A, Campos FPF, Martines JAS.

hepatoid lung carcinoma originates in ectopic liver tissue.1 Hepatoid and signet-ring cell cytomorphology as well as solid, papillary and micropapillary architectural patterns have been associated with chromosomal rearrangements leading to the constitutive activation of anaplastic lymphoma receptor tyrosine kinase (ALK). ALK rearrangements define a category of lung adenocarcinomas that may be suitable for targeted therapy with the ALK inhibitor crizotinib.21,22 The presence of hepatoid, signet-ring and solid features in the present case raise the hypothesis of an ALK-positive lung adenocarcinoma. The pneumonia-like gross pattern is classically associated with bronchioloalveolar mucinous carcinoma, although most pneumoniatype bronchioloalveolar carcinomas show a mixture with other subtypes, including an invasive component.23,24 To the best of our knowledge, a pneumonia-like gross pattern has not yet been reported in hepatoid lung adenocarcinoma. In the present case, a pneumonia-like consolidation could be attributable to the filling of alveolar spaces by tumor cells, inflammation, and desmoplastic reaction.

CONCLUSION The immediate cause of death in the present case was pulmonary thromboembolism, a wellknown paraneoplastic manifestation of lung cancer. Acute pulmonary edema as related to left ventricular hypertrophy and diffuse alveolar damage may have contributed as well. Gynecomastia has been reported in cases of lung cancer, but beta-hCG is usually detected in the serum or in the tumor in these cases.25,26 In the present case, serum betahCG levels were normal and immunohistochemistry was negative. Gynecomastia might be related to other hormonal imbalances or ectopic prolactin production, but further hormonal workup was not available in this case.

REFERENCES 1.

Ishikura H, Kanda M, Ito M, Nosaka K, Mizuno K. Hepatoid adenocarcinoma: a distinctive histological subtype of alphafetoprotein-producing lung carcinoma. Virchows Arch A Pathol

Hepatoid adenocarcinoma of the lung Anat Histopathol. 1990;417(1):73-80. PMid:1694332. http:// dx.doi.org/10.1007/BF01600112 2.

N a g a i E , U e y a m a T, Ya o T, Ts u n e y o s h i M . Hepatoid adenocarcinoma of the stomach. A clinicopathologic and immunohistochemical analysis. Cancer. 1993;72(6):1827-35. http://dx.doi. org/10.1002/1097-0142(19930915)72:6<1827::AIDCNCR2820720606>3.0.CO;2-8 Lazaro J, Rubio D, Repolles M, Capote L. Hepatoid carcinoma of the ovary and management. Acta Obstet Gynecol Scand. 2007;86(4):498-9. PMid:17486476. http:// dx.doi.org/10.1080/00016340600593117 Metzgeroth G, Ströbel P, Baumbusch T, Reiter A, Hastka J. Hepatoid adenocarcinoma - review of the literature illustrated by a rare case originating in the peritoneal cavity. Onkologie. 2010;33(5):263-9. PMid:20502062. http://dx.doi. org/10.1159/000305717 Papatsimpas G, Kamposioras K, Goula K, et al. Hepatoid pancoast tumor. A case report and review of the literature. Lung Cancer. 2012;77(2):239-45. PMid:22677427. http:// dx.doi.org/10.1016/j.lungcan.2012.05.102

Fornasa F. Soft-Tissue Localization of hepatoid adenocarcinoma: first case report. Case Rep Oncol. 2010;3(2):212-7. PMid:20740199 PMCid:2920002. http://dx.doi.org/10.1159/000317419

Fan Z, Van de Rijn M, Montgomery K, Rouse RV. Hep par 1 antibody stain for the differential diagnosis of hepatocellular carcinoma: 676 tumors tested using tissue microarrays and conventional tissue sections. Mod Pathol. 2003;16(2):137‑44. PMid:12591966. http://dx.doi. org/10.1097/01.MP.0000052103.13730.20

Lugli A, Tornillo L, Mirlacher M, Bundi M, Sauter G, Terracciano LM. Hepatocyte paraffin 1 expression in human normal and neoplastic tissues: tissue microarray analysis on 3,940 tissue samples. Am J Clin Pathol. 2004;122(5):721-7. PMid:15491968. http://dx.doi. org/10.1309/KC09YTF2M4DLUYQ6 Maitra A, Murakata LA, Albores-Saavedra J. Immunoreactivity for hepatocyte paraffin 1 antibody in hepatoid adenocarcinomas of the gastrointestinal tract. Am J Clin Pathol. 2001;115(5):689-94. PMid:11345832. http://dx.doi. org/10.1309/5C2C-FP3H-GE7Q-2XJ5

10. Pan CC, Chen PC, Tsay SH, Chiang H. Cytoplasmic immunoreactivity for thyroid transcription factor-1 in hepatocellular carcinoma: a comparative immunohistochemical analysis of four commercial antibodies using a tissue array technique. Am J Clin Pathol. 2004;121(3):343-9. PMid:15023038. http://dx.doi. org/10.1309/8BM44NK626997DJJ 11. Wieczorek TJ, Pinkus JL, Glickman JN, Pinkus GS. Comparison of thyroid transcription factor-1 and hepatocyte antigen immunohistochemical analysis in the differential diagnosis of hepatocellular carcinoma, metastatic

Autopsy and Case Reports 2013; 3(1): 5-14 adenocarcinoma, renal cell carcinoma, and adrenal cortical carcinoma. Am J Clin Pathol. 2002;118(6):911-21. PMid:12472285. http://dx.doi.org/10.1309/KKDP-MND2W794-P9EH 12. Pang Y, Von Turkovich M, Wu H, et al. The binding of thyroid transcription factor-1 and hepatocyte paraffin 1 to mitochondrial proteins in hepatocytes: a molecular and immunoelectron microscopic study. Am J Clin Pathol. 2006;125(5):722-6. PMid:16707373. http://dx.doi. org/10.1309/EBCB6H54K1N2P9QL 13. Butler SL, Dong H, Cardona D, et al. The antigen for Hep Par 1 antibody is the urea cycle enzyme carbamoyl phosphate synthetase 1. Lab Invest. 2008;88(1):78-88. PMid:18026163. http://dx.doi.org/10.1038/labinvest.3700699 14. Gu K, Shah V, Ma C, Zhang L, Yang M. Cytoplasmic immunoreactivity of thyroid transcription factor-1 (clone 8G7G3/1) in hepatocytes: true positivity or cross-reaction? Am J Clin Pathol. 2007;128(3):3828 . P M i d : 1 7 7 0 9 3 11 . h t t p : / / d x . d o i . o r g / 1 0 . 1 3 0 9 / CADCVWHR2QF6JMVN 15. Arnould L, Drouot F, Fargeot P, et al. Hepatoid adenocarcinoma of the lung: report of a case of an unusual alpha-fetoprotein-producing lung tumor. Am J Surg Pathol. 1997;21(9):1113-8. PMid:9298890. http://dx.doi. org/10.1097/00000478-199709000-00018 16. Hiroshima K, Iyoda A, Toyozaki T, et al. Alpha-fetoproteinproducing lung carcinoma: report of three cases. Pathol Int. 2002;52(1):46-53. PMid:11940206. http://dx.doi. org/10.1046/j.1440-1827.2002.01311.x 17. Nasu M, Soma T, Fukushima H, Kudo K, Matsubara O. Hepatoid carcinoma of the lung with production of alphafetoprotein and abnormal prothrombin: an autopsy case report. Mod Pathol. 1997;10(10):1054-8. PMid:9346187. 18. Carlinfante G, Foschini MP, Pasquinelli G, Scotti R, Cavazza A. Hepatoid carcinoma of the lung: a case report with immunohistochemical, ultrastructural and in-situ hybridization findings. Histopathology. 2000;37(1):88-9. PMid:10931226. http://dx.doi.org/10.1046/j.1365-2559.2000.00955-5.x 19. Hayashi Y, Takanashi Y, Ohsawa H, Ishii H, Nakatani Y. Hepatoid adenocarcinoma in the lung. Lung Cancer. 2002;38(2):211-4. http://dx.doi.org/10.1016/S01695002(02)00214-3 20. Kishimoto T, Nagai Y, Kato K, Ozaki D, Ishikura H. Hepatoid adenocarcinoma: a new clinicopathological entity and the hypotheses on carcinogenesis. Med Electron Microsc. 2000;33(2):57-63. PMid:11810459. http://dx.doi. org/10.1007/s007950070002 21. Nishino M, Klepeis VE, Yeap BY, et al. Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas. Mod Pathol. 2012;25(11):1462-72. PMid:22743652. http://dx.doi.org/10.1038/modpathol.2012.109

Autopsy and Case Reports 2013; 3(1): 5-14 22. Khozin S, Roth MJ, Rajan A, et al. Hepatoid carcinoma of the lung with anaplastic lymphoma kinase gene rearrangement. J Thorac Oncol. 2012;7(11):e29-31. PMid:23070248. http:// dx.doi.org/10.1097/JTO.0b013e3182697a23 23. Wislez M, Massiani MA, Milleron B, et al. Clinical characteristics of pneumonic-type adenocarcinoma of the lung. Chest. 2003;123(6):1868-77. PMid:12796162. http:// dx.doi.org/10.1378/chest.123.6.1868 24. Garfield DH, Cadranel JL, Wislez M, Franklin WA, Hirsch FR. The bronchioloalveolar carcinoma and peripheral adenocarcinoma spectrum of diseases. J Thorac

Cavalcante LB, Felipe-Silva A, Campos FPF, Martines JAS. Oncol. 2006;1(4):344-59. PMid:17409882. http://dx.doi. org/10.1097/01243894-200605000-00014 25. Liu G, Rosenfield Darling ML, Chan J, Jaklitsch MT, Skarin AT. Gynecomastia in a patient with lung cancer. J Clin Oncol. 1999;17(6):1956. PMid:10561237. 26. Okutur K, Hasbal B, Aydin K, et al. Pleomorphic carcinoma of the lung with high serum beta-human chorionic gonadotropin level and gynecomastia. J Korean Med Sci. 2010;25(12):18058. PMid:21165299 PMCid:2995238. http://dx.doi.org/10.3346/ jkms.2010.25.12.1805

Conflict of interest: None Submitted on: 16th December 2012 Accept on: 14th March 2013 Correspondence: Departamento de Patologia do Hospital das Clínicas Faculdade de Medicina da Universidade de São Paulo Av. Dr. Enéas Carvalho de Aguiar, 155 – 10º andar – Cerqueira Cesar – São Paulo/SP – Brazil Phone: +55 (11) 951564366 E-mail: livia_barreira@yahoo.com.br

Autopsy and Case Reports 2013; 3(1): 15-22

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Preventing misdiagnosis in amniotic band sequence: a case report Cristiane Rúbia Ferreiraa, Cibelle Freitas Pinto Limab, Ana Maria Andrello Gonçalves Pereira de Meloc Ferreira CR, Lima CFP, Melo AMAGP. Preventing misdiagnosis in amniotic band sequence: a case report. Autopsy Case Rep [Internet]. 2013;3(1): 15-22. http://dx.doi.org/10.4322/acr.2013.003

ABSTRACT Amniotic band sequence (ABS) is an uncommon and heterogeneous congenital disorder caused by entrapment of fetal parts by fibrous amniotic bands, causing distinctive structural abnormalities involving limbs, trunk, and craniofacial regions. The incidence ranges between 1/1200 and 1/15,000 live births, but is higher in stillbirths and previable fetuses. The intrinsic theory attributes the constriction band syndrome as an inherent development defect of embryogenesis while the extrinsic theory proposes that an early amnion rupture is responsible for the adherent bands. It is also suggested that amputations and constriction rings might be due to vascular disturbances. Anomalies resulting from amniotic bands are quite variable and sometimes may simulate chromosomal abnormalities. The authors report a case of a 36-week-gestation male neonate who lived for 29 hours after a vaginal delivery with an Apgar score of 8/9/9. The mother was primipara, and the prenatal was uneventful except for two episodes of urinary tract infections. The newborn examination depicted multiple anomalies characterized by exencephaly, bilateral labial cleft with distorted nostrils and palate cleft. There was also facial skin tag band, exophthalmos with hypoplasia of the eyelids. The limbs showed distal amputation of the fingers in both hands and feet, oligodactyly associated with syndactyly in the left foot, ring constriction in the right leg, the presence of right hyperextension, and clubfoot. The upper limbs showed length discrepancies. Karyotype analysis was normal at 46 XY. The authors conclude that the recognition of the malformations secondary to ABS is important in genetic counseling to prevent misdiagnosis between chromosomal and secondary disruption disorders. Keywords: Amniotic Band Sequence; Cleft Palate; Congenital Abnormalities; Neural Tube Defects.

Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. Department of Pathology – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. c Department of Pediatrics – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. a b

Autopsy and Case Reports 2013; 3(1): 15-22

CASE REPORT A 36-week-gestation male neonate weighing 2230 g was born to a 29-year-old female patient, primipara, by vaginal labor induced with oxytocin. The mother’s medical history was unremarkable, except for two episodes of urinary tract infection and a morphologic ultrasound examination at 19 weeks’ gestation showing exencephaly, medial labial cleft, and edema. After a breech delivery with a laceration of the umbilical cord during birth, a neonate with multiple malformations was born, with an Apgar score of 8/9/9. The neonate was referred to the neonatal ICU for palliative care. The parents were aware of the prognosis, with the malformations being incompatible with life. The karyotype analysis was normal, 46 XY (20 cells analyzed). During the ICU stay, the neonate was placed in a heated crib, prescribed serum, analgesic, fentanyl, and midazolam. The physical examination presented heart rate of 180 beats per minute and room air oximetry of 100%. The newborn evolved with grunting and died with 29 hours. An autopsy was performed.

Autopsy Findings The ectoscopic examination showed a male neonate with multiple malformations (Figure 1). Multiple craniofacial abnormalities were observed: central nervous system and skull defects were represented by asymmetric and anteriorly placed exencephaly in fronto-parietal topography; bilateral labial cleft with distorted nostrils; and palate cleft. There was also a facial skin tag band from the right

Ferreira CR, Lima CFP, Melo AMAGP.

nasal ala to the edge of the skin with the exencephaly. The exophthalmos was more prominent in the right eye with hypoplasia of the eyelids and a cutaneous appendix on the temporal scalp topography was also present (Figure 2). A thin winy-yellowish-colored membrane and areas with fibrinous material deposition coated the exposed surface of the brain. The brain showed multiple malformations with a lobulated appearance. The microscopic examination showed arachnoid-toamnion membrane adhesions, which showed signs of acute inflammation (Figure 3). The limbs showed predominantly distal deformities such as distal amputation of the fingers in both hands and feet, oligodactyly associated to syndactyly in the left foot with evident amniotic band, ring constriction in the right leg, presence of right hyperextension and clubfoot. Upper limbs showed length discrepancies (Figure 4). At the opening thoracic and abdominal cavities there was no abnormality in the organic topography neither in their gross examination. The weight of the organs is showed in Table 1. The heart showed foramen oval and a patent duct arteriosus. The lungs showed multiple petechiae scattered on the pleural surface and in the parenchyma (Figure 5). The microscopic examination depicted the lungs in the alveolar stage of development with multiple areas of alveolar hemorrhage. Hepatic extra medullary hematopoiesis was observed with no evidence of conspicuous nephrogenic zone in the kidneys—findings that are consistent with the 36th gestational week.

Figure 1 – Panoramic pictures of the neonate. A - Ventral sight showing multiple craniofacial malformations, mammary hypertelorism, limbs with distal deformities, and upper limb length discrepancy; B - Back view.

Preventing misdiagnosis in amniotic band sequence: a case report

Autopsy and Case Reports 2013; 3(1): 15-22

Figure 2 – Multiple craniofacial malformations. A - Exencephaly in fronto-parietal topography, bilateral labial cleft with distorted nostrils, and palate cleft; B - Facial skin tag band from the right nasal ala to the edge of the skin with the exencephaly (arrow) and right exophthalmy with hypoplasia of the eyelids; C - Bilateral labial cleft in continuity with palate cleft; D - Exencephaly with winy-yellowish-coated membranes and a skin tag on the scalp.

Table 1 – Weight of organs Organ

Weight (g) RV (g) 36th gestational week

Organ

Weight (g) RV (g) 36th gestational week

Thymus

13.2

7.7 ± 5.0

Spleen

5.3

8.1 ± 3.1

Right & left lungs

12.8/15.0

36.9 ± 17.5*

Right & left kidneys

12.6/11.7

21.7 ± 6.8*

Liver

73.1

96.3 ± 33.7

Pancreas

2.8

2.6 ± 0.7

Heart

14.0

15.0 ± 5.1

RV = reference value; *weight for both left and right organs.

We concluded that all malformations described above were caused by an amnion band disruption sequence. The placenta measured 16.0 × 13.0 × 2.5 cm and weighted 343.0 g. The marginal insertion of the membranes showed up opalescent. The umbilical cord had a central insertion and measured 40.0 cm in length and 1.0 cm in diameter, with three vases:

two umbilical arteries and one vein. Over the fetal face, the blood vessels were prominent and turgid. The maternal face was complete, showing a winy staining with opalescent areas. At the histological examination, chronic infarction areas, an increased number of syncytial knots, slight villous immaturity, foci of dystrophic calcification, and foci of chronic villitis with lymphocytes, histiocytes and focal granuloma were observed (Figure 6).

Autopsy and Case Reports 2013; 3(1): 15-22

Ferreira CR, Lima CFP, Melo AMAGP.

Figure 3 – A - Gross examination of the brain showing multiple malformations with the lobulated appearance. Photomicrographies: B - Arachnoid-to-amnion membrane adhesion (HE 100×); C and D - Winy meninges showing acute inflammation (HE 100× and 400×, respectively).

DISCUSSION We report a case of male neonate at 36 weeks’ gestation with multiple malformations secondary to disruption of development caused by amniotic band sequence (ABS). Disruption, also called secondary malformation, is a morphologic defect of an organ, part of an organ, or a larger region of the body resulting from a breakdown of, or interference with, an originally normal development process.1,2 A classical example of disruption is an amniotic band, but it can also be caused by environmental agents such as physical and infectious agents, drugs, chemicals, and maternal conditions.3 ABS is an uncommon and heterogeneous congenital disorder caused by the entrapment of fetal parts by fibrous amniotic bands, resulting in distinctive structural abnormalities involving limbs, trunk, and craniofacial regions, of variable severity.4 The spectrum of structural anomalies varies and depends on the stage of embryonic development and the severity of the disruptive event.5 Many

terms have been used as synonyms for this complex anomaly, namely: amniotic band disruption sequence, amniotic band syndrome, amniotic deformity adhesions and mutilation complex (ADAM), and limb body wall complex (LBWC). ABS occurs in approximately 1/12001/15,000 live births.4,6 There is a higher prevalence of ADS between previable fetuses and stillbirths, with 11.4 per 10,000 previable fetuses of less than 28 weeks’ gestation7 and 178.2 per 10,000 in fetuses from spontaneous miscarriages and induced abortions of 9-18 weeks’ gestation.8 The etiology of ABS remains debatable, and its physio pathogeny still remains unknown. The amniotic cavity is generated by epiblastic cells, which differentiate into amnioblasts during the second week post conception. This cavity enlarges relative to the extraembryonic coelomic cavity until the amnion fuses with the chorionic plate by 12 weeks post conception.9 Amniotic bands occur when the amnionic membrane fails to fuse with the

Preventing misdiagnosis in amniotic band sequence: a case report

Autopsy and Case Reports 2013; 3(1): 15-22

Figure 4 – Gross examination of the limbs. A and B - Distal finger amputations in both hands; C - Lower right limb ring constriction (arrow) and the presence of hyperextended right clubfoot, medial sight of the syndactyly in the left foot with evident amniotic band; D - Details of the oligodactyly associated with syndactyly in the left foot with evident amniotic band (arrow).

Figure 5 – A - Gross examination of the intrathoracic organs monoblock showing multiple petechiae on the pleural surfaces; B - Open right cardiac chambers view showing the patent foramen oval. chorionic plate, or when the amnion epithelium and stroma become detached from the deeper chorionic structures of the extraplacental membrane and chorionic plate.10 There are two main theories that explain the development of ABS. The first is the intrinsic theory, proposed by Streeter in 1930,11,12 which suggests that the constriction band syndrome

represents an inherent development defect in embryogenesis. The second is the extrinsic theory, and was described by Torpin in 1965.11,13 This theory proposes that an early amnion rupture is responsible for the formation of adherent bands that can constrict, entangle, and amputate limbs. As the amnion ruptures, it slips off the chorion to form the

Autopsy and Case Reports 2013; 3(1): 15-22

Ferreira CR, Lima CFP, Melo AMAGP.

Figure 6 – Photomicrography of histologic sections of placenta. A - Slight villous immaturity (HE 100×); B - Chronic infarction areas and increased number of syncytial knots (HE 100×); C and D - Foci of chronic villitis with lymphocytes, histiocytes, and a focal granuloma near decidua (HE 200×).

detaching mesoblastic fibrous strands; thereafter it becomes entangled around the digits or limbs. Even though the extrinsic theory seems to be more accepted, there is no agreement between different authors. Van Allen et al.14 suggested that amputations and constriction rings might be due to vascular disturbances. A prospective study conducted by Van Allen et al.15 observed, by magnetic resonance angiography in newborns with constrictions bands and limb reduction defects, vessel abnormalities in the affected limbs, such as bifurcation or trifurcation of major vessels, the absence of major vessels, atretic segments in the major limbs arteries and absent branches.16 Kalousek et al.17 divide the amnion defects into the LBWC, caused by an early defect of the amniotic sac, and ABS caused by amniotic bands. Tissue bands, sometimes running to the placental membranes are often, but not universally, observed, particularly in the mature fetus.18

Although we could not demonstrate fibrous amniotic strands in placenta, we undoubtedly observed evidence of amnion band constrictions on the neonate. The latter were represented by multiple craniofacial malformations with a facial skin tag band, arachnoid-to-amnion membrane adhesion, and ring constriction band in the limbs with distal amputations of the fingers. This finding may be in favor of the extrinsic theory. The etiology for ABS cannot be found in most pregnancies. According to the literature, ABS has been related to young maternal age, primigravida, use of acetaminophen, abdominal trauma, chorioamnionitis, vaginal bleeding during the first trimester, abortion, intrauterine contraception, chorionic villus sampling, amniocentesis, malformation of the uterus, prematurity, and noncephalic presentation.4,16,19 Except for the episodes of urinary tract infection treatment during pregnancy, the maternal history of this case report was unremarkable. The placental examination showed

Preventing misdiagnosis in amniotic band sequence: a case report

Autopsy and Case Reports 2013; 3(1): 15-22

foci of chronic villitis near the decidua, which could be related to these infectious episodes.

the occurrence of premature rupture of membranes in 71% of cases.26

Nevertheless, ABS has not been linked to chromosomal abnormalities or genetic bases. Some cases have been reported in families with collagen tissue disorders, more specifically Ehler-Danlos syndrome and osteogenesis imperfecta, due to the abnormality of amnion collagen formation.20,21 Anomalies resulting from amniotic bands may simulate chromosomal abnormalities especially when neural tube defects (NTD) evolve as the exencephaly observed in this case report. NTD may present as ex- or anencephaly, iniencephaly, encephalocele, meningomyelocele, or spina bifida in association with cranioschisis. NTD was observed in 3.6-6.7% of the intact embryos in cases of miscarriage. Most of these cases were chromosomally abnormal.22 Folic acid deficiency is also part of the pathology of NTD.23 Moreover, the midline facial defects observed in this case, with labial and palatal clefts, have a differential diagnosis with trisomy 13 and trisomy 18,24 but the karyotype study was normal.

The authors describe a case of ABS with multiple malformations with severe craniofacial abnormalities, oligodactyly, syndactyly, and limb distal amputation. The recognition of malformations described herein, secondary to ABS, is important in genetic counseling to prevent misdiagnosis between chromosomal and secondary disruption disorders.

CONCLUSION The prognosis of ABS depends on the type, the number of disruptions, and the stage of embryonic development. Newborns with early ABS who have severe neural tube and body-wall defects rarely survive. Surgical treatments for functional and aesthetic restoration may be indicated in some cases. Treatment must be individualized and the timing of surgery is determined by the disease severity and predicted skeletal growth. The possible surgical treatment, described in the literature, encompass cleft lip repair, cleft palate closure, distraction osteogenesis for severe micrognathia, ocular surgery for colobomas, hand surgery, and craniofacial surgery as fronto-orbital remodeling during the first months of life.11,25 Actually, current improvements in prenatal diagnosis and fetoscopic surgical techniques may eventually allow in utero treatment of ABS.26,27 Fetal limb abnormality interventions associated with ABS are described in fetuses with abnormal but present arterial Doppler flow to the distal limb. After evaluating the benefits and high risks of in utero therapy, the constriction band could be released and blood flow re-established. However, this “band lysis” surgery remains a high-risk procedure, with

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Oligny LL. Disorders of the anterior thoracic and abdominal walls. In: Potter’s pathology of the fetus, infant and child. 2nd ed. Gilbert-Barness E, editor. Philadelphia: Mosby‑Elsevier; 2007. p. 935.

10. Boyd TK, Redline RW. Pathology of the placenta. In: GilbertBarness E, editor. Potter’s pathology of the fetus, infant and child. 2nd ed. Philadelphia: Mosby-Elsevier; 2007. p. 663.

Autopsy and Case Reports 2013; 3(1): 15-22 11. Kawamura K, Chung KC. Constriction Band Syndrome. Hand Clin. 2009;25:257-64. PMid:19380064. http://dx.doi. org/10.1016/j.hcl.2008.10.007 12. Streeter GL. Focal deficiencies in fetal tissues and their realtion to intrauterine amputations. Contrib Embryol Carnegie Inst. 1930;22:1-44. 13. Torpin R. Amniochorionic mesoblastic fibrous strings and amniotic bands. Am J Obstet Gynecol. 1965;91:65-75. PMid:14245093. 14. Van Allen MI, Curry C, Walden CE et al. Limb-body wall complex: II. Limb and spine defects. Am J Med Genet. 1987;28:549-65. PMid:2962494. http://dx.doi. org/10.1002/ajmg.1320280303 15. Van Allen MI, Siegel-Bartelt J, Dixon J et al. Constriction bands and limb reduction defects in two newborns with fetal ultrasound evidence for vascular disruptions. Am J Med Genet. 1992;44:598-604. PMid:1481816. http://dx.doi. org/10.1002/ajmg.1320440513 16. Cignini P, Gloriandino C, Padula F, et al. Epidemiology and risk factors of amniotic band syndrome, or ADAM sequence. J Prenat Med. 2012;6:59-63. PMid:23272276 PMCid:3530965. 17. Kalousek DK, Fitch N, Paradice BA. Pathology of the human embryo and previable fetus: an atlas. New York: SpringerVerlag; 1990. PMCid:54875. http://dx.doi.org/10.1007/9781-4757-2111-9 18. Keeling JW, Kjaer I. Diagnostic distinction between anencephaly and amnion rupture sequence bsed on skeletal analysis. J Med Genet. 1994;31:823-9. http:// dx.doi.org/10.1136/jmg.31.11.823 19. Werler MM, Louik C, Mitchell AA. Epidemiologic analysis of maternal factors and amniotic band defects. Birth Defects Research. 2003;67:8-72.

Ferreira CR, Lima CFP, Melo AMAGP. 20. Burk CJ, Aber C, Connelly EA. Ehlers-Danlos syndrome type IV: keloidal plaques of the lower extremities, amniotic band limb deformity, and a new mutation. J Am Acad Dermatol. 2007;56:53-4. PMid:17224388. http://dx.doi. org/10.1016/j.jaad.2006.11.008 21. Van Der Rest M, Hayes A, Marie P, et al. Lethal osteogenesis imperfecta with amniotic band lesions: collagen studies. Am J Med Genet. 1986;24:433-46. PMid:3728562. http://dx.doi. org/10.1002/ajmg.1320240306 22. Coerdt W, Miller K, Holzgreve W, et al. Neural tube defects in chromosomally normal and abnormal human embryos. Ultrasound Obstet Gynecol. 1997;10:410-5. PMid:9476327. http://dx.doi.org/10.1046/j.1469-0705.1997.10060410.x 23. Bower C. Prevention of neural tube defects with folate. J Paediatr Child Health. 2013;49:2-4. PMid:23282182. http:// dx.doi.org/10.1111/jpc.12069 24. Gilbert-Barness, Oligny LL. Chromosomal abnormalities. In: Gilbert-Barness E, editor. Potter’s pathology of the fetus, infant and child. 2nd ed. Philadelphia: Mosby-Elsevier; 2007. p. 213-75. 25. Morovic CG, Berwart F, Varas J. Craniofacial anormalies of the amniotic band syndromes in serial clinica cases. Plast Reconstr Surg. 2004;113:1556-62. http://dx.doi. org/10.1097/01.PRS.0000117185.25173.38 26. Hüsler MR, Wilson RD, Horii SC, et al. When is fetoscopic release of amniotic bands indicated? Review of outcome of cases treated in utero and selection criteria for fetal surgery. Prenat Diagn. 2009;29:457-63. PMid:19235736. http://dx.doi.org/10.1002/pd.2222 27. Neuman J, Calvo-Garcia MA, Kline-Fath BM, et al. Prenatal imaging of amniotic band sequence: utility and role of fetal MRI as an adjunct to prenatal US. Pediatr Radiol. 2012;42:544-5. PMid:22134536. http://dx.doi.org/10.1007/s00247-011-2296-8

Conflict of interest: None Submitted on: 21st December 2012 Accept on: 5th March 2013 Correspondence: Serviço de Anatomia Patológica Hospital Universitário da Universidade de São Paulo Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP 05508-900 – Phone: +55 (11) 3091-9384 E-mail: crisrf@hu.usp.br

Autopsy and Case Reports 2013; 3(1): 23-28

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Rosai - Dorfman disease: a rare entity diagnosed at autopsy João da Costa Veloso Netoa, Sheila Aparecida Coelho Siqueiraa, Maria Claudia Nogueira Zerbinib,c Veloso Neto JC, Siqueira SAC, Zerbini MCN. Rosai-Dorfman disease: a rare entity diagnosed at autopsy. Autopsy Case Rep [Internet]. 2013;3(1): 23-8. http://dx.doi.org/10.4322/acr.2013.004

ABSTRACT Rosai-Dorfman disease (RDD) or Sinus histiocytosis with massive lymphadenopathy is a rare and benign histiocytic proliferative disorder first described by Juan Rosai and Ronald Dorfman in 1969, whose etiology remains unknown. Since then, many cases were reported in the literature. The disease primarily involves the lymph nodes, and is characterized by painless, bilateral cervical lymphadenopathy accompanied by fever, night sweats, malaise and weight loss, reason why many patients are clinically misdiagnosed as malignant lymphoma. In some cases, extranodal involvement may be present. Leukocytosis, elevated erythrocyte sedimentation rate, and hypergamaglobulinemia are often present. The authors report a case of a 52-year-old female patient admitted to the hospital with the diagnosis of pneumonia and progressed to multiple organs failure and death. During the hospitalization an attempt to diagnose a lymphoproliferative disease trough an axillary lymph node biopsy was disappointing. The autopsy was crucial for the diagnosis, illustrating a severe and unusual presentation of Rosai-Dorfman disease. Keywords: Histiocytosis, Sinus; Emperipolesis; Sepsis; Autopsy. CASE REPORT A 52-year-old female patient sought the medical assistance complaining of 6-month history of progressive weight loss of 16kg. More recently she started experiencing thoracic pain followed by pleural effusion, persistent cough and fever. She referred being previously prescribed an antibiotic course without improvement. Physical examination, at admission, showed an ill-looking patient, pale, dehydrated and febrile (38,2 °C); room air oximetry was 97%. Pulmonary examination revealed crepitation rales in the inferior two thirds of both lungs and the remaining exam

was unremarkable. No enlarged lymph nodes were detected. Initial laboratory work up is shown in Table 1. The patient was hospitalized with the diagnosis of pneumonia and antibiotic therapy was promptly started. Clinical outcome was unfavorable progressing with hypotension, respiratory failure, acute renal failure, thrombocytopenia and liver dysfunction, requiring mechanical ventilatory support, intravenous vasoactive drugs and hemodialysis. The β-2 microglobulin determination was 16.5 µg/mL (RV, 1.0-1.7 µg/mL).

Department of Pathology – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. Department of Pathology – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. c Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. a b

Autopsy and Case Reports 2013; 3(1): 23-28

Veloso Neto JC, Siqueira SAC, Zerbini MCN.

Table 1 – Initial laboratory work up Exam

Result

Exam

Result

Hemoglobin

9.0

12.3-15.3 g/dL

Platelet

230

150-400 × 103/mm3

Hematocrit

28.2

36.0-45.0%

Creatinine

0,72

0.4-1.3 mg/dL

Leukocytes

17.47

4.4-11.3 × 10³/mm3

Urea

10-50 mg/dL

Segmented

90.7

46-75%

Sodium

130

136-146 mEq/L

Eosinophil

1.2

1-4%

Potassium

4.4

3.5-5.0 mEq/L

Basophil

0.2

0-2.5%

AST

131

10-31 U/L

Lymphocyte

4.7

18-40%

ALT

9-36 U/L

Monocyte

3.2

2-9%

CRP

236

<5,0 mg/dL

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CRP= C reactive protein ; RV = reference value.

During the hospitalization, an enlarged axillary lymph node was detected and biopsied. The biopsy specimen showed hyperplasia with reactive paracortical pattern associated to focal aggregates of epithelioid histiocytes (CD68+/S100 negative). Additional sections of the paraffin block were analyzed, without contribution to the diagnosis. The patient progressed to neurological dysfunction and coma. The brain magnetic resonance imaging (MRI) showed a hemorrhagic lesion in the right cerebellar hemisphere. The patient did not recover and died after 2 weeks of hospitalization. An autopsy was performed.

Autopsy Findings The external examination showed an obese patient weighing 81 kg, measuring 167 cm showing signs of anasarca, ischemic necrosis at the tip of the tongue, fingers of the upper and lower limbs. At the opening of the cavities a generalized lymphadenomegaly was observed. Lymph nodes of the pulmonary hilum, periaortic, pelvic, and axillary were enlarged, measuring up to 1.8 cm. Microscopically, these lymph nodes showed a Castleman-like appearance, with germinal centers of lymphoid follicles replaced by a proliferation of follicular dendritic cells and deposits of amorphous matrix. The paracortical area was expanded and exhibited vascular proliferation, immunoblasts and histiocytic cells presenting intact lymphocytes emperipolesis. The sinuses were filled by these histiocytic cells some of them showing emperipolesis. These cells were histiocytes S-100+/CD68+/CD1a negative (Figure 1). Gross examination of the pleural cavity disclosed a bilateral, serosanguineaous pleural

effusion with 300 mL in each side. The left lung weighed 469 g (RV, 325-480 g), while the right lung weighed 500 g (RV, 360-570 g) and presented a mild friability in the middle and lower lobes. The microscopic examination showed alveolar septa thickening, intraalveolar edema and foci of neutrophils, histiocytes and desquamating pneumocytes. The pericardial sac overture disclosed a 100 mL of yellow-citrine effusion. The heart was normal in size, weighing 360g (RV, 200-350 g) but presented left ventricular hypertrophy with the posterior wall thickness of 2 cm (RV, 1,5 cm). In the abdominal cavity, the viscera were congested. The liver weighed 2.014 g (VR, 1.400-1.600 g) exhibiting a brownish coloring surface. At cut surface, there were some irregular, poorly defined whitish subcapsular areas, which corresponded to Zahn’s infarct. The spleen was congested, enlarged, weighing 400 g (VR, 150 g). On microscopic examination a lymphocytic depletion was evidenced, associated to S-100 and CD68 positive histiocytes showing lymphocytes emperipolesis. Splenic micro infarctions were also noted. Gastrointestinal tract still showed mild hemorrhagic suffusions in the stomach and in the gastro-esophageal transition. The kidneys were enlarged, weighing 252 g and 292 g, the right and the left respectively (RV, 120-150 g). At cut surface they exhibited a pale cortex, compatible with acute tubular necrosis, confirmed on microscopy. Several bleeding points, compatible with the diagnosis of acute hemorrhagic cystitis, covered bladder mucosa. The pelvic gross examination disclosed the absence of the uterus; a paraanexial hematoma measuring 8.0 × 7.0 cm on the right, a paratubarian cyst and atrophic ovaries.

Rosai - Dorfman disease: a rare entity diagnosed at autopsy

Autopsy and Case Reports 2013; 3(1): 23-28

Figure 1 – Photomicrography of the lymph node showing in A - Histiocytic cells showing emperipolesis (H&E 40×); B - Histiocytic cells S-100+ (40×); C - Histiocytic cells CD68+ (40×); D - Histiocytic cells CD1a negative (40×). The bone marrow was hypercellular, represented by 70% of hematopoietic cells, mainly at the expense of the granulocytic series. S-100+ and CD68+ histiocytes with emperipolesis were present, but in small number (Figure 2). At the opening of the skull, the brain was congested, weighing 1.226g (VR, 1.200-1.600 g), with an acute right cerebellar hemorrhage, measuring 4.0 × 2.6 cm surrounded by gliosis (Figure 3).

DISCUSSION Rosai-Dorfman disease (RDD) or sinus histiocytosis with massive lymphadenopathy is a rare, benign, and idiopathic disorder first described by Juan Rosai and Ronald Dorfman in 1969. It is a self-limiting proliferative histiocytic disorder, in which lymphadenopathy results from infiltration and dilatation of the lymph node sinuses by large foamy histiocytes which engulf intact lymphocytes and/or plasma cells within their cytoplasm, phenomenon known as emperipolesis.1-3 Emperipolesis is considered the most remarkable feature in Rosai-

Dorfman Disease, but may occur in other diseases such as H syndrome, carcinoma, neuroblastoma, multiple myeloma, leukemia, autoimmune hemolytic anemia, and malignant lymphomas (rarely).4-10 The disease affects any age group but occurs mainly in the first two decades of life. Men are slightly more affected (58%) than women and this predominance is highly observed among the African descendents. The most frequent clinical presentation (in 95% of cases) is a massive bilateral and painless cervical lymphadenopathy. Other symptoms include fever, night sweats, malaise and weight loss. Leukocytosis, elevated erythrocyte sedimentation rate and hypergamaglobulinemia, are frequent laboratory alterations.1-3,11 Although it has been investigated for over the last 20 years, the etiology remains fully uncertain. There are some theories that try to correlate the disease with an undefined reactive process or an immune defect triggered by a viral infection, namely: human herpes virus type 6 (HHV6), Epstein Barr virus (EBV) or cytomegalovirus (CMV).2,3,9,12 Although the most common presentation of the disease is represented by the involvement of

Autopsy and Case Reports 2013; 3(1): 23-28

Veloso Neto JC, Siqueira SAC, Zerbini MCN.

Figure 2 – Photomicrography of the bone marrow showing emperipolesis (H&E 40×) (note the enlarged picture on the left bottom depicting a histiocyte CD68+ with emperipolesis. the identification of infiltrating pale eosinophilic histiocytes demonstrating emperipolesis and expressing positivity for S-100, CD68, CD163 antigens, while Langherin and CD1a are typically negative. The RDD cells are moderate to large in size, with a large and round nuclei marginated by a pale chromatin. Some researchers attribute its origin to the bone marrow stem cells.1,3,9,13-16

Figure 3 – Photomicrography of the cerebellum showing acute cerebellar hemorrhage and gliosis (H&E 10×). peripheral or central (mediastinal or retroperitoneal) lymph nodes, extranodal involvement may also be observed, such as the skin, head and neck, breast, brain, gastrointestinal tract, respiratory tract, and orbit. The simultaneous involvement of lymph nodes and extranodal sites occurs in 43% of cases while isolated involvement of extranodal sites occurs in 23% of cases.1-4 Lymph node biopsy is the cornerstone for the diagnosis of RDD, which is characterized by

There is a relationship between the disease and immune disorders such as rheumatologic diseases (mainly rheumatoid arthritis), asthma, glomerulonephritis and Wiskott-Aldrich syndrome. RDD is also observed in association with hematological autoantibodies. Foucar, Rosai and Dorfman published a study, which examined 14 deaths of patients with RDD and found that the most frequent cause of death in this population was related to a marked impairment in the immune system.1,2,9,12,15,17,18 Some differential diagnoses include other histiocytic disorders like Langerhans cell histiocytosis (LCH), hemophagocytic syndrome, and nonspecific sinus hyperplasia. In LCH, the Langerhans cells have a homogeneously stained pink cytoplasm, lobulated nuclei, do not have phagocytic activity and are CD1a positive, besides having Birbeck

RosaiÂ -Â Dorfman disease: a rare entity diagnosed at autopsy

granules by electron microscopic. Hemophagocytic syndrome shows hemophagocytosis mainly of red cells, absence of emperipolesis, and the presence of pancytopenia and hepatosplenomegaly. In reactive sinus hyperplasia emperipolesis is absent. In these two last conditions, the histiocytes are S-100 negative.1,13,15 The generalized lymphadenopathy was the major finding of this autopsy case, which immediately caught the attention for the possibility of a lymphoproliferative disorder. However, the microscopic examination of the lymph nodes, showed the pattern of sinus histiocytosis with emperipolesis. This finding was detected on multiple lymph nodes of different chains, mainly those of deep chains. Although this lymph node commitment is not the typical presentation of Rosai-Dorfman disease, it remained the main hypothesis. The immunohistochemical profile of these histiocytes (S100+/CD68+ and CD1a negative), were conclusive for the final diagnosis. In addition to the lymph nodes, other sites related to the hematological system showed emperipolesis, such as the spleen and bone marrow featuring extranodal involvement of the disease. The impairment of the immune system related to RDD appears to have been responsible for the pneumonia and pleural effusion, ending with the septicemia and refractory shock. The prolonged hypotension in conjunction with vasoactive drugs administration and the possible intravascular disseminated coagulopathy were responsible for the splenic micro infarctions, liver ischemic necrosis, acute tubular necrosis, extremity necrosis (tip of the tongue and fingers), as well as the hemorrhagic findings in the pelvis, brain and gastrointestinal mucosae. The cerebellar hemorrhage, much probably was the immediate cause of death. According to some authors, RDD may show different stages of progression. In many cases, depending on the stage of the disease, the lymph node biopsy may not identify emperipolesis. It is believed that the transformation of monocytes in RDD histiocytes occurs at an early stage and emperipolesis takes some time to emerge. Biopsies performed during this early phase of exacerbation may fail to show emperipolesis and therefore the diagnosis may eventually be compromised. That was observed in this case report, when during hospitalization, the patient underwent an axillary lymph node biopsy, which showed sinus histiocytosis, CD68 positive, and S-100 negative, without emperipolesis.3

Autopsy and Case Reports 2013; 3(1): 23-28

The clinical behavior of RDD is usually benign or indolent presenting spontaneous regression in the majority of patients. In these cases treatment is unnecessary. But in a few patients the disease behaves progressively requiring treatment. Systemic symptoms, as well as lymph nodes enlargement require corticosteroid therapy. In case of compressive symptoms, surgery and highdose corticosteroids should be tried. Radiotherapy may be useful as curative or palliative therapy in resistant cases and when surgery is not feasible. Chemotherapy should be restricted to patients with life-threatening disease or in those non-responsive to standard therapy or after multiples relapses.2,13,18-23 Although rare, Rosai Dorfman disease should always be included in the differential diagnosis of lymphadenopathy. Despite showing striking diagnostic features, it is important to remember that the biopsy specimen may not contain all the elements needed for a final diagnosis, depending on the stage of the disease. Despite being defined as a disease of benign behavior, it is accompanied by severe immune disorders that may lead to severe infectious which can lead the patient to death. In this case autopsy was central to this case elucidation, showing once again the valuable contribution of this examination to clarify a seemingly simple case.

REFERENCES 1.

Chhabra S, Agarwal R, Garg S, Singh H, Singh S. Rosai-Dorfman Disease: a case report with extranodal thyroid involvement. Diagn Cytopathol. 2011;40:447-9. PMid:21630484. http://dx.doi.org/10.1002/dc.21737

Chen J, Tang H, Li B, Xiu Q. Rosai-Dorfman disease of multiple organs, including the epicardium: an unusual case with poor prognosis. Heart Lung. 2011;40:168-71. PMid:20561887. http://dx.doi.org/10.1016/j.hrtlng.2009.12.006

Iyer VK, Handa KK, Sharma MC. Variable extent of emperipolesis in the evolution of Rosai-Dorfman disease: diagnostic and pathogenic implications. J Cytol. 2009:26:111-6. PMid:21938169 PMCid:3168012. http:// dx.doi.org/10.4103/0970-9371.59398

Lopes LF, Bachi MM, Coelho KI, Antico Filho A, Bachi CE. Emperipolesis in a case of B-cell lymphoma: a rare phenomenon outside of Rosai-Dorfman disease. Ann Diagn Pathol. 2003;7:310-3. PMid:14571435. http://dx.doi. org/10.1016/j.anndiagpath.2003.06.002

Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign

Autopsy and Case Reports 2013; 3(1): 23-28 clinicopathological entity. Arch Pathol. 1969;87:63-70. PMid:5782438. 6.

Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a pseudolymphomatous benign disorder. Analisys of 34 cases. Cancer. 1972;30:1174-88. http:// dx.doi.org/10.1002/1097-0142(197211)30:5<1174::AIDCNCR2820300507>3.0.CO;2-S Djaldetti M, Strauss Z. Emperipolesis by megacaryocytes in patients with non Hodgkin’s lymphoma and megaloblastic anemia. J Submicrosc Cytol. 1982 Apr;14(2):407-13. PMid:7077719. Sobolewski S. Phagocytosis by megacaryocytes in malignant disorders. Br J Haematol. 1980;45:173. Colmenero I, Molho-Pessach V, Torrelo A, Zlotogorski A, Requena L. Emperipolesis: an additional common histopathologic finding in H Syndrome and RosaiDorfman disease. Am J Dermatopathol. 2012;34:315‑20. PMid:22356918. http://dx.doi.org/10.1097/ DAD.0b013e31823b99fc

10. Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Disease): review of the entity. Semin Diagn Pathol. 1990;7:19-73. PMid:2180012. 11. Maheshwari A, Seth A, Choudhury M, et al. Rosai-Dorfman disease: a case with lymphadenopathy and liver involvement. J Pediatric Hematol Oncol. 2009;31:200-2. PMid:19262248. http://dx.doi.org/10.1097/MPH.0b013e31818e5369 12. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: an analysis of 14 deaths occurring in a patient registry. Cancer. 1984;54:1834-40. http:// dx.doi.org/10.1002/1097-0142(19841101)54:9<1834::AIDCNCR2820540911>3.0.CO;2-F 13. Henter JI, Tondini C, Pritchard J. Histiocyte disorders. Crit Rev Oncol Hematol. 2004;50:157–74. PMid:15157664. http://dx.doi.org/10.1016/j.critrevonc.2004.01.002 14. Kushwaha R, Ahluwalia C, Sipayya V. Diagnosis of sinus histiocytosis with massive lymphadenopathy (RosaiDorfman Disease) by fine needle aspiration cytology. J Cytol. 2009;26:83-5. PMid:21938160 PMCid:3168026. http://dx.doi.org/10.4103/0970-9371.55229

Veloso Neto JC, Siqueira SAC, Zerbini MCN. 15. O’Malley DP, Duong A, Barry TS, et al. Co-occurrence of Langerhans cell histiocytosis and Rosai-Dorfman disease: possible relationship of two histiocytic disorders in rare cases. Mod Pathol. 2010;23:1616-23. PMid:20729813. http://dx.doi.org/10.1038/modpathol.2010.157 16. Einsen RN, Buckley PJ, Rosai J. Immunophenotypic characterization of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Disease). Semin Diagn Pathol. 1990;7:74-82. 17. Ohori NP, Yu J, Landreneau RJ, Thaete FL, Kane K. RosaiDorfman Disease of the pleura: a rare extranodal presentation. Hum Pathol. 2003;34:1210-1. http://dx.doi.org/10.1016/ S0046-8177(03)00402-7 18. Lai KL, Abdullah V, Ng KS, Fung NS, van Hasselt A. RosaiDorfman Disease: presentation, diagnosis and treatment. Head Neck. 2011 Nov [Epub ahead of print; cited 2012 Dec 20]. Available from: http://onlinelibrary.wiley.com/ store/10.1002/hed.21930/asset/21930_fta.pdf?v=1&t=hct 3eun4&s=57e663fd5bc671e35f8d7bf1d0377c8942808a77. http://dx.doi.org/10.1002/hed.21930 19. Pulsoni A, Anghel G, Falcucci P, et al. Treatment of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): report of a case and literature review. Am J Hematol. 2002;69:67-71. PMid:11835335. http://dx.doi.org/10.1002/ ajh.10008 20. Cooper SL, Chavis PS, Fortney JA, et al. A case of orbital Rosai-Dorfman disease responding to radiotherapy. J Pediatr Hematol Oncol. 2008;30:744-8. PMid:19011471. http:// dx.doi.org/10.1097/MPH.0b013e31817e4ac1 21. Oka M, Kamo T, Goto N, et al. Successful treatment of Rosai-Dorfman disease with low-dose oral corticosteroid. J Dermatol. 2009;36:237-40. PMid:19348664. http://dx.doi. org/10.1111/j.1346-8138.2009.00630.x 22. Horneff G, Jurgens H, Hort W, et al. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): response to methotrexate and mercaptopurine. Med Pediatr Oncol. 1996;27:187-92. http://dx.doi.org/10.1002/(SICI)1096911X(199609)27:3<187::AID-MPO10>3.0.CO;2-D 23. Komp, DM. The treatment of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Semin Diagn Pathol. 1990;7:83-6. PMid:2180015.

Conflict of interest: None Submitted on: 4th January 2013 Accept on: 15th March 2013 Correspondence: Departamento de Patologia Faculdade de Medicina da Universidade de São Paulo Av. Dr. Enéas Carvalho de Aguiar, 255 – 10o andar – São Paulo/SP – Brazil CEP: 05403-000 – Phone: +55 (11) 98352-1500 E-mail: joao-veloso@hotmail.com

Autopsy and Case Reports 2013; 3(1): 29-37

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Somatostatinoma syndrome: a challenging differential diagnosis among pancreatic tumors Paula Martinez Viannaa, Cristiane Rúbia Ferreirab, Fernando Peixoto Ferraz de Camposc Vianna PM, Ferreira CR, Campos FPF. Somatostatinoma syndrome: a challenging differential diagnosis among pancreatic tumors. Autopsy Case Rep [Internet]. 2013;3(1): 29-37. http://dx.doi.org/10.4322/acr.2013.005

ABSTRACT Among the neuroendocrine neoplasia, the pancreatic somatostatinproducing tumors are very rare. Usually functional, these tumors produce the somatostatinoma syndrome, which encompasses diabetes mellitus, diarrhea/steatorrhoea, and cholelithiasis. Other symptoms may include dyspepsia, weight loss, anemia, and hypochlorhydria. All theses symptoms are explained by the inhibitory actions of the somatostatin released by tumoral cells originated from pancreatic delta cells or endocrine cells of the digestive tract. The diagnosis is easy to overlook since these symptoms are commonly observed in other more common syndromes. Besides the clinical features, diagnosis is based on serum determination of somatostatin, and imaging exams, such as ultrasound, computer tomography and positron emission tomography. Pathologic examination is characterized by the positivity of immunohistochemical reaction for synaptophysin, chromogranin, and somatostatin. These tumors can be classified according to tumor size, mitotic index, neural or vascular invasion, and distant metastases. The authors describe the case of a 61-year-old female patient who sought medical care because of a 6-month history of watery diarrhea, weight loss, and depression. She was diagnosed with diabetes mellitus 3 years ago. Imaging examination revealed a tumoral mass of 4 cm in its longest axis in the topography of the head of the pancreas and calculous cholecistopathy. The patient’s clinical status was unfavorable for a surgical approach. She died after 20 days of hospitalization. The definitive diagnosis was achieved with the autopsy findings, which disclosed a pancreatic somatostatinoma. Keywords: Somatostatinoma; Weight Loss; Diarrhea; Depression; Diabetes Mellitus; Gallstones. CASE REPORT A 61-year-old female patient was brought to the hospital with a history of intermittent watery diarrhea for the past 6 months, which became constant during the last month. The diarrhea had no mucus, blood, or steatorrhea, nor was it

accompanied by abdominal pain. She referred being previously obese and used to present constipation. During the last 4 years she had been showing discouragement and a progressive loss of appetite, starting progressive anhedonia, failing to seek

Department of Pathology – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP - Brazil. c Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP - Brazil. a b

Autopsy and Case Reports 2013; 3(1): 29-37

Vianna PM, Ferreira CR, Campos FPF.

medical aid, and avoiding socializing. Concomitantly she presented a weight loss of 50 kg, which was more pronounced over the last 6 months. More recently, she could barely sustain her own weight in the upright position due to muscle atrophy. Her past medical history included the diagnoses of diabetes mellitus and hypertension, and was taking captopril and glibenclamide irregularly, without accurate monitoring. She denied smoking and consumption of alcoholic beverages. She was receiving assistance from neighbors who brought her to the hospital. The initial physical examination showed an illlooking patient, pale, cachectic (weight = 40.1 kg), height = 1.56 m, and body mass index (BMI) = 16.4. Blood pressure = 160/90 mm Hg, pulse rate was regular = 84 beats per minute, respiratory rate = 16 respiratory movements per minute, axillary temperature 36 °C, room air oximetry = 97%, and capillary glucose = 458 mg/dL (reference value (RV); 80-99 mg/dL). Physical examination of the lungs and heart was normal, and the abdomen was flaccid with tenderness on palpation of the hypogastrium (clinically interpreted as a full urinary bladder); intestinal sounds were normal and no other organ enlargement was noted. Initial laboratory work up is shown in Table 1. The patient was initially treated with volume replacement of saline, the potassium imbalance was corrected, and captopril and insulin were prescribed. The diagnostic investigation comprised an abdominal ultrasonography (USG) examination that revealed the presence of a heterogeneous nodular formation, measuring 3.7 × 2.5 × 4.0 cm, which was evidenced on the topography of the head of the pancreas. The gallbladder presented a thin wall

but was distended with multiple images compatible with calculi in its interior. The computed tomography (CT) examination of the abdomen confirmed the USG findings and was complemented with a slight ectasia of the common bile duct (which measured 8 mm). This stressed that the pancreatic lesion had poorly defined limits, showing heterogeneous enhancement after the contrast medium injection, and the duct of Wirsung was somewhat dilated (Figures 1 and 2). CT of the chest and brain, upper gastrointestinal endoscopy, and colonoscopy were normal. Others exams included: determination of serum B12 vitamin, folic acid, and TSH and free T4, which were normal. HIV, hepatitis B and C serologies were all negative. Determination of carcinoembrionic antigen (CEA) = 18 µg/L (reference value (RV) < 3 µg/L), carbohydrate antigen 125 (CA 125) = 7.6 U/ mL (RV < 35 U/mL) and CA 19-9 = 14 U/mL (RV < 37 U/mL). Thus the patient was diagnosed with chronic diarrhea, cachexia, uncontrolled diabetes mellitus, depression, calculous cholecystitis, and a tumor mass in the pancreatic head topography. She progressed presenting continuous epigastric pain and fever. A urinary tract infection was diagnosed and treated with ceftriaxone. On the eighth day of hospitalization, laboratory tests changed with elevation of AST, ALT, AP and γGT serum determinations. Total blood count changed to leukocytosis with neutrophilia accompanied by a shift to the left. Surgical treatment was contraindicated considering the patient’s clinical status to a high-grade severity surgery: gastroduodenopancreatectomy. The patient presented a progressive decrease in the level of consciousness and died on the twentieth day of hospitalization.

Table 1 – Admission laboratory workup RV

Hemoglobin

13.6

12.3-15.3 g/dL

Potassium

2.6

3.5-5.0 mEq/L

Hematocrit

36.0-45.0%

Sodium

140

3.5-5.0 mEq/L

Leucocytes

7200

4.4-11.3 10 /mm

ALT

136-146 mEq/L

Bands

1-5%

AST

9-36 U/L

Segmented

45-70%

γGT

1-24 U/L

Eosinophils

1-4%

10-100 U/L

Basophils

0-2.5%

Amylase

20-104 U/L

Lymphocytes

18-40%

Lipase

30-118 U/L

Monocytes

2-9%

Glucose

421

80-99 mg/dL

Platelets

226.103

150-400 × 103/mm3

HbA1c

16%

<5.4%

Urea

10-50 mg/dL

PT (INR)

1.18

Creatinine

0.5

0.4-1.3 mg/dL

Cai+

1.19

1.11-1.40 mmol/L

AF = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; Cai+ = ionized calcium; γGT = gamma-glutamyl transferase; HbA1c = glycated hemoglobin; INR = international normalized ratio; PT = prothrombin time; RV = reference value.

Somatostatinoma syndrome: a challenging differential diagnosis...

Autopsy and Case Reports 2013; 3(1): 29-37

Figure 1 – Axial computed tomography of the abdomen in the arterial phase. A - Heterogeneous mass in the topography of the head of the pancreas (white arrows) and dilation of the common bile duct (black arrow); B - Dilation of the pancreatic duct (white arrow) and the common bile duct (black arrow). was performed and is summarized in Table 2. This research showed tumor cells diffusely positive for somatostatin and chromogranin A, with a low proliferative rate (Ki-67 < 2%), which allowed the diagnosis of a well-differentiated pancreatic somatostatinoma (Figures 3 and 4).

Figure 2 – Axial computed tomography of the abdomen showing the heterogeneous mass in the topography of the head of the pancreas, a hydropic gallbladder surrounded by a thin liquid layer. Despite the long hospitalization stay, definitive diagnosis could not be done, which is why an autopsy was performed.

Autopsy Findings The abdominal cavity showed adhesion between the stomach, gallbladder and duodenum, with serositis. The pancreas weighed 131.0 g (RV range = 60-135 g), had a tumor located in the head, which was nodular and circumscribed, measuring 4.0 cm in its longest axis. The mass was homogeneous showing well-defined contours without areas of necrosis and hemorrhage. Microscopically, the tumor cells were relatively uniform and round, with finely granular eosinophilic cytoplasm and a centrally located round nucleus, arranged in a trabecular or ribbon pattern, separated by delicate fibrovascular stroma. The histological findings were consistent with pancreatic endocrine tumor. The immunohistochemical study

A distended gallbladder with dark greenish external surface was observed with deposition of friable material surrounded by a thick collection of peritoneal fluid. Upon opening, the gallbladder wall was thick, and contained a thick biliary secretion and micro calculi. The microscopic examination evidenced autolysis, acute inflammatory infiltrate in the wall, and serositis. This histological picture was compatible with acute cholecystitis with cholelithiasis (Figure 5). The common bile duct was dilated with a 1.0 cm diameter. At opening of the duodenum, the duodenal papilla was preserved, without calculous impaction, and with normal bile output with the gallbladder expression (Figure 6). The history of diarrhea and diabetes mellitus associated with the autopsy findings of cholelithiasis with acute cholecystitis allows the diagnosis of somatostatinoma syndrome. The thoracic cavity showed congestion in both lungs. The right lung weighed 417.0 g (RV range = 360‑570 g) and left lung 452.0 g (RV range = 325-480 g), with friable areas on digital pressure. Microscopic examination diagnosed bronchopneumonia, edema, and areas of diffuse alveolar damage (Figure 7). Acute cholecystitis and bronchopneumonia with diffuse alveolar damage led to septic shock.

Autopsy and Case Reports 2013; 3(1): 29-37

Vianna PM, Ferreira CR, Campos FPF.

Figure 3 – A - Gross macroscopic view of the somatostatinoma located in the head of the pancreas - histological appearance of the pancreatic somatostatinoma; B - Panoramic photomicrography of the tumor showing the well circumscribed border (arrow) and the normal pancreatic parenchyma (HE – 25×); C - Photomicrography of the tumor cells arranged in a trabecular or ribbon pattern, separated by delicate fibrovascular stroma (HE – 100×); D - Photomicrography of tumor cells with a relatively uniform and round shape, with fine granular eosinophilic cytoplasm and a central located round nucleus (HE – 400×). Table 2 – Immunohistochemical panel used for diagnosis Antigen

Result

Antigen

Result

Chromogranin A

Positive

Calcitonin

Negative

Somatostatin

Positive

Gastrin

Negative

ACTH

Negative

Glucagon

Negative

Serotonin

Negative

Insulin

Negative

Ki-67

Positive (< 2%)

ACTH = Adrenocorticotropic hormone, PP = pancreatic polypeptide.

Microscopically, the kidneys showed acute tubular necrosis, which may have contributed to the final events. The kidneys also showed benign nephrosclerosis. The heart weighed 334.0 g (RV range = 179-385 g) and showed the left ventricle wall with a mild concentric hypertrophy. The

abdominal aorta showed calcified, not ulcerated, atherosclerosis, which was consistent with the previous systemic arterial hypertension diagnosis. The remaining organs and tissues showed no significant alterations on gross and microscopic examination.

DISCUSSION Somatostatin-producing neuroendocrine tumor is a rare neoplasm usually arising in the pancreas and duodenum. Since its first description in 1977,1,2 less than 200 cases have been reported in the literature up until 2008. The annual estimated incidence is 1 in 40 million, with the median age at onset of 54 years (range, 24-84 years).2-4

Somatostatinoma syndrome: a challenging differential diagnosis...

Autopsy and Case Reports 2013; 3(1): 29-37

Figure 4 – Immunohistochemical photomicrography of the tumor. A - Somatostatin positive (100×); B - Chromogranin A positive (100×); C - Insulin negative in the tumor cells but focal positivity in a Langerhans islet (arrow) in the non-neoplastic parenchyma (100×); D - Ki-67 positive (<2%) (200×).

Somatostatinoma derive from the somatostatin-producing delta cells of the pancreas or the endocrine cells of the digestive tract5,6 and may be sporadic (93.1%) or familial (6.9%) in association with neurofibromatosis type 1 (NF1), multiple endocrine neoplasia type 1 (MEN1), and Von Hippel–Lindau syndromes.4,7-10 Most somatostatinomas (56%) originate in the pancreas and are usually functional. Extra-pancreatic somatostatinomas (44%) are located in the duodenum and occasionally in the biliary tract or small bowel.4,11-15 In most patients, these tumors are symptomatic, with variable nonspecific clinical presentation. Only a few patients may present with the typical clinical somatostatinoma syndrome, which consists of diabetes mellitus, diarrhea/steatorrhoea, and cholelithiasis. Somatostatinoma syndrome was described 2 years after the first somatostatinoma was reported by Krejs in 1979, being more common in pancreatic somatostatinomas than in the duodenal counterpart.16-18 Additional symptoms have been identified and include dyspepsia,

weight loss, anemia, and hypochlorhydria.16 All these symptoms can be explained by the inhibitory actions of somatostatin in the release or action of insulin, glucagon, gastrin, secretin, somatotrophin, thyrotropin, gastric inhibitory peptide, vasoactive intestinal peptide (VIP), pancreatic polypeptide (PP), and cholecystokinin.16,17 The patient of this report presented chronic diarrhea, cachexia, diabetes mellitus, depression, and calculous cholecystitis, which could be considered as symptoms of typical somatostatinoma syndrome. However, these symptoms seemingly were not observed together during the diagnostic process, and the diagnosis of pancreatic somatostatinoma was not taken into consideration. We suspected that the mood disorder (depression), which was probably a result of the pancreatic tumor, explained the delay in seeking medical attention. The unmotivated patient only sought treatment because she was being taken care of by neighbors, reaching the medical facility

Autopsy and Case Reports 2013; 3(1): 29-37

Vianna PM, Ferreira CR, Campos FPF.

Figure 5 – A and B - Gross macroscopic view of distended gallbladder with dark greenish and external surfaces, with deposition of friable material, surrounded by a thick collection; C - Photomicrography of the gallbladder showing evident autolysis and acute inflammatory infiltrate (HE – 25×); D - Photomicrography of the gallbladder wall showing, in detail, the acute inflammatory infiltrate (HE – 400×).

Figure 6 – A and B - Gross macroscopic examination of distended gallbladder and dilated common bile duct; C - Preserved duodenal papilla (arrow) with output of bile with the gallbladder expression.

Figure 7 – A - Gross macroscopic view of right lung showing congested lower lobe; B - Photomicrography of the pulmonary parenchyma showing edema and acute inflammatory infiltrate in the alveolar spaces and bronchus (HE – 100×); C - Area of diffuse alveolar damage with fibrin deposition in the alveolar lumen (HE – 100×).

Somatostatinoma syndrome: a challenging differential diagnosis...

presenting a debilitating nutritional status. During the diagnostic workup, the image of the tumor in the head of the pancreas added to the intense weight loss, probably led the surgeons to think of pancreatic adenocarcinoma. For a curative treatment, this would require a gastroduodenopancreatectomy, which represents a high-grade surgical procedure. As the patient was not clinically prepared for such a procedure, surgical treatment was disregarded. USG is the most sensitive method to demonstrate somatostatinomas of pancreas and duodenum. The sensitivity of trans abdominal USG for detection varies from less than 20% to as high as 80%.19-22 They appear as well circumscribed round or oval hypoechoic masses with smooth margins. The CT and positron emission tomography (PET) images show circumscribed solid masses that tend to displace surrounding structures. Smaller lesions tend to be more homogeneous, and larger lesions are more likely to demonstrate heterogeneous enhancement, a finding due to areas of cystic degeneration, necrosis, fibrosis, and calcification.20 When contrast material is administered, they demonstrate a hyper-vascular pattern.23. The diagnosis is confirmed by documentation of elevated plasma concentrations of somatostatin and the presence of the somatostatinoma syndrome. If the plasmatic basal levels of somatostatin do not indicate values at least three times the normal concentration, diagnostic tests, both stimulatory (with tolbutamide, calcium/pentagastrin, or secretin) and inhibitory (with diazoxide), can be performed.4,24,25 However, serum determination of somatostatin is often overlooked when patients present nonspecific symptoms, as it may happen with the somatostatinoma syndrome. In the case presented here, if the somatostatinoma syndrome had been taken into account, the somatostatin could have been determined. In turn, and the correct diagnosis would have been made, what which possibly could have changed the adopted approach. Pathological examination of the surgical specimen provides the definitive diagnosis. Grossly, somatostatinomas usually occur as solitary (up to 90%), are generally large by the time they are detected (average diameter, 5-6 cm in the pancreas and 2-5 cm in the duodenum), are wellcircumscribed, but not encapsulated, are soft, and nodules are gray-white to yellow-tan in color.1,4,26

Autopsy and Case Reports 2013; 3(1): 29-37

Microscopically, the growth pattern can be solid, nested, trabecular, ribbon like, tubuloacinar, or glandular, and mixed patterns are common in the same tumor.27,28 Psammoma bodies are commonly observed in duodenum somatostatinoma, but rarely in the pancreas.29,30 Immunohistochemical stains for synaptophysin and chromogranin A typically show diffuse positivity. In most cases, the histologic pattern does not determine the functional status of the tumors.31 The accurate diagnosis of somatostatinoma depends on the intense positive immunohistochemical reaction for somatostatin32. In the recent World Health Organization Classification of Tumours Pathology and Genetics of Tumours of Endocrine Organs, Heitz et al.27 proposed criteria for the clinicopathological classification of pancreatic endocrine tumors. Well-differentiated tumors are divided into those with ‘‘benign’’ behavior and those with “uncertain” behavior. The tumors considered as benign include those confined to the pancreas that are nonangioinvasive, without perineural invasion, and less than 2 cm in diameter, with fewer than 2 mitotic figures per 10 high-power fields and less than 2% Ki-67-positive cells. The tumors of uncertain behavior include those confined to the pancreas with any of the following features: greater than or equal to 2 cm in diameter, 2-10 mitoses per 10 high-power fields, greater than 2% Ki-67-positive cells, angioinvasion, or perineural invasion. Welldifferentiated endocrine carcinomas are diagnosed when there is local invasion or metastasis. Poorly differentiated endocrine carcinoma is diagnosed when there are more than 10 mitotic figures per 10 high-power fields.27 The patient of this report had a tumor classified as a well-differentiated tumor with uncertain behavior as it had 4 cm on its longest axis and no metastases. Most somatostatinomas are malignant (71.2%), presenting metastases commonly in the liver, peripancreatic lymph nodes, and bone.3,33 Tumor size is a pertinent prognostic factor.4 The diameter of 2 cm is considered the cut-off value, above which the risk of metastasis significantly increases.26,34 Indeed, by the time they are detected, nearly 30% of duodenal and 70% of pancreatic somatostatinomas have already metastasized to the regional lymph nodes or the liver.30 Treatment largely depends on the site and size of the tumor and the extent of the disease at the time of diagnosis.4 Surgical resection is the treatment of choice.35,36 In cases of locally advanced disease or

Autopsy and Case Reports 2013; 3(1): 29-37

widespread metastases, tumor debulking, chemoembolization of the primary tumor and of hepatic metastases, chemotherapy, somatostatin receptor subtype-selective (SSTR-analogs, octreotide), and interferon–alpha (IFN-α) can be used to control the clinical symptoms.37

CONCLUSION Early detection of pancreatic somatostatinoma could be difficult, in part, by the rarity of the disease and the presence of variable symptoms. This case report not only presents the autopsy findings of a rare entity, but also alerts physicians to the importance of recognizing all symptoms as being part of a syndrome that is usually overlooked. In this case, if the correct diagnosis had been made in her lifetime, perhaps the patient would have benefited from surgical treatment.

REFERENCES 1.

Larsson LI, Hirsch MA, Holst JJ, et al. Pancreatic somatostatinoma: clinical features and physiological implications. Lancet. 1977;309:666-8. http://dx.doi. org/10.1016/S0140-6736(77)92113-4 Soga J, Yakuwa Y. Somatostatinoma/inhibitory syndrome: a statistical evaluation of 173 reported cases as compared to other pancreatic endocrinomas. J Exp Clin Cancer Res. 1999;18:13-22. PMid:10374671.

Marakis G, Ballas K, Rafailidis S, Alatsakis M, Pat-siaoura K, Sakadamis A. Somatostatin-producing pancreatic endocrine carcinoma presented as relapsing cholangitis: a case report. Pancreatology. 2005;5:295-9. PMid:15849491. http://dx.doi. org/10.1159/000085286

Nesi G, Marcucci T, Rubio CA, Brandi ML, Tonelli F. Somatostatinoma: clinico-pathological features of three cases and literature reviewed. J Gastroenterol Hepatol. 2008;23:5216. PMid:17645474. http://dx.doi.org/10.1111/j.14401746.2007.05053.x

Ganda OP, Weir GC, Soeldner JS, et al. Somatostatinoma: a somatostatin-containing tumor of the endocrine pancreas. N Engl J Med. 1977;296: 963-7. PMid:321960. http://dx.doi. org/10.1056/NEJM197704282961703 Kaneko H, Yanaihara N, Ito S, et al. Somatostatinoma of the duodenum. Cancer. 1979;44:2273-9. http:// dx.doi.org/10.1002/1097-0142(197912)44:6<2273::AIDCNCR2820440641>3.0.CO;2-U Kainuma O, Ito Y, Taniguchi T, et al. Ampullary somatostatinoma in a patient with von Recklinghausen’s

Vianna PM, Ferreira CR, Campos FPF. disease. J Gastroenterol. 1996;31:460-4. PMid:8726843. http://dx.doi.org/10.1007/BF02355041 8.

Karasawa Y, Sakaguchi M, Minami S, et al. Duodenal somatostatinoma and erythrocytosis in a patient with von Hippel-Lindau disease type 2. Intern Med. 2001;40:3843. PMid:11201368. http://dx.doi.org/10.2169/ internalmedicine.40.38

Tomassetti P, Migliori M, Lalli S, Campana D, Tomassetti V, Corinaldesi R. Epidemiology, clinical features and diagnosis of gastroenteropancreatic endocrine tumours. Ann Oncol. 2001;12(Suppl. 2):S95-9. PMid:11762360. http:// dx.doi.org/10.1093/annonc/12.suppl_2.S95

10. Usui M, Matsuda S, Suzuki H, Hirata K, Ogura Y, Shiraishi T. Somatostatinoma of the papilla of Vater with multiple gastrointestinal stromal tumors in a patient with von Recklinghausen’s disease. J. Gastroenterol. 2002;37:947-53. PMid:12483251. http://dx.doi.org/10.1007/s005350200159 11. Takashi M, Matsuyama M, Furuhashi K, et al. Composite tumor of mucinous cystadenoma and somatostatinoma of the kidney. Int J Urol. 2003;10:603-6. PMid:14633085. http:// dx.doi.org/10.1046/j.1442-2042.2003.00698.x 12. Walsh IK, Kernohan RM, Johnston CF, Keane PF. Somatostatinoma in a horseshoe kidney. Br J Urol. 1996;78:958-9. PMid:9014735. http://dx.doi.org/10.1046/ j.1464-410X.1996.131935.x 13. Grundmann R, Thul P, Krestin GP, Krueger GR. Somatostatinoma of the liver. Leber Magen Darm. 1985;15:814. PMid:2985897. 14. Ohwada S, Joshita T, Ishihara T, et al. Primary liver somatostatinoma. J Gastroenterol Hepatol. 2003;18:12189. PMid:12974917. http://dx.doi.org/10.1046/j.14401746.2003.03151.x 15. Harris GJ, Tio F, Cruz Junior AB. Somatostatinoma: a case report and review of the literature. J Surg Oncol. 1987;36:816. PMid:3041116. http://dx.doi.org/10.1002/jso.2930360104 16. Krejs GJ, Orci L, Conlon JM. Somatostatinoma syndrome: biochemical, morphologic, and clinic features. N Engl J Med. 1979;301:285-92. PMid:377080. http://dx.doi. org/10.1056/NEJM197908093010601 17. Green BT, Rockey DC. Duodenal somatostatinoma presenting with complete somatostatinoma syndrome. J Clin Gastroenterol. 2001;33:415-7. http://dx.doi. org/10.1097/00004836-200111000-00015 18. Hamy A, Heymann MF, Bodic J, et al. Duodenal somatostatinoma. Anatomic/clinical study of 12 operated cases. Ann Chir. 2001;126:221-6. http://dx.doi.org/10.1016/ S0003-3944(01)00493-X 19. Pitre J, Soubrane O, Palazzo L, ChapuisY. Endoscopic ultrasonography for the preoperative localization of insulinomas. Pancreas. 1996;13:55-60. PMid:8783334. http://dx.doi.org/10.1097/00006676-199607000-00007

Somatostatinoma syndrome: a challenging differential diagnosis... 20. Buetow PC, Miller DL, Parrino TV, Buck JL. Islet cell tumors of the pancreas: clinical, radiologic, and pathologic correlation in diagnosis and localization. Radiographics. 1997;17:453‑72. PMid:9084084. 21. Fidler JL, Fletcher JG, Reading CC, et al. Preoperative detection of pancreatic insulinomas on multiphasic helical CT. AJR Am J Roentgenol. 2003;181:775-80. PMid:12933480. http://dx.doi.org/10.2214/ajr.181.3.1810775 22. Mansour JC, Chen H. Pancreatic endocrine tumors. J Surg Res. 2004;120:139-61. PMid:15172200. http://dx.doi. org/10.1016/j.jss.2003.12.007 23. Malagò R, D’Onofrio M, Zamboni GA, et al. Contrast-enhanced sonography of nonfunctioning pancreatic neuroendocrine tumors. AJR Am J Roentgenol. 2009;192:424‑30. PMid:19155405. http://dx.doi.org/10.2214/AJR.07.4043 24. Farr CM, Price HM, Bezmalinovic Z. Duodenal somatostatinoma with congenital pseudoarthrosis. J Clin Gastroenterol. 1991;13:195-7. PMid:2033227. 25. Roy J, Pompilio M, Samama G. Pancreatic somatostatinoma and MEN 1. Apropos of a case. Review of the literature. Ann Endocrinol (Paris). 1996;57:71-6. French 26. Tanaka S, Yamasaki S, Matsushita H, et al. Duodenal somatostatinoma: a case report and review of 31 cases with special reference to the relationship between tumor size and metastasis. Pathol Int. 2000;50:146-52. PMid:10792774. http://dx.doi.org/10.1046/j.1440-1827.2000.01016.x 27. Heitz PU, Komminoth P, Perren A, et al. Tumors of the endocrine pancreas. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, editors. Pathology and genetics of tumours of endocrine organs. Lyon: IARC Press; 2004. p. 175-208. (World Health Organization Classification of Tumours). 28. Kloppel G, Heitz PU. Tumors of the endocrine pancreas. In: Fletcher CD, editor. Diagnostic histopathology of tumors. 2nd ed. London: Churchill Livingstone; 2000. p. 1083-98.

Autopsy and Case Reports 2013; 3(1): 29-37 29. House MG, Yeo CJ, Schulick RD. Periampullary pancreatic somatostatinoma. Ann Surg Oncol. 2002;9:869‑74. PMid:12417508. http://dx.doi.org/10.1007/BF02557523 30. Mao C, Shah A, Hanson DJ, Howard JM. Von Recklinghausen’s disease associated with duodenal somatostatinoma: contrast of duodenal versus pancreatic somatostatinomas. J Surg Oncol. 1995;59:67-73. PMid:7745981. http://dx.doi.org/10.1002/jso.2930590116 31. Frankel WL. Update on pancreatic endocrine tumors. Arch Pathol Lab Med. 2006;130:963-6. PMid:16831051. 32. Zhang B, Xie QP, Gao SL, et al. Pancreatic somatostatinoma with obscure inhibitory syndrome and mixed pathological pattern. J Zhejiang Univ Sci B. 2010;11:22-6. PMid:20043348 PMCid:2801086. http://dx.doi.org/10.1631/jzus.B0900166 33. Tomono H, Kitamura H, Iwase M, Oyama T, Inui Y, Aoki J. A small, incidentally detected pancreatic somatostatinoma: report of a case. Surg Today. 2003;33:62-5. PMid:12560911. http://dx.doi.org/10.1007/s005950300012 34. Madeira I, Terris B, Voss M, et al. Prognostic factors in patients with endocrine tumours of the duodenopancreatic area. Gut. 1998;43:422-7. PMid:9863490 PMCid:1727238. http://dx.doi.org/10.1136/gut.43.3.422 35. Azimuddin K, Chamberlain RS. The surgical management of pancreatic neuroendocrine tumors. Surg Clin North Am. 2001;81:511-25. http://dx.doi.org/10.1016/S00396109(05)70140-7 36. Sato T, Konishi K, Kimura H, et al. Strategy for pancreatic endocrine tumors. Hepatogastroenterology. 2000;47:537-9. PMid:10791232. 37. Angeletti S, Corleto VD, Schillaci O, et al. Use of the somatostatin analogue octreotide to localise and manage somatostatin-producing tumours. Gut. 1998;42:792-4. PMid:9691916 PMCid:1727128. http://dx.doi.org/10.1136/ gut.42.6.792

Conflict of interest: None Submitted on: 16th January 2013 Accept on: 5th March 2013 Correspondence: Departamento de Patologia Faculdade de Medicina da Universidade de São Paulo Av. Dr. Enéas Carvalho de Aguiar, 155 – 10. andar – São Paulo/SP – Brazil CEP: 05403-000 – Phone: +55 (11) 2661-6090, 2661-6091, 2661-6092 E-mail: viannapaula@hotmail.com

Autopsy and Case Reports 2013; 3(1): 39-44

Article / Clinical Case Reports Artigo / Relato de Caso Clínico Adult Langerhans cell histiocytosis presenting as metachronous colonic polyps Aloísio Felipe-Silvaa,b, Mauricio Saab Assefa,c, Rodrigo Azevedo Rodriguesa,d, Carla Pagliarie Felipe-Silva A, Assef MS, Rodrigues RA, Pagliari C. Adult Langerhans cell histiocytosis presenting as metachronous colonic polyps. Autopsy Case Rep [Internet]. 2013;3(1): 39-44. http://dx.doi.org/10.4322/acr.2013.006

ABSTRACT Langerhans cell histiocytosis (LCH) is a rare disease characterized by proliferation of Langerhans-type cells that express CD1a, Langerin (CD207) and S100 protein. Birbeck granules are a hallmark by ultrastructural examination. LCH presents with a wide clinical spectrum, ranging from solitary lesions of a single site (usually bone or skin) to multiple or disseminated multisystemic lesions, which can lead to severe organ dysfunction. Most cases occur in children. Gastrointestinal tract involvement is rare and has been associated with systemic illness and poor prognosis especially in children under the age of 2 years. Adult gastrointestinal LCH is very rare. We report a case of a previously healthy, nonsmoking 48-year-old male who was referred for routine screening colonoscopy. Two sessile, smooth, firm and yellowish LCH polyps measuring 0.2 cm and 0.3 cm were detected in the sigmoid colon. Fifteen months later a second colonoscopy found two histologically confirmed hyperplastic polyps at the sigmoid colon. No other LCH lesions were seen. A third colonoscopy after 28 months of follow-up found a submucosal 0.5 cm infiltrated and ulcerated LCH polyp in the cecum, close to the ostium of the appendix. The patient had been asymptomatic for all this period. Imaging investigation for systemic or multiorgan disease did not find any sign of extracolonic involvement. On histology all lesions showed typical LCH features and immunohistochemical analysis showed strong and diffuse staining for CD1a and CD207. This case illustrates two distinct clinicopathologic features not previously reported in this particular clinical setting: metachronous colonic involvement and positivity for CD207. Keywords: Histiocytosis; Immunohistochemistry.

Langerhans

Cells;

Intestine,

Large;

Colonoscopy;

Polyps;

Fleury Medicina e Saúde, São Paulo/SP – Brazil. Anatomic Pathology Service – Hospital Universitário - Universidade de São Paulo, São Paulo/SP – Brazil. c Endoscopy Service – Santa Casa de São Paulo, São Paulo/SP – Brazil. d Universidade Federal de São Paulo, São Paulo/SP, Brazil. e Department of Pathology – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. a b

Autopsy and Case Reports 2013; 3(1): 39-44

INTRODUCTION Langerhans cell histiocytosis (LCH) is a proliferation of Langerhans-type cells that express CD1a, Langerin (CD207) and S100 protein, and shows Birbeck granules by ultrastructural examination.1 Discouraged historical synonyms include Histiocytosis X, eosinophilic granuloma, Hand-Schüller-Christian and Letterer-Siwe diseases.

Felipe-Silva A, Assef MS, Rodrigues RA, Pagliari C.

On histology all lesions showed typical LCH features: sheets of large cells with indistinct cell borders and abundant lightly eosinophilic cytoplasm, reniform-to-oval-shaped nuclei with fine, vesicular chromatin, nuclear grooves and single, inconspicuous nucleoli. The three lesions were predominantly submucosal and showed areas of central necrosis (Figure 1C). The cecal polyp showed mucosal infiltration (Figure 1D) and ulceration. Enlarged nucleoli, mitosis and giant cells were absent.

Although classically postulated to originate from mature skin Langerhans cells, recent gene expression profiles studies have shown that LCH is derived from a myeloid dendritic cell, which expresses the same antigens (CD1a, CD207) as the skin Langerhans cell.2

Immunohistochemical analysis of the lesions showed strong and diffuse staining for CD1a (Figure 1E) and CD207 (Figure 1F). Staining for S100 and CD68 was weakly positive and multifocal in both lesions.

LCH presents with a wide clinical spectrum, ranging from solitary lesions of a single site (usually bone or skin) to multiple or disseminated lesions within a single system or even a multisystem, sometimes leading to severe organ dysfunction.3 The incidence of LCH in adults is about 1-2 per million per year.4 Most cases occur in children (1 per 200,000).5 Gastrointestinal tract involvement is rare and has been associated with systemic illness and poor prognosis especially in children under the age of 2 years.6,7 Gastrointestinal LCH in adults is very rare and has been described only in case reports and small series.8-16

DISCUSSION

CASE REPORT A previously healthy, nonsmoking 48-yearold male was referred for routine screening colonoscopy, which revealed two sessile, smooth, firm and yellowish LCH polyps in the sigmoid colon, measuring 0.2 and 0.3 cm (Figure 1A). Fifteen months later a second colonoscopy found two histologically confirmed hyperplastic polyps at the sigmoid colon. No other LCH lesions were seen. A third colonoscopy after 28 months of follow-up found a submucosal 0.5 cm infiltrated and ulcerated LHC polyp in the cecum, close to the ostium of the appendix (Figure 1B). The sigmoid was normal. The patient had been asymptomatic for all this period. Imaging investigation for systemic or multiorgan disease did not find any sign of extracolonic involvement. No specific treatment has been recommended so far.

Adult colonic LCH is extremely rare. Fourteen cases have been reported to date.11-16 Most patients presented with a solitary, non-ulcerative, incidental colonic polyp at colonoscopy and had a benign course. The largest series of adult colonic LCH published to date included a total of eight cases. In this series, two out of eight adult patients with colonic involvement by LCH presented with multiple lesions, one of whom developed cutaneous disease 2 years after the initial diagnosis.14 One patient died of disseminated disease after approximately 5 years of the first symptom (right hip pain related to involvement of the femoral head).11 Most reported cases suggest a more likely benign course of the disease for patients with a solitary, non-ulcerative, incidental colonic LCH polyp identified at colonoscopy (Table 1). We think the present case illustrates two distinct, although not surprising, clinicopathologic features not previously reported in this particular clinical setting: metachronous colonic involvement and positivity for CD207. This might be useful information for future studies in this field. CD207 (Langerin) is a C-type lectin that binds sugar using carbohydrate recognition domains and acts as a pathogen recognition receptor in Langerhans cells. It is an intrinsic molecular component of the Birbeck granules and plays a significant role in their formation.17

Adult Langerhans cell histiocytosis presenting as metachronous colonic polyps

Autopsy and Case Reports 2013; 3(1): 39-44

Figure 1 – A - Endoscopic view of a sessile 0.3 cm LCH polyp in the sigmoid colon; B - Endoscopic view of an ulcerated and infiltrated 0.5 cm LCH polyp in the cecum; C - Photomicrography of a submucosal LCH nodule with central necrosis and ulceration (H&E, 100x); D - Photomicrography of LCH destructive infiltration of colonic crypt (H&E, 400x); E - CD1a immunostaining of infiltrative lesion showed in (D) (400x); F - CD207 immunostaining of the same lesion in (D) (400x). S100 positivity brings the differential diagnosis with malignant melanoma, which may present as a primary or metastatic lesion at the gastrointestinal tract.12 However, malignant melanoma may have different endoscopic and pathological features such as melanin pigmentation, more pleomorphic and atypical cells and immunostaining for other melanocytic markers like HMB45 and Melan A. Melanoma cells are negative for CD1a and CD207. In addition to differential diagnoses with other proliferative histiocytic lesions and malignant

melanoma, it is important to rule out infection, especially parasitic, as a cause of “histiocytic” aggregates with eosinophils in the colon. Of course this is particularly relevant in tropical countries like Brazil. Parasites were not detected in the present case. Another curious differential diagnosis is Crohn’s disease. LCH presenting with colonic skip lesions may simulate Crohn’s disease especially when accompanied by perianal fistulae or ulcers.16,18 Biopsies with careful pathological examination

[11]

[12]

[13]

[14]

[15]

[16]

Present case

Age(y)

Sex

Routine

Abdominal pain, diminished appetite, anemia

Routine

Cecal volvulus

Routine

Constipation

Routine

Anemia

Routine

Right hip and abdominal pain, bloody diarrhea

Abdominal pain, hypopituitarism

Clinical presentation

Polyps, focal ulceration

Ulcerative

Polyp

Ulcerative

Polyp

Ulcerative

Polyps

Endoscopy

Sigmoid, cecum

Colon (random)

Rectum

Cecum, AC

AC, TC, DC

Sigmoid

Cecum

Sigmoid

Cecum

Sigmoid, rectum

Location

Multiple

No.

2 – 5

Size (mm)

Biopsy

Right colectomy

Biopsy

Specimen

Metachronous; hyperplastic polyps

Perianal and gastric disease, metabolic syndrome

Hyperlipidemia; hyperplastic polyps

None

Hyperplastic polyp

None

Adenoma

Ex-smoker

Hypertension

Vulvar and multifocal bone disease

Perianal disease; bone marrow clear

Other findings

ANED (40)

NA; improved with prednisolone

ANED (12)

ANED (24)

Cutaneous Disease (24)

ANED (2)

ANED (5)

ANED (12)

ANED (26)

ANED (7)

ANED (21)

ANED (12)

Died of disease†

Probably ANED (18)

Follow up (mo)

AC = ascending colon; ANED = alive with no evidence of disease; DC = descending colon; F = female; M = male; mo = months; NA = not available; No. = number of lesions; Ref. = reference; TC = transverse colon; y = years. * Size was not specified for each patient; however, range was 1 – 8mm (mean = 4mm and median = 3mm). † Approximately 60 months after the first symptoms.

Ref.

Patient

Table 1 – Clinical and endoscopic findings of reported adult colonic LCH cases

Autopsy and Case Reports 2013; 3(1): 39-44 Felipe-Silva A, Assef MS, Rodrigues RA, Pagliari C.

Adult Langerhans cell histiocytosis presenting as metachronous colonic polyps

and immunohistochemistry make the correct diagnosis. Multiple and repeated biopsies might be necessary.19 Lee-Elliott et al. described a rare case of LCH complicating small bowel Crohn’s disease.20 Some less aggressive forms of LCH may remit spontaneously. For instance, adult pulmonary LCH is a disease of smokers in over 90% of the cases and is thought to represent a reactive process.21 About 20% of the patients are asymptomatic and cigarette-smoking cessation is the first step in the treatment strategy, followed by steroid treatment. As a result, clinical and radiographic improvements are reported.22 Considering the general benign behavior of isolated adult colonic LCH reported to date, we hypothesize that this may be a reactive process similar to adult pulmonary LCH. However, instead of cigarette-smoking, the noxious stimulus is unknown and further clonality studies with large case series are necessary. In summary, adult colonic LCH is a very rare presentation of LCH. To the best of our knowledge this is the first Brazilian case report. The usual clinical picture is that of multiple or solitary asymptomatic benign colonic polyps. Colonic or cutaneous recurrence might occur. Immunohistochemistry is necessary for confirmation and differential diagnosis. Clinical follow up is recommended.

REFERENCES 1.

Jaffe R, Weiss LM, Facchetti F. Tumours derived from Langerhans cells. In: Swerdlow SH, Campo E, Harris NL, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: International Agency of Research in Cancer; 2008. v. 2, p. 358-60.

Allen CE, Li L, Peters TL, et al. Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. J Immunol. 2010;184(8):4557-67. PMid:20220088 PMCid:3142675. http://dx.doi.org/10.4049/jimmunol.0902336

Chang KL, Snyder DS. Langerhans cell histiocytosis. Cancer Treat Res. 2008;142:383-98. PMid:18283796.

Baumgartner I, Von Hochstetter A, Baumert B, Luetolf U, Follath F. Langerhans’-cell histiocytosis in adults. Med Pediatr Oncol. 1997;28(1):9-14. http://dx.doi.org/10.1002/ (SICI)1096-911X(199701)28:1<9::AID-MPO3>3.0.CO;2-P

Bhatia S, Nesbit ME, Egeler RM, Buckley JD, Mertens A, Robison LL. Epidemiologic study of Langerhans cell histiocytosis in children. J Pediatr. 1997;130(5):774-84. http://dx.doi.org/10.1016/S0022-3476(97)80021-2

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Hait E, Liang M, Degar B, Glickman J, Fox VL. Gastrointestinal tract involvement in Langerhans cell histiocytosis: case report and literature review. Pediatrics. 2006;118(5):e1593-9.

Yadav SP, Kharya G, Mohan N, et al. Langerhans cell histiocytosis with digestive tract involvement. Pediatr Blood Cancer. 2010;55(4):748-53. PMid:20535829. http://dx.doi. org/10.1002/pbc.22663

Vazquez JJ, Ayestaran JR. Eosinophilic granuloma of the stomach similar to that of bone: light and electron microscopic study. Virchows Arch A Pathol Anat Histol. 1975;366(2):107‑11. http://dx.doi.org/10.1007/BF00433584

Nihei K, Terashima K, Aoyama K, Imai Y, Sato H. Benign histiocytosis X of stomach. Previously undescribed lesion. Acta Pathol Jpn. 1983;33(3):577-88. PMid:6605021.

10. Iwafuchi M, Watanabe H, Shiratsuka M. Primary benign histiocytosis X of the stomach. A report of a case showing spontaneous remission after 5 1/2 years. Am J Surg Pathol. 1990;14(5):489-96. PMid:2183638. http://dx.doi. org/10.1097/00000478-199005000-00010 11. Hofman V, Hourseau M, Musso S, Martin A, Hofman P. [Langerhans cell histiocytosis of the large bowel]. Ann Pathol. 2002;22(6):461-4. PMid:12594388. 12. Sharma S, Gupta M. A colonic polyp due to Langerhans cell histiocytosis: a lesion not to be confused with metastatic malignant melanoma. Histopathology. 2006;49:438‑439. PMid:16978213. http://dx.doi.org/10.1111/j.13652559.2006.02463.x 13. Kibria R, Gibbs PM, Novick DM. Adult Langerhans cell histiocytosis: a rare cause of colon polyp. Endoscopy. 2009;41(suppl2):E160-E161. PMid:19544280. http://dx.doi.org/10.1055/s-0029-1214689 14. Singhi AD, Montgomery EA. Gastrointestinal tract langerhans cell histiocytosis: A clinicopathologic study of 12 patients. Am J Surg Pathol. 2011;35:305-10. PMid:21263252. http:// dx.doi.org/10.1097/PAS.0b013e31820654e4 15. Shankar U, Prasad M, Chaurasia OP. A rare case of langerhans cell histiocytosis of the gastrointestinal tract. World J Gastroenterol. 2012;18(12):1410-3. PMid:22493557 PMCid:3319970. http://dx.doi.org/10.3748/wjg.v18.i12.1410 16. Roeb E, Etschmann B, Gattenlöhner S. Is it always Crohn’s disease in a patient with perianal fistulae and skip lesions in the colon? Gastroenterology. 2012;143(1):e7-8. PMid:22640732. http://dx.doi.org/10.1053/j.gastro.2011.12.013 17. Valladeau J, Ravel O, Dezutter-Dambuyant C, et al. Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity. 2000;12(1):71-81. http://dx.doi. org/10.1016/S1074-7613(00)80160-0 18. Mittal T, Davis MD, Lundell RB. Perianal Langerhans cell histiocytosis relieved by surgical excision. Br J Dermatol. 2009;160(1):213-5. PMid:19067696. http://dx.doi. org/10.1111/j.1365-2133.2008.08934.x

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Felipe-Silva A, Assef MS, Rodrigues RA, Pagliari C.

19. Magno JCC, D’Almeida DG, Magalhães JP, et al. Histiocitose de células de Langerhans em margem anal: relato de caso e revisão da literatura. Rev Bras Coloproct. 2007;27(1):83‑8. Portuguese. http://dx.doi. org/10.1590/S0101-98802007000100012

21. Yousem SA, Colby TV, Chen YY, Chen WG, Weiss LM. Pulmonary Langerhans’ cell histiocytosis: molecular analysis of clonality. Am J Surg Pathol. 2001;25(5):630‑6. PMid:11342775. http://dx.doi.org/10.1097/00000478200105000-00010

20. Lee-Elliott C, Alexander J, Gould A, Talbot R, Snook JA. Langerhan’s cell histiocytosis complicating small bowel Crohn’s disease. Gut. 1996;38(2):296-8. PMid:8801215 PMCid:1383041. http://dx.doi.org/10.1136/gut.38.2.296

22. Ng-Cheng-Hin B, O’Hanlon-Brown C, Alifrangis C, Waxman J. Langerhans cell histiocytosis: old disease new treatment. QJM. 2011;104(2):89-96. PMid:21084318. http://dx.doi. org/10.1093/qjmed/hcq206

Conflict of interest: None Submitted on: 3rd January 2013 Accept on: 4th March 2013 Correspondence: Grupo Fleury S/A – Setor de Anatomia Patológica Av. Gal. Valdomiro de Lima, 508 – São Paulo/SP – Brazil CEP: 04344-903 – Phone: +55 (11) 5014-7622 E-mail: aloisio.silva@grupofleury.com.br

Autopsy and Case Reports 2013; 3(1): 45-51

Article / Clinical Case Reports Artigo / Relato de Caso Clínico Late infra-renal aortic graft infection: a fearsome complication Fernando Peixoto Ferraz de Camposa, Erasmo Simão Silvab, Nelson De Lucciab, Vivian Helena Ribeirob, Brenda Margatho Ramos Martinesc, João Augusto dos Santos Martinesc Campos FPF, Silva ES, De Luccia N, Ribeiro VH, Martines BMR, Martines JAS. Late infra-renal aortic graft infection: a fearsome complication. Autopsy Case Rep [Internet]. 2013;3(1): 45-51. http://dx.doi.org/10.4322/acr.2013.007

ABSTRACT Since the 1950s, aortic graft infections (AGIs) constitute one of the most feared complications after reconstructive vascular surgery. This complication is not frequent, ranging from 1% to 2% in the recently reported series; however, the high rate of death and morbidity after therapeutic attempts justifies its dreadful fame. The majority of cases occur during the first month after surgery. Staphylococcus aureus is the cause of 70% of the early infection cases. Late infections, on the other hand, are even rarer, showing a strong relationship with low virulence microorganisms, where Staphylococcus epidermidis is the main cause. Gram-negative bacteria are also observed in late infections, mainly when an aortic or graft enteric fistula is present. Treatment modalities are plenty, but still debatable. The authors report a case of a woman who was operated on 6 years ago for a reconstructive aortic aneurysm with the implantation of an infrarenal Dacron graft in the aorto bifemoral position. She looked for medical assistance with a 2-month history of weight loss, abdominal/ back pain, and fever. Her clinical status rapidly deteriorated. A computed tomography of the abdomen disclosed the diagnosis of an AGI. The patient was promptly treated with antibiotics. Surgery was undertaken to explant the infected graft and another graft was placed into the axillobifemoral position. Culture from the infections site was negative. After surgery the patient quickly developed refractory septic shock and died immediately post-operatively Keywords: Aortic Aneurysm; Vascular Grafting; Infection; Diagnosis. CASE REPORT A 73-year-old female patient, previously diagnosed with hypertension, dyslipidemia, and pulmonary emphysema, sought medical assistance complaining of weight loss of 5 kg during the last 2 months. She referred back and abdominal pain, mainly in the hypogastrium and left iliac fossa, which worsened until the day of hospital arrival. She

referred episodes of melena during the last 2 weeks and one episode of enterorrhagia. More recently, she noted chills and fever of 38 °C. Nausea, vomiting, and loss of appetite were added to this clinical picture. She was taking regularly enalapril, hydrochlorothiazide, and simvastatin. She was a heavy smoker. She underwent a gastrectomy with

Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. Department of Vascular Surgery – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. c Diagnostic Imaging Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. a b

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Campos FPF, Silva ES, De Luccia N, Ribeiro VH, Martines BMR, Martines JAS.

Bilroth II reconstruction 10 years ago as she had been diagnosed with a peptic ulcer. Six years ago she was submitted to an infra renal aortic aneurysm angioplasty with a Dacron aorto bifemoral graft for correction of an abdominal aortic aneurysm.

and diffuse blurring of adipose plans around the infrarenal aortic portion were observed, suggesting graft infection (Figures 1 and 2). Splanchnic arteries were patent and the inferior vena cava showed normal caliber and contours. Lymphadenomegaly was evident in the great vessels chain (Figure 3).

Physical examination showed an illlooking patient, pale, and emaciated. Her blood pressure was 110/70 mmHg; pulse rate was irregular = 90 beats per minute; respiratory rate = 20 respiratory movements per minute; and she was afebrile. The heart examination showed arrhythmic cardiac sounds with a systolic murmur; the abdomen was flat, flaccid, but painful on hypogastrium and left iliac fossa palpation. Tenderness was evident on percussion of the left dorsal region. Abdominal sounds were normal, and no signs of peritonitis were detected. Digital rectal examination and anuscopy were normal, and upper gastrointestinal endoscopy ruled out any source of bleeding until the second duodenal portion. The initial laboratory workup is shown in Table 1. The abdominal ultrasound revealed the presence of patent aortoiliac bifemoral prosthesis, but no abnormalities were detected on the remaining accessible regions. The computed tomography scan of the abdomen revealed a tortuous and atheromatous aorta, slightly dilated in the thoracoabdominal transition.

Figure 1 – Computed tomography of the abdomen, arterial phase, and coronal reconstruction. The arrows point to a densification of soft tissue around the aortic prosthesis, with gaseous images in between.

An infrarenal endoprosthesis in aortobifemoral position was patent, without evidence of contrast leakage, but some tiny images associated with gas and enhancement of surround soft tissue Table 1 – Initial laboratory work up Exam

Result

Exam

Result

Hemoglobin

9.6

12.3-15.3 g%

Creatinine

1.5

0.4-1.3 mg/dL

Hematocrit

28.9

36-45%

Urea

10-50 mg/dL

Leukocytes

18.9

4.4-11.3 × 10 /mm 103.10 /mm

Na+

132

135-145 mEq/L

K+

3.5-5.0 mEq/L

AST

10-35 U/L

Myelocytes

Metamyelocytes

Bands

1-5%

Segmented

45-70%

Eosinophils

1-4%

ALT

9-43 U/L

Basophils

0-2.5%

T Bil

0.7

3-5 g/dL

Lymphocytes

18-40%

Amylase

20-104 U/L

Monocytes

2-9%

Platelets

427

150-450 × 103/mm3 103/mm3

INR

1.21

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; INR = international normalized ratio; K+ = potassium; Na = sodium; RV = reference value; T Bil = total bilirubin.

Late infra-renal aortic graft infection: a fearsome complication

Autopsy and Case Reports 2013; 3(1): 45-51

Figure 2 – Axial computed tomography of the abdomen in the arterial phase. Note densification of soft tissue around the aortic endoprosthesis, with gaseous images in between. Note the third portion of duodenum anteriorly displaced.

Figure 3 – Computed tomography of the abdomen. A - Axial plane; B - Coronal reconstruction. Both images show para-aortic lymph adenomegaly (arrow). With the hypothesis of infection of the aortic graft, vancomycin and piperacillin/tazobactan (Tazocin) were prescribed. Surgical treatment consisted in right axillobifemoral bypass with Dacron graft, followed by explant of the infected aortobifemoral graft and ligature of the infrarenal aorta. Surgery was long, eventful, required blood transfusion and the use of vasoactive drugs for hemodynamic stabilization after the infection site manipulation. No aortic or graft enteric fistulas was evidenced during surgery. Culture of the purulent secretion collected from the infection site resulted negative for aerobic bacteria. The patient died after 4 hours of post operatory due to septic shock.

DISCUSSION Since the 1950s, when reconstructive vascular surgery was first reported,1 the most feared complication remains as prosthetic infection

because of the elevated incidence of death and/ or mutilating surgery that surpasses the rate of 70%.2,3 The reported incidence of infection following open abdominal aortic reconstruction ranges from 1% to 2%.1,4-6 This rate may be up to 6% when the distal anastomoses are made to the femorals,7 and appears to be lower (0.45%) when endovascular stent implantation is the technique undertaken.8 The incidence rate of aortic graft infection (AGI) is thought to be underestimated because of the large variation between the interval of the primary surgery and the recognition of infection, and also because the hospital that manages the complication is usually not the same one where the procedure was first undertaken.1 Szilagyi et al.9 first classified the infections in three grades, where grades I and II were restricted to the skin and subcutaneous tissues, and grade III involved the aortic graft. Bunt et al.5 proposed a classification depending on the presence of aorto enteric fistula. Bandik et al.10 classified the infection

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Campos FPF, Silva ES, De Luccia N, Ribeiro VH, Martines BMR, Martines JAS.

based on the microorganisms involved in the process, characterizing those more frequently observed in acute or late complications. Brissonnière et al.11 proposed the classification based on the time of presentation; for example, 3 months before or after the procedure. AGI occurs frequently in the perioperative period until the first month post operative.12 In these cases, Staphylococcus aureus (S. aureus) is the microorganism isolated in 75% of the cases.13,14 This highly virulent microorganism endowed with the capacity of autolysis locally spreads the inflammatory process. More recently, an increase in resistant strains was observed in multiple vascular centers, in Europe and the United States.12 Hodgkiss-Harlow et al.12 showed four-fold increase (from 10% to 40%) in the incidence of methicillinresistant S. aureus (MRSA) in AGI from the year 1990 to 2000. Patient outcomes are less favorable when MRSA is involved compared with methicillinsensitive bacteria.15 A second peak of incidence is observed 25 to 41 months after the aortic reconstruction surgery.16,17 The number of cases of this group of patients increased recently. In these cases, low virulence microorganisms represent the etiological agents. Staphylococcus epidermidis (S. epidermidis) and Gram-negative bacteria are isolated in 40% of these cases. Mixed flora infection is reported in 10-15%.18 The infections caused by Gram-negative bacteria present less favorable behavior and are frequently associated with a high incidence of ruptures and anastomotic failure, probably due to their synthesis of endotoxins, elastase, and proteases.19 Whenever the AGI is related to Gram-negative bacteria, graft enteric erosion should be suspected,12 and Escherichia coli (E. coli)has to be considered first as the causative agent.17 In the case reported here, the microbiologic study resulted negative for isolation of the causative microorganism. Negative cultures are reported in 5-20% of cases.18 No fistula was detected during surgery or by computed tomography (CT). Nevertheless, antibiotic therapy was addressed to provide a wide coverage of possible microorganisms. Graft infections caused by fungi are much rarer and are frequently associated with immunosuppressive conditions like malignancies, chemotherapy, or corticosteroid therapy.1 Many factors are involved in the pathogenesis of AGI; namely, graft material and method of fabrication, site of implantation, duration of the surgery, use of antibiotic prophylaxis, host defense,

nutritional and clinical status of the patient, presence of remote infection, and pathogenicity of the infecting microorganism.10 Dacron vascular graft, used in the first surgery of this patient, has been reported to have a greater propensity for bacterial adherence than expanded polytetrafluoroethylene graft.20 Arterial interventions requiring a groin incision are associated with a higher incidence of graft infection (12%),12 probably due to the frequent wound infections in this region.18 Inappropriate preparation of the patient in emergency situations augments the risk of graft infection. There also an increased risk when the operation is performed in the presence of ischemic ulcers of the lower limbs or concomitantly with biliary, intestinal, or urologic procedures.7,19 Surgical technical difficulties may interfere with the duration of the surgery increasing the risk of operative breaks in sterile techniques.1 Revision of a failed vascular reconstruction also increases the probability of graft infection due to the presence of bacteria within the scar tissue, lymphoceles, suture materials, and on the surface of a previous surgical bed.19 Bacteria may contact the surgical site by several mechanisms, including colonized mural thrombus of a diseased atherosclerotic plaque or aneurysm; bacteremia; bacteria transport from the wound via lymphatic channels; and patient contamination of the surgical incision by noseto-hand transmission.12 The initial step in the infectious process relates to bacterial adhesion to the biomaterial surface, followed by microcolony formation. The inflammatory response involving the surrounding tissues of the graft, impairs the graft healing process, as well as damaging the anastomoses. Gram-negative and Gram-positive bacteria differ in their ability to adhere to biomaterials. In this setting, S. aureus has been shown to adhere to suture material better than E. coli.21 S. epidermidis produce a biofilm, which is an extracellular mucoid substance involved directly in its adherence capacity to medical devices and development of infection.22,23 Bandyk18 stated that the graft infections occurring lately are mainly caused by coagulase-negative staphylococci, which characteristically harbor and survive within the biofilm on biomaterial surfaces. With time, a graft biofilm infection can evolve to a more virulent infectious process, with superinfection by other bacteria such as methicillin-sensitive S. aureus or MRSA.12 Recent case reports have shown the appearance of unusual etiological agents as Streptococcus equi zooepidemicus in patients who had contact with animals or animal products.24

Late infra-renal aortic graft infection: a fearsome complication

After the graft implantation, a thin layer of fibrin covers the porous graft fabric, which is gradually replaced by collagen, resulting in a stable, relatively nonthrombogenic luminal surface resistant to late infection. Bacteria may contaminate the nonendothelized surface of the prosthesis not directly damaging the graft fabric but the surrounding host tissue, which ultimately weakens and disrupts the anastomoses. This disruption leads to a false aneurysm formation, sepsis, graft enteric fistula, hemorrhage, limb loss, or death.1,19 Late graft infections may also occur due to bacterial seeding on the luminal surface after bacteremia caused by dental extraction or dental foci manipulation, urinary tract manipulation, urosepsis, or endovacscular invasive procedures.1,19,25 Clinical diagnosis of AGI is sometimes difficult to outline due to the variety of nondescript and vague clinical complaints. Usually mild fever with little systemic repercussion is the first symptom. This pattern is frequently observed in the minimally symptomatic cases related to low-grade infection. The patient of this report presented a first stage of symptoms characterized by weight loss and fever, followed by 2 weeks of pain and clinical deterioration. After this initial phase, or concomitantly, the patient may complain of back and/or abdominal pain, nausea, vomiting, weight loss, anemia, leukocytosis, and elevated erythrocyte sedimentation rate (ESR) and C-Reactive protein. On the other hand, catastrophic presentations may occur and are represented by septic shock, gastrointestinal hemorrhage, and suture-line disruption.17 In the case of this report, besides having presented melena and hematochezia, it was not possible to find any aortic or graft enteric fistula. Retroperitoneal abscesses are described in 29% of cases; inguinal fistula in 14.5%; septic embolism in 11.3%; and hemorrhagic shock in 9.6%.26 The aorto-enteric fistula derived from an aortoiliac stent infection manifests itself 63% of the time as gastrointestinal bleeding. Occasionally, diagnosis of vascular graft infection can be difficult. Different diagnostic methods can be used to confirm the presence of AGI. CT is considered an accurate method in diagnosing advanced graft infection when, for example, periprosthetic abscess or aortoenteric ﬁstula is present. Perigraft air and/or fluid collections, enhanced perigraft soft tissues, and pseudoaneurysm formation are considered highly suspicious for infection. Considering these findings, CT sensitivity reaches 94% and specificity 85%.27 In the case of this report, CT enabled a diagnosis

Autopsy and Case Reports 2013; 3(1): 45-51

with the criteria listed above. Such CT accuracy is not always observed. In a study of 33 cases of AGI, Fukushi et al.28 demonstrated 64% CT sensitivity and 86% specificity, while Fiorani et al.29 reported an overall CT sensitivity of only 55.5%. CT failed to identify the cases with low-grade graft infection. Gutowski,17 studying 31 patients with deep aortoiliac graft infection, compared different diagnostic methods and concluded that isotopic study with 99m Tc labeled white blood cells showed a sensitivity of 88%, and a specificity of 97%. More recently, the usefulness and accuracy of ﬂuorodeoxyglucose positron emission tomography (FDG-PET) has been studied as a diagnostic tool for vascular graft infection. Activated inflammatory cells show an increased FDG uptake, which makes the method useful for this diagnosis, although its sensitivity varies between 93% and 91%, and specificity between 64% and 91%.28,30 Tegler et al.31 propose that the hybrid method combining FDG-PET and CT has the potential to become an important imaging tool in the management of suspected aortic graft infections. Magnetic Imaging Resonance (MRI) also represents a useful method for diagnosing AGI. In a series of 59 exams, MRI showed a positive predictive value of 95% and a negative predictive value of 80%.32 Management of AGI remains contentious.6 Most vascular surgeons have little experience of major graft infection due to its comparative rarity.7 Before 1986, mortality and amputation rates approached 50%, but it has been decreasing since then.1 A recent study comparing different modalities of treatment for AGI showed an early mortality rate of 33% and a morbidity of 43%, although others show rates between 25% and 35%.33 Batt et al.6 believe that these rates appear more attributable to the patient’s general condition than the choice of treatment. In general, the modalities of treatment are divided into surgical or conservative. Conservative therapy involves long-term antibiotic therapy. Surgical techniques include in situ graft replacement with or without the implant of antibiotics beads on the surgical bed, or the implant of an antibiotic embedded graft; and extra site graft replacement. Both techniques include infected graft explant. The choice of treatment and its consequent outcome will depend on the extension of the infection, the virulence of the involved agent, the presence (or absence) of a biofilm in the infection site, and the clinical status of the patient.

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Campos FPF, Silva ES, De Luccia N, Ribeiro VH, Martines BMR, Martines JAS.

CONCLUSION Despite technological advances regarding the manufacture of vascular grafts, as well as the advances in surgical techniques, infectious complications, although uncommon, are still a concern of vascular surgeons. Late prosthetic infections are among the most feared complications. The insidious and non-specific clinical presentation often hampers the diagnosis. Several therapeutic modalities are proposed, but better outcomes are linked to the patient’s clinical status. In this bleak scenario, the earlier the diagnosis the greater the possibility of a favorable outcome.

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Chiesa R, Astore S, Frigerio L, et al. Vascular prosthetic graft infection: epipdemiology, bacteriology, pathogenesis and treatment. Acta Chir Belg. 2002;102:238-47. PMid:12244902.

Mansfield AO, Sriussadaporn S, Stotter A. The infected vascular graft. Hospital Update 1992; September 1-6.

Naylor AR, Clark S, London NJM, Sayers RD, Macpherson DS, Barrie WW. Treatment of major aortic graft infection: preliminary experience with total graft excision and in situ replacement with a rifampicin bonded prosthesis. Eur J Endovasc Surg. 1995;9:252-6. http://dx.doi.org/10.1016/ S1078-5884(05)80101-7

Hayes PD, Nasim A, London NJ, et al. In situ replacement of infected aortic grafts with rifampicin-bonded prosthesis: the Leicester experience (1992 to 1998). J Vasc Surg. 1999;30:92‑8. http://dx.doi.org/10.1016/S07415214(99)70180-1

Bunt TJ. Synthetic vascular graft infections. Surgery. 1983;93:733-46. PMid:6344294.

Batt M, Jean-Baptiste E, O’Connor S, et al. Contemporary management of infrarenal aortic graft infection: early and late results in 82 patients. Vascular. 2012;20:129-37. PMid:22661612. http://dx.doi.org/10.1258/vasc.2011.oa0315

Quick CRG, Vassalo DJ, Colin JF, Heddle RM. Conservative treatment of major aortic graft infection. Eur J Vasc Surg. 1990;4:63-7. http://dx.doi.org/10.1016/S0950821X(05)80040-4 Ducasse E, Calisti A, Speziale F, Rizzo L, Misuraca M, Fiorani P. Aortoiliac stent graft infection: current problems and management. Ann Vasc Surg. 2004;18:521-6. PMid:15534730. http://dx.doi.org/10.1007/s10016-004-0075-9 Szylagyi DE, Smith RF, Elliot JP, et al. Infection in arterial reconstruction with synthetic grafts. Ann

Surg. 1972,176:321‑33. http://dx.doi.org/10.1097/00000658197209000-00008 10. Bandyk DF. Aortic graft infection. Semin Vasc Surg. 1990;3:122. 11. Association Universitaire de Recherche en Chirurgie, Goeau-Brissonnere O, Doyon F. et al. Étude prospective de 597 prothèses aorto-femorales: resultats preliminaires. 4th Congres International sur la prophylaxie des infections; 1996 Mai 6-7; Nice, France. French. 12. Hodgkiss-Harlow KD, Bandik DF. Antibiotic therapy of aortic graft infection: treatment and prevention recommendations. Semin Vasc Surg. 2011;24:191-8. PMid:22230673. http:// dx.doi.org/10.1053/j.semvascsurg.2011.10.013 13. Bandyk DF. Vascular surgical site infection: risks factors and prevention. Semin Vasc Surg. 2008;21:119‑23. PMid:18774446. http://dx.doi.org/10.1053/j. semvascsurg.2008.05.008 14. Armstrong PA, Back MR, Bandyk DF, et al. Selective application of sartorius muscle flap and aggressive staged surgical debridement can influence long-term outcomes of complex graft infections. J Vasc Surg. 2007;46:71-8. PMid:17606124. http://dx.doi.org/10.1016/j.jvs.2007.02.058 15. Cowie SE, Ma I, Lee SK, et al. Nosocomial MRSA infection in vascular patients: impact on patient outcome Vasc Endovasc Surg. 2005;39:327-34. 16. Goldstone J, Moore WS. Infection in vascular prosthesis: clinical manifestations and surgical manegement. Am J Surg. 1974;128:225-33. http://dx.doi.org/10.1016/00029610(74)90097-X 17. Gustowski P. Aortoiliac graft infection as a diagnostic and treatment problem. Ann Acad Med Stetin.1998;suppl 41:1-72. 18. Bandyk DF. Vascular grafts infections: epidemiology, microbiology, pathogenesis and prevention. In: Bernhard VM, Towes J, editors. Complications in vascular surgery. St Louis: Quality Medical Publishing; 1991. p. 223-34. 19. Bandyk DF. Infection in prosthetic vascular grafts. In: Rutherford RB, editor. Vascular surgery. 5th ed. Philadelphia: Saunders; 2000. p. 773-51. 20. Boyce B. Physical characteristis of expanded polytetrafluorethylene grafts. In: Stanley J, editor. Biologic and synthetic vascular prostheses. Michigan: Grune & Stratton; 1982. p. 553-61. 21. Chih-Chang C, Williams DF. Effects of physical configuration and chemical structure of materials on bacterial adhesion. Am J Surg. 1984;147:197-204. http://dx.doi.org/10.1016/00029610(84)90088-6 22. Bandyk DF, Berni GA, Thiele BL, Towne JB. Aortofemoral graft infection due to Staphylococcus epidermidis. Arch Surg. 1984;119:102-8. http://dx.doi.org/10.1001/ archsurg.1984.01390130084015

Late infra-renal aortic graft infection: a fearsome complication 23. Arciola CR, Montanaro L, Baldassarri L, et al. Slime production by Staphylococci isolated from prosthesis-associated infections. New Microbiol. 1999:22:337-41. PMid:10555204. 24. Altreuter M, Lange C, Myhre HO, Hannula R. Aortic graft infection and mycotic aneurysm with Streptococcus equi zooepidemicus: two cases with favorable outcome of antibiotic treatment. Vascular [Internet]. 2012 Feb 28; [Epub ahead of print; cited 2012 Dec 17]. 25. Veger HT, Hederman Joosten PP, Thoma SR, Visser MJ. Infection of endovascular abdominal aortic aneurysm stent graft after urosepsis: case report and review of the literature. Vascular [Internet]. 2012 May 22; [Epub ahead of print; cited 2012 Dec 17]. PMid:22619381. 26. Fiorani P, Speziale F, Calisti A, et al. Endovascular graft infection: preliminary results of an international enquiry. J Endovasc Ther. 2003;10:919-27. http://dx.doi. org/10.1583/1545-1550(2003)010<0919:EGIPRO>2.0.CO;2

Autopsy and Case Reports 2013; 3(1): 45-51 findings. J Vasc Surg. 2005;42:919-25. PMid:16275448. http://dx.doi.org/10.1016/j.jvs.2005.07.038 29. Fiorani P, Speziale F, Rizzo L, et al. Detection of aortic graft infection with leukocytes labeled with technetium 99m-hexametazine. J Vasc Surg. 2007;21:586-92. 30. Keidar Z, Engel A, Hoffman A, et al. Prosthetic vascular graft infection: the role of 18F-FDG PET/CT. J Nucl Med. 2007;48:1230-6. PMid:17631553. http://dx.doi. org/10.2967/jnumed.107.040253 31. Tegler G, Sörensen J, Björck M, et al. Detection of aortic graft infection by 18-fluorodeoxyglucose positron emission tomography combined with computed tomography. J Vasc Surg. 2007;45:828-30. PMid:17398393. http://dx.doi. org/10.1016/j.jvs.2006.12.018

27. Low RN, Wall SD, Jeffrey RB, et al. Aortoenteric fistula and perigraft infection: evaluation with CT. Radiology. 1990;175:157-62. PMid:2315475.

32. Shahidi S, Eskil A, Lundof E, Klaerke A, Jensen BS. Detection of abdominal aortic graft infection: comparison of magnetic resonance imaging and indium-labeled white blood cell scanning. Ann Vasc Surg. 2007;21:586-92. PMid:17823040. http://dx.doi.org/10.1016/j.avsg.2007.03.018

28. Fukushi K, Ishida Y, Higashi M, et al. Detection of aortic graft infection by flouorodeoxyglucose positron emission tomography: Comparison with computed tomographic

33. Lawrence PF. Conservative treatment of aortic graft infection. Semin Vascular Surg. 2011;24:199‑204. PMid:22230674. http://dx.doi.org/10.1053/j.semvascsurg.2011.10.014

Conflict of interest: None. Submitted on: 18th December 2012 Accept on: 5th March 2013 Correspondence: Divisão de Clínica Médica Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9200 E-mail: ffcampos@usp.br

Autopsy and Case Reports 2013; 3(1): 53-61

Article / Clinical Case Reports Artigo / Relato de Caso Clínico Neuromyelitis optica: a challenging diagnosis at secondary hospital Anna Paula Romero de Oliveiraa, Patrícia Tarantoc, Livia Herbstc, Andre Kiriharac, Maira Letícia Verasc, André Macedo Serafim Silvac, Marcio Ricardo Taveira Garciab, Angelina Maria Martins Linoc,d Oliveira APR, Taranto P, Herbst L et al. Neuromyelitis optica: a challenging diagnosis at secondary hospital. Autopsy Case Rep [Internet]. 2013;3(1): 53-61. http://dx.doi.org/10.4322/acr.2013.008

ABSTRACT Known since the 19th century, neuromyelitis optica (NMO), or Devic’s disease, is an idiopathic immune-mediated inflammatory demyelinating disease of the central nervous system selectively affecting the optic nerve and spinal cord. Commonly diagnosed in demyelinating diseases reference centers, we report an 18-year-old female patient who sought medical attention with a 3-month history of weight loss, headache, and vomiting, followed by diplopia, a burning sensation over the lower limbs, and difficulty walking. A few days prior to hospital admission, the muscle strength in her lower limbs became worse and ascended to the upper limbs associated with sensory changes in the trunk and voiding dysfunction. At admission, the neurological examination was consistent with a spinal cord syndrome. After few days of hospitalization, she was tetraplegic with severe signs of brainstem involvement requiring mechanical ventilatory support. Intravenous methylprednisolone and cyclophosphamide were promptly started after ruling out the diagnosis of infectious disease and cord compression. Due to no substantial early improvement, intravenous immunoglobulin was also used. From then on, the neurological status gradually improved. Magnetic resonance imaging showed extensive demyelinating features in the spinal cord, and the serum IgG autoantibody was negative. The patient was referred to a tertiary neurological reference center where she remains under treatment. Keywords: Neuromyelitis Optica; Demyelinating Diseases; Respiratory Insufficiency; Magnetic Resonance Imaging; Pulse Therapy; Drug. CASE REPORT A previously healthy, 18-year-old female patient of African descent sought medical care with a history of weight loss of 14 kg during the last 3 months simultaneously with headache and vomiting. Two weeks after the onset of the symptoms, she

started with diplopia and a burning sensation over the lower limbs that lasted for a month and progressed to face and scalp allodynia. She also had gait instability. A few days before hospital admission, the muscle strength of her lower limbs

Scientific Division – Instituto de Infectologia Emílio Ribas, São Paulo/SP – Brazil. Department of Radiology - Hospital das Clínicas - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP – Brazil. c Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. d Department of Neurology – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. a b

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Oliveira APR, Taranto P, Herbst L et al.

became impaired and ascended to the upper limbs. This was associated with sensory changes in the trunk and urinary incontinence.

resonance imaging (MRI) was not performed initially due to clinical instability and because transport to another institution was considered life threatening.

Initial examination showed an ill-looking patient with preserved cognitive functions, emaciated, pale, acyanotic, and with stable hemodynamic parameters. She denied dyspnea. Neurological examination showed slight asymmetric tetra paresis with muscular strength of grade 0 in the lower right limb and grade 3 in the upper right limb, and grade 1 in the lower left limb and grade 3 in the upper left limb. Deep tendon reflexes were absent in the upper limbs but were brisk with extensor plantar response in the lower limbs. All sensory modalities were compromised in limbs and trunk at T2 level. Cranial nerves were normal. Catheterization was necessary due to voiding dysfunction.

Based on the clinical prodrome (weight loss, vomiting, headache with unknown origin), neurological presentation (transverse myelitis, quickly progressing to brainstem dysfunction), compressive cord lesion dismessed by tomographic study, CSF inflammatory abnormalities, and negative workup to more common infectious agents, the diagnosis of neuromyelitis optica (NMO) was highly considered. Pulse therapy with methylprednisolone (1g/day for 5 days), in addition to cyclophosphamide (1 g), was started as soon as her neurological status became worse. After 1 week of pulse therapy, her neurological impairment remained unchanged, except for muscle strength grade 3 at wrist extension in both hands. Therefore, intravenous immune globulin (400 mg/kg/day for 5 days) was also prescribed. Prednisone 40 mg/ day was continued until the next pulse. From that time, her neurological deficits started to gradually improve. She received one more pulse before the hospital discharge. She was discharged without tracheostomy with normal ventilatory parameters, and independent for eating after 40 days of hospitalization. She was unable to walk, but was able to remain seated without aid. The muscle strength was grade 4 with distal predominance in the upper limbs, and was grade 3 proximal and grade 2 distal in the lower limbs. The deep tendon reflexes persisted as brisk in the lower limbs, and hypoactive in the upper limbs, but a brisk finger flexor response was obtained when bicipital reflex was searched in the left side. She also complained of visual blurring at the left eye with normal acuity, although a slightly pale optic disk was detected, and the vertical nystagmus was persistent. The sensory deficit remained at T2 level; however, there was an improvement of the vibratory perception at the knees. She regained the voiding control.

Initial laboratory workup included ANA and other inflammatory markers; serology for hepatitis B and C, HIV, HTLV, and syphilis showed negative results; blood and urine cultures were also negative. The lumbar cerebral spinal fluid (CSF) analysis disclosed slight inflammatory changes (Table 1) with negative results for China ink and cultures (aerobic, fungal, and acid fast bacilli). The brain and spine computed tomographies were normal. After 3 days in hospital, she rapidly evolved with plegia in all limbs, nasal voice and swallowing disturbances with preserved bulbar reflexes, vertical nystagmus, bilateral internuclear ophthalmoparesis, and acute respiratory failure that required mechanical ventilatory support. Magnetic Table 1 – Lumbar cerebrospinal fluid analysis Parameter

Result

Reference value

11 93 7 0

1-4 50-70 30-50 <2

63 1.7 70.8 2.5 5.8 10.4 1.7 10.0

15-40 3.0-7.0 45-70 3.0-7.0 5.0-11.0 7.0-13.0 4.0-10.0 5.0-14.0

2/3 glycemia

Adenosine deaminase U/L

1.23

<4.0

Lactate mg/dL

17.6

10-20

White blood count cell/mm Lymphocytes % Monocytes % Neutrophils %

Protein mg/dL Prealbumin % Albumin % α-1 Globulin % α-2 Globulin % β Globulin % δ Globulin % γ Globulin % Glucose mg/dL

Despite an MRI having been done 20 days after immunosuppressive treatment, areas of signal alteration in the brain stem, optic nerve and tract, left thalamus and basal ganglia with demyelinating features were found at brain imaging study (Figure 1 and 2) Diffuse signal alteration throughout the cervical and thoracic segment, characterized by elongated hyperintense areas on T2-weighted and FLAIR images, was observed. These areas were predominantly located at the periphery of the cervical

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Autopsy and Case Reports 2013; 3(1): 53-61

Figure 1 – Axial MRI images of the Brain weighted in T2 showing slight hyperintense areas in the brainstem (pons) (A), periaqueductal (B), and basal ganglia (C) with demyelinating features.

Figure 2 – Coronal MRI images of the Brain weighted in T1 gadolinium injection, showing thickness and contrast enhancement in left optic nerve (A) and tract (B). level, and centrally located at mid-thoracic level with small areas of vanished gadolinium enhancement. These alterations were continuous and confluent with slight expanding effect (Figure 3). Tested in a frozen (−20ºC) stored sample, serum IgG-NMO was negative.

DISCUSSION Devic’s disease or NMO is an idiopathic immune-mediated inflammatory demyelinating disease of the central nervous system (CNS) that selectively affects the optic nerve and spinal cord.1,2 Partial or complete, unilateral or bilateral, visual loss represents optic nerve impairment, while para- or tetraplegia or paresis, sensory loss, and sphincter dysfunction exemplify spinal cord involvement.

Historically, the first three cases were reported by Portal in 1804, Pescetto in 1844, and Clarke in 1865.3 The first association between myelitis and optic disorder was mentioned by Allbutt in 1870. In 1882, Dreschfeld first suggested that the combination of myelitis and optic neuritis was a clinical syndrome. Devic defined the clinical entity “neuromyélite optique” in 1894, and since then this condition has been called Devic’s disease.1,4 Several cases and series reports have been published and various diagnostic criteria have been proposed since then. Initially considered as a subtype or clinical variant of multiple sclerosis for many decades, NMO had its own clinical identity, which was defined in 2004 after the discovery of the specific autoantibody (IgG-NMO) whose antigen aquaporin-4 (AQP4) was characterized 1 year later.5,6 After the broad clinical NMO definition proposed by Gault and Devic, several diagnostic

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Oliveira APR, Taranto P, Herbst L et al.

Figure 3 – Sagittal MRI images, (A) of the cervical spine weighted in T2 showing peripheral lesions (arrows), while those of thoracic spine are centrally distributed in (C) (arrows). (B) - sagittal T1 MRI image of the cervical spine after gadolinium injection showing slight enhancement of lesions (arrow). Axial T2 MRI images of de cervical (D) and thoracic (E) spines show hyperintense intramedullary lesions (arrows). criteria appeared in the literature and some of them are presented in Table 2.7-11 They could roughly be divided into three periods: the first period may be coined as the pre-MRI era in which the diagnosis was only based on clinical findings of spinal cord and/or optic nerve lesion at the same time that other diseases that shared similar neurological symptoms and signs were ruled out. The second period is characterized by the inclusion of MRI abnormalities, and the third period was defined by serum IgGNMO status. Nowadays there is a growing trend to expand the NMO clinical spectrum.12

Commonly, the initial presentation of NMO can be visual loss (in 45% of patients) or myelopathy (38%) that usually appear 3 months apart in most cases. The simultaneous involvement of the spinal cord and optic nerve, as was observed in this case report, can occur in 17%.4,10 A prodrome of fever, myalgia, sore throat or headache is present in around one-third of cases. In pediatrics, NMO is preceded by infection in 72% of patients. After the inaugural neurological event, the clinical course may be either monophasic, with no further events, or relapsing with additional attacks of myelitis, optic neuritis or both.1,4 Relapsing NMO is twice as frequent than the

Neuromyelitis optica: a challenging diagnosis at secondary hospital

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Table 2 – Diagnostic criteria of neuromyelitis optica Year

Author(s)

Criteria

1894

Gaut and Devic1,3

Retrobulbar neuritis or papilitis + acute myelitis With/without other symptoms or signs not restricted to the spinal cord or optic nerve

1981

Shibasaki et al.6

Acute bilateral visual impairment and transverse myelitis occurring successively <4 weeks following a monophasic course

1993

Mandler et al.7

1996

O’Riordan et al.8

1999

Wingerchuk et al.9

All absolute criteria + one major supportive criterion or two minor supportive criteria Absolute criteria 1. Optic neuritis 2. Acute myelitis 3. No evidence of clinical disease outside of the optic nerve or spinal cord Major supportive criteria 1. Negative brain MRI at onset 2. Spinal cord MRI lesion extending over > 3 vertebral segments 3. CFS pleocytosis of > 50 WBC/mm3 or > 5 neutrophils/mm3 Minor supportive criteria 1. Bilateral optic neuritis 2. Severe optic neuritis with fixed visual acuity worse than 20/200 in at least one eye 3. Severe, fixed, attack-related weakness (MRC grade < 2) in one or more limbs

2006

Wingerchuk et al.10

Revised criteria for definite NMO Optic neuritis Acute myelitis At least two of three supportive criteria 1. Contiguous spinal cord lesion extending over > 3 vertebral segments 2. Bran MRI not meeting diagnostic criteria for multiple sclerosis 3. NMO-seropositive status

Clinical 1. Acute lesion of spinal cord and nerve optic, coincidental or separated by months or years 2. Without brainstem, cerebellar or cortical features Imaging 1. Enlargement and cavitation on spinal cord MRI 2. Normal-appearing brain MRI CFS 1. Decreased serum/CFS albumin ratio 2. Normal IgG synthesis 3. Usually absence of oligoclonal bands Pathology 1. Spinal cord necrosis and cavitation, thickened vessel walls, absence of inflammatory infliltrates 2. Demyelination of optic nerve with or without cavitation 3. No demyelinating lesions in brain, brainstem, or cerebellum 1. Complete transverse myelitis evolving over 1–14 days, with sensory level and in the absence of cord compression 2. Acute unilateral or bilateral optic neuropathy 3. No clinical involvement beyond the spinal cord or optic nerves 4. The disease can be monophasic or multiphasic

monophasic type and commonly associated with the female gender, older age onset, less severe motor impairment in the first myelitis attack, and the presence of systemic autoimmunity.1,4,10 The neurological impairment is usually more severe in

monophasic NMO. The severity of disease onset ranges from fulminant and fatal (around one-third) to recovery with varying degrees of disability. In pediatrics generally, the outcome is favorable with complete neurological recovery.4

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Table 3 – More common differential diagnosis in NMO syndrome Systemic immune-mediated inflammatory diseases

Systemic lupus erytemathosus Sjögren syndrome Mixed connective tissue disease Antiphospholipid antibody syndrome Sarcoidosis Paraneoplastic syndrome

Infections Viral

Cytomegalovirus Varicella-zoster virus Epstein-Barr virus Human immunodeficiency virus

Bacterial

Syphilis Tuberculosis Borreliosis

Parasites

Schistosoma mansonii Toxocara spp

Toxicity

Methanol Ethylene glycol Ethambutol Clioquinol Chemotherapeutic agents Radiation

Nutritional deficiency

Vitamin B12

Idiopathic central nervous system demyelinating diseases

Multiple sclerosis Neuromyelitis optica Acute disseminated encephalomyelitis Idiopathic optic neuritis

Neoplasia

Lymphoma

In the case of this report, the earliest symptoms were vomiting, weight loss, and headache. Currently, it is well known that approximately 15% of NMO patients have symptoms and signs indicating disease outside the optic nerve and spinal cord, which can antedate or occur during the course of the disease.1,10,12 Some of these cases could be justified by high expression of AQP4 and consequent susceptibility to immune attack by the antibody anti-AQP4. For instance, intractable hiccups, nausea, and vomiting are the most common brain symptoms in NMO due to involvement of the area postrema. In addition, hypothalamic lesions could explain anorexia and weigh loss, hyperphagia and obesity, hypothermia, fever, syndrome of inappropriate secretion of antidiuretic hormone and other endocrine dysfunction, diffuse anhydrose, bradycardia, hypotension, and recurring episodes of coma. Confusion, decreased consciousness, coma, ocular movement disturbances, retrochiasmal visual field defects, cortical blindness, seizures, and aphasia could be present as encephalopathic manifestations.

NMO has been associated with other autoimmune diseases, which are a part of large differential diagnosis presented in Table 3. Antinuclear antibodies (ANA), anti-SSA, antiSSB, anti-cardiolipin, perinuclear antineutrophil cytoplasmatic (ANCA), anti-thyroid peroxidase are some examples of circulating autoantibodies that can occur without their associated systemic clinical condition.1 Regardless of differences in the data collection and diagnostic criteria, several authors have reported that NMO is more prevalent in areas with Black, Asian, and Indian populations.1,13 For example, in North American and European countries, NMO constitutes less than 1% of CNS demyelinating diseases while it accounts for 98% and 17.3% in Nigerian and French AfricanCaribbean nationalities, respectively.4,14,15 Few Brazilian studies disclosed 11% of Devic’s disease diagnosed among African descendants.16,17 Women are overrepresented in all NMO series; for instance, 9:1 in China, 5:1 in Brazil, and 9:1 in Martinique. In the USA, rates of 1:1 in monophasic NMO and 5:1 in recurrent NMO are shown.1 The median age of

Neuromyelitis optica: a challenging diagnosis at secondary hospital

symptoms onset ranges from 40 years in relapsing NMO and 29 years in the monophasic type. The median age in pediatrics was 4.4 years.1,4,18 Since the phenotype of NMO can be shared with several diseases in which optic neuritis and myelitis are present isolated or simultaneously, the differential diagnoses are very broad and should be carefully explored (Table 3). An ally to cardinal neurological symptoms and signs, MRI is one of the most important auxiliary exams for NMO diagnosis. As observed in the case reported here, the spinal cord study shows longitudinally extensive areas of increased signal intensity on T2-weighted and FLAIR images (demyelinating features) extending through several vertebral segments, with varying degrees of gadolinium enhancement on T1-weighted images, and, in the acute phase, a marked swelling of the cord could simulate a tumorigenic lesion.12,19 A cavity is seen in cases with severe disease, and cord atrophy appears in late stages. Brain MRI may be normal or show nonspecific changes; when white matter abnormalities are present, they are considered “not typical for multiple sclerosis” or, characteristically, are found in areas with high expression of AQP4 (hypothalamus, areas surrounding the third and fourth ventricles).20 The optic nerve can show the same demyelinating features. Another diagnostic auxiliary exam is CFS analysis. Commonly, cell counts are less than 50 cells/mm3 in which neutrophils and eosinophils may be present.9 Generally, protein content is increased, IgG index is normal, and oligoclonal bands are usually absent.21 Serum identification of IgG-NMO has an important role in diagnostic workup. Nowadays there are several laboratory assays based on indirect immunofluorescence. The first and more widespread laboratory technique uses mouse brain tissues as substrate and shows a sensitivity ranging from 55% to 73% and specificity from 90% to 100%. Albeit not commercially available and using human AQP4-transfected cells as substrate, this test has 73–91% of sensitivity and 100% of specificity for NMO.1,12 Considering the immunopathogenesis of NMO, since very early the demyelination of optic nerve and spinal cord were observed along with polymorphonuclear infiltrates. In 1949, it

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was suggested that pathological lesion occurred in stages with perivascular inflammation being the earliest.22 As recently demonstrated in an autopsy series, immunoglobulin deposition, activated complement, eosinophils, and myelin protein reactive macrophages were found in the perivascular space of spinal cord blood vessels suggesting that this space was the target for humoral autoimmune attack.23 This research culminated in the identification of IgG-NMO that binds to AQP4 in the abluminal face of cerebral microvessels which correspond to astrocytic foot processes.5,6 Aquaporins encompass a family of water channels, which control the water transport in several organs. AQP4 is the most abundant aquaporin in the mammalian brain (astrocytes and ependymal cells) and its loss may result both in severe damage of myelin and axons in vulnerable areas in which it is overexpressed (spinal cord, optic nerves, hypothalamus, and periventricular and periaqueductal structures).24,25 Although useful for diagnostic purposes, IgG-NMO titer has no correlations with disease duration, the number of relapses, or the effects of immunotherapies.1 In addition, there is no definite evidence that anti-AQP4 antibody causes NMO because its administration to experimental models does not reproduce the disease and AQP4-knockout mice do not express the NMO phenotype. Also, other questions remain unanswered, such as the predominance of spinal cord and optic nerve lesions, while AQP-4 is ubiquitously expressed throughout – not only in CNS, but also in kidneys, lungs, inner ear, and intestine. Lastly, one could ask, what trigger event opens the blood-brain barrier? NMO treatment starts with high-dose intravenous methylprednisolone (1 g/day for 5 consecutive days).1 In cases of corticotherapy resistance, plasma exchange therapy is helpful but does not prevent further relapses.10,26 Lymphocytapheresis could be used in bilateral blinded and tetraplegic patients who were unresponsive to high-dose intravenous corticosteroid and plasma exchange or intravenous immunoglobulin treatment.27 This therapeutic protocol is also applied to recurrent attacks. Early prophylactic treatment is recommended, mainly in IgG-NMO-positive patients, to avoid future relapses.1 From anecdotal published experiences in NMO treatment, each service designed its own drug protocol, generally based on immunosuppressive drugs (azathioprine, cyclophosphamide, methotrexate, mitoxantrone, mycophenolate mofetil).28-31 More recently, rituximab

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(chimeric murine/human monoclonal anti-CD20) has been used showing a decrease in the relapse rate and improvement in neurological disability.32 Using neatly clinical criteria as stated by O’Riordan et al.9 in 1996, NMO was suspected in our patient. When MRI had been done, the 1999 Wingerchuck et al.10 criteria were obeyed. The longitudinally and extensive spinal cord and brain lesions at MRI studies were all concordant with literature data. Taking into account the low sensitivity of IgG-NMO commercially available, a negative result did not exclude this diagnosis. Taking in account the severity of clinical presentation, and bearing in mind the massive inflammatory infiltration pathological process involved in this entity, which can lead to tissue destruction (cavitation), an early immunosuppressant therapy was added to corticosteroid and thereafter complemented by intravenous immunoglobulin.

CONCLUSION In a secondary health setting, NMO diagnosis is a challenging one because MRI and IgG-NMO reactions are not easily available. These important subsidiary exams have to be done at tertiary or private hospitals and they take time. In severe neurological involvement, this delay can be life threatening. In addition, therapeutic options as plasma exchange and intravenous immunoglobulin are not easily available. After a fast exclusion of infectious diseases, we assume that prompt immune therapeutic intervention is fundamental for achieving more favorable outcomes.

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Jarius S, Wildemann B. The case of the Marquis de Causan (1804): an early account of visual loss associated with spinal cord. J Neurol. 2012;259:1354-7. PMid:22237820. http:// dx.doi.org/10.1007/s00415-011-6355-8

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Lennon VA, Kryser TJ, Pittock SJ, Verkerman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005;202:473-7. PMid:16087714 PMCid:2212860. http://dx.doi.org/10.1084/ jem.20050304

Shibasaki H, McDonald WI, Kuroiwa Y. Racial modification of clinical picture of multiple sclerosis comparison between British and Japanese patients. J Neurol Sci. 1981;49:253-71. http://dx.doi.org/10.1016/0022-510X(81)90083-6

Mandler RN, Davis LE, Jeffery DR, Kornfeld M. Devic’s neuromyeloitis optica: a clinical pahological study of 8 patients. Ann Neurol. 1993:34:162-8. PMid:8338340. http:// dx.doi.org/10.1002/ana.410340211

O’Riordan JI, Gallagher HL, Thompson AJ, et al. Clinical, CSF, and MRI findings in Devic’s neuromyelitis optica. J Neurol Neurosurg Psychiatry. 1996;60:382-7. PMid:8774400 PMCid:1073888. http://dx.doi.org/10.1136/jnnp.60.4.382

10. Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology. 1999;53:1107-14. PMid:10496275. http://dx.doi.org/10.1212/WNL.53.5.1107 11. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66:1485-9. PMid:16717206. http:// dx.doi.org/10.1212/01.wnl.0000216139.44259.74 12. Lana-Peixoto MA, Callegaro D. The expanded spectrum of neuromyelitis optica – evidences for a new definition. Arq Neuropsiquiatr. 2012;70:807-13. http://dx.doi.org/10.1590/ S0004-282X2012001000010 13. Nagaishi A, Takagi M, Umemura A, et al. Clinical features of neuromyelitis optica in a large Japanese cohort: comparison between phenotypes. J Neurol Neurosurg Psychiatry. 2011;82:1360-4. PMid:21665917. http://dx.doi. org/10.1136/jnnp-2011-300403 14. Osuntokun BO. The pattern for neurological illness in tropical Africa: experience of Ibadan, Nigeria. J Neurol Sci. 1971;12:417-20. http://dx.doi.org/10.1016/0022510X(71)90110-9 15. C a b r e P, H e i n z l e f O , M e r l e H , e t a l . M S a n d neuromyelitis optica in Martinique (French West Indies). Neurology. 2001;56:507-14. PMid:11222796. http://dx.doi. org/10.1212/WNL.56.4.507 16. Lana-Peixono MA, Lana-Peixoto MI. Is multiple sclerosis in Brazil and Asia alike? Arq Neuropsiquiatr. 1992;50:419‑25. http://dx.doi.org/10.1590/S0004-282X1992000400002

Neuromyelitis optica: a challenging diagnosis at secondary hospital 17. Papais-Alvarenga R, Miranda-Santos CM, PuccioniSohler M, et al. Optic neuromyelitis syndrome in Brazilian patients. J Neurol Neurosurg Psychiatry. 2002;73:429-35. PMid:12235313 PMCid:1738088. http://dx.doi.org/10.1136/ jnnp.73.4.429 18. Banwell B, Tenembaum S, Lennon VA, et al. Neuromyelitis optica-IgG in childhood inflammatory demyelinating CNS disorders. Neurology. 2008;70:344-52. PMid:18094334. http://dx.doi.org/10.1212/01.wnl.0000284600.80782.d5 19. Filippi M, Rocca MA, Moiola L, et al. MRI and magnetization transfer imaging changes in the brain and cervical cord of patients with Devic’s neuromyelitis optica. Neurology. 1999;53:1705-10. PMid:10563616. http://dx.doi. org/10.1212/WNL.53.8.1705 20. Pittock SJ, Weinshenker BG, Lucchinetti CF, Wingerchuk DM, Corboy JR, Lennon VA. Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol. 2006;63:964-8. PMid:16831965. http://dx.doi. org/10.1001/archneur.63.7.964 21. Nakashima I, Fujihara K, Fujinori J, Narikawa K, Misu T, Itoyama Y. Absence of IgG1 response in the cerebrospinal fluid of relapsing neuromyelitis optica. Neurology. 2004;62:144-6. PMid:14718720. http://dx.doi.org/10.1212/WNL.62.1.144 22. Stansbury FC. Neuromyelitis optica (Devic’s disease): presentation of five cases with pathological study and review of the literature. Arch Ophtalmol. 1949;42:465-501. http://dx.doi.org/10.1001/archopht.1949.00900050473014 23. Luccinetti CF, Mandler RN, McGovern D, et al. A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain. 2002;125:1450-61. http://dx.doi. org/10.1093/brain/awf151 24. Griesdale DE, Honey CR. Aquaporins and brain edema. Surg Neurol. 2004;61:34-9. PMid:15120208. http://dx.doi. org/10.1016/j.surneu.2003.10.047

Autopsy and Case Reports 2013; 3(1): 53-61 25. Benarroch. EE. Aquaporin-4, homeostasis, and neurologic diseases. Neurology. 2007;69:2266-8. PMid:18071147. http:// dx.doi.org/10.1212/01.wnl.0000286385.59836.e2 26. Weinshenker BG, O’Brien PC, Petterson TM, et al. A randomized trial of plasma exchange in acute inflammatory central nervous system demyelinating diseases. Ann Neurol. 1999;46:878-86. http://dx.doi.org/10.1002/15318249(199912)46:6<878::AID-ANA10>3.0.CO;2-Q 27. Nazaki I, Hamaguchi T, Komai K, Yamada M. Fulminant Devic’s disease successfully treated by lymphocytapheresis. J Neurol Neurosurg Psychiatry. 2006;77:1094-102. PMid:16614009 PMCid:2077763. http://dx.doi.org/10.1136/ jnnp.2005.086306 28. Mandler RN, Ahmed W, Dencoff JE. Devic’s neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology. 1998;51:1219-20. PMid:9781568. http://dx.doi.org/10.1212/WNL.51.4.1219 29. Minagar A, Sheremata WA. Treatment of Devic’s disease with methotrexate and prednisone. Int J MS Care. 2000;2:39-43. http://dx.doi.org/10.7224/1537-2073-2.4.43 30. Weinstock-Guttman B, Ramanathan M, Lincoff N, et al. Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic’s disease). Arch Neurol. 2006;63:957-63. PMid:16831964. http://dx.doi.org/10.1001/archneur.63.7.957 31. Falcini F, Trapani S, Ricci L, Resti M, Simonini G, Martino M. Sustained improvement of a girl affected with Devic’s disease over 2 years of mycophenolate mofetil treatment. Rheumatology. 2006;45:913-5. PMid:16638802. http://dx.doi. org/10.1093/rheumatology/kei263 32. Cree BAC, Lamb S, Morgan K, Chen A, Waubant E, Genain C. An open label study of the effects of rituximab in neuromyelitis optica. Neurology. 2005;64:1270-2. PMid:15824362. http:// dx.doi.org/10.1212/01.WNL.0000159399.81861.D5

Conflict of interest: None Submitted on: 26th December 2012 Accept on: 15th February 2013 Correspondence: Instituto de Infectologia Emílio Ribas – Divisão Científica Av. Dr. Arnaldo, 165 – São Paulo/SP – Brazil CEP: 01246-900 – Phone: +55 (11) 98231.7986 E-mail: annaminczuk@yahoo.com.br

Autopsy and Case Reports 2013; 3(1): 63-66

Article / Clinical Case Reports Artigo / Relato de Caso Clínico Transient elevation of ST-segment due to pneumothorax and pneumopericardium Rodrigo Martins Brandãoa, Amanda Cristina Maria Aparecida Gonçalvesb, Renata Paula Martins Brandãoc, Lucas Fernandes de Oliveiraa, Antonio Carlos Nogueiraa, Vitor Sérgio Kawabataa Brandão RM, Gonçalves ACMA, Brandão RPM, Oliveira LF, Nogueira AC, Kawabata VS. Transient elevation of STsegment due to pneumothorax and pneumopericardium. Autopsy Case Rep [Internet]. 2013;3(1): 63-6. http://dx.doi. org/10.4322/acr.2013.009

ABSTRACT ST-segment elevation, observed in the critically ill patients, almost always raises the suspicion of ischemic heart disease. However, nonischemic myocardial and non-myocardial problems in these patients may also lead to ST-segment elevation. Pneumothorax and pneumopericardium have been rarely reported as a cause of transient ST-segment elevation. The authors report the case of a patient admitted to the emergency care unit because of a respiratory failure requiring mechanical ventilatory support. As the patient showed signs of clinical deterioration, a pneumothorax was clinically diagnosed. Chest radiography after thorax drainage also disclosed a pneumopericardium. The 12-lead electrocardiogram recorded before the thoracic drainage revealed an ST-segment elevation, which normalized after the surgical procedure. Ischemic myocardial biomarkers were negative. The authors call attention to the right-sided pneumothorax associated with pneumopericardium as an unusual cause of ST-segment elevation. Keywords: Electrocardiography; Pneumothorax; Pneumopericardium; Asthma; Barotrauma. CASE REPORT A 47-year-old female patient was admitted to the emergency department with a 3-day history of dyspnea, cough, and wheezing. She denied fever and other complaints. She referred a past medical history of asthma and hypertension and was taking an inhaled bronchodilator and a corticosteroid. On physical examination, the patient was alert, oriented, and hydrated. The blood pressure (BP) = 150/80 mmHg, pulse rate = 152 beats per minute, respiratory rate = 32 respiratory movements per minute (rmpm). The patient looked distressed

using the accessory muscles of breathing during inspiration, and the room air pulse oximetry was 88%. Lung examination showed diffuse highpitched expiratory wheezes. The initial diagnosis was bronchospasm caused by an asthma attack. She was promptly treated with corticosteroids, magnesium sulphate, and inhaled bronchodilators. Non-invasive ventilation was attempted with continuous positive airway pressure of 10 cm H2O, followed by orotracheal intubation and mechanical ventilatory support.

Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. Nursing Department – Hospital Israelita Albert Einstein, São Paulo/SP, Brazil. c Department of Nephrology – Hospital Beneficência Portuguesa de São Paulo, São Paulo/SP, Brazil. a b

Autopsy and Case Reports 2013; 3(1): 63-66 Brandão RM, Gonçalves ACMA, Brandão RPM, Oliveira LF, Nogueira AC, Kawabata VS.

About 20 minutes after intubation, arterial hypotension (BP = 90/50 mmHg) associated with an increase in respiratory rate (RR = 40 rmpm), a decrease in the capillary oximetry, jugular venous distension, and hyperresonance on right hemithorax percussion raised the hypothesis of hypertensive pneumothorax. The electrocardiographic tracing on the bedside monitor, acquired at the supine position, showed the presence of ST-segment elevation, confirmed with the 12-lead electrocardiogram, which was characterized by ST-segment elevation of 3 mm in D2, 6 mm in D3 and 5 mm in aVF, accompanied by right axis deviation (SÂQRS= +100º) and small voltage of R wave in V1-V3 (Figure 1).

DISCUSSION

Emergency thoracentesis and pleural space drainage were performed followed by immediate improvement in oxygenation parameters accompanied by complete reversal of the ST segment elevation (Figure 2). Troponin and creatine kinase MB isoenzyme (CK-MB) were within normal limits. Echocardiography was normal.

ST-segment elevation may be observed in healthy people, called normal variants. In a study conducted by the US Air Force with 6014 healthy men (age range of 16–58 years old), the presence of ST-segment elevation was found in 91% in one or more leads, markedly in V2. This finding declines with age to 30% for men over the age of 76 years. Among women, the ST-segment elevation of 1 mm occurs in 20% and remains unchanged regardless of age.10

Chest radiography showed the presence of drained pneumothorax associated with pneumopericardium (Figure 3). The patient was referred to the Intensive Care Unit and was extubated on the fifth day.

In abnormal situations, ST-segment elevation is one of the electrocardiographic alterations associated with myocardial ischemia coined as a “current of injury.” Moreover, this alteration may also be observed in other clinical entities,

The 12-lead electrocardiogram is a low cost diagnostic tool, which is widely available, reliable, safe and easily performed. Its utility is immeasurable, as it is always helpful in the diagnosis of heart-related entities.1 Since the beginning of the twentieth century, ECG changes related to pneumothorax have been reported.2-3 In this context, the most common ECG changes include right axis deviation, reduced R-wave amplitude in precordial leads, QRS alterations (amplitude changes), and T-wave inversions.3-6 Electrocardiographic voltage alternations (electrical alternans) were also reported, as well as ST-segment elevation.3,7-9

Figure 1 – 12-lead ECG before pleural space drainage, showing sinus rhythm, right axis deviation, small voltage of the R wave in V1- V3 and ST-segment elevation (> 3 mm).

Transient elevation of ST-segment due to pneumothorax and pneumopericardium

Autopsy and Case Reports 2013; 3(1): 63-66

Figure 2 – 12-lead ECG after the pleural space drainage showing normalization of the ST-segment elevation. occurs independently of the mediastinal shift, bilateral or unilateral pneumothorax.11,12 Few reports exist of ST-segment elevation and they involve older patients with tension pneumothorax and previously known coronary heart disease.3

Figure 3 – Posterior-to-anterior chest radiography showing air entrapment in the right hemithorax, with a chest tube inserted, mediastinal shift to the left, with no trachea deviation. Pneumopericardium (arrow) is represented by a thin air layer detaching the pericardium. such as myocarditis, pericarditis, hyperkalemia, hypothermia, Brugada Syndrome, left ventricular hypertrophy, pulmonary embolism, cardioversion, and Prinzmetal’s angina.10 Several cases of ST-segment elevation have been described in association with other clinical situations, namely: pneumothorax, pneumopericardium, and pneumoperitoneum without the presence of myocardial injury.1 In the cases related to pneumothorax, this ECG change

It is suggested that ST-segment elevation and T-wave changes associated with pneumothorax are most likely attributable to transient hypoxia from impaired coronary blood flow, related to the hypotensive state. Other authors suggested that increased intrapleural pressures decreased the cardiac venous return and hence the cardiac preload, leading to decreased stroke volume. Tachycardia ensues to maintain cardiac output. The patient’s tachycardia would further increase myocardial oxygen demand, potentially leading to ischemia from underlying vessel disease.3 Many other reasons to explain these findings include clockwise cardiac rotation, compressive changes in the right ventricle and ventricular dilation (due to increased resistance in the pulmonary vessels), extrinsic compression of the right coronary artery, hypoxemia, and low cardiac output.4,13 Slay et al.14 were the first to report the association of pneumothorax and ST-segment elevation, and Brearley et al.4 report the ST-segment elevation associated to pneumopericardium.

Autopsy and Case Reports 2013; 3(1): 63-66 Brandão RM, Gonçalves ACMA, Brandão RPM, Oliveira LF, Nogueira AC, Kawabata VS.

In the case reported here, the presence of severe underlying respiratory disease and sudden distress, and the close temporal relationship with the development of ST-segment elevation associated to normalization after pleural space drainage and negative myocardial biomarkers, make the diagnosis of myocardial infarction less likely. Reports of ST-segment elevation are most commonly described when pneumothorax occurs on the left side.14 Krenke et al.15 reviewed the ECGs of 40 patients (age range, 18-86 years) admitted with spontaneous pneumothorax (22 left-sided, 18 rightsided), and found only 1 case with T-wave inversion and no cases with ST-segment elevations. This case report called attention to an unusual cause of ST-segment elevation, quite often related to myocardial infarction, especially among the critically ill patients. It is particularly interesting because of the rare occurrence of ST-segment elevation with pneumopericardium and right-sided pneumothorax.

REFERENCES 1.

Carneiro EF. O eletrocardiograma 10 anos depois. Rio de Janeiro: Enéas Ferreira Carneiro; 1997. p. 75-87. Portuguese.

Master AM. The electrocardiographic changes in pneumothorax in which the heart has been rotated. Am Heart J. 1928;3:472-83. http://dx.doi.org/10.1016/S00028703(28)90392-0

Shiyovich A, Vladimir Z, Nesher L. Left spontaneous pneumothorax presenting with ST-segment elevations: A case report and review of the literature. Heart Lung. 2011;40:8891. http://dx.doi.org/10.1016/j.hrtlng.2010.09.007

Brearley Junior WD, Taylor III L, Haley MW, Littmann L. Pneumomediastinum mimicking acute ST-segment elevation

myocardial infarction. Int J Cardiol. 2007;117:73-5. http:// dx.doi.org/10.1016/j.ijcard.2006.11.156 5.

Soltani P, Malozzi CM, Saleh BA, Omar B. Eletrocardiogram manifestation of spontaneous pneumothorax. Am J Emerg Med. 2009;27:750 e1-5.

Walston A, Brewer DL, Kitchens CS, Krook JE. The electrocardiographic manifestations of spontaneous left pneumothorax. Ann Intern Med. 1974;80:375-9.

Anderson R, Costello B, Kilpatrick D. Transient ST-segment elevation resembling acute myocardial infarction in a patient with a right secondary spontaneous pneumothorax. Heart Lung Circ. 2012 Jul 13; [Epub ahead of print; cited 2012 Dec 1]. Available from: http://www.sciencedirect.com/science/ article/pii/S144395061201089X

Kounis NG, Mallioris CN, Karavias D, Zavras G, Siablis D. Unusual electrocardiographic changes in intrathoracic conditions. Acta Cardiol. 1987;42:179-85.

Kuritzky P, Goldfarb AL. Unusual electrocardiographic changes in spontaneous pneumothorax. Chest. 1976;70:535-7. http:// dx.doi.org/10.1378/chest.70.4.535

10. Wang K, Asinger RW, Marriott HJL.ST-segment elevation in conditions other than acute myocardial infarction. N Engl J Med. 2003;349:2128-35. http://dx.doi.org/10.1056/ NEJMra022580 11. Monterrubio Villar J, Fernández Bergés D, Alzugaray Fraga RJ, Veiga MD, Córdoba López A, Corcho Díaz G. ST elevation in tension pneumothorax. Rev Esp Cardiol. 2000;53:467-70. 12. Price JW. Novel electrocardiographic changes associated with iatrogenic pneumothorax. Am J Crit Care. 2006;15:415-9. 13. Azzarelli S, Amico F, Giacoppo M, Argentino V, Fiscella D, Fiscella A. Transitorio sopraslivellamento del tratto ST causato da pneumoperitoneo iatrogeno. G Ital Cardiol. 2011;12:2178. Italian 14. Slay RD, Slay LE, Luehrs JG, Houston FS. Transient ST elevation associated with tension pneumothorax. JACEP.1979;8:16-8. http://dx.doi.org/10.1016/S03611124(79)80442-6 15. Krenke R, Nasilowski J, Przybylowski T, Chazan R. Electrocardiographic changes in patients with spontaneous pneumothorax. J Physiol Pharmacol. 2008;59(Suppl 6):361‑73.

Conflict of interest: None Submitted on: 21st December 2012 Accept on: 14th February 2013 Correspondence: Divisão de Clínica Médica Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9433 E-mail: r.m.brandao@bol.com.br

Autopsy and Case Reports 2013; 3(1): 67-8

Image in focus Imagem em foco Carcinoid heart disease Stephen A. Gellera, Fernando P. F. Camposb Geller SA, Campos FPF. Carcinoid heart disease. Autopsy Case Rep [Internet]. 2013;3(1): 67-8. http://dx.doi.org/ 10.4322/acr.2013.010

Pictures provided by Dr Stephen A Geller - personal archive.

The images are of the tricuspid valve and the pulmonic valve from the autopsy of a patient with mid-gut neuroendocrine carcinoma, carcinoid pattern, extensively metastatic to the liver. The patient had typical “carcinoid syndrome,” including clinical evidence of tricuspid and pulmonic stenosis and insufficiency. The tricuspid valve (left) shows slight retraction and distortion by the overlying endothelial deposition of plaque composed of acid mucopolysaccharide-rich matrix with varying amounts of smooth muscle cells and collagen fibers. The plaque material causes partial coalescence of chordae tendinae with effacement of the usual delicate strands. The pulmonic valve (right) shows more marked distortion with shrinkage and obliteration of cusps and coalescence at the commissures. Beneath the plaque the valves are intact. Neuroendocrine neoplasms (NEN) derive from scattered cells throughout the body, classically identifiable by their histochemical reactivity for chromium and silver salts, named as enterochromaffin cells, argentaffin cells, clear cells, enteroendocrine cells or Kultschitsky cells. Currently, immunohistochemical reactions are the a b

preferred and more sensitive means of confirming the identity of these tumors, with antibodies directed against a variety of cell products, including chromogranin A, synaptophysin, and various other secretory products. The biological behavior of this group of tumor varies from slow-growing to highly aggressive. These tumors may arise in almost any organ of the abdomen, thorax, neck, skin, and gonads, but they are most commonly observed in the gastroenteropancreatic system and the lung. The term “karzinoide” (carcinoid) was first used by Oberndorfer in 1907 to describe invasive tumors with relatively bland histologic features. These tumors synthesize, store and release as many as 40 products, including serotonin, histamine, tachykinins, kallikrein and prostaglandins. The liver inactivates these bioactive products secreted into the portal circulation, explaining why the carcinoid syndrome is typically observed when there are liver metastases. Exceptions to this occur when biologically active neuroendocrine tumors arise in organs not drained by the portal vein, such as lung and ovary, so the products are secreted directly into pulmonic veins to reach the general circulation and can lead to left-sided heart disease. Both right and left sided valves are affect in the rare instances of

Department of Pathology and Laboratory Medicine – David Geffen School of Medicine, UCLA, Los Angeles/CA – USA. Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil.

Autopsy and Case Reports 2013; 3(1): 67-68

shunting, as with a patent foramen ovale. Carcinoid syndrome is a symptom complex manifested by episodic flushing, secretory diarrhea, bronchospasm and hypotension. This syndrome occurs in 20% to 30% of patients at the time of diagnosis. Carcinoid heart disease (CHD) occurs in as many as 60% of patients with the carcinoid syndrome. Recognizable plaque-like endocardial fibrous tissue deposits characterize this cardiopathy. The extension and pattern of plaque deposits is highly variable from focal to diffuse. Tricuspid valve involvement predominantly results in regurgitation. In contrast, pulmonic valve disease is often both stenotic and regurgitant. The combination of pulmonic stenosis and tricuspid regurgitation results in unfavorable hemodynamic consequences, because the former increases the degree of tricuspid insufficiency. The precise pathogenesis of valve injury in CHD is not completely understood. Studies using cell cultures showed a stimulatory action of serotonin on subendothelial cell proliferation. In humans, the role of serotonin in the development of valvular pathology is based on indirect evidence, although it has been shown that the plasma levels of serotonin and 5-hydroxy-indolacetic acid (5-HIAA) correlate with the severity of right heart lesions. Other factors, such as genetic predisposition, could also play an important role, and apart from serotonin and 5-HIAA, NEN produce several other factors that could act synergistically in producing the characteristic cardiac lesions. CHD may become clinically evident 1-5 years after the onset of the carcinoid syndrome. Right-sided valve disease may be well tolerated for months. Up to 20% of patients with carcinoid syndrome will present with CHD at the time of diagnosis. Symptoms may include fatigue, exertional dyspnea, peripheral edema, ascites and hepatomegaly. Stephen A. Geller, M.D. Department of Pathology and Laboratory Medicine David Geffen School of Medicine, UCLA Los Angeles/CA - USA geller16st@gmail.com Fernando P. F. de Campos, PhD Department of Internal Medicine Hospital Universitário - USP São Paulo/SP - Brazil fpfcampos@gmail.com

Geller SA, Campos FPFC.

Resting 12-lead electrocardiography may be normal in up to 50% of cases, and Chest radiography is of limited value in the diagnosis of CHD. Echocardiographic examination is the key modality in the diagnostic evaluation of CHD and in the assessment of its severity. Characteristic features include thickening of valve leaflets/cusps that become retracted and immobile, resulting in a combination of regurgitation and stenosis. Thickening of the chordae and papillary muscles may also be present what result in greater degrees of valve dysfunction. In a Mayo Clinic report of 75 patients with CHD, tricuspid valve involvement was most common and regurgitation was the principal form of cardiac dysfunction. Pulmonary valve was often both insufficient and stenotic.

Keywords: Carcinoid Heart Disease; Tricuspid Valve; Pulmonary Valve; Carcinoma, Neuroendocrine; Serotonin. BIBLIOGRAPHY Lundin L, Norheim I, Landelius J, Oberg K, Thedorsson-Norheim E. Carcinoid heart disease: relationship of circulating vasoactive substances to ultrasound-detectable cardiac abnormalities. Circulation. 1988;77:264-9. PMid:2448062. http://dx.doi. org/10.1161/01.CIR.77.2.264 Palaniswamy C, Frishman WH, Aronow WS. Carcinoid heart disease. Cardiol Rev. 2012;20:167-76. PMid:22314145. http:// dx.doi.org/10.1097/CRD.0b013e31824c866e Robiolio PA, Rigolin VH, Wilson JS, et al. Carcinoid heart disease: Correlation of high serotonin levels with valvular abnormalities detected by cardiac catherization and echocardiography. Circulation. 1995:92:790-5. PMid:7641358. http://dx.doi. org/10.1161/01.CIR.92.4.790 Simula DV, Edwards WD, Tazelaar HD, Connolly HM, Schaff HV. Surgical pathology of carcinoid heart disease: a study of 139 valves from 75 patients spanning 20 years. Mayo Clin Proc. 2002;77:139‑47. PMid:11838647.