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ISSN 2236-1960

v.4, n.1, jan./mar. 2014


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Autopsy and Case Reports 2014; 4(1): 1-5

Editorial

The first three years of Autopsy and Case Reports: an interesting journey Aloísio Felipe-Silvaa Felipe-Silva, A. The first three years of Autopsy and Case Reports: an interesting journey [editorial]. Autopsy Case Rep [Internet]. 2014; 4(1): 1-5. http://dx.doi.org/10.4322/acr.2014.001

Autopsy and Case Reports (A&CR) completes three years of uninterrupted publication this month: March 2014. During these initial years, significant advancements have been made in the process of consolidating a reference journal in the fields of autopsy pathology, anatomoclinical correlation, and medical education. A total of 5 original research articles, 51 clinical case reports, 40 autopsy reports, 12 editorials, and 2 letters to the editor were published in the first three volumes. The section Image in Focus (in which iconic diagnostic images are discussed) was launched in 2013. Major achievements during this period include a broader international readership, constant improvements in graphics, preparation for insertion into scientific databases, and the rise of articles from other institutions that cite A&CR. Some of our editorial decisions are taken based on quantitative and qualitative analysis of the statistics from the A&CR website, as provided by the Google Analytics™ tool. In the period from April 2011 (the first month after launching and the beginning of the statistics) until December 2013, there were 16,881 website visits by 11,475 unique visitors in a total of 76,785 webpage views. Several factors can influence these metrics, such as the bounce rate (when someone exits the website without interacting with it—currently cumulated at 53.5%), which limits a finer analysis. However, the major trends seem to be valid and can be interpreted under the light of editorial policy. Figure 1 shows the total number of visits in these three years as well as the number of visits

a

by visitor language as identified by the software. In the years 2011 and 2012, we used systematic active advertisements, either in print, e-mail or through links in reference websites. The higher average number of monthly visits during this period (563/month) when compared to 2013 (422/month) probably reflects that policy. In fact, the maximum number of monthly visits (May 2011) coincided with the months after launching and the period of maximum publicity. On the other hand, 2014 is a promising year based on the months of January and February, when we received the highest number of visits since October 2011, but in this case, without any specific advertisement strategy. Since December 2011, the articles and the homepage have been published in English with the aim of increasing the journal’s access and visibility overseas. Moreover, we have the fundamental collaboration of international partners in the publishing process. Apparently, this was a wise move since we can note a clear increase in the number of English-speaking visitors and improved access from other countries. The rate of visits from English speakers reached 20.2% and 32.2% in March 2012 and August 2012, respectively. The first time that the rate of English-speakers’ visits (46.2%) exceeded the rate of Portuguese speakers (38.3%) was May 2013. Spanish speakers are the next highest number to access the journal’s website, with a cumulative rate of 1.9%. The cumulative rate of visitors that speak other languages is 5.1%. Another indicator of a broader international readership is the greater diversity of countries that visit the journal website (Table  1). The number

Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil.

Copyright © 2014 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-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided article is properly cited.

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Autopsy and Case Reports 2014; 4(1): 1-5

Felipe-Silva, A.

Table 1 – Share of A&CR webpage visits per year Year

2011

2012

of countries with more than a 1% share of visits jumped from two in 2011 to five in 2012 and then to seven in 2013.

2013

Total visits 5599 Country

4607

Access to the journal content has been fairly balanced between autopsy reports and clinical reports or investigative articles. Five of the top 10 article webpage views were autopsy reports (Table  2).1-10 In a total of 7557 abstract pages viewed, 4 of the top 10 most accessed were related to autopsies (Table 3).2,10-18 Finally, in a total of 675 full-text downloads, 2 of the top 10 downloaded articles were autopsy reports (Table 4). 4,6,19-26

5063

Visits share (%)

Brazil

89.87

74.18

56.43

USA

3.05

7.40

13.57

India

0.38

1.38

3.54

UK

0.45

1.53

3.26

Portugal

0.86

1.50

0.61

Australia

0.30

0.68

1.64

Canada

0.27

0.84

1.60

Phillipines

0.13

0.59

1.44

During the past two years, the first citations began to emerge.27-31 If we exclude self-citations and consider only citations in indexed journals, the citation per article index in two years (calculated

USA (United States of America); UK (United Kingdom). Shares >1% are highlighted.

Figure 1 – Visits to Autopsy and Case Reports website. Table 2 – Top 10 A&CR articles by webpage views (2011-2013) Rank

Ref.

Title

Views

1

[1]

Primary aortoesophageal fistula: a rare cause of acute upper gastrointestinal bleeding

467

2

[2]

Using the Graf method of ultrasound examination to classify hip dysplasia in neonates

299

3

[3]

Duodenal pseudomelanosis (pseudomelanosis duodeni): a rare endoscopic finding

288

4

[4]

Schistosomiasis: a case of severe infection with fatal outcome

206

5

[5]

Autopsy: a powerful tool for teaching and learning

202

6

[6]

Chronic meningococcemia: a rare presentation of meningococcal disease: case report

195

7

[7]

Acardiac fetus: a challenge to pathologists, obstetricians, and neonatologists

191

8

[8]

Hepatic necrosis associated with drug-induced hypersensitivity syndrome

184

9

[9]

Pyogenic liver abscess and pulmonary septic emboli in a diabetic woman

179

10

[10]

Acute coronary syndrome in young patients with atypical symptoms

178

Highlighted ranks are related to autopsies. Ref. = reference number in this editorial.

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The first three years of Autopsy and Case Reports: an interesting journey

Autopsy and Case Reports 2014; 4(1): 1-5

Table 3 – Top 10 A&CR abstract views (2011-2013) Rank

Ref.

Title

Views

1

[10]

Acute coronary syndrome in young patients with atypical symptoms

376

2

[11]

Síndrome de Baggio-Yoshinari: relato de caso

292

3

[12]

Tuberculous peritonitis: experience in a community hospital

177

4

[13]

Tribute to the centenary of Waterhouse-Friderichsen syndrome: a case report

166

5

[14]

Carcinomatous transformation of retroperitoneal endometriosis

156

6

[15]

Blunt traumatic diaphragmatic rupture

153

7

[16]

Fatal pulmonary thromboembolism associated with hemoglobin SC disease in a 15-year-old boy

136

8

[2]

Using the Graf method of ultrasound examination to classify hip dysplasia in neonates

130

9

[17]

Lemierre Syndrome – The forgotten disease

128

10

[18]

Adipositas cordis: a challenging differential diagnosis

126

Highlighted ranks are related to autopsies. Ref. = reference number in this editorial.

Table 4 – Top 10 A&CR downloaded articles (2011-2013) Rank

Ref.

Title

Downloads

1

[4]

Schistosomiasis: a case of severe infection with fatal outcome

135

2

[19]

Spindle-cell carcinoma of the prostate

75

3

[20]

Nodular lymphocyte predominance Hodgkin lymphoma of the parotid gland: a case report

59

4

[21]

“Nutrothorax” complicating a misplaced nasogastric feeding tube in a severely ill patient

57

5

[6]

Chronic meningococcemia: a rare presentation of meningococcal disease: case report

54

[22]

Descending necrotizing mediastinitis secondary to a dental infection

54

[23]

What does the future hold?

51

[24]

Aortic dissection-induced acute flaccid paraplegia treated with cerebrospinal fluid drainage

51

9

[25]

Pyopericarditis and tropical pyomyositis: unusual concomitance

41

10

[26]

Is an interatrial communication the same as an atrial septal defect?

38

7

Highlighted ranks are related to autopsies. Ref. = reference number in this editorial.

just as the Impact Factor) for 2013 (concerning the 2011-2012 biennium) is 0.0469. It is a modest but encouraging start, since self-citations are not included and some older indexed Brazilian journal rates are not much higher (0.06-0.08).32,33 There are still many challenges facing the A&CR journal. The institutional concentration of authors is decreasing, but it is still high. Submissions from other institutions are still infrequent, and probably depend on the indexing in databases such as PubMed and SciELO. A graphic and editorial renovation that incorporates new technologies is on the way, and it should facilitate the entry into more selective databases of greater impact. In our view, the balance of our progress over these three years is positive. We have started a free access online journal focusing on academic autopsies and anatomoclinical correlations with

global visibility, increasing international participation and a rising number of citations to its content. We will seek to consolidate this journal in the forthcoming years. The road ahead is long, and there is every reason to believe that our journey will continue with many exciting possibilities and achievements along the way.

REFERENCES 1.

Gomes SIM, Campos FPF, Martines BMR, Martines JAS, Tafner E, Maruta LM. Primary aortoesophageal fistula: a rare cause of acute upper gastrointestinal bleeding. Autopsy Case Rep [Internet]. 2011;1(4):57-63. http://dx.doi.org/10.4322/ acr.2011.018

2.

Jacobino BCP, Galvão MD, Silva AF, Castro CC. Using the Graf method of ultrasound examination to classify hip dysplasia in neonates. Autopsy Case Rep [Internet]. 2012;2(2):5-10. http://dx.doi.org/10.4322/acr.2012.018

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Autopsy and Case Reports 2014; 4(1): 1-5

Felipe-Silva, A.

3.

Felipe-Silva A, Campos FPF, Silva JGN. Duodenal pseudomelanosis (pseudomelanosis duodeni): a rare endoscopic finding. Autopsy Case Rep [Internet]. 2011;1(4):3944. http://dx.doi.org/10.4322/acr.2011.015

17. Marcello CE, Kim EIM, Smeili LAA, Bianqui L, Bazzi M. Síndrome de Lemierre – A doença esquecida. Autopsy Case Rep [Internet]. 2011;1(3):53-8. http://dx.doi.org/10.4322/ acr.2011.009

4.

Ferreira CR, Campos FPF, Ramos JG, Martines JAS, Kim EIM, Smeili LAA. Schistosomiasis: a case of severe infection with fatal outcome. Autopsy Case Rep [Internet]. 2012;2(1):717. http://dx.doi.org/10.4322/acr.2012.002

18. Ferreira CR, Campos FPF, Garcia Paez JI. Adipositas cordis: um difícil diagnóstico diferencial. Autopsy Case Rep [Internet]. 2011;1(1):20-32.

5.

Zerbini MCN. Autopsy: a powerful tool for teaching and learning. Autopsy Case Rep [Internet]. 2011;1(2):1-2.

19. Silva CHW, Rojas Claros O, Amselem I, Sá Filho NS, Fugita OEH. Spindle-cell carcinoma of the prostate. Autopsy Case Rep [Internet]. 2012;2(1):55-61. http://dx.doi.org/10.4322/ acr.2012.009

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Brandão AAGS, Prokopowitsch AS, Campos FPF, Yoshihara LAK. Chronic meningococcemia: a rare presentation of meningococcal disease: case report. Autopsy Case Rep [Internet]. 2012;2(1):29-35. http://dx.doi.org/10.4322/ acr.2012.005

20. Alves CAF, Gouveia MM, Queiroz AGS, et al. Nodular lymphocyte predominance Hodgkin lymphoma of the parotid gland: a case report. Autopsy Case Rep [Internet]. 2012;2(1):43-7. http://dx.doi.org/10.4322/acr.2012.007

7.

Ferreira CR, Simões AB, Quintal VS, Zerbini MCN. Acardiac fetus: a challenge to pathologists, obstetricians, and neonatologists. Autopsy Case Rep [Internet]. 2011;1(1):13-9.

21. Felipe-Silva A, Campos FPF. “Nutrothorax” complicating a misplaced nasogastric feeding tube in a severely ill patient. Autopsy Case Rep [Internet]. 2012;2(1):19-23. http://dx.doi. org/10.4322/acr.2012.003

8.

Campos FPF, Lima PP, Maragno L, Watanabe FT. Hepatic necrosis associated with drug-induced hypersensitivity syndrome. Autopsy Case Rep [Internet]. 2012;2(4):5-14. http://dx.doi.org/10.4322/acr.2012.029

9.

Felipe-Silva A, Laborda L. Pyogenic liver abscess and pulmonary septic emboli in a diabetic woman. Autopsy Case Rep [Internet]. 2011;1(1):33-41.

10. Daher G, Staniak HL, Bittencourt MS, Sharovsky R. Síndrome coronariana aguda em paciente jovem com sintomas atípicos. Autopsy Case Rep [Internet]. 2011;1(1):63-7. 11. Saraiva MD, Santomauro Junior AC, Simis NPB, Degenszajn J, Kim EIM. Síndrome de Baggio-Yoshinari: relato de caso. Autopsy Case Rep [Internet]. 2011;1(2):63-7. 12. Fonseca LG, Campos FPF, Felipe-Silva A. Tuberculose peritoneal: experiência em um hospital geral. Autopsy Case Rep [Internet]. 2011;1(2):3-9. 13. Shieh HH, Góes PF, Lima FR, Zerbini MCN, Bousso A. Tributo ao centenário da Síndrome de Waterhouse-Friderichsen: relato de caso. Autopsy Case Rep [Internet]. 2011;1(1):42-52. 14. Martines JAS, Martines BMR, Garzi DR, Lovisolo SM, Mitteldorf C, Margarido PFR. Transformação carcinomatosa de endometriose retroperitoneal. Autopsy Case Rep [Internet]. 2011;1(2):31-40. 15. Nogueira AC, Bazzi M, Soriano FG, et al. Rotura diafragmática no trauma abdominal fechado. Autopsy Case Rep [Internet]. 2011;1(3):39-45. http://dx.doi.org/10.4322/acr.2011.007 16. Amancio TT, Costa ACL, Borsato ML, Marins L, Bacchi LM, Zerbini MCN. Fatal pulmonary thromboembolism associated with hemoglobin SC disease in a 15-year-old boy. Autopsy Case Rep [Internet]. 2011;1(3):15-22. http:// dx.doi.org/10.4322/acr.2011.004

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22. Oliveira Junior EM, Moreira RT, Cavalcante TC. Descending necrotizing mediastinitis secondary to a dental infection. Autopsy Case Rep [Internet]. 2012;2(1):37-42. http://dx.doi. org/10.4322/acr.2012.006 23. Campos FPF. What does the future hold? [editorial]. Autopsy Case Rep [Internet]. 2012;2(1):3-5. http://dx.doi.org/ 10.4322/ acr.2012.001 24. Adam EL, Staniak HL, Sharovsky R, Silva AF, Castro CC, Bittencourt MS. Aortic dissection-induced acute flaccid paraplegia treated with cerebrospinal fluid drainage. Autopsy Case Rep [Internet]. 2012;2(1):25-8. http://dx.doi.org/10.4322/ acr.2012.004 25. Melo PHMC, Staniak HL, Felipe-Silva A, Santos IS, Bittencourt MS. Pyopericarditis and tropical pyomyositis: unusual concomitance. Autopsy Case Rep [Internet]. 2012;2(1):4953. http://dx.doi.org/10.4322/acr.2012.008 26. Anderson RH. Is an interatrial communication the same as an atrial septal defect? [editorial]. Autopsy Case Rep [Internet]. 2011;1(4):1-2. http://dx.doi.org/10.4322/acr.2011.010 27. Raso P, Raso LAM, Melo FA, Tafuri WL. Schistosoma mansoni granuloma in late evolutive phase, in a case of tumoral form in man. Rev Soc Bras Med Trop [online]. 2012; 45(5):62732. http://dx.doi.org/10.1590/S0037-86822012000500016 28. Wanderley BR, Maquiné GA, Vieira GN, Tallo FS, Lopes RD, Lopes AC. Tuberculose peritoneal: um diagnóstico diferencial no abdômen agudo: relato de caso [Peritoneal tuberculosis: a differential diagnosis in acute abdomen: case report]. Rev Bras Clin Med. São Paulo, 2012;10(6):544-6. Portuguese. 29. Deshmukh G. The role of ligamentum flavum calcification at lumbar spine causing cauda equina syndrome and lumbar radiculopathy: case report. J Evol Med Dent Sci [online]. 2013;2(42):8150-5.


The first three years of Autopsy and Case Reports: an interesting journey 30. Kumar S, Sharma N, Singh R, Bhalla A, Varma S. Pyopericardium complicated with cardiac tamponade: an unusual presenting manifestation of primary pyomyositis. Trop Doct. 2013;43(1):39-40. 31. Majid N, Bernoussi Z, Mrabti H, Errihani H. Celiac disease, enteropathy-associated t-cell lymphoma, and primary sclerosing cholangitis in one patient: a very rare association and review of the literature. Case Rep Oncol Med. 2013, 2013:838941. doi:10.1155/2013/838941 32. Scientific Electronic Library Online – SciELO. Jornal Brasileiro de Patologia e Medicina Laboratorial [Internet]. [cited 2014

Autopsy and Case Reports 2014; 4(1): 1-5

Mar 03]. Available from: http://statbiblio.scielo.org//stat_biblio/ index.php?state=05&lang=en&country=scl&issn=16762444&CITED%5B%5D=JORNAL+BRASILEIRO+DE+PA TOLOGIA+E+MEDICINA+LABORATORIAL&YNG%5B% 5D=2013 33. Scientific Electronic Library Online – SciELO. Revista Brasileira de Cirurgia Plástica [Internet]. [cited 2014 Mar 03]. Available from: http://statbiblio.scielo.org//stat_biblio/index. php?state=05&lang=pt&country=scl&issn=1983-5175&CIT ED%5B%5D=REVISTA+BRASILEIRA+DE+CIRURGIA+P LASTICA&YNG%5B%5D=2013

Correspondence: Aloisio Felipe-Silva Scientific Editor Autopsy and Case Reports Chief of Anatomic Pathology Service Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil E-mail: aloisiosilva@hu.usp.br

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Autopsy and Case Reports 2014; 4(1): 7-14

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Aortic stenosis concomitant with microscopic polyangiitis: a challenge in medical reasoning and thinking Paulo Sampaio Gutierreza, Vera Demarchi Aielloa Gutierrez PS, Aiello VD. Aortic stenosis concomitant with microscopic polyangiitis: a challenge in medical reasoning and thinking. Autopsy Case Rep [Internet]. 2014; 4(1): 7-14. http://dx.doi.org/10.4322/acr.2014.002

ABSTRACT Microscopic polyangiitis (MPA) is part of the anti-neutrophil cytoplasmic antibodies (ANCA)-related vasculitis, which usually presents as renal pulmonary syndrome. It is defined as a pauci-immune necrotizing small vessel vasculitis, which usually affects the kidneys, followed by the lungs. It also presents systemic symptoms. The etiology of MPA is still unclear, but evidence reinforces the autoimmune mechanisms as the main etiopathogenic factor. Aortic valve stenosis (AS) is not an uncommon disease whose etiology varies according to geographical differences and the patient’s age. The natural history of AS begins with a prolonged asymptomatic period, but when symptomatic, respiratory failure is one of its main clinical presentations. The authors present the case of a 55-year-old woman who was admitted with the diagnosis of renal failure, anemia, and a cardiac murmur. The patient had been recently diagnosed with pneumonia. During hospitalization, diagnostic workup disclosed a normal kidney size as well as parenchymal thickness. A renal biopsy was undertaken but the specimen was exiguous, showing 4 sclerotic glomeruli and 1 glomerulus with crescentic glomerulonephritis. The search for ANCA was positive. The investigation of the cardiac murmur disclosed AS. The patient, on hemodialysis, presented episodes of respiratory failure, which was interpreted as acute pulmonary edema, but a suspicion of ANCA-related pulmonary renal syndrome was raised. However, the aortic valve replacement was prioritized. While awaiting cardiac surgery, the patient died because of respiratory insufficiency. Autopsy findings concluded that MPA with pulmonary hemorrhage due to vasculitis was the immediate cause of death. Although AS was present at autopsy and classified as moderate/severe, this lesion was a bystander in the process of this patient’s end of life, demonstrating the value of autopsy for medical learning and reasoning purposes. Keywords: Systemic Vasculitis; Aortic Valve Stenosis; Renal Insufficiency; Respiratory Insufficiency; Antibodies, Antineutrophil Cytoplasmic; Glomerulonephritis.

a

Laboratory of Pathology – Instituto do Coração – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil.

Copyright © 2014 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-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided article is properly cited.

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Autopsy and Case Reports 2014; 4(1): 7-14

CASE REPORT A 55-year-old female patient sought the medical facility complaining of a 6-day history of diffuse abdominal pain radiating for flanks, accompanied by nausea and chronic constipation. She denied fever and vomiting. She had been using a non-steroid anti-inflammatory drug (NSAID) during the last week because of discomfort in her lower limbs. She referred recent treatment for pneumonia, and progressive exertion dyspnea during the last year, the latter of which did not disable her daily activities. Her past medical history included the diagnosis of a cardiac murmur for at least 11 years without symptoms of congestive heart failure; an appendectomy; a hysterectomy over 20 years ago; and tabagism of 90 packs/year. The initial physical examination revealed a pale but well-looking patient, afebrile, with normal hemodynamic parameters, and no peripheral edema. Lung examination was normal, and cardiac auscultation revealed an ejection murmur more audible over the aortic area. The abdomen was flat, although slightly tender; the bowel sounds were normal; and neither peritoneal irritation nor Giordano’s sign were present. Initial laboratory workup revealed renal failure: creatinine  =  7.6 mg/dL (reference value [RV]: 0.4-1.3 mg/dL) and urea = 191 mg/dL (RV: 10-50 mg/dL). The blood cell count was normal except for the low hemoglobin determination  =  8g/dL (RV: 12.3-15.3 g/dL) and hematocrit  =  27% (RV: 36.0-45.0%). (Iron profile tests were compatible with iron-deficiency anemia.) Potassium was 5.6 mEq/L (RV: 3.5-5.0 mEq/L) and the remaining electrolytes and pH were within normal limits. Urinalysis revealed hematuria; 24-hour proteinuria = 689 mg. Urinary tract ultrasonography revealed normal kidney size and parenchymal thickening. The echodopplercardiogram showed an enlarged left atrium (47 mm) and a left ventricular ejection fraction of 62%.b The septum measured 17 mm and the posterior wall 14 mm. Inferolateral hypokinesia was present. A calcified aortic valve with marked stenosis showed a maximum left ventricular aortic gradient pressure of 92 mmHg. The patient was admitted with the hypothesis of non-olyguric acute renal failure, which was initially considered as NSAID-induced acute interstitial nephritis, and severe aortic stenosis (AS). Therefore, Pombo JF, Troy BL, Russell RO Jr. Left ventricular volumes and ejection fraction by echocardiography. Circulation. 1971;43:480-90. b

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Gutierrez PS, Aiello VD.

she was started on prednisone 1 mg/kg/day, but no improvement of renal function was observed, so the patient went on hemodialysis treatment. A renal biopsy was undertaken, which revealed a crescentic glomerulonephritis with medullary lymphomonocytic infiltration. In the biopsy specimen, only five glomerules were represented, and four of them were sclerotic. Anti-nuclear antibody (ANA), tested by immufluorescence with HEP-2 cells and anti-DNA, were negative; complement determination was normal. Serologies for HIV, hepatitis B, and hepatitis C were negative. Protoplasmic anti-neutrophilic cytoplasmic antibody (p-ANCA) was positive > 1/80 (RV: non-reactive) as well as myeloperoxidase (MPO) 120U (RV: < 20U). Based on the clinical and laboratory results, the patient was diagnosed with renal insufficiency, which was probably due to ANCA-related vasculitis and AS. She was referred for aortic valve surgery, after angiocoronariography ruling out coronary artery disease and normal pulmonary function test. While waiting for the valvular surgery, she returned to the emergency room complaining of diffuse thoracic pain, dyspnea, and fatigue. She had lost 5 kg in 30 days. At admittance she was drowsy, cyanotic, tachypneic, tachycardic, and hypotensive, and had a room air oximetry of 76%. Pulmonary examination detected diffuse bilateral rales. Plain thoracic radiography was interpreted as pulmonary congestion, and the thoracic computed tomography revealed emphysema, bronchiolectasis, diffuse ground glass opacification, and paratracheal lymphadenopathy, besides the calcification of the aortic valve and a mild pericardial effusion. Urine culture isolated Klebsiella sp. Acute pulmonary edema and urosepsis were considered as a plausible diagnosis; therefore, the patient was treated with antibiotics, vasoactive intravenous drugs, respiratory assistance, and a 3-day course of methylprednisolone pulse therapy because of the suspicion of a pulmonary renal syndrome. After the corticosteroid, the respiratory function improved, but it could not be ascertained whether a cause and effect correlation was related to the corticosteroid? The recurrent pulmonary symptoms were interpreted as a consequence of the severe AS. After clinical recovery and stabilization of the hemodynamic and pulmonary function, she was referred to a cardiology center, where she presented a new episode of acute respiratory failure, which was firstly considered to be due to acute pulmonary


Aortic stenosis concomitant with microscopic polyangiitis...

edema, but soon after admission, she had a massive hemoptysis and died.

AUTOPSY FINDINGS At the autopsy, gross examination disclosed significant alterations in the lungs, kidneys, and heart. The lungs had extensive areas of hemorrhage (Figure 1) and both weighed 2160 g (RV: ~700–800 g). The kidneys showed yellowish, irregularshaped zones, suggestive of necrosis, mostly in the medullar region, but also at the cortex (Figure  2). The heart (Figure  3) weighed 560 g (RV: 300-350 g), with left ventricular hypertrophy and moderate/ severe AS with commissural fusion. In the right atrium, a friable mass was found close to the atrioventricular groove between the coronary sinus and the atrial appendage. Additionally, there was

Autopsy and Case Reports 2014; 4(1): 7-14

a dark red strip in the small bowel, indicative of hemorrhagic necrosis. At microscopy, vasculitis was detected in the pulmonary microcirculation, in capillary vessels, arterioles, and venules, with destruction of the wall causing hemorrhage (Figure 1). Both kidneys had chronic injuries (global and segmental glomerular sclerosis with fibroblastic crescents, and tubular atrophy with interstitial fibrosis) and acute injuries (medullary angiitis) (Figure 2). Vasculitis was not found in any other organ, including the bowel (with hemorrhagic infarction) and the heart. The aortic valve showed fibrosis and calcification, without significant inflammation; and there was perivascular fibrosis. The right atrial mass showed an organized thrombus, with no signs of infection. These cardiac alterations are also displayed in Figure 3.

Figure  1  –  A  –  Macroscopical view of the lungs showing diffuse hemorrhage, with a dark-reddish color, and small areas of emphysema, indicated by the black arrow; B – Capillary vessel showing inflammatory cells crossing its wall (H&E staining, objective magnification 5X); C – An arteriole, pointed by black arrow, presenting inflammation, leading to D – destruction of the elastic laminae, which should appear stained in black. (C – H&E staining; D– Miller’s staining; objective magnification 10X).

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Autopsy and Case Reports 2014; 4(1): 7-14

Gutierrez PS, Aiello VD.

Figure 2 – Kidney medullary necrosis, indicated by arrows: A – macroscopically; and B – microscopically; C – Glomerulopathy with crescents; D – Kidney arteritis, with inflammatory cells; E – Elastic tissue (in black); destruction in the same vessel. (B, C, and D – H&E staining; E – Miller’s staining for elastic tissue. Objective magnifications: B – 5X; C – 40X; D and E – 20X). Taking into account the positivity for p-ANCA and MPO, the main disease was considered to be microscopic polyangiitis (MPA), compromising lungs and kidneys, according to the Chapel Hill classification.1,2 Death was attributed to pulmonary hemorrhage, with hemorrhagic shock also causing a band of intestinal infarction. The right atrial thrombus was most probably caused by endocardial damage due to the dialysis catheter. Although it is a serious condition, we consider the AS to be a bystander lesion in the final event of this patient.

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DISCUSSION After the description of Dr. Adolf Kussmaul and Dr. Rudolf Maier in 1866, on what today is known as polyarteritis nodosa (PAN), all forms of vasculitis tended to be considered forms of PAN, irrespective of the size or type of vessel involved.3 Since then, other investigators have described other forms of vasculitis according to clinical and pathological particularities. In 1985, Savage  et  al.4 suggested that MPA was a distinct entity characterized by a


Aortic stenosis concomitant with microscopic polyangiitis...

Autopsy and Case Reports 2014; 4(1): 7-14

Figure 3 – Heart alterations. A – Aortic valve stenosis. There is commissural fusion and diffuse thickening of the semilunar leaflets; B – A microscopic aspect of the aortic valve, with dense calcification (in purple) and no inflammatory cells (H&E, objective magnification 5X); C – Mass (thrombus), indicated by the arrow, attached to the right atrial wall; D – Microscopic view of the mass showed in C, constituted by organizing thrombus (H&E, objective magnification 2.5X); E – Short-axis section of the heart, showing left ventricular hypertrophy; AM = right atrial myocardium F = fibrin; LV = left ventricle; OT = organizing portion of the thrombus; RV = right ventricle.

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Autopsy and Case Reports 2014; 4(1): 7-14

rapidly progressive glomerulonephritis frequently in conjunction with pulmonary capillaritis, associated— in the vast majority of cases—with the presence of ANCA. MPA is a small vessels ANCA-associated vasculitis. In these cases, ANCA is predominantly directed against myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA).5 The incidence of MPA is not well established since it varies depending on geographical differences. In the United Kingdom, the incidence of MPA was shown to be 5.9/million, during the period 1988–2010.6 A slight predominance among males is observed and the age of presentation peaks around 60–65 years of age.5 Although of unclear role, silica exposure has been suggested as a possible environmental factor linked with MPA etiopathogenesis.7 However, strong evidence argues favorably for an autoimmune mechanism as the main etiology of MPA.5 In this setting, the cornerstone is the presence of ANCA. Of patients with MPA, 95% are ANCA positive and 70% of them are MPO-ANCA, the titer of which frequently rises preceding the disease activity.8 The kidneys are affected in 80-90% of cases of MPA, and sometimes no other organs are affected. Clinically, renal involvement of MPA presents as a slight hematuria with non-massive proteinuria accompanied by a rapid deterioration of renal function.9 Lung involvement, which is somewhat less frequent (30% of the cases),10,11 clinically presents as dyspnea, cough, and hemoptysis—the latter being associated with poor prognosis. Pulmonary imaging consists of an alveolar filling pattern,5,12 which challenges the differential diagnosis due to its unspecificity. Weight loss, fever, arthralgia, myalgia, purpura, and peripheral nervous system involvement may also be present, but this occurs less frequently.5 The original Chapel Hill Consensus Conference Nomenclature of Vasculitides,1 revised in 2012,2 defines MAP as a small vessel (arterioles, capillaries, venules) pauci-immune necrotizing vasculitis, although medium-sized arteries may be present.5 Involvement of the skin resembles leukocytoclastic vasculitis; capillaritis with fibrinoid necrosis is the typical finding in the lungs, while necrotizing crescentic glomerulonephritis characterizes the renal lesions. Focal thrombosis of glomerular capillaries with fibrinoid necrosis is an early lesion, which is followed by rupture of the glomerular basement membrane and extracapillary proliferation. This results in crescent formation,

12

Gutierrez PS, Aiello VD.

which initially appear as cellular crescents, but later on become more fibrous crescents.5 The patient presented herein was admitted with the diagnosis of probable acute renal failure, initially interpreted as caused by the NSAID recently used, iron-deficiency anemia and an AS, which was asymptomatic for the last 11 years. The renal function did not show any improvement with corticosteroids, the presumed offending drug was withdrawn, and ultrasound found apparently normal kidneys. Therefore, a renal biopsy was undertaken, but the histology was not conclusive, due to the exiguity of the sample. Nevertheless, urinalysis and the presence of ANCA pointed towards a probable autoimmune etiology for the renal function impairment. Although gastrointestinal involvement in patients with granulomatosis with polyangiitis (GPA) or MPA is rare,13 and at the autopsy of this case no vasculitis was found at the infarcted bowel segment, it would not be absurd to suspect gastrointestinal involvement since in the patient’s initial symptom was abdominal pain. Moreover, there was an iron deficiency anemia, and at the autopsy a hemorrhagic infarction band was found. We preferred to consider this finding as result of the hemodynamic shock (because of the lack of histological evidence of vasculitis), but we are not totally convinced because in the case of infarction due to arterial hypotension we should expect larger ischemic areas. The presence of the AS with a peak left ventricular/aortic pressure gradient of 92 mmHg somehow overshadowed the clinical reasoning, directing it towards the hemodynamic effects of the AS to explain the respiratory symptoms. Unfortunately, this pressure gradient was not measured during the cardiac catheterization, and therefore could not be compared with the echo Doppler measurement. Even with the absence of the mean pressure gradient, valvular area information, and flow velocity, the AS was considered severe.14 The respiratory features of this patient were probably first misinterpreted when she was diagnosed with pneumonia (the first episode preceding the hospital admission), and acute pulmonary edema (during further events) due to hemodynamic effects caused by the AS. Pulmonary vasculitis was not considered as the cause of the respiratory discomfort. Therefore, the treatment of the patient was focused on the aortic valve replacement. However, the suspicion of ANCA-related vasculitis was considered at one point, so methyl prednisolone pulse therapy was


Aortic stenosis concomitant with microscopic polyangiitis...

prescribed. Unfortunately, the immunosuppression did not go further due to the presence of infection and the lack of support on the hypothesis of pulmonary vasculitis. The process of reaching a diagnosis is complex, involving recognition of signs and symptoms, clinical reasoning and experience, and, whenever possible, the demonstration of the pathologic process or any laboratory surrogate finding.15 In this case report, the diagnosis of MPA was left in the background, even in the presence of such evidence, illustrating how clinical reasoning can be diverted when some data (cardiac murmur and echodopplercardiogram) are more valued than others. With the findings of the autopsy, we surprisingly concluded that the medical staff may have overestimated the role of the AS concerning the respiratory features. It is not unlikely that AS was merely a bystander at this time. It is likely that the higher incidence of AS compared with MPA, and the medical staff’s familiarity to it, led to the treatment of AS being prioritized. Although committing some medium-sized vessels, what is unusual but may still happen,15 the vasculitis of this patient was classified as MPA. Clinical features (including the lack of eosinophilia and history of asthma), the positivity for ANCA antibodies, and the pathologic findings involving small vessels of the kidneys and lungs without granulomas, support this diagnosis. The cause of the aortic valve stenosis was not well disclosed. Aortic lesions—mostly aortic regurgitation—have been described in a few patients with vasculitis16 due to aortitis, which was absent in our case. The autopsy showed that the patient had no infective endocarditis, which may be either associated with or simulate the clinical features of vasculitides.17,18 Thus we considered the valve disease as a possible consequence of previous rheumatic heart disease, taking into account the commissural fusion and epidemiological data, even though there was no history of joint pain in the childhood, no significant inflammation at necropsy, and no concomitant mitral involvement. (Although decreasing, rheumatic valve disease is relatively common in Brazil). Another possibility to be considered is senile calcification, but such a condition is unusual under 70 years of age.

Autopsy and Case Reports 2014; 4(1): 7-14

We would like to remind the unicist clinical reasoning/thinking, which emphasizes, whenever possible, the use a sole entity to explain all signs and symptoms. We do not discard the doctors’ belief that an aortic valve replacement was necessary, but faced with the autopsy findings, we conclude that it should have been postponed until the autoimmune disease was under control.

REFERENCES 1.

Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitis. Proposal of an international consensus conference. Arthritis Rheum. 1994;37:187-92. http://dx.doi. org/10.1002/art.37715

2.

Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum. 2013;65:1-11. http://dx.doi. org/10.1002/art.37715

3.

Campos FPF, Geller SA. Churg-Strauss Syndrome: a syndrome described on clinical observation and autopsy findings [editorial]. Autopsy Case Rep [Internet]. 2013;3:1-4.

4.

Savage C, Winearts C, Evans D, Rees A, Lockwood C. Microscopic polyarteritis: presentation, pathology and prognosis. Q J Med. 1985;56:467-83.

5.

Kallenberg CGM. The diagnosis and classification of microscopic polyangiitis. J Autoimmun. 2014 Jan 22. In Press. http://dx.doi.org/10.1016/j.jaut.2014.01.023

6.

Watts RA, Mooney J, Skinner J, Scott DJ, Macgreggor AJ. The contrasting epidemiology of granulomatosis with polyangiitis and microscopic polyangiitis. Rheumatology. 2012;51:92631. http://dx.doi.org/10.1093/rheumatology/ker454

7.

Hogan SL, Satterly KK, Dooley MA, Nachman PH, Jennette JC, Falk RJ. Silica exposure in antineutrophil cytoplasmic autoantibody-associated glomerulonephritis and lupus nephritis. J Am Soc Nephrol. 2001;12:134-42.

8.

Terrier B, Saadoun D, Sane D, et al. Antimyeloperoxidase antibodies are a useful marker of disease activity in antineutrophil cytoplasmic antibody-associated vasculitides. Ann Rheum Dis. 2009;68:1564-71. http://dx.doi.org/10.1136/ ard.2008.094714

9.

Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum. 1999;42:421-30. http://dx.doi. org/10.1002/1529-0131(199904)42:3%3C421::AIDANR5%3E3.0.CO;2-6

10. Akikusa B, Sato T, Ogawa M, Ueda S, Kondo Y. Necrotizing alveolar capillaritis in autopsy cases of microscopic polyangiitis: incidence, histopathogenesis and relationship with systemic vasculitis. Arch Pathol Lab Med. 1997;121:144-9.

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Autopsy and Case Reports 2014; 4(1): 7-14 11. Brown KK. Pulmonary vasculitis. Pulmonary Vasculitis. Proc Am Thorac Soc. 2006;3:48-57. http://dx.doi.org/10.1513/ pats.200511-120JH 12. Niles JL, Bottinger EP, Saurina GR, et al. The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition. Arch Intern Med. 1996;156:440-5. http://dx.doi. org/10.1001/archinte.1996.00440040118013 13. Latus J, Koetter I, Fritz P, et al. Gastrointestinal involvement in granulomatosis with polyangiitis and microscopic polyangiitis: histological features and outcome. Int J Rheum Dis. 2013 Oct 29. http://dx.doi.org/10.1111/1756-185X.12203 14. Vahanian A, Otto CM. Risk stratification of patients with aortic stenosis. Eur Heart J. 2010;31:416-23. http://dx.doi. org/10.1093/eurheartj/ehp575.

Gutierrez PS, Aiello VD. 15. Jennette JC, Falk RJ. The role of pathology in the diagnosis of systemic vasculitis. Clin Exp Rheumatol. 2007; 25:S52-6. 16. Lacoste C, Mansencal N, Ben M’rad M, et al. Valvular involvement in ANCA-associated systemic vasculitis: a case report and literature review. BMC Musculoskelet Disord. 2011;12:50. http://dx.doi.org/10.1186/1471-2474-12-50 17. Chirinos JA, Corrales-Medina VF, Garcia S, Lichtstein DM, Bisno AL, Chakko S. Endocarditis associated with antineutrophil cytoplasmic antibodies: a case report and review of the literature. Clin Rheumatol. 2007;26:590-5. http://dx.doi.org/10.1007/s10067-005-0176-z 18. Teoh LS, Hart HH, Soh MC, et al. Bartonella henselae aortic valve endocarditis mimicking systemic vasculitis. BMJ Case Rep. 2010. pii: bcr0420102945. http://dx.doi.org/10.1136/ bcr.04.2010.2945

Conflict of interest: None Submitted on: 12th February 2014 Accepted on: 20th March 2014 Correspondence: Instituto do Coração HCFMUSP Av. Dr. Enéas Carvalho de Aguiar, 44 - São Paulo/SP – Brazil CEP: 05403-000 – Phone: +55 (11) 2661-5251 E-mail: paulo.gutierrez@incor.usp.br

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Autopsy and Case Reports 2014; 4(1): 15-19

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Small-cell neuroendocrine carcinoma of the esophagus: an autopsy case report Mariana Bellaguarda de Castro Sepulvidaa, Augusto Vieira Amarala, Pompeu Tomé Ribeiro de Camposa,b, Carlos Osvaldo Teixeiraa,b, Maria Aparecida Barone Teixeiraa,b Sepulvida MBC, Amaral AV, Campos PTR, Teixeira CO, Teixeira MAB. Small-cell neuroendocrine carcinoma of the esophagus: an autopsy case report.  Autopsy Case Rep [Internet]. 2014; 4(1): 15-19. http://dx.doi.org/10.4322/ acr.2014.003

ABSTRACT Small-cell neuroendocrine carcinoma is a well-known aggressive neoplasia, which is usually associated with a poor prognosis. The lung is the most common primary site, but other organs may be involved, especially those of the digestive tract. The authors report the case of a 71-year-old Caucasian, male patient who was admitted because of congestive heart failure and loss of vision accompanied by right proptosis. Skull and sinuses computed tomography showed a tumoral mass involving the posterior region of the right eye, local bones, and paranasal sinuses. Because of severe hemodynamic instability, the patient died and no diagnostic investigation could be performed. Autopsy findings revealed small-cell neuroendocrine carcinoma of the esophagus and metastases to the posterior region of the right ocular globe, which affected the sinuses, the muscles of the ocular region, the orbit bones, the skull, the meninges and the brain, plus the liver, adrenal glands, and the pericardium. This case called the author’s attention to the extent of the metastatic disease in a patient who was firstly interpreted as presenting solely with congestive heart failure. The autopsy findings substantially aid the understanding of the immediate cause of death. Keywords: Carcinoma, Squamous Cell; Neuroendocrine Cells; Carcinoma, Small Cell; Esophagus; Autopsy. INTRODUCTION Small cell carcinoma (SCC) is a poor differentiated neuroendocrine carcinoma, which frequently involves the lung. However, its extra pulmonary origin represents 2.5-5.9% of all cases, represented by gastrointestinal (GI) and genitourinary systems, plus skin and thymus involvement.1-6. Among the GI viscera, the esophagus is the most

commonly involved, although this histological tumor type represents only 0.4-3.1% of all esophageal neoplasms.1 Besides environmental factors, genetic alterations have a marked role in the pathophysiology of this tumor,7 independently of the primary site.

Anatomo-clinical Correlation Study Group (GECAC) – Faculdade de Medicina – Pontifícia Universidade Católica de Campinas – Campinas/SP – Brazil. b Internal Medicine Department – Faculdade de Medicina – Pontifícia Universidade Católica de Campinas – Campinas/SP – Brazil. a

Copyright © 2014 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-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided article is properly cited.

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Autopsy and Case Reports 2014; 4(1): 15-19

Sepulvida MBC, Amaral AV, Campos PTR, Teixeira CO, Teixeira MAB.

Among the environmental factors, smoking and alcohol consumption are the main components.2,6,8 Men are 1.3-3.2 times more affected than women mainly in the fifth or sixth decade of life. The initial symptoms are usually unremarkable, and even the clinical features of advanced disease are non-specific, like weight loss and instability of previous chronic diseases. Local symptoms, such as dysphagia and retrosternal pain, are associated with esophageal wall infiltration or occlusion of the esophageal lumen, which are associated with the worse prognosis in this setting.1,6,8-10 Pathological characteristics of SCC are the same, regardless of the primary site. The neoplastic cells are small, polymorphic, with scanty cytoplasm, and hyperchromatic nuclei, and they present a trabecular growth.2,3,8,9,11 The positivity for specific epithelial markers, such as epithelial membrane antigen (EMA), clonal cytokeratin (AE1/AE3), and cytokeratin 8 (CK8) identify these cells as being of epithelial origin.2,9,11 The neuroendocrine lineage is identified by other markers, such as neuron-specific enolase (NSE), synaptophysin (SyN), chromogranin A (CgA), and a neural cell adhesion molecule (CD56). About 36% of the esophageal SCC show histological heterogeneity, presenting endocrine and squamous lineages within the same tumor.9,11

CASE REPORT A 71-year-old Caucasian male patient sought medical care complaining of a 4-month history of exertion dyspnea and edema of the lower limbs. His past medical history included hypertension and congestive heart failure, and although he had been abstinent for 1 year, he had previously smoked 75 packs/year. On physical examination he was hypotensive and cyanotic; his pulse was arrhythmic; he had edema of the lower limbs; he had bulging jugular veins when in the supine position; there were rales in the lower two-thirds of both lungs; and tender hepatomegaly was present. The electrocardiogram showed atrial fibrillation, and the echodopplercardiogram estimated the left ventricle ejection fraction of 63% (Teicholz), eccentric left ventricular hypertrophy, marked mitral insufficiency, and a left atrium of 85 mm. Pulmonary systolic pressure was estimated at 62 mmHg with marked tricuspid valve insufficiency. There were no valvular morphological abnormalities. He was hospitalized with the diagnosis of hypertensive cardiomyopathy and cor pulmonale.

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He also complained of vision loss for 2 months accompanied by protrusion of the right eye globe. The ophthalmologic examination in the right eye revealed marked corneal deepithelization and edema, ocular protrusion, the absence of photomotor and consensual reflexes, and low visual acuity. The left eye was normal. Brain computed tomography and cranial magnetic resonance imaging (MRI) confirmed the presence of a neoplastic lesion infiltrating the paranasal sinuses and the frontal encephalic lobe (Figure  1). A tumoral biopsy was scheduled, but the patient died before the procedure could be done because of a refractory cardiogenic shock. Autopsy findings included marked cardiomegaly with four-chamber dilation; the interventricular septum measured 18 mm, and the ventricular wall (posterior, anterior, and lateral) measured 15 mm. Radiological findings were confirmed at autopsy as a metastatic lesion most probably from an epithelial neoplasm of the esophagus. A 2 cm wide ulcerated lesion was found in the middle third and other lesion with a vegetating appearance measuring 1 cm in the upper third of the esophagus (Figure  2) The tumor infiltrated the submucosa, muscular (Figure  3 and 4A), and adventitia layers and adhered to the paraesophageal structures mainly at the esophageal-ulcerated lesion. The histological examination showed a smallcell neuroendocrine carcinoma of the esophagus, since AE1/AE3 positive and synaptophysin (Figure 4B) were positive.

Figure  1  –  Cranial MRI showing the retroocular metastatic lesion.


Small-cell neuroendocrine carcinoma of the esophagus...

Autopsy and Case Reports 2014; 4(1): 15-19

Metastatic involvement was found in the paranasal sinuses, the muscles around the right eye, the orbital bones (Figure 5), the meninges, the right frontal lobe, the liver, the adrenal glands, and the pericardium.

DISCUSSION In 1952, the Pathology Institute of Belfast (Northern Ireland) first reported two cases of this neoplasia among 9,000 autopsies.1,12 Since then, around 350 cases of esophageal SCC have been published, showing its aggressive behavior and the challenging diagnosis in the great majority of cases, revealing the difficulty in establishing the best therapeutic option.1,9 Figure 2 – Gross view of the esophagus showing a vegetating pattern lesion (A) and an ulcerated lesion (B) at the proximal and middle thirds, respectively.

In our case, diagnosis was missed due to the absence of specific symptoms, according to the literature.1-16 It is most likely that interleukins 1 and

Figure  3  –  Photomicrography of the esophagus showing ulcerated lesions (arrows) with inflammatory infiltrate (arrowhead) involving the submucosa and muscular layers (HE, 40X).

Figure  4  –  Photomicrography of the esophageal ulcerated lesion showing in A - Neoplastic cells with hyperchromatic nuclei, “salt-and-pepper” chromatin and scant cytoplasm. (HE, 400X), and in B - positivity for synaptophysin,(400X).

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Sepulvida MBC, Amaral AV, Campos PTR, Teixeira CO, Teixeira MAB.

Figure 5 – A - Gross view of the retroocular mass involving the orbit muscles. B - Photomicrography of the retroocular mass showing neoplastic cells with the same pattern as the esophageal lesion (HE, 400X). 6, as well as the tumoral necrosis factor,16 may have contributed to the severe hemodynamic instability of the patient, which prevented any further diagnostic approach. Neuroendocrine carcinomas with retroocular metastasis are scarce in the literature. Among the patients with this diagnosis, the main described symptoms are: diplopia (48%), local pain (42%), and loss of vision (30%). The signs at presentation are: proptosis (63%), strabismus (62%), and loss of vision (30%).15 Except for the pain, the patient of the case reported herein presented the main described signs and symptoms. However, our patient did not present signs of carcinoid syndrome or paraneoplastic manifestations, since the latter is represented by three reports of esophageal SCC presenting sensory and motor neuropathy, inappropriate antidiuretic hormone secretion syndrome, and hypercalcemia.1,5,10,13 We did not attribute the heart failure to a possible carcinoid syndrome in our patient, since other manifestations of this syndrome were lacking, such as flushing, diarrhea, or bronchospasm. The carcinoid heart is characterized by an endocardial fibrous deposition, mainly at the outflow of the right cardiac chambers accompanied by valvular morphological derangement and dysfunction.17 On gross examination, esophageal SCC may present as infiltrating, polypoid, or ulcerated lesions10 mainly localized in the middle or lower third of the organ.1,6,8 The case reported herein presented an ulcerating lesion on the middle third, and another polypoid in the upper third, which is the site in 4–6% of all described esophageal SCCs.4,8,14 The tumor in this topography usually does not cause dysphagia. This patient already presented, at admission, an

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advanced metastatic disease to well-known sites such as the liver and bones, but, in contrast to the majority of cases, the lungs were not involved. Surprisingly, metastases were found in previously unreported sites for this tumor, namely: the frontal lobe, the meninges, the skull, the paranasal sinuses, the eye and adjacent structures, the adrenal glands, and the pericardium.1,5,6,8,14,15 This neoplasia presents an overall survival rate that ranges between 3.1 and 7.5 months after the diagnosis.1,2,8,9 Metastatic disease at diagnosis is found in 31-90% of the cases.6 The World Health Organization classifies all the neuroendocrine neoplasms in three categories, according to their morphology, independently of the primary site; for example, well-differentiated neuroendocrine tumors with low malignant potential, well-differentiated neuroendocrine carcinoma (which are more aggressive with metastatic potential) and poorly-differentiated neuroendocrine carcinomas (which are high grade malignancies with poor prognosis).7 The anatomopathological and immuno­ histochemical criteria for the diagnosis of SCC are the same regardless of the primary site, but for the GI tract, the immunohistochemical markers CK8, SyN, NSE, and CD56 show more than 90% accuracy.3,8,9,11 In our case, only SyN and AE1/AE3 were tested; therefore, we could not differentiate pure- or mixed-cell lineages in the tumor.

CONCLUSION Small-cell neuroendocrine carcinoma is an aggressive neoplasm with poor prognosis,


Small-cell neuroendocrine carcinoma of the esophagus...

Autopsy and Case Reports 2014; 4(1): 15-19

regardless the primary site. Its rarity and late clinical manifestation, mostly represented by metastatic disease or systemic symptoms delay the diagnosis and treatment.

7.

Dias AR, Sallum RAA, Zalc N, Ctenas BB, Ribeiro U Jr, Cecconello I. Squamous cell carcinoma and neuroendocrine carcinoma colliding in the esophagus. Clinics (Sao Paulo). 2010;65:114-7. http://dx.doi.org/10.1590/S180759322010000100018

In our case, the diagnosis wasn’t totally established in life due to the unusual retro-ocular metastatic presentation. Inflammatory factors related to the tumor probably aggravated the heart failure.

8.

Coral RP, Hartmann A, Mastalir FP, Mastalir ET. Small cell carcinoma of the esophagus. ABCD Arq Bras Cir Dig. 2007;20:216-8. http://dx.doi.org/10.1590/S010267202007000300017

9.

Schlittler LA, Lazaretti NS, Villaroel RU, Klitzke S, Dallagasperina VW. Carcinoma de pequenas células do esôfago: apresentação de dois casos. J Port Gastrenterol. 2011;18:243-6. Portuguese.

This case demonstrates the importance of the autopsy for didactic and diagnostic purposes.

REFERENCES 1.

Wang SY, Mao WM, Du XH, Xu YP, Zhang SZ. The 2002 AJCC TNM classification is a better predictor of primary small cell esophageal carcinoma outcome than the VALSG staging system. Chin J Cancer. 2013;32:342-52.

2.

Henry MACA, Lerco MM, Oliveira WK, et al. Carcinoma de pequenas células do esôfago: estudo clínico patológico de dois casos. ABCD Arq Bras Cir Dig. 2008;21:3840. Portuguese. http://dx.doi.org/10.1590/S010267202008000100008

3.

Yun JP, Zhang MF, Hou JH, et al. Primary small cell carcinoma of the esophagus: clinicopathological and immunohistochemical features of 21 cases. BMC Cancer. 2007;7:38. http://dx.doi.org/10.1186/1471-2407-7-38

4.

Casas F, Ferrer F, Farrús B, Casals J, Biete A. Primary small cell carcinoma of the esophagus: a review of the literature with emphasis on therapy and prognosis. Cancer.1997;80:1366-72. http://dx.doi.org/10.1002/ (SICI)1097-0142(19971015)80:8<1366::AIDCNCR2>3.0.CO;2-D

10. Sabanathan S, Graham GP, Salama FD. Primary oat cell carcinoma of the oesophagus. Thorax. 1986;41:318-21. http://dx.doi.org/10.1136/thx.41.4.318 11. Li AF-Y, Li AC-H, Hsu C-Y, Li WY, Hsu HS, Chen JY. Small cell carcinomas in gastrointestinal tract: Immunohistochemical and clinicopathological features. J Clin Pathol. 2010;63:6205. http://dx.doi.org/10.1136/jcp.2010.077024 12. McKeown F. Oat-cell carcinoma of the œsophagus. J Pathol. 1952;64:889-91. http://dx.doi.org/10.1002/path.1700640420 13. Shimoda T, Koizumi W, Tanabe S, et al. Small-cell carcinoma of the esophagus associated with a paraneoplastic neurological syndrome: a case report documenting a complete response. Jpn J Clin Oncol. 2006;36:109-12. http://dx.doi. org/10.1093/jjco/hyi241 14. Souza HP, Alves JM, Pandolfo G. Carcinoma de pequenas células do esôfago. Rev Col Bras Cir. 1998;25:2902. Portuguese. http://dx.doi.org/10.1590/S010069911998000400015 15. Peixoto RDA, Lim HJ, Cheung WY. Neuroendocrine tumor metastatic to the orbit treated with radiotherapy. World J Gastrointest Oncol. 2013;5:177-80. http://dx.doi.org/10.4251/ wjgo.v5.i8.177

5.

Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med. 2010;134:1628-38.

16. Silva AC, Alves RC, Pinheiro LS. As implicações da caquexia no câncer. e-Scientia. 2012;5:49-56. Portuguese.

6.

Vos B, Rozema T, Miller RC, et al. Small cell carcinoma of the esophagus: a multicentre Rare Cancer Network study. Dis Esophagus. 2011;24:258-64. http://dx.doi.org/10.1111/ j.1442-2050.2010.01133.x

17. Amador P, Mendes L, Gonçalves S, et al. [Carcinoid tumors: echocardiographic contribution to the diagnosis]. Acta Med Port. 2011;24:843-8. PMID: 22525639 Portuguese.

Conflict of interest: None Submitted on: 10th December 2013 Accepted on: 15th March 2013 Correspondence: Mariana Bellaguarda de Castro Sepulvida Rua Espírito Santo, 1136 – Cerâmica – São Caetano do Sul – São Paulo/SP – Brazil CEP: 09530-701 – Phone: +55 (19) 99341-5399 E-mail: mbellaguardasepulvida@yahoo.com.br

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Autopsy and Case Reports 2014; 4(1): 21-27

Article / Autopsy Case Reports Artigo / Relato de Caso de Autópsia Unusual clinical presentation of anaplastic large cell lymphoma Fernando Peixoto Ferraz de Camposa, Maria Claudia Nogueira Zerbinib, Aloisio Felipe-Silvac, Angélica Braz Simõesc, Silvana Maria Lovisoloc, Leonardo Gomes da Fonsecad, Lorena Labordaa Campos FPF, Zerbini MCN, Felipe-Silva A,  et  al. Unusual clinical presentation of anaplastic large cell lymphoma. Autopsy Case Rep [Internet]. 2014; 4(1): 21-27. http://dx.doi.org/10.4322/acr.2014.004

ABSTRACT Anaplastic large cell lymphoma (ALCL), a well-recognized entity, presents a varied clinical picture and epidemiological characteristics associated with the expression of the anaplastic lymphoma kinase (ALK) protein. When classic symptoms are present (weight loss, fever, and night sweats) and combine with enlarged and easily accessible peripheral lymph nodes, diagnosis is not that difficult. But when the clinical presentation is nonspecific, a tough diagnostic task is required. HIV infection is highly associated with neoplastic disorders— mainly with those of hematological origin. However, ALCL is exceptionally associated with HIV infection, and the few reported cases are ALK– ALCL. The authors report two cases of ALK+ ALCL with the unusual clinical presentation: one is associated with the HIV infection and the other presents as a fever of unknown origin (FUO) without peripheral lymphadenopathy. The latter was autopsied and was characterized by nodal and extra nodal involvement. The authors call attention to the plurality of clinical presentation of this group of lymphomas, and the early indication of bone marrow examination in cases of an FUO with elevated hepatic enzymes and lactic dehydrogenase. Keywords: Lymphoma, Large-Cell, Anaplastic; Acquired Immunodeficiency Syndrome; Fever of Unknown Origin; Autopsy.

CASE 1 A 34-year-old female patient sought the medical facility complaining of a painful and progressive-growing mass in the left groin during the preceding 2 months. Fever and diaphoresis supervened during the last month concomitantly with 5 kg of weight loss. Her past medical history

included the diagnosis of HIV infection since the last pregnancy 4 years ago, but under medical advice discontinued anti-retroviral therapy. The physical examination revealed a well-looking patient with normal hemodynamic parameters, afebrile, with a tender mass localized in the left groin measuring

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

Copyright © 2014 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-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided article is properly cited.

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Campos FPF, Zerbini MCN, Felipe-Silva A, et al.

Figure 1 – Photomicrography of the lymph node. A – Presence of large, atypical, sometimes multinucleated neoplastic cells (HE, 100X); B – CD30 positive, note the lymph node sinusoidal pattern infiltration (IH, 40X); C – ALK protein positivity (IH, 10X); D – High proliferation rate showed by Ki67 (IH, 10X). 10 cm at the longest axis, corresponding to adhered and hardened lymph nodes conglomerate, accompanied by unilateral left lower limb edema. Laboratory workup disclosed normal renal function, mild elevation of ALT, AST, and LDHe, peripheral blood count with mild leukopenia and lymphopenia. The CRPf was slightly increased and the CD4 count was less than 50 cell/mm3. Ultrasound Doppler of the left groin showed enlarged lymphadenopathy, with lymph nodes measuring up to 7.9 × 2.6 cm with signs of central necrosis. Deep venous thrombosis was ruled out. Abdominal computed tomography (CT) showed mesenteric, retroperitoneal lympha­ denopathy, along with left external iliac artery, and left inguinal region lymphadenopathy. Thoracic and neck CT did not show significant involvement of the lymphatic chains. An inguinal lymph node was biopsied; the histological examination of which revealed a partially involved lymph node with distended sinuses by the presence of large,

ALT = alanine aminotransferase, AST = aspartate aminotransferase, LDH = lactate dehydrogenase.

atypical, cohesive neoplastic cells, sometimes with multinucleation in a horseshoe pattern (“hallmark cells”). The immunohistochemical study showed positivity for CD45, CD30 (membranous and dot pattern), CD5, and anaplastic lymphoma kinase (ALK)-1, while CD20, CD3, Epstein–Barr virus (EBV), AE1/AE3 were negative. The proliferation rate, evaluated by Ki67, was positive in 99% of the neoplastic cell population (Figure 1). The unilateral bone marrow biopsy was normal without neoplastic infiltration. The final diagnosis was ALK+ ALCL in an HIV-positive patient, with B symptoms, Ann Arborg stage IIXSB. The patient was referred to an oncological center for chemotherapy and restarted highly active antiretroviral therapy (HAART). She received, at first, a COP cytoreductive regimen, followed by CHOP regimen for eight cycles with complete remission. However, 12 months later, she presented a recurrence of the disease, confirmed by a cervical

e

f

CRP = C-reactive protein.

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Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res. 1971;31(11):1860-1. g


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Figure 2 – Photomicrography of the bone marrow. A – (HE, 10X); and B – (HE, 100X) showing infiltration by large, atypical, neoplastic cells, with some multinucleated cells in a horseshoe pattern (“hallmark cells”); C – Immunohistochemistry positivity for CD-30 (100X); D – Immunohistochemistry positivity for ALK protein (100X).

lymph node biopsy, even though she was on HAART and the CD4 cell count was 666 cells/mm3. At this time, the lymphadenopathy involved the cervical, supraclavicular, axillary, mesenteric, and retroperitoneal regions. Treatment was reinitiated in accordance with the Ian Magrathh regimen (cyclophosphamide, methotrexate, and intrathecal cytarabine and methotrexate) for 3 cycles followed by an autologous bone marrow transplant for consolidation. During all the oncological treatment until the last followup consultation, the patient was taking HAART (lamivudine, lopinavir, ritonavir, and tenofovir). She has been free of relapse for the past 3 years.

Magrath IT, Shad AT, Sandlund JT. Lymphoproliferative disorders in immunocompromised individuals. In: Magrath IT, editor. The non-hodgkin’s lymphomas. 2nd ed. London: Oxford University Press, 1997. p. 955-74. h

CASE 2 A 20-year-old male patient sought the emergency unit complaining of high-grade fever and chills accompanied by malaise, headache, and weakness during the last 10 days. He referred loss of appetite and consequently 3 kg of weight loss (5% of total body weight). His physical examination was normal, as well as the ophthalmoscopy. Laboratory workup showed normal renal function, glucose determination, electrolytes, hepatic enzymes, liver function tests, protein electrophoresis, and urinalysis. Serology for HIV, hepatitis B and C, toxoplasmosis, EBV, syphilis, leptospirosis, and dengue fever were negative. Rubella and cytomegalovirus serologies showed IgG positive but IgM negative. Tests for antinuclear antibody, anti-neutrophil cytoplasmic antibody, and rheumatoid factor were also negative. The tuberculin skin test was negative as well as the acid-fast bacilli research in the sputum. The thoracic CT was normal and echodoppler of the lower limbs

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Figure 3 – Photomicrography of the lymph node. A – Effacement of the original architecture due to sinusoidal infiltration by large atypical multinucleated cells (HE, 100X); B – Immunohistochemistry positivity for CD30 (HE, 400X).

ruled out the diagnosis of deep venous thrombosis. The cerebrospinal fluid (CSF) examination was normal. Four sets of blood samples, urine, and CSF cultures were negative for bacteria, fungus, and acid-fast bacilli. The patient remained hospitalized presenting a daily temperature of 38.5 °C and 39 °C and was recorded as a fever of unknown origin (FUO). In this setting, he underwent a transesophageal echodopplercardiogram, which was normal. The determination of a high titer of ferritin was odd, which was interpreted as an inflammatory marker or even the possibility of Still’s disease, without other diagnostic criteria. The abdominal ultrasound and CT were normal despite the progressive raising determination of liver enzymes (AST, ALT, APh and γGT) and LDHi. Nevertheless he was submitted to a wedge liver biopsy through laparoscopy, which did not detect any abnormality in the abdominal cavity. The histological examination of the liver specimen showed non-specific findings: preserved lobular architecture, with moderate neutrophilic infiltration of portal tract with histiocytes, mild biliary ductal proliferation. The hepatocytes, Kupfer cells, as well as the central veins were also preserved. Bone marrow aspiration resulted in dry tap, which was followed by a bone marrow biopsy, which showed hypoplasia of the all hematopoietic series and focal infiltration by large lymphoid cells, with nuclear pleomorphism, atypia and evident nucleoli. The patient evolved with lower limb cellulitis and septic shock, and died before the complete diagnostic work up has been completed. Unfortunately

ALT = alanine transaminase; APh = alkaline phosphatase; AST = aspartate transaminase; γGT = gamma glutamyl transferase; LDH = lactate dehydrogenase. i

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the bone marrow biopsy was not prioritized over the other examinations, being undertaken lately in the course of the disease. The diagnosis was confirmed by the immunohistochemical report, which showed a profile consistent with ALK+ ALCL: (positive for CD30, ALK, and EMA, and negative for CD20, CD3, CD15, CD43, CD34, CD31, and myeloperoxidase) (Figure 2). The autopsy revealed generalized lymphadenopathy (lymph nodes measuring up to 2 cm) involving the axillary, mediastinal, abdominal, and lower limb chains, which showed sinusoidal infiltration by large, atypical multinucleated cells (Figure 3). The lungs, liver, and spleen also showed lymphomatous infiltration (Figure  4). The final diagnosis was ALK+ ALCL and the immediate cause of death was septic shock with massive bilateral pulmonary hemorrhage.

DISCUSSION In 1985, Stein  et  al.1 first described ALCL and since then its definition has greatly evolved. Nowadays, this lymphoma is fairly well characterized and currently recognized by the WHO2,3 as a defined entity. ALCL is characterized by a proliferation of large lymphoid cells with distinctive morphology: hallmark cells, marked sinus and perivascular growth (angiocentrism) pattern, a strong expression of CD30, and cytotoxic granules protein, expressing (or not) the ALK protein. This lymphoma comprises approximately 3% of adult and 10–30% of childhood


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Autopsy and Case Reports 2014; 4(1): 21-27

Figure 4 – A – Photomicrography of the liver showing microscopic and multifocal infiltration of the portal tract by large atypical multinucleated cells (HE, 400X); B  –  Photomicrography of the lung showing focal infiltration of large atypical multinucleated cells in the parenchyma and perivascular. Note hemorrhagic foci and organizing pneumonia (HE, 100X).

non-Hodgkin lymphomas (NHLs).4,5 Chromosomal translocations, such as t(2; 5)(p23; q35), t(1; 2)(p21; q23), t(2; 3)(p23; q21) and t(2; 17)(p23; q23), are responsible for the expression of the ALK protein, which apparently is associated with younger patients and a better prognosis. Therefore, ALCL is divided into three groups, namely: ALCL-ALK+, ALCL-ALK- and cutaneous ALCL. Disregarding the cutaneous group, this lymphoma may present clinically as a localized as much as extranodal widespread disease in non-HIV-infected individuals. Unusual clinical presentation, including fever, multiple organ failure, shock, and adrenal insufficiency can be associated with subtypes of ALCL, particularly in cases of extranodal involvement.6,7 This heterogeneous clinical presentation challenges the clinician and may be responsible for a considerably delayed diagnosis. Although it is decreasing in the era of HAART, the association of HIV infection and the development of various malignancies still remains high when compared with the general population.8,9 In this setting, B-cell NHLs are more frequently reported, unlike T-cell lymphomas, which account for 1.4% of 6,788 lymphomas in a population of 302,834 persons with AIDS. Although rare, the relative risk of T-cell lymphoma, estimated by standardized incidence ratio, was 15.0 (95% confidence interval: 10.0-21.7).10 In another study, the incidence of T-cell lymphoma was 2.6% in a series of 429 AIDSrelated lymphomas.5 Among the T-cell lymphomas in the AIDS population, ALCL is even more rarely

observed with the incidence ranging between 22% and 28%.5,11,12 Until the report of Perez  et  al. in 2010,13 37 cases of HIV-infected ALCL cases were identified. In the English literature in 2012, this number did not exceed 50 cases.8,14 These cases were characterized by the involvement of a young population (mean age 38 years), with male predominance (M:F = 4:1), a median CD4 count of 83 cell/mm3, a rare expression of the ALK protein, an exclusive extranodal presentation, and a very aggressive clinical course with the median overall survival of 5 months.8,12,13 Case 1, reported herein, calls attention to its unusual presentation: it affected a female patient; it presented as an inguinal bulky disease along with lymph node enlargement of the iliac and periaortic chains; there was no clinical or radiological evidence of extra nodal disease; there was a positive expression of the ALK protein; and a non-fatal outcome. In a study conducted by Mosunjac  et  al.6 5 cases of ALCL in a series of 23 presented clinically as an FUO. In this series beyond fever, other symptoms were nonspecific and the duration ranged from 1 week to 3 months. Among the laboratory findings, attention was called to leukocytosis with neutrophilia, thrombocytopenia, and abnormal coagulation tests. Lactic acidosis, elevated hepatic enzymes, APh, and LDH were present in 80% of the cases. Only one case showed large pre- and retrosternal masses misinterpreted as scar tissue of a previous coronary bypass grafting. All five cases were autopsied and the major findings were compatible with extranodal involvement of ALCL, and

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Campos FPF, Zerbini MCN, Felipe-Silva A, et al.

80% predominantly showed a slight enlargement of the deep-seated retroperitoneal, mediastinal, and abdominal lymph nodes. Extra nodal sites mainly characterized the involvement of the liver, lungs, spleen, bone marrow, and gut. This neoplastic infiltration was represented by gross tumor masses (predominantly in the liver and mediastinal lymph nodes) or diffuses microscopic involvement, which characterized the lung, gastrointestinal tract, bladder, kidneys, and thyroid. Hemophagocytosis was observed in the bone marrow of two cases. In this series, all but one case were ALK–.

CONCLUSION

Case 2, reported herein, showed an ALK+ ALCL in a young patient, which presented as an FUO, with a fast fatal outcome. The patient was thoroughly investigated and the diagnosis was, unfortunately, not concluded before the death. After the initial workup, the raise in LDH determination directed the investigation towards a hematological malignancy, through the bone marrow examination. The physical examination and the radiological study could not help in determining the diagnosis or lymphadenopathy, most probably because of their small size, which was further observed at the autopsy. This case is an example of a deceitful presentation form of ALCL, which means it appeared as an FUO without marked evidence of lymph node involvement. Our Case 2 presents some similar characteristics of the Mosunjac  et  al.6 series, but showed the presence of the ALK protein, which, in this case, did not show a favorable prognosis. In addition to the extranodal involvement, the lymph nodes were equally involved in a disseminated manner characterized by small lymph nodes, similar to that observed by Mosunjac  et  al.6 Extra nodal infiltration was characterized by a diffuse and microscopic pattern, concealing the clinical suspicion and challenging the imaging diagnosis. Systemic symptoms and the aggressive course of these cases of ALCL are thought to be related to increase in expression of cytokines such as G-CSF and IL-6 or IL-2.15 Janik  et  al.16 showed increased levels of the soluble IL-2 receptor in the serum of patients with ALK+ ALCL. In the series of Mosunjac  et  al.6 the strong membranous expression of CD25 (IL-2 receptor) confirmed Janik’s observation. The cytokines’ storm observed in these severe cases of ALCL are in accordance with the hemophagocytic syndrome also observed in some cases. Our Case 2 was ALK+ ALCL, which is associated with hypercytokinemia; therefore, the dramatic clinical course as well as the high level of ferritin may be manifestations of the release of the cytokines.

REFERENCES

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Even though ALCL is a well-defined entity, this neoplasia presents a plurality of clinical pictures, and has to be considered among HIVinfected patients and those with the diagnosis of an FUO. In the latter group of patients, we recommend early biopsy of the bone marrow if no peripheral and accessible lymph node is present, mainly in those cases where the LDH and hepatic enzymes are unexpectedly increased.

1.

Stein H, Mason DY, Gerdes J, et al. The expression of Hodgkin’s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cell. Blood. 1985;66:3681-95.

2.

Mason DY, Harris NL, Delsol G, et al. Anaplastic large cell lymphoma, ALK-negative. In: Swerdlow SCE, Campo E, Harris NL, et al., editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 317-9.

3.

Delson G, Falini B, Muller-Hermelink HL, et al. Anaplastic large cell lymphoma, ALK-positive. In: Swerdlow SCE, Campo E, Harris NL, et al., editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 312-6.

4.

Jafe ES. Anaplastic large cell lymphoma: the shifting sands of diagnostic hematopathology. Mod Pathol. 2001;14:219-28. http://dx.doi.org/10.1038/modpathol.3880289

5.

Arzoo KK, Bu X, Espina BM, Serevinatne L, Nathwani B, Levine AM. T-cell lymphoma in HIV-infected patients. J Acquir Immune Defic Syndr. 2004;36:1020-7. http://dx.doi. org/10.1097/00126334-200408150-00004

6.

Mosunjac MB, Sundstrom BJ, Mosunjac MI. Unusual presentation of anaplastic large cell lymphoma with clinical course mimicking fever of unknown origin and sepsis: Autopsy study of five cases. Croat Med J. 2008;49:660-8. http://dx.doi.org/10.3325/cjm.2008.5.660

7.

Campos FPF, Felipe-Silva A, Zerbini MCN. Anaplastic large cell lymphoma ALK-negative clinically mimicking alcoholic hepatitis - a review. Autopsy Case Rep [Internet]. 2013;3(3):119. http://dx.doi.org/10.4322/acr.2013.023

8.

Genet P, Chaoui D, Masse V, et al. Anaplastic large cell lymphoma occurring in an HIV-positive patient. Case Rep Hematol. 2012; Article ID 180204. http://dx.doi. org/10.1155/2012/180204

9.

Taniai H, Furusyo N, Murata M, et al. A case report of human immunodeficiency virus-associated anaplastic lymphoma


Unusual clinical presentation of anaplastic large cell lymphoma kinase protein-negative anaplastic large cell lymphoma. SpringerPlus. 2013;2:400-5. 10. Biggar RJ, Engels EA, Frisch M, Goedert JJ. Risk of T-cell lymphomas in persons with AIDS. J Acquir Immune Defic Syndr. 2001;26(4):371-6. http://dx.doi.org/10.1097/00126334200104010-00015 11. Castillo J, Beltran BE, Bibas M, et al. Prognostic factors in patients with HIV-associated peripheral T-cell lymphoma: a multicenter study. Am J Hematol. 2011;86:256-61. http:// dx.doi.org/10.1002/ajh.21947 12. Castillo J, Perez K, Milani C, Dezube BJ, Pantanowitz L. Peripheral T-cell lymphomas in HIV-infected individuals: a comprehensive review. J HIV Ther. 2009;14:34-40.

Autopsy and Case Reports 2014; 4(1): 21-27 13. Perez K, Castillo J, Dezube BJ, Pantanowitz L. Human immunodeficiency virus-associated anaplstic large cell lymphoma. Leuk Lymphoma. 2010;51:430-8. http://dx.doi. org/10.3109/10428190903572201 14. Kumar S, Wanchu A, Sharma A, et al. Spinal cord compression caused by anaplastic large cell lymphoma in an HIV infected individual. J Cancer Res Ther. 2010;6:376-8. http://dx.doi. org/10.4103/0973-1482.73358 15. Harada Y, Yamada S, Murakami S, et al. Ki-1 lymphoma with nodular involvement in liver and spleen: possible role of cytokines in systemic manifestation of fever and leukocytosis. Dig Dis Sci. 2000;45:2240-6. 16. Janik JE, Morris JC, Pittaluga S, et al. Elevated serum-soluble interleukin-2 receptor levels in patients with anaplastic large cell lymphoma. Blood. 2004;104:3355-7. http://dx.doi. org/10.1182/blood-2003-11-3922

Conflict of interest: None. Submitted on: 1st January 2014 Accepted on: 15th March 2014 Correspondence: Divisão de Clinica Médica Hospital Universitário da Universidade de São Paulo Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9275 E-mail: fpfcampos@gmail.com

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Article / Clinical Case Report Artigo / Relato de Caso Clínico Adult-onset opsoclonus-myoclonus-ataxia syndrome as a manifestation of brazilian lyme disease-like syndrome: a case report and review of literature Angelina Maria Martins Linoa,b, Raphael Ribeiro Speraa, Fernando Peixoto Ferraz de Camposb, Christian Henrique de Andrade Freitasa, Márcio Ricardo Taveira Garciac, Leonardo da Costa Lopesb, Aleksander Snioka Prokopowitschb Lino AMM, Spera RR, Campos FPF, et al. Adult-onset opsoclonus-myoclonus-ataxia syndrome as a manifestation of brazilian lyme disease-like syndrome: a case report and review of literature. Autopsy Case Rep [Internet]. 2014; 4(1): 29-37. http://dx.doi.org/10.4322/acr.2014.005

ABSTRACT Described in 1962, the opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare, neurologically debilitating disorder with distinct characteristics that may begin in childhood or adult life. Although many cases remain without etiological diagnosis, others are related to neoplasms and infectious diseases. We report a 41-year-old previously healthy male with an 8-day history of headache, vertigo, nausea, vomiting, and nystagmus. After a normal brain computed tomography and lymphocytic pleocytosis in cerebral spinal fluid (CSF), intravenous acyclovir therapy was initiated in the emergency room. On the third day of hospitalization, the diagnosis of OMAS was made based on the presence of chaotic and irregular eye movements, dysarthric speech, gait instability, generalized tremor, and myoclonic jerks. In the face of his neurological worsening, ampicillin followed by nonspecific immunotherapy (methylprednisolone and intravenous immunoglobulin) was prescribed, with mild clinical improvement. After a thorough laboratory workup, the definite diagnosis of neuroborreliosis was established and ceftriaxone (4 g/daily/3 wks) and doxycycline (200 mg/day/2 mo) was administered. Toward the end of the ceftriaxone regimen, the neurologic signs substantially improved. We believe this to be the first case description of OMAS as clinical presentation of Brazilian Lyme disease-like syndrome (Baggio-Yoshinari syndrome). Keywords: Opsoclonus-Myoclonus Syndrome; Lyme Neuroborreliosis; Borrelia burgdorferi. CASE REPORT A 41-year-old male Caucasian, who has lived in the city of Sao Paulo for the last 22 years came to the emergency room with an 8-day history of continuous, intense, bilateral occipital headache associated with photophobia, nausea,

and vomiting. Three days after the initial symptoms, he had fever, myalgia, and vertigo. In the following days he developed slurred speech, marked gait instability, and imbalance. His past medical history was uneventful (he denied the occurrence of oral

Department of Neurology – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. c Department of Radiology – Instituto do Câncer do Estado de São Paulo – São Paulo/SP – Brazil. a b

Copyright © 2014 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-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided article is properly cited.

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or genital ulcers, arthritis, or any skin lesions preceding the recent symptoms). He was not on any medication and denied alcoholism, smoking, use of illicit drugs, or neurologic complaints in the past. He had no familial history of neurologic disease. He has six cats that are well maintained and regularly vaccinated. He denied traveling during the last 2 years, but used to go camping between the age of 27 and 31 to a region where there were tick infestations. At the emergency room, the remarkable physical findings included an ataxic gait, which worsened with the Tandem maneuver, dysarthric speech, and nystagmus to the right. Brain computed tomography (CT) was normal, and the analysis of cerebral spinal fluid (CSF) revealed lymphocytic pleocytosis with 528 cells/mm3 (91% of lymphocytes, 8% monocytes, and 1% neutrophils), protein was 76.3 mg/dL (reference value [RV]: <40 mg/dL), glucose was 50 mg/dL (plasma glucose 94 mg/dL, RV: >2/3 plasma glucose). Chloride and lactate values were in the reference range. Gram stain, China ink, cultures for acid-fast bacilli, fungus, and usual bacteria were all negative. Although the clinical course was not characteristic for herpetic meningoencephalitis, intravenous acyclovir was started. On the third day of hospitalization, despite the maintenance of normal mental status, the patient presented involuntary, fast, arrhythmic, conjugated, multidirectional eye movements preventing him from fixing his gaze (opsoclonus) [video]. He also developed generalized rhythmic resting and action tremors associated with myoclonic jerks at postural fixation, and volitional limb movements, particularly in the right side. The cerebellar signs worsened, appearing as marked truncal-limb dyssynergia, bilateral limb dysmetria, dysdiadochokinesia, and cerebellar ataxia, which progressed to astasia and abasia. The motor and sensory examination (deep and superficial sensations) was unremarkable, as were all the deep tendon reflexes. The autonomic function and cranial nerves examinations were also unremarkable, except for hearing loss. The patient was unable to stand and walk, and became completely dependent for daily activities, such as eating, brushing teeth, shaving, and bathing. Based on these neurological signs, the diagnosis of opsoclonus-myoclonus-ataxia syndrome (OMAS) was raised and a wide diagnostic workup was carried out to identify unusual infectious agents and immune dysfunction, the more

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common cause of this syndrome in adults. Sodium valproate was prescribed for the relief of myoclonic movements. Ampicillin was empirically started in consideration of the diagnostic possibility of Listeria rhomboencephalitis and acyclovir was withdrawn. A new CSF test confirmed the lymphocytic pleocytosis with 210 cells/mm3 (99% lymphocytes, 1% neutrophils), protein was 84.7 mg/dL, glucose was 51 mg/dL, lactate and chloride values were within normal limits, adenosine deaminase was 3.05 UI/L (RV: 9 UI/L). In spite of the partial decrease in CSF cellularity, the patient’s neurological deficits were unchanged. Methylprednisolone (1g/day/5 days) regimen was administered followed by a 5-day course of intravenous immunoglobulin (400 mg/kg/ day) with mild clinical improvement. Cranial magnetic resonance imaging (MRI) showed a tenuous, poorly defined, oval-shaped hyper signal lesion in fluid-attenuated inversionrecovery (FLAIR) and T2-weighted sequences, measuring 1.5 cm, with no diffusion restriction or enhancement after contrast infusion, in the left thalamus. No abnormal signs were found in the brainstem, cerebellum, or cranial nerves (Figure 1). The electroencephalogram was normal. At the brainstem auditory evoked potential test, delay was registered in all wave latencies for the right ear, and in waves III and V for the left ear. However, all interpeak latencies were normal on both sides, indicating a distal cochlear nerve dysfunction in the right ear with preservation of intra-brainstem auditory pathways. Contrast abdominal, thoracic, and pelvic CT, as well as testicular ultrasonography, failed to demonstrate any abnormalities suggestive of neoplasia. Prostate-specific antigen determination was within normal limits. Renal and liver function tests, electrolytes, hepatic enzymes, blood cell count, lactic dehydrogenase (LDH), free-thyroxin, thyroid stimulating hormone (TSH), immunoglobulin dosage and protein electrophoresis were all non-contributory. Laboratory exams for systemic inflammatory activity disclosed C-reactive protein maximum value of 30 mg/L (RV: <5 mg/L) and erythrocyte sedimentation rate of 30 mm in the first hour (RV <15 mm in the first hour). ANA tested by indirect immunofluorescence with Hep-2 cells was unremarkable as was the test for rheumatoid factor.


Adult-onset opsoclonus-myoclonus-ataxia syndrome...

Autopsy and Case Reports 2014; 4(1): 29-37

Figure 1 – Cranial MRI. A – FLAIR axial imaging; B – T2 coronal imaging. Both images show a tenuous hyper-signal in the left thalamic region (arrows) compatible with vasogenic edema or gliosis. Note the lack of interruption of the hematoencephalic barrier or cytotoxic edema. Syphilis test results were negative in blood and CSF as well as cultures for fungus and bacteria. A polymerase chain reaction assay for Herpes virus 1, 2, and 6, Varicella zoster virus, cytomegalovirus, and Mycobacterium tuberculosis in the CSF were all negative. Immunological tests for HIV were negative in blood and CSF, and the immunological window was ruled out by a negative viral load count. Serological tests for Dengue virus, Hepatitis B and C virus, Leptospira sp. were negative. Serology for Epstein Barr virus, toxoplasmosis, and rubella showed positivity for IgG but negativity for IgM. In the meantime, the immunologic reaction (IgM) for Borrelia burgdorferi was positive in the CSF by enzyme-linked immunosorbent assay (ELISA) but negative in the serum (ELISA and Western Blott) performed in the Brazilian Lyme Disease Reference Laboratory1. With this result, the diagnosis of neuroborreliosis was highly considered and ceftriaxone (2 g/day) therapy was instituted for 3 weeks, followed by doxycycline 100 mg twice daily for 2 months. After 7 days of use of ceftriaxone, the cerebellar signs and opsoclonus improved [video 2], the myoclonic jerks disappeared, and the patient was able to stand up and walk with assistance.

1 Medical Research Laboratory in Rheumatology – LIM 17 – Faculdade de Medicina da Universidade de São Paulo

DISCUSSION

Opsoclonus-Myoclonus-Ataxia Syndrome (OMAS) In 1962, Marcel Kinsbourne,1 an Austrianborn pediatric neurologist, described six children with acute onset of a distinctive movement disorder, which was initially coined as myoclonic encephalopathy or Kinsbourne syndrome, and further known as “Dancing eyes syndrome,2-4 opsoclonus-myoclonus,5 and ataxia opsoclonusmyoclonus.6 The Children’s Cancer Group study finally called this entity opsoclonus-myoclonusataxia syndrome.7,8 OMAS is a rare and debilitating neurologic disease, showing acute or subacute onset in childhood or adult life, occurring in 1–2 people per 10 million per year.9-11 Opsoclonus is an important marker and a diagnostic clue for this syndrome. It is characterized by involuntary, chaotic, multidirectional, fast, conjugated eye movements (saccades), particularly pronounced when the patient tries to fix the gaze, but is also present at smooth pursuit and convergence, and could persist during sleep or eyelid closure.12 Although the pathophysiology is uncertain, the most accepted hypothesis suggests that disinhibition of the fastigial nucleus in the cerebellum due to dysfunction of Purkinje cells in

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the dorsal vermis or their inhibitory projections to the fastigial nucleus.12 Thus, affecting this network can cause opsoclonus independently of any etiological factor. Often, opsoclonus is accompanied by myoclonus, characterized by sudden, brief, shocklike involuntary movements, typically postural or movement-induced, compromising the trunk, the upper and lower limbs more frequently, but also may occur in the face, tongue, and palate.13-15 The myoclonic jerks can be so intense that they cause incoordination and falls, and can hamper the classical signs of cerebellar dysfunction, such as imbalance, dysarthria, and dysmetria. Thus, the ataxia (gait instability or imbalance) could result from myoclonus, cerebellar involvement, or both. To these three cardinal signs, cognitive, behavioral, and variable degrees of encephalopathy may also be associated. All these neurological signs are not necessarily present together at the onset of the syndrome. In children, the OMAS occurs equally in both genders, commonly before 3 years of age. In about half of patients it is seen as a paraneoplastic syndrome most commonly associated with neuroblastic tumors, with neuroblastoma in more than half the pediatric cases.1,10,16-18 Infectious, postinfectious, post-vaccinal, and idiopathic cases were also reported. The clinical presentation, detection of autoantibodies, response to immunosuppressive treatment, and the long-term outcome are similar concerning the idiopathic and neuroblastomaassociated cases.18 Neuroblastoma-associated OMAS is frequently has a favorable prognosis.7,8 Long-term follow-up studies have shown normal or near-normal motor outcome along with cognitive and neuropsychological deficits (language, attention, memory, visuomotor, and working memories) in almost 80% of pediatric patients.6,7,18 The identified risk factors for worse outcome were younger age, severe initial presentation, delayed immunosuppressive treatment, and relapses with steroid-dose tapering.18,19 Adult-onset OMAS is much less frequent. The literature is limited to case reports and small series that showed no gender predominance and 48.5 years (range 18-80 years) as median age of onset.2,15 In general, the disease progresses rapidly within a median time of 4 weeks with severe disability in most patients. In about 35% of patients other coexisting neurological signs may be associated, including mild behavioral, cognitive, and/or mood changes; encephalopathy; cranial nerve palsies; seizure; or Lambert-Eaton myasthenic syndrome.2,15,20 The

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clinical presentation and the early severe disability of the case reported herein were in accordance with published data. In over 50% of adult patients, OMAS is a paraneoplastic presentation, with smallcell lung, breast, and ovarian cancers the most commonly identified neoplasms.2,15 Rarer oncologic associations include melanoma,21-23 and other neoplasms of the gynecologic tract,10,24-27 as well as cancers of the urologic,15,28,29 hematologic,30-32 and gastrointestinal systems.15 Infections (mainly virus), idiopathic cases, and rarely toxic or metabolic disturbances account for the other half. In our case, an infectious cause was identified after an extensive laboratory investigation. In both idiopathic and paraneoplastic cases, the imaging diagnostic workup generally shows normal CT and MRI.2,15 In our case, the MRI showed a tenuous and unspecific thalamic hyper-signal in T2-weighted and FLAIR sequences. Even though the same findings had been described in one idiopathic case by Bataller et al.,15 Kobayashi  et  al.33 found thalamic lesions in the autopsy of a Borrelia burgdorferi-seropositive chronic encephalomyelopathy. Furthermore, blood and CSF tests are most useful in diagnosing an infection, but do not confirm or exclude a paraneoplastic or autoimmune etiology. Among the cases of immunologic etiology, CSF analysis may show normal results or mild increase in protein (47-137 mg/dl) and/or lymphocytic pleocytosis (898 cells/mm3).2 Higher cell counts do not rule out idiopathic or paraneoplastic causes, but should raise the suspicion of an isolated or associated infection as observed in our patient. In four previously reported patients with Borrelia-associated OMAS, the cell counts ranged from 28 to 244 cells/mm3 and the remaining CSF characteristics were very similar to our case.34-37 The pathophysiology of the OMAS remains obscure. In idiopathic and paraneoplastic cases, the tissue dysfunction has been attributed to humoral and/or cellular immune attack affecting the structures belonging to fastigial nucleus-Purkinje cells network. In this setting, several antibodies against cell surface or intracellular structures of nervous system have been identified, such as, glycine receptor, Hu (ANNA-1), Ri (ANNA-2), glutamate receptor, neurofilament, Yo, Ma1, Ma2, amphiphysin, CRMP-5/anti-CV2, and Zic.2,15,20,32,38-45 Although these antibody studies have contributed to understanding of immunopathogenesis, most


Adult-onset opsoclonus-myoclonus-ataxia syndrome...

OMAS patients present negative results in blood and CSF, limiting their diagnostic value. In addition, B and T cells expansion, favorable response to rituximab therapy, and OMAS occurrence during immune reconstitution phase in HIV infection have raised the role for cell-mediated mechanisms.46-48 Parainfectious causes may be diverse and include agents such as cytomegalovirus, EBV, Coxsackie virus, West Nile virus, HIV, varicella-zoster virus, Influenza A virus, hepatitis C virus, Mycoplama pneumoniae, Salmonella sp., Ricketsia, group A streptococci, mumps, Lyme Disease (LD), and psittacosis.2,10,14,17,34,36,49-59 OMAS was also described after measles, mumps, and rubella vaccine.60 In HIV infection, Kanjanasut  et  al.57 suggest that OMAS occurs at the time of seroconversion or during the immune reconstitution inflammatory response, what justified the request of HIV viral load count in the presence of a negative serology detected in our patient.

Borreliosis LD is a well-known infectious disease in the USA and Europe. In 1975, Steere et al.61 described 51 patients with arthritis of unknown cause and hypothesized an arthropod transmission, possibly a tick, due to findings of skin lesions in 25% of the patients. This lesion was similar to erythema chronicum migrans reported in 1909 in Europe, which had been associated with tick bites and clinical manifestations such as neuropathic pain, paralysis, or meningitis. From 1975 to 1984, the Yale University group reported the clinical spectrum of LD, which included the nervous system, the heart, and the joints.62 The infectious agent in LD was identified in 1982 by Burgdorfer  et  al.63 and further named as Borrelia burgdorferi (sensu stricto). Nowadays, tick-borne Borrelia spp. encompass three major phylogenetic groups, of which the Lyme borreliosis group—formerly named B. burgdorferi sensu lato— has 19 species with at least 10 being pathogenic to human beings.64 In North America, B. burgdorferi sensu stricto is the main LD pathogenic agent, while in Europe there are at least five pathogenic species, causing a wide clinical spectrum. Clinically, LD is conceptually divided into early and late phases, and chronic or postLyme borreliosis syndrome. The early-LD can

Autopsy and Case Reports 2014; 4(1): 29-37

be localized or disseminated, defined by the occurrence of erythema migrans, neuroborreliosis, carditis, or lymphocytoma.65 In the late-LD the usual manifestations are arthritis without neurological disease, acrodermatitis chronica atrophicans, or rarely central or peripheral neurological deficits. Chronic Lyme disease is poorly defined and most associated with persistent pain, fatigue, or neurocognitive complaints.65 In considering the extreme difficulty in demonstrating Borrelia organisms by PCR and cultures of CSF, and in view of dramatic clinical improvement with antimicrobial therapy, it was hypothesized that tissue-adhered spirochete, mainly in oligodendrocytes, is essential for disease manifestations, and the tissue damage is amplified by local immune response that encompasses expression of several pro-inflammatory cytokines and antibodies generated in some extent by molecular mimicry.66 Borreliosis’ laboratory workup is sometimes challenging since it relies on indirect detection methods.67 ELISA is the method for specific antibodies screening followed by immunoblot when samples are ELISA-positive, in the serum. Diagnostic sensitivity of ELISA for acute Borreliosis ranges from 70% to 90%.67 Intrathecal detection of Borreliaspecific antibody is important for neuroborreliosis diagnosis. These antibodies are exclusively detected in the cerebrospinal fluid (CSF) in 10% to 70% of the patients.68,69 When these antibodies are detected in both, serum and CSF, the antibodyindex67,70 will diagnose the intrathecal specificantibody production with 80% of sensitivity. This index is useful for the cases with less than 6-month of disease. Protein chain reaction and cultures may be useful in early infection, but microscope-based assays, lymphocyte transformation test, and others are not currently recommended. Considering the European criteria67 for neuroborreliosis (Table  1), our patient received the diagnosis of definite neuroborreliosis. In Brazil, the study of LD started in 1989 and until now much of the knowledge on Brazilian borreliosis is due to the research effort of a multidisciplinary team headed by Dr. Natalino H. Yoshinari.68,71 In a preliminary study of 19 patients, Yoshinari and coworkers found that 31.5% had skin lesions, 31.5% had arthritis, and 42% had neurological disorders.70 Particularly analyzing the neurological manifestation in 30 patients with Brazilian borreliosis, the same group showed

33


Autopsy and Case Reports 2014; 4(1): 29-37

Table  1 – Suggested criteria for diagnosis of neuroborreliosis67 Diagnostic category

Definite

Possible

Criteria fulfilled All three • Neurological symptoms without other obvious reasons • Cerebrospinal fluid pleocytosis • Intrathecal Borrelia-antibody production Two of the above criteria

meningismus, motor and/or sensory polyradiculitis, and peripheral nerve palsies in the early and late phases of the disease. In this series, ocular symptoms were reported in 37.5% of cases and occurred more commonly in the early phase. This involvement included eyelid ptosis, anisocoria, strabismus, and ophthalmoparesis, among others.72 The clinical presentation and outcome of patients with Brazilian borreliosis were very similar of that previously reported in the USA and Europe, despite epidemiological, clinical and laboratorial differences. The contributions of the Yoshinari group can not be overemphasized. They clarified the intriguing characteristics of Borrelia spp causing LD-like syndrome in Brazil, suggesting the existence of a new exotic tick borne disease in the country, different from classical zoonosis observed in Europe and USA.73

Lino AMM, Spera RR, Campos FPF et al.

progression, and the emergency treatment was acyclovir. Specific treatment was only started after a positive result of immunologic reaction for Borrelia; our patient showed an important improvement after ceftriaxone in accordance with reported patients.

CONCLUSION OMAS best treatment should always be, whenever possible, directed to the etiology. In idiopathic and paraneoplastic cases, the treatment and outcome are hard to evaluate and compare due to large drug variability among different series, as well as the number of cases in each series. Treatment options include high-dose corticosteroid, intravenous immunoglobulin, and plasmapheresis, isolated or combined.2 In general, parainfectious OMAS cases have a favorable prognosis and full recovery.59,74 In the literature, neuroborreliosis has been treated with parenteral antibiotics (ceftriaxone), although some European studies have suggested that oral doxycycline is as effective as ceftriaxone.65 To the best of our knowledge, this is the first case report of neuroborreliosis manifested as OMAS in Brazil, and probably the sixth case in the English language literature. Therefore, the authors call attention to this diagnostic possibility when searching the etiology of OMAS.

Nowadays due to epidemiological, etiological and clinical particularities, Brazilian borreliosis is named Lyme disease-like syndrome, Infectiousreactive Lyme disease-like syndrome or BaggioYoshinari syndrome. Ticks responsible for disease transmission do not belong to Ixodes ricinus complex and etiological agent belong to B. burgdorferi sensu lato complex or can be a new Borrelia specie different from those spirochetes composing classical complex. Clinically, Brazilian borreliosis can evolve with a long period of latency following acute infection and other distinguishing features include higher incidence of associated autoimmune disturbances. Brazilian researches suggest that Brazilian Borrelia spp is found at atypical morphologies known as cell wall deficient bacteria, justifying clinical and laboratorial particularities.68

ACKNOWLEDGEMENTS

Reviewing three adult cases of OMAS as a manifestation of LD previously reported in English literature,34,36 some similarities were found in our case. All presented with acute onset, fast

34

The authors would like to thank Nadia N. Mangini, M.D and Laura Guilhoto, MD, for interpretation of brainstem auditory evoked potencial and the electroencephalogram.

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72. Shinjo SK, Gauditano G, Marchiori PE, et al. Neurological manifestations in Baggio-Yoshinari syndrome (Brazilian Lyme disease – like syndrome). Bras J Rheumatol. 2009;49:492505.

64. Franke J, Hildebrandt A, Dorn W. Exploring gaps in our knowledge on Lyme borreliosis spirochaetes: updates on complex heterogeneity, ecology, pathogenicity. Ticks Tick Bourne Dis. 2013;4:11-25. PMid:23246041. http://dx.doi. org/10.1016/j.ttbdis.2012.06.007

73. Mantovani E, Marangoni RG, Gauditano G, Bonoldi VLN, Yoshinari NH. Amplification of the flgE gene provides evidence for the existence of a Brazilian borreliosis. Rev Inst Med Trop São Paulo. 2012;54:153-7. http://dx.doi.org/10.1590/ S0036-46652012000300007

65. Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis. Lancet. 2012;379:461-73. http://dx.doi.org/10.1016/S01406736(11)60103-7

74. Pooja D, Clarke C, David S. A case of poststreptococcal psoclonus-myoclonus syndrome. Mov Disord. 2007;22:14901. PMid:17486621. http://dx.doi.org/10.1002/mds.21513

Conflict of interest: None Submitted on: 30th December 2013 Accepted on: 9th March 2014 Correspondence: Divisão de Clínica Médica Hospital Universitário da Universidade de São Paulo Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9200 E-mail: angelina@usp.br

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Article / Clinical Case Reports Artigo / Relato de Caso Clínico Granulosa cell tumor of the testis in a newborn Oliver Rojas Clarosa, Américo Toshiaki Sakaia, Horácio Consolmagnoa, Marcos de Paula Nogueiraa, Leonardo Abreu Testagrossab, Oscar Eduardo Hidetoshi Fugitaa Claros OR, Sakai AT, Consolmagno H, Nogueira MP, Testagrossa LA, Fugita OEH. Granulosa cell tumor of the testis in a newborn.  Autopsy Case Rep [Internet]. 2014; 4(1): 39-44. http://dx.doi.org/10.4322/acr.2014.006

ABSTRACT Testicular neoplasms are uncommon tumors of childhood. These tumors comprise the germ cell tumors, and other tumors that may originate from histological testicular components, which are unrelated to the germinal lineage. Among the latter are the sex cord-stromal tumors (SCST), an important entity in newborns. SCSTs comprise, among others, granulosa cell tumors, which are more common in the ovary, but in rare cases may develop in the testis. The prognosis is excellent since it is universally benign. Diagnosis, which is sometimes challenging, is usually made after orchiectomy and pathological examination, which is characterized by morphological features and positive expression of inhibin, calretinin, and vimentin, and negative for alphafetoprotein. The authors present the case of a newborn with a right enlarged testis detected during the first examination after birth. Ultrasonography showed a heterogeneous solid/cystic mass in the right testis, without retroperitoneal lymphadenopathy. A right inguinal orchiectomy was performed 21 hours after birth. Pathologic examination revealed a juvenile granulosa cell tumor of the right testicle. After 4 years of follow-up, as expected, the child presented an uneventful outcome. Keywords: Sex Cord-Gonadal Stromal Tumors; Granulosa Cell Tumor; Testicular Neoplasms; Infant, Newborn; Testis. CASE REPORT A 28-year-old mother gave birth to a male newborn at the 40th week of gestational age, through an uneventful vaginal delivery. The newborn weighted 3040g, and the Apgar score was 9, 10, 10. During the initial post-delivery examination, the neonatologist detected, as the sole alteration, an irregular, asymmetric, and enlarged right testis of a term newborn. This finding was confirmed by an ultrasonographic examination that showed a a b

heterogeneous solid mass in the right testis without retroperitoneal lymph node involvement. Left testis was descended and external genitalia was normal Serum alpha-fetoprotein (AFP) and total human chorionic gonadotropin (hCG) determination was 97,819 ng/mL (within normal range for gestational age and birth weight) and 31,4 mUI/mL (reference value: < 5 mUI/mL), respectively.

Department of Surgery – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. Department of Pathology – Hospital das Clinicas – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil.

Copyright © 2014 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-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided article is properly cited.

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Autopsy and Case Reports 2014; 4(1): 39-44 Claros OR, Sakai AT, Consolmagno H, Nogueira MP, Testagrossa LA, Fugita OEH..

A right inguinal orchiectomy was performed at 21 hours of age. Gross examination of the surgical specimen showed a light-brown colored, round, and solid mass measuring 3.0 × 2.0 × 1.5 cm. At the cut surface, a solid and firm sharply defined neoplasia replaced most of the testicle parenchyma, displacing the epididymis peripherally. The morphology was characterized by solid areas, and focal cystic structures resembling follicles containing a light basophilic watery substance (Figure 1A, 1C and 1D). These follicular-resembling areas showed multi-stratified clusters of neoplastic cells. The solid areas predominated and showed a lobulated arrangement formed by large cells with light eosinophilic cytoplasm, with rounded hyperchromatic nuclei and visible nucleoli, besides occasional nuclear infolding (Figure  1B). Mitotic and apoptotic cells were frequent. Immunostainings revealed diffuse positivity for vimentin and focal calretinin and inhibin, and negativity for β-hCG, alpha-fetoprotein and cytokeratins (Figure  2), thus ruling out yolk sac tumor, which was the major differential diagnosis.

The final diagnosis was juvenile granulosa cell tumor of the right testicle. The epididymis and rete testis were not involved but were displaced to the periphery. Neither necrosis nor infiltration of the tunica albuginea, nerves, or vessels was found. Surgical margins were free of neoplasia. The 4-year follow-up showed a healthy child without evidence of any testicular or scrotum complaints.

DISCUSSION Testicular neoplasms are the most frequent tumor in young men, but are rare among children. Their incidence ranges between 0.5 and 2.0 cases per 1,000,000 children.1 Approximately 10% of all testicular tumors are diagnosed during the neonatal period,2 comprising less than 1% of all childhood cancers.3 Testis tumors are represented by germ cell tumors, which are the leading histology,4 but any other histological testicular component may give rise to neoplasia. In this setting are the sex cord-stromal tumors (SCSTs), which account for approximately

Figure 1 – Photomicrography of the testis tumor (H&E). A – Panoramic view showing the neoplasia with cystic and solid areas, (100X); B – Details of the neoplastic cells, with rounded hyperchromatic nuclei and visible nucleoli, and occasional nuclear infoldings, (400X); C and D – Neoplastic cells arranged in follicularlike structures enclosing watery basophilic substance (C 200X, D 100X).

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Granulosa cell tumor of the testis in a newborn

Autopsy and Case Reports 2014; 4(1): 39-44

Figure 2 – Photomicrography of the testis tumor. Immunohistochemistry. A – Calretinin positivity in neoplastic cells (200X); B – Diffuse vimentin positivity in neoplastic cells (400X); C – Focal inhibin positivity (200X); D – Smooth muscle actin (SMA) positivity highlighting the lobular pattern of the tumor (100X).

10–20% of all gonadal tumors during childhood, mostly during the neonatal period or infancy, indicating a prenatal origin of tumor development.5,6 Granulosa cell tumor of the testis is a SCST distinguished in the adult and juvenile types.7 In 1983, Crump8 first described a case of a SCST in a 30-week-old fetus, but juvenile granulosa cell tumor (JGCT) was recognized as a distinct entity in 1985 due to its similarity to the ovarian granulosa cell tumor.9,10 The juvenile type accounts for 1.2% of all prepubertal testis tumors, representing the most common stromal sex cord neoplasm of the testis in infancy, and the most common neoplasm of the testis in the first 6 months of life.11-13 Until 2002, 48 cases had been described and compiled by Nieto et al, including a case report by the same author.14 JGCT is thought to arise from a specialized gonadal stromal cell of the testicle, which, histologically, is very similar to the JGCT of the ovary. This tumor usually affects the right and left testis equally, and the age at diagnosis ranges from neonates to 21 months.9,12,15,16 Clinical features are

characterized by an asymptomatic testicular mass within the abdomen or inguinal region, or within the scrotal sac, and the lack of endocrinological features. Some cases present the contralateral testis as clinically normal but undescended. When associated to external genitalia abnormalities, like ambiguous genitalia or hypospadia, JGCT usually presents abnormal karyotypes involving X/XY mosaicism or structural abnormalities of the chromosome Y.12,17-19 Chromosomal abnormality linked to the Y chromosome was reported to be found in 20% of the cases.18,19 AFP is a glycoprotein normally and equally produced by the yolk sac, liver, and gastrointestinal tract in early embryogenesis.20-22 Although the importance and usefulness of AFP as a tumor marker is well established, the reference value of AFP in newborns is still under standardization. Bader  et  al.,22 studying 260 term and near-term newborns, found a reference interval for AFP concentrations at birth that was 15,700–146,500 ng/ mL, based on 95% confidence interval. The median value was 48,300 ng/mL, which constitutes a useful

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Autopsy and Case Reports 2014; 4(1): 39-44 Claros OR, Sakai AT, Consolmagno H, Nogueira MP, Testagrossa LA, Fugita OEH..

reference.23,24 Therefore, although elevated, the value of serum AFP of our patient was within normal limits for the gestational age and birth weight, which is in accordance with JGCT behavior and laboratory characteristics. As far as we know, and based on a thorough bibliographic research, elevation of hCG is not observed in JGCT of the testis. The mild elevation detected in our case was interpreted as a false-positive result, as observed in other testis tumors.25 Similarly, the method of dosage using Siemens kit accepts several interferences as causing false-positive results mainly in the range of 10–50 mUI/L. Therefore AFP and hCG determinations are considered useless tumor markers for this type of neoplasm.18,19 Imaging studies, mainly those obtained by ultrasound examination, show a complex cystic and solid mass. Grossly, the tumor appears as a tan to yellow mass, within the parenchyma of the testis, with a mixture of solid and cystic regions without necrosis or hemorrhage. These cysts are thin-walled follicle structures that vary in size from 0.8 cm to 6.5 cm, and contain viscid or gelatinous fluid or clotted blood.13,26,27 Microscopically, the cysts are lined with single or multiple layers of granulosa cells with or without solid nodules. In non-follicular areas, the cells grow in sheets, nodules, irregular clusters, and sometimes are dispersed loosely in the stroma. The nuclei are round to oval and hyperchromatic with visible nucleoli and varying amounts of eosinophilic cytoplasm. Mitoses may be prominent and often as numerous as 33 mitoses per 10 high power fields.9,13,26 The high number of mitotic figures most likely represents the proliferative activity of the neonatal tissue, since JGCT are universally benign.28 The granulosa cells stain positive for cytokeratin and vimentin.26,29 As a gonadal stromal tumor, immunohistochemistry is also positive for CD99, inhibin, and calretinin.7,30 Characteristically, JGCTs do not stain for AFP. Differential diagnosis includes yolk sac tumor, teratoma, cystic dysplasia of the testicle, Sertoli cell tumor, gonadoblastoma, and unclassified SCSTs.7,12,31 All these tumors have been described as having cystic and solid components on ultrasound. In this context, morphologic features and adjunctive studies are capable of excluding most of the considered diagnostic possibilities. The presence of polyhedral cells with clear cytoplasm, microfollicules (Call-Exner bodies, which are multilayered folliclelike structures containing mucin), expression of inhibin, and lack of expression of AFP help to ascertain the diagnosis of JGCT in most cases.10

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The prognosis is excellent because JGCT is a benign entity. The diagnosis is reached by pathological findings after orchiectomy, which remains the treatment of choice. However, in case of a pre-operatory high index of suspicion, and after definitive frozen sections diagnosis, it is possible to enucleate the tumor while sparing the remainder of testis.28 We report the case of a term newborn that presented a painless testicular mass diagnosed in the delivery room. The appropriate physical examination led to the early diagnosis, prompt treatment, and consequently, a favorable prognosis. Pediatric testicular tumors are uncommon and usually present as painless testicular growths. Continuous and meticulous physical examination is the cornerstone to assure the early diagnosis and subsequent good prognosis in the childhood and perinatal period.

REFERENCES 1.

Coppes MJ, Rackley R, Kay R. Primary testicular and paratesticular tumors of childhood. Med Pediatr Oncol. 1994;22:329-40. http://dx.doi.org/10.1002/mpo.2950220506

2.

Walsh TJ, Grady RW, Porter MP, Lin DW, Weiss NS. Incidence of testicular germ cell cancers in U.S. children: SEER program experience 1973 to 2000. Urology. 2006;68:402-5. PMid:16904461. http://dx.doi.org/10.1016/j. urology.2006.02.045

3.

Schneider DT, Terenziani M, Cecchetto G, et al. Gonadal and extragonadal germ cell tumors. In: Schneider DT, Brecht IB, Oslon TA, et al., editors. Sex cord stromal tumors and rare gonadal tumors. Heidelberg: Springer; 2012. p. 327402. PMid:22527330.

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Harms D, Gottschalk I, Jänig U. Pathological anatomy of germ cell tumors (especially testicular tumors) in children. Klin Padiatr. 1983;195:181-9. PMid:6876681. http://dx.doi. org/10.1055/s-2008-1034066

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Schneider DT, Jänig U, Calaminus G, Göbel U, Harms D. Ovarian sex cord-stromal tumors: a clinicopathologic study of 72 cases from the Kiel Pediatric Tumor Registry. Virchows Arch. 2003;443:549-60. PMid:12910419. http:// dx.doi.org/10.1007/s00428-003-0869-0

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Hofman M, Schlegel PG, Hippert F, et al. Testicular sex cord stromal tumors: Analysis of patientsfrom Makei study. Pediatr Blood Cancer. 2013;60:1651-5. PMid:23733594. http://dx.doi.org/10.1002/pbc.24607


Granulosa cell tumor of the testis in a newborn 7.

Zugor V, Labanaris AP, Witt J, Seidler A, Weingärtner K, Schott GE. Congenital juvenile granulosa cell tumor of testis in Newborns. Anticancer research. 2010;30:1731-4. PMid:20592370.

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Crump WD. Juvenile granulosa cell (sex cord-stromal) tumor of fetal testis. J Urol. 1983;129:1057-8. PMid:6854755.

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Lawrence WD, Young RH and Scully RE: Juvenile granulosa cell tumor of the infantile testis. A report of 14 cases. Am J Surg Pathol. 1985;9:87-94. PMid:3976984. http://dx.doi. org/10.1097/00000478-198502000-00003

10. Shukla AR, Huff DS, Canning DA, et al. Juvenile granulosa cell tumor of the testis: contemporary clinical management and pathological diagnosis. J Urol. 2004;171:19002. PMid:15076304. http://dx.doi.org/10.1097/01. ju.0000120223.29924.3b 11. Ross JH, Rybicki L, Kay R. Clinical behavior and a contemporary management algorithm for prepubertal testis tumors: a summary of the Prepubertal Testis Tumor Registry. J Urol. 2002;168:1675-8. http://dx.doi.org/10.1016/S00225347(05)64386-8 12. Chan YF, Restall P, Kimble R. Juvenile granulosa cell tumor of the testis: report of two cases in newborns. J Pediatr Surg. 1997;32:752-3. http://dx.doi.org/10.1016/S00223468(97)90025-7 13. Young RH. Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems. Mod Pathol. 2005;18:S81-S98. PMid:15502809. http://dx.doi.org/10.1038/modpathol.3800311 14. Nieto N, Torres-Valdiviedo MJ, Aguado P, et al. Juvenile granulosa cell tumor of the testis: case report and review of literature. Tumori. 2002;88:72-4. PMid:12004856.

Autopsy and Case Reports 2014; 4(1): 39-44 hermaphroditism. Am J Surg Pathol. 1994;18:316-22. http:// dx.doi.org/10.1097/00000478-199403000-00013 20. Teilum G, Albrechtsen R, Norgaard-Pedersen B. The histogenetic-embryologic basis for reappearance of alphafetoprotein in endodermal sinus tumors (yolk sac tumors) and teratomas. Acta Pathol Microbiol Scand. 1975;83:80-6. 21. Brewer JA, Tank ES. Yolk sac tumors and alpha-fetoprotein in first year of life. Urology. 1993;42:79-80. http://dx.doi. org/10.1016/0090-4295(93)90347-D 22. Bader D, Riskin A, Vafsi O, et al. Alpha-fetoprotein in the early neonatal period - a large sutudy and review of the literature. Clin Chim Acta. 2004;349:15-23. PMid:15469851. http://dx.doi.org/10.1016/j.cccn.2004.06.020 23. Hyvarinen M, Zeltzer P, Oh W, Stiehm ER. Influence of gestational age on serum levels of alpha-1 fetoprotein, IgG globulin, and albumin in newborn infants. J Pediatr.1973;82:430-7. http://dx.doi.org/10.1016/S00223476(73)80116-7 24. Caballero C, Vekemans M, Lopez del Campo JG, Robyn C. Serum alpha-fetoprotein in adults, in women during pregnancy, in children at birth, and during the first week of life: a sex difference. Am J Obstet Gynecol.1977;127:384-9. PMid:65129. 25. Ballieux BEPB, Weijl NI, Gelderblom H, van Pelt J, Osanto S. False-positive serum human chorionic gonadotropin (hCG) in a male patient with malignant germ cell tumor of the testis: a case report and review of literature. Oncologist. 2008,13:1149-54. PMid:18984875. http://dx.doi.org/10.1634/ theoncologist.2008-0159 26. Pinto MM. Juvenile granulosa cell tumor of the infant testis: case report with ultrastructural observations. Pediatr Pathol. 1985;4:277-89. http://dx.doi.org/10.3109/15513818509026901

15. Thomas JC, Ross JH, Kay R. Stromal testis tumors in children: a report from the prepubertal testis tumor registry. J Urol. 2001;166:2338-40. http://dx.doi.org/10.1016/S00225347(05)65583-8

27. Nistal M, Redondo E, Paniagua R. Juvenile granulosa cell tumor of the testis. Arch Pathol Lab Med. 1988;112:112932. PMid:3178427.

16. Uehling DT, Smith JE, Logan R, Hafez GR. Newborn granulosa cell tumor of the testis. J Urol. 1987;138:385-6. PMid:2439713.

28. Fagin R, Berbescu E, Landis S, Strumpf K, Patil U. Juvenile granulosa cell tumor of the testis. Urology 2003;62:351. http://dx.doi.org/10.1016/S0090-4295(03)00355-8

17. Young RH, Lawrence WD, Scully RE. Juvenile granulosa cell tumor - another neoplasm associated with abnormal chromosomes and ambiguous genitalia. A report of three cases. Am J Surg Pathol. 1985;9:737-43. PMid:4061731. http://dx.doi.org/10.1097/00000478-198510000-00005

29. Groisman GM, Dische MR, Fine EM, Unger PD. Juvenile granulosa cell tumor of the testis: a comparative immunohistochemical study with normal infantile gonads. Pediatr Pathol. 1993;13:389-400. http://dx.doi. org/10.3109/15513819309048227

18. Raju U, Fine G, Warrier R, Kini R, Weiss L. Congenital testicular juvenile granulosa cell tumor in a neonate with X/ XY mosaicism. Am J Surg Pathol. 1986;10:577-83. http:// dx.doi.org/10.1097/00000478-198608000-00008

30. Peterson C, Skoog S. Prenatal diagnosis of juvenile granulosa cell tumor of the testis. J Pediatr Urol. 2008;4:472-4 PMid:18760677. http://dx.doi.org/10.1016/j.jpurol.2008.04.005

19. Tanaka Y, Sasaki Y, Tachibana K, Suwa S, Terashima K, Nakatani Y. Testicular juvenile granulosa cell tumor in an infant with X/XY mosaicism clinically diagnosed as true

31. Alexiev BA, Alaish SM, Sun CC. Testicular juvenile granulose cell tumor in a newborn: case report and review of the literature. Int J Sug Pathol. 2007;15:321-5. PMid:17652550. http://dx.doi.org/10.1177/1066896907302423

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Autopsy and Case Reports 2014; 4(1): 39-44 Claros OR, Sakai AT, Consolmagno H, Nogueira MP, Testagrossa LA, Fugita OEH..

Conflict of interest: None Submitted on: 10th January 2014 Accepted on: 16th March 2014 Correspondence: Divisão de Clínica Cirúrgica Hospital Universitário da Universidade de São Paulo Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9291; 3091-9489 E-mail: oscareh@hu.usp.br

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Autopsy and Case Reports 2014; 4(1): 45-51

Article / Clinical Case Reports Artigo / Relato de Caso Clínico Malignant paratesticular mesothelioma Leonardo Gomes da Fonsecaa, Daniel Fernandes Marquesa, Tiago Kenji Takahashia, Fernando Nalesso Aguiara, Juliana Naves Ravaninib, Daniel Fernandes Saragiottoa Fonseca LG, Marques DF, Takahashi TK, Aguiar FN, Ravanini JN, Saragiotto DF. Malignant paratesticular mesothelioma. Autopsy Case Rep [Internet]. 2014; 4(1): 45-51. http://dx.doi.org/10.4322/acr.2014.007

ABSTRACT Mesothelioma of the tunica vaginalis testis (MTVT) is a rare tumor that usually affects patients after the sixth decade of life. Exposure to asbestos is a known risk factor. Enlargement of the scrotal volume is the most common initial clinical manifestation, and about 15% of cases present metastasis at diagnosis. The treatment relies on surgical resection while the role of adjuvant chemotherapy and radiotherapy remains unclear. The prognosis for patients is generally poor, with a lethal outcome in 30% over a 24-month period. The authors report a case of a 62-year-old patient with the diagnosis of MTVT without a history of asbestos exposure. After surgical treatment, metastatic disease ensued. Chemotherapy was initiated, but could not be continued due to marked and fast clinical deterioration. The authors call attention to the difficulty of early diagnosis of MTVT due to a nonspecific clinical picture, the lack of action by the patient when the scrotal enlargement was first noticed, and the lack of tumor markers. Delayed diagnosis is definitely related to unfavorable prognosis. Keywords: Mesothelioma; Chemotherapy, Adjuvant; Spermatic cord; Orchiectomy. CASE REPORT A 62-year-old man sought the Urology Department complaining of progressive enlargement of the left testicle during the last 12 months associated with 5 kg of weight loss (7.3% of total body weight). He denied fever, testicular pain, or other local inflammatory sign. His past medical history included hypertension and diabetes mellitus. He had been a smoker of 20 packs/year but was abstinent for years. There was no reported history of cancer in his family; neither was there an occupation related to asbestos exposure. The physical examination was normal except for thickening of the scrotal skin accompanied a b

by left testicle enlargement. Neither hernias nor lymphadenopathy were present bilaterally in the inguinal region. An ultrasonogram revealed a mild hydrocele on the right scrotal sac, and a heterogeneous testicular mass interspersed with some cystic areas on the left. The tumor measured 11.6 × 9.5 × 6.8 cm (Figure 1). Serum chorionic gonadotropin was <3 IU/L (reference value [RV] for men <3 IU/L), alphafetoprotein was 2.5 ng/mL (RV: <10 ng/mL) and lactic

Department of Oncology – Instituto do Câncer do Estado de São Paulo, São Paulo/SP – Brazil. Department of Pathology – Instituto do Câncer do Estado de São Paulo, São Paulo/SP – Brazil.

Copyright © 2014 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-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided article is properly cited.

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Autopsy and Case Reports 2014; 4(1): 45-51

Fonseca LG, Marques DF, Takahashi TK, Aguiar FN, Ravanini JN, Saragiotto DF.

dehydrogenase was 310 U/L (RV: 240-480 U/L). Complementary laboratory workup was normal. Abdominal computed tomography (CT) showed a single periaortic lymph node, which measured 2.8 cm at its longest axis. An uneventful inguinal left orchiectomy was performed 10 days after the first visit. The left testicle and part of the scrotal sac, weighting 430 g and measuring 13,5 × 8,5 × 7,0 cm constituted the surgical specimen. At cut surface, a tumoral mass, of firm consistency, predominantly paratesticular involved the testicle and the spermatic cord, displacing them inferiorly. The epididymis was nonidentified (Figure 2). The morphological features (Figure  3), associated to the Immunohistochemical panel (Table  1) were compatible with the diagnosis of biphasic (epithelioid and sarcomatoid) malignant paratesticular mesothelioma with desmoplasic

areas. The tumoral infiltration spread to testicular parenchyma, rete testis, epididymis, tunica vaginalis and albuginea and spermatic cord. Angiolymphatic infiltration was present as well as intratumoral necrosis.

Table 1 – Immunohistochemical panel Antigen

Result

Antigen

Result

Calretinin

Positive

P53

Positive

Vimentin

Positive

P63

Negative

Citokeratin 5

Positive

BerEp4

Negative

WT-1

Positive

CEA

Negative

CA125

Positive

MOC-31

Negative

D2-40

Positive

P16

Negative

Ki 67

High index

CD138

Negative

CA125  =  cancer antigen 125; CEA  =  carcinoembryonic antigen; WT-1 = Wilms tumor protein

Figure 1 – A and B – Ultrasonography of the left scrotal sac showing a heterogeneous mass with some scattered cystic areas (notedly in B).

Figure 2 – Gross view of the surgical specimen showing in: A – longitudinal section of left testicle and scrotal sac showing paratesticular tumor involving the testicle with fascicular areas, and in B – in detail, infiltration of testicular parenchyma in an area of discontinuity of the tunica albuginea.

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Malignant paratesticular mesothelioma

Autopsy and Case Reports 2014; 4(1): 45-51

Figure 3 – Photomicrography of the surgical specimen (paratesticular tumor) showing: in A – stromal infiltration by solid tumor with epithelioid pattern (HE, 200X); B – infiltration by sarcomatoid spindle cells (HE,200X); C – immunohistochemical positive reaction for calretinin (400X); D – immunohistochemical positive reaction for WT-1 (400X). The patient was referred to the clinical oncology department for post-surgery follow-up. After 3 months, he complained of pain and bulging in the left groin. A physical examination revealed an enlarged inguinal lymph node measuring 8 × 4 cm. Abdominal, thoracic, and pelvic CT showed multiple and confluent enlarged lymph nodes in the posterior mediastinum, retrocrural space, periaortic, along the left gonadal vein, iliac chains, and in the left groin. The largest lymph node measured 10 × 6.4 cm. An impairment of concentration and elimination of intravenous contrast by the left kidney accompanied by moderate hydronephrosis were found, as well as a few non-calcified pulmonary nodules scattered bilaterally with up to 1.1 cm in the superior segment of the right lower lobe (Figure 4). The patient received two cycles of chemotherapy, which included pemetrexed and cisplatin. After 20 days, he returned with a marked decline in performance status, complaining of weakness and intense abdominal pain due to the progression of the disease. Considering this scenario, he was referred to exclusive palliative care and died after 24 days.

DISCUSSION Malignant mesotheliomas are uncommon tumors, mostly involving the pleura, peritoneum, or pericardium, but rarely originating from the tunica vaginalis testis.1 In 1957, Barbera and Rubino2 described the first case of mesothelioma of the tunica vaginalis testis (MTVT), and since then, fewer than 230 cases have been reported.1,3 However, the first description of MTVT associated with asbestos was held by Fligiel and Kaneko in 1976.4 MTVT might be considered to be a variation of peritoneal mesothelioma, since the peritoneal lining extends into the scrotal sac.3,5 Since the description of Fligiel and Kaneko4 the association of MTVT and asbestos exposure has been widely reported.6-11 This association was noted to occur between 34% and 42% of the cases,8,9 although this is considered to be underestimated because of insufficient clinical information. The failure of a patient to report a history of asbestos exposure does not necessarily mean that no exposure occurred as many individuals may not know that they have been exposed in the workplace or in the community.3 According to some studies, family exposure to asbestos increases the

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Autopsy and Case Reports 2014; 4(1): 45-51

Fonseca LG, Marques DF, Takahashi TK, Aguiar FN, Ravanini JN, Saragiotto DF.

Figure 4 – Abdominal CT. A – Coronal reformation showing a heterogeneous mass involving the aorta and left iliac artery; B  –  Axial plane showing periaortic lymph nodes, delayed concentration/excretion of the contrast, and slight hydronephrosis; C – Axial plane showing lymph nodes conglomerate with signs of central necrosis along the left iliac artery; D – axial plane – multiple bilateral enlarged inguinal lymph nodes.

risk of pleural mesothelioma by 10 times.12 The frequency of exposure to asbestos among patients with MTVT is comparable to patients with pleural mesothelioma.8 Although asbestos exposure or contact with asbestos-containing material remain the only plausible risk factor, other studies suggest that hydrocele and trauma may also be risk factors for the development of MTVT.5 It is well known that there is a high coincidence rate between mesothelioma and hydrocele; some investigators consider it debatable whether hydrocele plays a role in the development of mesothelioma or vice versa.5 Radiation or radiotherapy, viral infections, and chromosomal abnormalities are also speculative

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hypotheses implicated in the oncogenesis of mesothelioma.13-15 Contrary to the usual pleural and peritoneal sites, the paratesticular disease is rare, and corresponds to 0.3-1.4% of all cases of malignant mesothelioma.1 Simultaneous involvement of other serosas has already been reported.16-18 MTVT may occur in a wide range of ages. Although 10% of cases occur in patients under 25 years old, including children,9,19 the higher incidence mostly affects patients between the sixth and eighth decades of life.1


Malignant paratesticular mesothelioma

The most frequent clinical manifestation of MTVT is a rapidly-growing hydrocele (56.3%) and a paratesticular mass (32.8%).1 Both signs may present concomitantly, but that is not the rule.1 The testis of both sides are equally affected, and bilateral tunical involvement is exceptional.20 When the hydrocele is the presenting sign, the paratesticular tumor is frequently overlooked. The lack of specific clinical features, as well as tumor markers, is responsible for the delayed definitive diagnosis, which constitutes the paramount problem of malignant MTVT. The diagnosis is usually raised during surgical resection by the intraoperative finding of hemorrhagic hydrocele and the presence of small nodules in the tunica vaginalis, but confirmation is only achieved with the histology.1 Clinical staging is usually performed with thoracic and abdominal CT. Positron emission tomography (PET) can be used, based on its reasonable accuracy to detect extra thoracic involvement in pleural mesothelioma.21,22 Morphologically, paratesticular meso­ theliomas are identical to mesotheliomas arising at other body parts and is comprised of three histological subtypes, namely: epithelial, which corresponds to about 70% of cases; biphasic, 27% of cases; and sarcomatous, 3% of cases.23 Three different architectural patterns can be observed. Papillary or tubulo-papillary are the two most common. Welldifferentiated patterns present a favorable prognosis and resemble a tumor arising from the intraabdominal peritoneum of young females. Besides, the absence of stromal infiltration and necrosis are also favorable morphology features.24 The third, and least frequent pattern, is multicystic mesothelioma, which shows a well-differentiated morphology. Multicystic mesothelioma is associated with large masses and is characterized as a favorable pattern in terms of prognosis.25 The immunohistochemical profile of this neoplasm includes positivity for cytokeratin 7 and 5/6, calretinin, EMA, D2-40, and thrombomodulin, and negativity for cytokeratin 20, BerEP4, B72.3, MOC-31, and Leu-M1.26,27 More recently it has been shown that tunical mesothelioma express positivity for WT1 and CD138;28 it is well known that the former is expressed by mesotheliomas of other sites, and the latter—although not routinely studied—is potentially helpful in target therapy.1 Vimentin varies from negative to diffusely positive according to its sarcomatous component.1 Positivity for calretinin differentiates mesothelioma from adenocarcinoma, and the negativity for BerEP4 stands for mesothelioma versus adenocarcinoma.29

Autopsy and Case Reports 2014; 4(1): 45-51

MTVT is locally invasive in 40% of cases while 15% present as metastatic disease at diagnosis.1 Metastases occur via lymphatics—most commonly to the inguinal and periaortic lymph nodes, while the liver and lungs are frequently involved via hematogenous metastatic dissemination.1 The presence of lymph node involvement at diagnosis relates to the worst prognosis. Advanced age at diagnosis also represents a significantly worse prognosis and is related to the aggressive course of the disease.9,30,31 Tumor recurrence occurs in more than 60% of cases over the first 2 years from diagnosis and in more than 90% of cases over the first 5 years from diagnosis.30 The final lethal course is observed in 30% of cases after a median survival of 24 months.1 A clinical examination and CT scan should be performed every 3 months for 2 years as the recommended strategy for routine clinical care after curative treatment.32 Treatment of MTVT is based on inguinal radical orchiectomy concomitantly with inguinal or periaortic lymphadenectomy.1 In the cases where surgical access violates the scrotal skin, radiotherapy is recommended after surgery. In metastatic or advanced disease, palliative chemotherapy may reduce tumor volume and seems to play a role in the survival of patients for up to 10 months.32 Due to the scarcity of cases, treatment protocols rely on small series or case reports. Chemotherapy regimens are analogous to that used in pleural mesothelioma.33 Plas et al.9 showed a better response in patients with metastatic disease using radiotherapy combined with chemotherapy when compared with chemotherapy alone. Radiotherapy should be considered in patients with local disease after tumor-free margin extensive resection and patients with disseminated disease with a good clinical condition.34 In general, younger patients and early diagnosis are related to better prognosis.9 The role of adjuvant chemotherapy and radiotherapy is still controversial and requires further studies. Sebbag  et  al.35 reported two cases of MTVT. One was a disseminated intra-abdominal disease, which underwent tumor resection plus peritonectomy and intraperitoneal chemotherapy with cisplatin, obtaining a disease-free survival of 5 years. The other case referred to a local disease treated with adjuvant chemotherapy with doxorubicin, obtaining a survival of 24 months.

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Autopsy and Case Reports 2014; 4(1): 45-51

Fonseca LG, Marques DF, Takahashi TK, Aguiar FN, Ravanini JN, Saragiotto DF.

CONCLUSION In the case reported herein, we could not evidence exposure to known risk factors, but the age and clinical presentation fit the reported MTVT clinical features. The long time between the onset of symptoms and the demand for medical attention is noteworthy, as well as the progressive and fast metastatic spreading after surgical treatment of an apparent local disease. Despite the rare occurrence, this tumor should be considered a differential diagnosis of mass or increase of scrotal volume, even if the first diagnosis is a hydrocele, regardless of a history of asbestos exposure or history of cancer in the family. Early diagnosis is of great importance for successful treatment and improved survival.

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Bisceglia M, Bem Dor D, Carosi I, Vario M, Pasquinelli G. Paratesticular mesothelioma. Report of a case with comprehensive review of literacture. Adv Anat Pathol. 2010;17:53-70.

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Plas E, RiedI CR, Pfluger H. Malignant mesothelioma of the tunica vaginalis testis. Review of the literature and assessment of prognostic parameters. Cancer. 1998;83:2437-46. http://dx.doi.org/10.1002/(SICI)10970142(19981215)83:12<2437::AID-CNCR6>3.0.CO;2-G

10. Attanoos RL, Gibbs AR. Primary malignant gonadal mesotheliomas and asbestos. Histopathology. 2000; 37:1509. http://dx.doi.org/10.1046/j.1365-2559.2000.00942.x 11. Perez-Ordonez B, Srigley JR. Mesothelial lesions of the paratesticular region. Semin Diagn Pathol. 2000;17:294-306. 12. Begin R. Asbestos exposure and pleuropulmonary cancer. Rev Mal Respir. 1998;15:723-30. 13. Peterson JT, Greenberg SD, Buffler PA. Non-asbestos-related malignant mesothelioma. Cancer. 1984;54:951-60. http:// dx.doi.org/10.1002/1097-0142(19840901)54:5<951::AIDCNCR2820540536>3.0.CO;2-A 14. Taguchi T, Jhanwar S, Siegfried J, Keller SM, Testa JR. Recurrent deletions of specific chromosomal sites in 1p, 3q, 6q and 9q in human malignant mesothelioma. Cancer. 1993;53:4349-55. 15. Stenton SC. Asbestos, Simian virus 40 and malignant mesothelioma. Thorax. 1996;51:1074-6.

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Barbera V, Rubino M. Papillary mesothelioma of the túnica vaginalis. Cancer. 1957;10:183-9. http://dx.doi. org/10.1002/1097-0142(195701/02)10:1<183::AIDCNCR2820100127>3.0.CO;2-1

16. Ascoli V, Facciolo F, Rahimi S, Scalzo CC, Nardi F. Concomitant malignant mesothelioma of the pleura, peritoneum, and tunica vaginalis testis. Diagn Cytopathol. 1996;14:243-8. http://dx.doi.org/10.1002/(SICI)10970339(199604)14:3<243::AID-DC9>3.0.CO;2-I

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Meisenkothen C, Finkelstein MM. Asbestos exposure and malignant mesothelioma of the tunica vaginalis testis: Case series and review of the literature. OA Case Reports. 2013;2:17.

17. Poggi A, Longo F, Mansueto G, et al. A case of mesothelioma of the tunica vaginalis testis, with involvement of the pleura and-peritoneum. Tumori. 2000;86:256-7.

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Fligiel Z, Kaneko M. Malignant mesothelioma of the tunica vaginalis propria testis in a patient with asbestos exposure. Cancer. 1976;37:1478-84. http://dx.doi.org/10.1002/10970142(197603)37:3<1478::AID-CNCR2820370333>3.0.CO;2-G

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Gurdal M, Erol A. Malignant mesothelioma of tunica vaginalis testis associated with long-lasting hydrocele: could hydrocele be an etiological factor? Int Urol Nephrol. 2001;32:687-9. http://dx.doi.org/10.1023/A:1014433203297

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Karunaharan T. Malignant mesothelioma of the tunica vaginalis in an asbestos worker. J R Coll Surg Edinb. 1986;31:253-4.

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Huncharek M, Klassen M, Christiani D. Mesothelioma of the tunica vaginalis testis with possible occupational asbestos exposure. Br J Urol. 1995;75:679-80. http://dx.doi. org/10.1111/j.1464-410X.1995.tb07437.x

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Jones MA, Young RH, Scully RE. Malignant mesothelioma of the tunica vaginalis. Clinicopathologic analysis of 11 cases with review of the literature. Am J Surg Pathol. 1995;19:81525. http://dx.doi.org/10.1097/00000478-199507000-00010

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18. Müller M, Stöckle M, Pecqueux JC, et al. Coincident manifestation of mesotheliomas of the tunica vaginalis and pleura. Case report and literature overview. Urologe A. 2008; 47:200-4. http://dx.doi.org/10.1007/s00120-007-1576-2 19. Antman K, Cohen S, Dimitrov NV, Green M, Muggia F. Malignant mesothelioma of the tunica vaginalis testis. J Clin Oncol. 1984;2:447-51. 20. Pelzer A, Akkad T, Herwig R, et al. Synchronous bilateral malignant mesothelioma of tunica vaginalis testis: early diagnosis. Urology. 2004;64:1031. http://dx.doi.org/10.1016/j. urology.2004.06.003 21. Sørensen JB, Ravn J, Loft A, Brenøe J, Berthelsen AK; Nordic Mesothelioma Group. Preoperative staging of mesothelioma by 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography fused imaging and mediastinoscopy compared to pathological findings after extrapleural pneumonectomy. Eur J Cardiothorac Surg. 2008; 34:1090-6. http://dx.doi.org/10.1016/j.ejcts.2008.07.050 22. Wilcox BE, Subramaniam RM, Peller PJ, et al. Utility of integrated computed tomography-positron emission


Malignant paratesticular mesothelioma

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tomography for selection of operable malignant pleural mesothelioma. Clin Lung Cancer. 2009;10:244-8. http:// dx.doi.org/10.3816/CLC.2009.n.033

mesothelioma versus adenocarcinoma. Am J Surg Pathol. 1991;15:779-84. http://dx.doi.org/10.1097/00000478199108000-00008

23. Magoha GA. Testicular cancers in Nigerians. East Afr Med J. 1995;72:554-6.

30. García de Jalon A, Gil P, Azua-Romeo J, Borque A, Sancho C, Rioja LA. Malignant mesothelioma of the tunica vaginalis. Report of a case without risk factors and review of the literature. Int Urol Nephrol. 2003;35:59-62. http://dx.doi. org/10.1023/A:1025952129438

24. Churg A. Paratesticular mesothelial proliferations. Semin Diagn Pathol. 2003;20:272-8. http://dx.doi.org/10.1053/j. semdp.2003.08.003 25. Amin MB. Selected other problematic testicular and paratesticular lesions: rete testis neoplasms and pseudotumors, mesothelial lesions and secondary tumors. Mod Pathol. 2005;18:S131-S145. http://dx.doi.org/10.1038/ modpathol.3800314 26. Ordóñez NG. The diagnostic utility of immunohistochemistry and electron microscopy in distinguishing between peritoneal mesotheliomas and serous carcinomas: a comparative study. Mod Pathol. 2006;19:34-48. http://dx.doi.org/10.1038/ modpathol.3800471 27. Suster S, Moran CA. Applications and limitations of immunohistochemistry in the diagnosis of malignant mesothelioma. Adv Anat Pathol. 2006;13:316-29. http:// dx.doi.org/10.1097/01.pap.0000213064.05005.64 28. Al-Salam S, Hammad FT, Salman MA, AlAshari M. Expression of Wilms tumor-1 protein and CD 138 in malignant mesothelioma of the tunica vaginalis. Pathol Res Pract. 2009;205:797-800. http://dx.doi.org/10.1016/j.prp.2009.01.012 29. Sheibani K, Shin SS, Kezirian J, Weiss LM. Ber-EP4 antibody as a discriminant in the differential diagnosis of malignant

31. Hassan R, Alexander R. Nonpleural mesotheliomas: meso thelioma of the peritoneum, tunica vaginalis, and pericardium. Hematol Oncol Clin North Am. 2005;19:1067-87. http:// dx.doi.org/10.1016/j.hoc.2005.09.005 32. Eden CG, Bettochi C, Coker CB, Yates-Bell AJ, Pryor JP. Malignant mesothelioma of the tunica vaginalis. J Urol. 1995;153:1053-4. http://dx.doi.org/10.1016/S00225347(01)67638-9 33. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003; 21:2636-44. http://dx.doi. org/10.1200/JCO.2003.11.136 34. Lee JD, Perez S, Wang HJ, Figlin RA, Holmes EC. Intrapleural chemotherapy for patients with incompletely resected malignant mesothelioma: the UCLA experience. J Surg Oncol. 1995;60:262-7. http://dx.doi.org/10.1002/jso.2930600410 35. Sebbag J, Yan H, Shmookler B, Suggarbaker P. Malignant mesothelioma of the male genital tract: report of two cases. Urol Oncol. 2001;6:261-4. http://dx.doi.org/10.1016/S10781439(01)00123-5

Conflict of interest: None Submitted on: 3rd January 2014 Accept on: 19th March 2014 Correspondence: Departamento de Oncologia Instituto do Câncer do Estado de São Paulo Av. Dr. Arnaldo, 251 – Pacaembu – São Paulo/SP – Brazil CEP: 01246-000 – Phone: +55 (11) 3893-2686 E-mail: leogfonseca@hotmail.com

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Article / Clinical Case Reports Artigo / Relato de Caso Clínico Medullary carcinoma of the thyroid metastatic to the breast: a case report and literature review Sebastião Nunes Martins Filhoa, Marcelo Abrantes Giannottia, Sheila Aparecida Coelho Siqueiraa Martins Filho SN, Giannotti MA, Siqueira SAC. Medullary carcinoma of the thyroid metastatic to the breast: a case report and literature review. Autopsy Case Rep [Internet]. 2014; 4(1): 53-57. http://dx.doi.org/10.4322/acr.2014.008

ABSTRACT Breast malignancies, apart from skin cancer, are the leading cause of cancer from cancer among the female population. Unlike the high prevalence of primary mammary malignancies, metastases to the breast are uncommon, and account for only 0.2-2.7% of all malignancies affecting this organ. We report the case of a 35-year-old woman who sought medical care because of a breast lump. A mammogram suggested a breast tumor, which was biopsied. The histopathological workup resulted in the diagnosis of a metastasis from a medullary thyroid cancer. The authors review the most useful clinical, radiological, histological, and immunohistochemical features concerning extramammary malignancy to the breast. Keywords: Breast Neoplasms; Carcinoma, Medullary; Neoplasm Metastasis.

CASE REPORT A 35-year-old female patient sought medical care complaining of a palpable nodule in the left breast. The mammogram revealed clustered calcifications in the left upper quadrant (BIRADS 3). Complementary ultrasound showed a hypoechoic lesion, without acoustic shadow. The patient was submitted to a core needle biopsy and 12 tissue samples were obtained. The histological examination revealed a well-differentiated carcinoma infiltrating the mammary parenchyma, with peripheral microcalcifications, but an absence of the in situ component (Figure  1). The main diagnostic hypothesis was invasive breast carcinoma nuclear and histological (Nottingham) grade 2.

a

The complementary immunohistochemical research revealed positivity for E-cadherin and negativity for hormone receptors (estrogen and progesterone), as well as for oncogene HER2 (c-ERB2), besides a low proliferation index identified by less than 5% of positivity for Ki-67 (Figure 2). The discrepancy between histological findings of invasive carcinoma and a triple negative phenotype, besides the low proliferative index, evoked an additional clinical workup. According to a clinical history, obtained in a second opportunity, the patient had previously had a total thyroidectomy for the treatment of a medullary thyroid cancer 5 years ago.

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

Copyright © 2014 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-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided article is properly cited.

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Martins Filho SN, Giannotti MA, Siqueira SAC.

Figure 1 – Photomicrography of the biopsied specimen (mammary tissue). A – Well-differentiated carcinoma infiltrating the mammary parenchyma (HE, 100X). B – In detail: note the cellular pattern arrangement and the scarcity of mitotic figures (HE, 400X).

Figure 2 – Photomicrography of the biopsied specimen (mammary tissue). Immunohistochemical preliminary workup. A – Negative for the nuclear estrogenic receptor (200X). B – Negative for the nuclear progesterone receptor (400X). C – Negative for cEBR (HER2) (400X). D – Proliferative index below 5% (Ki67) (400X).

In the course of the disease, the patient also presented suspicious metastatic lesions in the proximal tibia, sacrum e lumbar spine, mild enlargement of the mediastinal and axillary lymph nodes besides pulmonary and hepatic nodules. Biopsy of the tibia confirmed a metastatic lesion of the medullary thyroid cancer.

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In the light of these histological findings and additional clinical information, a new immunohistochemical panel was tested, which showed positive for chromogranin and calcitonin (Figure  3). Based on this new data, the diagnosis could be made of metastatic medullary thyroid cancer in the mammary parenchyma.


Medullary carcinoma of the thyroid metastatic to the breast...

Autopsy and Case Reports 2014; 4(1): 53-57

Figure  3  –  Photomicrography of the biopsied specimen (mammary tissue). Complementary immunohistochemical workup. A – Chromogranin positive. B – Calcitonin positive.

DISCUSSION Medullary thyroid cancer is an uncommon malignant neoplasia, accounting for less than 10% of all cancers of the thyroid. Local invasion is the most common behavior followed by metastatic dissemination through the cervical and mediastinal lymphatic chains. Generalized disease usually occurs late in the course of the illness and predominantly involves the liver, bones, central nervous system, and adrenal glands.1-4 To date, less than 10 cases of medullary carcinoma of the thyroid metastatic to the breast have been reported. The first reports date from 2007, but in all of those cases the thyroid neoplasm was previously known, even though the hypothesis of primary breast malignant disease was considered, which was probably due to the marked difference in the incidence of these two neoplasms. In all of those cases, the combined analysis, including clinical findings, radiologic examination, histologic and immunohistochemical studies, enabled the appropriate diagnosis.3-5 The Brazilian National Institute of Cancer (INCA) estimates that in 2014 there will be 57,120 new cases of breast cancer among females, but only only 8,050 thyroid malignancies. This high incidence of malignant breast cancer does not include breast metastatic involvement occurring independently of the primary site.6 The prevalence of mammary metastatic involvement (regardless of the primary site) is infrequent, varying between 0.2 and 2.7% of all malignant tumors affecting the breast.7-11 This rate

is slightly higher in post-mortem studies, where this finding reaches 7%.7,12 Hematologic malignancies especially diffuse large-cell lymphomas, represent the most common source of breast metastatic disease. The differentiation between primary lymphoma of the breast or secondary involvement of the mammary parenchyma follows clinical criteria. Other hematological malignancies also related to secondary involvement of the breast include low grade lymphomas (follicular and lymphocytic), leukemia, and exceptionally, multiple myeloma.7,13,14 The incidence of metastatic breast involvement from solid tumors is slightly smaller. However, the morphologic similarities with primary breast tumors impose a tough diagnostic challenge, especially in the absence of clinical information and/ or oncologic medical history. Gastric and pulmonary carcinomas are the solid tumors that are more likely to be responsible for breast metastatic involvement, followed by malignant melanoma, carcinoid tumors, carcinoma of the ovary (mainly the serous papillary carcinoma), liver, kidney, prostate, thyroid, and sarcomas.7-11,15,16 The previous or current diagnosis of malignancy of any primary site, other than the breast, consists the cornerstone for the diagnosis of secondary involvement of the mammary parenchyma. The suspicion is reinforced when multiple other sites are also involved. Clinical features that aid the diagnosis of breast metastatic involvement include a fast-growing painless breast lump, upper outer quadrant involvement and the the absence of peau d’orange or nipple retraction. The diagnosis of the primary tumor and the metastasis

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may vary widely between null to several years, but the mean time is 12 months.8,9 A well-circumscribed lesion is the main finding on a mammogram, as well as on an ultrasound, in which the lesion does not present an acoustic shadow.8,9,17 Spiculated lesions with calcifications greatly favor the diagnosis of primary breast tumors. Histologically, these lesions are usually well circumscribed. In some cases, specific morphological characteristics may suggest secondary mammary involvement, such as the presence of pigments or nuclear inclusion bodies (in case of melanomas), large and clear cytoplasm (renal cell carcinoma), and diffuse and monotonous lymphocytic infiltrate (low-grade lymphomas). On the other hand, in situ carcinoma, peritumoral elastosis, and the presence of microcalcifications will favor the diagnosis of primary breast neoplasia.7 Finally, the unexpected discrepancy of the histological suspicion and the immunohistochemical results should raise the hypothesis of metastatic lesion. Classic lobular carcinomas, tubular, cribriform, and low-grade invasive carcinoma of no special type (invasive ductal) usually present positive immunophenotype for hormonal receptors (luminal molecular subtype). On the other hand, high-grade invasive carcinomas of no special type usually express positivity for HER oncogene (HER2/ neu molecular subtype) or negativity for both (triple negative molecular subtype). The metaplastic and medullary carcinomas also are included in this latter group.18,19 Additionally, the proliferative index (Ki-67) of the negative hormone-receptor subtypes usually express positivity greater than 20%.20 Any discrepancy between clinical, radiological, histological, and immunohistochemical features should always require a complementary workup for an extramammary malignancy to the breast. In these situations, widening the immunohistochemical panel is the cornerstone procedure; however, it should be directed towards the most probable primary tumor site.7-9 We would like to emphasize, however, that the expression of an immunohistochemical marker, by itself, is not sufficient to assure a diagnosis. A positive reaction for both chromogranin and calcitonin, as shown in this case, is not pathognomonic for medullary carcinoma of the thyroid, but also are found in neuroendocrine tumors of other sites, such as lungs and stomach.21,22

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Martins Filho SN, Giannotti MA, Siqueira SAC.

The case reported herein represents the fundamental clinicopathological correlation in the diagnostic process of extramammary malignancies to the breast. The more clinical data that is given to the pathologist the more accurate and less expensive the final diagnosis will be. The lack of clinical data available to the pathologist is not uncommon, which challenges him to reach an accurate diagnosis without the complete clinical history.

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Instituto Nacional do Câncer (BR). Estimativa 2014: incidência de câncer no Brasil. Rio de Janeiro; 2014 [cited 2014 January 15]. Available from: http://www2.inca.gov.br/ wps/wcm/connect/0129ba0041fbbc01aa4fee936e134226/ Apresentacao+Estimativa+2014_final+corrigido+tireoide. pdf?MOD=AJPERES&CACHEID=0129ba0041fbbc01aa4 fee936e134226

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Medullary carcinoma of the thyroid metastatic to the breast... extramammary malignancies: a clinicopathologic study of 12 cases. Pol J Pathol. 2006;57:161-5. PMid:17219743. 10. Smymiotis V, Theodosopoulos T, Marinis A, et al. Metastatic disease in the breast from nonmammary neoplasms. Eur J Gynaecol Oncol. 2005;26:547-50. PMid:16285577. 11. Chaignaud B, Hall TJ, Powers C, Subramony C, Scott-Conner CE. Diagnosis and natural history of extramammary tumors metastatic to the breast. J Am Coll Surg. 1994;179:49-53. PMid:8019724. 12. Sandison A T. Metastatic tumours in the breast. Br J Surg. 1959;47:54–8. PMid:14441414. http://dx.doi.org/10.1002/ bjs.18004720111 13. Duncan VE, Reddy VVB, Jhala NC, Chhieng DC, Jhala DN. Non-Hodgkin’s lymphoma of the breast: a review of 18 primary and secondary cases. Ann Diagn Pathol. 2006;10:144-8. PMid:16730308. http://dx.doi.org/10.1016/j. anndiagpath.2005.09.018 14. Domchek S M, Hecht J L, Fleming MD, Pinkus GS, Canellos GP. Lymphomas of the breast: primary and secondary involvement. Cancer. 2002;94:6-13. PMid:11815954. http:// dx.doi.org/10.1002/cncr.10163 15. Sanguinetti A, Puma F, Lucchini R, et al. Breast metastasis from a pulmonary adenocarcinoma: Case report and review of the literature. Oncol Lett. 2013;5:328-32. PMid:23255943 PMCid:PMC3525463. 16. Dursun P, Yanik FB, Kuscu E, Gultekin M, Ayhan A. Bilateral breast metastasis of ovarian carcinoma. Eur J Gynaecol Oncol. 2009;30:9-12. PMid:19317248.

Autopsy and Case Reports 2014; 4(1): 53-57 17. Yeh CN, Lin CH, Chen MF. Clinical and ultrasonographic characteristics of breast metastases from extramammary malignancies. Am Surg. 2004;70:287-90. PMid:15098776. 18. Correa Geyer F, Reis-Filho JS. Microarray-based gene expression profiling as a clinical tool for breast cancer management: are we there yet? Int J Surg Pathol. 2009;17:285-302. PMid:19103611. http://dx.doi. org/10.1177/1066896908328577 19. Schnitt SJ. Will molecular classification replace traditional breast pathology? Int J Surg Pathol. 2010;18(3 Suppl):162S-6S. PMid:20484283. http://dx.doi. org/10.1177/1066896910370771 20. Aleskandarany MA, Green AR, Benhasouna AA, et al. Prognostic value of proliferation assay in the luminal, HER2positive, and triple-negative biologic classes of breast cancer. Breast Cancer Res. 2012;14:R3. PMid:22225836 PMCid:PMC3496118. http://dx.doi.org/10.1186/bcr3084 21. Sentani K, Oue N, Noguchi T, Sakamoto N, Matsusaki K, Yasui W. Immunostaining of gastric cancer with neuroendocrine differentiation: Reg IV-positive neuroendocrine cells are associated with gastrin, serotonin, pancreatic polypeptide and somatostatin. Pathol Int. 2010;60:291-7. PMid:20403031. http://dx.doi.org/10.1111/j.1440-1827.2010.02519.x 22. Oba H, Nishida K, Takeuchi S, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia with a central and peripheral carcinoid and multiple tumorlets: a case report emphasizing the role of neuropeptide hormones and human gonadotropin-alpha. Endocr Pathol. 2013;24:220-8. PMid:24006219. http://dx.doi.org/10.1007/s12022-013-9265-8

Conflict of interest: None Submitted on: 16th January 2014 Accepted on: 18th March 2014 Correspondence: Sebastião Nunes Martins Filho Rua Arruda Alvim, 145, apto 43 - Pinheiros - São Paulo/SP – Brazil CEP: 05410-020 – Phone: +55 (11) 3081-2775 E-mail: sebnmf@gmail.com

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Autopsy and Case Reports 2014; 4(1): 59-61

Article / Clinical Case Reports Artigo / Relato de Caso Clínico Nasotracheal tube wire support: a safety device in maxillofacial surgery technical note after five years of experience Fernando Melhem Eliasa, Fábio Ricardo Loureiro Satob, Flávio Wellington da Silva Ferraza Elias FM, Sato FRL, Ferraz FWS. Nasotracheal tube wire support: a safety device in maxillofacial surgery technical note after five years of experience. Autopsy Case Rep [Internet]. 2014; 4(1): 59-61. http://dx.doi.org/10.4322/acr.2014.009

ABSTRACT A well fixed endotracheal tube is essential for safety during general anesthesia. In maxillofacial surgeries, securely fixing a nasotracheal tube in place has always been problematic. The aim of this article is to describe a simple but effective technique to fasten the nasotracheal tube using a wire support that allows a full range of head movement without interference in the surgical field. During the last 5 years, this device was successfully used in almost two hundred patients with very few complications. Keywords: Surgery, Oral; Anesthesiology; Intubation INTRODUCTION Fixation of the endotracheal tube and assuring airway patency is of vital importance in any general anesthetic procedure. When the surgical field is not near the head and neck, endotracheal tube fixation does not represent a difficult task. However, in oral and maxillofacial surgeries, particularly when an intraoperative approach of the dental occlusion is required, fixation of the endotracheal tube may become a challenge. In such cases, nasotracheal intubation is the method of choice because it ensures airway patency and at

the same time provides maximum mobility for the patient’s head. Nevertheless, injuries to the nasal soft tissues and even unintentional extubation may occur when the nasotracheal tube is not properly fastened. In this note, we describe a technique to fix the nasotracheal tube using a wire support, made with the metallic guide of the tracheal tube, easily available in the operating room. Our team has successfully used this method during the last five years to prevent nasotracheal tube displacement and its hazardous consequences.

Description of the Technique After the induction of anesthesia, tracheal intubation is undertaken through the nose using either a preformed or an armored cuffed tube. Single black cotton U-suture thread is stitched through the nasal mucosa and cartilaginous septum, allowing a primary anchorage. After a first loose limiter a b

knot, which will impede ischemic damage to the nasal mucosa, a series of tight knots around the endotracheal tube will prevent its displacement. Then, a small surgical cloth or bandage is tightly fastened around the patient’s head with adhesive plaster tapes, creating a cloth turban. Additional

Department of Oral and Maxillofacial Surgery, Hospital Universitário, Universidade de São Paulo, São Paulo/SP - Brasil. Department of Oral and Maxillofacial Surgery, Hospital da Cruz Vermelha, São Paulo/SP - Brasil.

Copyright © 2014 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-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided article is properly cited.

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Autopsy and Case Reports 2014; 4(1): 59-61

tapes are used to fix the turban to the skin of the forehead and posterior neck. This step is of critical importance to avoid displacement of the turban during surgery. Once the turban is properly fastened, a small surgical compress is taped over it, creating a soft cushion to accommodate the intubation wire support, which was previously curved in an M letterform, with U-shaped curves at both extremities (Figure 1). The next step consists in attaching the wire support onto the compress. The tracheal tube will be tied to the supporting device with the strap that usually comes with the small surgical compress. Both the wire support and compress should be fixed not only to the turban but also to the forehead to avoid any displacement. Afterwards, the turban is curled over the breathing circuit extension connected to the endotracheal tube and fixed by adhesive tape. Finally, the tube extension is fixed to the surgical bed with adhesive tapes, reducing the weight over the wire support and pressure over the patient’s occipital region (Figure 2).

Figure 1 – Wire support bent in the M letter-form, with U-shaped curves at both extremities.

Elias FM, Sato FRL, Ferraz FWS.

From 2008 to 2013, this technique was used in 197 patients who underwent general anesthesia for orthognathic, trauma and tumor resection surgeries. For the great majority of patients anesthesia was uneventful. In 10 cases the turban became loose and required reattachment. Six out of these 197 patients experienced slight nasal hyperemia due to the tube pressure. Neither necrosis nor permanent tissue damage was observed. Six patients complained of postoperative occipital pain and two of them had localized alopecia four weeks later, which totally healed afterwards.

DISCUSSION The coordinated effort between the surgeon and anesthesiologist is expected during any surgical procedure including extensive maxillofacial surgeries. In this setting the anesthesiologist, apart from taking care of the anesthetic procedures, needs to ensure free movement of the patient’s head without kinking the endotracheal tube or accidental extubation. At the same time the surgeon should have full access to the operative field and focused attention without other concerns related to the anesthesia. Several techniques have been described to maintain the endotracheal tube in place including: the use of adhesive tapes,1 ligatures passed around or through the tube,2-4 disposable catheter strapping,5 suturing the anesthetic tube to the pericranium,6 supporting the tube by a Mayo table,7 and custommade splints.8 Adhesive tapes, although simple and non-invasive, have several disadvantages as they may interfere with the operative field, limit the access to the middle and upper thirds of the face and restrict movements of the endotracheal tube. Furthermore, the tapes may become wet or lose

Figure 2 – A - The wire support is taped onto the compress, allowing the tube fixation with a small cord (arrow); B  -  Nasotracheal tube fixed well away from the operative field, allowing wide range of head movement; C - After bimaxillary orthognathic surgery, neither dislocation of the nasotracheal tube nor damage to the nasal soft tissues were observed.

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Nasotracheal tube wire support...

adhesiveness in contact with moisture besides triggering allergic reactions. Suturing through the tube presents the risk of puncturing the cuff inflation line causing deflation. This could result in reduced protection of the respiratory tract, loss of the airtight seal necessary for mechanical ventilation and leakage of anesthetic vapors to the environment. Suturing the anesthetic tube to the pericranium may give adequate fixation but does not allow lateral rotation of the tube and could lead to bleeding and infection at the site of the stitch. Custom-made splints restrict the operative field by being placed on the nasal bridge. A common disadvantage of the reviewed methods is the risk of endotracheal tube kinking and compression over the nasal alar cartilage while rotating or tilting the patient’s head. These inconveniences are eliminated with the proposed technique described above. However, it is important to remember that this technique is not free of complications and therefore some degree of nasal cartilage injury may occur if the cloth turban loosens up. Another complication is occipital soft tissue injury that may occur due to excessive compression caused by the weight of the breathing extension when it is not properly fixed to the surgical bed. In our series, six patients complained of pain in the occipital region and two of them developed localized alopecia four weeks after the surgery, which healed afterwards. All these patients underwent long lasting orthognathic surgeries. A soft surgical head bolster may decrease the occurrence of such complication. In six cases, mild nasal soft tissue injury was observed coincidently with the laxity of the turban. However, we did not find septal or alar necrosis or unintentional extubation.

Autopsy and Case Reports 2014; 4(1): 59-61

Due to its advantages, including low cost and easy availability in most surgical theaters, it has gained extensive acceptance with oral surgeons and anesthesiologists.

REFERENCES 1.

Fenje N, Steward DJ. A study of tape adhesive strength on endotracheal tubes. Can J Anaesth. 1988;35:198-202. PMid:3356058. http://dx.doi.org/10.1007/BF03010665

2.

Wingate G, Stevenson GW, Pensler JM. Rigid endotracheal
tube stabilization during craniomaxillofacial surgery. Ann Plast Surg. 1989;23:459-60. PMid:2604335. http://dx.doi.org/10.1097/00000637-198911000-00016

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Rivera R, Tibballs J. Complications of endotracheal intubation and mechanical ventilation in infants and children. Crit Care Med. 1992;20:93-199. http://dx.doi.org/10.1097/00003246199202000-00008

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Ota Y, Karakida K, Aoki T, et al. A secure method of nasal endotracheal tube stabilization with suture and rubber tube. J Exp Clin Med. 2001;26:119-22.

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Donlon WC, Truta MP, Hilt DM. A simple method of nasoendotracheal tube fixation. Ann Plast Surg. 1989;23:4612. PMid:2604336. http://dx.doi.org/10.1097/00000637198911000-00017

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Altemir FH. Pericranial fixation of the nasotracheal tube. J Oral Maxillofac Surg. 1986;44:585. http://dx.doi.org/10.1016/ S0278-2391(86)80105-7

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Baek, RM. Song, YT. A practical method of surgical draping using the performed RAE (Ring-Adair-Elwyn) nasotracheal tube and the mayo table in maxillofacial surgery. Plast Reconstr Surg. 2003;112:1484-5. PMid:14504540. http:// dx.doi.org/10.1097/01.PRS.0000080503.88764.6C

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Starr DG, Fletcher IR. A new method for securing endotracheal tubes during orthognathic surgery. Br J Oral Maxillofac Surg. 1994;32:260-1. http://dx.doi.org/10.1016/02664356(94)90214-3

CONCLUSIONS We found this method of nasotracheal tube fixation effective and safe. It allows a wide range of head movement and seldom interferes with the operative field. Conflict of interest: None Submitted on: 21th September 2013 Accepted on: 22th January 2014

Correspondence: Departamento de Cirurgia, Prótese e Traumatologia Maxilofaciais Faculdade de Odontologia da Universidade de São Paulo Av. Prof. Lineu Prestes, 2227 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-7887 E-mail: fmelias@usp.br

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Autopsy and Case Reports 2014; 4(1): 63-64

Image in focus Imagem em foco Ureteric carcinoma Stephen A. Gellera, Fernando P. F. de Camposb Geller SA, Campos FPF. Ureteric carcinoma. Autopsy Case Rep [Internet]. 2014; 4(1): 63-64. http://dx.doi.org/10.4322/ acr.2014.010

Picture provided by Dr. Stephen A. Geller - personal archive.

Ureteric neoplasms are rare tumors. The annual incidence (during the period 1995-2005) was 0,95-1,15/100.000 person-year. They are almost always urothelial tumors, especially papillary transitional cell carcinoma, as in the image above, and are less common than tumors of the renal pelvis and 10 times less common than urinary bladder tumors. In a large series of 1249 cases of urothelial neoplasms of the upper urinary tract (pelvis and ureter) (upper urinary tract tumors; UUTT) 34% of the cases involved the ureter, and in 8% the neoplasia was found in both sites concomitantly. Concomitance with bladder tumors is also observed, either synchronously or methachronously. When metachronous; bladder tumors precede UUTT in 10,2% of cases, and when synchronous in 49%. Both ureters are equally involved and involvement of both ureters was found in 15 out of 930 cases. Although the distal ureter is the most common

a b

location of ureteral tumors, and multifocal implants may also occur, tumor location should not be used to predict outcomes neither clinical decisions. Ureteral neoplasms are more likely to present with organ-confined disease, possibly because small UUTT can cause early symptoms. When these tumors metastasize they usually spread to lymph nodes, lungs, liver, bone and brain. UUTT are more common in males (M:F  =  2:1). In the USA, it is estimated that 3000 new cases occur per year with the numbers increasing slowly each year. The median age at diagnosis is 71 years, and highergrade tumors are most likely to occur in the elderly. Environmental factors have been implicated. In 2013, Holmäng et al published a retrospective study of 930 UUTT cases and found a relationship to previous abdominal radiotherapy in 16,7% of cases generally with a latency period of at least 15 years. Phenacetin-containing analgesics is known to be

Department of Pathology and Laboratory Medicine – Weill Medical College of Cornell University, New York/NY – EUA. Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil.

Copyright © 2014 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-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided article is properly cited.

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Autopsy and Case Reports 2014; 4(1): 63-64

Geller SA, Campos FPF.

related to UUTT; Steffens and Nagel showed 22% of these tumors associated with analgesic abusers. In Taiwan, arsenic exposure was associated with the development of upper urinary tract cancer. Chinese herbs containing aristolochic acid may cause progressive renal fibroses and is also associated with significant increase in the incidence of urothelial tumors of renal pelvis or ureter. Other contributory factors include Balkan endemic nephropathy and Lynch syndrome. It is noteworthy that, in contrast to bladder cancer, cigarette smoking was not related to ureteric neoplasms.

BIBLIOGRAPHY

Over 90% of the UUTT are of urothelial origin (transitional cells) with almost 8% being squamous cell carcinoma The tumor growth pattern may be solid, papillary or mixed; the former presents a poor prognosis. Metastatic tumors can also affect the ureters. Clinically, the most frequent sign is hematuria occurring in 75%  -  90% of cases, followed by symptoms of obstruction mostly represented by flank pain (8%  -  40% of cases), bladder irritation and constitutional symptoms. The image also shows advanced hydroureter and hydronephrosis with marked renal parenchymal atrophy. Some patients are asymptomatic, with diagnosis established after screening urinalysis demonstrates microhematuria or when abdominal ultrasonography is performed for an unrelated reason. Physical examination is routinely unrevealing. Cytologioc studies of the urine can be difficult to interpret because of degeneration of tumor cells in the urine but imaging studies generally demonstrate the tumor as well as the hydronephrosis.

Keywords: Ureteral Neoplasms; Hydronephrosis.

Stephen A. Geller, M.D. Department of Pathology and Laboratory Medicine Weill Medical College of Cornell University New York – USA geller16st@gmail.com Fernando P. F. de Campos, PhD Department of Internal Medicine Hospital Universitário – USP São Paulo/SP – Brazil fpfcampos@gmail.com

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1.

Geller SA, Lin C-S. Ureteral obstruction from metastatic breast carcinoma. Arch Path. 1975;100:476-8.

2.

Holmäng S, Holmberg E, Johansson SL. A population-based study of tumours of the renal pelvis and ureter: Incidence, aetiology and histopathological findings. Scand J Urol. 2013;47:491-6. http://dx.doi.org/10.3109/21681805.2013 .795188

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Holmäng S, Johansson SL. Urothelial carcinoma of the upper urinary tract: comparison between the WHO/ISUP 1998 consensus classification and WHO 1999 classification system. Urology. 2005;66:274-8. http://dx.doi.org/10.1016/j. urology.2005.03.011

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Lynch HT, Ens JA, Lynch JF. The Lynch syndrome II and urological malignancies. J Urol. 1990;143:24.

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McCredie M, Stewart JH, Ford JM. Analgesics and tobacco as risk factors for cancer of the ureter and renal pelvis. J Urol. 1983;130:28-30.

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Nortier JL, Martinez MC, Schmeiser HH, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med. 2000; 342:1686-92. http://dx.doi.org/10.1056/NEJM200006083422301

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Olgac S, Mazumdar M, Dalbagni G, Reuter VE. Urothelial carcinoma of the renal pelvis: a clinicopathologic study of 130 cases. Am J Surg Pathol. 2004;28:1545-52. http://dx.doi. org/10.1097/00000478-200412000-00001

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Raman JD, Messer J, Sielatycki JA, Hollenbeak CS. Incidence and survival of patients with carcinoma of the ureter and renal pelvis in the USA, 1973-2005. BJU Int. 2011;107:1059-64. http://dx.doi.org/10.1111/j.1464-410X.2010.09675.x

9.

Raman JD, Ng CK, Scherr DS, et al. Impact of tumor location on prognosis for patients with upper tract urothelial carcinoma managed by radical nephroureterectomy. Eur Urol. 2010;57:1072-9. http://dx.doi.org/10.1016/j. eururo.2009.07.002

10. Steffens J, Nagel R. Tumours of the renal pelvis and ureter. Br J Urol. 1988;61:277-83. http://dx.doi.org/10.1111/j.1464410X.1988.tb13957.x 11. Yang MH, Chen KK, Yen CC, et al. Unusually high incidence of upper urinary tract urothelial carcinoma in Taiwan. Urology. 2002;59:681. http://dx.doi.org/10.1016/S0090-4295(02)01529-7


Autopsy & Case Reports  

Autopsy & Case Reports, Volume 4 number 1 2014, ISSN 2236-1960. Serviço de Biblioteca e Documentação Científica do Hospital Universitário da...

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