Autopsy & Case Reports

ISSN 2236-1960

v.2, n.4, out./dez. 2012

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Autopsy and Case Reports 2012; 2(4): 1-3

Editorial

In the pursuit of indexing Aloisio Felipe-Silvaa Felipe-Silva A. In the pursuit of indexing [editorial]. Autopsy Case Rep [Internet]. 2012;2(4):1-3. http://dx.doi.org/ 10.4322/acr.2012.028

The world, the science and the ways of communication have changed rapidly after the popularization of the Internet. The medical autopsy, an almost handmade procedure that has been in practice for teaching and research for centuries, needs to renew or reinvent itself in order to continue to demonstrate its known academic and scientific value in the twenty-first century.

Autopsy and Case Reports is an electronic publication that was born in this context, inspired by weekly autopsy conferences presented at the Department of Pathology of the Hospital Universitario – Universidade de São Paulo (Brazil). At these meetings, clinicians, pathologists, surgeons, medical residents, and students learn information based on the correlation between the clinical, radiological, and pathological findings of the autopsies. This type of conference has been a core of medical education for centuries, and largely overlaps with its history. However, autopsy conferences (or anatomoclinical sessions) have been losing ground in the global medical education field either because of the dramatic reduction in the number of academic autopsies1,2 or the uncritical belief in the infallibility of imaging methods. Systematically, and supported by the literature,3,4 autopsy discrepancy rates are still significant today. Even in concordant cases, integrated learning has immeasurable value.

Despite providing plenty of useful and high-quality information, the analytical approach of autopsy cases is rare in contemporary medical literature. The articles, particularly case reports, are extremely succint in their analytical potential.5

a

We took the initiative to spread this approach to the scientific community and, above all, we have been calling other partner services that share this vision to contribute with well-documented cases, which, like ours, may be useful to the reader.

The global decline in the number of academic autopsies is remarkable. This editorial board struggles against a potential practical extinction of the academic autopsy as we know it. We do believe that the teachings from autopsies are still important for graduates in the health sciences, especially for the medical students. The analytical approach of autopsy cases provides the opportunity to learn and to “see” the pathophysiology of important diseases as a whole and “real” process and not only a matter in the field of imagination. It is also a valuable exercise in the correlation of imaging findings with gross anatomical specimens. The autopsy conferences and case reports are also intended to be a tool for quality control of medical care since they allow the discussion of diagnostic discrepancies and the building of medical reasoning.

We were not able to find any other journal with this focus on autopsy case reports in databases from Brazil and Latin America. Even in the PubMed database we could not find a specialized periodical with this approach. Of note, the Revista Electronica de la Autopsia (ISSN 1699-2334), an electronic Spanish journal edited between 2003 and 2011, was the single specialized journal we could find in this field. Of course, there are many autopsy case reports dispersed in pathology and clinical journals elsewhere.

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

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution ­NonCommercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

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Autopsy and Case Reports 2012; 2(4): 1-3

Autopsy and Case Reports is currently indexed in databases to open access and electronic journals such as Sumários de Revistas Brasileiras (sumarios.org) and Sistema Regional de Información en Línea para Revistas Científicas de America Latina, el Caribe, España e Portugal (Latindex). One of the issues about indexing in major databases is the need for a high number of articles in the “original articles” category, which include original research and systematic reviews— but not case reports.

Many case reports published in Autopsy and Case Reports to date are accompanied by a literature review, providing the reader with an update on the issue at hand. Examples include the articles “Hemophagocytic lymphohistiocytosis of indeterminate cause: a fatal adult case,”6 and “Spindle-cell carcinoma of the prostate.”7 Although they do not have the obvious subtitle “case report and review of the literature,” they are, in fact, practical review articles, and could be classified as original articles according to current criteria. From the standpoint of an editor, here is the dilemma: should a systematic review in a case report be mandatory?

Otherwise, could a journal based on traditional case reports be indexed in major databases?

At this point we should consider, again, the purpose and the proposal of Autopsy and Case Reports, despite the systematic literature reviews: the teaching and dissemination of knowledge (common to most scientific journals) through case reports (this is, in fact, a peculiarity of a few journals). Notably when it comes to the scarce and “dying” art of academic autopsy1, any welldocumented case report duly submitted to the scrutiny of the peer review process becomes part of a common or “planetary” database in the Internet era. Case reports, especially taken collectively, are of great value not only in the spread, but also in the sedimentation of medical knowledge, and contribute significantly to the progress of science.8 The experience of “reading a real case” brings important learning. An example of this was exposed by Dr. Robert Anderson (England), a specialist and world reference in congenital heart diseases, who graced us with the editorial, “Is an interatrial communication the same as an atrial septal defect?”9 inspired by the article, “An inferior sinus venosus interatrial communication associated with a secundum atrial septal defect, clinically presenting in an adult patient: autopsy report.”10

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Felipe-Silva A.

It is worth noting that some publications specializing in case reports are indexed in Medline: BMJ Case Reports – ISSN: 1757-790X (electronic); Journal of Radiology Case Reports – ISSN: 19430922 (electronic); Pediatric Case Reviews – ISSN: 1533-0664 (electronic), among others. And there are others that, although not indexed, follow the same principle: Case Reports in Obstetrics and Gynecology [electronic resource] – ISSN: 2090-6692 (electronic); Case Reports in Pediatrics [electronic resource] – ISSN: 2090-6811 (electronic). It is no coincidence that many of these journals began fairly recently (in the 2000´s) and are in electronic format, which conveys this spirit of information disclosure with the ease of the Internet. Autopsy and Case Reports belongs to this new generation of journals, but with a unique proposition in terms of focus, scope, and approach.

We have the prospect of increasing the number of articles per issue, as well as engaging other departments and centers since a larger number of original papers and a reasonable level of intramural articles are important criteria for major database indexing. But we’re still new and therefore unfamiliar, and struggle to receive submissions that address the scope we have set for this journal.

We believe that in the near future we can achieve greater visibility within Brazil, Latin America, and the world medical community—in an attempt to show the enormous importance and current value of the autopsy in enhancing the quality of medical care, and in generating knowledge and education. This issue of Autopsy and Case Reports (December 2012) marks a two-year period of uninterrupted publication. We think that indexing databases should be aware of this current, contemporary, and innovative view of case reports journals. Indexing criteria should be revised on occasion to make room for the inclusion of case reports journals in major databases.

REFERENCES 1.

Shojania KG, Burton EC. The vanishing nonforensic autopsy.

N Engl J Med. 2008;358(9):873-5. PMid:18305264. http:// dx.doi.org/10.1056/NEJMp0707996

2.

Xiao J, Krueger GR, Buja LM, Covinsky M. The impact of declining clinical autopsy: need for revised healthcare policy.

Am J Med Sci. 2009;337(1):41-6. PMid:19155753. http:// dx.doi.org/10.1097/MAJ.0b013e318184ce2b

3.

Winters B, Custer J, Galvagno SM, et al. Diagnostic errors in the intensive care unit: a systematic review of autopsy

In the pursuit of indexing studies. BMJ Qual Saf. 2012;21(11):894-902. PMid:22822241. http://dx.doi.org/10.1136/bmjqs-2012-000803 4.

Wichmann D, Obbelode F, Vogel H, et al. Virtual autopsy as an alternative to traditional medical autopsy in the intensive care unit: a prospective cohort study. Ann Intern Med. 2012;156(2):123-30. PMid:22250143.

5.

Campos FPF. What does the future hold? [editorial].

Autopsy Case Rep. 2012;2(1):3-5. http://dx.doi.org/10.4322/ acr.2012.001

6.

Campos FPF, Lima PP, Lima FR, et al. Hemophagocytic lymphohistiocytosis of indeterminate cause: a fatal adult case. Autopsy Case Rep. 2012;2(2):11-20. http://dx.doi. org/10.4322/acr.2012.011

Autopsy and Case Reports 2012; 2(4): 1-3 7.

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

8.

Campos FPF. Sharing experience through case reports [editorial]. Autopsy Case Rep. 2012;2(2):1-3. http://dx.doi. org/10.4322/acr.2012.010

9.

Anderson RH. Is an interatrial communication the same as an atrial septal defect? [editorial]. Autopsy Case Rep. 2011;1(4):1‑2. http://dx.doi.org/10.4322/acr.2011.010

10. Lovisolo SM, Campos FPF, Aiello VD. An inferior sinus venosus interatrial communication associated with a secundum atrial septal defect, clinically presenting in an adult patient: autopsy report. Autopsy Case Rep. 2011;1(4):21-27. http://dx.doi.org/10.4322/acr.2011.013

Correspondence: Aloisio Felipe-Silva Scientific Editor Autopsy and Case Reports Assistant Physician 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 2012; 2(4): 5-14

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Hepatic necrosis associated with drug-induced hypersensitivity syndrome Fernando Peixoto Ferraz de Camposa, Patricia Picciarelli de Limab, Luciana Maragnoa, Fabio Toshio Watanabec 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

ABSTRACT Drug-induced hypersensitivity syndrome (DIHS; also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) is a life-threatening condition first described by Chaiken et al. in 1950. It is characterized by extensive mucocutaneous rash; fever; lymphadenopathy; hepatitis; hematological abnormalities; damage to several organs such as kidney, heart, lungs, and pancreas; and possible reactivation of human herpesvirus-6 (HHV-6) or other herpes virus. Rare and severe cases may present hepatic necrosis, and about 15% of them result in death or liver transplantation. A hallmark of this syndrome is the late onset of symptoms after the drug exposure. The most common culprit drugs are the aromatic anticonvulsants (in almost 30% of the cases) and the antibiotics (which in some series represent 20% of the cases). The authors report a case of a 41-year-old female who presented to the emergency department with erythroderma, acute hepatitis, acute pancreatitis and acute renal failure, and was then treated with corticosteroid after the diagnosis of DIHS/DRESS. A specific culprit drug could not confidently be determined due to the presence of multiple drugs used by the patient. The clinical and laboratory outcome was apparently satisfactory, but unexpectedly, on the sixth day of hospitalization, the patient complained of nonspecific malaise, drowsiness, which progressed in a few hours with signs and symptoms of hepatic failure, refractory shock, and death. The autopsy findings showed submassive hepatic necrosis, and the immediate cause of death was attributed to hepatic failure.

Keywords: Liver failure, acute; Massive hepatic necrosis; Drug toxicity; Autopsy.

CASE REPORT A 41-year-old female patient, previously diagnosed with rheumatoid arthritis, sought the emergency department complaining of pruritus and cutaneous eruption associated with anorexia, fever, and myalgia. Three days after the onset of symptoms, she referred epigastric pain, nausea,

vomiting, jaundice, choluria, and her skin started diffuse scaling. She referred urinary tract infection, which was treated with ciprofloxacin until two weeks before the initial symptomatology. On this occasion, she also used scopolamine, dipyrone, and diclofenac.

She had been taking prednisone 15 mg/day for the

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 Graduating – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. a b

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution ­NonCommercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

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Autopsy and Case Reports 2012; 2(4): 5-14

Campos FPF, Lima PP, Maragno L, Watanabe FT.

last 3 months after methotrexate withdrawal. She denied alcohol consumption, smoking, or recent travel. Physical examination showed a well-looking patient, icteric, hydrated, and febrile. Blood pressure was 80/50 mmHg; pulse rate was 88 regular beats per minute. Dermatological examination showed a diffuse morbilliform exanthematous rash with desquamation compromising face, trunk, abdomen and upper limbs (more than 50% of the body surface). Her face and periorbital area were edematous, and the oral mucous membranes were slightly involved. The liver was tender and enlarged, palpable until 4 cm below the right costal margin. Lungs and cardiac examination were unremarkable. The initial laboratory work-up is shown in Table 1.

The patient started receiving prednisone 0.5 mg/kg/day and showed a slight clinical improvement until the sixth hospitalization day when she started presenting nonspecific malaise, somnolence, tachycardia, and hypotension. Laboratory tests showed metabolic acidosis and deteriorating liver function.

The patient was referred to the intensive care unit but died in 12 hours because of refractory shock.

Retrospectively, in a frozen stored serum sample, serology was positive for immunoglobulin G (IgG) and negative for IgM for cytomegalovirus and Epstein-Bar virus. Human herpes virus-6 (HHV-6) serology, studied by indirect immunofluorescence, was positive for IgG and negative for IgM. The immunoglobulin dosage was within the normal range.

Urinalysis sowed proteinuria, occult blood, 21,000 leukocytes/mm3 and 10,000 erythrocytes/mm3.

Urine culture was negative. Upper abdominal ultrasonography (US) showed an enlarged liver and spleen, slightly distended gall bladder with no calculi images within the biliary system. Abdominal computerized tomography (CT) also showed the presence of lymphadenomegaly in the aortic and iliac chains, with lymph nodes measuring up to 2.2 cm, besides free liquid in the pelvis. Hepatitis A, B, and C and HIV serologies were all negative. Blood cultures were negative for all 6 samples collected.

AUTOPSY FINDINGS External examination showed jaundice and diffuse cutaneous desquamation on the face, trunk, and limbs (Figures 1A, B). Skin microscopy showed dermatitis with scales formation and microscopic skin changes suggestive of drug-induced hypersensitivity reaction in an organization phase. Keratinocytes apoptosis, mild edema of the superficial dermis, and areas of dermal-epidermal cleavage characterized the microscopy of the skin (Figure 1C).

The analysis of the laboratory tests allowed the conclusion of hepatic, kidney, and pancreatic involvement. Total blood cell count was characterized by leukocytosis, with lymphopenia and monocytosis.

These results pointed towards the diagnosis of druginduced hypersensitivity syndrome (DIHS).

Lymph nodes examination showed lymphoid depletion without eosinophilic infiltration (Figure 1D).

Table 1 – Initial laboratory examination work-up Exam

Result

RV

Exam

Result

RV

Hemoglobin

13.6

Hematocrit

41.6

12.3-15.3 g/dL

Sodium

130

136-146 mEq/L

36.0-45.0%

Potassium

3.9

3.5-5.0 mEq/L

Leukocytes

15,800

Bands

0

4.4-11.3 × 10 /mm

AST

345

10-31 U/L

1-5%

ALT

425

9-36 U/L

Segmented

84

Eosinophil

0

46-75%

AP

1372

10-100 U/L

1-4%

γGT

1593

2-30 U/L

Basophil

0

Lymphocyte

5

0-2.5%

Total bil.

21.3

0.3-1.2 mg/dL

18-40%

Amylase

781

20-104 U/L

3

3

Monocyte

10

2-9%

Lipase

918

< 60 U/L

Platelet

326

150-400 x 103/mm3

INR

1.11

1

Creatinine

2.2

0.4 -1.3 mg/dL

Fibrinogen

573

175-400 mg/dL

Urea

154

10-50 mg/dL

Triglycerides

315

<150 mg/dL

Ionized Ca+

1.06

1.15 -1.35 Mmol/L

Ferritin

1650

22-322 ng/mL

ALT = alanine aminotransferase; AP = Alkalline phosphatase; AST = aspartate aminotransferase; γGT = gamma-glutamyl transferase; INR = international normalization ratio; RV = reference value; Total bil = total bilirubins.

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Hepatic necrosis associated with drug-induced hypersensitivity syndrome

Gross examination of the thoracic cavity disclosed congestion in both lungs. The myocardium showed tiny, yellowish and hardened consistency lesions (Figure 2A), which, on microscopy, corresponded to multiple foci of dystrophic calcification (Figure 2B) and areas of myocardial cell injury in organization (Figure 2C). These histological findings could represent toxic myocardial cells injury in a healing phase.

Autopsy and Case Reports 2012; 2(4): 5-14

The abdominal cavity showed the presence of 700 mL of limpid and yellowish ascites. The viscera and fat tissue were diffusely stained by a yellow– gold color, due to bile impregnation. The pancreas showed slight edema weighing 86 g (reference value [RV] = 110 g).

Over the organ, on parenchymal surface cuts, as well in the peripancreatic tissue, numerous foci of fat necrosis were found (Figures 3A, B). These

Figure 1 – A and B - Gross examination of the body showing diffuse desquamation of the skin; C - Photomicrography (H&E) of the skin showing hyperkeratosis and flaking surface (long arrow) and multiple figures of keratinocyte apoptosis (small arrows); D - Photomicrography (H&E) of the lymph node showing lymphocyte depletion.

Figure 2 – A - Gross examination of the heart showing the presence of yellowish nodules (arrow); B - Photomicrography (H&E) of the myocardium showing multiple foci of dystrophic calcification; C - Photomicrography (H&E) of the myocardium showing areas of myocardial cell injury in organization.

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findings confirmed the diagnosis of acute edematous pancreatitis on microscopy (Figures 3C, D).

The liver had a yellowish color, was of soft consistency, and weighed 1735 g (RV range = 1140‑1450 g). The hepatic cut (Figure 4A) surface showed multiple bleeding points on the topography of the center-lobular hepatic vein, which was represented by extensive areas of necrosis and loss of the trabeculation on microscopic examination (Figures 4B‑D).

The spleen was enlarged and congested, weighing of 549 g (RV = 112 g) showing acute splenitis (Figure 5A). Gross examination detected wedge areas of yellowish and soft consistency tissue (Figure 5B) that on microscopy corresponded to ischemic necrosis (Figure 5C). Additional findings included generalized visceral congestion; moderate esophagitis; gastritis; small mucosal bleeding points scattered in the cecum and ascending colon; uterine fibroids and corpus luteum hemorrhagic cysts in the ovary; and lipid deposition in the abdominal aorta. Remaining organs and tissues showed no significant alterations on gross and microscopic examination.

Campos FPF, Lima PP, Maragno L, Watanabe FT.

DISCUSSION DIHS, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), is a life-threatening condition, which, in its complete form, is characterized by mucocutaneous rash, fever, lymphadenopathy, hepatitis, hematologic abnormalities, and damage to several organs such as kidney, heart, lungs, and pancreas.1 There is a trend to consider DIHS as the precise denomination for this syndrome.

A hallmark of this syndrome is its late onset after the culprit drug exposure, unlike other drug reactions, which occur earlier after drug exposure, like the acute generalized erythematous pustulosis and StevensJohnson syndrome/toxic epidermal necrolysis.2 This latency is fairly variable in the literature, described as being between 2 weeks and 3 months.1-3,4 Um et al.5 reported 6 cases in a series of 38 patients, and Ang et al. reported 3 cases in a series of 27,6 where this latency period was less than 1 week. This small latency was correlated to antibiotics and NSAIDs. The syndrome may develop after the very first use of the drug and after its re-administration.1

Figure 3 – A - Gross examination of the pancreas showing acute edematous pancreatitis with foci of fat necrosis on the surface of the organ (arrow) and in the cut surface of the parenchyma in B; C and D - Photomicrography (H&E) of the pancreas depicting pancreatic and peripancreatic fat necrosis.

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Hepatic necrosis associated with drug-induced hypersensitivity syndrome

Autopsy and Case Reports 2012; 2(4): 5-14

Figure 4 – A - Gross examination of the hepatic cut surface showing yellowish and hemorrhagic areas; B and C - Photomicrography (H&E) of the liver showing hepatic necrosis; D - Photomicrography of the liver (immunohistochemical staining for reticulin) showing the loss of the normal liver parenchyma trabeculation.

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

SAP = HU 1

2

3

4

5

6

7

8

9

10

11

12

Figure 5 – A - Gross appearance of the enlarged spleen; B - Gross examination of the splenic cut surface showing acute splenitis, and ischemic wedge yellowish areas; C - Photomicrography (H&E) of the spleen showing ischemic necrosis.

First described by Chaiken et al. in 1950,7 DIHS is an unpredictable reaction with an incidence ranging from 1 in 1000 to 1 in 10,000 patients.5,8,9 It occurs more frequently in adults, has no gender predominance1, and is not related to dose or serum concentration of the offending drug.10 Mortality is observed in 10-20% of the cases, especially those related to advanced age, renal impairment, and severe hepatic injury.1,11 The exact mechanism by which the drug triggers the syndrome remains to be fully determined.

Pathogenic data are more consistent with aromatic anticonvulsants as culprit drugs, but there is a trend to accept the same mechanisms when other dugs are involved. The ethiopathopenesis of DIHS/DRESS comprises: a) deficiency of the epoxide hydroxylase enzyme that detoxifies drug metabolites (in this case, the accumulation of arene oxides promotes direct cellular toxicity and/or triggers an immune response); b) reactivation of herpes virus family; and c) genetic predisposition (abnormal detoxification of some drugs is thought to be inherited in autosomic co-dominant fashion12 and familial cases have been reported

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Autopsy and Case Reports 2012; 2(4): 5-14

and certain human leukocyte antigen (HLA) alleles were shown to be closely associated with cutaneous reactions).1,5,13 Reactivation of HHV-6 or other herpes virus can be evidenced by increases in the title of IgG anti HHV-6 after the second week of the rash onset by the maintenance of elevated IgM levels during the course of reaction14 or by detection of viral genome by protein chain reaction (PCR) in the blood. The latter, when absent, raises the suspicion of other sites for the viral reactivation, such as the spleen or lymph nodes.11,15 The role of herpesvirus reactivation in the syndrome seems to be related to an immune response elicited by the drug, activating macrophages, lymphocytes, and cytokine release. The virus, housed in these cells, would therefore be jointly reactivated.16 Shiohara et al. proposed that the clinical symptoms during DIHS/DRESS do not only seem to be mediated by the expansion of drug-specific T cells, but also by antiviral T cells cross-reacting with drugs.1,16 Depending on the extent of macrophage activation and the cytokine storm, a hemophagocytic syndrome may be elicited. In this case, hyperferritinemia may reflect this hypercytokinemia.17 In this case report, viral serologic work-up was undertaken precociously, at the beginning of the syndrome. These serologies could not be repeated because of the unfavorable outcome; therefore it was not possible to demonstrate the viral reactivation.

A recent review of literature concerning drugs related to DIHS/DRESS found 44 different drugs related to 172 cases in the period from 1997 until 2009.18 The most common drugs involved in the pathogenesis of DIHS/DRESS are the aromatic anticonvulsants (almost 30% of the cases) such as phenytoin, carbamazepine, phenobarbital, lamotrigine, and primidone. However, other drugs are also well established as potential triggers, such as allopurinol, minocycline, calcium channel blockers, angiotensin converting enzymes inhibitors, beta-blockers, dapsone, terbinafine, NSAIDs, anti-retroviral drugs, quinine,19 sulfasalazine,20 bupropion,21 ranitidine, methimazole, propylthiouracil, azathioprine, and biologic agents.1,22 Antibiotics are being fully associated with DIHS/DRESS, after recent reports where they were involved in 20% of cases.5 Among them are trimethoprin-sulfamethoxazole, β-lactams, quinolones, and sulfonamide.1,3,5,11 In the case reported here, we observed the full clinical picture described for DIHS, precociously raising the suspicion. The latency period between the initial symptoms and the drugs’ exposure was 2 weeks, in accordance to the diagnostic requirements. In this case, it became difficult to confidently identify the culprit drug due to the presence of multiple drugs.

Even so, we raised the suspicion that ciprofloxacin was the most probably offending drug, once this drug

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Campos FPF, Lima PP, Maragno L, Watanabe FT.

has already been reported in the literature presenting similar clinical picture.23 Ciprofloxacin has been also recognized as a drug capable of causing hepatic injury. A study of cases from Drug-Induced Liver Injury Network (DILIN) from September 2004 to January 2010 found 12 cases (out of 679), related to fluoroquinolones hepatotoxicity. In this study,24 the average time between the drug and the onset of symptoms was 4 days (range 1-39 days); one of these cases died because of acute hepatic failure.

Ciprofloxacin was the drug in 6 of these cases.24 Fever as high as 38-40 °C is the most common symptom occurring in 90-100%25 of cases followed in frequency (90%)25 by involvement of the skin, which is characterized by a morbilliform rash, which is indistinguishable, in most cases, from other drug reactions. The face, upper trunk, and upper extremities are initially affected, with subsequent progression to the lower limbs. Swelling of the face, with marked periorbital involvement may be a diagnostic clue and is present in 25% of cases.25 The maculopapular eruption later becomes infiltrated, and vesicles are infrequent. Over time, the rash becomes purplish and ends with scaling.1,26 Another form of presentation is as exfoliative dermatitis, also associated with mucosal involvement.27 A skin biopsy does not establish the diagnosis but can assist in its confirmation, showing lymphocytic infiltration of the papillary dermis that may contain eosinophils and perivascular inflammatory infiltrate.6,28 The patient of this case report presented high grade fever from the onset until the end. Her cutaneous involvement was represented by generalized erythema (exanthematous rash) with scaling and facial edema.

Lymphadenopathy may be localized or generalized and occurs in 50-75% of the cases.5,25 The lymph nodes may present a benign pattern of lymphoid hyperplasia or a standard pseudolymphomatous aspect with disruption of normal architecture of the organ.1,29 In this case report, the lymph node involvement was detected by CT images and confirmed at autopsy. The histology was characterized by lymphocitary depletion, contrary to what has been described hitherto. This histological difference may be explained by the chronic use of corticosteroid and other immunosuppressant drugs used in the past.

Hematologic abnormalities occur in up to 50% of cases,25 and are characterized by marked leukocytosis (up to 50,000/mm3), eosinophilia (30% of cases), monocytosis, and lymphopenia. Atypical lymphocytes are not rare, usually appearing in the onset of symptoms,1,29 which is different from the

Hepatic necrosis associated with drug-induced hypersensitivity syndrome

eosinophilia that is observed 1-2 weeks later.30 More rarely, thrombocytopenia, leukopenia, or even pancytopenia may be observed.5 Hemophagocytic syndrome has been reported in the course of DIHS/ DRESS, usually after the second week of the drug eruption.

After lymphadenopathy, the most common visceral involvement refers to the liver (50-60% of patients). 25 More commonly, hepatic injury is represented by isolated elevation of hepatic transaminases, which is usually anicteric.1,29 Severe cases may present focal or spread hepatic necrosis, characterized by alanine transaminase (ALT) elevation of 10 times the reference value or by acute liver failure with coagulopathy and encephalopathy. This worse outcome is mostly observed in women in the fourth decade of life. Apparently it does not show a change in course with immunosuppressants. About 15% of cases result in death or liver transplantation.1,30 Splenomegaly is frequently observed accompanying hepatomegaly.30 The patient of this case report was a middle-aged woman who, after an initial apparent clinical improvement, developed a dramatic hepatic failure rapidly evolving to death. Splenomegaly was also present in this case. The autopsy found a submassive hepatic necrosis.

The renal involvement occurs in approximately 11-15.8% of the cases,5,25 which is outlined by an increase in serum urea and creatinine, and sometimes by hematuria proteinuria or eosinophiluria.5,30 The kidney histology generally reveals tubulointerstitial nephritis and granulomatous necrotizing angiitis.6,31 On admission laboratory tests, the patient of this report showed results being compatible with acute renal failure and an unquantified proteinuria on the urinalysis. The renal histology of the case reported here, was more compatible with a final event (acute tubular necrosis), but we assume the initial renal impairment, as due to DIHS/DRESS, once there was no other reason for the renal insufficiency.

Myocardial involvement is fairly variable, ranging between asymptomatic cases and heart failure, chest pain, dyspnea, and hypotension. The most severe presentation is represented by the acute necrotizing eosinophilic cardiogenic shock, implicated with drug hypersensitivity, which histology shows eosinophilic and lymphocytic infiltration with extensive myocardial cell necrosis.32 When symptomatic, the echocardiogram may show reduced left ventricular ejection fraction, and the chest x-ray shows an enlarged cardiac silhouette. The electrocardiogram is nonspecific with changes in the ST segment or T wave

Autopsy and Case Reports 2012; 2(4): 5-14

abnormalities, conduction delay, sinus tachycardia, and ventricular arrhythmias. The echocardiogram may show systolic dysfunction and occasional pericardial effusion.

Myocardial necrosis biomarkers may show elevation of creatine kinase-MB fraction and in severe cases of eosinophilic myocarditis troponin-I may also be raised.

Sudden cardiac death has been reported.3,30,33,34 In this case report, the autopsy findings represented by the yellowish nodules and the histologic demonstration of myocardiocyte injury were interpreted as a myocardial lesion of the DIHS/DRESS syndrome.

Pancreatitis occurring in association with DIHS/DRESS is rare; generally it occurs as a late consequence of multiorgan failure.29 Roquin et al. reported a case of pancreatitis associated with DIHS/DRESS in the early stage of the disease. Criado et al, reported another case of a young woman who developed DHIS/DRES after using carbamazepin, presenting acute pancreatitis with a fatal outcome.35 In the case reported here the elevation of lipase and amylase serum determinations were present at admission. The abdominal CT images did not elucidate a pancreatitis diagnosis, but the autopsy findings were indisputable.

Diagnosis of the syndrome is sometimes challenging due to incomplete clinical presentation.

Therefore Bocquet et al. first proposed diagnostic criteria,29 requiring eosinophilia and/or lymphocytic atypia for the diagnosis. In the cases where this criterion was not present, like DIHS, diagnosis could not be considered definite or typical. Hence, the Japanese study group (SCR-J) adopted other criteria in which eosinophilia was not a mandatory criterion, but the HHV-6 replication requirement became an obstacle for its wide use. The European group, RegiSCAR, more recently proposed a third diagnostic criteria published by Kardaun et al., best suiting up the different institutions and the needs for diagnosis.36 Our case meets the diagnostic criteria for the SCR-J as atypical DIHS because of the lack of demonstration of HHV-6 reactivation (for the reasons we discussed above). The RegiSCAR score of this case report was 5, namely: fever = 0/lymphadenomegaly = 1/skin rash extent suggesting DRESS = 2/organ involvement = 2 (liver, heart, pancreas). Unfortunately the criterion “other potential causes” could not be filled because of the lack of ANA testing. ANA was not tested because the patient had a history of rheumatoid arthritis and its positivity could be misinterpreted. Despite the abnormal renal function shown in Table 1, we did not consider the kidney in the list of involved organs because of the lack of microscopic findings at autopsy. Regardless

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Autopsy and Case Reports 2012; 2(4): 5-14

of the number of involved organs, RegiSCAR criteria permit a maximum score of 2 for this item.

The exclusion of other serious infections, neoplastic diseases, autoimmune, or connective tissue diseases, is advisable for the accurate diagnosis DIHS/DRESS.1,11,37 Awareness, early recognition of the diagnosis of DIHS/DRESS and withdrawal of the offending drug are the most important steps toward clinical improvement.1,16 Systemic corticosteroids (prednisone or methylprednisolone) have been widely used in the treatment of the syndrome. The dose can be reduced after clinical and laboratory improvement, and slowtapered over 6-8 weeks afterwards, in order to prevent recurrence.1,3,16 Intravenous immunoglobulin (IVIG), plasmapheresis, or a combination of these therapies can be used in the case of worsening symptoms.16,38,39 A consensus of experts on the therapeutic management of DIHS/DRESS was published in 2010.40 This case was treated with a systemic corticosteroid, which resulted in cutaneous improvement and apparent improvement of liver enzymes, total bilirubins, renal function, and pancreatic enzymes. Clinical worsening was sudden and overwhelming, giving no chance for other therapeutic options.

CONCLUSION This case report illustrates the potential severity of DIHS/DRESS, even in cases where control of the disease is supposedly achieved. We call attention to the diagnosis recognition and awareness of a possible fatal outcome.

REFERENCES 1.

Criado PR, Criado RFJ, Avancini JM, Santi CG. Drug reaction with eosinophilia and systemic symptoms (DRESS)/DrugInduced Hypersensitivity Syndrome (DIHS): a review of current concepts. An Bras Dermatol. 2012;87:435-49. http:// dx.doi.org/10.1590/S0365-05962012000300013

2.

Roquin G, Peres M, Lerolle N, et al. First report of lamotrigine-induced drug rash with eosinophilia and systemic symptoms syndrome with pancreatitis. An Pharmacother. 2010;44:1998‑2000. PMid:21098750. http:// dx.doi.org/10.1345/aph.1P350

12

Campos FPF, Lima PP, Maragno L, Watanabe FT. 3.

BourgeoisGP, Cafardi JA, Groysman V, Hughey LC. A review of DRESS-associated myocarditis. J Am Acad Dermatol. 2012;66:e229-36. http://dx.doi.org/10.1016/j. jaad.2010.11.057

4.

Tohyama M, Hashimoto K. New aspects of drug-induced hypersensitivity syndrome. J Dermatol. 2011;38:222–8. http://dx.doi.org/10.1111/j.1346-8138.2010.01176.x

5.

Um SJ, Lee SK, Kim YH, et al. Clinical features of druginduced hypersensitivity syndrome in 38 Patients. J Investig Allergol Clin Immunol. 2010;20:556-62. PMid:21313995.

6.

Ang C-C, Wang Y-S, Yoosuff E-LM, Tay Y-K. Retrospective analysis of drug-induced hypersensitivity syndrome: A study of 27 patients. J Am Acad Dermatol. 2010;63:219-27.

PMid:20605253. http://dx.doi.org/10.1016/j.jaad.2009.08.050

7.

Chaiken BH, Goldberg BI, Segal JP. Dilantin sensitivity; report of a case of hepatitis with jaundice, pyrexia and exfoliative dermatitis. N Engl J Med. 1950;242:897-8. PMid:15416921. http://dx.doi.org/10.1056/NEJM195006082422304

8.

Shear NH, Spielberg SP. Anticonvulsant hypersensitivity syndrome. In vitro assesment of risk. J Clin Invest. 1988;82:1826-32. PMid:3198757 PMCid:442760. http://dx.doi.org/10.1172/JCI113798

9.

Fiszenson-Albala F, Auzerie V, Mahe E, et al. A 6-month prospective survey of cutaneous drug reactions in a hospital setting. Br J Dermatol. 2003;149:1018-22. http://dx.doi. org/10.1111/j.1365-2133.2003.05584.x

10. Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern Med. 1995;155:2285-90. http://dx.doi. org/10.1001/archinte.1995.00430210033005 11. Gentile I, Talamo M, Borgia G. Is the drug-induced hypersensitivity syndrome(DHIS) due to human herpesvirus 6 infection or to allergy-mediated viral reactivation? Report of a case and review of literature. BMC Infect Dis. 2010;10:49.

Doi: 10.1186/1471-2334-10-49. http://dx.doi.org/10.1186/14712334-10-49 12. Gennis MA, Vemuri R, Burns EA, Hill JV, Miller MA, Spielberg SP. Familial occurrence of hypersensitivity to phenytoin.

Am J Med. 1991;91:631-4. http://dx.doi.org/10.1016/00029343(91)90216-K 13. Bohan KH, Mansuri TF, Wilson NM. Anticonvulsant hypersensitivity syndrome: implications for pharmaceutical care. Pharmacotherapy. 2007;27:1425-39. PMid:17896897. http://dx.doi.org/10.1592/phco.27.10.1425 14. Pritchett JC, Nanau RM, Neuman MG. The link between hypersensitivity syndrome reaction development and Human Herpes virus-6 reactivation. Int J Hepatol. 2012;2012:723062. http://dx.doi.org/10.1155/2012/723062 15. Shiohara T, Kano Y. A complex interaction between drug allergy and viral infection. Clin Rev Allerg Immunol. 2007;33:124-33.

PMid:18094951. http://dx.doi.org/10.1007/s12016-007-8010-9 16. Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay

Hepatic necrosis associated with drug-induced hypersensitivity syndrome

Autopsy and Case Reports 2012; 2(4): 5-14

among herpesviruses and anti-drug immune responses.

Allergol Int. 2006;55:1-8. PMid:17075280. http://dx.doi. org/10.2332/allergolint.55.1

(Drug Rash With Eosinophilia and Systemic Symptoms: DRESS). Sem Cutan Med Surg. 1996;1:250-7. http://dx.doi. org/10.1016/S1085-5629(96)80038-1

17. Myiazaki M, Tanaka M, Ueda A, et al. Acute liver failure caused by drug-induced hypersensitivity syndrome associated with hyperferritinemia. World J Gastroenterol. 2011;28:4928-31. http://dx.doi.org/10.3748/wjg.v17.i44.4928

30. Kano Y, Ishida T, Hirahara K, Shiohara T. Visceral involvements and long-term sequelae in drug-induced hypersensitivity syndrome. Med Clin N Am. 2010;94:743-59.

PMid:20609861. http://dx.doi.org/10.1016/j.mcna.2010.03.004

18. Cacoub P, Musette P, Descamps V, et al. The DRESS Syndrome: a literature review. Am J Med. 2011;124:58897. PMid:21592453. http://dx.doi.org/10.1016/j. amjmed.2011.01.017

31. Shiohara T, Takahashi R, Kano Y. Drug-induced hypersensitivity syndrome and viral reactivation. In: Picher WY, editor. Drug hypersensitivity. Basel: Karger; 2007. p.224-39. http://dx.doi.org/10.1159/000104205

19. Bankar RN, Kohnke A, Palani SB. Drug rash with eosinophilia and systemic symptoms syndrome due to quinine. J Postgrad Med. 2007;53:272-3. http://dx.doi.org/10.4103/00223859.37523

32. Aggarwal A, Bergin P, Jessup P, Kaye D. Hypersensitivity myocarditis presenting as cardiogenic shock. J Heart Lung Transplant. 2001;20:1241-4. http://dx.doi.org/10.1016/ S1053-2498(01)00313-8

20. Brooks H, Taylor HG, Nichol FE. The three week sulfasalazine syndrome. Clin Rheumatol. 1992;11:566-8. http://dx.doi. org/10.1007/BF02283121

33. Sabatine MS, Poh KK, Mega JL, Shepard JA, Stone JR, Frosch MP. Case records of the Massachusetts General Hospital. Case 36-2007. A 31-year-old woman with rash, fever, and hypotension. N Engl J Med. 2007;357:2167-78. http://dx.doi.org/10.1056/NEJMcpc079030

21. Bagshaw SM, Cload B, Gilmour J, Leung ST, Bowen TJ. Drug- induced rash with eosinophilia and systemic symptoms syndrome with bupropion administration. Ann Allergy Asthma Immunol. 2003;90:572-5. http://dx.doi.org/10.1016/S10811206(10)61853-4 22. Ganeva M, Gancheva T, Lazarova R, et al. Carbamazepineinduced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: report of four cases and brief review. Int J Dermatol. 2008;47:853-60. PMid:18717872. http://dx.doi.org/10.1111/j.1365-4632.2008.03637.x 23. Artuković M, Kustelega J, Lugović-Mihić L.DRESS syndrome with mild manifestations as a diagnostic and therapeutic problem: case report. Acta Clin Croat.2010;49:479-84.

PMid:21830461.

24. Andrade RJ, Camargo R, Lucena MI, González-Grande R. Causality assessment in drug-induced hepatotoxicity.

Expert Opin Drug Saf. 2004;3(4):329-44. PMid:15268650. http://dx.doi.org/10.1517/14740338.3.4.329 25. Kennebeck GA. Anticonvulsant hypersensitivity syndrome.

J Am Board Fam Pract. 2000;13:364-70. PMid:11001008.

26. Criado PR, Criado RF, Vasconcellos C, Pegas JR, Cera PC. Drug-induced hypersensitivity syndrome due to anticonvulsants in a two-year-old boy. J Dermatol. 2004;31:1009-13. PMid:15801266.

27. Eshki M, Allanore L, Musette P, et al. Twelve year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms. Arch Dermatol. 2009;145:67-72. PMid:19153346. http://dx.doi.org/10.1001/archderm.145.1.67 28. Tas S, Simonart T. Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): an update. Dermatology. 2003;206:353-6. http://dx.doi. org/10.1159/000069956 29. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hyper- sensitivity syndrome

34. Daoulah A, Alqahtani AA, Ocheltree SR, Alhabib A, Ocheltree AR. Acute myocardial infarction in a 56-year-old female patient treated with sulfasalazine. Am J Emerg Med. 2012;30:638. e1–3.

35. Criado PR, Lucena SK, Crivellaro APGS, et al. Sindrome de hipersensibilidade a anticonvulsivantes:relato de dois casos. Rev Bras Clin Terap. 2002;28:59-63.

36. Kardaun SH, Sidoroff A, Valeyrie-Allanore L, Halevy S, Davidovici BB, Mockenhaupt M, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol. 2007;156:609-11. PMid:17300272. http://dx.doi. org/10.1111/j.1365-2133.2006.07704.x 37. Kosseifi SG, Guha B, Nassour DN, Chi DS, Krishnaswamy G. The Dapsone hypersensitivity syndrome revisited: a potentially fatal multisystem disorder with prominent hepatopulmonary manifestations. J Occup Med Toxicol. 2006;1:9. PMid:16756657. PMCid:1524788. http:// dx.doi.org/10.1186/1745-6673-1-9 38. Kito Y, Ito T, Tokura Y, Hashizume H. High-dose intravenous immunoglobulin monotherapy for druginduced hypenssensitivity syndrome. Acta Derm Venereol. 2012;92:100-1. PMid:21681351. http://dx.doi. org/10.2340/00015555-1168 39. Higuchi M, Agatsuma T, Iizima M, et al. A case of drug induced Hypersensitivity syndrome with multiple organ involvement treated with plasma exchange. Ther Apher Dial. 2005;9:412-6. PMid:16202017. http://dx.doi.org/10.1111/ j.1744-9987.2005.00320.x 40. Descamps V, Ben-Saïd B, Sassolas B, et al. [Management of drug reaction with eosinophilia and systemic symptoms (DRESS)]. Ann Dermatol Venereol. 2010;137:703‑8.

French. PMid:21074653. http://dx.doi.org/10.1016/j. annder.2010.04.024

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Campos FPF, Lima PP, Maragno L, Watanabe FT.

Conflict of interest: None Submitted on: 25th September 2012 Accept on: 2nd November 2012 Correspondence: Divisão de Clínica Médica Av. Professor Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9200 E-mail: ffcampos@usp.br, fpfcampos@gmail.com

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Autopsy and Case Reports 2012; 2(4): 15-25

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Intramuscular metastatic squamous cell carcinoma of the cervix: autopsy case report Cristiane Rúbia Ferreiraa, Leonardo de Abreu Testagrossab, Fernando Peixoto Ferraz de Camposc, Marcia Yoshie Kanegaec, Noely Paula Cristina Lorenzid, Ricardo Santos Simõesd Ferreira CR, Testagrossa LA, Campos FPF, Kanegae MY, Lorenzi NPC, Simões RS. Intramuscular metastatic squamous cell carcinoma of the cervix: autopsy case report. Autopsy Case Rep [Internet]. 2012;2(4):15-25. http:// dx.doi.org/10.4322/acr.2012.030

ABSTRACT Cancer of the uterine cervix is the fourth leading cause of death in women in Brazil, accounting for 4800 fatal cases per year. The histology of this neoplasia is mainly represented by squamous cell carcinoma (80-85%), adenocarcinomas (10-15%), and, more rarely, mixed carcinomas. The Papanicolaou (Pap) smear test is the method of excellence in detecting incipient or pre-malignant lesions.

Since its implementation, the Pap test has been reducing the incidence of this neoplasia worldwide, despite its lack of high sensitivity and specificity.

Both incidence and mortality from cervical cancer have sharply decreased following the introduction of well-run screening programs. The cervical cancer typically spreads to adjacent structures by contiguity; pelvic and para-aortic lymph nodes are involved by lymphatic dissemination. Less frequently, hematogenic spread is observed, and when it occurs, the brain, breast, and skeletal muscle are rarely involved. The authors report a case of a young woman who underwent periodical gynecological examination with negative Pap tests and presented to the hospital with an advanced cervical metastatic disease involving thyroid, muscles, lymph nodes, and breast (among others sites). The diagnosis of the primary site was not elucidated during life. The patient died, and at autopsy an endophytic squamous cell carcinoma of the cervix was diagnosed.

Keywords: Neoplasms, squamous cell; Cervix uteri; Neoplasm metastasis; Muscle, skeletal.

CASE REPORT A 33-year-old female patient, previously diagnosed with hypertension, sought medical attention complaining of a three-month history of weight loss, fever, and the emergence of axillary

and supraclavicular nodules. More recently she complained of trismus and dysphagia and the emergence of similar nodules in the topography of the left thigh and right breast. She referred bloody

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

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

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution ­NonCommercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

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Autopsy and Case Reports 2012; 2(4): 15-25 Ferreira CR, Testagrossa LA, Campos FPF, Kanegae MY, Lorenzi NPC, Simões RS.

vaginal discharge outside her periods, two months ago. She was using captopril and denied a family history of cancer.

Her menarche was at age 12 and first sexual intercourse at 14. She had been pregnant six times with five normal deliveries and one spontaneous abortion. The first pregnancy was at the age of 18. Her clinical and gynecological follow-up was regular. She had an active sex life and underwent tubal sterilization. Her last Pap smear was collected 2 years ago and resulted in class II. On clinical examination she was pale and emaciated. Pulmonary examination was consistent with pleural effusion in the left hemithorax. Cardiac and abdominal examinations were unremarkable.

The gynecological examination revealed normal appearance of the uterine cervix on speculum examination; the external orifice was 0.5 cm opened and the bimanual touch revealed an increased uterine volume, non-movable and hardened. Breast examination revealed the presence of a 3 cm, painless nodule in the superior medial quadrant of the right breast. Several movable nodules (3 cm in its longest axis) in lymph node topography of the right supraclavicular, left axillary regions, as well as in the left thigh, were palpable.

Ultrasonography showed nodules of 2.5 cm in the vastus lateralis muscle and in the left thigh.

The same lesions were evidenced in the right and left suprascapular region. A left axillary lymph node of 2.9 cm with thick liquid in its core was present. The ultrasonography also showed, in the right breast, a 2 cm nodule also exhibiting central necrosis.

Transvaginal ultrasonography was considered normal. Cervical lymph node biopsy revealed a poorly differentiated metastatic carcinoma with necrosis and extra capsular extension into the adjacent adipose tissue. Immunohistochemistry is presented in Table 1.

Table 1 – Immunohistochemical panel used in the lymph node biopsy Antigen

Result

Antigen

Result

ER

Negative

Citoqueratine 7

Positive

PR

Negative

Citoqueratine 20

Negative

TTF1

Negative

CEA

Positive rare cells

Tg

Negative

34BE12

Positive

BRST 2

Negative

35BH11

Positive weak

BRST = breast; CEA = carcinoembryonic antigen; ER = estrogen receptor; PR = progesterone receptor; Tg = thyroglobulin; TTF1 = thyroid transcription factor.

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The immunohistochemical analysis associated with the morphologic findings allowed the diagnosis of poorly differentiated adenocarcinoma with ductal and squamous differentiation, disadvantaging the primary site of origin as breast, colon, lung, stomach, and thyroid (Figure 1). The correlation between immunohistochemical, clinical, and histological results favored the possibility of the salivary glands being the primary tumor.

The patient underwent head, neck, and chest computed tomography (CT), which ruled out the involvement of the parotid, submandibular, and sublingual glands. This examination also showed a heterogeneous enhancement of the contrast in the right and left supraclavicular fossa, skin, and subcutaneous tissues of the breast and left thoracic and abdominal wall. The brain CT scan showed diffuse hypoatenuating areas.

The patient’s outcome was unfavorable with respiratory failure, septic shock, and death.

AUTOPSY FINDINGS The abdominal and thoracic cavities were opened, revealing a mild serous ascites, pleural and pericardium effusions. In the retroperitoneum, there were enlarged lymph nodes as well as a firm whitish mass involving soft tissue, both adrenal glands, and the adjacent renal capsule. (Figure 2) The visceral peritoneum showed numerous small whitish nodules over the stomach and colon. There was a whitish mass in pelvic topography involving the bladder wall, but preserving its mucosal surface. Both ovaries were enlarged by whitish tumor infiltration, measuring up to 10 cm. The uterus presented with endometrium and myometrium preserved.

The cervix showed an irregularity in the endocervical canal and transformation zone, with thickened wall, and a firm, whitish, endophytic tumor on the section surface. The microscopic examination evidenced a large cell, moderately differentiated, non-keratinizing squamous cell carcinoma measuring 1.5 cm in extension and 1 cm in depth, with an endophytic growing pattern.

(Figure 3) There were also metastatic squamous cell carcinomas in the ovaries, fallopian tubes, bladder wall, peritoneal nodules, adrenal glands, and retroperitoneum lymph nodes.

Intramuscular metastatic squamous cell carcinoma of the cervix...

Autopsy and Case Reports 2012; 2(4): 15-25

Figure 1 – Photomicrography of the lymph node A - (HE – 40×) metastatic squamous cell carcinoma; B - (HE – 400×) Neoplasic cells with vacuolated cytoplasm in the subcapsular sinus; C - (HE – 40×) Immunohistochemical study showing diffuse positivity for CK7 antibody; D - (HE – 100×) immunohistochemical study showing diffuse positivity for p63 antibody.

Figure 2 – A - Gross section of kidney and adrenal gland (arrow) with a hardened and whitish tissue involving the adjacent adipose tissue; B - Photomicrography of the kidney and adjacent tissue (HE – 100×) showing metastatic squamous cell carcinoma infiltrating the connective tissue adjacent to renal capsule; C - Photomicrography of the (HE – 100×) adjacent adipose tissue and cortical adrenal gland showing infiltration by metastatic squamous cell carcinoma.

The thoracic cavity revealed enlarged mediastinal and peri-esophageal lymph nodes. The esophageal wall was thickened. There were axillary and cervical enlarged lymph nodes, and a gray– whitish mass involving soft tissue of the left cervical region and the left lobe of the thyroid gland. Both mammary glands presented a firm, central, necrotic mass measuring up to 3 cm. The vastus lateralis

muscle of the left thigh was also infiltrated by the mass. The microscopic examination revealed metastatic squamous cell carcinomas in each of these areas. (Figures 4 and 5) The lungs were congested and heavy.

Microscopic examination revealed diffuse alveolar damage and bronchopneumonia. (Figure 6) A

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Autopsy and Case Reports 2012; 2(4): 15-25 Ferreira CR, Testagrossa LA, Campos FPF, Kanegae MY, Lorenzi NPC, Simões RS.

Figure 3 – A - Panoramic view of the enlarged ovaries involved by a whitish mass and the cervix with a slight irregular external orifice; B - Panoramic photomicrography of the cervix (HE – 25×) showing an endophytic growing pattern of the squamous cell carcinoma; C - Photomicrography of the cervix (HE – 100×) showing preserved ectocervical epithelium above the infiltrating cervical squamous cell carcinoma; D - Photomicrography of the cervix (HE – 100×) showing the endocervical mucosa involved by the cervical squamous cell carcinoma. systemic finding of sepsis was observed in the spleen, represented by red pulp congestion and white pulp lymphoid hyperplasia in the microscopic examination.

No other significant gross or microscopic findings were detected.

Additional immunohistochemical analysis was undertaken in the previous cervical lymph node biopsy and the primary cervix tumor, revealing diffuse positive p63 immunophenotype in the tumor cells, compatible with squamous cell carcinomas.

DISCUSSION Cancer of the uterine cervix is common worldwide and ranks second among all malignancies affecting women. In Brazil, it is the fourth leading cause of death in women, with an average of

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4800 fatal cases per year. It is estimated that 17,540 new cases of uterine cervical cancer will be diagnosed in 2012.1 The colpocytology stained by the Pap test method is the screening test of excellence in assessing the degree of cellular alteration, able to detecting incipient lesions or those in the premalignant stage. Worldwide, the Pap test has been reducing the incidence of this neoplasia since its implementation.2,3 Both incidence and mortality from cervical cancer have sharply decreased after the adoption of well-run and periodically-performed screening programs using the Pap test.4-6 In Iceland, the mortality rate declined by 80% for more than 20 years, and in Finland and Sweden by 50% and 34%, respectively.4,7 Similar reductions have been observed in the United States and Canada. The decrease in incidence and mortality are proportional to the intensity of screening.4,7

Intramuscular metastatic squamous cell carcinoma of the cervix...

Autopsy and Case Reports 2012; 2(4): 15-25

Figure 4 – A - Photomicrography of the bladder (HE - 100×) showing infiltration by metastatic squamous cell carcinoma; B - Photomicrography of the thyroid gland (HE – 100×) showing infiltration by metastatic squamous cell carcinoma; C - Photomicrography of the parathyroid gland (HE – 100×) showing infiltration by metastatic squamous cell carcinoma; D - Photomicrography of the mammary tissue (HE – 100×) showing infiltration by metastatic squamous cell carcinoma.

Figure 5 – A - Gross section of the left thigh showing a hardened and whitish tissue mass involving the muscle; B - Photomicrography of the skeletal muscle (HE – 100×) showing infiltration by metastatic squamous cell carcinoma.

Although relatively low cost, as well as being effective in early detection of cervical cell dysplasia, the Pap smear is criticized by the false-negative results. The range of this false-negative result

varies between 6% and 68%.8 The occurrence of errors during the slide preparation9 and specimen fixation is not uncommon. Besides the possibility of cell overlapping and the presence of contaminant

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Autopsy and Case Reports 2012; 2(4): 15-25 Ferreira CR, Testagrossa LA, Campos FPF, Kanegae MY, Lorenzi NPC, Simões RS.

Figure 6 – Photomicrography of the lung. A - (HE – 100×) and B - (HE – 200×) showing deposition of fibrinous material in the alveolar wall and presence of macrophage and neutrophils into the alveolar lumen. inflammatory cells hampering the cytologic evaluation, there is also the subjectivity and misinterpretation, mainly in overloaded laboratories.

Felix et al.10 called attention to the aberrant expression of E-cadherin in cervical intraepithelial neoplasia as being responsible for false-negative Pap smears. The persistence of these adhesion molecules throughout the entire epithelium interfere with the natural exfoliation of the dysplastic cells interfering with the diagnosis of the malignancy. The grade of dysplasia considered as the test threshold for positivity also interfere with the results.11 Thus, a large sensitivity and specificity variation is observed, with the average of 58% (variation 11-99%) and 68% (variation 14-97%), respectively.11-14 The patient of this report had an endophytic pattern of growth tumor, which had been reported to be often related to false-negative Pap smears.15 The gross features of a more advanced tumor depend upon its site of origin, the pattern of growth, and the rate of necrosis. Patients with an endophytic growth pattern tumor may exhibit a tumorless speculum examination. Some cervical cancers remain entirely within the endocervix presenting superficial normal epithelium. The underlying tumor becomes grossly or cytologically unapparent by colposcopy exam or Pap test. These endophytic tumors may produce a “barrel-shaped” cervix, which has a diameter greater than 4 cm.16-18 The rate at which invasive cancer develops from cervical intraepithelial neoplasia is usually slow, measured in years and perhaps decades.19 This long natural history provides the opportunity for screening, which can effectively detect this process during the preinvasive phase, and thus allow early

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treatment and cure. However, the patient of this report seemed to present an “explosive” growth tumor, which became clinically evident in a very short period. These progressive and fast-growing cervical cancers are defined as cancers that have been diagnosed within 3 years of a last truenegative Pap smear.16,20,21 Although they do not represent a specific entity based on any particular histology, some authors have shown that this condition occurs more often in younger women, with a higher incidence of adenocarcinomas or adenosquamous carcinomas. Progressive and fastgrowing cervical cancer could represent cases with a false-negative Pap smear in which the endocervical component had not been adequately screened. In these cases the endocervical and the ectocervical squamous epithelium may be normal by cytological, histological, and colposcopy examinations. The nature of the cancer becomes apparent only when the tumoral cells reach the overlying surface.16 Most cervical cancers arise from human papillomavirus (HPV) infected cells. The Infection

by HPV (sexually transmitted) behaves transiently in most cases, with spontaneous clearance in more than 80% of infected women within 1-2 years, especially in adolescents and young adults.22 Epidemiological studies have shown that despite the high prevalence of HPV infection in sexually active women, only a small portion of them, infected by oncogenic types, will progress to high grade squamous intraepithelial lesions and cancer of the cervix. The persistence of HPV infection (particularly by types 16 and 18) is closely involved in the process of cervical carcinogenesis and is considered the strongest risk factor for the emergence of pre-malignant lesions of the cervix.23-26 Despite the evidence showing the important role of HPV infection in the pathogenesis

Intramuscular metastatic squamous cell carcinoma of the cervix...

of cervical cancer, other agents and cellular events still need to be determined, since most women with a cervical HPV infection never develop cervical cancer. 27 A young age at first intercourse, an increasing number of sexual partners, and multiparity increase the risk of cervical cancer.28,29 The International Agency for Research on Cancer (IARC) reported that women with seven or more term pregnancies had a higher risk of developing cervical cancer compared with nulliparae.30 The risk for developing squamous cell carcinoma of cervix is two times higher in smokers and is closely related with prolonged use and the daily number of smoked cigarettes.29-31 The association between oral contraceptive use and the risk in developing cervical cancer is still controversial.32-35 Among the histological types, the squamous cell carcinoma accounts for 80-85% of all cancers of the cervix (ectocervix).29,36 Adenocarcinomas represent 10-15% of cancers and originate from the mucous secreting endocervical glandular cells. The mixed carcinomas, neuroendocrine tumors, sarcomas or lymphomas are more rare.36 Regarding the immunohistochemical examination, it is important to remember that squamous cervical carcinoma can present an immunophenotype with positive cytokeratin 7 (CK7) and carcinoembryonic antigen (CEA) antibodies. The hormonal receptor ER and PR show decreased expression in cervical intraepithelial neoplasia and negative for invasive squamous cervical carcinoma.37-40 Those findings can lead to the misdiagnosis of adenocarcinoma, especially in poorly differentiated tumors. Although CK7 and CEA antibodies were usually related to adenocarcinomas of other anatomic sites (e.g. lungs), they could also be expressed in squamous cervical carcinoma in 87% and 57-90%, respectively.

In metastatic disease, it is worth adding the antibody p63 in the immunohistochemical panel.

This antibody is a p53 homologue gene involved in the development and maintenance of stratified epithelium, and because of that it is a useful antibody in the identification of myoepithelial and squamous cell carcinomas.41-42 In the female genital tract, p63 is expressed in the basal and parabasal layers of mature cervical, vaginal, and vulval squamous epithelium, and is useful to establish the diagnosis of cervical squamous cell carcinoma.43 In the revision of the case, the p63 antibody was added to the immunohistochemical panel, which showed a diffuse pattern of positivity. This way it was possible to exclude the diagnosis of adenosquamous

Autopsy and Case Reports 2012; 2(4): 15-25

carcinoma or poorly differentiated adenocarcinoma in the previous cervical lymph node biopsy.

The cervical cancer typically spreads to adjacent structures by contiguity. Pelvic and paraaortic lymph nodes are involved by lymphatic dissemination, and less frequently liver, lungs, and bones are involved by hematogenic dissemination.44 Metastases to the breast, adrenal, brain, or muscles are very rare. Chura et al.,45 in a review of 1560 cases of patients with carcinoma of the cervix, found 12 cases with brain metastasis. Baron et al.46 described a case of cervical cancer in the remnant cervix of a patient who underwent subtotal hysterectomy. In this case, metastases were found in both adrenal glands. Metastases to the breast have been reported in clinical and autopsy reports.

Badib et al.47 found four cases of breast metastases among 278 autopsied patients with cervical cancer.

The reported frequency of this metastatic site is 0.56.6%.

The first description of muscle metastasis was reported by Wittisch in 1854.48 In 1989, Stephen Paget49 also observed that skeletal muscles were rarely the site of tumor metastasis.

After Wittisch’s observation, until 1991 only 242 cases of muscle metastasis were reported in 82 publications.50 The exact incidence of skeletal muscle metastases is barely known since they can evolve without symptoms, they may not exhibit a clinically detectable size, they can not be detected by positron emission tomography or CT scan, and cancer-related deaths are not routinely autopsied. Even so, contemporary studies show metastatic muscle involvement in less than 1% of all malignancies, despite the rich muscle blood supply and the high percentage (nearly 50%) of the total body weight represented by the muscle mass.51 When muscle metastases occurs, it is generally associated with melanoma, lung, genitourinary, and gastrointestinal cancers. Menard and Parache,50 in a retrospective study of cancer patients seen between 1980 and 1990, found only seven cases of metastases to skeletal muscles, but in no cases was the cervix the primary tumor site.51 The rarity of muscle metastases may be justified by its contractile activity, local change in pH, toxic-free radical oxygen, accumulation of lactic acid, blood flow per unit weight (mL/min/kg), intramuscular blood pressure, and local temperature.48,52-55 Sudo et al.56 also consider the activity of protease inhibitors located in the basement membrane, and antitumor activity of lymphocytes and/or natural killer cells within the

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Autopsy and Case Reports 2012; 2(4): 15-25 Ferreira CR, Testagrossa LA, Campos FPF, Kanegae MY, Lorenzi NPC, Simões RS.

skeletal muscles. In vivo evidence supports that skeletal muscle peptidic factors may influence the metastasizing process.

In 2006, Ferrandina et al.51 found eight cases of cervical cancer with metastases to skeletal muscle, adding a new case report in their review. Among these nine cases, eight were histological squamous cell carcinomas and one small cell carcinoma. In 2010, Karunanithi et al.57 published another case of carcinoma of the cervix with metastasis to striated muscle, and in 2012, Tamam et al.58 reported a case of squamous cell carcinoma with metastasis to subcutaneous tissue and various muscle groups.

The most affected muscle groups were the psoas and Iliopsoas, but involvement of the biceps, deltoid, masseter, intercostal, buttock, thigh muscles, and abdominal wall were also reported.59-60 All cases of striated muscles metastasis occur in the context of advanced disease or immunocompromised patients, resulting in the observed poor prognosis.50 The diagnosis of muscle metastases can be difficult mainly when asymptomatic, but in most cases they are palpable and painfull.50

CONCLUSION This report calls attention to the dramatic and extensive presentation of cervical cancer, considering this histological type. Moreover, the patient of this case report followed the screening program. Even after a thorough investigation, the primary tumor could not be diagnosed, representing a dramatic and challenging situation in clinical practice.

It should be expected that maladies such as cancer of the cervix, which offers the possibility of early detection and consequently the possibility of a cure, if covered by a governmental program for prevention, would never reach such an outcome.

We wondered what was at fault for the misdiagnosis.

The endophytic pattern of growth probably led to the atypical natural history of this case. The normal speculum gynecological examination and the pattern of the metastases certainly contributed to the unaccomplished diagnosis.

REFERENCES 1.

22

Instituto Nacional do Câncer - INC. Colo do útero. Rio de Janeiro: INCA; 2012 [cited 2012 July 30]. Portuguese.

Available from: http://www2.inca.gov.br/wps/wcm/connect/ tiposdecancer/site/home/colo_utero 2.

Manos MM, Kinney WK, Hurley LB, et al. Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results.

JAMA. 1999;281:1605-10. http://dx.doi.org/10.1001/ jama.281.17.1605

3.

Joseph MG, Cragg F, Wright VC, Kontozoglou TE, Downing P, Marks FR. Cyto-histological correlates in a colposcopic clinic: a 1-year prospective study. Diagn Cytopathol. 1991;7:477‑81. http://dx.doi.org/10.1002/dc.2840070508

4.

Lăără E, Day NE, Hakama M. Trends in mortality from cervical cancer in the Nordic countries: association with organised screening programmes. Lancet 1987;1:1247-9. http://dx.doi.org/10.1016/S0140-6736(87)92695-X

5.

Johannesson G, Geirsson G, Day N. The effect of mass screening in Iceland, 1965-74, on the incidence and mortality of cervical carcinoma. Int J Cancer. 1978;21:418-25. http:// dx.doi.org/10.1002/ijc.2910210404

6.

Van der Aa MA, Pukkala E, Coebergh JW, Anttila A, Siesling S. Mass screening programmes and trends in cervical cancer in Finland and the Netherlands. Int J Cancer. 2008;122:1854‑8. http://dx.doi.org/10.1002/ijc.23276

7.

Sigurdsson K. Effect of organized screening on the risk of cervical cancer. Evaluation of screening activity in Iceland, 1964-1991. Int J Cancer. 1993;54:563-70. http:// dx.doi.org/10.1002/ijc.2910540408

8.

Tuon F, Bittencourt MS, Panichi MA, Pinto AP. Avaliação da sensibilidade e especificidade dos exames citopatológicos e colposcópicos em relação ao exame histológico na identificação de lesões intra-epiteliais cervicais. Rev Assoc Med Bras. 2002;48:140-4. Portuguese. http://dx.doi. org/10.1590/S0104-42302002000200033

9.

Amaral RG, Souza NLA, Tavares SBN, et al. Controle externo da qualidade dos diagnósticos citológicos no rastreamento do câncer cervical: estudo piloto. Rev Bras Anal Clin. 2006;38:79-81.

10. Felix JC, Lonky NM, Tamura K, et al. Aberrant expression of E-cadherin in cervical intraepithelial neoplasia correlates with a false-negative Papanicolau smear. Am J Obstet Gynecol. 2002;186:1308-14. http://dx.doi.org/10.1067/ mob.2002.123732 11. Nanda K, McCrory DC, Myers ER, et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med. 2000;132:810-9.

12. Fahey MT, Irwig L, Macaskill P. Meta-analysis of Pap test accuracy. Am J Epidemiol. 1995;141:680-9.

13. Soost HJ, Lange HJ, Lehmacher W, et al. The validation of cervical cytology. Sensitivity, specificity and predictive values. Acta Cytol. 1991;35:8-14.

Intramuscular metastatic squamous cell carcinoma of the cervix...

14. Benoit AG, Krepart GV, Lotocki RJ. Results of prior cytologic screening in patients with a diagnosis of Stage I carcinoma of the cervix. Am J Obstet Gynecol. 1984;148:690-4.

15. Kalir T, Simsir A, Demopoulos HB, Demopoulos RI. Obstacles to the early detection of endocervical carcinoma. Int J Gynecol Pathol. 2005;24:399-403. http://dx.doi.org/10.1097/01. pgp.0000170067.73452.72 16. Zheng W, Robboy SJ. Cervical squamous cell carcinoma. In: Robboy SJ, Bentley RC, Russell P, et al. editors. Robboy’s pathology of the female reproductive tract. 2nd ed. Churchill Livingstone: Elsevier; 2009. p. 234-5. http://dx.doi.org/10.1016/ B978-0-443-07477-6.50014-7 17. Hoffmann MS, Cardosi RJ, Roberts WS, et al. Accuracy of pelvic examination in the assessment of patients with operable cervical cancer. Am J Obstet Gynecol. 2004;190:986-93. http://dx.doi.org/10.1016/j.ajog.2004.01.019 18. Huang WC, Yang JM, Yang YC, Yang SH. Ultrasonografic characteristics and cystoscopic correlates of bladder wall invasion by endophytic cervical cancer. Ultrasound Obstet Gynecol. 2006;27:680-6. http://dx.doi.org/10.1002/uog.2775 19. Holowaty P, Miller AB, Rohan T, et al. Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst. 1999;91:252-8. http://dx.doi.org/10.1093/jnci/91.3.252 20. Schwartz PE, Hadjimichael O, Lowell DM, et al. Rapidly progressive cervical cancer: the Connecticut experience. Am J Obstet Gynecol. 1996;175:1105-9. http://dx.doi.org/10.1016/ S0002-9378(96)70012-1 21. Gallup DC, Nolan TE, Hanly MG, et al. Characteristic of patients with rapidly growing cervical cancer. South Med J. 1997;90:611-5. http://dx.doi.org/10.1097/00007611199706000-00006 22. Stanley M. Immune responses to human papillomavirus.

Vaccine. 2006;(24 Suppl 1):S16-22. http://dx.doi.org/10.1016/j. vaccine.2005.09.002 23. Bosch FX, Manos MM, Muñoz N, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective.

International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst. 1995;87:796-802. http:// dx.doi.org/10.1093/jnci/87.11.796 24. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999,189:12-9. http://dx.doi. org/10.1002/(SICI)1096-9896(199909)189:1%3C12::AIDPATH431%3E3.0.CO;2-F 25. Schiffman M, Herrero R, Desalle R, et al. The carcinogenicity of human papillomavirus types reflects viral evolution.

Virology. 2005;337:76-84. http://dx.doi.org/10.1016/j. virol.2005.04.002 26. Kjaer S, Høgdall E, Frederiksen K, et al. The absolute risk of cervical abnormalities in high-risk human papillomaviruspositive, cytologically normal women over a 10-year period.

Autopsy and Case Reports 2012; 2(4): 15-25 Cancer Res. 2006;66:10630-6. http://dx.doi.org/10.1158/00085472.CAN-06-1057 27. Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women.

N Engl J Med. 1998;338:423-8. http://dx.doi.org/10.1056/ NEJM199802123380703 28. Boccalini S, Tiscione E, Bechini A, et al. Sexual behavior, use of contraceptive methods and risk factors for HPV infections of students living in central Italy: implications for vaccination strategies. J Prev Med Hyg. 2012;53:24-9.

29. International Collaboration of Epidemiological Studies of Cervical Cancer. Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: Collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer. 2007;120:885-91. http://dx.doi.org/10.1002/ijc.22357 30. N, Franceschi S, Bosetti C, et al. International Agency for Research on Cancer. Multicentric Cervical Cancer Study Group. Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case-control study.

Lancet. 2002;359:1093-101. http://dx.doi.org/10.1016/ S0140-6736(02)08151-5 31. International Collaboration of Epidemiological Studies of Cervical Cancer, Appleby P, Beral V, et al. Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer. 2006;118:1481-95. http://dx.doi.org/10.1002/ijc.21493 32. Moreno V, Bosch FX, International Agency for Research on Cancer Multicentric Cervical Cancer Study Group, et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet. 2002;359:1085-92.

33. Smith JS, Green J, Berrington de Gonzalez A, et al. Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet. 2003;361:1159-67. http://dx.doi.org/10.1016/ S0140-6736(03)12949-2 34. Lacey JV, Brinton LA, Abbas FM, et al. Oral contraceptives as risk factors for cervical adenocarcinomas and squamous cell carcinomas. Cancer Epidemiol Biomarkers Prev. 1999;4:459‑67.

35. Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Nati Cancer Inst. 1993;85:958-64. http://dx.doi.org/10.1093/jnci/85.12.958 36. Sahdev A. Cervical tumors. Semin Ultrasound CT MR. 2010;31:399-413. http://dx.doi.org/10.1053/j. sult.2010.07.004 37. Kwasniewska A, Postawski K, Gozdzicka-Jozefiak A, et al.

Estrogen and progesterone receptor expression in HPV-

23

Autopsy and Case Reports 2012; 2(4): 15-25 Ferreira CR, Testagrossa LA, Campos FPF, Kanegae MY, Lorenzi NPC, Simões RS. positive and HPV-negative cervical carcinomas. Oncol Rep. 2011;26:153-60.

38. Kim KK, Jang TJ, Kim JR. HSP70 and ER expression in cervical intraepithelial neoplasia and cervical cancer. J Korean Med Sci. 1998;13:383-8.

39. Chu P, Wu E, Weiss LM. Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases.

Mod Pathol. 2000;13:962-72. http://dx.doi.org/10.1038/ modpathol.3880175 40. Toki T, Yajima A. Immunohistochemical localization of carcinoembryonic antigen (CEA) in squamous cell carcinoma of the uterine cervix: Prognostic significance of localization pattern of CEA. J Exp Med. 1991;165:25-32.

41. Yang A, Schweitzer R, Sun D, et al. p63 is essencial for regenerative proliferation in limb, craniofacial and epithelial development. Nature. 1999;398:714-8. http://dx.doi. org/10.1038/19539 42. Kim MJ, Shin HC, Shin KC, Ro JY. Best immunohistochemical panel in distinguishing adenocarcinoma from squamous cell carcinoma of lung: tissue microarray assay in resected lung cancer specimens. Ann Diagn Pathol [Internet]. 2012 Oct 3; [Epub ahead of print; cited 2012 Oct 20]. Available from: http://www.sciencedirect.com/science/article/pii/ S1092913412001037# 43. Houghton O, McCluggage WG. The expression and diagnostic utility of p63 in the female genital tract. Adv Anat Pathol. 2009;16:316-21. http://dx.doi.org/10.1097/ PAP.0b013e3181b507c6 44. Gravitt PE. The known unknowns of HPV natural history.

J Clin Invest. 2011;121:4593-9. http://dx.doi.org/10.1172/ JCI57149 45. Chura JC, Shukla K, Argenta PA. Brain metastasis from cervical carcinoma. Int J Gynecol Cancer. 2007;17:141-6. http://dx.doi.org/10.1111/j.1525-1438.2007.00808.x 46. Baron M, Hamou L, Laberge S, Callonnec F, Tielmans A, Dessogne P. Metastatic spread of gynaecological neoplasms to the adrenal gland: case reports with a review of the literature. Eur J Gynaecol Oncol. 2008;29:523-6.

47. Badib AO, Kurohara SS, Webster JH, Pickren JW. Metastasis to organs in carcinoma of the uterine cervix. Influence of treatment on incidence and distribution. Cancer. 1968;21:434-9. http://dx.doi. org/10.1002/1097-0142(196803)21:3%3C434::AIDCNCR2820210312%3E3.0.CO;2-3 48. Pop D, Nadeemy AS, Venissac N. Skeletal muscle metastasis from non-small cell lung cancer. J Thorac Oncol. 2009;4:1236‑41. http://dx.doi.org/10.1097/ JTO.0b013e3181b24509

24

49. Paget S. The distribution of secondary gowths in cancers of the breast. Lancet. 1889;1:571-3. http://dx.doi.org/10.1016/ S0140-6736(00)49915-0 50. Ménard O, Parache RM. Muscle metástases of cancers.

Ann Med Interne (Paris). 1991;142:423-8.

51. Ferrandina G, Salutari V, Testa A, et al. Recurrence in skeletal muscle from squamous cell carcinoma of the uterine cervix:a case report and review of the literature. BMC Cancer. 2006;6:169. http://dx.doi.org/10.1186/1471-24076-169 52. Acinas GO, Fernandez FA, Satué EG, et al. Metastasis of malignant neoplasms to skeletal muscle. Rev Esp Oncol. 1984;31:57-67.

53. Sridhar KS, Rao RK, Kunhardt BK. Skeletal muscle metastases from lung cancer. Cancer. 1987;59:1530-4. http:// dx.doi.org/10.1002/1097-0142(19870415)59:8%3C1530::AIDCNCR2820590824%3E3.0.CO;2-H 54. Weiss L. Biomechanical destruction of cancer cells in skeletal muscle: a rat-regulator for hematogenous metastasis. Clin Exp Metastasis. 1989;7:483-91. http://dx.doi.org/10.1007/ BF01753809 55. Seely S. Possible reasons for the high resistance of muscle to cancer. Med Hypotheses. 1980;6:133-7. http://dx.doi. org/10.1016/0306-9877(80)90079-1 56. Sudo A, Ogihara Y, Shiokawa Y, et al. Intramuscular metastasis of carcinoma. Clin Orthop. 1993;296:213-7.

57. Karunanithi G, Sethi P, Reddy KSS, Rani PR. Skeletal muscle metastasis from carcinoma cervix: a case report. J Gynecol Oncol. 2010;21:196-8. http://dx.doi.org/10.3802/ jgo.2010.21.3.196 58. Tamam MO, Mulazimoglua M, Aydinb T. Subcutaneous and intramuscular metastases of cervix cancer detected with 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography after the chemoradiation therapy. Rev Esp Med Nucl Imagen Mol [Internet]. 2012; [Epub ahead of print; cited 2012 Oct 19]. Available from: http://www.elsevier.es/sites/default/files/elsevier/eop/S2253654X(12)00117-5.pdf 59. Saâdi I, Hadadi K, Amaoui B, et al. [Muscle metastasis of squamous cell carcinoma of the uterine cervix]. Cancer Radiother. 2003;7:187-9. French. http://dx.doi.org/10.1016/ S1278-3218(02)00257-3 60. Pathy S, Jayalakshmi S, Chander S, Thulkar S, Sharma MC. Carcinoma cervix with metastasis to deltoid muscle.

Clin Oncol (R Coll Radiol). 2002;14:447-8. http://dx.doi. org/10.1053/clon.2002.0106

Intramuscular metastatic squamous cell carcinoma of the cervix...

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Conflict of interest: None Submitted on: 31th October 2012 Accept on: 10th November 2012 Correspondence: Divisão de Clínica Médica Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9200 E-mail: ffcampos@usp.br

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Autopsy and Case Reports 2012; 2(4): 27-33

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Renal tubular dysgenesis with hypocalvaria and ileocecal valve agenesis: an autopsy report Ariel Barreto Nogueiraa, Regina Schultza, Adolfo Wenjaw Liaob, Rossana Pulcineli Vieira Fanciscob, Marcelo Zugaibb Nogueira AB, Schultz R, Liao AW, Francisco RPV, Zugaib M. Renal tubular dysgenesis with hypocalvaria and ileocecal valve agenesis: an autopsy report. Autopsy Case Rep [Internet]. 2012;2(4):27-33. http://dx.doi.org/10.4322/acr.2012.031

ABSTRACT Renal tubular dysgenesis (RTD) is a rare, lethal, autosomal recessive disorder characterized by non-differentiation of the renal proximal convoluted tubules, resulting in oligohydramnios. It is usually diagnosed in the second trimester of pregnancy, following the oligohydramnios sequence, pulmonary hypoplasia and hypocalvaria. The prognosis is poor, and death usually occurs in utero or within the first few days of life. The pathogenesis of RTD is associated with the perinatal use of drugs, such as angiotensin- converting enzyme inhibitors, angiotensin II receptor antagonists, and anti- inflammatory drugs, as well as with fetal transfusion syndrome, genetic mutations in the pathway of the renin-angiotensin system pathway, cocaine snorting, or other pathological mechanisms that reduce renal blood flow. Here, we report the autopsy of a neonate born to consanguineous parents at 38 weeks of gestation, with RTD, decreased amniotic fluid, oligohydramnios sequence, hypocalvaria, pulmonary hypoplasia, and ileocecal valve agenesis. To our knowledge, the latter has never been reported associated with RTD. Keywords: Urogenital abnormalities; Craniofacial abnormalities; Ileocecal valve; Autopsy; Oligohydramnios.

CLINICAL CASE We report the case of a 20-year-old woman who was pregnant for the second time and who had previously had a vaginal delivery. She reported no alcohol consumption, smoking, illegal drug use, or use of medications other than those that are typically used during pregnancy. Prenatal serology was negative for HIV, syphilis, hepatitis B, and hepatitis C, as well as revealing immunity to toxoplasmosis and rubella.

a b

She gave birth to a male infant (gestational age, 38 weeks) via an assisted vaginal delivery for breech presentation. The infant presented with apnea and hypotonia at birth. The one-minute, five-minute, and ten-minute Apgar scores were 1, 4, and 4, respectively. Birth weight was 2,120 g.

After neonatal resuscitation, the infant started on mechanical ventilation and vasoactive drugs and was referred to the intensive care unit, having

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

Department of Obstetrics and Gynecology – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil.

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution ­NonCommercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

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remained anuric for the duration of his stay.

Intensive supportive measures were ineffective, and the infant died at 9 hours after delivery. An autopsy was performed, the legal guardians having given written informed consent. The parents were consanguineous (first cousins).

AUTOPSY FINDINGS Macroscopic examination revealed the presence of the oligohydramnios sequence, also known as Potter’s Sequence, i.e., retrognathism, a flattened nose, knee hyperflexion, ulnar deviation, and flat, clubbed feet (Figure 1), as well as the presence of amnion nodosum on the placenta.

Head circumference was 31 cm (reference range for the gestational age, 32-36.5 cm). The anterior fontanelle was wide and bulging. The calvarial bones were thin, a finding that was consistent with hypocalvaria. Kidneys were topic with fetal lobulation, an intact corticomedullary junction, a combined kidney weight of 19.7 g (normal weight, 24.8 ± 7.2 g), and an intact pyelocaliceal system.

Other findings included agenesis of the ileocecal valve, which was characterized by the absence of the ileocecal junction, dilated small bowel loops (up to 2 cm in diameter), and short, hypoplastic colon (up to 0.6 cm in diameter). The small intestinal contents

Nogueira AB, Schultz R, Liao AW, Francisco RPV, Zugaib M.

were thick and greenish. The contents of the colonic lumen were mucous and whitish. There were diffuse adhesions in the abdominal cavity. In addition, the abdominal organs had a greenish, finely granular outer surface. We found no intestinal perforation.

The lungs were hypoplastic and, together, weighed 20 g (normal lung weight for the gestational age, 40.6 ± 17.1 g), and the lung weight to body weight ratio was 0.009 (normal ratio, >0.012). The heart showed interatrial communication (patent foramen ovale).

Histological examination revealed kidneys with diffusely distributed glomeruli in the renal parenchyma, including the renal papilla. The renal tubules consisted of cuboidal cells with clear nuclei and scant basophilic cytoplasm (Figure 2A‑C).

Periodic acid-Schiff staining revealed a lack of proximal tubules, the brush border membrane, typical of these structures, having remained unstained (Figure 2D).1,2,3 Immunohistochemistry with the markers of proximal tubular differentiation, i.e., anti-CD10 antibodies (Figure 3A) and antiCD15 antibodies (Figure 3B), also showed proximal tubular hypoplasia.4,5 Immunohistochemical staining was diffusely positive for epithelial membrane antigen, which is characteristic of distal tubules (Figure 3C).1-4,6 The renal arteries were tortuous and had thickened walls (Figure 3D), findings that constituted further evidence of RTD.4-6 As a

Figure 1 – The oligohydramnios sequence: A - Wide and bulging fontanelle; B - Knee hyperflexion and ulnar deviation; C - Retrognathism; D - Knee hyperflexion.

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Renal tubular dysgenesis with hypocalvaria and ileocecal valve agenesis...

Autopsy and Case Reports 2012; 2(4): 27-33

Figure 2 – Photomicrography of the kidney - Renal tubular dysgenesis: A - Diffusely distributed glomeruli in the renal parenchyma (hematoxylin and eosin [H&E]; magnification, ×50); B - Diffusely distributed distal tubules (H&E; magnification, ×200); C - Distal tubules with cuboidal cells with clear cytoplasm (arrow) and thick-walled vessels (H&E; magnification, ×400); D - Histochemical analysis showing that the brush border membrane, which is characteristic of proximal tubules, remained unstained (periodic acid-Schiff staining; magnification, ×400). control, we used a kidney sample from a neonate (gestational age, 39 weeks and 2 days) who had normal kidney development and whose cause of death was unrelated to the genitourinary tract (Figure 4).

We found pulmonary hypoplasia secondary to oligohydramnios and RTD. In addition to our finding of decreased lung weight, we found that the alveoli were collapsed and reduced in number; bronchiolar structures were proportionally large and tortuous in the lung periphery, being accompanied by large vessels (Figure 5A and 5B). We found hyaline membrane formation within foci of enlarged alveoli (Figure 5B).

Ileocecal valve agenesis was confirmed by microscopic examination, which revealed, absence of valvar lumen. The ileum and cecum showed two joined layers of muscularis propria and no adjacent serosa. The intestinal crypts were malformed, dilated, and tortuous, sometimes showing basal branching (Figure 5C).

We found meconium peritonitis secondary to the ileocecal valve agenesis and probable intestinal perforation, a finding that has been reported in some cases of RTD.1,4 In the diaphragm and in the gastric and intestinal subserosas, we found lymphomononuclear inflammatory infiltrate, macrophages with greenish cytoplasmic granules, and vernix squames, some of which were calcified (Figure 5D). The presence of periventricular leukomalacia constituted further evidence of fetal distress.

DISCUSSION A rare disorder, RTD is characterized by oligohydramnios – usually diagnosed in the second trimester of pregnancy (20-23 weeks)4,7 – progressing to the oligohydramnios sequence, pulmonary hypoplasia,1,3,5,8,9 and early death, either in utero or within a few days after birth.2,4,7,9 There are only a few reports of survival past the neonatal period.5,10,11

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Nogueira AB, Schultz R, Liao AW, Francisco RPV, Zugaib M.

Figure 3 – Photomicrography of the kidney - Renal tubular dysgenesis, immunohistochemistry: A - with antiCD10 antibodies and B - with anti-CD15 antibodies, both showing a lack of proximal tubule differentiation (magnification, ×200); C - Diffuse staining for epithelial membrane antigen, characteristic of distal tubules (magnification, ×200); D - for smooth muscle actin, showing tortuous, thick-walled vessels (magnification, ×200).

Figure 4 – Photomicrography of the control kidney. A - Proximal tubule differentiation, rich in acidophilic cells (hematoxylin and eosin; magnification, ×200); B - Stained brush border membrane in proximal tubules (arrow; periodic acid-Schiff staining; magnification, ×400); C - Positivity for epithelial membrane antigen, the proximal tubules remaining unstained (immunohistochemistry; magnification, ×200); D - Immunohistochemistry for smooth muscle actin (magnification, ×200).

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Autopsy and Case Reports 2012; 2(4): 27-33

Figure 5 – Photomicrography of the lung. A - Pulmonary hypoplasia (H&E, magnification ×50); B - Collapsed alveoli and hyaline membrane formation (arrow) (H&E, magnification ×400); C - photomicrography of the ileocecal region showing agenesis of the ileocecal valve (H&E, magnification ×50); D - photomicrography of the peritoneum and diaphragm muscle showing meconium peritonitis, note macrophages with brownish granules (arrowhead) and calcification (asterisk) amid lymphomononuclear inflammatory infiltrate (H&E, ×400) Prolonged exposure to certain medications or illicit drugs, such as cocaine, can lead to decreased renal blood flow and hyperactivation of the reninangiotensin system (RAS), therefore leading to RTD. A similar mechanism explains RTD in cases of twin-to-twin transfusion syndrome.4 Recent studies have demonstrated numerous autosomal recessive mutations in RAS- related genes leading to RTD. 4,5,7,11,12 Consanguinity is identified in 12% to 32% of cases.1,4,5 The RAS controls extracellular volume and maintains peripheral resistance, blood pressure levels, renal function, and renal blood flow. Renin cleaves angiotensinogen, which is produced in the liver, in angiotensin I. Angiotensin I, an inactive decapeptide, is then converted to angiotensin II (Ang II), an active octapeptide, by the angiotensin-converting enzyme. Classically, Ang II acts on angiotensin II receptor type 1 (leading to vasoconstriction) and on angiotensin II receptor type 2 (leading to vasodilation). Under normal conditions, renin is the limiting factor in the cascade of reactions, all other components being produced in excess. Renin is produced by the

juxtaglomerular cells in the renal afferent arterioles, renin release being modulated by afferent arteriolar perfusion pressure and sodium concentration in the macula densa. In contrast, Ang II controls renin release through negative feedback. Therefore, the inhibition or absence of Ang II activity leads to an overexpression of renin.5,12 All RAS-components are expressed in human embryos.5 In humans, in whom nephrogenesis is complete before birth,13,14 renin and Ang II levels are higher in the embryonic period than in the neonatal period. The fetal RAS and the maternal RAS are independent, and it has been demonstrated that renin does not cross the placental barrier.5 However, during the second half of pregnancy, the fetal RAS responds to maternal stimuli, including low blood flow/hypoxemia and medications such as furosemide and RAS inhibitors.5 These data constitute evidence that the RAS plays a unique role in the development of RTD. In 1983, Allanson et al.15 reported the case of two stillbirths, in which RTD was first described.

Subsequently, just over 100 cases were reported.1

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Autopsy and Case Reports 2012; 2(4): 27-33

Studies have found topic kidneys, either normal or in which the findings were nonspecific.1,3,4,6-8 Macroscopic examination typically reveals normal kidneys.

Histological examination reveals a lack of proximal convoluted tubules (which are diffusely distributed) and diffuse distribution of the glomeruli (which show no histological changes). Because the tubules consist of primitive cells, it is difficult to characterize them only with hematoxylin and eosin staining. Periodic acid-Schiff staining reveals a lack of proximal tubules, the brush border membrane, typical of these structures, remaining unstained.1-3 Immunohistochemistry reveals diffusely distributed distal tubules, proximal tubules being scarce or absent.1,2,4 The renal arteries, particularly the renal interlobar arteries, are tortuous and have thickened walls.4,5,14 In the case reported here, in addition to findings that are typical of RTD, we found changes that were secondary to chronic hypotension, which is common in cases of RTD. Calvarial malformation is common, resulting in hypocalvaria and enlarged fontanelles.1-3,5,8,9 Pulmonary hypoplasia, which results from oligohydramnios, leads to refractory respiratory failure at birth.2-5,8 Persistent hypotension adds to the difficulty in treating such patients.

Ileocecal valve agenesis was an interesting autopsy finding in the case reported here. To our knowledge, this finding had not been reported in the literature on RTD. We hypothesized that the ileocecal valve agenesis was due to chronic arterial hypotension. We found no intestinal perforation.

However, the presence of diffuse chronic serositis, with macrophages containing greenish granules, was suggestive of phagocytosis of meconium content, constituting an indirect evidence of intestinal perforation.

Although the neonate received intensive care, respiratory failure persisted and he died at 9 h after delivery. Microscopic examination of the brain revealed periventricular leukomalacia, a finding that constituted further evidence of fetal distress.

Nogueira AB, Schultz R, Liao AW, Francisco RPV, Zugaib M.

be included in the differential diagnosis of cases in which anuria and severe hypotension are usually accompanied by a normal renal ultrasound. It is extremely important to determine the etiology of RTD, particularly in suspected cases of autosomal recessive disease, in which there is a 25% chance of recurrence. Genetic counseling is therefore mandatory.

Although meconium ileus and its associated gastrointestinal obstruction are usually related to RTD, this is the first reported case of the ileocecal valve agenesis. However, new case reports are required to permit the establishment of an association of this unusual finding with RTD.

REFERENCES 1.

Moldavsky M. Renal tubular dysgenesis in Israel: pathologist’s experience and literature review. Isr Med Assoc J. 2009;11(1):6-10. PMid:19344005.

2.

Milunsky JM, Genest DR, Milunsky A. Renal tubular dysgenesis with microcephaly. Pediatr Nephrol.

1997;11(4):494-6.PMid:9260254. http://dx.doi.org/10.1007/ s004670050325

3.

Kriegsmann J, Coerdt W, Kommoss F, Beetz R, Hallermann C, Müntefering H. Renal tubular dysgenesis (RTD) - an important cause of the oligohydramnion-sequence. Report of 3 cases and review of the literature. Pathol Res Pract.

2000;196(12):861-5. PMid:11156331.

4.

Lacoste M, Cai Y, Guicharnaud L, et al. Renal tubular dysgenesis, a not uncommon autosomal recessive disorder leading to oligohydramnios: Role of the ReninAngiotensin system. J Am Soc Nephrol. 2006;17(8):2253-63.

PMid:16790508. http://dx.doi.org/10.1681/ASN.2005121303

5.

Gubler MC, Antignac C. Renin-angiotensin system in kidney development: renal tubular dysgenesis. Kidney Int. 2010;77(5):400-6. PMid:19924102. http://dx.doi. org/10.1038/ ki.2009.423

6.

John U, Benz K, Hübler A, Patzer L, Zenker M, Amann K. Oligohydramnios associated with sonographically normal kidneys. Urology. 2012;79(5):1155-7. PMid:22088568. http:// dx.doi.org/10.1016/j.urology.2011.08.058

7.

Winyard P, Chitty LS. Dysplastic kidneys. Semin Fetal Neonatal Med. 2008;13(3):142-51. PMid:18065301. http:// dx.doi.org/10.1016/j.siny.2007.10.009

8.

Shirakawa T, Kondoh T, Takahashi R, et al. Renal tubular dysgenesis complicated with severe cranium hypoplasia.

Pediatr Int. 2004;46(1):88-90. PMid:15043673. http://dx.doi. org/10.1111/j.1442-200X.2004.01830.x

CONCLUSION A rare disorder, RTD is generally accompanied by oligohydramnios, which is diagnosed in the second trimester of pregnancy. The disorder should

32

Renal tubular dysgenesis with hypocalvaria and ileocecal valve agenesis...

9.

Schreiber R, Gubler MC, Gribouval O, Shalev H, Landau D. Inherited renal tubular dysgenesis may not be universally fatal. Pediatr Nephrol. 2010;25(12):2531-4. PMid:20607303. http://dx.doi.org/10.1007/s00467-010-1584-0

10. Uematsu M, Sakamoto O, Ohura T, Shimizu N, Satomura K, Tsuchiya S. A further case of renal tubular dysgenesis surviving the neonatal period. Eur J Pediatr. 2009;168(2):2079. PMid:18478260. http://dx.doi.org/10.1007/s00431-0080743-9 11. Zingg-Schenk A, Bacchetta J, Corvol P, et al. Inherited renal tubular dysgenesis: the first patients surviving the neonatal period. Eur J Pediatr. 2008;167(3):311-6. PMid:17443344. http://dx.doi.org/10.1007/s00431-007-0492-1 12. Michaud A, Bur D, Gribouval O, et al. Loss-of-function point mutations associated with renal tubular dysgenesis provide insights about renin function and cellular trafficking. Hum

Autopsy and Case Reports 2012; 2(4): 27-33

Mol Genet. 2011;20(2):301-11. PMid:21036942. http://dx.doi. org/10.1093/hmg/ddq465 13. Balbi AP, Francescato HD, Marin EC, Costa RS, Coimbra TM. Roles of mitogen-activated protein kinases and angiotensin II in renal development. Braz J Med Biol Res. 2009;42(1):38- 43. PMid:19219295. http://dx.doi.org/10.1590/ S0100- 879X2009000100007 14. Chen Y, Lasaitiene D, Gabrielsson BG, et al. Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. J Am Soc Nephrol. 2004;15(5):1232-43. PMid:15100363. http://dx.doi. org/10.1097/01.ASN.0000123690.75029.3F 15. Allanson JE, Pantzar JT, MacLeod PM. Possible new autosomal recessive syndrome with unusual renal histopathological changes. Am J Med Genet.

1983;16(1):57-60. PMid:6638071. http://dx.doi. org/10.1002/ ajmg.1320160110

Conflict of interest: None Submitted on: 22th July 2012 Accept on: 2nd August 2012 Correspondence: Ariel Barreto Nogueira Rua Teodoro Sampaio, 363 – apto. 601 – São Paulo/SP – Brazil CEP: 05405-000 – Phone: +55 (11) 8555-5048 E-mail: arielbarreto@gmail.com

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Autopsy and Case Reports 2012; 2(4): 35-44

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Strongyloides stercoralis disseminated infection and schistosomiasis in an AIDS patient Rodrigo Martins Brandãoa, Renata Paula Martins Brandãob, Amanda Cristina Maria Aparecida Gonçalvesc, Lorena Silva Labordaa, Patricia Picciarelli de Limad, Fernando Peixoto Ferraz de Camposa Brandão RM, Brandão RPM, Gonçalves ACMA, Laborda LS, Lima PP, Campos FPF. Strongyloides stercoralis disseminated infection and schistosomiasis in an AIDS patient. Autopsy Case Rep [Internet]. 2012;2(4):35-44. http:// dx.doi.org/10.4322/acr.2012.035

ABSTRACT Strongyloides stercoralis hyperinfection syndrome is classically associated with impaired host response and implies in an overburden of larvae in its usual cycle. It has been recognized as a severe and potentially fatal condition in immunocompromised individuals, especially those using oral corticosteroids.

Infection with Schistosoma mansoni not only increases the susceptibility to HIV infection, but also promotes progression to disease. The association of the most severe forms of strongyloidiasis and AIDS is scarcely described, even more when S. mansoni is also associated. The authors describe a case of a 34-year-old previously healthy male, admitted to the emergency department with a history of hematemesis associated with dyspnea, hemoptysis, and fever. He referred homosexual relations for 6 years. Physical examination showed an ill-looking patient, and was remarkable for tachycardia, tachypnea, diaphoresis, and pulse oximetry of 70% in room air. Lungs examination revealed the presence of rales in the left base. Chest radiography showed a diffuse and bilateral reticulo-nodular pattern. HIV serology was positive.

Empirical antimicrobial therapy and corticosteroids were initiated. On the third day of hospitalization, petechiae appeared over the periumbilical area, but no further investigation was undertaken because the patient died soon after. The autopsy findings were compatible with S. stercoralis disseminated infection, a hepatic intestinal chronic form of schistosomiasis, and septic shock as the primary cause of death. The authors call attention to this infrequent association.

Keywords: Acquired immunodeficiency syndrome; Strongyloides stercoralis; Schistosoma mansoni; Respiratory insufficiency; Autopsy.

Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil.

Departament of Nephrology – Beneficência Portuguesa de São Paulo, São Paulo/SP – Brazil. c Nursing Departament – Hospital Israelita Albert Einstein – São Paulo/SP – Brazil. d Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. a b

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution ­NonCommercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

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Autopsy and Case Reports 2012; 2(4): 35-44 Brandão RM, Brandão RPM, Gonçalves ACMA, Laborda LS, Lima PP, Campos FPF.

CASE REPORT A 34-year-old, previously healthy male patient, born in the northeast of Brazil who had recently moved to the city of São Paulo, was admitted to the emergency department with a history of moderate hematemesis associated with dyspnea, hemoptysis, and a non-measured fever for 4 days.

He denied other gastrointestinal or genitourinary complaints, as well as illicit drug use, and was not taking any medications. He referred homosexual relations with a single partner for 6 years.

Physical examination on admission revealed an ill-looking patient presenting tachycardia (pulse rate = 136 beats per minute), blood pressure = 100/58 mmHg, tachypnea (respiratory rate = 34 respiratory movements per minute) diaphoresis, coma Glasgow scale = 15, and pulse oximetry of 70% in room air. Lungs examination revealed the presence of rales in the left base.

The examination of the heart, abdomen, and limbs was normal. Endoscopy revealed the presence of hemorrhagic pangastritis without active bleeding, and moderate duodenitis. The bronchoscopy showed sparse mucosal bleeding with some blood clots adhered to the bronchial mucosa, but failed to show any obvious bleeding source.

Chest radiography showed a diffuse and bilateral reticulo-nodular pattern. Two blood culture samples and the microbiological examination of the broncoalveolar lavage was negative for bacterial, fungi, or acid-fast bacilli. The initial laboratory

workup is shown in The HIV serology was positive, viral load was >500,000 copies (Log > 5,7) and CD4 count was 58 cells/mm3.

Because of progressive respiratory insufficiency, the patient was transferred to the Intensive Care Unit where, after attempting to optimize therapy, orotracheal intubation was undertaken, and hemodynamic stabilization required vasoactive drugs. Table 1.

Empirical antimicrobial therapy was initiated with trimethoprim-sulfamethoxazole, ceftriaxone, and clarithromycin plus prednisone. On the third day of hospitalization, petechiae appeared over the periumbilical area. On this day another bronchoscopy was held attempting to collect another search on broncoalveolar lavage and lung biopsy.

Neither the biopsy nor the lavage did not help with the diagnosis. A few hours after the procedure, the patient developed a refractory shock, fever (axillary temperature of 41.9 °C), cardiac arrest, and death.

An autopsy was carried out.

The external examination was unremarkable.

External gross examination of the brain was normal, but at microscopy a mild meningeal inflammatory infiltrate in an organization stage was observed (Figure 1A). In a single slide of the brain parenchyma, a unique filamentary structure was detected in the perivascular location (Figure 1B). This finding, despite being single and with degenerative changes, was considered to supposedly be a filariform larva of Strongyloides stercoralis. Exhaustive searches in

Table 1 – Initial laboratory workup Exam

Result

RV

Exam

Result

RV

Hemoglobin

9.8

12.3-15.3 g%

Creatinine

0.6

0.4-.3 mg/dL

Hematocrit

28.5

36-45%

AST

79

10-35 U/L

Leukocytes

20.4

4.4-11.3 × 10 /mm

ALT

84

9-43 U/L

3

3

Myelocytes

1

0%

LDH

405

120-246 U/L

Metamyelocytes

3

0%

Amylase

106

20-104 U/L

Rods

34

1-5%

Albumin

3.1

3-5 g/dL

Segmented

53

45-70%

Lactate

7.4

4.5-19.8 mg/dL

Eosinophils

0

1-4%

CRP

140

<5 mg/L

Basophils

0

0-2.5%

Lymphocytes

2

18-40%

Monocytes

7

2-9%

Platelets

283

150-450 × 103/mm3

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

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Autopsy and Case Reports 2012; 2(4): 35-44

other areas of the brain could not detect any other similar lesion.

Cut surface exhibited a glossy, wine-colored and friable surface compatible with shock.

Gross examination of the thoracic cavity disclosed enlarged lungs showing a wine-colored and rubbery consistency. The right lung weighed 1100 g (reference value (RV) range = 360-570 g) and the left lung weighed 1240 g (RV range = 325‑480 g).

Microscopic examination revealed extensive intra-alveolar hemorrhage, diffuse alveolar damage, and the presence of a hyaline membrane (Figure 2A), as well as areas of a healing process (Figure 2B).

Figure 1 – A - Photomicrography (HE) of the meninges showing mild mixed inflammatory infiltration; B - Photomicrography (HE) of the brain tissue: showing filamentary structure suggestive of filariform larva of Strongyloides stercoralis (arrow).

Figure 2 – Photomicrography (HE) of the lung showing: A - Intra-alveolar hemorrhage and diffuse alveolar damage with hyaline membrane formation (arrow); B - Areas of organization; C - Fragments of Strongyloides stercoralis larvae (arrow) partially wrapped in giant cells; D - S. mansoni eggs (arrow), with macrophage with giant cells, and epithelioid cell reaction, sketching granulomas.

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Autopsy and Case Reports 2012; 2(4): 35-44 Brandão RM, Brandão RPM, Gonçalves ACMA, Laborda LS, Lima PP, Campos FPF.

The microscopic examination of the lungs also revealed fragments of structures compatible with the diagnosis of infective larvae of S. stercoralis partially surrounded by giant cells (Figure 2C).

Additionally, eggs of S. mansoni were detected (Figure 2D). Theses eggs were partially wrapped by macrophages, giant cells, and epithelioid cells, sketching out a granuloma. Stains for AFB and fungi were negative.

Gross examination of the stomach revealed extensive hemorrhagic gastritis (Figure 4A). On microscopy, numerous viable adult S. stercoralis females were found in the mucosa (Figures 4B, 4C, and 4D). The duodenum accompanied the hemorrhagic pattern, with areas of mucosal necrosis (Figure 5A) and countless S. stercoralis adult females were detected as well (Figures 5B, 5C, and 5D).

The liver was enlarged, yellowish, and had a soft consistency (Figure 3A). The cut surface showed multiple parenchymal bleeding points, which were represented, on microscopy, by ischemic areas of the centrilobular zone III and microvesicular steatosis (Figures 3B and 3C). These findings were concordant with the diagnosis of shock. The microscopic study of the liver showed infective larvae of S. stercoralis partially wrapped by giant cells (Figure 3C), as well as eggs of S. mansoni (Figure 3D), also wrapped by macrophage, giant cells, and epithelioid cells forming a granuloma.

In the large intestine, there was no hemorrhagic or ischemic mucosa, but larvae of S. stercoralis (Figure 6A) were also detected in the submucosa, as well as eggs of S. mansoni in the mucosa (Figures 6B and 6C).

Microscopic examination of the urinary bladder showed calcified eggs of S. mansoni in the mucosa (Figure 7A), and the presence of adult worms of S. mansoni within the venules (Figures 7B and 7C). Eggs of S. mansoni were also found in the seminal vesicle (Figure 7D, arrows). Generalized

Figure 3 – A - Gross examination of the liver showing an enlarged and yellowish organ; B - Photomicrography (HE) of the liver showing areas of ischemic centrilobular hepatocytes; C - Photomicrography (HE) of the liver showing fragments of S. stercoralis larvae, partially wrapped by giant cells; D - Photomicrography (HE) of the liver showing egg of S. mansoni (arrow) eliciting macrophage reaction, giant cells and epithelioid cells reaction, and granuloma formation.

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Autopsy and Case Reports 2012; 2(4): 35-44

Figure 4 – A - Gross examination of the stomach with extensive hemorrhagic gastritis; B, C, and D - Photomicrography (HE) of the stomach showing many adult females of S. stercoralis within the mucosal layer (arrows).

visceral congestion and reactive bone marrow were the remaining findings.

DISCUSSION S. stercoralis is an intestinal parasite, endemic in tropical and temperate areas of the world where climatic conditions of humidity and temperature allow their development and survival.1 Approximately 100 million people are infected worldwide.1 Low social and economic conditions, alcoholism, institutionalized patients, and farm workers are important risk factors for infection by S. stercoralis.1,2 HIV-1 infection and the use of corticosteroids are also described as risk factors for hyperinfection and development of disseminated forms of the disease.3 The prevalence of infection with S. stercoralis in AIDS patients in Brazil also seems to be high, varying with location, and ranging from 2.5% to 21.9%.4

Schistosomiasis, in turn, is also a common parasitic disease, considered to be of public health significance in many countries, and affecting around 207 million people in tropical and subtropical areas of the globe.5,6 In Brazil, the northeastern states represent the region of higher prevalence of this disease, which is where the patient of this report came from.

The chronic stage of schistosomiasis appears months to years after infection and results from granuloma formation around the schistosome eggs, which are entrapped in many tissues. Depending on the stage of the infection, the granulomas show different characteristics. In the acute phase, they are bulky and exhibit a necrotic–exudative pattern, with large numbers of macrophages, lymphocytes, and eosinophils.7,8 As the disease progresses to the chronic phase, the granulomas lose the exudative necrosis and some of them are found enclosing already calcified eggs.2 Along with the lack of hepatic portal fibrosis, it is likely that the patient of this case report presented with a previous subclinical chronic hepatointestinal form of schistosomiasis.3

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Autopsy and Case Reports 2012; 2(4): 35-44 Brandão RM, Brandão RPM, Gonçalves ACMA, Laborda LS, Lima PP, Campos FPF.

Figure 5 – A - Gross examination of a small intestine segment showing severe hemorrhagic enteritis and mucosal necrosis; B - Photomicrography (HE) of the small bowel showing females of S. stercoralis within the mucosa and into the lumen of the small intestine (arrows); C - Photomicrography (HE) of the small bowel showing female worms in cross section (arrow) and in D in longitudinal section.

Figure 6 – Photomicrography (HE) of the large intestine showing: A - larvae of Strongyloides stercoralis within the submucosal layer without inflammatory response. B and C - Egg of Schistosoma mansoni within the mucosa (arrows).

Similarly, most cases of S. stercoralis infection happen without symptoms, especially in areas of high endemicity. This form tends to course chronically and diagnosis is usually accompanied by peripheral eosinophilia. When symptomatic, the clinical picture is highly variable depending on the interactions between host and parasite.1 In this case, the clinical forms include acute infection, chronic infection with intestinal diarrhea, hyperinfection, and disseminated syndrome.1

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Disseminated disease refers to the presence of larvae outside the sites of the parasitic cycle.

In the disseminated form, by definition, larvae are observed in almost all organs, where liver, brain, and heart are the most common areas involved. In the case reported here, larvae were found in the liver and supposedly in the brain, characterizing the disseminated infection. Moreover, the mild meningitis, observed at microscopy, could also represent an extension of the central nervous

Strongyloides Stercoralis disseminated infection and schistosomiasis in an AIDS...

Autopsy and Case Reports 2012; 2(4): 35-44

Figure 7 – Photomicrography (HE) of the urinary bladder showing: A - calcified eggs of S.mansoni within the mucosal layer (arrows); B and C - Adult worms of S. mansoni within a vessel in the wall of the bladder (arrows); D - Photomicrography (HE) of the seminal vesicle with the presence of eggs of S. mansoni (arrow). system involvement by S. stercoralis, once other possible etiologies for chronic meningitis were ruled out. In their migration through the intestinal mucosa, the larvae may carry Gram-negative bacilli with them, resulting in bacteremia, metastatic infectious foci, and septic shock. The mortality rate in this form of the disease reaches 85% and is almost always associated with bacterial infections.1 This bacterial passage through the intestinal mucosa is also described in the S. stercoralis hyperinfection.9 Luna et al. recently described fever, pulmonary infiltrates, abdominal pain, and diarrhea as the most common signs and symptoms of severe forms of S. stercoralis infection. Periumbilical purple-colored lesions, although highly specific predictors of mortality, are usually a rare manifestation.10 Hyperinfection syndrome and the disseminated form of the disease have been recognized as being severe and potentially fatal conditions in immunocompromised individuals, especially those users of oral corticosteroids.

However, the association between AIDS patients and the two most severe forms of strongyloidiasis is scarcely described, even in endemic areas.1,11-14 As

far as we know, the association of strongyloidiasis, schistosomiasis, and AIDS has not been widely reported.

With the AIDS pandemia and its inherent deleterious effect on the immune system, an increased number of severe forms of S. stercoralis infection were expected, especially in countries like Brazil, but is not frequently observed in clinical practice.15 Until 2004, when a literature review was published, 35 patients were reported as being coinfected by HIV-1 and hyperinfection or disseminated infection.15 Ferreira et al. published the largest series in Brazil,13 comprising 25 cases of AIDS and strongyloidiasis co-infection. Among these 25 patients, 7 were diagnosed with hyperinfection syndrome, and all had a fatal outcome. In 2006, a case report of a patient with AIDS and S. stercoralis hyperinfection was also published in Brazil.14 In Latin America, a study regarding this coinfection, published in 2011, reported 21 cases in a 5-year period. Out of this 21 cases, 5 expressed hyperinfection with a fatality rate of 40%.1 In this

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Autopsy and Case Reports 2012; 2(4): 35-44 Brandão RM, Brandão RPM, Gonçalves ACMA, Laborda LS, Lima PP, Campos FPF.

study, the authors observed a correlation between the CD4 count and lethality.

Schistosome infection and HIV/AIDS has been recently investigated. Downs et al.16, observed that Tanzanian women infected with Schistosoma hematobium are four-fold more likely to be HIV-1 seropositive than the women without schistosomiasis. These findings are consistent with the observations of Kjetland et al.17 Similarly, in Uganda, individuals who had antibodies to S. mansoni were significantly more likely to be HIV-1 seropositive than were persons without evidence of schistosome infection.18 Some hypotheses were carried out to explain this higher susceptibility. As approximately 90% of HIV infection occurs via the mucosa route, any condition that disrupts the integrity of a mucosal barrier or recruits a great number of HIV-1-suceptible cells to a site of virus exposure will increase host susceptibility to infection. Beyond human evidence, the increased susceptibility to viral infection, at mucosal sites, comes from studies of S. mansoniinfected rhesus macaques. In S. mansoni infection, eggs pass through the intestinal mucosa eliciting granulomatous inflammation in rectal tissues.

Viral titration studies indicated that a 17-fold less virus was needed to infect animals with acute S. mansoni infection than the control animals.19 These observations suggest the predominant influence of schistosome infection on host susceptibility is a consequence of inflamed mucosae that permit the establishment of infection at a lower viral concentration.20 Along with the increased susceptibility to HIV infection, schistosome coinfection may promote progression to disease by increasing the viral load.20 Higher viral loads in schistosome-infected hosts have been associated with increased viral replication within cells, as well as increased infection and depletion of cells associated with the immune response to schistosome infection.19,21,22 Individuals coinfected with schistosome and HIV, that received early treatment, had a significantly slower rate of viral load increase than those whose treatment was delayed for 3 months.23 Studies in macaques infected by schistosome show a higher peak viral load despite being exposed to lower concentrations of virus than the control group.19 In addition to increasing viral replication, whether directly within antigen-specific cells19,22 or indirectly through activating other mechanisms

42

associated with greater viral replication,22 schistosome infections may contribute to HIV‑1 progression by reducing the ability of the host immune response to the control virus.20 On admission, the patient of this case report presented with an advanced immunosuppression valued by the CD4 count and viral load. According to the published studies, the coinfection of S. mansoni surely played an important role determining this exacerbated immunosuppression, facilitating the development of the disseminated strongyloidiasis.

The increased number of severe forms of strongyloidiasis in immunosuppressed patients may be explained by the decrease in the activation of humoral and cellular immune response (lymphocytes T helper).2 This lack of immune system activation may favor the transformation of rhabditiform into filariform larvae, which penetrate the intestinal mucosa or perianal skin.1 These changes are mostly observed in patients whose immune systems are suppressed by corticosteroids.1 Due to the possible parallelism that could be done between immunosuppression of diverse etiology and HIV infection, facilitation in the development of severe forms of S stercoralis infection in AIDS patients would be expected.

We dare raise the suspicion that, like in the case reported here, the coinfection with S. mansoni could enhance this phenomenon.

However, a cohort study15 found a negative relationship between the CD4+ cell count and the development of severe infections caused by S stercoralis. In this study,15 there were significant negative rank correlations between CD4+ cell counts and the proportions of free-living male and female worms. Thus, in individuals with preserved immune function, direct development of S. stercoralis is favored; whereas, in individuals with lesser immune function, indirect development is relatively more common.15 Other factors, such as the persistent presence of IgG against the parasite, may represent a protective role in the response to the migration of the larvae in patients with coinfection of HIV and S. stercoralis.

Administration of high doses of steroids for the treatment of pulmonary infection due to Pneumocystis jiroveci or in the chemotherapy for

Strongyloides Stercoralis disseminated infection and schistosomiasis in an AIDS...

non-Hodgkin lymphomas in patients with AIDS may be the facilitating mechanism for severe forms of infection with S stercoralis development. We raise the suspicion that the coinfection by S. mansoni could also be on the list of facilitating comorbidities.

Steroids, besides decreasing IgG production, also appear to have a direct trophic effect on the parasite, accelerating the transformation of rhabditiform larvae in filariform.1,15 Diagnosis of severe strongyloidiasis in AIDS patients may be challenging because of the conflict with other opportunistic infections and the presence of other diseases. The presence of unexplained gastrointestinal and pulmonary findings in these patients should be considered as alert signs.10 Non-specific laboratory tests seam to be of little help in the diagnosis of disseminated forms.

The presence of eosinophils in peripheral blood is uncommon. Serological methods such as ELISA, Western Blot, and GPIA have low sensitivity.10 Definitive diagnosis is based on detection of larvae in feces, bronchial alveolar lavage, gastric aspirate, or biopsy of stomach, jejunum, lung or skin.10 In this case report, stool examination would have not only enabled the diagnosis of both parasites, but also enhanced the patient’s immunity.

The tracheal aspirate showed the higher positivity rate, followed by direct research in gastric aspirates, and biopsies of skin and lungs.10 Contrary to what has been reported in the literature, so far, the patient of this case report died by a S. stercoralis hyperinfection counting on the HIV virus infection as the only cause of immunosuppression. We draw attention to the difficult diagnosis. The empirical treatment for these cases should always be advisable, since the therapy is inexpensive, well tolerated, and reasonably effective.

REFERENCES 1.

2.

Corti M, Villafañe MF, Trione N, Risso D, Abuín JC, Palmieri O. Infección por Strongyloides stercoralis: estúdio epidemiológico, clínico, diagnóstico y terapéutico en 30 pacientes. Rev Chilena Infectol. 2011;28:217‑22.

Spanish. PMid:21879146. http://dx.doi.org/10.4067/S071610182011000300003 Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol

Autopsy and Case Reports 2012; 2(4): 35-44

Rev. 2004;17:208-17. PMCid:321465. http://dx.doi. org/10.1128/CMR.17.1.208-217.2004 3.

Freedman DO. Experimental Infection of human subject with Strongyloides especies. Rev Infect Dis. 1991;13:1221-6. http://dx.doi.org/10.1093/clinids/13.6.1221

4.

Cimerman S, Cimerman B, Lewi DS. Prevalence of intestinal parasitic infections in patients with acquired immunodeficiency syndrome in Brazil. Int J Infect Dis. 1999;3:203-6. http:// dx.doi.org/10.1016/S1201-9712(99)90025-5

5.

Beck L, Van-Lüme DSN, Souza JR, et al. Discriminating acute from chronic human schistosomiasis mansoni. Acta Trop. 2008;108:229-33. PMid:18851939. http://dx.doi. org/10.1016/j.actatropica.2008.08.012

6.

Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J. Schistosomiasis and water resources a review, metaanalysis and estimates of people at risk. Lancet Infect Dis. 2006;6:411-25. http://dx.doi.org/10.1016/S1473-3099 (06)70521-7

7.

Lambertucci JR. Acute schistosomiasis mansoni: revisited and reconsidered. Mem Inst Oswaldo Cruz. 2010;105:422‑35. http://dx.doi.org/10.1590/S0074-02762010000400012

8.

Freitas LAR, Reis MG, Freitas JR, et al. Esquistossomose mansônica. In: Brasileiro Filho G, editor. Bogliolo patologia. 8. ed. Rio de Janeiro: Guanabara Koogan; 2011. p. 1387-98. Portuguese.

9.

Husni RN, Gordon SM, Longworth DL, Adal KA. Disseminated strongyloides stercoralis infection in an immunocompetent patient. Clin Infect Dis. 1996;23:663. http://dx.doi.org/10.1093/ clinids/23.3.663

10. Luna OB, Grasseli R, Ananias M, et al. Estrongiloidíase disseminada: diagnóstico e tratamento. RBTI. 2007;19:463-8.

11. Kao D. Disseminated strongyloidiasis in a patient with acquired immunodeficiency syndrome. Arch Dermatol. 1996;132:977-8. http://dx.doi.org/10.1001/archderm.1996.03890320127027 12. Celedon JC, Mathur-Wagh U, Fox J, Garcia R, Wiest PM. Systemic strongyloidiasis in patients infected with the human immunodeficiency virus: a report of 3 cases and review of the literature. Medicine (Baltimore). 1994;73:256-63.

13. Ferreira MS, Nishioka S, Borges AS, et al. Strongyloidiasis and infection due to human immunodeficiency virus: 25 cases at a Brazilian teaching hospital, including seven cases of hyperinfection syndrome. Clin Infect Dis. 1999;28:154-5.

PMid:10028097. http://dx.doi.org/10.1086/517188 14. Cimerman S, Teixeira MC, Girio D, et al. Hyperinfection strongyloides stercoralis in AIDS patient. Rev Panam Infectol. 2006;8:32-4.

15. Viney ME, Brown M, Omoding NE, et al. Why does HIV infection not lead to disseminated strongyloidiasis? J Infect Dis. 2004;190:2175-80. PMid:15551217. http://dx.doi. org/10.1086/425935

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Autopsy and Case Reports 2012; 2(4): 35-44 Brandão RM, Brandão RPM, Gonçalves ACMA, Laborda LS, Lima PP, Campos FPF. 16. Downs JA, Mguta C, Kaatano GM, et al. Urogenital schistosomiasis in women of reproductive age in Tanzania’s Lake Victoria region. Am J Trop Med Hyg. 2011;84:364-9.

PMid:21363971 PMCid:3042809. http://dx.doi.org/10.4269/ ajtmh.2011.10-0585 17. Kjetland EF, Ndhlovu PD, Gomo E, et al. Association between genital schistosomiasis and HIV in rural Zimbabwean women.

AIDS. 2006;20:593-600. PMid:16470124. http://dx.doi. org/10.1097/01.aids.0000210614.45212.0a 18. Stabinski L, Reynolds SJ, Ocama P, et al. High prevalence of liver fibrosis associated with HIV infection: a study in rural Rakai, Uganda. Antivir Ther. 2011;16:40511. PMid:21555823 PMCid:3142695. http://dx.doi.org/10.3851/IMP1783 19. Chenine AL, Shai-Kobiler E, Steele LN, et al. Acute schistosoma mansoni infection increases susceptibility to systemic SHIV clade C infection in rhesus macaques after mucosal virus exposure. PLoS Negl Trop Dis. 2008;2:e265.

PMid:18648516 PMCid:2447882. http://dx.doi.org/10.1371/ journal.pntd.0000265

20. Secor WE. The effects of schistosomiasis on HIV/AIDS infection, progression and transmission. Curr Opin HIV AIDS. 2012;7:254-9. PMid:22327410. http://dx.doi. org/10.1097/COH.0b013e328351b9e3 21. Secor WE, Shah A, Mwinzi PMN, et al. Increased density of human immunodeficiency virus type 1 coreceptors CCR5 and CXCR4 on the surfaces of CD4+ T cells and monocytes of patients with Schistosoma mansoni infection. Infect Immun. 2003;71:6668-71. PMCid:219584. http://dx.doi. org/10.1128/IAI.71.11.6668-6671.2003 22. Mwinzi PNM, Karanja DMS, Colley DG, et al. Cellular immune responses of schistosomiasis patients are altered by human immunodeficiency virus type 1 coinfection. J Infect Dis. 2001;184:488-96. PMid:11471107. http://dx.doi. org/10.1086/322783 23. Kallestrup P, Zinyama R, Gomo E, et al. Schistosomiasis and HIV-1 infection in rural Zimbabwe: effect of treatment of schistosomiasis on CD4 cell count and plasma HIV-1 RNA load. J Infect Dis. 2005;192:1956-61. PMid:16267767. http://dx.doi.org/10.1086/497696

Conflict of interest: None Submitted on: 25th September 2012 Accept on: 3rd November 2012 Correspondence: Divisão de Clínica Médica Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9200 E-mail: r.m.brandao@bol.com.br

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Autopsy and Case Reports 2012; 2(4): 45-51

Article / Clinical Case Reports Artigo / Relato de Caso Clínico Aortic aneurysm and diverticulum of Kommerell: a dreadful concomitance Fernando Peixoto Ferraz de Camposa, Erasmo Simão da Silvab, Brenda Margatho Ramos Martinesc, João Augusto dos Santos Martinesc Campos FPF, Silva ES, Martines BMR, Martines JAS. Aortic aneurysm and diverticulum of Kommerell: a dreadful concomitance. Autopsy Case Rep [Internet]. 2012;2(4):45-51. http://dx.doi.org/10.4322/acr.2012.032

ABSTRACT First described in 1936, the diverticulum of Kommerell (DOK) is a dilatation of the proximal segment of an aberrant subclavian artery. Appearing more frequently in the left-sided aortic arch, the aberrant right subclavian artery passes behind the esophagus toward the right arm, causing symptoms in the minority of cases. Diagnosis is generally incidental with this pattern. When symptomatic, dysphagia, respiratory symptoms, hoarseness, chest pain, and upper limb ischemia are the most common complaints. Although debatable, the origin of DOK is accepted as being degenerative or congenital. The degenerative condition is normally associated with atherosclerosis and occurs more frequently after the age of 50 years with no gender predominance.

Complications may be life threatening and are more commonly related to the diverticulum aneurysm or when associated with aortic diseases such as aneurysms or dissection. The authors present a case of a 67-year-old male with a history of acute chest pain, neurological disturbances, and hypertensive crisis. The diagnostic workup revealed an aortic arch aneurysm with intramural hematoma and a diverticulum aneurysm of Kommerell. Treatment was conservative at first. The patient presented a satisfactory outcome and was referred to an outpatient clinic for follow up and further therapeutic consolidation.

Keywords: Aorta; Aneurysm; Dissection; Aberrant subclavian artery; Chest pain; Atherosclerosis.

CASE REPORT A 67-year-old male patient, previously diagnosed with hypertension, diabetes mellitus, dyslipidemia and gout, was brought to the hospital with the history of acute interscapular pain followed by mental confusion and syncope. He denied dysphagia, or any respiratory symptoms, but lately

noticed frequent choking. He was a heavy smoker until the age of 60. He had never followed a regular treatment, and was hospitalized 16 years ago for a hypertensive crisis when an acute myocardial infarction was suspected. Recently, he was taking losartan, amlodipine, simvastatin, and gliclazide.

Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil.

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

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution ­NonCommercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

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Autopsy and Case Reports 2012; 2(4): 45-51

Campos FPF, Silva ES, Martines BMR, Martines JAS.

The initial physical examination revealed an agitated patient, unconscious, with isochoric pupils, and normal and symmetric muscular strength. He was afebrile, hydrated but pale. His blood pressure was 230/146 mmHg (symmetrical in both upper limbs), pulse rate was 124 beats per minute and regular, respiratory rate was 20 respiratory movements per minute, room air oximetry was 88%, capillary blood glucose was 194 mg/dL. The remaining physical examination was unremarkable.

With the diagnosis of hypertensive encephalopathy, the patient was treated with sodium nitroprusside, esmolol, morphine, and oxygen supplementation by Venturi mask. Gradual improvement of the level of consciousness and psychomotor agitation was observed. The initial laboratory tests are shown in Table 1.

The electrocardiogram showed sinus tachycardia with atrial extrasystoles and left ventricular hypertrophy. The chest radiography showed cardiomegaly with mediastinal enlargement (Figure 1). A brain CT scan was normal.

Due to the persistence of thoracic pain (which was also referred in the anterior area of the chest) and the image of mediastinal enlargement, the patient was submitted to a thoracic angiotomography that revealed a tortuous aorta with diffuse atheromatosis characterized by parietal thickening and calcified plaques. Dilatation of the aortic arch was evident, with a maximum diameter of 5.3 cm. The presence of a spontaneous hyper density was observed along the upper posterior wall, displacing the intima and intimal calcification, which suggested intramural hematoma (Figure 2).

An aberrant right subclavian artery emerging from the posterior portion of the aortic arch passing behind and displacing the esophagus anteriorly and to the right is shown in Figure 3, presenting in its proximal segment a dilatation with 4.1 cm diameter characterizing a diverticulum aneurysm of Kommerell (Figures 3, 4 and 5).

The transesophageal echocardiography, performed at the bedside under sedation and topical anesthesia, revealed preserved ventricular systolic function, no segmental dysfunction of ventricular walls mobility, and thickening of the aortic and mitral valve rings with mild to moderate insufficiency. Aortic diameters were measured: aortic valve sinuses 41 mm, tubular sinus junction 39 mm, ascending aorta 53 mm, and aortic arch 49 mm.

The descending aorta showed a marked intimal thickening extending to the transition of the aortic arch, probably corresponding to a hematoma or thrombus. A mobile filament image in the

Figure 1 – Chest radiography showing enlarged cardiac image and mediastinal widening.

Table 1 – Initial laboratory examination workup Exam

Result

RV

Exam

Result

RV

Hemoglobin

16.5

12.3-15.3 g/dL

Creatinine

1.3

0.4-1.3 mg/dL

Hematocrit

48.9

36.0-45.0%

Urea

57

10-50 mg/dL

Leukocytes

12.1

4.4-11.3. 10³/mm3

Ionized Ca+

1.22

1.15-1.35 Mmol/L

Bands

0

1-5%

Sodium

138

136-146 mEq/L

Segmented

65

46-75%

Potassium

4.1

3.5-5.0 mEq/L

Eosinophil

3

1-4%

CKMB

2.14

<5.0 ng/mL

Basophil

1

0-2.5%

Troponin I

0.04

<0.06 ng/mL

Lymphocytes

26

18-40%

Monocytes

5

2-9%

Platelets

193

150-400. 10³/mm3

Ca+= calcium; CKMB = creatine kinase – MB; RV = reference value.

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Aortic aneurysm and diverticulum of Kommerell: a dreadful concomitance

Autopsy and Case Reports 2012; 2(4): 45-51

Figure 2 – A - Axial computed tomography of the thorax without intravenous contrast medium injection showing hyperdensity on the posterior wall of the aorta displacing the intima and its calcification, compatible with intramural hematoma; B - Multidetector CT – angiography of the thorax – Sagittal reformatted image showing intramural hematoma in the aortic arch, behind the intimal calcifications.

Figure 3 – A - Axial computed angiotomography of the thorax after intravenous contrast medium injection showing dilatation and atheromatosis of the aberrant right subclavian artery (ARSA) (arrow); B - Multidetector CT – angiography of the thorax – Coronal reformatted image showing the ARSA and the displacement of the esophagus (arrow with E).

Figure 4 – A - Axial computed angiotomography of the thorax after intravenous contrast medium injection showing dilatation of the aberrant right subclavian artery with atheromatosis characterized by thickening and calcification of the vessel wall and mural thrombus; B - Note the compression and displacement of the esophagus (arrows).

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Autopsy and Case Reports 2012; 2(4): 45-51

Campos FPF, Silva ES, Martines BMR, Martines JAS.

Figure 5 – A and B - Three-dimensional volumetric reconstruction of the posterior view of the aortic arch showing the diverticulum aneurysm of Kommerell in the emergence of the aberrant right subclavian artery.

descending aorta, suggestive of thrombus, was also evident.

The adopted treatment was conservative once the intramural thrombus remained steady and because of the unfeasibility for percutaneous treatment by the presence of the dilated ascendant aorta associated with the aberrant right subclavian artery.

The patient was discharged to outpatient follow up after 16 days of hospitalization.

DISCUSSION Anomalous right subclavian artery has been described since 1735, but was first published 52 years later (1787) when David Bayford described the clinical symptom of dysphagia caused by the esophageal compression due to an aberrant right subclavian artery.1 He named the dysphagia as lusoria, from the Latin Lusus Naturae, which was kept up to the present. The English translation of Lusus Naturae means freak of nature.2 Aberrant subclavian artery (ASA) is one of the most common congenital anomalies of the aortic arch. The incidence of the aberrant right subclavian artery (ARSA) ranges from 0.4% to 2.3% in the general population and occurs in 37% of children with Down syndrome and congenital heart disease.3 Aberrant left subclavian artery (ALSA) is rare showing the incidence in only 0.05% of the general population.4

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Burckhard Friedrich Kommerell, a German radiologist born in 1901, described the first clinical diagnosis of an ASA. In 1936, examining a patient with a suspected diagnosis of stomach cancer he noticed a delayed passage of the barium contrast medium at the level of the aortic knob. In his report, he demonstrated that the esophagus was pushed and compressed forward. To the left and behind the esophagus there was a pulsatile mass construed to be a vessel. This finding was interpreted as being an aberrant origin of the right subclavian artery, and because of the size of the pulsatile mass it was attributed to an aortic diverticulum, from where the right subclavian artery originated.2 Since then the thoracic aortic diverticula were named after Kommerell. Nevertheless, the author called attention to the fact that an ASA does not always arise from a diverticulum (Figure 6).

The original Kommerell description comprised an aberrant artery arising from a left aortic arch. In this vascular anomaly, the right subclavian artery arises as the last branch of the aortic arch and courses from the proximal descending aorta to the right arm, passing behind the esophagus.

This anomaly generally courses without symptoms because of the lack of the trachea and esophagus encirclement by other vascular structures. This anomaly is associated with a diverticulum of Kommerell (DOK), in 60% of the cases.5,6 The newest edition of Rutherford’s Vascular Surgery7 describes DOK as a degenerative aneurismal change in the proximal portion of the ASA or its aortic origin, keeping the controversy about the congenital or degenerative nature of DOK

Aortic aneurysm and diverticulum of Kommerell: a dreadful concomitance

Autopsy and Case Reports 2012; 2(4): 45-51

Figure 6 – Schematic left anterior oblique view of the left sided aortic arch with an aberrant right subclavian artery (ARSA) and a diverticulum of Kommerell (DOK). Note that the ARSA passes behind the esophagus.

LCA = left carotid artery; LSA = left subclavian artery; PA = pulmonary artery; RCA = right carotid artery; SVC = superior vena cava. and how to distinguish it from a true aneurysm.4 Felson et al., addressed this difference of opinion well, dividing the entity into three categories: type 1 was the normal diverticulum described by Kommerell; type 2 was an aneurismal dilatation of this diverticulum; and type 3 was an aneurysm of the distal vessel separated from the diverticulum or aorta by a segment of normal caliber subclavian artery.8 However, he did not define the size of a ‘‘normal’’ diverticulum. Type 2 is called diverticulum aneurysm, and type 3 is the true ASA aneurysm.

These two types are usually degenerative changes from atherosclerosis, which is most frequently encountered in adults older than 50 years of either sex.4,7 Type 1 DOK, a congenital enlargement, can be seen in both pediatric and adult patients.4 The patient of this report presented a DOK of 3.8 cm in diameter, which was most probably of degenerative atherosclerotic origin.

Since the description of Kommerell, attention was called to the fact that the subclavian artery does not always arise from a diverticulum, and symptoms are not always present. Indeed, most patients with ASA are asymptomatic and the diagnosis is usually made incidentally or when investigating

aortic diseases nearby.4 Only 5% of patients with ARSA experience symptoms. Dysphagia of unclear etiology, also called dysphagia lusoria, is the most common presenting symptom.5 In children, a complete vascular ring formed by a ligamentum arteriosum or a ductus between the subclavian artery and the pulmonary artery compress the tracheobronchial tree and cause respiratory symptoms. Other reported symptoms are: dyspnea or coughing; chest pain; upper limb ischemia resulting from occlusive diseases, thromboembolism or rupture; and hoarseness due to compression of the recurrent laryngeal nerve.9 Symptoms are most apt to appear or to be aggravated (1) when the ASA is taut and stretches across the esophagus like a bow-string; (2) when the vessel becomes sclerotic and less elastic due to atherosclerosis;10,11 (3) when there is aneurysmal dilatation of the artery;12 or (4) when a vascular ring exists. The latter occurs when the right and left carotid arteries arise from the aortic arch together or in close proximity, so that the esophagus and trachea are hemmed in: dorsally by the aberrant right subclavian artery; and ventrally by the carotid fork.13 In the case of this report, the patient was poor of symptoms until recently when he referred frequent choking but not dysphagia.

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Autopsy and Case Reports 2012; 2(4): 45-51

Campos FPF, Silva ES, Martines BMR, Martines JAS.

We interpreted this symptom as resulting from the compression of the esophagus by the ARSA because of the atherosclerotic hardening of the vessel and the size of the diverticulum aneurysm.

Endovascular repair became the preferred intervention, but it depends on the anatomical evolvement of the ascendant aorta or aortic arch branches.

DOK may occur in other anomalies of the aorta arch system. In cases of right-sided aortic arch, which occurs in 0.5% of the general population, the ALSA occurs in 50% of these cases and arises from a diverticulum at the junction of the aortic arch and the right descending aorta. The ALSA passes obliquely upward behind the esophagus toward the left arm.5,6,14 The diverticulum occurs in 0.05-0.1% of these cases15,16 and is generally well developed because of the fetal ductus arteriosus at the junction of the aberrant artery.10,11

The patient of this case report presented to the hospital because of an aortic hematoma developed in a hypertensive crisis. The symptomatology started with interscapular pain that progressed to retrosternal pain, most probably because of the aortic dissection. He referred a recent choking, which we considered as a possible symptom of the ARSA with the diverticulum aneurysm, but this diagnosis was still considered as incidental. In this case, the adopted treatment was conservative, but the follow up will weight the necessity of surgical treatment. In the literature, surgical treatment for symptomatic DOK has shown good results when performed electively.

Aneurysms arising in an ASA are truly rare17 and may constitute a potentially lethal condition, which is treatable when precociously identified.6,18.

Complications of ASA aneurysms or DOK include: (1) rupture, occurring in 6-19%;18-20 (2) embolization;14 (3) dissection;14 (4) upper gastrointestinal bleeding caused by a fistula involving the esophagus and the diverticulum;14 and (5) inadvertent puncture of the subclavian artery during central venous access (occurring in 3.7% of cases).

ASA may be associated with thoracic aortic aneurysm or aortic dissection. The aorta of patients with ASA is also abnormal and more prone to aneurysm formation, rupture, and dissection.4 Until 2005, 67 documented cases of ARSA were reported with DOK complicated by aneurysms, while ALSA with DOK were involved in only 22 cases.6 The majority of the aneurysms involving an ARSA with DOK are of atherosclerotic origin. These aneurysms may be involved with adjacent aortic dissection or rupture. In theses cases, the overall survival rate is less than 20%.17,18 A specific strategy for surgical treatment of DOK has not yet been established because of the variety on anatomical and morphological presentations. Various surgical and endovascular repairs have already been applied, such as total arch replacement, replacement of the descending aorta with ASA-carotid transposition, isolated stent graft, stent graft with extra-anatomic bypass, fenestrated and branched stented graft, and ligation of the ASA.15,19

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REFERENCES 1.

Miller JM, Miller KS. A note on the historical aspects of dysphagia lusoria. Am Surg. 1992;58:502-3. PMid:1642389.

2.

Van Son J, Konstantinov IE. Burckhard F. Kommerell and Kommerell’s diverticulum. Tex Heart Inst J. 2002;29:109-12.

PMid:12075866 PMCid:116736.

3.

Kawashima A, Fishman EK, Kuhlman JE, Nixon MS. CT of posterior mediastinal masses. Radiographics. 1991;11:104567. PMid:1749849.

4.

Yang C, Shu C, Li M, et al. Aberrant subclavian artery pathologies and Kommerell’s diverticulum: A review and analysis of published endovascular/hybrid treatment options.

J Endovasc Ther. 2012;19:373:82.

5.

Brown DL, Chapman WC, Edwards, et al. Dysphagia lusoria: aberrant right subclavian artery with a Kommerell’s diverticulum. Am Surg. 1993;59:583-6.

6.

Fisher RG, Whigham CJ, Trinh C. Diverticula of Kommerell and aberrant subclavian arteries complicated by aneurysms.

Cardiovasc Intervent Radiol. 2005;28:553-60. PMid:16091992. http://dx.doi.org/10.1007/s00270-003-0229-0

7.

Timaran CH. Upper extremity aneurysm. In: Rutherford JB, Cronenwett JL, Johnston W, editors. Rutherford vascular surgery. 7th ed. Philadelphia: WB Saunders; 2010. http:// dx.doi.org/10.1016/B978-1-4160-5223-4.00137-2

8.

Felson B. Ruptured anomalous right subclavian artery: aneurysm or diverticulum? Semin Roentgenol. 1989;24:121‑6. http://dx.doi.org/10.1016/0037-198X(89)90033-3

Aortic aneurysm and diverticulum of Kommerell: a dreadful concomitance 9.

Autopsy and Case Reports 2012; 2(4): 45-51

Wu JY, Chen HY, Shu CC, et al. Kommerell diverticulum, right sided aorta, and left aberrant subclavian artery in a patient with dysphagia. J Thorac Cardiovasc Surg. 2010;139:e97-8.

PMid:19660293. http://dx.doi.org/10.1016/j.jtcvs.2009.01.010

15. Ota T, Okada K, Takanashi S, Yamamoto S, Okita Y. Surgical treatment for Kommerell’s diverticulum. J Thorac Cardiovasc Surg. 2006; 131:574-8. PMid:16515907. http:// dx.doi.org/10.1016/j.jtcvs.2005.10.012

10. Backer CL, Ilbawi MN, Idriss FS, et al. Vascular anomalies causing tracheoesophageal compression.

Review of experience in children. J Thorac Cardiovasc Surg. 1989;97:725-31. PMid:2651808.

16. Faucz RA, Furlan S, Barros AS, et al. Arco aórtico direito com artéria subclávia esquerda aberrante e divertículo de Kommerell. Radiol Bras. 2005;38:381-4. Portuguese. http:// dx.doi.org/10.1590/S0100-39842005000500014

11. Van Son JA, Julsrud PR, Hagler DJ, et al. Surgical treatment of vascular rings: the Mayo Clinic experience. Mayo Clinic Proc. 1993;68:1056-63. PMid:8231269.

17. Knight GC, Codd JE. Anomalous right subclavian artery aneurysms. Report of 3 cases, with a review of literature.

Texas Heart Inst J. 1991;18:209-18. PMid:15227483 PMCid:325000.

12. Gross RE. Surgical treatment for dysphagia lusorian. Ann Surg. 1946;124:532-634. http://dx.doi.org/10.1097/00000658194609000-00008

18. Austin EH, Wolfe WG. Aneurysmal of aberrant subclavian artery with a review of literature. J Vasc Surg. 1985;2:571‑7.

PMid:3892054.

13. Klinkhamer AC. Aberrant right subclavian artery. Clinical and roentgenologic aspects. Am J Roentgenol Radium Ther Nucl Med. 1966;97:438-46. PMid:5947142.

19. Cinà CS, Althani H, PasenauJ, Abouzahr L. Kommerell’s diverticulum and right-sided aortic arch: a cohort study and review of literature. J Vasc Surg. 2004;2:571-7.

14. Agematsu K, Ueda T, Hoshino S, Nishiya Y. Rupture of Kommerell diverticulum after total arch replacement. Interact Cardiovasc Thorac Surg. 2012;11:800-2. PMid:20829386. http://dx.doi.org/10.1510/icvts.2010.241802

20. Kouchoukos NT, Masetti P. Aberrant subclavian artery and Kommerell aneurysm: surgical treatment with a standard approach. J Thorac Cardiovasc Surg. 2007;133:888-92.

PMid:17382621. http://dx.doi.org/10.1016/j.jtcvs.2006.12.005

Conflict of interest: None Submitted on: 11th October 2012 Accept on: 8th November 2012 Correspondence: Divisão de Clínica Médica Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9200 E-mail: ffcampos@usp.br

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Autopsy and Case Reports 2012; 2(4): 53-60

Article / Clinical Case Reports Artigo / Relato de Caso Clínico Cervical lymphadenopathy in childhood: nasopharyngeal carcinoma as a challenging diagnosis Paula Martinez Viannaa, Cristiane Rúbia Ferreirab, Pedro José dos Santos Netoc, Brenda Margatho Ramos Martinesc Vianna PM, Ferreira CR, Santos Neto PJ, Martines BMR. Cervical lymphadenopathy in childhood: nasopharyngeal carcinoma as a challenging diagnosis. Autopsy Case Rep [Internet]. 2012;2(4):53-60. http://dx.doi.org/10.4322/ acr.2012.033

ABSTRACT Nasopharyngeal carcinoma (NPC) is a carcinoma that arises from the nasopharyngeal mucosa and differs from other head and neck carcinomas by its unique histologic, epidemiologic, and biologic characteristics. NPC is rare in most countries, especially Europe and North America. However, it has a high incidence in several regions of South China. The incidence variability of NPC, among different geographical and ethnic groups, indicates a combination of genetic susceptibility, infection by Epstein-Barr virus and environmental factors. NPC is classified into three histological subtypes according to the 1991 World Health Organization classification: squamous cell carcinoma, nonkeratinizing carcinoma, and basaloid squamous cell carcinoma. The symptoms of patients with NPC are related to the primary tumor site and the degree of dissemination. Therefore, patients can remain asymptomatic during a long period of time. Imaging exams and biopsy of the tumor mass generally are sufficient to establish the diagnosis. NPC is a rare disease among children. The authors report a case of a 12-year-old boy who sought medical attention complaining of a progressive growing tumoral mass on the right side of the neck. The computed tomography images of the head and neck and the histological examination of a cervical lymph node biopsy diagnosed a metastatic NPC. Keywords: Nasopharyngeal carcinoma; Lymph node excision; Tomography, x-ray computed; Immunohistochemistry.

CASE REPORT A 12-year-old male patient, previously healthy, sought medical attention complaining of a progressive growing tumoral mass on the right side of the neck, during the last month. The patient referred fever and oral bleeding since the beginning of the symptoms. He denied weight loss and night

sweats. His primary care physician prescribed antibiotics, without any improvement.

On physical examination, three painless enlarged lymph nodes were present on the anterior and posterior, right cervical chain, and on the

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

Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. c Diagnostic Imaging Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. a b

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution ­NonCommercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

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Autopsy and Case Reports 2012; 2(4): 53-60

anterior left cervical chain, measuring up to 5.0 cm. On palpation, all nodules were hard, fixed to surrounding tissues, without fluctuation points, and showed well-defined limits. The rest of the physical examination was unremarkable. Computed tomography (CT) of the neck revealed multiple, bilateral nodular masses images, some coalescent, on the pharyngeal, submandibular regions, and along the carotid arteries, measuring up to 4.0 cm.

Facial and abdominal CT were normal (Figures 1 and 2).

Laboratory workup was normal, and serology for toxoplasmosis (IgG and IgM), cytomegalovirus,

Vianna PM, Ferreira CR, Santos Neto PJ, Martines BMR.

hepatitis B virus, hepatitis C virus, hepatitis A virus, HIV, and syphilis were all negative. Serology for Epstein-Barr virus (EBV) was IgG positive and IgM negative.

An incisional biopsy was performed, and multiple, irregular fragments were removed, measuring 2.0 × 1.0 × 0.4 cm. All samples were submitted to histopathological evaluation, which revealed marked fibrosis and reactive lymphoid tissue with expanded paracortical zones. Focal areas of micro abscesses and cohesive groups of atypical cells with monotonous vesicular nuclei, prominent nucleoli, and lightly eosinophilic

Figure 1 – Multidetector computed tomography of the head and neck. Coronal reformatted images after intravenous contrast injection. A - Infiltrating rhinopharyngeal masses spreading to the retro and parapharyngeal spaces; B - Multiple confluent lymph nodes with cystic/necrotic central areas scattered in various cervical plans, bilaterally.

Figure 2 – Axial computed tomography of the head and neck. A - (Bone window) hypodense material fulfilling the mastoid cells (white arrow) and the middle ear (black arrow), compatible with ostomastoiditis; B - After intravenous injection of the contrast, rhinopharyngeal infiltrative tumoral mass (black arrows), larger on the right side, obliterating Rosenmüller’s fossa.

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Cervical lymphadenopathy in childhood: nasopharyngeal carcinoma...

cytoplasm with indistinct cell borders, resulting in a syncytial appearance were present (Figure 3).

The immunohistochemical study is summarized in Table 1 and Figure 4.

The histological findings combined with the immunohistochemical results were consistent with metastatic lymphoepithelial carcinoma. Based on histological diagnosis, endoscopic exam of the nasopharyngeal cavity was undertaken, resulting in a disclosure of a suspicious mass localized on the nasopharynx, confirmed by CT images (Figure 5).

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Given the histological, clinical, and tomographic findings, diagnosis was concluded as lymph node metastatic undifferentiated nonkeratinizing nasopharyngeal carcinoma (NPC).

DISCUSSION We report a case of a 12-year-old boy with a cervical mass that revealed a metastatic NPC after histopathological examination. NPC is

Figure 3 – A - Fibrosis and reactive lymphoid tissue; B - Islands of atypical cells with syncytial appearance; C and D - Atypical cells showing monotonous vesicular nuclei with prominent nucleoli, and lightly eosinophilic cytoplasm with indistinct cell borders (H&E).

Table 1 – Immunohistochemical panel used for diagnosis Antigen

Clone

Dilution

Manufacturer

Result

AE1–AE3

AE1–AE3

1:2000

Cell Marque

Positive on atypical cells

EBV

CS1/CS2/CS3/CS4

1:2000

DAKO

Positive on atypical cells

CD20

L26

1:6000

DAKO

Negative (positive on B lymphocytes)

CD3

policlonal

1:1500

DAKO

Negative (positive on T lymphocytes)

CD68

PG-M1

1:5000

DAKO

Negative (positive on B histiocytes)

CD30

Ber – H2

1:400

DAKO

Negative (positive on focal reactive lymphocytes)

CD21

2G9

1:1200

Novocastra

Negative (positive on dendritic cells)

CD138

MI15

1:1200

DAKO

Negative (positive on plasmocytes

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Vianna PM, Ferreira CR, Santos Neto PJ, Martines BMR.

Figure 4 – Immunohistochemistry. A - AE1-AE3 positive on atypical cells; B - EBV (LMP1) positive on atypical cells; C - CD20 positive only on small lymphocytes B; D - CD3- positive only on the small T lymphocytes.

Figure 5 – Multidetector computed tomography of the head and neck. Sagittal reformatted images after intravenous contrast injection, showing an infiltrative mass in the rhinopharinx (arrow). a carcinoma that arises from the nasopharyngeal mucosa and differs from other head and neck carcinomas by its unique histologic, epidemiologic, and biologic characteristics.1 It has as synonyms lymphoepithelioma, lymphoepithelioma-like carcinoma, and lymphoepithelial carcinoma.

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NPC is rare in most countries, especially in Europe and North America. In the United States, it accounts for 0.25% of all malignancies.2 However, it has a high incidence in several areas of Southern China,3 where the incidence ranges from 15% to 18% of all malignancies. It also accounts for 10-20% of childhood malignancies in Africa.2 Its incidence varies from less than 1 per 100,000 person-years in low-incidence regions to more than 20 per 100,000 person-years in endemic regions.4 In high-risk groups, NPC incidence raises after the age of 30 years and peaks at 40-60 years, declining afterwards. Gender predominance is observed with the relation between men and women of 2-3/1.2,5 In general, populations that migrate from high to low risk areas retain much of the elevated risk seen in their country of origin.6 NPC is a rare disease among children.7 Although great variability does exist concerning racial and geographical groups, this neoplasia constitutes from 1% to 5% of all cancers and from 20% to 50% of all primary nasopharyngeal malignant tumors in children.8-10 The mean age of NPC development is 13 years, and incidence is highest among males (male to female ratio 1.8:1) and Black people.11,12

Cervical lymphadenopathy in childhood: nasopharyngeal carcinoma...

The incidence variability of NPC between different geographical and ethnic groups indicates a combination of genetic susceptibility, infection by Epstein-Barr virus (EBV) and environmental factors (consumption of Chinese nitrosamine-rich salted fish and other salted food) in the pathogenesis of the disease.13 High antibody titers to EBV antigens (IgG and IgA) are useful diagnostic markers.2 A stepwise progression of histological features has been recently described. Patches of dysplasia are the earliest recognizable lesions, which are associated with allelic losses on the short arms of chromosomes 3 and 9, which result in inactivation of several tumor suppressor genes, particularly p14, p15, and p16. These dysplastic areas are the origin of the tumor, but are probably insufficient to lead its further progression. At this stage, latent EBV infection becomes critical and leads to the development of severe dysplasia.

Gains of genes on chromosome 12 and allelic loss on 11q, 13q, and 16q result in invasive carcinoma.

Metastases are associated with mutation of p53 and aberrant expression of cadherins.14,15 NPC is divided into three histological subtypes in accordance with the World Health Organization (WHO) classification of 1978, which are: squamous cell carcinoma (WHO type I), nonkeratinizing carcinoma (WHO type II), and undifferentiated carcinoma (WHO type III).16 In the 1991 WHO classification, the squamous cell carcinoma subtype (keratinizing squamous cell carcinoma) was maintained. The last two subtypes of 1978 WHO classification were grouped in a single category of “nonkeratinizing carcinoma”, and were subdivided as “differentiated” or “undifferentiated”.

The current WHO classification maintains the terminology of the 1991 classification, with the addition of a new category: basaloid squamous cell carcinoma.

Comparing keratinizing squamous cell carcinoma with nonkeratinizing carcinoma, a trend for locally advanced tumor growth in the former (76% vs 55%)17 as well as a lower incidence of lymph node metastasis (29% vs 70%).18 Keratinizing squamous cell carcinoma shows immunoreactivity for pancytokeratin, high molecular-weight cytokeratin, and focally epithelial membrane antigen.

The nonkeratinizing carcinoma can be subdivided in undifferentiated and differentiated subtypes. Syncytial-appearing large tumor cells with indistinct cell borders, round to oval vesicular

Autopsy and Case Reports 2012; 2(4): 53-60

nuclei, and large central nucleoli characterize the undifferentiated subtype, which is more common.

The lymph nodes can be involved extensively or subtly; the tumor takes the form of islands and strands, being intermingled with variable numbers of lymphocytes, plasma cells, and eosinophils.

In cases of cervical lymph node metastases, the differential diagnoses are Hodgkin lymphoma, anaplastic lymphoma, and diffuse large B-cell lymphoma. The differentiated subtype differs from the undifferentiated subtype by showing cellular stratification often paved by a plexiform growth, reminiscent of transitional cell carcinoma of the bladder.19 The tumor cells show well-defined cell borders and sometimes-vague intercellular bridges; there also may be exceptionally occasional keratinized cells.20 Nonkeratinizing NPC is associated with EBV infection in virtually 100% of cases, irrespective of the ethnic background of the patient. By contrast, EBV latent membrane protein-1 (LMP1) is usually positive in only 30-40% of cases, and the immunostaining is often patchy and weak. The simplest and most reliable way to demonstrate EBV is in-situ hybridization for EBV-encoded early RNA. Practically all tumor cells show a strong reaction for pan-cytokeratin (AE1/AE3, MNF-116).20 The case reported here, showed an immunohistochemistry expression of AE1/AE3 and EBV on atypical cells, and a negative reaction for other lymphoid markers, leading to the diagnosis of NPC. NPC often originates from the pharyngeal recess, the Rosenmüller’s fossa. The primary tumor may present as a smooth bulging mucosa, a discrete nodule with or without ulceration, or an infiltrating mass.21 In general, this tumor spread via nasopharyngeal mucosa and submucosa along adjacent muscle and adipose planes and into bone foramina. As in the case presented here, most patients present a disseminated disease on the first consultation.21,22 The symptoms of patients with NPC are related to the primary tumor site and its degree of dissemination. Because of the anatomical peculiarities of the nasopharynx and the insidious growth of the tumor in this area, the nasopharynx has been considered a “blind spot”, inaccessible to clinical evaluation. Therefore, patients can remain in a lengthy asymptomatic period.21,22 In children, the most common presenting symptom is a painless mass in the upper neck, which may be quite large at the first medical consultation. Local tumor effects

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include nasal obstruction, blood-tinged drainage, bleeding, and conductive hearing loss, or serous otitis caused by obstruction of the Eustachian tubes.

The two latter events can also cause earache and tinnitus. Headaches, facial pain, and neck pain may result from obstructive phenomena or invasion.

Nasopharynx is a relatively clinically silent area.

Therefore, isolated lymph nodes metastasis to the neck, without clinical or radiological evidence of disease in the nasopharynx, may be observed.12 In the case reported here, a tumoral mass was evidenced in the nasopharynx only after diagnosis was defined on lymph node metastasis.

NPC has the highest preponderance for regional lymph node metastasis among squamous cell carcinoma of the head and neck.23 The most commonly involved cervical lymph node regions include lateral retropharyngeal nodes and level II nodes with an overall probability of 69.4% and 70.4%, respectively. Certain cervical lymph node groups, including level I, level VI, parotid, and supraclavicular nodes have a very low risk for metastasis.24 Distant metastases include the bones (67%), lungs (20%), liver (30%), bone marrow (23%), and mediastinum.12 Sultan et al.1 compared the clinical features and outcomes of children, adolescents (<20 years old) and adults with diagnosis of NPC. Based either on the AJCC-6 staging system or on tumor volume, they observed that children presented a more advanced disease at diagnosis. However, their outcome was significantly better compared to those observed in adults. A higher fraction of favorable WHO types (II and III) was observed in children, but it does not fully explain the better prognosis. In the multivariate analysis, age was shown to be an independent prognostic factor, where children and adolescents have half the risk of death compared to young adults.

Imaging exams and biopsy samples of the tumor generally reveal the diagnosis. CT remains the imaging exam of choice adopted by most institutions for the evaluation of tumors of the head and neck. Beyond the staging of advanced cases, it can reveal subtle details concerning the cranial base involvement with lytic or sclerotic lesions. Other findings furnished by CT are: displacement and obliteration of cervical adipose plans; asymmetry of the shape and density of muscle planes; changes in the density of bone surrounding structures; and indirect signs of perineural dissemination such as foramina enlargement and bone fissures.2,21 CT is

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Vianna PM, Ferreira CR, Santos Neto PJ, Martines BMR.

still used for radiotherapy planning, and in some centers, is used with positron emission tomography (PET) using 18F-FDG. PET/CT has been shown to be of value in NPC staging, detecting distant metastasis.2 In the case presented here, there was no evidence of the perineural dissemination on CT images. In this regard, magnetic resonance imaging (MRI) has shown greater diagnostic accuracy. MRI is an accurate test for detecting subclinical cancers missed at endoscopy and endoscopy biopsies, and is also useful for ruling out this diagnosis.

The protocol for NPC includes unenhanced T1weighted images to detect skull base involvement and fat planes in at least an axial and sagittal plane. A T2-weighted fast spin-echo sequence in an axial plane is used for early parapharyngeal tumor spread, paranasal sinus invasion, middle ear effusions, and detection of cervical lymph nodes.

Axial and coronal contrast-enhanced T1-weighted images (with or without fat suppression) are used to detect tumor extent, including perineural spread and intracranial extension of the tumor. Whole body MRI for metastatic deposits of NPC is not currently recommended.2 Lymph node involvement is suspected when node size exceeds 10 mm and when there is a peripheral ring enhancement by contrast medium and a central hypodensity.25 The treatment in children follows guidelines established for adults. The main treatment strategy for all cases of locoregional NPC has been highdose radiotherapy to the nasopharynx and involved lymph nodes of the neck, and a moderate dose of radiation to uninvolved nodes and surrounding tissue. By contrast, surgery is generally not feasible due to potentially inadequate margins of resection.

Chemotherapy depends on metastatic or recurrent disease activity.12 Due to the low incidence of NPC in children, misdiagnosis or delayed diagnosis is frequent.

Therefore, the disease has to be included in the differential diagnosis of lymph node enlargement since isolated lymph nodes metastasis to the neck, without clinical or radiological evidence of disease in the nasopharynx, may be observed.

REFERENCES 1.

Sultan I, Casanova M, A Ferrari, Rihani R, RodriguezGalindo C. Differential features of nasopharyngeal carcinoma in children and adults: a seer study. Pediatr Blood Cancer. 2010;55:279-84. PMid:20582982. http:// dx.doi.org/10.1002/pbc.22521

Cervical lymphadenopathy in childhood: nasopharyngeal carcinoma...

Autopsy and Case Reports 2012; 2(4): 53-60

2.

Razek AAKA, King A. MRI and CT of nasopharyngeal carcinoma. AJR Am J Roentgenol. 2012;198:11-8.

PMid:22194474. http://dx.doi.org/10.2214/AJR.11.6954

3.

Spano JP, Busson P, Atlan D, et al. Nasopharyngeal carcinomas: an update. Eur J Cancer. 2003;39:2121-35. http://dx.doi.org/10.1016/S0959-8049(03)00367-8

15. Hui AB, Lo KW, Leung SF, et al. Detection of recurrent chromosomal and losses in primary nasopharyngeal carcinoma by comparative genomic hybridization. Int J Cancer. 1999:82:498-503. http://dx.doi.org/10.1002/ (SICI)1097-0215(19990812)82:4<498::AID-IJC5>3.0.CO;2-S

4.

Sun LM, Li CI, Huang EY, Vaughan TL. Survival differences by race in nasopharyngeal carcinoma. Am J Epidemiol. 2007;165:271-8. PMid:17090616. http://dx.doi. org/10.1093/aje/kwk008

16. Shanmugaratnam K, Sobin LH. Histological typing of upper respiratory tract tumours. Geneva: WHO; 1978.

5.

Ferlay J, Bray F, Pisani P, Parkin DM. Globocan 2000: cancer incidence, mortality and prevalence worldwide, version 1.0.

Lyon: IARC; 2001.

6.

Buell P. Race and place in the etiology of nasopharyngeal cancer: a study based on California death certificates.

Int J Cancer. 1973;11:268-72. http://dx.doi.org/10.1002/ ijc.2910110204

7.

Ayan I, Kaytan E, Ayan N. Childhood nasopharyngeal carcinoma: from biology to treatment. Lancet Oncol. 2003;4:13-21. http://dx.doi.org/10.1016/S14702045(03)00956-2

8.

Ingersol L, Woo SY, Donaldson S, et al. Nasopharyngeal carcinoma in the young: combined MD Anderson and Stanford experience. Int J Radiat Oncol Biol Phys. 1990;4:881-87. http://dx.doi.org/10.1016/0360-3016(90)90008-8

9.

Pao WJ, Husto HO, Douglass EC, et al. Pediatric nasopharyngeal carcinoma. Long-term follow-up of 29 patients. Int J Radiat Oncol Biol Phys. 1989;17:299-305. http://dx.doi.org/10.1016/0360-3016(89)90443-4

10. Deutsch M, Mercado R, Parsons JA. Cancer of nasopharynx in children. Cancer. 1978;41:1128-33. http:// dx.doi.org/10.1002/1097-0142(197803)41:3<1128::AIDCNCR2820410348>3.0.CO;2-S 11. Plowman PN. Rare tumors. In: Pinkerton CR, Plowman PN, editors. Paediatric Oncology. 2nd ed. Cambridge: Chapman and Hall; 1997. p. 561-75.

12. Ayan I, Altun M. Nasopharyngeal carcinoma in children: retrospective review of 50 patients. Int J Radiat Oncol Biol Phys. 1996;35:485-92. http://dx.doi.org/10.1016/S03603016(96)80010-1 13. Chan AT, Teo PM, Johnson PJ. Nasopharyngeal carcinoma.

Ann Oncol. 2002;13:1007-15. http://dx.doi.org/10.1093/ annonc/mdf179 14. Chan ASC, To KF, Lo WK, et al. High frequency of chromosome 3p deletion in histologically normal

nasopharyngeal epithelia from Southern Chinese. Cancer Res. 2000;60:5365-70. PMid:11034072.

17. Reddy SP, Raslan WF, Gooneratne S, Kathuria S, Marks JE. Prognostic significance of keratinization in nasopharyngeal carcinoma. Am J Otolaryngol. 1995;16:103-8. http://dx.doi. org/10.1016/0196-0709(95)90040-3 18. Neel 3rd HB. Nasopharyngeal carcinoma. Clinical presentation, diagnosis, treatment, and prognosis. Otolaryngol Clin North Am. 1985;18:479-90. PMid:2995899.

19. Shanmugaratnam K. Histological typing of tumours of the upper respiratory tract and ear. 2nd ed. Berlin: SpringerVerlag; 1991. http://dx.doi.org/10.1007/978-3-642-84474-4 20. Chan JKC, Bray F, McCarron R, et al. Nasopharyngeal carcinoma. In: Barnes EL, Everson JW, Rechert P, Sidransky D, editors. Pathology and genetics of head and neck tumours. Lyon: World Health Organization of Tumours, IARC Press; 2005. p. 85-97.

21. Miura T, Hirabuki N, Nishiyama K. Computed tomographic findings of nasopharyngeal carcinoma with skull base and lntracranial involvement. Cancer. 1990;65:29-37. http:// dx.doi.org/10.1002/1097-0142(19900101)65:1<29::AIDCNCR2820650109>3.0.CO;2-2 22. Su CY, Lui CC. Perineural invasion of the trigeminal nerve in patients with nasopharyngeal carcinoma: imaging and clinical correlations. Cancer. 1996;78:2063-69. http://dx.doi. org/10.1002/(SICI)1097-0142(19961115)78:10<2063::AIDCNCR5>3.0.CO;2-P 23. Sham JS, Choy D, Wei WI. Nasopharyngeal carcinoma: orderly neck node spread. Int J Radiat Oncol Biol Phys. 1990,19:929-33. http://dx.doi.org/10.1016/03603016(90)90014-B 24. Ho FC, Tham IW, Earnest A, Lee KM, Lu JJ. Patterns of regional lymph node metastasis of nasopharyngeal carcinoma: a meta-analysis of clinical evidence. BMC Cancer. 2012;12:98. PMid:22433671 PMCid:3353248. http://dx.doi.org/10.1186/1471-2407-12-98 25. Sham JST, Cheung YK, Choy D, Chan FL, Leong L. Nasopharyngeal carcinoma: CT evaluation of patterns of tumor spread. Am J Neuroradiol.1991;12:265-70. PMid:1902025.

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Vianna PM, Ferreira CR, Santos Neto PJ, Martines BMR.

Conflict of interest: None Submitted on: 16th September 2012 Accept on: 15th November 2012 Correspondence: Departamento de Patologia Faculdade de Medicina da Universidade de São Paulo Av. Dr. Enéas Carvalho de Aguiar, 155 – 10 andar – Cerqueira Cesar – São Paulo/SP – Brazil CEP: 055403-000 – Phone: +55 (11) 2261.7966 E-mail: viannapaula@hotmail.com

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Autopsy and Case Reports 2012; 2(4): 61-64

Article / Clinical Case Report Artigo / Relato de Caso Clínico Paroxysmal nocturnal hemoglobinuria: rare cause of acute renal failure Vilma Takayasua, Márcia Yoshie Kanegaea, Jairo Raysa Takayasu V, Kanegae MY, Rays J. Paroxysmal nocturnal hemoglobinuria: rare cause of acute renal failure. Autopsy Case Rep [Internet]. 2012;2(4):61-64. http://dx.doi.org/10.4322/acr.2012.034

ABSTRACT Paroxysmal nocturnal hemoglobinuria is a rare acquired disease, characterized by hemolytic anemia, recurrent infections, cytopenias, and vascular thrombosis. It occurs by non-malignant clonal expansion of one or more hematopoietic stem cells that acquired somatic mutations in PIG-A gene linked to chromosome X. This mutation results in lower erythrocyte expression of CD55 and CD59 surface proteins and consequently increased susceptibility to the complement system. The renal involvement is generally benign, resulting in mild impairment in urinary concentration. Acute renal failure requiring hemodialytic support accompanying PNH is rarely observed. The authors report a case of a 37-year-old male who presented with bicytopenia (hemolytic anemia and thrombocytopenia) associated with acute renal failure requiring dialysis. Diagnosis was challenging because of the rarity and unfamiliarity with this entity, but was confirmed by flow cytometry. In the course of the disease, acute pyelonephritis with multiple renal abscesses was diagnosed requiring prolonged antibiotic therapy. Patient outcome was favorable after the control of hemolysis and the infection treatment.

Keywords: Hemoglobinuria, Paroxysmal; Anemia, Hemolytic; Acute kidney injury; Flow cytometry.

CASE REPORT A 37-year-old male patient, a farmer, born and resident in a small town of northeast Brazil, sought medical attention complaining of recurrent episodes of gross hematuria alternating with brownish urine for 5 months. This symptom worsened 2 weeks ago, becoming continuous. Concurrently, he complained of asthenia, abdominal pain, nausea, and vomiting, which prevented him from exercising his daily activities. He denied the use of toxic substances or accidents with poisonous animals.

The admission physical examination showed a well-

a

looking patient, but pale, anicteric, and afebrile; no edema was evidenced. Pulse rate = 80 beats per minute, blood pressure = 130/70 mm Hg, respiratory rate = 18 breaths per minute, room air oximetry = 97%. Cardiac, pulmonary, and abdominal examination was normal. The initial laboratory tests showed the presence of uremia (BUN = 197 mg/ dL and creatinine = 25.9 mg/dL), hyperkalemia (potassium = 8.6 mEq/L) with electrocardiographic changes, and bicytopenia (anemia with hemoglobin = 6.5 g/dL and platelet

Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil.

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution ­NonCommercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

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Autopsy and Case Reports 2012; 2(4): 61-64

Takayasu V, Kanegae MY, Rays J.

count = 51,600/mm 3). The patient underwent hemodialysis, received packed blood red cells transfusion, and hyperkalemia was promptly treated.

The urinary tract ultrasound was normal except for cortical enhanced echogenicity. Colored Doppler echography of the renal arteries and veins were normal. Proceeding the lab workup, urinalysis showed 76,000 leukocytes/mL, 93,000 erythrocytes/mL, but casts were absent; 24-hours proteinuria was 411 mg in a 2475 mL volume. Urine culture failed to show any bacterial growth. Serum total protein was 5.5 g/dL, albumin 3.2 g/dL and globulins = 2.3 g/ dL. Hepatitis B antigen (HBsAg), antibodies to HIV, HCV and HBsAg, as well as antinuclear antibody (ANA) were negative; complement fractions C3 and C4 were normal. The search for schistocytes as well as direct and indirect Coombs was negative. Total bilirubin was normal but the lactate dehydrogenase was elevated (LDH = 940 U/L), reticulocytes count was reduced (0.3% and absolute = 8310/mm3) and myelogram showed slight hypercellularity with no atypical elements. Renal biopsy was not performed due to thrombocytopenia.

disclosed the recovery of renal function (BUN = 21 mg/ dL and creatinine = 1.2 mg/dL) allowing the removal of the temporary dialysis catheter. Reviewing the whole case the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) was considered. Flow cytometry showed a CD55 negativity in 58% of granulocytes, CD59 negativity in 65% of granulocytes and CD14 negativity in 56,4% of monocytes. Red blood cells failed to express CD55 in 17,8% of cells and 12,3% of cells for CD59. Red blood cells results should be interpreted with caution, because the cytometry was undertaken after hemotransfusion. These results were consistent with the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH). The patient received a packed red blood cells transfusion and 30 mg of prednisone daily aiming at hemolysis control. Joint evaluation with the urologist ruled out surgical intervention, opting for conservative treatment for 6 weeks. The patient presented a satisfactory outcome, weight gain, and fever defervescence. He was again discharged and was prescribed warfarin and folic acid.

The patient was discharged and referred to chronic hemodialysis treatment and a follow up in an outpatient clinic.

DISCUSSION

One month later, the patient returned to the emergency department complaining of back pain and fever. Urinalysis showed marked leukocyturia and urine culture showed growth of more than 105 colony-forming units of Escherichia coli, and blood culture was positive for the same pathogen. Diagnosis of acute pyelonephritis was done and ceftazidime was initiated and lasted 14 days. On this occasion, BUN = 40 mg/dL, creatinine = 3.2 mg/dL, hemoglobin 7.7 g/dL, hematocrit = 22.8%; leukocytes = 10.100/mm3 and platelets = 50,400/mm3. Approximately 3 days after the end of antimicrobial therapy, the patient presented with asthenia, chills, and anorexia, progressing to right flank pain, fever (38 ºC), and gross hematuria.

Although he had already lost 8 kg since the very beginning of symptoms, the patient still presented well-looking, anicteric but pale. Blood pressure was 88 × 62 mm Hg, pulse rate = 90 beats per minute, respiratory rate = 18 breaths per minute. Examination of the heart and lung remained unchanged, but costovertebral angle tenderness was detected on the right. The computed angiotomography of the abdomen showed signs of pyelonephritis in the right kidney with multiple small abscesses, homogeneous hepatomegaly, but no signs of renal arterial or venous thrombosis. New antibiotic regimen with cefepime and vancomycin was started. A new laboratory workup

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PNH is a rare hemolytic anemia, caused by non-malignant clonal expansion of one or more hematopoietic stem cells that have acquired somatic mutations in the PIG-A gene linked to chromosome X. These mutations result in a defect of synthesizing glycosylphosphatidylinositol (GPI) anchors, and thus, several proteins with specific functions, typically anchored by GPI on the cell surface, exhibit partial or complete absence. Among these are the CD55 (decay accelerating factor) and CD59 (membrane inhibitor of reactive lysis) that play an important role in regulating the activation of the complement system.

In patients with PNH, red blood cell clone that are CD55 and CD59 deficient are sensitive to the action of complement, thus subjected to chronic intravascular hemolysis.1 The main clinical manifestations of PNH are related to abnormalities in hematopoietic function including hemolytic anemia, hypercoagulability, bone marrow aplasia or hypoplasia, and progression to myelodysplasia and/or acute leukemia. Recurrent infections are also described.1,2 Renal lesions are usually benign and related to chronic hemosiderin deposition in the renal tubules.3 The occurrence of acute and chronic kidney injury are observed in recurrent hemolysis as observed in PNH.

Paroxysmal nocturnal hemoglobinuria: rare cause of acute renal failure

The initial clinical presentation, including asthenia, nausea, vomiting and abdominal pain, was initially interpreted as resulting from anemia and uremia. The investigation of anemia showed elevated LDH compatible with hemolysis. Other findings, which could reinforce the diagnosis of hemolysis, were not present, like hyperbilirubinemia and reticulocytosis. Besides anemia, the patient developed thrombocytopenia and the reduced reticulocyte count pointed towards relative bone marrow failure.

Common causes of renal failure, like diabetes and hypertension, and other such infections (HIV, hepatitis B and C), systemic lupus erythematosus, drug toxicity, and venomous animal accidents were ruled out. The absence of schizocytes excluded the possibility of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Autoimmune hemolytic anemia was eliminated because the negative result for Coombs test. Kidney biopsy was not undertaken because of the thrombocytopenia.

Initially, the patient was misdiagnosed with chronic kidney disease of unknown etiology and treated with hemodialysis.

As the renal function recovered after a few sessions of hemodialysis, the case was reviewed.

The association of paroxysmal reddish or brownish urine suggestive of hemoglobinuria, hemolytic anemia, abdominal pain and acute renal failure, raised the hypothesis of PNH, and prednisone was administered. Although there is no consensus on the use of corticosteroids in PNH, prednisone can assist in the reduction of hemolytic complement activation.

Although the patient already presented a clinical picture compatible with PNH since the first hospitalization, the delay in accurate diagnosis was due to its rarity and the unfamiliarity with this entity.

Autopsy and Case Reports 2012; 2(4): 61-64

impaired urinary concentration. Acute kidney injury with PNH patients who recovered renal function after a period of dialysis has been described. The renal biopsy of these cases shows acute tubular necrosis and intense deposition of hemosiderin in renal tubular cells. Although we have not performed a renal biopsy, we believe the patient had tubular injury secondary to massive hemolysis.3-6 Another important factor was the treatment of acute pyelonephritis and multiple renal abscesses.

Recurrent infections also occur frequently in PNH and deserve special attention. In the case reported here, the infection treatment was responsible for the hemolytic control as well as general clinical improvement.

Regarding thrombophilia, PNH has a predilection for intra-abdominal venous thrombosis, especially the hepatic veins. In this case report, the renal venous and arterial thrombosis was ruled out as the cause of renal failure. Thromboembolism is a leading cause of morbidity and mortality associated with PNH. It is estimated that approximately 40% of patients with PNH submit any thrombotic event during life and those with a larger clone are at higher risk for thromboembolism. Thus, patients with PNH and granulocytes clone greater than 50% that do not have contraindications for chronic anticoagulation should receive warfarin for thromboembolic disease prophylaxis.1,7

The reduction of hematopoiesis occurs in all patients with PNH and, in the patient of this report, was demonstrated by the presence of thrombocytopenia and reticulocytopenia.

We must consider that the only curative treatment available for PNH is hematopoietic stem cells transplantation.1,2,8 All other modalities are available for the control of clinical manifestations.

Currently, transplantation is indicated only in patients with bone marrow failure syndromes with severe cytopenias because of their considerable morbidity and mortality. Eculizumab, another available treatment, is a monoclonal antibody that binds to complement component C5 and inhibits complement terminal activation.1,2,9 This treatment is indicated in selected patients, namely: a) those that depend on frequent hemo transfusion; b) those who have refractory symptoms (fatigue, pain, and paroxysmal intense and frequent target organ damage); and c) for those who presented with thrombosis of unknown cause, despite the PNH clone size. Other immunosuppressive schemes (cyclosporine and anti-thymocyte globulin) may also be considered for patients with aplastic anemia or myelodysplasia related to the HPN.10,11

The renal lesion is usually benign and is secondary to hemosiderin deposition in the proximal renal tubules causing mild dysfunction recognized by

This report illustrates a case of acute kidney injury primarily considered to be of unknown etiology, but when it is associated with hematuria, hemolytic

Flow cytometry to study the expression of CD55 and CD59 is the choice test because of its high sensitivity and specificity in confirming the diagnosis of PNH. Hamâ&#x20AC;&#x2122;s test and the sucrose test, which have been used in the past, are currently replaced by cytometry.1,2

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Takayasu V, Kanegae MY, Rays J.

anemia, and/or other cytopenias, the possibility of PNH should always be considered.

6.

Peres, LAB, Ann HK, Camargo MTA, Rohde NRS, Uscocovich VFM, Souza DLCF, Beppu APK, Yukiharu R, Yamamoto T. Insuficiência renal aguda na hemoglobinúria paroxística noturna. relato de caso. J Bras Nefrol. 2008;30:76-8.

REFERENCES

7.

Baglin TP, Keeling DM, Watson HG. British Committee for Standards in Haematology. Guidelines on oral anticoagulation (warfarin): third edition--2005 update. Br J Haematol. 2006;132:277. PMid:16409292. http://dx.doi. org/10.1111/j.1365-2141.2005.05856.x

8.

Santarone S, Bacigalupo A, Risitano AM, et al. Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Haematologica. 2010;95:983-8.

PMid:20007144 PMCid:2878798. http://dx.doi.org/10.3324/ haematol.2009.017269 Kelly RJ, Hill A, Arnold LM, et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011;117:678692. PMid:21460245. http://dx.doi.org/10.1182/ blood-2011-02-333997

1.

Arruda MMAS, Rodrigues CA, Yamamoto M, Figueiredo, MS. Hemoglobinúria paroxística noturna: da fisiopatologia ao tratamento. Rev Assoc Med Bras. 2010;56:214-21.

Portuguese. PMid:20498998. http://dx.doi.org/10.1590/ S0104-42302010000200022

2.

Parker CJ. Bone marrow failure syndromes: paroxysmal nocturnal hemoglobinuria. Hematol Oncol Clin N Am. 2009;23:333-46. PMid:19327587. http://dx.doi. org/10.1016/j.hoc.2009.01.014

3.

Nair RK, Khaira A, Sharma A, Mahajan S, Dinda AK. Spectrum of renal involvement in paroxysmal nocturnal hemoglobinuria: report of three cases and a brief review of the literature. Int Urol Nephrol. 2008;40:471-5. PMid:18368508. http://dx.doi. org/10.1007/s11255-008-9356-5

9.

4.

Qi K, Zhang XG, Liu SW, Yin Z, Chen XM, Wu D. Reversible acute kidney injury caused by paroxysmal nocturnal hemoglobinuria. Am J Med Sci. 2011;341(1):68-70.

PMid:20944498. http://dx.doi.org/10.1097/ MAJ.0b013e3181f515b9

10. Paquette RL, Yoshimura R, Veiseh C, et al. Clinical characteristics predict response to antithymocyte globulin in paroxysmal nocturnal haemoglobinuria. Br J Haematol. 1997;96:92. PMid:9012693. http://dx.doi. org/10.1046/j.1365-2141.1997.d01-1984.x

5.

Kirkizlar O, Kendir M, Karaali Z, Ure U, Ozbay G, Selcuk D, Kazancioglu R. Acute renal failure in a patient with severe hemolysis. Int Urol Nephrol. 2007;39:651-4. PMid:17235485. http://dx.doi.org/10.1007/s11255-006-9096-3

11. Van Kamp H, Van Imhoff GW, De Wolf JT, et al. The effect of cyclosporine on haematological parameters in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 1995;89:79.

Conflict of interest: None Submitted on: 11th October 2012 Accept on: 23th October 2012 Correspondence: Divisão de Clínica Médica Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9200 E-mail: vilmatakayasu@uol.com.br

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Article / Clinical Case Reports Artigo / Relato de Caso Clínico Testicular Regression Syndrome: a case report Christiana de Freitas Vinhasa, Aloísio Felipe-Silvab, Ricardo Frank Coelho da Rochac Vinhas CF, Felipe-Silva A, Rocha RFC. Testicular Regression Syndrome: a case report. Autopsy Case Rep [Internet].

2012;2(4):65-68. http://dx.doi.org/10.4322/acr.2012.036

ABSTRACT Testicular Regression Syndrome (TRS) is defined as the absence or an incomplete development of the testis of varying degrees in 46XY patients with normal external genitalia. The prevalence ranges from 3-20% of cases previously diagnosed as cryptorchidism. We report the case of a 7-year-old boy who underwent surgical exploration with an initial diagnosis of cryptorchidism.

Testicular structure was not identified and presumed testicular remnants were sent for histological analysis. The histological sections showed a fibrovascular nodule, structures of the spermatic cord and calcification, supporting the diagnosis of TRS. Keywords: Cryptorchidism; Orchiopexy; Gonadal dysgenesis, 46, XY; Testis; Biopsy.

INTRODUCTION Testicular Regression Syndrome (TRS) is defined as the partial or total absence of testicular tissue, uni- or bilateral, with or without rudimentary epididymis and spermatic cord structures in 46XY individuals with normal external genitalia.1,2,8 It occurs in 1 in 20,000 male live births3 and the prevalence ranges from 3-20% of cases previously diagnosed as cryptorchidism.2 In a case of nonpalpable testis, surgical exploration is advised and orchiopexy should be done if the gonad is found.

Otherwise, removal of the remaining structures for histological analysis is recommended.1,8

Among the histological findings, the identification of a fibrovascular nodule tissue is considered a mandatory diagnostic criterion for TRS by some authors. Other findings that reinforce the diagnosis of TRS such as structures of the spermatic cord (testicular artery, pampiniform plexus, nerves and vas deferens), dystrophic calcification, hemosiderin deposits and rudimentary epididymis can also be found.1-3 In this report we present the case of a child who underwent surgical exploration with an initial diagnosis of cryptorchidism after clinical examination.

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

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

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution ­NonCommercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

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CASE REPORT Male patient, 7 years old, with normal external genitalia, topic right testicle and nonpalpable left testicle in the scrotum, with an initial diagnosis of cryptorchidism. The patient underwent surgical exploration, and a fragment of presumed left testicular remnants was removed and sent for histological analysis.

Vinhas CF, Felipe-Silva A, Rocha RFC.

skeletal muscle tissue. Areas of nodular fibrosis intermingled with some vessels, foci of hyalinization (Figure 3 and 4) and focal dystrophic calcification (Figure 5) could be seen. Perls´ Prussian blue stain for hemosiderin was negative. These findings were consistent with the histological diagnostic criteria for TRS.

Grossly, the removed fragment presented a funicular aspect with an average length of 6.5 cm and a diameter of 0.7 cm, a brownish color and fibroelastic consistency. Testis-like structures were not visible however, there was a 0.5 cm slight bulging and firm thickening in the region marked with a surgical thread. The entire specimen was subjected to microscopic analysis.

The histological sections showed hypoplastic vas deferens (Figure 1) amid venous vascular structures similar to a rudimentary pampiniform plexus (Figure 2). There was also nerves and

Figure 3 – Fibrovascular nodule (H&E, 25×).

Figure 1 – Hypoplastic vas deferens (H&E, 100×).

Figure 4 – Fibrovascular nodule (H&E, 100×).

Figure 2 – Hypoplastic vas deferens amid venous structures (H&E, 100×).

Figure 5 – Dystrophic calcification (H&E, 400×).

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Testicular Regression Syndrome: a case report

DISCUSSION There is much disagreement in the literature regarding the terms used in the absence of testicular tissue in 46XY individuals. Potter7 defines Testicular Regression Syndrome as the absence or varying degrees of incomplete development of the testis in 46XY individuals, including thus cases of testicular aplasia, gonadal dysgenesis and testicular regression at different stages of fetal development. However, other authors argue that the term TRS should not include cases of dysgenesis, despite the histological findings do not permit a distinction between these two entities. The differentiation between these terms would be based on the involvement or not of sexual development, especially the external genitalia. In cases of gonadal dysgenesis there is a serious commitment of sexual differentiation, while in cases of TRS external genitalia is normal. In the present report the child had normal external genitalia and one topic normal testicle. Histological criteria of the contralateral abnormal testicular remnants fulfilled proposed criteria for TRS, and this was the terminology at the time of pathological diagnosis.

In most studies, the frequency of this syndrome varies from 3-20% of cases clinically diagnosed as cryptorchidism.1,2,4-7 This frequency corresponds to about one half of the truly nonpalpable cryptorchid testes (approximately 20% of the total).6 Regarding the etiology of TRS, the theory of an ischemic event in early or late fetal stage is the most accepted because findings such as dystrophic calcification, hemosiderin deposits and giant cells corroborate this hypothesis.5 The common histological criteria according to different authors are blind-ending vas deferens, small fibrovascular nodule, calcification and hemosiderin. However, some authors consider the presence of blind-ending structures of the spermatic cord as a minimum criterion.5 We identified the fibrovascular nodule, structures of the spermatic cord and calcification in the present case, supporting the diagnosis of TRS. Some cases of non-palpable testis, especially on the left side, are associated with splenogonadal fusion, a rare congenital anomaly. Although it can be associated with various malformations (lower limbs, facial, cardiac, anorectal, diaphragmatic,

Autopsy and Case Reports 2012; 2(4): 65-68

spina bifida), cryptorchidism is the most common condition found in these cases. The diagnosis is intraoperative, and its importance lies in differentiating the splenogonadal fusion and a gonadal neoplasm, leading to unnecessary orchiectomy.11 As for the management of cases of nonpalpable testes on physical examination, most surgeons opt for laparoscopic exploration as the primary intervention. The laparoscopy is followed by inguinal exploration in cases where spermatic vessels and veins are seen passing through the internal inguinal ring.5,10 Surgeons emphasize the importance of identifying the vascular supply and drainage of the gonad. This is due to the fact that the testicles may not be present in the absence of the gonadal vein once the vein and the pampiniform plexus almost always indicate the location of the testis, regardless of the presence of the vas deferens and epididymis. These features are not emphasized by pathologists.1 Surgical exploration is required to perform the orchiopexy for those cases in which the testis is present but not topic (cryptorchidism). However there is disagreement regarding the removal of the remnants structures in cases of TRS. These structures were detected in up to 11% of reported cases and among these, cellular atypia was found in up to 26%.5,6 We found a single case report of malignant transformation of testicular remnants in a carrier or TRS.9 Most authors believe that the removal must be performed because of the lack of data regarding the risk of malignant transformation of testicular or paratesticular remnants containing germ cells. Some authors further claim the surgical fixation of the contralateral testis in order to reduce the risk of testicular torsion and thus ensuring good chances of fertility for the patients with TRS.2 Brauner3 and colleagues evaluated hormone levels and possible genetic mutations in 26 patients diagnosed with anorchia that, at birth, had at least one palpable testis in the scrotum. Low or undetectable levels of anti-Mullerian hormone and inhibin B, and high levels of FSH (hormones related to sexual differentiation) were shown in the plasma of these patients. Mutations in the NR5A1 gene (which plays a role in the gonadal development) were not detected.

Some studies show that the loss or absence of testicles can have negative psychological effects on adult men or children. Therefore, surgery for testicular prosthesis implantation is a solution that

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minimizes the psychological consequences of the absence of the testicle in the scrotum, providing similarity in size, weight and appearance of natural testicle.12 Altogether, these data support the conclusion that this patient fulfills clinical and pathological criteria for TRS. Furthermore, one should consider the possibility of orchiopexy and testicular prosthesis implantation to minimize the risk of testicular torsion of the viable testicle and negative psychological effects.

Vinhas CF, Felipe-Silva A, Rocha RFC. 5.

Bader MI, Peeraully R, Ba’Ath M, McPartland J, Baillie C. The testicular regression syndrome – do remnants required routine excision? J Pediatr Surg. 2011;46:384-6. PMid:21292092. http://dx.doi.org/10.1016/j.jpedsurg.2010.11.018

6.

Storm D, Redden T, Aguiar M, Wilkerson M, Jordan G, Sumfest J. Histologic evaluation of the testicular remnant associated with the vanishing testes syndrome: is surgical management necessary? Urology. 2007;70:1204-6. PMid:18158048. http:// dx.doi.org/10.1016/j.urology.2007.08.020

7.

Gilbert-Barness E, Gunasekaran S. Male reproductive system. In: Gilbert-Barness E, editor. Potter’s pathology of the fetus, infant and child. 2nd ed. Philadelphia: Mosby Elsevier; 2007. p. 1416-17.

8.

Nistal M, Paniagua R. Non-neoplastic diseases of the testis. In: Bostwick DG, Cheng L, editors. Urologic surgical pathology. 2nd ed. Mosby Elsevier; 2008. p. 632‑5. http:// dx.doi.org/10.1016/B978-0-323-01970-5.50014-2 Rozanski TA, Wojno KJ, Bloom DA. The remnant orchiectomy.

J Urol. 1996;155:712-4. http://dx.doi.org/10.1016/S00225347(01)66507-8

REFERENCES 1.

Spires SE, Woolums CS, Pulito AR, Spires SM. Testicular regression syndrome. a clinical and pathologic study of 11 cases. Arch Pathol Lab Med. 2000;124:694-8. PMid:10782149.

9.

2.

Smith NM, Byard RW, Bourne AJ. Testicular regression syndrome – a pathological study of 77 cases.

Histopathology. 1991;19:269-72. PMid:1916702. http:// dx.doi.org/10.1111/j.1365-2559.1991.tb00033.x

10. El Tayeb AA. The unilateral impalpable testis: does the order of the procedure affect the outcome? Ann Pediatr Surg. 2009;5:115-8.

3.

Brauner R, Neve M, Allali S, et al. Clinical, biological and genetic analysis of anorchia in 26 boys. Plos One. 2011;6:e23292. PMid:21853106 PMCid:3154292. http://dx.doi.org/10.1371/journal.pone.0023292

4.

A h e r n e WA , S c o t t J E S . T h e v a n i s h i n g t e s t i s .

Lancet. 1969;18:882-4.

11. Albuquerque J, Martins AP, Gonçalves M. Fusão esplenogonadal. Acta Pediatr Port. 2010;41:135-7.

Portuguese.

12. Bodiwala D, Summerton DJ, Terry TR. Testicular protheses: development and modern usage. Ann R Coll Surg Engl.

2007;89(4):349-53. PMid:17535609 PMCid:1963594. http:// dx.doi.org/10.1308/003588407X183463

Conflict of interest: None Submitted on: 12th September 2012 Accept on: 6th October 2012 Correspondence: Departamento de Patologia Faculdade de Medicina da Universidade de São Paulo Av. Dr. Enéas Carvalho de Aguiar, 155 – 10º andar – Cerqueira Cesar – São Paulo – SP – Brazil E-mail: kikavinhas@yahoo.com.br

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Nominata

Nominata of the Reviewers of the Volume 2, 2012.

The Editors of Autopsy and Case Reports thank the peer reviewers listed below for the excellent collaborative work, opinions and comments on the papers published in 2012. Their hard work certainly contributed to maintaining the scientific level of this.

Specialty

Institution

Albina Altemani

Pathology

UNICAMP

Alfredo José Mansur

Cardiology

INCOR HC FMUSP

Ana Cristina Aoun Tannuri

Pediatric Surgery

FMUSP

André Echaime Vallentsits Estenssoro

Vascular Surgery

HC FMUSP

Odontology

Superintendência de Saúde USP

Nefrology

HU USP

Hematology

FMUSP

Vascular Surgery

FMUSP

Odontology

Universidade Federal de Alagoas

Pathology

FMUSP

Gastroenterology

HC FMUSP

Hélio Rodrigues Gomes

Neurology

HC FMUSP

Ida Fortini

Neurology

HC FMUSP

Jairo Degenszajn

Neurology

HU USP

Dermatology

HC FMUSP

Infectious Diseases

Hospital Samaritano

Pathology

Instituto Português de Oncologia

Surgery

HC FMUSP

José Vassallo

Pathology

UNICAMP

Juliana Pereira

Hematology

HC FMUSP e ICESP

Laura Fernanda Alves Ferreira

Ortopedic

HU USP

Leonardo de Abreu Testagrossa

Pathology

HC FMUSP e Grupo Fleury

Luiz Antonio Machado César

Cardiology

INCOR HC FMUSP

Marcello Fabiano de Franco

Pathology

UNIFESP

Hematology

ICESP

Márcia Marcelino de Souza Ishigai

Pathology

UNIFESP

Márcio Ricardo Taveira Garcia

Radiology

ICESP

Surgery

HU USP

Endocrinology

HC FMUSP

Maria Aparecida Custódio Domingues

Pathology

UNESP

Maria Del Pilar Esteves Diz

Oncology

ICESP

Reviewers

Augusto Francisco Schulz Egidio Lima Dorea Elvira Deolinda Rodrigues Pereira Velloso Erasmo Simão da Silva Fernando José Camello de Lima Filomena Marino Carvalho Francisco José Bueno de Aguiar

João de Magalhães Avancini F. Alves Jorge Manoel Buchdid Amarante José Cabeçadas José Jukemura

Marcelo Bellesso

Marcos Scatolini Menten Maria Adelaide Albergária Pereira

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Nominata

Autopsy and Case Reports 2012; 2(4): 69-70

Specialty

Institution

Marina Penteado Sandoval

Pathology

Dermathology Group, Northern, New Jersey, EUA

Mônica Stiepcich

Pathology

Grupo Fleury

Infectious Diseases

HC FMUSP

Paulo Ricardo Criado

Dermatology

HC FMUSP

Renato Antonio Sernik

Radiology

InRAD HC FMUSP

Infectious Diseases

HC FMUSP e Hospital Emílio Ribas

Internal Medicine

HC FMUSP

Rosa Maria Affonso Moysés

Nefrology

HC FMUSP

Sheila Aparecida Coelho Siqueira

Pathology

HC FMUSP

Odontology

Faculdade de Odontologia-UNESP

Silvia Maria Ibidi

Pediatric

HU USP

Wilson Jacob Filho

Geriatrics

HC FMUSP

Zilton de Araújo Andrade

Pathology

FIOCRUZ

Reviewers

Olavo Henrique Munhoz Leite

Ricardo Tapajós Martins Coelho Pereira Rodolfo Milani Júnior

Sigmar de Mello Rode

LEGEND FIOCRUZ - Fundação Oswaldo Cruz.

FMUSP - Faculdade de Medicina da Universidade de São Paulo.

HC FMUSP - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo.

HU USP - Hospital Universitário da Universidade de São Paulo.

ICESP - Instituto do Câncer do Estado de São Paulo.

INCOR HC FMUSP - Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo.

InRAD HC FMUSP - Instituto de Radiologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo.

UNESP - Universidade Estadual Paulista “Julio de Mesquita Filho”.

UNICAMP - Universidade de Campinas.

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