Autopsy & Case Reports by Editora Cubo

ISSN 2236-1960

v.1, n.4, out./dez. 2011

Autopsy and Case Reports 2011; 1(4): 1-2

Editorial

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

It is, perhaps, unfortunate that those using Anglo-saxon tongues, as opposed to romantic languages such as French, Spanish, Italian, or Portuguese, should describe holes permitting shunting between the atrial chambers as septal defects rather than interatrial communications. This is because, of necessity, the understanding of deficiencies of the atrial septum is entirely dependent on the definition of the structures considered to represent the atrial septum. 1 Interatrial communications, on the other hand, describe all those holes that provide the facility for shunting between the atrial chambers. Those with limited interest in congenital cardiac malformations may well wonder why such details are of functional significance. The reason is that, of the five phenotypic arrangement known to produce interatrial communication, only 2 are due to deficiencies of the atrial septum. The most common defect is due to deficiency of the flap valve of the oval foramen, either because the flap valve is perforate, or else because the valve is of insufficient size to overlap the rims of the oval foramen. These defects are known as “secundum” defects, even though they are due to abnormal formation of the primary atrial septum, which forms the flap valve of the oval foramen.1 A second true septal defect, albeit very rare, involves the antero-inferior muscular buttress from which the flap valve is hinged. This is the socalled vestibular defect.2 The remaining holes that produce the potential for interatrial shunting are all outside the confines of the oval fossa, and hence are interatrial communications rather than septal defects. Of these three, the most common is the “ostium primum” defect, now well recognised as being an atrioventricular rather than an atrial septal defect. Its phenotypic feature is the commonality of

the atrioventricular junction, with the left valve being trifoliate, rather than representing a “cleft” mitral valve.3 The rarest interatrial communication is the coronary sinus defect, produced by absence of the walls that, in the normal heart, separate the cavities of the coronary sinus and left atrium.4 It is the third defect that is perhaps the most interesting. This is the sinus venosus defect, positioned most frequently in the mouth of the superior caval vein,5 but less frequently in relation to the inferior caval vein.6 In this issue of the journal, the group from Sao Paulo describe the finding of such an inferior sinus venosus defect coexisting, in an adult patient, with a large defect within the oval fossa.7 As they explain, the feature of the sinus venosus defect is the anomalous connections of the right inferior pulmonary veins, which connect anomalously to the inferior caval vein whilst retaining their connection to the left atrium. The morphogenesis of sinus venosus defects has been controversial. For some time, we believed ourselves that the essence of such defects was overriding of the rims of the oval fossa by one or other of the caval veins. This explanation was shown to be invalid, however, when we encountered unequivocal cases of the superior defect in which the superior caval vein was connected exclusively to the right atrium.8 As we showed in this most recent publication, in reality the lesions are veno-venous malformations, rather than septal defects. 8 We also showed that the alternative explanation, that of “unroofing” of the right pulmonary veins,9 was invalid simply because, in the normal heart, there is no party wall between the right pulmonary veins and the right atrium. The case described here provides additional evidence that the true essence of the sinus

Institute of Medical Genetics - Newcastle University, Newcastle upon Tyne - United Kingdom.

Copyright © 2011 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.

Anderson RH

Autopsy and Case Reports 2011; 1(4): 1-2

venosus defect is anomalous connection of one or more pulmonary veins to a systemic venous channel, with the anomalous pulmonary venous structures retaining their left atrial connection, thus producing an extracardiac conduit which provides the potential for interatrial shunting.

REFERENCES

Anderson RH, Webb S, Brown NA. Clinical anatomy of the atrial septum with reference to its developmental components. Clin Anat. 1999; 12:362-74. http://dx.doi. org/10.1002/(SICI)1098-2353(1999)12:5%3C362::AIDCA6%3E3.0.CO;2-F

Sharratt GP, Webb S, Anderson RH. The vestibular defect: an interatrial communication due to a deficiency in the atrial septal component derived from the vestibular spine. Cardiol Young. 2003; 13:184-90. PMid:12887076. http:// dx.doi.org/10.1017/S1047951103000349

Anderson RH, Ho SY, Falcao S, Daliento L, Rigby ML. The diagnostic features of atrioventricular septal defect with common atrioventricular junction. Cardiol Young. 1998; 8:3349. http://dx.doi.org/10.1017/S1047951100004613

Correspondence: Professor Robert H. Anderson 60 Earlsfield Road, London SW18 DN, United Kingdom E-mail: sejjran@ucl.ac.uk

Knauth A, McCarthy KP, Webb S, et al. Interatrial communication through the mouth of the coronary sinus. Cardiol Young. 2002; 12:364-72. http://dx.doi.org/10.1017/ S104795110001297X

Al Zaghal AM, Li J, Anderson RH, Lincoln C, Shore D, Rigby ML. Anatomical criteria for the diagnosis of sinus venosus defects. Heart. 1997; 78:298-304. PMid:9391294. PMCid:484934.

Crystal MA, Al Najashi K, Williams WG, Redington AN, Anderson RH. Inferior sinus venosus defect: echocardiographic diagnosis and surgical approach. J Thor Cardiothorac Surg. 2009; 137:1349-55. PMid:19464447. http://dx.doi.org/10.1016/j.jtcvs.2008.12.010

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 [Internet]. 2011; 1(4):21-27.

Butts RJ, Crean AM, Hlavacek AM, et al. Veno-venous bridges: the forerunners of the sinus venosus defect. Cardiol Young. 2011; 21:623-30. PMid:21729517. http:// dx.doi.org/10.1017/S1047951111000710

Van Praagh S, Carrera ME, Sanders SP, Mayer JE, Van Praagh R. Sinus venosus defects: unroofing of the pulmonary veins – anatomic and echocardiographic findings and surgical treatment. Am Heart J. 1994; 128:365-79. PMid:8037105.

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Article Artigo C-reactive protein as an inflammatory marker of acute infections outside intensive care settings: case report and evidence-based literature review Alcino Pires Gamaa, Itamar de Souza Santosa, Rodrigo Diaz Olmosa,b, Lucia Mendes de Oliveira Pintob, Isabela Judith Martins Benseñora, Paulo Andrade Lotufoa Gama AP, Santos IS, Olmos RD, Pinto LMO, Benseñor IJM, Lotufo PA. C-reactive protein as an inflammatory marker of acute infections outside intensive care settings: case report and evidence-based literature review. Autopsy Case Rep [Internet]. 2011;1(3):3-9. http://dx.doi.org/10.4322/acr.2011.011

ABSTRACT We present the clinical case of a 76-year-old woman with delirium caused by multiple factors, including pneumonia. Although this type of case is quite common in clinical practice, it provides us with an opportunity to discuss laboratory testing in this context, with a special focus on the role of C-reactive protein (CRP). We present data regarding the requests for determination of serum CRP levels at the University of São Paulo University Hospital over the past few years. We also present a review of the medical literature on the topic, as well as clinical epidemiology concepts related to the impact that CRP testing has on the medical decision-making process. Keywords: C-reactive protein; Internal medicine; Diagnostic techniques and procedures.

INTRODUCTION The objective of the present case report is to describe a common situation in the treatment of patients with acute community-acquired infections at a university hospital. We also present a critical evaluation of the ordering and interpretation of the results of tests to determine serum levels of C-reactive protein (CRP) as an inflammatory marker in this context.

METHODS We selected the case of a patient treated at the University of São Paulo University Hospital (USPUH) Emergency Department, located in the city of São a b

Paulo, Brazil. We performed a retrospective analysis of the medical chart of the patient in an attempt to determine whether the determination of serum CRP levels was necessary for the management of the case. The present case report was approved by the local research ethics committee.

CLINICAL CASE A 76-year-old woman sought treatment in the USPUH Emergency Department with a 3-day history of hypoactivity and loss of appetite. The patient reported that she had experienced a drop in

Department of Internal Medicine - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP - Brazil. Department of Internal Medicine - Hospital Universitário, Universidade de São Paulo, São Paulo/SP - Brazil.

Autopsy and Case Reports 2011; 1(4): 3-9

Gama AP, Santos IS, Olmos RD, Pinto LMO, Benseñor IJM, Lotufo PA.

the level of consciousness on the previous day. She also reported that she had fallen from standing height 15 days prior to the onset of the symptoms. The patient had a personal history of chronic obstructive pulmonary disease and had been on home oxygen therapy for the last six years. She reported that she did not have arterial hypertension or diabetes and had experienced no cardiovascular events. The patient had a family history of cancer, her father having died at age 52 years from carcinoma of the oropharynx and her mother having died from cancer, the primary site of which was unknown to the patient. Physical examination revealed dehydration, pallor, cyanosis, and extensive ecchymosis on the right side of the face. The patient presented with spatiotemporal disorientation (Glasgow coma scale score, 13). Her temperature was 36 °C, her blood pressure was 90/50 mmHg, her heart rate was 90 bpm, and her peripheral oxygen saturation was 68% on room air. There were no signs or symptoms of heart disease, lung disease, or abdominal disease. In addition, there were no signs or symptoms of upperor lower-limb disorders. Her capillary blood glucose level was 80 mg.dL–1. A presumptive diagnosis of hypoactive delirium was made, and tests were ordered (Table 1). A bedside chest X-ray was taken. Although it is technically difficult to interpret chest X-rays taken under such conditions, the findings were suggestive of a focus of infection in the right lung base (Figure 1). Because the information in the medical chart of the patient had been constantly updated, it was possible to compare the results of the arterial blood gas analysis performed at admission with those of that performed in 2004. The patient underwent aggressive hydration with saline solution. She was diagnosed with pneumonia (a PORT score of 236, risk class V) and exacerbation of chronic obstructive pulmonary disease. She was started on empirical treatment with 2 g/day of ceftriaxone. On the following day, clarithromycin (500 mg every 12 hours) was added. Her level of consciousness improved, as did her renal function and leukocyte count.

DISCUSSION An acute phase protein, CRP is generally found at high levels during inflammatory processes of various etiologies, including those of an infectious, autoimmune, or traumatic nature. The protein was

Table 1 – Laboratory tests performed in the Emergency Department Laboratory test

Results

Reference Value

Hemoglobin

11.0

12.3-15.3 g/dl

Hematocrit

36.0-45.0 %

Mean corpuscular volume

80 -96 fl

Mean corpuscular hemoglobin

27.5-33.2 pg

White blood cells

14.7. 10³

4.4-11.3 . 10³/mm³

Bands Segmented neutrophils

10 88

1-5(%) 45 -70 (%)

Platelets

147. 10³

150-400 . 10³ (/mm³)

Urea

105

10-50 (mg/dl)

Creatinin

1.0

0.4-1.3 (mg/dl)

Sodium

126

135-146 (mEq/l)

Potassium

4.6

3.5 -5.0(mEq/l)

Ionized calcium

0.96

1.1-1.4 (mmol/l)

Aspartate aminotransferase

10-35 (U/l)

Alanine aminotransferase

9-43 (U/l)

Prothrombin time (International Normalized Ratio – INR)

1.04

Urinalysis

pH= 5.5 6,000 leukocytes/ml 1,000 erythrocytes/ml

4.7-7.8 < 10000/mm³ < 10000 mm³

Arterial blood gases (room air)

pH = 7.32 pO2 = 32 pCO2 = 61 Bicarbonate = 31 Base Excess = +3.7 Arterial O2 sat = 66

7.34-7.44 75 -100 mmHg 35 -45 mmHg 22-26 mEq/l -3-+2.3 mEq/l 95-98 %

C-reactive protein

149

<5 (mg/l)

first described in 1930, having been isolated from the serum of patients with bacterial pneumonia.1 The physiological role of CRP is related to the ability of the protein to bind to cell wall components of various microorganisms, thus activating the classical complement pathway, acting as an opsonin and promoting phagocytosis.2,3 The determination of serum CRP levels has recently been described as playing a role in the treatment of intensive care unit patients with septic

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Autopsy and Case Reports 2011; 1(4): 3-9

Figure 1 â&#x20AC;&#x201C; Chest X-Ray showing heterogeneous opacity in right lung base and right costophrenic angle blurring, compatible with pneumonia. shock 4,5 and in the prognosis of cardiovascular diseases (when high-sensitivity CRP is assessed),6,7 as well as being a prognostic and diagnostic marker in patients with specific infectious diseases. The use of CRP testing in the follow-up of patients with infectious diseases outside the intensive care setting has yet to be standardized. Although the single determination of serum CRP levels is unexpensive, its indiscriminate use results in high costs, which is why standardization is required.

The Situation at the USPUH The USPUH is a community hospital that is dedicated to the care of ButantĂŁ residents, USP

staff, and USP students. In recent years, the number of requests for determination of serum CRP levels in the USPUH, more specifically in the emergency department and in the clinical ward, has increased considerably. This increase was not accompanied by a proportional increase in the number of consults and hospitalizations. The estimated cost of the reagent for each CRP test in the USPUH is R$9.22 (approximately US$5.00). Taking into account the costs related to the repetition of the test in cases of abnormal results, as well as those related to materials and others, the annual cost of the determination of serum CRP levels is approximately R$330,000.00 (US$185,000.00).

Autopsy and Case Reports 2011; 1(4): 3-9

Gama AP, Santos IS, Olmos RD, Pinto LMO, Benseñor IJM, Lotufo PA.

Here, we present a discussion of two studies that aimed at establishing the potential impact of the determination of serum CRP levels on the evaluation and treatment of patients suspected of having acute community-acquired infection. We also revisit certain clinical epidemiology concepts, which are required in order to interpret the results.

Highlights of our Review of the Literature on the use of CRP as a Marker of Inflammation for Patients in the Emergency Department Study no. 1 - Prognostic value of mortality in emergency department sepsis score, procalcitonin, and C-reactive protein in patients with sepsis at the emergency department8. That study compared the relationship between early mortality (0–5 days) and late mortality (6–30 days) of patients with sepsis initially evaluated in the emergency department. Three different tests, performed at admission to the emergency department, were compared: – determination of serum CRP levels;

times a negative result of a given test is more likely to be found in individuals with a given disease (false negatives) than in those without it. Similarly, the ratio between false negatives and true negatives is calculated (Chart 1). For a test that is more frequently positive in patients with a given disease and more frequently negative in those without it, as is common in clinical practice, the LR+ is a number greater than 1 and the LR– is a number between 0 and 1. A greater distance from the number 1 translates to a greater impact of the test on the clinical reasoning (Chart 1). Table 2 – MEDS scoring system. Adapted form Lee et al.8 Clinical variable

Score

Terminal illness

Tachypnea or hypoxia

Septic shock Platelets <150.000/mm

Bands >5%

Age >65 anos

Low respiratory tract infection

Nursing home resident

Altered mental status

Total

– determination of serum procalcitonin levels; – Mortality in Emergency Department Sepsis (MEDS) score9, a clinical and laboratory scoring system (Table 2). It is clear that the major part of the score (and therefore the greatest weight) is attributed to anamnesis and clinical examination. In addition, the laboratory tests employed (blood workup and, in the presence of signs of respiratory infection, chest X-rays) are those that are habitually ordered in order to evaluate patients with sepsis.

3 3

Chart 1 – How to calculate LR+, LR– and how to interpret test results. Adapted from Hatanaka.10 How to calculate LR+: Probability of positive test in individuals with disease Probability of positive test in individuals without disease How to calculate LR–: Probability of negative test in individuals with disease

The authors determined the cut-off point that was most accurate for each of the three evaluations. Sensitivity and specificity values (described below) were used in that study in order to calculate positive and negative likelihood ratios (LR+ and LR–, respectively). The LR+ expresses how many times a positive result of a given test is more likely to be found in individuals with a given disease than in those without it. The ratio between true positives and false positives is therefore calculated. The LR– expresses how many

Probability of negative test in individuals without disease LR >10.0 or LR< 0.1 Very good test, almost always impacts on clinical judgement LR 5.0-10.0 or 0.1-0.2 Intermediate test value, can impact on clinical judgement LR 2.0-5.0 or 0.2-0.5 Weak test, seldom changes clinical judgement LR 0.5-2.0 Test is incapable of changing clinical judgement, it must not be performed’

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Autopsy and Case Reports 2011; 1(4): 3-9

In clinical epidemiology terms, a greater distance between the LR and the number 1 translates to a greater impact of that result on the likelihood that the patient will have the disease (post-test probability). Fagan’s nomogram is used in order to illustrate this concept, as in our Figure 2. The figure shows the case of a patient who, before the test, has a 10% chance of having the disease (pre-test probability). If that patient undergoes a diagnostic test with a LR+ of 1.5, which confirms that result, the probability of having the disease increases to approximately 14%. However, if the patient undergoes a test with a LR+ of 5 or 15, the post-test probability is 35.7 and 62.5%, respectively. Let us return to study no. 1 8 in order to analyze the results of the comparison between the determination of serum CRP levels and the MEDS score in terms of their performance (Table 3). The determination of serum CRP levels is clearly inferior to the use of the MEDS score. The CRP-related PLR for early mortality has little influence on the evaluation of disease severity. More specifically, a high MEDS score at admission to the emergency department constitutes a far stronger indicator of disease severity and risk of death than do high serum CRP levels. Study no. 2 - Diagnostic value of C reactive protein in infections of the lower respiratory tract: systematic review.11 Study no. 2, published in the British Medical Journal, presents the results of a systematic review of the literature evaluating the diagnostic accuracy of CRP testing in detecting radiologically proved pneumonia, as well as the extent to which the CRP test results can allow the reader to differentiate between viral and bacterial infections of the lower respiratory tract. Regarding the diagnostic accuracy of CRP testing in detecting radiologically proven pneumonia, the authors found six studies, a total

Figure 2 – Fagan’s nomogram. Lines indicate the impact of three tests, with LRs of 1.5 (green), 5.0 (blue) and 15.0 (yellow), on disease probability of a person with a 10% pretest probability.

Table 3 – C-reactive protein determination and MEDS score performances to predict early (0–5 days) and late (6–30 days) mortality in sepsis. Adapted form Lee et al.8 Early Mortality (0–5 days)

Best cut-off value

Sensitivity

Speciﬁcity

LR+

LR–

C-reactive protein

>70 mg.dL–1

73%

63%

1.97

0.43

MEDS score

52%

93%

7.43

0.52

Late Mortality (6–30 days)

Best cut-off value

Sensitivity

Speciﬁcity

LR+

LR–

C-reactive protein

>60 mg.dL–1

64%

58%

1.52

0.62

MEDS score

46%

91%

5.11

0.59

Autopsy and Case Reports 2011; 1(4): 3-9

Gama AP, Santos IS, Olmos RD, Pinto LMO, Benseñor IJM, Lotufo PA.

of 1,178 patients having been evaluated. The determination of CRP levels has little impact on the clinical reasoning involved in the interpretation of infiltration seen on X-rays. For a cut-off point of 20 mg. dL–1 (the point of highest accuracy), the CRP test LR+ (2.86), LR– (0.28), sensitivity (80%), and specificity (72%) were shown to have little impact on clinical practice, and decisions based on those results might lead to errors in a significant number of cases. Eight studies were deemed appropriate to evaluate whether CRP was able to differentiate between viral and bacterial infections of the lower respiratory tract. The studies in question were quite heterogeneous in terms of methodology. The authors concluded that “the current evidence does not consistently and sufficiently support a wide introduction of CRP as a rapid test to guide antibiotics prescription”.

FINAL CONSIDERATIONS In the clinical case reported here, as occurs in many others, the determination of serum CRP levels did not aid in estimating the severity of the condition of the patient or in selecting medical approaches to management. It is of note that neither the decisions that were made nor the outcome would have changed had the test not been ordered. Requests for unnecessary tests result in material and human costs. It is important to maximize efforts to avoid such costs. The responsibility is even greater in the context of a teaching hospital. In addition, the possibility of making decisions based on the result of a laboratory test while there is still insufficient scientific evidence to support its use is a cause for concern. This evidence-based reasoning is quite common when selecting the therapeutic approach to a given patient. However, for some reason, the decision regarding which laboratory tests should be ordered is not always evidence-based. It is incorrect to assume that, unlike the administration of drugs, ordering unnecessary tests is not harmful to patients. False-positive results, which are inherent to any ancillary test, can lead to invasive diagnostic strategies and incorrect treatments. In adults, CRP has certain well-established roles, such as in the outpatient follow-up treatment

of connective tissue diseases and certain chronic infections. In the follow-up of patients with acute infections, CRP plays a potential role in intensive care patients, which is due to the multiple variables involved. Such patients are at risk of developing nosocomial infections, undergo multiple procedures, and are exposed to various factors that can worsen the clinical profile. Nevertheless, serum CRP levels can never be considered in isolation and can be normal even in patients with severe infection, especially at the early stages. For patients admitted to the emergency department or infirmary, where the objective is to diagnose and provide initial treatment for the infection, CRP has little impact on the clinical reasoning. The use of the test can even lead to a false sense of security and deprive patients with bacterial disease of the appropriate treatment. There is also no evidence to support the use of the test in patient follow-up. In addition, it is of note that the first-line treatment for the acute bacterial infections that are most common in clinical practice is likely to yield a favorable result. When this does not occur, clinical signs are generally sufficient to detect treatment failure. The data presented here underscore the need for coordinated efforts in order to rationalize the use of resources. In a teaching hospital, the attending physician has the responsibility of teaching medical students and residents the principles of good medical practice. This includes teaching the value of anamnesis and clinical examination in order to avoid submitting patients to unnecessary tests.

REFERENCES

Tillet WS, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med. 1930;52:561-71. PMid:19869788. PMCid:2131884. http://dx.doi.org/10.1084/jem.52.4.561

Du Clos TW. Functions of C-reactive protein. Ann Med. 2000;32:274-8. PMid:10852144. http://dx.doi. org/10.3109/07853890009011772

Casey R, Newcombe J, McFadden JJ, Bodman-Smith KB. The acute-phase reactant C-reactive protein binds to phosphorylcholine-expressing Neisseria meningitidis and increases uptake by human phagocytes. Infect Immun. 2008;76:1298-304. PMid:18195032. PMCid:2258818. http://dx.doi.org/10.1128/IAI.00741-07

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Povoa P, Coelho L, Almeida E, et al. Early identification of intensive care unit-acquired infections with daily monitoring of C-reactive protein: a prospective observational study. Crit Care. 2006;10:R63. PMid:16635270. PMCid:1550913. http://dx.doi.org/10.1186/cc4892

Lee C-C, Chen S-Y, Tsai C-L, et al. Prognostic value of mortality in emergency department sepsis score, procalcitonin, and C-reactive protein in patients with sepsis at the emergency department. Shock. 2008;29:322-7. PMid:17724429. http:// dx.doi.org/10.1097/SHK.0b013e31815077ca

Fraunberger P, Wang Y, Holler E, et al. Prognostic value of interleukin-6, procalcitonin and c-reactive protein levels in intensive care unit patients during first increase of fever. Shock. 2006;26:10-2. PMid:16783191. http:// dx.doi.org/10.1097/01.shk.0000215319.06866.bd

Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated c-reactive protein. N Engl J Med. 2008;359:2195-207. PMid:18997196. http://dx.doi.org/10.1056/NEJMoa0807646

Carpenter CR, Keim SM, Upadhye S, Nguyen HB. Best Evidence in Emergency Medicine Investigator Group. Risk stratification of the potentially septic patient in the emergency department: the Mortality in the Emergency Department Sepsis (MEDS) score. J Emerg Med. 2009;37:319-27. PMid:19427752. http://dx.doi. org/10.1016/j.jemermed.2009.03.016

Ridker PM, Paynter NP, Rifai N, Gaziano JM, Cook NR. C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds risk score for men. Circulation. 2008;118:2243-51. PMid:18997194. PMCid:2752381. http://dx.doi.org/10.1161/ CIRCULATIONAHA.108.814251

10. Hatanaka VMA, Benseñor IM. Avaliação de testes diagnósticos. In: Benseñor IM, Lotufo PA, editors. Epidemiologia: abordagem prática. 2nd ed. São Paulo: Sarvier; 2011. p. 272-302. Portuguese. 11. Van der Meer V, Neven AK, Van Den Broek PJ, Assendelft WJJ. Diagnostic value of C reactive protein in infections of the lower respiratory tract: systematic review. Br Med J. 2005;331:26. http://dx.doi.org/10.1136/bmj.38483.478183

Conflict of interest: None Submitted on: 18th October 2011 Accept on: 24th October 2011 Correspondence: Alcino Pires Gama Rua Ovídio Pires de Campos, 171/217 – Cerqueira Cesar - São Paulo - SP – Brazil CEP: 05403-010 – Phone: +55 (011) 7039-1514 E-mail: alcinopires@yahoo.com.br

Autopsy and Case Reports 2011; 1(4): 11-20

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Acute erythroid leukemia: autopsy report of a rare disease Cristiane Rúbia Ferreiraa, Fabiana Roberto Limaa, Edna Harumi Gotob, Elizabeth In Myung Kimb, Luciana Andréa Avena Smeilib, Fernando Peixoto Ferraz de Camposb, Maria Claudia Nogueira Zerbinic Ferreira CR, Lima FR, Goto EH, et al. Acute erythroid leukemia: autopsy report of a rare disease. Autopsy Case Rep [Internet]. 2011;1(4):11-20. http://dx.doi.org/10.4322/acr.2011.012

ABSTRACT Acute erythroid leukemia (AEL) is a rare subtype of acute myeloid leukemia (AML), characterized by predominant erythroid proliferation. The 2008 World Health Organization (WHO) classification of AML defined two AEL subtypes: erythroleukaemia (EL), in which erythroid precursors account for 50% or more of all nucleated bone marrow cells and myeloblasts account for 20% or more of the nonerythroid cell population; and pure erythroid leukemia (PEL), in which erythroid precursors account for 80% or more of all nucleated bone marrow cells. We report the case of an elderly female patient with wasting syndrome and pancytopenia without evidence of blasts in peripheral blood. A diagnosis of PEL was established on the basis of bone marrow biopsy findings. The patient died on postadmission day 20, and an autopsy was performed. We reclassified the disease as EL on the basis of the autopsy findings, which included myeloblasts accounting for more than 20% of the nonerythroid cells in the bone marrow, as well as leukemic infiltration and myeloid metaplasia in solid organs, such as the liver, spleen, kidneys, adrenal glands, and abdominal lymph nodes. A rare disease, AEL accounts for less than 5% of all AMLs and is practically a diagnosis of exclusion. Autopsy reports of AEL are extremely rare in the literature. We demonstrate that in the case reported here, leukemia cells tended to infiltrate solid organs with myeloid metaplasia. Our findings also show that a larger neoplastic bone marrow sample is crucial to the correct diagnosis of EL, which is based on morphological and quantitative criteria. Keywords: Leukemia; Leukemia erythroblastic acute; Autopsy. CASE REPORT Clinical Case An 86-year-old Black female patient sought medical attention with a 1-month history of generalized muscle weakness, dyspnea on minimal exertion, adynamia, apathy, loss of appetite, and depressed

mood, all of which coincided with the death of a son. She had also had episodes of diarrhea accompanied by weight loss, having lost approximately 5 kg during that same period.

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

Ferreira CR, Lima FR, Goto EH, et al.

Autopsy and Case Reports 2011; 1(4): 11-20

The patient reported that she had been diagnosed with anemia of unknown etiology 6 years prior, having once received blood transfusion but never having been treated with erythropoietin. She stated that she had never been diagnosed with or treated for any type of neoplasia. She had a history of diabetes mellitus (DM) and hypothyroidism, as well as a more than 30-year history of arterial hypertension (for which she had been under clinical treatment), together with a history of coronary heart disease, having undergone myocardial revascularization 7 years prior. She had been under treatment with metformin, gliclazide, levothyroxine, enalapril, amlodipine, cilostazol, and sertraline. The patient had been smoking hand-rolled cigarettes for 30 years.

syndrome, with a focus on hematologic malignancy and solid tumors.

Physical examination at admission revealed normal respiration, pallor, poor general health status, and a body weight of 46 kg. She presented with a heart rate of 72 bpm, a respiratory rate of 20 breaths/minutes, and a blood pressure of 134/56 mmHg. In addition, she presented with no edema, jugular stasis, or peripheral lymph node enlargement. Endoscopy revealed oral candidiasis. Although pulmonary auscultation revealed no abnormalities, cardiac auscultation revealed rhythmic heart sounds with aortic and mitral systolic murmur. The abdomen was normal, and abdominal palpation revealed no organomegaly. Neurological examination revealed no abnormalities. The clinical investigation was based on a working diagnosis of wasting

A blood workup was performed and revealed normocytic anemia, thrombocytopenia, and leukoerythroblastic reaction. Urinalysis revealed mild proteinuria with hyaline and granular casts. Serology for HIV, hepatitis B, and hepatitis C was negative. Serum levels of vitamin B12, folic acid, and iron were normal, as were those of the tumor markers carcinoembryonic antigen, cancer antigen 125, and cancer antigen 19-9. Upper gastrointestinal endoscopy revealed erosive antral gastritis. A computed tomography (CT) scan of the abdomen and pelvis revealed mild splenomegaly and atheromatous aorta. A CT scan of the chest revealed atheromatous aorta, normal lung parenchyma, and no lymph node enlargement. An echocardiogram showed mild left

During her hospital stay, the patient presented with loss of appetite, frequent nausea, diarrhea, and hematochezia. Despite low food intake, there was no additional weight loss. Sigmoidoscopy revealed moderate proctitis with signs of bleeding. During the sigmoidoscopy, a rectal biopsy was performed. Histopathological examination of the biopsy specimen revealed mild inflammatory infiltrate composed of lymphomononuclear cells in the superficial layer of the colonic mucosa, with reactive intestinal crypts. The results of the laboratory tests performed are shown in Table 1.

Table 1 – Laboratory test results Test

Measure

Value

Reference

Test

Measure

Value

Reference

Hemoglobin

g.dL–1

9.7

12.3-15.3

Creatinine

mg.dL–1

2.2

0.4-1.3

Hematocrit

36.0-45.0

Urea

mg.dL

121

10-50

MCV

80-96

Ionized calcium

mmol.L mEq.L

–1

1.14

1.15-1.35

–1

132

136-146

mEq.L–1

4.2

3.5-5.0

10-31

–1

RDW

16.1

11-16

Sodium

Leukocytes

mm3

9,000

4.4-11.3 × 103

Potassium

Myelocytes

AST

U.L

Metamyelocytes

ALT

U.L

9-36

U.L

1445

10-100

0.3

0.3-1.2

5.8

6.0-8.0

2.5

3.0-5.0

–1 –1

Band neutrophils

1-5

ALP

Segmented neutrophils

46-75

Total bilirubin

Eosinophils

1-4

Total proteins

g.dL

–1

Basophils

0-2.5

Albumin

g.dL

–1

Lymphocytes

18-40

DHL

U.L

Monocytes

2-9

TSH

Platelets

mm3

80,000

150-400 × 103

Prothrombin time

–1

mg.dL–1

3300

120-246

µUI.L

2.55

0.55-4.78

INR

1.23

–1 –1

MCV, mean corpuscular volume; RDW, red cell distribution width; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; TSH, thyroid stimulating factor; INR, international normalized ratio.

Acute erythroid leukemia: autopsy report of a rare disease

ventricular hypertrophy, inferior wall hypokinesia, mitral insufficiency, and aortic stenosis. There was a progressive decrease in leukocyte and platelet counts (which dropped to 1,100 and 5,000 cells.mm–3, respectively), accompanied by a worsening of renal function. After a failed bone marrow (BM) aspiration (i.e., a “dry tap”), the patient underwent BM biopsy, which revealed extensive infiltration of the BM by aggregates of large, atypical cells (approximately 70%), the immunophenotype of which was consistent with that of cells of the erythroid lineage (positive for glycophorin A and partially positive for CD117); other findings included extensive areas of necrosis, numerous mitotic figures, and markedly reduced BM reserve (Figure 1). Those findings were consistent with a diagnosis of pure erythroid leukemia (PEL), in accordance with the World Health Organization (WHO) classification of acute myeloid leukemia (AML),1 or M6, in accordance with the French-American-British (FAB) classification.2 Despite the supportive treatment administered, the patient presented with progressive worsening of overall health status, decreased hemoglobin levels (having received a transfusion of packed red cells), dyspnea, abdominal distension, and altered level of

Autopsy and Case Reports 2011; 1(4): 11-20

consciousness. The patient died on postadmission day 20, and an autopsy was performed.

Autopsy Findings The abdominal and thoracic cavities were opened, revealing no ectopia or effusion. There was mild hepatomegaly, the liver weighing 2,100 g (reference value, 1,400-1,600 g). On sectioning, the liver parenchyma had a mottled appearance, suggestive of passive congestion, with no evidence of nodular areas. The spleen showed a slight increase in volume (weight, 239 g; reference value, 150-250 g), the splenic parenchyma was homogeneous, as well as being wine-red on sectioning. The kidneys (right kidney weight, 180 g; left kidney weight, 200 g; reference value, 115-155 g) had a granular outer surface and an appearance typical of renal vascular disease, with multiple retention cysts of less than 1.0 cm in diameter. In the right kidney, we found a solid, yellowish nodule of 1.0 cm in diameter in the cortical region. The heart (weight, 385 g; reference value, 275 ± 75 g) showed fibrous adhesions to the pericardium. On sectioning, revealed left ventricular hypertrophy, the anterior wall of the left ventricle

Figure 1 – Photomicrographs of bone marrow biopsy findings: A- bone marrow with increased cellularity and infiltration by immature erythroid cells (some binucleated) with voluminous nuclei, prominent nucleoli, and basophilic cytoplasm (hematoxylin and eosin [H&E]; magnification, ×100); B- extensive area of coagulative necrosis of neoplastic cells (H&E; magnification, ×200); C- immature erythroid cells diffusely positive for glycophorin A (immunohistochemistry [IHC]; magnification, ×100); D- CD117-positive (IHC; magnification, ×200); E- cells of the granulocytic series focally positive for myeloperoxidase (IHC; magnification, ×100); and F- CD34 positivity in blasts (in the topography of myeloperoxidase-positive cells) and in small vessels (IHC; magnification, ×400).

Autopsy and Case Reports 2011; 1(4): 11-20

Ferreira CR, Lima FR, Goto EH, et al.

Figure 2 – Panoramic view of solid organs and the heart: A- liver parenchyma with a mottled appearance, suggestive of passive congestion; B- homogeneous, wine-red splenic parenchyma; C- right and left kidneys with granular surface and retention cysts; and D- heart, showing fibrous adhesions to the pericardium. showing a whitish area, which was suggestive of prior myocardial infarction (Figure 2). In the right lung (right lung weight, 355 g; reference value, 450 g—left lung weight, 295 g; reference value, 375 g), we identified a small, redwine colored nodule measuring 0.5 cm in diameter. We opened the gastrointestinal tract and found hyperemia of the rectal mucosa. The aorta was affected by severe atherosclerosis. No uterus was found. Microscopic examination of the BM from iliac crests and right and left ribs revealed extensive necrotic areas, interspersed with areas of infiltration by atypical undifferentiated cells with large nuclei and prominent nucleoli, sometimes binucleated and had a basophilic cytoplasm (about 80% of the nucleated cells). Residual hematopoietic tissue was represented by cells of the granulocytic lineage, with evident delay in maturation and very few megakaryocytes. Immunohistochemical analysis revealed that the immunophenotype of the atypical undifferentiated cells was similar to that of those analyzed after the BM biopsy, i.e., glycophorin A-positive and CD117-positive, as well as CD34-negative. The immunophenotype of

the granulocytic series was myeloperoxidase (MPO)positive and CD117-positive, as well as positive coexpression of CD34 (in 20-30% of the nucleated cells), showing the presence of myeloblasts in more than 20% of the nonerythroid nucleated cells (Figure 3). The malignancy was reclassified as acute erythroid leukemia (AEL) of the erythroleukaemia (EL) subtype (also known as erythroid/myeloid), in accordance with the WHO classification.1 Immunohistochemistry revealed membrane positivity for E-cadherin in very few of the cells of the BM biopsy, namely in those that were large and immature (Figure 4). In contrast, E-cadherin immunohistochemistry examination of the BM sections obtained during the autopsy revealed no such evidence. The solid organs, namely the liver, spleen, kidneys, adrenal glands, and abdominal lymph nodes, were found to be infiltrated by leukemia cells. The infiltration was accompanied by myeloid metaplasia, which was particularly evident in the spleen and liver. We also found severe megakaryocyte atypia,

Acute erythroid leukemia: autopsy report of a rare disease

Autopsy and Case Reports 2011; 1(4): 11-20

Figure 3 – Photomicrographs of autopsy findings in bone marrow: A- bone marrow with increased cellularity and infiltration by immature erythroid cells (hematoxylin and eosin [H&E]; magnification, ×100); B- immature erythroid cells (some binucleated) with voluminous nuclei, prominent nucleoli, and basophilic cytoplasm (H&E; magnification, ×200); C- immature erythroid cells diffusely positive for glycophorin A (immunohistochemistry [IHC]; magnification, ×100); D- medium-sized immature myeloid cells within sinusoids (H&E; magnification, ×200); E- myeloperoxidase-positive immature myeloid cells predominantly within sinusoids (IHC; magnification, ×200); and F- positivity for CD34 in blasts (in the topography of myeloperoxidase-positive cells) and in small vessels (IHC; magnification, ×400).

Figure 4 – Photomicrographs of bone marrow biopsy sample: A and B- very few cells (large and immature) showing positivity for E-cadherin (immunohistochemistry; magnification, ×400). including some with with multilobulated nuclei and coarse chromatin (Figures 5, 6, and 7). The nodule in the right lung represented diffuse alveolar damage. In the renal parenchyma, we found retention cysts and mesangioproliferative glomerulonephritis secondary to DM, as well as a small renal clear cell carcinoma in the 1 cm right kidney nodule described above.

DISCUSSION The pure erythroblast proliferation is very rare. AEL accounts for less than 5% of all AMLs.1 The diagnosis of AEL has been controversial since the initial concepts of the entity were first described by Di Guglielmo, in mid-1917. Di Guglielmo described two forms of the disease, namely erythremic myelosis (the more common form) and acute erythremia.2,3 In

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Ferreira CR, Lima FR, Goto EH, et al.

Figure 5 – Photomicrographs of the spleen: A- red pulp of the spleen infiltrated by immature erythroid cells, with atypical megakaryocytes (hematoxylin and eosin [H&E]; magnification, ×100); B- immature erythroid cells, with atypical megakaryocytes (H&E; magnification, ×200); C- immature erythroid cells (some binucleated) with voluminous nuclei, prominent nucleoli, and basophilic cytoplasm (H&E; magnification, ×200); and D- red pulp of the spleen showing myeloid metaplasia, represented by atypical megakaryocytes and erythroid cell colonies (H&E; magnification, ×200). 1976, and again in a revision made in 1985, the FAB Cooperative Group classified AEL as M6, a subtype of AML characterized by erythroblasts accounting for 50% or more of all BM hematopoietic cells and myeloblasts accounting for 30% or more of all nonerythroid cells.4,5 Some authors have informally expanded the category to include subtypes M6a (EL) and M6b (PEL).6-8 The 2001 WHO classification of AML officially recognized PEL by dividing AEL into two subtypes: EL (erythroid precursors accounting for at least 50% of the entire BM cell population and myeloblasts accounting for at least 20% of the nonerythroid cell population); and PEL (immature erythroid cells accounting for at least 80% of all BM cells, with no evidence of a significant myeloblastic component).9 Although the 2008 WHO classification of AML was essentially the same as the previous classification, stricter criteria were established, entities such as AML with myelodysplasia-related changes (an entity that can present with erythroid predominance and that now comprises cases with 20% or more blasts and dysplasia involving at least 50% of cells

of two or more lineages) and therapy-related AML having been created.1 We reported the case of an elderly female patient who presented with wasting syndrome and pancytopenia. On the basis of BM biopsy findings, we established an initial diagnosis of PEL. The analysis of a much larger BM sample during autopsy revealed that myeloblasts accounted for more than 20% of the nonerythroid cell population. This led us to establish a final diagnosis of EL. Although the understanding of AEL has increased over the years, the diagnostic criteria established in the AML classifications proposed by the FAB Cooperative Group4,5 and the WHO1,9 have always been based on morphological, quantitative, and immunophenotypic parameters, genetic markers having yet to be defined.6 The diagnostic criteria for AEL established in the latest WHO classification of AML1 are far stricter than were those established in previous

Acute erythroid leukemia: autopsy report of a rare disease

Autopsy and Case Reports 2011; 1(4): 11-20

Figure 6 – Photomicrographs of the liver: A and B- liver parenchyma with leukemic infiltration in sinusoids and portal tracts (hematoxylin and eosin [H&E]; magnification, ×100); C- leukemic infiltration in hepatic sinusoids, with atypical megakaryocytes and focal myeloid metaplasia (H&E; magnification, ×200); and Dleukemic infiltration in portal tract, with immature erythroid cells (H&E; magnification, ×200). classifications. According to the current WHO criteria, a history of myelodysplastic syndromes, myeloproliferative disorders, exposure to toxins such as benzene, cancer chemotherapy, immunotherapy, radiation therapy, or erythropoietin therapy rules out AEL.1,6 Such cases are currently diagnosed as AML with myelodysplasia-related changes or as therapy-related AML; this has significantly reduced the number of cases of AEL, which has practically become a diagnosis of exclusion.1,10 Although our patient presented with multiple comorbidities, she had no history of cancer treatment or diagnosis of myelodysplastic syndromes, her 6-year history of chronic anemia being possibly related to her chronic kidney disease and DM. The etiology of AEL is unknown, and its risk factors have yet to be identified.6 The disease principally affects adults (mean age, 50 years), manifesting as nonspecific clinical symptoms (including pallor, fever, and anemia), and varying degrees of leukopenia and thrombocytopenia, hepatosplenomegaly being observed in up to one third of patients. The diagnosis of AEL is typically

made within the first 3 months after a patient begins to report signs and symptoms.6,11 It is of note that, upon physical examination, our patient presented with no lymph node enlargement or organomegaly. However, mild splenomegaly was revealed by a CT scan of the abdomen. The autopsy revealed mild hepatosplenomegaly with leukemic infiltration, which also affected abdominal lymph nodes and other solid organs. This suggests that the tendency of neoplastic erythroblasts to involve solid organs is being underestimated, as has been reported by other authors.11 Also of note was the presence of myeloid metaplasia in the spleen and liver, a result of poor BM reserve. Myeloid metaplasia has been described in association with other BM diseases, especially myelofibrosis.12 We also found severe megakaryocyte atypia in the solid organs infiltrated by leukemia cells. Dysplastic megakaryocytes (or granulocytes) are more common and more significant in EL than in PEL.6 In cases of AEL, peripheral blood smears can show only cytopenias, with no evidence of blasts, which contributes to the difficulty in diagnosing the disease. Therefore, in order to establish a diagnosis of

Autopsy and Case Reports 2011; 1(4): 11-20

Ferreira CR, Lima FR, Goto EH, et al.

Figure 7 – Photomicrographs of the kidney and abdominal lymph node: A- renal parenchymal infiltration by immature myeloid cells (hematoxylin and eosin [H&E]; magnification, ×200); B- immature erythroid cells in the lumen of capillary vessels (H&E; magnification, ×200); C- lymph node infiltrated by immature erythroid cells, with atypical megakaryocytes in the subcapsular sinus (H&E; magnification, ×100); and D- immature erythroid cells and atypical megakaryocytes in the subcapsular sinus (H&E; magnification, ×200).

AEL, morphological examination of the BM specimens obtained by BM aspiration and biopsy, as well as a full panel of antibodies for leukemia immunophenotyping and exclusion of differential diagnoses, is needed.6 Immunophenotyping of AEL is best performed by flow cytometry of BM aspirates. However, in the case reported here, the diagnosis was established by immunohistochemical analysis of the BM biopsy specimen. This was due to a dry tap, which in turn was due to extensive necrosis. Immunohistochemistry reveals erythroblasts that are positive for glycophorin A and sometimes for CD117, similar to the normal pronormoblast population and the precursor cells of the granulocytic series in the BM.6 In cases of AEL, principally in those of the PEL subtype, the blasts are often negative for all erythroid-associated antibodies assessed by immunohistochemistry because many of the target antigens require some degree of erythroid maturation to be expressed, or a very dim expression may be detectable by immunohistochemistry.6

In the case reported here, immunohistochemical analysis of the BM biopsy specimen revealed an immature erythroid population with the following immunophenotype: glycophorin A-positive/CD117positive/CD34-negative/MPO-negative. The severe cytologic atypia, together with the formation of large cell aggregates, some of which were completely necrotic, were morphologically suggestive of metastatic epithelial cancer or high-grade non-Hodgkin’s lymphoma. Those hypotheses were ruled out by negativity for epithelial and lymphoid markers, as determined by immunohistochemistry. The evaluation of the BM sample obtained during the autopsy, a sample with greater representation of the hematopoietic tissue, revealed a significant quantity of blasts of the granulocytic lineage, the phenotype of which was diffusely positive for MPO/CD117 and focally positive for CD34 (>20% of nonerythroid nucleated cells). Those findings met the criteria for a diagnosis of EL. The immunohistochemical analysis of solid organs, such as the liver and spleen, revealed low or absent expression of glycophorin A in the immature erythroid

Acute erythroid leukemia: autopsy report of a rare disease

Autopsy and Case Reports 2011; 1(4): 11-20

cells (CD117-positive/MPO-negative), suggestive of undifferentiated neoplastic erythroblasts.

warrant a relocation of the case to another diagnostic category, AEL being the most likely diagnosis.

Liu et al.13 recently reported that, among the hematopoietic lineages, E-cadherin was apparently specific to the immature erythroid lineage, with weak to strong membrane positivity in most erythroblasts in PEL and only small positive groups in EL, suggesting that the association between the markers E-cadherin and glycophorin A is useful in distinguishing between mature and immature precursors in BM biopsy specimens analyzed by immunohistochemistry. In the case reported here, the erythroid precursor population was not diffusely positive for E-cadherin. Few of the cells in the BM biopsy specimen were positive for E-cadherin, whereas all of the cells in the BM sample collected during autopsy were negative for E-cadherin. Maybe this finding supports the diagnosis of EL.

In some cases, peripheral blood smears show only nonspecific cytopenias and not circulating blasts. Similarly, BM aspirate smears can be inconclusive because of hypocellularity, which is related to necrosis, cell fragility, or fibrosis. Therefore, in such cases, pathologists should establish the definitive diagnosis of AEL by examining the BM biopsy specimen.6 We emphasize the need for include the markers of hematologic lineages in malignancies with severe atypia in which the markers of primary metastatic sites are negative in BM samples and in samples from other organs.

The differential diagnosis of AEL includes benign and malignant entities. As previously discussed, the diagnostic criteria for AEL established in the current WHO classification of AML1 include the need to rule out myelodysplastic syndromes (on the basis of patient history or cytogenetic abnormalities), erythropoietin therapy, and previous cancer treatment. In addition, in the presence of undifferentiated erythroblasts (as determined by morphological evaluation), the differential diagnosis should include lymphoma, myeloma/plasmacytoma, and other forms of leukemia, such as acute megakaryoblastic leukemia. Furthermore, cases of PEL are reported with partial expression of CD41 or CD61; whether these cases are better classified as acute mixed erythroid-megakaryoblastic leukemia or not is uncertain.6 A number of non-neoplastic diseases can cause erythroid predominance in the BM and therefore must be excluded before the diagnosis of AEL can be established; among the most common nonneoplastic disorders that need to be excluded before the diagnosis of AEL is established is megaloblastic anemia due to nutritional deficiency of vitamin B12 or folate.1,6 In the case reported here, we believe that the combination of severe atypia with necrosis and numerous mitoses (as revealed by examination of the BM biopsy specimen) left no doubt as to the diagnosis of malignancy. The confirmation of the erythroid lineage and the exclusion of other lineages by the immunohistochemical panel were essential in order to establish the diagnosis. Although the dry tap prevented us from performing cytological examination of the BM aspirate, there were no clinical findings to

The prognosis of AEL is unfavorable. The clinical behavior of the disease is aggressive, the mean reported survival ranging from 1.5 months to 19 months.10,11 The presence of cytogenetic abnormalities has recently been reported to correlate with clinical and biological characteristics, as well as with survival and treatment response. Patients with AEL with a complex karyotype have a worse prognosis.10,14 Here, we described the BM biopsy findings and autopsy findings in an elderly female patient with a diagnosis of AEL of the EL subtype. Autopsy reports of AEL are extremely rare in the literature in English.11,15 The new, stricter, criteria established in the latest WHO classification of AML1 will certainly contribute to a deeper understanding of AEL and allow future molecular biology studies to define molecular markers of AEL. We emphasize that the collection of a larger BM sample plays an important role in the diagnosis of AEL, given that the disease can display an aggressive behavior, with infiltration of multiple organs, as observed in the case reported here.

ACKNOWLEDGEMENTS We are grateful to Rosa Maria C. Zanardi for the technical support on the visual work.

REFERENCES 1.

Arber DA, Brunning RD, Orazi A, et al. Acute myeloid leukemia, not otherwise specified. In: Swerdlow SH, Campo E, Harris NL, et al., editors. Tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. p.134-6. World Health Organization Classification of Tumors; vol. 2.

Ferreira CR, Lima FR, Goto EH, et al.

Autopsy and Case Reports 2011; 1(4): 11-20

Di Guglielmo G. Eritremie acute. Roma: Atti Congr. Ataliano Med. Int.; 1923.

Dameshk W, Baldini M. The di Guglielmo syndrome. Blood. 1958; 13:192-4. PMid:13510296.

Bennett JM, Catovsky D, Daniel MT, et al. Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French-American-British Cooperative Group. Ann Inter Med. 1985; 103:620-5. PMid:3862359.

Bennett JM, Catovsky D, Daniel MT, et al. Proposal for classification of the acute leukemia: French-AmericanBritish co-operative Group. Br J Haematol. 1976; 33:451-8. PMid:188440. http://dx.doi.org/10.1111/j.1365-2141.1976. tb03563.x

Zuo Z, Polski JM, Kasyan A, Medeiros LJ. Acute erytroid leukemia. Arch Pathol Lab Med. 2010; 134:1261-70. PMid:20807044.

Mazzella FM, Kowal-Vern A, Shrit MA, et al. Acute erythroleukemia: evaluation of 48 cases with reference to classification, cell proliferation, cytogenetics, and prognosis. Am J Clin Pathol. 1998; 110:590-8. PMid:9802343.

Kowal-Vern A, Mazzella FM, Cotelingam JD, Shrit MA, Rector JT, Schumacher HR. Diagnosis and characterization of acute erythroleukemia subsets by determining the percentages of myeloblasts and proerythroblasts in 69 cases. Am J Hematol. 2000; 65:5-13. http://dx.doi.org/10.1002/10968652(200009)65:1%3C5::AID-AJH2%3E3.0.CO;2-U

Brunning RD, Matutes E, Flandrin G, et al. Acute myeloid leukemia not otherwise categorized. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. Pathology and genetics

of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2001. p. 97-9. World Health Organization Classification of Tumors; vol. 3. 10. Kasyan A, Medeiros LJ, Zuo Z, Santos FP, et al. Acute erytroid leukemia as defined in the World Health Organization classification is a rare and pathogenetically heterogeneous disease. Mod Pathol. 2010; 23:1113-26. PMid:20473273. http://dx.doi.org/10.1038/modpathol.2010.96 11. Hasserjian RP, Howard J, Wood A, Henry K, Bain B. Acute erythremic myelosis (true etythroleukemia): a variant of AML FAB-M6. J Clin Pathol. 2001; 54:205-9. PMid:11253132. PMCid:1731380. http://dx.doi.org/10.1136/jcp.54.3.205 12. Abdel-Wahab OI, Levine RL. Primary myelofibrosis: update on definition, pathogenesis, and treatment. Annu Rev Med. 2009; 60:233-45. PMid:18947294. http://dx.doi. org/10.1146/annurev.med.60.041707.160528 13. Liu W, Hasserjian RP, Hu, Y, et al. Pure erytroid leukemia: a reassessment of the entity using the 2008 World Health Organization classification. Mod Pathol. 2011; 24:375-83. PMid:21102413. http://dx.doi.org/10.1038/modpathol.2010.194 14. Santos FPS, Faderl S, Garcia-Manero G, et al. Adult acute erythroleukemia: na analysis of 91 patients treated at a single institution. Leukemia. 2009; 23:2275-80. PMid:19741728. http://dx.doi.org/10.1038/leu.2009.181 15. Reiffers J, Bernard P, Larrue J, et al. Acute erythroblastic leukemia presenting as acute undifferentiated leukemia: a report of two cases with ultrastrutural features. Leuk Res. 1985; 9:413-20. http://dx.doi.org/10.1016/01452126(85)90064-5

Conflict of interest: None Submitted on: 22th October 2011 Accept on: 31th October 2011 Correspondence: Serviço de Anatomia Patológica – Hospital Universitário USP Av. Prof. Lineu Prestes, 2565, - Cidade Universitária - São Paulo/SP - Brazil CEP: 05508-900 – Phone: +55 (11) 3091-9384 E-mail: crisrf@hu.usp.br

Autopsy and Case Reports 2011; 1(4): 21-27

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia An inferior sinus venosus interatrial communication associated with a secundum atrial septal defect, clinically presenting in an adult patient: autopsy report Silvana Maria Lovisoloa, Vera Demarchi Aiellob, Fernando Peixoto Ferraz de Camposc Lovisolo SM, Aiello VD, Campos FPF. An inferior sinus venosus interatrial communication associated with a secundum atrial septal defect, clinically presenting in an adult patient: autopsy report. Autopsy Case Rep [Internet]. 2011;1(4):21-27. http://dx.doi.org/10.4322/acr.2011.013

ABSTRACT Atrial septal defects (ASD) are the most common congenital cardiac lesion in adults, representing up to 40% of acyanotic shunt lesions in patients older than 40 years. Secundum ASD comprises defects in the area of the oval fossa, and may be associated with other types of interatrial communications. We present a case of a 25 year-old female patient who was asymptomatic until the age 22 when she started presenting exertion dyspnea and lower limbs edema, during her third pregnancy. The patient was admitted in the emergency department because of a febrile respiratory distress syndrome dying in less than 36 hours after her arrival. The autopsy examination revealed pneumonia and a secundum ASD, associated with a rare form of interatrial communication, the inferior sinus venosus defect, which is characterized by an anomalous connection of the right pulmonary veins to the inferior caval vein at its opening in the right atrial cavity, while retaining partially their connection to the left atrium. A dysplastic and thickened mitral valve was also present. Signs of pulmonary hypertension confirm the Eisenmenger syndrome in this adult patient. Keywords: Congenital heart defects; Atrial septal defect sinus venosus; Heart septal defects; Atrial; Pulmonary hypertension; Pneumonia; Autopsy. CASE REPORT A 25 year-old female patient sought the emergency department complaining of dyspnea and cough for several months aggravated in the last three days when she began to present purulent sputum with bloody traces and daily fever of 38 °C. She had been presenting progressive dyspnea, orthopnea, increased abdominal volume and edema of lower limbs for the last three years. She started looking

for medical care one year after the initial symptoms when a cardiopathy was diagnosed and a heart surgery indicated at her local State of origin, but not performed due to the delay in scheduling. The patient lived in the interior of a northeastern state of Brazil far from a tertiary hospital. She denied any morbidity or physical limitation during childhood and adolescence. Her obstetrical history included

Anatomic Pathology Service - Hospital Universitário, Universidade de São Paulo, São Paulo/SP - Brazil. Laboratory of Pathology - Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo/SP - Brasil. c Department of Internal Medicine - Hospital Universitário, Universidade de São Paulo, São Paulo/SP - Brazil. a b

Lovisolo SM, Aiello VD, Campos FPF.

Autopsy and Case Reports 2011; 1(4): 21-27

three pregnancies and the symptoms began during the last gestation. On admission the patient was agitated, confused, presenting dyspnea, tachycardia, cyanosis, and was emaciated. Vital signs were: respiratory rate = 27 bpm, pulse rate = 120 bpm, blood pressure = 96 × 60 mmHg, temperature = 35.5 °C, oximetry = 65%. The pulmonary auscultation revealed the presence of rales in the left base, the precordium examination showed systolic thrill on the left sternal border. The cardiac sounds were rhythmic with loud S2, S3 present and a marked murmur was audible on the tricuspid area. The abdominal examination showed hepatomegaly and percussion was dull on the Traube’s space. Lower limb edema was present. Laboratory tests are shown in Table 1 and the electrocardiogram in Figure 1. The patient was initially treated with oxygen by Venturi mask followed by endotracheal intubation and mechanical ventilation, ceftriaxone and clarithromycin were prescribed considering the possibility of pneumonia. The hemodynamic instability was treated with saline volume expansion followed by intravenous vasoactive drugs. Despite the adopted treatment the patient died on the second day of hospitalization. An echocardiogram performed on admission with the patient on sitting position showed: aorta = 28 mm, left atrium = 30 mm, ventricular septum = 8 mm, posterior wall = 7 mm, left ventricle ejection fraction = 60%. There was also significant increase in the size of the right atrium and ventricle, hypokinetic right ventricle, mitral valve degeneration with prolapse and mild regurgitation, tricuspid valve reflux with important right ventricle-right atrium pressure gradient = 140 mmHg. The blood sample collected at admission showed growth of Streptococcus pneumoniae.

The autopsy findings showed an emaciated woman with signs of growth impairment, mild cyanosis and lower limb edema. The heart was enlarged, weighed 702 g (normal range, 248-431 g), and showed usual atrial arrangement, with concordant atrioventricular and ventriculo-arterial connections. There was massive enlargement of the right-sided cardiac chambers, with severe dilation and hypertrophy of the right ventricle. Examining the right atrial septal surface we detected a huge ASD located in the area of the oval fossa (secundum atrial septal defect). There was also an additional interatrial communication situated postero-inferiorly, close to the opening of the inferior caval vein into the right atrium, and where the right pulmonary veins were connected (Figures 2a and 2b). These veins retained, partially, their connection to the postero-inferior wall of the left atrium. The left atrium was small, receiving also the two left pulmonary veins, which were far from the sinus venosus defect. The mitral valve showed moderate thickening of the leaflets, mainly the anterior one, besides fusion of the postero-medial comissure and thick chordae. The left ventricle was normal in size. A schematic view of the heart with the anomalous connection of the right pulmonary veins and with a secundum atrial septal defect is exemplified in Figure 3. The right and left lungs weighed 935 and 850 g respectively (normal range, 360-570

Table 1 – Laboratory analysis on admission Exam

Un.

Result

Ref.V

Exam

Um.

Result

Ref.V

–1

14,8

12,3-15,3

RCP

ng.mL

334

36,0-45,0

Creatinine

mg.dL–1

1,0

0,4-1,3

3600

4,4-11,3 .10

mg.dL

10-50

Hemoglobin

g.dL

Hematocrit

Leukocytes

Metamyelocytes bastonetes segmentados

% % %

2 21 65

0 1-5 45-70

Lactate

mg.dL–1

46,1

4,5-19,8

Eosinophils

1-4

AST

U.L–1

10-31

Basophils

0-2,5

ALT

U.L–1

9-36

Linfocytes

18-40

Protrombine T (INR)

1,98

Monocytes

2-9

7,14

7,34 - 7,44

Platelets

/mm3m3

2110000

150-400.103

HCO3

22-26

–1

BUN

–1

mEq.L–1

Un. = unit, Ref.V = reference value, RCP = reactive C protein, BUN = blood urea nitrogen, AST = aspartate transaminase, ALT = alanine transaminase.

An inferior sinus venosus interatrial communication associated...

Autopsy and Case Reports 2011; 1(4): 21-27

and 325-480 g). The microscopic examination revealed diffuse infiltration of neutrophils filling the alveolar spaces accompanied by hemorrhagic and edematous areas with considerable destruction of alveolar septa (Figure 4) configuring the histological picture of bronchopneumonia; and thickening of the fibromuscular layer of the pre and intra-acinar peripheral pulmonary arteries (Figure 5) representing chronic pulmonary hypertension.

compatible with right sided heart failure, and peri-central

The liver weighed 1560 g (normal range 13302100 g) and showed chronic passive congestion

The gross and microscopic examinations of

hemorrhagic foci due to septicemia and shock. Systemic findings of sepsis and shock were also observed in other organs as acute reactive splenitis, renal tubular acute necrosis and hemorrhagic foci of cortical adrenal glands.

the other organs were unremarkable.

Figure 1 - Electrocardiogram showing sinus rhythm, heart = 120 bpm, PRi = 0,16 m.s–1, QRS axis +120°, rSr’ morphology compatible with right ventricle hypertrophy, and signs of left atrium enlargement (p wave negative in V1).

Figure 2 – Septal surface seen from the right atrium showing the abnormal insertion of the RPV at the mouth of the ICV and the interatrial communication which inferior border is marked by the dotted line. In B panel a closer view depicts the opening of the RPV. (RPV = right pulmonary veins; ICV = inferior caval vein; CS = coronary sinus; SD = secundum defect, in A* shows the opening o ICV.

Lovisolo SM, Aiello VD, Campos FPF.

Autopsy and Case Reports 2011; 1(4): 21-27

Figure 3 – Schematic posterior view of the heart showing in A the anomalous implantation of the right pulmonary veins close to the openning of the inferior caval vein. The dotted line shows where the right atrium was opened to demonstrate the inner structures; in B an opened view by the posterior wall of the right atrium depicting the inferior sinus venosus interatrial communication, the secundun atrial septal defect. RA = right atrium; LA = left atrium; RPV = right pulmonar veins; LPV = left pulmonar veins; CS = coronary sinus; SSD = secundum septal defect; Sp = septum primum, FO = fossa ovale.

DISCUSSION Atrial septal defects (ASD) are the most common congenital lesion in adults after bicuspid aortic valve,1-3 representing up to 40% of acyanotic shunt lesions in patients older than 40 years.4

Figure 4 – Photomicrography of the lung showing massive neutrophilic infiltration of the alveolar spaces, edema, haemorrhagic focci and destruction of alveolar septa (H&E stain, objective magnification – 10X).

Figure 5 – Photomicrography of the lung with depicting a pre-acinar pulmonary artery with thickening of the medial layer (H&E stain, objective magnification – 20X).

Although the defect is often asymptomatic until adulthood, potential complications of an undetected ASD include right ventricular failure, atrial arrhythmias, and pulmonary hypertension that can become irreversible and lead to right-to-left shunting (Eisenmenger syndrome) as was observed in the case related here.1 Secundum ASD comprises defects in the area of the oval fossa. This type of ASD accounts for 70 to 75% of all interatrial communications and is more common in females.5,6 They may be associated with or other interatrial communications, such as a sinus venosus defect or an ostium primum defect in the context of an atrioventricular septal defect. Mitral valve prolapse is present in up to 70% of patients with secundum ASD.1 The patient here reported presented a secundum ASD associated with a rare form of congenital anomaly, the inferior sinus venosus defect. While the defects within the confines of the oval fossa are considered true septal defects, those located close to the openings of the caval veins are not. In this regard, we should emphasize that the recognition of the true atrial septal structures is

An inferior sinus venosus interatrial communication associated...

based on the fact that they represent part of the atrial wall that when removed does not allow access to the extracardiac space. Only the floor of the oval fossa (flap valve) and its antero-inferior rim do fill this criterion. On the other hand, its superior rim, the socalled septum secundum, represents a deep infolding of the adjacent atrial walls filled with extracardiac fat tissue. Due to their location far from the true atrial septum, the sinus venosus defects should be better designated as interatrial communications, the same way as the so-called coronary sinus defects, which are the consequence of partial or total absence of the coronary sinus wall separating this venous channel from the left atrium.7 The commonest form sinus venosus defect is the superior variant, usually accompanied by an overriding superior caval vein over the superior rim of the oval fossa and anomalous insertion of the right pulmonary veins.8 The inferior variant of sinus venosus defects has not been so-well recognized clinically and by echocardiography. From the morphological point of view, on the other hand, it is clear that the essence of the malformation is an anomalous venoatrial connection of the inferior caval vein and pulmonary veins, in continuity with the walls of both the right and left atriums, thus allowing interatrial shunting.9 The differential diagnosis with a true secundum septal defect extending posteroinferiorly to the opening of the inferior caval vein is based on the absence of the posterior rim of the oval fossa in this situation, while in the inferior sinus venosus defect that rim is intact. In the case reported here, the combined area for interatrial shunting (ASD and sinus venosus defect) was large, not restrictive, and resulted in an increased pulmonary blood flow with development of pulmonary hypertension which became symptomatic early in the adult life. Most children and adolescents with an ASD, particularly an isolated secundum ASD, are asymptomatic even in the presence of large shunts.1 In a review of 481 patients with a secundum ASD were seen between 1957 and 1976 who underwent surgical correction before the age of 40, the defect was discovered on routine examination in 202 (42%).10 In comparison, patients who present in infancy, particularly with heart failure and/or failure to thrive, usually have associated cardiac defects.11

Autopsy and Case Reports 2011; 1(4): 21-27

Although our patient evolved to irreversible pulmonary hypertension early in her adult life, she carried out two asymptomatic pregnancies never presenting any disability during infancy and adolescence. We dare to conclude, in this case, that the inferior sinus venosus interatrial communication in itself did not alter significantly the natural history of the Secundum ASD once the latter was large. At present there are few studies of large numbers of patients with inferior sinus venosus defect based on anatomic diagnosis during life. Crystal et al. identified 11 children with median age of 1,2 years, who were clinically non cyanotic and presented with normal pulse rate and blood pressure. All children had normal jugular venous pulsation and none presented respiratory distress. As expected all children demonstrated a widely split second heart sound, a systolic ejection murmur was identified and a right ventricular heave was palpable in 5/11 patients.9 These findings show that isolated inferior sinus venosus interatrial communication create a left to right shunt clinically identifiable and with no signs of decompensate heart failure at this age. In the series of Banka et al, 45 patients with the diagnosis of ISVD were referred for surgery. These patients were younger than the overall group with isolated interatrial defects, possibly reflecting a greater degree of shunting demanding early surgical repair.12 The hemodynamic abnormality is the same in the two instances in which there is shunting between the atriums; therefore we believe that the association of both abnormalities presented the natural history of a non restrictive large ASD. When large, the defect does not restrict flow, there is no or nearly no pressure gradient between the atria and functionally the two atria can be regarded as a common chamber. The proportions of flow out of this common chamber will be determined by which ventricle is most easily filled, thus the ventricular diastolic properties are of paramount importance in this context.13,14 The increase in left-to-right shunting with age in many patients with uncorrected moderate to large ASDs increases the likelihood of developing symptoms. It is estimated that most patients with an ASD with significant shunt flow will be symptomatic and will require surgical correction by the age of 40.10 The development of severe irreversible pulmonary hypertension or Eisenmenger syndrome (irreversible pulmonary hypertension at near systemic

Lovisolo SM, Aiello VD, Campos FPF.

Autopsy and Case Reports 2011; 1(4): 21-27

levels and reversal of shunt flow to a predominantly right-to-left direction) is now uncommon because of surgical or percutaneous correction of the defect. However, there may be an appreciable lifetime incidence of severe pulmonary hypertension in unoperated ASDs, with some older estimates being in the range of 50% as was observed in the case of this report. Although Eisenmenger syndrome is much less common with ASDs than with ventricular septal defects, ASDs have been a common cause of the syndrome because of their greater prevalence.15 The prognosis is relatively poor once Eisenmenger physiology has been established. In the case reported here the symptoms started at the age of 22 and worsened during her third pregnancy. The patient lived in an area of poor medical resources; she did not look for pre natal consultations, if so she could have had the chance to be diagnosed earlier. Even when the diagnosis was made she was not operated, reflecting the discrepancies of the medical attention in different regions of Brazil.

CONCLUSION Atrial septal defects are common congenital anomalies in adults and may be forgotten as a cause of congestive heart failure. Early recognition may help the patients to have normal survival by means of early surgical repair. The operative management in the case reported here would include, besides the defect closure, the transference of the right pulmonary veins to the left atrium.

ACKNOWLEDGEMENTS We are grateful to Rosa Maria C. Zanardi for the technical support on the visual work of the images presented in this case.

REFERENCES

Wiegers SE, Sutton MGSJ. Management of atrial septal defects in adults. Waltham: UpToDate; 2011 [cited 2011 Oct 31]. Available from: http://www.uptodate.com/contents/ pathophysiology-and-clinical-features-of-atrial-septaldefects-in-adults?source=search_result&search=interat rial+communication&selectedTitle=3~150 Dickinson DF, Arnold R, Wilkinson JL. Congenital heart disease among 160,480 liveborn children in Liverpool 1960-1969,

implications of surgical treatment. Br Heart J 1981; 46(1):5562. http://dx.doi.org/10.1136/hrt.46.1.55 3.

Rosas M, Attie F, Sandoval J, et al. Atrial septal defect in adults ≥ 40 years old: negative impact of low arterial oxygen saturation. International J Cardiol. 2004; 93(2):145-55. http://dx.doi.org/10.1016/S0167-5273(03)00192-X

Therrien J, Webb G. Clinical update on adults with congenital heart disease. Lancet. 2003;362(9392):1305-13. http:// dx.doi.org/10.1016/S0140-6736(03)14574-6

Webb G, Gatzoulis MA. Atrial septal defects in the adult: recent progress and overview. Circulation. 2006; 114(15):164553. PMid:17030704. http://dx.doi.org/10.1161/ CIRCULATIONAHA.105.592055

Shah D, Achar M,Oakley CM, Cleland JG, Nihoyannopoulos P. Natural history of secundum atrial septal defect in adults after medical or surgical treatment: a historical prospective study. Br Heart J. 1994; 71(3):224-7. http:// dx.doi.org/10.1136/hrt.71.3.224

English RF, Anderson RH, Ettedgui JA. Interatrial communications. In: Anderson RH, Baker EJ, Penny DJ, Redington AN, Rigby ML, Wernovsky G, editors. Paediatric cardiology. 3rd ed. Philadelphia: Elsevier; 2009. p. 523-46.

Al Zaghal AM, Li J, Anderson RH, Lincoln C, Shore D, Rigby ML. Anatomical criteria for the diagnosis of sinus venosus defects. Heart. 1997; 78(3):298-304. PMid:9391294. PMCid:484934.

Crystal MA, Najashi KA, Williams WG, Redington AN, Anderson RH. Inferior sinus venosus defect: echocardiographic diagnosis and surgical approach. J Thorac Cardiovasc Surg. 2009; 137(6):1349-55. PMid:19464447. http://dx.doi. org/10.1016/j.jtcvs.2008.12.010

10. Rostad H, Sörland S. Atrial septal defect of secundum type in patients under 40 years of age. A review of 481 operated cases. Symptoms, signs, treatment and early results. Scand J Thorac Cardiovasc Surg. 1979; 13(2):1237. http://dx.doi.org/10.3109/14017437909100977 11. Manning PB, Mayer Junior JE, Sanders SP, et al. Unique features and prognosis of primum ASD presenting in the first year of life. Circulation. 1994; 90(5PT 2):II30-5. 12. Banka P, Bacha E, Powell AJ, Benavidez O, Geva T. Outcomes of inferior sinus venosus defect repair. J Thorac Cardiovasc Surg. 2011; 142(3):517-22. http://dx.doi. org/10.1016/j.jtcvs.2011.01.031 13. Rowe GG, Castillo CA, Maxwell GM, Clifford JE, Crumpton CW. Atrial septal defect and the mechanism of shunt. Am Heart J. 1961; 61:369-74. http://dx.doi.org/10.1016/00028703(61)90608-1 14. Weldon CS. Hemodynamics in acute atrial septal defect. Arch Surg. 1966; 93(5):724-9. PMid:5921293. 15. Waddell TK, Bennett L, Kennedy R, et al. Heart-lung or lung transplantation for Eisenmenger syndrome. J Heart Lung Transplant. 2002; 21(7):731-7. http://dx.doi.org/10.1016/ S1053-2498(01)00420-X

An inferior sinus venosus interatrial communication associated...

Autopsy and Case Reports 2011; 1(4): 21-27

Conflict of interest: None Submitted on: 3rd November 2011 Accept on: 21st November 2011 Correspondence: Serviço de Anatomia Patológica Av. Prof. Lineu Prestes, 2565 – Cidade Universitária - São Paulo/SP – Brazil CEP: 05508-900 – Phone: +55 (11) 3091-9384 E-mail: slovisolo@hu.usp.br

Autopsy and Case Reports 2011; 1(4): 29-37

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Infective endocarditis: a consumptive disease among the elderly Vilma Takayasua, Fabiana Roberto Limab, Fernando Peixoto Ferraz de Camposa Takayasu V, Lima FR, Campos FPF. Infective endocarditis: a consumptive disease among the elderly. Autopsy Case Rep [Internet]. 2011;1(4):29-37. http://dx.doi.org/10.4322/acr.2011.014

ABSTRACT The clinical presentation of infective endocarditis varies according to the etiologic agent and the host. In elderly individuals, infective endocarditis can be difficult to diagnose and poses a challenge for the physician. The course of subacute infective endocarditis is indolent, and the onset of cardiac structural lesion is slow and gradual. In elderly patients, anemia and weight loss are occasionally the only or the most striking symptoms. In such cases, the clinical reasoning process leads to a hypothesis of wasting syndrome or neoplastic disease, especially when there is no fever. We report the case of an elderly patient who had mitral insufficiency due to degenerative valve disease and presented with bacterial endocarditis due to Streptococcus mitis. The patient was not treated, because the diagnosis was not established in a timely manner. It is of note that the patient presented with marked weight loss and no fever. The autopsy revealed impairment of the mitral valve and left atrium due to endocarditis, as well as lung involvement due to chronic inhalation of smoke from biomass burning, such as that produced by wood-burning stoves. Keywords: Endocarditis bacterial; Mitral valve; Weight loss; Biomass. CASE REPORT A 73-year-old female patient, from the northeast of Brazil (the state of Bahia), was brought to our emergency room because of sudden-onset chest and neck pain accompanied by a drop in the level of consciousness. The patient had been diagnosed with systemic arterial hypertension, mitral insufficiency, and congestive heart failure. In addition, she reported a history of anorexia and weight loss, having lost 15 kg in 6 months. Transthoracic Doppler echocardiography performed 5 months prior showed severe mitral insufficiency, normal left ventricular systolic function, and pulmonary artery systolic pressure of 60 mmHg. The patient had a personal history of smoking and a b

exposure to smoke from wood-burning stoves. She had recently been hospitalized for acute pulmonary edema. The patient had been under treatment with furosemide, carvedilol, losartan, aspirin, hydralazine, isosorbide mononitrate, and simvastatin. She reported no fever. Physical examination revealed the following: torpor (Glasgow coma scale score, 9); dyspnea; pallor; blood pressure, 60/40 mmHg; heart rate, 130 bpm; respiratory rate, 28 breaths/minutes; delayed capillary refill; systolic thrill and systolic murmur in the mitral area. Pulmonary auscultation revealed rhonchi and wheezing. Neurological examination revealed no motor deficits. Examination of the abdomen and

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.

Autopsy and Case Reports 2011; 1(4): 29-37

Takayasu V, Lima FR, Campos FPF.

extremities was unremarkable. Laboratory test results are shown in Table 1. Urinalysis revealed the following: leukocytes, 220,000/mm 3; red blood cells > 1 million/mm 3; proteinuria; and the absence of casts and crystals.

Table 1 – Results of the laboratory tests performed at admission Variable Hb (g.dL–1)/Ht (%) Leukocytes (×103.mm ) –3

At admission

Reference value

7.7/23

12.3-15.3/36.0-45.0

6,700

4.4-11.3

Band neutrophils (%)

1-5

Segmented neutrophils (%)

45-70

Eosinophils (%)

1-4

Basophils (%)

0-2.5

Lymphocytes (%)

18-40

Monocytes (%)

2-9

Platelets (×103.mm )

96,000

150-400

Urea/Creatinine (mg.dL )

60/1.2

10-50/0.4-1.3

Na/K (mEq.L )

134/3.8

135-146/3.5-5.0

–3

–1

Ionized calcium (mmol.L–1)

1.1

1.1-1.4

Lactate (mEq.L–1)

18.2

136-146

Troponin I (ng.mL–1)

0.21

<0.06

CK-MB (ng.mL )

0.18

<5.0

Total proteins (g.dL )

5.7

6.0-8.0

Albumin (g.dL–1)

2.2

3.0-5.0

Globulins (g.dL )

3.5

1.5-3.5

CRP (mg.L )

131

–1

Hb/Ht, hemoglobin/hematocrit; Na, sodium; K, potassium; CK-MB, creatine kinase MB isoenzyme; CRP, C-reactive protein.

A chest X-ray revealed a normal cardiac silhouette, signs of pulmonary congestion, and a possible focus of pulmonary infection. An electrocardiogram showed sinus rhythm, left atrial overload, QRS axis of 0°, and ST-segment depression, as well as T-wave inversion in leads V4–V6, D1, and aVL. After having performed the initial ancillary tests, ceftriaxone and clarithromycin were prescribed because of the possibility of pulmonary infection. However, the patient developed shock that did not respond to saline overload or noradrenaline (at the usual dose or at progressively higher doses) and died on postadmission day 1. The culture of blood samples collected at admission revealed, after 12 hours, growth of Streptococcus mitis, which was found to be resistant to penicillin G and ceftriaxone but sensitive to clindamycin, chloramphenicol, erythromycin, and vancomycin. An autopsy was performed, and the findings included changes that were consistent with septic shock, the primary focus of infection being located near the mitral valve. The heart weighed 355 g (mean reference value, 243 g; range, 166-356 g) and showed left atrial enlargement secondary to the severe mitral valve prolapse. We found some brownish mitral valve vegetations measuring up to 1.2 cm, as well as smaller vegetations, with similar characteristics, close to the atrial endocardium (Figure 1).

Figure 1 – A – Panoramic view of the left heart; B – Multiple vegetations in the left atrium and mitral valve.

Infective endocarditis: a consumptive disease among the elderly

The histological study revealed infective endocarditis, with areas of abscess formation, accompanied by granulation tissue,1 which was suggestive of subacute endocarditis (Figure 2). The Brown-Hopps method revealed no bacteria,

Autopsy and Case Reports 2011; 1(4): 29-37

and the Grocott-Gomori methenamine-silver stain technique revealed no fungi. Mitral valve prolapserelated changes, such as myxomatous degeneration, fibrosis, and dystrophic calcification, were found (Figure 3).

Figure 2 – A – Vegetation on the mitral valve (hematoxylin and eosin; magnification, 100X); B – Transition between the granulation tissue and the area of abscess formation of endocarditis (hematoxylin and eosin; magnification, 200X); C – Mixed inflammation and neovascularization in the granulation tissue (hematoxylin and eosin; magnification, 400X); D – Neutrophilic exudate with pus cells and fibrin in the area of abscess formation of endocarditis (hematoxylin and eosin; magnification, 400X).

Figure 3 – A and B – Mitral valve prolapse with myxomatous degeneration and a focus of dystrophic calcification (hematoxylin and eosin; magnification, in A 25X and in B 400X).

Autopsy and Case Reports 2011; 1(4): 29-37

The macroscopic appearance of the lungs and adjacent lymph nodes was also remarkable. The right lung weighed 410 g (mean reference value, 450 g; range, 360-570 g), and the left lung weighed 390 g (mean reference value, 375 g; range, 325-480 g). We also found small, citrine, bilateral pleural effusion. Paratracheal lymph node enlargement was found in the carinal and peribronchial regions (the lymph nodes in the former measuring up to 5.0 cm), and there were nodules, measuring up to 1,5 cm, in the adjacent connective tissue surrounding the main and segmental bronchi, although only superficially in the peribronchial lung tissue (Figures 4A and 4B). There was no diffuse distribution of nodules in the lung parenchyma. Macroscopic examination revealed that the lesions were dark and, for the most part, firm, some being hard (Figures 4C and 4D). Microscopic examination revealed multiple, sometimes coalescent, oval-shaped nodules, some of which had spiculated margins; the nodules were characterized by severe fibrosis exhibiting thick collagen bands and numerous black-pigmented macrophages (Figures 5 and 6A).

Takayasu V, Lima FR, Campos FPF.

Some areas showed amorphous necrotic material and cholesterol crystal clefts, accompanied by foreign body giant cell reaction and groups of xanthomatous macrophages (Figure 6B). The Ziehl-Neelsen method and the GrocottGomori methenamine-silver stain technique were consecutively used in order to screen for acid-fast bacilli and fungi, and the results were negative. Some foci of osseous metaplasia were seen. Under polarized light, we found no birefringent particles in the lesions. The findings of abundant black pigment, severe fibrosis, and spiculated nodules were suggestive of mixed-dust pneumoconiosis.2 Many hemossiderine-laden macrophages (“heart-failure” cells) were found in intra-alveolar spaces. This finding is probably related to previous episodes of pulmonary edema in a pacient with leftsided heart failure. Adicionally, there were inhaled carbon pigment engulfed by alveolar and intersticial macrophages (pulmonary anthracosis).

Figure 4 – A – Panoramic view of the mediastinum with paratracheal and infracarinal lymph node enlargement; B – Partial cross sections of the lung showing dark nodules surrounding bronchovascular structures. The lung parenchyma is slightly red and has small foci of anthracosis; C – Cross section of a black, firm paratracheal lymph node mass; D – Intrathoracic lymph node enlargement.

Infective endocarditis: a consumptive disease among the elderly

Autopsy and Case Reports 2011; 1(4): 29-37

Figure 5 – Lymph nodes (in A and B) and peribronchial lung tissue (C and D) surrounded by oval or irregular nodules with severe fibrosis, dark pigmentation, and rare foci of amorphous material (hematoxylin and eosin; magnification, 25X).

Figure 6 – A – Note that the most common appearance of the nodules consisted of severe fibrosis and numerous macrophages containing black pigment (hematoxylin and eosin; magnification, 400X); B – Note that there were very few areas of amorphous necrotic material accompanied by cholesterol crystal clefts (hematoxylin and eosin; magnification, 200X).

The spleen weighed 221 g (mean reference value, 145 g; range, 75-245 g). Macroscopic examination of the spleen revealed that the red

pulp was extremely soft. The histological findings were consistent with acute splenitis secondary to sepsis.

Autopsy and Case Reports 2011; 1(4): 29-37

We found shrunken ischemic neurons, which were probably evidence of the cerebral hypoperfusion caused by the shock. There was severe atherosclerosis in the aorta, with calcifications and ulcerations. Atheromatous plaques were detected in the left renal and splenic arteries. The coronary arteries were rigid, and there were areas of fibrosis in the ventricles. Signs of cardiogenic shock or pulmonary hypertension were not detected on autopsy.

DISCUSSION Although the patient had a 6-month history of weight loss and anorexia, she sought emergency room treatment because of an acute profile, which was characterized by arterial hypotension associated with signs of tissue hypoperfusion (decreased level of consciousness, tachycardia, decreased capillary refill, oliguria, and respiratory distress). The congestive heart failure caused by hypertensive cardiomyopathy and the mitral valve disease can partially explain the weight loss in our patient. The acute profile was attributed to cardiogenic and septic shock. Because there was no recent ischemic electrocardiographic changes and because the markers of myocardial necrosis were not significantly increased, acute coronary syndrome was ruled out as the cause of cardiogenic shock. The initial hypothesis to explain the sepsis in this patient was pulmonary infection, for which she received antibiotic therapy. However, we should also have considered the possibility of bacterial endocarditis, given that our patient was an elderly individual with mitral valve disease and was therefore at a higher risk of developing that infection. The risk groups for infective endocarditis include individuals with rheumatic mitral valve disease, intravenous drug users, patients with heart valve prostheses, hemodialysis patients, individuals with intravenous catheters, and elderly individuals with degenerative valve lesions.3-5 The clinical presentation of infective endocarditis can be nonspecific and difficult to diagnose. When patients with valvular lesions and those in the risk groups for infective endocarditis present with fever and other nonspecific symptoms, such as weight loss, a diagnosis of infective endocarditis should always be considered. Nonbacterial thrombotic endocarditis is characterized by lesions ranging in size from 0.1 to

Takayasu V, Lima FR, Campos FPF.

0.5 cm, corresponding to non-invasive vegetation and without inflammatory reaction, weakly attached to the valve. The Libman-Sachs disease, found in systemic lupus erythematosus, is constituted by multiple vegetations measuring generally from 0.1 to 0.4 cm. These lesions show fibrinous eosinophylic material, hematoxylinic bodies; fibrinoid necrosis is observed when intense vasculitis is present.1 In the case presented here, the vegetations were bigger and a liquefactive necrosis of abscess was observed within the vegetations confirming the diagnosis of infective endocarditis, despite the lack of etiologic agent demonstration on histology. Although fever occurs in 80-90% of patients with infective endocarditis, it might be absent in severely debilitated patients, in patients with severe heart failure, in elderly patients, and in patients with renal failure. That frequency is lower in cases of subacute infective endocarditis than in those of acute infective endocarditis.5,6 The principal factor that determines the type of presentation is the etiologic agent. Acute endocarditis is generally caused by beta-hemolytic streptococci, S. aureus, and S. pneumoniae, whereas subacute endocarditis is caused by viridans group streptococci, enterococci, coagulase-negative staphylococci, and the HACEK group, which comprises Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae. For the detection of valvular vegetations, transesophageal echocardiography has a sensitivity of 90-100%, whereas transthoracic echocardiography has a sensitivity of 40-63%. The modified Duke criteria 3,5,7 assist in the diagnosis of infective endocarditis and underscore the importance of those ancillary tests. The treatment of infective endocarditis is based on bacterial eradication by antibiotic therapy in isolation or in combination with surgery. High serum concentrations of antibiotics are desirable in order to allow the drug to enter the vegetation. Prolonged treatment (4-6 weeks) is needed in order to eliminate the bacteria from the focus of infection. Surgery is required in up to 50% of cases, the principal indications being heart failure (generally related to valvular dysfunction), uncontrolled infection (associated with perivalvular extension accompanied by atrioventricular conduction defects), and prevention of systemic embolism.3,8

Infective endocarditis: a consumptive disease among the elderly

Critically ill patients who present with an acute clinical profile (as was the case for our patient) should receive empirical treatment as soon as possible (i.e., after blood sample collection for blood culture). The empirical treatment should cover the principal causative agents: staphylococci (2035%); streptococci (Streptococcus viridans, 3040%; other streptococci, 15-25%); and enterococci (5-18%). It has been suggested that patients should be started on penicillin, oxacillin, and gentamicin.9 The alternative choice for the initial treatment is the use of vancomycin.8,9 Although the number of viridans group streptococci that are partially or completely resistant to penicillin has increased worldwide, only a limited number of penicillin-resistant Streptococcus viridans strains have been reported to cause bacterial endocarditis.3,8,10 It is important to establish an accurate diagnosis of subacute bacterial endocarditis in order to administer the appropriate treatment. When this does not happen, the disease inexorably progresses to death. In the case reported here, it was impossible to treat the patient because she was admitted with septic shock and died less than 1 day after hospitalization. Although the patient had no fever, she had a 6-month history of constitutional symptoms, such as weight loss, asthenia, and anorexia, which were suggestive of a subacute profile. However, the diagnostic investigation was not conducted in a timely manner. The autopsy confirmed the diagnosis of infective endocarditis, and the absence of other diseases shows that the course of infective endocarditis can be similar to that of wasting syndrome. Another interesting aspect revealed by the autopsy was the presence of major lymph node enlargement (paratracheal and peribronchial lymph node enlargement) and nodules in the connective tissue surrounding pulmonary hilar structures, as well as in the adjacent superficial lung tissue. Those changes were suggestive of mixed-dust pneumoconiosis: anthracotic pigment (such as that caused by inhalation of coal dust) accompanied by other fibrogenic particles (e.g., silica). However, because the patient presented with significant weight loss, those changes could also have been interpreted as being suggestive of neoplasia. In the case of pneumoconiosis, the lesions are generally more diffusely distributed in the lung parenchyma, whereas in the case reported here the nodules were located more centrally.

Autopsy and Case Reports 2011; 1(4): 29-37

The patient not only inhaled pollutants derived from biomass burning (a wood-burning stove) but also had a history of chronic smoking, both of which can explain the histopathological findings. Worldwide, approximately 50% of all households and 90% of all households in rural areas use solid fuels (charcoal or biomass) as the principal source of energy, both for cooking and for indoor heating.11,12 Therefore, approximately half of the world population (i.e., nearly three billion people) is subject to the deleterious effects of combustion products. In the rural areas of Latin America, 30-75% of all households use biomass as fuel for cooking. In Brazil, wood-burning stoves are still used in many households (in 40.9% of all households in rural areas and in 2.6% of those in urban areas). In 2003, the Brazilian Institute of Geography and Statistics estimated that 8.6% of all households used wood as the primary fuel.13 Various biomass burning products are toxic or irritating to the respiratory system, including respirable particulate matter, which is the product that is most deleterious to the respiratory system.13,14 Larger particles are filtered in the nose and throat, whereas those smaller than 10 µm in diameter can settle in the respiratory tract. Fine particles (those smaller than 2.5 µm in diameter) can penetrate the alveoli, whereas ultrafine particles (those smaller than 0.1 µm in diameter) can pass through the alveoli and spread to other organs.13 Fine and ultrafine particles can reach the most distal parts of the respiratory system and are responsible for triggering the inflammatory process.13 Various studies have shown that long-term exposure to smoke from indoor biomass burning is associated with respiratory diseases. Systematic reviews and meta-analyses11,15-17 have shown that children who are under five years of age and are exposed to smoke from biomass burning are at a higher risk of developing pneumonia and other lower airway infections. Smoke inhalation affects various pulmonary defense mechanisms, including mucociliary transport and macrophage function. The risk of developing chronic obstructive pulmonary disease and chronic bronchitis more than doubles in adults exposed to smoke from biomass burning. The principal population at risk comprises women who use solid fuels for cooking, who can present with respiratory complaints such as chronic cough, increased pulmonary secretions, dyspnea, wheezing, and subsequent development of cor pulmonale.11,18,19 The smoke from the burning of coal is currently

Autopsy and Case Reports 2011; 1(4): 29-37

considered a carcinogen, whereas that from biomass burning is considered a probable carcinogen.11,20 The smoke from biomass burning has substantial concentrations of known carcinogens, such as polycyclic aromatic hydrocarbons (benzopyrene, and benzene) and formaldehyde.

Takayasu V, Lima FR, Campos FPF. 6.

Sexton DJ. Diagnostic approach to infective endocarditis. Waltham: UpToDate; 2011.

Lester SJ, Wilansky S. Endocarditis and associated complications. Crit Care Med. 2007;35(Suppl.):S384-91. PMid:17667463. http://dx.doi.org/10.1097/01.CCM.0000 270275.89478.5F

Other, previously described, health effects of biomass burning include asthma, pneumoconiosis, cataracts, blindness, tuberculosis, neoplasia, and adverse effects during pregnancy.11,15-17 Although such associations have been described, the results are still considered inconclusive.

Sexton DJ. Antimicrobial therapy of native valve endocarditis. Waltham: UpToDate; 2011.

Gilbert DN, Moellering RC, Eliopoulos GM, Sande, ME. The Sanford Guide to antimicrobial therapy. 39th ed. Sperryville: Antimicrobial Therapy Inc.; 2019. p. 25: Clinical approach to initial choice of antimicrobial therapy.

We conclude that infective endocarditis should be included in the differential diagnosis of consumptive syndrome in elderly patients who are at risk for developing infective endocarditis. Another important finding of our autopsy was major paratracheal and pulmonary hilar lymph node enlargement due to the inhalation of smoke from biomass burning. That finding could have been clinically interpreted as being suggestive of neoplastic disease.

10. Knoll B, Tleyjeh IM, Steckelberg JM, Wilson WR, Baddour LM. Infective endocarditis due to penicillin-resistant viridans group streptococci. Clin Infect Dis. 2007;44(12):1585-92. http://dx.doi.org/10.1086/518174

ACKNOWLEDGEMENTS

11. Torres-Duque C, Maldonado D, Perez-Padilla R, Ezzati M, Viegi G. Biomass fuels and respiratory diseases. A review of the evidence. Proc Am Thorac Soc. 2008;5(5):577-90. PMid:18625750. http://dx.doi.org/10.1513/pats.200707100RP 12. Gold JA, Jagirdar J, Hay JG, Addrizzo-Harris DJ, Naidich DP, Rom WN. Hut lung. A domestically acquired particulate lung disease. Medicine. 2000;79(5):310-7. PMid:11039079. http://dx.doi.org/10.1097/00005792-200009000-00004

We are grateful to Rosa Maria C. Zanardi, who kindly helped us with the documentation of the images presented in this case.

13. Arbex MA, Cançado JED, Pereira LAA, Braga ALF, Saldiva PHN. Queima de biomassa e efeitos sobre a saúde. J Bras Pneumol. 2004; 30(2):158-75. http://dx.doi.org/10.1590/ S1806-37132004000200015

REFERENCES

14. Junemann A, Legarreta CG. Chronic obstructive pulmonary disease produced by biomass fuels. Clin Pulm Med. 2008;15(6):305-12. http://dx.doi.org/10.1097/ CPM.0b013e31818cdb58

Schoen FS, Mitchell RN. The heart. In: Kumar V, Abbas AK, Fausto, Aster J, editors. Robbins and Cotran pathologic basis of disease. 8th ed. Philadelphia: Elsevier Health Science; 2009. p. 529-87. Travis WD, Colby TV, Koss MN, et al. Occupational lung diseases and pneumoconioses. In: King DW, Sobin LH, Stocker JT, Wagner B, editors. Non-neoplastic disorders of the lower respiratory tract. Washington: AFIP ARP; 2002. p. 793-857. Que YA, Moreillon P. Infective endocarditis. Nat Rev Cardiol. 2011;8(6):322-36. http://dx.doi.org/10.1038/ nrcardio.2011.43

Sexton DJ. Epidemiology, risk factors and microbiology of infective endocarditis. Waltham: UpToDate; 2011.

Karchmer AW. Infective endocarditis. In: Fauci A, Braunwald E, Kasper D, et al., editors. Harrison´s principles of internal medicine. 17th ed. New York: McGraw Hill; 2008. p. 789-98.

15. Po JYT, FitzGerald JM, Carlsten C. Respiratory disease associated with solid biomass fuel exposure in rural women and children: systematic review and meta-analysis. Thorax. 2011;66(3):232-9. PMid:21248322. http://dx.doi. org/10.1136/thx.2010.147884 16. Kurmi OP, Semple S, Simkhada P, Smith WCS, Ayres JG. COPD and chronic bronchitis risk of indoor air pollution from solid fuel: a systematic review and meta-analysis. Thorax. 2010;65(3):221-8. PMid:20335290. http://dx.doi. org/10.1136/thx.2009.124644 17. Hu G, Zhou Y, Tian J, et al. Risk of COPD from exposure to biomass smoke: a metaanalysis. Chest. 2010;138(1):20‑31. PMid:20139228. http://dx.doi.org/10.1378/chest.08-2114 18. Moran-Mendoza O, Pérez-Padilla JR, Salazar-Flores M, Vazquez-Alfaro F. Wood smoke-associated lung disease: a clinical, functional, radiological and pathological description. Int J Tuberc Lung Dis. 2008;12(9):1092-8. PMid:18713510.

Infective endocarditis: a consumptive disease among the elderly 19. Salvi S, Barnes PJ. Is exposure to biomass smoke the biggest risk factor for COPD globally? Chest. 2010;138(1):3‑6. PMid:20605806. http://dx.doi.org/10.1378/chest.10-0645

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20. Perez-Padilla R, Schilmann A, Riojas-Rodriguez H. Respiratory health effects of indoor air pollution. Int J Tuberc Lung Dis. 2010;14(9):1079-86. PMid:20819250.

Conflict of interest: None Submitted on: 5th October 2011 Accept on: 3rd November 2011 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

Autopsy and Case Reports 2011; 1(4): 39-44

Article / Clinical Case Reports Artigo / Relato de Caso Clínico Duodenal pseudomelanosis (pseudomelanosis duodeni): a rare endoscopic finding Aloísio Felipe-Silvaa, Fernando Peixoto Ferraz de Camposb, José Guilherme Nogueira da Silvac Felipe-Silva A, Campos FPF, Silva JGN. Duodenal pseudomelanosis (pseudomelanosis duodeni): a rare endoscopic finding. Autopsy Case Rep [Internet]. 2011;1(3):39-44. http://dx.doi.org/10.4322/acr.2011.015

ABSTRACT Duodenal pseudomelanosis (or pseudomelanosis duodeni) is a rare benign condition characterized by black-brown speckled pigmentation of the duodenal mucosa. Collections of pigment−laden macrophages are found in the tips of duodenal villi. The pigment is thought to be mostly composed of ferrous sulfide. Histochemichal stains for iron (Perl’s prussian blue) or melanin (MassonFontana) may be positive, but are usually negative or unpredictable. Duodenal pseudomelanosis occurs predominantly in middle-aged to old adults and more commonly in females. It is associated with chronic renal failure, arterial hypertension, diabetes mellitus and gastrointestinal bleeding. Medications such as ferrous sulfate, hydralazine, propranolol, hydrochlorothiazide and furosemide are thought to play a role as well. We report a case of a 86-year-old female who presented with a history of watery diarrhea and melena. The patient had a history of high blood pressure and ischemic stroke episodes. She was on multiple medication including hidralazine, captopril, hydrochlorthiazide and aspirin. She was dehydrated, her blood pressure was 96 × 60 mmHg and neurologic examination showed complete left hemiplegia with central VII nerve palsy. Laboratory tests showed normal serum electrolytes and renal function. Hemoglobin level was 10.7 g%. An upper endoscopy showed multiple diminutive black spots throughout the distal duodenal bulb and second portion. Histology showed multiple foci of a brown-black granular pigment inside macrophages within the tips of the villi (pseudomelanosis). Stains for iron and melanin were negative. She was treated with omeprazol, parenteral fluid replacement with saline and partial fasting. After complete recovery she was discharged for ambulatory follow up. Keywords: Melanosis; Pigmentation; Duodenum; Renal insufficiency; Hypertension; Iron. CASE REPORT A 86-year-old female presented with a history of watery diarrhea for the last three days. Her daughter, who was in charge of her care, noticed that the feces became progressively more liquid and dark colored resembling melena, sometimes with bloody traces. She denied abdominal pain, fever or vomiting. This was

the second similar episode within the last month. The patient had a history of high blood pressure and three distinct ischemic stroke episodes, the latter two years ago, since when she became bedridden. The patient was on multiple medication including hidralazine, captopril, hydrochlorthiazide and aspirin.

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

Felipe-Silva A, Campos FPF, Silva JGN.

Autopsy and Case Reports 2011; 1(4): 39-44

Physical examination revealed a conscious patient, slightly lethargic, with a slurred speech (since the previous stroke), dehidrated. Her blood pressure was 96 ×60 mmHg and pulse was 96 bpm. Neurologic examination showed complete left hemiplegia with central VII nerve palsy. Laboratory tests showed normal serum electrolytes and renal function. On blood cell count the hemoglobin was 10.7 g% with normal mean corpuscular volume and red cell distribution width, leukocytes and platelets were within the normal range.

Because of the suspicion of gastrointestinal bleeding an upper endoscopy was performed. Endoscopy showed esophageal hernia, Los Angeles A distal esophagitis, enantematous gastritis and gastric angiodysplasia without any evidence of bleeding. Duodenal mucosa was lightly pale with multiple diminutive black spots throughout the distal bulb and second portion (Figure 1). Duodenal biopsies were taken. Histological examination showed multiple foci of a brown-black granular pigment, mostly inside macrophages within the tips of the villi (Figure 2). Perls’ prussian blue stain for iron and Masson-Fontana

Figure 1 – Endoscopic view of duodenal bulb (A) and second portion (B), showing multiple and speckled black spots.

Figure 2 – A, B- Multiple foci of a brown-black granular pigment inside macrophages within the tips of the duodenal villi (H&E-200×, 400×). C- Masson-Fontana and D- Perls Prussian blue stain were negative. There was no change in the black-brown nature of the original pigment (400×)

Duodenal pseudomelanosis (pseudomelanosis duodeni) – a rare endoscopic finding.

stain for melanin were negative. The black-brown color seen in the special stains slides were interpreted as intrinsic pigmentation from pseudomelanosis. A diagnosis or duodenal pseudomelanosis was rendered. The recent change in bowel habits and hematochezia was interpreted as possible manifestation of ischemic colitis or colonic angiodysplasia, and because of the patient’s clinical status she was not submitted to a colonoscopy. She was treated with omeprazol, parenteral fluid replacement with saline and partial fasting. After complete recovery she was discharged for ambulatory follow up.

DISCUSSION Duodenal pseudomelanosis (or pseudomelanosis duodeni) is a rare benign condition first described by Bisordi & Kleinman in 19761 as “melanosis duodeni”, since the real nature of the black-brown pigmentation of the mucosa had not been further investigated. Originally the pigment was thought to be derived from melanin1-4 but it was later demonstrated to be mainly ferrous sulfide5-7 and distinct from melanin, hemossiderin8 or lipofuscin. This condition is characterized by collections of pigment−laden macrophages in the tips of duodenal villi, which may be detected at endoscopy as dark spots. Several case reports and a few case series have been described in the literature.9-35 The largest case series included 17 adult patients.36 Duodenal pseudomelanosis occurs predominantly in middle-aged to old adults and more commonly in females (1.2-2:1).14,36 Pediatric cases have been reported.22,37 There is a strong association with chronic renal failure, arterial hypertension, diabetes mellitus and the use of medications such as ferrous sulfate, hydralazine, propranolol, hydrochlorothiazide and furosemide.6,36 Some cases have been associated with gastrointestinal bleeding.38 As this patient completely recovered from diarrhea and hematochezia and also because of her clinical status, no further investigation by invasive methods was proposed. Apparently there is no correlation between duodenal pseudomelanosis and her symptoms, unless an occult previous upper gastrointestinal bleeding could not be detected at endoscopy. Alternatively, her symptoms were

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interpreted as a possible manifestation of ischemic colitis or colonic angiodysplasia. At upper endoscopy the duodenum mucosa is speckled with multiple discrete, flat, small dark spots (usually <2 mm), mainly in the proximal portions (bulb and second portion).2,3,19 Occasionally the brownishblack spots may be seen in the mucosa of stomach, jejunum or ileum.29,39,40 The diagnosis is usually made by mucosal biopsies. A collection of macrophages packed with a characteristic brown-black granular pigment is seen within the lamina propria of the villi on routine optical microscopy. Black-brown pigment may also be seen in epithelial cells or extracellular matrix.2,3,19,38 Histochemichal stains for iron (Perl’s prussian blue) or melanin (Masson-Fontana) may be positive, but are usually negative or unpredictable.6,36 On electron microscopy, angular crystalline plates, or sometimes rounded or irregularly shaped membrane bound, electron dense structures can be seen, occasionally contained within lysosomal bodies.6,9,10,38 Electron-probe X-ray analysis have demonstrated a high content of iron and variable contents of sulfur in the pigment granules.5,8,10,16 The pigment in duodenal pseudomelanosis has now been shown to consist largely of iron sulfide (FeS)13,41, with trace amounts of other elements like calcium, potassium, aluminum, magnesium, and silica.5 The detection of iron by histochemistry is variable in duodenal pseudomelanosis. 5,10,36 Iron sulfide, which is formed by ferrous iron (Fe2+), is known to give a negative reaction with Perl’s prussian blue once this method mainly stains ferric iron (Fe3+).42 Furthermore, iron sulfide may spontaneously become auto−oxidized to iron oxide, leading to variations in the iron staining properties even in the same patient.5,10 Masson-Fontana stain, which is commonly used for the identification of melanin in routine histopathology, may also be positive in duodenal pseudomelanosis; however, it is not specific because other reducing substances, including ferrous iron, can also stain by this method.6 It has been proposed that the coupling of iron and sulfur in iron sulfide leads to difficulty in iron transport and results in accumulation of these crystals in macrophages of the duodenal lamina propria.16 Interestingly, the proximal duodenum is

Felipe-Silva A, Campos FPF, Silva JGN.

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also the site of maximal iron absorption in normal physiology. However, the source of sulfur is not clear. It is noted that most of patients with duodenal pseudomelanosis have received antihypertensive medications. Therefore, some authors have proposed that antihypertensive medications containing a sulfur moiety such as furosemide and hydrochlorothiazide could be this source.17,22 Our patient was taking hydrochlorothiazide; however, several patients with duodenal pseudomelanosis were reported to be on medications that do not contain sulfur moieties.36 Microscopic diagnosis of duodenal pseudomelanosis is quite straightforward. However, endoscopic and histopathological differential diagnoses include metastatic melanoma (and its threatening manifestation of panenteric melanosis43) and other pigmentations including exogenous ingested substances like charcoal.44 The precise diagnostic and prognostic significance of duodenal pseudomelanosis is unknown. According to current knowledge, it seems to be a sign of the local microenvironment and not a disease itself.13,18 Duodenal pseudomelanosis has not been documented to cause local complications like fibrosis or strictures. No specific therapeutic or follow−up protocol is recommended.36 Resolution after discontinuation of oral iron therapy was described in a patient with B thalassemia, chronic renal insufficiency, diabetes and hypertension.45

ACKNOWLEDGMENTS We are grateful to Rosa Maria C. Zanardi for the technical support on the visual work.

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42. Meguro R, Asano Y, Odagiri S, Li C, Iwatsuki H, Shoumura K. Nonheme-iron histochemistry for light and electron microscopy: a historical, theoretical and technical review. Arch Histol Cytol. 2007;70(1):1-19. PMid:17558140. http:// dx.doi.org/10.1679/aohc.70.1

29. Weinstock LB, Katzman D, Wang HL. Pseudomelanosis of stomach, duodenum, and jejunum. Gastrointest Endosc. 2003;58(4):578. http://dx.doi.org/10.1067/S00165107(03)01874-1 30. Cantu JA, Adler DG. Pseudomelanosis duodeni. Endoscopy. 2005;37(8):789. PMid:16032511. http://dx.doi. org/10.1055/s-2005-870144 31. Koulaouzidis A, Habib S, Moschos J. Pseudomelanosis duodeni. Indian J Gastroenterol. 2008;27(3):134. PMid:18787289. 32. Yen HH, Chen YY, Soon MS. Pseudomelanosis duodeni: an unusual finding from upper gastrointestinal endoscopy. Clin

43. Kaplan MR, Knittel DR, Lawson P, Schafer TW. Panenteric melanosis: an ominous endoscopic finding. Gastrointest Endosc. 2005;61(6):762-5. http://dx.doi.org/10.1016/ S0016-5107(04)02783-X 44. Kim J, Hwang JK, Choi WS, et al. Pseudomelanosis ilei associated with ingestion of charcoal: case report and review of literature. Dig Endosc. 2010;22(1):56-8. PMid:20078667. http://dx.doi.org/10.1111/j.1443-1661.2009.00919.x 45. Piesman M, Tsuchida A. Pseudomelanosis duodeni resolution with discontinuation of oral iron therapy. Am J Gastroenterol. 2002;97(9):S179. http://dx.doi.org/10.1016/ S0002-9270(02)05025-6

Autopsy and Case Reports 2011; 1(4): 39-44

Conflict of interest: None Submitted on: 17th November 2011 Accept on: 23rd November 2011 Correspondence: Serviço de Anatomia Patológica Av. Prof. Lineu Prestes, 2565 – Cidade Universitária - São Paulo – SP – Brazil CEP 05508-900 – Phone: +55 (11) 3091-9379 E-mail: aloisiosilva@hu.usp.br

Felipe-Silva A, Campos FPF, Silva JGN.

Autopsy and Case Reports 2011; 1(4): 45-49

Article / Clinical Case Report Artigo / Relato de Caso Clínico Osteosarcoma with atypical location in an elderly female patient Daniel Cury Ogataa, Rafael Saviolo Moreirab, Alberto Ramos Gomesc, Elisiário Pereira Netoa, Daniel Oséias Sezerinoa, Matsue Braga Hiranod Ogata DC, Moreira RS, Gomes AR, Pereira Neto E, Sezerino DO, Hirano MB. Osteosarcoma with atypical location in an elderly female patient. Autopsy Case Rep [Internet]. 2011;1(4):45-49. http://dx.doi.org/10.4322/acr.2011.016

ABSTRACT Osteosarcoma most frequently affects long bones, particularly around the knee, and is therefore rare in the forearm. We report the case of a 67-year-old woman presenting with progressive lesion of the distal radius. A pathological diagnosis of osteoblastic osteosarcoma was suspected and was confirmed by needle biopsy. There had been two other cases of osteosarcoma in the same family. The patient was treated with neoadjuvant chemotherapy followed by amputation of the arm below the elbow. Keywords: Radius; Juxtacortical osteosarcoma; Amputation; Adjuvant chemotherapy; Chemotherapy. CASE REPORT A 67-year-old female patient noticed swelling in her distal radius, followed by local pain one month later. She had a family history of osteosarcoma (a daughter who had died from it and a nephew who was currently under treatment for it) but had no other risk factors for the disease. The patient initially underwent X-ray of the forearm. The X-ray showed lytic lesion of the distal radius, with irregular contours and heterogeneous areas of sclerosis in the adjacent bone marrow, together with periosteal alterations in the typical “sunburst” pattern (Figure 1).

imaging (MRI) showed a bulky primary lesion of the distal radius. The lesion had a prominent soft tissue component with a locally aggressive aspect (Figure 2).

On the basis of the X-ray findings and the family history, the working diagnosis was osteosarcoma. Subsequent magnetic resonance

The proposed treatment was neoadjuvant chemotherapy with doxorubicin and cisplatin. However, because the clinical response was

Based on these results, we chose to perform a needle biopsy, which revealed high-grade osteoblastic osteosarcoma. Additional imaging tests ruled out the possibility of metastatic disease at the time of diagnosis of the primary lesion. The Enneking stage was IIB.

Pathologist - Universidade do Vale do Itajaí – Balneário de Camboriú/SC – Brazil. Dental Surgeon - Universidade do Vale do Itajaí – Balneário de Camboriú /SC – Brazil. c Orthopedic Oncologist - Hospital Marieta Konder Bornhausen – Itajaí/SC – Brazil. d Medical Student - Universidade do Vale do Itajaí – Balneário de Camboriú /SC – Brazil. a b

Autopsy and Case Reports 2011; 1(4): 45-49

Ogata DC, Moreira RS, Gomes AR, Pereira Neto E, Sezerino DO, Hirano MB.

unsatisfactory, only three cycles were performed. The arm was then amputated below the elbow (Figure 3). The pathological examination of the lesion again confirmed that it was high-grade osteoblastic osteosarcoma and showed minimal (Huvos grade 1) tumor necrosis (Figure 4). Figure 1 – X-ray of the forearm. Lytic lesion of the distal radius, with irregular contours and heterogeneous areas of sclerosis in the adjacent bone marrow, together with “sunburst” periosteal reaction.

The surgical margins were free of neoplasia. Currently, the patient began adjuvant chemotherapy, using the same initial regimen adding ifosfamide. At this writing, the patient was healthy, although the short follow-up period precluded a prognostic analysis.

Figure 2 – Nuclear magnetic resonance imaging (left) and macroscopic view of the lesion in the longitudinal plane (right). Note large soft tissue component ventrally displacing the flexor tendons, with no clear planes between the lesion and the tendons. There are signs of invasion of various extensor muscles, together with involvement of the interosseous membrane and anterior interosseous artery.

Figure 3 – Amputated arm showing a prominence in the region of the distal radius.

Osteosarcoma with atypical location in an elderly female patient

Autopsy and Case Reports 2011; 1(4): 45-49

Figure 4 – Photomicrographs showing osteoid (asterisk, in A; hematoxylin and eosin [H&E]; magnification, ×200) produced by anaplastic cells (arrow, in B; H&E; magnification, ×400). The tumor infiltrates striated muscle tissue (ellipse, in C; H&E; magnification, ×200), and tumor necrosis is minimal (arrows, in D; H&E; magnification, ×200).

DISCUSSION Osteosarcoma is one of the most common types of primary malignant bone tumor, second only to multiple myeloma and lymphoma.1,2 Osteosarcoma of the forearm is extremely rare,1 accounting for approximately 4% of all cases, only about half of which involve the radius.2 Morphologically, osteosarcomas are defined as mesenchymal tumors whose malignant cells produce bone matrix in the form of osteoid or as immature bone.3 Although these tumors occur in all age groups, the age distribution is bimodal, 75% of cases occurring in individuals below 20 years of age. A smaller peak of incidence is observed in individuals in older age. In such cases, there is typically some predisposing condition, such as a history of irradiation, Paget’s disease, and bone infarction. In the case reported here, a family history of osteosarcoma was the only predisposing factor.3 Considering the rarity of this type of neoplasm, the number of cases in which a family history of osteosarcoma has been reported is impressive. The study of the genetics of such tumors has made an important contribution to the understanding of cancer in general, one example

being the identification of the retinoblastoma protein (pRb), which plays a major role in cell cycle control. Another important gene is p53, the product of which regulates DNA repair. Although the basic mechanisms of osteosarcoma development are unknown, defects in pRb and p53 clearly play an important role in this process. This association is evidenced by the rare patients with germline mutations in the pRb gene, as well as in those with Li-Fraumeni syndrome, which involves a germline mutation of the p53 gene. In such patients, the risk of developing osteosarcoma can be as much as 1,000 times higher than in those without such mutations.4 Osteosarcoma typically occurs in the metaphyses of long bones, the knee being affected in more than half of all cases.5 In adolescence, the occurrence of osteosarcoma seems to be related to the growth spurt of puberty, occurring in the regions of most active growth, probably due to osteoblast activity.4 These tumors grow circumferentially across the cortex, infiltrating soft tissue and, in rare cases, invading the intra-articular spaces.2 Histologically, osteosarcomas are divided into three subgroups, in accordance with the proportion

Autopsy and Case Reports 2011; 1(4): 45-49

Ogata DC, Moreira RS, Gomes AR, Pereira Neto E, Sezerino DO, Hirano MB.

of bone matrix produced: predominantly osteoblastic osteosarcoma; predominantly chondroblastic osteosarcomas; and predominantly fibroblastic osteosarcomas. The histological type is defined on the basis of the predominance of more than 50% of one of the matrices.3 This subdivision seems to be of no prognostic importance, given that there is no significant difference in survival among patients with high-grade osteosarcoma, regardless of the subtype. The neoplastic cells of osteosarcomas vary from spindle-shaped to polyhedral cells, their nuclei being pleomorphic and hyperchromatic. Mitotic figures are easily seen, and atypical forms are readily identified.3 Production of bone or osteoid by tumor cells is essential for the definitive diagnosis.1 Other, unusual, histological types of osteosarcoma include giant cell-rich osteosarcoma,6 and epithelioid osteosarcoma,7 as well as small cell osteosarcoma and osteoblastoma-like osteosarcoma.8 Another important point involving histology is the degree of primary tumor necrosis after preoperative chemotherapy, which has been considered one of the most important prognostic factors.9 A tumor showing more than 90% necrosis, for instance, tends to have a favorable prognosis, whereas those showing little or no necrosis, as occurred in the case reported here, usually have a poor prognosis.2,9 Radiological findings include tubular bone metaphyseal location, mixed pattern of osteolysis and osteosclerosis, cortical destruction, periostitis, and soft tissue mass. 1 Purely lytic lesions are uncommon, occurring in only 10% of cases. In such cases, the differential diagnosis should include nonosteoid producing lesions, such as malignant fibrous histiocytoma, fibrosarcoma, metastatic disease, and Ewing’s sarcoma. Special osteosarcoma subtypes, producing little osteoid, should also be included.1 Computed tomography and nuclear MRI are useful for demonstrating soft tissue invasion, which is common in osteosarcomas. Nuclear MRI can also be useful for showing discrete, “punched-out” lesions in the bone marrow.2 High-dose neoadjuvant chemotherapy is the most widely recommended form of treatment,2 the objective of which is to increase the chances of saving the affected limb.5 Neoadjuvant chemotherapy plays an important role in tumor growth inhibition, allowing increasingly conservative resections.10 Doxorubicin, cisplatin, high-dose methotrexate with leucovorin rescue, and ifosfamide are currently considered the most effective agents against osteosarcomas.11 However, the ideal combination has yet to be

defined.11 At certain health facilities, ifosfamidecyclophosphamide-doxorubicin cycles are used.12 The lesion must then be surgically removed, with wide resection margins.12 Bielack et al.10 noted that the overall mean survival was higher for patients with wide resection margins than for those with narrower resection margins. Unfortunately, the patient described here did not respond well to the neoadjuvant chemotherapy. This might be directly related to the initial chemotherapy regimen. Because there is no consensus regarding the best combination of drugs for the treatment of osteosarcomas, various protocols are currently used. Therefore, it is possible to suppose that a different regimen might have yielded better results. The prognosis depends on numerous variables, including tumor size, histological type, metastases, cytogenetic changes, age, sex, and response to neoadjuvant chemotherapy.13 The location of the tumor has been an important prognostic factor. Greater proximity of osteosarcoma to the trunk is usually associated with lower survival.4 Daecke et al.5 found that the overall survival rates for cases of osteosarcoma of the hands and forearms were higher than was the mean survival rate for all cases of osteosarcoma. We reported the case of an elderly female patient with osteosarcoma of the distal radius. Although the patient had no history of bone disease or irradiation, she did have a family history of osteosarcoma. Although the short follow-up period precluded a prognostic analysis, there was no evidence of recurrence or metastatic disease at this writing.

REFERENCES

Joo I, Choi JA, Chung JH, Oh JH, Hong SH and Kang HS. Fibroblastic type osteosarcoma of the ulna: a Case Report of a tumor in a rare location with atypical imaging findings. Korean J Radiol. 2009; 10(1):85-8. PMid:19182508. PMCid:2647176. http://dx.doi.org/10.3348/kjr.2009.10.1.85

Vigorita VJ. Bone tumors. In: Vigorita VJ, editor. Orthopaedic pathology. Philadelphia: Lippincott Williams and Wilkins; 2008. p. 338-79.

Klein MJ, Siegal GP. Osteosarcoma: anatomic and histologic variants. Am J Clin Pathol. 2006; 125(4):55581. PMid:16627266. http://dx.doi.org/10.1309/ UC6KQHLD9LV2KENN

Osteosarcoma with atypical location in an elderly female patient 4.

Kansara M, Thomas DM. Molecular pathogenesis of osteosarcoma. DNA Cell Biol. 2007;26(1):1-18. PMid:17263592. http://dx.doi.org/10.1089/dna.2006.0505

Daecke W, Bielack S, Martini AK, et al. Osteosarcoma of the hand and forearm: Experience of the cooperative osteosarcoma study group. Ann Surg Oncol. 2005;12(4):32231. PMid:15827675. http://dx.doi.org/10.1245/ ASO.2005.06.002

Fu HH, Zhuang QW, He J, Huang LZ, He Y. Giant cellrich osteosarcoma or giant cell reparative granuloma of the mandibule? J Craniofac Surg. 2011;22(3):11369. PMid:21586969. http://dx.doi.org/10.1097/ SCS.0b013e3182108fbf

Kaveri H, Rekha K, Punnya VA. Epithelioid osteosarcoma of the maxilla: report of an unusual case. Br J Oral Maxillofac Surg. 2009;47(2):143-5. PMid:18762359. http://dx.doi. org/10.1016/j.bjoms.2008.07.188

Andrade Filho JS, Pena GP, Aymoré IL. Sistema osteoarticular. In: Brasileiro Filho G, editor. Bogliolo patologia. 8. ed. Rio de Janeiro: Guanabara Koogan; 2011: p. 1049-52. Portuguese.

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Huvos AG, Rosen G, Marcove RC. Primary osteogenic sarcoma: pathologic aspects in 20 patients after treatment with chemotherapy, en bloc resection, and prosthetic bone replacement. Arch Pathol Lab Med. 1977;101(1):14-8. PMid:299812.

10. Bielack S, Kempf-Bielack B, Delling G, et al. Prognostic factors in high grade osteosarcoma of the extremities or trunk. An analysis of 1702 patients treated on cooperative osteosarcoma study group protocols. J Clin Oncol. 2002;20(3):776-90. PMid:11821461. http://dx.doi.org/10.1200/JCO.20.3.776 11. Ritter J, Bielack SS. Osteosarcoma. Ann Oncol. 2010;21(7):320-5. PMid:20943636. http://dx.doi. org/10.1093/annonc/mdq276 12. Cassone AE, Barbe-Gonçalves JC, Silva AAM, Epelman S, Amstaldem EMI. Tratamento multi-disciplinar do osteossarcoma. Rev Bras Ortop. 1998:33(11):835-40. Portuguese. 13. Castro HC, Ribeiro KCB, Bruniera P. Osteossarcoma: experiência do Serviço de Oncologia Pediátrica da Santa Casa de Misericórdia de São Paulo. Rev Bras Ortop [Internet]. 2008;43(4):108-15. Portuguese.

Conflict of interest: None Submitted on: 12nd September 2011 Accept on: 10th October 2011 Correspondence: Prof. Dr. Daniel Cury Ogata Rua Jacob Schimdt, 102/304 – Bairro Pioneiros Balneário Camboriú/SC – Brazil CEP: 88331-015 E-mail: daniel.ogata@gmail.com

Autopsy and Case Reports 2011; 1(4): 51-56

Article / Clinical Case Report Artigo / Relato de Caso Clínico Placental polyp: a rare cause of iron deficiency anemia Fernando Peixoto Ferraz de Camposa, Ricardo Santos Simõesb, Aloísio Felipe-Silvac, Milena Degaspari Gonzalesb, Eder Nisi Iláriob Campos FPF, Simões RS, Felipe-Silva A, Gonzales MD, Ilário EN. Placental polyp: a rare cause of iron deficiency anemia. Autopsy Case Rep [Internet]. 2011;1(3):51-56. http://dx.doi.org/10.4322/acr.2011.017

ABSTRACT Placental polyps are defined as pedunculated or polypoid fragments of placenta or ovular membranes retained for an indefinite period of time into the uterus after abortion or child birth. An important cause of retention is placental accretism, an abnormal adherence of the placenta into the uterine wall. Chronic cases are rarely reported in the literature. In these cases, the placental retention in the immediate postpartum is not followed by heavy bleeding what makes the diagnosis challenging. We report a rare case of iron-deficiency anemia in a multiparous 29-year-old female patient two years after the last delivery. She sought medical care with clinical symptoms of anemia and recent menses alterations. There was no history of abortion. On gynecological examination, there was a twofold enlarged uterus, and the pelvic ultrasound revealed an image compatible with an endometrial polyp. She underwent open hysterectomy because of uncontrollable bleeding followed by hypotension after curettage. The histolopathologic examination revealed a partially hyalinized and necrotic placental polyp. Keywords: Iron deficiency; Anemia; Uterine hemorrhage; Placenta accreta; Hysterectomy. CASE REPORT A 29-years-old, previously healthy, female patient sought medical care because of palpitations, breathlessness and the feeling of near syncope. She complained of dyspnea on moderate exertion and slight lower limbs edema during the last week. She also reported a significant increase in the menstrual flow, with large amounts of blood clots, what was out of her regular menses. She had been prescribed intramuscular progesterone every three months for the last two years as the contraceptive method, receiving the last dose seven months ago. Patient denied having noted any other bleeding site. She did not present any comorbidity, drug allergies, smoking or alcohol

consumption. She had an obstetric history of five pregnancies, one of them a twin gestation, five vaginal deliveries. She did not follow adequate prenatal care in any of the five pregnancies. She has been recently diagnosed with anemia when it was prescribed oral iron supplementation. The physical examination showed a pale, hydrated, anicteric, afebrile (T = 37.1 °C) patient. The respiratory rate was 16 rmpm, pulse oxymetry = 98%, heart rate = 90 bpm with symmetrical and rhythmic pulse, blood pressure = 115 × 60 mmHg. There were no clinical signs of heart failure. On cardiac auscultation, a systolic murmur in the mitral area was evidenced. Lung and abdominal examination

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

Campos FPF, Simões RS, Felipe-Silva A, Gonzales MD, Ilário EN.

Autopsy and Case Reports 2011; 1(4): 51-56

were unremarkable. Laboratory tests are listed in Table 1 and 2. Ascaris lumbricoides was detected in a stool test. The bimanual gynecological examination was painless while evaluating the adnexa as well as mobilization of the cervix. The uterus was retroverted and twofold increased in size. The specular examination revealed neither bleeding discharge from the cervix nor any free fluid collected in the cul-de-sac. The transvaginal ultrasonography showed an increased uterine volume 254 cm3 (normal range = 180 cm3)with an echogenic mass in the inner lining of the uterus, measuring 5.2 × 3.6 × 2.9 cm, comprising blood vessels in its interior, which could correspond to a polyp. Urinary pregnancy test (total human chorionic gonadotropin) was negative.The patient was treated with red blood cells transfusion and albendazole 400 mg single dose. During the hospital stay, she restarted the genital bleeding which dropped the hemoglobin level to 5.4 g.dL–1. A surgical approach was attempted. Hysteroscopy was performed showing an irregular endometrial cavity with a polypoid formation on the anterior wall and a sessile mass on the fundus. The tubal ostia could not be visualized. Curettage product revealed a moderate amount of friable, amorphous and fetid material. The curettage was immediately followed by an uncontrolled heavy bleeding which ensued a severe hypotension. A total abdominal hysterectomy was undertaken allowing clinical stabilization. The surgical specimen examination showed a sessile, friable and

fetid mass adherent to the myometrium (Figure 1). Pathological examination detected a fragment of partially necrotic placenta accreta measuring 3.0 cm in the greatest diameter in the uterine fundus, consistent with a hyalinized placental polyp. The histology of the polyp was composed primarily of necrotic and hyalinized placental chorionic villi, but also of areas with preserved trophoblast, which penetrated superficially the myometrium (accretism). An acute polymorphonuclear inflammatory infiltrate and areas of hemorrhage with fibrin were observed along with necrotic areas. The surrounding endometrium showed chronic inflammatory infiltrate with plasma cells and granulation tissue (Figure 2).

Figure 1 – Longitudinal section of formalinfixed uterus, showing a 3.0 cm polypoid mass at the fundus. Observe a thickened myometrium compatible with multiparity.

Table 1 – Laboratory tests D0

Hemoglobin

4,8

3,9

12,3-15,3 g%

Hematocrit

36,0-45,0%

70-100%

APTT

0,99

<1,25

5-25 mg.dL–1

MCV

80-96 fL

MCH

27,5-33,2 pg

BUN

RDW

15,6

17,7

11-16 %

Creatinine

0,7

Leucocytes

16.200

11,900

4,4-11,3 103/mm3

Mielocytes

Sodium

136

134

136-146 mEq.L–1

Rods

1-5%

Potassium

3,9

4,5

3,5-5,0 mEq.L–1

Segmented

45-70%

Total bilir

0,17

0,3-1,2 mg.dL–1

Eosinophils

1-4%

ALT

9-36 U.L–1

Basophils

0-2,5%

AST

10-31 U.L–1

Linfocytes

18-40%

LDH

142

120-246 U.L–1

Monocytes

Glucose

70-99 mg.dL–1

Platelets

380.10

TSH

0,9

0,55-4,78 mcUI.mL–1

4 3

499.10

2-9% 3

150-40010 /mm 3

0,4-1,3 mg.dL–1

D0 = admission Day, D5 = fifth hospital Day, MCV = mean cospuscular volume, MCH = mean corpuscular hemoglobin, RDW = red cell distribution width, PT = prothrombin time, APTT = activated partial thromboplastin time, BUN = blood urea nitrogen, ALT = alanine aminotranspherase, AST = aspartate aminotranspharese, LDH = lactate dehydrogenase, TSH = thyroid stimulating hormone.

Placental polyp: a rare cause of iron deficiency anemia

Autopsy and Case Reports 2011; 1(4): 51-56

Figure 2 – Photomicrographs of the placental polyp: A - (HE-100x) placental villous with central fibrosis and hemorrhagic areas on the right; B - (HE-100x) detail of accretism with villi penetrating directly through the myometrium, without interposition of decidua; C - (HE-200x) area of necrotic villi with acute polymorphonuclear inflammatory infiltrate; D - (HE-400x) surrounding endometrium with lymphoplasmacytic inflammatory infiltrate and proliferation of capillaries. Table 2 – Iron metabolism tests and reticulocytes

membranes retained for an indefinite period of time into the uterus after abortion or child birth.

VR Serum iron

37-145 mcg.dL–1

Transferrin

291

250-410 mcg.dL–1

Ferritin

10-291 ng.mL–1

Saturation of transferrin

20-50%

Reticulocytes

50,000

24,000-84,000/mm3

Serum HCG was retrospectively dosed in a frozen stored sample resulted in 184.7 mUI.mL–1 (normal range = <10 mUI.mL–1). The postoperative period was uneventful and the patient was discharged on the third postoperative day.

DISCUSSION Placental polyps are defined as pedunculated or polypoid fragments of placenta or ovular

Baer was the first to recognize this condition in 1884 and since then some cases have been reported in the literature.1-5 Polyps can arise from placenta accreta, gestational trophoblastic disease and choriocarcinoma. An important cause of retained placenta is the accretism which consists in the abnormal adherence of the placenta into the uterine wall. It is believed that uterine atony combined with placenta accreta contributes to placental polyps development.1,6 The disease is classified according to the depth of trophoblastic tissue invasion, which can be superficial in the myometrium (placenta accreta) invade the myometrium in depth (placenta increta) or penetrate to or through the uterine serosa with or without invasion of the surrounding organs (placenta percreta).7

Autopsy and Case Reports 2011; 1(4): 51-56

About 80% of cases of placental polyps derived from placenta accreta,8 as in the present case report. There are numerous risk factors for placenta accreta and its incidence has been increasing in recent decades. The most important risk factor for placenta accreta is the placenta previa associated with the presence of uterine scar derived from myomectomy, cesarean deliveries and curettage.9,10 Maternal age, multiparity, smoking during pregnancy, hypertension during pregnancy, endometrial defects are other risk factors.9,11-13 The clinical picture of placenta accreta usually involves massive hemorrhage in the immediate postpartum and may lead to hypovolemic shock and death, usually demanding interventions that range from curettage to total hysterectomy. Other complications are the invasion of organs like the bladder, ureters, and neurovascular structures, consumptive coagulopathy, adult respiratory distress syndrome, renal failure, infection and thromboembolism.14,15 Usually, the clinical suspicion of placenta accreta is made by the ultrasonographic examination performed during the second or third trimester of the prenatal period. The findings, in ultrasound examination, associated with placenta accreta are: loss of the hypoechoic image in the retro placental area, the presence of many round and linear vascular lacunae which produce a ‘‘motheaten’’ appearance to the placenta, placental tissue or blood vessels crossing the uterus placental border; reduced myometrium thickness (less than 1 mm) and the presence of lacunae that exhibit marked turbulent blood flow by color doppler scanning.16-18 In chronic cases, the placental retention usually does not cause massive bleeding immediately after child birth, which indeed makes the diagnosis very difficult. Chronic cases are scarce in the literature and are characterized by pelvic pain; mild or moderate bleeding in the postpartum that may require some medical intervention19 and puerperal infections. The time for diagnosis is extremely varied ranging from days to years after delivery or abortion. In the case reported here, as some others in the literature, total human chorionic gonadotropin (HCG) was detected in the blood in low level, suggesting that the polyp can maintain placental endocrine activity with gestational cytoplasmics markers.20 The placental membranes are normally reabsorbed by macrophages and leukocyte degranulation in the affected area. 21 During the menstrual cycle there is a marked neutrophil infiltration into the endometrial tissue, mediated by interleukin 8 (IL-8), their degranulation takes part in the endometrial

Campos FPF, Simões RS, Felipe-Silva A, Gonzales MD, Ilário EN.

sloughing. 22 It is reported that chorionic cells synthesize and release IL-8, being inhibited by the administration of medroxyprogesterone acetate,22 what could explain the retaining of placental tissue observed in the present case, where this hormone has been prescribed after her last child-birth. It is known that iron deficiency is the most prevalent nutritional scarcity in less-favored social classes. Thus, the first hypothesis to explain the detected iron-deficiency anemia was attributed to low food intake as well as by multiparity and lack of medical follow-up, which are significant causes of iron depletion.23-26 Excessive menstrual bleeding is another cause of anemia in women during menacme27-29 and it was also taken in account because of the recent change in the patient’s menstrual pattern. Adult women have less storage iron, depending upon the extent of menses, pregnancies, deliveries, lactation, and iron intake. The perception about the menstrual cycle may be variable29,30 explaining the chronic iron deficiency in women without gynecologic complaints. In the case reported here we hypothesized that the patient did not realize how intense her menstrual bleedings were. Moreover, she has never followed prenatal care or any regular consultation, despite the multiparity and lactation. Only when the symptoms of anemia caused restrictions in her daily activities, she sought medical attention, otherwise she would probably neglect the menstrual pattern change. For this reason, we call attention for gynecological, nutritional and social evaluation in the setting of an iron-deficiency anemia.

ACKNOWLEDGEMENTS We are grateful to Rosa Maria C. Zanardi for the technical support on the visual work.

REFERENCES

Dyer I, Bradburn DM. An inquiry into the etiology of placental polyp. Am J Obst Gynecol. 1971; 109:858-67. PMid:5313723.

Hagstrom HT. Late puerperal hemorrhages due to placental polyp. Am J Obst Gynecol. 1940; 39:879-81.

Placental polyp: a rare cause of iron deficiency anemia 3.

Kurtz GR, Comando EN. Tree cases of late puerperal hemorrhages caused by placental polyp. Am J Obst Gynecol. 1953; 66:663-7. PMid:13080360.

Swan RW, Woodruff JD. Retained products of conception: histologic viability of placental polyps. Obst Gynecol. 1969; 34:506-14. PMid:4309817.

Baer BF. Placental polypus which simulated malignant disease of the uterus. Philadelphia Med Times. 1884; 15:175.

Hoberman LK, Hawkinson JA, Beecham CT. Placental polyps: report of three cases. Obst Gynecol. 1963; 22:259. PMid:13954878.

Bauer ST, Bonanno C. Abnormal placentation. Semin Perinatol. 2009;33:88-96. PMid:19324237. http://dx.doi. org/10.1053/j.semperi.2008.12.003

Belfort, MA. Placental accreta. Am J Obst Gynecol. 2010; 203:430-9. PMid:21055510. http://dx.doi. org/10.1016/j.ajog.2010.09.013

Clark SL, Koonings PP, Phelan JP. Placenta previa/accreta and prior cesarian ressection. Obst Gynecol.1985; 66.89-92.

10. Usta IM, Hobeika EM, Musa AA, Gabriel GE, Nassar AH. Placenta previa-accreta: risk factors and complications. Am J Obst Gynecol. 2005; 193:1045-9. PMid:16157109. http://dx.doi.org/10.1016/j.ajog.2005.06.037 11. Wu S, Kocherginsky M, Hibbard JU. Abnormal placentation: twenty year analysis. Am Obst Gynecol. 2005; 192:1458-61. PMid:15902137. http://dx.doi.org/10.1016/j.ajog.2004.12.074 12. Miller DA, Chollet JA, Goodwin TM. Clinical risk factors for placenta previa/placenta accreta. Am J Obst Gynecol. 1997; 177:210-4. http://dx.doi.org/10.1016/ S0002-9378(97)70463-0 13. Gielchinsky Y, Mankuta D, Rojansky N, Laufer N, Gielchinsky I, Ezra Y. Perinatal outcome of pregnancies complicated by placenta acreta. Obst Gyneol. 2004; 104:527-30. http:// dx.doi.org/10.1097/01.AOG.0000136084.92846.95 14. Washecka R, Behling A. Urologic complications of placenta percreta invading the urinary bladder: a case report and review of the literature. Hawaii Med J. 2002; 61:66-9. PMid:12050959. 15. O’Brien JM, Barton JR, Donaldson ES. The management of placenta percreta: conservative and operative strategies. Am J Obst Gynecol. 1996; 175:1632-8. http://dx.doi. org/10.1016/S0002-9378(96)70117-5 16. Twickler DM, Lucas MJ, Balis AB, et al. Color flow mapping for myometrial invasion in woman with a pior cesarian delivery. J Matern Fetal Med. 2000; 9:330-5. http://dx.doi. org/10.1002/1520-6661(200011/12)9:6%3C330::AIDMFM1002%3E3.0.CO;2-O 17. Levine D, Hulka CA, Ludmir J, Li W, Edelman R. R: placenta accreta: evaluation with color doppler US, power Doppler US and MR imaging. Radiology. 1997; 205:773-6. PMid:9393534.

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18. Comstock CH, Love Junior JJ, Bronsteen RA, et al. Sonographic detection of placenta accreta in the second and third trimestres of pregnancy. Am J Obstet Gynecol. 2004; 190:1135-40. PMid:15118654. http://dx.doi. org/10.1016/j.ajog.2003.11.024 19. Takeda A, Koyama K, Imoto S, Mori M, Sakai K, Nakamura H. Placental polyp with prominent neovascularization. Fertil Steril. 2010; 93:1324-6. PMid:19394597. http://dx.doi. org/10.1016/j.fertnstert.2009.03.065 20. Lawrence WD, Qureshi F, Bonakdar MI. “Placental polyp”: light microscopic and immunohistochemical observations. Hum Pathol. 1988; 19:1467-70. http://dx.doi.org/10.1016/ S0046-8177(88)80243-0 21. Kelly RW, Illingworth P, Baldie G, Leask R, Brouwer S, Calder AA. Progesterone control of interleukin-8 production in endometrium and chorio-decidual cells underlines the role of the neutrophil in menstruation and parturition. Hum Reprod. 1994; 9:253-8. PMid:8027281. 22. Lockwood CJ, Kumar P, Krikun G, et al. Effects of thrombin, hypoxia, and steroids on interleukin-8 expression in decidualized human endometrial stromal cells: implications for long-term progestin-only contraceptive-induced bleeding. J Clin Endocrinol Metab. 2004; 89:1467-75. http://dx.doi. org/10.1210/jc.2003-030141 23. Schumann K, Elsenhans B, Maurer A. Iron suplementation. J Trace Elem Med Biol.1998; 2:129-40. http://dx.doi. org/10.1016/S0946-672X(98)80001-1 24. Adish AA, Esrey SA, Gyorkos TW, Johns T. Risk factors for iron deficiency anaemia en preschool children in northern Ethiopia. Public Health Nutr. 1999; 2:243-52. http://dx.doi. org/10.1017/S1368980099000336 25. Singh K, Fong YF, Arulkumaran S. Anaemia in pregnancy - a cross-sectional study in Singapore. Eur J Clin Nutr. 1998; 52:65-70. PMid:9481535. http://dx.doi.org/10.1038/ sj.ejcn.1600517 26. Van Der Broek NR, Letsky EA, White SA, Skenkin A. Iron status in pregnant women: which measurements are valid? Br J Haematol. 1998; 103:817-24. PMid:9858238. http:// dx.doi.org/10.1046/j.1365-2141.1998.01035.x 27. Puolakka J, Janne O, Pakarinem A, Vihko R. Serum ferritin in the diagnosis of anemia during pregnancy. Acta Obst Gynecol Scand Suppl. 1980; 95:57-63. http://dx.doi. org/10.3109/00016348009156381 28. Taylor DJ, Mallen C, McDougall N, Lind T. Effect of iron supplementation on serum ferritin levels during and after pregnancy. Br J Obst Gynaecol. 1982; 89:1011–7. http:// dx.doi.org/10.1111/j.1471-0528.1982.tb04656.x 29. Kepczyk T, Cremings JE, Long BD, Bachinki MB, Smith LR, McNally PR. A prospective, multidisciplinar evaluetion of premenopausal woman with iron deficiency anemia. Am J Gastroenterol. 1999; 94:109-15. PMid:9934740. http:// dx.doi.org/10.1111/j.1572-0241.1999.00780.x 30. Bothwell TH, Charlton RW. Iron deficiency in Women: a report of. Washington. New York: Nutrition Foundation; 1981.

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Campos FPF, Simões RS, Felipe-Silva A, Gonzales MD, Ilário EN.

Conflict of interest: None Submitted on: 5th November 2011 Accept on: 14th November 2011 Correspondence: Divisão de Clínica Médica Av. Prof. Lineu Prestes, 2565 - Cidade Universitária - São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9200 E-mail: ffcampos@usp.br

Autopsy and Case Reports 2011; 1(4): 57-63

Article / Clinical Case Reports Artigo / Relato de Caso Clínico Primary aortoesophageal fistula: a rare cause of acute upper gastrointestinal bleeding Samira Ineida Morais Gomesa, Fernando Peixoto Ferraz de Camposb, Brenda Margatho Ramos Martinesc, João Augusto dos Santos Martinesc, Edmar Tafnerd, Luis Masuo Marutad Gomes SIM, Campos FPF, Martines BMR, Martines JAS, Tafner E, Maruta LM. Primary aortoesophageal fistula: a rare cause of acute upper gastrointestinal bleeding. Autopsy Case Rep [Internet]. 2011;1(4):57-63. http://dx.doi.org/10.4322/ acr.2011.018

ABSTRACT Acute upper gastrointestinal bleeding is a potentially life-threatening emergency, especially in the elderly. This condition accounts for approximately 1% of all emergency room admissions. Among the causes of such bleeding is aortoesophageal fistula, a dreaded but apparently rare condition, first recognized in 1818. The great majority of cases are of primary aortoesophageal fistula, caused by atheromatous aortic aneurysms or, less frequently, by penetrating aortic ulcer. The clinical presentation of aortoesophageal fistula is typically characterized by the so-called Chiari’s triad, consisting of thoracic pain followed by herald bleeding, a variable, short symptom-free interval, and fatal exsanguinating hemorrhage. The prognosis is poor, the in-hospital mortality rate being 60%. Conservative treatment does not prolong survival, and the in-hospital mortality rate is 40% for patients submitted to conventional surgical treatment. Here, we report the case of a 93-year-old woman who presented to the emergency room with a history of hematemesis. The patient was first submitted to upper gastrointestinal endoscopy, the findings of which were suggestive of aortoesophageal fistula. The diagnosis was confirmed by multidetector computed tomography of the chest. Surgery was indicated. However, on the way to the operating room, the patient presented with massive bleeding and went into cardiac arrest, which resulted in her death. Keywords: Aortic aneurysm; Atherosclerosis; Esophageal fistula; Gastrointestinal hemorrhage. INTRODUCTION Acute upper gastrointestinal bleeding (UGIB) is a life-threatening emergency situation that requires hospitalization. The incidence of acute UGIB ranges from 37 to 172/100 000 population, and the condition is responsible for approximately 1% of all emergency

room admissions.1,2 In a study conducted in Scotland, Blatchford et al.3 showed that the incidence of acute UGIB rises sharply with advancing age, being almost 6 times higher among individuals over 75 years of age than among those in the 15-29 year age bracket,

Heart Institute - Hospital das Clínicas - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP - Brazil. Department of Internal Medicine - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. c Diagnostic Imaging Service - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. d Endoscopy Service - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. b

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Gomes SIM, Campos FPF, Martines BMR, Martines JAS, Tafner E, Maruta LM.

as has also been reported by other researchers.4-6 Various studies have shown that the predominant cause of acute UGIB is peptic ulcer (duodenal or gastric), followed by varices, esophagitis, esophageal ulcer, gastritis, duodenitis, Mallory-Weiss syndrome, and malignancy.1 Population-based studies of allcause acute UGIB have shown that mortality ranges from 3% to 14% and increases markedly in parallel with increasing age. Blatchford et al.3 also showed that the mortality rate for acute UGIB was 100 times greater among individuals over 75 years of age than among those in the 15-29 year age bracket. There are at least two situations in which acute UGIB becomes life-threatening: abnormal communication between the aorta and the esophagus; and abnormal communication between the aorta and the gastrointestinal tract. These are represented by aortoesophageal fistula (AEF) and aortoenteric fistula, respectively.6 These uncommon causes of acute UGIB are typically identified post-mortem after an exsanguinating hemorrhage.7 The first report of AEF was in 1818 by Dubrueil, who described the case of a soldier dying from massive upper gastrointestinal hemorrhage 5 days after esophageal impaction of a bone fragment, which had penetrated the thoracic aorta.7,8 Since then, numerous cases of AEF, attributed to various causes, have been reported in literature. When AEF occurs in patients with no history of thoracic surgery, it is classified as primary AEF, which accounts for 95% of all cases, whereas it is classified as secondary AEF, which accounts for only 5% of all cases, when it occurs after thoracic aortic or esophageal surgery. Chart 1 shows the causes of AEF documented in literature.

CASE REPORT A 93-year-old female patient sought treatment in the emergency room of the University Hospital of the University of São Paulo, presenting with acute upper gastrointestinal bleeding. She had a clinical history of hypertension and cardiomyopathy with chronic atrial fibrillation. She reported dyspnea on mild exertion, together with chronic leg edema. She had been under treatment with carvedilol, captopril, furosemide, and spironolactone for the last 2 years. She complained of epigastric and substernal pain followed by evacuation resembling melena for the last few days before admission. Her first upper gastrointestinal bleeding episode was characterized by the emission of a small amount of blood mixed with saliva from her mouth while sleeping, as noted by her family. Because the bleeding was minimal,

Chart 1 – Etiology of AEFa Primary AEF

Secondary AEF

(95%)

(5%)

Ruptured thoracic aneurysm (atherosclerotic, dissecting, mycotic, syphilitic)

Repair of thoracic aortic aneurism (primary, allograft, prosthetic)

Penetrating aortic ulcers

Patent ductus arteriosus ligation

Malignant thoracic neoplasms (esophageal, bronchial)

Repair of coarctation of aorta

Esophageal foreign bodies

Esophageal surgery

Corrosive ingestion

Endovascular aortic stent-grafting

Benign esophageal ulcer

Esophageal instrumentation

Barrett’s ulcer Infections (tuberculosis, mediastinal abscesses) Prolonged nasogastric intubation Other (blunt or penetrating thoracic trauma, radiotherapy) a

Compiled from various sources6,7,9,10.

she was taken to a primary care facility, where she remained under clinical observation after being started on vitamin K, omeprazole, and intravenous saline infusion. On the next day, she began to bleed again and was referred to our hospital for endoscopic examination. At admission, she was conscious and lucid, although emaciated and pale. There were traces of blood in the oral cavity. Her blood pressure was 95/69 mmHg, and her pulse was 100 bpm. Pulmonary examination revealed decreased breath sounds at the right lung base. The abdomen was slightly painful on gentle palpation of the epigastrium. Rectal examination failed to reveal melena. The laboratory test results are shown in Table 1. Upper gastrointestinal endoscopy revealed pulsatile extrinsic compression of the esophagus at 25 cm from the superior dental arch (Figure 1). At the most prominent area of the mass, we observed a small ulceration of the mucosa with whitish material, interpreted as probable atheroma, emerging into the esophageal lumen (Figure 2). Because of these findings, the examination was promptly interrupted. The patient was submitted to multidetector computed tomography (CT) of the chest. The scan showed an elongated, tortuous, atheromatous

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

Table 1 – Laboratory test results Variable

Result

Reference value

Hemoglobin (g.dL–1)

11.3

12.3-15.3

Hematocrit (%)

35.7

360-45.0

Leukocytes (mm )

8900

4.4-11.3 × 103

Platelets (mm3)

281 000

150-400 × 103

Prothrombin time (INR)

1.58

AST (IU.L–1)

10-35

ALT (IU.L–1)

9-43

20-104

Total bilirubin (mg.dL )

0.6

0.3-1.2

K (mEq.L–1)

4.2

3.5-5

Creatinine (mg.dL )

4.6

0.4-1.3

BUN (mg.dL–1)

10-50

Glucose (mg.dL )

111

70-99

Amylase (IU.L–1) –1

–1

INR, international normalized ratio; AST, aspartate aminotransferase; ALT, alanine aminotransferase; K, potassium; BUN, blood urea nitrogen.

Autopsy and Case Reports 2011; 1(4): 57-63

aorta, with wall thickening and calcified plaques. The descending aorta was irregular and fusiform, with an average diameter of 46 mm. Multiple parietal ulcers were seen on the descending aorta. A fistula, measuring 15 mm in diameter, was observed in the proximal descending aorta, with active contrast extravasation generating a hematoma of 60 × 46 mm, which compressed the esophagus (Figures 3A and B). A massive thrombus was observed on the descending thoracic aorta extending inferiorly to the thoracoabdominal junction (Figures 4, 5 and 6). Considering the severity of the illness, the advanced age of the patient, the presence of multiple comorbidities, and the relative hemodynamic stability, she was immediately referred to a tertiary hospital for surgical treatment. However, extensive rebleeding and cardiac arrest resulted in her death prior to surgery.

DISCUSSION

Figure 1 – Upper gastrointestinal endoscopy showing extrinsic compression of the esophagus at 25 cm from the superior dental arch.

Figure 2 – Upper gastrointestinal endoscopy showing extrinsic esophageal compression with exteriorization of a whitish fibrinoid material through the fistula.

Thoracic aortic aneurysms constitute the most common cause of AEF. In 1978, Carter et al.11 reported 24 cases of AEF,16 (66%) of which were caused by aortic aneurysms, most due to arteriosclerosis. In 1991, Hollander & Quick showed that the cause of AEF is thoracic aneurysm in 54% of cases, esophageal foreign body in 19%, and malignancy in 17%.12 An additional cause of AEF is penetrating aortic ulcer (PAU). 13 First described in 1934 by Shennan,14 PAUs are among the least common causes of acute aortic syndrome. Resulting from the ulceration of a previous atherosclerotic plaque, PAUs penetrate the aortic wall from the internal elastic lamina to the arterial media. The hematoma is initially contained by the tunica adventitia leading to a false aneurysm formation.15 In elderly patients with multiple comorbidities, PAUs are common, high blood pressure being the most frequent risk factor.15 The patient described in the present case report had fusiform dilatation of the descending aorta with multiple atheromatous plaques. The ulceration and rupture of one of those plaques may have initiated the formation of the AEF. Approximately 10% of thoracic aneurysms break into the esophagus, which is the third leading site of rupture, after the pericardium and left pleura.12 Another possible explanation for the AEF reported here is the development of a PAU, which was located in the distal aortic arch, as is typical. Some authors have reported that PAUs have a benign clinical course and present a low risk of progression. However, aortic rupture and other serious complications have also

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Gomes SIM, Campos FPF, Martines BMR, Martines JAS, Tafner E, Maruta LM.

Figure 3 – Multidetector CT angiography. Sagittal reformatted images through the thorax showing active aortic bleeding generating an anterior hematoma (black arrow in A), which is compressing the posterior wall of the esophagus (white arrow in B).

Figure 4 – Multidetector CT angiography. Sagittal reformatted images through the thorax showing an anterior hematoma (in A, arrow), which is compressing the posterior wall of the esophagus (better observed in B, arrows) and a mural thrombus (th) into the descending aorta. Note the enlarged left atrium (LA). been reported.16,17 Formation of an AEF occurs at the descending thoracic aorta, where the aorta and the esophagus are in direct contact. Erosion of the esophagus by mechanical compression and ischemia results in infectious destruction of the aneurysm wall and consequently in the creation of a fistula.12 In the case reported here, it is possible that the rupture of the ulcer led to the formation of a pseudoaneurysm that created the AEF. Chiari described the typical syndrome of AEF as a triad comprising central chest pain or dysphagia,

a short symptom-free interval, followed by a sentinel hemorrhage, another symptom-free interval of hours or days, and finally fatal exsanguinating hemorrhage.18 In rare cases, there are recurrent, large, self-limiting hemorrhages. In the study conducted by Carter et al.11, 80% of the patients evaluated had a history of sentinel bleeding, as did 75% of the patients evaluated by Pipinos & Reddy.19 In a review of 500 cases of AEF, it was found that 59% of all patients had central chest pain and 45% had dysphagia.12 A 30-year review comprising all reported cases of AEF revealed that only 45% of patients meet all 3 criteria of Chiari’s

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

triad,20 as did the case reported here. Central chest pain can be caused by distention, erosion, or localized dissection of the aortic wall, as well as by esophageal perforation with mediastinitis or tumor invasion of the aorta or pleura. The bleeding might halt temporarily because of hypotension, spasm of the aortic wall, or pressure from a periaortic hematoma. After the dissolution of the hematoma or once the blood pressure returns to normal, the patient rebleeds.7,9 The suspicion of AEF should arise when there is a fresh, red, upper gastrointestinal hemorrhage in a patient diagnosed with thoracic aorta aneurysm

Figure 5 – Multidetector CT angiography. Axial image through the thorax showing active bleeding generating an anterior hematoma (black arrow) and mild right pleural effusion (white arrow).

Autopsy and Case Reports 2011; 1(4): 57-63

or thoracic aorta dissection, as well as in those with a history of esophageal surgery, aortic surgery, or even foreign body ingestion. Chiari’s triad is usually diagnostic.7 Another situation in which AEF should be suspected is that in which there is a massive hematemesis but only minimal blood in the stomach and no obvious source of bleeding on subsequent endoscopy. Endoscopy can also reveal a pulsatile submucosal mass, with or without clots; bluish grey mucosa due to submucosal dissection by blood or intramural hematoma; foreign bodies; or, in rare cases, an opening fistula. Chest X-ray findings of mediastinal widening, tortuous aorta, or calcifications can also raise the suspicion of AEF.11,21,22 In cases of AEF, CT angiography of the aorta will show the thoracic aneurysm, as well as its relationship with the esophagus and surrounding structures, as in the case reported here. The fistulous communication is rarely identifiable.23 Because many patients have abdominal aneurysms, an abdominal aortogram should also be obtained.9 A CT scan can also show periaortic hematoma, foreign body, neoplasia, mediastinal abscess, adherence of the esophagus to the aorta, or the presence of gas in the aneurysmal sac or around an aortic prosthesis.24,25 Barium esophagogram is contraindicated in the presence of bleeding; when not so contraindicated, it can show extrinsic compression and deviation, usually anterior and to the right, because most AEFs arise from an aneurysm of the descending aorta.7 Naschitz et al.26 described a clinical and radiological triad that is suggestive of AEF: upper gastrointestinal bleeding; aneurysmal dilatation of the aorta; and a filling defect on esophagogram.

Figure 6 – Three-dimensional volumetric reconstruction showing a descending thoracic aortic pseudoaneurysm (arrows) on the anterior aortic wall, and multiple atheromatous plaques. (A, right oblique anterior view; B, left oblique posterior view).

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Gomes SIM, Campos FPF, Martines BMR, Martines JAS, Tafner E, Maruta LM.

The prognosis of AEF is extremely poor. As of 1997, only six survivors had been reported.9 However, survival rates have increased due to improvements in intensive care facilities and greater awareness of the condition. As of 2005, 55 cases of AEF survival had been reported.27-29 Two different surgical techniques have been employed in the treatment of AEF: management of aortic rupture, together with immediate esophageal repair, which consists of direct suture or esophageal resection with esophagogastroplasty or coloplasty; and delayed esophageal repair. Although surgery continues to be the standard treatment for AEF, survival after aortic stent-graft implantation has been reported at various centers.30 However, aortic stent-grafting does not repair the esophagus, which means that there is still a substantial risk of mediastinitis, as well as of stentgraft infection. Marone et al.13 reported two cases that were successfully treated with aortic endovascular grafting followed by surgical repair of the esophageal lesion. We conclude that AEF is a rare and usually fatal condition. With the increase in life expectancy and therefore in atherosclerotic complications, as well as the increasing numbers of thoracic aortic procedures being carried out worldwide, the incidence of AEF is likely to increase. Early recognition, a high index of suspicion, improved clinical care, and better emergency services could increase the number of cases recognized prior to fatal hemorrhage and consequently increase the number of survivors.

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Leerdam ME. Epidemiology of acute upper gastrointestinal bleeding. Best Pract Res Clin Gastroenterol. 2008; 22(2):20924. http://dx.doi.org/10.1016/j.bpg.2007.10.011 Kaviani MJ, Pirasthfar M, Azari A, Saberifiroozi M. Etiology and outcome of patients with upper gastrointestinal bleeding: a study from South of Iran. Saudi J Gastroenterol. 2010; 16(4):253-9. PMid:20871188. PMCid:2995092. http://dx.doi.org/10.4103/1319-3767.70608

Blatchford O, Davidson LA, Murray WR. Acute upper gastrointestinal haemorrhage in west of Scotland: case ascertainment study. BMJ. 1977; 315(7107):510-4. PMid:932930. PMCid:2127364. http://dx.doi.org/10.1136/ bmj.315.7107.510

Van Leerdan ME, Vreeburg EM, Rauws EA, et al. Acute upper GI bleeding: did anything change? Time trends analysis of incidence and outcome of acute upper GI bleeding between 1993/1994 and 2000. Am J

Gastroenterol. 2003; 98(7):1494-9. PMid:12873568. http:// dx.doi.org/10.1111/j.1572-0241.2003.07517.x 5.

Paspatis GA, Matrella E, Kapsoritakis A, et al. An epidemiological study of acute upper bleeding gastrointestinal in Crete, Greece. Eur J Gastroenterol Hepatol. 2000; 12(11):1215-20. http://dx.doi. org/10.1097/00042737-200012110-00008

Silva ES, Tozzi FL, Otochi JP, et al. Aortoesophageal fistula caused by aneurysm of the thoracic aorta: Successful surgical treatment, case report, and literature review. J Vasc Surg. 1999; 30(6):1150-7. http://dx.doi.org/10.1016/ S0741-5214(99)70056-X

Kapoor S, Singh RK, Chattopadhyay TK. Aortoesophageal fistula: A rare dreaded cause of gastrointestinal haemorrhage. Surg Pract. 2005; 9(3):68-74. http://dx.doi.org/10.1111/j.17441633.2005.00258.x

Dubreuil. Observation sur la perforation de l’oesophage et de l’aorte thoracique par une portion d’os avale. J Univ Sci Med.1818;9:357-63. French.

Amin S, Luketich J, Wald A. Aortoesophageal fistula. Case report and review of literature. Dig Dis Sci.1998; 43(8):166571. PMid:9724148. http://dx.doi.org/10.1023/A:1018850728928

10. Mestres G, Rodríguez R, García-Madrid C, et al. Endovascular treatment of penetrating aortic ulcers: mid-term followup. Rev Esp Cardiol. 2011 Oct 24 [Epub ahead of print; cited 2011 Oct 20]. PMID: 22030342. 11. Carter R, Mulder GA, Snyder Junior EN, Brewer LA. Aortoesophageal fistula. Am J Surg. 1978; 136(1):26-30. http://dx.doi.org/10.1016/0002-9610(78)90195-2 12. Hollander JE, Quick G. Aortoesophageal fistula: a comprehensive review of the literature. Am J Med. 1991; 91(1):279-87. http://dx.doi.org/10.1016/00029343(91)90129-L 13. Marone EM, Coppi G, Kahlberg A, Tshomba Y, Chiesa R. Combined endovascular and surgical treatment of primary aortoesophageal fistula. Tex Heart Inst J. 2010; 37(6):722‑4. PMid:21224956. PMCid:3014136. 14. Shennan T. Dissecting aneurysms. London: Medical Research Council; 1934. Special report series, n. 193. 15. Stanson AW, Kazmier FJ, Hollier LH, et al. Penetrating atherosclerotic ulcers of the thoracic aorta: natural history and clinicopathologic correlations. Ann Vasc Surg. 1986; 1(1):1523. PMid:3504683. 16. Patel HJ, Williams DM, Upchurch Junior GR, Dasika NL, Deeb GM. The challenge of associated intramural hematoma with endovascular repair for penetrating ulcers of the descending thoracic aorta. J Vasc Surg. 2010; 51(4):829-35. PMid:20347678. http://dx.doi.org/10.1016/j.jvs.2009.11.050

Primary aortoesophageal fistula: a rare cause of acute upper gastrointestinal bleeding 17. Quint LE, Williams DM, Francis IR, et al. Ulcerlike lesions of the aorta: imaging features and natural history. Radiology. 2001; 218:719-23. PMid:11230645. 18. Chiari H. Ueber Fremdkörperverletzung des Oesophagus mit aortenperforation. Ber Klin Wochenschr. 1914; 51:79. German. 19. Pipinos II, Reddy DJ. Secondary aortoesophageal fistula. J Vasc Surg. 1997; 26(1):144-9. http://dx.doi.org/10.1016/ S0741-5214(97)70160-5 20. Heckstall RL, Hollander JE. Aortoesophageal fistula: recognition and diagnosis in the emergency department. Ann Emerg Med. 1998; 32(4):502-5. http://dx.doi.org/10.1016/ S0196-0644(98)70182-9 21. Sinar DR, De Maria A, Kataria YP, Thomas FB. Aortic aneurysm eroding the esophagus: case report and review. Am J Dig Dis. 1977; 22(3):252-4. PMid:300222. http:// dx.doi.org/10.1007/BF01072285 22. Sosnowik D, Greenberg R, Bank S, Graver LM. Aortoesophageal fistula: early and late endoscopic features. Am J Gastroenterol. 1988; 83(12):1401-4. PMid:3195546. 23. Edwards BS, Edwards WD, Connoly DC, Edwards JE. Arterial-esophageal fistulae developing in patients with anomalies of the aortic arch system. Chest. 1984; 86(5):7325. PMid:6488911. http://dx.doi.org/10.1378/chest.86.5.732 24. 24. Tierney Junior LM, Wall SD, Jacobs RA. Aortoesophageal fistula after perigraft abscess with characteristic CT findings.

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J Clin Gastroenterol. 1984; 6(6):535-7. PMid:6512230. http://dx.doi.org/10.1097/00004836-198412000-00009 25. Longo JM, Lopez-Rasines G, Ortega E, Pagola MA. CT demonstration of an aortoesophageal fistula. Cardiovasc Intervent Radiol. 1987; 10(2):84-5. PMid:3107831. http:// dx.doi.org/10.1007/BF02577972 26. Naschitz JE, Bassan H, Lazarov N, Grishkan A. Upper gastrointestinal bleeding, aneurismatic dilatation of the thoracic aorta and filling defect on the esophagogram: a diagnostic triad suggesting fistula. Radiologe. 1982; 22(6):2835. PMid:6981826. 27. Guillem P, Porte H, Techer E, Wurtz A. Aortoesophageal fistula of uncommon origin: perforation of a Barrett’s ulcer. Dis Esophagus. 2003; 16(3):259-60. PMid:14641321. http:// dx.doi.org/10.1046/j.1442-2050.2003.00339.x 28. Cho Y, Suzuki S, Katogi T, Ueda T. Esophageal perforation of aortic arch aneurysm treated free of mediastinitis without manipulating esophagus. Jpn J Thorac Cardiovasc Surg. 2004; 52(6):314-7. PMid:15242088. http://dx.doi. org/10.1007/s11748-004-0051-x 29. Lam EC, Brown JA, Whittaker JS. Esophageal foreign body causing direct aortic injury. Can J Gastroenterol. 2003; 17(2):115-7. PMid:12605249. 30. D’Ancona G, DagenaisF, Bauset R. Endoluminal stenting of the aorta as treatment of aortoesophageal fistula due to primary aortic disease. Tex Heart Inst J. 2002; 29(3):2167. PMid:12224728. PMCid:124764.

Conflict of interest: None Submitted on: 25th August 2011 Accept on: 3rd October 2011 Correspondence: Divisão de Clínica Médica Av. Prof. Lineu Prestes, 2565 - Cidade Universitária - São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9200 E-mail: ffcampos@usp.br

Autopsy and Case Reports 2011; 1(4): 65-66

Nominata

Nominata of the Reviewers of the Volume 1, 2011 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 2011. Their hard work certainly contributed to maintaining the scientific level of this journal. Reviewers

Specialty

Institution

Aleksander Snioka Prokopovitsch

Rheumatology

HU-USP

Alfredo Elias Gilio

Pediatrics

FMUSP e HU-USP

Alfredo José Mansur

Cardiology

INCOR HC FMUSP

Aloísio Souza Felipe da Silva

Pathology

HU- USP

Ana Luiza Werneck da Silva

Endoscopy

HU-USP

Antonio Carlos Nogueira

Cardiology

HU-USP

Beatriz Monica Sugai

Surgery/Endoscopy

Grupo Fleury

Carlos Eduardo Marcello

Cardiology

HU-USP

Cláudia Regina Gomes Cardim de Oliveira

Pathology

IOT HC FMUSP

Claudio Campi de Castro

Radiology

FMUSP e HU-USP

Cornélius Mitteldorf

Surgery

FMUSP e HU-USP

Denise Maria Avancini Costa Malheiros

Pathology

HC FMUSP

Douglas Salmazo Rocha Moralez

Otorhinolaryngology

HU-USP

Eduardo Genaro Mutarelli

Neurology

FMUSP

Erasmo Simão da Silva

Surgery

FMUSP

Evandro Sobroza de Mello

Pathology

HC FMUSP e ICESP

Fabio Franco

Infectious diseases

HU-USP

Fernando Peixoto Ferraz de Campos

Internal Medicine

HU-USP

Filomena Marino Carvalho

Pathology

FMUSP

Gracia Aparecida Martinez

Hematology

HC FMUSP

Hélio Rodrigues Gomes

Neurology

HC FMUSP

Itamar de Souza Santos

Internal Medicine

FMUSP e HU-USP

José Jukemura

Surgery

FMUSP

Juliana Pereira

Hematology

HC FMUSP e ICESP

Leonardo de Abreu Testagrossa

Pathology

HC FMUSP

Lorena Silva Laborda

Infectious Diseases

HU-USP

Lucia Andrade

Nephrology

HC FMUSP e Instituto Emílio Ribas, BR

Luciana Maragno

Dermatology

HU-USP

Luiz Alberto Benvenuti

Pathology

INCOR HC FMUSP

Luiz Antonio Machado César

Cardiology

FMUSP

Luiz Aparecido Bortolotto

Cardiology

INCOR HC FMUSP

Luiz Cesar Peres

Pathology

Sheffield Children`s Hospital, UK

Nominata

Autopsy and Case Reports 2011; 1(4): 65-66

Reviewers

Specialty

Institution

Marcello Fabiano de Franco

Pathology

UNIFESP

Marcio Ricardo Taveira Garcia

Radiology

ICESP

Maria Del Pilar Esteves Diz

Oncology

ICESP

Maria Irma Seixas Duarte

Pathology

FMUSP

Marina Penteado Sandoval

Pathology

Dermathology Group, Northern, New Jersey, EUA

Olavo Henrique Munhoz Leite

Infectious Diseases

HC FMUSP

Paulo Andrade Lotufo

Internal Medicine/ Epidemiology

FMUSP e HU-USP

Paulo Schmidt Goffi Júnior

Surgery

HU-USP

Paulo Sampaio Gutierrez

Pathology

INCOR HC FMUSP

Regina Schultz

Pathology

HC FMUSP

Ricardo Tapajós Martins Coelho Pereira

Infectious Diseases

HC FMUSP

Richard Halti Cabral

Surgery

ICB USP

Robert Henry Anderson

Pathology

Newcastle University, UK

Rodolfo Milani Júnior

Internal Medicine

HC FMUSP

Rodrigo Diaz Olmos

Internal Medicine

FMUSP e HU-USP

Rosa Maria Affonso Moyses

Nephrology

HC FMUSP

Rosa Maria Rodrigues Pereira

Rheumatology

FMUSP

Roseli Antunes Patzina

Pathology

HC FMUSP

Sheila Aparecida Coelho Siqueira

Pathology

HC FMUSP

Temístocles Pie de Lima

Obstetrics/ Gynecology

Hospital e Maternidade Leonor Mendes de Barros, BR

Thais Mauad

Pathology

FMUSP

Vera Demarchi Aiello

Pathology

INCOR HC FMUSP

Vitor Sérgio Kawabata

Cardiology

HU-USP

LEGEND 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. ICB USP - Instituto de Ciências Biomédicas 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. UNIFESP - Universidade Federal de São Paulo.