Autopsy & Case Report by Editora Cubo

ISSN 2236-1960

v. 6, n. 3, july/sept. 2016

Photomicrography of a renal artery branch showing a gap between the internal (fragmented and duplicated) and external elastica membranes in a case of segmental arterial mediolysis (Verhoeff’s Van Gieson stain; 12.5X)

Hospital Universitário Universidade de São Paulo

ISSN 2236-1960 September 2016, volume 6 number 3

Electronic Journal of the Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil President of the University of São Paulo Professor Marco Antonio Zago Superintendent of the University Hospital Professor Waldir Antônio Jorge

Editorial committee Editor in chief Maria Claudia Nogueira Zerbini, MD, PhD Scientific Editors Aloisio Felipe-Silva, MD, PhD Fernando Peixoto Ferraz de Campos, MD Larry Nichols, MD Support Team Lucimar da Silva Prado - Website content, Hospital Universitário da Universidade de São Paulo Tatiana Massaro - Technical support Editora Cubo, desktop publishing

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Editorial

Are pathologists becoming mere technicians? Larry Nicholsa Nichols L. Are pathologists becoming mere technicians? [editorial]. Autopsy Case Rep [Internet]. 2016;6(3):1-2. http://dx.doi.org/10.4322/acr.2016.046

How many hours each workday do you spend interacting with a computer screen instead of a person? As a pathologist, if you are signing out digital slides, flow cytometry or molecular diagnostic tests, interacting with a computer screen instead of a human being probably takes up most of your workday. Looking at glass slides is also usually without interpersonal interaction. Now ask yourself: of the diseases you are diagnosing, how much knowledge of their clinical manifestations (such as signs and symptoms) are you using to diagnose them? You do need years of training in morphology and the technical aspects of pathology to make the diagnoses that you make. The technical knowledge that you need of immunohistochemical, flow cytometric and other types of patterns continues to grow by leaps and bounds. For example, years ago, a lung biopsy showing adenocarcinoma would be signed out using only routine hematoxylin and eosin (H&E) staining, but now it increasingly requires immunostaining to confirm that it is lung primary and molecular testing for mutations conferring sensitivity to targeted therapy. Pathology journals are filled with pattern recognition technical information. Routine H&E morphology is a rapidly decreasing part of most pathology journal articles, and often it is absent altogether. Gross pathology is rarely discussed and the working knowledge of it required for surgical pathology specimen processing has largely passed from pathologists to pathology assistants. Pathologists’ knowledge of how the gross and microscopic pathology relate to the signs, symptoms and other a

clinical manifestations of diseases is fading. Under relentless pressure to simply make more diagnoses and the necessity of escalating technical knowledge to make those diagnoses, pathologists are increasingly becoming pattern recognition specialists, and are losing touch with most of the clinical aspects of the diseases they are diagnosing. As pathologists retreat into their laboratories with their computers to make diagnoses without reference to the clinical manifestations of the diseases they diagnose, they become technicians. They remain highly trained experts, but function as mere technicians, who do not use their knowledge of clinical medicine to do their work. Under these circumstances, it is only a matter of time before economic forces drive their replacement by technicians, who do not have training in clinical medicine. Such technicians would be easier to produce, and - no doubt - cheaper to employ. If the diagnoses of non-physician technicians are as correct as those of physician pathologists, why not use them instead? If the work of pathology making diagnoses is done by non-physician technicians, what might be lost? Clinicopathologic correlation could become a lost art. Technicians without clinical training would not be able to provide explanations of the signs and symptoms of disease. They could not contribute to the collaborative decision-making about treatment at tumor boards. To them, therapy for the diseases they diagnose would be a black box into which they put their diagnosis in one slot and the treatment comes out another slot. Attending tumor board would be a

Department of Pathology - Mercer University School of Medicine, Macon/GA – USA.

Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2016. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided the article is properly cited.

Are pathologists becoming mere technicians?

waste of their time and they would most likely prefer to be at their computers making more diagnoses instead. There is an independent force driving clinicopathologic correlation to extinction. This is the decreasing teaching of gross and microscopic pathology in medical education. As the amount of pharmacology, genetics, biochemistry and other basic sciences that medical students need to learn increases, gross and microscopic pathology (morphology) join gross anatomy and histology as ever decreasing components of medical education. Something has to give. The number of hours in a day, the number of days in a week, and the number of weeks in a year are not increasing. Pathologic diagnosis is becoming a black box for clinicians into which they put their patients’ specimens in one slot and the diagnosis comes out another slot. Instead of withdrawing into roles of nothing more than back-room morphologist diagnosticians, pathologists can find ways of integrating their diagnoses and knowledge of pathology into patient care and medical education - ways that utilize their knowledge as physicians. Pathologists can make themselves less replaceable by non-physician technicians if they bring their diagnoses to direct encounters with patients (as a team member), to decision-making conferences

(e.g. tumor boards), to policy-making meetings (e.g. patient safety committees), to clinicopathologic conferences, to radiologic conferences and to clinical case-based teaching in medical education. For example, pathologists are in a unique position among medical educators to expertly edit a case presentation of lung primary adenocarcinoma to teach how the signs and symptoms relate to the radiology, microscopic pathology, treatment and prognosis. As another example, a pathologist can see the instructional value, the lessons to be learned for diagnosis and for patient care from an autopsy or surgical pathology specimen and can write up a case report in collaboration with the patient’s clinicians. Publishing such case reports is a valuable contribution to patient care and medical education. The replacement of physician pathologists who can practice the art of clinicopathologic correlation by non-physician technicians who can only make diagnoses may be inevitable. Physician pathologists may be dinosaurs after the giant meteor of scientific knowledge has hit the Earth and small mammal technicians may be inevitably taking over the Earth of pathology. Robots with artificial intelligence may inevitably take over from them.

Correspondence Larry Nichols Department of Pathology - Mercer University School of Medicine 1550 College Street – Macon/GA 31207 – USA Phone: 478-301-2405 Nichols_l@mercer.edu

Autopsy and Case Reports 2016;6(3):1-2

Image in Focus

Periprostatic venous thrombosis Eduardo Paulino Júniora, Pedro Lobo Alcântara Nevesa, Luiz Otávio Savassi Rochab Paulino E Jr, Neves PLA, Rocha LOS. Periprostatic venous thrombosis. Autopsy Case Rep [Internet]. 2016;6(3):3-5. http://dx.doi.org/10.4322/acr.2016.0400

Image courtesy Dr. Eduardo Paulino Júnior Figure. Pathological findings of a 33-year-old male who underwent a craniotomy for resection of a WHO grade 2 frontal lobe oligodendroglioma; A - Coronal section of the encephalic frontal lobe showing a poorly defined reddish smooth mass in the cortex and white matter, with enlargement of the affected area, especially the superior frontal gyrus on the left hemisphere; B - Photomicrography of the central nervous system tumor depicting a diffusely infiltrating glioma composed of monomorphic cells with uniform round vesicular nuclei, distinct small nucleoli, and perinuclear halo (“fried egg appearance”); C - Gross examination of the prostate gland and surrounding tissue with extensive recent periprostatic venous thromboses; D - Gross examination of the lung showing a wedge-shaped, hemorrhagic area, based on the pleura, which corresponds to a recent pulmonary infarct due to a pulmonary embolism. Pathology and Forensic Department - Faculty of Medicine - Universidade Federal de Minas Gerais, Belo Horizonte/MG – Brazil. Internal Medicine Department - Faculty of Medicine - Universidade Federal de Minas Gerais, Belo Horizonte/MG – Brazil.

Periprostatic venous thrombosis

Oligodendroglial tumors account for less than 10% of diffuse type gliomas, which are graded from low to high according to the WHO 2015 classification.1 Patients harboring brain tumors — especially those with high-grade gliomas (HGG) — have a higher risk of developing venous thromboembolism (VTE), including deep venous thrombosis (DVT) and/or pulmonary embolism (PE).2,3 Local synthesis of the tissue factor (TF), along with many other factors, is related to an increased VTE rate in these patients, especially those who have undergone cranial neurosurgical procedures — particularly a biopsy or a subtotal resection. The combination of a neurosurgical intervention and a remnant tumor constitute a higher risk for thromboembolic events.3 In a previous study,3 among 63 HGG patients who were followed over a median period of 348 days, 15 (24%) presented VTE; 6 (40%) had DVT, which was located in the lower extremity in five of them; and 9 (60%) had PE (three in combination with DVT). TF, 4–7 a potent procoagulant factor whose synthesis is up-regulated in a variety of neoplasms (including HGG), might play an important role in the VTE pathogenesis. TF acts as a high-affinity receptor/co-activator for the coagulation factor VII/VIIa and triggers the coagulation cascade. A complex TF/VIIa formation activates factor X and leads to the generation of thrombin, which catalyzes the formation of fibrin and the activation of platelets, resulting in vascular occlusion and ischemia as well as inflammation and angiogenesis. In glioma cells, the amount of TF expression correlates with the histological grade. Tumor dormancy is influenced by TF. 4,7 Thus, indolent human glioma cells deficient for TF remain viable in cell cultures, but are permanently dormant for nearly a year when they are injected at a specific site, while the expression of TF leads to a stepwise transition to latent and overt tumor growth phases — a process preceded by the recruitment of vascular cells (CD105+) and myeloid (CD11b+ and F4/80+) cells. Importantly, the microenvironment orchestrated by TF expression drives permanent changes in the phenotype gene expression profile, the DNA copy number, and the DNA methylation state of tumor cells that escaped from dormancy. Some authors postulate that procoagulant events in the tissue microenvironment (niche) may affect the fate of occult tumor cells, 4

including biological and genetic progression to initiate full-blown malignancy.4 Periprostatic or paravaginal areas are rarely considered to be sites of clot origin in patients with PE.8,9 The majority of emboli have been demonstrated to originate in the veins of the legs. As far as we know, the first reported case of PE as a result of thrombosis from the periprostatic venous plexus in a young patient with a normal prostate gland and no history of prostate trauma was published in 2003.8 Three other cases were described three years later.9 In 1819, Gilbert Breschet provided the first detailed anatomic description of the vertebral venous plexus (VVP). It was described as a large plexiform valveless network of vertebral veins consisting of three interconnecting divisions and spanning the entire spinal column with connections to the cranial dural sinuses, which were distributed in a longitudinal pattern and ran parallel to the venae cavae with which they communicated, with multiple interconnections.10 In 1940, Oscar V. Batson reported the true functionality of the VVP by proving the continuity of the prostatic venous plexus with the VVP and proposed this route as the most plausible explanation for the distribution of prostate metastatic disease. With his seminal work, Batson reclassified the human venous system to consist of caval, pulmonary, portal, and vertebral divisions. Further advances in imaging technology confirmed Batson’s results. Today, the VVP is considered part of the cerebrospinal venous system, which is regarded as a unique, large-capacitance, valveless plexiform venous network in which flow is bidirectional. This system plays an important role in the regulation of intracranial pressure with changes in posture and venous outflow from the brain; whereas, in disease states, it provides a potential route for the spread of tumors, infections, or emboli.10 Keywords: Cancer; Glioma; Neurosurgery; Pulmonary embolism; Periprostatic venous thrombosis

REFERENCES 1. Wesseling P, van den Bent M, Perry A. Oligodendroglioma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015;129(6):809-27. http://dx.doi. org/10.1007/s00401-015-1424-1. PMid: 25943885. Autopsy and Case Reports 2016;6(3):3-5

Paulino E Jr, Neves PLA, Rocha LOS

2. Smith TR, Nanney AD 3rd, Lall RR, et al. Development of venous thromboembolism (VTE) in patients undergoing surgery for brain tumors: results from a single center over a 10 year period. J Clin Neurosci. 2015;22(3):51925. http://dx.doi.org/10.1016/j.jocn.2014.10.003. PMid:25533212. 3. Simanek R, Vormittag R, Hassler M, et al. Venous thromboembolism and survival in patients with high-grade glioma. Neuro-oncol. 2007;9(2):89-95. http://dx.doi. org/10.1215/15228517-2006-035. PMid:17327573. 4. Magnus N, Garnier D, Meehan B, et al. Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations. Proc Natl Acad Sci USA. 2014;111(9):3544-9. http://dx.doi.org/10.1073/ pnas.1314118111. PMid:24520174. 5. Hamada K, Kuratsu J, Saitoh Y, Takeshima H, Nishi T, Ushio Y. Expression of tissue factor correlates with grade of malignancy in human glioma. Cancer. 1996;77(9):1877-83. http://dx.doi.org/10.1002/ (SICI)1097-0142(19960501)77:9<1877::AIDCNCR18>3.0.CO;2-X. PMid:8646688.

6. Jo JT, Schiff D, Perry JR. Thrombosis in brain tumors. Semin Thromb Hemost. 2014;40(3):325-31. http://dx.doi. org/10.1055/s-0034-1370791. PMid: 24599439. 7. D’Asti E, Fang Y, Rak J. Brain neoplasms and coagulationlessons from heterogeneity. Rambam Maimonides Med J. 2014;5(4):e0030. http://dx.doi.org/10.5041/ RMMJ.10164. PMid: 25386346. 8. Reddy PV, Solomon D. Pulmonary emboli from massive thrombosis of the periprostatic venous plexus mimicking acute respiratory distress syndrome. Chest. 2003;124(4):251S. http://dx.doi.org/10.1378/ chest.124.4_MeetingAbstracts.251S. 9. Elhammady G, Schubeck AT, El-Najjar V, Robinson MJ. Postmortem demonstration of the source of pulmonary thromboembolism: the importance of the autopsy. Case Rep Vasc Med. 2011(2011):1-3. http://dx.doi. org/10.1155/2011/108215. PMid: 22937459. 10. Nathoo N, Caris EC, Wiener JA, Mendel E. History of the vertebral venous plexus and the significant contributions of Breschet and Batson. Neurosurgery. 2011;69(5):100714, discussion 1014. PMid:21654535.

Conflict of interest: None Submitted on: May 20th, 2016 Accepted on: June 15th, 2016 Correspondence Eduardo Paulino Júnior Pathology and Forensic Department – Faculty of Medicine – Universidade Federal de Minas Gerais (UFMG) Av. Prof. Alfredo Balena, 190 – Belo Horizonte/MG – Brazil CEP: 30130-100 Phone: +55 (31) 3409-9755 edupatol@gmail.com

Autopsy and Case Reports 2016;6(3):3-5

Article / Autopsy Case Report

Fatal hemoperitoneum due to segmental arterial mediolysis Aloísio Felipe-Silvaa,b, Fernando Peixoto Ferraz de Camposc, João Augusto dos Santos Martinêsd Felipe-Silva A, Campos FPF, Martinês JAS. Fatal hemoperitoneum due to segmental arterial mediolysis. Autopsy Case Rep [Internet]. 2016;6(3):7-15. http://dx.doi.org/10.4322/acr.2016.049

ABSTRACT Spontaneous hemoperitoneum due to vascular injury is a life-threatening condition mostly associated with aortic or splanchnic arterial disease, which stems from atherosclerotic, inflammatory, or infectious origin. However, in 1976, Slavin and Gonzales described a nonatherosclerotic arterial disease that may render aneurysmal formation predominantly in the splanchnic arterial bed. The clinical presentation is diverse, but abdominal pain and shock prevail. We report the case of a middle-aged man who presented a hemoperitoneum due to a middle colic artery aneurysm rupture and died after undergoing a surgical treatment attempt. The preoperative imaging study revealed the presence of a huge hematoma in the epiplon retrocavity, and abdominal free liquid as well as extensive arterial disease with multiple aneurysms. The autopsy findings included hemoperitoneum, hematoma in the upper left abdominal quadrant, the surgical ligature of the middle colic artery, and histologic features consistent with segmental arterial mediolysis. The authors call attention to this rare entity and highlight the autopsy as a fundamental examination to accurately reach this diagnosis. Keywords Splanchnic Circulation; Aneurysm; Abdominal Pain; Fibromuscular dysplasia; Autopsy

CASE REPORT A 61-year-old Caucasian man sought medical care complaining of colicky hypogastric pain accompanied by nausea and hyperdefecation over the past 2 days. The initial clinical evaluation was unremarkable except for mild hypertension. The patient denied any previous diagnosis, but was a tobacco smoker of 10 packs/year. The clinical complaint worsened in the hours after admission with vomiting and fever despite the administration of painkillers, scopolamine, and metoclopramide concomitant with the rise in

blood pressure. A few hours after admission, the patient presented a decreased level of consciousness accompanied by cold extremities, tachycardia, and severe hypotension (blood pressure of 50/30 mmHg). The cardiac, pulmonary examination results were average, but the abdomen was diffusely tender, and a crural hernia was easily reducible. Rectal examination was normal, and the patients’ clinical status improved with saline volume resuscitation. Laboratory work-up showed normocytic normochromic

Anatomic Pathology Service - Hospital Universitário - Universidade de São Paulo, São Paulo/SP – Brazil. Department of Pathology - Medical School - Universidade de São Paulo, São Paulo/SP – Brazil. c Internal Medicine Department - Hospital Universitário - Universidade de São Paulo, São Paulo/SP – Brazil. d Imaging Service - Hospital Universitário - Universidade de São Paulo, São Paulo/SP – Brazil. a

Fatal hemoperitoneum due to segmental arterial mediolysis

anemia (hemoglobin: 7.8 g/dL; reference value [RV]: 13-15 g/dL), a normal remaining blood cell count, hyperglycemia (glucose: 276 mg/dL; RV: < 100 mg/dL), prolonged prothrombin time (INR = 1.69; RV: 1.0), and metabolic acidosis (pH = 7.26 with HCO3 = 12 mEq/L; RV: 14 mEq/L). Electrolytes, renal function tests, amylase, lipase, liver enzymes, and myocardium necrosis markers were normal. The electrocardiogram showed sinus tachycardia. The multidetector abdominal computed tomography showed, in the arterial phase, the presence of a hyperattenuating fluid in the epiplon retrocavity (Figure 1A) peripancreatic regions, and within the free abdominal cavity, consistent with intra-abdominal hemorrhage (Figure 1A, B). The angiographic study showed signs of small- and

medium-sized vessels arteriopathy. Several branches of the celiac trunk, and the superior and inferior mesenteric arteries, showed diffuse caliber reduction, contour irregularity associated with narrowing and dilation, as well as segmental thrombosis. Saccular aneurysms were also found in the branches of both renal arteries close to the hilum and in the medium colic artery that emerged from the celiac trunk, which was most likely the origin of the hemoperitoneum. Active bleeding signs were not identified during the tomographic examination (Figure 1C, D; Figure 2). Despite the adopted supportive measures, the clinical status rapidly deteriorated, and the patient was submitted to an exploratory laparotomy, which evidenced a huge hemoperitoneum (up to 3 L of bloody

Figure 1. Computed tomography of the abdomen. A and B - Axial plain showing a hematoma (H) in the epiplon retrocavity, and free liquid (fl) in the peritoneal cavity; C and D - Involvement of the medium sized splanchnic arterial bed with an aneurysm in the medium colic artery (arrow in C) and narrowing of the left colic artery by thrombosis and dissection (arrow in D). L = liver; S = spleen; UB = urinary bladder. 8

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Figure 2. 3D reformation of the computed tomography of abdomen showing the involvement of the small and medium sized splanchnic vascular bed with marked narrowing of the celiac trunk branches and superior mesenteric artery. In the central figure, small aneurysms are shown with the white arrows, and the medium colic artery aneurysm is shown with a black arrow. Note that the aorta and iliac arteries are free of lesions. effusion in the abdominal cavity) along with a huge hematoma in the infrapancreatic region (involving the body and the tail of the pancreas), and in the Treitz angle. After releasing the colonic splenic angle, active bleeding was depicted from arteries that could not have their origin precisely identified. Artery ligation was attempted, but the patient presented a cardiac arrest during the surgical procedure, which was promptly reversed with cardiac massage. Supposedly to stop the bleeding, surgical dressings were left in the cavity, and the surgical wound was sutured. Although the patient received a transfusion of a significant volume of blood components, and an infusion of vasoactive drugs, he died 5 hours after the surgical procedure.

AUTOPSY FINDINGS An autopsy was performed a few hours after the patient’s death. Upon inspection, the abdomen was moderately distended, and blood easily leaked from the surgical suture upon manipulation. The abdominal cavity showed a huge hemoperitoneum with surgical dressings soaked in blood. An extensive hematoma up to 1000 mL affected the pancreas, duodenal wall, left kidney, left adrenal gland, spleen, diaphragm, mesentery, and mesocolon (Figure 3A). A small Autopsy and Case Reports 2016;6(3):7-15

ruptured and sutured aneurysm was detected at the distal site of the middle colic artery (Figure 3B). The hematoma and local splanchnic vessels were sampled for histology. The kidneys and liver looked anemic due to massive intra-abdominal hemorrhage. The aorta showed some uncomplicated atherosclerotic plaques (mild atherosclerosis) and a normal diameter, without dissection or aneurysm. The heart showed moderate left ventricular hypertrophy (2.0 cm), and the coronary and cerebral arteries showed only mild atherosclerosis. On histologic examinations, acute arterial dissection was observed along the sampled middle colic artery. The ruptured aneurysm showed medial defects, such as a detachment of the adventitia from the outer media (gap-aneurysm) and accompanying dissecting hematoma, with fibrin deposition, hemorrhage, and necrosis. Dissection of the hematoma showed areas of internal elastica loss, and areas of expansion and compression of the adventitia (Figure 4). Areas of preserved medial muscle of the artery showed vacuolar change with membranous residues, apoptotic figures, and micro hemorrhages (Figure 5). Areas of thrombosis were seen amidst the interstitial hematoma. These findings were consistent with segmental arterial mediolysis in the injurious or acute phase. 9

Fatal hemoperitoneum due to segmental arterial mediolysis

Figure 3. A - Gross aspect of abdominal hematoma upon autopsy; B - Clot and surgical suture of the middle colic artery (arrow).

Figure 4. Photomicrography of the medium colic artery. A - Ruptured aneurysm with detachment of the adventitia (arrows) from the outer media (gap-aneurysm [asterisk]) with fibrin (F) and partial necrosis of the media (M) (H&E,Â 12.5X); B - Dissecting hematoma (asterisk) in the distal segment expansion, and compression of the adventitia (arrow) (H&E, 12.5X); C and D - Gap and rupture of the media (M) with areas of internal elastica (white arrow) loss. (C = H&E, 200X; D = Verhoeff, 12.5X original magnification). 10

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Additionally, the left renal artery showed a medial gap in a chronic phase with fibromuscular thickening of the media, and adventitial fibrosis and

thickening (Figure 6), while branches of the right renal artery showed focal medial muscle vacuolization and apoptosis. The splenic artery showed eccentric

Figure 5. Photomicrography of the medium colic artery. A - Vacuolar change in smooth muscle cells of the media layer (H&E, 200X); B - Vacuolar change, apoptotic cell (arrowhead) and micro hemorrhages (arrows) in the interface between the outer media and adventitia (A) (H&E, 400X).

Figure 6. Photomicrography of the left renal artery branch. A - Healed gap (asterisk) between media and adventitia with fibromuscular thickening and adventitial fibrosis (H&E; 12.5X); B - Detail of the fibromuscular gap (Masson’s trichrome; 100X); C - Dilated portion of the left renal artery (aneurysm) showing intimal medial fibrous hyperplasia (asterisk) and adventitial (A) fibrosis (H&E; 12.5X); D - Same artery as in image A. Healed phase of SAM showing a gap between internal (fragmented and duplicated) and external elastica membranes (Verhoeff’s Van Gieson stain; 12.5X). Autopsy and Case Reports 2016;6(3):7-15

Fatal hemoperitoneum due to segmental arterial mediolysis

adventitial fibrosis and mild intimal thickening. The inferior mesentery showed atherosclerotic intimal thickening. Curiously, as a microscopic autopsy finding, a couple of bronchial artery branches showed fibromuscular thickening, which was similar to the medial hyperplasia pattern described in fibromuscular dysplasia. The findings in the renal and splenic arteries were interpreted as healing or a chronic phase of segmental arterial mediolysis. Capillary and arteriolar sclerosis (arteriolosclerosis) were observed in the spleen and the small vessels of the kidneys, and were attributed to arterial hypertension. Ischemic signs of systemic shock were observed in the central nervous system (CNS), kidneys, and gastrointestinal tract.

DISCUSSION Descriptions on artery diseases dated from the 2nd century AD when the Greek surgeon Antyllus gave a clear description of the aneurysm and its potential for rupture.1 Even though it is not documented, Ruffer2,3 claimed that arterial degenerative diseases were prevalent amongst the Egyptians. Although preceded by many scholars, the founder of cardiovascular pathology–Giovanni Maria Lancisi (1654-1720)–began to study aneurysms more precisely, as shown in his work entitled “De Motu Cordis et Aneurysmatibus,” which was posthumously published in 1728.4 Nevertheless, the history of aneurysms includes additional works by William and John Hunter, Morgagni, Rokitansky, and Virchow, which further contributed to the knowledge of the pathophysiology of arterial diseases.3 Arterial diseases have been well studied; however, this knowledge is continuously growing, and new arterial diseases are still being described. In 1976, Slavin and Gonzales-Vitale 5 first described the “segmental mediolytic arteritis,” from studying three autopsied patients with arterial lesions in the abdominal muscular arteries characterized by either partial or total mediolysis, linear deposition of fibrin between the media and adventitia, and variable inflammatory infiltrate. This entity was further named segmental arterial mediolysis (SAM) because of the scarcity of the inflammatory findings. According to the original description, mediolysis is responsible for the development of arterial gaps, which become sites 12

prone to dissecting aneurysms, or arterial luminal occlusion. Massive life-threatening intra-abdominal or retroperitoneal hemorrhage, splanchnic ischemia, or organ injury are the results of such arterial disease. From 1976 to 2012, 85 cases of SAM were compiled and systematically reviewed by Shenouda et al., 6 which showed that SAM occurred mostly in the sixth decade of life with a slight predominance among men (male:female ratio is 1.5:1), and that systemic arterial hypertension was the unique associated comorbidity (found in 21% of the cases). Inada et al. 7 showed the mortality rate of 50% associated with aneurysm rupture. The case reported herein fulfilled the epidemiological and clinical features of SAM. Despite the multiple aneurysms presented in our patient’s imaging studies, the ruptured aneurysm was of the middle colic artery, which is frequently found in descriptions of the literature. Along with the involvement of the abdominal arteries, SAM is also described in the CNS (mostly in the internal carotids and vertebral arteries), renal arteries, aorta, and iliac arteries. The celiac trunk, splenic artery, hepatic artery (commonly, or its branches), middle colic artery, and gastroepiploic artery are the most involved abdominal vessels, in descending order of appearance.6,7 The involvement of the pericardial arteries has been reported in neonates, children, and young patients. 8-11 In one-third of cases, multiple arterial lesions are observed mostly within the abdominal cavity,7,11 and the simultaneous involvement of the CNS and splanchnic arteries also has been reported. 12,13 Although incidentally diagnosed, asymptomatic cases have been reported, and subclinical presentation cases are suspected, the clinical features of SAM are mainly characterized by abdominal pain, abdominal distension, and shock, which are followed by neurologic symptoms.6,7,14-16 Our patient presented imaging evidence of different phases of SAM; therefore, we deduced that the disease may have previously started without symptoms. At the time of the middle colic artery’s dissection and rupture, the patient’s complaint became disabling. It is probable that the initial episode of pain and intestinal habit alteration was due to the involvement of the left colic artery, which was revealed as entirely altered at the imaging examination. Based on the morphologic changes, Slavin 17 proposed that SAM is a vasospastic disorder due to Autopsy and Case Reports 2016;6(3):7-15

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hyperdense areas of alpha-1 adrenergic receptor on the membrane of the arterial medial smooth muscle cells. The hyperactivation of the muscle fibers promotes a cytoplasmic Ca + overload with consequent mitochondrial dysfunction, mediolysis, and/or apoptosis easing the detachment of the outer media from the adventitia. Nonetheless, the association of some cases of SAM with autoimmune diseases (e.g. systemic lupus erythematosus, Crohn’s disease, Grave’s disease, thyroiditis, and the presence of immunoglobulin G (IgG), IgM and the demonstration of the presence of complement’s components in the affected vessel wall, also favor the possibility of an immunological mechanism in the pathogenesis of SAM.18-21 The clinical history in the present case did not show evidence of any administered sympathomimetic drugs, weight-reducing or muscle-building agents that could trigger an abnormal adrenergic response. However, this hypothesis cannot be ruled out due to the acute presentation and the limited clinical data. The diagnosis of SAM relies on angiographic and histologic findings. The angiographic findings overlap with inflammatory vasculitis and collagen diseases, and include arterial dilation, single or multiple aneurysms, arterial stenosis, dissecting hematomas, and arterial occlusion.7,14,16 Histologic features include an acute injurious phase and a reparative phase. The initial lesion or mediolysis occurs in segments of the arterial bed. It is caused by cytoplasmic vacuolization of a circumferential sector or the entirety of the outer media smooth muscle cells that may evolve to the whole media, preserving the intima and internal elastica. This pattern of injury, when healed after granulation tissue repair, renders stenosis very similar to the histologic findings of fibromuscular dysplasia (FMD). Mediolysis may also be accompanied by the loss of the intima, and internal elastica, forming arterial gaps with subsequent saccular or fusiform aneurysms development. These aneurysms can rupture or resolve, depending on their size. Nevertheless, a dissecting aneurysm also may arise at the intact arterial wall of the gap, continuing the dissection between the outer media and the adventitia.16 These injury phases may be found concomitantly in different arteries or in different segments of the same vessel in the first weeks of bleeding.16 Our patient’s histologic findings were consistent with the diagnosis of SAM. Unfortunately, the sampling of many other abdominal arteries for Autopsy and Case Reports 2016;6(3):7-15

histology and pathologic examination was limited by the huge abdominal hematoma, although some of the main branches could be examined. Crucially, we managed to demonstrate the acute and chronic injurious phases of SAM in the sampled arteries. The differential diagnosis of SAM depends on the phase of the arterial lesions and includes cystic medial necrosis; systemic and inflammatory vasculitis (e.g. polyarteritis nodosa, Behçet syndrome); mycotic aneurysm; collagen vascular diseases (e.g. Ehler-Danlos syndrome); splanchnic atherosclerotic aneurysms; and FMD.22 Each one has its typical clinical or histologic features that permit their differentiation in most cases. The epidemiological, clinical, and histologic features presented by our patient were not consistent with any of the aforementioned diagnostic possibilities. Some cases diagnosed in the advanced stage of the reparative phase of SAM may show close similarity with FMD. However, these two entities exhibit different ages of onset, sex, distribution of the affected arteries, and clinical symptoms. In our case, we could evidence all the phases of SAM in different vascular beds.23 We dared to consider the pulmonary, renal, and splenic arterial findings (which resembled an FMD lesion) as an advanced reparative phase of SAM in the lung, which widened the spectrum of arterial involvement of our case to the bronchial vessels. In a recent review, Kim et al. 24 found 101 cases of SAM in a total of 76 studies, with 22% of SAM-related mortality and very rare involvement of arteries outside the abdomen. Our case set great store by the autopsy in revealing this uncommon diagnosis. Without the autopsy study, it is likely that this case would have been interpreted as an atherosclerotic splanchnic aneurysm, and the extension to the lung and spleen would not have been detected. We also call attention to this diagnostic possibility and strongly advise the angiographic study in older patients with abdominal pain of an unknown cause.

ACKNOWLEDGEMENTS The authors thank Dr. Richard Slavin for consultation on the pathological findings. Felipe-Silva A and Campos FPF contributed equally to the article. 13

Fatal hemoperitoneum due to segmental arterial mediolysis

REFERENCES 1. Fortner G, Johansen K. Abdominal aortic aneurysms. West J Med. 1984;140(1):50-9. PMid:6702193. 2. Ruffer MA. On arterial lesions found in Egyptians mummies. J Pathol & Bact. 1911;XV:453. 3. Stehbens WE. History of aneurysms. Med Hist. 1958;2(4):274-80. PMid:13599778. http://dx.doi. org/10.1017/S0025727300023978. 4. Fye WB. Profiles in Cardiology. Giovanni Maria Lancisi, 1654-1720. Clin Cardiol. 1990;13(9):6701. PMid:2208828. http://dx.doi.org/10.1002/ clc.4960130917. 5. Slavin RE, Gonzalez-Vitale JC. Segmental mediolytic arteritis: a clinical pathological study. Lab Invest. 1976;35(1):23-9. PMid:940319. 6. Shenouda M, Riga C, Naji Y, Renton S. Segmental arterial mediolysis: a systematic review of 85 cases. Ann Vasc Surg. 2014;28(1):269-77. PMid:23988553. http://dx.doi. org/10.1016/j.avsg.2013.03.003. 7. Inada K, Maeda M, Ikeda T. Segmental arterial mediolysis: unrecognized cases culled from cases of ruptured aneurysm of abdominal visceral arteries reported in the Japanese literature. Pathol Res Pract. 2007;203(11):771-8. PMid:17920781. http://dx.doi. org/10.1016/j.prp.2007.07.010. 8. Slavin RE, Inada K. Segmental arterial mediolysis with accompanying venous angiopathy: a clinical pathologic review, report of 3 new cases, and comments on the role of endothelin-1 in its pathogenesis. Int J Surg Pathol. 2007;15(2):121-34. PMid:17478765. http://dx.doi. org/10.1177/1066896906297684. 9. Slavin RE, Cafferty L, Cartwright J Jr. Segmental mediolytic arteritis: a clinicopathologic and ultrastructural study of two cases. Am J Surg Pathol. 1989;13(7):558-68. PMid:2660608. http://dx.doi.org/10.1097/00000478198907000-00003. 10. Lie JT, Berg KK. Isolated fibromuscular dysplasia of the coronary arteries with spontaneous dissection and myocardial infarction. Hum Pathol. 1987;18(6):6546. PMid:3596585. http://dx.doi.org/10.1016/S00468177(87)80368-4. 11. Inada K, Ikeda T. Fifty-two cases of segmental arterial mediolysis (SAM). Pathol Clin Med. 2008;26:185-94. 12. Ro A, Kageyama N, Takatsu A, Fukunaga T. Segmental arterial mediolysis of varying phases affecting both the intra-abdominal and intracranial vertebral arteries: an autopsy case report. Cardiovasc Pathol. 2010;19(4):24851. PMid:19375356. http://dx.doi.org/10.1016/j. carpath.2009.02.002. 13. Sakata N, Takebayashi S, Shimizu K, et al. A case of segmental mediolytic arteriopathy involving both 14

intracranial and intraabdominal arteries. Pathol Res Pract. 2002;198(7):493-500. PMid:12234069. http://dx.doi. org/10.1078/0344-0338-00290. 14. Kalva SP, Somarouthu B, Jaff MR, Wicky S. Segmental arterial mediolysis: clinical and imaging features at presentation and during follow-up. J Vasc Interv Radiol. 2011;22(10):1380-7. PMid:21840227. http://dx.doi. org/10.1016/j.jvir.2011.07.001. 15. Takagi C, Ashizawa N, Eishi K, Hatashi T, Tanaka K, Seto S, Yano K. Segmental mediolytic arteriopathy involving celiac to splenic and left renal arteries. Inter Med. 2003;42:818-23. 16. Slavin RE. Segmental arterial mediolysis: course, sequelae, prognosis and pathologic-radiologic correlation. Cardiovasc Pathol. 2009;18:352-60. 17. Slavin RE. Segmental arterial mediolysis: a review of a proposed vascular disease of the peripheral sympathetic nervous system: a density disorder of the alpha-1 adrenergic receptor? J Cardiovasc Dis Diagn. 2015;3(2):190. 18. Inayama Y, Kitamura H, Kitamura H, Tobe M, Kanisawa M. Segmental mediolytic arteritis; clinicopathologic study and three-dimensional analysis. Acta Pathol Jpn. 1992;42(3):201-9. PMid:1570742. 19. Juvonen T, Niemelä O, Reinilä A, Nissinen J, Kairaluoma MI. Spontaneous intraabdominal haemorrhage caused by segmental mediolytic arteritis in a patient with systemic lupus erythematosus: an underestimated entity of autoimmune origin? Eur J Vasc Surg. 1994;8(1):96100. PMid:8307224. http://dx.doi.org/10.1016/S0950821X(05)80128-8. 20. Juvonen T, Räsänen O, Reinilä A, et al. Segmental mediolytic arteritis: electronmicroscopic and immunohistochemical study. Eur J Vasc Surg. 1994;8(1):70-7. PMid:8307220. http://dx.doi.org/10.1016/S0950-821X(05)80124-0. 21. Basso MC, Flores PC, Marques AA, et al. Bilateral extensive cerebral infarction and mesenteric ischemia associated with segmental arterial mediolysis in two young women. Pathol Int. 2005;55(10):632-8. PMid:16185293. http:// dx.doi.org/10.1111/j.1440-1827.2005.01881.x. 22. Filippone EJ, Foy A, Galanis T, et al. Segmental arterial mediolysis: report of 2 cases and review of the literature. Am J Kidney Dis. 2011;58(6):981-7. PMid:21872379. http://dx.doi.org/10.1053/j.ajkd.2011.05.031. 23. Pillai AK, Iqbal SI, Liu RW, Rachamreddy N, Kalva SP. Segmental arterial mediolysis. Cardiovasc Intervent Radiol. 2014;37(3):604-12. PMid:24554198. http://dx.doi. org/10.1007/s00270-014-0859-4. 24. Kim HS, Min SI, Han A, Choi C, Min SK, Ha J. Longitudinal evaluation of segmental arterial mediolysis in splanchnic arteries: case series and systematic review. PLoS One. 2016;11(8):e0161182. PMid:27513466. http://dx.doi. org/10.1371/journal.pone.0161182. Autopsy and Case Reports 2016;6(3):7-15

Felipe-Silva A, Campos FPF, Martinês JAS

Conflict of interest: None Submitted on: September 2nd, 2016 Accepted on: September 19th, 2016 Correspondence Aloísio Felipe-Silva Anatomic Pathology Service - Hospital Universitário - Universidade de São Paulo (USP) Avenida Professor Lineu Prestes, 2565 CEP: 05508-000 Phone: +55 (11) 3091-9384 aloisiosilva@hu.usp.br

Autopsy and Case Reports 2016;6(3):7-15

Article / Autopsy Case Report

Sudden death in infective endocarditis Jussara Bianchi Castellia, Germana Almeidab, Rinaldo Focaccia Sicilianoc Castelli JB, Almeida G, Siciliano RF. Sudden death in infective endocarditis. Autopsy Case Rep [Internet]. 2016;6(3):17-22. http://dx.doi.org/10.4322/acr.2016.045

ABSTRACT The case fatality rate of infective endocarditis (IE) is high and is associated with varying causes. Among them, acute myocardial infarction due to an embolism in a coronary artery is rare; the incidence of this complication in the setting of IE is reported to be up to 1.5%. We report a case of sudden death in a 22-year-old woman diagnosed with systemic lupus erythematosus who was referred to the Cardiology Center for the treatment of mitral valve incompetence due to IE. She was hemodynamically stable with antibiotic therapy and vasoactive drugs, despite severe mitral valve regurgitation. Unexpectedly, she presented cardiac arrest and died. The autopsy showed total occlusion of the left main coronary artery by septic embolus, which originated from the mitral vegetation, as the cause of death. Thus, although a rare complication, it should always be kept in mind that a coronary embolism can be a lethal complication of IE, and the possibility of surgical treatment combined with the underlying antibiotic therapy should be raised. Keywords Lupus Erythematosus, Systemic; Endocarditis; Heart Arrest; Embolism; Coronary Vessels

CASE REPORT A 22-year-old female patient was recently diagnosed with systemic lupus erythematosus (SLE). The symptoms were fatigue, malaise, low-grade fever, muscle pain, and arthritis. The laboratorial work-up revealed normocytic anemia, leukopenia with lymphopenia, cylindruria, proteinuria at the nephrotic range, and hematuria; an elevated erythrocyte sedimentation rate; high titers of antinuclear antibody anti-double stranded DNA, and a positive Immunoglobulin G response to anticardiolipin. Soon after the diagnosis, the creatinine determinations rose substantially and rapidly, requiring hospitalization. With the hypothesis

of progressive glomerulonephritis, the patient was prescribed a 3-day pulse therapy of methylprednisolone with further creatinine normalization. A renal biopsy was not performed. Over the following weeks she became febrile, and blood cultures disclosed oxacillin sensitive Staphylococcus aureus on two separate occasions. A new systolic murmur in the mitral area was heard, and petechiae appeared on the conjunctiva. A transthoracic echocardiogram detected vegetation on the posterior mitral leaflet. The patient’s fever subsided, and her general status improved after oxacillin administration. However, 2 weeks later, she

Anatomic Pathology Department - Instituto do Coração - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP – Brazil. Internal Medicine Department - Instituto do Coração - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP – Brazil. c Infectious Disease Control Department - Instituto do Coração - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP – Brazil. a

Sudden death in infective endocarditis

developed acute pulmonary edema, along with the intensification of the regurgitant murmur in the mitral area. Rupture of the chordae tendineae was suspected, and she was transferred to the cardiology center for surgical evaluation. On admission, she reported intense fatigue. She was afebrile, with a blood pressure of 100/60 mmHg and a pulse rate of 96 beats per minute. Oximetry was normal at the expense of oxygen supplementation. Neither jugular distention nor peripheral edema was present. The heart auscultation disclosed a loud holosystolic murmur in the mitral area, with axillary irradiation. The pulmonary auscultation demonstrated sparse rales on the pulmonary bases, and peripheral perfusion was slightly diminished. Abdominal examination revealed a slight hepatomegaly but the spleen was not enlarged. A laboratory work-up disclosed hemoglobin of 8.0 g/dL (reference value [RV]: 12-14 g/dL), leukocytes of 6,900/ mm 3 (RV; 4.4-11.3 × 103/mm3) without a shift to the left, and platelets of 194,000/mm 3 (RV; 150-400 × 10 3/mm3), creatinine of 1.3 mg/dL

(RV: 0.4-1.3 mg/dL), and normal electrolytes. Bedside transthoracic echocardiogram showed normal left ventricular size and function. The mitral valve showed a marked regurgitation and a large vegetation attached to its posterior leaflet. Intravenous dobutamine was initiated, with overall improvement. Suddenly, the patient presented cardiac arrest and died. This occurred 47 days after the diagnosis of SLE and monitoring at the rheumatology unit, and fever with the diagnosis of endocarditis, during the last 10 days of life.

AUTOPSY FINDINGS A huge vegetation (20 × 15 × 4 mm), tissue corrosion on the posterior leaflet, anterior commissure of the mitral valve, and rupture of some chordae tendineae at that point was evident (Figure 1). At histology, the vegetation was composed of fibrin and neutrophils with numerous Gram-positive cocci and granulation tissue at the base (Figure 2).

Figure 1. Gross examination of the formalin-fixed heart showing the mitral valve with large vegetation (arrow) at the posterior leaflet, near to the posterior commissure, with the rupture of some chordae tendineae (arrowhead). LA = left atrium; MV = mitral valve. 18

Autopsy and Case Reports 2016;6(3):17-22

Castelli JB, Almeida G, Siciliano RF

Figure 2. Photomicrography of the vegetation showing clumps of Gram-positive cocci (Staphylococcus aureus): A - Low magnification of the vegetation showing the base of granulation tissue and the top composed of fibrin with polymorphonuclear leukocytes interspersed with bacteria clumps (arrows) (H&E, 25×); B, C - Detail of the top and the region near the base of the vegetation. The arrows points to some clumps of bacteria and the asterisk is at the granulation tissue area at the base, which is consistent with the time history of the endocarditis (H&E, 200× and 400×, respectively); D - The Brown-Hopps stain shows the coccus-shaped bacteria colonies (arrow) with a change in the dye affinity (red), with very few of them purple (Gram-positive) due to the antimicrobial treatment (Brown‑Hopps, 1000×).

The examination of the coronary arteries displayed

DISCUSSION

complete occlusion of the left main artery by an embolus with the same histological composition of the vegetation (Figure 3). There were no histological signals of myocardium infarction due to the short time that had elapsed since the patient’s death. In addition, there was also embolization to the skin, kidneys, spleen, and central nervous system, which formed small abscesses in organization. There were no signs of active SLE at the other organs. Autopsy and Case Reports 2016;6(3):17-22

This case illustrates a fatal outcome of infective endocarditis (IE) in a young patient diagnosed with SLE who was recently submitted to corticoid pulse therapy. The prevalence of cardiac involvement in patients with SLE varies from 30-50% to 52-80%.1 All the cardiac layers may be involved in SLE. The coronary arteries might be affected by vasculitis, thrombi, and atherosclerosis. The most common 19

Sudden death in infective endocarditis

Figure 3. Photomicrography of the transversae section of the left main coronary artery. A - Note the total occlusion of the lumen by the infected embolus, which originated from the vegetation of the mitral valve (H&E, 25×); B - The high magnification shows, in the arterial embolus, the same aspect observed at the mitral valve vegetation, namely, the clumps of coccus-shaped bacteria (arrows) (H&E, 200×) with a change in the dye affinity at the Brown-Hopps staining (inset, 1000×).

cardiac manifestation in lupus patients is pericarditis.2 There have been signs of inflammation in 75% of the cases at autopsy, either active or quiescent. Pericarditis is clinically evident in 20-30% of the patients along the course of their disease. Cardiac tamponade is rare, with an incidence ranging from 1.23% to 2.5% in two large retrospective series. 3,4 Clinical manifestations of myocarditis are also rare; however, the signs of inflammation have been seen in 40-80% at autopsy.5 Libman and Sacks 6 described a particular type of nonbacterial endocarditis, which constitutes one of the most common cardiac manifestations of SLE. These vegetations are sterile, small, flat, granular or verrucous and occasionally sessile. They firmly adhere to the endocardium and may cover a large area of the valve surface, with extension to the atrial and ventricular endocardium, chordae tendineae, and valve pockets. The mitral valve is the most commonly affected, and usually at the ventricular surface. The antiphospholipid syndrome accompanies SLE in 50-70% of cases,7 which increases the risk of coronary thrombosis, intramural thrombi, and valvar dysfunction. Although the Libman-Sacks endocarditis should always be remembered, in patients with SLE, there was no doubt that our case was infective in nature. This patient had two major criteria (typical microorganism isolated on two settings of blood 20

cultures, and vegetation on the echocardiogram) and one minor criterion (fever) for the definite clinical diagnosis of IE according to Duke’s modified criteria.8 The overall mortality for IE remains high, ranging between 20% and 25%. Fabri et al.9 studied 629 patients with IE and found the occurrence of 21.1% for embolic events, 47.4% for central nervous system involvement, 42.9% peripheral organs involvement, 9.7% for both central nervous system and peripheral organs involvement, and 1,5% for coronary arteries. Systemic embolization complicates IE in 22-50% of cases.10 Up to 65% of the embolic phenomena involve the central nervous system, leading to ischemic strokes, cerebral abscesses, and mycotic aneurysms, which occasionally rupture. These are accompanied by mortality rates of around 80%.11 The risk of embolization increases with (i) involvement of the mitral valve; (ii) vegetation size of more than 10 mm;12 (iii) the growth of vegetation size despite adequate therapy;9 and (iv) endocarditis caused by fungus or staphilococci.13 Embolization to coronary arteries represents another site with prognostic impact. Septic coronary embolism is an infrequent but dramatic complication of IE. The embolization to the coronaries as a cause of acute myocardial infarction is considered rare; the incidence of this event, which is secondary to IE, is hard to estimate. The literature includes case Autopsy and Case Reports 2016;6(3):17-22

Castelli JB, Almeida G, Siciliano RF

reports and case series describing mostly autopsy findings, after Virchow’s original report in 1856 of coronary emboli secondary to IE due to puerperal sepsis. 14-17 Wenger et al. 18 described 15 cases of embolization to the coronaries as the immediate cause of death, in which 8 cases had cardiac vegetation as the embolic source. The same authors, in a retrospective analysis of the literature, found 74 case reports of coronary embolization, and IE was the cause of the embolization in 47 cases (63%). Two-thirds of these cases had a fatal outcome. In more than half of these cases, the left main coronary artery and/or the descending anterior artery were involved, possibly due to the greater caliber and higher flow to this segment and the more favorable anatomy when compared to the right coronary artery. An embolectomy by a large lumen aspiration device could be a preferential therapeutic option.19,20

CONCLUSION IE still has a high mortality rate. An embolism to major vascular beds carries ominous prognostic implications. An embolism to the coronaries is often overlooked as a cause of acute myocardial infarction and may determine a fatal outcome, as was presented here. The postmortem examination was essential to clarify the cause of death in this young patient.

REFERENCES 1. Falcão CA, Lucena M, Alves I, Pessoa ÂL, Godoi ET. Lupus carditis. Arq Bras Cardiol. 2000;74(1):64-71. http://dx.doi.org/10.1590/S0066-782X2000000100007. PMid:10904281. 2. Kim MH, Abrams GD, Pernicano PG, Eagle KA. Sudden death in a 55-year-old woman with Systemic Lupus Erythematous. Circulation. 1998;98(3):271-5. http:// dx.doi.org/10.1161/01.CIR.98.3.271. PMid:9697828. 3. Castier M, Albuquerque E, Menezes ME, Klumb E, Albanesi FM Fo. Cardiac tamponade in systemic lupus erythematosus: report of four cases. Arq Bras Cardiol. 2000;75(5):446-8. http://dx.doi.org/10.1590/S0066782X2000001100008. PMid:11080755. 4. Kahl LE. The spectrum of pericardial tamponade in systemic lupus erythematosus: report of ten patients. Arthritis Rheum. 1992;35(11):1343-9. http://dx.doi.org/10.1002/ art.1780351115. PMid:1445451. Autopsy and Case Reports 2016;6(3):17-22

5. Doherty NE, Siegel RJ. Cardiovascular manifestations of systemic lupus erythematosus. Am Heart J. 1985;110(6):1257-65. http://dx.doi.org/10.1016/00028703(85)90023-7. PMid:3907317. 6. Libman E, Sacks B. A hitherto underscribed form of valvular and mural endocarditis. Arch Intern Med (Chic). 1924;33(6):701-37. http://dx.doi.org/10.1001/ archinte.1924.00110300044002. 7. Petri M. Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun. 2000;15(2):145-51. http://dx.doi. org/10.1006/jaut.2000.0409. PMid:10968901. 8. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345(18):1318-30. http://dx.doi. org/10.1056/NEJMra010082. PMid:11794152. 9. Fabri J Jr, Issa VS, Pomerantzeff PMA, Grinberg M, Barretto ACP, Mansur AJ. Time-related distribution, risk factors and prognostic influence of embolism in patients with left-sided infective endocarditis. Int J Cardiol. 2006;110(3):3349. http://dx.doi.org/10.1016/j.ijcard.2005.07.016. PMid:16213607. 10. Bayer AS, Bolger AF, Taubert KA, et al. Diagnosis and management of infective endocarditis and its complications. Circulation. 1998;98(25):2936-1948. http:// dx.doi.org/10.1161/01.CIR.98.25.2936. PMid:9860802. 11. Tunkel AR, Kaye D. Neurologic complications of infective endocarditis. Neurol Clin. 1993;11(2):419-40. PMid:8316194. 12. Mugge A, Daniel WG, Frank G, Lichtlen PR. Echocardiography in infective endocarditis: reassessment of prognostic implications of vegetation size determined by the transthoracic and the transesophageal approach. J Am Coll Cardiol. 1989;14(3):631-8. http://dx.doi. org/10.1016/0735-1097(89)90104-6. PMid:2768712. 13. Steckelberg JM, Murphy JG, Ballard D, et al. Emboli in infective endocarditis: the prognostic value of echocardiography. Ann Intern Med. 1991;114(8):63540. http://dx.doi.org/10.7326/0003-4819-114-8-635. PMid:2003709. 14. Pfeifer JF, Lipton MJ, Oury JH, Angell WW, Hultgren HN. Acute coronary embolism complicating bacterial endocarditis- operative treatment. Am J Cardiol. 1976;37(6):920-2. http://dx.doi.org/10.1016/00029149(76)90119-3. PMid:1266757. 15. Ueda M, Becker AE, Fujimoto T, Tamai H. Bacterial endocarditis of the aortic valve with septic coronary embolism and myocardial infarction in a 4-month old baby. Eur Heart J. 1986;7(5):449-51. PMid:3732295. 16. Kraus PA, Lipman J. Coronary embolism causing myocardial infarction. Intensive Care Med. 1990;16(3):215-6. http:// dx.doi.org/10.1007/BF01724807. PMid:2351783. 17. Brunson JG. Coronary embolism in bacterial endocarditis. Am J Pathol. 1953;29(4):689-701. PMid:13065415. 21

Sudden death in infective endocarditis

18. Wenger NK, Bauer S. Coronary embolism: review of the literature and presentation of fifteen cases. Am J Med. 1958;25(4):549-57. http://dx.doi.org/10.1016/00029343(58)90044-5. PMid:13582963. 19. Motreff P, Roux A, Souteyrand G. Aspiration therapy in septic coronary embolism complicating infectious

endocarditis. Heart. 2010;96(10):809. http://dx.doi. org/10.1136/hrt.2009.183285. PMid:20448135. 20. Dekam MJ, Depta JP, Lincoff AM. A rare complication of infective endocarditis. Cleve Clin J Med. 2010;77(5):2967. http://dx.doi.org/10.3949/ccjm.77a.09114 . PMid:20439561.

Conflict of interest: None Submitted on: August 10th, 2016 Accepted on: August 23rd, 2016 Correspondence Jussara Bianchi Castelli Avenida Dr. Enéas de Carvalho Aguiar, 44 – São Paulo/SP – Brazil CEP: 05403-000 Phone: +55 (11) 2661-5077 Fax Number: +55 (11) 2661-5279 jussara.castelli@hc.fm.usp.br

Autopsy and Case Reports 2016;6(3):17-22

Article / Autopsy Case Report

Rupture of an ascending aortic aneurysm as a cause of sudden death Cristielle Peres de Freitasa, Carla Andrade Petrinib, Ramon Souza Goes Araújob, Luiz Guilherme Cernaglia Aureliano Limac, Patrícia Picciarelli de Limaa, Amaro Nunes Duarte-Netoa,b Freitas CP, Petrini CA, Araújo RSG, Lima LGCA, Lima PP, Duarte-Neto AN. Rupture of an ascending aortic aneurysm as a cause of sudden death. Autopsy Case Rep [Internet]. 2016;6(3):23-28. http://dx.doi.org/10.4322/acr.2016.044

ABSTRACT An 84-year-old female patient was brought to the emergency department in cardiac arrest. Cardiopulmonary resuscitation maneuvers were performed but were unsuccessful. The patient had a past medical history of systemic arterial hypertension with target-organ lesions, including stroke and myocardial infarction. The autopsy was carried out, and the most striking finding was cardiac tamponade due to the rupture of an ascending aortic aneurysm at the site of a complex atheromatous plaque. Rupture is the most serious complication of a thoracic aneurysm and must be considered in the differential diagnosis of sudden death. Keywords Aortic Aneurysm; Death, Sudden; Atherosclerosis

CASE REPORT

AUTOPSY FINDINGS

An 84-year-old female patient was brought to the emergency department (ED) by the Pre Hospital Service in cardiac arrest (asystole). She had collapsed in the presence of relatives 30 minutes before, and the resuscitation maneuvers began 10 minutes before the hospital admission. In the ED, the cardiopulmonary resuscitation protocol for asystole lasted for a further 25 minutes, but was not successful. The relatives reported a previous medical history of systemic arterial hypertension (SAH), dilated cardiomyopathy, myocardial infarction, peripheral arterial disease, stroke, and transient ischemic attack. The autopsy was carried out with the agreement of the family.

The corpse weighed 78.0 kg and measured 1.69 m. The external examination was unremarkable with no signs of trauma. At the opening of the pleural and peritoneal cavities, no effusions were present. The mediastinal fat had hemorrhagic spots. The pericardial sac was bulging and tense, and after opening, a clot was found inside measuring approximately 750.0 mL in volume (Figure 1A). The heart weighed 430.0 g (mean reference value [mRV]: = 260 g) and had a thick layer of epicardial fat. The ventricular free walls were thickened, measuring 0.8 cm on the right (RV = 0.5 cm) and 2.0 cm on the left (RV = 1.5 cm), with a regular, brownish, and firm

Anatomic Pathology Department - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP – Brazil. Emergency Department - Hospital das Clínicas - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP – Brazil. c Anatomic Pathology Department - Instituto do Câncer do Estado de São Paulo - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP – Brazil. a

Rupture of an ascending aortic aneurysm as a cause of sudden death

Figure 1. Gross view of the heart and ascending aorta. A - A clot within pericardial sac, which was responsible for cardiac tamponade; B - External view of the anterior aspect of the entire heart showing the aneurysm of the ascending aorta, which measured 8.5 cm in diameter (white arrows); C - Internal view of the aorta, showing a fractured atheromatous plaque; D - The heart after formalin fixation. The left lateral view of the heart base and intrapericardial segments of the pulmonary trunk (PA) and aorta, showing the orifice of rupture with a surrounding hematoma (arrow).

myocardial cut surface. The histologic exam showed cardiomyocyte hypertrophy and cytoplasmic lipofuscin pigment. The atrioventricular valves had myxoid degeneration. The main coronary artery branches had atheromatous plaques, which obstructed at least 25% of the lumen. An ascending aortic aneurysm was detected, measuring about 8.5 cm in diameter (Figure 1B). At the opening of the arterial lumen, the endothelial surface was caked with atherosclerotic plaque. An area of the plaque was ruptured in the intra-pericardial portion of the ascending aorta (Figure 1C and 1D). On the left side, there was a dissection of the aortic wall 24

measuring 6.0 cm in length from the point of rupture. The microscopy showed fractured atherosclerotic plaques covered by thrombi, and bleeding in the media and adventitia producing delamination of the arterial wall with rupture and moderate neutrophilic infiltration (Figure 2A and 2B). The aortic branches had hard walls with ulcerated and calcified atherosclerotic plaques. The myocardial had interstitial fibrosis and cardiomyocyte hypertrophy (Figure 2C and 2D). The right kidney weighed 152.0 g, and the left kidney weighed 188.0 g (both RV = 120-150 g). The renal capsule was easily detached and the renal surface was finely granular, bilaterally. At microscopy, Autopsy and Case Reports 2016;6(3):23-28

Freitas CP, Petrini CA, Araújo RSG, Lima LGCA, Lima PP, Duarte-Neto AN

Figure 2. Photomicrographs of the aorta and myocardium. A - A low power view of the point of the rupture of the ascending aortic aneurysm: aorta with bleeding and clot (arrow), pulmonary artery (PA), and septal myocardium (arrow head (H&E, 5X); B - Detail of the fractured atheromatous plaque in the ascending aorta, with bleeding in the media and adventitia (H&E, 200X); C - Perivascular and interstitial myocardial fibrosis (H&E, 100X); D - Cardiomyocyte hypertrophy with cytoplasmic deposition of lipofuscin pigment (H&E, 400X).

the findings were: glomerulosclerosis; focuses of interstitial chronic inflammatory infiltrate with fibrosis and atrophic tubules; and acute tubular necrosis and arteriolosclerosis. In the brain, discrete atherosclerosis of the circle of Willis and a glial scar formation in the white matter of the temporal lobe was observed, and measured 2.0 cm in diameter. Other pathologic findings included lungs with chronic inflammatory peribronchial infiltration (lymphocytes and monocytes) and centrilobular emphysema with mild bronchitis; liver with microgoticular steatosis and intense sinusoidal Autopsy and Case Reports 2016;6(3):23-28

congestion (“nutmeg liver”); and chronic cystitis and an intramural uterine leiomyoma.

DISCUSSION The autopsy case reported herein represents a death as a consequence of a complication of SAH and generalized atherosclerosis. The patient experienced sudden death due to the rupture of an atherosclerotic plaque in an ascending aortic aneurysm, with dissection, followed by hemopericardium, which produced cardiac tamponade and hypovolemic shock. 25

Rupture of an ascending aortic aneurysm as a cause of sudden death

The autopsy also revealed lesions in target organs produced by the atherosclerosis and the SAH, such as myocardial fibrosis, nephrosclerosis, and a glial scar from a previous stroke. These findings revealed poor long-term control of SAH. The aortic dissection observed at the macroscopic exam can be classified as Stanford type A (when the aortic dissection involves the ascending aorta). In this case, the dissection was associated with a fusiform aortic aneurysm. Most of the thoracic aortic aneurysms (TAA) are consequent to degenerative diseases affecting the vascular wall, and atherosclerosis is responsible for almost one-third of all cases of aortic aneurysmal disease. Without treatment, especially regarding the control of SAH, the TAA evolves slowly, with progressive dilatation. The most common complications of an aortic aneurysm are dissection and rupture, which are important causes of death in the USA.1-4 It is important to explain that aneurysms can be complicated by wall rupture without dissection, and arterial wall dissection can occur without aneurysm.1-4 Aortic dissection has an incidence of 2.9 per 100,000 inhabitants/year and predominantly affects men between 60 and 80 years of age. Its main risk factors are high blood pressure (hypertension), dyslipidemia, smoking, Marfan syndrome, Ehlers‑Danlos syndrome, Turner syndrome, other connective tissue diseases, previous aortic valve disease, cerebral aneurysm, and family history.5,6 Tertiary syphilis, with cardiovascular manifestation, classically dilates the ascending aorta and causes aortic valve regurgitation due to plasmacytic vasculitis involving the vasa vasorum in the adventitia. In atherosclerotic disease, the inflammation of the arterial wall is seen in the media and surrounds the atheromatous plaque.7,8 The clinical picture of aortic dissection includes chest pain radiating to the back, which, occasionally, can be associated with pulse asymmetry, syncope, stroke, myocardial infarction, aortic insufficiency, and acute heart failure. These signs and symptoms are more common in cases with a Stanford type A dissection.1,2,9 Rupture of an aneurysm is considered the most serious complication, and can occur because of a weakness of the wall or an atherosclerotic penetrating ulcer, which produces an intramural hematoma, dissection, and subsequent rupture. The rupture of an ascending aorta aneurysm occurs inside the pericardial sac or in the thoracic cavity (most commonly in the left hemithorax), 26

producing intense chest pain, hypotension, shock, and sudden death.1,2 Cardiac tamponade is observed when the aneurysm rupture goes into the pericardial sac, as observed in this reported case. Occasionally, the aneurysm rupture passes into the esophagus through an aortoesophageal fistula. 10 In a cohort study on acute aortic dissection with 1,079 patients enrolled, Nienaber et al.3 found that women were less likely to have aortic dissection (346 cases [32.1%]). However, the women were older and arrived later at the hospital to get medical assistance than the men, and were more likely to have neurologic signs (coma), aneurysm rupture (periaortic, pericardial, or pleural), shock, cardiac tamponade, higher in-hospital mortality, and a worse surgical outcome. In a similar cohort study, Gilon et al.11 found 126 cases of cardiac tamponade (18.7%) among 674 patients with Stanford type A aortic dissection, with a 54% mortality rate. In a retrospective study evaluating ruptured TAA in Stockholm, Sweden, Johansson et al.12 found a total of 158 cases in 1980 and 1989, with 41% of the cases arriving alive in the ED, but with an overall mortality rate near to 100%. In the city of Malmö, Sweden, Svensjö et al.13 found 63 cases of death due to the rupture of the thoracic aorta in the autopsy records from 1958 to 1985, with an incidence of 0.9/100,000 for men and 1.0 per 100,000 for women. The size of the thoracic aneurysm can predict the risk of rupture. Davies et al.14 analyzed data from 721 patients with TAA; those patients with aneurysms greater than 6.0 cm in diameter had a 27-fold risk increase for rupture in a 5-year follow-up, with rupture and death occurring at a rate of 3.7% and 11.8% per year, respectively. In the case reported here, the patient had an aneurysm measuring 8.5 cm in diameter. For medicolegal reasons, or to evaluate the quality of medical assistance, a pathologist must give an estimate of the extent, localization, and time of the rupture, which are revealed during the autopsy of a deceased person from an aortic aneurysm rupture. This issue was competently addressed by Ma and Ang15 in the case report of an 82-year-old woman who died from spontaneous rupture of the descending thoracic aorta distal to the left subclavian artery ostium through an atheromatous plaque, without exhibiting a local aneurysm. Deaths immediately after such a rupture show an acute inflammatory response with neutrophils in the vessel wall. Signs of healing indicate that the Autopsy and Case Reports 2016;6(3):23-28

Freitas CP, Petrini CA, Araújo RSG, Lima LGCA, Lima PP, Duarte-Neto AN

rupture is old: tissue granulation and fibrosis appear after a week; and chronic pericarditis, fistula formation, and false aneurysm appear after 2-3 weeks.15-18 In the case reported herein, we could find hemorrhage and a discrete leukocyte infiltration in the adventitia by the area of rupture, indicating immediate death after the event. In many cases, the diagnosis of an aneurysm and its rupture is only made at autopsy. Vázquez Muñiz and Delgado Osorio19 evaluated 16 patients with acute dissection of the thoracic aorta. The type A dissection was more common (88%) and the overall mortality was 93%, with eight cases (50%) diagnosed at autopsy. Nine cases had cardiac tamponade (56%). Young and Ostertag 20 found 114 cases of aortic aneurysms, 95.6% due to atherosclerosis and SAH, among 3,375 autopsied cases during 5 years in Germany. The percentage of thoracic aneurysms, thoracic aneurysms with rupture, and rupture as the immediate cause of death were 22.8%, 41.2%, and 65.4%, respectively. SAH was a high risk factor for aneurysm rupture in this study.20 The present case represents how a thoracic aneurysm can be the cause of sudden death and must be listed in the differential diagnosis made by all doctors working in an ED. The diagnosis in the emergency room can be performed with imaging auxiliary methods, such as a bedside ultrasound or computed tomography, and the thoracic and cardiac surgery team must be immediately activated.21 However, the mortality rate is very high, even when the patients arrive alive at the hospital.11,12,14,19 Preventive health measures should be implemented for people with aortic aneurysms, such as blood pressure control, smoking cessation, and close observation of the aneurysm using imaging exams with surgical intervention, when properly indicated, to avoid lethal outcomes.1,2

REFERENCES 1. Hiratzka LF, Bakris LG, Beckman JA, et al. 2010 ACCF / AHA / AATS / ACR / ASA / SCA / SCAI / SIR / STS / SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation / American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and the Society for Vascular Autopsy and Case Reports 2016;6(3):23-28

Medicine. Circulation. 2010;121(13):E266. http://dx.doi. org/10.1161/CIR.0b013e3181d4739e. PMid:20233780. 2. Isselbacher MS. Thoracic and abdominal aortic aneurysms. Circulation. 2005;111(6):816-28. http:// dx.doi.org/10.1161/01.CIR.0000154569.08857.7A. PMid:15710776. 3. Nienaber CA, Fattori R, Mehta RH, et al. Gender-related differences in acute aortic dissection. Circulation. 2004;109(24):3014-21. http://dx.doi.org/10.1161/01. CIR.0000130644.78677.2C. PMid:15197151. 4. Tsai TT, Nienaber CA, Eagle KA. Acute aortic syndromes. Circulation. 2005;112(24):3802-13. http://dx.doi. org/10.1161/CIRCULATIONAHA.105.534198. PMid:16344407. 5. Meszaros I, Morocz J, Szlávi J, et al. Epidemiology and clinicopathology of aortic dissection. Chest. 2000;117(5):1271-8. http://dx.doi.org/10.1378/ chest.117.5.1271. PMid:10807810. 6. Coady MA, Davies RR, Roberts M, et al. Familial thoracic aortic aneurysms of patterns. Arch Surg. 1999;134:361. http://dx.doi.org/10.1001/archsurg.134.4.361. PMid:10199307. 7. Kennedy JL, Barnard JJ, Prahlow JA. Syphilitic coronary artery ostial stenosis resulting in acute myocardial infarction and death. Cardiology. 2006;105(1):25-9. http://dx.doi.org/10.1159/000088337. PMid:16179782. 8. Cabot RC, Scully RE, Mark EJ, et al. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises: case 10-1998. A 46-year-old man with chest pain and coronary ostial stenosis. N Engl J Med. 1998;338(13):897-903. http://dx.doi.org/10.1056/ NEJM199803263381308. PMid:9518283. 9. Hagan PG, Nienaber CA, Isselbacher IN, et al. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA. 2000;283(7):897903. http://dx.doi.org/10.1001/jama.283.7.897. PMid:10685714. 10. Ambepitiya SG, Michiue T, Bessho Y, Kamikodai Y, Ishikawa T, Maeda H. An unusual presentation of thoracic aortic aneurysm rupturing into the esophagus: an autopsy case report. Forensic Sci Med Pathol. 2010;6(2):1216. http://dx.doi.org/10.1007/s12024-009-9137-1. PMid:20087793. 11. Gilon D, Mehta HR, Oh JK, et al. Characteristics and in-hospital outcomes of patients with cardiac tamponade complicating acute aortic dissection type A. Am J Cardiol. 2009;103(7):1029-31. http://dx.doi.org/10.1016/j. amjcard.2008.12.013. PMid:19327436. 12. Johansson G, Markström U, Swedenborg J. Ruptured thoracic aortic aneurysms: a study of incidence and mortality rates. J Vasc Surg. 1995;21(6):985-8. http://dx.doi.org/10.1016/S0741-5214(95)70227-X. PMid:7776479. 27

Rupture of an ascending aortic aneurysm as a cause of sudden death

13. Svensjö S, Bengtsson H, Bergqvist D. Thoracic and thoracoabdominal aortic aneurysm and dissection: an investigation based on autopsy. Br J Surg. 1996;83(1):6871. http://dx.doi.org/10.1002/bjs.1800830122. PMid:8653370. 14. Davies RR, Goldstein LJ, Coady MA, et al. Yearly rupture or dissection for thoracic aortic aneurysms rates: simple prediction based on size. Ann Thorac Surg. 2002;73(1):17-27, discussion 27-8. http://dx.doi. org/10.1016/S0003-4975(01)03236-2. PMid:11834007. 15. Ma TK, Ang LC. Spontaneous rupture of thoracic aorta through an atheromatous plaque: case report and literature review. Am J Forensic Med Pathol. 1996;17(1):38-42. http://dx.doi.org/10.1097/00000433199603000-00006. PMid:8838468. 16. Shkrum MJ, Silver MD. Delayed rupture of spontaneous tear to the ascending aorta-report of two fatalities. Pathology. 1992;24(3):146-9. http://dx.doi. org/10.3109/00313029209063162. PMid:1437285.

17. Gore I, Seiwert VJ. Dissecting aneurysm of the aorta: pathologic aspects: an analysis of eighty-five fatal cases. Arch Pathol Lab Med. 1952;53(2):121-41. PMid:14884830. 18. Braunstein H. Pathogenesis of dissecting aneurysm. Circulation. 1963;28(6):1071-80. http://dx.doi. org/10.1161/01.CIR.28.6.1071. PMid:14082920. 19. Vázquez Muñiz CA, Delgado Osorio H. Acute dissection of the thoracic aorta: experience at the Puerto Rico Medical Center (1991 through 1995). Bol Asoc Med P R. 1997;89(10-12):161-6. PMid:9580383. 20. Young R, Ostertag H. Incidence, etiology and risk of rupture of aortic aneurysm. An autopsy study. Dtsch Med Wochenschr. 1987;112(33):1253-6. http://dx.doi. org/10.1055/s-2008-1068231. PMid:3608854. 21. Neves FF, Pazin A Jr, Santos JC, Nogueira-Barbosa MH, Elias J Jr, Muglia VF. Acute type A aortic dissection and cardiac tamponade. J Emerg Med. 2011;40(1):62-4. http://dx.doi.org/10.1016/j.jemermed.2008.01.030. PMid:19022611.

Conflict of interest: None Submitted on: April 29th, 2016 Accepted on: August 2nd, 2016 Correspondence Amaro Nunes Duarte Neto Pathology Department - Faculty of Medicine - University of São Paulo Av. Dr. Arnaldo, 455 – Cerqueira Cesar – São Paulo/SP – Brazil CEP: 01246-903 Phone: +55 (11) 98546-4225 amaro.ndneto@hc.fm.usp.br

Autopsy and Case Reports 2016;6(3):23-28

Article / Autopsy Case Report

Misdiagnosis of Streptococcus gallolyticus endocarditis Rodrigo Tzovenos Starostaa, Raquel Riverob, Francine Hehn de Oliveirab, Eron Lopesb, Marcelle Reesink Cerskib Starosta RT, Rivero R, Oliveira FH, Lopes E, Cerski MR. Misdiagnosis of Streptococcus gallolyticus endocarditis. Autopsy Case Rep [Internet]. 2016;6(3):29-33. http://dx.doi.org/10.4322/acr.2016.042

ABSTRACT Death certificate inaccuracy is of major concern both in the public health domain and in individual health care, since it may yield untruthful data on the incidence, prevalence, and lethality of medical entities, and may hamper prophylactic measures among those who share, with the deceased, the common genetic, environmental, or behavioral risk factors. An effective way to settle this haziness relies on the increase of autopsy performance, increasing manifold the exactitude as well as facing surprising diagnoses. In this report, the authors present the case of a middle-aged woman who sought medical care because of back pain accompanied by weight loss. She died suddenly and unexpectedly in the Emergency Room. In this case, due to the unusual clinical presentation and the patient’s unexpected death, the causa mortis would not have been elucidated if the autopsy had not been undertaken. Keywords Endocarditis, Subacute Bacterial; Streptococcus; Leriche Syndrome

CASE REPORT A 53-year-old Caucasian woman came to the hospital with a 1 month history of lower back pain radiating to the right lower limb, hampering her normal gait. In the same period, she referred weight loss (10 kg) accompanied by permanent tiredness and weakness. In the week before the admission, petechiae in the lower limbs overspread to the trunk and a reported fever (39°C) ensued. A laboratory work-up was undertaken before her admission, which showed high C-reactive protein and erythrocyte sedimentation rate; and high determinations of serum alkaline phosphatase, bilirubin, and gamma-glutamyl transferase. The platelet count was 37,000 per mm3, and leukocytosis of 14,800 per mm3 without a shift to the left. The lumbar spine magnetic resonance imaging

a b

(MRI) showed vertebral disc degeneration with a hernia at L5-S1 space. The Doppler ultrasonography of the lower limbs did not reveal any signs of venous flow disturbance. The physical examination at admission revealed blood pressure of 90/46 mmHg; a respiratory rate of 17 breaths per minute; a heart rate of 96 beats per minute, blood oxygen saturation of 98%; and an axillary temperature of 35.7°C. Jaundice and palpable purpura at the lower limbs were evident, but pulmonary and heart auscultation were unremarkable. The abdominal examination showed hepatomegaly, with the liver edge palpable up to 2 cm below the rib cage. No signs of edema or ischemia at the extremities were present.

Faculty of Medicine - Universidade Federal do Rio Grande do Sul, Porto Alegre/ RS – Brazil. Service of Surgical Pathology - Hospital de Clínicas de Porto Alegre - Universidade Federal do Rio Grande do Sul, Porto Alegre/RS – Brazil.

Misdiagnosis of Streptococcus gallolyticus endocarditis

During the observation period, the patient started complaining of pain in the left leg. She was re-examined, and, in the face of an unchanged physical examination, codeine was prescribed. During the following hours, the patient’s condition evolved and she began to complain of uneasiness, anxiety, and shortness of breath. Her heart rate rose to 120 beats per minute, and on auscultation a pericardial friction bruit was detected. The electrocardiogram showed right bundle block, supraventricular tachycardia, and deviation of the electrical axis to the right. Serum troponin I was of 2.01 ng/mL (reference value: <0.16 ng/mL). Soon after, she presented cardiac arrest in asystole. Advanced cardiac life support maneuvers were unsuccessful and the patient died. She was then referred to the pathology service for an autopsy.

AUTOPSY FINDINGS At autopsy, the patient was icteric and had several coalescing elevated petechiae bilaterally at the lower limbs, characterizing a palpable purpura. At the opening of the abdominal cavity, abscesses were found in the left adrenal gland, the liver parenchyma, the spleen, and the cortex of the left kidney, and hepatomegaly was confirmed. In the right internal iliac artery, there was an embolization resulting in subtotal occlusion of the lumen, which was likely to be the cause of the patient’s leg pain. No thrombus or embolus was found at the lower limbs or the iliac veins. On microscopic examination, the abscesses of

the adrenal, liver, spleen, and kidney were of septic origin, since bacterial clumps of Gram-positive cocci were found. The same findings were also present at the iliac artery embolus and in the glomerular capillaries— all of which yielded the diagnosis of systemic septic embolism. In the thoracic cavity several bilateral pulmonary subpleural hemorrhagic infarctions, a focus of acute bronchopneumonia, and edema were depicted. Mitral and aortic valves had vegetations (Figure 1A), and a thrombus of 6 cm in length extended from the right ventricle until the second-generation bifurcation of the right pulmonary artery (Figure 1B). The pulmonary thromboembolism was considered as the immediate causa mortis. The right atrium had a large-sized thrombus adhered to the free wall. Histology of the pulmonary embolus showed Zahn lines (alternating between erythrocyte and platelet‑fibrin aggregates deposition) (Figure 2), confirming the diagnosis of an embolus, and ruling out the suspicion of a postmortem clot. The lung parenchyma showed alveoli filled with plasma and several foci of hemosiderin-laden macrophages, which, along with the sinusoidal dilation and the hepatomegaly, were consistent with the diagnosis of cardiac insufficiency. The heart failure was interpreted to be much more a consequence of the valvular destruction than of the acute pulmonary embolism. There was a focus of bronchopneumonia in the right lung lower lobe, with a mixed inflammatory

Figure 1. Gross findings of: A - Mitral valve with protruding vegetations; B - The opened pulmonary artery with saddle embolus. 30

Autopsy and Case Reports 2016;6(3):29-33

Starosta RT, Rivero R, Oliveira FH, Lopes E, Cerski MR

infiltrate (both mononuclear and polymorphonuclear cells), engorged micro vessels, a low amount of alveolar and interstitial hemorrhage, and eosinophilic transudation material (Figure 3A). Gram stains were made but the results were inconclusive. Several micro emboli were found at the pulmonary microvasculature (Figure 3B), indicating an “embolic shower” and explaining the subpleural infarctions. In the cardiac muscle, we observed stretched, pale pink myocardial fibers with the infiltration of a few polymorphonuclear inflammatory cells, which were consistent with a subacute ischemic myocardial injury. The vegetations of the affected valves were sent for microbiological analysis, which revealed the growth of Streptococcus gallolyticus in both, confirming the

septic origin of the emboli (pathogen identification by Vitek-2 compact). A thorough search was undertaken for microscopic signs that could point towards the diagnosis of the chronic rheumatic valvular disease, but there were none. Previous history for rheumatic fever evaluation was unavailable. At the cut surface of the brain, several reddish spots scattered on the white matter were found to be microemboli at histology (Figure 4). The pineal gland was enlarged, measuring about 1.2 cm at its longest axis and weighed less than 1 g. Four distinct nodular gray matter heterotopias were spotted in the cerebral white matter of the temporal and parietal lobes. In the colonic lumen, there was a polypoid mass measuring 1.0 × 0.6 cm, which was diagnosed as a hyperplastic polyp at histology (Figure 5).

DISCUSSION

Figure 2. Photomicrography of an intralobar pulmonary artery with the end of the saddle embolus.

The microorganism S. gallolyticus, previously known as a subspecies of Streptococcus bovis biotype I, 1 is a common cause of infectious endocarditis in individuals with colonic neoplasia. In a recent systematic review and meta-analysis,2 64% of the patients with S. bovis endocarditis simultaneously presented gastrointestinal disease, although only 6% of all infectious endocarditides are caused by this pathogen,3 which is associated with a low mortality rate when compared with other bacteria.4 Although S. gallolyticus endocarditis and septicemia are classically associated with colonic neoplasia or dysplasia, there is

Figure 3. Photomicrography of the lung. A - Pulmonary alveoli filled with inflammatory cells and hyaline transudate; B - Peripheral pulmonary micro vessel with embolus. Autopsy and Case Reports 2016;6(3):29-33

Misdiagnosis of Streptococcus gallolyticus endocarditis

was assumed also to be due to S. gallolyticus, but unfortunately we could not substantiate it even with the aid of the Gram stain and the culture.

Figure 4. Photomicrography of the brain showing capillary vessel destroyed by micro thrombus. The pineal gland showed numerous full-formed cysts filled with amorphous, acellular, eosinophilic material of unknown origin, which is consistent with the diagnosis of simple pineal cysts. The central nervous system (CNS) microemboli, in contrast with those in the renal glomeruli, were of fibrinous origin and showed no bacteria or inflammatory cells.

Figure 5. Photomicrography of the hyperplastic colonic polyp. no evidence in the literature to support the hypothesis that hyperplastic polyps are also associated with it; therefore, in our case, we regarded the sole hyperplastic polyp to be an incidental finding. Several other findings in this autopsy could be attributed to the septicemia, including jaundice, bronchopneumonia, disseminated intravascular coagulation (especially in the brain and the lung), petechiae, bone marrow hypercellularity, and splanchnic abscesses. The bronchopneumonia 32

The lack of fever at the time of the emergency consultation may likely account for the misdiagnosis; however, the patient presented fever in her medical history. The low back pain (her main complaint) was likely attributed to degenerative causes, such as osteoarthritis and osteoporosis, considering the epidemiological data. However, in the setting of the autopsy findings, her back pain could have been due to infectious discitis, vertebral osteomyelitis—both complications of infectious endocarditis—or distention of the renal capsule. At gross postmortem inspection there were no signs of discitis, and at microscopy of the vertebral bone marrow there were no signs of osteomyelitis. The vertebral hernia spotted on the MRI was very small and did not interfere with any adjacent structure. Hence, the distention of the renal capsule of the left kidney by the presence of the renal abscess remains the probable cause of her back pain. Embolic events occur in nearly 27% of patients with infectious endocarditis; however, this rate is smaller in S. bovis endocarditis. 4 The main site of embolism involves the CNS, followed by the spleen, the kidney, the lungs, the peripheral arteries, the mesentery, and the eye. 5 Our patient had several septic emboli to the kidneys’ microvasculature and one semi-occlusive septic embolus into the iliac artery, besides the less obvious septic microemboli in the pulmonary and cerebral microvasculature. Pulmonary embolism is a potentially lethal condition characterized by the impaction of an embolus in some part of the pulmonary arterial tree, which is called “saddle embolism” or Leriche’s syndrome when the it impacts at the pulmonary artery bifurcation. Sometimes, the diagnosis of a pulmonary embolism is not straightforward, and estimates are that between 100,000 and 120,000 deaths occur each year in the United States because of this missed diagnosis.6 It is remarkable, in this case, that the clinical features and the final event were not enough to furnish a precise diagnosis. If the autopsy had not been performed, the case would have remained unclarified and certainly an inaccurate death certificate would have been reported. Death certificate information is a useful tool for epidemiologic and public health studies. The reliability of such certificates may be put under Autopsy and Case Reports 2016;6(3):29-33

Starosta RT, Rivero R, Oliveira FH, Lopes E, Cerski MR

suspicion when they are not endorsed by postmortem examination, especially in the case of unexpected death.7 The S. gallolyticus infection and the pulmonary thromboembolism would not have been diagnosed without the autopsy. This information is important both to the family regarding the eventual colon cancer screening procedures,8 and to the public health statistics, allowing more precise data of mortality by this infectious agent.

CONCLUSION Although infectious endocarditis is a relatively common disorder, this case was atypical because no colonic neoplasia or dysplasia was associated with the infection by S. bovis/gallolyticus. Moreover, the massive pulmonary thromboembolism is also not classically associated with S. gallolyticus endocarditis and sepsis. Also remarkable is the fact that the patient presented to the Emergency Room with vague complaints, which highlights the importance of being aware of signs of more severe, acute conditions in patients who seem otherwise stable in every scenario.

REFERENCES 1. Gómez-Garcés JL, Gil Y, Burillo A, Wilhelmi I, Palomo M. Cuadros clínicos asociados a bacteriemia causada por las nuevas especies incluidas en el antiguo grupo Streptococcus bovis. Enferm Infecc Microbiol Clin. 2012;30(4):175-9. http://dx.doi.org/10.1016/j. eimc.2011.09.015. PMid:22377494.

2. Boleij A, van Gelder MM, Swinkels DW, Tjalsma H. Clinical Importance of Streptococcus gallolyticus infection among colorectal cancer patients: systematic review and metaanalysis. Clin Infect Dis. 2011;53(9):870-8. http://dx.doi. org/10.1093/cid/cir609. PMid:21960713. 3. Alozie A, Köller K, Pose L, et al. Streptococcus bovis infectious endocarditis and occult gastrointestinal neoplasia: experience with 25 consecutive patients treated surgically. Gut Pathol. 2015;7(1):27-31. http://dx.doi. org/10.1186/s13099-015-0074-0. PMid:26473016. 4. Kupferwasser I, Darius H, Müller AM, et al. Clinical and morphological characteristics in Streptococcus bovis endocarditis: a comparison with other causative microorganisms in 177 cases. Heart. 1998;80(3):276-80. http://dx.doi.org/10.1136/hrt.80.3.276. PMid:9875088. 5. Thuny F, Di Salvo G, Belliard O, et al. Risk of embolism and death in infective endocarditis: prognostic value of echocardiography: a prospective multicenter study. Circulation. 2005;112(1):69-75. http://dx.doi. org/10.1161/CIRCULATIONAHA.104.493155. PMid:15983252. 6. Calder KK, Herbert M, Henderson SO. The mortality of untreated pulmonary embolism in emergency department patients. Ann Emerg Med. 2005;45(3):302-10. http:// dx.doi.org/10.1016/j.annemergmed.2004.10.001. PMid:15726055. 7. Mieno MN, Tanaka N, Arai T, et al. Accuracy of death certificates and assesment of factors for misclassification for underlying cause of death. J Epidemiol. 2016;26(4):191-8. http://dx.doi.org/10.2188/ jea.JE20150010. PMid:26639750. 8. Boleij A, Muytjens CM, Bukhari SI, et al. Novel clues on the specific association of Streptococcus gallolyticus subsp gallolyticus with colorectal cancer. J Infect Dis. 2011;203(8):1101-9. http://dx.doi.org/10.1093/infdis/ jiq169. PMid:21451000.

Conflict of interest: None Submitted on: May 29th, 2016 Accepted on: July 17th, 2016 Correspondence Rodrigo Tzovenos Starosta Service of Pathology - Faculty of Medicine - Federal University do Rio Grande do Sul (UFRGS) Rua Ramiro Barcellos, 2350 – Porto Alegre/RS – Brazil CEP: 90035-003 Phone: +55 (51) 8172-4749 rodrigo.starosta@ufrgs.br

Autopsy and Case Reports 2016;6(3):29-33

Article / Clinical Case Report

Myelolipoma of the posterior mediastinum in a patient with chronic dyserythropoietic anemia Cristiano Claudino Oliveiraa, Gilmar Felisberto Juniorb, Viviane Hellmeister Camolesea, Erica Nishida Hasimotob, Daniele Cristina Cataneob, Antônio José Maria Cataneob, Julio De Faveria Oliveira CC, Felisberto G Jr, Camolese VH, et al. Myelolipoma of the posterior mediastinum in a patient with chronic dyserythropoietic anemia. Autopsy Case Rep [Internet]. 2016;6(3):35-39. http://dx.doi.org/10.4322/acr.2016.047

ABSTRACT Myelolipoma (ML) is an uncommon benign mesenchymal neoplasia composed of mature adipose and hematopoietic tissues of uncertain etiology. Less than 3% of MLs occur in the mediastinal topography. The main differential diagnosis involves extramedullary hematopoiesis; therefore, pathological evaluation is essential for the definitive diagnosis. The authors report the case of a 50-year-old man diagnosed with congenital dyserythropoiesis and secondary hemosiderosis, who presented a posterior mediastinal tumor. The tumor was resected. It was macroscopically characterized by mature fat tissue with fibrous areas and soft consistency, which was yellowish at the cut surface. Histology revealed a well-defined nodule composed of adipocytes and hematopoietic tissue represented by erythroid, granulocytic, and megakaryocytic series, which was consistent with the diagnosis of ML located in the posterior mediastinum. There was no recurrence of the lesion during the 3-year follow-up. The aim of this report is to show the diagnosis of an unusual mediastinal lesion in the context of a chronic hematologic disease. Keywords Myelolipoma; Mediastinal Neoplasms; Mediastinum; Anemia

INTRODUCTION Myelolipoma (ML) is a benign mesenchymal neoplasm composed of hematopoietic and mature adipose tissue.1 The incidence of this tumor is estimated in up to 0.2% of mesenchymal tumors, and it can occur in various parts of the body, but predominantly in the adrenals. The extra-adrenal location is unusual (15%) and includes the retroperitoneum, pelvis, presacral region, stomach, and liver. In the lungs and mediastinum, the occurrence of ML is quite infrequent

accounting for 3% of all cases.1,2 This report shows an rare case of ML located in the posterior mediastinum in a patient with congenital dyserythropoiesis.

CASE REPORT A 50-year-old Caucasian male patient, previously diagnosed with congenital dyserythropoiesis, secondary hemosiderosis, and systemic arterial hypertension,

Department of Pathology - Botucatu School of Medicine - Universidade Estadual Paulista “Júlio de Mesquita Filho” (UNESP), Botucatu/SP – Brazil. b Department of Surgery and Orthopedics - Botucatu School of Medicine - Universidade Estadual Paulista “Júlio de Mesquita Filho” (UNESP), Botucatu/SP – Brazil. a

Myelolipoma of the posterior mediastinum in a patient with chronic dyserythropoietic anemia

presented a nodule in the right posterior mediastinum. Despite the diagnosis of chronic anemia, the patient was asymptomatic and was in steady control of the hemoglobin and the hematocrit levels. In a routine thoracic and abdominal computed tomography (CT), a nodule with soft tissue density, which measured 3.5 cm in diameter, was detected with enhancement after intravenous contrast injection localized in the right posterior mediastinum, in paravertebral topography (Figure 1). The patient was a former smoker and underwent a splenectomy and a liver biopsy 5 years ago. The spleen was congested and weighed 1280 g (reference value 150 g). Histologic review of the spleen and liver slides revealed splenic congestion, and hemosiderin deposits in both the spleen and the liver (Figure 2A to 2D). Immunohistochemistry failed to show myeloid metaplasia in the splenic samples. The patient did not have a bone marrow biopsy. In this clinical and radiological context, the video-assisted thoracic lesion resection was indicated considering the diagnostic hypothesis of paraganglioma, schwannoma, and nodal hematopoietic tumor infiltration. The gross examination of the surgical specimen revealed an oval-shaped tumor mass with a lobular surface, covered by a thin membrane, with soft consistency measuring 5.6 × 3.7 × 1.9 cm and weighting 10 g (Figure 3A). Histopathology revealed a well-defined nodular lesion (Figure 3B) predominantly consisting of adipose tissue, intermingled with

Figure 1. Thoracic axial computed tomography showing a paravertebral nodular lesion in the right posterior mediastinum with soft tissue density (arrow). 36

hematopoietic tissue, which was represented by an erythroid, granulocytic, and megakaryocytic series. Immunohistochemistry positivity for glycophorin A, myeloperoxidase, and Factor VIII confirmed the presence of erythroid cells, granulocytic lineage, and megakaryocytes, respectively, in the surgical specimen, which was consistent with the diagnosis of ML (Figure 4A-C). The patient was followed-up for 3 years without relapses; however, he was submitted to monthly bloodletting.

DISCUSSION MLs are benign and nonfunctioning tumors composed of mixed hematopoietic and mature adipose tissue, in varying proportions, which are usually located in the adrenal glands.3,4 Since the first descriptions in the early 20th century,1 other topographies have been reported in (i) the soft tissue; (ii) the retroperitoneum; (iii) the spleen; (iv) the liver; (v) the stomach; and (vi) the nasal cavity.4 The extra-adrenal MLs occur in up to 15% of cases.5,6 The lungs and mediastinum are unusual sites for such occurrences. In a literature review, Xu et al.5 reported 10 cases of intrapulmonary ML: 8 had isolated lesions, and 2 had a multifocal clinical presentation. The mediastinum is the site of occurrence in approximately 3.0% of cases.4 In a recent study, Xiong et al. 3 described the clinical and pathological aspects of 28 cases of mediastinal MLs.3 In this series, the symptoms, when present, were nonspecific and were represented by changes in the respiratory system (10%), such as dyspnea, hematopoietic abnormalities (9%), endocrine disorders (6%), and cardiovascular disorders (5%). Most cases (93%) occurred in the posterior mediastinum as a single lesion. The mean age of these 28 patients with mediastinal MLs was 64 years, with a slight male predominance. The series reported by Shen et al.2, which comprised 16 patients with thoracic ML, showed singular chest lesions in 13 cases.2 Patients with extra-adrenal MLs were older than those with adrenal lesions.6 The diagnosis of ML is often made incidentally by imaging studies, such as CT and magnetic resonance, due to the scarcity of typical symptoms. Similarly, imaging findings are also nonspecific.4 The reported tumoral mass of our patient was described as a nodular Autopsy and Case Reports 2016;6(3):35-39

Oliveira CC, Felisberto G Jr, Camolese VH, et al.

Figure 2. A and B - Photomicrography of the spleen; A - Splenic congestion, hypoplastic white pulp, and an absence of myeloid metaplasia (H&E, 200X); B - Hemosiderosis: hemosiderin deposits stained in blue (Perls, 400X); C and D - Photomicrography of the liver; C - Hepatocellular ballooning, and hemosiderin deposits (H&E, 400X); D Hemosiderosis: hemosiderin deposits stained blue (Perls, 400X).

Figure 3. A - Gross appearance of the oval shaped and lobular mediastinal tumor; B - Photomicrography of the myelolipoma: a panoramic view of the histological section of the specimen showing a circumscribed nodular area primarily consisting of adipose tissue (H&E, low magnification view). Autopsy and Case Reports 2016;6(3):35-39

lesion with soft tissue density, which showed some high-intensity regions with attenuation enhancement after intravenous contrast injection. This nonspecific imaging pattern of presentation supports the differential diagnosis of bronchial malignancies, lymphoproliferative disorders, neurogenic tumors, and lipomatous and metastatic lesions.1,4 In this setting, the gold standard examination for the diagnosis of ML is the histological examination.1,4 Macroscopically, generally, the ML are well-defined tumors that are often enclosed by a thin capsule measuring approximately 4-5 cm in diameter.2 The cut surface can be variegated, depending on the ratio between fat and hematopoietic tissues. In our patient, the lesion surface had a pale yellowish aspect due to the increased adipose tissue component. The histological examination showed the varied proportion of hematopoietic tissue intermingled with adult adipose tissue. The hematopoietic component was recognized by the presence of erythroid, granulocytic, and megakaryocytic series. In our patient, there were no bone spurs or hyperplasia of any hematopoietic component, and the adipose component did not present atypia.2,4 The pathogeny of ML is unknown. Shen et al.2 and Xiong et al.3 compiled some possible explanations for 37

Myelolipoma of the posterior mediastinum in a patient with chronic dyserythropoietic anemia

like Cushing’s syndrome, diabetes mellitus, Addison’s disease, Cohn’s syndrome, pheochromocytoma, obesity, and even hypertension that accompany ML may play a role in the genesis of this neoplasm. 2,3, Fonda et al. 7 proposed that ML may derived from projection of hematopoietic tissue (including stem cells) by bone microfractures. Some authors emphasize that the development of ML may be associated with prolonged and excessive steroid production or genome defects of the endocrine glands responsible for multiple endocrine neoplasia type 1.7,8 In general, patients with ML do not present with hematopoietic disorders. The presence of anemia or blood disorders does not exclude the diagnosis. The patient in this report presented the diagnosis of congenital dyserythropoiesis with hemosiderosis due to repeated blood transfusions, having undergone a splenectomy. Congenital dyserythropoiesis is a rare, inherited anemia that leads to the failure of erythroid maturation accompanied by hemosiderosis and extramedullary hematopoiesis.9 In this patient’s case, it is possible that the persistent erythropoietin stimulation, due to chronic anemia, may have played an important role in tumor development. It is interesting to note that extramedullary hematopoiesis occurs as mediastinal and paravertebral masses.

Figure 4. Photomicrography of the surgical specimen. A - Glycophorin positivity in the erythroid series colonies (Immunohistochemistry, 400X); B - Granulocytic lineage confirmed by positivity for myeloperoxidase (Immunohistochemistry, 400X); C - Megakaryocytes highlighted by the positivity for Factor VIII (Immunohistochemistry, 200X). the genesis of ML: (i) it could be derived from bone marrow emboli that may lodge in different regions of the organism; (ii) it could be derived from embryonic primitive mesenchymal cells; (iii) it could be derived from the metaplastic transformation of embryonic stromal cells after chromosomal translocation, similar to that observed in myelogenous leukemia; and iv) some disorders, such as the endocrine diseases 38

In this clinico-pathological context, an important differential diagnosis is extramedullary erythropoiesis. This is a commonly multifocal lesion that, when presented in the chest, develops in the perivertebral and mediastinal topography. 9 It is histologically characterized by an irregular shape, with a predominance of hematopoietic elements, especially erythroid and myeloid series; however there also may be hyperplasia of erythroid series.6,10 In contrast, our patient had chronic anemia due to the underlying blood disease and had a well-defined singular nodular lesion discovered incidentally on routine imaging. Additionally, the microscopy showed an abundant adipose component and all the hematopoietic series without atypia. These aspects were consistent with the diagnosis of ML. The most adopted therapeutic approach is to remove the lesion by conventional thoracotomy or a video-assisted method, depending on the size of the lesion. The prognosis is usually excellent.1-3 Autopsy and Case Reports 2016;6(3):35-39

Oliveira CC, Felisberto G Jr, Camolese VH, et al.

CONCLUSION This report presents the case of a patient with congenital dyserythropoiesis, with secondary hemosiderosis, whose tomographic follow-up examination revealed the presence of a tumor in the posterior mediastinum. The tumor was removed, and the pathology confirmed the diagnosis of ML—a rare tumor that was found in an unusual topography.

REFERENCES 1. Vaziri M, Sadeghipour A, Pazzoki A, Shoolami LZ. Primary mediastinal myelolipoma. Ann Thorac Surg. 2008;85(5):1805-6. PMid:18442597.. http://dx.doi. org/10.1016/j.athoracsur.2007.11.023.

4. Ema T, Kawano R. Myelolipoma of posterior mediastinum. Gen Thorac Cardiovasc Surg. 2014;62(4):241-3. PMid:23475269.. http://dx.doi.org/10.1007/s11748-0130230-8. 5. Xu Q, Yin X, Huang W, Sun J, Wu X, Lu L. Intrapulmonary myelolipoma and its computed tomography features: a case report and literature review. Oncol Lett. 2015;9(4):1677-80. PMid:25789022. 6. Franiel T, Fleischer BW, Raabc L, Füzesi L. Bilateral thoracic extraadrenal myelolipoma. Eur J Cardiothorac Surg. 2004;26(6):1220-2. PMid:15541988.. http://dx.doi. org/10.1016/j.ejcts.2004.08.024. 7. Fonda P, de Santiago E, Guijarro M, Gamallo C. Mediastinal myelolipoma with leukocytosis. BMJ Case Rep. 2013;2013:bcr2013010349. PMid:23813520. 8. Gao B, Sugimura H, Sugimura S, Hattori Y, Iriyama T, Kano H. Mediastinal myelolioma. Asian Cardiovasc Thorac Ann. 2002;10(2):189-90. PMid:12079954.. http://dx.doi. org/10.1177/021849230201000227.

2. Shen C, Han Z, Che G. A bilateral neoplasm in chest a case report and a review of literature. BMC Surg. 2014;14(1):42-7. PMid:25005140.. http://dx.doi. org/10.1186/1471-2482-14-42.

9. Foucar K. Anemias. In: Foucar K, Reichard K, Czuchlewski D. Bone marrow pathology. 3rd ed. Chicago: ASPC Press; 2010. p. 501-2. vol. 1.

3. Xiong Y, Wang Y, Lin Y. Primary myelolipoma in posterior mediastinum. J Thorac Dis. 2014;6(9):181-7. PMid:25276393.

10. Mohan K, Gosney JR, Holemans JA. Symptomatic mediastinal myelolipoma. Respiration. 2006;73(4):552. PMid:16131789.. http://dx.doi.org/10.1159/000088004.

Conflict of interest: None Submitted on: April 16th, 2016 Accepted on: September 6th, 2016 Correspondence Cristiano Claudino Oliveira Department of Pathology - Botucatu School of Medicine Universidade Estadual Paulista “Júlio de Mesquita Filho” (UNESP) Distrito de Rubião Junior, s/n – Botucatu/SP – Brazil CEP: 18618-970 cristiano_c_oliveira@hotmail.com

Autopsy and Case Reports 2016;6(3):35-39

Article / Clinical Case Report

Giant keratocystic odontogenic tumor: a challenging diagnosis Rachna Kaushika, Kumar Pushpanshua, Silky Rajesh Punyanib, Vineet Rajc Kaushik R, Pushpanshu K, Punyani SR, Raj V. Giant keratocystic odontogenic tumor: a challenging diagnosis. Autopsy Case Rep [Internet]. 2016;6(3):41-46. http://dx.doi.org/10.4322/acr.2016.043

ABSTRACT The keratocystic odontogenic tumor, although a benign lesion, is peculiarly aggressive with a high recurrence rate. Its involvement with the maxillary antrum is atypical. We report the unusual case of a 20-year-old male patient with an extensive antral tumor associated with an impacted third molar, which was initially misdiagnosed as a dentigerous cyst. Clinical, radiographic, and histopathologic aspects were analyzed to provide useful information for the correct diagnosis, treatment, and prognosis within a multidisciplinary approach. Keywords Carnoy’s solution; Molar, Third; Maxillary Sinus; Odontogenic Tumors.

INTRODUCTION The odontogenic keratocyst (OKC) was first described by Philipsen in 1956 as an odontogenic cyst with a keratinous epithelial lining and its distinctive histological features were elaborated by Pindborg and Hansen in 1962.1 However, in 1967, Toller suggested that the OKC should rather be regarded as a benign neoplasm and not as a typical cyst. 2 Ever since Mikulicz presented the first case of OKC, in 1876, as a “dermoid cyst,” this interesting lesion has been the subject of debate owing to its varied origin, debated development, peculiar behavior, unique tendency to recur, and disputed treatment modalities.3 Keratocystic odontogenic tumors (KCOTs) are very aggressive with high mitotic counts and epithelial turnover rates, and a relatively high recurrence rate.4 Additionally, the epithelial lining is not as inactive as that of other cysts and appears to have an innate growth potential, as observed with a benign tumor.1

These are designated as a consistent finding in Gorlin syndrome.5 Based on their biological behavior, neoplastic features, and recent research in genetics, the WHO in 2005 reclassified OKC as KCOT, which is now defined as a benign unicystic or multicystic, intraosseous tumor of odontogenic origin, with a characteristic lining of parakeratinized stratified squamous epithelium and potential for aggressive, infiltrative behavior.6,7 KCOT is a benign developmental intraosseous neoplasm of the jaws arising from cell rests of the dental lamina (the oral epithelial lining of the developing tooth follicle) and an extension of basal cells of overlying oral epithelium.1 KCOT is predominant in males; it occurs mainly in the second and third decade of life, and is most frequently found in the posterior body of the mandible and ascending ramus.7 In the maxilla, the canine region is the most common location for KCOT, and it is quite

Department of Dentistry - SriKrishna Medical College & Hospital, Muzaffarpur – India. Department of Oral Medicine and Radiology - People’s Dental Academy, Bhopal – India. c Department of Oral Pathology - Chandra Dental College, Barabanki – India. a

Giant keratocystic odontogenic tumor: a challenging diagnosis

unusual for it to occur in the maxillary sinus. Less than 1% of KCOTs are involved with the maxillary sinus.4,8 Clinically, KCOT is a fast-growing expansive lesion when it is involved near the maxillary sinus. It could easily expand to an enormous size occupying the entire maxilla. Maxillary sinus is a less dense structure, thus allowing the rapid growth of the lesion.7 Such an extensive lesion involving an unusual site often presents with diagnostic and, therefore, therapeutic challenges. The purpose of this report is to present a rare case of KCOT in the maxillary sinus associated with an impacted tooth in a young Asian male. In addition, we discuss relevant issues about the diagnosis, management, and prognosis of these lesions, within a multidisciplinary approach.

CASE REPORT A 20-year-old male patient reported for an evaluation of a right-side, unilateral, painless facial swelling of 6 months’ duration. The patient was apparently healthy with no significant medical, dental, or surgical history. On systematic clinical examination, a diffused swelling was evident, which extended from the right ala of the nose to the right outer canthus of the eye mediolaterally, and from the infra-orbital region to the level of right commissure, without the presence of lymphadenopathy (Figure 1).

of the sinus was also evident. The involved teeth showed no deviation; however, slightly resorbed roots were detected with right maxillary first and second premolars and right maxillary first molar. To visualize the lesion in more detail, computed tomography (CT) was performed, which revealed a large, well‑defined, non-enhancing, hypodense osteolytic lesion (5.2 × 5 × 4.7 cm) with a well‑defined margin. The lesion involved the right maxillary bone and the maxillary sinus, and caused complete opacification of the right antrum and displacement of the right maxillary third molar to the anteromedial wall of the sinus (Figure 2). The expansile cystic lesion caused thinning of the antral walls and erosion of the buccal cortical bone of the right maxillary bone. Based on these observations, a tentative pre-operative diagnosis of dentigerous cyst associated with the right maxillary third molar was proposed. An incisional biopsy was performed and the histopathological examination of hematoxylin and eosin stained sections revealed a cystic mass lined by a parakeratinized stratified squamous epithelium of variable thickness (four to eight cell layers). The epithelium showed a lack of rete ridges, a distinctive basal layer with palisaded and hyperchromatic nuclei, surface corrugations, and detachment from the capsule in focal areas (Figure 3A). The connective tissue capsule

A thorough intraoral examination disclosed a diffuse soft swelling of 5 × 3 cm diameter along the right maxillary alveolus, which caused the obliteration of the buccal vestibule and extended from the maxillary right canine to the maxillary right second molar region. Upon digital compression, the swelling was soft and fluctuant in consistency, which indicated buccal cortical plate resorption. All teeth were negative to percussion and mobility tests. No visual disturbance or nasal obstruction were reported or observed. Routine laboratory parameters were normal. Radiological examination depicted a single unilocular radiolucency with smooth, corticated margins extending from the root apex of the right maxillary canine to the right maxillary tuberosity region. The radiolucency was associated with an impacted maxillary right third molar displacing it superiorly into the opacified right maxillary antrum. Destruction of the posterior wall 42

Figure 1. Extraoral (frontal) view showing a swelling over the right maxillary region. Autopsy and Case Reports 2016;6(3):41-46

Kaushik R, Pushpanshu K, Punyani SR, Raj V

Figure 2. Axial CT of the sinuses. A - Complete opacification of the right antrum; B - Thinning and irregular destruction of the antral walls is evident; C - Displacement of right maxillary third molar; D - Coronal view showing the extensive lesion involving the right antrum and infiltrating into the right nasal cavity.

Figure 3. A - Photomicrograph of cyst wall showing parakeratinized lining epithelium with basal palisading and surface corrugations. Note the separation of epithelium from the underlying capsule (H&E, 200X); B - Photomicrograph of the lesion showing keratin-filled daughter cysts within the cystic capsule (H&E, 100X). Autopsy and Case Reports 2016;6(3):41-46

Giant keratocystic odontogenic tumor: a challenging diagnosis

was loose to moderately dense, and was fibro cellular in nature showing spindle shaped fibroblasts and foci of chronic inflammatory infiltrate composed of lymphocytes, macrophages, and plasma cells. A few daughter cysts and odontogenic rests were also seen within the capsule (Figure 3B). The histopathological findings were suggestive of KCOT. After careful evaluation, the expansile maxillary tumor was enucleated as a whole using the Caldwell-Luc procedure. The associated impacted right maxillary third molar was simultaneously removed to avoid tumor fragmentation, and prophylactic chemical cauterization was done using Carnoy’s solution. Betadine irrigation was performed and the borders of the wound were then sutured. The wound healed uneventfully, showing no recurrent sign during the follow-up period of more than 6 years.

DISCUSSION KCOT, formerly believed to be a cyst, has certain uniquely distinguishable clinical and histologic features. 5 The term “odontogenic keratocyst,” as it was previously named, is nonspecific and only indicates keratin formation. The production of keratin is attributed to epithelial squamous metaplasia, which can lead to the keratinization of other odontogenic cysts (dentigerous, radicular, and residual cysts) as well.9,10 The WHO’s re-classification of this lesion from cyst to tumor underscores its potential aggressive nature, which indeed is the main difference between KCOT and other jaw cysts. It has an active epithelial component having an innate growth potential and a relatively high recurrence rate. The epithelial lining demonstrates a high mitotic activity and turnover rate.1,4 The increased cell activity is confirmed by elevated levels of oxidative enzymes and acid phosphatase, which is indicative of high metabolic and lysosomal activities. The active epithelial lining may rarely develop into squamous cell carcinoma.11 The epithelium of KCOT has decreased apoptotic activity, allowing the survival of genetically unstable cells. The higher epithelial proliferation rate, and the inhibition of apoptosis of the damaged cells, are important steps in tumor development. 7 KCOT exhibits unique growth and biological behavior compared to common cysts, wherein the growth is due to the active proliferation of the epithelial lining. Most of the commonly occurring cysts grow mainly because 44

of the osmotic pressure of the cystic fluid. This pushing type of growth causes the buccal and lingual cortical plate expansion. KCOT, however, behaves like a benign tumor growing by extension rather than by expansion. Here, the osmotic pressure of the cystic fluid is quite low; thus, the extension is along the path of least resistance. The lesion mainly involves the cancellous bone and grows in the anteroposterior direction with little evidence of cortical expansion in the initial stages. They are poor bone resorbers that invade the compact bone much later.1,8,10 Clinically, KCOTs are often asymptomatic; however, they occasionally may cause swelling, pain, discharge, teeth mobility, and invasion of adjacent structures. If secondarily infected, symptoms like pain, swelling, and discharge are not uncommon, wherein the lesion can be easily confused with inflammatory conditions like sinusitis. In this case, the patient had a localized asymptomatic swelling, which is the most commonly reported symptom. 4 The swelling was soft and fluctuant, indicating buccal cortical plate resorption, which is not uncommon with large KCOTs in the posterior maxilla.12 The anatomical structure, loose maxillary bone density, and empty space of the maxillary antrum may be the contributing factors for the development of such an expansile tumor in the present case. KCOTs may cause the radicular displacement of adjacent teeth, but root resorption is rare.5 Contrary to this, none of the teeth showed any deviation; however, rhizolysis was detected in three teeth of our patient. Radiographically, KCOT appears as well-defined radiolucency with an osteosclerotic rim, which may be unilocular or multilocular. 4 Multilocularity of these lesions is attributed to their tendency to expand through the marrow spaces owing to their active epithelium.13 Scalloped margins are observed in the long standing lesions due to the regional resorption of the surrounding bone. 8 Even though KCOTs present a varied radiographic appearance, the lack of cortical expansion appears to be the only reliable radiographic parameter compared with odontogenic cysts or ameloblastomas.6 KCOT can occur anywhere within the jaws and can resemble other lesions that present with similar radiological features. Therefore, many cystic and neoplastic lesions can be considered as the differential diagnosis. These include dentigerous cysts, lateral periodontal cysts, radicular cysts, ameloblastomas, Autopsy and Case Reports 2016;6(3):41-46

Kaushik R, Pushpanshu K, Punyani SR, Raj V

adenomatoid odontogenic tumors, odontogenic myxomas, simple bone cysts, central giant cell granulomas, arteriovenous malformations, and a number of fibro-osseous lesions. It has been shown that an unerupted tooth is involved in the lesion in 25-40% of cases. Thus, clinically and radiologically, it mimics a dentigerous cyst, as was the scenario in the reported case. Therefore, a thorough preoperative differentiation between these lesions is of utmost importance as it leads to the choice of surgical method.4,14 With KCOT involving the maxillary antrum being a rarity, its detection solely by plain radiography may result in misdiagnosis. 1 CT and/or magnetic resonance imaging (MRI) examinations can eliminate the superimposition of anatomical structures leading to the three-dimensional geometric accuracy. 14 Additionally, these examinations may help to assess the infiltration following cortical perforation and soft tissue involvement. 5 Therefore, CT/MRI can aid both diagnosis and preoperative preparation of these lesions involving a rare site, compared to the traditional two‑dimensional views. Even with highly suggestive clinical and radiographic features, KCOT can often be misdiagnosed— and even more so when it involves the maxilla. Therefore, the best way to confirm its diagnosis is by recognizing its characteristic histopathologic features.2 The histopathologic features of KCOT are confirmatory with distinctly different epithelial lining. However, these classic features may be altered by inflammation, which can lead to confusion.6 Histologically, it has the characteristic lining of parakeratinized stratified squamous epithelium with an aggressive clinical presentation. 4 Previously considered a subtype, the orthokeratotic variety is currently considered as an “innocent” entity and is still believed to be a developmental odontogenic cyst.14 Histopathologic diagnosis is particularly important for adequate treatment planning and, hence, for preventing recurrences. 1 KCOT has a high rate of recurrence (up to 60%), which is comparable only to ameloblastoma.15 The involvement of a tooth— the third molar in particular—is considered to be an important risk factor for the development of recurrence.6 In the present case, KCOT involved the right maxillary antrum along with the right maxillary impacted third molar. The likelihood of recurrences depends on numerous variables, which are yet to be Autopsy and Case Reports 2016;6(3):41-46

clearly determined. There is no consensus regarding the best treatment option of KCOT, which must be managed in a case-by-case manner. The surgical treatment aims to control potential recurrence with the least possible morbidity. 5,6 Following careful assessment, we decided on an antral cystectomy using the Caldwell-Luc procedure, followed by treatment of the cavity with Carnoy’s solution. The Caldwell-Luc procedure provides a direct view of the maxillary sinus, and Carnoy’s solution kills the epithelial remnants or satellite cysts.1 Carnoy’s solution is a tissue fixative that kills epithelial remnants in the osseous margin because it can penetrate bone to a depth of 1.54 mm.8 KCOTs involving the maxillary sinus invariably become large expanded lesions, which present challenges in achieving complete hemostasis in the anatomically delicate areas. 7 Such cases, therefore, require a multidisciplinary collaboration between different specializations with careful treatment planning for a favorable prognosis, including the absence of KCOT recurrence. Due to the frequent recurrence of KCOT, patients are recommended to be kept under long-term supervision as recurrences can occur up to 10 years after treatment. However, it is more common during the first 5-7 years. 6 Our patient was observed for 6 years after treatment with no evidence of recurrence.

CONCLUSION The reclassification of KCOT from cyst to tumor underscores its aggressiveness, which should motivate the clinician to manage the disease aggressively. The lesion is unique in terms of its high recurrence rate, and it is a good mimic owing to its variety of clinical and radiographic appearances. Thus, only a cautious approach aided with wisely chosen diagnostic tests can help to make a preoperative diagnosis of this challenging tumor in an unusual site.

REFERENCES 1. Kwon HI, Lim WB, Kim JS, et al. Odontogenic Keratocyst associated with an ectopic tooth in the Maxillary sinus: a report of two cases and a review of the literature. Korean J Pathol. 2011;45(Suppl 1):S5-10. http://dx.doi. org/10.4132/KoreanJPathol.2011.45.S1.S5. 2. Chaudhary S, Sinha A, Barua P, Mallikarjuna R. Keratocystic odontogenic tumour (KCOT) misdiagnosed 45

Giant keratocystic odontogenic tumor: a challenging diagnosis

as a dentigerous cyst. BMJ Case Rep. 2013;2013 PMid:23429028. 3. El-Hajj G, Anneroth G. Odontogenic keratocysts: a retrospective clinical and histologic study. Int J Oral Maxillofac Surg. 1996;25(2):124-9. http://dx.doi. org/10.1016/S0901-5027(96)80057-9. PMid:8727585. 4. Cakur B, Miloglu O, Yolcu U, Göregen M, Gürsan N. Keratocystic odontogenic tumor invading the right maxillary sinus: a case report. J Oral Sci. 2008;50(3):3459 . h t t p : / / d x . d o i . o r g / 1 0 . 2 3 3 4 / j o s n u s d . 5 0 . 3 4 5. PMid:18818473. 5. Grasmuck EA, Nelson BL. Keratocystic odontogenic tumor. Head Neck Pathol. 2010;4(1):94-6. http://dx.doi. org/10.1007/s12105-009-0146-x. PMid:20237995. 6. Sánchez-Burgos R, González-Martín–Moro J, PérezFernández E, Burgueño-García M. Clinical, radiological and therapeutic features of keratocystic odontogenic tumours: a study over a decade. J Clin Exp Dent. 2014;6(3):e259-64. http://dx.doi.org/10.4317/ jced.51408. PMid:25136427.

9. Regezi JA, Sdubba JJ. Oral pathology: clinical-pathologic correlations. 2nd ed. Philadelphia: W.B. Saunders Company; 1993. p. 337-341. 10. R.A .Cawson, E.W.Odell. Cawson’s essentials of oral pathology and oral medicine. 8th ed. Edinburgh: Churchill Livingstone; 2008. 11. Scharffetter K, Balz-Herrmann C, Lagrange W, Koberg W, Mittermayer C. Proliferation kinetics-study of the growth of keratocysts: morpho-functional explanation for recurrences. J Craniomaxillofac Surg. 1989;17(5):22633. http://dx.doi.org/10.1016/S1010-5182(89)80074-5. PMid:2668340. 12. Makowski GJ, McGuff S, Van Sickels JE. Squamous cell carcinoma in a maxillary odontogenic keratocyst. J Oral Maxillofac Surg. 2001;59(1):76-80. http://dx.doi. org/10.1053/joms.2001.19297. PMid:11152194. 13. Haring JI, Van Dis ML. Odontogenic keratocysts: a clinical, radiographic, and histopathologic study. Oral Surg Oral Med Oral Pathol. 1988;66(1):145-53. http://dx.doi. org/10.1016/0030-4220(88)90082-5. PMid:2457195.

7. Byun JH, Kang YH, Choi MJ, Park BW. Expansile keratocystic odontogenic tumor in the maxilla: immunohistochemical studies and review of literature. J Korean Assoc Oral Maxillofac Surg. 2013;39(4):182-7. http://dx.doi. org/10.5125/jkaoms.2013.39.4.182. PMid:24471040.

14. Koçak-Berberoğlu H, Çakarer S, Brkić A, Gürkan-Koseoglu B, Altuğ-Aydil B, Keskin C. Three-dımensıonal cone- beam computed tomography for dıagnosıs of keratocystıc odontogenıc tumours; evaluatıon of four cases. Med Oral Patol Oral Cir Bucal. 2012;17(6):e1000-5. http://dx.doi. org/10.4317/medoral.17629. PMid:22549670.

8. Gupta A, Rai B, Nair MA, Bhut MK. Keratocystic odontogenic tumor with impacted maxillary third molar involving the right maxillary antrum: an unusual case report. Indian J Dent Res. 2011;22(1):157-60. http:// dx.doi.org/10.4103/0970-9290.79984. PMid:21525696.

15. DelBalso AM. An approach to the diagnostic imaging of jaw lesions, dental implants, and the temporomandibular joint. Radiol Clin North Am. 1998;36(5):855-90, vi. http://dx.doi.org/10.1016/S0033-8389(05)70067-1. PMid:9747192.

Conflict of interest: None Submitted on: March 9th, 2016 Accepted on: June 21st, 2016 Correspondence Kumar Pushpanshu Department of Dentistry - SriKrishna Medical College & Hospital Muzaffarpur, Bihar – India Pin code: 842001 Phone: +91 (85) 2178-5644 drpushpanshu@yahoo.co.in

Autopsy and Case Reports 2016;6(3):41-46

Article / Clinical Case Report

Amlodipine-induced gingival overgrowth in a child after liver transplant André Guolloa, Ana Paula Molina Vivasa, Rodrigo Nascimento Lopesa, Gilda Portab, Fábio Abreu Alvesa,c Guollo A, Vivas APM, Lopes RN, Porta G, Alves FA. Amlodipine-induced gingival overgrowth in a child after liver transplant. Autopsy Case Rep [Internet]. 2016;6(3):47-51. http://dx.doi.org/10.4322/acr.2016.041

ABSTRACT Drug-induced gingival overgrowth (GO) has been associated with phenytoin, cyclosporine, and calcium channel blocker therapies. This study reports the case of an 11-year-old girl who was referred for evaluation of GO, which had occurred over the last 6 months. Her medical history included a liver transplant due to biliary atresia 3 years ago, immunosuppressive therapy, and hypertension, which is why she was started on a daily intake of amlodipine. The intraoral examination showed generalized GO, and the treatment consisted of a gingivectomy. Subsequently, amlodipine was replaced with captopril and oral hygiene instructions. There was no recurrence of GO after 28 months of follow-up. Although GO may be related to the chronic use of amlodipine, such an association is uncommon in pediatrics, and the treatment consists of the replacement of medication combined with a surgical approach and plaque control. Keywords Amlodipine; Gingival Overgrowth; Liver Transplantation

INTRODUCTION Liver transplantation is the current treatment for end stage chronic liver disease and acute hepatic failure, even though it is a very demanding procedure. The most frequent indications are biliary atresia, fulminant liver failure, metabolic diseases, hepatic tumors, cirrhosis, and other cholestatic liver diseases. Liver-transplanted children have shown good overall patient/organ survival rates of 83.8/75.3% after 3 years, and 70.2/65.1% after 5 years of transplantation. This increase in survival time is mainly due to the improvement of surgical techniques, the management of complications, immunosuppressive medications, and multidisciplinary intervention.1,2

Liver transplant complications may be associated with the surgical procedure, infections, and immunosuppressive therapy. Tacrolimus, cyclosporine, and corticosteroids are most often used to prevent graft rejection.3,4 Calcium-channel blockers, such as nifedipine and amlodipine, are usually recommended for the treatment of hypertension after liver transplantation,5-8 since this complication represents a possible side effect associated with the immunosuppressive regimen. In 1993, Ellis et al. 9 first reported gingival overgrowth (GO) associated with the chronic use of calcium channel blockers; since then, its

Stomatology Department - A.C. Camargo Cancer Center, São Paulo/SP – Brazil. Department of Liver Transplantation - A.C. Camargo Cancer Center, São Paulo/SP – Brazil. c Stomatology Department - Universidade de São Paulo, São Paulo/SP – Brazil. a

Amlodipine-induced gingival overgrowth in a child after liver transplant

prevalence has been reported in nearly 3% of patients. The enlargement of the gingiva may hamper the appropriate oral hygiene, predisposing tooth decay and periodontal infections, requiring rigorous plaque control, anti-hypertensive drug schedule replacement, and surgical correction for aesthetic purposes.10,11 Although a liver transplant is commonly associated with cardiovascular alterations and the use amlodipine is not infrequent, to date, only a single report has shown the involvement of GO in a young patient after solid organ transplantation.12 The objective of this case study is to describe such an association in a child, and how this was managed.

CASE REPORT An 11-year-old girl was referred to the Stomatology Department due to gingival enlargement. The patient reported slow and progressive growth of the gums over the last 6 months. Her medical history included a liver transplant to treat biliary atresia when she was 8 years old. Since then, she had been using tacrolimus (0.25 mg once a week) and prednisone (10 mg daily)— to avoid organ graft rejection—and amlodipine (10 mg/day) for blood pressure control. Her dental history showed no particular treatment and she had regular visits to the dentist. The oral hygiene was proper and no dental caries was observed. However, many white spots were present in almost all teeth, which is consistent with enamel hypoplasia. In addition, an extensive fibrous GO in the anterior permanent teeth of both arches was observed. Such GO mainly affected the marginal gingiva, but also it affected the interdental papilla and covered the tooth crown 4 mm on average with standard color, without any inflammatory component. There was no bleeding during periodontal probing (Figure 1). The diagnostic suspicion was amlodipine-related GO. The treatment consisted of oral care instructions (the use of a soft brush at least three times a day and dental floss) and a gingivectomy. The surgery was performed under general anesthesia by two stomatologists after a preoperative work-up and an anesthetic evaluation. The internal bevel technique was used to remove all the gingival hyperplastic tissue, involving the anterior region of both dental arches. The patient received antibiotics 48

(clindamycin) for a total of 7 days, and an analgesic (dipyrone) for 3 days. The postoperative period was uneventful, and she was discharged after 2 days of hospitalization. The histopathological features showed hyperkeratosis, acanthosis, and some long epithelial rete pegs. In addition, intense fibrosis of the connective tissue and an increase in the number of blood vessels with slight chronic perivascular inflammation were observed (Figure 2). The amlodipine was replaced by captopril. After 28 months of follow-up, there was no GO recurrence (Figure 3).

DISCUSSION Although the survival rate of pediatric patients who undergo liver transplantations has substantially increased due to the immunosuppressive therapy, these drugs always have been associated with many complications and side effects. In this context, GO had been described in children who had undergone kidney or liver transplants. It was also associated with the long-term use of cyclosporine, nifedipine, and amlodipine, and is similar to the well-known side effect of the anticonvulsant, such as phenytoin.9,10,13,14 The case reported here showed an 11-year-old girl who developed GO after 30 months of amlodipine use. Calcium channel blockers act directly on vascular smooth muscle, reducing systemic vascular resistance and improving renal blood flow, thereby reducing the systemic blood pressure. 15 Some studies 11,16,17 showed the incidence of GO ranging between 1.3%

Figure 1. Intraoral examination showing GO in the anterior region of both arches. Autopsy and Case Reports 2016;6(3):47-51

Guollo A, Vivas APM, Lopes RN, Porta G, Alves FA

Figure 2. Photomicrography of the gingiva showing the histopathological features of the amlodipine-related GO. A - Slight hyperkeratosis, acanthosis, and B - long epithelial rete pegs; C - Intense fibrosis of the connective tissue, and D - an increased number of capillaries with slight chronic perivascular inflammation (H&E, 150X).

Figure 3. Intraoral examination after 28 months of follow-up, with no recurrence of gingival overgrowth. A - Anterior view; B - Occlusal view; C - Right side view; and D - Left side view. Autopsy and Case Reports 2016;6(3):47-51

Amlodipine-induced gingival overgrowth in a child after liver transplant

and 3.4% in hypertensive adults using amlodipine for at least 3 months. These drugs also have been used for hypertension control in post-liver transplantation patients. Interestingly, a higher frequency of GO was observed in patients simultaneously taking cyclosporine and calcium channel blockers (46.7%) compared to patients taking tacrolimus and calcium channel blockers (8.3%). 18 Based on the study of Shiboski et al.,19 tacrolimus was not related to GO, and, similar to his findings, in our institution, none of the children who underwent liver transplantation who were treated with tacrolimus presented GO.13 Furthermore, neither James et al.20 nor Greenberg et al.21 found any association between the use of tacrolimus and GO in renal transplant patients. However, Cezário et al.22 and Paixao et al.23 related an association rate of 7.25% and 8.3%, respectively. In our case, the diagnosis of amlodipine-induced GO was established. The pathogenesis of GO related to medications still remains unclear. However, a hypothesis involving anti-convulsants, calcineurin inhibitors, and calcium channel blockers has recently been described in a review14 that states that the cation flux reduces the folic acid active transport in gingival fibroblasts, causing the reduction of cellular folate uptake. The matrix metalloproteinase metabolism is changed, which impairs the collagenase activation and results in the increase of collagen synthesis. In addition, the presence of inflammation caused by bacterial plaque also induces connective tissue production.14 Poor hygiene, local inflammation, and bleeding also may be associated with GO. The anterior region is the most affected by GO, and the local factor, such as bacterial plaque, may exacerbate such cases, increasing susceptibility to oral infections, dental caries, and periodontal diseases.9,10,24 Similarly, the present patient was affected by GO in the anterior region of both arches, especially in the interdental papillae, without local factors, such as the presence of plaque and/or gingival bleeding. The treatment of this condition is the replacement of the “guilty drug,” which, in our case, was the amlodipine combined with removal of bacterial plaque if present. For aesthetic reasons, surgical intervention is recommended. The classic surgical approach of the internal bevel may be used in a gingivectomy.10,24 This technique is based on the principle of excising the tissue that is extended with a scalpel blade tilted 50

at an angle of 45 degrees in relation to the teeth, also contouring the papillae. Afterwards, interpapillary suturing must be performed to maintain the papillary position. The patient in this case report was successfully treated with the change of amlodipine to captopril and by undergoing a gingivectomy.

CONCLUSION The present case illustrates the diagnosis and management of GO associated with the use of amlodipine. In addition, children who have undergone a solid-organ transplant should have periodic follow-up with dentists due to oral side effects related to immunosuppressive therapy and other drugs, such as amlodipine.

REFERENCES 1. Martin SR, Atkison P, Anand R, Lindblad AS. Studies of pediatric liver transplantation 2002: patient and graft survival and rejection in pediatric recipients of a first liver transplant in the United States and Canada. Pediatr Transplant. 2004;8(3):273-83. http://dx.doi.org/10.1111/ j.1399-3046.2004.00152.x. PMid:15176966. 2. Tannuri U, Velhote MCP, Santos MM, et al. Pediatric liver transplantation: fourteen years of experience at the children Institute in São Paulo, Brazil. Transplant Proc. 2004;36(4):941-2. http://dx.doi.org/10.1016/j. transproceed.2004.03.101. PMid:15194325. 3. McDiarmid SV, Anand R, Lindblad AS. Studies of pediatric liver transplantation: 2002 update. An overview of demographics, indications, timing, and immunosuppressive practices in pediatric liver transplantation in the United States and Canada. Pediatr Transplant. 2004;8(3):284-94. http://dx.doi.org/10.1111/ j.1399-3046.2004.00153.x. PMid:15176967. 4. Spada M, Riva S, Maggiore G, Cintorino D, Gridelli B. Pediatric liver transplantation. World J Gastroenterol. 2009;15(6):648-74. http://dx.doi.org/10.3748/ wjg.15.648. PMid:19222089. 5. Galioto A, Semplicini A, Zanus G, et al. Nifedipine versus carvedilol in the treatment of de novo arterial hypertension after liver transplantation: results of a controlled clinical trial. Liver Transpl. 2008;14(7):1020-8. http://dx.doi.org/10.1002/lt.21442. PMid:18581464. 6. Carbone M, Sagar V, Ferguson J, Neuberger J. Calcium channel blockers or angiotensin-converting enzyme inhibitors for de novo hypertension after liver transplant: and the winner is …? Transplantation. 2012;93(2):24. http://dx.doi.org/10.1097/TP.0b013e31823c6811. PMid:22234315. Autopsy and Case Reports 2016;6(3):47-51

Guollo A, Vivas APM, Lopes RN, Porta G, Alves FA

7. Algarem N, Sholkamy A, Alshazly M, Daoud A. Newonset diabetes and hypertension as complications of liver transplantation. Transplant Proc. 2014;46(3):870-2. http://dx.doi.org/10.1016/j.transproceed.2013.12.007. PMid:24767368. 8. Lai HM, Pawar R, Wolf DC, Aronow WS. Impact of cardiovascular risk factors on long-term mortality after liver transplantation. Am J Ther. 2014. PMid:24897624. 9. Ellis J, Seymour RA, Thomason JM, Monkman SC, Idle JR. Gingival sequestration of amlodipine and amlodipine-induced gingival overgrowth. Lancet. 1993;341(8852):1102-3. http://dx.doi.org/10.1016/01406736(93)92470-E. PMid:8097007. 10. Srivastava AK, Kundu D, Bandyopadhyay P, Pal AK. Management of amlodipine-induced gingival enlargement: Series of three cases. J Indian Soc Periodontol. 2010;14(4):279-81. http://dx.doi.org/10.4103/0972124X.76931. PMid:21731258. 11. Tejnani A, Mani A, Sodhi NK, et al. Incidence of amlodipineinduced gingival overgrowth in the rural population of Loni. J Indian Soc Periodontol. 2014;18(2):2268. http://dx.doi.org/10.4103/0972-124X.131332. PMid:24872633. 12. Sucu M, Yuce M, Davutoglu V. Amlodipine-induced massive gingival hypertrophy. Can Fam Physician. 2011;57(4):436-7. PMid:21490356. 13. Vivas AP, Bomfin LE, Costa WL Jr, Porta G, Alves FA. Oral granulomatosis-like lesions in liver-transplanted pediatric patients. Oral Dis. 2014;20(3):97-102. http://dx.doi. org/10.1111/odi.12143. PMid:23781921. 14. Brown R, Arany P. Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis. Oral Dis. 2015;21(1):51-61. http://dx.doi.org/10.1111/odi.12264. PMid:24893951. 15. Textor SC, Taler SJ, Canzanello VJ, Schwartz L, Augustine JE. Posttransplantation hypertension related to calcineurin inhibitors. Liver Transpl. 2000;6(5):521-30. http://dx.doi. org/10.1053/jlts.2000.9737. PMid:10980050.

16. Jorgensen MG. Prevalence of amlodipine-related gingival hyperplasia. J Periodontol. 1997;68(7):676-8. http:// dx.doi.org/10.1902/jop.1997.68.7.676. PMid:9249639. 17. Ono M, Tanaka S, Takeuchi R, et al. Prevalence of amlodipine-induced gingival overgrowth. Int J OralMed Sci. 2010;9(2):96-100. http://dx.doi.org/10.5466/ ijoms.9.96. 18. Helenius-Hietala J, Ruokonen H, Grönroos L, et al. Oral mucosal health in liver transplant recipients and controls. Liver Transpl. 2014;20(1):72-80. http://dx.doi. org/10.1002/lt.23778. PMid:24142471. 19. Shiboski CH, Krishnan S, Besten PD, et al. Gingival enlargement in pediatric organ transplant recipients in relation to tacrolimus-based immunosuppressive regimens. Pediatr Dent. 2009;31(1):38-46. PMid:19320258. 20. James JA, Jamal S, Hull PS, et al. Tacrolimus is not associated with gingival overgrowth in renal transplant patients. J Clin Periodontol. 2001;28(9):848-52. http:// dx.doi.org/10.1034/j.1600-051x.2001.028009848.x. PMid:11493354. 21. Greenberg KV, Armitage GC, Shiboski CH. Gingival enlargement among renal transplant recipients in the era of new-generation immunosuppressants. J Periodontol. 2008;79(3):453-60. http://dx.doi. org/10.1902/jop.2008.070434. PMid:18315427. 22. Cezário ES, Cota LO, Ferreira SD, et al. Gingival overgrowth in renal transplant subjects medicated with tacrolimus in the absence of calcium channel blockers. Transplantation. 2008;85(2):232-6. http://dx.doi. org/10.1097/TP.0b013e3181604fad. PMid:18212628. 23. Paixao CG, Sekiguchi RT, Saraiva L, et al. Gingival overgrowth among patients medicated with cyclosporin A and tacrolimus undergoing renal transplantation: a prospective study. J Periodontol. 2011;82(2):251-8. http:// dx.doi.org/10.1902/jop.2010.100368. PMid:20722530. 24. Grover V, Kapoor A, Marya CM. Amlodipine induced gingival hyperplasia. J Oral Health Comm Dent. 2007;1(1):19-22.

Conflict of interest: None Submitted on: February 26th, 2016 Accepted on: July 12th, 2016 Correspondence Fabio Abreu Alves Stomatology Department - A.C. Carmago Cancer Center Rua Professor Antônio Prudente, 211 – São Paulo/SP – Brazil CEP: 01509-900 Phone: +55 (11) 2189-5129 / +55 (11) 2189-5133 falves@accamargo.org.br

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Article / Clinical Case Report

Vocal fold mobility alteration reversed after thyroidectomy Aline Paterno Miazakia, Vergilius José Furtado Araújo-Filhoa, Lenine Garcia Brandãoa, Vergilius José Furtado de Araujo-Netoa, Leandro Luongo Matosa,b, Claudio Roberto Cerneaa Miazaki AP, Araújo-Filho VJF, Brandão LG, Araujo-Neto VJF, Matos LL, Cernea CR. Vocal fold mobility alteration reversed after thyroidectomy. Autopsy Case Rep [Internet]. 2016;6(3):53-57. http://dx.doi.org/10.4322/acr.2016.039

ABSTRACT The involvement of the inferior or recurrent laryngeal nerve (RLN) in mobility derangement of the vocal folds occurs more frequently due to thyroid malignancy invasion. Although uncommon, the same derangement, which is caused by benign thyroid entities, is also described and reverts to normality after a thyroidectomy in up to 89% of cases. In these cases, the pathogenesis of the vocal cord mobility disturbance is attributed to the direct compression of the RLN by massive thyroid enlargement. The authors describe three cases of patients presenting unilateral vocal cord palsy, which, before surgery, was diagnosed by laryngoscopy concomitantly with large and compressive goiter. Vocal fold mobility became normal after the thyroidectomy in all three cases. Therefore, it is noteworthy that these alterations may present reversibility after appropriate surgical treatment. An early surgical approach is recommended to reduce the nerve injury as much as possible; to preserve the integrity of both RLNs since the nerve function will be restored in some patients. Keywords Goiter; Vocal Cord Paralysis; Thyroidectomy

INTRODUCTION The diagnosis of vocal cord palsy associated with nodular goiter always raises the suspicion of thyroid malignancy. However, although less frequent, mobility disturbance of the vocal cords also may occur due to the compressive effect of gland enlargement. The main vocal fold mobility derangements are represented by paresis when the mobility is decreased, or by palsy when there is no moving sketch of the vocal fold during phonation. Both alterations may be examined by laryngoscopy; they occur by the injury of the recurrent laryngeal or vagus nerves.1,2

common cause is benign nodular goiter (5-10%). 3

The most frequent causes of vocal cord palsy are idiopathic (13-27%) and malignancies (12-38%); a less

caused by goiter, which were each reversed after a

a b

Rowe-Jones et al.4 found 22 cases with preoperative vocal cord mobility disturbance among 2321 cases of goiter that were submitted to a thyroidectomy. In the same study, the authors detected the postoperative recovery of recurrent laryngeal nerve (RLN) function and vocal fold mobility in 19 patients (89% of recovery rate). The aim of this study is to present a series of three cases of vocal cord mobility derangement thyroidectomy.

Head and Neck Surgery Discipline - Hospital das Clínicas - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP - Brazil. Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo/SP - Brazil.

Vocal fold mobility alteration reversed after thyroidectomy

CASE REPORTS Case 1 A 77-year-old female patient complained of insidious dysphagia and dyspnea, which had worsened over the last 20 years. She denied dysphonia. She had undergone a right thyroid lobectomy with isthmusectomy 30 years previously and was being followed up at the same medical facility. The physical examination revealed an euphonic and eupneic patient presenting a neck scar and a huge, nodular left thyroid lobe enlargement with imprecise inferior limit, which resembled a plunging goiter. A laryngoscopy, performed 2 years before, showed normal mobility of the vocal folds. A fine needle aspiration biopsy revealed a cytological finding consistent with the diagnosis of adenomatous goiter. A current laryngoscopy showed the palsy of the left vocal fold (Figure 1). The computed tomography of the neck showed a voluminous plunging mass within the left thyroid lobe (estimated volume 286 cc) displacing the great vessels and the trachea to the right, which exhibited a luminal narrowing of up to 70%. A compression of the neurovascular bundle (involving the left vagus nerve, left internal jugular vein, and the left carotid artery)

caused by the mass against the first left rib was also identified (Figure 2). The patient underwent a left lobe thyroidectomy through a transverse lower midcervical incision preserving the left RLN. Intraoperative RLN monitoring was undertaken, with the presence of the nervous sign throughout the surgical procedure (signal conductibility of 115 µV at the moment of nerve identification and 195 µV at the end of surgery). Colloid goiter was the anatomopathological report of the surgical specimen. On the first postoperative day, the vocal cords presented normal mobility (Figure 3) at laryngoscopy, and the patient was discharged for routine follow-up with continuous hormone replacement.

Case 2 A 46-year-old woman diagnosed with substernal multinodular toxic goiter (estimated volume of 175 cc) presented an immobile left vocal fold in the paramedian position on preoperative laryngoscopy. Total thyroidectomy was undertaken with intraoperative RLN monitoring. Both RLN and vagus nerves exhibited normal function during the whole surgical procedure. The patient presented normal voice and vocal cords’ mobility at the laryngoscopy 1 week after surgery.

Figure 1. Preoperative laryngoscopy showing the left vocal fold palsy at inspiration (A) and at phonation (B). 54

Autopsy and Case Reports 2016;6(3):53-57

Miazaki AP, Araújo-Filho VJF, Brandão LG, Araujo-Neto VJF, Matos LL, Cernea CR

Figure 2. Chest radiography (A) and neck computed tomography (B - coronal plane and C - sagittal plane) showing a massive plunging mass into the superior mediastinum in the left thyroid lobe topography, displacing and narrowing the trachea. Note the displacement of the left neurovascular bundle and its compression against the first rib.

Figure 3. Postoperative laryngoscopy showing the left vocal fold mobility recovery at inspiration (A) and at phonation (B).

Case 3 An 80-year-old woman with the diagnosis of plunging multinodular goiter (ultrasonographic estimated volume of 230 cc) complained of long‑standing dysphonia. The preoperative laryngoscopy revealed a paralyzed left vocal fold in the paramedian position. She was submitted to a total thyroidectomy, and 1 week later she presented a normal voice without dysphonia. At the control laryngoscopy, the mobility of the vocal cords was normal. Autopsy and Case Reports 2016;6(3):53-57

DISCUSSION The cases described herein demonstrate that vocal cords palsy may happen in association with the thyroid benign entities and that its reversibility is possible after a thyroidectomy. The findings are corroborated by literature reports. O’Duffy and Timon3 found 9 patients (1.7%) with a paralyzed vocal fold among 830 patients submitted to thyroidectomy. In 6 of these patients, a benign 55

Vocal fold mobility alteration reversed after thyroidectomy

thyroid entity was identified; in 3 patients, the vocal cord palsy was associated with malignancy. In a study comprising 90 patients with unilateral vocal cord palsy, Srirompotong et al. 5 found that malignancy was the etiology in 29%. In this study, neck neoplasia was responsible for 10% of the cases, followed by pulmonary malignancy in 7%. Rowe‑Jones et al.4 studied 2408 patients who had undergone a thyroidectomy between 1947 and 1992. Preoperative palsy of one vocal fold was identified in 22 out of 2321 patients (0.95%) with benign thyroid disease, and in 7 of 87 patients (8%) with malignant thyroid disease. The recovery of nerve function and mobility of the vocal cords occurred in 17 patients with benign thyroid disease (89%). In 6 of these patients (35.3%), the nerve function, demonstrated by laryngoscopy, was re-established on the third postoperative day (similar to our series observation), while late recovery occurred after 12 and 18 months postoperatively. There are various possible explanations for vocal fold mobility alteration as well as some types and causes of the RLN injury associated with benign thyroid diseases.3,4,6-8 According to the Seddon9 classification, which was further modified by Sunderland,10 there are different grades and stages of nervous injury. The neuropraxia is the most common and mild neuronal lesion or injury, in which a transient conduction blockage occurs due to a local demyelination (by Schwann cells injury) with preservation of the axonal integrity. Usually, in this case, the nerve function is restored when the Schwann cells are repaired. The axonotmesis represents the second degree of a nerve lesion, which is associated— to a lesser extent—with nerve function recovery. 6,7 The neuropraxia was the lesion that most likely occurred in the cases presented herein, because of the fast functional recovery of the involved vocal fold. Rowe-Jones et al.4 proposed some mechanisms to explain the vocal fold palsy associated with thyroid enlargement: (i) a direct compression of the nerve or its blood supply against the spine or trachea stretching the nerve and eliciting an inflammatory response, and thrombosis of small arteries with subsequent neuronal surrounding fibrosis; (ii) the involvement of the nerve directly by thyroiditis; and (iii) the expansion of the thyroid could restrain the nerve in the pretracheal space bringing about a compartmental syndrome. 56

In this setting, the thyroidectomy provides the re-establishment of the nerve blood supply, which explains the prompt recovery of the nerve function and, consequently, the vocal fold soon after the surgical procedure, as exemplified by the Case 1 of this series. Similarly, O’Duffy and Timon 3 stated that the most accepted mechanisms are the compression or stretching of the nerve, and/or the detriment of the nerve blood supply by the nerve compressing against a hard structure, such as the spine or trachea, as observed in the presented cases of our series. The reversibility of the nervous lesion would depend on the duration of ischemia. Holl-Allen 8 observed that retrosternal goiters also could be responsible for similar palsy mainly by the involvement of the left RLN, which exhibits a longer route. This explanation is consistent with the three cases of retrosternal or plunging goiters of our reported series. Rueger 11 described different rates of nerve function recovery after a thyroidectomy due to benign thyroid entities, which ranged between 0% and 38% depending on the duration of the paralysis highlighting the necessity of the preoperative laryngoscopy to adequately evaluate the mobility of the vocal cords before the procedure. Equally important is the postoperative laryngoscopy, since voice normalization does not prove the recovery of the paralysis, since the contralateral vocal fold can amend the glottal gap. Pre‑and postoperative laryngoscopies were undertaken in all three cases reported herein, which evidenced vocal fold recovery after the thyroidectomy. Given the possibility of partial or transitory lesion of the RLN, which may reverse after a thyroidectomy, the observation, dissection, and preservation of nerve integrity throughout the whole surgery is recommended.12 Furthermore, the nerve can regenerate if an incomplete nerve lesion occurs.13 This precaution was undertaken in all the cases of this study. Therefore, nodular thyroid disease associated with vocal fold palsy does not always indicate malignancy; although rare, it also may occur among benign entities. The pre- and postoperative laryngoscopy and the surgical treatment should be undertaken as early as possible to preserve the RLN, since many patients recover its function after a thyroidectomy. The study was approved by the Research and Ethics Committee under the number 712/11. Autopsy and Case Reports 2016;6(3):53-57

Miazaki AP, Araújo-Filho VJF, Brandão LG, Araujo-Neto VJF, Matos LL, Cernea CR

REFERENCES 1. Abboud B, Tabchy B, Jambart S, Hamad WA, Farah P. Benign disease of the thyroid gland and vocal fold paralysis. J Laryngol Otol. 1999;113(5):473-4. http://dx.doi.org/10.1017/S0022215100144251. PMid:10505166. 2. McCall AR, Ott R, Jarosz H, Lawrence AM, Paloyan E. Improvement of vocal cord paresis after thyroidectomy. Am Surg. 1987;53(7):377-9. PMid:3605854. 3. O’Duffy F, Timon C. Vocal fold paralysis in the presence of thyroid disease: management strategies. J Laryngol Otol. 2013;127(8):768-72. http://dx.doi.org/10.1017/ S0022215113001552. PMid:23899778. 4. Rowe-Jones JM, Rosswick RP, Leighton SEJ. Benign thyroid disease and vocal cord palsy. Ann R Coll Surg Engl. 1993;75(4):241-4. PMid:8379624. 5. Srirompotong S, Sae-Seow P, Srirompotong S. The cause and evaluation of unilateral vocal cord paralysis. J Med Assoc Thai. 2001;84(6):855-8. PMid:11556465. 6. Mattsson P, Hydman J, Svensson M. Recovery of laryngeal function after intraoperative injury to the recurrent laryngeal nerve. Gland Surg. 2015;4(1):27-35. PMid:25713777. 7. Chhabra A, Ahlawat S, Belzberg A, Andreseik G. Peripheral nerve injury grading simplified on MR neurography: as

referenced to Seddon and Sunderland classifications. Indian J Radiol Imaging. 2014;24(3):217-24. http://dx.doi. org/10.4103/0971-3026.137025. PMid:25114384. 8. Holl-Allen RT. Laryngeal nerve paralysis and benign thyroid disease. Arch Otolaryngol. 1967;85(3):335-7. http:// dx.doi.org/10.1001/archotol.1967.00760040337018. PMid:6019250. 9. Seddon HJ. A classification of nerve injuries. BMJ. 1942;2(4260):237-9. http://dx.doi.org/10.1136/ bmj.2.4260.237. PMid:20784403. 10. Sunderland S. A classification of peripheral nerve injuries producing loss of function. Brain. 1951;74(4):491516. http://dx.doi.org/10.1093/brain/74.4.491. PMid:14895767. 11. Rueger RG. Benign disease of the thyroid gland and vocal cord paralysis. Laryngoscope. 1974;84(6):897-907. http://dx.doi.org/10.1288/00005537-197406000-00002. PMid:4832372. 12. Chang M, Khoo JB, Tan HK. Reversible recurrent laryngeal nerve palsy in acute thyroiditis. Singapore Med J. 2012;53(5):e101-3. PMid:22584984. 13. Jatzko GR, Lisborg PH, Muller MG, Wette VM. Recurrent nerve palsy after thyroid operations: principal nerve identification and a literature review. Surgery. 1994;115(2):139-44. PMid:8310401.

Conflict of interest: None Submitted on: March 23rd, 2016 Accepted on: June 16th, 2016 Correspondence Leandro Luongo Matos Universidade de São Paulo (USP) Av. Dr. Enéas de Carvalho Aguiar, 255, 8th floor, room 8174 – São Paulo/SP – Brazil CEP: 05403-000 Phone: +55 (11) 3069-6425 l.matos@fm.usp.br

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