Autopsy & Case Report by Editora Cubo

ISSN 2236-1960

v. 9, n. 1, jan./mar. 2019

Photomicrograph of the brain showing reactive astrocytes with bizarre atypical nuclei in a case of progressive multifocal leukoencephalopathy (H&E, 400X)

Hospital UniversitĂĄrio Universidade de SĂŁo Paulo

ISSN 2236-1960 March 2019, volume 9 number 1

Electronic Journal of the Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil President of the University of São Paulo Professor Vahan Agopyan Superintendent of the University Hospital Professor Dr. Paulo Francisco Ramos Margarido

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 Alex K Williamson, MD Ameer Hamza, MD Support Team Rubenildo Oliveira da Costa - Head of Library Lucimar da Silva Prado - Editorial assistant Wesley Algarve and Deise Gonçalves dos Santos - Technical support Editora Cubo, desktop publishing Sponsors Programa de Apoio às Publicações Científicas Periódicas da USP Hospital Universitário - University of São Paulo Indexing PubMed Central Lilacs Portal de Revistas da USP PKP IBICT Latindex Diadorin Seminarios.org Directory of Open Access Journals DOAJ

Editorial

Medical education needs typical cases of common diseases Larry Nicholsa How to cite: Nichols L. Medical education needs typical cases of common diseases. [editorial]. Autops Case Rep [Internet]. 2019;9(1):e2018080. http://dx.doi.org/10.4322/acr.2018.080

Reality is the best teacher. In a perfect world, students would learn the basic science of medicine by seeing real patients under the guidance of physicians who knew every aspect of basic science needed to understand each feature of each patient’s disease. In this perfect world, patients would show up with just the right diseases that students were ready to learn and in a logical order that allowed students to gradually build skyscrapers of understanding. For instance, seeing their patient Fernando with cardiac tamponade, they would be shown to measure the abnormally high drop in his blood pressure on inspiration and taught how impaired filling of his heart causes his pulsus paradoxus, and they would effortlessly remember it because they would remember Fernando. Of course, in a perfect world, there would be no disease. Seriously, though, case-based medical education seeks to approximate the perfect world of medical education. Case-based teaching of the basic sciences often uses clinical scenarios that are approximately the length of case presentations within case reports in the medical literature. One common way to use these clinical scenarios is to have small groups of students discuss each important concept of basic science illustrated by the case, guided by a medical school faculty tutor. This integrates the teaching of basic science with clinical science, which enhances learning.1 If these groups of medical students can be guided to create a list of these important concepts, assign learning about them among the group members and then have a later meeting with the tutor to teach each other, that is problem-based learning, which enhances a

skills in problem solving, teamwork and independent responsibility for learning.2 Clinical scenarios to serve the purpose of illustrating important basic science concepts, especially scenarios detailed enough to stimulate students to see these concepts on their own in problem-based learning, need to be robust. It is extremely difficult for medical school faculty to supply all the clinical scenarios needed for case‑based learning from their clinical practice. Real cases of any particular disease usually have features that are not typical. They often lack features that are typical. To make these cases work for medical education, faculty add typical features, subtract atypical features and change the features to suit pedagogical needs. Medical school curricula typically require teaching far more topics than the number of cases the students have time for, so cases of multiple diseases are edited to illustrate what is typical of so many different diseases than the resulting clinical scenario can become an impossible chimera, sometimes with contradictory features. Medical schools often lack real cases and simply invent them.3 Such approaches get farther and farther away from the perfect world of medical education. An ideal clinical scenario for introducing medical students to a disease is a case of a patient with only this disease or a cluster of diseases that naturally go with it. An example would be a patient with a myocardial infarction, who has a history of smoking, hypertension, obesity, diabetes mellitus and dyslipidemia. An ideal clinical scenario for medical education must be robust. A robust clinical scenario has a paragraph, or two, or three of the history of the present illness. A robust

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

Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2019. 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.

Medical education needs typical cases of common diseases

clinical scenario has a paragraph or more of the past medical history. Even a neonate has a past medical history of prenatal care, usually. A robust clinical scenario has a paragraph, or two, or three of the social history and family history. The family history is important for genetic diseases, and that includes cancer. A robust clinical scenario has a full set of vital signs (temperature, heart rate, blood pressure, respiratory rate and oxygen saturation by oximetry). A robust clinical scenario has a paragraph, or two, or three of thorough careful physical examination. A robust clinical scenario has both common routine laboratory test results and relevant less common laboratory test results. Common routine laboratory tests include a complete blood count of hemoglobin, white blood cell count and differential, platelet count, mean corpuscular volume and red cell distribution width. Common routine laboratory tests also include what is often called a basic metabolic panel with electrolytes (sodium, potassium, chloride, and bicarbonate), creatinine and glucose. Teaching specific diseases requires specific additional tests. For example, a case with acute renal insufficiency should include blood urea nitrogen as well because of the value of the ratio of blood urea nitrogen over creatinine in determining whether the renal insufficiency is pre-renal, due to inadequate renal perfusion. Similarly, a case with diabetes mellitus should include hemoglobin A1c because of the value of this blood test in determining blood glucose levels over the past few months. Images are essential for a good clinical scenario for medical education. For instance, if the patient has a skin condition, an image of this is crucial in teaching medical students how to recognize this skin condition. A verbal description will not suffice. A robust clinical scenario has an electrocardiogram and often a chest radiograph.

A case with focal neurological findings should have images of computed tomography or magnetic resonance imaging. A case with biopsy should have images of the microscopic pathology. A case with autopsy should have images of the gross and microscopic pathology. Case-based teaching of basic medical science to medical students needs typical cases of common diseases. They need to be robust to illustrate the concepts and principles of basic science. They need to be real cases to avoid anatomic, physiologic and pathologic implausibilities and contradictions, what should be regarded as medical educational fake news. Case reports in the medical literature are real cases, but they are the opposite of typical cases of common diseases. Cases are reported in the medical literature when they have uncommon manifestations of common diseases or are simply rare. This is what fully educated practicing physicians need. The worldwide community of medical education needs some noble, far-sighted journal to publish typical cases of common diseases.

REFERENCES 1. Malau-Aduli BS, Lee AY, Cooling N, Catchpole M, Jose M, Turner R. Retention of knowledge and perceived relevance of basic sciences in an integrated casebased learning (CBL) curriculum. BMC Med Educ. 2013;13(139):1-18. http://dx.doi.org/10.1186/14726920-13-139. PMid:24099045. 2. W o o d D F . P r o b l e m b a s e d l e a r n i n g . B M J . 2003;326(7384):328-30. http://dx.doi.org/10.1136/ bmj.326.7384.328. PMid:12574050. 3. Azer SA, Peterson R, Guerrero AP, Edgren G. Twelve tips for constructing problem-based learning cases. Med Teach. 2012;34(5):361-7. http://dx.doi.org/10.3109/014 2159X.2011.613500. PMid:22452277.

Conflict of interest: None Financial support: None Submitted on: March 1st, 2019 Accepted on: March 10th, 2019 Correspondence Larry Nichols Department of Pathology - Mercer University School of Medicine 1550 College Street – Macon/GA – USA 31207 Phone: (+1) 478 301-2405 nichols_l@mercer.edu 2-2

Autops Case Rep (São Paulo). 2019;9(1):e2018080

Letter to Editor

Massive hematemesis in a case of gastric amyloidosis masquerading as gastric carcinoma Vikram Singha, Sonal Singlaa, Harjeet Singhb, Vishal Sharmac, Ashim Dasa How to cite: Singh V, Singla S, Singh H, Sharma V, Das A. Massive hematemesis in a case of gastric amyloidosis masquerading as gastric carcinoma. Autops Case Rep [Internet]. 2019;9(1):e2018074. https://doi.org/10.4322/acr.2018.074

DEAR EDITOR We herein report a case of gastric amyloidosis masquerading as gastric carcinoma in a 47-year-old woman, who presented with massive hematemesis from a huge gastric ulcer and underwent a life-saving total gastrectomy. Amyloidosis is a group of disorders that can affect any organ in the body and is thought to be secondary to misfolding of extracellular proteins.1 Gastric amyloidosis may occur in isolation or as a part of generalized amyloidosis. About 10% of patients with systemic amyloidosis show gastric involvement.2 In this case, symptoms include nausea, vomiting, hematemesis, and epigastric pain.3 It may manifest clinically as gastric outlet obstruction, in the form of a submucosal tumor or by infiltration of the whole gastric wall to give a hard, non-distensible and non-collapsible stomach which resembles the ‘leather-bottle’ stomach of diffuse gastric carcinoma. A 47-year-old woman, with no known comorbidities, came to the emergency department complaining of abdominal pain and hematemesis. She experienced intermittent epigastric pain over the last three years, non-radiating, aggravated on food intake and relieved with proton pump inhibitors. She had six episodes of hematemesis and melena during the past three years and non-intentional

weight loss. There was no history of fever, jaundice or heavy non-steroidal anti-inflammatory drug use. On examination – Vitals were within normal limits. Pallor was present; however, there was no icterus, generalized lymphadenopathy or any stigmata of liver disease. Systemic examination was essentially normal. She had anemia. Hemoglobin was 7.7 g/dl (Reference Range [RR]; 11-13g/dl). Liver and renal function tests, and blood sugar profile were within normal limits. Urease test for H. pylori was negative. An upper gastrointestinal endoscopy (UGIE) showed large linear ulcer with adherent clot along the gastric greater curvature. (Figure 1A). The esophagus, the gastric antrum, and the first and second parts of the duodenum were endoscopically normal. The working diagnosis was upper gastrointestinal bleeding and the patient was promptly treated with proton pump inhibitors and intravenous fluids. On the day of admission, she had multiple bouts of hematemesis causing hemodynamic instability, requiring 5 units of packed red blood cells transfusion. In view of medical management failure, ongoing blood loss, chronicity of illness and requirement of multiple unit blood transfusion, she underwent explorative laparotomy. Intraoperatively,

Post graduate Institute of Medical Education and Research, Department of Histopathology. Chandigarh, India. Post graduate Institute of Medical Education and Research, Department of General Surgery. Chandigarh, India. c Post graduate Institute of Medical Education and Research, Department of Gastroenterology. Chandigarh, India. a

Massive hematemesis in a case of gastric amyloidosis masquerading as gastric carcinoma

Figure 1. A - Upper gastrointestinal endoscopy (UGIE) showing long linear ulcer along the gastric greater curvature; B - Surgical specimen showing the stomach filled with clots and fresh blood; C - Gross view of the gastric thickened mucosa with hemorrhage extending from the fundus to the body sparing the antrum and covering greater than half of the gastric surface; D - Detailed macroscopic view of nodules present on the mucosa of the body of the stomach (black arrow). there was no ascites or omental nodules. The stomach was filled with clots and fresh blood (Figure 1B). The mucosa of the body and the antrum was friable and easily sloughed off. Multiple nodules were present in the body and the antrum. The intraoperative impression was of a malignant lesion. The exact source of bleeding could not be identified and diffuse bleeding persisted, total gastrectomy and esophagojejunal Roux – en Y anastomosis was performed with a feeding jejunostomy. On the gross examination, the gastric wall was thickened and the mucosa was hemorrhagic over more than half of the gastric surface, but sparing the antrum (Figure 1C). In the body and the fundus of the stomach, few nodules were noted on the mucosal surface (Figure 1D). The microscopic examination of the gastric fundus and body showed an ulcerated surface epithelium. The lamina propria, 2-4

submucosa and, at places, the entire stomach wall showed extensive deposition of pale, acellular, homogenous, eosinophilic material, (Figure 2A) which was congophilic on Congo red stain (Figure 2B) besides demonstrating the characteristic apple-green birefringence on polarizing microscopy (Figure 2D). Thus, the histological study confirmed the diagnosis of amyloid. Immunohistochemistry for serum amyloid A (SAA) protein was diffusely positive both in the vascular and extracellular area suggesting secondary amyloidosis (Figure 2C). The surgical specimen was extensively sampled; however, no evidence of H. pylori, dysplasia or malignancy was noted. A duodenal biopsy, which was performed later, also showed the presence of SAA amyloid in the submucosal vessels. The mesenteric lymph nodes also showed the presence of similar amyloid in the perinodal vessels and sinusoids Autops Case Rep (São Paulo). 2019;9(1):e2018074

Singh V, Singla S, Singh H, Sharma V, Das A

Figure 2. Photomicrograph of the stomach. A - ulcerated surface epithelium of gastric mucosa. Lamina propria and submucosa showing presence of pale, acellular, homogenous, eosinophilic material (Amyloid) (H&E, 20X); B - Congo red stain - Both vascular and extracellular areas show presence of congophilic material (20X); C - Polarizing microscopy - showing characteristic apple-green birefringence on polarizing microscopy (40X); D - Serum amyloid A (SAA) protein Immunohistochemistry – SAA immunostain positivity was noted, both in the vascular and extracellular area (40X). in a background of reactive changes. Based on classic histological and IHC findings, a diagnosis of gastric amyloidosis, SAA type was made. Post-operative period was uneventful. Postoperatively, she was asymptomatic on regular follow-up. Serum amyloid A protein is an acute phase reactant which is produced by hepatocytes. It is the most common type of amyloid deposition in the gastrointestinal tract, which complicates a range of chronic inflammatory disorders such as rheumatoid arthritis, chronic infections like tuberculosis and certain malignant tumors of different lineages.4 The most common sites for AA amyloid deposition are the blood vessels, particularly in the submucosa, and lamina propria of the mucosa as seen in our case.5 Gastric amyloidosis presenting as massive hematemesis and requiring lifesaving surgery is rare and only a few case have been published.6 Diagnosing amyloidosis involves histological confirmation using Congo red dye with its characteristic Autops Case Rep (São Paulo). 2019;9(1):e2018074

demonstration of green birefringence under crosspolarized light. Given the nature of its presentation and ability to affect multiple organs, there is often a delay in diagnosis as amyloidosis may be confused with other pathological entities. To conclude, diagnosis of gastric amyloidosis requires a high level of suspicion by all clinicians but chiefly by the endoscopist, and one must keep it in mind as a differential diagnosis of cases of massive hematemesis refractory to medical management. Keywords Amyloidosis; Hematemesis; Serum associated A protein

REFERENCES 1. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med. 2003;349(6):583-96. http:// dx.doi.org/10.1056/NEJMra023144. PMid:12904524. 2. Ebert EC, Nagar M. Gastrointestinal manifestations of amyloidosis. Am J Gastroenterol. 2008;103(3):776-87. 3-4

Massive hematemesis in a case of gastric amyloidosis masquerading as gastric carcinoma

http://dx.doi.org/10.1111/j.1572-0241.2007.01669.x. PMid:18076735. 3. Menke DM, Kyle RA, Fleming CR, Wolfe JT 3rd, Kurtin PJ, Oldenburg WA. Symptomatic gastric amyloidosis in patients with primary systemic amyloidosis. Mayo Clin Proc. 1993;68(8):763-7. http://dx.doi.org/10.1016/ S0025-6196(12)60634-X. PMid:8331978. 4. Tan SY, Pepys MB. Amyloidosis. Histopathology. 1994; 25(5):403-14. http://dx.doi.org/10.1111/j.1365-2559.1994. tb00001.x. PMid:7868080.

5. Yamada M, Hatakeyama S, Tsukagoshi H. Gastrointestinal amyloid deposition in AL (primary or myelomaassociated) and AA (secondary) amyloidosis. Hum Pathol. 1985;16(12):1206-11. http://dx.doi.org/10.1016/S00468177(85)80032-0. PMid:4065883. 6. Usui M, Matsuda S, Suzuki H, Hirata K, Ogura Y, Shiraishi T. Gastric amyloidosis with massive bleeding requiring emergency surgery. J Gastroenterol. 2000;35(12):9248. http://dx.doi.org/10.1007/s005350070007. PMid:11573729.

Author contributions: Singh V., Singla S and Das A. collected the data and wrote the manuscript. Singh H. was the treating surgeon and Sharma V. the treating gastroenterologist. All authors proofread the manuscript and approved the final version for publication. The authors retain an informed consent and the manuscript is in compliance with ethical standards Conflict of interest: None Financial support: None Submitted on: January 20th, 2019 Accepted on: February 2nd, 2019 Correspondence: Ashim Das Department of Histopathology Postgraduate Institute of Medical Education and Research (PGIMER) Chandigarh – India Phone: +91 98772223744 ashim126@gmail.com

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Autops Case Rep (São Paulo). 2019;9(1):e2018074

Image in Focus

Kernicterus Ameer Hamzaa How to cite: Hamza A. Kernicterus. Autops Case Rep [Internet]. 2019;9(1):e2018057. https://doi.org/10.4322/ acr.2018.057

Figure 1. Macroscopic cross section of the brain demonstrating extensive yellow discoloration in the basal ganglia, thalamus, cerebellum, tegmentum (A) and floor of the ventricles (B). Lateral ventricles lined by germinal matrix and demonstrating minute hemorrhages (B). Image courtesy Dr. Ameer Hamza

Kernicterus is a bilirubin-induced brain damage most commonly seen in infants. Regions of the brain most commonly affected are the basal ganglia, hippocampus, geniculate bodies and cranial nerve nuclei.1 The exact incidence of kernicterus is unknown; however, most recent data from the United Kingdom and Canada suggests kernicterus occurring at a rate of 1 to 2 in 100,000 live births.2,3 The risk of developing kernicterus increases considerably in infants with bilirubin levels >25 mg/dL while levels >30 mg/dL are

associated with extremely high risk and irreversible damage.4 Any event that leads to increased bilirubin production or decreased elimination can lead to hyperbilirubinemia and thus kernicterus. These include, but are not limited to, polycythemia, hemolysis due to Rh isoimmunization and congenital inherited defects of enzymes involved in bilirubin metabolism. Additionally, systemic factors such as hypothyroidism, certain drugs and infections particularly meningitis increase the risk of kernicterus. The clinical presentation can

University of Texas, MD Anderson Cancer Center, Department of Pathology. Houston, Texas, USA.

Autopsy and Case Reports. ISSN 2236-1960. Copyright ÂŠ 2019. 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.

Kernicterus

be divided into three phases. In phase 1, the infant demonstrates decreased alertness, hypotonia, and poor feeding. This is followed by a phase of hypertonia of the extensor muscles. Progress to this phase invariably leads to long-term neurologic deficits. Phase 3 usually occurs in infants aged >1 week, and they typically demonstrate hypotonia. Work-up includes blood indices, comprehensive metabolic panel and quantitative measurement of total and direct bilirubin. Neuroimaging is of limited value, however, it can help rule out other diagnoses. The definitive treatment is removing bilirubin from the blood via exchange transfusion. From surgical pathology standpoint, a brain biopsy is rarely done to make a diagnosis. Historically, the term “kernicterus” referred to an anatomic diagnosis made at autopsy based on a characteristic staining of basal ganglia, observed in infants who died with marked hyperbilirubinemia. The neuronal changes include pyknotic nuclei, cytoplasmic vacuolation, and loss of the Nissl substance. The Figure refers to the gross appearance of the brain in a deceased 16-day-old infant born at 29 weeks of gestational age via normal spontaneous vaginal delivery to a G4 P3 mother with a history of pre-eclampsia and eclampsia in previous gestations, who did not receive prenatal care and tested positive for tetrahydrocannibinol on urine drug screen. After birth, the infant was noted to be in respiratory failure, was placed on positive pressure ventilation and transferred to the neonatal intensive care unit (NICU). NICU stay was notable for multiple episodes

of apnea, bradycardia, desaturations and persistent hyperbilirubinemia with bilirubin levels up to 31 mg/dl. Despite intensive phototherapy, the patient became more jaundiced and had feeding difficulties. Double volume exchange transfusion was planned and the patient had an IV catheter inserted by pediatric surgery; however, he went into cardiopulmonary failure and was pronounced dead. The detailed brain examination at autopsy revealed extensive yellow discoloration in the basal ganglia, thalamus, cerebellum, tegmentum, and floor of the ventricles (Figure 1A). The lateral ventricles were lined by germinal matrix and demonstrated mild hemorrhage (Figure 1B). Keywords Kernicterus; Bilirubin; Infant, Newborn, Autopsy.

REFERENCES 1. Springer SC. Kernicterus. New York: Medscape; 2014 [cited 2018 Dec 10]. Available from: https://emedicine. medscape.com/article/975276-overview#a6 2. British Paediatric Surveillance Unit. Surveillance of severe hyperbilirubinaemia in the newborn commenced the May. BPSU Quarterly Bulletin. 2003;11(2):2. 3. Sgro M, Campbell D, Shah V. Incidence and causes of severe neonatal hyperbilirubinemia in Canada. CMAJ. 2006;175(6):587-90. http://dx.doi.org/10.1503/ cmaj.060328. PMid:16966660. 4. Bhutani VK, Johnson L. Kernicterus in the 21st century: frequently asked questions. J Perinatol. 2009;29(S1, Suppl 1):S20-4. http://dx.doi.org/10.1038/jp.2008.212. PMid:19177056.

The case is from St. John Hospital and Medical Center, Detroit, MI, USA and is in accordance with the recommendations of institutional review board. Conflict of Interest: None Financial support: None Submitted on: October 15th, 2018 Correspondence Ameer Hamza Holcombe Blvd., 1515, Unit 0085 – Houston/TX – USA Zip Code: 77030 Phone: +1 (313) 318-7198 ameerhamza7@hotmail.com

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Autops Case Rep (São Paulo). 2019;9(1):e2018057

Image in Focus

Black esophagus Jean Michell Correia Monteiroa , Lucas Freire Casteloa , William George Giusti Fischera , Aloisio Felipe-Silvab,c  How to cite: Monteiro JMC, Castelo LF, Fischer WGG, Felipe-Silva A. Black esophagus. Autops Case Rep [Internet]. 2019;9(1):e20180077. https://doi.org/10.4322/acr.2018.077

Figure 1. A – A picture composition of the gross aspect of esophagus and adjacent organs. Note the dark appearance of esophageal mucosa and the sharp limit at the gastroesophageal junction. B – Endoscopic view of the distal esophagus. Note the darkened mucosa in every circumference of the organ. C – Microscopic aspect of the esophagus at autopsy showing superficial necrosis of the mucosa and neutrophilic inflammation (H&E 100x). Image courtesy Anatomic Pathology Service – Hospital Universitário - USP.

Universidade de São Paulo (USP), School of Medicine, Department of Internal Medicine. São Paulo, SP, Brazil. Universidade de São Paulo (USP), School of Medicine, Department of Pathology. São Paulo, SP, Brazil. c Universidade de São Paulo (USP), Hospital Universitário, Anatomic Pathology Service. São Paulo, SP, Brazil. a

Black esophagus

Black esophagus (BE) is an entity characterized by a striking circumferential black coloration of the esophageal mucosa, which is generally depicted on endoscopy due to acute necrotizing esophagitis. This entity was first described in 1990 by Goldenberg.1-3 Despite several articles describing the BE as a rare entity, the actual incidence is uncertain due to the great variability of the studied population; therefore, many cases seem to run underdiagnosed. It tends to be more frequent in critically ill patients, particularly those with refractory shock or systemic inflammatory disease. The estimated incidence ranges between 0.001% and 0.028% based on autopsy and endoscopic series.4-8 The etiology of the BE is not well understood. Chemical injury by gastric contents associated with esophageal ischemia, severe infectious diseases, emergency surgery, and hypovolemic shock are present in most cases. 2,3,9,10 However, drug abuse (e.g. cocaine 11 and alcohol 12), and diabetic ketoacidosis were reported, and are considered to be triggering events in the young.13,14 Hypothermia,15,16 anticardiolipin antibody syndrome,17 herpes simplex virus,18 cytomegalovirus,19,20 and candida21 infections were also reported, although they are less common. Anecdotal cases of BE associated with drugs such as haloperidol and erythromycin have also been reported.22,23 The typical BE is most frequently seen in the distal esophagus until the gastroesophageal junction, but the lesion may occasionally extend to the proximal part of the esophagus. Rare cases have been described involving only the proximal esophagus.3,24 Concomitant duodenal lesions can be found in a large number of patients,25 which has been attributed to a vascular watershed area and a lesser degree of vascularization of the distal esophagus. The esophageal vascularization is represented by three different vascular zones: (i) the proximal, which depends on the inferior thyroid arteries with support by subclavian and carotid branches; (ii) the median zone supplied by bronchial and intercostal arteries, which are aortic branches; (iii) the distal zone supported by branches of gastric and phrenic arteries, with possible contribution from hepatic and splenic vessels. This distal zone seems particularly vulnerable to the impairment of vascular support, thereby justifying the almost invariable implication of distal esophagus in the cases of BE.26 Histologically, the mucosa in the 2-4

BE is necrotic with disrupted muscle fibers without identifiable causative organisms or agents. Generally, BE involves the elderly, with a small predominance of male, and more than two comorbidities are usually present. Gastrointestinal bleeding, with hematemesis or melena occurs in about 70% to 90% of patients. 3,5 A series with 310 consecutive autopsy cases found an incidence of esophageal necrosis of 10.3%27 and showed that the most important differential diagnosis of the BE is hematin coloration; however, black pigmentation is described as a longitudinally striated appearance limited to the lower parts of the organ, and does not usually affect the entire esophagus in a circumferential pattern. Melanoma of the esophagus is rare and is a possible cause of black lesions on the esophagus, but it does not follow a vascular or circumferential pattern.28 There is a report of coal dust deposition simulating a BE.29 No specific treatment for BE is available. However, in the patient with this condition, the esophagus should never be used as a feeding route, and if an endoscopic examination is unavoidable, it should be performed with exceptional caution. Treatment should be directed to any underlying clinical entity, and any complications should be controlled as the treatment of shock, infections, and surgery may be indicated.2 The standard treatment for gastrointestinal bleeding should be considered.2,25 BE has a poor outcome with a mortality of 30%.2 The images above (Figure 1) refer to an autopsy specimen of a 75-year-old woman who died because of multiple organ failure due to septicemia. Her past medical history included hypertension, insulin‑dependent diabetes mellitus, heart failure, and chronic renal failure. She had a 2-year history of anemia and progressive weight loss, and was recently complaining of diffuse abdominal colic pain and intermittent diarrhea. She attended the emergency care unit after presenting hematemesis. On admission, she was cachectic, obtunded, pale, hypotensive, and hypoxemic. The physical examination depicted a flat abdomen with an easy palpable hardened mass in the right upper quadrant, along with lower limbs edema. The diagnostic work-up evidenced the presence of BE and duodenal ulcers on the upper digestive endoscopy, and unilateral deep venous thrombosis (popliteal vein). The abdominal ultrasound showed a mass in the Autops Case Rep (São Paulo). 2019;9(1):e2018077

Monteiro JMC, Castelo LF, Fischer WGG, Silva AF

topography of the right colon, and multiple hepatic images consistent with metastatic disease. The autopsy revealed a 5.5cm fungating adenocarcinoma at the cecum, invasion of subserosa (stage pT3), with metastases to the regional lymph nodes (pN2) and the liver, with extensive portal invasion. There was a microscopic peritumoral abscess, bronchopneumonia, and systemic signs of ischemia and shock. Diabetic nodular glomerulosclerosis and systemic arteriosclerosis were other remarkable autopsy findings. The BE was confirmed in the context of a severely ill patient with advanced cancer, septic shock, diabetes, and blockade of the portal system. Keywords Esophageal Diseases; Diabetes Mellitus; Colonic Neoplasms; Sepsis; Autopsy

REFERENCES 1. Goldenberg SP, Wain SL, Marignani P. Acute necrotizing esophagitis. Gastroenterology. 1990;98(2):493-6. http://dx.doi.org/10.1016/0016-5085(90)90844-Q. PMid:2295407. 2. Gurvits GE. Black esophagus: acute esophageal necrosis syndrome. World J Gastroenterol. 2010;16(26):321925. http://dx.doi.org/10.3748/wjg.v16.i26.3219. PMid:20614476. 3. Gurvits GE, Shapsis A, Lau N, Gualtieri N, Robilotti JG. Acute esophageal necrosis: a rare syndrome. J Gastroenterol. 2007;42(1):29-38. http://dx.doi. org/10.1007/s00535-006-1974-z. PMid:17322991. 4. Ramos R, Mascarenhas J, Duarte P, Vicente C, Casteleiro C. Acute esophageal necrosis: a retrospective case series. Rev Esp Enferm Dig. 2008;100(9):583-5. PMid:19025311. 5. Augusto F, Fernandes V, Cremers MI, et al. Acute necrotizing esophagitis: a large retrospective case series. Endoscopy. 2004;36(5):411-5. http://dx.doi. org/10.1055/s-2004-814318. PMid:15100949. 6. Moretó M, Ojembarrena E, Zaballa M, Tánago JG, Ibánez S. Idiopathic acute esophageal necrosis: not necessarily a terminal event. Endoscopy. 1993;25(8):534-8. http:// dx.doi.org/10.1055/s-2007-1009121. PMid:8287816. 7. Lacy BE, Toor A, Bensen SP, Rothstein RI, Maheshwari Y. Acute esophageal necrosis: report of two cases and a review of the literature. Gastrointest Endosc. 1999;49(4 Pt 1):527-32. http://dx.doi.org/10.1016/ S0016-5107(99)70058-1. PMid:10202074. 8. Etienne JP, Roge J, Delavierre P, Veyssier P. Esophageal necrosis of vascular origin. Sem Hop. 1969;45(23):1599606. PMid:4308181. Autops Case Rep (São Paulo). 2019;9(1):e2018077

9. Haviv YS, Reinus C, Zimmerman J. “Black esophagus”: a rare complication of shock. Am J Gastroenterol. 1996;91(11):2432-4. PMid:8931435. 10. Grudell AB, Mueller PS, Viggiano TR. Black esophagus: report of six cases and review of the literature, 1963-2003. Dis Esophagus. 2006;19(2):105-10. http://dx.doi.org/10.1111/j.1442-2050.2006.00549.x. PMid:16643179. 11. Ullah W, Abdullah HMA, Rauf A, Saleem K. Acute oesophageal necrosis: a rare but potentially fatal association of cocaine use. BMJ Case Rep. 2018;2018:bcr2018-225197. http://dx.doi.org/10.1136/bcr-2018225197. 12. Katsinelos P, Pilpilidis I, Dimiropoulos S, et al. Black esophagus induced by severe vomiting in a healthy young man. Surg Endosc. 2003;17(3):521. PMid:12488997. 13. Usmani A, Samarany S, Nardino R, Shaib W. Black esophagus in a patient with diabetic ketoacidosis. Conn Med. 2011;75(8):467-8. PMid:21980676. 14. Talebi-Bakhshayesh M, Samiee-Rad F, Zohrenia H, Zargar A. Acute Esophageal Necrosis: A Case of Black Esophagus with DKA. Arch Iran Med. 2015;18(6):384-5. PMid:26058936. 15. Brennan JL. Case of extensive necrosis of the oesophageal mucosa following hypothermia. J Clin Pathol. 1967;20(4):581-4. http://dx.doi.org/10.1136/ jcp.20.4.581. PMid:5602573. 16. Živković V, Nikolić S. The unusual appearance of black esophagus in a case of fatal hypothermia: a possible underlying mechanism. Forensic Sci Med Pathol. 2013;9(4):613-4. http://dx.doi.org/10.1007/s12024-0139445-3. PMid:23592023. 17. Cappell MS. Esophageal necrosis and perforation associated with the anticardiolipin antibody syndrome. Am J Gastroenterol. 1994;89(8):1241-5. PMid:8053443. 18. Nagri S, Hwang R, Anand S, Kurz J. Herpes simplex esophagitis presenting as acute necrotizing esophagitis (“black esophagus”) in an immunocompetent patient. Endoscopy. 2007;39(Suppl 1):E169. http://dx.doi. org/10.1055/s-2007-966619. PMid:17614059. 19. Trappe R, Pohl H, Forberger A, Schindler R, Reinke P. Acute esophageal necrosis (black esophagus) in the renal transplant recipient: manifestation of primary cytomegalovirus infection. Transpl Infect Dis. 2007;9(1):42-5. http://dx.doi.org/10.1111/j.13993062.2006.00158.x. PMid:17313471. 20. Barjas E, Pires S, Lopes J, et al. Cytomegalovirus acute necrotizing esophagitis. Endoscopy. 2001;33(8):735. http://dx.doi.org/10.1055/s-2001-16215. PMid:11490397. 21. Gaissert HA, Breuer CK, Weissburg A, Mermel L. Surgical management of necrotizing Candida esophagitis. Ann Thorac Surg. 1999;67(1):231-3. http://dx.doi. org/10.1016/S0003-4975(98)01144-8. PMid:10086557. 3-4

Black esophagus

22. Mangan TF, Colley AT, Wytock DH. Antibiotic-associated acute necrotizing esophagitis. Gastroenterology. 1990;99(3):900. http://dx.doi.org/10.1016/00165085(90)90997-F. PMid:2379793. 23. Hejna P, Ublová M, Voříšek V. Black esophagus: acute esophageal necrosis in fatal haloperidol intoxication. J Forensic Sci. 2013;58(5):1367-9. http://dx.doi. org/10.1111/1556-4029.12151. PMid:23692436. 24. Neumann DA 2nd, Francis DL, Baron TH. Proximal black esophagus: a case report and review of the literature. Gastrointest Endosc. 2009;70(1):180-1. http://dx.doi. org/10.1016/j.gie.2008.09.055. PMid:19152880. 25. Gurvits GE, Cherian K, Shami MN, et al. Black esophagus: new insights and multicenter international experience in 2014. Dig Dis Sci. 2015;60(2):444-53. http://dx.doi. org/10.1007/s10620-014-3382-1. PMid:25297468.

26. Manno V, Lentini N, Chirico A, Perticone M, Anastasio L. Acute esophageal necrosis (black esophagus): a case report and literature review. Acta Diabetol. 2017;54(11):1061-3. http://dx.doi.org/10.1007/s00592017-1028-4. PMid:28730566. 27. Jacobsen NO, Christiansen J, Kruse A. Incidence of oesophageal necrosis in an autopsy material. APMIS. 2003;111(5):591-4. http://dx.doi.org/10.1034/j.16000463.2003.1110509.x. PMid:12887512. 28. Yamamoto S, Makuuchi H, Kumaki N, et al. A Long Surviving Case of Multiple Early Stage Primary Malignant Melanoma of the Esophagus and a Review of the Literature. Tokai J Exp Clin Med. 2015;40(3):90-5. PMid:26369261. 29. Khan HA. Coal dust deposition--rare cause of “black esophagus”. Am J Gastroenterol. 1996;91(10):2256. PMid:8855776.

Authors contributions: Monteiro JMC, Castelo LF and Fischer WGG performed the literature review and wrote the manuscript. Felipe-Silva A. co-wrote the manuscript and was in charge of the pathological findings and pictures. All authors collectively proofread and approved the final version for publication. Conflict of interest: None Financial Support: None Submitted on: January 9th, 2019 Accepted on: February 9th, 2019 Correspondence Jean Michell Correia Monteiro Av Prof. Lineu Prestes, 2565 – São Paulo/SP, Brazil CEP: 05501-000 Phone: +55 (71) 991877883 jk_michell@hotmail.com

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Article / Autopsy Case Report

Progressive multifocal leukoencephalopathy: a challenging diagnosis established at autopsy Cesar Castello Branco Lopesa , Murillo Crivillarib, José Carlos Mann Pradoc, Cristiane Rubia Ferreirad, Pedro José dos Santos Netoe, Vilma Takayasuf, Lorena Silva Labordaf How to cite: Lopes CCB, Crivillari M, Prado JCM, et al. Progressive multifocal leukoencephalopathy: a challenging diagnosis established at autopsy. Autops Case Rep [Internet]. 2019;9(1):e2018063. https://doi.org/10.4322/acr.2018.063

ABSTRACT Progressive multifocal leukoencephalopathy (PML) is a feared entity that occurs most frequently in conditions of extreme immunodeficiency. The diagnosis is often made long after the onset of symptoms due to the physicians’ unfamiliarity, and the unavailability of diagnostic tests in some medical centers. Although the incidence of PML is decreasing among HIV patients with the advent of highly active antiretroviral therapy (HAART), in Brazil this entity is the fourth highest neurological complication among these patients. The authors present the case of a middle-aged man who tested positive for HIV concomitantly with the presentation of hyposensitivity in the face and the right side of the body, accompanied by mild weakness in the left upper limb. The clinical features worsened rapidly within a couple of weeks. The diagnostic work-up pointed to the working diagnosis of PML after brain magnetic resonance imaging; however, the detection of the John Cunningham virus (JCV) in the cerebral spinal fluid was negative. HAART was started but the patient died after 7 weeks of hospitalization. The autopsy revealed extensive multifocal patchy areas of demyelination in the white matter where the microscopy depicted demyelination, oligodendrocytes alterations, bizarre atypical astrocytes, and perivascular lymphocytic infiltration. The immunohistochemistry was positive for anti-SV40, and the polymerase chain reaction of the brain paraffin-embedded tissue was positive for JCV. The authors highlight the challenges for diagnosing PML, as well as the devastating outcome of PML among HIV patients. Keywords Leukoencephalopathy, Progressive Multifocal, Acquired Immunodeficiency Syndrome, JC Virus, Diagnosis, Autopsy

Universidade de São Paulo (USP), Faculty of Medicine, Department of Neurology. São Paulo, SP, Brazil. Institute of Infectology Emilio Ribas. São Paulo, SP, Brazil. c Universidade de São Paulo (USP), Biomedical Sciences Institute, Department of Microbiology, Laboratory of Oncovirology. São Paulo, SP, Brazil. d Universidade de São Paulo (USP), Hospital Universitário, Anatomic Pathology Service. São Paulo, SP, Brazil. e Universidade de São Paulo (USP), Hospital Universitário, Department of Radiology. São Paulo, SP, Brazil. f Universidade de São Paulo (USP), Hospital Universitário, Internal Medicine Division. São Paulo, SP, Brazil. a

Progressive multifocal leukoencephalopathy: a challenging diagnosis established at autopsy

CASE REPORT A 43-year-old man presented to the emergency room complaining of tongue paresthesia, slurred speech, and weakness. These symptoms had developed insidiously and progressively over the past 4 weeks. The patient described muscular weakness initially involving the left side of the body, which soon included the right side. He also referred a decrease in sensitivity in the left half of the body. He denied fever, headache, weight loss, dyspnea, convulsions, visual symptoms, incontinence, and vertigo. His past medical history was unremarkable, except for smoking (15 pack-years) and recreational alcohol consumption. The neurological examination revealed a hyposensitivity in the right hemiface, as in the right half of the body, and grade 4 of muscle strength of the left upper limb. The remaining physical examination was normal as were his vital signs. The initial laboratory work-up was normal; however, further investigation revealed a positive serology for HIV infection by the enzyme-linked immunosorbent assay and Western blotting. The TCD4+ peripheral count was 75 cells/µL, and the HIV-1 RNA viral load in the blood was 97,911 copies/mL (branched DNA) or Log 4991. The brain computed tomography (CT) revealed two hypodense foci in the right cerebral hemisphere’s white matter, in the right frontal lobe, and in the high parietal region, without contrast enhancement or midline shift. Due to the imaging findings in a patient with HIV, neurotoxoplasmosis was the initial working diagnosis. Therefore, pyrimethamine and sulfadiazine were promptly prescribed. Two weeks later, this antibiotic regimen was withdrawn since (i) the patient’s clinical features did not improve; (ii) the serology for toxoplasmosis tested negative for immunoglobulin IgG and IgM; and (iii) the lesions increased in size and became more evident in controlled CT. The brain magnetic resonance imaging (MRI) showed extensive discontinuous hyper signal areas on T2‑ and FLAIR‑weighted images in the hemispheric white matter, with predominance in the right frontotemporal subcortical region, as well as in the splenium of the corpus callosum and the brainstem (Figure 1). These findings raised the diagnosis of PML. At this time, the cerebrospinal fluid (CSF) examination showed leukocytes of 2 cells, erythrocytes of 14 cells, 2-11

Figure 1. Brain MRI. A – T2 weighted axial image demonstrates subcortical e periventricular white matter lesions in the right hemisphere, without significant associated mass effect; B – Flair weighted axial image shows subcortical confluent lesions on the right temporal lobe, internal capsule and thalamus; C – Flair weighted axial image shows pontine and right middle cerebellar peduncle confluent lesions; D – Post contrast T1 weighted coronal image demonstrates lack of contrast enhancement in the aforementioned described lesions.

protein of 25 mg/dL, and glucose of 58 mg/dL. CSF culture was negative for bacteria, mycobacteria, and fungus. The polymerase chain reactions (PCR) for Mycobacterium tuberculosis, Cryptococcus spp, Toxoplasma gondii, and JCV were negative, which permitted the initiation of highly active antiretroviral therapy (HAART). The patient’s outcome was troublesome with progressive worsening of his neurological status, and slow progression to spastic paraparesis. At the end of the fourth week of hospitalization the patient maintained only the distal movement of the right upper limb, hyperreflexia, tetraplegia in a pyramidal pattern, generalized spasticity and hypertonia, ophthalmoplegia, facial amimia, gaze fixation inability, Autops Case Rep (São Paulo). 2019;9(1):e2018063

Lopes CCB, Crivillari M, Prado JCM, et al.

anarthria, and the inability to swallow. According to this outcome, the diagnosis of PML was highly considered, and because of the deterioration of the neurological status concomitantly after HAART, the hypothesis of immune reconstitution inflammatory syndrome-PML (IRIS-PML) was considered. Thus, prednisone 1 mg/kg was started. However, no improvement was observed.

AUTOPSY FINDINGS

Meanwhile, the patient presented an episode of bronchoaspiration and septic shock, and died after 7 weeks of hospitalization.

ill‑defined brownish patches involving the white

An autopsy was performed after the informed consent signed by his wife.

in the subcortical topography became confluent

The examination of the central nervous system (CNS) showed vascular congestion in the meninges with mild cerebral edema (Figure 2A). The vessels of the circle of Willis were preserved (Figure 2B). The coronal section depicted small, irregular, and matter and the basal ganglia. These lesions were more prominent in the right hemisphere, where the patches (Figures 2C, 2D, and Figure 3).

Figure 2. Gross findings of the brain. A – Vascular congestion in the meninges and generalized edema characterized by flattened gyri and narrowed intervening sulci; B – Inferior and posterior view showing edema, but without signals of herniation. The circle of Willis vessels were preserved; C – Coronal section of the brain showing small, irregular, and ill-defined brownish patches of white matter, also compromising the basal ganglia; D – Presence of poorly defined areas of brownish patches in the subcortical topography, which became confluent plaques in the white matter, especially in the right parieto–occiptal hemisphere. Autops Case Rep (São Paulo). 2019;9(1):e2018063

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Progressive multifocal leukoencephalopathy: a challenging diagnosis established at autopsy

Figure 3. Gross examination of the cutting surface of the brain. A and B – Coronal section showing in detail the ill-defined brownish patches to confluent plaques in the white matter, with poorly defined limits between gray and white matter.

On microscopy, the boundary between the gray and the white matter was blurred by chronic inflammatory infiltrate with an increase in the number of oligodendrocytes, which showed typical glassy chromatin nuclei of viral inclusion. In the white matter, the parenchyma was disrupted by a dense infiltration of foamy macrophages, reactive astrocytes (which sometimes had bizarre atypical appearance), and perivascular lymphocytic inflammation (Figure 4).

consistent with a final outcome due to hemodynamic shock. There was also zone 3 passive congestion in liver parenchyma. Another finding related to AIDS was the splenic white pulp lymphocytic depletion (Figure 6C) and a focal chronic inflammatory infiltration in adrenal parenchyma (Figure 6D).

The immunohistochemistry study was positive for simian virus 40 (SV40) (clone MRQ-4, Cell Marque), which cross-reacts with polyomavirus (Figure 5), and was negative for cytomegalovirus and herpesvirus. The presence of the JC polyomavirus (JCPyV) was also detected in the formaldehyde-fixed, paraffin‑embedded, CNS by the specific amplification of genetic material from the DNA sample. For this purpose, the primers described by Agostini et al.1 were used along with DNA isolates from samples previously known as positives and negatives. Thus, the presence of genetic material of JCPyV in the neural tissue of the patient was assured.

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the CNS characterized by injury to the glial cells—in particular, the oligodendrocytes—caused by a polyomavirus called JCV. PML mostly occurs in immunosuppressed patients, and presents with a progressive, disabling, and often fatal clinical course. Since the HIV epidemic and the emergence of new immunosuppressive drugs, PML has become a significant source of concern and research.2,3

The lungs were congested and heavy. The microscopic examination revealed a diffuse alveolar edema and bronchopneumonia, possibly secondary to bronchoaspiration (Figure 6A). The pancreas examination showed necrosis and steatonecrosis (Figure 6B), while the kidney’s histology presented acute tubular necrosis—the findings of which were 4-11

DISCUSSION

In the 1950s, the cytotechnologist, Andrew Ricci, initially observed cells with large homogeneous nuclei in the urine, which he christened the “decoy cells” because of their benign origin mimicking cancer cells. The nature of the “decoy cells” was clarified in 1971 when Gardner et al.4 isolated the human polyomavirus from the urine of a renal transplant recipient with initials BK.5 This virus is a non-enveloped DNA viral group that belongs to the Polyomaviridae family, which infects humans, as well as apes, rodents, and parakeets. In humans, the infection is caused by the Autops Case Rep (São Paulo). 2019;9(1):e2018063

Lopes CCB, Crivillari M, Prado JCM, et al.

Figure 4. Photomicrographs of the brain. A – The limit between gray and white matter was blurred by chronic inflammatory infiltrate with augmented oligodendrocytes (H&E 100X); B – White matter parenchyma with dense infiltration of foamy macrophages, reactive astrocytes, and perivascular lymphocytic inflammation (H&E 200X); C – Detail of the reactive astrocytes showing bizarre atypical nuclei (H&E 400X); D – Gray matter with augmented oligodendrocytes showing typical glassy chromatin nuclei of viral inclusion (H&E 400X).

Figure 5. Photomicrographs of the brain. A and B – Immunophenotype positive for simian virus 40 highlighting the cells infected by the JCV. (Immunohistochemistry 400X). Autops Case Rep (São Paulo). 2019;9(1):e2018063

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Progressive multifocal leukoencephalopathy: a challenging diagnosis established at autopsy

Figure 6. Photomicrographs. A – Lung: pulmonary parenchyma showing bronchopneumonia and diffuse alveolar edema (H&E 100X); B – Pancreas: parenchyma showing diffuse ischemic necrosis with focal steatonecrosis (H&E 100X); C – Spleen: presence of white pulp lymphocytic depletion (H&E 100X); D – Adrenal: presence of focal chronic inflammatory infiltration in adrenal parenchyma (H&E 100X).

BK virus, which is associated with nephropathy in transplanted recipients, and JCV, which causes PML.6 The JCV is distributed worldwide with a prevalence of 50-70%.7-9 The transmission occurs through the fecal-oral and respiratory routes, and by tissue donation. The polyomavirus causes a latent asymptomatic infection with a persistent cycle of replication, which contributes to the spread of the virus. The replication cycles are associated with fluctuations of the immunity status, such as pregnancy and senility, or with severe immunosuppression, which occurs after transplant, chemotherapy, or HIV infection. Rare cases of PML in immunocompetent patients with or without an underlying disease have been reported.10 Those with an underlying disease have been 6-11

defined as PML in the presence of occult or transient immunosuppression, namely (i) hepatic cirrhosis; (ii) chronic renal failure; (iii) pregnancy; (iv) dementia; and (v) dermatomyositis. 11 Thus, PML should be considered in the differential diagnosis of patients with new-onset neurological symptoms, even without overt immunosuppressive risk factors. Over the years, the origin of the underlying immunosuppression has been changing because of the improvement in HIV treatment, and the emergence of new and widely used immunosuppressive drugs. A recent study on the incidence of PML in Sweden over 3 decades showed that HIV infection was the leading cause of immunosuppression in the first fifth (1988‑1992) of the study period, representing 48% of Autops Case Rep (São Paulo). 2019;9(1):e2018063

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cases of PML. However, in the last fifth of the study period (2008-2013), the autoimmune diseases took the lead (39% of the cases), while HIV infection dropped to 11%.12 Similarly, other studies showed a decline in the incidence of PML among HIV patients in Denmark13 and Switzerland.14 Despite this declining incidence, PML remains a significant CNS complication of patients with HIV/AIDS. A Brazilian study showed that PML was the fourth most frequent opportunistic infection in AIDS patients after toxoplasmosis, cryptococcal meningoencephalitis, and neurotuberculosis.15 Clinically, PML can present a broad constellation of neurologic signs and symptoms due to its ability to affect virtually any area of the brain, and the frequently multifocal nature of the lesions.2,3 Thus, it is difficult to establish a topographic neurological diagnosis, similar to that which occurs with other demyelinating diseases. The most common clinical features comprise motor weakness (hemiparesis or monoparesis), cognitive dysfunction, appendicular or gait ataxia, visual symptoms (hemianopsia, diplopia), and speech disturbances. Sensory loss, seizures, headache, and aphasia occur less frequently.12,13,15,16 In our case, the patient presented with motor weakness, impaired gait, speech disturbance, and sensory loss, which were consistent with the most cited features of PML. Based on the CT images and the positive result for HIV tests, neurotoxoplasmosis was the initial working diagnosis because of its leading cause of CNS infection in AIDS patients. The current treatment for neurotoxoplasmosis is highly effective and is accompanied by a rapid clinical recovery. In a large clinical series of patients,17 74% showed improved in their symptoms by day 7 of therapy, and 91% of them by day 14. Thus, it is reasonable to conclude that the failure of toxoplasmosis treatment should raise the suspicion for other differential diagnoses. In our case, the therapeutic failure after 2 weeks, which was associated with the negative serology for toxoplasmosis, made the diagnosis of neurotoxoplasmosis unlikely, and the suspicion for PML increased. With the increase in knowledge regarding PML, and the new techniques that help to diagnose JCV, new forms of CNS involvement and, therefore, new forms of clinical syndromes (hitherto not well‑known) have been described; such as (i) JCV granule cell neuropathy leading to a cerebellar syndrome; (ii) JCV Autops Case Rep (São Paulo). 2019;9(1):e2018063

encephalopathy due to cortical grey matter impairment; and (iii) JCV meningitis, which leads to meningeal syndrome without evidence of brain lesions.2,3 The diagnosis of PML faces some obstacles, such as its low incidence, the unfamiliarity of it among most physicians, and the eventual unspecificity of the clinical features and neuroimaging. The latter may mimic stroke, brain tumor, or cerebral toxoplasmosis, which often retard the diagnosis. In a retrospective study involving 111 PML cases,18 the median time from the initial symptoms to diagnosis was 74 days. In this study, misdiagnoses were done in nearly two-thirds of cases, and more than three-quarters of patients had their diagnosis delayed for more than 1 month. To avoid this delay, the inclusion of PML in the differential diagnosis of CNS lesions in patients with known risk factors together with early work-up directed towards this entity seems to be the better procedure. In 2013, the Neuroinfectious Disease Section of the American Academy of Neurology proposed the criteria9 to establish the diagnosis of PML. PML diagnosis is considered to be definitive by (i) securing the diagnosis with tissue sample; or (ii) determining the diagnosis with compatible clinical and radiographic features coupled with the demonstration of the virus in CSF. A lack of one or more of the aforementioned findings alters the diagnostic characterization to probable or possible. Therefore, in our case, the in vivo diagnosis of PML was considered possible due to the lack of demonstration of JCV in the CSF. The diagnosis based on neuropathology usually is not that difficult if the specimen shows the demyelination, the hyperchromatic and enlarged oligodendroglial nuclei, and the enlarged bizarre astrocytes with lobulated hyperchromatic nuclei accompanied by the detection of JCV. 9 However, the arduous task relies on obtaining the brain tissue. Although brain biopsy has been proved to be an effective way of diagnosing intracranial lesions, it requires a highly-specialized team and costly resources. The procedure is associated with a significant risk of fatal complications and a high index of morbidity. Moreover, the lesions may not be readily accessible, the biopsy size may be insufficient, and sometimes the patient’s clinical status does not allow the procedure to be undertaken.19-21 The detection of JCV in the brain tissue of PML may be achieved by immunohistochemistry (IHC) 7-11

Progressive multifocal leukoencephalopathy: a challenging diagnosis established at autopsy

using commercially anti-SV40 monoclonal antibody, in situ hybridization (ISH) and PCR. Zivanovic et al.21 reported the comparison of these three methods in a series of seven cases (four biopsies and four autopsies; one case had biopsy and was autopsied as well) and concluded that ISH was the more sensitive method followed by PCR and IHC, and recommended using a combination of at least two different methods for JCV detection. Muñoz-Mármol et al.,22 studying 14 paraffin-embedded postmortem brain specimens, showed better sensitivity for IHC and PCR. In this series, the IHC was more sensitive for the PAb 2003 antibody compared to the antibody anti-SV40. In our case, in vivo brain biopsy was unavailable and the definitive diagnosis of PML was made by postmortem tissue analysis. Along with the typical gross findings in autopsy, the microscopy was rich and consistent with the typical descriptions of the JCV histological findings. The IHC with anti-SV40 and the PCR were positive in the CNS tissue sample. It is worth pointing out that the number of altered oligodendroglial cells were high, which increased the chances of detecting the virus by using the different methods. Because of the cited obstacles for performing brain biopsy, the diagnosis of PML commonly relies on the analysis of the CSF. However, the PCR for JCV is not widely available in some medical centers, and its sensitivity decreases with HAART. Marzocchetti et al.23 compared the sensitivity of JCV by PCR in the CSF of HIV patients with suspected PML between 1992 and 2002, and found a drop in the positive detection from 89.5% in the pre-HAART era (1992-1995) to 57.5% in the HAART era (1996-2002), but no changes in the specificity were observed. Similarly, this discrepancy concerning the sensitivity of PCR tested in the CSF was observed comparing the studies of McGuire et al.24 and Bossolasco et al.25 The former found a sensitivity of 92% in the pre-HAART era (1995) and the latter found 76% in the HAART era (2005). The radiologic investigation helps to make the diagnosis and may allow its distinction from other diagnoses.9 MRI is the most appropriate examination for PML work-up since it detects early lesions. PML lesions appear as hyperintense areas in T2-weighted and fluid-attenuated inversion recovery (FLAIR) images, and as hypointense areas in T1-weighted images. In CT scans, brain lesions appear as asymmetric multifocal 8-11

areas of hypodensity. These lesions are frequently asymmetric, bilateral, and multiple, although they may occasionally be solitary, with variable shape and size, which become confluent and extensive with the progression of the disease. They are mainly subcortical and are located almost exclusively in the white matter, although eventual extension to the gray matter has been reported. Usually, there is no mass effect even in the extensive lesions, nor contrast enhancement.9,26-28 As reported in our case, the hypodense brain lesions found in the CT were non-specific, and did not add any information to achieve the final diagnosis. Neurotoxoplasmosis was assumed as the working diagnosis even in the absence of the typical contour contrast enhancement. Indeed, this finding may be absent or faint when CD4 is below 50 cells/mm3.29 In fact, the diagnosis of PML was highly considered after the MRI despite the negative PCR for JCV result in CSF. Several therapeutic regimens including cytarabine, camptothecin, topotecan, and cidofovir were studied and proposed as the PML treatment. These drugs have an anti-JCV replication action in vitro; however, the in vivo results were disappointing.3 The serotonin receptor blocker was also tested after the discovery of the interaction between JCV and serotonin receptors 5-HT-2a from glial cells.2 Nonetheless, no statistical significance in 1-year survival was observed between patients treated with mirtazapine and a control group.30 Thus, no specific, effective treatment for JCV is currently available. The most effective therapy for PML relies upon the early onset of HAART.31 One of the management challenges of PML and other infections associated with AIDS remains the identification of the immune reconstitution inflammatory syndrome (IRIS), which is characterized by clinical deterioration, despite virological clearance, usually within 4-8 weeks after the HAART outset. The pathophysiology of IRIS is not yet fully understood, but seems to be attributed to an exacerbated inflammatory response modulated by the presence of the opportunistic agent or its antigens. In the context of PML, IRIS can occur both in its “unmasking” form—when the previously asymptomatic patient begins to present symptoms after HAART prescription—or in its “paradoxical” form, which arises during or after PML’s treatment, when new clinical symptoms or worsening of the pre-existing symptoms arise. The latter often raises doubts as to whether there is a progression of Autops Case Rep (São Paulo). 2019;9(1):e2018063

Lopes CCB, Crivillari M, Prado JCM, et al.

PML or if it corresponds to an overlap with IRIS, along with the possibility of HAART’s adverse effects.32 The diagnosis of IRIS should be suspected whenever the clinical features of PML worsen or start 4-8 weeks after the introduction of HAART, and the CD4+ is <100 cell/mm3 before the onset of HAART; or when an immune or virological response is observed after the HAART onset. In the case presented herein, IRIS was suspected because the neurological worsening coincided with the third week of HAART. The diagnosis or suspicion of IRIS should not motivate the withdrawal of HAART. Untreated HIV patients with the diagnosis of PML show an increment in survival rate with HAART from 10% to 43-75%.33-35 The management of IRIS consists of using a non‑steroidal anti-inflammatory drug in mild cases, or prednisone at a dose of 1-2mg/kg, or equivalent, for 1-2 weeks in more severe cases. However, the use of anti-inflammatory agents to treat PML-IRIS remains debatable. A French review32 showed that corticosteroid therapy did not change the outcome of patients with PML-IRIS, and suggested that the corticosteroid prescription should be reserved for patients with severe neurological symptoms and/or massive cerebral inflammation, or brain herniation. In our case, prednisone was prescribed due to severe neurological worsening, but no improvement was observed. The clinical course of PML remains dreadful. However, the survival rate has improved over the years, which is probably related to the growing efficacy of HAART. In the pre-HAART era, Berger et al.33 reported a median survival of 6 months for AIDS-related PML, and only in 9% did the survival exceeded 1 year. In the Danish cohort study,13 the median survival time increased from 0.4 years in those diagnosed with PML before 1997 (pre-HAART era) to 1.8 years in those diagnosed with PML from 1997 to 2006. Despite the increment in the survival rate after HAART, most PML survivors present sequelae. In our case, the disease followed the progressive course without any remission period, leading to a fatal outcome approximately 3 months after the initial symptoms.

CONCLUSION Although PML is rare, clinicians should always keep this possibility in mind while working up diseases with a similar clinical presentation. Every immunosuppressed Autops Case Rep (São Paulo). 2019;9(1):e2018063

patient with CNS injury should include PML in the diagnostic process. A CT scan is non-specific and unreliable, and it may delay or mask the diagnosis. Therefore, MRI should—whenever possible—be requested, since it may be the primary diagnostic clue. Tissue samples accompanied by immunopathological and molecular studies should always be pursued to reach a definitive diagnosis. Nevertheless, much remains to be discovered and researched concerning PML and other polyomavirus-related diseases, as well as their best treatment.

REFERENCES 1. Agostini HT, Yanagihara R, Davis V, Ryschkewitsch CF, Stoner GL. Asian genotypes of JC virus in Native Americans and in a Pacific Island population: markers of viral evolution and human migration. Proc Natl Acad Sci USA. 1997;94(26):14542-6. http://dx.doi.org/10.1073/ pnas.94.26.14542. PMid:9405649. 2. T a n C S , K o r a l n i k I J . P r o g r e s s i v e m u l t i f o c a l leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol. 2010;9(4):425-37. http://dx.doi.org/10.1016/S14744422(10)70040-5. PMid:20298966. 3. Koralnik IJ. Progressive multifocal leukoencephalopathy revisited: has the disease outgrown its name? Ann Neurol. 2006;60(2):162-73. http://dx.doi.org/10.1002/ ana.20933. PMid:16862584. 4. Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet. 1971;297(7712):12537. http://dx.doi.org/10.1016/S0140-6736(71)91776-4. PMid:4104714. 5. Koss LG. On decoy cells. Acta Cytol. 2005;49(3):233-4. http://dx.doi.org/10.1159/000326142. PMid:15966282. 6. Ahsan N, Shah KV. Polyomaviruses and human diseases. In: Ahsan N, editor. Polyomaviruses and human diseases: advances in experimental medicine and biology. New York: Springer; 2006. (vol. 577). http://dx.doi. org/10.1007/0-387-32957-9_1. 7. Ryschkewitsch C, Jensen P, Hou J, Fahle G, Fischer S, Major EO. Comparison of PCR-southern hybridization and quantitative real-time PCR for the detection of JC and BK viral nucleotide sequences in urine and cerebrospinal fluid. J Virol Methods. 2004;121(2):217-21. http://dx.doi. org/10.1016/j.jviromet.2004.06.021. PMid:15381359. 8. Cayres-Vallinoto IMV, Vallinoto AC, Pena GP, et al. JC virus/human immunodeficiency virus 1 co-infection in the Brazilian Amazonian region. Braz J Infect 9-11

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Dis. 2016;20(4):360-4. http://dx.doi.org/10.1016/j. bjid.2016.05.005. PMid:27266589. 9. Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN neuroinfectious disease section. Neurology. 2013;80(15):1430-8. http://dx.doi.org/10.1212/WNL.0b013e31828c2fa1. PMid:23568998. 10. Johansen KK, Torp SH, Rydland J, Aasly JO. Progressive multifocal leukoencephalopathy in an immunocompetent patient? Case Rep Neurol. 2013;5(3):149-54. http:// dx.doi.org/10.1159/000354828. PMid:24163670. 11. Gheuens S, Pierone G, Peeters P, Koralnik IJ. Progressive multifocal leukoencephalopathy in individuals with minimal or occult immunosuppression. J Neurol Neurosurg Psychiatry. 2010;81(3):247-54. http://dx.doi. org/10.1136/jnnp.2009.187666. PMid:19828476. 12. Iacobaeus E, Burkill S, Bahmanyar S, et al. The national incidence of PML in Sweden, 1988-2013. Neurology. 2018;90(6):e498-506. http://dx.doi.org/10.1212/ WNL.0000000000004926. PMid:29321229. 13. Engsig FN, Hansen AB, Omland LH, et al. Incidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nationwide cohort study. J Infect Dis. 2009;199(1):77-83. http://dx.doi.org/10.1086/595299. PMid:19007313. 14. Khanna N, Elzi L, Mueller N, et al. Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV cohort study. Clin Infect Dis. 2009;48(10):1459-66. http://dx.doi. org/10.1086/598335. PMid:19348592. 15. Vidal JE, Oliveira ACP, Fink MCDS, Pannuti CS, Trujillo JR. AIDS-related progressive multifocal leukoencephalopathy: a retrospective study in a referral center in São Paulo, Brazil. Rev Inst Med Trop São Paulo. 2008;50(4):209-12. http://dx.doi.org/10.1590/S0036-46652008000400004. PMid:18813759. 16. Berger JR, Kaszovitz B, Post MJ, Dickinson G. Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection: a review of the literature with a report of sixteen cases. Ann Intern Med. 1987;107(1):78-87. http://dx.doi.org/10.7326/00034819-107-1-78. PMid:3296901. 17. Luft BJ, Hafner R, Korzun AH, et al. Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. Members of the ACTG 077p/ANRS 009 Study Team. N Engl J Med. 1993;329(14):995-1000. http://dx.doi. org/10.1056/NEJM199309303291403. PMid:8366923. 18. Miskin DP, Ngo LH, Koralnik IJ. Diagnostic delay in progressive multifocal leukoencephalopathy. Ann Clin Transl Neurol. 2016;3(5):386-91. http://dx.doi. org/10.1002/acn3.301. PMid:27231708. 10-11

19. Lee AM, Bai HX, Zou Y, et al. Safety and diagnostic value of brain biopsy in HIV patients: a case series and metaanalysis of 1209 patients. J Neurol Neurosurg Psychiatry. 2016;87(7):722-33. http://dx.doi.org/10.1136/jnnp2015-312037. PMid:26758989. 20. Zhang J, Liu X, Fu K, et al. Diagnostic value and safety of stereotactic biopsy in acquired immune deficiency syndrome patients with intracranial lesions: systematic review and meta-analysis. World Neurosurg. 2017;98:790-799.e13. http://dx.doi.org/10.1016/j. wneu.2016.11.151. PMid:27965075. 21. Zivanovic M, Savsek L, Poljak M, Popovic M. Possible pitfalls in the diagnostic of progressive multifocal leukoencephalopathy. Clin Neuropathol. 2016;35(2):6671. PMid:26754416. 22. Muñoz-Mármol AM, Mola G, Fernández-Vasalo A, Vela E, Mate JL, Ariza A. JC vírus early protein detection by immunohistochemistry in progressive multifocal encephalopathy: a comparative study with in-situ hybridization and polymerase chain reaction. J Neuropathol Exp Neurol. 2004;63(11):1124-30. http:// dx.doi.org/10.1093/jnen/63.11.1124. PMid:15581180. 23. Marzocchetti A, Di Giambenedetto S, Cingolani A, Ammassari A, Cauda R, De Luca A. Reduced rate of diagnostic positive detection of JC virus DNA in cerebrospinal fluid in cases of suspected progressive multifocal leukoencephalopathy in the era of potent antiretroviral therapy. J Clin Microbiol. 2005;43(8):41757. http://dx.doi.org/10.1128/JCM.43.8.4175-4177.2005. PMid:16081969. 24. McGuire D, Barhite S, Hollander H, Miles M. JC virus DNA in cerebrospinal fluid of human immunodeficiency virus-infected patients: predictive value for progressive multifocal leukoencephalopathy. Ann Neurol. 1995;37(3):395-9. http://dx.doi.org/10.1002/ ana.410370316. PMid:7695239. 25. Bossolasco S, Calori G, Moretti F, et al. Prognostic Significance of JC Virus DNA Levels in Cerebrospinal Fluid of Patients with HIV-Associated Progressive Multifocal Leukoencephalopathy. Clin Infect Dis. 2005;40(5):73844. http://dx.doi.org/10.1086/427698. PMid:15714422. 26. Sahraian MA, Radue E-W, Eshaghi A, Besliu S, Minagar A. Progressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis. Eur J Neurol. 2012;19(8):1060-9. http://dx.doi.org/10.1111/ j.1468-1331.2011.03597.x. PMid:22136455. 27. Smith AB, Smirniotopoulos JG, Rushing EJ. Central nervous system infections associated with human immunodeficiency virus infection: radiologic-pathologic correlation. Radiographics. 2008;28(7):2033-58. http:// dx.doi.org/10.1148/rg.287085135. PMid:19001657. 28. Whiteman ML, Post MJ, Berger JR, Tate LG, Bell MD, Limonte LP. Progressive multifocal leukoencephalopathy in 47 HIV-seropositive patients: neuroimaging with clinical Autops Case Rep (São Paulo). 2019;9(1):e2018063

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and pathologic correlation. Radiology. 1993;187(1):23340. http://dx.doi.org/10.1148/radiology.187.1.8451420. PMid:8451420.

multifocal leukoencephalopathy: a literature review. Front Immunol. 2017;8:577. http://dx.doi.org/10.3389/ fimmu.2017.00577. PMid:28588577.

29. Offiah CE, Turnbull IW. The imaging appearances of intracranial CNS infections in adult HIV and AIDS patients. Clin Radiol. 2006;61(5):393-401. http://dx.doi. org/10.1016/j.crad.2006.01.008. PMid:16679111.

33. Berger JR, Pall L, Lanska D, Whiteman M. Progressive multifocal leukoencephalopathy in patients with HIV infection. J Neurovirol. 1998;4(1):59-68. http://dx.doi. org/10.3109/13550289809113482. PMid:9531012.

30. Marzocchetti A, Tompkins T, Clifford DB, et al. Determinants of survival in progressive multifocal leukoencephalopathy. Neurology. 2009;73(19):1551-8. http://dx.doi.org/10.1212/WNL.0b013e3181c0d4a1. PMid:19901246.

34. Falcó V, Olmo M, del Saz SV, et al. Influence of HAART on the clinical course of HIV-1-infected patients with progressive multifocal leukoencephalopathy: results of an observational multicenter study. J Acquir Immune Defic Syndr. 2008;49(1):26-31. http://dx.doi.org/10.1097/ QAI.0b013e31817bec64. PMid:18667930.

31. Berger JR. Progressive multifocal leukoencephalopathy. Handb Clin Neurol. 2014;123:357-76. http:// dx.doi.org/10.1016/B978-0-444-53488-0.00017-1. PMid:25015495. 32. Fournier A, Martin-Blondel G, Lechapt-Zalcman E, et al. Immune reconstitution inflammatory syndrome unmasking or worsening aids-related progressive

35. Gasnault J, Costagliola D, Hendel-Chavez H, et al. Improved survival of HIV-1-infected patients with progressive multifocal leukoencephalopathy receiving early 5-drug combination antiretroviral therapy. PLoS One. 2011;6(6):e20967. http://dx.doi.org/10.1371/ journal.pone.0020967. PMid:21738597.

Author contributions: Lopes CCB, Crivillari M, Prado JCM, Ferreira CR, Santos Neto PJ, Takayasu V, Laborda LS collectively and equally contributed to the manuscript preparation. Similarly, all authors proofread and approved the manuscript’s final version for publication. Conflict of interest: None Financial support: None Submitted on: September 29th, 2018 Accepted on: November 13th, 2018 Correspondence Cesar Castello Branco Lopes Department of Neurology - Faculty of Medicine - Universidade de São Paulo (USP) Rua Teodoro Sampaio, 363, ap. 217 – Cerqueira Cesar – São Paulo/SP – Brazil CEP: 05406-900 Phone: +55 (43) 99978-3627 cesarcblopes@gmail.com

Autops Case Rep (São Paulo). 2019;9(1):e2018063

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Article / Autopsy Case Report

Sudden death caused by pulmonary fat embolism in a patient with miliary tuberculosis Katsuya Chinena,b , Kashima Itoc  How to cite: Chinen K, Ito K. Sudden death caused by pulmonary fat embolism in a patient with miliary tuberculosis. Autops Case Rep [Internet]. 2019;9(1):e2018059. https://doi.org/10.4322/acr.2018.059

ABSTRACT An 84-year-old Japanese woman with myelodysplastic syndrome was admitted with pyrexia and dyspnea, but died suddenly during diagnostic evaluation. The autopsy revealed miliary tuberculosis in addition to myelodysplastic syndrome in the bone marrow. The immediate cause of the patient’s sudden death was pulmonary fat embolism derived from bone marrow necrosis. This case shows that the infiltration of the myelodysplastic bone marrow by tuberculosis and consequent bone marrow necrosis and fat embolism can be the cause of sudden death. In this article, we report the autopsy results of this unusual cause of sudden death, and discuss tuberculosis-related sudden death with a review of the literature. Keywords: Tuberculosis; Death, Sudden; Bone Marrow; Necrosis; Embolism, Fat; Autopsy

CASE REPORT An 84-year-old Japanese woman was admitted with the history of fever (axillary temperature: 38.5°C) and dyspnea. As the patient presented leukocyturia, a urinary tract infection was the working diagnosis. Her past medical history included the diagnosis of diabetes mellitus, and myelodysplastic syndrome (MDS), refractory anemia with excess of blasts in transformation (RAEB-t) diagnosed 5 months ago, and humeral and pelvic fractures that occurred 5 and 4 months ago, respectively. She had been started on cyclosporine (100 mg/day) in addition to receiving blood transfusions after the diagnosis of MDS. The initial laboratory work-up is shown in Table 1. Despite the intravenous treatment with cefmetazole (2 g/day) for 7 days, the fever did not subside. She was found to have some hepatic nodules, up to 15 mm.

On the thoracic computed tomography, bilateral pleural effusion and mediastinal lymphadenopathy were detected. Also, the polymerase chain reaction (PCR) of her sputum was positive for Mycobacterium tuberculosis, and the diagnosis of tuberculosis (TB) was made. Anti-tuberculous therapy was not started because she suddenly died soon after the diagnosis was made on the 14th hospital day. Immediate antemortem (about 1 hour before death), she was able to talk and eat as usual. However, she developed sinus tachycardia at a rate of 140 beats per minute, followed by ventricular fibrillation, and collapsed. Cardiopulmonary resuscitation was not performed in accordance with the patient’s and family’s wishes. An autopsy was carried out 90 minutes after death.

Nerima General Hospital, Department of Pathology. Tokyo, Japan. Tokyo Healthcare Foundation, Institute for Health Care Quality Improvement. Tokyo, Japan. c Nerima General Hospital, Department of Cardiology. Tokyo, Japan. a

Sudden death caused by pulmonary fat embolism in a patient with miliary tuberculosis

Table 1. Laboratory data on admission Analyte Leukocyte

Result

Analyte

Result

3,600 /μL

(3,500-9,000)

Sodium

122 mEq/L

(135-145)

Hemoglobin

(11.5-15.5)

Potassium

4.3 mEq/L

(3.6-4.8)

Hematocrit

24.9 %

(34.0-46.0)

5.8 g/dL

(6.5-8.0)

MCV

112 fL

(83-100)

2.6 mg/dL

(0.4-1.3)

MCH

36.2 pg

(28-34)

18 U/L

(50-170)

MCHC

32.4 g/dL

(32-36)

AST

15 U/L

(10-35)

(150-380x10 )

ALT

13 U/L

(5-40)

(0.4-0.8)

LDH

397 U/L

Platelet

9.8 g/dL

59x10 /μL

Creatinine Urea

0.45 mg/dL

(120-220)

22 mg/dL

(8.0-20.0)

Chloride

86 mEq/L

(99-107)

Glucose

245 mg/dL

(80-110)

Calcium

8.0 mEq/L

(8.5-10.2)

CRP

16.3 mg/dL

(0-0.35)

ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; CK = creatine kinase; CRP = C-reactive protein; LDH = Lactate dehydrogenase; MCH = Mean corpuscular hemoglobin; MCHC = Mean corpuscular hemoglobin concentration; MCV = Mean corpuscular volume; NR = normal range; TB = Total Bilirubin; TP= Total protein.

AUTOPSY FINDINGS The liver weighed 790 g (reference range [RR]: 345–1250 g); at the cut surface, scattered yellowish, well-demarcated nodules, measuring up to 15 mm in diameter, were found (Figure 1). Some other larger lesions were also apparent and represented the confluence of the small nodules. Similar nodules, measuring up to 7 mm, were also found in (i) the left and right lungs, which weighed 180 g (RR: 85–500 g) and 210 g (RR: 100–620 g), respectively; (ii) the spleen (weighing 70 g, RR: 70–195 g); (iii) lymph nodes, and (iv) bone marrow. Microscopically, the nodules mentioned above were characterized by necrosis, but no Langhans giant cells were identified (Figures 2A, 3B, 5A). Epithelioid cell granuloma was not readily apparent, and the necrosis was surrounded by normal parenchymal cells with mild lymphocytic infiltration (Figure 2A). Ziehl–Neelsen staining revealed the presence of a few acid-fast bacilli (Figures 2B, 4B, 5B). These pathological findings, together with the result of PCR performed antemortem, led to the diagnosis of miliary TB. Apart from the miliary TB, the bone marrow of the sternum, ribs, and spinal bones showed many blast cells with small megakaryocytes, with hypolobulated nuclei being occasionally identified (Figure 3A). In addition, fat necrosis was observed in many bones (Figure 4B). In a vein near the left rib, a bone marrow embolism was confirmed. In the lungs, widespread pulmonary 2-10

Figure 1. Gross appearance of the cut section of the liver showing some scattered yellowish, well-defined tiny nodules and others of larger size representing their confluence.

fat embolisms (PFEs) were evident in the small arteries, arterioles, and capillaries of the interalveolar septa (Figures 5C, 5D, 6). The heart weighed 260 g (RR: 150–480 g), and the gross examination was unremarkable except for left ventricular hypertrophy (20 mm thickness). Except for PFE, there were no lesions that could have accounted for the patient’s sudden death (SD), such as myocardial infarction, myocarditis, or aortic dissection. Therefore, we concluded that the patient died of PFE. Autops Case Rep (São Paulo). 2018;9(1):e2018059

Chinen K, Ito K

Figure 2. Photomicrographs of the liver. A – Necrosis associated with mild lymphocytic infiltration. Note that the epithelioid cells are not readily apparent and Langhans giant cells are absent. The necrosis is surrounded by normal parenchymal liver cells (H&E, 100X). B – Ziehl–Neelsen staining demonstrates acid-fast bacilli (1000X).

Figure 3. Photomicrographs of the bone marrow. A – Hypercellular bone marrow with many blast cells. A hypolobulated micromegakaryocyte is observed (H&E, 1000X), B – Necrosis is apparent in the bone marrow (H&E, 100X).

Figure 4. Photomicrographs of the bone marrow. A – Note an acid-fast bacillus (arrow) demonstrated by Ziehl‑Neelsen staining (1000X), B – Necrotic adipose tissue is evident around bone trabecula (H&E, 200X). Autops Case Rep (São Paulo). 2018;9(1):e2018059

3-10

Sudden death caused by pulmonary fat embolism in a patient with miliary tuberculosis

Figure 5. Photomicrographs of the lung. A – Necrosis is evident with mild lymphocytic infiltration. Note that features of epithelioid cell granuloma are not readily apparent and Langhans giant cells are lacking (H&E, 100X). B – An acid‑fast bacillus demonstrated by Ziehl–Neelsen staining (1000X). C – Pulmonary fat embolism: Rounded clear vacuoles are apparent within the small pulmonary arterial branches and capillaries of the interalveolar septa (H&E, 200X). D – A cluster of fat cells within the small pulmonary artery (H&E, 200X).

DISCUSSION

Figure 6. Photomicrograph of the lung. Oil red-O staining demonstrates the fat globules within the pulmonary arterioles (400X). 4-10

TB, a potentially fatal contagious disease, which is caused by M. tuberculosis, can affect virtually any part of the body, but is mainly an infection of the lungs. Immunocompromised individuals—mostly those with cell-mediated immunity—are extremely susceptible. After the primary infection, the tubercle bacilli entrapped in the granulomatous foci can live in a state of microbial persistence for the individual’s lifetime. Any factor that disturbs the host immunity may cause endogenous reinfection. Miliary TB stands for the lymphohematogenous spread of the bacilli from the primary foci. In our case, the patient suffered from MDS and diabetes mellitus. In addition, cyclosporine therapy, which induces immunosuppression by means Autops Case Rep (São Paulo). 2018;9(1):e2018059

Chinen K, Ito K

of impairing T-cell function, must have decreased her cell-mediated immunological competence. As a consequence, a more severe and disseminated form of TB occurred. Indeed, in our case, necrosis was apparent but epithelioid cell granuloma was not readily apparent and Langhans giant cells were absent. The necrosis was surrounded by normal parenchymal cells. Although tubercle bacilli were not numerous, the histopathological features were similar to the histology of “non-reactive TB,”1 directly reflecting the immunological unresponsiveness of the host. This type of TB is always found in the liver, spleen, and bone marrow.1 In the present case, the immediate cause of SD was PFE, which most often follows blunt trauma, such as bone fracture, along with many other causes including severe burns, liposuction, acute pancreatitis, alcoholic fatty liver, sickle cell disease, and panniculitis. 2-6 Bone marrow necrosis (BMN) is another etiology of PFE and is well known to be frequently associated with hematological disorders, such as sickle cell disease, lymphoma, leukemia, and MDS.5-9 Occasionally, miliary TB can be responsible for BMN.8-11 The exact pathophysiologic mechanism that causes PFE is unknown. Two theories have been proposed.2,3 One is the so-called “mechanical theory,” according to which large fat droplets are released into the venous system. These droplets accumulate as deposits in the pulmonary capillary beds. Microvascular lodging of droplets further produces local ischemia and inflammation, with concomitant release of inflammatory mediators, platelet aggregation, and vasoactive amines. The other hypothesis, the “biochemical theory,” holds that hormonal changes caused by trauma and/or sepsis induce a systemic release of free fatty acids as chylomicrons. Acutephase reactants, such as C-reactive protein, cause chylomicrons to coalesce and create the physiologic reactions described above. The biochemical theory helps explain non-traumatic forms of PFE. In the present case, the patient suffered from bone fractures, but that was a long time ago before death; moreover, the bone marrow embolism was confirmed near the rib. Additionally, our patient was not submitted to cardiopulmonary resuscitation and therefore no embolic event was elicited by the sternal compression. Thus, we concluded that the PFE was derived from BMN, but not from previous bone fractures. In addition Autops Case Rep (São Paulo). 2018;9(1):e2018059

to MDS as a predisposition factor for BMN, we suspect that the miliary TB must have exerted an accelerating effect. BMN and consequent PFE12 should be recognized as a lethal complication in patients with miliary TB. Left untreated, TB runs a chronic debilitating course, with cachexia and wasting similar to metastatic cancer, and rarely causes SD. Most physicians do not regard it as a principal cause of SD.13 However, like our case, some affected patients die suddenly. 14-16 In order to better understand the pathophysiology of tuberculosis-related sudden death (TBRSD), we reviewed the literature and considered probable mechanisms of TBRSD. TB has a predilection for the pulmonary system, and autopsy studies dealing with TBRSD have indicated that pulmonary TB was the principal lesion in the majority of victims.14,15 Postmortem examination has revealed miscellaneous pathological findings in lungs, such as tuberculoma, necrotic cavities, miliary TB, abscesses, pneumonia, bronchiectasis, hemorrhage, airway compression, mucoid impaction, pulmonary edema, and pleural adhesions.13,15,17-22 In many TBRSD cases, respiratory failure is the common pathway leading to death, which has been often demonstrated by extensive pulmonary tissue damage on postmortem examination.23 The symbiotic relationship between the lungs and the heart means the failure of one leads to the downfall of the other. Thus, in many pulmonary TB patients, respiratory failure leads to cardiac failure; this is the accepted final endpoint leading to death.23 Alkhuja and Miller16 reviewed the literature on TBRSD and summarized that the majority of TB patients died from bronchopneumonia (64%) and that massive hemoptysis was the second leading cause (30%). Pulmonary hemorrhage and consequent hemoptysis are the most dramatic clinical presentations in pulmonary TB.21 Even though a pulmonary lesion is small and localized, hemorrhage can cause SD by hypovolemic shock after profuse bleeding, or by asphyxiation due to hemoaspiration.18,21,22 Even a small amount of blood can obstruct the airway. A variety of TB presentations with pulmonary hemorrhage are known, such as bronchiectasis, abscesses, scar carcinoma in old TB, the formation of mycetoma in the tuberculous cavity, the rupture of blood vessels inside a tubercular cavity, and fistulas between a major airway and a vessel.21 Rasmussen’s aneurysm— 5-10

Sudden death caused by pulmonary fat embolism in a patient with miliary tuberculosis

an inflammatory pseudo-aneurysmal dilatation of a branch of bronchial or pulmonary artery adjacent to a tubercular cavity—is reported to be associated with 5% of tuberculous cavity lesions,24 and can rupture, leading to massive hemoptysis and SD.25 Pulmonary TB is often associated with mediastinal lymph node involvement. Such pulmonary and mediastinal TB may extend to the surrounding structures, such as the heart and aorta, and consequently induce lethal complications, as discussed below. Although its incidence is very low, extrapulmonary TB also can account for SD. 16 In this context, the heart is the most important organ.23,26 Most patients with cardiac TB are asymptomatic before death, and antemortem diagnosis is extremely rare.26-31 Cardiac TB is usually secondary to lesions elsewhere in the body. The heart may be involved as (i) a direct extension from intrathoracic lesions; (ii) retrograde lymphatic spread through cardiac lymphatics; and (iii) hematogenous infiltration. 26 Although the pericardium is most commonly involved and myocardial involvement is rare,23 TB myocarditis is a factor in the majority of TB-related sudden cardiac deaths.23,26,32-38 The mechanism of SD in TB myocarditis has been hypothesized to be ventricular tachyarrhythmias,23,26,32-34,37,38 although direct records of ventricular arrhythmia are lacking.23,26,30,39 When the pericardium is affected by TB, pericarditis and/ or cardiac tamponade may develop, and they could be a cause of SD.31 TB involving the endocardium is extremely rare,35,40 and SD resulting from endocardial TB has not been reported so far. Once the endocardium is affected, a pedunculated tuberculoma and/or intracavitary mass may develop.29,40 These mass lesions within a cardiac chamber present an obvious risk for SD because they can cause outflow or inflow obstruction.29 Also, pulmonary and/or systemic embolization resulting from an intracardiac tuberculous lesion 41 may be responsible for SD. It is very rare for coronary arteries to be affected by TB,40,41 and subsequent myocardial ischemia accounts for SD. Rodríguez et al.42 reported the case of a 21-year-old man who suddenly died while playing basketball. His autopsy revealed that the coronary artery was involved by tuberculous granuloma, and showed luminal stenosis. Chow et al.43 described a TBRSD case of a 12-year-old girl showing coronary ostial obstruction originating from tuberculous aortitis. In addition to the aforementioned cardiac involvement, TB also may be associated with ventricular aneurysm, cardiac rupture, impaired myocardial contractility, 6-10

dilated cardiomyopathy, congestive heart failure, long QT syndrome, and complete heart block.26-28,33,39,41,44,45 These cardiac complications should be kept in mind as a probable cause of TBRSD. Acute blood loss resulting from extrapulmonary TB is another etiology of SD. Vessels affected by TB become fragile and prone to rupture. Both thoracic and abdominal aorta are susceptible to tuberculous involvement. Contiguous invasion from neighboring structures, such as mediastinal lymph nodes, is often observed. Rarely, hematogenous spread (miliary TB) may also occur. Aortic TB is associated with aortitis, aneurysms, dissection, and fistulas with neighboring organs, such as the esophagus.46-50 These aortic lesions may be responsible for aortic rupture and massive exsanguination, by presenting as hematemesis, hemoptysis, hemothorax, hemoperitoneum, and alimentary tract bleeding (e.g. aorto-esophageal fistula).48-50 Tuberculous aneurysms of splanchnic and peripheral arteries are also predisposed to massive exsanguination. Tuberculous aneurysms of renal, brachiocephalic, femoral, common iliac, and hepatic arteries have been reported. 51 Beeresha et al. 52 described a 13-year-old boy presenting with SD due to massive intraperitoneal bleeding, in whom the cause of death was an aneurysm rupture of the hepatic artery of tuberculous etiology. Splenic rupture due to splenic TB also has been reported as a cause of hemoperitoneum.53 The central nervous system is critical, and any lesions causing rapid functional deterioration of vital foci, such as the brain stem, which controls circulatory or respiratory function, may be responsible for SD. Brain stem tuberculoma54,55 may be an example of such a condition. Brain TB including tuberculous meningitis can become an underlying pathology of increased intracranial pressure, acute hydrocephalus, brain edema, and epilepsy.56-58 These neurological disorders are known to be associated with SD.59 To the best of our knowledge, there has been no case report dealing with brain TB-induced SD, but brain TB may be included in the list of probable causes of TBRSD.60 Apart from TB of the critical organs as mentioned above, TB of other sites also can cause SD indirectly by miscellaneous types of pathophysiology. As presented in this manuscript, TB-induced BMN and consequent PFE is just one example. Also, pancytopenia due to BMN is considered to be a risky condition for SD.10,61 TB of adrenal glands is one of the etiologies Autops Case Rep (São Paulo). 2018;9(1):e2018059

Chinen K, Ito K

of adrenal insufficiency (Addison disease), which may be responsible for SD. An autopsy case of SD due to adrenal tuberculosis has been reported. 62 Hugar et al.63 described an SD case due to pathological asphyxia as a result of upper airway obstruction by retropharyngeal abscesses secondary to tuberculous vertebral osteomyelitis (Pott’s disease). Hemophagocytic syndrome, with many severe clinical manifestations, such as cytopenia, splenomegaly, and cytokinemediated multiorgan dysfunction, is fatal unless treated.64,65 Lam et al.66 reported a TBRSD case of a 42-year-old man who presented with hemophagocytic syndrome and splenic rupture. To briefly summarize TBRSD, its causes can be divided into two categories: pulmonary TB and extrapulmonary TB. The former is frequent and SD may be caused by respiratory failure due to bronchopneumonia, pulmonary hemorrhage, and hemoptysis. The latter is rare but includes miscellaneous changes that induce rapid deterioration of the circulation and/or respiration. TB can occur in any part of the human body, and affected organs may be structurally destroyed and physiologically impaired. Therefore, there must be a large spectrum of causes of TBRSD, presumably including examples that have not been reported so far in the literature. The TB endemic is still a global feature and its spread in the past 3 decades has been facilitated by the acquired immunodeficiency syndrome pandemic and increased drug resistance.16 International travel and migration may increase the incidence of TB in industrialized countries. The presence of people with TB—especially with far-advanced active caseating and cavitating pulmonary TB—constitutes a public health hazard.13,18 Therefore, prompt and proper diagnosis is important when patients suffer from or die from TB.67,68 Especially, in the case of TBRSD, the precise diagnosis is essential through postmortem examination.18-20,34,36 From the viewpoint of both clinical practice and public health, the accumulation of relevant cases and the analyses of pathophysiology are necessary for a greater understanding of TBRSD.

the accumulation of studies on TBRSD is necessary for better clinical practice and public health.

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We report the autopsy case presenting as SD due to TB-induced PFE and discuss TBRSD with a review of the literature. Since causes of TBRSD are miscellaneous,

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31. Hayase N, Inokuchi R, Nakamura K, et al. Sudden cardiac arrest caused by tuberculous pericarditis with hemorrhagic pericardial effusion. Intern Med. 2012;51(22):3197-201. http://dx.doi.org/10.2169/internalmedicine.51.7958. PMid:23154733.

20. Dempers J, Sens MA, Wadee SA, Kinney HC, Odendaal HJ, Wright CA, PASS Network. Progressive primary pulmonary tuberculosis presenting as the sudden unexpected death in infancy: a case report. Forensic Sci Int. 2011;206(1-3):e27-30. http://dx.doi.org/10.1016/j. forsciint.2010.07.018. PMid:20705406. 21. Hugar BS, Jayanth SH, Chandra YPG, Shankar BS. Sudden death due to massive hemoptysis secondary to pulmonary tuberculosis: a case report. J Forensic Leg Med. 2013;20(6):632-4. http://dx.doi.org/10.1016/j. jflm.2013.03.034. PMid:23910849. 22. Thu M, Winskog C, Byard RW. Tuberculosis and sudden death. Forensic Sci Med Pathol. 2014;10(2):2668. http://dx.doi.org/10.1007/s12024-013-9501-z. PMid:24158683. 23. Liu A, Hu Y, Coates A. Sudden cardiac death and tuberculosis – how much do we know? Tuberculosis (Edinb). 2012;92(4):307-13. http://dx.doi.org/10.1016/j. tube.2012.02.002. PMid:22405969. 8-10

32. Behr G, Palin HC, Temperly JM. Myocardial tuberculosis. BMJ. 1977;1(6066):951. http://dx.doi.org/10.1136/ bmj.1.6066.951. PMid:851799. 33. Wallis PJW, Branfoot AC, Emerson PA. Sudden death due to myocardial tuberculosis. Thorax. 1984;39(2):155-6. http://dx.doi.org/10.1136/thx.39.2.155. PMid:6701827. 34. Chan ACL, Dickens P. Tuberculous myocarditis presenting as sudden cardiac death. Forensic Sci Int. 1992;57(1):4550. http://dx.doi.org/10.1016/0379-0738(92)90044-W. PMid:1468731. 35. Dada MA, Lazarus NG, Kharsany ABM, Sturm AW. Sudden death caused by myocardial tuberculosis: case report and review of the literature. Am J Forensic Med Pathol. 2000;21(4):385-8. http://dx.doi.org/10.1097/00000433200012000-00018. PMid:11111803. 36. Biedrzycki OJ, Baithun SI. TB-related sudden death (TBRSD) due to myocarditis complicating miliary TB: a case Autops Case Rep (São Paulo). 2018;9(1):e2018059

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51. Tsurutani H, Tomonaga M, Yamaguchi T, et al. Hepatic artery pseudoaneurysms in a patient treated for miliary tuberculosis. Intern Med. 2000;39(11):994-8. http://dx.doi.org/10.2169/internalmedicine.39.994. PMid:11065259.

40. Kannangara DW, Salem FA, Rao BS, Thadepalli H. Cardiac tuberculosis: TB of the endocardium. Am J Med Sci. 1984;287(3):45-7. http://dx.doi.org/10.1097/00000441198405000-00016. PMid:6731481. 41. Rose AG. Cardiac tuberculosis: a study of 19 patients. Arch Pathol Lab Med. 1987;111(5):422-6. PMid:3566473. 42. Rodríguez Y, de Armas Y, Capó V, Wissmann G, Goldani LZ, De Waard JH. Sudden death related to tuberculous coronary arteritis. Int J Cardiol. 2012;156(2):e289. http://dx.doi.org/10.1016/j.ijcard.2011.08.002. PMid:21880380. 43. Chow LTC, Chow WH, Lee JKC, Lie JT. Tuberculous aortitis with coronary ostial and left ventricular outflow obstruction: unusual cause of sudden unexpected death. Cardiovasc Pathol. 1996;5(3):133-8. http://dx.doi. org/10.1016/1054-8807(95)00121-2. PMid:25851474. 44. Menon TB, Rao CKP. Tuberculosis of the myocardium causing complete heart block. Am J Pathol . 1945;21(6):1193-7. PMid:19970856. 45. Díaz-Peromingo JA, Mariño-Callejo AI, GonzálezGonzález C, García-Rodríguez JF, Ameneiros-Lago ME, Sesma-Sánchez P. Tuberculous myocarditis presenting as long QT syndrome. Eur J Intern Med. 2000;11(6):3402. http://dx.doi.org/10.1016/S0953-6205(00)00113-8. PMid:11113659. 46. Delaval L, Goulenok T, Achouh P, et al. New insights on tuberculous aortitis. J Vasc Surg. 2017;66(1):20915. http://dx.doi.org/10.1016/j.jvs.2016.11.045. PMid:28254396. 47. Long R, Guzman R, Greenberg H, Safneck J, Hershfield E. Tuberculous mycotic aneurysm of the aorta: review of published medical and surgical experience. Chest. 1999;115(2):522-31. http://dx.doi.org/10.1378/ chest.115.2.522. PMid:10027455. 48. Nachega JB, Vandercam B, d’Udekem Y, et al. Chronic dissection of the thoracic aorta in a patient with tuberculous Autops Case Rep (São Paulo). 2018;9(1):e2018059

52. Beeresha, Ghotekar LH, Dutta TK, et al. Hepatic artery mycotic aneurysm of tubercular aetiology. J Assoc Physicians India. 2000;48(2):247-8. 53. Rathore S, George P, Deodhar M, et al. Spontaneous rupture of tuberculous spleen in a HIV seropositive patient on maintenance hemodialysis. Saudi J Kidney Dis Transpl. 2009;20(5):822-5. PMid:19736481. 54. Lyden PD. Tuberculoma of the brain stem. West J Med. 1987;147(2):198-200. PMid:3660781. 55. Talamás O, Del Brutto OH, García-Ramos G. Brainstem tuberculoma: an analysis of 11 patients. Arch Neurol. 1989;46(5):529-35. http://dx.doi.org/10.1001/ archneur.1989.00520410063025. PMid:2712750. 56. Ripamonti D, Barbò R, Rizzi M, et al. New times for an old disease: intracranial mass lesions caused by Mycobacterium tuberculosis in 5 HIV-negative African immigrants. Clin Infect Dis. 2004;39(5):e35-45. http:// dx.doi.org/10.1086/422876. PMid:15356800. 57. Komolafe MA, Sunmonu TA, Esan OA. Tuberculous meningitis presenting with unusual clinical features in Nigerians: two case reports. Cases J. 2008;1(180):1-5. 58. Salway RJ, Sangani S, Parekh S, Bhatt S. Tuberculosisinduced seizures. West J Emerg Med. 2015;16(5):6258. http://dx.doi.org/10.5811/westjem.2015.7.27758. PMid:26587082. 59. Chinen K. Neoplasm-related sudden death: causes and clinicopathological characteristics. In: Wu J, Wu J, editors. Sudden death: causes, risk factors and prevention. New York: Nova Science Publishers; 2013. p.151-69. 60. Mayers MM, Kaufman DM, Miller MH. Recent cases of intracranial tuberculomas. Neurology. 1978;28(3):256-60. http://dx.doi.org/10.1212/WNL.28.3.256. PMid:564480. 61. Lee YH, Hong YC, Yang CF, et al. Severe extensive bone marrow necrosis from miliary tuberculosis without granulomas and pulmonary presentations. J Chin Med 9-10

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Assoc. 2010;73(4):208-11. http://dx.doi.org/10.1016/ S1726-4901(10)70043-5. PMid:20457443. 62. Ward S, Evans CC. Sudden death due to isolated adrenal tuberculosis. Postgrad Med J. 1985;61(717):635-6. http:// dx.doi.org/10.1136/pgmj.61.717.635. PMid:4022897. 63. Hugar BS, Chandra YPG, Babu PRS, Jayanth SH, Vinay J. Fatal case of retropharyngeal abscess associated with Pott’s disease. J Forensic Leg Med. 2013;20(6):5679. http://dx.doi.org/10.1016/j.jflm.2013.06.007. PMid:23910833. 64. Brastianos PK, Swanson JW, Torbenson M, Sperati J, Karakousis PC. Tuberculosis-associated haemophagocytic syndrome. Lancet Infect Dis. 2006;6(7):447-54. http://dx.doi.org/10.1016/S1473-3099(06)70524-2. PMid:16790385.

65. Shea YF, Chan JFW, Kwok WC, et al. Haemophagocytic lymphohistiocytosis: an uncommon clinical presentation of tuberculosis. Hong Kong Med J. 2012;18(6):517-25. PMid:23223654. 66. Lam KY, Ng WF, Chan ACL. Miliary tuberculosis with splenic rupture: a fatal case with hemophagocytic syndrome and possible association with long standing sarcoidosis. Pathology. 1994;26(4):493-6. http://dx.doi. org/10.1080/00313029400169262. PMid:7892057. 67. Bobrowitz ID. Active tuberculosis undiagnosed until autopsy. Am J Med. 1982;72(4):650-8. http://dx.doi. org/10.1016/0002-9343(82)90476-4. PMid:7072745. 68. Lee JKM, Ng THK. Undiagnosed tuberculosis in hospitalized patients – an autopsy survey. J R Soc Health. 1990;110(4):141-3. http://dx.doi. org/10.1177/146642409011000411. PMid:2121983.

Author contributions: All authors have significantly contributed, and are in agreement with the content of the manuscript. Chinen K. wrote the manuscript and performed the autopsy. Ito K. was responsible for the patient’s medical care. The autopsy was authorized by an informed consent by relatives in the presence of two other persons, and the manuscript is in accordance with the Institutional Ethics Committee. Conflict of interest: None Financial support: None Submitted on: October 8th, 2018 Accepted on: November 2nd, 2018 Correspondence Katsuya Chinen Department of Pathology - Nerima General Hospital 1-24-1 - Asahigaoka/Nerima – Tokyo – Japan 176-8530 Phone: +81(3) 5988-2200 path.chinen@gmail.com

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Article / Autopsy Case Report

Pulmonary thromboembolism secondary to pelvic thrombosis related to giant ovarian tumor Alberto Amadasia, Salvatore Andreolaa, Marta Bianchia, Michele Boracchia, Guendalina Gentilea, Francesca Macioccoa, Matteo Marchesib, Riccardo Zojaa  How to cite: Amadasi A, Andreola S, Bianchi M, et al. Pulmonary thromboembolism secondary to pelvic thrombosis related to giant ovarian tumor. Autops Case Rep [Internet]. 2019;9(1):e2018061. https://doi.org/10.4322/acr.2018.061

ABSTRACT Pulmonary thromboembolism (PTE) is one of the major complications in oncologic patients. The incidence of PTE in these cases is 4 to 7 times higher than in non-oncologic patients. Ovarian tumors, specifically those of large sizes, may impair the blood flow through the pelvic veins as tumor pressure over the pelvic vessels increases the incidence of thrombosis. The authors report the case of the unexpected death of a 74-year-old female due to massive pulmonary thromboembolism, associated with an ovarian tumor almost of 15 kg of weight that filled the abdominal and pelvic cavities. The compressive effect on the walls of the pudendal and periuterine veins somehow facilitated the local thrombosis. According to the histological characterization on post-mortem samples, the mass was identified as an “atypical proliferative (borderline) mucinous tumor.” The case emphasizes the important association between pulmonary thromboembolism and ovarian tumors Keywords Autopsy; Sudden Death; Ovarian Neoplasms; Pulmonary Thromboembolism.

INTRODUCTION Deep vein thrombosis (DVT) and pulmonary thromboembolism (TEP) are severe1 and frequent 2 complications (42%) in women with advanced ovarian neoplasms, 1-4 large uterine fibromas 5 and in patients undergoing chemotherapy.6 In patients with large solid malignancies, besides the mechanism triggered by the immunologic, inflammatory and the released substances related to the tumor response, the pressing on the large vessels such as the inferior vena cava, pelvic and iliac veins may result in bloodstream stasis, turbulent flow and vessels injury, increasing

the probability for thombosis.7 Among all abdominal and pelvic tumors in women, ovarian neoplasms represent the main cause of pulmonary embolism and thrombophlebitis.8,9 The WHO classification of 2014 divides the surface epithelial tumors of the ovary into benign, borderline and malignant and the different histological types into serous, mucinous, endometrioid, clear cells, Brenner and seromucinous.10 Borderline ovarian tumors are characterized by a smaller aggressiveness when compared with other epithelial forms 11 and

Università degli Studi di Milano, Dipartimento di Scienze Biomediche per la Salute, Sezione di Medicina Legale e delle Assicurazioni. Milano, Italy. b Azienda Socio Sanitaria Papa Giovanni XXIII, Ospedale di Bergamo. Bergamo, Italy. a

Pulmonary thromboembolism secondary to pelvic thrombosis related to giant ovarian tumor

are currently defined “atypical proliferative epithelial tumors.” This type of tumor usually occurs in the third or fourth decade and is unilateral in 80% of cases.12 According to the tumor biology and behavior, the prognosis is usually favorable, but life-threatening outcomes may be observed by the compression on the surrounding structures when the tumor reaches large dimensions, leading to unexpected death.

until their segmental subdivision. The large thrombus entirely occluded the arterial lumen, reproducing the shape of the vessel as a “cast”, coated by the intimal surface, characterizing a bilateral massive pulmonary thromboembolism.

In this context, the main goal of this case report is to emphasize the important association between pulmonary thromboembolism and ovarian tumors of such greatness.

At the opening of the abdominal and pelvic cavities, the left uterine adnexa were represented by a smooth cystic tumor, weighing 15 kg (Figure 3) and measuring 33 cm in its longest axis. At the cut surface, the cyst was multiloculated and drained a yellowish mucinous material. No papillary excrescences were seen, but a partly necrotic and solid nodule of 8.5 cm was found adhered to the cystic wall.

CASE REPORT A 74-year-old female who lived alone was found dead in her home. The estimated time of death was evaluated to be of 48 hours. According to the relatives’ information, she was diagnosed with hypertension and was under a diagnostic workup of an ovarian cyst. The judicial authority required an autopsy, which was performed 2 days after the discovery of the corpse.

Autopsy Presentation The external examination revealed an apparent well-preserved corpse with a body mass index of 34.8, without any sign of external injuries. The examination of the head and neck was unremarkable. However, the examination of the lung depicted an extensive bilateral thrombosis of the main pulmonary arteries

According to the morphological characteristics, a thromboembolic nature was macroscopically confirmed (Figures 1 and 2).

The examination of the contralateral ovary and uterus was unremarkable, the latter showing an atrophic endometrium. The bilateral dissection of the deep vessels of the lower limbs failed to show thrombosis, while the exploration of the veins of the pudendal plexus (ovarian and periuterine veins) showed the presence of extensive thrombosis (Figure 4). No other noteworthy finding was detected. The cause of death was identified as massive pulmonary thromboembolism in a woman with a large ovarian neoplasm. During the autopsy, different organs were sampled (uterus, ovarian neoplasm, pudendal plexuses and thrombotic formations) for histopathologic investigation.

Figure 1. Macroscopic view of the thromboembolic events. A – Gross view of the thrombus in the pelvic vessels; B – Gross view of pulmonary thromboembolism. 2-6

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Moreover, samples of biological fluids (heart and femoral blood, urine, bile and gastric content) were taken for toxicological analyses. The search for

drugs and/or alcohol was performed and results were negative. Microscopically, the massive ovarian neoplasm was assessed as “atypical proliferating mucinous tumor (borderline)” (Figure 5) and the thrombotic nature of the occluding material in the periuterine veins was confirmed, with secondary thromboembolism in the pulmonary arteries.13 Therefore, the cause of death was identified as pulmonary thromboembolism due to pelvic thrombosis, concomitant with a giant ovarian neoplasm. According to the evidence provided by the autopsy and the histological findings, the compression effect of the mass on the pudendal venous plexus enabled the

Figure 2. Photomicrograph of thrombosis of a pelvic vein (Masson’s trichrome staining: 200 X).

formation of intravascular thrombi, whose detachment led to pulmonary embolism and death.

Figure 3. Macroscopic examination of the ovarian tumor. A – Gross view of the tumor, after the abdominal cavity overture; B – Macroscopic view of the tumor external wall; C – Inner surface view with the multiple cystic formations of varying sizes; D – Cut surface of the solid nodule adhered to the cystic wall. Autops Case Rep (São Paulo). 2019;9(1):e2018061

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Pulmonary thromboembolism secondary to pelvic thrombosis related to giant ovarian tumor

DISCUSSION In 1865, Trousseau14 described the correlation between tumors and venous thrombosis, and since then, neoplasms have been recognized as a risk factor for venous thromboembolism (VTE) and, consequently, pulmonary embolism (PE).15 The Virchow classic triad of endothelial damage, hypercoagulability and venous stasis is considered to be the mechanism responsible for the pathogenic onset.16 The Trousseau syndrome (tumor-associated thrombosis) is the second cause of death in oncologic patients after the progression of the disease itself.17 The risk of pulmonary embolism in this group of patients is 4 to 7 times higher if compared to non-neoplastic patients.4,17

Figure 4. Macroscopic examination of the thrombosis of the pudendal plexus sample in three different regions of the plexus.

Previous studies 18 report thrombotic events in 20% of patients with malignancy18 and up to 20% of these patients will present embolic events.19 Some neoplasms, especially pancreatic and gastrointestinal,20 are associated with higher rates of thrombosis.15,21 Other neoplasms of the peritoneal and pelvic cavities (i.e., endometrial or bladder tumors) and, in particular, ovarian and extrahepatic biliary ducts are usually linked to high incidence of pulmonary embolism.22,23 In particular, the highest prevalence of pulmonary embolism and thrombophlebitis has been witnessed in neoplastic ovarian patients, 8 especially among germinal types. 24 This is due to the combination of the pelvic blood flow obstruction by the mass,7 the effect of estrogen hormone treatment 25 and the overexpression of the tissue factor associated with high D-dimer levels, which is considered to be an important factor in hypercoagulability. 26 The coagulation cascade activation and the embolic events occur in association with neoplasms because of the tissue factor (TF) and cancer procoagulant (CP).27 Moreover, a crucial role may be played by inflammatory cytokines and the relationship between neoplastic cells, monocytes, macrophages, platelets and endothelial cells. Inaddition, thrombosis may be favored by chemotherapy, hormone therapy or radiotherapy. Other mechanisms that also may take part in thrombus formation are related to the relationship between the host and the tumor (i.e., acute phase inflammation,

Figure 5. In A, residual papillary structure of epithelium with multilayer cores (EE: 200X, in B higher magnification EE: 1000X), with evidence of moderate nuclear atypia. In C (periodic acid-Schiff stain, 32X) and D (Alcian blue pH 2.5,100X), high amount of mucus tightly fixed to the internal surface of neoformation. 4-6

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angiogenesis), decreased inhibitors of coagulation and impaired fibrinolysis.28,29

Oncol. 2007;105(3):784-90. http://dx.doi.org/10.1016/j. ygyno.2007.02.024. PMid:17408726.

It is evident that the development of the neoplasm highlights the importance of therapeutic choices, even in the case of benign neoplasms, along with the analysis and characterization of the social and cultural conditions of the patient. This case confirms what is reported in the literature 30,31 about the association between pulmonary embolism and epithelial neoplasms.

7. Pineo GF, Brain HC, Gallus AS, Hirsh J, Hatton MW, Regoeczi E. Tumors, mucus production, and hypercoagulability. Am NY Acad Sci. 1974;230(1):26270. http://dx.doi.org/10.1111/j.1749-6632.1974. tb14458.x. PMid:4522873.

CONCLUSION

9. Boger-Megiddo I, Weiss NS. Histologic subtypes and laterality of primary epithelial ovarian tumors. Gynecol Oncol. 2005;97(1):80-3. http://dx.doi.org/10.1016/j. ygyno.2004.11.054. PMid:15790441.

The presented case is peculiar because a sudden death occurred from complications related to ovarian neoplasm, with increased predisposition to deep venous thrombosis. According to Italian Law, all the material sampled during a Judicial Autopsy does not require any authorization by the family members of the deceased to be studied and published, except with the precaution of maintaining the anonymity of the patient.

REFERENCES 1. Svendsen E, Karwinski B. Prevalence of pulmonary embolism at necropsy in patients with cancer. J Clin Pathol. 1989;42(8):805-9. http://dx.doi.org/10.1136/ jcp.42.8.805. PMid:2475526. 2. Satoh T, Oki A, Uno K, et al. High incidence of silent venous thromboembolism before treatment in ovarian cancer. Br J Cancer. 2007;97(8):1053-7. http://dx.doi. org/10.1038/sj.bjc.6603989. PMid:17895896. 3. Abu Saadeh F, Norris L, O’Toole S, et al. Tumour expression of tissue factor and tissue factor pathway inhibitor in ovarian cancer- relationship with venous thrombosis risk. Thromb Res. 2013;132(5):627-34. http://dx.doi.org/10.1016/j.thromres.2013.09.016. PMid:24094893.

8. Levitan N, Dowlati A, Remick SC, et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy: risk analysis using medicare claims data. Medicine. 1999;78(5):28591. http://dx.doi.org/10.1097/00005792-19990900000001. PMid:10499070.

10. Kurman RJ, Carcangiu ML, Herrington CS, et al. WHO classification of tumours of female reproductive organs. 4th ed. Lyon: WHO Press; 2014. 11. Ayhan A, Guvendag Guven ES, Guven S, Kucukali T. Recurrence and prognostic factors in borderline ovarian tumors. Gynecol Oncol. 2005;98(3):439-45. http://dx.doi. org/10.1016/j.ygyno.2005.05.033. PMid:16009407. 12. Jetley S, Khetrapal S, Ahmad A, Jairajpuri ZS. Atypical proliferative endometrioid tumor of ovary: report of a rare case. J Postgrad Med. 2016;62(2):129-32. http://dx.doi. org/10.4103/0022-3859.168092. PMid:26497398. 13. Janssen W. Forensic histopathology. Berlin: Springer; 1977. 14. Trousseau A. Clinique médicale de l’Hôtel-Dieu de Paris. Paris: JB Bailliere et Fils; 1865. 15. Gunderson CC, Thomas ED, Slaughter KN, et al. The survival detriment of venous thromboembolism with epithelial ovarian cancer. Gynecol Oncol. 2014;134(1):737. http://dx.doi.org/10.1016/j.ygyno.2014.04.046. PMid:24793732. 16. Heath OM, van Beekhuizen HJ, Nama V, et al. Venous thromboembolism at time of diagnosis of ovarian cancer: Survival differs in symptomatic and asymptomatic cases. Thromb Res. 2016;137:30-5. http://dx.doi.org/10.1016/j. thromres.2015.11.030. PMid:26653367.

4. Zhang Y, Yang JX, Wu M, Shen K. Clinicopathological conference: an advanced ovarian carcinoma patient suddenly died of pulmonary embolism. Zhongguo Yi. Xue Ke Yuan Xue Bao. 2003;25:471-5.

17. Ikushima S, Ono R, Fukuda K, Sakayori M, Awano N, Kondo K. Trousseau’s syndrome: cancer-associated thrombosis. Jpn J Clin Oncol. 2016;46(3):204-8. http:// dx.doi.org/10.1093/jjco/hyv165. PMid:26546690.

5. Shiota M, Kotani Y, Umemoto M, et al. Risk factors for deep-vein thrombosis and pulmonary thromboembolism in benign ovarian tumor. Tohoku J Exp Med. 2011;225(1):1-3. http://dx.doi.org/10.1620/tjem.225.1. PMid:21817850.

18. Lee AY, Levine MN, Butler G, et al. Incidence, risk factors, and outcomes of catheter-related thrombosis in adult patients with cancer. J Clin Oncol. 2006;24(9):14048. http://dx.doi.org/10.1200/JCO.2005.03.5600. PMid:16549834.

6. Rodriguez AO, Wun T, Chew H, Zhou H, Harvey D, White RH. Venous thromboembolism in ovarian cancer. Gynecol

19. Caine GJ, Stonelake PS, Lip GY, Kehoe ST. The hypercoagulable state of malignancy: pathogenesis and

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current debate. Neoplasia. 2002;4(6):465-73. http:// dx.doi.org/10.1038/sj.neo.7900263. PMid:12407439. 20. Dvorak HF. Thrombosis and cancer. Hum Pathol. 1987;18(3):275-84. http://dx.doi.org/10.1016/S00468177(87)80010-2. PMid:3546076. 21. Rickles FR, Edwards RL. Activation of blood coagulation in cancer: Trousseau’s syndrome revisited. Blood. 1983;62(1):14-31. PMid:6407544. 22. Belt RJ, Leite C, Haas CD, Stephens RL. Incidence of hemorrhagic complications in patients with cancer. JAMA. 1978;239(24):2571-4. http://dx.doi.org/10.1001/ jama.239.24.2571. PMid:660790. 23. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer. 2007;110(10):2339-46. http://dx.doi. org/10.1002/cncr.23062. PMid:17918266. 24. Bakhru A. Effect of ovarian tumor characteristics on venous thromboembolic risk. J Gynecol Oncol. 2013;24(1):528. http://dx.doi.org/10.3802/jgo.2013.24.1.52. PMid:23346314. 25. Poller L. Oral contraceptives, blood clotting and thrombosis. Br Med Bull. 1978;34(2):151-6. http:// dx.doi.org/10.1093/oxfordjournals.bmb.a071485. PMid:350338.

26. Uno K, Homma S, Satoh T, et al. Tissue factor expression as a possible determinant of thromboembolism in ovarian cancer. Br J Cancer. 2007;96(2):290-5. http://dx.doi. org/10.1038/sj.bjc.6603552. PMid:17211468. 27. Molnar S, Guglielmone H, Lavarda M, Rizzi ML, Jarchum G. Procoagulant factors in patients with cancer. Hematology. 2007;12(6):555-9. http://dx.doi. org/10.1080/10245330701521416. PMid:17852460. 28. De Cicco M. The prothrombotic state in cancer: pathogenic mechanisms. Crit Rev Oncol Hematol. 2004;50(3):18796. http://dx.doi.org/10.1016/j.critrevonc.2003.10.003. PMid:15182825. 29. Kurman RJ. Blaustein’s Pathology of the female genital tract. 5th ed. New York: Springer; 2001. p. 791-904. 30. Srettabunjong S. Systemic thromboembolism after deep vein thrombosis caused by uterine myomas. Am J Forensic Med Pathol. 2013;34(3):207-9. http://dx.doi. org/10.1097/PAF.0b013e318298a456. PMid:23835533. 31. Srettabunjong S, Chuangsuwanich T. Inferior vena cava tumor thrombosis secondary to metastatic uterine cancer: a rare cause of sudden unexpected death. J Forensic Sci. 2016;61(2):555-8. http://dx.doi.org/10.1111/15564029.13032. PMid:27404631.

Author contributions: Amadasi A, Andreola S, Bianchi M and Boracchi M contributed to the conception and design of the study. Gentile G, Maciocco F and Marchesi M contributed to the acquisition, analysis and interpretation of the data. Zoja R critically revised the manuscript. All authors collectively proofread the final version and approved the manuscript for publication. Conflict of interest: None Financial support: None Submitted on: July 6th, 2018 Accepted on: October 20th, 2018 Correspondence Riccardo Zoja Sezione di Medicina Legale - Università degli Studi Via Luigi Mangiagalli, 37 – Milano – Italy C.A.P.: 20133 Phone: +39 (02) 50315685/Fax: +39 (02) 50315724 riccardo.zoia@unimi.it

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Article / Autopsy Case Report

Spontaneous perforation of small intestine followed by rupture of the cystic artery: the natural history of Vascular Ehlers-Danlos Syndrome Christopher Antônio Febres-Aldanaa, Amilcar Antonio Castellano-Sanchezb, John Alexisa How to cite: Febres-Aldana CA, Castellano-Sanchez AA, Alexis J. Spontaneous perforation of small intestine followed by rupture of the cystic artery: the natural history of Vascular Ehlers-Danlos Syndrome. Autops Case Rep [Internet]. 2019;9(1): e2018054. https://doi.org/10.4322/acr.2018.054

ABSTRACT Vascular Ehlers-Danlos Syndrome (VEDS) is a rare autosomal dominant disorder caused by mutations in the COL3A1 or COL1A1 genes. Its mortality is secondary to sudden and spontaneous rupture of arteries or hollow organs. The genotype influences the distribution of arterial pathology with aneurysms of intra-abdominal visceral arteries being relatively uncommon. We describe the case of a young man with probable VEDS who died of a spontaneous rupture and dissection of the cystic artery. The patient initially presented with abdominal pain due to an unrecognized spontaneous perforation of the small intestine complicated by sepsis. We postulate that inflammatory mediators may have triggered the arterial rupture due to remodeling and weakening of vessel walls. The phenotype of the patient’s vascular damage included bilateral spontaneous carotid-cavernous sinus fistulae and dissection with pseudoaneurysm formation of large- and medium-sized arteries, predominantly the abdominal aorta and its branches. The autopsy uncovered a long history of vascular events that may have been asymptomatic. These findings along with a positive family history supported the VEDS diagnosis. Loeys-Dietz, Marfan, and familial thoracic aortic aneurysm and dissection syndromes were ruled out based on the absence of arterial tortuosity, eye abnormalities, bone overgrowth, and the distribution of vascular damage among other features. Interestingly, microscopic examination of the hippocampus revealed a focus of neuronal heterotopia, commonly associated with epilepsy; however, the patient had no history of seizures. The natural course of VEDS involves the rupture and dissection of arteries that, if unrecognized, can lead to a rapid death after bleeding into free spaces. Keywords Aneurysm; Aneurysm, False; Ehlers-Danlos Syndrome; Intestinal Perforation; Aneurysm, Dissecting.

CASE REPORT A 30-year-old man complained of left lower abdominal pain associated with nausea and vomiting. The medical history included aneurysms of the abdominal aorta and some of its branches, a surgically repaired pseudoaneurysm of the left subclavian artery, a

coil embolization of the superior ophthalmic vein, right and left cavernous sinuses and recent coil embolization of an aneurysm of the splenic artery. His father had also developed multiple aneurysms. Physical examination revealed tenderness with guarding of the

Mount Sinai Medical Center, AM Rywlin MD Department of Pathology and Laboratory Medicine. Miami Beach, FL, United States of America. Florida International University, Herbert Wertheim College of Medicine. Miami, FL, United States of America.

Spontaneous perforation of small intestine followed by rupture of the cystic artery: the natural history of Vascular Ehlers-Danlos Syndrome

lower abdomen. Laboratory results on admission were relevant for normal hemoglobin (15.1 g/dL, reference range [RR]; 12,16 g/dL) and a white blood cell count of 8,800 cells/mm3 (RR; 4,800-10,800/mm3) with 84.2% neutrophils. An abdominal CT scan revealed ascites and changes consistent with prior aneurysms. In a repeat CT, there was a right pleural effusion and nonspecific enteritis involving small bowel loops in the left abdomen and descending colon. The clinical diagnosis was an intestinal obstruction, which improved after the placement of a nasogastric tube. On hospitalization day 7, the patient remained in stable condition with normal hematologic and clinical chemistry parameters; however, an abdominal X-ray still showed persistent dilation of small bowel loops. General and vascular surgery recommended medical management. On hospitalization day 11, he developed fever and leukocytosis associated with a sudden drop in hemoglobin to 6.5 g/dL. Right thoracentesis collected hazy pleural fluid. Later that night, the patient

developed respiratory distress and increased abdominal pain, and expired.

AUTOPSY PRESENTATION The postmortem period was 24 hours. On external examination, the skin was pale and elastic. There were widened atrophic scars in the left paratracheal and supraclavicular regions from prior surgical procedures. There were no apparent deformities of the axial or appendicular skeleton. On internal examination, there were bilateral serous pleural effusions (right, 150 mL; left, 50 mL). The visceral pleura exhibited numerous fibrous adhesions to the chest wall and pericardium, bilaterally. The pericardial sac was dry. There was hemoperitoneum, 900 mL of blood and 910 mL of clots. Fibrous and fibrinous adhesions between loops of small intestine and abdominal wall were present in the lower abdominal cavity associated with a 5-cm area of serosal purulent exudate. There was a perforation of the small intestine (Figure 1).

Figure 1. Abdominal cavity, after lifting up the greater omentum, with evidence of intestinal perforation. A – Purulent exudate in small intestinal loops (black arrow) with adhesions, and hemoperitoneum (white asterisks); B – Extensive small bowel edema, purulent exudate, and focal hemorrhage of mesenteric fat. 2-8

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The remainder of the small and large intestines exhibited thin and translucent walls with loss of mucosal folds and reduced circumference. An area of fresh soft tissue hemorrhage tracked down to the gallbladder neck and hepatic hilum. Careful dissection

Figure 2. Rupture and dissection of the cystic artery. Note the soft tissue hemorrhage around the gallbladder neck (arrow). Bar: 1 cm.

and microscopic examination of the gallbladder neck revealed rupture and dissection of the cystic artery (Figure 2, 3 and 4). The pancreaticobiliary tree was unremarkable. The liver weighed 1010 g (RR; 1500-1800 g) and showed hepatocellular cholestasis, mild steatosis, and scattered glycogenated nuclei. There was also mild portal inflammation and mild siderosis on iron stains. The heart weighed 240 g (RR; 270-360 g) and showed thin atrial walls and a 2.5-centimeter subendocardial hemorrhage within the septal wall of the left ventricle consistent with resuscitation efforts. The coronary arteries displayed normal courses and no evidence of atherosclerosis or thrombosis. The infrarenal segment of the abdominal aorta exhibited a 4-cm pseudoaneurysm associated with a 2.3-cm intraluminal endothelialized band (Figure 5). The right common iliac artery was dilated, dissected and focally calcified, measuring 2.6 cm in diameter.

Figure 3. Photomicrograph of the cystic duct (one asterisk), and cystic artery (two asterisks) showing dilatation, rupture (black arrow), and a dissecting track with double lumen formation (white arrow), (Verhoeff’s stain, 25x).

Figure 4. Photomicrographs of the cystic artery. A – Disruption of the elastic lamina of the cystic artery at point of rupture with blood extravasation, (Verhoeff’s stain, 200x); B – Dissecting track between the arterial adventitia and media with double lumen formation. True lumen demarcated by the inner elastic lamina (one asterisk). False lumen located between the inner and outer elastic laminae (two asterisks) (Verhoeff’s stain, 200x). Autops Case Rep (São Paulo). 2019;9(1):e2018054

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Spontaneous perforation of small intestine followed by rupture of the cystic artery: the natural history of Vascular Ehlers-Danlos Syndrome

Figure 5. Pathology of the abdominal aorta and iliac arteries. A – Posteriorly opened abdominal aorta with aneurysm and an endothelialized intraluminal band (solid arrow), and dissection and dilation of the iliac arteries with calcifications and hemorrhage (dashed arrow). Composite H&E images of cross-section at the level of endothelialized intraluminal band (asterisk) showing a false lumen or dissecting track (continuous line), and a true lumen (discontinuous line), on the top right; B – Point of cleavage between the adventitia and media (arrow) adjacent to the endothelialized intraluminal band (asterisk) (Verhoeff’s stain, 50x); C – False lumen lined by fibrin and fibrous tissue devoid of elastin fibers, which are conserved in the inferior mesenteric artery (asterisk) (Verhoeff’s stain, 100x); D – Vascular wall delimiting the true lumen with preservation of elastic fibers of the medial layer and intimal thickening (Verhoeff’s stain, 100x). There were pseudoaneurysms of the left common and internal iliac arteries containing old thrombi, each measuring 2.3 cm in diameter. The left external iliac artery exhibited a 1.8 cm calcified pseudoaneurysm. A 1.1 cm coiled pseudoaneurysm was present in the splenic artery. Microscopic examination revealed evidence of prior dissection of the aorta and its distal terminal branches by elastin stains (Figure 5).

deposition, and focal acute inflammation. The left lung weighed 275 g (RR; 325-480 g) and appeared shrunken with atelectasis and congestion in the lower lobe. There was no evidence of pulmonary thromboemboli. The brain weighed 1530 g (RR; 1100-1700 g) and showed signs of mild hypoxic-ischemic damage as well as a focus of neuronal heterotopia in the hippocampus (Figure 6).

The thoracic aorta was unremarkable. The renal arteries exhibited intimal fibrosis and mild myxoid changes. The right renal artery measured approximately three times the size of the left renal artery.

Metallic coils were present in the cavernous sinuses, bilaterally. There was congestive splenomegaly (230 g (RR; 150-200 g)). The bone marrow was normocellular with trilineage hematopoiesis. The adrenal glands were lipid-depleted consistent with an acute stress reaction. The kidneys and other genitourinary organs were grossly and microscopically unremarkable. Postmortem cultures of the serosal

The right lung weighed 415 g (RR; 360-570 g) and showed atelectasis and congestion in the upper lobe. Microscopically, the right pleura appeared markedly thickened with granulation tissue, fibrosis, fibrin 4-8

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Figure 6. Photomicrograph of the hippocampus. Cornu Ammonis-1 (CA1) showing a focus of neuronal heterotopia in the stratum moleculare (dashed arrow) and red neurons in the hippocampal pyramidal layer (solid arrow) (H&E, 100x).

intestinal exudate were positive for Escherichia coli and Enterococcus species. Lung and blood cultures were negative. No toxicology tests were performed.

CLINICAL DISCUSSION The differential diagnosis of conditions causing pseudoaneurysms is complex. An aneurysm is defined as a localized permanent pathologic dilation of a vessel with a diameter at least 50% larger than the expected normal diameter of the vessel in question. While in a true aneurysm all vascular layers are present, a pseudoaneurysm (false aneurysm) is delineated by only adventitia, periadventitial connective tissue or healed fibrous tissue. Interestingly, pseudoaneurysms may form after rupturing of true aneurysms and even replace them.1 Elastin stains help differentiate both types by demonstrating elastic fibers in the medial layer, and outer and inner elastic laminae in arteries. The distinction is relevant for accurate pathologic diagnosis. Hypertension, atherosclerosis, and inflammatory aortitis are the leading etiologies of aortic aneurysms.2 In these conditions, pressure or ischemia-related injury and destruction of the vasa vasorum causes degenerative changes of components of the vascular wall leading to progressive dilation Autops Case Rep (São Paulo). 2019;9(1):e2018054

and increased risk of rupture. On the other hand, a spontaneous rupture with dissection is the most common mechanism for pseudoaneurysm formation. Hypertension accounts for approximately 90% of aortic dissections, especially in older men, while inherited or acquired connective tissue disorders are more common in younger patients.2 In the case described herein, a young adult man presented with spontaneous perforation of the small intestine that was followed by fatal dissection and rupture of the cystic artery. The phenotype of his vascular disease included bilateral spontaneous carotid-cavernous sinus fistulae and dissection with pseudoaneurysm formation of large- and medium‑sized arteries, predominantly the abdominal aorta and its branches. Because of his age, family history and the absence of conventional cardiovascular risk factors, an inherited disease is the most plausible explanation for his clinical presentation. Hereditary diseases involving dissecting pseudoaneurysms of the aorta include abnormalities in extracellular matrix proteins such as Marfan syndrome and Ehlers-Danlos syndrome (EDS), smooth muscle cytoskeleton proteins, components of the transforming growth factor (TGF)-beta(β) signaling pathway, and metabolic disorders such as Fabry disease, polycystic kidney disease among others. 5-8

Spontaneous perforation of small intestine followed by rupture of the cystic artery: the natural history of Vascular Ehlers-Danlos Syndrome

Craniofacial developmental malformations and some immunological derangements such as allergies and inflammatory bowel disease have also been associated with an increased risk of aortic dissection.3 The autopsy findings along with the family history are consistent with the natural history of vascular type EDS (VEDS) although no confirmatory genetic testing was performed. VEDS is caused by mutations in the COL3A1 gene and more rarely in COL1A1, which are inherited in an autosomal dominant pattern. According to the Ehlers-Danlos Society, the most recent 2017 international diagnostic criteria includes: 1) family history of VEDS with documented causative mutation in COL3A1; 2) arterial rupture at a young age; 3) spontaneous intestinal perforation in the absence of other bowel pathology; 4) uterine rupture in the absence of previous C-section; and 5) carotid-cavernous sinus fistula formation in the absence of trauma. 4 We identified four major criteria sufficient to diagnose VEDS. Minor criteria including thin translucent skin, characteristic facial appearance (thin face, large appearing eyes, thin lips, thin nose), acrogeria, hypermobility of small joints, tendon and muscle rupture, talipes equinovarus, early onset varicosities, and gingival recession are subjective and difficult to evaluate post-mortem. Because some forms of Loeys-Dietz syndrome, Marfan syndrome, and familial arterial aneurysm and dissection syndromes exhibit overlapping features with VEDS, a definitive diagnosis may require confirmation by gene sequencing, deletion/ duplication testing, or analysis of type III procollagen in cultures of fibroblasts. 4 Loeys-Dietz syndrome is caused by mutations in TGF-β pathway genes and is characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula. The primary features of the Marfan syndrome are eye abnormalities including dislocated lenses, bone overgrowth and laxity, and aortic enlargement. These defects were all absent in our patient. Moreover, the vascular damage observed in Marfan, as well as familial thoracic aortic aneurysm and dissection syndromes, are limited to heart and large vessels.5 Individuals with VEDS have significantly shortened life spans with a median survival of 48 years (range, 6 to 73 years) due to the spontaneous rupture of blood vessels and visceral organs.4 These complications are uncommon during childhood. The most common first and second complication is an arterial rupture, even 6-8

after a first gastrointestinal complication. The lethality after rupture of any artery tends to be higher if there is bleeding into a free space in comparison to bleeding into a confined space that may be sealed because of tamponade. Aneurysms of intra-abdominal visceral arteries are relatively uncommon in VEDS.6 There are reports of spontaneous rupture of the splenic, hepatic, superior mesenteric, pancreaticoduodenal, and renal arteries. 7 To our knowledge, this is the first report of spontaneous rupture of the cystic artery in VEDS. The genotype influences the distribution of arterial pathology.8,9 Missense and in-frame shift mutations lead to the production of a minimal amount of normal collagen (10-15%), while nonsense and frameshift mutations cause haploinsufficiency leading to a mild to moderate reduction of normal collagen (50%). In a cohort study, 68 individuals were classified into two groups based on the type of COL3A1 mutations and their effect on the amount of normal collagen.8 Patients with higher production of normal collagen presented with more aortic involvement and late onset of disease compared to patients with a severe decrease (56% vs. 21%). On the other hand, visceral arterial involvement and early onset of disease were more common in patients with a severe decrease in the production of normal collagen.9 Perforation, spontaneous or iatrogenic, of intraabdominal viscera, is the second most common complication in VEDS. The most frequent anatomical location is the sigmoid colon.4 However, perforation of small intestine often occurs secondary to diverticula. Intramural vascular rupture with hematoma formation increases the risk of necrosis of the intestinal wall, which also may lead to perforation. 10 Of note, perforation of the small intestine in our patient preceded the rupture of the cystic artery. Formation and expansion of aneurysms have been associated with inflammation and tissue degradation.11-13 It is possible that chronic or acute inflammatory events increase the risk of vessel rupture in VEDS; although, this needs to be confirmed. Unexpectedly, a focus of neuronal heterotopia was identified during routine microscopic examination of the hippocampus in association with neurons depicting hypoxic/ ischemic damage (i.e. “red dead neurons”) as shown in Figure 6. Of interest, central nervous system disorders and epilepsy can accompany EDS.14,15 Structural abnormalities of the central nervous Autops Case Rep (São Paulo). 2019;9(1):e2018054

Febres-Aldana CA, Castellano-Sanchez AA, Alexis J

system appear to be the cause of seizures. It has been suggested that seizures may originate in areas of heterotopic neurons. Abnormal neuronal positioning in VEDS can be related to defects in extracellular matrix and disruption in cellular adhesion affecting neuronal migration.14 There is no apparent correlation between the extent and severity of the neuronal heterotopia and frequency of seizures. Despite the presence of neuronal heterotopia, our patient did not have a history of epilepsy or seizures. Therefore, the significance of this finding is unknown and requires further investigation.

CONCLUSION In conclusion, we describe the case of a man with VEDS presenting with intestinal perforation followed by a lethal and spontaneous rupture of the cystic artery. Spontaneous rupture of vessels, mainly large- and medium-sized arteries, and internal organs are responsible for the high mortality seen in young people with VEDS. Patients with this rare collagen disorder may survive several vascular events that might be asymptomatic, leading to progressive destruction of vessel walls, aneurysm formation, rupture, and dissection. In many instances, the triggering factor for the vessel rupture is unknown, but herein we found that an intestinal perforation preceded it. This sequence of events can be explained by the inflammatory effects of sepsis leading to remodeling and weakening of vessel walls. The natural course of VEDS involves the rupture and dissection of arteries that can lead to immediate death if there is bleeding into free spaces.

REFERENCES 1. Nomura M, Mori K, Tamase A, et al. Pseudoaneurysm formation due to rupture of intracranial aneurysms: case series and literature review. Neuroradiol J. 2017;30(2):12937. http://dx.doi.org/10.1177/1971400916684667. PMid:28059632. 2. Hiratzka LF, Bakris GL, 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 Autops Case Rep (São Paulo). 2019;9(1):e2018054

Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. J Am Coll Cardiol. 2010;55(14):e27-129. http:// dx.doi.org/10.1016/j.jacc.2010.02.015. PMid:20359588. 3. Bradley TJ, Bowdin SC, Morel CF, Pyeritz RE. The expanding clinical spectrum of extracardiovascular and cardiovascular manifestations of heritable thoracic aortic aneurysm and dissection. Can J Cardiol. 2016;32(1):8699. http://dx.doi.org/10.1016/j.cjca.2015.11.007. PMid:26724513. 4. Byers PH, Belmont J, Black J, et al. Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet. 2017; 175( 1) : 40- 7. http://dx.doi.org/10.1002/ ajmg.c.31553. PMid:28306228. 5. Meester JAN, Verstraeten A, Schepers D, Alaerts M, Van Laer L, Loeys BL. Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and LoeysDietz syndrome. Ann Cardiothorac Surg. 2017;6(6):58294. http://dx.doi.org/10.21037/acs.2017.11.03. PMid:29270370. 6. Parfitt J, Chalmers RT, Wolfe JH. Visceral aneurysms in Ehlers-Danlos syndrome: case report and review of the literature. J Vasc Surg. 2000;31(6):1248-51. http://dx.doi. org/10.1067/mva.2000.105667. PMid:10842163. 7. Chadha M, Ahuja C. Visceral artery aneurysms: diagnosis and percutaneous management. Semin Intervent Radiol. 2009;26(3):196-206. http://dx.doi. org/10.1055/s-0029-1225670. PMid:21326564. 8. Shalhub S, Black JH 3rd, Cecchi AC, et al. Molecular diagnosis in vascular Ehlers-Danlos syndrome predicts pattern of arterial involvement and outcomes. J Vasc Surg. 2014;60(1):160-9. http://dx.doi.org/10.1016/j. jvs.2014.01.070. PMid:24650746. 9. Frank M, Albuisson J, Ranque B, et al. The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome. Eur J Hum Genet. 2015;23(12):1657-64. http://dx.doi.org/10.1038/ ejhg.2015.32. PMid:25758994. 10. Burcharth J, Rosenberg J. Gastrointestinal surgery and related complications in patients with Ehlers-Danlos syndrome: a systematic review. Dig Surg. 2012;29(4):34957. http://dx.doi.org/10.1159/000343738. PMid:23095510. 11. Torra R, Cases A, Trilla A, Ordi J, López J, Revert L. Fatal rupture of a mycotic aneurysm of the subclavian artery: an unusual complication of methicillin-resistant Staphylococcus-aureus-related sepsis. Nephrol Dial Transplant. 1994;9(1):114-5. PMid:8177470. 12. Morissette R, Schoenhoff F, Xu Z, et al. Transforming growth factor-β and inflammation in vascular (type IV) Ehlers-Danlos syndrome. Circ Cardiovasc 7-8

Spontaneous perforation of small intestine followed by rupture of the cystic artery: the natural history of Vascular Ehlers-Danlos Syndrome

Genet. 2014;7(1):80-8. http://dx.doi.org/10.1161/ CIRCGENETICS.113.000280. PMid:24399159. 13. Newby D, Forsythe R, McBride O, et al. Aortic wall inflammation predicts abdominal aortic aneurysm expansion, rupture, and need for surgical repair. Circulation. 2017;136(9):787-97. http://dx.doi. org/10.1161/CIRCULATIONAHA.117.028433. PMid:28720724.

14. Verrotti A, Monacelli D, Castagnino M, Villa MP, Parisi P. Ehlers-Danlos syndrome: a cause of epilepsy and periventricular heterotopia. Seizure. 2014;23(10):81924. http://dx.doi.org/10.1016/j.seizure.2014.07.014. PMid:25131162. 15. Cortini F, Villa C. Ehlers-Danlos syndromes and epilepsy: an updated review. Seizure. 2018;57:1-4. http://dx.doi. org/10.1016/j.seizure.2018.02.013. PMid:29499446.

Author contributions: Febres-Aldana CA performed the autopsy, designed and wrote the manuscript. Castellano-Sanchez AA performed the brain examination and drafted the manuscript. Alexis J supervised the autopsy performance, guided microscopic examinations, and drafted the manuscript. All authors collectively proofread and approved the manuscript for publication. Conflict of interest: None Financial support: None Submitted on: September 12th, 2018 Accepted on: September 27th, 2018 Correspondence Christopher Antonio Febres-Aldana AM Rywlin M.D. Department of Pathology and Laboratory Medicine - Mount Sinai Medical Center 4300 Alton Rd, 33140 – Miami Beach/FL – United States of America Phone: +1 (305) 674-2277 christopher.febres@msmc.com

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Article / Autopsy Case Report

Troisier sign and Virchow node: the anatomy and pathology of pulmonary adenocarcinoma metastasis to a supraclavicular lymph node Matthew J. Zdillaa,b,c , Ali M. Aldawoodb, Andrew Platab, Jeffrey A. Vosb, H. Wayne Lambertb  How to cite: Zdilla MJ, Aldawood AM, Plata A, Vos JA, Lambert HW. Troisier sign and Virchow node: the anatomy and pathology of pulmonary adenocarcinoma metastasis to a supraclavicular lymph node. Autops Case Rep [Internet]. 2019;9(1):e2018053. https://doi.org/10.4322/acr.2018.053

ABSTRACT Metastatic spread of cancer via the thoracic duct may lead to an enlargement of the left supraclavicular node, known as the Virchow node (VN), leading to an appreciable mass that can be recognized clinically — a Troisier sign. The VN is of profound clinical importance; however, there have been few studies of its regional anatomical relationships. Our report presents a case of a Troisier sign/VN discovered during cadaveric dissection in an individual whose cause of death was, reportedly, chronic obstructive pulmonary disease. The VN was found to arise from an antecedent pulmonary adenocarcinoma. Our report includes a regional study of the anatomy as well as relevant gross pathology and histopathology. Our anatomical findings suggest that the VN may contribute to vascular thoracic outlet syndrome as well as the brachial plexopathy of neurogenic thoracic outlet syndrome. Further, the VN has the potential to cause compression of the phrenic nerve, contributing to unilateral phrenic neuropathy and subsequent dyspnea. Recognition of the Troisier sign/VN is of great clinical importance. Similarly, an appreciation of the anatomy surrounding the VN, and the potential for the enlarged node to encroach on neurovascular structures, is also important in the study of a patient. The presence of a Troisier sign/VN should be assessed when thoracic outlet syndrome and phrenic neuropathy are suspected. Conversely, when a VN is identified, the possibility of concomitant or subsequent thoracic outlet syndrome and phrenic neuropathy should be considered. Keywords Anatomy; Lung Cancer; Metastasis; Supraclavicular Node; Virchow; Troisier; Thoracic Outlet Syndrome

INTRODUCTION The Troisier sign represents an enlargement of a left-sided supraclavicular lymph node. The enlarged supraclavicular lymph node is known as a Virchow node (VN), Troisier node, or Virchow-Troisier node. 1 The eponyms “Troisier” and “Virchow” acknowledge the individuals who identified the enlargement of

supraclavicular nodes as a clinical sign of gastric cancer metastasis in the mid-to-late 19th century.2,3 The VN has been well-established as a signal node for the spread of gastric cancer.4-9 In addition, the VN has been identified as a seeding location for cancers arising from myriad locations apart from

West Liberty University, Department of Natural Sciences & Mathematics and Graduate Health Sciences. West Liberty, West Virginia, USA. West Virginia University School of Medicine, Department of Pathology, Anatomy & Laboratory Medicine. Morgantown, West Virginia, USA. c West Liberty University, Department of Graduate Health Sciences. West Liberty, West Virginia, USA. a b

Troisier sign and Virchow node: the anatomy and pathology of pulmonary adenocarcinoma metastasis to a supraclavicular lymph node

the stomach, including the intestines, 7 urogenital system,10-18 esophagus,19 common bile duct,20 liver,21-23 as well as the pancreas,24,25 and lungs.26 The VN has also been reported with squamous cell carcinoma and lymphoma.16,27,28 Furthermore active tuberculosis has manifested as a VN.29 Even a hydatid cyst has been reported to masquerade as a classic VN.30 Because of its diverse etiology, the Virchow node holds clinical significance for many medical specialties. Outside of its role as a signal node, the VN may, itself, cause signs and symptoms from its mass effect; the VN may lead to Horner syndrome.31 Therefore, its regional anatomy holds particular clinical significance. Despite the clinical significance of the VN, only a few studies have been performed regarding its regional anatomical relationships. Our report describes a case of a VN discovered during cadaveric dissection and found to arise from an antecedent pulmonary adenocarcinoma. The report includes anatomical studies as well as relevant gross pathology and histopathology.

CASE REPORT An enlarged left-sided supraclavicular lymph node, or Virchow node (VN), was observed during neck dissection of a 68-year-old white female cadaver, whose cause of death was recorded as chronic obstructive pulmonary disease.

ANATOMIC DISSECTION Dissection revealed an enlarged left supraclavicular lymph node situated at the jugulo-subclavian venous junction (venous angle), a typical location for a VN (Figures 1 and 2). The VN, measured with a digital caliper (Mitutoyo 0-8 in (0-203.2mm) ABSOLUTE™ digimatic caliper series 500), was 3.7 × 2.4 × 1.4 cm. The VN was deep to the platysma and clavicular head of the sternocleidomastoid muscle, underlying what would otherwise be considered the lesser supraclavicular fossa (Figure 2). Also, the superior pole of the VN was under the inferior aspect of the superior omohyoid muscle at its attachment with its intermediate tendon (Figure 3). The VN was located immediately lateral to the internal jugular vein and, along with the thoracic duct, was located just superior to the subclavian vein (Figure 3). Underlying the VN was the phrenic nerve, transverse cervical artery, and anterior scalene muscle. The VN was resected and macroscopically assessed, revealing that the node was enlarged by tumor (Figure 4). Histological studies revealed evidence of neoplastic cells, with a high nuclear-to-cytoplasmic ratio and aberrant nuclei and nucleoli, embedded within residual lymphoid tissue. Intra- and extra-cellular mucin was also identified. The VN gross and histological appearance spurred further investigation in order to identify a

Figure 1. Dissection of the left-sided posterior cervical triangle revealed the presence of a Virchow node obscured entirely by the platysma and clavicular head of the sternocleidomastoid muscle and partly by the superior belly of the omohyoid muscle. A - Superficial dissection revealing the platysma muscle (Plat); B - The sternocleidomastoid muscle (SCM) underlying the reflected platysma. 2-7

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Zdilla MJ, Aldawood AM, Plata A, Vos JA, Lambert HW

primary tumor. The right and left lungs weighed 650 g and 690 g, and were 24.2 × 11.2 × 7.0 cm and 24.0 × 11.1 × 5.2 cm, respectively. The overlying pleura

Figure 2. Dissection of the left-sided posterior cervical triangle, after reflection of both the platysma and sternocleidomastoid muscles, revealed a Virchow node (VN) in the region of the lesser supraclavicular fossa.

was tan and smooth and showed scattered areas of environmental pigmentation. A 3.0 × 2.0 cm area of fibrinous exudate located in the hilar region of the left lung. Pleural puckering was not seen. The lungs were divided into lobes and serially sectioned from superior to inferior. The inferolateral right lower lobe contained a 4.6 × 5.0 × 2.1 cm area of dark-red indurated hemorrhagic consolidation. In the left lung, the hilum of the upper lobe had a 4.0 × 3.5 × 3.0 cm area of environmental pigmentation and necrotic pale rubbery lymph nodes ranging from 0.8 to 1.2 cm, with areas of white friable material. In the left lower lobe, a 4.2 × 4.0 × 3.5 cm white, indurated mass encased the adjacent vasculature and abutted the hilum (Figure 5). The uninvolved parenchyma was tan with widened alveolar spaces. Comparison of the histopathology of the VN and the parahilar mass revealed marked similarities (Figure 6), indicative of a primary parahilar adenocarcinoma metastatic to the left supraclavicular VN.

CLINICAL DISCUSSION The Troisier sign/Virchow node (VN) has profound clinical importance. Though reports have described the VN in many clinical settings, a paucity of reports have described cadaveric analysis including gross and histopathological analysis of both the primary tumor site and the VN. Mizutani et al.32 performed a study of the end node of the thoracic duct, which would be deemed a VN if enlarged due to metastasis. Their study identified the presence of the end node in 5 of 35 individuals (14%; two males and three females of a sample of Figure 3. Gross dissection of the left-sided lower anterior cervical region revealing a Virchow node (VN). The node was partially obscured at its superior pole by the superior belly of the omohyoid muscle (Sup Omo m) which has been retracted in this image. The node joined the thoracic duct (TD) which joined together with the internal jugular vein (Int Jug v) to contribute to the subclavian vein (Subclav v). The platysma and sternocleidomastoid muscles are reflected posteriorly and proximal half of the clavicle was resected to reveal the Virchow node and its surrounding vascular anatomy. The long axis of the VN was oriented parallel to the internal jugular vein and the distal thoracic duct. Autops Case Rep (São Paulo). 2019;9(1):e2018053

Figure 4. Serial sections of the Virchow node. The cut surfaces are almost entirely replaced by a grossly evident metastatic tumor. 3-7

Troisier sign and Virchow node: the anatomy and pathology of pulmonary adenocarcinoma metastasis to a supraclavicular lymph node

15 males and 20 females). Of the five end nodes, two were tethered to the dorsal aspect of the carotid sheath and three were located anterior to the anterior scalene muscle. The VN in our case was anterior to the anterior scalene muscle, which is the normal location of the end node of the thoracic duct.32 For reference, an in vivo clinical image of a VN of similar size (3.0 x 2.5 cm) and location to that reported in this study has been presented by Siosaki and Souza.33

Figure 5. Transverse section of the lower lobe of the left lung showing a 4.2 × 4.0 × 3.5 cm solid, pale, indurated mass that encases the adjacent vasculature and abuts the hilum. The uninvolved parenchyma is tan with dilated air spaces and many areas of environmental pigmentation.

The VN described in this case was in close proximity to several anatomical structures that warrant discussion. For example, the anterior scalene was located posterior to the VN. Therefore, enlargement of the VN may compress the anterior scalene muscle. Because the anterior scalene forms the anterior boundary of the scalene triangle, through which the brachial plexus of nerves and the subclavian artery pass, enlargement of the VN may cause left-sided

Figure 6. Side-by-side histopathological comparison between the Virchow node and lung masses (Hematoxylin and eosin stain at 400X magnification) A & B - Virchow node sections revealing neoplastic cells embedded within residual lymphoid tissue. The cells have a high nuclear to cytoplasmic ratio and display marked bizarre nuclei with prominent macronucleoli. The neoplastic cells form mixed morphology consisting of glandular (A) and papillary (B) architecture. Intracellular as well as extracellular mucin is readily identified; C & D - Histological sections of the lung mass with morphologic findings that correspond with the characteristics found within the Virchow node, consistent with metastasis from the lung tumor. 4-7

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brachial plexopathy and decreased blood flow into the left upper extremity. Indeed, there have been several reports of brachial plexopathy as a result of compression by a tumor.34 Therefore, the VN should be considered as a cause of thoracic outlet syndrome – both neurogenic thoracic outlet syndrome and vascular thoracic outlet syndrome. This finding is particularly important with regard to individuals with chronic obstructive pulmonary disease (COPD), similar to the individual described in this report, because the forced breathing in COPD may contribute to scalene muscle hypertrophy, a narrow interscalene passage, and subsequent insult to the neurovascular bundle.35 The left phrenic nerve was located between the VN and the anterior scalene muscle. Therefore, enlargement of the Virchow node could encroach upon the left phrenic nerve, potentially contributing to unilateral phrenic neuropathy. Unilateral phrenic neuropathy may be entirely asymptomatic. However, it may cause weakness, of varied severity, to its ipsilateral hemidiaphragm. It is, therefore, important to consider the aforementioned anatomical relationship in the context of the individual presented in this case, whose cause of death was listed as chronic obstructive pulmonary disease but was determined to have pulmonary adenocarcinoma and increased alveolar dead space. Indeed, the VN compressing the phrenic nerve may have contributed to dyspnea in this individual. Hypothetically, if the VN were to develop from a metastasis of a Pancoast tumor, the encroachment upon the brachial plexus, subclavian artery, phrenic nerve, and, additionally, the cervical sympathetic chain, could be exacerbated by both the Pancoast tumor and VN.36 Indeed, the VN, even in the absence of a Pancoast tumor, has caused Horner syndrome.31

CONCLUSION Pulmonary adenocarcinoma, as well as several other forms of cancer, may metastasize through the thoracic duct and cause enlargement of a left supraclavicular lymph node. In addition to the importance of recognizing the enlargement of the lymph node as a sign of metastasis, it is important to regard the Virchow node (VN) as a potential source of neurovascular encroachment. As our report shows, the VN has the potential to contribute to varied Autops Case Rep (São Paulo). 2019;9(1):e2018053

neuropathies of the brachial plexus and phrenic nerve as well as compression of the subclavian artery and vascular thoracic outlet syndrome due to its anatomical location. Therefore, the presence of a Troisier sign/VN should be assessed when thoracic outlet syndrome and phrenic neuropathy are suspected. Conversely, when a VN is identified, the possibility of concomitant or subsequent thoracic outlet syndrome and phrenic neuropathy should be considered.

ACKNOWLEDGEMENTS Funding came from the NASA West Virginia Space Grant Consortium [NNX10AK62H]. The individual presented in this case willingly donated her body for the advancement of science. The authors would like to acknowledge the West Virginia Anatomical Board, who approved this research, and the WVU Human Gift Registry for providing the whole-body specimen. Most importantly, the authors would like to acknowledge the individual who donated her body for the advancement of science, without whom, this work would not have been possible. The cadaver was that of a woman who voluntarily donated her body for the advancement of science through the West Virginia University Human Gift Registry. The research was approved by the West Virginia Anatomical Board. REFERENCES 1. Morgenstern L. The Virchow-Troisier node: a historical note. Am J Surg. 1979;138(5):703. http://dx.doi. org/10.1016/0002-9610(79)90353-2. PMid:386813. 2. Virchow R. Zur Diagnose der Krebse in Unterleibe. Med Reform. 1848;45:248. 3. Troisier CE. L’adénopathie sus-claviculaire dans les cancers de l’abdomen. Arch Gen de Med. 1889;1:129-39; 297309. 4. Westreich R, Brower S, Lawson W. Primary lymph node malignant gastrinoma with metastasis to Virchow’s node: a case report. Otolaryngol Head Neck Surg. 2004;131(6):1027-8. http://dx.doi.org/10.1016/j. otohns.2004.03.017. PMid:15577814. 5. Sugawara H, Ichiki M, Sai K, et al. Noticeable clinical response to S-1/CDDP combination therapy for Virchow 5-7

Troisier sign and Virchow node: the anatomy and pathology of pulmonary adenocarcinoma metastasis to a supraclavicular lymph node

node recurrence after surgery for advanced gastric carcinoma with marked involvement of the esophagus report of a case. Gan To Kagaku Ryoho. 2009;36(5):8558. PMid:19461194. 6. Katayama M, Matsumoto H, Kanda T, et al. Complete histological response in advanced gastric cancer with Virchow’s node metastasis after chemotherapy including S-1/CDDP--report of a case. Gan To Kagaku Ryoho. 2010;37(11):2173-6. PMid:21084821. 7. Sundriyal D, Kumar N, Dubey SK, Walia M. Virchow’s node. BMJ Case Rep. 2013;2013(sep12 1):1-2. http:// dx.doi.org/10.1136/bcr-2013-200749. PMid:24031077. 8. Yoon EWT, Nishihara K. Virchow’s node together with an Irish node. Clin Case Rep. 2017;5(6):1046-7. http:// dx.doi.org/10.1002/ccr3.967. PMid:28588870. 9. Sato T, Mori M, Aoki J, Tanabe K. Pulmonary Tumor Thrombotic Microangiopathy due to Advanced Gastric Cancer with Virchow’s Node Metastasis. Int Heart J. 2018;59(2):443-7. http://dx.doi.org/10.1536/ihj.17-249. PMid:29503403. 10. Yamada Y, Honda N, Hayase Y, Senda H, Fukatsu H, Segawa A. Two cases of primary urethral carcinoma in females. Hinyokika Kiyo. 1983;29(8):941-5. PMid:6675444. 11. Cebesoy FB, Balatt O, Aydin A. Virchow’s node as a first manifestation of ovarian serous carcinoma: case report. Eur J Gynaecol Oncol. 2008;29(2):182-3. PMid:18459560. 12. Rahman M, Nakayama K, Rahman MT, Katagiri H, Ishibashi T, Miyazaki K. Enlarged Virchow’s node as an initial complaint of serous ovarian adenocarcinoma. Eur J Gynaecol Oncol. 2012;33(5):546-8. PMid:23185810. 13. Scott AF, Mohr DW, Ling H, Scharpf RB, Zhang P, Liptak GS. Characterization of the genomic architecture and mutational spectrum of a small cell prostate carcinoma. Genes (Basel). 2014;5(2):366-84. http:// dx.doi.org/10.3390/genes5020366. PMid:24823478. 14. Kemal Y, Kokcu A, Kefeli M, et al. Virchow’s node metastasis: an unusual presentation of ovarian cancer. Eur J Gynaecol Oncol. 2016;37(3):398-400. PMid:27352573. 15. Park EJ, Stroie FA, McArdle BJ, Psutka SP. Metastatic adenocarcinoma of the prostate presenting as supraclavicular and bulky generalized lymphadenopathy with a benign digital rectal exam. Urol Case Rep. 2017; 13: 128- 30. http://dx.doi.org/10.1016/j. eucr.2017.04.005. PMid:28567325. 16. Franzen A, Günzel T, Buchali A, Coordes A. Etiologic and differential diagnostic significance of tumor location in the supraclavicular fossa. Laryngoscope. 2018;128(3):646-50. http://dx.doi.org/10.1002/lary.26775. PMid:28727141. 17. de la Riva-Pérez PA, García-Gómez FJ, Buján-Lloret C, Calvo-Morón MC, Castro-Montaño J. Virchow Node 6-7

From Prostate Carcinoma by 18F-Choline PET/CT. Clin Nucl Med. 2018;43(4):271-2. PMid:29356745. 18. Werner RA, Andree C, Javadi MS, et al. A voice from the past: rediscovering the virchow node with prostatespecific membrane antigen-targeted 18F-DCFPyL positron emission tomography imaging. Urology. 2018;117:1821. http://dx.doi.org/10.1016/j.urology.2018.03.030. PMid:29626569. 19. Matono S, Fujita H, Sueyoshi S, Tanaka T, Yamana H, Shirouzu K. Long-term survival after three-field lymph-adenectomy for an adenocarcinoma in Barrett’s esophagus with metastasis to Virchow’s node. Jpn J Thorac Cardiovasc Surg. 2006;54(1):11-5. http://dx.doi. org/10.1007/BF02743777. PMid:16482930. 20. Ochiai T, Ikoma H, Inoue K, et al. Long-term survival of a patient with common bile duct cancer after Virchow’s node recurrence: Report of a case. Surg Today. 2011;41(10):1432-5. http://dx.doi.org/10.1007/s00595010-4447-1. PMid:21922372. 21. Mondal RK, Dutta A, Basu K, Chakraborti S. Virchows node: rare presentation of childhood hepatocellular carcinoma. Indian J Pediatr. 2005;72(2):177-8. http:// dx.doi.org/10.1007/BF02760707. PMid:15758545. 22. Selvasekaran R, Cherian JV, Venkataraman J. Metastasis of hepatocellular carcinoma to Virchow’s node: have the tumor cells gone astray? Hepatobiliary Pancreat Dis Int. 2007;6(6):650-2. PMid:18086635. 23. Loh KY, Yushak AW. Images in clinical medicine. Virchow’s node (Troisier’s sign). N Engl J Med. 2007;357(3):282. http://dx.doi.org/10.1056/NEJMicm063871. PMid:17634463. 24. Soto Iglesias S, Baltar Arias R, Vázquez Rodríguez S, et al. Virchow’s node as the form of onset of squamous cell carcinoma of the pancreas. Gastroenterol Hepatol. 2009;32(10):693-6. http://dx.doi.org/10.1016/j. gastrohep.2009.06.006. PMid:19748706. 25. Saif MW, Hotchkiss S, Brennan M, Kaley K. Pancreatic adenocarcinoma with supraclavicular lymph node metastasis: Is this the Virchow’s node? JOP. 2011;12(1):667, author reply 70. PMid:21206107. 26. Soussi G, Daboussi S, Mhamdi S, et al. Second lung malignancy and Richter syndrome in chronic lymphocytic leukemia: case report and literature review. Multidiscip Respir Med. 2017;12(1):24. http://dx.doi.org/10.1186/ s40248-017-0107-2. PMid:28975027. 27. Cervin JR, Silverman JF, Loggie BW, Geisinger KR. Virchow’s node revisited. Analysis with clinicopathologic correlation of 152 fine-needle aspiration biopsies of supraclavicular lymph nodes. Arch Pathol Lab Med. 1995;119(8):727-30. PMid:7646330. 28. Anastassiades CP, Poterucha TH. Virchow’s node, jaundice, and weight loss--lymphoma mimicking gastrointestinal malignancy. Nat Clin Pract Gastroenterol Hepatol. 2006;3(11):645-8. http://dx.doi.org/10.1038/ ncpgasthep0635. PMid:17068502. Autops Case Rep (São Paulo). 2019;9(1):e2018053

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29. Levy Z, Schottland E. Active tuberculosis presenting as enlarged Virchow node in an otherwise well patient. Crit Care Med. 2018;46:501. http://dx.doi.org/10.1097/01. ccm.0000529041.92531.7e. 30. Duman U, Yeşıl C, Gündüz M, Den z IK. Isolated left supraclavicular hydatid cyst mimicking Virchow’s node. Turk J Gastroenterol. 2012;23(5):612-4. http://dx.doi. org/10.4318/tjg.2012.0447. PMid:23161314.

33. Siosaki MD, Souza AT. Images in clinical medicine. Virchow’s node. N Engl J Med. 2013;368(6):e7. http:// dx.doi.org/10.1056/NEJMicm1204740. PMid:23388028. 34. Sanghvi DA, Merchant N, Iyer VR. Malignant brachial plexopathy: a pictorial essay of MRI findings. Indian J Radiol Imaging. 2010;20(4):274-8. http://dx.doi. org/10.4103/0971-3026.73543. PMid:21423902.

31. Maslovsky I, Gefel D. Virchow’s node and Horner’s syndrome. Am J Med. 2006;119(2):180-1. http://dx.doi. org/10.1016/j.amjmed.2005.07.067. PMid:16443433.

35. Szaraz ZT. The thoracic outlet syndrome: first rib subluxation syndrome. In: Gatterman MI, editor. Foundations of chiropractic: subluxation. St. Louis, Missouri: Elsevier Health Sciences; 2005. p. 461.

32. Mizutani M, Nawata S, Hirai I, Murakami G, Kimura W. Anatomy and histology of Virchow’s node. Anat Sci Int. 2005;80(4):193-8. http://dx.doi.org/10.1111/j.1447073X.2005.00114.x. PMid:16333915.

36. Pancoast HK. Importance of careful roentgenray investigation of apical chest tumors. JAMA. 1924; 83( 18) : 1407. http://dx.doi.org/10.1001/ jama.1924.02660180025007.

Authors contributions: All authors collectively and equally contributed to the manuscript preparation. Similarly, all authors proofread and approved the manuscript’s final version for publication. Conflict of interest: None Financial support: NASA West Virginia Space Grant Consortium [NNX10AK62H] Submitted on: July 11th, 2018 Accepted on: October 2nd, 2018 Correspondence Matthew J. Zdilla Department of Natural Sciences and Mathematics - West Liberty University CSC 139, West Liberty - WV – United States of America, 26074 P.O. Box 295 Phone: +1 304-336-8631 / Fax: +1 304-336-8266 mzdilla@westliberty.edu

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Article / Clinical Case Report

Bullous systemic lupus erythematosus – a case report Eduardo Messias Hirano Padrãoa , Lucas Faria Teixeiraa , Celina Wakisaka Marutab, Valéria Aokib, Aloisio Souza Felipe da Silvac,d, Elizabeth In Myung Kime, Luciana Avena Smellie How to cite: Padrão EMH, Teixeira LF, Maruta CW, et al. Bullous systemic lupus erythematosus – a case report. Autops Case Rep [Internet]. 2019;9(1):e2018069. http://autopsyandcasereports.org/article/doi/10.4322/acr.2018.069

ABSTRACT Skin involvement in systemic lupus erythematosus (SLE) occurs in more than 75% of patients with this condition. Vesicles and blisters in lupus erythematosus (LE) may be present in SLE secondary to interface vacuolar changes in the epidermis, in discoid LE also secondary to vacuolar epidermal changes, and in bullous LE secondary to antibodies anti-collagen VII deposits with neutrophilic aggregates. In addition, blisters can occur due to the association of SLE with other autoimmune blistering diseases (e.g. bullous pemphigoid). BSLE is a rare blistering disease that mainly occurs in females (30–40 years old), and less frequently in children and adolescents. The most common presentation is rapid and widespread development of tense vesicles and bullae over erythematous macules or plaques. Preferential sites are: superior trunk, proximal superior limbs, and face (lips) with symmetrical distribution. Mucosal involvement is common on perioral, pharyngeal, laryngeal, and genital areas. The involvement of sun-exposed areas is not mandatory. The lesions usually progress with no scarring, but hypo or hyperchromia may be present. We report an 18-year-old female patient with blistering lesions at admission, who was diagnosed with BSLE. She was initially treated with systemic prednisone and hydroxychloroquine. Her condition evolved with relapsing lesions, which required the introduction of Dapsone. The authors emphasize the relevance of recognizing BSLE—a rare presentation of SLE—which may evolve with marked clinical presentation. Keywords Lupus Erythematosus, Systemic, Blister, Dapsone, Diagnosis, Therapeutics

INTRODUCTION Skin involvement in systemic lupus erythematosus (SLE) occurs in more than 75% of patients with this condition. Vesicles and blisters in SLE may be detected in three different conditions: (1) due to an interface vacuolar dermatitis; (2) due to the association of SLE with other autoimmune blistering diseases (e.g. bullous pemphigoid); and (3) due to an autoimmune blistering disease related to antibodies anti-collagen

VII. This last condition refers to bullous systemic lupus erythematous (BSLE). BSLE is a rare blistering disease that mainly occurs in females (3–40 years old), and less frequently in children and adolescents.1-2 The involvement of sun-exposed areas is not mandatory, and is marked by the rapid and widespread development of tense vesicles and bullae over erythematous macules or

Universidade de São Paulo, Medical School, Department of Internal Medicine. São Paulo, SP, Brazil. Universidade de São Paulo, Medical School, Department of Dermatology. São Paulo, SP, Brazil. c Universidade de São Paulo, University Hospital Pathology. São Paulo, SP, Brazil. d Universidade de São Paulo, Department of Pathology. São Paulo, SP, Brazil. e Universidade de São Paulo, Hospital Universitário, Department of Internal Medcine. São Paulo, SP, Brazil. a

Bullous systemic lupus erythematosus – a case report

plaques. Preferential sites are: superior trunk, proximal superior limbs, and face (lips) 3 with symmetrical distribution. Mucosal involvement is common on perioral, pharyngeal, laryngeal, and genital areas. The lesions usually progress with no scarring, but hypo or hyperchromia may be present.

CASE REPORT An 18-year-old female was hospitalized presenting slightly painful and pruritic vesicles and bullae on the face, oral mucosa, abdomen, thighs, and dorsum over the last 2 weeks. She also reported weight loss, migratory polyarthralgia with morning stiffness longer than 30 minutes, myalgia, fatigue, fever, alopecia, and malar rash associated with photosensitivity over the last 2 months. She was taking medroxyprogesterone acetate every 3 months as a contraceptive method. Her past medical history included a pregnancy at the age of 17, with low titers in the Venereal Disease Research Laboratory test, and a negative treponemal test. The admission clinical examination revealed a prostrated and pale patient, with normal vital signs. Skin findings showed the presence of a malar rash, and multiple tense vesicles and bullae varying from 1 mm to 6 cm, over erythematous macules and plaques (Figure 1). These lesions were present on the face, including eyelids, arms, abdomen, dorsum, and thighs. Involvement of the vermilion border of the lips and oral mucosa was present. No lymphadenopathy and

signs of arthritis were detected; the remaining physical examination revealed no alterations. BSLE was considered as the first hypothesis, followed by the differential diagnosis of other conditions, such as: epidermolysis bullosa acquisita, bullous pemphigoid, dermatitis herpetiformis, linear immunoglobulin (Ig)A bullous dermatosis, and drug eruption. General laboratory evaluation showed a complete blood cell count with pancytopenia hemoglobin levels of 11.0 g/dL (reference range [RR]: 12.3–15.3 g/dL), leukocytes of 2880 per mm3 (RR: 4.4–11.3 × 103/mm3) and platelet count of 105,000 per mm3 (RR: 150–400 × 103 /mm3). The direct Coombs assay was positive, but lactate dehydrogenase and bilirubin were at normal levels. Urinalysis revealed the presence of proteinuria, hematuria, and leukocyturia, with no casts. The spot urine protein/creatinine ratio was 856 mg/g (RR: < 300 mg/g). Renal function was preserved (creatinine of 0.63 mg/dL [RR: 0.4–1.3 mg/dL] and urea of 15 mg/dL [RR: 5–25 mg/dL]). Complement was at low levels, C3 < 21 mg/dL (RR: 67–149 mg/ dL) and C4 = 7 mg/dL (RR: 10–38mg/dL); anti-nuclear antibody was positive (1/640) with a homogeneous nuclear pattern, anti‑double-stranded DNA and antihistone were positive. Skin histopathology revealed subepidermal cleavage with a neutrophilic inflammatory infiltrate (Figure 2). Direct immunofluorescence (DIF) showed positivity for IgG at the basement membrane zone (BMZ) in a linear pattern (Figure 3A). Salt-split skin indirect immunofluorescence showed the presence of IgG deposits at the dermal side of cleavage (negative for IgA and IgM) (Figure 3B). ELISA was positive for antibodies against type VII collagen. The clinical and laboratory findings confirmed the diagnosis of BSLE.

Figure 1. BSLE. Arciform and linear tense bullae of varying sizes over erythematous macules and plaques on abdomen, thighs (A) and dorsum (B). BSLE = bullous systemic lupus erythematous. 2-6

The patient was treated with oral prednisone 1 mg/kg/d along with hydroxychloroquine 400 mg/d 5 days per week. Skin lesions and other SLE symptoms markedly improved after 1 week of treatment and the patient was discharged. However, the skin lesions on the vermilion border of the lips, eyelids, forearms, dorsum, and thighs relapsed soon after, despite adherence to treatment. Hospitalization was necessary due to the extent of skin involvement and systemic symptoms. Dapsone 200 mg/d was added to the Autops Case Rep (São Paulo). 2019;9(1):e2018069

Padrão EMH, Maruta CW, Aoki V, Silva ASF, Teixeira LF

Figure 2. BSLE. Skin histopathology. A – Subepidermal cleavage with neutrophils. The inflammatory cells are disposed along the papillary dermis; B – Subepidermal cleavage partially filled with neutrophils; C – Subepidermal blister with neutrophils and inflammatory cells at the periphery of the bulla; D – Neutrophils are present in the superficial dermis. Note the thickening of the basement membrane. (H&E, A:100X; B, C, and D: 400X). BSLE = bullous systemic lupus erythematous.

Figure 3. A – Direct immunofluorescence shows homogenous IgG deposit at the basement membrane zone (400X); B – Indirect immunofluorescence (salt-split skin), human foreskin substrate: IgG deposits at the dermal side of the split (400X). Autops Case Rep (São Paulo). 2019;9(1):e2018069

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Bullous systemic lupus erythematosus – a case report

Table 1. Modified diagnostic criteria for BSLE21 1- Diagnosis of SLE according to the American College of Rheumatology 2- Vesicles and bullae arising upon but not limited to sun-exposed skin 3- Histopathology consistent with DH 4- Negative or positive indirect IF for circulating BMZ antibodies using separated skin as the substrate 5- DIF of lesional and non-lesional skin revealing linear or granular IgG and/or IgM and often IgA at the BMZ; if there is a linear pattern of Ig deposition, immunoelectron microscopy should be done to demonstrate the immune reactants below the basal lamina BMZ = basement membrane zone; BSLE = bullous systemic lupus erythematosus; DH = dermatitis herpetiformis; DIF = direct immunofluorescence; IF = indirect immunofluorescence; Ig = immunoglobulin; SLE = systemic lupus erythematosus.

therapeutic regimen, with subsequent improvement of the clinical features. Hydroxychloroquine was withdrawn due to hemolysis.

DISCUSSION BSLE is a rare autoimmune blistering disorder that usually presents as tense bullae and/or vesicles in patients with a previously known or concurrent diagnosis of SLE. Due to the rarity of the disease, epidemiologic data are limited. A French study4 showed an incidence of bullous skin disorders (excluding bullous pemphigoid) of 3.4 cases per million per year. The occurrence of BSLE among children and adolescents with SLE is around 1%.2 Data on BSLE are scarce; therefore, the knowledge about the disease is mostly based on case reports or case series. BSLE patients usually present with clinical features of SLE. The blisters predominantly occur on the face, neck, upper extremities, oral mucosa, and vermilion border. Development of bullae is triggered by sun exposure. Bullous lesions are tense and heal with no scarring. 5-13 Mucosal involvement features include either blisters or painless ulcers. Esophagitis dissecans was reported.14 Differential diagnoses usually include other subepidermal bullous diseases such as bullous pemphigoid (BP), epidermolysis bullosa acquisita (EBA), linear IgA bullous dermatosis, and dermatitis herpetiformis (DH).15 The histopathology of BSLE usually shows a subepidermal bullae with neutrophil-predominant inflammatory infiltrate below the bullae formation. The presence of micro abscesses in the dermal papillae is also frequent, which makes the histopathology features of BSLE very similar to DH.16 In BSLE, neutrophils tend to be in a dispersed arrangement (Figure 2C) and may extend into the papillary dermal collagen (Figure 2D). 4-6

Deposits of mucin are often seen in the deep dermis.17 In counterpart, the neutrophilic infiltrate in DH is focal and localized at the papillary dermis. The immunopathologic findings in BSLE include: direct immunofluorescence with linear IgG deposits at BMZ, and occasional granular IgA, IgM, and C3 deposits.17 Salt-split skin indirect immunofluorescence reveals IgG deposition at the dermal side of cleavage, and is a helpful tool for BSLE. 13 The presence of autoantibodies against type VII collagen may be detected in patients with BSLE.18,19 Camisa and Sharma20 were the first authors to establish diagnostic criteria for BSLE. In 1988, with the use of immunofluorescence, these diagnostic criteria were reviewed and are shown in Table 1.21,22 The current therapeutic regimens for BSLE are based on the pathogenesis of the disease, case‑reports, and case-series. Dapsone is used as first-line therapy 6,11,23-25 along with glucocorticoids and immunosuppressants. Other therapeutic options include mycophenolate mofetil5,7,13,26 methotrexate,27 rituximab, 28 hydroxychloroquine and intravenous immunoglobulin.8

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Padrão EMH, Maruta CW, Aoki V, Silva ASF, Teixeira LF

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Author contributions: All authors have significantly contributed, and are in agreement with the content of the manuscript for publication. The authors retain an Informed Consent signed by the patient, and the manuscript was approved by the Institutional Ethics Committee. Conflict of interest: None Financial support: None Submitted on: November 29th, 2018 Accepted on: December 08th, 2018 Correspondence Eduardo Messias Hirano Padrão Rua Leonardo Motta, 100, Apto 92 – Vila Indiana – São Paulo/SP – Brazil CEP: 05586-090 Phone: +55 (11) 97547-3987 padraoedu@gmail.com

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Autops Case Rep (São Paulo). 2019;9(1):e2018069

Article / Clinical Case Report

Early intestinal obstruction after infliximab therapy in Crohn’s disease Mitsuro Chibaa , Yuichi Tanakab, Iwao Onoc  How to cite: Chiba M, Tanaka Y, Ono I. Early intestinal obstruction after infliximab therapy in Crohn’s disease. Autops Case Rep [Internet]. 2019;9(1):e2018068. https://doi.org/10.4322/acr.2018.068

Abstract There is scarce knowledge on early intestinal obstruction in Crohn’s disease (CD) after infliximab treatment. Therefore, we describe two cases of early intestinal obstruction in a series of 46 CD patients treated with infliximab. Both our two cases were 21-year-old men with newly diagnosed CD who were diagnosed with perianal disease 2 years previously. They were suffering from diarrhea and abdominal pain, but there were no symptoms indicating bowel obstruction. Radiographic studies revealed stenotic sites in the terminal ileum in both cases. In both cases, infliximab 300 mg was infused, after which their abnormal laboratory data as well as symptoms such as diarrhea and abdominal pain clearly improved. However, on the 11th or 13th day post-treatment, they presented abdominal distension with air-fluid levels on imaging studies. Ileocolonic resection was performed in both cases. Early intestinal obstruction after infliximab therapy is characterized by initial improvement of the symptoms and the laboratory data, which is soon followed by clinical deterioration. This outcome indicates that infliximab is so swiftly effective that the healing process tapers the stenotic site, resulting in bowel obstruction. Thus, although unpleasant and severe, the obstruction cannot be considered as a side effect but rather a consequence of infliximab’s efficacy. CD patients with intestinal stricture, particularly the penetrating type with stricture, should be well informed about the risk of developing intestinal obstruction after infliximab therapy and the eventual need for surgical intervention. Keywords Infliximab; Ileus; Crohn’s Disease

INTRODUCTION Infliximab was the first monoclonal antibody biologic drug used to treat Crohn’s disease (CD), and it revolutionized therapeutic modalities for the disease. We consider inflammatory bowel disease to be a lifestyle disease mainly mediated by a westernized diet. 1 In this regard, we developed a plant-based diet as a countermeasure against the westernized diet. 1 We administered infliximab together with a plant‑based diet as first-line (IPF) therapy on an inpatient basis in 46 CD patients (A1 below

16 y: 6; A2 between 17 and 40 y: 33; A3 above 40 y: 7; L1 Ileal: 1; L2 Colonic: 13; L3 Ileocolonic 32; B1 Nonstricturing/nonpenetrating: 33; B2 Stricturing: 12; B3 Penetrating: 1; p perianal disease modifier: 33).2 Our plant-based diet was a lacto-ovo-vegetarian diet with fish once a week and meat every other week.1 Plant-based diets prevent chronic diseases and bring longevity. Therefore, they are recommended to the public.2 All patients achieved clinical remission by week 6 after the first infliximab infusion, except for two

Akita City Hospital, Division of Gastroenterology. Akita City, Japan. Nakadori General Hospital, Division of Surgery. Akita City, Japan. c Nakadori General Hospital, Division of Pathology. Akita City, Japan. a

Early intestinal obstruction after infliximab therapy in Crohn’s disease

patients who experienced obstruction within 2 weeks following the first infliximab infusion.2,3 Our protocol using infliximab 2 brought early improvement compared to the administration of adalimumab. 4 Mean Crohn’s Disease Activity Index (CDAI) scores were 314, 163, and 115 at baseline and weeks 1 and 2, respectively, for the infliximab group. 2 The scores for the adalimumab group were 313, 264, and 232, respectively.4 There have been brief statements or abstracts in the literature reporting early intestinal obstruction requiring surgical treatment after infliximab treatment in Crohn’s disease,5-7 but no precise reports are found.

CASE REPORT Case 1 A 21-year-old man was referred because of a perirectal abscess followed by right lower quadrant abdominal pain and diarrhea. The initial diagnostic workup revealed the cobblestone appearance of the mucosa and fissurings in the right colon (Figure 1), leading to a diagnosis of CD. At that time, his BMI was 19.8 after losing 6 kg in the previous 7 months. Physical examination was non-contributory, except for anal skin tags and a perianal fistula scar. Laboratory data revealed abnormalities consistent with CD (Table 1). Plain film of the abdomen showed an isolated air‑fluid level (Figure 2A), but he did not have symptoms indicating an intestinal obstruction. Therefore, routine examination and treatment for CD were performed.2 The patient received liquid infusion without meals during morphological studies to assess clinical types and intestinal stenosis. Enteroclysis revealed stenotic portions and longitudinal ulcers in the distal portion of the ileum (Figure 2C). On the 8th hospital day, infliximab 300 mg (Remicade 5 mg/kg; Centocor, Malvern, PA, USA) was infused.8 A plant-based diet1,2 (1700 kcal/day) was initiated on the day after the infusion. Laboratory data 1 week after the infusion showed apparent improvement (Table 1), and the patient felt better after the 1st infusion of infliximab. However, on the 13th day, he presented abdominal distension after the first infusion. Intestinal obstruction was diagnosed due to clear air-fluid levels on plain abdominal radiographs (Figure 2B). 2-8

Figure 1. Double-contrast barium enema of the colon showing inflammation of the ascending colon and the cecum. The bowel is narrowed at the lower portion of the ascending colon. Cobblestone appearance is seen in the upper portion of the ascending colon. Fissurings are indicated by arrows.

At this point, the erythrocyte sedimentation rate was further improved, but C-reactive protein (CRP) concentration was elevated (Table 1). The 2nd infusion8 was cancelled, and the patient underwent ileocolonic resection 2 weeks later. Critical stenosis was found in the terminal ileum at 40 cm from the ileocecal valve. Perioperative endoscopy did not reveal another stenotic site proximally. The resected specimen showed round ulcers at the proximal site and a longitudinal ulcer of approximately 30 cm (Figure 3). The pathological findings were consistent with CD, namely, non-caseating epithelioid cell granulomas. A registered dietitian designed dietary guidance on a plant-based diet before discharge, and he was prescribed mesalazine, 2.25 g/day. Autops Case Rep (São Paulo). 2019;9(1):e2018068

Chiba M, Tanaka Y, Ono I

Figure 2. Plain abdominal radiographs on admission (A) and 13 days after the first infusion of infliximab (B). Solitary air-fluid level is indicated by an arrow (A). Multiple air-fluid levels are seen (B); C – Picture of the enteroclysis. Two stenotic portions are observed in the distal part of the ileum (white arrows). At the sites of stenosis, white soft shadows are seen (hollowed arrows) indicating active ulcers. Pre-stenotic dilatation is not observed. Longitudinal ulcers are observed (arrowheads).

He was followed up every 8 weeks. Endoscopic remission was ascertained after 4 years of follow up, and medication was withdrawn 3 years later. The patient completed 13 years of follow-up, with normal laboratory tests, and no complications. His plant-based diet score,9 which evaluates adherence to the plant-based diet, was –2 before admission, Autops Case Rep (São Paulo). 2019;9(1):e2018068

followed by 38 and 20 out of 40 at 2 years and 9 years after discharge, respectively.

Case 2 A 21-year-old man was referred because of a long-lasting draining anal fistula, followed by diarrhea and abdominal pain. Colonoscopy revealed skipped 3-8

Early intestinal obstruction after infliximab therapy in Crohn’s disease

Table 1. Change in laboratory data after infliximab (IFX) treatment Case 1 Item

Normal range

Case 2

After IFX

Before IFX

1 week

After IFX

13 days

Before IFX

5 days

11 days

CRP

≤0.3 mg/dL

3.6

1.0

2.9

5.5

1.8

0.2

ESR

<15 mm/hr

13.8-17.5 g/dL

12.2

12.3

12.5

7.9

8.6

8.8

WBC

3900-8800/mm

7700

7800

4900

6000

3400

3600

Platelets

15.2-31.4x10 /mm

56.2

42.0

42.3

87.0

69.5

56.0

T. protein

6.7-8.2 g/dL

7.9

7.3

6.7

7.4

6.7

6.5

Albumin

3.8-5.2 mg/dL

4.0

3.7

2.8

3.1

T. cholesterol

110-220 mg/dL

147

139

120

124

110

α2-globulin

4.8-8.6%

13.7

10.5

10.1

14.0

12.1

10.2

FOB

<200 ng/mL

153

n.a.

211

154

820

377

183

115

CDAI

n.a.

CDAI = Crohn disease activity index; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; FOB = fecal occult blood; Hb = hemoglobin; IFX; infliximab; n.a. = not available; T. cholesterol = Total cholesterol; T. protein = total protein; WBC = white blood cells.

the descending colon (Figure 4A). He was diagnosed as having CD. After losing 10 kg over the last 4 months, his BMI was 18.9. The physical examination was unremarkable, except for an anal fistula. Laboratory data revealed an elevated CRP concentration, marked anemia, and moderate hypoalbuminemia (Table 1). Plain film of the abdomen was unremarkable, however, enteroclysis revealed entero-enteric fistulas and stenotic sites in the distal ileum (Figure 4B). On the 5th hospitalization day, 300 mg of infliximab was infused.

Figure 3. Gross examination of the resected specimen of case 1. Two round ulcers at the proximal site (arrowheads) and a longitudinal ulcer of 30 cm (arrows) are seen in the terminal ileum. Cobblestone appearance is seen in the ascending colon. The appendix (Ap) is swollen.

lesions in the colon and longitudinal ulcers in the sigmoid. Non-caseating epithelioid cell granuloma was found in the biopsy specimen. Barium enema study revealed shortening of the right colon, stenotic sites, fistulas in the terminal ileum (Figure 4), and a diffuse coarse mucosa from the sigmoid to the distal part of 4-8

A plant-based diet (800 kcal/day) was concomitantly started. Laboratory data 5 days after the infusion showed apparent improvement (Table 1). He felt better after the 1st infusion of infliximab. His caloric intake increased to 1100 kcal and then 1400 kcal/ day. However, he complained of abdominal distension and vomiting on the 11th day after the first infusion. Radiographic signs of intestinal obstruction were found (Figure 5A), and meals were withdrawn. At this point, CRP normalized and CDAI10 decreased from 377 to 115, which is considered to be remission (Table 1). The standard infliximab induction therapy8 proceeded to preserve the left colon. Colonoscopy after the 3rd infusion revealed endoscopic remission in the left colon including scars of the longitudinal ulcers in the sigmoid colon. Resumption of meals (800 kcal/day) resulted in Autops Case Rep (São Paulo). 2019;9(1):e2018068

Chiba M, Tanaka Y, Ono I

Figure 4. Double-contrast barium enema study. Entire picture of the colon (A) and enlarged picture of the ileocolic portion (B). A â&#x20AC;&#x201C; Shortening of the right colon is seen. Diffuse coarse mucosa from the sigmoid colon to the distal part of the descending colon is observed. B - Two stenotic sites in the terminal ileum are indicated by white arrows. There are two entero-enteric fistulas indicated by F. TC, transverse colon; AC, ascending colon; TI, terminal ileum; F, fistula.

Figure 5. Plain abdominal radiographs on the 11th day after the first infusion of infliximab (A) and the day following resumption of meals after the 3rd infliximab infusion (B). Air-fluid levels are indicated by arrows (A). Autops Case Rep (SĂŁo Paulo). 2019;9(1):e2018068

5-8

Early intestinal obstruction after infliximab therapy in Crohn’s disease

repetition of abdominal distension and air-fluid level on the following day (Figure 5B). He then underwent surgery. There were adhesions of the ileum and colon and ileocolonic fistulas (ileum‑ascending colon, ileum-sigmoid colon). He underwent ileo-right hemicolonic resection with side (the ileum) to side (the transverse colon) anastomosis and partial sigmoidectomy. The resected specimen showed longitudinal ulcers in the ileum and colon (Figure 6). Considering the signs of poor prognosis (penetrating type of CD, association of anal fistula, onset at a young age, and terminal ileal involvement),11-13 scheduled maintenance therapy with infliximab 14 was initiated. A few months later, although there were no symptoms, colonoscopy was performed because CRP had increased from 0.3 to 1.0 mg/dL and fecal occult blood test had deteriorated from 759 ng/mL to >1000 ng/mL. Endoscopic relapse, i.e., shallow circular ulceration at the site of anastomosis, was observed. Azathioprine (50 mg/day) was added to the therapeutic regimen. The patient has maintained clinical remission for nearly 6 years to the present (with 45 courses of infliximab). His CRP concentration was normal on six of seven occasions in the latest year,

and fecal occult blood tests were negative on all seven occasions. We plan to stop infliximab maintenance therapy when he achieves successive normal CRP concentrations and negative fecal occult blood tests for 2 years. His plant‑based diet score was 6 of 40 before admission and 24 of 40 at 27 months after discharge.

DISCUSSION Lichtenstein et al. 15 reported that infliximab therapy per se did not increase intestinal stenosis, stricture, or obstruction (SSOs) in CD. In their study, however, SSOs that did not necessitate surgery were included and the observation period extended to 1.8 years. There is no description of early development of obstruction necessitating surgery in their report.15 The intervals from infliximab infusion to development of an obstruction in our two cases were 11 and 13 days. In our cases, symptoms and laboratory data clearly improved after infliximab therapy (Table 1). The induction treatment with adalimumab did not obstruct any of the 97 patients with symptomatic small bowel stricture.16 Adalimumab was then switched to infliximab in 35 nonresponders. Eight out of these 35 patients subsequently required

Figure 6. Gross examination of the resected specimen of the case 2. The terminal ileum is fixed to the ascending colon by adhesion through fistulas. They were removed en bloc. Arrows indicate longitudinal ulcers (scar). 6-8

Autops Case Rep (São Paulo). 2019;9(1):e2018068

Chiba M, Tanaka Y, Ono I

intestinal resection. The exact timing of the resections is not described. 16 On the other hand, infliximab caused intestinal obstruction necessitating surgery in four of six patients with symptomatic small bowel stricture.17 Two patients underwent surgery 10 days after infliximab due to deterioration. The other two patients showed symptomatic relief first but deteriorated later, resulting in resection within 8 weeks after infliximab.17 Clinical improvement was achieved using infliximab in all 17 cases reported by Toy et al.6 and in all seven cases reported by Vasilopoulos et al.7 before obstructive symptoms appeared. Therefore, our observation together with others6,7,17 supports the interpretation that infliximab is so swiftly effective in healing ulcers18 that the healing process narrows, even more, the stenotic site, resulting in bowel obstruction. Early obstruction after infliximab administration cannot be categorized as a conventional side effect, but rather as an event due to the efficacy of infliximab. It is unlikely that the plant-based diet per se induced intestinal obstruction because the obstruction occurred in similar chronologic fashion in the absence of the plant-based diet.6,7,17 Considering that the early obstruction after infliximab administration was due to the efficacy of infliximab, IPF therapy was effective in all 46 cases.2 This supports our rationale of IPF therapy: infliximab as first-line treatment and incorporation of a plant‑based diet. 2 Immunomodulators were not needed for induction of remission in our IPF therapy. When biologics and/or immunomodulators should be withdrawn is an unsolved issue. 19 CD is relentless. The stable quiescent phase is ascertained by clinical remission and normal biomarkers (CRP, fecal occult blood). If these conditions last for 2 years and morphological remission is ascertained with endoscopy, we believe that relapse is unlikely to occur. Therefore, we withdraw infliximab first. If clinical course is uneventful for the next few years, then azathioprine is withdrawn. In the absence of signs of obstruction, stricture per se is no longer regarded as a contraindication for infliximab therapy.20,21 Indeed, no obstruction occurred after infliximab treatment in our 11-case series of patients with stricture.2 If bowel obstruction happens after infliximab therapy, it is surgically treated without any disadvantages due to infliximab use.22,23 Infliximab use may be an advantage in terms of improving the patient’s clinical condition because the obstruction Autops Case Rep (São Paulo). 2019;9(1):e2018068

will not occur if infliximab is ineffective.7 It is critical that CD patients with stricture, and particularly CD patients with the penetrating type like case 2 of this report, are fully informed about the risk of intestinal obstruction necessitating surgery prior to initiating infliximab therapy.

REFERENCES 1. Chiba M, Abe T, Tsuda H, et al. Lifestyle-related disease in Crohn’s disease: relapse prevention by a semi-vegetarian diet. World J Gastroenterol. 2010;16(20):2484-95. http:// dx.doi.org/10.3748/wjg.v16.i20.2484. PMid:20503448. 2. Chiba M, Tsuji T, Nakane K, et al. Induction with infliximab and a plant-based diet as first-line (IPF) therapy in Crohn disease: a single-group trial. Perm J. 2017;21(4):17-009. PMid:29035182. 3. Chiba M, Tsuji T, Nakane K, Ishii H, Komatsu M. How to avoid primary nonresponders to infliximab in Crohn’s disease. Inflamm Bowel Dis. 2017;23(11):E55-6. http://dx.doi.org/10.1097/MIB.0000000000001281. PMid:28991860. 4. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human antitumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology. 2006;130(2):323-33. http://dx.doi.org/10.1053/j. gastro.2005.11.030. PMID: 16472588. 5. D’Haens G, Van Deventer S, Van Hogezand R, et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology. 1999;116(5):1029-34. http://dx.doi.org/10.1016/S00165085(99)70005-3. PMid:10220494. 6. Toy LS, Scherl EJ, Kornbluth A, et al. Complete bowel obstruction following initial response to infliximab therapy for Crohn’s disease: a series of newly described complication. Gastroenterology. 2000;118:A569. 7. Vasilopoulos S, Kugathasan S, Saeian K, et al. Intestinal strictures complicating initially successful infliximab treatment for luminal Crohn’s disease. Am J Gastroenterol. 2000;95:2503. 8. Sandborn WJ, Hanauer SB. Infliximab in the treatment of Crohn’s disease: a user’s guide for clinicians. Am J Gastroenterol. 2002;97(12):2962-72. http:// dx.doi.org/10.1111/j.1572-0241.2002.07093.x. PMid:12492177. 9. Chiba M, Nakane K, Takayama Y, et al. Development and application of a plant-based diet scoring system for Japanese patients with inflammatory bowel disease. Perm J. 2016;20(4):62-8. PMid:27768566. 10. Hanauer SB, Sandborn W, Practice Parameters Committee of the American College of Gastroenterology. Management 7-8

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of Crohn’s disease in adults. Am J Gastroenterol. 2001;96(3):635-43. http://dx.doi.org/10.1111/j.15720241.2001.03671.x. PMid:11280528. 11. Greenstein AJ, Lachman P, Sachar DB, et al. Perforating and non-perforating indications for repeated operations in Crohn’s disease: evidence for two clinical forms. Gut. 1988;29(5):588-92. http://dx.doi.org/10.1136/ gut.29.5.588. PMid:3396946. 12. Beaugerie L, Seksik P, Nion-Larmurier I, Gendre JP, Cosnes J. Predictors of Crohn’s disease. Gastroenterology. 2006;130(3):650-6. http://dx.doi.org/10.1053/j. gastro.2005.12.019. PMid:16530505. 13. Solberg IC, Vatn MH, Høie O, et al. Clinical course in Crohn’s disease: results of a Norwegian populationbased ten-year follow-up study. Clin Gastroenterol Hepatol. 2007;5(12):1430-8. http://dx.doi.org/10.1016/j. cgh.2007.09.002. PMid:18054751. 14. Rutgeerts P, D’Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology. 1999;117(4):761-9. http://dx.doi. org/10.1016/S0016-5085(99)70332-X. PMid:10500056. 15. Lichtenstein GR, Olson A, Travers S, et al. Factors associated with the development of intestinal strictures or obstructions in patients with Crohn’s disease. Am J Gastroenterol. 2006;101(5):1030-8. http:// dx.doi.org/10.1111/j.1572-0241.2006.00463.x. PMid:16606351. 16. Bouhnik Y, Carbonnel F, Laharie D, et al. Efficacy of adalimumab in patients with Crohn’s disease and symptomatic small bowel stricture: a multicentre, prospective, observational cohort (CREOLE) study. Gut. 2018;67(1):53-60. http://dx.doi.org/10.1136/ gutjnl-2016-312581. PMid:28119352.

17. Louis E, Boverie J, Dewit O, Baert F, De Vos M, D’Haens G. Treatment of small bowel subocclusive Crohn’s disease with infliximab: an open pilot study. Acta Gastroenterol Belg. 2007;70(1):15-9. PMid:17619533. 18. Chiba M, Sugawara T, Tsuda H, Abe T, Tokairin T, Kashima Y. Esophageal ulcer in Crohn’s disease: disappearance in 1 week with infliximab. Inflamm Bowel Dis. 2009;15(8):1121-2. http://dx.doi.org/10.1002/ ibd.20769. PMid:18942761. 19. Torres J, Boyapati RK, Kennedy NA, Louis E, Colombel JF, Satsangi J. Systematic review of effects of withdrawal of immunomodulators or biologic agents from patients with inflammatory bowel disease. Gastroenterology. 2015;149(7):1716-30. http://dx.doi.org/10.1053/j. gastro.2015.08.055. PMid:26381892. 20. Sorrentino D. Role of biologics and other therapies in stricturing Crohn’s disease: what have we learnt so far? Digestion. 2008;77(1):38-47. http://dx.doi. org/10.1159/000117306. PMid:18285676. 21. Pelletier AL, Kalisazan B, Wienckiewicz J, Bouarioua N, Soule JC. Infliximab treatment for symptomatic Crohn’s disease strictures. Aliment Pharmacol Ther. 2009;29(3):279-85. http://dx.doi.org/10.1111/j.13652036.2008.03887.x. PMid:19035967. 22. Fumery M, Seksik P, Auzolle C, et al. Postoperative complications after ileocecal resection in Crohn’s disease: a prospective study from the REMIND Group. Am J Gastroenterol. 2017;112(2):337-45. http://dx.doi. org/10.1038/ajg.2016.541. PMid:27958285. 23. Kotze PG, Saab MP, Saab B, et al. Tumor necrosis factor alpha inhibitors did not influence postoperative morbidity after elective surgical resection in Crohn’s disease. Dig Dis Sci. 2017;62(2):456-64. http://dx.doi.org/10.1007/ s10620-016-4400-2. PMid:27933472.

Author contributions: Chiba M designed the study and wrote the manuscript. Tanaka Y performed surgery for intestinal obstruction and Ono I examined surgical specimens. All authors proofread and approved the manuscript for publication. The study ID number: UMIN000019061, UMIN000020335: Registration: http://www.umin.ac.jp Conflict of interest: None Financial support: None Submitted on: September 18th, 2018 Accepted on: November 11th, 2018 Correspondence Mitsuro Chiba Division of Gastroenterology, Akita City Hospital, 4-30 Matsuoka-machi, Kawamoto/Akita City, Japan 010-0933 Phone: +81 (18) 823-4171 mchiba@m2.gyao.ne.jp 8-8

Autops Case Rep (São Paulo). 2019;9(1):e2018068

Article/Clinical Case Report

Primary colonic liposarcomatosis: report of a case with review of literature Mahesh Sultaniaa, Dillip Mudulya, Shilpy Jhab, Madhabananda Kara, Suvradeep Mitrab How to cite: Sultania M, Muduly D, Jha S, Kar M, Mitra S. Primary colonic liposarcomatosis: report of a case with review of literature. Autops Case Rep [Internet]. 2019;9(1):e2018056. https://doi.org/10.4322/acr.2018.056

ABSTRACT The colon is a rare site of occurrence of liposarcoma, as either the primary site or by secondary involvement from a retroperitoneal liposarcoma. Liposarcomatosis denotes simultaneous occurrence of multiple liposarcomas. There are only 17 cases of primary colonic liposarcoma reported in the English literature—one of which was primary colonic liposarcomatosis. We depict the second case of primary colonic liposarcomatosis in a 57-year-old female who presented with abdominal swelling and pain. On exploratory laparotomy, two large masses were seen arising from the wall of the right colon along with multiple smaller masses attached to the colon. Right hemicolectomy with en bloc excision of the masses was performed along with hysterectomy and pelvic floor repair. Macroscopically, multiple exophytic masses and one endophytic mass were identified. The exophytic masses were of variable size and were found to hang from the colon by a thin pedicle simulating variable-sized appendices epiploicae. Histopathologically, the lesions showed the morphology of well-differentiated liposarcoma. This appears to be a case of primary colonic liposarcomatosis. There is only one other similar case reported in the English literature, to the best of our knowledge. Keywords Liposarcoma; Colonic Neoplasms; Proto-Oncogene Proteins c-mdm2

INTRODUCTION Liposarcoma is generally a slow growing, heterogeneous, locally aggressive tumor, which usually becomes symptomatic when the size of the tumor increases to a large extent. Histologically, liposarcoma is subdivided into well-differentiated, dedifferentiated, myxoid/round cell, or pleomorphic types.1 Rarely, the well-differentiated/dedifferentiated morphology can coexist with myxoid/round cell type or pleomorphic type.2 Liposarcomatosis is characterized by the synchronous presence of multiple liposarcomas. Liposarcoma generally occurs in the axial skeleton,

limbs, retroperitoneum (RP), and spermatic cord. Searching on PubMed and using the uniterms “primary colonic liposarcomatosis,” “primary colonic liposarcoma,” “colonic liposarcoma,” and “colon, liposarcoma,” we found 17 cases of primary colonic liposarcoma reported in the English literature. Most of the previously reported cases of primary colonic liposarcoma presented as solitary endoluminal masses arising from the submucosal adipocytes. However, only a few cases showed single large pedunculated exophytic masses.3 Primary colonic liposarcomatosis

All India Institute of Medical Sciences, Department of Surgical Oncology. Bhubaneswar, Orissa, India. All India Institute of Medical Sciences, Department of Pathology and Laboratory Medicine, Bhubaneswar, Orissa, India.

Primary colonic liposarcomatosis: report of a case with review of literature

is even rarer than liposarcoma, and only one case of primary colonic/mesenteric liposarcomatosis is described in the English literature.4 We describe a case of primary colonic liposarcomatosis where both endoluminal and exophytic growths were noted. Grossly and histomorpholgically, the exophytic growths appeared to arise from the appendices epiploicae with a spectrum of liposarcomatous transformation. Individual liposarcoma was well differentiated. We believe that this is the second case of primary colonic liposarcomatosis.

CASE REPORT A 57-year-old female presented with an abdominal swelling over the last 6 months, and pain during the last 2 months. She also had a prolapsed uterus, which was diagnosed 3 months ago. She had no co-morbidities. A history of radiation exposure or any previous surgery was absent. On examination, a large abdominopelvic lump was palpable, measuring about 25 cm in diameter. The lower border of the mass could not be felt. Routine investigations were within normal limits. The contrast-enhanced computed tomography (CECT) of the abdomen and pelvis scan showed a large abdominopelvic mass with homogeneous density and enhancement, predominantly on the right side, displacing the small bowel and urinary bladder to the left. The abdominal and pelvic CECT scan showed

a large abdominopelvic mass with homogeneous density and enhancement after contrast injection, predominantly on the right side, displacing the small bowel and the urinary bladder to the left. The CECT also showed multiple small lesions in the abdomen, with a large right iliac mass abutting the right iliac vessels (Figures 1A and 1B). There was no bowel or any other visceral infiltration. The imaging findings were consistent with the diagnosis of a retroperitoneal liposarcoma. On exploratory laparotomy, there was minimal free fluid in the abdominal cavity. A multilobulated soft tissue tumor measuring approximately 20 × 15 cm was seen arising probably from the mesentery or from the bowel wall of the right colon. Another mass measuring 8 × 6 cm was seen in the right iliac fossa abutting the iliac vessels (Figure 2). Multiple nodules of up to 3 cm were seen in the entire abdomen, and they appeared to be attached to the colon. The patient underwent a right hemicolectomy with en bloc excision of the mass, excision of right iliac fossa mass with hysterectomy and pelvic floor repair. The postoperative period was uneventful. The patient is currently doing well (3 months post-surgery) and is on regular follow-up. The excised mass was sent for histopathology. The right hemicolectomy specimen included part of the terminal ileum, the cecum, the appendix, the ascending colon, and the proximal part of the

Figure 1. Abdominal computed tomography (CT) (axial plane). A – An abdominopelvic mass (AM) occupying almost whole of the abdominal cavity. The small bowel (SB) is displaced to the left, while the right colon (RC) is abutted against the paracolic gutter; B – Pelvic CT (axial plane) showing right iliac vessels (arrow) adherent to the soft tissue mass. 2-9

Autops Case Rep (São Paulo). 2019;9(1):e2018056

Sultania M, Muduly D, Jha S, Kar M, Mitra S

Figure 2. Intraoperatively view of the mass possibly arising from the right colon mesentery or the bowel wall of the right colon. A – Distal ileum; B – Multilobulated soft tissue tumor; C – Transverse colon.

transverse colon. The respective lengths of the parts of bowel were 13.5 cm (terminal ileum), 5 cm (cecum), 8.5 cm (appendix) and 14 cm (rest of the colon). The same container contained the en bloc mass along with multiple separately lying nodules. The en bloc resected specimen showed multiple nodules and exophytic masses attached to and hanging from the colon. Most of the masses were found to hang by a tiny pedicle, simulating appendices epiploicae of variable size, while only a few appeared not to have any stalk. These nodules and masses ranged in size from 1 cm to 22.5 × 16.5 x 10 cm in its largest dimension. The cut surfaces of the smaller nodules were fatty and yellow with thin strands of fibrous septa dividing these nodules into fatty lobules. The thickness of the septa was greater in the larger nodules, and the even larger ones showed a grayish white and dominantly fibrous cut surface with only a few interspersed fat lobules. In places, the larger masses showed indentation/cleavage, and these areas appeared to be the zone of fusion of two or more adjacent exophytic masses, and the cut surfaces of such masses showed the same (Figure 3). It appeared to be the coalescence of multiple adjacent appendices. The largest nodules showed central myxoid areas and scattered calcific specks. All these masses appeared to arise from the appendices on gross morphology. In addition, the cecum showed a bulge measuring 2.4 × 0.8 × 0.6 cm, and on cutting Autops Case Rep (São Paulo). 2019;9(1):e2018056

Figure 3. Gross view of the specimen after formalin fixation with multiple fatty to solid gray pedunculated masses some of which appeared to arise from the coalescence of the smaller nodules (black arrowhead). Note the variable sizes of these pedunculated (exophytic masses) (white arrowheads); one mass was endophytic (black arrow) projecting within the cecal lumen. The white arrow highlights the ileocecal valve; the black star highlights the external aspect of the largest exophytic mass.

open showed a mass with a fibrofatty cut surface protruding into the cecum. No mucosal pathology was noted. The specimen was extensively sampled to demonstrate the pathology, and a spectrum of pathological changes was documented. The smallest nodules (both attached and freely floating) showed multiple lobules of mature adipocytes with thin fibrous septa. The larger the masses, the more the thickness, complexity, number of septa, and number of septal and atypical adipocytic cells and lipoblasts increased (Figures 4A-4C and 5). The large nodules showed only a few lobules of mature fat and dominantly fibrocollagenous areas, giving rise to a sclerosing pattern (Figure 5). The largest nodule showed well‑differentiated morphology with central areas of myxoid degeneration and atypical spindle cells in a myxoid matrix (Figure 6). The septal cells were moderate to highly pleomorphic, singly scattered, spindle-shaped with hyperchromatic nuclei, and inconspicuous to occasional prominent nucleoli and wispy eosinophilic cytoplasm (Figure 7A). Many of these cells displayed bizarre 3-9

Primary colonic liposarcomatosis: report of a case with review of literature

Figure 4. Photomicrographs of the appendices epiploicae of different size from smallest to the largest with gradual increase in the septal thickness and complexity (A-C), with the smallest one showing essentially normal morphology (A) and the larger one displaying thick septa (C).

Figure 5. The largest of the appendices showed a sclerosing phenotype with occasional lobules of fat (H&E, 100X). The hyperchromatic atypical stromal cells are evident.

Figure 6. The largest mass showed extensive myxoid stroma (H&E, 200X).

morphology, and giant cells and floret-like cells were also noted (Figure 7B). The larger nodules also showed atypical adipocytes with hyperchromatic nuclei and many scattered univacuolated and multivacuolated lipoblasts (Figure 7C). Mitotic figures were occasional (2–4/10 high-power field); necrosis was absent. Immunohistochemistry for MDM2 (Figure 7D) and S100 showed nuclear positivity in the atypical septal cells, lipoblasts, and many of the mature-looking adipocytes.

CD34, Desmin, SMA, and βcatenin were negative in the tumor cells. The cecal bulge showed an endoluminal liposarcoma arising within the submucosa and stretching the overlying mucosa. The remaining ileum, ileocecal valve, and the colon did not reveal any mucosal pathology. The diagnosis of well‑differentiated liposarcoma, adipocytic and sclerosing subtypes was rendered with the suspicion that the exophytic masses appeared to arise from the appendices epiploicae, which was consistent with the diagnosis

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Sultania M, Muduly D, Jha S, Kar M, Mitra S

Figure 7. Photomicrographs of the nodular mass. A and B – Thick septa separating the lobules of adipocytes. Note the septa with spindle-shaped singly scattered atypical stromal cells with hyperchromatic nuclei (H&E, 40X and 400X, respectively). C – Multivacuolated lipoblast (H&E, 400X). D – MDM2 immunohistochemistry showing strong nuclear positivity in the stromal cells as well as in the adipocytes (100X).

of liposarcomatosis. The spectrum of changes was mostly corroborated by the size of the mass with the larger mass showing thicker septa, fewer number of adipocytes, and an abundance of atypical septal cells, atypical-looking adipocytes, and lipoblasts. Only few of the smaller nodules showed a morphological pattern similar to large nodules in terms of septal thickness and complexity.

20% of all STS, and over 50% of RP sarcomas. 5 In contrast, primary colonic liposarcoma is a rare entity with only 17 cases reported in the English literature. Liposarcomatosis denotes the simultaneous presence of multiple liposarcomas, and there is only one case of primary colonic liposarcomatosis in the English literature.4 In contrast, multiple peritoneal implants following the removal of the primary tumor have been described by Turkoglu et al.6

DISCUSSION

The symptomatology of primary colonic liposarcomas depends on the location of the mass. Most of the previously described colonic liposarcomas were solitary. The endoluminal masses may present with features of obstruction (constipation), intussusception, or hematochezia. 4,7,8 In contrast,

Liposarcoma is a malignancy of fat cells. It commonly occurs in trunk, limbs, and RP. In fact, the most common variant of soft tissue sarcoma (STS) in the RP is the liposarcoma and accounts for Autops Case Rep (São Paulo). 2019;9(1):e2018056

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Primary colonic liposarcomatosis: report of a case with review of literature

abdominal pain and/or a lump in the abdomen are the usual presentations for exophytic masses similar to the index case.1,6 Dumbbell‑shaped masses can also occur.8 The abdomen and the RP are deep, expandable spaces; therefore, slow-growing tumors usually reveal signs and symptoms after a large extent of growth. The majority of these tumors present late after attaining a huge size and causing an increase in the abdominal girth, a palpable lump, or symptoms due to visceral compression. Anemia, diarrhea, and weight loss are the other clinical symptoms, and the former may be associated with sudden rupture and hemorrhage within the lesion, or mucosal ulceration.2,9 The only other previous case4 with liposarcomatosis presented with pain, constipation, and weight loss, and this case

had a dominant endoluminal mass; this is in contrast to our case, which presented with pain and swelling due to dominant exophytic masses. Most of the patients were middle-aged or older similar to the index case. However, Rudnicki et al.10 and Fernandes et al.7 have described two cases occurring in young individuals. Importantly, both these cases showed evidence of a predisposing/co-morbid condition in the form of metabolic syndrome and Crohn disease under medication (azathioprine).7,10 However, the case of Crohn disease did not show any disease activity at the time of surgery.7 Most of the colonic liposarcomas were reported to occur in the cecum or ascending colon similar to the index case, although both the descending colon and sigmoid also can be affected (see Table 1).

Table 1. Comparison of the reported cases of primary colonic liposarcoma Author

Age Sex

Origin

Clinical features

Site

Size (cm)

Histopathology

Outcome Death (2 years) Not reported Alive (6 months) Alive (2 years) Alive (1 year) Not reported Alive (6 months)

Wood et al. 11

USA

Pain, mass

Ileocecal valve

Myxoid

Parks et al. 12

Ireland

Pleomorphic

Italy

Ascending colon Cecum

Magro et al. 13

Discomfort, diarrhea, anemia, weight loss Intussusception, pain

Well differentiated

Chen et al. 14

USA

Pain, hematochezia

7.5

Well differentiated

Gutsu et al. 15

Moldova

Pain, mass

Myxoid

Shahidzadeh et al. 16

USA

Hematochezia

3.5

Well differentiated

Chaudhary et al. 17

India

Well differentiated

Jarboui et al. 18

Tunisia

Splenic flexure

Dedifferentiated

D’Annibale et al.4*

Italy

Pleomorphic

Korea

Mixed

Turkoglu et al.6

Turkey

Pain, mass

Dedifferentiated

Yaren et al.9

Turkey

Pain, diarrhea

Pleomorphic

Kito et al.8

Japan

Intussusception, pain

Dedifferentiated

Rudnicki et al.10

Poland

Well differentiated

Fernandes et al.7

Portugal

Sigmoid colon

3.5

Well differentiated

Chou & Chen3

China

Pain, constipation, flatulence Acute pain, prolapsed mass, hematochezia, constipation, tenesmus Mass

Hepatic flexure Ascending colon Transverse colon Ascending colon Ascending colon Sigmoid colon

5.2

Choi et al.2

Pain, mass, hematochezia, weight loss Pain, constipation, weight loss Pain, constipation, weight loss Pain, mass

Descending colon Ascending colon Hepatic flexure Descending colon

Myxoid

Sawayama et al.1

Japan

Asymptomatic

6.5

Present case 2018*

India

Pain, mass

Ascending colon Ascending colon Ascending colon

Well differentiated/ dedifferentiated Well differentiated and mixed

22.5

Alive (10 months) Death (2.5 years) Alive (2 years) Death (3 months) Alive (30 months) Not reported Not reported Alive (5 years) Death (14 months) Alive (1 year) Alive (3 months)

*Cases with liposarcomatosis. 6-9

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Sultania M, Muduly D, Jha S, Kar M, Mitra S

Histologically, liposarcoma can be subdivided into well-differentiated, dedifferentiated, myxoid/round cell, and pleomorphic subtypes. The well-differentiated liposarcoma/atypical lipomatous tumor can be further subdivided into adipocytic, sclerosing/spindle cell, and inflammatory subtypes. Choi et al. 2 had described a rare case of primary colonic liposarcoma with mixed histomorphology with a combination of well‑differentiated and myxoid features.2 The previous case of liposarcomatosis was histologically categorized as pleomorphic liposarcoma. 4 The index case was unique to show the presence of well-differentiated morphology in a case of liposarcomatosis. Our case showed numerous pedunculated exophytic masses attached to the colon, simulating variable-sized appendices epiploicae. Indeed, all such masses showed liposarcomatous changes on histopathology. The larger masses showed planes of cleavage between them with nodular cut surfaces, which prompted us to think that these masses could have arisen from the coalescence of the appendices. Moreover, our case showed the histomorphological spectrum of changes in these masses with the larger mass showing the increased thickness of the septa, fewer numerous adipocytes, and an abundance of atypical cells in the septa and the lipoblasts. We could not find any mention of such a phenomenon in the literature. This is possibly because we demonstrate only the second case of primary colonic liposarcomatosis. Our case represents multiple exophytic and single endophytic liposarcomas of the colon, and we are tempted to think that the exophytic masses had possibly arisen from the appendices epiploicae, based on their gross and histomorphological features. The natural behavior and outcome of STS are dependent on the age of the patient, anatomical site and depth, size, and resectability of the tumor, as well as histology, grade, nodal disease, and distant metastasis.19 Management of these tumors mandates a multidisciplinary approach ideally carried out at referral centers treating a high number of patients. The diagnostic investigation of choice is CECT scanning or magnetic resonance imaging (MRI) of the abdomen and pelvis.20,21 Imaging helps to identify the anatomical location of the tumor; its size and origin; the relationship to adjacent visceral and neurovascular structures; possible compression or invasion; and the presence of liver or lung metastases.21,22 Liposarcomas Autops Case Rep (São Paulo). 2019;9(1):e2018056

have a characteristic appearance on CT and MRI with a predominantly fatty component. Surgery is the mainstay of the treatment for primary colonic liposarcoma. Usually, an en bloc resection of the tumor is carried out with macroscopically negative margins. In most patients, location, density, and displacement, rather than the invasion of the adjacent organs, is diagnostic of the tumor and precludes the pre-treatment biopsy. However, in some patients, radiology may point towards different entities, such as lymphoma, neuroendocrine tumor, or gastrointestinal stromal tumor, which may necessitate a pre-treatment biopsy. In contrast to limb sarcomas, removal of the entire tumor in colonic liposarcoma/liposarcomatosis may not be achieved. As a consequence, disease recurrence and death may ensue. Adjuvant radiation therapy may constitute a valuable treatment option in order to improve local control, specifically with the involved margins or high-grade tumors. Chemosensitivity is determined by histological type and grade. Jones et al.23 investigated the response to chemotherapy in 88 patients with liposarcoma (43% located in the RP). They found a significantly higher response rate in myxoid liposarcoma compared to all other liposarcomas (48% vs. 18%, p = 0.012). The response rate was 25% in dedifferentiated liposarcomas, while none of the well-differentiated liposarcomas responded. Targeting MDM2 or CDK4 in well-differentiated liposarcoma and dedifferentiated liposarcoma has been of interest for several years.15 This may be a very promising approach, especially for advanced or unresectable well-differentiated and dedifferentiated liposarcomas.

CONCLUSION We describe a case of primary colonic liposarcomatosis. This appears to be the second such case in English literature. We also believe that this case is unique as most of the exophytic masses in the index case possibly arose from the appendices epiploicae. The extreme rarity of primary colonic liposarcoma/liposarcomatosis precludes the establishment of a standard management protocol in such cases. Further longitudinal studies are required in this regard. 7-9

Primary colonic liposarcomatosis: report of a case with review of literature

ACKNOWLEDGEMENTS We acknowledge both Dr. Kartik and Dr. Rasheeda, junior residents in the Department of Pathology for their help during the grossing of the specimen. REFERENCES 1. Sawayama H, Yoshida N, Miyamoto Y, et al. Primary colonic well-differentiated/dedifferentiated liposarcoma of the ascending colon: a case report. Surg Case Rep. 2017;3(1):96. http://dx.doi.org/10.1186/s40792-0170373-4. PMid:28856628. 2. Choi YY, Kim YJ, Jin SY. Primary liposarcoma of the ascending colon: a rare case of mixed type presenting as hemoperitoneum combined with other type of retroperitoneal liposarcoma. BMC Cancer. 2010;10(1):239. http://dx.doi.org/10.1186/1471-240710-239. PMid:20507577. 3. Chou CK, Chen ST. Computed tomography identification of an exophytic colonic liposarcoma. Radiol Case Rep. 2016;11(3):161-4. http://dx.doi.org/10.1016/j. radcr.2016.06.005. PMid:27594941. 4. D’Annibale M, Cosimelli M, Covello R, Stasi E. Liposarcoma of the colon presenting as an endoluminal mass. World J Surg Oncol. 2009;7(1):78. http://dx.doi. org/10.1186/1477-7819-7-78. PMid:19852822. 5. Dalal KM, Kattan MW, Antonescu CR, Brennan MF, Singer S. Subtype specific prognostic nomogram for patients with primary liposarcoma of the retroperitoneum, extremity, or trunk. Ann Surg. 2006;244(3):381-91. PMid:16926564. 6. Türkoğlu MA, Elpek GO, Dogru V, Calış H, Uçar A, Arıcı C. An unusual case of primary colonic dedifferentiated liposarcoma. Int J Surg Case Rep. 2014;5(1):8-11. http:// dx.doi.org/10.1016/j.ijscr.2013.10.013. PMid:24394854. 7. Fernandes SR, Rita Goncalves A, Lopes J, et al. Primary liposarcoma of the sigmoid presenting as colonic intussusception - A case report. Rev Esp Enferm Dig. 2016;108(9):591-4. PMid:26785977.

cases. Turk J Gastroenterol. 2014;25(3):314-8. http:// dx.doi.org/10.5152/tjg.2014.4010. PMid:25141322. 10. Rudnicki C, Romanowski M, Medrek-Socha M, StecMichalska K. The diagnosis of sigmoid liposarcoma in a young male with metabolic syndrome. J Clin Diagn Res. 2015;9(12):OD01-03. PMid:26816934. 11. Wood DL, Morgenstern L. Liposarcoma of the ileocecal valve: a case report. Mt Sinai J Med. 1989;56(1):62-4. PMid:2784186. 12. Parks RW, Mullan FJ, Kamel HM, Walsh MY, McKelvey ST. Liposarcoma of the colon. Ulster Med J. 1994;63(1):1113. PMid:8658985. 13. Magro G, Gurrera A, Di Cataldo A, Licata A, Vasquez E. Well-differentiated lipoma-like liposarcoma of the caecum. Histopathology. 2000;36(4):378-80. http://dx.doi.org/10.1046/j.1365-2559.2000.0855d.x. PMid:10841651. 14. Chen KT. Liposarcoma of the colon: a case report. Int J Surg Pathol. 2004;12(3):281-5. http://dx.doi. org/10.1177/106689690401200312. PMid:15306943. 15. Gutsu E, Ghidirim G, Gagauz I, Mishin I, Iakovleva I. Liposarcoma of the colon: a case report and review of literature. J Gastrointest Surg. 2006;10(5):6526. http://dx.doi.org/10.1016/j.gassur.2005.09.014. PMid:16773759. 16. Shahidzadeh R, Ponce CR, Lee JR, Chamberlain SM. Liposarcoma in a colonic polyp: case report and review of the literature. Dig Dis Sci. 2007;52(12):337780. http://dx.doi.org/10.1007/s10620-007-9806-4. PMid:17393311. 17. Chaudhary A, Arora R, Sharma A, Aggarwal S, Safaya R, Sharma S. Primary colonic liposarcoma causing colo-colic intusussception: a case report and review of literature. J Gastrointest Cancer. 2007;38(2-4):160-3. http://dx.doi. org/10.1007/s12029-008-9031-1. PMid:18972225. 18. Jarboui S, Moussi A, Jarraya H, et al. Primary dedifferentiated liposarcoma of the colon: a case report. Gastroenterol Clin Biol. 2009;33(10-11):1016-8. http:// dx.doi.org/10.1016/j.gcb.2008.11.014. PMid:19272723.

8. Kito Y, Fujii T, Nishiyama T, et al. Peduncular liposarcoma of the colon: a case report and literature review. J Gastrointest Cancer. 2014;45(Suppl. 1):248-51. http://dx.doi.org/10.1007/s12029-014-9647-2. PMid:25216753.

19. Lewis JJ, Leung D, Woodruff JM, Brennan MF. Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg. 1998;228(3):355-65. http:// dx.doi.org/10.1097/00000658-199809000-00008. PMid:9742918.

9. Yaren A, Degirmencioglu S, Calli Demirkan N, Gokcen Demiray A, Taskoylu B, Gokoz Dogu G. Primary mesenchymal tumors of the colon: a report of three

20. Thomas JM. Retroperitoneal sarcoma. Br J Surg. 2007;94(9):1057-8. http://dx.doi.org/10.1002/bjs.5967. PMid:17701955.

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21. Hughes TM, Spillane AJ. Imaging of soft tissue tumours. Br J Surg. 2000;87(3):259-60. http://dx.doi.org/10.1046/ j.1365-2168.2000.01412.x. PMid:10718790. 22. Hoffman A, Lazar AJ, Pollock RE, Lev D. New frontiers in the treatment of liposarcoma, a therapeutically resistant malignant cohort. Drug Resist Updat. 2011;14(1):52-

66. http://dx.doi.org/10.1016/j.drup.2010.11.001. PMid:21169051. 23. Jones RL, Fisher C, Al-Muderis O, Judson IR. Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur J Cancer. 2005;41(18):2853-60. http://dx.doi. org/10.1016/j.ejca.2005.07.023. PMid:16289617.

Author contributions: Mitra S., Jha S. and Sultania M. wrote the manuscript. Muduly D. and Kar M. performed the surgery. Mitra S. has reported the histopathology together with Jha S. All authors collectively proofread the manuscript and approved the final version for publication. The authors retain an informed consent. Conflict of interest: None Financial support: None Submitted on: August 12th, 2018 Accepted on: September 18th, 2018 Correspondence Dr. Suvradeep Mitra Department of Pathology and Lab Medicine Academic Block, 2nd Floor – AIIMS – Bhubaneswar/Orissa – Índia PIN: 751019 Phone: +919855663999 / Fax: +916742472215 sugreebm@gmail.com

Autops Case Rep (São Paulo). 2019;9(1):e2018056

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Article/Clinical Case Report

Tracheal stenosis due to endotracheal tube cuff hyperinflation: a preventable complication Márcio Teodoro da Costa Gaspara , Linda Ferreira Maximianob, Hélio Minamotoc, Jose Pinhata Otochb How to cite: Gaspar MTC, Maximiano LF, Minamoto H, Otoch JP. Tracheal stenosis due to endotracheal tube cuff hyperinflation: a preventable complication. Autops Case Rep [Internet]. 2019;9(1):e2018072. https://doi.org/10.4322/ acr.2018.072

ABSTRACT Endotracheal intubation injuries are rare, but may be devastating—mostly among the pediatric patients or when these occur in the distal trachea. Such complications typify a therapeutic challenge, which, besides requiring intellectual and technical resources, takes a long time to reach a resolution. The authors present the case of a 15-year-old girl admitted with an abnormal state of consciousness due to diabetic ketoacidosis. She was submitted to endotracheal intubation with hyperinflation of the tube cuff, which rendered tracheal necrosis and detachment of the tracheal mucosa, and consequent obstruction. Later, she developed scarring retraction and stenosis. The patient was successfully treated with an endotracheal prosthesis insertion. The aim of this report is to illustrate a preventable complication. Keywords Tracheal Stenosis; Intubation, Endotracheal; Prosthesis Implantation

INTRODUCTION Tracheal stenoses due to endotracheal intubation are rare and usually present a benign course. However, their treatment is complex and requires specialized evaluation. Endotracheal intubation is a procedure frequently necessary among severely ill patients, and may be performed by less-experienced physicians. In this setting, particularities of the procedure should be observed to avoid injuries while attempting to maintain the capillary pressure of the tracheal mucosa at around 20-40 mmHg. Exceeding tracheal cuff pressures will result in ischemic necrosis, which leads

to confluent mucosal ulceration, deep stromal necrosis, and perichondritis within 96 hours, and the chondritis will subsequently favor cartilage necrosis. The healing process of the extensive ulcers will cause stenosis due to fibrous tissue.1,2 The mechanisms of the airway injury associated with endotracheal intubation are (i) high pressure of the intubation tube cuff; (ii) tube support in the posterior commissure of the larynx; (iii) repetitive movement of the endotracheal tube causing mucosal injury; and (iv) repeated tracheal intubation. The tracheal tube

Clinica Multiperfil, General Surgery Service. Luanda, Angola. Universidade de São Paulo (USP), Hospital Universitário, Surgery Division. São Paulo, SP, Brazil. c Universidade de São Paulo (USP), Heart Institute, Thoracic Surgery Service. São Paulo, SP, Brazil. a

Tracheal stenosis due to endotracheal tube cuff hyperinflation: a preventable complication

(nasally or orally inserted) will always push the posterior larynx, which is where major mucosal injuries occur.3

CASE REPORT A 15-year-old girl was brought to the emergence care unit (ECU) because of acidosis and a decreased level of consciousness. She was diagnosed with type 1 diabetes with poor treatment adherence. She was referred to the intensive care unit (ICU) and was submitted to endotracheal intubation for 5 days. After 3 days of extubation, the patient showed respiratory distress due to stenosis of the trachea at the fourth tracheal ring, which was diagnosed by a nasofibroscopy. The cervical computed tomography (CT) study showed a segmental parietal concentric thickening of the trachea with 2 cm of craniocaudal extension associated with a marked luminal reduction at the T1 level directly below the thyroid gland (Figure 1A and 1B). The suspension videolaringoscopy evidenced ulcers in the lateral and posterior walls of the trachea, and necrosis of the mucosa at the fifth tracheal ring (Figure 2A). A complete resection of the necrotic tissue that measured 2 cm was undertaken. At the end of the procedure, the trachea resumed an almost normal caliber (Figure 2B). The histopathological examination of the surgical specimen was represented by tracheal necrosis (Figure 3).

The patient was discharged 3 days after the endoscopic necrosis resection. However, she returned to the ECU after 9 days, presenting severe respiratory distress due to upper airway obstruction, which required urgent fiberoptic bronchoscope-guided orotracheal intubation. A new rigid and eccentric stenosis was diagnosed (Figure 4A). In attempting the tracheal dilation with the bronchoscope, and with the intubation tube insertion, a rupture and laceration of the posterior pars membranacea of the trachea in its proximal stenotic portion occurred, with consequent pneumomediastinum, which was drained with a pigtail coupled to a Heimlich valve. The patient remained intubated for 24 hours and another suspended videolaringoscopy found a false path in the posterior tracheal wall measuring 4 cm, which extended 5 cm from the cricoid cartilage and 4 cm from the carina (Figure 4B). The lesion was better observed during positive pressure ventilation. An endoprosthesis (silicone Stening®) (Figure 5) was inserted along the whole extension of the tracheal injury fixed with polypropylene 3-0. Additionally, an upper digestive endoscopy was performed, which showed a Los Angeles-A esophagitis and biliary reflux. A control thoracic CT showed pneumomediastinum, a pneumothorax, extensive cervical subcutaneous emphysema, and a prosthesis surrounded by gas in the thoracocervical transition (Figure 6).

Figure 1. A – Cervical computed tomography (CT) – coronal plane; B – Thoracic CT – axial plane showing concentric stenosis of the trachea (arrows). 2-7

Autops Case Rep (São Paulo). 2019;9(1):e2018072

Gaspar MTC, Maximiano LF, Minamoto H, Otoch JP

Figure 2. Endoscopic view. A – Tracheal stenosis (white arrow) at the fourth tracheal ring and a narrow remaining lumen (black arrow); B – Post-resection of the necrotic tissue. Note the enlargement of the tracheal lumen.

Figure 3. Gross appearance of the surgical specimen represented by tracheal necrosis.

A Nissen-type anti-reflux valve was performed by laparoscopy 40 days after the last endoscopic procedure, due to the marked biliary reflux. The patient was discharged and has been kept on an outpatient Autops Case Rep (São Paulo). 2019;9(1):e2018072

clinic follow-up over the last year, with good control of the diabetes and with normal respiratory function. Surgery has been scheduled for the final tracheal injury correction. 3-7

Tracheal stenosis due to endotracheal tube cuff hyperinflation: a preventable complication

Figure 4. Endoscopic view. A – Scarring fibrotic stenosis 9 days after the exeresis of the necrotic tissue; B – Iatrogenic injury of the trachea with a false path (black arrow).

Figure 5. Endoscopic view of the silicon endoprosthesis placed along the entire tracheal lesion.

DISCUSSION The case presented herein illustrates a preventable complication of endotracheal intubation followed by a complex and troublesome treatment undertaken in a secondary hospital. This sort of complication is the 4-7

result of the invasive airway maneuvers developed in the 20th century and the survival of patients treated in ICUs.3 Several tutorials and programs have been developed to guide a safe endotracheal intubation for health professionals.4,5 However, despite all the care, Autops Case Rep (São Paulo). 2019;9(1):e2018072

Gaspar MTC, Maximiano LF, Minamoto H, Otoch JP

Figure 6. Thoracic computed tomography. A – Axial plane showing the endoprosthesis inserted in the trachea, and a posterior airspace corresponding to the traumatic false path (white arrow); B – Coronal plane showing the endoprosthesis placed in the middle third of the trachea (white arrow) surrounded by pneumomediastinum (arrowhead).

we still face such complications, mainly in pediatrics,6,7 A recent study8 evaluated the endotracheal intubation skill of 85 physicians from three different services: ICU, ECU, and pulmonology. This study concluded that the skill level was unsatisfactory, and that improvement in training was necessary to prevent complications. The diagnosis of laryngotracheal stenosis is suspected in the presence of (i) barking cough; (ii) hoarseness; (iii) inspiratory stridor; (iv) varying grades of respiratory dysfunction; (v) tachypnea; (vi) intercostal and suprasternal indrawing; (vii) shortness of breath; and (viii) agitation and imminent death sensation. Diagnosis is confirmed by imaging (CT, magnetic resonance imaging) and endoscopic examination. Although these methods are complementary, the latter could be performed when imaging methods are unavailable.9 Endoscopy should be avoided because the procedure, by itself, may worsen the original injury. Therefore, endoscopy should be reserved for therapeutic purposes. The treatment of choice for laryngotracheal stenosis is surgical; the reconstruction of the airway should be undertaken in centers with extensive experience. Nevertheless, it is associated with high rates of relapse.10 Alternative endoscopic treatments are being developed to treat surgical complications, to replace large operations, and to treat patients with high morbidity.11 Autops Case Rep (São Paulo). 2019;9(1):e2018072

Concerning endoscopic treatment, the use of tracheal prosthesis has been more used in specialized centers. Other options, such as endoscopic dilation, argon plasma coagulation, and laser therapy, are also available in some advanced centers. Since the number of patients with such endotracheal complications is increasing, other non-surgical therapeutic options are being developed. In this setting, spray cryotherapy has been used in a series of 26 patients with tracheal stenosis of diverse etiology with partial relief of symptoms, and without any substantial intraoperative or postoperative complications. It seems a safe adjunct therapy.12 We performed the treatment with suspension laryngoscopy; this was represented by the exeresis of the necrotic tissue followed by the insertion of the silicon prosthesis. Stents have been used since 1960s, and silicone ones have good efficacy and tolerance, with low costs and infrequent complications.13 Recent studies have confirmed its effectiveness.14 Technological development in the field of radiology enables new therapeutic aids for the treatment of tracheal stenosis. For example, Kuo et al.15 used CT images before 3D reconstruction to calculate the cross-sectional area and volume of the trachea to assist the physicians with the diagnosis and scheduling the treatment. 5-7

Tracheal stenosis due to endotracheal tube cuff hyperinflation: a preventable complication

In another approach, a group of Russian researchers suggest the use of biotechnology for the treatment and prevention of the stenoses with tissue auto transplant and tissue engineering (tissue culture), with promising short-term results.16,17 Our center has been following patients with tracheal stenosis for more than 20 years. During this period, our patients have been submitted to a suspension laryngoscopy to evaluate (i) the level and the grade of the stenosis; (ii) the need to insert a template to maintain steadiness during endoscopic dilation; and (iii) the need to perform a laryngofissure (cartilage graft with laryngeal molding). The patient with laryngeal stenosis often requires several interventions. We have also observed a frequent presence of biliary or acid reflux during the operative procedure. Even in the absence of dyspeptic symptoms, or the presence of an eventual interpretation of physiologic reflux, 18 we consider the possibility of reflux, which perpetuates the inflammatory process in the laryngotracheal region and postpones the possibility of tracheal decannulation. Therefore, many of our patients are submitted to impedanciometry and/or pH monitoring before a laryngoscopy is performed. If there is evidence of gastroesophageal reflux, it is treated surgically earlier. The incidence of recurrence of stenosis has been lower in the last 10 years, with successful decannulations. Much is said about the techniques to treat benign tracheal injuries. However, it seems that relieving this problem is much more difficult than preventing it. Therefore, we suggest that the entire health provider team involved with critical or potentially critical patients, maintains constant updating on airway management.

REFERENCES 1. Chagas AA Fo, Machado FS, Janiszewski M. Long-term post intubation tracheal stenosis. RBTI. 2005;17(1):40-3. 2. Sehgal IS, Dhooria S, Bal A, Aggarwal AN, Behera D, Agarwal R. Obstructive fibrinous tracheal pseudomembrane after endotracheal intubation. Respir Care. 2016;61(9):1260-6. http://dx.doi.org/10.4187/ respcare.04662. PMid:27247431. 3. Minamoto H, Terra RM, Cardoso PFG. Estenoses benignas da via aérea: tratamento endoscópico. Pulmão RJ. 2011;20(2):48-53. 6-7

4. Tucori LP. Traumas externos da laringe. In: Anais do 3º Congresso de Otorrinolaringologia da Universidade de São Paulo; 2002; São Paulo, Brazil. São Paulo: Fundação Otorrinolaringologia; 2002. 5. Tallo FS, Guimarães HP, Lopes RD, et al. Orotracheal intubation and rapid sequence technique: a review for the internist. Rev Bras Clin Med. 2011;9(3):211-7. 6. Sittel C. Pathologies of the larynx and trachea in childhood. GMS Curr Top Otorhinolaryngol Head Neck Surg. 2014;13:1-15. PMid:25587369. 7. Jefferson ND, Cohen AP, Rutter MJ. Subglottic stenosis. Semin Pediatr Surg. 2016;25(3):138-43. http://dx.doi.org/10.1053/j.sempedsurg.2016.02.006. PMid:27301599. 8. Yamanaka CS, Góis AFT, Vieira PCB, et al. Orotracheal intubation: physicians knowledge assessment and clinical practices in intensive care units. Rev Bras Ter Intensiva. 2010;22(2):103-11. http://dx.doi.org/10.1590/S0103507X2010000200002. PMid:25303750. 9. Parshin VD, Koroleva IM, Mishchenko MA. Evolution of diagnostic methods for cicatrical tracheal stenosis and tracheomalacia. Khirurgiia (Mosk). 2016;(5):1725. http://dx.doi.org/10.17116/hirurgia2016517-25. PMid:27271715. 10. Karapantzos I, Karapantzou C, Zarogoulidis P, Tsakiridis K, Charalampidis C. Benign tracheal stenosis a case report and up to date management. Ann Transl Med. 2016;4(22):451. http://dx.doi.org/10.21037/ atm.2016.11.18. PMid:27999785. 11. Amantéa SL, Silva APP. Clinical management of upper airway obstruction: epiglottitis and laryngotracheobronchitis. J Pediatr (Rio J). 1999;75(Suppl. 2):S177-84. http://dx.doi. org/10.2223/JPED.387. PMid:14685464. 12. Bhora FY, Ayub A, Forleiter CM, et al. Treatment of benign tracheal stenosis using endoluminal spray cryotherapy. JAMA Otolaryngol Head Neck Surg. 2016;142(11):10827. http://dx.doi.org/10.1001/jamaoto.2016.2018. PMid:27532803. 13. Ayub A, Al-Ayoubi AM, Bhora FY. Stents for airway strictures: selection and results. J Thorac Dis. 2017;9(Suppl 2):S116-21. http://dx.doi.org/10.21037/jtd.2017.01.56. PMid:28446974. 14. Terra RM, Bibas BJ, Minamoto H, et al. Decannulation in tracheal stenosis deemed inoperable is possible after longterm airway stenting. Ann Thorac Surg. 2013;95(2):4404. http://dx.doi.org/10.1016/j.athoracsur.2012.09.037. PMid:23201102. 15. Kuo CF, Leu YS, Kuo R, et al. Three-dimensional reconstruction of trachea using computed tomography imaging as therapy for tracheal stenosis in infants. Comput Methods Programs Biomed. 2016;132:17787. http://dx.doi.org/10.1016/j.cmpb.2016.04.027. PMid:27282237. Autops Case Rep (São Paulo). 2019;9(1):e2018072

Gaspar MTC, Maximiano LF, Minamoto H, Otoch JP

16. Kurgansky IS, Makhutov VN, Lepekhova SA. The methods for the treatment and prevention of cicatrix stenosis of trachea. Vestn Otorinolaringol 2016;81(1):66-71. PMid:27166482. 17. Jakobsen KK, Grønhøj C, Jensen DH, Fischer-Nielsen A, Hjuler T, von Buchwald C. Mesenchymal stem cell therapy for laryngotracheal stenosis: a systematic review of preclinical studies. PLoS One. 2017;12(9):3-

10. http://dx.doi.org/10.1371/journal.pone.0185283. PMid:28934345. 18. Guedes CC. Manifestações atípicas da doença do refluxo gastroesofágico [Internet]. [cited 2018 Nov 24]. Available from: http://abran.org.br/wp/wp-content/ uploads/2015/02/MANIFESTA%C3%87%C3%95ESAT%C3%8DPICAS-DA-DOEN%C3%87A-DOREFLUXO-GASTROESOF%C3%81GICO.pdf

Authors’ contributions: All authors contributed equally in the article’s preparation. Gaspar MTC wrote the manuscript and researched the literature. Maximiano LF performed the anti-reflux surgery. Minamoto H and Otoch JP performed the endotracheal procedures. All authors proofread and collectively approved the manuscript for publication. The authors retain the informed consent signed by the patient and have the approval of the Institutional Ethics committee. Conflict of interest: None Financial support: None Submitted on: April 6, 2018. Accepted on: October 8, 2018. Correspondence Márcio Teodoro da Costa Gaspar Clinica Multiperfil Rua Morro Bento, s/n – Samba – Luanda – Angola Phone: +244 923680961 marcio85gaspar@gmail.com

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Article / Clinical Case Report

Incidental diagnosis of breast cancer in the pursuit of the treatment of intestinal obstruction Isabel Armasa , Mariana Brandãob , Inês Guerreirob , João Loboc , Carla Freitasd , João Pinto-de-Sousad , Joaquim Abreu de Sousae  How to cite: Armas I, Brandão M, Guerreiro I, et al. Incidental diagnosis of breast cancer in the pursuit of the treatment of intestinal obstruction. Autops Case Rep [Internet]. 2019;9(1):e2018071. https://doi.org/10.4322/acr.2018.071

ABSTRACT Intestinal lipomatosis is rare and often asymptomatic but can present with intestinal obstruction. Occasionally, metastatic breast cancer is identified in the ovary before a breast primary is discovered. We report the case of a 50-year-old woman diagnosed with synchronous intestinal obstruction due to lipomatosis, and incidental ovarian metastases from breast cancer. The patient presented with a 12-day history of nausea, diffuse abdominal pain, and constipation. An abdominal x-ray showed air-fluid levels, and computed tomography documented small bowel distention. An explorative laparotomy was performed, which revealed small bowel distention, an obstructive lesion of the ileocecal valve, three terminal ileum lesions, ascites, and heterogeneous ovaries. Right ileocolic resection and left oophorectomy were performed. The pathological diagnosis revealed lipomatous submucosal lesion of the ileocecal valve and ileum, and 17 lymph nodes, which were all negative for malignant cells. The oophorectomy revealed ovarian metastasis from breast carcinoma. Ascitic fluid was positive for malignant cells. Mammography and breast/axillary ultrasonography showed a solid nodule of the left breast, ductal carcinoma, and multiple enlarged left axillary lymph nodes, which were positive for neoplastic cells. Immunohistochemical evaluation showed hormonal receptor positivity and C-erb2 negativity. Breast magnetic resonance imaging showed a 14 mm left nodule and a positron emission tomography scan revealed 18F-FDG uptake in the left breast, left axillary lymph nodes, right ovary, and peritoneum. The tumor was staged as stage IV ductal breast carcinoma, cT1N1M1, Grade 2, Luminal B-like. The multidisciplinary oncological meeting proposed chemotherapy, and a re-staging breast MRI after chemotherapy, which showed a complete response. The patient started treatment with letrozole and remains disease-free 22 months after finishing chemotherapy. Keywords Lipomatosis; Intestinal Obstruction; Breast Neoplasms; Neoplasm Metastasis; Ovary; Peritoneum

INTRODUCTION Diffuse intestinal submucosal lipomatosis is a sporadic condition with a few cases reported in the medical literature. 1 Usually, patients are

asymptomatic, but these lesions may present as perforation, obstruction, ulceration, intussusceptions or bleeding.2,3

Unidade Local de Saúde do Nordeste, General Surgery. Bragança, Portugal. Instituto Português de Oncologia do Porto, Medical Oncology. Porto, Portugal. c Instituto Português de Oncologia do Porto, Patology Department. Porto, Portugal. d Centro Hospitalar Tâmega e Sousa, General Surgery. Penafiel, Porto, Portugal. e Instituto Português de Oncologia do Porto, Surgical Oncology. Porto, Portugal. a

Incidental diagnosis of breast cancer in the pursuit of the treatment of intestinal obstruction

Breast cancer is the most common malignancy in women worldwide, and is one of the leading causes of death among women,4 with a reported incidence rate of 46.3% and a mortality rate of 13%.5 Metastatic breast cancer to the ovaries is not uncommon and represents 6-27.8% of all malignant ovarian tumors; however, it has been reported at autopsies in 50% of patients with breast cancer.6,7 Here, we report the case of a woman with synchronous intestinal lipomatosis that presented as an intestinal obstruction, and was revealed to be an incidental diagnosis of breast cancer metastatic to the ovary.

CASE REPORT A 50-year-old Caucasian woman presented to the emergency department with a 12-day history of nausea, diffuse abdominal pain, and constipation. She experienced menopause at the age of 42. Her past medical history included morbid obesity (BMI of 44 kg/m2), type 2 diabetes, arterial hypertension, hypercholesterolemia, and two cesarean sections. No relevant medical family history was informed. On physical examination, she presented a distended and tympanic abdomen, diffusely painful without guarding. The laboratory work-up showed a C-reactive protein of 29.9 mg/L (normal range <7.5 mg/L) with 13.1 × 103/μL leukocytes (normal range 4.5-11.0 × 103/μL), and a plain abdominal x-ray documented air-fluid levels.

Abdominal and pelvic contrast-enhanced computed tomography (CT) showed a minor small bowel distension without parietal enlargement, without a clear obstructive etiology, and with normal colon caliber. Conservative therapeutic measures for intestinal obstruction were unsuccessful; therefore, she underwent a laparotomy within 24 hours of admission. Surgical findings included an entire small bowel distention, an obstructive lesion of the ileocecal valve with retracting serosa and mesentery, three terminal ileum implants resembling carcinomatosis, moderate ascites, and heterogeneous ovaries. Accordingly, ileocolic resection and left oophorectomy were performed. Ascitic fluid was sent for cytologic evaluation. The post-operative period was uneventful; however, she was re-admitted 2 weeks after discharge due to wound infection, which resolved with antibiotics and dressings. The pathological diagnosis revealed a lipomatous submucosal lesion of the ileocecal valve and terminal ileum, and all 17 sampled lymph nodes were negative for malignant cells. The oophorectomy identified an ovarian metastasis from breast carcinoma (Figures 1 and 2). Ascites cytology was positive for malignant cells, which were most likely from an adenocarcinoma. The immunohistochemical evaluation revealed positivity for cytokeratin AE1/AE3, CK7 and hormonal

Figure 1. Photomicrograph of the ovary. A – Ovarian parenchyma almost entirely occupied by a proliferation of malignant epithelioid cells arranged in small nests and cords (H&E, 200x); B – Tumor cells were large, with irregular nuclei and prominent nucleoli (H&E, 400x). 2-7

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Armas I, Brandão M, Guerreiro I, et al.

Figure 2. Photomicrograph of the ovary. Tumor cells showed immunoexpression of estrogen receptor (ER) in A, and progesterone receptor (PR) in B – intense staining in 75-100% cells, plus strong and diffuse immunoexpression of CK7 in C and gross cystic disease fluid protein (GCDFP-15) in D.

receptors (HR) (75-100%), and negativity for CK20, e-cadherin, WT1, CA125, CDX2, and HER2 (score 0) (Figure 2).

for HR (75-100%), negativity for C-erb2 and Ki67 of 15-30%.

A complementary study with mammography and ultrasonography of the breast and axilla was performed, which revealed a solid heterogeneous, spiculated nodule with 10 × 8 × 10 mm in the transition of the outer quadrants of the left breast, and multiple enlarged left axillary lymph nodes—the most prominent of which was 34 mm with metastatic features. Biopsies were performed, which revealed the presence of ductal carcinoma in the breast nodule. The fine-needle aspiration of the axillary lymph node was positive for neoplastic cells.

A thoracic, abdominal and pelvic CT scan and an abdominal and pelvic magnetic resonance imaging (MRI) scan showed a 14 mm left breast nodule, multiple enlarged left axillary lymph nodes, a right normal ovary, and uterine fibromas.

Histological findings were reviewed, and confirmed ovarian metastasis from ductal carcinoma of the breast. The immunohistochemical evaluation showed positivity

The tumor was assessed as a stage IV ductal breast carcinoma, cT1N1M1 (ovarian and peritoneal metastasis), Grade 2, Luminal B-like (HR+, HER2−).

Autops Case Rep (São Paulo). 2019;9(1):e2018071

The upper and lower endoscopies were negative.

A positron emission tomography (PET) scan revealed 18 F-FDG uptake in the left breast, left axillary lymph nodes, right ovary, and peritoneum (Figures 3 and 4). The baseline cancer antigen (CA)15.3 was 76.17 U/mL (normal range < 30 U/mL).

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Incidental diagnosis of breast cancer in the pursuit of the treatment of intestinal obstruction

Figure 3. PET scan showing 18F-FDG uptake in the left breast.

Figure 4. PET scan showing moderate 18F-FDG uptake in right ovary area and less uptake posteriorly and inferiorly, which could be peritoneal implants.

The patient was referred to an oncological center and evaluated in a multidisciplinary oncological meeting, which proposed palliative chemotherapy. The patient completed six cycles of doxorubicin and cyclophosphamide with good tolerance. The re-staged breast MRI and PET scan showed complete response, and CA15.3 had dropped to 17.81 U/m. After re-evaluation by the multidisciplinary oncological meeting, the patient started hormonal 4-7

treatment with letrozole, and now remains in complete remission 22 months after the end of chemotherapy.

DISCUSSION Primary small intestinal tumors are uncommon, which account for about 1% of all gastrointestinal tumors, and primary lipomas of the small intestine are rare.8 The incidence rate of detection of intestinal Autops Case Rep (SĂŁo Paulo). 2019;9(1):e2018071

Armas I, Brandão M, Guerreiro I, et al.

lipomatosis at autopsy ranges from 0.04% to 4.5%.2 Lipomas of the intestine may be solitary, or multiple and encapsulated, or diffuse, discrete, non-capsulated lobules of adipose tissue, called lipomatosis. In 90% of the cases they are localized in the submucosa, but occasionally they extend into the muscularis propria, while up to 10% are subserosal.9 The colon is the most common site (65-75%) of lipoma location followed by the ileum.10 No predilection site has been mentioned for lipomatosis in the literature.11 The age of presentation is highly variable, ranging from the neonatal period to the seventh decade of life.3 No gender differences are observed.12 Most intestinal lipomas are asymptomatic, but they can sometimes precipitate a surgical emergency, especially when the ileocecal valve and small intestine are affected.13 The most frequent presenting symptom is abdominal pain.14 The etiology of lipomatosis is yet to be established. Hypothetical etiological factors include embryonic displacement of adipose tissue; degenerative disease with disturbance of fat metabolism; post-chemotherapeutic fat deposition; chronic irritation, such as chronic inflammatory bowel disease; low-grade infection; and hamartomatous syndromes.15 Clinical diagnosis may be difficult, but a pre-operative CT scan may be of value to characterize large submucosal masses, and to show the specific nature of a mass and the extent of disease.1 Plain abdominal films are non-specific and commonly demonstrate the presence of multiple air-fluid levels, which is suggestive of mechanical obstruction.1 The intraoperative appearance of the lesion can be confusing, and it may be difficult to exclude carcinoma on gross appraisal during surgery.1 This is similar to our case, which resembled ileocecal carcinoma or ileal carcinomatosis. Ovarian metastases from breast cancer generally reflect advanced breast disease,4 and in most cases are bilateral.16 The challenge of diagnosing a malignancy metastatic to the ovary is that the clinicopathological characteristics vary and the morphology can be different from the corresponding primary tumor.17 Autops Case Rep (São Paulo). 2019;9(1):e2018071

In this case, metastatic breast cancer was identified in the ovary before the primary breast tumor was suspected. The primary neoplasm may be quite small, and detailed imaging may be necessary for its detection.18 Lobular carcinomas are known to spread to the ovary more frequently than ductal carcinomas, but because ductal cancer is considerably more common, most diagnostic challenges are posed by tumors with a ductal morphology.7 Metastatic involvement of the peritoneum in the setting of breast cancer is rare.19 Therefore, it is mandatory to exclude other primary tumors, such as gastric and colorectal cancer, which more frequently present with peritoneal carcinomatosis. In this case, other etiologies were excluded with endoscopic studies, CT, MRI, and PET scans. Patients with metastatic breast cancer are unlikely to be cured of their disease with any treatment.20 The removal of the primary tumor in patients with stage IV breast cancer has not been associated with prolongation of survival, with the possible exception of bone-only disease, being considered only in selected patients to improve quality of life.20 Deviations to this approach may be made on a case-by-case basis in a multidisciplinary setting, although these instances are exceptional. Complete remissions from systemic chemotherapy are uncommon, and, indeed, only a small fraction of complete responders remain progression-free for a prolonged period (being mostly those with oligometastatic disease or low-volume metastatic disease). 20 The patient reported herein started chemotherapy and experienced a substantial response. However, such tumors expressing hormonal receptors should start with hormonal/endocrine therapy, even in cases of visceral disease. Chemotherapy should be reserved for non-responders or for patients with a high tumor burden, or whenever rapid disease/symptoms control (e.g. a visceral crisis) is needed.20 Furthermore, even in patients who progress after first-line endocrine therapy, there are now targeted agents (e.g. the CDK4/6 inhibitors), which can be added to endocrine therapy, with good long-term survival results.20 The median survival for patients with stage IV breast cancer is 18-24 months, although the range extends from only a few months to many years.21 5-7

Incidental diagnosis of breast cancer in the pursuit of the treatment of intestinal obstruction

CONCLUSION Intestinal lipomatosis is rare and frequently asymptomatic, but occasionally it can present as an intestinal obstruction and should be kept as a differential diagnosis in unusual cases. Pre-operative image findings and even intra-operative macroscopic findings can be misleading; therefore, histologic evaluation will confirm the diagnosis. Ovarian metastasis eventually can be an incidental finding and be identified before the primary breast tumor. Metastatic involvement of the peritoneum in breast cancer patients is rare; thus, it is important to exclude other primary tumors. Stage IV breast cancer should be managed with endocrine therapy, targeted therapy and/or chemotherapy, depending on the hormonal receptors and the C-erb2 status, plus the patient’s comorbidities, performance status, response to previous treatments, tumor burden, and associated symptoms. Our patient presented a rare cause of intestinal obstruction, a not-so-common case of ovarian and peritoneal carcinomatosis from breast cancer, and a rare case of complete response after chemotherapy in stage IV luminal breast cancer.

REFERENCES 1. Thakur B, Kishore S, Bhardwaj A, Kudesia S. Diffuse intestinal submucosal lipomatosis with incidental epidermal inclusion cyst of caecum clinically masquerading as carcinoma caecum. Rare Tumors. 2014;6(3):5380. http:// dx.doi.org/10.4081/rt.2014.5380. PMid:25276322. 2. Suárez Moreno RM, Hernandez Ramirez DA, Madrazo Navarro M, Salazar Lozano CR, Martínez Gen R. Multiple intestinal lipomatosis: case report. Cir Cir. 2010;78(2):163-5. PMid:20478119. 3. Bodas A, Rivilla F, Maluenda C. Intestinal lipomatosis in a 10-year-old girl. Eur J Pediatr. 2008;167(5):6012. http://dx.doi.org/10.1007/s00431-007-0530-z. PMid:17569084. 4. Abd El hafez A, Monir A. Diagnostic spectrum of ovarian masses in women with breast cancer; magnetic resonance imaging: histopathology correlation. Ann Diagn Pathol. 2013;17(5):441-7. http://dx.doi.org/10.1016/j. anndiagpath.2013.06.003. PMid:23891503. 5. Union for International Cancer Control (UICC). Global cancer incidence [Internet]. Geneva; 2018. Available from: https://www.uicc.org/new-global-cancer-dataglobocan-2018 6. Tserkezoglou A, Kontou S, Hadjieleftheriou G, et al. Primary and metastatic ovarian cancer in patients with 6-7

prior breast carcinoma. Pre-operative markers and treatment results. Anticancer Res. 2006;26(3B):2339-44. PMid:16821613. 7. Young RH. From Krukenberg to today: the ever present problems posed by metastatic tumors in the ovary. Part II. Adv Anat Pathol. 2007;14(3):149-77. http://dx.doi. org/10.1097/PAP.0b013e3180504abf. PMid:17452813. 8. Fang SH, Dong DJ, Chen FH, Jin M, Zhong BS. Small intestinal lipomas: diagnostic value of multi-slice CT enterography. World J Gastroenterol. 2010;16(21):267781. http://dx.doi.org/10.3748/wjg.v16.i21.2677. PMid:20518091. 9. Vasiliadis K, Katsamakas M, Nikolaidou A, Christoforidis E, Tsalis K, Tsalikidis A. Submucosal lipoma of the ascending colon as a source of massive lower gastro-intestinal bleeding: a case report. Acta Chir Belg. 2008;108(3):3569. http://dx.doi.org/10.1080/00015458.2008.11680239. PMid:18710116. 10. Thompson WM. Imaging and findings of lipomas of the gastrointestinal tract. AJR Am J Roentgenol. 2005;184(4):1163-71. http://dx.doi.org/10.2214/ ajr.184.4.01841163. PMid:15788588. 11. Parlak S, Erdogan Okay A, Altin L, Toprak U, Kuscuoglu G, Alp Karademir M. Lipomatosis of terminal ileum and ileocecal valve: multidetector computed tomography findings. Iran J Radiol. 2014;11(3):e4336. http://dx.doi. org/10.5812/iranjradiol.4336. PMid:25763082. 12. Tatsuguchi A, Fukuda Y, Moriyama T, Yamanaka N. Lipomatosis of the small intestine and colon associated with intussusception in the ileocecal region. Gastrointest Endosc. 1999;49(1):118-21. http://dx.doi.org/10.1016/ S0016-5107(99)70460-8. PMid:9869738. 13. Grasso E, Guastella T. Giant submucosal lipoma cause colo-colonic intussusception: a case report and review of literature. Ann Ital Chir. 2012;83(6):559-62. PMid:23110909. 14. Shenoy R, Rodrigues G, Gopashetty M, Kannaiyan L, Rao S. Segmental jejunal lipomatosis: a rare cause of intestinal obstruction. Yonsei Med J. 2003;44(2):359-61. http:// dx.doi.org/10.3349/ymj.2003.44.2.359. PMid:12728483. 15. Jeong IH, Maeng YH. Gastric lipomatosis. J Gastric Cancer. 2010;10(4):254-8. http://dx.doi.org/10.5230/ jgc.2010.10.4.254. PMid:22076194. 16. Gagnon Y, Tetu B. Ovarian metastases of breast carcinoma: a clinicopathologic study of 59 cases. Cancer. 1989;64(4):892-8. http://dx.doi. org/10.1002/1097-0142(19890815)64:4<892::AIDCNCR2820640422>3.0.CO;2-C. PMid:2743281. 17. Lobo J, Machado B, Vieira R, Bartosch C. The challenge of diagnosing a malignancy metastatic to the ovary: clinicopathological characteristics vary and morphology can be different from that of the corresponding primary Autops Case Rep (São Paulo). 2019;9(1):e2018071

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tumor. Virchows Arch. 2017;470(1):69-80. http://dx.doi. org/10.1007/s00428-016-2029-3. PMid:27757533. 18. McCluggage WG. Metastatic neoplasms involving the ovary. Surg Pathol Clin. 2011;4(1):297-330. http://dx.doi. org/10.1016/j.path.2010.12.010. PMid:26837297. 19. Borst MJ, Ingold JA. Metastatic patterns of invasive lobular versus invasive ductal carcinoma of the breast. Surgery. 1993;114(4):637-41. PMid:8211676.

20. Cardoso F, Senkus E, Costa A, et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4) dagger. Ann Oncol. 2018;29(8):163457. http://dx.doi.org/10.1093/annonc/mdy192. PMid:30032243. 21. Leung AM, Vu HN, Nguyen KA, Thacker LR, Bear HD. Effects of surgical excision on survival of patients with stage IV breast cancer. J Surg Res. 2010;161(1):83-8. http:// dx.doi.org/10.1016/j.jss.2008.12.030. PMid:19375721.

Author contributions: Armas I, Pinto-de-Sousa J, and Brandão M wrote the article. Armas I, Brandão M, Guerreiro I, Lobo J, Freitas C, Pinto-de-Sousa J and Sousa JA collectively reviewed the manuscript and approved it for publication. The patient signed an informed consent form. The paper is in accordance with the institutional ethical research committee. Conflict of interest: None Financial support: Lobo J is supported by Fundação para a Ciência e Tecnologia – fellowship (SFRH/BD/132751/2017). The remaining authors declare no financial support Submitted on: November 19th, 2018 Accepted on: December 24th, 2018 Correspondence Isabel Armas Hospital de Bragança Avenida Abade de Baçal 5301-852 – Bragança – Portugal Phone: +351 96 458 9214 isabel.armas@hotmail.com

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Article / Clinical Case Reports

Oral ulcerative lesions in a post-liver-transplantation patient Gabriele Prospero Nakamuraa, Renata Mendonça Moraesa, Juliana Mota Siqueiraa, Andrea Cruz Ferraz de Oliveirab, Maria Dirlei Ferreira de Souza Begnamib, Graziella Chagas Jaguara How to cite: Nakamura GP, Moraes RM, Siqueira JM, Oliveira ACF, Begnami MDFS, Jaguar GC. Oral ulcerative lesions in a post-liver-transplantation patient. Autops Case Rep [Internet]. 2019;9(1):e2018046. https://doi.org/10.4322/acr.2018.046

Abstract Oral involvement is rarely found in histoplasmosis, except in its disseminated form, which is mostly observed in the severely immunocompromised host. Herein, we presented the case of a 36-year-old female with a previous history of liver transplant, who was hospitalized due to fever, chills, night sweats, diarrhea, and painful oral lesions over the last 3 days. The oral examination revealed the presence of painful shallow ulcers lined by a pseudomembrane in the gingiva and the soft and hard palate. The initial working diagnosis comprised cytomegalovirus reactivation or herpes simplex virus infection. The diagnostic work-up included incisional biopsies of the gingiva and the sigmoid colon. Both biopsies confirmed the diagnosis of histoplasmosis. Intravenous itraconazole was administered with significant improvement after 7 days. Although oral involvement is rare, histoplasmosis should be included in the differential diagnosis of oral lesions, particularly when the patient is immunosuppressed. This study reports a rare presentation of histoplasmosis involving the mucosa of the oral cavity and the colon. Keywords Histoplasmosis; Liver Transplantation; Oral ulcer; Immunosuppression

INTRODUCTION Histoplasmosis is an opportunistic fungal infection caused by Histoplasma capsulatum, a dimorphic fungus that lives in soil that is rich in birds and bats droppings.1 It is more prevalent in some regions in North, Central, and Latin America, as well as in Africa, and is typically found in tropical and temperate rural areas. The disease mostly occurs in the lungs and is acquired through the inhalation of dust particles from the soil contaminated with bat or bird excrement, which contains fungal spores—the infectious form of the microorganism.1 After reaching the airways, the microconidia are phagocytosed by the macrophages where they start to

replicate. Hematogenous spread occurs within 2 weeks after infection. In immunocompetent patients, the macrophages have a fungicidal role by phagocytizing H. capsulatum, and therefore hamper the disease progression. 1 However, in immunocompromised patients, such as those who are HIV-positive, transplant recipients, and patients with hematological neoplasm, the clinical course is more aggressive, with disseminated disease involving the lungs, skin, intestines, and oral mucosa.2 Here, we present an uncommon case of oral histoplasmosis, which was clinically misconceived as a viral infection.

AC Camargo Cancer Center, Stomatology Department. São Paulo, SP, Brazil. AC Camargo Cancer Center, Pathologic Anatomy Department. São Paulo, SP, Brazil.

Oral ulcerative lesions in a post-liver-transplantation patient

CASE REPORT A 36-year-old woman presented to the Emergency Department of the Cancer Center, complaining of fever, chills, night sweats, diarrhea, and painful oral lesions, over the past3 days. The patient had a medical history of liver transplantation8 years before, due to biliary cirrhosis, and was taking prednisone 5mg/day and mycophenolate sodium 360 mg. She also reported cytomegalovirus (CMV) infection 3 months after the transplantation, which was successfully treated with ganciclovir. The oral examination showed three well‑defined shallow ulcerative lesions covered by fibrin with regular erythematous borders on the hard palate, measuring 1 cm (Figure 1A); on the vestibular and palatal gingiva between the 16 and 17 teeth measuring 0.5 cm (Figure 1B); and on the left soft palate near the uvula measuring 1.0 cm (Figure 1C). According to the clinical findings and the previous history of CMV, the main diagnostic hypotheses were CMV reactivation or herpes simplex virus (HSV) infection. Exfoliative cytology of oral lesions was performed and an anti-CMV immunoglobulin (Ig)G test was requested. Because of the immunosuppression, ganciclovir 300mg tid was prescribed, but no improvement was observed within 7 days. Since the exfoliative cytology and the anti-CMV IgG tests were negative, the hypothesis of viral infection became less probable. A chest x-ray was normal, which ruled out lung involvement. Due to the worsening of oral lesions and the presence of gastrointestinal tract symptoms,

two oral incisional biopsies—in the gingival and the palate—were taken, and a colonoscopy was performed with biopsy of a rectal lesion. The colonoscopy image showed areas with inflammatory process and eroded mucosa with an extensive ulcer measuring 2 cm on the descending colon extending to the rectum (Figure 2). Histological sections of oral cavity biopsies revealed fragments of squamous mucosa with intense histiocytic inflammatory infiltrate associated with rounded fungal structures, which were consistent with H. capsulatum, and were confirmed by Gomori–Grocott’s staining in the gum and the palate (Figure 3). Similar findings were observed in the rectal biopsy. Based on the clinical and histopathologic findings, the final diagnosis was histoplasmosis (Figure 4). The treatment consisted of itraconazole 300 mg/day with significant improvement of local and systemic symptoms after 7 days (Figure 5). The patient was followed up for 12 months with no further lesions.

DISCUSSION Clinical presentation of oral histoplasmosis is rare and the diagnosis is challenging. However, when present in the oral cavity, the involved sites include the tongue, the palate, the oral mucosa, the gingivae, and the pharynx. The mucosal involvement may occur as granular ulcerations, multiple painful ulcers and verrucous growths, as a deep ulcer surrounded by infiltrative edges with erythematous

Figure 1. Gross examination of the oral lesions. A – Flat lesion covered with a fibrin pseudo membrane with regular erythematous borders on the hard palate; B – Ulcer on the vestibular and palatal gingiva between the 16 and 17 teeth; C – Ulcer on the left soft palate near the uvula. 2-5

Autops Case Rep (São Paulo). 2019;9(1):e2018046

Nakamura GP, Moraes RM, Siqueira JM, Oliveira ACF, Begnami MDFS, Jaguar GC

or white areas with irregular surfaces, as hardened and irregular nodular lesions accompanied by local lymphadenopathy, all of which mimic other infectious diseases or malignant tumors. This case report shows a case of histoplasmosis, which was initially misconceived as a viral infection.

Figure 2. Colonoscopy image depicting area of inflammatory process with mucosal erosion and ulceration in the descending colon.

The differential diagnoses of oral histoplasmosis include viral infections such as CMV and HSV. CMV is a ubiquitous herpes virus, which, depending on the studied population, infects 50%-100% ofhumans.3,4 Primary CMV infection in immune competent individuals presents most commonly without symptoms. However, in individuals with compromised immunity (e.g. liver transplant recipients) clinical disease may be fatal.

Figure 3. Photomicrograph of the oral biopsy. A – Areas of squamous mucosa with intense histiocytic inflammatory infiltrate associated with rounded fungal structures consistent with Histoplasma spp. (H&E 200X); B – Gomori–Grocott’s staining showing positivity for fungi (H&E 200X).

Figure 4. Photomicrograph of the rectal biopsy. A – Areas with intense histiocytic inflammatory infiltrate associated with rounded fungal structures consistent with Histoplasma spp. (H&E 400X); B – Gomori–Grocott staining showing positivity for fungi(400X). Autops Case Rep (São Paulo). 2019;9(1):e2018046

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Oral ulcerative lesions in a post-liver-transplantation patient

Figure 5. Oral examination after the treatment. Note the complete healing of the lesions on the hard palate (A), gingiva (B), and soft palate (C). CMV infection is the most common viral infection after solid transplant and usually appears during the first year after transplantation as observed in our case. The incidence after liver transplantation varies between 22% and 29%.5 CMV causes febrile illness, which is often accompanied by bone marrow suppression, and in some cases, involves other tissues including the transplanted liver allograft and gastrointestinal tract, causing abdominal pain and diarrhea. The skin and oral lesions usually present as chronic ulcers.3 Our patient presented fever, diarrhea, cutaneous rash, and oral lesions—features that are consistent with the diagnosis of CMV infection. In contrast, HSV infection is a double-stranded DNA virus, which is usually acquired during childhood via infected saliva or direct contact with mucocutaneous lesions. After primary infection, the virus remains dormant until reactivation. The recurrent herpetic stomatitis is less common than the herpes labial and usually arises on keratinized surfaces.6 In immunocompromised patients, the recurrent HSV-1 infection may be atypical, with more extensive, slow‑healing, and extremely painful lesions.7,8 In our case, the involvement of the keratinized areas, such as the palate and the gingiva, supported the hypothesis of the HSV infection. The histopathological features of histoplasmosis are usually characteristic, but occasionally the organisms are scanty and not readily identified, which can preclude the correct diagnosis and consequently hamper the appropriate management.9 Fortunately, in the present case, the histopathologic examination results enabled a clear diagnosis of histoplasmosis. Systemic antifungals are used to treat severe acute histoplasmosis as well as all chronic and disseminated cases. However, even with adequate treatment, the 4-5

risk of failure and relapse does exist, so prolonged treatment is required.1 In the present case, the patient continues to be closely followed up to better evaluate the treatment response. In conclusion, a case of histoplasmosis involving the oral cavity in an immunosuppressed patient is reported, which was initially misdiagnosed due to her previous medical history of CMV disseminated infection. The early and accurate diagnosis of histoplasmosis is essential for the correct treatment and cure.

REFERENCES 1. Souza BC, Munerato MC. Oral manifestation of histoplasmosis on the palate. An Bras Dermatol. 2017;92(5, Suppl 1):107-9. http://dx.doi.org/10.1590/ abd1806-4841.20175751. PMid:29267463. 2. Wheat LJ, Slama TG, Zeckel ML. Histoplasmosis in the acquired immune deficiency syndrome. Am J Med. 1985;78(2):203-10. http://dx.doi.org/10.1016/00029343(85)90427-9. PMid:3871588. 3. Yadav SK, Saigal S, Choudhary NS, Saha S, Kumar N, Soin AS. Cytomegalovirus infection in liver transplant recipients: current approach to diagnosis and management. J Clin Exp Hepatol. 2017;7(2):144-51. http://dx.doi. org/10.1016/j.jceh.2017.05.011. PMid:28663679. 4. López-Oliva MO, Flores J, Madero R, et al. Cytomegalovirus infection after kidney transplantation and long-term graft loss. Nefrologia. 2017;37(5):515-25. http://dx.doi. org/10.1016/j.nefro.2016.11.018. PMid:28946964. 5. Simon DM, Levin S. Infectious complication soft solid organ transplantations. Infect Dis Clin North Am. 2001;15(2):521-49. http://dx.doi.org/10.1016/S08915520(05)70158-6. PMid:11447708. 6. Arduino PG, Porter SR. Herpes simplex virustype 1 infection: overview onrelevantclinico-pathological features. J Oral Pathol Med. 2008;37(2):107-21. Autops Case Rep (São Paulo). 2019;9(1):e2018046

Nakamura GP, Moraes RM, Siqueira JM, Oliveira ACF, Begnami MDFS, Jaguar GC

http://dx.doi.org/10.1111/j.1600-0714.2007.00586.x. PMid:18197856. 7. Al-Dhafiri SA, Molinari R. Herpetic folliculitis. J Cutan Med Surg. 2002;6(1):19-22. http://dx.doi. org/10.1177/120347540200600104. PMid:11896419. 8. Levitsky J, Duddempudi AT, Lakeman FD, et al. Detection and diagnosis of herpes simplex virus

infection in adults with acute liver failure. Liver Transpl. 2008;14(10):1498-504. http://dx.doi.org/10.1002/ lt.21567. PMid:18825709. 9. Iqbal F, Schifter M, Coleman HG. Oral presentation of histoplasmosis in an immunocompetent patient: a diagnostic challenge. Aust Dent J. 2014;59(3):386-8. http://dx.doi.org/10.1111/adj.12187. PMid:24819556.

Author contributions: Jaguar GC was in charge of the patient’s surgical procedure, and together with Nakamura GP, Moraes RM and Siqueira JM wrote the manuscript. Oliveira ACF and Begnami MDFS were the pathologists responsible for the pathological report. All authors proofread and collectively approved the final version for publication. The patient signed an informed consent authorizing the publication of the report as well as the images. The manuscript is in accordance with the Institutional Ethics Committee rules. Conflict of interest: None Financial support: None Submitted on: July 2nd, 2018 Accepted on: August 15th, 2018 Correspondence Graziella Chagas Jaguar Stomatology Department - AC Camargo Câncer Center Rua Prof. Antônio Prudente, 211 – Liberdade – São Paulo/SP – Brazil CEP: 01509-900 Phone: +55 (11) 2189-5129 graziellajaguar@gmail.com

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