Autopsy & Case Report

Page 1

ISSN 2236-1960

v. 7, n. 4, oct./dec. 2017

Photomicrography of the lung showing small fat droplets in the alveolar capillaries in a case of fat embolism syndrome associated with hemoglobinopathy SC hemolytic crisis (H&E, 400X)

Hospital UniversitĂĄrio Universidade de SĂŁo Paulo


ISSN 2236-1960 December 2017, volume 7 number 4

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

Editorial committee Editor in chief Maria Claudia Nogueira Zerbini, MD, PhD Scientific Editors Aloisio Felipe-Silva, MD, PhD Fernando Peixoto Ferraz de Campos, MD Larry Nichols, MD Alex K Williamson, MD Ameer Hamza, MD Support Team Rubenildo Oliveira da Costa - Head of Library Tatiana Massaro - 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 Portal de Revistas da USP PKP IBICT Latindex Diadorin Seminarios.org Directory of Open Access Journals DOAJ


Editorial

Declining rate of autopsies: implications for anatomic pathology residents Ameer Hamzaa How to cite: Hamza A. Declining rate of autopsies: implications for anatomic pathology residents. Autops Case Rep [Internet]. 2017;7(4):1-2. http://dx.doi.org/10.4322/acr.2017.036

All physicians and pathologists are well aware of the fact that the autopsy rate has been declining for the last few decades. An autopsy was performed on 40% to 60% of all hospital deaths in the United States before 1970.1,2 Now this rate has gone below 5%.1,2 Our educational institution had a 20-fold decrease in the number of autopsies performed in 2016 as compared to 1970s. This trend is not limited to the United States but is worldwide. Autopsy rates in the United Kingdom decreased from 25.8% in 1979 to just 0.69% of all hospital deaths in 2013.3 The reasons for this decline are manifold but advanced diagnostic modalities are a major contributor. The reasons for decline in autopsy rates, the benefits of autopsy and future of autopsy have been discussed in literature.1-8 Regarding future of autopsy, Laposata6 has proposed a new kind of autopsy; the Diagnostic and Management Autopsy (DMA). The DMA is a review of the diagnostic decisions related to the apparent cause of death by a panel of specialists. Autopsy is a major branch of anatomic pathology and is a broad topic to discuss. Declining autopsy rates have implications for pathology residents as well. As a part of the Accreditation Council for Graduate Medical Education (ACGME) accredited anatomic pathology residency training in the United States, pathology residents are mandated to do 50 autopsies. With the decline in autopsies this number is becoming harder to achieve. To overcome this problem, ACGME allows two residents to share an autopsy. Even this shared autopsy policy may not be sufficient to achieve the desired number of 50 autopsies in the near future, and

ACGME may have to reconsider this requirement for the pathology residents to be eligible for the American board of pathology (ABP) examination. It is not just about the ACGME requirements, what matters, even more, is the learning experience of the residents. Autopsies are considered a valuable tool in learning normal histology. The decline in autopsies is depriving the anatomic pathology residents of this invaluable tool for learning normal histology and usual anatomical and histological variations. Moreover, sometimes autopsies also provide means of microscopic examination of benign pathologic conditions that otherwise rarely come as a surgical pathology specimen. Autopsies have educational value not only for pathology residents but also for other specialties and medical students. Aiello8 emphasized the importance of autopsy in cardiology with respect to elucidating the precise cause of death; as an educational resource; and for research purposes. On the other hand, with ever increasing work load in surgical pathology this decline is a blessing in disguise, as the residents can invest more time in working up their surgical pathology cases. Despite the continuous decline in autopsy rates it is hard to imagine that autopsies will become completely extinct. From anatomic pathology residents’ perspective, however, pathology residency programs need to look into additional resources for a better learning of normal histology as well as benign pathology and ACGME may have to reconsider the requirement of 50 autopsies.

St. John Hospital and Medical Center, Department of Pathology. Detroit, MI, USA.

a

Autopsy and Case Reports. ISSN 2236-1960. Copyright Š 2017. 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.


Declining rate of autopsies: implications for anatomic pathology residents

REFERENCES 1. Shojania KG, Burton EC. The vanishing nonforensic autopsy. N Engl J Med. 2008;358(9):873-5. PMid:18305264. http://dx.doi.org/10.1056/NEJMp0707996. 2. Hoyert DL. The changing profile of autopsied deaths in the United States, 1972-2007. NCHS Data Brief. 2011;(67):18. PMid:22142988.

5. McPhee SJ. Maximizing the benefits of autopsy for clinicians and families: what needs to be done. Arch Pathol Lab Med. 1996;120(8):743-8. PMid:8718899. 6. Laposata M. A new kind of autopsy for 21st century medicine. Arch Pathol Lab Med. 2017;141(7):887-8. PMid:28661212. http://dx.doi.org/10.5858/arpa.20160317-ED.

3. Turnbull A, Osborn M, Nicholas N. Hospital autopsy: endangered or extinct? J Clin Pathol. 2015;68(8):6014. PMid:26076965. http://dx.doi.org/10.1136/ jclinpath-2014-202700.

7. Laposata M. Why have doctors stopped asking for autopsies? Will a different type of autopsy change this? Autops Case Rep. 2017;7(3):1-2. http://dx.doi. org/10.4322/acr.2017.023.

4. Nemetz PN, Tanglos E, Sands LP, Fisher WP Jr, Newman WP 3rd, Burton EC. Attitudes toward the autopsy-an 8-state survey. MedGenMed. 2006;8(3):80. PMid:17406199.

8. Aiello VD. The autopsy as the cornerstone for education and research in cardiology. Autopsy Case Rep. 2016;6(4):1-3. PMid:28210566. http://dx.doi. org/10.4322/acr.2016.055.

Conflict of interest: None Financial support: None Correspondence Ameer Hamza Department of Pathology - St John Hospital and Medical Center 22101 Moross Road – Detroit/MI – USA PO Box: 48236 Phone: +1 (313) 613-7511 ameerhamza7@hotmail.com

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Autops Case Rep (São Paulo). 2017;7(4):1-2


Letter to the Editor

Machine learning enhanced virtual autopsy Shane O’Sullivana, Andreas Holzingerb, Kurt Zatloukalc, Paulo Saldivaa,d, Mohammed Imran Sajide, Dominic Wichmannf How to cite: O’Sullivan S, Holzinger A, Zatloukal K, Saldiva P, Sajid MI, Wichmann D. Machine learning enhanced virtual autopsy. Autops Case Rep [Internet]. 2017;7(4):3-7. http://dx.doi.org/10.4322/acr.2017.037

STATE-OF-THE-ART AND OBJECTIVES In many cases, access to biological samples is needed for molecular analyses. Biopsies or other minimally-invasive sampling techniques, in the context of virtual autopsy (virtopsy), would reduce risk and improve societal acceptance when compared with traditional autopsies. We propose a study that compares and contrasts virtopsy with traditional autopsy, using large study groups based on four different levels of information: Macroscopic; Microscopic; Medical imaging; and Molecular phenotypes. This proposal includes the development of a machine learning enhanced virtual biobank to understand the process of diseases, and to evaluate clinical diagnosis and treatment. This virtual biobank, enhanced by machine learning and knowledge extraction approaches, will be composed of a unique collection of non-invasively generated autopsy images (e.g., X-ray, computerized tomography, magnetic resonance imaging, ultrasound) and digital pathology imaging data of corresponding biological samples. Based on this vast resource, we will experimentally design, develop, test and evaluate machine learning algorithms that can self-learn from, as well as make predictions (based on the virtual biobank data). These ambitious studies will help us go beyond

the state-of-the-art to demonstrate to what extent machine learning can enhance medical expertise, so as to understand the process of diseases and to evaluate both clinical diagnosis and treatment. The algorithms will make data-driven predictions or decisions, by building a model from sample inputs; a variety of subject data was used. We will use the same machine learning approach developed by a research group at the Medical University of Graz.1 They are world-leading experts in this field with long-standing experience in the application domain, health generally, pathology and metabolomics2 in particular. This strategy will allow achievement of results that include the use of fewer images when compared with conventional machine learning (e.g., deep learning approaches), and so helps to alleviate some major issues one would expect for this type of study set-up. In the application of virtopsy we do not have access to many cases, (i.e., sample-size is small, and not the large numbers in the thousands to millions which are usually necessary), and so consequently we need algorithms which are able to self-learn (with only a few examples), in the same way humans do. The chosen approach of interactive machine learning is an inventive way to overcome this problem. The intention is to utilize this

University of Sao Paulo (USP), Faculty of Medicine, Department of Pathology. São Paulo, SP, Brazil. Medical University of Graz, Institute for Medical Informatics/Statistics, Holzinger Group. Graz, Austria. c Medical University of Graz, Institute of Pathology. Graz, Austria. d University of de Sao Paulo (USP), Institute of Advanced Studies. São Paulo, SP, Brazil. e Wirral University Teaching Hospital, Department of Upper GI Surgery. Wirral, United Kingdom. f University Hospital Hamburg Eppendorf, Department of Intensive Care. Hamburg, Germany. a

b

Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2017. 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.


Machine learning enhanced virtual autopsy

method of smart injective machine learning. It is not a black box method, which demands the input of a massive amount of data. Instead, expert knowledge is fed directly into the algorithmic loop.1 This is an ingenious method to deal with standard limitations. The necessity of large amounts of data/sample-size and cases will always be a limitation for conventional machine learning. Our technique will have a unique resource to drive the project and achieve our anticipated results. Regarding virtual microscopy, digital pathology now provides an entirely innovative technique to analyze image data from tissues. We propose a study that conducts a systematic comparison between the morphology of tissue (as seen by digital pathology) and medical images such as magnetic resonance imaging (MRI). In addition, pathologists will provide images using a medical care standard digital camera for macroscopic documentation and analysis. This image will be compared with corresponding medical images, as different levels of imaging information add to the originality of this study. Finally, we propose to include nuclear mass resonance (NMR) spectroscopy in the active research of this study. This adds to the originality and scientific aspect as it involves a new level of information regarding metabolic status and morphology of tissue. Consequently, focus is not only on explaining disease biology, but it is also developing machine learning algorithms that provide image analysis – currently there is a lack of literature on large-scale programmes that compare MRI images with both NMR and microscopic images. NMR will enable us to obtain the metabolomic profile, as the metabolome provides detailed information about the chemical composition of the tissue. For NMR metabolomics, it is essentially the same principle as for MRI, but the read-out of the signal is different. This is scientifically challenging but relevant, as we can then compare MRI data with chemical composition of tissue investigated. In addition, we will compare this data with histological and macroscopic data. There has been no current literature to date demonstrating that this has been undertaken in such a coordinated approach as set out in our proposal. 4

Ideally, for this type of image analysis study, we intend to include many additional datasets from autopsies performed rapidly (~3 hours) after clinical death. This is important because virtopsy must be compared with traditional autopsy whilst avoiding autolysis. The proposed virtual biobank will be used to train algorithms to cope with effects due to autolysis and other post-mortem effects. This is also of huge relevance to forensic medicine. By performing autopsies in as early as 3 hours after clinical death, we are managing a more feasible situation when compared with secondary phenomena due to autolysis. As a result, we will collect better material for molecular studies, and this is cutting-edge research with the generation of new knowledge in the scientific approach. Furthermore, accessing the affected organs and tissues by traditional autopsy provides an opportunity for molecular analyses, such as metabolomics by using NMR spectroscopy. As discussed, the innovative aspect we will introduce to this study is to compare virtopsy with traditional autopsy using four different levels of data information: (1) Macroscopic appearance (viewed by eye traditional autopsy using digital photography);

in

(2) Microscopic appearance (examined by microscope in digital pathology); (3) Medical imaging appearance (e.g., seen by MRI, ultrasonography, etc.); and (4) Molecular phenotypes metabolomics).

(e.g.,

by

NMR-based

In brief, the main objective is to demonstrate that it is possible to create a self-learning system, which will assist pathologists and physicians in diagnosing certain medical conditions from digital data. This information technology (IT) learning approach is a major objective of the proposal. We will create an IT-based methodology that provides an innovative technique to perform autopsies. This includes all other issues with machine learning to facilitate physicians to determine the correct diagnosis; it revolutionizes the method of performing autopsies.

CORE SCIENTIFIC APPROACH The core scientific approach is the way in which we analyze imaging data and how we compare the MRI data with morphology or metabolic status. When we Autops Case Rep (SĂŁo Paulo). 2017;7(4):3-7


O’Sullivan S, Holzinger A, Zatloukal K, Saldiva P, Sajid MI, Wichmann D

use the power of machine learning to analyze imaging data, it is very similar in pathology versus radiology since the approaches are quite similar. However as discussed earlier, a conventional machine learning approach requires many thousands of datasets. Additionally, such a study requires exceptionally detailed annotation to achieve a particular goal; this is a valid prerequisite that one may expect to be unquestionable and leading to a great result. The limited number of datasets will constantly be an issue in any autopsy study, whether it is pathology or forensic medicine – there are simply not enough cases. This consistent limitation is overlooked by most machine learning researchers. However, by using the unique technique of interactive machine learning, we can reduce the number of datasets required at least by a factor of 10 or even more. Therefore, we increase our chances of obtaining a reasonable result very early on in the study - even with a low number of cases - and even after a short period of time, which places us in a very promising position within the specific area of artificial intelligence. We generate a solid case by applying this unique machine learning approach in this particular context. By making the systematic comparison of tissue alterations across different organs, we generate digital slides and then compare the histologic imaging features with medical imaging features, e.g., MRI; one of the techniques we use to link virtopsy to digital pathology. This study provides a systematic understanding that can distinguish between postmortem inflammation infarcted from autolysis, and thereby generates a new database for further imaging programs and algorithm developments. This is a “machine learning from images” study that has a novel scientific approach with a practical setup, a strong focus on what to look for, and an innovative way to analyze the data. In most countries, there are inadequacies with regards to conducting large-scale programs for this type of study. Firstly, for some subjects, pathologists do not receive approval from the relatives, and therefore they perform fewer autopsies. Secondly, the time lapse of consent is approximately one day, resulting in performing autopsies with a marked delay after death. Thus, it is most advantageous to include additional cases that examine a situation more closely related to a living body, which allows us to distinguish between Autops Case Rep (São Paulo). 2017;7(4):3-7

disease-related alterations and secondary alterations (caused by prolonged autolysis periods). The virtual biobank will facilitate data fusion, data mapping, data integration and data sharing on four different levels: (1) Macroscopic; (2) Microscopic; (3) Medical imaging; and (4) NMR. The virtual biobank will consequently be the basis for a fully-fledged and powerful machine learning pipeline. We propose to include analysis of in vivo and ex vivo brain structural changes in a large sample of subjects; adding a novel parameter to the study and enabling insight into entirely original, previously unknown aspects. A team with in-depth experience in machine learning and knowledge extraction will support and help in building the machine learning pipeline and novel knowledge extraction tools. In particular, the highly needed visualization tools that enable the experts to find, e.g., anomalies, similarities, dissimilarities in arbitrarily high dimensional data sets. These would be otherwise inaccessible to the human end user, if following an interactive machine learning approach with the doctor-in-the-algorithmic-loop.3,4 Our unique technique is that we propose to construct machine learning algorithms that self-learn from and make predictions based on the study group data stored in our virtual biobank. Imaging biomarkers depend on access to biomaterial, and these biological features are readily available at many medical universities. Some academic hospitals remain very open to both traditional and imaging autopsies for clinical and academic studies.5,6 The results from the proposed virtopsies are highly reproducible and most developed countries can facilitate and provide virtopsies. In most cases, a study of this kind would usually require 1-2 years of data collection. However, some research groups possess a record of previously existing virtopsy data, which can enable them to perform machine learning image analysis from the onset. This data allows researchers to develop algorithms which they then validate, adapt, use and test in the autopsy cases which are to be collected during the random period of their study. Initially, they can train the algorithms on existing datasets, which are available from previous virtopsy studies, improving the likelihood of achieving expected results. However, it is critical to include many datasets from autopsies performed rapidly (~3 hours) after 5


Machine learning enhanced virtual autopsy

clinical death to avoid the risk that ultimately the algorithms will fail to recognize autolysis, which is the most common phenomenon in these cases. The time-course advantage is invaluable for the validation of this study. Using an “early cohort” in the mix can address specific questions that cannot be explained by using a “delayed cohort”. Therefore, the “early cohort” allows to witness alterations in the dead body as early as possible, as well as to follow how this has changed over time and recognize how features are influenced by autolysis. Subsequently, the outcome is having a superimposition of the pre-existing disease – be it an inflammation, infarction or tumor. This is then superimposed by the effects of autolysis. The intention is to avoid making studies on autolysis in pathology since the primary aim is to discover the underlying disease.

EXPECTED RESULTS AND HYPOTHESIS The focus and strengths of this study are on novel integrative and interactive machine learning approaches, which can complement and extend current deep learning approaches. We also envision helping to solve problems that would occur when comparing radiology data with pathology data. With this unique opportunity, we can compare and contrast the digital pathology with the radiology to proceed further in viewing these images; the aspiration of many radiologists. We have an advantage in the ability to collect tissue from the deceased, as opposed to the case of living subjects. Additionally, we can access the lungs, the heart and the brain (if needed); which is a unique opportunity that drives the imaging field in general, not only in the context of virtopsy. The ability to compare radiology data with histology and digital pathology allows us to see how far the principles of machine learning image analysis can be applied - with different technologies and different imaging types. We create a biobanking library of digital images together with material data, which makes it a compelling resource. These are major factors of the core scientific approach that increase the likelihood of success. This virtopsy proposal aims to use autopsies while incorporating new technologies - such as medical imaging - to improve how infectious diseases are examined. This research will help to understand 6

the processes of diseases and evaluate both clinical diagnosis and treatment. It will enhance understanding in respect of therapy resistance by cancer patients with minimal tumor burden, and even the cause of death in such patients. Essential baseline data outcomes will quantify and compare tumor mass in cases involving diverse patients (according to their metabolic conditions). We hypothesize that virtopsy is dramatically more advantageous at mapping cardiovascular alterations, hemorrhages, and misuse of medical devices.7 As a result of its strong application opportunities and high impact, this study is scientifically significant and innovative – particularly the substantial savings in time and finance, and delivery of rapid reliable data and diagnosis: • Virtopsy provides new possibilities to clarify the pathogenesis of specific diseases, particularly those which affect organs or clinical conditions that impede in vivo tissue sampling. This is predominantly relevant to postmortem sampling of selected areas of the brain, that shed light on the biology of a variety of mental disorders such as dementia, Alzheimer’s disease, schizophrenia and depression; • In the recent episodes of Ebola, portable ultrasound imaging may have been applied in remote regions of Africa. In addition, this application may have led to a faster identification of Zika virus as being the cause of microcephaly during the recent outbreak in Brazil. It may have reduced the number of Ebola and microcephaly cases worldwide; • In circumstances where corpses are suspected to have high-risk pathogens or infectious diseases, imaging autopsies will protect medical staff. The innovative methods eliminate the risks of contamination associated with the use of knives, needles, and scissors in conventional procedures; • Virtopsy also obviates negative outcomes for DNA sequencing and pathogen detection, particularly in biopsies required for immune testing; • This project addresses many unanswered questions in digital pathology. These relate to the lack of international literature on large-scale programs. Such programmes that compare MRI data with molecular phenotypes in an incisive, coordinated way that is expounded in this study; • Image-guided biopsies have become an important factor in reference to the ethics of autopsies. They will detect the cause of death in the majority of cases; in doing so they improve quality control and diminish the economic burden of conventional autopsies;7 • The results from this project are highly reproducible in other countries. Medical imaging autopsy is a valid alternative method, and it will increase autopsy Autops Case Rep (São Paulo). 2017;7(4):3-7


O’Sullivan S, Holzinger A, Zatloukal K, Saldiva P, Sajid MI, Wichmann D

acceptance rates,7 particularly among cultures that oppose autopsies on ethical and/or religious grounds.

In summary, we plan to combine all the aforementioned diverse steps of autopsy and data analysis. The anticipated result will provide a new method of analyzing digital data from virtopsy and digital pathology; identifying improvements in diagnostic techniques, and assisting physicians with finding the correct diagnosis. We are confident that the entirety of our multi-faceted approach will provide the desired results and advance the state-of-the-art.

ACKNOWLEDGEMENTS We thank the organization CNPQ (Brazilian National Council for Scientific and Technological Development). This entity provided support that was invaluable to our research. The authors declare they have no actual or potential competing interests.

traveling salesman problem with the human-in-the-loop approach. In: Buccafurri F, Holzinger A, Kieseberg P, Tjoa A, Weippl E, editors. Availability, reliability, and security in information systems. Cham: Springer; 2016. p. 81-95. (Lecture Notes in Computer Science; 9817). CD-ARES 2016. http://dx.doi.org/10.1007/978-3-319-45507-56. 2. Cacciatore S, Hu X, Viertler C, et al. Effects of intra- and post-operative ischemia on the metabolic profile of clinical liver tissue specimens monitored by NMR. J Proteome Res. 2013;12(12):5723-9. PMid:24124761. http://dx.doi. org/10.1021/pr400702d. 3. Holzinger A. Interactive machine learning for health informatics: when do we need the human-in-the-loop? Brain Informatics. 2016;3(2):119-31. PMid:27747607. http://dx.doi.org/10.1007/s40708-016-0042-6. 4. Holzinger A. Introduction to Machine Learning & Knowledge Extraction (MAKE). Mach Learn Knowl Extr 2017;1(1):1. http://dx.doi.org/10.3390/make1010001. 5. Wichmann D, Obbelode F, Vogel H, et al. Virtual autopsy as an alternative to traditional medical autopsy in the intensive care unit. Ann Intern Med. 2012;156(2):123130. PMid:22250143. http://dx.doi.org/10.7326/00034819-156-2-201201170-00008.

REFERENCES

6. Wichmann D, Heinemann A, Weinberg C, et al. Virtual autopsy with multiphase postmortem computed tomographic angiography versus traditional medical autopsy to investigate unexpected deaths of hospitalized patients: a cohort study. Ann Intern Med. 2014;160(8):53441. PMid:24733194. http://dx.doi.org/10.7326/M132211.

1. Holzinger A, Plass M, Holzinger K, Crişan GC, Pintea CM, Palade V. Towards interactive Machine Learning (iML): applying ant colony algorithms to solve the

7. Saldiva PHN. Minimally invasive autopsies: a promise to revive the procedure. Autops Case Rep. 2014;4(3):13. PMid:28573111. http://dx.doi.org/10.4322/ acr.2014.021.

Keywords Artificial Intelligence; Autopsy; Machine Learning; Magnetic Resonance Imaging; Metabolomics

Conflict of interest: None Financial support: None Submitted on: July 26th, 2017 Accepted on: October 24th, 2017 Correspondence Shane O’Sullivan Department of Pathology - Hospital das Clínicas - Faculdade de Medicina - Universidade de São Paulo (USP) Av. Enéas Carvalho de Aguiar, 155 – São Paulo/SP – Brazil CEP: 05403-000 Phone: +55 (11) 3061-7173 doctorshaneosullivan@gmail.com

Autops Case Rep (São Paulo). 2017;7(4):3-7

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Review Article

Gelatinous transformation of bone marrow: rare or underdiagnosed? Khushdeep Kaur Shergilla, Gagandeep Singh Shergillb, Hari Janardanan Pillaic How to cite: Shergill KK, Shergill GS, Pillai HJ. Gelatinous transformation of bone marrow: rare or underdiagnosed? Autops Case Rep [Internet]. 2017;7(4):8-17. http://dx.doi.org/10.4322/acr.2017.039

ABSTRACT Gelatinous transformation of the bone marrow (GTBM) is a rare hematologic entity, which was first described by Paul Michael in 1930. GTBM is mostly associated with caloric intake/anorexia nervosa, although it also has been described accompanying other pathologic conditions, such as malignancy, systemic lupus erythematosus and HIV infections. Even though the diagnostic features of the hematopoietic tissue, such as hypoplasia, adipose cell atrophy, and deposition of a gelatinous substance in the bone marrow (which stains with Alcian blue at pH 2.5) are quite specific, the underlying pathogenic mechanisms remain poorly understood. Considering the evidence of reversibility—notably in cases of malnutrition and anorexia—this entity should be kept high on cards as a possible differential diagnosis of patients presenting with cytopenias and associated weight loss or starvation, especially in developing countries with nutritionally deprived populations. On an extensive review of the literature aimed at comprehensively addressing the evolution of the GTBM from the past century until now, we conclude that the lack of clinical suspicion and awareness regarding this pathologic entity has led to misdiagnosis and delayed diagnosis. Keywords: Bone Marrow Disease; Bone Marrow Examination; Bone Marrow.

INTRODUCTION Gelatinous transformation of bone marrow (GTBM)—also known as starvation marrow— gelatinous degeneration and serous atrophy of bone marrow is a well-defined hematologic entity.1,2 Although the first references were noticed in works of Virchow (1821–1902), Herter (1865–1910), and Adami (1862–1926), it was Paul Michael, in 1930, who first reported 11 cases of GTBM in the bone marrow of autopsied cases. 1 A large number of studies published at the end of the 20th century worldwide, considered GTBM as a histologic pattern originating from an associated cause rather than being a disease entity by itself.3

In fact, GTBM has been described in association with a variety of clinical scenarios, chiefly in the young with malnourishment and anorexia.3,4 In cases with high clinical suspicion, the diagnosis can be easily established by studying the bone marrow aspirate or bone biopsy with Alcian blue staining at pH 2.5, which loses positivity after pre-treatment with hyaluronidase.3 The reported rare incidence of GTBM might just be the tip of the iceberg, with the lack of clinical suspicion being the most probable culprit for so few diagnoses. This review was undertaken to study the epidemiological behavior and incidence of GTBM reports over the years while focusing on clinical

Armed Forces Medical College, Department of Pathology. Pune, India. Government Medical College, Department of Medicine. Amritsar, India. c Armed Forces Medical College, Department of Surgery. Pune, India. a

b

Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2017. 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.


Shergill KK, Shergill GS, Pillai HJ

profiles, hematologic parameters and investigations, and proposed pathogenic mechanism.

MATERIAL AND METHODS In our pre-specified protocol, we used the keywords “gelatinous transformation/degeneration of the bone marrow, starvation marrow, and serous atrophy of the marrow” to identify the target papers for a systematic literature search. The databases, PubMed, Medline, Google Scholar and Research Gate, were accessed to retrieve the articles published until June 2017. Case and series reports, original research articles, images, letters to editors with titles having the aforementioned keywords were included in the study. Data including the first author’s last name, publication year, country of origin and total number of cases reported in each study was compiled. All open access articles and abstracts of subscribed articles were included in the study. Articles published in a language other than English for which no translation or English abstract was available, were excluded. All articles fulfilling inclusion criteria were reviewed in duplicate and independently, and data extraction was held by two authors (KKS & GSS). All articles were assessed for following variables: total number of studies published with total number of cases; clinical profile including age, sex and the associated disease; altered hematological indices; diagnostic work-up modality (cytological and/or histologic parameters of bone marrow); reversal or improvement with treatment; and additional information reported with respect to the pathogenesis of GTBM by the different authors. Data were compiled in chronological order (decade wise); however, no quantitative data synthesis or statistical analysis could be performed due to considerable clinical and mathematical heterogeneity of the compiled data.

RESULTS Our literature search gathered 79 papers (N) with relevant titles, amounting the total of 522 reported cases (n) as shown in Table 1. Of these 79 papers, Autops Case Rep (São Paulo). 2017;7(4):8-17

66 were in the English language while 13 were in other languages, such as French, German, Dutch, and Polish. Of these 13 studies, 4 had an English language abstract. Hence the remaining 09 articles (n = 26) were excluded. A final list of 70 titles was compiled, which comprised 48 full articles (n = 394) and only 22 Abstracts (n = 102). Out of these, 48 open access articles were subjected to review by two authors independently and the remaining 22 subscribed articles only with abstracts were reviewed for available data. We observed that the research articles on GTBM, which constituted the bulk of cases, had limited information on the parameters of the individual cases. Hence, the scope for statistical analysis of data was limited. However, an overall trend was established based on the available data.

Incidence of Gelatinous Transformation of Bone Marrow Over the Last Century The first available published study on GTBM by Paul Michael (1930) comprised a total of 11 cases.1 Over the following three decades, no published data were available. In 1967, a study by Pearson5 surfaced, reporting GTBM in three cases of anorexia nervosa. In the subsequent decade; two more studies were published by Tavassoli et al.6 (1976) and Seamen et al.2 (1978) who described the condition in 9 and 14 cases, respectively. In the 1980s, six more studies were published, describing the condition in seven different patients. However, no open access article could be found on a literature search of the archives till 1990.7-12 The number of studies tripled (N = 18) in the 1990s with a total of 52 cases reported,13-30 including one original research article by Mehta et al.16 who described the condition in 22 patients with HIV—the first ever study from India—by Ray et al.17 in 1992, and another one by Basu et al.26 At the dawn of the 21st century, a deluge of research articles on GTBM were published. Among them, 21 new studies appeared in the first decade itself, including the largest study by Bohm3 (2000) who studied 80,000 bone marrow samples and reported the GTBM incidence of 0.2%.3,4,31-49 In the last 7 years, 30 new studies comprising 117 cases were published.50-79 Thus, a total of 79 studies with 522 individual cases of GTBM have been published in the last 87 years (Table 1). These data clearly indicate 9


10

1960-1969

6

18 (5-No abstract)

21 (2-No abstract)

30 (1-No abstract)

79 (9 removed)

1980-19897-12*

1990-19991330 **

200020093,4,31-49 ***

2010-201750-79

TOTAL

522 (26 removed)

117 (12 removed)

309 (5 removed)

52 (8 removed)

7 (1 removed)

23 (6 not studied)

3

11

Number of cases (n)

70:143:54:103

18:35:12:10 (30 cases btw 26 & 66 yrs)

50:106:36:83

Complete data NA

NA

0:1:6:10

2:1

(Average age: 40 years)

Age groups (<15: 15–40: 40–60: >60)

236:160

65: 40

150:110

-

-

11:6

0:3

10:1

M:F ratio

Anorexia/ Malnutrition: 44 Malignancy: 22 HIV: 9 Infections: 7+/–15

Anorexia/ Malnutrition: 79 Malignancy: 66 Infections: 53 Aplastic anemia: 17 Miscellaneous: 47

Anorexia/ Malnutrition: 10 HIV: 22 Post-chemo therapy: 10

Anorexia: 5 Malignancy: 1 SLE (overlap): 3

Malignancy: 7 Anorexia/ Malnutrition: 6 Miscellaneous: 4

Anorexia Nervosa: 3 Pneumonia: 1

Nothing published

Tuberculosis: 4, Malignancy: 3, Miscellaneous: 4

Associated entity, number of cases

2 cases without cytopenia. Most cases with anemia. Pancytopenia: 14

2 cases without cytopenia Mostly anemia Pancytopenia: 2

Mostly anemia

At least 1 cytopenia; Anemia most common. Pancytopenia: 1 case

At least 1 cytopenia; mostly anemia

1 case: leukopenia

Anemia: 10/11, Leukopenia: 1/11

Hematologic characteristics

BMA: 7/74 BMB: the remaining

BMB & BMA: 70 cases BMA: 54 cases BMB: 179 cases

-

-

BMA & BMB

BMA: 2 cases; BMA & BMB: 1 case

BMB

Diagnostic work-up

Cases improved withNutrition:12, PRBCs: 1, Growth factors: 1, Vitamin C: 1

23/36 cases improved (5 with nutrition, 1 with EPO)

-

-

Improved with nutrition in animals

Response to treatment

-

Follow-up

Anorexia/ Malnutrition: 147 Malignancy: 109 BMA = bone marrow aspirate; BMB = bone marrow biopsy; btw = between; EPO = erythropoietin; GTBM = gelatinous transformation of bone marrow; NA = not available; PRBCs = packed red blood cells; SLE = systemic lupus erythematosus. *No full published article was available during this time period; hence, data interpretation is limited. **Mehta et al.16 reported in 22/75 cases of HIV (86% males, mean age: 33 years; all were anemic, 50% cases hypocellular, aspirate more difficult). ***Jain et al.4 (India) studied 43 cases, 14 of which were children; mostly presented anemia and malnourishment.

2

sa1970-19792,6

5

1

1

1930-19391

1940-1959

Number of studies (n)

Year

Table 1. Data sheet of cases with GTBM (1930-2017)

Gelatinous transformation of bone marrow: rare or underdiagnosed?

Autops Case Rep (São Paulo). 2017;7(4):8-17


Shergill KK, Shergill GS, Pillai HJ

a rising trend in reporting the condition, especially in the last two decades.

Clinical Profiles Our analysis showed a total of 236 male patients compared to 160 females with a M:F ratio of 1.5:1. Cases were divided into four age groups: <15 years, 16-40 years, 41-60 years and >60 years. In the initial studies, the most commonly involved age group was 40-60 years and >60 years with an occasional case in the <15 years age group. However, with more cases of young patients being reported in the past two decades, a total of 143 cases were noted in the age group of 15-40 years, followed by the elderly age group of >60 years (103). In our analysis, a total of 70 cases were seen in the <15 years age group (Table 1). The most common reported etiologies associated with GTBM were anorexia nervosa, and malnutrition or malabsorption with weight loss (47 cases). Similarly, the majority of cases, reported by Jain et al.4 (the largest case series from India), also concluded that malnutrition is the most common condition associated with GTBM. Further GTBM associated with malignancy was reported in 109 cases and comprised several types of cancers, such as hepatocellular carcinoma,64 oral cancers,74 along with primary malignancies of the bone marrow, such as acute myeloid leukemia (AML),14 and chronic myeloid leukemia (CML)47. Another 60 cases were associated with different types of infective agents excluding those reported in HIV patients.16 A total of 17 cases of aplastic anemia with GTBM were reported in study by Sen et al.37 As in cases of malignancy, HIV infection and chronic infections, like tuberculosis, where weight loss is quite often an associated complaint, there seems to be an overlap leading to an underestimation of cases of GTBM associated with anorexia and malnutrition. A total of 40 cases were labeled as miscellaneous, which comprised different associated diseases, such as systemic lupus erythematosus, 15,49 visceral Leishmaniasis,17 hemochromatosis;48 and metabolic abnormalities, such as hyperthyroidism, adrenal insuffiency,74 pyrexia of unknown origin, and alcoholic pancreatitis have also been published.

Investigations The most common altered laboratory parameter found in the majority of the cases was the presence of at least one peripheral cytopenia. In this setting, Autops Case Rep (São Paulo). 2017;7(4):8-17

anemia was the most common. In some of the larger series, almost 100% of the cases were reported to have anaemia.4,16,37,63 Pancytopenia as the initial presentation was present in 22 cases. 58,64,65,68,70,73 However, cytopenias were occasionally lacking, 41,71 and a single case of myelofibrosis, accompanied by GTBM, had leukocytosis along with thrombocytosis.31 In all cases, the diagnosis was initially achieved either on a bone marrow aspirate or bone marrow biopsy; however, the bone marrow biopsy was reported to be the method of choice mainly in cases with a dry tap on bone marrow aspiration.3,63 Histological examination was characterized by different patterns of bone marrow cellularity, varying from hypocellularity to normocellularity—or even cases of hypercellularity with focal areas of hypocellularity surrounding the gelatinous deposits.31,63,65,66 Böhm3 graded the bone marrows from 1 to 4 based on the severity of gelatinous transformation. Bone marrows were stained with Alcian blue at pH 2.5 along with routine H&E stains and additional stains like Congo Red, and periodic acid–Schiff to rule out other differential diagnoses.

Prognosis Pearson 5 and Tavassoli et al. 6 firstly reported the reversibility of GTBM on animal experiments. In our review, we found 35 cases that showed the disappearance of the GTBM on follow-up on repeated biopsy/aspirate after the initiation of treatment, which was either in the form of nutritional diet (15 cases), 58,60,62,66 packed red blood cell (PRBCs) transfusion (one case),57 granulocyte colony stimulating factor (G-CSFs) (three cases) 51 or treatment of the underlying disease.

DISCUSSION Since 1930, there has been an increasing number of reported cases of GTBM. From the advent of the 21st century, more than 50 studies were published accounting for more than 400 new cases (Table 1). The majority of these cases were from countries like India where GTBM was unheard of before the 1990s. The reported incidence of GTBM varies from 0.2%,3 to 4.4%37 and 4.8%.66 This rising trend in its incidence over the years indicates that GTBM, in the 11


Gelatinous transformation of bone marrow: rare or underdiagnosed?

current scenario, is anything but rare. On review of the literature, Seaman et al.2 seems to aptly describe GTBM as “Not uncommon,” whereas the majority of studies continue to report it as “a rare condition.” Based on our analysis, we conclude that the low incidence observed in the 20th century can be ascribed to the lack of awareness about the existence of such an entity. Overall, there is a male preponderance in the cases reported so far.3,37 However, in certain studies, like Abella et al.,36 all 22 cases reported were females while in study by Mehta et al;16 86% cases were males. This may probably be due to a selection bias in such studies. Young adults and the elderly constitute the most commonly affected age; 3 however, there has been an increase in the number of cases reported in the pediatric age group over last two decades, most of which have been reported from India.4,37,65 Hence, it is noteworthy that no age group is immune to the condition, and thus GTBM should not be neglected as a differential diagnosis in any age group. The underlying disease spectrum associated with GTBM is heterogeneous. The most common association had been reported with cases of malnourishment/starvation resulting from various causes like anorexia, chronic infections, or malignancy.1 Though most of the initial case reports were associated with non-hematopoietic malignancies, recently GTBM has been reported in association with various hematopoietic malignancies like AML, 14,18,25 acute promyelocytic leukemia (APML) on All Trans Retinoic Acid,70 acute lymphocytic leukemia (with and without dasatinib), 61,63 CML on imatinib, 47,55,56,72 CML in chronic phase, 50 myelodysplastic syndrome, 45,59 multiple myeloma33and myelofibrosis,31 which also have been published from all over the world. In many of these cases, marked weight loss with anorexia was present,44,63,74,77 thus pointing to the possibility that the underlying mechanism resulting in the development of GTBM remains the same as in the cases of chronic infections and malignancies, anorexia, and malnutrition. A remarkable number of patients had bi- or pancytopenia at the initial presentation, and almost all had anemia, irrespective of the underlying associated disease. Even though no correlation between the severity of GTBM and the peripheral hematological parameters have been reported,3,63 it still should be kept in the differential diagnosis of 12

cytopenias. Regarding the investigation modality, bone marrow biopsy appears to be the gold standard, and it appears preferable to perform trephine biopsy along with aspirate in suspected cases rather than doing aspirate alone. In 2010, Sims80 described the characteristic findings of patchy areas of hyperintensity in T2-weighted images in cases of GTBM detected by magnetic resonance imaging (MRI). However, there are cases of GTBM misdiagnosed as spinal tumours32 or misinterpreted as technical errors on MRI.75 The diagnosis is easily achieved in bone marrow biopsy, which exhibits the features of hematopoietic hypoplasia, adipose cell atrophy, and the deposition of gelatinous substance in bone marrow that stains with Alcian blue at pH 2.5 (Figure 1).1,3,6 However, a large number of cases present normocellular or hypercellular marrows or focal areas of hypocellularity surrounding the gelatinous substance, which easily can be misinterpreted as bone marrow edema, necrosis, or amyloid. The misinterpretation occurs with a lack of suspicion or knowledge of this entity. (Table 2).3,69 Recently, GTBM post-chemotherapy has been reported without fat atrophy.18,33 Although the pathogenesis of GTBM remains unknown, the majority of the studies, especially in cases of nutritional deprivation, agree upon a common pathophysiologic mechanism of fat mobilization in the face of starvation followed by the deposition of hyaluronic acid.This excessive accumulation of extracellular gelatinous material interferes with the hematopoietic microenvironment leading to the suppression of hematopoiesis, which is reflected as peripheral blood cytopenias.51,59 In GTBM associated with infectious diseases, as in HIV infection, the secretion of cytokines, such as interleukin (IL)-1, IL-2, and the tumor necrosis factor, are considered to be the driving factors. 43 Similarly, it may hold true for the cases associated with malignancy. Alternate theory suggests that the tumor cells may play a role in the initiation of hyaluronic acid formation. 11 In the cases of GTBM following chemotherapy, the inhibition of tyrosine kinase activity leads to the blockage of downstream signal pathways affecting extracellular matrix deposition, and adipocyte differentiation has been proposed as the possible mechanism.72 Local milieu factors of the marrow as the systemic “stress factors” have been proposed as the inciting factors for the development of GTBM in cases associated with aplastic anaemia.37 Autops Case Rep (São Paulo). 2017;7(4):8-17


Shergill KK, Shergill GS, Pillai HJ

Figure 1. Photomicrography of the bone marrow. A – marked hypocellularity of the hematopoietic cells and scant fat tissue immersed in an amorphous eosinophilic material (H&E, 200X); B – this stains blue with Alcian blue staining (200X). This is consistent with the diagnosis of gelatinous transformation of the bone marrow in an autopsy case of a severely malnourished corpse (Figures provided by Dr. Aloísio Felipe-Silva, MD, PhD; chief of the Anatomic Pathology Service, Hospital Universitário, University of São Paulo). Table 2. Differential diagnosis of GTBM Marrow Necrosis

Marrow Edema

Extracellular eosinophilic amorphous material with fibrinous precipitate. Inverse relationship with fat vacuoles. Vacuole outlines prominent, ragged and irregular. Diffuse hypoplasia to only focal hypoplasia with surrounding areas showing normal cellularity

Eosinophilic granular material with the presence of cellular karyorrhectic debris

Hypocellular marrow areas with fat cells of normal size and in normal quantity

Congo Red

-

-

-

+++

Alcian blue pH 2.5

+++ (Stains blue)

-

-

-

Bone Marrow

GTBM

Microscopy

PAS Stains pink Pale pink GTBM = gelatinous transformation of bone marrow; PAS = periodic acid–Schiff.

Long-term outcomes and the prognosis of GTBM have not been well documented yet. A few authors have stated that GTBM, by itself, does not have any prognostic significance, and that the survival of patients who develop GTBM is dependent on the nature and stage of the underlying disease at the time of the diagnosis. 3,18,37,70,81 However, with the increasing number of case reports showing an improvement of the Autops Case Rep (São Paulo). 2017;7(4):8-17

Amyloid

Aplastic Anemia

Homogenous Loss of myeloid pink material in tissue without any the vessel wall, fat cell atrophy or interstitial with intact fat vacuoles. There is an increase in plasma cells

-

-

GTBM in patients after balanced nutrition,81 PRBCs,57, G-CSFs,51 erythropoietin,58 the irreversibility of GTBM has been questioned. Mant and Faragher81 reported that GTBM is a temporary condition, which reverses on balanced nutrition in cases of anorexia nervosa. The timely diagnosis and early treatment in such cases would reduce the costs of long-term health care expenses,51 especially in developing countries, like India. 13


Gelatinous transformation of bone marrow: rare or underdiagnosed?

CONCLUSION From an extensive review of the literature, we conclude that GTBM is a condition that is underdiagnosed because of the lack of clinical suspicion. Though large-scale prospective studies are required to establish the pathogenesis, GTBM should be considered as a differential diagnosis in all cases presenting with weight loss, malnutrition, and refractory peripheral cytopenias—irrespective of age profile and associated co-morbidities.

ACKNOWLEDGMENT We are indebted to Dr. Fernando Peixoto Ferraz de Campos, MD, Hospital Universitário, University of São Paulo, São Paulo, SP, Brazil, for his efforts in securing the photomicrographs, and Dr. Aloísio Felipe Silva, MD, PhD, Chief of the Anatomic Pathology Service Hospital Universitário, University of São Paulo, for providing the photographs for the manuscript.

7. C l a r k e B E , B r o w n D J , X i p e l l J M . G e l a t i n o u s transformation of the bone marrow. Pathology. 1983;15(1):85-8. PMid:6222282. http://dx.doi. org/10.3109/00313028309061408. 8. Maréchaud R, Abadie JC, Babin P, Lessart M, Sudre Y. Reversible bone marrow hypoplasia in a case of male anorexia nervosa. Ann Med Interne. 1985;136(1):36-40. PMid:4003995. 9. Steinberg SE, Nasraway S, Peterson L. Reversal of severe serous atrophy of the bone marrow in anorexia nervosa. JPEN J Parenter Enteral Nutr. 1987;11(4):422-3. PMid:3112434. http://dx.doi.org/10.1177/0148607187 011004422. 10. Woessner S, Lafuente R, Martin E, Florensa L, Marill MR. Gelatinous transformation of the bone marrow. Cytohistologic, histochemical and ultrastructural study of a case. Sangre. 1988;33(2):147-9. PMid:2969624. 11. Ifrah N, Saint-Andre JP, Gentile L, et al. Gelatinous transformation of the bone marrow: manifestation of an acute leukemia? Acta Haematol. 1989;82(3):165-8. PMid:2510441. http://dx.doi.org/10.1159/000205369. 12. Taguchi H, Enzan H, Shibuya K, et al. Gelatinous transformation of the bone marrow in anorexia nervosa: report of two cases. Journal of the Japan Soc Reticuloendothel Sys. 1990;30(3):193-9. http://dx.doi. org/10.3960/jslrt1961.30.193.

REFERENCES

13. Jensen KD, Anagnostaki L. Gelatinous bone marrow transformation. Ugeskr Laeger. 1990;152(3):171-2. PMid:2105551.

1. Michael P. Gelatinous degeneration of the bone marrow. J Pathol Bacteriol. 1930;33(3):533-8. http://dx.doi. org/10.1002/path.1700330304.

14. Feng CS. Gelatinous transformation of marrow in a case of acute myelogenous leukemia post-chemotherapy. A J Hematol. 1991;38(3):220-2.

2. Seaman JP, Kjeldsberg CR, Linker A. Gelatinous transformation of the bone marrow. Hum Pathol. 1978;9(6):685-92. PMid:730150. http://dx.doi. org/10.1016/S0046-8177(78)80051-3.

15. Feng CS, Ng MH, Szeto RS, Li EK. Bone marrow findings in lupus patients with pancytopenia. Pathology. 1991;23(1):5-7. PMid:2062568. http://dx.doi. org/10.3109/00313029109061430.

3. Böhm J. Gelatinous transformation of the bone marrow: the spectrum of underlying diseases. Am J Surg Pathol. 2000;24(1):56-65. PMid:10632488. http://dx.doi. org/10.1097/00000478-200001000-00007.

16. Mehta K, Gascon P, Robboy S. The gelatinous bone marrow (serous atrophy) in patients with acquired immunodeficiency syndrome: Evidence of excess sulfated glycosaminoglycan. Arch Pathol Lab Med. 1992;116(5):504-8. PMid:1580754.

4. Jain R, Singh ZN, Khurana N, Singh T. Gelatinous transformation of bone marrow: a study of 43 cases. Indian J Pathol Microbiol. 2005;48(1):1-3. PMid:16758772. 5. Pearson HA. Marrow hypoplasia in anorexia nervosa. J Pediatr. 1967;71(2):211-5. PMid:4226478. http://dx.doi. org/10.1016/S0022-3476(67)80074-X. 6. Tavassoli M, Eastlund DT, Yam LT, Neiman RS, Finkel H. Gelatinous transformation of bone marrow in prolonged self-induced starvation. Scand J Haematol. 1976;16(4):311-9. PMid:132697. http://dx.doi. org/10.1111/j.1600-0609.1976.tb01156.x. 14

17. Ray R, Bhoria U, Varma N, Bambery P, Dash S. Gelatinous transformation of bone marrow. J Assoc Physicians India. 1992;40(4):277-8. PMid:1452541. 18. Feng CS. A variant of gelatinous transformation of marrow in leukemic patients post-chemotherapy. Pathology. 1993;25(3):294-6. PMid:8265250. http:// dx.doi.org/10.3109/00313029309066592. 19. Sicard D, Casadevall N, Wyplosz B, Picart F, Blanene P. Anorexia nervosa and gelatinous transformation of bone marrow. Nouv Rev Fr Hematol. 1994;36(Suppl 1):S85-6. PMid:8177724. Autops Case Rep (São Paulo). 2017;7(4):8-17


Shergill KK, Shergill GS, Pillai HJ

20. Bailly D, Lambin I, Garzon G, Parquet PJ. Bone marrow hypoplasia in anorexia nervosa: a case report. Int J Eat Disord. 1994;16(1):97-100. PMid:7920588. http:// dx.doi.org/10.1002/1098-108X(199407)16:1<97::AIDEAT2260160112>3.0.CO;2-N. 21. Mehler PS, Howe SE. Serous fat atrophy with leukopenia in severe anorexia nervosa. Am J Hematol. 1995;49(2):171-2. PMid:7771474. http://dx.doi. org/10.1002/ajh.2830490219. 22. Yakoub-Agha I, Galland S, Colmar-Montiel C, Poilane B, Morice P. Gelatinous transformation of the bone marrow in anorexia nervosa. Ann Med Interne. 1995;146(3):2034. PMid:7653930. 23. Bachmeyer C, Lamotte I, Dhote R, et al. Pancytopenia and gelatinous transformation of the bone marrow in anorexia nervosa. Ann Med Interne. 1995;146(2):129-30. PMid:7598339. 24. Feugier P, Guerci A, Boman F, Stockemer V, Lederlin P. Gelatinous transformation of the bone marrow. Apropos of 3 cases. Rev Med Interne. 1995;16(1):159. PMid:7871266. http://dx.doi.org/10.1016/02488663(96)80660-6. 25. Arranz R, Gil-Fernandez JJ, Acevedo A, Tomas JF, Alegre A, Fernandez-Rañada JM. Gelatinous degeneration presenting as a preleukaemic syndrome. J Clin Pathol. 1996;49(6):512-4. PMid:8763271. http://dx.doi. org/10.1136/jcp.49.6.512. 26. Basu S, Mitra S, Marwaha RK, Garewal G. Gelatinous transformation of bone marrow. Indian J Pathol Microbiol. 1997;40(3):383-4. PMid:9354013. 27. Nonaka D, Tanaka M, Takaki K, Umeno M, Okamura T, Taketa H. Gelatinous bone marrow transformation complicated by self-induced malnutrition. Acta Haematol. 1998;100(2):88-90. PMid:9792939. http://dx.doi. org/10.1159/000040872. 28. Shultz A, Yam LT. Gelatinous transformation of bone marrow. J Ky Med Assoc. 1998;96(1):10-2. PMid:9470310. 29. Marie I, Levesque H, Heron F, Courtois H, Callat MP. Gelatinous transformation of the bone marrow: an uncommon manifestation of intestinal lymphangiectasia (Waldmann’s disease). Am J Med. 1999;107(1):99-100. PMid:10403358.

32. Chim CS, Wat NM, Ma SK. The irreplaceable image: Serous degeneration of the bone marrow. Haematologica. 2001;86(5):558. PMid:11410430. 33. Mathew M, Mathews I, Manohar C, Rao S. Gelatinous transformation of bone marrow following chemotherapy for myeloma. Indian J Pathol Microbiol. 2001;44(1):53-4. PMid:12561997. 34. Tieulie N, Sudaka I, Kaphan R, et al. Gelatinous transformation of bone marrow: 4 cases. Presse Medicale (Paris, France: 1983). 2001;30(24 Pt1):1209-10. 35. Singh H, Singh S, Gupta MS, et al. Gelatinous transformation of the bone marrow complicated by self induced starvation. J Assoc Physicians India. 2002;11(2):98. 36. Abella E, Feliu E, Granada I, et al. Bone marrow changes in anorexia nervosa are correlated with the amount of weight loss and not with other clinical findings. Am J Clin Pathol. 2002;118(4):582-8. PMid:12375646. http:// dx.doi.org/10.1309/2Y7X-YDXK-006B-XLT2. 37. Sen R, Singh S, Singh H, Gupta A, Sen J. Clinical profile in gelatinous bone marrow transformation. J Assoc Physicians India. 2003;51:585-8. PMid:15266925. 38. Wang C, Amato D, Fernandes B. Gelatinous transformation of bone marrow from a starch-free diet. Am J Hematol. 2001;68(1):58-9. PMid:11559938. http://dx.doi. org/10.1002/ajh.1149. 39. Orlandi E, Boselli P, Covezzi R, Bonaccorsi G, Guaraldi GP. Reversal of bone marrow hypoplasia in anorexia nervosa: Case report. Int J Eat Disord. 2000;27(4):480-2. PMid:10744856. http://dx.doi.org/10.1002/(SICI)1098108X(200005)27:4<480::AID-EAT14>3.0.CO;2-3. 40. Nishio S, Yamada H, Yamada K, et al. Severe neutropenia with gelatinous bone marrow transformation in anorexia nervosa: a case report. Int J Eat Disord. 2003;33(3):360-3. PMid:12655634. http://dx.doi.org/10.1002/eat.10143. 41. Chen SH, Hung IJ, Jaing TH, Sun CF. Gelatinous degeneration of the bone marrow in anorexia nervosa. Chang Gung Med J. 2004;27(11):845-9. PMid:15796262. 42. Stroup JS, Stephens JR, Baker DL. Gelatinous bone marrow in an HIV-positive patient. Proc Bayl Univ Med Cent. 2007;20(3):254-6. PMid:17637880.

30. Sasaki Y, Yamagishi F, Yagi T, Mizutani F. A case of pulmonary tuberculosis case with pancytopenia accompanied to bone marrow gelatinous transformation. Kekkaku. 1999;74(4):361-4. PMid:10355222.

43. Boullu-Ciocca S, Darmon P, Sebahoun G, Silaghi A, Dutour-Meyer A. Gelatinous bone marrow transformation in anorexia nervosa. Ann Endocrinol. 2005;66(1):7-11. PMid:15798582. http://dx.doi.org/10.1016/S00034266(05)81680-4.

31. Böhm J, Schmitt-Graff A. Gelatinous bone marrow transformation in a case of idiopathic myelofibrosis: a morphological paradox. Pathol Res Pract. 2000;196(11):775-9. PMid:11186174. http://dx.doi. org/10.1016/S0344-0338(00)80111-9.

44. Murugan P, Chandrakumar S, Basu D, Hamide A. Gelatinous transformation of bone marrow in acquired immunodeficiency syndrome. Pathology. 2007;39(2):287-8. PMid:17454770. http://dx.doi. org/10.1080/00313020701230989.

Autops Case Rep (São Paulo). 2017;7(4):8-17

15


Gelatinous transformation of bone marrow: rare or underdiagnosed?

45. Niscola P, Maurillo L, Palombi M, et al. Gelatinous degeneration of the bone marrow: two case reports showing different hematological features and clinical outcomes. Acta Haematol. 2007;118(3):165-6. PMid:17890850. http://dx.doi.org/10.1159/000108766.

with residual disease in imatinib mesylate-treated chronic myelogenous leukaemia (CML). Pathology. 2012;44(1):59. PMid:22157697. http://dx.doi. org/10.1097/PAT.0b013e32834e42df.

46. Thiel A, Heits F, Amthor M. Severe leukopenia and bone marrow hypoplasia with gelatinous transformation in anorexia nervosa. Deutsche Medizinische Wochenschrift. 2007;132(43):2256-8.

57. Niscola P, Palombi M, Fratoni S, et al. Long-term survival of a patient with bone marrow gelatinous degeneration of idiopathic origin. Korean J Hematol. 2012;47(4):309-10. PMid:23320013. http://dx.doi. org/10.5045/kjh.2012.47.4.309.

47. Ram R, Gafter-Gvili A, Okon E, Pazgal I, Shpilberg O, Raanani P. Gelatinous transformation of bone marrow in chronic myeloid leukemia during treatment with imatinib mesylate: a disease or a drug effect? Acta Haematol. 2008;119(2):104-7. PMid:18367829. http://dx.doi. org/10.1159/000121825.

58. Morii K, Yamamoto T, Kishida H, Okushin H. Gelatinous transformation of bone marrow in patients with anorexia nervosa. Intern Med. 2013;52(17):20056. PMid:23995005. http://dx.doi.org/10.2169/ internalmedicine.52.0912.

48. Munfus DL, Menke DM. Case of severe serous fat atrophy. Mayo Clin Proc. 2009;84(7):570. PMid:19567708. http:// dx.doi.org/10.1016/S0025-6196(11)60743-X. 49. Yamamoto M, Belmont HM, Utsunomiya M, Hidaka Y, Kishimoto M. Gelatinous transformation of the bone marrow in systemic lupus erythematosus. Lupus. 2009;18(12):1108-11. PMid:19762388. http://dx.doi. org/10.1177/0961203309106344. 50. Hong FS, Mitchell CA, Zantomio D. Gelatinous transformation of the bone marrow as a late morphological change in imatinib mesylate treated chronic myeloid leukaemia. Pathology. 2010;42(1):84-5. PMid:20025487. http://dx.doi.org/10.3109/00313020903434686. 51. Charania RS, Kern WF, Charkrabarty S, Holter J. Successful management of gelatinous transformation of the bone marrow in anorexia nervosa with hematopoietic growth factors. Int J Eat Disord. 2011;44(5):469-72. PMid:20593416. http://dx.doi.org/10.1002/eat.20833. 52. Rivière E, Pillot J, Saghi T, et al. Gelatinous transformation of the bone marrow and acute hepatitis in a woman suffering from anorexia nervosa. Rev Med Interne. 2012;33(7):38-40. PMid:22265096. 53. Brennan CM, Atkins KA, Druzgal CH, Gaskin CM. Magnetic resonance imaging appearance of scurvy with gelatinous bone marrow transformation. Skeletal Radiol. 2012;41(3):357-60. PMid:22223127. http://dx.doi. org/10.1007/s00256-011-1350-9. 54. Cotta CV. Gelatinous transformation. Blood. 2012;120(11):2166. PMid:23136659. http://dx.doi. org/10.1182/blood-2012-02-408815. 55. Agrawal P, Sharma P, Narang V, Varma N, Malhotra P, Varma S. Gelatinous marrow transformation in an imatinib-treated CML patient with pancytopenia following severe sepsis. Indian J Hematol Blood Transfus. 2014;30(1):72-4. PMid:24554832. http://dx.doi. org/10.1007/s12288-012-0188-1. 56. Thakral B, Higa B, Venkataraman G, Velankar MM. Bone marrow with gelatinous transformation associated 16

59. Nakanishi R, Ishida M, Hodohara K, et al. Prominent gelatinous bone marrow transformation presenting prior to myelodysplastic syndrome: a case report with review of the literature. Int J Clin Exp Pathol. 2013;6(8):1677-82. PMid:23923088. 60. Rafiullah F, Islam R, Mahmood R, Sitwala KV. Gelatinous bone marrow transformation secondary to unusual eating habits and drastic weight loss. BMJ Case Rep. 2013;2013:bcr2013200243. PMid:23861277. http:// dx.doi.org/10.1136/bcr-2013-200243. 61. Sharma SK, Choudhary D, Handoo A, et al. Gelatinous transformation of bone marrow following the use of dasatinib in a patient with philadelphia chromosomepositive acute lymphoblastic leukemia. Leuk Res Rep. 2013;2(1):7-8. PMid:24371767. http://dx.doi. org/10.1016/j.lrr.2012.11.004. 62. Osgood E, Muddassir S, Jaju M, Moser R, Farid F, Mewada N. Starvation marrow – gelatinous transformation of bone marrow. J Community Hosp Intern Med Perspect. 2014;4(4):24811. PMid:25317270. http://dx.doi. org/10.3402/jchimp.v4.24811. 63. Das S, Mishra P, Kar R, Basu D. Gelatinous marrow transformation: a series of 11 cases from a tertiary care centre in South India. Turk J Haematol. 2014;31(2):1759. PMid:25035676. http://dx.doi.org/10.4274/ Tjh.2012.0151. 64. Chang J, Park CJ. Gelatinous transformation of the bone marrow in hepatocellular carcinoma. Blood Res. 2015;50(2):71. PMid:26157774. http://dx.doi. org/10.5045/br.2015.50.2.71. 65. Dikondwar AR, Gupta AP, Kawthalkar SM, et al. Gelatinous transformation of bone marrow: a rare cause of pancytopenia. Annals Pathol Lab Med. 2015;2(2):13841. 66. Singh S, Gupta M, Singh G, et al. Gelatinous transformation of bone marrow: a prospective tertiary center study, indicating varying trends in epidemiology and pathogenesis. Indian J Hematol Blood Transfus. Autops Case Rep (São Paulo). 2017;7(4):8-17


Shergill KK, Shergill GS, Pillai HJ

2016;32(Suppl 1):358-60. PMid:27408437. http://dx.doi. org/10.1007/s12288-015-0514-5. 67. Villate A, Iquel S, Legac E. Gelatinous transformation of the bone marrow: a retrospective monocentric case series of 12 patients. Rev Med Interne. 2016;37(7):44852. PMid:26632481. http://dx.doi.org/10.1016/j. revmed.2015.10.349. 68. Schafernak KT. Gelatinous transformation of the bone marrow from anorexia nervosa. Blood. 2016;127(10):1374. PMid:28092875. http://dx.doi. org/10.1182/blood-2015-11-683946. 69. Barbin FF, Oliveira CC. Gelatinous transformation of bone marrow. A&CR. 2017;7(2):5-8. 70. Goyal M, Gupta A, Yarlagadda S, Handoo A. Fatty but starving marrow! Gelatinous transformation of bone marrow secondary to plasma cell disorder and all-transretinoic acid therapy: a report of two cases. South Asian J Cancer. 2017;6(1):40-1. PMid:28413801. http://dx.doi. org/10.4103/2278-330X.202563. 71. Sung CW, Hsieh KL, Lin YH, et al. Serous degeneration of bone marrow mimics spinal tumor. Eur Spine J. 2017;26(Suppl 1):80-4. PMid:27652677. http://dx.doi. org/10.1007/s00586-016-4778-8. 72. Chang E, Rivero G, Jiang B, et al. Gelatinous marrow transformation associated with imatinib: case report and literature review. Case Rep Hematol. 2017;2017:1950724. 73. Mohamed M, Khalafallah A. Gelatinous transformation of bone marrow in a patient with severe anorexia nervosa. Int J Hematol. 2013;97(2):157-8. PMid:23271414. http:// dx.doi.org/10.1007/s12185-012-1255-y.

74. Obata Y, Tamba S, Yamada Y, et al. Resolution of gelatinous bone marrow transformation following hormone replacement therapy in a patient with primary insufficiency of the adrenal and thyroid glands. Intern Med. 2013;52(17):1931-6. PMid:23994986. http:// dx.doi.org/10.2169/internalmedicine.52.0081. 75. Boutin RD, White LM, Laor T, et al. MRI findings of serous atrophy of bone marrow and associated complications. Eur Radiol. 2015;25(9):2771-8. PMid:25773942. http:// dx.doi.org/10.1007/s00330-015-3692-5. 76. Khanna R, Verma S, Singh VK, Belurkar S. Serous atrophy of bone marrow: a rare cause of paediatric cytopenia. Int J Pharma Bio Sci. 2017;8(3):849-53. http://dx.doi. org/10.22376/ijpbs.2017.8.3.b849-853. 77. Akhtar K, Rizvi W, Sherwani RK. Gelatinous transformation of the bone marrow: a rare presentation. Int J Pharmaceut Chem Sci. 2017;6(2):30-3. 78. Chari BM, Somal PK, Belurkar S, et al. Serous atrophy of the marrow in anorexia nervosa – a case report. Int J Med Sci Clin Invent. 2014;1(9):489-92. 79. Roper E, Jackett L. An example of gelatinousbone marrow transformation. Pathology. 2017;49(2):S85-6. http:// dx.doi.org/10.1016/j.pathol.2016.12.235. 80. Sims K. Musculoskeletal MRI. J Canadian Chiropractic Assoc. 2010;54(2):134. 81. Mant MJ, Faragher BS. The haematology of anorexia nervosa. Br J Haematol. 1972;23(6):737-49. PMid:4265027. http:// dx.doi.org/10.1111/j.1365-2141.1972.tb03488.x.

Author contributions: Shergill KK and Shergill GS conceptualized and contributed to literature search and manuscript editing. Pillai HJ compiled the results and proofread the final draft of the manuscript. Conflict of interest: None Financial support: None Submitted on: October 1st, 2017 Accepted on: October 24th, 2017 Correspondence Khushdeep Kaur Shergill Department of Pathology, Armed Forces Medical College (AFMC) Pune - Maharashtra - India - 411040 Phone: 070303991112 shergillkhushdeep@gmail.com

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Image in Focus

Pseudoxanthoma elasticum Bruna Morassi Sassoa, Maria Letícia Cintrab, Elemir Macedo de Souzaa How to cite: Sasso BM, Cintra ML, Souza EM. Pseudoxanthoma elasticum. Autops Case Rep [Internet]. 2017;7(4):18-21. http://dx.doi.org/10.4322/acr.2017.035

Pictures belong to the University of Campinas (Unicamp) compilation. Figure 1. A – Skin-toned papules coalescing together into large plaques situated at the anterior and lateral sections of the neck. Also, the skin became flaccid; B – Yellowish, small papules grouped together in the flexural area (axillar); C – Weigert van Gieson stain by light microscopy shows material in the middle dermis grouped, fragmented, and twisted, which is consistent with elastic fibers; D – Von Kossa stain examined by light microscopy demonstrates that this material in the middle dermis blends in black, which represents calcium deposition. Therefore, as noticed in sequence, it shows calcified elastic fibers. a b

University of Campinas (Unicamp), Hospital das Clínicas do Estado, Department of Dermatology and Pathology. Campinas, SP, Brazil. University of Campinas (Unicamp), Hospital das Clínicas do Estado, Department of Pathology. Campinas, SP, Brazil.

Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2017. 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.


Sasso BM, Cintra ML, Souza EM

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease of the connective tissue, which is characterized by mutations in the ABCC6 gene complex, located in chromosome 16p13. The precise prevalence is unknown, although it is estimated at 1/50,000 people. Diagnosing this condition is a challenge for physicians as the typical clinical features develop later in life, with cutaneous disorders being the earliest manifestation.1-3 Women are more often affected than men, in a ratio of 2:1. At birth, clinical manifestations are generally absent and the skin lesions start to develop in the first or second decade. As mentioned above, the cutaneous findings are frequently the first symptom of PXE. The most common areas affected are the lateral and posterior regions of the neck, the flexural areas (axillae, inguinal region, antecubital, and popliteal fossae), and the periumbilical area. The clinical feature is expressed by asymptomatic small papules (1-5 mm), yellowish or skin-tone, which blend together into large reticular plaques.4 Within the disease course, the patient starts presenting numerous cardiovascular manifestations, which include reduced peripheral pulse, hypertension, angina pectoris, and intermittent claudication. Since PXE patients may have premature atherosclerosis

(caused by the mineralization and fragmentation of the elastic fibers of the medium-sized arteries and the aorta) they can also have early acute myocardial infarcts and cerebrovascular accidents. Furthermore, they have a higher cardiovascular risk as a result of alterations in lipoprotein composition and hypertriglyceridemia.4 The most important histological feature of PXE is elastorrhexis, a pattern at the middle dermis, which shows progressive mineralization and disintegration of the elastic fibers. Using light microscopy and relevant specific stains—such as Verhoeff-Van Gieson, and for calcium (Von Kossa or Alizarin Red)— fragmented elastic fibers and mid-dermal calcification will be shown, respectively, which are essential for the diagnosis of PXE. This deterioration of the elastic fibers results in dermatologic, ophthalmologic, and vascular dysfunction.3,4 In 2010, Plomp et al. 5 proposed new criteria (Table 1) for the diagnosis of PXE. Their requirements are listed below, but it is also necessary to exclude causes of PXE-like disease, such as sickle cell anemia, beta-thalassemia, and PXE-like phenotype with cutis laxa and multiple coagulation factor deficiency (when mutational analysis of ABCC6 is negative or not available).

Table 1. Proposed criteria for the diagnosis of PXE, (based on Plomp et al.5) 1. a.

Major diagnostic Criteria

Minor diagnostic criteria

Skin

Eye

Yellowish papules and/or plaques on the lateral side of One AS shorter than one disk diameter; the neck and/or flexural areas of the body; or

b. 2. a.

Increased of morphologically altered elastin with fragmentation, clumping and calcification of elastic fibers in a skin biopsy taken from clinically affected skin

or One or more ‘comets’ or ‘wing signs’ in the retina

Eye Peau d’orange of the retina

Genetics A pathogenic mutation of one allele of the ABCC6 gene

or b.

One or more angioid streaks (AS), each at least as long as one disk diameter. When in doubt, fluorescein or indocyanine green angiography of the fundus is needed for confirmation

3.

Genetics

a.

A pathogenic mutation of both alleles of the ABCC6 gene or

b.

A first degree-relative (parent, sib, child) who meets independently the diagnostic criteria for definitive PXE

Table reproduced with the consent and acknowledgment of Jong PT5. Autops Case Rep (São Paulo). 2017;7(4):18-21

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Pseudoxanthoma elasticum

Criteria for the diagnosis of PXE are: a. Definitive diagnosis: The presence of two (or more) major criteria not belonging to the same category (skin, eye, genetics);

calcified elastic fibers (Weirgt von Gieson [Figure 1C] and Von Kossa [Figure 1D]), and resulted in the diagnosis of PXE. However, we also excluded sickle cell anemia beta‑thalassemia and coagulation factor deficiency.

b. Probable diagnosis: The presence of two major eye or two major skin criteria, or the presence of one major criterion and one or more minor criteria not belonging to the same category as the major criterion;

Keywords Pseudoxanthoma Elasticum; Elastic Tissue; Vascular Calcification

c. Possible diagnosis: The presence of a single major criterion, or the presence of one or more minor criteria.

REFERENCES

Despite the genetic progress in understanding this syndrome, no specific treatment is available. Some authors believe that a dietary supplementation with magnesium and a phosphate binder could have benefits in these patients, but this is still a controversial topic. Another study by Guo and colleagues6, utilizing Abcc6–/– mice, showed that starting a statin (atorvastatin) at age 4 weeks reduced lipid values and ameliorated vascular calcification (particularly at the higher dose)6. Some authors claim that statin is useful; however, further studies are needed.7 Nevertheless, the only fully accepted treatment is ocular manifestation, with the use of agents derived from the humanized monoclonal antibody to the vascular endothelial growth factor, which have shown effectiveness in choroidal manifestation.3 The above images refer to a 27-year-old woman who sought the dermatological clinic with a 15-year history of asymptomatic cervical and axillary cutaneous lesions. Her medical history included visual impairment, a former abortion after 12 weeks’ gestation, and a previous pregnancy with severe pre-eclampsia. On physical examination, the cervical and axillary regions presented a parchment-like elastic skin with yellowish papules clustered together forming plaques (Figure 1A and B). She also had loss of peripheral pulses and fundoscopy with bilateral angioid streaks. As suspected, the histopathological examination revealed grouped, fragmented, and twisted material in the middle dermis, which is consistent with

1. Germain DP. Pseudoxanthoma elasticum. Orphanet J Rare Dis. 2017;12(1):85. PMid:28486967. http://dx.doi. org/10.1186/s13023-017-0639-8. 2. Moitra K, Garcia S, Jaldin M, et al. ABCC6 and pseudoxanthoma elasticum: the face of a rare disease from genetics to advocacy. Int J Mol Sci. 2017;18(7):1488. PMid:28696355. http://dx.doi. org/10.3390/ijms18071488. 3. Uitto J, Jiang Q, Vàradi A, Bercovitch LG, Terry SF. Pseudoxanthoma elasticum: diagnostic features, classification, and treatment options. Expert Opin Orphan Drugs. 2014;2(6):567-77. PMid:25383264. http://dx.doi. org/10.1517/21678707.2014.908702. 4. Marconi B, Bobyr I, Campanati A, et al. Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanism, perspectives of treatment. Intractable Rare Dis Res. 2015;4(3):113-22. PMid:26361562. http:// dx.doi.org/10.5582/irdr.2015.01014. 5. Plomp AS, Toonstra J, Bergen AA, van Dijk MR, de Jong PT. Proposal for updating the pseudoxanthoma elasticum classification system and a review of the clinical findings. Am J Med Genet A. 2010;152A(4):104958. PMid:20358627. http://dx.doi.org/10.1002/ ajmg.a.33329. 6. Guo H, Li Q, Chou DW, Uitto J. Atorvastatin counteracts aberrant soft tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6-/-). J Mol Med (Berl). 2013;91(10):1177-84. PMid:23807484. http://dx.doi. org/10.1007/s00109-013-1066-5. 7. Luft FC. Pseudoxanthoma elasticum and statin prophylaxis. J Mol Med (Berl). 2013;91(10):1129-30. PMid:24026849. http://dx.doi.org/10.1007/s00109-013-1082-5.

Authors contributions: Sasso BM wrote the manuscript and photographed the patient. Cintra ML was responsible for the anatomopathological examination, photomicrography, and the manuscript’s review. Souza EM was responsible for reviewing the manuscript and the patient care. Conflict of interest: None 20

Autops Case Rep (São Paulo). 2017;7(4):18-21


Sasso BM, Cintra ML, Souza EM

Correspondence Bruna Morassi Sasso Rua Tessália Vieira de Camargo, 126 – Cidade Universitária Zeferino Vaz – Campinas/SP – Brazil CEP: 13083-887 Phone: +55 (19) 3521-7541 bruna.derma@gmail.com

Autops Case Rep (São Paulo). 2017;7(4):18-21

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Image in Focus

Holoprosencephaly Ameer Hamzaa, Martha Jaye Higginsa How to cite: Hamza A, Higgins MJ. Holoprosencephaly. Autops Case Rep [Internet]. 2017;7(4):22-25. http://dx.doi.org/10.4322/acr.2017.033

Pictures courtesy Dr. Ameer Hamza Figure 1. Macroscopic appearance of the brain depicting complex gyration without classical sulcal landmarks (A and B) and focal polymicrogyria (A), flattened cerebral hemispheres surrounding a single cystically dilated ventricle (C), fused right and left basal ganglia and diencephalic structures (C), unremarkable midbrain, cerebellum and medulla (D).

a

St. John Hospital and Medical Center, Department of Pathology. Detroit, Michigan, USA.

Autopsy and Case Reports. ISSN 2236-1960. Copyright Š 2017. 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.


Hamza A, Higgins MJ

Holoprosencephaly (HPE) is a brain malformation resulting from failure of prosencephalon (the forebrain of the embryo) to divide into two distinct cerebral hemispheres. It is the most common brain malformation with an incidence of 1:250 during embryogenesis and 1:16,000 among live births. 1 HPE has four subtypes: alobar holoprosencephaly, semilobar holoprosencephaly, lobar holoprosencephaly, and a middle interhemispheric fusion variant (syntelencephaly). 2 Alobar holoprosencephaly is the most severe form, and as the name implies, there is no separation of the cerebral hemispheres. In semilobar holoprosencephaly, the cerebral hemispheres separate posteriorly, however are fused anteriorly. Lobar holoprosencephaly is characterized by almost complete separation of the cerebral hemispheres. Syntelencephaly results from failure of separation of posterior frontal and parietal lobes. Since both the forebrain and midface arise from the prechordal mesoderm, majority of patients with HPE also manifest craniofacial abnormalities such as microcephaly, microphthalmia, cleft lip and palate, flat nose, absent nasal bridge, and cyclopia. Multiple genetic and environmental factors are involved in the pathogenesis of HPE. Maternal diabetes mellitus is a well-known risk factor. 3 Exposure to retinoic acid, diphenylhydantoin, aspirin, misoprostol, methotrexate, cholesterol-lowering agents and alcohol during pregnancy have been associated with HPE.4-9 Other environmental factors include TORCH infections during early pregnancy. 1 Genetic abnormalities associated with HPE include trisomy 13, trisomy 18, and triploidy.10,11 Syndromic association of HPE includes, but is not limited to Smith-Lemli-Opitz syndrome, Genoa syndrome, Meckel-Gruber syndrome, Lambotte syndrome, Pallister-Hall syndrome, Steinfeld syndrome, caudal dysgenesis and Aicardi syndrome.12-19 Mutations in SHH, ZIC2, SIX3, and TGIF genes have been implicated in non-syndrome associated HPE.20 Central nervous system abnormalities are identified on routine prenatal imaging and etiologic diagnosis can be done by prenatal or postnatal karyotype and testing for known gene mutations. Sub classification is based on MRI findings or autopsy findings if one is requested. Infants who survive have a myriad of clinical presentation. Some of the common physical findings include spasticity, hypotonia, choreoathetosis and Autops Case Rep (São Paulo). 2017;7(4):22-25

dystonia. Infantile spasms and seizures are common. Feeding difficulties, gastroesophageal reflux, and malnutrition occur commonly. Other problems include temperature dysregulation and respiratory tract infections. Death usually occurs due to brainstem dysfunction or manifestation and complications of associated syndromes. Treatment is mainly supportive. Prognosis depends upon subtype and associated syndrome.21 Those with alobar type die within days of birth.22 Around 50% with the isolated semilobar form survive beyond 1 year.22 Recurrence risk in subsequent pregnancies is high in established cases of parental carrier state and is low if the genetic abnormalities occur de novo.23,24 Figure 1 refers to gross appearance of brain in a 7-hour old female infant born to a 41-year old G1 P0 lady with limited prenatal care, past medical history of diabetes mellitus type 2 and alcohol use during first trimester of the pregnancy. On prenatal ultrasonography, the fetus had hydrocephalous and suboptimal development of cerebral and cerebellar hemispheres. Karyotyping showed normal signal pattern for chromosomes 13, 18 and 21. Autopsy findings included fetal macrosomia; craniofacial dysmorphogenesis to include hypertelorism, low set ears, cleft palate, absent nasal bridge and bossing of forehead; biventricular cardiomegaly, muscular ventricular septal defect and imperforated anus. The detailed brain examination revealed flattened frontal, temporal and occipital lobes with a rudimentary C-shaped interhemispheric fissure. The surface of the cystically dilated forebrain displayed complex gyration; however, without classical sulcal landmarks (Figure 1A and 1B). There were focal polymicrogyria patches (Figure 1A). Cortical pallium surrounded a single large cystic cavity (telencephalic vesicle) in which lateral ventricles and ventricular horns could not be discerned (Figure 1 C). At the base of cystically dilated cerebrum, there were fused right and left basal ganglia and diencephalic structures (Figure 1C). There was no corpus callosum. The midbrain, cerebellum and medulla appeared unremarkable (Figure 1D). Keywords Brain, Holoprosencephaly, Nervous system malformations 23


Holoprosencephaly

REFERENCES 1. Solomon BD, Gropman A, Muenke M. Holoprosencephaly overview. Seattle: University of Washington; 2016 [cited 2017 August 24]. Available from: http://www.ncbi.nlm. nih.gov/books/NBK1530/ 2. Barkovich AJ, Quint DJ. Middle interhemispheric fusion: an unusual variant of holoprosencephaly. AJNR Am J Neuroradiol. 1993;14(2):431-40. PMid:8456724. 3. Barr M Jr, Hanson JW, Currey K, et al. Holoprosencephaly in infants of diabetic mothers. J Pediatr. 1983;102(4):5658. PMid:6834191. http://dx.doi.org/10.1016/S00223476(83)80185-1. 4. Edison RJ, Muenke M. Gestational exposure to lovastatin followed by cardiac malformation misclassified as holoprosencephaly. N Engl J Med. 2005;352(26):2759. PMid:15987932. http://dx.doi.org/10.1056/ NEJM200506303522622.

12. Nöthen MM, Knöpfle G, Födisch HJ, Zerres K. Steinfeld syndrome: report of a second family and further delineation of a rare autosomal dominant disorder. Am J Med Genet. 1993;46(4):467-70. PMid:8357025. http:// dx.doi.org/10.1002/ajmg.1320460426. 13. Cunniff C, Kratz LE, Moser A, Natowicz MR, Kelley RI. Clinical and biochemical spectrum of patients with RSH/ Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism. Am J Med Genet. 1997;68(3):263-9. PMid:9024557. http://dx.doi.org/10.1002/(SICI)10968628(19970131)68:3<263::AID-AJMG4>3.0.CO;2-N. 14. Balci S, Teksen F, Dökmeci F, et al. Prenatal diagnosis of Meckel-Gruber syndrome and Dandy-Walker malformation in four consecutive affected siblings, with the fourth one being diagnosed prenatally at 22 weeks of gestation. Turk J Pediatr. 2004;46(3):283-8. PMid:15503488.

5. Su PH, Chen JY, Lee IC, Ng YY, Hu JM, Chen SJ. Pfeifferlike syndrome with holoprosencephaly: a newborn with maternal smoking and alcohol exposure. Pediatr Neonatol. 2009;50(5):234-8. PMid:19856868. http:// dx.doi.org/10.1016/S1875-9572(09)60069-3.

15. Verloes A, Dodinval P, Beco L, Bonnivert J, Lambotte C. Lambotte syndrome: microcephaly, holoprosencephaly, intrauterine growth retardation, facial anomalies, and early lethality--a new sublethal multiple congenital anomaly/mental retardation syndrome in four sibs. Am J Med Genet. 1990;37(1):119-23. PMid:2240028. http:// dx.doi.org/10.1002/ajmg.1320370128.

6. Kotzot D, Weigl J, Huk W, Rott HD. Hydantoin syndrome with holoprosencephaly: a possible rare teratogenic effect. Teratology. 1993;48(1):15-9. PMid:8351644. http://dx.doi.org/10.1002/tera.1420480105.

16. Sills IN, Rapaport R, Desposito F, Lieber C. Familial Pallister-Hall syndrome: three affected offspring. Am J Med Genet. 1994;52(2):251. PMid:7802025. http:// dx.doi.org/10.1002/ajmg.1320520231.

7. Orioli IM, Castilla EE. Epidemiological assessment of misoprostol teratogenicity. BJOG. 2000;107(4):519-23. PMid:10759272. http://dx.doi.org/10.1111/j.1471-0528.2000.tb13272.x.

17. Sato N, Matsuishi T, Utsunomiya H, et al. Aicardi syndrome with holoprosencephaly and cleft lip and palate. Pediatr Neurol. 1987;3(2):114-6. PMid:3508052. http://dx.doi.org/10.1016/0887-8994(87)90039-7.

8. Miller EA, Rasmussen SA, Siega-Riz AM, Frías JL, Honein MA. Risk factors for non-syndromic holoprosencephaly in the National Birth Defects Prevention Study. Am J Med Genet C Semin Med Genet. 2010;154C(1):6272. PMid:20104597. http://dx.doi.org/10.1002/ ajmg.c.30244. 9. Corona-Rivera JR, Rea-Rosas A, Santana-Ramírez A, Acosta-León J, Hernández-Rocha J, Miguel-Jiménez K. Holoprosencephaly and genitourinary anomalies in fetal methotrexate syndrome. Am J Med Genet A. 2010;152A(7):1741-6. PMid:20578136. http://dx.doi. org/10.1002/ajmg.a.33496. 10. Papp C, Beke A, Ban Z, Szigeti Z, Toth-Pal E, Papp Z. Prenatal diagnosis of trisomy 13: analysis of 28 cases. J Ultrasound Med. 2006;25(4):429-35. PMid:16567430. http://dx.doi.org/10.7863/jum.2006.25.4.429. 11. Solomon BD, Rosenbaum KN, Meck JM, Muenke M. Holoprosencephaly due to numeric chromosome abnormalities. Am J Med Genet C Semin Med Genet. 2010;154C(1):146-8. PMid:20104610. http://dx.doi. org/10.1002/ajmg.c.30232. 24

18. Martínez-Frías ML, Bermejo E, García A, Galán E, Prieto L. Holoprosencephaly associated with caudal dysgenesis: a clinical-epidemiological analysis. Am J Med Genet. 1994;53(1):46-51. PMid:7802035. http://dx.doi. org/10.1002/ajmg.1320530110. 19. Camera G, Lituania M, Cohen MM Jr. Holoprosencephaly and primary craniosynostosis: the Genoa syndrome. Am J Med Genet. 1993;47(8):1161-5. PMid:8291548. http:// dx.doi.org/10.1002/ajmg.1320470806. 20. Mercier S, Dubourg C, Garcelon N, et al. New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases. J Med Genet. 2011;48(11):752-60. PMid:21940735. http://dx.doi. org/10.1136/jmedgenet-2011-100339. 21. Olsen CL, Hughes JP, Youngblood LG, Sharpe-Stimac M. Epidemiology of holoprosencephaly and phenotypic characteristics of affected children: New York State, 1984-1989. Am J Med Genet. 1997;73(2):217-26. PMid:9409876. http://dx.doi.org/10.1002/(SICI)10968628(19971212)73:2<217::AID-AJMG20>3.0.CO;2-S. Autops Case Rep (São Paulo). 2017;7(4):22-25


Hamza A, Higgins MJ

22. Bullen PJ, Rankin JM, Robson SC. Investigation of the epidemiology and prenatal diagnosis of holoprosencephaly in the North of England. Am J Obstet Gynecol. 2001;184(6):1256-62. PMid:11349198. http://dx.doi. org/10.1067/mob.2001.111071. 23. Mercier S, Dubourg C, Belleguic M, et al. Genetic counseling and “molecular” prenatal diagnosis of holoprosencephaly (HPE). Am J Med Genet C Semin Med

Genet. 2010;154C(1):191-6. PMid:20104616. http:// dx.doi.org/10.1002/ajmg.c.30246. 24. Nanni L, Ming JE, Bocian M, et al. The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum Mol Genet. 1999;8(13):2479-88. PMid:10556296. http:// dx.doi.org/10.1093/hmg/8.13.2479.

Author contributions: All authors have significantly contributed, and are in agreement with the content of the manuscript. Hamza A designed and wrote the manuscript after gathering all the required information. Higgins MJ was the staff Pathologist. She conducted the autopsy, proof read the manuscript and gave valuable suggestions for improvement. Conflict of interest: None Financial support: None Correspondence Ameer Hamza, MD. Department of Pathology, St John Hospital and Medical Center 22101 Moross Road – Detroit/MI – USA 48236 Phone: +1 (313) 613-7511 / Fax: 313-343-8318 ameerhamza7@hotmail.com

Autops Case Rep (São Paulo). 2017;7(4):22-25

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Article / Autopsy Case Report

Pancreatic hamartoma in a premature Trisomy 18 female Patricia Isabel Delgadoa, Mayrin Correa-Medinaa, Claudia P. Rojasa How to cite: Delgado PI, Correa-Medina M, Rojas CP. Pancreatic hamartoma in a premature Trisomy 18 female. Autops Case Rep [Internet]. 2017;7(4):26-29. http://dx.doi.org/10.4322/acr.2017.041

ABSTRACT Pancreatic hamartomas are extremely rare tumors in adults and even more so in children. They are lesions characterized by acinar, islet and ductal components found in varying proportions and in a disorganized pattern. We report a case of a premature female with trisomy 18 diagnosed by amniocentesis. The newborn was delivered by cesarean section at thirty-three weeks of gestation and expired within one hour of birth. Postmortem examination exhibited numerous features associated with Trisomy 18 including lanugo on the torso and arms, micrognathia, microstomia, left low-set ear with small flat pinna, closed ear canal, clenched fists with overlapping fingers, rocker-bottom feet, narrow pelvis, large right diaphragmatic hernia and left pulmonary hypoplasia. Microscopic examination of the pancreas revealed an area, 1.2 cm in greatest dimension, with branching ducts and cysts lined by cuboidal epithelium intermingled within primitive mesenchymal proliferation and exocrine glands. The cysts measured up to 0.2 cm and were surrounded by a collarette of proliferating spindle cells as highlighted by Masson’s trichrome stain. A diagnosis of pancreatic hamartoma was rendered. A total of thirty-four cases of pancreatic hamartomas have been reported in the literature including twenty-seven in adults, five in children and two in newborns. Our case may be the third pancreatic hamartoma reported in association with Trisomy 18. We recommend that careful examination of the pancreas be performed in individuals with Trisomy 18 to further characterize this lesion as one of the possible abnormal findings associated with this syndrome. Keywords Edwards Syndrome, hamartoma, pancreas, pancreatic neoplasm, Trisomy 18

CASE REPORT The premature female was born at 33 weeks of gestation to a 25 years old mother, gravida 3 para 2, with a history of pre-eclampsia in the previous pregnancy. In this pregnancy, the fetus was found to have Trisomy 18 karyotype by amniocentesis. Fetal ultrasound at 21 weeks gestational age showed left displacement of the heart and absent nasal bone. The mother presented to at 33 weeks of gestation for

a

premature rupture of membranes and contractions. Fetal ultrasound performed at that time showed normal amniotic fluid volume, intrauterine growth restriction with estimated fetal weight of 1519 grams (less than the 10th percentile for gestational age), right side congenital diaphragmatic hernia with liver herniating into the thorax, left mediastinal shift of the heart, hypoplastic left lung, and clenched hands with

University of Miami, Jackson Memorial Hospital, Department of Pathology. Miami, FL, USA.

Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2017. 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.


Delgado PI, Correa-Medina M, Rojas CP

limited movement of upper extremities suggestive of arthrogryposis. Doppler interrogation of umbilical artery was normal. The baby was delivered by cesarean section. At the time of birth, the infant was floppy and apneic for approximately 8 minutes requiring stimulation and intermittent positive pressure ventilation. APGAR score was 1, 2 and 4 at 1, 5 and 10 minutes, respectively. Intubation and resuscitation were not performed given the poor prognosis, and she expired at less than one hour of life. On postmortem examination, the newborn exhibited numerous features associated with Trisomy 18 which included the following: lanugo on the torso and arms, micrognathia, microstomia, left low set ear with small flat pinna and closed ear canal, bilateral clenched fists with index and fifth fingers overlapping

the third and fourth fingers, rocker-bottom feet, narrow pelvis, large right diaphragmatic hernia, and left pulmonary hypoplasia. No cardiovascular and genitourinary defects were identified. The placenta was small for the gestational age weighing 250 grams (normal is 342 grams for 33 weeks of gestation). Although no abnormalities were noted on gross examination of the pancreas, microscopic examination revealed an area measuring 1.2 cm in greatest dimension characterized by branching duct‑like structures and cysts lined by cuboidal epithelium that measured up to 0.2 cm. Primitive mesenchymal proliferation and exocrine gland formation were found in between (Figure 1A, 1B and 1C). A proliferation of spindle cells forming a collarette around the cysts were highlighted by Masson’s trichrome stain (Figure 1D). A diagnosis of pancreatic hamartoma was rendered.

Figure 1. Photomicrography of the pancreatic hamartoma, showing in A, B and C – cysts and ducts lined by cuboidal epithelium, primitive mesenchymal proliferation and exocrine gland formation (H&E, 10X, 20X and 40X respectively); in D – mesenchymal proliferation by Masson’s trichrome stain (20X). Autops Case Rep (São Paulo). 2017;7(4):26-29

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Pancreatic hamartoma in a premature Trisomy 18 female

The uninvolved pancreatic parenchyma showed normal exocrine and endocrine components, congestion and extramedullary hematopoiesis.

18 to further characterize these lesions as one of the possible abnormal findings associated with Trisomy 18 Syndrome.

DISCUSSION

REFERENCES

Pancreatic hamartomas are characterized as lesions with acinar, islet and ductal cellular components present in varying proportions and in a disorganized pattern. The exocrine and endocrine pancreatic tissue is well differentiated, and the ductal elements are irregularly branching or cystically dilated. The endocrine component may be seen as single cells or small group of cells interspersed within the exocrine component. Fibrous tissue, fat and primitive mesenchyme is often found in between these elements.1-6

1. Burt TB, Condon VR, Matlak ME. Fetal pancreatic hamartoma. Pediatr Radiol. 1983;13(5):287-9. PMid:6622090. http://dx.doi.org/10.1007/BF00973350.

Pancreatic hamartomas are extremely rare tumors in adults but are even more so in children. Only a total of thirty-four cases of pancreatic hamartomas have been reported in the literature including twenty-seven in adults, five in children and two in newborns. Two of the five reported in children had Trisomy 18 and one adult had SAPHO syndrome, a chronic inflammatory disorder.1-23 In 1960, Smith et al. 23 originally described a pancreatic lesion in a two-month old girl with Trisomy 18 at the time of autopsy. The lesion was located at the tail of the gland, and was characterized by acinar and islet pancreatic tissue within a dense fibrous network and dilated ducts. In 1964, Rohde 22 and colleagues reported a second pancreatic lesion in a Trisomy 18 child. In his case, a two-and-a-half-month girl was found to have an unusual pancreatic lesion described as having prominent immature connective tissue with sparse or absent acini, and distorted, often dilated ducts. These areas were surrounded by normal pancreatic tissue. The histologic description of these lesions is very similar to those seen in our case, and, despite the fact that these lesions were not labeled as hamartomas, their microscopic description seem to indicate that they may be considered hamartomas as well. Our case then, may be the third pancreatic hamartoma reported in association with Trisomy 18 Syndrome. Ectopic pancreas has also been reported in association with Trisomy 18.22-24 It is, therefore, recommended that careful examination of the pancreas be performed in individuals with Trisomy 28

2. Flaherty MJ, Benjamin DR. Multicystic pancreatic hamartoma: a distinctive lesion with immunohistochemical and ultrastructural study. Hum Pathol. 1992;23(11):130912. PMid:1427759. http://dx.doi.org/10.1016/00468177(92)90301-I. 3. Izbicki JR, Knoefel WT, Müller-Höcker J, Mandelkow HK. Pancreatic hamartoma: a benign tumor of the pancreas. Am J Gastroenterol. 1994;89(8):1261-2. PMid:8053450. 4. McFaul CD, Vitone LJ, Campbell F, et al. Pancreatic hamartoma. Pancreatology. 2004; 4( 6) : 533- 7, discussion 537-8. PMid:15340246. http://dx.doi. org/10.1159/000080528. 5. Pauser U, Kosmahl M, Kruslin B, Klimstra DS, Klöppel G. Pancreatic solid and cystic hamartoma in adults: characterization of a new tumorous lesion. Am J Surg Pathol. 2005;29(6):797-800. PMid:15897746. http:// dx.doi.org/10.1097/01.pas.0000157748.18591.d7. 6. Nagata S, Yamaguchi K, Inoue T, et al. Solid pancreatic hamartoma. Pathol Int. 2007;57(5):276-80. PMid:17493175. http://dx.doi.org/10.1111/j.14401827.2007.02090.x. 7. Anthony PP, Faber RG, Russell RC. Pseudotumours of the pancreas. BMJ. 1977;1(6064):814. PMid:851741. http:// dx.doi.org/10.1136/bmj.1.6064.814. 8. Noltenius H, Colmant HJ. Excessive hyperplasia of the exocrine pancreatic tissue and Wernicke’s encephalopathy (author’s transl). Med Klin. 1977;72(50):2155-8. PMid:593198. 9. Wu SS, Vargas HI, French SW. Pancreatic hamartoma with Langerhans cell histiocytosis in a draining lymph node. Histopathology. 1998;33(5):485-7. PMid:9839177. http://dx.doi.org/10.1046/j.1365-2559.1998.0491c.x. 10. Sepulveda W, Carstens E, Sanchez J, Gutierrez J. Prenatal diagnosis of Congenital Pancreatic Cyst: Case Report and Review for the Literature. J Ultrasound Med. 2000;19(5):349-52. PMid:10811411. http://dx.doi. org/10.7863/ultra.19.5.349. 11. Pauser U, da Silva MT, Placke J, Klimstra DS, Klöppel G. Cellular hamartoma resembling gastrointestinal stromal tumor: a solid tumor of the pancreas expressing c-kit (CD117). Mod Pathol. 2005;18(9):1211-6. Autops Case Rep (São Paulo). 2017;7(4):26-29


Delgado PI, Correa-Medina M, Rojas CP

PMid:15803185. http://dx.doi.org/10.1038/ modpathol.3800406.

13. PMid:23715157. http://dx.doi.org/10.1097/ PAS.0b013e318283ce4c.

12. Thrall M, Jessurun J, Stelow EB, et al. Multicystic adenomatoid hamartoma of the pancreas: a hitherto undescribed pancreatic tumor occurring in a 3-yearold boy. Pediatr Dev Pathol. 2008;11(4):314-20. PMid:17990924. http://dx.doi.org/10.2350/07-040260.1.

18. Sueyoshi R, Okazaki T, Lane GJ, Arakawa A, Yao T, Yamataka A. Multicystic adenomatoid pancreatic hamartoma in a child: Case report and literature review. Int J Surg Case Rep. 2013;4(1):98-100. PMid:23143293. http://dx.doi.org/10.1016/j.ijscr.2012.10.001.

13. Sampelean D, Adam M, Muntean V, Hanescu B, Domsa I. Pancreatic hamartoma and SAPHO syndrome: a case report. J Gastrointestin Liver Dis. 2009;18(4):483-6. PMid:20076824. 14. Kawakami F, Shimizu M, Yamaguchi H, et al. Multiple pancreatic hamartomas: A case report and reviews of the literature. World J Gastrointest Oncol. 2012;4(9):2026. PMid:23293730. http://dx.doi.org/10.4251/wjgo. v4.i9.202. 15. Durczynski A, Wiszniewski M, Olejniczak W, Polkowski M, Sporny S, Strzelczyk J. Asymptomatic solid pancreatic hamartoma. Arch Med Sci. 2011;7(6):10824. PMid:22328895. http://dx.doi.org/10.5114/ aoms.2011.26624. 16. Kim HH, Cho CK, Hur YH, et al. Pancreatic hamartoma diagnosed after surgical resection. J Korean Surg Soc. 2012;83(5):330-4. PMid:23166894. http://dx.doi. org/10.4174/jkss.2012.83.5.330. 17. Yamaguchi H, Aishima S, Oda Y, et al. Distinctive histopathologic findings of pancreatic hamartomas suggesting their “hamartomatous” nature: a study of 9 cases. Am J Surg Pathol. 2013;37(7):1006-

19. Addeo P, Tudor G, Oussoultzoglou E, Averous G, Bachellier P. Pancreatic hamartoma. Surgery. 2014;156(5):1284-5. PMid:23652195. http://dx.doi. org/10.1016/j.surg.2013.02.021. 20. Inoue H, Tamed M, Yamada R, et al. Pancreatic hamartoma: a rare cause of obstructive jaundice. Endoscopy 2014;46(Suppl 1):E157-8. http://dx.doi. org/10.1055/s-0034-1364953. 21. Matsushita D, Kurahara H, Mataki Y, et al. Pancreatic hamartoma: a case report and literature review. BMC Gastroenterol. 2016;16(1):3. PMid:26762320. http:// dx.doi.org/10.1186/s12876-016-0419-2. 22. Rohde RA, Hodgman JE, Cleland RS. Multiple congenital anomalies in the E1-Trisomy (Group 16-18) Syndrome. Pediatrics. 1964;33:258-70. PMid:14117382. 23. Smith DW, Patau K, Therman E, Inhorn S. A new autosomal trisomy syndrome: multiple congenital anomalies caused by an extra chromosome. J Pediatr. 1960;57(3):338-45. PMid:13831938. http://dx.doi. org/10.1016/S0022-3476(60)80241-7. 24. Lewis AJ. The pathology of 18 trisomy. J Pediatr. 1964;65(1):92-101. PMid:14178832. http://dx.doi. org/10.1016/S0022-3476(64)80557-6.

Author contributions: Delgado PI, supervised the performance of the autopsy documented the findings of the autopsy, corroborated in writing the autopsy report and wrote the submitted manuscript. Correa-Medina M, performed the autopsy, documented the findings of the autopsy, wrote the autopsy report and corroborated in writing the manuscript. Rojas CP, the attending supervising the autopsy, oversaw the entire process, submitted the final autopsy report, and corroborated with the writing of the manuscript. Conflict of interest: None Financial support: None Submitted on: May 14th, 2017 Accepted on: November 12th, 2017 Correspondence Patricia Isabel Delgado, MD University of Miami School of Medicine Department of Pathology and Laboratory Medicine Jackson Memorial Hospital, East Tower 1611 NW 12th Ave, Suite 2147 Miami, FL, USA 33136 Phone: 1(305) 585-6637 patricia.delgado@jhsmiami.org Autops Case Rep (São Paulo). 2017;7(4):26-29

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Article / Autopsy Case Report

Intravascular large B-cell lymphoma with multi-organ failure presenting as a pancreatic mass: a case with atypical presentation and definite diagnosis postmortem Faisal Mahmudul Huq Ronnya, Margaret Ann Blacka, Arnaldo A. Arbinia How to cite: Ronny FMH, Black MA, Arbini AA. Intravascular large B-cell lymphoma with multi-organ failure presenting as a pancreatic mass: a case with atypical presentation and definite diagnosis postmortem. Autops Case Rep [Internet]. 2017;7(4):30-36. http://dx.doi.org/10.4322/acr.2017.034

ABSTRACT Intravascular large B-cell lymphoma (IVLBCL) is a very rare extra nodal lymphoma that tends to proliferate within small blood vessels, particularly capillaries and postcapillary venules while sparing the organ parenchyma. The cause of its affinity for the vascular bed remains unknown. Because of its rarity and unremarkable clinical presentation, a timely diagnosis of IVLBCL is very challenging. Here, we describe a case of IVLBCL presenting as pancreatic mass that was ultimately diagnosed at autopsy. A 71-year-old Caucasian female presented with a 3-month history of fatigue, abdominal pain, and weight loss. She was referred to the emergency room with a new diagnosis of portal vein thrombosis and lactic acidosis. During her hospital course she was found to have a 1.9 × 1.8 cm lesion in the pancreatic tail on imaging; The cytologic specimen on the mass showed a high-grade lymphoma. A bone marrow biopsy showed no involvement. The patient’s condition rapidly deteriorated and she, later, died due to multi-organ failure. An autopsy revealed diffuse intravascular invasion in multiple organs by the lymphoma cells. Based on our literature review—and to the best of our knowledge—there are virtually no reports describing the presentation of this lymphoma with a discernible tissue mass and associated multi-organ failure. The immunophenotypic studies performed revealed de novo CD5+ intravascular large B-cell lymphoma, which is known to be aggressive with very poor prognosis. Although it is a very rare lymphoma, it should be considered as a potential cause of multi-organ failure when no other cause has been identified. A prompt tissue diagnosis, appropriate high-dose chemotherapy and stem cell transplantation remain the only viable alternative to achieve some kind of remission. Keywords Pancreatic Neoplasm; Lymphoma, B-cell; Multiple Organ Failure; Autopsy

CASE REPORT A 71-year-old Caucasian female had a past medical history of arthritis, central serous retinopathy, remote deep vein thrombosis (not on anticoagulation), hyperlipidemia and osteoporosis. She presented with a 3-month history of fatigue, abdominal pain and loss of appetite. She was referred to the emergency room after an outpatient work-up for gradual

progression of fatigue and anemia. She had a hemoglobin of 10.7 g/dL (reference value [RV]: 13.7-17.5 g/dL), mild thrombocytopenia and abnormal liver function tests. During her hospital admission, she was afebrile with the following vital signs: pulse 110 beats/minute, blood pressure 115/80 mmHg, and O2 saturation of 95% on room air. Her notable lab

New York University Langone Medical Center, Department of Pathology, Division of Hematopathology. New York, NY, USA.

a

Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2017. 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.


Ronny FMH, Black MA, Arbini AA

values were Na+ 128 mmol/L (RV: 134-146 mmol/L), AST 110 U/L (RV: 15-56 U/L), ALT 73 U/L (RV: 11-50 U/L), GGTP 94 U/L (RV: 3.0-28.7 IU/L) and albumin 2.6 gm/dL (RV: 3.5‑5.0 gm/dL). The abdominal computed tomography suggested hepatic and portal vein thrombosis, with suspicion of hepatitis, pancreatitis, and colitis. On magnetic resonance imaging, right hepatic vein thrombosis and a 1.9 × 1.8 cm lesion in the pancreatic tail was noted; based on the imaging studies, a pancreatic carcinoma or a pancreatic neuro-endocrine tumor was suspected. A CT-guided needle core biopsy on the pancreatic tail mass showed multiple foci of large frankly neoplastic cells infiltrating normal‑appearing pancreatic lobules featuring scant

cytoplasm, nuclei with regular contour and prominent nucleoli; mitotic figures and numerous apoptotic bodies were noted. Extensive immunohistochemical work-up was unrevealing and proliferation index by Ki-67 was high (>95%). Ultimately, the patient was given a diagnosis of diffuse large B-cell lymphoma (DLBCL) on the concomitant cytology specimen, which was the actual diagnostic material. The cell block showed highly atypical large cells intermixed with pancreatic acini. Those cells were positive for CD20, CD79a, and CD45, and focally PAX-5 (Figure 1). Stain for MUM-1 was non-contributory, and a further sub-classification could not be performed. Subsequent bone marrow aspirate and biopsy showed no involvement.

Figure 1. Photomicrography of the cell block. A – Highly atypical large cells intermixed with pancreatic acini (H&E, 20X). Those cells were positive for CD20 and CD79a in B and C, respectively (10X). Autops Case Rep (São Paulo). 2017;7(4):30-36

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Intravascular large B-cell lymphoma with multi-organ failure presenting as a pancreatic mass: a case with atypical presentation and definite diagnosis postmortem

Her hospital course was complicated by Weisella confusa and Enterococcus faecalis bacteremia and she was treated with piperacillin-tazobactam (Zosyn R ). She was noted to have up-trending creatinine (0.7 mg/dL to 1.4 mg/dL to 1.7 mg/dL to 2.1 mg/dL; (RV: 0.6‑1.0 mg/dL) and elevated lactate dehydrogenase (LDH) (9.1 U/L to 3487 U/L to 8097 U/L to 5686 U/L to 4328 U/L to 4636 U/L; (RV:140-280 U/L) of unclear etiology reminiscent of tumor lysis albeit disproportionate to lymphomatous involvement that at the time was thought to be restricted to the pancreas. Her diastolic blood pressure was intermittently fluctuating from 50 to 90 mmHg and she had up-trending liver function tests (AST/ALT: 50/47 U/L to 108/69 U/L to 410/155 U/L to 172/101 U/L), all of which were refractory to intravenous fluid. Her antibiotic regimen was broadened to vancomycin and meropenem and later she was transferred to the intensive care unit (ICU). With septic shock in mind, she was started on metronidazole (FlagylR) and oral vancomycin for Clostridium difficile colitis, empirically. Fluids and a norepinephrine drip did not improve her lactic acidosis. She was intubated due to worsening respiratory status; antibiotics were again broadened to vancomycin, meropenem, amikacin, micafungin, oral vancomycin, and metronidazole. Stress dose steroids were also given. She subsequently developed disseminated intravascular coagulopathy, pulmonary emboli and rapidly evolved into irreversible multi-organ failure ultimately resulting in the patient’s demise at day 13 after admission. There was an informed consent for the autopsy, which was performed in accordance with the institution’s ethics guidelines.

AUTOPSY FINDINGS At autopsy, the patient was found to have a pancreatic mass (1.9 × 1.8) cm (Figure 2) composed of sheets of large lymphoma cells. Similar lymphoma cells were also seen within vessels (mainly in small vessels, capillaries, and venules) in nearly all the examined organs (lungs, liver, kidneys, thyroid, pancreas, ovary, uterus, bladder, leptomeninges, brain parenchyma, brain stem, and spinal cord dura). Larger organizing occlusive thromboemboli with predominant neoplastic cell components were identified in the left pulmonary artery (15.5 cm), and the segmental right upper and lower lobe pulmonary arteries, the right atrial thrombus 32

Figure 2. Post-mortem gross image of the pancreatic mass (arrow). (2.8 cm), and the intrahepatic right portal vein (6 cm). The pancreas showed a mass-forming 2 cm lesion composed of dysplastic lymphocytes, and the pancreas had multiple nodules of extravasated dysplastic cells (1.5 cm each). Pink-tan, friable, large (up to 2 cm) paraesophageal and perihepatic lymph nodes were identified at autopsy and sampled. Histopathologic examination showed hemorrhagic lymph nodes with complete effacement by large dysplastic lymphocytes and necrosis. The spleen weighted 350 gm and had an opaque purple-gray capsule. The parenchyma was dark‑red‑purple, congested, and grossly without distinct masses or nodules. On histopathologic evaluation, the white pulp was effaced with diffuse sinusoidal infiltration by large pleomorphic lymphocytes. Grossly, the liver (1520 gm) parenchyma had a yellow-brown nutmeg appearance and was diffusely infiltrated by small firm white nodules. The central liver was soft and brown, corresponding to histopathologic necrosis. There was a 6 cm occlusive thrombus in the right intrahepatic portal vein and a 2 cm occlusive thrombus in a branch of the left intrahepatic portal vein with a surrounding area (3.0 × 1.5 × 1.0 cm) that was firm, ill-defined, white, and infiltrative, which corresponded to extravasated neoplastic cells on histopathology. There were no signs of infection, grossly or histopathologically. The portal vein thrombosis was related to neoplastic involvement, as the thrombus was predominantly composed of neoplastic lymphocytes. Autops Case Rep (São Paulo). 2017;7(4):30-36


Ronny FMH, Black MA, Arbini AA

The neoplastic lymphoid cells were larger in size with large pleomorphic nuclei and irregular prominent nucleoli. Some anaplastic cells were seen with larger more atypical features. The tumor burdens were largely within the vasculature. CD20, PAX5, CD5, CD10, MUM1, CD3, and Ki-67 immunohistochemistry stains were obtained on the pancreatic mass (Figure 3) and the lung tissue (Figure 4). The malignant cells were positive for CD20 (strong), MUM1 (weak), Pax-5 (weak) and CD5, and were negative for CD3 and CD10. Ki-67 showed a high proliferative index (>90%). The Epstein‑Barr encoding region in situ hybridization was negative.

DISCUSSION We report the findings on a 71-year-old woman with no significant past medical history who presented with 3-month history of fatigue, anorexia, and

abdominal pain, who was found to be anemic, mildly thrombocytopenic, with abnormal liver function tests, and a ~2 cm pancreatic nodule diagnosed as DLBCL. The patient followed an inexplicably fulminant clinical course and succumbed less than 2 weeks after admission. The discrete pancreatic mass initially diagnosed as DLBCL at postmortem examination was proven to be a manifestation of widespread IVLBCL, which was an astounding discovery not previously described in the literature. A recent report has described a case of nodular goiter of the thyroid ultimately diagnosed as IVLBCL. 1 However, the lymphoma cells in the thyroid were harbored exclusively intravascularly. In our case, the radiographic findings of the pancreatic mass mostly resembled pancreatic carcinoma or neuroendocrine tumor, and the initial needle core biopsy proved inconclusive after extensive immunohistochemistry targeting those entities. However, evidence of lymphomatous origin

Figure 3. Photomicrography of pancreatic mass section is seen in A (H&E 10x). CD5, CD20 and Ki67(20x) immunohistochemistry stains in B, C and D, respectively, show intravascular infiltration of the lymphoma cells, which were positive for CD20 and CD5 with a high Ki67 proliferation index. Autops Case Rep (São Paulo). 2017;7(4):30-36

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Intravascular large B-cell lymphoma with multi-organ failure presenting as a pancreatic mass: a case with atypical presentation and definite diagnosis postmortem

was detected at cytologic examination of concomitant

intravascular component on the cytology specimen, but

fine needle aspiration; morphologic examination

it was clearly present on sections obtained at necropsy.

and immunostaining performed on the cytology cell

IVLBCL was first described in 1958 by Pfleger

block were diagnostic of DLBCL, which could not be

and Tappeiner as a very rare form of DLBCL that

further characterized due to tissue paucity. Subsequent

proliferates within small blood vessels.2 According

negative clinical staging suggesting that the lymphoma

to the 2008 WHO classification, this has been

was restricted to the approximately 2 cm pancreatic

categorized as a rare type of non-Hodgkin lymphoma.

nodule resulted in a clinical conundrum, as the patient’s

The main characteristic of IVLBCL is diffuse, occlusive,

general condition rapidly deteriorated despite robust

intravascular, lymphomatous proliferation affecting

antibiotic therapy, which drew increasing skepticism

the capillaries, small arteries, and veins. 3,4 IVLBCL

among infectious disease team members regarding

can involve any organ of the body, but typically the

the alleged infectious etiology. An incomprehensible

lymph nodes are spared. In 2014, Fonkem et al. 5

tumor lysis syndrome was contemplated but the

retrospectively analyzed 740 cases of intravascular

patient’s dismal conditions cautioned against systemic

lymphoma between 1959 and 2011, among which

chemotherapy while at the ICU. Only the postmortem

651 were IVLBCL. This retrospective research found

examination unveiled a widely disseminated IVLBCL,

that the central nervous system, bone marrow

which ultimately accounted for the patient’s demise.

spleen, skin, and lung involvement was present in

Retrospectively, we could not find evidence of an

60%, 11%, 11%, 8% and 7% of cases, respectively.

Figure 4. Photomicrography of representative lung section is seen in A (H&E 10x). CD20, CD5 and Ki67 immunohistochemistry stains in B, C and D, respectively, show intravascular infiltration by lymphoma cells positive for CD20 and CD5, with a high Ki67 proliferation index. 34

Autops Case Rep (São Paulo). 2017;7(4):30-36


Ronny FMH, Black MA, Arbini AA

The pathogenesis of IVLBCL is unclear, and an explanation accounting for its affinity to vascular beds remains elusive. Conceivably, adhesion molecule dysfunction would partly explain why lymphoma cells remain stationary within the lumen of vessels.6 Histologically, lymphoma cells are large and mitotically active with prominent nucleoli. Histopathology remains the gold standard for diagnosis, showing the classic appearance of large malignant lymphocytes filling the small vascular lumen. Immunohistochemically, the cells express B-cell markers with an aberrant expression of CD5 and, less likely, CD10, by a portion of cases. The clinical manifestations of IVLBCL are non-specific; fever, weight loss, progressive neurologic deficits, skin findings, and sweating are the most common presentations.7 Increased serum LDH and C-reactive protein are found in most cases, accompanied by anemia and decreased platelets and a white blood cell count.

achieve durable remission with early diagnosis and rituximab‑containing chemotherapy, which has improved the outcome of IVLBCL therapy.8-10

The pancreatic lesion described here with extravascular extension into the pancreatic parenchyma (as shown in Figure 3) is uncanny. We believe this represents a feature not previously described in other cases of IVLBCL. Apart from that, our case is indistinguishable from other IVLBCL, albeit we found other unusual features such as large vessel involvement, including portal vein and pulmonary arteries, and the infiltration of para‑esophageal and para-aortic lymph nodes. It is to be noted that CD5+ DLBCL often presents with low-level blood involvement, as well as visceral involvement of the liver, spleen, and bone marrow, which begs the question of a possible relationship reflecting the spectrum of a disease with common lymphomatous origin.

4. Nakamura S, Ponzoni M, Campo E. WHO classif tumours haematop lymphoid tissues. Lyon, France: IARC; 2008. p. 252-53.

While the diagnosis of IVLBCL is undisputable in light of the autopsy findings of extensive systemic small‑ and medium-sized vessel engorgement with large CD5+ lymphoma cells, the initial presentation of a discrete head of the pancreas mass that was biopsy proven CD5+ DLBCL, while the patient was still alive, represents a new clinical feature of this poorly understood lymphoma. In retrospect, this partly explains why the patient underwent tumor lysis after initial steroid therapy, which was out of proportion to the limited tumor burden she was thought to have at the time of diagnosis. This was attributed to concomitant sepsis, which the Infectious disease service deemed unlikely, although no better explanation could be hypothesized at the time. Therefore, it is important to consider this diagnosis in the appropriate settings because patients may Autops Case Rep (São Paulo). 2017;7(4):30-36

REFERENCES 1. Luo B, Chen JM, Liu J, et al. A case of intravascular large B cell lymphoma presenting as nodular goiter. Diagn Pathol. 2017;12(1):64. PMid:28841887. http://dx.doi. org/10.1186/s13000-017-0656-x. 2. Pfleger L., Tappeiner J. On the recognition of systematized endotheliomatosis of the cutaneous blood vessels (reticuloendotheliosis?). Hautarzt. 1959;10:359-63. 3. Ponzoni M, Ferreri AJM, Campo E, et al. Definition, diagnosis, and management of intravascular large B-cell lymphoma: proposals and perspectives from an international consensus meeting. J Clin Oncol. 2007;25(21):3168-73. PMid:17577023. http://dx.doi. org/10.1200/JCO.2006.08.2313.

5. Fonkem E, Lok E, Robison D, Gautam S, Wong ET. The natural history of intravascular lymphomatosis. Cancer Med. 2014;3(4):1010-24. PMid:24931821. http://dx.doi. org/10.1002/cam4.269. 6. Weitten T, Rozan-Rodier S, Guiot P, Andrès E, Mootien Y. Multiorgan failure caused by intravascular lymphoma: a highly rare and malignant hemopathy mimicking multisystemic disease. South Med J. 2008;101(9):9524. PMid:18708972. http://dx.doi.org/10.1097/ SMJ.0b013e318181291f. 7. Ferreri AJM, Campo E, Seymour JF, et al. Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the ‘cutaneous variant’. Br J Haematol. 2004;127(2):173-83. PMid:15461623. http:// dx.doi.org/10.1111/j.1365-2141.2004.05177.x. 8. Su DW, Pasch W, Costales C, Siddiqi I, Mohrbacher A. Asian-variant intravascular large B-cell lymphoma. Proc Bayl Univ Med Cent. 2017;30(2):186-9. PMid:28405077. 9. Makino K, Nakata J, Kawachi S, Hayashi T, Nakajima A, Yokoyama M. Treatment strategy for reducing the risk of rituximab-induced cytokine release syndrome in patients with intravascular large B-cell lymphoma: a case report and review of the literature. J Med Case Reports. 2013;7(1):280. PMid:24377366. http://dx.doi.org/10.1186/1752-1947-7280. 10. Tsuyama N, Ennishi D, Yokoyama M, et al. Clinical and prognostic significance of aberrant T-cell marker expression in 225 cases of de novo diffuse large B-cell lymphoma and 276 cases of other B-cell lymphomas. Oncotarget. 2017;8(20):33487-500. PMid:28380441. 35


Intravascular large B-cell lymphoma with multi-organ failure presenting as a pancreatic mass: a case with atypical presentation and definite diagnosis postmortem

Author contributions: Ronny FMH performed hematopathology tests, gathered data and prepared the manuscript. Black MA performed the autopsy and took the gross pictures. Arbini AA signed out the case and did the final review of the manuscript. Conflict of interest: None Financial support: None Submitted on: June 30th, 2017 Accepted on: September 20th, 2017 Correspondence Arnaldo A. Arbini Division of Hematopathology – Department of Pathology – NYU Langone Medical Center 240 East 38th Street, 22nd Floor – New York NY 10016 Phone: (1) 212-263-5967 arnaldo.arbini@nyumc.org

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Article / Autopsy Case Report

Respiratory distress of unknown etiology in a transplant recipient: think toxoplasmosis! Ameer Hamzaa, Ian Jacob Andersona, Basim Al-Khafajia How to cite: Hamza A, Anderson IJ, Al-Khafaji B. Respiratory distress of unknown etiology in a transplant recipient: think toxoplasmosis!. Autops Case Rep [Internet]. 2017;7(4):37-41. http://dx.doi.org/10.4322/acr.2017.038

ABSTRACT Disseminated toxoplasmosis is a life-threatening disease in immunocompromised individuals. Infection is contracted from handling contaminated soil, cat litter, or through the consumption of contaminated water or food. It is the third most common lethal foodborne infection in the United States. In transplant patients, most cases occur as a result of reactivation of a latent infection resulting from immunosuppression. We present a case of disseminated toxoplasmosis diagnosed at the time of autopsy. This case emphasizes the importance of maintaining a high index of clinical suspicion and active disease surveillance in this era of sophisticated diagnostic testing. Keywords: Autopsy; Allografts; Immunosuppression; Opportunistic infections; Kidney transplantation; Toxoplasmosis.

INTRODUCTION

CASE REPORT

Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii. It is a zoonotic disease with worldwide distribution and an opportunistic pathogen primarily infecting immunocompromised individuals. Global prevalence is 10-80%,1 but clinically significant disease is uncommon. In the United States, approximately 225,000 cases of toxoplasmosis are reported annually, resulting in 750 deaths, which makes T. gondii the third most common cause of lethal foodborne infection in the United States.2

A 49-year-old Caucasian male with a past medical history of end stage renal disease secondary to diabetes mellitus, status post deceased-donor kidney allograft and on immunosuppression with prednisone, tacrolimus and mycophenolate mofetil; hypertension, obesity, peripheral vascular disease, and anemia presented to the emergency department 6 weeks post-transplantation procedure with dehiscence of his right lower quadrant surgical wound. Upon admission, the patient was noted to be acidotic, hypovolemic, hyperkalemic, and in respiratory distress, necessitating intubation. He was urgently taken to the operating room for debridement and closure of the wound which he tolerated well; however, during the course of his hospital stay he exhibited altered mental status with continued respiratory distress. Despite receiving high flow supplemental oxygen, oxygen saturations were continually in the low 90% range. He also exhibited marked leukocytosis with a white blood cell count of 26,400/mm 3

In organ transplant recipients, toxoplasmosis is most commonly a result of reactivation of latent infection; however, donor-transmitted infection or de novo infection are known to occur. In these patients, the most common presentations are retinochoroiditis, cerebritis, pneumonitis, myocarditis, and disseminated disease. We describe the autopsy findings in a renal transplant recipient with disseminated toxoplasmosis diagnosed at autopsy.

St. John Hospital and Medical Center, Department of Pathology. Detroit, MI, USA.

a

Autopsy and Case Reports. ISSN 2236-1960. Copyright Š 2017. 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.


Respiratory distress of unknown etiology in a transplant recipient: think toxoplasmosis!

(normal range [NR]: 4000-11000/mm 3). Blood and urine cultures yielded no growth. CMV serology by PCR was negative with quantitative CMV DNA less than 250 CPY/ml (NR: < 250 CPY/ml). Toxoplasma serology was not ordered and was not done as a pre-transplant work up. His arterial partial oxygen pressure became critically low at 35.4 mmHg (NR: 80-100 mmHg) and he was intubated, however, there was no improvement of the respiratory status, and the patient experienced cardiorespiratory arrest. Resuscitative efforts were unsuccessful and the patient was pronounced

deceased with a postmortem examination requested and subsequently performed.

AUTOPSY FINDINGS Most significant finding at the autopsy was disseminated toxoplasmosis with T.gondii identified within the bilateral lungs, heart, liver, pancreas, bilateral native kidneys, transplanted kidney, spleen, bone marrow, and central nervous system (Figure 1 and 2).

Figure 1. Photomicrographs of the heart showing the T. gondii cyst (arrowhead and inset) (A – H&E, 400X; B – T.gondii stain 1000X).

Figure 2. Photomicrographs of the brain showing the T. gondii cysts in the Midbrain (A – H&E, 400X) and the Brainstem (B – H&E, 400X). 38

Autops Case Rep (São Paulo). 2017;7(4):37-41


Hamza A, Anderson IJ, Al-Khafaji B

Figure 3. Photomicrographs of the lungs exhibiting necrotizing bronchopneumonia (A – H&E, 100X). T. gondii cysts in Lungs (B-D, B-C – H&E, 400X and 1000X respectively, D – T. gondii stain 400X). Additional findings included cardiomegaly with left ventricular hypertrophy and moderate calcific atherosclerotic coronary artery disease; bilateral, multifocal necrotizing bronchopneumonia secondary to T.gondii (Figure 3); and hepatosplenomegaly. Immediate cause of death was cardiopulmonary arrest secondary to respiratory distress. Underlying cause was disseminated toxoplasmosis as a consequence of medical immunosuppression. Manner of death was natural. Autops Case Rep (São Paulo). 2017;7(4):37-41

DISCUSSION T. gondii infection in renal transplant patients is rare, but can be rapidly progressive and life threatening. Missed diagnosis is one of the causes of high mortality. Wulf et al.3 found that 43% of cases were diagnosed at autopsy. Recent data in this regard are not available; however, our case indicates that clinically missed toxoplasmosis in the setting of post-transplant immunosuppression remains a concern today. 39


Respiratory distress of unknown etiology in a transplant recipient: think toxoplasmosis!

T. gondii has two distinct life cycles. The sexual cycle occurs only in cats which are the definitive host. The asexual cycle occurs in other mammals, including humans and some avian species. In humans, infection occurs by ingestion of oocysts from handling contaminated soil or cat litter or through the consumption of contaminated water or undercooked meat of infected animals. Our patient, in fact, did own a cat. Clinical presentation is nonspecific. Fever occurs frequently, followed by flu like symptoms, lymphadenopathy, visual changes, pneumonia, and neurologic manifestations such as headache, seizures, altered mental status, and focal neurologic deficits. Our patient exhibited altered mental status and severe respiratory distress which correlated with the autopsy findings of bilateral, multifocal necrotizing bronchopneumonia and central nervous system involvement. Diagnosis is confirmed by serology, tissue biopsy, or PCR assay for the presence of T. gondii DNA. Serology is of limited value in the setting of reactivation of a latent infection. Moreover, interpretation of serologic tests in immunocompromised patients is not straightforward and absence of specific antibodies does not exclude active disease. The duration for which T. gondii can be detected in blood is not clear. Additionally, T. gondii is only present intermittently in cerebrospinal fluid for unknown reasons,4 which limits the use of PCR assay. However, it is found to be useful in acute primary infection.3 Tissue biopsy is not only an invasive procedure, but is also limited by sampling artifact. Maintaining a high index of clinical suspicion is therefore the cornerstone of proper diagnosis. Toxoplasmosis should be high on the list of differential diagnoses in a post-transplant patient with respiratory distress and culture negative sepsis. Imaging studies are valuable in cerebral and pulmonary toxoplasmosis. MRI is superior to CT scan in cerebral toxoplasmosis. Toxoplasma lesions on MRI appear as high-signal abnormalities on T2-weighted studies and demonstrate a rim of enhancement surrounding the edema on T1-weighted, contrast-enhanced images. CT scans show multiple bilateral cerebral lesions. Chest radiographs in toxoplasma pneumonia usually demonstrate interstitial infiltrate. In our patient, a CT of the head showed 40

asymmetric decreased attenuation in left frontal lobe white matter suggestive of microangiopathy or encephalomalacia. No acute intracranial abnormality or evidence pointing to T. gondii was noted. Chest x-ray showed mild to moderate prominence of the pulmonary vessels, interstitial infiltrates, and changes consistent with atelectasis. For more prevalent infections, such as HIV, HBV and HCV there is general agreement with respect to pre-transplant screening guidelines. Regarding screening for other infectious agents, including T. gondii, each transplant center follows different protocols. Many transplant centers screen both donors and recipients for anti-Toxoplasma antibody, especially in cases of heart transplant.5 Screening of donors and recipients for anti-Toxoplasma antibody is not routinely performed for noncardiac transplants, but is part of the screening panel at some transplant centers. 5 Seropositivity is not a contraindication to transplantation but allows for administration of appropriate prophylaxis.5 Our transplant center does not perform toxoplasma screening routinely. Moreover, trimethoprim-sulfamethoxazole prophylaxis against Pneumocystis jiroveci is thought to be effective in preventing toxoplasmosis.6 For these reasons routine pre-transplant screening for T. gondii is not recommended in kidney transplant donors and recipients, especially in low prevalence areas. Toxoplasma serology was neither performed on our patient nor the donor. The patient was initially started on trimethoprim-sulfamethoxazole prophylaxis; however, it was discontinued due to resultant hyperkalemia. Pyrimethamine is the mainstay of treatment. The most effective available therapeutic combination is pyrimethamine plus sulfadiazine or trisulfapyrimidines. Unfortunately, our patient expired before treatment could be initiated. This case emphasizes the importance of maintaining a high index of clinical suspicion and active disease surveillance in this era of sophisticated diagnostic testing. The manuscript is in accordance with St. John Hospital and Medical Center review board’s recommendations. Autops Case Rep (São Paulo). 2017;7(4):37-41


Hamza A, Anderson IJ, Al-Khafaji B

REFERENCES 1. Pappas G, Roussos N, Falagas ME. Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis. Int J Parasitol. 2009;39(12):1385-94. PMid:19433092. http://dx.doi.org/10.1016/j.ijpara.2009.04.003. 2. Hökelek M. Toxoplasmosis. 2017 [cited 2017 Oct 11]. Available from: http://emedicine.medscape.com/ article/229969-overview 3. Wulf MW, van Crevel R, Portier R, et al. Toxoplasmosis after renal transplantation: implications of a missed diagnosis. J Clin Microbiol. 2005;43(7):35447. PMid:16000502. http://dx.doi.org/10.1128/ JCM.43.7.3544-3547.2005.

4. Schoondermark-van de Ven E, Galama J, Kraaijeveld C, van Druten J, Meuwissen J, Melchers W. Value of the polymerase chain reaction for the detection of Toxoplasma gondii in cerebrospinal fluid of patients with AIDS. Clin Infect Dis. 1993;16(5):661-6. PMid:8507757. http://dx.doi.org/10.1093/clind/16.5.661. 5. Fischer SA, Lu K. Screening of donor and recipient in solid organ transplantation. Am J Transplant. 2013;13(Suppl 4):9-21. PMid:23464994. http://dx.doi.org/10.1111/ ajt.12094. 6. Gourishankar S, Doucette K, Fenton J, Purych D, Kowalewska-Grochowska K, Preiksaitis J. The use of donor and recipient screening for toxoplasma in the era of universal trimethoprim sulfamethoxazole prophylaxis. Transplant. 2008;85(7):980-5. PMid:18408578. http:// dx.doi.org/10.1097/TP.0b013e318169bebd.

Author contributions: All authors contributed significantly and are in agreement with the content of the manuscript. Conflict of interest: None Financial support: None Submitted on: October 23rd 2017 Accepted on: November 1st, 2017 Correspondence Ameer Hamza Department of Pathology - St John Hospital and Medical Center 22101 Moross Road – Detroit/MI – USA 48236 Phone: +1 (313) 613-7511 / Fax: +1 (313) 343-8318 ameerhamza7@hotmail.com

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Article / Autopsy Case Report

Bone marrow necrosis and fat embolism syndrome: a dreadful complication of hemoglobin sickle cell disease Eduardo Pelegrineti Targuetaa, André Carramenha de Góes Hiranoa, Fernando Peixoto Ferraz de Camposb, João Augusto dos Santos Martinesc, Silvana Maria Lovisolod, Aloisio Felipe-Silvad,e How to cite: Targueta EP, Hirano ACG, Campos FPF, Martines JAS, Lovisolo SM, Felipe-Silva A. Bone marrow necrosis and fat embolism syndrome: a dreadful complication of hemoglobin sickle cell disease. Autopsy Case Rep [Internet]. 2017;7(4):42-50. http://dx.doi.org/10.4322/acr.2017.043

ABSTRACT Sickle cell disease encompasses a wide range of genotypic presentation with particular clinical features. The entity affects millions of people, particularly those whose ancestors came from sub-Saharan Africa and other countries in the Western Hemisphere, Saudi Arabia, and India. Currently, the high frequency of S and C genes reflects natural selection through the protection of heterozygotes against severe malaria, the high frequency of consanguineous marriages, improvement of some public health policies and the nutritional standards in the poorer countries where newborns are now living long enough to present for diagnosis and management. Although there is a high burden of the disease, in many countries, the new-born sickle cell screening test is being performed and is rendering an early diagnosis; however, it is still difficult for sickle cell patients to find proper treatment and adequate follow-up. Moreover, in many countries, patients are neither aware of their diagnosis nor the care they should receive to prevent complications; also, they do not receive adequate genetic counseling. Hemoglobin SC (HbSC) disease is the most frequent double sickle cell heterozygosis found in Brazil. The clinical course tends to be more benign with fewer hospitalizations compared with double homozygotic SS patients. However, HbSC patients may present severe complications with a fatal outcome. We report the case of a 36-year-old man who presented to the emergency care facility with symptoms consistent with the diagnosis of sickling crisis. The outcome was unfavorable and death occurred just hours after admission. The autopsy revealed a generalized vaso-occlusive crisis by sickled red cells, bone marrow necrosis, and fat embolism syndrome. Keywords: Hemoglobin SC Disease; Bone Marrow; Necrosis; Embolism

CASE REPORT A 36-year-old mulatto male patient sought the emergency facility complaining of lumbar pain of progressive intensity over the past 3 days that worsened with trunk movement. This symptom irradiated to

the dorsum and was accompanied by breathlessness. Concomitantly, he complained of wheezing, a cough with mucoid sputum, which was soon followed by dark urine. He had known diagnosis of SCD since the age of

University of São Paulo (USP), Faculty of Medicine, Internal Medicine Department. São Paulo, SP, Brazil. University of São Paulo (USP), Hospital Universitário, Internal Medicine Department. São Paulo, SP, Brazil. c University of São Paulo (USP), Hospital Universitário, Radiology Department. São Paulo, SP, Brazil. d University of São Paulo (USP), Hospital Universitário, Anatomic Pathology Department. São Paulo, SP, Brazil. e University of São Paulo (USP), Faculty of Medicine, Anatomic Pathology Department. São Paulo, SP, Brazil. a

b

Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2017. 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.


Targueta EP, Hirano ACG, Campos FPF, Martines JAS, Lovisolo SM, Felipe-Silva A

23 years when he experienced an episode of priapism that required surgical intervention. Since then he had not followed any medical treatment. However, he experienced repeated episodes of bone pain, for which he used over-the-counter painkillers as self-medication. He ignored the same diagnosis among his relatives. He smoked for 2 years in his youth and still consumed alcoholic beverages. On physical examination, he was slightly pale, non-icteric and afebrile. His pulse rate was 124 beats per minute, blood pressure 110/80 mmHg, respiratory rate 28 respiratory movements per minute (rmpm), and room air oximetry was 83%. His body mass index was 25. No edema or lymphadenopathy were found. The heart and lungs examination was unremarkable; however, the abdomen was diffusely tender and the liver was palpable 2 cm below the right costal margin. The examination of his back and lumbar region was normal. The laboratory work-up disclosed normocytic normochromic anemia with a hemoglobin of 10.9 g/dL (reference value [RV]: 12.3-15.3 g/dL); hematocrit of 30.1% (RV: 36-45%); red cell distribution width of 20.6% (RV: 14%); leukocytosis with the presence of myelocytes and metamyelocytes in

the peripheral blood; and a normal platelet count. The peripheral blood film revealed the presence of poikilocytosis, target cells, and stomatocytes; rare erythrocytes showed the presence of Howell-Jolly bodies, 20 polychromatic, 19 orthochromatic erythroblasts per 100 leukocytes and occasional sickled erythrocytes. Reticulocyte count was not available. C-reactive protein was 173 mg/L (RV: <5 mg/L), lactate dehydrogenase 686 U/L (RV: <250 U/L), and a total bilirubin 1.49 mg/dL (RV: <1.2 mg/dL) at the expense of indirect bilirubin. The renal function tests, electrolytes, liver enzymes, and urinalysis were normal. Blood and urine cultures were negative. The chest x-ray and computed tomography (CT) revealed peri-hilar bilateral confluent ground-glass opacities rendering small consolidations (Figures 1 and 2). An apparently calcified spleen of reduced dimension was an additional finding. With the working diagnosis of hemolytic crisis, and a possible pulmonary infection, the patient was treated with saline, ceftriaxone, clarithromycin, morphine, and oxygen supplementation. His vital signs improved over the next 12 hours, but suddenly he presented

Figure 1. Chest radiograph showing bilateral air space opacification and cardiac silhouette enlargement. Autops Case Rep (São Paulo). 2017;7(4):42-50

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Bone marrow necrosis and fat embolism syndrome: a dreadful complication of hemoglobin sickle cell disease

Figure 2. Chest CT, pulmonary window, axial view in the upper (A), middle (B), and lower thirds (C) of the lungs and coronal reconstruction (D) showing multiple ground-glass opacities in all pulmonary lobes, tiny foci of consolidation associated with septal thickening mostly in the upper pulmonary fields.

worsened abdominal pain with nausea, vomiting and tachypnea (respiratory rate of 36 rmpm). He became obtunded and unresponsive to any stimuli, and presented cardiac arrest in pulseless electrical activity followed by asystole. Aspiration of vomiting was evident during the orotracheal intubation maneuver. The capillary electrophoresis of the hemoglobin undertaken after death revealed the presence of 1.9% HbF, 50.3% HbS, 3.6% HbA2, and 44.2% HbC, rendering the diagnosis of hemoglobinopathy SC.

AUTOPSY FINDINGS The lungs were edematous and boggy with multiple areas of friable consolidation and gross thromboemboli (Figure 3). 44

Microscopic examination showed acute and organizing thrombi, and mainly necrotic bone marrow embolism in pulmonary artery branches and arterioles, fat embolism in the alveolar septa capillary, and fibrin thrombi. There were multifocal areas of pulmonary congestion, hemorrhage, alveolar edema, and diffuse alveolar damage (Figure 4). Focal hemosiderin deposition was a sign of previous chronic hemorrhage. The kidneys showed congestion, acute tubular necrosis, and glomerular fat emboli. The bone marrow was hypercellular, mainly due to precursor erythroid cell hyperplasia, with large areas of infarction (about 50%), hemorrhage, and sickled cells (Figure 5). The brain was mildly congested and edematous. Microscopically, it showed intraparenchymal vascular Autops Case Rep (São Paulo). 2017;7(4):42-50


Targueta EP, Hirano ACG, Campos FPF, Martines JAS, Lovisolo SM, Felipe-Silva A

Figure 3. Gross picture of formalin-fixed left lung showing areas of hemorrhage and thromboemboli (arrowheads).

Figure 4. Photomicrography of the lung. A – Organizing thrombus and diffuse congestion (H&E 12.5X); B – Fibrin microthrombus (right) and a fat droplet in a capillary vessel (left) (H&E 400X); C – Small fat droplets (arrowheads) (H&E 400X); D – Adipocytes in the capillaries of alveolar septa (H&E 400X). Autops Case Rep (São Paulo). 2017;7(4):42-50

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Bone marrow necrosis and fat embolism syndrome: a dreadful complication of hemoglobin sickle cell disease

Figure 5. Photomicrography of the necrotic bone marrow (A) (H&E 400X) and branch of the pulmonary artery (B) showing embolization of necrotic bone marrow with interstitial adipocytes (H&E 100X). congestion and small foci of recent perivascular hemorrhage with sickled red cells and some pyknotic neurons. The liver was congested and microscopically showed diffuse sinusoidal congestion with sickled red cells, mild steatosis, and foci of extramedullary hematopoiesis. The spleen was diminished and atrophic, with fibrous plaques on the surface and extensive scarring fibrosis and calcifications in the parenchyma. Multiple Gamna-Gandy nodules with calcifications and hemosiderin deposits were seen. Other findings were systemic congestion with sickled red cells, foci of ischemic necrosis in the pancreas, adrenals, and gastrointestinal tract. The heart showed moderate hypertrophy of the left ventricle wall. The cause of the death was attributed to SCD crisis complicated by bone marrow necrosis and fat embolism syndrome with fatal impairment of lung function due to thrombosis, hemorrhage, and acute alveolar damage.

DISCUSSION Hemoglobin SC disease (HbSC) is part of a group of disorders called “sickle cell diseases” (SCDs), which comprises hemoglobin SC disease and other hemoglobinopathies such as SD, SE, and others.1 These are hereditary hemoglobinopathies, which, in due course of genetic alterations, result in 46

defective hemoglobin and consequent altered-form erythrocytes due to hemoglobin polymerization (which is the underlying mechanism for most of the complications of the disease). 2 In 2001, newborn screening for SCD started in Brazil when the National Newborn Screening Program (PNTN)/Guthrie test was founded. According to data from the Ministry of Health, around 3500 children are born with SCD each year in Brazil, and the estimated number of cases of the disease ranges between 25,000 and 30,000, which shows the high prevalence of this disease in the Brazilian population, and its importance to public health.1 SCD is not only relevant in Brazil, but also in other parts of the world, where it is considered a public health concern, especially in Africa.3,4 Among all of SCD, SS, and SC genotypes are the most common.5 The SS genotype (inheritance of 2 βS alleles), also known as sickle cell anemia (SCA), is a debilitating disease with severe pain crisis, hemolysis, increased susceptibility to infections, cerebrovascular events, chronic organ damage, frequent hospitalizations, and consequently low expectancy of life (42 years for men and 48 years for women).6 Although SC hemoglobinopathy has a more protracted course, both SC and SS may present with similar complications.7 Studies focused on laboratory biomarkers have shown that SCA individuals are more associated with endothelial dysfunction and hemolysis, while the HbSC genotype is more associated with increased blood viscosity and inflammatory disorders.8 Proliferating retinitis, osteonecrosis, and acute chest syndrome, may Autops Case Rep (São Paulo). 2017;7(4):42-50


Targueta EP, Hirano ACG, Campos FPF, Martines JAS, Lovisolo SM, Felipe-Silva A

have equal or higher incidence in HbSC compared to SCA.9 The first manifestation of HbSC usually appears around 20 years of age and irreversible organ failure is 10-35 years later than SCA. 10 Our patient first became aware he had SCD at the age of 23, when he experienced an episode of priapism. However, apparently, he was not well informed of the HbSC diagnosis, which was only confirmed post-mortem with the hemoglobin electrophoresis.

Bone marrow necrosis is a common finding in SCD patients. Due to the anatomy of trabecular bone, the material from the necrotic marrow enters the venules, gaining access to the veins and the systemic circulation.16 It is important to understand the difference between bone marrow embolism and fat embolism. The former has been observed mainly in the medium and small branches of pulmonary arteries, while the latter ends up in the microscopic circulation.19

During the patient’s brief stay in the hospital, the working diagnosis was of SCD, and there was evidence suggesting both SCA and HbSC as possible causes. The radiological findings of an atrophic and calcified spleen suggested SCA. In SCA, most patients present with autoinfarction and asplenia within the first 18-36 months of life. Meanwhile, HbSC patients often have preserved splenic function (only 36% of HbSC patients have asplenic findings).9,11,12 However, the laboratory findings with the hemoglobin of 10.9 g/dL and the hematocrit of 30.1% were more consistent with the diagnosis of HbSC or sickle cell trait.8

Although mechanical obstruction by the fat emboli is necessary for the occurrence of FES, it is not the only requirement. Pell et al.20 showed fat emboli passing through the heart (using transesophageal echocardiography) in cases of long bone fracture patients in a much higher frequency than FES occurs. Therefore, it has been hypothesized that biochemical factors, such as the agglutination of chylomicrons and very-low-density lipoprotein cholesterol and direct damage to the lung tissue by free fatty acids, play an important role in the pathogenesis of FES.21,22

Our patient’s cause of death, depicted at autopsy, was necrosis of the bone marrow with subsequent fat embolism syndrome (FES) and sickled red cells in the pulmonary capillaries. This clinical entity is the result of the release of fat globules into the circulation, causing respiratory and neurologic damage, cutaneous and hematological manifestations. 13 Although FES is most often associated with long bone fractures, occurring in up to 2.4% of multiple long bone fracture patients, it is a dreadful known complication of SC hemoglobinopathy.14 FES as a consequence of bone marrow necrosis in individuals with SCD was first described by Wade and Stevenson,15 in 1941, who found “widespread necrosis with marked reduction in the blood-forming constituents and fat, and fat emboli in the lung, liver, brain, spleen and kidneys.” In 2005, a review article16 retrieved 24 cases in the literature. Nine years later, Tsitsikas et al.17 reported 58 gathered cases. Out of these 58 patients, 11 (19%) had HbSS, 25 (43%) presented HbSC and 10 (17%) had HbSβ+. The higher frequency of FES in HbSC individuals may be explained by higher hematocrit and subsequent higher blood viscosity, although the entire pathogenesis of FES is still not fully understood.18 Autops Case Rep (São Paulo). 2017;7(4):42-50

There are still no definitive criteria for the diagnosis of FES, which is usually made on clinical grounds. However, biochemical and imaging tests may be ancillary tools. The classic triad is a red-brown petechial rash, mostly on the head, neck, anterior thorax, axillae, and sub-conjunctiva; central nervous system depression and pulmonary edema. Gurd’s 23 criteria is most commonly used for diagnosing FES, although its reliability has been questioned and other schemes have been proposed, such as Schonfeld’s and Lindeque et al.’s24 criteria. In the appropriate setting, the rash is very specific for FES. However, it is present in less than half the patients.25 Hypoxemia often occurs within the first 72 hours along with thrombocytopenia and leukocytosis.26 Chest radiography usually reveals unspecific diffuse or patchy bilateral opacities. 23 In contrast, chest CT may be useful to evaluate the patients with the potential diagnosis of FES, and, more importantly, to rule out or demonstrate an alternative diagnosis. The most common finding on the CT is the patchy ground-glass opacities, which are usually associated with interlobular septal thickening (crazy-paving pattern), and eventually airspace consolidation and small centrilobular nodules.27 Bronchoalveolar lavage also has been described as an ancillary tool for the diagnosis of FES. Patients with FES may present fat-laden macrophages in a 47


Bone marrow necrosis and fat embolism syndrome: a dreadful complication of hemoglobin sickle cell disease

percentage that ranges from 31% to 82%, while patients without FES present less than 2%. A cut-off value of 5% is apparently sensible for diagnosing FES, but with poor specificity. However, if the cut-off raises to 30% the specificity also raises substantially.28-32

2013;35(5):325-31. PMid:24255615. http://dx.doi. org/10.5581/1516-8484.20130110. 2. Brasil. Ministério da Saúde. Agência Nacional de Vigilância Sanitária. Manual de diagnóstico e tratamento de doenças falciformes. Brasilia: ANVISA; 2001. 10 p.

The mortality of SC crisis with FES is high. In their 2014 review, Tsitsikas et al.17 found 64% mortality. Comparing the patients of different groups that received exchange transfusion (ET), top-up transfusion, or no transfusion, the higher survival rate was observed in the ET group (mortality rate of 29%, 61%, and 91%, respectively), indicating that ET may be the cornerstone in the treatment of FES. However, clinical trials are lacking to support such an observation. The mortality rate of SCD complicated by FES might be underestimated because many cases are only diagnosed postmortem; and diagnosis of milder cases is often difficult and missed.17

3. World Health Organization (WHO). The health of the people: what works. The African Regional Health Report. Africa: WHO; 2014.

Our patient presented with abdominal and lumbar pain, hypoxemia, and bilateral lung opacities, and a history of sickle cell disease, which led to the diagnosis of vaso-occlusive crisis and acute chest syndrome (ACS). This clinical presentation fulfilled the criteria for ACS, since there was a new radiographic pulmonary infiltrate associated with hypoxemia, tachypnea, cough, and wheezing.33 Fat embolism is one of the proposed underlying mechanisms of ACS.34 Our patient had neither petechial rash nor central nervous system depression prior to his cardiac arrest. The diagnosis of FES was not made ante-mortem possibly because of the lack of its clinical hallmarks and its resemblance with ACS. The chest imaging also led to a diagnosis of a possible lung infection. Moreover, FES is a rare event in non-traumatic patients, whereas ACS is a frequent diagnosis in Brazilian emergency rooms.

7. Campos FPF, Ferreira CR, Felipe-Silva A. Bone marrow necrosis and fat embolism: an autopsy report of a severe complication of hemoglobin SC disease. Autops Case Rep. 2014;4(2):9-20. PMid:28580322. http://dx.doi. org/10.4322/acr.2014.012.

We conclude that SCD patients who present with back and abdominal pain associated with respiratory failure and laboratory findings consistent with hemolysis (even in the absence of marked sickled erythrocytes) should ever be treated in intensive care units and those who rapidly progress to neurological dysfunction should early be submitted to ET.

4. Grosse SD, Odame I, Atrash HK, Amendah DD, Piel FB, Williams TN. Sickle cell disease in Africa: a neglected cause of early childhood mortality. Am J Prev Med. 2011;41(6, Suppl 4):S398-405. PMid:22099364. http:// dx.doi.org/10.1016/j.amepre.2011.09.013. 5. Zago MA, Falcão RP, Paquini R. Hematologia: fundamentos e práticas. São Paulo: Atheneu; 2004. p. 295-297. 6. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease: life expectancy and risk factors for early death. N Engl J Med. 1994;330(23):1639-44. PMid:7993409. http://dx.doi.org/10.1056/NEJM199406093302303.

8. Aleluia MM, Fonseca TCC, Souza RQ, et al. Comparative study of sickle cell anemia and hemoglobin SC disease: clinical characterization, laboratory biomarkers and genetic profiles. BMC Hematol. 2017;17(1):15. PMid:28932402. http://dx.doi.org/10.1186/s12878-017-0087-7. 9. Nagel RL, Fabry ME, Steinberg MH. The paradox of hemoglobin C disease. Blood Rev. 2003;17(3):167-78. PMid:12818227. http://dx.doi.org/10.1016/S0268960X(03)00003-1. 10. Powars D, Chan LS, Schroeder WA. The variable expression of sickle cell disease is genetically determined. Semin Hematol. 1990;27(4):360-76. PMid:2255920. 11. Loureiro MM, Rozenfeld S. Epidemiology of sickle cell disease hospital admissions in Brazil. Rev Saude Publica. 2005;39(6):943-9. PMid:16341405. http://dx.doi. org/10.1590/S0034-89102005000600012. 12. Gardner CS, Boll DT, Bhosale P, Jaffe TA. CT abdominal imaging findings in patients with sickle cell disease: acute vaso-occlusive crisis, complications, and chronic sequelae. Abdom Radiol. 2016;41(12):2524-32. PMid:27600384. http://dx.doi.org/10.1007/s00261-016-0890-9.

REFERENCES

13. Mellor A, Soni N. Fat embolism. Anaesthesia. 2001;56(2):145-54. PMid:11167474. http://dx.doi. org/10.1046/j.1365-2044.2001.01724.x.

1. Pereira SA, Brener S, Cardoso CS, Proietti AB. Sickle cell disease: quality of life in patients with hemoglobin SS and SC disorders. Rev Bras Hematol Hemoter.

14. Tsai IT, Hsu CJ, Chen YH, Fong YC, Hsu HC, Tsai CH. Fat embolism syndrome in long bone fracture—clinical experience in a tertiary referral center in Taiwan. J Chin

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Med Assoc. 2010;73(8):407-10. PMid:20728851. http:// dx.doi.org/10.1016/S1726-4901(10)70088-5. 15. Wade LJ, Stevenson LD. Necrosis of the bone marrow with fat embolism in sickle cell anemia. Am J Pathol. 1941;17(1):47-54, 5. PMid:19970543. 16. Dang NC, Johnson C, Eslami-Farsani M, Haywood LJ. Bone marrow embolism in sickle cell disease: a review. Am J Hematol. 2005;79(1):61-7. PMid:15849760. http:// dx.doi.org/10.1002/ajh.20348. 17. Tsitsikas DA, Gallinella G, Patel S, Seligman H, Greaves P, Amos RJ. Bone marrow necrosis and fat embolism syndrome in sickle cell disease: increased susceptibility of patients with non-SS genotypes and a possible association with humen parvovirus B19 infection. Blood Rev. 2014;28(1):23-30. PMid:24468004. http://dx.doi. org/10.1016/j.blre.2013.12.002.

25. King MB, Harmon KR. Unusual forms of pulmonary embolism. Clin Chest Med. 1994;15(3):561-80. PMid:7982347. 26. Benoit PR, Hampson LG, Burgess JH. Respiratory gas exchange following fractures: the role of fat embolism as a cause of arterial hypoxemia. Surg Forum. 1969;20:2146. PMid:5383056. 27. Malagari K, Economopoulos N, Stoupis C, et al. Highresolution CT findings in mild pulmonary fat embolism. Chest. 2003;123(4):1196-201. PMid:12684311. http:// dx.doi.org/10.1378/chest.123.4.1196. 28. Chastre J, Fagon JY, Soler P, et al. Bronchoalveolar lavage for rapid diagnosis of the fat embolism syndrome in trauma patients. Ann Intern Med. 1990;113(8):583-8. PMid:2400168. http://dx.doi.org/10.7326/0003-4819113-8-583.

18. Castro O. Systemic fat embolism and pulmonary hypertension in sickle cell disease. Hematol Oncol Clin North Am. 1996;10(6):1289-303. PMid:8956017. http:// dx.doi.org/10.1016/S0889-8588(05)70401-9.

29. Roger N, Xaubet A, Agusti C, et al. Role of bronchoalveolar lavage in the diagnosis of fat embolism syndrome. Eur Respir J. 1995;8(8):1275-80. PMid:7489790. http:// dx.doi.org/10.1183/09031936.95.08081275.

19. Rappaport H, Raum M, Horrell JB. Bone marrow embolism. Am J Pathol. 1951;27(3):407-33. PMid:19970979.

30. Godeau B, Schaeffer A, Bachir D, et al. Bronchoalveolar lavage in adult sickle cell patients with acute chest syndrome: value for diagnostic assessment of fat embolism. Am J Respir Crit Care Med. 1996;153(5):16916. PMid:8630622. http://dx.doi.org/10.1164/ ajrccm.153.5.8630622.

20. Pell AC, Christie J, Keating JF, Sutherland GR. The detection of fat embolism by transesophageal echocardiography during reamed intramedullary nailing: a study of 24 patients with femoral and tibial fractures. J Bone Joint Surg Br. 1993;75(6):921-5. PMid:8245083. 21. Lehman EP, Moore RM. Fat embolism, including experimental production without trauma. Arch Surg. 1927;14(3):621-62. http://dx.doi.org/10.1001/ archsurg.1927.01130150002001. 22. Schuster DP. ARDS: clinical lessons from the oleic acid model of acute lung injury. Am J Respir Crit Care Med. 1994;149(1):245-60. PMid:8111590. http://dx.doi. org/10.1164/ajrccm.149.1.8111590.

31. Stanley JD, Hanson RR, Hicklin GA, Glazier AJ Jr, Ervanian A, Jadali M. Specificity of bronchoalveolar lavage for the diagnosis of fat embolism syndrome. Am Surg. 1994;60(7):537-41. PMid:7516631. 32. Mimoz O, Edouard A, Beydon L, et al. Contribution of bronchoalveolar lavage to the diagnosis of posttraumatic pulmonary fat embolism. Intensive Care Med. 1995;21(12):973-80. PMid:8750121. http://dx.doi. org/10.1007/BF01700658.

23. Gurd AR. Fat embolism: an aid to diagnosis. J Bone Joint Surg. 1970;52(4):732-7. PMid:5487573.

33. Ballas SK, Lieff S, Benjamin LJ, et al. Definitions of the phenotypic manifestations of sickle cell disease. Am J Hematol. 2010;85(1):6-13. PMid:19902523.

24. Lindeque B, Schoeman H, Dommisse G, Boeyens MC, Vlok AL. Fat embolism and the fat embolism syndrome: a double-blind therapeutic study. J Bone Joint Surg. 1987;69(1):128-31. PMid:3818718.

34. Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med. 2008;359(21):225465. PMid:19020327. http://dx.doi.org/10.1056/ NEJMra0804411.

Author contributions: All authors have significantly contributed, and are in agreement with the content of the manuscript. Targueta EP, Hirano ACG, Campos FPF designed and wrote the manuscript after gathering all the required information. Lovisolo SM performed the autopsy with Felipe-Silva A, who wrote the autopsy report and provided the pathology images. Martines JAS reported and provided the diagnostic imaging. Conflict of interest: None Financial support: None Autops Case Rep (São Paulo). 2017;7(4):42-50

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Bone marrow necrosis and fat embolism syndrome: a dreadful complication of hemoglobin sickle cell disease

Submitted on: 11th, November 2017 Accepted on: 23rd, November 2017 Correspondence Fernando Peixoto Ferraz de Campos Internal Medicine Department - Hospital Universitário - University of São Paulo (USP) Av. Prof. Lineu Prestes 2565 – Butantã – São Paulo/SP – Brazil CEP: 05508-000 Phone: +55 (11) 3091-9275 fpfcampos@gmail.com

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Article / Clinical Case Report

Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells reported in an asymptomatic patient: a rare case and literature review Ramen Sakhia, Ameer Hamzaa, Muhammad Siddique Khurramb, Warda Ibrara, Paul Mazzaraa How to cite: Sakhi R, Hamza A, Khurram MS, Ibrar W, Mazzara P. Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells reported in an asymptomatic patient: a rare case and literature review. Autops Case Rep [Internet]. 2017;7(4):51-57. http://dx.doi.org/10.4322/acr.2017.042

ABSTRACT Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UC-OGC) is a rare and poorly described pancreatic malignancy. It is comprised of mononuclear, pleomorphic, and undifferentiated cells as well as osteoclast-like giant cells (OGC’s). It constitutes less than 1% of pancreatic non-endocrine neoplasia and is twice as likely to occur in females as in males. Its histopathologic properties remain poorly understood. It is suspected that UC-OGC is of epithelial origin that can then transition to mesenchymal elements. As part of this study, we describe a case of a malignant pancreatic neoplasm that was discovered in a 69-year old patient as an incidental finding. We also provide an overview of previously published data to highlight UC-OGC’s clinical and pathologic features. Keywords Adenocarcinoma; Carcinoma, Pancreatic Ductal; Osteoclasts; Pancreatic Neoplasms.

INTRODUCTION Pancreatic carcinoma is the second most common type of gastrointestinal malignancy after colorectal carcinoma.1,2 Undifferentiated carcinoma of the pancreas (UCP) and undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UC-OGC) are rare neoplasms that make up 2% of pancreatic malignancies.3,4 UCP can be further sub classified into sarcomatoid carcinoma and carcinosarcoma.5 UCP has a much poorer prognosis than typical ductal adenocarcinoma of the pancreas.1,6 Survival in some reports has been on average as low as 5 months from the time of diagnosis.3,6 Based on histologic features, UCP subtypes and UC-OGC have notable overlap, such as the presence of heterologous elements including osteoid, muscle and cartilage.6 However, the presence

of OGC’s is a defining characteristic of UC-OGC in the World Health Organization (WHO) classification of pancreatic malignancies.7 This entity makes up less than 1% of pancreatic malignancies and has a distinct histopathological and clinical profile.1,8 We describe a case of UC-OGC with sarcomatoid features and abundant osteoid production in a previously asymptomatic patient.

CASE REPORT A 69-year old male with a past medical history of chronic hypercholesterolemia, hypertension and morbid obesity and remote history of alcohol and

St. John Hospital and Medical Center, Department of Pathology. Detroit, MI, USA. Vanderbilt University Medical Center, Department of Pathology. Nashville, TN, USA.

a

b

Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2017. 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.


Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells reported in an asymptomatic patient: a rare case and literature review

tobacco use was incidentally discovered to have a 2.5 cm partially calcified, cystic mass within the body of the pancreas. The mass was discovered as an incidental finding on CT angiogram of the abdomen (Figures 1A and 1B) during the evaluation for an abdominal aortic aneurysm. Follow-up esophagogastroduodenoscopy/endoscopic-ultrasound

highlighted a 2.7 × 2.6 cm hypoechoic, heterogeneous, partially calcified lesion abutting the splenic vein (Figure 1). EUS aspiration revealed a high grade malignant neoplasm of uncertain origin. The patient was not jaundiced and his total and direct bilirubin, lipase, amylase and CA19-9 were within normal limits. He denied

Figure 1. Abdominal Computed Tomography with intravenous and oral contrast: Sagittal (A) and Coronal (B) views demonstrating a well-circumscribed heterogeneous mass within the body of the pancreas (arrowheads), apparently without vascular invasion. 52

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Sakhi R, Hamza A, Khurram MS, Ibrar W, Mazzara P

having nausea, vomiting, diarrhea, constipation, abdominal pain, appetite changes or bloating. The patient subsequently underwent endovascular repair of his abdominal aortic aneurysm and his recovery remained unremarkable for any gastrointestinal symptoms. Six weeks later the patient underwent a fine needle aspiration (FNA) of the pancreatic mass which demonstrated numerous malignant cells with enlarged hyperchromatic nuclei with prominent nucleoli, as well as many multinucleated cells. Four weeks later the patient underwent an elective exploratory laparotomy that consisted of a subtotal pancreatectomy, splenectomy and omentectomy. The pancreatic mass

was found to have dense adhesions around the celiac trunk and splenic vessels which necessitated resection of the spleen and a portion of the inferior mesenteric vein. The lesion was a 3.5 × 2.5 cm firm, brown to yellow, well-circumscribed, heterogeneous nodule with focal areas of hemorrhage. There was no evidence of tumor extending beyond the pancreas. On microscopic examination, the tumor was predominated by pleomorphic, spindle cells associated with hemorrhage and abundant hemosiderin pigment (Figures 2A and 2B). The spindle cell sarcomatous component was diffusely immunoreactive with vimentin (Figure 2C). Notably, the tumor contained

Figure 2. Photomicrography of the pancreatic mass showing in A – Pleomorphic giant cells and malignant spindle cells (H&E, 200X); B – hemosiderin and red blood cells (H&E, 200X); C – staining positive for vimentin (200X); and D – Ductal carcinoma component (H&E, 200X) Autops Case Rep (São Paulo). 2017;7(4):51-57

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Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells reported in an asymptomatic patient: a rare case and literature review

several well-formed ductal structures (Figure 2D). With immunohistochemical staining the glandular structures were reactive with CK AE1/AE3 and CK Cam5.2 (Figures 3A and 3B). Osteoclast-like giant cells were present individually and in clusters (Figure 3C), staining positive for CD68 (Figure 3D), and were admixed within a background of numerous foamy histiocytes (Figure 4A). Areas of irregular calcification as well as malignant osteoid were evident within the tumor (Figure 4B). The foamy macrophages throughout the tumor as well as the osteoclast-like giant cells were immunoreactive with CD68 and CD31. The malignant spindle cells were positive for CD34, while CD31 highlighted adjacent

foamy macrophages and giant cells (Figures 4C and 4D). Several large vacuolated malignant cells were admixed with the numerous foamy macrophages that resembled lipoblasts. This morphology and immunohistochemistry staining pattern was consistent with undifferentiated carcinoma of the pancreas with osteoclast-like giant cells. No premalignant lesions, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms and mucinous cystic neoplasm were identified. Microscopically, the tumor did not involve the major vessels, including the inferior mesenteric vein, celiac trunk or the splenic vessels. These areas, however, were surrounded by dense fibrosis.

Figure 3. Photomicrography of the pancreatic mass showing in A – Ductal carcinoma component staining positive for CK AE1/AE3 (400X); and Cam 5.2 in B (200X); C – Osteoclast-like giant cells (400X) staining positive for CD68 in D (400X). 54

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Sakhi R, Hamza A, Khurram MS, Ibrar W, Mazzara P

Figure 4. Photomicrography of the pancreatic mass showing in A – Foamy histiocytes (H&E, 100X) and osteoid with partial calcification in B (H&E, 100X); C –Tumor staining positive for CD31 (200X) and CD 34 diffusely in D (200X).

DISCUSSION Tumors with osteoclast-like giant cells have been documented within a variety of organs including the kidney, breast, thyroid gland, heart, parotid and skin.1,7-10 Within the pancreas, they are typically large, usually greater than 3.5 cm.3,7,9-12 The mean tumor size in reported cases was 5-8 cm.6,7,9-12 The tumor is usually a heterogeneous mass that can cause compression of adjacent normal structures, or constitutional symptoms such as fatigue and weight loss.3,7,9-12 Two-thirds of cases in the literature reported abdominal or back pain, one-third presented with painless jaundice.6,7,9-12 One third also reported nausea.6,7,9-12 Weight loss and anorexia were also reported in half of the cases.6,7,9-12 Autops Case Rep (São Paulo). 2017;7(4):51-57

CA19-9 was elevated in two-thirds of cases described by Muraki et al.6 Our patient was asymptomatic and the tumor was discovered incidentally during evaluation of an abdominal aortic aneurysm. UC-OGC is more likely to occur within the body and tail of the pancreas, account for about 70% of reported cases.6,7,9-12 The majority of cases are diagnosed in the sixth to seventh decade of life, when the tumor is in late progression. This is mostly due to its asymptomatic profile in its early stages.6,7 Radiographically, unlike typical adenocarcinoma of the pancreas which is uniformly hypoechoic, UC-OGC commonly appears as a heterogeneous mass with distinct hyper- and hypoechoic regions.4,7,12 Pancreatic FNA or biopsy is usually performed in 55


Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells reported in an asymptomatic patient: a rare case and literature review

cases of pancreatic malignancies. In Muraki et al’s 6 study, 90% of the cases that underwent preoperative biopsy demonstrated malignancy, with a quarter having the diagnosis of OGC. Preoperative biopsy showed the OGC component was identified in a third of cases by Muraki et al.6 Our case demonstrated a diagnosis of malignant neoplasm on FNA. There is much debate in the literature as to the origin of the tumor, with many authors favoring mesenchymal origin, and others favoring epithelial origin.4,6,9-12 Consensus appears to be leaning toward an epithelial origin with some authors purporting that components of vimentin-positive carcinoma are mesenchymal transition from ductal cells.3,6 In reported cases, cytokeratin-positive ductal structures have been reported to comprise < 5% to 80% of the tumor.6 Our case was characterized by rare ductal structures and focal immunoreactivity with CK AE1/AE3 and Cam 5.2 (Figures 2B and 2C), and an atypical mesenchymal component with immunoreactivity with vimentin (Figure 3B). In a study by Luchini et al., 13 it was purported that UC-OGC’s are variants of pancreatic ductal carcinoma (PDC) due to the presence of shared mutations in KRAS and other critical tumor suppressor genes commonly associated with PDC (TP53, CDKN2A and SMAD4). OGCs in UC-OGC consist of benign giant cells within a background of infiltrating anaplastic mononuclear malignant cells.1,3 They are commonly considered to be of benign histiocytic origin, which is supported in our case by a lack of atypia, and immunoreactivity with CD68. It is hypothesized that OGC recruitment is a result of chemotactic factors produced by neoplastic cells.7 The presence of large sheets of foamy histiocytes within the tumor supports the concept of a histiocytic chemotactic factor. 7 Within the OGCs are phagocytized neoplastic cell remnants. 7 OGCs themselves may be few or may comprise the bulk of the tumor, occurring in sheets or cell clusters.6 OGCs are typically found in nodules associated with areas of hemorrhage. They can fill and replace ducts within the pancreas. 6 The OGC component can comprise the majority of the tumor and even resemble an osteoclastoma pattern with minimal amounts of the malignant components.6 With a greater osteoclast component, a more protracted clinical course is expected.6 One third of cases reported in the study by Muraki et al.6 had presence of metaplastic, 56

mature bone tissue. Many of the cases in the study showed associated pancreatitis. OGC and pancreatic intraepithelial lesions were observed in 47% of the UC-OGC cases.6 UC-OGC usually demonstrates lymph-vascular and perineural invasion. In a study by Muraki et al.,6 lymph-vascular invasion was present in 63% of the time in UC-OGC cases. Perineural invasion was present in 32% of cases as compared to 86% in PDCs (p < 0.0001).6 Our case showed no evidence of lymph-vascular or perineural invasion. Muraki et al.6 found that lymph node metastasis in UC-OGC was less as compared to PDC. It was present in 23% of cases of UC-OGC and 64% in PDC (p < 0.0001).6 Our case, however, showed no regional lymph node metastasis. UC-OGCs behave differently to other tumors of the pancreas. They appear to occur close to a decade earlier than PDCs with a mean age of 58 at diagnosis compared to 65 years in PDC.6 Although UCP has a very poor prognosis with average survival less than 1 year, compared to PDC, 6 UC-OGC has a more favorable prognosis with a 5-year survival rate of 59.1% compared to 15.6% for PDC. 3,6 Median survival in Muraki et al.6 study was 7.7 years compared to 1.6 years in patients with PDCs (p<0.0009). In our case, the patient has remained clinically free of tumor thirteen months post resection. UC-OGC has a propensity to invade adjacent structures, although, complete resection of the tumor can prove curative when the tumor is limited to the pancreas.3,6 Further research on this rare entity may help establish reliable management guidelines.

CONCLUSION It is important to differentiate UC-OGC from other pancreatic malignancies due to the relative improvement in prognosis. Due to its rarity, therapeutic guidelines are limited. Further studies may help establish treatment modalities and possible molecular biomarkers.

REFERENCES 1. Loya AC, Ratnakar KS, Shastry RA. Combined osteoclastic giant cell and pleomorphic giant cell tumor of the pancreas: a rarity: an immunohistochemical analysis Autops Case Rep (São Paulo). 2017;7(4):51-57


Sakhi R, Hamza A, Khurram MS, Ibrar W, Mazzara P

and review of the literature. JOP. 2004;5(4):220-4. PMid:15254351. 2. Moore JC, Bentz JS, Hilden K, Adler DG. Osteoclastic and pleomorphic giant cell tumors of the pancreas diagnosed via EUS-guided FNA: unique clinical, endoscopic, and pathologic findings in a series of 5 patients. World J Gastrointest Endosc. 2010;2(1):15-9. PMid:21160673. http://dx.doi.org/10.4253/wjge.v2.i1.15. 3. Jo S. Huge undifferentiated carcinoma of the pancreas with osteoclast-like giant cells. World J Gastroenterol. 2014;20(10):2725-30. PMid:24627610. http://dx.doi. org/10.3748/wjg.v20.i10.2725. 4. Maksymov V, Khalifa MA, Bussey A, Carter B, Hogan M. Undifferentiated (anaplastic) carcinoma of the pancreas with osteoclast-like giant cells showing various degree of pancreas duct involvement: a case report and literature review. JOP. 2011;12(2):170-6. PMid:21386647. 5. Kane JR, Laskin WB, Matkowskyj KA, Villa C, Yeldandi AV. Sarcomatoid (spindle cell) carcinoma of the pancreas: a case report and review of the literature. Oncol Lett. 2014;7(1):245-9. PMid:24348857. 6. Muraki T, Reid MD, Basturk O, et al. Undifferentiated carcinoma with osteoclastic giant cells of the pancreas. Am J Surg Pathol. 2016;40(9):1203-16. PMid:27508975. http://dx.doi.org/10.1097/PAS.0000000000000689. 7. Sah SK, Li Y, Li Y. Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells: a rare case report and review of the literature. Int J Clin Exp Pathol. 2015;8(9):11785-91. PMid:26617927.

8. Burkadze G, Turashvili G. A case of osteoclast-like giant cell tumor of the pancreas associated with borderline mucinous cystic neoplasm. Pathol Oncol Res. 2009;15(1):129-31. PMid:18493871. http://dx.doi. org/10.1007/s12253-008-9053-9. 9. Farah F, Mlika M, Eddiba T, Zermani R, Jilani SBB. Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas. Sci Rep. 2012;1:179. http://dx.doi. org/10.4172/scientificreports.179. 10. Kawamoto Y, Ome Y, Terada K, Hashida K, Kawamoto K, Ito T. Undifferentiated carcinoma with osteoclast-like giant cells of the ampullary region: Short term survival after pancreaticoduodenectomy. Int J Surg Case Rep. 2016;24:199-202. PMid:27281360. http://dx.doi. org/10.1016/j.ijscr.2016.04.057. 11. Hur YH, Kim HH, Seoung JS, et al. Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells. J Korean Surg Soc. 2011;81(2):146-50. PMid:22066115. http://dx.doi.org/10.4174/jkss.2011.81.2.146. 12. Georgiou GK, Balasi E, Siozopoulou V, Tsili A, Fatouros M, Glantzounis G. Undifferentiated carcinoma of the head of pancreas with osteoclast-like giant cells presenting as a symptomatic cystic mass, following acute pancreatitis: case report and review of the literature. Int J Surg Case Rep. 2016;19:106-8. PMid:26745313. http://dx.doi. org/10.1016/j.ijscr.2015.12.023. 13. Luchini C, Pea A, Lionheart G, et al. Pancreatic undifferentiated carcinoma with osteoclast-like giant cells is genetically similar to, but clinically distinct from, conventional ductal adenocarcinoma. J Pathol. 2017;243(2):148-54. PMid:28722124. http://dx.doi. org/10.1002/path.4941.

Author contributions: All the authors made significant contribution to the manuscript. Sakhi R designed and wrote the manuscript after gathering all required information. He also grossed and assisted in signing out the case. Hamza A wrote significant portions of the introduction and discussion and edited the entire manuscript. Khurram MS did the literature search and made valuable additions to the discussion. Ibrar W took the pictures, and wrote the figure descriptions. Mazzara P was the staff pathologist who signed out the case. He also proof read the manuscript and provided valuable input to improve it. Conflict of interest: None Financial support: None Submitted on: October 17th, 2017 Accepted on: November 19th, 2017 Correspondence Ramen Sakhi Department of Pathology - St John Hospital and Medical Center 22101 Moross Rd, 48236 – Detroit/MI – USA Phone: +1 (131) 409-0234 ramen_sakhi@hotmail.com Autops Case Rep (São Paulo). 2017;7(4):51-57

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Nominata

Nominata of the Reviewers of the volume 7, 2017 The Editors of Autopsy and Case Reports thank the peer reviewers listed below for the excellent collaborative work, opinions and comments on the papers published in 2017. Their hard work certainly contributed to maintaining the scientific level of this journal. Reviewer

Specialty

Institution

Alfredo Franco Júnior

Pulmonology

HU USP

Alfredo José Mansur

Cardiology

INCOR

Ameer Hamza

Pathology

St. John Hospital & Medical Center - MI - USA

Ana Maria Andrello G. Pereira de Melo

Pediatrics

HU USP

Ana Maria da Cunha Mercante

Pathology

ICESP and Heliópolis Hospital

Angelina Maria Martins Lino

Neurology

HU USP and HC FMUSP

Caio Robledo Quaio

Genetics

FMUSP and Fleury Group

Carlos Roberto Ribeiro de Carvalho

Pulmonology

INCOR

Carmen Gutierrez

Pathology

Faculty of Medicine, University of the Republic Montevideo - Uruguay

Cristiane Rubia Ferreira

Pathology

HU USP

Dani Ejzenberg

Gynecology

HC FMUSP

Dov Charles Goldenberg

Plastic Surgery

HC FMUSP

Erasmo Simão da Silva

Vascular Surgery

HC FMUSP

Erich Stoelben

Thoracic Surgery

Hospital of Cologne, University Witten/Herdecke - NRW - Germany

Fábio Rocha Fernandes Távora

Pathology

Argos Patologia - CE - Brazil

Fernando Antônio Maria Claret Arcadipane

Head and Neck Surgery FM Jundiaí

Hector Navarro

Neurosurgery

HC FMUSP

Ibere Cauduro Soares

Pathology

HC FMUSP

João Galizzi-Filho

Gastroenterology

UFMG

Jorge Manoel Buchdid Amarante

Infectious Diseases

Hospital Samaritano

José Benedito Dias Lemos

Oral and Maxillofacial Surgery

HU-USP

Juliana Pereira

Hematology

ICESP

Larry Nichols

Pathology

Mercer University School of Medicine - GA - USA

Luis Fernando Ferraz da Silva

Pathology

FMUSP

Luiz Otávio Savassi Rocha

Internal Medicine

UFMG

Marcelo Calderaro

Neurology

HC FMUSP

Márcia Marcelino de Souza Ishigai

Pathology

UNIFESP

Maria Claudia Nogueira Zerbini

Pathology

FMUSP

Maria del Pilar Estevez Diz

Oncology

ICESP

Marina Penteado Sandoval

Pathology

The Dermatology Group - NJ - USA

Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2017. 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.


Autopsy And Case Reports

Reviewer

Specialty

Institution

Melanie Bois

Pathology

Mayo Clinic - Rochester - NY - USA

Mirian Nacagami Sotto

Pathology

FMUSP

Monica M A Stiepcich

Pathology

Fleury Group

Paulo Merçon de Vargas

Pathology

UFES

Paulo Sampaio Gutierrez

Pathology

INCOR

Regina Schultz

Pathology

ICESP and HC FMUSP

Renato José Mendonça Natalino

Pathology

Fleury Group

Rosa Maria Affonso Moysés

Nephrology

FMUSP

Rosely Antunes Patzina

Pathology

HC FMUSP and IIER

Samuel Shinjo

Rheumatology

HC FMUSP

Sandra Fátima Menosi Gualandro

Hematology

HC FMUSP

Sérgio Listik

Neurosurgery

HC SBC

Sheila Aparecida Coelho Siqueira

Pathology

HC FMUSP

Tarso Augusto Duenhas Accorsi

Neurology

HC FMUSP

Thais Mauad

Pathology

FMUSP

Vanderlei Segatelli

Pathology

ICESP

Vera Capelozi

Pathology

FMUSP

Vera Lucia Aldred

Pathology

HC FMUSP

LIST OF ABBREVIATIONS FM Jundiaí - Faculdade de Medicina de Jundiaí FM Taubaté - Faculdade de Medicina de Taubaté FMUSP - Faculdade de Medicina da Universidade de São Paulo FMUSP - HU USP - Faculdade de Medicina da Universidade de São Paulo - Hospital Universitário da Universidade de São Paulo HC de São Bernardo do Campo - Hospital das Clínicas de São Bernardo do Campo HC de SBC - Hospital de Clínicas Municipal de São Bernardo do Campo HC FMUSP - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo HU USP - Hospital Universitário da Universidade de São Paulo ICESP - Instituto do Câncer do Estado de São Paulo INCOR - Instituto do Coração UFES - Universidade Federal do Espírito Santo UFMG - Universidade Federal de Minas Gerais UNIFESP - Universidade Federal do Estado de São Paulo

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