Surgical Pathology Case Study: A 42 Year Old Woman with an Enlarging Mass of the Forearm

Case History

A 42 year old female with a history of neurofibromatosis, hypertension and Hashimoto’s thyroiditis had noted a mass on her forearm approximately 15 years ago. According to the patient, the mass did not change in size and did not cause her any discomfort during that time. Approximately 6 months prior to presenting to her primary physician, the mass began to increase in size and caused discomfort and pain. Upon examination with the Orthopedic Surgery department, a 20 x 20 cm firm, smooth mass on her forearm with mild pain on palpation was noted (Image 1). On MRI, the mass appeared to partially surround the radius and ulna, and encased the median, radial and ulnar nerves. A needle core biopsy was subsequently performed on the mass revealing a high grade malignant peripheral nerve sheath tumor (MPNST). A CT scan of the chest showed no evidence of metastatic disease. During her clinical visit, the use of neoadjuvant chemotherapy and chemoradiotherapy were discussed, but based on the large size of the mass, tumor response would have to be significant in order to allow for limb conserving surgery. At the time that the patient was seen, MPNSTs were not known to be chemosensitive and the chances of significant tumor response was very low (clinical drug trials have since shown some improvements in this area). In light of the poor response to systemic therapy of these tumors and the potentially toxic side effects of chemotherapy, the decision was made to proceed with amputation of the arm through the humerus.

Diagnosis

Frozen sections were sent from all the major peripheral nerves, including the ulnar, radial and median nerves. There was no evidence of any tumor consistent with a high-grade MPNST, although there was evidence of neurofibromas. There were atypical cells with hyperchromasia in the ulnar nerve margin, however, this was not considered to be consistent with a high grade MPNST. Received in the surgical pathology lab was an above elbow amputation consisting of a 30.0 cm long distal arm, an attached hand measuring 17.0 cm in maximum length., and a 4.5 cm long exposed humerus. The specimen is covered by grossly unremarkable skin, with a palpable mass in the mid-portion of the forearm. Sectioning reveals an 18.0 x 12.0 x 11.0 cm well-circumscribed mass composed of bulging, myxoid, white-tan tissue with central areas of hemorrhagic degeneration and yellow-tan friable tissue (Image 2). The bulging white-tan tissue is mainly found peripherally and encompasses approximately two-thirds of the mass. The mass is confined to a thin translucent lining and does not grossly invade neighboring soft tissue or overlying skin. The radial, median and ulnar nerves are adjacent to but not invaded by the mass, although the distal aspect of the mass shares a translucent, myxoid-like tissue with the peripheral nerve sheath of the ulnar and median nerves.

In addition to the standard bone and soft tissue margins that are taken, representative sections of the mass with the closest approach to the overlying skin are submitted. Sections demonstrating the relationship of the distal mass to the radial, median and ulnar nerves are submitted in separate cassettes. Lastly, representative sections sampled from various areas of the mass are submitted in an additional 15 blocks.

Histologically, the tumor consisted of spindle cells arranged in a fascicular pattern with intermittent whorled areas. The cells contained pleomorphic, hyperchromatic nuclei and intervening myxoid hypocellular areas. Mitotic figures were observed with sparse areas of necrosis and hemorrhage. S-100 was ordered on the prior biopsy of the mass, which was weakly positive. Based on these findings, the specimen was signed out as a malignant peripheral nerve sheath tumor.

Image 1. Above elbow amputation with a large forearm mass.
Image 2. Longitudinal cross section of arm demonstrating a bulging, white-tan mass with areas of hemorrhage and necrosis.

Discussion

Malignant peripheral nerve sheath tumors (MPNST) are locally invasive tumors that are associated with medium to large nerves (as opposed to cranial or distal small verves) and commonly recur with eventual metastatic spread. Common sites for metastatic spread include lung, liver, brain, bones and adrenals. They are usually found in adults between the second and fifth decades of life, and account for only 5% of malignant soft tissue tumors. Approximately half of MPNSTs will occur sporadically, with the other half generally arising in the setting of neurofibromatosis type 1 (such as in this case). There is a high clinical suspicion for MPNST if the patient has a history of neurofibromatosis type 1 or if the tumor arises within a major nerve component.

Grossly, MPNST will present as a large, poorly defined, fleshy tumor that runs along a nerve and involves adjacent soft tissue. Often, these tumors will have areas of hemorrhage or necrosis and can track along the length of a nerve. Histologically, the tumors are composed of monomorphic spindle cells arranged in fascicles, palisades and whorls, with compact comma-shaped, wavy or buckled hyperchromatic nuclei with alternating hypocellular foci. (Image 3 and 4). Mitotic figures and necrosis are common, and although S-100 is considered the best marker for MPNST, there is a lack of specificity and sensitivity for immunohistochemical markers. Due to the lack of immunohistochemical markers and molecular findings, as well as the variability associated with the cells, it has traditionally been difficult to diagnose MPNST. The differential diagnosis includes fibrosarcoma, monophasic synovial sarcoma, desmoplastic melanoma, and pleomorphic liposarcoma. Goldblum et al put forth the idea that a diagnosis of MPNST can be made if the tumor falls into any one of the following three categories:

  1. The tumor arises along a peripheral nerve
  2. The tumor arises from a pre-existing benign nerve sheath tumor, such as a neurofibroma
  3. The histologic features are consistent with a malignant Schwann cell tumor

Unfortunately, due to the aggressiveness of the tumor and high recurrence rate, MPNST has a poor prognosis with a 2 year overall survival rate of around 57% and a 5 year survival rate around 39%.

Image 3. Low power photomicrograph showing a spindle cell neoplasm arranged in a fascicular pattern.
Image 4. High power photomicrograph demonstrating spindle cells with hypercellular nuclei in a whorled arrangement and adjacent myxoid hypocellular areas.

References

  1. Case of the week #443. Pathology Outlines. http://www.pathologyoutlines.com/caseofweek/case443.htm. Published November 15, 2017. Accessed March 10, 2019.
  2. Frosch MP, Anthony DC, De Girolami U. Malignant Peripheral Nerve Sheath Tumor. In: Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 8th edition. Philadelphia, PA: Elsevier, Inc. 2010: 1341-1342
  3. Guo A, Liu A, Wei L, Song X. Malignant Peripheral Nerve Sheath Tumors: Differentiation Patterns and Immunohistochemical Features – A Mini-Review and Our New Findings. J Cancer. 2012; 3:303-309. http://www.jcancer.org/v03p0303.html. Accessed March 9, 2019.
  4. Hirbe AC, Cosper PF, Dahiya S, Van Tine BA. Neoadjuvant Ifosfamide and Epirubicin in the Treatment of Malignant Peripheral Nerve Sheath Tumors. Sarcoma. https://www.hindawi.com/journals/sarcoma/2017/3761292/cta/. Accessed March 10, 2019.
  5. Ramnani, DM. Malignant Peripheral Nerve Sheath Tumor. WebPathology. https://www.webpathology.com/case.asp?case=499. Accessed March 9, 2019.
  6. Shankar V. Malignant peripheral nerve sheath tumor (MPNST). Pathology Outlines. http://www.pathologyoutlines.com/topic/softtissuempnst.html. Revised September 12, 2018. Accessed March 9, 2019.

-Cory Nash is a board certified Pathologists’ Assistant, specializing in surgical and gross pathology. He currently works as a Pathologists’ Assistant at the University of Chicago Medical Center. His job involves the macroscopic examination, dissection and tissue submission of surgical specimens, ranging from biopsies to multi-organ resections. Cory has a special interest in head and neck pathology, as well as bone and soft tissue pathology. Cory can be followed on twitter at @iplaywithorgans.

Hematopathology Case Study: A 39 Year Old Woman Presenting with Persistent Cough and Pericardial Effusion

Case history

The patient is a 39 year old woman presenting with a persistent cough. Upon work up, a pericardial effusion is noted. Pericardiocentesis is performed and a smear made from the pericardial fluid reveals atypical lymphoid cells.

Cytology of the Pericardial Fluid

Image 1. Pericardial fluid cytology showing reactive mesothelial cells surrounded by benign small lymphocytes and atypical large lymphocytes.

Additional imaging reveals an anterior mediastinal mass measuring 12.6 cm. Excision of the mediastinal mass is performed. Sections of mediastinal mass show a variable population of lymphoid cells ranging from small to medium lymphocytes and some atypical large lymphocytes. These atypical large lymphocytes have irregular nuclear contours with abundant cytoplasm, vesicular chromatin and prominent nucleoli. These atypical large lymphoid cells are consistent with Hodgkin Reed-Sternberg cells. Abundant eosinophilic and scattered neutrophilic infiltration are noted within the nodules. These nodules are surrounded by dense collagen bands.

Image 2. H&E sections showing small to medium sized lymphoid cells with scattered large Hodgkin Reed-Sternberg cells infiltrating through fibrosis (frozen section A) and inflammatory cells predominantly eosinophilic infiltration (B) Fascin (C) and CD30 (D) are positive for atypical lymphoid cells.

Immunohistochemistry studies are performed, atypical large lymphoid cells are positive for CD30, Fascin and PAX5, while rare small to medium sized lymphocytes are positive for CD20, however, large atypical lymphoma cells are negative for CD20. Tumor cells are negative for CD3, CD5, CD15, LCA, ALK and EBER ISH. CD3 and CD5 highlight the reactive T cells in the background.

Image 3. PAX5 is positive in some tumor cells.

Overall, the case is consistent with nodular sclerosis classic Hodgkin lymphoma.  The presence of sheets of large lymphoma cells is suggestive of the syncytial variant.

Discussion

Nodular sclerosis classic Hodgkin’s lymphoma (NSCHL) subtype has a distinct epidemiology, clinical presentation and histology. NSCHL is more common in females with peak aged between 15 and 34 years. The risk is higher in high socioeconomic status. The patients are presenting with particularly mediastinal mass and 40% B symptoms.

NSCHL can be distinguished from the other subtypes of Hodgkin’s lymphoma (HL) with characteristic histologic features. There is a nodular growth pattern and the nodules are surrounded by collagen bands representing nodular sclerosis.  The lymphoma is composed of variable number of Hodgkin Reed-Sternberg (HRS) cells, small to medium sized lymphoid cells and non-neoplastic inflammatory cells, predominantly eosinophils, neutrophils and histiocytes. HRS cells have multinucleated or binucleated with irregular nuclear contours and prominent nucleoli. HRS cells induce fibroblastic activity by expressing IL-13 and the fibrosis begins in the lymph node by invaginating into the lymph node along vascular septa.

Immunophenotypically, the lymphoma cells are mostly positive for CD30 and 75-85% positive for CD15. Association with EBV can be demonstrated with EBER in-situ hybridization.  The malignant lymphocytes in NSCHL are variably expressing CD20, PAX5 and CD79a, however, T cell antigen markers, particularly CD4 and CD2 are aberrantly expressed in NSCHL.

NSCHL is classified mostly as grade 2 and the prognosis is better than the other subtypes of HL.  Doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) is the most frequent induction regimen for NSCHL patients with over 70% response rate.

Patients with Syncytial Variant Nodular Sclerosis Classic Hodgkin Lymphoma experience a lower than expected rate of complete therapeutic response with shorter progression-free than non-SV NSCHL treated with standard therapy. Syncytial Variant NSCHL should therefore be recognized as a high-risk subgroup within the otherwise traditionally docile NSCHL classification. This case fits the classic presentation for syncytial variant with presentation as bulky (mediastinal) disease.

References

  1. Eberle FC, Mani H, Jaffe ES. Histopathology of Hodgkin’s Lymphoma. Cancer J. 2009 Mar-Apr;15(2):129-37.
  2. Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues (Revised 4th Edition). IARC: Lyon 2017.
  3. Sethi T, Nguyen V, Li S, Morgan D, Greer J. Differences in outcome of patients with syncytial variant Hodgkin Lymphoma compared with typical nodular sclerosis Hodgkin Lymphoma. Ther Adv Hematol 2017, Vol. 8(1):13-20.

Ayse Irem Kilic is a 2nd year AP/CP pathology resident at Loyola University Medical Center. Follow Dr. Kilic on twitter @iremessa.

Kamran M. Mirza, MD, PhD, MLS(ASCP)CM is an Assistant Professor of Pathology and Medical Education at Loyola University Health System. A past top 5 honoree in ASCP’s Forty Under 40, Dr. Mirza was named to The Pathologist’s Power List of 2018. Follow him on twitter @kmirza

Just Say Know! From Mentoring to High Performance: A Resident Perspective

As pathologists, we are responsible for increasingly intricate anatomic pathology and clinical laboratory services in a continually changing healthcare landscape that requires us to integrate emerging technologies for improved quality of medical care while also being hypervigilant to cost control and efficiency. Hospital systems working under managed care business models seek to expand their coverage networks and boost the number of patients served, and as such, it is going to be very critical for the next generation of pathologists to develop and implement the management skills and techniques necessary to effectively advocate for investment in their departments and meet such goals.

The problem, however, is that we are largely shielded from these issues during our undergraduate and even graduate medical education experiences. We focus, of course, on the basic sciences and clinical skills, which are undeniably important; however, we get significantly less instruction or discussion on functioning within our health care system, addressing quality issues, or general leadership training that is indispensable and highly valuable for practicing physicians.

Earlier in the summer, I saw a number of pathology folks on Twitter promoting and strongly encouraging residents to apply for the two-day “Just Say Know! From Mentoring to High Performance” program, formed through collaboration between ASCP and USCAP, on an approach to leadership, management, and business for pathology. I was highly intrigued and had a feeling this program was the sort of experience for which I had been looking. Traveling to Palm Springs in the middle of the Chicago winter was not a bad deal either!

Drs. Blair Holladay and David Kaminsky assembled an impressive collection of speakers for the weekend, which was divided into four focus areas: leadership, management, business and policy, and change. After an engaging introduction by Drs. Holladay and Kaminsky, current trainees Drs. Kabeer Shah and Melissa Hogan set the stage by highlighting the increasing importance of “management” and “leadership” as reflected in the ACGME milestones as well as recent literature suggesting expectations for newly-trained pathologists include these very skills (Post et al. Arch Pathol Lab Med 2017;141: 193-202).Above all, they encouraged all of the thirty residents and fellows in attendance to “be honest, be open, and be vulnerable,” and ask the tough questions of themselves to gain the most from the weekend.

Lotte Mulder from ASCP led an enlightening discussion on the differences between emotional intelligence (EI) and conventional IQ, as well as the critical need to be self-aware of how our emotions can affect our performance and to understand the extent of our own abilities, strengths, and weaknesses. Dr. Karen Kaul followed with a very timely overview of strategies for identifying mentors. She discussed how our mentorship needs will evolve over the course of our careers and that fulfilling the mentor role for another junior individual while having your own mentors is key to the professional development necessary in leadership positions.

 After lunch, Dr. Dan Milner from ASCP took us through some very interesting global health case studies that forced our group to think critically about the role of pathology and the clinical laboratory in underserved settings as well as the major obstacles and economic disparities that must be considered. There were a number of important teaching points from Dr. Milner’s international cases that will be equally helpful for understanding the disparities we encounter right here in our backyard.

Dr .Yael Heher led off the afternoon management focus series with a really comprehensive look into how she has championed quality improvement and patient safety reviews at her institution to address root causes for laboratory errors, followed by a well-timed interactive session in which we divided into groups to use the six sigma methodology to work in concrete steps through a real-life laboratory error. It was a great opportunity to see people from different institutions and backgrounds bring unique perspectives to a common problem. The first day of the program concluded with a very unique session on art and leadership in which Dr. Kaminsky led us into Downtown Palm Springs to view the Palm Springs Babies art installation set up by David Cerny. Our powers of observation as pathologists were put to the test as we were asked to describe and interpret the meanings behind the exhibit in the same way that we often use visual evidence in our day-to-day work.

The second day of the program focused on business and policy with talks by Dr. Gary Procop on how pathologists can help integrate interventions into the laboratory to improve system-level metrics and by Khosrow Shotorbani on how laboratory data can be used to optimize laboratory services in the model of the rideshare service, Uber. The morning also included an interactive session on negotiation skills, in which each of us assumed the roles of departmental chair and owner of a private practice group negotiating with newly-hired pathologists. The weekend concluded with Dr. Nathan Johnson’s 18 steps to make change a part of an organizational culture, which was based on his experiences in academic research, military operational theory, and real-life lab experiences.

The weekend provided an incredibly impactful and high-yield array of discussions, so much so that I am already finding myself applying many of the strategies and techniques described over the weekend in my role as chief resident as well as to some of the changes and initiatives that I am hoping to bring to our department. Most important, though, were the opportunities to interact with my peers from around the country. We all face similar challenges as residents, and the opportunity to learn each other’s perspectives and approaches to similar issues was just as illuminating as the structured portions of the program. I hope that the ASCP and USCAP continue to offer the Just Say Know! Program and enthusiastically join all those pathology folks on social media promoting the program last summer with my own strong recommendation to challenge yourself and be open to new ways of learning by considering participating in this event!

From Twitter, @Blair_Holladay, December 12, 2018
Photo by Imran Uraizee

-Imran Uraizee, MD, is currently chief resident and a third-year anatomic and clinical pathology resident at the University of Chicago. He also manages the Department of Pathology Twitter account, @UChicagoPath. He majored in Biology at Duke University before earning his MD at the University of Rochester School of Medicine and Dentistry. Dr. Uraizee can be followed on Twitter at @IUraizee3MD.

Dead Wrong About Forensic Pathology

(•_•)         ( •_•)>⌐■-■       (⌐■_■)

[Puts my sunglasses on dramatically]

[Won’t Get Fooled Again by The Who plays]

Image 1. Looks like this medical lab science blogger made quite the … shady… joke. CSI: Miami’s Lt. Horatio Caine (played by David Caruso) donned his shades at pivotal plot times. (Source: CBS)

Okay-okay, I couldn’t resist that. How many times have you just wanted a CSI-style joke on here? No? Just me? That’s fine…

Hello again everybody! Welcome back! Last month I talked a bit about “Just Culture,” a sort of bridge between the values we tout as clinical leaders in our laboratories and the medical culture’s evolving and value-informed paradigm shift. There was a little in there about the lessons paralleled in LMU and the benefits of interdisciplinary teamwork. This month, on the subject of interdisciplinary collaboration, I’d like to talk about our colleagues who often are secluded or in more remote areas in our hospitals, offices, and academic centers. Not here to stereotype; I’m talking about our friends in forensic pathology!

Before I get there, let me go back a bit. I’ve already written several times about the stereotypes that surround our field of lab medicine and there are two times when that is glaringly present: when you’re a medical student or when you’re in forensics. I got the chance to meet someone who falls into both categories.

I’ve just finished up my OB/GYN rotation. But before my last day, I went to the lab at our hospital and followed up on some pending biopsy results. Okay, I can’t lie to you guys: they wanted me to see if I could rush “my lab friends” to expedite the process of fixing, setting, cutting, staining, and reading/reporting—because that’s possible. So, I went to the lab and had a pleasant chat with the staff explaining the situation and they were happy to help. While I was there, however, I happened to see another short white coat (ironically from my same school) who was helping some lab personnel with some grossing. Turns out she wants to match into a pathology residency—just like me—and specifically was interested in forensic path, a field which I don’t know much about. After talking more, I asked if she’d like to share some information. Here’s my conversation with Kyla Jorgenson, a 3rd year medical student at AUC-SOM from Toronto, Canada:

I get lots of hassle when I say I want to become a pathologist. People often ask me, “what’s your back up choice” or “don’t you like patients?” It can be a challenge. What’s your experience been like?

You want to do autopsies, so you want to be a mortician, right? Not quite. Many times, I’ve been faced with blank stares when I say I want to be a forensic pathologist. Other times I get the other end of the spectrum, that’s so cool! Clearly, they’ve seen a few crime-shows and think that I’ll get to go to crime scenes in stiletto high heeled shoes with a song by The Who playing in the background as I arrive. Even today when talking with a dermatopathologist I got a, “well when you realize that hanging out with dead bodies every day isn’t the greatest, you might consider surg path.” Then after hearing my experience as an autopsy assistant and that I’m sure this is what I want to do it was the resigned sigh signalling that I was a lost cause already.

A “lost cause,” that’s frustrating. A lot of specialities rag on other ones, it seems to be part of the culture of medicine—hopefully not forever, but still can’t we all just get along?

So, my background leading to pathology involved me working for several years between college, graduate school, and medical school; in hospitals of various sizes. I have personal experiences in these fields and sort of feel “at home” when I’m dealing with hematopathology, transfusion medicine, cell therapy—that sort of thing. What piqued your interest in forensics?

I started my undergraduate degree in forensic biology at the University of Toronto in the fall of 2008 just as a major review of pediatric forensic pathology in Ontario was being released. After numerous issues came to light, the inquiry looked at policies, procedures, practices, accountability and oversight mechanisms, quality control measures and institutional arrangements within the field in Ontario from 1981 to 2001. Ontario Court of Appeal’s Honourable Justice Stephen T. Goudge developed 169 recommendations on how pediatric forensic pathology in Ontario needed to address and correct its systemic failings to restore public confidence.

(Read more about these inquiries here: https://www.attorneygeneral.jus.gov.on.ca/inquiries/goudge/index.html)

After studying the cases that prompted the inquiry and its recommendations in class, what left the greatest impression was the importance of having medicolegal autopsies performed by those trained in not just pathology, but specifically, forensic pathology. What I took away from the cases of accidental deaths falsely attributed as homicides due to lack of experience on behalf of the pathologist and other such issues, is that forensic pathology isn’t something to be dabbled in. While our patients are no longer alive, there are lives that can be affected by the work we do. In Ontario, false convictions not only stemmed from “junk science” but also from inadequacies in the training of pathologists working in a forensic capacity and also a general shortage of forensic pathologists.

Seems like a lot of us (of the few of us) who enter medical school knowing we want to go into pathology have to sort of wait their turn, as it were, collecting experiences which help make us competitive for residency matching—what keeps your “commitment algorithm” going?

Since discovering that forensic medicine is a career path as a high school student, I’ve geared my education towards training in forensics. First my undergraduate degree and then a side trip for my master’s degree in Forensic Death Scene Investigation and a job as a pathology technician at the Medical Examiner’s office on my way to medical school. I have in each step along the way, confirmed that both medicine and forensics fascinate me. Scroll through my Netflix account and you’ll find crime dramas (with the British shows being my favourite) or my podcast app filled with true crime shows; I am enraptured using science to figure out what happened.

Sidebar: at this point Kyla showed me a first-author published piece in the Journal of Forensic Sciences from 2017 that talked about law enforcement-involved firearm related deaths in Oklahoma, where she worked at the time. Basically, it showed through metadata analysis that gun-related deaths were on the rise. Not just over time, but number of times being shot. Remember when we talked about pathology’s role in the #StayInYourLane/#ThisIsOurLane discussion? Well which pathology speciality do you think works with this stuff directly? Chemistry? Cytology? Last time I checked GSWs don’t get screened for lead poisoning and you can’t FNA a bullet. Forensic pathology has often been tasked with seeing trends in morbidity and mortality and translating that to effective social and public health change: think seatbelts, stents, and maybe someday gun-related legislation changes.

Image 2a. Monthly aggregates of gun-related deaths over a 16-year period in OK. (Source: Jorgenson, K et al (2017) Trends in Officer-Involved Firearm Deaths in Oklahoma from 2000-2015, Journal of Forensic Sciences, doi: 10.1111/1556-4029.13499)
Image 2b. Number of gun shot wounds per victim over time. (Source: Jorgenson, K et al (2017) Trends in Officer-Involved Firearm Deaths in Oklahoma from 2000-2015, Journal of Forensic Sciences, doi: 10.1111/1556-4029.13499)

I was interested when I shadowed at the Cook County ME’s office a few years ago—I saw some cool things. I also remember learning a lot from the first real autopsy I saw in a hospital, ultimately it seems like a totally different field that maybe gets underappreciated even within the pathology umbrella. AP/CP residents have to do a certain number of autopsies to graduate, but the attitude I’ve noticed around the topic is a “necessary evil” and most are working towards not having to do that. So let me ask you definitively, why forensic pathology?

Medicine is science being applied to find out what happened in the body and how we can change or manipulate those variables to diagnose, prevent, treat and manage disease. Each diagnosis is solving a crime occurring within the cells in the body, if you will. In forensic medicine, not only do you get to do all that but add in the crime solving element and you get to be “Dr. Nancy Drew.” While medicolegal systems are different all over the US and Canada, chances are that as a forensic pathologist you won’t only be working on your stereotypical “forensics” cases, the gunshot wounds, stab wounds and other nefarious causes of deaths many associate with that term. You could get the generic, “cause of death atherosclerotic cardiovascular disease, manner of death natural,” for a large proportion of cases.

It’s not glamorous, you could spend your day with a two-week-old decomposing decedent that has a pulsating maggot mass devouring its torso or documenting 51 stab wounds or signing out your cases after reviewing your histology and toxicology reports or testifying on a homicide case you worked on. But for me, those all sound like pretty interesting ways to spend the day, sign me up. As a pathology technician assisting with the autopsies and external exams, I was never required to think about what was happening in the body, but I wanted to understand it all. Now as I progress through medical school and look towards residency and fellowship, I eagerly await the chance to perform my first autopsy as a physician, to put all the knowledge and experience I’ve gained towards helping move Ontario and forensic pathology forward.

Image 3. Kyla M. Jorgenson is a 3rd year medical student at the American University of the Caribbean School of Medicine with prior undergraduate and graduate studies in the field of forensic pathology, professional experience as an autopsy technician, as well as a vested interest in pursuing a career in the field moving forward in residency and fellowship. (Source: Kyla M. Jorgenson)

I’d like to thank Kyla for her time in talking with me and her willingness to share her insights with all of you. I wish her all the best of luck as she continues through her training with electives and core rotations both in the UK and state-side. If you have any questions to relay to her, please feel free to comment below and I will forward appropriately. And as always, don’t forget to share with your colleagues across every discipline!

Thanks for reading, I’ll see you next time where I’ll be writing from the Mayo Clinic Hospital in Rochester, Minnesota, conducting a formal rotation in Anatomic and Clinical Pathology! Don’t miss it, I’ll have lots to share while learning at one of the nation’s top institutions!

Until next time!

–Constantine E. Kanakis MSc, MLS (ASCP)CM graduated from Loyola University Chicago with a BS in Molecular Biology and Bioethics and then Rush University with an MS in Medical Laboratory Science. He is currently a medical student actively involved in public health and laboratory medicine, conducting clinicals at Bronx-Care Hospital Center in New York City.

Surgical Pathology Case Study: A 64 Year Old Man with History of Loose Stools and Abdominal Pain

Case History

A 64 year old male presented with a one year history of loose stools, lower abdominal crampy/gassy pain that improved with defection, and an unclear history of melena. A colonoscopy revealed a circumferential, villous, carpet-like lesion extending from 15 cm to the anal verge, with biopsies demonstrating fragments of a villous adenoma. A follow-up CT scan was negative for metastatic disease. The decision was then made to proceed with a low anterior resection with hand-sewn colo-anal anastomosis and diverting loop ileostomy.

Diagnosis

Upon opening the rectum, a 13.8 cm long circumferential, carpet-like lesion is identified, extending to the distal margin (Image 1). Sectioning demonstrated a lesion with a maximum thickness of 1.0 cm, which grossly appears to be confined to the mucosa. Due to the prior biopsy history of a villous adenoma, the entire lesion was completely submitted. This required 116 blocks to be submitted, which were then mapped out to show where each block would have been taken from (Image 2). Although there were many foci of intramucosal carcinoma present, clear cut submucosal invasion was not identified, and the specimen was signed out as a villous adenoma (Image 3).

Image 1. Opened rectum demonstrating the 13.8 cm-long carpet-like lesion.
Image 2. Mapping the lesion to show from where each block is taken.
Image 3. Photomicrograph showing the transition from normal mucosa (black arrow) to villous adenomatous tissue (red arrow).

Discussion

Polyps are an abnormal tissue growth that is a common occurrence within the colon, although they can also be found throughout the small intestine, stomach and esophagus. Polyps can be further classified as being neoplastic or non-neoplastic based on the histological pattern of the cells. The most common types of neoplastic polyps found within the GI tract are colonic adenomas, which are benign polyps that serve as precursors to the majority of colorectal cancers. Nearly half of adults in the Western world will develop adenomas by the age of 50, and there is no gender predilection. It is because of this that it is recommended that all adults get a colonoscopy by the age of 50 (even earlier when there is a family history of developing colorectal cancer).

Most polyps are small, measuring 0.5 cm or less, but can grow to be over 10 cm in size (as seen in this case). When a colonoscopy is performed, these polyps can appear as sessile, meaning flat, or pedunculated, meaning on a stalk. Due to the abnormal epithelial growth of the mucosa, the surface of an adenoma can have a velvety appearance, resembling that of a raspberry. Most patients will not demonstrate any symptoms from their polyps, with the exception of occult bleeding and anemia which are associated with larger polyps.

Dysplasia, which literally means “disordered growth”, occurs when the individual cells lose their uniformity and architecture, often resulting in cells with a hyperchromatic nuclei and a high nuclear to cytoplasmic ratio. The presence of dysplasia contained within the epithelium of a polyp is what classifies the polyp as an adenoma (Image 4). Based on their epithelial growth pattern, adenomas can be classified as either tubular adenomas or villous adenomas. Tubular adenomas tend to be smaller polyps, with a smoother surface and rounded glands on histologic examination. Villous adenomas, in contrast, tend to be larger polyps with long, slender villi noted on histology (Image 5). If an adenoma contains a mixture of tubular and villous elements, they are classified as tubulovillous adenomas. When a dysplastic cell is no longer contained within the epithelium, and instead breaches the basement membrane which separates the epithelium from the underlying tissue, it is termed invasive.

Image 4. Photomicrograph of the villous adenoma, demonstrating the dysplasia that is confined to the mucosa and not extending to the deeper tissue.
Image 5. Photomicrograph of the long, slender villi that are commonly seen in villous adenomas.

What makes this case so interesting is that there is a direct correlation between the size of an adenoma, and the risk of developing colorectal cancer. This is not true with most other cancers, however, as size plays no part in determining whether the tumor is cancerous or not. With colon polyps, the larger the polyp, the greater the chance of developing invasive carcinoma (i.e. cancer). This is why screening colonoscopies are so important. Studies have shown that regular colonoscopies, combined with the removal of the polyps found on the exam, reduce the incidence of colorectal cancer. Why this case is so interesting is that you could assume based on the size of this polypoid lesion, you would find some invasive component. However, after reviewing 116 blocks, not a single focus of invasion could be identified.

It should be stated that although there is a correlation between an adenomas size and the risk of developing cancer, the majority of adenomas will not progress to cancer, and in fact, there are no tools currently available that help to determine why one patient’s adenoma will progress to cancer, while another patient’s adenoma will not.

References

  1. Association of Directors of Anatomic and Surgical Pathology, adapted with permission by the American Cancer Society. Understanding Your Pathology Report: Colon Polyps (Sessile or Traditional Serrated Adenomas). cancer.org. https://www.cancer.org/treatment/understanding-your-diagnosis/tests/understanding-your-pathology-report/colon-pathology/colon-polyps-sessile-or-traditional-serrated-adenomas.html. Accessed February 14, 2019.
  2. Colon Polyps. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/colon-polyps/symptoms-causes/syc-20352875. Accessed February 14, 2019.
  3. Turner JR. Polyps. In: Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 8th edition. Philadelphia, PA: Elsevier, Inc; 2010: 815-820

-Cory Nash is a board certified Pathologists’ Assistant, specializing in surgical and gross pathology. He currently works as a Pathologists’ Assistant at the University of Chicago Medical Center. His job involves the macroscopic examination, dissection and tissue submission of surgical specimens, ranging from biopsies to multi-organ resections. Cory has a special interest in head and neck pathology, as well as bone and soft tissue pathology. Cory can be followed on twitter at @iplaywithorgans.


Compliments in Disguise, More than Meets the Eye

Hello again everyone!

As with most clinical situations, there is often more going on than you can see on the surface. The classic example being the lab values that might have derangements that aren’t apparent clinically; something we rely on heavily in medicine. While most of the situations in these cases apply to diagnostic methods in patient care, sometimes those nuances exist outside of patient care. For example, a simple comment or phrase can hint at an individual’s potential biases and/or carry with them a weight of opinion that means more than what it sounded like.

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Image 1. Emerging from their laboratory, a pathologist, lab manager, and shift supervisor arrive ready to discuss clinical lab metrics with hospital administration. Many of us transform our roles within and outside of the lab, creating a complex team of clinicians all for the sake of our patients. (Source: Transformers: The Movie, obviously)

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Image 2. Instruments get routine service visits from industry reps, while supervisors oversee, and bench techs commiserate all in matching lab coats. Laboratorians often enjoy the exclusivity of the laboratory, working mostly “with your own” can sometimes facilitate an easier experience. But beware of comfort zones: if you don’t spend your time learning about others’ scopes, they won’t learn about yours. (Source: The Simpsons)

 

Last January, I brought up the topic of stereotypes in pathology which seem to reflect common misconceptions about the field of laboratory medicine. This time I think I’d like to explore that topic a little more in-depth, as I’ve noticed a few things during my clinicals as a medical student. Those of us with careers or histories of lab work or pathology experience know that we’re mostly regarded as a “behind the scene” crowd. That can be true, and to a certain extent a necessary part of patient care, but what happens when these stereotypes catch up with you? What happens when they become a part of your training? Since I have the great luck to have been on both sides of this question, here are my thoughts on what it really means when lab folks are thought of as a mysterious secret hospital-basement society.

First of all, these stereotypes aren’t anything new. We’ve all been sharing and resharing the same story every couple of years from article to article. I shared a few last January: Dr. Lori Rasca’s “Lonely Life of a Clinical Pathologist,” Dr. Sarah Riley’s call to bring the lab to the forefront of medical practice, and survey after survey about things like burn-out and wages. Go ahead and google things about careers in pathology and you’ll get a mixed bag. Often times, you’ll see programs or departments tout the importance of a profession in clinical pathology. Yale University School of Medicine conducted a survey last March where they asked middle-school students “what does a pathologist do?” The responses varied—and were mostly wrong. So the department wrote a piece about the clinical roles of those in laboratory medicine addressing specialization, patient contact, and tech-innovation.  One line that stuck out to me: “[you’ll] sometimes hear a surgeon say, ‘I’m only as good as my pathologist.’” Fantastic, I wrote about that last June where I talked about how the relationships between surgery and pathology are critical. The fact of the matter is, pathology is always changing; and with it, the roles of pathologists do too. An article from April 2011 in the College of American Pathology’s CAP Today featured Dr. Sylvia L. Asa and she wrote at length about the future of pathology in response to current stereotypes:

“The 2020 pathologist should not be someone who hides in the basement of a hospital and looks at glass slides or even whole-slide images, but someone who’s able to take all the information from the clinical pathology lab, from radiology, from endoscopy, from slides and the molecular lab, and sit down with the patient to explain the disease he or she has. That is how we will stay relevant in the public eye and every patient will know who their pathologist is. And we should make sure that the patient’s pathologist is the person who, when the patient searches the Internet, is an expert in the field.”

Next, medical students experience a myriad of sifted and specialized knowledge which changes scope and tone from one month/service/attending to another. When you’re in internal medicine, ID specialists are lazy; when you’re in surgery, IM residents are flustered; when you’re in ED, the other attendings don’t have as many thrilling stories; and when you’re in clinic with family medicine staff, you know no one else can handle the “front lines” like you guys do…right? Basically, everyone has a point of view and we naturally find ourselves working with other professionals who have specialized in the same field as us. But when you get too comfortable with your homogenous staff, that’s when those (otherwise normal) opinions can get complicated. Most of the time, pathology is viewed as an outsiders’ specialty. People might think you’re socially inept, or don’t like patients, or even can’t “cut it” on the wards. (That was harder for me to type than for you to read, trust me.) But it does happen; and when it becomes a conversation piece, med students have two classic options: Smile and agree with everything your attending says because their word is gold and they ultimately sign your evaluations or take the chance to address misconceptions and stereotypes—which do you think is easier? Earlier this year, a medical student from Ireland named Robert Ta wrote about his path to pathology in an article published in the International Journal of Medical Students (yes, it’s a real thing—and it’s great!). In it he discussed his enlightening experiences observing laboratory medicine for the first time and falling for the interdisciplinary work and diagnostic algorithms pathology offers. He even cited all-too-familiar classics we’ve all heard such as ““you must really hate dealing with people,” “[you must] have no clinical skills,” “[you have] no social skills,” “[you are] only interested in research,” “[you] must love working with dead people,” and everyone’s favorite “but you’re great with patients … why you would want to go into pathology?”

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Image 3. “I know you just finished—and honored—your surgery rotation but those scalpel-jockeys don’t really know how to take care of patients. Room 12B has gout and I am not about to cut his toe off!” Every time we switch rotations, medical students hear what everyone thinks about everyone else’s specialties. It can be exhausting keeping it all straight—I think by the time you graduate it just means you’ve lost track of who’s who… (Source: Medscape)

For the minority of students that figure out what specialty they like early on, those siren-songs can be a barrage to your patience. What ultimately happens is you could create a narrative of why you like pathology as an ad nauseum auto-pilot response, or you could try and engage people for their viewpoints and glean what insights you can—maybe you could even share some insight yourself. But something really interesting happens when you pursue these conversations a bit further: you learn a little more about the other person(s) and a little more about yourself in the process. I had heard the lattermost in the above list of “hits” a million times, and I used to think of it as a sort-of backhanded compliment. It wasn’t until I heard it from an attending I really respected, that my perception changed. I had done a full day’s worth of med student work in a particular clinic alongside my attending. It was full of difficult cases, challenging patients, biopsies, spot diagnoses, etc. On a few occasions I nailed a couple questions (a med student feather-in-cap moment) alongside interns and other students. At the end of the day, a conversation came up about interest in specialties, and I said pathology. Being greeted with a few comments/questions about it, along with a brief but great conversation, the attending finally said that they were impressed with me and to say that my skills would be wasted in the lab is a misnomer. Rather, my “clinical skills/work ethic” wherever I’d end up would be a valuable asset to patients anywhere in the hospital. (Um, that was a gold-star day. I think it was also a Friday, so just amazing overall.) So these stereotypic comments that used to make me feel frustrated, just got turned into one of my most memorable compliments—and I couldn’t be more grateful.

Turns out, medicine is full of moments like this. Where suddenly you learn or adjust a small piece of information and your point-of-view shifts to a new outlook. Dr. Justin Kreuter, a clinical pathologist, at the Mayo Clinic in Rochester, MN, recently wrote a perspectives piece for Mayo Medical Laboratories. It was all about taking the time to critically reflect. He linked to a few interesting articles and talked about how he takes time each day to reflect on moments and experiences he had. A mindfulness of “deliberate practice” (one of the various ways we can practice becoming better at something) shows us that being aware of opinions, cause-and-effect relationships, and our roles in certain situations can shape how we move forward from various experiences. Check his articles out and take his advice; who knows what you might learn about frustrating moments in your day, when instead you might change the entire conversation?

See you all next time!

 

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–Constantine E. Kanakis MSc, MLS (ASCP)CM graduated from Loyola University Chicago with a BS in Molecular Biology and Bioethics and then Rush University with an MS in Medical Laboratory Science. He is currently a medical student actively involved in public health and laboratory medicine, conducting clinicals at Bronx-Care Hospital Center in New York City.

Hematopathology Case Study: A 67 Year Old Female with a Sore Throat

History 

A 67 year old female presents with a two-month history of sore throat. She endorses dysphagia and left-sided otalgia but denies voice changes, shortness of breath, hemoptysis, weight loss, fever or night sweats. She has smoked 1 pack/day for 41 years and occasionally drinks alcohol. Her past medical history is notable for systemic lupus erythematosus for which she takes Plaquenil.

Physical examination slightly elevated systolic blood pressure. She is afebrile. Pertinent neck exam findings include mild tonsillar asymmetry (left slightly larger than right), and a firm mass at left base of tongue, and a 3 cm lymph node in the neck (left level III). A biopsy sample was taken from the tongue mass. 

Biopsy

EBV-1

H&E stained sections reveal sheets of large lymphocytes. The lymphoid cells are medium to large in size with irregular nuclear contours and prominent nuclei. Areas of necrosis are prominent. No specific areas of epithelial ulceration are noted. Immunophenotypic characterization of the larger cells reveals positivity for CD20, CD30, CD79a, PAX5, MUM1, Epstein Barr virus encoded RNA (EBER) and a variable Ki-67 proliferation index, which is up to 60-70% in the larger cells, but around 20-30% overall. Only rare cells are positive for BCL-2 and BCL-6. The lymphoma cells are negative for keratin AE1/AE3, CD10, CD4, CD8, CD21, CD23, CD7, CD5, Cyclin D1, CD68, CD56, and CD43. The background T cells express CD5 and CD7 and are a mixture of CD4 and CD8 with CD4 predominance.

We considered the diagnosis of EBV-positive mucocutaneous ulcer (a more indolent entity); however, the lack of history of an ulcer/ulceration and the presence of a mass-lesion (with additional adenopathy) does not support this diagnosis.

The findings are most consistent with EBV-positive DLBCL, NOS (WHO 2017), previously known as EBV positive DLBCL of the elderly (WHO 2008). 

Discussion 

Epstein Barr Virus, a member of the Herpesviridae family is mostly known for causing Infectious Mononucleosis. However, the ubiquitous virus which is present in about 90% of adults but often asymptomatic1, has a predilection for epithelial cells including B-cells.2 Incorporation of the viral genome and viral takeover of the cells proliferative machinery underlies the pathogenesis of any EBV-related disease/malignancy. It has been associated with a gastric carcinoma, fulminant hepatitis, undifferentiated nasopharyngeal carcinoma, and B cell, T cell and NK cell lymphomas3, including EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS).

EBV-positive diffuse large B-cell lymphoma, not otherwise specified (EBV+ DLBCL-NOS) was formerly known as EBV-positive diffuse large B-cell lymphoma (DLBCL) of the elderly. The WHO classification substituted “not otherwise specified” in place of “for the elderly” to reflect two things: 1) EBV is associated with other specific neoplastic Large B-Cell diseases such as lymphomatoid granulomatosis, and 2) EBV+DLBCL can affect younger individuals as well as the elderly. 2

EBV+DLBCL-NOS patients may occur in nodal or extranodal sites, with up to 40% presenting with extranodal sites at least in the early stages. Patients may be asymptomatic with or without B symptoms but usually, patients present with rapidly enlarging tumors at single or multinodal sites, as well as at extranodal sites. 4

The patient’s presentation with sore throat and the finding of neck mass with EBV-positive large B-cells associated with ulcer-like necrosis raises a differential diagnosis that ranges from reactive to malignant. Table 1 shows a comparison between three differential diagnoses: EBV+DLBCL-NOS; EBV-positive mucocutaneous ulcer; and infectious mononucleosis.

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Table 1. Comparison of 3 EBV-positive differentials in the head and neck

Unfortunately, there is currently no uniformly agreed standard of treatment for EBV+DLBCL which has a worse prognosis than EBV negative DLBCL.2 The standard treatment for DLBCL (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone- R-CHOP) is used but it responds poorly to treatment, with a median survival of 2 years.

Therefore, early detection by clinical suspicion and testing all DLBCL patients for EBV is very important.2 

 References

  1. Tsuchiya S. Diagnosis of Epstein–Barr virus-associated diseases. Critical Reviews in Oncology and Hematology. 2002;44(3):227-238. https://www.sciencedirect.com/science/article/pii/S1040842802001142. doi: 10.1016/S1040-8428(02)00114-2.
  2. Murthy SL, Hitchcock MA, Endicott-Yazdani T, Watson JT, Krause JR. Epstein-barr virus–positive diffuse large B-cell lymphoma. Proceedings (Baylor University.Medical Center). 2017;30(4):443-444. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595389/.
  3. Okano, Motohiko, MD, PhD|Gross, Thomas G., MD, PhD. Acute or chronic life-threatening diseases associated with epstein-barr virus infection. American Journal of the Medical Sciences, The. 2012;343(6):483-489. https://www.clinicalkey.es/playcontent/1-s2.0-S0002962915309435. doi: 10.1097/MAJ.0b013e318236e02d.
  4. Swerdlow S, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber D, Hasserjian R, Le Beau M. WHO classification of tumours of haematopoietic and lymphoid tissues. 2017.
  5. Dunmire SK, Hogquist KA, Balfour HH. Infectious Mononucleosis. Current topics in microbiology and immunology. 2015;390:211-240. doi:10.1007/978-3-319-22822-8_9.

 

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-Adesola Akinyemi, M.D., MPH, recently earned his MPH-Health Policy and Management from New York Medical College. He plans on pursuing residency training in pathology. His interests include cytopathology, neuropathology, and health outcomes improvement through systems thinking and design.

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-Kamran M. Mirza, MD PhD is an Assistant Professor of Pathology and Medical Director of Molecular Pathology at Loyola University Medical Center. He was a top 5 honoree in ASCP’s Forty Under 40 2017. Follow Dr. Mirza on twitter @kmirza.