Hematopathology Case Study: A 7 Year Old Transplant Patient with Neck Swelling

A 7 year old male with a history of restrictive cardiomyopathy status-post orthotopic heart transplant in June, 2010 that was on maintenance doses of tacrolimus and mycophenolate mofetil presented to his primary pediatrician left neck swelling. Starting in January 2017, the patient began with neck pain and swelling in the context of a recent gastrointestinal illness. Per CT report of the neck, a rim enhancing well-defined suppurative level III lymph node measuring 1.4 x 1.2 x 2.1 cm with adjacent soft tissue inflammatory changes extending into the left parapharyngeal space was identified. The patient was subsequently started on antibiotics and was discharged home with some improvement of swelling and pain.

The patient then presented again with continued neck swelling, although painless this time, and the patient’s cardiologist was contacted, who recommended a decrease in tacrolimus dosing. An otolaryngology evaluation was requested and given the concerning findings, the patient was admitted for further work-up, including a biopsy with a lymphoma protocol.

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EBER

 

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Flow Cytometry

 

Results

Flow cytometry revealed a kappa restricted CD10 positive mature B-cell population.

On biopsy examination, a population of monotonous lymphoid cells that are large in size with round to mildly irregular nuclear contours, open chromatin, and multiple inconspicuous nucleoli are present in a diffuse pattern. Abundant apoptotic bodies and mitotic figures are noted and occasional “starry sky” features are present. By immunohistochemistry, BCL6 highlights the neoplastic lymphocytes while BCL2 highlights background T-cells. EBER is negative.

Overall, despite a negative t(8;14) IGH/MYC translocation, the findings are best considered to be of an EBV-negative post-transplant lymphoproliferative disorder with morphologic features consistent with Burkitt lymphoma.

Discussion

Post-transplant lymphoproliferative disorders (PTLD) are a relatively rare complication in a variety of transplants that occurs in 2-10% of post-transplant patients. Overall, following a solid organ transplant (SOT), PTLD development is 1-5% of recipients with the highest incidence in intestinal and multivisceral transplantations (5-20%). Another factor is EBV status of the recipient, for which those that are EBV-naïve and lack cellular immunity to EBV are susceptible to graft-mediated EBV infection and ultimately developing an increased incidence in early PTLD. This population is overrepresented by pediatric transplant recipients1.

The presentation is highly variable and ranges from benign proliferations to overt lymphoproliferative disorders. Classifications for PTLD include early lesions, which are oligo- or polyclonal proliferations of EBV positive B cells have either a predominant infectious mononucleosis-like proliferation or a plasmacytic hyperplasia form. Polymorphic PTLD is a similar concept to the early proliferative lesions but the host architecture of the native structure is disrupted. Lastly, monomorphic PTLD is an entity that fulfills criteria for a non-Hodgkin lymphoma and is diagnosed according to the criteria of non-transplant associated lymphomas. Within pediatric registry studies, monomorphic PTLD accounts for 35-83% of all PTLD cases. B-cell lymphomas, particularly DLBCL, comprise the vast majority of monomorphic PTLD with plasmacytoma and T-cell lymphoproliferative disorders much less common2.

In this particular case, with the patient having been 7 years post-transplant and negative studies for EBV present, it is not surprising that germinal center phenotypic markers are highly expressed, such as CD10 and BCL6, which has been well elucidated by Jagadeesh, et al. Although not many genetic studies have been performed on post-transplant B-cell lymphomas, regardless of EBV status, there is some data demonstrating trisomies of 9 and/or 11 with translocations 8q24.1 (C-MYC), 3q24 (BCL6), and 14q32 (IGH). Rinaldi et al. noticed a lack of genetic lesions characteristic of postgerminal center derivation, such as gain of chromosome 3 (FOXP1, BCL6, and NFKBIZ) and 18q (BCL2 and NFATC1) together with losses of 6q (PRDM1 and TNFAIP3) in post-transplant DLBCL.  A number of DNA mutations have also been described including genes associated with somatic hypermutation (SHM) such as PIM-1, PAX5, C-MYC, and RhoH/TTF. These particular mutations are also found to be independent of EBV status1.

Overall, post-transplant lymphoproliferative disorders occur in a variety of transplant settings across many age groups and can be dependent on EBV and CMV status as well as the type and degree of immunosuppression. Although many variations take place in PTLD, patients with the monomorphic type are diagnosed according to their non-transplant counterparts. Current perspective includes further analysis of molecular and cellular mechanisms incorporated into research projects, which could better aid in prognostic implications and future therapeutics.

  1. Morscio, et al. “Molecular pathogenesis of B-cell posttransplant lymphoproliferative disorder: What do we know so far?” Clinical and Developmental Immunology 2013.
  2. Mynarek, et al. “Posttransplant lymphoproliferative disease after pediatric solid organ transplantation,” Clinical and Developmental Immunology 2013.

 

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-Phillip Michaels, MD is a board certified anatomic and clinical pathologist who is a current hematopathology fellow at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. His research interests include molecular profiling of diffuse large B-cell lymphoma as well as pathology resident education, especially in hematopathology and molecular genetic pathology.

Hematopathology Case Study: A 54 Year Old Male with Acute Onset of Progressive Neck Swelling

Case History

A 54 year old male with a diagnosis of HIV (last CD4 count was 301 on 11/2016) currently on HAART presented to the Beth Israel Deaconess Medical Center (BIDMC) ED on 2/28/2017 with an acute onset of progressive neck swelling over the course of 4-5 days. Laboratory values on presentation was significant for a LDH of 1061 IU/L. Other laboratory values were stable. Upon CT imaging with contrast of the neck, an extensively necrotic right cervical lymphadenopathy was present and was extending into the supra- and infraclavicular chain. No mediastinal or hilar lymphadenopathy was noted.

On 3/1/2017, the patient underwent an ultrasound guided core needle biopsy of the right cervical mass (see images). By immunohistochemistry, the neoplastic cells are positive for CD138 and MUM1. PAX5 shows dim and heterogeneous staining in a subset of cells while CD79a highlights a minor component of the lymphoid population. CD3 and CD5 are positive in T-cells occupying a small subset of the lymph node. CD20, BCL2, BCL6, BCL1, CD30, CD56 and HHV8 are negative. By Ki-67 immunostaining, the proliferation index approaches 100%. In-situ hybridization for Epstein-Barr virus encoded RNA (EBER ISH) is positive in a major subset of cells.

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CD20 (left) and CD3
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MUM1 (left) and CD138
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EBER ISH (left) and Ki-67

By cytogenetic analysis, only two cells were available for metaphase interpretation and it showed a translocation between the long arms of chromosomes 8 and 14 and by FISH, a t(8;14)(q24.1;q32) was noted, indicating an IGH/MYC rearrangement.

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Overall, the morphologic, immunophenotypic, and cytogenetic findings in conjunction with the clinical features of a HIV positive male and EBV association, the diagnosis is in keeping with a plasmablastic lymphoma.

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Discussion

Plasmablastic lymphoma is a diffuse proliferation in which the cells resemble immunoblasts but share an immunophenotype similar to that of plasma cells. First described in the oral cavity, especially among HIV infected patients, it can present in a variety of extranodal sites, such as skin, soft tissue, and gastrointestinal tract. Although uncommon, plasmablastic lymphoma has its highest incidence among HIV infected individuals. Most patients are at stage III or IV at presentation with an intermediate to high risk IPI score. The tumor cells of plasmablastic lymphoma are invariably infected by Epstein-Barr virus (EBV) and are consistently negative for HHV8. According to Balague et al.2, up to 39% of plasmablastic lymphomas demonstrate a MYC translocation, all of which involved the IGH gene. Generally, plasmablastic lymphoma displays a complex karyotype, although some cases display an isolated MYC rearrangement without a complex karyotype. Taddesse-Heath et al.3 has shown a small cohort that is positive for gains in odd-numbered chromosomes 3, 5, 7, 9, 11, and/or 15, similar to that seen in plasma cell myeloma. The clinical course of plasmablastic lymphoma is quite aggressive with most patients dying within one year after diagnosis. Current first line treatment for plasmablastic lymphoma is dose-adjusted EPOCH with or without bortezomib, intrathecal prophylaxis, and possible autologous stem cell transplantation in first remission candidates. Future directions of therapy include chimeric antigen receptor (CAR) T-cells and small molecular inhibitors against the MYC bromodomain4.

References

  1. Swerdlow, S., et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th. ed., IARC press: 2008
  2. Balague, O., et al., “Plasmablastic lymphomas are genetically characterized by frequent MYC translocations [abstract],” Mod Pathol 2009; 22:255A.
  3. Taddesse-Heath, L., et al., “Plasmablastic lymphoma with MYC translocation: evidence for a common pathway in the generation of plasmablastic features,” Mod Pathol 2010; 23:991-999.
  4. Castillo, J., et al., “The biology and treatment of plasmablastic lymphoma,” Blood 2015; 125:2323-2330.

 

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-Phillip Michaels, MD is a board certified anatomic and clinical pathologist who is a current hematopathology fellow at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. His research interests include molecular profiling of diffuse large B-cell lymphoma as well as pathology resident education, especially in hematopathology and molecular genetic pathology.

Business and Legal Considerations for Pathology and Laboratory Service Providers

The legal considerations when providing pathology and laboratory services can be daunting. However, help is at hand! ASCP Press recently released a Business/Legal handbook. Also, in this podcast, an attorney gives listeners a basic rundown of some of the legal intricacies involved in running a laboratory.

ASCP Annual Meeting Call for Abstracts Now Open

The 2017 ASCP Annual Meeting is in Chicago, IL September 6-8. If you’d like to present your research at the meeting, the call for abstracts is now open. Summarize your work in 300 words or less and submit it through the online portal by March 20th, 2017.

Spread the word, and good luck!

 

Serotypes and Stereotypes: the Path to Pathology

Hello and welcome back! After a hiatus for the holidays, I’m now back at school and gearing up to write about more Arbovirus-related public health endeavors. But, with projects on hold until now, I’m going to briefly depart the world of mosquito source reduction and epidemiology to discuss something that relates to my experiences in medical school. If you read my Lablogatory bio, you’ll see I spent a number of years studying and working in some of Chicago’s great clinical laboratories. In the past decade, I’ve been very close to the field of pathology and laboratory medicine. As I reach the “half-way” mark in medical school now, I have become increasingly aware of the way people across healthcare professions and specialties view laboratory clinicians. One thing that stands out strikingly is, what I argue, a potential stereotype.

Let me tell you one of my pet peeves. As a medical student, I am fortunate enough to learn and work under the guiding hands of physicians, nurses, and other educators. I work my hardest to learn how to provide the best care possible as I learn the skills needed for my future practice. In debriefing from a simulation, a good performance might spark conversation which culminates to the paramount question: “Have you thought about a specialty?” My heart set on it for a while, I often remark “Pathology” before I correct myself to “Clinical Pathology” since I’ve learned to curtail jokes about autopsies. (Disclosure: autopsies are a very important part of medicine, and the number of autopsies have experienced an unfortunate downward trend.)

As a result of my AP/CP answer, many people are often surprised, citing that I’ve been “great with the patient(s).” So that begs the question: why does my current answer surprise people? And more importantly, what perpetuates the stereotype of an introverted, microscope jockey who doesn’t want to be near patients? Yes, hyperbole, but I’ll come back to this stereotype.

While I was stateside visiting family, I coordinated some clinical shadow time with a colleague and alumnus of my medical school in her pathology residency at University of Alabama at Birmingham (UAB). I spent time rounding with their teams in derm-path, watching sign-outs for endless cases, and getting up close and personal with autopsy training with another pathology resident. Each interaction with the faculty and staff were familiar and expected—full of enthusiasm and passion about their respective field of research or clinical work. What struck me as special, however, was that I was neither questioned for my motives in seeking pathology as a specialty, nor did I surprise anyone by being social and amicable. Everyone was quite sociable and proud of their work. My interactions were limited to the anatomic and clinical pathology departments so I suspect there may have been some bias. When I was a medical laboratory science student, I recall working with other disciplines, and, though I may have been in a nascent time in school to notice any stereotypes, they became clearer as I progressed through various jobs across the city. Large trauma centers, small community hospitals, even a shadow stint at the Cook County Medical Examiner’s Office, all taught me valuable lessons on varied scope and different professional perspectives. And all the while, people seemed surprised I would be interested in such a misunderstood specialty.

On Lablogatory, I’ve enjoyed just about every post and one of my favorites is a series by Dr. Lori Racsa, “Lonely Life of a Clinical Pathologist.” Dr. Racsa discussed things about laboratory medicine I had observed in my time as a medical laboratory scientist: the critical role of pathologists on committees, the value of built-in mentorships, the [aforementioned] mystery about the particularities of the job to clinicians and laypeople alike, and the value of technologists like myself! One of the most poignant posts she wrote addressed the potential for a clinical pathologist to round with other “floor” clinicians. That was something I thought I’d dreamed up in my ambition to go to medical school, blazing a trail in Path where I could put some cracks in that stereotype. Dr. Racsa cited a great article from Critical Values by Dr. H. Cliff Sullivan where he recommended pathologists become more actively involved with fellow clinicians to directly improve patient outcomes. Having freshly attended several events at the ASCP National Meeting in Long Beach just prior to his article, I rode a wave of his “rally call” for changing the face and accessibility of pathology as a specialty. I saw myself in both his and Dr. Racsa’s stories of interdisciplinary teams, rounds, and committees and I’ve been excited ever since.

Back to that stereotype. Those articles about pathologists’ roles in medicine reflect a distinct lack of visibility to fellow colleagues. While we all recognize that nearly 100% of cancers are lab-dependent diagnoses and 70% of patient records are tied to diagnostic laboratory data, why are nearly half the residency spots for Pathology in the US National Resident Matching Program unfilled for the past few years? According to recent surveys by the American Medical Association, Pathology has one of the lowest relative rates of physician burn-out compared to other specialties. Pathologists are earning within 15% of the average physician income, with one of the highest relative satisfaction scores to match. So with lifestyle and career quality reporting positive values, I would argue that the seeming lack of interest stems from the possible lack of exposure of pathology as a dynamic field. The stereotype I’ve been talking about might also be one of attrition—“out of sight, out of mind.” Some great pieces of work on Lablogatory focus on promoting the value of laboratory medicine as an integral part of any patient’s care. Just recently, Dr. Sarah Riley discussed CO poisoning and public health, while her bio calls for “bringing the lab out of the basement and into the forefront of global health.” I feel close to that cause myself, hopefully made evident in my previous posts. Stay tuned for next month’s where I’ll be discussing the next steps in our public health project on Sint Maarten. After celebrating a successful 2016 effort presented by the Ministry to the Global Health Securities Agenda, our team has a number of projects lined up to demonstrate effective integration of lab medicine, epidemiology/public health, and social outreach.

A friend and mentor once told me to keep a completely open mind about my medical career and let whatever specialty fits best “find me,” so to speak. I couldn’t have asked for more sound advice. I’ll admit I have my biases and comfort zones, and for now that’s what they’ll remain. In this post, I had hoped to shine some light on the disparities in career reputation between pathology versus other disciplines. Is the stereotype founded in any truths I may have missed? Don’t pathologists have the social tact to work up and down the ladder, working with lab assistants to government health officials? Have you ever been challenged for your career choices in pathology? What reasons do you think contribute to the stereotypes I mentioned? What words can you offer students like me just starting to find a foothold in their newfound careers in medicine?

Leave your comments below! Thanks!

 

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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 at the American University of the Caribbean and actively involved with local public health.

Lonely Life of a Clinical Pathologist: Thank You

I wanted to say thank you to everyone who has left comments on my past posts and shown encouragement to the topics discussed. I will be taking a break from blogging but wanted to encourage everyone in the clinical pathology field to keep up the hard work of patient care behind the scenes. I hope you can be ambassadors of laboratory services and help influence the care of patients in positive ways throughout the hospital systems you work in.

In lieu of a holiday card, I wanted to sign off blogging with a meme for all clinical pathologists out there:

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-Lori Racsa, DO, is the director of microbiology, immunology, and chemistry at Unity Point Health Methodist, and a Clinical Assistant Professor at the University Of Illinois College Of Medicine at Peoria. While microbiology is her passion, has a keen interest in getting the laboratory involved as a key component of an interdisciplinary patient care team.

The Lonely Life of a Clinical Pathologist: Finding a Mentor

Over the last few blog posts I have spoken about my involvement in the laboratory and hospital to find other people interested in clinical pathology. While this has helped fuel my passion for laboratory medicine, one of the issues that made me feel the loneliest was the responsibility I felt as a new pathologist and not having someone to help share that burden.

As a pathology trainee I saw several new pathologists start their positions in microbiology, hematology, and even anatomic pathology. They always seemed to be cool, calm, and collected (unless they were running around trying to get their research published).  What I did not focus on was that they also had a built-in mentor (the experienced pathologist) who was there to discuss a tough case or help them make a difficult decision.

When I took a community practice based job I was immediately entrenched in a decision making role. The sense of responsibility I felt to our patients, and making sure those decisions affected care in a positive way, was more overwhelming than I expected. The decisions included items such as which instruments to bring into the lab, when to report certain isolates, and even how to handle irate clinicians about the way we report our results. Every time I encountered a new situation I had not experienced first-hand in residency, I wanted to run my approach by someone to make sure it was the right way of doing things. I had one mentor I am pretty sure I texted every day the first two weeks of my job (thanks Dr. Lars Westblade!) for every single technical question that came up in microbiology. While it may seem excessive, it was the only thing that gave my decision making confidence at that time.

As the year went on, other mentors from training were also there for me, but I realized I needed a mentor on site that I could run major decisions by, as they understood the environment I was in more than my training mentors could. I was hesitant to seek advice from my bosses, as I was hired for my clinical pathology expertise, but as I reached out for guidance, I came to find the senior pathologist could guide me in the politics of my current situation while I could make decisions on the technical background. I can now see that having a senior pathologist with a wealth of information on how to handle situations and clinicians has been invaluable to the start of my career. The wisdom imparted has given me direction and experience in making decisions that residency could not fully prepare me for, such as handling physicians not happy with aspects of the lab or employees who did not want to perform tasks I asked of them.

Beyond individual mentors, another area that helped me with technical aspects of my job has been belonging to clinical pathology societies. American Society for Microbiology has several different list-serves you can post questions and get answers back from experts all over the country and world. The American Association for Clinical Chemistry has a board called “The Artery” that you can also post questions to and experts will answer. These formats have been priceless when seeking advice on certain topics literature does not seem to cover and are examples of why belonging to professional societies really bolsters your career.

As the year has progressed and I have made one decision after the next, my confidence has been built up so that I don’t have to discuss every decision with my mentors; that being said, I still have them on speed dial. While I think that responsibility is one area that residency was not able to fully prepare me for, I can see that it is a work in progress and one aspect of my job that will continue to motivate me to be the best I can be and make the best decisions for our patients.

Now to hear from you: did responsibility overwhelm you your first year of practice? How do you utilize mentors and professional societies to help approach unique and new situations?

 

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-Lori Racsa, DO, is the director of microbiology, immunology, and chemistry at Unity Point Health Methodist, and a Clinical Assistant Professor at the University Of Illinois College Of Medicine at Peoria. While microbiology is her passion, has a keen interest in getting the laboratory involved as a key component of an interdisciplinary patient care team.