Hematopathology Case Study: A 71 Year Old Man with a History of Multiple Myeloma

Case History

A 71 year old man with a history of multiple myeloma presented with urinary incontinence and confusion and was found to have hyperkalemia with renal failure. Imaging showed extensive inguinal lymphadenopathy with concern for new lymphoma.

Excisional Lymph Node Biopsy

H&E 40x

Diagnosis

Sections show an enlarged lymph node with complete effacement of the normal lymph node architecture by sheets of medium and large plasmablastic cells. The cells have round nuclear contours, large prominent nucleoli and moderate amounts of amphophilic cytoplasm. Frequent apoptotic cells and scattered mitoses are seen.

Immunohistochemical stains show that the neoplastic cells are immunoreactive for CD138, CD38, CD19 (dim) and MUM1. They are negative for CD20, which highlights only small admixed B-cells. The cells are kappa restricted by kappa and lambda immunostain. The Ki-67 proliferation index is greater than 90%.

Taken together, the morphologic and immunophenotypic features are of a high grade plasmablastic neoplasm. The differential diagnosis includes plasmablastic myeloma and a plasmablastic lymphoma. Given the patient’s history of a kappa restricted plasma cell dyscrasia, plasmablastic myeloma is favored.

Discussion

Multiple myeloma is a neoplasm of clonal plasma cells that accounts for 10% of all hematologic malignancies. It is most commonly seen in adult and elderly patients with a male predominance. Plasma cells are generally characterized by the presence of a “clockface” nuclei and distinct perinuclear Hof or clearing of the cytoplasm containing a large number of Golgi bodies. The morphology of plasma cell tumors can range from small mature plasma cells to anaplastic or plasmablastic morphology. In this case, the cells showed plasmablastic (PB) morphology, which is characterized by a large nucleus, large nucleolus, fine reticular nuclear chromatin pattern, lack of nuclear Hof and less abundant cytoplasm than typical plasma cells.1

The differential diagnosis for cases with this morphology primarily includes PB lymphoma and PB myeloma with extramedullary involvement. PB lymphoma is seen more commonly in HIV positive patients or patients with other causes of immunodeficiency. It typically occurs in adults and has a male predominance. The tumor generally presents outside of nodes and is most frequently seen in the oral cavity/jaw. Patients tend to present with advanced stage and bone marrow involvement. While PB lymphoma is categorized as a distinct subtype of diffuse large B-cell lymphoma, PB myeloma is considered an atypical morphologic variant of multiple myeloma and is treated with therapy geared towards plasma cell neoplasms. 2

Making the distinction between these entities is difficult due to similarities in morphology and immunophenotype. Ultimately, the diagnosis is generally made based on the clinical context. In one series of “plasmablastic” neoplasms by Ahn, et. al., 6 out of 11 cases were called PB lymphoma, 2 out of 11 were called multiple myeloma and 3 were called indeterminate. Among the PB lymphoma patients, 4 were either HIV positive or had a history of immunosuppression. All 6 cases were positive for CD138 and negative for CD20 with EBV in situ hybridization positivity in 3 out of 6 cases. The multiple myeloma cases had evidence of end organ damage without lymphadenopathy. One indeterminate case had peritoneal nodules, lytic lesions and an EBV positive neoplasm in the bone marrow, which precluded a definitive diagnosis. 3

The immunophenotypic pattern seen in this case is typical of these neoplasms and is characterized by the expression of plasma cell antigens (CD138, CD38, MUM1) with either weak or negative expression of B-cell antigens (CD20). A study by Vega et. al. looked at the immunophenotypic profiles in nine cases of PB lymphoma and seven cases of PB myeloma. They found that the profiles were nearly identical.  All cases were positive for MUM1/IRF4, CD138 and CD38 and negative for CD20, consistent with a plasma cell immunophenotype. PAX5 and BCL6 were weakly positive in 2/9 and 1/5 PB lymphomas and were negative in all PB myelomas. A high Ki-67, overexpression of P53 and loss of p16 and p27 were present in both tumors. There was no evidence of HHV8 detected in either neoplasm. The presence of EBV-encoded RNA, was seen in all PB lymphoma cases tested and negative in all plasma cell myeloma cases. This was found to be statistically significant. 4

Unfortunately, both PB lymphoma and PB myeloma are aggressive high grade neoplasms with a poor prognosis. A study conducted by Greipp et. al. assessed the prognostic significance of plasmablastic morphology in a cohort of patients from the Eastern Cooperative Oncology Group Myeloma Trial E9486. They looked at bone marrow aspirates from 453 newly diagnosed multiple myeloma cases in a 5 year period. Of the 453 aspirates, 8.2% were classified as PB morphology.  The overall survival of patients with PB morphology was significantly shorter than patients with non-PB morphology with a median of 1.9 years compared to 3.7 years. There did not appear to be a relationship between PB morphology to other clinical or laboratory features such as age, sex, bone lesions or type of M-protein. 5

References

  1. M Srija, P Zachariah, V Unni, et. al. Plasmablastic myeloma presenting as rapidly progressive renal failure in a young adult, Indian Journal of Nephrology, Volume 24(1): 2014, Page 41-44.
  2. JJ Castillo, M Bibas, RN Miranda, The biology and treatment of plasmablastic lymphoma, Blood, Volume 125, 2015, Page 2323-2330.
  3. J Ahn, R Okal, J Vos, et. al. Plasmablastic Lymphoma vs Myeloma With Plasmablastic Morphology: An Ongoing Diagnostic Dilemma, American Journal of Clinical Pathology, Volume 144(2): 2015, Page A125.
  4. F Vega, CC Chang, LJ Medeiros, et. al. Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles. Modern Pathology, Volume 18: 2005, Page 806-815.
  5. PR Greipp, T Leong, J Bennett, et. al. Plasmablastic Morphology – An Independent Prognostic Factor With Clinical and Laboratory Correlates: Eastern Cooperative Oncology Group (ECOG) Myeloma Trial 39486 Report by the ECOG Myeloma Laboratory Group, Blood, Volume 91: 1998, Page 2501-2507.

Chelsea Marcus, MD is a Hematopathology Fellow at Beth Israel Deaconess Medical Center in Boston, MA. She has a particular interest in High-grade B-Cell lymphomas and the genetic alterations of these lymphomas.

Working with Generation Z: How Other Generations Can Adapt

This generation is very new to the workforce. In fact, the majority has not had a job yet as they are all eighteen and younger at the time of this writing. However, it is important to know how to adapt to this generation as they are starting to enter the workforce and many people communicate with this generation daily on a personal level.

This generation experiences a tremendous amount of uncertainty in their early lives. From the economic downturn in the late 2000s and school and concert shootings, this generation cares about security. This security is important on both a physical but also on a professional level; they want to make sure that they have professional stability. They care about making a difference, but not to the extent of Generation Y, the Millennial Generation.

There is some concern about this generation’s ability to connect with people on a long-term social level, mainly due to technological and social media advances. However, they do have a preference for face-to-face communication, so even if they do not come with that skill to the workplace, they can learn and adapt to it. Additionally, they are competitive and good multitaskers. They also have an entrepreneurial and independent spirit; they want to be in charge of their own projects and start their own companies. They are also looking into different ways to get their education that do not involve higher education and student debt. They are an imaginative generation with an intellectual curiosity.

Generation Z is the most diverse and open-minded generation, which means that they bring a plethora of ideas, background, concepts, and experiences. Leaders can utilize their diverse base to foster diversity of thought, practice, and skills at organizations. Including this generation as interns and entry-level workers is a good start to begin the process of mentoring this generation while learning from everything they bring to the organizational table.

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-Lotte Mulder earned her Master’s of Education from the Harvard Graduate School of Education in 2013, where she focused on Leadership and Group Development. She’s currently working toward a PhD in Organizational Leadership. At ASCP, Lotte designs and facilitates the ASCP Leadership Institute, an online leadership certificate program. She has also built ASCP’s first patient ambassador program, called Patient Champions, which leverages patient stories as they relate to the value of the lab.

Global Health Narratives Interview Series: Meet Dr. Ann Marie Nelson

Ann Marie Nelson, MD has been a long-time hero of mine from afar. If you don’t know who she is and what she has done, then after reading this interview – you will see why! She is brilliant, selfless, kind hearted, and is simply an inspiration!

Dr. Nelson is an anatomic and clinical pathologist with more than 30 years’ experience in global infectious disease pathology and is committed to improving health care by promoting timely and accurate diagnoses, especially in parts of the world where resources are limited. She is currently Infectious Disease Pathology Consultant at the Joint Pathology Center and Professor of Pathology (visiting) at Duke University. The focus of her work has been in HIV/AIDS pathology in the US and in sub-Saharan Africa. Currently she works on educational projects and capacity building in anatomic pathology, and linking anatomic pathology to ongoing clinical and epidemiologic research. She is a founding member of InPaLa (International Pathology and Laboratory Medicine), ASAP (African Strategies for Advancing Pathology) and serves as co-chair of the subcommittee on education for the ASCP Partners in Pathology initiative.

Recently, I had the good fortune of meeting her in person and we sat down to talk about her amazing life and career, and what she continues to do to contribute to the world.

Q: Your entire career has been focused on improving the lives of others, through helping people get the care they need by improving access, education, and opportunity. What inspired you to pursue a career in global health in the first place especially as it relates to working through pathology?

A: I’ve always had a desire to travel even since I was young – I thought I wanted to do something involving travelling – something like photography. When I was older, I worked as a medical technician and the pathologist I worked under advised me to pursue medical school. It was Vietnam war time though, so the odds of going to medical school were 30:1 in California – but an opportunity arose to go to medical school in Guadalajara, Mexico. I did, and this was my first time living outside of the country. While there, I would participate in medical outreach projects orchestrated by the medical school to serve the rural community members. Naturally, since I was a Med Tech, I would run the laboratory point-of-care diagnostics for the outreach. We would screen for parasites for example, and this got me interested in infectious diseases.

I thought at first, I would pursue pediatrics, but pathology drew me in. In 1979, I took a course in ‘Parasites for Medical Technicians’ and met the folks in Tropical Medicine at UCLA.  I met Dr. Marietta Voge, who had written a book in Parasitology, and she became a mentor to me. Also, at the course, there was a pathologist named Dr. Daniel Connor, from the AFIP [Armed Forces Institute of Pathology], who was the editor of the ‘Atlas of Pathology of Tropical and Extraordinary Diseases’.  He gave a lecture on his fascinating work which took place all around the world, but at length in Uganda, and this was the inspiration for me.  I thought “that’s what I want to do!”. Dr. Connor would become like a father figure to me, and to this day my son calls him Grandpa. He has always been an important supporter and mentor throughout my career.

Fast forward, I finished my residency training in pathology and had the opportunity to spend four months at the AFIP working with the Infectious disease pathology department. A few months later, they invited me to take a job with them – which I did.

One of the hospitals in Africa that the AFIP supported was the Karawa hospital in the Ubangi territory in the former Zaire. I worked for a few months in the hospital there. While there, I met an African physician who had just returned from completing his master’s in public health at Tulane University. His name is Sambe Duale – I am now married to him. [She said this point with a smile and we both giggled at how charming this story was!]

Towards the end of my work at Karawa, I was asked to help bring pathology services to Kinshasa in a collaboration with the NIH, CDC, and the Tropical Medicine Institute of Antwerp to work on Project SIDA [the first project on AIDS in Africa]. I began working with Jim [James] Curran, Tom Quinn, and Peter Piot, who were some of the people leading the project. I worked at the Medical School in the Department of Pathology from the fall of 1986, and continued to work there until 1991 when we were evacuated out [by the US government due to the civil unrest that brought violence to the capital].

After that, I continued to work in infectious disease pathology in the US, waiting for my son to graduate from high school before considering working abroad again. In that time, I continued to be heavily involved in IAP [International Academy of Pathology], working to organize meetings, and contributing to building educational systems. I have given world-wide lectures in at least 23 countries, in all continents except for Antarctica. I retired from full time practice in 2015.

After my son graduated from high school, I decided to work in Africa again on a Fulbright in Tanzania and Uganda. Professor Nelson Sewankambo, who was the head of Makerere University College of Health Sciences, invited me to mentor the young pathologists at Makerere University. Robert Lukande was one of them – he is now Chair of the pathology department there. We worked and wrote several papers together, focusing on AIDS and autopsy. I gave lectures to multiple departments, mentored staff, and made connections. I went and built partnerships with everyone I could. You have to just go and talk to people, and ask them “What can we do?”

Q: You worked to conduct a landmark survey of African pathologists to determine the status of pathology resources in Sub-Saharan Africa. What were some of the key findings and how did you collect all this data?

A: The idea for the survey came when I was in Victoria Falls, South Africa for a pathology conference, when I was speaking with Martin Hale. The realization that most of the conference presenters were foreign pathologists, not African pathologists, struck us. We who had been working in Africa knew the answer as to why – there weren’t enough African pathologists. But there wasn’t any data, nobody knew how bad the situation really was. The idea evolved over the next decade, Dan Milner helped to put together an on-line survey that was translated into French and Portuguese.  When we finished the survey in 2014, there were less than 800 pathologists in Sub-Saharan Africa. The question then became, why aren’t there more African pathologists? How do you advocate for this to improve?

The data was largely based on person to person connections. We had to reach out individually, involving people who spoke multiple languages, made phone calls, sent emails…we worked for hundreds and hundreds of hours. You have to really just get out on the street and talk to people.

This was the starting point so that we could measure improvement. We are now working to update the survey and measure the progress that’s been made.

Q: I’ve heard you have the nickname “Mama” in and outside of Africa. How did this come about?

A: In 2006, it was the 100th anniversary of the IAP, and there was a pathologist from Nigeria who I had known, and he unofficially crowned me the “Mother of African Pathologists.” It stuck because people still refer to me as “Mama.” [Dr. Nelson told this story with a warm smile, and it was clear that this designation is an honor for her – I can easily tell that it is her kind soul and motherly nature that make people feel trust in her – “Mama” is absolutely a perfect fit.]


-Dana Razzano, MD is a Chief Resident in her third year in anatomic and clinical pathology at New York Medical College at Westchester Medical Center and will be starting her fellowship in Cytopathology at Yale University in 2020. She was a top 5 honoree in ASCP’s Forty Under 40 2018 and was named to The Pathologist’s Power List of 2018. Follow Dr. Razzano on twitter @Dr_DR_Cells.

Microbiology Case Study: An 81 Year Old Female with Persistent Fevers

Case History

The infectious disease service was consulted on an 81 year old female for persistent fevers. She initially presented a few weeks prior with cough & shortness of breath which was diagnosed as an acute chronic obstructive pulmonary disease (COPD) exacerbation for which she received levofloxacin and steroids. The patient continued to have a persistent cough and dysphagia after discharge. Her respiratory status and cough worsened and she was readmitted and intubated. Vancomycin, piperacillin/tazobactam and levofloxacin were started as well as fluconazole for suspected esophageal candidiasis. Her past medical history was significant for breast cancer, atrial fibrillation, and diabetes mellitus. Of note, patient was originally from Puerto Rico but moved to the United States 40 years ago and denied recent travel and any known tuberculosis exposures. She formerly worked in a deli packing cheeses. A bronchoscopy was performed and a brochoalveolar lavage (BAL) specimen as well as blood and stool specimens were submitted for bacterial culture and ova and parasite exam.

Laboratory Identification

Image 1. Multiple larval forms in the stood specimen from an ova and parasite exam. (Iodine stain, 100X).
Image 2. High power of the larvae with a short buccal cavity (red arrow) and prominent genital primordium (blue arrow), (Iodine stain, 1000x).

The bronchoscopy revealed a bloody fluid admixed with clots which was clinically consistent with diffuse alveolar hemorrhage. The roundworms depicted above were identified in both the BAL and stool O&P exam. Based on the presence of the short buccal cavity and the prominent genital primordium and the absence of eggs, the identification of Strongyloides stercoralis was made. Given the large amount of larvae present in both the lungs and gastrointestinal tract, the patient was diagnosed with a strongyloidiasis hyperinfection.  

Discussion

Strongyloides stercoralis is classified as a nematode (roundworm) and is the cause of strongyloidiasis in humans. The helminth is found worldwide, especially in warm climates and underdeveloped countries, and is the cause of 30-100 million infections. Infection is due to fecal contamination of soil, where free-living forms are found, or water. Infective filariform larvae penetrate intact skin, particularly bare feet, resulting in infection. The free living cycle begins with the rhabditiform larvae passed through the stool develops into the infective filariform larvae or when the  rhabditiform larvae mature into free living adult male & female forms that mate and produce eggs which then hatch and become infective filariform larvae that can infect humans. The parasitic life cycle begins with the infective filariform larvae penetrates human skin. The worm is then either coughed up from the lungs and swallowed or migrates to the small intestine where eggs are laid and hatch.

Patients may present with gastrointestinal symptoms such as abdominal pain, bloating, and diarrhea, pulmonary symptoms like dry cough and throat irritation, or skin rashes along points of entry (feet, ankles). When the larvae are in the lung, Loeffler’s syndrome, characterized by pneumonia symptoms with coughing and wheezing, may develop due to an accumulation of eosinophils in response to the parasitic infection. In patients who are immunocompromised, the rhabditiform larvae can develop into the filariform larvae in the host and can directly penetrate the bowel mucosa or perianal skin resulting in autoinfection, dissemination throughout the body, and high parasite burden. Symptoms of hyperinfection include bloody diarrhea, bowel perforation, destruction of lung parenchyma with bloody sputum, meningitis, and septicemia. Hyperinfection most commonly occurs after steroid administration for asthma or COPD exacerbation, but can also be seen in those receiving chemotherapy or who have had organ transplants.  

In the laboratory, the diagnosis of S. stercoralis is most often made by an ova and parasite exam of the stool, duodenal fluid, sputum or BAL specimens (Image 1). Most commonly the rhabditiform larvae are present and are identified by the presence of a short buccal cavity and prominent genital primordium (Image 2). These two features are helpful in distinguishing S. stercoralis from hookworms (Ancylostoma spp. and Necator americanus) which have a longer buccal cavity and indistinct genital primordium. The eggs of these two nematodes are also very similar, although typically S. stercoralis eggs hatch before they are passed in stool specimens. S. stercoralis can also be visualized on H&E histology sections in the crypts of intestinal biopsies where the adult female measures up to 2.2 mm in length. Finally, serologic testing can be helpful when there is a high suspicion of disease in the face of multiple negative stool exams, but cannot distinguish between a current or past infection. Most patients do not remember a specific exposure and prevention includes wearing gloves and shoes when handling or walking on soil that may contain contaminated fecal material. Treatment options for an acute or chronic S. stercoralis include a short course of ivermectin or albendazole. In the case of disseminated infection, ivermectin should be given until stool and sputum exams are negative for 2 weeks. In the case of our patient, she was started on ivermectin, but succumbed to the disease due to extensive pulmonary hemorrhage.   

-Jaswinder Kaur, MD, is a fourth year Anatomic and Clinical Pathology resident at the University of Mississippi Medical Center. 

-Lisa Stempak, MD, is an Assistant Professor of Pathology at the University of Mississippi Medical Center in Jackson, MS. She is certified by the American Board of Pathology in Anatomic and Clinical Pathology as well as Medical Microbiology. She is the Director of Clinical Pathology as well as the Microbiology and Serology Laboratories. Her interests include infectious disease histology, process and quality improvement, and resident education.

I Had a Blast

Hi again everyone!

Welcome back. Last month I talked about a colleague of mine, a fellow student who’s pursuing a career in pathology. The month before that I wrote a bit about Just Culture and how those of us in laboratory medicine ought to act as leaders for patient advocacy—especially when it comes to putting the needs of patients first. And in the spirit of progressing career timelines and fortuitous transitions, this month I want to talk about a place where Just Culture is tangible, where “patient come first” is a mission statement, and where I just spent the last month rotating in their Department of Laboratory Medicine and Pathology: The Mayo Clinic.

Image 1. Commemorative statue of the Mayo brothers in a park in front of the main building of the downtown campus at Mayo Clinic in Rochester, MN.

Before I go any further, if you haven’t seen the PBS Ken Burns’ documentary, I highly suggest you do; it’s fantastic. There are also a few excellent books on the hospital’s history and vision here and here. But back to the rotation: I can’t express how lucky I feel having spent time there or convey how much of a privilege it was to see pathology in a uniquely Mayo way. What I can do is try to talk a little bit about my experience and what that translates to regarding a culture of advocacy and collaboration; and I’ll share a case conference I presented on my last day in a topic I find fascinating.

Image 2. Ken Burns presents The Mayo Clinic: Faith, Hope, and Science on PBS, which aired September 2018.

Mission, Vision, and Values

As with any hospital, academic center, clinic, etc., you’re always going to have a driving philosophy that anchors the values of that particular institution. Some of my experiences in larger academic centers tout their strides at the forefront of medicine and translational research, others advertise that they treat the whole person body and spirit. Community hospitals sometimes lean into their integral part of, well, their communities as a center for trust and health. Sometimes institutions have specific populations to cater to or work intensely with industry and boast strong contributions to medical science. At the Mayo Clinic you’d be hard pressed to miss the message (in various forms) that “The Patients Come First”—in fact that line from many years ago comes from Dr. William Mayo delivering a commencement speech at a Rush Medical College graduation. (I was so happy to see so many Chicago-Mayo Clinic connections!)

Image 3. Dr. W. Mayo articulated the concept of patients’ “needs come first” in a graduation speech at Rush Medical College in Chicago on June 15, 1910.

It becomes very obvious that this culture of advocacy permeates into the daily proceedings there. The hospital makes a strong point to celebrate outreach, education, and research; and clinicians are given a cultivated environment in which to flex muscles of compassion for patient outcomes. It makes you a better clinician, and I argue, person. Everyone at this hospital has a voice and a seat at the table. I was continuously encouraged to interact with staff, clinicians, residents, fellows, and patients and contribute what I thought would benefit patient care. A unique perspective as a visiting medical student with previous MLS experience was both noted and celebrated.

Leadership in Pathology

In many of my pieces on this blog, I frequently discuss how we should champion active roles in testing stewardship, policy advocacy, and promoting positive patient outcomes. Granted, when you find yourself in larger, resource-rich, tertiary academic centers you can really push the envelope for progress. But generally, those of us on the ‘scopes operate in this margin between clinical medicine and translational research. Where does our leadership come in? What does it look like? I think it comes in the form of prolific contributions to societal guidelines and interdisciplinary work. Nowhere have I seen this more than my month in Rochester.

So many of their residents contributed abstracts and presentations at this year’s USCAP conference, some winning awards. The academic cycle of producing something great requires strong support from your home institution and that’s exactly what I saw. Not only were folks supported for their trips to conferences per usual, they were celebrated—hallway handshakes, accolades at morning conference, discussions post-meeting, and social media shares. Which, by the way, social media is now a leadership staple. You can’t go far in the present day without utilizing technology both inside and out of your practice. The Pathologist recently celebrated their first #TwitterPathAward for residents like Dr. Tiffany Graham at UAB for contributions to medical education and advocacy in pathology. Mayo clinicians, including residents, consultants, pathologist’s assistants, and more share case studies, educational material, and cutting-edge pathology news in terabytes! I now find myself increasingly active on social media representing pathology and interests within our field.

Image 4. A spring 2015 issue of The Pathologist discussed the increasing presence of pathology in social media and the trends of utilization for medical laboratorians abound.

Side note: I’ve followed a number of these social media pages about cases in pathology for a while, and when I was fortunate enough to be part of ASCP’s Top 40 Under Forty 2017, I connected with lots of awesome laboratorians. Some of which I got to meet this month! Including a fellow blogger on this site, some celebrated path assistants, and a prolific parasite-discussing clinical microbiologist.

Case Conference

So, my presentation was intense! I’ve given plenty of case reports and conference discussions before, but this was an opportunity for me to explore quite a rare case in genetics and connect it with my interests in hematopathology. This was a case of a patient with Li-Fraumeni Syndrome (LFS) who developed therapy-related Acute Myeloid Leukemia. It’s not a current case and has since been signed-out and closed, but I’ll only be talking about the pathologic entities involved.

Image 5. Remember that power of social media I mentioned earlier? Well, what better way to share information for other medical students interested in pathology and interested in visiting Mayo Clinic! Having my presentation grab an honorable mention amidst their productive and busy residents was great! #path2path #hemepath #lablogatory

Essentially, this patient was found to have Li-Fraumeni after the second manifestation of an acute sarcoma—the first being osteosarcoma in her teenage years and the second breast cancer in her 30s. Both cancer diagnoses were treated accordingly, and this patient was going through routine work-up for anemia before being referred to the Mayo Clinic. By the time the patient reached there, the clinical investigation included a battery of testing for causes of anemia—all within normal limits—so a bone marrow examination was performed which revealed a significant, though not acute (<20% blasts), myelodysplastic process. A follow-up in-house bone marrow collection revealed hypercellular marrow, now in acute myeloid proliferation, with abnormal myeloid cell maturation and very complex cytogenetics. She had a very complex karyotype and several detectable mutations which were consistent with the WHO’s classification and description of therapy-related myeloid neoplasm as a sequale to the treatments she received for her prior cancers. In the setting of a patient with LFS, it is almost impossible to avoid malignancy. The following slides are a (very abridged) summary taken from my presentation of this patient’s case:

Figure 1. Official LFS and AML discussion. As mentioned, this is the case of a patient with a history of osteosarcoma and breast carcinoma, both treated, now presenting status-post initial work-up for evaluating possible causes for anemia. Ultimately, when reaching a bone marrow examination, certain myelodysplastic features were discovered, referring this case for close investigation and expanding the differential to include various hematologic malignancies.
Figure 2. This bone marrow biopsy was evaluated at an outside institution and was reported to this patient’s case at Mayo Clinic. Note the presence of myeloid lineage blasts cells in the peripheral blood (PB) and bone marrow (BM) evaluations, however, at less than 20% this would not immediately indicate any acute myeloid crisis. There is a definitive left-shift in maturity with myeloid dysplasia.
Figure 3. This bone marrow evaluation was done about a month after the previous reported one. Note the significant increase in myeloid blasts present in both peripheral and bone marrow specimens. This time, there was significant dysplasia noted in multiple lineages as well as particular changes in granulocytic lines including left-shift and pseudo Pelger-Huet cells present. This diagnosis was upgraded from myeloid dysplasia to acute myeloid leukemia in the setting of myelodysplasia. The blast count has now crossed the 20% threshold and there are marked changes to morphology in several cell lines. Hypercellularity and cytogenetic testing were also highly contributory in this diagnosis. Not included in this slide but CD34+ cells that previously expressed CD15, CD33, and CD38 were now negative for those three markers. This indicates decrease in maturity and a poorer prognostic and clinical assessment of this malignancy.
Figure 4. A peripheral blood smear at the time of the second bone marrow specimen. In almost every field photographed, there were myeloid blast cells present. No Auer rods were seen, but many blasts had granules. There was left shift, and some immature granulocytes were present. Erythroid immaturity was demonstrated with morphology and circulating nucleated RBCs. Abnormalities in granulocytic lineages were present with hypogranular neutrophils and pseudo Pelger-Huet morphology.
Figure 5. At nearly any age, this bone marrow needle core biopsy on H&E stain would qualify as hypercellular. At low to medium power this is clearly evident. At higher powers, note the presence of predominantly immature granulocytes (with very few, if any, mature PMNs) as well as numerous blasts—on H&E blasts appear differently, but appreciate the increased number of cells with active nuclei, condensing chromatin, and prominent nucleoli.
Figure 6. Back to traditional hematology staining, you can still appreciate this bone marrow aspirate’s hypercellularity. There is a labeled megakaryocyte (which appears slightly abnormal) to scale against the numerous, immature and left-shifted granulocytes which overrun the fields. Myeloid blasts are seen in high numbers, with granules and prominent nucleoli. Increased levels of mitotic activity, abundant (and some abnormal) myeloid precursors, and a highly proliferative picture is appreciated.
Figure 7. Li-Fraumeni Syndrome (LFS) is a rare genetic predisposition to soft-tissue sarcomas. It is a germline mutation of either TP53 or CHECK2, more often the former. The mutation usually has an autosomal dominant inheritance pattern and has very high penetrance, more so in females (possibly due to the fact that the most common presentation of tumor formation in LFS is breast cancer). Note that this patient had a clinical history significant for both breast carcinoma and osteosarcoma which were treated with chemotherapy and radiation.
Figure 8a. Patients with LFS often have a germline mutation in p53, a very significant tumor suppressor gene, which is implicated in a wide host of cellular functions. Located on the short arm of Chromosome 17, when mutated this gene affects a myriad of pathways including cell senescence, growth cycle response, proliferation, DNA damage repair from mutations, epigenetic, or exogenous causes, and programmed cell death. If this downstream protection against severe DNA compromise is lost, this becomes a highly pre-cancerous environment for Knudsen’s “second hit” to negatively affect cells and ultimately lead to a vast array of malignancies.
Figure 8b. I mean just look! P53 is a serious player in cell survival and DNA damage recovery. It is the archetype example of a tumor suppressor gene and is implicated in an ever-growing number of cell survival and growth cycle pathways—of course a loss of p53 function would set the stage for high-risk.
Figure 9a. The World Health Organization (WHO) and its updated guidelines for diagnosing and addressing hematologic malignancies now includes a lot of new data regarding the molecular biology of cancer. Its applications to diagnostics in hematopathology are growing daily. In these guidelines, the WHO classify AML into seven general categories. For reasons relating to her clinical history of cancers and treatment, as well as the timeline she presented with, t-MN or therapy-related myeloid neoplasm would be an appropriate diagnosis.
Figure 9b. The American Society of Hematology (ASH) and the College of American Pathologists (CAP) co-wrote guidelines for the diagnosis of AML and published a number of recommendations in The Hematologist in 2017-2018. Essentially, proper laboratory test utilization and incorporation with significant clinical history is crucial. Staying organized and operating within WHO guidelines for hematologic malignancy diagnosis is just as important. The ASH/CAP guidelines tell diagnosticians to think about several key questions when approaching AML which further underscores the values of consistency, efficiency, and appropriate utilization.
Figure 10a. The reason for establishing a diagnosis of therapy-related AML is a significant one. The use of Topoisomerase II inhibitors, alkylating agents, antimetabolites, and radiation therapy all affect the genetic components relating to this particular leukemia. To correlate further, the patient had a 5q deletion, a complex karyotype, a history of receiving all treatments related to this entity, and a presentation of myelodysplasia which rapidly progressed to AML.
Figure 10b. LFS can cause leukemia on its own, AML can present as a hematologic malignancy on its own too; but this patient’s clinical history and treatment history lean the diagnosis away from de novo cancer to a myeloid process in response to a latent treatment effect.

Why All of This Matters

There are two main reasons why all of this is important enough to discuss in a case conference. First, as clinicians from the bench to the bedside we should all strive to talk through the toughest diagnoses and share with each other what best practices, lessons, and goals we can reach together. In the setting of Li-Fraumeni Syndrome it becomes critical to evaluate new onset (especially myeloid) neoplasms. TP53 mutations are associated with the lowest survival rates in acute myeloid leukemia, which has its own diagnostic and prognostic classifications set forth by the World Health Organization. Furthermore, understanding appropriate patient history, clinical information, and what appropriate lab investigation means is crucial. It not only keeps the needs and interests of the patient first, but also translates to the proper utilization of resources for the best results in the best timelines. Potential future implications of concurrent ongoing work in hematopathology and molecular genetics may yield therapeutic and diagnostic benefits we are not yet aware of—we must constantly include updates as we practice.

Second, this was an opportunity to share insights into the diagnosis and discussion of AML that came from my clinical experiences before rotating there. I previously mentioned the demonstrated value of including clinical viewpoints for the benefit of patient care outcomes, so appropriately I incorporated these topics into this case conference and included the following points to consider:

  • Hematologic premetastatic niches

When I was in graduate school at Rush University in Chicago, I did some research in hematopoietic responses to various therapies in the context of proliferation and understanding mobilization for transplant and engraftment. In this work, I became familiar with the concept of a reactive stroma and a “pre-metastatic niche.” There are small microenvironments in which hematopoietic, mesenchymal, and endothelial cell lines in the bone marrow thrive and develop which are full of cytokines and cell-cell interactions. My work focused on mobilizing all three lines with a CXCR4 target, but the concept holds true when considering germline and somatic mutability. In effect, those cells with pre-malignant mutations can cluster and affect the environment of other cells maturing in the same setting. The same way invasive cells can break through barriers to metastasize and spread past their in situ conditions, the same mobilizing spread can grow from pre-metastatic clusters. This, again, opens the discussion for treatment targets in future LFS and/or AML patients as molecular pathology expands.

  • Acute Myeloid Leukemia and Myeloid Sarcoma

In a recently published paper in Histopathology, I was part of a team at the UAB hospital’s department of pathology which discussed their experience with patients diagnosed with myeloid sarcomas (MS). The point was to look for correlations with MS to connect the entity with age, sex, location of tumor, AML status, genetics, etc. Ultimately, what became the highest predictor of disease was a complex karyotype, consistent with other concurrent literature. With respect to this patient, what if there was another soft tissue (or other location) sarcoma alongside her myelodysplastic picture. What if she had a low blast count, or hypocellular bone marrow, or necrosis/fibrosis, or had received G-CSF? Would AML with myeloid sarcoma be considered in this diagnostic setting, would myeloid sarcoma be something to worry about in her future or in her clinical history as a misdiagnosis? The take-home message would be to pay close attention to patient clinical history and stay both focused on the current diagnostic work-up but also open enough to avoid pitfalls in diagnostic challenges.

  • Misdiagnosis in clinical settings

In a case report from 2017 I discussed a patient who had bilateral lung nodules several years after being treated for breast carcinoma. It was initially thought to be relapse but was later correctly diagnosed as de novo peripheral T-cell lymphoma (PTCL). This could have very well been the same clinical scenario, with a different cell lineage. The lesson gleaned here is the same as those ASH/CAP guidelines: stay organized, consistent, and purposeful with your testing and investigation. What came down to a few immunohistochemical markers in this PTCL case could make all the difference in another case. Missing the clinical history and specific genetic mutations present in this LFS/AML patient could have led to a diagnosis of a myelodysplasia related AML instead of a therapy-related one, especially in the setting of such a severe germline pre-disposition.

  • Future plans for this patient

I thought it was ultimately important to discuss the patient’s future plans with the audience. In pathology we often sign-off after we sign-out. So, in order to make sure we emphasize the patient’s best interests moving forward from a poor prognostic diagnosis, we discussed her enrollment in a trial aimed at improving bone marrow donor matching based on HLA and KIR combination typing. This a relatively new and promising concept in the literature which I hold high hopes for.

If anything, this was something I learned last month: in order for you to call the quality of care the highest possible, you have to uphold many standards, both clinical and non-clinical. Clinically we all have to share with each other the latest and greatest in modern literature and advances in interdisciplinary or translational research. Aside from this, however, we have to keep each other human and connected to our patients. I never like to hear the stereotypes in pathology that place us in lab medicine miles away from patient care; instead, we do things every day that impact our patients’ lives greatly. And when we keep ourselves connected to that fact, like the philosophy at the Mayo Clinic, then we can boast our quality of care—from small community hospital to academic trauma center. Because its not the size of the lens on the scope, it’s the vast scope of impact we look through in a lens of compassion.

There you have it. That’s my month at Mayo and a case conference in a nutshell. It was a fantastic experience and I have to say it—I had a blast!

Thanks for reading, I’ll see you next time!

And have a Happy Lab Week 2019!

–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 63 Year Old Male with a ~60 Year Recurring Neck Mass

Case History

A 63 year old man presented with a long standing history of a recurring pleomorphic adenoma of the parotid gland. As a child, the patient had radiotherapy to the bilateral parotid glands for parotid swelling. He then developed a left parotid mass ~15 years later and underwent parotidectomy. After another recurrence ~15 years after the initial parotidectomy, he underwent a second resection of multiple masses in the preauricular region. The patient then developed a recurrence ~20 years after the second resection and underwent neutron beam therapy. The patient tolerated the treatment well noting mild dry mouth, which is persistent, and left ear pain, but otherwise has no major long-term sequelae from the treatment. Eighteen years after the neutron beam therapy, the patient developed a left submandibular mass. A subsequent biopsy of the mass revealed a pleomorphic adenoma.  Enlarged left and right submental and submandibular nodes were noted, with biopsies performed at an outside hospital of these nodes demonstrating metastatic poorly differentiated carcinoma within three lymph nodes. It was noted on this pathology report that the histological features, in light of the history, could represent a carcinoma ex pleomorphic adenoma. A CT scan of the head and neck revealed a large multiloculated, cystic, rim-enhancing mass within the left parotid gland, as well as large enhancing lymph nodes within the right anterior and posterior cervical triangle and the right submandibular space, the largest of which measured 2.1 cm. A PET scan showed increased activity within the right neck. Upon meeting with otolaryngology, a 4.0 x 7.0 cm lobular, non-fixed left parotid mass, and two level 1B right sided nodes, were palpated. Based on the patient’s history, physical exam, and prior biopsy results, it was decided to proceed with a parotidectomy and bilateral neck dissection. 

Diagnosis

Received in the Surgical Pathology laboratory is a soft tissue mass resection from the area of the left parotid gland measuring 9.0 x 6.0 x 4.2 cm. The specimen is oriented by a single long stitch designating the superior aspect, and a double long stitch designating the lateral aspect (Figure 1). The specimen is entirely inked black, and then bisected to reveal multiple discrete, white-tan, partially cystic masses ranging in size from 0.2-4.0 cm in greatest dimension and measuring 7.0 x 3.5 x 3.0 cm in aggregate dimension (Figure 2). The largest mass is partially cystic with the cystic component measuring 1.2 cm in greatest dimension. This largest mass abuts the anterior, medial and lateral margins. The remaining tumor deposits are located:

– 1.2 cm from the inferior margin

– 0.4 cm from the superior margin

– 0.9 cm from the posterior margin

No gross salivary gland tissue is identified. The remainder of the specimen consists of unremarkable yellow adipose tissue and red-brown skeletal muscle. The specimen is submitted as follows.

Cassette 1:   superior margin

Cassette 2:   representative sections of anterior margin

Cassette 3:   anterior superior margin

Cassette 4:   anterior inferior margin

Cassette 5:   posterior margin

Cassette 6-9:   representative sections of mass with approach to lateral margin

Cassette 10:   representative sections of mass with approach to medial margin

Cassette 11:   mass in relation to surrounding skeletal muscle

Cassette12-15:   representative sections of mass

On microscopy, the specimen contains nests of tumor cells ranging in size from 0.2 to 4.0 cm within a dense fibrous matrix. Although these deposits may represent lymph node metastases, no residual lymphoid tissue is present. The tumor is represented by residual pleomorphic adenoma and numerous soft tissue deposits of pleomorphic adenoma (Figure 3). Admixed are broad areas of high grade carcinoma with necrosis (Figure 4). Most regions show adenocarcinoma, although a rare focus of squamous differentiation is also present. The lateral margin is positive for carcinoma, and a pleomorphic adenoma component approaches within 0.1 cm of the medial margin. The anterior, posterior, inferior, and superior margins are all free of tumor. No salivary gland tissue is identified.

In addition, eleven frozen sections are submitted from various areas surrounding the mass, with five of the eleven frozen sections demonstrating tumor deposits. A right neck dissection is performed with following results:

Level IB: 2 of 3 positive (largest deposit: 1.8 cm)

Level II and III: 1 of 14 positive, Level II (1.9cm)

Level IV: 1 of 8 positive (2.0 cm)

Based on these results, the specimen was signed out as carcinoma ex-pleomorphic adenoma, and designated as pT4aN2cMx

Figure 3. 2x photomicrograph showing a classic appearing pleomorphic adenoma with satellite nodules along the periphery

Discussion

Carcinoma ex pleomorphic adenoma (CXPA) is a carcinoma that arises in a primary (de novo) or recurrent benign pleomorphic adenoma (PA). While a PA is the most common salivary gland tumor, accounting for approximately 80% of all benign salivary gland tumors, a CXPA is quite uncommon, accounting for only 3.6% of all salivary gland tumors. CXPA is predominantly found in the sixth to eighth decades of life, with a slight predilection for females. CXPA arises most commonly in the salivary glands, in particular the parotid and the submandibular glands. CXPA can also arise in the minor salivary glands in the oral cavity, although these tumors tend to be smaller than their counterparts in the parotid and submandibular gland. There have also been cases of CXPA in the breast, lacrimal gland, trachea, and nasal cavity.

Clinically, CXPA presents as a firm, asymptomatic mass that can go undetected for years since they are not generally invasive. When the patient does experience any symptoms, with pain being the most common, it is usually due to the mass extending to adjacent structures. If the mass was to involve the facial nerve, paresis or palsy can occur. Other signs and symptoms include skin ulceration, mass enlargement, skin fixation, lymphadenopathy, dental pain, and dysphagia. The onset of symptoms can range anywhere from 1 month up to 60 years (such as with this case), with a mean onset of 9 years. Half of patients will have a painless mass for less than 1 year. Since these symptoms are similar to those of a benign PA, it’s important that the treating physician be aware of the possibility of a CXPA, especially considering the rarity of the cancer.

Grossly, CXPA appears as a firm, ill-defined tumor, and can vary greatly depending on the predominant component. If the PA is the predominant component, the mass may appear gray-blue and translucent, and it could be possible to grossly differentiate between the PA areas and the CXPA areas. If the malignant component predominates, then the mass may contain cystic, hemorrhagic and necrotic areas.

Microscopically, CXPA is defined as having a mixture of a benign PA, admixed with carcinomatous components. Zbaren et al, in an analysis of 19 CXPA cases, found 21% of the tumors were composed of less than 33% carcinoma, 37% of the tumors were composed of 33-66% carcinoma, and 42% of the tumors were composed of greater than 66% carcinoma. Most often, the malignant component is adenocarcinoma, but can also include adenoid cystic carcinoma, mucoepidermoid carcinoma, salivary duct carcinoma, and other less common variations. In cases where the entire tumor is replaced by carcinoma, the diagnosis of CXPA will be based on the presence of a PA on the previous biopsy. Conversely, you could also have a tumor that is predominately composed of a PA, with sparse areas of malignant transformation, such as nuclear pleomorphism, atypical mitotic figures, hemorrhage and necrosis. The likelihood of malignant transformation increases with the length of the PA being present, from 1.5% at 5 years, up to 10% after 15 years.

CXPA can be further sub-divided into four categories based on the extent of invasion of the carcinomatous component outside the capsule: in-situ, non-invasive, minimally invasive, and invasive carcinoma.

#1) In-situ carcinoma occurs when nuclear pleomorphism and atypical mitotic figures are found within the epithelial cells, but do not extend out beyond the border of the myoepithelial cells (Figure 5).

#2) Non-invasive CXPA, which can include in-situ carcinoma, is maintained within the fibrous capsule of the PA, but extends beyond the confines of the myoepithelial cells. Non-invasive CXPA may begin to show malignant transformation, but will overall behave like a benign PA.

#3) Minimally invasive CXPA is defined as <1.5 mm extension into the extracapsular tissue, with a mix of benign PA components and carcinomatous components.

#4) Invasive CXPA is defined as a > 1.5 mm extension into the extracapsular tissue, and will begin to demonstrate more carcinomatous components, such as hemorrhage and necrosis.

As the carcinomatous areas begin to increase in prevalence, the PA nodules will begin to be composed of hyalinized tissue with sparse, scattered ductal structures, and the malignant cells will begin to decrease in size as they move away from the site of origin. Perineural and vascular invasion can be easily identified as the tumor extends into the neighboring tissue (Figure 6).

The development of CXPA has been shown to follow a multi-step model of carcinogenesis with a loss of heterozygosity at chromosomal arms 8q, followed by 12q, and finally 17p. Both PA and CXPA demonstrate the same loss of heterozygosity, however, the carcinomatous components exhibit a slightly higher loss of heterozygosity at 8q, and a significantly higher loss of heterozygosity at 12q and 17q. The early alterations of the chromosomal arm 8q in a PA often involves PLAG1 and MYC, with the malignant transformation of the PA to a CXPA being associated with the 12q genes HMGA2 and MDM2.

Treatment for CXPA involves surgery, radiotherapy and chemotherapy, with a parotidectomy being the most common procedure performed. If a benign PA had originally been resected, but residual remnants of the PA were left behind, then satellite PA nodules will arise in its place (Figure 3). If in-situ, non-invasive or minimally invasive carcinoma is suspected in the superficial lobe of the parotid gland, than a superficial parotidectomy can be performed. Invasive carcinoma will result in a total parotidectomy, with every attempt made to try and preserve the facial nerve. If metastasis is suspected to the cervical lymph nodes, a neck dissection may also be performed. Reconstructive surgery following the removal of the tumor may be necessary, depending on where the tumor was resected from. Other treatment options currently being considered include a combination therapy of trastuzumab and capecitabine, as well as the possibility of a WT1 peptide based immunotherapy.

Figure 5. 40x microphotograph demonstrating an in-situ carcinoma confined within the myoepithelial cells
Figure 6. 10x photomicrograph of carcinoma at the lateral margin with areas of perineural invasion

References

  1. Antony J, Gopalan V, Smith RA, Lam AK. Carcinoma ex pleomorphic adenoma: a comprehensive review of clinical, pathological and molecular data. Head Neck Pathol. 2011;6(1):1–9. doi:10.1007/s12105-011-0281-z
  2. Chooback N, Shen Y, Jones M, et al. Carcinoma ex pleomorphic adenoma: case report and options for systemic therapy. Curr Oncol. 2017;24(3):e251–e254. doi:10.3747/co.24.3588
  3. Di Palma S. Carcinoma ex pleomorphic adenoma, with particular emphasis on early lesions. Head Neck Pathol. 2013;7 Suppl 1(Suppl 1):S68–S76. doi:10.1007/s12105-013-0454-z
  4. Handra-Luca A. Malignant mixed tumor. Pathology Outlines. http://www.pathologyoutlines.com/topic/salivaryglandsmalignantmixedtumor.html. Revised March 21, 2019. Accessed April 5, 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.

Insulin Resistance Caused by Insulin Antibodies

Insulin antibodies are seen in two conditions: 1, in insulin-naïve type-1 diabetic patients, insulin antibodies are developed together with some other autoantibodies against pancreatic islet cells; 2, in patients being treated with insulin, antibodies can be developed against exogenous insulins, in both type-1 and type-2 diabetes. These antibodies against exogenous insulins are found in >95% of patients treated with porcine and bovine insulins (1). Although the prevalence has decreased after the introduction of human insulin and insulin analogues, it is still not uncommon to detect these antibodies in insulin treated patients (2). However, these antibodies are rarely of clinical significance and laboratory test for insulin antibodies in insulin-treated patients has limited clinical value, except in rare cases where these antibodies are found to have immunologic role, causing insulin resistance. In some of these cases, postprandial hyperglycemia and nighttime hypoglycemia are both described due to reversible binding of insulin from antibodies (3), and patients were reported to respond to immunosuppressive therapies, and plasmapheresis in severe cases. 

We recently worked up a case for possible immunologic insulin resistance caused by insulin antibodies. In this case, patient is a 45 years old female with uncontrolled type-1 diabetes. She was found to have all four antibodies positive, including zinc transporter 8, islet antigens glutamate decarboxylase 65 (GADA), IA-2A, and insulin antibodies. Patient has been on multiple dose insulin injection (MDI) therapy, including insulin determir, aspart and lispro. She was reported to be compliant with medications and low carb diet. However, patient has poor glycemic control and presents with recurrent diabetic ketoacidosis. She was given high doses of insulins, but still presented with recurrent DKA and occasional hypoglycemia. Her HbA1c was consistently at >10% with daily glucose measured up to 500 mg/dL.

Immunologic insulin antibody and insulin receptor antibody were considered after ruling out more common causes of her uncontrolled diabetes. These two tests were then performed at a reference laboratory and patient was found to have positive insulin antibodies to analog insulin (determir and lispro) and negative insulin receptor antibodies. Significant insulin resistance by insulin antibodies was not found and the antibodies level did not suggest immunosuppressive therapy. Still, given her poor controlled diabetes, patient’s insulin was switched to human insulin and she was also recommend for pancreas transplant.

  1. Greenfield JR, Tuthill A, Soos MA, Semple RK, Halsall DJ, Chaudhry A, O’Rahilly S. Severe insulin resistance due to anti-insulin antibodies: response to plasma exchange and immunosuppressive therapy. Diabet Med. 2009 Jan;26(1):79-82. doi: 10.1111/j.1464-5491.2008.02621.x.
  2. Hall TR, Thomas JW, Padoa CJ, Torn C, Landin-Olsson M, Ortqvist E, Hampe CS. Longitudinal epitope analysis of insulin-binding antibodies in type 1 diabetes. Clin Exp Immunol. 2006 Oct;146(1):9-14.
  3. Hao JB, Imam S, Dar P, Alfonso-Jaume M, Elnagar N, Jaume JC. Extreme Insulin Resistance From Insulin Antibodies (Not Insulin Receptor Antibodies) Successfully Treated With Combination Immunosuppressive Therapy. Diabetes Care. 2017 Feb;40(2):e19-e20. doi: 10.2337/dc16-1975. Epub 2016 Dec 1.
Xin-small

-Xin Yi, PhD, DABCC, FACB, is a board-certified clinical chemist, currently serving as the Co-director of Clinical Chemistry at Houston Methodist Hospital in Houston, TX and an Assistant Professor of Clinical Pathology and Laboratory Medicine at Weill Cornell Medical College.