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.

comp1
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)

comp2
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.

EVB-t1
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.

Hematopathology Case Study: A 72 Year Old Female with History of Lung Adenocarcinoma

Case history 

A 72 year-old female with a history of stage IA lung adenocarcinoma diagnosed in 2009 s/p resection underwent a surveillance CT scan of the chest which revealed an enlarged right upper lobe paramediastinal lung nodule. A subsequent MRI of the abdomen and PET scan revealed mediastinal lymphadenopathy with numerous boney lesions. Due to the prior history of lung cancer, a right iliac bone biopsy was performed.

Diagnosis

myesar-he-10
H&E, 10x

myesar-he-20
H&E, 20x

myesar-he-50
H&E, 50x

myesar-cd-45
CD45

myesar-cd-117
CD117

myesar-cd-34
CD34

myesar-cd-68
CD68

myesar-cd-56
CD56

myesar-mpo
MPO

myesar-cd-43
CD43

Sections of bone show an extensive intramedullary infiltration by large cells with moderate amounts of cytoplasm, irregular nuclear contours, moderately condensed chromatin and some cells with inconspicuous nucleoli.

By immunohistochemistry, the neoplastic cells are immunoreactive for CD45, MPO, CD68, CD56, and CD43. The cells are negative for cytokeratins, TTF-1, CD20, CD10, PAX5, BCL6, MUM1 and CD79a. CD3 and CD5 highlight rare scattered T-cells.

Overall, in the context of multiple osseous lesions, these findings are representative for a myeloid sarcoma.

Discussion 

Myeloid sarcoma is a tumor mass consisting of myeloid blasts with or without maturation occurring at any site other than the bone marrow. Infiltration of blasts at any site are not classified as a myeloid sarcoma unless there is effacement of tissue architecture. Frequent sites for involvement by a myeloid sarcoma include skin, lymph node, gastrointestinal tract, bone, soft tissue, and testis.

Detection of a myeloid sarcoma is considered as an equivalent diagnosis of acute myeloid leukemia. It may precede or coincide with AML as well as be a presenting finding in those that relapse from AML.

Morphologically, the blasts may or may not show features of maturation and efface the architecture of the involved site. Immunophenotypically, CD68 is considered the most commonly expressed marker followed by MPO, CD117, lysozyme, CD34, TdT, CD56, CD30, glycophorin and CD4. Interestingly enough, CD123 may be expressed in those cases that also have inv(16). It must be emphasized that those cases that meet criteria for a mixed phenotypic acute leukemia (MPAL) cannot be classified as a myeloid sarcoma.

By cytogenetics, 55% of myeloid sarcomas have aberrant cytogenetic findings including monosomy 7, MLL rearrangements, inv(16), and other chromosomal changes. In the pediatric population, t(8;21) may be observed and is less frequent in adults. NPM1 is mutated in 16% of cases.

Lastly, the differential diagnosis should be kept broad in cases that appear lymphoid in nature yet do not mark appropriately. It is often expressed that the primary morphologic differential is a lymphoma, including lymphoblastic lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, blastic plasmacytoid dendritic cell neoplasm, and other small round blue cell tumors of childhood.

Reference

  1. Swerdlow SH, Campo E, Harris NL, et al.  WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008

 

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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 68 Year Old Man with Dyspnea on Exertion

Case History

A 68 year old male with no significant past medical history who enjoys long distance cycling presented to an outside emergency department with dyspnea on exertion. Laboratory values at the outside facility showed profound anemia (Hb 10 g/dL) and physical exam revealed lymph adenopathy. The patient was discharged but presented again to his primary care physician with profound dyspnea on exertion, especially after climbing one flight of stairs. Of note, his anemia had worsened with a new Hb of 7 g/dL. For evaluation of the anemia, the patient had a Coomb’s test and it was positive, overall consistent with cold agglutinin disease. For evaluation of the lymphadenopathy, a CT abdomen and chest revealed celiac, portocaval, mesenteric and retroperitoneal lymphadenopathy as well as mild splenomegaly. Due to these findings, the patient presented to Beth Israel Deaconess Medical Center for further evaluation and biopsy of a retroperitoneal lymph node.

A core needle biopsy of a retroperitoneal lymph node was obtained per the recommendation of hematology/oncology.

Diagnosis

AITL-1
H&E, 10X

AITL-2
H&E, 20X

AITL-3
H&E, 50X

AITL-4
CD3

AITL-5
CD20

AITL-6
CD10

AITL-7
CD4

AITL-8
CD7

AITL-9
CD21

AITL-10
Ki-67

AITL-11
EBER ISH

AITL-12
PD1

AITL-13
CXCL13

The core needle biopsy material demonstrated a lymphoid population that was polymorphic in appearance with medium to large sized lymphocytes with moderate amounts of pale cytoplasm, irregular nuclei, vesicular chromatin, and some cells with prominent nucleoli. The background cellular population is composed of a mixed inflammatory component including small lymphocytes, scattered neutrophils, eosinophils, and histiocytes.

By immunohistochemistry, the medium to large sized cells with pale cytoplasm are positive for CD3, CD2, CD4, and CD5 with complete loss of CD7. CD20 highlights scattered background B-cells. CD21 is positive in disrupted follicular dendritic meshworks. CD10 and BCL6 are negative in neoplastic cells. PD1 is positive in neoplastic cells with a subset co-expressing CXCL13. By Ki-67 immunostaining, the proliferation index is 50-70%. By in situ hybridization for Epstein-Barr virus encoded RNA, a subset of cells are positive.

Overall, with the morphologic and immunophenotypic features present, the diagnosis is that of angioimmunoblastic T-cell lymphoma.

Discussion

Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common types of peripheral T-cell lymphoma and accounts for 15-20% of T-cell lymphoproliferative disorders and 1-2% of all non-Hodgkin lymphomas. Clinical features include presentation with late stage disease with associated generalized lymphadenopathy, hepatosplenomegaly, systemic symptoms, and polyclonal hypergammaglobulinemia. Of note, this patient did have an SPEP that was within normal limits. Other findings, although less common, include effusions and arthritis. Laboratory findings often include cold agglutinins with hemolytic anemias, a positive rheumatoid factor (RF), and anti-smooth muscle antibodies. A hallmark of AITL is the expansion B-cells positive for EBV is seen, which may be an indicator of underlying immune dysfunction. The clinical course is often aggressive with a median survival of less than three years and often succumb to infectious etiologies because of an immune dysregulation.1

The pathogenesis and relation to other TFH neoplasms of PTCL, NOS is poorly understood. Recent literature indicates dysregulation in key pathways, including the CD28 and TCR-proximal signaling genes, NF-kappaB/NFAT pathway, PI3K pathway, MAPK pathway, and GTPases pathway.2 The complexity of these pathways has long been an issue for TFH lymphoproliferative disorders and has provided insight to potential molecular signatures (see figure 1 adapted from Vallois 2016).

AITL-14
Figure 1 from Vallois 2016

Another recent publication provided additional information regarding molecular insights. Confirmed mutational analyses reveals a high proportion of cases carry a TET2 mutation with less frequent changes in DNMT3A, IDH2, RHOA, and PLCG1. Specifically, RHOA, PLCG1, and TNFRSF21 encode proteins critical for T-cell biology and most likely promote differentiation and transformation into an aggressive clinical course (see figure 2 adapted from Wang 2017).3

AITL-15
Figure 2 adapted from Wang 2017

Overall, AITL is an uncommon TFH cell derived lymphoproliferative disorder characterized by a TFH immunophenotype, expanded and arborizing high endothelial venules, expansion of the follicular dendritic cell meshworks, and EBV positive B-cells in a background of a polymorphic infiltrate. Although it is hypothesized that the underlying mechanism of neoplasia is related to immune dysfunction, new molecular insights have demonstrated that multiple events occur ranging from early molecular changes to later acquired mutations that allow for malignant transformation.

References

  1. Swerdlow, S., et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th. ed., IARC press: 2008
  2. Vallois, D., et al. “Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas,” 2016; 128(11): 1490-1502.
  3. Wang, M., et al., “Angioimmunoblastic T cell lymphoma: novel molecular insights by mutation profiling,” 2017; 8(11): 17763-17770.

 

 

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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.

Show Us Some Skin

Which epidermal layer is indicated by the arrow?

  • A. Stratum corneum
  • B. Stratum germinativum
  • C. Stratum granulosum
  • D. Stratum lucidum
  • E. Stratum spinosum

Skin1

 

The answer is E, stratum spinosum. The stratum spinosum, also known as the prickle cell layer of the skin, is often several cell layers deep, and is located immediately above the stratum germinativum. Cells in this layer are polygonal, and are connected to each other by numerous desmosomes. During fixation, the cell membrane retracts around desmosomal contact points, giving the cells a prickly appearance. The cells contain many bundles of intermediate filaments as well as keratinosomes, which are membrane-bound granules thought to deposit a “toughening” layer on the surface of the cell membrane.

Skin2

 

The stratum germinativum (also known as the basal layer) is composed of a single layer of cells adjacent of the basal lamina. The cells are tall cuboidal or columnar, and are connected to the basement membrane by hemidesmosomes, and to other cells by desmosomes. Cells in the basal layer are mitotically active, and contain numerous polyribosomes and intermediate filaments.

Skin3

 

The stratum granulosum is 3 to 5 cell layers thick, and is composed of flattened, polygonal cells arranged with the long axis parallel to the basement membrane. The cytoplasm of these cells contains numerous basophilic granules, called keratohyalin granules, which are thought to be keratin precursors.

The stratum lucidum is not truly a distinct layer of skin, but rather a staining artifact. It is visible in some sections of thick skin as a glassy-appearing, eosinophilic artifact at the bottom of the stratum corneum. It is not present in this particular image of epidermis.

Skin4

 

The stratum corneum is the outermost layer of skin. The thickness of this layer varies considerably from region to region in the body. The cells of this layer are dead, flattened, and fused together, with completely keratinized cytoplasm.

Skin5

 

Krafts

-Kristine Krafts, MD, is an Assistant Professor of Pathology at the University of Minnesota School of Medicine and School of Dentistry and the founder of the educational website Pathology Student.

Routine Pap Smear from a 33 Year Old Woman

You are reviewing a routine Papanicoloaou smear from a 33 year-old female. She has no complaints and appears healthy. A representative field from her Pap smear is shown here. What organism is the most likely cause of the morphologic changes seen here?

pap1

  1. Chlamydia trachomatis
  2. Human papillomavirus
  3. Trichomonas vaginalis
  4. Leptothrix
  5. Gardnerella vaginalis

 

 

The diagnosis in this case is Chlamydial infection. Genital infection by Chlamydia trachomatis is the most common sexually transmitted disease in the world. In women, chlamydial infection of the cervix is frequently asymptomatic, as it was in this patient. If untreated, however, the infection can lead to pelvic inflammatory disease, infertility and ectopic pregnancy.

Chlamydia trachomatis is a tiny, gram-negative bacterium that exists in two different forms: the elementary body, which is the infectious form, and the reticulate body, which is the replicative form. While Chlamydial organisms are too small to be visible with a gram stain, large, glassy inclusions containing both reticulate bodies and elementary bodies are occasionally clearly visible within cells, as seen in the squamous epithelial cells in this image (see arrows).

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Krafts

-Kristine Krafts, MD, is an Assistant Professor of Pathology at the University of Minnesota School of Medicine and School of Dentistry and the founder of the educational website Pathology Student.