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.

Hematopathology Case Study: An 83 Year Old Man with an Elevated PTT

Case History

An 83 year old man with rapidly growing squamous cell carcinoma of the left temple and scalp underwent workup prior to surgery which showed an elevated PTT and a slightly elevated PT. The patient denied a history of abnormal coagulation tests or excessive bleeding or bruising. He also noted that he had previous surgeries including dental procedures without excessive bleeding. In addition, he did not have a history of clot formation.

Lab Values

Differential Diagnosis

At this point, the differential diagnosis for a prolonged PTT included the presence of an inhibitor (specific factor inhibiter vs. non-specific lupus anticoagulant) vs. reduced levels/activity of intrinsic pathway factors that would prolong the PTT, but would not significantly affect clot formation. This would include factors XI and XII. 

Additional Testing

An inhibitor screen/mixing study was performed and was positive. An inhibitor screen is performed by mixing the patient’s plasma with pooled normal plasma and running a PT or PTT.  If the PT/PTT corrects than the screen is negative. This means that a factor or factors were deficient in the patient’s plasma and were replaced with the pooled normal plasma resulting in a correction of the PT/PTT. In this case, a PTT at time 0 of 68 seconds and a PTT at 2 hours of 66 seconds was a failure to correct and indicated that an inhibitor was present, thus a positive result was entered.

The dilute Russell’s viper venom time (dRVVT) was used to test for a lupus anticoagulant. The screening test is performed by adding Russell viper venom, which directly activates coagulation factor X in the presence of calcium and a phospholipid poor reagent to the patient’s plasma and calculating time to clot. The confirmation test is the same assay with added excess phospholipid. In the presence of phospholipid dependent antibodies, the time to clot will be shorter for the confirmation test. The screen and confirmation ratios are normalized ratios (NR) of the patient sample result in seconds divided by the mean of the normal range in seconds. If the screen is <1.20, the confirmation test will not be run. If the screen is greater than 1.20 as seen here, the confirmation test will be run. The end result is reported as a normalized ratio of the screening test over the confirmation test. If the NR is greater than 1.20, than a lupus anticoagulant is reported as present.

Specific factor assays are performed by mixing the patient’s plasma with substrate plasma that is severely deficient in the factor being measured. Factor deficient plasma would be expected to give a prolonged clotting time. When patient plasma is mixed with factor deficient plasma, the clotting time will shorten and the degree of correction is proportional to the factor level in the patient’s plasma. The clotting times for the patient sample are compared to a reference curve. The reference curve is made with dilutions of normal plasma (containing 100% factor) added to factor deficient substrate plasma. All tests are run with 3 dilutions at 25%, 50% and 100% and curves are checked for parallelism errors, which might indicate the presence of an inhibitor. For this patient, factor XI was initially resulted as 1%, which would indicate a factor deficiency.

This is an example of a factor assay that shows parallelism. The reference plasma calibration curve and the patient plasma are parallel lines. 1

Analysis

From the results, it initially appeared that there was both a lupus anticoagulant and a factor XI deficiency. However, it would be odd for a patient with no reported coagulation abnormalities to suddenly have both a lupus anticoagulant and a factor XI deficiency. The raw data from the factor XI assay was obtained.

Upon review, the factor XI assay did show parallelism errors. Parallelism is tested by performing serial dilutions of a standard with known normal concentrations of factor and recording the time to clot. This line is shown with the red arrow. In contrast, the patient sample appears to be a flat line that is not parallel to the calibration curve. Parallelism errors were flagged because from the 50% to 25% dilution, the corrected results more than doubled. If there is a >20% change between dilutions, this indicates possible interference and additional dilutions should be run to dilute out the inhibitor. The 25% dilution had a corrected result of 2.9, which was greater than a 20% increase from the 50% dilution result of 1.3. Once more dilutions were performed; the Factor XI level was ultimately close to 100%.

Additional factors were checked to see if they also increased with dilutions. This would add support to the theory of a non-specific inhibitor (lupus anticoagulant) that was affecting all of the factor levels, rather than a specific factor XI inhibitor or a concurrent factor XI deficiency. The curve from factor IX (below) showed a similar phenomenon. As the sample underwent additional dilutions, the corrected result increased significantly (from 12.8 at 50% to 26.8 at 25%). Ultimately, the factor level was close to 82%.

The curve from factor VIII also showed low results to begin with and ultimately normal levels with additional dilutions. Altogether, this supported the presence of a strong lupus anticoagulant that was non-specifically interfering with all of the factor levels and prolonging the PTT.

Discussion

A prolonged PTT can be caused by many factors. In a patient without a bleeding history, lupus anticoagulant and certain factor deficiencies are high on the differential. The most common specific factor inhibitors are to FVIII and FIX. These generally arise in hemophilia patients treated with factor concentrates. It is very rare for a patient to develop an inhibitor to factor XI or XII.

Factor XI acts in the intrinsic pathway of the clotting cascade and is important for hemostasis. Deficiency of factor XI is rare and mainly occurs in Ashkenazi Jews. Generally, it does not cause spontaneous bleeding; however excessive blood loss can occur during surgical procedures.

Lupus anticoagulants are directed against proteins that complex with phospholipids. Although they prolong the PTT, they are associated with an increase in thrombosis rather than bleeding. In addition to interfering with the PTT assay, lupus anticoagulants may interfere with individual factor assays and result in non-parallelism (patient curve is not parallel to calibration curve) as seen in this patient. With increasing dilutions, the lupus activity will be disproportionately neutralized and the coagulation factor activity will increase in a non-parallel manner. 1

In a letter to the editor by Ruinemans-Koerts et al., they performed a set of experiments to investigate whether lupus anticoagulants vs. individual FVIII and FIX inhibitors can cause non-parallelism in the one-stage factor assay.  Non-parallelism was only detected using lupus sensitive reagents in plasma with high titers of lupus anticoagulants. The FVIII and FIX inhibitor containing samples both resulted in curves that were parallel to reference sample.

This curve shows that the factor IX inhibitor line is parallel to the reference plasma, while the lupus anticoagulant line is not. 1

Ultimately, this demonstrates the importance of running dilutions and being aware of parallelism errors when performing factor assays. This is especially important in patients with known or suspected lupus anticoagulants. In this case, the unlikely presence of a FXI deficiency with no previously reported coagulation testing abnormalities or bleeding history raised the suspicion of an inhibitor interfering with the factor assay. With a concurrent positive inhibitor screen and lupus anticoagulant test, as well as interference demonstrated with multiple factor assays, the best unified conclusion was a strong lupus anticoagulant. 1

References

  1. Ruinesman-Koerts, J., Peterse-Stienissen, I, and Verbruggen, B. ”Non-parallelism in the one-stage coagulation factor assay is a phenomenon of lupus anticoagulants and not of individual factor inhibitors. “ Letter. Thrombosis and Hemostasis, 2010, p.104.5.

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.

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

Case history

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

Cytology of the Pericardial Fluid

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

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

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

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

Image 3. PAX5 is positive in some tumor cells.

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

Discussion

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

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

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

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

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

References

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

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

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

Hematopathology Case Study: A 43 Year Old Man with Difficulty Breathing

Case History

43 year old man presented with symptoms of superior vena cava syndrome including swelling of the head and neck and difficulty breathing. He was found to have a 9 cm anterior mediastinal mass on imaging.

Excisional Biopsy

Top: H&E morphology of diffuse large cells infiltrating through fibrotic tissue.
Bottom: Small lymphocytes with scattered large multinucleated Hodgkin and Reed-Sternberg (HRS) cells.
Left: CD30 showing dim/variable staining in the diffuse large cell component.
Right: CD30 highlighting Hodgkin and Reed-Sternberg cells with a golgi and membranous staining pattern.
Left: CD15 showing golgi staining in the diffuse large cell component.
Right: CD15 highlighting Hodgkin and Reed-Sternberg cells with a golgi and membranous staining pattern.
Left: CD20 diffusely highlighting the large cell infiltrate.
Right: CD20 highlighting small B-cells surrounding a negative HRS cell.
Left: PAX5 diffusely highlighting the large cell infiltrate.
Right: PAX5 showing bright staining in small B-cells surrounding a dimly stained HRS cell.
Left: Ki-67 showing a high proliferation index (90%) in the diffuse large cell component.
Right: Ki-67 showing increased staining in the HRS cells.

Diagnosis

Sections show fragments of fibrotic tissue with crush artifact. Two distinct morphologies are seen in different tissue fragments. Some tissue fragments show infiltration by cords and aggregates of abnormal large lymphoid cells with irregular nuclear contours, somewhat vesicular chromatin, small nucleoli and small to medium amounts of cytoplasm. Frequent apoptotic cells and mitotic figures are seen. In other tissue fragments, the large cell component is absent and there are focally vague nodules. The nodules are composed of small mature appearing lymphocytes, rare eosinophils and scattered medium and large mononuclear and multinucleated cells with prominent nucleoli consistent with Hodgkin cells and Reed-Sternberg cells, respectively. Admixed histiocytes are also seen.

By immunohistochemistry, the areas with different morphologies also show different staining patterns. The areas with the large cell infiltrate are immunoreactive for CD20, BCL6, and MUM1, dimly positive or negative for CD45 and negative for CD10. CD30 is variably positive in the large cell population and CD23 is largely negative. CD15 shows a golgi staining pattern. The Hodgkin and Reed-Sternberg (HRS) cells present in the areas without the large cell infiltrate are brightly immunoreactive for CD30 and CD15 (membranous and golgi pattern), dim positive for PAX5 and are negative for CD20. CD20 and PAX5 highlight small B-cells present in aggregates surrounding the HRS cells. By Ki-67 staining, the proliferation index is high (90%) within the diffuse large cell component and also highlights the HRS component.

Overall, the findings are of a composite lymphoma composed of both a diffuse large B-cell lymphoma (DLBCL) and a classic Hodgkin lymphoma (CHL).  

Discussion

Composite lymphomas occur when two morphologically and immunophenotypically distinct lymphomas occur at the same anatomical site. They are most commonly composed of two Non-Hodgkin B-cell lymphomas (NHL), however rare cases of composite CHL with NHL have been reported. In a review of the literature, Goyal et. al. documented 20 previously reported cases of composite lymphoma with CHL and DLBCL components. The median age at presentation was 51 years with 12 men and 9 women. Fifteen of the cases presented with nodal involvement and of those, three had mediastinal disease. The most common subtype of CHL was nodular sclerosis. Evaluation for IGH gene rearrangements was performed on both components of 6 cases, with either a complete or partial clonal relationship between the components seen in all of the cases tested. This suggests a shared origin from a common B-cell precursor.1

A review of literature by Wang et. al. documented 10 previously described composite lymphomas consisting of DLBCL and CHL. The most common site of occurrence was in lymph nodes, followed by three cases seen in the stomach, one case in the small intestine and one case in the anterior mediastinum. CHL is more commonly associated with EBV infection than NHL In the reviewed cases, 6 showed positivity for EBV infection in both the DLBCL and CHL components. This suggests that the lymphomas shared a common EBV-infected progenitor cell, and are also clonally related as seen in the Goyal review. 2

Composite lymphomas must be distinguished from another WHO defined entity called B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma. This entity has previously been referred to as “grey-zone lymphoma.” These lymphomas tend to present as mediastinal masses and can cause superior vena cava syndrome. They show a wide spectrum of histologic appearances within a single tumor and often show sheet-like growth of pleomorphic cells. Some areas may resemble CHL while others resemble DLBCL. The neoplastic cells typically do not show the characteristic immunophenotype of either CHL or DLBCL. Areas that may resemble CHL will show preservation of B-cell markers, while areas more characteristic of DLBCL might lose B-cell markers and express CD30 and CD15. These tumors will show clonal rearrangement of the immunoglobulin genes. They tend to have a more aggressive clinical course and worse outcome than either CHL or DLBCL. 3

This case was ultimately diagnosed as a composite lymphoma (CL) because it consisted of separate areas with the morphologic and immunophenotypic features of both classic Hodgkin lymphoma and diffuse large B-cell lymphoma. Patients tend to have a poor prognosis with short survival. There is no standardized treatment for composite lymphomas due to their rare occurrence; however cases with a component of DLBCL are generally treated with aggressive chemotherapy such as R-CHOP.

References

  1. Goyal, G. et al. “Composite Lymphoma with Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma Components: A Case Report and Review of the Literature.” Pathology – Research and Practice vol. 212,12(2016):1179-1190. http://www.ncbi.nlm.nih.gov/pubmed/27887763.
  2. Wang, Hong-Wei et al. “Composite diffuse large B-cell lymphoma and classical Hodgkin’s lymphoma of the stomach: case report and literature review” World journal of gastroenterology vol. 19,37(2013):6304-9.
  3. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoetic and Lymphoid Tissues (Revised 4th edition). IARC: Lyon 2017.

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.

Hematopathology Case Study: A 33 Year Old Man with a Mass Behind the Ear

Case History

A 33 year old man of Japanese ethnicity presents with a 2 month history of a mass behind the right ear. Examination reveals a non-tender local with no other local or generalized adenopathy or hepatosplenomegaly. Laboratory investigations reveal an elevated ESR, serum IgE and peripheral blood eosinophilia. The lesion is excised.

Biopsy Findings

H&E stained sections demonstrate a follicular hyperplasia. The germinal centers demonstrate polarity and tingible body macrophages (A). Focally, follicular centers reveal eosinophilic microabscesses (B, C). Immunohistochemical analysis with an IgE stain reveals deposition in germinal centers (D). A diagnosis of Kimura disease is rendered.

Discussion

Kimura disease, also known as eosinophilic lymphoid follicular hyperplasia is a rare, chronic inflammatory disorder of unknown etiology. While an infectious etiology has been suggested, no pathogen has been identified to be causal, to date. Historically, Kimura disease was considered to be the same as Angiolymphoid Hyperplasia with Eosinophilia (ALHE); however, these entities are not the same.

Generally occurring in Asian males, Kimura disease is most common in the 3rd decade of life and in a head/neck site. It presents as painless, slow-growing adenopathy. An association with nephrotic syndrome has been reported. Peripheral blood eosinophilia, elevated ESR, and serum IgE are common findings. Histologically, nodes reveal hyperplastic follicles with well-formed germinal centers and mantle zones with deposition of IgE and eosinophilic microabscesses, as seen in this case. Perinodal soft tissue may be involved. Necrosis may be present, but is not extensive. Cytologically, FNA material may reveal polymorphous cell population with many eosinophils.

Prognosis is indolent; however, most cases recur after excision and radiation therapy usually yields best outcome.

References:

  1. Zhou P. et al. Kimura disease. Dermatol Online J. 2017 Oct 15;23(10).
  2. García Carretero R et al. Eosinophilia and multiple lymphadenopathy: Kimura disease, a rare, but benign condition. BMJ Case Rep. 2016 Aug 31;2016. pii: bcr2015214211. doi: 10.1136/bcr-2015-214211.
  3. Sun QF et al. Kimura disease: review of the literature. Intern Med J 2008;38:668–72.  

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

Hematopathology Case Study: A 60 Year Old Man with Recurrent Bronchitis

Case History

60 year old man with recurrent bronchitis and extensive smoking history underwent CT scan. The CT scan showed an incidental finding of a 2.2 x 1.4 cm anterior mediastinal mass.

Excision

H&E4x
H&E 4x
H&E10x
H&E 10x
H&E20x
H&E 20x
cytokeratin cocktail
Cytokeratin cocktail
CD3
CD3
CD20
CD20
TdT
TdT

Diagnosis

The tissue shows nodules of epithelial cells in a lymphocyte-rich background. The epithelial cells have round to somewhat spindle shaped nuclei, vesicular chromatin and small mostly inconspicuous nucleoli. There is no high grade cytologic atypia, mitotic figures or necrosis seen. The nodules contain very few interspersed lymphocytes, but are surrounded by abundant lymphocytes which are small and mature appearing. A cytokeratin cocktail highlights the epithelial nodules and shows an absence of epithelial cells in the lymphocyte-rich areas. CD20 highlights stromal B-lymphocytes around the epithelial nodules which are arranged in follicles. CD3 highlights stromal T-lymphocytes, which surround the B-cell follicles and the epithelial nodules. TdT highlights only a very small subset of immature T-cells which are found scattered around the rim of the epithelial cell nodules. Overall, the findings are consistent with a micronodular thymoma with lymphoid stroma.

Discussion

The differential diagnosis for an anterior mediastinal mass includes thymoma, lymphoma, germ cell tumors, neurogenic tumors and benign cysts among other less common entities. Patients usually present with cough, chest pain, fever/chills or dyspnea and localizing symptoms are generally secondary to local tumor invasion. Typically, CT scans are the best modality to evaluate the mediastinum. Thymomas are the most common primary neoplasm of the anterior mediastinum, but are less than 1% of all adult malignancies. Patients are generally over 40 years old and between 30-50% of patients with a thymoma have myasthenia gravis, which occurs more frequently in women.1

The WHO has classified thymomas into 5 categories based on the morphology of the neoplastic epithelial cells along with the lymphocyte to epithelial cell ratio. Type A thymomas are composed of bland spindle/oval tumor cells with few or no admixed immature lymphocytes. Type B1 thymoma resembles normal thymus and has scattered epithelial cells in a dense background of immature T-cells. Type B2 thymoma is composed of epithelial cells in small clusters with a lymphocyte-rich background. Type B3 thymoma is primarily composed of mild to moderately atypical epithelial tumor cells in a solid growth pattern with few intermingled immature T-cells. Type AB thymomas are composed of lymphocyte-poor spindle cell (Type A) components as well as lymphocyte-rich (Type B) components.2

Micronodular thymoma with lymphoid stroma (MTWLS) is a rare type of thymoma and accounts for only 1% of all cases. Patients tend to be asymptomatic and the finding is usually incidental. The tumor tends to be well circumscribed and encapsulated with a tan cut surface. The histopathology is characterized by solid nests or nodules of epithelial tumor cells in a background of abundant lymphoid stroma. The tumor cells are bland spindle or oval cells without significant atypia or mitotic activity. The epithelial tumor cells are positive for pancytokeratins. The lymphoid stroma typically lacks keratin positive cells and consists of predominantly CD20 positive mature B-cells in follicles with admixed CD3 positive and TdT negative mature T-cells. There is typically a population of rare TdT positive immature T-cells that surrounds the epithelial nodules, as seen in this case. 2

Due to the rarity of MTWLS with only 74 cases reported since the first case described in 1999, there is limited data on its pathophysiology and prognosis. However, most cases are diagnosed as stage I/II disease according to the Masaoka-Koga staging criteria, involving only micro or macroscopic invasion into thymic or surrounding fatty tissue without invasion into neighboring organs.  Patients tend to have a very favorable prognosis with most patients alive without recurrence or metastasis many years after diagnosis.3

References

  1. Juanpere S, Cañete N, Ortuño P, Martínez S, Sanchez G, Bernado L. A diagnostic approach to the mediastinal masses. Insights Imaging. 2012;4(1):29-52.
  2. Travis WD, Brambilla E, Burke AP, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart (Revised 4th edition). IARC: Lyon 2015.
  3. Qu L, Xiong Y, Yao Q, Zhang B, Li T. Micronodular thymoma with lymphoid stroma: Two cases, one in a multilocular thymic cyst, and literature review. Thorac Cancer. 2017;8(6):734-740.

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.

Hematopathology Case Study: A 65 Year Old Male with a Skin Lesion on the Right Shoulder

Case History

A 65 year old Caucasian male presents with a skin lesion on his right shoulder. Physical examination reveals a 3 .0 cm  ×  1.5  cm hyperpigmented plaque with mild hyperkeratosis on his right shoulder and multiple scattered erythematous macules and plaques on the trunk and back Skin biopsy reveals involvement by Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). PET scan reveals no extracutaneous involvement.

The patient undergoes CHOP chemotherapy followed by autologous hematopoietic stem cell transplantation. He is subsequently treated systemically with lanolidomide, venetoclax, and idelalisib due to relapses of disease.

The patient returns to clinic three years later for follow-up. While his original cutaneous lesions are completely resolved, new lesions are noted on his back (representative lesion, Image 1). Hematologic evaluation is remarkable for pancytopenia with hemoglobin 8.7gm/dL, white blood cells 1.4 K/uL, and platelets 39 K/uL. A biopsy of the bone marrow is performed.

Image 1. Skin lesion on back.

Biopsy Findings

Core biopsy
CD56
Aspirate

H&E stained sections demonstrate a normocellular bone marrow with diminished trilineage hematopoiesis and sheets of amphophilic, blastoid cells with irregular borders occupying most of the marrow cells. Immunohistochemistry demonstrates a cellular population with CD56. The aspirate smears show similar findings with numerous clustered blastoid cells (92%) with a monocytoid appearance, often with basophilic vacuolated cytoplasm. There is also a decrease in myeloid and erythroid precursors.

Flow cytometric analysis performed on the bone marrow aspirate reveals a dim CD45 population with expression of CD4, CD56, partial CD7, dim and partial CD5, and CD38. The same population lacks expression of immaturity markers such as CD34, MPO, and TdT. The morphologic and phenotypic findings found in the marrow specimen are diagnostic of extensive involvement of the marrow by BPDCN.

Discussion

BPDCN is a rare and highly aggressive malignancy derived from precursors of plasmacytoid dendritic cells. Its nomenclature has constantly changed over years as the understanding of this entity has been improved. It has been variously known as blastic natural killer cell lymphoma/leukemia, agranular CD4+ natural killer cell leukemia, and CD4+CD56+haematodermic neoplasm. It is currently classified under acute myeloid leukemia and related precursor neoplasms in the most recent WHO classification of tumours of haematopoietic and lymphoid organs.

Limited data exist regarding the incidence of BPDCN; however, it is estimated to account for 0.7% of primary cutaneous skin lymphomas and 0.44% of all hematological malignancies. This hematodermic malignancy predominantly affects elderly male patients with mean age ranging from 60 to 70; however, a few cases have also been reported in childhood and infancy. As demonstrated in our case, the patients typically present with multiple violaceous skin lesions, which may be associate with erythema, hyperpigmentation, purpura, or ulceration. Extracutaneous involvement is reported to occur in the bone marrow, peripheral blood, and lymph nodes.

Diagnosis of BPDCN relies on histological and immunophenotypic findings. Histologically, BPDCN may show a monomorphic infiltrate of medium-sized immature blastoid cells with round nuclei, finely dispersed chromatin, and cytoplasmic vacuoles. They typically display immunophenotypic expression of markers CD4, CD56, CD123, and T-cell leukemia/lymphoma 1 (TCL1) without any lineage-specific markers of T cells or B cells. Chromosomal abnormalities involving 5q, 12p,13q, 6q, 15q, and 9p have been reported. The differential diagnosis entails, but is not limited to, mature T-cell lymphoma, nasal-type NK/T-cell lymphoma, myeloid sarcoma/acute myeloid leukemia and T-cell lymphoblastic lymphoma/leukemia

The clinical course of BPDCN is aggressive, with a median survival of 9 to 16 months. The patients with disease limited to the skin may have a better prognosis, while advanced age and advanced clinical stage are indicators of poor prognosis.  There is currently no consensus on optimal management and treatment because of low incidence of BPDCN; however, most patients are treated with regimens used for other hematopoietic malignancies (i.e. CHOP and hyperCVAD) followed by allogeneic stem cell transplantation for eligible patients. They often respond well to chemotherapy with complete resolution of skin lesions; however, relapse of disease can occur due to resistance to chemotherapeutic agents, which may have happened in our case.

References

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-Jasmine Saleh, MD MPH is a pathology resident at Loyola University Medical Center with an interest in dermatopathology and hematopathology. Follow Dr. Saleh on Twitter @JasmineSaleh.

-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.