Classification and challenges in the histopathological diagnosis of peripheral T-cell lymphomas, emphasis on the WHO-HAEM5 updates

Mature T-cell lymphomas represent neoplastic expansions of T-cell lymphocytes with a post-thymic derivation. Most of these tumors feature aggressive clinical behavior and challenging histopathological diagnosis and classification. Novel findings in the genomic landscape of T-cell lymphomas are helping to improve the understanding of the biology and the molecular mechanisms that underly its clinical behavior. The most recent WHO-HAEM5 classification of hematolymphoid tumors introduced novel molecular and histopathological findings that will aid in the diagnostic classification of this group of neoplasms. The current review article summarizes the most relevant diagnostic features of peripheral T-cell lymphomas with an emphasis on the updates that are incorporated at the WHO-HAEM5

Concurrent JAK2 V617F Acute Myeloid Leukemia (AML) and Leukemic non-nodal Mantle Cell Lymphoma (LN-MCL): Case study

Introduction/Objective: We report a unique case of concurrently occurring Acute Myeloid Leukemia (AML) and Leukemic non-nodal Mantle Cell Lymphoma (LN-MCL) in an 86-year-old male. To the best of our knowledge, this is the first report of AML occurring in the background of LN-MCL, with no known history of any malignancy or chemotherapy. Methods/Case Report: An 86-year old Caucasian male with unremarkable past medical history presented with pancytopenia, fatigue and generalized weakness. Abdominal CT scan was negative for lymphadenopathy or hepatosplenomegaly. Peripheral blood showed 2% blasts with atypical lymphocytes 89%. Bone marrow aspirate showed 30% myeloblasts expressing CD34, CD117, CD13, CD33, HLA-DR and CD56 (dim) by flow cytometry (FC). Lymphocytes accounted for 40% of bone marrow cellularity. FC identified a population of CD5+ kappa restricted clonal B cells 2%, consistent with a concurrent CD5+ B-lymphoproliferative disorder/lymphoma. The bone marrow biopsy was inadequate for further evaluation of the B- cell lymphoma. Chromosomal analysis revealed a normal male karyotype. FISH analysis was positive for t(11:14) CCND1::IGH rearrangement (in 3.5% of interphase cells) supporting involvement by MCL. Myeloid panel next generation sequencing (51 genes) was positive for JAK2 V617F (VAF, 38%) and ASXL1 P920Tfs*4 (VAF, 22%) variants. Conclusion: Concurrent presence of LN-MCL and AML as seen in our patient in the absence of prior history of malignancy or chemotherapy is rare. Presence of JAK2V617F mutation in de-novo AML is extremely rare (\u3c5%). There is no prior history of myeloproliferative neoplasm (MPN) or CBC data to suggest that this may have progressed from an MPN. While the absence of lymphadenopathy suggests that the CD5+ B-LPD likely represents LN-MCL, it is also likely that the CD5+, IgH/CCND1 rearranged B-cells may represent prior undetected circulating cells without overt LN-MCL development, similar to those reported in otherwise healthy individuals. It is unclear but tempting to speculate that the two co-occurring hematologic malignancies may have a common cell of origin

Isolated Ocular Manifestation of Relapsed Chronic Myelogenous Leukemia Presenting as Myeloid Blast Crisis in a Patient on Imatinib Therapy: A Case Report and Review of the Literature

Blast phase in chronic myelogenous leukemia (CML) has rarely been reported to involve extramedullary sites like skin, lymph nodes, and central nervous system. Clinical history, characteristic hematologic findings (elevated leukocyte counts, myelocytic predominance, and basophilia), and Philadelphia chromosome are of high diagnostic significance especially in isolated extramedullary presentations. We describe a unique case of CML relapse with blast phase involving the eye. A 66-year-old man with a known diagnosis of CML on imatinib and in molecular remission for 3 years presented with a painful blind eye. Histologic examination revealed diffuse involvement of choroid, iris, vitreous humor, and the optic nerve by blast cells. The blasts expressed CD34, aberrant TdT, and a myeloid phenotype (CD13, CD33, and CD117). Fluorescence in situ hybridization (FISH) of vitreous fluid detected BCR-ABL1 gene rearrangement. Additionally, trisomy 8 and gains of 9 and 22 were seen which were not present in the initial diagnostic marrow study 3 years ago. At relapse, the bone marrow, peripheral blood, and the cerebrospinal fluid were not involved by CML. Patient received induction chemotherapy and single dose prophylactic intrathecal methotrexate and was maintained on antityrosine kinase therapy and eventually underwent allogenic stem cell transplantation

Aurora-A and Polo-Like Kinases are Important Diagnostic and Therapeutic Markers in Hodgkin Lymphoma and Mimics

Background: Aurora-A (AA) and Polo-like kinases (PLK) are mitotic kinases that regulate the G2/M phase of the cell cycle. It has been demonstrated that AA acts as an upstream regulator of PLK, mediating its phosphorylation in the presence of a cofactor named Bora. PLK is activated by AA to promote checkpoint recovery in mitosis. AA and PLK are implicated in the tumorigenesis of solid tumors, and, recently, in B- and T-cell non Hodgkin lymphomas (NHL). They play a key role in tumor proliferation and disease progression in highly aggressive B-cell NHL. They also serve as indicators of disease activity and are thus attractive potential therapeutic targets. Expression of AA and/or PLK has not yet been assessed in Classic Hodgkin Lymphoma (CHL) and its mimics. This study assesses AA and PLK expression in different CHL types, such as nodular sclerosis type, mixed cellularity type, and lymphocyte rich type, and their mimics: nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and primary mediastinal B-cell lymphoma (PMBL).Design:We assessed 27 CHL cases, 16 NLPHL cases, and 8 PMBL cases for AA and PLK expression by immunohistochemistry. CHL cases included the following: 8 mixed cellularity CHL, 1 lymphocyte rich CHL, and 18 nodular sclerosis CHL. A mouse monoclonal AA-antibody (1:1000 dilution, Abcam, UK) and a PLK-antibody (1:500 dilution, Cell Signaling Technologies, USA) were used. Each case was semi-quantitatively graded for percentage of positive cells (\u3c50% vs. \u3e50%), for staining intensity (1-3+), and for localization (nuclear vs. cytoplasmic). Immunohistochemical analysis was performed independently by 2 pathologists (KMH and KVI). Statistical analysis was performed using Fisher\u27s exact test.Results:AA was expressed in 100% of CHL and NLPHL cases. AA stained predominantly cytoplasm of tumor cells in both NLPHL and CHL. PLK was expressed in 100% of NLPHL and 96% of CHL cases (1 mixed cellularity type CHL did not stain for PLK). PLK showed both nuclear and cytoplasmic staining for both NLPHL and CHL. In contrast, only 37% of PMBL cases were positive for AA and PLK (Table 1). In the CHL group, cases with more than 50% of tumor cells expressing PLK tended to present with higher stage and extranodal disease. In the NLPHL group, PLK correlated with higher stage (III-IV) disease at presentation (p=0.044). No statistically significant differences were found in either intensity or localization of AA or PLK within or between NLPHL and CHL cohorts.Aurora-A PositiveAurora-A NegativePLK PositivePLK NegativeClassic Hodgkin Lymphoma270261Nodular Lymphocyte Predominant Hodgkin Lymphoma160160Primary Mediastinal B-cell Lymphoma3535Table 1. AA and PLK positivity in CHL, NLPHL, and PMBL.AA was expressed in CHL but not PMBL (p=0.0002)PLK was expressed in CHL but not PMBL (p=0.0009)AA was expressed in NLPHL but not PMBL (p=0.0013)PLK was expressed in NLPHL but not PMBL (p=0.0013). Conclusion: AA and PLK are commonly expressed in CHL and NLPHL but not in PMBL. Thus, they are useful markers in the distinction of CHL or NLPHL from PMBL. PLK is a useful marker for the prognostication of NLPHL. AA and PLK are attractive potential therapeutic targets in the treatment of CHL and NLPHL. Additional studies are underway to characterize an array of hematopoietic lesions known to overlap with CHL.https://scholarlycommons.henryford.com/merf2019clinres/1027/thumbnail.jp

Isolated Ocular Manifestation of Relapsed Chronic Myelogenous Leukemia Presenting as Myeloid Blast Crisis in a Patient on Imatinib Therapy: A Case Report and Review of the Literature

Blast phase in chronic myelogenous leukemia (CML) has rarely been reported to involve extramedullary sites like skin, lymph nodes, and central nervous system. Clinical history, characteristic hematologic findings (elevated leukocyte counts, myelocytic predominance, and basophilia), and Philadelphia chromosome are of high diagnostic significance especially in isolated extramedullary presentations. We describe a unique case of CML relapse with blast phase involving the eye. A 66-year-old man with a known diagnosis of CML on imatinib and in molecular remission for 3 years presented with a painful blind eye. Histologic examination revealed diffuse involvement of choroid, iris, vitreous humor, and the optic nerve by blast cells. The blasts expressed CD34, aberrant TdT, and a myeloid phenotype (CD13, CD33, and CD117). Fluorescence in situ hybridization (FISH) of vitreous fluid detected BCR-ABL1 gene rearrangement. Additionally, trisomy 8 and gains of 9 and 22 were seen which were not present in the initial diagnostic marrow study 3 years ago. At relapse, the bone marrow, peripheral blood, and the cerebrospinal fluid were not involved by CML. Patient received induction chemotherapy and single dose prophylactic intrathecal methotrexate and was maintained on antityrosine kinase therapy and eventually underwent allogenic stem cell transplantation

Expression of estrogen receptor beta (er beta ) in low grade b-cell lymphomas: An immunohistochemical study

Most lymphoid malignancies are associated with higher incidence and poorer prognosis in men than women. Epidemiological data associate reproductive hormones and oral contraceptives with reduced risk in women, attributed to estrogen. Estrogen’s action is mediated by two nuclear receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), with different tissue distribution and actions. ERα promotes cell proliferation whereas ERβ shows anti- proliferative effects. Studies show ERβ to be predominantly expressed in lymphoid tissue. There is a dearth of studies about expression of ERβ in lymphoid malignancies. Hence, we characterized the expression of ERβ in low grade B- cell lymphomas by immunohistochemistry in men and women. Methods and Materials Low-grade B-cell lymphomas diagnosed between 2006 and 2016 were retrieved from archives. ERβ immunostaining was performed on formalin-fixed paraffin-embedded sections of 45 lymphoma cases with typical histology, flow cytometry, and cytogenetics: 10 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (six men, four women), nine mantle cell lymphomas (five men, four women), 10 marginal zone lymphomas (four men, six women), eight follicular lymphomas (four men, four women), four classical (two men, two women), and four nodular lymphocyte predominant (two men, two women) Hodgkin lymphomas. Control tissue from tonsils, lymph nodes, and spleen were also immunostained. Results Immunohistochemical ERβ staining of tonsils and lymph nodes in men and women show strong nuclear staining of lymphocytes in the germinal and mantle zone of the lymphoid follicles as compared to the paracortical region. The white pulp (periarteriolar lymphatic sheath) and red pulp in spleen show strong ERβ positivity. Strong nuclear staining of lymphocytes was seen in all cases of CLL/SLL, mantle, marginal, follicular, and Hodgkin lymphomas. No difference in staining was seen between men and women in normal lymphoid and lymphoma specimens. Conclusion All low-grade B- cell lymphomas strongly express ERβ in men and women, highlighting role of estrogens in pathogenesis. Since estrogen concentrations are higher in women, this might explain the sex predilection and poorer prognosis in men. Also, these results raise the possibility of using ERβ agonists as a novel therapeutic agent in these lymphomas