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Enhancer of zeste homolog 2 (EZH2) is a catalytic component of the polycomb repressive complex 2 (PRC2) which reduces gene expression via trimethylation of a lysine residue of histone 3 (H3K27me3). Expression of EZH2 has not been assessed systematically in mantle cell lymphoma (MCL). Expression of EZH2 was assessed by immunohistochemistry in 166 patients with MCL. We also assessed other PRC2 components and H3K27me3. Fifty-seven (38%) of MCL patients were positive for EZH2 using 40% cutoff. EZH2 expression was associated with aggressive histologic variants (65% vs. 29%, p < 0.001), high Ki-67 proliferation rate (median, 72% vs. 19%, p < 0.001), and p53 overexpression (43% vs. 2%, p < 0.001). EZH2 expression did not correlate with expression of other PRC2 components (EED and SUZ12), H3K27me3, MHC-I, and MHC-II. Patients with EZH2 expression (EZH2+) had a poorer overall survival (OS) compared with patients without EZH2 expression (EZH2-) (median OS: 3.9 years versus 9.4 years, respectively, p < 0.001). EZH2 expression also predicted a poorer prognosis in MCL patients with classic histology (median OS, 4.6 years for EZH2+ and 9.6 years for EZH2-negative, respectively, p < 0.001) as well as aggressive histology (median OS, 3.7 years for EZH2+ and 7.9 years for EZH2-negative, respectively, p = 0.046). However, EZH2 expression did not independently correlate with overall survival in a multivariate analysis. Gene expression analysis and pathway enrichment analysis demonstrated a significant enrichment in cell cycle and mitotic transition pathways in MCL with EZH2 expression. EZH2 expression detected by immunohistochemistry is present in 38% of MCL cases and it is associated with high proliferation rate, p53 overexpression, aggressive histologic variants, and poorer OS. Based on gene expression profiling data, EZH2 expression could potentiate cell cycle machinery in MCL. These data suggest that assessment of EZH2 expression could be useful to stratify MCL patients into low- and high-risk groups., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Mycosis fungoides with large cell transformation (MFLCT) can be difficult to distinguish from primary cutaneous CD30+ T cell lymphoproliferative disorders (PC CD30+ LPD), especially primary cutaneous anaplastic large cell lymphoma (PC-ALCL). This diagnostic distinction is critical for appropriate patient management. GATA3 has been proposed to be useful in the discrimination between these two entities. We identified 25 cases of MFLCT and 24 cases of PC CD30+ LPDs (including lymphomatoid papulosis (n=14), PC-ALCL (n=6), and CD30+ LPD, not otherwise specified (n=4)) diagnosed at our institution from 2002 to 2019. Sections from archived specimens were stained to evaluate for GATA3 expression by immunohistochemistry and compared among cutaneous CD30+ T cell LPDs. The majority of the MFLCT cohort had strong, diffuse expression of GATA3 ranging from 0 to 100% of dermal T cells (mean 53.20%) with 15/25 cases (60%) showing GATA3 expression greater than 50%, while the PC CD30+ LPD group showed variable, moderate GATA3 labeling ranging from 0 to 60% of dermal T cells (mean 23.26%), with 5/6 cases (83%) showing GATA3 expression less than 40% (p =0.003). The calculated sensitivity and specificity were 56% and 74%, while positive and negative predictive values were 70% and 61%, respectively. Based on the percent staining of positive cells, using 50% as a cutoff value for expression, GATA3 might be a useful immunohistochemical marker to discriminate MFLCT from PC CD30+ LPDs, including PC-ALCL., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

The role of MYC dysregulation has been studied extensively in B-cell lymphomas, but little is known about its significance in T cell lymphomas. This study, for the first time in the literature, assessed the clinicopathologic and prognostic significance of MYC expression in ALK+ anaplastic large cell lymphoma (ALCL) cases. Using ≥50% as the cutoff value for positive MYC expression by immunohistochemistry, 17 of 46 (37%) cases were MYC+. Patients with MYC+ tumors were older (median age, 39 versus 29 years, p = 0.04) and more often showed a common morphologic pattern (100% versus 69%, p = 0.02), when compared with those with MYC-negative tumors. By fluorescence in situ hybridization analysis, 9 of 31 (29%) cases showed increased MYC copy number, and 1 of 31 (3%) case had an MYC rearrangement, and the remaining 21 (68%) cases showed no MYC aberrations. Among the cases with increased MYC copy number, 5 of 8 (62%) cases showed MYC copy gain and/or amplification and 3 of 8 (38%) had polysomy 8. MYC expression was associated with increased MYC copy number (p = 0.01). MYC expression, but not increased MYC copy number, correlated with shorter overall survival (OS) (p = 0.03). In conclusion, MYC expression identified a distinct group of ALK + ALCL patients with more aggressive behavior and shorter OS. Our data suggest that MYC expression is an adverse prognostic factor and may be useful in stratifying or predicting the prognosis of patients with ALK+ ALCL., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm characterized by uniformly strong CD30 expression and common absence of T-cell markers. Most ALCL cases express CD4, but a small subset of ALCL cases has been reported to express CD8. Little is known about the clinicopathologic and prognostic features of CD8+ ALCL. In this study, CD8 was assessed in 158 patients with systemic ALCL: CD8 was positive in 13 of 67 (19%) ALK+ and 13 of 91 (14%) ALK-negative neoplasms. In ALK+ ALCL, the CD8+ subgroup more often showed a noncommon morphologic pattern (69% vs 13%, P = .0001) and was more often positive for CD2 (100% vs 45%, P = .001), CD3 (92% vs 24%, P = .0001), and CD7 (100% vs. 39%, P = .002), but less frequently positive for CD25 (50% vs. 100%, P = .02). Patients with ALK+ ALCL and CD8+ neoplasms also had a higher relapse rate (82% vs 48%, P = .05) and more often underwent stem cell transplant (73% vs 36%, P = .04). CD8 expression did not correlate with patient overall survival or progression-free survival regardless of ALK status (all P > 0.05). We conclude that CD8+ ALCL cases appear to be biologically different from the more common CD8-negative ALCL cases. Our data suggest that CD8 positivity in ALK+ ALCL helps to identify a subset of patients more prone to relapse or more in need of stem cell transplant during their clinical course, although there was no impact on survival in this cohort., (Copyright © 2020. Published by Elsevier Inc.)

The programmed cell death 1 (PD-1) pathway is a recently recognized mechanism of tumor immune evasion. In this study, programmed cell death ligand 1 (PD-L1) expression was evaluated in 95 patients with systemic anaplastic large cell lymphoma: 45 ALK+ and 50 ALK-. ALK+ anaplastic large cell lymphoma was more often positive for PD-L1 than ALK- anaplastic large cell lymphoma (76% vs 42%, p = 0.002). ALK- anaplastic large cell lymphoma showed a strong correlation between PD-L1 expression and STAT3 activation (measured by pSTAT3 Tyr705 ) (r = 0.8, p < 0.0001). In contrast, the PD-L1/pSTAT3 correlation was weaker in ALK+ anaplastic large cell lymphoma (r = 0.4, p = 0.08). In ALK- anaplastic large cell lymphoma, the PD-L1+ subgroup was more often EMA positive (69% vs 20%, p = 0.02) and tended to be less often CD2+ (50% vs 83%, p = 0.059). In ALK+ anaplastic large cell lymphoma, PD-L1 was not associated with pathologic features (all p > 0.05). Negative ALK status and high IPI score (≥3) were associated with shorter overall survival (p = 0.009 and p = 0.0005, respectively). Overall survival was not different between patients with PD-L1+ vs PD-L1- anaplastic large cell lymphoma (p = 0.44), regardless of ALK status and International Prognostic Index (IPI) score. We conclude that PD-L1 expression is more common in ALK+ anaplastic large cell lymphoma than ALK- anaplastic large cell lymphoma. In ALK- anaplastic large cell lymphoma, PD-L1 is strongly correlated with STAT3 activation and is associated with more frequent EMA and less frequent CD2 expression. PD-L1 has no prognostic significance in predicting the outcome of patients with systemic anaplastic large cell lymphoma, regardless of ALK status. PD-L1 expression on the anaplastic large cell lymphoma cells suggests these patients as potential candidates for PD-1 blockade immunotherapy.

The diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) has been based on the expression status of multiple markers, including CD123. TCF4 was discovered recently to be an obligatory master regulator of plasmacytoid dendritic cells. We postulated that a tissue-based assay designed to detect dual CD123 and TCF4 expression would provide a highly reliable and practical marker for BPDCN in biopsy material. We designed, optimized, and validated a dual-color TCF4/CD123 immunohistochemistry stain for use in formalin-fixed paraffin-embedded tissue sections. The performance characteristics of the TCF4/CD123 stain were evaluated in 48 confirmed BPDCN cases. TCF4/CD123 coexpression was detected reproducibly in plasmacytoid dendritic cells. In BPDCN, the TCF4/CD123 stain showed coexpression in all (48/48; 100%) cases analyzed. Cases with concurrent samples from different anatomic sites showed comparable staining characteristics. In contrast, of 464 non-BPDCN cases comprising a wide range of hematolymphoid neoplasms and cutaneous lesions that might enter in the differential diagnosis of BPDCN, we identified dual expression of TCF4 and CD123 in only 1 case of B-lymphoblastic leukemia/lymphoma. On the basis of these findings, the TCF4/CD123 dual-color immunohistochemical stain had an analytic sensitivity of 100% and a specificity of 99.8%. Receiver operator characteristic analysis demonstrated an area under the curve of 1.000 (95% confidence interval: 0.999-1.000). In summary, the dual-color TCF4/CD123 immunohistochemistry stain provides a robust standalone and cost-effective assay for the diagnosis of BPDCN.

Patients with double-hit or triple-hit lymphoma have a significantly worse prognosis compared to patients with diffuse large B-cell lymphoma without MYC rearrangement. However, the prognostic importance of extra copies of MYC, BCL2, or BCL6 has not been fully explored. We studied 663 patients with de novo diffuse large B-cell lymphoma in whom the status of MYC/8q24, BCL2/18q21, and BCL6/3q27 were assessed by fluorescence in situ hybridization. Cases of double or triple extra copy lymphoma were defined by the presence of increased MYC copies and increased BCL2 and/or BCL6 copies or rearrangement. In total, 76 patients with diffuse large B-cell lymphoma had MYC extra copies including 43 cases of double or triple extra copy lymphoma; 105 patients had diffuse large B-cell lymphoma with MYC-R including 56 double- or triple-hit lymphoma; and 482 diffuse large B-cell lymphoma patients had no MYC abnormality (MYC normal). Patients with MYC extra copies, similar to MYC-R, had a worse overall survival compared with MYC normal patients (both P<0.01). The prognosis between patients with MYC extra copies and MYC-R was not statistically significantly different (P=0.086). Cell-of-origin classification failed to correlate with survival in the MYC extra copies group, similar to the MYC-R patient group. Compared with patients with double- or triple-hit lymphoma, patients with double or triple extra copy lymphoma had a higher complete remission rate (P=0.02), but there was no significant statistical difference in overall survival (P=0.089). Intensive induction chemotherapy regimens improved the overall survival of patients with double or triple extra copy lymphoma, but there was no significant improvement of overall survival in patients with MYC-R tumors. Multivariate analysis showed that MYC extra copy in diffuse large B-cell lymphoma is an independent poor prognostic factor, similar to MYC rearrangement.

Follicular lymphoma (FL) with features reminiscent of hyaline-vascular Castleman disease (CD) is an unusual morphologic variant that may create diagnostic difficulties. To our knowledge, only 5 cases of this variant have been reported. We describe the clinicopathologic features of 6 cases including 2 men and 4 women with a median age of 63 years (range, 41-77). Morphologically, all lymph node biopsy specimens showed at least a focal area of conventional FL; 4 cases showed neoplastic follicles with hyalinized blood vessels penetrating into germinal centers (lollipop-like lesions); 4 cases had interfollicular areas with increased vascular stroma; 2 cases showed small neoplastic follicles with prominent, onionskin-like mantle zones; and 1 case showed 2 or more germinal centers within follicles (twinning). The small neoplastic follicles were more cellular than lymphocyte-depleted follicles of true hyaline-vascular CD, and the interface between germinal centers and mantle zones was ill defined. No cases showed dysplastic follicular dendritic cells. Immunohistochemistry for BCL-2 was positive in all 6 cases. Flow cytometry immunophenotypic analysis showed a monotypic B-cell population in 2 of 3 cases assessed. Conventional cytogenetic or fluorescence in situ hybridization studies performed in 3 cases showed t(14;18)(q32;q21) or IGH-BCL2, supporting the diagnosis of FL. The cases presented here add clinicopathologic data to the few cases of FL with hyaline-vascular CD-like features reported previously in the literature. Distinguishing this variant of FL from hyaline-vascular CD is important given the differences in treatment and prognosis of patients with each disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Rearrangements of FGFR1 result in the 8p11 myeloproliferative syndrome, a group of rare diseases that features a myeloproliferative neoplasm (MPN) that commonly progresses to lymphoblastic leukemia/lymphoma or acute myeloid leukemia. The most common partner of FGFR1 is ZMYM2, and patients with the ZMYM2-FGFR1 fusion often present with MPN and T-lymphoblastic lymphoma. There are 14 other partners that can fuse with FGFR1, and of interest is the BCR-FGFR1 fusion that results from t(8;22)(p11.2;q11.2). Patients with t(8;22) often show leukocytosis and present with an MPN resembling chronic myeloid leukemia or very rarely, with B-lymphoblastic leukemia (B-ALL). In this study, we analyzed the clinicopathological, cytogenetic, and molecular features of 2 new patients with the t(8;22)(p11.2;q11.2)/BCR-FGFR1 who presented with B-ALL. An underlying MPN became apparent when a morphologic remission of B-ALL was achieved after chemotherapy. We subsequently reviewed the literature and identified 18 additional cases reported with B-ALL in a background MPN or with the MPN as a chronic phase. Our data suggest that the t(8;22)(p11.2;q11.2)/BCR-FGFR1 may arise from a myeloid/B progenitor cell. It is important to recognize that neoplasms carrying the t(8;22)/BCR-FGFR1, although rare, can commonly with B lymphoblastic leukemia at the initial diagnosis, which could distract one from recognizing a possible underlying 8p11 myeloproliferative syndrome., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Primary cutaneous γδ T-cell lymphoma (PCGD TCL), an aggressive type of lymphoma, accounts for approximately 1% of all primary cutaneous lymphomas. We have occasionally observed changes in T-cell antigen expression (immunophenotypic [IP] shift) over time, a phenomenon that is considered rare in T-cell lymphoma including cutaneous T-cell lymphoma. Therefore, we assessed sequential biopsies of PCGD TCL for possible IP shifts of the lymphoma cells. We searched for cases of PCGD TCL with consecutive biopsies to perform a comprehensive immunohistochemical analysis of paired specimens. A median of 12 markers per case was tested. We evaluated the percentage of neoplastic lymphocytes and determined the differential expression of antigens (gain, loss, increase or decrease). We identified 9 patients with PCGD TCL with consecutive biopsies. All (100%) cases had IP shifts of at least 1 antigen, whereas overall 22 pairs of markers were shifted: gain of reactivity occurred in 7 (31.8%) and loss in 3 (13.6%); increased reactivity in 4 (18.2%) and decreased in 8 (36.4%). Molecular analysis of TCRγ showed identically sized monoclonal rearrangements between biopsy pairs in 4/4 (100%) patients. There was no correlation between IP shifts and the clinical appearance of lesions, histopathologic or cytologic features, or molecular rearrangements. IP shifts are common in PCGD TCL, occurring in all patients in this study and involving a variety of antigens. IP shifts do not seem to be linked to changes in the T-cell clone and are without obvious clinical or morphologic correlates. The occurrence of IP shifts in PCGD TCL suggests that antigen modulation may be involved in pathogenesis. IP shifts are somewhat frequent in T-cell lymphoma; however, it does not suggest a second neoplasm, and molecular studies can be used to determine clonal identity.

Primary cutaneous γ/δ T-cell lymphoma (PCGDTCL) accounts for <1% of all primary cutaneous lymphomas. These rare diseases are believed to originate from γ/δ lymphocytes. Clinical presentation may vary, but its clinical behavior is regarded as aggressive and long-term survival is anecdotal. This study describes the case of a 60-year-old man with multiple, rapidly progressing skin plaques on his head, arms, torso, buttocks, and legs. The histopathological changes seen in the skin biopsy were extraordinarily subtle with mild epidermal hyperplasia and a very sparse lymphoid infiltrate involving epidermis and superficial dermis. Immunohistochemical studies revealed the atypical intraepidermal hyperchromatic cells to be mostly positive for CD3 and CD7 and negative for both CD4 and CD8. The intraepidermal atypical lymphocytes were positive for TCR gamma, and negative for betaF1 and CD56. The clinical, morphologic, and immunohistochemical findings supported the diagnosis of PCGDTCL. This case illustrates a case of epidermotropic variant of PCGDTCL that, albeit a bland histopathological presentation, was associated with an aggressive clinical behavior.

Objectives: To analyze CD200 expression by flow cytometry in a large series of B-cell neoplasms in a variety of tissue types in comparison with benign B-lineage cells., Methods: We measured CD200 expression levels in 505 peripheral blood (PB), bone marrow (BM), and lymphoid tissue biopsy specimens, including 364 cases positive for B-cell leukemias and lymphomas., Results: CD200 expression in chronic lymphocytic leukemia cases was as bright as or brighter than normal PB B cells in nearly all cases, while mantle cell lymphoma (MCL) cases were usually dim or negative. However, rare MCL cases (about 5%) were moderately bright for CD200. Marginal zone lymphomas varied by subtype, with nodal cases brighter, splenic cases dimmer, and extranodal cases heterogeneous for CD200 expression. Follicular lymphoma (FL) cells were brighter for CD200 in BM specimens than in lymph nodes. In some BM specimens, dim CD200 could distinguish FL cells from background hematogones. Large B-cell lymphomas of the non-germinal center type tended to be brighter for CD200 than those of the germinal center type, while Burkitt lymphomas were negative., Conclusions: CD200 staining by flow cytometry can be useful in the differential diagnosis of B-cell neoplasms and in their detection in the BM., (Copyright© by the American Society for Clinical Pathology.)

T-cell regulatory lymphocytes (T reg) are identified by their reactivity with CD4, CD25, and FOXP3, and are variably present in the background of various neoplasms including hematopoietic tumors, and function modulating the immune response, including control of autoimmunity. Adult T-cell leukemia/lymphoma is an aggressive lymphoma associated with human T-lymphotrophic virus 1 infection characterized by the presence of neoplastic lymphocytes with a T reg phenotype; however, this phenotype is not characteristically found in other lymphomas. Here, we report 2 apparently immunocompetent human T-lymphotrophic virus 1-negative patients with nodal and extranodal peripheral T-cell lymphoma, not otherwise specified with a T reg immunophenotype, based on the strong CD25 and FOXP3 positivity of the neoplastic cells. One patient was a 48-year-old woman with an early stage tumor in the cavum, who despite of chemotherapy subsequently developed systemic disease and died of tumor progression 46 months from diagnosis. The second patient was a 65-year-old male with generalized adenopathy and B symptoms who received chemotherapy achieving a complete remission but had recurrence and died 36 months from diagnosis. The histopathology revealed a diffuse infiltrate with an interfollicular distribution in the second case, with nodal involvement, consisted of large cells with clear cytoplasm associated with vascular proliferation and abundant mitoses. Neoplastic cells of first case showed typical T reg phenotype, whereas the second case had a CD4/CD8 double negative T reg variant. Only a single similar case was found in a review of the literature. We conclude that peripheral T-cell lymphoma, not otherwise specified with a T reg phenotype may represent a distinct category of T-cell lymphoma with an aggressive clinical course and poor prognosis.