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BCL11B is an essential transcription factor for T-cell lineage commitment and differentiation, and its dysregulation has been shown to be associated with T-cell tumourigenesis. In this study, we investigated BCL11B expression by immunohistochemical analysis in 120 cases of mature T-cell lymphoma, 34 B-cell lymphomas, 11 NK-cell neoplasms and 17 reactive cutaneous conditions. All cases of mycosis fungoides (n=23), primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (n=8) and T-prolymphocytic leukaemia (n=6) were positive for BCL11B and the staining intensity was higher than that of reactive T-cells. Fourteen of 15 (93%) cases of angioimmunoblastic T-cell lymphoma, 10 of 12 (83%) T-large granular lymphocytic leukaemia and 14 of 20 (70%) peripheral T-cell lymphoma, not otherwise specified, were also positive for BCL11B with an intensity comparable to reactive T-cells. Other T-cell neoplasms were uncommonly positive including one of three (33%) cases of primary cutaneous gamma delta T-cell lymphoma, one of four (25%) cases of subcutaneous panniculitis-like T-cell lymphoma, one of four (25%) cases of hepatosplenic T-cell lymphoma, and one of 20 (5%) cases of anaplastic large cell lymphoma (8 ALK-positive, 12 ALK-negative). T-cells in reactive cutaneous infiltrates were also positive for BCL11B, but staining intensity was much weaker than in mycosis fungoides. All NK-cell (n=11) and B-cell neoplasms (n=34) were negative for BCL11B. In conclusion, BCL11B shows a distinct expression pattern in various T-cell neoplasms. BCL11B appears to have utility as another T-cell marker and may be useful in the differential diagnosis of lymphoid neoplasms.

The immunophenotype of pure erythroid leukemia (PEL) as determined by flow cytometry immunophenotypic analysis is not well characterized. The immunophenotypic difference between PEL and reactive conditions is under-explored.We assessed and compared the immunophenotype of 24 PEL cases and 28 reactive cases containing early erythroid precursors by flow cytometry.The neoplastic erythroid cells in all PEL cases were positive for CD36 and CD71. CD45 was also positive in all cases, but the expression level was often dimmer than granulocytes. CD117 expression ranged from partial to uniform, and CD235a was often only positive in the CD117-dim to negative cells, corresponding to more differentiated subset. PEL cases frequently (87%) showed decreased or negative CD38 expression, contrasting to reactive early erythroid precursors that showed bright CD38 (p 0.0001). CD7 (25%) and CD13 (29%) aberrant expressions were only observed in PEL but not in the reactive erythroid cells. Normal early erythroid precursors in all reactive bone marrows showed partial expression of CD4; In contrast, aberrant CD4 expression was detected in 71% PEL cases, either uniformly positive (50%) or completely negative (21%). While normal/reactive bone marrows almost always contained a small subset of CD34-positive early erythroid precursors, the neoplastic pronormoblasts in all PEL cases were CD34 negative. Although not increased in number, CD34-positive myeloblasts were frequently detected in PEL and demonstrated an aberrant immunophenotype in 90% PEL cases.PEL shows a distinctive immunophenotype which can be distinguished from reactive erythroid precursors by flow cytometry immunophenotyping.

Plasma cell neoplasms are notorious for having diverse morphological presentations, and less frequently, unusual immunophenotypical profiles. This unexpected immunomorphological variability could lead to erroneous impressions upon initial assessment, potentially delaying the generation of a final accurate diagnosis. In this review, we present a concise, yet comprehensive summary of both morphological and immunophenotypical variants of plasma cell neoplasms from the archives of MD Anderson Hematopathology Department, with emphasis on possible diagnostic pitfalls precluding a timely and accurate assessment.

Artificial intelligence-based tools designed to assist in the diagnosis of lymphoid neoplasms remain limited. The development of such tools can add value as a diagnostic aid in the evaluation of tissue samples involved by lymphoma. A common diagnostic question is the determination of chronic lymphocytic leukemia (CLL) progression to accelerated CLL (aCLL) or transformation to diffuse large B-cell lymphoma (Richter transformation; RT) in patients who develop progressive disease. The morphologic assessment of CLL, aCLL, and RT can be diagnostically challenging. Using established diagnostic criteria of CLL progression/transformation, we designed four artificial intelligence-constructed biomarkers based on cytologic (nuclear size and nuclear intensity) and architectural (cellular density and cell to nearest-neighbor distance) features. We analyzed the predictive value of implementing these biomarkers individually and then in an iterative sequential manner to distinguish tissue samples with CLL, aCLL, and RT. Our model, based on these four morphologic biomarker attributes, achieved a robust analytic accuracy. This study suggests that biomarkers identified using artificial intelligence-based tools can be used to assist in the diagnostic evaluation of tissue samples from patients with CLL who develop aggressive disease features. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

B-cell lymphoma/leukaemia 11B (BCL11B) is an essential transcription factor for T-cell lineage commitment and maturation. We investigated BCL11B expression by immunohistochemistry in T-lymphoblastic leukaemia/lymphoma (T-ALL/LBL) (n = 115). The majority (83%) of early T-cell precursor T-ALL/LBL (ETP-ALL) cases showed negative BCL11B expression, while most (84%) of non-ETP-ALL/LBL were positive for BCL11B. A simplified three-marker [BCL11B, cluster of differentiation 5 (CD5), CD13] immunophenotypic score discriminated reliably between ETP-ALL and non-ETP-ALL/LBL. In ETP-ALL, patients with positive BCL11B expression had a better overall survival than those with negative BCL11B (P = 0·009). In summary, BCL11B is a valuable marker for T-ALL/LBL subtyping and serves as a potential prognostic marker in patients with ETP-ALL.

Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) is characterized by a distinct immunophenotype (CD1a-negative, CD8-negative, CD5-negative or weak-positive

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) with unusual features, including some that can overlap morphologically with classic Hodgkin lymphoma (CHL), have been described. Herein, we describe 12 cases of NLPHL with fibrous bands and capsular fibrosis resembling, in part, nodular sclerosis (NS) CHL. Seven of 12 cases harbored Reed-Sternberg-like cells, further suggestive of CHL, but all cases lacked associated eosinophils and/or plasma cells in the background. In this cohort, all cases had areas of so-called pattern D (nodular T-cell rich) as a sole component in 7 (58%) cases or as a hybrid pattern along with pattern E (diffuse T-cell/histiocyte-rich) in 5 (42%) cases. The immunophenotype of the large neoplastic cells in these cases supported their being lymphocyte predominant cells of NLPHL, positive for CD20, CD79a, and OCT2, and negative for CD15 and CD30. However, PAX5 was weak in 9 of 11 cases similar to Hodgkin/Reed-Sternberg cells in CHL. We conclude that some cases of NLPHL are associated with fibrous bands and capsular fibrosis and resemble, in part, NS CHL. In our experience, NLPHL with NS-like features occurs in 10% to 15% of cases of NLPHL and is associated with a variant pattern (D and/or E). In addition, all patients in this cohort were not treated before biopsy, suggesting that the prominent sclerosis in these cases is inherent to disease biology. Recognition of NLPHL with NS-like features further expands the morphologic spectrum of NLPHL and helps avoid potential misdiagnosis as CHL.

Prompt diagnosis of acute promyelocytic leukemia (APL) is critical for patient care. In this study, we aimed to characterize the immunophenotype of APL and explore immunophenotypic difference between APL and its mimics using flow cytometric analysis.Eighty-five cases were collected, including 47 APL, 26 NPM1-mutated acute myeloid leukemia (AML) and 12 KMT2A-rearranged AML with an APL-like immunophenotype. Immunophenotypes were analyzed using flow cytometric analysis.APL showed four distinct patterns (designated a-d) based on CD45/SSC plots. Blasts in patterns a-c showed high side scatter, whereas blasts in pattern d had low side scatter and were located in the traditional blast gate. Compared with patterns a-c, pattern d of APL (APL-D) was more often positive for CD2 (p = 0.0005) and CD34 (p = 0.0002) in blasts. All NPM1-mutated AML and KMT2A-rearranged AML cases with an APL-like immunophenotype had blasts in the traditional blast gate on CD45/SSC, mimicking APL-D. In comparison, uniform CD13 and positive CD64 were seen in 100% (n = 13) APL-D cases and in only 2 of 26 (8%) NPM1-mutated AML cases (p 0.0001). In addition, APL-D cases were more likely to be positive for CD2 and/or CD34 than NPM1-mutated AML (p 0.0001 and p = 0.0007, respectively). In comparison with APL-D, KMT2A-rearranged AML cases were less often positive for myeloperoxidase (MPO) (p = 0.001), with none being strongly positive. Similar to NPM1-mutated AML and different from APL-D, KMT2A-rearranged AML cases were rarely positive for CD34 and all negative for CD2.APL and its immunophenotypic mimics share some immunophenotypic similarities but can be distinguished by CD2, CD13, CD34, CD64, and MPO.

Myeloproliferative neoplasms (MPNs) are frequently associated with classic driver mutations involving JAK2, MPL or CALR. SRSF2 is among the most frequently mutated splicing genes in myeloid neoplasms and SRSF2 mutations are known to confer a poor prognosis in patients with MPNs. In this study, we sought to evaluate the clinicopathologic spectrum of myeloid neoplasms harboring concurrent MPN-driver mutations and SRSF2 mutations. The study cohort included 27 patients, 22 (82%) men and five (19%) women, with a median age of 71 years (range, 51-84). These patients presented commonly with organomegaly (n = 15; 56%), monocytosis (n = 13; 48%), morphologic dysplasia (n = 11; 41%), megakaryocytic hyperplasia and/or clustering (n = 10; 37%) and bone marrow fibrosisMF-1 (17/22; 77%). About one third of patients either initially presented with acute myeloid leukemia (AML) or eventually progressed to AML. Eighteen (68%) patients had a dominant clone with SRSF2 mutation and nine (33%) patients had a dominant clone with a classic MPN-associated driver mutation. Our data suggest that the presence of an SRSF2 mutation preceding the acquisition of a MPN driver mutations is not a disease-defining alteration nor is it restricted to any specific disease entity within the spectrum of myeloid neoplasms. In summary, patients with myeloid neoplasms associated with concurrent SRSF2 and classic MPN driver mutations have clinical and morphologic features close to that of classic MPNs often with frequent dysplasia and monocytosis.

The development of clonally related hematologic neoplasms in the setting of primary mediastinal germ cell tumors (PMGCTs) has been recognized previously and is associated with a dismal prognosis. However, the presentation of hematologic neoplasms as chronic myelomonocytic leukemia (CMML) and hemophagocytic lymphohistiocytosis (HLH) has been rarely reported. Here we report two patients with PMGCTs and hematologic neoplasms. The PMGCT was composed mostly of yolk sac tumor whereas the hematologic neoplasms had morphologic features that resembled CMML and HLH. The hematologic neoplasms from both patients harbored isochromosome 12p [i(12p)] and TP53 mutations, supporting a clonal relationship between these tumors. This association represents a unique clinical syndrome that likely contributes to the poor clinical outcome of these patients.

AIMS Kikuchi-Fujimoto disease (KFD) is a self-limited disease characterised by destruction of the lymph node parenchyma. Few studies have assessed the immunohistological features of KFD, and most employed limited antibody panels that lacked many of the novel immunohistochemistry markers currently available. METHODS AND RESULTS We used immunohistochemistry to reappraise the microanatomical distribution of plasmacytoid dendritic cells (pDCs), follicular helper T cells and cytotoxic T cells, B cells, follicular dendritic cell (FDC) meshworks, and histiocytes in lymph nodes involved by KFD. The study group consisted of 138 KFD patients (89 women; 64.5%) with a median age of 27 years (range, 3-50 years). Cervical lymph nodes were most commonly involved, in 108 (78.3%) patients. The numbers of pDCs were increased, predominantly around and within apoptotic areas and the paracortex, and tapering off within xanthomatous areas. pDCs formed sizeable tight clusters, most notably around apoptotic/necrotic areas. T cells consisted mostly of CD8-positive cells with predominant expression of T-cell receptor-β. There were notable increases in the numbers of CD8-positive T cells within lymphoid follicles, and their numbers correlated with alterations in FDC meshworks (P

Aggressive natural killer-cell leukemia (ANKL) is a rare, lethal disease with pathologic features that are underdescribed in the literature, particularly in Western nations. In addition, although data on the molecular pathogenesis of ANKL has been reported, evaluation of such data in a clinicopathologic context remains limited. Patients diagnosed with ANKL were identified retrospectively. Detailed demographic and clinicopathologic data were analyzed. We assessed novel markers by immunohistochemistry and performed targeted next-generation sequencing analysis. The study group included 9 men and 3 women with a median age at diagnosis of 47.5 years (range, 20 to 75 y). Two distinct patterns of bone marrow involvement were identified: interstitial and sinusoidal. The neoplastic cells were positive for CD56 and CD94, and negative for surface CD3, CD5, and CD57 in all cases assessed. They were also positive for CD2 (10/12), c-MYC (6/8), BCL2 (6/8), CD16 (5/7), EBER (9/12), CD7 (6/11), pSTAT3 (3/8), CD8 (2/6), PD-L1 (2/8), CD4 (2/11), CD8 (2/6), and CD158 (1/5). Aberrant p53 expression was identified in most (7/8) cases; p53 was strongly expressed in 4 cases. Conventional cytogenetic analysis showed clonal abnormalities in 5 of 12 cases. TP53 mutations were detected in 3 of 6 cases, whereas ASXL1 and TET2 mutations were each detected in 2 of 6 cases. Patients had very poor outcomes despite intensive chemotherapy, with a median survival of 2 months. ANKL exhibits 2 distinct patterns of tissue involvement. Neoplastic cells in ANKL are commonly positive for c-MYC and EBER, and they have a high frequency of p53 overexpression, frequently with corresponding TP53 mutations.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is characterized morphologically by numerous small lymphocytes and pale nodules composed of prolymphocytes and paraimmunoblasts known as proliferation centers (PCs). Patients with CLL can undergo transformation to a more aggressive lymphoma, most often diffuse large B-cell lymphoma (DLBCL), known as Richter transformation (RT). An accelerated phase of CLL (aCLL) also may be observed which correlates with subsequent transformation to DLBCL, and may represent an early stage of transformation. Distinguishing PCs in CLL from aCLL or RT can be diagnostically challenging, particularly in small needle biopsy specimens. Available guidelines pertaining to distinguishing CLL from its' progressive forms are limited, subject to the morphologist's experience and are often not completely helpful in the assessment of scant biopsy specimens. To objectively assess the extent of PCs in aCLL and RT, and enhance diagnostic accuracy, we sought to design an artificial intelligence (AI)-based tool to identify and delineate PCs based on feature analysis of the combined individual nuclear size and intensity, designated here as the heat value. Using the mean heat value from the generated heat value image of all cases, we were able to reliably separate CLL, aCLL and RT with sensitive diagnostic predictive values.

Microsatellite instability (MSI) is caused by defects in DNA mismatch repair (MMR) components. Inactivation of any MMR gene(s), including hMLH1, hMSH2, hMSH6, and hPMS2, can result in MSI. Immunohistochemistry (IHC) is a sensitive and specific screening tool for MSI that can detect loss of expression of one or more MMR components. Of the four MMR markers, hMLH1 and hMSH2 are considered most informative of MSI status. There has been renewed interest in MSI status in view of its favorable association with response to immune checkpoint inhibitors in some cancers. MMR expression patterns in acute myeloid leukemia (AML) have not been evaluated systematically.We used clinically-validated IHC assays to assess the expression of hMLH1, hMSH2, hMSH6, and/or hPMS2 in formalin-fixed paraffin-embedded tissue sections of bone marrow core biopsies from patients diagnosed with AML. Mutation profiling was performed using next-generation sequencing to assess for mutations in MMR genes.The study group included 236 patients with AML, including a cohort treated on a clinical trial of azacitidine and nivolumab (NCT02397720). In addition, hMSH6, and/or hPMS2 expression was assessed in 99 AML patients with diploid karyotype. All patients, except two, had retained expression of all MMR markers assessed: One patient from the azacytidine+nivolumab group had zonal patchy loss of staining of hMLH1 and, to a lesser extent, a similar staining pattern of hMSH2; and one patient from the AML with diploid karyotype group had loss of hMSH2 but retained expression of hMLH1, hMSH6 and hPMS2. In addition, a retrospective analysis on a separate cohort of 139 patients with primary AML, on which next generation sequencing profiling was performed, identified 14 cases with alterations in MMR genes.MMR loss is a rare event in AML, thus does not appear to underlie response patterns to anti-PD1 therapy.

Well-differentiated systemic mastocytosis (WDSM) is a rare unique variant of systemic mastocytosis that has been described in few studies [1–11]. This entity has unique features that can cause pote...

The role of WT1 protein in hematopoiesis and leukemogenesisis incompletely elucidated. WT1 overexpression is common in acute myeloid leukemia (AML); however, WT1 mutations occur in only about 10% of cases, with increasing incidence in the setting of relapse. In this study, we investigated the clinical and molecular characteristics of WT1 mutations in NPM1-mutated AML, to enhance our understanding of the biology and potential therapeutic implications of WT1 mutations. Our study cohort included 67 patients with NPM1 mutated AML and a median follow-up of 13.7 months. WT1 mutations were identified in 7% (n = 5) of patients at the time of initial diagnosis. WT1 mutant clones were presumed to be present as co-dominant clones in 3/5 and in subclonal populations in 2/5 cases based on variant allelic frequency (VAF) when compared with NPM1 mutation VAF. All WT1 mutations became undetectable at time of MRD-negative (NPM1-wild type) remission. None of these patients experienced relapse at the time of last follow-up (median, 15 months; range, 4.5-20.2 months). A total of 15/67 (22%) patients relapsed; among these patient, four (27%) relapsed with WT1 mutant AML. Three of four patients had undergone allogeneic hematopoietic stem cell transplantation (HSCT). None of these patients had detectable WT1 mutations at the time of initial diagnosis. WT1 mutations were presumed clonal in two cases and subclonal in the other two cases, based on VAF. Our results indicate that WT1 mutations contribute to relapse in NPM1 mutated AML, especially in the setting of HSCT. These findings suggest that emerging WT1 mutations may serve as a conduit for relapse in NPM1-mutated AML, and that sequential molecular profiling to evaluate potential emergent WT1 mutations during surveillance and particularly at relapse likely has prognostic value in patients with NPM1 mutated AML.

Burkitt leukemia/lymphoma (BL) and high-grade B-cell lymphoma (HGBL) have a high incidence of central nervous system (CNS) involvement, which is associated with poor prognosis. The hyper-cyclophosphamide, vincristine, Adriamycin, and dexamethasone plus rituximab (CVAD-R) regimen includes systemic and intrathecal CNS-directed therapy to treat and prevent CNS disease. We report here the long-term safety and efficacy of the hyper-CVAD-R regimen in adults with BL and HGBL, focusing on its efficacy to prevent CNS relapse. Among 79 adults (54 BL, 25 HGBL), the median age was 44 years (25% ≥60 years old), 73% had bone marrow (BM) involvement, and 28% had CNS involvement. The complete response rate was 91% (BL 96%; HGBCL 79%; P = .16). The 5-year relapse-free survival (RFS) and overall survival (OS) rates were 58% and 52%, respectively. The cumulative incidence of relapse (CIR) was 21% (BL 14%; HGBCL 37%, P = .06) and was associated with baseline BM (27% vs 0%; P = .02) and CNS (42% vs 12%; P < .01) involvement. In multivariate analyses, age and CNS involvement were independent predictors for OS and RFS. The 5-year CNS CIR was 6% (BL 4%; HGBL 11%; P = .31); 16% with baseline CNS involvement (P = .03). Our data support the use of hyper-CVAD-R in preventing CNS relapse, especially among high-risk patients with BM or CNS involvement.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) with associated prior or concurrent hematologic malignancy (BPDCN-PCHM) is an emerging phenomenon, increasingly seen in clinical practice in the...

Context.— The main focus of education in most pathology residency and subspecialty pathology fellowships is the light microscopic examination of pathology specimens. Classes with multiheaded scopes are the most popular among pathology trainees. Until recently, it was difficult to imagine that this educational approach could change. In the beginning of March 2020, our country faced a serious challenge, which all of us now know as the coronavirus disease 2019 (COVID-19) pandemic. The rules of social distancing and work from home were applied. These types of restrictions were implemented in almost all parts of our life, including work and pathology education. Objective.— To share our experience in the Department of Hematopathology at the University of Texas MD Anderson Cancer Center during the COVID-19 pandemic. We describe our experience in modifying our approaches to education. We show how we overcame many obstacles to learning by building one of the largest virtual hematopathology educational platforms via Cisco WebEx and using social media, in particular Twitter. These tools facilitated the learning of hematopathology by medical students, pathology trainees, and practicing pathologists from all over the world. Data Sources.— During the first 3 months of the pandemic (April, May, and June, 2020), we evaluated the visitor attendance to the MD Anderson Cancer Center Hematopathology Virtual Educational Platform using data collected by the Cisco WebEx Web site. To determine the impact that the platform had on medical education for the hematopathology community on Twitter, the analytic metrics obtained from Symplur LLC (www.symplur.com, April 27, 2020) were used via its Symplur Signals program. Conclusions.— Our experience using the MD Anderson Hematopathology Virtual Platform showed that there is substantial global interest and desire for virtual hematopathology education, especially during the COVID-19 pandemic.

Light-chain restricted hematogones (LCR HGs) detected by flow cytometry analysis can mimic bone marrow involvement by B-cell lymphoma. This phenomenon can present a diagnostic pitfall and negatively impact patient management, as misinterpretation may upgrade disease stage. In this study, we characterized the immunophenotype of LCR HGs with an aim to differentiate them from B-cell lymphoma. We analyzed 24 patients with LCR HGs, 12 (50 %) were kappa light chain restricted and 12 (50 %) were lambda light chain restricted. LCR HGs account for 51 % (range, 1.5%-99%) of B cells, and 0.5 % (range, 0.1%-3.7%) of total cells. In 15 patients in whom multiple specimens were analyzed, 10 (67 %) showed persistent LCR HGs in more than 1 specimen, and the duration of the light chain restriction ranged from 4 months to 2 years. Among 24 patients, 4 (16.6 %) cases were concurrently involved by B-cell lymphoma/myeloma in addition to LCR HGs. With the exception of light chain restriction, LCR HGs showed a similar immunophenotype as normal HGs and had a distinct location on the CD45/Side Scatter (SSC) plot. They were also consistently positive for CD10, CD19, CD38 (bright), CD43, and CD200. CD20 expression showed a spectrum from dim/negative to positive.

Primary signet ring cell carcinoma of the pancreas (PSRCCP) is an extremely rare diagnosis that has not been extensively studied in literature. Primary and metastatic neoplasms to the pancreas may exhibit cytomorphological similarities to signet ring cells, posing diagnostic challenges. In this article, we review PSRCCP and provide a study of several primary pancreatic neoplasms that may mimic the appearance of PSRCCP upon cytopathology evaluation, shedding light on the existence of this dilemma, and helping cytopathologists in navigating similar scenarios in their practice.

We present a case of salpingoliths detected in peritoneal washing, during an elective bilateral salpingo-oophorectomy, in a 32 years old woman with history of familial BRCA gene mutation. Salpingoliths are psammoma body-like types of calcification that originate from the fallopian tubes and can be encountered in peritoneal washings. Unlike psammoma bodies, salpingoliths have been tagged to benign and hyperplastic processes more often than neoplastic processes. Misinterpreting salpingoliths as psammoma bodies in peritoneal washings can be misleading for both cytopathologists and clinicians, especially as in the presented case, where there is a high risk for ovarian carcinoma. In this article, we aim to shed light on this rare finding, and report theories explaining its pathogenesis, in addition we provide an example of its challenging cytological presentation, to increase awareness among cytopathologists.

Cercariform cells are slender cells with a bulbous end and a unipolar long cytoplasmic process, resembling Schistosoma cercariae. Since their first description in urothelial carcinoma, multiple studies have attempted to explore their utility in distinguishing metastatic urothelial carcinoma from other common malignant neoplasms, such as adenocarcinoma and squamous-cell carcinoma. Although not pathognomonic, they are most commonly encountered in urothelial carcinoma, but they can also be seen in other neoplasms, raising the possibility that this cytomorphological feature can be exploited to aid in diagnosis.

Anaplastic carcinoma of the pancreas (ACP) is a rare and aggressive variant of pancreatic ductal adenocarcinoma (PDAC). Several studies have attempted to characterize this subtype through case series or single case reports; however, ACP remains underrecognized by cytopathologists in particular, and often lumped under the umbrella of classic PDAC. Here, we review the most up to date data that literature provides about ACP, to bring familiarity with this entity to the cytopathology practice, and to elucidate the role cytopathologists can play in recognizing and diagnosing this subtype on pancreatic aspiration biopsy, before surgical resection. We also describe a rare case of ACP, demonstrating signet ring cell features, that was diagnosed on fine needle aspiration of a pancreatic mass.

In the spring of 2018, nematode-like organisms were first noted at the time of microscopic diagnosis on gynecologic (GYN) and anal pap specimens in our institution's cytopathology department. Due to their morphology and specimen source, we considered a diagnosis of pinworm. However, after identifying at least 30 more cases over 3 months from patients living in variable locations, we started favoring a contaminant. This report studies the steps that were initiated to figure the source of pap smear-preparation contamination and the molecular investigation to identify the nature of the contaminant.

Lymphomas and leukemias of T-cell and NK-cell lineages are highly heterogeneous disorders and lack effective therapeutic strategies. Targeted therapies including anti-CD94 agents are currently under clinical investigation, but studies of CD94 expression on mature T/NK-cell neoplasms are limited. In this study, we investigated the landscape of CD94 protein expression in 15 patients with reactive T/NK-cell proliferations and 124 patients with various T/NK cell neoplasms. CD94 expression was detected at a high level in reactive NK-cells, with a lower level of expression in a subset of reactive CD8 + T-cells; reactive CD4 + T-cells were negative for CD94 expression. All NK-cell neoplasms surveyed had high-level CD94 expression, which was significantly higher than that in T cell neoplasms (p = 0.0174). In neoplastic T-cell proliferations, CD94 expression was positive in all 10 hepatosplenic T-cell lymphoma cases tested, with a high mean fluorescence intensity. Fifty-six percent of T-cell large granular lymphocytic leukemia cases were positive for CD94 expression in a subset of neoplastic cells. All T-cell prolymphocytic leukemia and 97 % of peripheral T-cell lymphoma cases showed no CD94 expression. Our findings demonstrate a broad range of CD94 expression among T/NK-cell neoplasms, in some at levels that suggest therapeutic vulnerability to CD94-targeted therapies.

Monocytosis is a distinct but non-specific manifestation of various physiologic and pathologic conditions. Among hematopoietic stem cell neoplasms, depending on the criteria used for disease classification, monocytosis may be a consistent and integral component of diseases such as chronic myelomonocytic leukemia or acute myeloid leukemia with monocytic differentiation, or it may represent an inconsistent finding that often provides a clue to the underlying genetic changes driving the neoplasm. The purpose of this review is to provide the readers with a laboratory-based approach to neoplastic monocytosis. In-depth elucidation of the genomic landscape of myeloid neoplasms within the past few years has broadened our understanding of monocytosis and its implications for diagnosis and prognosis. Genetic findings also shed light on potential disease response — or lack thereof — to various therapeutic agents used in the setting of myeloid neoplasms. In this review, we provide our approach to diagnose neoplastic monocytosis in the context of case-based studies while incorporating the most recent literature on this topic.

Hematopathologists are witnessing very exciting times, as a new era of unsurpassed technological advances is unfolding exponentially, enhancing our understanding of diseases at the genomic and molecular levels. In the evolving field of precision medicine, our contributions as hematopathologists to medical practice are of paramount importance. Social media platforms such as Twitter have helped facilitate and enrich our professional interactions and collaborations with others in our field and in other medical disciplines leading to a more holistic approach to patient care. These platforms also have created a novel means for instantaneous dissemination of new findings and recent publications, and are proving to be increasingly useful tools that can be harnessed to expand our knowledge and amplify our presence in the medical community. In this Editorial, we share our experience as hematopathologists with Twitter, and how we leveraged this platform to boost scholarly activities within and beyond our subspecialty, and as a powerful medium for worldwide dissemination of educational material and to promote our remote teaching activities during the COVID-19 pandemic.

Lymphoid enhancer binding factor 1 (LEF1) is consistently upregulated in chronic lymphocytic leukemia (CLL) and in a subset of large B cell lymphoma. Knowledge of LEF1 expression in Hodgkin lymphoma is limited. In this study, we used immunohistochemistry to survey LEF1 expression in various subsets of Hodgkin lymphoma, de novo classic Hodgkin lymphoma (CHL) (n = 43), Hodgkin lymphoma associated with Richter syndrome (HL-RS) (n = 20), and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) (n = 9). LEF1 expression was significantly higher in HL-RS compared with de novo CHL (12/20, 60% vs. 12/43, 28%; p = 0.0248). Only a single case (1/9; 11%) of NLPHL showed LEF1 expression. Epstein-Barr virus encoded RNA (EBER) was detected in 17 (40%) cases of de novo CHL and 14 (70%) HL-RS. Notably, we identified a correlation between LEF1 expression and EBER positivity (p = 0.0488). We concluded that LEF1 is commonly positive in CHL but not in NLPHL, and such a distinction may be helpful in this differential diagnosis. The higher frequency of LEF1 upregulation in HL-RS relative to de novo CHL suggests that these neoplasms might have different underlying pathogenic mechanisms and warrants further investigation.

Recently, comprehensive genomic analyses have allowed a better molecular characterization of diffuse large B-cell lymphoma (DLBCL), offering novel opportunities in patient risk stratification and management. In the era of precision medicine, this has allowed us to move closer toward a more promising therapeutic outcome in the setting of DLBCL. In this review, we highlight the newly reported heterogeneous mutational landscapes of DLBCL (from two whole-exome sequencing studies, and from a more recent work targeting a 293-gene of a hematologic malignancy-designed panel. Altogether, these studies provide further evidence of the clinical applicability of genomic tests. We also briefly review established biomarkers in DLBCL (e.g., MYC and TP53), and our understanding of the germinal center cell reaction, including its epigenetic regulation, emphasizing some of the key epigenetic modifiers that play a role in lymphomagenesis, with available therapeutic targets. In addition, we present current data regarding the role of immune landscapes in DLBCL (inflamed versus non-inflamed), how the recently defined molecular DLBCL subtypes may affect the cellular composition of the tumor microenvironment and the function of the immune cells, and how this new knowledge may result in promising therapeutic approaches in the near future.

B-prolymphocytic leukemia (B-PLL) is included as a distinct entity in the current World Health Organization classification of hematolymphoid neoplasms. However, the diagnosis of B-PLL has presented several challenges since its conception, and over the past decades investigations of B-PLL have revealed substantial biologic and molecular heterogeneity. These data have shown that many B-PLL cases present many similarities with other types of small B-cell lymphomas, and that small B-cell lymphomas can undergo prolymphocytoid transformation. As a result, the frequency of B-PLL has markedly decreased, and currently B-PLL is a very rare entity. Most recent studies focused on B-PLL cases have been conducted on limited cohorts, precluding robust conclusions. In this article, we provide a concise historical review of B-PLL and describe the diagnostic and clinical challenges associated with establishing this diagnosis. We also argue that cases currently classified as B-PLL are unlikely to be a unique biologic entity, but rather represent a state of morphologic transformation characterized by many prolymphocytes that is shared by various types of small B-cell lymphoma.

Adenoid cystic carcinoma (ACC) of the breast is a rare type of breast cancer, which presents inconsistencies in the optimal management strategy. A retrospective review of prospectively collected data, spanning the last 20 years, was performed using the cancer registry database at our institution. Six patients were diagnosed with ACC of the breast, out of 5,813 total patients diagnosed with breast cancer (0.1%). Our identified patients had a median age of 66, all with the early stage cancer (Stage I/II). The average size of the breast lesion was 1.62 cm, and nodal status was negative for all cases. All patients had resection as primary therapy (partial or total mastectomy), with one patient also undergoing external beam radiation and tamoxifen hormonal therapy. Median follow-up was 85 months, with all patients being disease-free at last follow-up. ACC of the breast has an indolent course, despite triple negative status. Our study suggests that radiation may not be warranted and confirms the rarity of axillary node metastases, indicating that sentinel node excision may also not be necessary. Ultimately, the hope is that our findings along with the reviewed literature will aid in determining the most appropriate options for management of ACC of the breast.

We report a case of polymorphous hemangioendothelioma, a rare vascular neoplasm, arising in the liver of a 51-year-old woman. Microscopically, this neoplasm is characterized by a polymorphous blend of solid, primitive vascular and angiomatous areas in variable proportions. Polymorphous hemangioendothelioma is considered to be an intermediate-grade vascular neoplasm. In most of the reported cases, its occurrence has been in lymph nodes, but a few cases have been found in extranodal sites such as the mediastinum, spinal cord, and liver. Its classification among other soft tissue neoplasms is still controversial due to an insufficient number of cases to allow prediction of its biologic behavior. The aim of this article is to report a rare case of extranodal hepatic polymorphous hemangioendothelioma primary to the liver and to offer a summary of the reported cases in the literature, with emphasis on the differential diagnosis and diagnostic pitfalls in daily practice.

Salivary glands located in the head and neck area are known to have different lesions with prominent oncocytic features. Fine needle aspiration is usually the initial approach in the management of these lesions, whether they represent neoplastic or non-neoplastic processes. Owing to the limited material present upon cytopathologic examination, knowledge of variants and subtypes of various oncocytic lesions that can occur in this area is of major importance to provide the most accurate interpretation to the patients and clinicians. In this article, we selected rare lesions of the salivary glands that may exhibit oncocytic changes, and provided a brief discussion of each one of them, with emphasis on challenges in navigating the differential diagnosis that these cases may pose, from the cytopathology standpoint.

Lung adenocarcinoma transformation into small cell lung carcinoma is a well-established phenomenon. Several reports and studies have been published, describing the clinical and pathological clues to detect this transformation. This article will discuss the cytological aspect of this entity, highlighting pertinent features, to bring more attention to the existence of this transformation into the cytopathology practice.

Water clear cell adenoma of the parathyroid gland is a rare neoplasm composed of large clear cells with foamy cytoplasm and mild nuclear pleomorphism, compressing the residual nonneoplastic parathyroid tissue. The differential diagnosis includes a variety of neoplasms with clear cell features. In this article, we provide an overview of the entity with a historical perspective, in order to help pathologists in distinguishing it from other neoplasms in their daily practice.

Pituicytoma is a rare low-grade glial neoplasm that originates in the distribution of the neurohypophysis, including the posterior pituitary lobe and infundibular stalk. The tumor cells resemble pituicytes, which are specialized glial cells of the neurohypophysis. Pituicytoma can be misdiagnosed pre-operatively as a pituitary adenoma due to overlapping clinical and neuroimaging features between these two entities. Pituicytoma can also mimic other neoplasms of the sellar and parasellar regions microscopically - meningioma, schwannoma and pilocytic astrocytoma - and shares immunohistochemical expression of TTF-1 with spindle cell oncocytoma and granular cell tumor of the sellar region, suggesting a common histogenesis. In this short review, we present the key features of pituicytoma, discuss commonalities and distinguishing features from other neoplasms of the sellar and parasellar regions and highlight the importance of recognizing this tumor entity for clinical and surgical management.

Unlike the well-documented relation between radiation to the neck and development of papillary thyroid carcinoma, a causal association between radioactive iodine treatment for Graves’ disease and development of thyroid malignancy is less defined. However, patients with a background of thyroid dysfunction presenting with clinically palpable thyroid nodules are followed more closely than the average population, and fine needle aspiration is recommended in such circumstances. Cytological examination of aspirates, and histologic examination of tissue provided from patients with a known history of Graves’ disease, managed by radioactive iodine therapy can create a diagnostic dilemma, as the distinction between radiation effect and a malignant primary thyroid neoplasm can be very challenging. Thus, pathologists should be aware of the existence of these changes in the setting of radiation therapy for Graves’ disease. Providing pathologists with appropriate clinical history of Graves’ disease treated with radioactive iodine is of paramount importance in order to prevent an overdiagnosis of malignancy.