Xenotransplantation models represent powerful tools for the investigation of healthy and malignant human hematopoiesis. However, current models do not fully mimic the components of the human bone ...marrow (BM) microenvironment, and they enable only limited engraftment of samples from some human malignancies. Here we show that a xenotransplantation model bearing subcutaneous humanized ossicles with an accessible BM microenvironment, formed by in situ differentiation of human BM-derived mesenchymal stromal cells, enables the robust engraftment of healthy human hematopoietic stem and progenitor cells, as well as primary acute myeloid leukemia (AML) samples, at levels much greater than those in unmanipulated mice. Direct intraossicle transplantation accelerated engraftment and resulted in the detection of substantially higher leukemia-initiating cell (LIC) frequencies. We also observed robust engraftment of acute promyelocytic leukemia (APL) and myelofibrosis (MF) samples, and identified LICs in these malignancies. This humanized ossicle xenotransplantation approach provides a system for modeling a wide variety of human hematological diseases.
Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. ...Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.
Immunodeficiency-associated lymphoproliferative disorders (IA-LPDs) are pathologically and clinically heterogeneous. In many instances, similar features are shared by a spectrum of IA-LPDs in ...clinically diverse settings. However, the World Health Organization (WHO) classifies IA-LPDs by their immunodeficiency setting largely according to the paradigm of posttransplant lymphoproliferative disorders but with inconsistent terminology and disease definitions. The field currently lacks standardization and would greatly benefit from thinking across immunodeficiency categories by adopting a common working vocabulary to better understand these disorders and guide clinical management. We propose a 3-part unifying nomenclature that includes the name of the lesion, associated virus, and the specific immunodeficiency setting for all IA-LPDs. B-cell lymphoproliferative disorders (LPDs) are usually Epstein-Barr virus (EBV)+ and show a spectrum of lesions, including hyperplasias, polymorphic LPDs, aggressive lymphomas, and, rarely, indolent lymphomas. Human herpes virus 8–associated LPDs also include polyclonal and monoclonal proliferations. EBV− B-cell LPDs and T- and NK-cell LPDs are rare and less well characterized. Recognition of any immunodeficiency is important because it impacts the choice of treatment options. There is an urgent need for reappraisal of IA-LPDs because a common framework will facilitate meaningful biological insights and pave the way for future work in the field.
To create clinically relevant normative flow cytometry data for understudied benign lymph nodes and characterise outliers.
Clinical, histological and flow cytometry data were collected and ...distributions summarised for 380 benign lymph node excisional biopsies. Outliers for kappa:lambda light chain ratio, CD10:CD19 coexpression, CD5:CD19 coexpression, CD4:CD8 ratios and CD7 loss were summarised for histological pattern, concomitant diseases and follow-up course.
We generated the largest data set of benign lymph node immunophenotypes by an order of magnitude. B and T cell antigen outliers often had background immunosuppression or inflammatory disease but did not subsequently develop lymphoma.
Diagnostic immunophenotyping data from benign lymph nodes provide normative ranges for clinical use. Outliers raising suspicion for B or T cell lymphoma are not infrequent (26% of benign lymph nodes). Caution is indicated when interpreting outliers in the absence of excisional biopsy or clinical history, particularly in patients with concomitant immunosuppression or inflammatory disease.
Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review B-cell proliferations of varied malignant potential associated with ...immunodeficiency.
Methods: The Workshop Panel reviewed all cases of B-cell hyperplasias, polymorphic B-lymphoproliferative disorders, Epstein-Barr virus (EBV)–positive mucocutaneous ulcer, and large B-cell proliferations associated with chronic inflammation and rendered consensus diagnoses. Disease definitions, boundaries with more aggressive B-cell proliferations, and association with EBV were explored.
Results: B-cell proliferations of varied malignant potential occurred in all immunodeficiency backgrounds. Presentation early in the course of immunodeficiency and in younger age groups and regression with reduction of immunosuppression were characteristic features. EBV positivity was essential for diagnosis in some hyperplasias where other specific defining features were absent.
Conclusions: This spectrum of B-cell proliferations show similarities across immunodeficiency backgrounds. Localized forms of immunodeficiency disorders arise in immunocompetent patients most likely due to chronic immune stimulation and, despite aggressive histologic features, often show indolent clinical behavior.
Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review immunodeficiency-related lymphoproliferative disorders with plasmablastic ...and plasma cell differentiation.
Methods: The workshop panel reviewed human herpes virus 8 (HHV8)/Kaposi sarcoma herpesvirus (KSHV)–associated lesions and other lesions exhibiting plasma cell differentiation, including plasmablastic proliferations with features of myeloma/plasmacytoma, plasmablastic neoplasms presenting in extranodal sites and effusion-based lymphomas, and rendered a consensus diagnosis.
Results: The spectrum of HHV8/KSHV-associated proliferations ranged from multicentric Castleman disease (MCD) to MCD with plasmablastic aggregates to HHV8+ diffuse large B-cell lymphoma and germinotrophic lymphoproliferative disorder. Comparisons across effusion-based lymphomas with and without HHV8/KSHV and plasmablastic lymphomas in immunodeficient and immunocompetent patients were discussed.
Conclusions: The presence or absence of HHV8/KSHV is a defining feature in disorders associated with Castleman disease, although their differential diagnosis and recognition of progression may be challenging. Plasmablastic proliferations overlap with myeloma/plasmacytoma as well as extranodal and effusion-based lymphomas. The involvement of Epstein-Barr virus is typically variable.
Mesenchymal stromal cells (MSCs) support hematopoiesis and are cytogenetically and functionally abnormal in myelodysplastic syndrome (MDS), implying a possible pathophysiologic role in MDS and ...potential utility as a diagnostic or risk-stratifying tool. We have analyzed putative MSC markers and their relationship to CD34+ hematopoietic stem/progenitor cells (HSPCs) within intact human bone marrow in paraffin-embedded bone marrow core biopsies of benign, MDS and leukemic (AML) marrows using tissue microarrays to facilitate scanning, image analysis and quantitation. We found that CD271+, ALP+ MSCs formed an extensive branching perivascular, periosteal and parenchymal network. Nestin was brightly positive in capillary/arteriolar endothelium and occasional subendothelial cells, whereas CD146 was most brightly expressed in SMA+ vascular smooth muscle/pericytes. CD271+ MSCs were distinct by double immunofluorescence from CD163+ macrophages and were in close contact with but distinct from brightly nestin+ and from brightly CD146+ vascular elements. Double immunofluorescence revealed an intimate spatial relationship between CD34+ HSPCs and CD271+ MSCs; remarkably, 86% of CD34+ HSPCs were in direct contact with CD271+ MSCs across benign, MDS and AML marrows, predominantly in a perivascular distribution. Expression of the intercrine chemokine CXCL12 was strong in the vasculature in both benign and neoplastic marrow, but was also present in extravascular parenchymal cells, particularly in MDS specimens. We identified these parenchymal cells as MSCs by ALP/CXCL12 and CD271/CXCL12 double immunofluorescence. The area covered by CXCL12+ ALP+ MSCs was significantly greater in MDS compared with benign and AML marrow (P=0.021, Kruskal–Wallis test). The preservation of direct CD271+ MSC/CD34+ HSPC contact across benign and neoplastic marrow suggests a physiologically important role for the CD271+ MSC/CD34+ HSPC relationship and possible abnormal exposure of CD34+ HSPCs to increased MSC CXCL12 expression in MDS.
Context.--Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare, indolent Hodgkin lymphoma subtype with distinct clinicopathologic features and treatment paradigms. The neoplastic ...lymphocyte-predominant cells typically express bright CD20 and other B-cell antigens, which distinguishes them from Hodgkin/Reed-Sternberg cells of lymphocyte-rich classic Hodgkin lymphoma. Objective.--To characterize the clinicopathologic features of CD20-negative NLPHL at a single institution. Design.--A retrospective search for CD20-negative NLPHL in our pathology archives and medical records was conducted. Results.--Of 486 NLPHL patients identified with CD20 available for review, 14 (2.8%) had LP cells with absent CD20 expression. Patients with prior rituximab administration (n = 7) and insufficient clinical history (n = 1) were excluded, leaving 6 patients with rituximab-naive, CD20-negative NLPHL. A broad immunohistochemical panel showed the LP cells in all cases expressed B-cell antigens, particularly Oct-2, although PAX5 and CD79a were frequently also dim. CD30, CD15, and Epstein-Barr virus-encoded small RNAs were negative in all evaluated cases. Two patients had high-risk variant immunoarchitectural pattern D. One patient had extranodal disease, involving the spleen and bone, and was suspected to have large cell transformation. Standard NLPHL therapy was given, including local radiation and/or chemotherapy. Of 5 patients with available follow-up, 4 are alive in complete remission after therapy, and 1 is alive with relapsed disease. Conclusions.--NLPHL can lack CD20 de novo without prior rituximab therapy. In such cases, extensive immunophenotyping helps distinguish NLPHL from lymphocyterich classic Hodgkin lymphoma, which differ in clinical behavior and therapy. In our series, CD20-negative NLPHL showed both classic and variant histologic patterns and the expected range of clinical behavior seen in NLPHL, including 1 case with suspected large cell transformation. (Arch Pathol Lab Med. 2021;145:753-758; doi: 10.5858/arpa.2020-0135-OA
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