Matthew T. Howard

Follicular Lymphoma of the Spleen Multiparameter Analysis of 16 Cases

Follicular lymphoma (FL) involving the spleen must be distinguished from reactive hyperplasia and from other lymphomas. A prior study reported that splenic FLs frequently lack BCL2 expression, further complicating diagnosis. We examined 16 cases of splenic FL, including 12 cases initially diagnosed at splenectomy. Two morphologic patterns were identified: one with architectural abnormalities (AA) and one with an extensive architectural preservation (AP) pattern. Newly diagnosed AP cases were associated with older age (P = .051) and grade 1 histologic features (P = .023). All cases displayed a CD10+/BCL2+ phenotype. Cytogenetics and FISH identified IGH/BCL2 or BCL6 translocations in all tested cases. Splenic FLs display phenotypic and cytogenetic findings similar to nodal FLs. However, splenic FLs frequently display an exclusively intrafollicular growth pattern resembling so-called in situ FL. Recognition of subtle FL with preserved architecture is important because patients may have overt FL at other sites or the FL may progress to overt nodal disease.

Spectrum of myeloid neoplasms and immune deficiency associated with germline GATA2 mutations

Guanine‐adenine‐thymine‐adenine 2 (GATA2) mutated disorders include the recently described MonoMAC syndrome (Monocytopenia and Mycobacterium avium complex infections), DCML (dendritic cell, monocyte, and lymphocyte deficiency), familial MDS/AML (myelodysplastic syndrome/acute myeloid leukemia) (myeloid neoplasms), congenital neutropenia, congenital lymphedema (Embergers syndrome), sensorineural deafness, viral warts, and a spectrum of aggressive infections seen across all age groups. While considerable efforts have been made to identify the mutations that characterize this disorder, pathogenesis remains a work in progress with less than 100 patients described in current literature. Varying clinical presentations offer diagnostic challenges. Allogeneic stem cell transplant remains the treatment of choice. Morbidity, mortality, and social costs due to the familial nature of the disease are considerable. We describe our experience with the disorder in three affected families and a comprehensive review of current literature.

IgM multiple myeloma: pathologic evaluation of a rare entity.

OBJECTIVES To delineate the pathology of immunoglobulin M-producing multiple myeloma (IgM MM). METHODS Clinicopathologic data were reviewed for 15 cases meeting World Health Organization criteria for MM and having a serum IgM paraprotein. Immunohistochemistry was performed on diagnostic bone marrow specimens for common B-cell and plasma cell markers. RESULTS Of the 15 IgM MM bone marrows reviewed, 6 (40%) had lymphoplasmacytoid cytology, and 12 (80%) expressed CD19, CD20, and/or CD45. Cyclin D1 expression was common (11 cases, 73%) and usually associated with t(11;14). No cases expressed CD5 or had an associated CD5-positive B-cell population. CD117 was positive in 20% of cases. CONCLUSIONS The frequent B-cell-associated antigen expression by IgM MM distinguishes it from other MM types, causing significant pathologic overlap with lymphoplasmacytic lymphoma (LPL). However, IgM MM is usually distinguished from LPL by aberrant cyclin D1 expression or t(11;14). Therefore, assessing for these abnormalities is recommended when evaluating bone marrow involvement by IgM-associated lymphoplasmacytoid disorders.

Immunophenotypic features by multiparameter flow cytometry can help distinguish low grade B‐cell lymphomas with plasmacytic differentiation from plasma cell proliferative disorders with an unrelated clonal B‐cell process

Highly sensitive flow cytometry studies may incidentally identify B cell clones when used to assess plasma cell clonality in bone marrows. Clinical history, which can help differentiate related clones (low grade B cell lymphoma with plasmacytic differentiation/LBCL‐PD) from unrelated ones (plasma cell proliferative disorder (PCPD) with an unrelated B cell clone), is often unavailable in referred specimens. We sought to identify morphologic or phenotypic features that would help predict the significance of these clones in the absence of history. We included only cases with identical light chain B and plasma cell clones, as determined by 6‐color flow cytometry with additional DNA ploidy analysis, in which the relationship between clones could be established by review of medical records. There were 26 cases; 18 were related (14 were Waldenstrom macroglobulinemia) and eight were unrelated (seven multiple myeloma). Features seen exclusively in LBCL‐PD include CD19+/CD45+ clonal plasma cell phenotype (66·7%, P = 0·0022) and morphologic features such as paratrabecular bone marrow involvement, increased mast cells, and plasma cells surrounding B‐cell nodules. Aneuploidy was identified exclusively in PCPD cases (75%, P = 0·000028). We conclude that CD19+/CD45+ clonal plasma cell phenotype and aneuploidy are useful in distinguishing related clones (LBCL‐PD) from unrelated clones (PCPD).

Immunohistochemical phenotyping of plasma cells in lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia is comparable to flow cytometric techniques.

Lymphoplasmacytic lymphoma/Waldenströms macroglobulinemia (LPL/WM) can be difficult to distinguish from primary plasma cell neoplasms in bone marrow biopsies. Plasma cell immunophenotyping by flow cytometry can aid in this distinction as by this technique the plasma cells of LPL/WM express both CD19 and CD45 whereas primary plasma cell neoplasms are CD19 or CD45 negative. As immunophenotyping by flow cytometry has limitations, the comparative ability of immunohistochemistry to determine the plasma cell phenotype in WM/LPL was examined. The results indicate that immunohistochemistry yields results comparable to flow cytometry, and suggests that using both modalities in parallel compensates for the shortcomings of each.

Hodgkin lymphoma: pathology, pathogenesis, and a plethora of potential prognostic predictors.

Hodgkin lymphoma (HL) encompasses 2 unique clinicopathologic entities, classical Hodgkin lymphoma (CHL) (∼95% of cases) and nodular lymphocyte predominant HL (∼5% of cases). Both subtypes demonstrate a paucity of surreptitious (in CHL) neoplastic B cells within a background of reactive inflammatory cells underscoring both the relatedness of these 2 entities to each other, as well as their distinction from other types of lymphoid neoplasia. Clinically, they are primarily nodal diseases that disseminate in a predictable manner to contiguous nodal regions. The biology of HL as a whole, as well as the genetic and pathologic features that distinguish CHL from nodular lymphocyte predominant HL and other lymphomas has been the subject of a wealth of investigation in recent decades. The aim of this review is to detail the pathologic features of HL and to highlight the recent insights into its molecular basis and the myriad prognostic markers being described.

Lymphoplasmacytic Lymphoma With a Non-IgM Paraprotein Shows Clinical and Pathologic Heterogeneity and May Harbor MYD88 L265P Mutations

OBJECTIVES Lymphoplasmacytic lymphoma (LPL) with non-immunoglobulin M (IgM) paraproteinemia remains poorly understood. The goal of this study was to investigate the clinicopathologic features of LPL in the bone marrow in patients with immunoglobulin G (IgG) or immunoglobulin A (IgA) paraproteins and evaluate MYD88 L265P mutation status to determine the relationship of these cases to Waldenström macroglobulinemia (WM). METHODS Bone marrows from LPL cases with IgG or IgA paraproteins diagnosed between January 1, 2007, and June 30, 2014, were retrieved from the clinical archive. Clinicopathologic features were retrospectively reviewed. MYD88 L265P mutation status was assessed by allele-specific polymerase chain reaction prospectively on all cases. RESULTS Of 27 cases, four were reclassified as multiple myeloma, all MYD88 mutation negative. MYD88 L265P mutations were present in 10 (43%) of 23 remaining cases. No association between MYD88 status and bone marrow morphologic or phenotypic features, including the presence of Dutcher bodies, mast cells, expression of CD19 by plasma cells, or hemosiderin, was identified, although these features were present in a subset of cases, similar to WM. Clinical features of WM such as hyperviscosity were uncommon in this group and did not correlate with MYD88 status. CONCLUSIONS Non-IgM LPLs are a clinically and pathologically heterogeneous group and often harbor MYD88 L265P mutation, albeit at a lower rate than classic WM. MYD88 status does not correlate with any specific pathologic or clinical manifestations.

Morphologically occult systemic mastocytosis in bone marrow: clinicopathologic features and an algorithmic approach to diagnosis.

OBJECTIVES Bone marrow (BM) biopsy specimens involved by systemic mastocytosis (SM) typically show multifocal, compact, dense aggregates of spindled mast cells (MCs). However, some cases lack aggregate formation and fulfill the World Health Organization 2008 criteria for SM, based on minor criteria. METHODS We identified 26 BM cases of KIT D816V-mutated, morphologically occult SM in the BM. RESULTS All patients had some combination of allergic/MC activating symptoms. Peripheral blood counts were generally normal. BM aspirates showed 5% or less MCs, which were only occasionally spindled. BM biopsy specimens showed no morphologic classic MC lesions. Tryptase immunohistochemistry (IHC) demonstrated interstitial, individually distributed MCs (up to 5%) with prominent spindling, lacking aggregate formation. MCs coexpressed CD25 by IHC and/or flow cytometry. Spindled MCs constituted more than 25% of total MCs in all cases and more than 50% in 20 of 26 cases. CONCLUSIONS Morphologically occult involvement of normal-appearing BM by SM will be missed without appropriate clinical suspicion and pathologic evaluation by tryptase and CD25 IHC and KIT D816V mutation analysis. On the basis of these findings, we propose a cost-effective, data-driven, evidence-based algorithmic approach to the workup of these cases.

Broadening the Morphologic Spectrum of Bartonella henselae Lymphadenitis: Analysis of 100 Molecularly Characterized Cases.

Bartonella henselae lymphadenitis, or cat-scratch lymphadenitis (CSL), is classically associated with stellate microabscesses, occasional giant cells, and extension of the inflammatory infiltrate into perinodal soft tissue. Availability of B. henselae molecular testing on tissue specimens has broadened our understanding of the morphologic variation in this disease. Here we sought to describe the histopathologic features of the largest series to date of molecularly proven CSL. B. henselae polymerase chain reaction–positive tissue specimens from 2010 to 2012 were identified, and hematoxylin and eosin slides were reviewed. A single-step 16S-23S rRNA–based polymerase chain reaction testing was used to identify B. henselae on formalin-fixed, paraffin-embedded tissues. A total of 100 B. henselae–positive cases were identified. The median age of the patients was 26.5 years (range, 1 to 69 y). Ninety-two percent of cases presented in lymph nodes, with 66% of these occurring above the diaphragm, most commonly in the cervical chain. Of 100 cases, 57 had classical CSL features of necrotizing granulomas with microabscesses, with or without surrounding palisading histiocytes. In contrast, 43/100 cases lacked the prototypical microabscesses of CSL including: 23 cases (53.5%) with features of fungal/mycobacterial lymphadenitis, 6 (14%) cases with features of Kikuchi lymphadenitis, and 4 cases (9.3%) with the classic histologic triad of toxoplasma lymphadenitis. In summary, B. henselae lymphadenitis may lack the typical microabscesses in almost half of cases and may closely mimic other reactive, especially infectious, lymphadenopathies. Given the lack of specificity of many of these features, a low threshold for B. henselae molecular testing on tissue is warranted in the appropriate clinical context.

A Novel ELANE Mutation Associated with Inflammatory Arthritis, Defective NETosis, and Recurrent Parvoviral Infection

We describe a 38‐year‐old woman who presented with a history of inflammatory arthritis, rash, and daily fevers. She was noted to have chronic parvovirus infection with persistently detectable viral titers and a novel mutation in the ELANE gene. ELANE encodes neutrophil elastase, a neutrophil serine protease with important antimicrobial effects, and is found as part of neutrophil extracellular trap (NET) complexes. Pathogenic ELANE mutations have been identified in forms of hereditary neutropenia. However, our patient never had neutropenia. Because of the striking clinical scenario, we investigated this mutation functionally.