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ChaPTEr 79 Lymphomas 1067

the diagnosis and management of lesions at the very early stages which occasionally can manifest plasmacytoid differentiation.
of lymphomagenesis, refining diagnostic criteria for some entities, Many but not all patients with LPL may have clinical evidence
and detailing the expanding genetic/molecular landscape of of Waldenström macroglobulinemia (WM), which is based on
numerous lymphoid neoplasms and their clinical correlates. 3 the detection of an IgM monoclonal gammopathy of any con-
This chapter focuses on the classification of neoplasms derived centration and is associated with bone marrow involvement by
from mature B cells, T cells, and natural killer (NK) cells, with LPL (Chapter 80).
emphasis on malignant lymphomas. Other chapters in this volume In LPL, cells have surface and cytoplasmic Ig, usually IgM
cover lymphoid leukemias (Chapter 78) and immunosecretory (and usually lacking IgD), and express B cell–associated antigens
disorders, including plasma cell neoplasms (Chapter 80). Special (CD19, CD20, CD22, CD79a). They are generally negative for
attention is devoted to the impact of clinical features (e.g., age CD5 and cyclinD1, distinguishing LPL from CLL and MCL,
and anatomical site) on disease definition and a greater apprecia- respectively. CD25, CD10, or CD11c may be weakly expressed
tion of early events in neoplastic transformation. These early in some cases. The postulated normal counterpart is thought to
lesions can sometimes be detected in otherwise healthy individuals, be a postfollicular medullary cord B cell, based, in part, on the
and these lesions may or may not progress to overt lymphoma presence of somatic mutations in the Ig heavy-chain and light-
or leukemia. These entities appear to carry fewer genetic aber- chain variable region genes.
rations compared with the conventional forms of the disease, The recent identification of MYD88 L265P mutation (found
which perhaps explains their indolent clinical behavior. 4 in approximately 90% of WM cases) has become a reliable marker
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supporting a diagnosis of LPL. This mutation is also found in
a significant proportion of IgM, but not IgG or IgA, monoclonal
gammopathy of undermined significance (MGUS) cases.
CLINICaL PEarLS
Indolent Lymphomas Mantle-Cell Lymphoma
MCL usually presents in adults (median age 62; variable male
• Natural history: survival measured in years predominance) with advanced-stage disease—involving lymph
• Least sensitive to therapy nodes, Waldeyer ring lymphoid tissue, spleen, bone marrow, and
• Good response to low-dose oral alkylating agents, radiotherapy, and
steroids, but no curability peripheral blood. Gastrointestinal (GI) tract involvement is
• Higher response rate and complete remission with combination of common and is associated with a lymphomatous polyposis picture.
standard chemotherapy and anti-CD20 monoclonal antibody Retrospective studies have shown a poor prognosis (median
• Gene expression profiling can help identify patients who might benefit survival 3–5 years), with a high relapse rate following initial
from high-dose chemotherapy and autologous stem-cell transplantation, remission. MCL is composed of small lymphoid cells with slightly
which is a potentially curative modality
irregular nuclear contours, finely clumped chromatin, and scant
cytoplasm. Specifically, blastoid and pleomorphic variants have
been associated with a more aggressive clinical course. The
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+
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MATURE B-CELL NEOPLASMS postulated normal counterpart is a CD5 “naïve” sIgM and sIgD
B cell, found in peripheral blood and in the mantles of reactive
KEY CONCEPTS follicles.
MCL is characterized by a molecular hallmark, t(11;14)
Somatic Mutation in Relation to Normal (q13;q32)—involving cyclin D1 (CCND1) and the IGH genes;
B-Cell Development an overexpression of CCND1 is believed to be essential in the
+
• Premutational stage: circulating naïve B cells (immunoglobulin (Ig)M / pathogenesis. Rare variants negative for CCND1 but with similar
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+
D ) before antigen exposure immunomorphology and GEP have also been identified. Half
• Stage of somatic mutation, clonal expansion, and isotype switch: at of the CCND1 expression/rearrangement-negative forms have
the germinal center CCND2 translocations, often with IGK or IGL as a partner
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• Postmutational stage: selected B cells move to the periphery (post– locus, which could be of diagnostic utility. SOX11 is overex-
germinal center) or to the recirculating pool (memory B cells), or pressed in most CCND1-positive and CCND1-negative cases.
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undergo terminal differentiation (plasma cells)
Besides the CCND1/IGH translocation, additional alterations
involving other cell cycle regulatory proteins (RB, p53, CDK
inhibitors) have been described in the more aggressive forms
Lymphoplasmacytic Lymphoma of MCL.
Lymphoplasmacytic lymphoma (LPL) is a disease of adult life In-situ mantle cell neoplasia (ISMCN) (according to new
(median age in the 60s), usually presenting with generalized 2016 classification; previously “in-situ” MCL) describes clonal
lymphadenopathy, constitutional symptoms, and splenomegaly. proliferation of cyclin D1-positive cells restricted to the inner
Histologically, there is a diffuse interfollicular proliferation mantle cuffs in an otherwise reactive lymph node/lymphoid
of small lymphocytes (many with plasmacytoid features) and tissue and usually represents an incidental finding. Some cases
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plasma cells, with or without immunoglobulin (Ig)–filled will eventually progress to overt MCL ; however, the risk of
intranuclear inclusions (Dutcher bodies) and sparing of the progression is difficult to ascertain, as the number of reported
sinuses. An increased number of mast cells and iron-laden cases is few. Another newly identified nonnodal variant is
macrophages can be seen. Although many B-cell neoplasms characterized by a leukemic phase without nodal disease but
occasionally show maturation to plasmacytoid or plasma cells often long-standing splenomegaly. These cases develop from
with cytoplasmic Ig, the term LPL should be restricted to tumors IgHV-mutated SOX11-negative B cells, carry t(11;14) with few
lacking features of other well-defined entities, such as chronic additional chromosomal abnormalities but lack expression
lymphocytic leukemia (CLL) or mantle-cell lymphoma (MCL), of SOX11. 9