Small lymphocytic lymphoma

Small lymphocytic lymphoma and B-cell chronic lymphocytic leukemia are viewed as the same entity by the WHO classification. Although the major population of cells resembles small normal lymphocytes, larger cells resembling those seen in prolymphocytic leukemia are seen in the nodal tissue in areas known as proliferation centers (Figure 3 and Figures 2, 3 of Chapter 116). The small lymphocytic lymphomas are phenotypically identical to B-cell chronic lymphocytic leukemias but have fewer than 5000 circulating malignant B cells. They express HLA-DR, B-cell antigens CD19, CD20, CD23, weak surface immunoglobulin, and CD5. Cytogenetic abnormalities include trisomy 12 present in about 40% of cases, 13q in 45–55%, 11q abnormalities in 17–20%, and 17p abnormalities in 7–10% of cases. Cases with 13q deletions have the most favorable prognosis, whereas those with 11q or 17p abnormalities have an unfavorable prognosis.³¹

Recent studies suggest that 30–50% of these diseases have nonmutated immunoglobulin variable region genes and correspond to naïve B cells. These cases often express CD38 and the tyrosine kinase ZAP-70 and have a worse prognosis.³² The remaining 50–70% of cases have mutated immunoglobulin variable region genes, are derived from germinal center or postgerminal center B cells,³³ and have a favorable prognosis.³⁴ Deep sequencing studies of chronic lymphocytic leukemia have revealed a number of recurrent mutations, including NOTCH1, MYD88, and SF3B1 genes.³⁵

Small lymphocytic lymphomas makes up about 6% of all NHLs.²⁵ The clinical presentation is similar to FL. Unlike B-cell chronic lymphocytic leukemia, the peripheral blood may be normal or reveal only a mild lymphocytosis although the bone marrow is positive in 70–90% of cases. A serum paraprotein is found in about 20% of cases and hypogammaglobulinemia is present in about 40%. Small lymphocytic lymphomas and B-cell chronic lymphocytic leukemia can convert to DLBCL or less commonly HL (Richter syndrome, Figure 4).³⁶

Lymphoplasmacytic lymphoma

Lymphoplasmacytic lymphoma is an indolent lymphoma composed of diffuse proliferation of small lymphocytes with evidence of maturation to plasma cells.³⁷ Evidence of immunoglobulin is seen in these cells by special stains or inclusions. These tumors express B-cell antigens, CD19 and CD20, and surface immunoglobulin M isotype, and in general do not express CD5, CD10, or CD23. Deletions of 6q21 have been identified in 40–60% of patients with lymphoplasmacytic lymphoma and the syndrome associated with this is known as Waldenström’s macroglobulinemia. Activating mutations in MYD88, a protein involved in signaling pathways downstream of the Ig receptor, are present in close to 100% of cases.³⁸

Lymphoplasmacytic lymphoma represents about 1% of all NHLs. Clinically, this disease is similar to small lymphocytic lymphomas. The median age is early 60s, and virtually all patients have stage IV disease by virtue of bone marrow involvement, and lymph nodes and spleen are commonly involved. B symptoms and elevated serum LDH are rare. A serum M component is common. As with B-CLL, the paraprotein may have autoantibody or cryoglobulin activity. However, most cases with mixed cryoglobulinemia have been shown to be related to concurrent hepatitis C virus (HCV) infection³⁹ and may respond to therapy directed at hepatitis C. In the WHO clinical study, 5-year overall survival (OS) (58%) and failure-free survival (25%) were identical to that of small lymphocytic lymphomas.

Mantle cell lymphoma

MCL is generally an aggressive disease.^{50, 51} The neoplastic cells are counterparts of naive “mantle zone” B cells and are medium sized with irregular nuclei. The disease may have either diffuse architecture or a vaguely nodular appearance. Some cases of MCL have a predominance of “blastoid” cells with a high mitotic rate. The cells express B-cell antigens, surface immunoglobulin M with or without immunoglobulin D, CD5, and CD43, but lack CD10 and CD23, respectively, and overexpression of cyclin D1. Approximately 70% of MCLs have t(11;14)(q13;q32) that creates rearrangements of the bcl-1 (cyclin D1) gene. Eight percent of MCL cases are cyclin D1-negative and overexpress cyclin D2 and 4 or cyclin D3, without chromosomal rearrangements⁵² and are clinically similar to cyclin D1-positive cases.⁵³ Deep sequencing⁵⁴ has identified NOTCH1 mutations in a minority of cases, which may be associated with poor prognosis. SOX11 overexpression is also associated with a worse prognosis.^{52, 55}

MCL constitutes about 7% of all NHLs. About 75% of patients are males, with median age of 63. Approximately 70% of patients have stage IV disease, and B symptoms are observed in approximately one-third of patients. Typical sites of involvement are lymph nodes, spleen, liver, Waldeyer’s ring, and bone marrow. Peripheral blood involvement is present in 25–50% of patients at presentation. MCL can involve any region of the gastrointestinal tract, occasionally presenting as multiple intestinal polyposis. The median survival of patients with MCL is 3–6 years and patients with the blastic variant at diagnosis have a median survival of 18 months. Blastic transformation occurs in 35% of patients, with a risk of 42% at 4 years; the median survival is 3.8 months.⁵⁶ Mutations and deletions of p53 are also associated with a worse prognosis.⁵⁷

Diffuse large B-cell lymphoma

DLBCL consists of a diffuse proliferation of large cells with a high mitotic rate. The cells have a moderate amount of cytoplasm with either cleaved or noncleaved nuclei often with multiple nucleoli, although there can be great variability in the morphology (Figure 4). DLBCL represents many distinct disease entities.²² (Table 2) Gene expression profiling has been applied to DLBCL.^58–61 These studies subdivided DLBCL into distinct genetic entities. DLBCLs correspond to germinal center B cells or activated B cells. The tumor cells generally express B-cell antigens (CD19 and CD20), monoclonal surface immunoglobulin M, and occasionally other heavy chain isotypes. CD5-positive cases are uncommon and may have a worse prognosis.⁶² CD10 and bcl-6 support a germinal center origin, whereas expression of MUM1 supports a nongerminal center origin. Approximately 70% express bcl-6 protein, consistent with a germinal center origin.⁶³

Several chromosomal abnormalities have been observed in DLBCL. Bcl-6 is associated with chromosomal rearrangements involving 3q27.⁶⁴ Rearrangements of the gene occurs in 20–40% of diffuse aggressive lymphomas. t(14;18) has been observed in approximately 30% of patients with DLBCL. Some of these cases may represent histologic transformations of prior FL. By gene expression profile (GEP), the germinal center B-cell (GCB) type is often associated with the t(14;18) and amplifications of the REL oncogene on chromosome 2. In contrast, the activated B-cell (ABC) type is associated with loss of 6q21, trisomy 3, gains of 3q and 18q21–22, and mutations of EZH2.^{65, 66} ABC cases also have high-level activation of NF-κB.⁶⁷ MYC is rearranged in 10% of DLBCLs, with the partner gene being one of the Ig genes in 60% of cases and alternative genes in 40% of cases. Approximately 20% of MYC-rearranged cases have concurrent BCL2 or BCL6 rearrangements, a combination referred to as “double-hit lymphoma.”⁶⁸ Amplification and/or overexpression of MYC independent of rearrangements or amplification has also been described and is also associated with a poor prognosis.^{69, 70}

DLBCL constitutes 31% of all NHLs and is the most common histologic subtype. Patients who are generally middle-aged or older (median age 64 years) present with either nodal enlargement or extranodal disease. DLBCL presents in a localized (stage I or IE) manner approximately 20% of the time and 30–40% of patients will have I or II disease. Stage IV disease is seen in approximately 40% of patients. B symptoms occur in 30% of patients, and unlike most NHLs, LDH is elevated in over half the patients. During the course of the disease, the liver, the kidneys, the lung, the bone, and the peripheral nerves may be involved. Bone marrow involvement is initially found in 10–20% of patients. Extranodal diseases, specifically testicular, bone marrow, paranasal sinus, multiple extranodal sites, and elevated LDH, are other risks for CNS dissemination.⁷¹ Rare cases of DLBCL present with a disseminated intravascular proliferation of large lymphoid cells, involving small blood vessels, without an obvious tumor mass^72–74 most commonly involving the CNS, kidneys, lungs, and skin.

Within the DLBCL group is a distinct clinical entity known as primary mediastinal large B-cell lymphoma (PMLBCL) (7% of all cases of DLBCL).⁷⁵ Histologically, the cellular infiltrate is heterogeneous, and sclerosis is frequently present. The immunophenotype includes B-cell antigens (CD19, CD20), but they are often negative for surface and cytoplasmic immunoglobulin. GEP suggests that this is a distinct entity from germinal center or ABC types of DLBCL. Recent studies suggest that the GEP pattern of PMLBCL closely resembles the Reed–Sternberg cells of HL.^{76, 77} Copy number gains in the region on chromosome 9p containing the genes for JAK2 and programmed cell death ligand 1 and 2 (PDL1 and PDL2) and ligands for the programmed cell death receptor-1 (PD-1), which has a role in suppressing T-cell function, are common.⁶⁵ PMLBCL resembles classical HD by GEP.⁷⁶ PMLBCL has a female predominance, with a median age of 40. Over 70% of these patients present with stage I/II bulky disease involving the mediastinum. Pleural and pericardial effusions are seen in about one-third of patients. Superior vena cava syndrome is common. Similar to DLBCL, an elevated LDH is present in the majority, whereas bone marrow involvement is infrequent. The prognosis of patients with PMLBCL is similar to patients with DLBCL.

Peripheral T-cell lymphomas

Peripheral T-cell lymphomas (PTCLs) include a large number of entities that constitute 15% of all NHLs in adults.⁷⁸ Among these, in decreasing frequency, are PTCL, not otherwise unspecified (NOS); ALCL; angioimmunoblastic T-cell lymphoma (AITL), extranodal NK/T-cell lymphoma, nasal type; and much rarer entities, panniculitis-like T-cell lymphoma, enteropathy-type T-cell lymphoma, and hepatosplenic γ/δ T-cell lymphoma.

PTCLs can be nodal- or extranodal-based diseases. The diffuse cellular infiltrates range from a mixture of small and large cells; infiltrates of pleomorphic cells, often with a background of epithelioid histiocytes, plasma cells, eosinophils, and Reed–Sternberg-like cells; or predominantly large cells. In contrast to B-cell lymphomas, the pattern of expression of T-cell surface antigens is highly variable. The majority express CD2, CD3, and CD4, with a subset of expressing CD8.⁷⁹ In most cases, one or more “mature” T-cell antigens, such as CD5 or CD7, are lost. Many cases of PTCL express EBV, especially the extranodal NK/T-cell lymphomas, nasal type.⁸⁰ EBV positivity is associated with a poor prognosis.

Abnormal metaphases are seen in 90% of T-cell lymphomas. The most commonly seen translocations in PTCLs are t(7;14), t(11;14), inv(14), and t(14;14). AITL is associated with trisomy 3 and/or 5.⁸¹ These translocations involve genes for the TCR at 14q11, 7q34–35, and 7p15. Young patients with ALCL have t(2;5) and less commonly t(1;2).⁸² ALCL in adults generally lack t(2;5). Hepatosplenic γ/δ T-cell lymphomas are associated with isochromosome 7q and trisomy 8.⁸³

Patients with PTCL have a similar median age as patients with DLBCL. In contrast, 80% of patients with PTCL have stage III/IV disease and more frequently have B symptoms, hepatosplenomegaly, and extranodal disease, such as the skin. PTCL generally has a worse prognosis than DLBCL.^{84, 85} A number of uncommon subtypes of PTCL have unique histologic features. AITL, in addition to a pleomorphic heterogeneous cellular infiltrate, displays increased amounts of high endothelial venules, giving a hypervascular appearance. In this subtype, Ig heavy chains may be rearranged in 10% cases, and EBV genomes are detected in most cases and may be in either T or B cells.⁸⁶ AITL typically affects older adults who present with the acute onset of generalized lymphadenopathy, hepatosplenomegaly, skin rash, and B symptoms.⁸⁶ Immunologic abnormalities are common and include plasmacytosis, polyclonal hypergammaglobulinemia, and a positive Coombs test. The median survival is 30 months. Infection is the most common cause of death, followed by the T-cell lymphoma or development of EBV-positive DLBCL.

ALCL is a T-cell NHL that can present as primary systemic ALCL, ALK-positive; primary systemic ALCL, ALK-negative; and primary cutaneous ALCL. When involving nodes, ALCL characteristically fills the sinusoids of lymph nodes with bizarre large cells. Neoplastic cells derived from patients with ALCL also generally express the phenotype of mature activated T cells (HLA-DR, CD30, CD25). The ALK protein is detected in 40–60% of cases using the ALK1 monoclonal antibody, showing both nuclear and cytoplasmic stainings in cases with the t(2;5).⁸⁷ The resulting fusion gene encodes a chimeric NPM-ALK fusion protein with constitutive tyrosine kinase activity. ALK-positive cases are more common in children and younger adults and have a better prognosis than ALK-negative cases.⁸⁸

ALCL constitutes 2% of all NHLs in adults, but is the second most common T-cell lymphoma. The median age of patients with ALCL is 34 with a male predominance. There is a bimodal distribution of this disease, with peaks in childhood, young adults, and late adulthood. In adults, B symptoms, peripheral adenopathy, and retroperitoneal adenopathy are common. Skin is a frequent site of extranodal disease (about 25% of patients), whereas bone marrow involvement is uncommon. An unusual form of ALCL arises within the breast associated with breast implants.⁸⁹ The prognosis of adult patients with systemic ALK-positive ALCL is similar to patients with DLBCL.⁹⁰ When ALCL, PTCL NOS, and AITL are compared, ALCL has the highest OS, whereas AITL had the lowest.⁹¹

Precursor T- or B-lymphoblastic leukemia/lymphoma

LBL and acute lymphoblastic leukemia ALL (see Chapter 116) represent two presentations of the same disease with LBL defined as having <25% bone marrow involvement. The neoplastic cells have a high nuclear to cytoplasmic ratio, scant cytoplasm, and nuclei with fine chromatin with multiple small nucleoli and have a high mitotic rate. The nuclei can have folds or convolutions. Typically, nodes involved with LBL are effaced by malignant cells (Figure 5).

The vast majority of LBLs are of T-cell lineage. Several investigators have noted that most T-cell LBLs correspond to stages of thymocyte differentiation (see Chapter 116).

Although LBLs represent a major subgroup of childhood NHLs, they are unusual in adults (2% of adult NHLs). Patients are usually males in their 20s or 30s, who present with lymphadenopathy in cervical, supraclavicular, and axillary regions (50%) or with a mediastinal mass (50–75%). This entity may be associated with superior vena cava syndrome, tracheal obstruction, and pericardial effusions. Less commonly, patients present with extranodal disease (e.g., skin, testicular, or bony involvement). More than 80% of patients present with advanced stage disease, almost 50% have B symptoms, and the majority have elevated LDH. Although the bone marrow is frequently normal at presentation, virtually all patients develop bone marrow infiltration and a subsequent leukemic phase. Patients with bone marrow involvement have a very high incidence of CNS infiltration. B-cell LBL is a very rare variant, affecting patients with a median age of 39.⁹⁵ B-cell LBL presents without a mediastinal mass but instead involves lymph nodes and extranodal sites.

Burkitt’s lymphoma

BL cells resemble the small noncleaved cells within normal germinal centers of secondary lymphoid follicles. Because of the high mitotic rate, frequent mitotic figures are seen and, analogous to normal germinal centers, tingible body macrophages are seen, giving the classical “starry sky” appearance. It is generally agreed that the fraction of Ki-67 (proliferating cells) in BL should be 99% or greater.²²

BL is a tumor of B-lineage derivation identified by the expression of a variety of B-cell-restricted antigens including CD19, CD20, surface immunoglobulin M, CD10, and nuclear bcl-6 protein.⁹⁶ The endemic BL is EBV positive, whereas the vast majority of nonendemic BL is EBV negative. BL cells lack bcl-2 protein.

BL involves a translocation of chromosome 8q24 in over 95% of the cases with chromosome 14, 2, or 22.²² Pathologically identified Burkitt or histologically atypical Burkitt has a GEP that is associated with overexpression of myc target genes, differential expression of normal germinal center genes, and decreased expression of MHC class I and NF-κB target genes. These studies will help refine the histologic diagnosis of difficult to classify cases.^{92, 97, 98}

BL, in general, is a pediatric tumor that has three major clinical presentations. The endemic (African) form presents as a jaw or facial bone tumor that spreads to extranodal sites including ovary, testis, kidney, breast, and especially to the bone marrow and meninges. The nonendemic form has an abdominal presentation with massive disease, ascites, renal, testis, and ovarian involvement and, like the endemic form, also spreads to the bone marrow and CNS. Immunodeficiency-related cases more often involve lymph nodes and peripheral blood. BL has a male predominance and is typically seen in patients <35 years of age. These tumors have a high propensity to invade the bone marrow and CNS.

Adult T-cell leukemia/lymphoma

ATLL is a rare disease associated with infection by the HTLV-1 in 100% of cases.^99–101 ATLL is endemic in southern Japan, the Caribbean basin, Africa, and the southeastern United States. The normal counterparts of the neoplastic cells are activated CD4+ T cells expressing CD2, CD3, CD5, and CD25. The median age of patients is 60.¹⁰² The disease can present as four variants: acute (most common and highly aggressive), lymphomatous, chronic, and smoldering. The median survival of these variants is 6, 10, 24 months, and “not reached,” respectively.¹⁰³ Patients present with BM and peripheral blood involvement, high white blood cell count, hypercalcemia (owing to PTH-related protein, TGF-β, and RANK ligand), lytic bone lesions, lymphadenopathy, hepatosplenomegaly, skin lesions, and interstitial pulmonary infiltrates.

Aggressive NHLs

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