Lymphoma and related disorders

B-cell non-hodgkin lymphoma

The most common B-cell lymphoma subtypes include lymphoblastic, CLL/SLL, follicular, mantle, marginal, and diffuse large cell types ( Table 14.3 ). It is worth noting that nearly all these subtypes represent malignancies corresponding to distinct stages of normal B-cell maturation. For example, lymphoblastic lymphoma derives from precursor B lymphoblasts, SLL from naïve B cells, FL from germinal center (GC) B cells, MCL cells from pre-GC mantle zone B cells, and marginal cell lymphoma from post-GC marginal zone B cells ( Fig. 14.4 ). Also, the growth pattern of these lymphomas often recapitulates the microanatomic distribution of their normal counterparts, such as the follicular pattern of FL, the mantle zone pattern of MCL, and the marginal zone pattern of marginal zone lymphoma (MZL) .

B lymphoblastic lymphoma is an uncommon high-grade neoplasm of young, often male, adults who present with rapidly growing tumors of lymph nodes, skin, or bone. The tumor cells are precursor B cells (lymphoblasts) that express the B cell–specific membrane protein CD19 and the lymphoblast-specific intranuclear enzyme terminal deoxynucleotidyl transferase (TdT). Although the immature cells typically do not express surface Ig, in some cases, they may express cytoplasmic mu heavy chain, a finding characteristic of late-stage precursor B cells. Many features of this disease are shared with that of B lymphoblastic leukemia, so much so that the most widely used disease classification scheme combines these two diseases together as B lymphoblastic leukemia/lymphoma . However, in contrast to B lymphoblastic lymphoma, B lymphoblastic leukemia is a relatively common disease of young children who present with signs of bone marrow failure (i.e., anemia, neutropenia, thrombocytopenia, or a combination of these) along with bone pain and arthralgia. Somewhat surprisingly, the two most common cytogenetic abnormalities detected in B lymphoblastic leukemia/lymphoma, hyperdiploidy with more than 50 chromosomes per cell and translocation t(12;21) producing a TEL-AML1 fusion gene of uncertain function, are associated with a favorable prognosis. Other abnormalities including hypodiploidy, t(9;22) producing a BCR-ABL fusion gene with tyrosine kinase activity and t(1;19) producing an E2A-PBX1 fusion gene that may block cell differentiation are all associated with an unfavorable prognosis. More than 80% of children with B lymphoblastic leukemia are cured with multiagent chemotherapy. The most favorable outcomes are seen in children between the ages of 4 and 10 years, with a less favorable prognosis in infants and adults.

Chronic lymphocytic leukemia/small lymphocytic lymphoma is a relatively common low-grade neoplasm of older adults (mean age, 65 years), with a male predominance (male-to female ratio, 2 to 1), which presents with either generalized lymphadenopathy (a lymphomatous [SLL] presentation) or peripheral blood lymphocytosis with marrow involvement (a leukemic [CLL] presentation). In either case, most patients are asymptomatic at presentation. Progressive involvement of the bone marrow may lead to fatigue caused by anemia, pyogenic skin infections caused by neutropenia, mucocutaneous bleeding caused by thrombocytopenia, or a combination of these. Autoantibody production may lead to autoimmune hemolytic anemia, autoimmune thrombocytopenia, or both. The small tumor cells are derived from CD5+ CD23+ B cells, often with autoreactive specificity. CD5+ B cells normally represent a very small subpopulation of B cells of uncertain function located primarily in the abdominal region. The most common cytogenetic abnormalities in CLL are in the 13q14 gene (50%), associated with indolent disease, and trisomy 12 (20%), associated with aggressive disease. The small lymphocytic infiltrate in SLL is diffuse, often with vaguely defined aggregates of larger cells called proliferation centers (or pseudofollicles) ( Fig. 14.5 ).

The immunophenotypic diagnosis of CLL/SLL (as well as many other lymphomas and leukemias) can be made by flow cytometry . In flow cytometry, single-cell suspensions prepared from fresh tissue are stained with fluorochrome-tagged antibodies specific for cellular antigens and run through a flow cytometry instrument. Although most antibodies are designed to detect cell surface antigens, intracellular antigens may also be detected in cells pretreated with permeabilizing agents. Within the instrument, the labeled single-cell suspension is focused into a narrow stream of fluid that allows only single cells to pass through one at a time (hydrodynamic focusing). The stream of cells passes through a tightly focused beam of laser light designed to stimulate fluorescence of cell-bound antibody. A set of electronic detectors instantaneously records the magnitude of the light signals emitted by each cell. These signals include the following:

• 1.

  Laser light that is deflected by the cell along the forward angle (180-degree) axis (forward scatter)

• 2.

  Laser light that is deflected by the cell along the side angle (90-degree) axis (side scatter)

• 3.

  Fluorescent light emitted by the fluorochrome-labeled antibodies bound to the cell

The magnitude of the forward scattered light is directly proportional to the size of the cell, whereas the magnitude of the side scattered light is directly proportional to the cytoplasmic granularity of the cell. After interrogation of approximately 10 ⁴ cells per sample, the data for all three parameters from each cell can be displayed as a dot plot. On the dot plot, each cell can be plotted as a point on a two (or more) dimensional Cartesian plot. Typically, the cells are first displayed on a forward scatter ( x -axis)-side scatter ( y -axis) dot plot. This plot allows for identification of clusters of cell types in a complex cell mixture. For example, in blood and marrow, this plot allows for identification of granulocyte, monocyte, and lymphocyte subpopulations (see Fig. 2.4 B). By electronically gating on a cell population of interest (e.g., lymphocytes), the fluorescent data for this population can be selectively displayed to determine the precise antigen expression pattern (immunophenotype) of the cells of interest. The number of antigens that can be simultaneously evaluated on each cell is limited only by the number of fluorescent detectors on the instrument and the number of available fluorochrome-labeled antibodies with nonoverlapping emission spectra. New-generation instruments allow for six or more antigens detected per cell. Using this approach, the detailed immunophenotype of lymphomas and leukemias can be determined. For example, in the case of CLL/SLL, flow cytometry easily demonstrates the unique co-expression of CD5 and CD19 on the tumor cells ( Fig. 14.6 ).

Chronic lymphocytic leukemia can be subclassified into two variants based on the presence or absence of somatic hypermutation of the Ig heavy chain locus. Under normal physiologic circumstances, naïve B cells with unmutated Ig genes encounter antigen within the GC and undergo somatic hypermutation of the Ig genes to generate functional high-affinity antibody. CLL cells with evidence of somatic hypermutation ( activated CLL) presumably derived from mature post-GC cells) are less clinically aggressive than cases without somatic hypermutation ( naïve CLL) presumably derived from immature pre-GC cells. These two CLL subtypes can be distinguished based on expression of two surrogate cell membrane proteins CD38 and zeta-associated protein (ZAP-70), with positive expression marking naïve CLL (with adverse prognosis). Morphologically, CLL cells are small and “mature,” with round nuclei containing irregularly clumped chromatin and indistinct nucleoli. The CD5+ B cells of the closely related (but more aggressive) neoplasm MCL, unlike CLL/SLL, typically do not coexpress the low-affinity IgE receptor protein CD23. With time, some of the small slow-growing CLL tumor cells may acquire additional new mutations that lead to transformation into either large cell lymphoma ( Richter transformation ) or prolymphocytic leukemia , both of which are rapidly progressive neoplasms.

Follicular lymphoma is a common, often low-grade disease of middle-aged adults who typically present with asymptomatic generalized lymphadenopathy. This disease is rare in childhood. The tumor cells are derived from CD10+ Bcl-6+ GC B cells, including a variable number of small centrocytes and large centroblasts. Centrocytes are small lymphocytes with irregular cleaved nuclei and indistinct nucleoli, and centroblasts are larger lymphocytes with non-cleaved nuclei and distinct nucleoli. Most FLs are low-grade tumors composed primarily of centrocytes (grades 1 and 2), but those composed primarily of larger centroblasts are high-grade 3 tumors. Lymph node involvement is marked by effacement (replacement) of normal architecture with abnormal, haphazardly arranged lymphoid follicles ( Fig. 14.7 ). Bone marrow involvement at presentation is common, with a highly characteristic paratrabecular pattern of involvement ( Fig. 14.8 ). FL cells carry the highly specific chromosome translocation t (14;18) involving the Ig heavy chain gene on chromosome 14 and the Bcl-2 gene on chromosome 18. Insertion of the antiapoptotic Bcl-2 gene into the highly active Ig region leads to markedly increased production of Bcl-2 protein, which inhibits apoptotic cell death. The increased Bcl-2 expression of FL is a powerful clue to the diagnosis because normal GC B cells do not express detectable amounts of Bcl-2 by immunohistochemistry ( Fig. 14.9 ). The immortalized centrocytes and centroblasts undergo slow but inexorable proliferation with progressive enlargement of affected lymph nodes. The course of the disease is indolent (5-year survival rate, >70%) but is incurable with chemotherapy alone. However, combination chemotherapy supplemented with monoclonal anti-CD20 antibody (rituximab) has led to long-term remission. In a significant minority of cases (25%–35%), further cytogenetic defects lead to progression to high-grade large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype in adults (also seen in childhood), is an aggressive high-grade disease that presents as a rapidly growing tumor of lymph nodes or extranodal sites. The median age of DLBCL is 64 years, with a nearly equal gender ratio. Common extranodal sites include the skin, bone, GI tract, and central nervous system (CNS). The tumor is composed of a diffuse infiltrate of large morphologically diverse lymphoid cells with numerous mitotic figures ( Fig. 14.10 ). The most common molecular defects in DLBCL are activating translocations of Bcl-6, Bcl-2, and c-Myc genes into the Ig heavy chain gene locus. Bcl-6 is a transcription factor that induces growth and differentiation of GC-derived B cells. Bcl-2 is an antiapoptotic protein. c-Myc is a transcription factor that promotes cyclin-mediated G0 to G1 cell cycle entry. Translocation of these genes into the highly active Ig heavy chain locus leads to excessive production of these three growth-promoting proteins. Two prognostic subtypes of diffuse large B-cell lymphoma, the GC type and the nongerminal (activated) type, are based on differential tumor cell expression patterns of three proteins: CD10, Bcl-6, and MUM1/IRF4. Whereas the GC type (CD10+, or Bcl-6+ and MUM1/IRF4−) is associated with a favorable prognosis, the non-GC B-cell type (CD10−, Bcl-6+/−, and MUM1/IRF4+/−) is associated with a poor prognosis. Although aggressive, some diffuse large B-cell lymphomas are curable with combination chemotherapy, often supplemented with anti-CD20 immunotherapy. In addition to the non-GC phenotype, poor prognostic factors for diffuse large B-cell lymphoma include advanced age (older than 60 years), high serum LDH (related to large tumor burden), low physical performance status, and advanced stage with more than one extranodal site of involvement.

Burkitt lymphoma is a high-grade B-cell lymphoma with features distinct from diffuse large B-cell lymphoma. Morphologically, Burkitt lymphoma is composed of medium-sized post-GC B cells with deeply basophilic cytoplasm containing numerous small lipid vacuoles. The mitotic rate is high and apoptosis is prominent, with numerous debris-laden macrophages giving a “starry sky” appearance ( Fig. 14.11 ). The tumor cells invariably contain one of three translocations— t(8;14) , t(2;8) , or t(8;22 ) —all involving the c-Myc gene on chromosome 8 and the Ig heavy chain, kappa light chain, or lambda light chain loci, all leading to c-Myc protein overexpression and continuous cell cycling. Burkitt lymphoma occurs sporadically throughout the world as well as specifically in two highly characteristic settings: in young children (often a jaw tumor) in malarial endemic regions of equatorial Africa and New Guinea ( endemic Burkitt lymphoma ) and in patients with immune deficiency (immunodeficiency-associated Burkitt lymphoma). In the developed world, Burkitt lymphoma typically presents in older children as an abdominal (ileocecal) mass, a disease referred to as sporadic Burkitt lymphoma . Two other differences between endemic and sporadic Burkitt lymphoma are as follows:

• 1.

  Epstein-Barr virus (EBV) positivity is much more common in endemic (90%) than sporadic (<30%) tumors. EBV likely contributes to Burkitt tumor cell growth via constitutive CD40-like tyrosine kinase-based proliferative signaling induced by the EBV latent membrane protein 1 (LMP-1) .

• 2.

  Molecular sites of c-Myc chromosome translocation breakpoints are different.

Burkitt tumors are highly chemosensitive, and patients with large tumor burden are at increased risk of treatment-related tumor lysis syndrome.

Mantle cell lymphoma is a high-grade B lymphoma, seen primarily in men, derived from CD5+ mantle zone B cells that carry a specific translocation t(11;14) involving the cyclin D1 and Ig heavy chain genes. Increased expression of cyclin D1 protein induces mantle cell B-cell proliferation by driving the cells through the cyclin D1–dependent G1 cell cycle checkpoint. without cyclin D1 translocation carry a SOX-11 gene mutation. SOX-11 encodes for a transcription factor protein. Although MCL (like CLL/SLL) is derived from CD5+ B cells (as in CLL/SLL), the small centrocyte-like cells express a memory (mantle cell) B-cell phenotype and do not coexpress the low-affinity IgE receptor CD23. Lymph node involvement is often marked by a vaguely nodular infiltrate of cyclin D1–positive mantle zone cells that surround small atrophic GCs ( Figs. 14.12 and 14.13 ). Although the most common presentation is generalized lymphadenopathy, some patients may present with abdominal complaints (pain, diarrhea, constipation, or rectal bleeding) caused by GI involvement in the form of multiple lymphomatous polyps known as lymphomatous polyposis .

The characteristic chromosome translocation seen in MCL, t(11;14) , can be directly detected in individual tumor cells by fluorescence in situ hybridization. In this technique, two DNA probes, each specific for one chromosome (11 or 14) and each labeled with a specific fluorochrome (red or green), are hybridized to fixed cells either on cell smears or in tissue sections and viewed under a fluorescence microscope. Normal cells are marked by two red signals (normal chromosomes 11) and two green signals (normal chromosomes 14). Tumor cells are marked by at least one overlapping red-green signal that appears yellow ( Fig. 14.14 ). This same technique can be applied to a variety of other translocations in lymphoma and leukemia, including t(9;22) in CML, t(8;14) in Burkitt lymphoma, and t(14;18) in FL.

Marginal zone lymphoma is a low-grade lymphoma derived from post-GC B cells that presents most often as an extranodal mucosa-associated lymphoid tissue (MALT) lymphoma and less often as a node or spleen-based disease. MALT lymphomas are most often seen in association with a variety of chronic persistent infections and autoimmune conditions. Examples of MALT lymphoma include gastric lymphoma ( Fig. 14.15 ) with H. pylori infection, intestinal lymphoma with Campylobacter jejuni infection, thyroid lymphoma with Hashimoto thyroiditis , and parotid lymphoma with Sjögren syndrome . A characteristic biopsy finding in MALT lymphoma is the presence of lymphoepithelial lesions formed by lymphocytic infiltration of cytokeratin-positive glandular epithelium ( Fig. 14.16 ). These lymphomas apparently arise from neoplastic marginal B-cell clones that develop from of the intense chronic inflammation triggered by chronic infection. Early in the disease, these tumors may undergo complete remission with antibiotic therapy alone, begging the question of true malignancy. Clonal evolution with acquisition of mutations, including the t(11;18) translocation involving the apoptosis inhibitor 2 (API2) and MALT1 genes leads to higher grade disease for which antibiotic therapy is ineffective and conventional chemotherapy is required. MZL may also present as primary node-based disease, one-third of which occurs in association with a MALT lymphoma. Marginal cell lymphoma may also arise in the spleen as a primary splenic marginal cell lymphoma with marked expansion of the splenic marginal zone ( Fig. 14.17 ), often accompanied by circulating tumor cells with irregular cytoplasmic projections called villous lymphocytes.

Plasma cell myeloma (multiple myeloma) is the most common lymphoid malignancy in African Americans and the second most common lymphoid malignancy in European Americans. The disease is most often seen in older adults. The risk of myeloma is increased in cosmetologists, farmers, laxative takers, and those with exposure to pesticides, petroleum products, asbestos, rubber, and wood products, strongly suggesting a role for environmental exposure to toxins in development of the disease. Plasma cell myeloma is a tumor composed of malignant (monoclonal) plasma cells that most often arises in the bone marrow, causing painful lytic bone lesions, pathologic fractures, and hypercalcemia. Although usually more than 10% of the plasma cells in the bone marrow are abnormal, no minimal number of marrow plasma cells is required for diagnosis ( Fig. 14.18 ). Instead, the diagnosis is based on three criteria: the presence of a monoclonal serum or urine protein ( Fig. 14.19 ), monoclonal plasma cells in tissue, and related organ or tissue impairment (hypercalcemia, renal insufficiency, anemia, or bone lesions). Neoplastic plasma cells express the plasma cell markers CD138, MUM1, and either kappa or lambda light chain protein. Production of large quantities of monoclonal Ig ( paraprotein ) leads to renal tubular deposition of free light chains, known as Bence-Jones protein , and development of renal failure; to polyclonal hypogammaglobulinemia leading to recurrent bacterial infections; and in some cases, to deposition of free light chains in soft tissues throughout the body (amyloidosis). Smoldering myeloma is defined as asymptomatic disease marked by a monoclonal serum or urine protein and at least 10% clonal plasma cells. Extraosseous plasmacytoma is a plasma cell neoplasm presenting in an extramedullary site, most often the upper respiratory tract, with disease only rarely progressing to involve bone marrow. Osseous plasmacytoma presents as a solitary tumor in bone (not bone marrow). Many patients progress to involve marrow or other bone sites. Patients with localized plasma cell disease may be effectively treated by radiation therapy, but those with extensive disease (including myeloma) are treated with combination chemotherapy. The overall median survival period is 3 years. A common related condition, termed monoclonal gammopathy of undetermined significance , is a chronic asymptomatic condition of older adults (seen in 3% of adults older than 70 years of age) marked by the presence of monoclonal Ig in serum and accompanied by a slight increase (<10%) in bone marrow plasma cells. Up to 25% of patients with this condition eventually progress to plasma cell myeloma.

Amyloidosis is a disease process caused by deposition of insoluble fibrillary protein with beta-pleated sheet secondary structure in numerous tissues that may lead to heart failure, kidney failure, peripheral neuropathy, and abnormal bleeding. Light chain amyloidosis results from deposition of monoclonal light chain Ig produced by a clonal plasma cell disorder that in some cases meets the diagnostic criteria for plasma cell myeloma. Amyloid appears in biopsy material (often subcutaneous fat) as an eosinophilic extracellular material within the walls of small blood vessels ( Fig. 14.20 ) that can be confirmed by Congo red staining. Amyloidosis A is caused by tissue deposition of serum amyloid A (SAA) in chronic infectious and inflammatory states. SAA is an insoluble protein by-product derived from the circulating precursor protein apo-SAA that normally serves as an acute phase reactant.

Lymphoplasmacytic lymphoma is a rare low-grade neoplasm of older adults that is most often associated with a monoclonal serum IgM paraprotein and a MyD-88 gene mutation. The MyD-88 protein is involved in lymphocyte signal activation. The lymphoma is composed of plasmacytoid lymphocytes, small ovoid IgM+ lymphocytes with slightly eccentric nuclei, moderately abundant cytoplasm, and a prominent perinuclear Golgi region ( Fig. 14.21 ). The IgM paraprotein may in some cases lead to hyperviscosity syndrome (increased blood viscosity, fatigue, weakness, anorexia, and weight loss), cryoglobulinemia, and autoimmune phenomena such as peripheral neuropathy and coagulopathy caused by factor antibodies. Most patients who present with the clinical syndrome known as Waldenstrom macroglobulinemia (monoclonal serum IgM protein and symptoms of hyperviscosity) have LPL.

Cryoglobulinemia is a clinicopathologic condition caused by increased production of Igs that reversibly precipitate at temperatures below body temperature (37°C). Intravascular deposition of cryoprecipitate leads to necrotizing vasculitis and tissue damage. End organs that may be damaged include the skin, joints, peripheral nerves, kidneys, liver, CNS, and intestines. The most common symptoms include purpura, arthralgia, and weakness. There are three types of cryoglobulins:

• 1.

  Type I (monoclonal) cryoglobulin is composed entirely of monoclonal Ig, most often IgM (as in LPL).

• 2.

  Type II (mixed monoclonal–polyclonal) cryoglobulin is composed of a mixture of monoclonal and polyclonal Igs. The monoclonal component (most often IgM) has rheumatoid factor–like antibody specificity, and the polyclonal component is IgG. Type II cryoglobulinemia is often seen in hepatitis C infection and lymphoproliferative disorders.

• 3.

  Type III (polyclonal) cryoglobulin is composed entirely of polyclonal Ig. In most cases, some polyclonal Ig has rheumatoid factor–like anti-IgG activity such that much of the precipitate is composed of Ig–anti-Ig complexes. Type III cryoglobulinemia is seen in association with various infections and autoimmune diseases.

Mediastinal large B-cell lymphoma most often presents as a mediastinal mass in young women ( Fig. 14.22 ). Because Hodgkin lymphoma often presents as a mediastinal mass in young women and shares some histologic features with MLBCL, distinction from Hodgkin lymphoma in some cases may be difficult. In contrast to the Reed-Sternberg (RS) cells of Hodgkin lymphoma, the large cells of MLBCL are positive for CD45 and CD20, negative for CD15, and only weakly positive for CD30.

Lymphomatoid granulomatosis is a rare, often aggressive T cell–rich EBV+ B-cell lymphoma of middle-aged adults that presents as a necrotizing angiodestructive process in extranodal sites, most commonly the lung, kidney, or CNS. Clinical symptoms may include fever, cough, weight loss, and neurologic defects.

Primary effusion lymphoma (PEL) is a rare high-grade B-cell lymphoma most often seen in patients with human immunodeficiency virus/acquired immunodeficiency syndrome who present with a rapidly enlarging pleural, pericardial, or peritoneal serous effusion. The large tumor cells usually express a null (non-B, non-T) immunophenotype and are positive for human herpesvirus 8 and sometimes EBV. The B-cell origin of this tumor can be demonstrated by detection of clonal Ig gene rearrangements.