Chapter 90: Classification of Malignant Lymphoid Disorders

Lymphocyte and plasma cell malignancies present a broad spectrum of different morphologic features and clinical syndromes (Table 90–1). Lymphocyte neoplasms can originate from cells that are at a stage prior to T- and B-lymphocyte differentiation from a primitive stem cell or from cells at stages of maturation after stem cell differentiation. Thus, acute lymphoblastic leukemias arise from an early lymphoid progenitor cell that may give rise to cells with either B- or T-cell phenotypes (Chap. 91). On the other hand, chronic lymphocytic leukemia arises from a more mature B-lymphocyte progenitor (Chap. 92) and myeloma from progenitors at even later stages of B-lymphocyte maturation (Chap. 107). Disorders of lymphoid progenitors may result in a broad spectrum of lymphocytic diseases such as B or T cell lymphomas (Chaps. 98 and Chap. 104), hairy cell leukemia (Chap. 93), prolymphocytic leukemia (Chap. 92), natural killer cell large granular lymphocytic leukemia (Chap. 94),¹ myeloma, and plasmacytoma (Chap. 107). Hodgkin lymphoma also is derived from a neoplastic B cell that has highly mutated immunoglobulin genes that are no longer expressed as protein (Chap. 97).

To provide a unified international basis for clinical and investigative work in this field, the International Lymphoma Study Group proposed a classification termed the revised European-American Lymphoma (REAL) classification (Chap. 95),² which was modified in 2001 and again in 2008 by the World Health Organization (WHO).^3,4 The REAL/WHO classification scheme makes use of the pathologic, immunophenotypic, genetic, and clinical features of a given lymphocyte tumor to delineate them into separate disease entities (see Table 90–1 and Chap. 96).⁵ For some of these entities, the neoplastic lymphocytes have distinctive cytogenetic abnormalities, which can be identified using molecular techniques that increasingly are being used in clinical pathology laboratories.^6,7

The REAL/WHO classification recognizes a basic distinction between nodular lymphocyte-predominant Hodgkin lymphoma and classic Hodgkin lymphoma, reflecting the differences in clinical presentation and behavior, morphology, phenotype, and molecular features (Chap. 97).³ Studies have identified features that can be used to distinguish classical Hodgkin lymphoma from anaplastic large cell lymphoma and, to a lesser extent, between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma.

The updated WHO classification (summarized in Ref. 4) provided several revised guidelines for defining diseases such as chronic lymphocytic leukemia (CLL),⁸ Waldenström macroglobulinemia,⁹ plasma cell neoplasms,¹⁰ and diffuse large B-cell lymphoma (DLBCL).^11,12,13,14 The classification of several T-cell lymphomas were also refined including enteropathy-associated T-cell lymphoma, anaplastic large cell lymphoma (ALK-positive and ALK-negative), and subcutaneous panniculitis-like T-cell lymphoma.⁴ This chapter has summarized these new distinctions in Table 90–1.

Lymphomas of similar histology can have widely different spectra of associated clinical symptoms and clinical aggressiveness, making the categorization of lymphoid tumors impossible using a generic grading system based on morphology alone. For example, the neoplastic cells in mantle cell lymphoma appear smaller and more differentiated than those of anaplastic large cell lymphomas. However, the validation studies for the REAL classification revealed that patients with mantle cell lymphoma or anaplastic large cell lymphomas have a 5-year survival rate of approximately 30 percent and approximately 80 percent, respectively.^15,16 Generally, T-cell lymphomas/leukemias have a more aggressive clinical behavior than B-cell lymphomas of comparable histology. The tendency for more aggressive disease also applies to lymphoid tumors derived from natural killer cells. A helpful distinction is to divide the lymphoid tumors into one of two categories, namely, indolent lymphomas versus aggressive lymphomas, based upon on the characteristics of the disease at the time of presentation and the patients’ life expectancy if the disease is left untreated.^17,18 Clinical studies have verified that the different disease categories defined in the REAL/WHO classification each can be segregated into one or the other of these two major categories (Tables 90–2 and 90–3).¹⁵ Analyses of gene-expression patterns using microarray technology (Chaps. 11 and 12) have enabled identification of subcategories within some of the disease categories defined by the REAL/WHO classification that have different tendencies for disease progression, survival, and/or response rates to standard therapies (Chap. 96).^{19,20,21,22,23,24,25} An example of how gene-expression profiling has had a major impact on refining lymphoma diagnoses can be found with two newly defined working categories as “gray zone” lymphomas between Hodgkin lymphoma and primary mediastinal large B-cell lymphoma^12,26 and between Burkitt and DLBCL.^13,14 These new intermediate groups make clear distinctions between biologic and clinical features of conventional DLBCL and HL.

EARLY PRECURSOR LESIONS IN LYMPHOID NEOPLASMS

The 2008 WHO classification highlights several clinical, histologic, and immunophenotypic observations supporting the notion that lymphoid neoplasms arise from clonal expansion and ultimately, malignant transformation of precursor lesions. Monoclonal B-cell lymphocytosis (MBL) can be found in first-degree relatives of patients with CLL and in 5 to 15 percent of adults older than 60 years of age who present with lymphocytosis.^27,28 The documented rate of progression to CLL of 1 to 2 percent/year and immunophenotypic evidence of evolving CLL-like clones with cytogenetic anomalies suggest that mantle cell lymphoma may represent a potential precursor to CLL.²⁹ Other potential precursor lesions for follicular lymphoma and mantle cell lymphoma are currently under investigation.⁴

ABNORMAL PRODUCTION OF IMMUNOGLOBULIN

When B lymphocytes undergo neoplastic transformation and clonal proliferation, they can secrete monoclonal proteins inappropriately (Chaps. 105 and 106). If the monoclonal protein is immunoglobulin (Ig) M, IgA, or a member of certain subclasses of IgG (e.g., IgG₃), its presence may increase the viscosity of the blood, impairing blood flow through the microcirculation (Chaps. 107 and 109). This process may be impeded further by the associated homotypic erythrocyte aggregation (pathologic rouleaux) that often occurs in blood with a high concentration of immunoglobulin protein. Collectively, this situation may result in the hyperviscosity syndrome, manifested clinically by headache, dizziness, diplopia, stupor, retinal venous engorgement, or frank coma (Chap. 109).^30,31

Monoclonal immunoglobulin proteins also can interact with cell surfaces and impair granulocyte or platelet function, or they can interact with coagulation proteins to impair their function in hemostasis (Chap. 120). Excessive excretion of immunoglobulin light chains can lead to several types of renal tubular dysfunction and renal insufficiency (Chaps. 106 and 107). IgM deposited in glomerular tufts also can lead to renal disease (Chap. 109). Cryoglobulins (immunoglobulins that precipitate at temperatures below 37°C) can result in Raynaud syndrome, skin ulcerations, purpura, digital infarction, and gangrene (Chap. 54). These manifestations result from immune complex formation, complement activation, and precipitation of cryoglobulins in cutaneous blood vessels. Excessive production of monoclonal immunoglobulin or immunoglobulin fragments in myeloma (Chap. 107) or in heavy-chain disease (Chap. 110) may lead to formation of amyloid, resulting in primary amyloidosis (Chap. 108).

Production of autoreactive antibodies spontaneously or in relationship to a B-lymphocyte neoplasm may lead to autoimmune hemolytic anemia (Chap. 54), autoimmune thrombocytopenia (Chap. 117), or, rarely, autoimmune neutropenia (Chap. 65). Autoantibodies directed against tissues are implicated in the pathogenesis of diseases such as autoimmune thyroiditis, adrenalitis, encephalitis, and conditions with other organ involvement. Peripheral neuropathies as a result of demyelinization can occur in patients with monoclonal immunoglobulin (Chaps. 106, 107, and 109). The neural injury often is related to antibody activity against myelin-associated glycoproteins or absorption by nerve tissue.³¹ Rarely, the polyneuropathy is part of the polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome (Chap. 107).³²

MARROW AND OTHER TISSUE INFILTRATION

Well-differentiated malignant B lymphocytes, such as those found in the early stages of CLL or Waldrenstrom’s macroglobulinemia, may infiltrate the marrow extensively, causing impairment of hemopoiesis. Eventually, however, massive infiltration of marrow by malignant B lymphocytes can suppress normal hemopoiesis, resulting in varying combinations of anemia, neutropenia, and/or thrombocytopenia (Chap. 92). Malignant B-lymphocyte proliferation or infiltration may result in any combination of splenomegaly and lymphadenopathy of either superficial or deep lymph nodes. Diffuse large B cell lymphomas tend to involve isolated lymph node groups (Chaps. 97 and 98), whereas low-grade lymphomas (follicular lymphoma) and lymphoproliferative disorders (CLL) tend to present with more diffuse lymphadenopathy and splenic involvement (Chaps. 92 to 94). Prolymphocytic leukemia and hairy cell leukemia, two uncommon B-lymphocyte malignancies, are prone to infiltrate the marrow and spleen, sometimes causing bone marrow fibrosis and massive splenomegaly (Chaps. 92 and 93).

LYMPHOKINE-INDUCED DISORDERS

In addition to the consequences of monoclonal immunoglobulin and tumor proliferation, some lymphoid malignancies may produce cytokines that contribute to the disease morbidity. Recent work has identified several immune activation syndromes, mediated in large part as a result of unchecked inflammatory cytokines (interleukin [IL]-1, IL-6) and defects in perforin/granzyme pathways are associated with lymphomas and infection with oncogenic herpes viruses. Hemophagocytic lymphohistiocytosis and macrophage activating syndrome are two distinct complications arising from dysregulated effector lymphocyte-tumor interaction at the immunologic synapse and can lead to life-threatening complications if not rapidly diagnosed and treated with immunochemotherapy.³³ Patients with cutaneous T-cell lymphomas have elevated plasma levels of T-helper type 2 (Th2)-associated cytokines, which may account for the relatively high incidence of eosinophilia (Chap. 103) and eosinophilic pneumonia observed in patients with this disease.³⁴ In addition, the neoplastic plasma cells in myeloma may secrete various cytokines and osteoclast activating factors that stimulate osteoclast proliferation and activity leading to extensive osteolysis, severe bone pain, and pathologic fractures (Chap. 107).³⁵ Dysregulated extrarenal production of calcitriol, the active metabolite of vitamin D, appears to underlie the hypercalcemia associated with Hodgkin lymphoma and other lymphomas (Chaps. 95 and 97).³⁶

SYSTEMIC SYMPTOMS

Large cell lymphoma, poorly differentiated lymphoma, and Hodgkin lymphoma frequently are associated with fever, night sweats, weight loss, and anorexia-cachexia (Chaps. 95, 97, and 98). Patients with lymphomas or Hodgkin lymphoma have an increased incidence of localized or disseminated herpes zoster,³⁷ and 10 percent or more of these patients may be affected at some time during the course of their illness. Pruritus is common in Hodgkin lymphoma,³⁸ and its severity parallels disease activity (Chap. 97). Systemic symptoms may be present in Hodgkin lymphoma in the absence of obvious, bulky lymph node or splenic tumors, whereas in well-differentiated small cell lymphomas, such as CLL or Waldenström macroglobulinemia, fever, night sweats, and significant weight loss are uncommon despite generalized lymphadenopathy and splenomegaly. Rather, fever in patients with CLL or macroglobulinemia usually is secondary to infectious disease (Chaps. 92 and 109).

METABOLIC SIGNS

Lymphoid malignancies are associated with several dramatic metabolic disturbances associated with cancers (Chap. 95). Some lymphomas and lymphocytic leukemias may have a high proliferative rate, a high death fraction of cells, and, therefore, an enormous turnover of nucleoproteins, sometimes causing hyperuricemia and extreme hyperuricosuria. Highly proliferative neoplasms like Burkitt lymphoma or lymphoblastic lymphoma are particularly likely to cause an extreme degree of hyperuricemia, sometimes leading to renal failure complicating initiation of cytotoxic therapy (Chaps. 91 and 102). Also, because these and other lymphocytic malignancies are sensitive to cytotoxic drugs and glucocorticoids, cytotoxic therapy may cause a tumor lysis syndrome, characterized by extreme hyperuricemia, hyperuricosuria, hyperkalemia, and/or hyperphosphatemia.^39,40 Precipitation of uric acid in the renal tubules and collecting system can lead to acute obstructive nephropathy and renal failure unless precautions are taken, such as pretreatment with allopurinol, hydration, and alkalization of the urine.⁴¹ For extreme cases, or in cases in which allopurinol cannot be administered (e.g., drug allergy), the drug rasburicase may be required for treatment of hyperuricemia (Chap. 102).⁴²

Hypercalcemia and calciuria are common complications of myeloma because of osteolysis. Hypercalcemia also may occur during the course of lymphomas (Chap. 94) or myeloma (Chap. 107). This situation may be caused by several mechanisms, including tumor cell production of IL-1, ectopic parathyroid hormone elaboration, excessive bone resorption, and impaired bone formation.⁴³

EXTRANODAL INVOLVEMENT

T-cell leukemias and lymphomas, in addition to causing lymph node and spleen enlargement, may involve the skin, mediastinum, or CNS. As the name implies, cutaneous T-cell lymphomas have malignant cells that home to the skin,⁴⁴ sometimes producing a severe desquamating erythroderma, as in Sézary syndrome, or small (<2 cm) subcutaneous nodules, as in primary cutaneous CD30-positive T-cell lymphoproliferative disease or anaplastic large cell lymphoma,⁴⁵ or a variety of nodular infiltrative lesions, as in mycosis fungoides or adult T-cell leukemia/lymphoma associated with human T-cell leukemia virus type 1 (HTLV-1; Chap. 103).⁴⁶ T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma frequently cause mediastinal enlargement (Chap. 91). These diseases frequently involve testicles and the leptomeninges and other structures that are transverse to the subarachnoid space, such as the cranial and peripheral nerves.

B-cell lymphomas frequently may involve the salivary glands, endocrine glands, joints, heart, lung, kidney, bowel, bone, or, less frequently, other extranodal sites such as the CNS and testes (Chap. 95). These diseases may begin as an extranodal tumor, or the tumor may develop during the course of the disease. Aggressive lymphomas, such as Burkitt lymphoma,⁴⁷ primary testicular lymphoma,^47,48 and double-hit DLBCLs (Chap. 98),⁴⁹ frequently involve the CNS and require upfront assessment during diagnosis and treatment with either intrathecal chemotherapy or regimens capable of crossing blood–brain barrier that contain high-dose methotrexate. Marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type frequently involves the stomach and salivary glands, although the disease may be encountered in any extranodal site distinguished by the presence of a columnar or cuboidal epithelium.