Chapter 54: Classification and Clinical Manifestations of the Malignant Lymphoid Disorders

• Lymphocyte malignancies comprise a wide spectrum of different morphologic and clinical syndromes.

• The International Lymphoma Study Group proposed a new classification termed Revised European–American Lymphoma classification, or REAL classification which was modified in 2001 and updated in 2008 by the World Health Organization (WHO) (see Table 54–1).

• The REAL/WHO classification makes use of the pathologic, immunophenotypic, genetic, and clinical features to define separate disease entities (Table 54–1).

• Distinctive cytogenetic abnormalities are also described in Table 54–1.

• Tumors are divided into two categories: indolent versus aggressive (Tables 54–2 and 54–3).

Abnormal Production of Immunoglobulin

• Neoplastic B cells can secrete monoclonal immunoglobulin proteins inappropriately (see Chap 68).

• If the monoclonal protein is IgM, IgA, or some subclasses of IgG (namely IgG3), this may increase the viscosity of the blood, impairing flow through the microcirculation (see Chaps. 69 and 70).

• The microcirculation can be impeded further by associated erythrocyte–erythrocyte aggregation (pathologic rouleaux) that often occurs when the blood concentration of immunoglobulin is high.

• Impaired circulation because of high blood viscosity and rouleaux can result in the "hyperviscosity syndrome" (see Chap. 70).

  — Manifestations of the hyperviscosity syndrome include headache, dizziness, diplopia, stupor, retinal venous engorgement, and frank coma.

• Monoclonal immunoglobulins also can impair granulocyte or platelet function, or interact with coagulation proteins to impair hemostasis.

• Excessive excretion of immunoglobulin light chains can lead to several types of renal tubular dysfunction and renal insufficiency (see Chap. 69).

• Cryoglobulins (or immunoglobulins that precipitate at temperatures below 37°C) can result in Raynaud syndrome, skin ulcerations, purpura, or digital infarction and gangrene (see Chap. 25).

• Excessive production of monoclonal immunoglobulin can lead to formation of amyloid (see Chap. 72).

• Production of autoreactive antibodies in relationship to B-lymphocytic neoplasia may lead to:

  — Autoimmune hemolytic anemia (see Chaps. 24 and 25).

  — Autoimmune thrombocytopenia (see Chap. 74).

  — Autoimmune neutropenia (see Chap. 32).

• Autoantibodies directed against tissues are implicated in the etiopathogenesis of diseases such as autoimmune thyroiditis, adrenalitis, encephalitis, or other inflammation of other organs.

• Demyelinization can occur in patients with monoclonal immunoglobulin, resulting in peripheral neuropathies, or polyneuropathy (see Chaps. 68, 69, and 70).

• Occasionally, polyneuropathy is associated with organomegaly, endocrinopathy, a monoclonal protein, and skin changes, resulting in POEMS syndrome (see Chap. 69).

Marrow and Other Tissue Infiltration

• Neoplastic lymphocytes may infiltrate the marrow extensively, impairing hematopoiesis.

• Malignant lymphocyte proliferation or infiltration may result in any combination of splenomegaly and lymphadenopathy of either superficial or deep lymph nodes.

• Malignant lymphocytes also can infiltrate extranodal sites:

  — T-cell lymphomas and leukemias frequently involve the skin, mediastinum, or central nervous system.

  — B-cell lymphomas may involve the salivary glands, endocrine glands, joints, heart, lung, kidney, bowel, bone, or other extranodal sites.

  — Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, or MALT, frequently involves the stomach, lung, and salivary glands.

Lymphokine-Induced Disorders

• Neoplastic lymphocytes may elaborate cytokines that contribute to the disease morbidity.

• Cutaneous T-cell lymphomas may elaborate T_H2-type cytokines (e.g., interleukins 4, 5, 10, and 13), causing eosinophilia or eosinophilic pneumonia (see Chaps. 66 and 67).

• Neoplastic plasma cells may secrete interleukin-1 (IL-1), a cytokine that can stimulate osteoclasts (leading to extensive osteolysis, severe bone pain, and pathologic fractures) and enhance production of antidiuretic hormone (leading to a syndrome of inappropriate secretion of antidiuretic hormone) (see Chap. 69).

• Dysregulated extrarenal production of calcitriol, the active metabolite of vitamin D, may underlie the hypercalcemia associated with Hodgkin lymphoma and other lymphomas (see Chap. 59).

Systemic Symptoms

• Lymphomas may produce "B symptoms," e.g., fever, night sweats, and weight loss (see Chaps. 59 and 61).

• Pruritus is common in Hodgkin lymphoma, and its severity parallels disease activity.

• Systemic symptoms may be present in Hodgkin lymphoma in the absence of obvious, bulky lymph node or splenic tumors.

Metabolic Signs

• Aggressive lymphomas and acute lymphocytic leukemias may have high-proportions of rapidly dividing and dying cells, causing hyperuricemia and hyperuricosuria.

• Cytotoxic therapy of bulky disease may cause extreme hyperuricemia, hyperuricosuria, hyperkalemia, and hyperphosphatemia, referred to as the tumor lysis syndrome.

• Precipitation of uric acid in the renal tubules and collecting system can lead to acute obstructive nephropathy and renal failure.

• Hypercalcemia and calciuria are common complications of plasma cell myeloma.

Extranodal Involvement

• May also involve skin, mediastinum, or the central nervous system.

• B cell lymphomas may involve the salivary glands, endocrine glands, joints, heart, lung, kidney, bowel, bone, or other extranodal sites (see Chap. 60).