Williams Hematology



Associated Clinical Syndromes

Abnormal Production of Immunoglobulin

Marrow and Other Tissue Infiltration

Lymphokine-Induced Disorders

Systemic Symptoms

Metabolic Signs

Organ Infiltration (Extranodal Involvement)
Chapter References

This chapter outlines the category of neoplastic or pre-neoplastic lymphocyte and plasma cell disorders. It introduces a framework for evaluating neoplastic lymphocyte and plasma cell disorders, outlines clinical syndromes associated with such disorders, and presents a road-map to the chapters in the text that discuss each of these disorders in greater detail. The diseases caused by non-neoplastic disorders of lymphocytes and plasma cells are outlined in Chap. 86.

Acronyms and abbreviations that appear in this chapter include: IL-1, interleukin-1.

Lymphocyte malignancies comprise a wide spectrum of different morphologic and clinical syndromes (Table 96-1). 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 lymphocytic leukemias arise from a primitive lymphoid stem cell that may give rise to cells with either B- or T-cell phenotypes (see Chap. 97). On the other hand, chronic lymphocytic leukemia arises from a more differentiated B-lymphocyte progenitor (see Chap. 98), and multiple myeloma from progenitors at even later stages of B-lymphocyte maturation (see Chap. 106). Variability in expression of a lymphopoietic stem cell disorder may result in the spectrum of lymphocytic diseases, such as a B-lymphocyte or T-lymphocyte lymphoma (see Chap. 103), and different types of diseases, such as hairy-cell leukemia (see Chap. 99), prolymphocytic leukemia (see Chap. 98), natural killer cell large granular lymphocytic leukemia (see Chap. 100), or plasmacytoma (see Chap. 106).

TABLE 96-1

To provide a unified international basis for clinical and investigative work in this field, the International Lymphoma Study Group proposed a new classification termed revised European-American lymphoma (REAL) classification (see Chap. 101).1 This 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 96-1).2 Studies have verified the clinical utility of this classification scheme.3,4
When B lymphocytes undergo neoplastic transformation and clonal proliferation, they can secrete monoclonal proteins inappropriately (see Chap. 104). If the monoclonal protein is IgM, IgA, or a member of certain subclasses of IgG (e.g., namely IgG3), this may increase the viscosity of the blood, impairing blood flow through the microcirculation (see Chap. 106 and Chap. 108). This may be impeded further by the associated erythrocyte-erythrocyte aggregation (pathologic rouleaux) that often occurs in blood with a high concentration of immunoglobulin protein. Collectively this may result in the hyperviscosity syndrome, manifested clinically by headache, dizziness, diplopia, stupor, retinal venous engorgement, or frank coma (see Chap. 108).5,6
Monoclonal immunoglobulin proteins also can interact with cell surfaces and impair granulocyte or platelet function, or interact with coagulation proteins to impair their function in hemostasis. Excessive excretion of immunoglobulin light chains can lead to several types of renal tubular dysfunction and renal insufficiency (see Chap. 106). IgM deposited in glomerular tufts also can lead to renal disease (see Chap. 108). Cryoglobulins [or immunoglobulins that precipitate at temperatures below 37°C (98.6°F)] can result in Raynaud syndrome, skin ulcerations, purpura, and digital infarction and gangrene (see Chap. 56). These manifestations are the result of immune complex formation and complement activation as well as precipitation of cryoglobulins in cutaneous blood vessels. Finally, excessive production of monoclonal immunoglobulin or immunoglobulin fragments in plasma cell myeloma (see Chap. 106) of heavy-chain disease (see Chap. 109) may lead to formation of amyloid, resulting in primary amyloidosis (see Chap. 107).
Production of autoreactive antibodies spontaneously or in relationship to a B-lymphocyte neoplasia may lead to autoimmune hemolytic anemia (see Chap. 55), autoimmune thrombocytopenia (see Chap. 117), or, rarely, autoimmune neutropenia (see Chap. 71). Autoantibodies directed against tissues are implicated in the etiopathogenesis of such diseases as autoimmune thyroiditis, adrenalitis, encephalitis, or other organ involvement. Peripheral neuropathies, as a result of demyelinization, can occur in patients with monoclonal immunoglobulin (see Chap. 106 and Chap. 108). The neural injury is often related to antibody activity against myelin-associated glycoproteins or absorption by nerve tissue. Rarely, the polyneuropathy is associated with organomegaly, endocrinopathy, a monoclonal protein, and skin chains, or POEMS syndrome (see Chap. 106).
Well-differentiated malignant B-lymphocytes, such as those found in early stages of chronic lymphocytic leukemia or macroglobulinemia, may infiltrate the marrow extensively, causing minimal impairment of hemopoiesis. Eventually, however, further infiltration of marrow by malignant B lymphocytes can suppress normal hemopoiesis, resulting in varying combinations of anemia, granulocytopenia, and/or thrombocytopenia (see Chap. 98). Malignant B-lymphocyte proliferation or infiltration may result in any combination of splenomegaly and lymphadenopathy of either superficial or deep lymph nodes. Many B-cell lymphomas tend to involve isolated lymph node groups (see Chap. 102 and Chap. 103), whereas B-cell chronic lymphocytic leukemia and most low-grade lymphomas tend to involve many superficial and deep lymph node–bearing areas and the spleen (see Chap. 98 and Chap. 103). Prolymphocytic leukemia and hairy-cell leukemia, two uncommon B-lymphocyte malignancies, are prone to infiltrate the marrow and spleen, sometimes causing massive enlargement of the latter (see Chap. 98 and Chap. 99).
In addition to the consequences of monoclonal immunoglobulin and tumor proliferation noted above, some lymphocyte malignancies may elaborate cytokines that contribute to the disease morbidity. Patients with cutaneous T-cell lymphomas have been found to have elevated plasma levels of TH2-type associated cytokines (see Chap. 84), which may account for the relatively high incidence of eosinophilia and eosinophilic pneumonia observed in patients with this disease.7 In addition, the neoplastic plasma cells in multiple myeloma may secrete interleukin-1 (IL-1), a cytokine that can stimulate osteoclast proliferation and activity leading to extensive osteolysis, severe bone pain, and pathologic fractures (see Chap. 106).8 In addition, IL-1 may stimulate production of antidiuretic hormone and contribute to a syndrome of inappropriate secretion of antidiuretic hormone.9 Dysregulated extra-renal production of calcitriol, the active metabolite of vitamin D, appears to underlie the hypercalcemia associated with Hodgkin lymphoma and other lymphomas (see Chap. 102 and Chap. 103).10
Large-cell lymphoma, poorly differentiated lymphoma, and Hodgkin lymphoma frequently are associated with fever, night sweats, weight loss, and anorexia (see Chap. 102 and Chap. 103). Patients with lymphomas or Hodgkin lymphoma have an increased incidence of localized or disseminated herpes zoster, and 10 percent or more of these patients may be affected sometime during the course of their illness. 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, whereas, in well-differentiated small-cell lymphomas, such as chronic lymphocytic leukemia and Waldenström macroglobulinemia, fever, night sweats, and significant weight loss are uncommon, despite generalized lymphadenopathy and splenomegaly. Rather, fever in patients with chronic lymphocytic leukemia or macroglobulinemia usually is secondary to infectious disease.
Lymphocytic malignancies are associated with the most dramatic metabolic disturbances associated with cancers (see Chap. 103). Some lymphomas and lymphocytic leukemias may have an extremely high proliferative rate, a high death fraction of cells, and, therefore, an enormous turnover of nucleoproteins, sometimes causing hyperuricemia and extreme hyperuricosuria. Burkitt lymphoma or acute lymphocytic leukemia is particularly likely to cause an extreme degree of hyperuricemia, sometimes leading to renal failure prior to cytotoxic therapy. Also, because these and other lymphocytic malignancies are sensitive to cytotoxic drugs and glucocorticoids, cytotoxic therapy may cause extreme hyperuricemia, hyperuricosuria, hyperkalemia, and hyperphosphatemia.11 This has been called the tumor lysis syndrome. 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 pre-treatment with allopurinol, hydration, and alkalization of the urine.
Hypercalcemia and calciuria are common complications of multiple myeloma because of osteolysis. Hypercalcemia also may occur during the course of lymphomas (see Chap. 103) or plasma cell myeloma (see Chap. 106). This may be caused by several mechanisms, including tumor- cell- production of IL-1, ectopic parathyroid hormone elaboration, excessive bone resorption, and impaired bone formation.8
T-cell leukemias and lymphomas, in addition to causing lymph node and spleen enlargement, also may involve the skin, mediastinum, or central nervous system. As the name implies, cutaneous T-cell lymphomas have malignant cells that home to the skin, sometimes producing a severe desquamating erythroderma in Sézary syndrome, small (<2 cm) subcutaneous nodules in primary cutaneous CD30-positive lymphoma, or a variety of nodular infiltrative lesions in mycosis fungoides (see Chap. 103). T-cell acute lymphocytic leukemia and lymphoblastic lymphoma frequently cause mediastinal enlargement (see Chap. 103). These diseases frequently involve the leptomeniges 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, and, less frequently, other extra-nodal sites. These diseases may begin as an extranodal tumor, or the tumor may develop during the course of the disease. Marginal zone B-cell lymphoma of 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.

Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361, 1994.

Segal GH, Kjeldsberg CR: Practical lymphoma diagnosis: An approach to using the information organized in the REAL proposal. Revised European-American Lymphoid Neoplasm. Anat Pathol 3:147, 1998.

A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma: The Non-Hodgkin’s Lymphoma Classification Project. Blood 89:3909, 1997.

Fisher RI, Miller TP, Grogan TM: New REAL clinical entities. Cancer J Sci Am 4(suppl) 2:S5, 1998.

Kwaan HC, Bongu A: The hyperviscosity syndromes. Semin Thromb Hemost 25:199, 1999.

Kyle RA: Sequence of testing for monoclonal gammopathies. Arch Pathol Lab Med 123:114, 1999.

Hirshberg B, Kramer MR, Lotem M, et al: Chronic eosinophilic pneumonia associated with cutaneous T-cell lymphoma. Am J Hematol 60:143, 1999.

Roodman GD: Mechanisms of bone lesions in multiple myeloma and lymphoma. Cancer 80:1557, 1997.

Chubachi A, Miura I, Hatano Y, et al: Syndrome of inappropriate secretion of antidiuretic hormone in patients with lymphoma-associated hemophagocytic syndrome. Ann Hematol 70:53, 1995.

Seymour JF, Gagel RF: Calcitrol: The major humoral mediator of hypercalcemia in Hodgkin’s disease and non-Hodgkin’s lymphomas. Blood 82:1383, 1993.

Lorigan PC, Woodings PL, Morgenstern GR, Scarffe JH. Tumour lysis syndrome, case report and review of the literature. Ann Oncol 7:631, 1996.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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