Neoplasms of lymphocytes usually represent malignant counterparts of cells at discrete stages of normal lymphocyte differentiation. When bone marrow and peripheral blood involvement dominate the clinical picture, the disease is classified as a lymphoid leukemia. When lymph nodes and/or other extranodal sites of disease are the dominant site(s) of involvement, the tumor is called a lymphoma. The distinction between lymphoma and leukemia is sometimes blurred; e.g., small lymphocytic lymphoma and chronic lymphoid leukemia are tumors of the same cell type and are distinguished arbitrarily on the basis of the absolute number of peripheral blood lymphocytes (>5 × 109 /L defines leukemia).
Historically, lymphoid tumors have had separate pathologic classifications based on the clinical syndrome-lymphomas according to the Rappaport, Kiel, or Working Formulation systems; acute leukemias according to the French-American-British (FAB) system; Hodgkin's disease (HD) according to the Rye classification. Myelomas have generally not been subclassified by pathologic features of the neoplastic cells. The World Health Organization (WHO) has proposed a unifying classification system that brings together all lymphoid neoplasms into a single framework. Although the new system bases the definitions of disease entities on histology, genetic abnormalities, immunophenotype, and clinical features, its organization is based on cell of origin (B cell vs. T cell) and maturation stage (precursor vs. mature) of the tumor, features that are of limited value to the clinician. Table 67-1 Clinical Schema of Lymphoid Neoplasms lists the disease entities according to a more clinically useful schema based on the clinical manifestations and natural history of the diseases.
Lymphoid tumors are increasing in incidence. Nearly 141,000 cases were diagnosed in 2018 in the United States (Fig. 67-1. Relative Frequency of Lymphoid Malignancies), including 74,680 cases of non-Hodgkin's lymphoma, 8500 cases of Hodgkin's lymphoma, 30,770 cases of myeloma, 20,940 cases of chronic lymphoid leukemia, and 5960 cases of acute lymphoid leukemia.
The cause(s) for the vast majority of lymphoid neoplasms is unknown. The malignant cells are monoclonal and often contain numerous genetic abnormalities. Some genetic alterations are characteristic of particular histologic entities: t(8;14) in Burkitt's lymphoma, t(14;18) in follicular lymphoma, t(11;14) in mantle cell lymphoma, t(2;5) in anaplastic large cell lymphoma, translocations or mutations involving bcl-6 on 3q27 in diffuse large cell lymphoma, and others. In most cases, translocations involve insertion of a distant chromosome segment into the antigen receptor genes (either immunoglobulin or T cell receptor) during the rearrangement of the gene segments that form the receptors.
Three viruses-Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8) (both herpes family viruses), and human T-lymphotropic virus type I (HTLV-I, a retrovirus)-may cause some lymphoid tumors. EBV has been strongly associated with African Burkitt's lymphoma and the lymphomas that complicate immunodeficiencies (disease-related or iatrogenic). EBV has an uncertain relationship to mixed cellularity HD and angiocentric lymphoma. HHV-8 causes a rare entity, body cavity lymphoma, mainly in pts with AIDS. HTLV-I is associated with adult T cell leukemia/lymphoma (ATL). Both the virus and the disease are endemic to southwestern Japan and the Caribbean.
Gastric Helicobacter pylori infection is associated with gastric mucosa-associated lymphoid tissue (MALT) lymphoma and perhaps gastric large-cell lymphoma. Eradication of the infection produces durable remissions in about half of pts with gastric MALT lymphoma. MALT lymphomas of other sites are associated with either infection (ocular adnexae, Chlamydia psittaci; small intestine, Campylobacter jejuni; skin, Borrelia) or autoimmunity (salivary gland, Sjögren's syndrome; thyroid gland, Hashimoto's thyroiditis).
Inherited or acquired immunodeficiencies and autoimmune disorders predispose individuals to lymphoma. Lymphoma is 17 times more common in HIV-infected than in HIV-noninfected people. Lymphoma occurs with increased incidence in farmers and meat workers; HD is increased in wood workers.
Excisional biopsy is the standard diagnostic procedure; adequate tissue must be obtained. Tissue undergoes three kinds of studies: (1) light microscopy to discern the pattern of growth and the morphologic features of the malignant cells, (2) flow cytometry for assessment of immunophenotype, and (3) genetic studies (cytogenetics, DNA sequencing). Needle aspirates of nodal or extranodal masses are not adequate diagnostic procedures. Leukemia diagnosis and lymphoma staging include generous bilateral iliac crest bone marrow biopsies. Differential diagnosis of adenopathy is reviewed in Chap. 46 Lymphadenopathy and Splenomegaly.
Staging varies with the diagnosis. In acute leukemia, peripheral blood blast counts are most significant in assessing prognosis. In chronic leukemia, peripheral blood red blood cell (RBC) and platelet counts are most significant in assessing prognosis. Non-Hodgkin's lymphomas have five clinical prognostic factors; indolent and aggressive lymphomas share three of these, advanced stage, high lactate dehydrogenase (LDH) levels, and age >60 years. In follicular lymphoma, the last two factors are Hb <120 g/L (<12 g/dL) and more than four nodal sites of involvement. In a newer scheme for follicular lymphoma, marrow involvement and β2-microglobulin levels replace LDH and stage. In aggressive lymphoma, more than one extranodal site and performance status predict outcome. In myeloma, serum levels of paraprotein, creatinine, and β2-microglobulin levels predict survival.