64 LYMPHOID MALIGNANCIES
Harrison’s Manual of Medicine
Chronic Lymphoid Leukemias/Lymphomas
Acute Lymphoid Leukemias/Lymphomas
Plasma Cell Disorders
DEFINITION 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; for example, 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).
CLASSIFICATION 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 according to the Rye classification. Myelomas have generally not been subclassified by pathologic features of the neoplastic cells. Recently, 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 codifies and standardizes the definitions of disease entities based upon histology, genetic abnormalities, and cell surface immunophenotype, its organization is based upon 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 64-1 lists the disease entities according to a more clinically useful schema based upon the clinical manifestations and natural history of the diseases.
Table 64-1 Clinical Schema of Lymphoid Neoplasms
INCIDENCE Lymphoid tumors are increasng in incidence. Nearly 90,000 cases were diagnosed in 2000 in the U.S.
ETIOLOGY The cause(s) for the vast majority of lymphoid neoplasms is unknown. Like other cancers, 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, 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 Hodgkin’s disease and angiocentric lymphoma. HHV-8 causes a rare entity, body cavity lymphoma, mainly in patients with AIDS. HTLV-I is associated with adult T cell leukemia/lymphoma. Both the virus and the disease are endemic to southwestern Japan and the Caribbean.
Gastric Helicobacter pylori infection is associated with gastric MALT lymphoma and perhaps gastric large cell lymphoma. Eradication of the infection produces durable remissions in about half of pts with gastric MALT lymphoma.
Inherited or acquired immunodeficiencies and autoimmune disorders predispose individuals to lymphoma. Lymphoma occurs with increased incidence in farmers and meat workers; Hodgkin’s disease is increased in wood workers.
DIAGNOSIS AND STAGING 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 extraction). 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. 28.
Staging varies with the diagnosis. In Hodgkin’s disease, defining the anatomic extent of disease is essential to define the optimal treatment approach. In acute leukemia, peripheral blood blast counts are most significant in assessing prognosis. In chronic leukemia, peripheral blood red blood cell and platelet counts are most significant in assessing prognosis. In indolent lymphoma, which is usually widespread at diagnosis, and in aggressive lymphoma, age, stage, lactate dehydrogenase (LDH) level, number of extranodal sites, and Karnofsky index predict outcome. In myeloma, serum levels of paraprotein, creatinine, and b2-microglobulin levels predict survival.
CHRONIC LYMPHOID LEUKEMIAS/LYMPHOMAS
Most of these entities have a natural history measured in years (prolymphocytic leukemia is very rare and can be very aggressive). Chronic lymphocytic leukemia is the most common entity in this group and the most common leukemia in the western world.
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) Usually presents as asymptomatic lymphocytosis in pts >60 years. The malignant cell is a CD5+ B cell that looks like a normal small lymphocyte. Trisomy 12 is the most common genetic abnormality. Prognosis is related to stage; stage is determined mainly by the degree to which the tumor cells crowd out normal hematopoietic elements from the marrow (Table 64-2). Cells may infiltrate nodes and spleen as well as marrow. Nodal involvement may be related to the expression of an adhesion molecule that allows the cells to remain in the node rather than recirculate. Pts often have hypogammaglobulinemia. Up to 20% have autoimmune antibodies that may produce autoimmune hemolytic anemia, thrombocytopenia, or red cell aplasia. Death is from infection, marrow failure, or intercurrent illnesses. In 5%, the disease evolves to aggressive lymphoma (Richter’s syndrome) that is refractory to treatment.
Table 64-2 Staging of B Cell CLL and Relation to Survival
Subsets of CLL may exist based on whether the immunoglobulin expressed by the tumor cell contains mutations (more indolent course, good prognosis) or retains the germline sequence (more aggressive course, poor response to therapy). Methods to distinguish the two subsets clinically are not well defined; CD38+ tumors may have poorer prognosis.
Supportive care is generally given until anemia or thrombocytopenia develop. At that time, tests are indicated to assess the cause of the anemia or thrombocytopenia. Decreased red blood cell and/or platelet counts related to peripheral destruction may be treated with splenectomy or glucocorticoids without cytotoxic therapy in many cases. If marrow replacement is the mechanism, cytotoxic therapy is indicated. Fludarabine 25 mg/m2/d IV × 5 days every 4 weeks induces responses in about 75% of pts, complete responses in half. Glucocorticoids increase the risk of infection without adding a substantial antitumor benefit. Monthly IV immunoglobulin significantly reduces risk of serious infection but is expensive. Alkylating agents are also active against the tumor. Therapeutic intent is palliative in most pts. Young pts may be candidates for high-dose therapy and autologous or allogeneic hematopoietic cell transplantation; long-term disease-free survival has been noted. Mini- transplant, in which the preparative regimen is immunosuppressive but not myeloablative, may be less toxic and as active or more active in disease treatment than high-dose therapy.
See Chap. 112 in HPIM-15 for discussion of the rarer entities.
These entities have a natural history measured in years. Median survival is about 10 years. Follicular center lymphoma is the most common indolent lymphoma, accounting for about one-third of all lymphoid malignancies.
FOLLICULAR CENTER LYMPHOMA Usually presents with painless peripheral lymphadenopathy, often involving several nodal regions. “B symptoms” (fever, sweats, weight loss) occur in 10%, less common than with Hodgkin’s disease. In about 25%, nodes wax and wane before the pt seeks medical attention. Median age is 55 years. Disease is widespread at diagnosis in 85%. Liver and bone marrow are commonly involved extranodal sites.
The tumor has a folliular or nodular growth pattern reflecting the follicular center origin of the malignant cell. The t(14;18) is present in 85% of cases, resulting in the overexpression of bcl-2, a protein involved in prevention of programmed cell death. The normal follicular center B cell is undergoing active mutation of the immunoglobulin variable regions in an effort to generate antibody of higher affinity for the selecting antigen. Follicular center lymphoma cells also have a high rate of mutation that leads to the accumulation of genetic damage. Over time, follicular center lymphomas acquire sufficient genetic damage (e.g., mutated p53) to accelerate their growth and evolve into diffuse large cell lymphomas that are refractory to treatment. The majority of pts dying from follicular lymphoma have undergone histologic transformation.
Only 15% of pts have localized disease, but the majority of these pts are curable with radiation therapy. Although many forms of treatment induce tumor regression in advanced-stage pts, it is not clear that treatment of any kind alters the natural history of disease. No therapy, single-agent alkylators, nucleoside analogues (fludarabine, cladribine), combination chemotherapy, radiation therapy, and biologic agents (interferon-a, monoclonal antibodies such as rituxan, anti-CD20) are all considered appropriate. Over 90% of pts are responsive to treatment; complete responses are seen in about half of pts treated aggressively. Younger pts are being treated experimentally with high- dose therapy and autologous hematopoietic stem cells or mini-transplant. It is not yet clear whether this is curative. There is some evidence that combination chemotherapy with or without interferon maintenance may prolong survival and delay or prevent histologic progression, especially in pts with poor prognostic features.
See Chap. 112 in HPIM-15 for discussion of the other indolent lymphomas.
A large number of pathologic entities share an aggressive natural history; survival untreated is 6–8 months, and nearly all untreated pts are dead within 1 year. Pts may present with asymptomatic adenopathy or symptoms referable to involvement of practically any nodal or extranodal site: mediastinal involvement may produce superior vena cava syndrome or pericardial tamponade; retroperitoneal nodes may obstruct ureters, abdominal masses may produce pain, ascites, or GI obstruction or perforation; CNS involvement may produce confusion, cranial nerve signs, headache, seizures, and/or spinal cord compression; bone involvement may produce pain or pathologic fracture. About 45% of pts have B symptoms.
Diffuse large B cell lymphoma is the most common histologic diagnosis among the aggressive lymphomas, accounting for ~30% of all lymphomas. Aggressive lymphomas together account for ~55% of all lymphoid tumors. About 85% of aggressive lymphomas are of mature B cell origin; 15% are derived from peripheral (postthymic) T cells.
Approach to the Patient
Early diagnostic biospy is critical. Pt workup is directed by symptoms and known patterns of disease. Pts with Waldeyer’s ring involvement should undergo careful evaluation of the GI tract. Pts with bone or bone marrow involvement should have a lumbar puncture to evaluate meningeal CNS involvement.
Localized aggressive lymphomas are usually treated with 4 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) combination chemotherapy followed by involved-field radiation therapy. About 85% of these pts are cured. The specific therapy used for pts with more advanced disease is controversial. Treatment outcome with CHOP is influenced by tumor bulk (usually measured by LDH levels, stage, and number of extranodal sites) and physiologic reserve (usually measured by age and Karnofsky status). The influence of these factors on outcome is shown in Table 64-3. In most series, CHOP cures about one-third of pts. Some investigators have demonstrated cure rates about twice those achieved by CHOP using more aggressive combination chemotherapy regimens that do not require hematopoietic stem cell support. However, randomized trials have not shown significant outcome differences. Furthermore, the use of a sequential high-dose chemotherapy regimen in pts with high-intermediate- and high-risk disease has yielded long-term survival in about 75% of pts in some institutions. Other studies fail to confirm a role for high-dose therapy. The use of rituxan plus chemotherapy appears to improve response rates.
Table 64-3 The International Index and Prognosis in Diffuse Aggressive Non-Hodgkin’s Lymphoma
About 30–45% of pts not cured with initial standard combination chemotherapy may be salvaged with high-dose therapy and autologous hematopoietic stem cell transplantation.
Specialized approaches are required for lymphomas involving certain sites (e.g., CNS, stomach) or under certain complicating clinical circumstances (e.g., concurrent illness, AIDS). Lymphomas occurring in iatrogenically immunosuppressed people may regress when immunosuppressive medication is withheld. Lymphomas occurring postallogeneic marrow transplant may regress with infusions of donor leukocytes.
Pts with rapidly growing bulky aggressive lymphoma may experience tumor lysis syndrome when treated (Chap. 43); prophylactic measures (hydration, urine alkalinization, allopurinol) may be lifesaving.
ACUTE LYMPHOID LEUKEMIAS/LYMPHOMAS
ACUTE LYMPHOBLASTIC LEUKEMIA AND LYMPHOBLASTIC LYMPHOMA These are more common in children than adults. The majority of cases have tumor cells that appear to be of thymic origin, and pts may have mediastinal masses. Pts usually present with recent onset of signs of marrow failure (pallor, fatigue, bleeding, fever, infection). Hepatosplenomegaly and adenopathy are common. Males may have testicular enlargement reflecting leukemic involvement. Meningeal involvement may be present at diagnosis or develop later. Elevated LDH, hyponatremia, and hypokalemia may be present, in addition to anemia, thrombocytopenia, and high peripheral blood blast counts. The leukemic cells are more often FAB L2 in type in adults than in children, where L1 predominates. Leukemia diagnosis requires at least 30% lymphoblasts in the marrow. Prognosis is adversely affected by high presenting white count, age >35 years, and the presence of t(9;22), t(1;19), and t(4;11) translocations.
Successful treatment requires intensive induction phase, CNS prophylaxis, and maintenance chemotherapy that extends for about 2 years. Vincristine, L-asparaginase, cytarabine, daunorubicin, and prednisone are particularly effective agents. Intrathecal or high-dose systemic methotrexate is effective CNS prophylaxis. Long-term survival of 60–65% of pts may be achieved. The role and timing of bone marrow transplantation in primary therapy is debated, but up to 30% of relapsed pts may be cured with salvage transplantation.
BURKITT’S LYMPHOMA/LEUKEMIA This is also more common in children. It is associated with translocations involving the c-myc gene on chromosome 8 rearranging with immunoglobulin heavy or light chain genes. Pts often have disseminated disease with large abdominal masses, hepatomegaly, and adenopathy. If a leukemic picture predominates, it is classified as FAB L3.
Resection of large abdominal masses improves treatment outcome. Aggressive leukemia regimens that include vincristine, cyclophosphamide, 6-mercaptopurine, doxorubicin, and prednisone are active. Cure may be achieved in 50–60%. The need for maintenance therapy is unclear. Prophylaxis against tumor lysis syndrome is important (Chap. 43).
ADULT T CELL LEUKEMIA/LYMPHOMA (ATL) This is very rare, and only a small fraction of persons infected with HTLV-I go on to develop the disease. Some HTLV-I-infected pts develop spastic paraplegia from spinal cord involvement without developing cancer. The characteristic clinical syndrome of ATL includes high white count without severe anemia or thrombocytopenia, skin infiltration, hepatomegaly, pulmonary infiltrates, meningeal involvement, and opportunistic infections. The tumor cells are CD4+ T cells with cloven hoof- or flower-shaped nuclei. Hypercalcemia occurs in nearly all pts and is related to cytokines produced by the tumor cells.
Aggressive therapy is associated with serious toxicity related to the underlying immunodeficiency. Glucocorticoids relieve hypercalcemia. The tumor is responsive to therapy, but responses are generally short-lived. Zidovudine and interferon may be palliative in some pts.
PLASMA CELL DISORDERS
The hallmark of plasma cell disorders is the production of immunoglobulin molecules or fragments from abnormal plasma cells. The intact immunoglobulin molecule, or the heavy chain or light chain produced by the abnormal plasma cell clone, is detectable in the serum and/or urine and is called the M (for monoclonal) component. The amount of the M component in any given pt reflects the tumor burden in that pt. In some, the presence of a clonal light chain in the urine (Bence Jones protein) is the only tumor product that is detectable. M components may be seen in pts with other lymphoid tumors, nonlymphoid cancers, and noncancerous conditions such as cirrhosis, sarcoidosis, parasitic infestations, and autoimmune diseases.
MULTIPLE MYELOMA A malignant proliferation of plasma cells in the bone marrow (notably not in lymph nodes). About 14,000 new cases are diagnosed each year. Disease manifestations result from tumor expansion, local and remote actions of tumor products, and the host response to the tumor. About 70% of pts have bone pain, usually involving the back and ribs, precipitated by movement. Bone lesions are multiple, lytic, and rarely accompanied by an osteoblastic response. Thus, bone scans are less useful than radiographs. The production of osteoclast-activating cytokines by tumor cells leads to substantial calcium mobilization, hypercalcemia, and symptoms related to it. Decreased synthesis and increased catabolism of normal immunoglobulins leads to hypogammaglobulinemia, and a poorly defined tumor product inhibits granulocyte migration. These changes create a susceptibility to bacterial infections, especially the pneumococcus, Klebsiella pneumoniae, and Staphylococcus aureus affecting the lung and Escherichia coli and other gram-negative pathogens affecting the urinary tract. Infections affect at least 75% of pts at some time in their course. Renal failure may affect 25% of pts; its pathogenesis is multifactorial—hypercalcemia, infection, toxic effects of light chains, urate nephropathy, dehydration. Neurologic symptoms may result from hyperviscosity, cryoglobulins, and rarely amyloid deposition in nerves. Anemia occurs in 80% related to myelophthisis and inhibition of erythropoiesis by tumor products. Clotting abnormalities may produce bleeding.
Diagnosis Marrow plasmacytosis >10%, lytic bone lesions, and a serum and/or urine M component are the classic triad. Monoclonal gammopathy of uncertain significance (MGUS) is much more common than myeloma, affecting about 6% of people over age 70; in general, MGUS is associated with a level of M component <20 g/L, low serum b2-microglobulin, <10% marrow plasma cells, and no bone lesions. Lifetime risk of progression of MGUS to myeloma is about 25%.
Staging Disease stage influences survival (Table 64-4).
Table 64-4 Myeloma Staging System
About 10% of pts have very slowly progressive disease and do not require treatment until the paraprotein levels rise above 50 g/L or progressive bone disease occurs. Pts with solitary plasmacytoma and extramedullary plasmacytoma are usually cured with localized radiation therapy. Supportive care includes early treatment of infections; control of hypercalcemia with glucocorticoids, hydration, and natriuresis; chronic administration of bisphosphonates to antagonize skeletal destruction; and prophylaxis against urate nephropathy and dehydration. Therapy aimed at the tumor is usually palliative: melphalan 8 mg/m2 orally for 4–7 days every 4–6 weeks plus prednisone. About 60% of pts have significant symptomatic improvement plus a 75% decline in the M component. Experimental approaches using sequential high- dose pulses of melphalan plus two successive autologous stem cell transplants have produced complete responses in about 50% of pts <65 years. Long- term follow-up is required to see whether survival is enhanced. Palliatively treated pts generally follow a chronic course for 2–5 years, followed by an acceleration characterized by organ infiltration with myeloma cells and marrow failure.
HODGKIN’S DISEASE About 8000 new cases are diagnosed each year. Hodgkin’s disease (HD) is a tumor of Reed-Sternberg cells, aneuploid cells that usually express CD30 and CD15 but may also express other B or T cell markers. Most tumors are derived from B cells in that immunoglobulin genes are rearranged, but some tumors are of T cell phenotype. Most of the cells in an enlarged node are normal lymphoid, plasma cells, monocytes, and eosinophils. The etiology is unknown, but the incidence in both identical twins is 99-fold increased over the expected concordance, suggesting a genetic susceptibility. Distribution of histologic subtypes is 75% nodular sclerosis, 20% mixed cellularity, with lymphocyte predominant and lymphocyte depleted representing about 5%.
Clinical Manifestations Usually presents with asymptomatic lymph node enlargement or with adenopathy associated with fever, night sweats, weight loss, and sometimes pruritus. Mediastinal adenopathy (common in nodular sclerosing HD) may produce cough. Spread of disease tends to be to contiguous lymph node groups. SVC obstruction or spinal cord compression may be presenting manifestation. Involvement of bone marrow and liver is rare.
Infection—mononucleosis, viral syndromes, toxoplasma, histoplasma, primary tuberculosis
Other malignancies—especially head and neck cancers
Sarcoidosis—mediastinal and hilar adenopathy
Immunologic and Hematologic Abnormalities
Defects in cell-mediated immunity (remains even after successful treatment of lymphoma); cutaneous anergy; diminished antibody production to capsular antigens of Haemophilus and pneumococcus
Anemia; elevated ESR; leukemoid reaction; eosinophilia; lymphocytopenia; fibrosis and granulomas in marrow
Staging The Ann Arbor staging classification is shown in Table 64-5. It is important to determine extent of disease to guide choice of treatment; physical exam, CXR, thoracoabdominal CT, bone marrow biopsy; ultrasound examinations, lymphangiogram. Staging laparotomy should be used, especially to evaluate the spleen, if pt has early-stage disease on clinical grounds and radiation therapy is being contemplated.
Table 64-5 Ann Arbor Staging System
About 85% of pts are curable. Therapy should be performed by experienced clinicians in centers with appropriate facilities. Pts with stages I and II disease documented by negative laparotomy are treated with subtotal nodal radiation therapy. Those with stage III or IV disease receive six cycles of combination chemotherapy, usually either ABVD or MOPP-ABV hybrid therapy or MOPP/ABVD alternating therapy. Pts with any stage disease accompanied by a large mediastinal mass (>1/3 the greatest chest diameter) should receive combined modality therapy with MOPP/ABVD or MOPP-ABV hybrid followed by mantle field radiation therapy (radiation plus ABVD is too toxic to the lung). About two-thirds of pts not cured by their initial radiation therapy treatment are rescued by salvage combination chemotherapy. About one half of pts not cured by their initial chemotherapy regimen may be rescued by high-dose therapy and autologous stem cell transplant.
With long-term follow-up, it has become clear that more pts are dying of late fatal toxicities related to radiation therapy (myocardial infarction, second cancers) than from HD. It may be possible to avoid radiation exposure by using combination chemotherapy in early-stage disease as well as in advanced-stage disease.
For a more detailed discussion, see Armitage JO, Longo DL: Malignancies of Lymphoid Cells, Chap. 112, p. 715; and Longo DL: Plasma Cell Disorders, Chap. 113, p. 727, in HPIM-15.