• Malignancies of lymphoid cells range from the most indolent to the most aggressive human malignancies. • These cancers arise from cells of the immune system at different stages of differentiation, resulting in a wide range of morphologic, immunologic, and clinical findings. Insights on the normal immune system have allowed a better understanding of these sometimes confusing disorders. • Some malignancies of lymphoid cells almost always present as leukemia (i.e., primary involvement of bone marrow and blood), while others almost always present as lymphomas (i.e., solid tumors of the immune system). • However, other malignancies of lymphoid cells can present as either leukemia or lymphoma WHO CLASSIFICATION
• The classification of lymphoid cancers evolved steadily
throughout the twentieth century. The distinction between leukemia and lymphoma was made early, and separate classification systems were developed for each. • Leukemias were first divided into acute and chronic subtypes based on average survival. Chronic leukemias were easily subdivided into those of lymphoid or myeloid origin based on morphologic characteristics. • However, a spectrum of diseases that were formerly all called chronic lymphoid leukemia has become apparent (Table 110– 1). The acute leukemias were usually malignancies of blast cells with few identifying characteristics. When cytochemical stains became available, it was possible to divide these objectively into myeloid malignancies and acute leukemias of lymphoid cells. • Acute leukemias of lymphoid cells have been subdivided based on morphologic characteristics by the French- American-British (FAB) group (Table 110–2). • Non-Hodgkin's lymphomas were separated from Hodgkin's disease by recognition of the Sternberg-Reed cells early in the twentieth century. • The histologic classification for non-Hodgkin's lymphomas has been one of the most contentious issues in oncology. Imperfect morphologic systems were supplanted by imperfect immunologic systems, and poor reproducibility of diagnosis has hampered progress. • In 1999, the World Health Organization (WHO) classification of lymphoid malignancies was devised through a process of consensus development among international leaders in hematopathology and clinical oncology. The WHO classification takes into account morphologic, clinical, immunologic, and genetic information and attempts to divide non-Hodgkin's lymphomas and other lymphoid malignancies into clinical/pathologic entities that have clinical and therapeutic relevance. GENERAL ASPECTS OF LYMPHOID MALIGNANCIES ETIOLOGY AND EPIDEMIOLOGY • The relative frequency of the various lymphoid malignancies is shown in Fig. 110-1. • Chronic lymphoid leukemia (CLL) is the most prevalent form of leukemia in Western countries. It occurs most frequently in older adults and is exceedingly rare in children. In 2010, 14,990 new cases were diagnosed in the United States, but because of the prolonged survival associated with this disorder, the total prevalence is many times higher. • CLL is more common in men than in women and more common in whites than in blacks. This is an uncommon malignancy in Asia. The etiologic factors for typical CLL are unknown. • In contrast to CLL, acute lymphoid leukemias (ALLs) are predominantly cancers of children and young adults. The L3 or Burkitt's leukemia occurring in children in developing countries seems to be associated with infection by the Epstein-Barr virus (EBV) in infancy. However, the explanation for the etiology of more common subtypes of ALL is much less certain. Childhood ALL occurs more often in higher socioeconomic subgroups. Children with trisomy 21 (Down syndrome) have an increased risk for childhood ALL as well as acute myeloid leukemia (AML). Exposure to high-energy radiation in early childhood increases the risk of developing T cell ALL. • A number of environmental factors have been implicated in the occurrence of non-Hodgkin's lymphoma, including infectious agents, chemical exposures, and medical treatments. Several studies have demonstrated an association between exposure to agricultural chemicals and an increased incidence in non- Hodgkin's lymphoma. • Patients treated for Hodgkin's disease can develop non- Hodgkin's lymphoma; it is unclear whether this is a consequence of the Hodgkin's disease or its treatment. However, a number of non-Hodgkin's lymphomas are associated with infectious agents (Table 110–4). HTLV-I infects T cells and leads directly to the development of adult T cell lymphoma (ATL) in a small percentage of infected patients. • The cumulative lifetime risk of developing lymphoma in an infected patient is 2.5%. The virus is transmitted by infected lymphocytes ingested by nursing babies of infected mothers, bloodborne transmission, or sexually. The median age of patients with ATL is 56 years, emphasizing the long latency. HTLV-I is also the cause of tropical spastic paraparesis—a neurologic disorder that occurs somewhat more frequently than lymphoma and with shorter latency and usually from transfusion-transmitted virus IMMUNOLOGY
• All lymphoid cells are derived from a common hematopoietic
progenitor that gives rise to lymphoid, myeloid, erythroid, monocyte, and megakaryocyte lineages. • Through the ordered and sequential activation of a series of transcription factors, the cell first becomes committed to the lymphoid lineage and then gives rise to B and T cells. • About 75% of all lymphoid leukemias and 90% of all lymphomas are of B cell origin. A cell becomes committed to B cell development when it begins to rearrange its immunoglobulin genes. The sequence of cellular changes, including changes in cell-surface phenotype, that characterizes normal B cell development is shown in Fig. 110-2. • A cell becomes committed to T cell differentiation upon migration to the thymus and rearrangement of T cell antigen receptor genes Pathway of normal B cell differentiation and relationship to B cell lymphomas. HLA-DR, CD10, CD19, CD20, CD21, CD22, CD5, and CD38 are cell markers used to distinguish stages of development. Terminal transferase (TdT) is a cellular enzyme. Immunoglobulin heavy chain gene rearrangement (HCR) and light chain gene rearrangement or deletion (R or D, R or D) occur early in B cell development. The approximate normal stage of differentiation associated with particular lymphomas is shown. ALL, acute lymphoid leukemia; CLL, chronic lymphoid leukemia; SL, small lymphocytic lymphoma. • Malignancies of lymphoid cells are associated with recurring genetic abnormalities. While specific genetic abnormalities have not been identified for all subtypes of lymphoid malignancies, it is presumed that they exist. • Genetic abnormalities can be identified at a variety of levels including gross chromosomal changes (i.e., translocations, additions, or deletions); rearrangement of specific genes that may or may not be apparent from cytogenetic studies; and overexpression, underexpression, or mutation of specific oncogenes. Altered expression or mutation of specific proteins is particularly important. • Many lymphomas contain balanced chromosomal translocations involving the antigen receptor genes; immunoglobulin genes on chromosomes 2, 14, and 22 in B cells; and T cell antigen receptor genes on chromosomes 7 and 14 in T cells. • The rearrangement of chromosome segments to generate mature antigen receptors must create a site of vulnerability to aberrant recombination. B cells are even more susceptible to acquiring mutations during their maturation in germinal centers; the generation of antibody of higher affinity requires the introduction of mutations into the variable region genes in the germinal centers. Other nonimmunoglobulin genes, e.g., bcl-6, may acquire mutations as well. APPROACH TO THE PATIENT: LYMPHOID CELL MALIGNANCIES • Regardless of the type of lymphoid malignancy, the initial evaluation of the patient should include performance of a careful history and physical examination. These will help confirm the diagnosis, identify those manifestations of the disease that might require prompt attention, and aid in the selection of further studies to optimally characterize the patient's status to allow the best choice of therapy. It is difficult to overemphasize the importance of a carefully done history and physical examination. They might provide observations that lead to reconsidering the diagnosis, provide hints at etiology, clarify the stage, and allow the physician to establish rapport with the patient that will make it possible to develop and carry out a therapeutic plan. • For patients with ALL, evaluation is usually completed after a complete blood count, chemistry studies reflecting major organ function, a bone marrow biopsy with genetic and immunologic studies, and a lumbar puncture. The latter is necessary to rule out occult CNS involvement. At this point, most patients would be ready to begin therapy. In ALL, prognosis is dependent upon the genetic characteristics of the tumor, the patient's age, the white cell count, and the patient's overall clinical status and major organ function. • In CLL, the patient evaluation should include a complete blood count, chemistry tests to measure major organ function, serum protein electrophoresis, and a bone marrow biopsy. CLINICAL FEATURES, TREATMENT, AND PROGNOSIS OF SPECIFIC LYMPHOID MALIGNANCIES PRECURSOR B CELL LYMPHOBLASTIC LEUKEMIA/LYMPHOMA • The most common cancer in childhood is B cell ALL. Although this disorder can also present as a lymphoma in either adults or children, presentation as lymphoma is rare. • The malignant cells in patients with precursor B cell lymphoblastic leukemia are most commonly of pre–B cell origin. • Patients typically present with signs of bone marrow failure such as pallor, fatigue, bleeding, fever, and infection related to peripheral blood cytopenias. • Peripheral blood counts regularly show anemia and thrombocytopenia but might show leukopenia, a normal leukocyte count, or leukocytosis based largely on the number of circulating malignant cells. • Extramedullary sites of disease are frequently involved in patients who present with leukemia, including lymphadenopathy, hepato- or splenomegaly, CNS disease, testicular enlargement, and/or cutaneous infiltration. • The diagnosis is usually made by bone marrow biopsy, which shows infiltration by malignant lymphoblasts TREATMENT: PRECURSOR B CELL LYMPHOBLASTIC LEUKEMIA • The treatment of patients with precursor B cell ALL involves remission induction with combination chemotherapy, a consolidation phase that includes administration of high-dose systemic therapy and treatment to eliminate disease in the CNS, and a period of continuing therapy to prevent relapse and effect cure. The overall cure rate in children is 90%, while 50% of adults are long-term disease-free survivors. This reflects the high proportion of adverse cytogenetic abnormalities seen in adults with precursor B cell ALL. • Precursor B cell lymphoblastic lymphoma is a rare presentation of precursor B cell lymphoblastic malignancy. These patients often have a rapid transformation to leukemia and should be treated as though they had presented with leukemia. The few patients who present with the disease confined to lymph nodes have a high cure rate. B CELL CHRONIC LYMPHOID LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA • B cell CLL/small lymphocytic lymphoma represents the most common lymphoid leukemia, and when presenting as a lymphoma, it accounts for 7% of non-Hodgkin's lymphomas. • Presentation can be as either leukemia or lymphoma. The major clinical characteristics of B cell CLL/small lymphocytic lymphoma are presented in Table 110–10. • The diagnosis of typical B cell CLL is made when an increased number of circulating lymphocytes (i.e., >4 x 109/L and usually >10 x 109/L) is found (Fig. 110-6) that are monoclonal B cells expressing the CD5 antigen. Finding bone marrow infiltration by the same cells confirms the diagnosis. • The peripheral blood smear in such patients typically shows many "smudge" or "basket" cells, nuclear remnants of cells damaged by the physical shear stress of making the blood smear. If cytogenetic studies are performed, trisomy 12 is found in 25–30% of patients. • Abnormalities in chromosome 13 are also seen TREATMENT: B CELL CHRONIC LYMPHOID LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA • Patients whose presentation is typical B cell CLL with no manifestations of the disease other than bone marrow involvement and lymphocytosis (i.e., Rai stage 0 and Binet stage A; Table 110–7) can be followed without specific therapy for their malignancy. These patients have a median survival >10 years, and some will never require therapy for this disorder. If the patient has an adequate number of circulating normal blood cells and is asymptomatic, many physicians would not initiate therapy for patients in the intermediate stage of the disease manifested by lymphadenopathy and/or hepatosplenomegaly. However, the median survival for these patients is 7 years, and most will require treatment in the first few years of follow-up. • Patients who present with bone marrow failure (i.e., Rai stage III or IV or Binet stage C) will require initial therapy in almost all cases. These patients have a serious disorder with a median survival of only 1.5 years. It must be remembered that immune manifestations of typical B cell CLL should be managed independently of specific antileukemia therapy. For example, glucocorticoid therapy for autoimmune cytopenias and globulin replacement for patients with hypogammaglobulinemia should be used whether or not antileukemia therapy is given. • Patients who present primarily with lymphoma and have a low IPI score have a 5-year survival of 75%, but those with a high IPI score have a 5-year survival of <40% and are more likely to require early therapy. • The most common treatments for patients with typical B cell CLL/small lymphocytic lymphoma have been chlorambucil or fludarabine, alone or in combination. • Chlorambucil can be administered orally with few immediate side effects, while fludarabine is administered IV and is associated with significant immune suppression. • However, fludarabine is by far the more active agent and is the only drug associated with a significant incidence of complete remission. • The combination of rituximab (375–500 mg/m2 day 1), fludarabine (25 mg/m2 days 2–4 on cycle 1 and 1–3 in subsequent cycles), and cyclophosphamide (250 mg/m2 with fludarabine) achieves complete responses in 69% of patients, and those responses are associated with molecular remissions in half of the cases. Half the patients experience grade III or IV neutropenia. • For young patients presenting with leukemia requiring therapy, regimens containing fludarabine are the treatment of choice. Because fludarabine is an effective second-line agent in patients with tumors unresponsive to chlorambucil, the latter agent is often chosen in elderly patients who require therapy. DIFFUSE LARGE B CELL LYMPHOMA • Diffuse large B cell lymphoma is the most common type of non-Hodgkin's lymphoma, representing approximately one-third of all cases. This lymphoma makes up the majority of cases in previous clinical trials of "aggressive" or "intermediate-grade" lymphoma. Table 110–10 shows the clinical characteristics of diffuse large B cell lymphoma. • The diagnosis of diffuse large B cell lymphoma can be made accurately by an expert hematopathologist. Cytogenetic and molecular genetic studies are not necessary for diagnosis, but some evidence has accumulated that patients whose tumors overexpress the BCL-2 protein might be more likely to relapse than others. Patients with prominent mediastinal involvement are sometimes diagnosed as a separate subgroup having primary mediastinal diffuse large B cell lymphoma. This latter group of patients has a younger median age (i.e., 37 years) and a female predominance (66%). Subtypes of diffuse large B cell lymphoma, including those with an immunoblastic subtype and tumors with extensive fibrosis, are recognized by pathologists but do not appear to have important independent prognostic significance.