Non-Hodgkin's lymphomas: current classification and management
Authors: A. T. Skarin, D. M. Dorfman
Journal: CA A Cancer Journal for Clinicians (1997)

The non-Hodgkin's lymphomas constitute a heterogenous group of neoplasms of the lymphoid system that include distinct entities defined by clinical, histologic, immunologic, molecular, and genetic characteristics. Each entity represents clonal expansion of a normal precursor cell. Study of human lymphomas using modern techniques of research immunology and cell biology has contributed immensely to an understanding of both the immune system and neoplastic transformation. About 53,600 new cases of non-Hodgkin's lymphomas will be diagnosed in the United States in 1997, and slightly fewer than 50% of patients will die, making this disorder sixth in incidence and mortality among malignancies.l The incidence of non-Hodgkin's lymphomas is rising at a rate of 3% to 4% per year, or 50% during the last l5 years, which is one of the largest increases for any cancer group, according to the American Cancer Society.197 This includes not only the increase in AIDS-related lymphomas but also the increase in lymphomas occurring in patients older than 65 years. Various disease states, such as inherited and acquired immunodeficiency disorders and occupational and environmental exposures, have been associated with the development of non-Hodgkin's lymphomas.198, 199 Considerable progress has occurred in the classification of non-Hodgkin's lymphomas during the past 15 years. The morphologically oriented Rappaport system, which was introduced almost 50 years ago, allowed for the separation of non-Hodgkin's lymphomas into two clinically useful categories: those with a favorable prognosis (nodular lymphomas) and those with an unfavorable prognosis (diffuse lymphomas). The National Cancer Institute-sponsored international Working Formulation (WF) classification introduced in 1982 was meant to be a translation system for other classifications, including the Rappaport and the immunologically oriented Lukes and Collins and Kiel systems.200 The WF categories include low, intermediate, and high-grade lymphoma types, based upon decreasing survival rates, respectively (Table 1). Paradoxically, with the development of effective chemotherapy regimens, the prognosis changed because of the increasing cure rates of patients in the intermediate and unfavorable prognosis categories and the eventual relapse and death of most patients with favorable categories.201 The classification systems mentioned earlier do not include disorders such as chronic lymphocytic leukemia, hairy cell leukemia, plasmacytoma, and mycosis fungoides. In addition, new clinical pathologic entities have been described recently, coincidental with the wider use of immunochemistry and cyto-genetic and molecular analysis. These new entities— including mantle cell, marginal zone (mucosa-associated lymphoid tissue [MALT] and monocytoid B-cell), T-cell-rich B-cell, and anaplastic large-cell lymphomas—share some growth patterns and morphologic features with the classic and common non-Hodgkin's lymphomas. In 1994, the International Lymphoma Study Group proposed the revised European-American lymphoma classification (REAL) schema. The REAL classification was based on known disease entities and promoted the concept that a range of morphologic grades and degrees of clinical aggressiveness might be present within each entity.202 It is a consensus list of about 20 currently recognizable lymphoid neoplasms. The REAL schema classifies these neoplasms as B-cell, T/natural killer (NK)-cell, and Hodgkin's disease (Tables 1 and 2). T-cell and B-cell lymphomas are further divided into precursor and peripheral cell types. In this review, Hodgkin's disease will not be discussed. The REAL classification can be used with the more traditional WF lymphoma categories (Table 1), and a clinically useful REAL schema based upon indolent, aggressive, and highly aggressive lymphoma types has been proposed (Table 2).202 Some reservations exist about the clinical practicality and other aspects of the REAL classification.203 One European cooperative group, however, reclassified cases from the WF schema to the REAL schema and concluded that the latter offers additional information that may allow for design of more appropriate therapies with a better chance of success.204 Preliminary data analysis from the Southwest Oncology Group shows that the REAL classification allows for improved delineation of histologic risk groups.205 Full acceptance of the REAL classification of non-Hodgkin's lymphomas awaits further evaluation of its clinical utility. The REAL classification is based on known disease entities and the concept that a range of morphologic grades and degrees of clinical aggressiveness might be present within each entity. In contrast to patients with Hodgkin's disease, most patients with non-Hodg-kin's lymphomas present with advanced stage III or IV disease, which often is manifested as generalized adenopathy. In addition, non-Hodgkin's lymphomas may involve unusual sites, such as epitrochlear or popliteal nodes or Waldeyer's ring (nasopharynx), resulting in reduced hearing because of eustachian tube obstruction. Sites rarely involved in Hodgkin's disease but often seen in non-Hodgkin's lymphomas include skin (solitary or multiple lesions), thyroid, breast, gastrointestinal tract, brain, and ovaries or testes. Patients with indolent (low-grade) lymphomas have a long history of disease that is slowly progressive over many years, usually without any symptoms. The disease may temporarily regress, the so-called "spontaneous" remission, which is observed in 5% to 15% of cases. Indolent lymphomas also have a propensity to undergo histologic transformation, or conversion to a more aggressive lymphoma, usually of a large-cell type. This occurs in 15% to 30% or more of cases, usually after several years, and is not related to therapy. Patients with indolent non-Hodgkin's lymphomas present with three clinical patterns: disseminated disease with circulating malignant cells; primarily nodal disease; and primarily extranodal, slowly progressive disease. In contrast, aggressive non-Hodgkin's lymphomas (intermediate and high grade) grow rapidly and may be fatal within months if not treated. B symptoms (unexplained weight loss of more than 10% of body weight, unexplained fever with temperatures more than 38° C, and night sweats) occur mainly in patients with aggressive lymphomas and affect 40% to 50% of patients. The most common aggressive type is diffuse large B-cell lymphoma, which accounts for 60% to 70% of cases. Less common types include anaplastic large-cell lymphoma and peripheral T-cell lymphomas. Clinical features of certain newly recognized lymphomas and primary extranodal lymphomas are noted later in this article. Current histopathologic classification schemes for non-Hodgkin's lymphomas are shown in Tables 1 and 2. The WF scheme parallels biologic behavior; that is, categories A to C (low grade) exhibit indolent behavior in the untreated state, with survival of 5 to 10 or more years. Classes D to G (intermediate grade) exhibit more aggressive behavior, with survival of 2 to 5 years, and classes H to J (high grade) exhibit highly aggressive behavior, with survival of less than 6 months to 2 years. A comparison of the WF lymphoma classification with the REAL system is useful for understanding placement of recently described clinical pathologic entities relative to biologic behavior. The REAL clinical grouping (Table 2) further categorizes indolent lymphomas as disseminated, extranodal, or nodal and separates the highly aggressive, acute lymphomas and leukemias from the more common aggressive lymphomas. The Kiel classification system, popular in Europe, is detailed elsewhere.199 Small lymphocytic lymphoma shows a diffuse architectural pattern but may have a vaguely nodular appearance at low magnification because of the presence of pseudofollicular proliferation centers containing large nucleolated cells (A), which contrast with the small cells containing round nuclei and scan cytoplasm that make up the bulk of the neoplastic infiltrate (B). Such monotonous sheets of small lymphocytes also may be seen in lymph nodes and bone marrow of patients with chronic lymphocytic leukemia (C). In lymphoplasmacytoid lymphoma, small lymphoid cells with plasmacytic differentiation are seen. (D). Reproduced with permission from Skarin and Dorfman.253 The use of specific monoclonal antibodies directed against cell surface antigens has contributed considerably to the understanding of the immunology of non-Hodgkin's lymphomas. Use of this method along with molecular biological techniques has shown that most non-Hodgkin's lymphomas have normal cellular counterparts corresponding to stages in lymphocyte ontogeny. Approximately 85% are of B-cell type, and about 15% are of T-cell type. The most common B-cell lymphomas are follicular types and diffuse large-cell types. B-cell non-Hodgkin's lymphomas can be divided into prefollicular center cell type (CD5 positive, CD10 negative), follicular center cell type (CD5 negative, CD10 positive), and postfollicular center cell type (CD5 negative, CD10 negative). T-cell non-Hodgkin's lymphomas are generally considered to have an immunophenotype corresponding to the post-thymic stage of T-cell development. The exceptions are lymphoblastic lymphomas, which have an immature T-cell phenotype (Table 3). Many chromosomal and molecular biologic defects have been detected in various non-Hodgkin's lymphomas, and they often affect genes involved in the control of cell growth. Several chromosomal translocations have been identified, particularly involving sites of immunoglobulin heavy and light chain genes on chromosomes 2, 14, and 22, as discussed below and summarized in Table 3. Non-Hodgkin's lymphomas are ideally studied using histologic, immunophenotyic, and cytogenetic/molecular biologic methods, as shown in Table 4. Unfixed or fresh-frozen tissue is required for many of these methods. Assessment by a qualified hematopathologist is recommended. Monoclonality is confirmed in B-cell lymphomas by demonstration of the restricted expression of a single surface immunoglobulin light chain species in the neoplastic cell population, using immunophenotypic methods. T-cell mono-clonality is suggested by the absence of expression of one or more pan-T-cell antigens in the neoplastic cell population (antigen deletion). Monoclonality in B-cell and T-cell non-Hodgkin's lymphomas may be confirmed by molecular biologic methods that show a clonal immunoglobulin or T-cell receptor gene rearrangement, respectively, in the neoplastic cell population. Marginal zone lymphoma may have a nodular appearance, which results from the presence of neoplastic cells surrounding and infiltrating reactive lymphoid follicles, or it may show a diffuse architectural pattern. The neoplastic cells typically have a monocytoid to plasmacytoid appearance. Small lymphocytic lymphoma, which accounts for approximately 5% of non-Hodgkin's lymphomas in adults, is an indolent neoplasm that typically presents as a tumor mass without lymphocytosis. Lymph node architecture is diffusely effaced by small, round lymphoid cells with scattered pseudofollicular proliferation centers containing larger nucleolated cells (Fig. 1A and B). Neoplastic B cells characteristically coexpress the T-cell antigen CD5 and activation antigen CD23. Cytogenetic abnormalities, which include trisomy 12, 14q+, and abnormalities of 13q14, are associated with a poorer prognosis. Small lymphocytic lymphoma is morphologically indistinguishable from chronic lympho-cytic leukemia (Fig. 1C). Over time, 10% to 20% of cases of small lymphocytic lym-phoma progress to chronic lymphocytic leukemia.206 Lymphoplasmacytoid lymphoma, which may present with clinical features of Waldenstrom's macroglobulinemia, is another indolent neoplasm of older adults. Consisting of small lymphoid cells with plasmacytic differentiation, it was grouped with small lymphocytic lym-phoma in the past (Fig. 1D). Mantle cell lymphoma may grow in a nodular (marginal zone) or diffuse pattern. Neoplastic cells are small with round, irregular, or, occasionally, cleaved nuclei. This neoplasm is thought to originate from the postgerminal center B cells that are CD5 negative and have, in contrast to small lymphocytic lymphoma cells, undergone somatic hypermutation of immunoglobulin variable region genes.207 Chromosomal translocation t(9;14) is associated with lymphoplasma-cytoid lymphoma.208 This neoplasm, like small lymphocytic lymphoma, may transform to large-cell non-Hodgkin's lymphoma over time. Marginal zone lymphoma is a provisional classification that encompasses a group of low-grade B-cell neoplasms thought to originate in CD5/10/23-negative marginal zone cells of spleen, mucosa-associated lymphoid tissue, and lymph nodes.202 Neoplastic cells have more cytoplasm than do small lymphocytic lymphoma cells and may have a monocytoid appearance; monocytoid B-cell lymphoma is another term for the nodal form of this entity (Fig. 2). In the splenic form, neoplastic cells may have villous projections, in which instance the entity has been called splenic lymphoma with villous lymphocytes. Tumor behavior is indolent, and localized extranodal tumors (for example, in the gastrointestinal tract or lung) may be cured by surgical excision. Trisomy 3 is associated with marginal zone lymphoma; chromosome translocation t(11;18) has been reported in extranodal cases. Follicular center cell lymphoma presents as a nodular proliferation of neoplastic cells that are a mixture of small cells with irregular to cleaved nuclei (shown at low power [A] and higher power [B] with reticulin stain) and large cells with round to oval to irregular nuclei with distinct nucleoli (C). Reproduced with permission from Skarin and Dorfman.253 Mantle cell lymphoma, an entity first described in the mid-1970s, accounts for approximately 5% of non-Hodgkin's lymphoma in adults. It is composed of small lymphoid cells with irregular to occasionally cleaved nuclei that occur in a nodular (mantle zone) or diffuse form, typically in older adults (Fig. 3). The entity was previously classified as an intermediate (between well differentiated and poorly differentiated) lymphocytic lymphoma. (A) Diffuse large-cell lymphoma, B-cell type, consists of a population of large cells similar to those seen in follicular center cell lymphoma. In other cases, neoplastic cells may have an immunoblastic, multilobate, or anaplas-tic appearance. (B) Immunoperoxidase stain for the Ki-1 antigen (CD30) is characteristically positive in the large malignant cells of anaplas-tic large-cell lymphoma. Neoplastic cells are thought to originate in CD5-positive B cells of the mantle zone of lymphoid follicles; in contrast to the cells of small lymphocytic lym-phoma, these are CD23 negative. Mantle cell lymphoma cells express elevated levels of cyclin D1, a cell cycle regulatory protein usually associated with chromosomal translocation t(11;14). Cyclin D1 is thought to contribute to lymphoma genesis by shortening the G1 phase of the cell cycle in neoplastic cells. Prognosis is poorer than in the other small-cell non-Hodgkin's lymphomas, which are indolent, and poorer than in aggressive large-cell types. Median survival is 3 to 4 years.209 Small noncleaved cell lymphoma typically presents as a diffuse infiltrate of small to intermediate-size lymphoid cells with round nuclei that have one to three distinct nucleoli. The neoplasm is high grade, with numerous associated mitotic figures, necrotic cells, and macrophages, which may impart a starry sky appearance to the process at low magnification. Follicular center cell lymphoma, which accounts for approximately 35% of non-Hodgkin's lymphomas in adults, consists of a variable mixture of small lymphoid cells with cleaved nuclei and large cells that have round, oval, or irregular nuclei with distinct nucleoli, resulting in small cleaved cell, mixed small and large cell, and large-cell subtypes (Fig. 4). These tumors of CD5-negative, CD10-positive B cells usually originate in lymph nodes. Neoplastic cells express increased levels of bcl-2, an anti-apoptosis protein associated with chromosomal translocation t(14;18) and thought to contribute to lymphoma genesis. As many as 50% of follicular center cell lymphomas progress to diffuse large-cell lymphoma over time. Lymphoblastic lymphoma, another high-grade malignant neoplasm, typically consists of a population of precursor T cells of small to intermediate size with round to irregular nuclei and fine chromatin, as seen in lymphoblasts. Nucleoli are inconspicuous. Diffuse large B-cell lymphoma, an aggressive neoplasm, accounts for approximately 30% of non-Hodgkin's lymphomas in adults and 25% in children. Neoplastic cells have the appearance of large follicular center cell lymphoma cells or an immunoblastic or anaplastic appearance (Fig. 5). Approximately 20% to 30% of cases exhibit the chromosomal translocation t(14;18) noted earlier, and approximately 30% exhibit gene rearrangements at the 3q27 locus involving the bcl-6 gene. The latter are associated with extra-nodal involvement and favorable clinical features.210 Small noncleaved cell lymphomas form a group of highly aggressive neoplasms that includes Burkitt's and non-Burkitt's types. These lymphomas account for 5% or less of non-Hodgkin's lymphomas in adults but approximately 35% of non-Hodgkin's lymphomas in children. Small noncleaved cell lymphoma often presents as an abdominal or head and neck mass in children. Neoplastic B cells are small to intermediate in size and have one to three distinct nucleoli (Fig. 6). Often, many mitotic figures and necrotic cells are present, as expected in a high-grade neoplasm. Peripheral T-cell lymphomas constitute a heterogenous group of neoplasms that may be composed of small to large cells, including anaplastic cells. The latter may give the appearance of Reed-Sternberg cells typically seen in Hodgkin's disease, but immunophenotypically they can be shown to be T cells, a subset of which may express the Ki-1 activation antigen CD30. Burkitt's type small noncleaved cell lymphoma is associated with translocations t(8;14), t(2;8), and t(8;22) involving the c-myc oncogene, which, like cyclin D1, is thought to affect progression through the G2 phase of the cell cycle.211 Non-Burkitt's type (or Burkitt's-like) small noncleaved cell lymphoma is not associated with c-myc transloca-tions; rather, it is associated with bcl-2 translocations in 30% of cases.212 Small noncleaved cell lymphoma is morphologically indistinguishable from B-cell acute lymphoblastic leukemia, the L3 subtype of acute lymphoblastic leukemia. Lymphoblastic lymphoma, another highly aggressive non-Hodgkin's lymphoma, is uncommon in adults. It accounts for approximately 30% of pediatric non-Hodgkin's lymphomas, however, typically presenting as a mediastinal mass. Most cases are precursor T-cell type, expressing several phenotypic markers of immature T cells, including terminal deoxynu-cleotidyl transferase (TdT). A few cases are precursor B-cell type (Fig. 7). Lymphoblastic lymphoma is associated with several chromosomal translocations and other rearrangements involving T-cell receptor genes and transcription factor genes, such as TAL1, which may be rearranged in 25% of cases of lymphoblastic lymphoma and T-cell acute lymphoblastic lymphoma.211 Peripheral T-cell lymphomas form a heterogeneous group of neoplasms that account for 10% to 15% of non-Hodgkin's lymphomas in adults and children (Fig. 8). Angioimmunoblastic T-cell lymphoma is a common specific subtype. Peripheral T-cell lymphomas are aggressive neoplasms, often presenting as stage IV disease.213 Patients may have B symptoms, hepatosplenomegaly, pulmonary and skin lesions, eosinophilia and Coombs-positive hemolytic anemia, and various infections, which may be fatal. The immunophenotype varies but includes expression of several pan-T-cell antigens with frequent absence of expression of one or more of these antigens.214 T-cell receptor genes exhibit clonal rearrangements. In children, a significant number of cases of large-cell lymphoma are T-cell type with an associated chromosomal translocation t(2;5) thought to affect cell growth and differentiation.211 This translo-cation is associated with CD30-positive anaplastic large-cell lymphoma, a specific subtype of peripheral T-cell lymphoma, and with nonanaplastic lymphomas (Fig. 5B). About 20% of cases of anaplastic large-cell lymphoma express B-cell markers, and 5% lack evidence of T-cell or B-cell origin. The malignant cells are large, with bizarre, irregularly shaped or polylobated nuclei that have abundant basophilic cytoplasm. Because of the involvement of sinusoidal areas of lymph nodes and a cohesive growth pattern, a mistaken diagnosis of metastatic carcinoma may be made. Also, the large cells with prominent nucleoli may suggest Reed-Sternberg cells. Clinically, patients with anaplastic large-cell lymphoma may present with cutaneous lesions and a protracted course or generalized stage iv disease with an aggressive illness.215 Almost 25% of non-Hodgkin's lymphomas primarily involve extranodal sites. Most are diffuse large B-cell lymphomas (55% of gastric and intestinal; more than 90% of bone, central nervous system, and eye; 20% of ocular adnexa; and less than l5% of skin lymphomas).202 Mucosa-associated lymphoid tissue lymphomas often primarily involve the stomach (40%), intestine (20%), and ocular adnexae (30%); lung, breast, and thyroid are uncommon sites. Primary extranodal follicular lymphomas are often seen in ocular adenexae (40%) and skin (less than 15%) but are rare in the gastrointestinal tract, bone, and central nervous system. Extranodal Burkitt's and Burkitt's-like lymphomas occur mainly in the stomach, intestine, bone, and bone marrow. Bone marrow biopsy is indicated in most patients because bone marrow involvement is highly likely in non-Hodgkin's lymphoma. Clinical evaluation begins with a detailed history and physical examination. The presence or absence of B symptoms must be determined. Particular attention must be paid to the presence of any skin lesions or adenopathy and evaluation of Waldeyer's ring. The size of the liver and spleen should be noted. CT scan of the chest shows a large anterior mediastinal mass in a 25-year-old man with stage IIA diffuse large B-cell lymphoma who presented with superior vena cava syndrome. The trachea is compressed by the tumor mass. Routine blood counts and blood chemistry studies are necessary, particularly the lactate dehydrogenase (LDH) level, which is a prognostic parameter (Table 5). The peripheral blood smear should be carefully examined for any abnormal lymphoid cells, which often are seen in indolent B-cell lymphomas, as well as in highly aggressive B-cell and T-cell types. Analysis of peripheral blood by flow cytometry may reveal clonal excess that is diagnostic of circulating lymphoma cells even when the differential leukocyte count is normal.216 Detection of small numbers of malignant cells in the peripheral blood by polymerase chain reaction techniques is useful in research studies but usually not clinically practical. Bone marrow biopsy is indicated in most patients because in non-Hodgkin's lymphomas the likelihood of marrow involvement, which may not be associated with any cytopenia, is high. In some large-cell lymphomas, bone marrow involvement is characterized by the presence of discordant smaller lymphoid cells of the same lineage.217 Immunophenoty-pic analysis by flow cytometry of bone marrow, blood, body fluid, or lymphoid or splenic tissue samples detects the presence of abnormal cells and identifies lymphoma subtypes.218 Bone marrow involvement also may be detected by magnetic resonance (MR) imaging. (A) CT scan shows mesenteric and retroperitoneal adenopathy in a 58-year-old man with stage IVA small lymphocytic lymphoma. (B) Repeat CT scan l6 months after initiation of chemotherapy shows regression of all adenopathy, confirming a complete remission. A benign cyst of the right kidney is present. Reproduced with permission from Skarin and Dorfman.253 Gallium-67 scan of the same patient shown in Fig. 9 shows marked uptake in the mediastinal tumor mass. Repeat study after complete remission from combination chemotherapy showed no uptake of gallium-67. Radiographic staging studies include lateral and posteroanterior chest films. If findings are abnormal or symptoms are present, a computed tomography (CT) scan of the chest should be done to define any enlarged mediastinal or hilar nodes and parenchymal lesions (Fig. 9). Abdominal and pelvic CT scans also are important to determine involvement of organs, soft tissues, or lymph nodes (Fig. 10). Upper or lower gastrointestinal series are indicated in patients with gastrointestinal symptoms in conjunction with appropriate endoscopic studies. In patients with central nervous system symptoms, the brain is evaluated by CT scan with contrast or MR imaging using gadolinium. In patients with neurologic symptoms and those at risk of central nervous system involvement (e.g., those with aggressive and highly aggressive lymphomas, particularly with invasion of the blood, bone marrow, bone, orbit, nasal sinuses, or testes), examination of the spinal fluid for malignant cells may be indicated. Routine bone imaging is not done, but in patients with skeletal symptoms, a nucleide scan or selected CT or MR imaging studies may be important in the differential diagnosis. Gallium-67 scans are valuable in the staging of non-Hodgkin's lymphomas, particularly aggressive and highly aggressive types, because correlation can be made with CT imaging. In some cases, disease sites not visualized by CT scan may be detected.219 Gallium uptake also correlates with disease activity and thus is useful as an indicator of response and prognosis. Uptake of gallium-67 occurs in only about 50% of indolent lymphomas but in most aggressive and highly aggressive types (Fig. 11). The Ann Arbor staging system originally designed for Hodgkin's disease is traditionally used for non-Hodgkin's lymphomas. The schema is based on the number of lymph node sites, disease above or below the diaphragm, involvement of extranodal sites, and the presence or absence of systemic symptoms (Table 6). Unlike Hodgkin's disease, which spreads to contiguous lymph node groups, non-Hodgkin's lymphoma spreads unpredictably, and most patients present with stage III or IV disease. The Ann Arbor staging system is therefore less predictable in defining prognosis and survival. Several clinical and laboratory features of non-Hodgkin's lymphoma have been identified that more accurately predict disease outcome.220 They can be divided into three categories: the lymphoma's growth rate and invasive potential (LDH and β2-microglobulin levels, stage, size of mass, number of nodal and extranodal sites of disease, marrow involvement), the patient's response to the lymphoma (B symptoms and performance status), and the patient's ability to tolerate intensive therapy (age, performance status, and marrow involvement). Recent studies have documented the importance of gallium-67 uptake as a useful prognostic indicator in lymphomas. A prognostic index has been developed by the International Non-Hodgkin's Lymphomas Prognostic Factors Project based on data from 2,031 patients with aggressive (intermediate- and high-grade) lymphomas treated with regimens containing doxorubicin.221 The model used the following risk factors: age (younger than 60 years versus older than 60 years), LDH level (lower than normal versus higher than normal), performance status (0 or 1 versus 2 to 4), stage (I or II versus III or IV), and extra-nodal involvement (less than one site versus more than one site). Four risk groups were identified with predicted 5-year survival rates of 73%, 51%, 43%, and 26%, according to increasing number of adverse risk factors: none or one, two, three, and four or five, respectively. Patients older than 60 years were found to have complete remissions similar to those of patients younger than 60 years, but the duration was shorter with resultant poorer survival. Analysis of patients younger than 60 years revealed three clinical features that were independently associated with survival: stage, LDH level, and performance status. The importance of the prognostic index is that good-risk (low relapse rate) patients can be identified for standard therapy and poor-risk (high relapse rate) patients can be identified for new research protocols to improve the cure rate. In addition, treatment results among institutions and cooperative groups can be compared because standardized prognostic factors are used. The prognostic factor models have been tested in indolent lym-phomas and have proved useful in predicting relapse from complete remission and survival.222 Recent studies have documented the importance of gallium-67 uptake in lymphomas as a useful prognostic indicator. With conventional chemotherapy, only 25% of patients who were gallium-positive midway through therapy had durable responses, whereas 70% of those who were gallium-negative remained free of disease.223 With use of high-dose combination chemotherapy in aggressive lymphomas, only 14% of those who were gallium-positive midway through treatment obtained durable remission. In comparison, 91% of those who became gallium-negative remained disease free.223 Other prognostic factors have been described recently that reflect cellular and molecular features of lymphomas. They include tumor cell proliferation markers, immunophenotype, adhesion molecule expression, and karyotypic abnormali-ties.220 it is likely that these newly identified biologic variables will replace clinical surrogate features in new prognostic factor models in the future. Many chromosomal and molecular biologic defects, o