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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 130Non–Hodgkin’s Lymphomas

, MD and , MD.

The malignant lymphomas are neoplastic transformations of cells that reside predominantly within lymphoid tissues. Although Hodgkin’s and non–Hodgkin’s lymphomas (NHLs) both infiltrate reticuloendothelial tissues, their biologic and clinical behaviors are distinct. They clearly differ with regard to the neoplastic cell of origin, sites of disease, presence of systemic symptomatology, and response to treatment. Although both are among the most sensitive malignant neoplasms to radiation and cytotoxic therapy, their cure rates markedly differ. Hodgkin’s disease can be cured in nearly 75% of all patients employing both conventional and salvage treatment strategies whereas NHLs are cured in less than 35% of patients.

Epidemiology and Etiology

Incidence and Mortality

It was predicted that in 1999 there would be 56,800 new cases of NHLs in the United States, 5% of all new cancers in males, 4% in females.1 This is more than seven times the incidence of Hodgkin’s lymphoma and a greater number of cases than all forms of leukemia combined. There is a slight male-to-female predominance and a higher incidence in Caucasians than African Americans. Incidence rises steadily with age, especially after age 40 years. Although the total number of patients is relatively small compared with some of the more common solid tumors, the malignant lymphomas are among the commonest neoplasms of patients between the ages of 20 and 40 years. Moreover, the incidence of NHL nearly doubled between 1970 and 1990, but the rate of increase has slowed down since 1990.

There are striking differences in the age-dependent incidence of NHL by histopathologic subtype. In children, Burkitt’s, lymphoblastic, and diffuse large B-cell lymphomas (DLBCLs) are the most common. Histopathologic subtypes commonly diagnosed in adults, specifically the indolent lymphomas (small lymphocytic and follicular lymphomas) are extremely rare in children. DLBCLs are the most common histologic subtype in young adults. With increasing age, the incidence of follicular lymphomas and other aggressive lymphomas continues to rise. Small lymphocytic and follicular lymphomas are most commonly diagnosed in the patients over age 60 years. Although NHLs are commonly observed in young adults, the majority of cases still occur in patients over the age of 50 years.

NHL ranks as the sixth most common cause of cancer-related death in the United States in Caucasians, for both males and females.2 In 1999, 25,700 deaths from NHL were predicted, in contrast to 1,300 for Hodgkin’s disease.1 For males, NHL ranks as the fourth leading cause of cancer mortality for individuals under the age of 15 years. In the decades between 15 and 34 years, it ranks second for males and fifth for females as the leading cause of death from cancer. Even for males between the ages of 35 and 54 years, it still ranks as the third leading cause of cancer-related mortality. There is no significant difference in the 5-year survival rates for NHL between Caucasians and African Americans.

Exposures and Diseases Associated with Increased Risk of Developing Non–Hodgkin’s Lymphoma

There is evidence that infectious agents are involved in the pathogenesis of some NHLs (Table 130.1). Epstein-Barr virus (EBV) has a strong association with development of Burkitt’s lymphoma and HIV-1 related lymphoma.3 which includes small noncleaved as well as DLBCLs. Between 45 and 70% of HIV-1 related NHLs are EBV related. Essentially 100% of the primary central nervous system (CNS) lymphomas are EBV related in HIV-1–infected individuals. The natural killer (NK) and NK-like T-cell lymphomas which involve the upper aerodigestive tract as well as other extranodal sites such as skin also have EBV in the malignant cells.4,5 These infections are common in Asia as well as South and Central America. Human T-cell leukemia virus HTLV-16 is responsible for adult T-cell leukemia/lymphoma, which is endemic to the Caribbean and southern Japan. More recently, the primary gastric lymphomas, particularly those known as extranodal marginal zone or MALT type (mucosal associated lymphoid tissues), have been associated with Helicobacter pylori infection.7 The Kaposi’s sarcoma– associated herpes virus, also known as HHV-8, has been isolated from the neoplastic cells in patients with body cavity–based lymphomas among HIV-1 infected individuals.8

Table 130.1. Exposures and Diseases Associated with Increased Risk of Developing Non–Hodgkin’s Lymphoma.

Table 130.1

Exposures and Diseases Associated with Increased Risk of Developing Non–Hodgkin’s Lymphoma.

An increased risk of NHL has been associated with a number of exposures and/or disease states (see Table 130.1). Diphenylhydantoin can induce a lymphoid hyperplasia (pseudolymphoma) which is frequently difficult to distinguish pathologically from NHL.9 Although, in most cases, the hyperplasia regresses when the drug is withdrawn, rarely patients develop malignant lymphoma. There is controversial evidence that certain chemical exposures, specifically the herbicide phenoxyacetic acid, increase the risk of NHL.10–12 Other potential environmental associations include exposure to arsenic, pesticides, fungicides, chlorophenols, or the organic solvents13 halomethane, lead, vinyl chloride, and asbestos.14–16 Occupations associated with an increased risk include agricultural work, welding, and work in the lumber industry.17 There is an increased incidence of NHL in survivors of nuclear explosions or reactor accidents.18 NHL has been observed as a late complication of prior chemotherapy and/or radiation therapy. Specifically, patients with Hodgkin’s disease treated with radiation therapy and chemotherapy exhibit an increased risk of developing secondary large cell lymphomas.19

Diseases of inherited and acquired immunodeficiency as well as autoimmune diseases are associated with an increased incidence of lymphoma.20–22 The association between immunosuppression and induction of NHLs is compelling because when the immunosuppression can be reversed (e.g., discontinuing immunosuppressive agents following organ transplantation), a percentage of these lymphomas regress spontaneously.23 The incidence of NHL is nearly 100-fold increased for patients undergoing organ transplantation necessitating chronic immunosuppression and is greatest in the first year following the transplantation period. The NHLs that occur in the context of immunosuppression or immunodeficiency, including HIV-1 infection, are frequently associated with EBV.3,24 Histologically, diffuse large B-cell lymphomas are most frequently associated with immunosuppression and autoimmune diseases. Rare inherited immunodeficiency diseases, such as X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, Chédiak-Higashi syndrome, ataxia telangiectasia, common variable immunodeficiency syndrome, and HIV-1–associated lymphomas, are complicated by highly aggressive lymphomas (Burkitt’s, Burkitt’s-like lymphomas, diffuse large B-cell lymphomas). NHLs develop in up to 30% of HIV-1 infected individuals, and between 40 and 50% are EBV associated. EBV is also present in virtually all the primary CNS lymphomas seen in HIV-1 patients. A recently identified entity in patients primarily with HIV-1 infection is primary effusion lymphoma. The incidence of lymphoma in iatrogenic immunosuppression, acquired immunodeficiency syndrome (AIDS), and autoimmune disease (Felty’s syndrome, Sjögren’s syndrome, celiac disease, rheumatoid arthritis, and systemic lupus erythematosis) argues strongly for immune dysregulation contributing in the pathogenesis of some lymphomas.

Pathology, Immunobiology, and Natural History

Lymphoma classification schemas has evolved over the past 30 years.25–27 The histologic classification of NHLs is firmly based on assessment of the overall pattern of lymph node architecture as well as the cytologic classification of the neoplastic cells.28 With the understanding of normal B- and T-cell immunology and the availability of a large number of monoclonal antibodies (mAbs) which identify surface molecules on lymphoid cells, the classification of lymphomas has expanded to include “immunophenotype.” Finally, genetic aspects of these diseases have emerged and further add to our understanding and classification. Although the most recent and widely used REAL (Revised European-American classification of Lymphoid neoplasms) pathologic classification system is focused on morphology, immunophenotype, and genotype, it also relates to clinical features of the disease.29,30 REAL includes several new entities which were grouped with other histologic subtypes in earlier classification schemas, particularly some of the aggressive T-cell lymphomas. The entities in REAL, which will not be covered in this chapter, include chronic lymphocytic leukemia (CLL) prolymphocytic leukemia (PLL), hairy-cell leukemia, multiple myeloma, T/NK-cell (LGL), T-CLL/PLL, mycosis fungoides/Sézary syndrome, precursor acute lymphoblastic leukemia (T and B cell), adult T-cell lymphoma/leukemia, and lymphomas associated with HIV-1 infection. To provide a context for this classification, the large numbers of entities will be grouped in “indolent,” “aggressive,” and “highly aggressive” categories (Table 130.2).

Table 130.2. REAL: Classification for Non–Hodgkin’s Lymphoma.

Table 130.2

REAL: Classification for Non–Hodgkin’s Lymphoma.

NHLs are hypothesized to be the neoplastic counterparts of subpopulations of normal lymphoid cells by virtue of their cytologic appearance and cell surface immunophenotype. Moreover, some subtypes of NHL closely recapitulate the normal architecture of secondary lymphoid tissues. The identification of cell surface proteins on normal lymphoid cells has provided a context in which to examine histologic subtypes of NHLs.

Indolent Lymphomas

Follicular Lymphoma

Follicular lymphomas (FLs) are the most common type of indolent NHL and morphologically recapitulate normal germinal centers (GC) of secondary lymphoid follicles (Fig. 130.1). The neoplastic follicles may be present throughout the tumor tissue, or only in a portion, with a diffuse component occupying the rest of the tumor. FLs have been subdivided into “grades”on the basis of morphology, specifically whether there is a predominance of small cleaved cells (which resemble centrocytes in normal GCs) (Fig. 130.2), a mixture of small cleaved and large cells (which resemble centroblasts in normal GCs), or a greater number of large cells. It remains controversial how clinically significant the proportion of large cells is, but REAL includes three grades; grade I (0–5 large cells/high-power field); grade II (6–15 large cells/high-power field); and grade III (>15 large cells/high-power field).29 Similar to normal GCs, small numbers of T cells and follicular dendritic cells are present in the malignant follicles; however, tangible body macrophages are not observed.31 The interfollicular areas of FLs, although compressed, also resemble normal lymph nodes by the frequent large numbers of normal T cells located there. Involvement of the peripheral blood with malignant cells is not infrequently seen, and morphologically these cells have notches and have been referred to as “buttock cells.”

Figure 130.1. Follicular lymphoma grade I (low power).

Figure 130.1

Follicular lymphoma grade I (low power).

Figure 130.2. Follicular lymphoma grade I (high power).

Figure 130.2

Follicular lymphoma grade I (high power).3

Early studies suggested that follicular lymphoma and normal follicular center B cells were related by the expression of cell surface antigens, specifically C3 receptors.32,33 Additional immmunologic studies of normal lymph node and follicular lymphomas have further supported this hypothesis. Virtually all follicular lymphomas express monoclonal sIg.34 In most cases, the Ig isotype is μ±δ or μ±γ, although occasional cases lack sIg. Virtually all cases express HLA-DR, pan-B-cell antigens (CD19, CD20) CD21, CD10, but lack CD5. Lymphocyte functional antigen-1 (LFA-1) (CD11a/CD18) is more frequently noted on tumor cells at initial diagnosis (60–90% of cases) than at relapse. Other adhesion molecules including CD44, ICAM-1 (CD54), L-selectin (CD62L) and LFA-3 (CD58) are present in about half the cases examined.35,36

FLs account for approximately 22% of NHLs, with grade I subtype being the most common.30 While uncommon until the third and fourth decades, these lymphomas most frequently present in middle-aged individuals and the elderly, with a median age at diagnosis of 60 years. This histologic subtype is less common in Asians and blacks. Patients usually present with painless peripheral adenopathy in the cervical, axillary, inguinal, and femoral regions. Often, lymph node enlargement has been present for long periods of time, and the nodes have waxed and waned. Hilar and mediastinal nodes are often involved, but mediastinal masses are rare. Some patients present with asymptomatic large abdominal masses, with or without evidence of gastrointestinal and/or renal obstruction. Although patients may present with one or more sites of nodal disease, staging studies usually demonstrate widely disseminated disease with involvement of the spleen (40%), liver (50%), and bone marrow (60–70%). Bone marrow involvement in follicular lymphoma reveals a unique pattern of paratrabecular infiltration. Very few patients present with extranodal extramedullary disease, and only about 20% present with B symptoms or LDH elevation. Central nervous system involvement is uncommon although peripheral nerve compression and epidural tumor masses causing cord compression may develop. There are no characteristic laboratory abnormalities specifically associated with follicular lymphoma.

The course of this disease is quite variable. Some patients can be observed with waxing and waning disease for 5 years or more, without the need for therapy.37 Others present with more disseminated disease and rapid growth and require treatment because massive nodal or organ enlargement leads to pain and lymphatic or organ obstruction. Peripheral blood involvement is reported in up to one-third of patients. Historically, both disease-free and overall survival rates for these patients have not changed in spite of many different therapeutic approaches. These patients survive long periods, however. The median survival for patients with stages III and IV disease is between 7 and 10 years. Regardless of the long natural history, it should be stressed that except for uncommon presentations of stage I disease, virtually all patients eventually die of this disease.38

Histologic transformation from indolent to diffuse aggressive lymphoma occurs in up to 60% of patients with follicular lymphoma and is associated with rapid progression of lymphadenopathy, infiltration of extranodal sites, development of systemic symptoms, elevated serum LDH, and often a poor prognosis.39–45 The progression from follicular to DLBCL occurs regardless of whether the follicular lymphoma is treated aggressively or conservatively and occurs at a rate of about 5 to 10% per year depending on the degree of the large cell component.38 At autopsy, the overwhelming majority of patients (95%) with follicular lymphoma demonstrate some evidence of DLBCL.

Follicular lymphoma grade III is synonomous with what is often referred to as follicular large cell lymphoma. In contrast to other follicular lymphomas, this histologic variant has less infiltration of the marrow and presents with larger masses. Unlike the follicular small cleaved cell, the follicular large cell uncommonly circulates in the peripheral blood. Although the follicular morphology is preserved, the clinical presentation, behavior, and outcome with treatment are very similar to those of diffuse large B-cell lymphoma.46,47

Small Lymphocytic Lymphoma

Small lymphocytic lymphoma (SLL) represents the solid component of B-cell CLL. Although the major population of cells resemble small normal lymphocytes, larger cells resembling those seen in PLL are seen in the nodal tissue in areas known as proliferation centers (Fig. 130.3). This sometimes gives the tissue a pseudofollicular pattern. The SLLs are phenotypically nearly identical to B-CLL, by the expression of HLA-DR, pan B-cell antigens (CD19, CD20, CD22), CD21, CD23, weak sIgM±IgD, and CD5. The presence of the adhesion molecule LFA-1 on SLL, which is in contrast to CLL, may account for the differences in the anatomic sites of involvement of these two diseases. These tumors are generally L-selectin+ (60% of the cases), CD44+, CD11c/CD18, and generally lack LFA-3 and ICAM-1.35,48

Figure 130.3. Small lymphocytic lymphoma.

Figure 130.3

Small lymphocytic lymphoma.

SLL makes up about 6% of all NHLs.30 Patients usually seek medical attention for painless generalized lymphadenopathy, frequently present for several years prior to presentation. B symptoms are present in less than one-third of patients. Unlike CLL, the peripheral blood may be normal or reveal only a mild lymphocytosis (60% will have absolute lymphocytosis of < 4,000/mL at diagnosis). In contrast, the bone marrow is positive in 70 to 90% of cases. Serum paraprotein is found in about 20% of cases, and hypogammaglobulinemia is present in about 40%. Patients who present with an absolute lymphocytosis usually do not have a monoclonal gammopathy but rather a relatively high incidence of hypogammaglobulinemia and are the most likely to progress to a leukemic phase. SLL and CLL can convert to diffuse large B-cell lymphoma (Richter’s syndrome) (Fig. 130.4), circulating large cell lymphoma).43,49–52 These patients usually present with rapidly growing masses, elevated LDH, and B symptoms and usually experience short survival.53 For patients whose disease undergo transformation, terminal complications are the result of marrow replacement, with immunodeficiency complicated by infection or hypersplenism.

Figure 130.4. Diffuse large B-cell lymphoma.

Figure 130.4

Diffuse large B-cell lymphoma.

Lymphoplasmacytic Lymphoma (Immunocytoma)

Lymphoplasmacytic lymphoma is an indolent lymphoma composed of diffuse proliferation of small lymphocytes with evidence of maturation to plasma cells.54 Evidence of Ig is seen in these cells by special stains or inclusions. These tumors express pan-B-cell antigens CD19, CD20, CD22, and sIgM, and, in general, absence of CD5, CD10, CD23. Adhesion molecules expressed on approximately half these tumors include L-selectin, ICAM-1, CD44, and CD11c. The majority express LFA-1.

Lymphoplasmacytic lymphoma represents about 1% of all NHLs.30 Clinically, this disease is similar to SLL. The median age is early 60s, and virtually all patients have stage IV disease by virtue of bone marrow involvement. B symptoms and elevated serum LDH are uncommon. The disease can also involve peripheral blood. A serum M component is commonly seen. The median survival for these patients is less than that in SLL, in the range of 5 to 7 years.

Marginal Zone Lymphomas

Marginal zone lymphomas (MZL) are a group of distinct entities in REAL which includes nodal MZL, extranodal MZL, also known as the lymphomas of mucosal associated lymphoid tissues, and the splenic MZL.55–57 In nodal MZL, the tumor cells cytologically resemble “normal” monocytoid B cells and often involve lymph node sinuses. Phenotypically these tumors are similar to hairy cell leukemias by their expression of sIgM, pan-B-cell antigens (CD20), and the adhesion molecule CD11c.

The extranodal MZL58 tumor cells express pan-B-cells antigens (CD19, CD20), complement receptors (CD21 and CD35), and slgM (occasionally IgG or IgA) but lack IgD. It is hypothesized that these are malignancies of memory B cells. Cytologically, these tumor cells resemble monocytoid B cells as well as small cleaved cells. A pathopneumonic feature of extranodal MZL is a lymphoepithelial lesion associated with centrocytes. These tumors do not form follicles, but the malignant cells surround reactive follicles. When the extranodal MZL spreads to the lymph nodes, the neoplastic cells involve the marginal zones.

Splenic MZL is closely related to the other MZLs, with expansion of marginal zones in the spleen marrow and peripheral blood involvement (referred to as splenic lymphoma with villous or nonvillous lymphocytes) can be present. Cytologically, these cells range from small cells to large “blasts.” In contrast to the other MZLs, the splenic MZL cells express IgM and generally IgD, pan-B-cell antigens, and variable expression of CD21 and CD35. The majority of splenic MZL expresses many of the adhesion receptors, including LFA-1, CD11c/CD18, CD44, CD49d, CD29, and ICAM-1, but lack L-selectin.

Extranodal MZL constitutes about 5% of all NHLs.30 B symptoms are uncommon. Patients with extranodal MZL generally present with stage I or II disease. There is no age predilection for these tumors, which most commonly involve the gastrointestinal tract (stomach, most commonly), lung, lacrimal and salivary glands, skin, thyroid, and breast, but usually not peripheral blood and marrow. Patients can present with peptic ulcer disease, abdominal pain, and sicca syndrome, or a mass at the site of involvement.59 These lymphomas can disseminate to other mucosal associated lymphoid tissue (MALT) sites or marrow in about 30% of cases, more typically later in the course of the disease. These diseases have high complete remission rates and potentially long survival, as high as 80% at 10 or more years.60,61 There are a subset of gastric lymphomas which have high-grade features as well as evidence of “low-grade” MZL. The survival rates of these patients appear to be lower than those of patients with gastric MZL or DLBCL involving the stomach.

Nodal MZL constitutes 1% of all NHLs; the median age of patients is reported to be 44 years to as high as 58 years.30 Over 70% of patients present with stage III/IV disease, although bulky adenopathy is uncommon. The majority are asymptomatic. Bone marrow involvement is less common than in most indolent lymphomas, and gastrointestional involvement is unusual. The median suvival of these patients is in excess of 12 years.55,61

Splenic MZL constitutes <5% of all NHLs, with a median age of 65 years, uncommon before age 50 years.30 Patients present with splenomegaly (often with hypersplenism), often with peripheral blood and focal bone marrow involvement, and therefore, over 90% have stage IV disease. The liver is also involved as evidenced by biopsies. The survival of patients is in excess of 70% at 10+ years, with splenectomy being the treatment of choice.57

Similar to other indolent lymphomas, MZL has the potential to transform into a higher-grade lymphoma. There are also patients who present with extranodal MZL, with dissemination to nodal sites, spleen and bone marrow. In these cases, it is unclear exactly where the disease originated.

Aggressive Lymphomas

Mantle Cell Lymphoma

Although mantle cell lymphoma (MCL) is grouped with the “indolent” lymphomas in REAL, from a clinical viewpoint, MCL is more appropriately grouped with the aggressive diseases.62–66 MCL has been previously referred to as intermediate lymphocytic lymphoma, mantle zone lymphoma, centrocytic lymphoma, and lymphocytic lymphoma of intermediate differentiation.67,68 In the Rappaport and Working Formulation classifications, the majority of cases of diffuse small cleaved cell lymphomas on review are MCLs.29 These tumors are neoplastic counterparts of naive “mantle zone” B cells. Morphologically, MCLs can have either diffuse architecture or a vaguely nodular appearance, occasionally with expansion of the mantle zone of secondary lymphoid follicles. Cytologically, the neoplastic cells are medium sized, with irregular nuclei. Some cases of MCL have a predominance of “blastic” cells with a high mitotic rate. The immunophenotype can be variable, with cells expressing pan-B-cell antigens, IgM±D, and CD5 but, in contrast to follicular lymphoma and SLL, lack CD10 and CD23, respectively.69 When MCL involves the gastrointestinal tract (lymphomatous polyposis),70,71 the tumor cells express the adhesion molecule α4β7 integrin, which is normally involved in lymphocyte homing to the endothelial cells in the gastrointestional tract. Overexpression of cyclin D1 protein (intracellular) further distinguishes these tumors from other entities.

MCL constitutes about 5% of all NHLs.30,66 About three-fourths of patients are males, with a median age of 63 years. Approximately 70% of patients have stage IV disease, and systemic B symptoms are observed in approximately one-third of patients. Typical sites of involvement include diffuse adenopathy, spleen, liver, and bone marrow. Peripheral blood involvement is present in approximately 25% of patients at presentation. Mantle cell lymphoma can involve any region of the gastrointestinal tract, occasionally presenting as multiple intestinal polyposis. Over the course of the disease, MCL behaves progressively more aggressive. The median survival of patients with MCL is 3 to 4 years.

Diffuse Large B-Cell Lymphoma

DLBCL consists of a diffuse proliferation of large cells which have a high mitotic rate and frequent mitotic figures present. The cells have a moderate amount of cytoplasm with either cleaved or noncleaved nuclei often with multiple nucleoli, although there can be great variability in the morphology (see Fig. 130.4). The tumor cells generally express pan-B-cell antigens (CD19, CD20, CD22), monoclonal sIgM, but occasionally other heavy-chain isotypes. Uncommonly, DLBCLs are CD10+ or CD5+. Uncommonly, DLBCLs are sIg negative. Expression of activation antigens support the hypothesis that DLBCLs correspond to a subpopulation of activated B cells. The DLBCLs are heterogeneous for the expression of the family of adhesion structures with 50 to 75% of tumors expressing LFA-1 and CD44, although DLBCLs are rarely p150/95+.72 The expression of CD44 has been related to the clinical behavior of these tumors. High expression of CD44 is associated with disseminated and extranodal disease and poor outcome. Further insights have come from studies of expression of particular splice variants of CD44, suggesting that certain CD44 isoforms are expressed in patients with a highly aggressive subset of DLBCL.73–75

DLBCL constitutes about 30% of all NHLs and is the most common histologic subtype.30 Patients who are generally middle-aged or older (median age 64 years) present with either nodal enlargement (especially in the neck or abdomen) or extranodal disease (in the gastrointestinal tract, testis, bone, thyroid, salivary glands, skin, and brain). These tumors present in a localized (stage I or IE) manner approximately 20% of the time. The disease is confined to one side of the diaphragm (stage I or II) in approximately 30 to 40% of patients. Disseminated stage IV disease is seen in approximately 40% of patients and is usually defined by extranodal extramedullary infiltration.76–78 B symptoms are observed in approximately 30% of patients, and unlike most NHLs, the serum LDH is elevated in over half the patients. During the course of the disease, the liver, kidneys, and lung may be involved. DLBCL is highly invasive, with local compression of vessels or airways, involvement of peripheral nerves, and destruction of bone. Although bone marrow involvement initially is found in only 10 to 20% of patients, its detection is important because of its strong correlation with later spread to the CNS.78–80 Extranodal disease and elevated LDH are other risks for CNS dissemination.80 Therefore, cytologic examination of spinal fluid is important in patients with bone marrow infiltration.

Within DLBCL is a distinct clinical entity known as primary mediastinal large B-cell lymphoma.81–83 Histologically, the cellular infiltrate is heterogeneous, the neoplastic cells are pleomorphic, and sclerosis is frequently present. The immunophenotype of these lymphomas includes pan-B-cell antigens (CD19, CD20, CD22) but they are often negative for surface and cytoplasmic immunoglobulin.

Primary mediastinal large B-cell lymphoma has a female predominance, with age range of 30 to 40 years. Over 70% of these patients present with stage I/II bulky disease involving the mediastinum and pleural and pericardial effusions in about one-third. Similar to DLBCL, an elevated LDH is present in the majority, whereas bone marrow involvement is infrequent. The prognosis of patients with primary mediastinal larrge B-cell lymphoma is similar to that of patients with DLBCL.84

Peripheral T-Cell Lymphomas

The category of peripheral T-cell lymphomas (PTCL) includes a number of entities within REAL, which constitute less that 15% of all NHLs in adults.30 Among those in decreasing frequency of occurance are PTCL unspecified, anaplastic large cell lymphoma (including T-cell and null cell types), angioimmunoblastic T-cell lymphoma (AILD-like), and the much rarer entities, angiocentric T/NK-cell lymphoma, subcutaneous panniculitis–like T-cell lymphoma, intestinal T-cell lymphoma, hepatosplenic γ/δ T-cell lymphoma.

PTCLs can be nodal- or entranodal-based diseases, which generally show significant hetereogeneity of cellular features.29 The diffuse cellular infiltrates range from: a mixture of small and large cells; infiltrates of pleomorphic cells, often with a background of epithelioid histiocytes, plasma cells, eosinophils, and Reed-Sternberg–like cells, or predominantly large cells. In contrast to B-cell lymphomas, the pattern of expression of T-cell surface antigens is very variable. The majority will express CD2, CD3, and CD4, with a subset of tumors expressing CD8. In most cases, one or more “mature” T-cell antigens is lost, such as CD5, and CD7.

Histologically, there are uncommon subtypes of PTCL which have unique histologic features.29 The angioimmunoblastic T-cell lymphoma (AILD-like), in addition to a pleomorphic heterogeneous cellular infiltrate, has increased amounts of high endothelial venules present giving a hypervascular appearance. The angiocentric T/NK-cell-lymphoma are characterized by vascular invasion and extensive tissue destruction.85 EBV is present in the tumor cells in virtually all cases. The tumor cells express the phenotype of NK cells CD2, CD56, CD45RO, and CD43 but lack surface CD3 and T-cell receptor (TCR).5 Occasional cases are reported which express CD4 or CD8. The subcutaneous panniculitis–like T-cell lymphoma is characterized by subcutaneous nodules with cellular infiltrates in the subcutaneous fat, generally with sparing of the overlying skin.86 Intestinal T-cell lymphoma, often associated with gluten enteropathy, is characterized by mucosal ulceration or masses in the small bowel. The neoplastic infiltrate consists of anaplastic large cells. Often, the adjacent mucosa shows changes seen in celiac disease with villous atrophy and a lymphocytic infiltrate. These tumor cells are generally CD4-, and express CD103, which is an adhesion receptor on intestinal lymphocytes.87 Hepatosplenic γ/δ T-cell lymphoma is an extremely rare disease presenting with hepatosplenomegaly, often with marrow involvement and occasionally peripheral blood involvement.88,89 The tumor cells infiltrate the red pulp of the spleen and liver sinusoids. The tumor cells are CD2+, CD3+, variably CD8+, but also CD7+ and CD56+. In contrast to most PTCL, which express the α/β TCR, a unique feature of these tumors is expression of the γ/δ TCR.

Patients with PTCL have a similar median age as patients with DLBCL. However, in contrast to DLBCL, 80% of patients with PTCL have stage III/IV disease, and more frequently have B symptoms, hepatosplenomegaly, and extranodal disease (skin). PTCL generally has a worse prognosis that DLBCL. There are several other PTCLs which are uncommon entities. Angioimmunoblastic T-cell lymphoma (AILD-angioimmunoblastic lymphadenopathy) is a rare lymphoproliferative disorder.90–92 This disease usually affects older adults who present with the acute onset of generalized lymphadenopathy, hepatosplenomegaly, skin rash, and B symptoms. Immunologic abnormalities are common and include plasmacytosis, polyclonal hypergammaglobulinemia, and a positive Coombs’ test. The median survival is 30 months. Infection is the most common cause of death followed by the aggessive T-cell lymphoma.

The nasal/NK/T cell lymphomas (angiocentric lymphoma) are rare, typically present in males in their 60s. The vast majority of patients have localized disease with nasal obstruction and a destructive mass. Occasionally, the aerodigestive and gastrointestinal tracts and the testis are involved. B symptoms are uncommon. Over 60% of patients with stage I disease remain in long-term remission with treatment, while patients with stage II-IV disease have a poor prognosis. Subcutaneous panniculitis–like T-cell lymphoma is also a rare disease which presents with subcutaneous nodules, developing into progressive disseminated disease. Many of these patients have hemophagocytic syndrome, either at diagnosis or later on. Hepatosplenic γ/δ T-cell lymphoma is a highly aggressive lymphoma. It typically presents in younger males with hepatosplenomegaly, bone marrow infiltration and often peripheral blood involvement. These patients are generally pancytopenic and have a median survival of 1 to 2 years. The intestinal T-cell lymphomas are a rare aggressive disease which may or may not be associated with a history of gluten enteropathy. These patients present with intestinal obstruction, perforation, and bleeding. In some patients, there is a brief history of gluten sensitivity or worsening gluten enteropathy. Uncommonly, there is extraintestinal disease with dissemination to the lungs or skin. These patients have a very poor prognosis, with only occasional patients cured by surgical resection.

Anaplastic large cell lymphomas (ALCL) are a subtype of PTCL, which can have nodal, soft tissue, or cutaneous involvement.93 When involving the nodes, ALCL characteristically involves the sinusoids of lymph nodes with bizarre large cells. These tumors have been referred to as large cell anaplastic (Ki-1+) lymphomas by virtue of their expression of the CD30 antigen.94 Although originally described as a marker of Hodgkin’s disease cell lines, CD30 is present on normal stimulated T and B cells, and a subset of B- and T-cell NHLs. CD30 is a member of the nerve growth factor and tumor necrosis factor (TNF) receptor family of molecules. Following engagement with its ligand, CD30 can transmit growth signals to T cells.95 Neoplastic cells and cell lines derived from patients with ALCL also generally express the phenotype of mature activated T cells (HLA-DR, CD25). A minority expresses neither B- nor T-cell antigens.96–98 A condition that is hypothesized to be part of the spectrum of the ALCL involving the skin is lymphomatoid papulosis.93 This entity is a chronic dermatosis consisting of a proliferation of activated helper T cells. Grossly, these lesions consist of skin papules and nodules, which consist of an infiltrate of lymphocytes, atypical lymphocytes, and some cells that resemble Reed-Sternberg cells. The immunophenotype of these cells is that of activated CD4+ T cells, which also express CD30. Lymphomatoid papulosis can evolve into ALCL, Hodgkin’s disease, or other peripheral T-cell lymphomas.93

ALCL constitutes 2% of all NHLs in adults, but is the second most common T-cell lymphoma.30 The median age of patients with ALCL is 34 years with a male predominance. There is a bimodal distribution of this disease, with peaks in childhood/young adulthood, and late adulthood. In adults, B symptoms and, peripheral and retroperitoneal adenopathy are common. Skin is a common site of extranodal disease (about 25% of patients), whereas bone marrow involvement is infrequent. ALCL in adults generally lack t(2;5) in the tumor cells.93 The prognosis of these adult patients with systemic ALCL is similar to that of patients with DLBCL.99–101

Highly Aggressive Lymphomas

Precursor T- or B-Lymphoblastic Leukemia/Lymphoma

There is significant overlap between lymphoblastic lymphoma (LL) and acute lymphoblastic leukemia. Cytologically, LL cells are identical to ALL cells the majority having L1 morphology in the FAB classification. These cells have a high nuclear-to-cytoplasmic ratio, scant cytoplasm, and nuclei with fine chromatin with multiple small nucleoli, and have a high mitotic rate. The nuclei can have folds or convolutions. Typically the nodal tissue involved with lymphoblastic lymphoma is effaced by these malignant cells (Fig. 130.5).

Figure 130.5. T lymphoblastic lymphoma.

Figure 130.5

T lymphoblastic lymphoma.

The vast majority of lymphoblastic lymphomas are of T-cell lineage.102–106 Several investigators have noted that most (49%) T-cell LLs correspond to common (stage II) thymocytes (CD4+, CD1a+, CD8+) with the remaining cases early (30%) or late (20%) thymocytes (CD38+ or CD3+, CD4+ or CD8+, respectively).107 Crist and colleagues have examined the relationship between clinical outcome and maturational stage and found no differences among these subgroups.108 Most T-cell LLs also lack surface CD3 but express CD5, CD1, CD71, CD38, CD7, and the p75 subunit of the IL-2R.103,104,106,107,109–111 In addition, one-third of cases are HLA-DR+, and most express LFA-1 (CD11a/CD18).72 Again, as observed in T-cell LLs, the majority of the CD3- cases expressed cytoplasmic CD3. In contrast to these findings, T-cell LLs have been observed to be highly heterogeneous, with CD2 and CD38 (+/-CD1) expression being the most consistent cell surface phenotype. From a clinical point of view, as well as by cell surface markers, T-cell ALL and T-cell LLs have considerable overlap. Approximately 50% of T-cell LLs express the homing receptor/cell adhesion molecule CD44, and this expression correlates with stages of intrathymic differentiation. The CD4- CD8- T cell LLs are CD44+, whereas the CD4+ CD8+ cells are CD44-. The presence of CD44 did not correlate with leukemic presentation, however. One difference which has been noted is that approximately 40% of T-cell LLs express CD10, whereas less than 10% of T-cell ALLs are CD10+. Several cases of non–T-cell LL have been reported. These include rare cases where the neoplastic cells express antigens present on NK cells. Approximately 10 to 15% of LLs have a pre–B-cell phenotype by expression of HLA-DR, CD10, CD24, and, in some cases, cytoplasmic μ as well as surface IgM.

Although LLs represent a major subgroup of childhood NHLs, they are much less common in adults (2% of adult NHLs).30 Patients are usually males in their 20s or 30s who present with lymphadenopathy in the cervical, supraclavicular, and axillary regions (50%) or with a mediastinal mass (50–75%).112 In most patients, the mediastinal mass is anterior, bulky, and associated with pleural effusions. These masses can be associated with such complications as superior vena caval syndrome, tracheal obstruction, and pericardial effusions (with or without tamponade). Less commonly, patients present with extranodal disease (e.g., skin, testicular, or bony involvement). Abdominal involvement is very unusual, but when it does occur, it is found primarily in the liver and spleen. Greater than 80% of patients present with stage III or stage IV disease and almost 50% have B symptoms, and majority have elevated LDH. Although the bone marrow is frequently normal at presentation, approximately 60% of patients develop bone marrow infiltration and a subsequent leukemic phase indistinguishable from T-cell ALL.113 Patients with bone marrow involvement have a very high incidence of CNS infiltration. Regardless of whether the patients present with bone marrow involvement, evaluation of the spinal fluid is essential. Prior to current aggressive acute leukemia-type therapy, this disease was rapidly fatal. B-cell LL is a very rare variant, affecting patients with a median age of 39 years.114 B-cell LL presents without a mediastinal mass but instead involves lymph nodes and extranodal sites. The prognosis for these patients may be better than that for adults with T-cell LL.

Burkitt’s and Burkitt’s-Like Lymphoma

Cytologically, Burkitt’s lymphoma (BL) cells resemble the small noncleaved cells within normal germinal centers of the secondary lymphoid follicle. These cells differ from LL cells in two respects: (1) they have intermediate-sized nonconvoluted nuclei with coarse chromatin, and (2) the cells have more abundant cytoplasm. Due to the high mitotic rate, frequent mitotic figures are seen, and analogous to normal germinal centers, tingible body macrophages are seen giving the classical “starry sky” appearance. Although the Burkitt-like is similar to BL, the cells have greater pleomorphism and fewer nucleoli.115

BL is a tumor of B-lineage derivation by the expression of a variety of B-cell restricted antigens, including CD19, CD20, sIgM±D, as well as HLA-DR.116–120 Further examination of these lymphomas has demonstrated that these tumors express CD10.121 The expression of CD21, the EBV/C3d receptor is dependent upon the EBV status of the tumors. The endemic BL which are EBV positive express CD21, whereas the vast majority of nonendemic BL are EBV negative and lack CD21 expression. BL generally lack the adhesion molecules LFA-1 (CD11a/CD18), p150/95 (CD11c), and CD44. The normal B lymphocyte from which these lymphomas are derived is controversial. Studies of normal lymphoid tissues, including the observation that CD10, several B-cell activation antigens, and the BL–associated glycolipid antigen CD77 are detected in the germinal centers of lymph nodes, suggest that BL may be the neoplastic counterpart of a subset of normal activated B cells. The immunophenotype of Burkitt’s -like lymphomas is very similar to BL, although the expression of CD10 and CD21 is more variable.

BL is, in general, a childhood tumor that has two major clinical presentations. The endemic (African) form presents as a jaw or facial bone tumor that spreads to extranodal sites, including the ovary, testis, kidney, breast, and especially the bone marrow and meninges. The nonendemic or American form has an abdominal presentation with massive disease, ascites, and renal, testicular, and ovarian involvement and, like the endemic form, also spreads to the bone marrow and central nervous system. BL has a male predominance. Prior to aggressive therapeutic programs, all patients died rapidly. These tumors are now treated with aggressive chemotherapeutic programs with more gratifying results. BL is rare in adults, typically seen in patients less than 35 years of age, and occurs virtually always in the nonendemic form . Burkitt’s-like lymphomas, also a rare disease, occurs in patients with a median age of 55 years, but also has a male predominance. This is an aggressive disease involving the lymph nodes, the nasopharynx, and the gastrointestional tract. Occasionally, B-LL presents as solitary bone tumor. Like Burkitt’s lymphoma, these tumors have a high propensity to invade the bone marrow and CNS. LDH is often elevated and B symptoms present in about one-third of patients.

Cytogenetics and Molecular Basis of NHL

Developments in the understanding of the molecular basis of NHLs are among the most exciting areas in cancer cell biology. First, the observation that immunoglobulin and T-cell receptor genes rearrange during normal B- and T-cell development has led to the demonstration that virtually all NHLs are clonally derived from populations of B or T cells at distinct stages of development. Second, an increasing number of nonrandom chromosomal abnormalities have been identified, which are detected in histologically distinct subgroups of NHLs. These chromosomal translocations have led to the identification of genes located at these breakpoints which play an integral role in neoplastic transformation. The identification of unique chromosomal breakpoints, coupled with the development of sensitive techniques to detect the aberrant sequences which are expressed only in the neoplastic clone, may revolutionize our ability not only to diagnose but to detect minimal numbers of lymphoma cells. Finally, an understanding of the regulation of these genes may lead to the development of novel therapeutic strategies.

Chromosomal Abnormalities in NHL

Considering the diversity in the histology and clinical behavior of NHL, it is not surprising that a large number of chromosomal abnormalities have been observed (Table 130.3). It is important to distinguish whether the chromosomal abnormality was detected at the time of diagnosis or following treatment. At diagnosis, with modern sensitive banding techniques, the overwhelming majority (70–90%) of NHLs demonstrate one or more chromosomal abnormalities. At diagnosis, most NHLs demonstrate a modal number of 46 chromosomes. However, both additions (chromosomes 3, 4, 5, 7, 8, 12, 18, 21, and X) and deletions (chromosomes 2, 3, 6, 8, 13, and 20) are observed, with deletions occurring more commonly than additions.122–128 Compared with the incidence of additions and deletions, translocations are much more frequently observed. In many of the translocations, a transcriptionally active oncogene is likely to be juxtaposed to a gene which determines the lineage of a cell, for example, chromosome 14 carries the immunoglobulin heavy chain locus.125,129,130

Table 130.3. Consistent Chromosomal Abnormalities Associated with Non–Hodgkin’s Lymphomas.

Table 130.3

Consistent Chromosomal Abnormalities Associated with Non–Hodgkin’s Lymphomas.

There is clustering of chromosomal abnormalities associated with histologically defined subgroups. Table 130.3 summarizes the most frequent cytogenetic abnormalities observed for histologic subtypes within REAL. In the indolent lymphomas SLL/CLL, trisomy 12 is present in about 40 to 50% of cases, while t(14;19) is rare.131,132 A subset of the lymphoplasmacytic lymphomas have t(9;14)(p13;q32).133 Within the MZLs, the most common abnormalitiy is trisomy 3 (particularly the gastic extranodal MZL) and t(11;18)134, while other abnormalities are reported, including t(11;14), deletions of 7q, t(1;14), isochromosome 17q and 2p11 translocations.132,135,136. Approximately 85% of patients with FL have t(14;18), the bcl-2/IgH rearrangement.130,137

Among the diffuse lymphomas several subtypes have distinct chromosomal abnormalities. Approximately 70% of mantle cell lymphomas have t(11;14)(q13;q32) which is rearrangements of the bcl-1 (cyclin D1, PRAD1) gene.138,139 Additional abnormalities have been reported in MCL, including 13q14 and 17p deletion, as well as trisomy 12.140 Several chromosomal abnormalities have been observed in DLBCL. The bcl-6 is associated with chromosomal rearrangements involving 3q27.141–144 Rearrangements of the gene are found in a small proportion of FLs (6–13%) but in approximately one-third of diffuse aggressive lymphomas (approximately 30–35%).145 t(14;18) is not specific for FLs and has been observed in approximately 30% of patients with DLBCL. These cases may represent histologic transformations of prior FL. In cases of histologic transformation, mutations of p53 are observed at a high frequency and homozygous deletions at 9p21 which involve p15 and p16 tumor suppressors.146–148 Other abnormalities have been reported in DLBCL.149,150 Abnormal metaphases are seen in 90% of T-cell lymphomas.124,151–155 Young patients with anaplastic large cell lymphomas with t(2; 5)(93) and less commonly t(1;2),156 whereas hepatosplenic γ/δ T-cell lymphomas are associated with isochromosome 7q.157 Burkitt’s lymphoma most commonly involves a translocation of chromosome 8q24 in 90% of the cases studied with either chromosome 14, 2, or 22.158–162 In contrast, the Burkitt’s-like lymphomas have c-myc translocations in approximately one-third of cases, whereas dual translocations of bcl-2 and c-myc rearrangements are reported in one-third of cases and no other abnormality noted in the remaining one-third of cases.115

Molecular Basis of NHL

In Burkitt’s lymphoma,158–160,162,163 the c-myc oncogene on the long arm of chromosome 8 band q24 is juxtaposed with an immunoglobulin heavy (chromosome 14) or light chain gene (κ on chromosome 2 and λ on chromosome 22). The myc gene encodes for a family of proteins which are involved in protein dimerization and sequence-specific DNA binding. The myc proteins appear to be important in transcription and DNA replication and are important in regulating cellular proliferation and retarding differentiation. Translocations in Burkitt’s lymphoma result in increased or inappropriate synthesis of the myc protein, a DNA-binding protein that is likely to regulate key genes in the control of cellular proliferation and that has oncogenic potential when abnormally expressed. Although the t(8;14) appears to be constant at the cytogenetic level, there is considerable heterogeneity at the molecular level. The break in the myc gene generally occurs on the 5’ side, whereas the break in the immunoglobulin gene occurs at or close to the DNA elements which produce immunoglobulin heavy chain. Although the translocations associated with Burkitt’s lymphoma are believed to result in abnormal regulation of myc gene expression, the precise mechanism is unknown. Constitutive myc expression in Burkitt’s lymphoma appears to prevent cells from entering a resting state and, thus, may cause unrestricted proliferation.

Molecular analyses of the t(14;18) breakpoint led to the identification of the bcl-2 oncogene.164,165 The t(14;18) is observed in 85% of FLs and 30% of diffuse NHLs.165–170 In this translocation, the bcl-2 gene on chromosome 18 is juxtaposed to the transcriptionally active immunoglobulin heavy-chain region on chromosome 14. The chromosomal break points on bcl-2 have been shown to cluster at two main regions 3’ to the bcl-2–coding region. The major breakpoint region (MBR) is located within the 3’ untranslated region, and the minor cluster region (mcr) is located some 20 kbp downstream. Both regions have been cloned and sequenced. A number of studies have shed light on the function of the bcl-2 protein.165,171 Unlike oncogenes, which promote cellular proliferation, or tumor suppressor genes, which inhibit cell growth, the bcl-2 protein blocks programmed cell death. By blocking apoptosis, the expression of the bcl-2 protein can lead to prolonged cell survival as is typically observed in follicular lymphomas. Moreover, transgenic mice which express the bcl-2 gene develop a unique lymphoproliferative syndrome.172 Transgeneic mice bearing a bcl-2 gene in proximity to the IgH enhancer, analogous to t(14;18), develop regional lymphadenopathy, and polyclonal expansion of resting, yet responsive, IgM+IgD+ B cells. These lymphoid hyperplasias demonstrate prolonged cell survival but no increase in growth or neoplastic conversion. In approximately 50% of these mice, the lymphoproliferative syndrome progresses to a high-grade lymphoma which occurs in association with a myc translocation.

The t(11;14) occurs in MCL.69,151 In addition, this translocation has been observed in B-cell CLLs, some MZLs, and myelomas.132 The gene involved at chromosome 11q13 is the bcl-1 gene. This translation leads to dysregulated expression of the gene that codes for cyclin D1. Cyclin D1 is involved in the control of the G1 phase of the cell cycle. However, overexpression of cyclin D1 is probably insufficient to cause MCL, since transgenic mice which overexpress cyclin D1 do not develop lymphomas. Alterations in p53, p16, p18, p21, and p27 may play a role in the development and evolution of MCL.140

The bcl-6 (LAZ3) gene has been identified at the 3q27 breakpoint in a subset of DLBCL.141–145 bcl-6 encodes a transcriptional repressor with a POZ/zinc finger structure similar to several Drosophila development regulators. bcl-6 is expressed in germinal center B cells and is required for germinal center formation. By the fusion of bcl-6 with promotor regions of Ig genes, the protein is deregulated and may contribute to the development of lymphomas by blocking B-cell differentiation.

The t(2;5) in ALCL produces a fusion protein consisting of the NPM nucleolar phosphoprotein gene on chromosome 5q35, (as well as other genes on chromosomes 1 and 3), to a protein tyrosine kinase gene, alk on chromosome 2p23. Transfection of the constitutively active tyrosine kinase npm-alk into cell lines leads to a transformed phenotype. More importantly, overexpression of npm-alk in a murine retroviral gene transfer model causes B-lineage large cell lymphoma.173

Studies of three different translocations in indolent B-cell lymphomas has identified other genes involved in their pathogenesis. In lymphoplasmacytic lymphomas with t(9;14), the pax5 gene is juxtaposed with the IgH gene.174–176 pax5 encodes a transcription factor, BSAP (B-cell specific activator protein), which is expressed during B-cell development and is an important regulator of B-cell proliferation and differentiation. In extranodal MZL with t(1;14), a gene known as bcl-10 is overexpressed.177 This gene encodes an aminoterminal caspase recruitment domain which is involved in regulating apoptosis. Mutations in this gene in these lymphomas may provide survival advantages to the neoplastic B cells. Also in extranodal MZL with t(11;18), a gene known as apI2 which encodes an inhibitor of apoptosis, located at 11q21 is juxtaposed with mlt, at 18q21.178 mlt encodes a protein which contains Ig-like domains. Analogous to t(1;14), alteration in apI2 likely alters signals controlling apoptosis in these cells.

Differential Diagnosis and Sites of Disease at Presentation

More than two-thirds of patients with NHL present with persistent painless peripheral lymphadenopathy. At the time of presentation, differential diagnosis of generalized lymphadenopathy necessitates the exclusion of infectious etiologies, including bacteria, viruses (e.g., infectious mononucleosis, cytomegalovirus and human immunodeficiency virus) and parasites (toxoplasmosis) (Table 130.4). It is generally agreed that a firm lymph node larger than 1 cm that is not associated with a documentable infection and that persists longer than 4 to 6 weeks should be considered for biopsy. However, it is important to remember that lymph nodes in several histopathologic subtypes of NHLs frequently wax and wane. Therefore, incomplete regression does not exclude a diagnosis of NHL. In teenagers and young adults, infectious mononucleosis and Hodgkin’s lymphoma should be placed high in the differential diagnosis. A number of clinical features are suggestive of the diagnosis of NHL. Involvement of Waldeyer’s ring, epitrochlear, and mesenteric nodes are more frequently observed in patients with NHL than in those with, Hodgkin’s lymphoma. Unlike patients with Hodgkin’s disease, who present with weight loss, fever, or night sweats, less than 20% of patients with NHL present with systemic complaints. Systemic symptoms are more common in patients with aggressive histologies, especially in those with hepatic and extranodal involvement. Less frequent presenting symptoms include systemic complaints like fatigue, malaise, and pruritus occurring in less than 10% of patients.

Table 130.4. Generalized Lymphadenopathy Potentially Confused With Non–Hodgkin’s Lymphoma.

Table 130.4

Generalized Lymphadenopathy Potentially Confused With Non–Hodgkin’s Lymphoma.

NHLs also present with thoracic, abdominal, and/or extranodal symptomatology (Table 130.5).179,180 Although much less common than with Hodgkin’s disease, approximately 20% of patients with NHL present with mediastinal adenopathy. These patients most frequently present with persistent cough, chest discomfort, or without clinical symptomatology but have an abnormal chest radiograph. Occasionally, a superior vena caval syndrome accompanies the presentation. Differential diagnosis of mediastinal presentation includes infections (e.g., histoplasmosis, tuberculosis, infectious mononucleosis), sarcoidosis, Hodgkin’s lymphoma, as well as other neoplasms. Involvement of retroperitoneal, mesenteric, and pelvic nodes is common in most histologic subtypes of NHL. Unless it is massive or leads to obstruction, nodal enlargement in these sites usually does not produce symptoms. In contrast, patients who seek medical attention because of an abdominal mass, massive splenomegaly, or primary gastrointestinal lymphoma present with complaints similar to those caused by other abdominal space-occupying lesions. These complaints include chronic pain, abdominal fullness, early satiety, symptoms associated with visceral obstruction, or even acute perforation and gastrointestinal hemorrhage. Symptoms due to extralymphatic disease are common in some subtypes of aggressive NHL but are uncommon in indolent lymphomas. Rarely, patients present with symptoms of unexplained anemia. Those with aggressive NHLs can present with primary cutaneous lesions, testicular masses, acute spinal cord compression, solitary bone lesions, and rarely lymphomatous meningitis. Primary NHL of the CNS constitutes only 1% of all NHLs. However, with increasing incidence of HIV-1 infection, as well as the increasing use of high-dose immunosuppressive therapy, primary CNS lymphoma has become one of the most common types of primary brain tumors.181–183 Primary CNS symptoms include headache, lethargy, focal neurologic symptoms, seizures, or paralysis.

Table 130.5. Sites of Disease at Presentation Correlated with Working Formulation.

Table 130.5

Sites of Disease at Presentation Correlated with Working Formulation.

When NHL presents in an extranodal site, the differential diagnosis is more difficult. NHL uncommonly presents in the lung as bronchovascular-lymphangitic, nodular, or alveolar patterns of involvement.184,185 Between 25 and 50% of patients with NHLs present with hepatic infiltration, although relatively few present with large hepatic masses.179 Of those with advanced stage indolent lymphomas, nearly 75% of patients have microscopic hepatic infiltration at presentation. In contrast, primary hepatic lymphoma is extremely rare and nearly always has an aggressive histology.179 Another extranodal site of presentation occurring in less than 5% of patients is primary lymphoma of bone. This is virtually always diffuse large B-cell lymphoma which presents as a painful bony site. Most frequently lytic lesions are observed on the bone radiograph. The most common sites of primary lymphoma of bone include femur, pelvis, and vertebrae. Approximately 5% of NHLs present as primary gastrointestinal lymphoma.186,187 These patients present with hemorrhage, pain, or obstruction, since the stomach is most frequently infiltrated, followed by the small intestine and colon. Most gastrointestinal lymphomas are of the diffuse aggressive histologies, specifically DLBCL, mantle cell lymphoma, and the intestinal T-cell lymphoma. The most common site to be involved by extranodal marginal zone lymphomas is the stomach (gastric MALT lymphoma).58,188 A subset of mantle cell lymphomas presents as multiple intestinal polyposis involving any sites in the gastrointestional tract.70,71 An uncommon presentation of NHL is renal infiltration, and even less common is localized presentation in the prostate, testis, or ovary. The typical histologic subtypes of these sites are DLBCL or Burkitt’s/Burkitt’s-like lymphomas.189–192 Rare sites of primary lymphoma include the orbit, heart, breast, salivary glands, thyroid, and adrenal gland.193–196

Staging and Disease Detection

The Ann Arbor staging system developed in 1971 for Hodgkin’s disease was adapted for staging NHLs.197 This staging system focuses on the number of tumor sites (nodal and extranodal), location, and the presence or absence of systemic symptoms. Table 130.6 summarizes the essential features of the Ann Arbor system. In stages I and II, sites of disease are on the same side of the diaphragm, stage III disease involves both sides of the diaphragm, whereas stage IV is defined as extranodal lymphomatous involvement, most frequently of the bone marrow and liver. Systemic symptoms (fever, weight loss, and night sweats, i.e., B symptoms) are much less common in NHLs than in Hodgkin’s disease, which disseminates principally by contiguous lymphatic extension. Since NHLs most frequently disseminate hematogenously, this staging system has proven to be much less useful than for Hodgkin’s disease.

Table 130.6. Ann Arbor Staging System for Non–Hodgkin’s Lymphoma.

Table 130.6

Ann Arbor Staging System for Non–Hodgkin’s Lymphoma.

The concept of staging has less impact in NHL than in Hodgkin’s disease. Only 10% of patients with FL have localized disease at diagnosis,180 and the majority of patients with aggressive lymphomas have advanced-stage disease.180 It is generally accepted that there is little therapeutic benefit to distinguish between stage III and stage IV disease, since the treatment options are nearly identical. Multiple studies have demonstrated that the prognosis is far more dependent on histopathology and only secondarily influenced by clinical parameters, including age, extranodal disease, performance status. Since stage usually depends only on the location and number of disease sites, it is not a true measure of tumor burden which is clearly the important prognostic determinant in NHL. Thus, staging is undertaken in NHLs to identify the small numbers of patients who can be treated with local therapy or combined modality treatment and to stratify within histologic subtypes in order to determine prognosis and assess the impact of treatment.

Diagnosis and Initial Evaluation

The most critical diagnostic test is an accurate histopathologic evaluation of sufficient neoplastic tissue, preferably of a lymph node. Following histopathologic diagnosis of NHL, attention should be given to determining the extent of disease. Although not essential at the time of diagnosis, additional immunologic, cytogenetic, and molecular studies are desirable. Although not essential to obtain prior to initiating treatment, these data may be useful in future therapeutic decisions. Immunologic phenotypic analysis can be accomplished by employing single-cell mononuclear fractions and frozen or, in some cases, fixed tissue. In addition, fresh and, in some cases, fixed tissue can be studied for immunoglobulin or T-cell receptor gene rearrangements, cytogenetic abnormalities, and chromosomal translocations.

Staging must be undertaken in the context of the histology. A suggested evaluation for patients with follicular NHL is shown in Figure 130.6, and for diffuse aggressive NHL in Figure 130.7 After the initial biopsy, blood tests should be obtained, including complete blood count, routine chemistries, liver function tests, and serum protein electrophoresis to document the presence of circulating monoclonal paraprotein. Waldeyer’s ring involvement is often associated with intestinal involvement, and gastrointestinal contrast studies or endoscopy are indicated if the patient appears to have localized disease. Chest radiography is used to exclude mediastinal and hilar adenopathy, pleural effusions, and pulmonary parenchymal infiltration. Chest CT is used to more precisely assess the extent of disease and is recommended for patients with abnormal chest radiographs. However, abdominal/pelvic CT is essential for accurate staging to assess lymphadenopathy in retroperitoneal, mesenteric, and retrocrural areas. Unilateral percutaneous bone marrow biopsies must be performed, since the likelihood of lymphomatous involvement of the marrow is relatively high, especially in most indolent lymphomas, where marrow involvement occurs in up to 70% of cases. With any indication of hepatic abnormalities on blood tests or on liver scan, a percutaneous liver biopsy may be indicated in patients who would otherwise have stage I disease. In patients with aggressive lymphomas with marrow involvement, with paranasal sinus involvement, or if clinically indicated, examination of the cerebrospinal fluid (CSF) by lumbar puncture should be performed.

Figure 130.6. Diagnosis and staging recommendations for patients with follicular lymphoma.

Figure 130.6

Diagnosis and staging recommendations for patients with follicular lymphoma.

Figure 130.7. Diagnosis, staging, and initial treatment recommendations for patients with diffuse B-cell lymphoma.

Figure 130.7

Diagnosis, staging, and initial treatment recommendations for patients with diffuse B-cell lymphoma.

While staging laparotomy may occasionally be performed in patients with Hodgkin’s disease, this is not so in NHLs. In the aggressive NHLs, stages II, III, and IV can all be considered reflective of disseminated disease and are treated with chemotherapy. In contrast, only stage I disease or possibly stage II indolent lymphomas and occasionally DLBCL patients who might not be candidates for systemic therapy would be considered for local radiation alone. For most patients with NHL, it is less critical to ascertain the precise pathologic stage of disease, and therefore surgical staging should not considered in patients with NHL.

A number of other tests are becoming more important in both staging and further evaluating patients with NHL. Radionucleide scans, especially with gallium appears to have clinical utility. Gallium scans are positive in virtually all aggressive lymphomas and in about 50% of indolent lymphomas. Gallium scans, combined with single photon emission computed tomography (SPECT), are very sensitive in detecting tumor infiltration. These tests are also useful in monitoring response to therapy. To date, magnetic resonance imaging (MRI) appears to be most valuable for detecting occult marrow involvement and for evaluation of the brain and spinal cord.198 Positron emission tomography (PET) is being evaluated as an imaging tool in lymphoma.199 To date, it is investigational, although it appears to be sensitive for extranodal sites, including the marrow. Thallium scanning may be a useful diagnostic modality to assess tumor infiltration by FLs.200–202 Thallium appears to localize in those lymphomas, whereas there is little, if any, uptake by aggressive lymphomas. These studies suggest that thallium may be useful in distinguishing involved versus uninvolved lymph nodes in FLs.

Immunologic and Molecular Studies

Biologic studies, including cell surface markers, cytogenetics, and molecular techniques, are being integrated into diagnosis, staging, and minimal disease detection. Monoclonal antibodies directed against cell surface antigens expressed on lymphoid cells, and molecular techniques to define immunoglobulin and T-cell receptor gene rearrangements are sensitive tools with which to assess tumor cell infiltration more accurately. Immunophenotypic and cytogenetic studies can help determine histologic subtypes of lymphomas, in cases where the conventional histology is ambiguous, which may impact on treatment. Whereas conventional histologic analysis of the bone marrow can detect one lymphoma cell infiltrating 20 normal cells, immunologic flow cytometric and Southern blot analysis each improve this level of detection to approximately one lymphoma cell in approximately 100 normal cells.203,204 More recently employed molecular techniques suggest that minimal disease detection can be dramatically improved. For those NHLs with known chromosomal translocations, it is now possible to identify a unique chromosomal break point. For example, detection of the t(14;18) of follicular lymphomas or t(11;18) in MCL can be undertaken employing the technique of polymerase chain reaction (PCR).205,206 On the basis of DNA sequence, it is possible to amplify a unique stretch of DNA using specific oligonucleotide primers and PCR. With this approach, one tumor cell in 105 to 106 cells can be detected. Thus, while other tests may be negative, PCR can demonstrate that the blood or bone marrow is contaminated by lymphoma cells. Studies of minimal disease are providing important insights into whether patients are in molecular remission, prognostic information, and whether further therapy is required.207–210

Disease Parameters Which Influence Prognosis and Assessment of Disease Response

Clinical Prognostic Factors in Aggressive NHL

The analysis of a large group (2,031 patients) with diffuse aggressive NHLs led to the establishment of a prognostic model of predicting outcome, known as the International Prognostic Index (IPI)(Table 130.7).211 Prior to this analysis, many studies found that patient age and bulk and extent of disease were important prognostic variables. This model included diffuse aggressive histologies in the classification system used at that time, known as the Working Formulation; specifically, it included diffuse mixed small cleaved and large cell, diffuse large cell, and large cell immunoblastic lymphomas, treated with an anthracycline-containing regimen. By REAL, the cases would be reclassified as predominantly DLBCL and some PTCL. A large number of factors were examined for all patients studied: age (≤ 60 vs. > 60); serum LDH (≤ 1 × normal vs. > 1 × normal); performance status (0 or 1 vs. 2–4); stage I or II vs. III or IV); and extranodal involvement (≤ 1 site vs. > 1 site) were independently prognostic for overall survival. For patients age 60 years or less, only stage, LDH, and performance status were of prognostic significance. For relapse-free survival, age, stage, and performance status were significant parameters for predicting outcome. These data permitted the identification of four risk groups on the basis of the number of risk factors: low risk with 0 or 1 factor; low-intermediate with 2 factors; high-intermediate with 3 factors; and high with 4 or 5 factors. This model will be useful for the development of studies to examine the role of different treatment modalities in the aggressive NHLs.211,212

Table 130.7. The International Index and Age- Adjusted Index.

Table 130.7

The International Index and Age- Adjusted Index.

Response to Treatment

Response to treatment is one of the most important prognostic indicators, particularly in patients with aggressive NHL. Patients with aggressive NHL who do not respond or have less than a partial response (PR) to first-line therapy are considered to have “primary resistant” disease and generally have very short survivals, with salvage chemotherapy as well as high-dose therapy. Patients with large cell lymphoma who rapidly attain a complete remission (CR) appear to have a greater likelihood of long-term disease-free survival compared with patients who require additional treatment to attain a complete remission.213 Documentation of residual lymphoma by gallium-67 scanning after receiving about half the planned number of cycles of aggressive combination chemotherapy has been associated with significantly decreased disease-free survival in retrospective analysis.200,201 In patients under age 60 years with indolent NHL, the duration of first remission (PR or CR) is related to overall survival. Those patients with CR or PR lasting less than 1 year have median survivals of 2.4 years. In contrast, those patients with CR lasting > 1 year have a median survival of 5.9 years.214

Clinical Prognostic Factors in Indolent NHL

In contrast to aggressive lymphomas, prognostic variables for patients with indolent lymphomas remain controversial. In a large series of patients.42 splenomegaly, hepatosplenomegaly, abnormal liver function, B symptoms, anemia, and responsiveness to treatment, all had prognostic significance. Other studies have found that patients with extramedullary, extranodal disease, age (> 60 years), stage IV disease, and elevated LDH have a poor prognosis.215 Several groups have developed models based on pretreatment characteristics to predict outcome. A tumor burden model was developed based on the number of extranodal sites, node size, and degree of marrow involvement.216 Similar analyses have employed IPI for Aggressive Lymphomas.217,218. Using this model, discernable groups were identified using the variable for aggressive lymphomas.Those with the poorest prognosis constitute 10 to 15% of patients. Another model employing serum levels of beta-2 microglobulin and LDH also stratefies patients into risk groups. However, in all these models, the vast majority of patients were in low, low-intermediate, or high-intermediate risk groups with median survivals in excess of 10 years.217 This suggests that unlike aggressive lymphoma, these models may not be refined enough to be employed for stratifying patients with low-grade lymphomas for various treatment approaches.

Markers of Cell Proliferation and Regulators of Cell Cycle and Apoptosis

Ki-67, a nuclear antigen, is expressed on dividing tumor cells from patients with intermediate- or high-grade NHLs and correlates with disease-free survival. The Ki-67 antigen is expressed on dividing cells, regardless of their cellular origin. By quantifying the number of lymphoma cells which express Ki-67, the percentage of tumor cells which are cycling can be estimated. Patients with high expression of Ki-67 have a significantly worse prognosis (18% survival at 1 year) compared with patients who have low expression (82% at 1 year).219,220

Proliferating cell nuclear antigen (PCNA) is a protein associated with DNA polymerase that is expressed only in the nuclei of cells actively synthesizing DNA. The expression of PCNA has been examined in several studies with attempts to correlate with clinical characteristics and outcome. Analogous to the presence of Ki-67 in biopsy specimens, expression of PCNA correlates with grade of NHL.221

Increased uptake of tritiated thymidine or DNA aneuploidy correlates with cellular proliferation and therefore with decreased survival.222 Again, proliferative thrust correlates with higher grade and greater number of tumor cells in cycle. Determination of the fraction of cells in the S phase of the cell cycle (S-phase fraction,- SPF) has also been shown to correlate with histologic grade.223 Patients with lymphomas with an SPF lower than the median had significantly better 5-year and 15-year survival rates when compared with patients with lymphomas with higher SPF. However, this was only significant in patients with stage I or II lymphoma treated with radiotherapy only and in patients with stage III or IV lymphoma who did not receive combination chemotherapy.

Several investigators have explored whether expression of cell cycle and apoptosis regulatory proteins such as p53, p21, Rb, p27, and bcl-2 is related to clinical features and prognosis. High levels of Rb, low MDM2 are associated with increased survival.224 Mutations of p53 have been associated with lower rates of CR and lower overall survival,225,226 while high expression of p53 has been associated with high tumor burden.227 Overexpression of bcl-2 protein has been shown to be associated with shortened disease-free survival and advanced stage.224,227,228

Cell Surface Phenotype

Many studies have attempted to relate cell surface antigen expression to prognosis.229–233 A large body of evidence suggest that aggressive lymphomas of T-cell lineage have a worse prognosis than DLBCL.230,233–236 With the introduction of the IPI for diffuse aggressive lymphomas, the shortened disease-free and overall survivals of patients with PTCL is independent of the IPI,237 and the IPI is also useful for predicting outcome of patients with PTCL.238 Several studies have attempted to correlate the immunologic heterogeneity of DLCLs with clinical characteristics and survival. Patients whose tumors do not express HLA-DR had a significantly shorter survival duration, compared with HLA-DR–positive patients; no HLA-DR–negative patient survived beyond 1.5 years. A multivariate analysis, adjusting for prognostic factors of known clinical significance, confirmed the importance of the expression of HLA-DR as a prognostic factor.219 A recent study has reported that within the B-cell DLBCLs, patients whose tumors fail to express CD20, CD22, or HLA-DR have decreased survival. The overall survival for patients in this report, however, was low.233 A relationship between the adhesion molecule such as CD44 and advanced stage of NHL has been observed in low-, intermediate-, and high-grade disease.239,240 DLBCLs considered alone, CD44 positivity was present in more than half of the patients with stage III/IV disease, whereas 88% of CD44-negative cases had stage I/II disease. Furthermore, stage-matched patients with CD44+ tumors, independent of histologic subtype, had worse responses to therapy and shorter survivals than those withCD44-tumors.73 Consistent with the concept that absent cell-adhesion molecules may be associated with disseminated disease, ICAM-1–negative low-grade lymphomas have been observed to express a leukemic phase.


A number of karyotic parameters have been reported to influence prognosis adversely.241,242 Abnormalities which have been reported to be associated with a poor prognosis include absence of normal metaphase cells, complexity of the karyotype, the presence of specific chromosomal abnormalities including t(8;14), abnormality of the short arm of chromosome 1, trisomy 7, trisomy 18, deletions of chromosome 6, and the presence of abnormalities of chromosome 17. As expected, t(14;18), which is observed in the majority of FLs, correlated with a longer survival. However, within DLBCL, bcl-2 translocations predict for poor response to therapy, a lower disease-free survival, and shorter overall survival.168–170,243,244 One study found that the presence of a bcl-2 rearrangement was associated with prolonged survival following relapse of DLBCL. Rearrangement of the bcl-6 gene, present in approximately one-third of DLBCL patients, has been shown to be an favorable independent prognostic variable for freedom of progression and overall survival. The presence of t(2;5) is a favorable prognostic marker for patients with ALCL.93 In Burkitt’s-like lymphoma, dual trasnlocation of c-myc and bcl-2 is associated with a very aggressive disease and a poor outcome.245

Serum markers

Various serum proteins have been examined as prognostic markers in patients with NHL. The levels of interleukin (IL)-6 in serum is elevated in patients with aggressive NHL, as compared with normal controls. In addition, within DLBCL, elevated IL-6 levels is associated with B symptoms, poor performance status and, in one study, with lower rates of CR and failure-free and overall survival.246 Serum cross-reactive protein to behaves similarly to serum IL-6 levels.247 Tumor necrosis factor (TNF)-α and TNF receptor (p55) levels also correlate with poor prognostic features.248 Further studies will help to determine if the serum levels of these many markers are, in fact, independent prognostic factors for patients with aggressive lymphomas.

Minimal Residual Disease Detection

Minimal disease detection has been markedly improved through the use of sensitive molecular techniques, specifically PCR. This technique facilitates the detection of over 80% of B-cell NHL with t(14;18) and 40% of those with t(11;14) and is capable of reproducibly detecting one tumor cell with a bcl-2 rearrangement in 106 normal cells.166,205,249 Gribben and colleagues demonstrated that following treatment of advanced stage bcl-2–positive NHL with combination chemotherapy, approximately 50% of patients’ bone marrows became histologically normal.166 However, all marrows remained positive for a bcl-2 rearrangement as assessed by PCR demonstrating that a molecular complete remission had not been achieved. Following aggressive therapy with high-dose ablative therapy and autologous bone marrow transplantation, those patients who consistently lack a bcl-2 translocation in the bone marrow and the peripheral blood, have a highly significantly better disease-free survival than patients with PCR-detectable disease.207,208 In contrast to these studies with high-dose ablative therapy, it is controversial as to whether the presence of t(14;18)+ detectable cells in the peripheral blood and marrow of patients with stage III/IV disease following conventional therapy correlates with the outcome.210,250 This approach, until recently, would only apply to patients with amplifiable break points. However, the generation primers specific for the Ig heavy-chain gene DNA sequence of CDRIII regions through the use of consensus VH and JH primers permits the detection of lymphoma cells by PCR in about 70% of cases where a known amplifiable translocation cannot be detected.251 Therefore, we may soon be determining complete remission molecularly in all patients with NHL.

Therapeutic Approaches According to Real

To decide the appropriate treatment regimen, the clinician must know the histology and extent of disease. A suggested approach based on stage is shown for DLBCL in Figures 130.7 and 130.8 and for follicular NHL in Figure 130.9. The next decision is whether or not to treat and if the treatment option is selected, whether the goal is to palliate symptoms or attempt cure. Although there is concensus about the general principles of treatment of NHLs therapeutic approaches for all histologic subtypes are under active investigation. In choosing a therapeutic option, one must consider the patient’s age and the presence of comorbid diseases that might adversely affect end-organ toxicity.

Figure 130.8. Treatment recommendations for patients with diffuse large B-cell lymphoma (continued).

Figure 130.8

Treatment recommendations for patients with diffuse large B-cell lymphoma (continued).

Figure 130.9. Treatment recommendations for patients with follicular lymphoma.

Figure 130.9

Treatment recommendations for patients with follicular lymphoma.

Indolent Lymphomas

Early-Stage Indolent NHL

The majority of patients with indolent NHL present with advanced disease. Only 15 to 30% of patients have clinical stage I/II disease, and less than 10% have pathologic stage I/II.180 For this reason, limited studies are available concerning treatment for early-stage-disease. In the largest study with exceedingly long follow-up of 177 patients from Stanford, 44% patients had stage I and 56% had stage II disease.252 Patients were treated with either involved field irradiation (IF), extended field irradiation (EFI), with a limited number receiving total lymphoid irradiation (TLI). Survival rates at 10, 15, and 20 years were 64%, 44%, and 35%, respectively. The relapse-free survival at 10, 15, and 20 years, was 44%, 40%, and 37% respectively. The freedom from recurrance (FFR) was significantly better for patients under age 60 years and for patients who received radiation to both sides of the diaphragm (although there was no difference in overall survival). Late second tumors have been noted in 17% of the patients treated with extensive radiotherapy, whereas the incidence of second solid tumors was 6.8% in patients who received involved or extended field radiation. Patients treated with EFI generally relapsed in contiguous lymphatic sites, in contrast to patients treated with TLI who generally relapsed in extralymphatic sites. Several other studies have similarly observed that early stage patients treated with radiotherapy have 10-year relapse-free survival of 45 to 60%, with overall 10-year survivals of 60 to 80%.253,254

In low-stage disease, chemotherapy alone has rarely been used due to the radioresponsiveness of these tumors. Several studies have employed local radiotherapy with adjuvant chemotherapy (CVP), and there appears to be no significant advantage of combined modality over local radiotherapy.254–257 Monfardini and colleagues reported a 5-year relapse-free survival of 55% and overall survival of 62% for patients treated with radiotherapy, while patients treated with combined modality therapy had a 5-year relapse-free survival and overall survival of 63% and 93%, respectively. There was no statistically significant difference between these treatment arms. A retrospective study by McLaughlin and colleagues reported that the relapse-free survival was 64% versus 37% for patients receiving CHOP chemotherapy plus radiotherapy or radiotherapy alone, respectively. Whether these improved results are due to the more aggressive regimen used remains to be determined in a prospective randomized study. The benefit of chemotherapy in stage I/II indolent NHL remains uncertain.

The extranodal MZLs often present with localized disease involving the gastrointestional tract, salivary glands, thyroid, orbit, conjunctiva, breast, and lung.56,61 The gastric MZLs are managed differently from those involving other sites. Since many cases of gastric MZL appear to be a B-cell clonal expansion in response to Helicobacter pylori, treatment has been directed at the chronic gastritis. Therapy with antibiotics (metronidazole, amoxicillin, clarithromycin) and often a proton pump inhibitor induce regression of superficial low-grade MZL of the stomach in over 70% of patients. The long-term remission status of these patients remains unclear. For patients with localized disease who progress after antibiotic therapy or are H. pylori-negative, IFI with or without surgical resection has a 10-disease-free survival year of about 90%. For other sites of extranodal MZL, since these diseases tend to remain localized for long periods of time prior to systemic spread, surgery remains a highly effective approach, often with adjuvant IFI. The use of chemotherapy with alkylating agents for MZL has received limited attention.

Advanced-Stage Indolent NHL

The long natural history of indolent NHLs and the lack of symptoms in the majority of patients at diagnosis have fostered close observation as the initial approach to some of these patients.37,38 The advantages of this approach include a prolonged period free of treatment during which tumor cells will not be selected for drug resistance by continuous exposure to drugs. Moreover, spontaneous remissions of longer than 1 year have been reported from Stanford in 23% of patients, making treatment unnecessary in this subgroup of patients.37,258,259 Withholding therapy requires a cooperative patient and the need for close follow-up. The possibility of developing aggressive disease either by virtue of site or histologic change can occur despite close observation. In the study from Stanford University, where patients were randomized either to initial therapy or to deferred treatment until the time of symptoms (usually progressive bulky disease), there was no difference in the 4-year actuarial survival between the two groups. The median time until therapy was administered for the entire group of indolent lymphoma patients was 3 years. However, for the three histologic subtypes, the median time until requiring therapy differed: 16.5, 48, and 72 months for FL grade II (follicular mixed small cleaved and large cell), FL grade I (follicular small cleaved cell), and SLL, respectively.260

In general, systemic chemotherapy has been used for the treatment of advanced-stage indolent NHL. However, fractionated total body irradiation (TBI) has been employed in the treatment of patients with stage III/IV disease with a high CR rate (70–85%).260,261 The relapse-free survival has been reported to be approximately 25% at 5 years in studies from both Stanford University and the National Cancer Institute (NCI).

Indolent NHLs are very sensitive to both single-agent and combination chemotherapy.38 The CR rates of previously untreated patients to single alkylating agents range between 30 and 60%. However, the median duration of CR with either single alkyating agents, such as cyclophosphamide, or with combinations, such as CVP, is only about 2.5 years. A study from Stanford University which compared daily single alkylating agent treatment, combination chemotherapy (CVP), and TBI, in patients with FL grade I/II and SLL has similarly reported that there is no significant difference in relapse-free survival or overall survival with these different regimens.260 They did note that the median time to achieve CR was 12 months, 5 months, and 3 months for single-agent CVP and TBI, respectively. In general, with either single agents or CVP, only 20 to 25% of patients are disease free at 4 years.42 Following relapse, these diseases continue to be sensitive to single agents and CVP; and the median relapse-free survival progressively decreases with each subsequent relapse.

In an attempt to improve the relapse-free survival and overall survival in patients with indolent NHL, more aggressive combination chemotherapy regimens have been used.262–265 Regimens such as MOPP, BACOP, M-BACOD, CHOP, and BVCP have been observed to give CR rates of 35 to 70%, but the median disease-free survival remains similar to that seen with CVP, in the range of 1.5 to 3 years.

It has been suggested that the response of FL grade II (follicular mixed small cleaved and large cell) to aggressive therapy is different from FL grade I. Studies from the 1970s suggested that patients with FL grade II treated with combination chemotherapy (C-MOPP, CHOP-Bleo), had a high CR rate and significant number of patients (>50%) were still in CR 5-7 years after treatment. This suggested that FL grade II might be curable with aggressive combination chemotherapy.266–268 However, a prospective randomized trial comparing cyclophosphamide-prednisone, C-MOPP, and BCVP failed to demonstrate significant long-term disease-free survival for patients with FL grade II.269 With the difficulty of reproducible grading of these histologies, it is unclear whether patients with this histology have a different outcome than do patients with FL grade I.

Several randomized trials have looked at the impact of combination chemotehrapy in patients with advanced FL.270 When patients were randomized to cyclophosphamide-prednisone, BCVP, or CVPP, the progression-free survival was greater with CVPP, but no differences in survival were noted. When the role of Adriamycin was examined by comparing COP-Bleo with CHOP-Bleo (and CHOP-BCG), no differences were seen. Finally, when CHOP-Bleo was compared with cyclophosphamide alone in patients with FL, there was a survival advantage for the patients with FL grade II, although there has not been a recent update of this data.

The rationale for combined modality therapy stems from the observation that systemic extranodal sites of relapse are common following radiation therapy, and that radiation therapy provides excellent local control for low-grade lymphomas. Studies from the NCI and Stanford University failed to demonstrate an improved disease-free survival or overall survival for patients treated with CVP±TBI or CVP±TLI, respectively. Investigators at M.D. Anderson Cancer Center report in stage III patients with FL treated with CHOP-bleomycin and IFI an 81% CR rate, a 75% 5-year survival, and 52% relapse-free survival for the entire patient population.271 A study from NCI attempted to address two issues: first, the role of aggressive combined modality therapy; and second, whether early institution of aggressive therapy affects the natural history of the disease.272 In this study, patients with stage III/IV follicular and SLL were randomized to either no initial therapy or ProMACE-MOPP followed by TLI. Of the 104 patients, 14% were not randomized but required initial treatment with a 71% CR rate, but only 33% are in unmaintained remission with a median follow-up of 23+ months. The patients who were randomized to initial aggressive treatment had a high CR rate (78%), and 86% are in first CR from 1+ to 82+ months. In contrast, 44% of the patients initially randomized to observation have crossed over with a lower CR rate (43%) than those treated initially with combined modality treatment, and 71% of those treated remain in CR from 4+ to 40+ months. To date, there is no difference in the overall survival between patients treated initially and those treated after a period of observation, with over 75% of patients alive at 5 years. From this study, it appears that patients who have disease requiring initial treatment or progressive disease necessitating treatment have a lower CR rate than those treated initially.

Interferon-α is an active agent in relapsed indolent NHL (predominantly, follicular NHL). Several prosective randomized trials have examined the role of interferon when added to combination chemotherapy for advanced-stage disease patients.273–277 These studies have generally reported a significant effect on progression-free survival, with only two trials which involved maintenence interferon-α observing a significant prolongation in overall survival.

The purine analogues 2-chlorodeoxyadenosine (2-CdA) and fludarabine, which are very active agents in hairy-cell and chronic lymphocytic leukemia, respectively, are also active agents in indolent NHL.278–284 In previously treated patients, 2-CdA induced responses in about 40% of patients, half of which were CRs and the other half PRs, with a median duration of response of 5 months. The response rate (RR) to fludarabine ranges from 45 to 65%, with less than 20% CR. In previously untreated patients, the response rate to fludarabine was 84% RR, with 32% CR. Fludarabine has been used in combination with other drugs, including cyclophosphamide (100% RR, 89% CR) as well as mitoxantrone (91% RR, 43% CR, progression-free survival 63% at 2 years),285 with encouraging results. Ongoing phase III trials will attempt to address the efficacy of these combinations, as compared with standard regimens.

Monoclonal antibody (mAb) therapies have received much attention for the treatment of indolent NHL.286 The “humanized” anti-CD20 mAb Rituxin has a 50 to 60% RR, with 6% CR, in patients with previously treated FL.287 In SLL, the response rate is significantly lower, about 10%. The median duration of responses is about 9 months. The major toxicity of Rituxin is largely infusion related, with fevers, rigors, and hypotension usually associated with the first infusion. Rituxin has been combined with CHOP chemotherapy, with encouraging preliminary results. There are several radioimmunoconjugates which are being investigated in the treatment of indolent B-cell NHL, to deliver targeted radiotherapy.286 Bexxar which is a murine anti-CD20 mAb conjugated to 131-iodine appears to have a higher response rate than Rituxin in patients with relapsed disease (67% RR, 17% CR, median disease-free survival 20 months).288 A limited study in previously untreated patients with indolent lymphoma has shown very high CR rates, but follow-up is very limited. Another labelled antibody, 90-y/trium conjugated to the humanized anti-CD20 mAb also looks promising in indolent lymphomas.

Histologic Transformation

It is well recognized that part of the natural history of low-grade NHL is the progression to a higher-grade histologic subtype.38–41,43 The implications of histologic conversion on prognosis are controversial. Armitage and colleagues compared similarly treated patients who had histologic conversion to DLBCL with “de novo” DLBCL patients and found no instances of prolonged CR in the former group, and a significantly shorter median survival (12 vs. 40 months).40 The median survival of a large series of patients with follicular NHL undergoing histologic conversion is 11 months.44 An update from Stanford University suggests that patients who were never treated had a better prognosis, as were patients with limited disease.45 Although the median survival for the entire group was only 22 months, patients who achieved a CR after conversion had an actuarial survival of 75% at 5 years. As detailed below, a subgroup of patients with a history of indolent NHL who transform to a more aggressive histology may be cured by high-dose therapy and autologous bone marrow transplantation (ABMT).289

Aggressive Lymphomas

Aggressive lymphomas within REAL include: DLBCL; mantle cell lymphoma, the peripheral T-cell lymphomas (nonspecific and specific subtypes), and anaplastic large cell lymphoma. (see Table 130.2). For practical purposes of treatment options, the approaches are essentially identical for the various histologic subtypes, the major differences are whether they are localized or in an advanced stage.

Early-Stage Aggressive NHL

Less than 20% of patients with DLBCL have truly localized disease. DLBCLs with nonbulky stage I (I or IE) or limited stage II (II or IIE) disease have been treated with radiotherapy alone with variable results.253,290,291 Dosages in the range of 4,500 to 5,000 cGy appear to be necessary to maximize local control. Approximately 40% of clinically staged patients experience long-term disease-free survival with radiotherapy alone. A number of studies have demonstrated that patients who received local involved field radiation therapy followed by adjuvant chemotherapy did significantly better than patients who received radiation therapy alone.292–295 To address the role of radiotherapy in localized diffuse aggressive NHL, a randomized trial of patients with localized DLBCL compared eight cycles of CHOP to three cycles of CHOP plus IFI.296 Patients treated with three cycles of CHOP plus radiotherapy had a significantly better 5-year progression-free survival and overall survival than did patients treated with eight cycles of CHOP (77% vs. 64% for progression-free survival, 82 vs. 72% for overall survival). Overall life-threatening toxicity and cardiac toxicity were significantly higher in the patients receiving CHOP alone. The benefit of attenuated chemotherapy was largely in patients over the age of 60 years.

Advanced-Stage Aggressive NHL

The high CR rate and long-term disease-free survival observed for patients with DLBCL is one of the major success stories of aggressive combination chemotherapy. The treatment of DLBCL chronicles aggressive combination chemotherapy from its inception to the later concepts of resistance, dose intensity, addition of newer agents, and timing of therapy.119,297–299 Certain principles have been important in considering the management of aggressive lymphomas in the 1990s. First, aggressive combination chemotherapy should always be administered and dose reduction avoided, if at all possible. Second, attention to prognostic variables is important since they may suggest the need to be more or less aggressive. Third, newer approaches to assess response may ultimately dictate the type of therapy and its duration.

On the basis of the success of MOPP in the treatment of Hodgkin’s disease, the earliest combination chemotherapeutic regimens developed specifically for large cell lymphoma were C-MOPP and CHOP298,300(See Table 130.8). These regimens led to approximately 50% of patients achieving CR and 35% enjoying long-term disease-free survival (Table 130.9).300 With evidence for potential cure, additional “first-generation” regimens were developed including BACOP and COMLA.301,302 Comparison of these regimens in Table 130.8 demonstrated similar dose intensity of cyclophosphamide with the C-MOPP regimen. In BACOP, bleomycin, and in COMLA, methotrexate and cytosine arabinoside were added to overcome resistance. Although early reports suggested that complete remission rates were higher, most studies demonstrate no significant improvement of these regimens over C-MOPP or CHOP (Table 130.9). Addition of doxorubicin to COMLA (ACOMLA) added very little to the response rate or long-term disease-free survival.301 More importantly, the toxicity of these regimens was greater than was observed for C-MOPP or CHOP. Relapses were usually observed within 2 years, and survival following relapse was usually short.

Table 130.8. Combination Chemotherapeutic Regiments for the Treatment of Intermediate-Grade Non–Hodgkin’s Lymphoma.

Table 130.8

Combination Chemotherapeutic Regiments for the Treatment of Intermediate-Grade Non–Hodgkin’s Lymphoma.

Table 130.9. Treatment of Intermediate Grade Non–Hodgkin’s Lymphomas: Complete Remission and Approximate Percentage of Long-Term Survivors.

Table 130.9

Treatment of Intermediate Grade Non–Hodgkin’s Lymphomas: Complete Remission and Approximate Percentage of Long-Term Survivors.

The “second generation” of intensive regimens attempted to add non–cross-resistant agents to build upon C-MOPP and BACOP.303 There was much enthusiasm for the M-BACOD, m-BACOD, and ProMACE-MOPP regimens. In M-BACOD, high-dose methotrexate was added for CNS prophylaxis.299,304 Since significant advances were not achieved with the second-generation therapeutic regimens, a series of more aggressive third-line regimens have been devised and tested. All these regimens (ProMACE-CytaBOM, COP-BLAM-III, MACOP-B) have attempted to add more active agents in a shorter period of time.305,306 These regimens initially reported greater than 80% complete remission rates and greater than 60% long-term disease-free survival (Table 130.9).307

There are several issues which arose from the above studies. When responses were reported, the follow-up for most of the regimens was short, and when re-examined at more than 2 years, the true disease-free survival rate significantly decreased. Approximately 10% of patients relapsed beyond 4 years. Moreover, these single-institution response rates could not be repeated in single and multi-institution studies. Because of these results, the Southwest Oncology Group (SWOG) undertook a four-sided phase III study to enroll patients in a randomized trial comparing CHOP, m-BACOD, MACOP-B, and ProMACE-CytaBOM.308 The completed randomized four-arm study, in an analysis of 897 eligible patients with intermediate- or high-grade NHL found no difference in outcome, however, at a median follow-up of 31 months for CHOP, m-BACOD, ProMACE-CytaBom or MACOP-B. Irrespective of stage III or IV, the third-generation regimens failed to improve on CHOP for remission rate or survival. At 4 years, the patients alive without disease were CHOP 36.4%, m-BACOD 34.4%, ProMACE-CytaBOM 45.1%, MACOP-B 38.8% (p = .14). Fatal toxicities were 1%, 5%, 4%, and 6%, respectively.308 There have been additional randomized trials, including comparisons of MACOP-B versus ProMACE-MOPP,309 escalated versus, standard doses of doxorubin in the BACOP regimen,310 and CHOP versus m-BACOD,311 which have clearly demonstrated that more intensive regimens offer no improvement in remission rate and disease-free or overall survival, but increased toxicity.

In the context of the IPI for diffuse aggressive lymphomas,211 new therapeutic programs for the treatment of DLBCL are being developed. For those patients with the best prognosis, present therapeutic regimens are reasonably effective. In contrast, for those patients who fall into the worst prognostic subgroups, aggressive combination regimens are inadequate. More aggressive regimens, where the doses of cyclophosphamide and Adriamycin are escalated with hematopoietic growth factor support have shown impressive CR rates and durable remissions in phase I/II studies. Similarly, a number of studies have looked at the role of consolidative high-dose therapy and stem cell support for high-risk patients in first remission (see “Stem cell transplant” section).

For the myriad peripheral T-cell lymphomas, similar treatment approaches have been taken for patients with localized and advanced-stage disease. When patients are stratified by the IPI, the failure-free survival and overall survival are generally inferior for patients with aggressive T-cell lymphomas than for patients with B cell disease.

Aggressive Lymphoma in Older Patients

A significant proportion of patients with diffuse aggressive lymphoma are over age 60 years. In the analysis which led to the development of the IPI, the outcome for patients over age 60 years was significantly different from those age 60 years and less. The clinical characteristics of patients above or below age 60 years was similar, and the CR rates were similar or slightly lower than that seen in patients ≤ age 60 years. The relapse-free survival and overall survival for patients over age 60 years in the low- and low-intermediate-risk groups were significantly less than those for patients ≤ 60 years. The reasons for these differences may be related to less intensive treatment delivered as well as the presence of comorbid diseases.312 In some studies, increased deaths unrelated to lymphoma or its treatment have been reported, whereas in others an increased treatment-related mortality has been reported, often related to poor performance status.313,314

Several attempts have been made to modify the chemotherapy for elderly patients.315 One approach has been to divide the standard dose of CHOP where the total dose is given over 3 weeks rather than once every 3 weeks. In a randomized trial comparing weekly CHOP with the standard dose, the CR rate and progression-free survival were similar, while the overall survival was better with standard dose CHOP.316 In studies where anthracycline-containing regimens were compared with regimens without anthracycline, the myelosuppression has been higher, although treatment-related mortality was not significantly different. More importantly, the CR rate, time to treatment failure, and 5-year survival were better for the anthracycline-containing combination. Substitution of mitoxantrone for Adriamycin has resulted in lower CR rates and 3-year survival.317 To date, other regimens have not been shown to be superior to standard dose CHOP for elderly patients with diffuse aggressive NHL.318

Follicular Lymphoma Grade III (follicular large cell)

Follicular large cell lymphoma is clinically similar to DLBCL.38,46,47,319,320 Although stage I disease is very uncommon, there is a reported cure rate of nearly 90% with IFI or regional radiotherapy.320 However, many investigators argue that all patients should be treated with aggressive combination chemotherapy, with CR rates of about 80% and 50%, and overall survival of approximately 70% and 60% for stage I/II and III/IV patients, respectively.46

Mantle Cell Lymphomas

The median survival of patients with MCL is 3 to 4 years. The treatment of MCL generally involves alkylating agents, resulting in 30 to50% of patients having a CR, with median duration of 1 to 3 years.63,65,66,69 A randomized trial comparing CVP with CHOP demonstrated no benefit for the addition of doxorubicin in terms of overall survival. Generally, single alkylating agents offer similar results as combination chemotherapy. Newer agents, such as fludarabine and Rituxin, are giving response rates in the range of 30%, with remissions duration similar to that of alkylating agents.284,321,322 More intensive treatment is being examined in MCL. The results of high-dose therapy and autologous bone marrow transplantation have been generally disappointing in both previously untreated or relapsed patients. A more aggressive induction followed by stem cell transplantation has been investiagted at the M.D. Anderson Cancer Center. Hyper-CVAD regimen, with escalated doses of cyclophosphamide, high-dose methotrexate and cytarabine, has a very high response rate (38% CR).323 In this report, all patients went on to either autologous or allogeneic stem cell transplantation. The results for previously untreated patients was encouraging with 3-year event-free survival of 72%. Further study into new induction regimens, including combinations of mAbs and chemotherapy, as well as the role of allogeneic transplantation may impact on the outcome of these patients.

High Grade Lymphomas

Lymphoblastic, Burkitt’s, and Burkitt’s-like Lymphomas

Lymphoblastic lymphoma in adults has been treated with some success, although inferior to that seen in children.110,324 A 56% disease-free survival at 3 years has been reported in patients treated with CHOP plus high-dose methotrexate, L-asparaginase, and intrathecal methotrexate. When treated with regimens initially developed for childhood acute lymphoblastic leukemia (e.g., LSA2L2), about 40% of adults are reported to survive at 5 years. CNS prophylaxis is critical in treating this disease, since the CNS is a sanctuary site for recurrence in the absence of prophylaxis. The Burkitt’s and Burkitt’s-like lymphomas in HIV-1–negative adults have been similarly treated with regimens designed for the pediatric populations, which involve the use of high doses of cyclophosphamide, cytosine arabinoside, and CNS prophylaxis with methotrexate.325–328 Although CR rates are very high, the cure rate is generally less than is observed for DLBCL.329 In selected series, survivals of 50 to 70% have been reported, although with marrow or CNS disease, the long-term survival ranges from 0 to 30%. An analysis of 65 adults treated on the LMB pediatric protocol reported a CR rate of 89%, with 3-year survival of 74%.328 Future prospective trials will assess the efficacy of these regimens in Burkitt’s and Burkitt’s-like lymphomas in adults.

Recurrent Disease

Although significant advances have been made in the treatment of patients with NHL, the majority of patients are not cured with conventional therapy. Following relapse, at least 50% of patients remain sensitive to conventional treatment, but less than 10% of patients with aggressive NHL experience prolonged disease-free survival with second-line treatment regimens, and essentially all patients with indolent disease relapse.330

Following relapse, the principal curative approach for patients with NHL involves supralethal doses of chemotherapy, often in combination with radiation therapy331 (See Chapters on BMT). The major life-threatening toxicity of these treatment regimens is irreversible myelosuppression. To circumvent the attendant myelosuppression, bone marrow support from either syngeneic, allogeneic, or autologous bone marrow stem cells has been utilized as a source of hematopoietic repopulation. This approach has produced CRs in patients who have relapsed disease as well as those who fail to achieve CR with primary therapy. Although subgroups of patients clearly benefit from this approach, it still does not cure the majority of patients with relapsed or refractory NHL. Furthermore, randomized trials have begun to assess the efficacy of these approaches.

Conventional Salvage Therapy

The vast majority of patients with relapsed or refractory NHL have limited benefit from conventional salvage regimens. Patients with primary refractory disease who do not achieve a CR with initial therapy rarely achieve a CR when treated with a non–cross-resistant conventional regimen. Following relapse after a first CR, although a subset of patients achieves CR with standard-dose therapy, these remissions are generally not durable, and long-term disease-free survivors are rare. In a report of approximately 400 patients with relapsed NHL, treated with a variety of salvage regimens, only 3% were in continuous CR at 2 years.330

In an attempt to improve the disease-free survival for patients with relapsed or refractory disease, a number of regimens have been developed with non–cross-resistant drugs at higher doses. These regimens have included single-agent regimens, as well as combinations of cisplatin/carboplatin, etoposide, ifosfamide, and cytosine arabinoside.332–336 The response rates for these salvage regimens have ranged from 20 to 77% with upward of 30% CRs reported. The duration of these responses and overall survival of these patients is generally short. Another approach for salvage therapy has been the use of continuous infusions of cyclophosphamide, etoposide, doxorubicin (CDE, EPOCH). The overall responses are in the range of 40 to 80%, with approximately 20% CRs.337,338 Patients who relapse within 12 months of diagnosis of aggressive NHL have a significantly lower response rate to salvage therapy (DHAP) than patients who relapse 12 months or more after diagnosis (40% versus 69%).339 Although a higher response is seen in indolent NHLs, the response rate of patients with relapsed aggressive NHL to Rituxin is 31% (22% PR, 9% CR).322

Syngeneic and Allogeneic Bone Marrow Transplantation in NHL

Only a limited number of patients with NHL have undergone syngeneic BMT. The largest published series involved 8 patients, seven with aggressive NHL and 1 with indolent NHL.340 All were treated with cyclophosphamide and TBI followed by identical twin marrow re-infusion. The majority of patients were in resistant relapse, with 1patient in CR after BMT. Seven of the patients achieved CR and 4 patients were reported to remain in continuous complete remission (CCR) from 12 to 126 months after syngeneic BMT.

Allogeneic stem cell transplantation has received increasing attention for patients with relapsed and refractory NHL.341–346 Allogeneic transplant offers potential benefit of a tumor-free marrow and possible graft-versus-lymphoma effect. The majority of patients had aggressive lymphomas, although increasingly patients with indolent lymphomas are being considered for allogeneic transplantation. Nearly all patients had relapsed disease, many of whom were resistant to conventional-dose therapy. The majority of patients treated achieved a CR following high-dose ablative therapy, and the relapse rate is generally less than 20%. However, the treatment-associated mortality in these studies ranged from 20% to as high as 50%, usually due to complications of graft-versus-host disease (GVHD), opportunistic infections, or pneumonitis. The probability of long-term disease-free survival is in the range of 20 to 40%. In a prospective comparative trial of allogeneic or autologous BMT, there was no significant difference in event-free survival between the two sources of marrow; however, the probability of relapse was significantly greater in the autologous patients.346 Similar results have been seen in patients with indolent NHL. In an effort to reduce the morbidity and mortality associated GVHD, several groups have employed T-cell depletion for the prevention of GVHD.347,348 The incidence of significant (grade 2–4) GVHD in these studies is about 20%, and it is largely grade 2. The treatment related mortality is less than 20%, and the disease-free and overall survival between 50 and 60%. Other approaches to improve results of allogeneic transplants, such as nonmyeloablative conditioning and donor lymphocyte infusions, are under way.349

Autologous Stem Cell Transplantation (ASCT) for Relapsed Aggressive NHL

The disease sensitivity at the time of ASCT has remained the most significant prognostic variable for predicting treatment outcome.350–353 Several large series have shown that patients who undergo ASCT when the disease is resistant to the initial induction therapy have less than 10% probability of disease-free survival. Although many patients die of progressive lymphoma, in some studies, the treatment-related mortality has been higher in this patient population (20–30%). Those patients in sensitive relapse have a 30 to 60% probability of long-term disease-free survival. In contrast, 10 to 20% of patients with resistant disease are long-term survivors.

The question as to how autologous BMT compares with conventional salvage therapy for relapsed aggressive NHL was addressed by a multi-center trial known as the PARMA trial.354 Patients with relapsed aggressive NHL (largely DLBCL) received two cycles of DHAP and, if responsive, were randomized to continued DHAP for four additional cycles or high-dose chemotherapy (BEAC) and autologous BMT. With median follow-up in excess of 5 years, patients randomized to the high-dose arm had superior event-free survival (46% vs. 12%) and overall survival (53% vs. 32%). In a subsequent analysis of prognostic factors for the patients in this study, patients with IPI of > 0 at the time of relapse, prior to re-induction with two cycles of DHAP, had a significantly better overall survival when treated with autologous BMT.355 Furthermore, IPI at relapse was highly correlated with overall survival in patients treated with DHAP, but not those who underwent autologous BMT.

Analogous to relapsed highly aggressive lymphomas in the pediatric population, adult lymphoblastic lymphoma has been reported to be a disease where high-dose therapy has a role. A retrospective analysis of 109 patients undergoing marrow transplantation in second CR resulted in a 31% rate of actuarial overall survival at 6 years.356 Similar to other lymphomas, patients with resistant disease at the time of transplantation did relatively poorly with 15% overall survival at 6 years. In a retrospective analysis of EBMT registry data of allogeneic versus autologous BMT for lymphoma patients undergoing allogeneic BMT for lymphoblastic lymphoma in greater than first remission, the allogeneic transplant patients had a significantly lower rate of relapse when compared with patients undergoing autologous BMT, although the procedure-related mortality was significantly higher for the allogeneic BMT patients.345 For patients with Burkitt’s and Burkitt’s-like lymphoma, adults who underwent ASCT with sensitive disease have 3-year overall survival of 37%, while for chemoresistant patients the overall survival is 7%.357

The majority of relapses are seen in the first 2 to 3 years after ASCT. Approximately two-thirds of patients relapse in prior sites of disease, and nearly one-third relapse in entirely new sites. It is not possible to determine whether relapse results from endogenous tumor cells or re-infused cells contaminating the stem cell product (marrow or peripheral blood stem cells). Since most patients relapse in prior sites of bulk disease, re-infused tumor cells may not contribute to relapse or may selectively localize back to an affected site. The contribution of re-infused lymphoma cells to relapse is supported by gene marking studies as well as studies of minimal residual disease in the stem cell product.358,359 In studies by Gribben and colleagues, following ex vivo marrow treatment, PCR amplification of bcl-2 rearrangement detected residual lymphoma cells in the purged marrow in 50% of patients.209 The disease-free survival was highly significantly better in the patients who had no residual detectable bcl-2+ cells in the purged marrow, compared with those in whom cells were detectable after purging by PCR. Similarly, patients in whom lymphoma cells can be cultured from stem cell collections have a higher risk of relapse,360 In a study of mafosfamide purging of autologous marrow, patients who received a lower dose of CFU-GM re-infused had a better event-free survival. A lower CFU-GM cell dose re-infused was a surrogate marker for more effective ex vivo purging.

Autologous Stem Cell Transplantation for Relapsed Indolent NHL

In contrast to relapsed aggressive NHL, fewer patients with indolent NHL have undergone high-dose therapy and ASCT.361–365 Most of these studies have included patients with follicular NHL, although some patients with SLL and other indolent B-cell NHLs have undergone autologous BMT. The lack of interest in autologous BMT for indolent lymphomas has largely been based on the belief that this is a disease with a very long natural history where excessive treatment related toxicities associated with aggressive therapy would not be acceptable. Moreover, the high frequency of overt bone marrow and peripheral blood infiltration, has been a major obstacle. Many of these patients had disease resistant to conventional therapy prior to autologous BMT and the vast majority were selected for lack of bone marrow infiltration.

A large number of patients who received purged autologous bone marrow following high-dose therapy for follicular lymphoma have been reported. The Dana-Farber Cancer Institute has treated 153 patients with a history of follicular NHL in sensitive relapse or incomplete first remission with cyclophosphamide/TBI-conditioning and anti–B-cell, mAb-treated autologous BMT between 1985 and 1995.366 At diagnosis, 90% of patients had stage IV disease, 28% had B symptoms, and 30% had extranodal disease exclusive of the bone marrow. At bone marrow harvest, only 30% were in CR. As of March 1999, the disease-free survival and overall survival at 8 years following autologous BMT are 42% and 66%, respectively. The survival from diagnosis for the entire group of patients is 69% at 12 years.

St. Bartholomew’s Hospital have similarly treated 64 relapsed indolent lymphoma patients with anti–B-cell, mAb-purged autologous BMT.365 These patients were treated with the same cyclophosphamide/TBI-conditioning regimen. At autologous BMT, 34 were in CR, with 7 having bone marrow involvement at harvest. Following high-dose therapy, the treatment-related mortality has been very low, and 35 patients remain in CCR from 1+ to 8+ years. This study performed a retrospective analysis of patients undergoing autologous BMT in second remission and compared them with patients treated with conventional therapy. The patients undergoing autologous BMT have a significantly better disease-free survival as compared with those undergoing standard therapy. However, there was no difference in overall survival between the two groups of patients.

Since bone marrow involvement is so frequent in these diseases, the number of patients receiving unpurged bone marrow is limited. The University of Nebraska reported 13 patients with indolent FL undergoing autologous BMT with unmanipulated marrow.361,367 The 4-year failure-free and overall survival rates in these patients were 62% and 76%, respectively. An alternative to marrow purging for tumor-involved marrow in indolent NHL has been the use of PBSCs. The University of Nebraska has reported 100 patients treated (included were 26 patients treated with one prior regimen), with 4-year failure-free and overall survival rates of 44% and 65%, respectively.367 In this series, there was no statistically significant difference in the outcome between patients receiving unpurged marrow and those receiving PBSC. Similar results using PBSCs have been reported by Bastion and co-workers.368

Histologic conversion from indolent to an agggressive histology has been associated with a poor prognosis. There have been two recent studies of patients with chemosensitive disease and a good performance status after histologic transformation for follicular NHL. Nineteen patients in a minimal disease state from St. Bartholomew’s Hospital received an anti–B-cell purged autologous BMT within 1 year of histologic transformation.369 The median survival was 4.4 years, with three patients in remission at over 4 years of follow-up. In the series from Dana-Farber Cancer Institute, where 21 patients have undergone anti–B-cell purged autologous BMT for transformed FL, no acute in hospital deaths were seen, and the Kaplan-Meier estimate of the percentage of patients alive and disease free at 5 years is 46%, with follow-up from 12 to 120+ months.289 Patients who underwent histologic transformation within 18 months of diagnosis of FL had a significantly better overall survival, compared with patients whose disease transformed later. When pathology at relapse was available, all patients with DLBCL had recurrences. Aggressive therapy with ASCT is a reasonable treatment option for selected patients.

Autologous Stem Cell Transplantation for NHL in First Remission

In an attempt to improve the prognosis for patients with a poor prognosis following induction therapy, several studies have examined the role of high-dose therapy and ASCT in first CR/PR for patients with aggressive NHL.370–373 The disease-free survival at 3 years in most of these studies is 70 to 80%. The European Bone Marrow Transplant Group has reported a multi-center study of patients stratified by histology transplanted in first CR.330 The disease-free survival is approximately 50% for Burkitt’s lymphoma, 60% for lymphoblastic lymphoma, and 80% for other aggressive NHLs.374 All these studies suggest that early high-dose therapy may be highly effective in patients who are at high risk of relapse following conventional therapy. However, randomized trials which have examined the role of autologous BMT in first remission versus conventional therapy for patients with adverse prognostic factors at diagnosis have left this question largely unanswered. In four randomized trials, a significant difference in the event-free survival and freedom from progression in favor of high-dose therapy and stem cell transplantation was seen in only one study.375–379 However, in a retrospective analysis of one of the randomized trials, where patients were stratified by the IPI at diagnosis, a benefit for consolidative autologous BMT was seen for high-intermediate- and high-risk patients who achieved a CR with induction treatment. Additional prospective randomized studies evaluating high-dose therapy and ASCT versus conventional therapy for higher-risk patients defined by the IPI are ongoing. It remains controversial whether patients with aggressive NHL who attain only a PR with induction therapy have an improved prognosis with high-dose therapy and stem cell support. One randomized trial failed to show a benefit.380 The role of autologous BMT in patients with indolent NHL during first remission is being actively investigated.381,382 ASCT is clearly not the complete answer for curing patients with relapsed or high-risk lymphoma. Development of new strategies, particularly toward resistant cells and minimal residual disease, may make additional impact following high-dose therapy.

New Therapeutic Approaches

Although great strides have been made in the treatment of NHL with conventional, salvage, and high-dose ablative therapies, the majority of patients are not cured. Unlike most other cancers, many patients with NHL can achieve a CR. This suggests that the major obstacle to cure is subpopulations of resistant neoplastic cells. There are a number of approaches to the treatment of NHL, which may potentially overcome resistance. Conventional-dose therapy can be escalated to near-ablative doses by employing hematopoietic growth factor.383 There are a growing number of cytokines which may be either cytostatic or cytotoxic to neoplastic cells. Antisense oligonucleotides to, for example, bcl-2, are in clinical trials and may be useful agents for inducing apoptosis. Monoclonal antibodies, either unconjugated, conjugated to a toxin, or conjugated to radionuclides, are being used to treat NHLs.286 Combining anti-body based therapies with chemotherapy may be synergistic.384 Studies employing anti–B-cell (anti-CD20) mAbs conjugated to 131I have shown promising results with limited follow-up. This type of targeted therapy may be useful as a substitute for TBI as well as in the adjuvant setting.288,385 Endogenously or exogenously activated lymphocytes or natural killer cells can be used specifically to attack lymphoma cells. Infusion of cytokines (such as interleukin-2, or-12) which augment antitumor immunity are in clinical trials and may well have a role in treating the minimal disease state. Further ways to enhance host immunity against the patients’ own tumor cells has involved vaccination studies with the Ig-idiotype to induce specific immunotherapy against residual tumor cells.386–390 Another approach is to modify the tumor cells to make them more immunogenic and more susceptable to endogenous effector mechanisms.391 It is likely that multiple approaches will need to be put together to optimally eradicate tumor cells. Ongoing and future studies in these areas may provide novel alternatives and complement conventional therapy.


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Reference not available .
© 2000, BC Decker Inc.
Bookshelf ID: NBK20925


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