Leonard R. Prosnitz, Manisha Palta, and Christopher R. Kelsey
Non-Hodgkin lymphomas (NHL) are a heterogeneous group of malignancies of the lymphoid system characterized by an abnormal clonal proliferation of B cells, T cells, or both. Scientific knowledge regarding NHL has increased dramatically in the past two decades, resulting in specific advances in the spheres of molecular biology and immunobiology and leading to new histopathologic classifications and therapies.
EPIDEMIOLOGY
The U.S. age-adjusted incidence rate for NHL was 19.8 per 100,000 between 2004 and 2008, according to the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute.1 In 2010, the estimated number of new NHL cases in the United States was 65,500; deaths from NHL were 21,000.2 In 2008, worldwide estimated incidence was 356,000 new cases and 191,000 deaths. International NHL incidence rates vary, with the highest incidence rates in North America, Europe, and Australia/New Zealand. The lowest rates have been reported in Asia and the Caribbean.3 NHL is primarily a disease of older populations, with a median age of 65 at diagnosis.4
There has been a striking increase in NHL incidence rates over the past four decades, with a doubling between 1970 and 1990. The rate of increase has slowed since 1990, with a modest increase in incidence from 18.5 per 100,000 to 20.5 per 100,000 between 1990 and 2005.5 Incidence rates have remained at approximately 20 to 21 per 100,000 over the past decade. The mortality rate for NHL has risen steadily, peaking in the late 1990s, with more recent decline over the past decade. The U.S. mortality rate rose from 5.6 per 100,000 to 8.2 per 100,000 between 1975 and 2000. Since a peak of 8.9 per 100,000 in 1997, the mortality rate has steadily declined with most recent SEER data reports of 6.5 per 100,000 deaths in 2007.6 Similar increases have been noted in international cancer registries.7
The increased incidence of NHL has been partly attributed to advances in molecular diagnostic techniques, aging of the population, immunosuppression from human immunodeficiency virus (HIV), infectious agents, and occupational or environmental exposures.8 There are likely other contributing factors that remain unknown at present.
ETIOLOGY
Several genetic diseases, environmental agents, and infectious agents have been associated with the development of lymphoma. Familial clustering of NHL has been described. However, it is not clear whether the familial aggregations are due to hereditary factors or shared environmental exposures.9
Immunodeficiency
The frequency of NHL is greatly increased in immunocompromised patients. The two most common clinical circumstances are among HIV-infected patients and solid organ transplant recipients, both associated with prolonged immunosuppression.10,11 In HIV patients, NHL is the second most common malignancy, with a rate of 1.2% per year.12 The introduction of highly active antiretroviral therapy (HAART), however, has resulted in a decline with subsequent stabilization in the incidence. Treatment outcomes of NHL in this population have improved as well.13,14
Patients with autoimmune and chronic inflammatory disorders, including Sjögren syndrome, Hashimoto’s thyroiditis, systemic lupus erythematosus, and less commonly, celiac sprue also have an increased risk of NHL.15,16Several rare inherited disorders are associated with up to a 25% lifetime risk for development of lymphoma.17 These include severe combined immunodeficiency, hypogammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, Chediak-Higashi syndrome, and ataxia-telangiectasia. Lymphomas associated with these disorders are often Epstein-Barr virus (EBV) related and usually highly aggressive in their behavior.
Infectious Agents
A number of viral infectious agents are implicated in the pathogenesis of NHL. EBV is associated with Burkitt’s lymphoma, posttransplant lymphoproliferative disorders (PTLD), acquired immunodeficiency syndrome (AIDS)-associated primary central nervous system lymphoma (PCNSL), congenital immunodeficiency associated lymphomas, and natural killer (NK) T-cell lymphomas.18 The human T-cell lymphotropic virus type 1 (HTLV-1) is an RNA virus responsible for adult T-cell leukemia/lymphoma (ATL).19 In endemic areas, more than 50% of all NHL cases are ATL, although the risk for development of disease is only approximately 5% in infected patients. Human herpes virus 8 (HHV-8), the causative agent for Kaposi’s sarcoma, is also associated with several rare lymphoproliferative diseases, including primary effusion lymphoma.20 The hepatitis C virus (HCV) is linked with several NHL subtypes, including splenic marginal zone lymphoma.21,22
The strongest association between infectious agents and NHL is in marginal zone lymphomas (MZL). The bacterium Helicobacter pylori has been linked to gastric mucosa-associated lymphoid tissue (MALT) lymphomas.23,24 It has been suggested that several other bacteria, including Borrelia burgdorferi, Campylobacter jejuni, and Chlamydia psittaci, may also play a role in the pathogenesis of MZL of other sites.21,25,26
Environmental and Occupational Exposures
Occupations associated with a higher risk of developing NHL include farmers, teachers, dry cleaners, butchers, printers, wood workers, mechanics, and agricultural workers.27,28 Several studies have shown an increased risk of NHL in relation to pesticide exposure, particularly phenoxyl herbicides and organochlorines.29,30 The development of NHL has also been linked to hair dyes, organic solvents, high levels of nitrates in drinking water, arsenic, pesticides, fungicides, lead, vinyl chloride, and asbestos.29 Radiation has been suggested as a causative agent with increased lymphoma incidence in survivors of nuclear explosions or atomic reactor accidents.31 NHL is also observed as a late effect of prior radiation therapy or chemotherapy.32 Dietary factors and tobacco and alcohol use may affect the risk of developing NHL.33
TABLE 78.1 WORLD HEALTH ORGANIZATION 2008 CLASSIFICATION OF MATURE
PATHOLOGY AND IMMUNOBIOLOGY
NHL is a group of many different disease entities, often difficult to diagnosis, with a correspondingly complex histopathologic classification that has changed relatively frequently over the years. The changing classifications reflect new knowledge gained as well as difficulties with older systems that were recognized with the passage of time, such as interobserver variability, difficulties with reproducibility, and a somewhat confusing picture with respect to clinical–pathologic correlates. The predecessor to the currently utilized World Health Organization (WHO) classification was the Working Formulation.34 It subdivided NHL by biologic behavior; low grade, intermediate grade, and high grade; and indolent or aggressive behavior groups. This staging characterization has been abandoned in the new WHO classification. Such groupings were convenient and appeared clinically useful, but represented an oversimplification and did not account for several distinct clinical–pathologic entities.
The WHO 2008 classification divides NHL into B-cell and T-cell neoplasms, with over 40 different lymphomas delineated, as shown in Table 78.1.35 These specific entities are distinguished on the basis of reproducibly identifiable morphologic, immunologic, and genetic characteristics. The specific diseases described may be either indolent or aggressive in behavior. Within a given disease there may be a range of behaviors (e.g., anaplastic large cell lymphoma [ALCL]). Similarly, the histologic grade and the biologic behavior may vary within a specific disease entity (e.g., follicular lymphoma [FL]). In addition, the WHO classification describes new disease categories not clearly recognized in the Working Formulation, notably marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), peripheral T-cell lymphomas (PTCL), ALCL, and primary mediastinal large B-cell lymphoma.
A description of all the varieties of NHL is not practical and beyond the scope of this chapter. This chapter will focus on the most common entities in order of decreasing frequency, namely, diffuse large B-cell lymphoma (DLBCL), FL, MZL, MCL, PTCL, and chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), although other less common entities are also discussed. Incidence data are derived largely from the NHL Classification Project,36 which evaluated 1,403 cases of NHL at nine study sites around the world, establishing the frequency of the subtypes, geographic variation in incidence, and clinical correlates.
It must be emphasized that lymphoma pathology is complex with a long history of interobserver disagreement. National Comprehensive Cancer Network (NCCN) guidelines describe as “essential” specialized hematopathology review of all slides and adequate immunophenotyping to establish the diagnosis.37 Fine-needle aspiration alone is rarely acceptable for the initial diagnosis of lymphoma due to lack of nodal architecture.38
Diffuse Large B-Cell Lymphoma
DLBCL is a neoplasm of large, transformed B cells with a diffuse growth pattern and a high (>40%) proliferation fraction. The cells may resemble centroblasts, immunoblasts, multilobated cells, or anaplastic large cells. It is the most common type of NHL (31% of all cases, 33% if primary DLBCL of the mediastinum is included).36 DLBCL is a heterogeneous group of neoplasms with multiple distinct variants described in the current WHO classification.35In addition, DNA microarrays (oligonucleotides or cDNA probes) show that three different subgroups of DLBCL with unique molecular abnormalities can be identified.39 These include the germinal center B-cell subtype and the activated B-cell subtype. Primary mediastinal DLBCL also has a unique molecular signature that closely resembles classical Hodgkin lymphoma (HL).40 Models predictive of clinical outcome using gene-expression data have also been developed.41–42,43 Treatment tailored to molecular subclassification of this disease is premature at present but may become part of future routine clinical practice.
DLBCL express one or more pan B-cell markers (CD19, CD20, CD22, and CD79a), as well as CD45, and often surface immunoglobulin.44 Twenty-five percent to 80% in various studies express BCL-2 protein.45 Approximately 70% express BCL-6 protein, consistent with a germinal center origin.45,46 Most cases of DLBCL have somatic mutations in the immunoglobulin variable region genes, suggesting they have progressed through the germinal center where immunoglobulin affinity maturation occurs. The BCL-2 gene is rearranged in 15% to 30% of cases, the C-MYC gene is rearranged in 5% to 15%, and the BCL-6 gene is rearranged in 20% to 40% of cases.45
Follicular Lymphoma
The next most common type of NHL is FL (22% of all cases). In the Working Formulation, it was described as low grade or indolent. It has also been referred to as follicle center cell lymphoma.36 In North America, the frequency is somewhat higher at 31% versus 14% at other geographic sites.47 Thus, in North America FL and DLBCL are approximately equal in frequency.
FL is a tumor of follicle center B cells (centrocytes and centroblasts) with a follicular (nodular) pattern that morphologically is similar to normal germinal centers.48 The neoplastic follicles may be present in the entire tumor, or the lymphoma may contain a diffuse component as well. FL is graded based on morphology. There is either a predominance of small cleaved cells (grade 1), a mixture of small cleaved and large cells (grade 2), or predominantly large cells (grade 3). In the WHO classification, the number of large cells per high-power field (0 to 5, 5 to 15, >15) is used to assign grades (1 to 3, respectively). However, if there are diffuse areas comprised predominantly of blastic cells, a diagnosis of DLBCL is also made.
Clinically, grades 1 and 2 are closely related with no apparent differences in biologic behavior or response to therapy. FL grade 3 tends to have a somewhat higher relapse rate with an outlook favorably influenced by anthracycline-containing chemotherapy. Although grade 3 FL is not the same as DLBCL, it may contain areas of the latter, which further suggests the need for more aggressive therapy.
The tumor cells of FL are usually surface immunoglobulin positive, express pan-B-cell–associated antigens (CD19, CD20), CD21, CD10 (60% of the time), but lack CD5. Most cases are BCL-2 positive; nuclear BCL-6 is expressed by at least some of the neoplastic cells. T(14;18) and BCL-2 gene rearrangement are present in the majority of the cases (85%). BCL-2 protein is expressed in most cases, ranging from 100% in grade 1 to 75% in grade 3 FL.49
Marginal Zone Lymphomas
MZL is now recognized as a distinctive subtype of NHL in the WHO classification, accounting for approximately 10% of all cases of NHL. MZL entities include nodal MZL, splenic MZL, and extranodal MZL of MALT. MALT as a distinct clinical pathologic type of lymphoma was first described in 1983.50
Extranodal MZL is characterized by a polymorphous infiltrate of small lymphocytes, marginal zone (centrocyte-like) B cells, monocytoid B cells, and plasma cells, as well as rare large basophilic blast cells (centroblast- or immunoblast-like). In epithelial tissues, the marginal zone B cells typically infiltrate the epithelium, forming lymphoepithelial lesions defined by invasion and partial obstruction of mucosal glands by tumor cells.51 Although transformed large cells are typically present, they are in the minority. If present in large numbers, a diagnosis of DLBCL is warranted.
The tumor cells express surface immunoglobulin and lack immunoglobulin D. Forty percent to 60% have monotypic cytoplasmic immunoglobulin, indicating plasmacytoid differentiation. They express pan B-cell–associated antigens (CD19, CD20, CD22, CD79a) but are generally negative for CD5 and CD10. There is no specific marker for MZL at present. Immunophenotyping studies are useful in confirming malignancy (light chain restriction) and in excluding B-cell chronic lymphocytic leukemia (B-CLL; CD5+), mantle cell (CD5+), and follicular lymphomas (CD10+).52
Immunoglobulin genes are rearranged; the variable region has a high degree of somatic mutation, as well as intraclonal diversity consistent with a postgerminal center stage of B-cell development.53 The most common reported cytogenetic abnormalities are trisomy 3, seen in 60%, and t(11;18), seen in 25% to 40% of patients.52,54 These changes are characteristically found in extranodal but not nodal MZL.
The most common site of MALT is the stomach. Lymphoid tissue is not normally present in the stomach, but in response to an antigenic stimulus brought about by H. pylori, normally present T cells in the gastric mucosa attract a B-cell population, giving rise to lymphoid follicles and, after prolonged antigenic stimulation, lymphomas.55
Peripheral T-Cell Lymphomas
PTCLs are the group most confusing to clinicians. They were not a separate entity in the Working Formulation but were frequently classified as either diffuse poorly differentiated lymphocytic lymphoma or diffuse mixed lymphocytic-histiocytic lymphoma. The term peripheral T-cell lymphoma is often misinterpreted. It refers not to the anatomic distribution of the lymphomas but to their origin from so-called peripheral or mature T cells outside the thymus, as opposed to thymic (precursor) T lymphocytes. The T-cell lymphomas collectively make up approximately 10% of all NHL.56 They are a diverse group that includes 14 different entities (Table 78.1).
PTCLs constitute the most frequently occurring variety of T-cell lymphoma. In the International Lymphoma Study Group (ILSG) report, PTCLs comprised 7% of the total cases, making them approximately equal in frequency to MZL, SLL, and MCL.56 Their frequency is quite different, however, by geographic locale. ILSG data showed a roughly 3% incidence of PTCL in North America compared with 9% in South Africa, Hong Kong, and London.47 EBV may be associated with T-cell lymphomas originating in the nasal cavity.57
PTCLs typically contain a mixture of small and large atypical cells. The architectural pattern is diffuse. T-cell–associated antigens (CD2, CD3, CD4) are variably expressed, with some tumors expressing CD8. Sometimes the T-cell antigens CD5 and CD7 are lost. B-cell–associated antigens are lacking. The T-cell receptor genes (TCR) are usually, but not always, rearranged. No specific cytogenetic or oncogene abnormality has been reported.
ALCL is a special variant of PTCL.58,59 In the ILSG project, ALCL comprised 2% of all NHL.36 The tumor is usually composed of large cells with round, pleomorphic, or horseshoe-shaped nuclei with single or multiple prominent nucleoli and abundant cytoplasm, giving the cells an epithelial or histiocyte-like appearance. The cells express CD30 (Ki-1) and usually express CD25 and either T-cell or null lineage–specific antigens.58 CD30 was originally recognized on HL cells. In some cases, there may be confusion between ALCL and HL, but distinction between the two on the basis of immunophenotyping and morphology is usually possible.
The overexpression of a novel tyrosine kinase gene on chromosome 2 known as anaplastic lymphoma kinase (ALK) is a characteristic feature of ALCL.59 Approximately 60% of cases overexpress the ALK protein; such cases have a better prognosis than ALK-negative cases, except for skin cases. ALCL in children or young adults is usually ALK positive.59
Small Lymphocytic Lymphoma
SLL is the nodal equivalent of B-CLL.48 In the WHO classification these are considered a single entity (CLL/SLL). It is a neoplasm composed predominantly of small lymphocytes with condensed chromatin and round nuclei. Larger lymphoid cells (prolymphocytes and paraimmunoblasts) with more prominent nucleoli and dispersed chromatin are always present, usually clustered in pseudofollicles. SLL comprises approximately 7% of all NHL.
The tumor cells of SLL express human leukocyte antigen (HLA)-DR, B-cell–associated antigens (CD19, CD20, CD22, CD79a), and both CD5 and CD23 and have faint surface immunoglobulin. CD23 is particularly useful in distinguishing CLL/SLL from MCL.
Approximately 50% of cases have abnormal karyotypes.60 Trisomy 12 is reported in one-third of cases with cytogenetic abnormalities and correlates with atypical histology and an aggressive clinical course.60 Abnormalities of 13q are reported in no more than 25% of the cases and are associated with long survival. CLL/SLL can transform to DLBCL (Richter syndrome).61
Mantle Cell Lymphoma
MCL was first distinguished in the 1980s by Weisenburger et al.,62 who described a type of FL in which there were wide mantles of malignant cells around apparently benign germinal centers. The term mantle zone lymphoma was proposed, subsequently modified to mantle cell. It was thought to represent a variant of FL and was classified under the Working Formulation as a low-grade lymphoma. Its behavior, however, is more characteristic of aggressive disease. MCL represents about 7% of all NHL.36
Since the original description by Weisenburger et al.,62 additional features of this disease have been recognized. It is a neoplasm of small to medium-sized B cells with irregular nuclei that resemble the cleaved cells (centrocytes) of germinal centers. The morphologic pattern may be diffuse, nodular, a mantle zone, or some combination thereof. Tumor cells are typically CD5 positive, CD23 negative, CD20 positive, and CD10 negative. A characteristic cytogenetic abnormality is t(11;14) involving the BCL-1gene and resulting in the overexpression of cyclin D1. The product of the cyclin D1 gene can be detected in paraffin-embedded tissue sections with the immunoperoxidase technique and is useful in distinguishing MCL from other lymphoma variants.63,64
CLINICAL FEATURES: GENERAL
Nodal Versus Extranodal Disease
NHL is primarily a disease of older adults (in contrast to HL), with a median age at presentation from 55 to 65 years.65–67 There is a slight male over female preponderance (55% to 60% male). NHL may involve lymph nodes in almost any area of the body but may also present in extranodal sites, presumably arising from lymphoid tissue widely distributed throughout the body. Approximately two-thirds of NHL is nodal at presentation and one-third extranodal, again in contrast to HL, where extranodal presentation is rare.65,68
Patients with primarily nodal disease usually present with an asymptomatic lump in the neck or inguinal area; B symptoms (fevers, night sweats, weight loss) may be present in 20% to 30% of patients. There is often a history of some spontaneous regression and then regrowth of the nodes.
The most frequent sites of nodal involvement are the neck in approximately 70% of patients, the groin in approximately 60%, and the axilla in approximately half.66,67 Although patients with nodal presentations may appear to have localized disease initially, full staging evaluation results in assignment to a more advanced stage in two-thirds.69
Patients presenting with extranodal lymphoma, on the other hand, usually have localized disease. Indeed, some authorities conclude that the definition of primary extranodal disease should be restricted to those with stage I or II disease.70 The symptoms relate to the site of involvement. The gastrointestinal (GI) tract is the most common (25% to 35% of extranodal disease), followed closely by Waldeyer’s ring and other head and neck sites (18% to 28%) and skin.68,71 Epigastric discomfort, abdominal pain or bleeding, and sore throat or difficulty swallowing are among the usual symptoms for these locations.
The histologic picture of most primary extranodal lymphomas is that of DLBCL, although depending on anatomic site, other histologies are commonly seen (e.g., MALT lymphoma of the stomach). Nodal presentations, conversely, are more commonly FL. Nodal and extranodal disease of similar histologic type, stage, and other prognostic variables are treated in an equivalent fashion and have a similar outcome.72,73 For example, DLBCL, stage IA in the neck, treated with combination chemotherapy and radiotherapy, would have the same outcome as stage IA DLBCL in the stomach treated similarly. These characteristics are summarized in Table 78.2. There are notable exceptions, however. For example, localized disease in the central nervous system (CNS) has a much worse prognosis as does primary testicular disease and perhaps lymphoma in the breast (to be discussed subsequently).74,75,76
TABLE 78.2 CHARACTERISTICS OF NODAL VERSUS EXTRANODAL NON-HODGKIN LYMPHOMA
TABLE 78.3 CLINICAL, LABORATORY, AND RADIOLOGIC EVALUATION OF PATIENTS WITH NON-HODGKIN LYMPHOMA
FIGURE 78.1. Fused coronal positron emission tomography (PET) computed tomography images of a patient with diffuse large B-cell lymphoma before (A) and after (B) chemotherapy. The postchemotherapy PET was scored as positive in the mediastinum. Biopsy confirmed persistent disease.
Evaluation and Staging
A careful history and physical examination are required. The history should record presence or absence of B symptoms (fever, night sweats, weight loss), performance status, duration of lymph node enlargement and growth history, and any specific symptoms suggestive of extranodal involvement. All peripheral nodal areas should be examined clinically, enlarged nodes measured with suitable calipers and two-dimensional measurements recorded, and inspection of the skin, oral cavity, and tonsils performed. Patients with suspected or established head and neck lymphoma or GI tract involvement should undergo direct fiberoptic laryngoscopy or endoscopy.77 Staging procedures are summarized in Table 78.3.
The use of functional imaging, initially with gallium, now largely with positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) has increased dramatically in the past decade.78,79,80,81,82 PET has largely replaced gallium because of greater accuracy, particularly in the abdomen, convenience, and the ability to perform at one examination an integrated PET and computed tomography (CT) scan.79,83 The fused images obtainable from an integrated PET-CT increase the accuracy of diagnosis by more precisely localizing anatomically areas of increased isotope uptake (Fig. 78.1). The fused images are also very helpful to the radiation oncologist in planning radiation fields. A number of authors in relatively small series have suggested that PET imaging is the most sensitive indicator of disease present initially, surpassing CT scans in this regard with a sensitivity exceeding 90%, compared with 60% to 70% for conventional imaging.80,81
Some authors have suggested PET imaging at diagnosis is unnecessary in the presence of obvious generalized disease and should be omitted to conserve resources and reduce costs.84 Because PET is so often now performed to evaluate response (however, see below), a pretreatment scan is quite useful for comparison if resources permit. Further, PET-CT scanning (contrast-enhanced CT) eliminates the need for a separate CT.
PET with gallium scanning is particularly useful after therapy, where residual anatomic abnormalities on CT scan are common.85,86,87–88 Positive functional imaging studies after therapy are a poor prognostic sign, predicting for early relapse and suggesting that minimal cell kill has been accomplished by the therapy, because enough viable cells remain to take up the isotope in question. In contrast, patients with residual anatomic abnormalities as imaged on CT who have negative PET or gallium studies enjoy an outlook comparable with PET negative or gallium-negative patients without residual static abnormalities. A positive PET scan following salvage chemotherapy for relapsed DLBCL (in preparation for high-dose chemotherapy) has also been reported as a poor prognostic sign and a relative contraindication to proceeding with transplant.89,90
Other important staging studies include bilateral bone marrow aspirate and biopsy and routine blood studies, particularly lactate dehydrogenase (LDH), because this is an important prognostic factor. Patients should be evaluated for the presence of hepatitis B antigen because of concerns of reactivation of this virus with chemotherapy and particularly if rituximab is administered.91
Other staging studies will be indicated for suspected primary extranodal disease depending on the site of involvement. For example, lymphoma arising in the head and neck region may require magnetic resonance imaging (MRI) for precise anatomic delineation or lumbar puncture for CNS evaluation in the case of testicular or sinus lymphoma (see specific lymphoma sections for additional details).
The most widely used staging system is the anatomically based Ann Arbor system (Table 78.4), originally devised at a conference in Rye, New York, in 196592 and modified at Ann Arbor, Michigan, in 197093 and again at the Cotswolds conference in England in 1988.94 The principal changes introduced at Cotswolds were the use of the subscript “x” to designate “bulky” disease (i.e., a mass of ≥10 cm in maximum diameter), and the definition of criteria for liver or spleen involvement as evidence of focal defects with two or more imaging modalities. Abnormal liver function study results were to be ignored for staging purposes.
The Cotswolds conference and a subsequent workshop95 also discussed categories of response to treatment.96 It has been long recognized that many patients had good clinical responses with improvement but not complete disappearance of disease on follow-up static imaging such as CT scans. Although the Cotswolds conference did not consider functional imaging in the assessment of response, it has been incorporated by the International Working Group.96 A complete response has now been redefined to include residual masses on CT scan that have become PET negative.
Prognostic Factors
Anatomic stage of disease, tumor mass, and systemic symptoms are important prognostic indicators. Other prognostic variables investigated have included patient age, performance status, histologic type of lymphoma, tumor size, number of nodal or extranodal sites, tumor phenotype (B or T cell), LDH, β2-microglobulin levels, serum albumin, hemoglobin, and proliferation indices.97,98 Many of these variables were shown to be significant in univariate and multivariate analyses but in small series from individual institutions.
In an attempt to develop a better prognostic model, the International Non-Hodgkin Lymphoma Prognostic Factors project examined data on 2,031 patients, all with aggressive-histology NHL.99,100 Two indices were developed, the International Prognostic Index (IPI) and the Age Adjusted International Prognostic Index, because age was found to be a highly significant prognostic variable (>60 years vs. ≤60 years). For both indices, four risk groups were identified—low, low intermediate, high intermediate, and high—depending on the number of risk factors present in a given patient. Five prognostic variables were found to be significant: age, performance status, stage (I/II vs. III/IV), number of extranodal sites, and LDH (Table 78.5). When patients were divided by age, three factors remained independently significant: performance status, stage, and LDH.
TABLE 78.4 THE ANN ARBOR/COTSWOLDS STAGING CLASSIFICATION FOR HODGKIN LYMPHOMA AND NON-HODGKIN LYMPHOMA
TABLE 78.5 INTERNATIONAL PROGNOSTIC INDEX FOR DIFFUSE LARGE B-CELL LYMPHOMA
With the widespread utilization of rituximab therapy and improved outcome for patients with DLBCL, some authors have suggested revisions to the IPI to allow for more separation of prognostic groups.101 Essentially these authors regrouped the IPI into three rather than four groups, with the best outlook for those with zero adverse factors (94% survival), a good outcome for those with one or two adverse factors (80%), and a poor outcome (55% survival) for those with three or more adverse factors. The German High-Grade Non-Hodgkin Lymphoma Study Group has found, however, the IPI to still be a valid predictor in the rituximab era.102 Others have suggested an elderly prognostic index (for patients older than 70).103 At present, IPI remains the standard with no consensus on modifications.
The IPI was developed primarily for patients with DLBCL. It has also been successfully applied with some modifications to patients with PTCL.104,105,106 There were initial attempts to apply the IPI to FL, but here it was less useful because most patients fell into a favorable prognostic category. A recent international effort has addressed this problem, however.107 Patient characteristics were collected from 4,167 patients with FL diagnosed between 1985 and 1992. Five adverse prognostic factors were identified on multivariate analysis, including age (>60 years vs. <60 years), stage (I/II vs. III/IV), hemoglobin level (<120 g/L vs. ≥120 g/L), number of nodal areas (>4 vs. ≤4), and serum LDH. Three risk groups were identified: low risk (zero to one adverse factor), intermediate risk (two factors), and poor risk (three or more adverse factors). Patients were approximately equally divided among the three groups. There was good separation between the groups in terms of survival (Table 78.6). The resulting index is known as the follicular lymphoma international prognostic index (FLIPI).
The FLIPI has subsequently been revised to predict for progression-free survival (PFS) in the rituximab era.108 The significance of FLIPI-2 remains to be determined with additional follow-up studies. In the original FLIPI study, neither tumor size nor histologic grade was considered. Other groups have suggested these are important variables.109
The molecular features of DLBCL have been examined using gene-expression profiling as assessed by DNA microarrays or polymerase chain reaction (PCR). These studies have involved patients receiving chemotherapy for DLBCL who had been classified according to the IPI risk categories.43 One study used 13 key genes, another 17 to divide patients into two or four groups, respectively, with markedly different survival rates, accounting for IPI risk categories.42,43 In general, the outcome for patients with germinal center B-cell–like DLBCL differs from that of activated B-cell–like DLBCL, the latter being considerably worse.108
Gene-expression profiling has also been investigated in FL,110,111 with two reports differing significantly, in that one examined the molecular features of tumor infiltrating cells and the other the actual lymphoma cells. Dave et al.110 were able to group the patients into four quartiles with widely disparate median lengths of survival depending on two gene-expression signatures. This trial controlled for clinical features as determined by the IPI but not by the FLIPI. Similarly, the study by Glas et al.111 used gene-expression profiling to predicate clinical behavior. Again, the IPI was the clinical classification utilized rather than the FLIPI. Further investigation is needed to determine the value of gene-expression profiling in FL if patients are subdivided according to the FLIPI rather than the IPI. Additionally, it remains to be determined whether the tumor-infiltrating immune cells are the appropriate targets for gene-expression profiling or the tumor itself. In general, gene-expression profiling is not widely available clinically and must still be considered investigational.
A number of other biomarkers have been investigated for their influence on outcome in DLBCL, FL, and other histologic variants of lymphoma. Results, however, have been inconsistent so that clinical indices remain the standard prognostic evaluation tool at this time.45,112
TABLE 78.6 FOLLICULAR LYMPHOMA INTERNATIONAL PROGNOSTIC INDEX
CLINICAL–HISTOPATHOLOGIC CORRELATES
The pathology and immunobiology of the most frequently encountered varieties of NHL have already been discussed. This section examines the clinical features of the most commonly encountered NHLs. Data from the NHL classification project are invaluable in this regard.36,113
Diffuse Large B-Cell Lymphoma
Patients most often present with an enlarging peripheral nodal mass or with symptoms related to a primary extranodal site of involvement, such as abdominal or epigastric pain. DLBCL is primarily a disease of older adults, with a median age of 64 years and a slight preponderance of men (55%). B symptoms are present in approximately one-third of patients. Just over half the patients (55%) have localized disease (stages I or II) at onset. Just over half the patients with stage I or II disease have extranodal presentations. When subdivided according to IPI score, one-third of patients have a score of 0 or 1, one-half a score of 2 or 3, and the remainder a score of 4 or 5.36,113 Lymphomas that present extranodally are most commonly DLBCL.72
The WHO recognizes several distinct variants of DLBCL. The most notable include primary mediastinal DLBCL, T-cell/histiocyte-rich large B-cell lymphoma, and primary DLBCL of the CNS (discussed later).
Primary mediastinal DLBCL is believed to arise from thymic medullary B cells. Microarray studies have revealed a unique molecular signature for primary mediastinal DLBCL with a resemblance to nodular sclerosis HL.114There are characteristic genetic changes, notably absence of BCL2 and BCL6 rearrangements, as well as consistent increases in chromosome 9P and 2P, the former being rather specific for primary mediastinal DLBCL and observed in up to 75% of cases.
Primary mediastinal DLBCL comprises about 2.4% of all NHL, about 7% of all DLBCL. The disease affects primarily young women (median age 37) and is generally confined to the anterior mediastinum, sometimes with supraclavicular or cervical adenopathy. Relapses tend to be extranodal, however. When grouped according to the IPI, the prognosis is similar to that of DLBCL generally, perhaps a bit more favorable,114,115 with a plateau observed in the PFS curve after 18 to 24 months. Rituximab appears to improve outcomes to the same extent as other subtypes of DLBCL.116 The role of consolidation radiation therapy (RT) has been questioned, given the more favorable prognosis. However, omitting consolidation RT for early-stage primary mediastinal DLBCL has not been formally studied.115
T-cell/histiocyte-rich B-cell lymphoma consists of large malignant B cells with a florid background of inflammatory T cells, with or without histiocytes. Clinically, it occurs in a younger population compared with DLBCL, generally with a male predominance.117,118 This entity is also more likely to present with B symptoms and involve the spleen, liver, and bone marrow. Treatment recommendations are similar to DLBCL, not otherwise specified.
Follicular Lymphoma
FL affects primarily older adults (median age, 59 years). There is a slight female preponderance. In contrast to DLBCL, approximately 70% of patients present with generalized disease, most with stage IV disease. The bone marrow is the principal extranodal organ involved. Localized extranodal presentation is uncommon, reported in only 6% of the ILSG series, again in contrast to DLBCL.113 FL, in general, has a favorable outcome in the intermediate term, with 5- to 8-year survival rates from 70% to 80%. The failure-free survival (FFS) rate is considerably less, however, at approximately 40%.119–121 Furthermore, there is little evidence of flattening of the survival curves with time, suggesting that relapse occurs continually over the course of many years. An exception may be the small percentage of patients who present with localized disease and are treated definitively with radiotherapy, a significant number of whom may be cured with that treatment.122,123 Despite being considered an indolent disease, the leading cause of death is lymphoma, often after histologic transformation to DLBCL.
Marginal Zone Lymphoma
MZL includes both nodal and extranodal varieties and the unique entity of splenic MZL.124 The more familiar name for extranodal MZL is MALT lymphoma. Approximately 70% of MZL is extranodal, with the remainder divided about equally between splenic and nodal MZL. Two-thirds to three-fourths of patients have stage I or II disease, the former more common than the latter. The prognosis is generally excellent with 85% to 90% 5-year survival irrespective of stage, although FFS is less.74,125–127 In the MD Anderson Cancer Center series, splenic MZL had the best survival (93% at 5 years), although the disease was invariably stage IV at diagnosis, confirming the indolent nature of these diseases.128
Extranodal MALT lymphoma occurs primarily in the stomach, but a number of other anatomic sites are commonly seen, including the thyroid, parotid glands, orbit, and skin. Recently, an association with bacterial infection for MALT at sites other than the stomach has been described.21 C. psittaci has been found in many cases of ocular adnexal lymphoma; antibiotic treatment has been shown to result in lymphoma regression in some series but not in others.129,130 Additionally, B. burgdorferi and C. jejuni have been associated with MZL arising in the skin and small intestine.21,131 Unlike gastric MALT, the standard initial treatment for these conditions, however, remains local radiotherapy, with very high rates of complete response and local control in excess of 90%, similar to what has been reported for gastric MALT.127,132
Splenic MZL patients usually present with splenomegaly.126,133,134 Almost all have stage IV disease, principally because of bone marrow involvement. The disease is relatively indolent, with three-quarters of patients alive at 5 years, but a more aggressive subset does exist. The most effective therapy appears to be splenectomy. Indeed, the diagnosis is usually not clearly established until this time. Radiotherapy to the spleen has infrequently been used.
Peripheral T-Cell Lymphoma
The International Peripheral T-Cell Lymphoma Project recognized 12 varieties of PTCL, accounting for 5% to 10% of NHL in Western countries but 5% to 20% of NHL in Asia where NK/T-cell lymphoma and adult T-cell leukemia/lymphoma are far more common.135,136 This section will discuss only the more common variants.
Most common in the West is PTCL, not otherwise specified (NOS), accounting for about one-third of cases (vs. 20% in Asia). This is a disease of older adults, with a median age of 61 years.56,113,137–139 Slightly more than half of the affected patients are male. Most patients present with nodal disease in a similar fashion to B-cell lymphoma. In contrast to DLBCL, however, the great majority of patients (70%) have stage III or IV disease at diagnosis.137,139Approximately half of the patients have B symptomatology. The IPI also tends to be more advanced, with 52% of patients having a score of 2 or 3 and 31% with a score of 4 or 5. Many patients have some preceding disorder of the immune system (27% in the U.S. combined series) such as angioimmunoblastic lymphadenopathy, mononucleosis, lymphomatoid granulomatosis, or papulosis.137
Extranodal NK/T-cell lymphoma is a T-cell lymphoma of special interest. This lymphoma has a variety of names in the older literature, including angiocentric lymphoma, midline malignant reticulosis, polymorphic reticulosis, and lethal midline granuloma.140–143 It is much more frequent in Asia (about 22% of T-cell lymphomas) than in the United States and is often associated with EBV.144 In contrast to most lymphomas, tissue destruction of the nasal or facial area is common. The response to chemotherapy and radiotherapy is variable and slow, in contrast to the usual rapid response observed in most other lymphomas.145
ALCL is another T-cell lymphoma. Two forms may be distinguished: a systemic illness with widespread involvement of lymph nodes and extranodal sites and a type primarily limited to the skin.59,146,147–150 The systemic type may in turn be separated into those patients who are ALK positive and those who do not overexpress this protein. The clinical features and prognosis differ widely among these two categories. Patients with ALK-positive ALCL are predominantly young men and, despite advanced-stage disease, respond well to combination chemotherapy, with survival rates in the range of 75% to 90%. Patients who are ALK negative, in contrast, tend to be older with a more nearly equal male to female ratio. Their response to chemotherapy is much worse, with survival rates reported in the 20% range.
Cutaneous ALCL constitutes a special situation.146 It is almost invariably ALK negative but carries an excellent prognosis. It is often difficult to distinguish from benign lymphomatoid papulosis (LyP). The latter may spontaneously remit and tends to run a benign clinical course over many years. ALCL of the skin is quite responsive to localized radiotherapy (see the section on lymphomas of the skin).151
Overall ALCL has one of the best survival rates of any lymphoma, approximately 75% at 5 years in the ILSG study, despite its aggressive appearance under the microscope. The heterogeneity and complexity of this particular variant of NHL well illustrates past difficulties of attempting to group lymphomas into categories of low grade, intermediate grade, and high grade, indolent or aggressive, favorable or unfavorable, on the basis of histologic appearance alone.
Small Lymphocytic Lymphoma
SLL is morphologically and immunotypically identical to CLL; the two are classified as one entity by the WHO. Of combined cases, about 85% are CLL and 15% SLL. Clinically, SLL is distinguished from CLL by the absence of peripheral blood involvement and <30% infiltration of the bone marrow. SLL is generally manifest by widespread nodal involvement with or without hepatosplenomegaly.152 In those uncommon instances where it is localized, however, radiotherapy may make it curable. The median age is 65 years, the oldest for any lymphoma. The male to female ratio is approximately even. Ninety percent of cases are generalized (i.e., stages III or IV), with 90% of those being stage IV (or 80% of the total). This is truly an indolent lymphoma. Survival may be prolonged even in the absence of therapy. In the ILSG project, the overall survival (OS) rate was approximately 50% at 5 years; the FFS rate was considerably less, however, at 25%.
Mantle Cell Lymphoma
MCL has a 74% male preponderance and a median age of 63 years.113,153 Eighty percent of patients have stage III or IV disease at onset. IPI scores are high, with 23% of patients with a score of 4 or 5, 54% with a score of 2 or 3, and only 23% with a score of 0 or 1. In common with FL, the organ most likely to be involved is the bone marrow, which is positive in two-thirds of patients at the time of diagnosis. GI tract involvement is frequent as well.
Although originally classified among the low-grade/indolent tumors in the Rappaport system, the clinical course for MCL is unfavorable in the great majority of patients. The 5-year survival rate in the ILSG project was only 27%, with an FFS rate of 11%.113 This FFS rate is, in fact, among the worst for virtually any type of lymphoma. The poor overall 5-year survival rate is matched only by PTCL and lymphoblastic lymphoma. The shape of the survival curve is continually negative, with no plateau to suggest cure in any significant percentage of patients. The situation is somewhat analogous to FL, but the latter usually has a much more prolonged natural history.
PRINCIPLES OF TREATMENT
Surgery
Before modern radiotherapy and chemotherapy, surgical resection constituted the only potentially curative treatment for NHL. It was commonly used for extranodal sites such as the stomach or head and neck and was curative in a significant percentage of patients when the disease was truly localized. Similarly, patients with nodal presentations and localized disease were managed by radical surgical procedures. The surgical approach subsided rapidly with the development of radiotherapy and chemotherapy and the recognition of the unique radiosensitivity and chemotherapy responsiveness of lymphomas.
Surgery, however, is still widely used to establish a diagnosis by biopsy. That may involve a major surgical operation, such as exploratory laparotomy for the diagnosis of stomach, intestinal, retroperitoneal, or mesenteric lymphoma. This is becoming much less common, however, with the use of endoscopic and laparoscopic techniques. With an established diagnosis of lymphoma, surgical resection as primary treatment should be a rare event, with radiotherapy and chemotherapy forming the mainstays of treatment. For example, lymphoma of the stomach should almost never be primarily resected, as the results are equal or better with radiotherapy with or without chemotherapy.
Radiation Therapy
Dose of Radiation Therapy When Used Alone
Malignant lymphomas are, in general, uniquely sensitive to ionizing radiation. For the great majority of anatomic locations, the sensitivity of the tumor is greater than that of the corresponding normal tissue, usually by a considerable amount, a luxury not available when treating most solid tumors. As a consequence, radiation fields can often be somewhat larger to cover potential microscopic areas of spread. Three-dimensional treatment planning and intensity-modulated RT may be less important for lymphomas than for solid tumors because of the lower doses generally used but have a definite role in many situations.
Dose–response data for RT of NHL are sparse. Most data come from phase II retrospective analyses; almost all of these analyses were carried out years ago, well before the latest WHO pathologic classification. The diseases most often studied were what we now know as DLBCL and FL, with a reasonable amount of information also available for MALT lymphomas. On the other hand, diseases such as PTCL, MCL, and ALCL have never been analyzed separately, so one is forced to extrapolate from the data for DLBCL and FL.
The classic articles in this regard are from Stanford University and Princess Margaret Hospital. Fuks and Kaplan154 in 1973 reported that doses in the range of 44 Gy achieved local control of FL in >95% of instances. For diffuse histiocytic lymphoma (corresponding roughly to DLBCL), local failure rates, however, were in the range of 20% to 30%, regardless of the dose of RT delivered (Fig. 78.1). These data have been widely misinterpreted as suggesting or justifying a dose of 50 Gy for DLBCL. In fact, they suggest a subset of resistant disease in the range of 20%, regardless of the dose of RT delivered.
A series of articles from Princess Margaret Hospital also addressed this issue.155–157 Dose–response curves were constructed for both diffuse histiocytic lymphoma (mostly DLBCL) and FL. For DLBCL patients with medium- or large-bulk disease, defined as 2.5 to 5 cm in size and >5 cm, respectively, an approximately 50% local control rate was achieved with a dose of 20 Gy, rising to 70% at 30 Gy and 80% at 40 Gy with a plateau thereafter, and no apparent improvement with additional dose (Fig. 78.2). For patients with small volume (<2.5 cm) DLBCL, a local control rate >90% was achieved regardless of dose. For patients with nodular (follicular) disease, doses in the range of 25 to 35 Gy produced a local control rate >90%.158
Similar data were reported in a more contemporary series from the University of Florida.159 For patients with low-grade lymphomas treated with RT alone (mostly FL), doses of 30 Gy achieved local control in >90% of patients. For those with intermediate- or high-grade disease, doses of 30 to 50 Gy also achieved local control in >95% of instances.
There was a suggestion that tumor bulk appeared to influence the outcome. Patients with tumor size >6 cm were treated with combined modality therapy (CMT). It was suggested that doses of at least 40 Gy were necessary in these circumstances for optimal local control, although the data demonstrate local failure in 1 of 51 patients treated with >40 Gy as part of a CMT program versus 4 of 70 patients treated with doses of 30 to 40 Gy.
For MZL, particularly MALT of the stomach, high local control rates are achieved with doses of approximately 30 Gy. Data from Princess Margaret Hospital demonstrate a 96% complete response (CR) with 4% partial response (PR) and an overall local control rate of 95%.132,160,161 In a smaller series of patients from Memorial Sloan-Kettering Cancer Center, the response and local control rates were 100% with similar doses (30 Gy).162 One hundred percent local control with 30 Gy was also achieved in a Harvard series.127 Similar data, although in smaller numbers, are available for MZL at sites other than the stomach.
It is unclear if tumor size affects the dose required for local control in FL and MZL. Smaller tumors may do well with <30 Gy.
Recently a phase III dose–response trial was carried out by the British National Lymphoma Investigation (BNLI) group.163 This multicenter trial randomized 1,001 patients between 1997 and 2005, 361 with indolent lymphomas, predominantly FL and to a lesser extent MZL, and 640 with aggressive lymphomas, predominantly DLBCL, between two different radiation schedules: 24 Gy versus 40 to 45 Gy for indolent disease and 30 Gy versus 40 to 45 Gy for aggressive disease. About 20% of indolent disease patients had received chemotherapy, but 80% of aggressive histology patients did. Thus, this is primarily a trial of the dose of RT alone for indolent disease and the dose of RT in a combined modality program for aggressive disease. Tumor bulk was not considered in the randomization process.
For indolent disease the outcomes (survival, PFS, and local control) were virtually identical regardless of dose. The latter approximated 70% at 10 years (Fig. 78.2). From these data and the phase II data cited above, there is no justification for RT doses exceeding 30 Gy for indolent disease when RT is used as a single modality.
Dose of Radiation Therapy in a Combined Modality Therapy Program
For DLCBL, almost all patients, including those with localized disease, are treated with CMT, now typically R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy followed by RT. Thus, a more relevant question than the dose of RT required for local control in patients treated with RT alone is the required dose in a CMT program.
There are many phase II reports in the literature of CMT for DLBCL with rather widely varying doses of RT used. The Vancouver group reported 308 patients with stage I and II DLBCL treated with CHOP (and related combinations) followed by involved field radiotherapy (IFRT) to doses of 30 to 35 Gy (2 to 3 Gy per fraction).164 The 10-year cause-specific survival rate was 82%. In-field local failures occurred in 3% of patients.
Investigators at the MD Anderson Cancer Center reviewed 469 patients with DLBCL treated between 2001 and 2007 with R-CHOP (6 to 8 cycles) with or without RT. Forty percent had stage I or II disease and 60% had stage III or IV. Overall, 30% had consolidation IFRT following CR to chemotherapy with doses of 30 to 39 Gy. Local control was achieved in 100% of patients with all relapses outside the RT field.165
Krol et al.166 at the Daniel den Hoed Cancer Center in Rotterdam looked at 26 versus 40 Gy for patients with stage I DLBCL who had experienced a CR to CHOP. There was no difference in outcome for the two doses in this retrospective analysis.
At Duke University, the authors examined 45 patients with stage I and II DLBCL treated with CHOP who experienced a CR, defined by anatomic imaging and the presence of a negative gallium scan at the completion of therapy. Doses of RT ranged from 10 to 50 Gy but were clustered largely around 30 Gy. Durable local control was achieved in 92% of patients.
The phase III data from the BNLI again demonstrate virtually superimposable curves for local control, PFS, and OS for 30 versus 40 to 45 Gy.163 Again, there is no mention of bulk disease in the BNLI study nor was functional imaging commonly employed to determine CR.
FIGURE 78.2. Freedom from local progression (A), progression-free survival (B), and overall survival (C) for indolent and aggressive non-Hodgkin lymphomas according to radiation dose. (From Lowry L, Smith P, Qian W, et al. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. Radiol Oncol2011;100:86–92, with permission.)
FIGURE 78.3. Axial image from planning computer tomography scan of patients with marginal zone lymphoma of Waldeyer’s ring (base of tongue and bilateral tonsils). The clinical target volume (CTV) is labeled. The planning target volume was a 1-cm expansion around the CTV. The 15 Gy (pink) and 30 Gy (yellow) isodose lines are marked with white arrows. Note sparing of the parotid glands.
The issue of the dose of RT for FL or MZL in CMT programs has usually not been considered because of the lack of efficacy of chemotherapy for localized FL or MZL. Thus, the optimal RT dose in CMT programs (for aggressive histology patients achieving CR with chemotherapy) appears to be 30 Gy, on the basis of the phase II and III data cited above. Even smaller doses may suffice and are under investigation at Duke University. There is no convincing evidence that so-called bulk disease requires more, particularly if PET negative after systemic therapy. For patients who respond to chemotherapy but have persistent PET-positive disease (Fig. 78.1), higher doses of consolidation RT may be required to achieve optimal local control (~40 Gy).167
An unresolved and controversial question is what to do with the patient who is PET positive after chemotherapy. This section will address only the dose of RT to be used if RT alone is selected for treatment. The BNLI study found no difference in outcome between 30 and 40 to 45 Gy for the small number of aggressive histology patients treated with RT without chemotherapy, but no details are given. Nonetheless, in view of the phase II data above, the authors favor a dose 40 Gy under these circumstances.
Field Size and Treatment Volume
The optimal treatment volume or field size for RT of localized NHL is also a matter of some controversy, because definitive phase III trials to resolve the issues are not available. Many of the conclusions regarding appropriate field size are extrapolated from information regarding patterns of failure.
For DLBCL, the pattern of failure after CMT is usually disseminated disease, with a small percentage with local failure.168 After chemotherapy alone, more local failure occurs.168,169 Failure in nodal areas adjacent to the original disease is uncommon.
The question frequently arises as to the appropriate treatment volume or field size when the patient with DLBCL has experienced CR to chemotherapy. Should one treat the original prechemotherapy tumor volume, the postchemotherapy tumor volume, or the original volume plus adjacent nodal areas? What kind of margin should be employed? The policy at Vancouver, for example, was to cover the nodal or extranodal area in question with a margin of about 5 cm, without, however, specifying whether to treat the prechemotherapy or postchemotherapy volume.164
In view of the patterns of failure data cited above, treatment of the original volume plus adjacent nodal areas has pretty much been abandoned. Thus, IFRT seems most appropriate. Whether the involved field is the pre- or postchemotherapy tumor volume depends a lot on where the original tumor was and the tolerance of surrounding normal tissues. With DLBCL of the stomach, for example, the entire organ would be treated regardless of the response to chemotherapy. For patients presenting with nodal disease in the neck unilaterally, the entire neck on that side would generally receive RT after chemotherapy. It would not be necessary or desirable to “prophylactically” treat Waldeyer’s ring for neck presentations of DLBCL.
For tonsil, base of tongue, or nasopharynx presentations of DLBCL, after a CR to chemotherapy, the specific primary site should be radiated with appropriate three-dimensional planning at a minimum or IMRT (Fig. 78.3). One would usually not irradiate all of Waldeyer’s ring but only the specific primary site. In the absence of clinical involvement of the neck at diagnosis, it would not be necessary to “prophylactically” treat the neck. Indeed, omission of neck radiation in these instances would facilitate parotid-sparing treatment plans. Mouth dryness seems to be a real problem for these patients, despite a relatively modest dose of radiation.
Conversely, for a large mediastinal mass, concerns about excessive pulmonary toxicity usually lead to treatment of the reduced tumor mass in the lateral dimensions or the normal mediastinal and hilar structures in the event of a CR to chemotherapy, not the original tumor volume.170
For FL, a number of authors have reported on patterns of failure and appropriate field sizes for patients with stage I or II disease.158,171 For patients presenting with nodal disease, most studies have suggested that FFS is improved with the use of total lymphoid irradiation (TLI), as opposed to IFRT.123,157,159,172 None of these studies has shown an improvement in OS, however, leading most centers to conclude that the morbidity and expense of TLI are not justified.170
Recently the Vancouver group has explored the use of involved nodal RT compared with IFRT, the former defined as covering just the involved nodal group with a margin of up to 5 cm and the latter defined as the involved nodal group and one or more immediately adjacent uninvolved nodal groups.109 This retrospective study was done in 237 FL patients. There were no significant outcome differences.
RT may be used alone to treat stage IIIA FL, although seldom done currently.173 In this instance, TLI would be required. The techniques of TLI (i.e., the mantle, para-aortic nodes, spleen, and pelvis) are discussed in Chapter 77.
Two additional specialized techniques may be applicable to NHL. Total body irradiation (TBI) was used years ago for palliation of advanced FL but has largely been supplanted in this regard by a variety of newer systemic agents. It is still used, however, as part of various regimens of high-dose chemotherapy (HDC) in conjunction with stem cell transplantation.174 When used in the setting of a myeloablative conditioning regimen, TBI is typically administered in a dose of 12 to 15 Gy, 1.2 to 2.0 Gy per fraction, once or twice daily, all depending on institutional preference. One randomized trial of single-dose (10 Gy) TBI (dose rate 0.125 Gy/min) versus 14.85 Gy in 11 fractions over 5 days (dose rate 0.25 Gy/min) revealed similar therapeutic efficacy but a lesser degree of veno-occlusive disease in the fractionated group.175 Both groups had the lungs shielded after 8 to 9 Gy. In the setting of a nonmyeloablative conditioning regimen, 2 Gy TBI is often utilized.
Patients are treated at an extended source to skin distance, the exact arrangement depending on the geometry of the treatment room. At Duke University, patients typically sit on a stretcher with the knees drawn up. Treatment is administered utilizing lateral fields. Unlike TBI for acute leukemia, a testicular boost is not used. The arms are crossed over the chest to provide some self-shielding of the lungs. Dose to the lungs is usually in the neighborhood of 8 to 10 Gy for a 13.5 Gy overall dose, to reduce the risk of pneumonitis. Most, but not all, institutions use some type of lung shielding to reduce the lung dose to approximately 8 to 10 Gy. Other toxicities of TBI include nausea, vomiting, diarrhea, and suppression of the blood counts. This dose would also be expected to cause permanent ovarian ablation in the majority of premenopausal women, sterility in men, and the long-term risk of cataract formation.176,177 In contrast, the acute and late toxicity of 2 Gy TBI in nonmyeloablative regimens are expected to be much less.
Whole-abdomen irradiation (WAI) may also be undertaken more frequently in NHL compared with HL. Mesenteric lymph nodes are commonly involved in NHL, unlike HL. If treating with CMT in a patient with stage II disease and widespread abdominal involvement, the radiation oncologist might wish to use WAI or a modified version excluding the pelvis or liver. The usual Duke University technique is opposed anterior and posterior fields from the diaphragm to the superior portion of the pelvis or the inferior portion of the obturator foramen with partial shielding of the iliac bones and femoral heads. Unless there is known liver involvement, the right lobe of the liver is also shielded. If doses <18 Gy are being used, kidney blocks are not used. If higher doses are desired, either kidney blocks need to be used or different field arrangements made. This depends on the exact location of the disease to be treated. If treating only mesenteric nodes, cross-table lateral fields may be appropriate. Three-dimensional planning is done in most patients. The kidneys are easily localized with CT simulation or with intravenous contrast on a conventional simulator. Modified WAI may also be undertaken as single-treatment modality for FL of the mesentery.
Radiation Therapy for Palliation
RT is a very effective palliative agent and should be considered more often in patients not responding to multiple courses of drug treatment.170 Often relatively small doses of radiation in brief courses can be quite effective. A Dutch trial described 304 sites treated in 109 patients with indolent lymphomas (mostly FL).178 Patients received 4 Gy, either in 1 or 2 fractions, to the symptomatic areas. The overall response rate was 92% with a CR in 61% of patients and a PR in 31%. A French trial had similar results.179 The median time to local progression was 25 months. In this study the number of prior chemotherapy regimens did not influence the response rate. Patients with FL that is behaving in an indolent fashion may sometimes be managed with judicious palliative irradiation for many years without systemic therapy.122,143 For critical local problems occurring in the palliative setting, such as spinal cord compression, RT is the treatment of choice. In this setting, where the goal is to maximize the chances of long-term freedom from local progression, doses of 30 Gy (2 Gy per day) would achieve that objective in 90% to 95% of instances.
For the more aggressive NHL histologies, responses to such low doses would not be predicted, but, in fact, response rates of 50% to 80% have been reported with a dose of 2 Gy é 2 and a median time to progression of about 1 year.180,181 Certainly effective palliation can be accomplished with doses well below 30 to 40 Gy.
Chemotherapy
Chemotherapy forms the mainstay of treatment for the great majority of patients with NHL, because these diseases are most often generalized. As with radiation, malignant lymphomas are, in general, very responsive to chemotherapy. This responsiveness, unfortunately, does not translate to cure of the patient in most instances. Of all the pathologic variants of NHL in the WHO classification, consistent curability with advanced disease is seen only in patients with DLBCL and to a lesser extent in some patients with PTCL and ALCL. Some of the more “indolent” lymphomas such as FL do not appear curable with conventional chemotherapy. A few patients with advanced indolent disease may be curable with an allogeneic transplant.
A large variety of drugs are available for the treatment of malignant lymphomas, including alkylating agents such as cyclophosphamide, corticosteroids, vinca alkaloids, purine analogs, and anthracyclines. They are typically used in combination in order to circumvent problems of drug resistance. The most widely used combination for the treatment of DLBCL has been CHOP.182 For patients with advanced DLBCL, this combination produces an approximate 50% to 60% CR rate, just over half of which are durable responses, for an overall cure rate of approximately 30% to 40%. Results are significantly improved by the addition of the anti-CD20 antibody rituximab, so that R-CHOP has rapidly become the new standard.183,184
Similarly, R-CHOP is probably the most widely used combination in the United States for the treatment of FL,185 although its superiority to other less aggressive combinations has not been established in phase III studies. These data are discussed in greater detail in the sections on the specific types of NHL.
Stem Cell Transplantation and High-Dose Chemotherapy
There has been a great interest in the application of HDC with stem cell rescue in the treatment of malignant lymphomas, both for relapsed disease following initial treatment and for those patients deemed to be at high risk for relapse at diagnosis. The underlying concept is that larger doses of conventional chemotherapy will result in greater tumor cell kill and increased cure rates. The doses involved are so large that they would be lethal because of hematopoietic toxicity without a rescue strategy. Accordingly, hematopoietic progenitor cells are harvested from the patient before the HDC, either from the bone marrow itself or more often mobilized from the patient’s peripheral blood and then reinfused to re-establish marrow function (autologous stem cell transplantation [ASCT]). The high frequency of bone marrow involvement in certain types of NHL limits this strategy, as well as chemotherapy resistance.
Alternatively, an allogeneic transplant may be carried out in individuals with a suitable matched donor in which the stem cells are harvested from the donor. In this procedure, it is hoped that the infused donor stem cells will additionally mount an immunologic attack on the tumor. Allogeneic transplantation may be preceded by full-dose (myeloablative) chemotherapy designed to have not only an antitumor effect, but also to condition the patient for the infusion of the donor cells, or it may be preceded by a nonmyeloablative or reduced intensity conditioning (RIC) program designed primarily to enable the recipient to accept the donor stem cells. In this latter situation the major antitumor effect is postulated to derive from the infused donor stem cells. RIC allogeneic transplants are associated with a much lower treatment-related mortality (10% to 20%) compared with myeloablative allogeneic transplants (40% to 50%).186,187 TBI is often a component of the conditioning program, with doses varying quite widely from 2 to 13.5 Gy (see the section Principles of Treatment: Radiation Therapy).
Studies of ASCT have been carried out in many varieties of NHL but primarily in DLBCL. Numerous phase I, II, and III trials have been reported. An expert committee of the American Society for Blood and Marrow Transplantation has recently comprehensively reviewed all published trials and issued recommendations.188
In general, ASCT has been investigated in three types of situations: (a) patients who have been treated with conventional chemotherapy and then relapsed; (b) patients who fail conventional chemotherapy from the onset (so-called primary refractory disease); and (c) patients who have responded well to primary chemotherapy but are considered at high risk for relapse. The most widely accepted use is for the treatment of patients with DLBCL who have relapsed following initial CHOP or R-CHOP chemotherapy. In a phase III trial from the Parma group, patients with DLBCL who had relapsed following initial CHOP chemotherapy and who were responsive to a salvage program (dexamethasone, cisplatin, cytarabine [DHAP]) were then randomly assigned to receive either four additional cycles of DHAP or a high-dose chemotherapy program.189 Those receiving the HDC program had a markedly improved FFS and OS compared with those getting conventional chemotherapy (46% FFS vs. 12%, 53% OS vs. 32%). Note that in both arms of this trial, IFRT to original bulky sites of disease (≥5 cm) was utilized, with a dose of 35 Gy in 20 fractions in the conventional chemotherapy arm and 26 Gy in 1.3 Gy fractions twice a day in the HDC arm. All patients in the Parma trial were <60 years of age. Patients with a favorable IPI score of 0 did not benefit.190 Those with a short remission after initial chemotherapy had a worse outcome.191
The Parma trial and associated phase II studies have led to the adaptation of ASCT as standard of care for patients <60 years of age with DLBCL relapsing after initial chemotherapy, although the Parma trial is the only phase III investigation of relapsed DLBCL patients ever done. It is also important to note that in this as well as almost all other trials, patients who do not respond to the initial salvage program do poorly with subsequent HDC and are not considered good candidates. PET scanning has also been utilized to define response; those with a persistently positive PET after a salvage program do poorly with HDC.89
A number of groups have explored the incorporation of HDC programs into initial therapy for patients with aggressive histology lymphomas considered at high risk for relapse. Between 1999 and 2010, two meta-analyses and nine prospective randomized trials have examined this issue and are described by the American Society for Blood and Marrow Transplantation expert committee. Rituximab was not included in any of these trials. The committee concluded the evidence was insufficient to recommend HDC/ASCT for any patient group.188
The final issue addressed by ASCT studies is the role of this procedure in patients with primary refractory DLBCL (i.e., those who are chemotherapy-induction failures). This group, in general, has a very poor prognosis. Several studies have attempted to assess the role of HDC, none of them in phase III. An initial report from the University of Nebraska indicated no patients with primary refractory disease were disease free beyond 1 year after HDC.192,193These patients were not sensitive, however, to second-line chemotherapy. Other trials suggested better results could be obtained in patients responsive to second-line salvage programs.194–197 More recently, however, a large international phase III trial looking at salvage regimens demonstrated a 10% 3-year event-free survival in patients who had relapsed <12 months after induction therapy.198 The expert committee recommended against the use of HDC ASCT for newly diagnosed aggressive lymphoma patients with a partial response to induction chemotherapy without specifically addressing the issue of those patients who are nonresponders.
HDC and ASCT have generally not been successful in improving survival and curing patients with indolent disease (e.g., FL). These data have also been comprehensively reviewed recently.199 In brief, OS for indolent lymphomas does not appear to be improved with HDC/ASCT for relapsed disease. Late consequences, particularly the development of myelodysplasia or acute leukemia, are a real concern. The data on the use of allogeneic SCT are all from phase II trials, and, while promising, this procedure is still inhibited by the substantial treatment-related mortality, about 20% at 3 years for RIC transplants and 40% for myeloablative transplants. Thus, allogeneic SCT remains investigational.
The role of radiotherapy in patients undergoing HDC with SCT, either autologous or allogeneic, is undefined. The authors have recently reviewed this issue.200 The rationale for RT lies in the observation that most treatment failures after HDC SCT occur at sites of initial involvement. As mentioned above, consolidation RT was employed in the landmark Parma trial. It is also commonly used at a number of institutions, usually directed at bulk disease sites present before the start of salvage chemotherapy, but with considerable interinstitutional variation and without a clear definition of what constitutes bulk disease. There are a number of phase II trials but no phase III trials addressing this issue. The majority of phase II trials do suggest benefit. The authors recommend doses of 20 to 30 Gy for those patients who have not received prior RT, depending on clinical circumstances and also dependent on whether or not TBI is planned as part of the conditioning regimen. Generally, it is preferable to irradiate prior to reinfusion of stem cells.
Immunotherapy
Perhaps the most promising new approach to the treatment of NHL has been the recent development of effective immunotherapy. The malignant lymphomas express a variety of surface antigens, most notably the B-cell antigen CD20. The ubiquitous presence of the CD20 antigen in many varieties of B-cell lymphomas led to the genetic engineering of a human chimeric anti-CD20 antibody rituximab. In contrast to prior murine derived monoclonal antibodies, rituximab is quite well tolerated in humans. Rituximab was the first antibody of any type to receive U.S. Food and Drug Administration (FDA) approval (1997) for the treatment of any human malignancy.
Numerous trials of rituximab have been carried out in virtually all B-cell lymphomas.201–207 Responses as a single agent are seen frequently in FL, CLL, MCL, and MZL. Although responses are infrequent in DLBCL, the addition of rituximab to the standard CHOP program significantly improves outcomes.183,184 Indeed, the addition of rituximab to chemotherapy for DLBCL represents the major advance of the past several decades in the systemic treatment of DLBCL. The effect is so substantial as to force a re-evaluation of prognostic factors as well as other adjuvant therapies (such as stem cell transplantation or radiotherapy) in the rituximab era.
Rituximab is also employed frequently in combination with chemotherapy for FL, both in the induction phase as well as for maintenance, and significantly improves both response rate and duration of response. Its effect on survival for FL is less clear. It has been combined with chemotherapy for MCL as well.204,208,209,210–211
In parallel with the development of rituximab, efforts were undertaken to link radioactive isotopes to anti-CD20 antibodies, in view of the known radiosensitivity of lymphomas. Currently two such radiolabeled anti-CD20 antibodies have been successfully developed: iodine-131 [131I] tositumomab (Bexxar) and yttrium-90 [90Y] ibritumomab tiuxetan (Zevalin). Both of these agents were FDA approved in 2002 and 2003, respectively. Both demonstrate significant antilymphoma activity, either alone or in combination with other chemotherapeutic regimens.212,213 They demonstrate efficacy in patients resistant to both chemotherapy and rituximab.214
Most of the experience has been gained with FL. The overall response rates are in the range of 80% with approximately one-third of patients achieving CR. In relapsed large cell lymphoma patients, response rates are somewhat lower (approximately 40%). In one trial of untreated FL patients very high response rates of 95% overall with 75% CR were achieved.215 In a phase III Canadian trial for advanced FL, consolidation 90Y-ibritumomab tiuxetan significantly improved CR rates (53% vs. 87%) as well as the median PFS (13.3 vs. 36.5 months).216 There is additional evidence to suggest efficacy of radioimmunotherapy as consolidation for aggressive histologies.217 The optimal timing of radioimmunotherapy, selection of appropriate patients, and integration into other available therapeutic modalities has not been established. These data have recently been reviewed by the Seattle group.218
TABLE 78.7 RANDOMIZED TRIALS EVALUATING CONSOLIDATION RADIATION THERAPY IN EARLY-STAGE DIFFUSE LARGE B-CELL LYMPHOMA
TREATMENT OF SPECIFIC LYMPHOMAS
Diffuse Large B-Cell Lymphoma, Stage I or II
Historically in the prechemotherapy era, early-stage DLBCL was treated with RT alone.155,159,171,219–222 Ten-year FFS and OS in these series ranged from 30% to 60%, depending on the mix of patients and prognostic variables. The doses of RT varied widely from 30 to 60 Gy. The CR rate was high, usually >80%. Field sizes and arrangements also varied widely but, in general, IFRT was used.
The pattern of failure in these series was primarily distal, either organ involvement or nodal sites remote from the primary site. Patients with both nodal and extranodal disease were included in these series and appear to have equivalent prognoses. Stage II patients had a long-term FFS and OS in the range of 25%, in contrast to patients with stage I disease where the FFS and OS were in the 50% to 60% range.
In the late 1970s and early 1980s, efforts to improve on these results by the addition of combination chemotherapy were begun. The phase III trials in many instances antedated the phase II trials, but the former were typically carried out with older combinations such as CVP (cyclophosphamide, vincristine, prednisone) with results not as good as the more modern phase II studies incorporating CHOP.223,224 These latter trials demonstrated a substantial improvement in both FFS and OS with CMT compared with RT alone. CR rates of approximately 90% are reported with FFS and OS in the range of 70% to 85%.164,225
These studies differed widely in their design. The number of cycles of chemotherapy varied between 2 and 8. The radiation dose ranged from 20 to 60 Gy, with the larger doses of radiation generally for patients not experiencing a CR. None of the trials used rituximab as part of the therapy (now standard) nor was functional imaging employed for assessment of response. Radiotherapy fields were generally IFRT only, although the latter was vaguely, if at all, defined in most reports. Usually they covered the original site of disease before chemotherapy with a margin.
After improved outcomes were seen with the addition of chemotherapy, the question was raised whether RT was still necessary. Five randomized studies were subsequently conducted comparing chemotherapy with a combined modality program (Table 78.7).168,226–230 Again, none of these studies used rituximab as part of the treatment regimen nor was functional imaging utilized for response assessment. Interpretation of the trials can be challenging, given their individual peculiarities, requiring a brief overview of each.231
The South West Oncology Group (SWOG) study demonstrated that brief CHOP chemotherapy (3 cycles) plus RT was superior to a more extended CHOP regimen (8 cycles).168 Both PFS and OS were improved in the combined modality arm with less toxicity (Fig. 78.4). However, it has been reported that more late systemic relapses occurred in the combined modality arm with longer follow-up, suggesting that 3 cycles of chemotherapy may be inadequate to control systemic disease long term in some early-stage patients.229
The Eastern Cooperative Oncology Group study demonstrated that consolidation RT reduced the risk of relapse even with extended chemotherapy (8 cycles of CHOP in this case).227 Disease-free survival at 6 years was 73% with consolidation RT versus 56% with observation (P = .05) (Fig. 78.5).
The Groupe d’Etude des Lymphomes de l’Adulte study GELA-93-4 enrolled older patients (>60 years) with early-stage disease without adverse risk factors.226 Crude rates of local failure were less with RT (18% vs. 7%). However, neither PFS nor OS was improved with consolidation RT after 4 cycles of chemotherapy. Thus, older patients, especially those with favorable prognostic factors or medical comorbidities, may derive less benefit from consolidation RT.
GELA-93-1 demonstrated that an aggressive chemotherapy regimen was superior to CHOP plus RT, at the expense of increased toxicity.230 Quality control issues have been raised, however, regarding the RT in this trial. Despite the apparent advantage of the aggressive chemotherapy program, this regimen has not been generally adopted due to its toxicity profile.
Finally, International Extranodal Lymphoma Study Group (IELSG) enrolled a small number of patients with gastric DLBCL to CHOP versus CHOP plus RT. PFS was improved with the combined approach.228 These trials have led to a general acceptance of treatment with CMT therapy for early-stage DLBCL. The advantage of CMT has also been confirmed using SEER data.232
These results must be interpreted in the light of rituximab not having been used. A recent large retrospective analysis demonstrated an advantage of RT even with R-CHOP.165 However, no phase III trials comparing R-CHOP with or without RT for stage I or II DLBCL are in progress to the authors’ knowledge. Similarly, functional imaging was not utilized in any of the randomized studies, and how to incorporate interim and posttreatment PET response into a treatment algorithm remains an area of investigation.
Although a range of RT doses were utilized in the randomized trials, 30 Gy appears adequate in the setting of a CR after chemotherapy.163,227 The original extent of disease should be treated, if not an entire involved field, depending on the circumstances. It is generally appropriate to restrict treatment to the postchemotherapy volume in situations where excessive dose to normal tissue might result, such as with DLBCL of the mediastinum or abdomen. For these sites, the field reduction would typically be in the lateral dimensions to spare normal lung and kidney, but superior inferior margins may be more generous.
FIGURE 78.4. Progression-free survival for patients randomized to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) é 8 versus CHOP é 3 plus consolidation radiotherapy in the South West Oncology Group randomized trial. (From Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin lymphoma. N Engl J Med 1998;339:21–26, with permission; copyright Massachusetts Medical Society.)
FIGURE 78.5. Disease-free survival for complete remission patients in the Eastern Cooperative Oncology Group randomized trial. Observation (solid line) and consolidation radiotherapy (dotted line) are shown. (From Horning SJ, Weller E, Kim K, et al. Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol 2004;22:3032–3038, with permission.)
Diffuse Large B-Cell Lymphoma, Stage III or IV
The mainstay of treatment of disseminated DLBCL is clearly systemic chemotherapy. RT has been thought to play little, if any, role.233 A re-examination, however, may be in order, given some trials that do suggest benefit.234,235–236The standard chemotherapeutic combination has been CHOP, first introduced in the late 1970s.237 With this combination, CR in the range of 60% to 70% were reported with most of these (approximately 60%) being durable, for a long-term cure rate of 35% to 40%.182,238
Although these results were better than those in the past, they were far from optimal. Over the next several decades, there were numerous attempts to improve on the CHOP program with promising phase II trials of new combinations, but unfortunately, that promise was unsupported by follow-up phase III studies. The best known of the latter was the Intergroup/SWOG trial comparing CHOP, M-BACOD, Pro-MACE-CYTABOM (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, and vincristine) and MACOP-B (CHOP plus methotrexate and bleomycin).182 This trial analyzed approximately 900 patients. Three-year survival rates were 50% with 3-year FFS rates of 41% with no differences between the four-drug combinations. The least toxic combination, CHOP, thus became the standard treatment.
A recently published overview of chemotherapy for “aggressive” NHL histologic type reviewed 111 scientific reports including 35 randomized trials with a total of approximately 22,000 patients. The overview concluded that in unselected patients with advanced-stage disease, CHOP was curative in approximately one-third.239
A major improvement in the outcome for patients with DLBCL has come with the introduction of rituximab. Several phase III trials have now demonstrated the value of adding rituximab to standard CHOP. The GELA study compared CHOP alone with rituximab and CHOP in 399 patients >60 years old.183 FFS improved from 30% to 54% and 5-year OS from 45% to 58%.
Similarly, a European cooperative trial compared R-CHOP and CHOP in 824 patients aged 18 to 60 with stages II to IV DLBCL.184 Three-year FFS was 79% in the R-CHOP group compared with 59% in the CHOP group. Three-year OS was 93% and 84%, respectively. In this trial, unlike the GELA trial, RT was given to select patients with bulky disease or extranodal disease. These studies have led to the rapid adaptation of R-CHOP as standard initial therapy of DLBCL for all stages of disease.
There have also been attempts to improve on the CHOP combination by the introduction of HDC and ASCT for patients with a poor prognosis in first remission, as mentioned above. Thus far, no proven benefit has been demonstrated.240 The use of HDC/ASCT for DLBCL patients in first remission has not been explored in patients treated with R-CHOP.
A comparatively unexplored approach is the use of consolidation RT in combination with chemotherapy for advanced DLBCL. One rationale for the use of such RT is the tendency of patients with advanced lymphoma to relapse at sites of disease present at diagnosis and, in particular, sites of bulky disease present at diagnosis.241–243 This observation is somewhat controversial.233 In view of the efficacy of CMT in localized disease, the exploration of its value in more advanced disease appears worthwhile.
There have been a few reports regarding its use. Aviles et al.236,244 performed a phase III trial in which patients with DLBCL who experienced a CR with CHOP and who had pre-existing bulky disease were randomized to receive RT (40 to 50 Gy) to prior sites of bulky disease or not. The FFS rate was 72% in those receiving CMT compared with 35% in those treated with chemotherapy alone. Corresponding OS was 81% and 55%, respectively, all differences being statistically significant.
A retrospective analysis at MD Anderson Cancer Center compared a group of patients with stage III or IV DLBCL treated with chemotherapy only with a similar group treated with CMT.234 RT dramatically improved local control (89% vs. 52%) and freedom from progression (5-year rates of 85% vs. 51%), but not OS (87% vs. 81%).
A similar analysis from Milan examined 94 patients with stage III or IV DLBCL and bulky disease (tumor mass ≥6 cm).245 Forty patients received consolidation RT, whereas 54 did not. Doses and field sizes varied between 30 and 46 Gy. Improvements were noted in OS as well as FFS. These reports raise the issue of additional phase III trials to evaluate further this concept.234
TABLE 78.8 RADIATION THERAPY OF STAGE I/II FOLLICULAR LYMPHOMA SELECTED PHASE II TRIALS
Follicular Lymphoma, Stages I and II
The treatment historically for stage I or II FL has been RT alone. Representative series are shown in Table 78.8.123,155,159,171,172,221,246–249 The largest experiences are from the Princess Margaret Hospital,155 BNLI,221 and Stanford University.172 The reported series were accumulated over a long period, with patients staged in different ways and treated with differing doses and fields of radiation. Although these series are grouped as FL, most of them included patients with other histologic types classified as low-grade lymphoma in older pathologic classifications.
Despite the heterogeneity of the patient population and the lack of uniformity in data reporting, certain conclusions may be drawn:
1. Five- and 10-year OS is high, in the range of 75% to 90%, particularly if cause-specific survival is the quantity measured. Early deaths from lymphoma in this group are quite uncommon.
2. The FFS rate is less, with wide variability from 40% to 80%. Most series report much better FFS rates for patients with stage I versus stage II disease. Most series also suggest few relapses beyond 10 years.
3. Although radiation doses varied widely, local control was >90% in almost all instances with doses of ≥30 Gy, with no dose–response demonstrated above 30 Gy. A recent randomized trial confirmed that doses as low as 24 Gy are adequate for low-grade lymphomas.163
4. Radiation field sizes varied widely as well, with no evidence for improved survival with increasing field size. Prophylactic coverage of uninvolved adjacent lymph node regions does not decrease overall recurrence risk.109
5. Although a long median survival is observed, the leading cause of death is relapsed lymphoma.250
There have been a few attempts to improve on these results with the use of CMT. Two phase III trials published in the early 1980s that showed positive results for the effects of CMT, compared with RT alone for DLBCL, showed no benefit for the use of CMT in FL.223,224 Very small numbers of patients were included, however, so the studies were grossly underpowered to detect meaningful differences. Two additional phase III trials were published in the 1990s.251,252 The Memorial Sloan-Kettering Cancer Center trial similarly contained very small numbers of patients with FL. The BNLI had by far the largest number of patients. Single-agent chlorambucil was the chemotherapy; the trial was negative.
This lack of enthusiasm for CMT for stage I or II disease no doubt mirrors the general attitude toward advanced disease, where, to date, combination chemotherapy has not shown curative potential.119,253,254 As with DLBCL, all these series antedate rituximab, which has a profound effect on FL. Additionally, they antedate the introduction of the FLIPI, so whether certain prognostic groups might benefit from CMT is unknown.
The predominant pattern of failure for patients with stage I or II disease treated with RT alone is distant. Local failure of any type, either alone or combined with distant failure, occurs in <10% of patients. Nodal extension is an uncommon pattern of failure, seen in perhaps 20% of patients.
The question frequently arises as to whether patients with localized FL who respond well to RT and experience a prolonged disease-free survival are truly cured of their disease. Although the OS and FFS curves appear to flatten beyond 10 years, concern has been raised by reports of persistent molecular abnormalities in such patients. In particular, circulating t(14:18)-positive cells were noted in one-third of patients with FL in prolonged remission in one report.255 On the other hand, such cells were also found in 23% of normal individuals.256 Thus, the issue of molecular cure remains unsettled. Additionally, one Stanford University study suggests an equivalent outcome with a watch-and-wait policy for early-stage disease.257 Majority opinion, however, would support involved field RT for patients with early-stage FL. Nonetheless, the view that FL is an indolent process leads to underutilization of RT for localized disease. Recent studies have shown that only ~30% of patients with early-stage FL receive RT, despite national and international guideline recommendations.258,259 A SEER analysis suggested a possible detriment in long-term survival when RT is not given.259
Follicular Lymphoma, Stages III and IV
The treatment of advanced-stage FL is a special challenge. The disease has a long natural history.120,253,254,260 Median survivals ranging from 6 to 11 years have been described with or without treatment. FL is quite responsive to a variety of systemic agents, including alkylating agents, anthracyclines, purine analogs, vinca alkaloids, corticosteroids, and monoclonal antibodies. Examination of published survival curves after a variety of therapeutic approaches, however, demonstrates a continuing pattern of relapse and death, albeit over a long period, with no evidence for flattening of the survival curve, the pattern usually associated with cure. There is also no clear evidence for the superiority of any one drug or combinations of drugs in the treatment of this disease. Studied agents have ranged from single-agent chlorambucil or cyclophosphamide to aggressive combinations such as ProMACE/MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, Mustargen, vincristine, procarbazine). As would be expected, the CHOP combination has been extensively studied in FL. Although superior to less aggressive therapies for DLBCL, CHOP has no proven advantage in FL. An extensive review of multiple SWOG trials involving doxorubicin-containing combinations for the treatment of FL showed no benefit for this drug combination compared with less aggressive combinations.261
Accordingly, there remains interest in deferral of therapy for this disease. In selected patients with low tumor burden followed expectantly, OS was 73% at 10 years.120 Of interest, spontaneous regressions were noted in approximately 25% of patients. Histologic transformation to a higher-grade lymphoma occurred both before and after therapy with a frequency similar to that seen in patients treated at initial diagnosis. This study was nonrandomized, but similar findings have been observed in the randomized trial by Groupe d’Etude des Lymphomes Folliculaires.262
The lack of evidence that the natural history of FL is greatly altered by conventional chemotherapy has stimulated the search for new agents and new treatment strategies. Some of these approaches are as follows:
Immunotherapy: Rituximab produces responses in about 50% of relapsed FL patients as a single agent. As first-line therapy, the response rate is about 70%. More often, however, rituximab has been combined with chemotherapy. Numerous phase III trials have been conducted utilizing a variety of drug combinations with rituximab.208,211,263–265,266–267 These studies have consistently shown an improvement in OS when rituximab is added to a combination chemotherapy regimen. To which chemotherapy program one should add rituximab, however, is not clear. In the United States, the most popular combination has been R-CHOP.185
Of primary interest currently is the issue of immunotherapy in the maintenance setting. Multiple phase III trials, using various induction regimens, have demonstrated an improvement in PFS with rituximab maintenance,268–269,270with a meta-analysis demonstrating an OS benefit.268 However, the largest trial conducted to date, which used R-CHOP induction, did not show an advantage in overall survival, possibly due to more effective induction therapy, rituximab use at relapse, or simply inadequate follow-up.270 The optimal schedule and duration of maintenance rituximab has not been formally studied. The primary risk is infections.
Radioimmunotherapy: This has also been extensively investigated in FL, both for the treatment of relapsed disease as well as an initial therapy. The two agents in wide use are 90Y ibritumomab tiuxetan and 131I-tositumomab, the former a pure β-emitter, the latter a γ- and β-emitter. Both agents demonstrate comparable activity with response rates of 60% to 80% in relapsed FL patients.271–273 In a select group of previously untreated patients, a 95% response rate was obtained with 131I-tositumomab (75% CR) with half of the patients in continuous CR at 4 years.215 These radiolabeled antibodies have been cautiously combined with chemotherapy, because their primary toxicity is myelosuppression.
In a SWOG phase II trial of CHOP followed by 131I-tositumomab, 5-year FFS was 67% and OS was 87%.213 A phase III trial randomized patients with stage III or IV FL in CR or PR after a variety of induction regimens to observation or consolidation with 90Y ibritumomab.216 PFS was increased from 13.3 to 36.5 months (P <.0001) with manageable toxicity. This has not been widely adopted given the lack of rituximab in the control arm. The SWOG recently completed a randomized study comparing R-CHOP with CHOP and consolidation 131I-tositumomab. Final results have not yet been reported. There are no studies to the authors’ knowledge combining radioimmunoconjugates with external-beam radiotherapy.
Interferon: A large number of trials have been conducted examining the effect of this agent, both as a part of induction therapy and as maintenance after chemotherapy. A recent meta-analysis concluded that when given in the context of relatively intensive initial chemotherapy interferon-alfa prolongs both remission duration and survival.274 Nonetheless, its toxicity has inhibited widespread use, and further, all those trials preceded the rituximab era.
Stem cell transplantation: A number of studies have examined the role of autologous and allogeneic transplantation in FL, for both relapsed disease and FL in first remission following induction chemotherapy.275–282 Although a number of phase II trials looked promising, most phase III trials using ASCT have not shown an improvement in OS, although most have shown an improvement in PFS.
Allogeneic SCT has been used less frequently, particularly with myeloablative conditioning, given high rates of treatment-related mortality in the range of 30% to 40%. More recent studies have used RIC regimens, which are associated with less but still significant nonrelapse mortality.276,278,282 The curative potential of allogeneic SCT is evident, although many questions remain including optimal conditioning regimen, appropriate donor sources, graft versus host disease prophylaxis, and posttransplant interventions such as donor lymphocyte infusions.
Role of Radiation Therapy in Advanced Follicular Lymphoma
The curative potential of RT for localized FL together with the early HL experience led to the initiation of trials of TLI for patients with stage III FL, primarily by the Stanford University group.173 Sixty-six patients with stage III FL were treated either with TLI (61 patients) or TBI (5 patients). The FFS rate was 35% at 15 years, the cause-specific survival was 58%, and the OS was 35%, reflecting additional mortality from nonlymphoma causes. A small cohort of eight patients with a lower tumor burden, so-called limited stage III disease, defined as fewer than five disease sites and no tumor mass >10 cm, had an FFS of 88% and cause-specific survival of 100% at 15 years. Doses of RT used were 40 to 48 Gy, much larger than would be considered optimal currently. There were few relapses occurring beyond the 10th year. Similar data have been reported from the University of Florida, the Medical College of Wisconsin, and the MD Anderson Cancer Center.283–285
RT has also been advocated as consolidation therapy after chemotherapy in patients with advanced stage FL. A phase III trial by Aviles et al.286 randomized 118 untreated patients with stage III or IV FL to receive CVP chemotherapy alone or the same chemotherapy followed by IFRT to initially involved nodal sites, at doses of 35 to 45 Gy. The 7-year FFS was 33% in the group treated by chemotherapy alone and 66% in those receiving CMT. The 7-year OS was also doubled from approximately 40% to 80%. The improvement in FFS was highly significant, and the survival showed improvement of borderline statistical significance (P = .06). There have been no additional studies attempting to replicate these results.
Follicular Lymphoma, Grade 3
Grade 3 FL comprises cases where there are >15 centroblasts per high-power field. In the current WHO classification, patients with FL who have diffuse areas in the pathological specimen comprised predominantly or entirely of large blastic cells are also reported to have DLBCL.35 FL grade 3 is an uncommon variety of FL, comprising approximately 15% of all cases of FL.287–290 The biologic behavior of this specific type of lymphoma is somewhat controversial because of its infrequency and the relatively small number of patients reported in various retrospective series in the literature.
Initial reports suggested an unfavorable outlook; a median survival >10 years was reported in the Stanford University series, but only 22% of patients were disease free at that time.289 The advent of anthracycline-based chemotherapy appears to have resulted in some improvement in that prognosis and perhaps a plateauing of the FFS curve. The University of Nebraska group reported 3-year survival rates of 76% and 61% for patients with stage I or II disease and III or IV disease, respectively, but FFS rates of only 61% and 34%, respectively, results not that different from those seen with other FLs.287 On the other hand, the MD Anderson Cancer Center group reported 5-year survival rates of 72% in a series of 100 patients with stage I to IV disease and an FFS rate of 67%, with a “possible plateau in the FFS curve for patients with stage I–III disease.”290 In both series, patients received anthracycline-containing combination chemotherapy, with the patients with earlier-stage disease receiving IFRT as well in varying dosages. The aforementioned as well as other series have led to a consensus that patients with FL grade 3 should be treated similarly to patients with DLBCL in terms of chemotherapy.288,291 The prognosis, in general, is better than for DLBCL but median survivals are shorter than for FL.
Data regarding dose–response information for RT are lacking. Because virtually all patients are receiving chemotherapy, however, the authors consolidate patients with early-stage disease with 30 Gy IFRT in a fashion similar to that for early-stage DLBCL.
Marginal Zone Lymphomas
Extranodal MZL or MALT lymphomas are the most common variant, the most common location being the stomach. The treatment of MALT lymphoma of the stomach is discussed in the section on primary extranodal lymphomas. Other commonly involved extranodal sites include skin, salivary glands, and orbit (in descending order of frequency).128 MALT lymphoma involving sites other than the stomach and GI tract behaves similarly, but there is no association with H. pylori. The disease is very responsive to RT. Doses of approximately 30 Gy produce long-term control in more than 90% of patients. In one large series combining MALT of all sites, the overall local control rate was 97%, the OS was 96%, and FFS at 5 years was 76%.132,161 When MALT lymphoma relapses, it tends to have a prolonged clinical course.
Occasional patients with MALT lymphoma present with isolated organ involvement that is, however, bilateral (e.g., involvement of the salivary glands or conjunctivae). This behavior, referred to as lymphocyte homing, is not well understood. Such patients may be treated with local RT to both paired sites with apparent long-term FFS observed.292
MALT lymphoma is responsive to chemotherapy in a high percentage of patients. With single-agent chlorambucil, a 75% CR rate was observed in one series.293 A large SWOG analysis, however, indicated that FFS and OS rates were similar to those observed in FL, with no plateauing of the survival curve.294 Thus, chemotherapy is palliative and reserved for patients with generalized disease who are symptomatic. MALT lymphomas also respond well to rituximab, but either alone or in combination with chemotherapy this agent is not curative either.74 Asymptomatic individuals with generalized disease should be considered for observation, similar to patients with generalized FL because the course is so often indolent. Patients with generalized disease with symptoms due to a localized tumor mass may be easily palliated with modest doses of radiation to the mass in question. That approach is often superior to systemic chemotherapy.
Nodal and splenic MZL have been discussed previously in the section on clinical–histopathologic correlates. Both are most often generalized and managed similarly to advanced FL.
Peripheral T-Cell Lymphomas
PTCL of the nodal type, not otherwise specified, resembles DLBCL in its clinical characteristics and presentation.36,56,113,138,295–298 Overall, there is a worse outlook. PTCL is more often generalized, the IPI tends to be worse, and approximately half of patients have B symptomatology. Response to treatment is generally unsatisfactory. The International T-Cell Lymphoma Project reported 10-year survivals in the range of 20%.136 There was no clear benefit for the addition of anthracyclines to a chemotherapy program and no standardized regimen has emerged. CHOP is probably the most commonly employed regimen in the United States. Because this is a T-cell lymphoma, there is no role for rituximab. Patients who present with localized PTCL should be treated with chemotherapy (type and duration uncertain) and IFRT. Doses and field sizes of RT are probably comparable with those used for DLBCL. PTCL patients were included in the BNLI trial but constituted only 5% of aggressive histologies.163 Given these uncertainties and considering that PTCL is less responsive to chemotherapy then DLBCL, a dose of approximately 40 Gy in 2 Gy fractions is recommended. Few data exist regarding the role of RT for advanced disease. As for DLBCL, the concept may warrant further exploration.
In contrast to most patients with PTCL, those with ALCL have a much better prognosis, among the best of any of the lymphoma categories and certainly the best of the ostensibly “aggressive” histologic types. The presence of the anaplastic lymphoma kinase (ALK) translocation, with subsequent expression of the ALK protein, distinguishes prognostic groups. ALK-positive patients have a good prognosis when treated with CHOP. OS is around 70% at 10 years.299,300 ALK-negative patients have a considerably worse outlook, with OS from 14% to 40% following CHOP therapy. ALCL of the skin is discussed in the section on primary extranodal lymphomas.
Small Lymphocytic Lymphoma
SLL is a rare disease, histologically and phenotypically identical to CLL and subsumed into one category by the WHO classification. SLL is most often generalized. The distinction between SLL and CLL is somewhat arbitrary and depends on the absence of leukemic cells in the blood in the former (<5 é 109/L monoclonal lymphocytes in the peripheral blood). Treatment is essentially that of CLL except when localized. The purine analogs appear to be the most active agents.301,302 The disease is also responsive to alkylating agent chemotherapy such as chlorambucil or combination chemotherapy, with CHOP, for example. Rituximab also plays a major role. As with FL and MZL, there is neither evidence for a plateauing of the survival curve nor definite benefit from combination chemotherapy, as opposed to single-agent treatment.303,304
In that rare situation where the disease is localized (i.e., stage I or II nodal only), one would predict RT might achieve long-term FFS for some patients with doses and field sizes similar to those used for FL, namely, approximately 30 Gy in 3 weeks’ time to a generous involved field. Accordingly, RT has been recommended as the treatment of choice in this situation.152
Mantle Cell Lymphoma
The treatment of MCL is unsatisfactory. This recently designated disease is distinguished by one of the worst outlooks for any lymphoma. Another way of describing the survival pattern of MCL is that it resembles FL in its response to therapy and FFS (i.e., no plateauing of the FFS curve and thus no indication of cure), but DLBCL in its overall survival (i.e., much shorter than FL).305–308
The therapy of MCL has been explored in a number of retrospective analyses as well as prospective phase II and limited phase III trials using a variety of chemotherapy programs.153,306,308 Chemotherapy programs can be generally grouped as CHOP-like, now usually including rituximab, which does have activity in MCL, purine analog containing programs (e.g., R-FCM [fludarabine, cyclophosphamide, mitoxantrone]) or more intensive programs such as hyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytarabine, and methotrexate). High response rates are seen (80% to 90%), but relapse usually occurs with no plateauing of FFS. There is no clear evidence for superiority of one regimen over another. The addition of rituximab to chemotherapy does seem beneficial.309
HDC and SCT have also been employed, both autologous as well as allogeneic, both in first remission and for relapse.153,310,311 One phase III trial did demonstrate improved FFS for SCT in first remission, but no survival benefit as yet.312 Thus, SCT must still be considered unproven. It has been suggested that apparent improvements in survival with programs such as HDC and SCT may be attributed to better supportive care, patient selection, and failure to account for prognostic factors.307,313 NCCN guidelines indicate no standard therapy for MCL.314 Entry into clinical trial is recommended.
Patients with localized MCL (stage I or II) are seldom encountered. One small series from British Columbia has been reported, however.315 Seventeen patients treated with RT (30 to 35 Gy) with or without chemotherapy had a 5-year FFS of 68% and OS of 71%. Adjuvant chemotherapy did not seem to influence the outcome. Thus, RT appears to have an important role for those few patients with limited stage MCL. RT is also very effective palliation for patients with advanced disease.316 Clinically the disease is quite sensitive to radiation, and low doses (<20 Gy) may suffice.316
Finally, there may be a group of patients with MCL with favorable prognostic factors in whom observation is a reasonable strategy. In a small series from New York Hospital, survival was not compromised by an initial period of observation prior to initiation of therapy when and if disease progression occurred.307
PRIMARY EXTRANODAL LYMPHOMAS
Thus far this chapter has considered NHL primarily from the standpoint of the histopathologic classification. NHL may also be clinically divided, however, on the basis of origin from nodal or extranodal tissue; the latter may be further subdivided as to site of origin. The frequency of extranodal lymphoma (ENL) and certain characteristic clinical entities associated with lymphoma in various extranodal sites makes the discussion of ENL as such appropriate.
It is important to re-emphasize certain principles that recur in this section: localized disease, whether presenting nodally or extranodally, seems to have the same prognosis (Fig. 78.5). The management strategy for localized nodal lymphoma of a given histologic type usually applies as well to that same histologic type when presenting extranodally.
Extranodal disease accounts for approximately 35% to 40% of all patients with NHL and approximately half of those with stage I and II NHL.71,72,317 The most common sites of involvement are the GI tract, accounting for approximately 25% to 35% of all ENL, the head and neck region, which accounts for approximately 20% to 30% (including Waldeyer’s ring and other head and neck sites, but excluding brain), and skin, with a variety of miscellaneous sites accounting for the rest. PCNSL, which accounts for approximately 10% of all ENL, is discussed separately.
Histopathologically, ENLs are classified in much the same fashion as nodal lymphomas. The extranodal location may cause difficulties in histopathologic diagnosis. Immunophenotyping as well as cellular morphology may be helpful in this respect. Establishing the diagnosis of ENL on the basis of fine-needle aspirate or similarly sized biopsy, however, is an unwise practice. Accurate histopathologic classification is essential for proper management and almost always requires at least a core of tissue.38
Gastrointestinal Lymphoma
The stomach is the most common site of involvement (50% to 80% of all cases of GI lymphoma).72,318–320 The remaining GI lymphomas occur in the small and large intestines, primarily ileum, followed by colon and rectum, but lymphomas may arise in any of the GI tissues. Histopathologically, 90% to 95% of gastric lymphomas are MALT or DLBCL, the two being approximately equal in frequency.320–322
Patients with gastric lymphoma usually present with symptoms of abdominal pain (~80%).320 Other common complaints are loss of appetite (~50%), weight loss (25%), and bleeding (20%). B symptomatology is uncommon (10% of patients). In this regard, only fever and night sweats are significant because weight loss is so often a function of direct effects on the stomach. Perforation as an initial symptom is very uncommon, occurring in <2% of patients. Many cases of gastric MZL are detected incidentally during endoscopic examinations.
The diagnosis of gastric lymphoma is usually established endoscopically, although in past years laparotomy was often necessary.323 Surgical resection has traditionally been the cornerstone of treatment, followed by adjuvant RT or chemotherapy. This approach at the Princess Margaret Hospital, for example, resulted in an FFS of 81% and cause-specific survival of 88% in 149 patients treated between 1967 and 1996.324 Other surgical series have been extensively reviewed by Bozzetti et al.325 and Thirlby,326 with OS of 60% to 100% in stage I patients and 40% to 80% for stage II disease.
Beginning in the 1980s, however, some authors began to question the necessity for surgery in a disease that is usually quite responsive to RT or chemotherapy. Subsequently a number of reports showed equivalent outcomes when patients were treated with RT and chemotherapy without surgery.320,327–328,329,330 A large series of gastric lymphomas reported by the German GI Tumor Study Group is representative.330,331 They reported on 398 stage I and II patients with primary gastric lymphoma about equally divided between MALT and DLBCL. Three hundred thirty-five were managed conservatively without surgical resection; 63 had subtotal gastrectomy. Outcomes were essentially identical with an 80% 5-year survival.
Gastric Diffuse Large B-Cell Lymphoma
The historical experience with the treatment of localized DLBCL of the stomach without systemic therapy demonstrated an OS in the range of 25% to 50%, as with DLBCL generally. The use of systemic chemotherapy has resulted in considerable improvement. Multiple centers now report 5-year OS in the range of 70% to 80% for patients with localized disease treated with chemotherapy with or without RT.320,332–334 Although some authors have suggested that chemotherapy alone is adequate treatment,332,334 most studies have used CMT.
A multicenter randomized trial from the IELSG formally evaluated the role of RT in patients with high-grade NHL (principally DLBCL) of the stomach.228 Patients with a CR after 4 cycles of a CHOP-like regimen were randomized to consolidation RT (minimum of 30 Gy) or 2 additional cycles of chemotherapy. Patients with a PR after 4 cycles received an additional 2 cycles of chemotherapy, and if they obtained a CR, were then randomized to radiation versus observation. Due to poor accrual, the study was closed after enrolling 55 of a planned 125 patients. Four patients (three local failures and one distant failure) recurred in the chemotherapy alone arm, while there were no recurrences after consolidation RT, resulting in a disease-free survival of 100% with RT versus 82% without (P = .04).
Although most studies of gastric DLBCL have utilized CHOP, treatment should be initiated with R-CHOP in view of the results cited above. The risk of chemotherapy-induced gastric perforation is very low, 1% to 2%. The number of cycles is not well defined; 3 to 6 cycles have been most often used, with the precise number depending on the rapidity of response, initial volume of disease, and investigator preference, as with stage I and II disease in general.164,168 The response to chemotherapy should be assessed with appropriate imaging studies, usually a repetition of those studies that were positive before the onset of chemotherapy. Repeat endoscopic evaluation and biopsy are particularly useful for assessing the completeness of response.
Radiation doses and field sizes to be used for gastric DLBCL are not well defined. Excellent results have been reported in patients treated with 25 Gy after surgical resection.335 For patients treated without resection, a wide variety of radiation doses have been reported, ranging from 30 to 50 Gy, similar to what has been described for the treatment of nodal DLBCL. Treatment fields have also varied considerably from whole abdomen to IF. There is no apparent correlation between field size or dose and outcome. Local control in almost all the reported series has been high, in the range of 90%. FFS and OS for patients with stage I and II disease have also ranged from 70% to 80%.292,321,324,329,330,333,336
The radiation field should probably encompass the entire stomach and perigastric lymph nodes along the greater and lesser curvature of the stomach as well as any other involved nodal areas with an appropriate margin. Patients should be fasting for several hours prior to simulation and treatment. CT-based planning is preferred. Respiratory-induced motion should be assessed and accounted for using fluoroscopy or four-dimensional CT. The typical field arrangement is parallel-opposed anterior and posterior fields. More complex field arrangements may be necessary depending on the position of the kidneys in relation to the target volume. In the event the patient has responded completely to chemotherapy by negative endoscopic examination and biopsy, a dose of 30 Gy is appropriate, similar to what would be done for nodal disease (see the section Principles of Treatment). If there is persistent biopsy-documented disease after chemotherapy, other systemic therapy should be considered or higher doses of radiation must be used, in the range of 40 Gy.
Gastric Lymphoma, Mucosa-Associated
Lymphoid Tissue Type
MALT lymphoma is a distinct clinical-pathologic entity first described by Isaacson and Wright50 and occurring most often in the stomach. A unique feature of gastric MALT is the association with H. pylori infection, initially reported by Isaacson’s group.23,337 H. pylori can be identified in up to 92% of patients.23
Accordingly, first-line treatment for patients who are H. pylori positive is appropriate antibiotics. A frequently recommended combination is omeprazole, metronidazole, and clarithromycin.338 Numerous studies have confirmed the efficacy of antibiotics for gastric MALT. The complete remission rate is approximately 75%. Approximately two-thirds of complete responders remain in remission at 5 years,339,340,341 for an overall 5-year FFS of about 50%. The 5-year OS is much higher at 90% with most deaths due to causes other than lymphoma.341 Response of H. pylori-negative cases to antibiotics has also been reported.342
Several factors have been associated with resistance to antibiotics, including deep invasion of the gastric wall343,344 and the (11:18) translocation.345 Additionally, some patients in CR will have persistent B cell monoclonality on PCR analysis and are at higher risk of relapse.341
These results appear inferior to those achieved with RT where the CR rate exceeds 95% and the relapse rate is <10% with doses of 30 Gy,132 although no direct comparison has even been done. Nonetheless, national and international guidelines call for initial therapy with antibiotics and close follow-up because of the simplicity of this approach and the slow growth of MALT lymphomas.24,314 RT is reserved for patients who are H. pylori negative or who fail antibiotic therapy. The same techniques utilized for gastric DLBCL apply. Doses of 25 to 30 Gy are adequate. Interestingly, the initial clone can be detected by PCR in the majority of patients after RT, despite durable clinical remissions.346
There is no apparent role for adjuvant chemotherapy in localized gastric MALT lymphoma. Rituximab has been used in patients not suitable for RT with promising but very short-term results.347 For patients with advanced disease, chemotherapy is not a curative modality and observation may be warranted if the patient is asymptomatic. In general, management of advanced MALT is similar to advanced FL.
Intestinal Lymphomas
Small intestinal lymphomas may comprise 20% to 30% of all GI lymphomas.318,320,336,348 The majority are B-cell lymphomas, predominantly DLBCL.318,349,350 DLBCL of the intestine is seen primarily in Western countries and resembles primary DLBCL of the stomach. The clinical presentation is usually with abdominal pain, anorexia, and weight loss. However, ileus or perforation is much more common than in gastric lymphoma, occurring in approximately 40% of the patients in the German series.320 Most patients have localized disease at onset, but the usual staging workup is appropriate. PET-CT should be performed, primarily for delineation of disease outside the intestinal tract and determination of the size of mass lesions in the intestinal tract. Intraluminal disease is probably better visualized with conventional barium studies.
Because of the frequent presentation with obstructive signs and symptoms, along with the complexity of establishing a diagnosis endoscopically, surgery is more commonly used, both for diagnosis and for therapy, than it is for gastric lymphoma. For surgically resected, localized intestinal lymphoma of the DLBCL type, anthracycline-based chemotherapy with rituximab should be given after surgery, as for localized DLBCL of other sites. For completely resected disease, adjuvant RT is probably not necessary. In the case of localized disease incompletely resected, some authorities recommend the addition of WAI,324 although more conformal fields may be used if the target region can be appropriately demarcated.
From 20% to 30% of patients with B-cell lymphomas of the intestine present with histologies other than DLBCL, primarily MALT, although Burkitt’s, mantle cell, and FL have all been observed.330,349,350–351 Mantle cell lymphoma has a propensity to present with multicentric involvement.350 Primary FL of the duodenum is a rare presentation of FL and may have a more favorable prognosis compared with nodal FL. Complete and durable remissions after RT have been reported and would be the standard treatment for a localized FL.351 Even with no treatment, distant dissemination is rare.
MALT intestinal lymphomas are not thought to be H. pylori related. They are managed primarily with RT. The role of chemotherapy is limited. Crump et al.324 recommend WAI for intestinal MALT after surgical resection with a dose of 20 to 25 Gy in 1- to 1.25-Gy fractions. Depending on the segment of intestine involved and the extent, less than WAI may also be used to similar doses (25 to 30 Gy). CT-based planning with field arrangements that limit dose to the kidneys and liver is critical. The technique of cross-table laterals for treatment of mesenteric adenopathy may be applicable. Precise data as to the prognosis of localized intestinal B-cell lymphoma are lacking. Underlying histology affects prognosis. MZL appears to have the best prognosis, as would be expected, while the prognosis for mantle cell lymphoma is poor. Lymphomas of the ileocecal region are more likely to present with obstruction, leading to surgical resection. This may lead to a better prognosis.350
T-cell lymphomas account for approximately 10% to 20% of all intestinal lymphomas, and multiple subtypes have been known to arise in the bowel, including extranodal NK/T-cell lymphoma, anaplastic large cell lymphoma, and γδ T-cell lymphoma. A distinct intestinal lymphoma entity in the WHO classification is enteropathy-associated T-cell lymphoma, which occurs primarily in the presence of celiac disease. This has also been described as malignant histiocytosis of the intestine, but it is now known to represent a T-cell lymphoma.352 Patients with celiac disease have an approximately 200-fold increased risk for development of intestinal T-cell lymphoma.72
The clinical presentation is similar to that described for B-cell intestinal lymphomas. Diarrhea is prominent, reported in approximately 40% of patients. Presentation with perforation or obstruction occurs in approximately 40% of patients.353 There is a greater tendency for these patients to have widespread bowel involvement. The diagnosis is usually established with laparotomy. After surgical resection, treatment has usually consisted of anthracycline-based chemotherapy. The outcome, however, has been poor, with 5-year survivals of 20% to 25%.349,353 These patients usually have a worse performance status and tolerate chemotherapy poorly. Intestinal perforation after chemotherapy is not unusual.
There are no reported results for RT. For patients with residual disease after surgery, it is possible that a protracted course of RT with small fractions followed by chemotherapy might reduce the frequency of intestinal perforation reported after conventional doses of CHOP. Field sizes and arrangements would be similar to those described for intestinal MALT. More dose is presumably required (30 to 40 Gy) but would be difficult to administer because of tolerance problems.
Immunoproliferative small intestinal disease (IPSID), also referred to as Mediterranean lymphoma, occurs mainly in young adults in the Middle East and North Africa.354 In Western series it is quite uncommon. IPSID is a B-cell lymphoma, believed to arise from the clonal proliferation of B lymphocytes that produce immunoglobulin-A (IgA heavy chain). C. jejuni has recently been shown to have an etiologic role. In its early stages, the disease responds to antibiotic therapy. The disease frequently affects the entire small intestine. Symptoms of malabsorption predominate. Treatment has usually consisted of chemotherapy.354,355 The prognosis has been poor, with survival rates not exceeding 20%. WAI has been reported to be useful in selected patients.354
Head and Neck Lymphomas
Head and neck lymphomas are the second most frequent variant of ENL after those of the GI tract, representing approximately 20% of all ENL.68,71,72,317,356,357 They occur in a variety of sites, including Waldeyer’s ring, the thyroid, salivary glands, nasal cavity, paranasal sinuses, and orbit, with differing histologic types and clinical characteristics depending on the site of origin. Most appear to be of B-cell origin and most of those are DLBCL. MZL is less common but constitutes a majority of salivary gland lymphomas. A special entity is that of nasal NK/T-cell lymphoma.140–142,358,359 This disease for a number of years was of uncertain cause but is now believed to represent a T-cell lymphoma. It went by many names in the past, including angiocentric lymphoma, lethal midline granuloma, midline malignant reticulosis, and polymorphic reticulosis, reflecting its uncertain etiology. The preferred terminology, however, is NK/T-cell lymphoma.
Lymphomas presenting in Waldeyer’s ring typically involve the tonsil, base of tongue, or nasopharynx. The clinical symptoms are those associated with epithelial tumors in those sites, such as dysphagia, sore throat, nasal congestion, and eustachian tube blockage. The lesions are frequently clinically apparent on thorough head and neck examination. Neck adenopathy is common.
The usual lymphoma staging studies are appropriate, including CT or PET-CT scans of head and neck, chest, and abdomen and bone marrow examination. MRI may be necessary for precise anatomic delineation. There is a predilection for Waldeyer’s ring lymphomas to have GI tract involvement as well, so direct imaging (i.e., upper GI series or endoscopy) is indicated. Most cases are stage I or II after full staging evaluation.
The pathologic type is usually DLBCL. The treatment guidelines are those for nodal stage I and II DLBCL. Older series report results of RT alone: 50% survival rates in patients with stage I disease and 25% to 50% in stage II, but more often the former number, results clearly suboptimal.356,360 Consequently, almost all centers now report the use of CMT, 3 to 6 cycles of CHOP followed by IFRT. Again R-CHOP would now be the preferred combination. Retrospective analyses show an improvement in survival rates to approximately 80% for patients with stage I disease and 50% for those with stage II disease after CMT.356,361 Even better results would be expected today with the use of R-CHOP.
The one phase III study is that of Aviles et al.,362 who randomized 316 patients to RT alone, CMT, or chemotherapy alone. Although a CR was achieved in over 90% of patients in all three groups, relapses were frequent for the single-modality arms. The 5-year survival rate was approximately 90% in the CMT arm versus approximately 50% for the chemotherapy and RT alone arms.
Paranasal sinus and nasal cavity lymphomas are often grouped together but in reality appear to have a different prognosis and should be discussed separately. Most paranasal sinus tumors are B cell in origin and usually present in men in the sixth or seventh decade. The outlook when treated with RT alone seems to be particularly poor for both stage I and II disease, with 12% long-term survival in the Stanford University series and approximately 30% in an MD Anderson Cancer Center report.363,364 Some authors have described a predilection for CNS spread;363 others have not found this to be the case.142,364 In any event, the outlook improves markedly when patients are treated with CMT. In the MD Anderson Cancer Center report, FFS approximately doubled from 34% to 63% at 10 years with the addition of chemotherapy to RT.364 With CMT, survival rates in the range of 70% to 80% are expected, similar to those seen in other sites. CNS prophylaxis for these patients is controversial. In the MD Anderson Cancer Center series, only 1 of 70 patients relapsed in the CNS.364
Nasal cavity lymphomas, on the other hand, appear to be of predominantly T-cell origin and fall into the category of NK/T-cell lymphomas. They are seen more commonly in Asia and Central and South America. The disease affects primarily men, mostly in the fifth decade. It often presents as a destructive necrotizing process. Because of this, histologic diagnosis may be difficult. The disease appears to progress primarily locally with only a small predilection for regional or systemic failure.141 Treatment approaches have consisted of RT alone, chemotherapy alone, and the two combined. With RT alone, approximately two-thirds of patients achieved CR,141,142,358 but half of those relapsed. The prognosis appears somewhat worse for stage II than stage I.142
The contribution of chemotherapy to the management of NK/T-cell lymphoma is unclear. When treated initially with chemotherapy, CR occurs in only a minority of patients,142,143,145,365 in contrast to the results seen with most other head and neck lymphomas. Recently, Japanese and Korean investigators have reported the use of concurrent chemotherapy and radiation with encouraging results.366,367 The Japanese series used concurrent dexamethasone, etoposide, carboplatin, and ifosfamide with a dose of 50 Gy. The CR rate was 77% and the 2-year survival rate was 78% compared with historical controls of 45%.366 The Korean series employed concurrent cisplatin and radiation, with the dose of the latter 40 to 50 Gy, followed by 3 cycles of cisplatin, dexamethasone, ifosfamide, and etoposide. The CR rate was 83% and the 3-year survival rate was 86%.367 In both series, the number of patients is small (33 and 30 patients, respectively), but the results are quite promising and worthy of further study. The large experience with concurrent cisplatin and radiation in head and neck carcinomas argues for the feasibility of this approach in nasal type NK/T-cell lymphomas.
In contrast to most other head and neck lymphomas, salivary gland lymphomas are frequently of a more indolent histologic type (i.e., MZL).368 In Asian countries, the percentage of MZL may be lower. These patients usually present with painless enlargement of the parotid gland. There is an association with Sjögren syndrome.357 Treatment usually consists of RT alone. The prognosis is excellent, with survival >90%.357,368 One small randomized trial explored the use of chemotherapy in addition to RT.369 In this trial, 5-year survival rates of 90% were achieved with RT alone or with CMT. These data are consistent with the lack of improvement shown for the addition of chemotherapy to RT for MZL in other sites, as well as the lack of benefit for chemotherapy in addition to RT in localized FL.
There are occasional patients with salivary gland lymphomas presenting with bilateral paired organ involvement (e.g., both parotid glands). When the histologic type is MZL, such patients, although not stage II in the conventional sense, appear to do quite well with localized RT directed to both parotids.
The appropriate radiation dose for head and neck lymphomas may be derived from the general principles of lymphoma treatment. For DLBCL, which in almost all instances will be treated initially with R-CHOP or similar combinations, patients achieving CR should receive 30 Gy consolidation (2 Gy per fraction). Less information is available for those not achieving CR. Doses from 30 to 40 Gy are reasonable. For NK/T-cell tumors, few data are available. The authors recommend a dose of 40 to 50 Gy in combination with chemotherapy. The NCCN guidelines recommend a dose of at least 50 Gy. Indolent histologies involving the head and neck should be treated with RT alone to a maximum of 30 Gy.
The field size is involved region with a generous margin without prophylactic nodal radiation. IMRT should be utilized in most patients to maximize parotid sparing as well as shielding to the minor salivary glands. Lymphoma patients may have unusual susceptibility to xerostomia.370
Cutaneous Lymphomas
The term primary cutaneous lymphoma (PCL) is used to define those lymphomas that present in and are confined to the skin without evidence of extracutaneous disease. Including mycosis fungoides (discussed in Chapter 79), PCL is the third most common ENL, closely following GI and head and neck lymphomas. PCL is a relatively unique type of lymphoma whose clinical behavior seems to be governed more by presentation in the skin than by its histologic appearance, in contrast with most other lymphomas, where the histopathologic appearance predicts the clinical behavior. Further, where in the skin the disease originates may have a significant bearing on outcome. DLBCL originating on the legs has a much worse outlook than that originating on skin surfaces elsewhere.146,371 The biologic explanation for this phenomenon is unknown.
PCL is an uncommon entity with an overall incidence of 1 to 1.5 per 100,000. Separate pathologic classifications were devised by the European Organisation for Research and Treatment of Cancer (EORTC)372 and WHO48 but have recently been reconciled (Table 78.9).373 About 75% of all PCL is of T-cell origin and 25% of B-cell origin. Most cutaneous T-cell lymphomas are mycosis fungoides.
Most other cutaneous T-cell lymphomas consist of the closely related categories of LyP and primary cutaneous ALCL. LyP and cutaneous ALCL have overlapping clinical, histologic, and immunophenotypical characteristics. They are characteristically referred to as CD30-positive lymphoproliferative disorders. The largest reported experience is from the Dutch Cutaneous Lymphoma Group.146 These authors described 219 patients in the period 1983 through 1998, approximately equally divided between LyP and cutaneous ALCL. The distinction between the two was often difficult, but both had an excellent prognosis. The disease is almost invariably confined to the skin. Only 2% of patients with LyP and 4% of those with cutaneous ALCL died of lymphoma. This has implications for initial staging, where some authorities discourage imaging studies looking for systemic disease.374 LyP is often generalized (in the skin), and spontaneous remissions are a characteristic feature and an important clue as to diagnosis. Cutaneous ALCL, on the other hand, is localized or regional in approximately 80% of cases.
TABLE 78.9 WORLD HEALTH ORGANIZATION–EUROPEAN ORGANISATION FOR RESEARCH AND TREATMENT OF CANCER CLASSIFICATION OF CUTANEOUS LYMPHOMAS
The treatment of choice for cutaneous ALCL is local radiotherapy. A dose of 40 Gy is generally recommended.146 About 40% of patients will relapse elsewhere in the skin but may often still be sufficiently localized so they can be treated again with radiation. As stated above, death from lymphoma is infrequent. LyP, if it can be distinguished from cutaneous ALCL, should be left untreated as spontaneous regression is a characteristic feature. There is generally no role for chemotherapy for cutaneous ALCL, although a variety of agents have been tried for LyP that is sufficiently symptomatic to require treatment. The natural history of LyP and its tendency for spontaneous regression makes evaluation of various chemotherapeutic agents quite problematic.374
As mentioned previously, there is a difference between cutaneous ALCL arising in the skin and ALCL that originates elsewhere. The latter has a highly variable course depending on whether the ALK protein is overexpressed. ALK-negative patients have a worse outlook. ALCL in the skin, however, is ALK negative, with the determining factor in biologic behavior the site of origin.
Cutaneous B-cell lymphoma comprises about 25% of skin lymphomas. In the new WHO-EORTC classification, it is divided into primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous large cell lymphoma, leg type (PCLBCL-LT).373,375 The term diffuse large B-cell lymphoma of the skin is no longer used; these patients are now included in the PCFCL group, which also contains follicular lymphoma of the skin. An unusual feature of a minority of cases of PCMZL is the association with B. burgdorferi infection, in which case the disease may respond to antibiotics.21
Both PCFCL and PCMZL have an excellent prognosis. The treatment of choice is RT, with the dose of 40 Gy for the former and 30 Gy for the latter, as for MZL elsewhere. The 5-year disease-specific survival for both conditions exceeds 95%.371,373,375 Adjuvant chemotherapy is not recommended.
PCLBCL-LT, however, has a much worse prognosis with a cause-specific survival of about 50% at 5 years. In addition to local radiation, chemotherapy with R-CHOP is usually recommended, although it is not clear if this favorably influences outcome.371,376
Orbital Lymphomas
Lymphomas of the eye may involve either the extraocular orbital tissues such as the conjunctiva, retrobulbar region, or lacrimal gland, or may involve the globe itself. The latter condition is referred to as primary intraocular lymphoma and is, in essence, a subset of PCNSL in which lymphoma cells are initially present only in the eyes, without evidence of disease in the brain or other CNS tissues.377 Its management is essentially that of PCNSL, which is discussed later.
Orbital lymphomas comprise approximately 4% of all ENL. They typically arise in superficial tissues such as conjunctiva and eyelids and are most commonly seen in an older population, with a median age of approximately 60 years.72 Histopathologically, approximately two-thirds of these tumors are MZL. Most of the remainder are DLBCL.
Patients typically present with mass lesions in the conjunctivae or lids, described in the literature as “salmon pink” in color. Tumors of the retrobulbar region may present with swelling and proptosis and associated disturbances in function of the extraocular muscles. Bilaterality is not unusual, occurring in 10% to 15% of cases. Similar to salivary gland and skin tumors, this does not adversely affect prognosis.
The usual staging studies for systemic disease should be performed. MRI of the orbit should be done to delineate precisely the anatomic extent of disease for RT planning purposes.
The treatment principles for lymphomas generally apply. MZL is treated with RT alone. No more than 30 Gy is required for local control. Doses of 20 to 30 Gy have been reported as equally effective.378,379–381 The BNLI study provides support for doses at the lower end of this range.163 Local control exceeds 95% as does 5-year cause-specific survival. Most series report about 20% of patients relapsing, almost always at distant sites. There is, however, no established role for adjuvant chemotherapy or rituximab.
Field arrangements are somewhat controversial. Some authors suggest the entire orbit be treated to avoid marginal misses.378,380 This may be done with a single anterior field or a wedged pair. Three-dimensional planning and IMRT may be helpful. A lens shield is often used to prevent cataracts, but this may increase marginal misses. With whole-orbital doses of 20 to 30 Gy, cataract formation is the principal risk, occurring in 20% to 30% of patients.380Some dryness may result from inclusion in the field of a portion of the lacrimal gland and meibomian glands. As mentioned, orbital MZL may involve both eyes at presentation. Under these circumstances, RT alone remains the treatment of choice, with careful attention to treatment planning and prescribed dose to minimize eye complications.
Orbital MZL has recently joined the group of MZL’s associated with infectious agents, in this instance C. psittaci.25 A trial of antibiotic therapy has been suggested for patients in whom this organism is identified,382 but a meta-analysis has shown highly variable results of antibiotic therapy, with an overall incidence of C. psittaci of 23%.130 It has also been suggested that observation only is a reasonable strategy. In a Japanese series of 36 patients, 70% did not require treatment with a median follow-up of 7 years.383 However, radiotherapy remains the standard of care.
A much smaller percentage of patients (10% to 30%) presents with orbital disease that is DLBCL. The prognosis in the literature in the past has been poor—a 33% survival rate in Florida, and 50% at the Royal Marsden Hospital with RT alone.384,385 The treatment of choice is CMT, R-CHOP followed by IFRT. After CR to chemotherapy, the appropriate dose of RT is no more than 30 Gy. It is particularly important to minimize dose to the eye to avoid late complications. With this program, cure rates of 80% would be expected and have been reported.386
Extranodal Lymphomas of Other Sites
In addition to the areas previously described, NHL may arise in almost any organ or tissue of the body, including but not limited to bone, testis, ovary, kidney, bladder, female genital tract, breasts, and lung. Lymphoma in any of these sites is quite uncommon. General principles of evaluation and management apply. Accurate histopathologic diagnosis is essential, followed by full staging workup with treatment decisions governed by stage and histopathologic diagnosis.
A few brief comments regarding the special features of testicular, bone, breast, and lung lymphomas are appropriate. Testicular lymphoma is rare, accounting for approximately 2% to 3% of all ENL and <1% of all NHL.387,388,389It presents typically in elderly men in their seventh and eighth decades. Most patients have stage I or II disease. The histologic type is typically DLBCL. Approximately one-fourth of patients have stage IV disease at presentation, with a predilection for unusual sites of involvement such as CNS, skin, and lung. In most reported series, patients have been treated in a variety of ways because of the rarity of the disease and the long period over which cases are collected from any one institution.
The disease is typically diagnosed by orchiectomy. In the past that was frequently followed by RT to pelvic and para-aortic nodes in a fashion similar to that for testicular carcinoma. Such treatment programs were notably unsuccessful, with probably <20% OS.389 The introduction of CHOP combined with RT and surgery did not improved matters much. Treatment programs of surgery, CHOP, and RT have still resulted in only an approximately 30% long-term survival.390,391 There is a high predilection for both contralateral testis relapse as well as CNS relapse, with some 30% to 40% of patients failing in these sites as well as other generalized sites.389,392,393
Accordingly, more recent treatment programs have advocated the use of CNS prophylaxis coupled with prophylactic RT to the contralateral testis and sometimes pelvic and para-aortic nodes. The IELSG recently reported a multi-institutional series of 53 stage I or II patients treated with R-CHOP, 6 to 8 cycles, prophylactic intrathecal methotrexate, and radiotherapy to the contralateral testis and para-aortic and pelvic nodes in the case of stage II patients.76Five-year survival and PFS were 85% and 74%, respectively. In a previous IELSG study, both survival and PFS were about 50% at 5 years and declined further at the 10-year mark.393 The rarity of testicular lymphoma most likely precludes phase III trials.
ENL of bone is another uncommon entity, representing <5% of all ENL.394–396 Patients tend to be somewhat younger, with a median age in the fifth decade. The long bones are primarily affected. The presenting signs and symptoms are usually local bone pain, with or without soft tissue swelling, and occasionally a palpable mass lesion or a pathologic fracture. Approximately two-thirds to three-fourths of patients have stage I and II disease at presentation, with the remainder having stage IV disease. A recent large series from British Columbia showed 50% of patients with stage IV disease and equal involvement of long bones and spine.397 Histopathologically, 70% to 90% of patients have DLBCL.394 Staging studies should include the usual workup for systemic disease. MRI to determine the extent of disease in the bone in limited stage patients should be performed as well.
The disease is managed similarly to stage I or II NHL of other sites. Thus, for DLBCL therapy is initiated with R-CHOP followed by involved field RT. Although a dose of 30 Gy is appropriate for patients achieving CR, that determination may be difficult in bone disease. The normal reparative processes may cloud the imaging determination of a CR. Therefore, the authors often use 40 Gy consolidative RT but try and avoid this dose to entire joints because of the risk of avascular necrosis. Treatment volume should include the original tumor volume as determined by MRI with a margin of several centimeters. Radiation of the entire bone is probably unnecessary. FFS and OS are high, 85% to 95% in a recent series.396
Another quite uncommon variety of ENL is that arising in the lung.398,399 Although secondary involvement in the lung in NHL is common, primary involvement in the lung represents approximately 1% of all ENL presentations. The prognosis of primary lung lymphoma is good, because these are primarily MZL. They are known as BALT tumors because they arise from bronchus-associated lymphoid tissue. Five-year survival rates in the range of 90% have been reported from the Mayo Clinic and a large French series.398,400
Patients usually present with an asymptomatic abnormality on chest radiograph. It is difficult to obtain sufficient tissue at bronchoscopy with bronchial washings or with fine-needle aspirate to establish the diagnosis. An open procedure, either thoracoscopy or thoracotomy, is usually required. Most of the reported patients in the literature have been treated with surgical resection, sometimes followed by chemotherapy. There are very few patients reported treated with radiation, either alone or in combination with surgery and chemotherapy. Excellent local tumor control would be predicted for RT, however, in modest doses typical for MZL. It is therefore the treatment of choice in unresectable BALT lymphoma or where the extent of pulmonary resection would significantly compromise lung function. If only a small amount of lung needs to be surgically removed to encompass the tumor, surgical resection may carry less morbidity than RT.
The role of chemotherapy in BALT lymphoma is not well studied but would be predicted to be quite similar to that in MALT or FL—that is, the disease is chemotherapy responsive, with no data to suggest that the natural history is altered or survival prolonged by initiation of chemotherapy at diagnosis.
A small percentage of pulmonary lymphomas are DLBCL. These should be managed in accordance with the accepted principles of management of DLBCL, namely, R-CHOP. If the disease has been completely resected to establish the diagnosis, no additional RT appears necessary. If resection has not been accomplished, R-CHOP should be followed by RT, with the dose chosen reflecting the adequacy of response to R-CHOP. The treatment volume is problematic. A balance should be struck between treatment of the original tumor volume, which could conceivably involve a large amount of normal lung, and treatment of the postchemotherapy tumor volume, where the disease may all have disappeared.399
Breast is another quite uncommon primary site for lymphoma but with some unusual characteristics. Most cases are DLBCL, but FL and MZL have been reported as well. Most data are derived from two retrospective IELSG series reporting on DLBCL and indolent lymphomas involving the breast, respectively.74,401 For the DLBCL group treated largely with CHOP and radiation without rituximab, 5-year survival was 63%. Although some have reported a tendency for CNS relapse, which was not seen in the IELSG series, and CNS prophylaxis was not done. There was a tendency for opposite breast relapse as well as systemic failure. Appropriate treatment presently would consist of R-CHOP and radiotherapy to the whole breast, with a dose of 30 Gy for patients in CR. Mastectomy is unnecessary. For patients with indolent histologies, radiotherapy alone, with a dose of 26 to 30 Gy, is indicated without systemic therapy and without mastectomy.
Primary Central Nervous System Lymphoma
PCNSL is a rare form of extranodal NHL but with increasing incidence. From 1973 to 1992, the estimated frequency of brain lymphoma increased more than 10-fold, from 2.5 to 30 cases per 10 million population.402 This increase is, only partially, attributable to HIV-associated cases, with a significant rise in immunocompetent patients. The median age at presentation is 55 years for immunocompetent patients and 31 years for patients with AIDS. Neurologic symptoms are usually of brief duration, 3 months or less. Specific neurologic deficits depend on tumor location. Generalized symptomatology such as altered mental status, seizures, and symptoms of increased intracranial pressure such as headache, nausea, and vomiting may occur. Immunocompetent patients are more likely to have localized neurological deficits in contrast to patients with AIDS who more often have diffuse disease with generalized symptomatology.403,404
Radiologic imaging often suggests a diagnosis. PCNSL is usually isodense or hyperdense on nonenhanced CT scans, in contradistinction to other primary brain tumors or metastatic lesions. The preferred imaging modality for PCNSL is MRI, which can detect up to 10% of lesions missed by CT. Lesions appear isointense to hypointense on T1-weighted images and approximately 50% are hyperintense on T2-weighted imaging. Homogeneous contrast enhancement is commonly seen in immunocompetent patients.405 Despite the appearance of a focal mass on CT or MRI, diffuse parenchymal infiltration is underestimated by imaging. The location of the lesion may also suggest the diagnosis as the majority of PCNSLs occur in a periventricular distribution, involving the corpus callosum, thalamus, or basal ganglia. In patients with HIV infection, disease is often multifocal in the brain and may be difficult to distinguish from CNS infections.403
At diagnosis, although most patients with PCNSL have a solitary brain lesion, the presence of leptomeningeal and ocular involvement is seen in approximately one-third and 20% of cases, respectively. Evaluation of these areas is indicated, including lumbar puncture (if the intracranial pressure is not increased and it can be done safely) and full ophthalmologic evaluation of the eye. Staging to evaluate for extracranial disease is often done, although additional disease outside the CNS is rarely found.403,406 In the absence of specific signs or symptoms suggesting presence of extracranial disease, staging is of limited value.
The role of surgery in the management of PCNSL is limited to establishing the diagnosis, preferably by stereotactic biopsy. Corticosteroids, commonly used to alleviate symptoms including intracranial pressure, have a direct antitumor effect.406 Tumor regression may lead to difficulties in establishing diagnosis. Accordingly, steroids should be withheld, if possible, until after biopsy, if the diagnosis of lymphoma is suspected. PCNSL is usually not amenable to surgical resection due to deep location and involvement of critical structures. Occasionally, surgical decompression and shunt placement is necessary for relief of increased intracranial pressure. Cerebrospinal fluid (CSF) analysis, including immunoglobulin gene rearrangement studies, can identify clonal populations to establish the diagnosis of PCNSL.407
The histologic appearance of PCNSL in an immunocompetent patient is typically that of DLBCL. Further, immunophenotyping suggests the tumor is the same as DLBCL occurring outside the nervous system, raising the question as to why it responds so differently to therapy, a question that remains unanswered.408 In HIV-positive patients, aggressive or high-grade histopathologic pictures are common. In addition, the tumor is virtually always associated with EBV.409 EBV is rare in immunocompetent patients with PCNSL.
Almost all studies reveal age and performance status to be important independent prognostic factors. Patients <60 years had a 42% survival in the Princess Margaret series compared with 9% for those >60 years. A prognostic model developed at Memorial Sloan-Kettering Cancer Center from 338 patients with PCNSL incorporates age and Karnofsky performance status, dividing patients into three prognostic classes.410 The IELSG has also reported elevated LDH, increased CSF protein, and tumor location within the deep regions of the brain as significant prognostic variables.410–411,412
The management of PCNSL has evolved over recent years. Historically, the treatment was whole-brain radiotherapy (WBRT) alone to address the disease’s multifocal nature. Results were poor, however, despite the known radiosensitivity of NHL outside the CNS. Two representative series from the Radiation Therapy Oncology Group (RTOG) and Princess Margaret Hospital report median survivals of 12.2 months and 17 months, respectively, and 5-year survivals of 10% to 20%.413,414 Although the tumor initially responds to RT, regrowth is common and uncontrolled disease in the brain is the primary cause of death. Attempts at dose escalation beyond 50 Gy resulted in high toxicity rates without survival improvement in RTOG-8315, and a dose of 40 to 50 Gy was recommended.414
Given the poor results achieved with RT alone and the chemoresponsiveness of lymphomas generally, evaluation of systemic chemotherapy for PCNSL was soon undertaken. Initial programs consisted of CHOP and variations on that combination. Despite the efficacy of this combination in NHL outside the CNS, the results in PCNSL have been quite disappointing. A randomized trial by the Medical Research Council showed no benefit for CHOP added to RT.415 Other studies have come to similar conclusions. This lack of efficacy may be due to the failure of many drugs to penetrate the blood–brain barrier (BBB).
Methotrexate (MTX), particularly in high doses, is known to penetrate the BBB. It was first used for treatment of PCNSL in 1980, with subsequent use becoming widespread.403 There has been much variability in dosage, scheduling, and combinations with intrathecal MTX and other cytotoxics such as cytarabine, vincristine, or thiotepa. MTX appears to represent an important advance. The phase II RTOG-9310 study treated patients with combination chemotherapy, including high-dose MTX, and WBRT. The 5-year OS was 32% and the FFS 25%, results better than historically obtained with RT alone.416
A recent phase III noninferiority trial from Germany treated 550 patients with high-dose MTX and subsequent randomization to WBRT or no further therapy. WBRT was delivered to a dose of 45 Gy in 1.5-Gy daily fractions. There was no significant difference in median overall survival in the treatment arms, 32 months in MTX plus WBRT arm and 37 months in the chemotherapy-alone arm (estimated 5-year OS was 25% to 30%). However, 2-year PFS was 43.5% in the WBRT group and 30.7% in the group not receiving WBRT; this may represent a clinically significant advantage in selected populations. Neurotoxicity data were collected from a subset of patients in the WBRT arm. Forty-nine percent of patients in the WBRT arm experienced clinically defined neurotoxicity after a median of 20 months and 71% had evidence of delayed neurotoxicity as assessed by CT or MRI at a median of 50 months. The potential advantage in PFS must be balanced against the higher rates of neurotoxicity in the WBRT arm by clinical and radiographic assessment.417 Criticisms of this trial include poor protocol adherence, randomization caveats, low statistical power, and prolonged accrual time, leaving the question of consolidation WBRT unanswered.418 In addition, the inferior survival in the WBRT arm may be a function of neurotoxicity-associated death due, in part, to high radiation doses.
The Memorial Sloan-Kettering Cancer Center group evaluated 57 patients treated with MTX-based chemotherapy followed by selective WBRT to 45 Gy. Of the entire cohort, 30% of patients developed treatment-related neurotoxicity. Thirty-five patients received WBRT as salvage or initial therapy and 16 (46%) developed treatment-related neurotoxicity.419 In a series of 226 patient with PCNSL (162 received WBRT), a 26% rate of severe neurotoxicity was seen at 6 years.420
Neurologic complications can arise as early as 3 months posttreatment with symptoms of attention deficit, memory impairment, ataxia, and urinary incontinence and could ultimately lead to dementia.421 It is difficult to determine the precise incidence, because actuarial complication rates are seldom reported.
An additional multi-institutional retrospective series reported a 30% 5-year actuarial rate of neurotoxicity overall, while patients >60 years had a 58% risk of neurotoxicity at 7 years.422 Given higher neurologic toxicity rates in the elderly, many institutions treat this subset of patients with chemotherapy alone.423,424
In an effort to reduce neurologic complications, radiation dose reduction has been investigated. Bessell et al.425 reduced RT dose to 30 Gy in 26 patients who had achieved CR to chemotherapy. The 3-year overall survival was 92% versus 60% for a retrospective comparison group receiving 45 Gy plus a 10 Gy boost. This series, however, utilized eight drugs with a MTX dose of 1.5 g/m2 and delivered the 30.6 Gy of RT over 5 weeks.
Recently the Memorial Sloan-Kettering Cancer Center group has reduced the dose to 23.4 Gy for patients achieving CR to rituximab and MTX-based chemotherapy with promising short-term results. Two-year OS and PFS were 67% and 57%, respectively. With a median follow-up of 37 months, no treatment-related neurotoxicity was observed.426
In a recent phase II Italian trial, patients <60 years old received high-dose MTX and were randomized to cytarabine or no further chemotherapy. Patients who developed a CR were consolidated with WBRT to a dose of 36 Gy in both arms.427 The addition of cytarabine appeared to improve clinical outcomes.
Future areas of research include additional chemotherapeutic drugs in combination with high-dose MTX. Regimens including cytarabine and rituximab have been reported in the literature.426,427 Rituximab appears to be a reasonable addition to the chemotherapy regimen, given its efficacy in systemic DLBCL.
HDC with ASCT has also been evaluated. Soussain et al.428 reported a 96% CR after HDC and ASCT. Two-year OS was 45% among the entire cohort and 69% among the 27 patients undergoing HDC and ASCT. Additional studies have evaluated the use of HDC and ASCT, many in combination with WBRT, in newly diagnosed PCNSL.429–434 Currently, a randomized trial for patients <60 years old comparing WBRT or HDC-ASCT as consolidation after high-dose MTX is ongoing.421
Thus, the treatment of PCNSL remains unsettled with few phase III trials. High-dose MTX, >3 g/m2 every 2 to 4 weeks, is the cornerstone of therapy. Whether doses >3 g/m2 are helpful is unresolved. The addition of other drugs and the role of stem cell transplant remain controversial. The role of WBRT after high-dose MTX is especially controversial, particularly in patients achieving a CR and in those >60 years old. It seems clear that 45 Gy WBRT results in unacceptable toxicity in older patients and perhaps in younger ones as well. Given the overall unsatisfactory results of therapy, the addition of low-dose RT (24 Gy) to chemotherapy for patients achieving a CR is a promising approach.
CONCLUSION
Radiation therapy continues to play an important role in the management of NHL. Participation by radiation oncologists in the multi-disciplinary management of patients with these disorders is vital. This requires a sound understanding of the natural history and optimal treatment approach for each of the many NHL subtypes.
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