Between 1950 and 1999, the incidence of non-Hodgkin's lymphoma (NHL)rose by 90% in the United States, representing one of the largest increases ofany cancer. Some of this increase may be artifactual, resulting from improveddiagnostic techniques and access to medical care, or directly related to thedevelopment of NHL in 25- to 54-year-old men with human immunodeficiencyvirus (HIV) infection. However, additional factors must be responsiblefor this unexpected increase in frequency of NHL that has been observedthroughout the United States.
Between 1950 and 1999, the incidence of non-Hodgkin's lymphoma (NHL)rose by 90% in the United States, representing one of the largest increases ofany cancer. Some of this increase may be artifactual, resulting from improveddiagnostic techniques and access to medical care, or directly related to thedevelopment of NHL in 25- to 54-year-old men with human immunodeficiencyvirus (HIV) infection. However, additional factors must be responsiblefor this unexpected increase in frequency of NHL that has been observedthroughout the United States.The incidence of NHL per 100,000 persons has risen from 8.8 in 1972-1974 to19.1 in 1995-1999 (all histologic subtypes) in the United States. The increaseshave been more pronounced in whites, males, and the elderly, and rates haverisen more rapidly in rural than urban areas, although NHL is historicallymore common in urban than in rural areas. Similar findings have been reportedin other developed countries. NHL rates have decreased amongAmerican males aged 25 to 54 years in the middle to late 1990s (6%-16% peryear), although this may be in part due to improved HIV treatment.Currently, NHL represents approximately 4% of all cancer diagnoses (4% inmales and 4% in females), being the fourth most common cancer in womenand fifth in men. Estimates from the American Cancer Society indicate that in2005, some 56,390 new cases of NHL will be diagnosed in the United Statesand approximately 19,200 people will die of this disease.EpidemiologyGender The overall incidence of lymphoma is higher in men than in women.The incidence rate (per 100,000 population) between 1995 and 1999 was 50%higher in males (23.9) than in females (15.8). Only thyroid NHL is morecommon in women than in men.Age Overall, NHL incidence rises exponentially with increasing age. In personsolder than age 65, the incidence is 68.0 per 100,000 population. Exceptfor high-grade lymphoblastic and Burkitt's lymphomas (the most commontypes of NHL seen in children and young adults), the median age at presentationfor all subtypes of NHL exceeds 50+ years. Low-grade lymphomasaccount for 37% of NHLs in patients between the ages of 35 and 64 years atdiagnosis but for only 16% of cases in those younger than age 35.Race Incidence varies by race, with whites at higher risk than blacks andAsian-Americans (incidence rates increased 40%-70% in whites comparedwith blacks). Most histologies, particularly low-grade small lymphocytic andfollicular lymphomas, are more common in whites than in blacks. Only peripheralT-cell lymphoma is higher in blacks than in whites.Geography NHL is most common in developing countries, with the UnitedStates having the highest rate worldwide. The lowest NHL rates are found inChina and Thailand (2-3 per 100,000 population). Certain endemic geographicfactors appear to influence the development of NHL in specific areas.HTLV-1-associated NHL Human T-cell lymphotrophic virus-1 (HTLV-1)-associatedadult T-cell lymphoma/leukemia (ATLL) occurs more frequently whereHTLV-1 is endemic, in southern Japan and the Caribbean and occurs sporadicallyin Brazil, sub-Saharan Africa, the Middle East, and southeasternUnited States. The seroprevalence in southwest Japan is 16%, although thelifetime risk of ATLL for these persons is 2%-6%.Burkitt's lymphoma in Africa The incidence (per 100,000 population) of Burkitt'sNHL in Africa (Nigeria and Tanzania) is 6-8, as compared with 0.1 in theUnited States. The clinical features of Burkitt's lymphoma in Africa differfrom those of cases reported to the American Burkitt's Lymphoma Registry.Etiologic endemic factors include malaria as a source of chronic B-cell antigenicstimulation and Epstein-Barr virus (EBV)-induced immortalization ofB lymphocytes.Immunoproliferative small intestinal disease (α-chain disease) Heavy-chain diseaseis a disorder of B-lymphoid cells characterized by diffuse thickening of thesmall intestine due to a lymphoplasmacytic infiltrate with secretion of incompleteIgA heavy chains. This clinicopathologic entity is rarely encountered inindividuals other than those of Mediterranean ethnic origin.Follicular lymphomas are more common in North America and Europe but arerare in the Caribbean, Africa, China, Japan, the Middle East, and Latin America.Peripheral T-cell lymphomas are more common in Europe and China than inNorth America. They represent 7%-12% of lymphomas in Western countries.Disease site Malignant lymphomas are a heterogeneous group of neoplasmsthat usually arise or present in lymphoid tissues, such as lymph nodes, spleen,and bone marrow, but they may arise in almost any tissue. The most frequentsites for extranodal lymphomas, which constitute about 20%-30% of all lymphomas(peripheral T-cell NHL 80%; extranodal, follicular 9%), are the stomach,skin, oral cavity and pharynx, small intestine, and central nervous system(CNS). Although primary CNS lymphoma is rare, there has been a threefoldincrease in incidence, even if patients with HIV infection and other types ofimmunosuppression are excluded.Survival The 5-year relative survival rate of patients with NHL increasedfrom 28% between 1950 and 1954 to 55% between 1992 and 1998. Theseimprovements in survival occurred mainly in patients with intermediate/high-grade histologies. The potential for cure varies among the differenthistologic subtypes and is directly related to stage at presentation and responseto initial therapy. The natural history (survival rates for indolentlymphomas) has been unchanged from the 1950s to the early 1990s, althougha recent analysis from Iowa shows a potential change in survival trends.Etiology and risk factorsChromosomal translocations and molecular rearrangements Nonrandomchromosomal and molecular rearrangements play an important role in thepathogenesis of many lymphomas and correlate with histology andimmunophenotype (Table 1). The most commonly associated chromosomalabnormality in NHL is the t(14;18)(q32;q21) translocation, which is found in85% of follicular lymphomas and 28% of higher grade NHLs. This translocationresults in the juxtaposition of the bcl-2 apoptotic inhibitor "oncogene" atchromosome band 18q21 to the heavy-chain region of the immunoglobulinlocus within chromosome band 14q32.The t(11;14)(q13;q32) translocation results in overexpression of bcl-1 (cyclinD1/PRAD 1), a cell-cycle-control gene on chromosome 11q13, and has adiagnostic, nonrandom association with mantle cell lymphoma. Thet(3;16)(q27;p11) translocation makes the gene for the IL-2 (interleukin-2)receptor a partner of bcl-6, which is expressed in diffuse large cell lymphoma.Chromosomal translocations involving 8q24 lead to c-myc deregulation andare frequently seen in Burkitt's and Burkit's-like lymphomas, including thoseassociated with HIV infection.Environmental factors also may play a role in the development of NHL.Occupations Certain workers have a slightly increased risk of developing NHL,including farmers; pesticide applicators; grain (flour) millers; meat workers;wood and forestry workers; chemists; painters; mechanics; machinists; printers;and workers in the petroleum, rubber, plastics, and synthetics industries.Chemicals that have been linked to the development of NHL include a varietyof pesticides and herbicides (2,4-D-organophosphates, chlorophenols),solvents and organic chemicals (benzene, carbon tetra-chloride), wood preservatives,dusts (wood, cotton), and some components in hair dye.Chemotherapy and radiotherapy Patients who receive chemotherapy and/or radiationtherapy are also at increased risk of developing NHL.Viruses Several viruses have been implicated in the pathogenesis of NHL,including EBV; HTLV-1; Kaposi's sarcoma-associated herpesvirus (KSHV,also known as human herpesvirus 8, or HHV-8); and hepatitis C virus (HCV).Meta-analyses have shown 13%-15% HCV seroprevalence in certain geographicregions among persons with B-cell NHL.EBV is a DNA virus that has been associated with Burkitt's lymphoma, particularlyin endemic areas of Africa; Hodgkin's lymphoma; lymphomas in im
munocompromised patients (ie, organ transplantation and HIV infection);sinonasal lymphoma (Asia and South America); and sporadically in otherB- and T-cell lymphomas. In contrast to studies performed in Europeanpatients, Mexican patients with intestinal lymphomas show a high frequencyof EBV positivity; this finding is not limited to T-cell NHLs but rather includesa significant portion of B-cell NHLs. EBV can transform lymphocytesin culture. B lymphocytes from normal EBV-positive subjects grow as tumorsin mice with severe combined immunodeficiency.HTLV-1 is a human retrovirus that establishes a latent infection via reversetranscription in activated T-helper cells. A minority (5%) of carriers developATLL. An HTLV-1-like provirus has been detected in some patients withmycosis fungoides, although conflicting findings have been reported.KSHV or human herpes virus-8: KSHV-like DNA sequences are frequentlydetected in primary effusion lymphomas in patients with HIV infection andin those with multicentric (plasma cell variant) Castleman's disease.HCV infection is associated with the development of clonal B-cell expansionsand certain subtypes of NHL, particularly in the setting of essential (type II)mixed cryoglobulinemia. HCV may predispose B cells to malignant transformationby enhancing signal transduction upon binding to the CD81 (TAPA-1) molecule.Bacterial infections Infection with Borrelia burgdorferi, the etiologic agent inLyme disease, has been detected in about 35% of patients with primarycutaneous B-cell lymphoma in Scotland. A near-complete clinical and histologicremission of a primary marginal zone B-cell lymphoma was observedafter eradication of B burgdorferi with antibiotic treatment. Gastric mucosaassociatedlymphoid tissue (MALT) lymphoma is seen most frequently, butnot exclusively, in association with Helicobacter pylori infection. Recent studiesindicate that Campylobacter jejuni and immunoproliferative small intestinaldisease (?-chain disease) are related.Chlamydial infections A report noted an association between infection withChlamydia psittaci and ocular adnexal lymphoma. The infection was found tobe highly specific and does not reflect a subclinical infection widespreadamong the general population. Responses to antibiotics have been reported.Immunodeficiency Patients with congenital and acquired states of immunosuppressionthat are at increased risk include ataxia-telangiectasia, Wiskott-Aldrich syndrome, common variable hypogammaglobulinemia, X-linkedlymphoproliferative syndrome, and severe combined immunodeficiency.Acquired immunodeficiency states, such as HIV infection (relative risk of NHL is150-250 increased among patients with AIDS, usually high grade andextranodal), iatrogenic immunosuppression (ie, organ or blood stem-celltransplantation recipients, long-term survivors of Hodgkin's lymphoma), anda variety of collagen vascular and autoimmune diseases (eg, Sjgren's syndrome,rheumatoid vasculitis and Felty's syndrome, systemic lupus erythematosus,chronic lymphocytic thyroiditis, and angioimmunoblastic lymphadenopathy)also pose an increased risk of NHLAutoimmunity An increased incidence of GI lymphomas is seen in patientswith celiac (nontropical) sprue and inflammatory bowel disease, particularlyCrohn's disease. An aberrant clonal intraepithelial T-cell population can befound in up to 75% of patients with refractory celiac sprue prior to thedevelopment of overt T-cell lymphoma using immunophenotyping and T-cellreceptor gamma gene rearrangement PCR (polymerase chain reaction) techniques.Systemic lupus erythematosus and rheumatoid arthritis have beenassociated with B-cell lymphoma.Signs and symptomsFever, weight loss, and night sweats, referred to as systemic B symptoms, aswell as fatigue and weakness, are more common in advanced or aggressiveNHL but may be present in all stages and histologic subtypes.Low-grade lymphomas Painless, slowly progressive peripheral adenopathyis the most common clinical presentation in patients with low-grade lymphomas.Patients sometimes report a history of waxing and waning adenopathybefore seeking medical attention. Spontaneous regression of enlargedlymph nodes can occur and can cause a low-grade lymphoma to be confusedwith an infectious condition.Primary extranodal involvement and B symptoms are uncommon at presentation;however, both are common in advanced or end-stage disease. Bonemarrow is frequently involved, sometimes in association with cytopenias.Splenomegaly is seen in about 40% of patients, but the spleen is rarely theonly involved site at presentation.Intermediate- and high-grade lymphomas The clinical presentation of intermediate-and high-grade lymphomas is more varied. Although the majorityof patients present with adenopathy, more than one-third present withextranodal involvement, the most common sites being the GI tract (includingWaldeyer's ring), skin, bone marrow, sinuses, genitourinary (GU) tract, thyroid,and CNS. B symptoms are more common, occurring in about 30%-40%of patients.Lymphoblastic lymphoma often presents with an anterior superior mediastinalmass, superior vena cava syndrome, and leptomeningeal disease withcranial nerve palsies.American patients with Burkitt's lymphoma often present with a large abdominalmass and symptoms of bowel obstruction.Screening and diagnosisNo effective methods are available for screening or identifying populations athigh risk of developing NHL. A definitive diagnosis can only be made by biopsyof pathologic lymph nodes or tumor tissue. It is critical to performan excisional node biopsy (fine-needle aspirations are insufficient for diagnosticpurposes) to avoid false-negative results and inaccurate histologicclassification. When clinical circumstancesmake surgical biopsy of involved lymph nodesor extranodal sites prohibitive, a core biopsyobtained under CT or ultrasonographic guidancemay suffice but often requires the integrationof histologic examination andimmunophenotypic and molecular studies fordiagnosis. A formal review by an experthematopathologist is mandatory. Additionalstudies, such as immunophenotyping andgenotyping, are often necessary.Initial diagnostic evaluation of patients withlymphoproliferative malignancy shouldinclude the following:
The Working Formulation was proposed in 1982 as a modification of theRappaport classification of NHL based on morphology and biologic aggressiveness.Although many subtypes were not recognized, including Tcelllineage lymphomas, a revised European-American classification of lymphoidneoplasms (REAL classification) was introduced in 1994 incorporatingT-cell malignancies, subtypes of Hodgkin's lymphoma and newer definedlymphoma-proliferative disorders. The WHO (World Health Organization)classification for lymphomas (introduced in 1999) uses the principlesof the REAL classification and defines each entity according to morphologicfeatures, immunophenotype, genetic features, postulated normal counterpart,and clinical features. The WHO classification is similar to the REALclassification, with some modifications and reassessments based on currentdata (Table 3).
The most frequently occurring clinical entities recognized by the REAL/WHO classification are diffuse large B-cell lymphoma (31%), follicular lymphoma(22%), lymphoma of MALT type (8%), small lymphocytic lymphoma(7%), mantle cell lymphoma (6%), peripheral T-cell lymphoma (7%), primarymediastinal large B-cell lymphoma (2%), anaplastic large T-/null-cell lymphoma(2%), lymphoblastic lymphoma of T- or B-cell lineage, marginal zone(monocytoid) B-cell lymphoma (2%), lymphoplasmacytic lymphoma (2%),Burkitt's lymphoma (2%), and other (9%).The WHO modification of the REAL classification includes three types offollicular lymphoma (grades 1-3). Grades 1 and 2 correspond to follicularsmall-cleaved cell and follicular mixed small-cleaved and large cell lymphoma,which are considered to be low-grade lymphomas by the Working Formulation.Grade 3 corresponds to follicular large cell lymphoma, which is consideredan intermediate-grade NHL in the Working Formulation, and is generallytreated as a large cell lymphoma. The WHO/REAL classification considersB-cell small lymphocytic lymphoma to be synonymous with chronic lymphocyticleukemia.Other indolent lymphomas recognized by the WHO/REAL classification,but not by the Working Formulation, include lymphoplasmacytic lymphoma,splenic marginal zone B-cell lymphoma, extranodal marginal zone lymphomaof MALT type, and nodal marginal zone B-cell lymphoma.The REAL and WHO classifications have recognized marginal zone lymphomas(MZLs) as unique clinical and pathologic entities, ie, extranodal(MALT), nodal, and splenic NHL subtypes. MALT NHL is extremely indolentand presents as localized stage I-II disease, rarely disseminating. Thestomach is the most frequent site, but low-grade NHLs (and formerpseudolymphomas) of the lungs, thyroid, salivary gland, and orbit are ofthis type.
Staging and prognosis
Determining the extent of disease in patients with NHL provides prognosticinformation and is useful in treatment planning. However, histologic subclassification(WHO classification) is the primary determinant of survival andpotential for cure. Compared with patients with limited disease, those withextensive disease usually require different therapy, and certain extranodalsites of involvement, such as the CNS and testes, require specific treatmentmodalities.
Ann Arbor system
Although initially devised for Hodgkin's lymphoma, theAnn Arbor system has been routinely applied to NHL (Table 4). BecauseHodgkin's lymphoma commonly spreads via contiguous lymph node groups,this system is based primarily on the distribution of lymphatic involvementwith respect to the diaphragm and the presence of extralymphatic organinvolvement. The Ann Arbor system does not reflect the noncontiguousnature of disease spread in NHL, does not discriminate well between stageIII and IV intermediate-grade disease, and fails to account for tumor bulk ornumber of extranodal sites.Some trials in Burkitt's and Burkitt's-like lymphoma use the St. Jude/Murphystaging system (Table 5), in part to more completely describe the extent ofextranodal disease. Unlike the current WHO classification, this staging systemrecognizes Burkitt's leukemia as a separate entity. Moreover, this systemwas developed when surgery was used for diagnostic and therapeutic purposes.Patients are then also typically stratified into two risk groups, with
low-risk patients defined as having a normal LDH level and a single focus ofdisease measuring less than 10 cm and all others considered to be high risk.
Histology and morphology remain the major determinantsof treatment outcome and prognosis, but gene expression signaturesare likely to be the principal determinants in the future. Some patients withslow-growing low-grade lymphoma may remain well for many years withminimal or no initial therapy, whereas survival of patients with some types ofhigh-grade lymphoma is measured only in weeks, unless aggressive treatmentis initiated promptly. The biologic and clinical behavior of these disordersvaries among the different histologic subtypes.
International Prognostic Index (IPI)
was developed by 16 institutions andcooperative groups in the United States, Europe, and Canada as a prognosticfactor model for aggressive NHL treated with doxorubicin-containingregimens. Clinical features that were independently predictive of survival areincluded in Table 6.This index appears to be a useful guide for selecting treatment for patientswith aggressive diffuse large cell NHL by identifying subsets of patients inwhom intensified primary therapy may be warranted. Because younger andolder patients have markedly different prognoses and younger patients are
more likely to be considered for more intensive investigational regimens, anage-adjusted model for patients ≤ 60 years old has been proposed. In youngerpatients, stage (III or IV), high LDH level, and nonambulatory performancestatus are independently associated with decreased survival. Persons with noor one risk factor have a predicted 5-year overall survival of 73%, comparedwith 26% for high-risk patients with four or five risk factors.The IPI also appears to be useful in predicting outcome in patients with lowgradelymphoma, mantle cell lymphoma, and relapsed or refractory largeB-cell lymphoma in patients undergoing autologous stem-cell transplantation.A new prognostic factor model has been devised based on a study of 919cases of follicular lymphoma, known as the Follicular Lymphoma IPI (FLIPI;Table 7). Multivariate analysis showed that age (> 60 vs ≤ 60), Ann Arborstage (III-IV vs I-II), number of extranodal sites (> 4 vs ≤ 4), LDH level(above normal vs normal/below normal), and hemoglobin level(< 120 g/L vs ≥ 120 g/L) were predictors of overall survival. The FLIPI ismore useful than the IPI for follicular lymphoma. In follicular lymphoma,
the majority of cases are designated as low risk by IPI; the FLIPI distinguishesamong these lower-risk cases.
Time to complete remission has been identifiedas an important treatment-related prognostic factor in aggressive NHL. Patientswho require more than five cycles of standard chemotherapy to achieveremission have a high risk of relapse. Similarly, patients with gallium-avidtumors who have persistent gallium uptake at the midpoint of treatment areless likely to have durable remissions. Sequential PET scanning has demonstratedsimilar results.
Various immunobiologic factors have been suggestedas predictors of outcome in NHL.
Several studies have suggested that patients with aggressivenonanaplastic T-cell NHL have a higher relapse rate and decreased overallsurvival compared with patients with B-cell disease. These observations havebeen confirmed in updated REAL/WHO studies involving large numbers ofpatients.
Tumor cell proliferation
Studies using the Ki-67 antibody, a marker of nuclearproliferation, have shown that increased tumor cell proliferation is a poorprognostic factor in diffuse large cell lymphoma.
Cytogenetic abnormalities and oncogene expression
Lymphomas with abnormalitiesinvolving chromosomes 1, 7, and 17 have a worse prognosis than otherlymphomas of similar stage and bulk that do not exhibit these changes. Mutationsof
are associated with histologic transformation in follicular NHL,which is a phenomenon frequently associated with a poor prognosis. Expressionof
or CD5 in diffuse large cell lymphoma has also been associatedwith inferior survival, whereas
expression is a marker of germinalcenter derivation, a powerful predictor of a favorable outcome.
DNA microarray technology for gene expression profilinghas identified distinct prognostic subgroups in diffuse large B-celllymphoma (DLBCL) and follicular NHL. Studies with malignant DLBCLcells have characterized patients into the following subgroups: germinal centerB-like DLBCL, activated B-like DLBCL, and a heterogeneous subgrouptermed type-3 DLBCL. Patients with germinal center B-like DLBCL have asignificantly improved overall survival compared with the other molecularprofiles. Recent studies in follicular NHL have identified two gene expressionsignatures that also predicted survival: immune-response 1 and immuneresponse2. Interestingly, the genes that defined the prognostic signatureswere not expressed in the tumor cells but were expressed by the nonmalignanttumor-infiltrating cells (primarily T cells, macrophages, and dendriticcells).
The therapeutic approach for NHL differs for each subtype. Chemotherapyremains the most important modality (Tables 8 and 9). However, in select
instances, radiation therapy or surgical resection plays a critical role. Biologicapproaches, including interferons, monoclonal antibodies (Table 10),and recombinant toxins have shown significant activity and are now incorporatedinto treatment paradigms. Autologous and allogeneic stem-cell transplantations,traditionally reserved for recurrent or refractory disease, arebeing evaluated as part of initial therapy in high-risk settings. This sectionwill be organized by NHL subtype to best illustrate the biologic characteristicsand therapeutic considerations that determine the management strategyfor the individual patient. Common NHLs will be covered in depth,whereas less frequent entities will be described in more limited detail.
Follicular lymphoma comprises 22% of all NHL; only DLBCL is more common.The clinical presentation may be nodal or extranodal, and bone marrowinvolvement occurs in the majority of cases. Extensive intra-abdominaladenopathy without peripheral node enlargement is not uncommon. Clinicalbehavior is variable, reflecting the heterogeneity of the underlying biology;some patients survive decades whereas others progress rapidly to resistant disease or transform to a more aggressivehistology. There are rare spontaneousremissions. Transformation is common, occurringin 3%-6% of patients each year andultimately 30%-50% of all patients. Althoughgenerally responsive to treatment, the clinicalcourse is characterized by repeated relapses.Median survival for advanced-stagedisease is 6 years. Although there was noimprovement in survival for patients withfollicular lymphoma for many years, thereis new evidence that outcomes have improved,independent of the introduction ofrituximab (Rituxan).It is crucial to distinguish between reactivefollicular hyperplasia and follicular lymphoma,as the former is a benign condition.Morphologic features as well as the absenceof Bcl-2 staining within the follicle and theabsence of CD10 and/or Bcl-6 protein expressionin the interfollicular areas help todistinguish reactive follicular hyperplasiafrom follicular lymphoma. Follicular lymphomais graded according to the numberof admixed centroblasts within the neoplasticfollicles. Grade 3 follicular lymphoma,previously known as follicular large cell lymphoma,is now subdivided into two subtypes:Grade 3a follicular lymphoma is characterizedby a mixture of centrocytes andcentroblasts within the follicle, whereas 3b has only sheets of centroblastswith no residual centrocytes. The neoplastic lymphocytes in follicular lymphomaexpress the pan-B markers CD19, CD20, CD22, and CD79a andantigens of the germinal center (including CD10 and Bcl-6). Most follicularlymphomas express Bcl-2 protein, which is highly correlated with thet(14;18)(q32;q21), the cytogenetic hallmark of the disease. This translocationresults in the juxtaposition of the
oncogene into the immunoglobulin Hheavy-chain locus on chromosome 14, resulting in its constitutive expression.As previously mentioned, the FLIPI is a prognostic index designed specificallyfor follicular lymphomas based on five adverse prognostic factors (Table 7).Age is the most important factor. Three risk categories have been defined,each consisting of approximately one-third of the patients. More than twothirdsof low-risk patients but only one-third of high-risk patients survive 10years. Whereas clinical parameters are surrogates for biologic characteristics,DNA expression profiling using microarray technology may soon supersedeclinical prognostic indicators such as the FLIPI.
Treatment of early-stage disease
For the relatively small number of patientswith stage I or II follicular lymphoma, radiotherapy continues to bethe standard of care. A recent update from the Princess Margaret Hospital'sseries of involved-field radiotherapy (IFRT) for early-stage disease showedcumulative relapse rates of 54% and 56% at 15 and 25 years, with only a 2%risk of relapse beyond 15 years. Combined-modality therapy has also resultedin excellent disease control, and a randomized trial comparing IFRTwith combined-modality therapy is ongoing. Use of functional imaging withPET may improve the results of IFRT by more accurately identifying patientswith truly localized disease.For clinical stage I and IIA low-grade follicular lymphoma, irradiation aloneis directed to the entire involved lymphoid region, as defined by the Rai andAnn Arbor staging classifications, or the involved region plus one additionaluninvolved region on each side of the involved nodes. The recommendeddose is approximately 30 Gy for nonbulky disease showing prompt regressionand 36 Gy for bulky or slowly regressive disease, in 1.75 to 1.8 Gy dailyfractions. As the majority of subsequent relapses occur outside previousradiation fields, often in adjacent or distal lymph nodes, extended-field ortotal lymphoid irradiation has been used to try to improve cure rates. Clinicalseries have shown improvement in freedom from relapse only, with no significantdifference in long-term survival.
Treatment of advanced-stage disease
Watch and wait
The standard management of asymptomatic patients withfollicular lymphoma has been a "watch-and-wait" approach. Treatment isdelayed until symptoms or cytopenias intervene or there is impending compromiseof vital organs. Multiple phase III randomized trials comparingimmediate chemotherapy with observation for asymptomatic patients withadvanced-stage follicular lymphoma have shown no difference in outcome.In fact, for patients older than age 70, the chances of not requiring chemotherapywere 40% at 10 years in a recently published trial. The median time tofirst systemic therapy for patients randomized to the observation arm was 2.6years. Complete remission rates, however, were higher in the patients treatedimmediately after diagnosis than in those who were observed and later treated(63% vs 27%). The achievement of a complete remission may prove to beimportant if the ultimate goal is to administer postremission therapy (eg,vaccine) that is likely to be most effective in the presence of minimal residualdisease. A phase III trial comparing the watch-and-wait approach withrituximab therapy for asymptomatic advanced-stage disease is ongoing inEurope.
Irradiation for clinical stage III and IV, low-grade, extensivestageNHL is used locally for palliation of symptomatic sites of disease and isextremely effective. Abbreviated fractionated schedules (25 to 30 Gy in 2.5 to3 Gy daily fractions, respectively) are often used. Total-body irradiation,usually consisting of 12 Gy in 2 Gy fractions twice a day, is used as part ofpreparative regimens for bone marrow transplantation.
For patients with symptoms or other reasons for treatment, thereare many treatment options, including single or multiagent chemotherapy,monoclonal antibodies or radioimmunoconjugates, combinations of chemotherapyand immunotherapy with anti-idiotype vaccines, and new agentssuch as bortezomib (Velcade). Treatment with rituximab results in overallresponse rates of nearly 50%, with a medianresponse duration of approximately 1 year,in relapsed or refractory indolent lymphomas.In previously untreated patients, however,the overall response rate is 80% andthe median disease progression-free survivalis 18 months. Of note, 28% of all patientsand 34% of responders maintainedtheir responses for 5 or more years. To improveon response rates and duration ofresponse, additional doses of rituximabhave been administered as "maintenancetherapy." The median event-free survival isprolonged with this approach, especially forpreviously untreated patients. In previouslytreated patients, the total duration of benefitfrom rituximab appears to be the samewhether maintenance rituximab is administered on a scheduled basis orreinduction with rituximab is prescribed at the time of disease progression. Aconfirmatory trial in untreated patients is in progress.
The use of interferon (IFN)-alpha in follicular lymphomahas been extensively investigated both in combination with chemotherapyand as maintenance therapy, with varying results. In most studies, IFNalphawas associated with a prolongation of remission but not overall survival.The Southwestern Oncology Group (SWOG) recently reported theresults of a large phase III trial in which patients with indolent lymphomaswere randomized to receive IFN-alpha or observation following inductionwith an intensive anthracycline-containing regimen and in some cases radiotherapy.Postremission therapy did not prolong disease progression-free oroverall survival. Although the results of randomized trials in follicular lymphomaand toxicities associated with IFN-alpha have led many physicians toabandon its use altogether, a large phase III study is currently ongoing inGermany comparing standard vs intensive dose maintenance. Outside a clinicaltrial, treatment with IFN-alpha cannot be recommended for patients withfollicular lymphoma.
Chemotherapy with and without rituximab
Studies comparing single-agentchemotherapy with multiagent therapy in patients with advanced-stagefollicular lymphoma have not shown meaningful differences in outcomes.Fludarabine, identified in the 1980s as an active agent in follicular lymphoma,has been incorporated into combination regimens with high response rates(including molecular remissions) but has not been shown to prolong theduration of remission when compared with other multiagent regimens. Highresponse rates and durable remissions have resulted when rituximab wascombined with CHOP chemotherapy in a small number of patientswith follicular lymphoma, some of whom were treatment-naive. Four phaseIII trials comparing combinations of chemotherapy and rituximabwith chemotherapy alone in previously untreated patients have now beenreported. Overall response rates and either median time to treatment failureor event-free survival were superior in thechemoimmunotherapy arm in every series.
The anti-CD20radioimmunoconjugates Y-90 ibritumomabtiuxetan (Zevalin) and I-131 tositumomab(Bexxar) both deliver ionizing irradiationto target cells and their neighbors but alsoretain their capacity for mediating complement-mediated cytotoxicity, antibody-dependentcytotoxicity, and apoptosis. Bothhave proven to be relatively easy to administer,safe, and effective. Response rates arehigher and remissions more durable whenradioimmunoconjugates are used early inthe clinical course. Both agents are likely tohave their greatest impact when used in previously untreated patients.In previously treated patients, Y-90 ibritumomab tiuxetan, a high-energybeta-emitter, yielded an overall response rate of 80% for relapsed or refractoryfollicular or transformed CD20+ B-cell NHL, with a median duration ofresponse of 14 months. For patients refractory to rituximab, response rateswith Y-90 ibritumomab tiuxetan are high (74% overall response rate), but themedian duration of response is relatively short (6.4 months; range 0.5-25+months). The dose-limiting feature of this approach is hematologic toxicity.Short-lived myelosuppression occurs 7-9 weeks posttreatment. Dosing is basedon weight (0.4 mCi/kg), with a reduction (0.3 mCi/kg) for those with mildthrombocytopenia (< 100,000/mL).I-131 tositumomab is both a gamma- and beta-emitter and is individuallydosed on the basis of dosimetry to deliver 75 cGy of total-body irradiation.Similar to Y-90 ibritumomab tiuxetan, it is effective in both heavily pretreatedrelapsed and refractory patients. Heavily pretreated patients withrefractory low-grade or transformed NHL had an overall response rate of65% (20% complete response rate), with a median duration of response of 6.5months. These rates were notable in view of a response rate of only 28% inthe preceding chemotherapy regimen. Like Y-90 ibritumomab tiuxetan,tositumomab is associated with predictable myelosuppression. Secondarymyelodysplasia and leukemia have occurred in patients treated withradioimmunotherapy, but only in patients previously treated with chemotherapyand thereby already at risk. In previously untreated patients, thecomplete response rate was 75%, with a 5-year disease progression-free survivalof 62%.I-131 tositumomab has been used to consolidate responders following inductionwith CHOP chemotherapy. In a phase II trial of previously untreatedpatients with follicular lymphoma, the percentage of complete response/unconfirmedcomplete response increased from 39% following CHOP chemotherapyto 60% following consolidation with I-131 tositumomab. At 2 years,approximately 80% of patients remain disease free. Based on these phase IIresults and the encouraging outcome of patients treated with rituximab-CHOP(R-CHOP), the US Intergroup is currently comparing CHOP followed by I-131tositumomab with R-CHOP in treatment-naive patients.
Lymphoma-specific idiotypes serve as tumor-specific antigensin follicular lymphoma and constitute the basis for vaccine therapy. Inearly vaccine trials, immunized patients who generated an anti-idiotype responseexperienced longer remissions than those who failed to mount a response.Anti-idiotype vaccine has been shown to clear minimal residual diseasedetectable only by PCR after intensive chemotherapy. In phase I trials, vaccinationresulted in tumor shrinkage in some patients. Two phase III placebocontrolledtrials investigating this strategy are ongoing, and a third has beencompleted. While we await the results of these important studies, alternativemethodologies, including DNA vaccines and dendritic cell-based vaccination,are under investigation.
New agents targeting specificmolecular targets such as the ubiquitinproteasomepathway have shown promisein the treatment of follicular lymphoma. Inrecently reported phase II trials, bortezomibhas shown activity in follicular lymphoma aswell as in mantle cell lymphoma. New combinationsincluding bortezomib are now beinginvestigated. Novel antibodies such as anti-CD80 and combinations of antibodies havealso shown promise in the treatment of follicularlymphoma.
The natural historyof follicular lymphoma is characterizedby response to therapy but repeated relapsesand progressively shorter and shorterremissions, ultimately resulting in deathfrom progressive disease. Autologous andallogeneic stem cell transplantation are alternativestrategies that are often associatedwith durable remissions that may impactoverall survival. Unfortunately, immediate and long-term toxicities aresignificant and must be considered when assessing the appropriate role oftransplantation in the overall treatment plan for individual patients. The onlyphase III trial to address the role of autologous stem-cell transplantation(ASCT) in patients with relapsed follicular lymphoma closed prematurelybecause of poor accrual. Nonetheless, disease progression-free and overallsurvival were significantly longer with high-dose chemotherapy (HDCT)and ASCT (with purged or unpurged autografts) than with conventionalalkylator therapy. Whether any of the new therapeutic strategies will proveto be as effective as ASCT in the relapsed setting remains to be seen.Several groups have investigated the role of ASCT as consolidation therapyfor patients in first complete or partial remission. Although disease progression-free survival may be prolonged, overall survival is not affected. An increasedincidence of secondary myelodysplasia following ASCT in first remissionhas reduced enthusiasm for this approach.Single-institution studies as well as analysis of registry data suggest that atumor-free graft is an important determinant of outcome in follicular lymphoma.Administration of rituximab during stem-cell mobilization providesan "in vivo" purge, reducing contamination of the autograft with malignantlymphocytes. The long-term benefit of such an approach has not yet beendemonstrated.Allogeneic stem-cell transplantation has been investigated primarily in youngpatients with HLA-identical sibling donors and extensive disease and/ormarrow involvement. Low relapse rates suggest that this approach is poten-tially curative but is associated with hightreatment-related morbidity and mortality.Reduced-intensity transplantation is basedon the assumption that a graft-vs-lymphomaeffect is operative and has the potential tocure follicular lymphoma. Whether this approachwill reduce toxicity while maintainingthe low relapse rates associated withstandard myeloablative allotransplants remainsto be established. A randomized trialcomparing this strategy with ASCT in relapsedfollicular lymphoma has been initiatedin the United States.
Overall treatment strategy
Whereastreatment choices were once limited tosingle or combination alkylator-based treatment,we now are faced with choosingamong a wide variety of strategies. Thereare many unanswered questions that canonly be addressed through well-designedclinical trials. Hence, whenever possible,every patient should be enrolled on prospectiveclinical studies. In the absence ofsymptoms or other indications for treatment,patients should be observed. A combinationof rituximab and chemotherapyis suggested in the absence of a clinical trial.Selected patients with comorbidities maybe best served with rituximab alone.Radioimmunotherapy is recommended atthe time of relapse, with transplantationreserved for selected patients in first or subsequentrelapse.
CHRONIC LYMPHOCYTIC LEUKEMIA/
SMALL LYMPHOCYTIC LYMPHOMA
CLL/SLL is a malignancy of small, round, B lymphocytes involving peripheralblood, bone marrow, and lymph nodes. The term "SLL" is reserved forcases in which there are no circulating malignant lymphocytes. SLL generallypresents with lymph node and spleen involvement. Involvement of thebone marrow and peripheral blood may develop later in the courseof disease. At the time of presentation, patients may be asymptomatic,complain of only fatigue, or have symptoms related to cytopenias (includingautoimmune hemolytic anemia, lymphadenopathy, or splenomegaly). Theimmunophenotype helps to distinguish CLL/SLL from other B-cell leukemias/lymphomas, including mantle cell and leukemic forms of follicular lym-phoma. Typically, the malignant lymphocytes stain weakly with surface immunoglobulin,CD20, CD22, and CD79b; they are CD5+, CD23+, andFMC7-. Cytogenetic abnormalities are detected in the majority of caseswhen fluorescence in situ hybridization (FISH) analysis is used. Trisomy 12,deletions at 13q14, and deletions at 11 q22-23 are common. Many molecularmarkers of prognosis have been studied in CLL, including Zap-70, but theirvalue in SLL is unknown.Given the relatively small numbers of patients with SLL, they have generallybeen included in clinical trials of "indolent lymphoma." Conventional alkylatorbasedregimens as well as fludarabine and cladribine and combinations thereofhave been used when patients become symptomatic. Anthracyclines havenot been shown to benefit patients with SLL/CLL. When compared withfollicular lymphoma, CLL/SLL is less likely to respond to rituximab as asingle agent. Alemtuzumab (Campath), a potent therapy for CLL, is lesseffective in treating nodal disease than peripheral blood and bone marrowinvolvement. Transplantation, both autologous and allogeneic, has been studiedin selected patient populations but should be reserved for relapsed youngpatients with good performance status.
SPLENIC MARGINAL ZONE LYMPHOMA
Splenic marginal zone lymphoma (SMZL) is a rare disorder comprising lessthan 1% of NHLs. Clinically, this lymphoma most often presents as splenomegalywith splenic hilar node involvement but without peripheral adenopathy.The bone marrow is commonly involved, and malignant villous lymphocytesmay be detected in the peripheral blood. Sometimes confused withCLL or mantle cell lymphoma, SMZL may be distinguished by itsimmunophenotype. Typically, cells are CD20+, CD79a+, CD5-, CD10-,CD23-, and CD43-. Staining for cyclin D1 is negative, excluding mantle celllymphoma. The absence of CD103 helps to exclude hairy cell leukemia. Allelicloss of chromosome 7q21-32 is common. The clinical course is indolent.Cytopenias respond to splenectomy with long-lasting remissions. Anecdotalremissions have been seen following rituximab therapy. Transformation tomore aggressive histologies may occur.
NODAL MARGINAL ZONE LYMPHOMA
Nodal marginal zone lymphoma (NMZL) is a primary nodal B-cell disorderthat resembles lymph nodes involved by marginal zone lymphomas ofextranodal or splenic origin, without extranodal or splenic involvement. Lymphadenopathy(either localized or generalized) is the presenting complaint inmost cases. Extranodal lymphoma may be uncovered in the evaluation ofmany cases of suspected NMZL. The clinical course is usually indolent, similarto that of other marginal zone lymphomas.
Extranodal marginal zone B-cell lymphoma of MALT type
MALT lymphomas comprise only 7%-8% of B-cell lymphomas but nearly50% of all gastric lymphomas. Although the GI tract is most often involved,other common sites include the lungs, head and neck, ocular adnexae, skin,thyroid, and breasts. There often is an associated history of autoimmunedisorders, such as Sjgren' syndrome or Hashimoto's thyroiditis or chronicinflammatory processes secondary to infectious agents
(H pylori, B burgdorferi,
A form of MALT involving the small bowel (immunoproliferativesmall intestinal disease, previously known as ?-chain disease) has recentlybeen associated with
The majority of patients present with stage I orII disease. The frequency of bone marrow involvement appears to differdepending on the primary site of involvement. Multiple extranodal sites maybe involved at the time of presentation. Transformation to a high-gradelymphoma may occur in approximately 8% of cases.The malignant lymphocytes of MALT lymphoma are typically CD20+,CD79a+, CD5-, CD10-, and CD23-. The t(11;18)(q21;q21) is characteristic ofMALT lymphomas, particularly those involving the stomach or lungs. Thetranslocation creates a fusion between the MALT-1 gene, which is an essentialregulator of
-mediated NF-kB signaling, and the AP12 gene, whichinhibits apoptosis. This genetic abnormality is a marker of MALT lymphomasthat do not respond to antibiotic therapy for
infection, are associatedwith a more advanced stage, and do not transform into more aggressivehistologic subtypes. This translocation has not been associated with nodal orsplenic marginal zone B-cell lympomas or other types of lymphoma.Treatment of
infection with triple therapy (eg, omeprazole [Prilosec],metronidazole, and clarithromycin [Biaxin]) results in regression in the majorityof early lesions. However, tumors invadingbeyond the submucosa and lesionswith t(11;18) are associated with a failure torespond to
eradication, deep penetration,and distant spread.Localized MALT gastric lymphoma thatdoes not respond to antibiotics may be curedwith local irradiation with a field includingthe stomach and perigastric lymph nodes.This treatment is safe, extremely effective,and preserves the stomach. A single-institutionexperience reported a 96% completeresponse rate and a 90% freedom-fromtreatment-failure rate, at a median followupof 4 years. If local irradiation fails, chemotherapyor rituximab can be used and, insome instances, surgery. Alkylator-basedtherapy or purine analogs have been used with success for persistent ordisseminated disease. The typical dose of radiotherapy is 30 Gy in 20 fractionsdirected to the stomach and perigastric lymph nodes.
Lymphoplasmacytic lymphoma Waldenstrm's macroglobulinemia is a disorderof small B lymphocytes, plasmacytoid lymphocytes, and plasma cells,typically involving the bone marrow, lymph nodes, and spleen. It is usuallyassociated with a serum monoclonal protein (usually IgM) with associatedhyperviscosity or cryoglobulinemia. The clinical presentation is usually relatedto hyperviscosity with visual symptoms, stroke, or congestive heartfailure. Peripheral neuropathies occur in approximately 10% of patients relatedto reactivity of the IgM with myelin-associated glycoprotein or gangliosides.An association with HCV infection has been demonstrated. Characteristically,the immunophenotypic analysis reveals surface and cytoplasmicimmunoglobulin, usually IgM type, and B-cell-associated antigens (such asCD19, 20, 22, and 79a). The malignant cells are CD5-, CD10-, and CD23-.The clinical course is generally indolent. Asymptomatic patients may be observed.Plasmapheresis may be appropriatefirst therapy for those who present with hyperviscosity.The clinical status of the patient,not the level of the protein, determineswhen treatment is initiated. Choice oftherapy depends on many individual factors,including age, comorbidities, and the particularindication for therapy. Rituximab andnucleoside analogs (cladribine andfludarabine) as well as the traditional oralalkylators have shown efficacy. Combinationsof these agents are also under study.Bortezomib has shown activity inWaldenstrm's macroglobulinemia. Transplantation,both autologous and allogeneic,is being investigated in younger patients withrelapsed or refractory disease.
DIFFUSE LARGE B-CELL LYMPHOMA
DLBCL makes upabout one-third of the cases of NHL and isgenerally classified as a mature peripheralB-cell neoplasm by the WHO classificationand an intermediate-grade lymphoma by theREAL classification. The clinical presentationis variable, but generally patients presentwith either peripheral lymphadenopathy
(neck, axillae) or enlarged nodes in the mediastinum, in the mesenteric region,or in the retroperitoneum. These sites predict symptoms, which mayinclude chest pain, facial swelling and suffusion of the eyelids (superior venacava [SVC] syndrome from mediastinal disease), abdominal discomfort orascites (mesenteric) or back pain, or renal obstruction (retroperitoneal presentations).More than 30% of patients present with disease in extranodalsites, such as the GI tract (including Waldeyer's ring), skin, bone marrow,sinuses, GU tract, thyroid, and CNS. B symptoms, consisting of fever, sweats,and weight loss, are more common in DLBCL than in the indolent lymphomasand occur in about 30% of patients. The median age at presentation is 60years.Once the diagnosis is clearly established, staging studies are carried out todetermine treatment and define parameters for follow-up. Generally, imagingstudies of the chest, abdomen, and pelvis are obtained, and CT scansprovide the most accurate anatomic information. Recently, functional imagingusing PET scans (which have largely replaced gallium scans) has shownpromise as a means of distinguishing between residual scar and active diseaseafter treatment. Further, some investigators have shown that early responseby PET scan (after two to three cycles) is a good prognostic indicator. Inaddition to CT and PET scans, bone marrow aspirate and biopsy, serumLDH level, and serum beta-2 microglobulin level have been described asimportant predictors of outcome.
The diagnosis should be made by incisional orexcisional biopsy of an available lymph node, with adequate tissue for immunologicstudies such as flow cytometry or immunohistochemistry (IHC) toidentify the characteristic B-cell clonality (kappa or lambda restriction). Inmany cases of DLBCL, CD10 is present, indicating a germinal center origin.The CD 20 antigen is present in almost all cases of B-cell lymphomas and onalmost all normal B cells. In addition, markers for
offer prognosticinformation and are part of most diagnostic evaluations of DLBCL.The use of fine-needle aspiration (FNA) or core biopsy is to be discouragedand is acceptable only when tissue cannot be safely obtained by other means,and only if flow cytometry is used to help classify the disease and distinguishit from epithelial malignancies that can masquerade as lymphoma.
Clinical predictors of response have been identified andare now widely used to help design therapeutic plans and clinical trials. Thesepredictors include patient age (< or > age 60), performance status (0, 1 vs 2-4),number of extranodal sites (more than two), Ann Arbor stage (I or II vs IIIor IV), and serum LDH level (> normal; Table 6). Older patients, higherstage, poorer performance status, higher number of extranodal sites andhigher LDH level all predict for worse outcome, and this model has beenvalidated in more than 3,000 patients. These parameters have been called theIPI, and this index is used to plan therapy and clinical trials in the UnitedStates and abroad and may be used to predict survival (Table 11).More recently, genomics have been used to help predict outcome based onmolecular signature (see section on Molecular profiling). This molecular systemprovides prognostic information independent of the IPI. Several investigatorsusing similar statistical methodologies have yielded comparable results,and recently these analyses have been extended to other lymphomas.
Once the staging has been completed, treatment with aggressivecombination therapy, containing an anthracycline (usually CHOP), beginspromptly. Prior to the 1970s, most patients with stage I/II large cell lymphoma(intermediate grade in the Working Formulation) were treated withirradiation alone, with overall cure rates of 40%-50%. Patients with pathologicallyfavorable stage I/II disease had even better outcomes, but relapserates, even in these patients, were still 20%-30%. Pathologic staging, therefore,selected a group suitable for irradiation alone. This approach is nolonger appropriate, in view of the success of chemotherapy and irradiation inclinically staged patients.Coiffier et al found that the addition of rituximab improved results in elderlypatients with DLBCL, and recent data confirmthese observations for younger patientsas well. For patients with clinical stage I or IIdisease (by the Ann Arbor criteria), moststudies suggest that chemotherapy (CHOP,and most would add rituximab) for three tofour cycles followed by localized radiationtherapy is preferred. Excellent local and systemiccontrol is obtained with combinedmodalitytherapy. In an ECOG phase IIItrial, Horning et al showed that eight cyclesof CHOP and irradiation produced a 10-yeardisease-free survival rate of 57%, comparedwith 46% with CHOP alone (
= .04). Overallsurvival was 64% vs 60%, respectively(
= .23), and time to disease progressionwas 73% vs 63%, respectively (
= .07).Miller et al showed that CHOP (three cyclesof CHOP and irradiation) produced a dis-ease progression-free survival at 5 years of 77%, vs 64% for eight cycles ofCHOP alone (
= .03). Overall survival at 5 years was 82% vs 72%, respectively(
= .02). A recent update of this SWOG study was reported by Milleret al, with an 8.2-year median follow-up. The 5-year estimates for CHOP(three cycles plus irradiation) vs CHOP (for eight cycles) remained unchanged.Kaplain-Meier estimates now show overlapping curves at 7 years for failurefreesurvival and 9 years for overall survival. The treatment advantage forCHOP (for three cycles plus irradiation) for the first 7-9 years was diminishedbecause of excess late relapses and NHL deaths occurring between 5 and 10years. Patients with good IPI risk factors had a 5-year overall survival of 94%;patients with one adverse risk factor had an overall survival of 70%; thosewith three adverse risk factors had a 5-year survival of 50%. These resultswere confirmed by a single-arm (doxorubicin-containing chemotherapy) followedby IFRT conducted by the British Columbia Cancer Agency. However,two recent reports from European investigators question the value ofconsolidation irradiation in early-stage disease. These studies did not userituximab or
fluorodeoxyglucose (FDG)-PET staging, and details on theirradiation technique used are also not available.Until further studies define the optimal therapy for stage IA-IIA DLBCL(nonbulky), many investigators consider three to four cycles of CHOP withrituximab and IFRT the initial treatment of choice. For patients with bulkydisease, a minimum of six cycles of CHOP is typically administered. Irradiationdoses of 30-36 Gy, delivered in 1.75-1.8 Gy over 3-4 weeks after completionof systemic therapy, appear to be adequate. Radiation fields usuallyinclude involved lymph node sites or an involved extranodal site and itsimmediate lymph node drainage areas. Furthermore, the disease should beeasily encompassed in a radiation field with acceptable toxicity.Disease site or potential toxicities may influence the treatment plan:
For patients with more advanced stage (III or IV) disease, CHOP has beenthe standard (now with rituximab) for six to eight cycles or two cycles beyondremission. Recent data suggest an advantage to "dose-dense" therapy, shorteningthe interval between cycles from 3 to 2 weeks with growth factor support.More data are needed to validate these results. Many studies nowsuggest an advantage to the addition of immunotherapy in the form ofrituximab, and in almost every study, the combination or rituximab andchemotherapy has improved the responserate and disease-free survival. There appearsto be no advantage to maintenance therapywith rituximab in this setting, however, aslong as rituximab is included in the induction.Responses are seen in upward of 80%of patients, and approximately 50%-60%achieve a complete remission. It appears that50% of these patients (30%-50% overall) arelikely cured. For patients who either do nothave a complete remission or who relapse,alternative therapies are possible, but longtermresponses have been seen mostly withautologous or allogeneic stem celltransplantation. Patients who do not have responsive disease prior to transplantationgenerally do poorly. The IPI has been used to predict outcomefor transplantation in DLBCL. The role of ASCT for high-risk patientsremains open to debate. Investigational treatments include novel antibodies,radioimmunotherapy, and single-agent chemotherapy drugs.Nonmyeloablative stem-cell transplants are being evaluated in patients withrecurrent or refractory disease.Some investigators believe that irradiation for stage III and IV (advanced orextensive) DLBCL may be added after the completion of definitive chemotherapyif there is localized residual disease to improve local control. Irradiationmay also be delivered after chemotherapy to areas of initially bulkydisease, again to enhance local control. These recommendations are basedon the observation that when DLBCL relapses after definitive chemotherapy,it usually does so in initially involved or bulky areas of disease. The benefitsand potential side effects of irradiation should be weighed against the use ofalternative chemotherapy salvage regimens.
MANTLE CELL LYMPHOMA
By comparison with low-grade NHL, patients withmantle cell lymphoma are older (median age is 64 years), mostly male (75%),and more likely to have peripheral blood involvement (about 30%) andextranodal involvement (mostly the GI tract and CNS, as discussed below).The clinical course in mantle cell lymphoma is characterized by the worstfeatures of the aggressive lymphomas (an aggressive course) and the indolentlymphomas (frequent recurrences). The disease is often widespread atdiagnosis, and marrow involvement and splenomegaly are common. GI tractinvolvement is also common, and many centers suggest evaluation of the GItract at the time of diagnosis. CNS recurrences are frequent (up to 20%), butisolated CNS disease is a rare occurrence. Leukemic presentations havebeen described.
This disorder was originally classified as diffuse smallcleaved lymphoma by the REAL classification and represents less than 10%of all NHLs. In this disease, a homogeneouspopulation of small lymphoid cells with irregularnuclear borders arises from and expandsthe mantle zone surrounding the germinalcenters of the lymph nodes, spreadingdiffusely through the node as the germinalcenters are overrun. The lymphocytesexpress IgM or IgD, as in CLL, but in muchgreater density. It was recognized that thecells carry a translocation of the long armsof chromosomes 11 and 14 notated ast(11;14)(q13;q23). This molecular event juxtaposesthe
gene on chromosome 11 tothe immunoglobulin heavy chain gene onchromosome 14, leading to overexpressionof
. This gene encodes the cell-cycle regulatoryprotein cyclin D1, which is believed toplay a role in checkpoint control in DNAsynthesis. The immunophenotype is characteristic,and mantle cell lymphomas areusually CD5+, CD20+, CD10-, CD23-, andFMC7+. This immunophenotype is similarto that seen with CLL/SLL, except thatCD23 is most often expressed in CLL/SLLbut usually is not expressed in MCL. Thekey to the diagnosis is the demonstration intumor tissue or peripheral blood of thet(11;14) by FISH or the cyclin D1 protein byIHC. Inactivation of the
gene has beendescribed in mantle cell lymphoma.
Responses to aggressive chemotherapy(CHOP or R-CHOP) are seen, but patients relapse frequently, andmedian survival is short. Recent data suggest an advantage to stem-cell transplantationwhile patients are in remission, but more data are required tovalidate these results. Patients who have relapsed after ASCT have been"rescued" by allogeneic transplantation. The National Comprehensive CancerNetwork (NCCN) guidelines recommend clinical trials for patients withmantle cell lymphoma (there is no "standard" therapy), and ongoing trials areinvestigating a short course of R-CHOP followed by radioimmunotherapywith ibritumomab tiuxetan. Investigators have found that aggressivehyperfractionated chemotherapy with rituximab (R-Hyper-CVAD) may resultin long-term responses in patients with mantle cell lymphoma (Table 12).Anti-idiotype vaccine studies are also under way in this disease, and novelchemotherapy regimens/agents designed to take advantage of the molecularbiology of this disease (flavopiridol, bortezomib) are being tested.
BURKITT'S AND BURKITT'S-LIKE LYMPHOMA
These diseases present as three distinct clinical entities:endemic, sporadic, and immunodeficiency-related types. EndemicBurkitt's lymphoma most often presents in young children or adolescentswith large nodes in the neck, often involving the maxilla or mandible. Thesecases are most often seen in equatorial Africa and follow the distribution ofendemic malaria, hence its designation as "endemic Burkitt's lymphoma." InAmerican, or sporadic, Burkitt's or Burkitt's-like lymphomas, the diseasepresents in the abdomen and extranodal sites, especially in the GI tract.Sporadic Burkitt's lymphoma accounts for 1%-2% of all adult lymphomas inWestern Europe and the United States. The immunodeficiency type is seenin the setting of HIV infection but can be seen in patients with CD4 cellcounts > 200 cells/mL. In both endemic and sporadic Burkitt's and in Burkitt'slikelymphomas, males are affected more often than females.The LDH level is often elevated, owing to the high turnover rate of these cellsand the bulk of disease. The bone marrow and CNS are often involved, andif not involved initially, they are at risk, so CNS prophylaxis is needed. Astaging system for Burkitt's and Burkitt's-like lymphomas has been developedby Murphy and associates (Table 5).
These lymphomas are characterized by small, roundnoncleaved cells. They are the most rapidly proliferating of NHLs but makeup less than 1% of cases of NHL in adults in the United States. Under themicroscope, it is difficult to distinguish Burkitt's from Burkitt's-like lymphomasand either from the B-cell FAB L3 variant of acute lymphoblastic leukemia.Indeed, the WHO classification recognizes the lymphoma and leukemicphases as a single entity, a mature B-cell neoplasm. The disease is characterizedby medium-sized cells with an abundant basophilic cytoplasm with lipidvacuoles. There are round nuclei with clumped chromatin and multiplenucleoli; a diffuse pattern of infiltration is seen and is classic for Burkitt'slymphoma. The numerous macrophages that are usually seen in the lymphnode biopsy specimens give rise to the so-called starry-sky appearance.The proliferative rate of this tumor is high, and there are frequent apoptoticcells. In the Burkitt's-like variant, there is greater pleomorphism in nuclearsize and shape, and the nuclei have fewer nucleoli. There is a low level ofconcordance among pathologists (about 53%) when they attempt to distinguishBurkitt's from Burkitt's-like lymphomas, and even by clinical criteria,that distinction is difficult. The cells express surface IgM, CD19, CD20, CD22,CD10, and CD79a and do not express CD5, CD23, and TdT. Bcl-6, a zincfinger protein, is usually expressed. The major consideration in the differentialdiagnosis is precursor B-cell lymphoma/leukemia, which in contrast expressesTdT; surface immunoglobulin is mostly negative. CD20 may also benegative in this disorder. In Burkitt's lymphoma, the expression of CD10 andBcl-6 protein suggest that these cells originate from the germinal center, andindeed, this is confirmed by sequence analysis of the immunoglobulin variable heavychain and light chain genes. Somatic hypermutation of these genes has been described.
The almost constant genetic abnormality in Burkitt's lymphoma isoverexpression of the c-
oncogene, which in 80% of cases results from abalanced translocation between chromosomes 8 and 14, notated as t(8;14),where the c-
oncogene on chromosome 8 is juxtaposed to immunoglobulinheavy chain enhancer elements on chromosome 14. In the remaining 20%of cases, there are other translocations, including t(2;8)(p12;q24) andt(8;22)(q24;q11). There have been different breakpoints identified in Burkitt'slymphoma, and they have been associated with the sporadic and immunodeficiencysubtypes.
One cannot discuss these highly aggressive NHLs without discussingthe role of EBV. This virus, a member of the herpesvirus family, has theability to infect resting B cells and transform them into proliferating blasts,most likely by bypassing antigens on lymphocytes and activating signalingmolecules. By contrast, certain viruses (HCV) and bacteria (
) maycause lymphoma by activating lymphocytes in an antigen-specific manner.EBV infection results in a polyclonal proliferation of lymphoblasts that arelatently infected with the virus, as opposed to the infection seen in infectiousmononucleosis, which is a lytic infection. This process is regulated by theexpression of up to nine latent viral proteins, which are under the control ofthe transcription factor EBV nuclear antigen 2 (EBNA-2). It appears that thetype and result of EBV infection in lymphoid tissue are controlled by various"growth programs," each causing expression of different viral proteins, whichthen determine the fate of the infected cell. These in vitro events are differentfrom what occurs in healthy carriers of EBV (up to 90% of the population hasbeen exposed), where the viral proteins are not expressed because all of thelatently infected cells are resting memory B cells. It is in the germinal center of the
lymph node, however, that virally infected cells can transform into memory B cells,as the viral proteins are expressed within the B cells of the germinal center.Although EBV was found in patients with Burkitt's lymphoma over 40 yearsago, the role of EBV in the disease still remains uncertain. In Burkitt's lymphoma,a consistent lesion is the overexpression of the
oncogene,which results from a reciprocal translocation between chromosomes 8 and 14[t(8;14)]. The exact role of
overexpression in the pathogenesis of thedisease is not known, but
is known to play a role in cell-cycle progressionand cellular transformation. The EBV is found in over 95% of cases of"endemic Burkitt's lymphoma," which occurs in Africa, but its role in thepathogenesis of the disease is still not clear. It appears that none of thegrowth-promoting latent genes is expressed in Burkitt's lymphoma, and theonly latent protein of the virus that is present is EBNA-1. The possibility thenexists that although associated with Burkitt's lymphoma, EBV may only be apassenger rather than an etiologic agent. The reason therapy with antiviralagents (ganciclovir or acyclovir) cannot be used to treat EBV-associated lymphomasis that the required thymidine kinase (TK) gene is not expressed inlatent EBV infection. Recent studies using the small molecule arginine butyrateto upregulate the TK gene and protein expression with concomitantantiviral antibiotics have met with some success.
Patients must be treated quickly after diagnosis, which should bemade on a full biopsy so that adequate tissue is obtained. Tumor lysis syndromeoccurs most often with Burkitt's lymphoma, and attempts to reduce uric acidproduction with allopurinol or to degrade it with the enzyme rasburicase (Elitek)should be part of the management, as should aggressive hydration. Patientsshould be managed in a facility with access to support such as urgent dialysis,since it may be necessary if tumor lysis syndrome occurs. Treatment includesaggressive chemotherapy, with anthracyclines and cyclophosphamide as thecornerstone. Regimens incorporating hyperfractionated cyclophosphamide suchas hyper-CVAD, developed by Murphy and adopted by the M. D. Andersongroup, have been used: CODOX-M/IVAC (cyclophosphamide, vincristine,doxorubicin, high-dose methotrexate/ifosfamide [Ifex], etoposide, and highdosecytarabine; Table 13) and the French regimen all incorporate intensivetherapy given weekly in various combinations, and all incorporate intrathecalchemotherapy of high-dose methotrexate or high-dose cytarabine to facilitateCNS penetration. In children, the results are excellent, and about 80% ofpatients can be cured. In adults, the outcome is not as favorable, but withnewer more intensive regimens, 40%-60% of patients survive 5 years withoutdisease. New approaches using rituximab and early stem-cell transplantationare being investigated, as are new agents (flavopiridol and an analog ofresveratrol) with unique mechanisms of action, which may have relevance toBurkitt's and Burkitt's-like lymphoma.
PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA
Primary mediastinal large B-cell lymphoma (PMLBCL)occurs most often in young women (female:male ratio is 2:1) who presentwith mediastinal masses only. These masses are usually bulky and often invadesurrounding structures, such as pleura, lungs, pericardium, and chestwall, but rarely is disease found outside the chest cavity. At recurrence, however,extranodal sites such as the lungs, adrenal glands, liver, or kidneys maybe involved. Because of the location and bulk of the disease, patients complainof chest pain, cough, shortness of breath, and are often found to haveSVC. This can be subtle, with unexplained breast enlargement the onlysymptom in some cases. The diagnosis can be delayed if the clinician does notrecognize the signs and symptoms of SVC. This clinical presentation is similarto classical Hodgkin's lymphoma, and indeed, that is the primary differentialdiagnostic consideration when these patients are evaluated.
PMLBCL with sclerosis is a distinct clinical, pathologic,and molecular abnormality, which has evolved to be recognized asdifferent from other lymphomas. The pathology is characterized by a diffuseproliferation of large cells with clear cytoplasm, often accompanied by extensivesclerosis. The cells are mostly of B-cell origin and express CD20 andother B-cell markers but do not express surface immunoglobulin (Ig). Indeed,the discordant expression of CD79a and Ig expression is a distinguishingfeature of PMLBCL, There are data that describe gains of chromosomalmaterial in tissue specimens, most often 2p, 9p, 12q, and Xq. The
(interleukin-4 gene) oncogenes are overexpressed in tissue specimens. Iggenes have a high level of somatic hypermutation. All of these observationssuggest that this entity is unique, especially as compared with B-cell lymphomasthat arise in peripheral nodes. IL-13 expression and downstream effectorsof IL-13 signaling pathways were overexpressed, along with TNF familymembers and TNF receptor-associated factor-1.The overexpression of the
oncogene, previously described, was associatedalmost exclusively with the nucleus, consistent with NF?B pathwayactivation, and the
overexpression was confirmed in these gene arraystudies. These data help us to reorder our thinking about these clinicallyunique lymphomas and to begin to build a molecular story that is consistentwith the clinical observation that PMLBCL is more like classic Hodgkin'slymphoma than like DLBCL. Further, the observations that certain signalingpathways are involved provide a rationale to attack these pathways specificallyin a targeted approach.
The clinical course is variable; some report a poor outcome withconventional, CHOP-based chemotherapy regimens and radiation, and somereport an excellent outcome. It seems clear that bulk of disease and LDHlevel are important prognostic factors and that prediction of the outcome bythe IPI is useful. A variety of chemotherapy regimens have been evaluated,including CHOP and MACOP-B/VACOP-B (methotrexate or etoposide,Adriamycin, cyclophosphamide, Oncovin, prednisone, bleomycin), and morerecently rituximab has been incorporated into the management. Usually,radiation therapy is a part of the initial treatment. In general, in 2005, patientsreceive anthracycline-containing chemotherapy with rituximab and after fourto six courses, radiation therapy is given to patients with bulk disease. Thereare no randomized trials comparing radiation therapy or no radiation therapyin this setting. PET scanning may influence the use of consolidation radiationtherapy in the future.
PERIPHERAL T-CELL LYMPHOMA,
NOT OTHERWISE CHARACTERIZED
Peripheral T-cell lymphoma, not otherwise characterized (PTCL-noc) is predominantlya nodal lymphoma that represents the most common T-cell lymphomasubtype in Western countries, comprising approximately 50%-60% ofT-cell lymphomas and 5%-7% of all NHLs. PTCL-noc usually affects maleadults (5:1 male-to-female ratio) with a median age of 61 years (range, 17-90)with 25% of patients presenting in stage I or IIE, 12% in stage III, and 63% instage IV. Patients with PTCL-noc from this study, commonly presented withunfavorable characteristics, including B symptoms (40%), elevated LDH level(66%), bulky tumor ≥ 10 cm (11%), nonambulatory performance status (29%),and extranodal disease (56%), leading to the majority of patients (53%) fallinginto the unfavorable IPI category (score of 3 to 5).Most T-cell NHL patients are treated in the same manner as intermediategradeB-cell patients, with anthracycline-based combination chemotherapysuch as CHOP. Randomized trials comparing CHOP with other combinationregimens confirmed CHOP as a standard regimen for intermediate-grade BcellNHL; unfortunately, these trials do not allow for subset analysis of T-cellpatients. Rituximab should not be included in the treatment for PTCL-noc(unless other conditions such as immune thrombocytopenic purpura exist,as CD20 is not expressed. Other therapeutic agents tested in T-cell NHLinclude purine and pyrimidine analogs, denileukin diftitox (Ontak), and aretinoic acid/IFN-alpha combination.Denileukin diftitox is a novel recombinant fusion protein consisting of peptidesequences for the enzymatically active and membrane active and membranetranslocation domains of diphtheria toxin with recombinant IL-2 (CD25receptor); it has been studied mostly in cutaneous T-cell NHL, althoughclinical benefit has been reported in other T-cell NHL patients. Recently, thehistone deacetylase inhibitors SAHA and depsipeptide have shown significantactivity against PTCL-noc.
ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA
Angioimmunoblastic T-cell lymphoma (AITL), also known asangioimmunoblastic lymphadenopathy with dysproteinemia, is one of themore common T-cell lymphomas, accounting for 15%-20% of cases and4%-6% of all lymphomas. The mean age at presentation is 57 to 65 years old,with a slight male predominance, and the majority of patients present withstage III or IV disease. AITL is commonly a systemic disease with nodalinvolvement with various associated disease features, such as organomegaly,B symptoms (50%-70%), skin rash, pruritus, pleural effusions, arthritis,eosinophilia, and varied immunologic abnormalities (positive Coombs' test,cold agglutinins, hemolytic anemia, antinuclear antibodies, rheumatoid factors,cryoglobulins, and polyclonal hypergammaglobulinemia).Spontaneous disease regression is seen on rare occasions, although AITLtypically follows an aggressive clinical course. Treatment with anthracyclinebasedcombination chemotherapy results in complete remission (CR) ratesof 50%-70% of AITL patients, although only 10%-30% of patients are longtermsurvivors. One prospective, nonrandomized multicenter study treatednewly diagnosed "stable" AITL patients with single-agent prednisone andcombination chemotherapy for relapsing/refractory patients or initially if"life-threatening" disease was present at diagnosis. Complete remission was29% with single-agent prednisone, whereas CR for relapsed/refractory patientsor patients treated initially with combination chemotherapy was 56%and 64%, respectively. With a median follow-up of 28 months (range, 7 to 53),the overall survival and disease-free survival (DFS) was 40.5% (CI, 24% to56%) and 32.3% (CI, 17%-47%), respectively, although the median overallsurvival was 15 months. There are anecdotal reports of relapsed AITL patientswho have responded to immunosuppressive therapy, such as low-dosemethotrexate/prednisone, as well as reported responses to purine analogtreatment. Furthermore, cyclosporine has demonstrated activity in relapsedAITL patients in case reports, and the ECOG is studying this agent in aprospective study.
ANAPLASTIC LARGE-CELL LYMPHOMA,
T-/NULL-CELL, PRIMARY SYSTEMIC TYPE
Anaplastic large-cell lymphoma (ALCL), primary systemic type, accounts forapproximately 2%-3% of all NHLs. This disease mainly involves lymph nodes,although extranodal sites may be involved (not exclusively the skin; seesection on ALCL, CD30+ cutaneous type). This disease may be divided inpart based on the expression of the tyrosine kinase anaplastic lymphomakinase (ALK), created from a balanced chromosome translocation t(2;5).When heterogeneous patient populations are analyzed, the prevalence ofALK positivity in primary systemic ALCL cases is 50%-60%. ALK-positiveALCL is typically diagnosed in men prior to age 35 (male-to-female ratio,3:0), with frequent systemic symptoms and extranodal and advanced-stagedisease. ALK-negative patients are usually older (median age, 61 years), witha male-to-female ratio of 0:9 with a similar high incidence of extranodaldisease. In addition to the prognostic importance of ALK positivity, the IPIhas been identified as an independent prognostic factor within the group ofALK-positive ALCL patients, with a reported 5-year overall survival of 94%vs 41% for IPI 0 or 1 and 2 to 4, respectively. This better prognosis is apparentdespite ALK-positive patients more commonly presenting with poorer performancestatus and more advanced-stage disease compared with ALK-negativepatients.Therapy for pediatric ALCL is often based on prognostic risk factors, withtreatment regimens modeled after high-grade B-cell NHL protocols. Followinga brief cytoreductive prephase, short, intensified polyagent chemotherapyis administered, with the number of cycles dependent on stage of disease.
HEPATOSPLENIC T-CELL LYMPHOMA
Hepatosplenic T-cell lymphoma (HSTCL) is an uncommon T-cell lymphomathat is seen mainly in young males (median age, 35) presenting with B symptoms,prominent hepatosplenomegaly, mild anemia, neutropenia, thrombocytopenia(commonly severe), significant peripheral blood lymphocytosis,rare lymphadenopathy, and is associated with an aggressive clinical course(median survival, 12 to 14 months).The tumor cells are usually negative for CD4 and CD8 (85%); positive forCD2, CD3, and CD7 (negative for CD5); and express CD56 in 70%-80% ofcases. TIA-1 is present in almost all cases, but commonly granzyme B andperforin are not present, an indication of a nonactivated cytotoxic T-cellphenotype. Cells usually express the gamma/delta T-cell receptor (Vd1+/Vd2-/Vd3-) but are negative for EBV.Historically, patients have been treated with CHOP-like regimens. Early ASCThas been favored by some investigators based on anecdotal cases. A recentreport described activity with the purine analog pentostatin (Nipent) in relapsedHSTCL patients. Approximately 10%-20% of HSTCL cases arise inimmunocompromised patients, predominantly in the solid-organ transplantsetting.
EXTRANODAL NK/T-CELL LYMPHOMA,
NASAL AND NASAL-TYPE
Extranodal NK/T-cell lymphoma, nasal and nasal-type, formerly known asangiocentric lymphoma, is rare in Western countries, being more prevalent inAsia and Peru. The disease commonly presents in men at the median age of50. This entity is associated with EBV and is typically characterized byextranodal presentation and localized stage I/II disease, but withangiodestructive proliferation and an aggressive clinical course. These tumorshave a predilection for the nasal cavity and paranasal sinuses ("nasal"),although the "nasal-type" designation encompasses other extranodal sites ofNK/T-cell lymphomatous disease (skin, GI, testis, kidneys, upper respiratorytract, and rarely orbit/eye).Combined-modality therapy incorporating doxorubicin-based chemotherapy(minimum of six cycles for patients with stage III or IV disease), IFRT(median dose, 50 Gy; range, 30-67 Gy), and intrathecal prophylaxis is recommendedfor patients with extranodal NK/T-cell lymphoma, nasal, althoughthe benefit of the addition of chemotherapy to radiation therapy has notbeen confirmed for limited-stage disease.Patients with systemic disease have poor long-term survival (5-year overallsurvival, 20%-25%), with high locoregional (over 50%) and systemic failurerates (over 70%).
ENTEROPATHY-TYPE INTESTINAL T-CELL LYMPHOMA
Enteropathy-type intestinal T-cell lymphoma (EITCL) (also known as intestinalT-cell lymphoma), is a rare T-cell lymphoma of intraepithelial lymphocytesthat commonly presents with multiple circumferential jejunal ulcers inadults with a brief history of gluten-sensitive enteropathy. EITCL accountsfor less than 1% of NHLs, according to the International Lymphoma StudyGroup, and has been recognized to have a poor prognosis, with reported 5-year overall and disease-free survival rates of 20% and 3%, respectively. Thisis in part related to many patients presenting with poor performance statusand varied complications of locally advanced disease by the time a diagnosisof EITCL has been confirmed.EITCL may present without an antecedent celiac history, but most patientshave abdominal pain and weight loss. Evidence of celiac serologic markerssuch as positive antigliadin antibodies and/or HLA types such as DQA1*0501/DQB1*0201/DRB1*0304 may be present at diagnosis of EITCL. Moreover,these genotypes may represent celiac patients at higher risk for developmentof EITCL. Small bowel perforation or obstruction, GI bleeding, andenterocolic fistulae are recognized complications of this disease. Theimmunophenotype consists of pan-T-cell antigens, usually CD8+, and themucosal lymphoid antigen CD103 is often expressed.Following diagnosis of EITCL, doxorubicin-based combination chemotherapyshould be considered for each patient, and aggressive nutritionalsupport with parenteral or enteral feeding is critical in the care of thesepatients. Patients with known celiac disease should adhere to a gluten-freediet.
ADULT T-CELL LEUKEMIA/LYMPHOMA
The retrovirus HTLV-1 has been documented to be critical to the developmentof adult T-cell leukemia/lymphoma (ATL). HTLV-1 is known to causediseases other than ATL, including tropical spastic paraparesis/HTLV-1-associated myelopathy, infective dermatitis, and uveitis. In endemic areas inJapan, approximately 10%-35% of the population is infected with HTLV-1.Among these carriers, the overall risk of ATL is approximately 2.5% in patientswho live to age 70. Of the Caribbean population, 2%-6% are HTLV-1carriers, whereas less than 1% of the population in lower-risk areas, such asthe United States and Europe, are seropositive. HTLV-1 is transmittedthrough sexual intercourse, transfused blood products (products containing
white blood cells, not fresh frozen plasma), shared needles, breast milk, andvertical transmission. Transfusion of HTLV-1-contaminated blood productsresults in seroconversion in approximately 30%-50% of patients, at a medianof 51 days.The clinical features of 187 ATL patients included a median age at onset of 55years, lymphadenopathy (72%), skin lesions (53%), hepatomegaly (47%), splenomegaly(25%), and hypercalcemia (28%) present at diagnosis. The differentialdiagnosis between cutaneous ATL and mycosis fungoides is often difficult.ATL is separated into four subtypes divided by clinicopathologic fea-
tures and prognosis: acute, lymphoma, chronic, and smoldering. Shimoyamaand colleagues reported on the characteristics of 818 ATL patients in 1991.Patients with acute type present with hypercalcemia, leukemic manifestations,and tumor lesions and have the worst prognosis, with a median survivalof approximately 6 months. Patients with the lymphoma type presentwith low circulating abnormal lymphocytes (< 1%) and nodal, liver, splenic,CNS, bone, and GI disease; the median survival is 10 months. Patients withthe chronic type present with > 5% abnormal circulating lymphocytes andhave a median survival of 24 months, whereas the median survival of patientswith the smoldering type has not yet been reached.ATL is an aggressive neoplasm with resistance to conventional chemotherapy,in part due to the viral protein tax-mediated resistance to apoptosis andoverexpression of
-glycoprotein (the product of the multidrug resistance-1gene). Patients may initially respond to combination chemotherapy, but unfortunately,response durations are brief (5 to 7 months). El-Sabban andcolleagues combined arsenic trioxide with IFN-alpha, which induced cellcyclearrest and apoptosis. Response rates of 70%-90% to combination IFNalphaand zidovudine (Retrovir) therapy have been demonstrated in ATL,with associated increased median survival rates compared with those of his-toric control (11 to 18 vs 4 to 8 months, respectively). A recent clinical trial thatinvestigated initial cytoreductive therapy with CHOP followed byantinucleoside, IFN-alpha, and oral etoposide therapy demonstrated encouragingresults. Other agents with anecdotal activity in ATL includeirinotecan (Camptosar) and the purine analogs (2-deoxycoformycin and 2-chlorodeoxyadenosine), although 2-deoxycoformycin did not appear to improveoutcomes when added to combination chemotherapy. Future researchshould include the investigation of recombinant toxins and antibodies, suchas denileukin diftitox and alemtuzumab.
CUTANEOUS T-CELL LYMPHOMAS
Cutaneous T-cell lymphomas (CTCLs) constitute a group of cutaneous NHLswith clonal expansion of T lymphocytes into the skin. Several entities arerecognized by classification systems such as the European Organization forResearch and Treatment of Cancer (EORTC) and the WHO classification,which are based on morphologic, histopathologic, and molecular features(Table 14).External superficial irradiation is well tolerated and effective for local controlof CTCL. Radiation prescriptions are similar to those for the other lymphomasalready discussed.
MYCOSIS FUNGOIDES/SZARY SYNDROME
Mycosis fungoides represents the most common type of CTCL, comprising50% of CTCLs with a male predominance of approximately 2:1 and a predominanceof African-American patients of 1.6:1. It has a yearly incidence of0.36 cases per 100,000 population that has remained constant over the pastdecade. Clinical and histologic diagnosis of mycosis fungoides has proved tobe difficult, since in early stages, it may resemble other dermatoses such aseczematous dermatitis, psoriasis, and parapsoriasis.Clinically, mycosis fungoides is characterized by erythematous patches, evolvinginto plaques or tumors; however, the progress is variable. It is classifiedas an indolent lymphoma by the EORTC. Szary syndrome is the aggressive,leukemic, and erythrodermic variant of CTCL, which is characterized bycirculating, atypical, malignant T lymphocytes with cerebriform nuclei (Szarycells), and lymphadenopathy. For staging purposes, the tumor node metastasis(TNM) system is most commonly used.
Treatment of early-stage disease
At present, CTCLs are regarded as incurable.In early CTCL, the cell-mediated immune response is usually normal.Therefore, the majority of these cases can be treated successfully with topicalmodalities. Early aggressive therapy does not improve the prognosis of patientswith CTCL. The skin-targeted modalities include psoralen plus ultravioletA (PUVA); narrowband-ultraviolet B (NB-UVB); skin electron-beamradiation therapy; as well as topical preparations of steroids, retinoids,carmustine, or nitrogen mustard (Table 15).
Treatment of advanced stage disease
A limited number of patients progressinto more aggressive and advanced disease with either cutaneous orextracutaneous tumor manifestations. Treatment goals in advanced stagesshould be to reduce the tumor burden, relieve symptoms, and decrease therisk of transformation into aggressive lymphoma. Established treatment optionsinclude mono- or polychemotherapy including COP or CHOP regimens,extracorporeal photopheresis, interferons, retinoids, monoclonal antibodies(alemtuzumab), and recombinant toxins (denileukin diftitox). Combinationsare frequently used (Table 15).In mycosis fungoides, stage IA and IIA, only the skin is treated with lowenergyelectrons. The target volume does not exceed a depth of 5 mm. Significantmyelotoxicity is therefore unusual. Irradiation may consist of local ortotal skin, depending on the extent of disease. The standard dose for totalskinelectron-beam therapy is 36 Gy delivered by dual fixed-angle, six-fieldmethods 4 days a week. Electron-beam therapy results in a complete responserate of 56%-96% in patients with stage IA-IIA disease. There is a highrelapse rate in extensive cases after total skin electron-beam therapy withoutadjuvant therapy, such as topical chemotherapy and PUVA. Consequent relapsefreesurvival for patients with stage IA disease is 33%-52% at 10 years.
Lymphomatoid papulosis is most commonly associated with mycosisfungoides, CD30+ large T-cell lymphoma, and Hodgkin's lymphoma. Threehistologic types have been identified, characterized as types A, B, and C.Types A and C consist of large lymphocytes resembling Reed-Sternberg cells.Type A cells are embedded in a dense inflammatory background, whereastype C cells form large sheets imitating CD30+ large T-cell lymphoma. Type Bsimulates classic features of mycosis fungoides, with epidermotropism and adermal band-like infiltrate composed of small to medium cells. Lymphomatoidpapulosis lesions occasionally exhibit clonal gene rearrangements.Lymphomatoid papulosis represents a benign, chronic recurrent, self-healing,papulonodular, and papulonecrotic CD30+ skin eruption. However,10%-20% of patients may develop a lymphoid malignancy, but the prognosisfor patients with lymphomatoid papulosis is otherwise excellent, with a 100%5-year survival. There is no curative treatment available. Lymphomatoidpapulosis is managed by observation, intralesional steroid injection, ultravioletlight therapy, or low-dose methotrexate.
ALCL, CD30+ CUTANEOUS TYPE
Primary systemic CD30+ ALCL and primary cutaneous CD30+ ALCL representidentical morphologic entities, but they are clinically distinct diseases.The neoplastic cells of primary cutaneous CD30+ large T-cell lymphoma(CD30+ LTCL) are of the CD4+ helper T-cell phenotype with CD30 expression.It represents 9% of CTCLs and typically presents with solitary or localizednodules. This tumor has an excellent prognosis, as confirmed in severalstudies, in contrast to the transformation of mycosis lymphoma to a CD30-large cell variant. It shows histologic and immunophenotypic overlap withlymphomatoid papulosis. In most cases, tumor cells show anaplastic features,less commonly a pleomorphic or immunoblastic appearance. However,there is no difference in the prognosis and survival rate. Primary cutaneousCD30+ LTCLs rarely carry the t(2;5) translocation and are usuallyALK-negative. These lesions may undergo spontaneous regression, as dothe lesions of lymphomatoid papulosis. The mechanism of tumor regressionremains unknown.Spot radiation therapy or surgical excision is the preferred treatment, withsystemic chemotherapy reserved for cases with large tumor burden andextracutaneous involvement. More recently, there has been reported efficacyof recombinant IFN gamma-1b (Actimmune) and combined treatmentwith bexarotene (Targretin) and IFN-alfa-2a (Roferon-A).
LTCL, CD30- CUTANEOUS
Primary cutaneous CD30- large T-cell lymphomas (CD30- LTCL) do notproduce T helper 2 (Th2) cytokines and do not express CD30. Microscopically,a dense nodular or diffuse infiltrate characterized by pleomorphic mediumor large cells and immunoblastic lymphocytes is present. Large cellscomprise over 30% and might resemble classic mycosis fungoides undergoinglarge cell transformation.These lymphomas are aggressive neoplasms, with an estimated 15% 5-yearsurvival rate. Patients present with solitary, localized, or generalized plaques,nodules, or tumors without spontaneous regression. Multiagent systemicchemotherapy is recommended in most cases, with radiotherapy limited tolocalized disease.
PLEOMORPHIC T-CELL LYMPHOMAS
WITH SMALL/MEDIUM CELLS
The small/medium pleomorphic CTCL type appears clinically with singleerythematous to violaceous nodules or tumors and accounts for less than 3%of CTCL cases. Most cases have an unfavorable prognosis, with a mediansurvival of ≤ 24 months; however, the CD3+, CD4+, CD8-, CD30- subtypewith limited lesions might be associated with a better prognosis, with a reported45% 5-year survival rate.The optimal therapy for pleomorphic T-cell lymphomas with small/mediumcells has not been defined. Localized lesions have been treated with radiationtherapy or surgical excision. Only short-term outcome has been reported.Patients with generalized skin disease or progression have been treated effectivelywith systemic treatments, including multiagent chemotherapy,retinoids, interferons, and monoclonal antibodies.
SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA
Subcutaneous panniculitis-like T-cell lymphoma (SCPTCL) is a rare T-celllymphoma that infiltrates the subcutaneous fat without dermal and epidermalinvolvement, causing erythematous to violaceous nodules and/or plaques,and is often associated with a systemic hemophagocytic syndrome. Necrosisof fat and connective tissue is always seen but not with angiodestruction. Thephenotype consists of pan-T-cell antigens that are more commonly CD8+ >CD4-CD8- > CD4+, whereas CD56 is usually negative. SCPTCL is a diseasethat has been recognized to have diverse outcomes ranging from indolent toaggressive/fatal clinical courses.When treatment is warranted, most patients respond to systemic combinationchemotherapy or local radiation therapy, although the median survivalis typically less than 2 years. One case report described a patient with SCPTCLwith durable response following fludarabine, mitoxantrone (Novantrone),and dexamethasone (FND) therapy.
CUTANEOUS B-CELL LYMPHOMAS
Primary cutaneous B-cell lymphomas (CBCLs) are rare entities. They constituteup to 25% of all cutaneous lymphomas. However, the incidence of cutaneousB-cell lymphomas has been underestimated due to the absence ofimmunologic and molecular markers. In addition, their terminology and classificationremain controversial, with separate and distinct terminology promotedby the WHO and the EORTC. Primary CBCLs are distinct from nodallymphomas, and the majority of them have an excellent prognosis. Severaltypes are recognized, with the most common types being follicle center celllymphoma (FCCL) and MZL.
Follicle center cell lymphoma
FCCL is the most common subtype, comprising40% of CBCLs. It is classified as diffuse large B-cell lymphoma in theWHO classification. FCCL shows predilection for the head, neck, and trunkin elderly patients, with a median age of 60 years and a male predominance ofapproximately 1.5:1. The clinical course is usually indolent, with an excellentoverall survival of up to 97%. However, relapses occur frequently. The largeround cell morphology might be associated with a higher rate of diseaseprogression and poorer prognosis. FCCL is defined as a proliferation ofcentrocytes (small to large cleaved cells) and centroblasts (large round cellswith prominent nuclei), showing a nodular or diffuse infiltrate in the majorityof cases and presenting only rarely a true follicular pattern.Small centrocytes predominate in low-grade FCCL, whereas an increasednumber of large cells occur in high-grade FCCL; however, lesions with purehigh-grade disease may behave indolently and should not by themselvesdrive the treatment administered. In contrast to their nodal counterpart,
is usually not expressed in neoplastic cells, and the t(14;18) translocation israrely detected. More recently, low rates of
expression have been reported.In addition to CD10+ and
+ expression, FCCL also has anaberrant expression of CD45 RA and CD43 and thus provides a helpful clueto distinguish it from pseudolymphomas. Radiation therapy is often the preferredtherapy for solitary or localized group lesions. Surgical excision can beconsidered for small lesions. Chemotherapy, though effective, rarely resultsin cure. Rituximab has proven to be an effective alternative for palliation.Observation is a reasonable alternative in many instances.
Immunocytoma/marginal zone lymphoma
IC/MZL is a recently recognizedlow-grade lymphoma and represents the second most common subtype ofCBCL. It predominantly occurs on the upper and lower extremities. Themedian age at presentation is 55, and females are affected more than males.The reported survival rates are 97%-100%, although relapses commonly occur.Histologically, IC/MZL has features of MALT lymphomas and shows anodular or diffuse dermal infiltrate with a heterogeneous cellular infiltrate ofsmall lymphocytes, lymphoplasmacytoid cells, plasma cells, intranuclear inclusions(Dutcher bodies), and reactive germinal centers that may be infiltratedby neoplastic cells. Diagnosis can be difficult, because of the variablecomposition of the infiltrate that may be interpreted as a reactive process oras FCCL. In contrast to FCCL, MZL is negative for
and CD10. In 50%of cases, CD43 is highly expressed. Large cell transformation and a head andneck presentation may be associated with a worse prognosis. Therapeuticalternatives are similar to those described for FCCL.
LARGE B-CELL LYMPHOMA OF THE LEG (LBCLL)
Primary cutaneous large B-cell lymphoma of the leg (LBCLL) forms a separatecategory in the EORTC classification, as a more aggressive type confinedto elderly patients, with a median age of 76 at diagnosis and a female predominanceof 7:2. Most cases have a follicle center cell origin, and histologicevaluation shows a diffuse dermal infiltrate with predominance in large Bcells with multilobulated nuclei, comprised of centroblasts and immunoblasts,with presence of small-cleaved cells and a minor admixed infiltrate component.Eosinophilic intranuclear (Dutcher body) or intracytoplasmic (Russellbody) inclusions of immunoglobulin are common. Unlike FCCL, they consistentlyexpress
, although it is not associated with the t(14;18) translocation.The prognosis is less favorable than other CBCLs, with a 5-year survival rateof 50%-60%. Prognostic factors identified with a poor outcome include thepredominance of round cells (centroblasts/immunoblasts) over cleaved cells(centrocytes) in the tumor infiltrate, MUM1 expression, and multiple lesionsat presentation. The use of an IPI-based model is required to investigatewhether LBCLL is associated with a poorer prognosis. These lymphomasshould be treated as systemic diffuse large cell lymphomas with anthracyclinebasedchemotherapy. In patients presenting with a single small skin tumor,radiotherapy is a consideration. Rituximab has also been incorporated intocombination regimens.
Intravascular large B-cell lymphoma
The EORTC has proposed intravascularlarge B-cell lymphoma (IVLBCL) or angiotropic B-cell lymphoma as a provisionalentity. This subtype is rare and corresponds to the proliferation of malignantlymphocytes within lumina of small vessels, involving most frequently theskin and CNS. It was previously considered a vascular tumor and referred to asmalignant angioendotheliomatosis. Although the majority of cases are of B-cellorigin, few cases of T-cell lineage have been reported. The reason for intravascularlocalization is not clear, but association with an unknown surface receptoror dysfunction of lymphocyte-endothelial interaction affecting adhesion molecules has been suspected. IVLBCL is clinically characterized by tendererythematous, purpuric, indurated patches and plaques located on the trunkand thighs, where it can resemble panniculitis. Cases of generalized telangiectasiaover normal skin have been reported. Cytomorphology reveals intravascularocclusion of small vessels, filled with large atypical centroblast-like B lymphocytes.IHC shows CD19, CD20, CD45, and CD79a expression. Genotypicanalysis has demonstrated clonality, although it may not be positive in everycase. Generally, the prognosis of this aggressive type of lymphoma is poor,despite the use of combination chemotherapy, because of the initial or secondaryCNS involvement. Prognosis appeared better in some reports, if isolatedcutaneous involvement was present. However, no large series permitting aprecise prognosis to be determined are available.
Primary cutaneous involvement of plasmacytoma is uncommon and generallydevelops as a consequence of direct spread from an underlying multiplemyeloma. It represents 4% of extramedullary plasmacytomas and affectspredominantly elderly men with a median age of 60 years at diagnosis. It ischaracterized by a monoclonal proliferation of mature plasma cells. Cutaneousplasmacytomas are potentially curable, with a 5-year survival rate of> 90%. However, the presentation of multiple lesions is an important adverseprognostic factor. Histopathology shows a dense monomorphous dermalinfiltrate of plasma cells with a varying degree of maturation and atypia,admixed with few lymphocytes and histiocytes. Neoplastic plasma cells expressclonal immunoglobulin, CD38, and CD79a but are negative for CD20.Rarely, amyloid deposition within the tumor is demonstrated, which is morecommon in secondary cutaneous involvement of plasmacytoma. A recentorganized workshop on plasma cell dyscrasias questioned whether thesecases are true cutaneous plasmacytomas, represent reactive B-cell infiltratesassociated with an infectious etiology, or represent a variant of MZL with apredominant population of plasma cells. Diagnosis may rely on demonstrationof monoclonality by restriction of Ig light chain expression. Excision orradiation treatment is most commonly used.
The distinction between a true CBCL and B-cell pseudolymphoma is oftendifficult; however, IHC and molecular techniques make a distinction morelikely. It involves most commonly the face and chest, with a female predominance.Precipitating stimuli may be arthropod bites, drugs, tattoos, and injections.In Europe, an association with
infection has been reported.Microscopically, there is a dense polymorphous infiltrate with variousnumbers of eosinophils, plasma cells, T lymphocytes, and histiocytes.Histologic features may resemble IC/MZL. A transformation into malignantB-cell lymphoma has been observed.
Most lymphomas seen in patients who have HIV infection are of an aggressivehistology and advanced stage at presentation. Extranodal disease iscommon, with unusual sites of presentation, including the rectum, CNS, andmultiple soft-tissue masses. Some patients present with primary CNS lymphoma.Poor-risk factors include a high LDH level, large tumor bulk,extranodal disease, and low CD4 cell counts (< 100 cells/mL). Because oftheir increased risk of opportunistic infections and impaired hematologicreserve, historically many patients with HIV-related lymphomas were unableto tolerate aggressive chemotherapy regimens. Current antiviral medicationshave allowed for the use of more traditional regimens, including RCHOPand R-CHOEP (see Table 8), with results comparable to those ofother NHL patients with similar histologies and presentations.CNS prophylaxis with intrathecal chemotherapy is necessary to preventmeningeal dissemination. (For a more detailed discussion of HIV-relatedNHL, see chapter 27.)
Posttransplantation lymphoproliferative disorders(PTLDs) comprise a histologic spectrum, ranging from hyperplastic-appearinglesions to frank NHL or multiple myeloma histology. The incidence varies from1% in renal transplant recipients to 8% in lung transplant recipients, who requiremore potent immunosuppressive therapy. The use of anti-T-cell therapiesor T-cell depletion in stem-cell transplant recipients will increase the risk ofPTLD. More than 90% of tumors are associated with EBV. Reduction of immunosuppressioncan lead to disease regression. In anatomically limited PTLD,resection or targeted radiation treatment can be effective. Traditional chemotherapyhas been associated with significant toxicity but can result in long-termdisease-free remissions or cure. Biologic agents including IFN and more recentlyrituximab have shown significant promise. In vitro expanded EBVspecificcytotoxic T cells have been used for treatment and prophylaxis forPTLD following allogeneic stem-cell transplantation.
Primary CNS lymphoma
Primary CNS lymphoma is a rare form of NHL,arising within and confined to the CNS. Histologically, primary CNS lymphomasare indistinguishable from systemic NHLs. More than 40% of patientshave evidence of leptomeningeal dissemination, and 15% have oculardisease at presentation. A stereotactic needle biopsy is the procedure ofchoice for histopathologic diagnosis. Resection does not appear to improvesurvival. Modern management includes high-dose methotrexate alone orcombined with agents that penetrate the CNS (high-dose cytarabine, vincristine,and procarbazine [Matulane]). Whole-brain radiotherapy has been considereda standard component of treatment; however, long-term neurotoxicityremains a concern, and, therefore, alternative approaches are beingexplored.
Tumor lysis syndrome
is a common complication after treatment of highgrade,bulky NHLs (due to their exquisite sensitivity to therapy and highproliferative capacity). The syndrome is characterized by renal failure,hyperkalemia, hyperphosphatemia, and hypocalcemia.Measures to prevent this complication include aggressive hydration; allopurinol;alkalinization of the urine; and frequent monitoring of electrolytes,uric acid, and creatinine. Dialysis is sometimes required. Rasburicase, a recombinanturateoxidase enzyme, is now available for the prevention andtreatment of hyperuricemia. (For a more comprehensive discussion of thetumor lysis syndrome, see chapter 45.)
Follow-up of long-term survivors
The most important risk to patients with NHL is relapse. Amongpatients with diffuse aggressive lymphomas, most recurrences are seen withinthe first 2 years after the completion of therapy, although later relapses mayoccur. Physical examination and laboratory testing at 2- to 3-month intervalsand follow-up CT scans (with or without PET scan) at 6-month intervals forthe first 2 years following diagnosis are recommended.Early detection of recurrent disease is important because these patients maybe candidates for potentially curative high-dose therapy and stem-cell transplantation.Patients with advanced low-grade NHL are at a constant risk ofrelapse, and late recurrence of disease may be seen, sometimes after morethan a decade-old remission.
Long-term survivors are at increased risk of secondcancers. In a survey of 6,171 patients with NHL who survived 2 or moreyears, nearly 1,000 patients lived 15 or more years after diagnosis. Secondcancers were reported in 541 subjects, with significant excesses seen for allsolid tumors; acute myelogenous leukemia; melanoma; Hodgkin's lymphoma;and cancers of the lungs, brain, kidneys, and bladder. The actuarial risk ofdeveloping a second malignancy at 3-20 years after diagnosis of NHL was21%, compared with a population-expected cumulative risk of 15%.
With the decline in the role of irradiation as partof the initial therapy for NHL, the risk of certain radiation-induced complicationshas been reduced or eliminated in more recently diagnosed patients.Nevertheless, total-body irradiation is often used as a component ofmyeloablative conditioning regimens. Also, transplant recipients are at increasedrisk of secondary myelodysplasia and acute myeloid leukemia, regardlessof whether they received a radiation-containing conditioning regimen.Individual chemotherapy agents all have their own potential long-termmorbidity.Long-term survivors need continued follow-up for possible treatment-relatedcomplications. Some of these toxicities may still be unknown. Careful documentation of late complications will be important in the design of futuretreatment strategies aimed at preserving or improving response rates andduration of remission while reducing toxicity.
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