Intermediate- and High-Grade Non-Hodgkin's Lymphomas

April 1, 2005

The non-Hodgkin's lymphomas (NHLs) are a collection of lymphoid malignancies with a diverse pathology and natural history. This diversity is illustrated by the different histologic subtypes and classifications of NHL that have appeared over the years.

IntroductionEpidemiogy and EtiologyClinical Features and Diagnosis Staging and TreatmentIntermediate Grade NHLHigh-Grade TumorsConclusionReferences

 Introduction

The non-Hodgkin's lymphomas (NHLs) are a collection of lymphoid malignancies with a diverse pathology and natural history. This diversity is illustrated by the different histologic subtypes and classifications of NHL that have appeared over the years. With the rapid progress in our understanding of the biology of lymphomas, new systems of classification have better described this group of diseases. Although the number of classification systems has caused some confusion, in the mid-1970s, the National Cancer Institute (NCI) initiated the NHL pathologic classification project with the aim of standardizing classifications through a Working Formulation (Table 1). This formulation is based on the largest single cohort of patients reported to date and is the framework for this chapter [1,2].

Classifiable non-Hodgkin's lymphomasUnaccounted-for non-Hodgkin's lymphomas
Low-gradeMucosa-associated lymphomas,   CD5–, CD10–

Follicular, predominantly
  large-cell

Diffuse small-cleaved cell



Diffuse mixed small- and
  large-cell epithelioid  component

Diffuse large-cell cleaved, T-cell
  variants, non-cleaved

Large-cell, immunoblastic
  plasmacytoid, clear-cell,   
  polymorphous, epithelioid

Small non-cleaved cell
  Burkitt's
  Follicular areas

Composite
Mycosis fungoides/Szary
  syndrome
Histiocytic
Unclassifiable

The Working Formulation is useful as a source of prognostic information and a tool for treatment planning. However, several of its limitations deserve mention. First, nearly 10% of the lymphomas encountered in practice elude precise classification, particularly lymphomas presenting primarily in extranodal tissues where there is no lymph-node architecture. In these cases, clinical experience and certain tests can help to predict the natural history of the disease.

Second, within the broad histologic categories of low-, intermediate-, and high-grade lymphomas, there can be a wide spectrum of biologic behavior, as illustrated by the survival curves from the NCI project (Figure 1). Third, histopathologic classification alone is inadequate in some cases, as sometimes there is less-than-ideal interobserver agreement [3]. Immunophenotyping, cytogenetics, and specific oncogene studies have been found to be important factors in diagnosing clinically unique subtypes of NHL. Lymphomas not accounted for by the Working Formulation are listed in Table 1, with their unique immunophenotype or cytogenetic abnormalities next to the histologic subtype with which they are typically associated.

Figure 1. Actuarial survival curves for the 10 subtypes of the formulation shown individually (upper panel) and in the three prognostic categories (lower panel). Curves are discontinued when less than five patients are at risk. Adapted, with permission, from Cancer 1982 [1].

Indeed, the limitations of the Working Formulation have prompted further discussion, and another classification system has now been introduced (Table 2) [4]. This chapter, however, will follow the categorization of the Working Formulation.

Precursor B-cell neoplasms

Precursor B-lymphoblastic leukemia/lymphoma

Peripheral B-cell neoplasms

B-cell chronic lymphocytic leukemia/prolymphocytic
   leukemia/small lymphocytic lymphoma

Lymphoplasmacytoid lymphoma/immunocytoma

Mantle-cell lymphoma

Follicle center lymphoma, follicular

Marginal zone B-cell lymphoma

Provisional entity: Splenic marginal zone lymphoma
   (± villous lymphocytes)

Hairy-cell leukemia

Plasmacytoma/plasma-cell leukemia

Diffuse large B-cell lymphoma subtype: Primary mediastinal
   B-cell lymphoma

Burkitt's lymphoma

Provisional entity: High-grade B-cell lymphoma, Burkitt-like

Precursor T-cell neoplasm

Precursor T-lymphoblastic lymphoma/leukemia

Peripheral T-cell and NK-cell neoplasms

T-cell chronic lymphocytic leukemia/prolymphocytic leukemia

Large granular lymphocyte leukemia

Mycosis fungoides/Szary syndrome

Peripheral T-cell lymphomas, unspecified

Angioimmunoblastic T-cell lymphoma

Angiocentric lymphoma

Intestinal T-cell lymphoma (± enteropathy associated)

Adult T-cell leukemia/lymphoma

Anaplastic large-cell lymphoma, CD30+, T and null-cell types

Provisional entity: Anaplastic large-cell lymphoma, Hodgkin's-like

Lymphocyte predominance

Nodular sclerosis

Mixed cellularity

Lymphocyte depletion

Provisional entity: Lymphocyte-rich classic Hodgkin’s disease

Epidemiology and Etiology

At present, there is an emerging unexplainable epidemic of NHL [5]. In the United States, the incidence has increased from 6.9 per 100,000 population in 1947 to 1950 to 17.4 per 100,000 population in 1984 to 1988. Changes in exposure to described risk factors (Table 3) [5-14] do not explain this increase, much of which is largely caused by a rise in intermediate-grade lymphomas among the elderly. Another unexplained phenomenon is the slight but consistent predominance of NHL incidence in men (male:female ratio 1.5 to 1.25:1).

Risk factorsAssociated subtype of lymphoma

Hereditary immunodeficiency disorders

Ataxia-telangiectasia
Bruton-type agammaglobulinemia
Severe combined immunodeficiency
Wiskott-Aldrich syndrome
Duncan's syndrome
Chdiak-Higashi syndrome

Infections

Human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV)

EBV
 

Human T-lymphocyte virus-1   

Helicobacter pylori

Autoimmune disorders

Rheumatoid arthritis

Sjgren's disease
 

Hashimoto's thyroiditis

Celiac disease

Drugs

Immunosuppressants
 

Chemotherapeutic agents

Phenytoin

Blood transfusions

Environmental toxins

Herbicides
Vinyl chloride
Solvents
Hair dyes

African (endemic)
  Burkitt's NHL [7]

Specific peripheral T-cell NHL [8]

Gastric mucosa-associated lymphoid   tissue(MALT) lymphomas [9]

 

Variable [10]

Primary, salivary, and lacrimal gland   NHL [11]

Primary thyroid gland NHL [11]

Enteropathy-associated T-cell NHL

 

Post-transplant lymphoproliferative
  disorder [12]

Secondary diffuse large-cell NHL

Pseudolymphoma [13]

Variable [14]

 

Variable [5]

Intermediate- and high-grade tumors comprise nearly 55% of NHLs, with a proportionately higher number of high-grade tumors in children and young adults [1]. Ninety percent of childhood NHLs are Burkitt's NHL, T-cell acute lymphoblastic lymphoma (T-ALL), or diffuse large-cell lymphoma with a Ki-1 immunophenotype.

Despite the variation with age in the incidence of certain types of NHL, the biology, including underlying molecular defects, appears relatively uniform within a histologic subtype. There is no single defect that alone causes a lymphoma. The etiology and pathogenesis of intermediate- and high-grade lymphomas are considered parts of a multistep process in which the malignant phenotype develops gradually. Hereditary and environmental factors contribute to this process. Hereditary factors, childhood lymphomas, and high-grade tumors are closely associated. Some of these associations and others, are presented in Table 3 and referenced.

Three factors appear common to the etiology of lymphomas. The first is that certain patients may be predisposed to develop a type of lymphoma because of a generalized or, perhaps, specific immune defect. This “host” defect frequently includes autoimmune diseases. The second factor is the occurrence of a specific infection that is difficult to eradicate and that may alter normal lymphoid tissues. The third factor is that a single specific mutation or a number of specific mutations or chromosome translocations can alter suppressor genes or oncogenes, respectively, and result in a lymphoma. With any specific lymphoma, any or all of these factors may be at work.

A number of specific diseases illustrate how immune factors contribute to lymphomagenesis. Duncan's syndrome, or X-linked lymphoproliferative syndrome, is a particularly interesting example [15]. Males with this syndrome are unable to mount an appropriate immunologic response to an Epstein-Barr virus (EBV) infection. They develop a fatal lymphoproliferative syndrome when first infected. The precise immune defect in these patients is not known.

Posttransplant lymphoproliferative syndrome is strikingly similar [12]. Immunosuppression following solid-organ transplantation can cause an EBV infection-related polyclonal lymphoproliferative disease that can develop into a typical NHL if immunosuppression is not stopped. The primary central nervous system (CNS) lymphomas associated with the human immunodeficiency virus (HIV) may develop in a similar fashion following EBV infection [6]. These examples show how an immune defect coupled with an infection can lead to a lymphoma.

Viruses such as EBV, human T-cell leukemia virus-1 (HTLV-1), and HIV are not the only infectious agents that can interact to cause lymphomas. Helicobacter pylori is a bacterium that has been found to cause gastric ulcers as well as gastric lymphomas [9]. The pathogenesis is still being determined, but it is possible to cure some gastric lymphomas with the triple antibiotic regimen used to eradicate H pylori. Thus, removing an infectious agent can possibly lead to curing a lymphoma. Similarly, in posttransplant lymphoproliferative disease, stopping the immunosuppression early in the process can prevent the development of a lymphoma. In both posttransplant lymphoproliferative disease and H pylori associated gastric lymphoma, beyond a certain point, reversing the offending agent does not lead to the resolution of the lymphoma. This suggests that another step occurs, conferring a nonreversible malignant phenotype.

In some cases, this last step may involve the mutation of a suppressor gene causing loss of tumor suppression, or a chromosome translocation, causing the abnormal expression of an oncogene. Both of these processes may in turn cause the loss of normal cellular responses. Tumor-suppressor genes have a number of functions, but many of them seem to suppress tumors by regulating the cell cycle and, in turn, proliferation. A good example of this is the transformation of typical low-grade follicular NHL into intermediate NHL through the development of a p53 mutation [16]. Table 4 presents the known translocations and their oncogenes involved in lymphomagenesis [17].

LymphomaChromosomeAffected type translocation gene
Burkitt's NHLt(8;14) t(8;22) t(2;8)c-
DLCL-NHLt(3;14) t(3;4)BCL
Mantle NHLt(11;14)BCL
Transformed NHLt(14;18)BCL
NHL-B and -TInv 14TCR
T-NHLt(4;16)IL
Ki-1 anaplastict(2;5)NPM

Perhaps the single best example of the modern paradigm of lymphomagenesis is the pathogenesis of African or endemic Burkitt's NHL [7]. Endemic Burkitt's NHL is found in areas of Africa with a high incidence of malaria. Malaria may cause a defect in the immune system of children residing in these areas, which results in their inability to resolve EBV infections successfully. Following EBV infection, which is serologically documented in more than 90% of cases of endemic Burkitt's lymphoma, the lymphoma finally develops when a chromosome translocation brings the c-myc oncogene on chromosome 8 into the proximity of an immunoglobulin gene on either chromosome 2, 14, or 22 and its regulatory sequences. The c-myc oncogene then becomes overexpressed through its abnormal transcription mediated by the immunoglobulin gene-regulatory sequences, causing cellular proliferation and Burkitt's lymphoma.

Nonendemic Burkitt's NHL has a different presentation from that of endemic Burkitt's NHL; it is less frequently associated with EBV, and it has a different translocation breakpoint between the c-myc and immunoglobulin genes. All these factors suggest a different pathogenesis for nonendemic Burkitt's NHL [18]. The mechanism that causes one step to lead to the next still remains unknown. We are just beginning to scratch the surface of this complex problem, but as genes and their functions become better understood, it is likely that, in the future, lymphomas will be diagnosed and treated based on their specific genetic abnormalities.

Clinical Features and Diagnosis

Sites Of Presentation

The clinical manifestations of intermediate- and high-grade NHLs are diverse and depend on the site of disease involvement. These tumors have a rapid growth rate and present as masses that cause symptoms when they infiltrate tissues or obstruct organs. The more aggressive the lymphoma, the more frequently it is localized. Pain within an enlarged lymph node may also be noted if the tumor is rapidly growing.

Lymphomas appear most frequently in sites with the most lymphoid tissue. Thus, the lymphoid and reticuloendothelial system, which includes the lymph nodes, spleen, liver, and bone marrow, is most frequently involved, but any extranodal site may also be primarily involved. Certain lymphomas have classic anatomic presentations. However, these features are not invariably present, except perhaps in the cutaneous postthymic T-cell lymphomas, which include mycosis fungoides and Szary syndrome. Endemic Burkitt's NHL frequently presents as a head and neck mass in a child. T-ALL frequently presents with a mediastinal mass in younger patients [19].

Anaplastic large-cell lymphoma with positive Ki-1 staining (CD30+) in younger patients is another variant with frequent cutaneous presentation and a predilection for extranodal tissue [20]. A clinically distinct primary mediastinal B-cell diffuse large-cell lymphoma presents in young women [21]. The gastrointestinal tract is often involved in certain types of lymphoma. This is the case with many mucosa-associated lymphoid tissue (MALT) lymphomas, 15% of mantle-cell lymphomas, 10% of intermediate-grade lymphomas of Waldeyer's ring and sinuses, and rare lymphomas (enteropathy-associated T-cell NHL, immunoproliferative small-intestinal disease, and Mediterranean lymphoma) [22]. Certain predisposing conditions will also have a classic extranodal tissue presentation. Patients with Hashimoto's thyroiditis are predisposed to primary thyroid lymphomas, patients with Sjogren's syndrome to primary salivary and lacrimal gland NHL, and patients with celiac disease to enteropathy-associated T-cell NHL.

Involvement of “sanctuary” sites, which include the CNS and testicles, is more frequently associated with Burkitt's NHL and non-Burkitt's small-cell NHL, T-ALL, primary testicular diffuse large-cell lymphoma [23], HIV-associated aggressive B-cell lymphoma, and HTLV-1 associated lymphoma.

Systemic Features

As with Hodgkin's disease, NHL also presents with systemic B symptoms, including fever, which may or may not have the Pel-Ebstein relapsing pattern; drenching night sweats; and more than 10% weight loss. Generalized pruritus may also be present.

Paraneoplastic syndromes may also develop with these types of lymphomas. Nonparathyroid hormone induced hypercalcemia occurs in approximately 10% of patients [24]. Hypercalcemia also is frequently associated with HTLV-1 T-cell lymphomas. Subacute motor neuropathy and polymyositis may also be linked with NHL [25].

Diagnosis

A diagnosis of NHL, as well as suspected relapses, should be made based on the pathologic examination of a lymph node whenever possible. The accuracy of fine-needle aspiration (FNA) is variable. In one trial, lymphomas were diagnosed using FNA in 86% of cases and were accurately categorized into low, intermediate, or high grade in 68% of cases [26]. In some instances, it may be necessary to establish clonality to confirm malignancy. Clonality is established when one it can be proved that all cells in a lymphoma were derived from a single cell. In B-cell NHL, monotypic immunohistochemical staining for kappa or lambda light chain is often all that is needed to confirm clonality. In some cases, one may need to establish clonality by performing studies on either T-cell receptor rearrangement or J-H segment rearrangements of the B-cell immunoglobulin gene. Gene rearrangement studies are diagnostic and reliable in more than 96% of these cases [27]. Occasionally, a specific diagnosis can be made by cytogenetic analysis. Some of these specific chromosomal translocation fusion genes are amenable to polymerase chain reaction assays, which can then be used in studies of minimal residual disease (Table 4) [17].

Staging and Treatment

Staging allows clinicians to prognosticate and then treat appropriately. The staging of intermediate- and high-grade non-Hodgkin's lymphomas has become an area of intense research. For some time, NHL was staged anatomically, like Hodgkin's disease. It has become clear, however, that unlike Hodgkin's disease, NHL does not spread anatomically to contiguous nodal regions and, therefore, cannot be reliably staged solely by anatomic methods.

The treatment of Hodgkin's disease and NHL has formed the modern paradigm of cancer chemotherapy. The basic concepts were first established for infectious diseases and then applied to oncology. Skipper and colleagues, followed by Goldie and Coldman, established the principles of tumor resistance and, in turn, combination chemotherapy and non-cross-resistant chemotherapeutic regimens [28,29]. The curability of advanced cancer ushered in the modern era of oncology.

Today, the principal treatment for NHL is combination chemotherapy and radiation therapy. Surgery is used chiefly as a diagnostic tool, with some unique exceptions. Combination chemotherapy with cyclophosphamide (Cytoxan, Neosar), doxorubicin (Adriamycin, Rubex), vincristine (Oncovin), and prednisone-the CHOP regimen-was developed at M.D. Anderson Cancer Center and introduced in the 1970s. Since then, a number of second- and third-generation regimens and combinations of non-cross-resistant regimens for intermediate- and high-grade NHLs have been developed. The benefit of these newer regimens is now in question, but some issues are not yet clearly resolved. Current trials of chemotherapy for NHL may hold the answers.

Intermediate Grade NHL

Staging

A number of staging systems for intermediate-grade NHL have been developed based on retrospective evaluation of clinical, laboratory, radiologic, and pathologic data for patient cohorts. Table 5 [30-33] lists the individual prognostic factors studied to date that have been related to outcome in intermediate-grade NHL [30,34,35]. These factors can be grouped into categories that reflect different aspects of the disease: host factors, tumor burden, and tumor biology as they relate to pathogenicity and drug resistance. Performance status, lactate dehydrogenase (LDH) level, and extent of tumor have been validated prospectively as reliable prognostic factors [36].

Host factors

Age
"B" symptoms
Performance status

Tumor burden

Ann Arbor stage
Number of extranodal sites
Bulky sites
Serum LDH level
Serum beta-2-microglobulin

Tumor biology

Pathogenicity
  B- vs T-cell
  S-phase percent
  Ki-67 expression
  CD-44 expression
  HLA-DR expression
  IL-10 serum concentration
  Soluble IL-2 receptor levels in serum
  Cytogenetics 7-, 17P-
  BCL-2 expression
  BCL-6 expression

Drug resistance
  Response after three cycles of chemotherapy
  MDR-1 gene expression

Many of the other factors are still under investigation, and testing for some of the serologic parameters is not routinely performed. In the future, however, some of these factors may replace or complement existing ones, because even our best current prognostic models have less than desirable positive and negative predictive values.

At M.D. Anderson, disease is staged according to the “tumor score” system, which is compared in Table 6 with the other frequently used system, the International Index [34,35].

 Prognostic models
FactorInternational indexM.D. Anderson tumor score

Ann Arbor stage: 3 or higher

2 or more extranodal sites

2 or higher Zubrod
  performance status

High LDH > 250 IU at MDA 

Beta-2-microglobulin > 3.0
  at MDA

B symptoms

Number of sites of bulky
  (> 7 cm diameter) NHL

Total possible points

Yes = 1 point

Yes = 1 point

Yes = 1 point
 

Yes = 1 point

Not included
 

Not included

Not included
 

0 to 5 points

Yes = 1 point

Not included

Not included
 

Yes = 1 point

Yes = 1 point
 

Yes = 1 point

Yes = 1 point
 

0 to 6 points

The main advantage of the M.D. Anderson tumor score is that it appears to separate more clearly tumors with a good prognosis from tumors with a poor prognosis (Table 7).

M.D. Anderson tumor scoreCR rate (%)% Disease-free survival at 3 years

3 to 6

46

24

International index scoreCR rate (%)% Disease-free survival at 5 years

2

3

4 to 5

67

55

44

50

43

26

Localized and Good Prognosis Disease

It is possible to treat nonbulky, localized Ann Arbor stage-I NHL with involved-field radiation therapy alone, which yields a 5-year disease-free survival (DFS) rate of 77% with salvage chemotherapy [37]. However, most physicians treat localized intermediate-grade NHL with chemotherapy plus involved-field radiation therapy. Patients with good-risk stages-I and -II disease have achieved a 5-year DFS rate of 84% with 4 cycles of CHOP plus regional radiation therapy [38,39]. With the newer tumor staging systems, all these patients would have low scores and favorable disease, except the elderly and patients with bulky disease, who were shown in these studies to relapse more frequently. These latter patients with high-risk localized disease are now treated as patients with advanced disease at M.D. Anderson Cancer Center.

Localized extranodal NHL in the stomach, thyroid, sinuses, or Waldeyer's ring, unless the tumor is very small and localized, is best managed with combination chemotherapy and radiation therapy [31,40]. The issue of using prophylactic gastric resection to prevent perforation by chemotherapy in gastric lymphomas is still not resolved and will depend on the patient's condition [41]. Primary NHL of the CNS is a rare and not very favorable form of localized NHL, with a mean survival duration of approximately 19 months in patients without HIV [42]. Radiation therapy alone is standard treatment but has achieved disappointing results. The addition of high-dose intravenous methotrexate may improve the mean survival duration but increases the risk of leukoencephalopathy. Finally, testicular lymphoma frequently appears in the CNS or the contralateral testis; its management with prophylactic cranial and testicular irradiation has been debated [23].

Advanced Disease

Developed in the late 1960s at M.D. Anderson Cancer Center and tested by the Southwest Oncology Group (SWOG) in the 1970s, CHOP was the first combination chemotherapeutic regimen to demonstrate cures in intermediate-grade NHL. During the 1980s, a number of trials showed improved survival with the newer, more complex second- and third-generation chemotherapeutic regimens. This prompted the SWOG phase-III trial in patients with bulky disease Ann Arbor stage-II or higher who were stratified for age, marrow development, histology, bulky disease sites, and LDH level. This trial compared CHOP with methotrexate, bleomycin (Blenoxane), doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD); prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide (VePesid), cytarabine, bleomycin, vincristine, and methotrexate (ProMACE-CytaBOM); and methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (MACOP-B) [43].

This trial showed that eight cycles of CHOP chemotherapy was capable of inducing a complete response (CR) rate of 44% and an estimated 3-year DFS rate of 41%. The other regimens did not produce statistically better results; instead, they had more fatal and life-threatening toxic effects. One debated conclusion of this trial is that increasing the dose intensity of chemotherapy does not improve results. Another is that CHOP remains the standard of care for advanced intermediate-grade NHL, even though the results are far from ideal. We can now fairly accurately predict which patients have only a 20% chance of surviving for 3 years, and the current problem is how to best treat those poor prognosis patients.

One group of patients who fares poorly is those more than 60 years old. There has been some question as to whether the biology of tumors in the elderly differs somehow from that of tumors in younger age groups. A recent study of prognostic factors in elderly patients who had undergone chemotherapy where dose intensity was maintained found that age did not alter survival [44]. Elderly patients, it appears, are underdosed to avoid increased toxicity, even when they present with good performance status and marrow function. Dose intensity may be important not only in the elderly but in all patients [45,46]. In a related issue, the use of growth factors in NHL may most reasonably be applied to the maintenance of standard dose intensity in the compromised patient, even though no survival benefit has yet been shown [47]. Dose intensity is also maintained by experience with a particular regimen. Removing these confounding variables may reduce the influence of age on treatment response and outcome.

In terms of chemotherapy, it would then seem that less is bad, but more is not necessarily better. Again, the issue of dose intensity is not so simple. There are a number of biologic variables that may confound the data and obscure cases in which more is better or in which nothing works. Some progress is being made in this regard. There is some evidence that second- or third-generation combination chemotherapeutic regimens improve CR and DFS rates in young patients with primary mediastinal B-cell diffuse large-cell lymphoma and Ki-1 anaplastic T-cell NHL [48,49].

At M.D. Anderson, the alternating triple therapy (ATT) regimen, which consists of alternating non-cross-resistant regimens-ASHAP (doxorubicin, methylprednisolone, high-dose cytarabine, cisplatin), MBACOS (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, solumedrol), MINE (mesna, ifosfamide, mitoxantrone, and etoposide)- has shown a significant benefit in the highest-risk patients, although further follow-up is needed [50]. Greater dose intensity is also being used to treat other subgroups of patients [51]. On the other hand, some lymphomas may be inherently resistant to current chemotherapy. T-cell variants of diffuse large-cell NHL have poorer response rates than B-cell types [52,53]. The diffuse mantle-cell NHL is another subtype with poor response [54].

Patients who do not achieve a CR by the end of the first three cycles of the CHOP regimen also are at high risk [55]. One approach in these patients has been to switch therapy to a non-cross-resistant regimen and to include late dose intensification, which has shown some improvement over historic controls [56]. A recent investigation attempted to improve responses in these slowly responding patients by autologous bone marrow transplantation (ABMT), but no improvement in overall survival or DFS was shown at 3 years [57]. Further follow-up is needed, but at this stage, ABMT does not appear to be the answer.

In general, approximately 45% of patients with the worst prognosis will obtain a CR, but many will then relapse; only about 25% will survive long term. A major area of focus has been consolidation treatments that can prevent relapse. Radiation therapy for sites of bulky disease seems to improve results in certain subsets of patients but not in others [58]. ABMT is currently being compared with sequential conventional-dose combination chemotherapy in these patients; initial reports of ABMT seemed favorable [59], but a recent randomized trial of 464 patients did not show a benefit for ABMT overall [60]. Again, further follow-up is needed, and new approaches seem warranted.

Relapse and Primary Refractory Disease

In some patients, confirming the presence of persistent disease or early relapse can be difficult. Computed tomography scanning will readily identify residual masses in up to 40% of patients with bulky abdominal disease. Few of these patients, 5% in one review, actually had residual disease on laparotomy [61]. FNA biopsy may be inaccurate because of sampling errors, and gallium scans are operator-dependent [62]. These factors pose problems when interpreting results and managing some patients.

At present, there is no accepted standard of therapy for patients with primary refractory disease and relapsed disease. Current research has focused in two directions. The first approach has been high-dose chemotherapy with autologous stem-cell rescue to exploit the demonstrated dose-response curve of various chemotherapeutic agents. The second approach has been dose-intensive non-cross-resistant standard chemotherapeutic regimens to circumvent drug resistance. In the next few years, other avenues are likely to be explored.

ABMT is limited to patients younger than 60 years of age and has yielded 3-year DFS rates of 30% to 40% in patients who had a relapse after achieving a CR with conventional chemotherapy. Patients who had primary refractory disease and patients who achieved a partial response to conventional chemotherapy had 3-year DFS rates of 0% and 14%, respectively [63].

Nearly 10% of patients who relapse will be able to achieve long-term DFS with current salvage combination chemotherapy regimens. A variety of reasonably successful salvage regimens have been developed, including MIME (mesna, ifosfamide, methotrexate, and etoposide) [64], DHAP (dexamethasone, high-dose cytarabine, and cisplatin) [65], and ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) [66], which produce CR rates of 20% to 30%, and sequential MINE (mesna, ifosfamide, mitoxantrone, and etoposide)-ESHAP [66], which produces a CR rate of 43%. These CR rates are seen primarily in patients with a better prognosis who previously achieved a CR with standard chemotherapy and relapsed with a low-volume of disease more than 6 months after stopping treatment. A recent phase-III trial compared ABMT in a group of patients responding to salvage chemotherapy with another group who was continued on salvage chemotherapy. Although the results are preliminary, there appears to be no difference between the groups in the rate of DFS [68].

Various new approaches include continuous-infusion chemotherapy [69], the use of P-glycoprotein-blocking agents along with chemotherapy [70] and other biologic agents [71]. Allogeneic BMT has also been explored in a select subset of patients, with variable results [72].

High-Grade Tumors

Immunoblastic large-cell NHL is clinically indistinguishable from intermediate-grade NHL and is treated the same way. Lymphoblastic NHL, Burkitt's NHL, and non-Burkitt's NHL, on the other hand, behave more like ALL. These tumors double in size quicker than any other tumor, and they are rapidly fatal. The tumor lysis syndrome (see the chapter on Oncologic Emergencies) is commonly seen with the initiation of or even prior to therapy. Like ALL, these lymphomas have a predilection for the CNS. Prognostic factors are the same as those for ALL: age, LDH level, and CNS or bone-marrow involvement.

For adult lymphoblastic lymphoma, the treatment has been similar to that for adult ALL, which is based on vincristine, doxorubicin, and high-dose glucocorticoids [19,73]. CR rates have been as high as 95%, but DFS rates average 35% to 56%. These regimens are complex and protracted, with long maintenance phases, radiation therapy for the mediastinum, and CNS prophylaxis. (See the chapter on Acute Lymphocytic Leukemia).

The treatment of adults with Burkitt's and non-Burkitt's NHLs is based on high-dose alkylating agents, usually cyclophosphamide, plus other cell cycle phase-specific agents [74,75]. In patients with a good prognosis, the overall CR rate is nearly 77% to 85%, and the 5-year DFS rate is about 60%. Favorable patients can also be treated with more standard chemotherapeutic regimens for lymphoma, such as ProMACE-CytaBOM, with good results [76]. Patients with a poor prognosis have a decidedly worse outcome, with a DFS rate of 20% to 30%. The role of bone marrow transplantation in these patients has not been established, but this therapy is often attempted in patients whose disease relapses.

Special Cases

Human Immunodeficiency Virus: Patients with HIV are at particularly high risk of developing intermediate- and high-grade NHL. Nearly 10% of patients with HIV will die as a result of a lymphoma. Poor prognostic factors for these patients have been a poor performance status, prior AIDS (acquired immunodeficiency syndrome)-defining illness, a low CD4 count, marrow involvement, and an elevated LDH level [77,78]. Treatment of these patients is difficult and quickly evolving. For intermediate-grade NHL, full-dose chemotherapy for less-debilitated patients can be tolerated and has achieved a CR rate of 77% and a 2-year survival rate of 34%. More advanced patients have been treated with low-dose M-BACOD. When this treatment was compared with regular-dose M-BACOD plus granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]) [79], there was no difference between the two in CR or survival. Neither the role of CNS prophylaxis nor that of antiretroviral treatment has been established in this setting. The management of high-grade NHLs is based on individual factors because many patients cannot tolerate the intensive chemotherapy. Many high-grade lymphomas present as a primary CNS lymphoma in patients with HIV. In this situation, whole-brain radiation with a boost to the tumor is standard therapy and results in a CR rate of 50% and a mean survival duration of 2 to 4 months [42]. Survival is not altered in these cases, but quality of life is improved.

T-cell NHLs are a confusing group of diseases that are largely ignored by the working formulation but more clearly delineated by the new classification. Although some of these diseases have already been discussed (ALL, the Ki-1 [CD30+] anaplastic large-cell lymphoma, and the unspecified peripheral T-cell NHL), several others deserve mention.

Mycosis fungoides and Szary syndrome are clinically distinct types of postthymic (mature) T-cell NHL characterized by cutaneous plaques of CD4+ T-cells progressing to nodal and visceral involvement in the former and by a generalized erythroderma with circulating abnormal lymphocytes progressing to visceral involvement in the latter. Both diseases are generally indolent (behaving like a low-grade NHL), with a mean survival duration of at least 10 years with cutaneous involvement and of only about 2 years when the viscera are involved.

Neither is curable with current therapy [80]. Both diseases are amenable to effective palliative therapy. There are numerous treatment options; the choice depends largely on the extent of the disease. In general, early disease confined to the skin is best treated with either topical mechlorethamine hydrochloride, oral psoralens and photopheresis, or whole-skin electron-beam radiation therapy. As the disease progresses, systemic therapy with single-agent chemotherapy, interferon, or retinoids may be attempted. Lastly, some form of combination chemotherapy is often used [81]. A conservative approach is supported by the results of the NCI randomized trial comparing combination chemotherapy plus electron-beam radiation with topical chemotherapy, which did not show a difference in survival despite differences in responses [82].

HTLV-1-associated adult T-cell leukemia/lymphoma (ATLL) is another distinct type of T-cell lymphoma characterized by endemic regions of seropositivity for the virus in southwest Japan and the Caribbean, unique clinical features (including prominent systemic symptoms), frequent cutaneous involvement, hypercalcemia, and poor response to therapy. Several broad clinical stages of ATLL are recognized, from smoldering ATLL (in which a few circulating ATLL cells are present with transient skin lesions), through a chronic stage with lymphocytosis and mild nodal or visceral enlargement, to the acute form with marked lymphocytosis, hepatosplenomegaly, other organ involvement, systemic symptoms, and hypercalcemia. Another stage is characterized by the absence of lymphocytosis but the presence of prominent lymphadenopathy. This stage behaves aggressively, like the acute form [83]. Serum interleukin-2 receptor levels have been useful in separating patients with acute disease from patients with chronic disease and in predicting response to therapy [84]. The 2-year survival rate for the smoldering and chronic forms is 52% to 78% but only about 20% for the acute form [83]. Generally, no treatment is recommended for the smoldering and chronic forms, whereas combination chemotherapy has been attempted for the acute form, without appreciable improvement in survival.

Conclusion

Despite the great strides in our understanding of NHL, there remain many unanswered questions about its etiology in light of the current epidemic, its pathophysiology as it relates to advances in molecular biology, and its treatment in the case of patients with poor prognosis.

References:

References

1. National Cancer Institute-sponsored study of classifications of non-Hodgkin's lymphoma: Summary and description of a working formulation for clinical usage: The non-Hodgkin's Lymphoma Pathological Classification Project. Cancer 49:2112–2135, 1982.

2. Simon R, Durrlemann S, Hoppe RT, et al: The non-Hodgkin's Lymphoma Pathological Classification Project. Long-term follow-up of 1152 patients with non-Hodgkin's lymphomas. Ann Intern Med 109:939–945, 1988.

3. Sheibani K, Nathwani BN, Swartz WG, et al: Variability in interpretation of immunohistologic findings in lymphoproliferative disorders by hematopathologist: A comprehensive statistical analysis of interobserver performance. Cancer 62:657–664, 1988.

4. Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361–1392, 1994.

5. Hartge P, Devesa SS: Quantitation of the impact of known risk factors on the trends in non-Hodgkin's lymphoma incidence. Cancer Res 52(suppl):5566–5569s, 1992.

6. Raphael BG, Knowles DM: Acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma. Semin Oncol 17:361–366, 1990.

7. Purtilo DT, Stevenson M: Lymphotropic viruses as etiologic agents of lymphoma. Hematol Oncol Clin North Am 5:901–923, 1991.

8. Broder S, Bunn PA, Jaffe ES, et al: T-cell lymphoproliferative syndrome associated with human T-cell leukemia/lymphoma virus. Ann Intern Med 100:543–557, 1984.

9. Wotherspoon AC, Donglioni C, Diss TC, et al: Regression of primary low-grade B-cell gastric lymphoma of mucosal-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 342:575–577, 1993.

10. Isomaki HA, Hakulinen T, Joutsenlahti U: Excess risk of lymphomas, leukemia, and myeloma in patients with rheumatoid arthritis. J Chronic Dis 31:691–696, 1978.

11. Fishleder A, Tubbs R, Hesse B, et al: Uniform detection of immunoglobulin-gene rearrangement in benign lymphoepithelial lesions. N Engl J Med 316:1118, 1987.

12. Chen JM, Barr ML, Chadburn A, et al: Management of lymphoproliferative disorders after cardiac transplantation. Ann Thorac Surg 56:527–538, 1993.

13. Hyman G, Sommers S: The development of Hodgkin's disease and other lymphomas during anticonvulsant therapy. Blood 28:416, 1966.

14. Cerhan JR, Wallace RB, Folsom AR, et al: Transfusion history and cancer risk in older women. Ann Intern Med 119:8–15, 1993.

15. Purtilo DT: Epstein-Barr virus infection in the X-linked recessive lymphoproliferative syndrome. Lancet I:798, 1978.

16. Sander CA, Yano T, Clark HM, et al: p53 Mutation is associated with progression in follicular lymphomas. Blood 82:1994–2004, 1993.

17. Rabbitts TH: Chromosomal translocations in human cancer. Nature 342:143–149, 1994.

18. Magrath I: The pathogenesis of Burkitt's lymphoma. Adv Cancer Res 55:133–270, 1990.

19. Coleman NC, Picozzi VJ, Cox RS, et al: Treatment of lymphoblastic lymphoma in adults. J Clin Oncol 4:1628–1637, 1986.

20. Kadin ME: Primary Ki-1-positive anaplastic large cell lymphoma: A distinct clinical entity. Ann Oncol 5(suppl 1):S25–30, 1994.

21. Jacobson JO, Aisenberg AC, Lamarre L, et al: Mediastinal large cell lymphoma: An uncommon subset of adult lymphoma curable with combined modality therapy. Cancer 62:1893, 1988.

22. D'amore F, Brincker H, Gronbaek K, et al: Non-Hodgkin's lymphoma of the gastrointestinal tract: A population-based analysis of incidence, geographic distribution, clinicopathologic presentation features, and prognosis. J Clin Oncol 12:1673–1684, 1994.

23. Doll DC, Weiss RB: Malignant lymphoma of the testis. Am J Med 81:515, 1986.

24. Seymour JF, Gagel RF, Hagemeister FB, et al: Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin's lymphoma. Ann Intern Med 121:633–640, 1994.

25. Stefansson K, Arnason BGW: Neurologic manifestations of systemic neoplasia, in Braunwald E, Isselbacher KJ, Petersdorf RG, et al (eds): Harrison's Principles of Internal Medicine, 11th ed, pp 1601–1604. New York, McGraw-Hill Book Company, 1987.

26. Das DK, Gupta SK, Datta BN, et al: FNA cytodiagnosis of non-Hodgkin's lymphoma and its subtyping under working formulation of 175 cases. Diagn Cytopathol 7:487–498, 1991.

27. Cossman J, Zehnbauer B, Garrett CT, et al: Gene rearrangements in the diagnosis of lymphoma/leukemia guidelines for use based on a multi-institutional study. Hematopathology 95:347–354, 1991.

28. Skipper HE, Schabel FH, Wilcox WS: Experimental evaluation of potential anti-cancer agents XII: On the criteria and kinetics associated with `curability' of experimental leukemia. Cancer Chemother Rep 35:1–111, 1964.

29. Goldie JH, Coldman AJ: A mathematical model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63:1727–1731, 1979.

30. Shipp MA: Prognostic factors in aggressive non-Hodgkin's lymphoma: Who has `high risk' disease? Blood 83:1165–1173, 1994.

31. Doria R, Jekel JF, Cooper DL: Thyroid lymphoma. Cancer 73:200–206, 1994.

32. Stasi R, Zinzani PL, Galieni P, et al: Prognostic value of serum IL-10 and soluble IL-2 receptor levels in aggressive non-Hodgkin's lymphoma. Br J Haematol 88:770–777, 1994.

33. Yeun A, Sikic BI: Multidrug resistance in lymphoma. J Clin Oncol 12:2453–2459, 1994.

34. Shipp MA, Harrington DP, Anderson JR, et al: A predictive model for aggressive NHL: The International non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329:987, 1993.

35. Rodriguez J, Cabanillas F, McLaughlin P, et al: A proposal for a simple staging system for intermediate-grade lymphoma and immunoblastic lymphoma based on the `tumor score'. Ann Oncol 3:711–717, 1992.

36. Coiffier B, Lepage E: Prognosis of aggressive lymphoma: A study of five prognostic models with patients included in the LNH-84 regimen. Blood 74:558–564, 1989.

37. Jeffery GM, Mead GM, Whitehouse JMA, et al: Involved field radiotherapy or chemotherapy in the management of stage I intermediate-grade non-Hodgkin's lymphoma. Br J Cancer 64:933– 937, 1991.

38. Tondini C, Zanini M, Lombardi F, et al: Combined modality treatment with primary CHOP chemotherapy followed by locoregional irradiation in stage I or II histologically aggressive non-Hodgkin's lymphomas. J Clin Oncol 11:720–725, 1993.

39. Connors JM, Klimo P, Fairey RN, et al: Brief chemotherapy and involved field radiation therapy for limited stage histologically aggressive lymphoma. Ann Intern Med 107:25–30, 1987.

40. Economopoulos T, Asprou N, Stathakis N, et al: Primary extranodal non-Hodgkin's lymphoma of the head and neck. Oncology 49:484–488, 1992.

41. Gobbi PG, Dionigi P, Barbieri F, et al: The role of surgery in the multimodal treatment of primary gastric non-Hodgkin's lymphoma: A report of 76 cases and review of the literature. Cancer 65:2528–2536, 1990.

42. Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 119:1093–1104, 1993.

43. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 328:1002–1006, 1993.

44. Grogan L, Corbally N, Dervan PA, et al: Comparable prognostic factors and survival in elderly patients with aggressive non-Hodgkin's lymphoma treated with standard-dose Adriamycin-based regimens. Ann Oncol 5(suppl 2):S47–51, 1994.

45. Meyer RM, Hryniuk WM, Goodyear MDE: The role of dose intensity in determining outcome in intermediate-grade non-Hodgkin's lymphoma. J Clin Oncol 9:339–347, 1991.

46. Lepage E, Gisselbrecht C, Haioun C: Relative received dose intensity (DIE) in poor risk lymphoma patients: Higher DIE correlates with longer survival: A study from GELA. Blood 80(suppl 1):158a, 1992.

47. Canellos GP: Critical review of the role of hemapoietic growth factors in dose intensification and outcome in the treatment of non-Hodgkin's lymphoma. Ann Oncol 5(suppl 2):S121– 122, 1994.

48. Toedeschini G, Ambrossetti A, Tecchio C, et al: Third-generation regimens are the therapy of choice in patients with mediastinal large B-cell lymphoma (MLBCL) with sclerosis. Blood 84(suppl 1):165a, 1994.

49. Toedeschini G, Tecchio C, Degani D, et al: Anaplastic large cell lymphoma CD30+ (ALCL); Clinical features and long-term response in 40 consecutive patients. Blood 84(suppl 1):165a, 1994.

50. Cabanillas F: Non-Hodgkin's lymphomas: A review of the M. D. Anderson experience. Semin Oncol 19:11–13, 1992.

51. Shipp MA, Schulman LN, Kaplan WD, et al: Intensified induction therapy for patients with `high risk' aggressive NHL: High-dose CHOP. Blood 82(suppl 1):332a, 1993.

52. Armitage JO, Greer JP, Levine AM, et al: Peripheral T-cell lymphoma. Cancer 63:158–163, 1989.

53. Gasgoyne R, Tolcher A, Coupland R, et al: Prognostic significance of immunophenotype in diffuse large cell lymphomas. Lab Invest 70:109a, 1994.

54. Perry DA, Bast MA, Armitage JO, et al: Diffuse intermediate lymphocytic lymphoma: A clinicopathologic study and comparison with small lymphocytic lymphoma and diffuse small cleaved cell lymphoma. Cancer 66:1995–2000, 1990.

55. Armitage JO, Weisenburger DD, Hutchins M, et al: Chemotherapy for diffuse large-cell lymphoma: Rapidly responding patients have more durable remissions. J Clin Oncol 4:160–164, 1986.

56. Cabanillas F, Burgess MA, Bodey GP, et al: Sequential chemotherapy and late intensification for malignant lymphomas of aggressive histologic type. Am J Med 74:382–388, 1983.

57. Hagenbeek A, Verdonck L, Sonneveld P, et al: CHOP chemotherapy versus autologous bone marrow transplantation in slowly responding patients with intermediate- and high-grade malignant non-Hodgkin's lymphoma. Results from a prospective randomized phase III clinical trial in 294 patients. Blood 82(suppl 1):332a, 1994.

58. Shipp MA, Klatt MM, Yeap B, et al: Patterns of relapse in large-cell lymphoma patients with bulky disease: Implications for the use of adjuvant radiation therapy. J Clin Oncol 7:613, 1989.

59. Sweetham JW, Proctor SJ, Blaise D, et al for the Working Party of the European group for bone marrow transplantation: High-dose therapy and autologous bone marrow transplantation in first complete remission for adult patients with high-grade non-Hodgkin's lymphoma: The EBMT experience. Ann Oncol 5(suppl 2):S155–159, 1994.

60. Haioun C, Lepage E, Gisselbrecht C, et al for the groupe d'etude des lymphomes del'adulte: Comparison of autologous bone marrow transplantation with sequential chemotherapy for intermediate- grade and high-grade non-Hodgkin's lymphoma in first complete remission: A study of 464 patients. J Clin Oncol 12:2543–2551, 1994.

61. Surbone A, Longo DL, DeVita VT, et al: Residual abdominal masses in aggressive non-Hodgkin's lymphoma after combination chemotherapy: Significance and management. J Clin Oncol 6:1832–1837, 1988.

62. Kaplan WD, Jochelson MS, Herman TS, et al: Gallium-67 imaging: A predictor of residual tumor viability and clinical outcome in patients with diffuse large-cell lymphoma. J Clin Oncol 8:1966–1970, 1990.

63. Philip T, Armitage JO, Spitzer G, et al: High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med 316:1493–1498, 1987.

64. Cabanillas F, Hagemeister FB, Mclaughlin P, et al: Results of MIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol 5:407–412, 1987.

65. Velasquez WS, Cabanillas F, Salvador P, et al: Effective salvage therapy for lymphoma with cisplatin in combination with high-dose ara-C and dexamethasone (DHAP). Blood 71:117–122, 1988.

66. Velasquez WS, McLaughlin P, Tucker S, et al: ESHAP-an effective chemotherapy regimen in refractory and relapsing lymphoma: A 4-year follow-up study. J Clin Oncol 12:1169–1176, 1994.

67. Cabanillas F, Rodriquez MA: MINE-ESHAP salvage therapy for recurrent and refractory lymphomas. Semin Hematol 31(suppl 2):30, 1994.

68. Philip T, Guglielmi C, Hagenbeek A, et al: The PARMA international randomized prospective study in relapsed non-Hodgkin's lymphoma: Second interim analysis of 172 patients. Blood 80(suppl 1):67a, 1992.

69. Wilson WH, Bryant G, Bates S, et al: EPOCH chemotherapy: Toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. J Clin Oncol 11:1573–1582, 1993.

70. Cobb P, Burris G, Weiss G, et al: Phase I trial of PSC 883 and doxorubicin, vincristine, cyclophosphamide, and prednisone (DCVP) in patients with refractory non-Hodgkin's lymphoma. Blood 84(suppl 1):167a, 1994.

71. Longo DL: Biological agents and approaches in the management of patients with lymphoma: A critical appraisal. Hematol Oncol Clin North Am 5(5):1067–1087, 1991.

72. Shepard JD, Barnett MJ, Connors JM, et al: Allogeneic bone marrow transplantation for poor prognosis non-Hodgkin's lymphoma. Bone Marrow Transplant 12:591–596, 1993.

73. Levine AM, Foreman SJ, Meyer PR, et al: Successful therapy of convoluted T-lymphoblastic lymphoma in the adult. Blood 61:92–98, 1983.

74. Lopez TM, Hagemeister FB, Mclaughlin P, et al: Small noncleaved cell lymphoma in adults: Superior results for stages I-III disease. J Clin Oncol 8:615–622, 1990.

75. Bernstein JI, Coleman CN, Strickler JG, et al: Combined modality therapy for adults with small noncleaved cell lymphoma (Burkitt's and non-Burkitt's types). J Clin Oncol 4:847–858, 1986.

76. Longo DL, Duffey PL, Jaffe ES, et al: Diffuse small noncleaved-cell, non-Burkitt's lymphoma in adults: A high-grade lymphoma responsive to ProMACE-based combination chemotherapy. J Clin Oncol 12:2153–2159, 1994.

77. Hagemeister FB, Khetan R, Allen P, et al: Stage, serum LDH, and performance status predicts disease progression and survival in HIV-associated lymphomas. Ann Oncol 5(suppl 2):S41–46, 1994.

78. Levine AM, Louriero C, Sullivan-Halley J, et al: HIV-positive high- or intermediate-grade lymphoma: Prognostic factors related to survival. Blood 72;247a, 1990.

79. Levine AM: Acquired immunodeficiency syndrome-related lymphoma. Blood 80:8–20, 1992.

80. Sausville EA, Eddy JL, Makuch RW, et al: Histopathologic staging at initial diagnosis of mycosis fungoides and the Sézary syndrome: Definition of three distinct prognostic groups. Ann Intern Med 109:372–382, 1988.

81. Bunn PA, Hoffman SJ, Norris D, et al: Systemic therapy of cutaneous T-cell lymphomas (mycosis fungoides and the Sézary syndrome). Ann Intern Med 121:592–602, 1994.

82. Kaye FJ, Bunn PA, Steinberg SM, et al: A randomized trial comparing combination electron-beam radiation and systemic chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 321:1784–1790, 1989.

83. Shimoyama M, and members of the Lymphoma Study Group (1984–1988): Diagnostic criteria and classification of clinical subtypes of adult T-cell leukemia-lymphoma. Br J Haematol 79:428–437, 1991.

84. Shimoyama M, Ota K, Kikuchi M, et al: Major prognostic factors of adult patients with advanced T-cell lymphoma/leukemia. J Clin Oncol 6:1088, 1988.