FOLLICULAR LYMPHOMAS:

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LYMPHOMA

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FOLLICULAR LYMPHOMAS: Do Histologic Subtypes Predict Outcome? Thomas P. Miller, MD, Michael LeBlanc, PhD, Thomas M. Grogan, MD, and Richard I. Fisher, MD

The topic of follicular lymphomas, and more specifically, the relationship of histologic subtypes of follicular lymphomas to outcome, has periodically been the focus of extensive debate.', 7, l6 The results of such discussions are important to practicing clinicians with regard to patient care by setting expectations of prognosis and guiding therapy. Currently, the Working Formulation system of classifying non-Hodgkin's lymphomas provides the framework from which clinicians translate lymphoma histologic subtypes into outcome expectations and therapeutic strategiesZ6According to the Working Formulation, patients with low-grade histologic subtypes are generally thought to be incurable and are treated lo Low-grade histofor palliation of symptoms related to lymph~ma.~, logic subtypes of follicular lymphoma include follicular small cleavedcell and follicular mixed large- and small-cell types.26Intermediate and high-grade histologic subtypes, on the other hand, are known to be potentially curable and are treated with aggressive doxorubicin-containing combination chemotherapy." 24 Follicular large-cell lymphoma is currently classified as an intermediate-grade histology and is usually treated accordingly with curative intent.*,6, 26 Some investigators have previously argued that follicular mixed large- and small-cell lymphomas This work was written for the Southwest Oncology Group, San Antonio, Texas, and was supported in part by the following PHS Cooperative Agreement Grants awarded by the National Cancer Institute, DHHS CA-13612, CA-38926, CA-46282, and CA-32102

From the University of Arizona, Tucson, Arizona (TPM, TMG); the Fred Hutchinson Cancer Center, Seattle, Washington (ML); and the Loyola University Medical School, Maywood, Illinois (RIF) ~

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HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 11 NUMBER 5 * OCTOBER 1997

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MILLER et a1

also have a potential for cure and should also be treated with doxorubicin-containing chemotherapy.', 17,21 Recently, a group of internationally known expert hematopathologists proposed a new classification system, the Revised European-American Lymphoma Classification (REAL)?, In that system, the distinction between follicular lymphoma subtypes is minimized. The authors suggest the term grade be used instead of distinct names, to better reflect the reality of a cytologic c o n t i n ~ u mThese .~ investigators recognize that pathologists cannot reproducibly determine the proportion of large cells and, therefore, cannot reproducibly determine the histologic subtype of follicular lymphomas. This consensus decision to lump follicular subtypes will surely prompt another debate with regard to outcome relative to histology. In an attempt to test the clinical utility of the REAL proposal to lump follicular lymphoma subtypes, and to provide data for that debate, we have analyzed data from the Southwest Oncology Group (SWOG) including 389 patients with follicular lymphomas followed for up to 25 years. METHODS AND PATIENT SELECTION Patients having follicular subtypes of non-Hodgkin's lymphomas and previously registered on SWOG studies 7204, 7426, and 7713 were chosen for this updated analysis of survival.", 12, 2o These studies were selected to allow for adequate long-term follow-up of a group of uniformly staged and treated patients. All patients had biopsy-proven follicular subtypes of non-Hodgkin's lymphomas, had clinical stage I11 or IV disease according to Ann Arbor criteria, and received initial combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) at full doses. Some patients received additional immunotherapy with levamasole and/or bacillus Calmette-Guerin (bCG) scarification. Morphologic determination of histologic subtypes of follicular lymphoma was made using a three-tiered review system. Submitted institutional diagnoses were reviewed by a regional expert hematopathologist and, subsequently, by a pathologist at the Repository Center for Lymphoma Clinical St~dies.'~ Disputes and differences between the regional expert and the Repository Center were then reviewed by a panel of expert hematopathologists, the Pathology Panel.I5Thus, the final diagnosis is a refined diagnosis. Of the 389 patients studied, 105 patient biopsy specimens had further review by another ad hoc panel of seven experts convened to test reproducibility of various morphologic criteria for distinguishing histologic subtypes of follicular lymphoma.22,25 The final diagnosis, as used in this study, is thus a highly refined determination, and it likely represents the best possible diagnosis given the limits of morphologic reproducibility?* Survival time was plotted graphically according to the methods of Kaplan and Meier.I4The log-rank test of statistical significance was used

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to determine differences in survival and, importantly, deaths from all causes were included in the survival analysis to avoid inadvertent bias.ls All reported significance tests are two-sided. RESULTS

The current analysis updates survival for a subset of patients previously reported? The histologic subtypes and numbers of patients studied included 259 patients with follicular small cleaved-cell lymphoma (67%), 77 with follicular mixed large- and small-cell lymphoma (20%), and 53 with follicular large-cell lymphoma (14%). The clinical characteristics of these 389 patients are summarized in Table 1. There is remarkable constancy of important prognostic features distributed across histologic subtypes, except that a disproportionate number of patients with follicular small cleaved-cell lymphoma had stage IV disease (68%), as compared with follicular mixed (53%) and follicular largecell lymphoma (40%), and the difference is significant ( P < 0.01). Overall survival is shown in Figure 1 according to histologic subtype. The median follow-up for surviving patients is 17 years. There is no difference in overall survival between histologic subgroups ( P = 0.40). The median survival and 10-year estimates of survival (summarized in Table 2) are 94 months and 40% for follicular small cleaved-cell lymphoma, 76 months and 35% for follicular mixed large- and smallcell lymphoma, and 83 months and 37% for follicular large-cell lymphoma. In addition, the shapes of the three survival curves are similar and appear to be very nearly straight lines having nearly identical and constant slopes. There is no suggestion of a plateau for any of these curves.

Table 1. CLINICAL CHARACTERISTICS FOR 389 PATIENTS WITH FOLLICULAR LYMPHOMA ACCORDING TO HISTOLOGIC SUBTYPE Clinical Characteristic Sex: male female Age: 560 years >60 years Stage: Ill IV B symptoms: absent present Performance status: 0 1

Frequency (“h) FSC

FM

FLC

141 (54) 118 (46) 188 (73) 71 (27) 82 (32) 177 (68) 172 (66) 87 (34) 240 (93) 19 (7)

45 (58) 32 (42) 53 (69) 24 (31) 36 (47) 41 (53) 53 (69) 24 (31) 71 (92) 6 (8)

23 (43) 30 (57) 36 (68) 17 (32) 32 (60) 21 (40) 41 (77) 12 (23) 47 (87) 6 (13)

FSC = follicular small-cleaved cell; FM large cell.

=

Significance (P)

follicular mixed small- and large-cell; FLC

0.22 0.70 <0.01

0.30 0.62 =

follicular

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MILLER et a1

4h 80

1 0-Year At Risk Deaths Estimate

-

1

FSC FM FL

259 77 53

202 61 43

40% 35% 37%

1 Figure 1. Survival for 389 patients with follicular lymphoma plotted according to Working Formulation histologic subtype. There is no difference in overall survival and there is no evidence of potential cure for any subtype.

DISCUSSION The current analysis of long-term survival of patients having follicular non-Hodgkin's lymphomas treated with CHOP chemotherapy provides striking graphical evidence that these histologic subtypes are incurable using standard combination chemotherapy. There does not appear to be any change in the slope of the survival curves over time to indicate that a proportion of patients may have been cured. Furthermore, there is no significant difference in survival between patient groups having different histologic subtypes of follicular lymphoma. The absence of statistical significance does not appear to be artifactual, because adequate numbers of patients have been followed for substantial periods of time. The survival curves are very nearly superimposable and offer no suggestion that additional patients followed for longer periods of time may result in an analysis that might achieve statistical significance. The Table 2. SURVIVAL ENDPOINTS FOR 389 PATIENTS WITH FOLLICULAR LYMPHOMA ACCORDING TO HISTOLOGIC SUBTYPE

No. Patients Histology

("/.I

Median Survival (mo)

~~

Follicular small-cleaved Follicular mixed Follicular large-cell

259 (67) 77 (20) 53 (14)

10-year Survival

("/.I

~

94 76 a3

40 35 37

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current study does not, however, determine the best standard treatment for follicular lymphoma subtypes. It is possible that the equivalence of outcomes was achieved because higher-grade histologies were treated with a doxorubicin-containing regimen. There are several strengths of the current analysis worthy of emphasis. The histologic categorization of subtypes based on a three-tiered review system may represent the best possible determination of follicular subtypes. All patient biopsy specimens have had multiple pathologic reviews by expert hematopathologists, and a subset of 105 biopsy specimens has been the subject of intensive study to determine the optimal method for determining histologic subtypes.22,25 The final histologic diagnosis used to determine outcome in the current analysis is, thus, a highly refined determination. These efforts, and the fact that patients were registered on study from a wide range of localities, result in a distribution of histologic subtypes very similar to that reported by investigators participating in the NCI-sponsored Working Formulation Classification Project (Table 3) and significantly different from some other single-institution studie~.'~, Additional strengths of the current study include the relative homogeneity of patient selection (primarily stage) and uniform treatment of all patients entered (CHOP chemotherapy). The extent of disease (stage) has a significant impact on outcome for patients with follicular lymphoma.2By including patients with stage I or I1 disease, outcome analysis is confounded. Low-stage patients have an extraordinarily good outcome as measured by either relapse-free survival or by overall sur~ i v a l .As * ~ many as 75% of patients with stage I or I1 follicular lymphomas are alive at 10 years. If low-stage patients are included in an analysis, and if median follow-up is short, the overall survival curve will have an apparent "plateau." Most reports showing prolonged survival for patients with follicular large-cell lymphoma include stage I and I1 patients (Table 4),and the proportion of patients studied with stage I and I1 disease is high, varying from 19% to 38?'0.*,'~,'~,~~ Thus, it is likely that the apparent plateau observed in overall survival in these studies is the expected prognosis for the subset of low-stage patients. The current study is also distinguished from many previous reports,

Table 3. DISTRIBUTIONOF HISTOLOGIC SUBTYPES OF FOLLICULAR LYMPHOMA COMPARED FOR THREE SEPARATE STUDIES Histologic Frequency (%) Study

FSC

FM

FLC

Current study NCI Classification Projectz6 NebraskaTg

67 65 25

20 25 36

14 10 39

FSC = Follicular small-cleaved cell; FM large-cell

=

follicular mixed small- and large-cell; FLC = follicular

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MILLER et al

Table 4. FOLLICULAR LARGE-CELL LYMPHOMA: NUMBER OF PATIENTS STUDIED, LENGTH OF FOLLOW-UP, AND UNIFORMITY OF TREATMENT

Study NCF7 ECOGB M.D. Ander~on’~ Stanford2 NCIi6 Nebraskalg SWOG (current)

No. Patients 16 25 62 96 15 64 53

Median FOIIOW-UP (YW

4.3 5.2

-

3.8 17.0

Longest FOIIOW-UP (YW 11.2 5.0 8.0 18.0 12.5 11.3 25

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Stage I, II Included yes no yes yes no yes no

(19%) (24%) (36%) (38%)

and particularly from the patient group forming the basis of the Working Formulation, by including uniformly treated patients. For example, the Working Formulation included patients with treatment that varied from radiotherapy alone to single-agent alkylator chemotherapy to noncurative combination chemotherapy to doxorubicin-containing chemothera ~ yBy. current ~ ~ standards, the clinical database used to test the Working Formulation is unacceptable owing to extreme heterogeneity of patient selection. Perhaps the most important attribute of the current study is the length of follow-up of surviving patients (median of 17 years). No other reported series has such long follow-up (see Table 4). Studies with shorter follow-up underestimate the recurrence rate of these diseases and, thus, the fatality rate. Median follow-up for previously reported series typically ranges from 4 to 5 years, with maximum follow-up rarely exceeding 10 years2, 13, 16, 19, 27 The limits of these studies with short follow-up are highlighted by Figure 1, showing that only 50% of the deaths would have been predicted had follow-up of all patients reached 7 years. Follicular lymphoma has a remarkable capacity for very late relapse and eventual death following relapse.

CONCLUSION There are several ramifications of the current study. First, follicular lymphomas are more alike than different, and they probably should be classified as a single entity, as suggested by the newly proposed REAL classification system.3, We find no substantial differences in meaningful clinical characteristics between histologic subtypes. The characterization of follicular large-cell lymphoma as a distinct and higher-grade lymphoma by the Working Formulation classification system is misleading, at least to clinicians, in that follicular large-cell lymphoma is indistinguishable from other histologic variants in long-term analysis and has no propensity for cure when advanced stages of disease are treated with doxorubicin-containing chemotherapy. Furthermore, and as shown previously, it cannot be reproducibly categorized by expert hematopathologists.’, 22 Thus, separation of follicular lymphoma subtypes on morphologic criteria alone has no proven merit. Advocates of maintaining the status quo (Working Formulation) based on arguments of proven clinical utility and reproducibility by the general pathology

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community should reconsider that position in view of this study.** Second, it is now reasonable to test whether follicular large-cell lymphoma requires treatment with a doxorubicin-containing regimen to assure survival similar to that seen for other follicular subtypes. Third, new objective measures of lymphoma aggressiveness need to be developed to predict which patients with follicular lymphoma might require new and innovative treatment, and which patients can be expected to have long survival with currently available treatment. Although morphology does not distinguish clinically useful subtypes, heterogeneity clearly exists as evidenced by the fact that at least 20% of patients with follicular lymphoma have a fatal disease within 2 years of diagnosis and 20% survive 15 years or longer (see Fig. 1). Finally, and perhaps most important for future investigations, surrogate or intermediate markers of treatment effect must be developed to allow reproducible and timely analysis of treatment outcome. Progress in treating follicular lymphoma cannot be measured (at least modest changes in outcome) if 20 years of follow-up is required to accurately determine outcome.

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13. Kantarjian HM, McLaughlin P, Fuller L M Follicular large cell lymphoma: Analysis and prognostic factors in 62 patients. J Clin Oncol 2:811, 1984 14. Kaplan EL, Meier l? Nonparametric estimation from incomplete observations. Journal of the American Statistics Association 53:457, 1958 15. Kim H, Zelman RJ, Fox MA, et al: Pathology panel for lymphoma clinical studies: A comprehensive analysis of cases accumulated since its inception. J Natl Cancer Inst 68:43, 1982 16. Longo DL: What’s the deal with follicular lymphomas? J Clin Oncol 11:202, 1993 17. Longo DL, Young RC, Hubbard SM Prolonged initial remission in patients with nodular mixed lymphoma. Ann Intern Med 100651,1984 18. Mantel N Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50163,1966 19. Martin AR, Weisenberger DD, Chang WC, et al: Prognostic value of cellular proliferation and histologic grade in follicular lymphoma. Blood 85:3671, 1995 20. McKelvey EM, Gottlieb JA, Wilson H E Hydroxyldaunornycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer 38:1484, 1976 21. McLaughlin P, Fuller LM, Velasquez WS: Stage 111 follicular lymphoma: Durable remissions with a combined chemotherapy-radiotherapy regimen. J Clin Oncol 5:867, 1987 22. Metter GE, Nathwani B, Burke JS, et al: Morphologic subclassification of follicular lymphoma. Variability of diagnosis among hematopathologists: A collaborative study between the Repository Center and Pathology Panel for lymphoma clinical studies. J Clin Oncol 325, 1985 23. Miller Tl? Therapy of localized non-Hodgkin’s lymphomas. In DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology Updates 111 (6). Philadelphia, JB Lippincott, 1989, p 1 24. Miller TP, Jones SE: Initial chemotherapy for clinically localized lymphomas of unfavorable histology. Blood 62:413, 1983 25. Nathwani B, Metter GE, Miller TP, et al: What should be the morphologic criteria for the subdivision of follicular lymphoma? Blood 68:837, 1986 26. The Non-Hodgkin’s Lymphoma Pathologic Classification Project. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: Summary and description of a working formulation for clinical usage. Cancer 49:2112, 1982 27. Osborne CK, Norton L, Young RC: Nodular histiocytic lymphoma: An aggressive nodular lymphoma with potential for prolonged disease-free survival. Blood 56:98, 1980 28. Rosenberg Saul A Classification of lymphoid neoplasms. Blood M1359, 1994 29. Simon R, Durrleman S, Hoppe RT, et al: The non-Hodgkin lymphoma pathologic classification project Long-term follow-up 1153 patients with non-Hodgkin lyrnphomas. Ann Intern Med 109:939, 1988 Address reprint requests to Janet C. Graff Southwest Oncology Group Operations Office 14980 Omicron Drive San Antonio, TX 782453217