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© 1999 American Society for Clinical Oncology Small Noncleaved, Non-Burkitt's (Burkitt-Like) Lymphoma: Cytogenetics Predict Outcome and Reflect Clinical PresentationFrom the Divisions of Medical Oncology, Hematology, and Pathology, British Columbia Cancer Agency and University of British Columbia, Vancouver and Victoria, British Columbia, Canada. Address reprint requests to Richard Klasa, MD, Division of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Ave, Vancouver, BC V5Z 4E6, Canada; email rklasa{at}bccancer.bc.ca
PURPOSE: To correlate cytogenetic abnormalities with clinical presentation and outcome in Burkitt-like, small noncleaved non-Burkitt's lymphoma (SNC-NB). PATIENTS AND METHODS: Thirty-nine patients with SNC-NB lymphoma and a clonal karyotype were evaluated between January 1989 and January 1996. All were from British Columbia, Canada, underwent uniform clinical staging, and were treated on investigational protocols by a small group of clinicians. RESULTS: Three groups of patients were identified by clonal karyotype on cytogenetic analysis: (1) those with a c-myc translocation (n = 11); (2) those with dual translocation of c-myc and bcl-2 (n = 13); and (3) those with other cytogenetic abnormalities (n = 15). The c-myc group was younger, presented with earlier stage de novo disease, and had a better clinical prognostic factor profile. The dual-translocation and other groups were older and presented in advanced stage with poorer prognostic features, and a larger proportion of the dual-translocation group patients had transformed from previously diagnosed follicular lymphoma. The median overall survival (OS) time for all patients was 5 months. The median OS time for the dual-translocation group was only 2.5 months, as compared with 7 months and 8 months for the c-myc and other group, respectively (P < .001). There were no survivors beyond 7 months among the dual-translocation group, as opposed to 32% and 25% 2-year OS rates in the c-myc and other group. CONCLUSION: SNC-NB lymphoma is a clinically and cytogenetically heterogenous disease. Dual translocation of c-myc and bcl-2 is characterized by a rapid clinical course and extremely poor outcome. This latter entity may represent the most clinically aggressive lymphoma thus far characterized and warrants intensive investigational treatment where feasible.
BURKITT'S LYMPHOMA is a well-defined clinical, morphologic, and cytogenetic entity. In contrast, small noncleaved, non-Burkitt's lymphoma (SNC-NB), or Burkitt-like lymphoma, seems to be heterogeneous. Clinical outcome analysis has been confounded in part by a lack of uniform histologic criteria for SNC-NB, a significant problem with a lack of diagnostic reproducibility and a paucity of reported cytogenetic and molecular genetic data. The settings in which the diagnosis has been made range from de novo presentation of clinically aggressive disease in the pediatric population to transformation of antecedent indolent follicular lymphoma in the elderly. The recently completed clinical evaluation of the Revised European-American Lymphoma classification proposal found the least degree of consensus among pathologists in making the diagnosis of Burkitt-like lymphoma (53%), with difficulty distinguishing it from Burkitt's lymphoma or diffuse large B-cell lymphoma.1 The incidence and relevance of cytogenetic changes associated with this histologic subtype of lymphoma have been alluded to in reports of single cases and small series of patients. A recurring theme is speculation about the relative effects of c-myc oncogene deregulation by itself, c-myc and bcl-2 proto-oncogene deregulation working in concert, bcl-2 deregulation alone, or other cytogenetic abnormalities. In a recently reported series of 20 adult patients who presented with small noncleaved-cell lymphoma, all were of the non-Burkitt type.2 Patients with c-myc deregulation tended to be young with intra-abdominal disease and short survival, whereas those with bcl-2 deregulation were older with peripheral lymph node and bone marrow involvement and a longer survival. A foundation on which to build a model of disease development with clinical correlations rests in the cytogenetic abnormalities described in lymphoma cells. In lymphomas with the t(8;14) translocation, the c-myc oncogene located at chromosome band 8q24 translocates into the immunoglobulin heavy-chain locus at 14q32. In a minority of cases, the translocation is between chromosomes 2 and 8 or between 8 and 22, thus bringing c-myc into the proximity of the kappa or lambda light chain regions, respectively. This defect was initially reported in greater than 90% of Burkitt's lymphoma.3 It was recognized that all proliferating tissues express at least one member of the myc family, usually c-myc, which is downregulated when cells reach terminal differentiation or, in the case of lymphocytes, become long-lived memory cells resting in G0.4 Transfection experiments have shown that constitutive expression of c-myc can prevent inducible cell differentiation, whereas repression of c-myc by transfection with c-myc antisense constructs can induce cell differentiation.5,6 Thus c-myc expression seems closely related to the decision between further proliferation and differentiation in lymphoid tissue. The t(14;18) translocation detected in up to 90% of follicular lymphomas juxtaposes the bcl-2 proto-oncogene to the immunoglobulin heavy-chain joining region, resulting in overexpression of Bcl-2.7 B cells from bcl-2–transgenic mice display a prolonged survival time in vitro but no increase in cell cycling.8 In mouse transgenic experiments and studies of growth factor–dependent cell lines, Bcl-2 overexpression has been shown to inhibit apoptosis as part of an elaborate network of finely tuned regulators of cell-death pathways.4,9 The coexistence of translocations characteristic of follicular lymphoma t(14;18) and Burkitt's lymphoma t(8;14), a situation we will refer to as dual translocation, has been reported sporadically in aggressive histology lymphomas,7,10-17 with the largest published series consisting of six patients.16 However, survival data were minimal and the outcome in comparison with SNC-NB patients with other cytogenetic abnormalities was not available. In late 1988, we recognized a significant problem with interobserver reproducibility for the diagnosis of SNC-NB lymphoma and hypothesized that this histologic entity likely included several distinct biologic subgroups. Furthermore, we reasoned that only classical cytogenetics would be sufficient to separate these groups because variant c-myc translocations cannot be detected using molecular techniques, including Southern blot analysis. Therefore, we studied the clinical outcome in 39 cases of SNC-NB lymphoma using standard cytogenetic analysis to divide the patients into the following three groups: (1) c-myc translocation alone; (2) dual translocation of both c-myc and bcl-2; and (3) other abnormalities, which include a spectrum of cytogenetic changes but lack a c-myc translocation. Four of the cases with dual translocations were reported previously,17 and the current study provides the details of 35 additional patients with SNC-NB.
This study included all patients with SNC-NB who presented to the British Columbia Cancer Agency and had histopathology review with cytogenetic and immunophenotypic analysis performed on biopsy specimens at the time of diagnosis. Staging evaluations included the following: a complete history and physical examination; a biochemical profile with serum lactate dehydrogenase (LDH), alkaline phosphatase, AST, bilirubin, serum protein electrophoresis, calcium, and creatinine and uric acid levels; bone marrow aspiration and biopsy; a chest radiograph (posteroanterior and lateral views); and a computed tomography scan of the abdomen and pelvis. Clinical staging was based on the Ann Arbor classification. Bulky disease was defined as any single mass 10 cm or greater in maximum diameter. Charts were reviewed retrospectively to document treatment received, short- and long-term toxicity, and survival parameters.
Morphologic Analysis
Immunophenotyping
Cytogenetic and Molecular Genetic Analysis
Statistical Analysis
Outcome was analyzed with respect to overall survival. Survival times were calculated from the date of pathologic diagnosis to either the last follow-up visit for live patients or to death of any cause. For patients who transformed from follicular lymphomas, survival was calculated from the date of pathologic transformation to SNC-NB lymphoma. Survival curves were generated using the product-limit method of Kaplan and Meier.20 Survival times were compared by both the log-rank and
Patient Characteristics Thirty-nine patients with SNC-NB lymphoma and a clonal karyotype presented to the British Columbia Cancer Agency from January 1989 to January 1996. This represents 1.8% of the 2,146 new patients with non-Hodgkin's lymphoma seen at our institution during this time period. Eleven patients had a c-myc translocation by standard cytogenetic analysis, 13 had dual translocations of c-myc and bcl-2, and 15 patients had other cytogenetic abnormalities. Eleven patients transformed from follicular small cleaved-cell lymphoma (two in the c-myc group, six in the dual-translocation group, and three in the other group). There were 21 men and 18 women. The median age was 53 years (range, 16 to 93 years). The median age of the subsets was 41 years for the c-myc translocation group, 65 years for the dual-translocation group, and 63 years for the patients with other cytogenetic abnormalities. Table 1 lists the patient characteristics at the time of diagnosis (for de novo disease) or transformation (preexisting follicular lymphoma). Prognostic variables were assessed according to the International Prognostic Index (IPI) using age at diagnosis, Ann Arbor stage, serum LDH, Eastern Cooperative Oncology Group performance status, and the number of extranodal sites of disease.22 Complete data for calculation of the IPI was present for the c-myc and other groups, but information on three of the 13 patients in the dual-translocation group was incomplete. In one case, the patient was 93 years old when the diagnosis became evident and a decision not to offer treatment abrogated the need for a full assessment. In the other two cases, performance status or LDH was not recorded before initiation of treatment in acutely ill patients.
In a review of these characteristics, a number of factors stand out. The c-myc group had a larger proportion of patients who were younger with de novo early-stage disease and a better prognostic-factor profile. The dual-translocation group revealed the opposite trend, in part a reflection of the larger proportion of patients with c-myc transformation of a long-standing previously treated follicular lymphoma. However, these trends did not reach statistical significance in the small groups of patients studied. The full karyotypic results are listed in Table 2.
Treatment
Standard-dose chemotherapy consisted of one of a number of protocols that are variants of the cyclophosphamide/doxorubicin/vincristine/prednisone regimen.23,24 ACOP-12 is a 12-week regimen of doxorubicin 50 mg/m2, cyclophosphamide 350 mg/m2, and vincristine 1.2 mg/m2 given at 2-week intervals with continuous prednisone 40 mg/m2. VACOP-B consists of etoposide 150 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 350 mg/m2, vincristine 1.2 mg/m2, bleomycin 10 U/m2, and prednisone 45 mg/m2 given in a similar 12-week schedule. COPA is an 8-week regimen for patients who are elderly, containing doxorubicin 35 mg/m2, cyclophosphamide 300 mg/m2, and vincristine 1.2 mg/m2 given for four courses at 2-week intervals with continuous prednisone at 40 mg/m2. Standard-dose cyclophosphamide and methotrexate as used in the treatment of Burkitt's lymphoma included cyclophosphamide 1,200 mg/m2 every 3 weeks for six cycles and methotrexate 3 gm/m2 with leucovorin rescue on day 10 of each cycle. Nineteen of the patients received one of these standard-dose chemotherapy regimens. High-dose treatment without BMT consisted of high-dose cyclophosphamide and etoposide after four cycles of ACOP-12 and was given to five patients. Drug doses were cyclophosphamide 5,400 mg/m2 and etoposide 2,100 mg/m2 with subsequent granulocyte colony-stimulating factor to foster hematopoietic recovery without stem-cell support. Eight patients underwent intensive therapy with hematopoietic stem-cell support (four allografts and four autografts). Intensive therapy included cyclophosphamide (6 g/m2 in four patients, 180 mg/kg in three patients, and 150 mg/kg in one patient) and fractionated total-body irradiation in all patients (12 Gy in four patients, 10 Gy in three patients, and 7.5 Gy in one patient), with the addition of etoposide (1.8 g/m2) in five patients. The allografts were from sibling donors in three patients (full match in two patients and one-antigen mismatch in the other) and an unrelated donor in one patient (full match). Graft-versus-host disease prophylaxis was with cyclosporine and methotrexate in the four allografted patients. The autografts were with marrow treated in vitro with a cyclophosphamide derivative (4-hydroper-oxycyclophosphamide in two patients and mafosfamide in two patients). A decision to treat with only symptom palliation or no active treatment was made in seven patients with poor-performance status who presented with extensive disease in which delivering treatment with curative intent was not thought feasible. These patients were either elderly or demonstrated a clear inability to tolerate chemotherapy during initial standard treatment.
Survival
Twelve of the 13 patients in the dual-translocation group had stage IV disease at diagnosis and eight had two or more extranodal sites of disease. Five of 11 patients in the c-myc group and 11 of 15 patients in the other group had stage IV disease. Thus, at diagnosis, the dual-translocation group presented with more advanced-stage disease and had more sites of extranodal disease. Using the IPI, patients with dual translocations had more poor prognostic variables, with nine of 10 fully documented patients having three or more poor prognostic variables, compared with seven of 12 patients and 12 of 15 patients in the c-myc and other groups, respectively. These trends did not reach statistical significance. Only three patients in the dual-translocation group underwent high-dose chemotherapy (with or without BMT), although three others who were scheduled for this approach had their disease progress so rapidly after an initial standard-dose cycle of chemotherapy that no further treatment could be delivered. Six patients in this group, therefore, received standard-dose chemotherapy and four received symptom palliation only (Table 3). In the c-myc group, five patients were given high-dose chemotherapy and the remainder had standard treatment. Five patients in the other group were given high-dose chemotherapy, one had palliative treatment, and the remainder had standard treatment. Thus, the dual-translocation patients had less intensive treatment as a group; those receiving palliative treatment were elderly and of poor-performance status. When patients who had received no potentially curative treatment were removed from the survival curves, the survival difference for the dual-translocation compared with the c-myc and other groups still remained significant at P < .02 using the log-rank test.
Complications
Morphology and Molecular Genetics The c-myc and other cytogenetic cases had similar histologies, with a starry-sky pattern, increased mitotic activity, and scattered tingible body macrophages. Both of these groups had some admixed cells with round or oval nuclear contours and demonstrated less nuclear irregularity than the dual-translocation cases. The c-myc cases uniformly failed to express Bcl-2 protein (data not shown) in contrast to both the dual translocation and other cases that, for the most part, expressed Bcl-2 protein. All three cytogenetic subgroups had high mitotic rates as assessed using MIB-1, but minor differences in apoptotic rates were seen (Macpherson et al, manuscript in preparation). Representative examples of the histology of each cytogenetic group are shown in Fig 2. Flow cytometric immunophenotyping failed to disclose any differences among the three cytogenetic groups.
Molecular genetic data were available on a limited subset of cases, including five cases with dual translocations, two cases with c-myc alone, and four cases with other translocations. These data are listed in Table 5. Of note, four of the 11 cases with c-myc translocation alone and eight of the 13 cases with dual translocations had variant c-myc rearrangements, including either t(2;8) or t(8;22) translocations (Table 2), and would not have been detected using Southern blot analysis.
We have examined the clonal karyotype and clinical outcome of 39 adult cases of SNC-NB lymphoma. Although SNC-NB lymphoma that contains both c-myc and bcl-2 translocations has been reported sporadically in the past, the clinical course has not been correlated with the clonal karyotype.7,10-17 SNC-NB lymphomas seem similar morphologically, but when separated on the basis of their cytogenetic features, it is clear that they do not represent the same disease process. The median survival times for the c-myc, other cytogenetic abnormalities, and dual-translocation groups were 7 months, 8 months, and 2.5 months, respectively. There were no survivors at 2 years in the dual-translocation group, but 32% and 25% were alive in the c-myc and other groups. We hypothesized that the SNC-NB category was both molecularly and cytogenetically heterogeneous, partly accounting for the variable clinical outcome in this lymphoma. Our finding of three cytogenetic subgroups within the category of SNC-NB seems to contradict previous reports.25,26 Yano et al25 described 29 cases of SNC lymphoma, including 18 with Burkitt's morphology and 11 cases that fulfilled the criteria of non-Burkitt's lymphoma. The Burkitt's cases were shown to have a c-myc rearrangement by Southern analysis in 17 of 18 cases tested, in contrast with none of the 11 cases with non-Burkitt's histology. The latter category contained three bcl-2–positive cases, leading these authors to conclude that despite subtle pathologic differences distinguishing Burkitt's from non-Burkitt's lymphoma, the molecular differences establish meaningful biologic differences. In a similar study of SNC cases in human immunodeficiency virus–positive patients, c-myc alterations were found in 10 of 10 cases tested of Burkitt's lymphoma but in only two of the 10 SNC-NB cases.26 These authors reached conclusions similar to those of Yano et al,25 suggesting that the SNC-NB cases were related more closely to diffuse large B-cell lymphoma. Our study was purposefully designed to be based on cytogenetic findings and not on molecular genetic results. If it is assumed that the presence of a c-myc translocation is a defining biologic event that contributes to the clinical course of the patient, then four of the 11 cases in the c-myc translocation-only group and eight of the 13 cases in the dual-translocation group (total, 12 of 24) with variant translocations would not have been detected using Southern blot analysis. Thus, we detected cases that would have been considered negative by molecular techniques in the previous two studies, yet all of these cases had c-myc translocations. Hence, the prevailing opinion to abolish this lymphoma subtype in modern classifications and to include these cases either with Burkitt's lymphoma or within the category of diffuse large B-cell lymphoma seems ill advised. To do so will significantly curtail understanding of SNC-NB lymphoma as well as confound the interpretation of clinical outcome for these other lymphoma subtypes by including molecularly different diseases. The lack of molecular data in our study precludes us from making definitive statements about the molecular mechanisms of the c-myc rearrangements. Thus, we cannot exclude that the cases with cytogenetic abnormalities involving the c-myc locus are molecularly distinct from those in de novo Burkitt's lymphoma. However, the clinical course of the patients, the histologic findings, and the presence of classical t(8;14) or its variants are consistent with c-myc deregulation. In contrast to Laydanyi et al,27 who reported four cases of t(14;18)-negative follicular lymphoma with novel t(8;14) translocations that were molecularly distinct from the t(8;14) seen in high-grade lymphomas, we have not encountered de novo follicular lymphomas with these cytogenetic changes in more than 200 cases studied (D.H., unpublished observations, 1998). Although we cannot exclude this possibility in the two cases from the c-myc group with antecedent follicular lymphomas, both had variant t(8;22) translocations and neither case was studied for cytogenetics at the time of initial diagnosis. Six patients in the dual-translocation group had documented transformation from follicular lymphomas, compared with two in the c-myc group and three in the other-translocation group. There is a possibility that because the patients in the dual-translocation group were older and more heavily pretreated, they were less likely to respond to chemotherapy. The dual-translocation group had a higher tumor stage and more adverse prognostic factors as measured by the IPI. Also, the dual-translocation group was treated less aggressively, with fewer patients who received high-dose chemotherapy and more patients who received palliative treatment because of these factors. None of these differences among the three groups reached statistical significance, possibly because of the small number of patients in each, but the trend must be acknowledged. However, when all patients who did not receive potentially curative treatment are removed from analysis, the survival difference between dual-translocation patients and all other patients remains statistically significant. We think part of the reason that the dual-translocation patients presented with more advanced disease and had such disappointing median survival lies in the biology of this presentation of lymphoma. The bcl-2 translocation has been shown to increase cell survival by abrogating apoptosis, whereas the c-myc translocation enhances cell proliferation.8,28-32 Tumor cells with both translocations would therefore have a combination of characteristics that would predict rapid cell accumulation in a short time, thus bringing about the death of the host within a brief period.4 This has been demonstrated in bcl-2–transgenic mice, in which progression from lymphoid hyperplasia through polyclonal and then monoclonal disease led, over a long latency period, to immunoblastic lymphomas in some animals.33 Half of these lymphomas showed rearrangement of the c-myc gene in addition to bcl-2. Additional murine data may apply. Mononuclear cells from dual-transgenic mice (bcl-2 and myc) show increased viability and increased proliferation, whereas bcl-2–transgenic mouse cells have only increased cell viability, and cells from c-myc–transgenic mice exhibit increased proliferation and an increased cell-death rate.34 The mean latency-to-tumor development in the bcl-2 mice is 15 months, in the c-myc mice, 5 months, and in the dual-transgenic mice, only 3 weeks. The apoptotic index (the percentage of tumor cells possessing fragmented DNA) in lymphomas arising in the mice with bcl-2 is 2%, compared with a value of more than 8% in the mice with c-myc. In contrast, the apoptotic index in the bcl-2 and c-myc lymphomas is less than 2%. The mitotic indices of the combined bcl-2 and c-myc lymphomas and myc-only lymphomas are not significantly different. The genetic complementation seen can be ascribed to suppression of c-myc–associated apoptosis by bcl-2. Thus, experimental models strongly support the hypothesis that the dual translocation by itself would be sufficient to confer a poorer prognosis in our patient population. In conclusion, we found that despite aggressive chemotherapy, the dual translocation of bcl-2 and c-myc in SNC-NB lymphoma confers a significantly inferior outcome compared with the other two groups (P < .001). This is in agreement with observations made in experimental in vitro and in vivo systems in which the bcl-2 defect induces prolonged cell survival, c-myc induces enhanced proliferation, and the dual translocation (bcl-2 and c-myc) increases cell survival and proliferation, leading to rapid tumor growth. This study demonstrates that SNC-NB lymphoma is clinically and cytogenetically heterogeneous and that the specific pattern of cytogenetic abnormalities correlates with the clinical presentation and is useful in predicting outcome. Importantly, we caution against the design of further studies of this histologic subtype based solely on molecular genetic analysis because this approach will fail to detect the variant c-myc translocations and thus significantly underestimate the involvement of c-myc in the biology of SNC-NB lymphoma. Whenever possible, an aggressive therapeutic approach is warranted at diagnosis when a dual translocation is present. Because of the extremely poor outcome of this subgroup, these patients should be candidates for innovative experimental approaches.
The authors thank Carol Ireland for secretarial assistance, Yulia D'yachkova for statistical help, H. Gosling, C. Salski, C. Clemens, K. Hepburn and W. Barrett for cytogenetic analysis, K. McNeil, M. Anderson and G. Huart for molecular analysis, and the members of the Lymphoma Tumor Group of the British Columbia Cancer Agency for clinical management of the cases.
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ABSTRACT
INTRODUCTION
2 statistic, in which sample sizes were five or greater, or Fisher's exact test, for smaller samples.
