Divisions of 1 Medical Oncology, 2 Pathology and Laboratory Medicine and 3 Radiation Oncology, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada
Received 29 January 2003; revised 27 April 2003; accepted 17 June 2003
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Abstract |
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Mantle-cell lymphoma (MCL) is known to have a poor outcome, however, most patients present with advanced-stage disease. Little information is available on limited-stage MCL.
Patients and methods:
We retrospectively reviewed clinicopathological information on all patients with limited-stage MCL seen at the British Columbia Cancer Agency since 1984.
Results:
Twenty-six patients had low bulk (<10 cm) stage IA (12 patients) or IIA (14 patients) MCL. Initial therapy was involved-field radiation therapy (RT) with or without chemotherapy (CT), 17 patients; CT alone or observation, nine patients. Fifteen patients are alive at a median follow-up of 72 months (range 14194). Progression-free survival (PFS) at 2 and 5 years was 65% and 46%, and overall survival (OS) 86% and 70%, respectively. Five patients surviving beyond 8 years. Only age and initial use of RT significantly affected PFS. Five-year PFS for patients <60 years of age was 83%, compared with 39% for those aged 60 years, P = 0.04. Patients receiving RT with or without CT (n = 17), had a 5-year PFS of 68%, compared with 11% for those not receiving RT (n = 9, P = 0.002). Receiving RT eliminated the impact of age on PFS (with RT the 5-year PFS was 83% for those aged <60 years and 57% for those
60 years, P = 0.17). Although OS for the whole group was 53% at 6 years, it was 71% for those initially treated with RT, but only 25% for those not given RT (P = 0.13).
Conclusion:
In our experience, patients with limited-stage MCL had an improved PFS when treated with regimens including RT, with a trend towards improved OS. These results suggest a potentially important role for RT in limited-stage MCL.
Key words: chemotherapy, limited-stage mantle-cell lymphoma, non-Hodgkins lymphoma, radiation therapy
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Introduction |
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MCL arises from immature peripheral B lymphocytes in which immunoglobulin (Ig) heavy and light chain rearrangement has taken place. The majority of MCLs show a pre-germinal center pattern of Ig gene rearrangement with no somatic mutation of variable regions identified [6, 810]. Histological examination of excisional lymph node biopsies shows small to medium sized cells that are monomorphic, with irregular nuclear contours and inconspicuous nucleoli, and correspond to those found in the mantle zone of the primary follicle [11, 12]. Several growth patterns of classic MCL are recognized, including nodular, diffuse and mantle-zone types, with some suggestion that histological subtype may correlate with clinical behavior [2, 3, 7, 13, 14]; however, criteria for the recognition of subtypes are not well-defined.
Description of clinico-pathological features was previously hampered by the fact that classification schemes before the Revised EuropeanAmerican Lymphoma and World Health Organization classifications [11, 15] did not recognize MCL as a separate entity, and cases of MCL were thus included in a number of NHL subtypes in studies before the 1990s. Recognition of MCL has been aided by the widespread use of immunohistochemistry and flow cytometry for the identification of cell surface antigen expression such as the pan-B-cell antigens CD19, CD20, CD22 and CD79, as well as surface Ig, CD5 and FMC-7, and lack of CD23 and CD10 (reviewed in [6, 11, 16, 17]). The diagnosis of MCL is thus made based on typical histology and/or immunophenotype supported by cytological or cytogenetic features [16].
The distinguishing molecular feature of MCL is juxtaposition of the cyclin D1 locus and regulatory regions of the Ig heavy chain gene via the t(11;14)(q13;q32), resulting in the overexpression of cyclin D1. This translocation can be identified by cytogenetics, metaphase/interphase fluorescence in situ hybridization or PCR [6, 11, 17] and cyclin D1 overexpression by immunohistochemistry in virtually all cases of MCL, even when the t(11;14) cannot be demonstrated. Cyclin D1 interacts with gene products involved in cell cycle control or DNA repair, thus presumably contributing to the lymphomatous phenotype (reviewed in [6, 17]).
In other forms of lymphoma presenting with limited-stage disease, localized radiation therapy (RT) is used with or without a brief course of chemotherapy (CT) with curative intent and high success rates [1828]. Because MCL usually presents in advanced stage, for which CT-based strategies are generally employed, the potential role of RT has not been examined in detail. However, observations from other lymphomas indicate that RT may play an important role in the treatment of patients with limited disease, and the optimized use of local RT and brief CT has yielded results superior to those seen with either modality alone.
Patients with MCL in general have short remission duration. Relapse and disease progression appear inevitable with currently available treatments, which yield a median survival of about 3 years [2, 17]. Approximately 20% of patients with MCL present with limited-stage disease and little information is available concerning their disease course. This report describes the features and clinical outcome of 26 patients identified in British Columbia (BC) since 1984 with limited-stage MCL.
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Patients and methods |
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The diagnosis was determined by one of three hematopathologists using standard diagnostic criteria. In the case of patients diagnosed before 1992, MCL cases were identified retrospectively during review of specimens being examined as part of histopathological verification for other studies. MCL were subtyped into those with nodular, diffuse or mantle-zone patterns as previously described [3]. Immunophenotypic evaluation by immunohistochemistry and flow cytometry included positivity for B-cell markers, co-expression of CD5 and positivity for cyclin D1 or presence of a t(11;14) by cytogenetics in all cases [29].
Patients were treated according to standard protocols, using single-agent CT, multiagent CT and/or involved-field (IF) RT. Complete response (CR) was defined as the disappearance of all clinical evidence of lymphoma, maintained for at least 4 weeks following the completion of therapy. Partial response (PR) was defined as >50% decrease in the sum of the products of the largest perpendicular diameters of all measurable lesions, maintained for at least 4 weeks following the completion of therapy. Progression was defined as the regrowth of previously responding lesions or the appearance of disease at a new site. Progression-free survival (PFS) was defined as the time from diagnosis to the time of documented progression or recurrence of lymphoma. Overall survival (OS) was defined as the time from diagnosis to the time of death from any cause. Patients still alive were censored at the last known date of contact.
PFS and OS were determined by the KaplanMeier method and the significance of differences in actuarial survival by the log-rank method employing SPSS for Windows, version 10.1. OS and PFS were compared in subgroups defined by age, stage, histological subtype, ECOG PS, primary site (nodal versus extranodal) and initial treatment. As the maximum possible number of International Prognostic Index (IPI) factors in patients with limited-stage MCL was three, an analysis of IPI score was considered to be of limited value in this study and is not further described [30].
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Results |
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Fifteen patients are alive at a median follow-up for living patients of 59 months (range 585). Of 11 deaths, 10 were from lymphoma and one was from coronary artery disease while in CR. PFS for the whole group is shown in Figure 1. PFS at 2 and 5 years was 60% and 45%, and median PFS was 4.3 years. OS for the whole group is shown in Figure 2. OS at 2 and 5 years was 87% and 68%, with five patients surviving beyond 8 years. Median OS was 6.8 years.
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Discussion |
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The median age at diagnosis, 68 years, was similar to that previously reported in all stages [3, 7, 31, 38, 39], but some other baseline characteristics differed in this series. MCL is usually reported to have a male predominance (male:female ratio up to 3:1) [7, 31, 38, 39], but we found a ratio of 1.2:1 in the current series. Increased LDH was seen in fewer patients with limited-stage disease (8%) than in all stages (40%) [7, 31, 38]. Extranodal disease excluding bone marrow involvement occurred in 1548% of patients of all stages [3, 7, 31, 38, 39], and in 46% in the current group. Only 917% of patients in the all-stage series presented with involvement of ENT soft tissues [3, 31, 38, 39], as opposed to 42% in the current group, suggesting the possibility that an ENT site of presentation may facilitate diagnosis at an earlier stage. Poor PS was seen with a frequency similar to that in previous series (12%), but did not have a significant impact on PFS in the current series.
There are no widely accepted criteria for determining histological subtype in MCL [6], which may lead to problems with reproducibility. In the context of this limitation, diffuse, nodular and mantle-zone subtypes occurred in frequencies similar to those of previous reports of all stages [3, 7]. None of our patients had blastic transformation. We found a trend towards better PFS in those with a nodular (100%) rather than diffuse subtype (35%; P = 0.06). In summary, we found a slightly different gender distribution, more frequent extranodal (especially ENT) presentation, and less frequent elevation of LDH in patients with limited-stage MCL compared with patients of all stages. However, there were no striking differences in age, frequency of histological subtype, or PS, which often influence outcome in NHL.
Our results demonstrate a median OS of 6.8 years for patients with limited MCL as compared with a median OS of 3 years in all stages. That patients with limited-stage MCL should have better outcome than those with advanced-stage disease may reflect either inherent biological characteristics of the malignancy or possible lead-time bias. Some studies of IgH rearrangement and VH mutational status indicate that MCL may represent malignant transformation at more than one stage of B-cell ontogeny [6, 810, 40]. It might be of interest to determine whether examination of these parameters in MCL in limited-stage indicates an origin from a more restricted precursor B-cell stage than that seen in MCL in all stages. In the Nebraska study, advanced stage was an adverse prognostic factor for OS and PFS, and in the all-stage BC series, patients with advanced stage showed a trend towards shorter OS. The British National Lymphoma Investigation group reported that stage (limited n = 23; advanced n = 77) was predictive of OS [39], and in a series of 94 patients from Finland, stage was one of several factors predictive of CR attainment, time to treatment failure and OS [38]. Although not statistically significant, a trend towards improved PFS was seen in the current series when comparing patients with stage IA MCL with patients with stage IIA disease (5-year PFS 73% for stage IA, 20% for stage IIA; P = 0.06).
The most striking finding in this series, despite limited numbers of patients, was the difference in PFS in patients receiving RT as part of initial management. The 5-year PFS of the 17 patients receiving RT was 73%, compared with 13% in the nine patients not receiving RT (P = 0.01). More importantly, in patients receiving RT there was a plateau in the PFS curve at ~60% and six of 17 patients were alive without progression at >5 years. This implies significant activity of RT in MCL and a potentially important role for control of disease that can be readily encompassed within reasonable radiation fields. Moreover, while age appeared to portend better PFS (5-year PFS 83% for patients <60 years, 39% for patients 60 years; P = 0.04), the use of RT appeared to eliminate the impact of age on PFS (5-year PFS for patients receiving RT 83% for those <60 years, n = 7, 57% for those
60 years, n = 10; P = 0.17). This indicates that receiving RT was the more important factor for improved PFS. Similarly, there was a trend towards improved OS in patients receiving RT. As a plateau in OS was seen beyond 6 years, OS between groups was compared at this point. OS for the whole group was 48% at 6 years, 71% for those initially treated with RT with or without CT and 25% for those not given RT (P = 0.13). These results extend the experience reported by Vandenberghe et al. [39], in which 15 of 16 patients with limited-stage MCL received RT, with 12 attaining CR. Although 11 of these patients ultimately developed progressive disease, four patients remained in CR at up to 192 months. Meusers and Hense [41] found in addition that eight of 13 patients with limited-stage disease receiving extended-field RT exhibited stable disease for up to 60 months.
Radiosensitivity is a common feature of both Hodgkins lymphoma and NHL. MCL has been associated with inactivation of the ATM gene by somatic mutation [42]; ATM is a tumor suppressor gene involved in DNA repair and cell cycle control. Alterations in these may contribute to the apparent radiosensitivity of MCL. These observations may have implications for the treatment of MCL in all stages. In one study of patients with advanced-stage MCL, including total body irradiation in the conditioning regimen before autologous stem cell transplantation had no detectable impact on outcome of patients with MCL [43], but in others appeared to contribute to improved disease control [4447]. Radiolabeled antibodies deliver continuous low-dose radiation as compared with the intermittent high-dose radiation of external-beam regimens. It is possible that such targeted methods of delivering radiation to tumor cells might improve outcome [4853].
In the group receiving RT, six patients received CT in addition, of whom four received anthracycline-containing multiagent CT and two received single-agent CT. Because of small numbers, no formal comparison between CT strategies within the RT group was undertaken. However, all four patients treated with multiagent CT plus RT are alive and in first remission at a follow-up of 575 months, whereas both patients receiving single-agent CT with RT died of lymphoma. Eight of 11 patients receiving RT only are alive and in first remission at 37132 months. Two of nine patients in the group receiving no RT were treated with anthracycline-containing multiagent CT; both died of lymphoma. Within the limitations of small numbers, these results indicate a possible advantage to receiving multiagent CT in combination with RT for the treatment of microscopic and clinically evident disease, respectively. Of 16 evaluable patients receiving RT, one patient refused further therapy after receiving one of a planned 10 fractions of RT and had no response, and there were four relapses following CR attainment, all at distant sites. Of four patients receiving CT without RT, there were four relapses following CR attainment, three at the original site of disease and one at a distant site. Thus, although numbers are too small to draw firm conclusions, relapses in patients receiving RT occurred out of the radiation field, while in patients receiving CT only, relapse occurred both at the site of initial disease and at distant sites. These results are consistent with a possible advantage to receiving RT with respect to local disease control.
It has recently been shown that up to 88% of patients with MCL in advanced stage have biopsy-documented involvement of the gastrointestinal tract, despite clinical signs, symptoms or gross findings at endoscopy being limited to a minority [54, 55]. Although similar studies have not been carried out in limited-stage MCL, it is possible that subclinical disease outside planned radiation fields may occur. In this series, of seven patients who survived beyond 6 years, only one received multiagent CT plus RT, suggesting that subclinical disease requiring systemic treatment was not common. However, of 12 relapses, one was in a gastrointestinal site; this patient had received RT without CT.
The patients with MCL in this series were identified by retrospective review and thus a selection bias may be present and the patients may not be representative of limited-stage MCL in the population. Only 26 patients were identified, limiting the power of comparisons that could be made. However, data on limited-stage MCL are few [39, 41], and this report is the first to describe the outcome of these patients in detail. Within these limitations, we noted improved PFS in patients with stage IA or IIA MCL treated with regimens including RT, with a trend towards improved OS, suggesting a potentially important role for RT in this setting. While numbers are small, there is a possible advantage to combining multiagent CT with RT in this patient population. Similar to strategies employed in other lymphoproliferative malignancies such as diffuse large B-cell lymphoma or Hodgkins lymphoma in limited-stage, and until more definitive information is available regarding the role of additional staging including gastrointestinal endoscopy and biopsy, we advocate a strategy of brief multiagent CT to eliminate subclinical disease in combination with RT to sites of clinical involvement for patients with limited-stage MCL.
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Acknowledgements |
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Footnotes |
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