Lymphoma

Blastic variant of mantle cell lymphoma: a rare but highly aggressive subtype

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Abstract

The blastic variant (BV) form of mantle cell lymphoma (MCL) is considered to be a very aggressive subtype of non-Hodgkin's lymphoma (NHL). In order to determine its clinico-biological features and response to therapy we studied 33 patients (17%) out of 187 suffering from MCL who were diagnosed with a BV of MCL. Blastic variant was diagnosed according to histopathological patterns, immunophenotyping, and bcl1 gene rearrangement and/or cyclin D1 overexpression. Three patients initially diagnosed with large cell NHL were classified as BV. Patients received front-line therapy including CHOP-like regimen or CVP (n = 29), or chlorambucil (n = 4) and CHOP or ESAP as second-line therapy. High-dose intensification with stem cell transplantation (SCT) was performed in 11 cases (autoSCT, n = 8; alloSCT, n = 3). All but two patients were in complete remission (CR) at the time of transplant (CR1, n = 5; CR2, n = 4). Clinical and biological characteristics did not differ from those of the common form of MCL. The median age was 62 years (29–80), with a sex ratio (M/F) of 2.6:1. Of the 33 patients, 66% had extranodal site involvement, 85% had an Ann Arbor stage IV, and 82% had peripheral lymphadenopathy. Circulating lymphomatous cells were seen in 48% of cases. Twelve patients (36%) entered a CR1 with a median duration of 11 months. Fifteen patients (46%) failed to respond and rapidly died of progressive disease. Second-line therapy led to a 26% (6/23) CR2 rate. Nine patients relapsed after high-dose therapy. Twenty-two of the 33 patients (66%) died of refractory or progressive disease. Median overall survival (OS) time was 14.5 months for the 33 BV patients as compared to 53 months for the 154 patients with a common form of MCL, P <0.0001. In the univariate analysis, OS was influenced by age, extranodal site involvement, circulating lymphomatous cells, and international prognosis index (IPI). In the multivariate analysis, only IPI affected OS: patients with IPI 2 had 8 months median OS as compared to 36 months median OS for patients with IPI <2, P = 0.003. Blastic variant is one of the worst forms of NHL. An improved recognition of BV of MCL is required, particularly in high-grade CD5+ NHL using immunophenotyping and bcl1 molecular study. Standard therapy using anthracycline or even high-dose intensification produce poor results and an alternative treatment should be proposed to such patients.

Introduction

Mantle cell lymphoma (MCL) is now recognised as a rare but distinct entity in the revised European–American classification of lymphoid neoplasms (REAL) and WHO classification.1,2 It represents less than 10% of all non-Hodgkin's lymphoma (NHL) subtypes.3,4 This tumour is characterised by a diffuse and more rarely nodular proliferation of immature CD5+ CD23 B cells developing in the follicular mantle zone of lymph nodes.5 It is associated with a chromosomal translocation t(11;14)(q13;q32) resulting in the rearrangement of bcl1 gene and overexpression of cyclin D1/PRAD1.6 It is now well recognised that MCL represent a broad spectrum of different histopathological subtypes.3,5,7 The common form, corresponding to cases classified as centrocytic NHL in the Kiel classification, is composed of a homogeneous population of small- to medium-sized cells with scant cytoplasm, variably irregular nuclei, invisible nucleoli and low proliferative index. In this form, large cells with abundant cytoplasm or prominent nucleoli are rare or absent. Two variant forms had initially been distinguished although the terminology was sometimes confusing.3,7 The term blastic or blastoid variant (BV) was generally used to describe cases with a homogeneous population of cells displaying lymphoblastic morphology. Another variant form was related to the pleiomorphic subtype which was composed of a more heterogeneous population of large cells with ovoid or irregular cleaved nucleoli. These two variants were associated with high proliferative activity. In the updated WHO classification, only one blastic variant is recognised which includes a broad spectrum of morphological cases from lymphoblastic subtypes to cases featuring larger or more pleiomorphic cells.2

The blastic form of MCL may be difficult to diagnose and is akin to centroblastic large cell or lymphoblastic lymphoma. However, immunophenotyping and molecular analysis show typical MCL patterns.

It has recently been suggested that the variant form of MCL is of poor prognosis.8,9 However, the previous series focused on a small number of cases (<10), usually including the common form of MCL. There are very few clinical data on the specific response to standard- and high-dose chemotherapy of BV of MCL.

In the present study, we retrospectively analysed the clinical features, prognostic factors and response to therapy of 33 patients with BV of MCL and compared these results with the 154 patients with the common form of MCL.

Patients and methods

Patients

From 1994 to 1999, 209 patients recruited from 15 centres were initially considered as having MCL. All patients underwent classic staging including physical examination, complete blood count, LDH and β2 microglobulin level, liver tests, chest X-ray, CT-scan of the thorax and abdomen, and bone marrow biopsy. Performance status was assessed according to the ECOG scale. Patients were classified using Ann Arbor staging, and assigned prognostic scores according to the International Prognostic Index (IPI).10

Tumour characteristics and identification of blastic subtype of MCL

Two independent pathologists reviewed the 209 cases of MCL. Twenty-two cases (9%) which did not fulfill morphological and immunophenotypic characteristics of MCL were excluded. Histological analyses were performed on paraffin-embedded tissues. Bone marrow or lymph node biopsy samples were fixed and stained with hematoxylin and eosin, and giemsa.

Diagnostic criteria of the common form of MCL

One hundred and fifty-four patients were diagnosed as having a common form of MCL according to the following criteria:3 the lymphoma cells were characterised by a monotonous proliferation of small- to medium-sized lymphocytes with scant cytoplasm, variably irregular nuclei with condensed chromatin and inconspicuous nucleoli (Figure 1a). In these cases, the diagnosis of MCL was emphasised by CD5+/CD23 phenotype and/or cyclin D1 overexpression.

Figure 1
figure1

(a) The common form of MCL is characterized by a monotonous proliferation of small- to medium-sized lymphocytes with scant cytoplasm, and irregular nuclei with inconspicuous nucleoli. (b) The lymphoblastic subtype of variant form of MCL. The cells are medium-sized with scant basophilic cytoplasm, regular nuclei with finely dispersed chromatin and indistinguishable nucleoli. (c) The large cell subtype of the variant form of MCL. The cells display centroblastic morphology with prominent nucleoli, fine chromatin, and a moderate amount of basophilic cytoplasm.

Diagnostic criteria of BV of MCL

Thirty-three cases were diagnosed as having BV of MCL. The diagnosis was made on histological samples (marrow or lymph node) on 27 samples, or on blood/marrow smears (in cases of leukemic presentation without peripheral adenopathy) on six samples. The diagnosis of BV was made according to the recent published recommendations2,3 after careful examination of histological or cytological features.

We included the cytological forms of blastic subtypes, which are quite different from the common form (Figure 1a). In the lymphoblastic type, cells are medium-sized with scant indistinct cytoplasm and finely dispersed chromatin, and barely distinguished nucleoli (Figure 1b). Some cases display centroblastic morphology with large cells having round nuclei, fine chromatin, prominent nucleoli and a moderate amount of basophilic cytoplasm (Figure 1c).

Immunophenotyping

Immunophenotyping of the lymphomatous cells was performed in 31 cases using immunohistochemistry on frozen tissue sections (n = 11) or flow cytometry on cell suspensions (n = 20) obtained from lymph node, blood, bone marrow, or pleural effusion and using the following MoAbs: CD10, CD19, CD20, CD23, CD38, κ/λ light chains for B cell markers, and CD2, CD4, CD5, and CD8 for T cell markers. The phenotype was CD5+/CD19+/CD23 in 29 cases. In two cases, lymphomatous B cells coexpressed CD5 and CD23 but bcl1 rearrangement was observed in both samples. In the two cases where immunophenotyping was not performed, overexpression of cyclin D1 and typical histological pattern of BV of MCL were observed.

Molecular study and cytogenetic analysis

Bcl1 gene rearrangement was assessed using the following three techniques in 28 cases: (1) conventional cytogenetic analyses or FISH detected t(11;14)(q13;q32) in 11 cases.11 (2) Bcll gene rearrangement using PCR was found in two cases.12 (3) Using RT-PCR or the slot-blot technique,13,14 cyclin D1 overexpression was detected in 15 cases.

In the five cases in which molecular analysis could not be performed, histological examination was consistent with blastic form and the cells showed CD5+/CD23 phenotype.

Therapy

All but four patients received combined chemotherapy. Twenty-six patients were treated with an anthracyclin-based regimen: CHOP (n = 19), chlorambucil-VAD (n = 7). Three patients received CVP. Chlorambucil was administered as single therapy in four cases. Eight patients underwent autologous bone marrow transplantation (BMT): the conditioning regimen consisted of a BEAM regimen or melphalan/TBI. Three patients had an allogeneic BMT after CY/TBI. Other different treatments included DHAP or ESAP (n = 15) for relapsing or refractory patients. No patients received maintenance therapy.

Statistical analysis and prognostic factors

Overall survival (OS) time was calculated from the date of diagnosis until death from any cause or loss of follow-up. For the 187 patients, disease-free survival (DFS) was calculated from the date of first remission until the date of disease progression. Actuarial survival curves were estimated by the Kaplan–Meier method and compared using the log-rank test.15 The chi-square test was used in the univariate analysis to determine whether variables were predictive for response. P values <0.05 were considered to indicate statistical significance.16 A multivariate Cox regression analysis was performed for parameters statistically associated with survival.

Results

Clinical and biological features

Table 1 lists the main clinical and biological characteristics of the 33 BV patients as compared to 154 patients with the common form of MCL. In the BV group, these characteristics were as follows: the median age was 62 years (range, 29–80 years), the sex ratio was unbalanced, M/F equal to 2.6:1, and the majority of patients had generalised lymphadenopathy (82%). Extranodal site involvement was frequently observed (66%), especially in lung and pleural cavities (n = 10, 30%). Circulating lymphomatous cells and bone marrow infiltration were seen in 48% and 82% of cases, respectively. Gastro-intestinal infiltration was documented in two patients, but digestive endoscopy was not systematically performed in patients with disseminated disease. Finally clinico-biological presentation did not differ between the BV and the common form of MCL.

Table 1 Comparative clinico-biological characteristics of patients with BV of MCL and the common form of MCL on diagnosis

Histological and cytological findings

The large cell centroblastic variant and lymphoblastic subtype were observed in 19 and 14 cases, respectively. All 33 cases had specific phenotypic and/or molecular features of MCL as demonstrated by immunophenotyping and or bcl1 gene rearrangement. Three patients were initially diagnosed as having a centroblastic NHL by the histological review and confirmed the diagnosis of BV of MCL.

Response to therapy

After front-line therapy, only 12 (36%) entered CR, and six were in PR (overall response, 54%) (Table 2). Patients treated with CHOP (n = 19) had a better response (79% of CR + PR rate) than those treated with chlorambucil-VAD (n = 7), 28% of CR + PR rate, P <0.02. Fifteen patients failed to respond, and seven died of progressive disease. The median duration of CR1 was 11 months (range, 2–25 months). Four patients with localised disease had local radiotherapy: all relapsed, one in an irradiated site.

Table 2 Response to therapy

Second-line therapy was administered in 23 patients either with ESAP or DHAP (n = 15) regimen if they initially received CHOP, or CHOP (n = 8) for patients who did not receive CHOP as front-line therapy. The overall CR rate was 26%, equal to 33% after ESAP/DHAP and 13% after CHOP. Six patients entered CR2 lasting less than 8 months. A total of nine patients died after receiving second-line therapy.

Eleven patients underwent high-dose intensification. Eight patients had autologous PBSC transplantation, and three had allogeneic BMT: two after relapsing post-autologous transplantation and one in CR1. All but two patients were in CR at the time of transplant, five in CR1, and four in CR2. One patient was in PR after six cycles of C-VAD and one underwent allogeneic BMT while progressing. Nine patients relapsed after high-dose therapy (82%) and rapidly died of disease progression: seven relapsed after autotransplant and two after alloBMT. Only two patients are alive and well after autotransplant (n = 1) and alloBMT (n = 1). There were no toxic deaths secondary to high-dose therapy. Relapse occurred in CSF in two patients and with skin infiltration in three patients.

The surviving patients were monitored for a median time of 24 months (5–72 months). Twenty-two of the 33 (67%) patients died of refractory or progressive disease, three and eight patients are alive in CR or PR, respectively. The median overall survival (OS) and disease-free survival (DFS) time was 14.5 months and 13 months, respectively (Figure 2). We compared the clinical outcome of the 33 BV of MCL to the other 154 patients with a common form of MCL. These patients were comparable in terms of age, clinical and biological features, IPI, and treatment. There was a significantly lower OS for the BV of MCL than for the common forms of MCL, 14.5 months (95% confidence interval: 6.8–22.1) vs 53 months (95% confidence interval: 23.6–82.3), P <0.0001 (Figure 3).

Figure 2
figure2

Overall survival (OS) and disease-free survival (DFS) of BV of MCL (n = 33).

Figure 3
figure3

Overall survival according to histological subtype.

In the univariate analysis, 10 parameters were included (Table 3). Four of these were found to have a negative prognostic impact upon survival: lymphomatous circulating cells (P = 0.02), age superior to 60 years (P = 0.04), extranodal involvement (P = 0.003), and high IPI (P = 0.001), (Figure 4). Overall survival was not influenced by high-dose therapy or Ann Arbor staging. In the multivariate regression analysis, only high IPI significantly influenced overall survival (P = 0.003).

Table 3 Prognostic factors influencing overall survival of BV of MCL
Figure 4
figure4

Overall survival according to the IPI.

Discussion

Many studies have raised the poor prognosis of MCL.4,8,9,17 The median overall survival with standard therapy ranges from 3 to 4 years and the CR rate is usually less than 30%. The optimal therapy for such patients is still debated. Some authors have suggested that blastic variant forms of MCL are more aggressive than the common forms of MCL, and are frequently refractory to chemotherapy.8,9 However, there are very few studies specifically focusing on BV. These studies include a low number of patients making it difficult to draw definite conclusions as to the clinical features of this rare subtype of NHL. We report our clinical data on a series of 33 patients with BV out of 187 cases of MCL.

The clinical and biological features are comparable to those of classic forms of MCL.4,8,17 Blastic variant of MCL is usually diagnosed on initial presentation and more rarely in the course of common forms. Patients are predominantly male and over 60 years of age. The majority of patients have mainly stage IV disease, lymphadenopathy and extranodal involvement. Sixteen patients have circulating lymphomatous cells. Increased LDH (63%) and β2 microglobulin (51%) levels are observed with the same frequency in BV as in common forms. One third of patients have B symptoms, and distribution according to the modified IPI index is similar to that of classic forms of MCL: 52% are low-risk, and 48% are high-risk.

The major differences lie in the response to therapy, especially the duration of response. So far, there is no standard therapy for MCL. This explains why patients received heterogeneous treatments, although most received anthracycline-based chemotherapy. The overall response (CR + PR) to CHOP was 79% which is much closer to the response rate of aggressive NHL than that previously reported in MCL.17,18,19 Only one out of seven patients entered CR after chlorambucil-VAD which is substantially fewer in our experience than patients with classic forms of MCL.20 The response to single agent or CVP was very poor with only one response out of seven patients. However, the overall duration of response after first-line therapy was very short, estimated at 11 months and 10 of the 12 complete responders relapsed. Twenty-three patients received second-line therapy. We observed a 47% response rate after DHAP/ESAP which emphasises the initial results21 with this regimen in common forms of MCL. However, the median duration of CR2 was 8 months shorter than that of CR1. Eleven patients underwent high-dose therapy either with autologous or allogeneic stem cell transplantation. Nine of the 11 transplanted patients were in CR at the time of transplant and relapsed. It is still controversial whether or not high-dose intensification is of use in MCL. Few studies have reported the feasibility of such therapy in MCL, but the heterogeneity of patients and the absence of randomisation make it difficult to draw any definite conclusions. A study of 28 patients undergoing anti-B purging autologous BMT reported no evident clinical benefit with a DFS of 31% at 4 years.22 Similarly, Ketterer et al23 reported a median survival of 29 months after high-dose therapy in 16 MCL patients. However, in these two studies the majority of patients did not undergo transplantation as front-line therapy. As already reported in a number of studies on autologous PBSC transplantation, status on transplant influenced clinical outcome. Recent studies have reported encouraging results when patients underwent initial aggressive induction therapy rapidly followed by stem cell transplantation.24,25 In another study, patients receiving a TBI regimen have a 4-year OS and DFS of 89% and 74%, respectively.26 Whether or not patients with BV of MCL may benefit from autologous transplantation remains to be determined. Milpied et al25 underlined the poor outcome of three BV patients with a median DFS of 6 months. In our study, neither the type of conditioning regimen nor the status at the time of transplant (CR1 or CR2) influenced the outcome in statistical terms. However, the number of patients who underwent high-dose therapy is limited and this approach has to be evaluated prospectively as a front-line therapy in BV. Very few studies have been reported on allogeneic BMT in MCL. A potential GVL effect has been suggested.27 We observed one patient allografted in CR2 with a DFS lasting more than 42 months.

Finally, we confirm the very poor clinical outcome of BV of MCL with a median OS of 14.5 months which is very close to the limited series of Bosh et al.8 We identified IPI as the major prognostic factor as already reported in other subtypes of NHL. Neither Ann Arbor staging nor bone marrow or blood involvement influenced clinical outcome.

Several studies have raised the presence of molecular and biological abnormalities in BV of MCL. High mitotic activity and proliferation index are detected in 54% and 55% of the cases of BV as compared with 21% and 27% in the common form of MCL.28 p53 protein overexpression and p53 mutations are also found in the majority of cases.29,30 Additionally, alterations in cell cycle regulation may participate in the pathogenesis of aggressive cases of MCL and p21INK4c and p16NK4c deletions have been reported in BV of MCL.31,32 An increasing number of genetic abnormalities has recently been outlined in BV of MCL. Bea et al33 have reported chromosome imbalances such as gain of chromosomes 3q, 7p, and 12q, and loss of 17p. They also showed c-myc and BMI-1 amplification. Many of these alterations are statistically associated with a poor clinical outcome. Tetraploidy is also often observed in aggressive forms of MCL.28,34 In contrast with classic MCL, the occurrence of somatic hypermutation in the rearranged VH genes has been reported in some cases of BV.35 As a whole, these results suggest that BV of MCL have features quite distinct from common forms of MCL explaining their particularly aggressive behaviour and resistance to therapy.

Recognition of BV of MCL is usually determined on cytological or histological features. Classic forms of MCL are now well recognised. Some remaining cases are difficult to diagnose, especially atypical CLL. In some cases, and especially in large cell NHL and recently described B CD5+ high-grade NHL, BV may be misdiagnosed.36,37,38 We recommend that complete immunophenotyping and bcl1 gene rearrangement be done in such cases.

This study outlines the very poor prognosis of BV of MCL with a 14.5-month and 13-month median OS and DFS clearly indicating that it is one of the worst forms of NHL. Whether or not a subclassification of MCL is required remains controversial since there is currently no effective therapy.2 New approaches using a combination of chemotherapy and rituxan have recently been reported with encouraging results. It remains to be seen whether BV of MCL could benefit from such therapy.39 Meanwhile, we believe that recognition of BV should be considered for two reasons: to avoid misdiagnosis of CD5+ high-grade NHL, and to administer homogeneous treatment in this rare NHL to enable definite conclusions to be drawn.

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Acknowledgements

This work was supported by ADHO-Rennes (Association Développement Hématologie Oncologie).

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Correspondence to T Lamy.

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Bernard, M., Gressin, R., Lefrère, F. et al. Blastic variant of mantle cell lymphoma: a rare but highly aggressive subtype. Leukemia 15, 1785–1791 (2001) doi:10.1038/sj.leu.2402272

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Keywords

  • mantle cell lymphoma
  • blastic variant
  • clinical features

Further reading