|Year : 2008 | Volume
| Issue : 3 | Page : 315-322
|A clinicopathologic study of mantle cell lymphoma in a single center study in India
S Gujral1, A Agarwal1, V Gota2, R Nair2, S Gupta2, SK Pai2, M Sanger2, T Shet1, PG Subramanian1, M Muckaden3, S Laskar3
1 Department of Pathology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
3 Department of Radiation Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
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| Abstract|| |
We present clinical features, histopathology and results of treatment in cases of mantle cell lymphoma (MCL) at our hospital. We had 93 cases (2.1%) of MCL out of total 4301 cases of non-Hodgkin's lymphoma (NHL) in a 4-year period. It included 68 cases (1.7%) of MCL from 3987 cases of NHL diagnosed on histopathology. Remaining 25 cases (7.9%) diagnosed solely on peripheral blood examination were excluded. Thirty-six (85%) patients had advanced-stage disease. Sixty-three were nodal and five were extranodal (all gastrointestinal tract). Common patterns were diffuse (64%), nodular (25%) and mantle zone type (11%). Sixty-two cases had lymphocytic while six had blastic morphology (all nodal). Tumor cells expressed CD20 (100%), CD43 (94%), CD5 (89%) and cyclin D1 (85%). Bone marrow was involved in 25 (59%) cases. Thirty-two patients could be treated. Median recurrence-free survival was 22.23 months. Diffuse pattern of nodal involvement had a lower overall survival.
Keywords: Mantle cell lymphoma, histopathology, extranodal
|How to cite this article:|
Gujral S, Agarwal A, Gota V, Nair R, Gupta S, Pai S K, Sanger M, Shet T, Subramanian P G, Muckaden M, Laskar S. A clinicopathologic study of mantle cell lymphoma in a single center study in India. Indian J Pathol Microbiol 2008;51:315-22
|How to cite this URL:|
Gujral S, Agarwal A, Gota V, Nair R, Gupta S, Pai S K, Sanger M, Shet T, Subramanian P G, Muckaden M, Laskar S. A clinicopathologic study of mantle cell lymphoma in a single center study in India. Indian J Pathol Microbiol [serial online] 2008 [cited 2020 Jul 4];51:315-22. Available from: http://www.ijpmonline.org/text.asp?2008/51/3/315/42503
| Introduction|| |
Mantle cell lymphoma (MCL) is a distinctive disease entity characterized by specific histopathologic, immunologic and cytogenetic features and has an aggressive clinical course. MCL comprises approximately 2-10% of all non-Hodgkin's lymphoma (NHL). ,,,, Although MCL is recognized in the NHL classification proposal put forth by the International Lymphoma Study Group,  the grading of MCL remains a controversial issue. The cytology and growth pattern of MCL can be quite variable and the clinical significance of these features is unclear. We investigated the incidence of MCL using the WHO classification of lymphoid neoplasm and studied clinicopathologic characteristics of various histologic subtypes of MCL. Our aim was not to uncover novel diagnostic features of MCL, but to illustrate clinicopathological features of this disease in Indian population. With these issues in mind, we undertook a review of our Lymphoma Study Group experience with this disease entity.
| Materials and Methods|| |
Database included search from the computer records, case files, requisition forms and registers for patients with a diagnosis of MCL. We identified 72 cases of MCL in our histopathology files from year 2001 to 2004. Four cases, which did not fulfill morphological and immunophenotypic criteria of MCL, were excluded. Out of the remaining 68 cases, 42 had adequate clinical details and 32 of these received treatment at our center. Cases in which diagnosis was based solely on peripheral blood/bone marrow findings were excluded. Records from our leukemia lab revealed 25 such cases (7.9%) of mantle cell leukemia from 314 cases of chronic lymphoproliferative disorder, where the diagnosis was established on flow cytometric analysis of the peripheral blood (PB).
Diagnostic and staging procedures
Diagnostic work-up and staging procedures on presentation included history, physical examination and parameters such as age, gender, clinical details including "B" symptoms, site of involvement (nodal or extranodal) at presentation and staging. Laboratory parameters, such as complete blood cell count, lactate dehydrogenase (LDH), beta-2 microglobulin, liver enzymes, alkaline phosphatase, creatinine and albumin, were recorded. Serological markers for Human immunodeficiency virus, hepatitis C virus and hepatitis B virus were also noted. Radiological investigations included chest X-ray, computed tomography scan and magnetic resonance imaging of the chest, the abdomen and the pelvis. Histopathological slides of biopsy material from lymph node (LN), bone marrow (BM) and gastrointestinal tract (GIT) were retrieved from archives and studied. Additional immunohistochemistry (IHC) was done as required on case-to-case basis. BM biopsy performed as a routine for staging purpose was available in 42 cases. Correlation between LN biopsy pattern with BM involvement and morphology was carried out. Immunophenotyping by flow cytometry (FCM) was available in two out of five cases with peripheral blood (PB) involvement. Clinical stage was evaluated in accordance with conventional Ann Arbor criteria.  History of fever, night sweat and loss of weight or appetite (B symptoms) was recorded. Largest dimension of the largest site of disease was measured and bulky disease was reported as being <7 cm or ≥7 cm. Number of extranodal disease sites were recorded as ≤1 or >1. Spleen and Waldeyer's ring were classified as nodal sites. Complete clinical, serological and radiological details were available in 42 cases.
Only newly diagnosed cases of MCL were selected. Five out of 68 cases were extranodal in origin involving GIT. Primary diagnoses based on hematoxylin and eosin (H and E) sections with IHC slides were further reviewed by two pathologists. Additional IHC was performed as and when required. Strict histologic and recently updated criteria were applied and patients with a confirmed diagnosis of MCL were included in the study. ,, Tumor cells with classical morphological features in a CD20-positive NHL, expressing CD5 and/or cyclin D1, while negative for CD23 and CD10 were a requirement for diagnosis of MCL.  Cases with a nodular pattern of growth showing residual germinal center were considered to have a MCL with a mantle zone growth pattern. Cases were labeled nodular or mantle zone pattern if 10% or more of the tumor had such a pattern. Cases were labeled blastic if 20% or more cells were transformed. ,,
Histologic and IHC analysis
Slides were evaluated for pattern (diffuse, nodular and mantle), cytology (conventional lymphocytic and blastic) and other features like presence of mitosis, pink histiocytes, hyalinized capillaries, large nucleolated cells and the cytological composition of the background reactive inflammatory cells. IHC was performed using standard avidin-biotin complex peroxidase method (Vector peroxidase ABC kit, PK4001 and PK4002; Vector Laboratories, Burlingame, CA, USA). Pretreatment was done by heating in a microwave oven in 0.01 m citrate buffer (pH 6.0), EDTA buffer (pH 8.0), or using pepsin. Antibodies used were obtained from commercial source (Dako) and included CD20, CD3, CD5, CD23, CD43, Bcl2, Tdt, Mic2, CD10 and MiB1. Antibodies for cyclin D1, CD3 and Tdt were polyclonal, while others were monoclonal. Number of antibodies used in a given case was dependent on morphologic evaluation and varied from 8 to 12 per case.
Response to therapy
Response was evaluated in 32 patients who received chemotherapy at our center. Thirty patients received cyclophosphamide, doxorubicin, vincristine, prednisolone chemotherapy out of which 23 patients received 6 cycles, two received 8 cycles, three received 3 cycles and two received 1 cycle only. One patient received 6 cycles of cyclophosphamide, vincristine, prednisolone with prednisolone and leukeran. One patient was given only supportive care. None of our patients received rituximab. Overall survival (OS) was measured from the beginning of the treatment to the date of death from any cause or to the date of the last follow-up evaluation. Recurrence-free survival (RFS) was defined as the time from the beginning of treatment to disease progression or relapse.
For this study, SPSS 11.0 for windows was used. The categorical data were analyzed using the chi-squared test and the recurrence and survival rates were examined using the Kaplan-Meier analysis  and the log-rank method; P < 0.05 was considered to be statistically significant.
| Results|| |
We had a total of 5340 cases of lymphoma in a 4-year period (2001-2004) in our lymphoma registry. It included 93 cases (2.1%) of MCL out of 4301 cases of NHL in a 4-year period (including cases presenting as mantle cell leukemia). However, MCL diagnosed on histopathology alone were 68 cases (1.7%) out of a total 3987 cases of NHL. Remaining 25 cases (7.9%) of mantle cell leukemia were from 314 cases of chronic lymphoproliferative disorder, where the diagnosis was established on flow cytometric analysis of the PB. Complete clinical details were available of 42 patients.
The patients ranged from 28 to 77 years with median age at presentation of 57 years and a mean age of 56.3 years. Majority were males (54/68), male to female ratio being 3.8:1. Fifty-nine patients had generalized lymphadenopathy, which involved cervical group of LNs in all these cases. Other sites involved were axillary and inguinal nodes. Three patients had enlarged epitrochlear nodes (along with cervical nodes). Three patients had a tonsillar mass (Waldeyer's tonsillar ring) and one had supraclavicular LN only. Abdominal, mediastinal, thoracic, retroperitoneal and pelvic adenopathy was seen in seven patients. The disease involved LNs (92%), BM (59%), spleen (28%), GIT (7%) and PB (7%). B symptoms (fever, night sweat and loss of weight or appetite) were present in 18 out of 42 cases. Other complaints were abdominal distension (five cases), dysphagia (three cases), ecchymotic patches (two cases) and bleeding per rectum (one case).
Hemoglobin ranged from 4.2 to 13.7 gm/L. Total leukocyte counts ranged from 36 to 680 × 10 9 /L. Platelets ranged from 104 to 530 × 10 9 /L. Erythrocyte sedimentation rate ranged from 6 to 80 mm fall in first hour. Beta-2 microglobulin ranged from 1.1 to 12.1 mg/L. Chest X-ray revealed hilar lymphadenopathy in four cases, mediastinal mass in two cases and pleural effusion in one case. Twenty-five cases had normal chest X-ray. BM involvement at presentation was seen in 25 (59%) patients, PB spill in five (15%) patients. Tumor size varied from 1 × 1 × 1 cm to 25 × 10 × 7 cm. Serology for HIV, HCV and HBV was negative in all 42 cases. Only 32 patients received chemotherapy. Twenty-seven patients presented in stage 4, nine in stage 3, five in stage 2 and one in stage 1. Thus, most patients (36/42) were presented in advanced stage disease (3 or 4).
Histopathological and phenotypic analysis
Lymph node biopsy specimens were obtained from 60 patients at presentation, whereas biopsy specimens were obtained from other sites in the remaining eight cases (three in Waldeyer's ring and five in GIT). These cases were studied based on patterns (diffuse, nodular and mantle), cytology (lymphocytic and blastic) and other features.
Patterns: Lymph node architecture was completely effaced in 48 cases and partly effaced in 12 cases (five cases had GIT and three had tonsillar involvement). Occasional residual follicles were seen in seven cases. MCL were further subdivided into three major subtypes, namely diffuse (44), nodular (17) and mantle zone (7) patterns [Figure 1],[Figure 2],[Figure 3]. Diffuse pattern also revealed focal nodular pattern (four cases). All six cases of blastic MCL had diffuse pattern. Five cases of GIT and three cases of Waldeyer's ring did not show any definite evidence of nodularity, hence assigned to the diffuse category.
Cytology: Tumor was classified into two subtypes, lymphocytic and blastic cytology. Lymphocytic cytology revealed small lymphoid cells with mild to moderate nuclear irregularity, no nucleoli. Blastic cytology revealed small to intermediate sized tumor cells with finely dispersed nuclear chromatin and small nucleoli. Lymphocytic cytology was seen in 62 [Figure 4] and blastic in six cases [Figure 5]. All five cases of extranodal lymphomas (GIT) had a lymphocytic cytology.
Other morphological features: Thickened capsule was seen in 11, perinodal extension in 37 and capillary hyalinization in 55 cases. Pink histiocytes (non-phagocytic histiocytes) were seen in 56 cases. Occasional nucleolated centroblasts-like cells were seen in 10 cases (seven of mantle zone pattern and three of diffuse pattern). Mitotic count ranged from as low as 2/10 HPF to as high as 92/10 HPF. Median mitotic count was 60/10 HPF in blastic MCL and 15/HPF in lymphocytic MCL. Mitotic rate was particularly very low in GIT lymphomas. Blastic MCL showed increased mitotic counts and a diffuse pattern.
Bone marrow biopsy: Bone marrow infiltration was found in 25 (59%) cases [Table 1]. Common patterns of BM involvement were interstitial followed by diffuse. Three cases with interstitial involvement in addition revealed focal paratrabecular deposits. There was no discrepancy in the morphological and IHC features between BM and LN biopsies of 25 involved BM. There was no case showing involvement on aspirate while negative on BM biopsy. Circulating lymphoma cells, BM aspirate and BM biopsy involvement was seen in 12%, 42% and 59% cases, respectively. PB and the BM aspirate smears examination revealed polymorphous, intermediate to large blast-like cells. Nucleus was large, irregular with coarse chromatin, one to two small nucleolus and thin rim of dark blue cytoplasm. Lymphoglandular bodies were seen. Morphology was distinct and the closest differential was the large cell lymphoma. Immunophenotyping by FCM was done in two cases and tumor cells expressed CD19, CD5, CD20, FMC7 and cyclin D1.
All five cases of extranodal MCL were in lower GIT, out of which three were in ileocecal region and other two in colon. Three of these patients were males. Diagnosis was established on endoscopic (3) and open (2) biopsies. All cases showed sheets of atypical cleaved lymphoid cells with scanty pale cytoplasm. Two cases in addition showed nodular aggregates of lymphoid cells. Mitotic activity was very sparse and ranged 2-10/10 HPF. Three cases showed mucosal infiltrates and other two showed ulcerated mucosa. MZL and FL were close morphological differentials. Three of these cases revealed multiple polypoidal mucosal lesions and were labeled as lymphomatous polyposis. GIT lesions were small sized, ranging from 1 × 2 × 2 cm to 3 × 2 × 2 cm. One case had an abdominal mass (retroperitoneal lymph node) measuring 15 × 10 × 07 cm. None of them had peripheral LN involvement. Only one of these five cases had BM involvement.
MCL has different architectural and cytological patterns and each subtype has many look-alikes. In our 44 cases with diffuse pattern, common differentials were small lymphocytic lymphoma (in six cases) and FL (in three cases). In 17 cases with nodular pattern, common differentials were FL (in nine cases) and SLL (in two cases). All seven cases of MCL with mantle zone pattern had close differentials of SLL, MZL and diffuse large B-cell lymphoma (DLBCL). All six cases of blastic MCL had a differential of lymphoblastic lymphoma (LL), extramedullary myeloid cell tumor and DLBCL.
All cases required IHC for a final diagnosis. CD20 (a B-cell marker) was positive in all cases, along with CD5 and/or cyclin D1 expression. CD23 and CD10 were negative in all cases. Cytogenetic and molecular studies were available in few cases only. Seven out of 68 cases did not express CD5, while 10 other cases were negative for cyclin D1. None was negative for both CD5 and cyclin D1. CD43 was expressed in 64 out of 68 cases [Table 2]. Follicular dendritic cell meshwork, as highlighted by CD23 staining, was more pronounced in seven cases of MCL with mantle zone pattern. Almost all cases showed scanty normal T and B cells in the background. Two cases in addition showed a focal increase in plasma cells. None of the blastic MCL expressed Tdt and Mic2. CD34 stain was negative in four cases. Aberrant phenotypic expression (myeloid or any other T cell) was not seen.
Treatment and outcome
Out of 32 cases treated, 29 were nodal and three were GIT lymphoma. Twenty-eight cases had conventional lymphocytic morphology and four had blastic morphology, while 20 had diffuse, nine had nodular and three had mantle zone pattern. Out of the 32 cases treated, 28 had lymphocytic, while four had blastic cytology. Thirty patients received CHOP chemotherapy (23 completed 6 cycles, two received 8 cycles, three received 3 cycles while two could received 1 cycle only). One patient received 6 cycles of COP with prednisolone and leukeran. One patient was given palliative therapy only. None of our patient received rituximab. Two of the extranodal MCL cases (lymphomatous polyposis) received adjuvant radiotherapy to a dose of 45Gy/25 fractions over 5 weeks.
Pretreatment hemoglobin (≤10 vs . >10), LDH (normal vs . high) and age at diagnosis (≤60 vs . >60) were not predictive of response in our study ( P > 0.05). Patients with diffuse pattern had a poor response rate compared to patients with other patterns, although the difference was not statistically significant ( P = 0.11). Complete response rate was higher in females as compared to males (4/10 vs . 3/22; P = 0.09).
We tried to look at age (≤60 vs . >60), pattern (diffuse vs . non-diffuse), pretreatment hemoglobin (≤10 vs . >10) and LDH (normal vs . high) as possible prognostic factors for OS and RFS. None of them could prognosticate OS in our study. Apart from hemoglobin, none of the other factors prognosticated RFS. Patients with pretreatment hemoglobin ≤10 g/dL had better RFS as compared to those with >10 g/dL ( P = 0.02).
Survival data was available for all cases. The median duration of follow-up was 11.4 months. Eight patients died at the time of analysis. Median survival had not been reached. One-year OS was 75%.
Eleven patients had recurrence at the time of analysis. The median RFS was 22.23 months (7.9-39.5 months) [Figure 6]. One-year RFS was 80% and 3-year RFS was 28%.
| Discussion|| |
Mantle cell lymphoma is a type of B-cell NHL with distinctive morphologic and immunophenotypic features and a characteristic cytogenetic abnormality, the t(11;14)(q13;q32). Tumor cells express BCL-1 also called as cyclin D1 and CCND1. Approximately 70% and 50% of the MCL at the cytogenetic level and genomic level, respectively, showed a specific chromosomal rearrangement, t(11;14) (q13;32), involving the BCL-1 locus on chromosome 11q13 and the immunoglobulin heavy chain gene complex on chromosome 14q32. ,,,,,, This genetic event is thought to have an important role in pathogenesis of MCL, because overexpression of cyclin D1 protein is thought to lead to deregulation of normal cell cycle, particularly at the G1-S phase transition.  Median OS has been defined to be only 3-4 years, which has not changed in the last two decades. , There are conflicting reports of benefits of anthracycline-based chemotherapy on OS when compare with less aggressive regimen. ,
The histopathology of MCL is well defined in western literature, ,,,,,, but there is no data from Indian subcontinent. Distribution of NHL subtypes in India is different with those from the rest of the world. FL and MCL are less common in India when compared with Europe and the USA.  Previous published reports from India have stated incidence of MCL to be 3.4% and 2%. , Our incidence of MCL (2.1%) is low in comparison to published incidence of MCL (2-10%). ,,,, MCL constituted 2.1% (93 cases) from a total of 4301 cases of NHL (including mantle cell leukemia). Clinical characteristics in our series were similar to those reported elsewhere. ,,, With regards to gender distribution, our results confirm that the incidence in men is higher than in woman. ,,,,, Thirty-six out of 42 (86%) patients presented in stage 3 or 4, in agreement with previous reports. [1-6] Leukocytosis was observed in six (16%) out of 36 patients.
MCL has been morphologically sub-classified according to patterns (nodular, diffuse and mantle zone) and cytology (lymphocytic and blastic). ,, Clinical significance of these features is unclear. Common patterns were diffuse (17 cases, 66%), nodular (17 cases, 25%) and mantle zone (seven cases, 10.3%). Fourteen cases with diffuse pattern in addition revealed focal nodular areas. Similar findings have been described in previous studies. ,,,,, However, there are reports showing a high incidence of 55% of mantle zone pattern of MCL.  None of our cases showed any admixture of areas characteristic of MCL and of other larger nucleolated cells, indicating any histological progression or a composite lymphoma. Diffuse pattern and the lymphocytic cytology was commonest subtype in our series, as seen elsewhere. , Clinicobiological presentation did not differ between patterns and cytological variants of MCL, a finding similar to as seen by others.  Diffuse pattern of MCL was associated with poorer OS as also seen by others.  MCL with mantle zone pattern in our series had a better OS as reported elsewhere. ,, There are other studies showing no relation of OS with various morphological patterns. , All six blastic MCL had a diffuse pattern of involvement. We did not have any pleomorphic or centroblastic variant of blastic MCL as described elsewhere. , CD23 was a useful stain to highlight follicular dendritic cells and hence the follicles. Pink histiocytes and hyalinized blood vessels were seen in 53 (77%) and 58 (85%) cases, respectively, in concordance with as reported previously. ,, Mitosis was more prominent in the blastic variants as reported previously.  There are a few reports available, which examine the prognostic importance of cytology and patterns in MCL. Blastic MCL and diffuse MCL are reported to have very aggressive disease, while lymphocytic cytology and nodular and mantle zone patterns have comparatively better prognosis.  In our series too, patients with diffuse pattern and blastic morphology had a poor response rate compared to patients with other patterns, although the difference was not statistically significant ( P = 0.11). Others  have reported blastic MCL with good overall median survival. We did not find any statistically different survival rates in blastic and non-blastic MCL as cases of blastic MCL were few.
Common differentials on morphology were SLL, FL, MZL, DLBCL and LL. IHC was required in all cases for a definitive diagnosis and showed a classical phenotype (CD20, CD5 and cyclin D1) in 51 (75%) cases. Seventeen (25%) cases had an atypical IHC profile, where seven cases were CD5-negative and another 10 cases were cyclin D1-negative. Cyclin D1 was expressed (nuclear stain) in 58 (85%) cases. All cases were negative for CD3, CD10 and CD23, thus differentiating it from SLL and FL. However, none was negative for both CD5 and cyclin D1. Cyclin D1 stain negativity may be truly negative as it is well known.  Up-regulation of cyclin D2 or D3 may substitute for cyclin D1 in the pathogenesis of MCL.  It may be due to high false-negativity because of poor tissue fixation. Both the cyclin D1-positive and -negative cases were characterized by male predominance and advanced stages of the disease, as described previously.  Few studies have shown poorer survival in cyclin D1-positive MCL in comparison to cyclin D1-negative cases,  while others have noticed no difference in behavior and survival.  Survival comparison could not be carried out as we had fewer cases of cyclin D1-negative MCL in our series. More objective criteria such as high Ki67 proliferation index and p53 gene mutation lead to more aggressive outcome. ,, Blastic MCL constituted only 8.6% in our series, while others have reported it to be as high as 17%.  Lower percentage of blastic MCL could be either a true incidence or else may be due to lack of standardized criteria to diagnose this entity. Mib1 proliferation index in four cases of blastic MCL ranged from 50% to 70%, while it ranged from 15% to 40% in 12 cases of lymphocytic MCL. Morphology, mitotic count and Mib1 proliferation index were thus helpful in diagnosing blastic variants of MCL. Blastic MCL had poorer outcome in agreement with previous reports,  but the number of cases was low to be statistically significant. Tdt was not expressed in any of the blastic variants. LDH and beta-2 microglobulin levels did not correlate with various morphological patterns, a finding similar to as described by others.  We did not have any case of in situ MCL. 
Peripheral blood, BM aspirate and BM biopsy involvement in our 68 cases of MCL was 12%, 42% and 59%, respectively. Incidence and patterns of BM involvement is similar to as described elsewhere.  Common patterns of BM involvement were interstitial in 11 (26%), diffuse in 10 (23%) and nodular in four (9%) cases, similar to as seen by others. ,,, BM aspirates revealed very characteristic intermediate to large sized, polymorphous tumor cells with coarse nuclear chromatin and scanty cytoplasm. Morphological close differential was a large cell lymphoma. This was unlike common practice where SLL, FL and MCL are lumped together in low-grade lymphomas. PB involvement was seen in five cases (12%, in the diagnosed cases of MCL), in comparison to 25% as published elsewhere.  Data from our leukemia lab revealed 25 (7.8%) cases of mantle cell leukemia from 314 new cases of chronic lymphoproliferative disorders in the PB in a 4-year period (2001-2004). Incidence of PB involvement reported elsewhere is 25%.  Incidence of mantle cell leukemia (7.8%) at our center was much more common than nodal MCL (1.7%). LN biopsy was not obtained in cases diagnosed as mantle cell leukemia on FCM. However, true incidence of MCL (including cases of mantle cell leukemia) is 2.1%, still very low in comparison to other studies. 
Extranodal MCL have been described at various sites, including stomach, ileum, colon, ocular soft tissues, skin etc. ,, Frequency of extranodal manifestations of nodal MCL is often underestimated.  Central nervous system infiltration was not seen in any of our cases as oppose to other reports.  Three of our cases involved Waldeyer's ring, which is considered as nodal lymphoma. MCL in GIT may occur as primary or as part of a generalized presentation and great majority of MCL patients show GIT involvement at the time of diagnosis, in the form of minute lymphoid infiltrate.  Extranodal MCL in GIT was seen in five (7%) out of 68 cases, far less than 15-30% incidence reported elsewhere. ,,, GIT involvement is reported in 10-28% of MCL cases.  Others have reported that GIT MCL presents mostly in asymptomatic patients and is detected microscopically in 50% of patients after a biopsy of a visually benign mucosa.  All our patients were symptomatic and had primary GIT MCL. None had a blastic morphology, unlike other reports of high incidence of extranodal blastic MCL.  Classical growth pattern of nodal lymphomas was not seen or not evaluable because of small size of the biopsy specimens. Common morphological differentials were marginal zone lymphoma, follicular lymphoma and DLBCL. Two cases of GIT MCL were cyclin D1-negative. This is in contrast to earlier reports that extranodal MCL are mostly cyclin D1-positive. 
No specific treatment guidelines are defined for treatment of MCL. Targeted therapies have shown promise and may have a role in maintenance and/or initial therapy.  Treatment was heterogeneous in our cases due of inherent reasons like patient's compliance and high cost involved in chemotherapy. Patients received chemotherapy as defined protocols. , Median OS was not reached at 11.4 months of follow-up. Seventy-five percent of our patients were surviving at the end of 1 year. The median OS reported in literature is 49 months.  RFS of 32 patients is graphically shown in [Figure 6], with a median RFS of 22.23 months ranging from 7.9 to 39.5 months. We could not establish any relation between survival and different parameters like hemoglobin, LDH, beta-2 microglobulin, blastic morphology, mitosis and proliferation index (Mib1). Survival data was available for all cases. The median duration of follow-up was 11.4 months. Eight patients had died at the time of analysis. Median survival had not been reached. One-year OS was 75%. Eleven patients had recurrence at the time of analysis. The median RFS was 22.23 months (7.9-39.5 months, [Figure 6]). One-year RFS was 80% and 3-year RFS was 28%.
Cases with low hemoglobin had a better RFS ( P < 0.05). We have no conceptual explanation for this and it is possible that the observation was purely due to chance. Alternately, patients with apparently normal hemoglobin concentration were indeed anemic but were treated with packed cell transfusions before presenting in our hospital for management. There was no statistically significant difference in the response rate and OS between the two groups.
To conclude, MCL is a rare B-cell lymphoma that has never been characterized in India. It constitutes approximately 2.1% of all our NHL, including cases of MCL diagnosed on histopathology (68 cases, 1.7%) and mantle cell leukemia presenting as chronic lymphoproliferative disorder (25 cases, 7.9%). Incidence of MCL is less in India as compared to the west. Most laboratories doing IHC do a limited panel, mainly LCA, CD20 and CD3. Referral centers like ours receive cases requiring extensive IHC work-up. Closest differentials on morphology were FL, SLL, DLBCL and follicular center cell lymphoma - diffuse variant. Close differentials of blastic MCL were DLBCL and LL. IHC is a must for diagnosis, though we had few cases negative for cyclin D1 and CD5. GIT is the commonest extranodal site involved. BM was involved in 25 (59%) cases. Morphology of tumor cells in BM aspirate and PB smears was like a large cell lymphoma, unlike common practice where SLL, FL and MCL are lumped together in the category of chronic lymphoproliferative disorders/low-grade lymphomas.  Nodular pattern was commonly associated with lymphocytic cytology, while the diffuse form showed both lymphocytic and blastic variants. Diffuse pattern of nodal involvement had a lower OS. Median RFS was 22.23 months. Although overall incidence of MCL is low, the usual morphological variants and subtypes of nodal and extranodal MCL that occur in west are seen in India with almost similar incidence and frequency.
| References|| |
|1.||Jaffe ES, Harris NL, Stein H, Vardiman JW. World Health Organization Classification of Tumors. Pathology and Genetics, Tumors of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001.p. 168-70. |
|2.||Argatoff LH, Connors JM, Klasa RJ, Horsman DE, Gascoyne RD. Mantle cell lymphoma: A clinicopathologic study of 80 cases. Blood 1997;89:2067-78. [PUBMED] [FULLTEXT]|
|3.||Oinonen R, Franssila K, Teerenhovi L, Lappalainen K, Elonen E. Mantle cell lymphoma: Clinical features, treatment and prognosis of 94 patients. Eur J Cancer 1998;34:329-36. [PUBMED] [FULLTEXT]|
|4.||Bosch F, Lopez-Guillermo A, Campo E, Ribera JM, Conde E, Piris MA, et al . Mantle cell lymphoma presenting features, response to therapy and prognositc factors. Cancer 1998;82:567-75. |
|5.||Velders GA, Kluin-Nelemans JC, De Boer CJ, Hermans J, Noordijk EM, Schuuring E, et al . Mantle-cell lymphoma: A population-based clinical study. J Clin Oncol 1996;14:1269-74. [PUBMED] [FULLTEXT]|
|6.||Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al . A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 1994;84:1361-92. [PUBMED] [FULLTEXT]|
|7.||Beahrs O, Henson D, Hutter R, Kennedy BJ. Non-Hodgkin's lymphoma. In : American Joint Committee on Cancer manual for staging of cancer. 4th ed. Philadelphia: JB Lippincott; 1992. p. 257-9 |
|8.||Banks PM, Chan J, Cleary ML, Delsol G, De Wolf-Peeters C, Gatter K, et al . Mantle cell lymphoma: A proposal for unification of morphologic, immunologic and molecular data. Am J Surg Pathol 1992;16:637-40. [PUBMED] |
|9.||Bernard M, Gressin R, Lefrere F, Drenou F, Branger B, Caulet-Maugendre S, et al . Blastic variant of mantle cell lymphoma: A rare but highly aggressive subtype. Leukemia 2001;15,1785-1791 |
|10.||Weisenburger DD, Armitage JO. Mantle cell lymphoma: An entity comes of age. Blood 1996;87:4483-94. [PUBMED] [FULLTEXT]|
|11.||Weisenburger DD, Vose JM, Greiner TC, Lynch JC, Chan WC, Bierman BJ, et al . Mantle cell lymphoma: A clinicopathologic study of 68 cases from the Nebraska Lymphoma Study Group. Am J Hematol 2000;64:190-6. |
|12.||Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81. |
|13.||de Boer CJ, Schuuring E, Dreef E, Peters G, Kluin PM, van Krieken JH. Cyclin D1 protein analysis in the diagnosis of mantle cell lymphoma. Blood 1995;86:2715-23. [PUBMED] [FULLTEXT]|
|14.||Yatabe Y, Suzuki R, Tobinai K, Matsuno Y, Ichinohasama R, Okamoto M, et al . Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: A clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma. Blood 2000;95:2253-61. [PUBMED] [FULLTEXT]|
|15.||Aguilera NS, Bijwaard KE, Duncan B, Krafft AE, Chu WS, Abbondanzo SL, et al . Differential expression of cyclin D1 in mantle cell lymphoma and other non-Hodgkin's lymphomas. Am J Surg Pathol 1998;153:1969-76. |
|16.||Barista I, Romaguera JE, Cabanillas F. Mantle cell lymphoma. Lancet Oncol 2001;3:141-8. |
|17.||Pittaluga S, Wlodarska I, Stul MS, Thomass J, Verhoef G, Cassiman JJ, et al . Mantle cell lymphoma: A clinicopathological study of 55 cases. Histopathology 1995;26:17-24. |
|18.||Majlis A, Pugh WC, Rodriquez MA, Benedict WF, Cabanillas F. Mantle cell lymphoma: Correlation of clinical outcome and biologic features with three histologic variants. J Clin Oncol 1997;15:1664-71. |
|19.||Weisenburger DD, Nathwani BN, Diamond LW, Winberg CD, Rappaport H. Malignant lymphoma, intermediate lymphocytic type: A clinicopathologic study of 42 cases. Cancer 1981;48:1415-25. [PUBMED] |
|20.||Brittinger G, Bartels H, Common H, Duhmke E, Fulle HH, Gunzer U. Clinical and prognostic relevance of the Keil classification of non-Hodgkin's lymphoma: Results of a propspective multicentric study by the Keil Lymphoma Study Group. Heamtol Oncol 1984;2:269-306. |
|21.||Teodrovic I, Pittaluga S, Kluin-Nelemans JC, Meerwaldt JH, Hagenbeek A, van Glabbeke M. Efficacy of four different regimens in 64 mantle cell lymphoma cases: Clinicopathologic comparison with 498 other non-Hodgkin's lymphoma subtypes. J Clin Oncol 1995;13:2819-26. |
|22.||Yatabe Y, Suzuki R, Matsuno Y, Tobinai K, Ichinohazama R, Tamaru J, et al . Morphological spectrum of cyclin D1-positive mantle cell lymphoma: Study of 168 cases. Pathol Int 2001;51:747-61. [PUBMED] [FULLTEXT]|
|23.||Naresh KN, Srinivas V, Soman CS. Distribution of various subtypes of non-Hodgkin's lymphoma in India: A study of 2773 lymphomas using REAL and WHO classifications. Ann Oncol 2000;11:63-7. |
|24.||Sahni CS, Desai SB. Distribution and clinicopathologic characteristic of non-Hodgkin's lymphoma in India: A study of 915 cases using WHO classification of lymphoid neoplasms. Leuk Lymph 2007;48:122-33. |
|25.||Zelentez AD. Mantle cell lymphoma: an update on management. Ann Oncol 2006;17:iv12-4. |
|26.||Zucca E, Roggero E, Pinotti G, Pedrinis E, Cappella C, Venco A, et al . Patterns of survival in mantle cell lymphoma. Ann Oncol 1995;6:257-62. [PUBMED] [FULLTEXT]|
|27.||Pittaluga S, Wlodarska I, Stul MS, Thomas J, Verhoef G, Cassiman JJ, et al . Mantle cell lymphoma: A clinicopathological study of 55 cases. Histopathology 1995;26:17-24. [PUBMED] |
|28.||Fisher RI, Dahlberg S, Nathwani BN, Banks PM, Miller TP, Grogan TM. A clinical analysis of two indolent lymphoma entities: Mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): A Southwest Oncology Group study. Blood 1995;85:1075-82. [PUBMED] [FULLTEXT]|
|29.||Lardelli P, Bookman MA, Sundeen J, Longo DL, Jaffe ES. Lymphocytic lymphoma of intermediate differentiation: Morphologic and immunophenotypic spectrum and clinical correlation. Am J Surg Pathol 1990;14:752-63. [PUBMED] |
|30.||Norton AJ, Matthews J, Pappa V, Shamash J, Love S, et al . Mantle cell lymphoma: Natural history defined in a serially biopsied population over a 20-year period. Ann Oncol 1995;6:249-56. [PUBMED] [FULLTEXT]|
|31.||Duggan MJ, Weisenburger DD, Ye YL, Bast MA, Pierson JL, et al . Mantle zone lymphoma: A clinicopathologic study of 22 cases. Cancer 1990;66:522-9. [PUBMED] |
|32.||Montserrat E, Bosch F, Lopez-Guillermo A, Graus F, Terol MJ, et al . CNS involvement in mantle cell lymphoma. J Clin Oncol 1996;14:941-4. |
|33.||Fu K, Weisenburger DD, Greiner TC, Dave S, Wright G, Rosenwald A, et al . Lymphoma-leukemia Molecular Profiling Project: Cyclin D1-negative mantle cell lymphoma, A clinicopathologic study based on gene expression profiling. Blood 2005;106:4315-21. [PUBMED] [FULLTEXT]|
|34.||Lennert K. Centrcytic lymphoma. In : Lennert K, editor. Histopathology of non-Hodgkin's lymphoma (based on the Keil classification). New York, NY: Springer-Verlag; 1981. p. 57-62. |
|35.||Richard P, Vassallo J, Valmary S, Missoury R, Delsol G, Brousset P. "In situ-like" mantle cell lymphoma: A report of two cases. J Clin Pathol 2006;59:995-6. [PUBMED] [FULLTEXT]|
|36.||Romaguera J, Hagemeister FB. Lymphoma of the colon. Curr Opin Gastroenterol 2005;21:80-4. [PUBMED] [FULLTEXT]|
|37.||Ferry JA, Fung CY, Zukerberg L, Lucarelli MJ, Hasserjian RP, Preffer FI, et al . Lymphoma of the ocular adnexa: A study of 353 cases. Am J Surg Pathol 2007;31:170-84. [PUBMED] [FULLTEXT]|
|38.||Motegi S, Okada E, Nagai Y, Tamura A, Ishikawa O. Skin manifestation of mantle cell lymphoma. Eur J Dermatol 2006;16:435-8. [PUBMED] [FULLTEXT]|
|39.||Ott G, Kalla J, Ott MM, Schryen B, Katzenberger T, Muller JG, et al . Blastoid variants of mantle cell lymphoma: Frequent bcl-1 rearrangements at the major translocation cluster region and tetraploid chromosome clones. Blood 1997;89:1421-9. |
|40.||Swerdlow SH, Williams ME. From centrocytic to mantle cell lymphoma: A clinicopathologic and molecular review of 3 decades. Hum Pathol 2002;33:7-20. [PUBMED] [FULLTEXT]|
|41.||Salar A, Juanpere N, Bellosillo B, Domingo-Domenech E, Espinet B, Seoane A, et al . Gastrointestinal involvement in mantle cell lymphoma: A prospective clinic, endoscopic and pathologic study. Am J Surg Pathol 2006;30:1274-80. [PUBMED] [FULLTEXT]|
|42.||Brody J, Advani R. Treatment of mantle cell lymphoma: Current approach and future directions. Oncol Haematol 2006;58:257-65. |
|43.||Witzig TE. Current treatment approaches for mantle-cell lymphoma. J Clin Oncol 2005;23:6409-14. [PUBMED] [FULLTEXT]|
|44.||Bain B, Barnett D, Linch D, Matutes E, Reilly JT. Revised guidelines on immunophenotyping in acute and chronic lymphoproliferative disorders. Clin Lab Hematol 2002;24:1-13. |
Department of Pathology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]
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