The term mantle is derived from the Latin word mantellum, which means external covering or symbol of preeminence. The mantle zone is the outer covering of the secondary follicle located in the lymph node cortex. It engulfs the germinal center of the secondary follicle and is, in turn, surrounded by the marginal zone area. Mantle cell lymphoma (MCL) was previously called centrocytic lymphoma or intermediately differentiated lymphoma and was initially included in the Working Formulation along with diffuse small cleaved-cell lymphoma.[1] With further characterization of this lymphoma as a separate entity, its aggressive behavior became more apparent.[2] Pathologic and Biologic Characteristics Morphology
MCL has several architectural and cytologic patterns that differ in their biologic behavior.[3-5] Cytologically, two main variants are recognized- typical, or classic, and blastoid, or blastic (Figure 1). The typical MCL variant is composed of small to medium-sized lymphocytes with scanty cytoplasm, irregular nuclei, and condensed chromatin. In a minority of cases, the atypical lymphocytes may have round nuclei with little atypia, mimicking chronic lymphocytic lymphoma, or abundant pale cytoplasm, mimicking marginal zone lymphoma. In the blastoid category, two subgroups are recognized-classic blastoid and pleomorphic blastoid. The classic blastoid variant is characterized by medium-sized lymphocytes with scanty cytoplasm and round nuclei with finely dispersed chromatin and high mitotic index, resembling lymphoblasts. The pleomorphic blastoid variant is composed of heterogeneous large cells with irregular cleaved nuclei, finely dispersed chromatin, and small distinct nucleoli.[5,6] Architecturally, three different patterns are recognized in nodes involved by MCL: mantle zone, nodular, or diffuse (Figure 2). The mantle zone pattern (3%-26% of cases) resembles a normal node with expansion of the mantle zone with malignant cells. This pattern is considered a low-grade subtype of MCL. The nodular pattern (13%-39% of cases) has ill-defined follicle-like nodules with neoplastic cells blending with the nonneoplastic cells, and germinal centers are absent. The diffuse pattern (28%-78% of cases) is composed of small neoplastic cells replacing the node, with loss of normal architecture and absent follicles. The blastoid variant (up to 39% of cases) often causes a diffuse pattern.[ 5] Clinically, it is important to recognize mantle-zone-pattern MCL and blastoid MCL. The incidence of these subtypes of MCL has varied with different reports. Histologic progression between the different patterns is uncommon, although rare progression from typical MCL to the blastoid variant has been documented.[7,8] Bone marrow involvement is present in more than 50% of patients with MCL and may be nodular, diffuse, paratrabecular, or a combination of these patterns.[9,10] Immunophenotype
Neoplastic cells in MCL are related to the mature B-mantle cells of the follicular lymphoid cuff. These are monoclonal B cells expressing the Bcell markers CD19, CD20, CD22, CD79a, and intense surface immunoglobulin (Ig)M ± IgD with a tendency to express more lambda light chain than kappa light chain. In addition, the neoplastic cells express CD5, CD43, Bcl-2, and cyclin D1, and lack CD10, Bcl-6, and CD23 antigens useful in differentiating from follicular lymphoma and chronic lymphocytic leukemia (Table 1). Cytogenetics
The t(11;14)(q13;q32) is a characteristic alteration in MCL. In this translocation, the heavy-chain joining region in chromosome 14 is juxtaposed to the Bcl-1 region on 11q13 (Figure 3). The CCND1 gene encoding for cyclin D1 is positioned in t(11;14) chromosomal translocation adjacent to the enhancer region of the immunoglobulin heavy-chain gene, resulting in upregulation of the CCND1 gene (Bcl-1/ PRAD-1) and overexpression of cyclin D1 protein.[11] Cyclin D1 protein expression is universal in MCL and can be detected by immunohistochemical staining, polymerase chain reaction (PCR) analysis, or flow cytometry.[ 12-14] Translocation (11;14) is detected in 65% of MCL cases by classic cytogenetic analysis, and in nearly all cases, by fluorescent in situ hybridization (FISH).[15] Other chromosomal changes, particularly in blastoid variants of MCL, include gains in chromosomes 3q, 8q, and 12q, and losses in chromosomes 1p, 9p, 11q, and 13q.[16,17] The ataxia telangiectasia (ATM) gene has been described in a few MCL cases with 11q22-23 deletion.[18] Molecular Biology
Altered apoptosis pathways with downregulation of the apoptotic genes FADD, PDCD1, and PAIDD have been detected by oligonucleotide microarray in a few MCL patients.[19] Mutations in p53 and overexpression of p53 protein occur in blastoid MCL.[20] The frequency of chromosomal imbalances and DNA amplifications are higher in blastoid MCL than in the common variant.[17] Cyclin/cyclin-dependent kinase (CDK) complexes play an essential role in regulation of cell-cycle progression through various cell-cycle checkpoints (cell-cycle-positive regulators). In MCL, cyclin D1 binds to CDK4 and forms cyclin/CDK complex, which binds to the retinoblastoma protein, leading to its phosphorylation and the loss of its suppressor activity on cell-cycle progression through the release of transcription factors E2F that promote cell-cycle progression into the S phase.[21,22] Mutations in p53 and inactivation of CDK inhibitors (p16, p18, p21, p27)-both negative regulators of the cell cycle-have been reported mostly in the aggressive variants of MCL.[20] Proteosome activity might be responsible for the degradation of some of these CDK inhibitors.[23] Differential Diagnosis of MCL
MCL has been confused with other lymphomas due to morphologic similarities (Table 1). Nodular MCL with residual germinal centers may be morphologically similar to follicular lymphomas. However, follicular lymphomas are usually CD5-negative, CD43-negative, Bcl-6-positive, and CD10-positive, whereas MCL is the opposite. Both MCL and marginal zone lymphomas have a tendency to involve the gastrointestinal tract and bone marrow. Marginal zone lymphomas are usually CD5-negative and cyclin D1-negative. Small lymphocytic lymphoma/chronic lymphocytic leukemia may resemble MCL morphologically. However, although both are CD5-positive and CD43-positive, usually small lymphocytic leukemia/ chronic lymphocytic leukemia is CD23-positive and MCL is CD23- negative. Blastoid MCL might also be confused with lymphoblastic lymphoma, which is terminal deoxynucleotidyl transferase (TdT)-positive. Immunophenotype, cytogenetics, FISH, and flow cytometry are sensitive and useful tools for identifying t(11;14)(q13;q32) and cyclin D1 overexpression- both of which are characteristic of MCL-in tissue obtained from tumor sites and bone marrow biopsies. Clinical Presentation of MCL
MCL is diagnosed at a median age of 60 years, with a male-to-female ratio of 4:1 (Table 2). Patients usually present with advanced disease. Approximately 60% of patients fall into the intermediate-prognostic group (International Prognostic Index 2/3). The incidence of generalized lymphadenopathy is about 70%, and of B symptoms, 30%. Lactate dehydrogenase and beta-2-microglobulin levels are elevated in about 50% of patients. Bone marrow involvement is common and occurs in about 60% of patients, irrespective of peripheral blood involvement. Lymphocytosis and peripheral blood involvement occurs in 30% of cases, and extranodal involvement in more than one site, in about 10% of patients. The most common sites of extranodal involvement are the spleen, liver, and gastrointestinal tract. Extensive lymphomatous polyposis involvement of the bowel can occur, although nonmacroscopic involvement is more common. Central nervous system involvement is more common in blastoid MCL.[4,24-26] Prognostic Factors and Outcome
Tumor-associated prognostic features are mainly related to the morphologic pattern (Table 3). The mantle zone variant has an indolent behavior similar to that of low-grade lymphomas, while the blastoid variant has an aggressive clinical behavior.[25,27] High mitotic index and elevated Ki- 67 index have also been correlated with poor outcome.[27-29] Peripheral blood involvement at diagnosis predicts poor outcome, whereas bone marrow involvement does not.[10] In one small study, no difference in survival was seen between patients with t(11;14) and those with no detected translocation.[27] Mutations in p53 and abnormalities in the CDK inhibitors p16 and p21 are usually associated with aggressive MCL.[30,31] Mutated VH genes and low CD38 expression are described in a subset of mantle cell lymphoma with an indolent course.[32] Older age, male sex, poor performance status, B symptoms, advanced disease at presentation, lymphocytosis, elevated beta-2-microglobulin, and splenomegaly are also poor prognostic factors.[33] Treatment Chemotherapy
Since MCL was first recognized as a separate disease entity, response rates and overall survival have been noted to be poor. Fisher et al reported the results of a Southwest Oncology Group study designed to determine the natural history of patients with MCL and marginal zone lymphoma treated with the CHOP regimen (cyclophosphamide [Cytoxan, Neosar], doxorubicin(Drug information on doxorubicin) HCl, vincristine [Oncovin], prednisone(Drug information on prednisone)) between 1972 and 1983.[34] The failure-free survival was significantly shorter for the 36 MCL patients compared to the 348 remaining patients. The 10-year failure- free survival estimate for MCL patients was only 6%, compared to 25% for patients with other indolent lymphomas. Multiple chemotherapeutic regimens have been tested, but none has demonstrated a clear superiority (Table 4).[33-61] Reported overall response rates range from 30% to 90%, and complete response rates, from 10% to 90%.[35-38] Despite large differences in reported overall response rates, overall survival has remained essentially the same across many of the studies (range: 24 to 60 months).[4,8,33-46]

• Role of Anthracyclines-Several randomized clinical trials comparing anthracycline-containing to non- anthracycline-containing regimens have been reported.[38,39,52] In 1989, Meusers et al reported the first randomized clinical trial in MCL to compare COP (cyclophosphamide, vincristine, prednisone) to the more aggressive anthracycline-containing regimen CHOP in 63 newly diagnosed patients.[38,39,52] No significant difference was found between those treated with COP vs those treated with CHOP with respect to complete response (41% vs 58%), partial response (43% vs 31%), relapse rate (73% vs 67%), relapse-free survival (10 vs 7 months), or overall survival probability (32 vs 37 months). A second randomized study by Teodorovic et al included data from two European Organization for the Research and Treatment of Cancer (EORTC) Lymphoma Cooperative Group trials performed between 1985 and 1992.[38] In these studies, 64 MCL patients were treated with four different regimens: two intermediategrade non-Hodgkin's lymphoma (NHL) regimens and two low-grade NHL regimens. The intermediategrade regimens were CHVmP-VB (cyclophosphamide, doxorubicin HCl, teniposide [Vumon], prednisone, vincristine, bleomycin(Drug information on bleomycin) [Blenoxane]) and modified ProMACE-MOPP (prednisone, methotrexate(Drug information on methotrexate), doxorubicin [Adriamycin], cyclophosphamide(Drug information on cyclophosphamide), etoposide(Drug information on etoposide), mechlorethamine [Mustargen], vincristine, procarbazine(Drug information on procarbazine) [Matulane]). The low-grade regimen was CVP (cyclophosphamide, vincristine, prednisone) followed by randomization to 1 year of maintenance with interferon-alpha or observation. Al- though the overall and complete response rates were better with the intermediate- (83% and 52%) vs the low-grade therapy (60% and 40%), the median survival was 45 months in both treatment arms. In addition, no benefit was noted with interferonalpha maintenance therapy. A third randomized prospective study in MCL was conducted by the German Low-Grade Lymphoma Study Group (GLSG).[52] A total of 45 patients were randomized to either COP or PmM (prednimustine, mitoxantrone(Drug information on mitoxantrone) [Novantrone]) followed by a second randomization to interferonalpha or observation. The two regimens had similar overall response rates-COP, 80%, and PmM, 79%- although PmM was associated with a better complete response rate (27%) compared to COP (5%). A significant improvement in event-free interval was also noted among patients achieving a complete response with PmM compared to COP-31 vs 14 months. However, the estimated median overall survival in both treatment arms was 28 months. These three randomized trials, in addition to several nonrandomized trials, failed to show improvement in overall survival with anthracyclinecontaining regimens.[4,33,39,43] In contrast, Zucca[41] and Oinonen[37] reported a survival advantage among patients treated with anthracyclinecontaining regimens compared with nonanthracycline regimens (CVP or single-agent chlorambucil(Drug information on chlorambucil) [Leukeran]).
• Nontraditional Regimens-Other investigators have studied regimens not traditionally used in the treatment of intermediate-grade lymphomas. Gressin and colleagues retrospectively analyzed data from 30 patients treated with the multiple myeloma regimen VAD (vincristine/doxorubicin/dexamethasone) with or without chlorambucil.[ 44] There was a significantly improved complete response rate with VAD plus chlorambucil (61%) vs VAD (17%). Although these data demonstrate the activity of VAD in MCL, the results are not significantly different from data with CHOP-like regimens. Decaudin conducted a phase II trial of fludarabine (Fludara) in 15 patients with relapsed or refractory MCL and achieved an overall response rate of 33% with no complete responses; however, the median overall survival was 60 months. Foran et al reported improved response rates in a phase II trial of fludarabine in newly diagnosed MCL patients.[45] The overall response rate was 41% (7/17 patients), with 5 complete responses, 2 partial responses, and a median overall survival of 22 months. Other novel agents such as flavopiridol (a CDK inhibitor), topotecan(Drug information on topotecan) (Hycamtin), and cladribine(Drug information on cladribine) (Leustatin) have not demonstrated activity in MCL.[48,50,51,53] Since the choice of chemotherapy agent does not appear to have a significant impact on outcome in MCL, investigators have sought to clarify the role of dose intensity. Khouri et al demonstrated a survival benefit with intensive chemotherapy using hyper- CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone(Drug information on dexamethasone), methotrexate, cytarabine(Drug information on cytarabine); see Table 5) followed by autologous stem cell transplant, compared to historical controls treated with CHOP.[36] HyperCVAD resulted in 3-year event-free and overall survival rates of 92% and 72%, respectively, compared to 56% and 28% in control patients.