Management of Mantle Cell Lymphoma

Introduction

Mantle cell lymphoma is a recent addition to the group of malignancies lumped under the term “non-Hodgkin’s lymphomas.”[1-2] However, despite being newly recognized, the disease itself is not new. In the 1970s, investigators in both Europe and America recognized that some lymphomas of small cells did not fit well into previously utilized categories. In the United States, Berard et al proposed the term, “lymphocytic lymphoma of intermediate differentiation” to describe a group of lymphomas that were not easily classifiable as diffuse well-differentiated lymphocytic lymphoma or diffuse poorly differentiated lymphocytic lymphoma using the Rappaport Classification.[3-5] At approximately the same time in Europe, Lennert et al proposed an entity they termed “centrocytic lymphoma.”[7-9] In both cases, the tumors were B-cell lymphomas that expressed surface immunoglobulin. The nuclei were intermediate in shape between the round cells of small lymphocytic lymphoma and the cleaved cells of follicular lymphoma.

In the 1980s, Weisenburger et al, and Palutke et al, described a type of follicular lymphoma that was atypical in that there were wide mantles of malignant cells around apparently benign general centers.[10,11] Weisenburger et al proposed the term “mantle zone lymphoma” for these tumors, and believed that the malignancy might represent the follicular counterpart of the diffuse intermediate lymphocytic lymphoma described by Berard et al.[10,12]

Immunologic, cytogenetic, and molecular genetic studies all contributed to resolving this dilemma. Immunologic studies showed that the tumors called diffuse intermediate lymphocytic lymphoma, centrocytic lymphoma, and mantle zone lymphoma were usually positive for CD5 (eg, a T-cell antigen) and negative for CD10. However, they were consistently positive for CD20 and expressed surface immunoglobulin confirming their B-cell origin.[14-17]

The cytogenetic abnormality t(11;14)(q13;q32) that was originally described in patients with chronic lymphocytic leukemia is the characteristic cytogenetic abnormality seen in mantle cell lymphoma.[18,19] Studies of the break point in the (11;14) identified the immunoglobulin heavy chain on chromosome 14 as one break point and a new oncogene designated bcl-1 on chromosome 11.[20] The oncogene has also been referred to as PRAD1 and in codes for the protein cyclin, D1, which is overexpressed in almost every case of mantle cell lymphoma, but rarely expressed in other malignancies.[21,22]

The combination of characteristic immunologic, cytogenetic, and molecular genetic abnormalities confirmed the existence of a new clinical/pathologic entity that is now termed “mantle cell lymphoma” and unified the diagnosis of pathologists on both sides of the Atlantic (Table 1).[1,2] Mantle cell lymphoma is one of the entities incorporated into the Revised European American Lymphoma (REAL) Classification.[23] In a clinical evaluation of that new classification involving study sites in North America, Europe, Africa, and Asia, mantle cell lymphoma made up approximately 6% of non-Hodgkin’s lymphomas.[24]

Clinical Characteristics

The study performed by the non-Hodgkin’s lymphoma classification project investigators found 83 cases of mantle cell lymphoma.[24] The diagnosis of mantle cell lymphoma was able to be made accurately in 70% of cases on stained slides without the need for immunologic studies.[24] The addition of immunologic staining improved the accuracy of diagnosis to 87%.[24] The availability of clinical information did not further improve the accuracy of the diagnosis. Thus, with expert pathologists working with clear definitions, mantle cell lymphoma can be diagnosed quite accurately. However, the availability of immunologic studies makes a significant improvement in the accuracy of the diagnosis. Mantle cell lymphoma is not a rare diagnosis and is the fifth most common B-cell non-Hodgkin’s lymphoma.[24]

Mantle cell lymphoma is largely a tumor of males, with a 74% male predominance in the Non-Hodgkin’s Lymphoma Classification Project study (NLCP).[24] Mantle cell lymphoma is rarely seen in young patients; the median age of patients is 63 years (Table 2).[24] In the non-Hodgkin’s lymphoma classification project, mantle cell lymphoma is one of the lymphomas most likely to have bone marrow involvement, with 63% of the cases studied having positive bone marrow biopsies.[24] There is a high proportion of cases with disseminated disease and only 19% of the cases are clinical Stage I or II using the Ann Arbor staging system.[24]

An improved method of predicting treatment outcome in non-Hodgkin’s lymphoma utilizes the International Prognostic Index.[25] This system, developed after a study of patients with diffuse large-cell lymphoma, predicts the outcome of patients with other subtypes of non-Hodgkin’s lymphoma. The International Prognostic Index simply sums the number of adverse prognostic characteristics. These include an age of 60 years or greater, a depressed performance status, a serum lactic dehydrogenase level higher than normal, more than one extra nodal site of involvement by lymphoma, and disseminated disease as indicated by Ann Arbor Stage III or IV. Only 19% of patients with mantle cell lymphoma had an International Prognostic Index score of 0 or 1, and 19% had an International Prognostic Index score of 4 or 5.[24]

Surprisingly, given the existence of a small-cell, B-cell lymphoma, the clinical course has been unfavorable in patients with mantle cell lymphoma. In the Non-Hodgkin’s Lymphoma Classification Project study, the 5-year overall survival for mantle cell lymphoma was 27%, and the 5-year failure-free survival was 11%.[24] Only peripheral T-cell lymphoma and lymphoblastic lymphoma had a comparably poor 5-year overall survival, and mantle cell lymphoma stood alone with the poorest 5-year failure-free survival. The shape of the failure-free survival curve is not encouraging in suggesting a significant proportion of cured patients.

Most patients with mantle cell lymphoma present with enlarged lymph nodes and a biopsy leads to the diagnosis. However, there are other presentations characteristic of this entity. Mantle cell lymphoma can present as chronic lymphocytic leukemia and should be considered in the differential diagnosis of that disorder. The cytologic characteristics of the tumor, immunologic staining, and cytogenetic and molecular genetic studies should help resolve any confusion. Mantle cell lymphoma is the most common lymphoma to present with multiple polyps in the colon. The entity that sometimes has been called lymphomatous polyposis, usually represents mantle cell lymphoma. Mantle cell lymphoma can present with isolated involvement of essentially any organ.

Histopathologic Subtyping of Mantle Cell Lymphoma

A number of histologic subtypes have been proposed for mantle cell lymphoma. As was noted previously, a subset of these lymphomas has a “follicular” appearance with the tumor cells forming wide mantles around normal germinal centers.[10-12] At least focal appearance of this pattern is seen in approximately one-quarter of the cases of mantle cell lymphoma.

The other major subdivision of patients with mantle cell lymphoma that has been proposed is a distinction between the cases with more mature nuclei with coarse chromatin and inconspicuous nucleoli, and other cases with larger nucleoli, finer, more dispersed chromatin, and more obvious nucleoli. The latter have been referred to as blastic variants of mantle cell lymphoma, making up approximately 20% of all mantle cell lymphomas. [14,15,26-28]

Some studies have suggested that mantle cell lymphomas retaining a follicular growth pattern have a more indolent natural history, and those tumors with more immature or blastic nuclei pursue a more unfavorable clinical course.[26] It is unclear whether this is simply a reflection of tumor proliferative rate, or other molecular genetic abnormalities in the blastic subtypes.[29,30]

The Differential Diagnosis of Mantle Cell Lymphoma

As was noted previously, mantle cell lymphoma is a diagnosis that can be made accurately by experienced hematopathologists. Each case should be reviewed by an expert hemataopathologist before therapy is initiated. Even so, the clinician should always consider the possibility in any new patient with non-Hodgkin’s lymphoma that the diagnosis might not be correct. The most serious error would be the diagnosis of mantle cell lymphoma in a patient who has a benign condition. Confusion here would be most likely in cases of Castleman’s disease and benign lymph node hyperplasia.[31] Both of these conditions would be more likely in young patients, which should raise a flag about the possibility of a misdiagnosis of mantle cell lymphoma. Demonstration of monoclonality and a characteristic immunologic staining pattern along with bcl-1 overexpression will usually help resolve any confusion.

In the Working Formulation, mantle cell lymphoma was found most often in the category of diffuse small-cleaved-cell non-Hodgkin’s lymphoma. It was also sometimes diagnosed as small lymphocytic lymphoma, follicular small-cleaved-cell non-Hodgkin’s lymphoma, diffuse large-cell lymphoma, and lymphoblastic lymphoma. The possibility that patients diagnosed with any of these entities might truly have mantle cell lymphoma should always be considered.