ABSTRACT: Manifestations of mantle cell lymphoma were recognized in the 1970s as distinct from those associated with the more readily classifiable lymphomas. It was not until the 1990s, however, that observation of a combination of immunologic, cytogenetic, and molecular genetic abnormalities characteristic of this new malignancy confirmed its existence. The clinical and pathologic entity was named mantle cell lymphoma and in 1994 was incorporated into the Revised European American Lymphoma Classification. Mantle cell lymphoma is a CD5 positive, B-cell lymphoma that usually displays the t(11;14). The lymphoma has a striking male predominance and is widely disseminated at diagnosis in 80% of patients. Mantle cell lymphoma responds poorly to available therapies, and the median survival is approximately 3 years.[ONCOLOGY 12(Suppl 8):49-55, 1998]
Mantle cell lymphoma is a recent addition to the group of
malignancies lumped under the term non-Hodgkins
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. 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. 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-Hodgkins lymphomas.
The study performed by the non-Hodgkins lymphoma classification
project investigators found 83 cases of mantle cell lymphoma. 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. The addition of immunologic staining improved the
accuracy of diagnosis to 87%. 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-Hodgkins lymphoma.
Mantle cell lymphoma is largely a tumor of males, with a 74% male
predominance in the Non-Hodgkins Lymphoma Classification
Project study (NLCP). Mantle cell lymphoma is rarely seen in
young patients; the median age of patients is 63 years (Table
2). In the non-Hodgkins 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. 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.
An improved method of predicting treatment outcome in
non-Hodgkins lymphoma utilizes the International Prognostic
Index. This system, developed after a study of patients with
diffuse large-cell lymphoma, predicts the outcome of patients with
other subtypes of non-Hodgkins 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.
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-Hodgkins Lymphoma Classification Project
study, the 5-year overall survival for mantle cell lymphoma was 27%,
and the 5-year failure-free survival was 11%. 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.
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. It is unclear whether this is simply
a reflection of tumor proliferative rate, or other molecular genetic
abnormalities in the blastic subtypes.[29,30]
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-Hodgkins 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
Castlemans disease and benign lymph node hyperplasia. 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-Hodgkins
lymphoma. It was also sometimes diagnosed as small lymphocytic
lymphoma, follicular small-cleaved-cell non-Hodgkins 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.
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