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CHAPTER 100 intermediate-size cells with irregular, cleaved nuclei, dense chromatin,
Based on cytology, the classical form is characterized by small to
MANTLE CELL LYMPHOMA and indistinct nucleoli. A small cell variant, resembling chronic lympho- 4
cytic leukemia (CLL), may be associated with a more indolent course.
In contrast, the blastoid cell variant, including a blastic and a pleomor-
phic phenotype, displays a more aggressive clinical course. 3
Martin Dreyling Histologically, MCL most frequently displays a diffuse infiltration
of the lymph nodes, less commonly a nodular pattern, and, rarely, a
mantle zone pattern, the latter of which may represent an earlier phase
5
of the disease. The immunophenotype of the cells resembles the lym-
SUMMARY phocytes in the mantle zone of normal germinal follicles, and is char-
acterized by coexpression of B-cell antigens (CD19+, CD20+, CD22+,
Mantle cell lymphoma is a distinct subtype of non-Hodgkin lymphoma with a CD43+, CD79+, secretory immunoglobulin [sIg] M+, sIgD+) and the
pathognomonic chromosomal translocation t(11;14), leading to constitutive T-cell associated marker CD5+. Based on their predominantly preger-
cyclin D1 overexpression. The clinical presentation usually is characterized by minal center origin, MCL cells stain strongly for the antiapoptotic pro-
widespread disease, occurring more often in male patients older than age tein BCL-2, but are negative for germinal center markers like CD10 and
60 years. Despite high initial response rates, early relapses occur frequently BCL-6. 3
after conventional chemotherapy resulting in a median survival of only 3 to Because of the morphologic heterogeneity of MCL, detection of
5 years. However, 10 to 15 percent of patients present with a more indolent, the MCL genetic hallmark, either by immunohistochemistry (cyclin
chronic course. Dose-intensified treatment regimens containing cytarabine, D1 overexpression) or fluorescence in situ hybridization (chromosomal
translocation t[11;14][q13;q32]) is crucial to confirm the diagnosis. In
rituximab, and autologous stem cell transplantation can achieve long-term rare cases that are negative for cyclin D1, staining for SOX11, a tran-
remissions in patients fit enough to tolerate such aggressive therapy. For scription factor specifically expressed in more than 90 percent of MCL
the majority of elderly patients, rituximab maintenance therapy can result cases, may help to establish the diagnosis. 6
in prolonged survival. Targeted approaches, including proteasome inhibitors,
immunomodulatory drugs, and inhibitors of the B-cell receptor pathway, EPIDEMIOLOGY
have proven highly efficacious in patients with relapsed disease and should be
implemented in a multimodal treatment plan. MCL represents approximately 6 percent of all non-Hodgkin lympho-
7,8
mas, although a lower incidence has also been reported. Between 1992
and 2004, the age-adjusted annual incidence more than doubled from
about 0.3 to 0.7 cases per 100,000. The incidence is more than twice
DEFINITION AND HISTOLOGY as high in males and increases with age. Median age at presentation is
approximately 65 years. No specific etiologic agent has been associated
Mantle cell lymphoma (MCL) was originally named centrocytic lym- with MCL.
phoma or subsumed under the term intermediate lymphocytic lym-
phoma. In 1992, the term mantle cell lymphoma was adopted for this
entity because of morphologic and immunophenotypic similarities ETIOLOGY AND PATHOGENESIS
of the malignant cells to lymphocytes of the mantle zone of germinal The chromosomal translocation t(11;14) results in overexpression of
centers. In 1994, the term mantle cell lymphoma was incorporated cyclin D1, a cell-cycle protein not normally expressed in lymphoid cells.
1
into the revised European-American classification of the International The very rare cyclin D1–negative cases usually overexpress cyclin D2 or
Lymphoma Study Group, and remains a distinctive lymphoma subtype D3. The cytogenetic abnormality t(11;14) is the primary event in the
6
in the World Health Organization classification of malignant lymphoid pathogenesis of MCL, facilitating the deregulation of the cell cycle at the
disorders. 2,3 G –S phase transition. However, additional genetic events are required
9
1
for the clinical manifestation of MCL. Thus, a low copy-number of the
t(11;14) translocation has been found in the blood cells of 1 to 2 percent
10
of healthy individuals without evidence of clinical disease. Cytoge-
netic studies have identified frequent secondary genetic alterations that
Acronyms and Abbreviations: ASCT, autologous stem cell transplantation; are involved in cell-cycle dysregulation and DNA repair, which may
ATM, ataxia-telangiectasia mutant; BR, bendamustine and rituximab; BTK, Bruton explain why MCL has one of the highest levels of genomic instability
tyrosine kinase; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; among the malignant lymphoid neoplasms. These genetic abnormalities
CLL, chronic lymphocytic leukemia; DHAP, dexamethasone, high-dose cytarabine, include losses in chromosomes 1p13–p31, 2q13, 6q23–27, 8p21, 9p21,
and cisplatinum; E2F, elongation factor 2; LDH, lactate dehydrogenase; MCL, mantle 10p14–15, 11q22–23, 13q11–13, 13q14–34, 17p13, and 22q12; gains in
cell lymphoma; MIPI, Mantle Cell Lymphoma International Prognostic Index; mTOR, chromosomes 3q25, 4p12–13, 7p21–22, 8q21, 9q22, 10p11–12, 12q13,
mammalian target of rapamycin; MTX, methotrexate; NF-κB, nuclear factor-κB; PI3K, and 18q11q23; and high copy-number amplifications of certain chro-
phosphoinositol 3′-kinase; PFS, progression-free survival; R-CHOP, rituximab, cyclo- mosomal regions. 11
phosphamide, doxorubicin, vincristine, and prednisone; R-CVP, rituximab, cyclophos- Figure 100–1 depicts a proposed scheme relating genetic derange-
phamide, vincristine, and prednisone; R-hyperCVAD, rituximab, hyperfractionated ments with specific MCL subtypes. Cell-cycle dysregulation is a hall-
cyclophosphamide, vincristine, doxorubicin, and dexamethasone; sIg, secretory mark of MCL. The overexpressed cyclin D1 complexes with CDK4,
immunoglobulin; TBI, total-body irradiation. which results in phosphorylation of the retinoblastoma gene RB1 and
release of elongation factor 2 (E2F) transcription factors and progression

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