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1654 Part XI: Malignant Lymphoid Diseases Chapter 100: Mantle Cell Lymphoma 1655

“Indolent” (15%) “Classical” (80%) “Transformed” (5%) Figure 100–1. Proposed model of molecular
pathogenesis of mantle cell lymphoma (MCL).
The t(11;14) translocation leads to the consti-
Naive B cell Early MCL Classical MCL Blastoid MCL tutive deregulation of cyclin D1. Acquired inac-
tivation of DNA damage response pathways
may facilitate additional genetic alterations
Germline
and the development of classical MCL. Further
ATM genetic alterations may target genes of the cell
CHK2 cycle and senescence regulatory pathways,
leading to more proliferative and aggressive
t(11;14) ATM INK4A/CDK4/RB1 variants of MCL. (Modified with permission from
Cyclin D1 CHK2 ARF/MDM2/p53 Jares P, Colomer D, Campo E: Genetic and molec-
ular pathogenesis of mantle cell lymphoma:
Perspectives for new targeted therapeutics. Nat
Rev Cancer 7(10):750–762, 2007.)
RB1 p27 Complex High
karyotypes proliferation

of the lymphoma cells into S-phase. In addition, mutation of the atax- TABLE 100–1. Patient Characteristics at Presentation (304
ia-telangiectasia mutant (ATM) gene facilitates genomic instability in
lymphoma cells through impaired response to DNA damage. Phospho- Cases)
inositol 3′-kinase (PI3K) and mammalian target of rapamycin (mTOR) Characteristic Number
are important downstream targets of this signaling pathway. Finally, Age (years)
specific gene alterations, namely p53 or p16/CDKN2, are associated with
the blastoid variant and poor clinical outcome. 12,13 <60 123
According to the characteristic cyclin D1 overexpression, molec- >60 178
ular profiling has identified a cell proliferation gene signature that dis- Sex
tinguishes patient subsets that differ by more than 5 years in median Male 230
survival. A five-gene model to predict survival in MCL based on for-
14
malin-fixed, paraffin-embedded tissue has been devised. In the clinical Female 71
15
setting, only Ki-67 expression, a cell-cycle–related protein, as deter- Stage
mined by immunohistochemistry, has been prospectively confirmed as I–II 23
a reliable prognostic marker, which allows the identification of high-risk III–IV 267
patients (Ki-67 >30 percent) who may qualify for more-aggressive ther-
apeutic approaches. This marker is independent of clinical features Status (World Health Organization)
5,16
including the Mantle Cell Lymphoma International Prognostic Index 0–1 233
(MIPI) score (see Clinical Features and Risk Factors 20,21 below). ≥2 43
Lactate dehydrogenase
Elevated 56
CLINICAL FEATURES AND RISK Normal 140
FACTORS International Prognostic Index

MCL typically presents in an older male patient with lymphadenopa- 0–1 15
thy in several sites (e.g., cervical, axillary, inguinal). The patient may ≥2 75
be asymptomatic but some experience fever, night sweats, or weight Marrow involvement
loss (Table 100–1). The spleen is enlarged in 40 percent of patients.
5,17
Marrow is involved with MCL in the vast majority of patients, and 50 Yes 207
percent of patients present with blood involvement, sometimes with an No 81
overt leukemic phase. B symptoms
In 25 percent of cases, there is symptomatic gastrointestinal
involvement, typically presenting as polyposis coli. Gastrointestinal Yes 107
18
symptoms may include abdominal pain and diarrhea, signs of small- No 155
bowel obstruction, or hematochezia. The intestinal polyps usually Extranodal involvement
appear in the ileocecal region, and histopathologic analysis and immu- Yes 161
nocytochemistry are required to confirm the diagnosis of MCL involve-
ment. Asymptomatic gastrointestinal involvement may be detected in No 16
up to 90 percent of cases; thus, endoscopy and histologic analysis of Data from Tiemann M, Schrader C, Klapper W, et al: European MCL
random biopsies are recommended, especially in the few cases with Network: Histopathology, cell proliferation indices and clinical out-
localized stage. come in 304 patients with mantle cell lymphoma (MCL): A clinico-
The frequency of CNS disease is low at first diagnosis but pathological study from the European MCL Network. Br J Haematol
increases with subsequent relapses and correlates with elevated 131(1):29–38, 2005.

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