Chapter 63: Mantle Cell Lymphomas

INTRODUCTION

• Mantle cell lymphoma (MCL) cells display an immunophenotype similar to lymphocytes in the mantle zone of normal germinal follicles, surface immunoglobulin (sIg) M+, sIgD+, CD5+, CD20+, CD10–, CD43+. In contrast to chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), MCL cells typically do not express CD23.

• MCL had been previously classified as an intermediate-grade lymphoma and called "intermediate lymphocytic lymphoma." It also had been termed centrocytic lymphoma and previously confused with other types of lymphoma or leukemia, such as SLL, CLL, or marginal zone lymphoma.

PATHOPHYSIOLOGY

• Insight into the pathophysiology of MCL was realized with discovery of the cytogenetic abnormality t(11;14) (q13;q32) in the tumor cells, a translocation resulting in the over expression of the cell cycle regulator cyclin D1.

• However, it is almost certain that additional genetic events are involved in development of the fully transformed state as low numbers of cells carrying the t(11;14) translocation have been found in the blood of some healthy individuals without any evidence of disease.

• The ATM (ataxia-telangiectasia mutant) gene is mutated in approximately 40 percent of patients. ATM inactivation facilitates genomic instability in lymphoma cells through impaired response to DNA damage.

• Additional genetic anomalies that could contribute to the disease include losses in chromosomes 1p13-p31, 2q13, 6q23-27, 8p21, 9p21, 10p14-15, 11q22-23, 13q11-13, 13q14-34, 17p13, and 22q12; gains in chromosomes 3q25, 4p12-13, 7p21-22, 8q21, 9q22, 10p11-12, 12q13, and 18q11q23; and high copy-number amplifications of certain chromosomal regions.

CLINICAL FEATURES

• The typical presentation is that of an older patient with lymphadenopathy in several sites (e.g., cervical, axillary, inguinal).

• The patient may be asymptomatic but a significant proportion may have fever, night sweats, or weight loss.

• The liver may be enlarged and the spleen is enlarged in 40 percent of patients at the time of diagnosis. In 25 percent of the cases, there is symptomatic gastrointestinal involvement.

• A number of adverse prognostic features of MCL have been identified, including the expression of the Ki67 proliferation antigen in a high proportion of lymphoma cells, high serum level of β₂-microglobulin in the absence of renal dysfunction, high serum levels of lactic acid dehydrogenase (LDH), presence of blastoid cytology, advanced patient age, late Ann Arbor stage, extranodal presentation, constitutional symptoms, among others.

• A prognostic model called the Mantle Cell International Prognostic Index (MIPI) has been introduced, which uses four independent prognostic factors: age, performance status, LDH, and leukocyte count.

• There is no consensus on the risk of central nervous system (CNS) disease in patients with MCL or the need to give CNS prophylaxis. Studies have reported an incidence of CNS of 4 percent and a 5-year actuarial risk of 26 percent.

LABORATORY FEATURES

• Approximately 50 percent of patients present with blood and marrow involvement, sometimes with an overt leukemic phase, but more often with subtle involvement as detection of the malignant lymphocyte ...