Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (368 page)

MANTLE CELL LYMPHOMA (MCL)

   Definition

MCL is a CD-5–positive mature B-cell lymphoma. MCL is considered one of the most aggressive lymphomas. Recently, a subgroup of patients with an indolent course has been identified through gene expression profile studies. MCL comprises about 7% of non-Hodgkin lymphomas. The t(11;14)(q13;q32), which involves CCND1 and IGH, is usually present. The translocation determines the ectopic and deregulated expression of cyclin D1, which is considered the primary molecular event in the pathogenesis of MCL. Less common are the variant CCND1 rearrangements with IGK or IGL genes. Rarely (approximately 5%), mantle cell lymphoma can results from dysregulation of CCND2 (12p13) and CCND3 (6p12) genes. These genes can be seen rearranged with IGH, IGK, or IGL. The MCL-affected cells are usually positive for CD5, creating difficulties in the differentiation from CLL/SLL.

   Who Should Be Suspected?

Elderly patients with generalized disease: constitutional symptoms, nonbulky lymphadenopathy, possibly hepatosplenomegaly, lymphocytosis, bone marrow invasion, some with multiple lymphomatous polyposis of the intestine, and constitutional symptoms.

   Laboratory Findings

Laboratory diagnosis of MCL is based mainly on lymph node morphology, flow cytometry, and cytogenetics.

   
CBC
: Anemia and thrombocytopenia are commensurate with the clinical stage, the degree of bone marrow infiltration, or may reflect chemotherapy. Increasing lymphocyte count, characterized by a leukemic phase, denotes a poor prognosis.

   
Lymph node biopsy
shows lymphoid proliferation with vaguely nodular, diffuse, or mantle zone pattern. Lymphocytes are homogenous, small to medium in size with irregular or “cleaved” nuclei, and inconspicuous nucleoli.

   
Immunophenotype
: Cells express intense surface IgM/IgD and show lambda light chain restriction in up to 80% of cases. The cells are positive for CD5, CD19, CD20, and FMC-7. They are negative for CD10, BCL6, and in contrast to CLL/SLL, CD23 is negative or weakly positive. All cases are BCL2 positive. Nuclear staining for cyclin D1 (BCL-1) is positive in 95% of cases.

   
Molecular genetics
: Immunoglobulin heavy and light chain genes are rearranged. The IgV region genes lack somatic mutations in most cases, indicating a pregerminal center stage of differentiation, consistent with an origin from immunologically naive mantle zone B cells. The neural transcription factor SOX11 is overexpressed in most MCL but is not detected in other mature B-cell lymphomas nor in normal lymphoid cells. Gene expression profiles may play a future role in subclassifying MCL.

   
Cytogenetics
: The
t(11;14)(q13;q32)
is present in most cases of MCL. (See above.)

   
Other
: LDH elevation is associated with poor prognosis.

   Transformation

   Transformation is characterized morphologically by increase in cell size (blastic variant), frequent mitoses, and an aggressive clinical course.