mantle cell lymphoma

Introduction

An intermediate grade lymphoma.

Classification

• working formulation category: diffuse small cleaved cell lymphoma
• Kiel classification: centrocytic lymphoma
• revised European-American classification: mantle cell lymphoma

Epidemiology

• older males (median age 60 years)
• male:female ratio 2.3:1
• 2-6% of all non-Hodgkin's lymphomas
• 24% of non-follicular, small B-cell lymphomas

Pathology

• cells of origin are immature B-cells that leave the bone marrow & form primary lymphoid follicles & mantle zones of secondary lymphoid follicles
• expansion of the mantle zone area of the lymph node with a homogeneous population of malignant small lymphoid cells with slightly irregular nuclear outlines & scant cytoplasm
• with disease progression, the germinal centers become destroyed by the neoplastic infiltrate
• diffuse involvement
  • disseminated lymph node involvement
  • leukemia is less common
  • lymphomatous polyposis of the gastrointestinal tract is clinical variant (reports of uncommon to 15%)
  • involvement of the bone marrow is common

Microscopic pathology

• four histologic patterns
  • mantle zone (better prognosis)
  • nodular
  • diffuse (worse prognosis)
  • blastic
• small to medium sized, irregular, inconspicous nucleolus

Immunophenotype

• surface IgM +
• surface IgD +
• lambda > kappa
• CD19, CD20, CD22, CD79a + (B-cell surface antigens)
• CD5 + (CD5 is a T-cell marker, but may be found on a small population of B-cells)
• CD10 -/+
• CD23 -
• CD43 +
• CD11c -
• CD25 -

Genetics

• IgH & IgL genes rearranged
• t(11:14) in > 50% of cases, rearranged bcl-1* gene on chromosome 11 with the Ig heavy chain on chromosome 14
• t11q13:14q32 involving CCND1 & IgH gene
• overexpression of CCND1/cyclin D1/PRAD1 mRNA is noted regardless of whether or not bcl-1 gene rearrangements are detected
• inactivation of p53 in 20% of cases (poor prognosis)
• inactivation of p16ink4A by deletion, mutation, hypermethylation in 50% of cases with blastic morphology
• associated with defects in ATM gene
• ARHGAP29 is down-regulated

* also known as CCND1/cyclin D1/PRAD1

Clinical manifestations

• generalized lymphadenopathy
• splenomegaly (may be massive)
• hepatomegaly
• patients generally present with stage III/IV disease
  • involvement of GI tract, bone marrow & bloodstream is common
• B symptoms* occur in < 50% of patients

* B symptoms: weight loss, fever, night sweats.

Laboratory

• complete blood count (CBC)
  • may show lymphocytosis (20-40%)
  • mild anemia may be present
  • thrombocytopenia is uncommon (< 15%)
• protein electrophoresis is generally normal
• renal function tests
• liver function tests (including serum LDH)
• serum uric acid
• serum Ca+2
• serum beta-2 microglobulin
• bone marrow biopsy
• excisional lymph node biopsy

Radiology

• chest X-ray
• computed tomography (CT) of abdomen & pelvis

Differential diagnosis

• Castleman's disease
• mantle zone hyperplasia

Management

• prognosis
  • considered intermediate grade, but may behave as low grade
  • generally more agressive than small lymphocytic lymphoma, CLL or MALT lymphoma
  • mantle zone variant: mean survival is 90 months
  • diffuse variant: mean survival is 30 months
• treatment has not been shown to result in cure
• chemotherapy
  • rituximab-based chemotherapy (R-CHOP, R-CVP)
    • R-CHOP with less toxicity & better survival than R-CVP
    • bendamustine plus rituximab with longer progression-free survival & fewer toxic effects than R-CHOP
    • median survival > 3 years
    • patients with undetectable minimal residual disease after induction therapy benefit from maintenance rituximab
• fludarabine & cladribine may have activity
• acalabrutinib (breakthrough therapy designation) Aug 2017
  • acalabrutinib (Calquence) FDA-approved in 2022
• ibrutinib + venetoclax may improve outcomes in patients with poor prognosis
• ibrutinib alone 86% with 3 year failure-free survival (3yFFS) superior to hematopoietic stem-cell transplantation (72% 3yFFS)
  • ibrutinib + hematopoietic stem-cell transplantation (86% 3yFFS)
• radiation therapy is generally not useful, because the disease is often disseminated on presentation
• alpha-interferon administration after conventional chemotherapy has been used to prolong remission duration
• allogeneic hematopoietic stem cell transplantation
  • may produce long-term remission, even in patients in relape
  • associated with substantial morbidity & mortality

More general terms

• peripheral B-cell lymphoid neoplasm
• diffuse small cell lymphoma

Additional terms

• 2-chlorodeoxyadenosine (2-CdA) [cladribine] (Leustatin)
• angiofollicular lymph node hyperplasia; Castleman lymphadenopathy
• cellular tumor antigen p53; tumor suppressor p53, phosphoprotein p53; antigen NY-CO-13 (TP53, p53)
• chromosomal translocation t11q13.3:14q32 (mantle cell lymphoma)
• cyclin D1 (parathyroid adenomatosis-1 [PRAD1] protein or bcl-1 proto-oncogene protein, CCND1, BCL1)
• cyclophosphamide/doxorubicin/vincristine (Oncocin)/prednisone (CHOP)
• cyclophosphamide/vincristine (Oncocin)/prednisone (CVP, COP)
• DNA methylation (promoter methylation)
• fludarabine (Fludara)
• p16ink4A; cyclin-dependent kinase inhibitor 2A, isoforms 1/2/3; cyclin-dependent kinase 4 inhibitor A; CDK4I; p16-INK4a; p16INK4A; p16-INK4; multiple tumor suppressor 1; MTS-1; p16MTS1 (CDKN2A, CDKN2, MTS1)
• rituximab (Rituxan, Mabthera, Truxima, Ruxience, Riabni)

Patient information

mantle cell lymphoma patient information