Mantle cell lymphoma, MCL

Definition

A neoplasm of monomorphous B-cells resembling centrocytes. They are thought to be pre-germinal centre B lymphocytes that home to primary lymphoid follicles and to the mantel zones of secondary follicles. Neoplastic follicles are lacking.

Synonyms

Mantle zone lymphoma, lymphocytic lymphoma of intermediate grade of differentiation. This entity was previously known as centrocytic lymphoma. It is now recognised that the neoplastic cells are more closely related to mantle cells than to follicle centre centrocytes.

Epidemiology

3-10% of non-Hodgkin lymphomas. Occurs in middle aged to elderly (median 60 years) with a male predominance of at least 2:1¹⁵.

Clinical features

Presentation is with lymphadenopathy (90%), splenomegaly (55%, frequently massive), hepatomegaly (35%), bone marrow involvement (75%) or blood involvement (25%), involvement of the gastrointestinal tract (15%) in the form of multiple lymphomatous polyposis or Waldeyer's ring (10%)³. More than 25% of cases are associated with a leukaemic component; a marked lymphocytosis may resemble prolymphocytic leukaemia. Most patients present with stage III or IV disease.

Histopathology

The architecture may be diffuse or nodular, with or without residual germinal centres, or in a mantle zone growth pattern. Follicular dendritic cells may be present in loose or tight aggregates. The neoplastic cells are small to medium sized with irregular nuclei, fine chromatin, small inconspicuous nucleoli and pale indistinct scant cytoplasm, resembling centrocytes. Blastic cells (cells resemble centroblasts, immunoblasts or paraimmunoblasts) are rare or absent. However, at relapse, some cases show enlarged nuclei as seen in the "blastoid variant" of MCL. Hyalinised vessels are common. Scattered epithelioid histiocytes may give a "starry sky" appearance. Non-neoplastic plasma cells may be present.

Variant

• Predominance of small round cells, mimicking small lymphocytic lymphoma. Prominent foci of cells with abundant pale cytoplasm may resemble proliferation centres.

• Mantle cell lymphoma with a follicular growth pattern. Mantle cell lymphoma is typically diffuse or vaguely nodular. However, there may rarely (1/37 cases⁷, 2/138 cases⁸) be colonisation an preservation of non-neoplastic follicles, giving an architecture which closely resembles follicular lymphoma. As a result, there may be surviving admixed follicle centre cells, including centroblasts.

• Blastoid mantle cell lymphoma; arise de novo or by transformation¹⁵; may show cytogenetic abnormalities of p16 and p18

  • classical⁸; there is a close resemblance of lymphoblastic lymphoma with dispersed chromatin and a high mitotic rate (>10/10 HPF, usually at least 20-30/10HPF). However, the CD5 positivity / TdT negativity of mantle cell lymphoma is retained. (Many lymphoblastic lymphomas are distinguished by being of T cell immunophenotype.) The proliferation index using Ki67 or MIB-1 is somewhat lower (~50%) than that in lymphoblastic lymphoma (~90%). Many cases show Cyclin D1 gene rearrangement¹³, overexpression of p53 and show multiple chromosomal imbalances or are tetraploid^4,5,13. Blastoid transformation is associated with a worse prognosis⁴.

  • pleomorphic⁸; cells have large cleaved to oval nuclei, usually with prominent nucleoli, and pale cytoplasm Giemsa (or MGP) stain. May be tetraploid. This variant may give rise to a leukaemic component resembling prolymphocytic leukaemia¹¹.

• With clonal plasma cell differentiation: the plasma cells within the nodules or mantle zones show light chain restriction and harbour the t(11;14)(q13;q32) translocation; they are negative for cyclin D1¹⁶.

• There are variants resembling:

  • marginal zone⁹ / monocytoid B-cell lymphoma There are prominent foci of cells with abundant pale cytoplasm.

  • hairy cell leukaemia

  • plasma cell type of Castleman's disease⁸.

• Cyclin D1 negative patients have significantly better prognosis, suggesting that these patients probably have other low-grade lymphomas resembling mantle cell lymphoma³.

Immunohistochemistry

CD5	usually positive15
CD10	negative15
CD11c	positive
CD19†	positive15
CD20	positive15
CD22	positive15
CD23†	negative15 or weakly positive
CD25	negative
CD43	positive15
Cyclin D1	70% to 100% of cases (including the rare CD5 negative cases)1,2, 16/1815
bcl-2
bcl-6	negative: rare aberrant expression may occur (positivity was found in 5 of 315 cases: three of these cases had the typical morphology of mantle cell lymphoma, two were initially diagnoses as DLBCL, but were found to be cyclin D1 positive. Two cases were negative for CD5 and one was positive for CD10. All cases showed t(11;14)(q13;q32) translocations. Four cases had bcl-6 translocations, the fifth an extra copy of the bcl-6 gene.)14
FMC7	positive
SIgM and SIgD	positive
a4b7 homing receptor	positive in gastrointestinal cases
CDK4	14/1615

CD21 and CD35 demonstrate loose meshworks of FDCs.

Cytogenetics

• t(11;14)(q13;q32) in 95% of cases by FISH, although it may not be apparent by standard cytogenetics. This translocation juxtaposes the immunoglobulin heavy chain and the Cyclin D1 gene, resulting in overexpression of cyclin D1, overcoming the suppressor effects of pRB and KIP1 in the regulation of the cell cycle¹². Cyclin D3 is downregulated¹².

• Blastoid variants also show tetraploidy, CCND1 amplification, p53 mutation and p16 deletions.

Differential diagnosis

• Other low grade non-Hodgkin's lymphomas: immunophenotypes

• follicular colonisation needs to be distinguished from progressive transformation of germinal centres¹⁰.

Prognosis

Mantle cell lymphoma has the worst 5-year survival (11%) among all lymphoma types² and a median survival of only 3 to 4 years³. A more aggressive course is associated with:

• increased mitotic activity
  

• blastoid morphology^4,6,15
  

• peripheral blood involvement⁶
  

• karyotypic complexity
  

• trisomy 12
  

• 17p loss and associated p53 inactivation¹² / overexpression⁴
  

• 9p loss associated with p16 gene laterations¹⁵.
  

• INK4a inactivation occurs in approximately 50% of mantle cell lymphomas and is associated with greater cellular proliferation¹².
  

• International prognosis index⁶
  

• CD5 negative cases may be more indolent

Transformation to typical large cell lymphoma does not occur.

References

World Health Organization Classification of Tumours, Tumours of the haematopoietic and lymphoid tissues, IARC Press 2001.

Wotherspoon AC, Hasserjian RP. Immunophenotyping in the differential diagnosis of histologically low grade B cell lymphomas Current Diagnostic Pathology 2000;6:55-63.

¹ de Boer, C. J. van Krieken, J. H. Schuuring, E. Kluin, P. M. Bcl-1/cyclin D1 in malignant lymphoma. Ann Oncol 1997;8(suppl2):109-17.

² Chan, J. K., Miller, K. D., Munson, P., Isaacson, P. G. Immunostaining for cyclin D1 and the diagnosis of mantle cell lymphoma: is there a reliable method? Histopathology 1999;34:266-268.

³ Swerdlow, S. H., Williams, M. E. From centrocytic to mantle cell lymphoma: a clinicopathologic and molecular review of 3 decades. Human Pathol 2002;33;7-20.

⁴ Zoldan, M. C., Inghirami, G., Masuda, Y. et al. Large-cell variants of mantle cell lymphoma: cytologic characteristics and p53 anomalies may predict poor outcome. Br J Haematol 1996;93:475-86.

⁵ Bea, S., Ribas, M., Hernandez, J. M. et al. Increased number of chromosomal imbalances and high-level DNA amplifications in mantle cell lymphoma are associated with blastoid variants. Blood 1999;93:4365-74.

⁶ Bernard, M., Gressin, R., Lefrere, F. et al. Blastic variant of mantle cell lymphoma: a rare but highly aggressive subtype. Leukemia 2001;15:1785-91.

⁷ Swerdlow, S. H., Zukerberg, L. R., Yang, W. I., Harris, N. L., Williams, M. E. The morphologic spectrum of non-Hodgkin's lymphomas with BCL1/cyclin D1 gene rearrangements. Am J Surg Pathol 1996;20:627-40.

⁸ Yatabe, Y., Suzuki, R., Matsuno, Y. et al. Morphological spectrum of cyclin D1-positive mantle cell lymphoma: study of 168 cases. Pathol Int 2001;51:747-61.

⁹ Anagnostopoulos, I., , Foss, H. D., Hummel, M., Trenn, G., Stein, H. Extranodal mantle cell lymphoma mimicking marginal zone cell lymphoma. Histopathology 201;29:561-5.

¹⁰ Jones D. Dismantling the germinal center: comparing the processes of transformation, regression and fragmentation of the lymphoid follicle. Advances in Anatomic Pathology 2002;9:129-138.

¹¹ Wong, K.F., So, C.C. and Chan, J.K. Nucleolated variant of mantle cell lymphoma with leukemic manifestations mimicking prolymphocytic leukemia. Am J Clin Pathol 2002;117:246-51.

¹² Leoncini, L., Lazzi, S., Bellan, C. and Tosi, P. Cell kinetics and cell cycle regulation in lymphomas. J Clin Pathol 2002;55:648-55.

¹³ Ott, G., J. Kalla, et al. (1997). "Blastoid variants of mantle cell lymphoma: frequent bcl-1 rearrangements at the major translocation cluster region and tetraploid chromosome clones." Blood 89(4): 1421-9.

¹⁴ Camacho, F. I., J. F. Garcia, et al. (2004). "Aberrant Bcl6 protein expression in mantle cell lymphoma." Am J Surg Pathol 28(8): 1051-6.

¹⁵ Parrens M, Belaud-Rotureau MA, Fitoussi O, et al. Blastoid and common variants of mantle cell lymphoma exhibit distinct immunophenotypic and interphase FISH features. Histopathology 2006; 48:353-62

¹⁶ Young KH, Chan WC, Fu K, et al. Mantle Cell Lymphoma With Plasma Cell Differentiation. Am J Surg Pathol 2006; 30:954-961

This page last revised 19.8.2006.

©SMUHT/PW Bishop