Tag Archives: Mantle Cell Lymphoma

Mantle cell lymphoma

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm, which represents 2-3% of cases of non-Hodgkin lymphoma in the US.  The IgH/Cyclin D1 translocation is characteristic of this lymphoma, and can be confirmed by FISH testing in almost all cases.  Clincially, patients often present with widespread disease.  In addition to adenopathy, patient often have involvement of blood (20-40%) and other organ sites (gastrointestinal tract, liver spleen,  bone marrow).
Morphology
MCL is typically characterized by a small to intermediate sized lymphocytes with an irregular nuclear membrane (CLL/SLL tends to have a smoother nuclear membrane and follicular lymphoma has cleaved cells).  A subset of cases have a larger size and increased mitotic rate and can be confused with acute lymphoblastic lymphoma, and are referred to as the “blastoid” variant of MCL.
 
2008 WHO Classification identifies multiple morphologic variant including: blastoid variant (resembles ALL with increased mitoses), pleomorphic (also aggressive), small cell variant (resembles CLL/SLL), and marginal zone-like morphology.  Architectural pattern can have a diffuse pattern (often with scattered histiocytes within the infiltrate) or nodular (resembling follicular lymphoma).  Minimal lymph node involvement can show expansion of the mantle zones with relative intact lymph node architecture.  Bone marrow involvement can have a varied appearance, but can mimic follicular lymphoma with paratrabecular aggregates.
2016 WHO Classification Revision
Two subtypes of mantle cell lymphoma are now recognized, which center around the mutation status of IgHV.
  • IgHV unmutated/minimally mutated (mostly SOX11+) – classical disease that is aggressive, typically involves lymph nodes and other extra nodal sites.
  • IgHV mutated (SOX11 negative) – associated with indolent non-nodal disease with peripheral blood and bone marrow involvement.  Some of these cases may have been difficult to separate from CLL/SLL in the past.
Half of cyclin D1 negative cases show a CCND2 rearrangement.
Molecular Characteristics
  • FISH + for t(11;14)
  • Cytogenetics + t(11;14) ~70% of cases
  • 50% of Cyclin D1 negative cases have CCND2 rearrangements
Immunophenotypic Expression Pattern

 

 

Marker
Comment
Negative
Positive (93-95%).  Some data indicates up to 12% of MCL cases may be negative for CD5.
Negative.  Up to 8% of cases may express CD10 (expression will usually be <30%).
Positive
Positive
Negative.  21% may express CD23.
Positive.  Nuclear expression.  The rabbit monoclonal antibody clone SP4 appears to have the highest sensitivity and stain intensity.  Sensitivity ~95%.
Positive
Negative (~12% of cases may have expression)
Usually negative (35% may be positive, of these 2/3rds will also be bcl-6+)
Highlights the residual FDC meshwork.
Inverse relationship between quantitative Ki-67 index and prognosis.  Ki-67 >40% is an adverse prognostic factor.
 Expressed in classic form and lack of expression is associated with more indolent variant of MCL.
Important caveats
Cyclin D1 expression is not entirely specific for mantle cell lymphoma.  Some expression can be seen in a zonal pattern in CLL/SLL in proliferation centers.   Other entities such as plasma cell myeloma (up to 50%) and hairy cell leukemia can also express cyclin D1.  CD10 (8%), Bcl-6, and CD23 (21%) has been reported to be expressed in a small number of cases.  Loss of CD5 (12%) has been noted in some cases.  Most of these studies were by flow cytometry.
 
CD5 expression on a B-cell lymphoma should practically result in testing for exclusion of a t(11;14) IgH/Cyclin D1 gene fusion.  There are other B-cell lymphomas, which may also have CD5 expression (e.g. DLBCL, CLL/SLL, etc.) that are not MCL and have separate prognostic characteristics because of/or separate from CD5 expression.
 
Rarely, plasmacytic differentiation may be identified.  Classic MCL is derived form naive B-cells, which tends to not to progress to plasmacytic differentiation, compared to post germinal center derived B-cell lesions, which more commonly have plasmacytic differentiation.
 
Ki-67 staining index has been shown to be directly proportional the aggressiveness of the clinical course (higher staining index, more aggressive).

References
WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues.  SH Swerdlow,et al.International Agency for Research on Cancer. Lyon, 2008. p. 229-231.
 
Robbins and Cotran Pathologic Basis of Disease.  V Kumar, et al. 9th Edition. Elsevier Saunders. 2015. pp. 602-603.
 
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127: 2375–2390. doi:10.1182/blood-2016-01-643569
 
Katzenberger T, Petzoldt C, Höller S, Mäder U, Kalla J, Adam P, et al. The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma. Blood. 2006;107: 3407. doi:10.1182/blood-2005-10-4079
 
Gao J, Peterson L, Nelson B, Goolsby C, Chen Y-H. Immunophenotypic variations in mantle cell lymphoma. Am J Clin Pathol. 2009;132: 699–706. doi:10.1309/AJCPV8LN5ENMZOVY
 
Boyd SD, Natkunam Y, Allen JR, Warnke RA. Selective immunophenotyping for diagnosis of B-cell neoplasms: immunohistochemistry and flow cytometry strategies and results. Appl Immunohistochem Mol Morphol. 2013;21: 116–131. doi:10.1097/PAI.0b013e31825d550a
 
Young KH, Chan WC, Fu K, Iqbal J, Sanger WG, Ratashak A, et al. Mantle cell lymphoma with plasma cell differentiation. Am J Surg Pathol. 2006;30: 954–961.
 
Gualco G, Weiss LM, Harrington WJ, Bacchi CE. BCL6, MUM1, and CD10 expression in mantle cell lymphoma. Appl Immunohistochem Mol Morphol. 2010;18: 103–108. doi:10.1097/PAI.0b013e3181bb9edf
 
Wang H-Y, Zu Y. Diagnostic Algorithm of Common Mature B-Cell Lymphomas by Immunohistochemistry. Arch Pathol Lab Med. 2017;141: 1236–1246. doi:10.5858/arpa.2016-0521-RA

CD23

CD23 is a transmembrane glycoprotein expressed by different hematopoietic cells and is a low-affinity receptor for IgE.  It is also involved in promoting survival of B-cells in the germinal center.  CD23 is useful as a follicular cell dendritic cell marker and is classically expressed in cases of CLL/SLL.  CD23 has been identified in many types of lymphomas, but is most commonly used to differentiate between CLL/SLL (CD23+) and mantle cell lymphoma (CD23-).  This testing is typically performed by flow cytometry, but immunohistochemisty for CD23 is available.  Expression of CD23 has been associated with better prognosis (at least in limited published data) in follicular lymphoma, CLL/SLL, mantle cell lymphoma, and diffuse large B-cell lymphoma dependent upon expression characteristics.  CD23 is not commonly performed/used as a prognostic marker for B-cell lymphomas.
 
Rarely CD23 may be expressed in cases of Hairy cell leukemia (17%) and DLBCL (16%).  Approximately 70% of Mediastinal large B-cell lymphoma cases express CD23.  Practically, this IHC marker is used as a follicular dendritic cell marker and to help differentiate CLL/SLL from mantle cell lymphoma.  Follicular dendritic cell tumors will also express CD23 like CD21.  CD21 is more sensitive compared to CD23 as a follicular dendritic marker.
 
Follicular Lymphoma (FL) – CD23 has been found to be expressed in some cases of FL, especially from inguinal lymph nodes, and prognosis appears comparatively better.   Olteanuet. al found that 87% of inguinal lymph nodes expressed CD23, compared to 61% from other sites, and that survival was prolonged more in CD23+ cases. 
 
Diffuse Large B-Cell Lymphoma – A subset of DLBCLs may express CD23, which may have a better prognosis (CD23 is not commonly performed for this purpose).
 
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) – CD23 expression is characteristic of CLL/SLL, particularly in comparison to another CD5+ lymphoma, mantle cell lymphoma.  Strong membrane expression has been associated with a better outcome.  DiRaimondo,et. al found ~6% of CLL cases to be CD23 negative (flow cytometry), and they had a worse prognosis.  Many of these cases may have been misdiagnosed mantle cell lymphomas.
 
Mantle Cell Lymphoma (MCL) – CD23 is characteristically negative in MCL, which helps to differentiate it from CLL/SLL.  However, ~21% of cases of MCL were found to be CD23+ by Gao,et. al, and other studies have shown CD23 expression in MCL ranging from 0% to 45% (most data appears to be based on flow cytometry).
CD23 Expression Pattern
  • CLL/SLL – characteristically expressed (6% may be negative, probably much lower)
  • Mantle cell lymphoma may be CD23+ (21%+, 0-45%)
  • B-cell Lymphomas (e.g. some DLBCL and follicular lymphomas may show expression)
  • Follicular Dendritc Cells (not as sensitive as CD21)
  • B-cells in mantle zone of lymphoid follicles

Photomicrographs
CD23 - Tonsil
CD23 expression highlighting follicular dendritic meshwork in a normal tonsil.

Reference
Bone Marrow IHC.  Torlakovic, EE, et. al. American Society for Clinical Pathology Pathology Press © 2009.  pp. 69.
 
Linderoth J, Jerkeman M, Cavallin-Stahl E, et al. Immunohistochemical expression of CD23 and CD40 may identify prognostically favorable subgroups of diffuse largeB-cell lymphoma: a Nordic Lymphoma Group Study.ClinCancer Res.2003;9:722-728.
 
Olteanu H, Fenske TS, Harrington AM, Szabo A, He P, Kroft SH. CD23 Expression in Follicular Lymphoma: Clinicopathologic Correlations. Am J Clin Pathol. 2011;135: 46–53. doi:10.1309/AJCP27YWLIQRAJPW
 
Gao J, Peterson L, Nelson B, Goolsby C, Chen Y-H. Immunophenotypic variations in mantle cell lymphoma. Am J Clin Pathol. 2009;132: 699–706. doi:10.1309/AJCPV8LN5ENMZOVY
 
Troxell ML, Schwartz EJ, van de Rijn M, Ross DT, Warnke RA, Higgins JP, et al. Follicular dendritic cell immunohistochemical markers in angioimmunoblastic T-cell lymphoma. Appl Immunohistochem Mol Morphol. 2005;13: 297–303.
 
Dalton RR, Admirand JH, Medeiros LJ. Small Lymphocytic Lymphoma. Pathology Case Reviews. 2004;9: 7.
 
DiRaimondo F, Albitar M, Huh Y, O’Brien S, Montillo M, Tedeschi A, et al. The clinical and diagnostic relevance of CD23 expression in the chronic lymphoproliferative disease. Cancer. 2002;94: 1721–1730. doi:10.1002/cncr.10401

CD5

CD5 is a T-cell marker, although it is the least specific of the group (CD2, CD3, CD4, CD5, CD7, and CD8).  CD5 co-expression on B-cells is characteristic of certain lymphomas, specifically CLL/SLL and Mantle Cell Lymphoma.  A subset of DLBCLs may also express CD5, although there may be a question as to if that represents de novo lymphoma vs.  “transformed” CLL/SLL or Mantle Cell Lymphoma.
 
The expression level of CD5 will often be less than the expression on background T-cells in cases of CLL/SLL and Mantle Cell Lymphoma, and this expression differentiation may be helpful by both IHC and flow cytometry.
CD5 Expression
Many different B and T-cell lymphomas have reported CD5, and while it is a useful marker, specificity should be determined with a broader set of markers in addition to the morphology of the lymphoma.  Molecular studies may also be helpful.

Photomicrographs
CD5 - Benign Tonsil
CD5 – Benign Tonsil
CD5 - Mantle Cell Lymphoma
CD5 – Mantle Cell Lymphoma
CD5 - CLL/SLL
CD5 – CLL/SLL
CD5 - Benign Tonsil
CD5 – Benign Tonsil

References
Dong HY, Gorczyca W, Liu Z, Tsang P, Wu CD, Cohen P, et al. B-cell lymphomas with coexpression of CD5 and CD10. Am J Clin Pathol. 2003;119: 218–230. doi:10.1309/U98A-DVKU-C26R-2RJA
 
Gao J, Peterson L, Nelson B, Goolsby C, Chen Y-H. Immunophenotypic variations in mantle cell lymphoma. Am J Clin Pathol. 2009;132: 699–706. doi:10.1309/AJCPV8LN5ENMZOVY
 
Dalton RR, Admirand JH, Medeiros LJ. Small Lymphocytic Lymphoma. Pathology Case Reviews. 2004;9: 7.
 
Jaso JM, Yin CC, Wang SA, Miranda RN, Jabcuga CE, Chen L, et al. Clinicopathologic Features of CD5-Positive Nodal Marginal Zone Lymphoma. Am J Clin Pathol. 2013;140: 693–700. doi:10.1309/AJCPEMVXES72DUIF
 
Went P, Zimpfer A, Tzankov A, Dirnhofer S. CD5 expression in de novo diffuse large B-cell lymphomas. Annals of Oncology. 2009;20: 789–790. doi:10.1093/annonc/mdn793
 
Cook JR. Nodal and leukemic small B-cell neoplasms. Mod Pathol. 2013;26 Suppl 1: S15–28. doi:10.1038/modpathol.2012.180
 
Bone Marrow IHC.  Torlakovic, EE, et. al. American Society for Clinical Pathology Pathology Press © 2009.  pp. 27.