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Lymphoma & related disorders

Mature B cell neoplasms

Mantle cell lymphoma

MCL-classic

Authors: Mahsa Khanlari, M.D., Chi Young Ok, M.D.

Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.

Last author update: 11 February 2020

Last staff update: 12 August 2022

Copyright: 2001-2024, PathologyOutlines.com, Inc.

PubMed Search: Mantle cell lymphoma, classic

Table of Contents

Cite this page: Khanlari M, Ok CY. MCL-classic. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomaMCL.html. Accessed December 23rd, 2024.

Definition / general

Clinically aggressive, mature B cell lymphoma
Small to medium sized lymphoid cells (monomorphic, except in pleomorphic variant)

Essential features

Associated with t(11;14)(q13;q32) or IGH/CCND1 and cyclin D1 overexpression

Terminology

Obsolete names:
- Centrocytic lymphoma (Br J Cancer Suppl 1975;2:29)
- Lymphocytic lymphoma of intermediate differentiation (Semin Diagn Pathol 2011;28:245)
- Mantle zone lymphoma (Cancer 1982;49:1429)

ICD coding

ICD-O: 9673/3 – mantle cell lymphoma
ICD-10: C83.1 – mantle cell lymphoma

Epidemiology

7% of B cell lymphomas (Blood 1997;89:3909)
~10% of non-Hodgkin lymphomas
Age adjusted incidence: 0.6/100,000 person years
Median age: 68 years
M:F = 2 - 3:1

Sites

Lymph node, bone marrow (50 - 90%), peripheral blood (20 - 70%), spleen (50%), liver (20%) (Am J Clin Pathol 1996;106:196, Am J Clin Pathol 1997;108:302)
Frequent extranodal site involvement : gastrointestinal tract, Waldeyer ring, lungs, pleura, skin, CNS
Extranodal involvement without lymphadenopathies: 4 - 15%

Pathophysiology

Virtually all mantle cell lymphomas have t(11;14) IGH/CCND1
Promotes G1 to S phase progression during cell cycle
References: Blood 2010;116:953, Kumar: Robbins and Cotran Pathologic Basis of Disease, 9th edition, 2014

Etiology

Pregerminal center origin (SOX11+, unmutated IGHV)
Postgerminal center origin, a subset (SOX11-, hypermutated IGHV)
Reference: Cancer Res 2012;72:5307

Clinical features

70%: stage IV disease (at presentation)
Two subtypes:
- One more aggressive with SOX11+, nodal presentation
- One more indolent with SOX11- disease, leukemic presentation, and non-nodal disease
Generalized lymphadenopathies
Hepatomegaly / splenomegaly
Peripheral blood:
- Atypical lymphoid cells: present virtually in all cases by flow cytometry (Cancer 2007;109:2473)
- Leukemic involvement at diagnosis: 20 - 70% of patients
Multiple intestinal polyps (lymphomatous polyposis)
Progress to blastoid / pleomorphic variant
- In relapse (22%)

Diagnosis

Tissue biopsy (lymph node / extranodal sites): monomorphic proliferation of small to intermediate sized B cells with overexpression of cyclin D1 or SOX11
t(11;14)(q13;q32) IGH/CCND1
Reference: Cancer Res 2012;72:5307

Laboratory

Anemia and thrombocytopenia: 10 - 40%
High LDH and β2 microglobulin: 50%
A monoclonal serum component (low level): 10 - 30%
Atypical lymphocytosis
Reference: Cancer 1998;82:567

Prognostic factors

Median survival: 5 - 7 years
- Mantle cell lymphoma international prognostic index (clinical) (Blood 2008 Jan;111:558)
- Age, performance status, lactate dehydrogenase, leukocyte count
- 3 morphologic groups with significantly different prognoses
Adverse outcome (histopathology / molecular)
- High mitotic rate (> 50/mm²) (Br J Haematol 2005;131:29)
- Ki67 or MIB1 IHC stains (> 30%) (Histopathology 2013;62:334)
- Blastoid and pleomorphic variants (See Mantle cell lymphoma (MCL), aggressive variants)
- MYC rearrangement (Am J Surg Pathol 2017;41:216)
- TP53 mutation / overexpression / loss (17p) (Blood 2015;126:604)
- CDKN2A deletion (9p) (Blood 2015;126:604)
- Gains in 3q, deletions of 9q (J Clin Oncol. 2007;25:1216)

Case reports

60 year old man with mantle cell lymphoma involving the prostate with features of granulomatous prostatitis (Int J Surg Pathol 2012;20:610)
63 year old man with Hodgkin and Reed-Sternberg cells in a recurrent mantle cell lymphoma (Appl Immunohistochem Mol Morphol 2019;27:8)
64 year old man with right conjunctival mass as an initial presentation of mantle cell lymphoma (BMC Res Notes 2012;5:671)
69 year old man with a history of systemic nodal mantle cell lymphoma who presented with subcutaneous nodules on his lower extremities (J Cutan Pathol 2019;46:538)
A case of mantle cell lymphoma showing cyclin D1 overexpression by immunohistochemistry and a t(11;12)(q13;p11.2) by conventional cytogenetic studies (Hum Pathol 2017;64:207)

Treatment

Fit for high dose therapy
- Hyper CVAD chemotherapy or R-DHAP / R-CHOP with autologous stem cell transplantation
Fit for conventional dose therapy
- Rituximab (R)-CHOP or R-bendamustine
Unfit for conventional dose therapy
- R-bendamustine or R-lenalidomide
Indolent disease (low risk)
- Watch and wait
New biologic agents
- Ibrutinib (Bruton tyrosine kinase inhibitor)
- Idelalisib (phosphoinositide-3 kinase inhibitor)
- Bortezomib (proteasome inhibitors)
- Temsirolimus (mTOR inhibitors)
- Lenalidomide (immunomodulatory)
References: F1000Res 2018;7:1136, Best Pract Res Clin Haematol 2018;31:99

Gross description

Lymph node
- Generalized enlargement
- Homogenous tan cut surface
- With or without nodules
- Not distinctive
Spleen
- Generalized micronodular pattern
- Perivascular infiltration
GI
- Lymphomatoid polyposis
- Multiple lymphoid polyps, small and large bowel
- Ulcers, tumor masses and diffuse thickening of the mucosa (Histopathology 1995;26:413)
- Note: Microscopic infiltration without gross lesion is common (Cancer 2003;97:586)

Frozen section description

Same criteria applied in microscopic evaluation
Cytogenetics, flow cytometry, preparation of imprints should be considered
The nuclear shape, size and chromatin structure are helpful in smears
Reference: Jaffe: Hematopathology, 2nd Edition, 2016

Microscopic (histologic) description

Diffuse > nodular > mantle zone growth patterns
- Nodal (> 50% nodular), diffuse growth pattern (< 50% nodular)
Small to medium monomorphic lymphoid neoplasm
Irregular nuclear border, clumped chromatin and inconspicuous nucleoli
No proliferation centers
Centroblasts, immunoblasts or paraimmunoblasts are absent
Hyalinized vessels
Epithelioid histiocytes
Variants
- Aggressive variants
  - Blastoid: lymphoblast-like in appearance, monomorphism
    - >20 - 30 mitoses per 10 high power fields
    - Resemble lymphoblastic lymphoma
  - Pleomorphic: large cells with irregular nuclear border, cerebriform nuclei, multinucleation, lack of monomorphism
    - Prominent nucleoli and abundant pale cytoplasm
    - Resemble DLBCL
- Other variants
  - Small cell: small round lymphocytes with more clumped chromatin
    - Resemble CLL
  - Marginal zone-like: abundant pale cytoplasm
    - Resembling marginal zone or monocytoid B cells
  - Lymphoplasmacytic differentiation, some cases (Am J Surg Pathol 2006;30:954)
Follicular dendritic cell (FDC) meshwork
- Nodular pattern
  - Primary follicle-like pattern
  - Germinal center-like pattern
- Diffuse pattern
Bone marrow
- Nodular, interstitial or paratrabecular or combination
Peripheral blood (see below)
- Similar spectrum seen in tissue sample
- Nucleoli are sometimes more prominent
Spleen
- White pulp nodules involved (enlarged)
- Variable involvement of the red pulp
- Residual naked germinal centers
- Tumor cells: similar monotonous morphology
- Some cases may show a marginal zone-like area (Histopathology 1998;33:230)
GI
- May mimic lymphoepithelial lesions in marginal zone lymphoma (Histopathology 1995;26:413)
Relapse
- Loss of a mantle zone growth pattern
- Increase in nuclear size
- Pleomorphism and chromatin dispersal
- Increase in mitotic activity and Ki67
- Cases that are blastoid at diagnosis may relapse with classic morphology (Histopathology 2013;62:334)

Microscopic (histologic) images

Contributed by Chi Young Ok, M.D.

Monotonous population of small lymphoid cells

Follicular localization of lymphoid cells

Spleen involvement

Cyclin D1 expression

Mantle zone pattern

Pink histiocytes

Cyclin D1 and SOX11 in mantle zone pattern

Ki67 in mantle zone pattern

Bone marrow involvement

Follicular dendritic cell meshwork

Cytology description

A monotonous population of small to intermediate sized lymphoid cells
Nuclear clefts with fine stippled chromatin
Inconspicuous nucleoli
Distinct pale or basophilic cytoplasm
Reference: Jaffe: Hematopathology, 2nd Edition, 2016

Cytology images

Contributed by Chi Young Ok, M.D.

Small to intermediate centrocytes in cytology

Peripheral smear description

Mantle cell lymphoma cells may be polymorphous (in contrast to tissue)
Nuclear size and shape vary
Chromatin has a reticulated pattern
Nucleoli can be prominent
May mimic B cell chronic lymphocytic leukemia
Reference: Wang: Diagnosis of Blood and Bone Marrow Disorders, 1st Edition, 2018

Peripheral smear images

Contributed by Chi Young Ok, M.D.

Atypical mature cell in peripheral blood

Positive stains

Cyclin D1
CD19+, CD20+, sIg+, IgM with or without IgD
CD43
CD5+ (> 95%), SOX11+ (> 90%)
Exceptions:
- SOX11 negative cases
  - More indolent
  - Leukemic / non-nodal involvement (Am J Surg Pathol 2019;43:710)
  - Mutated IGHV
- CD5 negative cases (Am J Surg Pathol 2019;43:1052)
  - Cyclin D1 positive
- Cyclin D1 negative cases
  - SOX11 positive
MUM1/ IRF4 (50% in small subset of cells)
BLIMP1 (50%) and XBP1 (30%)
Small number of mantle cell lymphomas are positive for CD10 (Oncotarget 2017;9:11441)
Ki67 count (J Hematop 2009;2:103)
- Five independent high power fields count
- Avoidance of residual germinal centers, hot spots and proliferating T cells
CD23 and CD21 highlight FDC meshwork (see microscopic description)

Negative stains

CD10, BCL6
CD200
- May be positive in a subset of SOX11 negative mantle cell lymphomas
LEF1
- Can be positive in 4 - 9% of mantle cell lymphomas (Ann Diagn Pathol 2017;26:57)

Flow cytometry description

CD5+, CD19+, CD20+, CD22+, CD79b+, FMC7+
Monotypic Ig (usually moderate intensity)
CD3-, CD10-, CD11c+/-, CD23-, CD43+/-, CD200-/+
Rare cases have atypical immunophenotype: CD5- or CD10+, CD200+ or CD23+ (dim ~ 10%)
Reference: Wang: Diagnosis of Blood and Bone Marrow Disorders, 1st Edition, 2018

Flow cytometry images

Contributed by Chi Young Ok, M.D.

Aberrant B cell population with immunophenotype: CD5+, CD19+, CD20+, CD38+, lambda+, CD10-, CD23-, CD200- and kappa-

Molecular / cytogenetics description

IG genes are clonally rearranged
IGHV genes are unmutated or minimally mutated in most cases
t(11;14)(q13;q32)
- FISH is convenient because it can be performed on fixed tissue sections
- Conventional cytogenetics if fresh material available
- Most PCR assays usually detect 1 major breakpoint region in mantle cell lymphoma
Cyclin D2 rearrangements by FISH in some of cyclin D1(-) cases
Secondary chromosomal aberrations
- Gains of 3q26 (in 31 - 50%)
- 7p21 (16 - 34%),
- 8q24 (MYC, 16 - 36%)
- 13q31 (24%)
- Losses of 1 p13-31 (29 - 52%)
- 6q23-27 (TNFAIP3, 23 - 38%)
- 9p21 (CDKN2A which codes for p16 INK4a and p14 ARF, 18 - 31%)
- 11q22-23 (ATM, 21 - 59%)
- 13q11-13 (22 - 55%)
- 13q14-34 (43 - 51%)
- 17p13 (TP53, 21 - 45%) (Blood 1999;93:436, Blood 2005;105:4445, Oncogene 1992;7:1401)

Molecular / cytogenetics images

Contributed by Chi Young Ok, M.D.

Abnormal FISH result

Abnormal karyotype result

Sample pathology report

Inguinal lymph node, left, needle biopsies:
- Mantle cell lymphoma, diffuse pattern, classic variant (see comment)
- Comment: Histologic sections show needle core shaped lymphoid tissue. Lymph node architecture is entirely effaced by malignant lymphoma. The lymphoma demonstrates a diffuse pattern and the lymphoma cells are intermediate sized. Lymphoma cells have irregular nuclear contours, relatively closed chromatin, inconspicuous nucleolus and moderate to large amount of cytoplasm. Scattered epithelioid histiocytes with eosinophilic cytoplasm (“pink histiocytes”) are seen in the background. No sheets of large cells or necrosis are seen. Mitotic figures are rarely present.
  Flow cytometric analysis using concurrent cytologic sample demonstrates clonal B cells with surface kappa light chain expression, positive for CD5, CD19, CD20, CD22 ,CD38, CD43 (partial), CD44, CD79b, while they are negative for CD3, CD4, CD8, CD10, CD11c, CD23, CD30, CD34, CD56 and CD200. The clonal B cells comprise approximately 62.4% of total analyzed cellular events and 70.7% of the lymphoid population.
  Immunohistochemical studies were performed on formalin fixed, paraffin embedded tissue. Lymphoma cells are positive for CD20, PAX5, cyclin D1 and SOX11. They are negative for CD3 and p53. Ki67 proliferation rate is estimated at 10 - 20%.
  In summary, morphologic, flow cytometric and immunohistochemical studies are diagnostic of mantle cell lymphoma, classic variant.

Differential diagnosis

Nodal mantle cell lymphoma
- Chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL)
  - Proliferation centers
  - Mixture of small lymphocytes, prolymphocytes and paraimmunoblasts
  - Cells express dim surface Ig, CD5 and CD23 but not cyclin D1
  - Proliferation centers in chronic lymphocytic leukemia may be cyclin D1 positive
  - Negative for t(11;14)
- Follicular lymphoma
  - Follicular pattern composed of centrocytes and centroblasts
  - Cells express CD10 but not CD5, CD43 or cyclin D1
  - t(14;18) IGH-BCL2
- Nodal marginal zone B cell lymphoma
  - Neoplastic B cells with or without monocytoid cytoplasm
  - Reactive germinal centers are common
  - CD5- and cyclin D1-
- Splenic marginal zone lymphoma (SMZL)
  - A micronodular pattern of splenic involvement are seen in both mantle cell lymphoma and splenic marginal zone lymphoma
  - Villous cells in PB may be seen in mantle cell lymphoma
  - Mantle cell lymphoma expresses CD5 and cyclin D1
  - 7q deletion is a relatively specific marker for splenic marginal zone lymphoma (40% of cases)
- Reactive follicular hyperplasia
  - Thinner mantle zones
  - Composed of small, round, mature lymphocytes
  - Prominent germinal centers
  - No evidence of monoclonality
- Castleman disease, hyaline vascular type
  - Large localized mass in a young person
  - Architecture not entirely effaced
  - Hyaline vascular follicles
  - Onion skin lymphocytes around germinal centers
Leukemic mantle cell lymphoma
- Hairy cell leukemia (HCL)
  - Hairy cell leukemia may be cyclin D1 positive
  - Refer to flow cytometry section for more detail
- Chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL)
  - CD23 expression in non-CLL is often weak or subset positive
  - CD200 is rarely expressed in mantle cell lymphoma
- Prolymphocytic leukemia
  - Many B-PLL cases may actually be leukemic mantle cell lymphoma
  - This is especially likely in cases that are either cyclin D1 positive or t(11;14) IGH/CCND1 positive (Am J Clin Pathol 2001;115:571)
- Lymphoblastic leukemia
  - Mostly in DDx with blastoid mantle cell lymphoma (refer to mantle cell lymphoma variants)