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Lymphoma & related disorders

Mature B cell neoplasms

Mantle cell lymphoma

MCL-aggressive variants


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

Last author update: 7 February 2020
Last staff update: 19 August 2022

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

PubMed Search: Mantle cell lymphoma aggressive

Mahsa Khanlari, M.D.
Chi Young Ok, M.D.
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology and etiology | Clinical features | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Gross description | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Peripheral smear description | Peripheral smear images | Positive stains | Negative stains | Flow cytometry description | Flow cytometry images | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Khanlari M, OK CY. MCL-aggressive variants. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomaMCLaggressive.html. Accessed December 22nd, 2024.
Definition / general
  • 2 types: blastoid and pleomorphic
  • Blastoid: cells resemble lymphoblasts with high mitotic rate (> 20 - 30 mitoses /10 high power fields) (Blood 1997;89:1421)
  • Pleomorphic: large, pleomorphic cells with variable sizes, prominent nucleoli
  • Definition is based on the morphology
Essential features
  • Associated with t(11;14)(q13;q32) or IGH/CCND1 and cyclin D1 overexpression
  • High proliferation index and unfavorable outcome
Terminology
  • Blastoid variant
    • Mantle cell lymphoma (MCL), lymphoblastoid variant
    • Mantle cell lymphoma (MCL), blastic
  • Pleomorphic variant
    • Mantle cell lymphoma (MCL), large cell variant
    • Mantle cell lymphoma (MCL), anaplastic
    • Mantle cell lymphoma (MCL), nucleolated variant
ICD coding
  • ICD-O: 9673/3 – mantle cell lymphoma
Epidemiology
Sites
  • Lymph node, spleen, bone marrow
  • Extranodal sites:
    • Gastrointestinal tract is the most common site
    • CNS: More frequently involved by blastoid / pleomorphic variant than classic variant
  • Peripheral blood:
    • Leukemic involvement at diagnosis
Pathophysiology and etiology
  • CCND1 at 11q13 with IGH at 14q32
    • New CCND1 will reposition near the nucleoli (nucleolin and RNA polymerase II) (Blood 2014;123:2044)
    • Higher level of cyclin D1 RNA, when 3'-untranslated region is deleted (common in blastoid mantle cell lymphoma) (Blood 2007;109:4599)
  • Higher level of chromosomal aberration in blastoid / pleomorphic mantle cell lymphoma than in classic mantle cell lymphoma (Hum Pathol 2003;34:1022)
  • Frequent tetraploidy in blastoid / pleomorphic mantle cell lymphoma than in classic mantle cell lymphoma (Blood 1997;89:1421)
  • 8q24 abnormalities (MYC gene) in blastoid mantle cell lymphoma (Mod Pathol 2002;15:1266)
  • High level of p53 expression in a subset of blastoid mantle cell lymphomas (Blood 2017;130:1903)
  • Mutated NOTCH1 and NOTCH2: affects signaling pathway (Blood 2012;119:1963, Proc Natl Acad Sci U S A 2013;110:18250)
  • De novo or from classic mantle cell lymphoma progression
Clinical features
  • Median age: sixth and seventh decades
  • Clinical picture resembles classic mantle cell lymphoma
  • Male predominance (M:F = 2 - 3:1)
  • Ann Arbor clinical stage III/IV in most cases (Leukemia 2001;15:1785)
  • Short duration of clinical response after chemotherapy (Leukemia 2001;15:1785)
  • Poorer overall survival compared with classic mantle cell lymphoma (Leuk Lymphoma 2016;57:1327)
  • More common B symptoms
  • Blastoid variant: often presents de novo
  • Pleomorphic variant: often history of classic mantle cell lymphoma
  • Generalized lymphadenopathy
  • Extranodal involvement is common
  • Leukemic forms of mantle cell lymphoma (Am J Clin Pathol 2002;117:246)
Diagnosis
  • Based on clinical presentation (refer to Clinical features)
  • B symptoms
  • Tissue biopsy (lymph node / extranodal sites)
  • Cytology
  • Peripheral blood exam / bone marrow biopsy
Laboratory
  • Anemia and thrombocytopenia
  • High LDH and β2 microglobulin
  • A monoclonal serum component (low level)
  • Atypical lymphocytosis
  • Reference: Cancer 1998;82:567
Prognostic factors
Case reports
  • 45 year old man with blastoid mantle cell lymphoma presenting in leukemic phase (J Clin Diagn Res 2017;11:ED16)
  • 65 year old man with blastic transformation of mantle cell lymphoma presenting with acute onset binocular diplopia and proptosis of the left eye (Ocul Oncol Pathol 2019;5:245)
  • 66 year old man with cyclin D1 negative blastoid mantle cell lymphoma exhibiting cleaved to bilobated cytomorphology (Blood 2017;129:2711)
  • 67 year old woman with triple hit blastoid mantle cell lymphoma presenting like acute leukemia (Blood 2017;129:2593)
  • 74 year old man with ascites, liver lesions and growing 5 cm soft tissue abdominal mass (Case #499)
  • A case of double hit mantle cell lymphoma (Am J Clin Pathol 2020;153:49)
Treatment
  • Aggressive chemotherapy or stem cell transplantation
    • Ibrutinib with rituximab (IR) induction
    • Followed by R-HCVAD-methotrexate / ara-C
    • R-HyperCVAD used at many institutions
      • Rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone
      • Alternating with methotrexate and cytosine arabinoside (ara-C)
    • Venetoclax may be added in some trials
  • Stem cell transplant (allogenic versus autologous)
  • CNS prophylaxis
  • Reference: Am J Hematol 2019;94:710
Gross description
  • Lymph node
    • Generalized enlargement
    • Homogenous tan cut surface
    • With or without nodules
    • Not distinctive
  • GI
    • Lymphomatoid polyposis
    • Multiple lymphoid polyps, small and large bowel
    • Ulcers, tumor masses and diffuse thickening of the mucosa
  • Spleen
    • Generalized micronodular pattern
    • Perivascular infiltration
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
Microscopic (histologic) description
  • Blastoid variant
    • The growth pattern is usually diffuse
    • Less frequently nodular pattern
    • Starry sky appearance common in low power
    • Intermediate sized cells
    • Monotonous population
    • Immature chromatin
    • Scant cytoplasm
    • High mitotic rate > 20 - 30/10 high power fields
    • Resembles, in part, lymphoblastic lymphoma
  • Pleomorphic variant
    • Variable size / heterogenous cell population including large cells
    • Prominent nucleoli +/-
    • High mitotic rate often seen
    • At least 10 mitoses per 10 high power fields and often higher rates
    • Resembles, in part, diffuse large B cell lymphoma
    • Peripheral blood lymphocytes are intermediate sized with prominent nucleoli
    • Resemble prolymphocytes to variable degree
    • Multinucleation or cerebriform nuclei often seen
Microscopic (histologic) images

Contributed by Chi Young Ok, M.D.
 

Monotonous immature cells

PAX5 immunohisto-
chemical stain

CD5 immunohisto-
chemical stain

Proliferation index, Ki67

Follicular dendritic cell meshwork


 

Large cells with variable sizes

Cyclin D1 immunohisto-
chemical stain

p53 pattern of staining

Diffuse involvement of bone marrow



Contributed by Patricia Tsang, M.D., M.B.A. (Case #499)
H&E stained section of the abdominal wall mass   H&E stained section of the abdominal wall mass   H&E stained section of the abdominal wall mass

Abdominal wall mass

PAX5


CD5

Ki67

Cyclin D1

SOX11

Cytology description
  • Blastoid variant
    • Monomorphic proliferation of intermediate sized to large lymphoid cells
    • Round to oval nuclear contours
    • Dispersed chromatin
    • Small / inconspicuous nucleoli
    • Scant, pale blue cytoplasm
  • Pleomorphic variant
    • Large, pleomorphic cells
    • More nuclear irregularity
    • More variation in size of cells
    • Vesicular, open chromatin
    • Prominent nucleoli often seen (Br J Haematol 1996;93:475)
Cytology images

Contributed by Chi Young Ok, M.D.
 

Immature monotonous cells in cytology

Peripheral smear description
  • Prolymphocytoid-like morphology (leukemic form of mantle cell lymphoma)
  • Blastoid morphology (leukemic form of blastoid mantle cell lymphoma)
Peripheral smear images

Contributed by Chi Young Ok, M.D.

Lymphoma cells in peripheral blood

Positive stains
Negative stains
Flow cytometry description
  • CD5+, CD19+, CD20+, CD22+, CD79b+, FMC7+
  • Monotypic Ig (high level expression of surface light chains)
  • CD11c variable, CD43 variable, CD200 variable
  • CD3-, CD10-, CD23-
  • Rare cases have atypical immunophenotype:
    • CD5- or CD10+, CD200+ or CD23+ (dim ~10%)
Molecular / cytogenetics description
  • Karyotypes are often complex (≥ 3 abnormalities)
  • Tetraploid clones are more frequently found in pleomorphic (80%) and blastoid (36%) variants
  • Some abnormalities may be specifically involved in pathogenesis
    • Chromosome 17p deletions (TP53)
    • Chromosome 9p deletions (CDKN2A)
    • Chromosome 8q24 translocations or amplification (MYC)
    • Chromosome 3q27translocations (BCL6)
  • Expression abnormalities can be simplified into 2 general types by array CGH
    • Cell cycle dysregulation / impaired DNA repair (ATM, cyclin D1, TP53 mutations)
    • Impaired apoptosis (BIRC3)
  • IG genes are clonally rearranged
  • IGV genes are unmutated or minimally mutated in most cases
  • t(11;14)(q13;q32)
    • FISH is convenient; it can be performed on fixed tissue sections
    • Conventional cytogenetics if fresh material available
    • Most PCR assays detect 1 major breakpoint region in mantle cell lymphoma
  • Aggressive variants of mantle cell lymphoma
    • TP53 or p16 mutations are common
    • t(8;14)(q24;q32)(IGH/MYC) in a small subset of cases
    • Mutations in many genes
      • ATM (~ 40%), TP53 (~ 25%), CDKN2A (TP16) (10 - 20%)
  • Other mutations correlated with blastoid or pleomorphic variant
    • KMT2D/MLL2 (~ 10%), WHSC1 (~ 10%), BIRC3 (~ 5%)
    • NOTCH1 (~ 5%), NOTCH2 (~ 5%), MEF2B (~ 3%), MYD88 (~ 1%)
    • CARD11 (10%)
Molecular / cytogenetics images

Contributed by Chi Young Ok, M.D.

Complex karyotype

Deletion of TP53 gene

Sample pathology report
  • Left retroperitoneal lymph node, needle biopsies:
    • Mantle cell lymphoma, diffuse pattern, blastoid variant (see comment)
    • Comment: Routinely stained histologic sections reveal needle shaped fragments of tissue with partial crush artifact infiltrated by a diffuse monotonous infiltrate with focal starry sky pattern composed of large cells with irregular nuclei, blastoid chromatin, small nucleoli and scant cytoplasm. There is single cell apoptosis and mitotic figures are increased (45/10 high power fields).
      We performed immunohistochemical studies using paraffin embedded tissue, which show that the neoplastic cells are positive for cyclin D1, SOX11 (diffuse nuclear) and p53 (> 90%); while negative for TDT. Ki67 demonstrates a proliferation index of 100%. PAX5/CD5 immunohistochemical cocktail shows that the neoplastic cells are positive for PAX5 without co-expression of CD5.
      Fluorescence in situ hybridization (FISH) studies for t(11;14) translocation and MYC rearrangements are in progress and will be reported separately.
      Flow cytometry immunophenotyping detected a lambda restricted B cell population positive for CD10, CD19, CD20, CD22, CD38, CD79b; while negative for CD5, CD11c, CD30, CD43, CD44, CD200 and kappa light chain.
    • Addendum:
      • Positive for IGH/CCND1 gene rearrangement
      • Negative for MYC gene rearrangement
Differential diagnosis
Board review style question #1
    In the blastoid variant of mantle cell lymphoma, which of the following is the correct option?

  1. Morphology is composed of cells with variable size and prominent nucleoli
  2. Most cases are CD5 negative and CD23 positive
  3. Most cases are Cyclin D1 and SOX11 positive
  4. Ki67 index is typically below 20%
Board review style answer #1
C. Most cases are Cyclin D1 and SOX11 positive

Comment Here

Reference: Mantle cell lymphoma, aggressive variant
Board review style question #2


    This is the concurrent fine needle aspiration flow cytometry of the lymph node in a 70 year old man with lymphadenopathy. Cytology smears show intermediate to large lymphoid cells in a necrotic background. What is the most probable preliminary diagnosis before further work ups on the excised lymph node?

  1. Nodal marginal zone lymphoma
  2. Follicular lymphoma, grade 3A
  3. Mantle cell lymphoma
  4. Chronic lymphocytic lymphoma
Board review style answer #2
C. Mantle cell lymphoma

Comment Here

Reference: Mantle cell lymphoma, aggressive variant
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