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Hematopathology WHO > Mantle Cell Lymphoma > Flashcards

Mantle Cell Lymphoma Flashcards

1
Q

What is the definition of

Mantle cell lymphoma ?

A
  • mature B cell neoplasm
  • monomorphic, small to medium sized lymphoid cells
  • irregular nuclear contours
  • >95% of cases there is a CCND1 translocation
  • generally an aggressive and incurable lymphoma
    • but there are more indolent variants
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2
Q

What are the aggressive

variants of Mantle Cell Lymphoma ?

A
  • Blastoid
    • cells resemble lymphoblasts with dispersed chromatin
    • High mitotic rate (usually > 20-30 mitoses per 10 HPF)
  • Pleomorphic
    • cells are pleomorphic but many are large with oval to irregular nuclear contours, generally pale cytoplasm
    • often have prominent nucleoli in at least some of the cells
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3
Q

What are the other (non-aggressive)

variants of Mantle Cell Lymphoma ?

A
  • Small cell
    • cells are small, round lymphocytes with more clumped chromatin, either admixed or predominant
    • mimick a SLL/CLL
  • Marginal zone-like
    • prominent foci of cells with abundant pale cytoplasm resembling marginal zone or monocytoid B cells
    • paler areas may look like proliferation centers of CLL/SLL
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4
Q

What is the epidemiology of

Mantle Cell Lymphoma?

A
  • accounts for ~3-10% of non-Hodgkin lymphomas
  • middle age to older people
    • median age around 60
  • marked male predominance
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5
Q

What is the localization of

Mantle Cell Lymphoma ?

A
  • lymph nodes are the most commonly involved site
  • spleen and bone marrow with or without peripheral blood involvement also occurs
  • Other extranodal sites:
    • gastrointestinal tract (lymphomatous polyposis)
    • Waldeyer’s ring
    • lungs
    • pleura
    • CNS - most frequently at time of relapse
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6
Q

What is the clinical presentation/features

of Mantle Cell Lymphoma?

A
  • most patients present with stage III or IV disease
    • lymphadenopathy, splenomegaly, bone marrow involvement
    • extranodal involvement is fairly common
    • peripheral blood
  • Note:
    • some patients have pronounced lymphocytosis which can mimic prolymphocytic leukemia
  • IMP
    • some patients present with leukemic, non-nodal disease
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7
Q

What are the microscopic findings

of Mantle Cell Lymphoma ?

A
  • vaguely nodular, diffuse mantle zone or rarely a follicular growth pattern
    • if there is a a mantle zone pattern, you must differentiate from mantle cell lymphoma in situ
  • most cases:
    • small to medium sized cells
    • slight to markedly irregular nuclear contours
      • many look like centrocytes
      • transformed cells like like centroblasts, immunoblasts, or paraimmunoblasts
    • inconspicuous nucleoli
      • more prominent nucleoli in PB and BM
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8
Q

What variant of Mantle cell lymphoma

is frequently seen in the leukemic, non-nodal form?

A
  • small cell variant
  • marginal zone variant
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9
Q

Is Mantle cell lymphoma graded?

What must be reported histologically ?

A
  • mantle cell lymphoma is not graded
  • must evaluate the proliferation index by ki67
    • IMP for prognosis
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10
Q

What background microscopic features can

suggest the diagnosis of Mantle cell ?

A
  • hyalinized vessels
  • aggregates of foamy, epitheloid histiocytes
    • IMP: occaisonally in the blastoid and pleomorphic variants the histiocytes can create a starry sky appearance
  • non-neoplastic plasma cells can be present
  • IMP
    • true plasmacytic differentiation is rare but can be seen
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11
Q

What is the pattern of involvement of

the spleen ?

A
  • white pulp and variable red pulp involvement can be seen
    • can mimic splenic marginal zone lymphoma
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12
Q

Does Mantle cell lymphoma undergo

transformation to a higher grade lymphoma?

A
  • transformation to a typical DLBCL does not occur
  • however some of these features can be seen when the disease progresses:
    • loss of a mantle zone growth pattern
    • increase in nuclear size and pleomorphism
    • chromatin dispersal
    • increase in mitotic activity and Ki67 proliferation indices
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13
Q

What is the immunophenotype

of Mantle cell lymphoma ?

A
  • relatively intense surface IgM/IgD
  • more frequently lambda vs. kappa restriction
  • uniformly BCL2 positive
  • usually positive for CD5, FMC7 and CD43
  • sometimes positive for IRF4/MUM1
  • negative for CD10 and BCL6
  • CD23 can be negative or weakly positive
  • Nuclear Cyclin D1 is expressed by >95% of mantle cell
    • including the minority of cases that are CD5 negative
  • Sox11
    • >90% are positive including cyclin D1 cases and blastoid variants
    • caution: sensitivity and specificity of SOX11 antibodies vary widely
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14
Q

What are some of the aberrant immunophenotype

described in Mantle cell lymphoma ?

A
  • sometimes aberrant immunophenotypes are associated with the blastic and pleomorphic variants
  • absence of CD5 with expression of CD10 and BCL6
  • CD200 positive
    • can be seen in the leukemic, non-nodal variant
  • Rare cases express markers associated with CLL
    • LEF1
      • more likely to be the blastoid or pleomorphic variant
    • CD200
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15
Q

What is the postulated normal counterpart?

A
  • peripheral B cell of the inner mantle zone
  • Note:
    • the possibility that mantle cell lymphoma can arise from more than one lymphoid compartment has been suggested
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16
Q

What are the changes in antigen receptors

in Mantle Cell Lymphoma ?

A
  • IG are clonally rearranged
  • IGV genes are unmutated or minimally mutated
    • 15-40% of cases show somatic hypermutation
    • but mutation burden is much lower when compared to CLL
  • Interestingly,
    • a substantial proportion of mantle cell lymphomas show evidence of antigenic drive
17
Q

What are the cytogenetic abnormalities in

Mantle Cell lymphoma ?

A
  • t(11;14)(q13;q32) IGH gene and CCND1
    • encodes cyclin D1
    • considered the primary genetic event
    • present in >95% of cases
    • variant CCND1 translocations with IG light chains have been reported but are very uncommon
    • translocation results in disregulated overexpression of mRNA
  • MCL with truncated transcripts have very high levels of cyclin D1 expression
    • they have high proliferation rates and are more aggressive
18
Q

How does overexpression/deregulation of

Cyclin D1 drive the lymphoma ?

A
  • over expression is thought to overcome the suppressive effects of RB and p27 in the cell cycle
  • BUT
    • it is not sufficient on it’s own to drive the lymphoma
    • mantle cell lymphomas also carry a large number of non-random, secondary chromsomal aberrations
      • see p. 288
19
Q

What other genetic changes are

seen in Mantle Cell lymphoma ?

A
  • SNP studies show copy-neutral LOH in as many as approximately 60% of cases
    • the region in which the copy number losses are found are typically in the TP53 region
  • trisomy 12 has been reported in 25% of cases
    • but is usually seen with other alterations
  • Tetraploid clones
    • more common in the pleomorphic and blastoid variants
20
Q

What translocation, other than CCND1, has been

described in Mantle Cell lymphoma ?

A
  • t(8;14)(q24;q32)
    • translocation with variant MYC translocation
      • associated with a more aggressive clinical course
    • BCL6 translocations are also repoted and may lead to BCL6 over expression
21
Q

What other oncogenic alterations have been

described in Mantle cell lymphoma ?

A
  • inactivating mutations of ATM at 11q22-23
    • seen in 40-75% of cases
  • CCND1 mutated in 35% of cases
  • KMT2D (MLL2) mutated in 14% of cases
  • NOTCH1 5-12% of cases
    • this mutation is important prognostically and for therapy
22
Q

What mutations have been described in

SOX11 positive Mantle cell lymphoma ?

A
  • ATM
  • KMT2D
  • NOTCH1/2
23
Q

What is a mutation often seen in

highly proliferativce Mantle cell lymphomas?

A
  • TP53 mutations are frequent
  • CDKN2A homozygous deletions
  • and various others including microdeletions of the RB1 gene
24
Q

What is the definition of

Cyclin-D1 negative Mantle Cell Lymphoma ?

A
  • lack cyclin D1 and t(11;14)
  • but the gene expression profile and clinical/morphologic features are those of mantle cell lymphoma
  • Half the cases have CCND2 translocations
    • usually paired with IG (IgL or IgK)
    • high expression of Cyclin D2
    • IMP: staining with cyclin D2 or D3 is not useful because other B cell lymphomas are positive
    • Sox11 is useful
      • in the absence of this stain diagnosis should be cautious
  • IMP: some cyclin D1 positive cases do not have the translocation and vice versa
25
Q

Is there a genetic heritability

in Mantle Cell lymphoma ?

A
  • familial aggregation of mantle cell lymphoma and mantle cell with other B cell neoplasms has been reported
26
Q

What are the prognosis and predictive

factors of Mantle Cell Lymphoma ?

A
  • median survival is 3-5 years
  • vast majority of patients do not get cured despite newer treatment modalities
  • Proliferation index is critical
    • >30% of ki67
    • >10-37 mitosis/15 HPF
    • adverse prognosis
    • <10% ki67
      • indolent prognosis
27
Q

What features have been reported in

some studies to be adverse prognostic factors?

A
  • blastoid or pleomorphic variant
  • karyotypic complexity
  • TP53 mutation/overexpression and or loss
  • CDKN2A deletion
  • Variety of clinical factors including:
    • overt PB involvement in the setting of adenopathy
28
Q

Lack of SOX11 expression has been

associated with what ?

A
  • some studies say more indolent disease while other say…
  • more aggressive because they tend to acquire TP53 mutations

IMP: the small cell variant has also been described to be more of an indolent course

29
Q

What two molecular alterations have been shown

to have an independent negative prognosis even aside

from the proliferation index?

A
  • 9p (CDKN2A)
  • 17p (TP53)
30
Q

What is the definition of leukemic,

non-nodal Mantle cell lymphoma ?

A
  • this disease inolves the PB, bone marrow and sometimes the spleen
  • no significant adenopathy is allowed
    • peripheral LN <1-2 cm
    • no adenopathy detected on CT if performed
  • these cells may reversibly infiltrate areas of extranodal inflammation (H.pylori gastritis) or localize to the LN mantle zones and mimic mantle cell neoplasia in situ
31
Q

What is the typical morphology of

leukemic, non-nodal Mantle cell lymphoma ?

A
  • more likely to be small and resemble CLL-type cells
  • more likely to be SOX11 negative
  • more likely to have somatic IG hypermutation
  • CD5 expression may be less common
  • IMP
    • 30-40% show CD38 positivity
    • >2% show CD200 positivity
    • can mimic CLL in the PB
32
Q

How is the genetic background different

in leukemic non-nodal Mantle cell lymphoma?

A
  • usually only the CCND1 translocation is present
  • otherwise there are very few abnormalities
    • classic Mantle cell lymphoma has more genomic instability and a more complex karyotype
33
Q

What is the prognosis for patients with

leukemic Mantle cell lymphoma ?

A
  • generally have a better prognosis compared to classic Mantle cell
    • may not require any therapy for a while before progressing
  • a subset of this type can progress quickly without the development of any significant lymphadenopathy
    • can develop rapid splenomegaly
    • transform to blastoid or pleomorphic variant
    • can acquire TP53 or other genetic alterations which drive the progression
34
Q

Interesting fact ….

A
  • at least 7% of healthy individiuals have circulating cells with the IGH/CCND1 translocation
    • these persist for years and increase over time
35
Q

What is the definition of in situ

Mantle cell Neoplasia ?

A
  • the presence of Cyclin D1 positive lymphoid cells with CCND1 rearrangements restricted to the mantle zone of otherwise hyperplastic appearing lymphoid tissue
    • cyclin-D1 positive cells are scattered in the inner mantle zone area
  • Peripheral blood involvement or involvement at more than one site does not exclude the diagnosis.

IMP: expanded Mantle zones with cyclin D1 positive cells is more appropriate for Mantle cell lymphoma with a mantle zone growth pattern.

36
Q

What is the immunophenotype of

in situ Mantle cell neoplasia?

A
  • usually CD5 negative
  • can be positive or negative for Sox11
  • usually an incidental finding when working up another lymphoma
  • most patients do well with this and do not progress to overt Mantle cell lymphoma
    • but occasional cases of progression have been described

Hematopathology WHO (29 decks)

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