Mantle Cell Lymphoma Flashcards
What is the definition of
Mantle cell lymphoma ?
- 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
What are the aggressive
variants of Mantle Cell Lymphoma ?
- 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
What are the other (non-aggressive)
variants of Mantle Cell Lymphoma ?
- 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
What is the epidemiology of
Mantle Cell Lymphoma?
- accounts for ~3-10% of non-Hodgkin lymphomas
- middle age to older people
- median age around 60
- marked male predominance
What is the localization of
Mantle Cell Lymphoma ?
- 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
What is the clinical presentation/features
of Mantle Cell Lymphoma?
- 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
What are the microscopic findings
of Mantle Cell Lymphoma ?
- 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
What variant of Mantle cell lymphoma
is frequently seen in the leukemic, non-nodal form?
- small cell variant
- marginal zone variant
Is Mantle cell lymphoma graded?
What must be reported histologically ?
- mantle cell lymphoma is not graded
- must evaluate the proliferation index by ki67
- IMP for prognosis
What background microscopic features can
suggest the diagnosis of Mantle cell ?
- 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
What is the pattern of involvement of
the spleen ?
- white pulp and variable red pulp involvement can be seen
- can mimic splenic marginal zone lymphoma
Does Mantle cell lymphoma undergo
transformation to a higher grade lymphoma?
- 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
What is the immunophenotype
of Mantle cell lymphoma ?
- 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
What are some of the aberrant immunophenotype
described in Mantle cell lymphoma ?
- 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
- LEF1
What is the postulated normal counterpart?
- 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
What are the changes in antigen receptors
in Mantle Cell Lymphoma ?
- 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
What are the cytogenetic abnormalities in
Mantle Cell lymphoma ?
- 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
How does overexpression/deregulation of
Cyclin D1 drive the lymphoma ?
- 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
What other genetic changes are
seen in Mantle Cell lymphoma ?
- 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
What translocation, other than CCND1, has been
described in Mantle Cell lymphoma ?
- 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
- translocation with variant MYC translocation
What other oncogenic alterations have been
described in Mantle cell lymphoma ?
- 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
What mutations have been described in
SOX11 positive Mantle cell lymphoma ?
- ATM
- KMT2D
- NOTCH1/2
What is a mutation often seen in
highly proliferativce Mantle cell lymphomas?
- TP53 mutations are frequent
- CDKN2A homozygous deletions
- and various others including microdeletions of the RB1 gene
What is the definition of
Cyclin-D1 negative Mantle Cell Lymphoma ?
- 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
Is there a genetic heritability
in Mantle Cell lymphoma ?
- familial aggregation of mantle cell lymphoma and mantle cell with other B cell neoplasms has been reported
What are the prognosis and predictive
factors of Mantle Cell Lymphoma ?
- 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
What features have been reported in
some studies to be adverse prognostic factors?
- 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
Lack of SOX11 expression has been
associated with what ?
- 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
What two molecular alterations have been shown
to have an independent negative prognosis even aside
from the proliferation index?
- 9p (CDKN2A)
- 17p (TP53)
What is the definition of leukemic,
non-nodal Mantle cell lymphoma ?
- 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
What is the typical morphology of
leukemic, non-nodal Mantle cell lymphoma ?
- 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
How is the genetic background different
in leukemic non-nodal Mantle cell lymphoma?
- 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
What is the prognosis for patients with
leukemic Mantle cell lymphoma ?
- 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
Interesting fact ….
- at least 7% of healthy individiuals have circulating cells with the IGH/CCND1 translocation
- these persist for years and increase over time
What is the definition of in situ
Mantle cell Neoplasia ?
- 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.
What is the immunophenotype of
in situ Mantle cell neoplasia?
- 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
