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Hematopathology WHO > Follicular Lymphoma > Flashcards

Follicular Lymphoma Flashcards

1
Q

What is the definition of follicular lymphoma ?

A
  • lymphoma of follicle centre (germinal centre) B cells
    • usually both centrocytes and centroblasts
    • usually at least a partial follicular pattern
  • progression in cytological grade is common during the natural history of the disease
  • FL is usually exclusively a disease of older adults with rare cases in patients <18
    • pediatric follicular lymphoma is completely separate entity
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2
Q

What are the four types of follicular lymphoma?

A
  • follicular lymphoma in situ
  • Duodenal-type follicular lymphoma
  • Testicular follicular lymphoma
  • Diffuse variant of follicular lymphoma
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3
Q

What is the epidemiology of follicular lymphoma ?

A
  • accounts for ~20% of all lymphomas
  • more common in the US and Western European countries
  • median age is in the 6th decade
  • 2-3x more common in whites than in blacks
  • M : F ratio is 1: 1.7
  • Agricultural exposure to pesticides and herbicides has been associated with increased risk
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4
Q

What is seen in the peripheral blood of

people exposed to high levels of pesticides?

A
  • they show increased numbers of cells carrying the t(14;18)(q32;q21) (IGH/BCL2) translocation
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5
Q

What are the typical sites of involvement for

Follicular lymphoma ?

A
  • usually peripheral lymph nodes but can involve other sites
    • spleen, bone marrow, peripheral blood and Waldeyer’s ring (less common)
  • pure extranodal site presentation is very rare
  • Common sites of extranodal presentation:
    • GI tract (mesenteric lymph nodes with extension)
    • soft tissue
    • breast
    • ocular adnexa
  • IMP: many extranodal FL are higher grade (grade 3) and may lack Bcl2 expression and the translocation
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6
Q

What is the clinical presentation of FL ?

A
  • most patients have widespread disease at presentation
  • Bone marrow is involved in 40-70% of cases
  • usually asymptomatic despite widespread disease
    • B symptoms (fever, weight loss) are uncommon
    • waxing and waning of the disease without treatment is also common
  • The disease is a chronic one with frequent relapses
  • Staging with FDG-PET is less useful unless assessing for higher grade disease
  • Bone marrow staging is essential
    • paratrabecular lymphoid aggregates
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7
Q

What are the macroscopic findings of

lymph nodes involved by FL ?

A
  • vaguely nodular pattern
  • neoplastic follicles often have a bulging appearance
    • BUT reactive follicular hyperplasia can also have this appearance
  • spleens
    • uniform expansion of the white pulp
    • usually no evidence of involvement of the red pulp
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8
Q

What is the follicular pattern of growth

for FL ?

A
  • closely packed follicles that efface the nodal architecture
  • neoplastic follicles are often poorly defined and usually have attenuated or absent mantle zones
  • In follicular lymphoma, centrocytes and centroblasts are randomly distributed
    • No tingible body macrophages are seen
  • Follicles may become irregular or serpiginous
    • this growth pattern does not constitute progression to a diffuse growth pattern
    • CD21 and CD23 (FDC Markers) can highlight intact FDCs
    • Interfollicular infiltration is common and does not mean it is a diffuse growth pattern
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9
Q

What is the morphology of the interfollicular

infiltrating neoplastic cells ?

A
  • often are centrocytes, but they are smaller than those in the germinal centers
    • less irregular nuclear contours
    • may show immunophenotypic differences from the cells in the germinal centers
  • Note: some cases of FL have a floral growth pattern:
    • resembles progressive transformation of the GC
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10
Q

What histologic finding can be seen with follicular lymphoma?

A
  • hyalinizing sclerosis
  • often seen when the lymphoma extends beyond the lymph node capsule
    • common in mesenteric and retroperitoneal locations
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11
Q

What is the definition of a diffuse growth pattern in FL ?

A
  • an area of tissue completely lacking any follicles as defined by CD21/CD23 FDCs
  • must differentiate from an extensive interfollicular component
    • diffuse areas of centrocytes are not clinically significant
  • IMP: must report relative proportions of diffuse vs. follicular patterns of growth
  • IMP:
    • diffuse areas of grade 3 (any grade 3) are classified as a DLBCL and must be a separate diagnosis
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12
Q

What are the cutoffs to report diffuse vs. follicular growth patterns?

A
  • Follicular (>75% follicular)
  • Follicular and diffuse (25-75% follicular)
  • Focally follicular, predominantly diffuse (<25% follicular)
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13
Q

What can be seen with Follicular lymphoma grade 3B ?

A
  • they can be negative for CD10 and lack the Bcl2 translocation
  • they can also show positivity for MUM-1
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14
Q

What is the morphology of a centrocyte ?

A
  • small to medium-sized cells
  • angulated, elongated nucleus
    • looks cleaved or twisted
  • scant, pale cytoplasm
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15
Q

What is the morphology of a centroblast?

A
  • large cells (usually dsipersed)
  • round or oval nuceli
  • vesicular chromatin
  • 1-3 peripheral nucleoli
  • rim of cytoplasm
  • usually they are >3x the size of a normal lymphocyte, but on occasion they can be smaller
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16
Q

What is the morphology of follicular dendritic cells?

A
  • usually are binucleated
  • nuclei are round with flattening of the adjacent nuclear membranes
  • bland, dispersed chromatin with one, small centrally located nucleolus
  • usually cannot see the cytoplasm
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17
Q

Can follicular lymphoma be composed of blastoid-appearing

cells ?

A
  • Rare cases have been reported where FL has blastoid cells with dispersed chromatin resembling lymphoblasts.
  • this variant has a clinically aggresive course, similar to grade 3
  • don’t see starry sky histiocytes
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18
Q

What morphologic feature can be seen in

about 10% of follicular lymphomas ?

A
  • discrete foci of marginal zone or monocytoid appearing B cells
  • usually at the periphery of the neoplastic follicles
  • IMP: these cells are part of the neoplastic clone

Note: plasmacytic differentiation can also be seen in FL

  • plasmacytoid cells have an interfollicular distribution and carry the BCL2 translocation
  • they are part of the neoplastic clone
  • IMP: some t(14;18) negative cases with interfollicular growth pattern may indicate a marginal zone lymphoma with follicular colonization
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19
Q

What is the morphology of FL in the bone marrow and blood?

A
  • FL localizes to the paratrabecular region and may spread to the interstitial areas
  • sometimes can see a follicular growth pattern and an FDC meshwork
  • the grade in the bone marrow may differ as compared to the one in a lymph node (discordance, not uncommon)
  • usually more centrocytes in the bone marrow and blood
    • buttock cell
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20
Q

What is the definition of Diffuse follicular lymphoma variant ?

A
  • diffuse growth pattern and absence of the t(14;18) IGH-BCL2 translocation
  • often see small follicles (micro-follicles) with weak to absent BCL2 staining.
  • usually localized as a large mass in the inguinal region
    • CD10 positive and most are CD23 positive
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21
Q

What are the genetic findings of the diffuse follicular

lymphoma variant ?

A
  • cases cluster around typical FL by gene expression profiling
  • Deletion 1p36
    • recurrent genetic aberration that is seen in most cases
    • not specific to this variant
    • region contains TNFRSF14, which is commonly affected in translocation positive FL
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22
Q

What is the definition of testicular follicular lymphoma ?

A
  • distinct variant of FL
  • higher frequency in children but rarely can be seen in adults
  • IMP:
    • lack BCL2 translocation
    • usually are high grade cytologically (3A)
    • good prognosis even with just surgical excision
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23
Q

What is the immunophenotype of FL?

A
  • positive for surface Ig (usually IgM, maybe see IgD, IgG or rarely IgA)
  • B cell associated antigens are positive
  • usually positive for CD10, Bcl6, and Bcl2
    • loss of CD10 with retention of Bcl6 can be seen in grade 3B
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24
Q

What is the pattern of CD10 expression in

FL ?

A
  • CD10 expression is often stronger in the follicles than in the interfollicular neoplastic cells
    • it can be negative in the interfollicular lymphocytes, areas of marginal zone differentiation, peripheral blood and bone marrow involvement
25
Q

What is the pattern of staining for Bcl6 in

follicular lymphoma ?

A
  • downregulated staining in the interfollicular areas
  • variable expression in the follicles as compared to normal germinal centers
26
Q

What is the pattern of expression of

CD5 in follicular lymphoma ?

A
  • should be negative
  • but rare cases of CD5 positive FL have been reported
    • seen more frequently with the floral variant
27
Q

What is the role of BCL2 in FL?

A
  • overexpression of Bcl2 is the hallmark of FL
  • the amount of expression can vary based on the grade of the lymphoma with higher grades losing Bcl2 expression
  • in some cases the absence of Bcl2 expression is due to mutations that eliminate the epitopes targeted by the common antibodies, just need to use a different antibody to detect it
  • Absence of Bcl2 does NOT exclude FL and it’s presence does not help differentiate it from other small B cell lymphomas
    • most of which also express Bcl2
  • IMP:
    • T cells, primary follicles and mantle zones are Bcl2 +
28
Q

What is the immunophenotype of follicular T

helper cells often found in germinal centers ?

A
  • CD3+, CD4+, CD57+, PD1/CD279a+, CXCL13+
29
Q

What can be seen and what is the differential

diagnosis for a CD10 negative FL ?

A
  • a subset of CD10 negative FL often are positive for IRF4/MUM1
  • frequently these lack Bcl2 translocation
  • contain a Bcl6 amplification
  • seen in elderly patients and are higher grade (3A or 3B)

IMP: differential diagnosis

  • Large B cell lymphoma with IRF4 rearrangement
    • oftentimes has at least a partial follicular growth pattern
30
Q

What is the pattern of Ki67 expression

in Follicular lymphomas ?

A
  • typically ki67 correlates with histological grade
  • most low-grade 1-2 have a ki67 of <20%
  • most high grade (3) have a ki67 of >20%

IMP:

  • a subgroup of low grade FL have a high proliferation index and these cases behave more aggressively
  • good to report increased ki67 in these cases
31
Q

What is the postulated normal counterpart

for follicular lymphoma ?

A
  • normal counterpart is the germinal center B cell
  • The cases that contain the t(14;18) IGH/BCL2
    • this occurs in the bone marrow pre-B cells
    • full malignant transformation of these translocation primed B cells occurs during re-entry in the the germinal centers in secondary lymphoid organs
32
Q

How is follicular lymphoma graded ?

A
  • count the absolute number of centroblasts in 10 neoplastic follicles
  • must evaluate 10 HPFs within different follicles
    • should pick follicles that are representative and not just those with increased large cells.

IMP: pure grade 3B follicular lymphoma is quite rare, most contain diffuse areas classified as DLBCL.

  • Translocations for Bcl2 in these cases are rare
33
Q

What are the alterations in the antigen

receptor genes for follicular lymphoma ?

A
  • IG heavy and light chain genes are both rearranged
    • IGV genes show extensive and ongoing somatic hypermutation
  • clonalilty detection approximates 100% when primers detecting IGH DJ and light chain gene rearrangements are included.
  • IMP:
    • FL undergoes clonal evolution over time
    • can be linear but most of the time is divergent with multiple subclones
      • transformation usually occurs in one of the earlier clones rather than a subclone
34
Q

What is the characteristic translocation

seen in follicular lymphoma ?

A
  • t(14;18)(q32;q21) between IGH and BCL2
    • alternative translocation between BCL2 and the IG light chains is seen
    • 90% of grade 1-2 follicular lymphomas have this translocation
    • IMP: variation in breakpoint regions, FISH is more sensitive than PCR-based testing
35
Q

CAUTION: cytogenetics cannot differentiate

between what?

A
  • IGH/BCL2 translocation and IGH/MALT1 translocation
36
Q

What is true about FL that are negative

for the BCL2 translocation ?

A
  • they are more likely to have a late germinal center gene expression profile
  • absence of the translocation does not appear to change prognosis
  • BUT
    • BLC2 rearrangements are much less likely to be seen in grade 3 FL
    • IMP: testicular FL (often seen in young boys) is negative for BCL2 gene rearrangement
    • abnormalities of BCL6 (3q27.3) or rearrangement are seen in 15% of FLs and have al been reported in testicular FL
37
Q

What is a commonly occurring genetic alteration

in FL ?

A
  • TNFRSF14 (region 1p36)
    • copy number alterations, acquired copy number neutral LOH, and mutations
    • seen in all forms of FL including the diffuse variant and pediatric variant
    • thought to be associated with adverse prognosis but other studies have not shown this

Note: in general the number of genetic alterations increases with histologic grade and transformation.

38
Q

What is a rare translocation that can be seen

in FL ?

A
  • t(8;14)(q24;q32) in combination with t(14;18)
    • these may progress to the high-grade double hit lymphomas and may contain translocations of both BCL2 and MYC
39
Q

What are early genetic events in follicular

lympoma that are frequently encountered ?

A
  • Gains of function mutations in the H3K27 methyltransferase, EZH2
  • Additionally, driver mutations in CREBBP and KMT2D (chromatin regulator genes) play a key role in FL

IMP: these 3 genes all together have been proposed as possible therapeutic agents

Tumor microenvironment has also been shown to be very important in evolution and progression of FL

40
Q

What are proposed pathways of genetic

progression of FL to DLBCL ?

A
  • inactivation of TP53 and CDKN2A or
  • activation of MYC

IMP: Dr. Zu uses TP53 in follicular lymphoma to help him see if there are higher grade areas or potentially a DLBCL (remember the ovary case).

41
Q

Is there an association with genetic

susceptibility in patients who develop follicular lymphoma?

A
  • Five susceptibility loci have been detected in FL
  • FL is increased in patients with a history of lymphoma in a first degree family member
42
Q

What are key prognosis factors in FL ?

A
  • prognosis is closely related to the extent of the disease
  • Five independent predictors of inferior survival
    • age >60
    • hemoglobin concentration <12 g/dL
    • elevated serum LDH
    • Ann Arbor stage III/IV
    • and >4 involved nodal areas
43
Q

What is the median survival for

patients with FL grades 1-3A ?

A
  • median survival is >12 years
  • patients have continued relapses over time with no plateau in survival curves
  • transformation/progression to DLBCL occurs in 25-35% of cases
    • rarely patients who present with DLBCL at the beginning relapse to a FL later
    • transformation usually involves additional genetic abnormalities, usually MYC translocations
      • MYC with BCL2 is particularly aggressive
44
Q

What is a rare and possible transformation of

Follicular lymphoma ?

A
  • B acute lymphoblastic leukemia/lymphoma
    • this is clonally related to the FL
    • involves the acquisition of a MYC rearrangement
    • BCL2 rearrangement is present
    • BUT
      • do not diagnose transformation as High Grade B cell lymphoma with MYC and BCL2 is there is lymphoblastic transformation
  • Hodgkin lymphoma
    • will also carry the BCL2 translocation
45
Q

What is a rare tumor that has been described

in association with FL but not necessarily

arising from it ?

A
  • Histiocytic or dendritic cell sarcoma
    • the sarcoma can hold a BCL2/IGH rearrangement
    • but the sarcomas do not show any B cell positivity
    • it is postulated that both the sarcoma and FL arise from a common precursor that has undergone IG rearrangment rather than a de-differentiation of the FL
46
Q

What is the definition of in situ follicular neoplasia?

ISFN

A
  • partial or total colonization of germinal centers by clonal B cells carrying the BCL2 translocation
    • this is seen in an otherwise reactive lymph node
    • can be seen in extranodal sites as well, such as the spleen
  • ISFN
    • biologically similar to cells found in peripheral blood carrying the BCL2 translocation when they are essentially asymptomatic
    • Must distinguish ISFN from partial involvement of a lymph node by FL (biologically different)
47
Q

What is the epidemiology of ISFN ?

A
  • this lesion can be detected in 2% of randomly sampled lymph nodes
  • FL-like B cells are more commonly found in patients with increased environmental exposures to herbicides and pesticides.
  • FL-like B cells can be detected in as many as 70% of patients over the age of 50
    • very rare under 18 years of age
  • Most cases are found incidentally, can be seen with other B cell lymphomas or nodes dissected for carcinoma
48
Q

What are the microscopic features of ISFN ?

A
  • ISFN is not appreciated on routine H&E sections
  • lymph nodes contain reactive follicles with well-formed germinal centers
  • the affected follicles are similar in size and shape do the adjacent uninvolved follicles
    • this is also seen in extranodal sites
  • can be associated with other lymphomas including:
    • CLL, Mantle cell, Marginal Zone, Diffuse large B cell, and CHL
49
Q

What is the difference between ISFN and

partial lymph node involvement by FL ?

A
  • these are distinct diagnosis
  • partial involvement by FL can be seen by routine H&E sections
    • IMP: ISFN can only be seen by IHC
  • partial involvement is usually only seen with lower stage disease but progression can occur.

IMP: please see summary table p. 275 WHO

50
Q

What is the immunophenotype of ISFN ?

A
  • BCL2 strongly highlights the areas of ISFN
    • higher intensity than the adjacent T cells or mantle zones
  • BCL2 positive centrocytes also show co-expression of CD10
  • Flow cytometry:
    • can demonstrate CD10 positive, light chain restricted B cells with BCL2 co-expression
    • there may be a background of more numerous CD10 + or CD10(-) B cells
51
Q

Are the ISFN cells positive for the

characteristic FL translocation ?

A
  • yes they have the t(14;18) and very few other genetic aberrations
  • Occasional reports of the following have been seen:
    • EZH2
    • Deletions of 1p36 (encompassing TNFRSF14)

Note:

  • partial involvement by FL of a lymph node also have low levels of these alterations
52
Q

What is the prognosis of patients with ISFN ?

A
  • risk of subsequent FL is very low (<5%)
  • Most studies have not found that the number of follicles involved within a single lymph node predicts subsequent risk of lymphoma

IMP:

  • High levels of FL-like B cells in the PB are associated with an increased risk of subsequent FL, but low levels only identified by PCR carry no increased risk

However, ID of ISFN should prompt biopsy of any other enlarged LN due to association with other B cell lymphomas.

53
Q

What is the definition of duodenal-type

follicular lymphoma ?

A
  • specific variant of FL
  • predominantly found in the 2nd portion of the duodenum presenting as multiple small polyps
    • often incidental on endoscopy
  • most patients have localized disease
  • some can have more extensive involvement of the small intestine (~80% of patients) with further endoscopic examination

IMP: if the features are not classic, systemic FL with small intestine involvement must be further evaluated.

  • infiltration into the muscularis propria or variation in cytology
54
Q

What is the epidemiology of duodenal-type FL ?

A
  • most patients are middle aged with an equal M:F ratio
55
Q

What are the typical microscopic findings

of duodenal-type FL ?

A
  • neoplastic follicles in the mucosa and submucosa without infiltration into the muscularis propria
    • cells infiltrate into the lamina propria (that’s ok)
  • uniformly composed of centrocytes with very few centroblasts
    • Grade 1-2 disease
56
Q

What is the immunophenotype of

duodenal-type FL ?

A
  • similar to nodal type FL
  • (+)
    • CD20, BCL2, CD10 with variable BCL6 expression
  • Low proliferation rate
  • Follicular dendritic cells, highlighted by CD21 are usually restricted to the periphery of the follicles
  • Neoplastic cells usually express IgA heavy chain
57
Q

What is the postulated normal counterpart

for duodenal-type FL ?

A
  • B cell that expresses germinal centre markers and has features of memory B cells
58
Q

What is the genetic profile of

duodenal-type FL ?

A
  • cells carry the t(14;18)(q32;q21)
    • they are thought to be memory cells
    • show evidence of somatic hypermutation of the IgH gene
  • Gene expression profiling does show some overlap with MALT lymphoma
    • overexpression of CCL20 and MADCAM1 genes
    • these are not found upregulated in nodal FL
  • lower frequency of other genetic aberrations compared to nodal FL
    • but in common has recurrent deletion of 1p encompassing TNFRSF14 gene as well as mutations in that gene
59
Q

What is the prognosis of duodenal type follicular lymphoma ?

A
  • long term survival is excellent even with local recurrences in the intestine
  • there is <10% risk of progression to nodal disease
  • a watch and wait approach is reasonable
    • but can use radiation, chemotherapy and or rituximab

Hematopathology WHO (29 decks)

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