Follicular Lymphomas Flashcards
Variants of follicular lymphoma that lack BCL2 rearrangement
Pediatric-type FL
Primary cutaneous follicle center lymphoma
Both have an excellent prognosis
Most common stage at presentation of follicular lymphoma
stage 3 or 4
Tends to be extensive at diagnosis
Classical follicular lymphoma genetics
IGH::BCL2 translocation in 85-90%
Loss of function in chromatin remodelers: KMT2D, CREBBP, ARID1A, MEF2B, KMT2C
Gain of function in polycomb protein EZH2
Pediatric-type follicular lymphoma
Localized follicular proliferation of germinal center B cells occurring in lymph nodes of children or young adults, usually males (10:1 M:F ratio). ‘
In contrast to classical FL, excision of the involved lymph node(s) is curative in pediatric-type.
Rather than being driven by BCL2 rearrangements and chromatin remodeler deficiencies, 60% show MAPK mutations (most often MAP2K1). 1p36 loss of heterozygosity and IRF8 mutations are also common. TNFRSF14 mutations are occasionally present.
Morphologically characterized by large, expansile follicles and/or serpiginous follicles with intermediate-sized lymphoid cells that at least partially efface lymph node architecture. Any areas diagnostic for DLBCL (sheets of centroblasts) exclude the diagnosis of pediatric-type FL.
Neoplastic cells are CD20+, PAX5+, CD79a+, CD10+, BCL6+, but are BCL2 weak or negative. Ki67 is higher (>30%) than conventional FL.
FISH demonstrating negativity for BCL2 and BCL6 rearrangements is required for accurate diagnosis, to exclude conventional follicular lymphoma.
BCR-rearrangement-negative and CD23-positive Follicle Center Lymphoma
Typically presents with localized (stage I-II) lymphadenopathy. Histologically, predominantly composed of centrocytes (grade 1-2 of 3), usually growing in a diffuse pattern with scattered microfollicles and frequent interstitial sclerosis.
Neoplastic cells express CD10 and BCL6, CD23, and variably express BCL2.
In terms of molecular features, these cases have recurrent deletions of 1p36 (involving TNFRSF14) and deletion of 16p (involving CREBBP and SOCS1), and/or mutations in CREBBP and STAT6 or SOCS1.
This group of lymphomas has an excellent prognosis.
Primary cutaneous follicle center lymphoma
Makes up ~30-50% of all primary cutaneous lymphomas, and 10% of lymphomas involving the skin.
Presents with plaques or tumors at a solitary cutaneous site, most often on the scalp or forehead.
Morphologically characterized by dermal infiltration (often perivascular/periadnexal) by neoplastic lymphocytes, often sparing the epidermis. May have a follicular, diffuse, or mixed follicular/diffuse growth pattern. Composed of large centrocytes with irregular, angulated nuclei, larger in size than classic nodal FL, along with admixed centroblasts.
Most cases have an excellent prognosis, even when multifocal involvement is present, however cutaneous recurrence occurs in 30% of cases.
Unlike metastatic classical FL to the skin, these cases lack BCL2 rearrangements and are much less likely to have mutations in chromatin remodelers and EZH2.
The IHC pattern includes CD20+, PAX5+, CD79a+, usually BCL6+, but usually weak to absent CD10 (especially when diffuse). Ki67 is generally high (>30%), and CD21 staining for FDC meshworks often is weak or negative.
While one can suspect PCFCL, definitive diagnosis really requires ruling out the presence of extracutaneous disease with adequate staging.
Primary cutaneous DLBCL, leg type
On the ddx for PCFCL, particularly the diffuse variant.
Has unique immunohistochemical features:
IgM+, MUM1+, non-GC phenotype.
Molecularly, MYD88 mutations and inactivating CDKN2A and CDKN2B mutations are common, all of which are not seen in PCFCL.
Grading of follicular lymphoma
Grade 1-2: 15 or fewer centroblasts per HPF (80% of cases)
Grade FL3U: High-grade features and unconventional morphology
Grade 3A: 16 or greater centroblasts per HPF
Grade 3B: Solid sheets of centroblasts
Standard HPF: 0.159 mm2
Should be counted in 10-20 fields and averaged, with adjustment for the field diameter.
Unconventional morphology = “cleaved cells” or small-medium-sized blasts.
Controversies over FL grading
Mounting evidence suggests that there is no clinical difference between even FL1-2 and FL3A.
Based on this, the WHO5 does not even recommend grading FL at all. Rather, FL3B is designated as Follicular LBCL, a separate entity under the FL umbrella.
POD24
After first-line therapy, 20% of FL cases recur/progress within 24 months.
If the patient makes it past POD24 without recurrence, their long term prognosis is substantially better.
This is currently the most important prognostic factor for follicular lymphoma, and has no correlation with grade.
WHO5’s four caterogies of follicular lymphoma
- Classical FL (FL grades 1-3A)
- Diffuse FL
- FL with unusual features (FL3U)
- Follicular LBCL (FL3B)
Duodenal-type follicular lymphoma
Most cases are localized to the duodenum, although other portions of the intestinal tract are occasionally involved. Gives the involved mucosa a characteristic nodular appearance.
Morphologically, composed of a follicular infiltrate that centers in the lamina propria of involved mucosa, with predominantly cells with centrocytic morphology. Neoplastic follicles may be surrounded by a non-neoplastic mantle cell layer.
The immunophenotype of neoplastic DFL B cells is similar to classic nodal FL, CD20+, PAX5+, CD79a+, CD10+, BCL6+, and usually BCL2+. FDC meshworks tend to be less well developed and pushed to the periphery of follicles. The Ki67 proliferation index is usually low (less than 20%).
Genetically similar to classic nodal FL, with BCL2 rearrangements and mutations in TNFRSF14, EZH2, KMT2D, and/or CREBBP. Less genetic complexity than classic FL with a lower frequency of these mutations and fewer cases with multiple mutations. Chronic inflammation expression profile suggests chronic inflammation may be involved in pathogenesis.
Large cell lymphoma with IRF4 rearrangement
Can be a mimic of follicular lymphoma
On IHC, characteristically strongly and diffusely MUM1+. This can be used as a screening to then proceed for IRF4 FISH.
Tends to occur in younger patients (under age 18) affecting Waldeyer’s ring and has a very good prognosis.
Primary follicular lymphomas of other visceral sites.
Can be seen in testicle, ovary, thyroid, conjunctiva, lower female genital tract, etc. However, all are individually very rare.
Tend to occur in young male patients and lack BCL2 rearrangements and chromatin remodeler mutations. More frequently have MAPK alterations such as MAP2K1 mutation.
BCL-2-R negative classic follicular lymphomas
May harbor other genetic alterations:
BCL-6 rearrangements
TNFRSF14 mutations
1p36 alterations
Frequent mutations in epigenetic regulators
STAT6 mutations
This group is highly heterogeneous and has variable clinical presentation and malignant behavior.
Caveat: Some BCL-2 negative FLs by IHC actually do have the BCL-2-R, but have mutations in the epitope recognized by major comercially available antibodies.
