Follicular Lymphoma

Epidemiology:

• adults

Common sites:

Gross features:

Histologic features:

• nodular architecture
• follicles distributed throughout lymph node
• no zonation in follicles
• back to back follicle density
• homogenous follicles
• thin or absent mantle zone
• no polarization
• homogenous follicle centre cell population
• tingible body macrophages absent
• mitoses uncommon
• follicles in perinodal tissue
• light chain restriction of follicle centre cells
• mixture of small (small cleaved cells) and large cells
• irregular nuclear margins
• grooves
• grading:
• based on amount of large cells within follicles
• grade 1 – 0-5 centroblasts per HPF
• grade 2 – 6-15 centroblasts per HPF
• grade 3 – > 15 centroblasts per HPF
• grade 3a – centrocytes still present amongst centroblasts
• grade 3b – solid sheets of centroblasts with no residual centrocytes
• pattern:
• follicular:
• > 75% follicular
• Follicular and diffuse:
• 25 to 75% follicular
• Focally follicular:
• < 25% follicular
• diffuse follicle centre cell lymphoma:
• grade 1 – 0-5 centroblasts per HPF
• grade 2 – 6-15 centroblasts per HPF
• cutaneous follicle centre lymphoma:

Immunophenotype:

Marker:	Sensitivity:	Specificity:
Surface Ig (M +/- D, G, A)
CD10	>95%
CD5 (neg)
CD19, 20, 22, 79a
Bcl-2
Bcl-6
CD23 (neg)	Some positive
Cyclin D1 (neg)
Light chain restriction: (follicle centre cells) Kappa > lambda
CD43 (neg)
CD11c (neg)
CD25 (neg)

Molecular features:

• IgH and IgL gene rearrangements
• Extensive and ongoing somatic hypermutation of variable region genes
• May hamper primer binding for PCR (up to 40% of FL depending on primer set)
• BCL2 rearrangements:
• t(14;18)(q32;q21) (70-95%) (not totally specific)
• up to 90% of grade 1-2 FL
• much less frequent in grade 3B FL
• detected in PB of healthy donors (25-75%) and in reactive nodes
• particularly with sensitive nested or RT-PCR assays
• may be present normally in memory B cells
• breakpoints:
• 60-70% of cases the translocation occurs within the major breakpoint region (MBR) of bcl-2 on chromosome 18
• 25% have a breakpoint 20kb 3’ to MBR at the minor cluster region (MCR)
• UHN protocol tests for both of these breakpoints
• joins to chromosome 14 at one of six J segments of the immunoglobulin heavy chain locus
• thought to arise from a failed VDJ recombination
• variant breakpoints:
• 3’ BCL2 (12%)
• 5’ MCR (6%)
• also seen in:
• DLBCL
• ?CLL in addition to trisomy 12
• BCL2 rearrangements with light chains (rare)
• Breakpoints:
• 5’ end of BCL2 locus typically
• BCL6 rearrangements and or 3q27 abnormalities (5-15%)
• 10% in t(14;18) positive FL and grade 1 & 2 FL
• 55% in FL3b with a DLBCL
• FL-3B associated with DLBCL has rearrangement frequency similar to DLBCL
• Less frequently express BCL2 and CD10
• Various partners including IGH, IGK, IGL, and many others
• BLC6 promoter is substituted by the promotor of the partner
• Considerable heterogeneity of the breakpoints molecularly
• Differ in frequency between FL and DLBCL
• 1p36 deletions (~25%) (poor prognosis?):
• Grade 3 > grade 1/2
• Distinctive subtype of t(14;18) negative FL
• Predominantly diffuse growth pattern
• Other genetic alterations (90%)
• Number increases with grade and transformation
• Losses:
• 1p, 6q, 10q, 17p
• Gains:
• 1, 6p, 7, 8, 12q, X, 18q/dup
• Gains or amplifications of 18q11-q21 occurred in 32% of t(14;18) positive FLs but were not detectable in t(14;18)-negative FLs (Blood, 23 July 2009, Vol. 114, No. 4, pp. 826-834.)
• Transformation:
• MYC activation
• MYC translocations particularly
• TP53 inactivation
• p16^INK4a inactivation
• t(8;14) or t(2;8) or t(8;22) involving MYC and IGH or IGK or IGL (rare) (poor prognosis)
• often? seen at transformation
• t(8;14;18)(q24;q32;q21)
• recurrent aberration in FL progression
• MYC and BCL2 are deregulated from a common IG fragment between them

Other features:

• indolent course
• prognostic factors:
• IPI, particularly FLIPI
• Grade
• Grade 1-2 indolent, not usually curable
• Grade 3 significantly more aggressive
• Proliferation fraction
• Cytogenetics with worse prognosis:
• > 6 chromosomal breaks
• Complex karyotype
• del(6)(q23~26)
• del(17)(p)
• 1p-
• +12
• +18p
• +Xp
• t(14;18) and t(8;14)
• TP53 mutations
• Transformation (25-35%)
• DLBCL
• Burkitt or intermediate occasionally
• Usually rapidly progressive clinical course refractory to treatment and death
• B-ALL (rare)
• Histiocytic/dendritic cell sarcomas (?de-differentiation)

References:

• Essentials of Anatomic Pathology, 2^nd Ed (2006)
• Heim & Mitelman, Cancer Cytogenetics, 3^rd ed (2009)
• Swerdlow SH et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4^th ed. WHO Publications (2008).
• Leukemia (2005) 19, 1058–1063
• Blood, 23 July 2009, Vol. 114, No. 4, pp. 826-834.
• J Cancer Res Clin Oncol (2007) 133:455–470