follicularlymphoma-250226084110-f8ddff79.pptx

Follicular lymphoma new classification hematolymphoid who 5

1. Follicular lymphoma Dr. Yasmin M. AlSaidat, M.D.

2. In-Situ Follicular B-Cell Neoplasm Essential and desirable diagnostic criteria Essential : - Variable numbers of B-cells within germinal centres staining intensely for BCL2. - Maintained lymph node or extranodal lymphoid tissue architecture, and lacking features of classic FL . Desirable : - Strong CD10 expression in the BCL2-positive B-cells within the follicles.

3. In-situ follicular B-cell neoplasm -Strong aberrant reactivity for BCL2 in two germinal centers showing a slightly stronger staining than the surrounding marginal zone B- and T-cells. -The overall nodal architecture is well preserved. - CD10 expression—in contrast with reactive follicles—is also unusually strong.

4. In-Situ Follicular B-Cell Neoplasm In the vast majority of cases, no subsequent FL will develop; however, in some patients, staging procedures reveal concurrent established FL or other types of lymphoma such as mantle cell lymphoma or chronic lymphocytic leukemia . Only a small number of patients will ever develop FL or other types of lymphoma subsequent to the diagnosis of ISFN.

5. Conceptually, ISFN maybe be viewed as the first recognizable tissue manifestation of circulating t(14;18)-positive FL-like B-cells that already have acquired additional mutations. In addition, mutations in CREBBP, KMT2D und TNFRSF14, deletions in 1p36, and acquisition of N-glycosylation sites have been reported. Cases of FL that are preceded by an ISFN have acquired additional mutations to those already present in the ISFN such as in EZH2 . Up to now, no t(14;18)-negative ISFN has been reported.

6. Follicular lymphoma Definition Follicular lymphoma (FL) is a neoplasm of germinal centre B-cells with varying proportions of centrocytes (CC) and centroblasts (CB) or large transformed cells and at least a partially follicular growth pattern. In rare cases with an entirely diffuse growth pattern, the neoplastic cells should still show germinal centre B-cell morphology and immunophenotype.

7. Essential and desirable diagnostic criteria Essential : B-cell lymphoma composed of varying proportions of centrocytes (CC) and/or centroblasts (CB)/large transformed cells, with the dominance of CC in the overwhelming majority of cases. Immunophenotype compatible with germinal center B-cell origin with positivity to markers such as CD10, BCL6, MEF2B, GCET1, GCET2 or LMO2 Desirable : At least partly follicular growth pattern BCL2

8. Localization Predominantly lymph nodes. Involvement of spleen and bone marrow is frequent. More commonly affected sites: Gastrointestinal tract, soft tissue, thoracic vertebrae, breast, ocular adnexa. Rarely Waldeyer’s ring and peripheral blood.

9. Clinical features and epdemiology Most patients have widespread disease at diagnosis. BM involvement : 40-70%. Often asymptomatic. account fo r10-20% of all lymphomas. predominantly affect adult , median age 65 years. No sex predilection (slight male predominance).

10. Etiology Unknown. Agricultural exposure to malathion and dichlorodiphenyltrichoroethane, cigarette smoking in females, occupational spray painters, hepatitis C virus infection and Sjögren’s syndrome have been associated with an increased risk. For younger patients, obesity and having a first-degree relative with FL, NHL or haematological malignancieshave been reported as risk factors

11. Pathogenesis FL with BCL2 rearrangement (BCL2-R FL), 85-90% of cFL. FL with BCL6 rearrangement (BCL6-R FL), Their frequency is 15-20% in BCL2-R FL Higher (about 35%) in FLs lacking BCL2 rearrangement. In FLBCL, structural alterations involving BCL6 can be found in about 40% Closer biological relationship to DLBCL. FL lacking BCL2 and BCL6 rearrangements 10-15% of cFL STAT6 (more than 50%). KMT2D (less frequently).

12. Macroscopic appearance Vaguely nodular pattern. Splenicinvolvement by FL shows a uniform expansion of the white pulp.

13. Histopathology 1) Classic Follicular lymphoma (FL) 2) Follicular large B-cell lymphoma (FLBCL) 3) FL with uncommon features (uFL)

14. 1) Classic Follicular lymphoma (FL) CCs and CBs are located mostly within the neoplastic follicles but are often found between and outside the follicles as well. Patterns: Most cases present with at least a focal follicular pattern identifiable by morphology but may be facilitated by immunostaining. Spread beyond the nodal capsule is often associated with sclerosis or diffuse areas. Most neoplastic follicles display attenuated or absent mantle zones, with ill defined borders. They usually lack polarization of the GCs. The ‘starry-sky’ pattern is usually not seen. Massive necrosis can be found in rare cases but does not necessarily indicate transformation. In the BM, paratrabecular infiltration is typical for FL, although interstitial areas may be also involved.

15. Immunophenotype FL cells express B-cell antigens (CD19, CD20, CD22, CD79a, PAX-5). They also express GC-associated markers CD10, BCL6, GCET1, HGAL (GCET2), LMO2, AID, MEF2B, and Stathmin.

16. Classic FL This is a typical example of classic FL (FL grade 1/2 ) with a predominance of centrocytes (red arrows) and only a few interspersed centroblasts (black arrows). In this example, the number of large, transformed cells (centroblasts, black arrows) is distinctly higher (>15 centroblasts per high-power-field (FL grade 3A according to WHO-HEAM4R), however, centrocytes (red arrows) are still present.

17. 2) Follicular large B-cell lymphoma (FLBCL) FLBCL (formerly FL grade 3B) is commonly regarded as a particular subtype of FL with a close clinical and biological relationship to DLBCL. FLBCL is defined by the presence of a follicular pattern with follicles composed of ‘sheets’ of centroblasts and absence of centrocytes. BCL2 translocation isuncommon. FLBCL rarely coexists with cFL, but frequently coexists with DLBCL. Due to the extreme rarity of pure FLBCL, the possibility of concurrent DLBCL must be excluded by careful sampling. Therefore, a definite diagnosis of this entity should not be made on a needle core biopsy. A presumptive diagnosis of FLBCL should prompt additional investigations, such as BCL6 or MYC rearrangement. IRF4 FISH analysis is required if MUM1 is strongly expressed, to exclude LBCL with IRF4 rearrangement.

18. 3) FL with uncommon features (uFL) FL with unusual cytological features: In rare cases, FL may be composed of predominantly mediumsized cells with immature or blastoid chromatin. Other infrequent morphologies include large cells with cleaved/irregular nuclei, i.e., so-called “large centrocytes”. The prognosis of these cases may differ from cFL. FL with predominantly diffuse growth pattern: A diffuse pattern ( supported by the absence of demonstrable FDCs). BCL2 immunostaining is often weak to absent in remnant follicles. Sclerosis and interstitial fibrosismay be observed. DFL mainly occurs in the inguinal region and may form large tumour masses. Infrequently disseminates. Patients often present with limited stage disease and have a favourableprognosis. Neoplastic cells are usually positive for CD10 and CD23, but CD10 expression may be absent. Although not specific, 1p36 deletion and mutations in STAT6 are more frequently observed.

19. Follicular lymphoma with unusual cytological features -There is a predominance of small to medium-sized blastoid cells with round nuclei, finely dispersed chromatin and in part small nucleoli. -Note the increased number of mitotic figures. -This case had a proliferation index of 80%.

20. Grading Traditional Optional!

21. Prognosis cFL is an indolent disease with a median survival of >17 years with current therapies. Histologic transformation of FL to DLBCL occurs at a risk of 1-3% per year. The median time to transformation is 2.5 - 4.1 years.

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23. Paediatric-type follicular lymphoma Definition Localized, nodal mature B-cell lymphoma occurring predominantly in the paediatric and adolescent age group. It is characterized by a clonal proliferation of germinal centre B-cells with a pure follicular growth pattern, altered lymph nodal architecture, a high proliferation index, and absence of BCL2, BCL6, and IRF4 rearrangements.

24. Pediatric-type follicular lymphoma (PTFL) Essential and desirable diagnostic criteria Essential - Paediatric and young adult age group (usually age <40 years, most 2-25 years) - Localized nodal disease - Purely follicular growth with marked architectural distortion and germinal center marker expression - Predominance of intermediate to large-sized ‘ blastoid’cells and high proliferation fraction - Absence of diffuse proliferation of large cells meeting criteria for DLBCL - Evidence of B-cell monoclonality by immunophenotyping or genetics - Absence of BCL2 , BCL6 , and MYC rearrangements - Absence of strong, uniform MUM1 expression and/or absence of IRF4 rearrangement Desirable - Markedly expansile follicles - Mutations in MAP2K1 and TNFRSF14

25. Localization Virtually all cases of PTFL manifest as limited-stage peripheral lymphadenopathy. Most patients present with a single enlarged lymph node in the head and neck region or, less commonly, an enlarged inguinal, femoral, or axillary lymph node. Para-aortic and mesenteric lymph node involvement has not been reported. Extranodal presentation is excluded by definition.

26. Clinical features and Epidemiology Most patients present with localized painless lymph node enlargement without B symptoms. Most patients are adolescents or young adults, 8 to 36 years of age (median, 18 years) but patients aged up to 60 years have been reported. There is a marked male predominance, with a male to female ratio of >10:1. PTFL accounts for 1-2% of childhood non-Hodgkin lymphomas.

27. Pathogenesis PTFL shows low genomic complexity and lacks translocations found in other germinal centre-derived lymphomas (e.g. BCL2, BCL6, MYC). PTFL also lacks IRF4 rearrangements that characterize large B-cell lymphoma with IRF4 rearrangement. Recurrent alterations in PTFL include deletions and copy-neutral loss of heterozygosity at 1p36 (including TNFRSF14; 25-40%) and mutations of TNFRSF14 (44-54%) and MAP2K1 (43-49%). A hot-spot mutation affecting IRF8 has also been reported.

28. Macroscopic appearance Enlarged lymph node without sclerosis or necrosis.

29. Histopathology The normal lymph node architecture is extensively altered by atypical, enlarged and, sometimes floral, serpiginous, or confluent follicles. Mantle zones are attenuated or absent. Germinal centers are expansile, often lack zonation, but contain tingible body macrophages. A rim of residual reactive lymph nodal tissue is frequent, “node-in-node” phenomenon. PTFL usually consists of medium to large 'blastoid cells', cytologically intermediate between centrocytes and centroblasts. Any diffuse area of large cells consistent with a diffuse large B-cell lymphoma will exclude a diagnosis of PTFL .

30. Immunophenotype The neoplastic cells co-express B-cell markers (e.g., CD20, CD79a, and PAX5) and germinal center markers (e.g., BCL6 and CD10, with CD10 expression being frequently strong). These markers, together with CD21- and CD23-positive follicular dendric cell meshworks, highlight the pure follicular architecture and restriction of the neoplastic cells to the follicles, and the relative absence of neoplastic cells in interfollicular areas. The neoplastic germinal center B-cells are negative for BCL2 in most cases, although weak or partial BCL2 expression might be seen. Neoplastic cells are also negative for IRF4/MUM1. The Ki-67 proliferation index is usually >30%, and the proliferating cells often lack polarity.

31. Diagnostic molecular pathology A monoclonal IG gene rearrangement can be detected in nearly all cases and is helpful in the differential diagnosis from florid reactive follicular hyperplasia. Exclusion of BCL2, BCL6 and MYC translocations by fluorescence in-situ hybridization is required for the diagnosis of PTFL. IRF4 FISH should additionally be performed to rule out large B cell lymphoma with IRF4 translocation, in cases where neoplastic cells show strong uniform MUM1 expression.

32. Prognosis and prediction PTFL does not necessarily require chemotherapy due to an overall excellent outcome. Survival rates exceed 95%. Based on the available literature, watch and wait after complete excision of localized disease (performed at diagnosis or after a diagnostic biopsy) is considered an adequate therapeutic approach.

33. Duodenal-type follicular lymphoma Definition Duodenal-type follicular lymphoma (DFL) is a variant of follicular lymphoma restricted to the intestine, mainly to the second portion of the duodenum. It is a neoplasm of germinal centre B cells showing follicular architecture and is mostly limited to the mucosa. They are of low histological grade and have an indolent clinical course and excellent outcomes

34. Duodenal-type follicular lymphoma Essential and desirable diagnostic criteria Essential : Germinal centre B-cell lymphoma with tumour cells confined predominantly to the mucosa of the intestine, and characterized by follicles composed predominantly of centrocytes , and with positivity for germinal center markers and BCL2. Desirable : Exclusion of secondary involvement

35. Localization DFL is particularly common in the second (descending) portion of the duodenum. In most cases, there are additional lesions throughout the small intestine and, less commonly, in the stomach, colon, and rectum.

36. Clinical features and Epidemiology Patients are asymptomatic. The disease is usually incidentally discovered on endoscopy performed routinely or for other reasons. The majority have localized disease (stage IE) Endosonography is often negative or shows restriction of the process to the mucosa and submucosa. DFL accounts for about 4% of all gastrointestinal lymphomas. Median age of patient is 52 – 65 years in larger retrospective series. While some studies show a female predominance, others show no sex predilection..

37. Pathogenesis DFL shows many similarities with early pathogenetic steps of nodal/systemic FL pathogenesis in that t(14;18)(q32;q21) (IGH::BCL2) and recurrent mutations in TNFRSF14, EZH2, KMT2D, and/or CREBBP genes are found in almost all cases. However, DFL displays a lower frequency of KMT2D mutations, especially of multiple mutations, compared to nodal/systemic FL, as well as lower genetic complexity.Virtually all cases show decreased expression of Activation-Induced cytidine Deaminase (AID) compared to nodal/systemic FL.

38. Macroscopic appearance Most patients present with grey to whitish granular lesions or small nodules on endoscopy.

39. Histopathology The lymphoid infiltrate with a follicular pattern is located mainly in the mucosa, but may show minimal submucosal extension. The follicles are composed of small to medium-sized centrocytes, morphologically similar to those seen in classic follicular lymphoma, specifically grade 1-2. Tumour cells often invade into the villi beyond the follicles, and the enlarged villi may show a "glove balloon sign".

40. Immunophenotype Similar to nodal/systemic FL

41. Prognosis and prediction The prognosis is excellent.

42. Primary cutaneous follicle centre lymphoma Definition Primary cutaneous follicle centre lymphoma (PCFCL) is a tumour of follicle centre cells, including centrocytes and variable numbers of centroblasts, with a follicular, follicular and diffuse, or diffuse growth pattern, that generally presents in the skin of the head or trunk.

43. Primary cutaneous follicle center lymphoma Essential and desirable diagnostic criteria Essential: - Follicular and/or diffuse proliferation of centrocytes and admixed centroblasts (diffuse lymphomas comprising exclusively centroblasts / immunoblasts are excluded) - B cells with co-expression of germinal center markers (BCL6 and/or CD10 or other germinal centre markers) - No extracutaneous involvement by lymphoma Desirable: - Localization to head or trunk - Evidence of B-cell monoclonality - Absent or weak BCL2 expression (usually) - Lack of MUM1 expression - Lack of BCL2 rearrangement (usually)

44. Localization PCFCL characteristically presents with solitary or localized skin lesions on the head/neck or the trunk. Approximately 5% present with skin lesions on the legs, and 15% with multifocal skin lesions.

45. Clinical features Patients present with firm erythematous to violaceous non-ulcerating plaques, nodules or tumours of variable size. Particularly on the trunk, tumours may be surrounded by erythematous papules and slightly infiltrated, sometimes figurate plaques, which may precede the development of tumourous lesions by months or years.

46. Epidemiology PCFCL makes up approximately 50% of primary cutaneous B-cell lymphomas and 10% of all primary cutaneous lymphomas. It mainly affects middle-aged adults with a male to female ratio of approximately 1.5:1.

47. Pathogenesis PCFCL is a monoclonal proliferation of germinal center-derived B cells, which harbour clonally rearranged immunoglobulin genes, with somatic hypermutation. In most studies, cases of PCFCL with disease limited to skin on staging rarely show BCL2 rearrangements. The presence of BCL2 rearrangements at diagnosis is associated with a higher risk of later systemic spread. Deletion of chromosome 14q32.33 containing the oncogene AKT1, as well as the immunoglobulin heavy chain locus has been reported. PCFCL harbours mutations in CREBBP (25%), KTM2D (21%), and BCL2 (0%) much less frequently than in classic FL, in which these genes are frequently mutated.

48. Histopathology PCFCL shows perivascular and periadnexal, or diffuse infiltrates with sparing of the epidermis. The infiltrates may show a follicular, follicular, and diffuse or diffuse growth pattern. Histologic grading is not applicable in PCFCL. The Ki-67 proliferative fraction in diffuse primary cutaneous follicle centre lymphomas is generally high.

49. Immunophenotype The neoplastic cells express CD20 and CD79a but are usually Ig negative. PCFCL consistently expresses BCL6. CD10 may be positive in cases with a follicular growth pattern but is generally negative in cases with a diffuse growth pattern. A disrupted meshwork of CD21+/CD35+ follicular dendritic cells is frequently seen in the atypical follicles but might be absent in cases with a diffuse growth pattern.. Most cases do not express BCL2 or show faint BCL2 staining (weaker than admixed T cells). several studies have reported BCL2 expression in 8.5-61% of PCFCL. Staining for MUM1 and FOXP1 are negative in most cases, while CD5 and CD43 are always negative.

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