Mature Lymphoproliferative disorders (2): Mature B-cell Neoplasms. Dr. Douaa Mohammed Sayed

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1 Mature Lymphoproliferative disorders (2): Mature B-cell Neoplasms Dr. Douaa Mohammed Sayed

2 Small lymphocytic lymphoma/b-cell chronic lymphocytic leukemia

3 BMB: nodular, interstitial, diffuse or a combination of the three CLL atypical morphology

4 Scoring System for the diagnosis of CLL Marker 1 0 SmIg Weak Moder/strong CD5 positive negative CD23 positive negative FMC7 negative positive mcd22,cd79b Weak Moder/strong

5 Scores in B-lymphoproliferative disorders Scores CLL Other B-cell leukemia B-NHL 5 52% 0% 0% 4 35% 0% 0.5% 3 10% 1% 4% 2 3% 10% 23% 1 0.2% 33% 39% 0 0.2% 56% 33%

6 CLL cases may arise from a pre germinal center cell with unmutated IgVH genes or from post germinal center cell with mutated IgVH gene. These represent 2 groups with 2 different prognosis and survival, worse in the unmutated type. CLL cases with >30% CD38 +ve cells have shorter survival and more aggressive course. ZAP 70: intracytoplasmic protein correlated closely with IgVH gene mutation status.

7 The molecular pathogenesis of SLL/B-CLL is largely unknown. None known to date has been shown to associate selectively with SLL/B-CLL. Deletions of chromosome 13q14 occur in approximately 60%, but tumor suppressor gene involved has not been identified Mutations of p53 occur in 10% of cases and the frequency increases substantially in late stages of the disease, suggesting that it may be involved in tumor progression.

8 Prognosis and predictive factors Clinical course is indolent. CLL/PL and diffuse BM involvement Rapid lymphocyte doubling time (<12 months) Trisomy 12 Germline VH regions Expression of CD38 or ZAP 70 Poor prognosis Transformation to high grade lymphoma (Richter Syndrome) in 3.5% of cases mostly to DLBL

9 BMB: diffuse infiltration B-PLL

10 B-PLL Marker SmIg PLL Strong CD5 -/+ Pan-B ++ CD23 neg FMC7 ++ CD22 ++ Poor response to therapy and short survival CD79b ++ CD25 neg CD103 neg

11 Lymphoplasmacytic lymphoma Associated with HCV infection Nodular and/or a diffuse interstitial infiltration. Express pan B marker, surface and cytoplasmic IgM, negative for CD5,CD23 and CD10 Clinical course is indolent. Transformation into DLBL is rare and associated with poor survival.

12 Lymphoplasmacytic lymphoma 50% associate with the t(9;14)(p13;q32). Translocation preferential with Waldenström s macroglobulinemia. PAX-5 encodes a B-cell specific transcription factor involved in the control of proliferation and differentiation. Ig heavy chain on chromosome 14.

13 SLVL In the BM there is a nodular interstitial infiltrate Intrasinusoidal lymphoma cells are characteristic. In blood lymphoma cells characterized by short polar villi, some may appear plasmacytoid Clinical course is indolent.

14 SLVL Marker SLVL SmIg Strong CD5 -/+ Pan-B ++ CD23 -/+ FMC7 ++ CD22 ++ CD79b +/++ CD25 -/+ CD103 -/+

15 Hairy cell Leukemia Pancytopenia and splenomegaly Monocytopenia is characteristic Hairy cells: oval or indented (bean-shaped) nucleus, nucleoli are absent with circumferential hairy projections TRAP positive BMB: fried egg appearance Increase reticulin fibers results in a dry tap Production of cytokines cause hematopoitic suppression

16 Hairy cell Leukemia Marker SmIg CD5 HCL Strong neg Pan-B ++ CD23 neg FMC7 ++ CD22 ++ CD79b + CD25 ++ CD103 ++

17 HCL-V Rare disease Circulating cells: round nucleus and prominent nucleols and moderately basophilic villous cytoplasm. High WBC No monocytopenia

18 HCL-V Marker HCL-V SmIg Strong CD5 neg Pan-B ++ CD23 neg FMC7 ++ CD22 ++ CD79b + CD25 neg CD103 +

19 Scoring System for the diagnosis of HCL Marker 1 0 CD11c positive negative CD25 positive negative HC2 positive negative CD103 positive negative

20 Scores in B-cell disorders with hairy lymphocytes Scores HCL HCL-variant SLVL 4 87% 0% 0% 3 11% 0% 0% 2 2% 44% 22% 1 0% 44% 55% 0 0% 12% 23%

21 Mucosa-associated lymphoid tissue (MALT) lymphoma In case of gastric MALT lymphoma, the majority associated with Helicobacter pylori infection. The most common genetic alteration of MALT is t(11;18). Fuses API2 gene, encoding an inhibitor of apoptosis, to MLT gene, generating a novel fusion protein with antiapoptotic functions. More rarely, t(1;14) leads to transcriptional deregulation of the BCL-10 gene, a negative regulator of apoptosis. BCL-6 rearrangements and p53 mutations have detected at very low frequency. Several abnormalities involved in these tumors, including trisomy 3.

22 Follicular Lymphomas The pattern is reported as: Follicular (>75% follicular) Follicular and diffuse (25-75% follicular Or minimally follicular (<25% follicular) Interfollicular involvement by neoplastic cells is common and does not constitute a diffuse pattern

23 Follicular Lymphomas Two types of cells: Small to medium sized centrocytes or cleaved FCC. Large transformed cells known as centroblasts or noncleaved FCC. Centrocytes typically predominate. FL is graded by the proportion of ccentroblast.

24 Follicular Lymphoma Marker FL SmIg Strong CD5 -/+ Pan-B ++ CD23 -/+ FMC7 ++ CD22 ++ CD79b +/++ CD25 neg CD10 ++

25 Follicular Lymphomas t(14;18)(q32;q31). Present in 85-90% of follicular lymphomas. bcl-2 on chromosome 18, regulator of apoptosis. Ig heavy chain on chromosome 14. BCL-2 controls the cellular apoptotic. Thus, deregulation of BCL-2 expression lead to the abnormal survival of B cells with accumulation of additional genetic lesions.

26

27 Follicular Lymphomas Deletions of chromosome 6 at 6q27 in 20% of cases. Significant fraction of FL evolves into DLBL. This transformation is frequently associated with p53 mutations/deletions. In some cases, transformation is accompanied by inactivation of p16 by deletion, mutation or hypermethylation. In rare cases, the progression of FL involves c-myc rearrangements or 6q deletions.

28 Mantle Cell Lymphoma Monomorphic lymphoid proliferation with nodular, diffuse or mantle zone growth pattern CD5 and FMC7 +ve, CD10 and CD23 ve cyclin D1 +ve and bcl-6 -ve t(11;14)(q13;q32) bcl-1 or PRAD oncogene encoding cyclin D1 protein on chromosome 11, regulates cell division. Ig heavy chain region on chromosome 14.

29 Diffuse large B-cell lymphoma (DLBCL) DLBCL is characterized by a marked heterogeneity in phenotype and clinical behavior. The genetic lesions associated with DLBCL are also heterogeneous. Aggressive but potentially curable

30 DLBCL Morphologic variants: Centroblastic Immunoblastic T-cell/histiocyte rich Anaplastic Immunophenotyping: Surface and/or cyt Ig CD30 in anaplastic Some express CD5 or CD10

31 DLBCL BCL-6 gene involved in the majority of DLBCL cases. BCL-6 is a transcription factor containing zincfingers, and functions by inhibiting the expression of genes carrying its specific DNA-binding motif. Within the B cell lineage, BCL-6 expression is restricted to the GC, and is required for GC formation. Up to 75% of DLBCL display multiple somatic mutations clustering in the BCL-6, suggesting that some mutations may be selected for their ability to alter its transcriptional regulation

32 DLBCL

33 Burkitt s lymphoma Large round cells with deeply basophilic cytoplasm and vacuoles. Three clinical variants: Endemic (Africa, Jaw) Sporadic ( abdominal mass Immunodeficiency associated Express membrane IgM with light chain restriction and CD10 bcl-6

34 Burkitt s Lymphoma Associated chromosomal translocations include t(8;14), t(2;8), t(8;22). t(8;14)(q24;q32) c-myc to IgH t(8;22)(q24;q11) c-myc to Igλ t(2;8)(p11;q24) Igκ to c-myc C-myc product regulates gene transcription.

35 Burkitt s Lymphoma c-myc breakpoint differs in sporadic and endemic Burkitt s. Epstein-Barr Virus: 97% of endemic Burkitt s % of sporadic cases.

36 Burkitt s Lymphoma Several lines of experimental evidence document that deregulated expression of c-myc can influence the growth of B-cells in vitro and in vivo. Other genetic lesions of BL: - Infection by EBV: The consistent monoclonality of EBV infection in BL suggests that infection precedes clonal expansion of the tumor, consistent with a pathogenetic role of the virus. Notably, however, BL cells fail to express the EBV transforming antigens LMP-1 and EBNA-2, rendering the role of EBV infection unclear.

37 -Inactivation of p53 is detected in approximately 30-40% of BL cases, independent of their geographic origin or of the presence of EBV infection. -Inactivation of p16 occurs in 30-40% of BL through mutation, deletion or hypermethylation. -As in many other NHL types, BL is also associated with deletions of 6q.

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