LINFOMA B (INCLASIFICABLE) CON RASGOS INTERMEDIOS ENTRE LINFOMA DE BURKITT Y LINFOMA B DIFUSO DE CÉLULAS GRANDES.
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1 Congreso Nacional SEAP LINFOMA B (INCLASIFICABLE) CON RASGOS INTERMEDIOS ENTRE LINFOMA DE BURKITT Y LINFOMA B DIFUSO DE CÉLULAS GRANDES. Santiago Montes Moreno Servicio de Anatomía Patológica, HUMV Santander, España.
2 LARGE B CELL LYMPHOMA: FROM BL TO ACTIVATED B CELL TYPE DLBCL BURKITT LYMPHOMA I BL-DLBCL DLBCL
3 Hummel et al NEJM (2006), Dave et al. NEJM (2006), Love et al. Nature Genetics (2012) LARGE B CELL LYMPHOMA: FROM BL TO ACTIVATED B CELL TYPE DLBCL. BIOLOGY ID3 VPREB1 CD10 SOX11 SMARC4 LEF1 STAT3 CD44 NFKB1A
4 L di Lisio et al. unpublished data, L di Lisio et al BCJ 2012 LARGE B CELL LYMPHOMA: FROM BL TO ACTIVATED B CELL TYPE DLBCL. BIOLOGY BL I BL-DLBCL DLBCL
5 LARGE B CELL LYMPHOMA: FROM BL TO ACTIVATED B CELL TYPE DLBCL. BIOLOGY Love et al. Nature Genetics (2012)
6 B CELL LYMPHOMA UNCLASSIFIABLE WITH FEATURES INTERMEDIATE BETWEEN DLBCL AND BL. PATHOLOGY
7 CASE 1 53 years old male with a previous history of T cell large granular cell leukemia and sudden onset of cervical lymph node enlargement.
8 CD20 CD3 CD10 BCL6
9 KI67 BCL2 λ k MYC FISH (BA): C-MYC, BCL2, BCL6 NEGATIVE FOR TRANSLOCATIONS/GAINS.
10 CASE 2 36 years old male with multiple abdominal lymphadenopathies and infiltration of the gallbladder.
11
12 CD20 CD10 KI67 BCL2 FISH (BA): C-MYC AND BCL2 POSITIVE FOR TRANSLOCATION. DOUBLE HIT Wu et al. Am J Clin Pathol (2010), Johnson et al. Blood (2009)
13 CASE 3 46 year old female with large retroperitoneal mass.
14 CD20 CD10 C-MYC BCL2
15 KI-67 Kluk et al. PLOSone (2012)
16 C-MYC (clon Y69) 70% of MYC positive cells: 100% sensitivity, 93% specificity for MYC rearrangement. Ruzinova Am J Surg Pathol 2010, Green et al Am J Surg Pathol 2012
17 MYC and BCL2 immunohistochemical overexpression as surrogate markers for C-MYC and BCL2 alterations by FISH. Perry et al. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B- cell lymphoma and burkitt lymphoma: study of 39 cases. 79% cases strongly expressed BCL2 (44% had BCL2 rearrangements) Of 13 cases with BCL2 rearrangements 12 (92% expressed BCL2 protein) The median expression of C-MYC protein was 50% of the cells and, of the cases with MYC rearrangement. 69% had MYC protein expression in 50% of the cells. Copy number gains of MYC was associated with variable levels of MYC protein expression (10, 40, 80%). Hu et al. MYC/BCL2 protein co-expression is associated with high-risk gene signatures and contributes to the inferior prognosis of activated B-cell subtype of DLBCL. A report from the International DLBCL Rituximab-CHOP consortium Program Study. Blood N 700 (404 BCL2, 308 MYC) Rearrangement of the BCL2 gene was significantly associated with BCL2 protein expression (58/72 cases positive by IHQ, 81%, p<0.0001), 101/272 (37%) positive by IHQ were negative by FISH. Gain/amplification of BCL2 gene was also associated with BCL2 protein overexpression (73% p =00001). Rearrangement of the MYC gene was significantñy associated with MYC ptotein expression (27/31, 87%, p=0.0087). 175/274 (64%) positive by IHQ were negative by FISH. DLBCL with MYC/BCL2 co-expression had a higher frequency of MYC/BCL2 rearrangements (6% vs 0,4%, p= ) Problem with BCL2 mutated cases?. 124 clone vs E17 clone vs SP66 clone. Perry et al. BJH 2013, Hu et al Blood 2013
18 BURKITT LYMPHOMA I BL-DLBCL DLBCL MORPHOLOGY BL CD10+BCL6+BCL2- Ki67 >95% homogeneous. C-MYC + MORPHOLOGY ATYPICAL BL/BL-LIKE BLASTOID CD10+BCL6+ BCL2 + (~50%), C-MYC+ Ki67 usually >90% homogeneous (60-100%) MORPHOLOGY DLBCL GCB-ABC Ki67 usually <90% heterogeneous (30-100%). C-MYC (~60%). MYC SINGLE (IG) MYC 50% (non IG) OTHER OTHER (BCL %, BCL6 30%) MYC (10 %) (non IG) DOUBLE HIT/TRIPLE HIT (MYC+BCL2, MYC+BCL6, MYC+BCL2+BCL6)
19 DOUBLE HIT LYMPHOMAS. CYTOGENETICS. Aukema et al. Blood 2010
20 DOUBLE HIT LYMPHOMAS. CLINICAL FEATURES. Aukema et al. Blood 2010
21 DOUBLE HIT LYMPHOMAS. CLINICAL FEATURES. Snuderl et al. Am J Surg Pathol 2010, Li S, et al. Mod Pathol 2012.
22 DOUBLE HIT LYMPHOMAS. CLINICAL FEATURES. 23 cases DH BCL6/MYC 7 BL/DLBCL, 5 BL, 6 DLBCL, 1 PEL, 4 other. 10/13 cases involved extranodal extramedullary locations at diagnosis. Median survival 10 months. Pillai et al. Am J Surg Pathol 2013.
23 INTERMEDIATE BL/DLBCL LYMPHOMAS. CLINICAL FEATURES. Perry et al. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and burkitt lymphoma: study of 39 cases. Median age : 69 years Advanced stage disease (62%), high (3-5) International Prognostic Index Score (54%). Median OS was 9 months and 5 year OS was 30%. Genetic heterogeneity : double hit lymphomas, 11 cases (MYC&BCL2 8 cases, MYC&BCL6, 3 cases). MYC only, 6 cases (5 IGH-MYC, 1 MYC-IGL), BCL2 only (5 cases), BCL6 only (1 case). No abnormalities detected (7 cases). 5 cases with copy number changes without translocations. None of the immunohistochemical (Ki67, GCB phenotype 74%) nor genetic features was predictive of survival. Patients with low IPI scores (0-2) had a better survival than those with high scores (3-5). Perry et al. BJH 2013
24 INTERMEDIATE BL/DLBCL. TREATMENT OPTIONS.
25 B CELL LYMPHOMA WITH FEATURES INTERMEDIATE BETWEEN BL AND DLBCL. ITS BORDERS WITH DLBCL. BURKITT LYMPHOMA I BL-DLBCL DLBCL DLBCL with DH by FISH DLBCL with isolated MYC translocation DLBCL with coexpression of MYC and BCL2
26
27 CASE 4 30 year old female with autoimmune thyroiditis and a thyroid nodule. CD20 CD10 C-MYC ki67 BCL2 Edad <60 a, Estadio (I), LDH baja, ECOG 1, 1 sitio extranodal (MO neg). IPI bajo riesgo FISH BCL2 negativo.
28 MYC+ shorter time to CNS relapse. 35/245 (14%) MYC+ 26/35 (74%) MYC&BCL2 10/35 (26%) MYC&BCL6 7/35 TRIPLE HIT Savage et al Blood 2009 Barrans et al JCO 2010
29 C-MYC BCL2
30
31 Hu et al Blood 2013
32 Hu et al Blood 2013
33 Concurrent immunohistochemical expression of C-MYC and BCL2 proteins in DLBCL. PUBLICATION NUMBER OF PATIENTS AND THERAPY % FISH DH (C-MYC & BCL2) % IHQ DH CUTTOFF IHQ % PROGNOSTIC IMPACT (IHQ DH) Johnson et al. JCO R-CHOP 14/305 (5%) 64/305 (21%) MYC 40%, BCL2 50% HR OS T 1.9 (p 0.036), OS V 1.8 (P 0.048) HR PFS T 1.6 (p 0.13), PFS V 1.6 (p 0.067) Prognostic impact (OS) IPI y GCB-ABC, independent Green et al. JCO R-CHOP R- CHOP validation 21/189 (11%) 54/185 (29%) T MYC 40%, HR OS T 4.06 (p<0.001), OS V (P 0.078) 35/114 (30%) V BCL2 70% HR PFS T 2.79 (p<0.001), PFS V (p 0.008) IPI and GCB-ABC independent in T set, only for PFS in V Hu et al, Blood R-CHOP (466 T V) 10/394 (3%) T 157/466 (34%) T 74/234 (32%) V MYC 40%, BCL2 70% HR OS 2.52 (p<0.0001), PFS 2.45 (p<0.0001) Independent of B symptoms, IPI score, COO subtypes and tp53 mutation. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28): Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28): Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 protein co-expression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program Study. Blood
34 SUMMARY B cell lymphoma, unclassifiable with features intermediate between DLBCL and BL is a provisional category that comprises a heterogeneous group of neoplasms that do not fit in classical BL or conventional DLBCL categories. Allows for the classification of atypical cases (i.e BL-like in adults). Morphological features is the basis for the diagnosis and allows for the recognition of these tumours (WHO). Genetic and phenotypic diversity. Uniform DLBCL morphology excludes the diagnosis irrespective of the results of the IHC and molecular tests. Double hit agressive B cell lymphomas by FISH. Heterogeneous morphological features. IHQ scoring for C-MYC and BCL2 expression as an adequate surrogate for the screening of FISH abnormalities. It is recomended to incorporate FISH to confirm the suspected double hit cases in cases with overexpression of MYC and BCL2. FISH (BA): C-MYC, BCL2, BCL6 (+/-IGH). DLBCL with MYC and BCL2 coexpression. Particular gene expression signature GCB-ABC independent. Patients with poor prognosis when treated with RCHOP. B cell lymphoma, unclassifiable with features intermediate between DLBCL and BL, more common in adults with high risk clinical features and poor prognosis with conventional therapies including RCHOP. Patients require a personalized therapeutic approach based on clinical risk factors. Swerdlow et al WHO (2008), AM Perry et al, BJH
35 Santiago Montes Moreno
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