Monoclonal B-cell Lymphocytosis
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1 Entity Centred Approach Lymphoma Classification: WHO and Beyond Clinically meaningful categories Dr Stefan Dojcinov University Hospital of Wales, Cardiff WHO UPDATE - NEW ENTITIES Early lesions lymphoma in situ Age as a defining aspect Site specific impact Borderline Grey Zone categories Monoclonal B-cell Lymphocytosis Clonal population of CD5+ cells in healthy individuals (families with CLL) 3.5-5% population > 65 Stable condition 1%/year progression Phenotype identical to CLL Common 13q - Different usage of Ig repertoire (Marti Curr.Top.Microbiol.Immunol.12, 182: ) (Rawstron, Hematology.Am.Soc.Hematol.Educ.Program 200) New Criteria for CLL/SLL Follicular Lymphoma In Situ Definition based on B-cell count not absolute lymphocyte count Clonal B-cell lymphocytosis >5000 Extramedullary disease 1
2 Bcl-2 Cong et al. Blood. 2002;: Adam et al. Am J Surg Pathol 2005;2: Sotomayor et al. Exp Mol Pathol 83 (2007) Colonisation by clonal Bcl2+ cells Bcl-2 CD10 Follicular Lymphoma In Situ 70% of >50 IGH/BCL-2 + circulating cells BCL-2 rearrangement 1 st step Cells with immunological memory GC traffic and homing Additional genetic hits required for progression Follicular Lymphoma In Situ Follow up 28 patients (Jaffe et al, USCAP 2011) 80% No progression 14% Systemic FL at diagnosis 3% FL later (48 months) 3% DLBCL (48 months) Cong et al. Blood. 2002;: Adam et al. Am J Surg Pathol 2005;2: Sotomayor et al. Exp Mol Pathol 83 (2007) Follicular Lymphoma In Situ Partial LN involvement by FL Incidental findings Uncertain clinical significance No treatment CD10 New terminology Follicular Lymphoma Like B-cells of Uncertain Significance Bcl 2 2
3 Mantle Cell Lymphoma In Situ FL in Situ Partial Involvement Intact architecture Follicle size normal Follicles widely scattered Intact mantles Sharp edge BCL-2 uniformly strong Pure centrocytes Altered architecture Follicle size expanded Follicles clustered Absent mantle Blurred edge BCL-2 /CD10 not as strong Centrocytes and centroblasts Bassarova et al Virchows Arch 2008; 453: Richard et al. J Clin Pathol. 2006; 5():5-6 Espinet Human Pathol 2005; 36: Nodit et al. Human Pathology 2003; 34, (10):1030 Schlette et al. Mod Pathol 2001;14(11): Cyclin D1 Mantle Cell Lymphoma In Situ Other Borderline Lesions Minimal involvement by disease Small atypical circulating cells and lymphocytosis; splenomegaly Excellent prognosis VH mutated genotype SOX11 negative Extranodal T-cell & NK-cell Proliferations Reactive vs. Lymphoma? Cutaneous T-cell lymphomas Primary cutaneous CD4+ small medium T- cell LPD CD30+ LPD/ LYP SPTCL vs. Lupus panniculitis Indolent CD8+ T-cell proliferations of the gastrointestinal tract and NK-cell enteropathy Seroma associated ALCL Refractory celiac disease & chronic ulcerative jejunitis Seroma-associated anaplastic large cell lymphoma, ALK-negative Seen with a variety of breast implants, both saline and silicone Usually years after implant Symptoms: accumulation of seroma fluid in cavity surrounding the implant Diagnosis best made by cytology Cells grow within cavity and on surface of cavity lining, usually without invasion 3
4 CD30 Flow cytometry: Positive for CD30, CD2, CD25, CD4, partial CD7 Negative for: CD3, CD5, and B-cell markers. TCR PCR negative Biological Features Clonal TCR reported in most cases Indolent course, despite very atypical cytological features Roden et al. Mod Pathol, 2008 Therapy varies in literature Chemo, Radiation, Observation following removal Removal of implant is probably adequate therapy in most cases NK-cell Enteropathy An atypical proliferative lesion mimicking lymphoma Mansoor, A., S. et al. Blood 117: , cases: M:F 1:3; Median age 4 (27-70) Vague GI symptoms, but negative for celiac disease Superficial lesions with hemorrhage, edema, ulceration Lesions in stomach, small intestine, and colon 4
5 Colon biopsy CD56 CD56 Cytoplasmic CD3, EBV neg Negative for surface CD3 by flow cytometry CD3 Immunophenotype: NK-cell Enteropathy (8 cases) CD56 strongly + TIA-1+/ GrB+ ccd3+, CD7+, CD2 variable T-cell ag negative: CD4, CD8, CD5, BF1 PCR neg for TCR gene rearrangement EBV-negative PB and BM: normal in all six studied NK-cell Enteropathy - Follow Up Persistent but non-progressive disease in most patients (85%) Follow up for up to 10 years 3 patients had CHOP chemotherapy +/- auto BMT with recurrence following treatment but no progression 5
6 Indolent CD8+ T-cell LPDs of cutaneous and mucosal sites Indolent CD8+ lymphoid proliferation of the ear (Petrella et al, 2007) Dense, non-epidermotropic; Clonal Rx with local radiotherapy or excision Local recurrence in some, but no progression Indolent CD8+ lymphoid proliferation of GI tract (Egawa et al 15; Ranheim et al. 2000) Multiple mucosal and intestinal sites Relapsing but non-progressive 38 yo. male with lesion of ear CD8 CD8 Age as Significant Feature Paediatric Follicular Lymphoma Paediatric Marginal Zone Lymphoma EBV+ T-cell and NK cell lymphoproliferative disorders of childhood 38 yo male with lesions of stomach, sm bowel, colon over 2 yrs EBV+ B-cell LPD of elderly Paediatric Follicular Lymphoma First 2 decades of life Tonsil, GI tract, neck nodes, testis Male preponderance Localised disease / indolent course FL Grade 3B morphology Bcl2-, BCL2 not rearranged 6
7 Paediatric Marginal Zone Lymphoma First 2 decades Strong male preponderance Neck nodes Association with PTGC Localised Indolent course CD10 Bcl-2 Taddese-Heath et al Am J Surg Pathol, Vol. 27, No. 4, 2003 Immunosenescence Natural decay of the immune system taking place with ageing Oyama et al. Am J Surg Path 27(1): 16-26, 2003 Immunosuppression due to Immunosenescence >60 EBV+ Diffuse Large (and polymorphous ) B-cell Lymphoma of the Elderly Extranodal presentation Poor prognosis Oyama, T., et al. Clin.Cancer Res (2007): Shimoyama, Y. J.Clin.Exp.Hematop (2006):
8 T-cell Competence 20 million specificities in young age 100 fold reduction in old age Cell numbers remain the same ¾ reactivity to persistent viruses (CMV & EBV) Olsson J, Wikby A, Johansson B, et al. Mech Ageing Dev. 2000;121: Ouyang Q, Wagner WM, Zheng W, et al. Exp Gerontol. 2004;3: Vescovini R, Telera A, Fagnoni FF, et al. Exp Gerontol. 2004;3: Wikby A, Johansson B, Olsson J, et al. Exp Gerontol. 2002;37: CD20 CD30 PAX5 Oct-2 BOB-1 CD15 68% Polymorphous PTLD Polymorphous Age Related Lymphoma Age Related EBV+ B-cell LPD Median survival Poly N 27 m DLBCL 24 m Dojcinov et al. Blood. 2011;117(18):
9 EBV+ Mucocutaneous Ulcer Localised Ulcerating Mucosal and Cutaneous Lesions Immunosenescence Iatrogenic systemic IS (SLE, Sarcoidosis, RA, IBD, Transplant) HIV Dojcinov et al. Am J Surg Pathol 2010; 34: Methotrexate Cyclosporin A Azathioprine MMF Topical steroid treatment EBER
10 CD45 CD30 CD15 (43%) CD20 Pax5 Oct2 BOB1 EBER July 2012 September 2012, 4 weeks post diagnosis November 2012, weeks post diagnosis Impact of Anatomical Site on Disease Definition Intestinal follicular lymphoma Cutaneous follicular lymphoma Diffuse large B-cell lymphoma of leg Intestinal Follicular Lymphoma Polypoid duodenal lesions t(14;18)+ Mucosa specific homing IgA+ integrin alpha-4-beta-7 Local recurrences Indolent clinical course Overlap with FL in situ Yoshino et al Am J Surg Pathol : Poggi et al J Clin Gastroenterol Feb;34:155- Bende et al Am J Pathol 2003, 162: Damaj et al Annals of Oncology 2003, 14: Bcl2 CD10 10
11 Cutaneous Follicle Centre Lymphoma Diffuse Large B-cell Lymphoma Leg Type Cutaneous FCL Phenotype LBCL of Leg Type Borderline and Overlapping Categories Burkitt lymphoma and DLBCL Hodgkin lymphoma and DLBCL CD10 Bcl2 MUM1 CD10 Bcl2 MUM1 B-cell Lymphoma with Features Intermediate Between DLBCL and chl Epigenetic Profile Oct2 CD20 CD30 CD15 Eberle et al. Haematologica 2011; 6(4):
12 Progression-Free Survival (%) PMBL vs MGZL (EPOCH-R) B-cell Lymphoma, unclassifiable, with features intermediate between DLBCL and BL PMBL MGZL Poor outcomes Salvage Radiotherapy Morphology intermediate between BL and DLBCL Typical morphology but atypical phenotype Double hit lymphomas P< Years on study Dunleavy et al. ASH 200 Exclude typical DLBCL morphology +MYC Exclude atypical BL morphology with the right phenotype and genotype Classical Burkitt Lymphoma CD20 CD3 CD10 bcl2 Ki67 CD10 1 Bcl 2 CD20 CD10 Bcl2 Ki67 Ki67 IgH / 12
13 CD10 Bcl 2 Ki67 1 IgH / IgH / c- p53 TdT CD10 Bcl 2 Ki67 Role of BCL2 and MYC IHC DLBCL with MYC 6-8% MYC expression 30% Non-translocation related epigenetic mechanism of MYC upregulation Non-GC DLBCL particularly affected BCL2 and MYC co-expression independent pathological prognostic marker (15% of high IPI DLBCL with extremely poor prognosis) Epitomics MYC, 1/50, MYC and BCL2 rearranged lymphoma Epitomics MYC, 1/50, MYC multiple copies (DLBCL non-germinal centre) Acknowledgements Dr Elaine Jaffe, NCI Dr Eve Gallop-Evans 13
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