WHO Classification Defines separate diseases (entities) with their CLINICAL AGGRESSIVENESS REVIEW OF MOST COMMON LYMPHOMA ENTITIES Dr Stefan Dojcinov LOW GRADE / HIGH GRADE (June 2014) The Non-Hodgkin Lymphoma Classification Project. Blood (1997) 89: 3909-3918 REAL/WHO Classification The REAL/WHO classification recognises distinct clinico-pathological entities Diagnosis is based on: Clinical findings Morphology Immunophenotype Genotype Lymphoma Entities AWLP File (%) NHL T-cell with features of angioimmunoblastic T cell lymphoma NHL T-cell prolymphocytic leukaemia NHL T-cell Monoclonal intraepithelial intestinal T-cell proliferation NHL T-cell hepatosplenic NHL T cell lymphoma - cutaneous NOS NHL Primary cutaneous diffuse large B-cell lymphoma - leg type NHL Plasmablastic lymphoma NHL peripheral T-cell Subcutaneous panniculitis-like NHL peripheral T-cell lymphoma, NOS EBV+ NHL peripheral T-cell Lymphoma, Lennert's type NHL Peripheral T-cell lymphoma (NOS) NHL Peripheral T-cell follicular type NHL NK/T cell lymphoma, nasal type NHL NK/T Cell leukaemia / lymphoma NHL Mycosis fungoides Pagetoid reticulosis NHL Mycosis fungoides large cell transformation NHL Mycosis fungoides folliculotropic NHL Mycosis fungoides NHL Large gralular lymphocyte leukaemia/lymphoma NHL Enteropathy type T-cell lymphoma, type 1 NHL Enteropathy type T-cell lymphoma NHL EBV+ T-cell lymphoproliferative disorder of childhood NHL cutaneous gama / delta T-cell lymphoma NHL Cutaneous + T-cell lymphoproliferation NHL Angioimmunoblastic T-cell lymphoma and EBV+ DLBCL NHL Angioimmunoblastic T-cell lymphoma NHL Anaplastic large cell (T/null-cell) ALK1+ NHL Anaplastic large cell (T/null-cell) ALK1- NHL Anaplastic large cell (T/null) - NOS PTLD HL nodular lymphocyte predominant HL classical Hodgkin lymphoma NHL Non-aggressive (low grade) B-cell (NOS) NHL B-cell NOS NHL Aggressive (high grade) B-cell lymphoma (NOS) NHL T-cell-rich B-cell Lymphoma NHL T cell adult leukaemia/lymphoma HTLV1+ NHL Splenic diffuse red pulp BCL NHL Primary effusion B-cell lymphoma NHL Precursor T-cell (Lymphoblastic) Lymphoma/Leukaemia NHL Precursor B-cell (Lymphoblastic) leukaemia/lymphoma NHL Plasmacytoma/Myeloma NHL Plasmablastic lymphoma, microlymphoma HIV associated NHL Mediastinal Large B-cell Lymphoma NHL Marginal zone lymphoma - splenic NHL Marginal zone lymphoma - NOS NHL Marginal Zone Lymphoma - MALT type NHL Marginal zone B-cell lymphoma (nodal) NHL Marginal zone B-cell lymphoma (cutaneous) NHL Mantle cell lymphoma NHL Lymphatoid granulomatosis NHL Large B-cell lymphoma Sinusoidal + NHL Large B-cell lymphoma of the elderly NHL Large B-cell lymphoma ALK1+ NHL Intravascular lymphoma NHL Hairy cell leukaemia NHL Folliculr lymphoma - paediatric type NHL Follicular lymphoma in situ NHL Follicular lymphoma G1-3A NHL Follicular lymphoma (grade 3B) NHL follicular lymphoma - primary intestinal NHL Follicular lymphoma - diffuse variant NHL Follicel centre lymphoma- primary cutaneous NHL Diffuse large B-cell lymphoma NHL Composite Marginal zone lymphoma and diffuse large B cell lymphoma NHL Composite Follicular lymphoma and Diffuse large B-cell lymphoma NHL Burkitt lymphoma NHL B-cell unclassifiable intermediate between DLBCL and Burkitt NHL B-cell lymphoma with features intermediate between DLBCL and Classical Hodgkin NHL B-cell CLL / SLL EBV + B-cell LPD (not PTLD) 0 5 10 15 20 25 30 35 Common Problem Areas Is it lymphoma? Differential diagnosis of nodular small BCLs Differential diagnosis HL vs NHL DLBCL vs HL HL vs TCL HL vs EBV associated LPD HL or non-haematological malignancy Problematic diagnosis of uncommon entities 1
Nodular infiltrates: Most common diagnoses Follicular lymphoma Marginal zone lymphoma Mantle cell lymphoma Chronic lymphocytic leukaemia / Small lymphocytic lymphoma Grade 1 Grade 3a Grade 3b Ki67 CD10 bcl 6 bcl 2 +, CD79a+, CD5-, CD43-, CD10+, CD23+ or-, Bcl6+, Bcl2+, usually low Ki67 10 neoplastic follicles on HPF Grade 1 0-5 centroblasts Grade 2 6-15 centroblasts Grade 3a >15 centroblasts with centrocytes Grade 3b >15 centroblasts without centrocytes Diffuse areas with grade 3 cytology = DLBCL Adult Follicular Lymphoma Grade 3B Grade 1 Grade 3A Grade 3B Grade 3b Grade 3B (adult) different disease BCL-6 rearrangement BCL-2 rearrangement lacking Increased ploidy / cytogenetic complexity Clinical implication Grade1,2,3A versus 3B Aggressive R-CHOP chemotherapy Ott eta al. Blood 2002, 99: 3806-3812 Gu et al. Mod Pathol 2009; 9:1251-1257 2
Marginal Zone Lymphoma Mantle Cell Lymphoma CLL/SLL Lymphoplasmacytic lymphoma ICC in the differential diagnosis of clinically non-aggressive NHL Follicular lymphoma CLL / SLL Mantle cell lymphoma Lymphoplasma cytic lymphoma Marginal zone lymphoma CD5 Neg Pos Pos Neg Neg Neg HCL CD10 Pos Neg Neg Neg Neg Neg CD23 Neg Pos Neg Nrg Neg Neg Cyclin D1 Neg Neg Pos Neg Neg Pos/Neg Bcl-2 Pos Pos Pos Pos Pos Pos AnexinA1 Neg Neg Neg Neg Neg Pos Immunophenotype: CD45+, * + and (bimodal), CD79a+, CD5-, CD10-, CD23-, CD43var, CD38+, IgM+, IgD-, bcl2+, bcl6- ; Genotype: no constant finding 3
Classical HL DD HL vs NHL DIFFERENTIAL DIAGNOSIS OF CLASSICAL HL MEDIASTINAL LBCL IS & AGE RELATED EBV+ LPD ALCL LYMPHOMATOID GRANULOMATOSIS Classical HL AITL Non-Haem Malignancies NLPHL TCRBCL CLASSIFICATION OF HODGKIN LYMPHOMA HL INCIDENCE RYE 1965 Nodular sclerosing Mixed cellularity Lymphocyte depletion Lymphocyte predominance WHO 1995/2008 Nodular sclerosis (NS1/2) Mixed cellularity Lymphocyte depletion Lymphocyte rich Nodular lymphocyte predominant Nodular sclerosis 40-70% Mixed cellularity 15-20% Lymphocyte rich <5% Lymphocyte depletion <5% Nodular lymphocyte predominant 5% CLASSICAL LACUNAR PLEOMORPHIC NECROBIOTIC HODGKIN POPCORN / L&H 4
Nodular lymphocyte predominant HL Birefringent collagen bands IMMUNOPHENOTYPE chl (VAR) CD15 Oct2 Bob1 Pax5 CD45 EBER 5
NLPHL MEDIASTINAL SCLEROSING BCL Pax5 Bob1 Oct2 CD15 CD4 CD57 EMA CD21 B-cell Lymphoma with Features Intermediate Between DLBCL and chl T-CELL RICH B-CELL LYMPHOMA CD45 Oct2 Oct2 PAX5 CD15 6
NLPHL chl TCRBCL EBV+ Age Related Lymphoma / CD45 / CD15 Oct2 / BOB1 PAX5 Oct-2 BOB-1 CD15 68% Age Related EBV+ LP (AREBVLP) or chl? AREBVLP Presentation Nodal and extranodal Nodal (primarily) Morphology Phenotype Range of cell sizes Histiocytes, lymphocytes and PCs Angioinvasion Necrosis common Granulomas could be seen Numerous EBER+ cells (variable size) CD45+/- +/- PAX5+ OCT2+ BOB1+ MUM1+ + CD15+/- (68%) chl HRS cells only Mixed infiltrate (NP, EO) No angioinvasion Necrosis not so common Granulomas could be seen Fewer EBER+ cells (uniform size) CD45- - PAX5+ (weak) OCT2- BOB1- MUM1+ + CD15+ 7
EBV+ MCU or chl? EBV+ MCU Presentation Mucosa and skin Nodal Never mucosa and skin Morphology Phenotype Behaviour Range of cell sizes Histiocytic and lymphocytic background Angioinvasion Necrosis common Numerous EBER+ cells (variable size) Circumscription (lymphocytic rim) CD45+/- +/- PAX5+ OCT2+ BOB1+ MUM1+ + CD15+/- (68%) Self limiting disease Response to IS withdrawal chl HRS cells only Mixed infiltrate (EO, NP) No angioinvasion Necrosis not common Fewer EBER+ cells (uniform) CD45- - PAX5+ (weak) OCT2- BOB1- MUM1+ + CD15+ Progressive disease not responsive to conservative measures Lymphomatoid Granulomatosis Extranodal EBV associated B-cell LPD Angiocentricity and angiodestruction Immunological deficit CD8 dysfunction Association with ID (WA, HIV, HTLV1, Transplant) LyG Epidemiology & Presentation AWLP Age 30s-40s M:F=2:1 Western population Lung Skin Liver Kidney Brain No lymphadenopathy No bone marrow involvement 8
PAX5 CD3 LMP1 CD15 EBER LyG or chl? Angioimmunoblastic T-cell Lymphoma (AIL) Presentation Morphology Phenotype LyG Extranodal Nodal (primarily) No diagnosis without lung involvement Range of cell sizes Mainly lymphocytes Angioinvasion No granulomas Necrosis Numerous EBER+ cells (variable size) CD45+ + PAX5+ OCT2+ BOB1+ + CD15- LMP1- chl HRS cells only Mixed infiltrate (NP, EO) No angioinvasion Granulomas could be seen Necrosis not so common Fewer EBER+ cells (uniform size) CD45- - PAX5+ (weak) OCT2- BOB1- MUM1+ + CD15+ 15%-20% of TCL Elderly patients, M=F Generalised lymphadenopathy Hepatosplenomegaly Hypergammaglobulinemia Skin rush Aggressive course Median <5years Bx No 9
Follicular T-cell Lymphoma CD15 CD3 CD4 EBER PAX5 OCT2 Origin follicular helper cells CD10 PD1 CXCL13 ICOS CD21 10
PD1 PD1 CXCL13 ICOS CD10 ANAPLASTIC LARGE CELL LYMPHOMA CD3 CD4 TIA1 ALK1 EMA ALCL 11
Anaplastic Large Cell Lymphoma (ALCL) CD15 Three entities! Primary Systemic ALK1+ Primary Systemic ALK1- Primary Cutaneous?Primary cutaneous ALK1+? Genotype ALK1+: t(2;5) Favorable prognosis of ALK1+ type 70%/5 year ALK1 ALCL ALK1- vs PTCL NOS LYMPHOEPITHELIOMA LIKE CARCINOMA CGH profiles TCL(NOS) overlap ALCL (ALK1-) 5q- 1p+ 7q+ 6q- 9p- 13q- 12p- 12p+ Savage et al. Blood. 2008;111: 5496-5504 17p- Zetti et al Am J Pathol 2004, 164:1837 1848 AE1 / AE3 CD45 CD2 CAM5.2 CK5/6 PLAP AFP TTF1 CD68 CD15 CD1a 12
CLASSICAL SEMINOMA, LYMPH NODE MET CD21 CD21 CD23 CD35 podoplanin B2 THYMOMA INFLAMMATORY MYOFIBROBLASTIC TUMOUR METASTATIC CARCINOMA BREAST Diffuse Large B-cell Lymphoma DLBCL PROGRESSED PRIMARY CLL/SLL DLBCL NOS SPECIAL TYPES LPL T-cell rich B-cell MZLs FL MEDIASTINAL SCLEROSING INTRAVASCULAR CHR. INFL. ASSOCIATED LyG PRIMARY CNS CUTANEOUS LEG TYPE EBV+ AGE RELATED ALK1+ PLASMABLASTIC PBL from MC Castleman PRIMARY EFFUSION AE1/AE3 13
Germinal centre Non-Germinal centre Primary DLBCL of CNS CD10 CD10 Primary CNS presentation with no systemic disease No immunodeficiency Bcl6 Bcl 6 MUM1 MUM1 Primary Cutaneous DLBCL Leg Type Ulcerating lesions on lower part of the body Intravascular Large B-cell Lymphoma Bcl 2 Widely disseminated, intravascular growth. Neurological symptoms, MOF Pathology may be subtle. Usually aggressive CD10 MUM1 14
Plasmablastic Lymphoma Mouth involvement HIV+, Immunosuppressed, Elderly EBV positive CD138 Oral cavity Lymph nodes CD79a EBER Primary effusion lymphoma Ascites Solid variant HIV, elderly, PTLD, alcoholic cirrhosis CD138 PATHOPHYSIOLOGY OF T-CELL SUBTYPES Innate Immune System T/NK Toll like receptors Not MHC restricted Adoptive Immune System B-cell T-cell APC Innate - Gamma/delta T-cells Splenic red pulp Intestinal epithelium Other epithelial sites CD3+/CD56+/Granzyme+ EBER KSV Cytokines Chemokines Antigen Complement Ag specific presenting by receptors dendritic cells in on B + T-cells Apoptotic & Necrotic context of MHC cell death pathways NK-cell leukaemia Spectrum of nodal TCL EBV+ T-cell LPD of childhood Adult T-cell leukaemia/lymphoma Hepatosplenic T-cell lymphoma Anaplastic Large Cell Lymphoma EATL Angioimmunoblastic T-cell lymphoma Peripheral TCL NOS Jaffe ES, Hematology Am Soc Hematol Educ Program. 2006:317-22. Adaptive IS Heterogeneous CD4+ regulatory cells CD4+/CD57+/CD10+ helper T-cells CD8+ cytotoxic 15
T-cell LINEAGE MARKERS NK/CYTOTOXIC CD16, CD56, CD57, TIA1, GRANZYME GERMINAL CENTRE DERIVATION CD10, Bcl6, PD1, CXCL13, CXCR5 T-REGs CD4+, FOXP3+ TCL - PRESENTATION PATTERNS Often leukemic or disseminated T-cell prolymphocytic leukaemia T-cell granular lymphocytic leukaemia Aggressive NK-cell leukaemia Adult T-cell lymphoma/leukaemia (HTLV1+) Hepatosplenic T-cell lymphoma Extranodal/Cutaneous Cutaneous TCL Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mainly nodal Peripheral T-cell lymphoma, unspecified Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma (systemic) Extranodal NK/T-cell lymphoma, Nasal Type Must Know Adult patients Asia, Mexico, Central & South America Nasopharyngeal region, GI tract, other extranodal sites Cytogenetics: germline TCR Extremely aggressive clinical course CD3 CD4 CD8 CD56 EBER EATL Subtypes EATL 1 (80%) 48% Coeliac HLA DQ2 +9q, 16q- EATL 2 (20%) 27% Coeliac +8q 16
Refractory Coeliac Disease (Type 2) Intraepithelial Lymphoma CD3 CD8 EATL 1 EATL 2 EATL - Immunophenotype Type 1 CD3+, CD5-, CD7+, CD8-/+, CD4- CD103+ TIA1/Granzyme+ Beta > Gamma variable Type 2 CD4- CD8+ CD56+ CD3 CD8 17
Hepatosplenic TCL Rare (<1% NHL) Young adults (35-45), M>F Long term immunosuppression (transplantation) Azathioprine for IBD Aggressive lymphoma median survival ~2 years CD7 CD4 Granzyme B CD5 CD8 TIA1 CD7 TCR beta TIA1 18
Peripheral TCL Unspecified 50% of TCL Variable morphology Variable immunophenotype Diagnosis of exclusion 19