Coding Haematological Malignancies in Cancer Registries part II : Lymphoid malignancies Pr Marc Maynadié Registre des Hémopathies Malignes de Côte d'Or Faculté de Médecine de Dijon marc.maynadie@u-bourgogne.fr

Definition Lymphoid malignancies = « Lymphoma » proliferation developped from a lymphoid cell, initiated in a lymphoid organ : Nodal extra nodal

Cellule souche myéloïde Cellule souche totipotente Cellule souche myéloïde (CFU-GEMM) Cellule souche lymphoïde pro B M T Prothymocyte O H E Y pré B Thymocyte cortical CD3+ CD1+ L M Phase centrale de différenciation indépendante L U B immature E S Thymocyte cortical CD4+ CD8+ B mature naïve M.O. Foll. I Sang Thymocytes médullaires matures CD4+ CD8+ Activation centroblastes Foll. II Sang Org L. II Phase périphérique de différenciation centrocytes M.O. LT mémoire Org L. LT CD4 ⊕ LT CD8 ⊕ Lymphocyte B mémoire Plasmocytes "helper" "cytotoxique"

Lymphoid territories

Lymphoid territories Lymph nodes

Lymph node: small ball-shaped organ of the immune system distributed widely throughout the body and linked by lymphatic vessels.

Zone Sombre Apoptose B B émergeant recirculant B-blaste Cb Cc B mémoire T Zone Sombre CDF Zone claire Zone marginale Plasmocyte Manteau IgD IgM IgG/A/E CD23 CD39 CD10 CD38 CD77 Bcl2 Ki67 Bcl6 Mutations somatiques Commutation isotypique CD138

lympho-plasmocytic cell Large B-cell NHL Paracortical area Lymphoplasmocytic NHL Medullar area lympho-plasmocytic cell Immunoblast Ag B Marrow Follicle I cIgM, CD20 Mutations sIgM-D CD19+ CD5+ CD23+ CD38- B Marrow LLC/SLL Naive B cell Precursor Secondary follicle : germinal center Marrow CD19+ CD10+ Tdt+ cµ CD19+ CD23+ CD5+ sIgM-D CD38+ unmutated Memory cell Mantle LNH Burkitt Follicular lymphomas Plasmocytes Blaste B cµ CD23- CD77+ CD10+ Centrocyte LAL IgG, A CD20- CD138+ CD38+ CD10- CD77- CD23+ IgM Mantle cell Marginal zone cell LLC/SLL CD19+ CD5+ CD23- sIgM-D Centroblast IgM, G bcl2 CD39+ CD10- CD77- Myeloma Diffuse Large B-cell NHL Mantle Dark area Clear zone LNH marginal zone (SLVL)

Explain the numerous entities and changes in the classification Very complex system: Lineages: B, T, NK Organs: primary and secondary lymphoid organs Steps of differentiation Explain the numerous entities and changes in the classification All now grouped under the term « Lymhoma »

Epidemiology Incidence : Very important increase since mid 1970’s in NHL USA : +75% since 1975 Northern Europe : x2 France: x2,5 In both sexes Risk factors mainly unknown : virus, immunodeficiencies,… multifactorial process Stabilisation since 2000

Panama 6,6 France : 13,3

Panama: 0,1 France: 2,43

Non Hodgkin Lymphoma Multiple Myeloma Hodgkin Lymphoma

Incidence and mortality estimates in France by NHL 1980-2005 : +2.7% /y in men +2.9%/y in women 2000-2005 : -0.1%/y in men +0.4%/y in women

Incidence and mortality estimates in France by Hodgkin L

Urbain – Rural (WPS Incidence) Men 9,2 5,4 Women 5,9 3,7 Données RHEMCO 1980-2005

Incidence rate by entities M W Total Sex ratio Diffuse large B-cell L 2,65 1,81 2,02 1,46 Follicular L. 1,77 1,86 0,95 Mantle cell L. 0,34 0,13 0,23 2,62 Marginal Zone L. 0,61 0,43 0,51 1,42 Burkitt L. 0,36 0,14 0,25 2,57 Lymphoplasmocytoid L 0,58 0,35 0,46 1,66 T NHL 1,56 0,86 1,18 RHEMCO 1980-2005

Proportion of different entities from Morton et al., Blood, 2007

Evolution of incidence by entities Données RHEMCO 1980-2005

Incidence according to age of NHL âge moyen : H : 61,9 ± 0,7 F : 66,1 ± 0,7*** âge moyen : H : 61,9 ± 0,7 F : 66,1 ± 0,7 p < 0,001 RHEMCO 1980-2005

Incidence and mortality in France according to age by Hodgkin L

Epidemiology Relative Survival : Non Hodgkin Lymphoma Women Men

Epidemiology Relative Survival : Multiple Myeloma Women Men

Relative Survival evolution NHL in USA from Pulte et al., 2000

Principle of classification of Lymphoid proliferations B lineage Issued from immature cells : Precursor Acute lymphoblastic leukemia and Lymphoblastic lymphoma Issued from matured cells Non Hodgkin lymphoma Hodgkin lymphoma T/NK lineage Issued from immature cells : Precursor Acute lymphoblastic leukemia and Lymphoblastic lymphoma Issued from matured cells T Non Hodgkin lymphoma Natural Killer cells proliferations

Principle of classification of Lymphoid proliferations Histiocytic and dendritic cells Post-transplant proliferations

Coding practice Pathology/Cytology report mandatory Morphology code : ICD-O-3 Clinical chart mandatory Topography code Stage Treatment Follow up

Precursor lymphoid neoplasms Cytology : blast cells Immunophenotype : immature lymphoid B or T cells Morphology : ICD-O-3 Topography : C42.1 = Bone marrow Stage : no ICD-O-4

Precursor Lymphoid Neoplasm Leucémie lymphoblastique B 9836/3 Lymphome lymphoblastique B 9728/3 Leucémie aiguë lymphoblastique T 9837/3 Lymphome lymphoblastique T 9729/3 Leucémie aiguë lymphoblastique, NOS 9835/5 Lymphome lymphoblastique, NOS 9727/3 Regroupement confirmé Seuil des blastes utilisé antérieurement non conservé 9836/3 9837/3 9835/3

Precursor lymphoid neoplasms B immature cells CD19+ CD10+ CD20+ µ chain cyt Kappa or Lambda chain s T Immature cells CD3 cyt/s ; TCR ; CD99 CD1, CD4-, CD8- CD1-, CD4+ and CD8+ CD4 + or CD8+

Precursor Lymphoid Neoplasm B lymphoblastic leukemia /lymphoma 9836/3 or 9728/3 B Lymphoblastic leukemia/lymphoma, NOS 9811/3 B Lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2) 9812/3 B Lymphoblastic leukemia/lymphoma with t(v; 11q23) (MLL) 9813/3 B Lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) 9814/3 B Lymphoblastic leukemia/lymphoma with hyperdiploïdy 9815/3 B Lymphoblastic leukemia/lymphoma with hypodiploïdy 9816/3 B Lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) 9817/3 B Lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) 9818/3 T Lymphoblastic leukemia/lymphoma 9837/3 or 9729/3 9837/3

Mature Neoplasms ICD-O-4 Morphology : ICD-0-3 Topography : Nodal lymphoma, code C77.-. Many lymph nodes, code C77.8 Nodal but unknown location, code C77.9 Extra-nodal: coding the organ Stage : Ann Arbor, others ICD-O-4

Morphology coding rules Avoid « NOS » codes as far as possible 9590/3 Lymphoma, NOS 9591/3 Non Hodgkin Lymphoma, NOS 9650/3 Hodgkin lymphoma, NOS 9680/3 Large B-cell lymphoma, NOS 9690/3 Follicular lymphoma, NOS 9702/3 T-cell lymphoma, NOS 9727/3 Lymphoblastic lymphoma, NOS

B cell Non Hodgkin Lymphoma Chronic lymphocytic leukemia/small lymphocytic lymphoma 9823/3 B-cell prolymphocytic leukaemia 9833/3 Splenic marginal zone lymphoma 9689/3 Hairy cell leukaemia 9940/3 Splenic B-cell lymphoma/leukaemia, unclassifiable 9591/3 Splenic diffuse red pulp small B-cell lymphoma 9591/3 Hairy cell leukaemia-variant 9591/3 Lymphoplasmacytic lymphoma 9671/3 Waldenström macroglobulinemia 9761/3 Heavy chain diseases 9762/3 Alpha heavy chain disease 9762/3 Gamma heavy chain disease 9762/3 Mu heavy chain disease 9762/3 Plasma cell myeloma 9732/3 Solitary plasmacytoma of bone 9731/3 Extraosseous plasmocytoma 9734/3

CLL/SLL Hyperlymphocytosis > 4500L/mm3 Presence of B-cells with the phenotype : CD19+, CD5+, CD23+, Ig low intensity Bone marrow aspirate Bone marrow biopsy Karyotype : iso 17p : usefull for pronostic and treatment

B prolymphocytic leukemia Hyperlymphocytosis >>> 4500L/mm3 Presence of B-cells with proeminent nucleoli Non specific phenotype : CD19+, CD5+/-, CD23-, Ig high intensity Bone marrow aspirate Bone marrow biopsy Karyotype

+ low ++ high CLL ProL L HCL HCLv SLVL ML FL CD 19 CD 10 CD 20 CD 22 FMC-7 Ig s HC-2 CD 43 + - +/- -/= + low (K>L)(MD) -/+ ++ ++ high (L>K)(D) ++ h

B cell Non Hodgkin Lymphoma Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) 9699/3 Nodal marginal zone lymphoma 9699/3 Paediatric nodal marginall zone lymphoma 9699/3 Follicular lymphoma 9690/3 Paediatric follicular lymphoma 9690/3 Primary cutaneous follicle centre lymphoma 9597/3 Mantle cell lymphoma 9673/3 Diffuse large B-cell lymphoma (DLBCL), NOS 9680/3 T-cell histiocyte riche large B-cell lymphoma 9688/3 Primary DLBCL of the CNS 9680/3 Primary cutaneous DLBCL, leg type 9680/3 EBV positive DLBCL of the elderly 9680/3 DLBCL associated with chronic inflammation 9680/3 Lymphomatoid granulomatosis 9766/3 Primary mediastinal (thymic) large B-cell lymphoma 9679/3 Intravascular large B-cell lymphoma 9712/3 ALK positive large B-cell lymphoma 9737/3

B-cell Non Hodgkin Lymphoma Plasmoblastic lymphoma 9735/3 Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease 9738/3 Primary effusion lymphoma 9678/3 Burkitt lymphoma 9678/3 B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma 9680/3 B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma 9596/3

Entities Main abnormalities % Genes Ig genes Follicular Lymphoma t(14;18)(q32;q21) t(2 ;18) (p11 ;q21) t(18 ;22) (q21 ;q11) 90 % BCL-2 Apoptose mutated Mantle cell lymphoma t(11;14)(q13;q32) 70 % BCL-1/CCND1 Cycle cellulaire Unmutated and mutated Marginal zone Lymphoma Trisomies du 3, du 12, du 18 del7q 6-10 % ?? Mutated and unmutated MALT lymphoma t(11;18)(q21;q21) t(1;14)(p22;q32) 50 % API2/MLT apoptose BCL-10 Mutated

Lympho plasmocytoid lymphoma t(9;14)(p13;q32) 50 % PAX-5(transcription) Différentiation/Prolifération Mutated CLL/SLL Trisomy 12, del7q ?? unmutated and mutated Large B-cell NHL Abnormalities 3q27 35-45 % BCL-6 (transcription) Différentiation B Burkitt L t(8;14)(q24;q32) t(2 ;8) ( p11 ; q24) t(8 ;22) (q24 ;q11) 80 % c-MYC prolifération Hodgkin ? Anaplastic Lymphoma t(2;5)(p23;q35) and variants 60 % NPM/ALK tyrosine kinase (signalisation) -

Lymphomes de Hodgkin ≈ 30 % des lymphomes Caractéristiques communes : développement ganglionnaire, surtout région cervicale la plupart surviennent chez des adultes jeunes présence d'un petit nombre de cellules grandes mono ou multinuclées : cellules de Hodgkin ou de Reed Stenberg Cellules tumorales souvent entourées de lymphocyte T en rosette

Phénotype des cellules malignes identiques Deux types d'affections :  Hodgkin nodulaire avec des lymphocytes prédominants  Hodgkin classique : 4 sous-types : Sclérose nodulaire à cellularité mixte riche en lymphocytes déplété en lymphocytes Phénotype des cellules malignes identiques

LH nodulaire avec lymphocytes prédominants ≈ 5 % des Hodgkin Prolifération de cellules B monoclonales caractérisées par des grandes cellules appelées Popcorn ou LH cells. Synonyme : Paragranulome de Poppema-Lennert patients masculins adénopathie périphérique localisée le plus souvent Documents diagnostiques : compte rendu Anatomo-pathologique stades de la classification Ann-Arbor Pronostic : bon avec 80 % de survie à 10 ans pour les stades I, II 9843/3

Lymphomes de Hodgkin classiques 9650/3 Proliférations monoclonales de cellules B composées en proportions variables de cellules mononuclées de Hodgkin, de cellules plurinucléées de Reed-Sternberg, au sein d'un infiltrat réactionnel fait de petits lymphocytes, d'éosinophiles, de neutrophiles, d'histocytes, de plasmocytes, de fibroblastes et de fibres de collagène. Epidémiologie : 95 % des Lymphomes de Hodgkin pics entre 15-35 ans et après 70 ans rôle de l'EBV encore discuté

4 types : Sclérose nodulaire (70 %) 9663/3 atteinte médiastinale dans 80 % Cellularité mixte (20-25 %) 9652/3 surtout ganglions périphériques et rates Riche en lymphocytes (5 %) 9651/3 surtout ganglions périphériques Déplété en lymphocytes (< 1 %) 9653/3 souvent associée à HIV – Ganglions rétropéritoneaux

Immunité innée Immunité acquise Lymphomes T Périphériques NK CD16, CD56, CD57 CD2, CD7, +/- CD8 KiR Rate Muqueuse Sang L Tgd CD3 TCRa5 CD4-, CD8- Peau Immunité innée Moelle Thymus Immunité acquise Ag Cortex zone sous Cortex Médullaire Précurseur capsulaire T Organes lymphoïdes secondaires Thymocyte corticaux Thymocytes communs Thymocytes médullaires Progéniteur T Prothymocyte Tdt CD3c CD1Θ Tdt CD3s CD1a CD5 CD7 TCR ab CD4 +CD8+ CD4 CD8 surtout nodaux chez l’adulte LAL / Lymphome lymphoblastique Lymphomes T Périphériques

Mature T-cell and NK-cell neoplasms T-cell prolymphocytic leukemia 9834/3 T-cell large granular lymphocytic leukemia 9831/3 Chronic lymphoproliferative disorder of NK-cells 9831/3 Aggressive NK cell leukemia 9948/3 Systemic EBV positive T-cell lymphoproliferative disease of childhood 9724/3 Hydroa vacciniforme-like lymphoma 9725/3 Adult T-cell leukemia/lymphoma 9827/3 Extranodal NK/T cell lymphoma, nasal type 9719/3

Nature T-cell and NK-cell neoplasms Hepatosplenic T-cell lymphoma 9716/3 Subcutaneous panniculitis-like T-cell lymphoma 9708/3 Mycosis fungoides 9700/3 Sezary syndrome 9701/3 Primary cutaneous CD30 positive T-cell lymphoproliferative disorders Lymphomatoid papulosis 9718/1 Primary cutaneous gamma-delta T-cell lymphoma 9718/3 Primary cutaneous CD8 positive aggressive epidermotropic cytotoxic T-cell lymphoma 9709/3 Primary cutaneous CD4 positive small/medium T-cell lymphoma 9709/3 Peripheral T-cell lymphoma, NOS 9702/3 Angioimmunoblastic T-cell lymphoma 9705/3 Anaplastic large cell lymphoma, ALK positive 9714/3 Anaplastic large cell lymphoma, ALK negative 9702/3

Leucémie Prolymphocytaire T Synonyme : Leucémie Lymphoïde Chronique T Prolifération de lymphocytes T de phénotype mur envahissant le sang, la moelle, les ganglions, la rate, le foie et la peau.

Eléments diagnostiques Numération formule sanguine : hyperlymphocytose Immunophénotype : lymphocytes T : CD3, CD2, CD7 CD1Θ CD4, 60 % CD4, CD8, 25 % CD4Θ, CD8, 15 % Biol. Mol. : TCR réarrangé Caryotype : anomalie en 14q11 et q32 Pronostic : mauvais – médiane de survie < 1 anS

Leucémie/lymphome T de l'Adulte (ATLL) 9827/3 Prolifération causée par le virus HTLV-1 Endémie : Sud Ouest Japon, Afrique Centrale, Caraïbes Contact avec virus très jeune  longue latence Pléomorphisme cellulaire (Flower cells) 3 formes cliniques : smouldering, chronique, aiguë Phénotype : CD3, CD2, CD5 mais CD7 Θ, CD4 Pronostic : mauvais

Diagnostic sur le CR anatomo-clinique +++ Mycosis fongoïdes 9700/3 Lymphome T cutané le plus fréquent (env. 50 % LNH cutanés) Infiltration cutanée progressive (tache, plaque, tumeur) Cellules CD4 Diagnostic : difficile surtout au début Pronostic : fonction de l'extension Diagnostic sur le CR anatomo-clinique +++

Syndrome de Sézary 9701/3 LNH cutané T rare (< 5 %) Associe : adénopathies érythrodermie cellules malignes cérébriformes monoclonales T dans le sang > 1000 cellules de Sézary/mm3 dans le sang Phénotype : CD3, CD4, CD7Θ Pronostic : mauvais

Lymphomes T périphériques, NOS 9702/3 Ensemble hétérogène de lymphomes T matures, nodaux ou extranodaux qui ne correspondent à aucune entité décrite...  Diagnostic par défaut Inclus : LNH anaplasique à grandes cellules, AlkΘ

LNH anaplasiques à grandes cellules Alk  9714/3 LNH T avec implication du gène Alk (chrom. 2) et expression de CD30 Diagnostics différentiels nombreux : ALCL AlkΘ ALCL cutanés primitifs autres LNH B ou T avec traits anaplasiques ou exprimant CD30 Difficile - S'en tenir au CR anatomoclinique

Syndrome myéloprolifératif T cutanés primitifs CD30 9718/3 2ème groupe de LNH cutanés T (30 %) Inclus : LNH anaplasique à grandes cellules cutanés primitif Papulose lymphomatoïde (non maligne) Borderline

T CLL LPL T LG-L T LGL NK MF CD1a CD 2 CD 3 CD 5 CD 7 CD 4 CD 8 CD 25 TCR + + (s) + (65 %) + (21 %) 4-/8+ - + (cyt) +/- -/+ < < (33 %)

Histiocytic and dendritic cell neoplasms Histiocytic sarcoma 9755/3 Langerhans cell histiocytosis 9751/3 Langerhans cell sarcoma 9756/3 Interdigitating dendritic cell sarcoma 9757/3 Follicular dendritic cell sarcoma 9758/3 Fibroblastic reticular cell tumour 9759/3 Indeterminate dendritic cell tumour 9757/3 Disseminated juvenile xanthogranuloma

Post-transplant lymphoproliferative disorders (PTLD) Early lesions Plasmocytic hyperplasia 9971/3 Infectious mononucleosis-like PTLD 9971/1 Polymorphic PTLD 9971/3 Monomorphic PTLD (B- and T/NK-cell types)* Classical Hodgkin lymphoma type PTLD* *These lesions are classified according to the leukemia or lymphoma to which they correspond, and are assigned the respective ICD-0 code.

Mature Neoplasms ICD-O-4 Morphology : ICD-0-3 Topography : Nodal lymphoma, code C77.-. Many lymph nodes, code C77.8 Nodal but unknown location, code C77.9 Bone Marrow code C42.1 Extra-nodal: coding the organ Stage : Ann Arbor, others ICD-O-4

Nodal areas Nodal, NOS C77.9 Multiple territories (≥ 2) C77.8 Pelvis C77.5 Inguinal and leg C77.4 Axillary and Arm C77.3 Intra-abdominal C77.2 Intra-thoracic C77.1 Head, neck and face C77.0

Nodal Lymphoid areas Lingual tonsils C02.4 Palatal tonsils C09.9 Pharynx tonsils C11.1 Waldeyer’s ring C14.2 Ileum C17.2 Appendix C18.1 Thymus gland C37.9 Spleen C42.2

Extra nodal coding rules +/- 30% of NHL are extra nodal Stomach > small Intestine > Skin > Bone > CNS > Colon > Breast, … Unique involved organ : coding the specific topography : i.e. Stomach = C16.x more than one organ is involved : C77.8

Topography coding rules Bone Marrow C42.1 Multiple lymph nodes C77.8 Unique (extra-lymphatic) organ : organ code Multiple organs C77.8 Lymph node(s) + Bone Marrow C42.1 Lymph node (s) + unique organ : organ code Lymph node(s) + multiples organs C77.8 Bone Marrow + organ(s) +/- lymph node C42.1 Bone Marrow > multiple LN or organ > organ > lymph node

Mature Neoplasms ICD-O-4 Morphology : ICD-0-3 Topography : Nodal lymphoma, code C77.-. Many lymph nodes, code C77.8 Nodal but unknown location, code C77.9 Extra-nodal: coding the organ Stage : Ann Arbor, others ICD-O-4

Ann Arbor staging Usefull in NHL and in Hodgkin lymphoma

Ann Arbor staging Stage I - disease in single lymph node or lymph node region. Stage II - disease in two or more lymph node regions on same side of diaphragm.  Stage III - disease in lymph node regions on both sides of the diaphragm are affected.  Stage IV - disease is wide spread, including multiple involvement at one or more extranodal (beyond the lymph node) sites, such as the bone marrow. A: absence of constitutional symptoms; a: of biological symptoms B: presence of constitutinal symptoms; b: of biological symptoms E: the disease is "extranodal" (not in the lymph nodes) or has spread from lymph nodes to adjacent tissue. X: the largest deposit is >10 cm large ("bulky disease"), or whether the mediastinum is wider than 1/3 of the chest on a chest X-ray. S: the disease has spread to the spleen.

Multiple Myeloma Stage I : Stage II: overall between I and III Low monoclonal protein levels: IgG<50g/L ; IgA<30g/L; Urine BJ<4g/24h No or solitary bone lesion Normal Hb, serum calcium, Ig levels Stage II: overall between I and III Stage III: any of one or more of the following High M-protein: IgG>70g/L; IgA>50g/L; Urine light chain >12g/L Advanced, multiple lytic bone lesions Hb<8.5g/dL; serum calcium >12mg/dL A: serum creatinine<2mg/dL; B: >2mg/dL

Chronic Lymphocytic Leukemia Binet’s stage Stage A : 2 or less lymph nodes involved Stage B: 3 or more lymph nodes involved Stage C: Hb<10g/dL or platelets<100,000/mm3

Preguntas? Exercicios