overexpression! of! the! Th2! (GATA3)>! or! Th1! (TBX21)>associated! transcription! factors,! or! of!
cytotoxic! genes.! These! discrete! subgroups! can! be! identified! using! immunohistochemistry!
(IHC)!and!it!is!suggested!that!they!associate!with!different!molecular!pathways!and,!though!
still!controversial,!a!worse!prognosis!of!the!cytotoxic!and!GATA3!subsets.!Although!further!
studies! are! needed! to! validate! these! findings,! this! means! that! every! case! of! PTCL>NOS! >! a!
diagnosis! of! exclusion! >! requires! in! the! routine! practice! the! most! extensive! panel! of! IHC!
markers! –together! with! molecular! investigations! when! necessary>! to! exclude! a! better!
defined!PTCL!entity,!especially!a!PTCL!of!TFH!origin,!ALCL,!or!involvement!by!an!extranodal!
PTCL.!!
Most!extranodal((non(cutaneous)(PTCL!are!tumors!which!appear!to!originate!from!discrete!
subsets!of!cytotoxic!cells!of!the!innate!immune!system!(NK,!γδ T!cells,!a!subset!of!αβ!T!cells).!
Despite! some! differences! in! their! genetic! landscape,! they! share! biological! features! with!
frequent!activation!of!the!JAK>STAT!pathway!resulting!from!activating!recurrent!mutations!in!
genes!such!as!STAT3,(STAT5B,(JAK3,(JAK1,!a!pattern!also!found!in!ALK>negative!ALCL,!another!
cytotoxic! PTCL.! Interestingly,! it! is! now! established! that! each! of! these! entities! EATL,! large!
granular!lymphocyte!leukemias!of!both!T>cell!and!NK>cell!types,!NK/T>cell!lymphoma!nasal>
type,! hepatospenic! T>cell! lymphoma! (HSTL)! show! plasticity! in! term! of! cell! of! origin,! with!
cases! in! a! single! entity! having! an! αβ! phenotype,! others! a! γδ! T>cell! or! even! NK! derivation,!
likely!indicating!that!cell!function!in!a!context!of!antigen!stimulation!plays!a!major!initial!role!
in!their!pathogenesis.!!
According! to! the! updated! WHO! classification,! the! term! “enteropathy>associated! T>cell!
lymphoma! (EATL)”! is! now! restricted! to! cases! formally! known! as! “type! I! EATL”,! typically!
associated!with!celiac!disease!whereas!the!formerly!“type!II!EATL”,!due!to!a!proliferation!of!
monomorphic! CD8! (often! CD56>positive)! cells! with! epitheliotropism,! is! now! given! a! new!
name! “Monomorphic! epitheliotropic! intestinal! T>cell! lymphoma! (MEITL)”! due! to! its!
distinctive!features!and!lack!of!association!with!celiac!disease.!Recent!genome!wide!studies!
have!shown!that!MEITL,!thought!to!be!more!prevalent!in!Asian!countries,!likely!discloses!a!
specific! genetic! landscape! with! almost! constant! mutations! of! STAT5B( and! also! SETD2,! a!
methyltransferase!also!found!recurrently!mutated!in!HSTL.!!MEITL!needs!to!be!distinguished!
from!“Indolent!T>cell!lymphoproliferative!disorder!(LPD)!of!the!gastrointestinal!tract”!which!
designates! a! new! indolent! provisional! entity! characterized! by! a! superficial! monoclonal!
intestinal! proliferation! of! small! CD8+! (or! CD4+)! mature! T! lymphocytes! with! a! low! (<5%)!
proliferative!rate,!and!an!indolent!outcome!with!rare!cases!showing!progression.!Such!cases!
show! overlapping! features! with! “primary! cutaneous! acral! CD8! TCL”! now! recognized! as! a!
provisional!entity.!The!later!is!characterized!by!cutaneous!acral!lesions,!localized!to!a!single!
site,!most!commonly!the!ear,!due!to!a!clonal!proliferation!of!atypical!low!proliferative!CD8+!
T! cells! with! an! indolent! clinical! course.! The! pathogenesis! and! the! optimal! management! of!
these!indolent!T>cell!lymphoproliferative!disorders!need!to!be!determined.!
Among! cutaneous( PTCL,! besides! the! increasingly! recognized! spectrum! of! Lymphomatoid!
papulosis! (LyP),! it! is! emphasized! that! several! cutaneous! T>cell!
lymphomas/lymphoproliferative! disorders! may! occasionally! derive! from! γδ! T! cells! such! as!
mycosis!fungoides!or!lymphomatoid!papulosis,!meaning!that!the!latter!need!to!be!excluded!
prior!to!a!diagnosis!of!primary!cutaneous!γδ!T>cell!lymphoma.!
Despite! major! advances! in! our! knowledge! of! PTCL! which! have! yielded! novel! diagnostic!
criteria!for!several!entities,!the!outcome!of!the!majority!of!PTCL!patients!(with!the!notable!
exception! of! ALCL,! ALK>positive)! remains! poor! with! limited! efficacy! of! conventional!