implies! the! need! to! examine! as! much! tissue! as! possible,! needle! biopsies! being! not!
necessarily! representative! of! the! complexity! of! the! tumour! by! catching! only! one! of! the!
neoplastic!components!(4).!The!difficulties!encountered!in!diagnosing!GZLs!is!highlighted!by!
a!contribution!published!this!year!based!on!gene!expression!profiling!of!85!of!these!cases,!
collected!by!the!LYSA!and!British!Columbia!Cancer!Agency!(5).!Their!signature!was!compared!
with! the! one! of! examples! of! CHL! and! PMBL.! The! main! biological! pathways! underlying! the!
GZL! spectrum! were! related! to! cell! cycle,! reflecting! tumor! cell! content,! and! extracellular!
matrix! signatures! related! to! the! cellular! tumor! microenvironment.! Differential! expression!
analysis! and! phenotypic! characterization! of! the! tumor! microenvironment! highlighted! the!
predominance! of! regulatory! macrophages! in! GZL! compared! with! CHL! and! PMBCL.! Two!
distinct! subtypes! of! GZL! were! distinguishable! that! were! phenotypically! reminiscent! of!
PMBCL! and! DLBCL,! an! association! of! PMBCL>type! GZL! being! observed! with! clinical!
presentation!in!the!“thymic”!anatomic!niche.!Also!this!year,!the!first!NGS!study!on!GZLs!has!
been!published!(6).!The!coding!sequence!mutations!of!50!EBV>negative!GZLs!were!compared!
to!cHL,!PMBL,!and!DLBCL.!Exomes!of!21!GZL!cases!along!with!paired!normals!were!analyzed!
as!a!discovery!cohort!followed!by!targeted!sequencing!of!217!genes!in!an!extension!cohort!
of!29!GZLs.!GZL!cases!with!thymic!niche!involvement!(anterior!mediastinal!mass)!displayed!a!
mutation!profile!closely!resembling!CHL!and!PMBL,!with!SOCS1((45%),!B2M((45%),!TNFAIP3!
(35%),!GNA13!(35%),!LRRN3!(32%),!and!NFKBIA((29%)!being!the!most!recurrently!mutated!
genes,!as!observed!also!in!the!presented!case.!In!contrast,!GZL!cases!without!thymic!niche!
involvement!had!a!significantly!distinct!pattern,!enriched!in!mutations!related!to!apoptosis!
defects! TP53! (39%),! BCL2( (28%),! BIRC6! (22%))! and! depleted! in! GNA13,! XPO1! or! NFKB!
signaling! pathway! mutations! (TNFAIP3,! NFKBIE,! IKBKB,! NFKBIA).! They! also! presented! more!
BCL2/BCL6!rearrangements!as!opposed!to!thymic!GZL.!These!studies!are!of!great!biological!
value! but! do! not! yet! provide! a! diagnostic! tool! to! be! applied! to! the! daily! routine.! As! the!
diagnostic!scenario!of!these!neoplasms!remain!gray,!the!same!holds!true!for!the!therapeutic!
one.! No! standardized! approach! does! exist! and! the! treatment! is! mainly! based! on! the!
experience! gained! by! each! Centre! (7).! Immunotherapy! and! CAR>T! cells! may! represent!
options!that!need!to!be!further!explored.!
!R
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