LGCB ricco in linfociti T/istiociti
•
•
•
•
•
10% dei LGCBD
Linfonodi, midollo osseo, fegato e milza
Bcl-6+, Bcl-2+/-, EMA+/D.D. con LHPL (fondamentale!)
Decorso clinico estremamente
aggressivo, non responsivo alle terapie
correnti
LGCB ricco in linfociti T e/o istiociti
CD20
CD68
“Diffuse large-B-cell lymphoma is the most
common type of lymphoma worldwide,
making up to 30% of all non-Hodgkin’s
lymphomas, and approximately 90% of
primary CNS lymphomas”
Batchelor TT, Buchbinder BR and Harris NL.
New Engl J Med 2005, 352:185-194.
CNS lymphoma
CD79a
Camilleri-Broet S et al. A uniform activated Bcell-like immunophenotype might explain the
poor prognosis of primary central nervous
system lymphomas: analysis of 83 cases.
Blood. 107(1). 190-196. 2006.
Ponzoni M et al. Reactive perivascular T-cell
infiltrate predicts survival in primary central
nervous system B-cell lymphomas. Br J
Haematol. 138(3). 316-323. 2007.
CD3
CD20
Loss of 6p21.32-p25.3: comune ai linfomi del
SNC e del testicolo -> alterata regolazione dei
geni di HLA e di geni coinvolti nell’apoptosi,
compresa la via di p53.
Gain di 12q15-21.1 e di 12q24.32-p25.3 = CNS
Gain di 19q13.12-q13.34 = testicolo
The formerly poor prognosis has been
remarkably ameliorated by novel
chemotherapeutic protocols that include
methotrexate.
LINFOMA B A GRANDI
CELLULE DELLA GAMBA
• Pazienti anziani (>70aa);
F>M; malattia confinata
alla gamba.
• Lesioni tumorali rossobluastre, talvolta ulcerate.
• Outcome: peggiore dei
linfomi con istologia
simile ma interessanti
altri siti (es. testa e
tronco).
B CELL LYMPHOMA OF
THE LEG
• “Pattern” usualmente diffuso
• Grandi cellule
(prevalentemente centroblasti
ed immunoblasti).
• Profilo fenotipico: CD20+;
CD10-; Bcl-6+; IRF4+; CD138-;
Bcl-2+.
• Dal punto di vista
molecolare, PLBCL-leg porta
con sé ipermutazioni dei geni
IgG e, nella maggior parte dei
casi, mutazioni di Bcl6.
• La ricerca di EBV e HHV-8 è
negativa.
Bcl-6
Linfomi B cutanei e “gene profiling”
La “hierarchical
analysis” dei PCFCCL
e PCLBCL “leg type”
ha dimostrato profili di
espressione simili,
rispettivamente, a
quelli tipo “germinal
center like” e tipo
“activated B cell like
diffuse large B cell
lymphoma”.
Linfomi B cutanei e “gene
profiling”
L’analisi di “gene profiling” ha
evidenziato l’ ”up-regulation” di
geni con diversa prevalenza
rispettivamente espressi nel
PCLBCL “leg type” e nei PCFCCL.
Ad esempio:
- “leg type”: ciclo cellulare/
proliferazione; sintesi/
replicazione/ riparazione DNA;
regolazione trascrizione, ecc..;
- PCFCCL: adesione; antigene HLA;
processing RNA,ecc..
Oyama T et al. Clin Cancer Res 2007;
13:5124-32.
• Processo linfoproliferativo clonale EBV+ che occorre in
un Paziente di oltre 50 anni senza pregressa storia
clinica di immunosoppressione o tumore.
• 8-10% dei LGCBD in Asia.
• Correlato alla senescenza del sistema immunitario.
• 70% extranodale.
• Citologia polimorfa od a grandi cellule, con elementi
simil-RS.
• CD10-, Bcl-6-, IRF4+, EBER+, EBNA2+, LMP1+, CD30v.
• Mediana di sopravvivenza: 2 anni.
Morphologic and phenotypic characteristics
Polymorphic type
Large cell type
Geographic necrosis
EBNA2
LMP1
EBER
CD10
IRF4
CD30
Original contribution
Epstein-Barr virus–positive diffuse large B-cell
lymphoma in elderly patients is rare in Western
populations
S. Hoeller, A. Tzankov, S. A. Pileri, P. Went and S. Dirnhofer
Institute of Pathology, University Hospital, University of Basel, 4031 Basel, Switzerland
Department of Hematology and Oncological Sciences “L. and A. Seràgnoli”, Hematopathology
Section, Bologna University School of Medicine, St. Orsola Hospital, 40138 Bologna, Italy
Institute of Pathology, Triemli Hospital, Birmensdorferstrasse 497, 8063 Zürich, Switzerland
Human Pathology 2009, E-pub ahead of print.
• Median age: 70 yrs.
• M/F = 12.3/1
• 5-yr-OS: 20-35%
DLBCL associated with chronic inflammation
EBV-ISH
CD79a
VDJ
ACT
HHV8-IS-PCR
Pyothorax-associated
Ann Oncol, 8:1133, 1997
• Liu A et al.: Alterations of
DNA damage-response
genes ATM and ATR in
pyothorax-associated
lymphoma. Lab Invest
2005; 85(3): 436-46.
• Nishiu M et al.: Distinct
pattern of gene expression
in pyothorax-associated
lymphoma (PAL), a
lymphoma developing in
long-standing
inflammation. Cancer Sci
2004; 95(10): 828-34.
IFI27
HLA class I
• Nakatsuka S et al: Pyothorax-associated lymphoma: a review of 106
cases. J Clin Oncol 2002; 20(20): 4255-60.
• Liu A et al.: Alterations of DNA damage-response genes ATM and
ATR in pyothorax-associated lymphoma. Lab Invest 2005; 85(3):
436-46.
• Nishiu M et al.: Distinct pattern of gene expression in pyothoraxassociated lymphoma (PAL), a lymphoma developing in longstanding inflammation. Cancer Sci 2004; 95(10): 828-34.
• Cheuk W et al: Metallic implant-associated lymphoma: a distinct
subgroup of large B-cell lymphoma related to pyothorax-associated
lymphoma? Am J Surg Pathol 2005; 29(6): 832-6.
• Hojo N et al.: Non-Hodgkin's lymphoma developing in a pacemaker
pocket. Int J Hematol 2003; 77(4): 387-90.
• Molinie V et al: Primary Epstein-Barr virus-related non-Hodgkin's
lymphoma of the pleural cavity following long-standing tuberculous
empyema. Arch Pathol Lab Med 1996; 120(3): 288-91.
Granulomatosi linfomatoide (LYG)
Processo EBV-correlato ad insorgenza extranodale.
Polmone, encefalo, rene, fegato, cute.
Condizioni di immunodeficienza:
trapianto d’organo allogenico,
sindrome di Wiskott-Aldrich,
infezione da HIV,
sindrome linfoproliferativa “X-linked”,
oppure pazienti con alterata funzione immune.
• Differenzia da: linfoma nasale/tipo nasale (T/NK; EBV+;
extranodale).
• Altamente aggressivo.
•
•
•
LYG
Grado I:
infiltrato linfoide polimorfo,
necrosi non prominente,
blasti EBV+/B rari (EBER <5/HPF),
clonalità Ig -.
Grado II:
infiltrato linfoide polimorfo,
necrosi prominente,
blasti B (RS simili) EBV+ molto abbondanti,
clonalità Ig +/- (anche diverse in sedi diverse).
Grado III:
quadro da linfoma a grandi cellule B,
(approccio clinico-terapeutico da LGCBD),
clonalità Ig +.
Lymphomatoid granulomatosis
Cute
SNC
Polmone
EBER
EBNA2
LMP1
ZEBRA
Thymus: normal B lymphocytes
Thymic follicles
Extrathymic perivascular
space
Medullary B lymphocytes
CD23+ asteroid B-cells
Fend F et al, Virchows Arch B 60:381, 1991.
CD27+: Remotti D et al. J Clin Pathol (Suppl), 2002.
CD23+: Calaminici MR et al, Histopathology 45:619, 2004.
TCL1-,
CLINICA
Predilezione per donne nella
IV decade di vita.
Malattia in I/II stadio all’esordio, con frequente
massa bulky (∅≥10 cm) e sindrome della vena
cava superiore.
Possibile diffusione al polmone, fegato, rene,
gonadi, intestino e SNC.
Molto sensibile al MACOP-B (in associazione con
la radioterapia, più recentemente al Rituximab).
Sclerosi con compartimentalizzazione
Cellule chiare
Cellule acidofile
FENOTIPO
CD30
CD45 e marcatori B
CD15
EBV
Bcl-6
IRF4
Bcl-2
Ig (anche ISH) (BOB.1+/Oct-2+/PU.1+)
Proteina MAL
FIG1
C-rel
86%
100%
80%
} CG
75%
80%
70%
75%
100%
CD30
Bcl-6
IRF4
Oct.2
BOB-1
Ig
GENOTIPO
Mutazioni di BCL-6
Mutazioni somatiche dei geni delle Ig
Amplificazione in 9p24
Break point in 16p13.13
CG
9p
NF-kB – C-REL
Large neoplastic cells within the lumina
of vessels, particularly capillaries, with
exception of larger arteries and veins.
Phenotype, Genotype
Clinical features
CD5+ DLBCL
IVL
Neurological signs
Cutaneous lesions
Respiratory disturbance
Histology, Clinical features
• When characteristic neurological and dermatologic
abnormalities are absent, the diagnosis of IVLBCL is
usually difficult, and often not made until autopsy.
• IVLBCL is usually associated with nonspecific
symptoms, such as fever, malaise and anemia,
probably due to dysregulation of inflammatory
cytokines.
• Many of the IVLBCL patients among Japanese are
associated with hemophagocytic syndrome (Murase
et al.1997).
Ki-67
IVLBCL
Asian
variant
Anthracycline-based chemotherapies are
effective for IVLBCL
1.0
Probability
.8
Log-lank
P<0.0001
.6
(N=61)
Ant hracycline
.4
Yes(N=62)(N=14)
censored
.2
No (N=17)
0.0
censored
0
1000
2000
Survival (Days)
3000
, 2008
ALK+ DLBCL: IgA/ALK+, CD30-, CD45+w, EMA+,
CD4+, CD57+
Median survival:
11 months
t(2;17)/CLTR/ALK, full-length ALK or t(2;5)/NPM/ALK
Linfoma Plasmoblastico
• Maschi HIV+ di età compresa fra 11 ed 86 anni (mediana:
50).
• Altre cause: immunosoppressione iatrogena.
• Costante presenza dell’EBV nel genoma delle cellule.
• Markers “plasmacellulari” (CD38, CD138, VS38c,
hTPD52, IRF4); negatività per CD20, PAX5 e CD45;
CD79a+; CIg+/-.
• Estrema aggressività (decesso entro 12 mesi).
IRTA1-, CD45 , CD20 ,
CD45-, CD20-,
markers plasmacellulari
linfoplasmocitico
markers plasmacellulari+
plasmoblasto
plasmacellula
Linfoma plasmoblastico (CD20-, CD45-, CD138+)
Chetty R et al. Histopathol 42:605-9, 2003
EBER
LGCBD in malattia di Castleman HHV8+
• Pazienti HIV+ con malattia di Castleman
multicentrica HHV8+ (Africa e Mediterraneo).
• Possibile associazione con il sarcoma di
Kaposi.
• Linfonodi, milza ed eventualmente sangue
periferico.
• Linfoma plasmoblastico.
• Sopravvivenza di pochi mesi.
HHV8
IgM
κ
λ
Primary effusion lymphoma:
Immunodeficiency (HIV).
HHV8-associated (+EBV).
Pleural, pericardial or peritoneal cavity + GIT or soft
tissues; no lymph node involvement.
Morphology: very pleomorphic
- cells with some
plasmacellular differentiation.
Phenotype:
CD45+, CD30+, CD38+, CD138+or -, LMP-1-,
B-cell markers- or + (IRF4). ISH: EBER+.
Prognosis:
rapidly fatal.
Primary effusion lymphoma
HHV8+ DLBCL
LANA > IL10 & IL6
Rectum – HIV+ patient
HIV+ patient
CMV
IRTA-1
Lambda
CD20
LANA
κ
V-IL6
λ
• Most cases have morphologic features intermediate
between BL and DLBCL.
• Some of them have been previously classified as
Burkitt-like lymphoma.
• They more often have high proliferation rate, starry-sky
pattern and immunophenotype consistent with BL.
• Some cases may be morphologically more typical of BL
but have an atypical immunophenotype or genetic
features that preclude a diagnosis of BL.
• These relatively rare lymphomas are more often widely
disseminated and observed in old individuals.
mBL index >.95
Trainingset
mBL index <.05
Typical Burkitt morphology
Impact of MYC breaks on survival of molecular subgroup
mBL
MYC break = favorable prognosis
NonNon-mBL/Intermediate MYCMYC-
NonNon-mBL/Intermediä
mBL/Intermediär MYC+
MYC break = unfavorable
prognosis
Definition of a novel prognostic
subgroup in aggressive B-NHL or
DLBCL
Age distribution
kein MYC Bruch
MYC Bruch
Genetic features
mBL
Intermediate
NonmBL
Genetic Complexity
3,5
8,8
9,3
MYC break (total)
91%
54%
7%
IGIG-MYCMYC-break
91%
33%
4%
NONNON-IGIG-MYCMYC-break
0%
21%
3%
