Sandro Francavilla
Tumori Germinali Tumori Germinali
Del TesticoloDel Testicolo
EuropeanTraining Centre for Clinical Andrology
Università dell’Aquila
Focus on Endocrine Neoplasia, Roma, Luglio 2010
McGlynn, J Clin Oncol 2005
GCTE’ il tumore maschile più diffuso nelle fascia di età tra i 15 ed i 45 anni
EPIDEMIOLOGIA
Rejpert-De-Meyts, Ann NY Acad Sci1120, 2007
GCT EPIDEMIOLOGIA
TESTIS CANCER INCIDENCE RATE IN EUROPE
Differenze etnico-geografiche-fattori ambientali ?-fattori genetici ?
Immigration studies indicate potential environmental factors acting during fetal life
ENVIRONMENTAL EFFECT
(Hemminki, 2002: Danish migrating in Sweden)
Comparison of testis cancer incidence between first and second generations
The first generation immigrants retained the incidence as in theirCountry of origin, whereas the second generation (born in Sweden)Had a similar risk to native Swedes
ENVIRONMENTAL EFFECT
?
Maternal risk factors
Cook, Int J Epidemiol 38, 2009
GCT EPIDEMIOLOGIA
Peng, Plos One 4, 2009
Subfertility and GCTs risk
RR
Cryptorchidism RR: 2-10 fold
GCT EPIDEMIOLOGIA
GENETIC FACTORS
DIFFERENT INCIDENCE IN DIFFERENT ETHNIC GROUPS
WHITE POPULATION (USA AND SOUTH ENGLAND) 5 fold HIGHER riskIN RESPECT TO BLACK POPULATION
?
BROTHER: 8 fold risk
Sharing common:genetic factorsintra uterine environmental factors
FATHER: 4 fold risk
Sharing common:-genetic factors
FAMILIARITY for Testis “cancer” (Testicular Germ Cell Tumor,TGCT)
is the STRONGEST RISK FACTOR
Copyright restrictions may apply. Crockford, G. P. et al. Hum. Mol. Genet. 2006 15
GENETIC FACTORS
Candidate gene approach:Candidate gene approach:gene-environment interaction:-AR (CAG)n -ESR1-P450 genesGerm cell development (mouse model)-DND1-PDE11A
Search for GENETIC FACTORSSearch for GENETIC FACTORS
K. Krausz, Univ. Firenze
Chromosome 12 Chromosome analyses
cDNA microarray analyses
Rodriguez,Oncogene, 22, 2003
Chromosome number in the triploid range and shows specific chromosomal gains at chromosomne 7, 8, 12, 21 and X, and Losses at 11, 13, 18
80% TGCT
POTENTIAL GENETIC FACTORS INVOLVED IN TGCTsPOTENTIAL GENETIC FACTORS INVOLVED IN TGCTs
ESR1ARP450
Modified from Chanock, Nat. Genet. 2009
12p
4q
The migratory pathway of primordial germ cells
OCT4; AP PGCs
Francavilla. J Submicr Cytol Path 1990
Rejpert-De-Meyts, Ann NY Acad Sci1120, 2007
Marcatori di PGCs
Francavilla. J Submicr Cytol Path 1990
OCT-3/4
Seminoma
Marcatori di PGCs
AP-2Y
CIS
WHO
Horwich, Lancet, 367, 2006
Horwich, Lancet, 367, 2006
J Urol, 180, 2008
Second Cancers in pts with testis cancer (S & NS) who survive > 10 yrs
RR (95% CI)
Connective Tissue 4.0 (2.3-6.3)Stomach 4.0 (3.2-4.8)Pancreas 3.6 (2.8-4.6)Mesothelioma 3.4 (1.7-5.9)Bladder 2.7 (2.2-3.1)Colon 2.0 (1.7-2.5)Esophagus 1.7 (1.0-2.6)Lung 1.5 (1.2-1.7)
Tumor (solid) RR (95% CI)
derived from Travis LB et Al, J Natl Cancer Inst 2005 ;97:1354
Rischio Neoplasia
Seminoma
Non Seminoma
Rischio CVD
Risk for second Cancer &/orCVD
Chirurgia
Radio Ter
Chemio
Urology, 67, 2006
SEMINOMI STADIO I : SORVEGLIANZA
SEMINOMI : STADI II
CHT in caso di N multipli ed in prossimità del rene Krege S Europ Urol 2008
6 aaRFS
Ricadute globali 0-15%Ricadute nel volume irradiato 0-2%OS > 99%II B 89% Classen JJ Clin Oncol 2003
II A 95%
166 pazienti
PAZIENTI IN
AZOOSPERMIA
DOPO CHEMIOTERAPIA
3 cicli PEB
PAZIENTI IN
AZOOSPERMIA
DOPO RADIOTERAPIA
dose totale 2600 cGy
3%6%12%34%37%
24 Mesi
12 Mesi
9
Mesi
6 Mesi
3 Mesi
6%9%19%26%4%
24 Mesi
12 Mesi
9
Mesi
6
Mesi
3
Mesi
CRIO 3 MESI 6 MESI 24 MESI
Tot/ejac. 83.6±78.3
10.9±15.2
*** 23.6±33.8
*** 146.8±101.4
**
Mot.rett. 31.6±16.9
11.8±12.8
** 14.5±17.4
* 41.4±14.0
**
Atipie 66.8±13.3
85.2±13.8
*** 84.4±16.4
*** 62.7±7.7
ns
PARAMETRI SEMINALI PRE E POST
CHEMIOTERAPIA
TUMORI TESTICOLARI
Modificato da: Gandini et al. 2006
CRIO 3 MESI 6 MESI 24 MESI
Tot/ejac. 115.9±110.1
30.0±51.9
** 25.1±46.1
*** 111.2±81.1
ns
Mot.rett. 33.2±16.0
17.8±16.3
*** 15.9±19.2
** 39.6±13.1
ns
Atipie 64.6±15.8
80.5±15.8
*** 80.1±22.1
*** 62.4±12.8
ns
PARAMETRI SEMINALI PRE E POST
Radioterapia
TUMORI TESTICOLARI
Modificato da: Gandini et al. 2006
LA RIPRESA DELLA SPERMATOGENESI
DOPO TERAPIA
NON E’ FUNZIONE
DELLA QUALITÀ DEI PARAMETRI SEMINALI
PRE-TERAPIA
Tumori Germinali Del TesticoloTumori Germinali Del Testicolo
E’ il tumore maschile più diffuso tra i 15 ed i 45 anni
ENVIRONMENTAL EFFECT
?GENETIC FACTORS
Origina da PGCs
Elevata Sopravvivenza
Rischio per Seconda Neoplasia & CVD
Rischio per Infertilità Irreversibile
Csilla Krausz Università di Firenze
Loredana Gandini Università di Roma “La Sapienza”