Tumori Germinali Del Testicolo European Training Centre for Clinical Andrology Università dell’Aquila Tumori Germinali Del Testicolo Sandro Francavilla Focus on Endocrine Neoplasia, Roma, Luglio 2010

GCT EPIDEMIOLOGIA E’ il tumore maschile più diffuso nelle fascia di età tra i 15 ed i 45 anni McGlynn, J Clin Oncol 2005

GCT EPIDEMIOLOGIA Rejpert-De-Meyts, Ann NY Acad Sci1120, 2007

Differenze etnico-geografiche -fattori ambientali ? TESTIS CANCER INCIDENCE RATE IN EUROPE Differenze etnico-geografiche -fattori ambientali ? -fattori genetici ?

? ENVIRONMENTAL EFFECT Immigration studies indicate potential environmental factors acting during fetal life (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 their Country of origin, whereas the second generation (born in Sweden) Had a similar risk to native Swedes ENVIRONMENTAL EFFECT

parental subfertility? GCT EPIDEMIOLOGIA Maternal risk factors Cook, Int J Epidemiol 38, 2009 parental subfertility?

GCT EPIDEMIOLOGIA Subfertility and GCTs risk RR Cryptorchidism RR: 2-10 fold Peng, Plos One 4, 2009

? GENETIC FACTORS DIFFERENT INCIDENCE IN DIFFERENT ETHNIC GROUPS WHITE POPULATION (USA AND SOUTH ENGLAND) 5 fold HIGHER risk IN RESPECT TO BLACK POPULATION

FAMILIARITY for Testis “cancer” (Testicular Germ Cell Tumor,TGCT) is the STRONGEST RISK FACTOR BROTHER: 8 fold risk Sharing common: genetic factors intra uterine environmental factors FATHER: 4 fold risk Sharing common: -genetic factors

GENETIC FACTORS Crockford, G. P. et al. Hum. Mol. Genet. 2006 15 Copyright restrictions may apply. Crockford, G. P. et al. Hum. Mol. Genet. 2006 15

Search for GENETIC FACTORS Candidate gene approach: gene-environment interaction: -AR (CAG)n -ESR1 -P450 genes Germ cell development (mouse model) -DND1 -PDE11A K. Krausz, Univ. Firenze

Genetic changes in TGCTs 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 Chromosome 12 Chromosome analyses cDNA microarray Rodriguez,Oncogene, 22, 2003

POTENTIAL GENETIC FACTORS INVOLVED IN TGCTs 4q ESR1 AR P450 Modified from Chanock, Nat. Genet. 2009

The migratory pathway of primordial germ cells OCT4; AP PGCs Francavilla. J Submicr Cytol Path 1990

Marcatori di PGCs Rejpert-De-Meyts, Ann NY Acad Sci1120, 2007 Francavilla. J Submicr Cytol Path 1990

Marcatori di PGCs AP-2Y CIS OCT-3/4 Seminoma

Pathology

Pathology WHO Horwich, Lancet, 367, 2006

Pathology 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

Seminoma Non Seminoma Rischio Neoplasia Rischio CVD

Radio Ter Risk for second Cancer &/or CVD Chemio Chirurgia

SEMINOMI STADIO I : SORVEGLIANZA Urology, 67, 2006

SEMINOMI : STADI II CHT in caso di N multipli ed in prossimità del rene Krege S Europ Urol 2008 Ricadute globali 0-15% Ricadute nel volume irradiato 0-2% OS > 99% II B 89% Classen JJ Clin Oncol 2003 II A 95% 6 aa RFS

PAZIENTI IN AZOOSPERMIA PAZIENTI IN AZOOSPERMIA 3% 6% 12% 34% 37% 24 Mesi 12 Mesi 9 Mesi 6 Mesi 3 Mesi 9% 19% 26% 4% 6 3 PAZIENTI IN AZOOSPERMIA DOPO CHEMIOTERAPIA 3 cicli PEB PAZIENTI IN AZOOSPERMIA DOPO RADIOTERAPIA dose totale 2600 cGy

PARAMETRI SEMINALI PRE E POST CHEMIOTERAPIA TUMORI TESTICOLARI 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 Modificato da: Gandini et al. 2006

PARAMETRI SEMINALI PRE E POST TUMORI TESTICOLARI PARAMETRI SEMINALI PRE E POST Radioterapia 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 Atipie 64.6 ±15.8 80.5 80.1 ±22.1 62.4 ±12.8 Modificato da: Gandini et al. 2006

LA RIPRESA DELLA SPERMATOGENESI DELLA QUALITÀ DEI PARAMETRI SEMINALI DOPO TERAPIA NON E’ FUNZIONE DELLA QUALITÀ DEI PARAMETRI SEMINALI PRE-TERAPIA

crioconservazione preventiva Tumori 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 crioconservazione preventiva

RINGRAZIAMENTI Loredana Gandini Università di Roma “La Sapienza” Csilla Krausz Università di Firenze