同时和异时性多发性 胃肠道间质瘤 Synchronous and metachronous sporadic multiple GIST

1. 同时和异时性多发性胃肠道间质瘤Synchronous and metachronous sporadic multiple GIST 侯英勇 复旦大学附属中山医院病理科

2. Aims • Sporadic multiple gastrointestinal stromal tumor (GISTs) especially metachronous GISTs are extremely rare • The metachronous GISTs raise the challenge in adjuvant therapy in imatinib era • The aim of this study was to investigate the clinical, phenotype, genetic characteristic, and biological behavior of synchronous and metachronous GISTs

3. Methods • Retrospectively investigation from archive file of Zhongshan Hospital • Dec 2002 to Dec 2009 • 427 primary GIST+195 consultant patient (622 cases) • Thirty-two paraffin blocks of multiple GISTs and 15 normal tissues were obtained • Reviewing HE slides • Immunohistochemical staining • KIT and PDGFRA gene mutation analysis

4. Results • the frequency of occurrence was 2.4% (15/622) • There were 5 males and 10 females • the age at diagnosis ranged from 49 to 84 years (mean 66.9 years) • 13 patients had synchronous GISTs • the number of GIST were 2 in 11 patients and 3 in 2 patients • Two patients was defined as metachronous GIST • one had a new gastic GIST 7 month after the initial duodenal GIST surgery • one had a new gastric GIST 43 months after the initial gastric GIST resection

8. A total of 31 gastric GIST and 1 duodenal GIST from 15 patients were available • The tumor sizes ranged from 0.2 to 12 cm (mean 2.7 cm) • The size ratio of different tumors in each patient ranged from 1.2 to 12 (median 3.2 and mean 5.4)

9. Spindle shaped in 27 (84.3%), mixed cell type in 3 (9.4%), and epithelioid cell type in 2 (6.3%) • Histopathological patterns within a patient were uniform in 12 patients, 3 patients presented with different cell shape in each tumor mass • Mitotic figures were 0 in 20 GISTs, 1 in 3 GISTs, 2 in 1 GISTs, 3 in 1 GIST, 4 in 3 GISTs, 5 in 1 GIST, 7 in 1 GIST, 9 in 1 GIST and 25 in 1 GIST per 50 high-power fields • Nonmalignant in 26 GISTs, low malignant in 6 GISTs

11. CD117 were positive in 90.6% of multiple GISTs (29/32) • CD34, smooth muscle actin (SMA), S-100 protein, and desmin were positive in 90.6%, 9.4%, 0%, and 0%, respectively

13. Twenty six GIST masses from 15 patients showed mutations on exon 11 of KIT gene • 1 tumor showed D842V mutation in exon 18 of PDGFRA gene • 5 GIST masses showed no mutation in examined exons, the overall mutation rate was 84.4% (27/32)

14. There was 11 point mutation involving 557, 559, 560 and 576 codons respectively • 8 deletions, of them, 5 involving 557-558 codons • 4 duplication involving 573-587 codons • and another 3 were point mutation plus deletion

15. Of the 15 patients • 6 patients with multiple GIST masses had the same genotype with or without gene mutation • 9 patients were found the different mutation type and codon site within each GIST mass • in patients with 3 GIST masses • in 2 patients with metachronous GISTs

18. One patient lost follow up • two patients died of esophageal carcinoma 4 years later and one patient died of gastric adenocarcinoma 2.1 years later • 12 patients are still alive at 3 to 51 month • No patients had any associated clinical manifestations of hyperpigmented lesion, systemic mastocytosis, or NF-1, Carney’s symdrome and family GIST.

19. In summary • synchronous and metachronous sporadic multiple GISTs experienced indolent clinical course • most of them presented with polyclonal KIT or PDGFRA gene mutation • multiple GISTs especially metachrounous multiple GISTs indicated that in rare situation GIST suspected as recurrent or metastatic disease are not truly malignant, but polycolonal primaries • It is challenge for us in imatinib era • Meticulous evaluations including clincopathological, immunohischemical and genetic evaluation are helpful for patients to selecting therapeutic strategies