Gastrointestinal stromal tumors (GISTs) and second malignancies

Abstract

Several evidences showed that patients with gastrointestinal stromal tumors (GISTs) develop additional malignancies. However, thorough incidence of second tumors remains uncertain as the possibility of a common molecular pathogenesis.A retrospective series of 128 patients with histologically proven GIST treated at our institution was evaluated. Molecular analysis of KIT and PDGFR-α genes was performed in all patients. Following the involvement of KRAS mutation in many tumors’ pathogenesis, analysis of KRAS was performed in patients with also second neoplasms.Forty-six out of 128 GIST patients (35.9%) had a second neoplasm. Most second tumors (52%) raised from gastrointestinal tract and 19.6% from genitourinary tract. Benign neoplasms were also included (21.7%). Molecular analysis was available for 29/46 patients with a second tumor: wild-type GISTs (n. 5), exon 11 (n. 16), exon 13 (n. 1), exon 9 (n. 1) KIT mutations, exon 14 PDGFR-α mutation (n. 2) and exon 18 PDGFR-α mutation (n. 4). KIT exon 11 mutations were more frequent between patients who developed a second tumor (P = 0.0003). Mutational analysis of KRAS showed a wild-type sequence in all cases. In metachronous cases, the median time interval between GIST and second tumor was 21.5 months.The high frequency of second tumors suggests that an unknown common molecular mechanism might play a role, but it is not likely that KRAS is involved in this common pathogenesis. The short interval between GIST diagnosis and the onset of second neoplasms asks for a careful follow-up, particularly in the first 3 years after diagnosis.

Cross-testing of major molecular markers indicates distinct pathways of tumorigenesis in gastric adenocarcinomas and synchronous gastrointestinal stromal tumors

“…Our results provide further support to this, since only six of our cases carried mutations in c-KIT or PDGFRα, whereas the rest three cases proved to be negative for all of the investigated exons. The most frequently mutated exon was the c-KIT exon 11, concordantly with other studies 5,6,10,13 . One mutation in the exon 18 of the PDGFRα (D842V) is reported to be associated with resistance to imatinib 11,40 .…”

“…Several studies reported high sporadic coincidence of GISTs and other neoplasms and described GISTs as "sentinel tumors" 13,21,50 . In the case of adjacent synchronous tumors, we speculate that the gastrointestinal adenocarcinoma provides a growth factor-rich microenvironment, which induces the development of GIST from the nearby Cajal cells.…”

“…Since GISTs were identified as a separate entity in the '80s, several issues have remained unanswered. The rising number of diagnosed MGs has drawn the attention to its synchronous presentation with other gastrointestinal malignancies, especially with gastric adenocarcinomas 3,9,[13][14][15][16] . In order to explore this phenomenon, we comprehensively characterized gastric adenocarcinomas with coincidental MGs from the epidemiology of its synchronous presence to the analysis of the major molecular pathways of both tumors.…”

Gastrointestinal stromal tumors and second primary malignancies: a retrospective monocentric analysis

“…Neurofibromatosis, in which GISTs are associated with multiple additional benign and malignant tumors [7,8]. In several single institution case series and reviews, patients with sporadic GIST are reported to have an increased incidence of synchronous or metachronous secondary neoplasms at rates from around 4.5% to 43% [8][9][10][11][12][13][14][15][16][17][18][19][20].…”

“…The revolutionary survival increase of GIST patients is a key example of how the advancement in screening, diagnosis, treatment and follow up have increased the life expectancy of cancer patients and, consequently, how cancer survivors live long enough to develop second primary tumors. Rodriquenz et al[8] indeed suggested tumor important component of the clinical management and follow up of GIST patients, especially in the first years after GIST diagnosis. This is most important to highlight because, even today, many symptoms and new lesions in GIST patients are still misinterpreted.…”