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Gastrointestinal stromal tumors increase risk for additional malignancies

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May 19, 2015

Patients with gastrointestinal stromal tumors faced an increased risk for developing additional cancers before and after their diagnosis, according to results of a SEER analysis.

“Only 5% of patients with gastrointestinal stromal tumors have a hereditary disorder that predisposes them to develop multiple benign and malignant tumors,” Jason K. Sicklick, MD, of the division of surgical oncology at the UC San Diego Moores Cancer Center, said in a press release. “The research indicates that these patients may develop cancers outside of these syndromes, but the exact mechanisms are not yet known.”

Researchers used the SEER database to identify 6,112 patients diagnosed with gastrointestinal stromal tumor (GIST) between 2001 and 2011. Fifty-three percent of patients were men, and the most common age range at diagnosis was 60 to 69 years (25%). Researchers excluded patients younger than 20 years at the time of diagnosis because they had a high likelihood of having hereditary syndromes.

Researchers calculated standardized prevalence ratios (SPR) — or cancer occurrence before GIST diagnosis — and standardized incidence ratios, or the risk for cancer after GIST diagnosis, by comparing data from the patients with data from the general U.S. population in 2000.  

Seventeen percent of patients (n = 1,047) had additional cancers, which represented one in every 5.8 patients with GIST. More patients were diagnosed with other cancers before GIST vs. during the same month or after GIST diagnosis (62.2% vs. 44.6%).

Patients with a GIST had a 44% (SPR = 1.44; 95% CI, 1.33-1.55) increased prevalence of additional cancers before a GIST and a 66% (SIR = 1.66; 95% CI, 1.52-1.81) increased risk for developing cancers after a GIST compared with the general population.

Malignancies that occurred significantly more frequently among patients before and after a GIST diagnosis included other sarcomas (SPR = 5.24; SIR = 4.02), neuroendocrine-carcinoid tumors (SPR = 3.56; SIR = 4.79), non-Hodgkin’s lymphoma (SPR = 1.69; SIR = 1.76) and colorectal adenocarcinoma (SPR = 1.51; SIR = 2.16).

Malignancies with significantly increased occurrence rates only prior to a GIST diagnosis included esophageal adenocarcinoma (SPR = 12), bladder adenocarcinoma (SPR = 7.51), melanoma (SPR = 1.46) and prostate adenocarcinoma (SPR =1.2).

Occurrence rates were significantly increased only after a GIST diagnosis for ovarian carcinoma (SIR = 8.72), small intestine adenocarcinoma (SIR = 5.89), papillary thyroid cancer (SIR = 5.16), renal cell carcinoma (SIR = 4.46), hepatobiliary adenocarcinoma (SIR = 3.1), gastric adenocarcinoma (SIR = 2.7), pancreatic adenocarcinoma (SIR = 2.03), uterine adenocarcinoma (SIR = 1.96), non–small cell lung cancer (SIR =1.74) and transitional cell carcinoma of the bladder (SIR =1.65).

Researchers observed a higher incidence of additional cancers before a GIST diagnosis among non-Hispanic white patients compared with Hispanic patients (P = .02).

Further, patients whose primary tumors were 10 cm or smaller displayed increased rates of second cancers, and patients whose tumors were 2 cm or smaller were at the greatest risk.

The researchers acknowledged these data may be limited by a detection bias during the evaluation for symptomatic patients or follow-up after GIST treatment, which may lead to elevated occurrences of additional cancers.

“Further investigation is necessary to link the histologically confirmed, epidemiological findings from this and other population-based studies with relevant clinical decision making,” Sicklick and colleagues concluded. “In addition, the development of a national registry is necessary to capture patients with potential syndromes, raise awareness, identify prevention strategies and elucidate the role of genetic counseling.”

These data have the potential to increase awareness and detection of GISTs, Constantine A. Stratakis, MD, DMedSci, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the NIH, wrote in an accompanying editorial.

“Whatever the mechanism explaining the observation of the authors, the implications of their findings are significant for those of us who take care of patients with GISTs,” Stratakis wrote. “As [the researchers] suggest, counseling of these patients should include the possibility of finding another tumor, and clinicians should bear in mind that another, totally unrelated lesion may be found as they screen for possible metastasis of the primary GIST. Patients with other tumors may also be found to be carrying a GIST, and in both cases, whether the other lesion is found before or after a GIST, the possibility of genetic and/or syndromic association should be considered.” – by Cameron Kelsall

Disclosure: The researchers report no relevant financial disclosures.

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Charis Eng

Charis Eng

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumor of the GI tract, have always captured the imagination because of its notoriety as a component of the Carney Triad (CT). CT was reported in 1983 by J. Aiden Carney, MD, PhD, as the triad of gastric epithelioid leiomyosarcoma, extra-adrenal paraganglioma and pulmonary chondroma. Gastric epithelioid leiomyosarcoma is now known as GIST. GIST was not recognized as a distinct molecular entity until 1998 when somatic driver mutations in the KIT proto-oncogene were identified. This formed the basis of targeted therapy, initially with imatinib (Gleevec, Novartis). Subsequently, other somatic mutations — eg, in PDGFRA — were identified as contributing to GIST pathogenesis.
After Carney’s first description of CT, several case series have described individuals with GISTs having prevalent or subsequent other neoplasias, beyond those found in CT. Except for the association between GIST and leukemia, various other associations have been descriptive and have never been quantified. Murphy and colleagues used the NCI SEER database to quantitate malignancies associated with GIST diagnosed between 2001 and 2011. Among 6,112 patients with a GIST diagnosis, 17.1% were found to have a prevalent (standardized prevalence ratio = 1.44) or subsequent (standardized incidence ratio = 1.66) malignancy diagnosis. Ironically, the association with leukemia could not be confirmed. Instead, eight sites were overrepresented before GIST was diagnosed, and 15 different solid tumor types were diagnosed after GIST.
One of the clinical “red flags” signaling heritability is multiple malignancies. As pointed out by the authors, germline mutations in PDGFRA and in KIT have been described in familial GIST. Similarly, germline mutations in one of the four genes which encode mitochondrial complex II or succinate dehydrogenase have been described in Carney Dyad (Carney-Stratakis syndrome comprising GIST and paraganglioma). GIST is believed to be caused by germline mutation in a known Mendelian susceptibility gene in 5% of cases. Taken together, the pattern of prevalent and subsequent neoplasias of GIST consistent with these syndromes account for about 7% in this study. The authors suggest other etiologies must explain their association. In the era of massively parallel sequencing, the time is ripe to exome or genome sequence the germline from those with GIST and one or more primary neoplasms. Despite the caveats discussed by the authors, such as therapy-related neoplasias, it is possible that the heritable fraction of GIST is well over 5%, perhaps encompassing all 17% of the patients with GIST who developed a second cancer. Only a decade ago, pheochromocytoma/paraganglioma is known as the “10% tumor” because 10% were believed to be hereditary. Over the decade with the discovery of SDHx genes and at least 10 genes for pheochromocytoma/paraganglioma, we now know that the heritable fraction here is greater than 40%. Why is it important to identify which individuals with GIST have a germline mutation? Not only would this allow for prediction of those who with GIST would have a high likelihood of second and subsequent primary neoplasias, but it may also help select treatment and even prevention.
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Neumann HP, et al. N Engl J Med. 2002;doi:10.1056/NEJMoa020152.
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Charis Eng, MD, PhD
HemOnc Today Editorial Board member
Cleveland Clinic

Disclosure: Eng reports no relevant financial disclosures.