An estimated five-to-six thousand new cases of GIST are diagnosed annually with 10% to 30% of these being malignant [
2]. Most tumors are sporadic, affecting individuals in their 5th or 6th decade with some evidence indicating a male predominance [
2]. GISTs can also present earlier and this is often seen in one of the rare “GIST syndromes”, which include neurofibromatosis type 1 (NF1), the Carney-Stratakis dyad and familial GIST syndrome [
2]. These tumors may occur anywhere in the gastrointestinal tract but most commonly present in the stomach and small intestine. They can also occur in the surrounding structures such as the peritoneum, omentum, liver, pancreas, ovaries, and uterus [
2]. Many GISTs are asymptomatic and are discovered incidentally; however, over half of gastric GISTs present with signs of GI bleeding and anaemia with a smaller proportion presenting with abdominal pain or as an abdominal mass [
10].
GISTS are diagnosed based on the morphological and immunohistological features. Histology can often be varied, but GISTs are broadly divided into spindle, epithelioid, or mixed cell types. In general, the risk of malignancy is greater in epithelioid tumors than in spindle-celled neoplasms [
11,
12]. With the advent of immunohistology, the differentiation of GIST from other mesenchymal tumours has been made possible. Previously, sarcomas, undifferentiated carcinomas, and melanomas would have featured heavily in the differential diagnosis; however, these can largely be excluded with identification or absence of specific immunohistochemical markers [
13]. The three most well-described immunohistochemical markers in GISTs are CD117 (c-Kit), PDGFRA, and CD34 [
13,
14]. Kit is positive in over 95% of GISTs and only 5–8% of tumors are Kit negative and PDGFRA positive [
14]. CD34 is a less sensitve marker for GISTs but is reported in up to 60–70% of the tumors [
14]. Miettinen and Lasota who have carried out the largest ever studies on GISTs define these tumors as generally Kit-positive and Kit or PDGFRA mutation-driven mesenchymal tumors of the GI tract with a set of characteristic histologic features including spindle cell, epithelioid, and rarely pleomorphic morphology [
14].
We present the case of a malignant GIST of the gallbladder which demonstrated spindle cell morphology and was PDGFRA positive and Kit negative. There have been a small number of gallbladder GISTs described in the literature, of which only four were malignant and all were Kit positive. To our knowledge this presents the first ever recorded presentation of such a GIST. The significance of the Kit negative genotype has implications on the response to further management. The identification of specific cellular markers has led to the development of effective targeted agents, namely, tyrosine kinase inhibitor (TKI) therapy (e.g., imatinib). These have had dramatic effects in prolonging progression free survival in advanced unresectable disease [
15]. Most Kit positive tumors are sensitive to imatinib; however, the majority (80%) of PDGFRA mutations are resistant to treatment [
16].
Primary GISTs, as in the case here, have the potential for curative treatment with surgical resection. Overall 5-year survival rates for resectable GISTs have been shown to range from 46% to 78.5%; however, predicting the recurrence rate of primary resectable GISTs has been very challenging [
17,
18]. The survival rates from the reported gall bladder GISTs are mixed with only short-term followup noted in some of the cases. Although the mutation status is important, the current most important prognostic factor for GISTs is tumor size, mitotic count, and tumor location [
19]. This scheme has evolved from studies initially outlined by the National Institute of Health (NIH) and were greatly expanded on by the work of Miettinen and Lasota [
13,
14]. The patient in this case had a very large tumor, with 50 mitosis/50 HPF, and was located in the gallbladder. The first two findings alone place this GIST in the high-risk group for recurrence. This is likely compounded by the Kit negative immunohistology which would potentially reduce the benefit of tyrosine kinase inhibitors treatment. It is important to mention that the immunohistochemical examination does not provide information on the exon affected on the type of mutation both of which may be prognostically important.
Kit and PDGFRA
cells/mm3, Total Bilirubin/Direct Bilirubin (TBil/DBil) of 4.80/3.60
