We reported a rare case of a primary pancreatic GIST: the small size, the well circumscribed margins of the lesion, and the contrast enhancement at CT examination suggested a diagnosis of neuroendocrine tumor of the pancreas. GISTs reported outside the gastrointestinal tract as apparent primary tumors are defined as ‘extra-gastrointestinal stromal tumors’ (EGISTs). The concept of GIST has recently been established, due to the progress in immunohistochemical analyses. It is presumed that these tumors originate from the interstitial cells of Cajal (ICCs), pacemaker cells, which are present throughout the wall of the gastrointestinal tract and which regulate the motility. ICCs share many characteristics with EGISTs, including expression of CD117 and CD34 [
2]. In fact, the most selective immunohistochemical markers differentiating GISTs from true smooth muscle tumors is the expression of the c-Kit receptor tyrosine kinase (CD117 antigen) in 95% of GISTs. In 2004, Yamamoto et al. [
31] reported that EGISTs show similar KIT mutations of typical GISTs suggesting that these tumors have a similar origin. However, at present the origin of EGISTs remains controversial. Some authors believe that GISTs and EGISTs arise from the common precursor cell of ICCs and the smooth muscle cells of the gut, which may account for their growth within and outside the gastrointestinal tract [
33]. Other, simpler, explanation suggests that EGISTs are in fact mural GISTs with extensive extramural growth, resulting in eventual loss of their connection with the gut wall [
33].
Pancreatic GISTs are extremely rare. We collected only 21 cases (including our patient) from the English literature: their clinicopathologic features and outcomes are summarized in Table
1. The age of the patients ranges from 30 to 84 years, with a mean age of 55.0 years. The male:female ratio was 10:11. Ten of 21 (48%) tumors occurred in the head of the pancreas, five in the tail (34%), four involved both body and tail (19%), and two occurred in the uncinate process (%). EGIST rarely (
n = 1.5%) involved the entire pancreas [
24]. There is a great variation in size (range, 2.4 to 34 cm). The mitotic count was <5/50 HPFs in eight cases (38%) and >10/50 HPFs in four cases (19%). Molecular biology of EGIST has been investigated in only two reports [
14,
22] and in our patient: two exhibited deletion of base pairs in exon 11, and one showed DNA polymorphism of L862L in exon 18 of c-KIT gene [
22]. All but one patient underwent surgery: one patient with metastatic disease died 5 days after admission without operation. One patient underwent palliative operation (cystojejunostomy) and the remaining 17 patients underwent pancreatic resection (in 5 extended to adjacent organs), one had local resection, and one (our case) enucleation of the tumor. Follow-up was available in 19 cases. Disease recurrence following surgery was reported in five cases: three patients underwent re-resection and are alive and free after 30, 41, and 48 months, respectively. Overall, 18 patients are alive with a median survival time of 17.5 months (range, 1 to 66 months). Despite the limited number of cases and the short follow-up time, it appears that resection of pancreatic GISTS may offer a good prognosis, even in recurrent disease.
Table 1
Clinicopathologic features, treatment, and outcome of EGISTs reported in the English literature
| 2004 | 67 | F | Body and tail/DP + Imatinib | 20 | 120; CD117(+) CD34(+) | A, Relapse, 1 |
| 2004 | 54 | F | Tail/DP | 14 | Few; CD117(-) CD34(+) | A, NED, 30 |
| 2005 | 38 | F | Body and tail/DP | 17 | 1; CD117(-) CD34(+) | A, NED, 30 |
| 2005 | 70 | F | Head/PD + Imatinib | 10 | 2; CD117(+) CD34(-) | A, NED, 6 |
| 2008 | 72 | F | Tail/DP | 7 | 3; CD117(+) CD34(-) | A, NED, 27 |
| 2008 | 47 | M | Uncinate process/NR | 2.4 | 3; CD117(+) CD34(-) | NA |
| 2008 | 55 | M | Body and Tail/DP + Imatinib | NR | NR; CD117(+) CD34(+) | Relapse, 24,- A, NED,41 |
Harindhanavudhi et al. [ 18] | 2008 | 63 | F | Body/Cystojejunostomy + Imatinib | 16 | <5; CD117(+) CD34(+) | NA |
| 2009 | 52 | F | Head/PD | 10.5 | 6; CD117(+) CD34(+) | A, NED, 10 |
| 2009 | 58 | M | Head/PD | 9 | >10; CD117(+); CD34 (-) | A, NED, 60 |
| 2010 | 42 | F | Body and tail/DP | 35 | 6-8; CD117(+) CD34(+) | A, NED, 10 |
| 2010 | 31 | M | Head/PD + Imatinib | 8 | 48; CD117(+) CD34(-) | A, Relapse, 9 |
| 2010 | 61 | M | Tail | 34 | NR | A, NED, 3 |
| 2010 | 84 | M | Whole pancreas/NOP | 34 | NR; CD117(+) CD34(+) | Dead day 5 of admission |
| 2011 | 40 | M | Head and body/PD + Imatinib | 6.5 | 8-10; CD117(+) CD34(+) | Relapse, 24; A, NED 30 |
| 2011 | 74 | F | Tail/DP | 11 | <5; CD117(+)CD34(+) | A, NED, 66 |
| 2011 | 35 | M | Head/PD + Imatinib | 6.5 | 12-15; CD117(+) CD34(-) | Relapse, 24; A, NED 48 |
| 2012 | 39 | M | Head/PD + Imatinib | 9 | 5; CD117(+) CD34(+) | A, NED, 24 |
| 2012 | 55 | M | Tail/DP + Imatinib | 15.8 | 7; CD117(+) CD34(-) | A, NED, 4 |
| 2012 | 55 | F | Head/local resection | 5 | 6-8; CD117(+); CD34 (+) | A, NED, 11 |
Present case | 2013 | 63 | F | Uncinate process/enucleation | 2.4 | 1; CD117(+) | A, NED, 6 |
The clinical presentation of EGISTs is variable, depending on the location and size of the tumors. The tumor may even be found incidentally. The most frequent clinical symptoms are: abdominal pain, ileus, bleeding, anemia, and weight loss. Our patient presented with a small, solid, hyperintense lesion resembling a neuroendocrine tumor. A similar finding of small, solid tumor in the uncinate process of the pancreas was reported by Yan et al. [
16] in a case of GIST diagnosed by EUS fine-needle aspiration (FNA): unfortunately, biopsy was not available for our patient. Interestingly, 50% (11/21) of the reported cases showed radiologic features of heterogeneously mass (necrotic areas) or solid-cystic appearance; thus, problems in differential diagnosis with cystic neoplasms of the pancreas could be arise. The accuracy of CT determination of the pathological diagnosis of a pancreatic cystic lesion is less than 50% [
34,
35], but endoscopic ultrasound-guided FNA may be helpful for the diagnosis of pancreatic lesions [
36]. The diagnosis of GIST is based on histological, immunohistochemical, and molecular features. Microscopically, this tumor, consisted of spindle cell and epithelioid cells. The cytologic differential diagnosis for these spindle cell proliferations includes leiomyoma, schwannoma, fibromatosis, inflammatory fibroid polyps, and gastrointestinal muscularis sampling [
16]. Immunoistochemical positivity of CD117 confirms the diagnosis of GIST. GISTs exhibit a broad spectrum of clinical behaviors, with some low-risk lesions remaining stable for years, while others progress rapidly to metastatic disease. Various parameters are proposed to predict the malignant potential of GIST, such as tumor size, mitotic activity, tumor location, non-radical resection, tumor rupture, peritoneal dissemination, metastasis, and invasion into adjacent organs. National Institute of Health (NIH) consensus criteria (Fletcher’s criteria) [
37] proposed risk stratification of tumor behavior into risk categories of very low, low, intermediate, and high risk of metastasis, based on its size and mitotic activity. Tumors larger than 10 cm in size and with more than 10 mitoses per 50 HPF are at high risk of aggressive behavior [
33,
37]. Standard treatment for primary GIST is complete surgical resection with the aim to obtain negative microscopic margins of resection [
13,
38,
39]. Lymphatic spread of GISTs is uncommon; therefore, a systematic lymph node dissection is not a standard surgical management. In our patient we performed a simple tumor’s enucleation because of a preoperative diagnosis of neuroendocrine tumor. However, after discussion with oncologists, the small size of the lesion and the low-risk according to previously reported prognostic criteria [
37], suggested that it was an adequate operation, as reported in a recent study [
40]. The patient is alive and free of disease 1 year after operation. The surgical management may offer primary surgery at the time of diagnosis, neoadjuvant chemotherapy followed by surgery, adjuvant therapy after surgery, or debulking surgery in patients with metastatic or advanced disease. Observation only was recommended in case with R0 resection or low-risk GIST. In recent decades, medical therapy for GIST is improved (Imatinib, Sunitinib, Nilotinib, Sorafenib, Dovitinib, and so on) and consequently disease-free survival after surgery is also much improved: in fact, it is recommended in patients with R1 or R2 resection [
41]. The results of some clinical trials [
42‐
49] with targeted therapy of GIST are reported in Table
2. Obviously, data about targeted therapy for EGIST are limited. In the review of the literature, among 19 high-risk EGISTs, only nine cases (47%) received adjuvant Imatinib therapy (Table
1).
Table 2
Selected agents investigated in the management of GIST
| 2002 | 147 | II | Imatinib | OR | 81.6% | |
| 2006 | 312 | III | Sunitinib/placebo | TTP | 27.3 vs. 5.4 weeks | <0.0001 |
| 2008 | 746 | III | Imatinib 400 mg/ | PFS | 18 vs. 20 months | 0.13 |
Imatinib 800 mg | OS | 55 vs. 51 months | 0.83 |
| 2009 | 713 | III | Imatinib/placebo | PFS | 98% vs. 83% | <0.0001 |
| 2009 | 30 | II | Masitinib | PFS | 165.2 weeks | |
| 2011 | 35 | II | Nilotinib | PFS | 16 weeks | |
| 2011 | 31 | II | Sorafenib | PFS | 4.9 months | |
OS | 9.7 months |
| 2012 | 400 | III | Imatinib 12mo/36mo | RFS & OS | 65.6% vs. 47.9% | <0.0001 |
| | | | | | 92.0% vs. 81.7% | 0.019 |