Extra-Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common type of gastrointestinal mesen- chymal tumors. C-Kit genetic mutation and KIT (CD117) expression have been observed in the majority cases of GIST [1, 2]. The prognosis of patients with GISTs is correlated with the tumor site, mitotic count, size, and expression of Ki-67 [3, 4]. The observations of mesenchymal tumors growing outside of the gastrointestinal tract, also called extra-gastrointestinal stromal tumors (EGISTs), have been increasingly report- ed in recent years; these tumors present the morphology, immunohistochemical features, and molecular biological characteristics, which are similar to those of GISTs. Only a few reports of EGISTs are available in the literature due to its low incidence compared with other tumors. In this retrospective study, we analyzed several predictive factors including clinical and patho- logical parameters on the diseases-free surviv- al (DFS) of 42 EGISTs patients.

The present case can be considered a primary hepatic GIST because of the following two findings. First, pre- operative gastroscopy and colonoscopy imaging studies and extensive pathological examination of the resected stomach failed to detect any other GISTs, except for a hepatic tumor. Second, there was no evidence of recur- rence and no neoplastic lesions after hepatectomy in the absence of adjuvant chemotherapy. ICCs are normally present in the myenteric plexus of the gastrointestinal tract, and they have not been identified in the liver. Con- sequently, is it possible that primary GISTs can occur in the liver? We initially suspected that primary hepatic GISTs might originate from the biliary system in the liver. Ahmadi et al. reported that ICCs were identified in the extrahepatic bile ducts [10]; unfortunately, the exist- ence of ICCs was not recognized in intrahepatic bile ducts. However, Popescu et al. demonstrated that ICCs are present in human exocrine pancreas; such cells were named pancreatic ICC and later called ICLCs [8]. Subse- quently, ICLCs were identified in many sites such as the following: the upper and lower urinary tracts, blood ves- sels, pancreas, male and female reproductive tracts, mammary glands, placenta, the heart, and the gut. Re- cently, ICLCs have been mostly referred to as telocytes (TCs) [6]. Padhi et al. reviewed 19 reported cases of pan- creatic extra-gastrointestinal stromal tumors and con- cluded that with the discovery and characterization of pancreatic TCs, the origin of stromal tumors reminis- cent of GIST seemed a real possibility [26]. Further- more, Fu et al. have reported that TCs were identified in the liver and were diminished in liver fibrosis [7]. Regardless, TCs have not been identified in the nor- mal liver; primary GISTs might have developed from TCs in the liver. Further investigations regarding the relationship between hepatic GISTs and TCs are necessary.

The clinical presentation of EGISTs is variable, depend- ing 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 pa- tient. Interestingly, 50% (11/21) of the reported cases showed radiologic features of heterogeneously mass (nec- rotic areas) or solid-cystic appearance; thus, problems in differential diagnosis with cystic neoplasms of the pan- creas 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, im- munohistochemical, and molecular features. Microscopic- ally, this tumor, consisted of spindle cell and epithelioid cells. The cytologic differential diagnosis for these spindle cell proliferations includes leiomyoma, schwannoma, fibro- matosis, inflammatory fibroid polyps, and gastrointestinal muscularis sampling [16]. Immunoistochemical positivity of CD117 confirms the diagnosis of GIST. GISTs exhibit

37.9 and 33.1%, respectively). There is solid evi- dence that compared with gastric tumors’, small intestinal tumors with similar size and mitotic activity have a markedly worse prognosis. Across the board GISTs localized outside of the stomach were larger, had a higher mitotic rate and had worse 5-year DFS (34.2 vs 58.1%) in comparison with gastric tumors. As mentioned above, comparison between tumors with KIT exon 9 and KIT exon 11 mutations (both, KIT del-inc557/558 and other KIT exon 11) of non- gastric origin did not show differences in tumor clinical behavior as assessed by survival analysis. Thus, the authors concluded that in extra-gastric sites, the worse prognosis of KIT exon 9 mutants is related to the tumor location itself rather than to an intrinsic aggressive biologic nature of this mutation. In further support for this hypothesis, six out of seven gastric KIT exon 9 mutants in the ConticaGIST series study were classified as nonhigh risk, with only one of these patients developing progressive disease (PD), following a relatively long DFS of 56 months [13] .

tumors are associated with intact tunica serosa. Mucosal ulcer- ation or tumor invasion of nutrient vessels leads to bleeding. In Figure 1, the tumor was ulcerated and bleeding was seen under endoscopy. Ulcers cause cancer-like umbilicated lesions. Some controversy remains as to whether these forms represent tumor rupture. Nevertheless, it has been mentioned in the literature that stromal tumors with hemorrhage may be independent risk factors for recurrence of stromal tumors.

The actual incidence of the GIST is not easy to determine as the medical science came to know its existence in the recent past only. GISTs are categorized as a separate entity in late 90s. Furthermore many of these smaller tumors grow insidiously and are identified only at the time of autopsy or gastrectomy performed for other causes.[21] The incidence of GIST is estimated to be approximately 10-20 per million people, per year. Malignancy possibility is 20-30%.[6,22,23] In the United States, GIST has an estimated annual incidence of approximately 3,000-4,000, making it the most common primary mesenchymal tumors of the gastrointestinal tract.[18,24] A few studies done to estimate the burden of Article History:

Liver and peritoneum are the most common metastatic sites in malignant GISTs. Lymph node metastases are very uncommon, in our second case have mesenterial node metastases. Glivec (Imatinib®), a tyrosine kinase in- hibitor, has been used with good results in metastatic or unresectable GISTs. Postoperative imatinib treatment is recommended if the tumor is removed grossly, but the operative specimen has positive microscopic margins, designated as R1 resection, or if a gross visible tumor was left behind designated as R2 resection. Observation is all that is recommended if an R0 resection (negative microscopic margins) was achieved. The consensus at this time is to treat patient in a multidisciplinary approach based on biopsy margin, tumor size, mitotic rate, site, immunohistochemical staining, and mutational status [9] in our second case the size reduce 2 cm on USG and CT examination before surgery. A phase III trial, ACOSOG Z9001, was the first to demonstrate that one year of imatinib as compared to placebo in the adjuvant setting, is effective in decreasing recurrences. The tumor size > 10 cm is a risk factor of prognosis in rectal GIST. The appropriate treatment for rectal GIST is complete resec- tion without residual tumors, with complete removal of metastases even in patients with recurrence. Future stu- dies should focus on neo-adjuvant treatment strategies [3] [8] [9].

Abstract: Gastrointestinal stromal tumors (GISTs) are the most common sarcoma of the gastrointestinal tract, with transformation typically driven by activating mutations of c-KIT and less commonly platelet-derived growth factor receptor alpha (PDGFRA). Successful targeting of c-KIT and PDGFRA with imatinib, a tyrosine kinase inhibitor (TKI), has had a major impact in advanced GIST and as an adjuvant and neoadjuvant treatment. If treatment with imatinib fails, further lines of TKI therapy have a role, but disease response is usually only measured in months, so strategies to maximize the benefit from imatinib are paramount. Here, we provide an overview of the structure and signaling of c-KIT coupled with a review of the clinical trials of imatinib in GIST. In doing so, we make recommendations about the duration of imatinib therapy and suggest how best to utilize imatinib in order to improve patient outcomes in the future. Keywords: adjuvant, c-KIT, mutations, resistance, treatment, gastrointestinal stromal tumors, imatinib

The majority of GIST is present in the stomach (60– 70%) or small intestine (25–30%). The colon, rectum, appendix, (together 5%) and esophagus (2–3%) are rare sites [3]. Gastrointestinal stromal tumors are specifically KIT (CD117) positive. Positive for nestin (90–100%) and CD34 (70%) has also been reported. Stromal tumors arising outside the gastrointestinal tract are extremely rare and are known as extragastrointestinal stromal tumor (EGISTs), accounting for less than 5% of all GISTs. Eighty percent of EGISTs are located in the omentum or mesentery, and the remainder develops in the retroperitoneum. A high percentage of EGISTs represent Figure 4: Immunohistochemistry showing positive for (A)

Immunohistochemical staining demonstrated that tumor cells were positive for c-kit and CD34 expres- sion (Fig. 6c, d). The tumor cells were negative for the S-100 protein. The histological features and staining pattern were consistent with a GIST. Inter- rupted elastic fiber of the IVC was shown, although there was continuity of the elastic fiber in the outer layer of this tumor as determined via elastica van Gieson stain (Fig. 7). The immunohistochemical pro- file, including c-kit and CD34 co-expression and ab- sence of desmin and actin, specifically identified this tumor as GIST outside the tubular gastrointestinal tract. Based on these findings, we diagnosed that this

A diffuse large-cell lymphoma (DLCL) of B-cell origin is a lymphoid neoplasm with diverse clinical manifestations. These neoplasms present as masses and grow rapidly, and cause symptoms when they infiltrate tissues or obstruct organs. These neoplasms can present either with B symptoms (fever, drenching night sweats, and weight loss) or pain when the lymphomatous mass enlarges rapidly. 1 Gastrointestinal stromal tumors (GISTs)

Imatinib mesylate is a selective inhibitor of certain protein tyrosine kinases: the intracellular ABL kinase, the chimeric BCR-ABL fusion oncoprotein of chronic myeloid leukemia, the trans-membrane receptor KIT, and the platelet-derived growth factor receptors. Imatinib is highly active in patients with chronic myeloid leukemia and other Philadelphia chromosome–positive leukemias, in which it inhibits the dysregulated kinase activity of the BCR-ABL fusion protein. Imatinib blocks the constitutive activity of KIT receptor tyrosine kinase in the cells of gastrointestinal stromal tumors. This was supported by pre-clinical and clinical trials. Exposure of these cells to Imatinib blocked the kinase activity of KIT, arrested proliferation, and caused apoptotic cell death. 3

Approximately 85% to 90% of all cases of gastrointestinal stromal tumors (GIST) are associated with gain-of-func- tion mutations in the gene KIT [1-4]. A further 5% to 10% of cases of GIST are associated with activating mutations in the platelet-derived growth factor receptor alpha (PDGFRα) gene [1,4,5]. Activating Kit mutations in GIST occur principally in the extracellular domain, the jux- tamembrane domain (which regulates receptor dimeriza- tion), kinase domain I, and kinase domain II (or activation loop) [1]. Imatinib, a small-molecule inhibitor of Kit and PDGFRα, represents an effective first-line ther- apy option for patients with advanced GIST [6]. Imatinib is a potent inhibitor of wild-type Kit and juxtamembrane domain Kit mutants, while Kit activation loop mutants are resistant [1,7]. Secondary imatinib resistance is most

Standard treatment for localized GIST involves complete surgical excision. Lymph node dissection is not standard practise as tumor spread is typically hematogenous rather than through the lymphatic system. If complete surgical resec- tion with negative margins (R0 resection) is not achieved at first attempt and can be safely accomplished by repeat surgery, this option may be considered. In cases where R0 surgery cannot be achieved due to technical reasons or entails significant morbidities, then consideration may be given to a peri-operative course of imatinib with aims for cytoreduction. This approach was demonstrated to be safe and feasible in a Radiation Therapy Oncology Group (RTOG)-led prospective non-randomized phase II study. In this study 52 analyzable patients with KIT-positive GIST, 30 with locally advanced disease (defined as tumors 5 cm) and 22 with potentially operable recurrent metastatic disease (defined as tumors 2 cm) were enrolled and treated with imatinib 600 mg/day over a period of 8 to 12 weeks prior to definitive surgery. Patients were then treated with imatinib for 2 years as postoperative adjuvant treatment. 13 Results of

therapy of imatinib and ipilimumab immuno- therapy was explored in metastatic or unresect- able solid tumors. Among the 26 patients three objective responses were seen, in one GIST (PR) and two melanoma patients (CR + PR), respec- tively. Notably, both melanoma responders had KIT mutations, while the GIST responder was of KIT/PDGFRA wild-type. Responders in this trial suggested that this combination at maxi- mum tolerated dose has antitumor activity in KIT/PDGFRA wild-type GIST and KIT-mutant melanoma and merits further investigation.

sensitivity analyses using different algorithms to identify recurrence. First, we shortened the time interval between initial surgical resection and detection of a recurrence from 90 to 60 days using the original surgical procedures to iden- tify recurrence. Second, keeping the days between the index date and identification of a recurrence fixed at 90 days, we added the following: 1) additional procedure/HCPCS codes for biopsy (32405), excision (11642, 22900, 49201), radiation (77413, 77300), chemotherapy (96408, 96410– 96412, 96549, Q0085), and other surgical procedures (88172, 88305, 43235, 43239); 2) a surgical procedure coupled with an ICD-9 cancer diagnosis (140–239 excluding benign tumors) on the same date; and 3) identification of inpatient hospitalization with an ICD-9 cancer diagnosis (140–239 excluding benign tumors).

Ménétrier disease and gastrointestinal stromal tumors (GISTs) are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases (RTKs). In Ménétrier disease, overexpression of TGF-α, a ligand for the RTK EGFR, results in selective expansion of surface mucous cells in the body and fundus of the stomach. In GISTs, somatic mutations of the genes encoding the RTK KIT (or PDGFRA in a minority of cases) result in constitutive kinase activity and neoplastic transformation of gut pacemaker cells (interstitial cells of Cajal). On the basis of the involvement of these RTKs in the pathogenesis of these disorders, Ménétrier disease patients have been effectively treated with a blocking monoclonal antibody specific for EGFR and GIST patients with KIT and PDGFRA tyrosine kinase inhibitors.

Gastrointestinal stromal tumors (GISTs), although rare, are the most common submucosal tumors (SMTs) of the gastrointestinal (GI) tract [1]. GISTs may arise from any- where throughout the digestive tract, with 50–70% in the stomach and 30–45% in the small bowel (SB) [2, 3]. Tumor size, mitotic count, and tumor site of origin are the three key predictors of aggressive behavior and recurrence [4]. SB GISTs exhibit worse prognosis, especially in the ileum, compared to those arising in the stomach or colon [3, 5].

GI-schwannomas are supposed to arise from the myenteric plexus of the GI wall because of their immu- nophenotypic similarities; both schwannomas and myenteric plexus cells express S-100 protein and GFAP [7, 11]. Pathologically, GI schwannomas are considered to be notably different tumors from conventional schwannomas, which arise from central nervous system and soft tissues [7, 21]. Macroscopically, these tumors are round or fusiform and their cut surface reveals smooth, glistening, grey-white appearance. Microscopic- ally, unlike conventional schwannomas, GI schwanno- mas are not always encapsulated, but mostly well circumscribed. Cystic areas of hemorrhage and calcifica- tion may be present. These tumors are composed of uniformly spindled schwann cells arranged in a inter- lacing fascicles, often with germical centers [4, 21].

While clinical and radiographic findings may be suggestive, the definitive diagnosis of GIST relies on tissue diagnosis. Histologically, GIST can have a variable appear- ance, but has been classified in the past as frequently displaying features of smooth muscle tumors. A key observation in GIST diagnosis and therapy was the central role of mitogen receptor and GIST marker, c-Kit; gain-of-function of this receptor is crucial for tumor growth in most cases of GISTs. 6 Overexpression of c-Kit protein is detected