Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up

Gastrointestinal (GI) stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, are the most common mesenchymal tumors of the GI tract. In this study, we analyzed 1869 cases originally classified as smooth muscle tumors of the stomach and found that 1765 (94%) of these were GISTs. The GISTs had a slight male predominance (55%) with a median age of 63 years. Only 2.7% of tumors occurred before the age of 21 years and 9.1% before the age of 40 years. The tumors varied from 0.5 to 44 cm (median, 6.0 cm) and most commonly presented with GI bleeding; 12% were incidentally detected. Several histologic variants were recognized among the spindle cell tumors (sclerosing, palisaded-vacuolated, hypercellular, and sarcomatous) and of epithelioid tumors (sclerosing, dyscohesive, hypercellular, and sarcomatous). Outcome was strongly dependent on tumor size and mitotic activity. Only 2% to 3% of tumors <10 cm and <5 mitoses/50 HPFs metastasized, whereas 86% of tumors >10 cm and >5 mitoses/50 HPFs metastasized. However, tumors >10 cm with mitotic activity <5/50 HPFs and those <5 cm with mitoses >5/50 HPFs had a relatively low metastatic rate (11% and 15%). A small number of patients survived intra-abdominal metastasis up to over 20 years. Tumor location in fundus or gastroesophageal junction, coagulative necrosis, ulceration, and mucosal invasion were unfavorable factors (P <0.001), whereas tumor location in antrum was favorable (P <0.001). KIT expression was detected in 91% of the cases, CD34 in 82%, smooth muscle actin in 18%, and desmin in 5%; the latter two were favorable (P <0.001). KIT exon 11 mutations were detected in 119 cases; patients with point mutations fared better than those with deletions (P <0.01). PDGFRA exon 18 mutations (total 86 cases) were common in epithelioid GISTs and most commonly represented a D842V point mutation; none of these was prognostically significant. The above results may be helpful for setting the criteria for adjuvant treatment such as Gleevec.     

Secondary recurrent multiple EGIST of the mesentary: A case report and review of the literature

INTRODUCTIONGastrointestinal stromal tumors (GISTs) are rare intra-abdominal tumors arising from mesenchymal stromal cells. EGISTs are mesenchymal tumors that originate outside the GI tract and tend to have similar characteristics to GISTs. To the best of our knowledge, few cases of long standing recurrent EGIST have been reported.PRESENTATION OF CASEWe present the case of a rare recurrent EGIST in the mesentery of a 39 year old female patient. The tumor was symptomatic at the time of complaint and measured 8.4 cm × 7.7 cm × 7.6 cm. Histological analysis revealed a spindled pattern with fusiform cells arranged in long fascicles and little atypia. Immunochemistry showed positivity for CD117 and was negative for CD34, S-100, Desmin, and MSA. B-catenin was weakly positive. A Ki-67 staining shows approximately 5% positivity revealing a low proliferative rate. The patient was doing well postoperatively and was discharged on 400 mg imanitib regimen.DISCUSSIONWhile GISTs are the most common tumors of the GI tract, recurrent EGISTs of the mesentery are extremely rare. Factors that indicate poor prognosis include tumor size greater than 5 cm, mitotic rate greater than 1–5/10 HPF, presence of tumor necrosis or metastasis and most recently the c-kit mutation. Our patient had a very long time between recurrence of disease.CONCLUSIONThe current literature on EGISTs is limited. Our patient presents a very interesting case due to the time elapsed between disease recurrence and lack of metastasis or excessive growth.     

Exophytic gastrointestinal stromal tumor of the stomach. Report of two cases

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Most GISTs occur in the stomach (60-70%). Their diagnosis is established immunohistochemically and reveals that the tumor cells are immunoreactive for the antigens CD117 and CD34. The infiltration of the adjacent organs, the large tumor size (>5cm) and the mitosis count of the cells (>5/50 CHPFs) are typical characteristics of GIST malignancy. GISTs rarely infiltrate adjacent organs and usually push them back. The clinical behaviour of GISTs is highly variable and tumor size mitotic rate and location are prognostic determinants.The biologic behaviour of GIST is variable. The majority were previously thought to be benign due to their characteristically bland histopathologic features. However, it is becoming increasingly clear that with long follow-up, virtually all GISTs have the potential for malignant behaviour, even those 2 cm or less with bland histologic features. Thus, it is not appropriate to define any GIST as "benign" per se.We present two cases of exophytic gastric GIST which were recently treated successfully in our Clinic with “wedge” gastric resection. The margins were negative and there was neither rupture of the tumor, nor spillage.     

Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: a clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases.

Gastrointestinal stromal tumors (GISTs), the specific KIT-positive mesenchymal tumors of the gastrointestinal tract, have been sporadically reported in the rectum, but there are few clinicopathologic series. In this study we analyzed the clinicopathologic features of 133 anorectal GISTs, 3 intramural leiomyomas (LMs), and 8 leiomyosarcomas (LMSs) from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki. Ninety-six GISTs were documented as KIT-positive and three additional ones as CD34-positive. Thirty-four tumors were included by their histologic similarity to KIT- or CD34-positive cases. GIST-specific c-kit gene mutations, mostly in exon 11, were documented in 18 of 29 cases (62%). The GISTs occurred in adults with the age range of 17-90 years (median 60 years) with a significant male predominance (71%). The tumors ranged from small asymptomatic intramural nodules to large masses that bulged into pelvis causing pain, rectal bleeding, or obstruction. They were mostly highly cellular spindle cell tumors; four tumors had an epithelioid morphology. The tumors coexpressed CD34 and KIT and were rarely positive for smooth muscle actin or desmin and never for S-100 protein. Seventy percent of patients with tumors >5 cm with more than 5 mitoses/50 high power fields (HPF) (n = 31) died of disease, whereas only one tumor <2 cm with <5 mitoses/50 HPF (n = 21) recurred and none caused death. Long latency was common between primary operation and recurrences and metastases; either one occurred in 60 of 111 patients with follow-up (54%). Distant metastases were in the liver, bones, and lungs. Three benign actin- and desmin-positive and KIT-negative intramural LMs, similar to those seen in the esophagus, were identified. There were eight LMSs, six of which formed a polypoid intraluminal mass and were actin-positive and KIT-negative. Despite high mitotic counts, only one LMS patient died of disease. A great majority of rectal smooth muscle and stromal tumors are GISTs, which have a spectrum from minimal indolent tumors to overt sarcomas. Intramural LMs are exceptional, and true LMSs are rare, and similar to colonic ones, often present as intraluminal polypoid masses that appear to have a better prognosis than GISTs with similar mitotic rates.     

Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases.

Gastrointestinal stromal tumor or smooth muscle tumor (GIST) is the designation for a major subset of gastrointestinal mesenchymal tumors that histologically, immunohistochemically, and genetically differ from typical leiomyomas, leiomyosarcomas, and schwannomas. Because GISTs, like the interstitial cells of Cajal, the gastrointestinal pacemaker cells, express CD117 (c-kit protein), the origin of GISTs from the interstitial cells of Cajal has been recently proposed. Comparison of GISTs primary in the omentum and mesentery to GISTs primary in the tubular gastrointestinal tract is of particular diagnostic and histogenetic interest in view of the possible similarity of these tumors with the GIST group. In this study, we analyzed 14 omental and 12 mesenteric primary mesenchymal tumors representing smooth muscle tumors or GISTs. These tumors were phenotypically compared with gastric and small intestinal GISTs, leiomyomas of the esophagus, and leiomyosarcomas of the retroperitoneum. Most (13 of 14) omental and mesenteric (10 of 12) tumors showed histologic features similar to GISTs with elongated spindle cells or epithelioid cells with high cellularity; most of these tumors showed low mitotic activity. Omental and mesenteric GISTs were typically positive for CD117 and less consistently for CD34. They often showed alpha-smooth muscle actin reactivity but were virtually negative for desmin and S-100 protein. One omental and two mesenteric tumors showed features of leiomyosarcoma with ovoid, less elongated nuclei, cytoplasmic eosinophilia; all these tumors had significant mitotic activity. These tumors were positive for alpha-smooth muscle actin and two of them for desmin, but all were negative for CD34 and CD117, similar to retroperitoneal leiomyosarcomas. Tumor-related mortality occurred in the group of mesenteric GISTs, but not in the group of omental GISTs. In contrast, all three patients with a true leiomyosarcoma of the omentum or mesentery had documented liver metastases or died of tumor. In summary, we show that tumors phenotypically identical with GISTs occur as primary tumors in the omentum and mesentery. The occurrence of CD117-positive tumors outside the gastrointestinal tract militates against an origin of these tumors exclusively from the interstitial cells of Cajal.     

Gastrointestinal stromal tumors express ras oncogene: a potential role for diagnosis and treatment

BACKGROUND: Gastrointestinal stromal tumors (GISTs) constitute the largest category of nonepithelial neoplasms of the gastrointestinal tract. Histologically, they have a spindle cell appearance but stain by immunohistochemistry for the proto-oncogene, c-kit (CD117). There is some evidence that phosphorylation of these receptors leads to a cascade that may activate the ras/mitogen-activated protein kinase pathway, which may, in turn, allow other oncogenes to become active. HYPOTHESIS: Immunohistochemical staining pattern of GISTs will aid in their differentiation from other spindle cell tumors and predict clinical outcome in patients. DESIGN AND SETTING: Retrospective review of patient records and paraffin block specimens of spindle cell tumors. PATIENTS: We have identified 65 patients with spindle cell tumors of the gastrointestinal tract at our institution in the past 10 years. Tumors were diagnosed by their morphology as leiomyomas, leiomyoblastomas, or leiomyosarcomas. MAIN OUTCOME MEASURES: CD117 and ras p21 were stained by immunohistochemistry on formalin-fixed, paraffin-embedded sections of normal and tumor tissues. RESULTS: Of the 65 patients, there were 23 patients diagnosed as having GIST confirmed by CD117 expression and 42 patients without GIST. Gastrointestinal stromal tumor samples of 17 (77%) of 22 patients stained positive for ras protein compared with 0 of 27 patients with leiomyomas (P<.001). CONCLUSIONS: To our knowledge, this study is the first to demonstrate that GISTs stain positive for ras p21. This molecular trait may be a useful diagnostic tool in addition to the c-kit (CD117) to separate GISTs from leiomyomas and leiomyosarcomas. In the future, ras inhibitors may potentially be a therapeutic to treat GISTs.     

Gastrointestinal stromal tumors and leiomyosarcomas in the colon: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases

Gastrointestinal stromal tumors (GISTs), mesenchymal tumors largely specific for the gastrointestinal tract, have been well defined in the stomach and small intestine, but have not been extensively documented or contrasted with true smooth muscle tumors in the colon. This study was undertaken to determine the clinicopathologic features of GISTs of the colon, excluding the rectum, and to compare them with leiomyosarcomas (LMSs) of the same location. A total of 37 colonic GISTs and seven LMSs from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki were analyzed. The GISTs occurred predominantly in adults older than 50 years of age (median, 67 yrs), and most were histologically malignant; four small benign tumors (< or = 1 cm) were incidentally detected, and 10 others had minimal mitotic activity (five or fewer mitoses per 50 high-power fields). The colonic GISTs were typically transmural tumors with frequent intraluminal and outward bulging components. Histologically, they usually showed a spindle cell pattern (92%), whereas 8% were epithelioid. Most tumors (19 of 25) were positive for CD117 (KIT) and for CD34 (16 of 27); six tumors coexpressed alpha-smooth muscle actin and CD117; none showed desmin or S-100 protein. C-kit mutations in exon 11 were seen in 5 (36%) of 14 colonic GISTs. None of the patients with incidental small tumors had a recurrence, whereas 2 of 10 patients with tumors larger than 1 cm but minimal mitotic activity died of the disease with liver metastasis. Nearly all patients whose tumor was larger than 1 cm and showed more than five mitoses per 50 high-power fields died of disease; half had evidence of metastasis. LMSs were typically intraluminally bulging, polypoid masses that showed a histologic likeness to differentiated smooth muscle cells. They occurred in five men and two women with a median age of 61 years. Most LMSs were high-grade histologically and showed smooth muscle actin, desmin, or both. All were negative for CD34 and CD117 and lacked c-kit mutations. Five of the seven patients died of disease, and two had a long-term survival, despite high mitotic activity. These results show that KIT-positive GISTs are more common than LMSs of the colon, and these tumor groups have clinicopathologic differences that warrant their separation.     

Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up

Gastrointestinal (GI) stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, are the most common mesenchymal tumors of the GI tract. This study analyzed 1091 tumors originally classified as smooth muscle tumors of the small intestine (including jejunum or ileum and excluding duodenum), and found that 906 (83%) of these were GISTs. The GIST patients had 55:45 male-to-female ratio with a median age of 59 years (range, 13-94 years). Only 0.6% of tumors occurred before the age of 21 years and 13.6% before the age of 40 years. The tumors varied from 0.3 to 40 cm (median, 7.0 cm) and most commonly presented with GI bleeding or acute abdomen; 18% were incidentally detected. Histologically, the tumors were relatively monotypic with spindle cell (86%), epithelioid (5%), or mixed patterns (9%). Skeinoid fibers were present in 44% of cases, and their presence was associated with a favorable course. Most epithelioid tumors were malignant, and this morphology sometimes emerged from less cellular and less mitotically active spindle cell tumors, suggesting that it represented a transformation. KIT was immunohistochemically detected in 98%, CD34 in 40%, smooth muscle actin in 34%, desmin in 0.2%, and S-100 protein in 14% of the tumors tested. Outcome was strongly dependent on tumor size and mitotic activity, with an overall 39% tumor-related mortality, twice that for gastric GISTs. Only <3% of tumors <5 cm and < or = 5 mitoses/50 HPF metastasized, whereas 86% of tumors >10 cm and >5 mitoses/50 HPF metastasized. In stark contrast to corresponding gastric tumors, tumors >10 cm with mitotic activity < or = 5/50 HPF and those < or = 5 cm with mitoses >5/50 HPF had a high metastatic rate (>50%); tumors >5 cm < or = 10 cm with low mitotic rate had a 24% metastatic rate. The median survival times of patients with low mitotic rate tumors who died of disease decreased by increasing tumor size. KIT exon 11 mutations were detected in 90 cases, exon 9 mutation in 17 cases, and exon 17 mutation in 1 case; the presence of mutation or mutation type was not prognostically significant. There were no PDGFRA exon 12 or 8 mutations. Systematic data on prognosis of small intestinal GISTs of various size and mitotic activity categories can be helpful in management and surveillance of patients with these tumors.     

Esophageal stromal tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 17 cases and comparison with esophageal leiomyomas and leiomyosarcomas

Although rare elsewhere in the gastrointestinal tract, leiomyomas (LMs) are the most common esophageal mesenchymal neoplasms. In contrast, gastrointestinal stromal tumors (GISTs) predominate in the stomach and intestines but have not been documented in the esophagus. This study was undertaken to determine the clinicopathologic features and frequency of esophageal GISTs compared with LMs and leiomyosarcomas (LMSs) of the esophagus. A total of 68 stromal/smooth muscle tumors from the Armed Forces Institute of Pathology and the Haartman Institute of University of Helsinki were reclassified by current histologic and immunohistochemical criteria. There were 17 GISTs, 48 LMs, and three LMSs. The esophageal GISTs occurred in 12 men and five women with a median age of 63 years (range, 49-75 years). All tumors were from the lowest third of the esophagus, and the most common complaint was dysphagia, whereas two tumors were detected incidentally. Histologically the tumors had an overall basophilic appearance and showed combinations of solid, myxoid, and perivascular collarlike patterns with a spindle cell histology in 13 patients and epithelioid histology in four patients. All tumors were positive for CD117 and for CD34, whereas two patients were also positive for alpha-smooth muscle actin (SMA) and three patients were positive for desmin. One patient showed a unique immunophenotype with coexpression of CD117, CD34, SMA, and desmin. Nine patients died of disease, including all who had a tumor larger than 10 cm, and also one patient whose tumor showed five mitoses per 50 high-power fields. In comparison, esophageal LMs (n = 48) occurred in a younger population (median age, 35 years) but, similar to the GIST group, men predominated (67%). All LMs were clinically indolent tumors with no tumor-related mortality. The LMs showed eosinophilic cytoplasm, and were positive for desmin and SMA, and negative for CD117 and CD34. All three LMSs were large high-grade tumors that showed muscle cell markers but no CD117. All patients died of disease. Esophageal GISTs showed mutations in exon 11 of c-kit as described previously in gastric and intestinal GISTs. The separation of GISTs from esophageal LMs is important diagnostically because the former group has a high risk of malignant behavior.     

Mutations in exon 11 of the c-kit gene in a myogenic tumor and a neurogenic tumor as well as in gastrointestinal stromal tumors. Utility of c-kit mutation as a prognostic biomarker for gastrointestinal mesenchymal tumor

BACKGROUND/AIMS: Gain-of-function mutations in exons 9, 11 and 13 of the c-kit gene in gastrointestinal stromal tumors (GISTs) have been identified, and it has been reported that the prognosis is worse for patients with mutation-positive GISTs than for those with mutation-negative GISTs. We studied c-kit mutations in gastrointestinal mesenchymal tumors. By chance, the c-kit mutation in exon 11 was found in myogenic and neurogenic tumors as well as in GISTs. Furthermore, we studied the clinical prognostic utility of these mutations. METHODS: Ten gastrointestinal mesenchymal tumors were stained with HE and immunohistochemically analyzed with alpha-smooth muscle actin, S-100 protein, CD34 and c-kit. In these tumors, as well as in 11 cases of leiomyomas, PCR-amplified DNA from the juxtamembrane (JM) domain of exon 11, the extracellular domain of exon 9 and the tyrosine kinase domain 1 of exon 13 showed a high frequency of c-kit mutation and was sequenced. RESULTS: Although c-kit mutations have previously been reported only in GISTs, we found c-kit mutations in the JM domain of exon 11 in one myogenic and one neurogenic tumor as well as in two GISTs. No c-kit mutation was seen in the 11 cases of leiomyomas. In addition, all four cases with c-kit mutation in exon 11 suffered a relapse sooner than the other cases without c-kit mutations. CONCLUSION: Clinically, the prognosis was worse for the patients with mutation-positive gastrointestinal mesenchymal tumors than for those with mutation-negative tumors. We therefore conclude that the gain-of-function mutation in exon 11 of the c-kit gene is an important prognostic factor for gastrointestinal mesenchymal tumors, including myogenic and neurogenic tumors as well as GISTs.     

At last,an effective therapy for non-differentiated GI sarcomas (gastro intestinal stromal tumor)

Gastrointestinal stromal tumors (GISTs) are non differentiated sarcoma of the gastrointestinal tract and have for a long time been confused with well differentiated tumors and classified as leiomyosarcoma. These tumors are characterized immunohistochemically by CD 117 staining. This marker represents the expression of c-kit which is a receptor for growth factor with enzymatic activity (tyrosine kinase). Recent studies have found that an inhibitor of specific tyrosine kinase is effective in the treatment of GIST with an estimated response rate of more than 60%. This new drug could significantly improve the prognosis of these aggressive chemoresistant tumors.     

Neoadjuvant imatinib in a gastrointestinal stromal tumor of the rectum: Report of a case

Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal tract, and of these, GISTs involving the rectum are uncommon. This report describes a case of effective neoadjuvant therapy for a rectal GIST expressing the c-kit gene, where a laparoscopic ultralow anterior resection was successfully performed, thus preserving the anus. A 57-year-old woman visited our hospital due to constipation and was found by a digital examination to have a soft mass on the right wall of the rectum. Computed tomography revealed an 8.0 × 5.0-cm mass with an unclear margin adjacent to the rectum. A biopsy specimen was positive for CD34 and the c-kit gene product, but it was not positive for smooth muscle actin or S-100 protein, and thus the tumor was diagnosed as GIST. An abdominoperineal resection is generally essential for large rectal GISTs; however, she refused this operation. Neoadjuvant treatment with Imatinib decreased the tumor size (4.0 × 3.5 cm) and the anus was preserved by a laparoscopic ultralow anterior resection with direct coloanal anastomosis. She had no evidence of disease for 24 months postoperatively. To preserve the anus, a rectal GIST expressing the c-kit gene is best treated with Imatinib as neoadjuvant therapy.     

Gastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen's disease)

Gastrointestinal stromal tumor (GIST), as well as the hyperplastic lesions of intestinal neural tissue and its supporting structures, is a gastrointestinal complication of type 1 neurofibromatosis (NF1) (von Recklinghausen's disease). In the present study, we analyzed the histologic and immunohistochemical features, and the c-kit and PDGFRA gene mutations of 36 GISTs derived from 9 NF1 patients. Distinctively, multiple GISTs arose preferentially in the small intestine. The histologic features of NF1-associated GISTs are almost similar to those of non-NF1 GISTs, but characteristically most of the NF1-associated GISTs contained skeinoid fibers. Thirty-three GISTs (92%) showed immunoreactivity for KIT, and 23 tumors (64%) showed diffuse or mosaic-like immunoreactivity for S-100 protein. Hyperplasic lesions, which may be the hyperplasia of interstitial cells of Cajal, were observed around some GISTs. Exons 9, 11, 13, and 17 of the c-kit gene and exons 12 and 18 of the PDGFRA gene were amplified and directly sequenced. Point mutations of c-kit gene or PDGFRA gene were identified only in three (8%) and two (6%) tumors, respectively. NF1-associated GISTs, showing the dual differentiation of interstitial cells of Cajal and Schwann cells, develop in close association with the myenteric nerve structure of gastrointestinal tract of NF1 patients. The point mutations of c-kit and PDGFRA gene may play a limited role in the tumorigenesis of NF1-associated GISTs.     

Clinicopathological and Immunohistochemical Features of Extragastrointestinal Stromal Tumors: Report of Two Cases

CD117 (c-kit proto-oncogene protein product) is expressed in most gastrointestinal stromal tumors (GISTs) and plays a crucial role in the pathogenesis and treatment of this disease. However, the clinicopathological and immunohistochemical features of CD117-positive mesenchymal tumors without connection to the gastrointestinal tract, known as extragastrointestinal stromal tumors (EGISTs), are not well documented because these tumors are rare. We describe the clinicopathological and immunohistochemical features of two cases of EGIST and compare them with those of GIST. Of the 1855 abdominal or esophageal tumors resected during the past 10 years at our hospital, 23 were GISTs and 2 were EGISTs. The clinicopathological or immunohistochemical characteristics do not seem to differ remarkably between EGISTs and GISTs. Although rare, CD117 positivity should be tested in abdominal mesenchymal tumors that have no connection to the gastrointestinal tract. The clinicopathological features of CD117-positive abdominal mesenchymal tumors may not depend on whether the tumor is connected to the gastrointestinal tract.     

An incidental finding of duodenal GIST in a patient with penetrating abdominal trauma: A case report

Introduction and importanceDuodenal Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the digestive tract. The tumors are derived from interstitial cells of Cajal and usually they present as gastrointestinal bleeding or non-specific abdominal pain, but they can also be asymptomatic even when they have reached considerable size.Case presentationWe report a case of a 40-year-old male presented to our emergency department after sustaining a stab wound on the abdomen. Abdominal imaging tests weren't done; instead an emergency laparotomy was undertaken upfront in an attempt to catch up with a “golden hour”. Intra-operatively, an incidental solid mass measuring 4 × 5 cm was noted on the third/fourth portion of the interior duodenal flexure. Histopathologically, the lesion demonstrated spindled shaped cells which were immunopositive for positive CD117. The patient fared well postoperatively and during subsequent follow up visits.Clinical discussionHigh-risk GISTs have malignant potential. In some cases, GIST is diagnosed as incidentally finding, mostly during surgical procedure, upper endoscopy or radiological studies related to GI tract. Surgical resection is recommended curative option and its extension depends on different factors. Tyrosine kinase inhibitors are of the utmost importance in high-risk and metastatic disease.ConclusionEven considerably large duodenal GISTs can be asymptomatic, thus incidentally found during an abdomino-pelvic imaging tests. Histopathological evaluation of the operative specimen plays a key role in assessing the need of adjuvant therapy, with a significant impact on the patients' survival.     

Gastrointestinal stromal tumors (GIST) of the stomach as a cause of upper gastrointestinal bleeding

Gastrointestinal stromal tumors (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. GIST is currently defined as a gastrointestinal tract mesenchymal tumor containing spindle cells (less commonly epitheloid cells or rarely both) and showing CD 117 (c-kit protein) positivity in more than 95% of cases. Although they may arise throughout the gut, the commonest site are stomach (60-70%), small intestine (20-30%), colorectum (5%) and esophagus (up to 5%). Rarely, GISTs develop in the retroperitoneum, omentum or mesentery. GIST originates from the intestinal cell of Cajal (ICC). ICCs are located in and around the myenteric plexus and are thought to function as intestinal pacemaker cells. Historicaly, GIST were often misclassified as leiomyomas or leiomyosarcomas. Subsequently, it has been determined that GISTs have distinct ultrastructural features and immunophenotypical markers compared with smooth muscle and smooth muscle tumors. GIST predominantly occur in middle aged and older patients, with no significant difference in the sex incidence. Data from the recent population study suggest an incidence of about 10-22 cases per million persons per year. Clinical presentation of GIST varies widely, and depends on tumor size and location. GISTs that caused symptoms tended to be larger with an average size of 6cm versus 2cm for asymptomatic GISTs. Symptoms are most commonly related to mass effect or bleeding. GISTs can grow very large before producing symptoms. Commonest symptom of gastric GIST is manifest or occult bleeding. Abudant, life-threateting bleeding that require urgent surgery is rare. For patient with primary, localized, nonmetastatic GIST, complete surgical resection represents the only chance for cure. Lymhadenectomy is not necessary, because lymph node metastasis is very rare. The 5 year survival rate in patients with resected primary GISTs ranges from 48-65%. Conventional chemotherapy and radiation therapy is ineffective in the treatment of GIST. Imatinib mesilate (a tyrosine kinase inhibitor) was confirmed to be effective against metastatic or unresectable GISTs.     

Gastrointestinal stromal tumors,intramural leiomyomas,and leiomyosarcomas in the duodenum: a clinicopathologic,immunohistochemical, and molecular genetic study of 167 cases

In this study we analyzed the clinicopathologic features of duodenal smooth muscle or stromal tumors, including 156 GISTs, 6 leiomyomas (LMs), and 5 leiomyosarcomas (LMSs) from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki. GISTs were documented as KIT positive (n = 109); 47 tumors were also included because of their histologic identity to KIT-positive cases. GIST-specific c-kit gene mutations were documented in exon 11 in 9 of 30 cases (30%) and exon 9 in 4 of 30 cases (13%). The GISTs occurred in patients with an age range of 10-88 years (median 56 years); 54% were male. Ten patients had neurofibromatosis type I; six of them had multiple GISTs. The GISTs ranged from small asymptomatic intramural or external nodules to large masses that extended into the retroperitoneum (median size 4.5 cm). They were mostly spindle cell tumors; three malignant GISTs had an epithelioid morphology, and 81 cases had skeinoid fibers. The tumors often coexpressed CD34 and KIT (54%) and were variably positive for smooth muscle actin (39%) and S-100 protein (20%) but never for desmin. A total of 86% of patients with tumors >5 cm with >5 mitoses/50 high power fields (HPF) (n = 21) died of disease, whereas no tumor <2 cm with <5 mitoses/50 HPF (n = 12) recurred or caused death. Long latency was common between primary operation and recurrences or metastases; either one occurred in 49 of 140 patients with follow-up (35%). No formula could accurately predict metastases, which occasionally developed even if mitotic activity was <5/50 HPF and size <5 cm. Metastases were in the abdominal cavity, liver, and rarely in bones and lungs but never in lymph nodes. Four actin- and desmin-positive and KIT-negative benign intramural LMs were similar to those more often seen in the esophagus. There were five LMSs, one of which formed a polypoid intraluminal mass; all were actin positive and KIT negative. The great majority of duodenal mesenchymal tumors are GISTs, which have a spectrum from small indolent tumors to overt sarcomas. LMs and LMSs are rare.     

Emergence of Imatinib Resistance Associated with Downregulation of C-Kit Expression in Recurrent Gastrointestinal Stromal Tumor (GIST): Optimal Timing of Resection

Introduction  

Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal mesenchymal tumors. The activating mutation in the KIT (c-kit; CD117) proto-oncogene with subsequent tyrosine kinase activation plays a central role in the pathogenesis of GIST. Tyrosine kinase inhibitors are an integral part of GIST therapy. Initial response to neoadjuvant imatinib can be expected in up to 70% of the patients, thus offering an opportunity to surgically treat those with locally advanced primary or recurrent GIST. This favorable response to imatinib, however, is plagued with development of secondary resistance during the course of therapy.     

Management of gastrointestinal stromal tumors

A gastrointestinal stromal tumor (GIST) is a rare mesenchymal malignancy of the gastrointestinal (GI) tract. Malignant GISTs were first defined as a separate entity from a collection of nonepithelial malignancies of the GI tract in the 1980s and 1990s based on pathologic and clinical behavior. The discovery of activating KIT mutations as a near-uniform occurrence in these tumors greatly influenced the classification [1] and revolutionized therapeutic management of these tumors. To meet the next challenges, newer tyrosine kinase inhibitors and targeted agents are being developed with the goal of providing improved response rates or alternative therapies for patients progressing on established agents. In this article, the authors describe the management of GISTs, concentrating on surgical management and targeted therapies.     

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目的探讨胃肠间质瘤病人的临床病理特征及c-kit/血小板源性生长受体α(PDGFRA)基因突变频率和突变类型。方法收集2002年1月至2011年10月于北京大学肿瘤医院就诊并经病理组织学确诊的660例胃肠间质瘤病人的临床病理资料及肿瘤组织标本,运用直接测序方法检测组织标本中c-ki(t外显子9、11、13和17)、PDGFRA基因(外显子12和18)的突变状态,统计学分析基因型与临床病理特征的相关性。结果 660例胃肠间质瘤病人中,男389例(58.9%),女271例(41.1%)。中位年龄56(15～82)岁。原发部位以胃(37%)和小肠(35%)为主,转移部位以肝脏及腹腔最常见。酪氨酸激酶受体(CD117)阳性率95.0%,DOG1阳性率88.1%。360例病人接受基因突变检测,其中c-kit基因外显子11突变241例(66.9%),外显子9突变43例(11.9%),外显子13突变6例(1.7%),外显子17突变4例(1.1%),PDGFRA基因外显子12突变1例(0.3%),外显子18突变7例(1.9%),野生型病人58例(16.2%);c-kit外显子9突变主要见于小肠,而PDGFRA12/18突变主要见于胃;基因突变频率与肿瘤大小与和分裂像未见相关性。结论胃肠间质瘤最常发生在胃和小肠;c-kit基因外显子11为最常见的基因突变类型;基因突变类型与原发部位相关。