Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Approximately 80% of advanced metastatic gastrointestinal stromal tumors (GISTs) respond to treatment with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, the majority of patients suffer disease progression at a median of 2 years due to drug resistance. In general, progressing GISTs retain their typical morphology. Herein, we report 5 cases of progressing metastatic GIST with heterologous rhabdomyoblastic differentiation after TKI treatment. Histologic, immunohistochemical, and mutational analyses were performed on histologically classic GISTs and components with rhabdomyoblastic differentiation. There were 3 men and 2 women (ranging from 35 to 66 y of age). Three tumors were localized at presentation (2 stomach and 1 small bowel) and 2 presented with metastases. All localized primary tumors were high risk. Two tumors showed spindle cell morphology and 3 were epithelioid, including 1 with marked pleomorphism. After resection of the 3 localized primary tumors, intra-abdominal (2 patients) and liver (1 patient) metastases developed. All patients were treated with imatinib and showed partial clinical responses (4 patient) or stable disease (1 patient). Four patients subsequently progressed; 2 patients were treated with sunitinib after progression with minor responses. Four patients underwent surgical debulking. At last follow-up (range: 20 to 87 mo), 2 patients died of disease, 2 were alive with metastatic disease resistant to TKIs, and 1 was alive without evidence of disease. In all cases, rhabdomyoblastic differentiation was identified adjacent to areas with classic GIST morphology in at least 1 metastatic site; in 1 case, the primary tumor (after treatment with TKIs) showed heterologous differentiation. The rhabdomyoblastic components showed strong and diffuse positivity for desmin and expressed myogenin, whereas KIT was negative in the rhabdomyoblastic component in all cases. Primary KIT mutations were detected in both the conventional GIST and rhabdomyoblastic components from all patients: KIT exon 11 mutations in 4 cases and a platelet-derived growth factor receptor alpha gene exon 18 deletion in 1 case. No secondary mutations of the type associated with TKI resistance were identified in the rhabdomyoblastic areas. This is the first report of rhabdomyoblastic differentiation occurring in GISTs that progressed on TKI therapy. It is associated with loss of KIT expression, but retention of the receptor tyrosine kinase mutation of the precursor GIST. The rhabdomyoblastic differentiation can represent a diagnostic pitfall. The molecular mechanisms for this form of TKI-resistant clonal evolution remain to be determined.
 ...
PMID:Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after tyrosine kinase inhibitor therapy: a novel form of tumor progression. 1883 Jan 21

Gastrointestinal stromal tumors (GISTs) comprise a great majority of small intestinal mesenchymal tumors previously designated as smooth muscle tumors (SMTs), but true SMTs occur with a low-frequency encompassing both leiomyomas and leiomyosarcomas (LMSs). In this study, we analyzed 25 tumors in the spectrum of primary SMTs of the small intestine. Metastatic tumors and those with external attachment only were excluded. These tumors occurred in 15 men and 10 women of median age of 62 years (range: 18 to 80 y). There were 9 well-differentiated SMTs with no atypia and low mitotic activity [< or = 5/50 high-power fields (HPFs)] and these were considered leiomyomas. All 6 tumors examined were positive for SMA and desmin, and negative for KIT; all 3 tumors in female patients that were tested were negative for estrogen receptor. Two leiomyomas, a 5 mm, and another, 2 cm tumor, were examples of a muscularis mucosae leiomyomas. The other 7 were considered intramural leiomyomas; their median diameter was 4.5 cm (range: 0.8 to 9 cm). No patient with these tumors experienced recurrences or metastases, and 6 patients were alive with a median follow-up of 16 years (range: 9 to 28 y). Sixteen tumors had atypia and mitotic activity warranting the designation of LMS. One of these tumors, a 16 cm diverticular tumor, had mitotic activity of only 1/50 HPFs, and this tumor recurred 4 times. All other LMSs had > or =35 mitoses/50 HPFs. Four of 5 such LMSs with follow-up recurred or metastasized, and at least 3 patients died of disease; several others had a short survival but cause of death could not be determined. One patient, an 18-year-old woman, who died of LMS, was a survivor of a Wilms tumor radiated in infancy. All 6 LMSs studied for GIST-specific KIT and platelet-derived growth factor receptor alpha mutations showed wild-type sequences. This series demonstrates that primary small intestinal SMTs are rare (estimated frequency 1 SMT for 36 GISTs). A majority of these are mitotically active tumors with atypia warranting the diagnosis of LMS, and have a high malignant potential. The number of LMS cases is too small for stratification for risk assessment. True SMTs of small intestine should be separated from GISTs because of different pathogenesis and treatment.
 ...
PMID:True smooth muscle tumors of the small intestine: a clinicopathologic, immunhistochemical, and molecular genetic study of 25 cases. 1897 81

This report reviews the methods and goals of treatment of gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the gastrointestinal tract. GISTs express CD117, which serves as an immunohistochemical diagnostic marker. Surgical excision is the definitive treatment for all primary GISTs greater than 2 cm without evidence of peritoneal seeding or metastasis. Preoperative or intraoperative biopsy is not indicated except when the differential diagnosis includes another type of malignancy. Resection may be performed by traditional open surgery or by laparoscopic or laparoscopy-assisted procedures. Regardless of the approach, oncological precautions must be strictly observed. Tumor disruption is to be avoided at all costs; tumor enucleation leaves a tumor-seeded pseudocapsule behind and is considered insufficient. Because GISTs rarely metastasize through the lymphatics, routine lymphadenectomy is not indicated. The importance of achieving negative microscopic margins is controversial, although patients who undergo incomplete microscopic resection may be at greater risk of locoregional recurrence. Other factors, such as tumor grade and size, may play a more significant role in predicting recurrence. Cases of advanced disease or involvement of adjacent structures should be evaluated on an individual basis by a multidisciplinary team.
 ...
PMID:Surgical management of gastrointestinal stromal tumors: analysis of outcome with respect to surgical margins and technique. 1907 50

Gastric gastrointestinal stromal tumors (GIST) commonly present as an incidental finding on upper gastrointestinal endoscopy. Advances in endoscopic technology have allowed some to perform attempted excision of these lesions endoscopically. The oncologic implications of such an approach remain unclear. A-74-year-old man initially presented with an incidental finding of a 1.6 x 1.8-cm c-kit-positive gastrointestinal stromal tumor with low mitotic activity in the gastric fundus. The patient underwent an attempted endoscopic resection of this mass resulting in incomplete excision and gastric perforation. There was immediate conversion to a celiotomy and the patient underwent partial gastrectomy; there was no evidence of metastatic GIST. Three years later, the patient was noted to have an asymptomatic large pelvic mass (4 x 7 cm) on CT scan and was referred for evaluation. Subsequent surgical exploration revealed a single mass adherent to the pelvic sidewall that was resected. Subsequent pathology demonstrated a c-kit-positive GIST consistent with metastatic disease. Eighteen months later, the patient remains free of disease. Complications from endoscopic resection of gastric GIST may be associated with peritoneal dissemination of disease. This should be considered when formulating a strategy for management of gastric GIST. Complete transperitoneal excision (either open or laparoscopic) with clear margins and without tumor rupture remains the gold standard for management of gastric GIST.
 ...
PMID:Is endoscopic resection of gastric gastrointestinal stromal tumors safe? 1909 34

Gastrointestinal stromal tumors (GISTs) are a rare and heterogeneous group of spindle cell neoplasms that have also been reported outside of gastrointestinal (GI) tract. These tumors are characterized by somatic mutations of c-KIT (CD117), a proto-oncogene that encodes a receptor tyrosine kinase normally expressed in the interstitial cell of Cajal that control the GI smooth muscle peristalsis, and an exquisite sensitivity to the action of the tyrokinase inhibitor imatinib mesylate (STI571; Gleevec). We report two cases of gastrointestinal stromal tumor identified on prostatic biopsies, where a primary prostatic sarcoma was considered in the differential diagnosis. In one of the cases, there was extensive local disease involving prostate, rectum, and pelvic wall, as well as metastatic disease that quickly lead to the patient's death despite aggressive treatment with imatinib mesylate and conventional chemotherapy. In the other case, the tumor was mostly confined to the rectum but also focally extended into the prostate capsule. The patient underwent resection and was alive without disease 18 months after surgery. In both cases, tissue samples from prostate and the rectum showed a malignant spindle cell neoplasm, which was positive for CD117 (c-kit). Given their unique clinical management, gastrointestinal stromal tumors should be considered in the differential diagnosis of spindle cell lesions on prostatic needle biopsies and CD117 should be added to the immunohistochemical panel in the work-up of such lesions to avoid misinterpreting them as primary prostatic neoplasms.
 ...
PMID:Gastrointestinal stromal tumors presenting as a prostatic mass. 1922 92

Because of its relatively low toxicity and significant efficacy in the treatment of GIST, imatinib has dramatically altered the natural history of this disease. Early studies, however, have not adequately addressed the optimal length and dose of adjuvant and neoadjuvant imatinib therapy, defined the subset of candidates most likely to benefit from such therapy, determined the long-term impact on OS and use of second-line therapy, nor evaluated the extent and timing of surgery in patients with metastatic disease. With the expectation that advances in biology will lead to more effective chemotherapy for a variety of solid tumors, lessons learned in GIST management will provide a model for multimodality treatment that can be broadly applied.
 ...
PMID:Controversies in the surgical management of GIST in the era of imatinib. 1928 22

The response of gastrointestinal stromal tumors (GISTs) to tyrosine kinase receptor inhibitors (TKR-I) has been a breakthrough for small molecular therapy. We report here on the very different long-term outcome of a synchronous metastatic GIST with complete remission of the primary tumor and progressive liver metastases under TKR-I therapy. In 2003, a 52-year-old patient was diagnosed with gastric GIST and synchronous multiple liver metastases. Therapy with imatinib, 400 mg daily, was started immediately. Fifteen months later, the primary was no longer detectable by endoscopy. In 2006, progression of the liver metastases was observed. Mutation analysis of the initial biopsy specimen from the primary, as well as the biopsy from the three main liver metastases after 3 years of imatinib treatment, revealed the common KIT exon 11 deletion (W557_K558del) in all tumor samples. Two of the metastases had a separate secondary mutation in KIT exon 14 and 17, respectively, while the largest cystic metastatic lesion had no other mutation. Imatinib was then increased to a daily dose of 800 mg, and in April 2007 the treatment was changed to sunitinib. Fifty-two months after initial diagnosis, the patient died of liver failure. At no time point, relapse of the gastric primary tumor was observed. Whilst TKR-Is are commonly very effective in treating GISTs, the present case illustrates their varying effects regarding the clinical behavior and genetic variations within different tumors of the same patient after long-term treatment.
 ...
PMID:Analysis of a case with disappearance of the primary gastrointestinal stromal tumor and progressive liver metastases under long-term treatment with tyrosine kinase inhibitors. 1929 38

Gastrointestinal stromal tumor (GIST) is the most common form of sarcoma and can vary in size and clinical outcome from an incidental finding at the time of surgery to life-threatening metastatic disease. Surgery is the standard of care for primary disease, and the oral drug imatinib is the standard of care for metastatic disease. Sunitinib was approved in the United States in early 2006 for GIST refractory to imatinib. The pathology of GIST, surgical options for primary and metastatic disease, and findings leading to the use of imatinib and sunitinib for GIST are reviewed in this manuscript, with attention to the mutation statuses of c-kit and PDGF receptor that lead to imatinib sensitivity or resistance.
 ...
PMID:Gastrointestinal Stromal Tumors (GIST) and Their Management. 1936 Jan 54

Gastrointestinal stromal tumors (GISTs) rarely metastasize to the skin. We describe 5 patients with GIST with subcutaneous and cutaneous metastases. The mean age at metastasis was 54 years (range 30-68 years) with a male predominance (4:1). Primary tumors occurred in the stomach (n = 3), small bowel (n = 1), and abdomen, not otherwise specified (n = 1). The average time from primary tumor resection to the resection of skin metastases was 59 months (range 11-155 months). The metastases occurred in the scalp (n = 2), cheek (n = 1), and abdomen (n = 2) with 3 patients presenting with solitary nodules and 2 patients with multiple nodules. The average size was 2 cm (range 0.6-4 cm). Histologically, 2 cases were spindled and 3 cases demonstrated mixed epithelioid and spindle cell morphology. All were confirmed to have CD117 reactivity. KIT genotyping was performed in 4 of 5 cases. Two cases harbored a mutation in exon 11, and the remaining 2 cases were wild type in exons 9, 11, 13, and 17. All 5 patients had multiple concurrent or subsequent abdominal and/or hepatic metastases. In 4 patients with an average follow-up of 32 months (range 6-75 months), after the resection of the metastases, 2 were alive with disease and 2 died of disease. Cutaneous metastases seem to be a late complication of GIST, but their presence does not necessarily herald a rapid demise of the patient.
 ...
PMID:Cutaneous and subcutaneous metastases of gastrointestinal stromal tumors: a series of 5 cases with molecular analysis. 1938 74

A 61-year-old woman with no significant past history underwent gastric biopsies demonstrating a strongly c-kit-positive epithelioid malignancy, initially thought to represent gastrointestinal stromal tumor (GIST). Subsequent clinical and immunohistochemical evaluation proved the neoplasm to represent metastatic lobular carcinoma. This case illustrates that although c-kit is highly specific and sensitive for GIST, its expression may occur in a variety of other neoplasms, some of which morphologically resemble GIST and may present in the gastrointestinal tract as metastases. Therefore, a review of other c-kit-positive lesions is also highlighted.
 ...
PMID:C-kit-positive gastric metastasis of lobular carcinoma of the breast masquerading as gastrointestinal stromal tumor. 1946 11


<< Previous 1 2 3 4 5 6 7 8 9 10