Zheng S, Huang KE, Jia J, et al.
Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after imatinib resistance: a potential diagnostic pitfall.
Exp Biol Med (Maywood). 2013; 238(1):120-4 [PubMed]

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the digestive tract and characterized by expression of protein-tyrosine kinase (KIT) protein. Treatment of advanced GISTs has been improved dramatically following the development of imatinib. Despite the often long-lasting clinical benefit seen in most patients treated with imatinib, many will eventually suffer disease progression. In general, progressing GISTs retain their typical morphology. In this study, we present a patient with metastatic GISTs, who received more than 16 months of treatment with imatinib and whose tumors changed their morphological and immunohistochemical characteristics after imatinib-resistance. Histological, immunohistochemical and mutational analysis was performed on the prior and post-imatinib treatment GIST samples. The imatinib-resistant tumor cells in the progressing metastases showed marked pleomorphism which proved to be rhabdomyoblastic differentiation with Desmin and Myogenin immunopositivity. However, there was no secondary mutation of KIT, PDGFRA, KRAS and BRAF genes found in the imatinib-resistant lesion, except primary KIT V559D mutation. To our knowledge, this case represents the few reports on this unusual type of transdifferentiation in GISTs under imatinib therapy. Awareness of this phenomenon would help to avoid diagnostic confusion when evaluating post-imatinib samples from GISTs.

Edris B, Willingham SB, Weiskopf K, et al.
Anti-KIT monoclonal antibody inhibits imatinib-resistant gastrointestinal stromal tumor growth.
Proc Natl Acad Sci U S A. 2013; 110(9):3501-6 [PubMed] Free Access to Full Article

Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract and arises from the interstitial cells of Cajal. It is characterized by expression of the receptor tyrosine kinase CD117 (KIT). In 70-80% of GIST cases, oncogenic mutations in KIT are present, leading to constitutive activation of the receptor, which drives the proliferation of these tumors. Treatment of GIST with imatinib, a small-molecule tyrosine kinase inhibitor, inhibits KIT-mediated signaling and initially results in disease control in 70-85% of patients with KIT-positive GIST. However, the vast majority of patients eventually develop resistance to imatinib treatment, leading to disease progression and posing a significant challenge in the clinical management of these tumors. Here, we show that an anti-KIT monoclonal antibody (mAb), SR1, is able to slow the growth of three human GIST cell lines in vitro. Importantly, these reductions in cell growth were equivalent between imatinib-resistant and imatinib-sensitive GIST cell lines. Treatment of GIST cell lines with SR1 reduces cell-surface KIT expression, suggesting that mAb-induced KIT down-regulation may be a mechanism by which SR1 inhibits GIST growth. Furthermore, we also show that SR1 treatment enhances phagocytosis of GIST cells by macrophages, indicating that treatment with SR1 may enhance immune cell-mediated tumor clearance. Finally, using two xenotransplantation models of imatinib-sensitive and imatinib-resistant GIST, we demonstrate that SR1 is able to strongly inhibit tumor growth in vivo. These results suggest that treatment with mAbs targeting KIT may represent an alternative, or complementary, approach for treating GIST.

Natasa N, Snezana P, Nemanja Z, et al.
Case of leptosuccin induced malignant hyperthermia in a patient with GIST of the rectum.
Acta Chir Iugosl. 2012; 59(2):121-3 [PubMed]

Malignant hyperthermia (MH) is a form of myopathy that is usually triggered by volatile anaesthetics such as halothane, sevoflurane and desflurane and depolarising muscle relaxants such as succinylcholine. Pathologic response in MH include increase in oxygen consumption, increase in endtidal CO2, tachycardia, hyperthermia, hyperkalemia and muscle rigidity. Immediate recognition and treatment are crucial to avoid lethal outcome. Molecular genetic studies have confirmed that ryanodine muscle receptors are responsible for MH. We present a case of leptosuccin induced MH with masseter muscle rigidity, mild pCO2 increase (6.3 kPa), elevated body temperature measured with esophageal temperature probe (39.5 degrees C), tachycardia (115 beats/min) and respiratory and metabolic acidosis (pH was 7,23) in a patient who underwent low anterior resection of the rectum for gastrointestinal stromal tumor (GIST) of the rectum.

Agashe SR, Patil PP, Phansopkar MA, et al.
Gastro-intestinal stromal tumour--a case report.
J Indian Med Assoc. 2012; 110(6):404-5 [PubMed]

Gastro-intestinal stromal tumours are rare tumours of the gastro-intestinal tract. Among non-epithelial tumours of gastro-intestinal tract, gastro-intestinal stromal tumours are the commonest but as they are not extensively documented, they are underestimated, poorly understood and inadequately treated for various reasons, particularly at peripheral centres in India. The gravity of the problem increases further as these tumours respond poorly to conventional cytotoxic chemotherapy and radiation therapy. Here a case of gastro-intestinal stromal tumour is reported. The patient was a 35-year-old male who was admitted with evidence of subacute intestinal obstruction. The haematological and biochemical tests showed moderate anaemia, raised serum aminotransferase aspartate (AST, SGOT) and mild hypoproteinaemia. Laparatomy revealed a jejunal tumour which was resected. The routine histopathological examination revealed a spindle cell tumour suggestive of gastro-intestinal stromal tumour -intermediate risk group. Immunohistochemical study showed strong positivity for c-kit confirming the diagnosis of gastro-intestinal stromal tumour. The patient was then referred to oncology centre for further management.

Antonescu CR, Romeo S, Zhang L, et al.
Dedifferentiation in gastrointestinal stromal tumor to an anaplastic KIT-negative phenotype: a diagnostic pitfall: morphologic and molecular characterization of 8 cases occurring either de novo or after imatinib therapy.
Am J Surg Pathol. 2013; 37(3):385-92 [PubMed]

Most gastrointestinal stromal tumors (GISTs) can be recognized by their monotonous cytologic features and overexpression of KIT oncoprotein. Altered morphology and loss of CD117 reactivity has been described previously after chronic imatinib treatment; however, this phenomenon has not been reported in imatinib-naive tumors. Eight patients with abrupt transition from a classic CD117-positive spindle cell GIST to an anaplastic CD117-negative tumor were investigated for underlying molecular mechanisms of tumor progression. Pathologic and molecular analysis was performed on each of the 2 components. Genomic DNA polymerase chain reaction for KIT, PDGFRA, BRAF, and KRAS hot spot mutations and fluorescence in situ hybridization for detecting KIT gene copy number alterations were performed. TP53 mutational analysis was performed in 5 cases. There were 7 men and 1 woman, with an age range of 23 to 65 years. Five of the primary tumors were located in the stomach, and 1 case each originated in the small bowel, colon, and rectum. In 3 patients, the dedifferentiated component occurred in the setting of imatinib resistance, whereas the remaining 5 occurred de novo. The dedifferentiated component had an anaplastic appearance, including 1 angiosarcomatous phenotype, with high mitotic activity and necrosis, and showed complete loss of CD117 (8/8) and CD34 (5/8) expression and de novo expression of either cytokeratin (4/8) or desmin (1/8). There was no difference in the KIT genotype between the 2 components. However, 2 imatinib-resistant tumors showed coexistence of KIT exon 11 and exon 13 mutations. Fluorescence in situ hybridization showed loss of 1 KIT gene in 3 cases and low-level amplification of KIT in 2 other cases in the CD117-negative component, compared with the CD117-positive area. TP53 mutation was identified in 1/5 cases tested, being present in both components. In summary, dedifferentiation in GIST may occur either de novo or after chronic imatinib exposure and can represent a diagnostic pitfall. This phenomenon is not related to additional KIT mutations, but might be secondary to genetic instability, either represented by loss of heterozygosity or low level of KIT amplification.

Bravou V, Papanastasopoulos P, Verras D, et al.
Transforming growth factor β repressor, SnoN, is overexpressed in human gastrointestinal stromal tumors.
J BUON. 2012 Oct-Dec; 17(4):684-90 [PubMed]

PURPOSE: The transforming growth factor bgr; (TGF-β)/ Smad pathway is implicated in the development of interstitial cells of Cajal. The aim of this study was to examine the role of this pathway in human gastrointestinal stromal tumors (GISTs).
METHODS: The expression of TGF-β receptor II (TβRII), phosphorylated Smad2 (p-Smad2), SnoN, p21(WAF17sol;CIP1) and p27(KIP1) was examined by immunohistochemistry in 30 hu-man GISTs in relation to prognostic factors.
RESULTS: TβRII was expressed in 76.9% of the cases. All cases were positive for p-Smad2 and SnoN, with significantly higher expression levels in small intestinal compared to gastric GISTs. Downregulation of p21(WAF1/CIP1) and p27(KIP1) was found in 78.6% and 46.4% of the cases respectively, while cytoplasmic expression of p27(KIP1) was also noted in 50% of GISTs.
CONCLUSIONS: TGF-β/Smad pathway may contribute to GIST pathogenesis. SnoN overexpression and low levels of p21(WAF1)/CIP1 and p27(KIP1) may be of importance in GISTs.

Eisenberg BL
The SSG XVIII/AIO trial: results change the current adjuvant treatment recommendations for gastrointestinal stromal tumors.
Am J Clin Oncol. 2013; 36(1):89-90 [PubMed]

Although adjuvant imatinib (IM) for high risk GIST is an accepted treatment consideration, the duration of therapy remains controversial. The recently published SSGXVIII/AIO randomized clinical trial of 3 years vs. 1 year of adjuvant IM has established a benefit of RFS and OS for the 3 year cohort. Future studies are necessary to continue to further delineate risk variables for GIST recurrence.

Vlenterie M, Flucke U, Hofbauer LC, et al.
Pheochromocytoma and gastrointestinal stromal tumors in patients with neurofibromatosis type I.
Am J Med. 2013; 126(2):174-80 [PubMed]

BACKGROUND: Neurofibromatosis I may rarely predispose to pheochromocytoma and gastrointestinal stromal tumors.
METHODS: A 59-year-old woman with neurofibromatosis I presented with pheochromocytoma of the left adrenal gland. During surgery, 3 gastrointestinal stromal tumors adjacent to the stomach and small intestine were removed. Despite appropriate thrombosis prophylaxis, the patient died of a pulmonary embolus 2 days postoperatively. The second patient, a 55-year-old man with neurofibromatosis I and bilateral pheochromocytomas, had several small gastrointestinal stromal tumors adjacent to the jejunum during surgery. A review of the literature was conducted to identify patients with neurofibromatosis I with concurrence of pheochromocytoma and gastrointestinal stromal tumors and to define the specific clinical features of these patients.
RESULTS: In addition to our 2 patients, 12 other cases of neurofibromatosis I with concomitant occurrence of pheochromocytomas and gastrointestinal stromal tumors have been reported. Pheochromocytomas had adrenal locations in all patients. Two of the 14 patients had a mixed pheochromocytoma/ganglioneuroma. In 4 of the 14 patients, gastrointestinal stromal tumors were located along the stomach. The gastrointestinal stromal tumors in our 2 patients showed no somatic mutations in KIT and PDGFRA genes. A pulmonary embolism was diagnosed in 4 patients.
CONCLUSIONS: The simultaneous occurrence of pheochromocytoma and gastrointestinal stromal tumor should be considered in all patients with neurofibromatosis I presenting with an abdominal mass with symptoms suggestive of pheochromocytoma. Therefore, a pheochromocytoma should be excluded before a patient with neurofibromatosis I undergoes surgery for a gastrointestinal stromal tumor because an undiagnosed pheochromocytoma carries a high risk of life-threatening cardiovascular complications during surgery. Finally, this combination may be associated with an increased risk for thromboembolic events, but more studies are necessary to confirm this.

Hapkova I, Skarda J, Rouleau C, et al.
High expression of the RNA-binding protein RBPMS2 in gastrointestinal stromal tumors.
Exp Mol Pathol. 2013; 94(2):314-21 [PubMed]

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and are often associated with KIT or PDGFRA gene mutations. GIST cells might arise from the interstitial cells of Cajal (ICCs) or from a mesenchymal precursor that is common to ICCs and smooth muscle cells (SMCs). Here, we analyzed the mRNA and protein expression of RNA-Binding Protein with Multiple Splicing-2 (RBPMS2), an early marker of gastrointestinal SMC precursors, in human GISTs (n=23) by in situ hybridization, quantitative RT-PCR analysis and immunohistochemistry. The mean RBPMS2 mRNA level in GISTs was 42-fold higher than in control gastrointestinal samples (p<0.001). RBPMS2 expression was not correlated with KIT and PDGFRA expression levels, but was higher in GISTs harboring KIT mutations than in tumors with wild type KIT and PDGFRA or in GISTs with PDGFRA mutations that were characterized by the lowest RBPMS2 levels. Moreover, RBPMS2 levels were 64-fold higher in GIST samples with high risk of aggressive behavior than in adult control gastrointestinal samples and 6.2-fold higher in high risk than in low risk GIST specimens. RBPMS2 protein level was high in 87% of the studied GISTs independently of their histological classification. Finally, by inhibiting the KIT signaling pathway in GIST882 cells, we show that RBPMS2 expression is independent of KIT activation. In conclusion, RBPMS2 is up-regulated in GISTs compared to normal adult gastrointestinal tissues, indicating that RBPMS2 might represent a new diagnostic marker for GISTs and a potential target for cancer therapy.

Diaconescu MR, Diaconescu S
Mesenchymal (non-epithelial) "non-GIST" tumors of the digestive tract.
Chirurgia (Bucur). 2012 Nov-Dec; 107(6):742-50 [PubMed]

Morphological, immunohistochemical and ultrastructural but also clinical and prognostic differences between multiple types of mesenchimal (stromal, nonepithelial) tumors of the gastrointestinal tract prompted us the remembrance of an anecdotic series of sixteen observations of mesenchymal "nonstromal" gastrointestinal tumors (MNSGIT) encountered in four decades of surgical practice. The diagnosis was mainly established on clinical grounds (dyspepsia, pains, digestive hemorrhage or obstruction, palpable tumor) - some lesions being incidentally discovered - and confirmed by radiology, endoscopy, intraoperative exploration and microscopic pathology examination which revealed 9 schwannomas, three leiomyomas, two lipomas, fibroma and "mixoma" one case each. Our cases were located on the stomach (n=12), small bowell (n=1) and right colon (n=3). All the cases were operated on being practiced tumor exeresis with mucous or parietal ruff excision, atypical, conservative and standard (segmentar or sectorial) visceral resection. There was no postoperative morbidity or mortality in our series. Median follow-up for our cases was 24 (range 6 - 60) months and there are not evidence of recurrences or metastatic disease. Even if the actual concerns are prioritary oriented towards the study of GIST, the current nosology of the tiny subgroup of mesenchymal (non-epithelial) "non-GIST" lesions of the digestive tract must be reloaded helping the practioner which can be confronted with this pathology to a better evaluation and optimal therapy.

Yan Y, Li Z, Liu Y, et al.
Coexistence of gastrointestinal stromal tumors and gastric adenocarcinomas.
Tumour Biol. 2013; 34(2):919-27 [PubMed]

The purpose of this study is to detect the clinicopathology of gastrointestinal stromal tumors (GISTs) occurring synchronously with gastric adenocarcinomas and to unveil the potential underlying relationship between the synchronous GIST and gastric adenocarcinoma. This study included 15 patients with incidental GISTs found during operations for gastric adenocarcinoma and 30 patients who underwent gastrectomy for gastric cancer without discovering GIST between January 2005 and December 2010 at the Beijing Cancer Institute. We collected the clinicopathological data and analyzed the KIT/PDGFRA mutational status of GISTs, corresponding gastric adenocarcinoma specimens, and the normal tissue around the cancer lesions. Additionally, as a control group, the mutational status of the patients with gastric adenocarcinoma and no other tumors was assayed. Overall, 18 GISTs were found in 15 gastric adenocarcinoma patients. Multiple GIST lesions were found in three cases (20 %). The patients' age ranged from 46 to 85 years, with an average of 67.6 years. The average size of the GISTs was 0.85 cm. All mesenchymal lesions showed low proliferative activity, were of low or very low risk, and were identified as CD117-positive by immunostaining. In GIST lesions, mutations in KIT were detected in 7 out of 13 cases, and of these mutations, 6 were found in exon 11 (46.2 %), and 1 was found in exon 9 (7.7 %). A total of five deletions and one point mutation were in exon 11, and one insertion was in exon 9. Mutations were not detected in exon 17 or 13 of KIT. There was no remarkable mutation analyzed in the gastric adenocarcinoma lesions or normal tissues from either the test or control groups. Clinicopathological profiles and molecular analysis of KIT/PDGFRA showed no obvious relationship between gastric cancer and GISTs in tumor genesis, such as similar oncogene mutations.

Miettinen M, Killian JK, Wang ZF, et al.
Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation.
Am J Surg Pathol. 2013; 37(2):234-40 [PubMed] Article available free on PMC after 01/02/2014

A subset (7% to 10%) of gastric gastrointestinal stromal tumors (GISTs) is notable for the immunohistochemical loss of succinate dehydrogenase (SDH) subunit B (SDHB), which signals the loss of function of the SDH complex consisting of mitochondrial inner membrane proteins. These SDH-deficient GISTs are known to be KIT/PDGFRA wild type, and most patients affected by this subset of GISTs are young. Some of these patients have germline mutations of SDH subunit genes SDHB, SDHC, or SDHD, known as Carney-Stratakis syndrome when combined with paraganglioma. More recently, germline mutations in SDH subunit A gene (SDHA) have also been reported in few patients with KIT/PDGFRA wild-type GISTs. In this study we immunohistochemically examined 127 SDHB-negative and 556 SDHB-positive gastric GISTs and 261 SDHB-positive intestinal GISTs for SDHA expression using a mouse monoclonal antibody 2E3 (Abcam). Cases with available DNA were tested for SDHA, SDHB, SDHC, and SDHD gene mutations using a hybridization-based custom capture next-generation sequencing assay. A total of 36 SDHA-negative GISTs (28%) were found among 127 SDHB-negative gastric GISTs. No SDHB-positive GIST was SDHA negative. Among 7 SDHA-negative tumors analyzed, there were 7 SDHA mutants, most germline. A second hit indicating biallelic inactivation of SDHA was present in 6 of those cases. These patients had no other SDH subunit gene mutations. Among the 25 SDHA-positive, SDHB-negative GISTs analyzed, we identified 3 SDHA mutations (1 germline), and 11 SDHB, SDHC, or SDHD mutations (mostly germline), and 11 patients with no SDH mutations. Compared with patients with SDHA-positive GISTs, those with SDHA-negative GISTs had an older median age (34 vs. 21 y), lower female to male ratio (1.8 vs. 3.1) but similar mitotic counts and median tumor sizes, with a slow course of disease in most cases, despite a slightly higher rate of liver metastases. SDHA-negative GISTs comprise approximately 30% of SDHB-negative/SDH-deficient GISTs, and SDHA loss generally correlates with SDHA mutations.

Wan P, Li C, Yan M, et al.
Laparoscopy-assisted versus open surgery for gastrointestinal stromal tumors of jejunum and ileum: perioperative outcomes and long-term follow-up experience.
Am Surg. 2012; 78(12):1399-404 [PubMed]

Whether laparoscopy-assisted resections for gastrointestinal stromal tumors (GISTs) of small bowel can achieve more benefits on the aspect of postoperative outcomes than open surgery remains a question. The aim of this study is to evaluate the benefits of laparoscopy-assisted surgery for GISTs of jejunum and ileum on the perioperative outcomes and long-term relapse-free survival. From January 2004 to December 2010, 81 patients who underwent either laparoscopy-assisted (LAP group, n = 43) or open surgery (OPEN group, n = 38) were included in final analysis after the eligibility criteria. Clinicopathological characteristics of the selected patients were similar between the two groups. Oral intake was significant earlier (P < 0.001) and postoperative hospital stay duration was significantly shorter (P < 0.001) in the LAP group than in the OPEN group. The complication rate of patients in the LAP group and OPEN group was 9.3 and 26.3 per cent, respectively (P = 0.04). No significant difference was observed in terms of 5-year relapse-free survival between LAP and OPEN groups (91.1 vs 93.8%, P = 0.4). Laparoscopy-assisted surgery for GISTs of jejunum and ileum could get preferable short-term postoperative outcomes and similar long-term relapse-free survival compared with open surgery, so it should be recommended for GISTs of the small intestine.

Lima DC, Alberti LR
Endoscopic resection of a cardia gastrointestinal stromal tumour (GIST) after echoendoscopy.
Acta Gastroenterol Latinoam. 2012; 42(3):230-3 [PubMed]

Gastrointestinal stromal tumours (GISTs) previously were thought to represent smooth muscle tumours of the gastrointestinal tract and were formerly classified as leiomyomas and leiomyosarcomas. GISTs are the most common mesenchymal tumours of the gastrointestinal tract and are of clinical relevance because in at least 10% to 30% of cases they are malignant. In the past, GISTs chemo and radio-resistance made treatment a challenging issue for physicians, while criteria for evaluation of the malignant potential of GISTs were lacking. Currently, identification of reliable prognostic factors and the development of molecular-targeted anticancer strategies for GIST have given new hope to these patients. The objective of the present work was to report a case of endoscopic resection of a cardia GIST.

Gronchi A
Risk stratification models and mutational analysis: keys to optimising adjuvant therapy in patients with gastrointestinal stromal tumour.
Eur J Cancer. 2013; 49(4):884-92 [PubMed]

Imatinib is a standard of care in the adjuvant treatment of patients with resected gastrointestinal stromal tumour (GIST). Two important trials have shown a reduction in GIST recurrence rates for patients treated with imatinib 400 mg daily for 1 year; one of these trials also demonstrated a significant improvement in overall survival for patients with GIST at high risk of recurrence who were treated for 3 years. However, not all patients will benefit from adjuvant treatment. Considering the patient types in both trials, treatment decisions must take into account a number of factors including risk of recurrence and mutational status. Tumour characteristics including tumour size, location and mitotic index are the main prognostic factors of recurrence-free survival (RFS) after surgical resection of GISTs. Research, much of it in the advanced/metastatic setting, shows that mutational analysis is definitely predictive of treatment efficacy and probably prognostic of RFS. Patients on imatinib whose tumours harbour mutations in exon 11 of the KIT gene tend to have superior RFS compared with patients with exon 9 mutations. In contrast, patients with wild-type GIST often have disease that follows an indolent course and has limited sensitivity to imatinib in most cases. As such, increased use of existing risk-stratification schemes and mutational analysis will be essential for optimising tailored treatment approaches. In this review, the development and prognostic/predictive utility of key risk stratification tools and mutational analysis of GIST are discussed herein with the goal of facilitating adjuvant treatment decisions for patients with GIST.

Giljača V, Grohovac D, Kovač D, Štimac D
Gastrointestinal stromal tumors characteristics in Croatian Northern Adriatic region.
Hepatogastroenterology. 2012 Nov-Dec; 59(120):2512-5 [PubMed]

BACKGROUND/AIMS: Gastrointestinal stromal tumors (GISTs) have fairly recently been identified as a new type of tumor, thanks to advances in immunohistochemistry. Aim of our work was to investigate and describe GISTs in our hospital in a 10-year period.
METHODOLOGY: Records of patients treated for GIST were analyzed and data describing demographics, comorbidities, primary tumor site, initial symptoms, immunohistochemical characteristics, method of detection and grade of malignancy were shown for each patient.
RESULTS: A total of 31 patients were analyzed. There was 54.8% of women and 46.7% of men with GIST. The mean age was 61.9±12.8 years. Predominant symptoms and signs were abdominal pain and anemia, bloody stool or melena, even though a significant portion of patients did not have any, or only mild symptoms. Stomach was the most frequent location of the tumor. CD117 was positive in all but two biopsy specimens.
CONCLUSIONS: We observed approximately the same incidence of GISTs as in other published data. However, we reported less asymptomatic cases at the time of diagnosis. Also, we reported more women diagnosed with GIST in our population. Even though many tumors were diagnosed by other methods, immunohistochemistry remains the definitive diagnostic method.

Demetri GD, Reichardt P, Kang YK, et al.
Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
Lancet. 2013; 381(9863):295-302 [PubMed]

BACKGROUND: Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib.
METHODS: We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computer-generated randomisation list and interactive voice response system; preallocated block design (block size 12); stratified by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01271712.
RESULTS: From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4·8 months (IQR 1·4-9·2) for regorafenib and 0·9 months (0·9-1·8) for placebo (hazard ratio [HR] 0·27, 95% CI 0·19-0·39; p<0·0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%).
INTERPRETATION: The results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients.
FUNDING: Bayer HealthCare Pharmaceuticals.

Wu J, Joseph SO, Muggia FM
Targeted therapy: its status and promise in selected solid tumors part I: areas of major impact.
Oncology (Williston Park). 2012; 26(10):936-43 [PubMed]

"Targeted therapy" is becoming the centerpiece of current therapeutic strategies, and is often mentioned as the desirable direction for future progress. Why and how it is replacing past approaches in the management of solid tumors is the subject of this two-part overview. Here, in Part I, we describe areas where major inroads were initially achieved by targeting angiogenesis (central to the biology of renal cell carcinoma and hepatocellular cancer) and by unraveling pathways in the heterogeneous tumors of mesenchymal origin--spurred by the identification of c-Kit-activating mutations in gastrointestinal stromal tumors (GIST) and the regressions that ensued when tumors harboring these mutations were exposed to the tyrosine kinase inhibitor imatinib (Gleevec). More recently, the successes in the treatment of the notoriously refractory malignant melanoma via the targeting of a specific BRAF mutation and via immune activation represent an unprecedented achievement of this new therapeutic direction. For each cancer discussed in the first part of our overview, as well as in Part II, which will deal with more common cancers, we briefly cover the tumor biology, how targeting was achieved, the introduction of immune modulation or immune-conjugates, and the impact these therapies are having in the disease.

Stoidis CN, Spyropoulos BG, Misiakos EP, et al.
Surgical treatment of a giant mesenteric fibromatosis mimicking a gastrointestinal stromal tumor: a case report and current treatment aspects.
Acta Chir Belg. 2012 Sep-Oct; 112(5):386-9 [PubMed]

Intra-abdominal fibromatosis (IAF), usually located at the mesenteric level, is a locally invasive tumor of fibrous origin. Although lacking the ability to metastasize, it has the tendency to recur. The case described here is a case of mesenteric fibromatosis with involvement of the bowel wall, which had the appearance of a gastrointestinal stromal tumor (GIST), a tumor with malignant behavior. This report outlines the fact that certain non-typical cases of IAF with involvement of the bowel wall can be misdiagnosed as GIST. It is of outmost importance to make an early and correct diagnosis in such equivocal cases, so that the appropriate treatment can be closed.

Montemurro M, Gelderblom H, Bitz U, et al.
Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib, and nilotinib: A retrospective analysis.
Eur J Cancer. 2013; 49(5):1027-31 [PubMed]

BACKGROUND: Tyrosine kinase inhibitors (TKI) improve the outcome of patients with advanced gastrointestinal stromal tumour (GIST), but treatment failure is frequent, and prognosis then bleak. Smaller trials in this setting suggested activity for sorafenib, a multikinase inhibitor of receptor tyrosine kinases and RAF serine/threonine kinases.
PATIENTS AND METHODS: We retrospectively evaluated the efficacy of sorafenib, starting dose 400mg twice daily, in a large community-based cohort of 124 patients treated in 12 European and one United States (U.S.) cancer centre. All but one patient had a WHO performance score 0-2. All had failed both imatinib and sunitinib, 68 patients nilotinib and 26 had failed investigational therapy, too.
RESULTS: Twelve (10%) patients responded to sorafenib and 70 (57%) patients achieved disease stabilisation. Sorafenib was moderately tolerated, and toxicity reported in 56% of the patients. Rash, hand-foot-syndrome and diarrhea occurred frequently. Sorafenib dosage was reduced in a third of patients, but this did not have an impact on progression-free survival (PFS) (p=0.15). Median PFS was 6.4 months (95% confidence interval [CI], 4.6-8.0 months) and median overall survival (OS) 13.5 months (95% CI, 10.0-21.0 months). Patients with a good performance status and those who responded to sorafenib had a significant better PFS.
CONCLUSION: We conclude that sorafenib is active in GIST resistant to imatinib, sunitinib and nilotinib. These results warrant further investigation of sorafenib or similar molecules in GIST.

Schiavon G, Ruggiero A, Schöffski P, et al.
Tumor volume as an alternative response measurement for imatinib treated GIST patients.
PLoS One. 2012; 7(11):e48372 [PubMed] Article available free on PMC after 01/02/2014

BACKGROUND: Assessment of tumor size changes is crucial in clinical trials and patient care. We compared imatinib-induced volume changes of liver metastases (LM) from gastro-intestinal stromal tumors (GIST) to RECIST and Choi criteria and their association with overall survival (OS).
METHODS: LM from 84 GIST patients (training and validation set) were evaluated using manual and semi-automated Computed Tomography measurements at baseline, after 3, 6 and 12 months of imatinib. The ability of uni-dimensional (1D) and three-dimensional (3D) measurements to detect size changes (increase/decrease) ≥20% was evaluated. Volumetric response cut-offs were derived from minimally relevant changes (+20/-30%) by RECIST, considering lesions as spherical or ellipsoidal.
RESULTS: 3D measurements detected size changes ≥20% more frequently than 1D at every time-point (P≤0.008). 3D and Choi criteria registered more responses than RECIST at 3 and 6 months for 3D-spheres (P≤0.03) and at all time-points for 3D-ellipsoids and Choi criteria (P<0.001). Progressive disease by 3D criteria seems to better correlate to OS at late time-points than other criteria.
CONCLUSION: Volume criteria (especially ellipsoids) classify a higher number of patients as imatinib-responders than RECIST. Volume discriminates size changes better than diameter in GIST and constitutes a feasible and robust method to evaluate response and predict patient benefit.

Daldoul S, Moussi A, Triki W, et al.
Jejunal GIST causing acute massive gastrointestinal bleeding: role of multidetector row helical CT in the preoperative diagnosis and management.
Arab J Gastroenterol. 2012; 13(3):153-7 [PubMed]

In this report, we describe a 34-year-old man with a jejunal gastrointestinal stromal tumour (GIST) accompanied by an unusual severe haemorrhage. Because oesophagogastroduodenoscopy proved inconclusive in determining the source of the bleeding and also because of gradually dropping haemoglobin levels and persistence of the melena not allowing colonic preparation, colonoscopy was cancelled and a mesenteric angio-computed tomography (angio-CT) was deemed necessary. The results of this analysis showed a 5-cm heterogeneous mass located in the jejunal loop surrounded by abnormal arterial structures. This multidetector computed tomography (MDCT) appearance was highly suggestive of GIST. The patient then underwent an urgent laparotomy and, peroperative findings being compatible with angio-CT descriptions, a small-bowel resection was performed. The results of the histopathological examination confirmed the diagnosis of GIST. Angio-CT helps define the size of GIST as well as its range and location and can be used as the primary routine test for patients suffering from lower-GI bleeding.

Agaimy A, Vassos N, Croner RS
Gastrointestinal manifestations of neurofibromatosis type 1 (Recklinghausen's disease): clinicopathological spectrum with pathogenetic considerations.
Int J Clin Exp Pathol. 2012; 5(9):852-62 [PubMed] Article available free on PMC after 01/02/2014

Neurofibromatosis type 1 (NF-1, Recklinghausen disease) is the most common hereditary multitumor syndrome with an incidence at birth of approximately 1:3000. However, the significant variation in the expression of the disease not infrequently precludes early diagnosis. As a consequence of non-familiarity with their frequency and wide clinicopathological spectrum, gastrointestinal manifestations of NF-1 are seldom thought of in routine clinical practice and might thus be significantly under-recognized. Their heterogeneous spectrum ranges from localized microscopic proliferative lesions of autonomic nerves and interstitial cells of Cajal and diffuse microscopic ganglio/neuro/fibromatosis to grossly recognizable mass-forming neurofibromas and gastrointestinal stromal tumors (GIST). Furthermore, neuroendocrine neoplasms, particularly of the periampullary duodenum seem to be quite characteristic of this disease. Based on our own experience and the available literature, this review summarizes and discusses the clinicopathological spectrum of gastrointestinal manifestations of NF-1 including putative proliferative precursor lesions with emphasis on the differential diagnostic aspects of these disorders and their molecular pathogenesis. In addition, this review underlines the great value of specific gastrointestinal findings in uncovering undiagnosed or missed NF-1 cases.

Eisenberg BL, Pipas JM
Gastrointestinal stromal tumor--background, pathology, treatment.
Hematol Oncol Clin North Am. 2012; 26(6):1239-59 [PubMed]

Gastrointestinal stromal tumor (GIST) represents the most common mesechymal tumor of the gastrointestinal tract. Discovery of the relationship between unregulated KIT kinase and GIST transformation has led to diagnostic and therapeutic targeting. Imatinib is the recommended first-line treatment of metastatic GIST. In addition, the combination of surgery and imatinib for primary GIST is indicated in the adjuvant setting of high-risk patients and there may be benefit for this combination in the neoadjuvant setting. The success of molecular targeted therapy in GIST represents an important and exciting advance in solid tumor oncology.

Kim KH, Kim MC, Jung GJ, et al.
Long term survival results for gastric GIST: is laparoscopic surgery for large gastric GIST feasible?
World J Surg Oncol. 2012; 10:230 [PubMed] Article available free on PMC after 01/02/2014

BACKGROUND: Recently, laparoscopic resection for relatively small sized gastric gastrointestinal stromal tumors (GISTs) has been widely accepted as minimally invasive surgery. However, no report on the long-term safety and efficacy of this surgery for large sized gastric GISTs has been published to date.
METHODS: Between July 1998 and January 2011, 104 consecutive patients who underwent resection for gastric GISTs were enrolled in this retrospective study. We assessed the clinicopathological characteristics, postoperative outcomes, patient survival, and tumor recurrence.
RESULTS: Of the 104 patients with gastric GISTs who were included in the study, there were 47 males and 57 females whose mean age was 59.8 years. Sixty-four patients (61.5%) had symptoms associated with tumor. Ten patients included in the group 1, 49 in the group 2, 15 in the group 3a, 9 in the group 5, 14 in the group 6a, and 7 in the group 6b. There was one minor complication and no mortalities. Recurrence was noted in 5 patients, with a median follow-up period of 49.3 months (range, 8.4 to 164.4). The 5-year overall and disease free survival rates of 104 patients were 98.6% and 94.8%, respectively. When comparing large tumor (5-10 cm) between laparoscopic and open surgery, there were statistically differences in age, tumor size, tumor location, and length of hospitalization. There were no statistical differences in the 5-year survival rate between laparoscopic and open surgery for large tumor (5-10cm).
CONCLUSION: Laparoscopic surgery is feasible and effective as an oncologic treatment of gastric GISTs. Moreover, laparoscopic surgery can be an acceptable alternative to open methods for gastric GISTs of size bigger than 5 cm.

Macías-García L, De la Hoz-Herazo H, Robles-Frías A, et al.
Collision tumour involving a rectal gastrointestinal stromal tumour with invasion of the prostate and a prostatic adenocarcinoma.
Diagn Pathol. 2012; 7:150 [PubMed] Article available free on PMC after 01/02/2014

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are the most common primary mesenchymal neoplasia in the gastrointestinal tract, although they represent only a small fraction of total gastrointestinal malignancies in adults (<2%). GISTs can be located at any level of the gastrointestinal tract; the stomach is the most common location (60-70%), in contrast to the rectum, which is most rare (4%). When a GIST invades into the adjacent prostate tissue, it can simulate prostate cancer. In this study, we report on a case comprising the unexpected collision between a rectal GIST tumour and a prostatic adenocarcinoma.
FINDINGS: We describe the complexity of the clinical, endoscopic and radiological diagnosis, of the differential diagnosis based on tumour biopsy, and of the role of neoadjuvant therapy using imatinib prior to surgical treatment.
CONCLUSIONS: Although isolated cases of coexisting GISTs and prostatic adenocarcinomas have previously been described, this is the first reported case in the medical literature of a collision tumour involving a rectal GIST and prostatic adenocarcinoma components. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1238437468776331.

Ürün Y, Utkan G, Yalcin Ş, et al.
Lack of any relationship between ABO and Rh blood groups and clinicopathological features in patients with gastrointestinal stromal tumors: Turkish Oncology Group.
Asian Pac J Cancer Prev. 2012; 13(8):4129-31 [PubMed]

BACKGROUND: An association between the ABO blood group and the risk of certain malignancies, including pancreatic and gastric cancer, has been reported previously. However, it is unclear whether this association is valid for gastrointestinal stromal tumors (GIST). In this study, ABO blood groups and the Rh factor were investigated in a series of GIST cases.
MATERIAL AND METHODS: In 162 patients with GIST, blood group and Rh factor were examined and compared with a control group of 3,022,883 healthy volunteer blood donors of the Turkish Red Crescent between 2004 and 2011. The relationship of blood groups with tumor size, mitotic activity, and age were also evaluated.
RESULTS: Overall, the ABO blood group and Rh factor distributions of the 162 patients with GIST were similar to those of the general population. There were no significant differences between both ABO blood types and Rh factor in terms of tumor size, mitotic activity, and age.
CONCLUSION: This is the first study reported on this issue. In our study, we didn't find any relationship between GIST and ABO blood group and Rh factor. However further studies with larger number of patients are needed to establish the role of blood groups in this population.

Vassos N, Agaimy A, Günther K, et al.
A novel complex KIT mutation in a gastrointestinal stromal tumor of the vermiform appendix.
Hum Pathol. 2013; 44(4):651-5 [PubMed]

Gastrointestinal stromal tumors of the vermiform appendix are rare. To date, only 11 cases have been reported in the English literature. Here, we present a new case of appendiceal gastrointestinal stromal tumor associated with complete situs inversus. A 48-year-old man was operated on due to appendicitis-like symptoms. Laparotomy revealed a ruptured conglomerate tumor in the lower abdomen associated with extensive peritoneal adhesions. Histology showed a spindle cell gastrointestinal stromal tumor with prominent sclerosis and calcification without low mitotic activity. The tumor cells expressed strongly CD117 and CD34. The mutation analysis revealed a heterozygous deletion/insertion involving exon 11 of KIT (pK558_V559delNNins). Because the tumor was ruptured intraoperatively, a high risk was assigned according to the revised National Institute of Health criteria and adjuvant therapy with imatinib mesylate was recommended. The patient is currently alive without evidence of progression 27 months after surgery.

Tielen R, Verhoef C, van Coevorden F, et al.
Surgical treatment of locally advanced, non-metastatic, gastrointestinal stromal tumours after treatment with imatinib.
Eur J Surg Oncol. 2013; 39(2):150-5 [PubMed]

AIMS: Patients with locally advanced gastrointestinal stromal tumours (GISTs) have a high risk of tumour perforation, incomplete tumour resections and often require multivisceral resections. Long-term disease-free and overall survival is usually impaired in this group of patients. Induction therapy with imatinib followed by surgery seems to be beneficial in terms of improved surgical results and long-term outcome. We report on a large cohort of locally advanced GIST patients who have been treated in four centres in the Netherlands specialized in the treatment of sarcomas.
METHODS: Between August 2001 and June 2011, 57 patients underwent surgery for locally advanced GISTs after imatinib treatment. Data of all patients were retrospectively collected. Endpoints were progression-free and overall survival.
RESULTS: The patients underwent surgery after a median of 8 (range 1-55) months of imatinib treatment. Median tumour size before treatment was 12.2 (range 5.2-30) cm and reduced to 6.2 (range 1-20) cm before surgery. No tumour perforation occurred and a surgical complete (R0) resection was achieved in 48 (84%) patients. Five-year PFS and OS were 77% and 88%. Eight patients had recurrent/metastatic disease.
CONCLUSIONS: Imatinib in locally advanced GIST is feasible and enables a high complete resection rate without tumour rupture. The combination of imatinib and surgery in patients with locally advanced GIST seems to improve PFS and OS.

Dwight T, Benn DE, Clarkson A, et al.
Loss of SDHA expression identifies SDHA mutations in succinate dehydrogenase-deficient gastrointestinal stromal tumors.
Am J Surg Pathol. 2013; 37(2):226-33 [PubMed]

Succinate dehydrogenase-deficient gastrointestinal stromal tumors (SDH-deficient GISTs) are a unique class of GIST defined by negative immunohistochemical staining for succinate dehydrogenase B (SDHB). SDH-deficient GISTs show distinctive clinical and pathologic features including absence of KIT and PDGFRA mutations, exclusive gastric location, common lymph node metastasis, a prognosis not predicted by size and mitotic rate, and indolent behavior of metastases. They may be syndromal with some being associated with the Carney Triad or germline SDHA, SDHB, SDHC, or SDHD mutations (Carney-Stratakis syndrome). It is normally recommended that genetic testing for SDHA, SDHB, SDHC, and SDHD be offered whenever an SDH-deficient GIST is encountered. However, testing for all 4 genes is burdensome and beyond the means of most centers. In this study we performed SDHA mutation and immunohistochemical analyses for SDHA on 10 SDH-deficient GISTs. Three showed negative staining for SDHA, and all of these were associated with germline SDHA mutations. In 2 tumors, 3 novel mutations were identified (p.Gln54X, p.Thr267Met, and c.1663+3G>C), none of which have previously been reported in GISTs or other SDH-associated tumors. Seven showed positive staining for SDHA and were not associated with SDHA mutation. In conclusion, 30% of SDH-deficient GISTs in this study were associated with germline SDHA mutation. Negative staining for SDHA can be used to triage formal genetic testing for SDHA when an SDH-deficient GIST is encountered.