Gastrointestinal Stromal Tumors Lesions Research Articles

Long-term outcomes of combined endoscopic/laparoscopic intragastric enucleation of presumed gastric stromal tumors.

Definitive surgical treatment of gastric myogenic neoplasms such as gastrointestinal stromal tumors (GISTs) typically involves full-thickness resection of the lesion with normal gastric wall as the margin. This is not readily possible with proximal gastric lesions near the gastroesophageal junction, nor necessary for small incidental lesions. We have employed a combined endoscopic/laparoscopic intraluminal enucleation technique for selected patients and report long-term surveillance following this novel technique. Retrospective review of patients who have undergone intraluminal laparoscopic resection from 1994 to 2008. Fifteen patients who underwent intraluminal enucleation were followed up for a median of 61months. There were eight men and seven women with a mean age of 62.1±3.38years. Eight patients (53%) underwent endoscopy for gastrointestinal bleeding, six for dyspepsia (40%), six for anemia (40%), and four for abdominal pain (27%). Eight lesions (53%) were located in the fundus/cardia: six (40%) in the body and two (13%) in the antrum. The mean tumor size was 3.5±0.45 (1.5-7.0) cm. GIST lesions with benign histologic features predominated. All operations were successfully completed, including full-thickness resections with no conversion to open procedure, major morbidity, or mortality. Complete endoscopic and endosonographic surveillance was accomplished in 14 patients with no local or distant recurrence and no symptomatic follow-up in any patient. Enucleation of intact gastrointestinal stromal tumors can be accomplished with low risk of recurrence when done with a combined endoscopic/laparoscopic intraluminal technique. It should be the preferred approach considered for small, proximal, intraluminal tumors.

Üst gastrointestinal sistem stromal tümörlerinin endosonografik ve histopatolojik özelliklerinin karşılaştırılması: Tek merkez deneyimi

Background and Aims: Gastrointestinal stromal tumors are mesenchymal tumors mostly prevalent at middle ages. Since endoscopy is insufficient for evaluation of gastrointestinal stromal tumors, endoscopic ultrasound is preferred and mostly used imaging technique. Gastrointestinal stromal tumor lesions with high mitotic activity and large tumor size are usually considered to have a malign potential. We aimed to investigate the correlation between the endoscopic ultrasound findings and histopathologic characteristics of gastrointestinal stromal tumors. Materials and methods: Twenty five patients who underwent endoscopic ultrasound fort he suspicion of gastrointestinal stromal tumor and have the definitive diagnosis of gastrointestinal stromal tumor histopathologically were included to the study (13M, 12F, mean age 52.1±16.3). Results: All gastrointestinal stromal tumors were located in the stomach; five of them in the fundus, 17 in the corpus and 3 in the antrum. There were ulcerations on 10 (%40) gastrointestinal stromal tumor lesions. Mean diameter of the gastrointestinal stromal tumors measured during endoscopic ultrasound evaluation (51.59±20.37mm) was highly correlated with the real tumor size (54.30±24.86 mm, r: 0.817, p

Importance of PET for surgery of gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the digestive tract. The GIST differ substantially from gastrointestinal carcinomas regarding tumor biology, treatment strategies and indications for surgery. Every surgeon involved in the treatment of GIST should be acquainted with these aspects. The aims of this article are to discuss the value of positron emission tomography (PET) in the surgical treatment of patients with GIST and to provide an outlook on the development of molecular tracers specifically tailored for GIST. PET is an invaluable decision aid in the multimodal therapy of GIST and particularly for deciding on surgical indications. Specific scenarios in which PET is used are primary staging monitoring during neoadjuvant therapy and staging and response assessment in the metastatic setting. The routinely used tracer is 18F-fluorodeoxyglucose (18F-FDG) and uptake reliably correlates with the metabolism of GIST lesions. Compared to computed tomography and magnetic resonance imaging (CT/MRI), 18F-FDG-PET often allows a more timely and accurate response assessment. GIST-specific molecular tracers, which could provide a direct prognosis regarding response and development of resistance to treatment, are currently in preclinical development. However, pharmacokinetic and immunological issues still need to be resolved. A distant aim is the development of "theranostics", i.e. substances which serve both diagnostic and therapeutic purposes. PET has an established value in the multimodal treatment of GIST and is particularly useful for deciding on surgical indications.

Gastric Gastrointestinal Stromal Tumor with Bone Metastases – Case Report and Review of the Literature

Gastrointestinal stromal tumors (GISTs) represent rather rare neoplasms. Most GISTs are benign; malignant tumors account for 20- 30% of cases (overall, approximately 10- 30% of GISTs exhibit malignant behavior). GISTs most commonly metastasize to the liver and abdominal cavity. Distant metastases to other sites, especially to the bones, are relatively rare. We report a case of a 62 year old man with metastatic spread of GIST to skull, ribs and both sacroiliac joints manifesting six months after surgical resection of a gastric tumor. Although bone metastases from GISTs are rare and there are only a few reported cases in the literature, this case emphasizes that metastatic disease should always be considered in a patient with gastric GIST and suspicious bone lesions.

Mutation Analysis of Gastrointestinal Stromal Tumors in a Pathology Laboratory with 42 Cases of Formalin-Fixed Paraffin-Embedded Specimens

Background: This study aimed to establish a standard gene analysis procedure for successful mutation analysis in pathology laboratories using formalin-fixed paraffin-embedded gastrointestinal stromal tumor (GIST) specimens. Methods: Twenty-six cases of GIST were retrospectively collected and subjected to polymerase chain reaction (PCR) for exons 9, 11, 13, and 17 of KIT and exons 12 and 18 of PDGFRA genes, comparing four groups of previously reported primer sets with one group of novel primer sets. Amplified DNA was directly sequenced with or without subsequent subcloning. The standardized procedure established in the retrospective study was used to prospectively analyze 16 additional cases of GIST. Results: The novel primer sets provided the highest percentages (92%-96%) of successful amplification of all the exons, except for KIT exon 9. In total, 15 double-band samples on electrophoresis after PCR for KIT exon 11 carried a deletion- or insertion-type mutation. Nine single-band samples presented superimposed consecutive double peaks on direct sequencing, and subcloning confirmed a deletion- or insertion-type mutation. Fourteen single-band samples carried a point mutation that presented single base-pair double peaks on direct sequencing. Six single-band samples carried no mutation in any of the exons. In the prospective study, we found KIT-negative GISTs, simultaneous mutations of both KIT and PDGFRA genes, and phenotypic and genotypic changes in pre- and post-imanitib treated GIST lesions. Conclusions: The validity of the standardized procedure was confirmed in the prospective study. This standardized procedure can make GIST mutation analysis more readily available to pathology laboratories. (243 words).

DCE-CT in the follow-up of targeted therapy in GISTs

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancy that initiate from the gastrointestinal tract. GISTs most often metastasize to the liver or the peritoneum. The effect of conventional chemotherapy and radiotherapy do only have very limited therapeutic effect in GISTs. However, the introduction of targeted therapy has dramatically changed the management of advanced GISTs when improved tumor control, progression-free survival, and overall survival are considered. The size reduction of GIST lesions during targeted therapy regimens most often is modest and lesions may even enlarge during successful treatment. Progressive disease does not necessitate the presence of new lesions, and the phenomenon of a nodule within a mass may represent progressive disease. So, the most widely used assessment of response of cancer treatment based on the sum of the largest diameter of target lesions (RECIST) (1) may underor overestimate the effect of targeted therapies in GISTs; due to that fact Choi et al. (2) introduced computed tomography (CT) criteria that also focused on changes in lesion attenuation. These criteria which rely on additional CT enhancement are a better predictor of prognosis than criteria which rely only on changes in size. 18-FDG PET has shown to be very sensitive in detecting early response and as a predictor of long-term response to targeted therapy in GIST. PET/CT may combine metabolic and morphologic issues. However, the term PET/CT shall be reserved to protocols that indeed perform diagnostic CT with diagnostic acquisition parameters and a state of the art contrast media policy. A CT scan used for attenuation correction in a “PET/CT” cannot be considered diagnostic. However, due to limited availability and high costs, and due to the fact that up to 20% of GIST lesions on pretreatment scans do not show increased uptake of glucose, in general CE-CT is used as the standard modality in the follow-up of treatment in GISTs supplemented with MRI or PET/CT when needed. The morphological response assessment in GISTs using CT as modality is not only based on size and density measurements. Pseudo progression and pseudo regression have to be evaluated visually and integrated in the final assessment. Since the introduction of DCE-CT by Miles (3) the discipline has evolved dramatically due to enhanced computer power, the development of MDCT, and the development of software tools. In a recent report recommendations and guidelines for DCE-CT are presented (4). It was concluded that DCE-CT scans can robustly assess tumor vascular support and that DCE-CT has reached technical maturity for use in therapeutic trials in oncology. Betz et al. (5), in this issue of Acta Radiologica, present a pictorial review demonstrating that CE-CT easily can be combined with a DCE-CT protocol, so pseudo responses in the follow-up of treatment with targeted agents in GISTs probably can be diminished. DCE-CT can produce a range of physiological parameters that can be displayed as parametric maps, and as shown in (5) be used for quantitative as well as qualitative evaluation. The subjective lesion delineation is an issue that hampers imaging disciplines which rely on signal changes over time in user defined ROIs/VOIs. No guidelines for the delineation of such lesions have yet been agreed upon. Another issue for techniques which rely on time-signal curves to create surrogate molecular imaging markers is the problem with movement artifacts. In the presented manuscript by Betz et al. (5) image registration software that correct for movement artifacts has been included. However, it is obvious that such tools can be improved, especially when tissue near the diaphragm is considered. Although semi-automatic segmentation of a whole lesion volume now is technical possible, and a sample volume in the z-axis that in practice will cover the whole lesion considered, the technique cannot cover the whole body and may serve as complementary to CE-CT as all tumors and metastases do not necessarily behave the same way during treatment. The parameters derived from the DCE-CT discipline depends on the CT system used, acquisition parameters, contrast media policy, and data processing. Although very illustrative parametric color display shows details of tumor characteristics that supplement the findings seen in the corresponding morphological CE-CT, there is a need to have statistics for reproducibility and standards for how to define a ROI in GISTs when considering quantitative measurements. A study that illustrates the impact of the supplementary DCE-CT figures on endpoints as progression-free survival and overall survival compared to morphological response evaluation criteria in longitudinal studies is also warranted. Another important question is if pre-therapeutic DCE-CT figures can act as prognostics in GISTs.

Which is the best surgical approach for anorectal gastrointestinal stromal tumors in the post-imatinib era?

Anorectal gastrointestinal stromal tumors (GISTs) represent about 5 % of all GISTs. Local recurrence, although with a long latency period, occurs in more than a half of cases and is a major concern. Prognostic factors for recurrence are the tumor size and the mitotic index. However, for anorectal lesions, the particular location represents a main obstacle to achieving a radical (R0) resection. Surgery is the treatment of choice for patients with localized or potentially resectable GIST lesions. The goal is to achieve complete gross resection of the tumor with an intact pseudocapsule. Current guidelines recommend wide resection with clear margins (such as abdominoperineal or anterior resection) [1, 2]. Local removal of the tumor has also been proposed, performed by a transanal, transsacral, or transvaginal approach, even if abdominal surgery is more likely to result in negative margins than local surgery [3]. In the article by Centonze et al. [4], a new local technique has been proposed for anorectal GIST excision. A transsphincteric approach was used, with a right ischiorectal fossa incision. Although in the two cases presented the tumor size was C8 cm and the mitotic index was high, the procedure seems feasible, with low morbidity and good early oncological outcomes. Both the patients underwent adjuvant therapy with imatinib, as recommended for high risk GISTs. There are two important considerations to be made. The first concerns the preoperative workup. All anorectal GIST patients should be managed by a multidisciplinary team with expertise in sarcoma. The workup should include: history, physical examination, abdominal/pelvic computed tomography (CT) scan with contrast and/or magnetic resonance imaging (MRI), and chest imaging. A positron emission tomography (PET) scan is not a substitute for CT, however, it may be used to clarify ambiguous findings seen on CT or MRI. Finally, endoscopic ultrasound-guided fine needle aspiration biopsy is necessary to confirm the diagnosis of primary GIST prior to the initiation of any preoperative therapy [5]. The second concerns the use of imatinib associated with surgery. This selective inhibitor of the KIT protein tyrosine kinase has drastically improved the prognosis of patients with GIST. The results of a recently completed trial suggest that in patients with a high risk of recurrence adjuvant imatinib administered for 36 months significantly improves relapse-free and overall survival compared to 12 months of imatinib therapy [6]. Since sphincter-sparing surgery is a primary goal in treating rectal tumors, the use of preoperative imatinib has also been investigated. The published trials show that preoperative imatinib is safe, and associated with a higher R0 rate, lower risk of tumor rupture, acceptable perioperative morbidity, and good disease-free survival [7–10]. However, the survival benefit is not well determinable since most of the patients included in these studies also received imatinib postoperatively for at least 2 years [7–9]. Thus, at the present time, the decision to use preoperative therapy for patients with resectable primary, locally advanced, or recurrent GIST should be made on an individual basis. In our opinion, patients with high risk anorectal GIST (tumor size > 5 cm and/or documented mitotic rate > 5 mitoses/50 high power field) should be treated with preoperative imatinib, followed by sphincter-saving surgery. Adjuvant imatinib for high-risk patients should be S. Pucciarelli (&) I. Maretto Clinica Chirurgica I, Department of Surgery, Oncology, and Gastroenterology, University of Padua, Via Giustiniani, 2, 35128 Padua, Italy e-mail: puc@unipd.it

Coexistence of gastrointestinal stromal tumors and gastric adenocarcinomas

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.

Rare cystic liver lesions: A diagnostic and managing challenge

Cystic formations within the liver are a frequent finding among populations. Besides the common cystic lesions, like simple liver cysts, rare cystic liver lesions like cystadenocarcinoma should also be considered in the differential diagnosis. Thorough knowledge of each entity's nature and course are key elements to successful treatment. Detailed search in PubMed, Cochrane Database, and international published literature regarding rare cystic liver lesions was carried out. In our research are included not only primary rare lesions like cystadenoma, hydatid cyst, and polycystic liver disease, but also secondary ones like metastasis from gastrointestinal stromal tumors lesions. Up-to date knowledge regarding diagnosis and management of rare cystic liver lesions is provided. A diagnostic and therapeutic algorithm is also proposed. The need for a multidisciplinary approach by a team including radiologists and surgeons familiar with liver cystic entities, diagnostic tools, and treatment modalities is stressed. Patients with cystic liver lesions must be carefully evaluated by a multidisciplinary team, in order to receive the most appropriate treatment, since many cystic liver lesions have a malignant potential and evolution.

Presentation and Management of Gastrointestinal Stromal Tumors of the Duodenum: A Multi-Institutional Analysis

Duodenal gastrointestinal stromal tumors (GISTs) are a small subset of GISTs, and their management is poorly defined. We evaluated surgical management and outcomes of patients with duodenal GISTs treated with pancreaticoduodenectomy (PD) versus local resection (LR) and defined factors associated with prognosis. Between January 1994 and January 2011, 96 patients with duodenal GISTs were identified from five major surgical centers. Perioperative and long-term outcomes were compared based on surgical approach (PD vs LR). A total of 58 patients (60.4%) underwent LR, while 38 (39.6%) underwent PD. Patients presented with gross bleeding (n = 25; 26.0%), pain (n = 23; 24.0%), occult bleeding (n = 19; 19.8%), or obstruction (n = 3; 3.1%). GIST lesions were located in first (n = 8, 8.4%), second (n = 47; 49%), or third/fourth (n = 41; 42.7%) portion of duodenum. Most patients (n = 86; 89.6%) had negative surgical margins (R0) (PD, 92.1 vs LR, 87.9%) (P = 0.34). Median length of stay was longer for PD (11 days) versus LR (7 days) (P = 0.001). PD also had more complications (PD, 57.9 vs LR, 29.3%) (P = 0.005). The 1-, 2-, and 3-year actuarial recurrence-free survival was 94.2, 82.3, and 67.3%, respectively. Factors associated with a worse recurrence-free survival included tumor size [hazard ratio (HR) = 1.09], mitotic count >10 mitosis/50 HPF (HR = 6.89), AJCC stage III disease (HR = 4.85), and NIH high risk classification (HR = 4.31) (all P < 0.05). The 1-, 3-, and 5-year actuarial survival was 98.3, 87.4, and 82.0%, respectively. PD versus LR was not associated with overall survival. Recurrence of duodenal GIST is dependent on tumor biology rather than surgical approach. PD was associated with longer hospital stays and higher risk of perioperative complications. When feasible, LR is appropriate for duodenal GIST and PD should be reserved for lesions not amenable to LR.

Effectiveness of radiation therapy in GIST: A case report.

Over the last decade, gastrointestinal stromal tumor (GIST) became the most commonly diagnosed mesenchymal tumor of the gastrointestinal tract (2,3)Population-based studies suggest an annual incidence of between 11 and 14.5 per million and a prevalence of 129 per million (8). The immunohistochemistry of GIST shows the presence of cellsurface antigen CD117 (KIT), which represents a defining characteristic of GIST (4-7). Immunostaining is essential to differentiate GISTs from other more rare mesenchymal tumors. Differential diagnosis includes leiomyosarcomas, leiomyomas and schwannomas (8). It is believed that GISTs arise from a neoplastic transformation of the intestinal pacemaker cells known as the interstitial cells of Cajal (ICC) (6,9). Prior to 2002, the only available therapeutic option for patients with localized GISTs was surgical resection (10). Unfortunately, even when excised in negative surgical margins, the recurrence rate for lesions larger than 3 cm was found to be significant. Introduction of the first tyrosine k inase inhibitor, imatinib mesylate, has dramatical ly changed the management options avai lable for GIST patients (11). The role of radiation therapy in the treatment of GISTs has not been documented (12). In the past, clinicians were reluctant to use radiation therapy due to concerns over the dose received by normal tissues, mostly the potential gastrointestinal toxicity. As such, radiation therapy has been uti l ized rarely, mostly for pall iation purposes (13). In this report, we describe the successful use of intensity modulated radiation therapy to treat an individual with large intra-abdominal GIST lesions (Figure 1), which were deemed unresectable. An initial attempt at systemic treatment with imatinib was not tolerated by the patient and did not produce a significant response.

Endoscopy dissection of small stromal tumors emerged from the muscularis propria in the upper gastrointestinal tract: Preliminary study

To investigate the feasibility and safety of the treatment of an upper gastrointestinal (GI) submucosal tumor with endoscopic submucosal dissection (ESD). A total of 20 patients with esophageal and gastric submucosal tumors emerged from the muscular layer identified by endoscopic ultrasonography were collected from January 2009 to June 2010. Extramural or dumbbell-like lesions were excluded by an enhanced computerized tomography (CT) scan. All patients had intravenous anesthesia with propofol and then underwent the ESD procedure to resect these submucosal tumors. The incision was closed by clips as much as possible to decrease complications, such as bleeding or perforation, after resection of the tumor. All the specimens were collected and evaluated by hematoxylin, eosin and immunohistochemical staining, with antibodies against CD117, CD34, desmin, α-smooth muscle actin and vimentin to identify the characteristics of the tumors. Fletch's criteria was used to evaluate the risk of gastrointestinal stromal tumors (GISTs). All patients underwent a follow-up endoscopy at 3, 6 and 12 mo and CT scan at 6 and 12 mo. The study group consisted of 5 men and 15 women aged 45-73 years, with a mean age of 60.2 years. Three tumors were located in the esophagus, 9 in the gastric corpus, 4 in the gastric fundus, 3 lesions in the gastric antrum and 1 in the gastric angulus. Apart from the one case in the gastric angulus which was abandoned due to being deeply located in the serosa, 94.7% (18/19) achieved complete gross dissection by ESD with operation duration of 60.52 ± 30.32 min. The average maximum diameter of tumor was 14.8 ± 7.6 mm, with a range of 6 to 30 mm, and another lesion was ligated by an endoscopic ligator after most of the lesion was dissected. After pathological and immunohistochemical analysis, 12 tumors were identified as a GI stromal tumor and 6 were leiomyoma. Mitotic count of all 12 GIST lesions was fewer than 5 per 50 HPF and all lesions were at very low (9/12, 75.0%) or low risk (3/12, 25.0%) according to Fletch's criteria. Procedure complications mainly included perforation and GI bleeding; perforation occurred in 1 patient and conservative treatment succeeded by a suturing clip and no post-operative GI bleeding occurred. All patients were followed up for 6.5 ± 1.8 mo (range, 3-12 mo) by endoscopy and abdominal CT. Local recurrence and metastasis did not occur in any patient. ESD shows promise as a safe and feasible technique to resect esophageal and gastric submucosal tumors and the incidence of complications was very low. Clinical studies with more subjects and longer follow-up are needed to confirm its treatment value.

Correlation of measurements from diffusion weighted MR imaging and FDG PET/CT in GIST patients: ADC versus SUV

PurposeWe investigated the correlation relationship between ADCs measured by MRI and SUVs measured by PET/CT of lesions on GIST (gastrointestinal stromal tumor) patients to verify if MR is able to replace or serve as an alternative to PET/CT in GIST staging and treatment monitoring. Materials and methodsBetween September 2010 and January 2011, five patients with histologically proven metastatic GIST in Queen Mary Hospital, Hong Kong were enrolled into our study. All patients underwent both MRI and PET/CT scans at prognosis. Pearson's correlations of twenty-nine lesions were conducted between 5 pairs of ADCs and SUVs values. ResultsLesions in the liver, peritoneum or bowel loops were found by PET/CT and no extra-abdominal lesion was identified. All twenty-nine lesions are identifiable by MRI with sensitivity of 100%. Significant inverse correlation were found between ADCmean and SUVmean (P=0.006), ADCmean and SUVmax (P=0.010), ADCmin and SUVmax (P=0.014), ADCmin and SUVmean (P=0.026), rADCmin and rSUVmax (P=0.047). ConclusionDWI is comparable to PET/CT in visually detecting the GIST lesions’ location. Significant inverse correlations were found between ADCs from DWIBS and SUVs from PET/CT on data of GIST patients. This finding demonstrates that DWI is potentially capable of offering similar information for diagnosis and treatment response evaluating in GIST's patients as PET/CT does. Furthermore, ADCmin, which is determined by single pixel, is not as reliable as ADCmean, which is weighted average value of the whole lesion volume.

Clinical, radiological and biological features of lung metastases in gastrointestinal stromal tumors (Case reports)

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that most frequently arise in the gastrointestinal tract. The liver and peritoneum are common sites of distant GIST lesions, whereas lung metastases are infrequent, accounting for 7% of all lesions. The clinical significance of these metastases remains unknown. Although lung metastases are relatively rare in the natural history of GIST, they may become more prevalent due to increased patient life expectancy. The present report describes four patients with GIST who had lung metastases. Two were female (54 and 28 years of age), and two were male (64 and 44 years of age). The primary GISTs were localized in the stomach in two patients and in the small intestine in the other two patients. Three patients presented with multiple lung lesions and one presented with one lung lesion. Lung metastases were present at the time of initial diagnosis in one patients, and were observed during the follow-up period in the other three. In this report we detail the clinical presentation and radiological features of the lung lesions as observed by computed tomography (CT) and computed tomography/ positron emission tomography (CT/PET). We describe each patient's clinical history and treatment which included surgery and the tyrosine kinase inhibitors, imatinib and sunitinib, and the novel therapy, nilotinib. Moreover, we discuss some biological aspects of this relatively rare occurrence and the resulting clinical implications. These findings may help clinicians to manage lung metastases arising from GISTs in future.

Correlation of multi-slice spiral CT features to clinicopathologic manifestations of gastrointestinal stromal tumor: a report of 49 cases

Gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal tumors of the digestive system. Imaging examination plays an important role in preoperative diagnosis and postoperative evaluation for it. This study was to describe the multi-slice spiral computed tomographic (MSCT) findings and pathologic features of GIST, and to analyze their correlation. MSCT and pathologic reports of 49 patients with 53 pathologically confirmed GIST lesions were reviewed and compared. Of the 53 GIST lesions, 14 were at very low biological risk, 11 at low risk, ten at moderate risk and 18 at high risk; 36 (67.9%) were found in first visit by CT scans. On CT images, the GIST lesions with maximal diameter of > or =50 mm showed irregular shape, invasive growth, presence of cystic area and heterogeneous enhancement, and most of them were at high risk; the lesions with maximal diameter of <50 mm showed regular shape, expansive growth, and homogeneous enhancement, and most of them were at risk of moderate or below. No lymph node metastasis was found. Only three lesions showed S100-positive, which presented infiltration along the gastric wall or bowel ring on CT images. CT examination is helpful in risk prediction for GIST, but it is difficult to detect small lesions (< 2 cm) by CT scans. Due to the infiltrative growth of GIST with neural differentiation (S100-positive), it is difficult to distinguish GIST from gastric cancer on CT images.

Synchronous incidental gastrointestinal stromal and epithelial malignant tumors

To investigate the incidence of incidental gastrointestinal stromal tumor (GIST) and its etiopathogenesis. From January 1, 2000 to December 31, 2007, 13804 cases of gastrointestinal epithelial malignant tumor (EMT) and 521 cases of pancreatic adenocarcinoma (PAC) were successfully treated with surgery at the Department of General Surgery and the Department of Thoracic Surgery, West China Hospital, Sichuan University, China. The clinical and pathologic data of 311 cases of primary GIST, including 257 cases with clinical GIST and 54 cases of incidental GIST were analyzed. Of the 311 patients, 54 had incidental GIST, accounting for 17.4%. Of these tumors, 27 were found in 1.13% patients with esophageal squamous cell carcinoma (ESCC), 22 in 0.53% patients with gastric adenocarcinoma (GAC), 2 in 0.38% patients with PAC, 2 in 0.03% patients with colorectal adenocarcinoma, and 1 in one patient with GAC accompanying ESCC, respectively. Patients with incidental GIST presented symptoms indistinguishable from those with EMT. All incidental GIST lesions were small in size, and the majority had a low mitotic activity while only 1.9% (5/257) of clinical GIST lesions had a high risk. Incidental GIST may occur synchronously with other tumors and has a high prevalence in males. Surgery is its best treatment modality.

Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor

Kit receptor-activating mutations are critical in the pathogenesis of gastrointestinal stromal tumors (GIST). We investigated mechanisms of oncogenic Kit signaling and the consequences of therapeutic intervention in a mouse model of human GIST. Treatment of GIST mice with imatinib decreased cell proliferation and increased apoptosis in the tumor. Analysis of tumor tissue from imatinib-treated mice showed diminished phosphatidylinositol 3-kinase (PI3-kinase) and mammalian target of rapamycin (mTOR) signaling suggesting that oncogenic Kit signaling critically contributes to the translational response in GIST. Treatment with RAD001 (everolimus), an mTOR inhibitor, diminished the translational response and cell proliferation in tumor lesions, pointing to mTOR inhibition as a therapeutic approach for imatinib-resistant GIST. Analysis of RNA expression profiles in GIST lesions with and without imatinib treatment showed changes in expression of IFN-inducible genes and cell cycle regulators. These results convincingly show that KitV558Delta/+ mice represent a unique faithful mouse model of human familial GIST, and they demonstrate the utility of these mice for preclinical investigations and to elucidate oncogenic signaling mechanisms by using genetic approaches and targeted pharmacological intervention.

Patterns of PET response after long-term sunitinib therapy in patients (pts) with imatinib (IM)-resistant gastrointestinal stromal tumors (GIST)

9547 Background: Sunitinib malate (previously known as SU11248) is an active therapy for GIST patients resistant to or intolerant of IM. During initial development, sunitinib was administered in 4–6 week cycles, with 2–4 weeks of drug dosing followed by 2 weeks off treatment. We previously reported suppression of tumor-related 18FDG avidity on PET imaging during sunitinib dosing, with rebound tumor uptake while off drug. This rebound, seen in 80% with initial PET suppression, did not correlate with lack of clinical benefit. We asked if this pattern persists in pts who benefited from long term (&gt; 2 years) sunitinib therapy. Methods: Of 77 pts in our initial Phase I/II study, 7 remain on therapy with sunitinib for more than 2 years, 4 of whom had matched baseline PET and CT data to assess tumor metabolic activity on and off sunitinib dosing. PET scans were obtained at baseline, during initial treatment, during the off-treatment period, and again after &gt; 2 years therapy. These 4 pts were followed for a median 39 months (range 35–45 months) and for a median of 35 cycles (range 27–47). Two achieved PR and two SD. Results: Initially, all 4 exhibited suppression of tumor FDG avidity with treatment followed by rebound during the off-treatment period. By 6 months, all showed complete suppression of FDG activity. After &gt; 2 years on sunitinib, GIST lesions in 2 pts showed no activity on PET, even while off sunitinib, while GIST in 2 pts demonstrated rebound flare when off therapy. The GIST lesions have not progressed despite the transient metabolic rebound while off sunitinib. Conclusions: Metastatic lesions in pts with IM-resistant GIST benefiting from long-term sunitinib therapy display two patterns on PET imaging. GIST in certain pts who benefit from therapy demonstrates metabolic rebound of activity when off dosing, while lesions in other pts remain metabolically inert on PET even during the brief dosing breaks. Functional imaging may yield insights to differences in the underlying biology of GIST subtypes in different pts. [Table: see text]

Immunohistochemical and genetic features of gastric and metastatic liver gastrointestinal stromal tumors: Sequential analyses

Metastatic gastrointestinal stromal tumors (GIST) have an extremely poor prognosis; however, their immunohistochemical and genetic features have not been assessed satisfactorily and the mechanisms responsible for their high malignant potential remain unclear. We examined the immunohistochemical differences between gastric GIST and metastatic lesions in the liver of four patients who had undergone a postgastrectomy hepatectomy for metachronous liver metastases. We also carried out genetic analysis of the tumors in three of the four cases. In all cases, the immunoreactivity profiles, including KIT (CD117), CD34, smooth muscle actin (SMA), desmin, S-100 and vimentin, were similar between the gastric and metastatic tumors, but the Ki67 labeling index in the metastatic GIST was higher than that of the primary GIST. Interestingly, in the case who had received neoadjuvant imatinib therapy before gastrectomy, its therapeutic effect was observed in most of the primary lesion, with the exception of a specific small area with high cellularity. Genetic analysis revealed no acquired mutations in the c-kit or PDGFRA genes in the metastatic lesions in any of the patients, but loss of heterozygosity (LOH) of the c-kit gene was observed mainly in the metastatic tumors in two of the three cases. Furthermore, in the case of neoadjuvant imatinib therapy, LOH of the c-kit gene was shown in the high cellularity area in the primary lesion and metastatic liver GIST. It is suggested that LOH of the c-kit gene is an important event that leads to imatinib resistance and metastatic progression of GIST. In conclusion, both gastric and metastatic GIST had almost the same immunohistochemical features, except for their proliferative activity, and LOH of the c-kit gene played an important role in the process of liver metastasis.

Safety and efficacy of percutaneous radio-frequency ablation (RFA) in patients (pts) with metastatic gastrointestinal stromal tumor (GIST) with clonal evolution of lesions refractory to imatinib mesylate (IM)

9024 Background: IM is a highly effective treatment for metastatic/unresectable GIST. Although pts may exhibit durable systemic disease control, with time clonal evolution of lesions refractory to IM emerge and require alternative treatment approaches. We have evaluated the role of percutaneous RFA in this subset of pts with single or oligoclonal progressing GIST lesions who are in good performance status. Methods: Pts with limited sites of GIST progressing despite continuation of IM were treated with CT-guided RFA. All pts had staging with CT/MRI as well as functional imaging with 18FDG PET scans, both before and after RFA. Biopsy of the target lesions was performed before RFA. Results: Nine pts treated with imatinib for a median of 25 months (m) (range 18–36 m) underwent RFA for single or limited site(s) of progressing disease. Sites of progression: 8/9 pts with liver metastases, 1/9 with soft tissue disease. 5/9 of these pts developed a new nodule within a pre-existing GIST lesion, the remaining 4/9 had anatomic progression of pre-existing sites or developed a new site of disease. Pts undergoing the procedure were asymptomatic and had a good baseline performance status (ECOG 0–1). Progressing lesions were not 18FDG-avid by PET scanning in 5 pts. No pt developed early or late complications from the procedure. With median follow-up of 4.2 m (range 1–11 m), all pts had their lesions completely ablated. 5/9 pts progressed systemically and had an increase in their imatinib dosing (from 400 or 600mg/d to 800mg/d), resulting in disease control for an additional 1–6 m (median 3.5 m). 4 pts remain stable on continued treatment with imatinib (median follow-up 5.8 m). Conclusion: In this small cohort, percutaneous RFA appears to be a safe and effective treatment for localized sites of progression. This procedure helps to manage limited IM-resistant GIST. Continuation of IM to control systemic sites of IM-sensitive GIST despite emergence of limited clonal resistance can be justified on the basis of this exploratory work. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis; Pfizer Novartis; Pfizer