Long-term outcome after surgical resection of non-high-risk gastrointestinal stromal tumours without adjuvant therapy.

BACKGROUND: Gastrointestinal stromal tumour (GIST) is the most common intra-abdominal sarcoma. Risk classification systems, commonly the modified National Institutes of Health consensus criteria, identify tumour properties relating to patient outcomes. However, owing to limited long-term evidence, most guidelines recommend up to 10-year follow-up for all risk groups except very low-risk GIST. METHODS: This retrospective multicentre study included patients who had complete resection of primary, non-metastatic GIST from three Scandinavian sarcoma centres: Gothenburg (2004-2020), Stockholm (2000-2019), and Oslo (2000-2017). Medical records were reviewed for clinical details regarding diagnosis, treatment, and follow-up, and recurrence-free and disease-specific survival evaluated. RESULTS: The total cohort consisted of 1213 patients with GIST. High-risk patients and those treated with tyrosine kinase inhibitors were excluded. The remaining 649 patients were included in the present analysis: 118 with very low-, 381 with low-, and 150 with intermediate-risk GISTs. Five-year recurrence-free survival rates were 100, 98.5, and 100 per cent for the intermediate-, low-, and very low-risk groups respectively (P = 0.246). Disease-specific survival rates 10 years after surgery were 100, 98.4, and 100 per cent for the intermediate-, low-, and very low-risk groups respectively (P = 0.262). CONCLUSION: Patients with completely resected non-high-risk GISTs have an excellent long-term outcome, irrespective of risk group. Follow-up programmes to detect disease recurrences in these patients are probably not indicated.

Gastrointestinal stromal tumours (GISTs) originate from the muscle layer of the gastrointestinal tract. They are divided into risk groups according to size, location, and how quickly they grow. Patients with GIST, regardless of risk group, have been followed with imaging for several years after their tumour has been successfully removed with an operation. The aim of this study was to evaluate whether follow-up is necessary for patients in the lower-risk groups. Six hundred and forty-nine patients with GISTs from the lower-risk groups were followed for 5 years (median). Only 1.2 per cent of the patients experienced a recurrence of their cancer. It was concluded that patients with GIST in the lower-risk groups do not need follow-up with imaging after a successful operation.

Integrating Anatomical, Molecular and Clinical Risk Factors in Gastrointestinal Stromal Tumor of the Stomach.

BACKGROUND: Adjuvant imatinib for 3 years is recommended to patients with high-risk gastrointestinal stromal tumor (GIST). Risk stratification is inaccurate, and risk assessments are further complicated by the increased use of neoadjuvant treatment. Anatomical criteria for prognostication have not been investigated. METHODS: Clinical, molecular, and anatomical variables were retrospectively studied in a population-based cohort of 295 patients with gastric GIST resected between 2000 and 2018. Gastric subsite was divided into the upper, middle, and lower thirds. Growth pattern was classified as luminal, exophytic, or transmural based on imaging and surgical reports. RESULTS: Of 113 tumors in the upper third of the stomach, 103 (91.2%) were KIT mutated, 7 (6.2%) were PDGFRA mutated, and 104 (92.0%) harbored genotypes sensitive to imatinib. Transmural tumors were strongly associated with a high mitotic index. Five-year recurrence-free survival (RFS) was 71% for patients with transmural tumors versus 96% with luminal or exophytic tumors (hazard ratio [HR] 8.45, 95% confidence interval [CI] 3.69-19.36; p < 0.001), and, in high-risk patients, 5-year RFS was 46% for patients with transmural tumors versus 83% with luminal or exophytic tumors (HR 4.47, 95% CI 1.71-11.66; p = 0.001). Among 134 patients with tumors > 5 cm, there were 29 recurrences. Only five patients with exophytic or luminal tumors had recurrent disease, of whom four had tumor rupture. Five-year RFS for patients with exophytic/luminal tumors >5 cm without rupture was 98%. CONCLUSIONS: In the upper third, over 90% of tumors were sensitive to imatinib. Patients with exophytic or luminal tumors without rupture, irrespective of size, had an excellent prognosis and may not benefit from adjuvant therapy.

Defining Tumor Rupture in Gastrointestinal Stromal Tumor.

Tumor rupture is an important risk factor predictive of recurrence after macroscopically complete resection of gastrointestinal stromal tumors (GISTs), and an indication for defined interval or even lifelong adjuvant therapy with imatinib according to guidelines. However, there is no consensus or universally accepted definition of the term 'tumor rupture', and, consequently, its incidence varies greatly across reported series. Without predefined criteria, the clinical significance of rupture has also been difficult to assess on multivariate analysis of retrospective data. We reviewed the relevant literature and international guidelines, and, based on the Oslo criteria, proposed the following six definitions for 'tumor rupture': (1) tumor fracture or spillage; (2) blood-stained ascites; (3) gastrointestinal perforation at the tumor site; (4) microscopic infiltration of an adjacent organ; (5) intralesional dissection or piecemeal resection; or (6) incisional biopsy. Not all minor defects of tumor integrity should not be classified as rupture, i.e. mucosal defects or spillage contained within the gastrointestinal lumen, microscopic tumor penetration of the peritoneum or iatrogenic damage only to the peritoneal lining, uncomplicated transperitoneal needle biopsy, and R1 resection. This broad definition identifies GIST patients at particularly high risk of recurrence in population-based cohorts; however, its applicability in other sarcomas has not been investigated. As the proposed definition of tumor rupture in GIST has limited evidence based on the small number of patients with rupture in each retrospective study, we recommend validating the proposed definition of tumor rupture in GIST in prospective studies and considering it in clinical practice.

Recurrence-Free Survival After Resection of Gastric Gastrointestinal Stromal Tumors Classified According to a Strict Definition of Tumor Rupture: A Population-Based Study.

BACKGROUND: In gastrointestinal stromal tumors (GISTs), rupture is a high-risk feature and an indication for adjuvant treatment; however, the independent impact of rupture on prognosis is uncertain and the term is inconsistently defined. In the present study, a previously proposed definition of 'tumor rupture' was applied on a population-based cohort of gastric GISTs. METHODS: Patients undergoing surgery for non-metastatic gastric GISTs from 2000 to 2015 were identified in the regional sarcoma database of Oslo University Hospital. Tumor rupture included spillage or fracture, piecemeal resection, incisional biopsy, blood-tinged ascites, gastric perforation, and microscopic adjacent infiltration. Minor defects of tumor integrity were not considered rupture, i.e. core needle biopsy, peritoneal tumor penetration, superficial peritoneal rupture, and R1 resection. Risk was assessed according to the modified National Institutes of Health consensus criteria. RESULTS: Among 242 patients, tumor rupture occurred in 22 patients and minor defects of tumor integrity occurred in 81 patients. Five-year recurrence-free survival (RFS) for patients with tumor rupture, minor defects of tumor integrity, and no defect was 37, 91, and 96%, respectively (p < 0.001). In the high-risk group, 5 year RFS for patients with rupture was 37%, versus 77% without rupture (hazard ratio 3.56, 95% confidence interval 1.57-8.08, p = 0.001). On multivariable analysis, tumor rupture and mitotic index were independently associated with recurrence. Of 13 patients who received adjuvant imatinib after tumor rupture, 11 relapsed. CONCLUSIONS: Tumor rupture according to the present definition was independently associated with recurrence. With tumor rupture, patients relapsed despite adjuvant treatment. Without rupture, prognosis was good, even in the high-risk group.

Multimodal kreftbehandling av gastrointestinal stromal tumor.

Gastrointestinal stromal tumour (GIST) is a subtype of sarcoma that may occur in any part of the gastrointestinal system, most frequently in the stomach and small intestine. The most common symptoms are bleeding and abdominal pain. In this clinical review, we summarise the progress made with this condition and discuss the recommended diagnostics and treatment of GIST.

Prediction of long-term survival in patients with metastatic gastrointestinal stromal tumor: analysis of a large, single-institution cohort.

BACKGROUND: A subset of patients with metastatic GIST become long-term survivors, and a more precise prediction of outcome could improve clinical decision-making. MATERIAL AND METHODS: One-hundred and thirty-three patients diagnosed with metastatic GIST from 1995 to 2013 were identified from the sarcoma database at Oslo University Hospital. Clinical data prospectively registered in the database were supplemented with retrospective review of medical records. Factors associated with survival were analyzed using Kaplan-Meier curves, log-rank test, univariate and multivariate Cox regression analyses. RESULTS: One-hundred and fifteen patients with metastatic GIST were included in the final study cohort. Median overall survival (OS) was 6.9 years (95% CI 5.6-8.3). Factors associated with long-term survival in univariate analysis were good baseline performance status (ECOG ≤1; p < .001), young age (p = .022), oligometastatic disease (OMD) (≤3 metastases; p < .001), maximum tumor diameter <5 cm (p < .001), surgery for metastatic disease (p = .005), surgery of the primary tumor (p < .001), normal baseline hemoglobin level (p = .05), normal baseline albumin level (p = .001) and normal baseline neutrophil count (p = .03). On multivariate analysis, good performance status, small tumor diameter and, OMD were the factors associated with long-term survival. Five and 10-year OS for patients with OMD were 89% and 71%, respectively, compared to 38% and 20% for patients with polymetastatic disease (p < .001). CONCLUSIONS: In this single-institution cohort of patients, OMD was as a strong prognostic factor in patients with metastatic GIST. Patients with OMD had an outcome similar to patients with high-risk localized disease, and should be regarded as a separate category among patients with metastatic GIST.

Genomic Complexity as a Biomarker to De-Escalate Adjuvant Imatinib Treatment in High-Risk Gastrointestinal Stromal Tumor.

PURPOSE: Adjuvant imatinib treatment is recommended for patients with localized gastrointestinal stromal tumor (GIST) at high risk of recurrence. Almost half of high-risk patients are cured by surgery alone, indicating a need for improved selection of patients for adjuvant therapy. The aim of this study was to investigate if genomic tumor complexity could be used as a prognostic biomarker. METHODS: The discovery cohort consisted of patients who underwent resection of primary GIST at Oslo University Hospital between 1998 and 2020. Karyotypes were categorized as simple if they had ≤ 5 chromosomal changes and complex if there were > 5 chromosomal aberrations. Validation was performed in an independent patient cohort where chromosomal imbalances were mapped using comparative genomic hybridization. RESULTS: Chromosomal aberrations were detected in 206 tumors, of which 76 had a complex karyotype. The most frequently observed changes were losses at 14q, 22q, 1p, and 15q. The 5-year recurrence-free survival (RFS) in patients classified as very low, low, or intermediate risk was 99%. High-risk patients with a simple tumor karyotype had an estimated 5-year RFS of 94%, and patients with a complex karyotype had an estimated 5-year RFS of 51%. A complex karyotype was associated with poor RFS in patients with and without adjuvant imatinib treatment and in multivariable analysis adjusted for tumor site, size, mitotic count, and rupture. The prognostic impact of genomic complexity was confirmed in the validation cohort. In both cohorts, the 5-year disease-specific survival was > 90% for high-risk patients with genomically simple tumors. CONCLUSION: Genomic tumor complexity is an independent prognostic biomarker in localized, high-risk GIST. Recurrences were infrequent for tumors with simple karyotypes. De-escalation of adjuvant imatinib treatment should be explored in patients with cytogenetically simple GISTs.

Cytogenetic and molecular analyses of 291 gastrointestinal stromal tumors: site-specific cytogenetic evolution as evidence of pathogenetic heterogeneity.

Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm with variable behavior. An increased understanding of the tumor pathogenesis may improve clinical decision-making. Our aim was to obtain more data about the overall chromosome aberrations and intratumor cytogenetic heterogeneity in GIST. We analyzed 306 GIST samples from 291 patients using G-banding, direct sequencing, and statistics. Clonal chromosome aberrations were found in 81% of samples, with 34% of 226 primary tumors demonstrating extensive cytogenetic heterogeneity. 135 tumors had simple (≤5 changes) and 91 had complex (>5 changes) karyotypes. The karyotypically complex tumors more often were non-gastric (P < 0.001), larger (P < 0.001), more mitotically active (P = 0.009) and had a higher risk of rupture (P < 0.001) and recurrence (P < 0.001). Significant differences between gastric and non-gastric tumors were found also in the frequency of main chromosome losses: of 14q (79% vs. 63%), 22q (38% vs. 67%), 1p (23% vs. 88%), and 15q (18% vs. 77%). Gastric PDGFRA-mutated tumors, compared with gastric KIT-mutated, had a lower incidence of 22q losses (18% vs. 43%) but a higher rate of 1p losses (42% vs. 22%). The present, largest by far karyotypic study of GISTs provides further evidence for the existence of variable pathogenetic pathways operating in these tumors' development.

APC mosaicism in a young woman with desmoid type fibromatosis and familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is usually caused by germline mutations in the adenomatous polyposis coli (APC) gene. The classic form is characterized by hundreds to thousands of adenomas in the colorectum and early onset colorectal cancer (CRC) if left untreated. FAP is also associated with multiple extra-colonic manifestations such as gastroduodenal polyps, osteomas, epidermoid cysts, fibromas and desmoids. Most desmoid tumours in FAP patients occur intra-abdominally. Approximately 15-20% of the APC mutations are de novo mutations. Somatic mosaicism has been reported in some sporadic cases of polyposis but is probably an underestimated cause of the disease. This case report presents the detection of a mosaic APC mutation in a 26-year-old woman who as a child had been diagnosed with desmoid type fibromatosis. FAP was suggested when she presented with extensive extra abdominal fibromatosis. Our findings indicate that APC mutations may be suspected in patients presenting with a desmoid regardless of its location. If there is clinical evidence that the patient has FAP, adenomas and colonic mucosa in addition to leukocyte DNA should be included in the screening, preferably using methods that are more sensitive than Sanger sequencing.

[Protective silicone prosthesis prior to radiotherapy of recurrent colonic cancer]. / Skjermende silikonprotese ved bestråling for residiv av coloncancer.

Radiation therapy for abdominal recurrence of colon cancer is rarely an option due to subsequent bowel injury. Our case is a woman who underwent resection for a large retroperitoneal recurrence of caecal cancer. Tumour deposits encasing the iliac vessels had to be left behind. A silicone breast prosthesis for displacement of the abdominal content was implanted, allowing postoperative irradiation with 50 Gy. The prosthesis was removed once radiotherapy was accomplished; tumour regression was then complete. Complications are described, so are indications for surgical management of local recurrences of colonic origin as well as technical aspects of abdominal implantation of displacing prostheses. At follow-up after eighteen months the patient has no signs of enteropathy, she enjoys a good quality of life, and she is free of disease. Still, her prognosis is considered uncertain.