10. Specific sarcoma subtypes and localizations – Soft Tissue Sarcoma
10.1 Gastrointestinal stromal tumors (GIST)
Surgical therapy
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Surgical resection in healthy individuals represents the primary curative treatment [627]. R0 resection corresponds to a complete removal of the tumor surrounded on all sides by healthy tissue including a possible puncture channel or biopsy site.
Biopsy
Preoperative histological confirmation of tumors of the digestive tract with suspected GIST shall be performed for locally advanced tumors that can only be removed by complete resection of the affected organ or by multivisceral resection.
In the case of biopsy evidence of locally advanced GIST, the mutational status shall be assessed in light of the predictive value of neoadjunt therapy.
- Consensus
- Strong consensus
In locally advanced GIST and evidence of an imatinib-sensitive mutation, neoadjuvant drug therapy with imatinib should be undertaken with the goal of reducing the extent of surgery.
- Consensus
- Strong consensus
Background
In cases of high level suspicion of GIST and primary resectability without loss of organ function, biopsy need not be mandated. Analogous to the recommendations for sarcomas of the extremities, a tumor size of approximately 3 cm can be applied as a threshold for biopsy, depending on the location.
Histological confirmation is required for tumors with differential diagnosis, e.g., to malignant lymphoma, leiomyosarcoma, or desmoid [628]. Histological confirmation should also be sought in all locally advanced tumors that can only be removed by organ resection (gastrectomy, rectumextirpation) and those tumors whose resection results in functional changes of the GI tract (esophagocardial junction, duodenum, deep rectum).
Despite the fact that GIST are often very soft, fragile tumors that can easily rupture if not managed properly, biopsy backup for advanced GIST has not had a negative impact on patient prognosis [629].
For GIST that can only be removed by organ resection or for which functional changes of the GI tract are foreseeable during resection, preoperative therapy with imatinib should be considered [630]. This is especially true for tumors that require multivisceral resection for resection. In the presence of an imatinib-sensitive mutation, a 6- to 12-month pretreatment can significantly reduce the extent of surgery in almost all patients.
With imatinib-sensitive mutation, tumor regression is usually detectable by CT or MRI after 2-3 months. When tumor response is analyzed by PET, a highly significant reduction in tumor metabolism can be detected as early as 48 hours [631]. Neoadjuvant therapy is typically continued until no further tumor remission can be achieved, meaning that the extent of surgery cannot be further minimized.
A positive side effect of drug pretreatment is that the strong vascularization of GIST disappears. Otherwise, this often necessitates multivisceral resection in order to operate in regions with less blood supply. Gastric loss in particular should be avoided for patients with locoregionally advanced GIST, as adjuvant therapy is compromised by this. Patients with gastrectomy have significantly lower blood levels of imatinib, which may then be in the subtherapeutic range [632]. Limited resection can also be achieved with neoadjuvant therapy in patients with GIST of the Oesophago-gastric junction or rectum and Recto-vaginal septum [633], [634], [635].
GIST of the rectum and spatium rectovaginale
If neoadjuvant treatment could reduce perioperative morbidity, imatinib shall be pretreated in the case of an imatinib-sensitive mutation.
- Consensus
- Strong consensus
When resecting a primary GIST, an R0 resection shall be achieved.
The extent of the safety margin can be less than a 1cm as long as an R0 resection is achieved.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- ⊕⊕⊕⊝
Local recurrence
- Consensus
- Strong consensus
- References
- [152]
If the location is favorable (stomach, small intestine) and expertise is available, GIST can also be removed minimally invasively. The oncological principles shall be applied in the same way as in conventional open surgery.
- Consensus
- Strong consensus
Systematic lymphadenectomy shall not be performed because of the low frequency of lymph node metastases.
This excludes patients with SDH-deficient GIST who have clinical suspicion of lymph node involvement.
- Consensus
- Strong consensus
Tumor rupture during preparation or retrieval of the specimen shall be avoided.
- Consensus
- Strong consensus
In case of R1 resection of GIST and a very low to low risk of tumor recurrence, a „wait-and-see“ strategy can be discussed with the patient.
- Consensus
- Strong consensus
GIST of the stomach less than 2 cm in diameter may be monitored regularly by endoscopic ultrasound.
- Consensus
- Strong consensus
Background
Rectal GIST and GIST of the recto-vaginal septum represent approximately 5 % of all GIST. GIST of the colon outside the rectum are extremely rare. Therefore, therapy should be performed on a case-by-case basis analogous to the therapeutic principles of GIST outlined above [20]. While GIST of the rectum were often radically operated in the era before imatinib, local and function-preserving resections are almost always possible today after neoadjuvan therapy with imatinib. Single smaller retrospective studies could show a positive effect of neoadjuvant therapy. Prospective randomized data are not available for this rare tumor. The study by Cavnar et al. showed that even with positive resection margins after local function-preserving resection, no local recurrences occurred if perioperative therapy with imatinib was given [636], [637].
Resection is indicated for GIST with tumor size of 2 cm or more (with the exception of the rectum, where smaller GIST even below 2 cm should be removed), as these tumors are at higher risk for metastasis. However, subsequent growth cannot be ruled out even for small GIST. Therefore, even for smaller GIST, resection may be weighed against long-term follow-up. It should be noted that there is only high or low risk in GIST of the rectum. In the AFIP classification based on 111 GIST of the rectum, only tumors less than 5 cm with less than 5 mitoses/5 mm2 have a risk of metastasis of 8.5 %, All other tumors (>5 cm or any tumor size with > 5 mitoses/5 mm2) have a risk of recurrence of 52 % - 71 % [115].
The principle of resection treatment of GIST is guided by achieving tumor-free resection margins (R0). Prospective randomized data on the extent of the safety margin are not available. Complete monobloc R0 resection of GIST is the standard procedure. Because GIST mostly do not show lymphatic or vascular or perineural spread, safety margins of 1 cm in the longitudinal direction are considered sufficient. An analysis by the Scandinavian Sarcoma Group demonstrated that resection with tumor-involved resection margins resulted in significantly less favorable survival (RR 2.4[1.1-4.3], p=0.02) [152].
Any GIST, regardless of tumor size, is potentially malignant. The risk for malignant behavior is influenced by factors such as mitotic rate/5 mm² and mutational status, data that are often not available at primary tumor resection. In this respect, oncologic resection should always be performed.
Enucleation of the tumor has significantly higher recurrence rates. In particular, endoscopic resection in multiple parts leads to R1 resection and high recurrence rates. In such cases, laparoscopic resection is often the procedure more likely to result in R0 resection.
For gastric GIST, wedge resection or segmental resection is the treatment of choice; GIST of the small bowel are adequately treated by segmental resection.
Especially for gastric GIST and those of the small bowel, minimally invasive approaches (laparoscopy, robotic-assisted) can also be considered for resection. There are many reports, including comparative studies, on laparoscopic resection, especially of GIST of the stomach. The studies all show a very favorable perioperative course and R0 resection rates comparable to access by laparotomy. However, few long-term data are available for the mostly small tumors in the published series [638], [639].
Laparoscopic resection is not recommended for larger tumors with the risk of tumor rupture.
Systematic lymphadenectomy is not necessary due to the low frequency of lymph node metastases (less than 1%). Only in the rare SDH-deficient GIST, which occurs mainly in pediatric patients and young adults with Carney-Stratakis syndrome or a familial mutation, is the lymph node metastasis rate higher [640]. Lymph node dissection should then be discussed and also performed if the lymph nodes are abnormal.
R0 resection during primary surgery is the most important prognostic factor for local tumor control - besides mitotic index, tumor size, tumor location (gastric vs. non-gastric) and tumor rupture [116], [641]. Macroscopic incomplete resection (R2) of a GIST primary tumor has the least favorable prognosis. Intraoperative tumor rupture with contamination of the abdominal cavity by vital tumor cells also falls into this category. Without drug therapy, almost all patients suffer tumor recurrence [642], [643]. Patients with tumour rupture should be treated as for metastatic disease, i.e. continuous drug therapy depending on the mutation status.
In the risk classification of Joensuu [116], which best reflects the tumor biological aspects, but also in the classification of Rutkowski [642], tumor rupture is represented with its own risk classification. Therefore, intraoperative tumor rupture should be avoided under all circumstances. This necessitates the use of a salvage bag in minimally invasive resection. Conversion of a minimally surgically initiated procedure to an open procedure for safe specimen salvage should be generously considered.
Regarding microscopic incmplete resection (R1), close margins resection, or resection in healthy tissue (R0), there are no clear prospective data for GIST. In large adjuvant therapy trials, R1 resection rates have ranged from 6.5 % [644], 7.3 % [645], and 19 % [646]. Metastasis-free survival is not affected by R0 resection.
In an analysis of 410 patients, including 47 R1 resections and 52 tumor perforations, R1 resection had no unfavorable effect on recurrence-free survival, which was highly significantly negatively affected by tumor rupture [641].
If an R1 situation is found in the frozen section or in the final histology, a re-resection should be performed whenever possible. After R1 resection in the final histology (marginal resection with margin-forming tumor cells), re-resection can be considered if no major functional limitations are expected from the re-resection.“ In the case of R1 resection of a very low to low risk tumor, a wait-and-see „strategy should also be advocated and discussed with the patient [647].
In an analysis of patients with an R1 resection from the US adjuvant Z9001 trial [644] (1 year imatinib vs. placebo), there was no significant difference in recurrence-free survival in the treatment arm with a HR of 1.095 (95% CI 0.66-1.82, p=0.73) and in the placebo arm with a HR of 1.51 (95% CI 0.76-2.99, p=0.24). A systematic review on the impact of R1 resection demonstrated that R1 compared with R0 resection negatively influenced disease-free survival (HR 1.596, 95 % CI 1.128-2.258; I2 = 37.5 %, p = 0.091) [648]. However, an impact on overall survival could not be demonstrated (HR 1.430, 95 % CI 0.608-3.363; I2 = 60.8 %, p = 0.013). It should be taken into account that adjuvant therapy naturally attenuates the recurrence rate.
In this respect, individual consideration is required for re-intervention, as these operations are not always easily performed and the prognostic impact of R1 resection has not been established.
GIST of the stomach with a diameter smaller than 2 cm are very often incidental findings in the course of endoscopy for other reasons, or they are discovered intraoperatively by chance, e.g., in the course of bariatric or gynecologic surgery.
In all risk classifications, these tumors have a minimal risk of metastasis. Small GIST of the stomach can be safely followed up by endoscopic ultrasound at 6-monthly intervals and at annual intervals if the findings are consistent. A biopsy is required if the tumors are continuously growing. A punch biopsy or fine needle¬biopsy under endoscopic control is the method of choice. If the limit of 2 cm is exceeded, resection is the appropriate treatment.
For intraoperative incidental findings of small GIST of the small bowel, resection in healthy tissue is the treatment of choice. Risk classification is based not only on tumor size but also on mitotic rate per 5 mm2. In most cases, this cannot be determined with certainty on a biopsy. Since GIST of the small bowel cannot be reliably monitored by ultrasound or CT with regard to their size progression, they should be resected intraoperatively by an appropriately experienced physician [649].
10.1.1 Pathological diagnostics of GIST
10.1.1.1 Minimum requirements reports
The diagnosis of gastrointestinal stromal tumor should be established with an immunohistochemical antibody panel in addition to morphologic diagnosis (minimum: CD117, CD34, DOG1, Ki67, SDHB).
- Consensus
- Strong consensus
When diagnosing GIST on a resected tumor, R status, primary location, tumor size (largest longitudinal diameter), number of mitoses per 5 mm², and a determination of whether tumor rupture is present shall be included in the pathology report.
- Consensus
- Strong consensus
Background
More than 90 % of GIST diagnoses can be made when immunohistochemical methods are used [650], [651], [652], [653]. If there is doubt about the diagnosis, further immunohistochemical testing may be necessary to differentiate it from other mesenchymal tumors (e.g., desmin, MDM2, S-100 protein, Sox-10, Melan A). In addition, for the rare equivocal findings, molecular confirmation of findings should be sought or reference pathologic co-evaluation should be performed.
For patients with localized GIST, the location, size, and number of mitoses / 5 mm² represent the most important independent risk factors [115], [654]. There is a consensus that mitoses are counted in 5 mm² instead of 50 HPF. In modern microscopes, this corresponds to about 20 fields of view at 400x magnification (high power fields /HPF).
Complete documentation of risk factors in the pathology report is a prerequisite for correct risk classification using risk tables and contour maps [116], [115], [654]. The first risk classifications used a dichotomous division of mitotic count (≤5 vs. >5 mitoses). This may lead to an overestimation of the risk of metastasis, especially in tumors with mitoses just above 5 per 5 mm², and thus may also cause overtreatment. The proportion of GIST with mitoses between 6 and 10 mitoses per 5 mm² is about 10 %. Therefore, newer classifications use further gradations, which is why the exact number of mitoses per 5 mm² should always be used for pathological reports and not only the indication of > 5 mitoses.
10.1.1.2 Molecular diagnostics
Molecular pathologic analysis shall be performed for all GISTs that are at least intermediate risk or for which drug therapy is being considered.
- Consensus
- Strong consensus
Background
Genotype should be available in all patients, whether localized or metastatic, prior to initiation of drug therapy. This influences dose selection in KIT-mutated GIST [655] and may be a predictor of primary therapy resistance (e.g., PDGFRα D842V mutations or some rare primary exon 17 mutations of KIT) [656], [657], [658]. Exons 9, 11, 13, and 17 of the KIT gene and exons 12, 14, and 18 of the PDGFRA gene will be sequenced. Exon 14 of the KIT gene may also be affected if the tumor has become resistant to therapy [657], [659].
Mutation analyses can also be performed sequentially according to the frequency of affected exons, however, increasingly most GIST are investigated simultaneously in these gene segments using deepsequencing. In typical cases of sporadic GIST without KIT or PDGFRA mutation at initial diagnosis and without evidence of genetic predisposition and (older age of the patient at disease onset, no neurofibromatosis), diagnosis should therefore be performed by deep sequencing to detect mutations with lower allelic frequency. Here, the expertise of reference centers is helpful.
For patients who do not show mutations in the KIT or PDGFRA gene, further molecular analysis shall be performed to rule out the presence of genetic alterations relevant for treatment.
- Consensus
- Strong consensus
Background
Patients without evidence of a KIT or PDGFRA mutation have long been grouped together as „wild-type“ GIST. This term should no longer be used, as it has (incorrectly) subsumed quite different genotypes that are actually well characterized [660].
In cases without evidence of KIT or PDGFRA mutation, the presence of SDH deficiency, NF1 mutation, BRAF mutation or rare gene fusions must be investigated. There may be a tumorpredisposition syndrome (Carney-Stratakis syndrome, neurofibromatosis, germline mutation in KIT or PDGFRA) or primary imatinib resistance. In these cases, referral to specialized
Familial GISTs are diagnosed, among other things, as part of the diagnostic workup for iron deficiency anemia. In people with Carney-Stratakis syndrome, GIST screening can be performed using blood counts at annual intervals.
- Consensus
- Strong consensus
Background
If SDH deficiency is detected, the possibility of heredity (risk of Carney-Stratakis syndrome) must be considered. This is also true if an NF1 mutation is present (neurofibromatosis) or if other family members have GIST and have an identical genotype.
Intestinal bleeding with development of symptomatic anemia is among the most common symptoms leading to the diagnosis of GIST. Therefore, in individuals with familial GIST syndromes, annual screening by blood counts is performed by individual centers. The value of regular cross-sectional imaging (whole-body MRI) or even gastroscopy must be weighed against the lifetime risk of GIST together with human geneticists and patients [661], [651][662]. Again, linking affected individuals to specialized GIST centers is recommended.
10.1.1.3 Risk classification of localized tumors
For the treatment decision on postoperative adjuvant therapy with imatinib, a risk classification should be used that includes tumor rupture in addition to primary site, absolute mitotic count/5 mm² and tumor size. In this regard, the modified consensus criteria and contour maps have proven most useful.
The TNM classification for GIST has no added clinical value.
- Consensus
- Strong consensus
Background
For patients with localized tumors, a determination of the risk for metastasis postoperatively should be made during histological examination of the primary tumor. The AFIP classification allows an accurate assignment of a percentage risk of recurrence [662]. However, the dichotomous division of mitotic rates leads to artificial jumps in recurrence risk for mitotic counts around 5/5 mm². The modified criteria of the contour maps with continuous assessment of the mitotic rate have proven useful for discussion with the patient [116]. In addition to a finer division of mitoses, the high prognostic value of tumor rupture is also taken into account. The use of TNM classification cannot be recommended for GIST because the classification is not based on validated data.
To date, mutation status has not been integrated into risk classifications. Nevertheless, distinct natural histories are found in some genotypes. Especially in patients without KIT or PDGFRA mutations, the peculiar clinical courses (multiple primary tumors, very late metastasis, indolent course) should be considered for patient counseling.
In patients with GIST of the stomach, mutations in exon 11 of KIT leading to deletion of amino acids 557 and 558 appear to be associated with an increased risk of relapse [663], [664], [665].
* modified according to Miettinen and Lasota [115].
The reference to 50HPF no longer corresponds to today's recommended mitotic rate of 5mm2. For citation reasons, the original data are shown.
Top row maps are used when tumor rupture status is unknown (A,B,C), middle row maps when tumor is not ruptured (D,E,F), and bottom row maps when tumor rupture has occurred (G,H,I). Red areas represent high risk, blue areas represent low risk, and white areas indicate missing data. The percentages associated with each color (key) indicate the probability of GIST recurrence within the first 10 years of follow-up after surgery. For example, the middle map left column (D) shows that the 10-year risk of GIST recurrence in a patient diagnosed with a 10-cm gastric GIST with five mitoses per 50 HPFs of microscope and no rupture is 20-40 %. The 10-year risk associated with a similar tumor when the mitotic count is ten per 50 HPF increases to 40-60 %.
E-GIST = GIST arising outside the gastrointestinal tract.
10.1.2 Staging
For staging GIST of the stomach, small bowel, and rectum, contrast-enhanced CT abdomen or contrast-enhanced MRI abdomen with imaging of the pelvis should be performed. For GIST of the esophagus, a contrast-enhanced CT thorax should also be performed. For GIST of the rectum, additional MRI of the pelvis should be performed for more accurate assessment of local disease extent.
- Consensus
- Strong consensus
Background
For the diagnosis of spread in GIST, the particular pattern of metastasis should be used as a rationale for the choice of diagnosis. For GIST of the stomach and small bowel, virtually only peritoneal or hepatic metastases are found when metastasis is synchronous at the time of diagnosis. Therefore, contrast-enhanced CT of the abdomen or, as an alternative, MRI of the abdomen are the staging modality of choice. Chest CT may be performed once as part of the diagnosis; however, pulmonary metastases are rare at diagnosis with the exception of rectal GIST. For rectal GIST, MRI should be performed preoperatively to assess operability.
10.1.3 Adjuvant drug therapy of localized, R0 resected GIST.
Patients at significant risk of relapse after primary tumor resection who have an imatinib-sensitive KIT or PDGFRA mutation in their tumor shall receive adjuvant therapy with imatinib for 3 years.
Patients receiving only year or two years of adjuvant treatment with imatinib after resection of a primary GIST have a benefit only uring the treatment period. No significant impact on overall survival could be demonstrated.
- Level of evidence
- ⊕⊝⊝⊝
Overall survival (median follow-up: NR)
⊕⊕⊝⊝Overall survival (median follow-up: 19.7 months) (ACOSOG Z9001 study).
⊕⊕⊝⊝Overall survival (median follow-up: 74 months) (ACOSOG Z9001 study).
⊕⊕⊝⊝Recurrence-free survival (median follow-up: 19.7 months) (ACOSOG Z9001 study).
⊕⊕⊝⊝Recurrence-free survival (median follow-up: 74 months) (ACOSOG Z9001 study).
⊕⊕⊝⊝Recurrence-free survival (median follow-up: 14 months)
- Consensus
- Strong consensus
- References
- [644] [667] [668] [669]
Background
Three randomized trials evaluated the value of adjuvant therapy with imatinib in completely resected GIST. In the Z9001 trial, 359 patients were randomized in a double-blind fashion between 1 year of therapy with imatinib 400 mg and placebo control after complete resection of a GIST 3 cm in diameter or larger [644]. Recurrence-free survival of patients in the treatment arm was significantly improved (HR 0.6, CI 0.43-0.75) while overall survival showed no significant difference.
In the EORTC 62024 trial, 908 patients at intermediate or high risk of relapse were randomized between adjuvant therapy with imatinib 400 mg daily for 24 months versus no therapy, according to NIH Consensus [650]. Recurrence-free survival was found to be significantly better in the treatment arm than in the control group (RR 0.75, CI 0.62-0.91) with a median follow-up of 56.4 months [667]. However, overall survival of patients in the two groups was not significantly different (RR 1.14, CI 0.7-1.84). Considering the two risk groups ‚intermediate‘ and ‚high‘, a non-significant trend for better survival was detectable only in the high-risk group.
In the SSG XXVIII-AIO study, 400 patients who were classified in the high-risk group according to NIH Consensus and were macroscopically tumor-free intraoperatively after primary tumor resection were randomized between 1 year of imatinib 400 mg therapy and 3 years of treatment [646]. Significantly better relapse-free survival (HR, 0.46; 95 % CI 0.32-0.65; p<0.001; 5-year RFS, 65.6 % vs. 47.9 %), as well as significantly better overall survival (HR, 0.45; 95 % CI 0.22-0.89; p=0.02; 5-year OS, 92.0 % vs. 81.7 %), were demonstrated in the 3-year treatment arm. The significant survival benefit was also confirmed after a median follow-up of 10 years after randomization [670].
A prerequisite for successful adjuvant therapy is the detection of an imatinib-sensitive mutation in the primary tumor.
Patients with imatinib-sensitive KIT or PDGFRA mutations and a high risk of relapse should receive adjuvant therapy at 400 mg for 3 years. For patients with a KIT exon 9 mutation in the tumor, some centers use a dose of 800 mg/d in analogy to the treatment in the metastatic setting. However, the benefit of higher dosing has not been prospectively demonstrated for adjuvant therapy.
A therapeutic benefit for adjuvant therapy with imatinib has not been demonstrated for patients with SDH-deficient, NF1-mutated, or BRAF-mutated GIST or those without evidence of a mutation and is therefore not indicated.
10.1.4 Clinical management of metastatic GIST
Patients with metastatic GIST and patients with metastasis occurring after completion of adjuvant imatinib therapy should be treated with imatinib. The genotype of the tumor should be available for indication and dosing.
- Level of evidence
- ⊕⊕⊝⊝
Overall survival (follow-up: 24 months)
⊕⊕⊝⊝Progression-free survival (follow-up: 24 months)
- Consensus
- Strong consensus
- References
- [671]
Patients with metastatic or unresectable GIST harboring a D842V mutation in the PDGFRA gene should receive therapy with avapritinib at the recommended daily dose of 300 mg.
- Consensus
- Consent
Background 10.19 and 10.20
Gastrointestinal stromal tumors were often classified as gastrointestinal leiomyomas or leiomyosarcomas until the late 1990s based on immunohistochemical similarities and were also treated with chemotherapy in clinical trials. Retrospective analyses in this regard identify GIST as refractory to classical chemotherapies [672]. Until the introduction of imatinib, there was no effective therapy and the median survival of patients with locally advanced or metastatic disease was 12-18 months [673]. Because of the dramatic clinical benefit of imatinib in phase II trials, a placebo-controlled randomized phase III trial had been omitted. In historical comparisons, median overall patient survival more than tripled with the use of imatinib [674]. The two confirmatory phase III trials therefore compared only two different doses (400 mg vs. 800 mg daily) [674], [675]. A joint analysis of the two trials (META-GIST analysis) showed a median progression-free survival of 1.6 to 2.0 years (p= 0.04) and a median survival in both dose arms of 4 years. Genotype analysis showed a significant benefit for progression-free survival as well as a trend for better overall survival in favor of the 800 mg/d treatment arm only in patients who had a primary mutation in exon 9 of the KIT gene.
Therefore, for patients with metastatic GIST without pretreatment or with tumor recurrence after completion of adjuvant therapy, imatinib at a daily dose of 400 mg/d is the standard of care. In the presence of a KIT exon 9 mutation, a higher dose (800 mg/d) should be considered.
Given the background of primary imatinib resistance in patients with primary KIT exon 17 mutations as well as certain mutations of the PDGFRA gene, the results of genotype determination should be available before initiating therapy to avoid ineffective treatment [657], [676]. In cases of urgent treatment indicatio, initiation of therapy without the presence of the genotype may be warranted.
Avapritinib has been approved by the FDA and EMA for patients with a PDGFRA-D842V mutation [677], [678]. All previously approved tyrosine kinase inhibitors are ineffective in this mutation type and thus not indicated. Avapritinib was specifically designed to target the D842V mutation and steric alteration of the PDGFRA receptor and thus is currentlc unique. Patients with a D842V mutation in the primary tumor often have a benign course without metastases. Patients who develop metastasis usually have rapid disease progression and with an urgent need for treatment. Therapy with avapritinib has an objective remission rate of 88% (95 % CI 76-95), with long remission duration, so the median progression-free survival in the NAVIGATOR study has not yet been reached even with a follow-up of 19 months. Of 56 pa-tients, 37 (66 %) were still on therapy [677]. The recommended daily treatment dose is 300mg, and the maximum tolerated daily dose was 400mg. Treatment-associated grade 3-4 toxicity developed in 57% of patients, including anemia (17 %).
Cognitive side effects (cognitive impairment) occur with avapritinib - a first for approved GIST therapies. These patients require close, sensitive, and dedicated side effect management.
To date, only nilotinib has been randomized versus imatinib in first-line treatment. The trial, which was designed to show superiority of nilotinib over imatinib, failed to demonstrate an advantage (median PFS of 26 versus 30 months for imatinib). Nilotinib was ineffective in patients with primary KIT exon 9 mutation; in patients with exon 11 mutation, there was comparable effect to imatinib. The side effect profile for both drugs was similarly favorable. In patients with primary exon 11 mutation and rare imatinib intolerance, nilotinib represents a treatment alternative. The compound is approved for the treatment of CML (off-label use for GIST).
Patients with metastatic GIST without a drug-sensitive mutation in the KIT or PDGFRA gene shall be treated in cooperation with a GIST-experienced center.
- Consensus
- Strong consensus
Background 10.21
Patients in whom no mutations in the KIT or PDGFRA gene can be detected require intensive molecular pathological clarification, as many therapeutic implications arise. Here, patients should be treated in cooperation with GIST-experienced centers (centers with high study activity and molecular pathology that has comprehensive diagnostics available).
Different mutations even within the same exon (e.g., KIT exon 17 or PDGFRA exon 18) can result in resistance to imatinib as well as be imatinib sensitive [657], [676]. Therefore, for the therapeutic decision in these cases, a molecularly adjusted classification of the mutation must be performed, if necessary by a molecular tumor board.
Patients with SDH-deficient GIST not infrequently show an indolent disease course so that a wait-and-see approach regarding active therapy should also be considered initially until clear evidence of progression. The therapeutic benefit of imatinib is also unclear, as imatinib is a moderately potent inhibitor of wild-type KIT, but on the other hand, the oncogenic dependence on KIT seems to be lower in this molecular subgroup [65], [679]. Remissions on imatinib are virtually never observed. Therefore, many centers favor primary treatment with sunitinib when there is a systemic treatment indication.
In very rare cases, typical BRAF mutations (so far exclusively pV600E) are found as the major driver mutation (KIT and PDGFRA are not mutated). This mutation is predictive of primary imatinib resistance, which is why imatinib is not indicated either in the adjuvant or metastatic setting. Due to the uncoupling of the oncogenic mutation from the KIT receptor, it is also not possible to derive a rationale for other specific KIT inhibitors. A treatment response has been described for a single patient on regorafenib. This is most likely explained by the broad inhibitory profile of regorafenib, which also has activity against BRAF and mutant BRAF. However, because of its high entity-independent efficacy, therapy with a BRAF inhibitor in combination with a MEK inhibitor should primarily be considered here [680], [681]. In other disease entities, the combination results not only in better efficacy but also in better tolerability.
Patients with GIST who have NTRK fusion have also been reported. Again, no activating mutation of KIT or the PDGF receptor is then found. In this case, NTRK inhibitors (larotrectinib, entrectinib) should primarily be used according to the licence indication [660], [682].
To evaluate the response to systemic therapy in patients with GIST, the change in contrast uptake on CT or MRI should be determined in addition to the size of the metastases to detect possible pseudoprogression.
- Consensus
- Strong consensus
Background 10.22
Patients with hepatic metastatic GIST not infrequently have a similar density in the margins of the metastases as the liver tissue itself. In response to therapy, this may result in demarcation of previously liver-isodense foci, which can be misinterpreted as progression [683], [684]. This pseudoprogression can usually be easily classified as such by a clear decrease in density.
To ensure maximum comparability, changes in diagnostic modalities (from CT to MRI and vice versa) should be avoided.
Positron emission tomography (PET) is a highly sensitive method for assessing response to imatinib [683], however, assessment by CT or MRI is sufficient in the vast majority of cases. In addition, genotype is usually sufficient to predict treatment response (in the first line of therapy).
A daily dose of 800 mg imatinib should be used in patients with a KIT exon 9 mutation.
- Consensus
- Strong consensus
Background 10.23
Patients with a KIT exon 9 mutation have significantly better progression-free survival (Relative Risk Reduction: 42 %, p=0.017, Wald test) and a significantly higher remission rate (47 % vs. 21 %, p=0.0037) when dosed at 800 mg/d [655]. The META-GIST analysis, which evaluated both phase III trials together, also showed a trend for better overall survival, but statistical significance was not demonstrated. A daily dose of 800 mg is therefore considered the standard for this genotype. Most centers start with a dose of 400 mg and increase to 800 mg imatinib within the first 4-6 weeks because of better tolerability. In case of unacceptable toxicity, the dose can be titrated in 100 mg increments to a dose acceptable to the patient.
Patients with metastatic disease shall receive therapy with imatinib continuously until progression or development of intolerance.
- Consensus
- Strong consensus
Background 10.24
The BFR14 trial randomized patients with metastatic GIST on ongoing imatinib therapy (stable disease) to interruption of therapy at one, three, and five years [685]. This demonstrated that regardless of remission status and duration of prior therapy, interruption of imatinib treatment is associated with a very high risk of disease progression. In particular, rapid progression after discontinuation of therapy is associated with poor progression-free survival after resumption of therapy. Therefore, imatinib therapy should be maintained continuously until progression or intolerance develops. Therapy breaks should be kept to a minimum [686].
In patients with metastatic disease, resection of regressed, residual tumor on imatinib therapy may be offered if macroscopic tumor resection can be achieved with acceptable surgical morbidity.
The decision and surgery shall be performed exclusively at GIST-experienced centers.
- Consensus
- Strong consensus
Background 10.25
A prospective study to test the value of metastasectomy has not yet been successful due to lack of recruitment. Nevertheless, a number of retrospective studies are available that suggest a clinical benefit of resection is likely, but more importantly, also suggest no evidence of harm. Particularly for patients who can be completely resected macroscopically (R0/R1) at the time of treatment response (without evidence of progression), very long progression-free courses can be observed in some cases. Compared with patients who did not undergo surgery, significant survival advantages are found [687], [688], [689], [690]. However, due to the retrospective nature, the influence of selection bias cannot be excluded here, as patients with non-resectable disease may have an increased tumor burden and thus a worse prognosis anyway [691], [692].
The optimal time window for resection is considered to be 6 to 12 months after initiation of therapy with imatinib [687], [693]. In principle, however, the risks of surgery y must be weighed against the patients' chance of achieving long-term tumor control without surgery. Even if a surgically complete resection is achieved, continuation of imatinib treatment postoperatively is required.
Radical surgery in patients with progressive disease should be considered very cautiously [687], [689], [690], [693], [694]. Here, most centers set the goal of symptom relief as a prerequisite for surgery – a prognostic improvement is not expected according to the data available. In the case of focal progression, resection can be considered; a number of cases have been described in which imatinib could be continued for long periods without further evidence of progression [693], [695].
The decision and surgery should be performed at sarcoma centers that have proven GIST experience (regular participation in studies, experience in the sarcoma board, surgical experience).
Patients who do not respond or no longer respond to therapy with imatinib shall receive therapy with sunitinib.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- ⊕⊕⊝⊝
Overall survival (median follow-up: 41.7 months)
⊕⊕⊝⊝Progression-free survival (median follow-up: 41.7 months)
⊕⊕⊕⊝Overall survival (median follow-up: NR)
⊕⊕⊝⊝Progression-free survival (Follow up: NR)
- Consensus
- Strong consensus
- References
- [696] [697]
Background 10.26
In case of evidence of progression or the rare case of imatinib intolerance, the tyrosine kinase inhibitor sunitinib represents the approved standard therapy. Imatinib intolerance may only be assumed if intensified side effect management has occurred and dose modifications have been made, possibly including plasma level determinations, therapy trial with nilotinib (see above). For these cases, linkage to centers with specialized GIST consultations is also recommended.
In a a phase III trial using a daily dose of 50 mg in a 6-week treatment cycle (4 weeks of therapy followed by 2 weeks off) [696] sunitinib demonstrated a nearly 5-month improvement over placebo, with a median progression-free survival of 6.2 months. There was no survival benefit; however, patients were also allowed to crossover to the treatment arm.
Mucosal and skin toxicity and arterial hypertension represent common and distressing side effects for patients. Although no formal comparative study has been conducted, continuous therapy with 37.5mg sunitinib daily (without pause) appears to have comparable efficacy but is associated with a more favorable side effect profile [698]. This regimen can therefore be used as an alternative option on an individual basis. For sunitinib, maximum utilization of supportive therapy measures and in-dividualized dosing and regimens, should be used to achieve the best possible tolerability. However, daily doses below 25 mg usually have no therapeutic benefit.
Sunitinib appears to be particularly active against resistance mutations in exon 13 and 14 of the KIT gene, whereas secondary mutations in exon 17 and 18 are barely inhibited [699], [700], [701]. However, the clinical utility of determining resistance mutations (by tumor biopsy or plasma sequencing) has not been prospectively studied to date and should not influence the order of second- or third-line therapy outside of clinical trials.
Patients who do not respond or no longer respond to therapy with sunitinib shall receive therapy with regorafenib.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- ⊕⊕⊝⊝
Overall survival (median follow-up: NR)
⊕⊕⊕⊝Progression-free survival (median follow-up: NR)
⊕⊕⊝⊝QoL (EQ-5D, during treatment)
- Consensus
- Strong consensus
- References
- [702] [703]
Background 10.27
In third-line therapy, regorafenib is the therapy of choice after clear progression or unacceptable toxicity with sunitinib. The approval of regorafenib is based on data from the GRID trial, which compared regorafenib (160 mg daily, 3 weeks of therapy, 1 week off) with placebo therapy [703]. Regorafenib had a median progression-free survival of 4.8 months vs. 0.9 months for placebo (HR 0.27; p<0.0001). Regorafenib, like sunitinib, inhibits a broad spectrum of tyrosine kinases; both were originally developed as potent VEGFR inhibitors. Therefore, in contrast to more specific KIT inhibitors such as imatinib and nilotinib, higher-grade side effects such as arterial hypertension and also severe hand-foot syndrome and mucositis with gastrointestinal symptoms are found much more frequently. Here, in analogy to sunitinib, close monitoring of patients as well as intensive side effect management must be pursued, especially at the beginning of therapy.
The VOYAGER study, a phase III trial, evaluated the efficacy and safety of avapritinib vs. regorafenib as a third-line or later treatment in patients with unresectable or metastatic GIST. The primary endpoint was not met. There was no significant difference in median progression-free survival between avapritinib and regorafenib in patients with molecularly unselected late-stage GIST.
Patients who fail or no longer respond to therapy with three or more kinase inhibitors, including imatinib, shall receive therapy with ripretinib at the recommended daily dose of 150mg.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- ⊕⊕⊝⊝
Overall survival
⊕⊕⊕⊝Progression-free survival
⊕⊕⊝⊝QoL (EQ-5D VAS)
⊕⊕⊝⊝EORTC QLQ-C30 (Physical Function, Role Function)
- Consensus
- Strong consensus
- References
- [704]
Evidence tables (1)
Ripretinib - INVICTUS StudieBackground 10.28
In the case of tumor progression during treatment with three or more tyrosine kinase inhibitors, including imatinib, the switch-pocket inhibitor ripretinib was approved by the EMA for fourth-line treatment. The INVICTUS trial, a double-blind, randomized phase III study, evaluated ripretinib versus placebo in patients after failure or intolerance to imatinib, sunitinib and regorafenib [704]. A total of 129 patients in 12 countries were enrolled in the trial and randomized to ripretinib (n=85) or placebo (n=44). 64% of patients had 3 prior therapies, and 36% of patients had 4-7 prior therapies. There was a highly significant improve-ment in progression-free survival in the ripretinib arm (6 months vs. 1 month; p<0.0001 according to independent central review). Median survival was 15 months in the treatment arm and 7 months in the placebo arm, which could not be formally tested for statistical significance due to the hierarchical test design. In an analysis of the impact of genomic heterogeneities on treatment outcome, neither the primary mutation (exon 9 vs. 11) nor the various secondary-mutations significantly affected the efficacy of ripretinib [705]. The most common (in ≥20% of patients) treatment-related side effects of ripretinib included alopecia, myalgia, nausea, fatigue, hand-foot syndrome, and diarrhea. Treatmentassociated adverse events with grade 3 or 4 in the ripretinib group included lipase elevation (5%), hypertension (4%), fatigue (2%), and hypo-phosphatemia (2%).
In patients with metastatic disease who no longer respond to available drugs and in whom only individual metastases show progression, local therapy may be offered.
The decision shall be made at centers experienced in GIST.
- Consensus
- Strong consensus
Background 10.29
Resection of metastases at the time of progression to first-, second-, or third-line drug therapy are usually associated with a very short progression-free time and often short median survival in retrospective series [634], [706]. This is particularly true for multifocal progression. In contrast, in patients with only isolated progressive foci (e.g. „nodules within a mass“ [707]), continuation of e.g. imatinib therapy can be achieved by isolated resection or even a local ablative procedure.
Non-surgical procedures include thermoablation (radiofrequency or microwave ablation), but also selective internal radiation therapy (radioembolization with Y-90 microspheres) [536], [708], [709], [710], [711], [712], [713].
In any case, a careful risk-benefit assessment must be made here, preferably in consultation with centers experienced in GIST.
Patients with metastatic disease who no longer respond to multiple tyrosine kinase inhibitors can be offered therapy with imatinib again.
Decisions shall be made at GIST-experienced centers.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- ⊕⊕⊝⊝
Overall survival (median follow-up: 5.2 months)
⊕⊕⊕⊕Progression-free survival (median follow-up: 5.2 months)
⊕⊕⊝⊝QoL (EORTC QLQ-C30, general health status, 8 weeks after treatment).
- Consensus
- Strong consensus
- References
- [714] [715]
Background 10.30
In particular, the INVICTUS trial has very powerfully demonstrated that discontinuation of TKI therapy in a late line of treatment leads to rapid progression and is associated with a very unfavorable survival prognosis. Resistance development in GIST is generally clonal [716], [717], [718]. That is, at the time of progression, there is a coexistence of metastases that still respond to therapy and those that are resistant due to secondary mutation. Discontinuation of any therapy therefore often leads to a global growth spurt („tumor flare“), which is why TKI treatment beyond progression should always be favored. If possible, therapy should be given in the setting of clinical trials.
Alternatively, inhibitors that have been given before can be used („Rechallenge“). In the RIGHT trial, after failure of imatinib and sunitinib (but not regorafenib), a rechallenge with imatinib was studied compared to placebo. This showed a small but significant benefit (1.8 months vs. 0.9 months) of imatinib over placebo [714], [715].
Prospectively, a placebo-controlled trial in 81 patients compared the efficacy of pazopanib versus placebo (PAZOGIST, [719]). Inclusion criteria for the study were progression or intolerance to imatinib and sunitinib. Pazopanib significantly improved progression-free survival compared with placebo (HR 0.59, CI 0.37-0.96) [719]. There was no improvement in overall survival. Pazopanib is approved for second-line metastatic sarcoma therapy, but not for GIST therapy.
A randomized phase III trial evaluating nilotinib after imatinib and sunitinib failure showed no advantage over best-supportive care in progression-free or overall survival and therefore cannot be recommended [720].
10.1.5 Follow-up
Patients after resection of localized GIST should have risk-adapted follow-up.
- Consensus
- Strong consensus
Background
There is no prospective study on the benefit of routine follow-up. However, metastases in GIST patients usually lead to clinical symptoms late. In turn, a high tumor burden represents an unfavorable prognostic factor in the metastatic setting.
Tumor recurrences occur almost exclusively in the liver and/or peritoneum, which is why cross-sectional imaging of the abdomen is sufficient for most patients.
For patients with very low risk of recurrence (very low risk according to NIH or AFIP), many centers do not perform regular follow-up.
For patients at low to intermediate risk, a follow-up interval of (6-)12 months for 5 years is appropriate, although in individual cases follow-up up to 10 years is acceptable.
Most patients at high risk of relapse receive adjuvant therapy with imatinib. Under ongoing therapy, if compliance is good and a KIT exon 11 mutation is present, follow-up can be every 6 months (CT or MRI abdomen). As data from the SSG XVIII trial have shown, the risk of recurrence after the end of adjuvant therapy is highest in the first 2-3 years [721]. Therefore, follow-up intervals of 3-4 months in the first two years after the end of adjuvant therapy seem reasonable. Thereafter, the interval can be stretched to 6 months for a total of 5 years and then annually for another 5 years [722].
10.2 Epithelioid sarcomas
This sarcoma subtype occurs predominantly in young (including pediatric) patients on the extremities. A distal (hand, foot) and a proximal type are distinguished, up to 20 % of tumors are primarily multifocal (skip lesions) and up to 30 % metastasize to lymph nodes with a high tendency to recur [723].
Loss of integrase interactor 1 (SMARC1/INI1) function occurs in nearly 90 % of cases and is a consequence of biallelic deletion of the SMARCB1 gene or epigenetic dysregulation [724]. This results in EZH2 becoming an oncogenic driver in tumor cells.
Data on doxorubicin-based combination chemotherapy show a response rate of 22 % with a median PFS of 6 months [725].
As of January 2020, tazemetostat, a selective oral EZH inhibitor has been FDA approved for therapy in advanced epithelioid sarcoma. In a multicenter study in patients with proven INI-1 loss, the ORR for the 62 patients was 15 % (95 % CI: 7 %, 26 %), with complete remission of 1.6 % and partial remission of 13 %; 67 % of these patients showed a continued response over a time frame of more than 6 months [726].
10.3 Solitary fibrous tumors (SFT)
Solitary fibrous tumors (SFT) and hemangiopericytomas (HPC) are now grouped together as distinct forms of a spectrum of mesenchymal tumors with fibroblastic or myofibroblastic differentiation [727]. SFTs can occur ubiquitously. Pedunculated tumors of the visceral pleura are a particular localization and usually require surgical resection.
Solitary fibrous tumors exhibit recurrent gene fusion of NAB2 and STAT6, which cause upregulation of the oncogenic EGR-1 gene. The NAB2-STAT-6 fusion variants correlate with the anatomic localization of the tumors and their morphology. Nuclear overexpression of STAT6 on immunohistochemistry is a diagnostic landmark.
SFTs may be associated with hypoglycemia (Doege-Potter syndrome, insulin receptor activation) or with hypertrophic osteoarthropathies (Pierre-Marie-Bamberg syndrome) as paraneoplastic syndromes.
The proportion of malignant SFT has been described as high as 20 % with a higher proportion in extrapulmonary tumors. The four variables patient age >55 years, tumor size, mitotic count/10HPF and tumor necrosis (> 10 %) allowed discrimination between patients at low, intermediate and high risk for metastasis-free survival (p = 0.0005 [728]).
SFT rarely respond to systemic chemotherapy, so radiotherapy may be considered if neoadjuvant intent is considered. There is no standard ‚therapy‘ in the metastatic setting. Remissions are rarely reported for classical cytostatic agents. For sunitinib tumor stabilizations (according to RECIST) in 18 of 35 patients and up to 45 % partial remissions according to Choi criteria (14/29 pat.) with a median PFS of 6 months have been described [729]. In addition, long-lasting disease stabilizations are sometimes found under anti-VEGFA antibody bevacizumab in combination with temozolomide [730].
10.4 Angiosarcomas
Angiosarcomas are classified as malignant vascular tumors and represent approximately 2% of all soft tissue sarcomas. Epithelioid hemangioendotheliomas are also classified as malignant vascular tumors in the current WHO classification.
Cytogenetically, complex aberrations are found. In the majority, VEGF(-A) and VEGFR expression are detectable. Radiation-induced angiosarcomas of the breast almost always show MYC and FLT4 (VEGFR-3) overexpression [731].
Angiosarcomas show a higher than average incidence of lymphatic and hematogenous (usually pulmonary) metastasis and can manifest multifocally, especially when occurring after prior radiotherapy. They can occur at all body sites. Cerebral metastasis is also found more frequently.
Epithelioid hemangioendotheliomas (see below) are commonly found in the liver or lung and are characterized by specific translocations (WWTR1-CAMTA1 or YAP1-TFE3).
The 5-year survival rates are less favorable than for other sarcoma subtypes and are usually < 40% [732].
Anthracyclines and taxanes show high efficacy with remission rates of 30-70% for doxorubicin and approximately 20-80% for taxanes [733]. Angiosarcomas of the scalp show a particularly high response rate to paclitaxel [734]. In a retrospective analysis of the EORTC-STBSG database, combination therapy with adriamycin plus ifosfamide was superior to monotherapy in terms of PFS (HR 0.53; p = 0.010) and overall survival (HR 0.53; p = 0.018) [735]. For gemcitabine, a long-lasting treatment response has been shown in several phase II trials. Pazopanib represents another therapeutic option [736], possibly in combination with taxanes (6-month PFS of 46 % in the overall group and 61.1 % for cutaneous angiosarcomas [737]). In scalp angiosarcomas, remissions with immune checkpoint inhibitors have been described [738].
10.5 Clear cell sarcomas
Clear cell sarcomas were previously also referred to as malignant melanoma of the soft tissues, but can be clearly separated by molecular pathology. The tumors develop in the deep soft tissues with relation to tendons and aponeuroses. Younger adults are usually affected and lymph node metastases occur in up to 40 % of patients.
Clear cell sarcoma is usually characterized by a reciprocal translocation t(12;22) resulting in rearrangement of the EWSR1 gene with-ATF1, with consequent MET overexpression.
Clear cell sarcomas are frequently refractory to cytostatic chemotherapy, and even aggressive therapies such as doxorubicin+ifosfamide induce only low remission rates [739]. Targeted (‚targeted‘-) therapy also does not exist, in MET-positive clear cell sarcomas the response rate with crizotinib was only 3.8 % [740]. In this respect, surgical measures also come to the fore in the metastatic situation.
10.6 Alveolar soft tissue sarcomas
Alveolar soft-part sarcoma (ASPS) occurs predominantly in young adults (median age 25 years) at the extremities. Characteristically, in addition to lung and liver metastases, there is (often primary) cerebral metastasis, making MRI of the skull obligatory for staging. Even in the metastatic stage, the course is often indolent.
The tumors are characterized by a translocation, t(X;17) (p11.2;q25) resulting in a fusion gene ASPSCR1–TFE3. The ASPL-TFE3 fusion protein activates MET transcription among other c-MET gene transcription. Alveolar soft tissue sarcomas usually show a slow progression tendency.
Alveolar soft tissue sarcomas are considered refractory to conventional chemotherapy. In a double-blind, placebo-controlled study, the VEGFR inhibitor cediranib resulted in a median PFS of 10.1 months (IQR 5.3-19.0) versus 4.9 months (IQR 1.9-20.0) with placebo (p=0.001) was described with the VEGF inhibitor cediranib [741]. Unfortunately, the compound is not available for therapy. The results of therapy with pazopanib or sunitinib have been reported retrospectively [742], however, clinical benefit is also regularly observed.
A study with axitinib plus the immune checkpoint inhibitor pembrolizumab showed a 3-month PFS of 72.7 % (95 % CI 37.1-90.3) in ASPS patients [743], final study results are currently not available. Activity against ASPS has also been reported in other clinical trials involving immune checkpoint inhibitors e.g. sunitinib plus nivolumab [Martin-Broto, J et al. 2020].
10.7 Inflammatory myofibroblastic tumors.
Inflammatory myofibroblastic tumors (IMT) are rare soft tissue tumors of ubiquitous localization in children and younger adults. The tumors tend to be locally invasive, may have an indolent course, and rarely metastasize.
In more than 50 % of IMT there is a genetic rearrangement of the anaplastic lymphoma kinase (ALK) on chromosome 2p.23.13. Another group of the tumors shows ROS1 translocations.
In a retrospective analysis of different chemotherapies in 38 patients from 9 sarcoma centers, surprisingly good remission rates of 47.6 % are reported with a median PFS of 6.3 months for doxorubicin-based therapy [745].
Data from the CWS study group showed remission in 3 of 11 pediatric patients with a treatment protocol for rhabdomyosarcoma [746].
In the prospective EORTC CREATE [747] study with central histologic review, half of ALK-positive IMT developed partial remission with crizotinib therapy. The disease control rate was 100 % (85.7 % in ALK-negative tumors). At one year, 73.3 % of patients (95% CI 37.9-90.6) were progression-free. Crizotinib is currently not approved for the treatment of the disease in Germany.
10.8 PEComa
Tumors of perivascular epithelioid cells (PEC) (PEComas) express melanocytic (HMB-45, melan A) and smooth muscle markers (actin, desmin). The group of PEComas includes pulmonary lymphangioleiomyomatosis in young women, as well as angiomyolipomas, most commonly located perirenally but also found in subcutaneous tissue. PEComas occur ubiquitously and 70-80 % are found in women.
There is an association with mutations in one of the tuberous sclerosis complex genes, TSC1 or TSC2. This results in activation of mTORC1 [748], [749].
Metastasis is found in about 7 % of patients at diagnosis, usually pulmonary, hepatic, bone or cerebral. Effective cytostatic chemotherapy does not exist.
mTOR activation suggests the value of therapy with antagonists such as sirolimus, temsirolimus, or everolimus. Indeed, 18 of 25 patients had tumor regression of 53.2 % [750] after 1 year of therapy with sirolimus. However, tumor regrowth to 86 % of base-line size occurred after treatment discontinuation. This may open options for preoperative therapy in locoregionally advanced PEComa.
10.9 Epithelioid hemangioendotheliomas (EHE)
Epithelioid hemangioendotheliomas (EHE) are extremely rare malignant tumors with an incidence < 0.1/100,000 population for which there is no good evidence for therapy and mainly retrospective data have been published. The entity was not delineated until the 1980s. The tumors show vascular differentiation and are a low-grade malignancy [751]. At the time of diagnosis, the tumors may be unifocal, multifocal (multiple lesions in one organ or compartment), or multicentric (mainly in lung/liver/bone). Therefore, whole-body CT or MRI (in case of bone involvement) is required for staging.
EHE are commonly found in liver or lung but also in deep soft tissues, bone [752] and pleura. In visceral organs, they often appear multifocal or metastatic at diagnosis [753]. However, very indolent courses often occur even in metastatic stages. Spontaneous remissions have also been described for pulmonary EHE [754].
In half of the cases, a relation to the blood vessels can be established and angio-centric EHE often become symptomatic due to deep vein thrombosis. The tumors are characterized by specific translocations t(1;3)(p36.3;q25) with a WWTR1-CAMTA1 fusion gene or, in in tumors lacking the typical translocation, a YAP1-TFE3 fusion gene [755]. Detection of the translocation allows the tumors to be distinguished from other hemangioendotheliomas such as the pseudomyogenic or retiform subtype with more favorable biology. The definitive diagnosis should be made only after reference pathology has been performed. Regarding older literature reports, it must be kept in mind that patients were often included without a confirmed diagnosis. Liver transplantation outcomes have been linked to the diagnostic criterion of detection of factor VIII-associated antigen [756] and traced back to the early 1980s [751]. Histopathologically, high-risk tumors for aggressive behavior are those with primary tumor size of >3cm and >3 mitoses/10mm2 [757].
According to recently published data from MSKCC, two groups of EHE can be delineated [753]. One is patients with single lesions of the soft tissues or multifocally in the lung, who may have a relatively indolent course, and in whom R0 resection may be cu-rative. Indolent courses also occur in patients with EHE of the liver, so that therapeutic waiting is more warranted in the recurrence situation. In a series of 10 patients, six patients with diffuse involvement and slow growth could be treated without surgical intervention with a 5-year survival rate of 67 % [758] (see also Section Chapter 10.10). On the other hand, patients with pleural involvement or lymph node metastases often have a very aggressive course. For EHE of soft tissues, metastasis can be expected in about 20 % of patients [757].
The options for locoregional treatment are highly dependent on localization and multifocality. In general, unifocal, resectable EHE should be resected after an observation period indicating disease progression, R0 if necessary. For EHE of bone and soft tissue, the principles of sarcoma surgery apply. Unifocal tumors of the liver can be resected by segmental liver resection and treated with e.g. radiofrequency or microwaveablation for multiple lesions - also as a bridge to rarely indicated liver transplantation. The results of liver transplantation report 5-year survival rates of more than 50% [759], [760]. In the European Transplant Registry, 10-year survival in 149 patients is 74.4 % with the above limitations.
EHE are considered radiosensitive, so that after R1 resection additional radiotherapy (60 Gy) is recommended. If surgical therapy is feasible only with unacceptable morbidity or loss of function, ablative procedures, such as definitive radiotherapy (60 Gy), may be considered [761]. For palliative purposes, doses of 40 Gy [762] may also be used. According to a literature compilation of published individual cases, this also applies to skeletal EHE [763].
In the metastatic setting, anthracycline-based chemotherapies are ineffective. A prospective phase II study with sorafenib reported a response rate of 13 % with a median PFS of 6 months and a 2-year survival rate of 24 % [764]. Recently published results from 38 patients with a molecularly confirmed diagnosis of EHE and progressive disease who received therapy with sirolimus show disease stabilization in 86% with a median PFS of 13 months and median survival of 18.8 months [765].
There are very well established and networked patient support groups in the UK(www.ehercc.org.uk) and the USA(www.fightehe.org). A consensus recommendation on therapy for EHE, agreed with patient representatives, has been published in June 2021 [766].
10.10 Sarcomas of the liver
Due to the relatively low proportion of mesenchymal cells, the liver is rarely a localization for primary sarcomas, but much more frequently a metastatic site of GIST or abdominal leiomyosarcomas. However, the liver offers specific treatment options for some tumors (local ablative procedures, transplantation) that deserve special consideration in the treatment concept of sarcoma therapy. The incidence of autochthonous sarcomas of the liver in adults is low, with 30 patients reported in a 25-year period at MSKCC [758]. The authors conclude that histologic subtype is the primary factor influencing treatment outcome.
The principles of sarcoma therapy also apply to mesenchymal malignancies that are obviously not metastases of other primary tumors, i.e., biopsy verification first. Given the many subtypes and rarity of sarcomas, it is important to delineate tumors for which there is established therapy (see Table 12) as:
- Kaposi sarcoma (most common tumor of the liver in HIV patients),
- extraskeletal Ewing sarcoma (primary systemic therapy analogous to Ewing protocol),
- Rhabdomyosarcoma (primary systemic therapy analogous to RMS protocol),
- Epstein-Barr virus associated follicular dendritic sarcoma (FDCS, extremely rare entity between sarcoma and lymphoma which may respond to CHOP chemotherapy [767], if the disease is not resectable [768]).
A primary surgical approach is indicated especially for low grade (G1) leiomyosarcomas, which may arise from the retrohepatic vena cava, for example. G3 leiomyosarcomas should rather be treated by preoperative systemic chemotherapy (e.g. doxorubicin + dacarbazine (see also Chapter 7.1). Solitary fibrous tumors of the liver that are already very large at diagnosis are also an indication for primary surgical therapy, as neoadjuvant treatment is unlikely to result in tumor shrinkage [769].
Angiosarcomas represent a special subgroup, which frequently occur in the liver secondary to radiation and are always highly malignant (G3). Causes historically were the alpha emitter thorium dioxide which was used as an X-ray contrast agent (thorotrast) until about 1950 [770], [771]. Currently, whole-body radiotherapy as a myelo-ablative procedure prior to allogeneic stem celltransplantation is considered causative [772]. Angiosarcomas are almost always multifocal, accordingly the results after resection alone are rather disappointing (4/9 patients still alive after 15.5 months [773]. In angiosarcomas, rupture risk is described because of the high vascularization [713], however, transarterial chemoembolization resulted in a median survival of only 19 days in 3 patients.
In the pediatric setting, hepatoblastomas, undifferentiated embryonal sarcomas (UESL), and embryonal rhabdomyosarcoma of the bile ducts are delineated malignancies [774]. Unfortunately, these are often grouped together with adult sarcomas in reviews, leading to misinterpretations regarding tumor rupture risk, lymphatic metastasis, jaundice, or Kasabach-Merritt syndrome. However, UESL also occurs in adulthood [775]. After R0 resection and adjuvant chemotherapy, median survival was 29 months.
10.11 Sarcomas of the spermatic cord/groin
The groin represents a special localization for sarcomas. In women, the ligamentum teres (or rotundum) uteri, which is inserted here, is the connection to the angle of the tube and can, in extremely rare cases, serve as the origin of a leiomyosarcoma [776].
Much more often in men, under the suspected diagnosis of inguinal hernia [777] or hydrocele testis, a soft tissue tumor of the scrotum or spermatic cord is resected, which usually corresponds to a lipoma, in 20-30% of cases histologically is a malignancy. The tumors may arise from the tunica vaginalis testis, the spermatic cord, or the epididymis, are also grouped together as paratesticular sarcomas [778] (C63.0-C63.8), and are reported to have an incidence of 0.3/1 million population [779]. Clinically, there is usually a unilateral, slowly enlarging mass in the inguinal canal or scrotum.
In an analysis of 4741 orchiectomy specimens, 31 rhabdomyosarcomas were found in younger patients (median age 18 years) [780], this patient groupoe also develops lymph node metastases and should be treated similarly to pediatric rhabdomyosarcoma protocols.
In the 6th and 7th decades of life, G1 liposarcomas are predominant histologically, but dedifferentiated liposarcomas [781], leiomyosarcomas, and pleomorphic (G3) sarcomas are also present [782]. Highly malignant (G3) tumors are reported in up to 50 % of cases [783], [784]. Lymph node metastases in this group are very rare.
In most cases, the tumors are not diagnosed as sarcoma preoperatively and hence resections are unlikely to be R0. Accordingly, the local recurrence rate is high [785]. When technically feasible, there is an indication for radical R0 resection [786]. In an analysis of 72 patients treated between 1981 and 2011 (67 % liposarcomas, 19 % leiomyosarcomas, 61 % high-grade tumors), 48 patients could be R0 re-resected by high orchiectomy with placement of the spermatic cord at the inguinal junction and had a good chance of recurrence-free survival. It did not matter whether the resection was performed within 5 months of the initial surgery or later [786]. Data from two European centers (Milan and Birmingham) with 82 patients followed up also confirm the importance of R0 resection for liposarcomas while for subgroups such as leiomyosarcoma and rhabdomyosarcoma distant metastasis has a greater impact on survival [784].
Liposarcomas are characterized by a slowly enlarging, painless tumor with suspected inguinal hernia. In two papers with a total of 42 and 25 patients, respectively [781], [787] with dedifferentiated liposarcomas, about half of whom underwent additional radiotherapy, multivariate analysis found no prognostic factors for local recurrence. In R1 resection, high recurrence rates have been reported despite additive radiation [783], [784]. The role of radiotherapy is inconsistently assessed in the literature [788]. Because of the high likelihood of local recurrence, adjuvant radiotherapy with a typical dose of 60-65 Gy should be given after R0 resection, usually resulting in a low local recurrence rate [788], [789]. In case of R1 resection and unclear localization of incomplete resection, especially in liposarcomas, it may be possible to wait for the development of local recurrence and then perform neoadjuvant irradiation.
For tumors infiltrating beyond the spermatic cord into the surrounding area, a co-resection of the abdominal wall, re-resection of the spermatic cord up to the inner inguinal ring and reconstruction may be necessary. If infiltration of the scrotum occurs, hemiscrotectomy may be necessary. Simple resection is not sufficient [783], [785], as residual tumor is found in 27%-33% of cases.
For patients with leiomyosarcomas of the spermatic cord, a European multicenter study of 23 patients showed that testis-preserving procedures were possible without recurrence in tumor sizes of median 12 mm. In all patients, however, a tumor was suspected preoperatively and clarified by ultrasound and CT. In the orchiectomized patients, whose tumors had a median size of 3 cm, recurrences occurred in 50% of the cases [790].
Prognostically, a 5-year disease-specific survival rate of 92% was found in the analysis of 82 patients treated from 1992-2013, with a local recurrence rate of 26% and a distant metastasis rate of 24%. Patients with sarcomas of the spermatic cord should be followed up long-term, as late recurrences can occur in up to 42% at 15-year follow-up [782], [788].
Evidence tables
Ripretinib - INVICTUS Studie
| A Phase 3, INterVentional, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of DCC-2618 In Patients With AdvanCed Gastrointestinal Stromal TUmorS Who Have Received Treatment With Prior Anticancer Therapies(NCT03353753) | |||||||
| Short Name | Design | Population | Intervention | Comparator | Outcomes | ||
|---|---|---|---|---|---|---|---|
| INVICTUS DCC-2618-03-001 |
Randomized, Parallel Assignment, Phase 3 quadruple-blind study | Pretreated with ECOG 0-2 Gastrointestinal Stromal Tumors for 3rd Line, >3rd Line or Palliative treatment | 1. Ripretinib (N=85)1 | 1. Placebo (N=44) |
|
||
| Levels of Evidence | |||||||
| GRADE | ⊕⊕⊕⊕ | We are very confident that the true effect lies close to that of the estimate of the effect. | |||||
| 1: 150 mg QD Ripretinib | |||||||
| Outcome | Ripretinib N=85 | Placebo N=44 | Effect Estimate | GRADE | |||
| Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.: Blay, JY 2020. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.. ; 21 (7); 923-934* | |||||||
| Dichotomous Outcomes | |||||||
| OS - Time To Event | N=85 | 15.1 [12.3; 15.1] | N=44 | 6.6 [4.1; 11.6] | HR 0.36 [0.21; 0.62] | ⊕⊕⊖⊖a,b | |
| PFS - Time To Event1,2,3 | N=85 | 4.7 [4.2; 8.2] | N=44 | 1.0 [0.9; 1.4] | HR 0.19 [0.12; 0.32] | ⊕⊕⊕⊖a | |
| Age | |||||||
| ≥75 | N=8 | N=10 | HR 0.03 [0; 0.56] | ||||
| 18-64 | N=57 | N=22 | HR 0.25 [0.14; 0.45] | ||||
| 65-74 | N=20 | N=12 | HR 0.18 [0.06; 0.56] | ||||
| ECOG | |||||||
| 0 | N=38 | N=19 | HR 0.33 [0.16; 0.68] | ||||
| 1 or 2 | N=47 | N=25 | HR 0.1 [0.05; 0.21] | ||||
| Gender | |||||||
| Female | N=38 | N=18 | HR 0.19 [0.09; 0.38] | ||||
| Male | N=47 | N=26 | HR 0.18 [0.1; 0.35] | ||||
| Number of prior therapies | |||||||
| ≥4 | N=31 | N=17 | HR 0.24 [0.12; 0.51] | ||||
| 3 | N=54 | N=27 | HR 0.15 [0.08; 0.29] | ||||
| Race | |||||||
| Non-white | N=13 | N=7 | HR 0.46 [0.15; 1.42] | ||||
| Not reported | N=8 | N=4 | HR 0.11 [0.01; 0.97] | ||||
| White | N=64 | N=33 | HR 0.14 [0.07; 0.25] | ||||
| Region | |||||||
| Non-US | N=45 | N=24 | HR 0.23 [0.12; 0.43] | ||||
| US | N=40 | N=20 | HR 0.15 [0.07; 0.31] | ||||
| PFS - Time To Event4 | N=85 | 6.3 [4.6; 6.9] | N=44 | 1.0 [0.9; 1.7] | HR 0.15 [0.09; 0.25]; p<0.0001 | ⊕⊕⊕⊕ | |
| ORR - TuDD | N=85 | 8 (9.41%) | N=44 | 0 (0%) | RR 9.76 [0.55; 173.186]; p=0.1205 | ⊕⊖⊖⊖a | |
| TAE-D (Any) | N=85 | 1 (1.18%) | N=44 | 1 (2.27%) | RR 0.52 [0.033; 8.08]; p=0.6386 | ⊕⊖⊖⊖a | |
| TAE-Disc (Any) | N=85 | 4 (4.71%) | N=44 | 1 (2.27%) | RR 2.07 [0.239; 17.971]; p=0.5091 | ⊕⊕⊕⊖a | |
| TSAE (Any) | N=85 | 8 (9.41%) | N=44 | 3 (6.82%) | RR 1.38 [0.385; 4.945]; p=0.6205 | ⊕⊕⊖⊖a | |
| *Database cutoff: 29.05.2019 | |||||||
| 1: advanced GIST patients; 2: as per investigator assessment; 3: subgroup analyses listed in appendix; 4: assessed by BICR | |||||||
| a: hoher Anteil nicht in die Auswertung eingegangener Patienten (> 10 %); b: Post-hoc Analysis | |||||||
| Any: Any Grade; ORR: Objective Response Rate; OS: Overall Survival; PFS: Progression-Free Survival; TAE-D: Treatment-related Adverse Events Leading to Death; TAE-Disc: Treatment-related Adverse Events Leading to Treatment Discontinuation; TSAE: Treatment-related Serious Adverse Events; TuDD: Time to Definitive Deterioration | |||||||
| Outcome | Ripretinib N=85 | Placebo N=44 | Effect Estimate | GRADE | |||
| Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.: Blay, JY 2020. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.. ; 21 (7); 923-934* | |||||||
| Continuous Outcomes | |||||||
| EQ-5D (VAS) | N=70 | 3.7 [-1.1; 8.6] | N=32 | -8.9 [-15.9; -1.9] | ⊕⊕⊖⊖a,b | ||
| EORTC QLQ-C30 | N=71 | 1,6 [-2.5; 5.7] | N=32 | -8.9 [-14.8; -3] | MD 10.5 [3.4; 17.6] | ⊕⊖⊖⊖a,b | |
| EORTC QLQ-C30 - Time To Change | N=70 | 3.5 [-3.4; 10.5] | N=42 | -17.1 [-27; -7.1] | MD 20.6 [8.6; 32.6] | ⊕⊕⊖⊖a,b | |
| *Database cutoff: 29.05.2019 | |||||||
| a: hoher Anteil nicht in die Auswertung eingegangener Patienten (> 10 %); b: Outcome reporting bias - failing to report MCID | |||||||
| EORTC QLQ-C30: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30; EQ-5D: European Quality of Life 5 Dimensions; MCID: Minimal Clinically Important Difference; VAS: Visual Analogue Scale | |||||||
References
[627] Casali, P. G., Abecassis, N., Aro, H. T., Bauer, S., Biagini, R., Bielack, S., et.al. Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann Oncol, 2018. 29(Suppl 4): p. iv68-iv78., https://www.ncbi.nlm.nih.gov/pubmed/29846513
[628] Dumont, A. G., Rink, L., Godwin, A. K., Miettinen, M., Joensuu, H., Strosberg, J. R., et.al. A nonrandom association of gastrointestinal stromal tumor (GIST) and desmoid tumor (deep fibromatosis): case series of 28 patients, Ann Oncol, 2012. 23(5): p. 1335-1340., https://www.ncbi.nlm.nih.gov/pubmed/21994214
[629] Eriksson, M., Reichardt, P., Sundby Hall, K., Schutte, J., Cameron, S., Hohenberger, P., et.al. Needle biopsy through the abdominal wall for the diagnosis of gastrointestinal stromal tumour - Does it increase the risk for tumour cell seeding and recurrence?, Eur J Cancer, 2016. 59: p. 128-133., https://www.ncbi.nlm.nih.gov/pubmed/27033260
[630] Landi, B., Blay, J. Y., Bonvalot, S., Brasseur, M., Coindre, J. M., Emile, J. F., et.al. Gastrointestinal stromal tumours (GISTs): French Intergroup Clinical Practice Guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO), Dig Liver Dis, 2019. 51(9): p. 1223-1231., https://www.ncbi.nlm.nih.gov/pubmed/31387778
[631] Stroobants, S., Goeminne, J., Seegers, M., Dimitrijevic, S., Dupont, P., Nuyts, J., et.al. 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec), Eur J Cancer, 2003. 39(14): p. 2012-20., https://www.ncbi.nlm.nih.gov/pubmed/12957455
[632] Demetri, G. D., Wang, Y., Wehrle, E., Racine, A., Nikolova, Z., Blanke, C. D., et.al. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors, J Clin Oncol, 2009. 27(19): p. 3141-7., https://www.ncbi.nlm.nih.gov/pubmed/19451435
[633] Wang, D., Zhang, Q., Blanke, C. D., Demetri, G. D., Heinrich, M. C., Watson, J. C., et.al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132, Ann Surg Oncol, 2012. 19(4): p. 1074-80., https://www.ncbi.nlm.nih.gov/pubmed/22203182
[634] Hohenberger, P., Eisenberg, B., Role of surgery combined with kinase inhibition in the management of gastrointestinal stromal tumor (GIST), Ann Surg Oncol, 2010. 17(10): p. 2585-600., https://www.ncbi.nlm.nih.gov/pubmed/20407930
[635] Jakob, J., Hohenberger, P., Neoadjuvant Therapy to Downstage the Extent of Resection of Gastrointestinal Stromal Tumors, Visc Med, 2018. 34(5): p. 359-365., https://www.ncbi.nlm.nih.gov/pubmed/30498703
[152] Catena, F., Di Battista, M., Ansaloni, L., Pantaleo, M., Fusaroli, P., Di Scioscio, V., et.al. Microscopic margins of resection influence primary gastrointestinal stromal tumor survival, Onkologie, 2012. 35(11): p. 645-8., https://www.ncbi.nlm.nih.gov/pubmed/23147540
[20] Ma, G. L., Murphy, J. D., Martinez, M. E., Sicklick, J. K., Epidemiology of gastrointestinal stromal tumors in the era of histology codes: results of a population-based study, Cancer Epidemiol Biomarkers Prev, 2015. 24(1): p. 298-302., https://www.ncbi.nlm.nih.gov/pubmed/25277795
[636] Cavnar, M. J., Wang, L., Balachandran, V. P., Antonescu, C. R., Tap, W. D., Keohan, M., et.al. Rectal Gastrointestinal Stromal Tumor (GIST) in the Era of Imatinib: Organ Preservation and Improved Oncologic Outcome, Ann Surg Oncol, 2017. 24(13): p. 3972-3980., https://www.ncbi.nlm.nih.gov/pubmed/29058144
[637] Jakob, J., Mussi, C., Ronellenfitsch, U., Wardelmann, E., Negri, T., Gronchi, A., et.al. Gastrointestinal stromal tumor of the rectum: results of surgical and multimodality therapy in the era of imatinib, Ann Surg Oncol, 2013. 20(2): p. 586-92., https://www.ncbi.nlm.nih.gov/pubmed/22965573
[115] Miettinen, M., Lasota, J., Gastrointestinal stromal tumors: pathology and prognosis at different sites, Semin Diagn Pathol, 2006. 23(2): p. 70-83., https://www.ncbi.nlm.nih.gov/pubmed/17193820
[638] Ronellenfitsch, U., Hohenberger, P., Surgery for Gastrointestinal Stromal Tumors: State of the Art of Laparoscopic Resection and Surgery for M1 Tumors, Visc Med, 2018. 34(5): p. 367-374., https://www.ncbi.nlm.nih.gov/pubmed/30498704
[639] Ronellenfitsch, U., Staiger, W., Kahler, G., Strobel, P., Schwarzbach, M., Hohenberger, P., Perioperative and oncological outcome of laparoscopic resection of gastrointestinal stromal tumour (GIST) of the stomach, Diagn Ther Endosc, 2009. 2009: p. 286138., https://www.ncbi.nlm.nih.gov/pubmed/19343179
[640] Bachet, J. B., Landi, B., Laurent-Puig, P., Italiano, A., Le Cesne, A., Levy, P., et.al. Diagnosis, prognosis and treatment of patients with gastrointestinal stromal tumour (GIST) and germline mutation of KIT exon 13, Eur J Cancer, 2013. 49(11): p. 2531-41., https://www.ncbi.nlm.nih.gov/pubmed/23648119
[116] Joensuu, H., Vehtari, A., Riihimaki, J., Nishida, T., Steigen, S. E., Brabec, P., et.al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts, Lancet Oncol, 2012. 13(3): p. 265-74., https://www.ncbi.nlm.nih.gov/pubmed/22153892
[641] Holmebakk, T., Bjerkehagen, B., Hompland, I., Stoldt, S., Boye, K., Relationship between R1 resection, tumour rupture and recurrence in resected gastrointestinal stromal tumour, Br J Surg, 2019. 106(4): p. 419-426., https://www.ncbi.nlm.nih.gov/pubmed/30507040
[642] Rutkowski, P., Nowecki, Z. I., Michej, W., Debiec-Rychter, M., Wozniak, A., Limon, J., et.al. Risk criteria and prognostic factors for predicting recurrences after resection of primary gastrointestinal stromal tumor, Ann Surg Oncol, 2007. 14(7): p. 2018-27., https://www.ncbi.nlm.nih.gov/pubmed/17473953
[643] Hohenberger, P., Ronellenfitsch, U., Oladeji, O., Pink, D., Strobel, P., Wardelmann, E., et.al. Pattern of recurrence in patients with ruptured primary gastrointestinal stromal tumour, Br J Surg, 2010. 97(12): p. 1854-9., https://www.ncbi.nlm.nih.gov/pubmed/20730857
[644] Dematteo, R. P., Ballman, K. V., Antonescu, C. R., Maki, R. G., Pisters, P. W., Demetri, G. D., et.al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial, Lancet, 2009. 373(9669): p. 1097-104., https://www.ncbi.nlm.nih.gov/pubmed/19303137
[645] Hohenberger, P., Bonvalot, S., van Coevorden, F., Rutkowski, P., Stoeckle, E., Olungu, C., et.al. Quality of surgery and surgical reporting for patients with primary gastrointestinal stromal tumours participating in the EORTC STBSG 62024 adjuvant imatinib study, Eur J Cancer, 2019. 120: p. 47-53., https://www.ncbi.nlm.nih.gov/pubmed/31479947
[646] Joensuu, H., Eriksson, M., Sundby Hall, K., Hartmann, J. T., Pink, D., Schutte, J., et.al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial, JAMA, 2012. 307(12): p. 1265-72., https://www.ncbi.nlm.nih.gov/pubmed/22453568
[647] McCarter, M. D., Antonescu, C. R., Ballman, K. V., Maki, R. G., Pisters, P. W., Demetri, G. D., et.al. Microscopically positive margins for primary gastrointestinal stromal tumors: analysis of risk factors and tumor recurrence, J Am Coll Surg, 2012. 215(1): p. 53-9; discussion 59-60., https://www.ncbi.nlm.nih.gov/pubmed/22726733
[648] Zhi, X., Jiang, B., Yu, J., Roe, O. D., Qin, J., Ni, Q., et.al. Prognostic role of microscopically positive margins for primary gastrointestinal stromal tumors: a systematic review and meta-analysis, Sci Rep, 2016. 6: p. 21541., https://www.ncbi.nlm.nih.gov/pubmed/26891953
[649] Nishida, T., Blay, J. Y., Hirota, S., Kitagawa, Y., Kang, Y. K., The standard diagnosis, treatment, and follow-up of gastrointestinal stromal tumors based on guidelines, Gastric Cancer, 2016. 19(1): p. 3-14., https://www.ncbi.nlm.nih.gov/pubmed/26276366
[650] Fletcher, C.D., Berman, J.J., Corless, C., Gorstein, F., Lasota, J., Longley, B.J., et.al. Diagnosis of gastrointestinal stromal tumors: a consensus approach, Int. J. Surg. Pathol, 2002. 10(2): p. 81-89., http://www.ncbi.nlm.nih.gov/pubmed/12075401
[651] Zhang, L., Smyrk, T. C., Young, W. F., Jr., Stratakis, C. A., Carney, J. A., Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases, Am J Surg Pathol, 2010. 34(1): p. 53-64., https://www.ncbi.nlm.nih.gov/pubmed/19935059
[652] Novelli, M., Rossi, S., Rodriguez-Justo, M., Taniere, P., Seddon, B., Toffolatti, L., et.al. DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours, Histopathology, 2010. 57(2): p. 259-70., https://www.ncbi.nlm.nih.gov/pubmed/20716168
[653] Miettinen, M., Majidi, M., Lasota, J., Pathology and diagnostic criteria of gastrointestinal stromal tumors (GISTs): a review, Eur J Cancer, 2002. 38 Suppl 5: p. S39-51., https://www.ncbi.nlm.nih.gov/pubmed/12528772
[654] Casali, P. G., Abecassis, N., Aro, H. T., Bauer, S., Biagini, R., Bielack, S., et.al. Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann Oncol, 2018. 29(Suppl 4): p. iv68-iv78., https://www.ncbi.nlm.nih.gov/pubmed/29846513
[655] Gastrointestinal Stromal Tumor Meta-Analysis, Group, Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients, J Clin Oncol, 2010. 28(7): p. 1247-53., https://www.ncbi.nlm.nih.gov/pubmed/20124181
[656] Cassier, P. A., Fumagalli, E., Rutkowski, P., Schoffski, P., Van Glabbeke, M., Debiec-Rychter, M., et.al. Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era, Clin Cancer Res, 2012. 18(16): p. 4458-64., https://www.ncbi.nlm.nih.gov/pubmed/22718859
[657] Heinrich, M. C., Corless, C. L., Demetri, G. D., Blanke, C. D., von Mehren, M., Joensuu, H., et.al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor, J Clin Oncol, 2003. 21(23): p. 4342-9., https://www.ncbi.nlm.nih.gov/pubmed/14645423
[658] Debiec-Rychter, M., Sciot, R., Le Cesne, A., Schlemmer, M., Hohenberger, P., van Oosterom, A. T., et.al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours, Eur J Cancer, 2006. 42(8): p. 1093-103., https://www.ncbi.nlm.nih.gov/pubmed/16624552
[659] Muhlenberg, T., Ketzer, J., Heinrich, M. C., Grunewald, S., Marino-Enriquez, A., Trautmann, M., et.al. KIT-Dependent and KIT-Independent Genomic Heterogeneity of Resistance in Gastrointestinal Stromal Tumors - TORC1/2 Inhibition as Salvage Strategy, Mol Cancer Ther, 2019. 18(11): p. 1985-1996., https://www.ncbi.nlm.nih.gov/pubmed/31308077
[660] Nannini, M., Urbini, M., Astolfi, A., Biasco, G., Pantaleo, M. A., The progressive fragmentation of the KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GIST), J Transl Med, 2017. 15(1): p. 113., https://www.ncbi.nlm.nih.gov/pubmed/28535771
[661] Rednam, S. P., Erez, A., Druker, H., Janeway, K. A., Kamihara, J., Kohlmann, W. K., et.al. Von Hippel-Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood, Clin Cancer Res, 2017. 23(12): p. e68-e75., https://www.ncbi.nlm.nih.gov/pubmed/28620007
[662] Miettinen, M., Lasota, J., Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis, Arch Pathol Lab Med, 2006. 130(10): p. 1466-78., https://www.ncbi.nlm.nih.gov/pubmed/17090188
[663] Joensuu, H., Wardelmann, E., Sihto, H., Eriksson, M., Sundby Hall, K., Reichardt, A., et.al. Effect of KIT and PDGFRA Mutations on Survival in Patients With Gastrointestinal Stromal Tumors Treated With Adjuvant Imatinib: An Exploratory Analysis of a Randomized Clinical Trial, JAMA Oncol, 2017. 3(5): p. 602-609., https://www.ncbi.nlm.nih.gov/pubmed/28334365
[664] Wozniak, A., Rutkowski, P., Schoffski, P., Ray-Coquard, I., Hostein, I., Schildhaus, H. U., et.al. Tumor genotype is an independent prognostic factor in primary gastrointestinal stromal tumors of gastric origin: a european multicenter analysis based on ConticaGIST, Clin Cancer Res, 2014. 20(23): p. 6105-16., https://www.ncbi.nlm.nih.gov/pubmed/25294914
[665] Martin-Broto, J., Gutierrez, A., Garcia-Del-Muro, X., Lopez-Guerrero, J. A., Martinez-Trufero, J., de Sande, L. M., et.al. Prognostic time dependence of deletions affecting codons 557 and/or 558 of KIT gene for relapse-free survival (RFS) in localized GIST: a Spanish Group for Sarcoma Research (GEIS) Study, Ann Oncol, 2010. 21(7): p. 1552-1557., https://www.ncbi.nlm.nih.gov/pubmed/20231303
[666] Joensuu, H., Eriksson, M., Sundby Hall, K., Reichardt, A., Hartmann, J. T., Pink, D., et.al. Adjuvant Imatinib for High-Risk GI Stromal Tumor: Analysis of a Randomized Trial, J Clin Oncol, 2016. 34(3): p. 244-50., https://www.ncbi.nlm.nih.gov/pubmed/26527782
[667] Casali, P. G., Le Cesne, A., Poveda Velasco, A., Kotasek, D., Rutkowski, P., Hohenberger, P., et.al. Time to Definitive Failure to the First Tyrosine Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas, J Clin Oncol, 2015. 33(36): p. 4276-83., https://www.ncbi.nlm.nih.gov/pubmed/26573069
[668] Cohen, M. H., Cortazar, P., Justice, R., Pazdur, R., Approval summary: imatinib mesylate in the adjuvant treatment of malignant gastrointestinal stromal tumors, Oncologist, 2010. 15(3): p. 300-7., https://www.ncbi.nlm.nih.gov/pubmed/20200041
[669] Corless, C. L., Ballman, K. V., Antonescu, C. R., Kolesnikova, V., Maki, R. G., Pisters, P. W., et.al. Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial, J Clin Oncol, 2014. 32(15): p. 1563-70., https://www.ncbi.nlm.nih.gov/pubmed/24638003
[670] Joensuu, H., Eriksson, M., Sundby Hall, K., Reichardt, A., Hermes, B., Schutte, J., et.al. Survival Outcomes Associated With 3 Years vs 1 Year of Adjuvant Imatinib for Patients With High-Risk Gastrointestinal Stromal Tumors: An Analysis of a Randomized Clinical Trial After 10-Year Follow-up, JAMA Oncol, 2020. 6(8): p. 1241-1246., https://www.ncbi.nlm.nih.gov/pubmed/32469385
[671] Blay, J. Y., Shen, L., Kang, Y. K., Rutkowski, P., Qin, S., Nosov, D., et.al. Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial, Lancet Oncol, 2015. 16(5): p. 550-60., https://www.ncbi.nlm.nih.gov/pubmed/25882987
[672] Muler, J. H., Baker, L., Zalupski, M. M., Gastrointestinal stromal tumors: chemotherapy and imatinib, Curr Oncol Rep, 2002. 4(6): p. 499-503., https://www.ncbi.nlm.nih.gov/pubmed/12354362
[673] DeMatteo, R. P., Lewis, J. J., Leung, D., Mudan, S. S., Woodruff, J. M., Brennan, M. F., Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival, Ann Surg, 2000. 231(1): p. 51-8., https://www.ncbi.nlm.nih.gov/pubmed/10636102
[674] Verweij, J., Casali, P. G., Zalcberg, J., LeCesne, A., Reichardt, P., Blay, J. Y., et.al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial, Lancet, 2004. 364(9440): p. 1127-34., https://www.ncbi.nlm.nih.gov/pubmed/15451219
[675] Blanke, C.D., Rankin, C., Demetri, G.D., Ryan, C.W., Von Mehren, M., Benjamin, R.S., et.al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033, J. Clin. Oncol, 2008. 26(4): p. 626-632., http://www.ncbi.nlm.nih.gov/pubmed/18235122
[676] Heinrich, M. C., Corless, C. L., Duensing, A., McGreevey, L., Chen, C. J., Joseph, N., et.al. PDGFRA activating mutations in gastrointestinal stromal tumors, Science, 2003. 299(5607): p. 708-10., https://www.ncbi.nlm.nih.gov/pubmed/12522257
[677] Heinrich, M. C., Jones, R. L., von Mehren, M., Schoffski, P., Serrano, C., Kang, Y. K., et.al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial, Lancet Oncol, 2020. 21(7): p. 935-946., https://www.ncbi.nlm.nih.gov/pubmed/32615108
[678] European Medicines Agency (EMA), Ayvakyt (avapritinib): An overview of Ayvakyt and why it is authorised in the EU, 2020., https://www.ema.europa.eu/en/documents/overview/ayvakyt-epar-medicine-overview_en.pdf, [abgerufen, am, 01.10.2020]
[65] Boikos, S. A., Pappo, A. S., Killian, J. K., LaQuaglia, M. P., Weldon, C. B., George, S., et.al. Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic, JAMA Oncol, 2016. 2(7): p. 922-8., https://www.ncbi.nlm.nih.gov/pubmed/27011036
[679] Janeway, K. A., Liegl, B., Harlow, A., Le, C., Perez-Atayde, A., Kozakewich, H., et.al. Pediatric KIT wild-type and platelet-derived growth factor receptor alpha-wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors, Cancer Res, 2007. 67(19): p. 9084-8., https://www.ncbi.nlm.nih.gov/pubmed/17909012
[680] Robert, C., Karaszewska, B., Schachter, J., Rutkowski, P., Mackiewicz, A., Stroiakovski, D., et.al. Improved overall survival in melanoma with combined dabrafenib and trametinib, N Engl J Med, 2015. 372(1): p. 30-9., https://www.ncbi.nlm.nih.gov/pubmed/25399551
[681] Falchook, G. S., Trent, J. C., Heinrich, M. C., Beadling, C., Patterson, J., Bastida, C. C., et.al. BRAF mutant gastrointestinal stromal tumor: first report of regression with BRAF inhibitor dabrafenib (GSK2118436) and whole exomic sequencing for analysis of acquired resistance, Oncotarget, 2013. 4(2): p. 310-5., https://www.ncbi.nlm.nih.gov/pubmed/23470635
[682] Cocco, E., Scaltriti, M., Drilon, A., NTRK fusion-positive cancers and TRK inhibitor therapy, Nat Rev Clin Oncol, 2018. 15(12): p. 731-747., https://www.ncbi.nlm.nih.gov/pubmed/30333516
[683] Antoch, G., Kanja, J., Bauer, S., Kuehl, H., Renzing-Koehler, K., Schuette, J., et.al. Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors, J Nucl Med, 2004. 45(3): p. 357-65., https://www.ncbi.nlm.nih.gov/pubmed/15001674
[684] Antoch, G., Kanja, J., Bauer, S., Kuehl, H., Renzing-Koehler, K., Schuette, J., et.al. Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors, J Nucl Med, 2004. 45(3): p. 357-65., https://www.ncbi.nlm.nih.gov/pubmed/15001674
[685] Le Cesne, A., Ray-Coquard, I., Bui, B. N., Adenis, A., Rios, M., Bertucci, F., et.al. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial, Lancet Oncol, 2010. 11(10): p. 942-9., https://www.ncbi.nlm.nih.gov/pubmed/20864406
[686] Patrikidou, A., Chabaud, S., Ray-Coquard, I., Bui, B. N., Adenis, A., Rios, M., et.al. Influence of imatinib interruption and rechallenge on the residual disease in patients with advanced GIST: results of the BFR14 prospective French Sarcoma Group randomised, phase III trial, Ann Oncol, 2013. 24(4): p. 1087-93., https://www.ncbi.nlm.nih.gov/pubmed/23175622
[687] Bauer, S., Rutkowski, P., Hohenberger, P., Miceli, R., Fumagalli, E., Siedlecki, J. A., et.al. Long-term follow-up of patients with GIST undergoing metastasectomy in the era of imatinib -- analysis of prognostic factors (EORTC-STBSG collaborative study), Eur J Surg Oncol, 2014. 40(4): p. 412-9., https://www.ncbi.nlm.nih.gov/pubmed/24491288
[688] Mussi, C., Ronellenfitsch, U., Jakob, J., Tamborini, E., Reichardt, P., Casali, P. G., et.al. Post-imatinib surgery in advanced/metastatic GIST: is it worthwhile in all patients?, Ann Oncol, 2010. 21(2): p. 403-408., https://www.ncbi.nlm.nih.gov/pubmed/19628568
[689] Raut, C. P., Posner, M., Desai, J., Morgan, J. A., George, S., Zahrieh, D., et.al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors, J Clin Oncol, 2006. 24(15): p. 2325-31., https://www.ncbi.nlm.nih.gov/pubmed/16710031
[690] Sato, S., Tsujinaka, T., Masuzawa, T., Yamamoto, K., Takahashi, T., Yamashita, Y., et.al. Role of metastasectomy for recurrent/metastatic gastrointestinal stromal tumors based on an analysis of the Kinki GIST registry, Surg Today, 2017. 47(1): p. 58-64., https://www.ncbi.nlm.nih.gov/pubmed/27194124
[691] Ford, S. J., Gronchi, A., Indications for surgery in advanced/metastatic GIST, Eur J Cancer, 2016. 63: p. 154-67., https://www.ncbi.nlm.nih.gov/pubmed/27318456
[692] Van Glabbeke, M., Verweij, J., Casali, P. G., Le Cesne, A., Hohenberger, P., Ray-Coquard, I., et.al. Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study, J Clin Oncol, 2005. 23(24): p. 5795-804., https://www.ncbi.nlm.nih.gov/pubmed/16110036
[693] Keung, E. Z., Fairweather, M., Raut, C. P., The Role of Surgery in Metastatic Gastrointestinal Stromal Tumors, Curr Treat Options Oncol, 2016. 17(2): p. 8., https://www.ncbi.nlm.nih.gov/pubmed/26820287
[694] Du, C. Y., Zhou, Y., Song, C., Wang, Y. P., Jie, Z. G., He, Y. L., et.al. Is there a role of surgery in patients with recurrent or metastatic gastrointestinal stromal tumours responding to imatinib: a prospective randomised trial in China, Eur J Cancer, 2014. 50(10): p. 1772-1778., https://www.ncbi.nlm.nih.gov/pubmed/24768330
[695] von Mehren, M., Joensuu, H., Gastrointestinal Stromal Tumors, J Clin Oncol, 2018. 36(2): p. 136-143., https://www.ncbi.nlm.nih.gov/pubmed/29220298
[696] Demetri, G. D., van Oosterom, A. T., Garrett, C. R., Blackstein, M. E., Shah, M. H., Verweij, J., et.al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial, Lancet, 2006. 368(9544): p. 1329-38., https://www.ncbi.nlm.nih.gov/pubmed/17046465
[697] Demetri, G. D., Garrett, C. R., Schoffski, P., Shah, M. H., Verweij, J., Leyvraz, S., et.al. Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure, Clin Cancer Res, 2012. 18(11): p. 3170-9., https://www.ncbi.nlm.nih.gov/pubmed/22661587
[698] George, S., Blay, J. Y., Casali, P. G., Le Cesne, A., Stephenson, P., Deprimo, S. E., et.al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure, Eur J Cancer, 2009. 45(11): p. 1959-68., https://www.ncbi.nlm.nih.gov/pubmed/19282169
[699] Heinrich, M. C., Corless, C. L., Liegl, B., Fletcher, C. D., Raut, C. P., Donsky, R., et.al. Mechanisms of sunitinib malate (SU) resistance in gastrointestinal stromal tumors (GISTs), Journal of Clinical Oncology, 2007. 25(18_suppl): p. 10006-10006., https://ascopubs.org/doi/abs/10.1200/jco.2007.25.18_suppl.10006
[700] Gramza, A. W., Corless, C. L., Heinrich, M. C., Resistance to Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors, Clin Cancer Res, 2009. 15(24): p. 7510-7518., https://www.ncbi.nlm.nih.gov/pubmed/20008851
[701] Corless, C. L., Barnett, C. M., Heinrich, M. C., Gastrointestinal stromal tumours: origin and molecular oncology, Nat Rev Cancer, 2011. 11(12): p. 865-78., https://www.ncbi.nlm.nih.gov/pubmed/22089421
[702] Demetri, G. D., Reichardt, P., Kang, Y. K., Blay, J. Y., Rutkowski, P., Gelderblom, H., 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): p. 295-302., https://www.ncbi.nlm.nih.gov/pubmed/23177515
[703] Poole, C. D., Connolly, M. P., Chang, J., Currie, C. J., Health utility of patients with advanced gastrointestinal stromal tumors (GIST) after failure of imatinib and sunitinib: findings from GRID, a randomized, double-blind, placebo-controlled phase III study of regorafenib versus placebo, Gastric Cancer, 2015. 18(3): p. 627-34., https://www.ncbi.nlm.nih.gov/pubmed/24957256
[704] Blay, JY, Serrano, C, Heinrich, MC, Zalcberg, J, Bauer, S, Gelderblom, H, et.al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial., Lancet Oncol, 2020. 21 (7)(7): p. 923-934., https://pubmed.ncbi.nlm.nih.gov/32511981/
[705] Bauer, S, Heinrich, MC, George, S, Zalcberg, JR, Serrano, C, Gelderblom, H, et.al. Clinical Activity of Ripretinib in Patients with Advanced Gastrointestinal Stromal Tumor Harboring Heterogeneous , Clin Cancer Res, 2021. 27 (23)(23): p. 6333-6342., https://pubmed.ncbi.nlm.nih.gov/34503977/
[706] Bauer, S., Rutkowski, P., Hohenberger, P., Miceli, R., Fumagalli, E., Siedlecki, J. A., et.al. Long-term follow-up of patients with GIST undergoing metastasectomy in the era of imatinib -- analysis of prognostic factors (EORTC-STBSG collaborative study), Eur J Surg Oncol, 2014. 40(4): p. 412-9., https://www.ncbi.nlm.nih.gov/pubmed/24491288
[707] Shankar, S., vanSonnenberg, E., Desai, J., Dipiro, P. J., Van Den Abbeele, A., Demetri, G. D., Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate, Radiology, 2005. 235(3): p. 892-8., https://www.ncbi.nlm.nih.gov/pubmed/15833985
[536] Rathmann, N., Diehl, S. J., Dinter, D., Schutte, J., Pink, D., Schoenberg, S. O., et.al. Radioembolization in patients with progressive gastrointestinal stromal tumor liver metastases undergoing treatment with tyrosine kinase inhibitors, J Vasc Interv Radiol, 2015. 26(2): p. 231-8., https://www.ncbi.nlm.nih.gov/pubmed/25434477
[708] Yamanaka, T., Takaki, H., Nakatsuka, A., Uraki, J., Fujimori, M., Hasegawa, T., et.al. Radiofrequency ablation for liver metastasis from gastrointestinal stromal tumor, J Vasc Interv Radiol, 2013. 24(3): p. 341-6., https://www.ncbi.nlm.nih.gov/pubmed/23352855
[709] Hakime, A., Le Cesne, A., Deschamps, F., Farouil, G., Boudabous, S., Auperin, A., et.al. A role for adjuvant RFA in managing hepatic metastases from gastrointestinal stromal tumors (GIST) after treatment with targeted systemic therapy using kinase inhibitors, Cardiovasc Intervent Radiol, 2014. 37(1): p. 132-9., https://www.ncbi.nlm.nih.gov/pubmed/23589213
[710] Jung, J. H., Won, H. J., Shin, Y. M., Kim, P. N., Safety and Efficacy of Radiofrequency Ablation for Hepatic Metastases from Gastrointestinal Stromal Tumor, J Vasc Interv Radiol, 2015. 26(12): p. 1797-1802., https://www.ncbi.nlm.nih.gov/pubmed/26603498
[711] Ronellenfitsch, U., Henzler, T., Menge, F., Dimitrakopoulou-Strauss, A., Hohenberger, P., [Advanced gastrointestinal stromal tumors : What role does surgery currently play in multimodal concepts?], Chirurg, 2016. 87(5): p. 389-97., https://www.ncbi.nlm.nih.gov/pubmed/27080051
[712] Yoon, I. S., Shin, J. H., Han, K., Kim, P. N., Kim, K. H., Kang, Y. K., et.al. Ultrasound-Guided Intraoperative Radiofrequency Ablation and Surgical Resection for Liver Metastasis from Malignant Gastrointestinal Stromal Tumors, Korean J Radiol, 2018. 19(1): p. 54-62., https://www.ncbi.nlm.nih.gov/pubmed/29354000
[713] Pierce, D. B., Johnson, G. E., Monroe, E., Loggers, E. T., Jones, R. L., Pollack, S. M., et.al. Safety and Efficacy Outcomes of Embolization in Hepatic Sarcomas, AJR Am J Roentgenol, 2018. 210(1): p. 175-182., https://www.ncbi.nlm.nih.gov/pubmed/29090997
[714] Kang, Y. K., Ryu, M. H., Yoo, C., Ryoo, B. Y., Kim, H. J., Lee, J. J., et.al. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial, Lancet Oncol, 2013. 14(12): p. 1175-82., https://www.ncbi.nlm.nih.gov/pubmed/24140183
[715] Yoo, C., Ryu, M. H., Nam, B. H., Ryoo, B. Y., Demetri, G. D., Kang, Y. K., Impact of imatinib rechallenge on health-related quality of life in patients with TKI-refractory gastrointestinal stromal tumours: Sub-analysis of the placebo-controlled, randomised phase III trial (RIGHT), Eur J Cancer, 2016. 52: p. 201-8., https://www.ncbi.nlm.nih.gov/pubmed/26699729
[716] Desai, J., Shankar, S., Heinrich, M. C., Fletcher, J. A., Fletcher, C. D., Manola, J., et.al. Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors, Clin Cancer Res, 2007. 13(18 Pt 1): p. 5398-405., https://www.ncbi.nlm.nih.gov/pubmed/17875769
[717] Garner, A. P., Gozgit, J. M., Anjum, R., Vodala, S., Schrock, A., Zhou, T., et.al. Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients, Clin Cancer Res, 2014. 20(22): p. 5745-5755., https://www.ncbi.nlm.nih.gov/pubmed/25239608
[718] Wardelmann, E., Thomas, N., Merkelbach-Bruse, S., Pauls, K., Speidel, N., Buttner, R., et.al. Acquired resistance to imatinib in gastrointestinal stromal tumours caused by multiple KIT mutations, Lancet Oncol, 2005. 6(4): p. 249-51., https://www.ncbi.nlm.nih.gov/pubmed/15811621
[719] Mir, O., Cropet, C., Toulmonde, M., Cesne, A. L., Molimard, M., Bompas, E., et.al. Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial, Lancet Oncol, 2016. 17(5): p. 632-41., https://www.ncbi.nlm.nih.gov/pubmed/27068858
[720] Reichardt, P., Blay, J. Y., Gelderblom, H., Schlemmer, M., Demetri, G. D., Bui-Nguyen, B., et.al. Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib, Ann Oncol, 2012. 23(7): p. 1680-7., https://www.ncbi.nlm.nih.gov/pubmed/22357255
[721] Joensuu, H., Eriksson, M., Sundby Hall, K., Hartmann, J. T., Pink, D., Schutte, J., et.al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial, JAMA, 2012. 307(12): p. 1265-72., https://www.ncbi.nlm.nih.gov/pubmed/22453568
[722] Joensuu, H., Reichardt, P., Eriksson, M., Sundby Hall, K., Vehtari, A., Gastrointestinal stromal tumor: a method for optimizing the timing of CT scans in the follow-up of cancer patients, Radiology, 2014. 271(1): p. 96-103., https://www.ncbi.nlm.nih.gov/pubmed/24475826
[723] Czarnecka, A. M., Sobczuk, P., Kostrzanowski, M., Spalek, M., Chojnacka, M., Szumera-Cieckiewicz, A., et.al. Epithelioid Sarcoma-From Genetics to Clinical Practice, Cancers (Basel), 2020. 12(8):, https://www.ncbi.nlm.nih.gov/pubmed/32751241
[724] Hornick, J. L., Dal Cin, P., Fletcher, C. D., Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma, Am J Surg Pathol, 2009. 33(4): p. 542-50., https://www.ncbi.nlm.nih.gov/pubmed/19033866
[725] Frezza, A. M., Jones, R. L., Lo Vullo, S., Asano, N., Lucibello, F., Ben-Ami, E., et.al. Anthracycline, Gemcitabine, and Pazopanib in Epithelioid Sarcoma: A Multi-institutional Case Series, JAMA Oncol, 2018. 4(9): p. e180219., https://www.ncbi.nlm.nih.gov/pubmed/29800950
[726] Stacchiotti, Silvia, Schoffski, Patrick, Jones, Robin, Agulnik, Mark, Villalobos, Victor Manuel, Jahan, Thierry Marie, et.al. Safety and efficacy of tazemetostat, a first-in-class EZH2 inhibitor, in patients (pts) with epithelioid sarcoma (ES) (NCT02601950), Journal of Clinical Oncology, 2019. 37(15_suppl): p. 11003-11003., https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.11003
[727] Robinson, D. R., Wu, Y. M., Kalyana-Sundaram, S., Cao, X., Lonigro, R. J., Sung, Y. S., et.al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing, Nat Genet, 2013. 45(2): p. 180-5., https://www.ncbi.nlm.nih.gov/pubmed/23313952
[728] Demicco, E. G., Wagner, M. J., Maki, R. G., Gupta, V., Iofin, I., Lazar, A. J., et.al. Risk assessment in solitary fibrous tumors: validation and refinement of a risk stratification model, Mod Pathol, 2017. 30(10): p. 1433-1442., https://www.ncbi.nlm.nih.gov/pubmed/28731041
[729] Stacchiotti, S., Negri, T., Libertini, M., Palassini, E., Marrari, A., De Troia, B., et.al. Sunitinib malate in solitary fibrous tumor (SFT), Ann Oncol, 2012. 23(12): p. 3171-3179., https://www.ncbi.nlm.nih.gov/pubmed/22711763
[730] Park, M. S., Patel, S. R., Ludwig, J. A., Trent, J. C., Conrad, C. A., Lazar, A. J., et.al. Activity of temozolomide and bevacizumab in the treatment of locally advanced, recurrent, and metastatic hemangiopericytoma and malignant solitary fibrous tumor, Cancer, 2011. 117(21): p. 4939-47., https://www.ncbi.nlm.nih.gov/pubmed/21480200
[731] Kacker, C., Marx, A., Mossinger, K., Svehla, F., Schneider, U., Hogendoorn, P. C., et.al. High frequency of MYC gene amplification is a common feature of radiation-induced sarcomas. Further results from EORTC STBSG TL 01/01, Genes Chromosomes Cancer, 2013. 52(1): p. 93-8., https://www.ncbi.nlm.nih.gov/pubmed/23012233
[732] Fury, M. G., Antonescu, C. R., Van Zee, K. J., Brennan, M. F., Maki, R. G., A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy, Cancer J, 2005. 11(3): p. 241-7., https://www.ncbi.nlm.nih.gov/pubmed/16053668
[733] Penel, N., Bui, B. N., Bay, J. O., Cupissol, D., Ray-Coquard, I., Piperno-Neumann, S., et.al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study, J Clin Oncol, 2008. 26(32): p. 5269-74., https://www.ncbi.nlm.nih.gov/pubmed/18809609
[734] Schlemmer, M., Reichardt, P., Verweij, J., Hartmann, J. T., Judson, I., Thyss, A., et.al. Paclitaxel in patients with advanced angiosarcomas of soft tissue: a retrospective study of the EORTC soft tissue and bone sarcoma group, Eur J Cancer, 2008. 44(16): p. 2433-6., https://www.ncbi.nlm.nih.gov/pubmed/18771914
[735] Young, R. J., Natukunda, A., Litiere, S., Woll, P. J., Wardelmann, E., van der Graaf, W. T., First-line anthracycline-based chemotherapy for angiosarcoma and other soft tissue sarcoma subtypes: pooled analysis of eleven European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials, Eur J Cancer, 2014. 50(18): p. 3178-86., https://www.ncbi.nlm.nih.gov/pubmed/25459395
[736] Kollar, A., Jones, R. L., Stacchiotti, S., Gelderblom, H., Guida, M., Grignani, G., et.al. Pazopanib in advanced vascular sarcomas: an EORTC Soft Tissue and Bone Sarcoma Group (STBSG) retrospective analysis, Acta Oncol, 2017. 56(1): p. 88-92., https://www.ncbi.nlm.nih.gov/pubmed/27838944
[737] Pink, Daniel, Bauer, Sebastian, Brodowicz, Thomas, Reichardt, Peter, Kasper, Bernd, Richter, Stephan, et.al. Treatment of angiosarcoma with pazopanib and paclitaxel: Results of the phase II trial of the German Interdisciplinary Sarcoma Group (GISG-06 EVA) study, Journal of Clinical Oncology, 2018. 36(15_suppl): p. 11570-11570., https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.11570
[738] Hamacher, Rainer, Kämpfe, Dietrich, Reuter-Jessen, Kirsten, Pöttgen, Christoph, Podleska, Lars E., Farzaliyev, Farhad, et.al. Dramatic Response of a PD-L1–Positive Advanced Angiosarcoma of the Scalp to Pembrolizumab, JCO Precision Oncology, 2018. p. 1-7., https://ascopubs.org/doi/abs/10.1200/PO.17.00107
[739] Cornillie, J., van Cann, T., Wozniak, A., Hompes, D., Schoffski, P., Biology and management of clear cell sarcoma: state of the art and future perspectives, Expert Rev Anticancer Ther, 2016. 16(8): p. 839-45., https://www.ncbi.nlm.nih.gov/pubmed/27253849
[740] Schoffski, P., Wozniak, A., Stacchiotti, S., Rutkowski, P., Blay, J. Y., Lindner, L. H., et.al. Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 'CREATE', Ann Oncol, 2017. 28(12): p. 3000-3008., https://www.ncbi.nlm.nih.gov/pubmed/28950372
[741] Judson, I., Morden, J. P., Kilburn, L., Leahy, M., Benson, C., Bhadri, V., et.al. Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial, Lancet Oncol, 2019. 20(7): p. 1023-1034., https://www.ncbi.nlm.nih.gov/pubmed/31160249
[742] Stacchiotti, S., Tamborini, E., Marrari, A., Brich, S., Rota, S. A., Orsenigo, M., et.al. Response to sunitinib malate in advanced alveolar soft part sarcoma, Clin Cancer Res, 2009. 15(3): p. 1096-104., https://www.ncbi.nlm.nih.gov/pubmed/19188185
[743] Wilky, B. A., Trucco, M. M., Subhawong, T. K., Florou, V., Park, W., Kwon, D., et.al. Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial, Lancet Oncol, 2019. 20(6): p. 837-848., https://www.ncbi.nlm.nih.gov/pubmed/31078463
[745] Baldi, G. G., Brahmi, M., Lo Vullo, S., Cojocaru, E., Mir, O., Casanova, M., et.al. The Activity of Chemotherapy in Inflammatory Myofibroblastic Tumors: A Multicenter, European Retrospective Case Series Analysis, Oncologist, 2020. 25(11): p. e1777-e1784., https://www.ncbi.nlm.nih.gov/pubmed/32584482
[746] Kube, S., Vokuhl, C., Dantonello, T., Scheer, M., Hallmen, E., Feuchtgruber, S., et.al. Inflammatory myofibroblastic tumors-A retrospective analysis of the Cooperative Weichteilsarkom Studiengruppe, Pediatr Blood Cancer, 2018. 65(6): p. e27012., https://www.ncbi.nlm.nih.gov/pubmed/29480552
[747] Schoffski, P., Sufliarsky, J., Gelderblom, H., Blay, J. Y., Strauss, S. J., Stacchiotti, S., et.al. Crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumours with and without anaplastic lymphoma kinase gene alterations (European Organisation for Research and Treatment of Cancer 90101 CREATE): a multicentre, single-drug, prospective, non-randomised phase 2 trial, Lancet Respir Med, 2018. 6(6): p. 431-441., https://www.ncbi.nlm.nih.gov/pubmed/29669701
[748] Kenerson, H., Folpe, A. L., Takayama, T. K., Yeung, R. S., Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms, Hum Pathol, 2007. 38(9): p. 1361-71., https://www.ncbi.nlm.nih.gov/pubmed/17521703
[749] Wagner, A. J., Malinowska-Kolodziej, I., Morgan, J. A., Qin, W., Fletcher, C. D., Vena, N., et.al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors, J Clin Oncol, 2010. 28(5): p. 835-40., https://www.ncbi.nlm.nih.gov/pubmed/20048174
[750] Bissler, J. J., Kingswood, J. C., Radzikowska, E., Zonnenberg, B. A., Frost, M., Belousova, E., et.al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial, Lancet, 2013. 381(9869): p. 817-24., https://www.ncbi.nlm.nih.gov/pubmed/23312829
[751] Mehrabi, A., Kashfi, A., Fonouni, H., Schemmer, P., Schmied, B. M., Hallscheidt, P., et.al. Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy, Cancer, 2006. 107(9): p. 2108-21., https://www.ncbi.nlm.nih.gov/pubmed/17019735
[752] Angelini, A., Mavrogenis, A. F., Gambarotti, M., Merlino, B., Picci, P., Ruggieri, P., Surgical treatment and results of 62 patients with epithelioid hemangioendothelioma of bone, J Surg Oncol, 2014. 109(8): p. 791-7., https://www.ncbi.nlm.nih.gov/pubmed/24643837
[753] Rosenbaum, E., Jadeja, B., Xu, B., Zhang, L., Agaram, N. P., Travis, W., et.al. Prognostic stratification of clinical and molecular epithelioid hemangioendothelioma subsets, Mod Pathol, 2020. 33(4): p. 591-602., https://www.ncbi.nlm.nih.gov/pubmed/31537895
[754] Kitaichi, M., Nagai, S., Nishimura, K., Itoh, H., Asamoto, H., Izumi, T., et.al. Pulmonary epithelioid haemangioendothelioma in 21 patients, including three with partial spontaneous regression, Eur Respir J, 1998. 12(1): p. 89-96., https://www.ncbi.nlm.nih.gov/pubmed/9701420
[755] Tanas, M. R., Sboner, A., Oliveira, A. M., Erickson-Johnson, M. R., Hespelt, J., Hanwright, P. J., et.al. Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma, Sci Transl Med, 2011. 3(98): p. 98ra82., https://www.ncbi.nlm.nih.gov/pubmed/21885404
[756] Grotz, T. E., Nagorney, D., Donohue, J., Que, F., Kendrick, M., Farnell, M., et.al. Hepatic epithelioid haemangioendothelioma: is transplantation the only treatment option?, HPB (Oxford), 2010. 12(8): p. 546-53., https://www.ncbi.nlm.nih.gov/pubmed/20887322
[757] Deyrup, A. T., Tighiouart, M., Montag, A. G., Weiss, S. W., Epithelioid hemangioendothelioma of soft tissue: a proposal for risk stratification based on 49 cases, Am J Surg Pathol, 2008. 32(6): p. 924-7., https://www.ncbi.nlm.nih.gov/pubmed/18551749
[758] Weitz, J., Klimstra, D. S., Cymes, K., Jarnagin, W. R., D'Angelica, M., La Quaglia, M. P., et.al. Management of primary liver sarcomas, Cancer, 2007. 109(7): p. 1391-6., https://www.ncbi.nlm.nih.gov/pubmed/17315167
[759] Nudo, C. G., Yoshida, E. M., Bain, V. G., Marleau, D., Wong, P., Marotta, P. J., et.al. Liver transplantation for hepatic epithelioid hemangioendothelioma: the Canadian multicentre experience, Can J Gastroenterol, 2008. 22(10): p. 821-4., https://www.ncbi.nlm.nih.gov/pubmed/18925305
[760] Lai, Q., Feys, E., Karam, V., Adam, R., Klempnauer, J., Oliverius, M., et.al. Hepatic Epithelioid Hemangioendothelioma and Adult Liver Transplantation: Proposal for a Prognostic Score Based on the Analysis of the ELTR-ELITA Registry, Transplantation, 2017. 101(3): p. 555-564., https://www.ncbi.nlm.nih.gov/pubmed/28212256
[761] Sardaro, A., Bardoscia, L., Petruzzelli, M. F., Portaluri, M., Epithelioid hemangioendothelioma: an overview and update on a rare vascular tumor, Oncol Rev, 2014. 8(2): p. 259., https://www.ncbi.nlm.nih.gov/pubmed/25992243
[762] Sybert, D. R., Steffee, A. D., Keppler, L., Biscup, R. S., Enker, P., Seven-year follow-up of vertebral excision and reconstruction for malignant hemangioendothelioma of bone, Spine (Phila Pa 1976), 1995. 20(7): p. 841-4., https://www.ncbi.nlm.nih.gov/pubmed/7701400
[763] Albakr, A., Schell, M., Drew, B., Cenic, A., Epithelioid hemangioendothelioma of the spine: case report and review of the literature, J Spine Surg, 2017. 3(2): p. 250-259., https://www.ncbi.nlm.nih.gov/pubmed/28744509
[764] Chevreau, C., Le Cesne, A., Ray-Coquard, I., Italiano, A., Cioffi, A., Isambert, N., et.al. Sorafenib in patients with progressive epithelioid hemangioendothelioma: a phase 2 study by the French Sarcoma Group (GSF/GETO), Cancer, 2013. 119(14): p. 2639-44., https://www.ncbi.nlm.nih.gov/pubmed/23589078
[765] Stacchiotti, S., Simeone, N., Lo Vullo, S., Baldi, G. G., Brunello, A., Vincenzi, B., et.al. Activity of sirolimus in patients with progressive epithelioid hemangioendothelioma: A case-series analysis within the Italian Rare Cancer Network, Cancer, 2021. 127(4): p. 569-576., https://www.ncbi.nlm.nih.gov/pubmed/33107985
[766] Stacchiotti, S., Miah, A. B., Frezza, A. M., Messiou, C., Morosi, C., Caraceni, A., et.al. Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts, ESMO Open, 2021. 6(3): p. 100170., https://www.ncbi.nlm.nih.gov/pubmed/34090171
[767] Shek, T. W., Ho, F. C., Ng, I. O., Chan, A. C., Ma, L., Srivastava, G., Follicular dendritic cell tumor of the liver. Evidence for an Epstein-Barr virus-related clonal proliferation of follicular dendritic cells, Am J Surg Pathol, 1996. 20(3): p. 313-24., https://www.ncbi.nlm.nih.gov/pubmed/8772785
[768] Shinagare, A. B., Ramaiya, N. H., Jagannathan, J. P., Hornick, J. L., Swanson, R. S., Primary follicular dendritic cell sarcoma of liver treated with cyclophosphamide, doxorubicin, vincristine, and prednisone regimen and surgery, J Clin Oncol, 2011. 29(35): p. e849-51., https://www.ncbi.nlm.nih.gov/pubmed/22042944
[769] Shinde, R. S., Gupta, A., Goel, M., Patkar, S., Solitary fibrous tumor of the liver - An unusual entity: A case report and review of literature, Ann Hepatobiliary Pancreat Surg, 2018. 22(2): p. 156-158., https://www.ncbi.nlm.nih.gov/pubmed/29896577
[770] Tokarskaya, Z. B., Zhuntova, G. V., Scott, B. R., Khokhryakov, V. F., Belyaeva, Z. D., Vasilenko, E. K., et.al. Influence of alpha and gamma radiations and non-radiation risk factors on the incidence of malignant liver tumors among Mayak PA workers, Health Phys, 2006. 91(4): p. 296-310., https://www.ncbi.nlm.nih.gov/pubmed/16966873
[771] Sharp, G. B., The relationship between internally deposited alpha-particle radiation and subsite-specific liver cancer and liver cirrhosis: an analysis of published data, J Radiat Res, 2002. 43(4): p. 371-80., https://www.ncbi.nlm.nih.gov/pubmed/12674201
[772] Baker, K. S., Leisenring, W. M., Goodman, P. J., Ermoian, R. P., Flowers, M. E., Schoch, G., et.al. Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation, Blood, 2019. 133(26): p. 2790-2799., https://www.ncbi.nlm.nih.gov/pubmed/30992266
[773] Tripke, V., Heinrich, S., Huber, T., Mittler, J., Hoppe-Lotichius, M., Straub, B. K., et.al. Surgical therapy of primary hepatic angiosarcoma, BMC Surg, 2019. 19(1): p. 5., https://www.ncbi.nlm.nih.gov/pubmed/30630447
[774] Putra, J., Ornvold, K., Undifferentiated embryonal sarcoma of the liver: a concise review, Arch Pathol Lab Med, 2015. 139(2): p. 269-73., https://www.ncbi.nlm.nih.gov/pubmed/25611111
[775] Lenze, F., Birkfellner, T., Lenz, P., Hussein, K., Langer, F., Kreipe, H., et.al. Undifferentiated embryonal sarcoma of the liver in adults, Cancer, 2008. 112(10): p. 2274-82., https://www.ncbi.nlm.nih.gov/pubmed/18361435
[776] Kirkham, J. C., Nero, C. J., Tambouret, R. H., Yoon, S. S., Leiomyoma and leiomyosarcoma arising from the round ligament of the uterus, J Am Coll Surg, 2008. 207(3): p. 452., https://www.ncbi.nlm.nih.gov/pubmed/18722953
[777] Thomas, K. L., Gonzalez, R. J., Henderson-Jackson, E., Caracciolo, J. T., Paratesticular Liposarcoma Masquerading as an Inguinal Hernia, Urology, 2018. 113: p. e5-e6., https://www.ncbi.nlm.nih.gov/pubmed/29203187
[778] Keenan, R. A., Nic An Riogh, A. U., Stroiescu, A., Fuentes, A., Heneghan, J., Cullen, I. M., et.al. Paratesticular sarcomas: a case series and literature review, Ther Adv Urol, 2019. 11: p. 1756287218818029., https://www.ncbi.nlm.nih.gov/pubmed/30671140
[779] Rodriguez, D., Barrisford, G. W., Sanchez, A., Preston, M. A., Kreydin, E. I., Olumi, A. F., Primary spermatic cord tumors: disease characteristics, prognostic factors, and treatment outcomes, Urol Oncol, 2014. 32(1): p. 52 e19-25., https://www.ncbi.nlm.nih.gov/pubmed/24239475
[780] Priemer, D. S., Trevino, K., Chen, S., Ulbright, T. M., Idrees, M. T., Paratesticular Soft-Tissue Masses in Orchiectomy Specimens: A 17-Year Survey of Primary and Incidental Cases From One Institution, Int J Surg Pathol, 2017. 25(6): p. 480-487., https://www.ncbi.nlm.nih.gov/pubmed/28459169
[781] Kryvenko, O. N., Rosenberg, A. E., Jorda, M., Epstein, J. I., Dedifferentiated liposarcoma of the spermatic cord: a series of 42 cases, Am J Surg Pathol, 2015. 39(9): p. 1219-25., https://www.ncbi.nlm.nih.gov/pubmed/25828386
[782] Ballo, M. T., Zagars, G. K., Pisters, P. W., Feig, B. W., Patel, S. R., von Eschenbach, A. C., Spermatic cord sarcoma: outcome, patterns of failure and management, J Urol, 2001. 166(4): p. 1306-10., https://www.ncbi.nlm.nih.gov/pubmed/11547063
[783] Catton, C., Jewett, M., O'Sullivan, B., Kandel, R., Paratesticular sarcoma: failure patterns after definitive local therapy, J Urol, 1999. 161(6): p. 1844-7., https://www.ncbi.nlm.nih.gov/pubmed/10332450
[784] Radaelli, S., Desai, A., Hodson, J., Colombo, C., Roberts, K., Gourevitch, D., et.al. Prognostic factors and outcome of spermatic cord sarcoma, Ann Surg Oncol, 2014. 21(11): p. 3557-63., https://www.ncbi.nlm.nih.gov/pubmed/24802908
[785] Coleman, J., Brennan, M. F., Alektiar, K., Russo, P., Adult spermatic cord sarcomas: management and results, Ann Surg Oncol, 2003. 10(6): p. 669-75., https://www.ncbi.nlm.nih.gov/pubmed/12839852
[786] Murray, K. S., Vertosick, E. A., Spaliviero, M., Mashni, J. W., Jr., Sjoberg, D. D., Alektiar, K. M., et.al. Importance of wide re-resection in adult spermatic cord sarcomas: Report on oncologic outcomes at a single institution, J Surg Oncol, 2018. 117(7): p. 1464-1468., https://www.ncbi.nlm.nih.gov/pubmed/29473967
[787] Khandekar, M. J., Raut, C. P., Hornick, J. L., Wang, Q., Alexander, B. M., Baldini, E. H., Paratesticular liposarcoma: unusual patterns of recurrence and importance of margins, Ann Surg Oncol, 2013. 20(7): p. 2148-55., https://www.ncbi.nlm.nih.gov/pubmed/23591942
[788] Rodriguez, D., Olumi, A. F., Management of spermatic cord tumors: a rare urologic malignancy, Ther Adv Urol, 2012. 4(6): p. 325-34., https://www.ncbi.nlm.nih.gov/pubmed/23205059
[789] Fagundes, M. A., Zietman, A. L., Althausen, A. F., Coen, J. J., Shipley, W. U., The management of spermatic cord sarcoma, Cancer, 1996. 77(9): p. 1873-6., https://www.ncbi.nlm.nih.gov/pubmed/8646687
[790] Bozzini, G., Albersen, M., Romero Otero, J., Margreiter, M., Garcia Cruz, E., Mueller, A., et.al. Feasibility and safety of conservative surgery for the treatment of spermatic cord leiomyosarcoma, Int J Surg, 2015. 24(Pt A): p. 81-4., https://www.ncbi.nlm.nih.gov/pubmed/26578108