Preoperative or intraoperative biopsy for pathological identification is not a prerequisite unless presurgical molecular diagnosis is necessary for targeted medication, which is not routinely recommended in cases with removable primaries to avoid the potential possibility of tumor rupture, bleeding, and diffusion (11). Among multiple biopsy approaches, endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is mostly used in clinical practice with distinct advantages of accuracy, safety, and relatively low possibility of dissemination. Potential limitations are inevitable considered that it is only applicable for GISTs situated in the lumen and fewer samples often lead to uncertainty of pathological diagnosis (24–26). Postoperative pathology report is of great value for the confirmation of diagnosis (27).

Surgery indications often refer to non-gastric GISTs, tumor size larger than or equal to 2 cm, or symptoms presented such as abdominalgia and gastrointestinal bleeding without regard to tumor size and location. Even though GISTs are located in the stomach with size less than 2 cm, attention should be paid on the risk under EUS or pathology for further determination of the implementation of operation. Higher risk tends to include irregular and unclear border, echogenic foci, high mitotic rate, cystic degeneration, strong echo, ulcer, hemorrhage, and heterogeneity (21, 28, 29). Without the presentation of these manifestations, regular follow-up surveillance is recommended.

It has been well-recognized that radical surgical resection is the first-line cornerstone and mainstay for the treatment of localized primary GISTs, which is the exclusive way for potentially thorough cure (30, 31). Surgery should be performed by experienced surgical specialists when open surgery or laparoscopy management was planned (7). The fundamental principle is to carefully complete en bloc removal of the tumor entity securing a sufficient histopathologically negative margin (R0 resection) achieving minor complications without damage of organ function and violation of tumor pseudocapsule prior to or during procedure as much as possible, which might contribute to accidental tumor perforation and rupture with tremendous risk of intraperitoneal implantation and spreading of tumor cells. To this end, “no touch, less compression” code and “extract bag” approach are available (21). Tumor excision incorporating peripheral tissues, whenever and wherever necessary and possible, in the case surrounding tissues or organs, is involved so as to realize the principle of R0 resection (7, 28). R0 resection is considered as the well-recognized favorable prognosis indicator for patients with localized primary GISTs (32). R1 resection (microscopically positive margins) is inclined to the development of tumor relapse, which occurs practically in all cases with tumor rupture (33). With respect to the situation where preoperative medication is unavailable or shows obscure benefits in patients with R0 resection that implicated major sequelae, R1 resection is recommended to be taken into consideration with no demonstration of correlation with dismal outcome especially in low-risk cases (23, 34). In addition, reoperation is a substitute for discussion as an individualized management after unexpected R1 resection and R2 excision (macroscopic incomplete excision) (7, 35). Inconsistent with surgical treatment of other malignancies, the proportion of lymphatic dissemination is comparatively diminutive and extensive lymphadenectomy is not regularly indicated with an exception of proof-positive lymphadenopathy, which implicated SDH-deficient genotyping especially in pediatric GISTs (27, 36, 37).

Preoperative neoadjuvant molecular targeted chemotherapy with TKIs like imatinib was indicated in situations where R0 resection is laborious to perform accompanied by alarmingly significant surgery risk and morbidity and increased possibility of perioperative complication like tumor rupture and bleeding or common postoperative functional sequelae, which will seriously affect organ function (23, 38). More often than not, potential occasion refers to large tumor size (>10 cm in maximal diameter) or difficult and unfavorable tumor sites located in operatively challenging areas such as the esophagus, esophagogastric junction (EGJ), duodenum, and rectum (39–41).

The rationale is that relatively large tumor size is reported to be positively correlated with the decreased rate of radical removal and increased risk of tumor recurrence (42). Consequently, shrinkage of tumor volume by neoadjuvant administration is of great significance for subsequent surgery, which not only contributes to improving the success rate of R0 resection and function preservation of involved organ and normal tissues to the greatest extent, as the avoidance of extended total gastrectomy and preservation of the anal sphincter, but also improve the 5-year overall survival (OS) and progression-free survival (PFS) (43–45). Simultaneously, genotyping tests prior to TKI therapy are essential for the identification of types of targeted drugs, and vigilant focus should be paid on imatinib-insensitive tumors such as PDGFRA D842 V mutations (46). Prior to the operation, neoadjuvant therapy should be conducted for 6–12 months so as to realize maximal chemotherapy outcome (29, 35). With respect to the embarking moment of surgery, the ESMO–EURACAN guidelines recommend to stop neoadjuvant therapy just before surgery and resume immediately after patients’ postoperative recovery (23). Further potent evidence based on large-scale multicenter clinical trials for the consolidation of efficaciousness of preoperative neoadjuvant medication remains to be developed.

Apart from aforementioned GISTs population with preoperative neoadjuvant chemotherapy with TKI, postoperative adjuvant therapy is often indicated as an indispensable part of standard treatment. Pertinent scenarios mainly refer to those categorized as “high risk” of recurrence and metastasis according to various classification criteria and those with R1 resection (11). According to a long-term randomized multicenter clinical trial, the postsurgical administration of TKI adjuvant chemotherapy was recommended for at least 3 years (47). Individualized evaluation is often recommended for moderate-risk patients to discuss whether to carry out adjuvant chemotherapy or follow-up surveillance (35).

Even though the tumor is completely removed through operation and TKI therapy presents amenable effectiveness, recurrence and metastasis are fairly commonplace, especially in high-risk patients with adverse 5-year OS and relapse-free survival (RFS) (48). Systemic therapy with TKI targeted medication based on genotyping is the first therapy and gold standard in recurrent, metastatic, or inoperable circumstances, and surgery is not generally recommended as a primary choice but considered as an available alternative and non-contraindication (28, 41, 49). As gross tumor volume (GTV) of GISTs is investigated to be positively correlated with tumor progression and negatively associated with the survival outcome of patients, debulking surgery and cytoreduction potentially decreased the likelihood of imatinib-resistant clones emerging, and the risk of secondary mutations has become a significant component of management in patients with recurrence or metastasis scenario (50, 51). Of note, debulking surgery is found to be efficacious in outcome improvement for most TKI-respondent patients and should be conducted before tumor progression (51, 52). Postoperatively, complete removal of tumor along with TKI therapy provides preferable outcomes for patients with more effectiveness and minimal complications and side effects compared with TKI alone (49, 53). As mentioned above, for those administrated with preprocedural TKI neoadjuvant regimens, adjuvant chemotherapy after surgery needs to be resumed as soon as possible (35). Specifically, patients who develop disease progression with TKI resistance will not benefit from identical TKI regimen used preoperatively, and postsurgical genetic test that is dedicated to identifying further therapeutic target is of vital value under this circumstance (41).

The indication of surgical administration in selected patients is as follows: better responding with imatinib therapy and tumor transfer from unresectable to resectable entity with minor operation-associated risk in residual lesions; localized progression with TKI resistance after targeted therapy including both sunitinib second-line therapy (54) and regorafenib third-line therapy (55) in addition to first-line treatment with imatinib (56); advanced tumor with a relatively small gross tumor volume of which lesion foci is evaluated to be completely removed through procedure; relatively limited and isolated metastatic foci or superficial lesions with operative feasibility; excision in cases with high risk of rupture necrotic metastases foci; patients in generally good condition and surgical tolerability; symptoms such as uncontrollable hemorrhage, perforation, and obstruction or acute pain with palliative emergency operation being necessary (28, 35). Surgical management for patients with general and disseminated progression following TKI medication is absolutely inadvisable, which could not present favorable survival benefits (21, 35).

Liver is one of the most common metastatic sites of GISTs; transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) play a palliative adjunctive role in tumor control with feasibility and safety in addition to surgery (57–59). However, RFA is inclined to be suitable for tumors with a maximum diameter of 3 cm and is contraindicated in patients in whom tumor is contiguous with large vessels or supersedes liver capsule (7). Efforts has been made for the establishment of successful cases of liver transplantation but prospective research are still limited, and this management regimen is not regularly considered in clinical practice with scrupulous discussion processing required by multidisciplinary specialists for comprehensive prognosis evaluation of patients and conducted in experienced transplant centers (60, 61).

Taken together, multidisciplinary cooperation should be taken into consideration for the evaluation of feasibility of debulking operation and metastasectomy for patients with recurrent or metastatic GISTs and provide them with individualized treatment algorithm-integrated systemic medication with localized palliative procedure for further outcome improvement. If surgery is planned to be conducted, with the premise of ensuring R0 or R1 excision as much as possible, scrupulous consideration of patient selection refers to feasibility and complexity of operation, the degree of disease progression, the involvement of adjacent organs, the patient's age, physical condition, possible complications, postoperative recovery time, benefits, and risks.

Esophageal GISTs are comparably rare and ordinarily occur in the esophagogastric junction (62). Patients with relatively larger GISTs that are situated in the esophagogastric junction could benefit from TKI therapy followed by localized resection with avoidance of traumatic total gastrectomy, realizing organ function preservation to the greatest extent. Once the diagnosis of GISTs is established, surgery is suggested to be conducted immediately for such special anatomic location with operation difficulty (21). Choosing either complete esophagectomy or enucleation procedure is primarily based on the tumor size, location, and surgery-related risk (63). The enucleation technique could be a feasible alternative for relatively smaller and posterior wall GISTs, while radical esophagectomy is indicated for large tumors (4).

The gastric subgroup constitutes a majority of occurrence sites for GISTs. As mentioned above, on the premise of the absence of risk presentation under EUS, gastric GISTs with GTV of less than 2 cm without tumor-related symptom is indicated for follow-up surveillance. Surgery is recommended for cases inconsistent with these scenarios such as those in extragastric sites.

Due to the possibility of associated risk of local recurrences, enucleation is not generally recommended (35). However, in order to preserve normal organ function, enucleation approach could be tried with regard to small GISTs situated in the posterior wall (4). GISTs with a tumor size ≤4 cm located in the stomach are reported to benefit from resection by endoscopic techniques with adjuvant therapy or additional operation, when necessary, based on risk evaluation while superiority is not shown in cases with tumor size >4 cm in which surgery is often necessary (64). Surgical resection approaches of gastric GISTs primarily incorporate wedge resection (WR) or larger resection securing a margin of 1–2 cm (65). In the case where wedge resection is not feasible, segmental resection is an appropriate option referring Biliroth I, Biliroth II, and total gastrectomy with gastroduodenostomy, gastrojejunostomy, or Roux-en-Y reconstruction (4). Partial gastrectomy or total gastrectomy rather than proximal gastrectomy is recommended in GISTs located near the cardia or its extension (28, 35). Located in relatively favorable anatomic sites, greater curvature, or anterior wall of gastric body with tumor size of <5 cm is indicated for the application of laparoscopic procedure with safety, feasibility, less invasiveness, and comparable outcome compared to open surgery (21, 66, 67), and laparoscopic–endoscopic hybrid partial gastrectomy is a successful surgical method that secures complete resection without excessive violation of the normal anatomical structure (68). Simultaneously, this endoscopy-assisted laparoscopic operation is a recommendable alternative of open gastrectomy for gastric GISTs with feasibility and safety profile (69).

Duodenum GISTs account for a practically small proportion of all GISTs with its second part, descending part, being the most preferred site (70). Operative procedure to completely remove tumor securing an adequate margin remains to be the optimal choice for radical cure in localized primaries with resectable feasibility. However, the complex and special anatomical position of the duodenum itself, which is contiguous with the head of pancreas, common bile duct, pancreatic duct, mesenteric blood vessels, and ampulla of Vater combined with relatively insufficient procedural experience owing to its rarity, brings about enormous challenge for performing the surgery (71, 72). The available operative approaches based on diverse instruments primarily consist of open surgery, endoscopy, laparoscopy, and hybrid surgery such as endo–laparoscopic cooperative procedure. Open surgery is applicable in most cases after feasibility and safety evaluation especially in ampulla of Vater and pancreas involved complex cases in which pancreaticoduodenectomy (PD), known as Whipple resection, is ordinarily necessary but with enormous invasiveness and damage to normal organ function (73, 74). Segmental intestinal resection can be performed when the tumor size is small and lesion is remote from the essential ampulla location. Followed by presurgical neoadjuvant TKI administration, limited resection instead of PD is often accessible, which decreases compromising the proximal structures due to large invasiveness. Limited resection approaches often incorporate WR and segmental duodenum resection with intestinal anastomosis according to the lesion site and extension (75). Endoscopic resection remains challenging and is intractable to securely perform with a comparable risk of nonradical resection and tumor rupture although there are advances in endoscopy techniques identically due to anatomic characteristics of the duodenum (76). In recent years, laparoscopy and endo–laparoscopic approaches combined hybrid surgery have been explored in the operative management of GISTs, with predominant advantages of minimal invasiveness, decreased perioperative complications, and long-term survival (77–80). Consequently, meticulous consideration should be taken referring to size, location, and invasiveness to adjacent structures for the individualized evaluation of optimal procedure option.

The small intestine is the second most common site of gastrointestinal stromal tumors consisting of nearly a third of all GISTs (81). Open operation is ordinary practice while laparoscopic surgery should be taken into consideration for exploring and locating the corresponding lesion (21). In comparison with laparotomy, however, laparoscopic surgery is reported to assume less operation duration and less postsurgical complications as there was no significant between-group difference in oncological outcome according to a meta-analysis (82). Similarly, a retrospective review found that laparoscopic operation is safe and effective comparable to open operation in oncological prognosis and preferable in perioperative indicators (83). As for small intestine GISTs with size <10 cm in diameter, laparoscopic surgery can be recommended based on subgroup RFS analysis (84). Under normal circumstances, segmental resection with end-to-end intestinal anastomosis is recommended according to French clinical practice guidelines (35).

Consistent with their incidence in the esophagus and the duodenum, GISTs situated in the colorectum are similarly rare. Compared with the left colon, GISTs tend to occur in the right side (85). All colon GISTs are recommended to be surgically resected regardless of tumor size and malignancy degree (86). Segmental resection with end anastomosis is the frequently used operative approach parallel with GISTs in the small intestine (35). Unsophisticated laparoscopic appendectomy is often applicable for particularly rare appendiceal GISTs (4).

GISTs located in rectum together with rectal vaginal space are strongly recommended for complete resection regardless of the tumor size since there are comparable risks for postsurgical recurrence and metastasis once diagnosis of GISTs is established (7) and enucleation is not regularly recommended (35). Considering that surgical difficulty and possibility of multivisceral resection will significantly increase with the enlargement of tumor size, operation should perform as early as possible (21).

There are different operative methods based on corresponding tumor location with respect to rectum GISTs. Low anterior resection and end-to-end intestinal anastomosis along with temporary colostomy are applicable for the upper section of the rectum with adequate distance to the anal sphincter. As for GISTs located in the lower rectum adjacent to the anal sphincter, abdominoperineal combined resection, known as Miles’ operation, with permanent sigmoid colostomy are commonly performed (4). Research reported that transanal full-thickness resection (FTR) presents more benefits concerning lower rectum GISTs and should be discussed when referring to minor tumor size (65). Original sphincter-sparing operation approaches with less invasiveness have been explored such as transanal endoscopic operation (TEO) (87) and transanal minimally invasive surgery (TAMIS) (88). Laparoscopic resection is another applicable option for lesions located in the upper rectum of <2 cm but not regularly recommended when the tumor increases in size (21). Preoperative neoadjuvant chemotherapy is necessary for the preservation of sphincter function as much as possible by tumor shrinkage with the improvement of outcomes (89). A multicenter cohort research performed by Wang et al. (90) was investigated to the compare oncologic outcomes in patients with low rectum GISTs between a local resection cohort and a radical resection cohort; they found that local resection presented a significant superiority in sphincter preservation, minimizing operation time. and postoperative complications compared to radical resection. However, in terms of tumor size >2 cm, there was a preferable survival outcome in the radical resection cohort.

Actually, a great number of extragastrointestinal GISTs (EGISTs) reported are metastases foci of primary GISTs. Mesentery and omentum are common tumor sites of genuine primary EGISTs (91, 92). Other rare and unusual locations are pancreas (93), prostate (94), and pleura (95). With rare and aggressive malignancy, patients with EGISTs often have comparatively poor survival outcome, classified as high-risk lesions (96). Early identification and en bloc surgical excision as complete as possible remain the preferred treatment (97). Risk and cost-effectiveness of treatment regimens should be taken into account, and surgery combined with systemic neoadjuvant or adjuvant medication are often necessary (98) Cytoreductive debulking surgery might act as a potential palliative therapeutic strategy for symptomatic remission (99). Laparoscopy has been used for the surgical practice in EGISTs and achieved successful resection of tumor mass and oncological outcome as an available procedure option (100).

Table 8 summarizes corresponding researches of EAWR technique. With real-time monitoring, locating, and marking done by endoscopists, the lesion was removed by conventional laparoscopic wedge resection using a linear endoscopic gastrointestinal stapler. Subsequently, the mass resected was retrieved through the laparoscope followed by endoscopic examination of the existence of residual lesion and potential complications. EAWR is applicable for lesion not only in the anterior wall of the stomach but also in the posterior gastric wall, EGJ, and pyloric ring, which is more recommendable for an ultrasonic shear device or a vascular sealing system to avoid pertinent damage or stenosis (144, 145). More often than not, lesions situated in the posterior wall of the gastric body, limited to the central sections, were recommended for EAWR, which were easily accessible through the mentum or gastrocolic ligament by creating a small incision (146). In addition, the lesion with exophytic characteristic is another indication for EAWR.

EATR is more applicable for lesions located in the posterior gastric wall with a relatively large size or with intraluminal growth or near the EGJ (150, 151) (Table 9). As mentioned above, lesions located in the posterior gastric wall of the fundus or antrum instead of the body were preferred for this approach (146). With the assistance of endoscopic identification of the lesion location by palpation and diaphanoscopy, gastrotomy of the anterior gastric wall was performed by a laparoscopic team and the corresponding lesion was exposed. Subsequently, routine inverted laparoscopic wedge resection or full-thickness resection was conducted. Finally, the defect in the anterior gastric wall was closed using endoscopic stapler devices or laparoscopic sutures. Lesions located in the posterior of the duodenum were also indicated for applying EATR with robotic assistance. Based on the comparison analyses of Marzano et al., EAWR was recommended as the first choice for most gastric submucosal tumors (SMTs) than EATR due to gastrotomy and related complications such as increased operative time and blood loss, digestive fluid leakage, and the risk of abdominal cavity spread (152).

Endoscopy played a significant role in identifying lesion location, and then several laparoscopic trocars penetrated both the abdominal wall and the anterior stomach wall into the gastric cavity. Stay sutures could facilitate the lift of the anterior gastric wall to the abdominal wall. With the real-time monitoring and assistance of endoscopy during the operation, the lesion was resected through wedge resection or full-thickness resection by the laparoscopic team. Finally, the lesion specimen resected was retrieved perorally, and perforation and defect were closed by endoscopists and the laparoscopic team. Gastrotomy was performed when necessary, concerning large specimen with difficulty to be retrieved though the mouth (153, 154).

LIGS was first reported by Ohashi in 1995 and often recommended in lesions situated in the posterior gastric wall with intraluminal growth and relatively small tumor size (155, 156). Compared to EATR, LIGS is safer and with decreased blood loss and postsurgical complications through gastric perforation instead of gastrotomy.

In recent years, a modified LIGS technique, known as single-incision LIGS (sLIGS), has been reported by researchers. Only a 3 cm longitudinal incision was made near the umbilicus and a wound-protecting device was placed. Following a mini-size gastrotomy, three to four ports were placed through a single port device in the single incision. The lesion resection was similar with conventional LIGS and defect of gastrotomy and abdominal wall were closed. The indications for sLIGS were parallel to those of the routine LIGS technique. Of note, single incisions often correlated with higher perioperative security and decreased complications (157–160). Researches of LIGS technique are summarized in Table 10.

LECS has been reported to successfully resect gastric submucosal GISTs, which is known as classical LECS (Table 11). First, ESD was performed via intraluminal endoscopy for circumferentially dissecting three quarters of the tumor submucosa. Next, the seromuscular layer was dissected by laparoscopy along the corresponding cut line, and the tumor was laparoscopically resected by a stapling device. There are several advantages of this technique, according to researchers’ opinion, such as it is independent of the tumor location without excessive sections of healthy tissues (164, 165). Theoretically, the application of the LECS technique is not restricted by the size of the tumor as the lesion is retrieved through the abdominal wall. However, LECS is shown to be more applicable for relatively small GISTs (166) and not recommended in large (> 5 cm) or ulcerative cases due to the increased risk of peritoneal contamination and tumor dissemination (167). Based on the research by Ri et al., subepithelial tumor located in the esophagogastric junction has a risk of conversing operation procedure from LECS to proximal gastrectomy, which is safer (168).

With the assistance of laparoscopy, the EFTR procedure achieved considerable improvement of avoiding excessive resection of normal tissues, and an original cooperative surgery based on the principles of LECS, called laparoscopy-assisted endoscopic full-thickness resection (LAEFR), has been developed by Abe et al. (175) (Table 12). Described as a hybrid natural orifice transluminal endoscopic surgery (NOTES), ESD followed by EFTR was endoscopically performed for the resection of 2/3 to 3/4 of tissue with the assistance of a laparoscopic team, which facilitates the exposure, and then the remaining tumor was completely resected and retrieved either perorally or through a laparoscope. The gastric wall defect was then hand-sewn and closed by laparoscopy. Apart from the accurate and complete removal of the tumor, the advantages of LAEFR incorporate minimal invasiveness, inexpensiveness in comparison with other laparoscopic surgery, and less perioperative adverse events managed via laparoscopic therapy. It is noteworthy that the closure of the artificial gastric wall perforation is easier and safer by means of laparoscopy compared to endoscopy (176). This technique is especially applicable for the resection of GISTs located in the MP layer with intraluminal growth modality (177).

In 2019, there was a case report in which a patient with remnant stomach GIST received inverted LECS for full-thickness resection with sound postoperative outcome (180) (Table 13). The brief operation modality of inverted LECS is described as follows. The first step is the identification of resection line and circumferential elevation of the gastric wall like a crown using stitches. Then, the seromuscular layer is dissected after artificial perforation followed by conducting EFTR. A .laparoscopic stapler is used to dissect the residual gastric wall, and tumor tissue is perorally retrieved. The final step is the defect suture by laparoscopic devices (181). In general, inverted LECS is performed with the traction inversion of tumor toward the intragastric cavity as a crown. There is, however, still relatively lower risk of gastric content spillage during this technique owing to gastric lumen exposure. Moreover, not all sites were feasible for inverted LECS such as the posterior wall.

For the purpose of the reduction of tumor cells seeding into the abdominal cavity, several newer innovative “nonexposure” techniques, originated from the classical LECS procedure for full-thickness resection, named as a combination of laparoscopic and endoscopic approaches to neoplasia applying nonexposure technique (CLEAN-NET), nonexposed endoscopic wall-inversion surgery (NEWS), and closed-LECS, have been developed.