Multiple recurrences and metastases in abdominal cavity following surgery for a ruptured giant gastrointestinal stromal tumor: a case report

Introduction

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Originating from interstitial cells of Cajal, they are predominantly found in the stomach and small intestine, with a lower incidence in the esophagus, colon, rectum, and other regions (1-3). Although surgery remains the preferred treatment for GISTs, there is a significant risk of postoperative recurrence due to the intrinsic nature of the disease. Used as a postoperative adjuvant therapy, imatinib can mitigate the risk of postoperative recurrence in patients with intermediate- and high-risk disease. It also serves as the first-line treatment for locally advanced, inoperable/unresectable, and metastatic GISTs (4). However, some patients exhibit primary resistance to imatinib, and the majority of patients who initially respond to imatinib treatment will ultimately develop secondary resistance (5). Here we present a case of a giant gastrointestinal stromal tumour that was removed and treated with imatinib for 3 years without signs of recurrence. However, 1 year after stopping the drug, the tumour recurred intraperitoneally. Before undergoing surgery again, the tumour shrank significantly after oral imatinib and the patient underwent surgery. The patient is currently being treated with repatinib after surgery and has shown no signs of relapse. The management of postoperative recurrence is of particular urgency and significance for the survival and quality of life of GIST patients. We present this case in accordance with the CARE reporting checklist (available at https://gist.amegroups.com/article/view/10.21037/gist-24-8/rc).

Case presentation

A 41-year-old man with acute abdominal pain and distension was admitted to The Third People’s Hospital of Chengdu. Physical examination revealed slight bulging of the left upper quadrant (LUQ), in which a 15-cm mass with tenderness was palpable. No other positive sign was noted. The plain abdominal computed tomography (CT) scan revealed a giant complex mass located in the LUQ (Figure 1A). Surgery was performed on 29 December 2018, and intraoperative exploration uncovered a 15 cm × 15 cm giant mass in the LUQ. Originating from the posterior side of the stomach, the mass had necrosed and formed an abscess with surrounding inflammatory adhesions. Following the dissection of adhesions, en bloc resection of the mass was performed, along with a wedge resection of the involved portion of the gastric body. Histopathological analysis of the surgical specimens indicated the presence of a high-risk GIST (Figure 1B). Genetic testing indicated a mutation in the C-KIT gene, specifically within exon 11. Following three years of adjuvant therapy with 400 mg/day imatinib, the medication was stopped. One year after imatinib discontinuation, the patient reported lower left abdominal fullness, and abdominal CT on 27 January 2023 revealed a 3.9 cm × 2.1 cm × 3.6 cm mass in the lower right quadrant and a 7.8 cm × 5.7 cm × 4.8 cm mass in the left iliac fossa, both with heterogeneous enhancement and indistinct margins (Figure 1C). The possibility of multiple recurrences from the primary GIST was considered. Oral 400 mg/day imatinib therapy was re-initiated, lasting for 2 months. A follow-up abdominal CT scan was performed on 6 June 2023 (Figure 1D). It was evident that the mass in the right lower quadrant had well resolved, with the response being assessed as complete response (CR). In contrast, the mass in the left iliac fossa had not satisfactorily resolved, and the efficacy was classified as stable disease (SD). According to the imaging studies, microscopically margin-negative (R0) resection of the mass in the left iliac fossa was possible. Then, surgical excision was performed on 9 June 2023. Intraoperative exploration revealed a cystic and solid mass within the small mesentery, measuring approximately 3 cm × 2 cm × 1 cm. A cystic and solid mass was seen within the left posterior peritoneum of the iliac fossa, sized about 6 cm × 4 cm × 3 cm. There was also a complex cystic and solid mass in the wall of the small intestine 150 cm away from the ileocecal region, with a size of about 0.5 cm × 0.2 cm × 0.2 cm. No swollen lymph node was observed in the mesentery. After en bloc resection of the tumors, the samples were sent for pathological examination (Figure 1E). Genetic testing indicated a mutation in the C-KIT gene, specifically within exons 11 and 17. The pathological examinations after the patient’s two operations both showed a spindle cell type, while the second examination found only a small number of spindle cells, which was consistent with the results after oral imatinib. Following the surgical intervention, the patient is currently being managed with 150 mg/day ripretinib, and no tumor recurrence was found on abdominal CT 1 year after the surgery. The patient’s condition is summarised in the Figure 2.

Figure 1 The patient’s treatment process and some examination results. (A) Abdominal CT before the patient’s first surgery. The arrows point to the tumour. (B) Pathological examination results after the patient’s first surgery (a: CD34, IHC staining, 100× visual field; b: CD117, IHC staining, 100× visual field; c,d: HE staining 100× visual field; e: Dog-1, IHC staining, 100× visual field; f,g: HE staining 400× visual field). (C) Abdominal CT re-examination after 1 year of discontinuing imatinib. The arrows point to the tumour. (D) Abdominal CT re-examination after two months of imatinib treatment (compared with Figure 1C, the tumour was significantly reduced). The arrow and circle indicate the tumour. (E) Pathological examination results after the patient’s second surgery. (a: Dog-1, IHC staining, 100× visual field; b: CD117, IHC staining, 100× visual field; c,d: HE staining 100× visual field; e: CD34, IHC staining, 100× visual field; f,g: HE staining 400× visual field). CT, computed tomography; IHC, immunohistochemical; HE, hematoxylin & eosin.

Figure 2 Time overview of patient condition development and treatment. CT, computed tomography.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

International Multidisciplinary Team (iMDT) discussion

Discussion among physicians from The Third People’s Hospital of Chengdu

Section for Gastrointestinal Surgery

GISTs constitute approximately 3% of all gastrointestinal neoplasms (6). As relatively rare malignancies, GISTs arise from interstitial cells of Cajal, which are pacemaker cells of gastrointestinal motility that are predominantly located in the smooth muscle layer of the gastrointestinal tract and around the myenteric plexus (7,8). The clinical manifestations of GISTs are non-specific. These tumors can be asymptomatic in the early stages and are often incidentally identified during digestive endoscopy or imaging studies conducted for other purposes (9). As the disease progresses, symptoms such as gastrointestinal hemorrhage and its consequent anemia, melena, abdominal pain/bloating, and gastrointestinal obstruction become more evident, although gastrointestinal perforation is infrequent (9-11). In patients with larger tumors, a mass may be palpated in the abdomen. Most (about 85%) GISTs are driven by mutations in the KIT or PDGFRA genes, particularly in KIT exon 11 (65–80%), PDGFRA exon 18 (5–14%), and KIT exon 9 (6–10%), and, rarely, KIT exon 17 (1%). GISTs that do not harbor mutations in the KIT or PDGFRA genes are categorized as wild-type GISTs (WT GISTs) (3,12,13). Surgery remains the preferred treatment for the majority of GISTs. Appropriate adjuvant therapies can be employed based on the results of tumor risk stratification and genetic testing. Although most patients initially respond to the KIT/PDGFRA tyrosine kinase inhibitor imatinib, they will eventually become resistant. First-line therapy for advanced GISTs using imatinib can achieve remission or tumor control in over 80% of patients. Nevertheless, Blay et al. reported that approximately 50% of patients with advanced GISTs experienced progressive disease (PD) within 24 months, and the projected 10-year progression-free survival (PFS) rate was 9% (14). Imatinib resistance is divided into primary and secondary forms. Secondary resistance predominantly occurs due to the emergence of secondary mutations within the KIT gene, leading to its reactivation (15). Following imatinib treatment, a 70.7% incidence of secondary mutations among patients with KIT exon 11 mutations has been reported, with KIT exon 17 mutation being the most frequently observed (54.4%), followed by mutations in KIT exon 13/14 (16). Primary and secondary drug resistance remains a major problem for patients and a significant challenge to their survival and quality of life in terms of reducing post-operative recurrence or halting disease progression (17,18).

In our present case, the patient initially presented with an acute abdomen resulting from tumor rupture, which can occur in patients who are asymptomatic in the early stage of the tumor and have not undergone digestive endoscopy or imaging studies. Tumor rupture is recognized as a substantial risk factor that influences tumor recurrence and disease-free survival (DFS) (19). Tumor rupture is significantly correlated with recurrence in patients undergoing resection with positive microscopic margins (R1 resection). In a systematic review and meta-analysis conducted by Kong et al., the recurrence-free survival (RFS) or DFS was significantly shorter in the R1 group than in the R0 group among patients experiencing GIST rupture; in contrast, among patients without GIST rupture, R1 resection did not adversely impact the prognostic outcomes of resectable GISTs when compared to R0 resection (20) (Figures 3,4). In the absence of tumor rupture, the majority of patients undergoing R1 resection did not experience recurrence (19,21). McCarter et al. (21) retrospectively analyzed a cohort of 819 patients with GISTs, wherein 72 patients underwent R1 resection. Patients with tumor rupture had a 3-year RFS rate of 60%, versus 80% for those without rupture. Excluding tumor rupture, R1 patients had a 3-year RFS rate of 79%, similar to R0 patients at 80%. Significant risk factors associated with R1 resection included tumor size (>10 cm), location of GISTs outside the stomach and small intestine, and tumor rupture (21).

Figure 3 Forest plot of RFS/DFS. This figure was reused with the permission from Elsevier (20). SE, standard error; IV, instrumental variable; CI, confidence interval; df, degree of freedom; R0, negative microscopic margin; R1, positive microscopic; RFS, recurrence-free survival; DFS, disease-free survival.

Figure 4 Forest plot of RFS/DFS without tumor rupture. This figure was reused with the permission from Elsevier (20). SE, standard error; IV, instrumental variable; CI, confidence interval; R0, negative microscopic margin; R1, positive microscopic; RFS, recurrence-free survival; DFS, disease-free survival.

Following surgical intervention, tumors in our present case were categorized as high-risk according to the risk stratification criteria for primary GISTs (22) (Table 1). In addition, genetic testing revealed a mutation in the C-KIT exon 11. Adjuvant therapy with imatinib was administered for a duration of three years. One year following the medication discontinuation, the patient was diagnosed with multiple recurrences within the abdominal cavity. Following re-initiation of imatinib therapy, some lesions showed satisfactory regression, whereas others exhibited negligible regression. Given the presence of drug resistance, the patient was re-assessed, and the results showed that an R0 resection was possible. Genetic testing following a second surgery indicated a mutation in the C-KIT gene, specifically within exons 11 and 17. An in vitro kinase inhibition study demonstrated that ripretinib potently inhibited KIT mutations in exons 11, 13, 14, and 17 and PDGFRA mutations in exon 18. In contrast, imatinib, sunitinib, and regorafenib failed to inhibit the KIT exon 17 D816V mutation (23). In a subgroup analysis of the phase 3 INTRIGUE study, which compared ripretinib to sunitinib as second-line therapy in a head-to-head fashion, it was observed that in patients harboring KIT exon 17/18 mutations, the median PFS (mPFS) was 14.2 months for ripretinib versus 1.5 months for sunitinib, the objective response rate (ORR) was 44.4% for ripretinib versus 0% for sunitinib, and overall survival (OS) was not evaluable (NE) for ripretinib compared to 17.5 months for sunitinib (24). Due to the presence of a secondary mutation in the KIT gene, adjuvant therapy with ripretinib was initiated. No tumor recurrence was detected at the six-month and one-year follow-up visits.

Several issues in the diagnosis and treatment of this patient require further discussion

Question 1: Is neoadjuvant therapy recommended for a patient with a large GIST that has not ruptured?

Expert opinion: Dr. Nicolò Fabbri

Currently, in cases of large GISTs, neoadjuvant therapy is recommended for all patients who can tolerate it, although the primary treatment approach remains radical R0 surgery.

In cases of large GISTs resected without contamination during surgery, the rationale for this choice lies in the ability of GISTs to spread both by proximity and through the bloodstream. This suggests that postoperative therapy with imatinib may reduce complications by eliminating residual tumor cells.

Question 2: For patients undergoing surgery for tumor rupture, are there other treatment options besides oral targeted therapy to reduce the risk of recurrence?

Expert opinion: Dr. Nicolò Fabbri

In patients undergoing surgery for GIST who experienced tumor rupture, in addition to en bloc resection and oral adjuvant therapy (preferably with a combination protocol rather than imatinib monotherapy), it may also be useful to evaluate the use of intraoperative hyperthermic chemotherapy.

However, this approach requires confirmation through experimental studies, which are currently unavailable, and should be assessed by a multidisciplinary team and reserved for centers with adequate experience.

Question 3: For patients who need adjuvant therapy, is it necessary to switch to a drug with more targets after a period of treatment with imatinib to reduce the risk of relapse?

Expert opinion: Dr. Nicolò Fabbri

For patients undergoing adjuvant therapy, the most advanced treatment protocols should consider combining multiple drugs, particularly to reduce the risk of recurrence in the first five years, when the recurrence rate is highest. This is especially relevant in cases of tumors less sensitive to first-line imatinib.

Currently, the first line of treatment is imatinib, the second is sunitinib, and the third is regorafenib.

Based on current clinical experience and biological knowledge of the disease, there is evidence that re-challenging with imatinib may provide some benefit in slowing the progression of overt disease.

Question 4: In patients with multiple lesions, how can you distinguish between primary and secondary lesions?

Expert opinion: Dr. Nicolò Fabbri

In patients with multiple synchronous GIST lesions, the first approach to distinguishing between synchronous tumors and metastases from a primary tumor is to examine the origin of the lesion. It is known that GIST incidence is higher in the small intestine and stomach, while it is extremely rare in more distal locations, although documented cases of rectal GISTs do exist.

However, GIST-like masses outside the gastrointestinal tract should never be considered primary lesions.

Conclusions

Surgery remains an important treatment option for GISTs. As multiple recurrences occurred in our present case, the timing of surgery was carefully selected based on the therapeutic response to the medications. Adjuvant therapy was administered according to the results of genetic testing, with simultaneous monitoring and adjustments for drug resistance and the emergence of secondary gene mutations. However, as the postoperative follow-up interval was only 1 year following the recurrences, further follow-up surveillance is warranted.

Acknowledgments

Funding: This study was supported in part by Chengdu Third People’s Hospital (No. CSY-YN-01-2023-036 to Y.W.).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gist.amegroups.com/article/view/10.21037/gist-24-8/rc

Peer Review File: Available at https://gist.amegroups.com/article/view/10.21037/gist-24-8/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gist.amegroups.com/article/view/10.21037/gist-24-8/coif). Y.W. reports grant support from the Chengdu Third People’s Hospital (No. CSY-YN-01-2023-036). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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