Characterization of subepithelial tumors of upper gastrointestinal tract by endoscopic ultrasound

Abstract

In this article we comment on the paper by Xu et al describing retrospective data on endoscopic treatment outcome of esophageal gastrointestinal stromal tumors (GISTs). Esophageal GIST is a rare type of mesenchymal tumor. GISTs originate from the interstitial cells of Cajal, which are pacemaker cells involved in gut motility. GISTs are most commonly found in the stomach and small intestine, but esophageal involvement is rare. Esophageal GISTs account for < 1% of all GISTs. Endoscopic resection remains the mainstay for small, localized tumors with excellent outcomes. However, larger tumors may require multidisciplinary strategies to provide the best oncological outcomes. Here, we discuss the usefulness of endoscopic ultrasound (EUS) of subepithelial tumors of the upper gastrointestinal tract. EUS is a crucial tool in the diagnosis, staging, and management of subepithelial masses. Given the subepithelial nature of these tumors, standard endoscopy is not adequate, making EUS essential for a comprehensive assessment. EUS provides accurate tumor size assessment and enables fine needle aspirations guided biopsy, for treatment planning.

Key Words: Subepithelial tumors; Esophageal gastrointestinal stromal tumors; Endoscopic ultrasound; Artificial intelligence; Endoscopic resection

Core Tip: Esophageal gastrointestinal stromal tumor (GIST) is a rare type of mesenchymal tumor. Esophageal GISTs account for < 1% of all GISTs. Endoscopic resection remains the mainstay for small, localized tumors with excellent outcomes. Endoscopic ultrasound (EUS) is a crucial tool in the diagnosis, staging, and management of esophageal GIST. Given the submucosal nature of these tumors, standard endoscopy is not adequate, making EUS essential for a comprehensive assessment. EUS provides accurate tumor sizing, and enables fine needle aspiration guided biopsy of carefully selected large inoperable tumors or where diagnosis is in doubt, which is critical for risk stratification and treatment planning.

TO THE EDITOR

In this article we comment on the paper describing retrospective data on endoscopic treatment outcome of esophageal gastrointestinal stromal tumors (GISTs) by Xu et al[1] in World Journal of Gastroenterology. The authors performed endoscopic resection of the esophageal subepithelial lesions with optimal outcomes (R0 resection). However, it is not clear if the authors performed endoscopic ultrasound (EUS) prior to the planned resection to assess the tumor size and other aspects necessary for surgical planning. We discuss some salient points associated with esophageal GISTs and the role of EUS in treatment of these tumors. The common subepithelial tumors of the upper gastrointestinal tract are GISTs, lipomas, leiomyoma, carcinoid tumors and ectopic pancreatic tissue. These lesions are diagnosed and differentiated based on their unique histochemical staining and the gastrointestinal layer of origin. Most lesions are identified incidentally and considered benign; however, some tumors such as GISTs and carcinoids have a strong propensity for malignant transformation[2,3].

Esophageal GIST is a rare type of mesenchymal tumor. GISTs originate from the interstitial cells of Cajal, which are pacemaker cells involved in gut motility. These tumors are most commonly found in the stomach and small intestine, and esophageal involvement is rare. Esophageal GISTs account for < 1% of all GISTs. They typically occur in the lower esophagus and are characterized by spindle or epithelioid cells. Most GISTs, including of the esophagus, display mutations in the c-KIT (CD117) or PDGFRA genes. Certain rare molecular, familial types such as neurofibromatosis neurofibromin 1, succinate dehydrogenase, BRAF or NTRK genes are also associated with GISTs and generally show primary resistance to standard tyrosine kinase inhibitors (TKIs)[4,5]. Common symptoms include dysphagia, sensation of food stuck in the esophagus, chest pain or discomfort. This may lead to weight loss. Erosion of the overlying mucosa may cause hematemesis. Smaller lesions may be asymptomatic[3,6].

Diagnostic modalities and tumor markers

Diagnostic modalities include upper gastrointestinal endoscopy, which may detect a submucosal bulge into the esophageal lumen and may have superficial ulcerations. Biopsy is usually not necessary as it may lead to capsule disruption and tumor spread. EUS helps assess tumor size, morphology and depth[6,7]. However current endoscopic imaging tools struggle to differentiate GISTs from leiomyomas. Recently, a few studies have demonstrated that incorporation of real-time artificial intelligence (AI) systems during EUS examinations can assist endoscopists in rapidly and accurately differentiating various types of subepithelial tumors of the upper GI tract, facilitating improved diagnostic and therapeutic decision-making. A cohort of 59 participants with subepithelial tumors was prospectively enrolled and compared to that of endoscopists to assess the real-time clinical application of the AI system. The AI system was superior in differentiating between GISTs and leiomyomas diagnosis, respectively, markedly surpassing endoscopists[8].

Similarly, an automatically optimized radiomics modeling system (AORMS) based on EUS images was evaluated for the diagnosis and the risk stratification of gastric GIST. A total of 205 patients with EUS images of small (< 2 cm) gastric GISTs were retrospectively enrolled in the development phase of AORMS and compared to 178 patients with images obtained by endoscopists from different centers. The performance of AORMS was compared to that of endoscopists in the development set and evaluated in the independent testing set. AORMS outperformed endoscopists by > 20% in diagnosing small gastric GISTs[9]. A computed tomography scan of the abdomen and pelvis is necessary for assessment of the size of the mass, regional lymphadenopathy (although uncommon with GIST) and local extraluminal abutment associated with these tumors. The characteristic biomarkers associated differentiating these tumors from other mesenchymal tumors of the gastrointestinal tract include immunochemistry markers positive for c-KIT (CD117), discovered on GIST 1 (DOG 1), and smooth muscle actin[3-5].

Esophageal GISTs are subepithelial tumors and out of reach of conventional biopsy forceps and pose a diagnostic challenge for gastroenterologists. Standard upper endoscopy is inadequate, making EUS essential for a comprehensive assessment[7-9]. EUS is indispensable in diagnosing and managing subepithelial gastrointestinal tumors. It provides detailed imaging, enables guided biopsy, aids in risk assessment, and helps guide treatment decisions. EUS provides accurate tumor sizing and delineates tumor borders with high resolution, which is critical for risk stratification and treatment planning. EUS is useful to confirm the layer of origin, as these tumors arise from the muscularis propria or submucosa which is typical for GISTs. Benign small tumors are generally hypoechoic with well-delineated borders. Heterogeneous echotexture may indicate necrosis or malignancy. Use of contrast-enhanced EUS has demonstrated the ability to differentiate GISTs with early and clear enhancement from leiomyomas that displays little or no enhancement[6,10].

EUS-fine needle aspiration (FNA) enables histological and immunohistochemical analysis [CD117, discovered on GIST (DOG-1) etc.] to confirm the diagnosis. However, some studies have demonstrated that EUS-FNA tissue acquisition does not reliably reflect the mitotic index and GIST proliferation[11]. Smaller lesions (< 2 cm) have a poor diagnostic yield with EUS-FNA. Biopsy is generally not necessary for smaller tumors as it may lead to capsule disruption and tumor spread and it may be feasible to proceed immediately with endoscopic resection for histological diagnosis. Pre-resection EUS, however, will help assess tumor size and depth. Resection of small subepithelial lesions of ≤ 2 cm can be accomplished en bloc with an endoscopic cap band mucosectomy device[6,7].

If FNA is inconclusive, EUS-guided core biopsy may be needed. It is especially useful when distinguishing GISTs from other submucosal lesions such as leiomyomas, schwannomas and malignant sarcomas. For larger lesions, tissue diagnosis is necessary. For larger lesions of the fourth hypoechoic layer, EUS-FNA and core biopsy are safe and have a good diagnostic yield. EUS features, suggestive of high malignant potential include heterogeneous mass with irregular borders, ulceration of overlying mucosa, size > 5 cm, and presence of enlarged lymph nodes[7].

Management modalities

The primary treatment for localized esophageal GIST < 3 cm is surgical resection with a disease-free, 1-mm margin, i.e., R0 resection. In carefully selected patients this may be accomplished by endoscopic enucleation as is demonstrated by Xu et al, with optimal results and excellent prognosis[1]. Larger lesions may pose a significant problem due to their location and abutment into the periesophageal tissues and organs and require a careful multidisciplinary approach. Minimally invasive approaches, i.e., robotic-assisted abdominal laparoscopy or thoracoscopy, can be considered for resection. There is no indication routinely to perform lymph node dissection, as most GISTs do not metastasize to lymph nodes with the possible exception of some succinate-dehydrogenase-deficient GISTs, which may metastasize to lymph nodes. Esophagectomy is usually not necessary; however, it may be required if the tumor is larger and does not respond to neoadjuvant therapy[4,5,7]. Targeted therapy with TKIs is necessary as first-line treatment for unresectable, metastatic, or high-risk GISTs. Imatinib (400 mg daily orally for 6 months) is most commonly used to shrink large locally invasive tumors and make them amenable for resection. However, there remains a proportion of patients with tumors resistant to imatinib and other newer second- and third-generation TKIs are recommended, i.e., sunitinib and regorafenib, respectively, as well as the new broad-spectrum TKI ripretinib[4,5].

Prognosis

The prognosis of esophageal GIST depends on several factors, including tumor size, mitotic index, nongastric site, tumor rupture and presence of metastases[4]. Esophageal GISTs are rare and tend to have a worse prognosis compared to GISTs from other parts of the gastrointestinal tract. The prognosis depends on several factors, including tumor size, mitotic rate, molecular mutations, and resectability. In general, smaller tumors < 2 cm with a low mitotic index have an excellent prognosis after complete resection. Tumor size (≥ 10 cm) and high mitotic rate (> 5/5 mm²) with deletion mutation in KIT exon 11 involving codons 557–558 and a positive microscopic margin are associated with increased risk for recurrence and metastasis[12]. KIT/PDGFRA mutations may influence response to therapy. Some PDGFRA mutations are resistant to imatinib. For large tumors with a high mitotic index, adjuvant therapy with imatinib 400 mg daily for 3 years is recommended to reduce recurrence[3,5,7]. The 5-year survival rates vary; for localized disease (completely resected, small tumors with low mitotic index) it is greater than 70%–80%. For higher risk features, i.e., large tumors with high mitotic index, the 5-year survival decreases to 30%–50%, while for metastatic or unresectable tumors, the survival is < 20%. The overall 5-year disease-free survival and disease-specific survival were 65.1% and 65.9%, respectively[13]. Surveillance with computed tomography scan or magnetic resonance imaging is recommended every 6 mo to yearly for 5 years[3,5,7].

Conclusion

Esophageal GIST is a rare type of mesenchymal tumor. Esophageal GISTs account for < 1% of all GISTs. Endoscopic resection remains the mainstay for small, localized tumors, with excellent outcomes. EUS is a useful tool in the diagnosis, staging and management of esophageal GIST. Given the submucosal nature of these tumors, standard endoscopy is inadequate, making EUS essential for a comprehensive assessment. EUS provides accurate tumor sizing, and enables FNA-guided biopsy for carefully selected large inoperable tumors or where diagnosis is in doubt, which is critical for risk stratification and treatment planning.