Advances in the Treatment of Rare Gastrointestinal Stromal Tumors - A Discussion

Introduction:

Submucosal tumors (SMTs) consist of a varying range of lesions protruding from the GI (gastrointestinal) tract wall covered with intact mucosa. They can possibly arise from any layers beneath the epithelium including, muscularis mucosa, submucosa, muscularis propria, and serosa. They are further divided into tumors that do not have malignant potential, such as lipomas, mesenchymal tumors, schwannomas, leiomyomas, desmoid tumors, pancreatic rests, inflammatory fibroid polyps, duplication cysts, and giant cell tumors. Tumors with a malignant potential include granular cell tumors, glomus tumors, carcinoids, and gastrointestinal stromal tumors (GISTs). GISTs are the most common type of SMTs in the upper gastrointestinal tract. Among the submucosal tumors, GIST is the most common mesenchymal tumor and the most prevalent intramural submucosal tumor compared to others occurring in the GI tract.

What Is the Etiology, Incidence, and Prevalence of Gastrointestinal Stromal Tumors?

The incidence of gastrointestinal stromal tumors in clinical settings has been steadily increasing, however, its prevalence is exactly unknown. Gastrointestinal stromal tumors are arising from the interstitial cells of Cajal. The majority of the GISTs occur as a result of a mutation in the platelet-derived growth factor receptor alpha gene, or c-kit gene. Another type called wild-type GISTs, may not have these mutations, and they account for up to 15 % of GISTs.

What Are the Symptoms of Gastrointestinal Stromal Tumors?

Small gastrointestinal stromal tumors usually do not produce any signs or symptoms. As they grow in size, patients visit the clinic with abdominal pain, gastrointestinal bleeding due to mucosal ulceration, or obstruction due to the mass effect. Mostly, gastrointestinal stromal tumors look like spindle cell tumors, but they can also be epithelioid or mixed types. GISTs can be of varying sizes, ranging from 2.7 centimeters to 8.9 centimeters. Patients who have gastrointestinal stromal tumors are mostly asymptomatic. In case of an increase in the size of the GISTs, patients may present to the clinic with various symptoms pertaining to the location of the tumor. They are commonly seen in the small bowel or the stomach. A suspected GIST on imaging and endoscopic studies can be confirmed with immunohistochemical staining. The size, location, and mitotic index help in studying the aggressiveness of tumors.

• Around 50 % of cases present mucosal ulceration over the luminal surface of the gastrointestinal stromal tumors.

• Gastric GISTs can cause melena, nausea, dyspepsia (indigestion), hematemesis (vomiting blood), vomiting, or early satiety.

• Duodenal GISTs can be round or oval and have well-defined subepithelial masses. They are usually located in the duodenum and do not cause any duodenal obstruction or lymphadenopathy. However, they can result in bleeding, jaundice, and ampullary obstruction. They can also spread often to the peritoneum and liver. About 15 % of duodenal GISTs and 10 % of cases of gastric GISTs can present with GI bleeding.

• Gastrointestinal stromal tumors of the small intestine can present with fatigue, small bowel bleeding, intestinal obstruction, and abdominal pain. They cause acute pain compared to duodenal gastrointestinal stromal tumors. Out of the GISTs occurring in the small intestine, 40 % occur in the jejunum and 60 % in the ileum. In esophageal GISTs, there can be dysphagia.

• Abdominal masses are found in omental or mesenteric GISTs. Out of these eight percent of cases usually present with an emergency as a result of peritonitis and small bowel rupture. Tumor rupturing into the peritoneal cavity is a very rare incidence and complicates into peritoneal tumor cell seeding and intraabdominal bleeding. The GISTs often are found to spread to the intra-abdominal cavity and liver. Less often they metastasize to the bones and lungs.

• Anorectal GISTs range an average size of 6.9 cm, and they are well-defined sub-epithelial tumors representing five percent of all GISTS. They are asymptomatic and usually identified in endoscopic or imaging studies. Some patients may complain of rectal bleeding (25 %) or proctalgia (34 %).

How Are Gastrointestinal Stromal Tumors Diagnosed?

Gastrointestinal stromal tumors are accidentally found in three percent of cases during endoscopy procedures for other problems, as these tumors are mostly asymptomatic. Endoscopic ultrasound will help in better visualization of the origin, size, extension, feeding vessels, features of malignancy, and associated lymph node involvement. A histopathological diagnosis can also be confirmed through fine needle aspiration, biopsy, and cytology, as conventional endoscopic biopsies are not beneficial or have low benefits.

Gastric GISTs are classified into four types endo-sonographically based on their location in the muscularis propria (MP):

• Type I GIST: These tumors protrude like a polyp into the lumen. It is seen attached by a narrow connection with the muscularis propria.

• Type II GIST: These also seem to be protruding into the lumen. But these are attached by a wider connection to the muscularis propria.

• Type III GIST: These are located in the center of the gastric wall.

• Type IV GIST: It seems to protrude outwards towards the serosa of the gastric wall.

How Are Gastrointestinal Stromal Tumors Managed?

According to the ASGE (American Society for Gastrointestinal Endoscopy) recommendations, surveillance endoscopic ultrasound (EUS) is suggested in gastrointestinal stromal tumors that are less than two centimeters in size. Surgery is recommended for colorectal and gastric GISTs that are more than two centimeters in size and those with high-risk malignancy features. In cases of unresectable gastrointestinal stromal tumors, large GISTs, and metastatic GISTs tyrosine kinase inhibitors have been extremely beneficial in the management. Treatment strategies include chemotherapy, radiotherapy, hepatic artery embolization, radiofrequency ablation, and chemoembolization.

What Are the Advances in the Treatment of Rare Gastrointestinal Stromal Tumors?

The mainstay of treatment was either watchful waiting for small, asymptomatic submucosal tumors or surgical excision for complicated and larger ones in the past. But, certain studies show that even after the resection of small asymptomatic submucosal tumors, 71 % of them had a malignancy potential. An endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is the conventional endoscopic resection technique beneficial in superficial SMTs. Endoscopic muscularis dissection (EMD) or endoscopic submucosal excavation (ESE) is an advanced form of ESD. This part of the muscularis propria is excised along with the lesion. These techniques, however, had the drawback of incomplete tumor resection. As a result of the expansion of endoscopic resection techniques and innovation of the third-space endoscopy, certain novel techniques had evolved to overcome the limitations of the conventional methods. due to their curative potential, endoscopic full-thickness resection (EFTR) and submucosal tunneling endoscopic resection (STER) are getting more attention.

Endoscopic Resection:

This procedure is used in gastrointestinal stromal tumors present in the upper gastrointestinal tract that have not spread and there is no recurrence. Various methods of endoscopic resection are there:

1. Endoscopic Band Ligation (EBL): Type III and type IV GISTs can be treated by this method. Small gastric GISTs that are less than four centimeters in size, can be resected safely although high-risk GISTs require adjuvant chemotherapy and recurrence can be treated through EBL.

2. Endoscopic Submucosal Excavation (ESE): Type III and type IV GISTs can be treated by this method.

3. Endoscopic Enucleation: In type 1 and type 2 GISTs this can be done.

4. Endoscopic Submucosal Dissection (ESD): Type III and type IV GISTs can be treated by this method.

5. Submucosal Tunneling Endoscopic Resection (STER): Type III and type IV GISTs can be treated by this method.

6. Endoscopic Full-Thickness Resection (EFTR): Type III and type IV GISTs can be treated by this method.

7. Laparoscopic and Endoscopic Cooperative Surgery (LECS): Type III and type IV GISTs can be treated by this method.

Conclusion:

The incidence of gastrointestinal stromal tumors has increased by a significant amount in the past few decades. The advancements in imaging and endoscopic study have led to the increased detection of these tumors. Since it is an important gastrointestinal tumor, and remain asymptomatic, they have to be managed when found in imaging studies that are done for other symptoms or conditions.