Gastrointestinal Stromal Tumor: Epidemiology, Pathogenesis, Risk Factors, Symptoms, Diagnosis, Treatment and Prognosis

Gastrointestinal Stromal Tumour (GIST): Pathobiology, Clinical Features, Diagnosis, and Evolving Therapeutic Strategies

Gastrointestinal Stromal Tumour (GIST) is the most common mesenchymal neoplasm of the gastrointestinal (GI) tract, arising from the interstitial cells of Cajal (ICCs) or their precursors. These tumors represent a distinct clinical and molecular entity characterized by activating mutations in receptor tyrosine kinases, most notably KIT and PDGFRA. While GISTs account for only about 1–3% of all GI tract malignancies, they hold significant clinical importance due to their unique biology, potential for malignant transformation, and responsiveness to targeted therapy.

~Introduction and Epidemiology

GISTs were historically misclassified as leiomyomas or leiomyosarcomas until the discovery of KIT expression clarified their origin. They can occur anywhere along the gastrointestinal tract, with the following distribution:

• Stomach: ~60–70% of cases

• Small intestine: 20–30%

• Colon/rectum: 5%

• Esophagus: <5%

• Extra-GI locations (e.g., mesentery, omentum): rare

GISTs occur predominantly in adults aged 40–70, although they may also appear in children and young adults, particularly in association with hereditary syndromes. Slight male predominance is observed, and incidence worldwide ranges from 10 to 20 cases per million annually.

~Origin and Pathogenesis

GISTs originate from interstitial cells of Cajal (ICCs), the pacemaker cells regulating peristalsis in the GI tract. Their pathogenesis is primarily driven by gain-of-function mutations in genes encoding receptor tyrosine kinases.

1. Molecular Drivers

a. KIT Mutations

• Present in ~75–80% of GISTs.

• Typically involve exons 11, 9, 13, or 17.

• Lead to constitutive activation of KIT signaling and uncontrolled cell proliferation.

b. PDGFRA Mutations

• Occur in ~8–10% of GISTs.

• Most frequently affect exon 18, including the well-known D842V mutation, which confers resistance to imatinib.

c. Wild-Type (WT) GIST

GISTs lacking KIT or PDGFRA mutations comprise ~10–15% and include:

• SDH-deficient GISTs

• BRAF-mutated GISTs

• NF1-associated GISTs

These subtypes have distinct biological behavior and therapeutic responses.

~Risk Factors and Hereditary Syndromes

Most GISTs occur sporadically, but some are associated with inherited syndromes:

1. Neurofibromatosis Type 1 (NF1)

• Patients may develop multiple small-intestinal GISTs.

• Typically lack KIT/PDGFRA mutations.

2. Carney Triad

A rare condition typically affecting young women, characterized by:

1. GIST

2. Pulmonary chondromas

3. Paragangliomas

3. Carney–Stratakis Syndrome

• Caused by germline SDH mutations.

• Involves GIST and paraganglioma.

SDH-deficient tumors often present in younger patients and show resistance to standard tyrosine kinase inhibitor (TKI) therapy.

~Clinical Presentation

Symptoms depend on tumor location, size, and presence of complications. Many GISTs remain asymptomatic for years.

1. Common Symptoms

• Abdominal pain or discomfort

• Early satiety

• Fatigue (often due to chronic blood loss)

• Nausea or vomiting

2. GI Bleeding

One of the most frequent presenting symptoms, caused by ulceration of the overlying mucosa. Patients may experience:

• Hematemesis

• Melena

• Occult bleeding leading to anemia

3. Mass Effect and Complications

Large tumors may cause:

• Abdominal distention

• Bowel obstruction

• Perforation (rare but life-threatening)

4. Metastasis

GISTs typically metastasize via the bloodstream, most commonly to:

• Liver

• Peritoneum
  Lymph node metastasis is rare.

~Diagnosis

1. Imaging Studies

a. Contrast-enhanced CT scan

The primary imaging modality for:

• Detecting tumor location and size

• Evaluating invasiveness

• Assessing metastasis

GISTs often appear as well-defined masses, sometimes with central necrosis.

b. MRI

Useful for:

• Rectal GIST evaluation

• Liver metastasis characterization

c. PET Scan

Detects early metabolic response to therapy, especially imatinib.

2. Endoscopic Techniques

a. Endoscopy

Helps visualize intraluminal masses or mucosal ulcerations.

b. Endoscopic Ultrasound (EUS)

Highly valuable for:

• Assessing tumor layer of origin (usually the muscularis propria)

• Guiding fine-needle aspiration (FNA) biopsy

3. Histology and Immunohistochemistry

GISTs have:

• Spindle cell, epithelioid, or mixed morphology.

Key immunohistochemical markers:

• CD117 (KIT): Positive in ~95% of cases

• DOG1: Highly sensitive marker, used particularly in KIT-negative tumors

• CD34: Positive in ~70%

• SDHB: Negative in SDH-deficient GISTs

Biopsy is typically avoided for resectable tumors due to risk of bleeding or tumor rupture but is essential in metastatic or unresectable cases.

~Risk Stratification

Risk of recurrence depends on:

1. Tumor size

2. Mitotic index

3. Tumor location

For example:

• Gastric GISTs generally have a better prognosis than small-intestinal GISTs of the same size and mitotic rate.

Standard systems include:

• NIH-Fletcher criteria

• AFIP-Miettinen classification

These help guide decisions regarding adjuvant therapy.

~Treatment Approaches

1. Surgical Resection

The primary treatment for localized GIST.

Goals:

• Complete resection with negative margins (R0 resection)

• Avoid tumor rupture (strongly associated with recurrence)

• Lymph node dissection is not routinely performed due to low incidence of nodal metastasis

Approaches:

• Laparoscopic surgery for small tumors

• Open surgery for large or complex tumors

2. Tyrosine Kinase Inhibitor (TKI) Therapy

The discovery of imatinib revolutionized GIST treatment.

a. Neoadjuvant Therapy

Used to shrink large or borderline-resectable tumors—especially near critical structures—to enable safer surgery.

b. Adjuvant Therapy

Indicated for high-risk tumors after surgery, typically:

• Imatinib 400 mg daily for 3 years

Significantly reduces recurrence and improves survival.

3. Treatment of Advanced or Metastatic GIST

Standard therapy follows a sequential TKI approach:

1. Imatinib

• First-line treatment.

• Effective in most KIT and some PDGFRA mutations.

• Dose escalation to 800 mg may benefit KIT exon 9 mutations.

2. Sunitinib

• Second-line for imatinib-resistant or intolerant patients.

3. Regorafenib

• Third-line therapy.

4. Ripretinib

• Fourth-line treatment with broad inhibitory activity.

5. Avapritinib

• Highly effective against PDGFRA exon 18 mutations, including D842V.

4. Management of TKI-Resistant GIST

Resistance develops through secondary mutations. Emerging strategies include:

• Combination therapies

• Next-generation TKIs

• Investigational immunotherapies

• Personalized molecular-guided treatment

~Prognosis

Prognosis is influenced by:

• Tumor size

• Location

• Mitotic rate

• Molecular subtype

General Trends:

• Gastric GISTs typically have better outcomes.

• Small (<2 cm) tumors with low mitotic activity have excellent prognosis.

• Metastatic disease, though serious, can be controlled for years with TKIs.

Survival Rates:

• Localized disease: 5-year survival >80%

• Metastatic disease: 5-year survival has improved dramatically with TKI therapy

~Follow-Up and Surveillance

Post-treatment monitoring is crucial due to the risk of recurrence.

Typical follow-up schedule:

• Every 3–6 months for the first 3 years

• Then every 6–12 months up to 10 years

CT scans are the preferred imaging modality.

~Special Considerations

1. Pediatric GIST

• Rare

• Often SDH-deficient

• Higher recurrence but slower progression

• Limited response to imatinib

2. Extra-Gastrointestinal GIST (EGIST)

Occur in mesentery, omentum, or retroperitoneum.

• Similar histology

• Often more aggressive

3. Tumor Rupture

Considered a high-risk factor equivalent to metastatic disease—requires long-term TKI therapy.

~Research and Future Directions

Ongoing studies aim to improve outcomes through:

• Novel TKIs targeting resistant subclones

• Immunotherapies (PD-1/PD-L1 inhibitors, vaccines)

• Combination therapies targeting the tumor microenvironment

• Liquid biopsies (circulating tumor DNA) for real-time monitoring

• AI-enhanced imaging for early detection and better risk stratification

These advancements promise further improvements in survival and quality of life for GIST patients.

~Conclusion

Gastrointestinal Stromal Tumour is a unique and biologically distinct neoplasm of the GI tract, driven primarily by KIT and PDGFRA mutations. Its diagnosis and management have undergone a paradigm shift over recent decades, largely due to the advent of targeted therapy. Early and accurate diagnosis, proper risk stratification, and individualized treatment plans are essential for optimizing outcomes. While localized GISTs can often be cured with surgery, advanced cases are increasingly manageable with precision therapies. Continued research holds the potential to overcome resistance mechanisms and enhance long-term survival.