Gastrointestinal Stromal Tumour

• Most common mesenchymal tumour; interstitial cells of Cajal
• Characteristic c-KIT expression; treatable with tyrosine kinase inhibitor
• Middle-aged and elderly adults, Carney triad
• Well-circumscribed, enhancing submucosal mass in the stomach or small bowel. Benign or malignant.

Description

Gastrointestinal stromal tumour (GIST) is a distinctive form of neoplasm that originates from the interstitial cells of Cajal or their stem cell-like precursors within the muscularis propria layer of the gastrointestinal tract. They are known for their variable biological behaviour ranging from small incidentally detected benign lesions (majority of GISTs) to aggressive, malignant tumours. They represent the most common mesenchymal tumour of the gastrointestinal tract.

Pathogenesis

GISTs primarily arise due to mutations in the KIT (75-80%) or PDGFRA (5-10%) genes, resulting in uncontrolled cell growth and division. The remainder of GISTs are termed ‘wild type’ and are negative for KIT and PDGFRA mutations. Subtypes of GISTs are mainly determined by the specific mutation and the location within the gastrointestinal tract.

Epidemiology, Risk Factors & Associations

Although 80% of gastrointestinal sarcomas are GISTs, they are relatively rare with an estimated incidence of 10-20 cases per million population. They typically present in adults over the age of 50, with an equal incidence in men and women. There are no established lifestyle risk factors.

Vast majority are sporadic. However, certain genetic syndromes increase the risk of GISTs:

• Neurofibromatosis Type 1 (von Recklinghausen’s disease): This autosomal dominant disorder affects approximately 1 in 3,000 people. GISTs are found in 3.9-25% of patients with this condition, typically in the small bowel. GISTs in NF1 patients do not exhibit the common KIT or PDGFRA mutations.
• Carney-Stratakis Syndrome: This autosomal-dominant condition leads to the development of GISTs and paragangliomas in affected individuals. It is caused by a germline mutation in the SDHB, SDHC, or SDHD genes. The exact incidence is unknown but it is considered extremely rare.
• Carney Triad: This non-hereditary condition involves the triad of gastric GIST, pulmonary chondroma, and extra-adrenal paraganglioma. It typically affects young women. It is extremely rare, with less than 100 cases reported as of 2021.
• Familial GIST syndrome: This is caused by germline mutations in the KIT (more common) or PDGFRA genes. It is very rare, and the exact incidence is unknown.

Clinical Features

Clinical manifestations of GISTs are non-specific and are largely dependent on the location and size of the tumour. Some patients may remain asymptomatic. When symptoms do arise, they can include gastrointestinal bleeding (leading to anaemia and associated fatigue), abdominal pain, or a palpable abdominal mass. Acute presentation can occur with complications such as bowel obstruction or perforation.

Can occur anywhere along gastrointestinal tract:

• Stomach (60%)
• Jejunum and ileum (30%)
• Duodenum (5%)
• Rectum (3%)
• Colon (1%)
• Oesophagus (< 1%)

In up to 10% of cases, GISTs can occur outside the gastrointestinal tract (retroperitoneum, mesentery, omentum).

Complications

Potential complications of GISTs include

• Ulceration leading to gastrointestinal haemorrhage
• Bowel obstruction due to mass effect
• Perforation and peritonitis.

Additionally, malignant GISTs have the potential to metastasise, most commonly to the liver and peritoneum.

Pathological Features

Morphology

GISTs often appear as well-circumscribed, non-encapsulated masses. The cut surface can be whorled, with areas of haemorrhage or necrosis in larger tumours.

Histopathology

Macroscopic

Size is subdivided into four categories:

• ≤2 cm
• >2 cm to ≤5 cm
• >5 cm to ≤10 cm
• >10 cm

Tumours greater than 5 cm are more likely to be malignant.

Microscopic

GISTs can have a spindled (70%), epithelioid (20%), or mixed morphology (10%).

Biochemistry

GISTs typically express the protein KIT (CD117), detected in 95% of cases. 70% stain positive for CD34.

Genetics

• c-KIT gene: An oncogene that encodes for a transmembrane growth factor receptor called CD117. >90% of GIST patients have mutations, leading to increased tyrosine kinase activity and altered cell growth
• PDGFRA gene: An oncogene associated with intracellular signalling pathways similar to c-KIT. Less than 10% of GIST patients have PDGFRA mutations.

Immunohistochemistry

Immunohistochemical staining for KIT and DOG1 can aid in the diagnosis of GISTs.

Radiological Features

General

• GISTs are located within the wall of the gastrointestinal tract and may cause non-obstructive luminal narrowing or mass effect on adjacent structures.
• Small GISTs are round, well-defined and demonstrate avid, homogeneous arterial enhancement with an intramural growth pattern.
• Large GISTs are lobulated and demonstrate mild, heterogeneous, gradual enhancement and heterogeneity with intratumoral cystic/necrotic change – more likely high-grade/malignant. They have a transmural or intra/extraluminal growth pattern and invade adjacent structures (uncommon)
• Calcification is uncommon
• Features suggesting malignancy:
  • Exogastric growth
  • Diameter >5 cm
  • Central necrosis
  • Extension to other organs
• Lymph node enlargement is not a classic feature
• Central necrosis is characteristic.
• A gastric GIST may have mucosal ulceration.

CT

• Modality of choice for examination
• A well-defined soft-tissue exophytic mass, inseparable from gastric or bowel wall.
• Smaller GISTs demonstrate avid arterial enhancement whereas larger GISTS demonstrate more heterogenous enhancement
• Peripheral enhancement with central low-density suggests necrosis. Fluid-fluid levels, intratumoral gas and pooling of contrast may be seen in larger masses.

MRI

• Variable appearance based on necrosis/hemorrhage.
• T1: Low signal solid component
• T2: High signal solid component
• T1 C+: Larger lesions demonstrate mild heterogenous gradual enhancement. Smaller lesions demonstrate strong homogenous arterial enhancement.
• Necrotic/haemorrhagic areas have varying signal intensity.
• Viable tumour demonstrates avid enhancement.
• Possible detection of liver and peritoneal/serosal metastatic disease.
• Intratumoural cystic changes and lower mean ADC values indicate higher malignancy risk in GISTs.

PET

• FDG-PET: Useful for staging and response to therapy. Central areas of photopaenia suggest necrosis.

Diagnosis

The diagnosis of Gastrointestinal Stromal Tumors (GISTs) is based on specific criteria as outlined in the WHO classification of soft tissue and bone tumours (5th edition). The essential criteria for diagnosis include:

• Location: The tumour must be intramural, submucosal, or subserosal within the gastrointestinal tract.
• Morphology: The tumour cells should have spindle cell, epithelioid, or mixed cell morphology.
• Immunopositivity: The tumour should test positive for KIT (CD117) and/or DOG1 (Discovered on GIST-1), which are protein markers commonly found in GISTs.
• SDHB Gene Mutation: In GISTs that are SDH-deficient (a less common subtype), a mutation in the SDHB gene must be present.

Additionally, there are desirable criteria for a comprehensive diagnosis:

• KIT or PDGFRA Gene Mutations: Approximately 85% of GISTs have mutations in either the KIT or PDGFRA genes, which play a role in tumour growth and development.

Grading and Staging

The staging of GISTs is based on tumour size, location, and mitotic rate. The higher the size and mitotic rate, the more aggressive the tumour is likely to be.

Differential Diagnosis

Imaging-based

• Leiomyoma: Often shares the same location as GISTs, typically in the gastrointestinal tract. Leiomyomas usually have well-defined margins and are less likely to be ulcerated or necrotic compared to GISTs. On histology, they are smooth muscle tumours, positive for Desmin and negative for CD117, in contrast to GISTs. Radiologically, these typically appear as well-circumscribed, homogeneous lesions on CT and MRI. They enhance uniformly after contrast administration and usually lack the necrotic or cystic changes that may be seen in GISTs.
• Leiomyosarcoma: Similar to leiomyoma but malignant. Leiomyosarcomas are often larger and show more aggressive features on imaging compared to GISTs. Histologically, they show significant nuclear pleomorphism and high mitotic rate, and are Desmin positive and CD117 negative. On CT imaging, leiomyosarcomas often appear as large, heterogeneous masses with areas of necrosis or haemorrhage. On MRI, they show a heterogeneous signal intensity on both T1- and T2-weighted images, which is different from the more uniform signal seen in GISTs.
• Schwannoma: A neurogenic tumour that can occur anywhere in the body, including the gastrointestinal tract. Schwannomas usually have a ‘target sign’ on T2-weighted MRI images, with a hyperintense centre and hypointense rim, unlike GISTs. Histologically, they are S100 positive and CD117 negative. On CT, schwannomas typically present as a well-defined mass with a heterogeneous enhancement after contrast. On MRI, a characteristic ‘target sign’ may be seen, with a hyperintense centre and hypointense rim on T2-weighted images, which is not seen in GISTs.
• Adenocarcinoma: Typically found within the stomach or small bowel. Adenocarcinomas are more likely to present with weight loss, anaemia, or signs of bowel obstruction. They are typically negative for CD117 and DOG1 on immunohistochemistry. These typically present as irregular, poorly defined masses and are rarely a large exophytic mass (like GIST). They usually more circumferential (diffuse type) which limits gastric distension and peristalsis.
• Lymphoma: Histologically, lymphomas show a proliferation of lymphoid cells, and they are CD20 positive in the case of B-cell lymphomas and CD3 positive in T-cell lymphomas. On CT, lymphomas usually present as multiple, homogeneous, low-attenuating circumferential mass which causes non-obstructive aneurysmal dilatation of bowel. It may be associated with lymphadenopathy and splenomegaly. GISTs, in contrast, are typically singular and can be heterogeneous due to areas of haemorrhage or necrosis.
• Metastasis: Metastatic deposits from melanoma, breast, or lung cancer can occasionally mimic GISTs in the gastrointestinal tract. Patient history, the presence of primary malignancy elsewhere, and the existence of multiple lesions could help differentiate metastasis from GIST. Metastases will not stain for CD117 or DOG1, unlike GISTs. Metastatic lesions can vary widely in appearance depending on their primary origin. They often present as multiple lesions and may involve organs or lymph nodes, which would be atypical for GISTs.
• Inflammatory fibroid polyp: These can mimic smaller GISTs and are typically found in the stomach or small bowel. They often show an ‘onion-skin’ appearance on histology and are negative for CD117 and DOG1. On CT, these appear as well-defined, submucosal masses, which enhance homogeneously after contrast administration. They may be associated with bowel obstruction, which is less common with GISTs.
• Ectopic pancreas (Pancreatic Rest): Often found in the stomach or proximal small bowel, these lesions may mimic small GISTs. They will show pancreatic acini and ducts on histology, unlike GISTs. On CT or MRI, ectopic pancreas often appears as a small, well-defined, submucosal nodule which can differentiate it from GISTs.
• Duplication cysts: These can mimic GISTs, particularly when they contain ectopic gastric mucosa. However, they usually appear as well-circumscribed cystic masses on imaging, unlike GISTs. On imaging, these appear as well-circumscribed, anechoic or hypoechoic cystic lesions on ultrasound or CT/MRI, unlike GISTs which are typically solid masses.
• Desmoid tumour: Often occurs in the abdominal wall or within the abdominal cavity. Associated with Gardener syndrome. Desmoids usually demonstrate aggressive local infiltration and may mimic the appearance of GISTs. However, they are beta-catenin positive and CD117 negative on immunohistochemistry. On CT, these appear as well-defined, often infiltrative, soft-tissue masses that can be iso- to hypo-attenuating compared to muscle. They typically show homogeneous enhancement after contrast administration. On MRI, they can have varying signal intensities but often show a bright T2 signal, unlike GISTs.
• Primary peritoneal malignancies (such as mesothelioma): These tumours may present with intra-abdominal masses that could be confused with GISTs, particularly if the GIST is exophytic and extends into the peritoneum. Patient history and imaging findings of widespread peritoneal disease can help differentiate these conditions. On histology, primary peritoneal malignancies will show characteristics consistent with their respective histogenesis and are CD117 negative. On imaging, these typically present with diffuse peritoneal thickening and enhancement, ascites, and possible nodular or mass-like lesions. These widespread peritoneal disease features can help differentiate these conditions from GISTs, which are typically singular intra-abdominal masses.

Management

• Management of GISTs often involves a multidisciplinary team, including surgical oncology and medical oncology.
• Surgical resection is the mainstay of treatment for localised disease.
• In cases of advanced or metastatic disease, targeted therapies, such as tyrosine kinase inhibitors (e.g., imatinib), are commonly used.