Gastrointestinal Stromal Tumors (GISTs)

What are Gastrointestinal Stromal Tumors (GISTs)

Gastrointestinal stromal tumors are tumors that grow in the gastrointestinal (GI) tract, usually inside the stomach or small intestine. Some GISTs are not cancerous (are benign). Others are cancerous (malignant). GISTs grow when cells called ICCs (interstitial cells of Cajal) develop in the GI tract.

What causes Gastrointestinal Stromal Tumors?

This condition is caused by abnormal changes in genes (gene mutations). The exact cause of these changes is usually not known.

What increases the risk?

The following factors may make you more likely to develop Gastrointestinal Stromal Tumors:

• Having a rare kind of genetic syndrome.
• Having a family history of GIST.

What are the symptoms of Gastrointestinal Stromal Tumors?

Symptoms of Gastrointestinal Stromal Tumors include:

• Pressure in the abdomen.
• Nausea.
• Vomiting, or vomiting blood.
• Loss of appetite.
• Weight loss.
• Anemia.
• Feeling tired (fatigue).

How is this diagnosed?

Gastrointestinal Stromal Tumors may be diagnosed based on:

• Your symptoms, your medical history, and a physical exam.
• Tests, such as:
  • CT or MRI scan.
  • Endoscopy. In this test, a thin lighted tube with a camera at the end (endoscope) is inserted into the GI tract.
  • Biopsy. A sample of tissue from the tumor is removed so it can be examined under a microscope.

How is Gastrointestinal Stromal Tumors treated?

Treatment for Gastrointestinal Stromal Tumors depends on the location of the tumor, whether it is cancerous, and whether cancer has spread. Treatment may include:

• Surgery to help remove the tumor from your body.
• Medicine to attack a tumor’s genes and proteins (targeted therapy).These medicines attack the genes and proteins that allow a tumor to grow while limiting damage to healthy cells.
• A procedure in which an electric current is used to heat the tumor (radiofrequency ablation) or a procedure to inject the tumor with heat, cold, or alcohol (ethanol ablation). These procedures may be done if a tumor has spread to the liver.

Your health care provider may monitor your condition by performing an endoscopy a few times a year.

Follow these instructions at home:

• Learn about your disease and possible side effects from treatment. This will help you talk about your choices with your health care provider and decide on treatments that are right for you.
• Take over-the-counter and prescription medicines only as told by your health care provider.
• Return to your normal activities as told by your health care provider. Ask your health care provider what activities are safe for you.
• Eat a healthy diet. A healthy diet includes lots of fruits and vegetables, low-fat dairy products, lean meats, and fiber.
  • Make sure half your plate is filled with fruits or vegetables.
  • Choose high-fiber foods such as whole-grain breads and cereals.
• Limit alcohol intake to no more than 1 drink a day for nonpregnant women and 2 drinks a day for men. One drink equals 12 oz of beer, 5 oz of wine, or 1½ oz of hard liquor. You may be instructed to avoid alcohol completely.
• Get regular exercise. Aim for 30 minutes of moderate-intensity activity 5 times a week. Examples of moderate-intensity activity include walking and yoga. Be sure to talk with your health care provider before starting any exercise routine.
• Keep all follow-up visits as told by your health care provider. This is important.

Contact a health care provider if:

• Your stools are black in color.

Get help right away if:

• Your are unable to eat or drink without vomiting.
• You are vomiting blood.

Summary

• Gastrointestinal stromal tumors (GISTs) are tumors that grow in the gastrointestinal (GI) tract, usually inside the stomach or small intestine.
• Symptoms of this condition include pressure in the abdomen, nausea, vomiting, and weight loss.
• Treatment may include surgery to remove the tumor from your body.

Information in detail

• Gastrointestinal stromal tumors are relatively rare mesenchymal neoplasms, but they are the most common mesenchymal tumors originating in the digestive tract
• Can occur anywhere in gastrointestinal tract but are most common in stomach and small intestine
• Clinical presentation may be acute or chronic; symptoms are nonspecific, commonly involving gastrointestinal bleeding, and vary by tumor site, size, and aggressiveness
• May be an incidental finding
• Diagnosis is based on anatomic site of tumor and examination of tumor tissue (morphology and immunohistochemical staining for KIT)
• Management depends on tumor site, size, extent of spread, and clinical presentation
• Complete surgical resection is the cornerstone of management and the only curative therapy
• Adjuvant therapy with imatinib yields the best outcomes for patients with localized disease
• Tyrosine kinase inhibitors are the mainstay of therapy for metastatic disease, recurrent disease, and progressive disease; cytoreductive surgery may also have a role in some patients

Pitfalls

• It is important to distinguish pseudoprogression, which can be caused by myxoid degeneration or intratumoral hemorrhage, from real disease progression when monitoring treatment response with CT or MRI 

• Gastrointestinal stromal tumors are relatively rare mesenchymal neoplasms but are the most common mesenchymal tumors originating in the digestive tract 
• Can occur anywhere in gastrointestinal tract but are most common in stomach and small intestine 
• May rarely occur in extravisceral locations (eg, omentum, mesentery, retroperitoneum) 
• Gastric tumors smaller than 2 cm have indolent behavior regardless of mitotic index and are essentially benign, whereas tumors in other locations and those with a high mitotic index are more aggressive 

Classification

• Most tumors previously diagnosed as leiomyomas, leiomyoblastomas, or leiomyosarcomas, and many tumors previously classified as neurofibromas or schwannomas, are now defined as gastrointestinal stromal tumors 
• Primary tumor site 
  • Gastric (60%-70%)
  • Small bowel (20%-30%)
    • Duodenum (4%-5%)
  • Rectum (4%-5%)
  • Colon (less than 2%)
  • Esophagus (less than 1%)
  • Peritoneum, mesentery, or omentum (rare)
• Histologic subtype 
  • Spindle cell type (70%)
  • Epithelioid type (20%)
  • Mixed type, with both epithelioid and spindle cells (10%)
• TNM classification for staging (limited in clinical utility and often not used; European guideline describes it as “not recommended”) 
  • Primary tumor
    • TX: primary tumor cannot be assessed
    • T0: no evidence of primary tumor
    • T1: tumor up to 2 cm (greatest dimension)
    • T2: tumor larger than 2 cm and up to 5 cm
    • T3: tumor larger than 5 cm and up to 10 cm
    • T4: tumor larger than 10 cm
  • Regional lymph nodes
    • N0: no regional lymph node metastasis
    • N1: regional lymph node metastasis
  • Distant metastasis
    • M0: no distant metastasis
    • M1: distant metastasis
  • Histologic grade based on mitotic activity
    • GX: grade cannot be assessed
    • G1: low grade (mitotic rate of 5 or fewer cells per 50 high-power fields)
    • G2: high grade (mitotic rate of more than 5 cells per 50 high-power fields)
  • Anatomic stage/prognostic groups
    • Gastric or omental stromal tumor
      • IA: T1 or T2, N0, M0, G1
      • IB: T3, N0, M0, G1
      • II: T1, N0, M0, G2; T2, N0, M0, G2; T4, N0, M0, G1
      • IIIA: T3, N0, M0, G2
      • IIIB: T4, N0, M0, G2
      • IV: any T, N1, M0, any G; any T, any N, M1, any G
    • Small intestinal, esophageal, colorectal, mesenteric, or peritoneal stromal tumor
      • I: T1 or T2, N0, M0, G1
      • II: T3, N0, M0, G1
      • IIIA: T1, N0, M0, G2; T4, N0, M0, G1
      • IIIB: T2, N0, M0, G2; T3, N0, M0, G2; T4, N0, M0, G2
      • IV: any T, N1, M0, any G; any T, any N, M1, any G
• Risk classification
  • Several risk classification systems have been proposed based on primary tumor site, size, and mitotic index using a high-power field covering 5 mm² of tissue
    • Joensuu risk criteria (based on earlier NIH consensus criteria) are the most comprehensive 
      • Very low risk of progressive disease
        • 2 cm or smaller, 5 or fewer mitotic cells in 5 mm², any site
      • Low risk of progressive disease
        • Larger than 2 cm and up to 5 cm, 5 or fewer mitotic cells in 5 mm², any site
      • Intermediate risk of progressive disease
        • 5 cm or smaller, 6 to 10 mitotic cells in 5 mm², gastric site
        • Larger than 5 cm and up to 10 cm, 5 or fewer mitotic cells in 5 mm², gastric site
      • High risk of progressive disease
        • Tumor rupture
        • Larger than 10 cm, any mitotic index, any site
        • More than 10 mitotic cells in 5 mm², any size, any site
        • Larger than 5 cm, more than 5 mitotic cells in 5 mm², any site
        • 5 cm or smaller, more than 5 mitotic cells in 5 mm², any nongastric site
        • Larger than 5 cm and up to 10 cm, 5 or fewer mitotic cells in 5 mm², any nongastric site

Clinical Presentation

History

• Clinical presentation may be acute or chronic; symptoms are nonspecific and vary by tumor site, size, and aggressiveness 
  • Acute
    • Gastrointestinal bleeding manifesting in hematemesis or melena
    • Sudden and severe abdominal pain in cases of tumor rupture 
    • Rarely, bloating, abdominal pain, nausea, vomiting, or constipation due to bowel obstruction
  • Chronic
    • Fatigue, dizziness, dyspnea, and syncope due to anemia
    • Abdominal swelling or early satiety due to mass effect
    • Nonspecific abdominal pain 
    • Dysphagia
• May be asymptomatic and present as incidental finding during surgery, imaging, or endoscopy 
  • Reported in less than 20% of patients 

Physical examination

• Signs of anemia
• Palpable abdominal mass
• Abdominal pain on palpation
• Abdominal distention (in case of tumor rupture into abdomen)
• Skin or mucous membrane hyperpigmentation (in some cases of familial syndromes that include gastrointestinal stromal tumors) 

Causes

• Gastrointestinal stromal tumors arise from precursors of interstitial cells of Cajal in myenteric plexus, primarily as a result of activating mutations in either of 2 receptor protein tyrosine kinases: KIT (CD117) or PDGFRA (platelet-derived growth factor receptor alpha) 

Risk factors and/or associations

Age

• Most patients are between ages 40 and 80 years at diagnosis 
  • Median age range at diagnosis is 60 to 65 years 
  • Extremely rare in patients younger than 30 years 

Sex

• In adults, there is a slight predominance in men 
• In children, predominant in girls 

Genetics

• Approximately 85% of gastrointestinal stromal tumors are associated with activating mutations in KIT, and about 5% have mutation in PDGFRA 
  • KIT and PDGFRA gene mutations are absent in 10% to 15% of cases: these are referred to as wild-type tumors 
    • Germline autosomal dominant mutations in KIT or PDGFRA are rare; affected families develop multiple gastrointestinal stromal tumors at an early age 
• Many wild-type tumors have been found to have mutations in the SDHC gene or hypermethylation of the SDHC promoter contributing to epigenetic inactivation of succinate dehydrogenase. These result in succinate dehydrogenase–incompetent gastrointestinal stromal tumors 
  • The state of succinate dehydrogenase competency versus succinate dehydrogenase deficiency is becoming more important in overall classification of gastrointestinal stromal tumors 
    • Succinate dehydrogenase–competent gastrointestinal stromal tumors include those with mutations of KIT, PDGFRA, NF1, and BRAF as well as more recently identified genes
    • Succinate dehydrogenase–deficient gastrointestinal stromal tumors include the rare syndromic gastrointestinal stromal tumors (ie, Carney triad, Carney-Stratakis dyad)

Ethnicity/race

• Incidence is higher in Black and Asian and Pacific Islander populations compared to that in White populations 

Other risk factors/associations

• Cancer-predisposing syndromes 
  • Carney triad 
    • Sporadic syndrome defined by gastrointestinal stromal tumors associated with paraganglioma and pulmonary chondroma
    • Not associated with a heritable genetic alteration
    • Hypermethylation of the SDHC promoter contributes to epigenetic inactivation of succinate dehydrogenase
    • Gastrointestinal stromal tumors in these patients tend to be multifocal with epithelioid morphology
  • Carney-Stratakis dyad (Carney-Stratakis syndrome) 
    • Autosomal dominant cancer-predisposing syndrome associated with gastrointestinal stromal tumors and paragangliomas
    • Germline mutation in SDHB, SDHC, or SDHD (which encode succinate dehydrogenase complex subunits)
    • Gastrointestinal stromal tumors in these patients are usually multifocal, are located in stomach, and have spindle cell morphology
  • Neurofibromatosis type 1 
    • Small, mitotically inactive, clinically indolent gastrointestinal stromal tumors, often in small intestine
    • Absence of KIT and PDGFRA mutations

Diagnostic Procedures

Primary diagnostic tools

• Suspect gastrointestinal stromal tumor upon finding subepithelial nodule at endoscopy or during diagnostic imaging to investigate gastrointestinal bleeding or other nonspecific symptoms; it may also be an incidental finding
• Diagnose based on anatomic site of tumor and examination of tumor tissue, including morphology and immunohistochemical staining for KIT 
  • Preoperative biopsy is not routinely required if tumor is easily resectable; it is indicated if preoperative initiation of tyrosine kinase inhibitor therapy is planned or tumor is unresectable 
  • Tissue for histopathologic examination may be obtained by endoscopic ultrasonography–guided fine-needle biopsy or at surgical resection 
  • Percutaneous biopsy is usually avoided owing to risk of tumor rupture and dissemination; however, it may be appropriate to confirm metastatic disease 
• Initial workup includes:
  • History and physical examination 
  • CBC and liver function tests to evaluate for extent of anemia and evidence of hepatic involvement 
  • Contrast-enhanced abdominal and pelvic CT or MRI to characterize tumor and determine its extent and presence of metastasis 
    • Chest imaging, with chest radiography or CT for all gastrointestinal stromal tumors larger than 2 cm and in nongastric locations 
    • Baseline PET scan if this modality will be used in follow-up
  • Endoscopy, with or without endoscopic ultrasonography in selected cases of primary gastric or duodenal tumors 
  • Endoscopic ultrasonography to further delineate tumor and guide fine-needle biopsy 
  • Genotyping for all patients when medical therapy is anticipated 

Laboratory 

• CBC
  • May demonstrate anemia due to gastrointestinal bleeding
• Liver function test panel
  • May demonstrate hepatic dysfunction due to metastasis

Imaging

• Contrast-enhanced CT scan
  • Recommended for delineation of incidentally identified small tumors 
  • High reliability for tumor detection and staging and for monitoring of therapy response 
  • Tumors show as well-circumscribed exoluminal masses exhibiting heterogeneous enhancement 
  • Large tumors may appear complex owing to necrosis, hemorrhage, and degenerating components 
  • Visualizing the gastrointestinal tract layer from which the tumor originates by CT scan may be difficult with small tumors 
• MRI
  • Useful alternative to CT 
  • Recommended for surgical planning in rectal tumors, for evaluation of liver lesions that are indeterminate on CT, and in cases in which CT is contraindicated 
  • Shows gastrointestinal stromal tumors as well-defined masses that enhance with IV contrast 
  • Demonstrates internal tumor architecture of liver metastases, including septa and relative variable density 
  • Measurements of signal intensity (absolute tumor density) are less reliable than CT scan data 
• PET scan
  • Highly sensitive and specific for detecting gastrointestinal stromal tumors 
  • Gastrointestinal stromal tumors are typically positive on fludeoxyglucose F 18 PET, which may find small metastases that would otherwise be missed and may characterize ambiguous findings on CT or MRI
  • Small gastrointestinal stromal tumors have homogeneous uptake, whereas larger lesions (larger than 4 cm) may have heterogeneous uptake 
• Endoscopic ultrasonography
  • Can assess depth of invasion and allow biopsy by fine-needle aspiration
  • Shows gastrointestinal stromal tumors as hypoechogenic masses, sometimes with cystic, necrotic, and/or hemorrhagic areas (high-risk features not found in all tumors) 

Procedures

• Collection of tissue specimen for histopathologic examination, performed via open surgical excision, endoscopically, or percutaneously
  • Excisional biopsy: an entire lump or suspicious area is removed
  • Incisional biopsy (core biopsy): a sample of tissue is removed, and the histologic architecture of the sample tissue is preserved
  • Aspiration biopsy: a sample of tissue or fluid is removed with a needle, but the histologic architecture of the sample tissue is not preserved
• Best approach for biopsy depends on site and size of suspected primary tumor, as determined by imaging 
  • Tumor tissue may be obtained at laparoscopic or open surgical resection if it is easily resectable and if preoperative initiation of therapy is not required 
  • Echoendoscopic-guided biopsy is technique of choice if preoperative biopsy is required 
    • CT-guided percutaneous biopsy is an alternative at specialized centers; skillful technique can avoid risk of intra-abdominal dissemination 
    • Standard endoscopic biopsy techniques are not recommended
• In patients with obvious metastatic disease, a biopsy of a metastatic focus is sufficient for diagnosis 
• Obtain tissue for diagnosis, histologic classification, and identification of biomarkers
• Uncontrolled bleeding diathesis
• Biopsy of gastrointestinal stromal tumors poses a risk of tumor rupture and subsequent intraperitoneal seeding 
• Pathology report must include 3-dimensional tumor measurement, existence and quantification of necrosis, and distance between lesion and margin 
• Histologic patterns 
  • Predominantly spindle cells
    • Short fascicles or whorls
  • Predominantly epithelioid cells
    • Diffuse or nested architecture
  • Mixture of spindle and epithelioid cells
• Mitotic count
  • For gastrointestinal stromal tumors, defined as number of mitoses in 5 mm² (50 high-power microscopic fields) 
  • Used for risk prognostication along with tumor size and tumor site to predict risk of metastasis
• Immunohistochemistry
  • Most gastrointestinal stromal tumors are KIT-positive 
  • Other commonly expressed markers include CD34, CD117, and DOG1 
  • Generally negative for desmin and S100 protein but can be positive for smooth muscle actin and muscle-specific actin 
  • Succinate dehydrogenase immunohistochemistry is useful for identifying succinate dehydrogenase–deficient gastrointestinal stromal tumors
• Mutational analysis 
  • Mutational analysis of both KIT and PDGFRA genes may confirm diagnosis in KIT-positive tumors with atypical features or in KIT-negative tumors 
  • May help differentiate from desmoid tumors, weakly KIT-positive high-grade sarcomas, or other neoplasms 
  • Presence of certain KIT and PDGFRA mutations may identify patients at higher risk of recurrence after resection of primary tumor and may predict response to tyrosine kinase inhibitor therapy in advanced or metastatic tumors 
  • Diagnosis can be challenging to establish in KIT-negative tumors
    • Genotypic analysis may identify PDGFRA mutations, and immunostaining for PDGFRA may be helpful 
    • BRAF mutation or an NTRK gene rearrangement may be present 
  • In gastrointestinal stromal tumors without detectable mutations in KIT or PDGFRA, perform immunohistochemistry for succinate dehydrogenase complex subunit B to identify succinate dehydrogenase–deficient gastrointestinal stromal tumor 
  • In quadruple-negative gastrointestinal stromal tumor, exclude an unrecognized underlying type 1 neurofibromatosis syndrome 

Differential Diagnosis

Most common

• Various cancers have clinical presentation indistinguishable from that of gastrointestinal stromal tumors 
• All may present with nonspecific gastrointestinal signs and symptoms or as an incidental mass found on imaging or endoscopy
• Differentiated based on morphology and immunohistochemistry; may require referral to a pathologist with expertise in this area 
• As an uncommon disease, gastrointestinal stromal tumors may not be diagnosed before surgical resection and postoperative pathologic assessment 
• Main histologic differential diagnoses for gastrointestinal stromal tumors include the following: 
  • Metastatic melanoma
    • Patient with metastatic melanoma would likely have a known history of a primary melanoma
    • Morphology is histologically similar to that of epithelioid cell gastrointestinal stromal tumors 
    • Immunohistochemistry: diffusely S100-positive but can be focally KIT-positive 
  • Leiomyomas and leiomyosarcomas
    • Morphology is histologically similar to that of spindle cell gastrointestinal stromal tumors
    • Immunohistochemistry: desmin-positive and KIT-negative 
  • Schwannoma
    • Morphology is histologically similar to that of spindle cell gastrointestinal stromal tumors
    • Immunohistochemistry: strongly and diffusely S100-positive and KIT-negative
  • Malignant peripheral nerve sheath tumor and desmoid fibromatosis
    • Morphology is histologically similar to that of spindle cell gastrointestinal stromal tumors
    • Immunohistochemistry: KIT-negative
  • Sarcomatoid carcinoma
    • Morphology is histologically similar to that of spindle cell gastrointestinal stromal tumors but tends to be pleomorphic; tissue is highly mitotically active
    • Immunohistochemistry: cytokeratin-positive, KIT-negative, and CD34–negative

Treatment Goals

• Eradicate tumor
• Prevent recurrence and metastasis

Admission criteria

• Admit patients for whom resection of tumor is planned

Recommendations for specialist referral

• Refer for multidisciplinary treatment planning, ideally to a center that includes pathologists, radiologists, surgeons, medical oncologists, gastroenterologists, and nuclear medicine specialists with experience treating these tumors 

Treatment Options

General overview

• Complete surgical resection is the cornerstone of management and the only curative therapy 
• Management depends on tumor site, size, extent of spread, and clinical presentation
  • Localized primary tumor
    • Surgery is first line therapy if tumor is technically resectable and risk for morbidity is acceptable 
      • Resect tumors 2 cm or larger, and resect rectal tumors of any size
        • Resect symptomatic tumors smaller than 2 cm
        • Management of incidentally found tumors smaller than 2 cm remains controversial; their clinical significance is unclear 
          • Observation may be used in select cases without high-risk features on endoscopic ultrasonography (eg, large size, irregular extraluminal border, cystic spaces); tumor can be resected if it grows larger or becomes symptomatic 
            • Optimal endoscopic ultrasonography surveillance intervals are not well established
          • Surgical management is recommended if there are high-risk features on endoscopic ultrasound 
      • Surgical approach is tailored to site and nature of tumor. Segmental resection of the stomach or intestine, with the goal of achieving negative microscopic margins and intact pseudocapsule, is performed; sometimes gastrectomy or pancreaticoduodenectomy is required
        • May require en bloc resection of adjacent tissue if adherent
        • Lymph node dissection or lymphadenectomy is usually unnecessary, as lymph node metastasis is rare
        • Smaller tumors may be amenable to laparoscopic or laparoscopically assisted techniques, which are not recommended for larger tumors owing to risk of tumor rupture and dissemination
    • Preoperative neoadjuvant therapy with imatinib or avapritinib is an option for more advanced local disease (ie, large, poorly localized, or unresectable tumors) 
      • May reduce tumor size, thereby improving resectability and reducing surgical morbidity
      • If the tumor is responsive to imatinib but still not completely resectable, cytoreductive surgery may confer a survival advantage 
      • Consider on an individual basis
      • Avapritinib is approved for use in patients with PDGFRA exon 18 mutations that are not sensitive to imatinib 
    • Surgery is followed by adjuvant therapy with the first line tyrosine kinase inhibitor imatinib for patients at intermediate or high risk for progression 
      • Risk stratification after resection is based on tumor size, location, and mitotic rate
        • A variety of risk stratification systems have been proposed, including NIH, Joensuu-modified NIH, Armed Forces Institute of Pathology, and Memorial Sloan Kettering Cancer Center nomogram 
        • Risk stratification influences management
      • For patients with complete resection who received preoperative imatinib, continue it postoperatively for at least 2 years 
      • Continue therapy for at least 36 months for high-risk patients with complete resection who did not receive preoperative imatinib 
        • Adjuvant therapy is not indicated for patients at low risk of relapse. These patients can be cared for with observation
      • When there is persistent gross disease following resection (R2 resection), initiate (or continue) imatinib treatment 
      • Mutational analysis can contribute to decisions for adjuvant therapy, as some genotypes are insensitive to imatinib
      • Adjuvant tyrosine kinase inhibitor therapy in pediatric patients is less effective and thus not recommended 
  • Recurrent, metastatic, locally advanced, or inoperable disease
    • Treatment with tyrosine kinase inhibitors is standard approach; imatinib is first line agent 
      • Patients with KIT exon 9 mutations have greater progression-free survival with a higher dose of imatinib, which should be the standard treatment for this patient population
      • Avapritinib is used in patients with PDGFRA exon 18 mutations that are not sensitive to imatinib
    • If treatment fails or in rare cases of imatinib intolerance, patients can be moved to second and third line tyrosine kinase inhibitors 
      • Sunitinib has proven progression-free survival efficacy for patients with confirmed progression or intolerance during imatinib course
      • Regorafenib, a third line therapy option, has proven progression-free survival efficacy for patients with confirmed progression on sunitinib
      • Change to ripretinib if progression occurs on regorafenib
      • Consider dasantinib for patients with PDGFRA exon 18 mutations 
      • NTRK inhibitors (larotrectinib, entrectinib) are useful in patients with NTRK mutated tumors 
      • BRAF inhibitors (including BRAF–MEK inhibitor combinations) may be beneficial for tumors with BRAF mutations 
    • Continue therapy indefinitely with imaging monitoring; continue as long as there is a clinical response or as long as patient remains stable 
      • Continuation of tyrosine kinase inhibitor treatment is an option even in patients with demonstrated disease progression, as there is evidence that these treatments may slow down disease progression
      • Also may be continued throughout life for palliation of symptoms
    • Surgical resection of residual metastatic disease is generally not indicated, as it has not demonstrated definitive benefit
      • Cytoreductive surgery may be considered in recurrent or metastatic disease that is stable or responsive to tyrosine kinase inhibitor therapy when complete resection is possible, when there is evidence of secondary drug resistance in an isolated clone while other sites of disease remain stable, or in emergency situations
    • Palliative radiation therapy may be considered for selected patients 

Rationale

• Up to 50% of patients treated with surgery alone develop local or distant recurrence; neoadjuvant or adjuvant therapy with imatinib is associated with improved progression-free survival and overall survival 
• Cytotoxic chemotherapy and radiotherapy are ineffective for the treatment of gastrointestinal stromal tumors 

Outcomes

• 5-year overall survival rate after complete resection is 50%; median time to recurrence after resection of high-risk primary tumor is 2 years 
  • Complete gross resection with intact pseudocapsule and negative microscopic margins is required for optimal surgical outcome 
  • Prognostic implications of positive microscopic margins are unfavorable 
• After resection of high-risk primary tumors, postoperative adjuvant therapy with imatinib is standard; with a 3-year course, it has been associated with overall survival rate of 92% and recurrence-free survival rate of 71.4% at 5 years and an overall survival rate of 79% and recurrence-free survival rate of 52.5% at 10 years 
• Extended follow-up of patients with intermediate- and high-risk tumors confirmed adjuvant imatinib therapy for 2 years improved recurrence-free survival at 10 years 
• Combination of neoadjuvant imatinib before surgery for primary tumors measuring 5 cm or more plus postoperative therapy for 2 years has been associated with overall survival rate of 77% and progression-free survival rate of 57% at 5 years 

Drug therapy

• Tyrosine kinase inhibitors 
  • Imatinib
  • Sunitinib
  • Regorafenib
  • Avapritinib
  • Ripretinib

Nondrug and supportive care

Procedures

Surgical removal of tumor

General explanation

• Surgical procedure depends on site of tumor

Special populations

• Pediatric patients
  • Pediatric gastrointestinal stromal tumors are clinically and pathologically distinct from adult tumors; they typically do not have KIT and PDGFRA mutations 
    • Typically are succinate dehydrogenase–deficient tumors (tumors with silencing or mutations of the genes encoding subunits of the succinate dehydrogenase enzyme complex)
  • Pediatric tumors typically present insidiously with anemia due to bleeding from a gastric nodule, predominantly in girls 
  • Course is indolent and associated with longer survival than for adult tumors, despite high rate of recurrence 
  • There are no consensus guidelines for management of pediatric gastrointestinal stromal tumors 
  • Therapy is similar to that for adult patients with similar tumor mutational profile
  • Adjuvant therapy with tyrosine kinase inhibitors is less efficacious in pediatric patients and is not recommended 

Monitoring

• There are no formal recommendations for optimal follow-up frequency 
  • Abdominal/pelvic CT or MRI scans are recommended for high-risk patients every 3 to 6 months for at least 5 years, then every 6 months until 5 years from stopping adjuvant therapy and annually for an additional 5 years 
    • Low-risk category patients may be followed less frequently (eg, every 6-12 months for 5 years) 
  • Fludeoxyglucose F 18 PET is recommended for early treatment response assessment when CT scan is inconclusive 
    • Some guidelines recommend fludeoxyglucose F 18 PET as a preferred method for monitoring treatment response, in addition to CT scan 
• For patients with completely resected, incompletely resected, or metastatic disease: 
  • History and physical examination every 3 to 6 months 
  • Abdomen/pelvis CT every 3 to 6 months for 3 to 5 years and then annually; use PET CT to clarify any ambiguous findings 
    • For low-risk tumors or tumors smaller than 2 cm, less frequent imaging may be considered 
• Relapses occur most often in the liver or peritoneum but may occur along the course of metastatic disease treated with multiple lines of therapy. High-risk patients usually relapse within 1 to 3 years after discontinuing adjuvant tyrosine kinase inhibitor therapy 

Complications

• Intratumoral hemorrhage 
• Tumor rupture 
• Distant metastasis
  • Liver and peritoneal metastasis is most common
  • Lung and other extra-abdominal metastases are generally seen only in very advanced disease

Prognosis

• Median overall survival since introduction of imatinib is 11.7 years 
  • Representative median overall survival time is 13.6 years in patients with only primary disease at diagnosis and 6.4 years in those with metastatic disease at diagnosis 
  • Younger age at diagnosis has been associated with longer overall survival rate 
  • Female sex also confers a survival advantage 
  • Intestinal tumors tend to be more aggressive than gastric tumors 
• 5-year relapse-free survival rates vary according to risk group; for example, 5-year relapse-free survival rates for Joensuu risk groups are as follows: 
  • Very low risk: 94%
  • Low risk: 94%
  • Intermediate risk: 86%
  • High risk: 29%
• KIT mutational status influences prognosis 
  • KIT mutations are associated with recurrence, metastasis, high mitotic index, large tumor size, and decreased 3-year overall survival
  • KIT exon 9 mutations are associated with higher risk of progression than KIT exon 11 mutations
  • 5-year relapse-free survival is higher in patients with KIT exon 11–deleted disease than in those with other types of KIT exon 11 alterations
    • Lowest 5-year relapse-free survival in patients with KIT exon 11 alterations is in those with codon 557-558 deletions
• Other factors associated with poorer overall survival or increased risk of recurrence include 
  • Gastrointestinal hemorrhage (tumor rupture)
  • High Ki67 index
  • Low prognostic nutritional index
  • Tumor necrosis
  • Age older than 50 years

References

1: National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Gastrointestinal Stromal Tumors (GISTs). Version 1.2021. NCCN website. Updated October 30, 2020. Accessed December 16, 2021. https://www.nccn.org/

2. Kalkmann J et al: Consensus report on the radiological management of patients with gastrointestinal stromal tumours (GIST): recommendations of the German GIST Imaging Working Group. Cancer Imaging. 12:126-35, 2012 Reference