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GIST

GIST in the Esophagus (Shackleford)

  1. Epidemiology and Clinical Features:
    • Prevalence and Demographics:
      • GISTs, although rare in the esophagus, represent the most common soft tissue sarcoma of the gastrointestinal tract. The median age of presentation is in the sixth decade, and it is uncommon in individuals under 30 years of age.
      • There is a slight male predominance with a reported incidence of 54% in men and 46% in women.
    • Symptoms:
      • Symptoms often mimic those of leiomyomas and may include dysphagia (difficulty swallowing), globus sensation (feeling of a lump in the throat), chest pain, and upper GI bleeding. Due to the submucosal nature of these tumors, symptoms typically present late, often when the tumor has grown significantly.
    • Location:
      • GISTs in the esophagus typically develop in the lower third, which is consistent with the distribution of interstitial cells of Cajal (ICC), from which these tumors are believed to originate.

  2. Pathology and Diagnosis:

    • Histology:
      • Most esophageal GISTs are of the spindle cell type (comprising the majority), with fewer being epithelioid. Some tumors may exhibit a combination of these patterns.
    • Molecular Markers:
      • CD117 (KIT) and CD34 positivity are hallmark features of GISTs, distinguishing them from other mesenchymal tumors like leiomyomas and schwannomas. About 5% of GISTs may be KIT-negative, in which case DOG1 protein serves as an alternative marker.

    • Diagnostic Imaging and Procedures:

      • Endoscopy is typically the first-line diagnostic tool. Tumors greater than 2 cm require a staging work-up with CT scans of the abdomen, pelvis, and chest to assess for metastatic disease.
      • PET scans are helpful in ambiguous cases or for evaluating metastatic potential, though it's noted that leiomyomas may also exhibit FDG avidity.
      • EUS (Endoscopic Ultrasound) is utilized to characterize the tumor's echogenicity and to guide FNA (Fine Needle Aspiration) for cytological analysis. EUS-FNA has a high sensitivity (95%) and specificity (100%) for diagnosing GISTs.

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    • Management of Suspicious Lesions:

      • For tumors suspected to be GISTs and that are resectable, some experts suggest avoiding preoperative FNA due to the risk of tumor rupture and dissemination, which could complicate surgical margins and prognosis.
    • Treatment and Prognosis:
    • Surgical Intervention:
      • Indications for resection include tumors larger than 2 cm, symptomatic lesions, or those that show growth under surveillance. For small GISTs with low-risk features, surveillance via EUS every 6 to 12 months may be appropriate.
      • Surgical techniques include enucleation for small, low-risk tumors and more extensive resections, including esophagectomy for larger, invasive, or recurrent tumors. The key surgical principles involve obtaining negative margins and avoiding tumor pseudocapsule violation to prevent complications such as bleeding, tumor rupture, and dissemination.
    • Adjuvant Therapy:
      • Imatinib, a tyrosine kinase inhibitor, has significantly improved outcomes for patients with resectable, unresectable, or metastatic GISTs. It is particularly effective for tumors expressing KIT or PDGFRA mutations. For high-risk GISTs, adjuvant therapy with Imatinib for at least 3 years is recommended.
    • Prognosis:
      • Even with complete resection, recurrence is common, with about 50% of patients experiencing recurrence or metastasis within two years. Esophageal GISTs generally have a worse prognosis than gastric GISTs, partly due to the complexity of surgical resection and the lack of serosal covering in the esophagus.

GIST in the Stomach (GIST SKF)

  1. Epidemiology:
    • Prevalence and Location:
      • GISTs are the most common mesenchymal tumors in the gastrointestinal tract, with the stomach being the most frequent site (56%), followed by the small intestine (32%), colon and rectum (6%), and the esophagus (<1%). The remaining 5% occur in less common locations such as the mesentery, omentum, pancreas, and liver, collectively known as extragastrointestinal stromal tumors (EGISTs).
    • Incidence:
      • The incidence of GISTs ranges from 7 to 15 cases per million people, with more recent SEER data estimating about 6.8 cases per million in the U.S.
  2. Pathology and Diagnosis:
    • Histology:
      • GISTs exhibit three primary histological types: spindle cell (70% of cases), epithelioid, and mixed types. Rare histological features may include myxoid stroma, neuroendocrine differentiation, and signet ring cells.
    • Molecular Pathogenesis:
      • The majority of GISTs are characterized by gain-of-function mutations in the KIT gene, leading to constitutive activation of the KIT tyrosine kinase receptor, which drives tumorigenesis. A subset of GISTs involves mutations in PDGFRA or BRAF.
      • CD117 (KIT) positivity is seen in over 95% of cases and is a cornerstone for diagnosis. Other markers such as DOG1 and PDGFRA are also important, particularly for KIT-negative tumors.
    • Diagnostic Imaging:
      • Contrast-enhanced CT and MRI are essential for the preoperative evaluation of GISTs, revealing hypervascular, heterogeneous masses that displace but rarely invade adjacent structures. Smaller GISTs may appear as more homogeneous, polypoid masses.
      • Endoscopy often identifies submucosal masses, with EUS playing a key role in assessing tumor characteristics and guiding FNA, especially for small (<2 cm) gastric GISTs.

  3. Malignant Potential and Staging:

    • Risk Assessment:

      • The malignant potential of GISTs spans a broad spectrum, and while very small gastric GISTs (<2 cm) with low-risk histologic features may behave benignly, most GISTs have some degree of malignant potential.
      • Fletcher and Joensuu criteria are widely used to stratify risk based on tumor size, mitotic rate, location, and the presence of tumor rupture. Gastric GISTs generally have a less aggressive behavior compared to GISTs in other locations.

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  4. Treatment:

    • Surgical Management:
      • Complete surgical resection with negative margins is the cornerstone of treatment for primary GISTs. For gastric GISTs, partial gastrectomy or wedge resection is often sufficient to achieve negative margins, sparing the morbidity associated with total gastrectomy.
      • Minimally invasive approaches, such as laparoscopic resection, are increasingly utilized, especially for smaller gastric GISTs. Guidelines generally recommend limiting laparoscopic resections to tumors <5 cm.
    • Systemic Therapy:
      • Imatinib is the first-line therapy for high-risk, unresectable, or metastatic GISTs. It has dramatically improved survival rates, with response rates of up to 70% in metastatic settings.
      • Sunitinib and Regorafenib are second- and third-line therapies for GISTs resistant to or intolerant of Imatinib.
    • Neoadjuvant Therapy:
      • Neoadjuvant Imatinib is used in locally advanced GISTs to reduce tumor size and facilitate organ-preserving surgery. Studies have shown high rates of complete resection (R0) and favorable long-term outcomes with neoadjuvant therapy.
    • Follow-up and Recurrence:
      • Post-resection follow-up includes regular clinical and imaging assessments to monitor for recurrence, with CT scans every 3-6 months for the first 3-5 years, then annually thereafter. Despite complete resection, recurrence rates remain high (40-50%).
  5. Pediatric and Hereditary GISTs:
    • Pediatric GISTs are rare and often exhibit different genetic features from adult GISTs, such as a higher rate of wild-type tumors lacking KIT or PDGFRA mutations. These tumors tend to follow a more indolent course despite a higher rate of metastases.
    • Hereditary GISTs are associated with syndromes like NF1 mutation, Carney triad, and familial GIST syndrome. These tend to be indolent and are managed similarly to pediatric GISTs.

Joensuu modification of the National Institutes of Health (NIH) Consensus Classification for selecting patients with Gastrointestinal Stromal Tumors (GIST) for adjuvant therapy:

Risk Category Tumor Size (cm) Mitotic Index (per 50 HPFs) Tumor Site Additional Factors
Very Low Risk <2.0 ≤5 Any -
Low Risk 2.1–5.0 ≤5 Any -
Intermediate Risk <5.0 6–10 Any -
5.1–10.0 ≤5 Gastric -
High Risk >10.0 Any Any -
Any >10 Any -
>5.0 >5 Any -
2.1–5.0 >5 Nongastric -
5.1-10 <5 Non gastric
Any Any Any Tumor rupture

MCQ:

Correct Answer: D - 8 cm tumor, gastric location, Mitotic index 4/50

Explanation:

  • Option A (5 cm tumor, non-gastric location, Mitotic index >5/50 HPFs):
    • This falls under the High-Risk category because the tumor is >2.0 cm in a non-gastric location with a mitotic index >5/50 HPFs.
  • Option B (2 cm tumor, gastric location, Mitotic index 2/50 HPFs, tumor rupture):
    • Despite the small size and low mitotic index, tumor rupture classifies it as High-Risk.
  • Option C (12 cm tumor, gastric location, Mitotic index 3/50 HPFs):
    • This is considered High-Risk because of the large tumor size (>10 cm), regardless of the mitotic index or tumor location.
  • Option D (8 cm tumor, gastric location, Mitotic index 4/50 HPFs):
    • This does not denote a high-risk criterion according to the Joensuu classification. The tumor is >5 cm but is located in the stomach (gastric) and has a low mitotic index (≤5/50 HPFs), placing it in a lower risk category, likely Intermediate Risk.

MCQ Callout: Surgical Resection of GIST

Answer: A and D

Explanation:

  1. No difference in recurrence between R0 and R1 resection (Statement A):
    • This statement is true. Studies from large multi-institutional trials involving over 800 patients have shown that there is no significant difference in recurrence-free survival (RFS) between patients who underwent R0 (complete resection with negative margins) and those with R1 (microscopic positive margins) resections. This holds true even when systemic therapy is added, suggesting that an R1 resection does not necessarily confer a worse prognosis compared to R0.
  2. Lymphadenectomy should be done in all patients (Statement B):
    • This statement is false. The background knowledge clearly indicates that routine lymphadenectomy is not required for GISTs since they rarely spread to regional lymph nodes. Lymphadenectomy should only be considered if pathologically enlarged nodes are present on imaging or detected intraoperatively.
  3. Tumor size less than 10 cm is an indication for laparoscopic resection (Statement C):
    • This statement is partially false. While laparoscopic resection is considered for smaller GISTs, the general recommendation is to limit this approach to tumors less than 5 cm. Tumors larger than this may pose technical challenges and increased risk during laparoscopic procedures, thus are typically not candidates for laparoscopic resection.
  4. 40-50% of GISTs will have recurrence even after R0 resection (Statement D):
    • This statement is true. Approximately 40-50% of GISTs will recur or metastasize even after a complete (R0) resection. This high recurrence rate underlines the importance of careful postoperative monitoring and possibly adjuvant therapy to mitigate the risk of recurrence.

Summary Key Points:

  • R0 vs. R1 Resection: No significant difference in recurrence rates between R0 and R1 resections in GIST.
  • Lymphadenectomy: Not routinely recommended; only necessary if pathologically positive nodes are identified.
  • Laparoscopic Resection: Generally recommended for GISTs less than 5 cm, not 10 cm.
  • Recurrence Rate: 40-50% of GISTs recur even after complete resection (R0), emphasizing the need for vigilant follow-up and possible adjuvant therapy.

Minimally Invasive approach for GIST :

  • A 2008 study proposed a classification schema (Fig. 81.5) to identify three distinct minimally invasive approaches to resecting gastric GISTs based on tumor location in the stomach.
  • Type I tumors were located in the fundus or greater curvature and were treated using a laparoscopic stapled partial gastrectomy.
  • Type II tumors were located in the antrum/prepyloric region and were approached using laparoscopic distal gastrectomy.
  • Type III tumors were located in the lesser curvature near the gastroesophageal junction and were resected by laparo- scopic transgastric resection (Fig. 81.6).

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  • Simultaneous intraoperative endoscopy was also used in select cases to aid in obtaining grossly negative margins.

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MCQ Callout: Role of Imatinib in Treatment of GIST

Answer: D

Explanation:

  1. Indicated in recurrent, metastatic, neoadjuvant, and adjuvant settings (Statement A):
    • True. Imatinib is a cornerstone in the treatment of GISTs, particularly for patients with recurrent, metastatic, unresectable disease, and is used both as a neoadjuvant therapy (to shrink tumors preoperatively) and as adjuvant therapy (post-surgical) to reduce the risk of recurrence.
  2. Patients with exon 9 mutation are started on an 800 mg dose (Statement B):
    • True. Patients harboring the KIT exon 9 mutation are typically started on a higher dose of Imatinib (800 mg daily) because studies have shown that these patients have a better response to this higher dosage compared to the standard 400 mg dose.
  3. Patients with PDGFRA D842V mutation have a poor response (Statement C):
    • True. The PDGFRA D842V mutation is associated with a poor response to Imatinib, making it less effective for patients with this specific mutation. These patients might need alternative therapeutic strategies.
  4. Optimal duration of adjuvant therapy is 1 year (Statement D):
    • False. The optimal duration of adjuvant therapy with Imatinib has been shown to be longer than 1 year. Studies have indicated that extending adjuvant therapy to 3 years significantly improves recurrence-free survival compared to just 1 year of therapy. Therefore, a 1-year duration is no longer considered optimal for high-risk patients.

Commentary on the Role of Imatinib and Other Adjuvant Therapies

Role of Imatinib in GIST:

  • Indications: Imatinib is widely used in the management of GISTs across various clinical scenarios:
    • Adjuvant Therapy: Post-surgical adjuvant therapy with Imatinib is recommended, especially for high-risk patients, to improve recurrence-free survival. The ACOSOG Z9001 trial demonstrated significant improvement in recurrence-free survival with 1 year of adjuvant Imatinib.
    • Neoadjuvant Therapy: Used preoperatively to shrink large tumors, making them more resectable and allowing for more conservative surgery.
    • Recurrent and Metastatic GISTs: Imatinib is the first-line treatment for these patients, showing high response rates and prolonging progression-free survival.

Trials Involved in Imatinib Therapy:

ACOSOG Z9001 Trial: A pivotal study that led to the FDA approval of Imatinib as an adjuvant therapy for patients with completely resected GISTs. The study showed a significant improvement in recurrence-free survival with 1 year of Imatinib therapy.

Scandinavian Trial: This study demonstrated that extending Imatinib therapy to 3 years further improves outcomes compared to 1 year, establishing 3 years as the optimal duration for high-risk patients.

Role of Other Adjuvant Therapies:

  • Sunitinib (Sutent): Used for Imatinib-resistant GISTs or in patients who cannot tolerate Imatinib. It is effective in prolonging progression-free survival in these cases.
  • Regorafenib (Stivarga): A third-line option for patients who have progressed on both Imatinib and Sunitinib. It has been shown to provide a benefit in patients with advanced GIST.

Commentary on Mutations and Response to Therapy:

  1. KIT Mutations:
    • Exon 11 mutations: These are the most common mutations in GIST and are associated with a good response to Imatinib.
    • Exon 9 mutations: Patients with this mutation require a higher dose of Imatinib (800 mg) for optimal response.
    • Exon 13 mutations : require lower doses of imatinib
  2. PDGFRA Mutations:
    • D842V Mutation: This specific mutation is associated with primary resistance to Imatinib, making it a less effective treatment option. Patients with this mutation may require alternative therapies or participation in clinical trials exploring other agents.
  3. Wild-Type GISTs:
    • These tumors lack mutations in both KIT and PDGFRA genes. They often have other mutations, such as in SDH or BRAF genes, and may not respond as well to Imatinib. These cases might require different treatment approaches, such as Sunitinib or Regorafenib.

Summary Key Points:

  • Imatinib is the first-line treatment for GIST in multiple settings: adjuvant, neoadjuvant, recurrent, and metastatic.
  • Optimal adjuvant therapy duration is 3 years for high-risk GISTs, but it can continue up to a lifetime as per FDA recommendations, especially for those with high recurrence risk.
  • Adjuvant Therapy Indications:
    • High-risk GISTs: According to NCCN guidelines, indicated for tumors >5 cm and/or >5/50 mitoses.
    • FDA guidelines: Indicated for tumors >3 cm and/or >5/50 mitoses; not recommended for low-risk GISTs.
  • Mutation-specific responses:
    • Exon 9 mutation: Requires a double dose of Imatinib (800 mg daily) for optimal response.
    • Exon 11 mutation: Associated with a better response to Imatinib.
    • PDGFRA D842V mutation: Associated with poor response to Imatinib; alternative therapies may be needed.
    • Not indicated in GISTs related to SDH, NF, or PDGFRA D842V mutations.
  • Alternative therapies such as Sunitinib and Regorafenib are effective for Imatinib-resistant or intolerant GISTs.

Pediatric and Hereditary GISTs

Pediatric GISTs:

  • Rarity: Pediatric GISTs are exceptionally rare and differ significantly from adult GISTs in terms of genetic features and clinical behavior.
  • Demographics: These tumors show a predilection for females and are more likely to present with GI bleeding. Approximately 85% of pediatric GISTs occur in the stomach.
  • Histology: Pediatric GISTs are more often of the epithelioid or mixed type rather than the spindle cell morphology seen in adults.
  • Clinical Course: Despite a higher rate of metastases and local recurrence, pediatric GISTs tend to follow a more indolent course and have a more favorable long-term prognosis compared to adult GISTs.
  • Molecular Characteristics:
    • Wild-Type GISTs: The majority of pediatric GISTs are "wild-type," meaning they lack KIT or PDGFRA mutations, which are common in adult GISTs.
    • These tumors may harbor mutations in other genes such as IGF1R, BRAF, SDH, and NF1.
  • Treatment: Due to the lack of KIT mutations, tyrosine kinase inhibitors like Imatinib may have limited efficacy in pediatric GISTs. Surgery remains the primary treatment, with systemic therapies reserved for unresectable or symptomatic lesions.

Hereditary GISTs:

  • Prevalence: Hereditary GISTs are very rare, with only about 5% of GISTs being familial in origin.
  • Associated Syndromes:
    • Neurofibromatosis type 1 (NF1) Mutation: Linked to multiple GISTs, typically presenting in the small intestine.
    • Carney Triad: A rare syndrome involving GIST, pulmonary chondroma, and paraganglioma (pheochromocytoma).
    • Familial GIST Syndrome: Caused by mutations in c-Kit or PDGFRA genes, leading to multiple GISTs in affected family members.
    • Carney-Stratakis Syndrome: A dyad of GIST and paraganglioma associated with mutations in SDHD, SDHC, and SDHB genes.
  • Genetic Testing: It is recommended for patients suspected of having a familial GIST, especially those with multiple GISTs or syndromic features. Family members may also undergo genetic testing if a syndrome is identified.
  • Clinical Behavior: Hereditary GISTs tend to be indolent, similar to pediatric GISTs, and may require tailored treatment approaches.

Key Points:

  • Pediatric GISTs:
    • More common in females, often present with GI bleeding, primarily in the stomach.
    • Typically lack KIT/PDGFRA mutations but may involve other mutations like IGF1R, BRAF, SDH, and NF1.
    • Generally indolent despite higher recurrence and metastasis rates.
  • Hereditary GISTs:
    • Associated with specific syndromes like NF1, Carney triad, Familial GIST syndrome, and Carney-Stratakis syndrome.
    • Genetic testing is crucial for diagnosis and family screening.
    • Typically exhibit indolent behavior and may require different management strategies compared to sporadic GISTs.