Gastrointestinal Stromal Tumor- Introduction and management.pptx

GIST

1. GIST Nabin Paudyal

2. Introduction Most common mesenchymal neoplasm of GI tract Most common variety of soft tissue sarcoma (STS) Derived from Intestinal cells of Cajal, pacemaker cells of mesenchymal decent Can originate from any part of alimentary canal within myenteric plexus Most common sites: stomach (40-60%), small bowel (20-40%) , rectum (5-15%). Morphologically, resembles spindle cell neoplasm CD117 (KIT gene) and calcium-activated chloride channel (DOG1) are common markers between Cajal cells and GIST

3. Cont.… Median age of diagnosis is 65 years Often are larger with median size of 6 cm at diagnosis ; can reach up to 20 cm In 20% cases, GIST are malignant with metastasis Metastasis occurs mostly in Liver

4. Mechanism of signaling of KIT gene PDGFR family

5. GIST tumors are differentiated on the basis of CD34, CD117 and DOG1 expression and lack of smooth muscle staining 70% of GISTs have KIT gene mutation 7% have PDGFRα mutation 15% wild type KIT and PDGFRα genotypes In Carney’s triad, mutations affecting mostly succinate dehydrogenase , BRAF, KRAS and NF1 are seen

6. Clinical symptoms Incidental to symptomatic Symptoms include  Early satiety (Important feature) , pain, nausea, vomiting, GI blood loss. In small intestine tumors, bowel obstruction may occur. Age often > 50 years. Endoscopy GIST are usually smooth submuscular tumors, that externally impinges on the visceral lumen. Rarely, ulceration may also be present. CT Well encapsulated, heterogenous contrast enhancement because of necrosis within the tumor. If metastasis is present, may be found in liver and peritoneal surface Familial syndromes (5% are heritable) NF-1, germline SDH (succinyl dehydrogenase) mutation, Carney- Stratakis syndrome, vHL disease.

7. Biopsy and Diagnosis Can’t be biopsied by endoscopic forceps due to submucosal location EUS directed FNA has sensitivity of 82% and specificity of 100%. Diagnostic modalities: Double-balloon enteroscopy Capsule endoscopy Endoscopic USG guided needle biopsy  Spindle cell neoplasm Immunohistochemistry CD-117, CD 34, PDGFR α , anoctamycin-1 (98% sensitive) CECT abdomen and pelvis (IV and oral contrast), chest MRI is done for patients with Rectal GISTs or in patients with C/I to contrast

8. Appearance of tumors Gross Firm Gray-white lesions Whorled appearance on cut surface Microscopic Well-differentiated Smooth muscle cells

9. Management

10. Risk stratification of GIST

11. Management Localized lesions  Resection with grossly negative surgical margins Care should be taken not to compromise the capsule of the tumor Rupture of capsule during tumor resection can cause seeding of tumor OT note must clearly document the integrity of tumor capsule as it can profoundly affect the recommendation for adjuvant therapy Pathology report must contain Tumor site Size Tumor focality Mitotic rate Immunohistochemical status Margin status Results of molecular genetic studies

12. Treatment More than 2 cm in diameter tumors must be resected. < 2cm tumors with irregular margin, ulceration, echogenic foci, heterogenous tumors must also be resected. < 2 cm tumors without high risk features must be observed with repeat endoscopy and EUS at 6-12 months interval. Operative choices Wide local excision Enucleation Sleeve gastrectomy Total gastrectomy Timing of surgery in patients with GIST is 6-9 months after initiation of neoadjuvant chemotherapy.

13. Entities mimicking GIST Melanoma, Paraganglioma, NET, Nerve sheath tumors Classification of GIST TNM based classification is divided into Gastric and omental tumors Non-gastric tumors This distinction is important as prognosis, surgical planning is done based on this classification Sites on the basis of prognosis (good to bad): Gastric>>Jejunal/ Ileal>>Colorectal GIST Tool to estimate prognosis after resection of GIST Memorial Sloan-Kettering Cancer Center nomogram

14. Memorial Sloan-Kettering Cancer Center nomogram

15. Modified NIH criteria Tools like MSKCC, modified NIH scales are often used to assess the NEED FOR ADJUVANT THERAPY and PREDICT CLINICAL OUTCOME. The specific KIT exon in which the GIST mutation resides affects the molecular and clinical phenotype. E.g. Exon 13  Susceptible to imatinib therapy Exon 9  (principally causes in small bowel or colon GIST) less susceptible to imatinib therapy

16. Routine genetic analysis at GIST diagnosis to determine the precise mutated exon is strongly recommended by consensus guidelines as this information may alter treatment recommendations and patient outcome. Systemic therapy After GIST resection, for adjuvant therapy Prior GIST resection as neoadjuvant therapy for unresectable or locally advanced tumors. Indications of neoadjuvant therapy Locally advanced tumor Borderline resectable In patients in whom tumor shrinkage would increase the likelihood of organ preservation Imatinib (KIT mutation) Dasatinib (PDGFRα mutation) and KIT resistant cases Sunitinib and Regorafenib are other useful chemotherapeutic agents Tumors are recurrent as even in patients who have completed chemotherapy, recurrence is seen. Duration of imatinib and patient characteristics whom to prescribe the drug is subject of research Tumors where recurrence is seen, metastasis is seen in liver primarily.

17. Important TRIALS in GIST ACOSOG trial  Imatinib given to patients with tumor > 3cm, c-KIT positive Had statistically significant improvement in recurrent free survival Joensuu and colleagues  RISK stratification score Based on mitotic rate, origin, size, tumor rupture and duration of imatinib therapy. Found that non gastric tumors with high mitotic rate had more risk of recurrence. Scandinavian Sarcoma Group XVIII trial  36 month adjuvant chemo+ 12 months extension after OT in patients with high risk GISTs (> 10 cm tumor, mitotic count > 5 per 50 HPF, tumor rupture)  better results. This trial is important as it established a 3-year course of standard care after surgical resection of high-risk GIST. PERSIST-5 trial  5 years of adjuvant imatinib therapy showed no recurrence in patients with GIST.

18. Small intestinal GIST

19. Introduction 20 % of malignant neoplasms of small bowel Common in jejunum and ileum Diagnosed in 5 th -6 th decade of life M>>F Usually, malignant GISTS are > 5cm at the time of diagnosis in 80% of people Arise from muscularis propria and grow extramurally Indications for surgery  Bleeding, Obstruction, Perforation

20. Metastasis GISTs of small intestine typically invade locally Spread to adjacent tissues by direct extension and hematogenously to liver, lungs and bone. Size of tumor, mitotic index and evidence of tumor invasion into lamina propria are the factors that indicate survival and risk for metastasis

21. Treatment Based on localized vs metastatic GIST Surgical management  Complete resection for localized GISTs without capsule rupture If capsule rupture occurs before surgery Adjuvant chemotherapy During surgery It is recommended to perform en-bloc resection for prevention of capsular rupture If capsule ruptures during surgery Recurrence is 100% Laparoscopic removal is large GIST  STRONGLY DISCOURAGED

22. When NOT to resect GIST? Infiltration of Major blood vessels (Celiac trunk, SMA, Portal vein) For GIST < 2CM No further treatment if found incidentally in surgical specimens For GIST < 2 cm Surgery is mainstay If R0 resection has been obtained, no need for Imatinib If R0 resection cannot be achieved  Neoadjuvant Imatinib for tumor shrinkage for up to 1 year For metastatic GIST and high risk cases Imatinib Sunitinib Duration 3 years

23. Relapsed GIST Risk stratification systems are available for relapse cases which include: NIH GIST consensus criteria, American Forces Institute of Pathology criteria, Joensuu risk criteria, prognostic nomograms and mutational risk analysis Deletion of Exon 11 codon 557/558 of c-kit gene and D842V PDGFR α mutations have increased risk of recurrence within first 3 to 4 years after surgery. Adjuvant imatinib is not given to resistant cases with D842V PDGFR α mutation

24. Metastatic GIST Imatinib (400 mg OD) is recommended In patients with exon 9 mutation  400 mg BD is recommended. In refractory cases  Sunitinib, Regorafenib, Dasatinib Dasatinib provides best response in patients with D842V PDGFR α mutation.

25. Some memorable slides…