GASTRIC GIST(Gastrointestinal stromal tumors (GISTs) are typically benign tumors that most commonly occur in the gastrointestinal (GI) tract)pptx

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract, accounting for 80% of all such GI tumors, and 0.1 to 3% of all gastrointestinal malignancies.[1] Approximately 30% of GISTs are malignant.

1. GASTRIC GIST Dr.Sabin Shrestha MBBS MS (General Surgery) Nepalgung Medical College

2. Overview Definition Epidemiology Etiology Pathogenesis Anatomy Pathology Diagnosis Staging Prognostic factor Localized diseases Advanced/ inoperable/Metastasis Follow up Conclusion

3. GIST Most common mesenchymal neoplasms of GI tract(80%) Thought to arise from pacemaker interstitial cells of Cajal Gastrointestinal stromal tumors (GISTs) are rare neoplasms Although they represent only 0.1% to 3% of all gastrointestinal malignancies 95% of GISTs stain positively for KIT (CD117) Also express CD34

4. GIST Occur anywhere in GI tract Stomach 40-60% Small intestine 30% Colon & rectum 15 % Esophagus <5% Omentum , mesentery, bladder(extraintestinal GISTs) Behavior is driven by mutations in the KIT gene (85%), PDGFRA gene (10%), or BRAF kinase (rare) Route of spread- Heamatogenous

5. History In 1983 GIST” term was coined by Mazur & Clark In 1998 Hirota et all reported Near universal expression of transmembrane receptor tyrosine kinase KIT in GIST Mutations in c-kit proto-oncogene Classified as leiomyomas, leiomyosarcomas, Schwannomas prior to this

6. Identification of constitutively active signals (oncogenic mutation of the c-KIT and platelet derived growth factor alpha [PDGFRA] gene-encoding receptor tyrosine kinases) and Development of therapeutic agents that suppress tumor growth by specifically targeting and inhibiting these signals

7. Epidemiology Rare cancer Incidence ~1.5 out of 100000 per year Median age 50-65 years Men > Female

8. Familial When this syndrome is caused by a change (mutation) in the  KIT  gene, other issues can include: Skin hyperpigmentation (darkening of areas of the skin) Trouble swallowing GI autonomic nerve tumors, such as paragangliomas When this syndrome is caused by a change in the  PDGFRA  gene, other issues can include: Intestinal fibromatosis (overgrowth of cells in the lining of the gut) Inflammatory fibroid polyps (benign tumors in the GI tract)

9. The GIST is diagnosed before age 50 A person has more than one GIST Two or more close relatives have been diagnosed with a GIST A person with a GIST also has a close relative with another rare tumor type A person with a GIST also has neurofibromatosis type 1 (NF1), multiple moles

10. Pediatric   R are in children or young adults M> F MC symptom : Chronic gastrointestinal bleeding MC Histology : Epithelioid Mostly tend to arise within defined syndromes, including the Carney triad and Carney- Stratakis syndrome 85% of pediatric GISTs lack mutations in KIT or PDGFRA

11. MOLECULAR PATHOGENESIS R elatively heterogeneous and complex group of lesions D rivers of disease: KIT and PDGFRA R eside on chromosome 4q12 Gain-of-function mutations of these oncogenes can be found in approximately 80% of GISTs

12. They are  mutually exclusive and result in constitutive activation of either KIT or PDGFRA, which normally are autoinhibited, being activated by binding of their respective ligands (i.e., stem-cell factor and platelet-derived growth factor A) Activation of receptor binds two molecules of KIT or PDGFRA (dimerization), giving rise to downstream oncogenic signaling, which for both KIT and PDGFRA involves RAS/MAPK.

13. Pathophysiology Tyrosine kinase receptor  mutations Over 85% of GISTs have activating KIT mutations Commonly occur in Exon 11(57-71%) Exon 9 (10-18%) Exon13 (1-4%) Exon 17(1-4%) One third of GISTs lacking KIT mutations have mutations in gene encoding PDGFRA, Mutated KIT remain active in absence of ligand binding resulting in unregulated growth and malignant transformation Wild type GISTs are few that do not show KIT or PDGFRA mutation

14. Pathology Gross Well-circumscribed  lesions arising within wall of stomach or intestine Fleshy tan-white, cut-surface with foci of cystic degeneration, hemorrhage or necrosis. Ulceration of mucosa when large size of tumor.

15. Microscopy Spindle cell(70%) Epethelioid cell (20%) Mixed (10%) Spread Spread to lymph nodes is rare Liver, peritoneum and omentum – common

16. Clinical presentation Generally   detected when they become symptomatic Nonspecific symptoms Vague abdominal pain & fullness Early satiety Malaise F atigue Symptoms due to obstruction or bleeding Hematemesis or Malena Dysphagia(Esophageal) Obstructive jaundice(duodenal tumor) Features of small bowel obstruction or peritonitis Constipation(colorectal )

17. Immunohistochemistry Immunohistochemistry (IHC) uses antibodies to detect antigens in a tissue sample. IHC is commonly used  to diagnose cancer, predict treatment response and determine likely outcomes (prognosis) of the disease

18. Hallmark -  positive for KIT (CD117) and DOG-1 • Some are CD117 negative, which is typical of PDGFRA-mutated GISTs, but immunohistochemical status does not reflect the mutational status with regard to KIT and PDGFRA, per se, so that it has no concrete predictive value for sensitivity to TKIs .

19. GIST stain with KIT(CD117) antibody

20. GIST-Differential diagnosis Lymphoma Schwannoma Leiomyoma L eiomyosarcoma Immunohistochemistry helps in differentiating GISTs from these lesions

21. GIST-Diagnosis   USG abdomen & pelvis Upper GI endoscopy and biopsy Contrast CT of abdomen & pelvis Endoscopic ultrasonography directed FNA MRI of abdomen & pelvis FDG-PET Immunohistochemistry Reverse-transcriptase polymerase chain reaction analysis for KIT mutations may be required to confirm a diagnosis.

22. CT SCAN I maging modality of choice to further evaluate an abdominal mass or nonspecific abdominal symptoms. CT appearance : solid, smoothly contoured mass that enhances brightly with intravenous contrast.

23. Endoscopy, Fine-Needle Aspiration, and Biopsy Endoscopically, a primary GIST may appear as a submucosal lesion, with or without ulceration, present in the upper or lower gastrointestinal tract. Often indistinguishable from other gastrointestinal tumors of smooth muscle origin, such as leiomyomas Central ulceration is occasionally seen

24. Endoscopic ultrasound 

25. Preoperative biopsy   Generally   not done Tumor seedling Bleeding Endoscopic biopsy : Less bleeding Metastatic disease If neoadjuvant imatinib planned.

26. Surgery

27. GIST-TNM staging

28. AJCC TNM staging system The extent of the main (primary)  tumor (T):  How large is the cancer? The spread to nearby lymph  nodes   (N):  Has the cancer spread to nearby lymph nodes? (This is uncommon in GISTs.) The spread ( metastasis ) to distant sites  (M):  Has the cancer spread to distant parts of the body? (The most common sites of spread are the liver, bones, lungs, and the tissue layers lining the inside of the abdomen.) The  mitotic rate:  This is a lab test measurement of how fast the cancer cells are growing and dividing. It is described as either low or high. A low mitotic rate predicts a better outcome

29.   Mitotic count : Main prognostic factor, proportionally correlating to the risk of relapse. Tumor size : Very small gastric lesions (<2 cm) - watchful surveillance if incidentally discovered endoscopically Lesions > 5 to 10 cm -- worse prognosis. Site Of Origin : Gastric lesions have a better prognosis than small bowel and rectal

30. PRINCIPLES OF SURGERY   Goal Complete gross resection with an intact pseudocapsule Surgery usually is a wedge or segmental resection of the involved gastric or intestinal tract A lymphadenectomy is not routinely required.

31. Treatment Localized GIST Surgery   is definitive therapy for localized GIST Principle: A chieve negative microscopic margin(R0) En bloc resection of adjacent involved organs, such as colon, spleen, or liver for locally invasive tumor Routine lymphadenectomy not indicated Adjuvant treatment with imatinib has improved recurrence free survival 400mg PO/day X 3 years Neoadjuvant treatment with imatinib is undergoing various trials with encouraging results

32. All GISTs ≥2 cm in size should be resected 1-2cm either observation or resection A ny small symptomatic GIST (e.g., bleeding from erosions through the mucosa) or increases in size on serial follow-up should be resected

33. Localized GIST Wedge   or segmental resection of the involved stomach or bowel more often is feasible Large gastric tumors require total/subtotal gastrectomy Subcentimeter gastric GISTs may be followed up by endoscopy Risks and benefits of surgery versus observation should be discussed with patient for gastric GISTs of 1-2cm

34. Medical management Small  molecule tyrosine kinase inhibitors ( tkis ) Prototype : Imatinib B lock signaling via KIT and PDGFRA by binding to adenosine triphosphate-binding pocket required for phosphorylation and activation of receptor. E nd result is inhibition of tumor proliferation.

35.   Scheme of management 

36. Unresectable/metastatic GIST Targeted  therapy with tyrosine kinase inhibitors(TKI) Imatinib mesylate 400mg PO/day 400mg twice daily in progressive disease Sunitinib malate 50mg PO/day for 4 weeks + 2 weeks of drug free interval as second line treatment Regorafenib 160mg PO/day for 21 days of 28days cycle when advanced GISTs no longer respond to imatinib or sunitinib Surgery Palliative resection may benefit in select cases responding to targeted therapy

37. Prognosis   Despite a  macroscopically complete resection, 50 % recurrences are noted at median of 24 months Overall 5 year survival rates 30-60% Localized primary Median survival of 5 years Metastatic or recurrent disease Median survival 10-20 months

38. Prognostic factors Tumor   size Smaller the size better prognosis Mitotic index Low mitotic rate ≤ 5 – better prognosis Tumor site of origin Gastric GISTs have better prognosis Stage of disease L ocalized primary have better prognosis R0 or R1 resection has better prognosis than R2 Mutational status KIT exon11 mutation has better prognosis

39. Follow  up Localized GIST History, physical examination and contrast CT abdomen & pelvis every 3-6 months for the first 3-5 years then annually Endoscopic surveillance for gastric GISTs without high risk features at 6-12 months interval Metastatic/gross residual GIST History and physical examination and abdominal/pelvic CT every 3-6 months.

40. Conclusion (GISTs) are most common mesenchymal neoplasms of GI tract(80%) 95% of GISTs stain positively for KIT (CD117) Over 85% of GISTs have activating KIT mutations Every GIST carries risk of malignancy from very low to very high Occurs in stomach more commonly(40-60%) Surgery is principal & only potentially curative treatment for GIST T reatment of localized GIST is R0 resection + adjuvant Imatinib Targeted therapy using TKI form mainstay of treatment for advanced GISTs  

41. TKI therapy has shown improved prognosis of localised & advanced GISTs Cytoreductive surgery may be considered in a subset of patients with advanced disease Recurrences are common needing lifelong follow up

42. REFERANCE Bailey and love short practice of surgery 28 th edition. Sabiston Textbook of Surgery 21 st edition. Schwartz principle of surgery 11 th edition Maingot's Abdominal Operations 13 th edition

43. THANK YOU