GIST -Current Trends Prof SM Chandramohan Professor and HOD Department of Surgical Gastroenterology Center of Excellence for Upper GI Surgery Rajiv Gandhi Government General Hospital Madras Medical College Chennai

smchandra@yahoo.com

Epidemiology Most common mesenchymal neoplasm of the GI tract. 0.1%-3% of all GI malignant tumors Median age of 60 years (40-80) No predilection for either gender (Miettinen M, Eur J Cancer 2002, Rossi CR, Int J Cancer 2003; )

Clinicopathological features, Treatment implications. Unique Biologic behavior, Clinicopathological features, Molecular mechanisms Treatment implications.

Clinical Spectrum Benign Intermediate Malignant

History 1960 Smooth muscle neoplasm of GIT 1980 Immunohistochemistry Smooth muscle & neuronal differentiation and null 1983 MAZUR &CLARK Coined the term GIST 1998 c-KIT proto-oncogene

Location <

Multicentric GISTs - <5% “Extra” GISTs Sites Other than GIT, - genito urinary,portal vein, pancreas “Micro” GISTs - Size <2 cm “Giant” GISTs - ? 5 cm ? 10 cm

CELL OF ORIGIN Interposed between smooth muscle and nerve endings. Pacemaker—propagates intrinsic peristalsis Interstitial” cells of CAJAL Santiago ramon y cajal -1893

CELL OF ORIGIN –Nobel laureate

Biomarkers in GIST C KIT

KIT is a 145-kDa glycoprotein CD117 -epitope on the extra-cellular domain of the KIT receptor. Steel factor (SLF) stem-cell factor ligand for KIT. Binding of SLF to KIT -activation of KIT tyrosine kinase activity -downstream signaling pathways -uncontrolled cell proliferation

KIT Mutations 20 mutations Exon 11 Most common Better response to imatinib Exon 9 Common in small bowel Poor response to imatinib.

Wild-type GIST (WT-GIST) GISTs that have no detectable KIT or PDGFRA mutations- (10%-15%) DOG gene Discovered On GIST-1 gene in CH 11q13 DOG1 is a calcium dependent, receptor activated chloride channel protein expressed in GIST-independent of mutation type

Immunohistochemistry Gastrointestinal Mesenchymal Tumor C-kit (+) or CD 34 (+) GIST (80%) C-kit (-) or CD 34 (-) SMA (+) or Desmin (+) Leiomyoma (15%) S-100 (+) Neurinoma (5%)

GIST CD 117 - >95% CD 34 – 60-70% Vimentin Actin - 15-30% Lymphoma B-cell- CD 20,CD 79 T-Cell- CD 3,CD 5

D/D

Pathology Few millimeters to more than 30 cm, (median size -5 and 8 cm.) Muscularis propria layer of GI wall Exophytic growth. Mucosal ulceration-50% cases. Mass attached to the stomach, projecting into the abdominal cavity and displacing other organs.

Pathological types Exophytic Endophytic Combined

Smooth Gray and white tumors Well circumscribed Pseudocapsule Small areas of hemorrhage Cystic degeneration Necrosis

Spindle cell Epitheloid Mixed pattern HistoPathology Nuclear palisading or prominent perinuclear vacuolization pattern Spindle cell Solid pattern or a myxoid pattern, with a possible compartmental pattern Epitheloid Both spindle cell and epitheloid pattern Mixed pattern

Histology Spindle pattern Epitheliod pattern

CLINICAL PRESENTATION… Asymptomatic, Especially early in tumor development, Discovered incidentally by CT or endoscopy

Symptomatic GISTs Vague abdominal discomfort (60%-70%). Bleeding (30%-40%). Perforation (20%) Anorexia, weight loss, nausea, anemia, and additional GI complaints

Site specfic symptoms Esophageal GISTs -dysphagia, Gastric and small intestinal GISTs - Bleeding &Intestinal obstruction. Duodenal GISTs - Biliary Obstruction Colorectal GISTs – -pain and GI obstruction, and lower intestinal bleeding.

Acute Presentation Bleeding peritoneal cavity- Ruptured Gist GI tract lumen- hematemesis, melena or anemia Obstruction Over growth Intussusception Volvulus

Syndromes linked to GISTs (i) Carney triad Gastric GISTs, Paraganglioma, Pulmonary chondromas. (ii) Type-1 neurofibromatosis Generally wild-type Predominantly located at the small bowel Possibly multicentric . (iii) Carney-Stratakis syndrome Germ-line mutations of succinate dehydrogenase Dyad of GIST and paraganglioma

UGI Scopy

EUS- Management process

Contrast enhanced computed tomography (CECT) Modality of choice. To characterize the lesion&evaluate its extent. To assess the presence or absence of metastasis at the initial staging workup. Monitoring response to therapy Performing follow-up surveillance of recurrence

Magnetic Resonance Imaging Provides better soft-tissue contrast resolution and direct multiplanar imaging Helps to localise the tumour Delineate the relationships of the tumour and adjacent organs. Particularly of benefit in anorectal disease.

MRI Axial T2-weighted MR image Extraluminal mass arising from the greater curvature of the stomach. The mass shows high signal intensity

Benign gastric fundal GIST- MRI Axial T1-weighted Axial T2-weighted Axial enhanced T1-weighted Homogeneous iso-intensity Homogeneous medium lintensity Homogeneous moderate enhancement

CT or MRI large exophytic tumor with heterogeneous contrast enhancement, arising from the stomach or small bowel. Metastases, if present, are usually to the liver or peritoneum. Lymph node enlargement is uncommon.

CT&MRI-D/D Lymphomas Circumferential with homogeneous enhancement Lymph node enlargement. Carcinoid tumors Found in the distal ileum,or root of the mesentery, Desmoplastic reaction with calcifications. Large carcinomas More likely to cause visceral obstruction.

FDG-PET Reveals small metastases Establish baseline metabolic activity Assess therapy response Helps to clarify ambiguous findings seen on CT or MRI To assess complex metastatic disease in patients who are being considered for surgery

Changes in the metabolic activity of tumors precede anatomic changes on CECT. used to assess the response to Imatinib therapy. Routine use of PET for surveillance after resection is not yet recommended

FNAC/BIOPSY FNA- controversial -risk of rupture and dissemination Resectable lesion in the absence of metastatic disease “Preoperative diagnosis may be unnecessary”

Biopsy-Indications If diagnosis would impact the extent of resection Prior to Neoadjuant therapy Unresectable GISTs Metastatic GISTs

Fletcher 2002 Size Mitotic count Very Low risk <2 cm <5/50 HPF Intermediate risk <5 cm 5-10 cm 6-10/50 HPF High risk >5 cm >10 cm Any size >5/50 HPF Any count >10/50 HPF

UICC 2010 TNM 7th Edition

Management Guidelines International Conference and Workshop, ESOINDIA GUIDELINES International Conference and Workshop, Jan 2014,Chennai.

Management strategies Surgery Surgery + adjuvant Imatinib Neoadjuvant Imatinib + surgery

Site specific surgery Esophagus: Esophagectomy Esophageal sparing wide local excision Stomach Small-wedge resection Large-subtotal/total gastrectomy (BlumMG et al,AnnThoracSurg2007; WinfieldRDetal.AmSurg2006; WayneJD et al SurgClinNorthAm2005).

Duodenum: Partial duodenal resection Whipple’s Procedure Small Intestine: Segmental resection Colon: Colectomy Rectum: Anterior resection/ Abdominoperineal resection (Blay JY et ai.Ann Oncology 2005;16:566-57 )

Principles of surgery AIM: To obtain complete resection with maximal organ preservation with macroscopic negative margin. Great care should be taken to avoid rupture of pseudocapsule Re resection is generally not indicated for microscopically positive margins on final pathology Lymphadenectomy is not required

Irregular border Cystic spaces Ulceration Echogenic foci Heterogeneity

Resection margin 1-2 cm margin is necessary for an adequate resection Tumor size Main determining factor for survival Complete resection with gross negative margin is acceptable. De Matteo et al,Ann Surg 2000

Esophageal GISTs

Gastric GIST- CECT- Coronal multiple planar reformation Exophtic-growth Heterogeneous enhancement. Intact mucosa

Laparoscopic Approach -NCCN Guidelines Select GISTs in favorable anatomic locations -Greater curvature or Anterior wall of stomach -Jejunum or ileum Preservation of pseudo capsule Specimen retrieval through Plastic bag -Avoidance of tumor spillage & port site seeding

Minimally invasive (Privette et all-2008) Type1: Lap. Stapled partial gastrectomy Type2: lap.distal gastrectomy Type3: lap.transgastric resection.

Lap. Transgastric ….

LEGGS-Laparoscopic endoscopically- guided gastric surgery LECS-Laparoscopic and endoscopic cooperative surgery

Laparoscopic and endoscopic cooperative surgery (LECS). Mucosal&submucosal dissection – Endoscopy Seromuscular resection by laparoscopy Enables tumor resection with minimal surgical Margin. Useful in esophagogastric junction or pyloric ring GISTs

Small bowel GISTs May occur throughout the small intestine Signs and symptoms of obstruction or rarely with hemorrhage . They may appear as intramural masses or intraluminal polyps, and may show extension into adjacent mesentery

Small bowel Vs Gastric GISTs More commonly associated with Neurofibromatosis 1 More frequent exon 9 mutations More frequently malignant Intestinal obstruction more common than bleeding

Small bowel GIST-CT -exophytic mass with an irregular margin, heterogeneous contrast enhancement, Central gas within the tumor with a gas-fluid level (arrow). Central calcifications (arrow).

Extension into the adjacent small bowel colon, bladder, ureter, and abdominal wall may occur. Adenocarcinoma annular lesion in the proximal small intestine Lymphoma. similar features associated lymphadenopathy

Anorectal GISTs Well-defined, eccentric mural masses that expand the rectal wall and may contain mucosal ulceration. The mass spreads via extension into the ischiorectal fossa, prostate, or vagina. As in GISTs at other locations, central areas of hemorrhage can be seen

Rectal GIST MRI should be used in rectal GIST as it provides better preoperative staging information Endoscopic ultrasound and MRI assessment followed by biopsy and wide excision is the standard approach, regardless of tumor size.

Colonic GISTs Transmural tumors that involve the intraluminal and extraserosal surfaces of the colon. Cystic change, hemorrhage, necrosis, or calcification are common Circumferential growth with secondary dilatation of the affected colonic segment.

Imatinib Therapy

Neoadjuvant imatinib GIST that is resectable with negative margins but with significant morbidity A multivisceral resection is indicated To optimize timing of surgery To facilitate organ function-sparing resections.

Imatinib-Dosage Initial dose 400 mg daily Dose escalation Pts with Progressive disease Pts with KIT mutation in exon 9 Upto 800mg daily(400 mg BD) depending upon the tolerance

Imatinib- Duration of Threapy Preop 6–12 months until max.response is reached Periop stopped 2–3 days before surgery resumed promptly when the patient recovers from surgery. Post op High Risk of relapse- 3 years (Level 1 a) Low Risk - Adjuvant therapy not recommended. Intermediate Risk- Controversial

PET-Response to imatinib Decreases the tumour avidity for 18F-FDG PET imaging could detect the biological activity of imatinib far earlier than changes in anatomic measures on CT scanning. PET changes as early as 24 hours following a single dose of imatinib.

Sunitinib -second-line drug treatment. -For patients whose GIST tumors become resistant to imatinib.   Regorafenib -FDA-2013 approved as a third- line drug for patients whose tumors are not responding to imatinib or sunitinib.

Metastatic GISTs Distant metastases most commonly involve liver (50-65%) & peritoneum (21-43%) Only 10% of metastatic lesions occur in the lungs or bones GISTs rarely spread to regional lymph nodes (<10%) On presentation, 41-47% of malignant GISTs are metastatic.

Metastatic GISTs

Prognostic factors for RFS Large tumor size, High mitotic count, Nongastric location, Presence of rupture, Male sex (H. Joensuu et al, The Lancet 2011.)

Prognosis… The 5-year survival for malignant GIST 28 to 80%. Median survival after incomplete surgery 10–23 months. The median survival for metastatic or recurrent disease 12 to 19 months.

FOLLOW UP-ESMO Guidelines High-risk patients CT scan or MRI Every 3–6 months for first 3 years Every 3 months for next 2 years, Every 6 months for next 3 years Annually for an additional 5 years. For low-risk tumors, CT scan or MRI every 6–12 months for 5 years. Very low-risk GISTs -probably do not deserve routine followup, although one must be aware that the risk is not nil.