Presentation on theme: "GIST -Current Trends Prof SM Chandramohan Professor and HOD"— Presentation transcript:
1GIST -Current Trends Prof SM Chandramohan Professor and HOD Department of Surgical GastroenterologyCenter of Excellence for Upper GI SurgeryRajiv Gandhi Government General HospitalMadras Medical CollegeChennai
3Epidemiology Most common mesenchymal neoplasm of the GI tract. 0.1%-3% of all GI malignant tumorsMedian age of 60 years (40-80)No predilection for either gender(Miettinen M, Eur J Cancer 2002,Rossi CR, Int J Cancer 2003; )
12KIT 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
13KIT Mutations 20 mutations Exon 11 Most common Better response to imatinibExon 9Common in small bowelPoor response to imatinib.
14Wild-type GIST (WT-GIST) GISTs that have no detectable KIT or PDGFRA mutations- (10%-15%)DOG geneDiscovered On GIST-1 gene in CH 11q13DOG1 is a calcium dependent, receptor activated chloride channel protein expressed in GIST-independent of mutation type
15Immunohistochemistry Gastrointestinal Mesenchymal TumorC-kit (+) or CD 34 (+)GIST (80%)C-kit (-) or CD 34 (-)SMA (+) or Desmin (+)Leiomyoma (15%)S-100 (+)Neurinoma (5%)
16GIST CD 117 - >95% CD 34 – 60-70% Vimentin Actin - 15-30% Lymphoma B-cell- CD 20,CD 79T-Cell- CD 3,CD 5
18Pathology Few millimeters to more than 30 cm, (median size -5 and 8 cm.)Muscularis propria layer of GI wallExophytic growth.Mucosal ulceration-50% cases.Mass attached to the stomach, projecting into the abdominal cavity and displacing other organs.
20SmoothGray and white tumorsWell circumscribedPseudocapsuleSmall areas of hemorrhageCystic degenerationNecrosis
21Spindle cell Epitheloid Mixed pattern HistoPathology Nuclear palisading or prominent perinuclear vacuolization patternSpindle cellSolid pattern or a myxoid pattern, with a possible compartmental patternEpitheloidBoth spindle cell and epitheloid patternMixed pattern
23CLINICAL PRESENTATION… Asymptomatic,Especially early in tumor development,Discovered incidentally by CT or endoscopy
24Symptomatic GISTs Vague abdominal discomfort (60%-70%). Bleeding (30%-40%).Perforation (20%)Anorexia, weight loss, nausea, anemia, and additional GI complaints
25Site specfic symptoms Esophageal GISTs -dysphagia, Gastric and small intestinal GISTs- Bleeding &Intestinal obstruction.Duodenal GISTs- Biliary ObstructionColorectal GISTs –-pain and GI obstruction, and lower intestinal bleeding.
26Acute Presentation Bleeding peritoneal cavity- Ruptured Gist GI tract lumen-hematemesis, melena or anemiaObstructionOver growthIntussusceptionVolvulus
27Syndromes linked to GISTs (i) Carney triadGastric GISTs,Paraganglioma,Pulmonary chondromas.(ii) Type-1 neurofibromatosisGenerally wild-typePredominantly located at the small bowelPossibly multicentric .(iii) Carney-Stratakis syndromeGerm-line mutations of succinate dehydrogenase Dyad of GIST and paraganglioma
30Contrast 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 therapyPerforming follow-up surveillance of recurrence
31Magnetic Resonance Imaging Provides better soft-tissue contrast resolution and direct multiplanar imagingHelps to localise the tumourDelineate the relationships of the tumour and adjacent organs.Particularly of benefit in anorectal disease.
32MRI Axial T2-weighted MR image Extraluminal mass arising from the greater curvature of the stomach.The mass shows high signal intensity
34CT or MRIlarge 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.
35CT&MRI-D/D Lymphomas Circumferential with homogeneous enhancement Lymph node enlargement.Carcinoid tumorsFound in the distal ileum,or root of the mesentery,Desmoplastic reaction with calcifications.Large carcinomasMore likely to cause visceral obstruction.
36FDG-PET Reveals small metastases Establish baseline metabolic activity Assess therapy responseHelps to clarify ambiguous findings seen on CT or MRITo assess complex metastatic disease in patients who are being considered for surgery
37Changes 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
38FNAC/BIOPSY FNA- controversial -risk of rupture and dissemination Resectable lesion in the absence of metastatic disease“Preoperative diagnosis may be unnecessary”
39Biopsy-Indications If diagnosis would impact the extent of resection Prior to Neoadjuant therapyUnresectable GISTsMetastatic GISTs
44Management Guidelines International Conference and Workshop, ESOINDIA GUIDELINESInternational Conference and Workshop,Jan 2014,Chennai.
45Management strategies SurgerySurgery + adjuvant ImatinibNeoadjuvant Imatinib + surgery
46Site specific surgery Esophagus: Esophagectomy Esophageal sparing wide local excisionStomachSmall-wedge resectionLarge-subtotal/total gastrectomy(BlumMG et al,AnnThoracSurg2007; WinﬁeldRDetal.AmSurg2006;WayneJD et al SurgClinNorthAm2005).
48Principles of surgery AIM: To obtain complete resection with maximal organ preservation with macroscopic negative margin.Great care should be taken to avoid rupture of pseudocapsuleRe resection is generally not indicated for microscopically positive margins on final pathologyLymphadenectomy is not required
50Resection margin 1-2 cm margin is necessary for an adequate resection Tumor sizeMain determining factor for survivalComplete resection with gross negative margin is acceptable.De Matteo et al,Ann Surg 2000
54Laparoscopic Approach -NCCN Guidelines Select GISTs in favorable anatomic locations-Greater curvature or Anterior wall of stomach-Jejunum or ileumPreservation of pseudo capsuleSpecimen retrieval through Plastic bag-Avoidance of tumor spillage & port site seeding
57LEGGS-Laparoscopic endoscopically- guided gastric surgery LECS-Laparoscopic and endoscopic cooperative surgery
58Laparoscopic and endoscopic cooperative surgery (LECS). Mucosal&submucosal dissection – EndoscopySeromuscular resection by laparoscopyEnables tumor resection with minimal surgical Margin.Useful in esophagogastric junction or pyloric ring GISTs
59Small 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
60Small bowel Vs Gastric GISTs More commonly associated with Neurofibromatosis 1More frequent exon 9 mutationsMore frequently malignantIntestinal obstruction more common than bleeding
61Small 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).
62Extension into the adjacent small bowel colon, bladder, ureter, and abdominal wall may occur. Adenocarcinomaannular lesion in the proximal small intestineLymphoma.similar featuresassociated lymphadenopathy
63Anorectal GISTsWell-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
64Rectal GISTMRI should be used in rectal GIST as it provides better preoperative staging informationEndoscopic ultrasound and MRI assessment followed by biopsy and wide excision is the standard approach, regardless of tumor size.
65Colonic GISTsTransmural tumors that involve the intraluminal and extraserosal surfaces of the colon.Cystic change, hemorrhage, necrosis, or calcification are commonCircumferential growth with secondary dilatation of the affected colonic segment.
67Neoadjuvant imatinibGIST that is resectable with negative margins but with significant morbidityA multivisceral resection is indicatedTo optimize timing of surgeryTo facilitate organ function-sparing resections.
68Imatinib-Dosage Initial dose 400 mg daily Dose escalation Pts with Progressive diseasePts with KIT mutation in exon 9Upto 800mg daily(400 mg BD) depending upon the tolerance
69Imatinib- Duration of Threapy Preop6–12 months until max.response is reachedPeriopstopped 2–3 days before surgeryresumed promptly when the patient recovers from surgery.Post opHigh Risk of relapse- 3 years (Level 1 a)Low Risk Adjuvant therapy not recommended.Intermediate Risk- Controversial
70PET-Response to imatinib Decreases the tumour avidity for 18F-FDGPET 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.
71Sunitinib-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.
72Metastatic GISTsDistant metastases most commonly involve liver (50-65%) & peritoneum (21-43%)Only 10% of metastatic lesions occur in the lungs or bonesGISTs rarely spread to regional lymph nodes (<10%)On presentation, 41-47% of malignant GISTs are metastatic.
74Prognostic factors for RFS Large tumor size,High mitotic count,Nongastric location,Presence of rupture,Male sex(H. Joensuu et al, The Lancet 2011.)
75Prognosis… The 5-year survival for malignant GIST 28 to 80%. Median survival after incomplete surgery –23 months.The median survival for metastatic or recurrent disease12 to 19 months.
76FOLLOW UP-ESMO Guidelines High-risk patientsCT scan or MRIEvery 3–6 months for first 3 yearsEvery 3 months for next 2 years,Every 6 months for next 3 yearsAnnually 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.