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Prof SM Chandramohan Professor and HOD Department of Surgical Gastroenterology Center of Excellence for Upper GI Surgery Rajiv Gandhi Government General.

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Presentation on theme: "Prof SM Chandramohan Professor and HOD Department of Surgical Gastroenterology Center of Excellence for Upper GI Surgery Rajiv Gandhi Government General."— Presentation transcript:

1 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

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3 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; )

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

5 Clinical Spectrum Benign Intermediate Malignant

6 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

7 < Location

8 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

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

10 CELL OF ORIGIN –Nobel laureate

11 Biomarkers in GIST C KIT

12  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

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

14 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

15 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%)

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

17 D/D

18  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.

19 Pathological types  Exophytic  Endophytic  Combined

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

21 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

22 Histology Spindle pattern Epitheliod pattern

23  Asymptomatic,  Especially early in tumor development,  Discovered incidentally by CT or endoscopy

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

25 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.

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

27 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

28 UGI Scopy

29 EUS- Management process

30  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

31 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.

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

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

34 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.

35 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.

36 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

37  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

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

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

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41 Fletcher 2002 SizeMitotic count Very Low risk<2 cm<5/50 HPF Low risk2-5 cm<5/50 HPF Intermediate risk<5 cm 5-10 cm 6-10/50 HPF <5/50 HPF High risk  >5 cm  >10 cm  Any size  >5/50 HPF  Any count  >10/50 HPF

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43 UICC 2010 TNM 7 th Edition

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

45 Management strategies  Surgery  Surgery + adjuvant Imatinib  Neoadjuvant Imatinib + surgery

46 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).

47  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: )

48 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

49 Irregular border Cystic spaces Ulceration Echogenic foci Heterogeneity

50 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

51 Esophageal GISTs

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

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54 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

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

56 Lap. Transgastric ….

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

58 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

59 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

60 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

61 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).

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

63 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

64 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.

65 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.

66 Imatinib Therapy

67 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.

68 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

69 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

70 PET-Response to imatinib  Decreases the tumour avidity for 18 F-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.

71  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.

72 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.

73 Metastatic GISTs

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

75 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.

76 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.

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