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

[email protected]

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, Molecular mechanisms Biologic behavior, Treatment implications.

Unique

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

Interstitial” cells of CAJAL Santiago ramon y cajal -1893

•

Interposed between smooth muscle and nerve endings.

•

Pacemaker —propagates intrinsic peristalsis

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

D

iscovered

O

n

G

IST-1 gene in CH 11q13  DOG1 is a calcium dependent, receptor activated chloride channel protein expressed in GIST-independent of mutation type

Immunohistochemistry

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

 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

HistoPathology

Spindle cell

• Nuclear palisading or prominent perinuclear vacuolization pattern

Epitheloid

• Solid pattern or a myxoid pattern, with a possible compartmental pattern

Mixed pattern

• Both spindle cell and epitheloid pattern

Histology

Spindle pattern Epitheliod pattern

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

 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

 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

Very Low risk Low risk Intermediate risk High risk Size <2 cm 2-5 cm <5 cm 5-10 cm



>5 cm



>10 cm



Any size Mitotic count <5/50 HPF <5/50 HPF 6-10/50 HPF <5/50 HPF



>5/50 HPF



Any count



>10/50 HPF

UICC 2010 TNM 7

th

Edition

Management Guidelines 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.

D/D  Adenocarcinoma intestine annular lesion in the proximal small  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 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.

 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.