GIST -CURRENT TRENDS

Prof SM ChandramohanProfessor and HOD

Department of Surgical GastroenterologyCenter of Excellence for Upper GI Surgery

Rajiv Gandhi Government General HospitalMadras 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; )

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” GISTsSites 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

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

HistoPathology

• Nuclear palisading or prominent perinuclear vacuolization patternSpindle cell

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

• Both spindle cell and epitheloid patternMixed

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 enhanced T1-weightedAxial T2-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

Low risk 2-5 cm <5/50 HPF

Intermediate risk <5 cm5-10 cm

6-10/50 HPF<5/50 HPF

High risk >5 cm>10 cmAny size

>5/50 HPF Any count>10/50 HPF

UICC 2010 TNM 7th Edition

Management Guidelines

ESOINDIA GUIDELINESInternational 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 borderCystic spaces

UlcerationEchogenic fociHeterogeneity

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

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.