Gastrointestinal Stromal Tumors - Department of Surgery … · of gastric gastrointestinal stromal...

Gastrointestinal Stromal Tumors

Grand Rounds

Sept 9, 2010

www.downstatesurgery.org

Outline

• Case• Epidemiology• Pathology• Clinical presentation• Treatment for primary/recurrent/metastatic

disease• Adjuvant / Neoadjuvant therapy• Laparoscopic resection


Case - History

• HPI: – 61 yo M, recent h/o bilat inguinal hernia repair.– Abdominal CT for post-op pain revealed gastric

mass.– Endoscopic bx consistent with GIST.– At presentation, denied GI symptoms (bleeding,

dysphagia, N/V, fullness, hematochezia).

• PMH: neg• PSH: per HPI


Case - Exam

• AF, 76, 108/74

• WNWD male; appearance consistent with age

• NC, neck supple, no LA

• RRR

• CTAB

• SNTND, no organomegaly; well-healed bilat inguinal hernia scars


Case – Labs

• Na 143

• K 4.0

• Cl 107

• BUN 15

• Cr 0.78

• Ca 9.1

• Alb 4.5

• T Bili 0.6

• AP 53

• AST 17

• ALT 16

• WBC 3.9

• Hgb 14.2

• Hct 42.4

• Plt 149


Case – CT Scanwww.downstatesurgery.org

Case – Tumor Locationwww.downstatesurgery.org

Case – Operation

• Laparoscopic approach.

• 4x4cm tumor freed from lesser omentum using harmonic scalpel taking care to identify L gastric and hepatic arteries.

• Gastric wall abutting mass was resected with endoGIA ensuring 1 cm margin.

• Concurrent endoscopy to visualize gastric lumen.


Case – Pathology

• GIST tumor – 3 x 4 cm.

• CD117 immunostain positive.

• Tumor arises within gastric wall.

• Negative margins.

• Low mitotic rate.

• Stage – pT4 Nx Mx.

• Prognosis – low risk.


Case – Postop

• Tolerating diet, discharged on POD 2.

• FU:– Followed by oncology.

– Started on Gleevec.

– Pt doing well; without complaints.


Epidemiology

– Most common sarcoma of GI tract

– Only 0.2% of all GI tumors

– 7-20 cases per 1 million persons per year in the US


History

• The term ‘GIST’ first used in early 1980s.• Referred to spindle and epithelioid tumors

arising from stromal/mesenchymalcomponents of GI tract.

• True GISTs lacked complete muscle or neural differentiation.

• Up to 2/3 of GISTs were CD34 positive.– Initially used as marker for GISTs.– Neither selective or specific.


History

• CD117 antigen identified– Near-universally expressed in GISTs

– Not expressed in leiomyomas, true leiomyosarcomas, and other spindle-cell tumors


Histology

• Heterogeneous

• Long fascicles of bland spindle cells

• Occasionally epithelioid with eosinophilic cytoplasma and nuclear atypia

• Based on immunohistology, GIST cells thought to arise from Interstitial Cells of Cajal, which are components of intestinal autonomic nervous system that serve as pacemaker cells.


Histologywww.downstatesurgery.org

Molecular Biology

• Molecular basis for GIST is gain of function of KIT proto-oncogene.

• KIT receptor is a Tyrosine Kinase, which is activated when bound to a ligand known as steel factor or stem cell factor.


Molecular Biology

• KIT is important in the development and maintenance of components of hematopoesis, gametogenesis, and intestinal pacemaker cells.

• KIT mutation identified in neoplasms involving:– Mast cell tumors

– Myelofibrosis

– CML

– Germ cell tumors

– GIST


Molecular Biologywww.downstatesurgery.org

Molecular Biology

• 68% - mutation at exon 11

• 11% - mutation at exon 9

• 0.6-4% - mutation at exon 13 or 17

• 7% - gain of function mutation at PDGFRA


Immunohistochemistry

Type CD117 CD34 SMA S100 Desmin

GIST + (>95%) + (60-70%) ± (30-40%) − rare

Leiomyoma − + (10-15%) + − +

Leiomyosarcoma − − + − +

Schwannoma − − − + −


Clinical Presentation

• 40-60 years of age (described in children as young as 10)

• Equal sex distribution

• No racial predilection


Presenting Symptoms

• Most asymptomatic.– Discovered incidentally on imaging or laparotomy

for other reasons.

• Symptoms– Bleeding – MC

– Vague abdominal pain

– Bowel obstruction

– Perforation


DDx of Submucosal Tumors of Intestine

• GIST• Leiomyoma• Leiomyosarcoma• Schwannoma• Malignant peripheral nerve sheath tumor• Solitary fibrous tumor• Inflammatory myofibroblastic tumor• Desmoid tumor• Metastatic melanoma


Evaluation

• Endoscopy

• EUS with FNA

• CT

• PET– Important when assessing chemotherapy

response.


Anatomic Presentation

• Primary GIST can arise throughout GI tract

• Stomach (40-70%)

• Small bowel (20-40%)

• Colorectum (5-15%)

• Esophagus (<5%)


Metastasis

• 15-50% present with overt metastatic disease

• Almost entirely intra-abdominal– Liver and peritoneum MC met sites

– In diffuse disease, may stud omentum, diaphragm, bowel serosa

– Can develop tumor-associated ascites

• Pulmonary metastasis – 5%


Prognostic Features

• Poor prognosis associated with– Large size

– Increased mitotic rate

– Location in SB


Risk Classification for Metastasis

Risk category Size Mitotic Count

Very low < 2 cm < 5 per 50 HPF

Low 2-5 cm < 5 per 50 HPF

Intermediate < 5 cm 6-10 per 50 HPF

5-10 cm < 5 per HPF

High > 5 cm > 5 per 50 HPF

> 10 cm Any mitotic rate

Any size > 10 per 50 HPF


Rates of Progression-free Survival

Tumorsize [cm]

Mitotic rate [HPF]

Gastric Jejunum/ileum

Duodenum Rectum

≤ 2 ≤5/50 100 100 100 100

2 to 5 ≤5/50 98.1 95.7 91.7 91.5

5 to 10 ≤5/50 96.4 7666 43

> 10 ≤5/50 88 48

≤ 2 >5/50 100 50 - 46

2 to 5 >5/50 84 27 50 48

5 to 10 >5/50 45 1514 29

> 10 >5/50 14 10


Presenter

Presentation Notes

Based on long-term follow-up studies on 1055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal cancers. * Data are combined for tumors >5 cm. • Small number of cases. Adapted from: Miettinen, M, et al. Semin Diagn Pathol 2006; 23:70.

Imatinib (Gleevec)www.downstatesurgery.org

Imatinib (Gleevec)

• Imatinib mesylate - Glivic in Europe

• Originally developed to treat CML

• Oral

• Inhibits KIT and PDGFRA protein kinases– Lodges in an ATP-binding pocket that forms upon

receptor dimerization.


Imatinib (Gleevec)

• Effective use in GIST patients first reported in 2001.

• Initially approved for use in US and Europe for advanced or metastatic disease.


Imatinib – Side Effects

• SE– Edema– Nausea– Muscle cramps– Diarrhea– Headache– Dermatitis– Fatigue– Anemia– Neutropenia

• Most SE mild to moderate and tend to resolve with ongoing therapy


Imatinib – KIT Mutation

• Response depends on mutation location– Exon 11 – 72% response

– Exon 9 – 32% response

• Survival dependent on mutation location– Exon 11 – 22.5 months event free

– Exon 9 – 6.6 months

– No mutation – 2.7 months


Surgical Management of Localized Primary Disease

• Surgery is standard therapy for all resectable nonmetastatic tumors.

• Resectable in 70-80% of patients.

• Tumor rupture or violation of tumor pseudocapsule associated with increased risk of recurrence, including disseminated disease.

• If adjacent organs are involved, en bloc resection recommended.


Surgical Management of Localized Primary Disease

• Optimal resection margin has not been established.– As GIST generally do not exhibit infiltrative spread,

a 1 cm margin is usually sought.

• Wider resection of uninvolved tissue confers no additional benefit.

• Routine lymphadenectomy is unnecessary because nodal metastases are rare.


Management of Primary Diseasewww.downstatesurgery.org

Postop Surveillance

• Typical sites of tumor recurrence following resection include:– Resection bed.– Liver.– Peritoneum.

• Timing variable; has been seen as early as 3 months.

• Because more recurrences occur within the first 5 years, imaging every 6 months are routine.

• No serum markers.


Recurrence

• Recurrence rates vary:– 2-15% for low risk

– 70-90% for high risk

• Without adjuvant therapy, at 5 years:– Appx 50% of pts with curative surgery will develop

local or metastatic disease.

– Only 40-55% will survive.


Management of Metastatic Disease

• All unresectable, recurrent, and metastatic GIST are considered for life-long imatinib therapy.

• Median time to response is 3 months.

• Complete response rare.

• 2 year survival for responders – 85-90%.


Adjuvant Therapy

Placebo-Controlled Randomized Trial of Adjuvant Imatinib Mesylate Following the Resection of Localized, Primary Gastrointestinal Stromal Tumor (GIST). Lancet, Mar 2009.

• ACOSOG – sponsored.• Randomized phase 3, double-blind, placebo-

controlled, multicenter trial.• Study period: 2002-2007.


Adjuvant Therapy

• 713 pts randomized to receive imatinib or placebo for 1 year successful primary GIST resection.

• Pts stratified by tumor size.• Pts were allowed to cross over with disease recurrence.• Accrual stopped early based on interim analysis.• Imatinib significantly prolonged RFS compared to

placebo (98% vs 83% at 1 year; HR 0.66; p < 0.0001).• Overall 1 year survival was similar (99.2% vs 99.7%; HR

0.66; p = 0.47).


Recurrence Free Survivalwww.downstatesurgery.org

Overall Survivalwww.downstatesurgery.org

Adjuvant Therapy

• Study addressed questions regarding:– Rx efficicacy vs placebo.– Rx efficicacy stratified by tumor size.

• Study did not address:– Optimal dosing.– Optimal duration of therapy (EORTC, SSG studies

ongoing)

• FDA approved Imatinib for adjuvant therapy for GIST > 3 cm.


Neoadjuvant Therapy

• Surgery is the only potentially curative option for GIST.

• Setting where neoadjuvant therapy may be beneficial:– Unresectable or borderline resectable primary tumor.

– Resectable tumor that requires extensive organ disruption.

• Goal: to facilitate surgery and/or preserve surrounding organs.


Neoadjuvant Therapy

• No randomized trials.• Multicenter RTOG/ACRIN prospective phase II

trial.– Rx for 8-12 weeks preop.– For primary disease, 7% response, 83% stable disease.– For metastatic disease, 5% response, 91% stable

disease.– At median FU of 3 years, 2 year:

• Primary disease – PFS: 83%, OS: 93%.• Met disease – PFS: 77%, OS: 91%.


Long-term Outcomes of Laparoscopic Resection

Long-term outcomes of laparoscopic resection of gastric gastrointestinal stromal tumors. Carolinas Medical Center. Annals of Surgery, 2006.

• Case series of 50 pts over 10 years.

• Laparoscopic resections of gastric GISTs.


Long-term Outcomes of Laparoscopic Resection

• Patient Characteristics– Mean age 60 years (range 34-84 years)– Mean size 4.4 cm (range 1.0 – 8.5 cm)– 9 pts had 10 or more mitotic figures on HPF

• Outcomes at mean follow-up of 36 months– 46 pts (92%) were disease free– 1 pt alive with metastatic disease– 1 pt with met dz, died of cardiac reasons– 2 pt died due to met dz


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