Gastro-Intestinal Stromal Tumor (GIST)

The experience of Chia-Yi Chang-Gung Hospital

葉重宏 王正儀 嘉義長庚紀念醫院 大腸直腸外科

Introduction Gastro-intestinal Stromal Tumors (GIST

s) Mesenchymal tumors which express sp

ecially c-kit (CD117) and/or CD34

less than 0.1 % of all colorectal malignancies.

Cases Presented

Case 1 Name : x x x

Age : 62 Y/O

Sex : Male

Chart No. : 360xx07

Chief Complaint

A perianal mass was noted for 2 years

Brief history The 62 Y/O male patient was generally

healthy before. A perianal mass was noted since 2 years ago. The mass became larger recently, and he came to our OPD for help.

Past History : denied history of systemic disease Personal History : allergic history of penicillin Family history : Non-contributory

Physical examination Consciousness : Clear HEENT : Not icteric, not anemic Chest : Symmetric expansion Heart : RHB, No murmur Abdomen : No palpable mass Extremities : Full and free Perineum : A perianal tumor over L’t lat. aspect – Hard, fixed, pain +, tenderness (–) Diameter : 5 cm x 5 cm

C X R Film

Fibrocolonoscopy

ABD CT Scan (I)

ABD CT Scan (II)

Trans-rectal ultrasound sonography

5 cm level 4 cm level

2 cm level Anal verge

Preoperative Diagnosis

Para-rectal tumor R/O Rectal GIST

Operative procedure

Abdomino-Perineal Resection ( APR )

Operative finding

A para-rectal tumor over L’t lat. to L’t post. aspect, locating beneath the dentate line.

Well circumscribed, lobulated, solid, light tan, firm, Adhering with the lower rectal wall and anal sphincter

Pathological Report Anorectum, Abdominoperineal resection -- An anorectal tumor composed of lobules

of spindle cells with mild nuclear atypia and high mitotic rate ( > 20 MFS/10 HPF )

Immunohistochemical Stain : c-KIT (+), CD34 (+), S-100 (-), SMA (-) Lymph Node, Regional --Negative for malignancy ( 28/28 ) Gastrointestinal Stromal Tumors

H. E. Stain

C-KIT Positive Stain

CD34 Positive Stain

ABD CT Scan follow up (I)

ABD CT Scan follow up (II)

Case 2 Name : x x x

Age : 69 Y/O

Sex : Female

Chart No. : 9208xx80

Chief Complaint

Lower back pain was noted for 2 months

Brief history The 69 Y/O female patient was a case 0f malignant ne

urilemoma post ATH +BSO at TCVGH 2 years ago. The post-operative courses was smooth. Lower back pain was noted since 2 months ago, and recurrent pelvic tumor was noted. She accepted therapy of STI-571 for 7 weeks at MMH. Then she came to our OPD for help.

Past History : denied history of systemic disease except thrombocytopenia Personal History : Denied any allergic history Family history : Non-contributory

Physical examination Consciousness : Clear HEENT : Not icteric, not anemic Chest : Symmetric expansion Heart : RHB, No murmur Abdomen : No palpable mass Extremities : Full and free Perineum : An extramural tumor over mid-

rectum with moderate induration, pain + Diameter : 3 cm x 2 cm

C X R Film

Fibrocolonoscopy

ABD CT Scan (I)

ABD CT Scan (II)

ABD CT Scan (III)

ABD CT Scan (IV)

Preoperative Diagnosis

Recurrent pelvic Gastrointestinal Stromal Tumor (GIST)

Operative procedure

Restorative proctectomy with colonic-J-pouch anal anastomosis with diverting T-loop colostomy

Operative finding

A para-rectal tumor over R’t lat. pelvic side wall with mesorectal invasion, 2 cm above the dentate line. Vaginal stump invasion (+)

Pathological Report Rectum, restorative proctectomy -- A 2x1.5 cm induration tumor composed of

lobules of spindle cells with mild nuclear atypia and low mitotic rate ( <3 MFS/50 HPF )

Invasion the rectal serosa, Vaginal (-), pelvic side wall (-) Immunohistochemical Stain : c-KIT (+), CD34 (+), S-100 (+), SMA (-) Lymph Node, Regional --Negative for malignancy ( 11/11 ) Recurrent Gastrointestinal Stromal Tumors

Case 3 Name : x x x

Age : 43 Y/O

Sex : Male

Chart No. : 354xx29

Chief Complaint

Tenesmus and perineal soreness were noted for several months

Brief history The 43 Y/O male patient was a case of huge rectal

GIST ( 9 x 8 x 5 cm3 ) post restorative proctectomy with T-loop colostomy at LKCGMH one and a half years ago. The post-operative courses was smooth. Frequent bowel movement, tenesmus and perineal soreness were noted for several months, and recurrent GIST was noted after trans-rectal needle biopsy. He came to our OPD for help.

Past History : denied history of systemic disease Personal History : Denied any allergic history Family history : Non-contributory

Physical examination Consciousness : Clear HEENT : Not icteric, not anemic Chest : Symmetric expansion Heart : RHB, No murmur Abdomen : No palpable mass, Op Scar + Extremities : Full and free Perineum : An induration lesion over anastomotic ring, R’t post. Aspect . pain + Tenderness + Diameter : 2 cm x 2 cm

C X R Film

ABD CT Scan (I)

ABD CT Scan (II)

Preoperative Diagnosis

Recurrent Rectal Gastrointestinal Stromal Tumor (GIST)

Operative procedure

Abdominoperineal Resection (APR)

Operative finding

An induration lesion around previous anastomotic site with extension to L’t para-prostate tissue and R’t pelvic side wall with R’t ureter invasion ( U-V junction ), 1 cm above the dentate line.

Pathological Report Anorectum, APR -- A 2x2 cm induration tumor composed of highly cell

ular spindle cells with moderate cell pleomorphism and high mitotic rate ( 1-2 MFS / HPF ), located within the muscular layer

Local abscess formation(+) Immunohistochemical Stain : c-KIT (+), CD34 (+), S-100 (-), SMA (-) Lymph Node, Regional --Negative for malignancy ( 11/11 ) Recurrent Gastrointestinal Stromal Tumors

H. E. Stain

C-KIT Positive Stain

CD34 positive stain

Gastrointestinal Stromal Tumor

G I S T

INTRODUCTION (1)

1983 – Mazur and Clark –the term Describe gastrointestinal non-epithelial neop

lasms lacking the immunohistochemical features of Schwann cells and the ultrastructural characteristics of smooth-muscle cell

1988 – Hirota and colleagues Discovery of gain-of-function mutation in the

KIT proto-oncogene in GISTs

INTRODUCTION (2) Mesenchymal tumors of GI tract which

express specially c-kit (CD117) and/or CD34

Previously regarded as : Leimyoma Leimyosarcoma Leiomyoblastoma Neurilemoma

INTRODUCTION (3) Histology Highly cellular spindle cell or epithelioid me

senchymal tumors Immunohistochemical study Expression of c-kit protein CD34 70% Smooth muscle actin 20~30% S-100 protein 10% Desmin 2~4%

Prevalence– 0.2% of gastrointestinal (GI) tumours– Incidence: 3000 to 5000 cases in the US

Similar male-to-female ratio Highest incidence in 5th to 7th decade

s of life

Distribution Stomach 60 ~ 70% Small intestine 25 ~ 35% Colon, rectum 5% Esophagus < 2% Omentum, mesentery, retroperitoneum GISTs of the colon and the rectum are

less than 0.1 % of all colorectal malignancies.

Clinical Presentation Vague GI pain or discomfort

GI hemorrhage

Other symptoms include anorexia, weight loss, nausea, anemia, and additional GI complaints

Often asymptomatic, especially early in tumor development

Malignant GISTs are about 20% ~ 30 %

Prediction of malignancy >= 5 mitosis / 50 HPF Tumor size > 5 cm -- High frequency of intra-abdominal recurrenc

e and liver metastasis

Malignant Behaviour of the GISTs

Distant metastasis : Liver Lung Bone Brain Local recurrence Intra-abdominal dissemination

Treatment

Surgical resection **

Resistant to chemotherapy

Resistant to radiotherapy

Imatinib mesylate (STI-571) ***

Outcome of Surgical treatment Surgery is primary treatment modality for

GISTs– 5-year survival 50% to 65%– Recurrence after a decade or more

If incomplete resection/metastatic at presentation– Median survival <1 year– 5-year survival <35%

If disease unresectable– Median survival 9 to 12 months

Outcome of Surgical treatmentof Rectal GISTs Local resection : 67.5% ~ 86 % local recurrence

Abdominoperineal Resection : : 19.5% local recurrence

Surgical Outcome of Rectal GISTs of CGMH 40 cases of rectal GISTs with radic

al resection　　　

1-year 3-year 5-yearOverall survival 97% 90% 75%Disease-free survival 90% 59% 46%

Imatinib mesylate (STI-571)

( Gleevec, Glivec )

A specific inhibitor of c-Kit tyrosine kinase activity, and blocks c-Kit–mediated downstream signaling

The Biology of c-Kit c-Kit is found in many normal tissues and is

essential for– Haematopoiesis – Melanogenesis– Gametogenesis– Interstitial cells of Cajal development

Activation of c-Kit plays a critical role in different cell functions– Proliferation – Differentiation – Apoptosis/survival – Adhesion/chemotaxis

Gain-to-function mutation in the c-kit proto-oncogene

constitutive activation of Kit receptor tyrosine kinase

induce cellular proliferation and decrease

apoptosis

Imatinib: CML Phase II Results

% of Patients (CI95%)

Study 0110 Chronic Phase IFN- Failure

(N=454)

Study 0109 Accelerated

Phase (N=235)

Study 0102 Blast Crisis

(N=229)

Haematological response 95%

_

71%

(61.8–75.7)

31%

(24.7–37.0)

Major cytogenetic response

60%

_

26%

(17.8–30.6)

16%

(11.6–21.6)

Complete 41% 17% 7% Partial 19% 7% 9%

Kantarjian et al. N Engl J Med. 2002;346:645-652.Talpaz et al. Blood. 2002;99:1928-1937.Sawyers et al. Blood. 2002;99:3530-3539.

GIST Phase II: Best Confirmed Responses

-- July 10, 2001

n (%)Complete response (CR) 0Partial response (PR) 59 (40)Stable disease (SD) 61 (41)

Unconfirmed PR 28 (19)25% to 49% reduction in tumor19 (13)

Progressive disease (PD) 18 (12)

Nonevaluable 7 (5)

Unknown (UNK) 2 (1)

Summary Colon and rectal GISTs are rare colon

and rectal malignancies

Radical resection provide the only chance of curative treatment.

STI-571 ( Glivec ) may be beneficial for the cases of unresectable tumors, distant metastasis, and carcinomatosis.

Thank You !