Case Presentation

254-60-51

History

55 years old male, resident of Chaman, Balochistan

Presenting complain: Black stools (melena)- Three months ago

History of presenting complaint:

Complained of black stools for three to four days three months ago. Stool was soft in consistency and no history of constipation or diarrheaAt that time also experienced severe weakness, dizziness and shortness of breath. Family members noticed that he seemed pale and weak. Went to Quetta National Hospital where he was transfused 2 liters of fresh blood (4 packs) anemia

• History of melena one year back, but no weakness at that time

• No history of abdominal discomfort or pain • No nausea or vomiting • No dyspepsia or heart burn• No sour brash • Did complain of early satiety and loss of

appetite• Undocumented weight loss

Review of systems

• Constitutional: weight loss, generalized weakness, no fever

• Respiratory: no cough, wheeze, respiratory difficulty

• Cardiovascular: no tachypnea, dyspnea, edema

• GU: no urinary complaints • MSK: No muscle or joints pains

Past Medical History

• No HTN or DM • No history of PUD/Gastritis • No history of Liver disease, Cirrhosis or Hepatitis• No history of NSAID use, burns, trauma or

surgeries

Medications

• Currently taking Esmoprazole, Motilium and Gaviscon for three months

• No history of NSAID use• No history of Iron supplement • No known allergies to any medications

Personal History

• Appetite reduced • Reduced oily and spicy food in diet • No change in mood • Was a shopkeeper in Chaman • Never smoked or consumed alcohol

Physical Examination

• General Physical • Height: 175 cm, Weight: 63 kg • BMI: 20.6• Pulse: 80 BP: 130/90• Afebrile • No jaundice or anemia• No cervical or supraclavicular

lymphadenopathy

Systemic Examination

• Chest: Clear, NVB bilaterally• CVS: S1 + S2 and no added sounds• Abdomen: soft non tender, GS +ve

• No ascites, hepatosplenomegaly or signs of CLD

Summary

• 55 years of male, no known comorbid, complaining of melena, weakness, loss of appetite and weight loss for one year.

• Differentials?

Differentials

• Gastric Cancer

• Peptic Ulcer Disease

• Gastritis

• Next step in management?

Investigations

• CBC • Clotting profile: PT, APTT• LFT, Albumin, Cr, BUN • Endoscopy (EGD) with biopsy

Labs • Hb: 13.8 Hct: 42• WBC: 6.7• Platelet: 250 • Cr. 0.8 BUN: 11• Albumin: 4.8• PT: 11 sec APTT: 32 sec• SGPT: 35 • SGOT: 30

Endoscopy (27th July 2013) • Esophagus: Normal

• GE Junction at 38 cm

• Stomach: Mild erythema with polypoidal mushroom like growth with central pitting like ulceration seen along the greater curvature. Biopsy of mass taken

• Duodenum: Normal

Biopsy (3rd August 2013)• Histopathology report:

• Specimen was 0.5 X 0.8 cm in size. Overlying normal gastric mucosa. Composed of sheets of elongated spindle shaped cells in short fascicles that stained positive for CD 117 and CD 34. Tissue specimen insufficient to comment on mitotic rate

• Diagnosis: Gastrointestinal Stromal Tumor

CT scan (for metastatic work-up)

• Done on 28th August 2013

• Report: • Soft tissue density on posterior

wall along the greater curvature of stomach measuring 5.7 X 6.8 cm

• No evidence of abdominal lymphadenopathy

• No evidence of ascites or metastasis to liver, lungs or bones

Treatment

Surgery or Chemotherapy?

Sleeve Gastrectomy On 17th September 2013

Intaoperative findings• Tumour with endophytic and exophytic element,

8 x 7 cm• Freely mobile tumour • No local invasion• No ascites or liver metastasis

Procedure• Midline laporotomy• Lesser sac opened• Greater curvature mobilised• Left gastro-epiploic liagated • Wedge resection done around tumour keeping

margins 2-3 cm

Future Management Plan • Referred to Oncology for adjuvant Imatinib therapy

Gastrointestinal Stromal Tumors

Stomal (mesenchymal) tumours (1%):

GIST (neural crest cell origin)

lipomas, liposarcomas, leiomyomas (myogenic origin)

Background • GISTs are thought to arise from interstitial cells of Cajal (ICC)• c-kit is a gene that encodes for a transmembrane receptor for

a growth factor termed stem cell factor(scf) expressed by ICC• Around 95 percent of GISTs result from abnormalities in KIT

pathway• More than 85% GISTs are associated with a mutations

resulting in overexpression of c-kit gene• The CD117 antigen is part of the KIT transmembrane receptor

tyrosine kinase (RTK)

• Mutations generally occur in the DNA encoding the intracellular part exon 11 (75%) which has tyrosine kinase enzyme activity .

• Mutations in the exons 9 and rarely 13 and 17 also result in uncontrolled KIT signaling.

• Most GIST cells with wildtype (i.e. not mutated) c-kit instead have a mutation in another gene, PDGFR-α which is a related tyrosine kinase.

Epidemiology • Incidence vary widely, from 4 to 40 cases per million

population, which corresponds to between 200 and 2000 new cases per year in England and Wales.

• In the US reported 7-20 cases per million • Recent epidemiological data from Sweden suggest that the

incidence of GIST is in the region of 15 per million per year. • Approximately half of new cases of GIST are likely to be

metastatic and/or unresectable on first presentation. • Although GIST can occur at any age, the mean age of

presentation is between 50 and 70 years.

Pathophysiology • Location:

• Stomach (50-705)• Small intestine (20-30%)• Rectum (5-15%)• Esophagus (<5%)

• Submucosal lesions, can be exophytic or endophytic • Range in size from smaller than 1 cm to as large as 40 cm

• All GIST tumors are considered to have malignant potential• GISTs frequently metastasize to liver and peritoneum and

rarely to regional lymph nodes.

Outcome

The overall 5-year survival rate ranges from 28-60%. This can be stratified for patients presenting with

localized primary disease with median survival rate in the former group is 5 years

metastatic or recurrent disease with median survival

rate approximately 10-20 months.

Clinical Presentation • Upper GI bleeding: hematemesis or melena in 40-65% of

patients. • Symptoms of enlarging abdominal mass: abdominal pain,

anorexia, nausea, vomiting, weight loss, epigastric fullness, and early satiety.

• Overt GI bleeding — 40 percent• Abdominal mass — 40 percent• Abdominal pain — 20 percent

Work up Endoscopy with biopsy Histologic diagnosis in more than 80% of casesImportance in metastatic or unresectable disease

CT scan

tumor invasion to adjacent structures metastasis to liver, omentum, and peritoneal cavity

Endoscopic ultrasonography: • V

aluable when the diagnosis or location is in doubt

• most accurate method for distinguishing leiomyomas from other submucosal lesions

Tumours more likely to metastasize• > 5 cm, • lobulated, • enhance

heterogeneously• have mesenteric fat

infiltration, • ulceration, • regional

lymphadenopathy• exophytic growth

pattern

Histology • Light microcopy

• Spindle cells in 70-80%• Epitheloid aspect in 20-30%• Mixed

• By light microscopy alone, the distinction among GISTs and other tumors in the differential diagnosis (particularly leiomyomas, true leiomyosarcomas, and GI tract schwannomas) can be difficult

• Important to see for cellular atypia and mitotic rate

• Immunohistochemistry • Positive for CD117 (95%)• Other possible markers include

CD34 (60-70%), SMA (30-40%),DOG-1, S-100 protein (5 %), Desmin (1-2%), and vimentin

Importance of CD117/ cKIT mutation in therapy

StagingMost staging systems employ 3 most important survival predictors—tumor size, histologic grade, location of tumor.

Other prognostic factors: cellular atypia, local invasion, ulceration, non-Kit mutations

Lower stage (good prognosis)• Mitotic rate less

than 5 per 10 high-power fields (HPF),

• Size smaller than 2 cm

• Stomach

Higher stage (bad prognosis)• Mitotic rate greater

than 5 per 10 high-power fields (HPF),

• Size larger than 5 cm• Small

intestine/colon/rectum

MANAGEMENT• SURGICAL VS MEDICAL

EGD +Biopsy:

GIST

Metastic Workup

Resectable

• YES

Surgery with clear

Margins R0 resection

Staging

Low risk: Follow up

Intermediate to high risk:

Imatinib

Negative

Palliative/Imatinib

NOImatinib and

then debulking

Positive

Surgery

Surgical resection remains the treatment of choice and offers the only chance for cure from GIST

• For small gastric tumors, wedge or segmental resection is adequate, if technically possible. Larger tumors necessitate subtotal or total gastrectomy.

• For locally invasive tumors, en bloc resection of adjacent involved organs, such as colon, spleen, or liver, may be indicated.

The main operative principle is resection of the tumor with negative microscopic margins. Wide resection of the tumor with at least 1-2 cm margin usually the goal

Medical

The current recommendation by the NCCN is to consider prescribing imatinib in the adjuvant setting in any patient with intermediate-risk or high-risk GIST and to treat for at least 12 months

Sunitinib is a newer tyrosine-kinase inhibitor that has been shown to provide significant clinical benefit in imatinib-resistant advanced GIST.

Metastatic Disease

• Imatinib treatment at 400 mg/day is recommended as first-line management of people with KIT (CD117)-positive unresectable or metastatic gastro-intestinal stromal tumours (GISTs). (NICE guidelines)

• The two year survival of patients with advanced disease has risen to 75–80% following imatinib treatment.

• Patients should have been on at least 6 months treatment• Up to 70% of patients able to undergo an resection with stable

or partially responsive disease enjoy a progression-free survival as long as 4 years.

Rutkowski et al Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate.J Surg Oncol. Mar 15 2006;93(4):304-11.

Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors

Patients randomly assigned to receive

a single dose of 400 mg (n = 73) or 600 mg (n = 74) of

imatinib.

Patients received treatment for a

median of 21 months

The combined survival rate from

the start of treatment was 88% at 1 and 78% at 2-year follow-up.

Median survival had not been reached after 31 months of

follow-up.

Study CSTI571-B2222 is a published ongoing phase II uncontrolled trial of imatinib treatment in 147 patients (91% of whom were c-KIT-positive) with unresectable and metastatic GIST, which formed the basis of the license application.

“Imatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic gastrointestinal stromal tumor”

Safety of Imatinib • Study CSTI571-B2222 (registration study) reported that at

least one adverse event had been experienced by all 147 patients by 21 months' follow-up.

• A total of 15 (10%) patients withdrew from the study because of adverse events

• Most commonly reported side effects of imatinib include nausea, diarrhoea, periorbital oedema, muscle cramps, fatigue, rash and headache.

• The most common serious adverse events were unspecified haemorrhage and neutropenia, each event occurring in approximately 5% of patients.

• Overall, imatinib was well tolerated

References• Bailey and Love's Short Practice of Surgery 25th Edition

Norman S. Williams (Editor), Christopher J.K. Bulstrode (Editor), P. Ronan O'Connell (Editor)

• CURRENT Diagnosis & Treatment: Surgery, 13e. Edited by Gerard M. DohertyMedscape

• NCCN Task Force Report: Optimal Management of Patients with Gastrointestinal Stromal Tumor (GIST)—Update of the NCCN Clinical Practice Guidelines http://www.nccn.org/JNCCN/PDF/GIST2007.pdf

• NICE guidelines: Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours

THANK YOU