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Neoplasia gastrica cistica: GIST o leiomiosarcoma? Sebastiano Cacciaguerra U. O. Chirurgia Pediatrica Ospedale Garibaldi Catania

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Neoplasia gastrica cistica:GIST o leiomiosarcoma?

Sebastiano CacciaguerraU. O. Chirurgia Pediatrica

Ospedale GaribaldiCatania

Neoplasia gastrica cistica:GIST o leiomiosarcoma?

Aims of presentation• Atypical clinical presentation of a tumour rarely reported in paediatric age• Stimulation towards re-visitation of cases of g.i. tumours previously labelled otherwise• Proposal of collection of cases for genetic studies

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

D.L. d.o.b 16.7.91

• Cardiac symptoms (ECG and cardiac sonography performed elsewhere)

• Huge, soft abdominal mass

• Abdominal sonography and CT scan

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

C.T. scan

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

C.T. scan

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

C.T. scan

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

C.T. scan

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

Tumoral Markers

• Alpha Feto Protein: 1,6 ng/ml• CEA 0,6 ng/ml• Ca 125 10 UI/ml• Ca 15.3 9 UI/ml• Ca 19.9 3 UI/ml• Ferritin 33 ng/ml• Corionic Gonadotropin 0,6 mIU/ml

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

PATHOLOGY

• Mesenchymal mixoid and epithelioid neoplasm infiltrating the whole thickness of gastric wall

• IHC: Actin -, Desmin -, S100 -, CD34 -, KIT -, PDGFRA +

CONCLUSION: High Risk GIST

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

Well – differentiated leiomiosarcoma, low grade malignancyG1

Histology revision 1(Padova)

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

• CD117 (KIT) IHC NEGATIVE• Muscle markers IHC POSITIVE• CD 34 IHC POSITIVE• PDGFRA gene POSITIVE (exon 12 mutation)

CONCLUSIONS MIXOID / EPITHELIOID GIST – uncertain risk grade

Histology revision 2(IEO – Milan)

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

SUBSEQUENT TREATMENT

• No adjuvant terapy

• 21 months’ follow-up: FREE OF DESEASE

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

GIST overall epidemiology

• Old: 1.5/106 people• New: 16/106 people

900 NEW CASES/ YEAR IN ITALY

5000 NEW CASES/ YEAR IN THE UNITED STATES

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

Cajal’s cells

mast cells

KIT/CD117

KIT and Cajal’s cells

• Interstitial cells of Cajal act as the interface between the autonomic neural network of the intestinal wall and the muscle layers• Studies on mice with defective KIT proteinhad disturbance of intestinal motility and died of paralytic ileusRequirement of c-kit for development of intestinal pacemaker system.Maeda et al. Development 1992; 116: 369-375

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

KIT and Cajal’s cells

• Anorectal malformations• Chronic intestinal pseudo-obstruction• Transient neonatal pseudo-obstruction• Infantile hypertrophic pyloric stenosis• Hirschsprung disease and related

disorders• Ulcerative colitis

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

WHAT’S A GIST NOWADAYS

• KIT protein in GIST is constitutionallyactivated in a ligand-independent manner

• KIT expression is the most sensitive and specific phenotypic marker

• GIST is a distinctive group of KIT-expressingmesenchymal neoplasms of the GI tract

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

KIT-negative GIST

The term GIST should apply only toneoplasms KIT-immunopositive with very

rare exceptions (2 - 5%)

“spindle cell (or epithelioid) stromalneoplasm most consistent with GIST”

Fletcher et al. Hum Pathol, 2002U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

KIT-negative GISTWhether or not KIT positivity should berequired for a diagnosis of GIST is more

contentious, since there is a small, problematic group of tumors that are in the histologic range but do not express KIT and

the classification of such tumors with a “null-phenotype” is still open

Miettinen & Lasota. GIST- definition, clinical, histological, immunohistochemical, and moleculargenetic features and differential diagnosis. VirchowsArchiv 2001; 438: 1-12 U.O. di Chirurgia Pediatrica

Ospedale Garibaldi – NesimaCatania

Platelet Derived Growth Factor Receptor Alpha(PDGFRA)

• PDGFR is a type III tyrosine kinase similarto colony stimulating factor (CSF)-1 receptor and KIT • PDGFR-alpha and beta (homodimer/heterodimer)• Five extracellular Ig-like domains and an intracellular TK

domain• The binding to the ligand PDGF (A, B, C) provokes

important cellular events: cell growth, inhibition of apoptosis and neoangiogenesis

• PDGFR-alpha and beta are inhibited by STI571 and otherTKI (i.e., SU11248)

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

KIT-negative GISTPDGFRA activating mutations

in gastrointestinal stromal tumorsHeinrich et al. Science 2003; 299: 708-710

Gain-of-function mutations of Platelet-Derived Growth Factor Receptor Alpha

gene in gastrointestinal stromal tumorsHirota et al. Gastroenterology 2003; 125: 660-667

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

DOG1 and GIST

• Gene FLJ10261 (DOG1) encoding anhypothetical protein of unknownfunction is specifically expressed in GISTs (98%) irrespective of c-kit or PDGFR-alpha muts or tumor location

• No expression in sarcomas mimickingGIST (desmoids, schwannomas, etc

West et al. Am J Pathol 2004;165: 107-113 U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

GIST: prognostic factors

> 5/50 HPFany

> 10/50 HPF

> 5 cm> 10 cm

any

High risk

6-10/50 HPF< 5/50 HPF

< 5 cm5-10 cm

Intermediate risk

< 5/50 HPF2-5 cmLow risk

< 5/50 HPF< 2 cmVery low risk

SIZE MITOTIC RATE

Fletcher et al. Hum Pathol, 2002

GIST: prognostic factors

Tumours with PDGFRA mutations might be less aggressive than those with KIT

mutations

Lasota J et al. Lab Invest 2004; 84:874-83

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

GISTs in Kids• Metastatic disease occurs in more than 50%

of paediatric patients (higher than in adults• Major site of occurrence: stomach• Female predominance• Mostly epithelioid• Symptoms: abdominal pain, bleeding,

anemia, massLadd AP, Grosfeld JL. Semin Pediatr Surg 2006; 15: 37 – 47

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

GISTs in Kids

• Mostly no mutations• Mostly epithelioid morphology

Miettinen et al. Am J Surg Pathol 2005; 29:1373-81Prakash S. et al. J Pediatr Hematol Oncol 2005; 27: 179-187

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

GISTs of the stomach in Kids• 44 cases- 32 females /12 males• None of the 13 analyzed GISTs had c-

kit exons 9, 11, 13, 17 or PDGFR-alphaexons 12 and 18 muts

• Mainly epithelioid morphology• Unpredictable but slow course of

disease

Miettinen et al. Am J Surg Pathol 2005;29:1373-81 U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

GISTs of the stomach in Kids• Multifocal distribution of gastric GISTs

with the presence of nodules of variable number and size separated by normal gastric tissue

• Regional lymph node metastases

Kerr JZ et al. Cancer 1999 85: 220-230 U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

THERE IS CURRENTLY NO STANDARDIZED

TREATMENT PROTOCOL FOR GISTs in PAEDIATRIC

AGELadd AP, Grosfeld JL. Semin Pediatr Surg 2006; 15: 37 - 47

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania

TREATMENT

• surgical excision

• KIT and PDGFRA kinase inhibitors imatinib, sunitinib, nilotinib (80% of cases are responsive) in case of metastatic localization or recurrence

• KIT transcriptional repressorFLAVOPIRIDOL U.O. di Chirurgia Pediatrica

Ospedale Garibaldi – NesimaCatania

FOLLOW UP

Clinical +

• US?• Endoscopy? • CT scan?• PET scan?

U.O. di Chirurgia PediatricaOspedale Garibaldi – NesimaCatania