Post on 10-Dec-2018
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
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
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
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
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