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

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

2 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

3 D.L. d.o.b Cardiac symptoms (ECG and cardiac sonography performed elsewhere) Huge, soft abdominal mass Abdominal sonography and CT scan

4 C.T. scan

5 C.T. scan

6 C.T. scan

7 C.T. scan

8 Tumoral Markers Alpha Feto Protein: CEA Ca 125 Ca15.3 Ca19.9 Ferritin Corionic Gonadotropin 1,6 ng/ml 0,6 ng/ml 10 UI/ml 9 UI/ml 3 UI/ml 33 ng/ml 0,6 miu/ml

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13 PATHOLOGY Mesenchymal mixoid and epithelioid neoplasm infiltrating the whole thickness of gastric wall IHC: Actin -, Desmin -, S100 -, CD34 -, KIT -, PDGFRA + CONCLUSION: High Risk GIST

14 Histology revision 1 (Padova) Well differentiated leiomiosarcoma, low grade malignancy G1

15 Histology revision 2 (IEO Milan) 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

16 SUBSEQUENT TREATMENT No adjuvant terapy 21 months follow-up: FREE OF DESEASE

17 GIST overall epidemiology Old: 1.5/10 6 people New: 16/10 6 people 900 NEW CASES/ YEAR IN ITALY 5000 NEW CASES/ YEAR IN THE UNITED STATES

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23 mast cells Cajal s cells KIT/CD117

24 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 protein had disturbance of intestinal motility and died of paralytic ileus Requirement of c-kit for development of intestinal pacemaker system. Maeda et al. Development 1992; 116:

25 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

26 WHAT S A GIST NOWADAYS KIT protein in GIST is constitutionally activated in a ligand-independent manner KIT expression is the most sensitive and specific phenotypic marker GIST is a distinctive group of KIT-expressing mesenchymal neoplasms of the GI tract

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30 KIT-negative GIST The term GIST should apply only to neoplasms KIT-immunopositive with very rare exceptions (2-5%) spindle cell (or epithelioid) stromal neoplasm most consistent with GIST Fletcher et al. Hum Pathol, 2002

31 KIT-negative GIST Whether or not KIT positivity should be required 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 molecular genetic features and differential diagnosis. Virchows Archiv 2001; 438: 1-12

32 Platelet Derived Growth Factor Receptor Alpha(PDGFRA) PDGFR is a type III tyrosine kinase similar to 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 other TKI (i.e., SU11248)

33 KIT-negative GIST PDGFRA activating mutations in gastrointestinal stromal tumors Heinrich et al. Science 2003; 299: Gain-of-function mutations of Platelet-Derived Growth Factor Receptor Alpha gene in gastrointestinal stromal tumors Hirota et al. Gastroenterology 2003; 125:

34 DOG1 and GIST Gene FLJ10261 (DOG1) encoding an hypothetical protein of unknown function is specifically expressed in GISTs (98%) irrespective of c-kit or PDGFR-alpha muts or tumor location No expression in sarcomas mimicking GIST (desmoids, schwannomas, etc West et al. Am J Pathol 2004;165:

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36 GIST: prognostic factors SIZE MITOTIC RATE Very low risk < 2 cm < 5/50 HPF Low risk 2-5 cm < 5/50 HPF Intermediate risk High risk < 5 cm 5-10 cm > 5 cm > 10 cm any 6-10/50 HPF < 5/50 HPF > 5/50 HPF any > 10/50 HPF Fletcher et al. Hum Pathol, 2002

37 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

38 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, mass Ladd AP, Grosfeld JL. Semin Pediatr Surg 2006; 15: 37 47

39 GISTs in Kids Mostly no mutations Mostly epithelioid morphology Miettinen et al. Am J Surg Pathol 2005; 29: Prakash S. et al. J Pediatr Hematol Oncol 2005; 27:

40 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-alpha exons 12 and 18 muts Mainly epithelioid morphology Unpredictable but slow course of disease Miettinen et al. Am J Surg Pathol 2005;29:

41 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 :

42 THERE IS CURRENTLY NO STANDARDIZED TREATMENT PROTOCOL FOR GISTs in PAEDIATRIC AGE Ladd AP, Grosfeld JL. Semin Pediatr Surg 2006; 15: 37-47

43 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 repressor FLAVOPIRIDOL

44 FOLLOW UP Clinical + US? Endoscopy? CT scan? PET scan?

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