ENDOCRINE CELLS OF THE GASTROENTROPANCREATIC TRACT Stomach Small Large CellMain ProductPaCFAnDJIApCR P/D 1 Ghrelinf+rr EC5HTr DSomatostatin++++rr+r+ LGLI/PYYr+++++ AGlucagon+f PPPP+f BInsulin+ ECLHistamine+ GGastrin ++ CCKCCK ++r SSecretin++ GIPGIP++r MMotilin++r NNeurotensinr++ Rindi et al., Digestion 2000, 62(S1):19 Intestine

GASTROENTERPANCREATIC ENDOCRINE TUMORS cell type, site and possible hyperfunctional syndromes Tumor Main Stomach Small Large Possible TypeCell TypePaCFAnDJIAp CRSyndrome WellB+PHH DifferentiatedA+glucagonoma PP+- (?)++WDHA D+++somatostatinoma EC “carcinoid” ECL +“atypical carcinoid” G++++ZES L Poorly Differentiated Rindi et al., Digestion 2000, 62(S1):19 Intestine

WELL DIFFERENTIATED endocrine neoplasia 1 - tumor (carcinoid) 2 - carcinoma (malignant carcinoid) POORLY DIFFERENTIATED endocrine carcinoma 3 - Small or large cell carcinoma DES TUMORS GENERAL CATEGORIES

DES TUMORS Well Differentiated Structural features Nests / solid islets Trabeculae /cords Acini Mixed Cytological features Monomorphism Mild to moderate atypia Occasional mitosis

Solid nests Pseudoglandular Trabecular Well differentiated tumors - Structural patterns

MARKER EXPRESSION IN TUMORS OF THE DIFFUSE ENDOCRINE SYSTEM Well differentiated endocrin neoplasm General Markers CgAINTENSE AND DIFFUSE Syn““ NSE““ PGP9.5““ Specific Markers variousVARIABLE PP CgA

WELL DIFFERENTIATED ENDOCRINE TUMORS OF THE GASTROENTEROPANCREATIC TRACT HISTOPATHOLOGICAL PARAMETERS WITH POTENTIAL PROGNOSTIC IMPACT CYTOLOGIC ATYPIA MITOSES Ki67 INDEX P53 EXPRESSION PLOIDY STATUS

WELL DIFFERENTIATED ENDOCRINE TUMORS OF THE GASTROENTEROPANCREATIC TRACT HISTOPATHOLOGICAL PARAMETERS WITH POTENTIAL PROGNOSTIC IMPACT SIZE INFILTRATION ANGIOINVASION PERINEURAL SPACE INVASION CD31

GASTRIC ECL CELL TUMORS DIAGNOSTIC CATEGORIES Well Differentiated CAG-associated (type I) Well Differentiated ZES / MEN1-associated (type II) Well Differentiated Sporadic (type III) Poorly differentiated WHO Histological Typing of Endocrine Tumours, 2000

Gastric ECL cells Diffuse hyperplasia

Micronodular hyperplasia Dysplasia

Gastric ECL carcinoid

Carcinoma endocrino poco differenziato

MARKER EXPRESSION IN TUMORS OF THE DIFFUSE ENDOCRINE SYSTEM Poorly differentiated (small cell) endocrine carcinoma General markers CgASCANT OR ABSENT SynDIFFUSE AND VARIABLE NSE““ PGP9.5““ Specific markers VariousABSENT Syn PGP9.5

Clinicopathologic classification of gastric endocrine tumours 1. Well differentiated endocrine tumour Confined to mucosa-submucosa, with moderate cellular atypia a) Lower risk: Nonangioinvasive, <1 cm, nonfunctioning. Mostly ECL cell tumors with hypergastrinemia and A- type cron.atr.gastr. or MEN1 syndrome; occasional EC cell carcinoid or gastrin cell tumour. b) Higher risk: Angioinvasive, >1 cm or functioning. ECL cell tumors, sporadic or with MEN1 or A-CAG; occasional EC cell carcinoid or gastrin cell tumour. 2. Well differentiated endocrine carcinoma Low grade malignant, deeply invasive (muscolaris propria or beyond) ormetastatic ECL cell, mostly sporadic, sometimes with atypical carcinoid syndrome; EC cell, serotonin producin, occasionally with typical carcinoid syndrome; rare gastrin, ghrelin or ACTH producing tumors, with or without syndrome. 3. Poorly differentiated endocrine carcinoma High grade malignant, small to large cell; reactive with some neuroendocrine markers but usually nonfunctioning; occasionally with inappropriate hormonal syndrome.

Poorly differentiated : 3 cases

Site: 1/4 multiple tumors ileum, appendix, Merkel’s diverticulum, jejunum, caecum –rare in duodenum, stomach, distal colon and rectum. Histology: –well differentiated, solid nests –peripheral palisading of serotonin rich, highly granular tumor cells –deep infiltration of muscular wall and mesenteric fibroblastic reaction –argyrophilic, argentaffin, diazonium, formalehyde induced fluorescence, chromogranin+, serotonin+, substance P+ –pleomorphic/osmiophilic granules. Metastases: 2% ( 2 cm) Behavior: low grade malignant Most of symptomatic cases are metastatic Symptoms: obstruction (mesenteric retraction) –Carcinoid syndrome (7%), all with liver metatases Argentaffin EC cell tumors (carcinoids)

Endocrine tumor of small bowel. Panoramic view showing submucosal nodule

Panoramic view of ileal endocrine tumor showing full thickness involvement with a largely preserved mucosa

5-HT

WHO Histological Typing of Endocrine Tumours, 2000

ENETS STAGING PROPOSAL PANCREAS Size increase Mets presence