ENDOCRINE CELLS OF THE GASTROENTROPANCREATIC TRACT

Stomach Small Large

Cell Main Product Pa CF An D J I Ap C R

P/D1 Ghrelin f + r r EC 5HT r + + + + + + + +

D Somatostatin + + + + r r + r +

L GLI/PYY r + + + + +

A Glucagon + fPP PP + fB Insulin +ECL Histamine +G Gastrin + +CCK CCK + + rS Secretin + +GIP GIP + + rM Motilin + + rN Neurotensin r + +

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

Type Cell Type Pa CF An D J I Ap C R Syndrome

Well B + PHH

Differentiated A + 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 differentiatedtumors

-Structural patterns

MARKER EXPRESSION IN TUMORS OF THE DIFFUSE

ENDOCRINE SYSTEMWell differentiated endocrin neoplasm

General Markers

CgA INTENSE AND DIFFUSE

Syn “ “

NSE “ “

PGP9.5 “ “

Specific Markers

various VARIABLE

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

CgA SCANT OR ABSENT

Syn DIFFUSE AND VARIABLE

NSE “ “

PGP9.5 “ “

Specific markers

Various ABSENT

Syn

PGP9.5

Clinicopathologic classification of gastric endocrine tumours 1. Well differentiated endocrine tumour

Confined to mucosa-submucosa, with moderate cellular atypiaa) 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% (<1cm), 50% (1-2 cm), 80% (>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 PROPOSALPANCREAS

Size increase

Mets presence