Supplementary Table 1 Main clinical characteristics of gastroenteropancreatic endocrine tumors derived from foregut, midgut or
hindgut.1,6–8,19,25–26,33,51,59
Main locations / Head and neck, thymus, bronchus, esophagus, gastric, pancreas, duodenum, upper jejunum / Lower jejunum, ileum, appendix, ascending colon / Descending colon, rectum
Hormone secretions
Routine biological markers
Main hormone-related clinical syndromes / Multiple, diverse
Chromogranin A
Pancreatic GEP ET: insulinoma, gastrinoma, VIPoma, glucagonoma, somatostatinoma
Other primaries: gastrinoma, Cushing’s and carcinoid syndromes, ectopic growth hormone-releasing hormone or parathyroid hormone-related protein secretions / Low number, reproducible
Chromogranin A, urinary 5-HIAA
Carcinoid syndrome / Rarely found
None
None
Details of carcinoid syndrome / Serotonin- or histamine-dependent bronchus and gastric GEP ET: purplish red coloring, whole body affected, prolonged, tearing, rhinitis; pseudo-urticaria if gastric; may exist in the absence of liver metastases / Serotonin-dependent ileum GEP ET: low intensity, short-term redness of face, neck, and upper trunk; it reflects the existence of liver metastases / Rarely found
Incidence of hereditary predisposition syndrome / 0–25% / Absent / Absent
Incidence of poorly differentiated forms of GEP ET / <5% / <1% (Colon) / <5%
Incidence of the liver as the first distant metastatic organ / 80% / >95% / 95%
Abbreviations: 5-HIAA, 5-hydroxy-indol acetic acid; GEP ET, gastroenteropancreatic endocrine tumor; VIP, vasoactive intestinal peptide.
Supplementary Table 2 Histological classification of gastroenteropancreatic endocrine tumors according to the WHOa.6–8
Thymus and lung / Digestive tract / Pancreas
Well or poorly differentiated / Well / Well / Poorly / Poorly / Well / Poorly / Well / Poorly
Phenotype / Typical carcinoid / Atypical carcinoid / Large-cell carcinoma / Small-cell carcinoma / Benign behavior / Uncertain behavior / Carcinoma / Large- or small-cell carcinoma / Benign behavior / Uncertain behavior / Carcinoma / Large- or small-cell carcinoma
Features on histological examination / Organoid / Organoid / Solid, ill-defined / Solid, ill-defined / Organoid / Organoid / Organoid / Solid, ill-defined / Organoid / Organoid / Organoid / Solid, ill-defined
Atypical cellularity / No or mild / Moderate / Frequent / Frequent / No or mild / No or mild / No or mild / Frequent / No or mild / No or mild / No or mild / Frequent
CgA or synaptophysin staining / Strong / Strong / Absent or weak / Absent or weak / Strong / Strong / Strong / Absent or weak / Strong / Strong / Strong / Absent or weak
Size (cm) / >0.5 / >0.5 / NA / NA / £1–2b / >1–2b / NA / NA / <2 / ³2 / NA / NA
Mitoses per 10 HPF / <2 / 2–10 / >10 / >10 / £2 (Usually) / £2 (Usually) / >2 (Usually) / >10 / <2 / 2–10 / NA / >10
Cells staining for Ki67 (%) / NA / NA / NA / NA / £2 (Usually) / £2 (Usually) / >2 (Usually) / >15 / <2 / ³2 / NA / NA
T stage (in-depth invasion) / NA / NA / NA / NA / T1c / T1c / T2c / NA / NA / NA / NA / NA
Vascular and/or perineural invasion / NA / NA / NA / NA / Absent / Present / NA / Prominent (often) / Absent / Present / NA / NA
Necrosis / Absent / Rare / Frequent / Frequent / NA / NA / NA / Frequent / NA / NA / NA / Frequent
Local spread / NA / NA / NA / NA / Absent / Absent / Present / NA / Absent / Absent / Present / NA
Metastases / NA / NA / NA / NA / Absent / Absent / Present / NA / Absent / Absent / Present / NA
aAmong the features, the major criteria for each classification are shown in bold. bOne centimeter for gastric, duodenum, jejunum, and ileum endocrine tumors but 2|cm for appendix and colon–rectum. cT2 for all digestive endocrine tumors except the appendix, for which invasion of mesoappendix or beyond is required: T1, confined to the mucosa–submucosa; T2, invasion of the muscularis propria or beyond except for appendix for which invasion of mesoappendix or beyond (so-called T4) is required. Abbreviations: CgA, chromogranin A; HPF, high-powered fields; NA, not taken into account for classification.
Supplementary Table 3 Main clinical and prognostic characteristics of well-differentiated endocrine carcinomas as compared with poorly differentiated large-cell carcinomas.1,2,4,5,12–14,19,22,27,29,39
Feature / Well-differentiated GEP ET / Poorly differentiated (large-cell) GEP ETPrevalence among non-small-cell ET / 95% / 5%
Tobacco habit / Not all / Virtually all
Gender / Same in women and men / Preponderance in men
Positive diagnosis / Light microscopy, intense chromogranin A staining / Immunostaining positive for >1 neuroendocrine marker
Main differential diagnosis / Medullary thyroid carcinoma, pheochromocytoma, melanoma, kidney or other GEP ET metastasis, mixed tumors, large cell endocrine carcinoma / Poorly differentiated carcinoma, sarcoma, thymoma, lymphoma, mixed tumors, well-differentiated endocrine tumor, melanoma
Time elapsing before diagnosis / Long (years) / Short (months)
Mixed tumor / Rare / Frequent
General condition / Good / Poor
Primary / Entire body / Mainly foregut; not reported in the appendix and ileum
Revealing functional tumors / 5–10% / <1%
General biological markers / Chromogranin A > neuron-specific enolase / Neuron-specific enolase > chromogranin A
Hereditary syndrome of predisposition / 0–25% / Absent
Metastases at diagnosis / <50% / >50%
First-line scintigraphic imaging / Somatostatin receptor scintigraphy / PET with fluorodeoxyglucose
Cisplatin-based chemotherapy objective response / <10% / 50%
Five-year survival / >50% / <20%
Abbreviation: GEP ET, gastroenteropancreatic endocrine tumor.