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
Feature
Foregut-derived GEP ET
Midgut-derived GEP ET
Hindgut-derived GEP
ET
Main locations
Head and neck, thymus, bronchus, esophagus, gastric, Lower jejunum, ileum, appendix,
Descending colon,
pancreas, duodenum, upper jejunum
ascending colon
rectum
Hormone secretions
Multiple, diverse
Low number, reproducible
Rarely found
Routine biological markers
Chromogranin A
Chromogranin A, urinary 5-HIAA
None
Main hormone-related clinicalPancreatic GEP ET: insulinoma, gastrinoma, VIPoma, Carcinoid syndrome
syndromes
glucagonoma, somatostatinoma
Other primaries: gastrinoma, Cushing’s and carcinoid
syndromes, ectopic growth hormone-releasing
hormone or parathyroid hormone-related protein
secretions
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:
Rarely found
low intensity, short-term redness of face,
neck, and upper trunk; it reflects the
existence of liver metastases
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 80%
>95%
95%
first distant metastatic organ
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
Feature
WHO 1999 classification
WHO 2000 classification
WHO 2004 classification
Thymus and lung
Well or poorly
differentiated
Well
Well
Digestive tract
Poorly
Typical
Atypical Large-cell
Phenotype
carcinoid carcinoid carcinoma
Features on histological
Solid, illexamination
Organoid Organoid defined
Atypical cellularity
No or mild Moderate Frequent
CgA or synaptophysin
Absent or
staining
Strong
Strong weak
>0.5
>0.5
Size (cm)
NA
Poorly
Well
Poorly
Large- or
Small-cell Benign
Uncertain
small-cell
carcinoma behavior behavior Carcinoma carcinoma
Solid, illSolid, illdefined Organoid Organoid Organoid defined
Frequent No or mild No or mild No or mild Frequent
Absent or
Absent or
weak
Strong
Strong
Strong
weak
b
b
1–2
>1–2
NA
NA
NA
2
2
>2
>10
(Usually) (Usually) (Usually) >10
2
2
>2
NA
(Usually) (Usually) (Usually) >15
Pancreas
Well
Benign
behavior
Poorly
Uncertain
behavior
LargeCarcinoma cell ca
Organoid Organoid
No or mild No or mild
Organoid
No or mild
Solid,
Frequ
Strong
<2
Strong
NA
Absen
NA
Strong
2
<2
2–10
>10
<2
2–10
Mitoses per 10 HPF
NA
Cells staining for Ki67
<2
2
(%)
NA
NA
NA
NA
T stage (in-depth
T1c
T1c
T2c
invasion)
NA
NA
NA
NA
NA
NA
NA
NA
Vascular and/or
Prominent
Absent
Present
Absent
Present
perineural invasion
NA
NA
NA
NA
NA
(often)
NA
Absent
Rare
Frequent
Frequent NA
Frequent
Necrosis
NA
NA
NA
NA
NA
Absent
Absent
Present
Absent
Absent
Present
Local spread
NA
NA
NA
NA
NA
Absent
Absent
Present
Absent
Absent
Present
Metastases
NA
NA
NA
NA
NA
a
Among 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.
>10
NA
NA
NA
Frequ
NA
NA
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
Prevalence among non-small-cell ET
Tobacco habit
Gender
Positive diagnosis
Main differential diagnosis
Time elapsing before diagnosis
Mixed tumor
General condition
Primary
Well-differentiated GEP ET
95%
Not all
Same in women and men
Light microscopy, intense chromogranin A
staining
Medullary thyroid carcinoma,
pheochromocytoma, melanoma, kidney or other
GEP ET metastasis, mixed tumors, large cell
endocrine carcinoma
Long (years)
Rare
Good
Entire body
Revealing functional tumors
5–10%
General biological markers
Chromogranin A > neuron-specific enolase
Hereditary syndrome of predisposition
0–25%
Metastases at diagnosis
<50%
First-line scintigraphic imaging
Somatostatin receptor scintigraphy
Cisplatin-based chemotherapy objective
<10%
response
Five-year survival
>50%
Abbreviation: GEP ET, gastroenteropancreatic endocrine tumor.
Poorly differentiated (large-cell) GEP ET
5%
Virtually all
Preponderance in men
Immunostaining positive for >1 neuroendocrine
marker
Poorly differentiated carcinoma, sarcoma,
thymoma, lymphoma, mixed tumors, welldifferentiated endocrine tumor, melanoma
Short (months)
Frequent
Poor
Mainly foregut; not reported in the appendix and
ileum
<1%
Neuron-specific enolase > chromogranin A
Absent
>50%
PET with fluorodeoxyglucose
50%
<20%