List of the participants (front authors excluded) in the “Consensus Conference on the ENETS Guidelines for the Diagnosis and Treatment of Neuroendocrine Gastrointestinal Tumors, Part 2: Midgut and Hindgut Tumors” held in Frascati (Rome, Italy), November 1–4, 2006.
Håkan Ahlman, Institute for Surgical Sciences, Dept. of Surgery, Sahlgrenska sjukhuset, S-41345 Gothenborg (Sweden); Rudolf Arnold, Wittelsbacherstr. 6, 80469 Münich (Germany); Christoph Auernhammer, Medizinische Klinik II, Grosshadern Klinikum der Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377 Münich (Germany); Martyn Caplin, Royal Free Hospital London, Centre for Gastroenterology, London NW3 2QG (UK); Emanuel Christ, Endokrinologie für Erwachsene, Inselspital, Freiburgstrasse, CH-3010 Bern (Switzerland); Wouter de Herder, Department of Internal Medicine, Section of Endocrinology, Erasmus MC, Dr. Molewaterplein 40, 3015 GD Rotterdam (The Netherlands); Gianfranco Delle Fave, Ospedale S. Andrea, Via di Grottarossa 1035, 00189 Rome (Italy); Barbro Eriksson, Medical Department, Endocrine Unit, University Hospital, S-75185 Uppsala (Sweden); Massimo Falconi, University of Verona, Medicine and Surgery, General Surgery Section, MED/18 - General Surgery, Via dell´Artigliere 8, 37129 Verona, (Italy); Diego Ferone, Departments of Internal Medicine and Endocrinological and Metabolic Sciences, University of Genoa, 16132 Genoa (Italy); Peter Goretzki, Städtisches Klinikum Neuss, Lukas-Krhs., Chirurgische Klinik I, Preussenstr. 84, 41456 Neuss (Germany); David Gross, Dep. of Endocrinology & Metabolism, Hadassah University Hospital, 91120 Jerusalem (Israel); Rudolf Hyrdel, University Hospital Martin, II. Internal med. dept., Kollarova 2 (street), SVK 036 59, Martin, (Slovakia); Robert Jensen, National Institutes of Health, Cell Biology Section, Building 10, Room 9C-193, Bethesda, MD, (USA); Gregory Kaltsas, G. Genimatas Hospital, Mesogion Ave., 10443 Athens (Greece); Fahrettin Keles̥timur, Erciyes University Medical School, Department of Endocrinology and Metabolism, 38039 Kayseri (Turkey); Reza Kianmanesh, UFR Bichat-Beaujon-Louis Mourier, Service de Chirurgie Digestive, Hôpital Louis Mourier, 178 Rue des Renouillers, 92700 Colombes (France); Wolfram Knapp MHH, Klinik für Nuklearmedizin, Carl-Neuberg-Str. 1, 30625 Hannover, (Germany); Ulrich-Peter Knigge, Dept. of Surgery, C 2122, Rigshospitalet Blegdamsuej, DK-2100 Copenhagen (Denmark); Beata Kos-Kudta, Slaska Akademia Medyczna, Klinika Endokrynologii, ul. 3 Maja 13/15, 41-800 Zabrze (Poland); Eric Krenning, Erasmus MC, Dr Molewaterplein 40, 3015G, Rotterdam (The Netherlands); Matthew Kulke, Dana-Farber Cancer Institute, 44 Binney Street, Dana 1220, Boston, MA 02115 (USA); Larry Kvols, H. Lee Moffitt Cancer Center/University of South Florida, Magnolia Drive 12902, Tampa, FL, 33612 (USA); Dik J. Kwekkeboom, Department of Nuclear Medicine, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam (The Netherlands); Riccardo Manfrodi, Istituto di Radiologia, Policlinico GB Rossi, Piazzale LA Scuro, 37134 Verona (Italy); Bruno Niederle, Universität Wien, Abt. Chirurgie, Allgemeines Krankenhaus Wien, Währinger Gürtel 18–20, Ebene 3L, A-1090 Vienna (Austria); George Nikou, 68, Plataion St, 15235 Vrilissia, Athens (Greece); Ola Nilsson, Dept. of Pathology, Sahlgrenska sjukhuset, S-41345 Gothenborg (Sweden); Kjell Öberg, Dept. of Internal Medicine, Endocrine Unit, University Hospital, S-75185 Uppsala (Sweden); Juan O’Connor, Instituto Alexander Fleming, Crámer 1180, C1426ANZ, Buenos Aires (Argentina); Dermot O’Toole, Service de Gastroentérologie, Centre Hospitalier Universitaire d'Angers, 49000 Angers (France); Ulrich-Frank Pape, Charité Universitäts Medizin, Department of Internal Medicine, Division of Hepatology and Gastroenterology, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, (Germany); Marianne Pavel, Medizinische Klinik I, Universitätsklinikum Erlangen, Krankenhausstr. 12, 91054 Erlangen (Germany); Ursula Plöckinger, Charité Universitäts Medizin, Campus Virchow-Klinikum, Department of Hepatology and Gastroenterology, Augustenburger Platz 1, 13353 Berlin (Germany); John Ramage, Dept of Gastroenterology, North Hamsphire Hospital, Aldermaston Rd, Basingstoke, RG249NA, Hampshire (UK); Jens Ricke, Otto-von-Guericke-Universität Magdeburg, Klinik für Radiologie und Nuklearmedizin, Leipziger Str. 44, 29120 Magdeburg, (Germany); Philippe Ruszniewski, Service de Gastroentérologie, Hôpital Beaujon, 100, avenue de Général Leclerc, 92118 Clichy (France); Ramon Salazar, Institut Català d´Oncologia, Av. Gran Via s/n, 08907 Barcelona (Spain); Maria Isabel Sevilla Garcia, Hospital Virgen de la Victoria, C/Colonia Santa Ines s/n, 29010 Malaga (Spain); Thomas Steinmüller, Vivantes Humboldt-Klinikum, Chirurgische Klinik, Am Nordgraben 2, 13509 Berlin, (Germany); Anders Sundin, Uppsala University Hospital, Department of Radiology, SE 751–85, Uppsala (Sweden); Babs Taal, Netherlands Cancer Centre, Plesmanlaan 121, 1066 (CX) Amsterdam (The Netherlands); Marie-Pierre Vullierme, Service de Radiologie, Hôpital Beaujon, 100, avenue de Général Leclerc, 92118 Clichy (France); Stefan Wildi, University Hospital of Zürich, Dept. of Visceral and Transplantation Surgery, CH-8091 Zürich (Switzerland); James C. Yao, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 (USA).
Background
Based on recognized differences in morphology, function and clinical behavior [
1,
2,
21,
30], the current WHO classification provides a prognosis-oriented definition of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [
3,
5,
8,
12,
13,
34].
All GEP-NETs probably have a malignant potential, but their biological behavior differs from tumor type to tumor type [
9,
10,
14‐
17,
22,
25,
26,
36]. Given their rarity [
10,
14‐
17], correct diagnosis and appropriate treatment are often difficult in nonexpert settings and even for appendiceal “carcinoids,” probably the best known GEP-NETs with the most benign behavior [
31]. Recent data on ileal, appendiceal, and rectal carcinoids, also indicated several variables influencing survival and prognosis [
6,
15,
29,
35].
Guidelines for the management of patients with GEP-NETs were developed by the recently established European Neuroendocrine Tumor Society (ENETS) [
23,
37]. In two separate meetings a consensus was sought on these guidelines. The papers deriving from the first conference dedicated to foregut tumors, including a detailed tumor–node–metastasis (TNM)/staging and grading proposals, have been published meanwhile [
4,
27]. The “Consensus Conference on the ENETS Guidelines for the Diagnosis and Treatment of Neuroendocrine Gastrointestinal Tumors, Part 2: Midgut and Hindgut Tumors” was held in Frascati (Rome, Italy) from November 1 to 4, 2006. In this paper, we present the TNM staging and grading proposals for pure NETs of the lower jejunum/ileum, appendix, and colon/rectum.
Materials and methods
Fifty-seven experts in the field of GEP-NETs from 18 different countries attended the consensus conference. The attendees represented all medical branches involved in managing patients with GEP-NETs. They formed four working groups according to their specific clinical expertise: (1) pathology and genetics (11 participants, all listed as coauthors), (2) surgery (8 participants), (3) imaging and radiology (7 participants), (4) medicine and clinical pathology (31 participants, including the coauthor B.W.). Most of the participants also attended the first consensus conference held in Frascati in November 2005.
The conference was divided sequentially into five sessions devoted to specific topics on an anatomical basis (ileal well-differentiated NETs; appendiceal well differentiated NETs; colorectal well differentiated NETs; NETs metastatic to the liver; poorly differentiated neuroendocrine carcinomas of midgut and hindgut origin).
A working booklet with the ENETS guidelines text [
23] and specific queries had been prepared in advance by the organizing committee. The work was organized as previously detailed [
4,
27]. This procedure was followed for all five sessions. The TNM staging proposal was prepared by the pathology and genetics working group and amended and approved by the plenary session of the consensus conference. The grading system was mainly discussed and defined by the pathology and genetics working group.
Results and discussion
The consensus guidelines have been reported elsewhere. The TNM staging proposal for NETs of midgut and hindgut origin together with a grading system is intended to reflect, like its forerunner for the NETs of the stomach, duodenum and pancreas [
27], the prognostic assessment by the pathologist. The intestinal NETs were separated into lower jejunum/ileum, appendix, and colon/rectum, but were not distinguished according to specific functional activity, main tumor cell type, or genetic background.
TNM staging proposal
The currently published TNM format was adopted as working template (see Tables
1,
2,
3,
4,
5, and
6) [
32].
Table 1
Proposal for a TNM classification for endocrine tumors of lower jejunum and ileum
T-primary tumor |
TX | Primary tumor cannot be assessed |
T0 | No evidence of primary tumor |
T1 | Tumor invades mucosa or submucosa and size ≤1 cm |
T2 | Tumor invades muscularis propria or size >1 cm |
T3 | Tumor invades subserosa |
T4 | Tumor invades peritoneum/other organs |
For any T add (m) for multiple tumors |
N regional lymph nodes |
NX | Regional lymph nodes cannot be assessed |
N0 | No regional lymph node metastasis |
N1 | Regional lymph node metastasis |
M | Distant metastasis |
MX | Distant metastasis cannot be assessed |
M0 | No distant metastases |
M1a
| Distant metastasis |
Table 2
Disease staging for endocrine tumors of lower jejunum and ileum
Stage I | T1 | N0 | M0 |
Stage IIA | T2 | N0 | M0 |
Stage IIB | T3 | N0 | M0 |
Stage IIIA | T4 | N0 | M0 |
Stage IIIB | Any T | N1 | M0 |
Stage IV | Any T | Any N | M1 |
Table 3
Proposal for a TNM classification for endocrine tumors of the appendix
T-primary tumor |
TX | Primary tumor cannot be assessed |
T0 | No evidence of primary tumor |
T1 | Tumor ≤1 cm invading submucosa and muscularis propria |
T2 | Tumor ≤2 cm invading submucosa, muscularis propria and/or minimally (up to 3 mm) invading subserosa/mesoappendix |
T3 | Tumor >2 cm and/or extensive (more than 3 mm) invasion of subserosa/mesoappendix |
T4 | Tumor invades peritoneum/other organs |
N-regional lymph nodes |
NX | Regional lymph nodes cannot be assessed |
N0 | No regional lymph node metastasis |
N1 | Regional lymph node metastasis |
M-distant metastasis |
MX | Distant metastasis cannot be assessed |
M0 | No distant metastases |
M1a
| Distant metastasis |
Table 4
Disease staging for endocrine tumors of the appendix
Stage I | T1 | N0 | M0 |
Stage IIA | T2 | N0 | M0 |
Stage IIB | T3 | N0 | M0 |
Stage IIIA | T4 | N0 | M0 |
Stage IIIB | Any T | N1 | M0 |
Stage IV | Any T | Any N | M1 |
Table 5
Proposal for a TNM classification for endocrine tumors of colon and rectum
T-primary tumor |
TX | Primary tumor cannot be assessed |
T0 | No evidence of primary tumor |
T1 | Tumor invades mucosa or submucosa |
| T1a size <1 cm |
| T1b size 1–2 cm |
T2 | Tumor invades muscularis propria or size >2 cm |
T3 | Tumor invades subserosa/pericolic/perirectal fat |
T4 | Tumor directly invades other organs/structures and/or perforates visceral peritoneum |
For any T add (m) for multiple tumors |
N-regional lymph nodes |
NX | Regional lymph node status cannot be assessed |
N0 | No regional lymph node metastasis |
N1 | Regional lymph node metastasis |
M-distant metastases (subspecification as in small bowel) |
MX | Distant metastasis cannot be assessed |
M0 | No distant metastases |
M1a
| Distant metastasis |
Table 6
Disease staging for endocrine tumors of colon and rectum
Stage IA | T1a | N0 | M0 |
Stage IB | T1b | N0 | M0 |
Stage IIA | T2 | N0 | M0 |
Stage IIB | T3 | N0 | M0 |
Stage IIIA | T4 | N0 | M0 |
Stage IIIB | Any T | N1 | M0 |
Stage IV | Any T | Any N | M1 |
The TNM staging system proposed here for midgut and hindgut NETs closely follows its forerunner for foregut tumors [
27]. It has the same basis, i.e., the current WHO classifications of GEP-NETs, and results from a consensus conference held by specialists and practicing physicians involved in the management of patients with GEP-NETs. The grading system described here is substantially identical to that proposed for foregut NETs and again attempts to close the gap between the advances of the most recent WHO classifications and the need for a better prognostic assessment of NETs. These proposals, as well as those already published, await confirmation by clinicopathologic work.
Acknowledgements
Source of support: grants from MIUR (COFIN 2005) and the University of Parma to GR. The Consensus Conference Part 2 in Frascati was supported by a generous grant to ENETS from Novartis Oncology.
Open Access This is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (
https://creativecommons.org/licenses/by-nc/2.0
), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.