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WHO Classification of Tumours
Nomenclature and classification of neuroendocrine neoplasms of the digestive system


One of the major problems in the management of patients with gastrointestinal (neuro)endocrine tumours (NETs) is the lack of universally accepted standards, both for nomenclature (i.e. the clinical significance of current definitions) and for staging of disease
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Modlin IM, Moss SF, Chung DC, Jensen RT, Snyderwine E (2008)
Priorities for improving the management of gastroenteropancreatic neuroendocrine tumors.
J Natl Cancer Inst 100: 1282-9



. Based on a wealth of evidence, the most recent WHO classification of 2000
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Solcia E, Klöppel G, and Sobin LH (eds.)
Histological Typing of Endocrine Tumours
Springer-Verlag: Berlin-New York 2000



provided a rational approach to the nomenclature and classification of NETs of the digestive system, developing a coherent terminology and allowing the prognostic stratification of these neoplasms. This WHO classification has served as a basis for establishing criteria for practical management, as reflected in the guidelines of many scientific societies
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Oberg K, Astrup L, Eriksson B, Falkmer SE, Falkmer UG, Gustafsen J, Haglund C, Knigge U, Vatn MH, Välimäki M, (2004)
Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part I-general overview.
Acta Oncol 43: 617-25




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Oberg K, Astrup L, Eriksson B, Falkmer SE, Falkmer UG, Gustafsen J, Haglund C, Knigge U, Vatn MH, Välimäki M, (2004)
Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part II-specific NE tumour types.
Acta Oncol 43: 626-36




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Oberg K, Jelic S, (2009)
Neuroendocrine gastroenteropancreatic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up.
Ann Oncol 20 Suppl 4: 150-3




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Plöckinger U, Rindi G, Arnold R, Eriksson B, Krenning EP, de Herder WW, Goede A, Caplin M, Oberg K, Reubi JC, Nilsson O, Delle Fave G, Ruszniewski P, Ahlman H, Wiedenmann B, (2004)
Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS).
Neuroendocrinology 80: 394-424




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Ramage JK, Davies AH, Ardill J, Bax N, Caplin M, Grossman A, Hawkins R, McNicol AM, Reed N, Sutton R, Thakker R, Aylwin S, Breen D, Britton K, Buchanan K, Corrie P, Gillams A, Lewington V, McCance D, Meeran K, Watkinson A, (2005)
Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours.
Gut 54 Suppl 4: iv1-16



. However, while most institutions in the European Union (EU) adhere to the WHO 2000 classification scheme, the scheme has not achieved widespread acceptance in diagnostic practice in the United States of America (USA). The reasons for this include:
(1) the embedding of stagerelated information within a grading system;
(2) the complicated clinical–pathological classification schemes; and
(3) the category “uncertain behaviour,” which has met with resistance from both clinicians and pathologists

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Ferrone CR, Tang LH, Tomlinson J, Gonen M, Hochwald SN, Brennan MF, Klimstra DS, Allen PJ (2007)
Determining prognosis in patients with pancreatic endocrine neoplasms: can the WHO classification system be simplified?
J Clin Oncol 25: 5609-15



.
In addition, the continued widespread use of the term “carcinoid,” with its largely incorrect benign connotation, hampered universal acceptance of this classification system. Taking into account the considerations stated above, the European Neuroendocrine Tumor Society (ENETS) has recently proposed two complementary classification tools – a grading classification and a site-specific staging system

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Rindi G, Klöppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, Erikssson B, Falchetti A, Falconi M, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B, , (2006)
TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system.
Virchows Arch 449: 395-401




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Rindi G, Klöppel G, Couvelard A, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B (2007)
TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system.
Virchows Arch 451: 757-62



. The intention was to improve the WHO 2000 classification by strengthening its appreciation of the following concepts:
(1) tumour heterogeneity, i.e. tumours differ according to the site of origin;
(2) tumour differentiation i.e. tumours differ according to tumour cell differentiation status; and
(3) malignancy, i.e. long-term follow-up indicates that NETs as a category are malignant.

Such concepts stem from evidence that biological characteristics and stage at diagnosis largely determine the clinical behaviour of NETS. As it does for other epithelial neoplasms, the ENETS grading and staging system formally recognizes the malignant potential of NETs and organizes their classification according to grade and stage.

> WHO 2010 classification
In the present volume of the WHO classification of tumours, we attempt to bridge the above-mentioned classification gap by introducing a grading scheme and applying the terms NET and NEC as widely accepted and used by clinicians in both the EU and USA. The term “neuroendocrine” is adopted here to indicate the expression of neural markers in neoplastic cells with otherwise exquisitely endocrine properties and phenotype. The term "neuroendocrine neoplasm" can be used synonymously with "neuroendocrine tumour".

> Grading
Grading is performed on the basis of morphological criteria (see individual chapters) and the assessment of proliferation fraction according to the ENETS scheme

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Rindi G, Klöppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, Erikssson B, Falchetti A, Falconi M, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B, , (2006)
TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system.
Virchows Arch 449: 395-401




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Rindi G, Klöppel G, Couvelard A, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B (2007)
TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system.
Virchows Arch 451: 757-62



. Evidence that the proliferation fraction has prognostic significance is available for NETs of foregut origin, including stomach and pancreas
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Bettini R, Boninsegna L, Mantovani W, Capelli P, Bassi C, Pederzoli P, Delle Fave GF, Panzuto F, Scarpa A, Falconi M (2008)
Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours.
Ann Oncol 19: 903-8




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Ferrone CR, Tang LH, Tomlinson J, Gonen M, Hochwald SN, Brennan MF, Klimstra DS, Allen PJ (2007)
Determining prognosis in patients with pancreatic endocrine neoplasms: can the WHO classification system be simplified?
J Clin Oncol 25: 5609-15




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La Rosa S, Klersy C, Uccella S, Dainese L, Albarello L, Sonzogni A, Doglioni C, Capella C, Solcia E (2009)
Improved histologic and clinicopathologic criteria for prognostic evaluation of pancreatic endocrine tumors.
Hum Pathol 40: 30-40




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Pelosi G, Bresaola E, Bogina G, Pasini F, Rodella S, Castelli P, Iacono C, Serio G, Zamboni G (1996)
Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: a comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables.
Hum Pathol 27: 1124-34




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Rigaud G, Missiaglia E, Moore PS, Zamboni G, Falconi M, Talamini G, Pesci A, Baron A, Lissandrini D, Rindi G, Grigolato P, Pederzoli P, Scarpa A (2001)
High resolution allelotype of nonfunctional pancreatic endocrine tumors: identification of two molecular subgroups with clinical implications.
Cancer Res 61: 285-92




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Rindi G, Azzoni C, La Rosa S, Klersy C, Paolotti D, Rappel S, Stolte M, Capella C, Bordi C, Solcia E (1999)
ECL cell tumor and poorly differentiated endocrine carcinoma of the stomach: prognostic evaluation by pathological analysis.
Gastroenterology 116: 532-42




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Rindi G, Luinetti O, Cornaggia M, Capella C, Solcia E (1993)
Three subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a clinicopathologic study.
Gastroenterology 104: 994-1006



. The proposed grading based on proliferation has three tiers (G1, G2, G3) with the following definitions of mitotic count and Ki67 index:
– G1: mitotic count, < 2 per 10 high power fields (HPF) and/or = 2% Ki67 index;
– G2: mitotic count 2–20 per 10 HPF and/or 3–20% Ki67 index;
– G3: mitotic count > 20 per 10 HPF and/or > 20% Ki67 index.
The grading requires mitotic count in at least 50 HPFs (1 HPF = 2 mm2) and Ki67 index using the MIB antibody as a percentage of 500–2000 cells counted in areas of strongest nuclear labelling ("hot spots"). If grade differs for mitotic count compared with Ki67 index, it is suggested that the higher grade be assumed. Evidence to support this grading scheme is available for the stomach, duodenum and pancreas NETs

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Ekeblad S, Skogseid B, Dunder K, Oberg K, Eriksson B (2008)
Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution.
Clin Cancer Res 14: 7798-803




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Fischer L, Kleeff J, Esposito I, Hinz U, Zimmermann A, Friess H, Büchler MW (2008)
Clinical outcome and long-term survival in 118 consecutive patients with neuroendocrine tumours of the pancreas.
Br J Surg 95: 627-35




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La Rosa S, Klersy C, Uccella S, Dainese L, Albarello L, Sonzogni A, Doglioni C, Capella C, Solcia E (2009)
Improved histologic and clinicopathologic criteria for prognostic evaluation of pancreatic endocrine tumors.
Hum Pathol 40: 30-40




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Pape UF, Jann H, Müller-Nordhorn J, Bockelbrink A, Berndt U, Willich SN, Koch M, Röcken C, Rindi G, Wiedenmann B (2008)
Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors.
Cancer 113: 256-65



, but is still lacking for NETs of the intestine.

> Site-specific staging system
Grading is combined with a site-specific staging system to improve prognostic strength. Since the grading and staging schemes are still evolving, it is expected that the grade definitions as well as sitespecific definitions of TNM (tumour, node, metastasis) stage

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Sobin, LH, Gospodarowicz, MK., Wittekind, C.
TNM classification of malignant tumours
7th
Wiley-Blackwell: Oxford 2009



may need adjustment in the future, following accumulation of additional follow-up or molecular data. We feel that the introduction of an approach that combines the classification of grade and stage provides a framework that can be applied to NETs in all body organs. Furthermore, distinction of grading and staging allows prognostically relevant grading information to be applied to NETs in metastatic sites whereas, previously, all such NETs were grouped together in the classification system. The TNM staging classifications are presented in each relevant chapter, together with other histo-pathological variables with recognized prognostic value. In addition, the WHO 2010 classification system reports in brackets the WHO 2000 definitions linked to the codes for the International Classification of Disease Oncology (ICD-O)
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Fritz A, Percy C, Jack A, Shanmuragatnam K, Sobin LH, Parkin DM, Whelan S
International Classification of Diseases for Oncology.
3rd
World Health Organization: Geneva 2000



(Table 1).

> Definition of neuroendocrine tumour (NET)
A NET is defined as a well-differentiated, neuroendocrine neoplasm composed of cells with features similar to those of the normal gut endocrine cell, expressing general markers of neuroendocrine differentiation (usually diffuse and intense chromogranin A and synaptophysin) and hormones (usually intense but not necessarily diffuse) according to site, with mildto-moderate nuclear atypia and a low number of mitoses (< 20 per 10 HPF); grade G1 and G2 are defined according to proliferation fraction and histology. This definition encompasses neoplasms termed “carcinoid tumour” in the WHO 2000 classification

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Solcia E, Klöppel G, and Sobin LH (eds.)
Histological Typing of Endocrine Tumours
Springer-Verlag: Berlin-New York 2000




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Williams ED, Siebenmann RE, and Sobin LH (eds.)
Histological Typing of Endocrine Tumours
World Health Organization: Geneva 1980



(Table 1).

> Definition of neuroendocrine carcinoma (NEC)
A NEC is a poorly differentiated, highgrade malignant neoplasm composed of small cells or large to intermediate cells, sometimes with organoid features resembling NET, diffusely expressing the general markers of neuroendocrine differentiation (diffuse expression of synaptophysin; faint or focal staining for chromogranin A), with marked nuclear atypia, multifocal necrosis and a high number of mitoses (> 20 per 10 HPF); high grade (G3) defined according to the proliferation fraction and histology. This definition refers to neoplasms previously classified as small cell carcinoma, large cell (neuro)endocrine carcinoma, or poorly differentiated (neuro)endocrine carcinoma

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Hamilton SR, Aaltonen LA (Eds.)
World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System.
3rd Edition
IARC Press: Lyon 2000




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Solcia E, Klöppel G, and Sobin LH (eds.)
Histological Typing of Endocrine Tumours
Springer-Verlag: Berlin-New York 2000



(Table 1).

> Definition of mixed adenoneuroendocrine carcinoma (MANEC)
MANECs have a phenotype that is morphologically recognizable as both glandforming epithelial and neuroendocrine, and are defined as carcinomas since both components are malignant and should be graded. A component of squamous cell carcinoma is rare. Arbitrarily, at least 30% of either component should be identified to qualify for this definition. The identification in adenocarcinoma of scattered neuroendocrine cells by immuno histo-chemistry does not qualify for this definition.

> Reporting of the NETs
Minimum requirements for the reporting of NETs are the exact site and size and the distance from the resection margins (for resection specimens; see specific chapters for site-specific requirements)

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Klimstra DS, Modlin IR, Adsay NV, Chetty R, Deshpande V, Gönen M, Jensen RT, Kidd M, Kulke MH, Lloyd RV, Moran C, Moss SF, Oberg K, O'Toole D, Rindi G, Robert ME, Suster S, Tang LH, Tzen CY, Washington MK, Wiedenmann B, Yao J (2010)
Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set.
Am J Surg Pathol 34: 300-13




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Klöppel G, Couvelard A, Perren A, Komminoth P, McNicol AM, Nilsson O, Scarpa A, Scoazec JY, Wiedenmann B, Papotti M, Rindi G, Plöckinger U, , (2009)
ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification.
Neuroendocrinology 90: 162-6



.

Microscopically, the number of mitoses counted per 10 HPF, the number of HPF assessed and the Ki67 index are essential. Assessment of endocrine function should be provided upon specific clinical request. The diagnosis should contain: (1) the classification of the lesion (NET or NEC); (2) the grade (G1, G2 or G3); (3) the relevant TNM stage (for resection specimens; see specific chapters); and (4), upon specific request the cell type and functional activity. One may add in parentheses the WHO 2000 definitions according to staging (well-differentiated endocrine tumour [WDET], well-differentiated endocrine carcinoma [WDEC] or poorly differentiated endocrine carcinoma [PDEC]).

Finally, the suffix "oma" following the name of a hormone (e.g. somatostatinoma, gastrinoma) is only appropriate when there is a clinical syndrome related to excess production of that hormone. In case of immunohistochemical evidence only, terms such as somatostatin-producing NET or gastrin-producing NET are not encouraged; rather, the staining result may be apended to the broad NET diagnostic category (e.g. NET with immunohistochemically demonstrated gastrin production).

Table 1 Transition scheme for the new classification (WHO 2010
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Bosman FT, Carneiro F, Hruban RH, Theise ND (Eds.)
WHO Classification of Tumours of the Digestive System.
4th Edition
International Agency for Research on Cancer: Lyon 2010



) including previous definitions for neuroendocrine neoplasms of the digestive system (WHO 1980 and 2000)
WHO 1980 WHO 2000 WHO 2010
I Carcinoid 1. Well-differentiated endocrine tumour (WDET)a
2. Well-differentiated endocrine carcinoma (WDEC)a
3. Poorly differentiated endocrine carcinoma/small cell carcinoma (PDEC)
1. NET G1 (carcinoid)b

2. NET G2b

3. NEC (large cell or small cell type)b,c
II Mucocarcinoid
III Mixed forms carcinoidadenocarcinoma
4. Mixed exocrine-endocrine carcinoma (MEEC) 4. Mixed adenoneuroendocrine carcinoma (MANEC)
IV Pseudotumour lesions 5. Tumour-like lesions (TLL) 5. Hyperplastic and preneoplastic lesions

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Goetz M, Toermer T, Vieth M, Dunbar K, Hoffman A, Galle PR, Neurath MF, Delaney P, Kiesslich R (2009)
Simultaneous confocal laser endomicroscopy and chromoendoscopy with topical cresyl violet.
Gastrointest Endosc 70: 959-68




Click for details
Solcia E, Klöppel G, and Sobin LH (eds.)
Histological Typing of Endocrine Tumours
Springer-Verlag: Berlin-New York 2000




Click for details
Williams ED, Siebenmann RE, and Sobin LH (eds.)
Histological Typing of Endocrine Tumours
World Health Organization: Geneva 1980




G, grade (for definition, see text); NEC, neuroendocrine carcinoma; NET, neuroendocrine tumour.
a The difference between WDET and WDEC was defined according to staging features in the WHO 2000 classification. G2 NET does not necessarily translate into WDEC of the WHO 2000 classification.
b Definition in parentheses for the International Classification of Diseases for Oncology (ICD-O) coding.
c “NET G3” has been used for this category but is not advised, since NETs are by definition well-differentiated.








Guido Rindi
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Guido Rindi
Institute of Anatomic Pathology
Catholic University Sacro Cuore, Policlinico A. Gemelli
Rome
Italy




Rudolf Arnold
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Rudolf Arnold
Universtity of Marburg
Munich
Germany




Fredrik T. Bosman
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Fredrik T. Bosman
Institut Universitaire de Pathologie
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne
Switzerland




Carlo Capella
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Carlo Capella
Department of Pathology
Ospedale di Circolo
Varese
Italy




David S. Klimstra
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David S. Klimstra
Department of Pathology
Memorial Sloan-Kettering Cancer Center
New York
USA




Günter Klöppel
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Günter Klöppel
Department of Pathology
Technical University of Munich
München
Germany




Paul Komminoth
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Paul Komminoth
Institute of Pathology
City Hospital Triemli
Zurich
Switzerland




Enrico Solcia
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Enrico Solcia
Department of Human Pathology and Genetics
University of Pavia and IRCCS
Pavia
ITALY