8249/3 Atypical carcinoid tumor


Synonyms

Neuroendocrine tumor, grade 2


Definitions

Stomach
ICD-O-3 topography code: C16
ICD10: C16
           

/span> neuroendocrine tumour (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 mild- to-moderate nuclear atypia and a low number of mitoses.
The proposed grading based on proliferation with the following definitions of mitotic count and Ki67 index:
? G1 (NET G1): mitotic count, <2 per 10 high power fields (HPF) and/or ≤2% Ki67 index;
? G2 (NET G2): mitotic count 2?20 per 10 HPF and/or 3?20% Ki67 index1
 
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



.



Most endocrine tumours of the stomach are well differentiated, nonfunctioning enterochromaffin-like (ECL) cell carcinoids arising from oxyntic mucosa in the corpus or fundus. Three distinct types have are recognized:
> Type I, associated with autoimmune chronic atrophic gastritis (A-CAG)
> Type II, associated with muliple endocrine neoplasia type 1 (MEN-1)OMIM and Zollinger-Ellison syndrome. The term gastrinoma is reserved for G-cell tumors that produce hypergastrinemia and are the source of the Zollinger-Ellison syndrome (ZES).
> Type III, sporadic, i.e. not associated with hypergastrinaemia or A-CAG.

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Click to access Pubmed
Tang LH, Modlin IM, Lawton GP, Kidd M, Chinery R (1996)
The role of transforming growth factor alpha in the enterochromaffin-like cell tumor autonomy in an African rodent mastomys.
Gastroenterology 111: 1212-23



. Linear hyperplasia or more advanced changes have been shown to represent a risk factor for the development of gastric ECL cell tumours in patients with MEN1-ZES 4
Click to access Pubmed
Berna MJ, Annibale B, Marignani M, Luong TV, Corleto V, Pace A, Ito T, Liewehr D, Venzon DJ, Delle Fave G, Bordi C, Jensen RT (2008)
A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: identification of risk factors.
J Clin Endocrinol Metab 93: 1582-91



, while the presence of dysplastic lesions has been proven to markedly increase the risk of developing ECL cell tumours 5
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Annibale B, Azzoni C, Corleto VD, di Giulio E, Caruana P, D'Ambra G, Bordi C, Delle Fave G (2001)
Atrophic body gastritis patients with enterochromaffin-like cell dysplasia are at increased risk for the development of type I gastric carcinoid.
Eur J Gastroenterol Hepatol 13: 1449-56



.



Esophagus
ICD-O-3 topography code: C15
ICD10: C15
           

A neuroendocrine tumour (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 mild- to-moderate nuclear atypia and a low number of mitoses.
The proposed grading based on proliferation with the following definitions of mitotic count and Ki67 index:
? G1 (NET G1)G1: mitotic count, <2 per 10 high power fields (HPF) and/or ≤2% Ki67 index;
? G2 (NET G2): mitotic count 2?20 per 10 HPF and/or 3?20% Ki67 index
6
 
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





In the esophagus, neuroendocrine tumours (NETs) are exceedingly rare. Most of the reported cases are neuroendocrine carcinomas (NEC) or mixed adenoneuroendocrine carcinoma (MANEC), the latter with either an adenocarcinoma or a squamous cell carcinoma component
7
 
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



.





Pancreas
ICD-O-3 topography code: C25
ICD10: C25
           

Pancreatic NETs and NECs (neuroendocrine carcinomas) are classified on the basis of criteria similar to those for other neuroendocrine neoplasms of the gastrointestinal tract as below:

A neuroendocrine tumour (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 mild- to-moderate nuclear atypia and a low number of mitoses.
The proposed grading based on proliferation with the following definitions of mitotic count and Ki67 index:
? G1 (NET G1): mitotic count, <2 per 10 high power fields (HPF) and/or ≤2% Ki67 index;
? G2 (NET G2): mitotic count 2?20 per 10 HPF and/or 3?20% Ki67 index
8
 
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



.



Pancreatic NETs can be associated with characteristic clinical syndromes owing to hormone hypersecretion (?functioning NETs? or ?syndromic NETs?) or they can be nonfunctioning (?nonsyndromic NETs?. Although routine immunohistochemical staining for peptide hormones is not suggested for clinically nonfunctional pancreatic NETs, for cases in which the production of a specific hormone has been demonstrated in the majority of the neoplastic cells, it is acceptable to supplement the diagnosis of pancreatic NET to reflect the corresponding cell type (e.g. ?α cell/glucagon-producing NET,? ?β cell/insulin-producing NET,? ?G cell/gastrin- producing NET?), but specific functional terms (e.g. ?glucagonoma,? ?insulinoma,? ?gastrinoma?) should not be used in the absence of a hormonal syndrome. Changes to the classification of pancreatic neuroendocrine neoplasms since the third edition of the WHO Classification of Tumours include the use of ?neuroendocrine? rather than ?endocrine? (to parallel the terminology of the remainder of the gastrointestinal tract) and the replacement of the hybrid grade- and stage-based classification system with a purely grade-based system determined by proliferative rate. Pancreatic NETs should also now be staged, since stage is an independent prognostic indicator
9
 
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



.



Colon and rectum
ICD-O-3 topography code: C18-C20
ICD10: C18-C20
           

/span> neuroendocrine tumour (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 mild- to-moderate nuclear atypia and a low number of mitoses.
The proposed grading based on proliferation with the following definitions of mitotic count and Ki67 index:
? G1 (NET G1): mitotic count, <2 per 10 high power fields (HPF) and/or ≤2% Ki67 index;
? G2 (NET G2): mitotic count 2?20 per 10 HPF and/or 3?20% Ki67 index
10
 
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



.



> nMouseOut="hideNote('note193604031')";>12
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Dujardin F, Beaussart P, de Muret A, Rosset P, Waynberger E, Mulleman D, de Pinieux G (2009)
Primary neuroendocrine tumor of the sacrum: case report and review of the literature.
Skeletal Radiol 38: 819-23



13
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Kim T, Grobmyer SR, Liu C, Hochwald SN (2007)
Primary presacral neuroendocrine tumor associated with imperforate anus.
World J Surg Oncol 5: 115



14
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Liang JJ, Alrawi S, Fuller GN, Tan D (2008)
Carcinoid tumors arising in tailgut cysts may be associated with estrogen receptor status: case report and review of the literature.
Int J Clin Exp Pathol 1: 539-43



15
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Luong TV, Salvagni S, Bordi C (2005)
Presacral carcinoid tumour. Review of the literature and report of a clinically malignant case.
Dig Liver Dis 37: 278-81



16
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Song DE, Park JK, Hur B, Ro JY (2004)
Carcinoid tumor arising in a tailgut cyst of the anorectal junction with distant metastasis: a case report and review of the literature.
Arch Pathol Lab Med 128: 578-80



. An origin from hind - gut remnants in the region has been proposed, 12 of the reported cases being associated with teratoma or tailgut cysts, one case being associated with imperforate anus 17
Click to access Pubmed
Kim T, Grobmyer SR, Liu C, Hochwald SN (2007)
Primary presacral neuroendocrine tumor associated with imperforate anus.
World J Surg Oncol 5: 115



. Patients are more often female, age ranging from 18 to 72 years, presenting with mass-related symptoms and often pain. Neuroendocrine neoplasms of the presacral region are NETs displaying histological and immunohistochemical features similar to those of rectal NETs, with trabecular-gyriform structure, bland cytology and immunoreactivity for chromogranin A and synaptophysin [[746]]. One case also showed positive nuclear immunohistochemistry for estrogen and progesterone receptors 18
Click to access Pubmed
Liang JJ, Alrawi S, Fuller GN, Tan D (2008)
Carcinoid tumors arising in tailgut cysts may be associated with estrogen receptor status: case report and review of the literature.
Int J Clin Exp Pathol 1: 539-43



. The low mitotic rate, the absence of necrosis and the low Ki67 index reported qualify most presacral region NETS as G1 19
Click to access Pubmed
Dujardin F, Beaussart P, de Muret A, Rosset P, Waynberger E, Mulleman D, de Pinieux G (2009)
Primary neuroendocrine tumor of the sacrum: case report and review of the literature.
Skeletal Radiol 38: 819-23



20
Click to access Pubmed
Kim T, Grobmyer SR, Liu C, Hochwald SN (2007)
Primary presacral neuroendocrine tumor associated with imperforate anus.
World J Surg Oncol 5: 115



21
Click to access Pubmed
Liang JJ, Alrawi S, Fuller GN, Tan D (2008)
Carcinoid tumors arising in tailgut cysts may be associated with estrogen receptor status: case report and review of the literature.
Int J Clin Exp Pathol 1: 539-43



. Malignant NETs with proven metastatic capacity also displayed foci of necrosis, angioinvasion and increased Ki67 index, qualifying these NETs as G2 22
Click to access Pubmed
Luong TV, Salvagni S, Bordi C (2005)
Presacral carcinoid tumour. Review of the literature and report of a clinically malignant case.
Dig Liver Dis 37: 278-81



23
Click to access Pubmed
Song DE, Park JK, Hur B, Ro JY (2004)
Carcinoid tumor arising in a tailgut cyst of the anorectal junction with distant metastasis: a case report and review of the literature.
Arch Pathol Lab Med 128: 578-80



. Patients with sacrococcigeal NETs in general have a good prognosis, largely depending on appropriate management with either surgery or local radiation therapy, one patient being alive and well after 28 years of evolution 24
Click to access Pubmed
Dujardin F, Beaussart P, de Muret A, Rosset P, Waynberger E, Mulleman D, de Pinieux G (2009)
Primary neuroendocrine tumor of the sacrum: case report and review of the literature.
Skeletal Radiol 38: 819-23



. A poor outcome is reported for G2 cases 25
Click to access Pubmed
Liang JJ, Alrawi S, Fuller GN, Tan D (2008)
Carcinoid tumors arising in tailgut cysts may be associated with estrogen receptor status: case report and review of the literature.
Int J Clin Exp Pathol 1: 539-43



26
Click to access Pubmed
Luong TV, Salvagni S, Bordi C (2005)
Presacral carcinoid tumour. Review of the literature and report of a clinically malignant case.
Dig Liver Dis 37: 278-81



27
Click to access Pubmed
Song DE, Park JK, Hur B, Ro JY (2004)
Carcinoid tumor arising in a tailgut cyst of the anorectal junction with distant metastasis: a case report and review of the literature.
Arch Pathol Lab Med 128: 578-80



28
 
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



.



Small intestine
ICD-O-3 topography code: C17
ICD10: C17
           

/span>ntestinal neuroendocrine tumours (NETs) and neuroendocrine carcinomas (NECs) are classified on the basis of criteria common to all gastrointestinal and pancreatic neuroendocrine neoplasms:
A neuroendocrine tumour (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 mild- to-moderate nuclear atypia and a low number of mitoses.
The proposed grading based on proliferation with the following definitions of mitotic count and Ki67 index:
? G1 (NET G1): mitotic count, <2 per 10 high power fields (HPF) and/or ≤2% Ki67 index;
? G2 (NET G2): mitotic count 2?20 per 10 HPF and/or 3?20% Ki67 index
29
 
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



.



Neuroendocrine neoplasms of the small intestine exhibit site-related differences, depending on their location in the duodenum and proximal jejunum when compared with distal jejunum, ileum and Meckel diverticulum.

>



Hypopharynx, Larynx and Trachea
ICD-O-3 topography code: C13, C32, C33
ICD10: C13, C32, C33
           





Gallbladder and extrahepatic biliary tract
ICD-O-3 topography code: C23-C24.0
ICD10: C23-C24.0
           

A neuroendocrine tumour (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 mild- to-moderate nuclear atypia and a low number of mitoses.

The proposed grading based on proliferation with the following definitions of mitotic count and Ki67 index:
? G1 (NET G1): mitotic count, <2 per 10 high power fields (HPF) and/or ≤2% Ki67 index;
? G2 (NET G2): mitotic count 2?20 per 10 HPF and/or 3?20% Ki67 index
30
 
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









Region of the ampulla of Vater
ICD-O-3 topography code: C24.1
ICD10: C24.1
           

/span> neuroendocrine tumour (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 mild- to-moderate nuclear atypia and a low number of mitoses.
The proposed grading based on proliferation with the following definitions of mitotic count and Ki67 index:
? G1 (NET G1): mitotic count, <2 per 10 high power fields (HPF) and/or ≤2% Ki67 index;
? G2 (NET G2): mitotic count 2?20 per 10 HPF and/or 3?20% Ki67 index
31
 
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



.



>



Bronchus and lung
ICD-O-3 topography code: C34
ICD10: C34
           





Nasal cavity and Sinuses
ICD-O-3 topography code: C30-C31
ICD10: C30-C31
           





Anus and anal canal
ICD-O-3 topography code: C21
ICD10: C21
           

A neuroendocrine tumour (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 mild- to-moderate nuclear atypia and a low number of mitoses.
The proposed grading based on proliferation with the following definitions of mitotic count and Ki67 index:
? G1 (NET G1): mitotic count, <2 per 10 high power fields (HPF) and/or ≤2% Ki67 index;
? G2 (NET G2): mitotic count 2?20 per 10 HPF and/or 3?20% Ki67 index.



Anal NETs
Neuroendocrine tumours may arise in the anus
32
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Fenger C, Lyon H (1982)
Endocrine cells and melanin-containing cells in the anal canal epithelium.
Histochem J 14: 631-9



33
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Hörsch D, Fink T, Göke B, Arnold R, Büchler M, Weihe E (1994)
Distribution and chemical phenotypes of neuroendocrine cells in the human anal canal.
Regul Pept 54: 527-42



. They are, however, conventionally classified as rectal. An immunohistochemical study of 17 rectal neuroendocrine tumours showed that most were of L cell type 34
Click to access Pubmed
Chetritt J, Sagan C, Heymann MF, Le Bodic MF (1996)
[Immunohistochemical study of 17 cases of rectal neuroendocrine tumors].
Ann Pathol 16: 98-103



35
 
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



.





Thymus
ICD-O-3 topography code: C37
ICD10: C37
           





Cervix uteri
ICD-O-3 topography code: C53
ICD10: C53
           

Atypical carcinoids are characterized by cytologic atypia with increased mitotic activity and by foci of necrosis
36
 
Tavassoli FA, Devilee P (Eds.)
World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs.
3rd Edition
IARC Press: Lyon 2003



.



Breast
ICD-O-3 topography code: C50
ICD10: C50
           

Atypical carcinoids belong to the group of neuroendocrine tumours. They are characterized by cytologic atypia with increased mitotic activity and by foci of necrosis. The majority of patients are in the 6th or 7th decades of life
37
 
Tavassoli FA, Devilee P (Eds.)
World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs.
3rd Edition
IARC Press: Lyon 2003



.