About Carcinoid Tumors

Classification of Neuroendocrine Tumors

The classification of neuroendocrine tumors (NETs) can help guide diagnosis. In 2010, the World Health Organization (WHO) updated its classification of NETs based on tumor site of origin, clinical syndrome, and differentiation.1,2

Site of Origin

Carcinoid tumors and pancreatic NETs (pNETs) are commonly divided by site of origin (eg foregut, midgut, hindgut 1 [Figure 2]).Of note, pNETs are considered to orginate in the foregut.1 Distal tumors include NETs in other locations such as the ear, heart, and ovaries.1

Figure 2. Classification of NETs1,3,4,5

neuroendocrine-tumors-classification.jpg/ Neuroendocrine Tumors Classification (NETs)

NETs also exhibit gender distribution: females are more likely to have a primary carcinoid tumor in the lung, stomach, appendix, or cecum; males are more likely to have a primary NET in the thymus, duodenum, pancreas, jejunum/ileum, or rectum.2

Grade and Differentiation

The grade of a tumor refers to its biologic aggressiveness.6 For carcinoid tumors and pNETs, the grading system is based on the rate of proliferation, which is defined by the number of mitoses per 10 high-power microscopic fields or per 2 mm2 (mitotic rate), or as the percentage of tumor cells that immunolabel positively for the Ki-67 antigen (Ki-67 index).6 Mitotic rate and Ki-67 index are listed by tumor grade in Table 1. Briefly, low-grade tumors are characterized by low proliferative indices and are considered indolent in nature.7 High-grade tumors tend to be poorly differentiated, have high proliferative indices, and are thus very aggressive.7

NETs can also be classified based on differentiation, which refers to the extent to which cancerous, or neoplastic, cells resemble normal cells.6 Well differentiated NETs have a typical organoid arrangement of cells with nesting, trabecular, or gyriform patterns.6 Well differentiated NET cells produce large amounts of secretory granules with diffuse immunoexpression of neuroendocrine markers.6 In contrast, poorly differentiated NETS have atypical, sheet-like, diffuse and irregular nuclei, less cytoplasmic secretory granules, and limited biomarker immunoexpression.6 Well differentiated NETs are usually of low or intermediate grade; poorly differentiated NETs are usually high grade.1,7 The histological classification of NETs including grade (G) and differentiation is outlined in Table 1.7,8

Reproduced from Strosberg J et al. Gastrointest Cancer Res. 2:113-125, with permission from the International Society of Gastrointestinal Oncology 2008. Images courtesy of Nasir Aejaz, MD, Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.7,8

WHO classification-neuroendocrine-tumors.jpg/WHO Classification of Neuroendocrine Tumors

Table 1. Histopathology of Neuroendocrine Tumors7,8

Histological Classification

Well Differentiated (Low Grade, G1)

Moderately Differentiated (Intermediate Grade, G2)

Poorly Differentiated (High Grade, G3)

Appearance

Monomorphic population of small, round cells

*

Cellular pleomorphism

Prognosis

Prolonged survival

Intermediate

Poor

Mitotic Rate

<2

220

>20

Ki-67 Index+

<3%

320%

>20%

Necrosis

Absent

*

Present

*Not well defined in the medical literature.

+ Ki-67 index applies only to WHO and European Neuroendocrine Tumor Society (ENETS) classification of gastroenteropancreatic NETs.

Clinical Syndrome

NETs can also be classified as functional or non-functional.3 NETs are considered functional when a specific clinical syndrome is induced due to the excessive production of hormones by the tumor cells; approximately two-thirds of NETs are functional.1 Examples of functional NETs include carcinoid tumors, which can result in carcinoid syndrome, and functional pNETs (insulinomas, gastrinomas, vasoactive intestinal peptide (VIP)omas, glucagonomas, and somatostatinomas).3

Non-functional NETs are not associated with a clinical syndrome, but can still produce symptoms related to the presence of the tumor or its metastases (eg abdominal pain and bloating).6,9 Generally, non-functional pNETs occur approximately twice as frequently as insulinomas, which are in turn generally more frequent than gastrinomas > glucagonomas > VIPomas > somatostatinomas.10 Functional and non-functional pNETs may be benign or malignant.3 Up to 90% of pNETs are malignant with the exception of locoregional insulinomas, which are primarily benign.3

Pathology

Pathology is essential in the classification and diagnosis of carcinoid tumors and pNETs.7,11 Immunohistochemistry can help identify the type of NET, as well as serve as a biomarker for diagnosis.11

Microscopic appearance may also be used to differentiate between carcinoid tumors and pNETs.10 For example, there is a unique occurrence of psammoma bodies in somatostatinomas (functioning pNET) localized within the duodenum.10 Somatostatin inhibits the release of growth hormone and other proteins secreted by NETs.1 Most carcinoid tumors and pNETs overexpress each of the five somatostatin receptors.1 The pathology report should contain basic, uniform, and reproducible information in order to facilitate an accurate diagnosis and decision making by a multidisciplinary management team.11 The minimum data set required in the pathology report includes the site of tumor/metastasis, grade, stage, mitotic rate, proliferation rate, diagnosis, and immunohistochemical staining.7,11

Extent of Disease

Carcinoid tumors and pNETs can also be classified by extent of disease as having either local, regional, or distant involvement2 (Figure 3). Even if a primary tumor appears to be small, it is important to be aware that the patient may have developed extensive regional and/or bulky distant metastatic disease.9 (Figure 3).

Figure 3. NETs Classified by Extent of Disease

net-carcinoid-tumor-classified.jpg/Metastatic Neuroendocrine Tumors Classified by Extent of Disease

Images courtesy of James C. Yao, MD; Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. Figures courtesy of Rodney F. Pommier, MD, Division of Surgical Oncology, Oregon Health & Science University, Portland, OR.

Staging

The European Neuroendocrine Tumor Society and the American Joint Committee on Cancer classify, or stage, NETs by primary tumor (T), lymph node involvement (N), and distant metastasis (M).12,13 This TNM staging represents a new system of NET classification.6 The definition of TNM varies by each primary tumor site; however, staging relies predominantly on the size of the tumor and the extent of invasion into anatomical structures (Tables 2 and 3).6 For example, according to Table 2, a NET in the colon that is invading the muscularis propria with no lymph node involvement or distant metastases would be considered Stage IIA or IIB.12 The North American Neuroendocrine Tumor Society (NANETS) recommends that pathology reports provide a TNM stage based on a system that is specifically referenced in the pathology report.6

TNM Staging of NETs

Table 2. American Joint Committee on Cancer Staging for NETs of the Stomach Small Intestine, Colon and Rectum12

Stage 0

TiS

Stomach

Carcinoma in situ/dysplasia (tumor size less than 0.5 mm), confined to mucosa

N0
No regional lymph nodes metastasis

M0
No distant metastasis

Stage I

T1*

Stomach/Duodenum/ Jejunum/Ileum

Tumor invades lamina propria or submucosa and size 1 cm or less**

Ampulla

Tumor 1 cm or less

Colon or rectum

T1

Tumor invades lamina propria or submucosa and size 2cm or less

T1a

tumor size less than 1 cm in greatest dimension

T1b

tumor size   1 -2cm in greatest dimension

Stage IIA

T2*

Stomach/Duodenum/ Jejunum/ Ileum

Tumor invades muscularis propria or size greater than 1cm

Ampulla

Tumor greater than 1cm

Colon or rectum

Tumor invades muscularis propria or size more than 2 cm with invasion of lamina propria or submucosa

Stage IIB

T3*

Stomach

Tumor penetrates subserosa

Duodenum/Ampulla/ Jejunum/Ileum

Tumor invades muscularis propria into subserosal tissue without penetration of overlying serosa (jejuna or ileal tumors) or invades pancreas or retroperitoneum (ampullary or duodenal tumors) or into non-peritonealized tissues

Colon or rectum

Tumor invades throughmuscularis propria into the subserosa, or into non-peritonealized pericolic or perirectal tissues

Stage III A

T4*

Duodenum/Ampulla/ Jejunum/Ileum

Tumor invades visceral peritoneum (serosa) or other organs or adjacent structures

Colon or rectum

Tumor invades peritoneum or other organs

Stage III B

Any T

N1
Regional lymph node metastasis

Stage IV

Any T

Any N

M1
Distant metastasis

*For any T, add (m) for multiple tumors

**Note: Tumor limited to ampulla of Vater for ampullary gangliocytic paraganlioma M, distant metastasis; N, lymph node involvement; T, primary tumor; Tis, carcinoma in situ.

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Handbook. 7th ed. (2010) published by Springer Science and Business Media LLC, www.springerlink.com.

Table 3. American Joint Committee on Cancer Staging for
Pancreatic NETs12

Stage 0

Tis
Carcinoma in situ*

N0
No regional lymph node metastasis

M0
No distant metastasis

Stage IA

T1
Tumor limited to the pancreas ,2 cm or less in greatest dimension

Stage IB

T2
Tumor limited to the pancreas more than 2 cm in greatest dimension

Stage IIA

T3
Tumor extends beyond the pancreas without involvement of the celiac axis or the superior mesenteric artery

Stage IIB

T1, T2, or T3

N1
Regional lymph node metastasis

Stage III

T4
Tumor involves celiac axis or the superior mesenteric artery (unresectable primary tumor)

Any N

Stage IV

Any T

M1
Distant metastasis

*This also includes the "PanInIII" classification.

M, distant metastasis; N, lymph node involvement; T, primary tumor; Tis, carcinoma in situ

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Handbook. 7th ed. (2010) published by Springer Science and Business Media LLC, www.springerlink.com.

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References
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  2. Yao JC, Hassan M, Phan A et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063-3072.
  3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: neuroendocrine tumors. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed August 9, 2011.
  4. Vinik AI, Renar IP. Neuroendocrine tumors of carcinoid variety. In: De Grool L, ed. Endocrinology. 3rd ed. Philadelphia, PA: WB Saunders; 1995:2803-2814.
  5. National Cancer Institute. General information about pancreatic neuroendocrine tumors (islet cell tumors). Available at: http://www.cancer.gov/cancertopics/pdq/treatment/isletcell/Patient. Accessed March 28, 2012.
  6. Kulke MH, Anthony LB, Bushnell DL et al. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39:735-752.
  7. Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39:707-712.
  8. Strosberg JR, Nasir A, Hodul P, Kvols L. Biology and treatment of metastatic gastrointestinal neuroendocrine tumors. Gastrointest Cancer Res. 2008;2:113-125.
  9. Modlin IM, Oberg K, Chung DC et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9:61-72.
  10. Vinik AI, Woltering EA, Warner RR et al. NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas. 2010;39:713-734.
  11. The Neuroendocrine Tumor Alliance. Essential elements of a pathology report for neuroendocrine tumors: the importance of accurate classification, grading and staging. A Novartis Pharmaceuticals Pathology Brochure. 2010;1-15.
  12. Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Handbook. 7th ed. New York, NY: Springer, 2010.
  13. Anthony LB, Strosberg JR, Klimstra DS et al. The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (NETs): well-differentiated NETs of the distal colon and rectum. Pancreas. 2010;39:767-774.