Classification of NETs

"Unlike lung cancer, which arises from the lung, or a breast cancer that arises from the breast, neuroendocrine tumors arise from a cell type. These neuroendocrine cells can really arise from [almost] anywhere in the body."
–Dr Lowell Anthony

Neuroendocrine neoplasms can be classified by1,2:

  • Anatomic site of origin
  • Histology: well-differentiated (G1 and G2) NETs, poorly differentiated (G3) carcinomas, or undifferentiated neoplasms
  • Extent of disease: local, regional, or distant metastases

By anatomic site of origin

Many of the characteristics of NETs are site specific.3 Most NETs are characterized as arising in the GI tract (stomach, appendix, duodenum, and small intestine), the bronchopulmonary system (lungs and thymus), the pancreas, and the colon and rectum.4

Broad generalizations that can be made about the site-specific characteristics of NETs include the following:

  • Pancreatic NETs and bronchial NETs are disparate tumors that are sometimes associated with syndromes caused by the secretion of hormones3,5
  • NETs arising in the small intestine and proximal colon are relatively homogeneous tumors strongly associated with typical carcinoid syndrome3,6
  • NETs arising in the distal colon and rectum usually are nonfunctional and cause symptoms owing to increasing mass3,7

By histology

Consensus about a recognized uniform grading system for neuroendocrine neoplasms has been difficult to achieve, but the systems proffered by the American Joint Committee on Cancer (AJCC), World Health Organization (WHO), European Neuroendocrine Tumor Society (ENETS), and others provide useful prognostic information.4,8 The WHO 2010 guidelines for GI NETs not only represent a useful classification system for these neoplasms but also provide a general guide for grading pancreatic NETs.2

The WHO guidelines divide neuroendocrine neoplasms into 2 clinically distinct pathologic classes: well- and poorly differentiated.2

  • Well-differentiated NETs can be classified as either grade 1 or grade 2 depending on proliferation and histology (see comparison table below). Well-differentiated grade 1 and grade 2 NETs traditionally have been referred to as carcinoids, regardless of grade or site of origin.2,9,10 The WHO 2010 guidelines apply the term "carcinoid" to grade 1 NETs only2
  • Poorly differentiated grade 3 neuroendocrine carcinomas are characterized by rapid dissemination, resistance to therapeutic interventions, and a highly aggressive course

By grade

Some of the biological behavior exhibited by neuroendocrine neoplasms is highly correlated with neoplasm grade.1,8

  • Grade 1 NETs are relatively slow growing8
  • Grade 2 NETs have a less predictable, moderately aggressive course1
  • Grade 3 neuroendocrine carcinomas can be highly aggressive8

Mitotic rate and proliferative index of the tumor are the most important features used for grading (see table).1

  • Mitotic rate is assessed by counting mitotic figures, usually expressed as the number of mitoses per 10 high-power microscopic fields (HPF) (or 2 mm2). The sensitivity of this technique is limited in small-volume biopsy samples, and it is generally considered to be more applicable to high-grade NETs1
  • Proliferative index is expressed as the percentage of tumor cells labeled by immunohistochemistry for the proliferation marker Ki-67 (Ki-67 index).1 This technique is generally considered to be more applicable to low-grade NETs. The Ki-67 labeling index is used more widely in Europe than it is in the United States to assess proliferation8

For neuroendocrine neoplasms, the presence of necrosis also plays an important role in grading.8,12 For example, G1/G2 bronchial NETs (typical/atypical carcinoids) and G3 bronchial neoplasms (large cell neuroendocrine carcinoma [LCNEC] and small cell lung carcinoma [SCLC]) exhibit markedly different behavior, and the presence or absence of necrosis, along with mitotic activity, is a key distinguishing feature between these 2 groups of tumors.12,13

Despite all of the challenges inherent in grading NETs, a grade should always be stated in the pathology report, along with the specific grading system used.8

By extent of disease

Extent of disease as shown by computed tomography (CT)

Images courtesy of Dr James Yao (2008)

The 2010 WHO guidelines also address tumor-node-metastasis (TNM) staging of NETs, which heretofore has been relatively limited. In the guidelines, the fundamental staging landmarks for NETs parallel those used for carcinomas of the corresponding organs. The SEER program database also uses a "localized," "regional," and "distant" system to stage disease, but both WHO and AJCC classification systems reflect the widespread recognition that NETs should be staged using TNM criteria.2,8

By presence of associated secretory symptoms

Although the presence or absence of associated symptoms of hormone hypersecretion is not considered in formal classification guidelines, NETs can be classified by whether or not they can produce hormonal substances.1 Functional NETs are associated with symptoms that can be attributed to the secretion of specific hormones or peptides.9 Nonfunctional NETs, on the other hand, are only associated with symptoms related to increasing mass (eg, pain, obstruction, bleeding). Some NETs remain asymptomatic indefinitely.14

Symptoms caused by functional NETs include flushing, fatigue, diarrhea, hypoglycemia, skin changes, abdominal pain/discomfort, and wheezing.9,15,16. (see More on NET symptoms)

Functional NETs may also cause different clinical syndromes to occur.7 One of these is carcinoid syndrome, which occurs in approximately 8% to 35% of patients with well-differentiated tumors, most typically in the GI tract, with incidence ranging from 1.7% to 18.4%.9,17 Carcinoid syndrome most frequently occurs when a GI NET metastasizes to the liver, allowing secreted serotonin and other vasoactive substances to reach the systemic circulation via the hepatic vein.9,18

Well-differentiated NETs arising in the lungs may also secrete peptides that cause carcinoid syndrome (less than 5% of cases), but they may also produce histamine, which can cause atypical carcinoid syndrome, as well as ACTH, which causes Cushing syndrome. Well-differentiated lung NETs are also associated with other syndromes due to the secretion of hormones that are nontypical to the tissue of origin.5

Other syndromes are associated primarily with the inappropriate secretion of hormones and other bioactive substances by pancreatic NETs.19,20 In fact, roughly half of all pancreatic NETs are functional and capable of producing hormonal syndromes.21 These syndromes may also be caused by tumors arising in specific areas of the GI tract.19,20

Grading, staging, and classification system comparison8

Although the 2010 WHO guidelines for classifying GI NETs have attempted to standardize the different methods currently in use, confusion and inconsistent nomenclature remain within the disease state.2 One recent journal article attempted to reconcile various grading, staging, and classification systems for NETs (below).8 The grading systems are displayed along the x-axis (top) and the staging systems, along the y-axis (left). The WHO systems for gastrointestinal and pancreatic NETs include a combination of grading and staging information and are displayed with the box (lower right). The overlaps between different systems are approximate, and within each section the various nomenclature of each system is used.

Reprinted with permission from Klimstra D et al. Am J Surg Pathol. 2010;34(3):300-313.

1. 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(6):707-712.
2. Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carniero F, Hruban RH, Theise ND, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:13-14.
3. Strosberg JR, Nasir A, Hodul P, Kvols L. Biology and treatment of metastatic gastrointestinal neuroendocrine tumors. Gastrointest Cancer Res. 2008;2(3):113-125.
4. 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(18):3063-3072.
5. Modlin IM, Öberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9(1):61-72.
6. Kaltsas GA, Besser GM, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev. 2004;25(3):458-511.
7. Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis of 146 metastatic neuroendocrine tumors of the mid-gut. Neuroendocrinology. 2009;89(4):471-476.
8. Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg Pathol. 2010;34(3):300-313.
9. Vinik AI, Thompson N, Eckhauser F, Moattari AR. Clinical features of carcinoid syndrome and the use of somatostatin analogue in its management. Acta Oncologica. 1989;28(3):389-402.
10. Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid syndrome. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1559-1574.
11. Moran CA, Suster S, Coppola D, Wick MR. Neuroendocrine carcinomas of the lung: a critical analysis. Am J Clin Pathol. 2009;131(2):206-221.
12. Travis WD. The concept of pulmonary neuroendocrine tumours. In: Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; 2004:19-20.
13. Phan AT, Öberg K, Choi J, et al. NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the thorax (includes lung and thymus). Pancreas. 2010;39(6):784-798.
14. Capella C, Heitz PU, Höfler H, Solcia E, Klöppel G. Revised classification of neuroendocrine tumours of the lung, pancreas and gut.Virchows Arch. 1995;425(6):547-560.
15. Toth-Fejel S, Pommier RF. Relationships among delay of diagnosis, extent of disease, and survival in patients with abdominal carcinoid tumors. Am J Surg. 2004;187(5):575-579.
16. Mamikunian G, Vinik AI, O'Dorisio TM, Woltering EA, Go VLW. Diagnosing and treating gastroenteropancreatic tumors, including ICD-9 codes. In: Neuroendocrine Tumors: A Comprehensive Guide to Diagnosis and Management. 4th ed. Inglewood, CA: Inter Science Institute; 2009:1-43.
17. Rorstad O. Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract. J Surg Oncol. 2005;89:151-160.
18. Bhattacharyya S, Davar J, Dreyfus G, Caplin ME. Carcinoid heart disease. Circulation. 2007;116(24):2860-2865.
19. Kulke MH, Anthony LB, Bushnell DL, et al. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39(6):735-752.
20. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135(5):1469-1492.
21. Ong SL, Garcea G, Pollard CA, et al. A fuller understanding of pancreatic neuroendocrine tumours combined with aggressive management improves outcome. Pancreatology. 2009;9(5):583-600.