Staging and Grading of Neuroendocrine Tumors


Until recently, there was no approved staging classification available for neuroendocrine cancers. However, nowadays, the standard TNM system of classification is used for NET staging accompanied by tumor grading to indicate the degree of involvement of these organs specifically.


A few years ago, NET did not have an official TNM-based staging system, however, the data submitted to the National Cancer Institute’s Surveillance, Epidemiology, and Outcome (SEER) program divided tumors into local, regional, and distant staging based on lymph nodes or distant metastases. Still, no primary tumor classification changes were undertaken. In fact, the TNM staging system was recently proposed. The American Joint Cancer Committee recently published a new TNM staging manual covering the entire anatomical region of the NET, and ENETS previously published guidelines for staging TNM in the Gastroenteropancreatic NET.

Although there are some differences between these systems, especially for primary tumours of the pancreas and appendix, there are also essential overlaps. In addition, the staging criteria for both systems depend primarily on the size of the tumor and the degree of invasion at a similar site used to stage non-European carcinoma in a similar area. In addition to providing TNM stages using a reference system, it is recommended to specifically indicate the degree of involvement of these organs in the pathology report.

Until recently, WHO’s gastrointestinal tract NET classification (2000) and pancreatic (2004) NETs used a hybrid classification system that included staging information (tumor size and volume only at the primary metastasis site) and classification. Although this system could predict the stratification of NETs, ​​classification information was not available at advanced disease stages, preventing prognosis after metastasis and making treatment decisions. In addition, the result of this classification was that the NET names at the primary sites were different from the names used for the same tumor after the onset of further metastasis, a relatively common phenomenon in some NETs. Because of these limitations, the latest WHO classification of all gastrointestinal networks has abandoned the hybrid classification system for separate tumor classification and staging. In fact, this will bring the WHO system into line with other widely used methods.

TNM staging system

One of the tools doctors use to describe their staging is the TNM system. In fact, the stage of TNM is usually determined after the tumor has been surgically removed and evaluated by a pathologist. Doctors use various diagnostic tests and imaging techniques to answer the following questions:

  • Tumor (T): What is the size of the primary tumor and where is it located?
  • Node (N): Has the tumor spread to lymph nodes and if so, where and how much?
  • Metastasis (M): It denotes the spread of cancer to other parts of the body and it also indicates the location and the amount of spread.

The results are therefore combined to determine each individual’s cancer stage.

In fact, the NET of the pancreas has four stages: I through IV (1 through 4). Staging provides a general way to describe cancer so doctors can work together to plan the best treatment for you.

Cancer stage grading

Doctors combine the T, N, and M information to determine the stage of cancer.

In fact, the grades of neuroendocrine cancer for various cancer types are summarised in below table

GradeLung and ThymusGEP-NETsPancreas
Low gradeNeuroendocrine carcinoma, grade 1Neuroendocrine neoplasm, grade 1Well-differentiated pancreatic endocrine neoplasm, low grade
Intermediate gradeNeuroendocrine carcinoma, grade 2Neuroendocrine neoplasm, grade 2Well-differentiated pancreatic endocrine neoplasm, intermediate grade
High gradeNeuroendocrine carcinoma, grade 3, small cell carcinomaNeuroendocrine neoplasm, grade 3, small cell carcinomaPoorly-differentiated pancreatic endocrine carcinoma, small cell carcinoma
Neuroendocrine carcinoma, grade 3, large cell carcinomaNeuroendocrine neoplasm, grade 3, large cell carcinomaPoorly-differentiated pancreatic endocrine carcinoma, large cell carcinoma