Making Sense of a Complex Disease

A Practical Approach to Managing Neuroendocrine Tumors

Janie Y. Zhang, MD; Pamela L. Kunz, MD


J Oncol Pract. 2022;18(4):258-264. 

In This Article

Classification and Staging

Nomenclature for the pathologic classification of NETs is complex and has evolved over time. Efforts have been made to standardize classification of NETs in any anatomic location.[2] In the 2019 WHO classification of tumors of the digestive tract, well-differentiated gastroenteropancreatic (GEP)-NETs are stratified by grade (low, intermediate, or high), mitotic activity, and Ki-67 proliferation index into three categories (NETs, G1-G3).[3] High mitotic activity and Ki-67 index have been associated with more aggressive disease and worse outcomes in NETs.[4] Of note, well-differentiated, high-grade (G3) GEP-NETs have recently been classified separately from poorly differentiated GI NECs, recognizing biologic differences between these groups. Well-differentiated NETs are often characterized by loss of DAXX and ATRX protein expression, whereas poorly differentiated NECs are usually characterized by abnormal p53, Rb, and SMAD4 expression.[5] It is important to note that classification of lung NETs still relies on the 2015 WHO classification and continues to use the terms typical carcinoid and atypical carcinoid to describe low-grade and intermediate-grade thoracic NETs, respectively (Table 1).[6]

Because the pathologic classification of NENs is important for treatment and prognosis, certain minimum data elements should be included in pathology reports: anatomic site, degree of differentiation, WHO grade, mitotic rate, and Ki-67 proliferation index. We also recommend that tumor size, presence of multicentric disease, vascular and perineural invasion, margin status, and the number of positive lymph nodes versus number of total lymph nodes examined should be included in the pathologic report.

An important clinical categorization of NETs is by anatomic location (pancreatic v extrapancreatic), as it influences the choice of systemic therapies. When the primary site is unknown, effort should be made to find the origin of the neoplasm to guide treatment.

The staging of NETs is based on the anatomic site of primary tumor and revised in the eighth edition of the AJCC Cancer Staging Manual. Stage has been validated in retrospective analyses of small-bowel and pancreatic NET (pNET) cohorts to prognosticate survival.[7,8]