In 2010 and 2017, the World Health Organization revised the nomenclature for neuroendocrine neoplasms with specific emphasis on the distinction between welldifferentiated neuroendocrine tumors(WD-NET) and poorly-differentiated neuroendocrine carcinomas (PD-NEC), which are vastly different in tumor biology, clinical presentation, therapeutic strategies, and prognosis. Pathological grading of NETs is based on tumor proliferative activity, i.e., mitotic figures and Ki67 index (see table below). PD-NECs are always high grade. However, proliferative activity alone may not be sufficient to determine whether the tumor is a WD-NET or a PD-NEC, particularly in small and suboptimal biopsies. Additional clinical information, immunohistochemical workup, and molecular testing may be necessary to confirm the correct diagnosis.

Bronchial NETs have a slightly different classification system using the older terminology:
• Typical Carcinoid (Grade 1)
• Atypical Carcinoid (Grade 2)
• Poorly-Differentiated (Grade 3)

The standard pathology assessment of a neuroendocrine neoplasm should include:
• Clear definition of WD-NET or PD-NEC
• Immunohistochemical markers to confirm NET/NEC (synaptophysin and chromogranin)
• Mitotic activity: number of mitoses/10 high power fields for biopsies; and number of mitoses/50 high power fields for surgical specimens.
• Ki67 proliferative index by immunohistochemistry
• Presence or absence of tumor necrosis

In cases of unknown primary tumors, additional immunohistochemical markers may indicate possible primary sites. For example, TTF-1 expression is often associated with bronchial carcinoids; CDX2 is commonly seen in NETs of the gastrointestinal tract, etc. Some molecular tests of a biopsy specimen may also help determine the primary site (Cancer TYPE ID).

The American Joint Commission on Cancer (AJCC) has updated the staging system for NETs of the digestive tract and the pancreas in its 8th edition (2018).

It is important to recognize that tissue pathology gives information at only one point in time unless it is repeated as tumor grade may change. Tumor grade is indicative of the biologic behavior of NETs and can predict the clinical course and outcome of disease. Tumor stage (based on the TNM classification)reflects the extent of disease at the time of initial diagnosis, which can help physicians determine initial therapeutic strategies (local or systemic therapy).

WD-NET--G1 less than 2/10 HPF less than 3%
WD-NET--G2 2-20/10 HPF 3-20%
WD-NET--G3 greater than 20/10 HPF greater than 20%
PD-NEC greater than 20/10 HPF greater than 20%
(small and large cell carcinoma)