Grading and staging is a critical element in treatment planning and should be clearly documented in the patient’s medical record.

The pathological biopsy should be reported or reviewed by a pathologist with expertise in NETs. NETs are graded pathologically based on the mitotic count (expressed as mitoses per 2mm2), the Ki-67 proliferative index and the presence of necrosis. Different cut-offs of Ki-67 index and mitotic rate are used to grade tumours of different sites, and for some sites the presence of necrosis increases the grade.

Other critical elements in the pathological reporting of NETs are:

• tumour site and size
• multifocality
• lymphovascular and perineural invasion
• extent of local invasion
• surgical margins
• nodal status
• presence of background disease.

In addition to mitotic count, Ki-67 index and the reporting of tumour necrosis (subject to site), which are considered mandatory in all NETs, other ancillary tests that may be useful in selected circumstances include (Perren et al. 2017):

• DAXX/ATRX immunohistochemistry (loss favours pancreatic origin)
• p53/pRb immunohistochemistry (p53 mutation and loss of RB1 favours NEC over NET)
• SSTR2 (may be used to predict positivity on 68Ga-DOTATATE PET/CT scans)
• MGMT immunohistochemistry or promoter methylation (potential predictor of response to temozolomide)
• immunohistochemistry for pancreatic hormone expression in context of a clinical hormonal syndrome (e.g. insulin and glucagon)
• SDHB immunohistochemistry (loss of expression makes syndromic disease due to germline mutation of one of the SDH genes highly likely).

See figure 4 (below) for classification of neuroendocrine tumour with corresponding imaging features and treatment options.

* GaTate: 68Ga-DOTATATE PET/CT; a specialised Gallium 68-dotatate tracer is injected and binds to somatostatin receptors on the cell surface of neuroendocrine cells (I-Med Radiology Network 2020). The presence of these receptors enables appropriate treatment choice.

* FDG: 18F-FDG PET/CT: The most common radiotracer is F-18 fluorodeoxyglucose (FDG), a molecule similar to glucose. Cancer cells are more metabolically active and may absorb glucose at a higher rate. 18-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) avidity in NETs has been associated with higher grade disease (Chan et al. 2020).

The presence of active uptake of 18F-FDG PET/CT enables appropriate treatment choice.
Source: Hofman & Hicks 2012

Classifying NETs into one of the 4 stages is site-specific and should be in the form of the tumour, nodes and metastases (TNM) system – refer to the 8th edition of the American Joint Committee on Cancer’s Staging Manual.

Staging for NETs may involve these tests:

• CT scan
• MRI
• 68Ga-DOTATATE PET/CT
• 18F-FDG PET/CT
• 18F-DOPA (for metastatic MTC, and for certain phaeochromocytomas)
• I-123-MIBG or I-131 MIBG imaging (for phaeochromocytomas and paragangliomas) – choice of imaging depends on availability and local preference.

Note: Phaeochromocytomas/paragangliomas should never be biopsied

More information

Visit the Cancer Institute New South Wales website for information about understanding the stages of cancer.