What is the staging for neuroendocrine tumors (NETs) of unknown primary origin?

From the Guidelines

Staging for neuroendocrine tumors (NETs) of unknown primary origin should follow a comprehensive approach that includes both anatomical and functional imaging, with a focus on identifying the primary tumor and assessing metastatic disease, as recommended by the most recent guidelines 1. The initial evaluation should include contrast-enhanced CT or MRI of the chest, abdomen, and pelvis to identify the primary tumor and assess metastatic disease.

• This should be complemented by somatostatin receptor imaging, preferably with gallium-68 DOTATATE PET/CT, which has superior sensitivity for detecting NETs compared to conventional imaging, with sensitivities ranging from 87-96% for pancreatic NETs 1.
• For poorly differentiated NETs, FDG-PET may be more useful as these tumors often have lower somatostatin receptor expression. Key aspects of the staging process include:
• Laboratory evaluation with chromogranin A, 24-hour urinary 5-HIAA (for suspected carcinoid tumors), and specific hormones based on clinical symptoms.
• Tissue diagnosis is essential, with immunohistochemical staining for chromogranin A, synaptophysin, and Ki-67 proliferation index to determine tumor grade.
• The WHO classification system divides NETs into three grades based on mitotic count and Ki-67 index, which significantly impacts prognosis and treatment decisions, as noted in earlier guidelines 1. Despite extensive workup, the primary site remains unidentified in about 10-15% of cases, but this should not delay appropriate treatment based on tumor grade, differentiation, and extent of disease, emphasizing the importance of a comprehensive staging approach 1.

From the Research

Staging for Neuroendocrine Tumors (NETs) of Unknown Primary Origin

• The staging for NETs of unknown primary origin is challenging due to the difficulty in localizing the primary tumor 2, 3, 4.
• The workup for NETs of unknown primary origin includes a thorough family history, immunohistochemistry, imaging, and OctreoScan 4.
• Functional imaging using Ga-radiolabeled DOTATATE positron emission tomography/computed tomography has been shown to be effective in identifying the primary tumor site 2, 5.
• A genomic approach, molecular tumor classification based on differential gene expression, has also demonstrated high diagnostic accuracy in identifying NET subtypes and primary sites 5.

Treatment and Prognosis

• The treatment for NETs of unknown primary origin is often initiated based on the grade and level of differentiation of the tumor, with well- and moderately differentiated tumors treated as carcinoid tumors, whereas poorly differentiated tumors are treated similarly to small cell tumors 4.
• Early surgical exploration and aggressive debulking have been shown to be effective in identifying the primary tumor site and improving survival in patients with NETs of unknown primary origin 6.
• The prognosis for NETs of unknown primary origin is not always poor, and timely surgical exploration and debulking can result in improved outcomes 6.

Diagnostic Approaches

• A combination of radiological, endoscopic, and functional imaging is often used to localize the primary tumor site 2.
• Somatostatin receptor scintigraphy (SRS) has been used historically, but newer PET radiotracers such as (68)Ga-labeled somatostatin analogs and (18)F-DOPA have shown promise in detecting NETs of unknown primary origin 2.
• A proposed algorithm for the workup of NETs of unknown primary integrates functional imaging, genomic approaches, and other diagnostic modalities to improve NET subtype identification and treatment optimization 5.