Current Practices and Novel Techniques in the Diagnosis and Management of Neuroendocrine Tumors of Unknown Primary

Abstract

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms in which tumor staging/prognosis and response to treatments depend heavily on accurate and timely identification of the anatomic primary site or NET subtype. Despite recent technological advancements and use of multiple diagnostic modalities, 10% to 14% of newly diagnosed NETs are not fully characterized based on subtype or anatomic primary site. Inability to fully characterize NETs of unknown primary may cause delays in surgical intervention and limit potential treatment options. To address this unmet need, clinical validity and utility are being demonstrated for novel approaches that improve NET subtype or anatomic primary site identification. Functional imaging using Ga-radiolabeled DOTATATE positron emission tomography/computed tomography has been shown to overcome some false-positive and resolution issues associated with octreotide scanning and computed tomography/magnetic resonance imaging. Using a genomic approach, molecular tumor classification based on differential gene expression has demonstrated high diagnostic accuracy in blinded validation studies of different NET types and subtypes. Given the widespread availability of these technologies, we propose an algorithm for the workup of NETs of unknown primary that integrates these approaches. Including these technologies in the standard workup will lead to better NET subtype identification and improved treatment optimization for patients.

FIGURE 1

Distribution of NETs by primary tumor site. The proportional distribution of NETs was determined from the ratio between the incidence of NETs from individual primary sites and the total incidence.

FIGURE 2

Diagnostic algorithm of NET-UPs. The integration of clinical findings, biochemical testing, imaging results, and pathology can identify the NET subtype based on the anatomic primary site in 85% of cases, leading to subtype-specific treatment and better outcomes. ⁶⁸Ga-radiolabeled DOTATATE PET/CT (⁶⁸Ga-PET/CT) may be considered for patients who have clinical or biochemical evidence of a NET but negative SRS results. Biopsy tissue should be conserved for molecular testing by the 92-gene assay in patients who have clinical evidence of a NET but negative ⁶⁸Ga-PET/CT results. Furthermore, in cases of limited biopsy tissue such that complete pathology characterization is not possible, or for poorly differentiated tumors that are not amenable to functional imaging, molecular tumor classification by the 92-gene assay provides a molecular determinant of NET tumor type and subtype that can inform treatment decisions. 5-HIAA, 5-hydroxyindoleacetic acid; FNA, fine needle aspirate; IHC, immunohistochemistry.