Histopathological Revision for Gastroenteropancreatic Neuroendocrine Neoplasms in Expert Centers: Does It Make the Difference?

BACKGROUND: The correct histopathological diagnosis of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is crucial for treatment selection and prognostication. It is also very challenging due to limited experience in nonexpert centers. Revision of pathology is standard of care for most patients who are referred to NEN expert centers. OBJECTIVES: To describe the clinical impact of histopathological revision for GEP-NEN patients referred to an expert center. METHODS: Retrospective multicenter analysis of all GEP-NENs receiving a histopathological revision in 6 European NEN expert centers (January 2016 to December 2016) to evaluate the impact on patient management. RESULTS: 175 patients were included and 14.7% referred for a second opinion. Histological samples were 69.1% biopsies, 23.4% surgical specimens, and 7.5% endoscopic resections. Histopathological changes due to revision included first assessment of Ki67 in 8.6% of cases, change in grading in 11.4% (3.4% G1 to G2; 5.7% G2 to G1; 0.6% G2 to G3; 1.7% G3 to G2), definition of tumor invasion in 10.8%, additional immunohistochemical staining in 2.3%, diagnosis of mixed adenoneuroendocrine carcinoma in 3.4%, exclusion of NEN in 3.4%, first diagnosis of NEN in 2.3%, and tumor differentiation for G3 in 1.7%. The revision had a clinical impact in 36.0% of patients, leading to a new therapeutic indication in 26.3%. The indication to then perform a new imaging test occurred in 21.1% and recommendation to follow-up with no further treatment in 6.3%. CONCLUSIONS: Histopathological revision in expert centers for NENs can change the diagnosis, with a significant clinical impact in about one third of patients.

NETest liquid biopsy is diagnostic of small intestine and pancreatic neuroendocrine tumors and correlates with imaging.

INTRODUCTION: Current monoanalyte biomarkers are ineffective in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). NETest, a novel multianalyte signature, provides molecular information relevant to disease biology. AIM(S): Independently validate NETest to diagnose GEP-NETs and identify progression in a tertiary referral center. MATERIALS AND METHODS: Cohorts: 67 pancreatic NET (PNETs), 44 small intestine NETs (SINETs), 63 controls. Well-differentiated (WD): PNETs, n=62, SINETs, all (n=44). Disease extent assessment at blood draw: anatomical (n=110)- CT(n=106), MRI(n=7) and/or functional- 68Ga-SSA-PET/CT(n=69) or 18F-FDG-PET/CT (n=8). Image positive disease (IPD) was defined as either CT/MRI or 68Ga-SSA-PET/CT/18F-FDG-PET/CT-positive. Both CT/MRI and 68Ga-SSA-PET/CT-negative in WD-NETs was considered image negative disease (IND). NETest (normal: 20): PCR (spotted plates). DATA: mean±SD. RESULTS: Diagnosis: NETest was significantly increased in NETs (n=111; 26±21) vs. controls (8±4, p<0.0001). 75 (42 PNET, 33 SINET) were image-positive. Eleven (8 PNET, 3 SINET; all WD) were IND. In IPD, NETest was significantly higher (36±22) vs. IND (8±7, p<0.0001). NETest accuracy, sensitivity, specificity: 97%, 99%, 95%. Concordance with imaging: NETest was 92% (101/110) concordant with anatomical imaging, 94% (65/69) with 68Ga-SSA-PET/CT, 96% (65/68) dual modality (CT/MRI and 68Ga-SSA-PET/CT). In 70 CT/MRI-positive, NETest was elevated in all (37±22). In 40 CT/MRI-negative, NETest was normal (11±10) in 31. In 56 68Ga-SSA-PET/CT-positive, NETest was elevated (36±22) in 55. In 13 68Ga-SSA-PET/CT-negative, NETest was normal (9±8) in 10. Disease status: NETest was significantly higher in progressive (61±26; n=11) vs. stable disease (29±14; n=64; p<0.0001) (RECIST 1.1). CONCLUSION: NETest is an effective diagnostic for PNETs and SINETs. Elevated NETest is as effective as imaging in diagnosis and accurately identifies progression.