A three-marker immunohistochemistry (IHC) panel helps determine the primary site of malignancy among patients with metastatic neuroendocrine tumors, according to findings from a study (NET Abstract #BT9) presented at the 7th Annual Neuroendocrine Tumors (NET) conference in Nashville, TN. The meeting was organized by the North American Neuroendocrine Tumors Society (NANETS).

“Three-marker IHC is a simple and accurate initial test to determine the primary site from NET metastases,” reported lead author Jessica E. Maxwell, MD, MBA, of the Department of Surgery at the University of Iowa Carver College of Medicine in Iowa City, IA, and colleagues.

The authors developed the IHC gene-expression panel to improve determination of the primary tumor origin of NETs. The site of primary tumors in metastatic NET “has important therapeutic and prognostic implications,” Dr. Maxwell noted. But the primary tumor sites are unknown in approximately 20% of metastatic small bowel neuroendocrine tumors (SBNET) and pancreatic neuroendocrine tumors (PNET) “despite optimal workup,” and metastatic SBNET and PNET tumor biopsies are histologically similar, she said.

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The IHC panel measured gene expression of CDX2, PAX6, and ISLET-1 using RNA extracted from 109 metastatic SBNET and PNET tumors from patients’ liver and lymph node tissues.

“Although it made no incorrect classifications, 15% of metastases were indeterminate, necessitating a supplemental test,” Dr. Maxwell said of the three-marker IHC panel. A previously developed gene expression classifier (GEC) panel of BRS3 and OPRK1 expression served as the supplemental test and demonstrated “excellent overall accuracy (94%) and identified the primary tumor site in all cases where IHC failed,” Dr. Maxwell noted.

“In the 27 metastases tested by both GEC and IHC, 26/27 (ie, 96%) were correctly classified by GEC,” she explained. “IHC correctly classified 23/27 (ie, 85%) of samples, while the remaining 4 had ‘indeterminate’ staining.”

All neuroendocrine tumors that were missed by one of the two methods were correctly classified by the other method, Dr. Maxwell reported.

“This suggests that performing IHC, followed by GEC for indeterminate cases, will identify the primary site of SBNET and PNET metastases in virtually all patients,” she concluded.