Subtypes of Pancreatic Neuroendocrine Tumors and Effect on Disease Recurrence
Researchers have discovered two distinct subtypes of pancreatic neuroendocrine tumors (pNETs) associated with different risks of recurrence following surgical treatment. The finding could yield predictive tests while focusing vigilant follow-up monitoring on patients with pNETs that have a higher rate of recurrence. These findings were published by Cejas et al in Nature Medicine.
Until now, these pNETs were viewed as relatively identical from a clinical point of view. Although some pNETs never develop recurrent metastases following removal of the primary tumor, other patients experience recurrence within a few years, and there has been no specific way to predict these outcomes. Physicians use tumor size as a guideline, with nonfunctional pNETs larger than 2 centimeters considered the most likely to metastasize following surgery.
Scientists led by Ramesh Shivdasani, MD, PhD, of Dana-Farber Cancer Institute, and Bradley Bernstein, MD, PhD, of Massachusetts General Hospital, identified molecular information that may help predict the likelihood of recurrence of nonfunctional pNETs, which do not secrete hormones and are often discovered incidentally.
“This finding moves us closer to being able to identify patients with a high risk for metastasis at diagnosis and initial treatment,” said Dr. Shivdasani. “These patients can be monitored vigilantly for recurrent cancers, which may be treatable if detected early, while patients with the less aggressive kind of pNET can be advised that their prognosis is excellent.”
Methods and Subtypes
The researchers used molecular analytic methods to describe new subtypes of pNETs that differ in the expression of specific regulatory proteins and found that the differences correlated with the risk of recurrence following surgical treatment. The regulatory proteins ARX and PDX1 are epigenetic modifiers that are involved in development of the pancreas.
The scientists found that tumors whose cells exclusively expressed the protein ARX had more than a 35% risk of recurrence following surgery, compared to less than a 5% risk if the tumor lacked ARX but expressed PDX1. Among study participants whose tumors showed high ARX levels, cancers recurred in the liver within 1 to 4 years, compared to the rare recurrence of tumors that expressed PDX1.
Dr. Shivdasani and his colleagues studied molecular findings first in about a dozen pNETs and then analyzed the molecular profiles of another 142 pNET specimens. They found that about half of the pNETs expressed the regulatory protein ARX and resembled normal alpha cells in the pancreas, whereas the other half expressed the PDX1 regulatory protein and resembled normal beta pancreatic cells. The presence or absence of those proteins was strongly correlated with outcomes: among 103 cases the researchers studied, distant metastatic relapses occurred almost exclusively in patients whose tumors expressed the ARX protein but not the PDX1 protein.
“This robust molecular stratification provides insight into cell lineage correlates of nonfunctional pNETs, accurately predicts disease course, and can inform postoperative clinical decisions,” the authors wrote.
On the basis of these findings, said Dr. Shivdasani, pathologists could easily test specimens of pNET tumors to classify them as type A (expressing ARX) or type B (expressing PDX1). “Now you can tell patients with type B that their recurrence risk after surgery is very small…,” said Dr. Shivdasani. For patients whose tumors are type A, with a higher risk of recurrence, close follow-up could be undertaken to detect new metastases, which may be treatable with chemotherapy or other methods.
Disclosure: The research was supported by the Neuroendocrine Tumor Research Foundation. For full disclosures of the study authors, visit nature.com.
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