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J Clin Endocrinol Metab. 2016 Feb;101(2):353-8. doi: 10.1210/jc.2015-3684. Epub 2015 Dec 17.

Neuroendocrine Tumor of the Pancreas as a Manifestation of Cowden Syndrome: A Case Report.

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Endocrine Oncology Branch (V.N., S.M.S., E.K.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; Molecular Genetics Section (J.Z., K.K., P.M.), Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892; and Laboratory of Pathology (M.A.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.



Germline mutations in the phosphatase and tensin homolog (PTEN) tumor suppressor gene are found in the majority of patients with Cowden syndrome (CS), who have an increased risk of breast, thyroid, and endometrial cancer. According to our current understanding of genetic changes in the PTEN gene and the resultant phenotypic features of CS, pancreatic neuroendocrine tumors (NETs) are not considered part of the clinical spectrum of CS.


We report a unique case of an advanced NET of the pancreas in a patient with CS. The germline DNA sequencing confirmed the clinical diagnosis of CS and revealed a PTEN mutation c.697C→T (p.R233*) causing a premature stop codon in exon 7. The tumor DNA sequencing showed no loss of heterozygosity or any copy number changes and no other deleterious genetic alterations, including those commonly mutated in sporadic pancreatic NETs: MEN1, ATRX, DAXX, TP53, and genes involved in the mammalian target of rapamycin pathway. In addition, the high-throughput transcriptome analyzed by RNA-seq did not reveal any missed genetic alterations, aberrant splicing variants, gene fusions, or gene expression alterations. The immunohistochemical staining of the tumor for PTEN revealed an abnormal, uniformly strong cytoplasmic staining of tumor cells with virtually absent nuclear staining.


The results from genetic testing and histopathological techniques used to confirm CS diagnosis and characterize this unusual tumor tempted us to believe that in this case, the pancreatic NET was not a sporadic malignancy that occurred by coincidence, but rather represented a new entity in the spectrum of malignancies associated with CS.


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