Poster Presentation ESA-SRB Conference 2015

MEN1 and paraganglioma: expanding the clinical spectrum of MENIN mutations. (#259)

Jessica E Harris 1 , Daryl Goldman 2 , Melissa Clarke 3 , Anthony J Gill 4 5 , Emma L Duncan 2 3 6
  1. The University of Queensland Diamantina Institute, Woolloongabba, QLD, Australia
  2. University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
  3. Department of Endocrinology and Diabetes, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australai
  4. University of Sydney, Sydney, NSW
  5. Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, , Royal North Shore Hospital , Sydney, NSW, Australia
  6. School of Medicine, Faculty of Medicine and Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia

Multiple endocrine neoplasia type 1 (MEN1) classically consists of parathyroid, pituitary and pancreatic tumours.  Here we report two unrelated cases with MEN1 with asymptomatic paragangliomas.

P1 had a strong family and personal history of MEN1.  Given the presence of pancreatic lesions with mild elevation of gastrin, a 68Ga-DOTATATE scan was undertaken.  Unexpectedly this demonstrated uptake in the left carotid region suggestive of paraganglioma.  P1 had no symptoms or biochemical evidence of catecholamine excess.  Histology of the resected mass showed a paraganglioma with  weak but positive staining for SDHB unlikely to be consistent with germline SDHx mutations.

P2 also had a strong family and personal history of MEN1.  Although biochemically stable, he had an increasing pancreatic mass (>3cm diameter) with marked uptake on 68Ga-DOTATATE.  FDG-PET suggested a high grade/poorly differentiated lesion and he underwent a Whipple’s resection.  Histology demonstrated a Grade 1 neuroendocrine tumour (35mm diameter) and a second lesion (8mm diameter) consistent with an extraadrenal paraganglioma that stained positively for SDHB, (SDHx mutation thus unlikely).

Germline screening of all exons of MENIN showed that P1 was heterozygous for a c.1716delC mutation in exon 10, resulting in a frameshift and introduction of a premature stop codon.  P2 was heterozygous for a c.1319delG mutation (exon 9), with similar effect.

Sanger sequencing of DNA extracted from each tumour demonstrated loss of wildtype allele.  Microarray genotyping (assessing for large copy number alteration) demonstrated loss of heterozygosity of chromosome 11 in both tumours, including the MENIN locus.  Of note, there was differential aneuploidy of the paraganglioma and adjacent islet cell tumour in P2.

The combination of paraganglioma in MEN1 has been reported extremely rarely (four cases).  P1 and P2 are undergoing germline screening for known phaeochromocytoma/paraganglioma susceptibility genes.  However, if negative, our data suggest that paraganglioma may rarely be part of the MEN1 syndrome.