Gastrointestinal: Pancreatic NETs with GCGR heterozygous mutation: Mahvash disease.

Abstract

A 61 year old female was found to have a pancreatic tumor in 2013. Preoperative laboratory tests showed fasting and 2-h postprandial glucagon levels were more than 400 pg/mL (upper limit, 150 pg/mL) with normal gastrin, blood glucose, and insulin. Preoperative contrast-enhanced CT (CECT) showed diffusely enlarged and inhomogeneously enhanced pancreas with a 2-cm high-density tumor in the pancreatic body. The tumor was obviously enhanced (Fig. 1a–c). Octreotide imaging showed high somatostatin receptor expression in the tumor. The patient underwent subtotal distal pancreatectomy and splenectomy. On postoperative pathological examination, two gray and white solid tumors were found, measuring 1.2 and 2 cm, respectively. On histology, diffuse hyperplastic islets, dysplasia, and microadenomas were detected in residual pancreatic tissue and the pancreatic resected stump. The two lesions were immune-positive for Ki-67 (index 1%), chromogranin A, synaptophysin, E-cadherin, glucagon, gastrin, and insulin (partial) (Fig. 2). The patient was treated with octreotide acetate 20 mg per injection after surgery. But postoperative fasting glucagon level was still high, fluctuating from 513.16 to 3197.49 during 7-year follow-up. Meanwhile, postoperative CECT showed enlargement of the residual pancreatic head (Fig. 1d). Whole-genome sequencing of peripheral blood demonstrated heterozygous mutation of c.1345C>T, which lead to premature termination of translation, and c.922C>T, which lead to arginine replaced by tryptophan. The case was finally diagnosed as Mahvash disease. Mahvash disease is a rare autosomal recessive hereditary pancreatic neuroendocrine neoplasms caused by defective glucagon receptor gene (GCGR) in the liver and associated reactive pancreatic α-cell hyperplasia. Although whole-genome sequencing demonstrated two heterozygous mutations of GCGR, the clinical and pathological features highly suggested Mahvash diagnosis. Diffusely enlarged and unevenly enhanced pancreas indicated coexistence of hyperplastic α cell, hyperplastic islets, and microadenomas. Significant hyperglucagonemia without glucagonoma syndrome further strengthen diagnostic confidence. Most Mahvash diseases were homozygous mutation, and heterozygous mutation are extremely rare. However, reports of patients with heterozygous mutation often showed sub-centimeter lesions (5.5 mm reported by Miller et al. and 5 mm reported by Henopp et al.). To our knowledge, this is the first time large lesions (>1 cm) has been reported in patient with heterozygous mutation of GCGR. There is possibility that heterozygous mutation of GCGR can also be Mahvash disease.