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Open access

Chad Bisambar, Andrew Collier, Fraser Duthie and Carron Meney

Summary

A 40-year-old Caucasian female presented with hyperglycaemia, polyuria, polydipsia and weight loss of 6 kg over a 1-month period. There was no personal or family history of malignancy or diabetes mellitus. On examination, she was jaundiced with pale mucous membranes and capillary glucose was 23.1 mmol/L. Initial investigations showed iron deficiency anaemia and obstructive pattern of liver function tests. HbA1c was diagnostic of diabetes mellitus at 79 mmol/mol. Malignancy was suspected and CT chest, abdomen and pelvis showed significant dilatation of intra- and extra-hepatic biliary tree including pancreatic duct, with periampullary 30 mm mass lesion projecting into lumen of duodenum. Enlarged nodes were seen around the superior mesenteric artery. This was confirmed on MRI liver. Fasting gut hormones were normal except for a mildly elevated somatostatin level. Chromogranin A was elevated at 78 pmol/L with normal chromogranin B. Duodenoscopy and biopsy showed possible tubovillous adenoma with low-grade dysplasia, but subsequent endoscopic ultrasound and biopsy revealed a grade 1, well differentiated neuroendocrine tumour. The patient was started on insulin, transfused to Hb >8 g/dL and Whipple’s pancreatico-duodenectomy was undertaken. This showed a well-differentiated neuroendocrine carcinoma arising in duodenum (Grade G1 with Ki67: 0.5%), with areas of chronic pancreatitis and preservation of pancreatic islet cells. There was complete resolution of diabetes post Whipple’s procedure and patient was able to come of insulin treatment. Her last HBA1C was 31 mmol/mol, 4 months post tumour resection.

Learning points:

  • Diabetes mellitus and malignancy can be related.

  • A high index of suspicion is needed when diabetes mellitus presents atypically.

  • Non-functional neuroendocrine tumours can present with diabetes mellitus.

Open access

Jerena Manoharan, Caroline L Lopez, Karl Hackmann, Max B Albers, Anika Pehl, Peter H Kann, Emily P Slater, Evelin Schröck and Detlef K Bartsch

Summary

We report about a young female who developed an unusual and an aggressive phenotype of the MEN1 syndrome characterized by the development of a pHPT, malignant non-functioning pancreatic and duodenal neuroendocrine neoplasias, a pituitary adenoma, a non-functioning adrenal adenoma and also a malignant jejunal NET at the age of 37 years. Initial Sanger sequencing could not detect a germline mutation of the MEN1 gene, but next generation sequencing and MPLA revealed a deletion of the MEN1 gene ranging between 7.6 and 25.9 kb. Small intestine neuroendocrine neoplasias (SI-NENs) are currently not considered to be a part of the phenotype of the MEN1-syndrome. In our patient the SI-NENs were detected during follow-up imaging on Ga68-Dotatoc PET/CT and could be completely resected. Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients. Whether an aggressive phenotype or the occurrence of SI-NENs in MEN1 are more likely associated with large deletions of the gene warrants further investigation.

Learning points

  • Our patient presents an extraordinary course of disease.

  • Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients, besides the typical MEN1 associated tumors.

  • This case reports indicate that in some cases conventional mutation analysis of MEN1 patients should be supplemented by the search for larger gene deletions with modern techniques, if no germline mutation could be identified by Sanger sequencing.

Open access

G K Dimitriadis, K Gopalakrishnan, R Rao, D K Grammatopoulos, H S Randeva, M O Weickert and N Murthy

Summary

We report the case of a 70-year-old previously healthy female who presented acutely to the Accident and Emergency department with left-sided vasomotor symptoms including reduced muscle tone, weakness upon walking and slurred speech. Physical examination confirmed hemiparesis with VIIth nerve palsy and profound hepatomegaly. A random glucose was low at 1.7 mmol/l, which upon correction resolved her symptoms. In hindsight, the patient recalled having had similar episodes periodically over the past 3 months to which she did not give much attention. While hospitalized, she continued having episodes of symptomatic hypoglycaemia during most nights, requiring treatment with i.v. dextrose and/or glucagon. Blood tests including insulin and C-peptide were invariably suppressed, in correlation with low glucose. A Synacthen stimulation test was normal (Cort (0′) 390 nmol/l, Cort (30′) 773 nmol/l). A computed tomography scan showed multiple lobulated masses in the abdomen, liver and pelvis. An ultrasound guided biopsy of one of the pelvic masses was performed. Immunohistochemistry supported the diagnosis of a gastrointestinal stromal tumour (GIST) positive for CD34 and CD117. A diagnosis of a non islet cell tumour hypoglycaemia (NICTH) secondary to an IGF2 secreting GIST was confirmed with further biochemical investigations (IGF2=96.5 nmol/l; IGF2:IGF1 ratio 18.9, ULN <10). Treatment with growth hormone resolved the patient's hypoglycaemic symptoms and subsequent targeted therapy with Imatinib was successful in controlling disease progression over an 8-year observation period.

Learning points

  • NICTH can be a rare complication of GISTs that may manifest with severe hypoglycaemia and neuroglucopenic symptoms.

  • NICTH can masquerade as other pathologies thus causing diagnostic confusion.

  • Histological confirmation of GIST induced NICTH and exclusion of other conditions causing hypoglycaemia is essential.

  • Mutational analysis of GISTs should be carried out in all cases as it guides treatment decision.

  • Tailored management of hypoglycaemia, in this case using growth hormone and targeted cyto-reductive therapy, minimizes the risk of possible life-threatening complications.

Open access

Shweta Birla, Viveka P Jyotsna, Rajiv Singla, Madhavi Tripathi and Arundhati Sharma

Summary

Multiple endocrine neoplasia type 1 (MEN-1) is a rare autosomal-dominant disease characterized by tumors in endocrine and/or non endocrine organs due to mutations in MEN1 encoding a nuclear scaffold protein‘menin’ involved in regulation of different cellular activities. We report a novel 14 bp MEN1 deletion mutation in a 35-year-old female with history of recurrent epigastric pain, vomiting, loose stools and weight loss. On evaluation she was diagnosed to have multifocal gastro-duodenal gastrinoma with paraduodenal lymph nodes and solitary liver metastasis. She was also found to have primary hyperparathyroidism with bilateral inferior parathyroid adenoma. Pancreatico-duodenectomy with truncalvagotomy was performed. Four months later, radiofrequency ablation (RFA) of segment 4 of the liver was done followed by three and a half parathyroidectomy. MEN1 screening was carried out for the patient and her family members. MEN-1 sequencing in the patient revealed a heterozygous 14 bp exon 8 deletion. Evaluation for pathogenicity and protein structure prediction showed that the mutation led to a frameshift thereby causing premature termination resulting in a truncated protein. To conclude, a novel pathogenic MEN1 deletion mutation affecting its function was identified in a patient with hyperparathyroidism and gastrinoma. The report highlights the clinical consequences of the novel mutation and its impact on the structure and function of the protein. It also provides evidence for co-existence of pancreatic and duodenal gastrinomas in MEN1 syndrome. MEN1 testing provides important clues regarding etiology and therefore should be essentially undertaken in asymptomatic first degree relatives who could be potential carriers of the disease.

Learning points

  • Identification of a novel pathogenic MEN1 deletion mutation.

  • MEN1 mutation screening in patients with pituitary, parathyroid and pancreatic tumors, and their first degree relatives gives important clues about the etiology.

  • Pancreatic and duodenal gastrinomas may co-exist simultaneously in MEN1 syndrome.

Open access

M A W Hermans, B M L Stelten, H R Haak, W W de Herder and M W Dercksen

Summary

This paper reports on two patients with a long-standing diagnosis of an ENETS stage IV neuroendocrine tumour (NET) of the small intestine who developed neurological symptoms. The first patient only had bulbar symptoms and tested positive for acetylcholine receptor antibodies. The second patient had more classical symptoms of fatigable diplopia and muscle weakness of the legs, but no detectable antibodies. The diagnosis of paraneoplastical myasthenia gravis (MG) was postulated. Both patients were treated with pyridostigmine for MG and octreotide for the NETs. Interestingly, treatment of the NETs resulted in improvement of myasthenic symptoms. Paraneoplastic MG has been described to occur with certain malignancies, mainly thymoma. Herein, we prove that the association with gastrointestinal NETs, however, rare, is also one to be considered by clinicians dealing with either of these diseases. The pathogenesis has yet to be elucidated.

Learning points

  • NETs are rare malignancies with a wide variety of symptoms.

  • Paraneoplastic MG can occur with various types of malignancies.

  • Herein, we provide evidence of paraneoplastic MG in association with a grade IV NET of the small intestine.

  • Treatment of the NETs resulted in remission of myasthenic symptoms in one patient.

Open access

I Huguet, C Lamas, R Vera, A Lomas, R P Quilez, A Grossman and F Botella

Summary

Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms whose management can be problematic. In many cases, multiple tumours may occur in the same patient or his or her family, and some of these have now been defined genetically, although in other cases the underlying gene or genes involved remain unclear. We describe a patient, a 63-year-old female, who was diagnosed with a medullary thyroid carcinoma (MTC), which was confirmed pathologically after thyroidectomy, but whose circulating calcitonin levels remained elevated after thyroidectomy with no evidence of metastatic disease. Subsequently, an entirely separate and discrete duodenal NET was identified; this was 2.8 cm in diameter and was removed at partial duodenectomy. The tumour stained immunohistochemically for calcitonin, and its removal led to persistent normalisation of the circulating calcitonin levels. There was no germline mutation of the RET oncogene. This is the first identification of a duodenal NET secreting calcitonin and also the first demonstration of a second tumour secreting calcitonin in a patient with MTC. We suggest that where calcitonin levels remain high after removal of a MTC a search for other NETs should be conducted.

Learning points

  • NETs are a complex and heterogeneous group of related neoplasms, and multiple tumours may occur in the same patient.

  • Calcitonin can be produced ectopically by several tumours outside the thyroid.

  • Persistently elevated calcitonin levels after removal of a MTC may not necessarily indicate persisting or metastatic disease from the tumour.

  • The real prevalence of calcitonin-producing NETs may be underestimated, as serum determination is only recommended in the diagnosis of pancreatic NETs.