The citric acid cycle, also known as the Krebs cycle, plays an integral role in cellular metabolism and aerobic respiration. Mutations in genes encoding the citric acid cycle enzymes succinate dehydrogenase, fumarate hydratase and malate dehydrogenase all predispose to hereditary tumour syndromes. The succinate dehydrogenase enzyme complex (SDH) couples the oxidation of succinate to fumarate in the citric acid cycle and the reduction of ubiquinone to ubiquinol in the electron transport chain. A loss of function in the succinate dehydrogenase (SDH) enzyme complex is most commonly caused by an inherited mutation in one of the four SDHx genes (SDHA, SDHB, SDHC and SDHD). This mechanism was first implicated in familial phaeochromocytoma and paraganglioma. However, over the past two decades the spectrum of tumours associated with SDH deficiency has been extended to include gastrointestinal stromal tumours (GIST), renal cell carcinoma (RCC) and pituitary adenomas. The aim of this review is to describe the extended tumour spectrum associated with SDHx gene mutations and to consider how functional tests may help to establish the role of SDHx mutations in new or unexpected tumour phenotypes.

Summary A 38-year-old female was identified as carrying a heterozygous pathogenic MEN1 variant (c.1304delG) through predictive genetic testing, following a diagnosis of familial hyperparathyroidism. Routine screening for parathyroid and pituitary disease was negative. However, cross-sectional imaging by CT revealed a 41 mm pancreatic tail mass. Biopsy via endoscopic ultrasound confirmed the lesion to be a well-differentiated (grade 1) pancreatic neuroendocrine tumour (pNET) with MIB1<1%. Biochemically, hyperinsulinaemic hypoglycaemia was confirmed following an overnight fast, which was subsequently managed by diet alone prior to definitive surgery. Pre-operative work-up with octreotide SPECT CT demonstrated avid tracer uptake in the pancreatic lesion and, unexpectedly, a focal area of uptake in the left breast. Further investigation, and subsequent mastectomy, confirmed ductal carcinoma in situ pT2 (23 mm) grade 1, N0 (ER positive; HER2 negative). Following mastectomy, our patient underwent a successful distal pancreatectomy to resect the pNET. Loss of heterozygosity (LOH) at the MEN1 locus was found in both the breast tumour and pNET, thereby in keeping with a 'two-hit' hypothesis of oncogenesis, a suggestive but non-definitive clue for causation. To obtain further support for a causative relationship between MEN1 and breast cancer, we undertook a detailed review of the published literature which overall supports the notion that breast cancer is a MEN1-related malignancy that presents at a younger age and histologically, is typically of ductal subtype. Currently, clinical guidance regarding breast cancer surveillance in MEN1 does not exist and further research is required to establish a clinical and cost-effective surveillance strategy). Learning points We describe a case of pNET and breast cancer diagnosed at a young age of 38 years in a patient who is heterozygous for a pathogenic MEN1 variant. Loss of the wild-type allele was seen in both breast tissue and pNET specimen. Breast cancer may be an under-recognised MEN1-associated malignancy that presents at a younger age than in the general population with a relative risk of 2–3. Further research is required to determine the cost-effectiveness of breast cancer surveillance approach at a younger age in MEN1 patients relative to the general population .

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SummaryA 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.

Aims: To determine the cause of death of people with type 2 diabetes in Ayrshire and Arran between 2009 and 2014 compared to the national mortality rate. Methods: The primary cause of death (as noted on the death certificates) of 2116 patients with type 2 diabetes between the years 2009 and 2014 were collated. The causes of death were clustered into nine categories- heart disease, stroke, infection, renal failure, respiratory disorders, cancer, mental health, decompensated diabetes and other. The total rates were then compared to national rates using Standardised Mortality Ratio (SMR) and then individually due to heart disease, cerebrovascular disease and cancer. Results: The most common cause of death in the cohort was cancer (27.8%) followed by heart disease (24.1%). SMR for type 2 diabetes was 145 (95% CI 139,152; p&lt;0.01) and was greater than 100 in all age bands. The SMR was higher in the younger age bands: SMR 35-44 years 330 (95% CI 180,553), SMR 45-55 years 232 (95% CI 177, 299) and SMR 55-64 years 188 (95% CI 163,216) (p values all &lt;0.01). The SMR was consistently higher for females particularly in the younger age groups. SMR for heart disease was significantly greater than 100 for both genders in all age bands under 85 years and was consistently higher for females. There was no difference in mortality causes related to duration of diabetes (&lt;5 years, 5-10years, 10-15 years, &gt;15 years). SMR for strokes was elevated in the 55-74 age range with no significant gender difference. Cancer deaths in males was not significantly elevated (SMR 109) but it was elevated in females (120, 95% CI 104,137) (p&lt;0.05). Conclusions: The all-cause mortality for patients with type 2 diabetes was consistently higher across all age brackets. The greatest differences were noted in females with heart disease aged less than 65. Disclosure C. Meney: None. A. Collier: None. M.D. Hair: None. L. Cameron: None. C. Bisambar: None. J. Ilyas: None.

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.