Case history: A frail 79 years old lady with dementia presented with frequent falls since 2 years ago. Neurologists assessment had attributed her fainting episodes to migraine. She later was found to have biochemically evident recurrent hypoglycaemia requiring multiple admissions and eventually continuous glucose infusion to maintain euglycemia.
Investigations: The severe spontaneous hypoglycaemia in this non-diabetic lady prompted investigations. TFT and Short Synacthen Test excluded thyroid dysfunction and hypoadrenalism. The anterior pituitary profile was normal. During the event of hypoglycaemia (blood glucose 1.57 mmol/l), inappropriate elevation of C-peptide 4210 pmol/l (174960 pmol/l) and proinsulin >200 (07 pmol/l) was noted, along with a suppressed Insulin at 12 pmol/l(0180). However, a contrasted CT revealed a normal pancreas. Unexpectedly, a heterogeneously enhancing mass (6.6 cm) was identified at the lower pole of the left kidney consistent with renal cell carcinoma. Concomitantly there were extensive peripherally enhancing heterogeneous mass lesions in the liver, the largest measuring at 12 cm. IGF-II:IGF-I ratio during hypoglycaemia was less than 10, which was inconsistent with non-islet cell tumour induced hypoglycaemia (NICTH).
Results and treatment: In view of multiple comorbidities, a palliative approach was taken. The post-mortem confirmed a clear cell renal carcinoma of the left kidney. Unexpectedly, the liver metastases has morphology and immunoprofile consistent with proinsulin secreting neuroendocrine tumour. The immunostaining showed focal strong insulin immunoreactivity, as well as widespread CD56, synaptophysin, and chromogranin A, with negative staining for RCC.
Conclusions and points for discussion: Proinsulinomas are rare and can be missed if plasma proinsulin concentration is not measured along with insulin. Proinsulin cross-reacts variably with c-peptide and insulin assays; the effect is assay dependent. In this case the discrepancy between the insulin and c-peptide concentrations was too great to be accounted for by the faster clearance of insulin, raising the suspicion of assay interference. The Diasorin liaison C-peptide assay used here has been shown to be 100% cross reactive with proinsulin based on spiking studies with a pro-insulin reference preparation. While reported cases of proinsulinoma are typically pancreatic in origin, this case has radiologically unremarkable pancreas despite concomitant renal and liver lesions. The unexpected radiological findings raised doubts if the hypoglycaemia was caused by the high malignancy load or NICTH. These were then confirmed to be completely separate entities immunohistochemically: Proinsulinoma of the liver, with a renal cell carcinoma. In view of proinsulinomas rarity, no conclusive association had been drawn between the two to our knowledge.
16 - 18 Apr 2018
Society for Endocrinology