Metastatic Glucagonoma transforming to Insulinoma following Chemotherapy

N. Iqbal, A. Byard, B. M. Singh, H. N. Buch

Nosheen Iqbal MRCP Specialist Registrar in Endocrinology.  Alison Byard MB ChB Senior House Officer in Endocrinology.  Baldev Singh MD FRCP Consultant Endocrinologist.  Harit Buch MRCP Consultant Endocrinologist

Diabetes and Endocrine CentreNew Cross Hospital Wolverhampton WV10 0QP UK

Correspondence to:  Dr.N Iqbal, SpR Diabetes and Endocrinology, Diabetes Centre, Kings Mill Hospital, Sutton in Ashfield NG17 4JL 

E-mail: nosheen26@hotmail.com

SMJ 2006 52(1): 55


Abstract

A 75 year-old man diagnosed to have a glucagonoma and as he was deemed unfit for curative surgery, was managed conservatively. Over the next 7 years as a result of increase in tumour size and development of hepatic metastases he became progressively more symptomatic and chemotherapy was administered for palliation. Six months later, he experienced several episodes of symptomatic hypoglycaemia, which persisted despite withdrawal of insulin therapy. Biochemical assessment confirmed spontaneous endogenous hyperinsulinaemia. Hypoglycaemic symptoms responded partially to somatostatin analogues although over the next few months he continued to deteriorate and 8 years after the initial diagnosis died of tumour-related cachexia. This patient presents an unusual scenario where a neuroendocrine tumour initially presented as a glucagonoma with subsequent change in the predominant hormone secretion to insulin. In view of its temporal association, we postulate that following chemotherapy; one cell type was more successfully reduced as compared to others, resulting in predominance of insulin secreting cells.


Introduction

Neuroendocrine tumours are uncommon and often present difficult therapeutic challenges. They may be composed of different cell types and may be multihormonal. We present a case that illustrates several interesting features of neuro-endocrine tumours.

 

Case Report

In 1995, a 68-year old man presented with a 12-month history of watery diarrhoea, weight loss, flushing, upper abdominal pain but no skin rash. He was on lifelong warfarin for 2 previous episodes of deep vein thrombosis. Full blood count, renal function and oesophago-duodenoscopy were normal. Abdominal CT scan showed a 5cm pancreatic mass and lymphadenopathy around coeliac axis. The patient had an exploratory laparotomy although only partial excision could be performed as the mass was densely adherent to the coeliac axis and patient was deemed unfit for a Whipple’s procedure necessary for total excision. Histological appearance was consistent with that of a neuroendocrine tumour with presence of poorly defined islands of small, regular non-mitotic cells staining positive for agyrophil granules. Plasma glucagon was elevated on two occasions (94 and 116 pmol/l (normal <50 pmol/l)). Remaining gastrointestinal hormones, urinary 5-H1AA and catecholamines were within the reference ranges. Soon after initial presentation the patient developed hyperglycaemia, which was well controlled on small doses of insulin (HbA1C 5.3%).

 

A diagnosis of glucagonoma was made.  Over the next 7 years, he was managed symptomatically in conjunction with an oncologist. In 2002, in view of worsening symptoms he underwent a repeat CT scan that showed an increase in tumour size to 8.5 cm and an octreoscan showed the presence of at least three areas of liver metastases, which were not seen on CT scan.  He received 5 cycles of Carboplatin and Etoposide with a view to reducing tumour load. Six months after completion of chemotherapy he developed episodes of spontaneous hypoglycaemia, which persisted despite discontinuation of insulin. During one such episode biochemical assessment showed plasma glucose of 2.0 mmol/l, plasma insulin 166 pmol/L, C-peptide 1285 pmol/L, proinsulin 196 pmol/l, a normal IGF-1 and a negative sulphonylurea screen. This confirmed spontaneous hyperinsulinaemic hypoglycaemia and the dominant tumour product appeared to have changed from glucagon to insulin. Hypoglycaemia was partially controlled with long acting somatostatin analogue. However over the next few months he continued to deteriorate and died of tumour-related cachexia 8 years after first diagnosis.

 

Discussion

We have presented a patient with metastatic neuroendocrine tumour in whom there was a change in the predominant secretory product from glucagon to insulin. This was accompanied by a corresponding change in the clinical picture from that of insulin requiring hyperglycaemia to that of episodic spontaneous hypoglycaemia. A change in the secretory product is a recognised phenomenon with neuroendocrine tumours although a change from glucagon to insulin is unusual. Reports have shown that in a series of 24 patients with pancreatic endocrine tumours, 11 had glucagonomas, who then went on to develop elevated levels of other hormones during follow up.1 In common with our patient, most of the patients in this series had metastatic disease at initial diagnosis. The median time to elevation of a second hormone was 19 months from the original diagnosis, and was associated with new clinical symptoms and deterioration in health. There are several hypotheses for the underlying mechanism for a change in secretory product of a neuroendocrine tumour. One of these suggests a spontaneous de-differentiation of tumour cells to pluripotent cells with subsequent differentiation to cells with capability of producing a different hormone. Studies have shown that in animal studies using rats that cultured clonal cell lines from insulinomas dedifferentiated, and were then able to express the genes for insulin, glucagon, somatostatin and angiotensin.2, 3 Another postulates the co-existence of two tumours with one of them manifesting later than the other. The literature has two case reports of patients with co-existing tumours and one of the patients had a coexisting glucagonoma and insulinoma. However we believe, that in our patient, the tumour was co-secreting both glucagon and insulin. It is known that up to 69% of patients have polyfunctional endocrine tumours that secrete more than one hormone, but only present with a clinical syndrome due to the predominant one.4, 5, 6 Insulin is the most common hormone that is co-secreted with glucagon. Chemotherapeutic agents could have selectively influenced glucagon-producing cells while sparing insulin-secreting cells leading to unopposed action of insulin. The temporal association with administration of chemotherapy and the relatively “mild” diabetes mellitus support this hypothesis. 92% of patients in the above series had received chemotherapy prior to the onset of secondary syndrome.

 

The diagnosis of glucagonoma was based on typical symptoms, presence of diabetes, history of deep vein thrombosis and a glucagon level greater than twice the upper limit of the reference range (116pmol/l, normal <50) although typical skin rash had not yet developed over 8 years in our patient, which is a recognised feature. Plasma glucagon was only mildly raised, although in cases reported in literature glucagon level have ranged from 82 to 14,300 pg/ml (<61 pg/ml) in patients with confirmed glucagonoma. It is well recognised for the clinical symptoms to be disproportionate to plasma glucagon levels as was seen in our patient.6

 

Another interesting feature was the failure of CT scan to detect the presence of hepatic metastases that were demonstrated on the octreoscan performed around the same time. This interesting radiological paradox of the lower sensitivity of CT and MRI in demonstrating metastases from a neuroendocrine tumour has been shown previously.7

 

Our patient survived for 9 years after he was diagnosed to have an inoperable pancreatic neuroendocrine tumour. Prolonged survival in inoperable and metastatic pancreatic endocrine tumours is recognised.8 In one series,9 only 9 out of 21 patients with glucagonoma had tumour related deaths while another10 noted a 10-year survival of 28% in another series of patients with malignant glucagonomas.

 

Conclusion

We report a case of a patient with an inoperable and metastatic neuroendocrine tumour, with a prolonged survival after the initial diagnosis. The dominant tumour secretion changed from glucagon to insulin after 7 years and following 5 cycles of chemotherapy. The reason for this transformation is postulated to be due to selective reduction in one type of tumour cells as compared to another following administration of chemotherapy.

  

Learning Points

§         Varying effects of neuroendocrine tumours can be seen in the same patient following treatment

§         Clinical presentations in the acute setting may indeed change from hyperglycaemia to hypoglycaemia or vice-versa

§         Neuroendocrine tumours can have a slow progression over time though metastatic features may be present


References

  1. Wynick D, Williams SJ, Bloom SR. Symptomatic secondary hormone syndromes in patients with established malignant pancreatic endocrine tumours. N Engl J Med 1988; 319(10): 605-07.

  2. Lips CJM, van der Sluys Veer J, van der Donk JA, van Dam RH. Common precursor molecule as origin for the ectopic hormone producing tumour syndrome. Lancet 1978; 1: 16-8.

  3. Baylin SB, Mendelsohn G. Ectopic (inappropriate) hormone production by tumours: mechanisms involved and the biological and clinical implications. Endocr Rev 1980; 1: 45-77.

  4. Ohneda A, Otsuki M, Fujiya H, Yaginuma N et al. A malignant insulinoma transformed into a glucagonoma syndrome. Diabetes 1979; 28(11): 962-69.

  5. Leichter SB. Clinical and metabolic aspects of glucagonoma. Medicine 1980; 59(2): 100-13.

  6. Wermers RA, Fatourechi V, Kvols LK. Clinical Spectrum of Hyperglucagonemia associated with malignant neuroendocrine tumours. Mayo Clinic Proceedings 1996; 71(11): 1030-38.

  7. Shi W, Johnston CF, Buchanan KD, Larkin C et al. Localization of neuroendocrine tumours with [111In] DTPA-octreotide scintigraphy (Octreoscan): a comparative study with CT and MR imaging QJM 1998; 91(4): 295-301.

  8. D’Arcangues CM, Awoke S, Lawrence GD. Metastatic insulinoma with long survival and glucagonoma syndrome. Ann Intern Med 1984; 100(2): 233-35.

  9. Wermers RA, Fatourechi V, Wynne AG, Kvols LK, Lloyd RV. The glucagonoma syndrome: clinical and pathologic features in 21 patients. Medicine 1996; 75(2): 53-63.

  10. Grama D, Eriksson B, Matersson H, Cedermark B et al. Clinical characteristics, treatment and survival in patients with pancreatic tumours causing hormonal syndromes. World J Surg 1992; 16(4): 632-9.

 

Back to February Contents