Gaurav Kapur
Case history
A 67-year-old man with a long-standing history (dating back 9 years) of recurring hypoglycaemic attacks, was referred by his GP. His earlier symptoms had been relieved when he was given glucose. More recently, the symptoms had progressed both in frequency and severity—the patient developed symptoms of diarrhoea, abdominal pain, and nocturnal cramps. In view of this, his GP had commenced him on mebeverine and temazepam. A Boehringer Mannheim (BM) test gave an average blood glucose monitoring result of 2mmol/L. The full blood count (FBC), liver function tests, and urea and electrolytes (U&Es) were normal. Table 10.1 shows the results of a 48-h fast.
Table 10.1 Results of the 48-h fast
|
Insulin |
84pmol/L |
(0–60) |
|
C-peptide |
1757pmol/L |
(174–960) |
|
Fasting glucose |
2.0mmol/L |
(3.5–7.0) |
|
Sulfonylurea screen |
Negative |
Questions
1. What is your provisional diagnosis?
2. How would you investigate the case further?
Answers
1. What is your provisional diagnosis?
Insulinoma. The diagnostic criteria for insulinoma, called the Whipple triad, are
♦ symptoms of hypoglycaemia
♦ plasma glucose ≤2.2mmol/L
♦ relief of symptoms with glucose.
The diagnosis is confirmed by inappropriately high levels of insulin during a spontaneous or induced episode of hypoglycaemia.
A 72-h fast does not normally produce symptomatic hypoglycaemia due to a hormonally mediated increase in glucose production. However, if there is any defect in the ability to maintain normoglycaemia, such as an excess of insulin, a prolonged fast will result in hypoglycaemia. Though 72-h fast has been the standard test for the diagnosis of insulinoma, one study suggests that a 48-h fast is sufficient to make a diagnosis.
The fast is ended when the plasma glucose concentration is ≤45mg/dl (2.5mmol/L), the patient has symptoms or signs of hypoglycaemia, 72 h have elapsed, or when the plasma glucose concentration is less than 55mg/dl (3mmol/L) if the Whipple triad was documented on a previous occasion.
At the end of the fast 1mg of glucagon is given intravenously and plasma glucose is measured at 10, 20, and 30 min post-administration.
The European Neuroendocrine Tumor Society (ENETS) guidelines recommend the presence of the following criteria in addition to symptoms to make a diagnosis of insulinoma:
1. documented blood glucose levels ≤2mmol/L
2. concomitant raised insulin levels of ≥36pmol/L
3. C-peptide levels of ≥200pmol/L
4. pre-insulin levels ≥5pmol/L
5. beta-hydroxybutarate levels ≤2.7 mmol/L
6. absence of sulfonylurea in the plasma or urine.
A plasma insulin concentration of 20.8pmol/L when the plasma glucose concentration is below 3.0mmol/L is consistent with hyper-insulinaemia (e.g. insulinoma).
Plasma C-peptide distinguishes endogenous from exogenous hyperinsulinaemia. Normal subjects who are hypoglycaemic will have lower values. Because of the antiketogenic effect of insulin, plasma beta-hydroxybutyrate concentrations are lower in patients with insulinoma than in normal subjects.
Sulfonylureas are only present in the plasma in hypoglycaemia induced by oral hypoglycaemic agents.
Insulin is antiglycogenolytic and hyperinsulinaemia allows for the retention of glycogen within the liver. Therefore, patients with insulin-mediated hypoglycaemia respond to the administration of 1mg of intravenous glucagon (a glycogenolytic agent) by releasing glucose. Normal subjects will have released virtually all glucose from the liver at the end of the 72-h fast and cannot respond as vigorously to intravenous glucagon as a patient with an insulinoma. At the end of the fast, patients with an insulinoma have an increase in plasma glucose of 1.4mmol/L or more in 20 to 30 min, whereas normal subjects have a smaller increment.
2. How would you investigate the case further?
Once a diagnosis of an insulinoma is suspected, staging scans with a CT abdomen ± EUS of the pancreas should be performed.
Questions
3. What does the CT scan show (Fig. 10.1)?
4. How do you proceed?
Fig. 10.1
Answers
3. What does the CT scan show (Fig. 10.1)?
There is a large (8cm × 8cm) avidly enhancing mass lying within the left peritoneal cavity, with some central necrosis (thin arrow-figure 10.1a) and calcification (thick arrow-figure 10.1a) Multiple lateral large vessels are seen passing through the mass (arrow-figure 10.1b). The mass is abutting many retroperitoneal and intraperito-neal structures but is not obviously arising from them.
4. How do you proceed?
A biopsy of the mass should be performed to confirm the diagnosis.
A core biopsy of the mass was performed. This showed sheets and interconnecting trabeculae of polygonal cells in which there are round to oval nuclei and abundant eosiniphilic granular cytoplasm with an extensive fine vascular stromal network. The cells stained positively for CD56 and chromogranin but were negative for TTF-1.
Question
5. How would you interpret the histology and immunohistochemistry. What is the unifying diagnosis?
Answer
5. How would you interpret the histology and immunohistochemistry. What is the unifying diagnosis?
This is a neuroendocrine tumour, not arising from the lung. The unifying diagnosis would be an insulinoma.
The immunohistochemocal markers of neuroendocrine tumours are CD56, synaptophysin, and chromogranin. Histological features of the tumour do not usually correlate with the anatomical sites or hormone production, but if amyloid deposition is noted on histopathological assessment it often indicates an insulin-secreting pancreatic neuroendocrine tumour. TTF-1 is a marker for lung tumours, and in the absence of any other supporting evidence is useful for excluding a bronchial origin for the tumour.
The patient underwent a distal pancreatectomy and splenectomy. The post-operative histology confirmed the diagnosis of neuroendocrine tumour. The study of tumour proliferation indices showed a Ki-67 index of 2–5% and four mitoses per high-power field (HPF).
Questions
6. What does the Ki-67 index indicate?
7. Would you advise any post-operative treatment?
Answers
6. What does the Ki-67 index indicate?
The Ki-67 protein is a cellular marker for proliferation, and is present during all active phases of the cell cycle (G1, S, G2, and mitosis) but is absent from resting cells (G0). These values indicate that this is a well-differentiated tumour. The Ki-67 index also correlates with survival (high values indicate a poorer prognosis).
Mitotic activity is a measure of the proliferative potential, and along with the Ki-67 index is used for grading purposes. The optimal cut-off values for both Ki-67 and mitoses/HPF have not been established. Table 10.2 shows the current ENETS classification.
Table 10.2 The ENETS classification
|
Differentiation |
Ki-67 |
Mitosis/10HPF |
|
Well differentiated |
≤2% |
<2 |
|
Moderately differentiated |
3–20 |
2–20 |
|
Poorly differentiated |
>20 |
>20 |
Adapted with permission from Rindi G, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Archiv: the European Journal of Pathology 449: 395–401. Copyright © springer-verlag 2006.
7. Would you advise any post-operative treatment?
The patient was put on a surveillance programme with 3-monthly clinic reviews, with a history, clinical exam, and tumour markers [chromogranin A, urinary 5-hydroxyindoleacetic acid (5-HIAA)] at each visit, CT imaging at 6-monthly visits, and an annual octreotide scan. Haemoglobin A1C levels were checked at each visit to obtain an understanding of his glycaemic control, with other tests such as insulin to be done if clinically indicated.
Nine months later he developed recurrent symptoms of hypoglycaemic attacks and abdominal discomfort. Insulin levels were 46mmol/L, with elevated chromogranin A levels. He had re-staging with a CT scan and an octreotide scan (Fig. 10.2).
Fig. 10.2
Questions
8. What do these scans show?
9. What further management would you institute at this point?
Answers
8. What do these scans show?
There are multiple enhancing intrahepatic lesions characteristic of metastases from a neuroendocrine carcinoma. These tumours are highly vascular (A) and may appear isodense with the liver during certain contrast phases. They generally enhance intensely with intravenous contrast during the early arterial phases of imaging, with washout during the delayed portal venous phase. The octreotide scan shows avidity in most sites of metastatic disease (B).
9. What further management would you institute at this point?
Given the avid disease on octreotide scan, the appropriate treatment would be a somatostatin analogue (octreotide LAR 20mg 4-weekly).
Somatostatin analogues (growth hormone-inhibitory hormone) inhibit the release of various peptide hormones in the gut, pancreas, and pituitary, antagonize growth factor effects on tumour cells, and, at very high doses, may induce apoptosis. Whilst octreotide is highly effective in controlling the symptoms associated with glucagonomas, VIPomas, and carcinoid tumours, it is less predictable for symptomatic patients with insulinoma. Nevertheless, it is a reasonable choice for patients with persistent hypoglycaemia that is refractory to diazoxide. In this case the patient refused treatment with diazoxide due to concerns over certain side-effects of the drug, and therefore was commenced on octreotide LAR.
Diazoxide is an antihypertensive agent with hyperglycaemic effects, and is usually effective in controlling symptoms of hypoglycaemia in patients with insulinomas. Adverse effects include oedema, hirsuitism, weight gain, and renal dysfunction. There are two commercially available long-acting somatostatin analogues:
Sandostatin LAR—given in doses of 10, 20, or 30mg, every 4 weeks as a deep intramuscular injection
Lanreotide—given in doses of 60, 90, or 120mg every 4 weeks as a deep subcutaneous injection.
The patient responded well to somatostatin analogues for 2 years, with no further hypoglycaemic episodes, normalization of bowel movements, and good reduction in chromogranin A levels. Average blood glucose levels were around 4.5mmol/L. However, after 2 years there was clinical, biochemical, and radiological evidence of progression.
Question
10. What are the further treatment options?
Answer
10. What are the further treatment options?
The treatment options include:
♦ radionuclide targeted therapy
♦ streptozotocin- or temozolomide-based chemotherapy
♦ new agents such as sunitinib (tyrosine kinase inhibitor) or everolimus [a mammalian target of rapamycin (mTOR) inhibitor].
Targeted radionuclide therapy is useful for patients with inoperable or asymptomatic neuroendocrine tumours and has become a standard of care in the UK and Europe. The radiolabels of choice are yttrium-90 and lutetium-177. The most commonly used peptides include DOTA-TOC and DOTA-TATE.
At 6–8-week intervals, 3–6GBq of 90Y-DOTA-TOC or 90Y-DOTA-TATE is administered to a cumulative dose of 12–18GBq. Most patients report subjective benefits, often with improved tumour markers, within two treatment cycles. At 6–10-week intervals, 3.7–7.4GBq of 177Lu-DOTA-TATE is administered to cumulative activities of 22–29.6GBq. Partial response rates of 28% and minor response rates/stable disease in 54% have been reported. In more recent trials streptozotocin-based chemotherapy regimens resulted in a response rate of 36–38%.
Sunitinib and everolimus are licensed for the use in advanced and progressive well-differentiated pancreatic neuroendocrine tumours. Sunitinib, at a dose of 37.5mg orally per day, has been shown to double PFS from 5.5 to 11.4 months. Everolimus has improved PFS from 4.6 to 11.0 months compared with placebo.
The patient opted for treatment with targeted radionuclide therapy. He was assessed and found suitable for treatment with 177Lu-DOTA-TATE. He received four treatments at 2-monthly intervals. Post-treatment he was found to have stable disease radiologically, with a good biological and clinical response (haemoglobin A1C 5.8%).
Eighteen months later he had evidence of further disease progression, with a significant increase in the size of the retroperitoneal lesions, and new deposits in the liver. He was not considered to be suitable for further radionuclide therapy due to a suboptimal GFR and was commenced on therapy with sunitinib.
Question
11. What other aspect of treatment should you consider in this patient?
Answer
11. What other aspect of treatment should you consider in this patient?
A referral to a clinical geneticist should be made. Neuroendocrine tumours may occur as part of familial endocrine cancer syndromes such as multiple endocrine neoplasia type 1 (MEN1), MEN2, neurofibromatosis 1, von Hippel–Lindau disease, and Carney complex (see Fig. 10.3). Although most are sporadic, 5% of insulinomas are associated with MEN1 and should therefore be referred for genetic screening.
Fig. 10.3 UKI NETS (UK and Ireland Neuroendocrine Tumour Society) algorithm for treatment of neuroendocrine tumours.
Reproduced from Ramage et al, An international peer-reviewed journal for health professionals and researchers in gastroenterology and hepatology, GUT, Volume 61, Issue 1, pp. 6–32, Copyright © 2012, with permission from BMJ Publishing Group Ltd.
Further reading
Ramage JK, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut 2012; 61: 6–32.