Endocrinology: Neuroendocrine tumours

Endocrinology: Neuroendocrine tumours

Definition

Historically referred to as carcinoid tumours, neuroendocrine tumours (NETs) arise from neuroendocrine cells, which
are widely distributed in the body. They are rare tumours (incidence: 5/100 000) but ‘common’ primary sites include the
gastrointestinal tract (especially the appendix and terminal ileum), pancreas and lung.

Aetiology

The risk factors for tumour development are not well understood. A small proportion arise on the background of an inherited endocrine cancer syndrome, including MEN-1 (Chapter 33), von Hippel–Lindau syndrome (associated with pancreatic NETs), neurofibromatosis type 1 (NF1) and tuberous sclerosis.

Symptoms and signs

Because of their wide distribution, the spectrum of presentation is diverse. Many are discovered incidentally during a diagnostic work-up undertaken for other reasons. Patients with gastrointestinal NETs can present with bowel obstruction while fewer than 10% present with classic carcinoid syndrome (characterised by dry flushing and diarrhoea) (Figure 31.1). This occurs when vasogenic peptides, including serotonin, gain access to the systemic circulation, most commonly as a result of liver metastases from an intestinal primary. Patients with pancreatic NETs present with symptoms related to the tumour mass (abdominal pain, weight loss) or a hypersecretory syndrome (Figure 31.2).

Diagnosis

Biochemistry

Plasma chromogranin A is a useful general neuroendocrine marker that has high sensitivity for most types of NET. Falsely raised readings can be seen in patients with renal disease and in those taking proton pump inhibitor therapy.
Most intestinal NETs secrete serotonin. Its breakdown product, 5-hydroxyindoleacetic acid (5-HIAA), can be measured
in a 24-hour urine collection and is typically elevated in patients with intestinal NETs and metastatic liver disease. A fasting gut hormone profile (measuring gastrin, glucagon, vasoactive intestinal peptide, somatostatin and pancreatic polypeptide) should be measured in patients with pancreatic NETs. Patients with suspected insulinoma require a supervised inpatient fast to establish the diagnosis (Chapter 34).

Radiology

A variety of imaging modalities are used to help establish the site of the primary tumour and to document the extent of the disease. Cross-sectional imaging (CT or MRI) (Figure 31.3) is used commonly while endoscopy, endoscopic ultrasound and selective venous sampling are useful in selected cases, especially in patients with pancreatic disease. Somatostatin receptor scintigraphy (SSRS; Octreoscan®) is used widely, not only to define the extent of disease, but also to determine suitability for somatostatin analogue therapy and peptide receptor radionuclide therapy.

Pathology

This is considered the gold standard for diagnosis. Immunohistochemistry directed against a panel of general
neuroendocrine markers will confirm a neuroendocrine origin, supplemented where necessary with immunostaining for specific hormones (e.g. gastrin in suspected gastrinoma). A key part of the pathology report is to estimate the proliferative potential and grade of the tumour by measuring the Ki67 proliferation index and/or mitotic count. This helps determine prognosis but can also influence treatment choice (e.g. chemotherapy can be used in NETs with a high Ki67 index).

Neuroendocrine tumours: management

Treatment should always aim to cure if possible but as most patients present with local or distant metastases this is
often not possible. Under such circumstances, the goals of treatment are to control symptoms and halt or reverse tumour growth for as long as possible. For many patients, this is achievable for several years even in the presence of metastases because of the indolent nature of many NETs. Treatment choice is influenced by histological grade, stage, symptoms and radionuclide (Octreoscan®) uptake. Importantly, treatment decisions should be undertaken by a multidisciplinary team with experience in managing NETs (Figure 32.1).

Treatment

Surgery

This should be undertaken for patients with potentially curative disease. Increasingly, surgery is also considered in patients with liver metastases confined to one lobe, or in bilobar disease and a single dominant lesion causing symptoms.

Drug therapy

Somatostatin analogues form the mainstay of treatment for most patients with NETs. Immediate-release octreotide has
now been largely superseded by long-acting depot preparations (octreotide LAR or lanreotide autogel), given every 3–4
weeks. These preparations lead to significant symptomatic improvement in patients with carcinoid syndrome or functional pancreatic NETs, and reduce the time to tumour progression in symptomatic or asymptomatic tumours. Two new drug therapies, sunitinib (a tyrosine kinase inhibitor) and everolimus (an mTOR pathway inhibitor), have recently become licenced for pancreatic NETs.
Chemotherapy is not widely used in the management of NETs but does have a role in higher grade NETs, especially those of pancreatic origin.

Radiological techniques

Radiofrequency ablation and transarterial hepatic embolisation can lead to symptomatic improvements in patients with liver-predominant disease.

Carcinoid heart disease

About 20–30% of patients with carcinoid syndrome develop carcinoid heart disease. This typically affects the right-sided
heart valves (tricuspid more commonly than pulmonary) and is best diagnosed by echocardiography. Symptomatic relief can be obtained with diuretic therapy, but valve replacement surgery is often needed as definitive treatment.

Prognosis

This is highly variable and dependent on a number of factors including histological grade, stage, primary tumour site and co-morbidities. It is important to recognise that patients with well-differentiated, low grade tumours can live for many years even in the presence of metastatic disease, hence quality of life is a very important treatment goal.

Inherited endocrine tumour syndromes

Multiple endocrine neoplasia type 1

Three tumour types predominate in MEN-1 (Figure 33.1):
1 Parathyroid adenomas (90–100%)
2 Pancreatic neuroendocrine tumours (NETs; 30–75%)
3 Pituitary adenomas (40%).

Genetic testing

The presence of two out of these three main tumours establishes a working diagnosis of MEN-1. It has a prevalence of roughly 1 in 10 000 and is inherited as an autosomal dominant trait. The MEN1 gene is located on chromosome 11q13. Genetic testing for mutations should be considered in an index case with at least two out of the three main MEN-1 related tumours, and extended to asymptomatic first degree relatives if positive. Genetic testing should also be considered in patients with multiple parathyroid tumours at a young age, recurrent hyperparathyroidism, gastrinoma or multiple islet cell tumours,

Primary hyperparathyroidism

Primary hyperparathyroidism is the presenting feature in most patients, reaching 100% penetrance by the age of 50. Measurement of PTH and calcium should therefore commence on an annual basis from age 8 in a known carrier. The treatment is parathyroid surgery, although the timing and extent of surgery needs to be considered on an individual basis. Options are near-total parathyroidectomy, which will ultimately require re-operation because of growth of residual tissue, or total parathyroidectomy, needing lifelong vitamin D replacement.

Pituitary tumours

Although all types of pituitary adenomas can occur in patients with MEN-1, prolactinomas (60%) and somatotroph adenomas (30%, causing acromegaly) account for the majority. Measurement of prolactin and IGF-1 should therefore be performed annually in mutation carriers. Imaging (MRI) and treatment should proceed along the same lines as for sporadic adenomas.

Pancreatic NETs

Islet cell NETs are usually multicentric. Gastrinomas (usually arising in the duodenal submucosa) are the most common and are managed with high dose proton pump inhibitors with or without surgery. Other tumour types, including non-functioning NETs, can require surgery depending on size and symptoms. Screening with annual fasting gut hormone profile and MRI every 1–3 years should commence from age 20.

Multiple endocrine neoplasia type 2

MEN-2, which occurs because of mutations in the RET gene and is inherited in an autosomal dominant manner, is characterised by (Figure 33.2):

  • Medullary thyroid carcinoma (MTC; 100%)
  • Phaeochromocytoma (0–50%)
  • Parathyroid adenomas (0–20%).
    It is subdivided along phenotypic lines into MEN-2a (75% cases) and several rare variants, including familial MTC and MEN-2b (characterised by a Marfanoid body habitus, intestinal and mucosal ganglioneuromas). In contrast to MEN-1, there is a strong relationship between genotype and phenotype in MEN-2. This has important practical implications in relation to the timing of thyroidectomy, which should be undertaken in the first year, first 5 years, or later depending on the ‘risk’ group of the RET mutation. Phaeochromocytoma is screened for annually with measurement of metanephrines and managed as per sporadic disease. Hyperparathyroidism usually runs a mild course but can be managed with subtotal parathyroidectomy.

Carney complex

This is a rare autosomal dominant condition characterised by spotty skin pigmentation, cardiac myxomas, peripheral nerve lesions and one or more endocrine disorders, of which Cushing’s syndrome caused by primary pigmented adrenal disease is the most common. GH-secreting tumours, testicular, ovarian and thyroid tumours (benign or malignant) are other recognised manifestations.

McCune–Albright syndrome

This syndrome, which arises from a somatic mutation in the GNAS1 gene, is characterised by the triad of café au lait patches (Figure 33.3), polyostotic fibrous dysplasia (Figure 33.4) and multiple endocrinopathies: precocious puberty, gigantism or acromegaly, hyperprolactinaemia, thyroid nodules and hyperthyroidism, and Cushing’s syndrome.

Spontaneous hypoglycaemia

Hypoglycaemia can be defined as a plasma glucose of <2.5 mmol/L with symptoms of neuroglycopaenia. The
mechanisms include excessive or inappropriate insulin, impaired counter-regulatory hormonal response (e.g. GH or
cortisol) and impaired hepatic glucose output because of liver disease. The causes of spontaneous hypoglycaemia are broadly categorised into two groups according to whether the symptoms occur in the fasting or postprandial state.

Fasting hypoglycaemia

The symptoms of fasting hypoglycaemia occur several hours after food (e.g. on waking or at night) or can be precipitated by exercise (Figure 34.1). Causes include:

  • Drugs (insulin, sulphonylureas, quinine, salicylates, alcohol)
  • Organ failure (liver/renal failure)
  • Hormone deficiency (Addison’s disease, hypopituitarism)
  • Insulinoma (Figure 34.2)
  • Non-islet cell tumours (fibrosarcoma, hepatocellular carcinoma, mesothelioma)
  • Autoimmune (insulin receptor-stimulating antibodies)
  • Infection (septicaemia, malaria)
  • Inborn errors of metabolism (glycogen storage disease, hereditary fructose intolerance, maple syrup disease)
  • Beta cell hyperplasia.

Postprandial hypoglycaemia

Symptoms usually occur 2–5 hours after food. Causes include:

  • Post-gastrectomy
  • Alcohol-induced
  • Incipient diabetes mellitus.

Assessment

The history should look to elucidate adrenergic (pallor, sweating, tachycardia, tremor) and neuroglycopaenic (impaired
concentration, irritability, change in behaviour, confusion, seizures or coma) symptoms in addition to clarifying whether
they occur in the fasting or postprandial state. A history of relevant drug exposure, known diabetes, renal, liver or endocrine disease should be sought. Fingerprick capillary glucose readings (‘BMs’) are unreliable for low glucose concentrations, hence a laboratory plasma glucose should always be measured to confirm true hypoglycaemia (<2.5 mmol/L). Liver and renal function should be checked, in addition to a septic screen and ethanol levels if relevant. A Synacthen test should be considered to exclude adrenal insufficiency.

Further investigation of fasting hypoglycaemia

Rarer causes of fasting hypoglycaemia should be considered if the above tests are normal. Fasting insulin, C-peptide, ketones and glucose should be measured during a confirmed episode of hypoglycaemia (Table 34.1). This may need to be undertaken as part of a prolonged (up to 72 hours) supervised fast. In the presence of hypoglycaemia, inappropriately elevated insulin suggests insulinoma or exogenous insulin or sulphonylurea therapy. The C-peptide will be suppressed in patients on exogenous insulin but inappropriately elevated in insulinoma or sulphonylurea therapy. Ketones will also be suppressed in the presence of insulin.

Further investigation of postprandial hypoglycaemia

A prolonged 75 g OGTT with frequent measurement of glucose for up to 6 hours can confirm postprandial hypoglycaemia.

Management

The acute treatment of hypoglycaemia is detailed in Chapter 54. Treatment is directed at the underlying cause. Insulinomas should undergo surgical resection if possible, after appropriate localisation. Islet tumours can be difficult to localise as they are often small. Several tests may be needed including MRI/CT (first line), endoscopic ultrasound, octreotide scanning and/or selective venous sampling. Where surgery is not curative or not feasible, symptoms can be controlled by diazoxide or octreotide. Postprandial hypoglycaemia can be treated with a low carbohydrate diet and/or frequent small meals in the first instance.