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JormaKomulainen

Rare Endocrine Tumours

Neuroendocrine tumours of the gastrointestinal tract and pancreas

  • Tumours that earlier were called carsinoids are according to the new WHO classification called neuroendocrine (NE) tumours (table T1).
    • The WHO 2010 classification does not take stand on the malignancy of the tumour.
  • About 2% of cancers of the gastrointestinal tract and pancreas are neuroendocrine tumours.
    • Most commonly located in the caecum
  • Annual incidence
    • Gastrointestinal tract 8.4/100 000
    • Pancreas 1/100 000 (insulinoma 0.5/100 000, gastrinoma 0.05/100 000, vipoma 1/10 million)
  • 10% of NE tumours are associated with the MEN1 syndrome. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=652
  • Treatment decisions are guided by the WHO class and histological grade of the tumour.
    • First-line treatment is surgery.
    • The most commonly used drugs include somatostatin analogues, interferon, combination of streptozotocin and 5-fluorouracil as well as combination of etoposide and carboplatin or cisplatin.

WHO 2010 classification of neuroendocrine tumours

WHO classDescriptionProliferation index (PI; Ki-67)Size
INeuroendocrine tumour (NET)< 2%<2 cm
IINeuroendocrine tumour (NET)3-20%≥2 cm
IIINeuroendocrine carcinoma (NEC)≥ 20%Large
IVMixed adenoneuroendocrine carcinoma (MANEC)
VHyperplastic and preneoplastic lesions
  • In addition, the tumours are classified according to their site of origin in relation to the embryonic gut.
  • TNM classification describes the stage of the tumour.

Symptoms and clinical picture

  • The majority of tumours are asymptomatic
  • The symptoms are either local (pain, obstruction, bleeding) or caused by the substances secreted by the tumour into the circulation (e.g. serotonin, tachykinin, ACTH, growth hormone, ADH).
    • Neuroendocrine tumours of the pancreas and duodenum (insulinoma, glucagonoma, somatostatinoma, gastrinoma) typically produce one hormone, but about half of these tumours are inactive.
  • Carcinoid syndrome
    • Most often caused by a tumour that originates in the ileum or colon, does not occur in rectal tumours
    • Serotonin and tachykinin are essential in the development of the carcinoid syndrome.
    • Almost always associated with liver metastases; a hormone produced by a primary intestinal tumour is transported via the portal circulation into the liver for metabolization and thus does not lead to the syndrome.
    • Symptoms: diarrhoea, flush, bronchial obstruction, heart disease characterized by endocardial thickening of the valves, atria and ventricles
    • Diagnosis: serotonin metabolite 5-HIAA in serum
    • Interventions directed at a carcinoid tumour as well as anaesthesia may trigger a carcinoid crisis. Symptoms include hypotension, sometimes hypertension, arrhythmias, bronchospasm and CNS symptoms.
  • Insulinoma
    • Symptoms of hypoglycaemia (blood glucose < 2.7 mmol/l): disturbances of consciousness, visual disturbances, lack of concentration, convulsions, feeling of hunger, sweating
    • In a serum insulin sample (or C-peptide sample) taken during hypoglycaemia the result is disproportionately high.
  • Gastrinoma
  • Vipoma
    • Causes the WDHA syndrome characterized by watery diarrhoea, hypokalaemia and acidosis.
  • Glucagonoma
    • Typical symptoms include erythema, weight loss and cachexia, anaemia, thromboembolism, mild diabetes, diarrhoea, stomatitis and glossitis.
  • Somatostatinoma
    • Typical symptoms include cholelithiasis, steatorrhea, impaired glucose tolerance and achlorhydria.

Adrenal gland tumours

  • Investigations of adrenal tumours are carried out at specialist centres.
  • Incidentaloma = an adrenal tumour detected incidentally in association with imaging for some other reason
  • The most common type is adrenal cortical adenoma (active or inactive); about 50% of all adrenal tumours.
  • Other possible tumours: pheochromocytoma, carcinoma, lymphoma, metastasis, lipoma, cyst, etc.
  • Investigations aim at assessing the functional activity of the tumour and possible signs of malignancy.
    • Symptoms: episodic, adrenergic symptoms
    • Clinical findings: features suggesting hypercortisolism, hypertension, hyperglycaemia, osteopenia or osteoporosis
    • Hormonal investigations: serum metanephrin and normetanephrin, dexamethasone suppression test (1 or 1.5 g), electrolytes, renin and aldosterone assays (only if the patient has hypertension or hypokalaemia), androgens and oestrogens (only if there are signs of virilism or hyperoestrogenism)
    • CT scan: size, shape, structure, changes during follow-up, density of the adrenal gland

Pheochromocytoma

  • Tumour originating in the adrenal medulla producing, storing, metabolizing and secreting catecholamines
    • May occur at any age, most commonly at the age of 40-50 years
    • Sporadic or hereditary (MEN2, von Hippel-Lindau or pheochromocytoma-paraganglioma syndrome)
    • May produce both adrenaline and noradrenaline, but noradrenaline production is dominant in most cases.
  • High blood pressure is caused by pheochromocytoma in about 0.1% of patients with hypertension.
  • The most common clinical symptoms in the order of frequency: hypertension (in 72%), symptoms coming in attacks, headache, excessive sweating, palpitations, diabetes, nausea, tremor, fatigue, anxiety or nervousness, loss of weight (in 30%)
    • The symptoms are typically paroxysmal
    • In addition to catecholamines, the tumour may also produce peptide hormones, which may modify the clinical picture.
  • Diagnosis is essentially based on determination of serum metanephrine and normetanephrine.
    • The tumour is located by MRI or CT scan of the adrenal gland, and by MIBG (meta-iodobenzylguanidine) scan if necessary.
    • The hereditary nature of the tumour is always explored in patients who are less than 50 years of age when the disease is diagnosed.
  • The tumour is surgically removed.
    • Preoperative medication (an alpha blocker) is administered in order to prevent excessive effect of catecholamines or to normalize their production.
  • Total removal of the pheochromocytoma normalizes blood pressure in three of four patients; in the rest, the remaining high blood pressure is probably a sign of essential hypertension.
    • Blood pressure is followed up annually in patients who have undergone surgery.
    • In hereditary cases and in cases that are suspicious as regards malignancy, the patients are also followed up by biochemical tests and by imaging if needed, because the tumour may recur in the remaining adrenal gland.

Multiple endocrine neoplasia

  • Autosomal dominant inheritance; review of the family history is always warranted.
  • MEN1
    • Caused by mutation in the MEN1 gene
    • Should be suspected if a patient has two tumours associated with the disease or one tumour and a relative with MEN1
    • Hyperparathyroidism in 90-100% of the patients, often already at the age of 20 years and usually as the first manifestation of the disease
    • Endocrine tumours of the pancreas or duodenum in up to 80-100%
    • Tumours of the anterior lobe of the pituitary gland in up to 50%
    • Other diseases associated with the syndrome: adrenal gland tumours, neuroendocrine tumours, thyroid diseases, lipomas, angiofibromas, collagenomas
  • MEN2
    • Medullary thyroid cancer in almost all patients
    • Pheochromocytoma in about half of the patients
    • Hyperparathyroidism in 10-20% of patients with MEN2A syndrome
    • Ganglioneuromas of the mouth and gastrointestinal tract in almost all patients with MEN2B syndrome
    • The diagnosis can be made using molecular genetics (RET proto-oncogene). Prophylactic thyroidectomy improves prognosis.
  • von Hippel-Lindau disease http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=892
    • Susceptibility to pheochromocytoma that often develops at a younger age than usual
    • Endocrine diseases of the pancreas
    • Hemangioblastomas of the retina and central nervous system
    • The disease is caused by mutation in the VHL gene. Many patients belong to a family with a history of von Hippel-Lindau disease, but sporadic cases also occur.
  • Familial pheochromocytoma-paraganglioma syndrome
    • Paragangliomas mainly in the head and neck area associated with pheochromocytoma
    • Four known subtypes
    • Autosomal dominant inheritance
    • The genetic change does not always lead to a clinically manifest disease.