Approach

Treatment varies depending on specific manifestations of multiple endocrine neoplasia type 1 (MEN1) (e.g., hyperparathyroidism, gastrinoma, pancreatic lesion, pituitary adenoma) or multiple endocrine neoplasia type 2 (MEN2) (e.g., hyperparathyroidism, medullary thyroid cancer, phaeochromocytoma).

All tumours are surgically evaluated. However, surgical cures are often not possible, because there may be multiple primary tumours and because metastasis may have occurred before primaries are evident.[63] When tumours are deemed inoperable, medical therapies are used to reduce morbidity and relieve symptoms by controlling excess hormone production.

Treatment of patients with >1 manifestation of MEN1 or MEN2 is subject to clinical judgment on a case-by-case basis.

MEN1

Hyperparathyroidism

  • Asymptomatic patients can be medically treated with bisphosphonates, calcium mimetics and loop diuretics. First-line therapy is adequate hydration (at least 3 L fluid per day). Vitamin D repletion should be ensured to minimise the dual insult of vitamin D deficiency and a hyperparathyroidism effect on bone. The decision for surgery is based on symptoms and evidence of end-organ damage (e.g., osteoporosis, nephrocalcinosis). It is debatable whether asymptomatic patients should undergo surgery or whether surgery should be deferred until glands have enlarged and are easier to identify.

  • Parathyroid surgery is first-line therapy for symptomatic patients.[8] During surgery all parathyroid glands are identified and explored, taking into consideration that at least 5% of patients with MEN1 have 5 parathyroid glands. Subtotal parathyroidectomy (at least 3.5 glands) or total parathyroidectomy is recommended.[3][64] Small parathyroid remnants can either be left in place (marked by clips) or can be autotransplanted into forearms (to avoid the development of permanent hypoparathyroidism). Retrospective studies and one prospective study have failed to show any difference in outcome when comparing subtotal parathyroidectomy with total parathyroidectomy and autotransplantation in patients with MEN1.[65] Subtotal thymectomy is also suggested at the time of surgery.[3][37]

  • In patients with non-operable hyperparathyroidism, morbidity is reduced by controlling calcium levels. Hypercalcaemia is traditionally managed with a multifaceted approach including liberal fluids for hydration. Possible additions if needed, include intermittent intravenous bisphosphonate infusions, following adequate hydration. The calcium mimetic agent cinacalcet has been used to decrease parathyroid hormone production, and has been shown to be effective in a small cohort of patients with MEN1.[66][67][68] The use of cinacalcet after unsuccessful surgery for primary hyperparathyroidism is off label.[64] Loop diuretics increase urinary calcium excretion but should be used with caution, as intravascular depletion and hypercalciuria can worsen renal impairment and increase the risk of renal calculi.[69]

Gastrinoma/Zollinger-Ellison syndrome

  • The first-line treatment is medical management aimed at controlling gastric acid production with high-dose proton-pump inhibitors such as omeprazole.[8] Fifteen-year survival with this treatment approach is over 50%.[70] Gastrin secretion is increased by calcium, making medical control of hyperparathyroidism with or without surgery important in the treatment of gastrinoma.[71]

  • Duodenopancreatectomies (Whipple procedures) and pancreas-sparing procedures have been performed for gastrinoma but surgical approaches are controversial because cure is rare and it is difficult to assess the impact of surgery, partly because proton-pump inhibitor treatment is so effective.[8]

  • One long-term cohort study found that <20% of patients with MEN1 are disease-free even immediately after gastrinoma surgery, only around 6% are disease-free after 5 years, and none are disease-free at 10 years.[72]

  • Surgical opinion is required when considering gastrinoma surgery.

Pituitary adenomas

  • Treatment of MEN1-related pituitary adenomas is similar to that of sporadic adenomas.[8]

  • Non-functioning tumours are usually observed until mass effect threatens other structures such as the optic chiasm and prolactinomas are generally managed medically with dopamine agonists.

  • Transsphenoidal surgery is the preferred initial approach to patients with adrenocorticotrophic or growth hormone-producing tumours. However, transcranial approaches are occasionally required due to tumour location or size. To optimise patients for surgery, medical control of hypercortisolaemia can be achieved with metyrapone and/or ketoconazole. Preoperatively, treatment with somatostatin analogues for patients with acromegaly and with a steroidogenesis inhibitor for patients with Cushing’s disease should be considered to control the disease.

Other neuroendocrine tumours

  • Decisions around the management of neuroendocrine tumours in MEN1 can be difficult. Consensus guidelines have recently been developed but in all cases management must be individualised.[43] There are no clear criteria for performing pancreatic lesion surgery that are specific to MEN rather than drawn from information about sporadic tumours.[3][73] Distal pancreatectomies can be performed for tail lesions and duodenopancreatectomies (Whipple procedures) can be performed for head and neck lesions. Both procedures may be complemented by intraoperative ultrasound and manual palpation to localise additional lesions that may then be individually resected by enucleation.

  • Octreotide injections can help to stabilise hormone production in patients with pancreatic neuroendocrine tumours that express somatostatin receptors.[74] Randomised controlled trials (not specific to MEN syndromes) have demonstrated an impact on progression free survival, as well as on secretory syndromes, from long-acting somatostatin analogues.[75][76] Octreotide efficacy may be attributable to an anti-proliferative effect.[77][78]​​​​​

MEN2

Hyperparathyroidism

  • Asymptomatic patients can be medically treated with bisphosphonates and calcium mimetics. It is debatable whether asymptomatic patients should undergo surgery or whether surgery should be deferred until glands have enlarged and are easier to identify.

  • Parathyroid surgery is first-line therapy for symptomatic patients with the surgical approach similar to that used in MEN1.[64] Subtotal thymectomy is also usually performed.[37] Surgical approaches in some centres have evolved over time to encompass minimally invasive focussed approaches as an alternative to 4-gland exploration.[79]

  • In patients with non-operable hyperparathyroidism, morbidity is reduced by controlling calcium levels. Hypercalcaemia is traditionally managed with a multifaceted approach including liberal fluids for hydration. Possible additions if needed, include intermittent intravenous bisphosphonate infusions, following adequate hydration. The calcium mimetic agent cinacalcet has been used to decrease parathyroid hormone production.[66] The use of cinacalcet after unsuccessful surgery for primary hyperparathyroidism is off label.[64] Loop diuretics increase urinary calcium excretion but should be used with caution, as intravascular depletion and hypercalciuria can worsen renal impairment and increase the risk of renal calculi.[69]

Family history of MEN2

  • Neoplasia often develops at young ages and may be metastatic by the time it is clinically apparent. Prophylactic thyroidectomy is recommended in children once carrier status is confirmed.[5][7][80]

  • MEN2B patients with mutations in codons such as 883, 918, or 922 have the highest risk of very early metastatic disease. Most of these patients require thyroidectomy and central neck dissection as infants. Children with mutations conferring a more intermediate risk of aggressive disease require surgery before the age of 5 years. However, their need for central neck dissection is more controversial, as the risk of surgical complications (e.g., hypoparathyroidism, recurrent laryngeal nerve damage) may outweigh the likelihood of metastatic disease.[81] Children with mutations conferring a lesser risk of aggressive disease also require prophylactic thyroidectomy in childhood, although there is less of a consensus about the timing.

  • Long-term thyroid hormone replacement is required after thyroidectomy.

Medullary thyroid cancer

  • Ideally, patients will be diagnosed genetically and on the basis of family screening before pathology develops and this can enable early prophylactic thyroidectomy.[7] The recommended age for this surgery is dependent on the pathogenicity of the RET mutation carried by the patients.[5]

  • Patients with disease that is localised to the neck require surgery. Total thyroidectomy with central neck dissection is performed unless there is evidence of disease in the lateral neck. Lymph node dissection of ipsilateral and/or contralateral neck regions with or without mediastinal exploration may be performed concurrently, dependent on disease extent. Lateral neck dissection in the absence of visible lymph node disease is controversial.[82]

  • Medical therapies are used when surgical cure is not possible (when disease is locally invasive, even in the absence of distant metastases and it is only possible to debulk rather than cure). Chronic diarrhoea symptoms may be treated medically.

Metastatic medullary thyroid cancer

  • Standard systemic therapies such as radiation and chemotherapy are ineffective as disease cures. Operations are usually only indicated to control local effects such as tracheal compression, but debulking surgery is possible to decrease symptomatic calcitonin levels (there are no medical anti-calcitonin therapies).[83]

  • Chronic diarrhoea symptoms may be treated medically.

Phaeochromocytoma

  • Adrenalectomy is the treatment for phaeochromocytoma. Bilateral adrenalectomy is considered in patients presenting with bilateral disease or in those with high-risk mutations. Preoperative adrenergic blockade reduces the risk of hypertensive crisis during surgery. Patients should be fully alpha-blocked before surgery, with the addition of beta-blockade if indicated by pulse and blood pressure. Adrenal cortical-sparing surgery is a successful treatment option and is associated with a reduced risk of adrenal insufficiency.[84]

  • When a surgical cure is not possible, long-term alpha-blockers should be used. Once alpha-blockade is maximised, beta-blockers are added. Short-acting agents, such as propranolol, are used to titrate the dose to achieve goal heart rates between 60 and 80 bpm. Longer-acting agents are started once this is achieved and short-acting agents are stopped. Patients are often symptomatic from orthostatic hypotension. In these cases, salt loading with up to several grams of salt daily can be used for symptom relief if cardiac function is normal.

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