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Approach to therapy in multiple endocrine neoplasia type 2

Approach to therapy in multiple endocrine neoplasia type 2
Author:
Douglas W Ball, MD
Section Editor:
Mimi I Hu, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jan 2024.
This topic last updated: Sep 08, 2023.

INTRODUCTION — Multiple endocrine neoplasia type 2 (MEN2) is subclassified into two distinct syndromes: types 2A (MEN2A) and 2B (MEN2B) (table 1). Affected patients have germline mutations in the RET proto-oncogene.

MEN2A is a heritable predisposition to medullary thyroid cancer (MTC), pheochromocytoma, and primary parathyroid hyperplasia. There are four variants of MEN2A.

MEN2B shares the inherited predisposition to MTC and pheochromocytoma found in MEN2A, but there is no parathyroid gland involvement. Patients with MEN2B tend to have, in addition, mucosal neuromas, intestinal ganglioneuromas, and a Marfanoid habitus.

In both syndromes, there is an occurrence of multicentric tumor formation in all organs where the RET proto-oncogene is expressed. This topic will review the therapy of these endocrine tumor syndromes. The classification, genetics, clinical features, diagnosis, and evaluation of MEN2 are discussed separately. (See "Classification and genetics of multiple endocrine neoplasia type 2" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

Treatment of sporadic MTC is also discussed in more detail elsewhere. (See "Medullary thyroid cancer: Surgical treatment and prognosis".)

MEDULLARY THYROID CANCER

Established disease — Among patients with multiple endocrine neoplasia type 2 (MEN2), virtually all develop clinically apparent medullary thyroid cancer (MTC), often early in life [1]. Patients with MTC can be cured only by complete resection of the thyroid tumor and any local and regional metastases. We recommend total thyroidectomy for patients with hereditary forms of MTC (MEN types 2A [MEN2A] and 2B [MEN2B]).

The American Thyroid Association (ATA) has published guidelines on the management of patients with either the inherited or sporadic forms of MTC [1]. Our recommendations are largely in keeping with these guidelines. The treatment of hereditary MTC is discussed briefly below and in more detail separately. (See "Medullary thyroid cancer: Surgical treatment and prognosis".)

Preoperative evaluation — When the biochemical diagnosis of MEN2-related MTC is established, preoperative thyroid and neck ultrasound are important to determine the appropriate extent of surgery. Additional imaging based upon the elevation in serum basal calcitonin is reviewed in more detail separately. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging", section on 'Radiologic evaluation'.)

Preoperative evaluation should also include testing for coexisting tumors. We measure serum calcium (to rule out hyperparathyroidism requiring concomitant surgical intervention) and plasma fractionated metanephrines (as the initial screen for pheochromocytoma). If pheochromocytoma is found, it should be removed first. (See "Clinical presentation and diagnosis of pheochromocytoma" and 'Pheochromocytoma' below and "Treatment of pheochromocytoma in adults".)

If the initial screening tests for coexisting tumors are negative, it is important to evaluate for pheochromocytoma (MEN2A and 2B) and hyperparathyroidism (MEN2A) regularly (table 2). In addition, family members should undergo RET mutation screening. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Screening for MEN2-associated tumors' and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Genetic screening'.)

Thyroidectomy — We recommend total thyroidectomy as the minimal operation for patients with hereditary forms of MTC. The multicentric and bilateral nature of MTC (and its precursor C-cell hyperplasia) in all the MEN2 syndromes means that total thyroidectomy is the only way to cure MEN2-related MTC [2-4]. MTC in patients with MEN2B is more aggressive than in MEN2A, and total thyroidectomy is often not curative [5,6]. In such cases, surgery can lead to a reduction in tumor burden or effective palliation. In one large follow-up study published in 1985, death from MTC occurred in 50 percent of those with MEN2B but only 9.7 percent of those with MEN2A [5].

Cervical nodal metastases are common in patients with palpable MTC or higher calcitonin levels [7]. Prophylactic dissection of nodal tissue in the central compartment from the hyoid bone to the innominate veins and medial to the jugular veins is routinely performed except in patients with very low levels of calcitonin, where total thyroidectomy alone may be preferred (see 'Preventive surgery' below). The lateral jugular and mediastinal nodes should be carefully evaluated, followed by modified neck and/or mediastinal dissections if positive nodes are identified. (See "Medullary thyroid cancer: Surgical treatment and prognosis", section on 'Surgical approach' and "Thyroidectomy".)

Postoperative management — Immediately after surgery, the patient should be monitored closely for the development of hypoparathyroidism or injury to either the recurrent or superior laryngeal nerves. (See "Differentiated thyroid cancer: Surgical treatment", section on 'Complications'.)

Postoperative management and the longer-term monitoring of patients with MEN2-associated MTC are essentially the same as for sporadic MTC (see "Medullary thyroid cancer: Surgical treatment and prognosis", section on 'Postoperative management' and "Medullary thyroid cancer: Surgical treatment and prognosis", section on 'Persistent hypercalcitoninemia'):

Thyroid hormone therapy to restore/maintain euthyroidism; suppressive doses are not necessary, as C cells are not thyroid-stimulating hormone (TSH) responsive

Serial monitoring of serum calcitonin and carcinoembryonic antigen (CEA) concentrations

Periodic physical exams

Neck ultrasound, especially if serum calcitonin is elevated

Additional imaging (computed tomography [CT] or magnetic resonance imaging [MRI] of neck, chest, and abdomen; bone scan or bone MRI in patients suspected of having skeletal metastases) if calcitonin is greater than 150 pg/mL

Neither postoperative radioiodine nor TSH-suppressive therapy with T4 (levothyroxine) is recommended for patients with MTC in the absence of concomitant epithelial cell-derived differentiated thyroid cancer [1].

Management of residual or recurrent disease — The management options for patients with persistent or recurrent locoregional MTC include one or more repeat neck operations, external beam radiotherapy (EBRT), or active surveillance. Palliative radiation therapy may be used to diminish the tumor burden in the neck and to prevent local recurrence. Whether morbidity or mortality is improved remains questionable. The management of residual or recurrent disease is reviewed in more detail elsewhere. (See "Medullary thyroid cancer: Surgical treatment and prognosis", section on 'Management of persistent/recurrent disease'.)

Patients with progressive metastatic disease who cannot be treated by surgery or radiotherapy should be considered candidates for systemic therapy. Newer, target-directed drug therapies are promising, including highly selective RET inhibitors [8]. The molecular profile may influence the response to drug therapy. This topic is discussed in detail elsewhere. (See "Medullary thyroid cancer: Systemic therapy and immunotherapy".)

Preventive surgery — In patients with MEN2, there is predictable progression from multicentric hyperplasia of the parafollicular C cells of the thyroid gland to MTC, with a penetrance approaching 100 percent [2]. The goal in patients with known RET mutations (but without clinically apparent disease) is to perform a prophylactic thyroidectomy before MTC develops or when it is still confined to the thyroid gland [1]. Children with certain RET mutations can develop clinically apparent MTC at an early age (table 3).

In observational studies, the 10-year survival of MTC ranges from 61 to 76 percent [3,9,10]. The important prognostic factors that predict adverse outcome include older age at diagnosis, extent of primary tumor, nodal disease, and distant metastases [9-12]. In children identified as carrying a RET mutation by genetic screening, MTC can be cured or prevented by early thyroidectomy. In some studies of children with MEN2 mutations undergoing preventive surgery, there were no lymph node metastases or postoperative residual MTC when the basal serum calcitonin levels were <30 to 40 pg/mL [13-15].

Timing of surgery — Although there is not universal agreement, our approach to determining the optimal timing of thyroidectomy is based upon the specific DNA mutation in the RET proto-oncogene occurring in the family and, in some cases, serum calcitonin levels (table 4) [16]. In an analysis of 50 children identified through genetic screening who had undergone a previous total thyroidectomy, 88 percent had undetectable stimulated serum calcitonin levels 5 to 10 years later; children with undetectable levels had undergone their surgery before age eight years [17].

Although some RET mutations (eg, RET codons 634 and 918) are uniformly associated with more aggressive and earlier onset MTC, there is heterogeneity in presentation with other RET mutations, even among different families with the same mutation or within an individual family having the same RET mutation. Therefore, measurement of serum calcitonin (basal or stimulated) may be helpful for establishing the timing of thyroidectomy. This approach is consistent with clinical practice guidelines published by the ATA [1].

RET mutations can be categorized as highest, high, and moderate risk, referring to the potential risk for local and distant MTC metastases at an early age (table 4) [1,16]. The suggested timing of thyroidectomy is based upon evidence of age-dependent and codon-specific progression of early MTC [18-20].

Highest risk – For children with a predisposition for MEN2B, most commonly associated with a germline mutation in codon 918, we suggest thyroidectomy during the first year of life [21-27]. Total thyroidectomy and central neck dissection during the first year of life is advocated, given that metastatic disease has been reported in one-year-old children [6] and that later surgery is often not curative [6,28]. Typical physical features are not necessarily present in an affected neonate within an MEN2B family [5], so the absence of such features does not obviate the need for early diagnosis.

High risk – For children with mutations in codons 634 or 883, we suggest thyroidectomy at or before age five years, with the exact timing based on detection of an elevated serum calcitonin level (above the upper limit of normal).

Moderate risk – For patients with MTC and RET mutations other than M918T, C634, and A883F in codons 609, 611, 618, 620, 630, 666, 768, 790, 804, 891, and 912, we suggest total thyroidectomy during childhood or young adulthood, based on detection of an elevated serum calcitonin level (above the upper limit of normal) [29-32].

Patients with a single mutation on codon 804 are thought to have atypical MEN2B [23,33,34]. This mutation has low penetrance. While initially thought to be associated with late onset of MTC and an indolent course, compared with the codon 918 and 634 mutations [35], early onset with metastatic disease has been reported, and these MTCs are associated with a second germline or somatic (tandem) mutation [27]. We therefore recommend that these individuals undergo surgery by an age depending on the identity of this second (tandem) mutation.

Fewer than 1 percent of MEN2 families have no detectable RET mutation [5,27]. If no genetic information is available to show a specific germline RET mutation from an affected individual in a known MEN2 family, prophylactic thyroidectomy should be guided by annual monitoring of serum calcitonin and neck ultrasound (table 4) [1]. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Medullary thyroid cancer'.)

Surgical approach — In addition to total thyroidectomy, prophylactic central lymph node dissection should also be performed in patients with a germline mutation in codon 918 who are undergoing preventive operations, and in other patients if the baseline calcitonin level is already elevated (>40 pg/mL). In very young children, the parathyroid glands may be difficult to identify intraoperatively, thus increasing the risk of postsurgical hypoparathyroidism. If the parathyroid glands cannot be identified and there are no suspicious lymph nodes on preoperative ultrasound or intraoperative inspection, the surgeon may reasonably forgo central neck dissection [1].

A more limited central node dissection, taking care to avoid disrupting the parathyroid glands or laryngeal nerves, has yielded good results in children who were regularly screened biochemically for MTC with a calcium infusion test and operated on when the test first became positive [4]. One would expect similarly good results from this surgical approach in patients who carry the gene for MTC and are operated on before they have any clinical or biochemical evidence of MTC.

Given the rarity of this disease and the potential complications of a total thyroidectomy in young children, all patients should be referred to academic centers with expertise in MEN2, where an experienced pediatric or endocrine surgeon can perform the required surgery.

PHEOCHROMOCYTOMA — Pheochromocytoma occurs in approximately 40 percent of patients with multiple endocrine neoplasia type 2A (MEN2A) and in approximately 50 percent of those with type 2B (MEN2B) [2,6]. There is, however, large variability in the penetrance of pheochromocytoma among different reported kindreds, depending upon the specific RET germline mutation [2].

The disease tends to progress slowly from its precursor, adrenal medullary hyperplasia. There is an increased likelihood of bilateral pheochromocytoma in patients with MEN2 versus the unilateral and unicentric tumors that are almost always found in patients with sporadic pheochromocytoma [36]. Extraadrenal pheochromocytoma is rare in MEN2 but does occur [37].

Surgical approach — For patients with bilateral pheochromocytomas, bilateral adrenalectomy is necessary. It should also be considered in a patient with unilateral disease when other family members have had unusually aggressive bilateral adrenal medullary disease. For most other patients with a unilateral pheochromocytoma, unilateral adrenalectomy is the treatment of choice. Prior to unilateral or bilateral adrenalectomy, patients should be treated with alpha blockade and counselled regarding volume expansion. (See "Treatment of pheochromocytoma in adults", section on 'Alpha-adrenergic blockade'.)

Bilateral adrenalectomy has been advocated for MEN2 patients with apparently unilateral pheochromocytomas [38-40]. However, we and others think unilateral adrenalectomy in those patients who have a normal-appearing contralateral gland is more appropriate [37]. The rationale for this approach includes the following:

Approximately one-third of patients undergoing unilateral surgery eventually require surgery for pheochromocytoma in the remaining adrenal [37]. However, the second tumor may not appear for many years, and initial unilateral surgery obviates the need for glucocorticoid and mineralocorticoid replacement (with its attendant risks and morbidity) in the interim.

No deaths from catecholamine crisis have been reported in patients with MEN2 who underwent unilateral adrenalectomy, were followed, and then developed contralateral disease [37].

Metastatic pheochromocytoma has not been reported in a patient with MEN2 after unilateral adrenalectomy [37].

If a bilateral adrenalectomy is planned preoperatively, the patient should receive glucocorticoid stress coverage while awaiting transfer to the operating room. Peri- and postoperative management of patients undergoing adrenalectomy are reviewed separately. (See "Treatment of pheochromocytoma in adults", section on 'Adrenalectomy' and "Treatment of adrenal insufficiency in adults", section on 'Surgery'.)

One technique that has been used in an attempt to avoid causing adrenal insufficiency from bilateral adrenalectomy is to perform adrenal-sparing surgery (partial or cortex-sparing adrenalectomy). However, because of the diffuse medullary disease in MEN2 patients, many groups advise complete bilateral adrenalectomy when bilateral disease is evident on imaging. The choice of cortex-sparing adrenal surgery should be balanced by the consideration that this will increase the risk of recurrence. This topic is reviewed in detail elsewhere. (See "Treatment of pheochromocytoma in adults", section on 'Familial pheochromocytoma'.)

PRIMARY HYPERPARATHYROIDISM — Primary hyperparathyroidism occurs in 10 to 25 percent of patients with multiple endocrine neoplasia type 2A (MEN2A) and is almost always multiglandular [2]. The hyperparathyroidism in MEN2A is often clinically occult. Primary hyperparathyroidism is not a feature of MEN type 2B (MEN2B) (table 1).

Some centers have described a markedly diminished incidence of hyperparathyroidism in patients with MEN2A who have undergone early total thyroidectomy for cure or prevention of medullary thyroid cancer (MTC) [41,42]. In one report, as an example, hyperparathyroidism developed in none of 22 patients treated with early thyroidectomy [42]. Why this might occur is not known. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Primary hyperparathyroidism'.)

Whether or not there is a decreased incidence of hyperparathyroidism after successful treatment or prevention of MTC, the already low penetrance of hyperparathyroidism in MEN2A and the success of treatment if it develops argue strongly against prophylactic total parathyroidectomy at the time of thyroidectomy. This approach would have a substantial risk of hypoparathyroidism with a low likelihood of benefit [43].

Once the biochemical diagnosis of primary hyperparathyroidism is confirmed in a patient known or presumed to have MEN2A, the indications for surgical intervention are similar to those in patients with sporadic primary hyperparathyroidism [44]. (See "Primary hyperparathyroidism: Management".)

Management of asymptomatic disease — For patients with MEN2A-related hyperparathyroidism who are asymptomatic, it is acceptable to defer surgery. If surgery is not performed, then it is appropriate to recommend supportive-preventive measures with adequate monitoring. Asymptomatic patients who do not undergo surgery require long-term monitoring for worsening hypercalcemia, renal impairment, and bone loss. The development of any of these findings indicates disease progression and the need for surgical intervention. Similar to the periodic monitoring performed in patients with asymptomatic sporadic primary hyperparathyroidism, we monitor serum calcium and creatinine annually and bone density (hip, spine, and forearm) every one to two years. (See "Primary hyperparathyroidism: Management", section on 'Preventive measures' and "Primary hyperparathyroidism: Management", section on 'Monitoring'.)

Symptomatic disease — Patients with symptomatic primary hyperparathyroidism (nephrolithiasis, symptomatic hypercalcemia) should have parathyroid surgery, which is the only definitive therapy. Other indications for surgery include marked hypercalcemia, major hypercalciuria, and evidence of bone loss. (See "Primary hyperparathyroidism: Management", section on 'Candidates for surgery'.)

Evidence of pheochromocytoma should be sought before parathyroidectomy and, if present, the pheochromocytoma(s) should be removed before the parathyroid surgery.

Preoperative localization — Because of the polyglandular nature of hyperparathyroidism in MEN2A, preoperative localization studies are not indicated in patients with MEN2A who have not had previous neck surgery. However, we recommend preoperative localization studies (such as ultrasonography, sestamibi scan, and/or neck and chest computed tomography [CT]) in patients who have had previous neck surgery for MTC and for those with recurrent or persistent disease. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)

Surgical approach — Bilateral neck exploration in an attempt to find all glands should always be performed in patients with known or suspected MEN2A. Beyond that, controversy exists as to the ideal surgical approach. Options include [1]:

Resection of the visibly enlarged glands only, with intraoperative monitoring of serum parathyroid hormone (PTH) levels to document removal of hyperfunctioning parathyroid tissue

Subtotal parathyroidectomy (usually removal of three and one-half glands, often with cervical thymectomy) leaving one gland or a piece of one gland in situ or with forearm grafting

Total parathyroidectomy, which carries a higher risk of hypoparathyroidism, with forearm grafting

We typically prefer the first option. However, in patients with four-gland enlargement, we prefer subtotal parathyroidectomy. In patients who require repeated neck surgeries for MTC, early forearm parathyroid gland autografting may reduce the risk of subsequent permanent hypoparathyroidism.

When performed in centers with major experience in parathyroid surgery, as surgery for MEN2 patients should be, results utilizing the different approaches are equivalent and complication rates are low [45,46]. In such instances, institutional preferences should be followed.

The recurrence rate after apparently successful subtotal parathyroidectomy, performed by expert parathyroid surgeons, appears to be low; in one report, as an example, none of 18 patients had recurrent disease after a mean follow-up of 5.8 years [45]. In comparison, a retrospective study noted recurrence in two of eight patients treated with subtotal parathyroidectomy at a mean of 11.5 years after surgery; however, the initial surgery was not necessarily performed at a specialized center [41].

Medical therapy — Certain medications, particularly estrogen plus progestin and bisphosphonates, inhibit bone resorption and can increase bone density and possibly lower serum calcium concentrations in patients with hyperparathyroidism. Others, such as calcimimetics or vitamin D analogues, suppress PTH release or counteract the effects of hyperparathyroidism at the level of the PTH receptor. None of these medical therapies have been rigorously studied in patients with MEN2. Medical therapy in patients with sporadic primary hyperparathyroidism is discussed elsewhere. (See "Primary hyperparathyroidism: Management", section on 'Poor surgical candidates'.)

OTHER ASSOCIATED DISEASES — The treatment of Hirschsprung disease (HD) and cutaneous lichen amyloidosis (CLA; lichen planus amyloidosis [LPA]) are reviewed separately. (See "Congenital aganglionic megacolon (Hirschsprung disease)", section on 'Management' and "Acquired hyperpigmentation disorders", section on 'Primary cutaneous amyloidosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Medullary thyroid cancer".)

SUMMARY AND RECOMMENDATIONS

Medullary thyroid cancer treatment

Preoperative evaluation – Preoperative evaluation should include testing for coexisting tumors. We measure serum calcium (to rule out hyperparathyroidism requiring concomitant surgical intervention) and plasma fractionated metanephrines (as the initial screen for pheochromocytoma). If pheochromocytoma is found, it should be removed before thyroidectomy and after appropriate alpha-adrenergic blockade. (See 'Preoperative evaluation' above and "Clinical presentation and diagnosis of pheochromocytoma".)

Total thyroidectomy – Among patients with multiple endocrine neoplasia type 2 (MEN2), virtually all patients develop clinically apparent medullary thyroid cancer (MTC), often early in life. Patients with hereditary forms of MTC (MEN types 2A [MEN2A] and 2B [MEN2B]) should undergo total thyroidectomy. The multicentric and bilateral nature of MTC (and its precursor C-cell hyperplasia) in the MEN2 syndromes means that total thyroidectomy is the only way to cure MEN2-related MTC. (See 'Established disease' above.)

Postoperative management – After surgery, the patient should be monitored closely for the development of hypoparathyroidism or injury to either the recurrent or superior laryngeal nerves. (See "Differentiated thyroid cancer: Surgical treatment", section on 'Complications'.)

Postoperative management and the longer-term monitoring of patients with MEN2-associated MTC are essentially the same as for sporadic MTC. (See "Medullary thyroid cancer: Surgical treatment and prognosis", section on 'Postoperative management' and "Medullary thyroid cancer: Surgical treatment and prognosis", section on 'Management of persistent/recurrent disease' and "Medullary thyroid cancer: Systemic therapy and immunotherapy".)

Medullary thyroid cancer prevention

Prophylactic thyroidectomy – The goal in patients with known RET mutations (but without clinically apparent disease) is to perform a prophylactic thyroidectomy before MTC develops or when it is still confined to the thyroid gland. (See 'Preventive surgery' above.)

Timing of preventive surgery – We time prophylactic thyroidectomy in family members based upon the specific DNA mutation in the RET proto-oncogene occurring in the family (table 4). (See 'Timing of surgery' above.)

These pathogenic variants can be categorized as highest, high, and moderate risk, referring to the potential risk for local and distant metastases at an early age, as follows:

-Highest risk – For children with a predisposition for MEN2B, most commonly associated with a germline mutation in codon 918, we suggest thyroidectomy during the first year of life (Grade 2C).

-High risk – For children with RET mutations in codons 634 or 883, we suggest total thyroidectomy at or before age five years (Grade 2C).

-Moderate risk – For patients with MTC and RET mutations other than M918T, C634, and A883F in codons 609, 611, 618, 620, 630, 666, 768, 790, 804, 891, and 912, we suggest total thyroidectomy during childhood or young adulthood, based on detection of an elevated serum calcitonin level (above the upper limit of normal) (Grade 2C).

Pheochromocytoma treatment – For patients with bilateral pheochromocytomas, bilateral adrenalectomy is necessary. It should also be considered in a patient with unilateral disease when other family members have had unusually aggressive bilateral adrenal medullary disease. For most other patients with a unilateral pheochromocytoma, we recommend unilateral adrenalectomy as the treatment of choice (Grade 1C). (See 'Pheochromocytoma' above and "Treatment of pheochromocytoma in adults".)

Primary hyperparathyroidism treatment

Asymptomatic disease – For patients with mild hyperparathyroidism who are asymptomatic, it is acceptable to defer surgery. If surgery is not performed, then it is appropriate to recommend supportive-preventive measures with adequate monitoring for worsening hypercalcemia, renal impairment, and bone loss. (See 'Management of asymptomatic disease' above.)

Symptomatic disease – Once the biochemical diagnosis of primary hyperparathyroidism is confirmed in a patient known or presumed to have MEN2A, the indications for surgical intervention are similar to those in patients with sporadic primary hyperparathyroidism. These include symptomatic or marked hypercalcemia, nephrolithiasis, major hypercalciuria, and evidence of bone loss. Evidence of pheochromocytoma should be sought before parathyroidectomy and, if present, the pheochromocytoma(s) should be removed before the parathyroid surgery. (See 'Symptomatic disease' above and "Primary hyperparathyroidism: Management".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Cornelis J Lips, MD, PhD, who contributed to earlier versions of this topic review.

  1. Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25:567.
  2. Raue F, Frank-Raue K, Grauer A. Multiple endocrine neoplasia type 2. Clinical features and screening. Endocrinol Metab Clin North Am 1994; 23:137.
  3. American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009; 19:565.
  4. Gagel RF, Robinson MF, Donovan DT, Alford BR. Clinical review 44: Medullary thyroid carcinoma: recent progress. J Clin Endocrinol Metab 1993; 76:809.
  5. Wells SA Jr, Dilley WG, Farndon JA, et al. Early diagnosis and treatment of medullary thyroid carcinoma. Arch Intern Med 1985; 145:1248.
  6. O'Riordain DS, O'Brien T, Crotty TB, et al. Multiple endocrine neoplasia type 2B: more than an endocrine disorder. Surgery 1995; 118:936.
  7. Scollo C, Baudin E, Travagli JP, et al. Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. J Clin Endocrinol Metab 2003; 88:2070.
  8. Subbiah V, Yang D, Velcheti V, et al. State-of-the-Art Strategies for Targeting RET-Dependent Cancers. J Clin Oncol 2020; 38:1209.
  9. Cupisti K, Wolf A, Raffel A, et al. Long-term clinical and biochemical follow-up in medullary thyroid carcinoma: a single institution's experience over 20 years. Ann Surg 2007; 246:815.
  10. Modigliani E, Cohen R, Campos JM, et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'étude des tumeurs à calcitonine. Clin Endocrinol (Oxf) 1998; 48:265.
  11. Miccoli P, Minuto MN, Ugolini C, et al. Clinically unpredictable prognostic factors in the outcome of medullary thyroid cancer. Endocr Relat Cancer 2007; 14:1099.
  12. Baloch ZW, LiVolsi VA. Prognostic factors in well-differentiated follicular-derived carcinoma and medullary thyroid carcinoma. Thyroid 2001; 11:637.
  13. Rohmer V, Vidal-Trecan G, Bourdelot A, et al. Prognostic factors of disease-free survival after thyroidectomy in 170 young patients with a RET germline mutation: a multicenter study of the Groupe Francais d'Etude des Tumeurs Endocrines. J Clin Endocrinol Metab 2011; 96:E509.
  14. Niccoli-Sire P, Murat A, Rohmer V, et al. When should thyroidectomy be performed in familial medullary thyroid carcinoma gene carriers with non-cysteine RET mutations? Surgery 2003; 134:1029.
  15. Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab 2005; 90:2029.
  16. Frank-Raue K, Rondot S, Raue F. Molecular genetics and phenomics of RET mutations: Impact on prognosis of MTC. Mol Cell Endocrinol 2010; 322:2.
  17. Skinner MA, Moley JA, Dilley WG, et al. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 2005; 353:1105.
  18. Marini F, Falchetti A, Del Monte F, et al. Multiple endocrine neoplasia type 2. Orphanet J Rare Dis 2006; 1:45.
  19. Machens A, Dralle H. Genotype-phenotype based surgical concept of hereditary medullary thyroid carcinoma. World J Surg 2007; 31:957.
  20. Machens A, Ukkat J, Brauckhoff M, et al. Advances in the management of hereditary medullary thyroid cancer. J Intern Med 2005; 257:50.
  21. Gimm O, Marsh DJ, Andrew SD, et al. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab 1997; 82:3902.
  22. Smith DP, Houghton C, Ponder BA. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene 1997; 15:1213.
  23. Cranston AN, Carniti C, Oakhill K, et al. RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. Cancer Res 2006; 66:10179.
  24. Miyauchi A, Futami H, Hai N, et al. Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Jpn J Cancer Res 1999; 90:1.
  25. Kameyama K, Okinaga H, Takami H. RET oncogene mutations in 75 cases of familial medullary thyroid carcinoma in Japan. Biomed Pharmacother 2004; 58:345.
  26. Iwashita T, Murakami H, Kurokawa K, et al. A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. Biochem Biophys Res Commun 2000; 268:804.
  27. Menko FH, van der Luijt RB, de Valk IA, et al. Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918. J Clin Endocrinol Metab 2002; 87:393.
  28. Duh QY, Sancho JJ, Greenspan FS, et al. Medullary thyroid carcinoma. The need for early diagnosis and total thyroidectomy. Arch Surg 1989; 124:1206.
  29. Lips CJ, Höppener JW, Van Nesselrooij BP, Van der Luijt RB. Counselling in multiple endocrine neoplasia syndromes: from individual experience to general guidelines. J Intern Med 2005; 257:69.
  30. Yip L, Cote GJ, Shapiro SE, et al. Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg 2003; 138:409.
  31. Machens A, Niccoli-Sire P, Hoegel J, et al. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 2003; 349:1517.
  32. Cote GJ, Gagel RF. Lessons learned from the management of a rare genetic cancer. N Engl J Med 2003; 349:1566.
  33. Lesueur F, Cebrian A, Cranston A, et al. Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients. J Clin Endocrinol Metab 2005; 90:3454.
  34. Learoyd DL, Gosnell J, Elston MS, et al. Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations. Clin Endocrinol (Oxf) 2005; 63:636.
  35. Lombardo F, Baudin E, Chiefari E, et al. Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804. J Clin Endocrinol Metab 2002; 87:1674.
  36. Webb TA, Sheps SG, Carney JA. Differences between sporadic pheochromocytoma and pheochromocytoma in multiple endocrime neoplasia, type 2. Am J Surg Pathol 1980; 4:121.
  37. Evans DB, Lee JE, Merrell RC, Hickey RC. Adrenal medullary disease in multiple endocrine neoplasia type 2. Appropriate management. Endocrinol Metab Clin North Am 1994; 23:167.
  38. Utiger RD. Medullary thyroid carcinoma, genes, and the prevention of cancer. N Engl J Med 1994; 331:870.
  39. Jansson S, Tisell LE, Fjälling M, et al. Early diagnosis of and surgical strategy for adrenal medullary disease in MEN II gene carriers. Surgery 1988; 103:11.
  40. Lips KJ, Van der Sluys Veer J, Struyvenberg A, et al. Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome). Am J Med 1981; 70:1051.
  41. Herfarth KK, Bartsch D, Doherty GM, et al. Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Surgery 1996; 120:966.
  42. Gagel RF, Tashjian AH Jr, Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med 1988; 318:478.
  43. Scholten A, Schreinemakers JM, Pieterman CR, et al. Evolution of surgical treatment of primary hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Endocr Pract 2011; 17:7.
  44. Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab 2014; 99:3561.
  45. O'Riordain DS, O'Brien T, Grant CS, et al. Surgical management of primary hyperparathyroidism in multiple endocrine neoplasia types 1 and 2. Surgery 1993; 114:1031.
  46. Wells SA Jr, Donis-Keller H. Current perspectives on the diagnosis and management of patients with multiple endocrine neoplasia type 2 syndromes. Endocrinol Metab Clin North Am 1994; 23:215.
Topic 7866 Version 15.0

References

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