Continuing Education Activity

Multiple endocrine neoplasia type 2 is a rare hereditary cancer syndrome associated with germline mutations and a near-universal lifetime risk of medullary thyroid cancer, along with pheochromocytoma and other endocrine and nonendocrine manifestations. Delayed recognition, incomplete genetic evaluation, and suboptimal surveillance may increase the risk of metastatic disease, endocrine complications, and missed opportunities for early intervention in affected relatives. This activity addresses an important practice gap in the timely diagnosis, risk stratification, and longitudinal treatment of patients with multiple endocrine neoplasia type 2. Participants will strengthen their ability to recognize key clinical features, interpret genotype-phenotype correlations, apply evidence-based screening and surgical strategies, and anticipate major complications. The activity also emphasizes genetic counseling, family-based evaluation, and interdisciplinary coordination to support earlier diagnosis, individualized treatment planning, and improved patient-centered outcomes across the life span.  

Objectives:

• Identify the germline RET mutations and their phenotypic correlates in multiple endocrine neoplasia type 2.
• Implement the current American Thyroid Association guidelines regarding screening and timing of prophylactic total thyroidectomy for medullary thyroid cancer in patients diagnosed with multiple endocrine neoplasia type 2.
• Evaluate patients with known multiple endocrine neoplasia type 2 for pheochromocytoma prior to an interventional procedure. 
• Apply effective strategies to improve care coordination among interprofessional team members to facilitate genetic counseling and testing for patients diagnosed with multiple endocrine neoplasia type 2 and their first-degree relatives. 

Introduction

Multiple endocrine neoplasia type 2 (MEN2) refers to a rare group of hereditary cancer syndromes caused by gain-of-function mutations in the rearranged during transfection (RET) proto-oncogene. Inherited in an autosomal dominant manner with high penetrance and variable expressivity, affected individuals are at high risk of developing benign and malignant neoplasms involving various endocrine glands, including, but not limited to, the thyroid, adrenal glands, and parathyroids, in descending order of frequency. Other organ systems, such as the gastrointestinal tract, musculoskeletal system, and skin, may also be involved. Despite its rarity, prompt diagnosis remains essential for evaluating and treating affected patients and their families.

John Sipple first described 6 cases of pheochromocytoma associated with thyroid cancer in 1961, noting a 14-fold higher incidence of thyroid cancer compared to the general population.[Sipple JH. The Association of Pheochromocytoma With Carcinoma of the Thyroid Gland. Am J Med. 1961] The term multiple endocrine neoplasia type 2 (MEN2) was first proposed by Steiner et al in 1968 after evaluation of a family affected by medullary thyroid cancer (MTC), pheochromocytoma, hyperparathyroidism (HPTH), and Cushing syndrome, because MEN1 had been identified earlier by Wermer.[1] In 1993, germline mutations in the RET proto-oncogene were identified in families diagnosed with MEN2.[2][3][4]

MEN2 is further subdivided into MEN2A, also known as Sipple syndrome, and MEN2B, also called mucosal neuroma syndrome and previously called Wagenmann-Froboese syndrome, based on clinical features and distinct RET mutations. MEN2A accounts for 95% of all MEN2 cases. In both subtypes, nearly 100% of patients eventually develop medullary thyroid cancer (MTC), and up to 50% develop pheochromocytomas. Although primary hyperparathyroidism may occur in approximately 25% of patients with MEN2A, the condition is rarely seen (<1%) in MEN2B. Further evaluation of affected families with MEN2A led to the identification of the following 4 variants:

• Classical MEN2A
• MEN2A with cutaneous lichen amyloidosis (CLA)
• MEN2A with Hirschsprung disease (HD)
• Familial medullary thyroid cancer (FMTC)[5]

Etiology

Located on chromosome 10 (band 10q11.21), the RET proto-oncogene encodes a transmembrane receptor with tyrosine kinase activity. Activation of RET transduces growth and differentiation signals in several tissues, particularly those derived from neural crest cells. MEN2 is caused by germline gain-of-function point mutations in RET that drive tumorigenesis and developmental defects in tissues and organs derived from the neural crest. This pattern contrasts with most hereditary cancer syndromes, which are characterized by loss-of-function mutations in tumor suppressor genes. MEN2 is thus also an example of a neurocristopathy, which is a syndrome characterized by abnormal migration, differentiation, division, or survival of neural crest cells. In 5% to 9% of patients with MEN2A and 75% of patients with MEN2B, these mutations arise de novo, while the remainder are inherited in an autosomal dominant manner.[5][6] Notably, almost all reported de novo mutations are paternal in origin, and some authors have postulated that this may be due to advancing paternal age. Very rarely, families also meet the clinical criteria for MEN2A or MEN2B but have normal RET gene sequencing.

RET alterations have been detected in multiple cancers and developmental disorders in addition to MEN2. Somatic gain-of-function RET mutations also occur in 40% to 70% of sporadic MTCs; the remainder may show mutations in the Harvey rat sarcoma viral oncogene homolog, Kirsten rat sarcoma viral oncogene homolog, or, rarely, neuroblastoma rat sarcoma viral oncogene homolog (HRAS), the Kirsten rat sarcoma viral oncogene homolog (KRAS), or, rarely, neuroblastoma rat sarcoma viral oncogene homolog (NRAS). Activating RET gene rearrangements and fusions have been found in 5% to 20% of papillary thyroid carcinoma, 1% to 2% of non–small cell lung carcinoma, and rarely in chronic myelomonocytic leukemia and other solid cancers.[5][7] Selective RET kinase inhibitors (selpercatinib and pralsetinib) were approved by the US Food and Drug Administration in 2020 for the treatment of RET-fusion positive non–squamous cell lung carcinoma and RET-altered thyroid cancer (including RET-mutant MTC) after clinical trials.[7] Inactivating mutations or deletions of RET have been identified in both hereditary and sporadic forms of Hirschsprung disease.[5][7] 

RET Structure and Physiology

The extracellular domain of RET consists of 4 cadherin-like domains and a cysteine-rich region upstream of the single transmembrane domain. The intracellular portion comprises 2 tyrosine kinase (TK) domains, TK1 and TK2. RET activation requires the formation of a ternary complex with 1 of 4 different ligands belonging to the glial cell line–derived neurotrophic factor (GDNF) family and their corresponding GDNF family receptor. The 4 ligands are GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN). Subsequent RET dimerization activates the RET kinase and downstream signaling. This mechanism is essential for the normal development of neural crest cells, the enteric nervous system, and the genitourinary tract.[7]

RET Mutations in MEN2

More than 100 alterations have been described in patients with hereditary MTC. The vast majority of mutations in patients with MEN2A occur in exons 10 and 11, which encode the cysteine-rich domain of RET. Mutations in exons 8, 13, 14, 15, and 16 are also known to cause MEN2A. A single 918 Met-to-Thr mutation (M918T) in exon 16 is responsible for more than 95% of cases of MEN2B.[8] The remaining cases (<5%) occur due to a mutation in exon 15 (A883F). Both codons 15 and 16 form the intracellular TK2 domain.

There is a strong correlation between the genotype and clinical features (phenotype) in MEN2A and MEN2B with respect to the risk of developing MTC and its behavior, the occurrence of other neoplasms, and nonendocrine features, as illustrated by Table 1.[5][9]

Table

Table 1: Common RET Mutations and Their Associated Risk of Medullary Thyroid Cancer, Pheochromocytoma, Hyperparathyroidism, Cutaneous Lichen Amyloidosis, and Hirschsprung Disease.

Epidemiology

With an estimated prevalence of 1 in 40,000, MEN2A accounts for about 95% of cases of MEN2. MEN2B is extremely rare, with an estimated prevalence of 1 per 600,000 to 4 million people.[9]

Pathophysiology

Individuals with both MEN2A and MEN2B are at elevated risk of developing multicentric tumors. Some individuals may also demonstrate involvement of nonendocrine organs. The following structures are most commonly involved:

Thyroid Gland

Medullary thyroid cancer (MTC) is a calcitonin-secreting malignant tumor arising from the C-cells or parafollicular cells of the thyroid gland. Although it comprises 4% to 7% of thyroid cancers, it is responsible for 15% of all deaths from thyroid cancer.[10][11] Unlike other thyroid neoplasms, MTC is a neuroendocrine tumor because C cells, arising from ultimobranchial bodies, are derived from neural crest tissue. On histopathology, MTC appears as nests of round or spindle-shaped tumor cells in a vascular stroma. (See Image. Medullary Carcinoma of the Thyroid). More than half of MTCs exhibit a characteristic deposition of amyloid (composed of calcitonin) with the classical apple-green birefringence on Congo red staining (See Image. Medullary Thyroid Cancer.) These cells stain positively for cytokeratins (CK7 and CK18) and thyroid transcription factor 1 on immunohistochemistry. However, the diagnosis of MTC requires demonstrating specific markers, such as calcitonin (Ctn), carcinoembryonic antigen (CEA), and chromogranin A, and the absence of thyroglobulin by immunohistochemistry.[5]

About 75% of MTCs are sporadic, and the remaining 25% are considered hereditary. Sporadic MTCs are generally unifocal in origin and are diagnosed in the fourth to sixth decades of life. By contrast, hereditary or familial MTCs occur within the first to third decades of life. Nearly 100% of patients with MEN2A and MEN2B eventually develop MTC, often heralding the diagnosis of MEN in these individuals. Familial MTC is mostly multicentric in origin and arises in the background of a premalignant entity called C-cell hyperplasia. C-cell hyperplasia is considered distinct from reactive secondary C-cell proliferation, in which multifocal nests of atypical C cells extend beyond the basement membrane and invade the surrounding stroma or follicles. The following criteria are used to define C-cell hyperplasia:

• An increased number of diffusely scattered cells, numbering more than 7 per cluster
• Complete surrounding of thyroid follicles by C cells
• Distribution of C cells beyond the normal anatomic location, normally restricted to the junction of the upper third and lower two-thirds of the lateral thyroid lobes

Identification of C-cell hyperplasia on histopathology in a patient initially suspected of having sporadic MTC should prompt evaluation for RET germline mutations.[5][10]

Adrenal Glands

Pheochromocytomas are predominantly benign neuroendocrine tumors arising from the adrenal medulla, another derivative of neural crest cells. Up to 50% of patients with MEN2B and MEN2A, depending on the underlying RET mutation, develop pheochromocytomas, which are mostly multicentric and bilateral. Although pheochromocytomas are frequently identified during routine screening in patients with known or suspected MEN2, they can be the initial manifestation in a minority of patients.

In a series of 85 patients with MEN2A or MEN2B and a history of pheochromocytoma, the median age at diagnosis was 32 years, and the majority had bilateral pheochromocytomas (72%). Among these patients, 6% presented with pheochromocytoma without prior MTC, while 34% had synchronous MTC and pheochromocytoma at index presentation.[12] Pheochromocytomas arising in patients with MEN2 may be associated with diffuse nodular adrenal medullary hyperplasia, particularly in patients with RET germline mutations in codons 918 and 634. Up to half of patients with unilateral pheochromocytoma eventually develop a contralateral tumor within 10 years.[13]

Parathyroid Glands

Primary hyperparathyroidism occurs in approximately 25% of patients with MEN2A and is not a feature of MEN2B. Unlike with MEN1, primary hyperparathyroidism in MEN2A is often mild and frequently asymptomatic. Some RET mutations, particularly those involving exon 11, have a higher penetrance. Between 1 and all 4 glands may be enlarged, often identified only at the time of thyroidectomy in patients with normal calcium levels. In results from a recent study involving a nationwide cohort of 204 patients with MEN2A, only 16 patients (8%) were found to have primary hyperparathyroidism, with a median age at diagnosis of 45 years. Seventy-five percent of patients with hyperparathyroidism were asymptomatic, and 69% were successfully treated after a surgical procedure.[14]

Skin

Cutaneous lichen amyloidosis (CLA), also known as lichen planus amyloidosis, is a rare skin condition that may occur sporadically or in association with other disorders. CLA is believed to represent a neuropathic process, and affected patients usually present with pruritus that improves with sun exposure and worsens with stress. Pruritus is followed by the development of pigmented, scaly lesions in the interscapular region, dermatomes T2 to T6, secondary to excoriation. CLA has been found in certain patients with MEN2A, almost exclusively those with RET codon 634 mutations.[15] As 1 of 4 MEN2A variants, CLA may even precede MTC in some patients.[5]

Gastrointestinal Tract

Hirschsprung disease (HD), also known as congenital aganglionic megacolon, is characterized by the failure of neural crest cells to migrate and innervate all intestinal segments, resulting in the absence of ganglionic cells and functional obstruction of the affected large-bowel segment, typically the most distal segment. HD may occur in up to 7% of patients with MEN2A, and all have mutations in exon 10 of RET. Although most patients with HD are diagnosed in infancy, HD should be considered in the differential diagnosis of older patients with MEN2A and persistent constipation. Similarly, 2% to 5% of patients with HD may have MEN2A.[5] Conversely, a considerable proportion of patients with MEN2B exhibit mucosal neuromas on the lips and tongue or intestinal ganglioneuromas, which are defining clinical features of the syndrome. These patients may also have gastrointestinal symptoms and occasionally develop intestinal obstruction, but not from HD.

Musculoskeletal

Patients with MEN2B may exhibit a unique physical appearance with distinctive facial features, including a long and narrow face with enlarged lips, and skeletal malformations, including Marfanoid body habitus, high-arched palate, kyphoscoliosis and lordosis, pectus excavatum, pes cavus, joint hypermobility, and slipped capital femoral epiphyses. The presence of these phenotypic features should prompt testing for MEN2B, because MTC can develop within the first year of life, and these tumors are highly aggressive.

Ophthalmologic

Prominent or medullated corneal nerves and the inability to produce tears during crying are clinical findings that can help diagnose MEN2B. Mild ptosis and thick, everted eyelids have also been reported.

History and Physical

A detailed history, including past and current comorbidities and an extensive family history spanning multiple generations, is essential for establishing a diagnosis of MEN2 and guiding genetic counseling for family members. MTC most commonly presents as a solitary thyroid nodule with or without adjacent cervical lymphadenopathy. The tumor may cause compressive symptoms and complications by invading surrounding structures, such as the recurrent laryngeal nerves, the aerodigestive tract, or nerves supplying the upper extremity. Rarely, diarrhea and facial flushing may occur due to excessive production of hormones by the tumor, including calcitonin.[10] MTC may also secrete corticotropin-releasing hormone or adrenocorticotropic hormone, causing ectopic Cushing syndrome as a paraneoplastic disease. 

Pheochromocytoma may present with classic clinical features such as paroxysmal spells of headache, anxiety, diaphoresis, palpitations, and hypertension that occur due to episodes of catecholamine release. Although hyperparathyroidism in MEN2A is generally not severe, symptoms of hypercalcemia, such as polyuria, polydipsia, constipation, weakness, neuropsychiatric effects and confusion, nausea and vomiting, fatigue, anorexia, nephrolithiasis, renal dysfunction, peptic ulcers, and pancreatitis, should be sought. Untreated hyperparathyroidism with prolonged bone loss may result in osteopenia or osteoporosis with subsequent fragility fractures.

In addition to examining the neck (including the thyroid gland, cervical lymph nodes, and parathyroid glands) and the abdomen, certain physical findings should be sought in patients suspected of having MEN2. The presence of pruritic, scaly papules in the interscapular region, consistent with CLA, may point toward MEN2A. Certain facial features, including narrow facies with enlarged lips, Marfanoid body habitus, mucosal neuromas of the lips and tongue, joint laxity, ectopic lens, and poor dentition, could also suggest MEN2B.

The clinical diagnosis of MEN2A is established upon finding 2 or more MEN2A-associated tumors, MTC, pheochromocytoma, or parathyroid adenoma or hyperplasia, in a single individual or in close relatives. Similarly, MEN2B can be clinically diagnosed in the presence of MTC, pheochromocytoma, mucosal neuromas of the lips and tongue, medullated or prominent corneal nerve fibers, facial features, Marfanoid habitus, or the inability to produce tears when crying. A rare minority of these patients may lack any detectable RET mutations.

Evaluation

Genetic Testing for MEN2

The diagnoses of MEN2A and MEN2B should be considered in all cases of MTC, even those initially considered sporadic, and these patients should undergo testing for germline RET mutations. Other indications for genetic testing include:

• First-degree relatives of patients with proven hereditary MTC
• Parents whose infants or young children have the clinical features of MEN2B
• Patients with CLA
• Infants or young children with HD and germline exon 10 RET mutations, as well as adults with MEN2A due to exon 10 mutations and symptoms suggestive of HD [5]

All pheochromocytomas and paragangliomas should also undergo genetic analysis; this approach may sometimes identify MEN2 before the development of MTC. MEN2 may therefore be identified through this evaluation before MTC develops. A diagnosis of isolated primary hyperparathyroidism does not warrant additional testing for MEN2A.[16]  

Targeted testing can be offered to individuals in a family with hereditary MTC or MEN2 in which a RET mutation has already been identified. In index cases of suspected MEN2A, the revised American Thyroid Association (ATA) guidelines (initially published in 2015) recommend genetic testing for RET mutations in exons 10 and 11, followed by exons 8, 13, 14, 15, and 16. This approach accounts for the most common hotspot mutations. Similarly, for index patients with a MEN2B phenotype, a stepwise approach was recommended, testing for M918T in exon 16 followed by A883F in exon 15. Sequencing the entire coding region was recommended only in patients with a clinical diagnosis of MEN2 in whom tiered genetic testing did not identify mutations, or in whom clinicians suspected a significant discrepancy between the detected mutation and phenotype, to minimize cost.[5] Over the past decade, with ongoing advances in genetic testing and falling costs, sequencing the entire RET gene at the onset can be considered. 

Evaluation of Medullary Thyroid Cancer 

Thyroid nodules are evaluated by ultrasonography to determine the need for fine-needle aspiration biopsy based on both size and appearance, with different systems proposed by the ATA [17] and the American College of Radiology (ACR); the latter is the Thyroid Imaging Reporting and Data System.[18] In addition to microscopic examination and immunohistochemistry, the diagnostic accuracy of fine-needle aspiration can be enhanced by measuring calcitonin (Ctn) levels in the FNA washout fluid. Results from a meta-analysis of 6 studies showed a pooled sensitivity of 54% for FNA cytology alone, which increased to 98% when Ctn levels in FNA washout fluid were used to diagnose MTC.[19]

In addition to genetic counseling and RET mutation testing, all patients with a confirmed diagnosis of MTC should undergo neck ultrasonography and have baseline Ctn and CEA levels measured. Metastatic disease should be suspected in patients with extensive neck disease, compatible symptoms and signs, or a Ctn level greater than 500 pg/mL. In such cases, cross-sectional imaging with contrast-enhanced computed tomography or magnetic resonance imaging should be pursued.[5]

Evaluation of Pheochromocytoma

Pheochromocytomas in patients with MEN2 generally occur in the third or fourth decade of life. Patients with MEN2 who are planning to undergo an interventional procedure, including thyroidectomy for MTC, or who may become pregnant, should undergo testing to exclude a pheochromocytoma, even if asymptomatic. A catecholamine-induced hypertensive crisis in a previously unrecognized pheochromocytoma can be associated with significant morbidity and mortality.[20] The demonstration of elevated plasma fractionated metanephrines has a sensitivity of 97% and a specificity of 93% for diagnosing pheochromocytoma.[16] High levels of urinary fractionated metanephrines and catecholamines can also be used to establish the diagnosis, but require a 24-hour urine collection. After elevated catecholamine levels have been demonstrated, a contrast-enhanced computed tomography scan of the abdomen and pelvis should be obtained; magnetic resonance imaging is an acceptable alternative.

Evaluation of Hyperparathyroidism

Hyperparathyroidism (associated only with MEN2A) is often mild and asymptomatic, with a median age at diagnosis of 33.7 years.[5] All patients who test positive for a RET mutation should undergo evaluation for hyperparathyroidism at the time of diagnosis. Only 25% of patients with evidence of hyperparathyroidism on investigations may be symptomatic when diagnosed.[14] After demonstrating hypercalcemia by measuring serum calcium levels, corrected for albumin or directly as ionized calcium, the presence of concurrent high or inappropriately normal parathyroid hormone levels confirms the diagnosis. Preoperative imaging to localize the hyperfunctioning gland (s) can be obtained with ultrasonography, computed tomography, or technetium 99m (Tc99m)-sestamibi, especially in patients who develop hyperparathyroidism after a prior thyroidectomy.[5]  

Treatment / Management

Screening for Medullary Thyroid Cancer in MEN2

Virtually all patients with MEN2 eventually develop MTC. Because MTC is considered a systemic disease and is rarely curable once regional lymph node metastases occur, the goal of treatment should be prophylactic thyroidectomy to intervene before the overt spread of MTC beyond the thyroid gland. The timing of surveillance and prophylactic thyroidectomy in patients diagnosed with MEN2 is determined by the underlying RET mutation (see Table 2). Surveillance includes an annual physical examination, neck ultrasonography, and measurement of serum Ctn levels. Stimulated Ctn levels following intravenous calcium or pentagastrin infusions may be obtained to inform the decision to proceed with thyroidectomy, although there are no established cutoffs, and reference ranges for basal Ctn levels vary by assay and laboratory.[5] Patients with RET mutations classified as moderate risk may require surveillance for several decades. The option of a thyroidectomy, starting at an early age, instead of long-term surveillance, should be discussed with the child’s parents using shared decision-making.

Table

Table 2: Revised American Thyroid Association Guidelines for Surveillance and Prophylactic Thyroidectomy for Medullary Thyroid Cancer in Patients with MEN2 .

 Reference for the table.[5][10]

Screening for Pheochromocytoma and Hyperparathyroidism in MEN2

Screening for pheochromocytoma is performed using biochemical studies, usually measuring free plasma metanephrines and normetanephrines, or 24-hour urinary metanephrines and normetanephrines, followed by imaging of the adrenal glands with computed tomography or magnetic resonance imaging if screening results are positive. As mentioned earlier, all patients with MEN2 planning to undergo an elective procedure or conceive (for women) should be tested to exclude a pheochromocytoma and the risk of a hypertensive crisis. The ATA recommends simultaneous surveillance for hyperparathyroidism using albumin-corrected or ionized calcium measurements, with or without PTH, when screening patients with MEN2A for pheochromocytomas.[5] The age at which screening should be offered depends on the pathogenic RET variant (see Table 3). The National Comprehensive Cancer Network (NCCN) recommends annual biochemical surveillance for pheochromocytomas.

Table

Table 3: Revised American Thyroid Association Guidelines for Surveillance of Pheochromocytoma and Hyperparathyroidism in Patients with MEN2 .

 Reference for the table.[5][10]

Management of Medullary Thyroid Cancer in MEN2

Surgical resection is the mainstay of treatment for both sporadic and hereditary MTC. Unlike patients with sporadic MTC who sometimes develop unilateral tumors amenable to lobectomy, patients with MEN2 are prone to developing multicentric tumors from premalignant C-cell hyperplasia, warranting total thyroidectomy. All patients with MEN2 should be screened for pheochromocytoma to avoid a hypertensive crisis and hyperparathyroidism, which may be addressed concurrently during the surgical procedure before undergoing thyroidectomy.

In patients with MTC and no evidence of cervical lymph node metastases on ultrasonography or distant metastases, a total thyroidectomy and bilateral central neck dissection (level VI lymph nodes) should be performed. Therapeutic ipsilateral or bilateral neck dissection of lateral cervical lymph nodes (levels II to V) should be pursued for clinically or radiologically identifiable disease. In the absence of demonstrable disease, Ctn levels may be used to guide decision-making regarding the extent of cervical lymph node dissection.[5][10] Because MTC is derived from C cells that do not concentrate iodine, there is no role for treatment or monitoring with iodine-131. Given that C cells also lack thyroid-stimulating hormone receptors, levothyroxine supplementation following thyroidectomy is provided solely to maintain euthyroidism, not for thyroid-stimulating hormone suppression, unlike in other thyroid cancers.

In the presence of locally advanced or metastatic disease, considered incurable, surgical resection, if pursued, should prioritize overall functioning, including speech, swallowing, parathyroid function, and shoulder mobility, over clearance, because the intervention is palliative in nature. Adjuvant external beam radiation therapy to the neck and mediastinum can be considered, but is associated with significant toxicities.[5] Ctn and CEA levels should be checked 3 months after the surgical procedure. If elevated, these tumor markers should be repeated at least semiannually to estimate the doubling time, an important independent prognostic factor. Ctn levels above 150 pg/mL following thyroidectomy should prompt imaging to detect distant metastases, with notable sites being the liver, lungs, bones, brain, and skin, if examination and ultrasonography of the neck are unrevealing.[10]

Surgical procedures, external beam radiation therapy, or focal ablative procedures are modalities that can be used to treat pain, mechanical compression, or signs and symptoms of hormonal excess arising from metastatic disease. Although systemic therapy for MTC in the form of tyrosine kinase inhibitors is available, these drugs should be used judiciously owing to their significant adverse effects and the fact that many patients with metastatic MTC may have stable disease that progresses slowly. In RET-mutated MTC, NCCN guidelines recommend treatment with 1 of 2 RET-specific inhibitors: selpercatinib or pralsetinib. The antiangiogenic multikinase inhibitors vandetanib and cabozantinib are also approved for the treatment of locally advanced or metastatic MTC.

Management of Pheochromocytoma in MEN2

After biochemical testing and imaging localization, surgical resection is the main treatment for pheochromocytoma. Before the surgical procedure, patients require treatment with combined α- and β-adrenergic blockade to optimize blood pressure and avoid catecholamine-induced hypertensive crises. Initial α-receptor blockade can be achieved with nonselective phenoxybenzamine or α1-selective doxazosin while liberalizing salt and fluid intake. β-Blockers are initiated thereafter.[16] 

A solitary pheochromocytoma can be treated with unilateral adrenalectomy, following which patients do not develop adrenal insufficiency. However, synchronous bilateral pheochromocytomas are common in patients with MEN2. Patients undergoing bilateral adrenalectomy require glucocorticoid coverage, stress dosing perioperatively, and lifelong mineralocorticoid and glucocorticoid replacement thereafter. These patients are also at risk of developing adrenal crisis. Partial or cortical-sparing adrenalectomy, retaining 10% to 15% of cortical tissue, preserves sufficient adrenal function to avoid glucocorticoid supplementation but is associated with a greater risk of tumor recurrence.[5][21]

Management of Hyperparathyroidism in MEN2A

The ATA and NCCN both recommend that in patients with MEN2A with hyperparathyroidism, only glands that are visibly enlarged be removed. Intraoperative parathyroid hormone monitoring can guide the surgical procedure, with normalization of PTH allowing for the operation to be confidently terminated. If all 4 glands appear enlarged, either a subtotal parathyroidectomy with preservation of a piece of 1 gland or a total parathyroidectomy with a heterotopic autograft may be performed to minimize the risk of developing subsequent hypoparathyroidism. Calcimimetic drugs, such as cinacalcet, can be considered for patients who are not good surgical candidates or have persistent hyperparathyroidism despite surgical intervention.[5]

Management of Other Manifestations of MEN2

The pruritus associated with CLA is difficult to treat, but local therapies, including moisturizing creams and lotions, topical corticosteroids, and phototherapy, and systemic therapies, including antihistamines, can be trialed. Pruritus may also improve with tyrosine kinase inhibitor therapy for MTC.[5] Surgical resection of the aganglionic bowel segment is the cornerstone of treatment for Hirschsprung disease.

Differential Diagnosis

The differential diagnosis includes:

• Multiple endocrine neoplasia type 1
• Familial hyperparathyroidism
• Familial hypocalciuric hypercalcemia
• Sturge-Weber syndrome
• Tuberous sclerosis
• Von Hippel-Lindau syndrome
• Neurofibromatosis type 1 (von Recklinghausen disease)

Prognosis

Following the identification of RET mutations in patients with MEN2 and the adoption of prophylactic thyroidectomy, mortality from MTC decreased from 15% to 20% to approximately 5% in more recent years.[22] Similarly, although the historical operative mortality for patients with pheochromocytoma approached 50%, the use of preoperative adrenergic blockade has drastically reduced the risks in patients who undergo appropriate preparation. Advances in surgical techniques, with the development of laparoscopic and retroperitoneoscopic approaches, have also reduced morbidity and hospital length of stay.[23][24]

Despite major advances in diagnosis and management, the average time to diagnosis for these patients may be as long as 4 years. Delayed diagnosis increases the risk of complications and worsening symptoms from undiagnosed neoplasms.[22] Patients with MEN2 may also experience significant impairment in their quality of life due to their symptoms and complex medical needs, which ultimately pose significant psychosocial burdens.

Complications

Medullary thyroid cancer, if untreated, metastasizes to the cervical lymph nodes as well as to distant organs, including the liver, lungs, bones, brain, and skin. Direct mechanical compression or invasion by the primary tumor or nodal metastases can involve the soft tissue, the aerodigestive tract, or surrounding nerves. Tumor involvement of these structures can result in debilitating symptoms, including respiratory distress from airway obstruction, loss of speech, altered swallowing, arm or shoulder dysfunction, and pain.

Metastases to distant sites can cause organ dysfunction by mechanical compression and invasion. Distant metastases are often painful and may not respond to medical therapy. Brain metastases can result in severe neurologic deficits and, despite treatment with a surgical procedure or radiation therapy, are usually lethal. Vertebral metastases may result in pathologic fractures and even spinal cord compression. Large or multiple lung and liver metastases may result in pain and bleeding. Patients with MEN2 and advanced liver disease due to metastases frequently develop severe diarrhea due to the secretion of hormones, including calcitonin. In addition to local therapies that address the disease burden, patients can be treated with antimotility agents, and some patients may also benefit from somatostatin analogs. Cushing syndrome may occur as a paraneoplastic disease due to ectopic production of adrenocorticotropic hormone or cosyntropin-releasing hormone. In addition to treatment of MTC, medical therapy to reduce cortisol production with ketoconazole, mifepristone, aminoglutethimide, metyrapone, or mitotane can be attempted. Bilateral adrenalectomy can be considered for patients who do not benefit from medical treatment.[5]

Apart from the risks associated with a catecholamine-induced hypertensive crisis,[20] catecholamine-producing tumors, such as pheochromocytomas and paragangliomas, may cause diverse cardiovascular complications in up to 28% of patients. Other acute complications include stress-induced takotsubo cardiomyopathy, myocardial infarction, and venous thromboembolism, whereas chronic damage occurs from accentuated atherosclerosis and arterial sclerosis, resulting in arterial hypertension. These tumors may also cause secondary diabetes mellitus through increased insulin resistance.[25] Uncontrolled hypercalcemia from primary hyperparathyroidism may present with symptoms of polyuria, polydipsia, dyspepsia, nausea, muscle weakness, constipation, fatigue, and generalized weakness. Other complications include osteopenia or osteoporosis with pathological fractures, nephrolithiasis, nephrocalcinosis, renal dysfunction, peptic ulcer disease, and pancreatitis.[14]  

Deterrence and Patient Education

All patients with suspected MEN2 should undergo genetic counseling prior to testing. If patients are found to have a germline RET mutation, genetic counseling should also be offered to their first-degree relatives, followed by testing with informed consent. The ATA specifically recommends that children with MEN2 be referred to tertiary centers with experienced teams for treatment.[5] These centers of expertise can provide optimal treatment and continuity of care, including addressing the unique psychosocial challenges that these patients face.[22]

With the growing use of glucagon-like peptide-1 receptor agonists (GLP-1RA) for the treatment of type 2 diabetes mellitus and obesity, clinicians should recognize that the US Food and Drug Administration issued a boxed warning against the use of these medications in patients with a personal or family history of MTC, including associated hereditary conditions such as MEN2. The boxed warning was based on rodent studies demonstrating a link between GLP-1RA use and the development of MTC.[26] Although data regarding the risk of thyroid cancer in humans treated with GLP-1RA are conflicting, patients with a personal or family history of MEN2 have been excluded from clinical trials and should be counseled about the risk these medications may pose, given their inherent elevated risk of developing MTC.  

Enhancing Healthcare Team Outcomes

Almost all patients diagnosed with MEN2 will eventually develop MTC, as well as neoplasms involving other endocrine glands. A confirmed diagnosis warrants the testing of first-degree relatives after genetic counseling. Early recognition and diagnosis of affected individuals require a collaborative approach among health care professionals to ensure patient-centered care and reduce mortality and morbidity.

Clinicians, surgeons, specialty nurses, clinical geneticists, counselors, and pharmacists, along with other health care professionals, play an essential role in the diagnosis, evaluation, and treatment of these patients. Treatment is complex, requiring multiple biochemical and radiologic studies at frequent intervals beginning in childhood, even infancy, lifelong monitoring, and possibly several surgical procedures. Coordination of care and an interdisciplinary approach are essential to ultimately improve patient outcomes and enhance team performance in the treatment of patients with MEN2.

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References

1.

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Disclosure: Devraj Lath declares no relevant financial relationships with ineligible companies.

Disclosure: Catherine Anastasopoulou declares no relevant financial relationships with ineligible companies.

Disclosure: Anup Kasi declares no relevant financial relationships with ineligible companies.