Multiple Endocrine Neoplasia Medical Services in China

Multiple Endocrine Neoplasia (MEN) is a group of rare, inherited autosomal dominant disorders characterized by the development of tumors—often benign but sometimes malignant—in two or more endocrine glands. The three main clinical subtypes are MEN1, MEN2A, and MEN2B, each defined by distinct genetic mutations, tumor spectra, and natural histories. MEN1 is caused by inactivating mutations in the *MEN1* tumor suppressor gene on chromosome 11q13, leading to hyperplasia and neoplasia primarily in the parathyroid glands (90–95% prevalence), anterior pituitary (30–40%), and pancreaticoduodenal neuroendocrine tissues (30–80%, including gastrinomas, insulinomas, and non-functioning tumors). MEN2 syndromes arise from gain-of-function mutations in the *RET* proto-oncogene on chromosome 10q11.2; MEN2A features medullary thyroid carcinoma (MTC, nearly 100% penetrance), pheochromocytoma (50%), and primary hyperparathyroidism (20–30%), while MEN2B adds mucosal neuromas, marfanoid habitus, and aggressive MTC with early onset. Pathogenesis centers on dysregulated cell proliferation, apoptosis evasion, and hormone hypersecretion due to germline mutation-driven endocrine cell transformation. Epidemiologically, MEN1 affects approximately 1 in 30,000 individuals, with no gender predilection; MEN2 occurs in roughly 1 in 35,000–50,000. Penetrance is high (>95% for key components by age 50), and de novo mutations account for <5% of cases. Key risk factors include a confirmed pathogenic germline variant and a first-degree relative with MEN—making genetic counseling and predictive testing critical for at-risk family members. Diagnosis relies on clinical criteria, biochemical screening (e.g., serum calcium, PTH, prolactin, gastrin, calcitonin, metanephrines), imaging (MRI, CT, Ga-68 DOTATATE PET/CT), and confirmatory germline genetic testing. Untreated or suboptimally managed MEN significantly impairs quality of life: recurrent hypercalcemia causes fatigue, nephrolithiasis, and cognitive fog; hormone-secreting tumors provoke debilitating symptoms (e.g., Zollinger–Ellison syndrome diarrhea/ulcers, insulinoma-induced neuroglycopenia, pheochromocytoma-related hypertension crises); surgical interventions carry risks of hypoparathyroidism or adrenal insufficiency; and lifelong surveillance generates psychological burden, financial strain, and occupational limitations. Early diagnosis, risk-stratified prophylactic surgery (especially thyroidectomy in *RET* carriers), targeted medical therapies (e.g., everolimus for progressive pancreatic NETs, vandetanib for advanced MTC), and multidisciplinary care—including endocrinology, endocrine surgery, nuclear medicine, genetics, and oncology—are essential to mitigate morbidity, prevent metastatic disease, and preserve long-term function and well-being.

Multiple Endocrine Neoplasia (MEN) syndromes are rare, autosomal dominant hereditary disorders characterized by the development of tumors in two or more endocrine glands. The three principal subtypes—MEN1, MEN2A, and MEN2B—differ in genetic basis, tumor spectrum, and clinical behavior. MEN1 is caused by germline mutations in the *MEN1* tumor suppressor gene on chromosome 11q13 and commonly involves parathyroid adenomas (≥90%), pancreatic neuroendocrine tumors (pNETs; 30–80%), and pituitary adenomas (15–50%). MEN2A and MEN2B result from gain-of-function mutations in the *RET* proto-oncogene (chromosome 10q11.2); MEN2A features medullary thyroid carcinoma (MTC; nearly 100% penetrance), pheochromocytoma (50%), and primary hyperparathyroidism (20–30%), whereas MEN2B presents with aggressive MTC (earlier onset), pheochromocytoma, mucosal neuromas, and marfanoid habitus—but rarely parathyroid disease. Management requires lifelong, multidisciplinary surveillance and individualized intervention guided by genotype-phenotype correlations, tumor burden, functional status, and growth kinetics.

Conservative treatment forms the cornerstone of long-term care and emphasizes vigilant monitoring rather than immediate intervention. For asymptomatic or biochemically stable patients—particularly those with small, nonfunctional pNETs (<2 cm), microprolactinomas, or mild primary hyperparathyroidism—active surveillance is recommended. This includes annual serum calcium, intact PTH, fasting gastrin, insulin, glucagon, chromogranin A, plasma metanephrines, and calcitonin; biannual neck ultrasound; triennial abdominal MRI or contrast-enhanced CT for pNET screening; and periodic pituitary MRI and visual field testing. Surveillance intervals are intensified for high-risk *RET* codon mutations (e.g., M918T in MEN2B) or documented tumor progression. Lifestyle counseling—including calcium/vitamin D optimization, avoidance of dopamine antagonists in prolactinoma carriers, and strict blood pressure control in pheochromocytoma-prone individuals—is integral to conservative strategy.

Pharmacotherapy serves adjunctive or palliative roles but is rarely curative. Somatostatin analogues (octreotide LAR, lanreotide) are first-line for symptomatic, well-differentiated pNETs (e.g., insulinoma, gastrinoma) to control hormonal hypersecretion and slow tumor growth; they reduce diarrhea, flushing, and hypoglycemia while demonstrating antiproliferative effects in NETs expressing SSTR2/5. Tyrosine kinase inhibitors (vandetanib, cabozantinib) are FDA-approved for progressive, metastatic MTC refractory to surgery, improving progression-free survival by targeting RET, VEGFR2, and EGFR pathways. For prolactinomas, dopamine agonists (cabergoline, bromocriptine) normalize prolactin and shrink tumor volume in >80% of cases. Alpha- and beta-adrenergic blockade (phenoxybenzamine followed by propranolol or atenolol) is mandatory preoperatively in pheochromocytoma to prevent intraoperative catecholamine crisis. Calcimimetics (cinacalcet) may temporize hypercalcemia in MEN1-related hyperparathyroidism when surgery is contraindicated, though they do not prevent parathyroid hyperplasia progression.

Surgical treatment remains the only potentially curative modality and is dictated by syndrome subtype and tumor biology. Prophylactic total thyroidectomy is indicated in all *RET* mutation carriers: timing is risk-stratified—by age 5 years for highest-risk (MEN2B, codon M918T), by age 5–10 years for high-risk (MEN2A, codons C634, A883F), and by age 10–20 years for moderate-risk (codons G533C, V804M/L). Central lymph node dissection is performed concurrently if calcitonin elevation or nodal involvement is evident. For pheochromocytoma, laparoscopic adrenalectomy is standard; bilateral disease warrants cortical-sparing resection when feasible to avoid lifelong glucocorticoid dependence. Parathyroidectomy in MEN1 typically involves subtotal (3.5-gland) or total parathyroidectomy with autotransplantation, given the near-universal multiglandular hyperplasia. Pancreatic surgery is selective: enucleation for small, benign insulinomas; distal pancreatectomy ± spleen preservation for larger or multifocal pNETs; and Whipple procedure only for duodenal gastrinomas with local invasion. Pituitary surgery (transsphenoidal resection) is indicated for acromegaly, Cushing disease, or mass effect—not for incidental microadenomas.

Treatment advantages in China include centralized expertise at national referral centers (e.g., Peking Union Medical College Hospital, Shanghai Ruijin Hospital), where integrated endocrine-oncology-genetics teams deliver standardized, protocol-driven care aligned with international guidelines (ATA, ENETS, NANETS). China’s robust genomic infrastructure enables rapid, cost-effective *RET* and *MEN1* sequencing (turnaround <10 days), facilitating early diagnosis in probands and cascade testing in at-risk relatives. Minimally invasive surgical techniques—including robotic-assisted thyroidectomy and fluorescence-guided parathyroid mapping—are widely adopted in tier-1 hospitals, reducing complication rates (e.g., recurrent laryngeal nerve injury <1%, permanent hypoparathyroidism <5%). Moreover, China’s National Reimbursement Drug List includes vandetanib, octreotide LAR, and cabergoline, significantly improving accessibility compared to regional counterparts. Clinical trial participation is expanding, with Chinese sites actively enrolling in global phase III studies of novel RET inhibitors (e.g., selpercatinib, pralsetinib) and peptide receptor radionuclide therapy (¹⁷⁷Lu-DOTATATE) for advanced NETs.

Recovery advice emphasizes structured, lifelong follow-up. Patients must adhere strictly to scheduled biochemical and imaging surveillance—even after successful surgery—as recurrence or new primary tumors remain likely. Post-thyroidectomy, levothyroxine replacement is titrated to suppress TSH without inducing atrial fibrillation or osteoporosis; calcitonin and CEA monitoring continues every 6 months indefinitely. After parathyroid surgery, serum calcium and PTH require weekly checks initially, then quarterly, with oral calcium and calcitriol supplementation as needed until gland function stabilizes. All MEN patients should wear medical alert identification and carry emergency hydrocortisone kits if adrenalectomized. Genetic counseling is mandatory before family planning; prenatal testing and preimplantation genetic diagnosis are available. Psychosocial support—including peer networks facilitated by the Chinese Endocrine Society—is encouraged to mitigate anxiety related to chronic cancer risk. Finally, patients should avoid iodinated contrast media unless absolutely necessary (due to interference with radioactive iodine scans in MTC follow-up) and consult their endocrinologist before initiating any new medication, especially NSAIDs (gastrinoma risk) or calcium channel blockers (pheochromocytoma interaction). With coordinated, proactive management, 10-year survival exceeds 90% for MEN2A and 75% for MEN1—underscoring that precision surveillance and timely intervention transform MEN from a fatal prognosis into a chronically manageable condition.