Most calcitonin cases are sporadic and present as a new thyroid nodule. The workup proceeds similarly to that of non-medullary thyroid cancers. Detailed assessment of personal and family history and physical examination is followed up with thyroid ultrasound and FNA.

All patients with confirmed or suspected medullary thyroid cancers should also have measurements of serum calcitonin and CEA. Calcitonin is not only useful for detection of MEN2B s but prognostication as well since very high calcitonin levels correlates with a higher stage of disease. Both CEA and calcitonin are followed post-treatment to determine the success of treatment and to monitor for recurrence. Routine calcitonin testing as part of the workup for thyroid nodules without suggestive features of MTC is helpful.

The MEN2 syndromes were originally known as Sipple syndrome when the tumor constellation comprising of pheochromocytoma, medullary thyroid cancers and parathyroid adenoma was first described in 1961. As understanding of this syndrome increased, it became recognized that there are distinct variants of MEN2: MEN2A and MEN2B. Both are caused by pathogenic activating mutations of the proto-oncogene RET. The RET gene is located on chromosome 10q11.2 and codes for a transmembrane receptor tyrosine kinase involved in many cell-signaling pathways. Mutations causing constitutive activation of this kinase promote cell proliferation, survival and migration, often leading to tumorigenesis. The distinct differences between the different variants of MEN2 are largely determined by the location of the mutation.

MEN2A

Based on the American Thyroid Association recommendations on MTC, there are 4 variants of MEN2A: classical MEN2A, MEN2A with cutaneous lichen amyloidosis (MEN2A with CLA), MEN2A with Hirschsprung’s disease (MEN2A with HD), and Familial Medullary Thyroid Cancer (FMTC).

Classical MEN2A Classical MEN2A is the most common variant of MEN2A and represents the phenotype that was originally described by Sipple. It most commonly involves RET mutations in exons 10 or 11. Nearly 100% of patients will develop medullary thyroid cancers while rates of pheochromocytoma and primary hyperparathyroidism vary based on the specific RET mutation. Codon 634 mutations in exon 11 are associated with higher rates of pheochromocytoma and hyperparathyroidism. Overall, about 50% of patients with classical MEN2A will develop pheochromocytoma and 20-30% will have parathyroid disease.

The parathyroid disease in MEN2A is usually in the form of benign parathyroid adenomas and less often multi-gland hyperplasia. Patients are often asymptomatic or have mild symptoms. Severe clinical hyperparathyroidism is rare in MEN2A. If detected prior to or concurrently with medullary thyroid cancers, most cases of hyperthyroidism can be treated with parathyroidectomy at the time of surgery for medullary thyroid cancers.

The pheochromocytomas of MEN2A are usually benign and bilateral, though about 4% are malignant. Pheochromocytoma can be the first expression of MEN2 syndromes, and diagnosis of a pheochromocytoma should prompt evaluation for a RET mutation. If discovered concurrently with MTC, pheochromocytomas must be treated first. Symptomatic blood pressure control is initially achieved with alpha-blockers such as phenoxybenzamine. Occasionally beta-blockade is required to treat the reflex tachycardia caused by alpha-blockade. Surgical resection of the pheochromocytoma is performed after blood pressure has been normalized.

MEN2B

MEN2B manifests early, usually within the first year of life. MEN2B can develop in infancy and is typically highly aggressive with early metastasis. About 50-75% of MEN2B cases are caused by de novo mutations, and only 25-50% of cases occur within families with established histories of hereditary. 95% of MEN2B is caused by the M918T mutation in exon 16. Patients have long and narrow facies and develop lip and tongue mucosal neuromas. Skeletal abnormalities are common resulting in Marfanoid body habitus, chest malformations, scoliosis and joint deformities. Patients are also prone to ganglioneuromas of the gastrointestinal tract that may cause constipation, diarrhea, nausea, and even bowel obstructions that require surgery. Most mortalities result from advanced medullary thyroid cancer and establishing the diagnosis early is essential to timely treatment.

Hereditary pheochromocytoma and paraganglioma

A total of 10 pheochromocytoma or paraganglioma susceptibility genes have been identified to date: RET, VHL, NF1, SDHA, SDHAF2, SDHB, SDHC, SDCD, TMEM127 and MAX. Germline mutations in one of these 10 genes have been found in most hereditary cases and 10-20% of sporadic cases. Of note, MEN1 syndrome has also been very rarely associated with pheochromocytoma but is more typically linked to adrenocortical tumors. In addition to germline mutations in the pheochromocytoma susceptibility genes, many somatic mutations have been discovered in sporadic pheochromocytoma. All pheochromocytoma or paraganglioma -associated genes discovered to date can be grouped into 3 clusters.

Detailed personal and family history taking should focus on the presence of syndrome-associated features such as history of medullary thyroid cancer and hyperparathyroidism (MEN2); history of CNS hemangioblastomas and renal cell carcinomas (VHL), and history of GIST, papillary thyroid cancer, pituitary adenomas, and other neuroendocrine tumors (hereditary PPGL syndromes). Suspicion for a specific syndrome may be increased or decreased based on the presence of these associated features, and genetic testing can be targeted accordingly. Mutations in RET and VHL can be detected by single-gene testing. Testing for neurofibromatosis 1 typically involves chromosomal microarray analysis. Genetic testing for hereditary pheochromocytoma or paraganglioma syndromes can be performed with multigene panels that include all the known causative genes (SDHA, SDHAF2, SDHB, SDHC, SDCD, TMEM127, MAX).