MOLECULAR-BASED MEDICAL MANAGEMENT IN MEN 2
RET testing in MEN 2 is considered the paradigm for the practice of clinical cancer genetics. Since RET mutations have been identified in >95 % of individuals with MEN 2, RET gene testing as a molecular diagnostic and predictive test is standard practice (Eng et al. 1996a, b, 2001; Kloos et al. 2009). In addition, all cases of MTC, irrespective of syndromic features or family history, should be offered RET gene testing in the setting of clinical cancer genetic consultation if possible.
In a MEN 2 family without a known mutation, RET testing should begin with an affected individual. Once a family-specific mutation is found, all at- risk family members should be offered testing before the age of 5 years in MEN 2A/ FMTC and before the age of 2 years, preferably within the first year, in MEN 2B (Kloos et al. 2009). For those individuals found to have a mutation, a prophylactic total thyroidectomy is recommended for all MEN 2 subtypes. This should be completed before the age of 5–6 years for MEN 2A/FMTC and before the age of 2 years, some believe 6 months, for MEN 2B (Wells et al. 1994; Kloos et al. 2009). The precise timing of prophylactic surgery remains controversial for FMTC, and in cases with codon 609, 768, and 804 mutations, which seem to have a lower penetrance and perhaps later onset of MTC (Eng et al. 1996a, b; Shannon et al. 1999; Frank-Raue et al. 2011), current ATA Guidelines suggest that prophylactic thyroidectomy can wait beyond age 5 if basal/stimulated calcitonins and neck ultrasounds are normal (Kloos et al. 2009). Clinical surveillance following thyroidectomy is dictated by what is found during the surgery. If the patient is found to have invasive MTC at the time of surgery, screening should include calcium-stimulated calcitonin testing every 3–6 months for the first 2 years, every 6 months from 3 to 5 years after surgery, and then annually. If only a small focus of MTC is found at the time of surgery, follow-up screening should involve annual basal (unstimulated) calcitonin for 5–10 years. If no cancer is present in the thyroid at the time of prophylactic surgery, no follow-up screening is indicated, even if C cell hyperplasia is present. All individuals who have undergone thyroidectomy need thyroid hormone replacement therapy and monitoring.
MEN 2-related PC almost always occurs after MTC. All mutation-positive individuals should undergo annual screening for PC beginning at 6 years. This usually consists of 24-h urine studies for VMA, metanephrines, and catecholamines. Some centers also advocate annual serum measurements for catecholamine levels and chromogranin-A. Abdominal ultrasound or CT/MRI scans for routine surveillance remains controversial.
In MEN 2, HPT is usually later onset and has age-related penetrance (Schuffenecker et al. 1998; Frank-Raue et al. 2011). Clinical surveillance in MEN 2A includes annual measurement of serum ionized calcium and intact parathyroid hormone levels beginning at the time of MEN 2 diagnosis. Once HPT is detected, removal of all four parathyroid glands is necessary. At that time or at the time of thyroidectomy, whichever occurs first, all glands and the thymus are removed. Half of the parathyroid gland should be pulverized and autografted into an easily accessible muscle of the arm or neck to control the body’s calcium levels and can be easily removed should HPT recur (Wells et al. 1994; Kloos et al. 2009). Since clinically evident HPT is rare in MEN 2B, parathyroid screening is not generally recommended for this subtype.
Management of RET mutation-negative MEN 2 families remains a conundrum. If there are sufficient clinically affected members in such families, linkage analysis using 10q11 markers within and around RET could be performed. In the event that the family is not large enough or informative for linkage, then management should follow that in the pre-RET testing era, and at-risk individuals should undergo annual screening for MTC (stimulated calcitonin screening), PC, and HPT from the age of 6–35 years. Prophylactic thyroidectomy is usually not routinely offered to this subgroup.