Pheochromocytoma Screening and Management in Medullary Thyroid Carcinoma

Mandatory Screening Populations

The National Comprehensive Cancer Network recommends that all patients with medullary thyroid carcinoma (MTC) who have MEN 2A, MEN 2B, or familial MTC must undergo pheochromocytoma screening before any planned surgery, regardless of age, and any detected pheochromocytoma must be treated first to prevent life-threatening intra-operative hypertensive crisis 1, 2
Pheochromocytoma screening is absolutely required for all patients with germline RET proto-oncogene mutations associated with MEN 2A (codons 609, 611, 618, 620, 630, 634, 768, 790, 791, 804, or 891) 1, 2
Pheochromocytoma screening is also required for all patients with MEN 2B (codon 918, 883, or compound heterozygous mutations) and all patients with familial medullary thyroid carcinoma 1, 2
Screening must occur before any planned surgery and pregnancy, regardless of age 3, 4

The recommended screening tests are plasma free metanephrines and normetanephrines (sensitivity approximately 100% for both sporadic and familial pheochromocytomas) 5
24-hour urinary fractionated metanephrines (sensitivity 86-97%, specificity 86-95%) are an acceptable alternative 3, 4

Pre-operative alpha-adrenergic blockade must be initiated 7-14 days before any surgery, with gradually increasing dosages until blood pressure targets are achieved 3, 4, 5
The pheochromocytoma must be removed first (with appropriate alpha-blockade) before proceeding to thyroidectomy for MTC 5
Never perform beta-blockade alone before alpha-blockade, as this can precipitate severe hypertensive crisis due to unopposed alpha-adrenergic stimulation 6

Never perform adrenal biopsy without excluding pheochromocytoma first, as this can trigger life-threatening hypertensive crisis 6, 5
Never proceed to imaging (especially contrast-enhanced CT) without biochemical confirmation, as contrast can precipitate catecholamine crisis 6
Never perform thyroidectomy before addressing confirmed pheochromocytoma 5

Annual biochemical screening for pheochromocytoma should continue lifelong in MEN 2A and 2B patients 1
For some lower-risk RET mutations (codons 768, 790, 804, or 891), less frequent screening may be appropriate 1
Screening should commence at age 11 years for carriers of "high" and "highest" risk alleles, and at age 16 years for "moderate" risk alleles 3, 4

Plasma free metanephrines (and normetanephrines) are the preferred first‑line screening tests for MEN2A patients after thyroidectomy, offering the highest sensitivity and negative predictive value 7.
24‑hour urinary fractionated metanephrines are an acceptable alternative, especially in pediatric patients or when plasma collection is impractical 7.
Plasma free metanephrines achieve 97–100 % sensitivity for detecting MEN2‑associated pheochromocytomas 7.
Urinary fractionated metanephrines provide 86–97 % sensitivity, which remains superior to catecholamine measurements 7.

Annual biochemical screening should begin at age 11 for individuals carrying “high” or “highest” risk RET mutations (codons 883, 918, 922, 609, 611, 620, 630, 634, 804, 891) 7.
Screening should start at age 16 for carriers of “moderate” risk RET mutations (codons 768, 790, 791) 7.
Lifelong yearly surveillance is required even after total thyroidectomy, because pheochromocytomas typically develop later than medullary thyroid carcinoma in MEN2A 7.

Biochemical screening for pheochromocytoma must be performed before any planned surgery or pregnancy, irrespective of patient age or time since thyroidectomy 7.
Imaging of the adrenal glands should only be undertaken after a positive biochemical test; performing imaging without prior biochemical confirmation is discouraged 7.

Approximately 30–50 % of MEN2‑associated pheochromocytomas are bilateral at initial diagnosis, with additional cases developing contralateral tumors during follow‑up 7.
Because of the high bilateral occurrence, both adrenal glands must be imaged when biochemical testing is positive 7.