Is pheochromocytoma screening recommended before surgery for medullary thyroid carcinoma (MTC), especially in patients with a family history of multiple endocrine neoplasia (MEN) 2A or 2B syndromes?

Pheochromocytoma Screening Before Medullary Thyroid Carcinoma Surgery

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

Mandatory Screening Populations

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
• All patients with MEN 2B (codon 918,883, or compound heterozygous mutations) 1
• All patients with familial medullary thyroid carcinoma 1
• Screening must occur before any planned surgery and pregnancy, regardless of age 1, 2

The rationale is critical: pheochromocytoma occurs in approximately 50% of MEN 2 patients overall, with variable penetrance from 10-80% depending on the specific RET mutation 3. Unrecognized pheochromocytoma can cause fatal hypertensive crisis during surgery 1, 2.

Biochemical Testing Protocol

The recommended screening tests are:

• Plasma free metanephrines and normetanephrines (sensitivity approximately 100% for both sporadic and familial pheochromocytomas) 2
• 24-hour urinary fractionated metanephrines (sensitivity 86-97%, specificity 86-95%) as an acceptable alternative 1

For optimal accuracy, plasma free metanephrines should ideally be collected from an indwelling venous catheter after the patient has been lying supine for 30 minutes to limit false positive results 1. However, in the context of pre-surgical screening for known MEN 2 patients, standard venipuncture is acceptable given the high pre-test probability 2.

Critical Management Sequence

If pheochromocytoma is detected, the following sequence is mandatory:

1. Pre-operative alpha-adrenergic blockade must be initiated 7-14 days before any surgery, with gradually increasing dosages until blood pressure targets are achieved 1, 2
2. The pheochromocytoma must be removed first (with appropriate alpha-blockade) before proceeding to thyroidectomy for MTC 2
3. Never perform beta-blockade alone before alpha-blockade, as this can precipitate severe hypertensive crisis due to unopposed alpha-adrenergic stimulation 4

This sequence is non-negotiable because the mortality risk from unrecognized pheochromocytoma during surgery far exceeds any delay in MTC treatment 1, 5.

Timing and Natural History Considerations

The chronology of pheochromocytoma relative to MTC varies significantly:

• Pheochromocytoma occurs first in 25.1% of MEN 2 cases (2-15 years before MTC diagnosis) 5
• Pheochromocytoma occurs after MTC in 40.2% of cases (2-11 years later) 5
• Both are diagnosed simultaneously in 34.7% of cases 5
• Mean age at pheochromocytoma diagnosis is 39.5 years in MEN 2A and 32.4 years in MEN 2B 5

This variable timing underscores why screening cannot be omitted based on patient age or MTC status alone 5, 3.

Bilateral Disease and Malignancy Risk

Important characteristics of MEN 2-related pheochromocytoma:

• Bilateral involvement occurs in 67.8% of cases 5
• Malignancy rate is only 4% in MEN 2-related pheochromocytoma 5
• SDHB mutations (not typical in MEN 2) are associated with higher malignancy risk and require more intensive surveillance 4

Mortality Data Supporting Mandatory Screening

The consequences of undetected pheochromocytoma are severe:

• Among 39 deaths in 300 MEN 2 patients with pheochromocytoma, 64.1% were linked to pheochromocytoma complications, compared to only 23.1% from MTC 5
• This mortality pattern demonstrates that pheochromocytoma poses a greater immediate threat than MTC in many cases 5

Common Pitfalls to Avoid

Critical errors that must be prevented:

• Never perform adrenal biopsy without excluding pheochromocytoma first, as this can trigger life-threatening hypertensive crisis 4, 2
• Never proceed to imaging (especially contrast-enhanced CT) without biochemical confirmation, as contrast can precipitate catecholamine crisis 4
• Never assume absence of pheochromocytoma based on lack of symptoms—clinical expression can be poor in MEN 2 patients 5
• Never perform thyroidectomy before addressing confirmed pheochromocytoma 2

Ongoing Surveillance Requirements

After initial screening and surgery:

• 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 1

The evidence overwhelmingly supports mandatory pheochromocytoma screening before any surgery in MEN 2-related MTC, with proper alpha-blockade and sequential surgical management when pheochromocytoma is detected 1, 2, 5.