Can additional studies be performed to determine whether a deceased relative's thyroid cancer was medullary thyroid carcinoma (MTC)?

Posthumous Testing for Medullary Thyroid Carcinoma in Deceased Relatives

Yes, archived tissue from the deceased relative's thyroid cancer can be tested for calcitonin immunohistochemistry and RET proto-oncogene mutations to definitively determine if it was MTC, which is critical for guiding genetic screening of living family members. 1

Why This Matters for Living Family Members

If the deceased relative had MTC, all first-degree relatives require immediate RET genetic testing regardless of symptoms, as 25% of MTC cases are hereditary with autosomal dominant inheritance, meaning each child has a 50% chance of carrying the mutation. 1, 2, 3

• RET proto-oncogene mutations are found in at least 95% of MEN2A kindreds and 88% of familial MTC cases. 1
• Early identification of RET mutation carriers allows for prophylactic thyroidectomy before MTC develops, which is often curative and dramatically reduces mortality. 1, 4
• Delays in diagnosis among MEN2 carriers are associated with significant increases in both morbidity and mortality. 1

Specific Testing Approach on Archived Tissue

Request the pathology department to perform calcitonin immunohistochemistry on the archived paraffin-embedded tissue blocks from the deceased relative's thyroid cancer. 1

• Medullary carcinoma may require additional immunohistochemical studies (specifically calcitonin staining) to confirm the diagnosis when the original pathology was unclear. 1
• If calcitonin immunohistochemistry is positive, request RET proto-oncogene mutation analysis on the same archived tissue to identify the specific familial mutation. 1
• This specific mutation identification is essential because it allows targeted "familial mutation testing" of at-risk relatives rather than comprehensive gene sequencing. 1

Critical Genotype-Phenotype Correlations

The specific RET codon mutation determines the aggressiveness of disease and timing of intervention for identified carriers. 1

• MEN2B (typically M918T mutation): MTC develops in early childhood with >95% lifetime risk; these patients do not develop hyperparathyroidism. 1
• MEN2A "High risk" alleles (commonly codon 634): MTC develops in adolescence/early adulthood with >95% lifetime risk, 50% risk of pheochromocytoma, and 20-30% risk of hyperparathyroidism. 1, 3
• "Moderate risk" alleles (codons 611,618,620): Later onset with 10-50% pheochromocytoma risk depending on specific allele. 1, 3

Screening Protocol for At-Risk Living Relatives

If MTC is confirmed in the deceased relative, living first-degree relatives require RET genetic testing starting at age 3-5 years for MEN2A, or during the first year of life for suspected MEN2B. 1, 4

• Before any surgical intervention in identified RET carriers, mandatory screening for pheochromocytoma (plasma metanephrines) must be performed, as 50% of MEN2 patients develop pheochromocytomas that can cause hypertensive crisis during surgery. 5
• Screen for hyperparathyroidism (calcium, PTH) in MEN2A carriers, as 20-30% develop this condition. 1, 5
• Genetic counseling should be provided to all family members before testing. 1

Common Pitfall to Avoid

Do not rely on calcitonin screening alone in living relatives without genetic testing, as approximately 6% of apparently sporadic MTC cases carry germline RET mutations, allowing new kindreds to be identified. 1 The traditional approach of pentagastrin or calcium stimulation testing is no longer recommended because pentagastrin is unavailable in the United States and elevated calcitonin is neither specific nor adequately sensitive for MTC. 1