The role of genetic screening in medullary thyroid cancer: a clinician’s view on the recent ATA guidelines

Abstract

The American Thyroid Association recently released its revised guidelines on the management of medullary thyroid carcinoma. This editorial highlights the American Thyroid Association recommendations on genetic screening for medullary thyroid carcinoma and briefly discusses the future perspectives from the clinician’s standpoint.

Keywords:

• medullary thyroid cancer
• MEN2
• mutation
• RET
• • thyroid

Medullary thyroid cancer (MTC) comprises 3–4% of all thyroid cancer types. Very recently, the American Thyroid Association (ATA) released its revised guidelines for the management of MTC in order to aid the clinicians caring for these patients [1].

A significant change of the revised guidelines is the re-classification of risk categories, changing the A through D classification to three new categories; specifically, risk D RET mutations (M918T in multiple endocrine neoplasia [MEN]2B individuals) now represent the ‘highest risk’ (HST) category, whereas risk C (including C634 mutations in MEN2A) is re-classified as ‘high risk’ (H) category. Finally, A and B risk categories are now combined in a new ‘moderate risk’ (MOD) category, for all RET codon mutations besides M918T and C634.

This change combined with the recommendations on prophylactic thyroidectomy give a clearer direction to the clinicians regarding the timing of thyroidectomy. Children in the ATA-HST category – with MEN2B harboring an M918T mutation – should undergo surgery in the first year of life, even in their first months, given the very aggressive course of the disease. The question of whether or not to perform central neck dissection depends on the risk of damage to the parathyroid glands; if they can be identified and left intact or auto-transplanted, a skilled surgeon should proceed with central compartment neck dissection. Thyroidectomy should be performed at age 5 years in children in the ATA-H category (with a C634 mutation), or earlier in case of elevated serum calcitonin levels, with annual screening (including physical examination, neck ultrasound and serum calcitonin measurement) starting at age 3 years. Factors prompting central neck dissection include elevated calcitonin levels (over 40 pg/ml) and documentation of abnormal lymph nodes on imaging. Lastly, children in the MOD category should be evaluated annually starting at around 5 years of age, since the disease shows significant variability.

An important issue that is also discussed is of non-compliance on a long-term evaluation program. It is possible that individuals at risk may become tired of repeated ultrasound and biochemical studies, leading to difficult or loss to follow-up, especially because they do not have any signs or symptoms of clinically evident disease [2]. The result is that they may seek medical evaluation many years later, when MTC has already developed and is possibly at an advanced stage. Therefore, the Guidelines Task Force recommends that parents of children in the ATA-MOD category may choose to proceed with thyroidectomy as early as 5 years of age, in consultation with the child’s pediatrician and surgeon, and draw special attention to the need for an experienced surgeon in a tertiary care center [1].

Inherited MTC is a rare disease with aggressive course involving children, a sensitive population, who are not capable of making decisions for themselves; age and stage of the disease at diagnosis are independent prognostic factors. Hence, ‘patient centricity’ and disease awareness are important aspects when caring for families with inherited MTC. It is important that clinicians and geneticists are in close contact with the parents, offering genetic counseling, clearly explaining the diagnostic and therapeutic approaches available for individuals at risk, as well as communicating prenatal and pre-implantation options to RET mutation carriers in order to prevent transmission of the disease. The recent guidelines provide a useful and easy-to-comprehend framework that can guide clinicians, even with modest background on genetics, in the management of MTC patients.

When clinicians select genetic screening in MTC, an important question that arises is which targets of the RET proto-oncogene to sequence in the DNA analysis. When the specific mutation in a family is unknown, the current recommendation is to analyze exon 10 (codons 609, 611, 618 and 620) and exon 11 (codons 630 and 634), where most mutations are found, followed by exons 8 and 13–16. The analysis could be either single or two-tiered, that is, analyze the most frequently mutated regions, and if the results are negative or inconsistent with the phenotype, then proceed with the remaining RET exons.

Based on the revised guidelines, the entire coding region of the RET proto-oncogene should be sequenced only in cases with negative initial findings or discrepancy between the genotype and the MEN2 phenotype [1]. However, the underlying risk is that the less-common double or multiple RET mutations may be missed. Tandem germline RET mutations have been identified in patients with atypical forms of MEN2B (involving codons V804M and Y806C, S904C, E805K or Q781R) and based on in silico algorithms, their transforming ability was high correlating with a more aggressive clinical course [3,4]. Multiple RET mutations have also been found in kindreds with familial MTC, a variant of MEN2A [5]. An individual harboring multiple mutations may have an uncommon clinical presentation of the MEN2 syndrome, which makes it critical not to miss these rare cases. As an example of an unusual genotype–phenotype correlation, a recent study reported five Brazilian families with atypical MEN2A, associated with two co-existing RET mutations, Y791F and C634Y [6]. Also, novel sequence variants, such as Y791F, S649L and I852M, have been recently described under the newly coined term ‘variants of unknown significance’ [7,8]. They may represent polymorphisms not increasing the risk for MTC or very mild mutations, and they exhibit significant phenotypic variability. Functional in vitro characterization of their properties and long-term follow-up of the affected families will provide useful information to guide our therapeutic approach in these cases. The decision to perform or forego thyroidectomy in carriers of these variants should not only rely on the mutation status, but also factor in baseline and stimulated calcitonin values.

Although the cost of sequencing all RET coding exons is higher than that of codon-oriented analysis, the expense of sequencing has significantly decreased in the last years, and will be even further reduced, especially with the introduction and growing use of next-generation sequencing, such as whole exome or whole genome sequencing. Therefore, the approach of directly analyzing the entire RET coding region in a new family with hereditary MTC may not be regarded as prohibiting and should probably not be reserved only for isolated cases, but rather expanded to include all families with hereditary MTC under investigation, and possibly also individuals with apparently sporadic MTC. A relatively higher cost in the initial genetic screening will be outweighed by the effective decrease in morbidity- and mortality-related expenses occurring from treating MTC patients at later stages of the disease. This is a subject that could be revisited in future recommendations. After all, we treat what we diagnose. It is important that we not only diagnose what we know, but also search for the least expected.

The course of MTC in MEN2 syndromes can be very aggressive and impact survival and quality of life; therefore, disease awareness and timely diagnosis of individuals at risk are cornerstones of optimal management. This is the main step that will eventually modify the surgical approach in MTC families from being therapeutic to purely prophylactic and preventive.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.