The NCCN practice update for the management of different types of thyroid carcinoma elucidates the expanding role of molecular testing, implications of the new pathologic diagnosis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features, and the addition of a new targeted therapy option.

Thyroid carcinoma is rare - but it is the most frequent endocrine malignancy. The cancer is more often found in women than in men, with data estimating it to be the fifth most common malignancy diagnosed in women.

Thyroid carcinoma is divided into the following histologic types:

• Differentiated thyroid carcinoma (DTC) - Includes papillary, follicular, and Hürthle cell
• Medullary thyroid carcinoma (MTC)
• Anaplastic thyroid carcinoma (ATC)

The prognosis is generally favourable, especially in cases presenting with DTC - which have a 10-year survival rates exceeding 90% to 95%. ATC, on the other hand, is an aggressive undifferentiated tumor and present with low survival rates.

Molecular Testing for DTC

Molecular testing for DTC may be conducted for diagnostic, prognostic or predictive purposes. Prognostic markers can evaluate suspicious thyroid nodules so that appropriate treatment options can be determined. Predictive markers can be used to guide treatment with specific targeted therapies.

If clinically significant or suspicious cervical lymph nodes are identified during ultrasonographic evaluation, fine-needle aspiration (FNA) should be considered. Cytologic examination of an FNA specimen is normally categorized based on the 2017 Bethesda System for Reporting Thyroid Cytopathology.

Molecular diagnostic testing to detect individual mutations (BRAF V600E, RET/PTC, RAS, PAX8/PPARγ) or pattern recognition approaches using molecular classifiers may be useful in evaluating FNA samples that cannot establish management decisions.

Most of the NCCN panel members agreed that they are using molecular diagnostics for evaluating FNA results of follicular neoplasm/suspicious for follicular neoplasm or atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS).

However, they expressed uncertainty regarding whether the testing really helped to guide treatment. The structure of THYR-4 placing too much emphasis on the role of molecular diagnostics was another matter of concern.

Considering all the above points, the algorithm on THYR-4 has been restructured to deemphasize molecular diagnostic testing and to allow an option for active surveillance when molecular diagnostics are not performed for AUS/FLUS.

The limitations of molecular testing for Hürthle cell lesions were elaborated in the 2017 and 2018 NCCN updates. However, positive data from recent trials suggest that Afirma Genomic Sequencing Classifier and the ThyroSeq v3 Genomic Classifier may be good options for molecular testing of Hürthle cell neoplasms. The panel expressed that although the data were encouraging, they were not yet mature enough to make a recommendation for molecular testing in Hürthle cell lesions.

Predictive Markers

Molecular markers help in diagnostics and can be used to guide treatment with specific targeted therapies. Due to limited efficacy of traditional cytotoxic systemic chemotherapy in metastatic DTC, novel treatments options have been evaluated. Recent data demonstrate that the BRAF inhibitors vemurafenib and dabrafenib can be effective treatment options for DTC harboring the BRAF V600E mutation – a mutation which is commonly observed in papillary thyroid cancers. Studies have also shown that anaplastic lymphoma kinase (ALK) inhibitors may be effective in patients with papillary carcinoma who have ALK gene fusion.

In response to the encouraging results observed with targeted therapies, the panel now recommends genomic testing to identify actionable mutations for patients with advanced, progressive, or threatening DTC. Molecular testing is also important to inform eligibility for clinical trial participation.

The panel voted to include vemurafenib and dabrafenib as treatment options for patients with BRAF mutation–positive DTCs that are locally recurrent, advanced, and/or metastatic, are not surgically resectable, are not amenable to radioactive iodine, and are progressing and/or symptomatic.

NIFTP pathologic diagnosis

Even though NIFTP is a subset of papillary carcinoma, they have low malignant potential and hence, do not require completion thyroidectomy after lobectomy.

The panel recommends that after lobectomy and histologic diagnosis of NIFTP, no further treatment is required. Active surveillance with thyroglobulin measurement and anti-Tg antibodies 6 to 12 weeks after lobectomy should be considered. Levothyroxine therapy may be used to maintain normal levels of thyroid-stimulating hormone.

The panel also clarified that noninvasive encapsulat­ed follicular variant of papillary thyroid carcinoma (EFVPTC) has been reclassified as NIFTP.

Systemic therapy for ATC- a subtype with poor prognosis and few treatment options

ATC is the most lethal and aggressive form of thyroid cancer. Therapy for ATC is usually multimodal and comprises surgery, systemic therapy, and/or radiation therapy. As ATC presents with poor treatment outcomes, all patients (regardless of surgical resection) should be considered for clinical trials.

The NCCN panel strongly recommends molecular testing (to detect actionable mutations) in all patients with ATC who are considering systemic therapy. The panel members suggest that dabrafenib/trametinib combination therapy can be considered in BRAF V600E mutation–positive ATC. However, the panel does not intend for the recommendation regarding molecular testing to only apply to BRAF mutations; any targeted therapies that are effective against an identified mutation/alteration may be considered (eg, crizotinib for ALK mutations).

There was also a discussion regarding whether the dabrafenib/trametinib recommendation should be limited to only BRAF V600E, because deep sequencing will often yield multiple actionable mutations in this tumor type. The decision was to specify V600E mutation because there are currently no data to guide how to treat ATC with other mutations.