Biology, Genetics Guide Diagnosis and Treatment of Thyroid Cancers

October 2016, Vol 7, No 9

Recent advances in the management of thyroid cancer have evolved directly from improved knowledge of the underlying genetics and molecular biology, an understanding that will continue to improve in the future, according to a recent review.

Recognition that thyroid cancer comprises multiple subtypes has led to improved diagnosis and the effective application of targeted therapies, concluded James A. Fagin, MD, Chief, Endocrinology Service, Memorial Sloan Kettering Cancer Center, New York, NY, and Samuel A. Wells, Jr, MD, Medical Geneticist, National Cancer Institute (Fagin JA, Wells SA Jr. N Engl J Med. 2016;375:1054-1067).

“We have no doubt that this progress will continue with the development of more effective therapies that are based on new compounds with greater specificity for oncogenic targets and combinatorial regimens that overcome resistance to single agents,” Dr Fagin and Dr Wells advised.

Thyroid cancer evolves through either the transformation of endodermal-derived thyroid follicular cells or the neural crest−derived thyroid C-cells.

Transformed follicular cells lead to the 2 principal types of differentiated thyroid cancer—papillary and follicular. Papillary thyroid carcinoma is the predominant form of thyroid cancer, accounting for approximately 85% of cases. Most papillary thyroid carcinomas are clinically indolent and are discovered incidentally.

Genetics in Thyroid Cancers

Papillary thyroid carcinoma has a low mutation density, which contributes to the historical view of thyroid cancer as a single disease entity, they noted. Improved understanding of the genetics of thyroid cancer led to the recognition of several subtypes that are exclusively associated with mutations in specific genes, which influence signaling in the MAPK pathway. BRAF V600E accounts for 60% of the mutations, followed by RAS and chromosomal rearrangements that affect the expression of various tyrosine kinases. Driver mutations remain unidentified for the remaining cases.

Exposure to ionizing radiation increases the risk for papillary thyroid cancer. Germline variants in chromosomes 9 and 14 are associated with as many as 9% of differentiated thyroid carcinomas.

Lesions that are at high risk for cancer can be identified by ultrasound. Papillary thyroid carcinomas of <1 cm occur in as many as 30% of the general population, but most never evolve into clinically significant lesions. As a result, papillary microcarcinomas do not warrant biopsy in the absence of extrathyroidal invasion, nodal spread, a positive family history, or documented exposure to radiation. Cytopathology can discriminate between benign and malignant lesions, but is inconclusive as often as 30% of the time.

Management of Thyroid Carcinomas

Surgery can be avoided or deferred in select cases of thyroid cancer. Lobectomy and total thyroidectomy are the standard treatments for tumors that are 1 cm to 4 cm. The omission of prophylactic neck dissection may be appropriate for select noninvasive, node-negative T1 or T2 papillary carcinomas and for the majority of follicular thyroid carcinomas. The authors noted that lymph nodes that are clinically involved should be resected, and complete thyroidectomy with resection of the involved nodes is recommended for tumors >4 cm. Recent studies have demonstrated a 10-year disease-specific mortality rate of <5% for patients with differentiated thyroid carcinomas.

Clinical guidelines no longer recommend radioiodine for low-risk thyroid tumors, and data for the treatment of intermediate-risk disease remain less than compelling. Radioiodine may be appropriate, however, for a subgroup of patients with intermediate-risk tumors associated with high postoperative thyroglobulin levels and persistent structural disease.

BRAF mutation–positive tumors and thyroid cancers that have positive fluorodeoxyglucose positron emission tomography scans often demonstrate refractoriness to radioiodine therapy.

Systemic therapy is reserved for metastatic, radioiodine-refractory thyroid cancers, and cancers that threaten vital structures and are not amenable to local therapy. Palliative radiotherapy with or without low-dose chemotherapy may offer disease control to patients with unresectable regional or metastatic disease.

The FDA has approved the multikinase inhibitors sorafenib (Nexavar) and lenvatinib (Lenvima) to treat patients with radioiodine-refractory metastatic thyroid cancer. The drugs have not been compared in head-to-head trials, but lenvatinib has shown greater efficacy than sorafenib, according to Dr Fagin and Dr Wells. Clinical trials of tyrosine kinase inhibitor combination therapies are in various stages of development.

Poorly Differentiated, Anaplastic, and Medullary Thyroid Cancers

Accounting for approximately 6% of thyroid cancers, poorly differentiated tumors have an aggressive biology associated with a mean survival of 3.2 years. For patients with poorly differentiated thyroid carcinoma, radioiodine therapy offers limited benefit, and most patients receive systemic therapies.

Approximately 1% of thyroid cancers are anaplastic thyroid carcinoma, which has an extremely aggressive phenotype; patients with this tumor type have a mean survival of 6 months. Palliative care may be the only treatment option for anaplastic thyroid carcinoma, especially for patients with unresectable disease.

Medullary thyroid carcinoma accounts for 3% to 5% of thyroid cancers, and the preferred approach to diagnosis is ultrasonography and cytologic testing of thyroid nodules. Surgery is the primary method for treating sporadic or hereditary medullary thyroid cancer, and, depending on the patient’s age and extent of disease, ranges from lobectomy to thyroidectomy with or without central neck dissection to complete thyroidectomy with central neck dissection and dissection of the involved unilateral or bilateral lymph nodes.

The FDA approved vandetanib (Caprelsa) and cabozantinib (Cometriq) for the treatment of medullary thyroid carcinoma on the basis of phase 3 clinical trials demonstrating improved progression-free survival.

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