Thyroid Cancer: A Clinical Overview and A Useful Laboratory Manual

Thyroid nodules are frequently found in the overall population. The clinical relevance of evaluating thyroid nodules is to rule out thyroid cancer. After history, physical examination, and TSH determination, neck ultrasonography is the most important tool to evaluate the risk of a particular nodule to be cancer, and to select patients for FNA. This chapter discusses these aspects.

Thyroid nodules can be identified in approximately 5% of the population. The American Thyroid Association guidelines indicate fine needle aspiration as the most accurate method for the evaluation of a thyroid nodule; however in up to 20% of cases, cytology produces indeterminate or suspicious results that require surgery to complete the diagnosis. This chapter reviews molecular markers, which can be detected using protein-based assays, to improve the sensitivity of FNA.

Indeterminate nodules at FNAC are usually candidates for surgical therapy, but, at final histology, most of them are benign. An alternative to improve the diagnostic accuracy of FNAC might be the identification of molecular alterations characteristic of malignant thyroid nodules in the material obtained by FNA. To do that, it is necessary to know which oncogene(s) are mainly involved in thyroid cell transformation, the pathway(s) they stimulate and the mutation responsible for oncogene(s) activation. These aspects will be discussed in this chapter.

Several oncogenes are involved in the development of thyroid cancer. In the last 10 years, different techniques have been applied to study point mutations and genetic rearrangements. Some of them have been used only on thyroid specimens and need to be tested on FNAC material. Generally, these modifications can be studied by various PCR-based techniques, and results depend on the quality and quantity of the starting material. By carefully selecting the appropriate methods, researchers have demonstrated that the detection of genetic alterations is feasible in a FNAC samples. This may refine the diagnosis of thyroid cancer, especially for those samples which are deemed cytologically inadequate.

Familial non-medullary thyroid cancer is a clear clinical distinct entity characterized by multifocality and a more severe phenotype and is defined as the presence of two or more first-degree relatives affected by differentiated thyroid cancer of follicular origin. In some cases, the disease is associated with rare hereditary syndromes such as Carney complex, Werner syndromes, FAP and Cowden syndromes. However, in the majority of the cases, patients have thyroid cancer as the only disease manifestation. Several studies have tried to identify the genetic alteration(s) responsible for the development of FNMTC with promising results although none of the genes/loci identified accounts for the majority of cases of FNMTC and cannot be generalized to the larger at-risk population.

Medullary thyroid carcinoma is a tumor of the parafollicular C cells which accounts approximately 3% of thyroid cancer. It may occur as sporadic form or hereditary cancer both alone or associated with syndromes. In this chapter, epidemiology, genetic, diagnosis and treatment of medullary thyroid cancer will be discussed.

“Tyrosine kinase inhibitors” (TKI) are small molecules responsible for selectively inhibiting cellular pathways involved in cell proliferation or migration. These molecules have been developed as alternative therapy for refractory or minimal responsive cancers to standard treatments. In this chapter, TKI currently used for anaplastic thyroid cancer, medullary thyroid cancer and/or refractory differentiated thyroid cancer will be described.

Some of the genetic alterations described in thyroid cancer, such as RET/PTC rearrangements, RAS point mutations and PAX8/PPARγ rearrangements, have also been found in benign lesions. The only exception is the point mutation V600E of BRAF oncogene, which is specific for the malignant histology. For this reason, researchers are seeking new markers expressed only by cancer tissues. Among these, telomerase activity and expression, together with miRNAs expression, have been proposed to be able to distinguish benign from malignant lesions both in tissues and FNAC samples with high specificity.