Elsevier

The Lancet

Volume 381, Issue 9871, 23–29 March 2013, Pages 1058-1069
The Lancet

Series
Progress in molecular-based management of differentiated thyroid cancer

https://doi.org/10.1016/S0140-6736(13)60109-9Get rights and content

Summary

Substantial developments have occurred in the past 5–10 years in clinical translational research of thyroid cancer. Diagnostic molecular markers, such as RET-PTC, RAS, and BRAFV600E mutations; galectin 3; and a new gene expression classifier, are outstanding examples that have improved diagnosis of thyroid nodules. BRAF mutation is a prognostic genetic marker that has improved risk stratification and hence tailored management of patients with thyroid cancer, including those with conventionally low risks. Novel molecular-targeted treatments hold great promise for radioiodine-refractory and surgically inoperable thyroid cancers as shown in clinical trials; such treatments are likely to become a component of the standard treatment regimen for patients with thyroid cancer in the near future. These novel molecular-based management strategies for thyroid nodules and thyroid cancer are the most exciting developments in this unprecedented era of molecular thyroid-cancer medicine.

Introduction

Epithelial follicular-cell-derived thyroid cancer is the most common endocrine malignancy with a rapid worldwide rise in incidence in the past few decades.1, 2, 3, 4 Age-standardised incidence of thyroid cancer is estimated to be 9·1 per 100 000 females and 2·9 per 100 000 males in developed countries.5

This rapid rise in incidence of thyroid cancer parallels the increase in incidence of diagnosed thyroid nodules, which have an overall malignant risk of about 5–10%. The prevalence of thyroid nodules is about 5–10% in adults on physical palpation of the thyroid gland; it is much higher on thyroid ultrasonography—up to 50–70% in people older than 60 years.6, 7 The main goal in the assessment of patients with thyroid nodules is to distinguish thyroid cancer from benign nodules. Although this goal can be achieved in most patients with conventional diagnostic techniques, including ultrasonography and fine needle aspiration biopsy (FNAB), conventional diagnostic methods cannot provide definitive diagnoses in many cases.8

Several histological types of thyroid cancer exist, including papillary thyroid cancer, follicular thyroid cancer, poorly differentiated thyroid cancer, and anaplastic thyroid cancer. Papillary thyroid cancer and follicular thyroid cancer are differentiated thyroid cancers, which account for more than 90% of all thyroid malignancies. Differentiated thyroid cancer is generally associated with an indolent disease course and is usually curable. Anaplastic thyroid cancer is rare but associated with high mortality.9 Poorly differentiated thyroid cancer has a disease course that is between those of differentiated thyroid cancer and anaplastic thyroid cancer. The classic treatment of thyroid cancer is total thyroidectomy, followed by, in some cases, radioiodine treatment. Surgically inoperable and radioiodine-refractory differentiated thyroid cancers, poorly differentiated thyroid cancer, and anaplastic thyroid cancer are currently the major causes of deaths related to thyroid cancer and do not have effective treatments. Although differentiated thyroid cancer is associated with low mortality, disease recurrence is high, at 20–30%, or even higher in some subgroups of patients.10, 11 In most patients with differentiated thyroid cancer, however, occurrence of recurrence is low as discussed in the accompanying review by Donald McLeod and collegues.12 Overcoming the challenges of accurate assessment of the risk of individual patients is important so that they can be appropriately treated for the best outcomes. A core issue is how to balance treatment-associated benefits against treatment-associated harms.

Much progress has been made in understanding the molecular mechanisms of thyroid cancer in the past 5–10 years.13 This progress is best represented by the elucidation of the MAPK and PI3KCA/AKT pathways and related molecular pathogenesis in thyroid cancer (figure 1). This provides an unprecedented opportunity for the identification of novel diagnostic and prognostic molecular markers as well as novel therapeutic targets, on the basis of which more effective management strategies for thyroid cancer are being developed. In this review, we discuss this exciting area of modern thyroid-cancer medicine from a clinical perspective.

Section snippets

Cytology

FNAB and cytological assessment have been a cornerstone of diagnostic thyroid nodule management since the 1980s and this basic preoperative assessment has substantially reduced the number of patients sent for diagnostic surgery for nodules that ultimately prove to be benign. A meta-review of 11 large studies from the USA, published between 2002 and 2010, showed that a median of 72% (range 62–85%) of FNAB undertaken were benign, 5% (1–8%) were malignant, 17% (10–26%) were indeterminate, and 6%

Molecular prognostication

Several prognostic molecular markers in thyroid cancer, particularly genetic markers—including mutations in RAS, PIK3CA, PTEN, P53, ALK, and BRAF genes—show promise. Some of them occur only in poorly differentiated thyroid cancer or anaplastic thyroid cancer, such as mutations in P5343, 44 and ALK.45 Some, such as AKT1 mutations, were reported only in metastatic lesions but not in primary thyroid-cancer tissue.46 These mutations could be markers for thyroid cancer aggressiveness. RAS, PIK3CA,

Radioiodine-refractory thyroid cancer

Radioiodine refractory thyroid cancer is rare, with an estimated incidence of four cases per million population (5% of patients with clinical cancer).95 It is defined in patients with advanced disease either by the presence of at least one tumour focus without any uptake of radioiodine or by progression of the disease during the year after a radioiodine treatment course; in patients with persistent disease after the administration of a cumulative activity of 22 GBq (600 mCi) radioiodine, the

Conclusions

On the basis of recently identified diagnostic and prognostic molecular markers and therapeutic targets, novel effective management strategies have been (or are being) rapidly developed for thyroid cancer. With these unprecedented achievements, we have now entered an exciting modern era of molecular thyroid cancer medicine.

Search strategy and selection criteria

We searched PubMed with the key words “thyroid nodule”, “thyroid cancer”, “thyroid nodule markers”, “thyroid cancer prognostic markers”, and “molecular-targeted novel therapy of thyroid cancer” for related publications from the past 25 years, weighted toward those from the past 5–10 years, and publications in English. The last search was done on Jan 15, 2013. We also included relevant studies cited in reports identified by this search strategy and relevant work from our own scientific

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