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Recent advances in differentiated thyroid cancer

Recent advances in differentiated thyroid cancer

Data on the incidence of individual cancers places thyroid cancer as one which is increasing at one of the most rapid rates.1,2 This is partially due to the widespread use of highly sensitive diagnostic imaging techniques, particularly high-resolution neck ultrasonography. A significant number of cases are discovered incidentally during imaging of the neck or chest areas for unrelated reasons.1,3,4 Most of these cases are small tumours that carry excellent prognosis even when treated conservatively.5,6 This has led to a paradigm shift in the management of these tumours,7 alongside advances in the molecular understanding of thyroid cancer pathogenesis aiding in their assessment and risk stratification.8,9 This article briefly discusses the modern approach to management of differentiated thyroid cancer (DTC) in view of these advances.

Classification of differentiated thyroid cancer

For a long time, DTC has been classified into two main categories: papillary (PTC) and follicular (FTC) subtypes, with several variants described in the last decades.10,11 In the 2017 World Health Organization Classification, 15 subtypes of DTC were described.12 One new entity is the non-invasive follicular tumour with papillary-like structures (NIFTP).13 This variant is a follicular tumour that has the nuclear features of PTC but is encapsulated and non-invasive.13,14 These features have suggested that this variant is not cancer and it has subsequently been reclassified as a benign thyroid tumour. Most cases with this variant were previously classified as follicular variant PTC. This new classification was based on critical review of a series of cases, comparing these tumours with another series of tumours with angio-invasive and capsular invasive features. On long-term follow up, none of the NIFTP cases developed local or distant recurrence nor were associated with mortality.13 FTC is classified into 3 variants: 1) minimally invasive with only capsular but no vascular invasion; 2) encapsulated angio-invasive subtype with some vascular but no capsular invasion; and 3) widely invasive FTC with significant vascular and capsular invasion.12,15 Hurthle cell cancer, for a long time considered to be a variant of FTC, is now considered as a separate entity as it has significant distinct molecular and histopathological features from FTC.15 Finally, poorly differentiated thyroid cancer (PDTC) is also listed as a distinct entity based on the recently described Turin criteria, with an intermediately aggressive course between anaplastic thyroid cancer and well-differentiated thyroid cancer.16


The two widely used staging system are the American Joint Cancer Committee/Union Internationale Contre le Cancer TNM staging system for thyroid cancer, which estimates the risk of mortality, and the American Thyroid Association staging system which estimates the risk of recurrence.7,17 The TNM staging system places major emphasis on the age of the patient, and invasiveness and spread to locoregional lymph nodes and distant sites.17 The 8th edition of the TNM staging system has raised the age limit from 45 years to 55 years and does not consider minimal extrathyroidal extension and regional lymph node metastasis as staging criteria.17,18 With these modifications to the staging system, many patients are expected to be down-staged and only 5-10% of cases will be in stage III or IV and associated with a higher risk of mortality.19 The staging system proposed by the ATA in 200920 was based on limited data at that time and was more of an expert opinion. It has been validated in a number of studies and was used as the basis of the 2015 ATA guidelines with further modifications based on available evidence.7 In addition, a number of other histopathological features and molecular markers have been suggested to refine staging and the risk of tumour recurrence.7

ATA guidelines proposed a unified disease status and response to therapy based on serum thyroglobulin, thyroglobulin autoantibodies and imaging studies.7 After initial treatment, these data would place patients in one of four categories: excellent response, biochemically incomplete, structurally incomplete or an indeterminate response.7 The ATA also emphasize the newly introduced concept of dynamic staging in which the status of the disease varies over time and may change from one status to another.7


Initial surgical management

As most cases of low-to-intermediate risk DTC have an excellent prognosis, the question has been posed as to whether a more conservative management approach could be followed.7 This is exemplified by the extreme case of optional active surveillance instead of surgery for patients with small, subcentimeter, well-differentiated PTC.21,22 Risk for well-selected patients with this type of tumour is minimal and data from Japan and the United States are consistent in showing that this approach is an acceptable alternative to surgery in patients with PTC of 1.0–1.5 cm in size without extrathyroidal extension, lymph node or distant metastasis.21-23 In addition, intra-thyroid DTC up to 4.0 cm without evidence of locoregional or distant metastasis or aggressive histopathology can be treated with hemithyroidectomy instead of the previously recommended total thyroidectomy.7,24 Prophylactic central lymph node dissection is not recommended for the majority of cases, especially those in low-to-intermediate ATA risk categories.7

Radioactive iodine (RAI) remnant ablation

Similarly to the recommended conservative surgical approach, the use of RAI for remnant ablation is recommended with caveats.25 There is no indication to administer RAI for patients with incomplete surgery (those who had undergone a hemithyroidectomy for low risk tumours). Similarly, RAI is not recommended for subcentimeter tumours. Low-risk patients who have undergone complete surgical therapy and have no evidence of disease on postoperative evaluation do not generally benefit from RAI ablation.7,25 For low and intermediate risk patients, serum thyroglobulin level 4–6 weeks after surgery provides reliable information about the future risk of disease. Post complete surgery patients with low serum thyroglobulin in the absence of anti-thyroglobulin antibodies and with no evidence of suspicious findings on ultrasonographic examination of the neck do not generally benefit from RAI.7 Only high risk patients are routinely prescribed adjuvant RAI or therapeutic therapy. Not only have the indications for RAI become limited, but also the recommended level of RAI administered is also becoming less.26 This is based on two large multicenter European clinical trials which showed that 30 mCi and 100 mCi with recombinant human TSH or with conventional thyroxine therapy withdrawal achieve similar ablation results.26,27

The conservative management approach extends to the level of TSH suppression following initial surgery with or without RAI.7 Suppression of TSH to <0.001 mU/L is recommended for high risk patients or those with residual or persistent cancer tissue (biochemically or structurally incomplete).7,28 For patients with an indeterminate status, mild suppression (TSH 0.1–0.5 Mu/L) is recommended.7 Patients who respond well do not need TSH suppression and it is recommended that their TSH level should be in the lower half of the normal range (0.5–2.0 mU/L).7

Management of progressive metastatic RAI-refractory disease  

Until a few years ago, patients with metastatic progressive disease had limited treatment options and would usually succumb to their disease.29,30 Over the last decade, there has been significant progress in our understanding of the molecular basis of DTC, and testing and introduction of new therapeutic agents.31 Two multikinase inhibitors, sorafinib and lenvatinib, have been approved for the management of RAI-refractory progressive metastatic DTC – with both drugs shown to significantly improve the progression-free survival and quality of life of patients.32,33 Other drugs are being tested in phase II and III trials. Selumatinib and dabrafenib are specific BRAF inhibitors and have been shown to be effective in BRAF+ metastatic DTC. These drugs may have a role in redifferentiating thyroid cancer cells so they become less aggressive and absorb more radioactive iodine.34,35


Accumulated clinical and molecular data over the last decade have significantly impacted the clinical practice and management of DTC. Considering the excellent prognosis of most cases of DTC, there has been a major paradigm shift towards more conservative approaches with less surgery, more selective use of radioactive iodine for ablation and less thyroid hormone suppression. Better understanding of the biology and natural course of some forms of DTC has led to their reclassification to benign tumours and sub-classification of others to specific subtypes with implications for their management. The staging systems have been refined to more accurately assess the risk of recurrence and mortality. Finally, better understanding of the molecular basis of DTC has led to the introduction, testing and use of multikinase inhibitors as new therapeutic agents that have significantly changed the outlook for a small but important group of patients with progressive RAI-refractory DTC


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Ali Saeed Alzahrani

Scientist and Head Molecular Endocrinology Section
Department of Molecular Oncology
King Faisal Specialist Hospital & Research Centre
Riyadh, Saudi Arabia
Consultant Endocrinologist
Department of Medicine
AlFaisal University
Riyadh, Saudi Arabia
Professor of Medicine and Endocrinology
AlFaisal University
Riyadh, Saudi Arabia
thyroid cancer