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Here, we will review the main advances regarding the staging and management of DTC.

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The fourth edition of the World Health Organization histologic classification of endocrine tumors, published in June 1 , contains important revisions, which may have a broad impact on clinical practice. First, the follicular-derived neoplasms now include a new entity within the group of tumors with borderline histological features: the non-invasive follicular thyroid tumor with papillary nuclear features NIFTP 2 , 3 , an encapsulated follicular-variant PTC with no evidence of capsular or vascular invasion.

The explicitly stated objective is to reduce the intensity of treatment and follow-up and the psychological consequences of the diagnosis of cancer. This entity was first proposed by an international panel of pathologists and other professionals and has been endorsed by the American Thyroid Association ATA.

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However, the seemingly excellent outcomes still need to be confirmed in long-term prospective studies. The current evidence is retrospective and of only moderate quality 2. Other relevant changes include the identification of 15 PTC variants and the distinction of follicular thyroid cancers FTCs into three subgroups minimally invasive FTCs with capsular invasion only, encapsulated angioinvasive FTCs, and widely invasive FTCs , which reflect the prognostic relevance of vascular invasion.

Poorly differentiated thyroid cancer is also a separate entity, in accordance with the Turin criteria 5 , 6. This system is aimed at predicting mortality not recurrences. The eighth edition of this staging system contains important modifications.

The age cutoff was raised from 45 to 55 years 7 , the presence of minimal extrathyroidal extension is no longer relevant for the T classification, and the tumor stages have been redistributed Table 1 and Table 2. Regional lymph node metastases or the presence of gross extrathyroidal extension limited to strap muscle no longer mandate stage III but stage II.

The presence of macroscopic invasion beyond strap muscle subcutaneous tissue, larynx, trachea, esophagus in T4a tumors or carotid artery, prevertebral fascia or mediastinal vessels in T4b tumors is an unfavorable prognostic factor. In the edition of its practice guidelines, the ATA also revised its system for stratifying the risk of recurrent disease. The new variables considered include new pathologic features of the tumor for example, histopathological variant, vascular invasion, number of metastatic lymph nodes, size of the largest metastatic lymph node, and the presence of extranodal extension as well as its molecular characteristics mutational status of BRAF and the TERT promoter 11 , when available These changes are expected to allow more precise estimates of the likelihood of recurrence.

The dynamic risk classification process used during follow-up assigns patients to one of four subgroups and may be modified at each follow-up examination: responses to therapy are classified as excellent, biochemically incomplete, structurally incomplete, or indeterminate response. Current international guidelines advocate personalized decision-making—based on the risk of recurrence and disease-specific death—regarding the extent of surgery, the use of radioactive iodine RAI therapy, the intensity and length of follow-up, and the degree of thyroid-stimulating hormone TSH suppression.

Age below 40 at diagnosis was an independent risk factor for disease progression In terms of cures, delayed surgical treatment of these tumors was as effective as immediate treatment In a study conducted in the United States, patients with cytologically suspicious or malignant thyroid nodules Bethesda class V or VI measuring 1.

The percentages of tumors displaying growth were 2. The latter label may be applied on the basis of nodule-related features subcapsular location adjacent to the recurrent laryngeal nerve [RLN], suspicion of extrathyroidal extension, and invasion of the RLN or trachea—all three of which can be difficult to exclude on neck ultrasound [US]—fine-needle aspiration [FNA] cytology findings suggestive of an aggressive histotype, and a documented increase in size of at least 3 mm in a confirmed PTC or patient-related factors metastatic disease, age below 18 years, refusal of the surveillance-alone approach, poor adherence to the follow-up protocol or physician-related factors limited experience with thyroid cancer management or neck US or both or a combination of these factors Also, there is a need for biomarkers that can identify those rare microcarcinomas that are likely to grow, so they can be promptly referred for surgery.

According to the ATA guidelines 12 , thyroid lobectomy TL may be used for low-risk, intrathyroidal tumors up to 4 cm in size with no lesions in the contralateral lobe. Total thyroidectomy TT was previously considered the preferred approach for these tumors. In a retrospective analysis of 52, cases in the Surveillance Epidemiology and End Results SEER database, TL for tumors measuring at least 1 cm was associated with small but statistically significant increases in the risks for recurrence 9.

A recent retrospective analysis with a more extensive risk stratification found no such difference in terms of overall survival 19 , but, in another meta-analysis, the risk of recurrence after TL was significantly higher than that after TT 8. Levothyroxine treatment has been reported to prevent benign nodule relapse, but the evidence for this effect is limited TL offers several advantages over TT. First, the rate of side effects is lower with TL. It virtually eliminates the risks of permanent hypoparathyroidism and bilateral RLN palsy 25 and reduces the rates of permanent unilateral RLN palsy 0.

Second, surgical hypothyroidism after TT requires lifelong levothyroxine LT4 replacement therapy. The rate of hypothyroidism after TL varies from However, two relatively small studies have failed to detect any difference 28 , 29 and thus further investigation of this issue is needed. The ATA guidelines do not advocate prophylactic central neck dissection for low-risk patients 12 despite the high frequency of subclinical lymph node metastasis in DTC In fact, microscopic lymph node metastases that are not clinically detected before surgery have a questionable role in patient outcome 31 , and central compartment neck dissection carries an increased rate of surgical complications, hypoparathyroidism in particular 32 , In a prospective study of patients with no preoperative evidence of lymph node metastasis who were randomly assigned to undergo TT alone or TT with central compartment neck dissection, no difference in outcomes was found after five years of follow-up In the past, routine use of RAI ablation therapy after surgery was justified first by the need to eliminate residual normal thyroid tissue, to achieve an undetectable serum thyroglobulin Tg level.

It also allowed the identification of persistent neoplastic tissue with a I whole-body scan WBS and was likely to destroy any occult nests of neoplastic cells, thereby improving long-term outcomes. These indications have been questioned in recent years 12 , 34 , Claiming uncertainties and ambiguities in the evidence, the European Association of Nuclear Medicine refused to endorse these recommendations 36 and noted that there are no prospective, controlled study data that allow us to identify the patients with low-risk DTC who may not benefit from RAI ablation.

However, the Association did not emphasize that a treatment should be given only in patients in whom it may be beneficial and did not acknowledge that uncertainties persist concerning benefits of RAI administration in low- and intermediate-risk patients. It is generally agreed that RAI has no role in the management of patients with intra-thyroidal microcarcinomas.

In other low- and intermediate-risk patients, the decision to ablate can be based on individual prognostic factors and on the serum Tg level measured 6 weeks after surgery either on LT4 treatment with a sensitive assay or following recombinant human TSH rhTSH injections. An undetectable or a low serum Tg level at that time supports a decision to avoid RAI administration. When it is indicated, it should consist of the administration of 1. Two randomized clinical trials in Europe are enrolling low-risk patients and aim to obtain reliable data on the indications for post-operative RAI administration.

The primary outcomes in the two studies are disease-free survival rates at 3 and 5 years, respectively. In contrast, early minimally detectable levels have a low positive predictive value: the majority of patients with these findings remain free of structural disease during prolonged follow-up Tg trends over time—instead of absolute values—should be monitored: declining levels are reassuring, whereas increases suggest the presence of growing thyroid tissue normal or neoplastic In the presence of Tg autoantibodies TgAbs , serum Tg levels determined by immunometric assays may be falsely low.

In these cases, management can be guided by the temporal trends in the TgAb titers themselves Novel biomarkers are emerging as replacements for serum Tg in these difficult cases, such as circulating microRNAs and other nucleic acids, but still need to be standardized and clinically validated 42 — The use of mass spectrometry for measuring serum Tg levels in the presence of TgAb also needs to be validated 45 , Sensitive Tg assays that can detect serum concentrations as low as 0.

RhTSH-stimulated Tg levels are now measured during the follow-up only in those few patients with low but detectable serum Tg on LT4 treatment In these patients, a substantial increase in the stimulated Tg level may indicate the presence of neoplastic tissue. Neck US provides useful information. PTC almost always spreads first to the cervical lymph nodes, where it can be identified sonographically using specific criteria 48 , thus eliminating the need for diagnostic I WBS.

US is more cost-effective, eliminates radiation exposure, and has no adverse effects.

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Surgical treatment of lymph node metastases is recommended for lesions with smaller diameters exceeding 10 mm for lateral N1 or 8 mm for central N1 , and there is no need for discovering small N1 of only a few millimeters in diameter. However, US is notoriously operator-dependent, and some findings are non-specific and classified as indeterminate.

Lesions with such features display significantly lower rates of persistence and growth than those with more suspicious US characteristics Suspicious findings can be confirmed by US-guided FNA with cytologic assessment and assay of Tg in the needle-washout fluid Distant metastases are rare in patients with negative findings on neck US.

However, in the presence of rising Tg levels or suspicious clinical features, second-line functional diagnostic I WBS and fluorodeoxyglucose positron emission tomography scan or cross-sectional computed tomography or magnetic resonance imaging imaging studies may be performed Risk assessment is a dynamic process: the response to therapy is re-assessed on the basis of findings at each follow-up visit and expressed as excellent, indeterminate, biochemically incomplete, or structurally incomplete 12 , 39 , During long-term follow-up, even patients who initially displayed a high risk of persistent or recurrent disease can be re-classified as having lower-risk disease, and their follow-up program can be less intensive than originally planned.

Lifelong surveillance is still recommended TSH stimulates the proliferation of normal and neoplastic thyrocytes 54 , and levothyroxine treatment significantly reduces DTC recurrence and cancer-related mortality The optimal TSH level is unclear.

Manual Thyroid Cancer: From Emergent Biotechnologies to Clinical Practice Guidelines

TSH suppression increases the risk for atrial fibrillation and osteoporosis in older patients and the risk of angina in patients with ischemic heart disease Suppressive therapy should take into account both the likelihood of complications and the risk of increasing tumor cell proliferation. For this reason, levothyroxine treatment is no longer recommended for low- and intermediate-risk patients with no evidence of disease. The goal in these cases is a serum TSH level within the normal range. Suppressive therapy is advocated only in patients with structural disease and no contraindications Traditionally, thyroid hormone withdrawal has been the preferred method of preparation for this type of patient because it is associated with higher neoplastic tissue uptake and slower clearance of RAI than that achieved with rhTSH preparation.

Observational data have suggested that rhTSH preparation may also be effective in terms of response to treatment in these patients 57 , but the evidence in support of this conclusion is currently insufficient to recommend rhTSH use in patients with metastatic DTC The activity of RAI for the treatment of distant metastases can be calculated dosimetrically or a fixed empiric dose can be used.

A large retrospective study of DTC patients with distant metastases found similar overall survival with the two approaches 58 after adjustments for age and tumor burden Specific molecular profiles are more likely to result in RAI-refractory disease 60 , Even in the presence of distant metastases, most patients have asymptomatic, slowly progressive disease. RAI-refractory patients should benefit from local treatments surgery, external beam radiotherapy, or thermal ablation, depending on the site of the lesion and local expertise if they have symptoms or a high risk of local complications.

When disease progression occurs at multiple sites in patients with target lesions of more than 1—2 cm in diameter, treatment with tyrosine kinase inhibitors TKIs should be considered. These drugs have been shown to prolong the progression-free survival of patients with progressive RAI-refractory DTC, as compared with placebo However, multitarget TKIs have side effects Greater experience in their use and better knowledge of the risk factors for these adverse effects 65 , 66 are likely to improve their tolerance.

Treatments capable of restoring RAI uptake have attracted great interest. Immunotherapy also appears to be a promising approach to thyroid cancer, alone or in association with other drugs 70 NCT and NCT These agents have yet to be approved by regulatory agencies, such as the U. Enrollment in clinical trials for patients with progressive metastatic disease should be considered and encouraged in order to improve both clinical case outcomes and medical knowledge in the field In recent years, DTC treatment has become considerably more conservative, with less extensive surgery or no surgery at all , reduced use of radioisotopes, and less intensive follow-up of low- and intermediate-risk patients.

Furthermore, the systems used to histologically classify and stage DTCs have recently been refined, along with the ATA scheme for estimating their risk of recurrence, and more patients are now considered to be at low or intermediate risk. There is a need for new, prospective data to clarify how these changing practices will impact the long-term outcome of these patients.

e-book Thyroid Cancer: From Emergent Biotechnologies to Clinical Practice Guidelines

On the other hand, patients with more advanced or high-risk disease now have a broader portfolio of treatment options, including multitarget TKI therapy, more selective BRAF inhibitors, combination therapies, and immunotherapy. However, the indications for each, their optimal starting times and dosing schedules, and their long-term safety profiles remain to be clarified in coming years. No competing interests were disclosed. F Faculty Reviews are written by members of the prestigious F Faculty. They are commissioned and are peer reviewed before publication to ensure that the final, published version is comprehensive and accessible.

The reviewers who approved the final version are listed with their names and affiliations. Alongside their report, reviewers assign a status to the article:. Competing interests: No competing interests were declared. All Comments 0. Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list:.


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