Current Understanding of Papillary Thyroid Carcinoma

The term thyroid neoplasm incorporates tumors that originate from follicular cells and those that arise from parafollicular cells (C cells). Differentiated thyroid cancer, which originates from follicular cells, includes papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), oncocytic cell carcinoma (Hürthle), poorly differentiated carcinoma, and anaplastic thyroid carcinoma (ATC). PTC tends to have an indolent clinical course with low morbidity and mortality. However, this entity has a broad range of biological and clinical behavior that can result in disease recurrence and death, depending on patient and tumor characteristics and the initial treatment approach. PTC is the most common form of well-differentiated thyroid cancer (WDTC) and based on the most recent statistics, accounts for approximately 89.4% of all thyroid malignancies. PTC appears as an irregular solid or cystic nodule in normal thyroid parenchyma. PTC has the propensity for lymphatic invasion, but it is less likely to have hematogenous spread. Around 11% of patients with PTC present with distant metastases outside the neck and mediastinum. This manuscript with review the current understanding of the epidemiology, pathology, molecular characteristics, prognostic factors, and dynamic risk stratification of PTC centered on an evidence-based and personalized approach.


Introduction
Papillary thyroid cancer (PTC) tends to have an indolent clinical course with low morbidity and mortality. Nevertheless, this entity has a broad range of biological and clinical behavior that can result in disease recurrence and death, depending on patient and tumor characteristics and the initial management approach. PTC is the most common form of well-differentiated thyroid cancer (WDTC) and based on the most recent statistics, accounts for approximately 89.4% of all thyroid malignancies, and is the predominant histology observed in patients exposed to radiation [1] [2] [3] [4] [5]. The average age of diagnosis of PTC is between 30 and 40 years, women are affected more frequently than men at a 2:1 ratio [6] [7] [8]. PTC appears as an irregular solid or cystic nodule in normal thyroid parenchyma [9]. Notwithstanding its well-differentiated characteristics, PTC may be blatantly or minimally invasive. In fact, these tumors may spread easily to other organs [10]. PTC has the propensity for lymphatic invasion but it is less likely to have hematogenous spread [9]. Roughly 11% of patients with PTC present with distant metastases outside the neck and mediastinum [9]. In the past, regional lymph node metastases were thought to be aberrant (supernumerary) thyroids because they contained well-differentiated PTC, but occult regional lymph node metastases are now known to be a very common finding in patients with PTC [9] [11] [12] [13]. From 1920 to 1960, therapeutic irradiation was used to treat tumors and benign conditions, including acne; excessive facial hair; tuberculosis in the neck; fungus diseases of the scalp; sore throats; chronic coughs; and enlargement of the thymus, tonsils, and adenoids. Approximately 5% to 10% of individuals who were treated with head and neck irradiation for such disorders developed thyroid cancer after a latency period of 30 to 50 years [32].

Methods
The greater exposure to diagnostic radiation, particularly computed tomography, is a potential culprit for the increased incidence of PTC [26]. Individuals who receive radiotherapy for certain types of head and neck cancer, especially during childhood, may have an increased risk of developing thyroid cancer [25].
Factors that heighten the risk for developing PTC after exposure to radiation include female gender, radiation for childhood cancer, and a family history of thyroid cancer [25].
There is some small evidence that polybrominated diphenyl ethers (PBDEs), that are flame retardants, that may be found in electrical appliances, plastics, televisions, computers, building supplies, foams, carpets, and upholstery, could possibly contribute to the development of thyroid cancer [33] [34]. PBDEs and their metabolites have a structural similarity to thyroxine and can accumulate in tissues [35]. These compounds have been shown to be endocrine disrupters, with thyroid and estrogen effects being the most common [33]. PBDEs have been shown to have increased oncogenic potential in other tissues which has made them a desirable candidate for additional research in thyroid cancer pathogenesis [36] [37].
Obesity has repeatedly been cited as a possible etiologic factor in the pathogenesis of thyroid cancer and has been postulated to be a possible origin of the increase incidence of this disease worldwide. Undeniably, being overweight and obesity have been associated with an increased risk of developing numerous malignancies, including thyroid, breast, colorectal, kidney, and endometrial cancers [14] [38] [39]. In the United States from 1995 to 2015, one out of every six PTC and two thirds of PTC greater than 4 cm in size have been linked to being overweight or obesity, based on an analysis of data from three large national US databases [40]. Kitahara et al. projected that the total relative risk for PTC was 1.26 for persons who are overweight (body mass index [BMI] 25 to 29 kg/m 2 ) and 1.30 for those who are obese (BMI ≥ 30 kg/m 2 ), compared with persons with normal-weight BMI (18.5 to 24.9 kg/m 2 ) [40]. The risk in PTCs greater than 4 cm in size was nearly 3-fold higher (hazard ratio [HR] = 2.93, 95% CI 1.25 -6.87) with overweight individuals, and more than 5-fold higher (HR = 5.42, 95% CI 2.24 -13.1) in obese individuals compared with normal-weight individuals. A study by Leitzmann et al. [41], found that obese adults had a nearly 40% higher risk for developing thyroid cancer when compared with normal-weight individuals. More research is needed to define the exact role of obesity in the development of thyroid cancer, particularly as the incidence of obesity continues to climb throughout the world [42] [43]. Most thyroid cancers are sporadic in nature; nonetheless, roughly 5% of nonmedullary thyroid cancers are hereditary [44]. These hereditary cases have been divided into two groups: those tumors associated with a familial cancer syndromes, such as Cowden's disease, familial adenomatous polyposis (FAP), and its variant Gardner's syndrome, Carney's complex type 1, and Werner's syndrome, and those with thyroid neoplasm's as the primary feature such as familial non-medullary thyroid cancer (FNMTC) [45]. Particularly FAP is associated with an elevated risk of developing a rare variant of PTC called cribriform morula variant of PTC (CMV-PTC) [46]. In a study by Uchino et al. [46], of 129 patients with FAP who underwent screening with cervical ultrasound identified 11 cases of PTC, eight of which were CMV-PTC. All the patients with CMV-PTC were women 35 years of age or younger [46]. FNMTC is defined by the presence of three or more first-degree relatives with well-differentiated thyroid cancer [47]. When only two family members are affected, only 38% will have FNMTC. When three or more family members are affected there is a 96% likelihood of having FNMTC [47]. The pattern of inheritance is autosomal dominant with incomplete penetrance [44]. Individuals with FNMTC will have a more aggressive biology compared to their sporadic counterparts [48].
Numerous articles have shown a connection between iodine deficiency and thyroid cancer [49]. Various

Pathology
To make an accurate diagnosis of classic/conventional PTC the presence of nuclear features including intranuclear inclusions and nuclear grooves is a requisite [55]. The nuclei are larger than normal and often overlap and some may appear empty and are named "Orphan Annie nuclei." In PTC its nuclear characteristics differentiate it from other thyroid neoplasms, permitting it to be diagnosed on fine-needle aspiration (FNA) [56]. Furthermore, PTC is depicted by having branching papillae with a central fibrovascular stalk (Figure 1) [5] [57]. The branching papillae are covered by cells with eosinophilic cytoplasm [57] [58].
Cell polarity may be abnormal or completely lost in some tumors [51]. In some cases, squamous metaplasia may be present [57]. "Ghosts" of infarcted papillae, better known as Psammoma bodies, are essentially pathognomonic of PTC [59].
Some tumors may also contain multinucleated giant cells [5] [57]. Classical PTC, is typically unencapsulated with invasive and ill-defined margins [5] [61]. All the same, this common pathologic variant generally has an excellent prognosis [1] [5].  The macroscopic appearance of PTC can be very variable. Most PTC tend to be distinctly well circumscribed, solid, firm, and white in color, but a significant percentage of tumors can be cystic [5] [57]. A relatively common presentation of PTC is cystic metastases to region lymph nodes and the presence of a solid primary tumor [62]. PTC may have depending on it biological aggressiveness can have an infiltrating growth pattern within the thyroid gland or may show a direct extrathyroid extension to adjacent tissues [8] [58]. Contrasting with a normal thyroid gland or benign thyroid neoplasms that protrude on sectioning, PTC remains flat [5] [60].
PTC has multiple pathologic variants (Table 1) [8], because this process can be rather problematic and contentious [63] [64]. The overall prognosis of FVPTC is similar to the conventional variant of PTC. An exemption to this is the diffuse or multinodular follicular variant, which has a more aggressive clinical course [8]. The prognosis of FVPTC also depends on whether they are entirely encapsulated or invasive [8] [65]. FVPTC can look similar to a follicular neoplasm except for the cytological features making them easily confused with follicular adenomas and follicular carcinomas, so the use of immunohistochemical and molecular markers can be very useful in confirming the diagnosis [57].
The tall cell variant (TCV) is made up of cells whose height is at least two to three times their width. In TCV PTC the cells have abundant eosinophilic cytoplasm and nuclear features similar to conventional PTC ( Figure 3). Nuclear pseudo inclusions may be more prominent. TCV PTC tend to be larger than the classic PTCs, so necrosis, mitotic activity and extrathyroidal extensions are more prevalent. Most patients are older and present with large bulky tumors and are biologically more aggressive than the usual PTC, so they are more likely to demonstrate invasion, metastasis, and recurrence [7]    ( Figure 4) [68]. In roughly one third of cases vascular invasion and extrathyroidal extension are present [8] [57]. SCV of PTC is typically seen in children with a history of radiation exposure [57].
Oncocytic variant of PTC (OV) has a distinctive brown color on macroscopic inspection comparable to Hurthle cell neoplasms. OV PTC can have a follicular or papillary architecture ( Figure 5) [69]. This oncocytic tumor has abundant lymphocytic stromal infiltrate, hence the name ''Warthin-like'' and is often seen with Hashimoto's thyroiditis [8] [57] [70]. The diagnosis is typically based on the nuclear features of PTC [57].     and thyroglobulin is inconsistently positive [7] [8] [57]. While various researchers consider columnar cell variant of PTC to be more aggressive than the conventional PTC, this conclusion is a bit more contentious. As with other subtypes of PTC, columnar cell variant of PTC that are entirely encapsulated are less likely to metastasize [57].
Diffuse sclerosing variant (DSV) represents approximately 5% of all PTCs and is diagnosed more commonly in the pediatric age group and in patients between 15 and 30 years of age exposed to radiation [72] [73] [74]. DSV is a highly and diffusely infiltrative tumor, it is usually a bilateral tumor with 70% of the cases associated lymph node metastases [75]. Pathologically DSV PTC can be con-     Figure 10) [80]. MFV of PTC is typified clinically by its non-aggressive biological behavior, with a low incidence of metastases. When metastatic disease to regional lymph nodes is present it usually retains the macrofollicular pattern [72].
PTC with prominent hobnail features is a recently described rare variant [81] [82]. To determine the diagnosis of PTC with prominent hobnail features at least 30% of cells in the tumor are needed to display a hobnail-micro papillary pattern, though minor hobnail-micro papillary features are of consequence and should be noted in a pathology report (Table 2)     of myofibroblasts [85].

Molecular Markers in PTC
RET/PTC rearrangement are found in roughly 5% to 80% of PTC with a highly variable depending on the geographic regions of the different research studies performed [57] [99]. Numerous fusions of the tyrosine kinase domain of RET have been reported with the RET/PTC1 been the most common followed by the RET/PTC3. In pediatric patients with PTC secondary to radiation exposure, the RET/PTC3 fusion is the dominant rearrangement [99].
Chromosomal rearrangements affecting the TRK gene are identified in approximately 10% of PTC, which arise from the fusion of tyrosine kinase domain of TRK on chromosome 1q22 to the tropomyosin gene [99]. Activating point mutations of the RAS proto-oncogene ensue in a very small proportion of PTC.
The most frequent one is the N-RAS codon mutation. FVPTC has a greater incidence of RAS mutations than in other subtypes of PTC. Nevertheless, RAS mutations are also identified in follicular carcinomas and adenomas [99].
The BRAF mutation (V600E) has been recognized to be fairly limited to PTC and ATC and is very valuable in the differential diagnosis difficult thyroid neoplasms (  These studies have identified that normal thyroid tissues and follicular adenomas express low levels of HMGA2 and IMP3 mRNA compared to PTC. The levels of expression in PTC range from 1.5 to greater that ten-fold higher than in normal thyroid tissues or adenomas, so measurements of the levels by quantitative RT-PCR helps to separate benign from low grade PTC [68] [100]. These tactics should help the pathologist to utilize molecular methods in resolving difficult cases.

Factors Influencing Prognosis
Patient outcomes and primary tumor size are intimately associated with PTC. In a study by Bilimoria et al. [101] of 52,173 patients with PTC diagnosed between 1985 and 1998 from the National Cancer Data Base (NCDB), found that 10-year cumulative recurrence rates increased incrementally from 5% for tumors less than 1 cm to 25% for tumors greater 8 cm and that cancer-specific mortality rates increased incrementally from 2% for tumors less than 1 cm to 19% for tumors greater than 8 cm indicating that the tumor size is intimately linked with PTC outcome, including higher rates of locoregional and distant metastases [89].
They also demonstrated a slightly better 10-year relative overall survival (OS) for total thyroidectomy as compared to thyroid lobectomy ( [89] disappeared when further adjustment was made for additional variables related to complexity and severity of illness. In nearly 30% of patients extrathyroidal extension can be identified by central compartment dissection [14] [103]. This is linked with a higher risk of recurrent or persistent disease [104], an increased likelihood of regional lymph node metastases [105], and reduced OS [89], as compared to patients without extrathyroidal spread. Gross extrathyroidal extension identified at the time of surgery is seen in up to 9% of patients [106] [107]. Invasion into the surrounding structures (musculature, esophagus, or trachea) has been associated with elevated recurrence rates and reduced OS [106] [107], and in this settings they may benefit from external beam radiotherapy [108] after aggressive surgery [109] [110].
Prognosis may be affected by tumor multifocality and bilaterality. PTC localized to one thyroid lobe has a roughly 45% chance of having PTC in the contralateral lobe [60]. This is one of the motives why recurrence rates have been reported to be slightly higher in patients treated with thyroid lobectomy although recent data have demonstrated that in properly selected patients, clinical outcomes are very similar following unilateral or bilateral thyroid surgery [111] [112] [113] [114] [115]. Perrino et al. [104] reported that tumor multifocality was related to a higher risk of persistent or recurrent disease, even in patients managed with total thyroidectomy. In patients with papillary thyroid microcarcinomas (PTMC) tumor multifocality has also been found. The only risk factors significantly influencing recurrence rates in patients with PTMC were the number of histologic foci and the extent of initial thyroid surgery [13].
Regional lymph node metastases can be identified at the time of the operation in as many as 53% of patients with PTC [116]. Nevertheless, the incidence rates vary substantially, depending on the mode of detection. Prophylactic central compartment dissections yield high rates of lymph node micro-metastases (53% to 65%) [92] [116], whereas macro-metastases, when lymph node metastases are discovered by preoperative ultrasound or during surgery, are found in approximately 30% to 40% of patients [107]. The magnitude of neck ultrasound on the management of PTC was emphasized by a study in which patients with preoperative positive lateral compartment regional lymph node metastasis on ultrasound had considerably worse lymph node recurrence-free survival (RFS) as compared to patients without preoperatively detectable lateral compartment lymph node metastases [117]. Patients who did not have lymph node metastases on neck ultrasound before surgery obtained no benefit in terms of RFS when prophylactic neck dissection was performed [117]. Additional series have confirmed that lymph node macro-metastases identified by ultrasound are related with lower RFS for patients PTMC [118]. There is an inverse relationship between the number of grossly involved lymph nodes and RFS, however the impact of metastatic disease to regional lymph nodes on cancer-specific survival is less clear [118]. Numerous studies have not been able to establish that lymph Int. J. Otolaryngology and Head & Neck Surgery node metastasis increase mortality rates, while other studies have shown reduced OS [119]. The discrepancy among series regarding the effect of metastatic disease to regional lymph node on mortality may be explained through a probe of the SEER database in which patient age at the time of lymph node surgery was scrutinized; those over age 45 years with lymph node involvement had a 46% increased risk of death as compared with similarly aged patients without lymph node metastases. In contrast, in patients less than age 45 years with lymph node metastases there was no effect on survival [120].
The prognosis of patients with PTC is associated to age, gender, and stage ( der of frequency, are most common in the regional lymph nodes and lung, followed by the bone, brain, liver, and other sites. As mentioned previously the metastatic potential seems to be related to the tumor size. A study by Yu et al.
identified that PTMC are generally associated with an excellent prognosis; however, roughly 0.5% of patients with PTMC may die [121]. Table 4 shows the risk factors for OS.

Diagnosis
PTC is diagnosed as an incidentaloma in the preponderance of cases during imaging studies (ultrasonography, computed tomography, positron emission tomography, or magnetic resonance imaging) performed for reasons unrelated to the thyroid gland [5]. The bulk of patients with PTC have no specific symptoms and the results of these incidentalomas will trigger a diagnostic evaluation. The initial sign is often the finding of a new thyroid nodule, an increase in size of a  The clinical importance of thyroid nodules lies in the need to rule out thyroid cancer, which occurs between 7% and 15% of cases, fluctuating according to age, gender, radiation exposure history, and family history [122] [123]. The prevalence of palpable thyroid nodules in the general population is roughly 5% to 7% in women and 1% in men living in parts of the world with sufficient iodine [5] [124] [125]. In contrast, high-resolution neck and thyroid ultrasound can detect thyroid nodules in approximately 19% to 68% of randomly selected people, with higher frequencies in women and the elderly [122] [126].
If a thyroid nodule larger than 1 cm in any diameter is identified, a serum level of thyroid stimulating hormone (TSH) should be obtained (recommendation 2 ATA) [56]. When the TSH is low, a thyroid scan should be performed (which is the only indication today to perform this study) to record if the thyroid nodule is hyper-functional ("hot", that is, the uptake of the marker is greater than the normal thyroid), isofuncionante ("warm", that is, the uptake of the marker is equal to the surrounding thyroid) or none functioning ("cold", that is, it has a lower uptake than the thyroid tissue) [ [152]. Due to the high risk of cancer, the diagnosis of suspicious papillary carcinoma is an indication for surgery [56].
If the FNAB results in a suspicious cytology for papillary thyroid carcinoma, surgical treatment should be very similar to the management of a frankly reported FNAB. Factors that we must take into account in offering the definitive treatment with a suspicious cytology for papillary thyroid carcinoma, are the clinical risk factors, the ultrasonographic characteristics, the patient's preference and possibly the results of the molecular tests (BRAF, RAS, RET/PTC, PAX8/ PPAR) (ATA recommendation 17) [56].
If the cytological result is a diagnosis of primary thyroid malignancy, Bethesda VI, surgery is generally recommended (ATA recommendation 12) [56]. A diagnostic cytology of primary thyroid malignancy will almost always lead to thyroid surgery. However, in some parts of the world under active research protocol active surveillance can be offered as an alternative to immediate surgery in certain patients who meet some very specific criteria [129] [156] [157]: • Patients with very low risk tumors (for example, papillary microcarcinomas without clinically evident metastases or local invasion, and without convincing cytological evidence of aggressive disease). • Patients with high surgical risk due to multiple comorbidities.
• Patients with a relatively short lifespan (for example, severe cardiopulmonary disease, other malignant diseases, very old age).
• Patients with concurrent medical or surgical problems that must be addressed before thyroid surgery.

Dynamic Risk Stratification for Thyroid Cancer
Instead of using information that is only obtainable at one point in time, the new risk stratification models in thyroid cancer highlight the importance of dynamic risk assessment, where the initial assessment is changed over time as new information becomes accessible. These dynamic risk assessments models allow us to integrate response to therapy with the underlying individual tumor biology, to offer real-time risk assessments at any point in the course of the patient's disease [158].
The modern view of risk stratification begins with the detection of a suspicious thyroid nodule (peri-diagnostic period) [158]. It continues through the stages of diagnosis, treatment, adjuvant therapy, and follow-up. From a real-world perspective, in the postoperative period the eighth edition of the American Joint Committee on Cancer/tumor node metastasis (AJCC/TNM) staging system helps to predict disease-specific mortality. The American Thyroid Association (ATA) modified risk stratification system helps to predict the risk of recurrent or persistent disease [56]. These initial risk estimates are then revised over time using the descriptions from the ATA guidelines to define the patient's response to therapy at any point during follow-up (Table 7).  These modified risk estimates are used to plan ongoing treatment. Lately, the move toward deferred intervention (active surveillance) of very low-risk thyroid cancers and a more minimalistic approach to thyroid surgery has expanded the risk-stratification sphere to include not only the intraoperative and postoperative time periods but also the peri-diagnostic period that initiates with the discovery of a suspicious thyroid nodule. In this peri-diagnostic time period it is key to identify low-risk thyroid cancers that may be treated appropriately with either an active surveillance management approach (with or without cytological confirmation) or for a minimalistic surgical intervention, such as thyroid lobectomy without neck dissection. Conversely, it is similarly imperative to identify, in the peri-diagnostic period, those patients who would be most likely to benefit from more aggressive initial interventions that could include a total thyroidectomy, with or without prophylactic or therapeutic neck dissection, radioactive iodine treatment, external beam radiation or upfront systemic therapy [158].
It is essential to recognize that highly sensitive disease-detection tools that can often detect small foci of PTC that may not require immediate diagnosis and management. The ATA guidelines provide numerous examples where an observational management approach, often without cytologic confirmation of the disease process is recommended as the preferred or alternative treatment approach to small-volume disease [56]: An active surveillance treatment approach is acceptable for carefully selected patients with either: • Highly suspicious sub-centimeter asymptomatic thyroid nodules without the need for cytologic confirmation. therapeutic intervention, it is crucial that we create a risk-stratification decision-making framework to differentiate actionable findings from non-actionable findings. Whether considering a highly suspicious sub-centimeter thyroid nodule without cytologic confirmation of disease, a biopsy-proven thyroid nodule with low-risk thyroid cancer, or persistent/recurrent disease in the neck or somewhere else, it useful to consider five key factors that when taken together, permit us to predict the probability that a specific tumor focus represents clinically actionable disease that may require further evaluations, ongoing observation, or therapeutic intervention [158]. Together tumor size and tumor location are major factors that determine whether a tumor focus is likely to cause clinically significant invasion into local structures, such as the recurrent laryngeal nerve, airway, gastrointestinal tract, major vessels, or other important structures. Another crucial factor is the tumor growth rate, measured as tumor volume doubling time, with an observational management approach being much more appropriate for tumors either, predicted to have a slow tumor growth rate, actual recorded slow growth rates over time, or tumors that are either symptomatic or likely to have symptomatic progression would be considered actionable. Patient inclination plays a crucial role when determining whether a specific lesion is actionable or non-actionable as it is imperative to incorporate the patient's grasp of the risks and benefits of intervention vs. observation with their value system and goals, in addition to offering early guidance as to whether the detectable lesion is actionable at the time of detection, ongoing re-evaluation of these same factors using the simple concepts of dynamic-risk stratification, that can help the clinician in the determining when it is time to transition from an active surveillance approach to an active management approach [158].
Dynamic-risk stratification commences as soon as a suspicious thyroid nodule is identified utilizing a peri-diagnostic risk-stratification system that incorporates tumor imaging features, medical team characteristics, and patient preferences to risk stratify patients as ideal, appropriate, or inappropriate for minimalistic initial treatment options, such as active surveillance or thyroid lobectomy.
This clinical framework tackles the basic factors that distinguish actionable from non-actionable disease [158].
Patients with small, asymptomatic thyroid nodules, typically ≤ 1 cm maximal diameter, 1 cm 3 , or 1 mL volume, confined to the thyroid gland and surrounded by normal thyroid parenchyma can be monitored with active surveillance with or without cytologic confirmation, especially in patients who appreciate their normal thyroid function and who wish escaping thyroid surgery [56]. Patients who have tumors larger than 1.5 cm to 2.0 cm, tumors in sub-capsular locations adjacent to important structures (such as the trachea and recurrent laryngeal nerve), tumors with documented growth rate doubling times of less than two-years are usually deemed unsuitable for observation and would be regarded to have actionable disease. If the tumor growth rate is undetermined at the time of nodule discovery, then this can be established with serial ultrasound examinations Int. J. Otolaryngology and Head & Neck Surgery performed roughly every six months for one to two years. The regularity of ultrasound examinations and long-term follow-up depends on the tumor size, tumor location, and the ascertained growth rate. With the use of this concept active surveillance continues until there is a three-millimeter increase in tumor diameter which represents a 100% growth in tumor volume. The detection of metastatic disease or the direct extension of the tumor into surrounding structures of the thyroid gland will lead to discontinue active surveillance based on patient preference [158].
This risk-stratified, minimalistic treatment approach to very low-risk thyroid cancers has been proven to be safe and successful over 5 to 10 years of follow-up in studies from Japan, Korea, and the United States [56] [159] [160]. In the first 10 years of active surveillance only 2% to 8% of PTMC enlarge ≥ 3 mm in maximum diameter, 12% to 14% will show and an increase in tumor volume of greater than 50% (which is the minimum change in a thyroid nodule volume that can be reproducibly measured) and new regional lymph node metastases are identified in 2% to 4% of the cases. The probability of disease progression is greater in younger patients than in older patients. One important thing to tell the patient that is critical in decision making for the patient is that at the time of disease progression delayed surgical intervention is fairly efficacious with superb outcomes and no disease-specific mortality.
The ATA guidelines now acknowledge a minimalistic surgical approach (thyroid lobectomy without neck dissection) to manage intra-thyroidal PTC less than 4 cm in appropriately selected patients [56]. Meticulous peri-diagnostic, preoperative, and intra-operative risk stratification are the bases for effective use of thyroid lobectomy without needing to perform an undesirable rate of early-completion thyroidectomies. Patients classified as being ideal for thyroid lobectomy would have PTMC that are confined to the thyroid gland in the scenario of an otherwise normal thyroid on ultrasound and clinically negative neck.
Patients are categorized as appropriate for lobectomy if the tumor is 1 to 4 cm in maximum diameter if the contralateral lobe is entirely normal or if there are other irregularities on ultrasound, such as thyroiditis or benign-appearing nodules (again, in the setting of the clinically negative neck). Patients with extra-thyroidal extension, clinical N1 disease, or distant metastasis would be considered inappropriate for thyroid lobectomy as initial management option.
In addition to the significance of peri-diagnostic and preoperative risk stratification with respect to the selection of thyroid lobectomy as primary management option, it is imperative to acknowledge that there are intra-operative findings that could modify the initial management option and lead to an immediate total thyroidectomy. We urge patients to find a surgeon who they trust and to authorize him or her to make a final assessment in the operating room concerning the initial extent of surgery that should be carry out (this can vary from lobectomy to total thyroidectomy, with or without neck dissection) [56] [158].
Nonetheless, even with a proper preoperative and intra-operative risk stratifi-Int. J. Otolaryngology and Head & Neck Surgery cation as many as 6% to 20% of patients will have unforeseen findings on the final pathology results that may lead to a completion thyroidectomy and typically, radioactive iodine. An added 5% to 10% may require at some point in time a completion thyroidectomy during follow-up for diagnostic or therapeutic purposes. The frequency of early-completion thyroidectomy, carry out following analysis of the initial pathology report, will vary depending on how aggressive each management team is with regard to the use of radioactive iodine for either remnant ablation or adjuvant treatment. If minor factors, such as minor extra-thyroidal extension, very small-volume lymph node metastasis, or small tumors with aggressive histologic features frequently lead to the use of radioactive iodine therapy then the completion thyroidectomy rate may be as high as 20% [56] [158]. The most frequent cause for a completion thyroidectomy is unexpected, the extensive vascular invasion that could not be visualized preoperatively or intra-operatively. As a result of these, patients need to comprehend that the final determination of whether a thyroid lobectomy is the appropriate initial management approach can only be attained by the incorporation of preoperative, intra-operative, and postoperative risk stratification [56] [158].
The guidelines for the staging of well-differentiated PTC underwent considerable changes, including an increase of the age cutoff from 45 years to 55 years at diagnosis, elimination of microscopic extra-thyroidal extension as a crucial component of the staging system, no longer requiring allocation of stage III to older patients with microscopic extra-thyroidal extension or lymph node metastases, creation of a new T3b category for tumors of any size that exhibit gross extra-thyroidal extension involving only the surrounding strap muscles [56] [158].
The AJCC Differentiated Thyroid Cancer Committee cautiously studied the possibility of incorporating the use of molecular markers (specifically, BRAF V600E and TERT promoter mutations) in the AJCC prognostic staging definitions.
While both of these mutations, especially when present at the same time have been proven to be prognosticators of poor clinical outcomes, they showed to add only a minimal benefit to the conventional anatomic staging factors. Consequently, molecular classification of differentiated PTC, while providing some prognostic information, were not compelling enough to warrant upstaging of PTC to prognostic stages beyond those mandated by TNM risk factors. Nevertheless, analogous to the method used in the ATA risk-stratification system, molecular results can be used to enhance and individualize risk within the risk groups or stages. The three critical factors that determine the prognostic staging groups of the eighth edition AJCC/TNM cancer staging system include the age at diagnosis, the presence or absence of distant metastases, the presence or absence of gross extra-thyroidal extension [56] [158].
In the eighth edition of the AJCC/TNM cancer staging system it was foreseen that the preponderance of patients would be categorized as stage I or stage II exhibiting the excellent outcomes expected in the majority of PTC patients. A minor number of patients particularly the older patients with either distant metas-Int. J. Otolaryngology and Head & Neck Surgery tases or gross extra-thyroidal extension were predicted to do worse and are consequently classified as stage III or IV [56] [158].

Conclusion
PTC accounts for roughly 89% of all thyroid malignancies. Some subtypes of PTC such as tall cell and columnar cell variants seem to have a more aggressive biological course. PTC is a multifaceted and often unpredictable disease that necessitates numerous management tools and careful analysis of the patient's response to therapy, which in the final consideration is the key to the patient's long-term outcome. The noticeable increase in the prevalence and incidence of PTC over the last 10 to 20 years has required a re-assessment of the conventional one-size-fits-all approach to its diagnosis and management. The conversion to more individualized management has led to a much more risk-adapted approach to the diagnosis, initial therapy, adjuvant therapy, and follow-up of patients with PTC.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.