Papillary thyroid cancer: Clinical features and prognosis

INTRODUCTION — Thyroid follicular epithelial-derived cancers include papillary, follicular, and anaplastic cancer. Papillary and follicular cancers are considered differentiated cancers, and patients with these tumors are often treated similarly despite numerous biologic differences. The general pathogenetic, pathologic, and prognostic features of papillary thyroid cancer and its variants will be discussed here. The staging and treatment of well-differentiated thyroid cancers as well as an overview of follicular thyroid cancer are discussed separately. (See "Differentiated thyroid cancer: Clinicopathologic staging" and "Differentiated thyroid cancer: Overview of management" and "Follicular thyroid cancer (including oncocytic carcinoma of the thyroid)".)

INCIDENCE — In a report based upon the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2018, the incidence of papillary cancer increased from 4.8 to 14.9 per 100,000, stabilized, and then appeared to decline to approximately 13.5 per 100,000 by 2018 (figure 1) [1,2]. The death rates (0.5 per 100,000 male and female per year) did not change significantly. The 5-year relative survival remains quite high at 98.3 percent (2011 to 2017 data).

The precise reasons for the increase, apparent plateau, and subsequent decrease in incidence rate in papillary thyroid cancer are unknown. The initial increase in thyroid cancer in the United States incidence was seen in both sexes and all ethnic backgrounds (figure 2 and figure 3) [3,4]. The usual female-to-male ratio of papillary thyroid cancer is approximately 2.5:1, with most of the female preponderance occurring during the fourth and fifth decades of life.

The increased incidence was thought to partially reflect earlier detection of subclinical disease (ie, small papillary cancers) secondary to more widespread use of neck ultrasonography and fine-needle aspiration (FNA) of very small thyroid nodules [5-7]. However, an analysis of the National Cancer Institute's SEER database found an increase in the rates of differentiated thyroid cancer of all sizes, including tumors greater than 4 cm [8]. Subsequently, there has been a move in the medical community away from the previous widespread practice of immediate biopsy of very small asymptomatic suspicious nodules incidentally detected on imaging. More selective use of FNA in small thyroid nodules along with more judicious use of thyroid ultrasonography, in general, could lead to a decrease in incident rates. However, another primary cause of thyroid cancer (as yet unidentified) has not been excluded.

RISK FACTORS

Radiation exposure — Radiation exposure of the thyroid during childhood is the most clearly defined environmental factor associated with benign and malignant thyroid tumors [9]. Potential sources of radiation exposure include therapeutic uses of radiation (eg, treatment of childhood malignancies), environmental exposure secondary to fallout from atomic weapons (eg, Nagasaki/Hiroshima, Japan), or nuclear power plant accidents (eg, Chernobyl). In the past, ionizing radiation was used to treat a wide variety of benign conditions of the head and neck, although this practice essentially ceased in the late 1950s to early 1960s due to increased appreciation of the carcinogenic effects of radiation on the thyroid. (See "Radiation-induced thyroid disease".)

Family history — A history of thyroid cancer in a first-degree relative or a family history of a thyroid cancer syndrome (eg, familial polyposis, Carney complex, multiple endocrine neoplasia type 2 [MEN2], Werner syndrome, or Cowden syndrome) increases the risk that a nodule may be malignant. In one study, there was a 10-fold increased risk of thyroid cancer in relatives of thyroid cancer patients [10]. In a second report, the standardized incidence ratio for papillary cancer was 3.2 with an involved parent, 6.2 with an involved sibling, and 11.2 for a female with an involved sister [11]. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

Other — A number of other possible (but not proven) risk factors have been reported. Their relative importance appears to be small but not completely defined. Potential risk factors include the following:

●Occupational and environmental exposures [12,13]

●Hepatitis C-related chronic hepatitis (odds ratio [OR] 12.2 in one report) [14]

●Increased parity and late age at first pregnancy [15]

●Obesity or overweight [16]

PATHOGENESIS — Mutations or rearrangements in the genes encoding for the proteins in the mitogen-activated protein kinase (MAPK) pathway are critical to the development and progression of differentiated thyroid cancer (figure 4) [17,18]. The importance of this pathway is demonstrated by nonoverlapping, mutually exclusive mutations of genes encoding effectors that signal through the MAPK pathway. Activating mutations in BRAF V600E are most common (60 percent) followed by RAS mutations (15 percent), and chromosomal rearrangements that activate kinase domains of BRAF or receptor kinases such as RET, NTRK, or ALK (12 percent). The remaining 13 percent usually have copy number alterations but without an identifiable driver mutation [19].

The molecular profile of Hürthle cell thyroid carcinomas (oncocytic thyroid cancers) has been shown to be quite different from papillary or follicular thyroid cancers. Rather than having the classic activation of the MAPK pathway seen in papillary/follicular thyroid cancers, Hürthle cell carcinomas demonstrate widespread mitochondrial losses, mitochondrial DNA mutations, and a series of novel putative driver mutations [20]. (See "Oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer", section on 'Papillary thyroid cancer'.)

CLINICAL FEATURES

Clinical presentation — Thyroid cancer typically presents as a thyroid nodule. Thyroid nodules come to clinical attention when noted by the patient; during routine physical examination; or when incidentally noted during a radiologic procedure, such as carotid ultrasonography, neck computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) scanning. Nonpalpable nodules (incidentalomas) have the same risk of malignancy as palpable nodules of the same size.

A history of rapid nodular growth, fixation of the nodule to surrounding tissues, new-onset hoarseness or vocal cord paralysis, or the presence of ipsilateral cervical lymphadenopathy all raise the suspicion that a nodule may be malignant. Regardless of how thyroid nodules are discovered, the diagnosis of thyroid cancer is usually made by fine-needle aspiration (FNA) biopsy (picture 1). (See "Diagnostic approach to and treatment of thyroid nodules", section on 'History and physical examination' and "Diagnostic approach to and treatment of thyroid nodules", section on 'Evaluation'.)

Histology

Classic form — Papillary cancers are typically unencapsulated and may be partially cystic. Microscopically, most are characterized by the presence of papillae consisting of one or two layers of tumor cells surrounding a well-defined fibrovascular core; follicles and colloid are typically absent (picture 2).

The morphologic diagnosis is based upon an aggregate of typical cytologic features (picture 1), none by itself pathognomonic of papillary cancer. The nuclei are large, oval, and appear crowded and overlapping on microscopic sections. They may contain hypodense powdery chromatin, cytoplasmic pseudoinclusions due to a redundant nuclear membrane, or nuclear grooves.

Approximately one-half of papillary cancers contain calcified psammoma bodies, the scarred remnants of tumor papillae that presumably infarcted (picture 3). Inflammatory cells may surround or infiltrate areas of malignant growth, although this does not usually indicate the presence of chronic autoimmune thyroiditis (Hashimoto's disease).

Papillary thyroid cancer is often multifocal. In some cases, this represents intraglandular metastases from the primary tumor [21]. However, in one study of 10 women with multifocal papillary cancer, individual tumor foci were shown to have independent clonal origins in 5 of the 10 women [22]. In a second study, discordant patterns of BRAF mutations were found in 40 percent of the multifocal papillary cancers [23].

Variant forms — Variant forms of papillary cancer include the follicular variant; tall cell variant (a more aggressive tumor accounting for approximately 1 percent of papillary cancers); and insular, hobnail, and diffuse sclerosing variants.

Follicular variants — Follicular variant papillary thyroid cancer demonstrates a follicular growth pattern but cytologically, the tumors display the typical features of common-type papillary cancers, including large, overlapping nuclei with hypodense chromatin, nuclear pseudoinclusions, and nuclear grooves; most also contain psammoma bodies (picture 3) [24].

Of the several histologic subtypes of papillary carcinoma, the follicular variants are probably the most common. The incidence of follicular variant papillary cancer has been increasing, while that of the classical form has been decreasing. In a single-center study, nearly 40 percent of the papillary cancers were follicular variants [25], and in a multicenter study, 23 percent of papillary cancers were the noninvasive, well-circumscribed subtype (noninvasive follicular thyroid neoplasm with papillary-like nuclear features, NIFTP) [26].

According to the 2017 World Health Organization classification of endocrine tumors, follicular variants of papillary thyroid cancer are subtyped as being either (1) infiltrative or (2) encapsulated with invasion [27]:

●Infiltrative – The infiltrative subtype demonstrates invasive tongues of tumor infiltrating into non-neoplastic thyroid parenchyma and lacks a well-defined tumor capsule [28]. The infiltrative subtype has a biological behavior and molecular profile that is more similar to classic papillary thyroid cancer than follicular cancers [28,29]. For example, the infiltrative subtype is more likely to have lymph node metastases and BRAF V600E mutations, while being less likely than follicular thyroid cancers to have distant metastases or RAS mutations.

●Encapsulated with invasion – The encapsulated with invasion subtype demonstrates both a well-defined tumor capsule and either invasion of the tumor capsule or invasion into vessels within or beyond the tumor capsule. The encapsulated variants, particularly those with vascular invasion, have a tumor biology (often RAS mutation) and biological behavior (more likely to have distant metastases, less likely to have lymph node metastases) that is more similar to follicular thyroid cancer than to classical papillary thyroid cancer. It is the presence of either vascular or tumor capsular invasion that differentiates an encapsulated follicular variant of papillary thyroid cancer (capsular and/or vascular invasion present) from noninvasive encapsulated follicular variant of papillary thyroid cancer (NIFTP; no capsular or vascular invasion present).

In the past, encapsulated follicular variant of papillary thyroid cancer without evidence for either vascular or tumor capsule invasion were considered noninvasive variants of papillary thyroid cancer [26,30,31]. However, noninvasive encapsulated follicular variants of papillary thyroid cancer have a very low malignant potential and are uniformly cured with lobectomy [32,33]. Because of the very low malignant potential, this type was renamed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), emphasizing that this tumor can be managed as a neoplasm rather than a malignancy [32,33]. Both the American Thyroid Association [34] and the World Health Organization have endorsed this change in nomenclature [27].

While thyroid surgery is required to distinguish NIFTP from the encapsulated with invasive subtype, therapy beyond thyroid lobectomy is usually not required (ie, thyroid-stimulating hormone [TSH] suppression and radioactive iodine ablation is not required) [32,34,35]. Proper use of the NIFTP nomenclature requires adherence to strict histopathological criteria, which means that tumors previously classified as noninvasive encapsulated follicular variant of papillary thyroid cancer cannot be assumed to be NIFTP tumors. Because the entire tumor capsule may not have been sampled or preserved at the time of initial diagnosis, it is often not possible to determine if an archived tumor sample meets all the diagnostic criteria to be reclassified as an NIFTP tumor [33]. (See "Evaluation and management of thyroid nodules with indeterminate cytology in adults", section on 'Repeat FNA indeterminate'.)

Tall cell variant — The tall cell variant form of papillary cancer has the potential to be a more aggressive tumor than classical papillary cancer [36,37]. These tumors account for approximately 1 percent of papillary cancers and are typically associated with a V600E mutation in the BRAF gene (see 'Molecular characteristics' below). They are characterized by tumor cells with eosinophilic cytoplasm that are twice as tall as they are wide. The primary tumors tend to be large, they are often invasive, and many patients have both local and distant metastases at the time of diagnosis [36]. Most patients have evidence of disease after initial therapy, and the five-year mortality rate is higher than in patients with classical papillary cancers.

Other variants — Several other variant types of papillary cancer have been described, also based upon histologic differences from classical papillary cancers but considered to be papillary cancers because of the characteristics of the tumor cell nuclei:

●The insular variant of papillary cancer is characterized histologically by solid nests of tumor, often separated by fibrous bands, but the tumor cell nuclei have the same characteristics as do the nuclei of classical papillary cancers.

●The columnar variant, which consists of elongated cells with palisading nuclei.

●The Hürthle or oxyphilic variant, which has cellular features of Hürthle cell carcinomas but cells that are arranged in papillary formations.

●The solid or trabecular variant.

●The clear cell variant, which must be distinguished from clear cell carcinomas of other organs such as the kidney or colon that have metastasized to the thyroid.

●The diffuse sclerosing variant, characterized by diffuse involvement of the thyroid, stromal fibrosis, and prominent lymphocytic infiltration.

●The cribriform morular variant, which has a prominent cribriform pattern with solid and spindle cell areas as well as squamous morules. This variant is often associated with familial adenomatous polyposis.

●The hobnail variant frequently, which harbors BRAF V600E mutations and appears to be associated with a high risk of distant metastases and an increased disease-specific mortality [38,39].

These variants are all rare, and therefore, little information about their characteristics is available. In general, however, they are thought to be more aggressive than classical papillary cancers. As a result, patients with these tumors are usually managed more aggressively than are those with classical papillary cancer of the same stage (table 1). (See "Differentiated thyroid cancer: Overview of management", section on 'Subsequent management based on risk classification' and "Differentiated thyroid cancer: Radioiodine treatment" and "Differentiated thyroid cancer: Surgical treatment".)

Lymph node involvement — The incidence of nodal metastases in adults depends upon the extent of surgery. Among patients who undergo a modified radical neck dissection, up to 80 percent have lymph node metastases (half of which are microscopic), and even among patients with papillary microcarcinomas who have prophylactic central node dissection, microscopic metastases have been reported in 37 to 64 percent [40]. At diagnosis, clinically detectable regional lymph node metastases are more common in children (approximately 50 percent) than adults.

Invasion of either the thyroid capsule or a lymph node capsule into surrounding soft tissue has been reported in 5 to 35 percent of surgical specimens, whereas vascular invasion is seen in only approximately 5 to 10 percent.

Metastases — From 2 to 10 percent of patients have metastases beyond the neck at the time of diagnosis [1]. Among such patients, two-thirds have pulmonary and one-fourth have skeletal metastases. Rarer sites of metastasis are the brain, kidneys, liver, and adrenals.

Growth pattern — The growth pattern and biologic behavior of papillary cancer are variable.

●At one end of the spectrum is the common microcarcinoma (formerly called occult papillary cancer), defined as a tumor <1 cm in diameter. These microcarcinomas are found in 15 to 30 percent of thyroid glands at autopsy. This high frequency, coupled with the rarity of clinically detected papillary cancer, suggests that the presence of a single focus of microcarcinoma in a thyroidectomy specimen is likely to be an incidental finding of no clinical importance.

●At the other end of the spectrum is a large, locally invasive cancer with distant metastases noted at the time of diagnosis. These tumors are also far more likely than microcarcinoma to metastasize through intrathyroidal lymphatic channels and form multifocal tumors or involve regional lymph nodes.

PROGNOSTIC FEATURES — Most patients with papillary cancer do not die of their disease. As an example, in one series of patients with a median follow-up of 16 years, the cancer-related mortality in patients without metastases at presentation was only 6 percent [41].

While there are a wide variety of staging systems available to predict disease-specific survival and risk of structural disease recurrence, there are a small set of key factors that identify the relatively small group of patients that are likely to do poorly [42]. Patients at highest risk of dying from thyroid cancer are older patients (>55 years of age at diagnosis) presenting with distant metastases or gross invasion of the tumor into the airway, nerves, or major vessels of the neck (table 2) [43]. Similarly, patients at highest risk of structural recurrence demonstrate gross invasion into major neck structures, distant metastases, palpable metastatic lymph node metastases, extensive microscopic vascular invasion, or inappropriately elevated serum thyroglobulin after initial therapy (table 1) [42].

The extent of initial surgery and the use of radioiodine therapy in advanced papillary cancers are associated with improved outcomes. (See "Differentiated thyroid cancer: Surgical treatment", section on 'Choice of procedure' and "Differentiated thyroid cancer: Radioiodine treatment", section on 'Patient selection'.)

Age — Thyroid cancer mortality increases progressively with advancing age, without a specific age cutoff that stratifies mortality risk [44]. This was illustrated in an analysis of 53,581 patients in the Surveillance, Epidemiology, and End Results (SEER) database, in which the five-year survival rate decreased with increasing age at diagnosis (stratified in five-year categories from 20 to 84 years) [45]. There was a continuum of disease-specific mortality with increasing age. Survival remained above 90 percent for patients <65 years at diagnosis.

Tumor size — The prognosis is poorer in patients who have large tumors [46,47]. In one series, as an example, 20-year cancer-related mortality rates were 6, 16, and 50 percent for patients whose primary tumor diameters were 2 to 3.9 cm, 4 to 6.9 cm, or 7 cm or larger, respectively [46].

While small tumors usually have an excellent prognosis, clinically evident recurrences are not infrequently detected. A survey of 299 patients with thyroid cancers less than 1.5 cm found no deaths over a mean follow-up of 45 months, but 14.4 percent had evidence of persistent/recurrent disease. Persistent or recurrent disease was associated with nonincidental cancer, lymph node metastases at presentation, or bilateral tumor but not size [48]. This study only compared tumors greater or less than 1 cm. In another study of 3965 patients with thyroid cancer (65 percent with tumors ≤2 cm), 10-year recurrence rates to the thyroid, lymph nodes, and distant organs for tumors ≤2 cm were 0.3, 1.9, and 0.4 percent, respectively [49]. Recurrence rates increased with tumor size (for tumors >4 cm 1.9, 8.1, and 3.4 percent, respectively). Mortality was low in both groups (0.04 and 0.4 percent, respectively).

Soft-tissue invasion — When present, clinically apparent, gross soft-tissue invasion increases the risk of death fivefold. It can also cause substantial morbidity if there is involvement of the trachea, esophagus, recurrent laryngeal nerves, or the spinal cord. It is important to note that it is gross soft-tissue invasion (usually described as extrathyroidal extension) identified on clinical examination, intraoperatively, or on imaging that conveys an increased risk of mortality. Extrathyroidal extension that is only identified on histopathologic examination is not a major factor for mortality, as reflected in the changes in the eighth edition American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system where minor extrathyroidal extension no longer upstages a patient to stage III (table 2). (See 'Staging' below.)

Distant metastases — The rate of survival in patients with distant metastases is variable, depending upon the site of metastases. Among patients with small pulmonary metastases but no other metastases outside of the neck, the 10-year survival rate is 30 to 50 percent; even higher survival rates have been reported in patients whose pulmonary metastases were detected only by radioiodine imaging [50]. Conversely, the median survival of patients with brain metastases is only approximately one year [51].

In multivariate analysis, fluorodeoxyglucose (FDG) positivity was the most powerful predictor of death in a large cohort of patients with metastatic disease. Patients with large-volume, intense FDG uptake had a three-year, disease-specific survival less than 50 percent from the time of the positron emission tomography (PET) scan [52]. This may be due in part to lower radioiodine avidity in papillary cancers demonstrating a high FDG uptake.

Histologic subtype — Several studies have demonstrated a poorer prognosis for specific subtypes of papillary thyroid cancers, including tall cell, insular, and hobnail variants [38,53]. (See 'Variant forms' above.)

In one study of 62 patients with the tall cell variant of papillary cancer without extrathyroidal extension at presentation, prognosis was still worse compared with classic papillary cancer; 6.4 percent developed distant metastases versus none of the patients in a comparison group with classic papillary cancer [53]. However, among patients without initial lymph node metastases or extrathyroidal invasion, no one developed metastatic disease.

Patients with aggressive histologic subtypes are usually treated more aggressively than are those with common-type papillary cancer of the same stage (table 1). (See "Differentiated thyroid cancer: Overview of management", section on 'Risk classification'.)

Molecular characteristics — In addition to the traditional histopathologic risk factors, specific molecular profiles (eg, BRAF, telomerase reverse transcriptase [TERT]) may be used to predict risk of extrathyroidal extension, lymph node metastases, and even distant metastases [54-56]. While these observations need further validation, it is likely that the specific molecular profile of the primary tumor may have significant prognostic value that could be incorporated into stratification systems.

As examples:

●In a cohort of low-risk patients with intrathyroidal papillary thyroid cancer (<4 cm, N0, M0; 33 percent with BRAF mutation), the overall risk of having structural disease recurrence over five years of follow-up was 3 percent [57]. However, BRAF V600E mutated tumors had a recurrence rate of 8 percent (8 of 106) compared with only 1 percent (2 of 213) in BRAF-negative tumors. Furthermore, in multivariate analysis, the only clinicopathologically significant predictor of persistent disease after five years of follow-up was the presence of mutated BRAF V600E.

●TERT mutations have been described in 7 to 22 percent of papillary and 14 to 17 percent of follicular thyroid cancer but with a significantly higher prevalence in aggressive thyroid cancer [58-61]. In the largest reported series (332 papillary and 70 follicular thyroid cancer followed on average for eight years), TERT mutation was an independent predictor of persistent disease (odds ratio [OR] 4.68, 95% CI 1.54-14.27) and mortality (hazard ratio [HR] 10.35, 95% CI 2.01-53.24) for well-differentiated thyroid cancer [58].

●Expression of vascular endothelial growth factor (VEGF, a potent stimulator of endothelial cell proliferation) in thyroid cancer specimens may help predict the presence of metastases. As an example, in a retrospective study of 19 patients with papillary cancer, a high level of immunostaining for VEGF correlated with a high risk of metastatic disease [62]. In a second report, elevated preoperative serum VEGF-C concentrations were an independent risk factor for nodal metastases and advanced tumor stages [63].

A broader genetic analysis may provide more accurate tumor prognostication. Specifically, a growing body of data suggest that a more aggressive clinical course can be expected in tumors that carry: (1) BRAF V600E in combination with other driver oncogenic mutations such as PIK3CA, TP53, AKT1, or RET/PTC mutation [64-66]; (2) TERT mutations, isolated or in combination with BRAF [58,67]; or (3) TP53 mutations [68].

These results, although pending confirmation in other studies, suggest that specific molecular profiles may eventually prove to be a useful adjunct to risk stratification. (See "Oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer" and "Differentiated thyroid cancer: Clinicopathologic staging", section on 'Other prognostic factors'.)

Whether the presence of BRAF independently predicts mortality is uncertain. Although in a retrospective analysis, the presence of a BRAF V600E mutation was associated with thyroid cancer mortality (overall mortality 5.3 versus 1.1 percent in BRAF V600E-positive versus mutation-negative patients), the association was no longer significant after adjusting for clinical and histopathologic features, including lymph node metastases, extrathyroidal invasion, and distant metastasis [69,70]. However, BRAF V600E mutation does appear to have a significant interaction with important clinicopathologic risk factors as the risk of mortality was higher in BRAF mutated versus BRAF wild-type tumors in the setting of lymph node metastases, distant metastases, and age greater than 45 years at diagnosis [69].

Other factors — Other factors associated with a minor increase in the risk of either recurrence or death are [71,72]:

●Multicentricity of intrathyroidal tumor

●Bilateral or mediastinal lymph node involvement

●Greater than 10 nodal metastases

●Nodal metastases with extranodal extension

●Male sex

●Delay in primary surgical therapy of more than one year after detection of a thyroid nodule

STAGING — Postoperative staging, based upon the clinicopathologic features of each case, is important for providing prognostic information. We use both the tumor, node, metastasis (TNM) classification scheme for prediction of disease-specific mortality (table 2) and the American Thyroid Association (ATA) risk of recurrence staging system for initial assessment of risk of recurrence (table 1). While initial risk stratification can be used to guide initial therapeutic and diagnostic follow-up strategy decisions, it is important to recognize that initial risk estimates may need to change as new data are accumulated during follow-up for each individual patient. Staging is reviewed in more detail elsewhere. (See "Differentiated thyroid cancer: Clinicopathologic staging".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Thyroid cancer (The Basics)")

SUMMARY

●Incidence – The incidence of papillary thyroid cancer in the United States increased dramatically between 1975 and 2012, plateaued, and then subsequently declined (figure 1). The precise reasons for the increase, apparent plateau, and subsequent decrease in incidence rate in papillary thyroid cancer are unknown. The recent decrease may be related, in part, to changing practice with more judicious use of thyroid ultrasonography and more selective use of fine-needle aspiration (FNA) of small thyroid nodules. (See 'Incidence' above.)

●Risk factors – Risk factors for papillary thyroid cancer include a history of radiation exposure during childhood, a history of thyroid cancer in a first-degree relative, or a family history of a thyroid cancer syndrome. (See 'Risk factors' above.)

●Pathogenesis – Mutations or rearrangements in the genes encoding for the proteins in the mitogen-activated protein kinase (MAPK) pathway are critical to the development and progression of differentiated thyroid cancer (figure 4). Activating mutations in BRAF V600E are most common (60 percent) followed by RAS mutations (15 percent), and chromosomal rearrangements that activate kinase domains of BRAF or receptor kinases such as RET, NTRK, or ALK (12 percent). (See 'Pathogenesis' above.)

●Clinical features – Thyroid cancer typically presents as a thyroid nodule. Thyroid nodules come to clinical attention when noted by the patient; during routine physical examination; or when incidentally noted during a radiologic procedure, such as carotid ultrasonography, neck computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) scanning. Nonpalpable nodules (incidentalomas) have the same risk of malignancy as palpable nodules of the same size. (See 'Clinical presentation' above and "Diagnostic approach to and treatment of thyroid nodules".)

●Histologic subtypes

•Classic form – Papillary cancers are typically unencapsulated and may be partially cystic. Microscopically, most are characterized by the presence of papillae consisting of one or two layers of tumor cells surrounding a well-defined fibrovascular core; follicles and colloid are typically absent (picture 2). (See 'Classic form' above.)

•Variant forms – Variant forms of papillary cancer include follicular, tall cell, insular, and hobnail variants. Of the several histologic subtypes of papillary carcinoma, the follicular variants are probably the most common.

-Follicular variants – According to the 2017 World Health Organization classification of endocrine tumors, follicular variants of papillary thyroid cancer are subtyped as being either (1) infiltrative or (2) encapsulated with invasion.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP, formerly called noninvasive follicular variant of papillary thyroid cancer, but subsequently reclassified as a nonmalignant variant because it does not have either vascular or tumor capsule invasion) has an excellent prognosis. While thyroid surgery is required to distinguish NIFTP from the encapsulated with invasion subtype, therapy beyond thyroid lobectomy is usually not required. (See 'Follicular variants' above.)

-Tall cell and other variants – Other variant forms of papillary cancer are thought to be more aggressive than common-type papillary cancers. As a result, patients with these tumors are usually managed more aggressively than are those with common-type papillary cancer of the same stage. (See 'Tall cell variant' above and 'Other variants' above and "Differentiated thyroid cancer: Overview of management", section on 'Risk classification'.)

●Prognostic features – Clinical and pathologic features associated with a somewhat higher risk for tumor recurrence and cancer-related mortality include older age at diagnosis, size of primary tumor, and the presence of soft-tissue invasion or distant metastases. (See 'Prognostic features' above.)

●Management – The management of differentiated thyroid cancer is discussed separately. (See "Differentiated thyroid cancer: Overview of management".)