Thyroid, Papillary Carcinoma, Early

Updated: May 07, 2021
Author: Eric J Lentsch, MD; Chief Editor: Arlen D Meyers, MD, MBA 



Much attention has been generated regarding the topic of thyroid neoplasia and papillary thyroid carcinoma. This attention can be attributed to the frequency of benign thyroid nodules and the clinical difficulty in distinguishing these nodules from malignant thyroid lesions.

History Of The Procedure

Theodor Billroth, who performed many thyroidectomies in the mid-1800s, was the first to observe side effects of total thyroidectomy in the form of postoperative cretinoid changes. He noticed his patients became sluggish, fat, cold, and even mentally deranged, a condition that would later be termed myxedema.

Thyroidectomy began to be used in the treatment of toxic goiters in 1907. Prior to this point, the surgery was used to treat nontoxic goiters, with toxic goiter patients considered poor surgical candidates. Radioactive iodine was introduced as a therapeutic intervention in 1942 by Means, Evans, and Hertz. This was followed by the introduction of thiouracil, in 1943, by Edwin Bennet Astwood.

Landmark innovations in many disciplines, particularly in anesthesia, physiology, and radiology, as well as in methods of hemostasis and antisepsis, contributed to the development of the surgical treatment of thyroid disease. Technologic innovations, such as video-assisted thyroidectomy, have further contributed to making these operations safer .[1]


Thyroid nodules are found in up to 7% of the population. Only 4-6.5% of these nodules are malignant. Malignant tumors of the thyroid account for only about 1% of all cancers and only 0.4% of cancer-related deaths. The prognosis for papillary thyroid carcinoma is favorable; however, controversy exists regarding management of this cancer. Surgery is the primary mode of therapy for treatment, but the most appropriate type of resection for this disease is controversial. Open and minimally invasive procedures are illustrated below.

Standard open thyroidectomy. Standard open thyroidectomy.
Minimally invasive video-assisted thyroidectomy. C Minimally invasive video-assisted thyroidectomy. Courtesy of Ruggieri et al. BMC Surgery 2005 5:9 doi:10.1186/1471-2482-5-9



The American Cancer Society estimated that 44,280 new cases of thyroid cancer would be diagnosed in 2021.[2] Papillary thyroid carcinoma accounts for about 80% of all thyroid carcinomas in the United States.

The US incidence of thyroid cancer has more than tripled since the late 20th century, growing from nearly 5.0 new cases per 100,000 persons in 1975 to 15.5 new cases per 100,000 persons per year in the period between 2014 and 2018.[3, 4] Much of the increase has been due to a rise in the incidence of papillary thyroid cancer, which grew from 7.8 cases per 100,000 persons in 2003 to 15.4 cases per 100,000 persons in 2013.[4]

Despite the growth in the incidence of thyroid cancer, the disease's mortality rate has remained the same (0.5 deaths per 100,000).[5] Between 1988 (the first year the Surveillance, Epidemiology, and End Results [SEER] program collected data on tumor size) and 2002, 49% of the increase in thyroid cancer was attributable of tumors measuring 1 cm or smaller.

These trends, combined with the known existence of a substantial reservoir of subclinical cancer and stable overall mortality, have suggested that the rise in thyroid cancer's incidence has reflected increased detection of subclinical disease. Nonetheless, although controversy exists, there is growing evidence that the expanded incidence of reported thyroid cancer may be due to an increase in new cases.[6]

Thyroid cancer tumors most often occur in individuals aged 20-50 years. In adults, the female-to-male ratio of clinically diagnosed papillary carcinoma of the thyroid is 3:1; in children, the tumor is distributed nearly equally by sex. Although this condition is more common in females, they have a better overall prognosis. Papillary thyroid carcinoma occurs more often in whites than in blacks.


The etiology of papillary carcinoma has yet to be elucidated, but a number of associations have been made. Multiple genetic and epigenetic mutations result in the activation of signaling pathways that precipitate thyroid cancer. Common mutations include point mutations of the BRAF and RAS genes and chromosomal rearrangements of RET/PTC and PAX8/PPARG.[7]

Moreover, research indicates that a link exists between higher body mass index (BMI) and greater tumor size, extrathyroidal invasion, and advanced tumor, node, metastasis (TNM) staging.[8]


Activation of receptor tyrosine kinases (RET/PTC, TRK, MET), whether by rearrangement or gene amplification, appears to be specific for the transformation of thyroid follicular cells into papillary thyroid carcinomas. Often associated with exposure to ionizing radiation, these rearrangements produce chimeric proteins with tyrosine kinase activities that contribute to the development of the malignant phenotype. Approximately 40% of adults with sporadic papillary carcinoma have RET gene rearrangement, and about 15% have NTRK1 rearrangement. This rearrangement is higher (60%) in children.

Somatic point mutation in the BRAF gene may be the most common mutation among papillary thyroid cancers. Considered to be a poor prognostic marker, it varies from 29-69% in different series. This gene encodes a serine/threonine kinase acting on the RAS-RAF-MEK-MAPK signaling pathway. BRAF mutations seem to be much less common in childhood thyroid carcinomas. Identification of the BRAF mutation is making inroads into clinical practice as a diagnostic tool for the management of papillary thyroid cancers.

A 10-fold increased risk of thyroid cancer in relatives of patients with thyroid cancer suggests a genetic basis for susceptibility to these tumors. A correlation between papillary thyroid carcinoma and human leukocyte antigen (HLA)-DR7 has also been observed. Also, a parallel incidence has been described for this tumor in monozygotic twins.

Iodine excess

Papillary thyroid cancer has been induced in animals with the administration of excess iodine. In Vienna, Austria, during a period when iodide intake was low in the population, papillary carcinoma accounted for only 25% of all thyroid cancers instead of the expected 80%.

In areas where goiters are endemic, the addition of iodine to the diet has increased the proportion of papillary carcinomas relative to follicular thyroid cancer. However, these cancers are less aggressive and have a better prognosis for long-term survival.

While iodine excess has been linked to point mutations, however, a study of post-Chernobyl thyroid cancer indicated that an association exists between RET/PTC chromosomal rearrangements and iodine deficiency.[9] Conversely, excess iodine has been shown to have an antioncogenic role during RET/PTC3 oncogene activation. Studies have demonstrated a decreased papillary thyroid carcinoma rate in radiation-exposed regions where populations have an iodine-rich diet.[10]


External radiation to the neck increases the incidence of papillary carcinoma of the thyroid later in life. Irradiation during childhood has been associated with the greatest risk for acquiring papillary thyroid cancer. As many as 9% of children irradiated for conditions such as tonsillar hypertrophy, thymic enlargement, and acne have developed thyroid cancer over a period of 20 years. Of the survivors of the atomic bomb explosions in Japan, 6.7% developed papillary thyroid cancers.

This percentage is much higher than what is expected in the general population. More recently, data have become available from studies of over 4000 people who developed thyroid cancer after the Chernobyl nuclear accident in 1986.[11] They revealed that radiation exposure during childhood carries an increased risk of thyroid cancer and that the risk is radiation dose dependent. The youngest children are most sensitive to radiation-induced carcinogenesis, and the minimal latent period for thyroid cancer development after exposure is as short as 4 years. The vast majority of these cancers are papillary carcinomas. On the molecular level, chromosomal rearrangements (such as RET/PTC) are more common than point mutations of BRAF and other genes.

Most studies have found that radiation exposure increases the risk of developing thyroid cancer without affecting the patient's prognosis or the aggressiveness of the tumor. Some studies, however, have suggested that radiation may induce a more aggressive course.[12] While treatment with radioactive iodine has not been shown to raise the incidence of thyroid cancers, a meta-analysis demonstrated an increase in the risk of thyroid, kidney, and stomach cancer at diagnostic doses of greater than 1 Gy.[13]


Gross description

Papillary carcinomas can range in size from microscopic, clinically undetectable lesions to masses of up to 10 cm in diameter. The average tumor size at diagnosis is 2.3 cm. Up to 75% of these tumors are multifocal within the thyroid. Most are pale and firm on gross examination; less than 10% of papillary carcinomas are truly encapsulated, with larger nodules usually unencapsulated and locally invasive. Penetration of the capsule of the thyroid gland occurs in about 40% of cases.

Microscopic description

Well-differentiated thyroid carcinomas are the most common types of thyroid carcinoma. These include papillary and follicular thyroid carcinomas. Both arise from the endodermally-derived follicular cells that synthesize thyroxine and thyroglobulin. This is in contrast to medullary thyroid carcinoma, which is derived from the neuroendocrine calcitonin-producing parafollicular C cells of the thyroid.

Papillary tumors can have pure papillary histopathology, but more than one half contain an admixture of follicular elements. Regardless of the precise proportions, all neoplasms containing some papillary areas have identical biologic behavior; therefore, they are classified under the papillary, rather than the follicular, carcinomas.

The histopathologic diagnosis of follicular variant of papillary thyroid carcinoma (FVPCA) can be difficult. Lloyd (2004) examined interobserver variation by 10 experienced thyroid pathologists in the diagnosis of FVPCA in 87 tumors.[14] A concordant diagnosis of FVPCA was made by all 10 reviewers with a cumulative frequency of 39%. Diagnostic criteria used to diagnose FVPCA, including pseudoinclusions, nuclear grooves, and powdery nuclei, are clearly not uniformly recognized, even by experts. Immunohistochemical markers, such as single nucleotide polymorphisms and messenger ribonucleic acid (mRNA) expression of VEGF-A, are being shown to provide more objective diagnostic criteria.[15, 16]

Initially, the immunohistochemical expression of cytokeratin 19, galectin-3 and HBME-1, 3 malignancy-related markers in thyroid papillary carcinoma, including its follicular variant, was used with caution.[17, 18] However, a study by de Matos et al found that these biomarkers can be used to accurately diagnose malignant and benign lesions both preoperatively and postoperatively.[19]

Thus, genetic alterations in papillary carcinoma of the thyroid may hold the ultimate key to diagnosis. Three genetic alterations, including BRAF point mutations, RET/PTC rearrangements, or RAS point mutations, have been recognized in this regard. In a study by Adeniran (2006), these alterations have been shown to be associated with distinct microscopic, clinical, and biologic features of thyroid papillary carcinomas.[20] BRAF mutations were associated with older age, taller cell appearance, and more advanced tumor stage at presentation. RET/PTC rearrangements presented at a younger age, showed typical papillary histology, and were associated with a high rate of lymph node metastases. Tumors with RAS mutations were exclusively of FVPCAs.

The identification of these alterations has increasingly led to the diagnostic and prognostic use of genetic studies in papillary thyroid carcinoma. Several genetic panels have been developed to identify genes specific to thyroid cancer and are now in clinical use.[21, 22] These involved genes may also serve as targets for cancer chemotherapy in patients in whom standard thyroid cancer treatment has not been effective.

The histologic features of papillary carcinoma of the thyroid include branching papillae composed of a central fibrovascular core and a single or stratified lining of cuboidal to columnar cells. Tumor cells may form colloid-containing follicles, and foci of squamous metaplasia are frequently found. Nuclear atypia is also an important diagnostic feature.

In more than half of these tumors, the nuclei have a characteristic ground-glass appearance; laminated calcific spherules known as psammoma bodies are also often found within the histological framework. In fact, the presence of psammoma bodies is virtually diagnostic for papillary carcinoma because they are rarely found in other lesions.

Papillary thyroid carcinomas typically invade the lymphatics and spread to other sites within the thyroid gland, as well as to the regional lymph nodes. Lymph node metastases have been reported in the range of 46-90% of cases of papillary carcinoma. Vascular invasion is uncommon; however, if it does occur, the spread of tumor is usually to the lungs and bones. Direct extension into the soft tissues of the neck occurs in approximately 25% of cases.


The variants of papillary thyroid carcinoma include the following:

  • Encapsulated tumors: About 10% of papillary carcinomas are completely surrounded by a dense fibrous capsule; the prognosis for patients with such tumors is better than the prognosis for patients with unencapsulated papillary carcinoma

  • Diffuse sclerosing variant: Occurring at a younger age, the diffuse sclerosing variant constitutes 2% of papillary carcinomas and may cause a diffuse goiter without palpable nodules that can be mistaken for goitrous autoimmune thyroiditis; diffuse involvement of one or both lobes occurs with dense sclerosis, patchy lymphocytic infiltration, and abundant psammoma bodies; prognosis for individuals with the diffuse sclerosing variant is less favorable than that for individuals with typical papillary thyroid carcinoma

  • Oxyphilic (Hürthle) cell type: The oxyphilic (Hürthle) cell type variant has typical papillary architecture but may be more aggressive than usual papillary carcinoma

  • Follicular variant: The follicular variant has a purely follicular architectural pattern but may be recognized by the typical cellular features of papillary carcinoma

  • Tall cell carcinoma: Tall cell carcinoma is a more aggressive form of thyroid carcinoma that differs from the usual form by showing tall columnar cells; the frequency of more aggressive behavior is higher, but the carcinoma resembles papillary carcinoma in other morphologic and clinical aspects

  • Columnar cell carcinoma: Columnar cell carcinoma is a distinctly more aggressive form of papillary thyroid carcinoma that occurs more often in older men and is associated with a poor prognosis

  • Solid cell variant: The lesion is made up of sheets of tumor cells that have the cytologic features of typical papillary thyroid carcinoma; about one third of cases exhibit vascular invasion and extrathyroidal extension; the tumors arise more often in pediatric patients with a history of radiation exposure[23]

  • Papillary thyroid carcinoma with prominent hobnail features: Research indicates that usually more than 30% of the tumor has hobnail features; a small percentage of these lesions have been found to have tall cell and diffuse sclerosing patterns; the carcinomas are very aggressive, with mortality from metastatic papillary thyroid carcinoma reported in 50% of cases[23]


The mainstays of the preoperative diagnosis of papillary carcinoma are a thorough history and physical examination, including an assessment of risk factors, along with ancillary tests such as cervical ultrasonography and aspiration cytology.

The most common presentation of thyroid cancer is a nontender palpable nodule. However, a diagnostic dilemma is present as this is the presentation of most benign thyroid conditions. A palpable nodule occurs in up to 7% of the general female population. A single nodule has a 5-12% malignancy rate, while multiple nodules have a 3% malignancy rate in the general population.

Papillary carcinoma may also present as a nodule with enlarged cervical lymph nodes or cervical lymphadenopathy in the absence of a palpable thyroid nodule. Benign thyroid tissue can be found in the neck anywhere medial to the sternocleidomastoid muscle. Any thyroid tissue lateral to the sternocleidomastoid muscle should be considered malignant.

Unlike follicular thyroid carcinoma, distant metastases of papillary thyroid carcinoma are rarely observed at the time of presentation. When distant metastases are present at the time malignancy is discovered, the primary tumor is almost invariably large and easily palpable.


During routine physical examination or ultrasonography, symptoms of dysphagia, odynophagia, or shortness of breath may lead to the discovery of a thyroid mass. The presence of a mass in the thyroid requires further investigation, especially in high-risk patients.

Lobectomy is indicated in patients who have isolated, indeterminate, solitary nodules who prefer a more limited surgical procedure. Lesions of less than 1 cm that are low-risk, unifocal, or intrathyroidal in the absence of prior head and neck irradiation can also qualify for lobectomy. Total thyroidectomy is indicated for the following:

  • Lesions of greater than 1 cm

  • Indeterminate nodules that have large tumors (>4 cm) with atypia on biopsy

  • Biopsy readings that are suspicious for papillary carcinoma

  • Patients with a family history of thyroid carcinoma

  • Patients with a history of radiation exposure

  • Patients with indeterminate nodules who have bilateral nodular disease[24]

In patients with clinically involved central or lateral neck lymph nodes, total thyroidectomy should be accompanied by clearance of the central neck of disease by therapeutic central-compartment (level VI) neck dissection. If the central neck lymph nodes are clinically uninvolved, patients with papillary thyroid carcinoma can still undergo prophylactic, ipsilateral or bilateral central-compartment neck dissection. However, in patients with small (T1 or T2), noninvasive papillary thyroid cancer that is clinically node-negative, thyroidectomy without central neck dissection may be appropriate.[24]

Lateral neck compartmental lymph node dissection is indicated when there is biopsy-proven metastatic lateral cervical lymphadenopathy.[24]

Relevant Anatomy

Knowledge of the anatomy of the infrahyoid neck and thyroid region aids in the identification and preservation of structures (eg, recurrent laryngeal nerve, superior laryngeal nerve, superior thyroid artery, inferior thyroid artery). The isthmus of the thyroid usually overlies the third tracheal ring, although this middle portion of the gland may be absent altogether in some individuals. The thyroid gland consists of a superior pole that may extend as far as the oblique line of the thyroid cartilage, and an inferior pole that may extend as far as the sixth tracheal ring.

The external branch of the superior laryngeal nerve innervates the cricothyroid muscle near the superior pole. The left recurrent laryngeal nerve lies in the tracheoesophageal groove, while the right recurrent laryngeal nerve approaches the thyroid gland from a more lateral position. The superior thyroid artery is the first branch of the external carotid artery and often accompanies the external laryngeal branch of the superior laryngeal nerve near the superior pole of the thyroid as it runs superficially toward the isthmus. The inferior thyroid artery arises from the thyrocervical trunk, which comes off of the subclavian artery. This artery runs in the tracheoesophageal groove and sends branches to the posterior aspect of the lateral thyroid lobe. The inferior thyroid artery has a longitudinal branch that anastomoses with the superior thyroid artery near the superior pole.


Surgical excision of papillary thyroid carcinoma has no absolute contraindications. Even people with distant metastasis would benefit from surgical removal of the primary disease, neck dissection, and ablation with iodine-131.

A total thyroidectomy may be contraindicated in people with disease limited to only one lobe of the thyroid who are likely to be noncompliant with thyroid replacement therapy. These individuals may be better suited for a hemithyroidectomy.



Laboratory Studies

Lab studies in the evaluation of papillary thyroid carcinoma include the following:

  • Fine-needle aspiration cytology: Fine-needle aspiration is a mainstay of preoperative diagnosis of papillary carcinoma of the thyroid; the use of fine-needle aspiration cytology can increase the diagnostic accuracy of thyroid malignancy cases to 92%

  • Molecular markers: Molecular markers can be used to guide therapy in patients with indeterminate cytology[25]

  • Thyroid-stimulating hormone (TSH): Serum thyroid-stimulating hormone (TSH) levels, along with imaging studies, should be obtained if a thyroid nodule of over 1 cm (any diameter) is found or if diffuse or focal thyroidal uptake occurs on an 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scan[25]

  • Thyroglobulin: Serum thyroglobulin level can be used as a postoperative tumor marker for well-differentiated thyroid cancer (ie, papillary, follicular); however, it is not recommended that routine serum thyroglobulin measurement be used in the initial evaluation of thyroid nodules[25]

  • Electrophoresis: Two-dimensional gel electrophoresis has also been used as a diagnostic tool to identify tumor-specific proteins from well-differentiated thyroid cancers, but this technique is still being investigated

New diagnostic tests are emerging that offer more precise diagnosis of papillary thyroid carcinoma in its earliest stages. For example, the companies Illumina, Inc. and Life Technologies Corp. developed MiSeq and Ion Torrent, respectively, as research-use-only tests to screen for cancer-specific gene mutations. The ThyroSeq panel, a customized Ion Torrent platform developed at an academic center, identifies 12 genes specific to thyroid cancer, including RAS, BRAF, RET, and TP53. Several tests have become commercially available, with the companies Veracyte, Inc. and Asuragen, Inc. having developed Afirma and miRInform Thyroid, respectively. As it stands, Afirma has greater clinical utility for its sensitivity, while miRInform functions best for its specificity. These tests have made their way into clinical practice, but controversy exists over their best use, and their full potential has yet to be determined.[21, 22]

Fine-needle aspiration

For years no central method for the evaluation of fine-needle aspiration existed. This led to much confusion among cytopathologists and referring physicians until the Bethesda System for Reporting Thyroid Cytopathology was developed by the National Cancer Institute to address terminology and other issues related to fine-needle aspiration. The following are the recommended diagnostic categories:

  • Nondiagnostic or unsatisfactory: Cyst fluid only, virtually acellular specimen, other (obscuring blood, clotting artifact, etc.)

  • Benign: (a) Consistent with a benign follicular nodule (includes adenomatoid nodule, colloid nodule, etc.), (b) consistent with lymphocytic (Hashimoto) thyroiditis in the proper clinical context, (c) consistent with granulomatous (subacute) thyroiditis

  • Atypia of undetermined significance or follicular lesion of undetermined significance

  • Follicular neoplasm or suspicious for a follicular neoplasm

  • Suspicious for malignancy: (a) Suspicious for papillary carcinoma, (b) suspicious for medullary carcinoma, (c) suspicious for metastatic carcinoma, (d) suspicious for lymphoma, (e) other

  • Malignant: (a) Papillary thyroid carcinoma, (b) poorly differentiated carcinoma, (c) medullary thyroid carcinoma, (d) undifferentiated (anaplastic) carcinoma, (e) squamous cell carcinoma, (f) carcinoma with mixed features (specify), (g) metastatic carcinoma, (h) non-Hodgkin lymphoma, (i) other[26]

Imaging Studies

Routine preoperative use of computed tomography (CT) scanning, magnetic resonance imaging (MRI), or PET scanning is not recommended.


Cervical ultrasonography with fine-needle aspiration cytology is the mainstay of the preoperative diagnosis of carcinoma of the thyroid. Iodine-131 scans and CT scans occasionally reveal cold thyroid nodules, requiring a follow-up ultrasonogram and fine-needle aspiration. Similarly, FDG-avid nodules incidentally found on PET scans are occurring with increasing frequency and may require similar clarification.

FDG-PET scanning

PET scanning with FDG depicts many malignancies, including thyroid cancers. The role of FDG-PET scanning in differentiated thyroid cancer has been well described.[27] Efforts to distinguish benign from malignant nodules remain controversial, however, and the modality's expense precludes routine use when malignancy is first diagnosed.[28, 29]

Undifferentiated thyroid carcinomas and recurrent or metastatic thyroid cancer may have decreased iodine-131 avidity and consequently present a diagnostic and therapeutic dilemma. In the setting of elevated thyroglobulins and a negative iodine-131 scan, FDG-PET/CT offers improved sensitivity, frequently revealing abnormal, FDG-avid lesions. Use of FDG-PET/CT during surgical planning for non-iodine – avid recurrent disease has been shown to have significant benefit, especially when ultrasonography is equivocal.

Relative to ultrasonography, the use of FDG-PET scanning as a staging tool remains an expensive imaging modality. It fails to provide any additional staging information that would change surgical treatment, therefore it still has not been recommended as a preoperative diagnostic tool. However, it does continue to have utility in less-differentiated cancers such as H ü rthle cell or anaplastic thyroid carcinoma.[30]

PET and PET/CT scans

In addition to data in the literature demonstrating accurate detection of thyroid cancer by PET, one study has hinted that PET may play a role in the management of patients with inconclusive cytologic diagnosis of a thyroid nodule. In this study, PET reduced the number of negative hemithyroidectomies by 66%. Whether the sensitivity of PET and its cost outweighs the costs and risks associated with thyroid surgery have yet to be determined.

Diagnostic Procedures

Ultrasonographically guided fine-needle aspiration remains the mainstay diagnostic procedure for papillary thyroid cancer. However, a noninvasive technique, real-time ultrasonographic elastography (USE), can be used to evaluate the stiffness of tissue caused by malignancies. Using external pressure, it measures tissue elasticity by distorting tissue structures. Differences in the hardness of the tissues are displayed in color. Malignant histology in thyroid nodules has been predicted to satisfactory levels of certainty using this technique.[31, 32]

Histologic Findings

See Pathophysiology.


Tumors, nodes, and metastases for papillary carcinoma of the thyroid are classified as follows using the American Joint Committee on Cancer (AJCC) staging system:

  • Primary tumor (T)

    • TX: Primary tumor cannot be assessed.

    • T0: No evidence of primary tumor is found.

    • T1: Tumor size is 2 cm or less in greatest dimension and is limited to the thyroid.

    • T2: Tumor size is greater than 2 cm but less than 4 cm, and tumor is limited to the thyroid.

    • T3: Tumor size is greater than 4 cm, and tumor is limited to the thyroid or any tumor with minimal extrathyroidal extension (extension to sternothyroid muscle of perithyroid soft tissues).

    • T4a: Tumor extends beyond the thyroid capsule and invades any of the following: subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve.

    • T4b: Tumor invades prevertebral fascia, mediastinal vessels, or encases the carotid artery.

  • Regional lymph nodes (N)

    • NX: Regional nodes cannot be assessed.

    • N0: No regional node metastasis is found.

    • N1a: Metastasis is found in level VI (pretracheal and paratracheal, including prelaryngeal and Delphian) lymph nodes.

    • N1b: Metastasis is found in unilateral, bilateral, or contralateral cervical or upper/superior mediastinal lymph nodes.

  • Distant metastasis (M)

    • MX: Distant metastasis cannot be assessed.

    • M0: No distant metastasis is found.

    • M1: Distant metastasis is present.

Table 1. Stages of Papillary Carcinoma of the Thyroid (Open Table in a new window)


Younger Than 45 Years

Age 45 Years and Older

Stage I

Any T, Any N, M0

T1, N0, M0

Stage II

Any T, Any N, M1

T2, N0, M0

Stage III


T3, N0, M0, T1, T2, T3, N1a, M0

Stage IVa


T1, T2, T3, N1b, M0, T4a, N0, N1, M0

Stage IVb


T4b, any N, M0

Stage IVc


Any T, any N, M1



Medical Therapy

Adjuvant therapy

Thyroid-stimulating hormone (TSH) suppression therapy using administration of thyroid hormone has been employed for many years; however, the recurrence and survival rates among TSH-suppressed and TSH-nonsuppressed postoperative patients with low-risk papillary thyroid carcinoma are similar. Most centers do not administer thyroid hormone to suppress TSH in euthyroid patients with low-risk papillary thyroid carcinoma.[33]

Iodine-131 can be used to ablate the remaining thyroid gland in patients with a near-total thyroidectomy and in high-risk patients with persistent disease. If uptake of iodine-131 is inadequate, external beam radiation can be used.

Research indicates that in patients with low-risk papillary thyroid cancer, lithium increases the efficacy of thyroid remnant ablation and may therefore be preferable to using higher doses of iodine-131.[34]

However, a study by Hay et al indicated that in adult patients with low-risk papillary thyroid carcinoma who have undergone bilateral lobar resection with curative intent, subsequent radioiodine remnant ablation does not reduce the rate of either cause-specific mortality or tumor recurrence. For example, in patients treated between 1995 and 2014, the 20-year cause-specific mortality and tumor recurrence rates were 0% and 9.2%, respectively, for those who underwent resection, while the rates were 1.4% and 21.0% for individuals who were treated with both resection and ablation.[35]

A study by Suman et al indicated that in patients with papillary thyroid carcinoma with high-risk features, the timing of postthyroidectomy radioiodine therapy does not affect overall survival time. The study included 9706 high-risk patients, with some undergoing early radioiodine therapy (3 mo or less postoperatively), and others undergoing delayed radioiodine treatment (3-12 mo postthyroidectomy). Median survival time was 74.7 months, with adjusted Cox multivariable analysis showing no additional survival benefit to the earlier postoperative therapy. Propensity-matched patients also demonstrated no timing-based survival benefit.[36]

Surgical resection of any involved structures from local extrathyroidal spread is also used in adjuvant therapy.

Surgical Therapy

Thyroidectomy, surgical technique

Conventional thyroidectomy

Thyroidectomy dates to around 1170; however, in the early centuries it remained a rarely performed procedure because of its high morbidity and mortality. The danger of the operation usually came from uncontrolled bleeding and sepsis. However, in the last century, advances in general anesthesia, antisepsis, and hemostasis have paved the way for safe thyroid surgery.

At the forefront of these developments was Theodor Kocher, who performed thousands of thyroidectomies and, through development of specific surgical technique, was able to decrease the mortality of the procedure to less than 1%. Today, we continue to use his time-honored technique for thyroidectomy. This technique involves a midline cervical incision, usually 4-8 cm in length; careful ligation of the thyroid vasculature; identification and preservation of the parathyroid glands; identification and preservation of the recurrent laryngeal nerve; mobilization and removal of the gland; and meticulous hemostasis and closure. In the hands of an experienced surgeon, conventional thyroidectomy is an extremely safe and effective procedure.

Minimally invasive endoscopic thyroidectomy

Over the last several years, novel endoscopic approaches to thyroidectomy have been developed because of a growing desire for the establishment of less-invasive approaches throughout the surgical community. Minimally invasive procedures involve smaller neck incisions compared with conventional thyroidectomy and, as such, tend to demonstrate improved cosmesis, reduced postoperative pain, and shortened hospital stays.

Minimally invasive thyroid surgery can be performed in various ways. True “endoscopic” techniques create a working space within the neck using CO 2 insufflation, with both axillary and neck approaches as starting points for dissection. This technique, however, has resulted in severe hypercarbia and massive cervical subcutaneous emphysema. A more popular technique is the video-assisted technique, which was developed, refined, and popularized in Italy and Japan; it was subsequently established in the United States.

Perhaps the biggest proponent of this technique is Paolo Miccoli, who published his experience with over 550 minimally invasive video-assisted thyroidectomies between 1998 and 2003.[37] The procedure requires a small central neck incision and uses external retraction without neck insufflation. This approach combines a mini incision (1-2 cm) and an approach that is familiar to head and neck surgeons. More importantly, this technique allows treatment of both small benign nodules and small thyroid malignancies. Miccoli showed that patients treated with minimally invasive thyroidectomy demonstrated significantly lower postoperative pain, reduced postoperative distress, and improved cosmesis compared with patients undergoing conventional thyroidectomy procedures.

Other issues regarding the development of minimally invasive techniques for thyroid surgery include their safety, morbidity, and ease of performance when compared with conventional open techniques. Complications rates for recurrent laryngeal nerve palsy and hypoparathyroidism have been similar to those found in open procedures. Operative times appear to be equivalent, after a moderate learning curve is taken into consideration.

Although the indications for minimally invasive thyroidectomy procedures have become standardized for thyroid nodules, some controversy still exists regarding their appropriateness for known thyroid cancer. Several studies have attempted to clarify the growing role for these procedures in thyroid cancer.

In a 2006 report, Takami and Ikeda noted that patients with benign follicular adenomas, low-risk papillary carcinomas less than 10 mm, and oxyphilic cell tumors less than 4 cm could be managed with endoscopic thyroidectomy.[38] In 2005, Caliceti et al examined 15 patients with papillary thyroid carcinoma (none >2 cm) who underwent minimally invasive total thyroidectomy.[39] Although follow-up was limited, they found that results of this technique were similar to those obtained with open thyroidectomy, except that shorter hospital stays and smaller neck wounds were more common in the minimally invasive group.

These studies indicate that minimally invasive techniques are safe for some thyroid cancer patients, but what about the oncologic effectiveness of these procedures? A 5-year follow-up study comparing minimally invasive, video-assisted thyroidectomy with conventional open thyroidectomy showed no significant difference in oncologic effectiveness between the two techniques, although the minimally invasive procedure had better cosmetic results.[40]

Another study, by Miccoli et al, studied the completeness of thyroid resection when performed via a minimally invasive, video-assisted technique. A prospective study of patients with papillary thyroid carcinoma was performed by measuring iodine-131 thyroid bed uptake and serum thyroglobulin levels one month after either minimally invasive thyroidectomy or conventional thyroidectomy. The differences between the 2 techniques were not statistically significant. Several follow-up studies have reinforced these findings, hinting that it is a good surgical option in patients with small papillary thyroid carcinoma. However, long-term results must be evaluated before declaring it equivalent to conventional thyroidectomy.[41]

Because conventional endoscopic surgery has limitations with regard to the manipulation of tissues and the obtainment of adequate visualizations, the da Vinci S surgical robot system was developed. It avoids the use of a neck incision, instead reaching the thyroid via an approach from the axilla across the chest. However, despite offering better visualization and manipulation of tissues, the system has been associated with longer operating times, as well as a significant learning curve, and it comes with an increased cost.[42] Robotic surgery has been shown to be a safe and feasible alternative when compared with conventional open thyroid surgery,[43] but in comparison with conventional endoscopic procedures, it does not appear to have any advantage. The videos below demonstrate several aspects of minimally invasive thyroidectomy.

Minimally invasive thyroidectomy; incision and exposure.
Minimally invasive thyroidectomy; initial dissection.
Minimally invasive thyroidectomy; identification of the recurrent laryngeal nerve.
Minimally invasive thyroidectomy; superior pole release.
Minimally invasive thyroidectomy; division of isthmus and delivery.
Minimally invasive thyroidectomy closure.

Thyroidectomy, extent of surgery


Patients with papillary carcinoma can be separated into low- and high-risk categories for mortality based on prognostic factors. These factors include age, distant metastatic disease, extrathyroidal invasion, and size of primary lesion. Some surgeons believe that hemithyroidectomy is the most appropriate treatment for low-risk papillary carcinoma that is macroscopically localized in one lobe or for patients with occult papillary thyroid cancers. This balances the risk of complications from a more involved surgery with the chance of recurrence. A study of 889 patients, 528 who underwent total thyroidectomy and 361 who underwent hemithyroidectomy, showed similar survival rates among both groups. Comparison of both groups showed no difference in local or regional recurrence.[44] This surgery may be a good choice for patients who may not be compliant with thyroid hormone replacement postoperatively.

Near-total thyroidectomy

A near-total thyroidectomy can be performed to decrease the risk of damage to the recurrent laryngeal nerve or parathyroid glands. Some thyroid tissue is left during the resection and subsequently can be ablated with iodine-131.

Total thyroidectomy

Total thyroidectomy remains the criterion standard treatment for papillary thyroid carcinoma. Total thyroidectomy is recommended if the primary tumor is 1.0 cm or greater, or if extrathyroidal extension or metastases is present. This surgical procedure removes all thyroid tissue so that postoperative iodine-131 is more effective in treating occult disease, eliminates the risk of leaving occult disease in the thyroid, and allows serum thyroglobulin levels to be more sensitive in detecting recurrent or persistent disease. Although the risk of surgical complication is higher than that of hemithyroidectomy or near-total thyroidectomy, most experts agree that the risk of recurrent disease is lower and the survival rate is higher after total thyroidectomy.

Neck disease

The thyroid gland has a rich lymphatic network. Papillary thyroid carcinoma readily enters the intrathyroidal lymphatics and spreads to lymph nodes in the anterior compartment of the neck.

Cervical lymph node involvement is common in papillary thyroid carcinoma, with positive adenopathy in 35% of cases and micrometastatic lymphatic deposits in up to 80% of cases. Up to 10% of patients with papillary thyroid carcinoma have a recurrence in the neck; however, prolonged survival is the norm even in the setting of extensive neck disease. In large longitudinal and case-control studies, positive neck disease had little impact on survival from papillary thyroid carcinoma after controlling for patient age, male sex, extent of disease, and tumor grade.

Elective neck dissection does not offer a benefit in the setting of small (< 1 cm) primary papillary cancers since the 5-year recurrence rates are extremely low in both undissected and dissected necks (< 0.5%). In the setting of multifocal disease within the thyroid, however, the odds of nodal recurrence are 6 times greater than those seen with a single foci of tumor. Performing elective central node dissection in the setting of larger (> 1 cm) and multifocal papillary thyroid carcinomas has several advantages. They are as follows:

  • Provides more tissue for accurate tumor staging

  • Decreases rate of local recurrence

  • Reduces likelihood of a more challenging reoperation that carries a higher risk of complications

  • Reduces local tumor load, which may increase radioactive iodine uptake in distant metastatic foci, if present

  • Renders more patients athyroglobulinemic, again by reducing local tumor load and thus allowing better surveillance

  • Addresses tumors with poor radioactive iodine uptake (papillary tall cell variant, Hürthle cell carcinoma)

Elective neck dissection results in higher rates of temporary recurrent nerve paresis and hypocalcemia; however, these risks may be reduced by injecting the thyroid with isosulfan blue or other tracer to clearly visualize the draining lymph nodes. Lateral neck dissections are reserved for palpable neck disease since subclinical disease usually responds to postoperative radioactive iodine.

Preoperative Details

Cervical lymph node involvement is seen in 20-50% of cases and may be coexistent even when the primary tumor is small and intrathyroidal. Preoperative ultrasonography is the first-line imaging modality used to identify suspicious cervical lymph nodes, but by itself, it identifies only half of the lymph nodes found at surgery. Malignancy in suspicious lymph nodes is confirmed via ultrasonographically guided fine-needle aspiration and/or by measuring thyroglobulin in the needle washout. Routine preoperative use of CT scanning, MRI, and PET scanning is not recommended, but these modalities may be beneficial in patients with large, rapidly growing, or retrosternal or invasive tumors.[24]

Intraoperative Details

The goals of surgical therapy are the removal of the primary tumor and of cancer that has extended beyond the thyroid capsule, as well as the removal of any involved cervical lymph nodes. Minimizing treatment-related morbidity is important, as is accurate staging of the disease, which can aid in prognostication. Surgery must facilitate postoperative treatment with radioactive iodine where appropriate, as this permits accurate, long-term surveillance for disease recurrence. As with most surgical procedures, operative therapy minimizes the risk of disease recurrence and metastatic spread.[24]

Determining the location of lesions in relationship to their surrounding structures is an intraoperative consideration that greatly affects outcome and quality of life. Strap muscles and the recurrent laryngeal nerve, trachea, esophagus, and larynx are often involved with lesions that have extrathyroidal extension. While the strap muscles can be resected with minimal morbidity and resection of the recurrent nerve can occur without change in symptoms, resection of the airway can result in significant morbidity or even mortality. A thorough assessment of the airway and anatomy is critical in decision making in such cases.[45]

Tumors extending to the infrahyoid strap muscles and perithyroid soft tissues can be managed by resection of the involved structure with minimal morbidity. If the malignancy is adherent to the recurrent laryngeal nerve but can be dissected free, then this should be the aim. If the nerve is infiltrated by carcinoma or is completely surrounded by cancer, total removal of the tumor should take priority, and it should be resected.[45]

Extension into the laryngotracheal axis predicts a poor outcome, and controversy exists over the management of airway invasion. Be that as it may, obtaining negative surgical margins remains the hallmark of adequate surgery.[45]

Postoperative Details

Postoperative staging is used to determine prognosis, make decisions regarding postoperative adjunctive therapy and follow-up, and enable accurate communication between health-care providers. AJCC/International Union Against Cancer Control (UICC) staging is recommended for all patients.[24]

Radioactive iodine ablation

It is recommended that all patients undergo radioactive iodine ablation if they have known distant metastases, gross extrathyroidal extension of the tumor (regardless of tumor size), or primary tumor size of greater than 4 cm even in if other higher-risk features are not present.[24]

Radioactive iodine ablation is also recommended for selected patients with thyroid cancers of 1-4 cm that are confined to the thyroid or who have documented lymph node metastases or other higher-risk features. It is not recommended for patients with unifocal cancer of less than 1 cm if higher-risk features are absent or for patients with multifocal cancer if all foci are below 1 cm.[24]

Radioactive iodine ablation can take place after thyroxine withdrawal or recombinant human TSH stimulation. It is recommended that the minimum activity (30-100 mCi) needed for successful remnant ablation be employed. In cases of suspected or documented residual microscopic disease or in the presence of more aggressive tumor histology, higher activities (100-200 mCi) can be used. In patients undergoing radioactive iodine remnant ablation, a low-iodine diet is recommended for 1-2 weeks, particularly if iodine intake is high.[24]

Posttherapy scanning is recommended for patients who have undergone radioactive iodine remnant ablation, with such scanning typically taking place 2-10 days after the therapeutic dose has been administered.[24]

Other therapies

TSH suppression is needed to treat patients with thyroid cancer to decrease recurrence risk. Papillary thyroid cancer, which expresses the TSH receptor on cell membranes, responds to TSH stimulation. It is recommended that TSH initially be suppressed to below 0.1 mU/L in high- and intermediate-risk thyroid cancer patients. TSH levels for low-risk patients can be maintained at 0.1-0.5 mU/L.[24]

In patients over age 45 years with grossly visible extrathyroidal extension, treatment of the primary tumor with external-beam irradiation should be considered. Chemotherapy has no routine adjunctive use in patients with papillary thyroid cancer.[24]


For long-term follow-up care, perform a physical examination and obtain a serum thyroglobulin level, using an immunometric assay that is calibrated against the CRM-457 standard, every 6-12 months. Every serum thyroglobulin measurement should include a quantitative thyroglobulin antibody assessment. In patients who have undergone less than total thyroidectomy and in persons who have had a total thyroidectomy but no radioactive iodine ablation, consider periodically measuring serum thyroglobulin and performing neck ultrasonography.[46]

To verify that the disease is absent, measure serum thyroglobulin after thyroxine withdrawal or recombinant human TSH stimulation about 12 months after ablation in low-risk patients who have undergone remnant ablation, demonstrated negative cervical ultrasonographic results, and been found to have undetectable TSH-suppressed thyroglobulin within the first year after treatment.[46]

Yearly clinical examination and thyroglobulin measurements on thyroid hormone replacement can be the primary means of following low-risk patients who have undergone remnant ablation, demonstrated negative cervical ultrasonographic results, and shown undetectable TSH-stimulated thyroglobulin.[46]

A diagnostic whole-body radioactive iodine scan (DxWBS) is used during follow-up when little or no normal thyroid tissue remains. If disease does not appear on DxWBS regardless of the activity of iodine-131 used, it may occasionally be revealed on a therapeutic whole body scan (RxWBS) performed after the administration of larger, therapeutic doses of iodine-131.[46]

Cervical ultrasonography should be performed 6-12 months after surgery to assess the thyroid bed and the central and lateral cervical nodal compartments.[46]

Serum TSH should be maintained at less than 0.1 mU/L indefinitely in patients with persistent disease.[24] In disease-free patients who are still considered to be at high risk, consider using TSH suppressive therapy to maintain their serum TSH levels at 0.1-0.5 mU/L for 5-10 years.[46]


Complications of resection of papillary thyroid carcinoma are those associated with thyroidectomy. Damage to the recurrent laryngeal nerve can lead to vocal cord paralysis and hoarseness. Damage to the external laryngeal branch of the superior laryngeal nerve may produce dysphonia because it denervates the cricothyroid muscle, which regulates pitch. Transection of the internal branch of the superior laryngeal nerve causes the mucosa of the piriform sinus and false vocal cords to become insensate, thereby placing the patient at an increased risk for chronic aspiration. Resection of the thyroid without reimplantation of parathyroidal tissue may result in hypocalcemia.

In addition to complications arising from surgery, cumulative, dose-related effects can result from radioactive iodine therapy, including the development of nasolacrimal duct obstruction, dental caries, salivary gland damage, and secondary malignancies. Sour candies, hydration, amifostine, and cholinergic agents have been used to prevent salivary gland damage.[24]

A retrospective study by Pajamäki et al indicated that therapy reducing thyroid-stimulating hormone (TSH) levels to under 0.1 mU/L in patients with differentiated thyroid cancer leads to an increased cardiovascular disease (CVD) morbidity rate. However, these patients were found to have a lower CVD mortality rate than did controls, which the investigators suggested might be because the thyroid cancer patients were subject to follow-up examinations, possibly leading to earlier detection and treatment of cardiovascular risk factors.[47]

Outcome and Prognosis

In general, the prognosis for papillary carcinoma of the thyroid is excellent. A long-term survival rate of approximately 90% exists. One study showed a 1-year survival rate of 97.5%, a 5-year survival rate of 92.8%, a 10-year survival rate of 89.5%, and a 20-year survival rate of 83.9%.

Prognostic factors include tumor size, patient age, extrathyroidal spread, and histological variant. The presence of vascular invasion, even within the thyroid gland, is associated with more aggressive disease at diagnosis and has a higher incidence of tumor recurrence. About 30% of patients develop tumor recurrence. Two thirds of recurrences are within the first decade after therapy. Tumors recur outside of the neck in about 21% of those patients with recurrence. The most common site for distant metastasis is the lung. Mortality rates are lower when recurrences are detected early based on radioiodine scans rather than clinical signs. A long delay in initiating the previously described treatment results in more than 2 times the 30-year cancer mortality rate.

Quality of life and psychosocial issues

Despite the relatively favorable prognosis of papillary thyroid carcinoma, multiple studies have demonstrated that the quality of life among these patients is lower than would be expected, both in the initial year after diagnosis and long term.

Follow-up monitoring for thyroid cancer can have profound effects on patients' lives, as they are required to undergo levothyroxine withdrawal prior to whole-body scanning. This places the patient in the position of trying to maintain normal activity and function while experiencing the well-documented effects of hypothyroidism, including increased fatigue, memory loss, mood disturbances, decreased motor skills, and the many other effects of thyroid dysregulation. The impact of this experience on work performance, family relationships, and social life can be detrimental to the well-being of these patients.

Although the significant effects of levothyroxine withdrawal have been documented for some time, significant deficits in the health-related quality of life and psychometric functionality of patients while on maintenance levothyroxine have recently been reported. Although these deficits are less severe than those experienced during periods of levothyroxine withdrawal, they can be significant, as levothyroxine supplementation therapy typically continues for the remainder of a patient's life.

Future and Controversies

Controversy has emerged over changes in epidemiology. The incidence of thyroid cancer has increased rapidly since the beginning of the 21st century. The reasons for this are not completely understood, but increased detection and increased true incidence due to multiple factors are the prevailing theories.

Controversy also exists regarding the treatment of papillary thyroid carcinoma. Treatment with total or near-total thyroidectomy results in a higher surgical complication rate, but more conservative measures result in a higher rate of postoperative cancer recurrence. Determination of prognostic factors to classify patients with papillary carcinoma into high- or low-risk categories for mortality after surgery is ongoing. To date, these prognostic factors include age, histologic grade, extrathyroidal invasion, distant metastases, and sex. Classification into high- and low-risk categories can aid in the determination of the most appropriate type of resection.

While surgery is the cornerstone of treatment for papillary thyroid cancer, the extent of primary surgery needed in low-risk disease is also under debate. Some argue that because papillary thyroid cancer is commonly multifocal and bilateral, total thyroidectomy should be performed to remove all disease. Others favor hemithyroidectomy, because disease-specific survival rates are excellent and recurrence risk is low with this procedure, and because it may allow patients to avoid levothyroxine therapy.[48]

Much of current clinical research on papillary thyroid carcinoma is focused on finding better methods of detection and better prognostic indicators. Headway is being made in the identification of genetic markers in tumor cells that indicate prognosis in general, as well as in the tendency of the cancer to metastasize. Gene expression patterns have been found that can differentiate between benign thyroid tissue and papillary thyroid carcinomas, as well as between papillary and follicular carcinomas.

Although surgery can adequately treat most patients, targeted therapies are being clinically evaluated for individuals who develop progressive, metastatic spread of papillary thyroid carcinoma. For example, the tyrosine kinase inhibitors axitinib, sorafenib, and pazopanib have demonstrated efficacy in phase II trials. In the future, growth modulators, apoptosis modulators, immunomodulators, angiogenesis inhibitors, and gene therapy may aid patients who do not respond to traditional therapy.[49]



Guidelines Summary

Guidelines Contributor: Kemp M Anderson Medical University of South Carolina College of Medicine


The following organizations have released guidelines for the diagnosis and/or management of thyroid cancer:

  • American Thyroid Association (ATA) [50]
  • National Comprehensive Cancer Network (NCCN) [51]
  • American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi (AACE/ACE/AME) [52]  

All of the guidelines advocate ultrasonographic (US) evaluation of thyroid nodules along with measurement of serum thyroid-stimulating hormone (TSH) levels to determine whether a fine needle aspiration biopsy (FNAB) is indicated. A routine measurement of serum thyroglobulin (Tg) for the initial evaluation of thyroid nodules is not recommended, because Tg levels are elevated in most benign thyroid conditions.[50, 51, 52]

Although all of the guidelines recommend FNAB as the procedure of choice in the evaluation of solid thyroid nodules, there is variance in the size of the nodule as an indication for FNAB, as follows[50, 51, 52] :

  • ATA - Nodules ≥1cm with high- or intermediate-risk US features; nodules ≥1.5 cm with low-risk US features; for nodules ≥2 cm with very–low-risk US features, consider FNAB (observation is a reasonable alternative in such cases) [50]
  • AACE/ACE/AME - US high-risk nodules ≥1 cm; US intermediate-risk nodules >2 cm; US low-risk nodules only when >2 cm and increasing in size or associated with a risk history and before thyroid surgery or minimally invasive ablation therapy [52]
  • NCCN - Nodules >1 cm if suspicious US features are present; nodules >1.5 cm if no suspicious US features are present [51]

AACE/ACE/AME and NCCN suggest a serum calcitonin assay as an optional test, [51, 52]  but the ATA guidelines make no recommendation on the routine measurement of serum calcitonin, because of insufficient evidence. [50]  All three guidelines recommend radionuclide imaging in patients with a low TSH level.[50, 51, 52]

Differentiated Thyroid Cancers

Differentiated thyroid cancers arise from thyroid follicular epithelial cells and constitute 90% of all thyroid cancers. The subtypes and approximate frequencies of differentiated thyroid cancers are as follows:

  • Papillary - 85%
  • Follicular - 10%
  • Hürthle or oxyphil - 5%

ATA guidelines state that FNAB provides the most economic and accurate methodology for diagnosing differentiated thyroid cancers. Due to potential false negatives or sampling error, it is recommended that FNAB procedures be performed under US guidance. US guidance is particularly important for nodules located posteriorly and for those that are difficult to palpate. Additionally, certain features found on US examination are predictive for malignancy and may guide FNAB decision-making.[50]  

Papillary thyroid cancer is characterized by the following US features:

  • Solid or predominantly solid
  • Hypoechoic
  • Microcalcifications (highly specific)
  • Infiltrative irregular margins (common)
  • Increased nodular vascularity

Follicular thyroid cancer is characterized by the following US features:

  • Isoechoic to hyperechoic
  • Thick irregular halo

Benign US features are as follows:

  • Purely cystic nodule
  • Spongiform appearance (aggregation of multiple microcystic components >50% volume)

Malignancy risk

Cytologic analysis of FNAB specimens is used to estimate malignancy risk. The most appropriate cytologic classification of malignancy risk is the Bethesda system for thyroid cytopathology, which includes the following categories[53] :

  • Malignant (risk 97-99%)
  • Suspicious for malignancy (risk 60-75%)
  • Follicular neoplasm or suspicious for follicular neoplasm (risk 15-30%)
  • Atypia of undetermined significance or follicular lesion of undetermined significance (risk 5-15% based on repeated atypicals)
  • Nondiagnostic or unsatisfactory (risk 1-4%)
  • Benign (risk 0-3%)

For cytology “diagnostic of” or “suspicious for” papillary thyroid cancer, surgery is recommended.[50]

If FNAB cytology is indeterminate, the use of molecular markers such as BRAF, RAS, RET/PTC, Pax8-PPARɣ, or galectin-3 may be considered to guide management.[50]

An iodine-123 (123I) thyroid scan may be considered if the cytology report documents a follicular neoplasm, especially if serum TSH is in the low-normal range.[50] No radionuclide scan is needed for a reading of “suspicious for papillary carcinoma” or “Hürthle cell neoplasm,” as either lobectomy or total thyroidectomy is recommended, depending on the nodule size and risk factors.

The NCCN recommends that FNAB should be the primary test for differentiated thyroid cancer. If FNAB reveals papillary carcinoma, follicular neoplasm, follicular lesion of undetermined significance, or Hürthle cell neoplasm, the following diagnostic recommendations should be undertaken (these are uniform for all differentiated thyroid carcinomas)[51] :

  • Thyroid and neck ultrasonography (including central and lateral compartments) if not previously done
  • CT scanning/MRI for fixed, bulky, or substernal lesions (iodinated contrast optimal for cervical imaging)
  • Consider evaluation of vocal cord mobility


The treatment of choice for papillary thyroid cancer is surgery, whenever possible, followed by radioiodine (131I) in selected patients and thyrotropin suppression in most patients, according to the National Comprehensive Cancer Network (NCCN) guidelines.[51]

NCCN guidelines recommend total thyroidectomy for patients who meet any of the following criteria[51] :

  • Radiation history
  • Known distant metastases
  • Bilateral nodularity
  • Extrathyroidal extension
  • Tumor >4 cm in diameter
  • Cervical lymph node metastases
  • Poorly differentiated tumor

The NCCN considers either total thyroidectomy or lobectomy to be acceptable for patients who meet all of the following criteria[51] :

  • No prior radiation
  • No distant metastases
  • No cervical lymph node metastases
  • No extrathyroidal extension
  • Tumor < 4 cm in diameter

If a lobectomy is performed, completion of the thyroidectomy is recommended for any of the following[51] :

  • Tumor >4 cm in diameter
  • Positive margins
  • Extrathyroidal extension
  • Macroscopic multifocal disease
  • Macroscopic nodal metastases
  • Confirmed contralateral disease
  • Vascular invasion

American Thyroid Association (ATA) guidelines recommend near-total or total thyroidectomy for all patients with thyroid cancer >1 cm, unless there are contraindications to this surgery. Lobectomy may be considered for small (< 1 cm), low-risk, thyroidal papillary carcinomas in the absence of prior radiation or clinically involved cervical nodal metastases.[50]

Both the NCCN and ATA recommend that therapeutic neck dissection for patients with clinically involved central or lateral neck lymph nodes should accompany total thyroidectomy to provide clearance of disease from the central neck. Prophylactic central-compartment neck dissection (level VI) may be considered in patients with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors (T3 or T4).[50, 51]