Papillary Thyroid Carcinoma

Practice Essentials

Papillary carcinoma (PTC) is the most common form of well-differentiated thyroid cancer, and the most common form of thyroid cancer to result from exposure to radiation. Papillary carcinoma appears as an irregular solid or cystic mass or nodule in a normal thyroid parenchyma.

Despite its well-differentiated characteristics, papillary carcinoma may be overtly or minimally invasive. In fact, these tumors may spread easily to other organs. Papillary tumors have a propensity to invade lymphatics but are less likely to invade blood vessels.

PTC has several histologic variants, which show different patterns of behavior. For example, tall cell PTC (TPPTC) is an uncommon but relatively aggressive variant that is more likely to demonstrate invasion, metastasis, and recurrence.^[1] In contrast,  the encapsulated follicular variant of PTC (eFVPTC) without capsular or vascular invasion poses so little risk that the American Thyroid Association has recommended that it no longer be considered a carcinoma, and instead be reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).^[2]

The life expectancy of patients with PTC is also related to their age. The prognosis is better for younger patients than for patients who are older than 45 years.

Of patients with papillary cancers, about 11% present with metastases outside the neck and mediastinum. Some years ago, lymph node metastases in the cervical area were thought to be aberrant (supernumerary) thyroids because they contained well-differentiated papillary thyroid cancer, but occult cervical lymph node metastases are now known to be a common finding in this disease.^{[3, 4, 5, 6, 7, 8]}

Fine-needle aspiration biopsy (FNAB) is considered the best first-line diagnostic procedure for a thyroid nodule (see Workup). Surgery is the definitive management of papillary thyroid cancer. Approximately 4-6 weeks after surgical thyroid removal, patients may have radioiodine therapy to detect and destroy any metastasis and residual tissue in the thyroid. See Treatment.

For patient education information, see the Thyroid and Metabolism Center, as well as Thyroid Problems.

For discussion of other thyroid cancers, see the following:

• Anaplastic Thyroid Carcinoma
• Follicular Thyroid Carcinoma
• Medullary Thyroid Carcinoma
• Pediatric Thyroid Cancer
• Thyroid Lymphoma
• Thyroid Cancer

An image depicting a thyroid mass can be seen below.

View Image

Standard open thyroidectomy.

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Pathophysiology

Several chromosomal rearrangements have been identified in papillary thyroid carcinoma.The first oncogenic events identified in papillary thyroid carcinoma were chromosomal rearrangements involving the rearranged during transfection (RET) proto-oncogene, which arises from a paracentric inversion of chromosome 10.^[9] RET fusion proteins (the RET/PTC family) appear to play an oncogenic role in approximately 20% of papillary thyroid carcinomas, with RET/PTC1, RET/PTC2, and RET/PTC3 accounting for most cases.^{[10, 9]} In addition, the NTRK1 and the MET proto-oncogene may be overexpressed and/or amplified.^{[11, 12]}

Evidence also suggests that some molecules that physiologically regulate the growth of the thyrocytes, such as interleukin-1 and interleukin-8, or other cytokines (eg, insulinlike growth factor-1, transforming growth factor-beta, epidermal growth factor) could play a role in the pathogenesis of this cancer.

Mutation in the BRAF gene resulting in the BRAF V60E protein is prominent in papillary thyroid carcinoma. A single-institution study by Mathur et al reported increasing rates of BRAF V600E mutations in papillary thyroid cancer from 1991 to 2005, suggesting that this may be contributing to the rise in thyroid cancer rates.^[13] The BRAF V600E mutation is associated with aggressive clinicopathological characteristics of papillary thyroid carcinoma, including lymph node metastasis, extrathyroidal invasion, and loss of radioiodine avidity, which may lead to failure of radioiodine treatment and disease recurrence.^{[14, 15]}

There is also a clear association between radiation exposure (from radiotherapy or fallout) and incidence of papillary thyroid carcinoma.^[16] Port et al reported that papillary thyroid cancers in patients exposed to radiation from the Chernobyl accident could be completely distinguished from sporadic papillary thyroid cancers in patients with no history of radiation exposure, on the basis of gene expression patterns involving seven genes (ie, SFRP1, MMP1, ESM1, KRTAP2-1, COL13A1, BAALC, PAGE1).^[17]

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Etiology

The thyroid is particularly sensitive to the effects of ionizing radiation. Both accidental and medical exposure to ionizing radiation has been linked to increased risk for thyroid cancer.

Approximately 7% of individuals exposed to the atomic bombs in Japan developed thyroid cancers.^[18] Individuals, especially children, who lived in Ukraine during the time of the Chernobyl nuclear event may have increased risk of papillary thyroid cancer.^[19]

From 1920-1960, therapeutic irradiation was used to treat tumors and benign conditions, including acne; excessive facial hair; tuberculosis in the neck; fungus diseases of the scalp; sore throats; chronic coughs; and enlargement of the thymus, tonsils, and adenoids. Approximately 10% of individuals who were treated with head and neck irradiation for such disorders developed thyroid cancer after a latency period of 30 years.

Exposure to diagnostic x-ray beams does not increase the risk of developing thyroid cancers. However, patients who receive radiotherapy for certain types of head and neck cancer, especially during childhood, may have an increased risk of developing thyroid cancer.

Several reports have shown a relationship between iodine deficiency and the incidence of thyroid carcinomas. Many other conditions have been considered as predisposing to papillary thyroid cancer, including oral contraceptive use, benign thyroid nodules, late menarche, and late age at first birth.^{[20, 21]} Tobacco smoking seems to be associated with a decreased risk of thyroid cancer, but, obviously, it poses more health hazards than benefits.^[22]

Unlike medullary thyroid carcinoma, papillary thyroid cancer is not a part of multiple endocrine neoplasia syndromes. However, uncommon familial syndromes such as familial adenomatous polyposis (FAP), Gardner syndrome (Gardner's syndrome), and Cowden disease (Cowden's disease) may be associated with thyroid papillary tumors in about 5% of cases.^[23]

In particular, FAP is associated with elevated risk of the rare cribriform-morula variant of papillary thyroid carcinoma (CMV-PTC). A study of 129 Japanese patients with FAP who underwent screening with neck ultrasonography found 11 cases of papillary thyroid cancer, eight of which were CMV-PTC. All the patients with CMV-PTC were women 35 years of age or younger.^[24]

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Epidemiology

Thyroid cancers account for only 1.5% of all cancers in adults and 3% of all cancers in children. In females, however, thyroid cancers are the fifth most common cancer, comprising 6% of all cases.^[24] In addition, the rate of new cases has been increasing in recent decades.^[25]

The American Cancer Society estimates that approximately 56,870 new cases of thyroid cancer will occur in the United States in 2017, with about 42,470 occurring in women and 14,400 in men, and that about 2,010 people (1,090 women and 920 men) will die of thyroid cancer.^[26] The highest incidence of thyroid carcinomas in the world is found among female Chinese residents of Hawaii.

Of all thyroid cancers, 74-80% of cases are papillary cancer. Follicular carcinoma incidences are higher in regions where goiter is common.

Mortality/Morbidity

In contrast to many other cancers, thyroid cancer is almost always curable. Most thyroid cancers grow slowly and are associated with a very favorable prognosis. The mean survival rate after 10 years is higher than 90%, and is 100% in very young patients with minimal nonmetastatic disease. Distant spread (ie, to lungs or bones) is very uncommon.

The 5-year relative survival rates by stage of diagnosis are as follows^[26] :

• All stages: 96.7%>
• Local: 99.7%
• Regional: 96.9%
• Distant: 56%

Race

This cancer occurs more frequently in whites than in blacks. The 5-year relative survival rates by race increased from 1975 to 2003, as follows^[26] :

• Whites: Increase from 93% to 97%
• African Americans: Increase from 91% to 94%
• All races: Increase from 93% to 97%

Sex

Thyroid cancer is approximately three times more common in females than males. The female-to-male ratio varies by patient age, as follows:

• In patients younger than 19 years, the female-to-male ratio is 3.2:1
• In patients aged 20-45 years, the female-to-male ratio is 3.6:1
• In patients older than 45 years, the female-to-male ratio is 2.8:1

Age

Thyroid carcinoma is common in persons of all ages, with a mean age of 49 years and an age range of 15-84 years. In the younger population, papillary thyroid carcinoma tends to occur more frequently than follicular carcinoma, with a peak in patients aged 30-50 years.

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Prognosis

The prognosis in patients with papillary thyroid cancer is related to age, sex, and stage. In general, if the cancer does not extend beyond the capsule of the gland, life expectancy is minimally affected. Prognosis is better in females and in patients younger than 40 years. The survival rate is at least 95% with appropriate treatments.

If neglected, any thyroid cancer may result in symptoms because of compression and/or infiltration of the cancer mass into the surrounding tissues, and the cancer may metastasize to lung and bone. Metastases, in descending order of frequency, are most common in the neck lymph nodes and lung, followed by the bone, brain, liver, and other sites. Metastatic potential seems to be a function of the primary tumor size. Metastases in the absence of thyroid pathology in the physical examination findings are rare in patients with microscopic papillary carcinoma (occult carcinomas).

In a long-term follow-up study of children and adolescents with papillary thyroid cancer, Hay et al found that all-causes mortality rates did not exceed expectation through 20 years after treatment, but the number of deaths was significantly higher than predicted from 30 through 50 years afterward. Nonthyroid malignancy accounted for 68% of deaths, and, of that group, 73% had received postoperative therapeutic irradiation.^[27]

A study by Yu et al found that papillary thyroid microcarcinomas are generally associated with an excellent prognosis; however, 0.5% of patients may die. Risk factors for overall survival include the following:

• Age older than 45 years
• Male sex
• Minority race
• Node metastases
• Extrathyroidal invasion
• Distant metastases

If two or more risk factors are present, patients should be considered for more aggressive management.^[28]

A study by Miyauchi et al found that serum thyroglobulin doubling time was a significant prognostic predictor in patients with papillary thyroid carcinoma. The authors concluded that this finding was superior to classical prognostic factors, including TNM stage, age, and gender.^[29]

In a study of 39,562 patients with papillary thyroid carcinoma from the National Cancer Data Base, risk factors for central lymph node metastasis included the following^[30] :

• Age ≤45 years
• Male sex
• Asian race
• Tumor >1 cm

A family history of papillary thyroid carcinoma is an independent risk factor for disease recurrence in patients with papillary thyroid microcarcinoma.^[31]

For patients found to be at intermediate risk on the basis of established prognostic factors, Brennan and colleagues report that gene expression signatures may permit classification into intermediate-good prognosis and intermediate-poor prognosis groups. The authors note that their findings require validation, but they observe that tests that routinely measure expression of hundreds of genes are already commercially available.^[32]

A retrospective study of clinicopathological outcomes of 6282 patients with PTC demonstrated significant differences in recurrence and disease-specific patient survival with three histologic variants of PTC. Particularly in patients at least 45 years old, patients with tall-cell PTC had the worse prognosis; those with conventional PTC had an intermediate prognosis, and those with follicular-variant PTC had the best prognosis.^[1]

Indeed, the American Thyroid Association has recommended that the encapsulated follicular variant of PTC (eFVPTC) without capsular or vascular invasion be reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).^[2] Recurrence of NIFTP is extremely rare, even in patients treated with surgery alone, without radioactive iodine therapy, and ceasing to classify it as a cancer may help clinicians avoid unnecessary aggressive treatment.^[33]

Diffuse sclerosing papillary thyroid carcinoma (DSPTC) is an uncommon variant of papillary thyroid carcinoma. A systematic review and meta-analysis by Vuong et al concluded that DSPTC should be considered a high-risk condition, because it has a high propensity for tumor invasion, metastasis, relapse, and mortality, compared with classic papillary thyroid carcinoma.^[34]

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History

The most common presentation of thyroid cancer is an asymptomatic thyroid mass or a nodule that can be felt in the neck. For any patient with a thyroid lump that has developed recently, record a thorough medical history to identify any risk factors or symptoms. In particular, obtain a history regarding every prior exposure to ionizing radiation and the lifetime duration of the radiation exposure. Consider a family history of thyroid cancer.

Some patients with thyroid cancer have persistent cough, difficulty breathing, or difficulty swallowing. Pain is seldom an early warning sign of thyroid cancer. Other symptoms (eg, pain, stridor, vocal cord paralysis, hemoptysis, rapid enlargement) are rare, and can be caused by less serious problems.

At the time of diagnosis, 10-15% of patients with papillary thyroid carcinoma have distant metastases to the bones and lungs. Initially, these patiens are evaluated for pulmonary or osteoarticular manifestations (eg, pathologic fracture, spontaneous fracture).

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Physical Examination

The clinician should palpate the patient's neck to evaluate the size and firmness of the thyroid and to check for any thyroid nodules. The principal sign of thyroid carcinoma is a palpable nodule, usually solitary, in the thyroid area that has the following characteristics:

• Painless
• Hard consistency
• Average size of less than 5 cm
• Ill-defined borders
• Fixed in respect to surrounding tissues
• Moves with the trachea at swallowing

If cervical lymphadenopathy is present, it may be palpable on either the ipsilateral or contralateral side.

Some patients have a tight or full feeling in the neck, hoarseness, or signs of tracheal or esophageal compression.

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Approach Considerations

The following workup should be considered for the diagnosis of papillary carcinoma, a relatively common well-differentiated thyroid cancer:

• Thyroid function studies
• Thyroid-stimulating hormone (TSH) suppression test
• Thyroid ultrasound
• Fine-needle aspiration biopsy (FNAB)

If possible, assessment of the RET proto-oncogene expression should be performed in any patient having a relative with a history of papillary thyroid cancer. Papillary thyroid cancer is strongly associated with some specific rearrangements of RET.^[38]

The serum level of carcinoembryonic antigen (CEA) can be measured (reference range is < 3 ng/dL). However, the implications of an elevated CEA level are not specific; CEA levels are high in several cancers, and numerous healthy people may have small amounts of CEA, especially pregnant women and heavy smokers.

Procedures

FNAB is considered the best first-line diagnostic procedure for a thyroid nodule. A thyroid biopsy can also be performed using the classic Tru-Cut or Vim-Silverman needles, but the FNAB technique is preferable. Patients comply best with FNAB.

Perform indirect or fiberoptic laryngoscopy to evaluate airway and vocal cord mobility and to have preoperative documentation of any unrelated abnormalities.

Imaging studies

Chest radiography, computed tomography (CT), and magnetic resonance imaging (MRI) are not usually used in the initial workup of a thyroid nodule. National Comprehensive Cancer Network (NCCN) guidelines recommend CT or MRI for the evaluation of fixed, bulky, or substernal lesions.^[8] Chest x-ray may be considered in patients with apparent metastatic disease at presentation.

A study by Choi et al concluded that preoperative [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)/CT did not provide any additional information compared with neck sonography in patients with papillary thyroid carcinoma.^[39]

Cabrera et al reported that single-photon emission computed tomography (SPECT)/CT and radioguided sentinel lymph node biopsy (rSLNB) can affect therapy by detecting occult cervical lymph node metastases in patients with papillary thyroid carcinoma. In their study, rSLNB results prompted management changes in 14 of 37 patients, with use of higher radioiodine ablation doses and closer clinical surveillance.^[40]

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Thyroid Function Studies

Perform a complete assessment of thyroid function in any patient with thyroid nodules. No available blood tests are specific for papillary cancer of the thyroid. Higher-than-normal levels of thyroxine (reference range is 4.5-12.5 mcg/dL), triiodothyronine (reference range is 100-200 ng/dL), and thyroid-stimulating hormone (TSH) (reference range is 0.2-4.7 mIU/dL) may or may not be associated with thyroid cancer.

If the TSh level is low, thyroid scintigraphy is indicated. If the scan reveals an autonomously functioning (hot) nodule, the patient should undergo evaluation for thyrotoxicosis, as malignancy is rare in such cases.^[8]

Evaluate serum levels of thyroglobulin. Calcium and calcitonin may be elevated in medullary carcinoma of the thyroid.

TSH suppression test

Thyroid cancer is autonomous and does not require TSH for growth, whereas benign lesions do require TSH. When exogenous thyroid hormone feeds back to the pituitary to decrease the production of TSH, thyroid nodules that continue to enlarge are likely to be malignant. However, 15-20% of malignant nodules are suppressible.

Preoperatively, the TSH suppression test is useful for patients with nontoxic solitary benign nodules and for women with repeated nondiagnostic test results. Postoperatively, the test is useful for monitoring papillary thyroid cancer cases.

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Thyroid Ultrasound

Thyroid ultrasound is the first imaging study to perform in any patient with possible thyroid malignancy. Ultrasound is noninvasive and inexpensive, and it represents the most sensitive procedure for identifying thyroid lesions and for determining the diameters of a nodule.

Ultrasound is also useful for localizing lesions when a nodule is difficult to palpate or is deeply seated. The images can help determine if a lesion is solid or cystic and can help detect the presence of calcifications.

Ultrasound may be used to help direct a fine-needle aspiration biopsy (FNAB).

Pulsed and power Doppler ultrasound may provide important information about the vascular pattern and the velocimetric parameters. Such information can be useful preoperatively to reach a correct differential diagnosis of malignant or benign thyroid lesion.

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Scintigraphy

Before the advent of fine-needle aspiration biopsy (FNAB), thyroid scintigraphy (or thyroid scanning) performed with technetium Tc 99m pertechnetate (99mTc) or radioactive iodine (I¹³¹ or I¹²³) was the initial diagnostic procedure of choice for a thyroid evaluation. The procedure is not as sensitive or specific as FNAB for distinguishing benign nodules from malignant nodules. Iodine-containing compounds and seafood interfere with any tests using radioactive iodine.

Scintigraphic images of the thyroid are acquired 20-40 minutes after intravenous administration of the radionuclide. In more than 90% of cases, clearly benign nodules appear as hot nodules because they are hyperfunctioning and have a high captation rate of radionuclide and, physiologically, of iodine. Malignant nodules usually appear as cold because they are not functioning.

Findings from thyroid scanning are helpful and specific in the preoperative and immediate postoperative periods for localization of cancer or residual thyroid tissue and in observing for tumor recurrence or metastasis. Thyroid scanning can also be useful for diagnosing benign lesions (by FNAB) or solid lesions (by echography).

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Fine-Needle Aspiration Biopsy

Fine-needle aspiration biopsy (FNAB) is considered the best first-line diagnostic procedure for a thyroid nodule. FNAB is a safe and minimally invasive procedure.

To perform FNAB, administer local anesthesia at the puncture site, then guide the aspiration biopsy needle (21- or 23-gauge) into the mass. Hold the nodule with the fingers of the left hand while introducing the needle through the skin into the thyroid nodule with the right hand. After aspiration, the material is deposited on a glass slide, fixed with alcohol-acetone, and then stained according to the Papanicolaou test protocol.

The accuracy of FNAB results is better than any other test for detecting papillary thyroid carcinoma. The sensitivity of the procedure is near 80%, the specificity is near 100%, and errors can be diminished using ultrasonographic guidance. False-negative and false-positive results occur less than 6% of the time, as the pathologist may experience difficulty distinguishing some benign cellular adenomas from their malignant counterparts.^[41]

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Histologic Findings

Papillary thyroid carcinoma usually appears as a grossly firm mass that is irregular and not encapsulated. Microscopically, it is multifocal, and a net invasion of the lymphatics may be demonstrated. Complete or partial papillary architecture with some follicles is present. Otherwise, in some patients, the tumor may lack any papillary pattern.

The thyrocytes are large and show an abnormal nucleus and cytoplasm with several mitoses. In some cases, the thyrocytes may have so-called "Orphan Annie eyes," that is, large round cells with a dense nucleus and clear cytoplasm. Another typical feature of this cancer is the presence of psammoma bodies, probably the remnants of dead papillae.

On immunohistochemistry, papillary thyroid carcinoma usually exhibits the following pattern:

• Carcinoembryonic antigen (CEA) negative
• Calcitonin negative
• Thyroglobulin positive
• Keratin positive

A study by Liu et al found that when hematoxylin and eosin staining demonstrates loss of cellular polarity/cohesiveness (LOP/C) in the invasive front of papillary thyroid carcinoma, this finding may indicate lymph node metastasis and aggressive clinical behavior of the cancer. LOP/C of 20% or greater correlated significantly with extrathyroid invasion, advanced tumor stage, and recurrence after surgery.^[42]

 The Afirma gene expression classifier (GEC) test uses thyroid cells obtained at the time of biopsy to screen for molecular markers (genes) that are associated with thyroid cancer. Its manufacturer claims that the test can predict which indeterminate nodules are likely to be benign (with 95% certainty), and therefore do not require surgery, from those that are likely cancerous (with 50% certainty) and need to be referred to surgery. The hope is that this test will prevent unnecessary thyroid surgeries.

In a multicenter study of Afirma GEC testing of cytologically indeterminate nodules in 393 patients, GEC results significantly altered care recommendations, as 4 of 175 GEC benign nodules were recommended for surgery, versus 141 of 149 GEC suspicious nodules. Of 121 cytologically indeterminate/GEC suspicious nodules surgically removed, 53 (44%) proved to be malignant. On clinical follow-up for an average of 8.5 months, one of 71 GEC-benign nodules proved cancerous.^[43]

The encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) demonstrates highly indolent behavior. To distinguish this variant from conventional papillary thyroid cancer—and reduce the psychological and clinical consequences associated with the diagnosis of cancer—an international team of thyroid pathologists, and the the American Thyroid Association, have recommended reclassifying EFVPTC as "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP).^{[44, 2]}

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Staging

The staging of well-differentiated thyroid cancers follows the tumor, node, metastasis (TNM) classification system. Staging differs, depending on whether the patient is younger or older than 45 years of age.

Staging for patients younger than 45 years is as follows:

• Stage I - Any T, any N, M0 (cancer in thyroid only)
• Stage II - Any T, any N, M1 (cancer spread cervical lymph nodes or to distant organs)

Staging for patients aged 45 years and older is as follows:

• Stage I - T1, N0, M0 (cancer only in thyroid, and less than 2 cm)
• Stage II - T2, N0, M0 and T3, N0, M0 (cancer only in thyroid and between 2-4 cm)
• Stage III - T4, N0, M0 and any T, N1, M0 (tumor greater than 4 cm or cancer spread outside thyroid but not outside of the central neck compartment)
• Stage IV - Any T, any N, M1 (cancer spread to either cervical lymph nodes outside of the central neck or distant organs)

See Thyroid Cancer Staging for more information.

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Approach Considerations

Surgery is the definitive management of papillary thyroid cancer. Approximately 4-6 weeks after surgical thyroid removal, patients may have radioiodine therapy to detect and destroy any metastasis and residual tissue in the thyroid.

External beam radiotherapy has been used as adjuvant therapy in patients with papillary thyroid cancer who were older than 45 years and had locally invasive disease. Some improvements in 10-year survival rates have been reported with this approach.

Patients require lifelong thyroid hormone replacement therapy, especially after total thyroidectomy. Treatment consists of levothyroxine in a dosage of 2.5-3.5 mcg/kg/d.

For summarized information on treatment, see Thyroid Cancer Treatment Protocols.

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Surgical Care

Surgery is the definitive management of thyroid cancer. Various types of operations may be performed, ranging from lobectomy with isthmectomy to total thyroidectomy.

Lobectomy with isthmectomy is the minimal operation for a potentially malignant thyroid nodule. It is an option for patients younger than 40 years who have papillary thyroid carcinoma nodules that are smaller than 1 cm, well-defined, minimally invasive, and isolated. However, an important consideration in considering this approach is that approximately 10% of patients who have had only a lobectomy develop a recurrence in the contralateral lobe, and residual tissue has the potential to dedifferentiate to anaplastic cancer.

Subtotal thyroidectomy is a near-total thyroidectomy. The argument for this form of surgical intervention is that total thyroidectomy does not improve long-term prognosis, and subtotal thyroidectomy has a lower incidence of complications (eg, hypoparathyroidism, superior and/or recurrent laryngeal nerve injury) than total thyroidectomy.

Total thyroidectomy

Total thyroidectomy (removal of all thyroid tissue but preservation of the parathyroid glands) is commonly performed for patients with papillary carcinoma who are older than 40 years and in any patient with bilateral disease. In addition, total thyroidectomy is used in most patients with a thyroid nodule and a history of irradiation.

National Comprehensive Cancer Network guidelines recommend total thyroidectomy for patients who meet any of the following criteria^[8] :

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

Total thyroidectomy is considered by many to be the surgical treatment of choice for papillary tumors of the thyroid, for a number of reasons. Papillary foci involving both lobes are found in some 60-85% of patients. About 5-10% of patients who have had a lobectomy develop recurrences in the remaining lobe. Also, at 20 years after initial surgery, patients who had undergone total thyroidectomy had a recurrence rate of 8%, whereas those who had received lobectomy only had a recurrence rate of 22%. Survival rates were, however, comparable.

Total thyroidectomy also facilitates earlier detection and treatment of recurrent or metastatic carcinoma. This surgical option is mandatory in patients with papillary carcinoma discovered on postoperative histology (ie, if a very well-differentiated tumor is discovered) after a lobectomy, with or without isthmectomy.

When the primary tumor spreads outside the thyroid and involves adjacent vital organs (eg, larynx, trachea, esophagus), these organs are preserved at the first surgical approach. However, the surrounding soft tissues, including the muscles and involved areas of the trachea and/or esophagus, may be sacrificed if they are directly involved with the differentiated thyroid carcinoma and local resection is feasible.

Surgical techniques include video-assisted and robotic-assisted thyroidectomy.^{[45, 46]} Video-assisted thyroidectomy is rarely used to treat thyroid cancer. A study by Lee et al found that the application of robotic technology to endoscopic thyroidectomy may overcome the limitations of conventional surgery, in a patient population where neck incision is considered culturally averse. However, additional complications such as brachial plexus injury may occur with this technique.^[47]

Central neck dissection

The routine addition of central neck dissection to total thyroidectomy has been debated over the years. Advocates cite a lower risk of later reoperation, since reoperations for recurrence can lead to higher rates of recurrent nerve injury. Critics cite the fact the upfront recurrent nerve injury rate may be higher and that no survival benefit has been demonstrated over total thyroidectomy alone.In a retrospective cohort study of 812 patients with papillary thyroid carcinoma, including 102 who underwent total thyroidectomy with elective central neck dissection and 478 who underwent total thyroidectomy alone, elective central neck dissection increased the risk for complications, but did not decrease local recurrence rates.^[48]

A study by Roh et al found that subclinical metastases are highly prevalent in the ipsilateral central neck of patients with papillary thyroid carcinoma. The study also revealed that although contralateral central metastases are uncommon, they are associated with ipsilateral central metastases. The authors conclude that these findings may suggest the necessity and extent of prophylactic unilateral or bilateral central lymph node dissection.^[49]

A study by Popadich et al found that the addition of routine central lymph node dissection in patients with cN0 papillary thyroid carcinoma reduced the need for reoperation in the central compartment and was associated with lower postoperative thyroglobulin levels.^[50]

Complications

Surgical treatment of thyroid cancer may cause complications, partly because of the variable anatomy of the neck. These possible complications include the following:

• Hypothyroidism
• Dysphagia due to damage of the upper laryngeal nerve
• Vocal cord paralysis due to damage of recurrent laryngeal nerve
• Hypoparathyroidism due to parathyroid gland ablation

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Radioiodine Therapy

Approximately 4-6 weeks after surgical thyroid removal, patients may have radioiodine therapy to detect and destroy any metastasis and residual tissue in the thyroid. The decision for radioactive iodine depends on the size of the tumors removed, the prognostic features (eg, lymphovascular invasion) and the individual endocrinologist’s level of aggressiveness and interpretation of the literature. Patients with low-risk differentiated papillary thyroid cancer have shown excellent responses to total thyroidectomy without radioiodine remnant ablation.^[51]

After thyroidectomy, patients are given thyroid replacement therapy for approximately 4-6 weeks. Thyroid replacement is then discontinued, to induce a hypothyroid state and promote high serum thyroid-stimulating hormone (TSH) levels.

A diagnostic dose of radioiodine (¹³¹I or ¹²³I) is then given, and a whole-body scintiscan is performed to detect any tissue taking up radioiodine. If any normal thyroid remnant or metastatic disease is detected, a therapeutic dose of¹³¹ I is administered to ablate the tissue. The patient is then placed back on thyroid hormone replacement (levothyroxine) therapy.

Therapy is administered until radioiodine uptake is completely absent. Radioiodine treatment may be used again 6-12 months after initial treatment of metastatic disease, for cases in which disease recurs or has not fully responded.

Some patients have elevated stimulated thyroglobulin concentrations after reoperation for recurrent or persistent papillary thyroid cancer. Yim and colleagues found that in such patients, adjuvant radioiodine therapy resulted in no significant differences compared with no additional radioiodine therapy.^[52]

Patients receiving radioiodine therapy need to follow radiation precautions, to maintain the safety of themselves, their familes, and the public. The American Thyroid Association Taskforce on Radioiodine Safety released recommendations to help guide physicians and patients in safe practices after treatment, including reminders in the form of a checklist.^[53]

Complications

Potential adverse effects of radioiodine administration include  the following:

• Radiation thyroiditis and transient thyrotoxicosis in patients with simple lobectomy
• Sialoadenitis, because radioiodine is taken up by the salivary glands
• Nausea, anorexia, and headache (uncommon)
• Pulmonary fibrosis in patients with large lung metastases
• Brain edema in patients with brain metastases (may be prevented by glucocorticoid therapy)
• Permanent sterility and transient oligospermia or menstrual irregularities
• Teratogenesis and spontaneous abortions
• A small increase in the risk for leukemias (in particular, acute myeloid leukemia^[54] ) or breast and bladder carcinomas

Because radioiodine treatment may cause either teratogenesis or spontaneous abortions, patients should delay pregnancy for at least 1 year after radioiodine treatment.

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Treatment of Advanced Disease

A study by Heilo et al determined that ultrasonography-guided percutaneous ethanol injections were an excellent alternative to surgery in patients with a limited number of neck metastases from papillary thyroid carcinoma. The authors suggest that this strategy could replace “berry picking” surgery.^[55]

In patients with stage T4 disease, external beam radiation therapy (EBRT) may be performed to control local tumor growth in areas such as the neck, lungs, mediastinum, bone, and central nervous system. Radiation therapy may be indicated when a large, unresectable tumor is present and the uptake of radioiodine is limited, or when intractable bone pain exists. The American College of Radiology recommends that EBRT use of EBRT for thyroid cancer be considered on a case-by-case basis, as it has not been tested in well-designed, randomized, controlled trials.^[56]

Chemotherapy with cisplatin or doxorubicin has limited efficacy, producing occasional objective responses (generally for short durations), and high toxicity. Chemotherapy may be considered in symptomatic patients with recurrent or advancing disease, and it may improve the quality of life in patients with bone metastases. However, a standard protocol for chemotherapeutic management has not been developed for these patients.

Novel agents are under active investigation as options for systemic therapy.^[57] Agents that have been studied in patients with metastatic thyroid carcinoma includemultitargeted kinase inhibitors (eg, levatinib, sorafenib, sunitinib, axitinib, vandetanib, pazopanib) and BRAF V600E mutation inhibitors (eg, vemurafinib, dabarafenib).^[58] Preliminary data suggest that anaplastic lymphoma kinase (ALK) inhibitors such as crizotinib may be useful in PTC with fusion of the striatin (STRN) and the ALK genes.^[59]

The American College of Radiology recommends encouraging patients with metastatic thyroid cancer that is not iodine avid to enroll in clinical trials of these agents.^[56]

A discussion of recently available targeted therapies for use in advanced differentiated thyroid cancer no longer responsive to radioablation may be found in the Chemotherapy section of Follicular Thyroid Carcinoma.

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Consultations

Consult an otolaryngologist, especially in thyroid patients who have voice disturbances. Systematic psychotherapeutic intervention may be very helpful.

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Long-term Monitoring

Repeat the radioiodine scintiscan 6-12 months after ablation and every 2 years thereafter. Before the scan, levothyroxine must be withdrawn for approximately 4-6 weeks to maximize thyrotropin stimulation of the any remaining thyroid tissue.

At 6 and 12 months after the cancer treatment (medical or surgical),patients with a history of papillary thyroid carcinoma require follow-up monitoring that includes the following:

• Complete physical examination
• Thyroid-stimulating hormone (TSH) and thyroglobulin measurement
• Antithyroglobulin antibodies titer

Continue to evaluate thyroglobulin serum levels every 6-12 months for at least 5 years. Consider a level greater than 20 ng/mL, after TSH suppression, to be abnormal. A rise in the thyroglobulin level is consistent with recurrence of thyroid cancer. A study by Brassard et al found that thyroglobulin measurements allow prediction of long-term recurrence with excellent specificity. TSH stimulation may be avoided when thyroglobulin levels measured 3 months after ablation are less than 0.27 ng/mL during levothyroxine treatment.^[60]

Perform thyroid hormone suppression tests in all patients who have undergone total thyroidectomy and in all patients who have had radioactive ablation of any remaining thyroid tissue. Individualize the degree of suppression to avoid complications, such as subclinical hyperthyroidism.

In pattients who were treated with radioactive iodine ablation and who have a negative thyroid ultrasound, a stimulated thyroglobulin level < 2 ng/mL with negative antithyroglobulin antibodies, and negative radioactive iodine imaging (if performed), the National Comprehensive Cancer Network advises that follow-up may consist of annual measurement of unstimulated thyroglobulin levels and periodic neck ultrasound. TSH-stimulated testing or other imaging, as clinically appropriate, may be considered if there is any clinical suggestion of recurrent disease.^[8]

A meta-analysis demonstrated that an undetectable serum thyroglobulin finding during thyroid hormone suppression of TSH is often misleading. Patients with endogenous subclinical hyperthyroidism have an increased risk of cardiovascular disease and dysrhythmia.^[61] Accordingly, the authors propose a new surveillance guideline for patients who have undergone total or near-total thyroidectomy and radioactive iodine ablation and have no clinical evidence of residual tumor with a serum thyroglobulin level less than 1 mcg/L during thyroid hormone suppression of TSH.

Subclinical hypothyroidism may also occur. However, the clinical significance of subclinical hypothyroidism, and the benefits of treating it, remain uncertain.^{[62, 63]}

Guidelines from the American Association of Clinical Endocrinologists (AACE) and the American Association of Endocrine Surgeons include recommendations for follow-up in patients with thyroid carcinoma.^[7]

Patients require lifelong thyroid hormone replacement therapy, especially after total thyroidectomy. Treatment consists of levothyroxine in a dosage of 2.5-3.5 mcg/kg/d. A patient who has had a thyroidectomy without parathyroid preservation requires vitamin D and calcium supplementation for life.

• References

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)^[64]
• National Comprehensive Cancer Network (NCCN)^[8]
• American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid Association (AACE/AME/ETA^[65]  (diagnosis only)

Diagnosis

All the guidelines advocate ultrasound 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.^{[64, 8, 65]}

Although all 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.^{[64, 8, 65]}

• >0.5 cm in diameter (ATA)^[64]
• >1 cm, in the absence of suspicious sonographic features (AACE/AME/ETA)^[65]
• ≥1 cm if suspicious sonographic features are present; ≥1.5 cm if no suspicious sonographic features are present (NCCN)^[8]

Although all 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.333435 AACE/AME/ETA indications for FNAB according to size are as follows^[65] :

• Lesions ≥10 mm with high-risk US features
• Lesions ≥20 mm with intermediate-risk US features
• Lesions >20 mm with low-risk US features, but that are increasing in size or associated with a risk history and before thyroid surgery or minimally invasive ablation therapy

Other guidelines provide the following recommendations:

• >0.5 cm in diameter (ATA)^[64]
• ≥1 cm if suspicious sonographic features are present; ≥1.5 cm if no suspicious sonographic features are present (NCCN)^[8]

AACE/AME/ETA and NCCN suggest a serum calcitonin assay as an optional test, ^{[8, 65]}  but the ATA guidelines make no recommendation on the routine measurement of serum calcitonin because of insufficient evidence. ^[64]  All three guidelines recommend radionuclide imaging in patients with a low TSH level.^{[64, 8, 65]}

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 economical 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 ultrasound (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.^[64]  

Papillary thyroid cancer is characterized by the following US features:

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

Follicular thyroid cancer is characterized by the following US features:

• Iso- to hyper-echoic
• Thick irregular halo

Benign US features are as follows:

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

Malignancy risk

Cytological analysis of FNAB specimens is used to estimate malignancy risk. The most appropriate cytological classification of malignancy risk is the Bethesda system for thyroid cytopathology, which comprises the following categories^[66] :

• 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)
• Non-diagnostic or unsatisfactory (risk 1-4%)
• Benign (risk 0-3%)

For cytology “diagnostic of” or “suspicious for” papillary thyroid cancer, surgery is recommended. 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.^[64]

An iodine-123 (¹²³I) thyroid scan may be considered if the cytology report documents a follicular neoplasm, especially if serum thyroid-stimulating hormone (TSH) is in the low-normal range^[64] . 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.^[64]

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)^[8] :

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

• References

Treatment

The treatment of choice for differentiated thyroid cancers 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.^[8]

NCCN guidelines recommend total thyroidectomy for patients who meet any of the following criteria^[8] :

• 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, ^[8] :

• 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^[8] :

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

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.^[64]

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).^{[64, 8]}

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Medication Summary

The most useful drugs for the treatment of papillary thyroid carcinomas (a relatively common well-differentiated thyroid cancer) after surgery are levothyroxine and radioiodine.For metastases, palliation with antineoplastic agents (eg, doxorubicin) may be useful.

• References

Levothyroxine (Synthroid)

• Dosing, Interactions, etc.

Clinical Context:  In active form, influences growth and maturation of tissues. Involved in normal growth, metabolism, and development.

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Class Summary

These drugs are useful to prevent hypothyroidism and to stop TSH stimulation.

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Sodium iodide I 131 (Iodotope)

Clinical Context:  Radioiodine is taken up by thyroid tissue and cannot be used in metabolic pathways. Emits beta and gamma radiation that causes destruction of thyroid tissue along a diameter of 400-2000 µm. Results in destruction of all residual thyroid tissues, either pathologic or normal.

• References

Class Summary

These agents reduce serum thyroid hormone levels.

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Cisplatin (Platinol)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits DNA synthesis and, thus, cell proliferation by causing DNA crosslinks and denaturation of double helix. Dose is related to body surface area.

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Doxorubicin (Adriamycin)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA. Combination of these 2 events, in turn, can inhibit growth of neoplastic cells.

• References

Class Summary

These medications inhibit cell growth and proliferation and may be helpful in palliating symptoms in metastatic disease.

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Lenvatinib (Lenvima)

• Dosing, Interactions, etc.

Clinical Context: 

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Sorafenib (Nexavar)

• Dosing, Interactions, etc.

Clinical Context: 

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Pazopanib (Votrient)

• Dosing, Interactions, etc.

Clinical Context: 

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