Pediatrics

Differentiated thyroid cancer

OVERVIEW: What every practitioner needs to know

Are you sure your patient has differentiated thyroid cancer? What are the typical findings for this disease?

Approximately 1.5% of pediatric patients may have a palpable thyroid lesion and up to 18% may have a thyroid abnormality that is detectable by medical imaging. Although thyroid nodules are less common in children than in adults, the risk of malignancy is fivefold greater. The vast majority of these malignancies are differentiated thyroid cancers (DTCs) derived from the follicular cells of the thyroid gland.

At the time of diagnosis most patients with DTC are asymptomatic, the diagnosis being made incidentally on physical examination or unrelated imaging studies of the head and neck. Between 40% and 90% of children diagnosed with DTC already have metastases to the regional lymph nodes at the time of diagnosis; approximately 15%-20% already have distant metastases, typically to the lungs. Regional spread may be quite significant and therefore one must consider thyroid cancer in the differential diagnosis of persistent cervical lymphadenopathy.

Adolescent girls are four times more likely to develop thyroid cancer than are adolescent boys.

The incidence of thyroid cancer is increasing and is currently the second most common cancer in white girls 15-19 years of age.

Patients with two or more relatives with a history of thyroid cancer may be at greater risk of having a thyroid malignancy.

When signs or symptoms are present, they are typically due to mass effect from the tumor, resulting in any of the following findings:

Thyroid or neck mass; metastases to the neck may result in persistent cervical lymphadenopathy

Dysphagia from pressure on the esophagus

Hoarseness due to invasion of the recurrent laryngeal nerve

Are there different types of differentiated thyroid cancer? How are they distinguished?

DTC arises in two important patterns: papillary thyroid cancer and follicular thyroid cancer. DTCs are derived from the follicular cells of the thyroid. The majority of these tumors are sensitive to the growth-promoting effect of thyroid-stimulating hormone (TSH), produce thyroglobulin (Tg), and retain the ability to actively transport and cause organification of iodine.

Papillary thyroid cancer represents about 85%-90% of cases and tends to spread through the lymphovascular system, making regional metastases quite common.

Diagnosis is established by fine-needle aspiration biopsy of the thyroid nodule and confirmed on histologic assessment after surgical resection.

There are three primary variations seen in children: (1) classic papillary thyroid cancer, (2) follicular variant of papillary thyroid cancer, and (3) diffuse sclerosing variant of papillary thyroid cancer.

Disease-specific mortality is very low; however, 30%-40% may recur, at times decades after presentation.

Follicular thyroid cancer represents about 5% of pediatric thyroid cancers and tends to metastasize hematogenously rather than by lymphatic spread. Because of this, there is a lower likelihood of regional metastasis.

The most common sites of metastatic disease are lung, brain, and bone.

Diagnosis cannot be made by fine-needle aspiration biopsy because the diagnosis is dependent on identification of the tumor having invaded into the tumor capsule and/or blood vessels. This is discussed in greater detail below.

The approach to surgical resection of follicular thyroid cancer is very similar to papillary thyroid cancer with the exception that there may be less need for extensive neck dissection.

Medullary thyroid cancer occurs very rarely as a sporadic thyroid cancer in pediatric patients. The majority of children are brought to medical attention because of a family history of multiple endocrine neoplasia (MEN) type 2. The majority of patients will be found to have a mutation in the RET protooncogene; the specific mutation and family history predict the likelihood and timing for the development of associated tumors.

MEN 2B often occurs without a family history, secondary to a de novo mutation in the RET protooncogene. MEN 2B may present with medullary thyroid cancer during childhood, with metastasis risk increased the later the diagnosis is made. This should be expected in a patient with a thyroid nodule and/or neck mass with typical physical features, such as a marfanoid habitus (tall and slender) and mucosal neuromas (soft, small fleshy tumors) on the tongue, eyelid, and intestine.

What other disease/condition shares some of these symptoms?

Thyroid enlargement (goiter) may be due to primary hypothyroidism, benign thyroid adenomas, colloid nodules, or thyroid cysts. Thyroid enlargement may be asymmetric, with one side affected more than the other, and thus may present as a large nodule. Thyroid ultrasonography is very effective in discerning between thyroid lobe asymmetry due to a nodule, congenital malformation, or autoimmune thyroid disease.

Two additional congenital abnormalities should be included in the differential diagnosis:

A thyroglossal duct cyst may also present as a central neck mass, may fluctuate in size, and is typically mobile with swallowing.

An intrathyroidal thymic remnant may appear as a hypoechoic lesion with microcalcifications; however, the shape is often quite unusual and the lesion typically extends caudally beyond the edge of the thyroid.

Painless cervical lymphadenopathy may be due to subclinical upper respiratory tract infections but may also be due to lymphoma, syphilis, and tuberculosis.

Persistent cervical lymphadenopathy may be a manifestation of regional metastatic thyroid cancer but is more commonly benign. Distinguishing reactive, nonmalignant nodes from metastases may be challenging. Concerning features of lymph nodes on ultrasonography include rounded appearance, increased peripheral blood flow, cystic changes and microcalcifications. Obliteration of the normal lymphatic hilum with the aforementioned features, especially in the presence of a thyroid nodule, is bothersome for malignancy and warrants fine-needle aspiration biopsy of both the lymph node and any associated thyroid lesion.

Cervical pain can occur from compression of surrounding structures in the neck or from bleeding into a nodule. Thyroid lesions more typically associated with pain include subacute thyroiditis or infectious thyroiditis. Cervical lymphadenitis can also be painful and may be secondary to streptococcal pharyngitis, cat scratch disease, brucellosis, or mycobacterial and other infections.

What caused this disease to develop at this time?

Although the exact cause is rarely found, there are multiple risk factors associated with the development of thyroid nodules and thyroid cancer. The greatest risk factor is related to exposure to environmental or medical radiation. The risk associated with exposure to internalizing radiation (environmental) increases in relation to the degree of iodine deficiency and is preventable with the deployment of a cold-iodine emergency plan.

For survivors of a nonthyroid primary malignancy such as Hodgkin and non-Hodgkin lymphoma, head and neck tumors (brain, rhabdomyosarcoma), and patients who receive total body irradiation for bone marrow transplantation, the risk is related to the amount of therapeutic or medical radiation and the age of the patient at the time of exposure:

The lower the dose of radiation the greater the risk. There is a linear relationship between risk of exposure and risk of thyroid cancer developing between 0.1 Gy and 20 Gy. Within this range, the maximum estimated relative risk of thyroid cancer developing is about 15-fold greater than in a patient without exposure. At greater than 20 Gy, there is decreased risk secondary to the killing and sclerosing effect of the radiation.

The younger the age at exposure, the shorter the time (latency) to development of a thyroid nodule and/or cancer. The risk of thyroid cancer seems to increase 5 years after exposure in younger children; older children are at greater risk after about 10 years and this increases as more time passes.

The relative risk is expressed over decades and, as such, survivors of pediatric cancer need lifelong surveillance.

Other risk factors include:

Iodine deficiency

Being an adolescent girl (prepubertal boys and girls are equally affected)

Personal or family history of thyroid disease (congenital or acquired)

Genetic tumor syndromes: Cowden syndrome (PTEN mutations), Carney complex ( PRKAR1A mutations), familial adenomatous polyposis (APC mutations), McCune-Albright syndrome (GNAS mutations), and Werner syndrome ( WRN mutations).

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

TSH levels should be checked in every patient with a thyroid mass. If the TSH is suppressed, a nuclear medicine uptake scan should be performed to ascertain if the suspected nodule has autonomous function (a "hot" nodule). In pediatrics, the treatment may still involve surgical resection, but the likelihood of malignancy is much lower when compared with a "cold" nodule, and lobectomy may be a more reasonable approach in the case of a solitary, autonomous nodule.

If the TSH level is normal, there is no role for a nuclear medicine uptake and scan. Rather, thyroid ultrasonography and fine-needle aspiration biopsy would be the preferred approach to evaluation.

Calcitonin levels may be drawn in patients for whom medullary thyroid cancer seems likely. In the absence of a family history and/or concerning physical features, the routine use of calcitonin screening is not recommended, simply because sporadic medullary thyroid cancer is rare in children.

Would imaging studies be helpful? If so, which ones?

Ultrasonographic evaluation of the neck is the most useful imaging study and should be the first imaging study chosen in all cases unless the TSH level is suppressed. No other imaging study provides as much information with regard to nodule location and structure; ultrasonography answers the question, "should this be biopsied?"

Ultrasonography alone cannot reliably discriminate benign from malignant lesions, and therefore biopsy should be performed if the nodule is of sufficient size. In adults, criteria to perform fine-needle aspiration often include a solid nodule larger than 1 cm. In a pediatric patient, size is relative to the developing thyroid gland. In prepubertal children, any nodule should be considered for biopsy if the history and ultrasonographic features are concerning for malignancy. Once a child completes puberty, adult size criteria may be appropriate.

Ultrasonographic features that are concerning for malignancy include solid architecture, hypoechoic appearance, irregular or indistinct borders, increased intranodular blood flow, an appearance on transverse view that is taller than it is wide, and the presence of micro- or macrocalcifications. The sensitivity and specificity of these features is increased when more than one ultrasonographic finding is associated with the nodule.

Ultrasonographic features that are more consistent with a benign lesion include purely cystic architecture, hyperechoic appearance, smooth borders, and "halo" borders.

Lymph nodes may also be inspected by ultrasonography normal lymph nodes typically have a flattened appearance with a distinct hilum, whereas those with metastatic thyroid disease tend to be more rounded, have peripheral rather than central blood flow and cystic areas and/or microcalcifications.

Ultrasonography ordered to evaluate thyroid nodules must include interrogation of the lateral neck to evaluate for evidence of lymph node metastases. The most common neck regions for metastases are levels VI (central neck), III, IV, and II, in decreasing order of prevalence.

Before thyroidectomy, investigation of the central neck (level VI) is often limited by the thyroid gland itself. Because of the decreased sensitivity for ultrasound to detect abnormal adenopathy in level VI, and the high rate of regional metastasis in pediatric patients, prophylactic central neck dissection should be strongly considered in patients with malignant cytologic features.

Magnetic resonance imaging (MRI) of the neck may also be performed in addition to ultrasonography to evaluate for evidence of metastatic disease in the deep central neck and substernal regions.

Computed tomography (CT) of the neck can be done; however it is not superior to MRI and does result in additional radiation exposure to the patient. If CT is favored by your institution, it is important to avoid the use of iodine-containing intravenous contrast because this may delay the ability to give radioactive iodine therapy if the lesion is diagnosed as DTC.

Radioactive iodine uptake and scan should not be done as part of the assessment of a thyroid nodule unless the TSH level is suppressed. Although identification of a cold nodule on the scan does increase the risk of malignancy, specificity is low, and it is an unnecessary additional step in evaluation.

Positron emission tomography (PET) should likewise not be done as part of the assessment of thyroid nodules. Increased PET uptake in a thyroid lesion does increase the risk of malignancy by 30%-50%, but it does not replace ultrasonographic imaging. Further, the radiation exposure and cost for this study are substantial and unnecessary. An incidental finding of PET uptake in the thyroid should prompt routine evaluation of the thyroid nodule as detailed above (ultrasonography and fine-needle aspiration biopsy).

Confirming the diagnosis

Once a nodule or suspicious lymph node has been identified by ultrasonography, the next step is to perform an ultrasonographically guided fine-needle aspiration biopsy of the lesion. Ultrasonography is extremely helpful, as it allows the physician to guide the needle to the most suspicious lesion or area within a lesion, enhancing diagnostic yield to nearly 95%. Biopsy guided by palpation alone is not advised. Fine-needle aspiration biopsy is optimally performed with the child under conscious sedation. A cytopathologist should be at the bedside to confirm adequacy of the sample before completion of the procedure. If multiple lesions are seen, all lesions with differing ultrasonographic features should be biopsied.

Suspicious lymph nodes, especially those seen in the lateral neck, should also undergo fine-needle aspiration biopsy. A saline washout of the biopsy lesion can be obtained to measure Tg levels if cytologic analysis is indeterminate. The presence of Tg in a washout from a lymph node biopsy strongly suggests that the patient has metastatic disease.

In 2009, the Bethesda Criteria of classification for thyroid fine-needle aspiration biopsy specimen reporting and clinical follow-up became standardized and is summarized as follows:

Nondiagnostic (1%-4% risk of malignancy): Samples with inadequate cellular material for diagnosis

Recommended management: Repeated biopsy

Benign (0%-3% risk of malignancy): all cells seen show no evidence of malignancy

Recommended management: clinical follow-up

Atypia or follicular lesion of undetermined significance (5%-15% risk of malignancy): Predominantly benign sample with cells that have some questionable features

Recommended management: clinical follow-up and repeated biopsy

Follicular neoplasm (15%-30% risk of malignancy): predominantly follicular cells on the biopsy sample compatible with follicular adenoma or carcinoma

Recommended management: lobectomy because it is impossible to distinguish follicular adenoma from follicular carcinoma on fine-needle aspiration or frozen section

Suspicious for malignancy (60%-75% risk of malignancy): subtle features of malignancy are seen on biopsy but not enough to clearly define a cancer

Recommended management: near-total thyroidectomy or surgical lobectomy

Malignant (97%-99% risk of malignancy): Clear evidence of cancer on the biopsy sample

Recommended management: near-total thyroidectomy with strong consideration for central neck compartment dissection

If you are able to confirm that the patient has differentiated thyroid cancer, what treatment should be initiated?

Surgical resection of the thyroid gland and diseased lymph nodes is the most important intervention to treat thyroid cancer. This should be performed by an experienced "high-volume" surgeon who performs greater than 30 cervical/thyroid procedures per year in a pediatric setting capable of providing pediatric-specific supportive care (pediatric anesthesia and pediatric intensive care at a minimum).

Suboptimal surgery for malignant disease is associated with an increased rate of persistent disease and increased recurrence, often necessitating repeated surgery.

Radioactive iodine ablation therapy is necessary for most DTCs in children, the exception being if the cancer is very small and isolated to the thyroid. The role of radioactive iodine ablation is to destroy any small amount of remnant thyroid tissue that is left after surgical resection and thus facilitate monitoring patterns in Tg. Tg is made exclusively by follicular cells of the thyroid and serves as an excellent biomarker of disease.

Patients are placed on a low iodine diet so that they may become relatively iodine deficient and thyroid hormone is withheld so that the TSH level rises to more than 30 mIU/L. These measures increase the expression of the iodine transporter, resulting in more avid uptake of radioactive iodine.

Radioactive iodine dosing is determined empirically (based on a percentage of a standard adult dose) or by dosimetry (calculating the individual patient's iodine clearance).

After administration of the dose of radioactive iodine, a whole-body isotope scan provides insight into the location of any regional or distant metastatic disease.

It is crucial that the patient not receive iodine-containing medications or iodinated contrast for imaging studies before the ablative dose is given, as it may take several months for the patient to become iodine deficient again after this exposure.

It is important to remember that every state has specific laws that govern the use of radiopharmaceutical agents. Therefore, some patients may require in-hospital admission after the dose is given in an effort to protect the family and public from radiation exposure.

To maximize safety, patients must have access to a bathroom, living space, and sleeping quarters completely separate from others for at least several days after the dose is given. Detailed safety instructions must be given to the patient and their family, and there must be reasonable confidence that the instructions can be followed at home, otherwise the patient should be admitted to the hospital until the radioactive iodine is adequately cleared from the body.

Once the initial cancer has been treated with surgery and ablation, patients are placed on levothyroxine at high doses to suppress TSH, with a goal level of less than 0.1 mIU/L. Certain foods and medications (calcium, iron, and multivitamins being the most common) may decrease the absorption of levothyroxine and they should be taken at separate times.

What are the adverse effects associated with each treatment option?

Risks of surgery are directly related to the extent of the disease and the experience of the surgeon. These observations highlight the importance of appropriate selection of patients for surgery by using a team of radiologists, pathologists with extensive experience in accurately diagnosing thyroid cancer, as well as high-volume pediatric thyroid surgeons who do a high volume of these operations in a fully capable and staffed pediatric medical center. Patients who receive suboptimal surgery require repeated operations, and all operative risks increase significantly in this case. Surgical risks include the following:

Hypocalcemia is seen in 30%-40% of patients in the immediate postoperative phase resulting from manipulation of the parathyroid glands during removal from the posterior aspect of the thyroid gland. In the vast majority of incidences, decreased parathyroid gland function is temporary; however it is difficult to determine which patients will recover in the immediate postoperative phase.

For patients in whom hypoparathyroidism develops, high doses of calcium supplementation as well as calcitriol are needed to maintain normal calcium values. Over the ensuing weeks, the requirement should decrease in transient cases.

In patients who require extensive neck dissection, or if there is any concern that the vascular supply of the parathyroid gland was disrupted during surgery, the glands can be autotransplanted into the sternocleidomastoid muscle to preserve function. In experienced centers, approximately 1% of patients will have permanent hypoparathyroidism.

Recurrent laryngeal nerve injury is seen in less than 3% of patients undergoing surgical therapy. Unilateral injury may result in hoarseness, dysphagia, dyspnea, and aspiration in the weeks after surgery. Bilateral injury results in the rapid development of dyspnea and stridor. In severe bilateral injury, some patients may require a tracheostomy tube.

Hypothyroidism is the expected permanent effect of good surgery. Patients should expect to require thyroid hormone supplementation for the rest of their lives.

Radioactive iodine therapy is usually very well tolerated but there are some adverse effects that should be noted:

Immediately after therapy some patients report nausea, fatigue and sialoadenitis. These symptoms may be ameliorated by administering antiemetics, pushing fluids, and using sialogogues and stool softeners. Restarting thyroid hormone therapy 48 hours after administration of the radioactive iodine may also help decrease symptoms of fatigue.

Late effects of therapy: In adults there is increasing evidence that radioactive iodine may induced second, nonthyroid primary malignancy. Data for children treated and then followed for a long time are lacking, but there is a reasonable suggestion that children may be at the same, if not greater, risk of acquiring a secondary malignancy. Therefore, it is important to be judicious in dosing radioactive iodine and being certain that initial surgical interventions are as complete as possible to limit radioactive iodine therapy requirements.

Risk of leukemia appears to increase after the total dose of exposure exceeds 500 mCi. Additional cancers that may be increased include those of the organs in which iodine is absorbed (salivary glands) or cleared after ingestion (stomach, gastrointestinal tract, and bladder).

Reproductive dysfunction may be seen in men who receive cumulative doses of radioactive iodine greater than 400 mCi. Women should avoid pregnancy for at least 1 year after therapy. To date, there are no data to show decreased fertility or an increase in birth defects for women treated with radioactive iodine.

Radiation-induced pulmonary fibrosis may be seen in patients with pulmonary metastases after high-dose ablative therapy. It is difficult to know if this is secondary to the disease itself or to a combination of the disease and radioactive iodine. Patients should undergo pulmonary function testing before radioactive iodine administration if possible and then on a regular basis. If available, dosimetry, rather than empirical dosing, should be used to determine the safest dose of radioactive iodine.

Thyroid hormone suppressive therapy is the mainstay of medical therapy to reduce the risk of thyroid cancer recurrence. The degree of TSH suppression should be balanced with the extent of disease and the risk of inducing symptoms of mild hyperthyroidism.

There are no studies in children demonstrating the long-term side effects of using TSH suppressive therapy.

In adults, there is an increased risk of osteopenia and bone fracture with sustained subclinical hyperthyroidism. The risk of atrial fibrillation is also increased in adults, but this has not been reported in children.

It is reasonable to optimize calcium and vitamin D supplementations while encouraging patients to engage in regular physical activity to promote optimal bone health. If the patient takes a calcium supplement, this should not be given at the same time as the thyroid hormone replacement, as calcium will interfere with thyroid hormone absorption.

How are patients with this disease monitored and treated for recurrence?

Follow-up in the first year is fairly intense for most thyroid cancer patients:

Six weeks after surgery: A stimulated Tg level is obtained at the time of the radioactive iodine ablation. Along with the diagnostic whole-body scan, this should be used to assess how much disease remains after surgery and aids in determining the optimal ablative or treatment dose of radioactive iodine.

Three months after surgery: A detailed neck examination is performed; repeat TSH, T4, Tg and Tg antibody (TgAb) determinations to ensure adequate thyroid hormone suppressive therapy.

Six months after surgery: A detailed neck examination is performed; repeat TSH, T4, Tg and TgAb determinations along with neck ultrasonography.

Nine months after surgery: A detailed neck examination is performed; repeat TSH, T4, Tg, and TgAb determinations.

Twelve months after surgery: A detailed neck examination is performed; repeat TSH, T4, Tg, and TgAb determinations.

At some point between 6 and 12 months after surgery, stimulated Tg and TgAb levels will be obtained along with a repeated radioactive iodine whole-body scan to screen for persistent disease.

If the patient has no evidence of persistent disease after 12 months (i.e., the patient has undetectable stimulated Tg, negative TgAb levels, and a whole-body scan negative for Tg), the patient can be considered to be in remission and follow-up may be spaced to every 4-6 months.

Most patients will have stimulated Tg and TgAb levels checked every year until they have consistent evidence of no persistent or recurrent disease for several years. After this, an annual surveillance physical examination and nonstimulated Tg and TgAb levels every 6-12 months should be followed.

TgAb must always be checked at the same time as Tg levels because new antibody formation makes it impossible to interpret the measured Tg level.

"Stimulated testing" is achieved when the TSH is elevated to greater than 30 mIU/L at the same time as the laboratory tests or imaging study of interest are obtained.

Stimulated remnant thyroid tissue makes more Tg and absorbs more radioactive iodine, thereby increasing the sensitivity of testing. This may be accomplished by either withholding thyroid hormone therapy for 2-3 weeks or by using recombinant TSH injections. Thyroid hormone withdrawal may cause worsening symptomatic hypothyroidism than the use of recombinant TSH; however, the use of recombinant TSH is controversial because although data in adults are encouraging, recombinant TSH is neither approved by the US Food and Drug Administration nor proved effective in children.

What is the approach to persistent or recurrent disease?

Persistent or recurrent disease requires further therapy.

If screening tests suggest recurrence, patients should be evaluated for recurrent bulky disease with neck ultrasonography and radioactive iodine whole-body scan. If the results of these tests are negative, neck MRI, chest CT without intravenous contrast, and/or PET may be used to identify the location of recurrent disease.

Bulky disease must be surgically resected.

Nonbulky disease may respond to radioactive iodine ablation, particularly if there is an increase in uptake on the whole-body scan. Repeated dosing of radioactive iodine should be based on Tg elevations that have decreased in response to radioactive iodine before.

Approximately 30% of pediatric patients with pulmonary disease may have chronic stable disease that does not respond to repeated radioactive iodine dosing. In these patients, repeated radioactive iodine ablation is not warranted and patients should be followed with serial Tg measurements, as outlined above, and with pulmonary function testing every 6-12 months.

Tyrosine kinase inhibitors such as sorafenib and sunitinib have not been shown to be safe or effective in children with radioactive iodine–responsive or stable disease. In adults, these agents have been used to stabilize persistent disease, but they are not effective in inducing remission. They should be considered only if there is advancing disease that is unresponsive to conventional therapy. Ideally this should occur in a research setting with informed consent.

There is no role for systemic chemotherapy in pediatric patients with thyroid cancer.

External beam radiation therapy is only effective in treating bone metastases; there is no role for this treatment in routine thyroid cancer care.

What are the possible outcomes of differentiated thyroid cancer?

DTCs are associated with a very good prognosis. However, recurrence-free survival is limited, with 30% of pediatric patients at risk of recurrence up to 40 years after initial diagnosis. With this in mind, the concept of cure may not be truly achievable, and the patient and family should view thyroid cancer as a chronic disease that requires lifelong surveillance.

Disease-free survival is most favorable when patients receive optimal surgery and, with very few specific exceptions, radioactive iodine ablative therapy.

Most recurrences are in the first 3-5 years; altogether the 30-year disease-free survival is about 70%.

The low incidence of disease and the high level of expertise required to ensure accurate diagnosis and optimal care suggests that thyroid cancer in pediatric patients is best cared for in regional centers that have invested in developing a multidisciplinary center. The centers should partner with adult providers to gain expertise, ensure lessons learned, and set up appropriate transition of care when the patient reaches adulthood. Collaboration between these theoretical regional centers of excellence would afford an opportunity to more completely describe the disease course and develop individualized care, balancing risks of therapy with risks of disease progression.

What complications might you expect from the disease or treatment of the disease?

Nonmedical complications include the impact of the diagnosis on quality of life for the patient and family. The concept of a chronic cancer raises the risk for behavior and mood disorders, including depression and anxiety. These potential complications highlight the need to offer patients access to appropriate support, to include oncology-trained social workers, behavioral health providers, and educational assessment experts. This can only be accomplished under the organization of a multidisciplinary center with experience in treating thyroid cancer.

Are additional laboratory studies available; even some that are not widely available?

There are no other proven tests that add to the ability to predict or treat DTC in children.

How can differentiated thyroid cancer be prevented?

With the exception of reducing exposure to radiation, there is no evidence that thyroid cancer can be prevented. There are increasing data and efforts to reduce exposure to medical radiation, including decreasing the use of radiologic examinations and decreasing radiation exposure in oncology protocols (i.e., decreased use of cervical radiation therapy in the treatment of Hodgkin lymphoma).

Survivors of pediatric cancer who received radiation therapy to the head and neck, including total-body irradiation, should receive annual thyroid examinations, beginning after diagnosis, and have annual surveillance thyroid ultrasonograms performed starting 3-5 years after exposure to medical radiation therapy.

Patients with a family history of thyroid cancer (two or more relatives affected) or a history of a multiple tumor syndrome should receive regular neck examinations and consideration for regular ultrasonographic surveillance.

What is the evidence?

Cibas, ES, Ali, SZ. "The Bethesda System for reporting thyroid cytopathology". Am J Clin Pathol. vol. 132. 2009. pp. 658-65.

Niedziela, M. "Pathogenesis, diagnosis and management of thyroid nodules in children". Endocrine-Related Cancer.. vol. 13. 2006. pp. 427-453.

Rachmiel, M, Charron, M, Gupta, A. "Evidence-based review of treatment and follow up of pediatric patients with differentiated thyroid carcinoma". J Pediatr Endocrinol Metab. vol. 19. 2006. pp. 1377-93.

Sawka, AM, Thabane, L, Parlea, L. "Second primary malignancy risk after radioactive iodine treatment for thyroid cancer: a systematic review and meta-analysis". Thyroid. vol. 19. 2009. pp. 451-7.

Tuggle, CT, Roman, SA, Wang, TS. "Pediatric endocrine surgery: Who is operating on our children?". Surgery. vol. 144. 2008. pp. 869-77.

Waguespack, SG, Francis, G. "Initial management and follow-up of differentiated thyroid cancer in children". J Natl Compr Canc Netw. vol. 8. 2010. pp. 1289-1300.

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