Pediatric Thyroid Cancer

Frequency

United States

Thyroid cancer, the most common pediatric endocrine neoplasm, represents 3% of all pediatric malignancies and 5-5.7% of malignancies in the head and neck. Only 5% of all thyroid cancers occur in children and adolescents.[19] Thyroid nodules occur in up to 35% of the general adult population and in only 1-2% of the pediatric population. These numbers are estimated using a compilation of data from multiple reports.[16, 20, 21]

Paradoxically, despite the lower incidence of thyroid nodules in children, a pediatric thyroid nodule has a greater risk of containing or developing a malignancy. Whereas 5% of nodules in adults are malignant, in the pediatric population, the percentage of malignant nodules is 26.4%.[8] The incidence of malignancy in multinodular goiter is 1-7% and 10-25% in solitary nodules.[16] Pediatric thyroid cancer (3% prevalence) in adolescents is also associated with juvenile autoimmune thyroiditis.[22]

A study by Bernier et al found that in the United States, between 1998 and 2013, the rate of pediatric differentiated thyroid cancer significantly increased among individuals aged 0 to 19 years, rising by 4.43% per year. This increase was seen in both sexes, with the rates rising in non-Hispanic whites, non-Hispanic blacks, and Hispanics. With regard to cancer stage, the annual rate increases for localized, regional, and distant tumors were 4.06%, 5.68%, and 8.55%, respectively, with the yearly increases for tumors less than 1 cm, 1-2 cm, and over 2 cm in size being 9.46%, 6.92%, and 4.69%. Owing to the climb in large and late-stage differentiated thyroid cancer rates, the investigators suggested that improved medical surveillance cannot entirely account for the changes.[23]

Papillary thyroid cancer is by far the common thyroid malignancy in children, constituting 83% of all pediatric thyroid malignancies.[24] Although papillary carcinoma is more aggressive in children than in adults, pediatric papillary cancer carries a much better prognosis that adult thyroid cancer.[25]

Medullary thyroid cancer (MTC), which constitutes 5% of pediatric thyroid malignancies, is usually associated with multiple endocrine neoplasia type 2 (MEN2) in the pediatric population. The inheritance pattern occurs either sporadically or as familial MTC without other associated endocrine abnormalities. MEN2 consists of MTC and pheochromocytoma and either hyperparathyroidism (2A) or mucosal neuromas (2B). MTC associated with MEN2B is more virulent and may occur and metastasize early in infancy.

International

After the Chernobyl nuclear power plant disaster, individuals living in Russia, Ukraine, and Eastern Europe were exposed to significant levels of radioactive iodines, primarily iodine 131 (131 I). This radioactivity, which is concentrated in the thyroid gland, has resulted in a substantial increase in pediatric thyroid cancer rates among this cohort of children.[26, 27]

Mortality/Morbidity

Pediatric thyroid malignancies are usually a well-differentiated papillary subtype or the papillary-follicular subtype, but all histologic types have been observed. Children commonly present with advanced disease. At presentation, 70% of patients have extensive regional nodal involvement, and 10-20% of patients have distant metastasis.[10] The lungs are the most common sites of metastasis.

Pediatric patients seem to have higher local and distant recurrence rates than adults, but they tend to respond rapidly to therapy. The prognosis for children is excellent, with mortality rates of less than 10%.[28] Benign tumors such as follicular adenomas should be considered at risk for tumor progression toward follicular thyroid carcinoma, and they must be surgically addressed.[8]

A retrospective study by Gruszczynski et al found that although 2- and 5-year overall and disease-specific survival in pediatric thyroid cancer was close to 100% in the report’s patients, various factors, including male sex, non-Caucasian race, poverty, and language isolation, were associated with worse overall survival in these persons. Moreover, male and Black pediatric patients were more likely to present with a higher overall American Joint Committee on Cancer (AJCC) stage.[29]

Sex

Thyroid carcinoma is 2-3 times more common in females.[30]

The gender distribution of thyroid carcinoma differs between adults and children. Thyroid cancer is 4 times as common in women as in men. This difference is not seen in individuals younger than 15 years; the girl-boy ratio is as low as 1.5:1. However, in individuals aged 15–20 years, the female-to-male ratio is 3:1.[31] This implies that female sex hormones, especially during puberty, play a significant yet still undefined role in the increased incidence of thyroid cancer in females.[19]

Age

Age is a major determinant of both the incidence and recurrence of pediatric thyroid carcinoma. Pediatric thyroid carcinoma occurs more frequently in adolescents, although it has been reported in the neonatal period.[32] In children younger than 10 years, identified thyroid lesions are more likely to be malignant.[33] Children younger than 10 years are also more likely to have recurrent cancer.[28]

Thyroid carcinoma in pediatric patients usually manifests as an asymptomatic neck mass, with a reported incidence of cervical lymphadenopathy ranging from 35-83%.[7] The neck masses are typically discovered incidentally by parents or patients or by physicians during routine physical examination.

Focal fold paralysis in children with thyroid malignancy is much less common than in adults with thyroid malignancy.[8] Niedziela and Korman (2002) studied 37 children in Poland with thyroid cancer, none of whom presented with vocal cord paralysis or associated hoarseness.[11]

Additionally, unlike adults, young patients with thyroid nodules often do not report pain, tenderness, compression of the respiratory tract, problems with swallowing, or inappropriate fixation of the neck. Even young patients who have lung metastases usually do not report pulmonary symptoms.[9] However, 10-20% of patients present with distant metastasis (most commonly to the lungs), and 70% of patients present with extensive regional nodal involvement.[10]

Many young patients have a family history of thyroid cancer. For example, 25% of medullary thyroid cancer (MTC) cases are hereditary, while over 75% are sporadic. A family history of MTC, pheochromocytoma, or hyperparathyroidism may indicate multiple endocrine neoplasia 2A (MEN2A) or multiple endocrine neoplasia 2B (MEN2B), both of which are inherited in an autosomal dominant fashion. All family members should be genetically screened for this mutation, especially given its autosomal dominant mode of inheritance. A history of Graves disease, hypothyroidism, or goiter should suggest a benign thyroid disease process, although long-term suppression of Graves Disease with antithyroid drugs may lead to increased risk of malignant thyroid transformation.[8]

Finally, patients who report a rapid growth rate of cancer may have a poorer prognosis, although that observation is controversial. Pain is rarely associated. Local tenderness is attributed to either thyroid cyst formation or hemorrhage into a rapidly growing nodule. Autoimmune disease, which often results in rapidly enlarging thyroid glands, confounds any associated glandular nodularity for which malignancy must be excluded.[9]

Thyroid carcinoma usually presents with one or more painless firm neck nodules. Most malignant nodules detected in children were 1.5 cm or larger in size.[34] Tenderness of the nodule suggests hemorrhage into a nodule, a cyst, or an inflammatory process. For instance, if the skin is warm, erythematous, and diffusely tender, a diagnosis of acute suppurative thyroiditis is most likely and an inflammatory workup should be pursued.[35]

A soft compressible nodule is less likely to be malignant than a firm one.

Fixation of the mass to surrounding tissues and vocal fold paralysis suggest malignancy, although this process is rare.[11] Lymphadenopathy further increases the likelihood of malignancy.

Diffuse thyroid enlargement or multiple nodules are more suggestive of a benign process. Mucosal neuromas of the tongue, palpebral conjunctiva, and lips with marfanoid body habitus may suggest MEN2B syndrome with medullary carcinoma, which often manifests in infancy.[9]

Thyroid carcinoma is a known sequela of radiation exposure. From the 1920s to the 1960s, external beam radiation was used for treatment of benign lesions (eg, tinea capitis, tonsillar hypertrophy, acne, thymic enlargement, hemangiomas) prior to recognition of its carcinogenic effects.[36, 37, 38, 39, 40] The Chernobyl disaster in 1986 caused up to a 100-fold increase in the incidence of pediatric thyroid carcinoma in the exposed population. Cases associated with radiation exposure are mostly papillary carcinoma, and those associated iodine-deficient areas are more likely follicular.[39, 41, 9]

Radiation and chemotherapy for other pediatric malignancies also have been implicated in thyroid malignancy. Children who undergo pretreatment radiation therapy prior to bone marrow transplant and children who undergo primary radiation treatments for Hodgkin lymphoma are at increased risk for thyroid cancer. The risk for thyroid cancer is dose dependent.[42]

Congenital hypothyroidism (CH), due to either dyshormonogenesis or an iodine transporter defect, increases the risk of thyroid nodules. Chronic thyroid-stimulating hormone (TSH) elevation increases the risk of neoplastic transformation of thyroid. The benign nodules usually respond to thyroxine treatment. Those that remain or enlarge despite suppression therapy should undergo biopsy.[11]

Thyroglossal duct cysts, the most common developmental thyroid anomaly, carry an increased, albeit small, risk of malignant transformation. This is one of the reasons excision with the Sistrunk procedure (removal of cyst, central hyoid bone, and core from the base of the tongue) is recommended. However, only 8 cases of malignant thyroglossal duct transformation have been reported in the literature.[43]

Levels of serum triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) are usually within reference ranges in malignancy. Therefore, although these blood studies have no predictive value for thyroid cancer, they help shape the differential diagnosis of a child's thyroid mass.[8]

Antithyroid antibodies are helpful in diagnosing chronic lymphocytic thyroiditis. Thyroglobulin levels may be elevated in differentiated thyroid carcinoma and may help in postoperative monitoring. The thyroglobulin level should not be measured until at least 14 days after fine-needle aspiration (FNA) to prevent an artificial level elevation from the needle instrumentation.[44]

Traditional screening for both medullary thyroid cancer (MTC) and thyroid C-cell hyperplasia is performed by measuring calcitonin levels before and after pentagastrin stimulation. Screening for multiple endocrine neoplasia 2 (MEN2) is now possible with DNA analysis for specific mutations in the ret protooncogene.

Serum carcinoembryonic antigen (CEA) should be measured in those in whom MTC is suspected. Unfortunately, a negative value may be found in advanced stages of the disease.[45]

Obtain a 24-hour urine collection to screen for catecholamines metabolites, as a pheochromocytoma or paraganglioma should be surgically removed before thyroidectomy to avoid a hypertension crisis during surgery.

Obtain genetic testing at birth in children at risk for MEN2B and no later than age one year in children at risk for MEN2A.[7, 46]

Imaging studies reveal the malignant potential and the extent of disease, and they provide an anatomical roadmap for surgical planning. The following are the imaging studies with the highest yield.

Ultrasonography

Ultrasonography, a safe and widely available technique, is the first-line screening diagnostic test in all pediatric patients with thyroid nodules.

In particular, children with a history of radiation exposure should be observed with serial ultrasonography. Nodules that enlarge even a few millimeters should undergo FNAB.

Ultrasonography is useful in differentiating solid from cystic lesions and in revealing nonpalpable lesions. Many investigators consider cystic lesions to be benign lesions that represent hemorrhage into or degeneration of an adenomatous nodular goiter.

A solid nodule is more likely to be malignant; however, up to 50% of malignant lesions may have a cystic component, and approximately 8% of cystic lesions represent malignancies.[47, 10]

Ultrasonography reveals critical information regarding the risk of benign versus malignant disease. Benign features on ultrasound include multiple, solid isoechogenic or nonechogenic lesions and a uniform peripheral halo.[11] Malignant features include a thick irregular halo.[48]

A study by Lim-Dunham et al indicated that the aforementioned 2015 American Thyroid Association (ATA) guidelines on the management of pediatric thyroid nodules and differentiated thyroid cancer may offer, through their composite, ultrasonography-based risk stratification criteria, an effective means of assessing malignancy risk for pediatric thyroid nodules. Using the criteria, all 12 malignant nodules in the study were designated as having a high level of suspicion, as were nine out of 21 (43%) benign nodules.[49]

Color-Doppler sonography may aid in the diagnosis in patients with hyperfunctioning nodules (hot on scintigraphy [SC] and usually benign histologically), indicating an intensive vascular flow within a highly vascularized lesion and no visible flow through the remaining suppressed thyroid gland.[50] Color-Doppler sonography is also valuable in distinguishing a cystic lesion (with no vascular flow) from a solid neoplasm (with intranodular flow).[50]

One of the most helpful capabilities of ultrasonography is guidance of percutaneous needle biopsy.[13, 14]

Radionucleotide scanning (scintigraphy)

Thyroid scintigraphy is most useful in revealing tissue function in thyroglossal duct cysts (eg, ensuring that thyroid tissue in the normal location is functioning) and in diagnosing ectopic thyroid. However, thyroid scintigraphy has not proven worthwhile in distinguishing malignant from benign disease.

Classic hot nodules show uptake only in the nodule area of the thyroid and are associated with about a 6% incidence of malignancy. Harach et al (2002) wrote that untreated hot nodules can progress to carcinoma.[51] Surgical treatment is advisable for all children and adolescents with autonomously functioning thyroid nodules because of the risks of hyperthyroidism and thyroid carcinoma.[52, 11]

Cold nodules are usually benign adenomas, although, in children, a larger number of them are carcinomas.[53] Solid lesions that are cold on scintigraphy are malignant in about 30% of children.[54]

Total-body radioactive iodine (RAI) scans often reveal pulmonary nodal metastases, which are missed on radiography.

Computed tomography (CT) scanning

Noncontrast CT scans can be helpful in patients with substernal extension, local invasion, or lymph node metastasis. At initial evaluation, approximately 20% of children have pulmonary metastasis that can be revealed by either chest radiography or CT scan.[19]  Children have a much higher incidence of pulmonary involvement than adults.

The CT-scan lung findings, which usually consist of diffuse miliary spots and, less often, infiltrating nodules, are often also best noted with RAI scans.[9]

See the list below:

• Fine-needle aspiration biopsy

  • FNAB is the criterion standard in the diagnostic workup of adult thyroid nodules. Several studies report efficacy in the pediatric population.

  • High diagnostic accuracy with experienced pathologists improves the selection of pediatric patients for surgery and is an adjunct to guide further management.[55, 20, 21, 56]

  • Ultrasonography can be a useful guide for percutaneous needle biopsy when the lesion is difficult to identify with palpation.[13, 14]

  • FNAB is often not practical in children younger than 10 years; excisional biopsy under general anesthesia is recommended in this population.[57]

  • Using molecular polymerase chain reaction (PCR) studies on FNAB aspirate is mostly beneficial in the clinical research setting. It can be used in a very small number of patients for diagnostic purposes, but it remains expensive.[8]

Follicular adenoma is the most common cause of solitary nodules of the thyroid in the pediatric population.[12] Adenomas are solitary, well circumscribed, and well encapsulated and are composed of glandular epithelium. Most are histologically follicular but are occasionally papillary.

• Most thyroid cancers (papillary, follicular, anaplastic) originate from follicular cells. Medullary thyroid cancers (25% hereditary vs 75% sporadic) are of C-cell (calcitonin-producing) origin.[58]

• Thyroid malignancies in children are usually well-differentiated papillary or papillary-follicular subtypes, but all histologic types have been observed. Papillary carcinoma lesions, which comprise an estimated 72% of pediatric thyroid cancers, are irregular, solid, or cystic masses that arise from follicular epithelium.

• Microscopically, these masses have fronds of epithelium and distinct uniform cells with rare mitoses. Most contain both papillary and follicular components. The cells contain pink, finely granular cytoplasm with large pale nuclei (Orphan Annie eyes) and nuclear grooves. Psammoma bodies are rounded calcified deposits and can be found in approximately 50% of the lesions. Papillary carcinoma has frequent lymphatic and pulmonary metastases.

• Follicular carcinoma lesions, which comprise 18% of pediatric thyroid cancers, are usually encapsulated and have highly cellular follicles and microfollicles with compact dark-staining nuclei of fairly uniform size, shape, and location. Pathologic diagnosis can be made only when invasion of the capsule, adjacent glands, lymphatics, or blood vessels is seen. Follicular carcinoma metastasizes intravascularly to the lungs, brain, and bones. When a portion of the cells in the tumor are found to be oxyphilic (Hürthle cells), it is called a Hürthle cell tumor. These lesions tend to have a less favorable prognosis.

• MTC arises from the thyroid parafollicular or C cells, which secrete calcitonin and are derived from the neural crest and ultimobranchial body. Hyperplasia of the C cells is thought to represent a precancerous state. Histologically, MTC is composed of columns of epithelial cells and dense stroma that typically stain for amyloid and collagen. The nuclei are hyperchromatic, and mitoses are common. The cells have a fusiform shape and may form a whirling pattern. Calcifications are observed in 50% of these lesions.

Definition

The American Joint Committee on Cancer (AJCC) created the following staging system:[59, 60]

• T1 - Tumor diameter 2 cm or smaller

• T2 - Primary tumor diameter greater than 2-4 cm

• T3 - Primary tumor diameter greater than 4 cm limited to the thyroid or with minimal extrathyroidal extension

• T4a - Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve

• T4b - Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels

• TX - Primary tumor size unknown, but without extrathyroidal invasion

• NO - No metastatic nodes

• N1a - Metastases to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes)

• N1b - Metastasis to unilateral, bilateral, contralateral cervical, or superior mediastinal mode metastases

• NX - Nodes not assessed at surgery

• MO - No distant metastases

• M1 - Distant metastases

• MX - Distant metastases not assessed

Stage I (any T, any N, M0)

Stage II (any T, any N, M1)

See Thyroid Cancer Staging for information on stage groupings.

Radioactive therapy with iodine 131 (131I) is indicated to ablate residual normal thyroid and to treat functioning metastases in differentiated thyroid tumors. Because pediatric patients are few and the prognosis is generally excellent, The use of 131I is usually recommended only for patients with extensive unresectable cervical nodal involvement, invasion of vital structures, or distant metastases. Very few instances of solid tumors or leukemia associated with 131I treatment have been reported.[17]

Selpercatinib is the first targeted therapy to be approved by the US Food and Drug Administration (FDA) for tumors that have rearranged-during-transfection (RET) mutations. It is indicated for children aged 12 years or older with advanced or metastatic RET fusion–positive thyroid cancer in whom systemic therapy is required and who (if radioactive iodine is appropriate) are radioactive iodine-refractory. It is also indicated for children aged 12 years or older in whom advanced or metastatic RET-mutant medullary thyroid cancer requires systemic therapy.[61]

Treatment for thyroid malignancy is primarily surgical. Because of the unusual combination of an excellent prognosis and an advanced-stage disease presentation, the initial extent of surgery is controversial. Some recommend that the initial surgical approach should be conservative, while others advocate aggressive management with total thyroidectomy and radioactive iodine (RAI) for all patients. The relative infrequency of thyroid malignancy makes this controversy difficult to resolve.

Thyroid lobectomy is the initial procedure of choice for most solitary thyroid lesions. This procedure adequately removes the pathologic region but spares enough thyroid tissue to maintain a euthyroid state.[62] The thyroid lobule should be sent immediately for frozen section. If the frozen section confirms carcinoma, total or subtotal thyroidectomy can be completed. If the initial frozen section is indeterminate, one should wait for the final report. If the final pathology finding reveals carcinoma, then a total or subtotal thyroidectomy can be performed at a later date.

The need for total versus near-total or subtotal thyroidectomy is controversial. Proponents for near-total or subtotal thyroidectomy believe that these procedures decrease the incidence of complications such as recurrent nerve injury and parathyroid devascularization, although the need to identify and preserve these structures remains.[18] A near-total thyroidectomy with radical lobectomy on the side of the primary lesion and subtotal removal of the contralateral lobe is recommended if the lesion is proven to be or suggestive of carcinoma.[15]

Although total thyroidectomy has not been proven to decrease recurrence, supporters of this method argue that remaining thyroid tissue may interfere with the use of radioactive iodine (RAI) in the postoperative diagnostic scanning and in the treatment of microscopic regional and distant disease.

Residual thyroid tissue also provides a source of thyroglobulin that may postoperatively diminish the specificity of the test as a tumor marker.[28]

Medullary carcinoma

Total thyroidectomy and central neck dissection are indicated for biopsy-proven medullary carcinoma. Prophylactic total thyroidectomy may be indicated in children with a family history of multiple endocrine neoplasia (MEN) syndrome. Genetic screening is now possible for the MEN2 gene, and prophylactic surgery may be performed in patients as young as 5 years to prevent the occurrence of C-cell hyperplasia or carcinoma.[63]

Neck dissection

Selective ipsilateral neck dissection in pediatric thyroid surgery is indicated for proven or suspected regional lymph node metastasis. During the dissection, lymph nodes in the paratracheal region, tracheoesophageal groove, and lateral areas can be inspected. Suspicious nodes are excised.[15]

Formal neck dissection has not been shown to improve outcome and has an increased risk of minor surgical complications.[30, 64]

The authors advocate the use of total thyroidectomy with selective neck dissection for the treatment of pathologically confirmed thyroid carcinoma.

A study by Yap et al indicated that in children with clinically node-negative T1 papillary thyroid tumors, the lymph node yield needed to detect a metastatic lymph node is probably infeasibly high. According to the investigators, in T1, T2, and T3 papillary thyroid cancers, predicting nodal positivity with greater than 90% sensitivity requires 14, 8, and 6 lymph nodes, respectively.[65]

Postoperative suppression of TSH with thyroid hormone may decrease recurrence and is more effective in papillary and papillary-follicular carcinomas.

Postoperative therapy

• Radioactive iodine (RAI) therapy should be administered to all children and young adults with cervical lymphadenopathy after a total thyroidectomy to reveal and treat all distant metastases in the lungs.[19]

• Thyroid hormone replacement with levothyroxine is started in the first few days after total thyroidectomy. This replacement is withheld in patients who will receive131 I therapy.131 I is administered only to patients with extensive neck disease or distant metastases.

• Cytomel or synthetic T3 is often used in place of levothyroxine prior to a postoperative nuclear scan or radioactive iodine (RAI) treatment. Cytomel has a shorter half-life, minimizing the period in which no suppression or replacement occurs and maximizing the uptake of radionuclide used in the scan or radioiodine therapy. A control thyroid scan is usually performed 2-3 weeks after surgery or radioiodine therapy. TSH-suppressive doses (150-200 mcg/d of T4) are thought to decrease recurrence in differentiated carcinomas.[15]

• Thyroid carcinoma has been found to recur up to 33 years after treatment. Patients should receive close follow-up care with pulmonary function tests, chest radiography, CT scans, and thyroid function tests.[66] Thyroglobulin levels should be monitored for indications of medullary carcinoma.

• Postoperative local external beam radiation is not recommended because of a possible carcinogenic effect in children.

Serum calcium levels are measured daily for the first 2-4 postoperative days in all patients who have undergone a total or subtotal thyroidectomy. The calcium level usually drops slightly (to about 7 mg/dL) as the remaining parathyroid tissue recovers from surgical trauma. Mild hypocalcemia of this level requires treatment only if symptomatic. Mild symptoms include a positive Trousseau or Chvostek sign, mild cardiac arrhythmia, or perioral tingling. Treatment of these mild symptoms requires only oral calcium combined with vitamin D. Intravenous calcium gluconate is used for a more rapid replacement with severe arrhythmia or impending tetany.

Perioperative antibiotics are often used, and postoperative pain medications are standard, in addition to suppressive or replacement T4.

Surgical complications include recurrent laryngeal nerve injury, hypoparathyroidism, hypothyroidism, and wound infection.[67]

• The most common complication of a total thyroidectomy in children is parathyroid gland injury. In 6-15% of patients, parathyroid gland injury results in permanent hypoparathyroidism.[63, 30, 46]

• Hypothyroidism in all patients after total thyroidectomy is avoided with thyroid hormone replacement.

• Hypothyroidism occurs in 6.5-49% of patients who have undergone subtotal thyroidectomy.

• Secondary operations are more hazardous.[62]

Whereas the degree of invasion and metastases corresponds to prognosis in adults, this relationship is not seen in the pediatric population. In fact, the presence of lymph nodes does not affect the prognosis in children and adolescents.[19] The reason for this is multifactorial and can be attributed to an overwhelming majority of well-differentiated cancers, low incidence of bone metastasis, and excellent response to RAI.

• Bone metastasis also has a low incidence in childhood thyroid cancers, occurring in less then 5% of patients.

• Individuals with radiation-induced thyroid cancer are at an increased risk for additional cancer later in life.[39]

Pediatric patients have higher local and distant recurrence rates than adults, but they tend to respond rapidly to therapy. The prognosis is excellent in children, with mortality rates of less than 10%.

The overall 20-year survival rate is 92-100%.

Some studies report young age as the major determinant of recurrence in pediatric-differentiated thyroid carcinoma, which suggests a difference in tumor biology.

Rearrangements in the ret protooncogene have been observed in those exposed to radiation, with a reported ret rearrangement rate between 50 and 70%.[28] Williams et al studied Chernobyl-induced thyroid tumor behavior and found that thyroid tumors associated with the ret and PTC3 oncogenes were more aggressive, faster growing, and less differentiated.[26] Thyroid tumors with the ret/PTC1 oncogene had more benign characteristics and were slower growing.