Cancerous Goiter

Cancerous Goiter

Summarize

The annual incidence of thyroid cancer among persons under the age of 19 is 4.8 to 5.9 cases per million, accounting for about 1.5 per cent of all cancers in that age group. The incidence of thyroid cancer is higher among children aged 15 to 19 (17.6 cases per million), accounting for about 8 per cent of cancers in that age group. The incidence of thyroid cancer is higher among females than among males.

        Papillary thyroid carcinoma is the most common type, accounting for about 60% of all cases. The second most common type is the papillary follicular variant (20-25%), followed by the follicular type (10%) and the medullary type (less than 10%). The incidence of papillary thyroid carcinoma and its follicular variant peaks between the ages of 15 and 19. Medullary thyroid carcinoma has the highest incidence in the 0 to 4 age group, then decreases.

Epidemiological

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Etiology & Risk Factors

Risk factors for disease

 

 

        Risk factors for thyroid cancer in children include:

 

Radiation exposure: Exposure to radiation, whether due to environmental pollution or the use of ionizing radiation for diagnosis or treatment, increases the risk of developing papillary thyroid adenoma and cancer. The risk increases if the average radiation dose exceeds 0.05Gy to 0.1Gy (50-100mGy). Within an average radiation dose of 30Gy, the higher the exposure, the greater the risk. When the dose exceeds 30Gy, the risk of cancer begins to decrease. This increased risk is more pronounced in younger individuals and persists for up to 45 years after exposure. Papillary thyroid carcinoma is the most common type of thyroid cancer caused by radiation exposure, and molecular changes, including chromosomal rearrangements, are frequently observed in these tumors, with RET/PTC rearrangements being the most common. ​

Genetic inheritance: A subgroup of thyroid cancer is associated with genetic factors. In children, medullary thyroid carcinoma is caused by dominant inheritance or new gain-of-function mutations in the RET proto-oncogene. This type of cancer is linked to multiple endocrine neoplasia (MEN) syndrome type 2, MEN2, MEN2A, or MEN2B, depending on the specific mutation. When it occurs in patients with MEN syndrome, thyroid cancer may be associated with the development of other types of malignant tumors.

Family history: For follicular cell thyroid cancer, the familial cancer rate is only 5 to 10 percent.

Classification & Staging

Classification and risk grouping

 

        Despite limited pediatric data, the American Thyroid Association (ATA) Pediatric Thyroid Cancer Working Group recommends using the tumor-node-metastasis (TNM) classification system to divide patients into three risk groups. This classification strategy is designed to determine the risk of persistent neck disease and identify which patients should be checked for distant metastasis after surgery to determine staging.

        ATA pediatric low-risk: This category includes patients with thyroid involvement, no regional lymph node metastasis (N0), or an inability to assess distant metastasis (NX), as well as those with incidental ipsilateral cervical lymph node metastasis (N1A) (a few central cervical lymph nodes are visible under a microscope). These patients have the lowest risk of distant disease but may still have residual cervical disease, especially if central cervical lymph node dissection was not performed during the initial surgery.

        ATA moderate risk: extensive ipsilateral cervical lymph node metastasis (N1A) or mild bilateral or contralateral cervical lymph node metastasis (N1B). These patients have a lower risk of distant metastasis but an increased risk of incomplete lymph node resection and persistent neck disease.

        ATA pediatric high risk: extensive bilateral or contralateral cervical lymph node metastasis (N1B) or locally infiltrative extracapsular thyroid metastasis (T4), with or without distant metastasis. This group of patients has the highest risk of incomplete resection, persistent disease, and distant metastasis.

 

 

 

3.5.4 Postoperative staging and long-term monitoring.

 

 

The initial staging should be performed within 12 weeks after surgery to assess the presence of persistent local disease and to identify patients who may benefit from 131I (131I) as an adjuvant therapy. The previously described American Thyroid Association (ATA) pediatric risk level assessment helps determine the extent of postoperative examination.

 

ATA pediatric low risk: ​

Initial postoperative staging includes thyroglobulin levels under thyroid-stimulating hormone suppression. A diagnostic scan with 123I is not required.

The target of TSH suppression is serum level 0.5〜1.0mIU/L.

For patients who no longer show signs of disease, monitoring should include an ultrasound examination 6 months after surgery, followed by examinations every six months or one year until 5 years post-surgery, after which the frequency can be further reduced. For patients on thyroid hormone replacement therapy, a thyroglobulin level test should be performed every 3 to 6 months for the first two years, and then annually thereafter.

50. ATA Pediatric Moderate Risk:
50. Initial postoperative staging includes thyroglobulin levels after thyroid-stimulating hormone stimulation and a diagnostic 123I whole body scan for further staging and to determine whether 131I treatment is used.
50. The target of TSH suppression is serum level 0.1 to 0.5 mIU/L.
50. For patients who have not developed the disease, monitoring should include an ultrasound examination six months after surgery, followed by examinations every six months or annually for up to five years post-surgery. After this period, the frequency of examinations can be further reduced. For patients on thyroid hormone replacement therapy, a thyroglobulin level test should be conducted every three to six months for the first three years, and then annually thereafter.
50. Patients who have undergone 131I therapy should consider checking thyroglobulin levels after TSH stimulation and having a diagnostic 123I scan within 1 to 2 years.
50. ATA pediatric high risk:
50. Initial postoperative staging includes thyroglobulin levels after thyroid-stimulating hormone stimulation and a diagnostic 123-I whole body scan for further staging and to determine whether 131-I is used.
50. The target of TSH suppression is a serum level below 0.1mIU/L.
50. For patients who have not developed the disease, monitoring should include an ultrasound examination six months after surgery, followed by examinations every six months or annually for up to five years post-surgery. After this period, the frequency of examinations can be further reduced. For patients on thyroid hormone replacement therapy, thyroid globulin levels should be checked every three to six months for the first three years, followed by annual checks.
50. Patients treated with 131I should consider checking thyroglobulin levels after TSH stimulation within 1 to 2 years, and a diagnostic 123I scan if possible.
50. For patients with anti-thyroglobulin antibodies, except for those with stage T4 (extracapsular metastasis) and M1 (distant metastasis), postoperative staging can be delayed to allow time for the antibody to be cleared from the body.

Clinical Manifestations

Clinical manifestations and prognosis

 

Differentiated thyroid cancer

 

        Patients with thyroid cancer typically present with a thyroid mass, which may or may not be accompanied by painless cervical lymphadenopathy. Studies based on medical history, family history, and clinical case summaries suggest that thyroid cancer may be part of a group of tumor genetic susceptibility syndromes. Other such syndromes include multiple endocrine neoplasia, APC-related polyposis, PTEN hamartoma tumor syndrome, Carney syndrome, and Dicer1 syndrome.

        According to existing research, the younger the patient with differentiated thyroid cancer, the higher the recurrence rate of the tumor. Compared to adult patients, children have a higher incidence of lymph node involvement and lung metastasis. Larger tumors (>1 cm), extra-thyroidal extension, and multifocal disease are associated with lymph node involvement and nodular malignancy. Compared to adolescents, prepubescent children experience faster tumor progression, with a higher risk of extra-thyroidal extension, lymph node involvement, and lung metastasis. However, there is a similar prognosis between prepubescent and adolescent groups.

        In well-differentiated thyroid cancer, male sex, larger tumors and distant metastasis have been found to be prognostic for early death; however, even in the highest-risk population with distant metastasis, there is a 90% survival rate.

 

 medullary carcinoma of thyroid gland

 

        In children with hereditary multiple endocrine neoplasia (MEN) type 2B, medullary thyroid cancer can be detected before the age of one, and lymph node metastasis may occur before the age of five. The RET M918T mutation associated with MEN type 2B is typically new in the patient. Early identification and diagnosis are crucial, which involves recognizing mucosal neurofibromas, dry eyes, constipation due to enteric neurotrophic dysregulation, and symptoms similar to those of Marfan syndrome. Approximately 50% of patients with MEN type 2B will develop pheochromocytoma. In patients with MEN type 2A, some may also develop pheochromocytoma, but the risk differs.

Clinical Department

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Examination & Diagnosis

 histology

 

        Thyroid tumors are classified as either adenomas or cancers. Adenomas are benign, with clear boundaries and a complete capsule. They can cause the entire or part of the gland to enlarge, extending to both sides of the neck and can be quite large. Some tumors may secrete hormones. In certain cells, adenomas can turn into malignant cancer and spread to the cervical lymph nodes and lungs. Approximately 20% of pediatric thyroid nodules are malignant.

        The following are the general histological categories for diagnosing malignant thyroid cancer:

50. Differentiated thyroid cancer: Papillary and follicular thyroid cancers are commonly referred to as differentiated thyroid cancer. The pathological classification of pediatric differentiated thyroid cancer follows the World Health Organization's standard definitions, which are the same as those for adults. Children and adolescents with differentiated thyroid cancer have a good long-term prognosis, with a 10-year survival rate exceeding 95%.
50. Papillary thyroid carcinoma: Papillary thyroid carcinoma makes up over 90% of all differentiated thyroid cancers that occur in childhood and adolescence. This type of cancer can exhibit various histological features, such as typical, dense, follicular, or diffuse sclerosis. Papillary thyroid carcinoma is typically multifocal and bilateral, and it often spreads to local lymph nodes in most children. In up to 25% of cases, there is a hematogenous lung metastasis.
50. Follicular thyroid cancer is a rare type of cancer. It is typically a single-focal tumor that is more likely to metastasize to the lungs and bones through the bloodstream, with very few cases spreading to local lymph nodes. The histological features of follicular thyroid cancer can vary, including Hurthle cells (acidophilic cells), clear cell carcinoma, and poorly differentiated island-like carcinoma.
50. Medullary thyroid carcinoma: Medullary thyroid carcinoma is a rare form of thyroid cancer that originates from calcitonin-secreting parafollicular C cells and accounts for less than 10% of all thyroid cancer cases in children. In children, medullary thyroid carcinoma is often associated with RET gene mutations in multiple endocrine neoplasia syndrome type 2.
50. Anaplastic carcinoma: Less than 1% of pediatric thyroid cancers are anaplastic.

 

 diagnostic analysis

 

 

        The initial evaluation of a child or adolescent with thyroid nodules includes:

Ultrasound of the thyroid

Thyroid-stimulating hormone (TSH) levels in serum

Serum thyroglobulin levels

        The patient's thyroid function tests are usually normal, but thyroglobulin may be elevated. Fine needle aspiration as the initial diagnostic method is sensitive and useful. However, when a definitive diagnosis cannot be made, open biopsy or excision should be considered.

Clinical Management

Treatment of papillary and follicular thyroid carcinoma

 

        The treatment options for papillary and follicular (differentiated) thyroid cancer include:

50.  surgical operation
50. Radioactive iodine ablation therapy

        In 2015, the Pediatric Thyroid Cancer Working Group of the American Thyroid Association (ATA) published guidelines for the treatment of thyroid nodules and differentiated thyroid cancer in children and adolescents. These guidelines are based on scientific evidence and expert panel opinions, and a careful evaluation of the level of evidence is summarized as follows:

 

 

Preoperative evaluation

 

        A comprehensive ultrasound of all areas of the neck should be performed by an experienced ultrasound technician using a high resolution probe and Doppler technology. A complete ultrasound should be performed prior to surgery.

        If there is suspicion of tumor invasion into the trachea or esophagus, consider adding cross-sectional imaging (contrast-enhanced CT or MRI). If iodine-based contrast agents are used and further evaluation or treatment with radioactive iodine is required, it may be necessary to delay the procedure by 2 to 3 months until the systemic iodine load has decreased.

        For patients with extensive cervical lymphadenopathy, chest imaging (X-ray or CT) may be considered.

        A thyroid nuclear scan should only be performed when the patient has a suppressed thyroid-stimulating hormone (TSH).

        Routine use of bone scans or fluorine F18-fluorodeoxyglucose positron emission tomography (PET) is not recommended.

 

 surgical operation

 

Ideally, pediatric thyroid surgery should be performed by a surgeon with experience in pediatric endocrine surgery in a hospital with a well-established pediatric specialty care system.

        Thyroidectomy:

        For patients with papillary or follicular carcinoma, total thyroidectomy is the preferred treatment. For patients with a small, localized tumor on one side of the gland, subtotal thyroidectomy —— which involves preserving a small amount of thyroid tissue (less than 1%-2%) at the entrance to the recurrent laryngeal nerve or the upper parathyroid glands, can be considered to minimize permanent damage to these structures.

        The use of radioactive iodine imaging and therapy has also been optimized in total thyroidectomy.

        Cervical central resection:

50. If central or lateral neck metastasis is found clinically, therapeutic central neck lymph node dissection should be performed.
50. For patients without clinical evidence of extrathyroidal infiltration or local metastasis, a prophylactic central neck dissection may be considered based on the tumor's location and size. Since central lymph node dissection increases the risk of related complications, the risks and benefits of different levels of dissection must be carefully analyzed for each case
50. Cervical neck dissection:
50. Cytological examination of metastatic lateral cervical lymph nodes is recommended before surgery.
50. Preventive lateral neck lavage is not recommended as a routine procedure.

 

 

Radioactive iodine ablation therapy

 

 

        The goal of 131I treatment is to reduce the risk of recurrence and reduce mortality by eliminating goiter.

 

50. It is recommended that 131I be used for the treatment of persistent local hyperiodine or lymphadenopathy in patients with unresectable or known or presumed distant metastases. For patients with persistent disease following 131I therapy, a personalized treatment plan should be developed based on clinical data and previous response to determine whether additional 131I therapy should be continued. ​
50. To promote the uptake of 131I in patients with residual hyperthyroidism, thyroid-stimulating hormone (TSH) levels should be above 30 mIU/L. This can be achieved by stopping levothyroxine for at least 14 days. For patients who cannot achieve sufficient TSH or cannot tolerate severe hypothyroidism, synthetic TSH can be used.
50. Therapeutic 131I administration is typically based on experience or whole-body dose measurements. Due to the lack of comparative data between empirical treatment and dose measurement, no specific method can be recommended. Given that children's body sizes and iodine clearance rates differ from those of adults, it is advised that the use of 131I should be calculated by experts with pediatric dosing experience.
50. A post-treatment whole body scan is recommended for all children 4 to 7 days after 131I treatment. SPECT/CT combined with conventional CT may help to delineate the anatomical location of key iodine uptake sites.

        Although late side effects of 131I therapy are rare, they can still occur, including salivary gland dysfunction, bone marrow suppression, pulmonary fibrosis, and secondary malignancy.

     

Treatment of recurrent papillary and follicular thyroid cancer

 

        Although children with differentiated thyroid cancer often exhibit more advanced disease features than adults, they generally have good survival rates and relatively few side effects.

Radioactive iodine ablation with Iodine-131 (131I) is usually effective for recurrence. For patients with refractory 131I disease, molecular targeted therapy with kinase inhibitors may be an alternative therapy.

Tyrosine kinase inhibitors (TKIs) that have shown efficacy in adult treatment include:

 

50. Sorafenib (Sorafenib). Sorafenib is a receptor inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and RAS kinase. In a Phase III clinical trial, sorafenib improved the progression-free survival (PFS) in adult patients with locally advanced or metastatic differentiated thyroid cancer that was resistant to radioactive iodine, compared to placebo (from an average of 5.8 months to 10.8 months). Sorafenib was approved by the U.S. Food and Drug Administration (FDA) in November 2013 for the treatment of adult patients with advanced metastatic differentiated thyroid cancer. Pediatric data on sorafenib are limited; however, one report indicated that sorafenib responded to metastatic papillary thyroid cancer in children under 8 years old. ​
50. Lenvatinib (Lenvatinib). Lenvatinib is an orally administered inhibitor of the vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor, as well as the kinase RET and KIT. In a Phase III clinical trial involving adults with 131I-refractory differentiated thyroid cancer, Lenvatinib significantly improved progression-free survival and response rates compared to placebo. In February 2015, the U.S. Food and Drug Administration (FDA) approved Lenvatinib for the treatment of adult patients with advanced radioiodine-refractory differentiated thyroid cancer.
50. BRAF inhibitors. In an open-label, non-randomized Phase II clinical trial, vemurafenib achieved a 38.5% response rate in adult patients with BRAF-V600E-positive papillary thyroid cancer who were resistant to 131I and unresponsive to tyrosine kinase inhibitors. For patients with metastatic or advanced BRETAFV600E-mutated anaplastic thyroid cancer, the combination of dabrafenib and trametinib showed a 69% response rate

 

 

Treatment of medullary thyroid carcinoma ​

 

 

        Medullary thyroid cancer is often associated with type 2 multiple endocrine neoplasia syndrome, a condition in which the cancer progresses faster and 50 percent of cases have blood metastases at the time of diagnosis.

The treatment options for medullary thyroid carcinoma include:

        1. Surgery: The primary treatment for pediatric medullary thyroid carcinoma is surgery. This type of cancer often occurs in individuals with a genetic predisposition to multiple endocrine neoplasia (MEN) syndromes 2A and 2B. In these familial cases, early genetic testing and counseling are essential, and children with congenital RET gene mutations are recommended to undergo preventive surgery. Given the strong genetic link between this disease and its onset, the American Thyroid Association has developed guidelines for the prophylactic thyroidectomy in children with hereditary medullary thyroid carcinoma (see Table 2), which include screening criteria and the age at which preventive thyroidectomy should be performed.

 

 

        ​2. Tyrosine kinase inhibitors (TKIs) therapy: Several tyrosine kinase inhibitors have been approved for patients with advanced thyroid cancer.

        Vandetanib (RET kinase inhibitor, which also inhibits vascular endothelial growth factor receptor (VEGFR) and is involved in epidermal growth factor receptor signaling) has been approved by the U.S. Food and Drug Administration for the treatment of symptomatic or progressive medullary thyroid carcinoma in adults with unresectable, locally advanced or metastatic disease.

        In a Phase I/II clinical trial of vandetanib for treating locally advanced or metastatic medullary thyroid cancer in children, only 1 out of 16 patients showed no response, while 7 had partial responses, achieving an objective response rate of 44%. In a long-term efficacy evaluation of 17 children and adolescents with advanced medullary thyroid cancer who received vandetanib, the median progression-free survival was 6.7 years, and the 5-year overall survival rate was 88.2%.

        Cabozantinib (RET kinase, MET kinase and vascular endothelial growth factor receptor inhibitor) has also shown efficacy in unresectable medullary thyroid cancer. Cabozantinib was approved by the US Food and Drug Administration in November 2012 for the treatment of metastatic medullary thyroid cancer in adults.

Prognosis

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Follow-up & Review

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Daily Care

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Cutting-edge therapeutic and clinical Trials

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References

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Audit specialists

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