QInclude papillary, follicular including the Hurtle cell variant.
Differentiated thyroid cancer (DTC), is the most common endocrine cancer: it’s three histological subtypes or papillary, follicular, and Hurthle cell cancers.
The National Cancer Institute estimates that 62,980 Americans were diagnosed with thyroid cancer and 1890 died from the disease in 2014.
The majority of patients with thyroid cancer are at low risk for recurrence at less than 5%, and the risk of cancer related death is even lower.
The vast majority of patients with DTC have clinical stage I or stage II disease, with rates of death from this disease that approach zero.
DTC is the most common type of thyroid cancer, accounting for approximately 95% of all thyroid cancers:80% papillary, 10–15% follicular and Hurtle cell 5-10%’
Differentiated thyroid carinomas have properties similar to normal follicular cells, with response to TSH, secrete thyroglobulin, trap and retain iodine.
Differentiated thyroid cancers are usually asymptomatic and frequently discovered incidentally.
Distant metastases are present in 10% of patients with differentiating thyroid cancer with about half of them detected at the initial diagnosis and the remaining discovered during the follow up, after initial treatment.
Disease recurrences are far more common than is death and staging estimates are based on the number of pathological features, including tumor multifocality,size, capsulation, or angioinvasion, degree of cervical lymph node involvement, and the existence of predictive somatic mutations, such as BRAF V 600E.
Approximately 85% of patients are cured of differentiated thyroid cancer after treatment with surgery, radioiodine therapy, thyroid stimulating hormone suppression, or a combination of these therapies.
5 to 15% of patients with differentiated thyroid cancer have resistance to or become resistant to radioiodine and are categorized as having radioiodine refractory DTC.
The five-year survival for metastatic relapsed/resistant differentiate thyroid cancer remains low at 10%.
The determination of serum thyroglobulin to monitor for residual or recurrent cancer after thyroidectomy is also a risk determinant with low thyroid globulin levels of less than 0.2 to 0.5 mg/mL predicting freedom from disease.
Treatment strategies include: active surveillance, surgery, and radio iodine therapy.
The prognosis is relatively favorable, but up to 15% of patients develop radioiodine refractory metastatic disease and have a poor prognosis.
After thyroidectomy, radioactive iodine 131 is generally administered both to ablate residual normal thyroid tissue to treat persistent disease.
Two large randomized trials have shown in patients with low risk thyroid cancer, the postoperative administration of low activity radioiodine after injections of recombinant human thyrotropin was non-inferior to administration of high activity radio iodine after withdrawal of thyroid hormone treatment with respect to ablation success rate at one year and recurrence rate at five years.
In a French study patients with low risk thyroid cancer undergoing thyroidectomy that did not involve use of radioactive iodine after, was non-inferior to ablation strategy with radioactive iodine regarding a recurrence of functional, structural, and biological events at three years.
Observational studies show that the majority of patients with low or intermediate risk disease generally do well regardless of whether they receive radio iodine therapy.
TSH is necessary as a growth factor for differentiation of thyroid follicular cells, and stimulates thyroid cancer cell adhesion, migration and invasion.
TSH suppression by thyroid hormone is important to prevent recurrence of differentiated thyroid cancer after thyroidectomy.
Radioactive iodine is given when TSH is elevated by stopping thyroid hormone for several weeks or with the administration of human recombinant TSH.
Up to 40% of patients with well-differentiated thyroid cancer, receive radioactive iodine treatment, even though there is no proven benefit in this population.
Sodium iodide symporter, a plasma membrane protein, has a critical role in uptake and active support of iodine from blood into the thyroid follicle.
Iodide symporter remains intact in many differentiated thyroid cancers and facilitates uptake of radioactive iodine by thyroid cells during therapy for such lesions.
TNM classification for thyroid cancer
Primary Tumor (T)
TX Primary tumor cannot be asssesed
T0 No evidence of primary tumor
T1 Tumor 2 cm or less in greatest dimension limited to the thyroid
T1a Tumor 1 cm or less, limited to the thyroid
T1b Tmor more than 1 cm but not more than 2 cm in greatest dimension, limited to the thyroid
T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension limited to the thyroid
T3 Tumor more than 4 cm in greatest dimension limited to the thyroid, or with minimal extrathyroid extension.
T4a Moderately advanced disese. Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve.
T4b Very advanced disease. Tumor invades prevertebral fascia or encases the carotid artery or mediastinal vessels.
Regional lymph nodes (N)
NX Regional lymph nodes canot be assessed
N0 No regional lymph node metastases
N1 Regional lymph node metastasis
N1a Metastasis to level VI (pretracheal, paratracheal, Prelaryngeal)
N1b Metastases to unilateral, bilateral, or contralateral cervical (Levels I-V) or retropharyngeal or superior mediastinal lymph nodes (Level VII).
Distant Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Anatomic Stage
45 years or younger
Stage I Any T Any N M0
Stage II Any T Any N M1
45 years or older
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
T1 N1a M0
T2 N1a M0
T3 N1a M0
Stage IVA T4a N0 M0
T4a N1a M0
T1 N1b M0
T2 N1b M0
T3 N1b M0
T4a N1b M0
Stage IVB T4b N1b M0
Stage IVC Any T Any N M1
Staging systems are useful in predicting survival in patients with that did not adequately assess the risk of persistent or recurrent disease.
The main clinical factor for predicting recurrence is age greater than 45 years, which is associated with reduction in disease free survival
Male gender is associated with a worse disease free survival.
Lesions can be stratified as LOW, with disease confined to the thyroid, INTERMEDIATE with regional metastases and worrisome histology, extrathyroid extension or vascular invasion or HIGH RISK, with distant metastases or gross extrathyroidal extension, for recurrent disease
Accounts for 95% of incident cases of thyroid cancer and is associated with a 10 year survival of 90-95%.
Most patients with differentiated thyroid carcinoma can be cured, with a 5 year survival rate of 97.8 (SEER).
targeted therapies is demonstrated by next generation sequencing reveals about 61% of patients have potentially druggable mutations or fusions: BRAF mutations, RET mutations, NTRK mutations
Surgery is the primary treatment modality and goals include complete removal of the tumor, minimizing morbidity and providing necessary pathological specimens for adequate staging.
The two most accepted surgical procedures:are total thyroidectomy and thyroid lobectomy with or without isthmusectomy.
Total thyroidectomy results in removal of the entire thyroid gland with preservation of the recurrent and superior laryngeal nerves and parathyroid glands.
Thyroid lobectomy is similar but does not remove the contralateral thyroid lobe.
Subtotal resection is associated with increased risk of cancer recurrence, and decreased long-term survival rates, and increased complication rate, and is inadequate management of thyroid cancer.
Thyroidectomy facilitates the use of radioactive iodine for adjuvant therapy allows the measurement of serum thyroglobulin for disease surveillance, and allows improved neck ultrasound studies for identification of residual or recurrent disease.
Thyroid lobectomy acceptable surgical procedure for patients with tumors less than 1 cm in size, confined to one thyroid lobe and without findings in the contralateral lobe.
Thyroid lobectomy is associated with greater recurrence rates compared to thyroidectomy, but long-term survival is not affected.
In an analysis of 52,173 patients from the National Cancer Data Base there was a statistically significant increase in recurrence rates and decrease in survival among patients with tumors larger than 1 cm and who underwent thyroid lobectomy alone.
There is a 36-61% rate of occult cancer, and a 5-10% rate of cancer recurrence within the contralateral lobe.
Metastases to regional lymph nodes is common in patients with differentiated thyroid cancer, especially papillary carcinoma.
Cervical lymph node metastases are seen in 20-50% of patients with differentiated thyroid cancer.
When lymph node specimens are evaluated with techniques to detect micrometastases up to 90% of patients had such involvement.
The significance of lymph node metastasis remains unclear, however it likely denotes a greater risk for poor outcome.
Appropriate surgery allows the ability to use radioactive iodine ablation, provide long-term followup, and limit recurrent or metastatic disease.
Treatment consists of total thyroidectomy followed by long-term levothyroxine to suppress thryotropin.
Adjuvant radioiodine 131 is often administered after surgery.
10- year recurrence rate is 20-30% among patients who are older, have a lesion greater than 4 cm in diameter, have tumor extension beyond the thyroid and in patients with extensive nodal metastases.
10-year survival rate in patients with radioiodine resistant metastatic disease.
Patients with lung metastases have a better prognosis than patients with bone metastases, especially if the lung metastases are small.
Increased expression of vascular endothelial growth factor is characteristic finding in such lesions, and is associated with increased growth rate, progression and tumor invasiveness.
Increased VEGF associated with decreased recurrence free survival.
PET scans can localize sites of metastases and demonstrate radioactive iodine resistance, as thyroid carcinomas were low iodine and daily at higher glucose metabolism and are more likely to be positive on PET scans.
Radioactive iodine has little or no therapeutic effect on PET scan positive tumors and tumors that concentrate radioactive iodine are not likely to be active on PET scan.
FDG avidity is the most practical and reproducible definition of radioactive iodine resistance disease in thyroid cancer with a median sensitivity and specificity of 77% in 78%, respectively.
Patients with papillary cancer have an overall better survival than those with follicular carcinoma.
Most patients present with early stage disease.
Ten year survival of papillary cancer of the thyroid is 93% and for follicular cancer is 85%.
Patients presenting with distant metastases is seen in 1-9% of cases.
Treatment usually includes total thyroidectomy followed by radioactive iodine.
In a randomized controlled, non-inferiority trial of radioiodine in patients with low risk thyroid cancer versus no radio iodine therapy: after three years of follow-up there was no clinically meaningful differences in any in points between the two groups, with approximately 4% of patients in each group having disease related events (Leboulleaux S).
May require multiple doses of radioactive iodine for tumor control.
Older patients have a poorer cancer specific survival than younger patients.
Patients under the age of 45 years have a 10-year survival rate of greater than 90%.
Patients under the age of 45 years have a 10-year survival rate of greater than 90%.
Long term survival for older patients is 36-43%.
Treatments for patients with iodine refractory disease include tyrosine kinase inhibitors sorafenib and levantinib and cabozantinib.
With sorafenib progression free survival was five months and overall response rate 12%.
With Levantinib free survival was 14 months with the overall response rate of 65%.
With cabozanitinib progression free survival was 11 months and over response rate of 28%.