Endocrinology Metabolism

Differentiated thyroid cancer

Are you sure the patient has differentiated thyroid cancer?

Your patient has a thyroid nodule or an enlarged cervical lymph node and the fine needle aspiration (FNA) biopsy is consistent with thyroid cancer. What do you do? The treatment plan depends on the type of thyroid cancer. Differentiated thyroid cancers (DTC) of thyroid epithelium account for >90% of thyroid cancer.

In areas of sufficient iodine nutrition, about 85% of DTC are papillary, 10% are follicular and 3% are Hurthle cell carcinomas. The DTC retain many of the physiological functions of thyroid cells, including thyrotropin stimulating hormone (TSH) stimulation of growth, iodine uptake, and thyroid hormone production. Papillary thyroid carcinoma tends to be indolent, slow growing, and metastasizes locally by lymphatic spread into cervical lymph nodes. Follicular and Hurthle cell carcinomas tend to be more aggressive and spread hematogenously to distant sites. In iodine-deficient areas, the ratio of papillary:follicular carcinoma is closer to 1:1, rising to ~6:1 after improvement in iodine nutrition. Prognosis for the different types of DTC is the same at each AJCC/UICC stage (I-IV), despite the difference in the methods of metastatic spread.

Approximately 5% of thyroid tumors are medullary thyroid carcinoma, which arises from calcitonin “C” cells that migrate into the thyroid gland during development. These “C” cells are of different embryonic origin that thyroid follicular cells and are not a type of DTC. The remaining <3% of thyroid malignancies include more aggressive tumors, such as primary thyroid lymphoma, anaplastic thyroid carcinoma, and hematogenous metastasis to the thyroid from other primary tumor sites.

Who is at risk for developing the differentiated thyroid cancer?

Micropapillary thyroid carcinoma (<1 cm; AJCC/UICC T1a) is very common in adults; the incidence has risen every year for the last decade. These small tumors are found incidentally in up to 24% patients after thyroidectomy for benign nodular disease. The risk for death is nearly zero in patients with these small tumors demonstrating a typical papillary thyroid histology, absence of extrathyroidal extension, and no lymph node metastases. The assessment of risk for DTC is difficult because of the high prevalence of small, clinically unimportant disease. DTC can be found in about 10% of first degree relatives of patients with papillary thyroid carcinoma.

Patients with the PTEN hamartoma tumor syndrome/Cowden’s syndrome have an elevated standardized incidence ratio of 72 (95% confidence interval 51-99) for DTC (primarily follicular thyroid carcinoma), with an estimated lifetime risk of 35.2% (CI 19.7%-50.7%). Other syndromes associated with DTC include familial adenomatous polyposis/Gardner syndrome, Carney complex type 1, Werner syndrome, and Pendred syndrome. External radiation of the thyroid and exposure to ionizing radiation from nuclear fallout, especially during childhood and whole body radiation for bone marrow transplantation, are associated with a significantly increased risk of papillary thyroid carcinoma.

What is the cause of differentiated thyroid cancer?

Etiology

Thyroid cancer is the most rapidly increasing cancer in men and women. It is the 5th most common cancer in woman and the most common cancer in women under 45 years old with a yearly incidence rate which has doubled since 1970. The current incidence rate for thyroid cancer is 16.4/100,000 for women and 5.6/1000,000 for men. Based on 2006-2008 rates, the National Cancer Institute estimates that 0.97% of men and women or 1 in 104 people will be diagnosed with thyroid cancer at some time during their lifetime. It is anticipated that there will be 56,460 new cases discovered in 2012. The increase in incidence is primarily from papillary thyroid carcinoma, as the incidence of other types of DTC (follicular and hurthle) has been relatively stable. Although many oncogenes have been found in papillary thyroid cancers (BRAF, RET/PTC, RAS, TRK) and follicular thyroid cancers (RAS, PTEN, PAX8/PPAR gamma), it is not clear that these mutations alone are carcinogenic. RET/PTC1 is frequently found in papillary thyroid cancers that occur after external radiation, while a BRAF mutation is most common in older patients (45%) with papillary thyroid carcinoma. The cause of the increased incidence of DTC is unknown, but may be, in part, from increased incidental detection on imaging studies.

Pathophysiology

Dietary iodine is taken up through the gut and concentrated in the thyroid. In the follicle cells of the thyroid gland, 4 and 3 atoms of iodine are incorporated into each molecule of thyroid hormone, L-thyroxine (T4) and triiodothyronine (T3), respectively. TSH is trophic and will increase follicular thyroid cell growth, iodine uptake, production of thyroid hormone precursor, thyroglobulin, and release of thyroid hormone into the circulation. The postoperative management of thyroid cancer relies on the thyroid cancer cell maintaining these differentiated functions.

Key laboratory and imaging tests

Expected results of diagnostic studies

Recent guidelines by two professional endocrine societies, the American Thyroid Association and the American Association of Clinical Endocrinologists, agree that after a diagnosis of DTC is made by fine needle aspiration (FNA) biopsy, an assessment of adenopathy should be performed by an ultrasound of the central and lateral neck by professionals trained in performing this exam for thyroid cancer. Sonographic features suggestive of metastatic nodes include loss of fatty hilum, rounded shape, cystic change, calcifications, and peripheral vascularity.

If an abnormal-appearing node is found in the central or lateral neck, a FNA biopsy should be confirmed by ultrasound-guided FNA aspiration for cytology and measurement of thyroglobulin measurement of the needle washout. Malignant nodes need to be confirmed by aspiration, as the result directs the extent of nodal dissection during thyroidectomy. Approximately 20-50% of patients, particularly those with papillary thyroid carcinoma, will have clinically involved metastatic nodes (nodes seen on imaging or detected during surgery). Other anatomical imaging for metastatic disease in the neck is not routinely necessary.

The sensitivity of computed axial tomography (CT) scan and positron emission tomography for DTC metastatic to cervical lymph nodes is relatively low (30-40%). In particular, CT scanning with iodinated contrast should not be performed unless the trachea or mediastinum requires assessment, as the high amount of iodine in the contrast will prevent diagnostic imaging and therapy with radioactive iodine for at least 6 weeks. If anatomic imaging is needed, either CT without contrast or MRI with gadolinium contrast can be performed. Without specific symptoms, such as bone pain or hemoptysis, additional imaging (e.g. bone scans and PET scans) are not necessary in the pre-operative evaluation of DTC.

Diagnosis confirmation

The diagnosis of a DTC by FNA cytology of a thyroid nodule, an abnormal neck lymph node, or after post-surgical thyroid histology is highly accurate. Only approximately 2-5% of nodules with a pre-surgical FNA biopsy showing thyroid cancer will be benign on post-surgical histology. Molecular markers, such as BRAF, have been suggested to help guide the extent of the initial thyroidectomy and lymph node dissection. The BRAF mutation is associated with a higher risk of extrathyroidal tumor extension, cervical adenopathy, and worse disease free survival. Currently, there are no studies that demonstrate an improved outcome (disease free survival or mortality) when the extent of surgery is determined by pre-operative BRAF tumor testing.

Other tests that may prove helpful diagnostically

What you should be alert for in the history

The history should be focused on family history of thyroid cancer and risk factors for DTC. Risk factors for differentiated thyroid malignancies include a primary relative with DTC, head and neck radiation during childhood, and extremes of age (<30 or >60 years old). Worrisome symptoms include rapid growth of a thyroid mass over several weeks or months. Tracheal compression or invasion by thyroid cancer can result in dyspnea or cough, especially with exertion or in the recumbent position, or hemoptysis. Initially, esophageal compression or invasion by thyroid cancer will cause dysphagia at the level of the lower neck to solids and pills, but not to liquids. Posterior invasion by DTC may result in recurrent laryngeal nerve damage, vocal cord dysfunction, and hoarseness.

Characteristic findings on physical exam

In order to feel a thyroid nodule, it is important to know where it is located in the anterior neck. The thyroid isthmus usually is located anterior and just below the cricoid cartilage of the trachea. Thyroid glands in young, thin women are often located in the mid-neck, while in older adults, the thyroid is located lower in the neck near the sternal notch. Thyroid nodules can be soft to palpation and may not be easily identified on exam. The thyroid exam should ascertain the length of each lobe, texture (firm or hard) of the gland, whether individual nodules can be felt, the presence or absence of tracheal deviation, and whether the thyroid extends below the clavicles, thus suggestive of a substernal goiter.

The presence of clinically important obstruction is confirmed by the Pemberton’s maneuver. A positive Pemberton’s sign is the development of facial flushing and/or distended jugular veins when both arms are raised at the side of the head for 1 minute. This is evidence of impaired venous outflow from the head and neck and may be associated with arterial or airway compromise from a retrosternal goiter that fills the thoracic inlet. Invasion of tumor outside the thyroid gland can be detected on exam when a nodule does not move up and down with swallowing. Careful exam for adenopathy of the central (paratracheal) area and along the jugular chain (lateral neck) should be performed, especially ipsilateral to the thyroid nodule.

Management and treatment of the disease

The management of thyroid cancer is individualized and must take into account risk factors for death and recurrence. Therapy is tailored based on the combined risk factors of tumor size, extrathyroidal extension, completeness of resection, histology, central vs lateral nodal involvement, gross invasion of structures, distant disease, and iodine avidity. Therapy is individualized and should be directed by physicians with experience in initial and long-term management of thyroid cancer.

Generally, management should be directed by an endocrine physician with special expertise in thyroid cancer in conjunction with a multi-disciplinary team. The team should include a high volume thyroid surgeon (>50 thyroid surgeries/year) experienced in central and lateral neck dissection and a nuclear medicine physician. Generally, medical oncologists and radiation oncologists do not manage DTC patients unless the tumor becomes non-iodine avid or radioiodine unresponsive and is locally invasive and widely metastatic.

Surgical Treatment

Near-total or total thyroidectomy is the recommended procedure for all patients with differentiated thyroid cancer (DTC). An exception may be patients with micropapillary thyroid carcinomas found incidentally after lobectomy for benign nodular disease. Completion thyroidectomy is suggested for all patients with a DTC >1 cm found after lobectomy, especially if additional nodules are seen in the contralateral lobe by ultrasound. DTC usually initially metastases to the paratracheal (central or level VI) nodes and then sequentially to the lateral neck (lateral to the jugular and carotid artery) nodes.

Risk of recurrent disease rises when the number of lymph nodes found at surgery is >2-5 or if there is extrathyroidal invasion of the tumor outside the thyroid. Risk of death rises when nodes are found in the lateral neck (AJCC/UICC stage IVA) or there is gross invasion (AJCC/UICCstage stage IVB) or distant metastases (AJCC/UICCstage stage IVC). Removal of individual nodes (node or berry picking) is not recommended. When there is tumor involvement of a nodal compartment, dissection of the compartment with removal of all nodes should be performed. Therapeutic central or lateral neck dissection (removing all nodes without removal of normal structures) should be performed when pathologic nodes are found on pre-operative imaging (and confirmed by biopsy) or detected during surgery.

Prophylactic central neck dissection (no known disease before surgery) should be performed with larger tumors (>4 cm), when there is known metastatic nodes in the lateral neck or when there is distant disease. Prophylactic lateral neck dissection is not recommended as it does not change the risk of mortality. Surgery should be performed by a high-volume surgeon experienced in thyroid surgery, as the complications of surgery (injury to the recurrent laryngeal nerve, hypoparathyroidism) is more common in patients with thyroid cancer compared to patients with benign thyroid disease.

Recently, studies have examined the impact of microscopic metastases of DTC in cervical lymph nodes. In general, it is felt that microscopic (<0.2 cm and not found by imaging or during surgery) does not impact recurrence or mortality and should not upgrade a patient with a small tumor to AJCC/UICC stage III (nodal metastases in the paratracheal, level VI area) or AJCC/UICC stage IV (lateral or mediastinal nodes).

Medical Treatment

Long-term follow-up of tumor includes decision for the appropriate level of TSH suppression by thyroid hormone, periodic serum thyroglobulin levels and neck ultrasound exams for recurrent tumor. Because TSH is a known growth factor for thyroid cells, thyroid hormone (levothyroxine) dose is adjusted until the TSH is suppressed below the normal range. The American Thyroid Association guidelines suggest that the TSH goal for patients should be adjusted based on their risk of persistent or recurrent disease and risk of death from thyroid cancer.

The TSH goal of patients with persistent disease is <0.1 mIU/L. If the patient is disease-free but at high risk for recurrence, the TSH goal is slightly higher (0.1-0.5 mIU/L). In patients who are disease-free with low risk of recurrence, the TSH can be maintained in the lower half of the reference range (~0.3-2 mIU/L). Neck sonograms and serum thyroglobulin levels are also important in the long-term management of patients with DTC.

In the absence of antigen (i.e., no residual thyroid cancer or thyroid remnant after thyroidectomy and RAI ablation), the serum thyroglobulin antibody titer generally falls with time. Patients with persistent or progressive disease with show thyroglobulin antibody titers that rise with time due to continued antigen stimulation of the immune system. However, 10-15% of patients with DTC will have thyroglobulin antibodies that will prevent the current immunometric (IMA) test from accurately measuring serum thyroglobulin.

In these cases, serum thyroglobulin antibody levels may be used as a surrogate tumor marker. It may also be helpful to request thyroglobulin measurement by a different assay method, such as by radioimmunoassay (RAI). This assay is not as sensitive as the IMA assay, but generally has less interference by the thyroglobuin antibodies.

Radioiodine therapy (RAI)

It has been recognized that significant complications of RAI can occur, including dose-dependent sialadenitis (up to 54% of patients with dry mouth), chronic parotid gland swelling and discomfort, and increased tooth caries and tooth loss. RAI therapy is associated with second primary malignancies, primarily those of the GI tract and leukemia, with a relative risk of ~1.19). However, the absolute increase in numbers of cancers is small (4.6 excess cases per 10,000 person-years at risk).

The American Thyroid Association guidelines currently recommend the selective use of radioactive iodine in patients with DTC. RAI ablation therapy is recommended for all patients with DTC with known distant metastases, gross extrathyroidal extension of the tumor, or tumor size >4 cm. RAI ablation is recommended for selected patients with a 1-4 cm DTC tumor with lymph node metastases, extrathyroidal extension or aggressive histology.

RAI is not recommended for patients with unifocal or multifocal <1cm papillary thyroid cancers when there are no nodal metastases, no extrathyroidal extension, and no unusual papillary histology. RAI ablation (30-100 mCi) is done in the presence of a high serum TSH level, which increases the iodine uptake into the tumor and allows delivery of higher doses of therapeutic radiation.

Remnant ablation can be performed following thyroxine withdrawal with endogenous TSH elevation or injections of recombinant human TSH (rhTSH) to achieve an elevated serum TSH level. Tuttle et al has shown that the clinical outcome is similar between these two treatment modalities. It is also recommended that the RAI is administered after the patient has been on a diet low in iodine. Iodine is found in many foods, including iodized salt, dairy products, egg yolks, and some breads.

High levels of non-radioactive iodine will reduce the amounts of RAI entering the tumor, resulting in a reduction in the effectiveness of the RAI therapy. Higher doses of RAI (100-250 mCi) may be given for persistent microscopic disease, distant metastatic disease, or aggressive histologies (tall cell, insular, columnar cell variants), providing that there is evidence that the metastases will concentrate the RAI. A post-therapy whole body scan should be performed with a gamma camera 2-10 days after the RAI therapy for staging purposes. About 10-15% of patients are staged at a higher level after the post-therapy scan if it is positive for additional disease.

It is not recommended to treat patients with non-iodine avid DTC (RAI scan negative), with the exception of a single empiric dose 100-200 mCi to localize persistent progressive disease. Under this circumstance, 18FDG-PET/CT scanning should be considered for localizing metastases, especially if the serum thyroglobulin level is >10 ng/mL or in patients with aggressive histologies that typically do not take up RAI (i.e., Hurthle cell thyroid or anaplastic thyroid carcinomas).

Adjunctive external beam radiation therapy

External beam therapy is used in DTC as a palliative treatment for locally advanced or otherwise unresectable disease in patients older than 45 years. It is used when there is gross residual tumor and additional surgery or RAI would be ineffective. Expansile bone lesions associated with severe pain, fracture or neurological complications may also be treated with external beam radiation and glucocorticoid therapy to minimize radiation-related tumor expansion.

Chemotherapy

There is no data which demonstrates that conventional chemotherapy is effective. The American Thyroid Association guidelines suggest that patients with progressive, non-iodine avid or non-iodine responsive disease should bypass traditional chemotherapy and be entered into a clinical trial with a targeted multikinase therapy. Doxorubicin may act as a radiosensitizer and could be considered for patients with locally advanced disease receiving external beam therapy.

Targeted multikinase (anti-angiogenic tyrosine kinase inhibitor) therapy

While the majority of patients with DTC are adequately treated with surgery and RAI therapy, there are patients with persistent biochemical (measurable serum thyroglobulin with negative imaging studies) and structural (gross tumor seen on imaging) disease. Biochemical evidence of persistent tumor without evidence of active growth does not require treatment, but should be monitored for progression with periodic serum thyroglobulin levels and neck ultrasound exams. It is not necessary to ablate non-progressive biochemical disease (stable serum thyroglobulin levels) without evidence of structural disease.

In patients with serum thyroglobulin levels arising from non-iodine avid macroscopic disease, clinical trials have shown that multikinase therapies (axitinib, motesanib and sorafenib) in phase II/III studies have been effective at stabilizing the progressive disease. Despite these advances, only a minority of patients achieve a partial response (decrease in target tumor size by 30%), and there have been no reports of patients with a complete response. However, the overall benefit (stable + partial response) approaches 80% of patients treated with these agents, alone or in combination. None of these agents are approved for the treatment of metastatic DTC. If the patient cannot participate in a clinical trial, then treatment by an oncologist with one of the FDA-approved tyrosine kinase inhibitors should be considered.

Prevention/Avoidance

Thyroid irradiation is the only modifiable cause of DTC. Therapeutic radiation is necessary and should not be avoided because of thyroid exposure. Diagnostic radiation in which the thyroid is not the object of examination should be limited when possible (for example, by the use of a “thyroid shield” during dental x-ray procedures.)

What is the prognosis of differentiated thyroid cancer?

Thyroid malignancies usually are slow growing. The cause-specific 5 year survival is 97% and the 10 year survival is 93%. However, a small number of cancers are aggressive. These may demonstrate local invasion into the trachea, esophagus, and recurrent laryngeal nerve causing respiratory symptoms, cough, hemoptysis, dysphagia and hoarseness. Distant metastatic disease typically travels hematogenously to the lungs and bone. Often pulmonary disease is asymptomatic, but bone disease may result in pain and pathological fractures.

What’s the Evidence?/References

AJCC cancer staging manual. Springer. 2002.

(Staging system for DTC. AJCC staging is an excellent predictor of mortality but not of recurrence.)

Cooper, DS, Doherty, GM, Haugen, BR, Kloos, RT, Lee, SL. "Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer". Thyroid. vol. 19. 2009. pp. 1167-214.

(The authors, all experts in thyroid disease, present evidence based recommendations for the diagnosis and management of thyroid nodules and thyroid cancer.)

Aslam, R, Steward, D. "Surgical management of thyroid disease". Otolaryngol Clin North Am.. vol. 43. 2010. pp. 273-83.

(The authors examine the recommendations of thyroid surgery for benign and malignant disease.)

Cohen, EE, Rosen, LS, Vokes, EE, Kies, MS, Forastiere, AA. "Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study". J Clin Onc. vol. 28. 2008. pp. 4708-13.

(Phase II study of the use of axitinib in advanced thyroid cancers.)

Cohen, EEW, Needles, BM, Cullen, KJ, Wong, S, Wade, J. "Phase 2 study of sunitinib in refractory thyroid cancer". J Clin Oncol. vol. 26. 2008.

(Phase II study of the use of sunitinib in advanced thyroid cancers.)

Davies, L, Welch, HG. "Increasing incidence of thyroid cancer in the United States, 1973-2002". JAMA.. vol. 295. 2006. pp. 2164-7.

(This paper was the first to recognize the rising incidence of thyroid cancer in the United States.)

Fish, SA, Langer, JE, Mandel, SJ. "Sonographic imaging of thyroid nodules and cervical lymph nodes". Endocrinol Metab Clin North Am. vol. 37. 2008. pp. 401-17.

(The authors, thyroid experts, provide a practical guide for the ultrasound appearance of benign and malignant thyroid nodules and cervical lymph nodes.)

Gharib, H, P.E., Paschke, R, Duick, DS, Valcavi, R, Hegedus, L, Vitta, P. "American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical Guidelines for Clinical Practice for th the Diagnosis and Management of Thyroid Nodules". Endocr Practice. vol. 16. 2010. pp. 1-43.

(The authors, all experts in thyroid disease, present evidence based and expert opinion recommendations for the diagnosis and management of thyroid nodules and thyroid cancer.)

Gupta-Abramson, V, Troxel, AB, Nellore, A, Puttaswamy, K, Redlinger, M, Ransone, K. "Phase II trial of sorafenib inadvanced thyroid cancer". J Clin Oncol. vol. 26. 2008. pp. 4714-9.

(Phase II study of the use of sorafenib in advanced thyroid cancers.)

Hay, I.D., Thompson, G.B.. "Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940–1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients". World Journal of Surgery. vol. 26. 2002. pp. 879-85.

(One of the largest studies of papillary thyroid cancer from the Mayo Clinic. This study examines the effect of initial treatment with the long term outcome of patients with papillary thyroid cancer.)

Mazzaferri, E.L., Young, R.L.. "Papillary thyroid carcinoma: a 10 year follow-up report of the impact of therapy in 576 patients". American Journal of Medicine. vol. 70. 1981. pp. 511-18.

(The first large cohort study of patients with thyroid cancer in the United States.)

Mazzaferri, E.L., Jhiang, S.M.. "Long-term impact of initial surgical and medical therapy on papillary and follicular cancer". American Journal of Medicine. vol. 89. 1994. pp. 418-28.

(One of the most important papers examining the outcome based on initial management of a large cohort of patients with DTC.)

Pacini, F. "Management of differentiated thyroid cancer of the follicular epithelium". Annals of Medicine. 2011.

(Recent concise summary by a thyroid expert on the management of DTC.)

Pacini, F., Molinaro, E., Castagna, M.G.. "Recombinant human thyrotropin-stimulated serum thyroglobulin combined with neck ultrasonography has the highest sensitivity in monitoring differentiated thyroid carcinoma". Journal of Clinical Endocrinology and Metabolism. vol. 8. 2003. pp. 3668-73.

(Evidence that rhTSH stimulated thyroglobulin and neck US is the most sensitive method of monitoring for tumor recurrence from DTC.)

Pacini, F, Ladenson, PW, Schlumberger, M, Driedger, A, Luster, M, Kloos, RT. "Radioiodine ablation of thyroid remnants after preparation with recombinant human Thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study". J Clin Endocrinol. vol. 91. 2006. pp. 926-32.

(Evidence that radioactive iodine treatment after injections of rhTSH is as effective as during hypothyroidism.)

Sherman, SI. "Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers". J Clin Endocrinol Metab.. vol. 94. 2009. pp. 1493-9.

(Summary paper by a thyroid expert on targeted therapies for advanced DTC.)

Tuttle, RM. "Risk-adapted management of thyroid cancer". Endocrine Practice. vol. 14. 2008. pp. 764-74.

(The first thyroid expert to suggest using the AJCC/UICC staging plus risk categories (see 2009 ATA guidelines) to direct management of patient with DTC. This was the beginning of individualized, risk-adapted management of thyroid cancer.)
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