Aminah Keats, ND
Cancers of the endocrine system are very uncommon and constitute less than 1% of all malignancies (Casciato, 2004). Thyroid cancer is the most common type of endocrine malignancy, accounting for the majority of deaths due to endocrine cancers (DeVita, 2005). There are 14,000 cases diagnosed each year in the United States and 1,100 deaths annually (Casciato, 2004).
Risk Factors
- External radiation to the cervical region is a significant risk factor for thyroid carcinoma, i.e. thymic irradiation in childhood, irradiation for tonsillar or adenoidal enlargement, irradiation in teenagers for acne, neck irradiation in Hodgkin’s lymphoma. Radiation exposure poses increased risk particularly in papillary thyroid carcinoma.
- Total body irradiation in bone marrow transplantation
- Radioactive isotopes of iodine may have a tumorigenic effect on the thyroid gland as a consequence of nuclear fallout.
- Medical history of adenomatous polyposis and Cowden’s disease poses a greater risk of developing papillary thyroid carcinoma.
- Family history of a pheochromocytoma, hyperparathyroidism, or other manifestations of Multiple Endocrine Neoplasia-2 (MEN-2) increases the likelihood of medullary thyroid cancer.
- Family history of thyroid cancer in a first degree relative
Histological Subtypes
The four main types of thyroid cancer are papillary, follicular, medullary, and anaplastic.
- Papillary thyroid carcinoma (PTC) constitutes 70% of all thyroid cancers in the United States (Becker, 2001). It commonly presents with local metastasis involving the cervical lymph nodes and mediastinum. Distant metastasis is uncommon, but lung and bone are the most common sites. Fewer than 5% of patients have distant metastases at the time of diagnosis, and another 5% develop metastasis later (Becker, 2001).
- Follicular thyroid carcinoma (FTC) accounts for 5-10% of all thyroid cancers in the United States (Becker, 2001). Distant metastasis is more common in FTC compared to PTC with spread to bone, lung, the central nervous system, and other soft tissues.
- Medullary thyroid carcinoma (MTC) constitutes 10% of all thyroid cancers (Becker, 2001). It arises from the calcitonin-secreting C cells of the thyroid gland. Medullary tumors may also secrete ACTH and histaminase. Approximately 20% are familial tumors that are transmitted as an autosomal dominant trait and are often associated with other endocrine neoplasms (Becker, 2001). Metastasis most commonly occurs in the neck and mediastinal lymph nodes. Metastatic spread to the liver, lung, and bones is usually slow growing.
- Anaplastic thyroid cancer (ATC) is one of the most aggressive and difficult human malignancies to treat and subsequently is one of the most lethal (DeVita, 2005). It is common to have metastatic spread to the lymph nodes and adjacent organs, i.e. trachea, esophagus, vessels, muscles, and skin, at the time of diagnosis. Distant metastasis can occur to the lungs, bone, liver, and brain. The median survival rate is four to five months. ATC constitutes 1% to 3% of all thyroid cancers (Becker, 2001).
Clinical Presentation and Diagnosis
The typical presentation of thyroid cancer is an asymptomatic thyroid nodule found on routine examination, or in screening programs for patients with a history of head and neck irradiation. Carcinoma should be suspected if a hard, irregular thyroid nodule is found, ipsilateral lymph nodes are enlarged or compressive symptoms are present, or if there is a history of progressive increase in the size of the nodule (Rubin, 2001). Generally, only nodules larger than 1 cm should be evaluated. Occasionally there may be nodules smaller than 1 cm that require evaluation due to suspicious ultrasound findings or concerning risk factors (Cooper et al., 2006).
The American Thyroid Association guidelines recommend that evaluation of thyroid nodules consist of a detailed history of the patient (including family history of thyroid cancer) and measurement of serum levels of thyroid stimulating hormone (TSH). If the TSH is abnormally low, a thyroid uptake scan should be performed; if the TSH is not low, an ultrasound scan and possibly a fine-needle biopsy of the nodule should be performed (Medscape). Fine-needle aspiration biopsy is the best test for distinguishing between benign and malignant thyroid nodules (Rubin, 2001). False-negative and false-positive results are rare. Ultrasound-guided needle-aspiration biopsy is recommended for non-palpable nodules.
Local invasion may occur affecting the recurrent laryngeal nerve, trachea, or esophagus. In this case patients may present with hoarseness, dyspnea, or dysphagia. Hemoptysis may also occur. ATC can present as masses infiltrating the skin of the neck or as respiratory distress. ATC can also be associated with paraneoplastic syndromes such as humoral hypercalcemia of malignancy due to production of parathyroid hormone-related protein and leukocytosis caused by production of granulocyte colony stimulating factor (Becker, 2001).
Chest radiographs and serum alkaline phosphatase levels should be obtained to look for evidence of metastatic disease involving the lung, liver, or bone (Casciato, 2004). Further evaluation of liver and bone is required with elevated serum alkaline phosphatase levels.
Increased levels of calcitonin are associated with medullary thyroid cancer. It has been demonstrated that screening thyroid nodules with serum calcitonin measurement allows the diagnosis and treatment of MTC at an earlier stage resulting in an improved outcome (Elisei et al., 2004).
Carcinoembryonic antigen (CEA) may be elevated in MTC also.
Treatment
Surgery
Total or near total thyroidectomy is the treatment of choice for all types of thyroid cancer (Casciato, 2004).
Papillary and Follicular Thyroid Carcinoma
Lobectomy is usually performed in patients with well-encapsulated tumors with normal contralateral lobes. A total thyroidectomy is more likely in patients who present with contralateral disease and history of neck irradiation. A total thyroidectomy is often advocated because of the high incidence of multicentric involvement of both lobes of the gland and the possibility of dedifferentiation of any residual tumor to the anaplastic cell type (National Cancer Institute). Papillary carcinomas are more likely to be multifocal and bilateral (Simpson et al., 1978).
Although lobectomies hold a lower incidence of complications, i.e. hypoparathyroidism and recurrent nerve injuries, 5 to 10 percent of patients who undergo lobectomy develop recurrent disease (Hay et al., 1998).
In patients diagnosed with PTC, a midneck dissection on the ipsilateral side is performed due to the likelihood of regional lymph node metastasis. In follicular carcinoma, lymph node dissection is performed if the diagnosis is established during surgery or when lymph nodes are palpable at surgery (Rubin, 2001).
Medullary Thyroid Carcinoma
In patients with clinical MTC, surgery includes a total thyroidectomy, with a dissection of the central compartment of the neck, and bilateral modified neck dissection (Rubin, 2001). More than 75% of patients with palpable MTC have associated nodal metastasis. This suggests that routine central and bilateral functional neck dissections should be considered in all patients with medullary thyroid carcinoma (Moley et al., 1999).
If serum calcitonin levels remain elevated following surgical resection, further evaluation is required to search for regional and distant metastasis. Workup should include CT scan of the neck, chest, and abdomen. Ultrasound of the liver and bone scan are also recommended.
Anaplastic Thyroid Carcinoma
Surgery is performed with as complete of a resection as possible. Tracheostomy is necessary when tumor invades local structures. In the presence of periesophageal disease or loss of swallowing reflexes, a percutaneous gastric feeding tube may be placed (Becker, 2001).
Iodine-131 Therapy and Hormone Therapy
Papillary and Follicular Thyroid Carcinoma
Post-operative iodine-131 therapy is indicated in high-risk patients with papillary and follicular carcinomas to eliminate the post-surgical thyroid remnant. The goal is to decrease the risk for recurrent locoregional disease. Reduced tumor recurrence and mortality was found in patients with papillary and follicular tumors greater than or equal to 1.5 cm in diameter when treated with thyroidectomy followed by I-131 and thyroid hormone therapies (Mazzaferri et al., 1994). Iodine-131 therapy is usually performed 4 to 6 weeks following surgery. Thyroxine therapy is initiated thereafter. Studies have shown decreased rates of recurrence with depressed TSH levels (National Cancer Institute).
Radioactive iodine and TSH suppression is not indicated in medullary or anaplastic thyroid cancers. Studies have failed to show any benefit.
External-beam Radiation
Papillary and Follicular Thyroid Carcinoma
External radiotherapy to the neck and mediastinum is indicated only in older patients in whom surgical excision is impossible and the tumor tissue does not take up iodine-131, or when no tumor regression is observed following iodine-131 treatments (Rubin, 2001). Moderate doses of radiation therapy in papillary and follicular cancers may eradicate microscopic disease and cause regression of gross tumor (Simpson et al., 1978).
Medullary Thyroid Carcinoma
Radiotherapy is indicated when serum calcitonin levels remain elevated following surgery and absence of metastatic disease following workup. Radiotherapy is also used
for palliation in locally recurrent tumors. External radiation therapy has not been shown to increase survival times in this population (Brierley et al., 1996).
Anaplastic Thyroid Carcinoma
Radiotherapy in anaplastic cancer is typically part of a combined treatment which follows surgical excision of tumor and systemic chemotherapy. Complete resection of ATC combined with postoperative adjuvant chemotherapy and irradiation resulted in long-term survival, even with persistent minimal disease that remained on vital structures (Haigh et al., 2001).
Chemotherapy
There are no data to support the use of adjunctive chemotherapy in the management of papillary and follicular thyroid cancer. Doxorubicin may act as a radiation sensitizer in some tumors of thyroid origin and could be considered for patients with locally advanced disease undergoing external-beam radiation (Cooper et al., 2006).
Systemic chemotherapies for metastatic medullary cancer have been of limited effectiveness (Elisei et al., 2004). Chemotherapy with dacarbazine and 5-fluorouracil is well tolerated and may provide partial response in patients with advanced medullary thyroid carcinoma (Orlandi et al., 1994).
Palliation may be achieved in patients with advanced anaplastic and medullary thyroid cancers who receive bleomycin, cisplatin, and doxorubcin (De Besi et al., 1991). The combination of doxorubicin and cisplatin may cause an improved quality of response in patients with metastatic ATC compared to doxorubicin alone (Shimaoka et al., 1985).
Conclusion
Relapsing disease develops in about 12% of patients who have no evidence of disease after primary therapy. Tumors that are not treatable with the combination of surgery, thyroxine therapy, and repeat doses of I-131 therapy respond poorly to radiation therapy and chemotherapy (Casciato, 2004).
Targeted therapies are being considered for patients with thyroid cancer who are unresponsive to conventional treatment, particularly papillary, follicular, and medullary thyroid cancers. Angiogenesis inhibitors (sorafenib, sunitinib, motesanib, axitinib, and vandetanib) have shown promising activity in papillary and follicular thyroid cancers. Vandetanib may also be promising in medullary thyroid cancer (Malouf et al., 2009).
Oncogene inhibitors, modulators of growth or apoptosis, angiogenesis inhibitors, immunomodulators, and gene therapy are all under investigation for their possible role in the treatment of thyroid cancer.
Aminah Keats, ND received her undergraduate degree in psychology from Spelman College in Atlanta, Georgia in 1996. She then received her naturopathic doctorate from the University of Bridgeport College of Naturopathic Medicine in 2004 and completed a two-year residency at Cancer Treatment Centers of America in naturopathic oncology and continues to work as a staff naturopathic doctor at CTCA in Philadelphia, PA
References
Abeloff MD et al. Clinical Oncology ed 3. Philadelphia, 2004, Elsevier Churchill Livingstone.
Becker KL et al: Principles and Practices of Endocrinology and Metabolism ed 3. Philadelphia, 2001, Lippincott Williams and Wilkins.
Brierley JD et al: External radiation therapy in the treatment of thyroid malignancy, Endocrinol Metab Clin North Am Mar 25(1)141-57, 1996.
Casciato DA: Manual of Clinical Oncology. Philadelphia, 2004, Lippincott Williams and Wilkins.
Cooper DS et al: Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer, American Thyroid Association 16(2): 2006.
De Besi P et al: Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer, J Endocrinol Invest Jun 14(6):475-80, 1991.
DeVita VT et al: Cancer: Principles and Practice of Oncology ed 7. Philadelphia, 2005, Lippincott Williams and Wilkins.
Elisei R et al: Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders, J Clin Endocrinol Metab Jan 89(1):163-8, 2004.
Haigh PI et al: Completely resected anaplastic thyroid carcinoma combined with adjuvant chemotherapy and irradiation is associated with prolonged survival, Cancer Jun 15;91(12):2335-42, 2001.
Hay ID et al: Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period, Surgery Dec 112(6):1139-47, 1992.
Hay ID et al: Unilateral total lobectomy: is it sufficient surgical treatment for patients with AMES low-risk papillary thyroid carcinoma, Surgery Dec 124(6):958-66, 1998.
Henderson YC et al: Sorafenib potently inhibits papillary thyroid carcinomas harboring RET/PTC1 rearrangement, Clin Cancer Res Aug 1;14(15):4908-14, 2008.
Malouf G et al: Advances in the treatment of thyroid cancer in the era of molecularly targeted therapies, Bull Cancer Feb 96(1):95-101, 2009.
Mazzaferri EL et al: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer, Am J Med Nov 97(5):418-28, 1994.
Medscape: Measuring Serum Calcitonin in Patients with Thyroid Nodules Detects Medullary Thyroid Cancer. http://www.medscape.com/viewarticle/564671
Moley JF et al: Patterns of nodal metastasis in palpable medullary thyroid carcinoma: recommendations for extent of node dissection, Ann Surg Jun 229(6):880-8, 1999.
National Cancer Institute: http://www.cancer.gov/cancertopics/pdq/ treatment/thyroid/ HealthProfessional/page2
Rubin P: Clinical Oncology: A Multidisciplinary Approach for Physicians and Students. New York, 2001, W.B. Saunders Company.
Sherman SI: Advances in Chemotherapy of Differentiated Epithelial and Medullary Thyroid Cancers, J Clin Endocrinol Metab Mar 3, 2009
Shimaoka K et al: A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma, Cancer Nov 1;56(9):2155-60, 1985.
Simpson WJ et al: The role of external radiation in the management of papillary and follicular thyroid cancer, Am J Surgery Oct 136(4):457-60, 1978.
Skeel RT: Handbook of Cancer Chemotherapy ed 6 . Philadelphia, 2003, Lippincott Williams and Wilkins.
