Thyroid Nodules

In the general population, the prevalence of thyroid nodules varies from 4% by palpation to 67% by ultrasonagraphy, and 8-65% by autopsy.(1),(2),(3) With the increased use of imaging in clinical medicine, thyroid incidentalomas are noted in more patients. The improved sensitivity of ultrasonography has also led to the detection of incidentalomas. Approximately 40% of patients undergoing an examination for suspected parathyroid disease and 13% of patients undergoing carotid ultrasonography are noted to have thyroid nodules.(1)

The prevalence of thyroid nodules increases with age. Six to ten percent of older patients have solitary nodules by palpation; goiters and multinodular glands tend to be more common in the elderly.(4) By the age of 65 years, approximately 50% of individuals have nodules by ultrasonagraphy.(5) A prospective study examining the prevalence of thyroid nodules in asymptomatic North American subjects showed a tendency toward an increased probability of thyroid nodules with increasing age, with peak frequencies identified in those aged 48 to 50 and 56 to 60 years, but the relationship between age and an abnormal thyroid ultrasound was not statistically significant.(2) In a survey, the prevalence of goiter in the elderly population in a mildly to moderately iodine deficient area was 74% in patients aged 55-75 years and 54% in patients aged 76-84 years. The prevalence of nodular goiter in these groups was 25% and 21%, respectively.(6)

In the older patient population, hyperfunctional nodules may result in T3- toxicosis characterized by thyrotoxicosis associated with an elevated T3 concentration and a normal T4 concentration. A cross-sectional study that included 634 patients with a mean age of 67 years in Spain reported nontoxic multinodular goiter (51.3%) as the most common cause of a goiter, followed by toxic multinodular goiter (23.8%).(7) Other causes of a goiter in this study were: solitary thyroid nodule (9.8%), toxic adenoma (5%), Graves’ disease (4.3%), Hashimoto’s thyroiditis (3.9%), simple goiter (1.3%), and thyroiditis (0.5%). In an older study from the Mayo Clinic, 60% of patients over the age of 60 with multinodular goiter were reported to be thyrotoxic.(8)

Thyroid nodules can represent benign adenomas, cancer, cysts, or inflammation. The approach to a solitary nodule in an older individual is the same as that in a younger patient. The first step should be measurement of serum TSH. If the TSH is suppressed and a radioiodine scan shows increased uptake in the nodule, it is hyperfunctional, and further workup for thyroid cancer is unnecessary. However, if the thyroid function tests are normal, fine needle aspiration (FNA) of the nodule should be performed to make a specific diagnosis. For a complete discussion on the evaluation and management of thyroid nodules, please refer to Chapter 18, and for evaluation and management of multinodular goiter, please refer to Chapter 17.

Thyroid Cancer

Thyroid cancer accounts for 1% of all malignancies and 0.3% of cancer deaths in the United States annually.(9) Only 5% of the palpable nodules are diagnosed as malignant. The incidence of thyroid cancer has increased by a little over 2-fold between 1973 and 2002. This increase in incidence is due almost entirely to an increase in papillary thyroid cancer, which increased by approximately 3-fold between 1973 and 2002.(10) The majority of this increase is the result of detecting small papillary cancers measuring less than 1 cm to 2 cm.(10) Despite the rise in incidence of thyroid cancer, mortality has remained unchanged, which suggests that the rise in incidence reflects an increased detection of early disease that has a very good prognosis.

In adults between 50 and 70 years of age, the prevalence of clinically apparent thyroid cancer is only 0.1%.(1) In a retrospective review of 3,629 Taiwanese subjects who underwent thyroid surgery, thyroid cancer revealed two peaks in age, one in patients aged 20 to 29 years and the second in patients over 65 years of age.(11) Lin et al conducted a retrospective analysis of 204 thyroid cancer patients aged 60 years and older; 142 (70%) thyroid cancers were well differentiated (68% papillary, 30% follicular, and 2% Hurthle cell), and 3 (2%) were medullary thyroid cancer.(12) Fifty-nine (29%) of the thyroid cancers were poorly differentiated (39 anaplastic, 9 metastatic cancers to the thyroid, 7 lymphoma, 4 squamous cell, and 4 without enough cells for interpretation).

Age at diagnosis of thyroid cancer influences prognosis.(13) Among 340 cases of thyroid cancer followed for ten years (and reported forty years ago), there was a steady fall in survival with age: 100% survival at 10 years in patients younger than 20 years of age, 55% in patients aged 31 to 40, 31% in patients between 41 to 50 years old, and less than 5% for those older than 60.(14) The steady decline in survival with age occurred with both well-differentiated (papillary, follicular, and Hurthle cell cancer) and poorly differentiated (medullary, anaplastic, and undifferentiated) thyroid cancers. In a retrospective study, age was a significant prognostic factor.(15) None of the 157 patients younger than 40 years died, while the patients over 60 years had a 10-year survival rate of 79%. In a large retrospective study that included 53, 856 cases of thyroid carcinoma, Hundahl et al confirmed the influence of age on prognosis.(9) In patients less than 45 years of age with papillary thyroid cancer, the 10-year survival rate was 97%, and in those 45 years of age or older, the 10-year survival rate was 47-85%. Patients less than 45 years of age with follicular cancer had a 10-year-survival rate of 98%, while those 45 years of age or older had a survival rate of 57-66%. With medullary thyroid cancer, the 10-year-survival rate decreased from 84% for those who were less than 45 years of age to 63-80% for those who were 45 years of age or older. Surprisingly, patients less than 45 years of age with anaplastic thyroid cancer had a 5-year survival rate of 55%, and those 45 years of age or more had a survival rate of only 13%.

Recurrence of thyroid cancer is also influenced by age. Cady et al followed 600 patients with differentiated thyroid cancer for 15 to 45 years.(16) In women less than 50 years of age, the overall risk of recurrence was 10% and the risk of death was 3%; in contrast the risk of recurrence and death in women older than 50 years was 32% and 30%, respectively.(16) Of the patients in whom disease recurred or metastases developed, 89% of the women over age 50 died and only 30% of those less than 50 years of age died. In men, the risk of recurrence was approximately 32% in those older than 40 years of age and approximately 12% in those who were younger than 40.

In older patients with thyroid cancer, extension of disease outside of the thyroid gland dramatically worsened prognosis while it did not alter the good prognosis in young patients.(16) The recurrence rate and death rate increased to approximately 67% and 60%, respectively, in older patients, while in younger patients the recurrence rate and death rate were 12% and 4%, respectively. Distant metastases are a more ominous sign in older patients with thyroid cancer.(16) The risk of death in older patients with distant metastasis is approximately 96%, but in younger patients the risk of death is 63%. A recent study of 246 patients followed for 5.8 years found that age and tumor size were not helpful to predict recurrence; instead extra-thyroid invasion and positive lymph nodes correlated with recurrence, indicating that surgical pathology findings are better prognostic indicators than TNM staging.(17)

Papillary Thyroid Cancer

Papillary thyroid cancer (PTC) is the most common type of thyroid cancer accounting for approximately 80% of all thyroid cancers.(4),(9) It has a bimodal frequency, with the peak incidence being in the third and sixth decades, and it affects women more commonly than men (3:1). In patients over 60 years of age, papillary thyroid cancer accounts for only 50% of all thyroid carcinomas.(10) A history of radiation exposure increases the risk of PTC.(18) The prevalence of occult papillary thyroid cancer, based on autopsy results, is estimated to be about 6-9% in patients over 80 years of age, which is similar to patients who are <50 years of age.(19)

The most common presenting complaint of patients with PTC is a lump in the neck.4 Patients may also complain of lymphadenopathy, hoarseness, neck discomfort or pain, cough, or dysphagia. In a case-control study of 56 lethal cases of PTC, hoarseness and vocal cord paralysis secondary to locally invasive thyroid cancer were found to predict death from papillary carcinoma.(20) Tollefsen et al also noted a 20% incidence of recurrent laryngeal nerve paralysis in those dying from PTC.(21) Papillary thyroid cancer spreads via the lymphatics to the regional lymph nodes, and bilateral involvement is present in approximately one-third of the cases. In the Mayo Clinic series,(22) 10% of the patients presented with only cervical lymphadenopathy. Occasionally patients may present with distant metastasis involving the lungs, bones, brain, and soft tissues.

Papillary thyroid cancer is generally associated with a low mortality rate in patients younger than age 40. However, in older patients the mortality rate is higher. In the Mayo Clinic series, five of the six patients in the intrathyroid papillary carcinoma group (lesion >1.5 cm and confined within the thyroid capsule) who died were more than 60 years of age. In addition, in two of the five older patients who died, there was marked Hurthle-cell transformation. In an autopsy series, 525 papillary tumors were detected (12% of the autopsies), but only three were fatal and all three subjects were older than 60 years of age and had distant metastases.(23) In a retrospective case-matched control study, age was one of the variables that significantly affected prognosis.(20) The mean age for the lethal PTC group, 59.1 years, was significantly higher than the mean age of 42.4 years for the nonlethal PTC group.

Follicular Thyroid Cancer

Follicular thyroid cancer (FTC) is the second most common tumor of the thyroid gland and constitutes approximately 15% of all thyroid cancers. Follicular thyroid cancer tends to be more common in areas of iodine deficiency.(4) The peak incidence is in the sixth decade of life. Woolner et al found that 76% of FTCs were found in adults between the ages of 40 and 69 years.(22) Like PTC, FTC is more common in women than men (3:1). Differentiation of FTC from follicular adenoma requires invasion of the capsule, adjacent thyroid tissue, or blood vessels.

The most common presenting complaint of patients with FTC is an asymptomatic neck mass. In a retrospective analysis of follicular thyroid cancer conducted by the Mayo Clinic, 85% of the patients had a neck mass: 53% of patients noted the mass themselves, in 32% the primary care provider noted the mass, and in 15% another family member noted the lesion.(24) Cervical lymph node involvement (4-6%) is less common compared to PTC, but distant metastasis is more frequent.

Follicular thyroid cancer is associated with a higher mortality than PTC because of its tendency to metastasize. In the Mayo Clinic multivariate analysis of 100 patients with follicular thyroid cancer, age greater than 50 years, marked vascular invasion, and distant metastatic disease were independent predictors of thyroid cancer-related death.(24) The 20-year survival rate was approximately 95% for patients less than age 50 and about 50% for patients older than age 50. In patients over 50 years of age who had either marked vascular invasion or metastatic disease at the time of diagnosis, the cumulative thyroid cancer mortality was 53% at 5 years and 92% at 20 years; in patients who were less than 50 years of age with no vascular invasion or metastatic disease, the 5-year mortality rate was 1% and the 20-year mortality rate was 14%. Ladurner et al reported a worse prognosis in patients older than 50 years of age at the time of diagnosis of follicular thyroid cancer, and Crile et al reported a worse prognosis for patients older than 60 years of age.(25),(26)

The increased mortality in older patients with FTC may be related to the greater frequency of extraglandular recurrences; intraglandular recurrences are more common in younger patients. Cady et al found that 67% of recurrences in older patients were extraglandular while only 12% of recurrences were extraglandular in younger patients.(16)

Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) constitutes approximately 2-5% of all thyroid malignancies, but it is responsible for up to 13.4% of all deaths from thyroid cancer.(27) It is a well-differentiated type of tumor that arises from the parafollicular (C cells) of the thyroid gland, and therefore it is categorized as a neuroendocrine tumor. In 70-80% of patients, medullary thyroid cancer occurs sporadically, but in about 20% of patients there is a family history of medullary carcinoma. Familial medullary thyroid cancer is inherited in an autosomal dominant pattern with virtually 100% penetrance. A germline mutation in the RET protooncogene, which encodes a transmembrane tyrosine kinase receptor, predisposes individuals to develop hereditary MTC. In the sporadic form, the tumor occurs as a result of a mutation involving only the somatic cells.

Medullary thyroid cancer is considered to be less aggressive than anaplastic thyroid cancer, but more lethal than papillary and follicular carcinomas. Sporadic forms of MTC are more common in older patients (mean age at presentation about 47 years), while the hereditary forms of MTC are more common in younger patients.(27) The prevalence of MTC is about the same in both males and females. The parafollicular cells secrete calcitonin. Serum calcitonin is greatly elevated in almost all patients with MTC.(4) In addition, there appears to be a direct correlation of calcitonin level and the extent of thyroid involvement by medullary carcinoma. Serum histamine, serotonin, prolactin, vasoactive intestinal polypeptide, and prostaglandin levels can also be elevated in patients with MTC. In some cases, Cushing’s syndrome may develop as a result of ectopic adrenocorticotrophic hormone (ACTH) secretion from the tumor.(4)

While most patients with MTC typically present with a palpable nodule in the upper part of the thyroid lobe, some patients may present with systemic symptoms associated with distant metastases. In the retrospective review of 104 patients with MTC by Kebebew et al, 74.2% of the patients in the sporadic group presented with a thyroid mass, 15.5% had local symptoms (dysphagia, dyspnea, or hoarseness ), and 10.3% had systemic symptoms (bone pain, flushing, and/or diarrhea) attributable to the cancer.(27) All of the patients with sporadic MTC who presented with systemic symptoms had distant metastases at the time of presentation.

Older age at diagnosis is associated with a worse prognosis. Kebebew et al followed patients with MTC for a mean time of 8.6 years.(27) Age and stage of disease at diagnosis were independent predictors of survival. The 5-year survival rates by stage were 100% (stage I), 90% (stage II), 86.5 % (stage III), and 55.5% (stage IV). Patients who were less than 45 years of age, female, and with MTC confined to the thyroid had the best overall prognosis (100% at 10 years).(27) Saad et al reported similar findings; patients younger than 40 years old at the time of diagnosis of MTC had a significantly better survival rate than those who were older.(28) In addition, women had a better prognosis than men, who were 1.9 times more likely to die of MTC than women. Scopsi et al reported a worse prognosis in patients with sporadic MTC who had extrathyroid tumor invasion, distant metastases, or age greater than 60 years at the time of diagnosis.(29)

Anaplastic Thyroid Cancer

Anaplastic thyroid cancer (ATC) accounts for only 1-2% of all thyroid cancers.(18) It is a very aggressive, highly malignant tumor that is most commonly seen in older people. The peak incidence of ATC is the seventh decade of life and more than two thirds of all ATC affects people over the age of 65 years.(4) Women are more commonly affected than men (approximately 1.5:1).

Unlike PTC and FTC, the most frequent presenting complaint in patients with ATC is a rapidly growing mass with tightness in the neck.(30) Patients may also complain of dysphagia, hoarseness, dyspnea, neck pain, sore throat, and cough. Anaplastic thyroid cancer can be seen in several contexts: 1) a patient with differentiated thyroid carcinoma whose disease suddenly becomes fulminant after an interval of several years; 2) a patient with a longstanding goiter that suddenly grows at a rapid rate; 3) a patient without previous thyroid disease who develops a rapidly growing neck mass; 4) a patient whose pathological sections reveal a focus of anaplastic carcinoma in the thyroid specimen; and 5) a patient with widespread metastases whose biopsy of an accessible metastasis suggests an anaplastic cancer. In a retrospective analysis of 84 patients with ATC, 21% had a history of differentiated thyroid cancer, 37% had a longstanding goiter with sudden rapid growth, 30% had no previous thyroid disease, and 6% had widespread metastatic disease.(30)

Examination of the neck usually reveals a fixed, large, firm mass that usually makes it difficult to detect neck nodes clinically. Hemorrhage and necrosis within the tumor may result in soft, fluctuant masses. Large axillary nodes are sometimes seen. Rarely, patients with massive tumor extension into the mediastinum may present with superior vena cava syndrome. Most patients with anaplastic carcinomas present with stage IV disease. In the review of Aldinger et al, 78 of 84 (93%) patients presented with stage III and stage IV disease.(30)

Age at diagnosis of anaplastic thyroid cancer is a strong predictor of prognosis. In a cohort of 516 patients with anaplastic thyroid cancer, on multivariate analysis, Kebebew et al noted that patients who were less than 60 years and those who had intrathyroidal tumor survived longer.(31) There was a 28% difference in mortality between patients who were less than 60 years of age and patients who were 60 years of age and older. They also reported a 45% difference in mortality at one-year follow-up between patients who had distant metastasis and patients who had intrathyroidal ATC.

Anaplastic thyroid carcinoma has a grave prognosis and is reputed to be the most aggressive of all cancers.(32),(33) Aldinger et al reported a five-year survival rate of only 7.1% (six survivors) with a mean survival period of 6.2 months from the time of tissue diagnosis and 11.8 months from the time of onset of symptoms.(30) They found that the long-term survivors had a very small focus of anaplastic cells. Tolfensen et al also reported that eight patients with a minute focus of anaplastic cells had a mean survival of nine years.(21) In Lin et al’s retrospective review of thyroid carcinomas in aging patients, thirty-two (82%) patients died of anaplastic thyroid cancer during the follow-up period of up to ten years.(12) Seventy-five percent of these patients had distant metastases to the lung, bone, mediastinum, and peritoneum at the time of diagnosis.

In summary, anaplastic carcinomas are much more common in older patients, and are likely to develop in a site of well-differentiated thyroid carcinoma in nearly half of the patients. The patient has an increased chance of survival if the anaplastic carcinoma exists in only a small area, but in a bulky and clinically aggressive tumor, even a small focus of anaplastic cells leads to a rapidly fatal course.

Thyroid Lymphoma

Primary thyroid lymphoma is a relatively rare thyroid malignancy, accounting for only 0.6% to 5% of all thyroid cancers.(34) The peak incidence of thyroid lymphoma is between 50 and 80 years of age, and it occurs three times more frequently in women than men. Almost all patients with thyroid lymphoma have Hashimoto’s thyroiditis with or without hypothyroidism.(35)

Rapid enlargement of the thyroid gland is the presenting feature in about 70% of cases.(36),(37) Patients may present with shortness of breath and difficulty swallowing related to infiltration of the trachea and esophagus by the cancer. Hoarseness may be a consequence of recurrent laryngeal nerve palsy. Obstructive symptoms are more common in patients with invasive, inoperable cancers.(38) The diagnosis of primary thyroid lymphoma may be difficult to make by fine-needle aspiration biopsy alone because of coexisting lymphocytic thyroiditis, so that excisional biopsy may be necessary to make the diagnosis. On palpation, the lymphoma feels like a hard, smooth, rubbery mass. The cut surface is characteristically smooth, white, and homogeneous.(35) Unlike papillary and follicular thyroid cancers, thyroid lymphoma does not concentrate iodine.

In the older literature, patients with primary thyroid lymphoma were reported to have a grave prognosis, especially if the cancer extended beyond the thyroid capsule.(38) In a retrospective review of forty-six cases of primary thyroid lymphoma by Woolner et al, survival ranged from 15% in patients with extracapsular invasion or regional lymph node involvement of the cancer who were followed for 5 to 13 years to 75% in patients with noninvasive cancer who were followed for 2 to 25 years. In more recent studies, the reported five-year survival has ranged from 53% to nearly 100%.(35),(39) The combination of the diagnostic use of fine needle biopsy and treatment with both chemotherapy and external radiation has dramatically improved the prognosis of thyroid lymphoma.

The treatment of thyroid lymphoma is unique in that surgical resection is no longer a routine part of therapy.(35),(40) In a review of 62 patients treated at the Mayo Clinic, complete remission was obtained in 88% of patients who underwent diagnostic biopsy plus adjuvant therapy compared to 85% for patients in whom debulking plus adjuvant therapy was used.(39) In addition, there was no difference in survival between the two groups. In Matsuzuka et al’s review of 119 Japanese patients with thyroid lymphoma, radiation combined with six cycles of CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) chemotherapy resulted in a survival rate of 100% at 8 years.(35)

Treatment of Thyroid Cancer

The management of thyroid cancer in an older patient is the same as that in a younger individual. In most patients, near total or total thyroidectomy followed by radioactive iodine ablation of the remaining tissue is the accepted approach.

Surgical Therapy

In older patients who have other medical illnesses, surgery is often approached with caution because of the belief that older age carries an increased surgical risk. Older patients tend to have more aggressive cancers. Age itself should not be a contraindication to surgery when it is indicated on clinical grounds. Because thyroid cancer is more aggressive in the elderly, surgical thyroidectomy should not be delayed. In papillary thyroid cancer patients over 70 years of age, Uruno et al found that the 5-year overall survival rate in 327 patients treated by surgery was 97.2% which was significantly higher than the 5-year overall survival rate of 62.6% in 55 patients not operated on because of high surgical risk or complication by other illnesses.(41)There are no studies that indicate watchful waiting is a beneficial approach for patients with differentiated thyroid cancer after it is clinically apparent. The one exception to this policy is papillary microcarcinoma; ultrasound studies in Japan showed no progression in 70% of patients with papillary thyroid cancers less than 7 mm during an average 4 year follow-up.(42)

Radioiodine Therapy and Thyroglobulin Measurement

Radioiodine ablation of thyroid remnants after surgery is indicated for all patients with papillary or follicular cancer larger than 1.5 cm, as recommended in the recently published guidelines of the American Thyroid Association.(43) Follow-up by measurement of serum thyroglobulin (Tg) at intervals of 4 to 6 months on thyroxine suppression therapy is recommended. One year after radioiodine ablation measurement of thyroglobulin under TSH stimulation is useful because it is about two-fold more sensitive than thyroglobulin measurement on thyroxine suppression. TSH stimulation may be achieved in several ways: (1) maintain the thyroxine suppressive dose and use recombinant human TSH (the main problem with this approach is the high cost of recombinant human TSH); (2) switch the patient to triiodothyronine at a dose of 50 mcg/day for four weeks, then withdraw it for two weeks; (3) or reduce the thyroxine dose by 50% for four weeks, then reduce it to 25% of the suppressive dose for two additional weeks before measuring serum thyroglobulin.(44) If the stimulated thyroglobulin level is greater than 2 ng/ml to 5 ng/ml, diagnostic imaging studies should beperformed to locate the residual thyroid tissue. The authors start the process with a neck ultrasound. If the neck ultrasound reveals a concerning lymph node or mass, fine-needle aspiration with measurement of thyroglobulin from the needle washout should be done. If the thyroglobulin is detectable, then the individual is referred for surgery.

If the ultrasound is not diagnostic, additional imaging is carried out by radioiodine scan, magnetic resonance imaging, or positiron-emission tomography-computed tomography, depending on the circumstances. When no resectable tumor can be found, a single “blind” dose of 100 to 150 mCi ¹³¹I may be given during thyroid hormone withdrawal that achieves TSH >30 mU/L. Post-therapy scans 7 to 10 days later may disclose regions of uptake that were not apparent in the diagnostic scan.

External Radiation

External radiation to the neck region is appropriate for patients with aggressive cancers that cannot be completely resected surgically.(45), (46) Schwartz et al treated 131 patients with extraglandular spread, or positive surgical margins, or gross residual disease

with a mean of 60 Gy (38-72 Gy); they reported that high risk pathology, metastases, and gross residual disease gave inferior survival, 30% at 5 years compared with 80% in those without gross residual disease.(47) When the thyroid cancer is aggressive and incompletely resected, it is probably not worthwhile to delay external radiation in order to treat with ¹³¹I because the delay may allow the cancer to spread and jeopardize the efficacy of the external radiation. Scans to determine the uptake of radioiodine are carried out after completion of the external radiation.

Thyroxine Suppression Therapy

A vital component of therapy for differentiated thyroid cancers includes suppressive treatment with levothyroxine to maintain serum TSH levels in the subnormal range. In patients with more advanced tumors, (Stages 2 - 4), it is appropriate to maintain the serum TSH at <0.1 mU/L. In patients with Stage 1 disease, a better target may be a serum TSH in the range of 0.1 to 0.3 mU/L in order to reduce the complications of subclinical thyrotoxicosis. It is important to note that thyroxine degradation is reduced in the elderly, so that TSH-suppressive doses of 2-2.2 mcg/kg often required in younger patients with thyroid cancer may be excessive in the elderly.

In older patients, thyroxine suppression therapy (equivalent to subclinical thyrotoxicosis) may trigger atrial fibrillation. In the Framingham Heart Study, individuals greater than 60 years of age with TSH values of 0.1 mU/L or less had an adjusted relative risk of 3.8 for developing atrial fibrillation during a 10-year follow-up and those with TSH values between 0.1 mU/L and 0.4 mU/L had an adjusted relative risk of 1.6.(48) In a retrospective study, Auer et al reported a similar adjusted relative risk of 2.8 in subjects with subclinical hyperthyroidism compared with those with normal concentrations.(49) More recently, in a prospective cohort study that included 3233 individuals aged 65 years or older, those with subclinical hyperthyroidism had a greater incidence of atrial fibrillation over a 13-year follow-up than the euthyroid group, with an adjusted relative risk of 1.98.(50) The authors repeated the analyses limiting it to individuals with a TSH of 0.1 to 0.44 mU/L. The adjusted relative risk in this group was 1.85. All of the above studies excluded participants taking thyroid hormone medication. There are no studies examining the effect of iatrogenic subclinical hyperthyroidism on atrial fibrillation in older patients with thyroid cancer.

The effect of prolonged subclinical hyperthyroidism due to L-thyroxine therapy on bone mineral density is controversial. A meta-analysis that included 13 studies, in which 50% of the patients with L-thyroxine-induced subclinical hyperthyroidism had thyroid cancer, reported average bone mass loss of 0.91% per year over a 10-year period in postmenopausal women.(51) This decline in bone mass was statistically significant when compared to controls. In addition, premenopausal women had a non-significant decline in bone mass of 0.31% per year over a 9-year period when compared to normal controls. In contrast, Reverter et al performed a cross-sectional study in a group of 88 women on long-term thyroxine suppression therapy for differentiated thyroid carcinoma with a mean age of 51 years and found no difference in bone mineral density or N-telopeptide, a marker of bone turnover, between patients and controls.(52) Interestingly, they found the bone mineral density in the lumbar spine was significantly lower in controls than in patients on suppressive doses of L-thyroxine. When premenopausal and postmenopausal women were compared to their respective controls, bone mineral density was similar in the femoral neck and lumbar spine. In another meta-analysis, thyroxine suppression therapy had a detrimental effect on bone mineral density in postmenopausal women but not on premenopausal women or men.(53) In conclusion, it appears that postmenopausal women are the principal group at risk for osteoporosis when taking TSH suppressive dose of thyroxine.

The beneficial effect of TSH suppression is a significant reduction in recurrence rate of differentiated thyroid cancer.(54) In patients with more aggressive tumors and advanced stages, this benefit outweighs the potential complications of the suppressive therapy. Nevertheless, patients should be advised about these side effects, and monitoring of bone mineral density is advisable. When there is good evidence that the cancer has been cured, the dose of thyroxine can be reduced to maintain the serum TSH in the low-normal range.

Chemotherapy

Older cytotoxic drugs have shown little benefit for progressive, advanced, or metastatic papillary or follicular thyroid cancer while causing significant side effects. Improved understanding of the pathogenesis of these cancers is leading to the development of new agents aimed at specific oncogenic mechanisms: RET, BRAF, EGFR, VEGFR. Angiogenesis is currently being explored as a target for the treatment of advanced differentiated thyroid cancer. Differentiated thyroid cancers are characterized by an increased expression of vascular endothelial growth factor (VEGF), which is a potent angiogenesis stimulator. Motesanib diphosphate is an oral inhibitor of VEGF receptors 1, 2, and 3; platelet-derived growth-factor; and KIT. In an open-label, single-group phase 2 study, 93 patients with radioiodine-resistant differentiated thyroid cancer were treated with 125 mg of motesanib diphosphate once a day taken orally.(55) Fouteen percent of patients were noted to have a partial response to treatment while stable disease was observed in 67% of patients. Eight percent of individuals had progressive disease. Ninety-four percent of patients had at least one treatment-related adverse event some of which included diarrhea, hypertension, fatigue, and weight loss. Motesanib as well as other tyrosine kinase inhibitors increase the requirement for levothyroxine detected by elevation of serum TSH on the pretherapy dose of levothyroxine. These drugs may alter thyroxine absorption or metabolism.

Sorafenib, an oral multi-kinase inhibitor, was administered to 30 patients with advanced thyroid cancer in an open-label phase II trail at a dose of 400 mg orally twice daily for a minimum of 16 weeks.(56) Twenty-three percent of patients had a partial response while 53% had stable disease. Seventeen of nineteen patients showed a decrease in serum thyroglobulin levels with a mean decrease of 70%. The median progression-free survival was 79 weeks. The most common side effects included palmar-plantar erythema, rash, fatigue, weight loss, stomatitis, and musculoskeletal pain. Patients with progressive metastatic disease for whom conventional therapy, including surgery, radioiodine, and external radiation have been ineffective, should be referred for consideration in a clinical trial of new chemotherapeutic agents (www.clinicaltrials.gov). Older age should not be a basis for exclusion from such trials, unless the quality of life is already severely compromised by other diseases.

For an extensive discussion of the treatment of thyroid cancer, please refer to Chapter 18.