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Identification and Treatment of Aggressive Thyroid Cancers (Part 1)

Identification and Treatment of Aggressive Thyroid Cancers (Part 1)

Most thyroid cancers are slow-growing, easily treatable tumors with an excellent prognosis after surgical resection and targeted medical therapy. Unfortunately, 10% to 15% of thyroid cancers exhibit aggressive behavior and do not follow an indolent course. Approximately one-third of patients with differentiated thyroid cancers will have tumor recurrences. Distant metastases are present in about 20% of patients with recurrent cancer. Approximately half of patients with distant metastases die within 5 years. The loss of the ability to concentrate radioiodine and produce thyroglobulin is a sign of dedifferentiation, which occurs in about 30% of patients with persistent or recurrent thyroid cancer. Dedifferentiation is associated with poorer responses to conventional therapy and difficulty monitoring tumor burden. Clinicians must identify tumors with more aggressive biology and treat them accordingly with more aggressive regimens. Part 1 of this two-part article describes in detail the distinct types of thyroid cancer, as well as risk factors, outcomes, and prognostic factors, with a focus on thyroid cancers of follicular cell origin. Part 2, which will appear in next month’s issue, covers risk assessment and staging, findings that suggest the presence of aggressive tumors, recurrent/metastatic disease, and the value of treatment with chemotherapy and external-beam radiotherapy. Experimental treatments utilizing molecular targets, redifferentiation agents, and gene therapy are covered briefly as well.

Thyroid cancers are generally thought to be slow-growing and easily treatable, with an overall excellent prognosis after appropriate surgical and medical therapy. This assumption is accurate for the majority of well-differentiated cancers of follicular cell origin. Unfortunately, 10% to 15% of thyroid cancers do not follow this paradigm of overall good prognosis. Most notably contrary to this model is anaplastic thyroid cancer (ATC), which is considered to be one of the most aggressive human neoplasms for which surgery, radiation, and chemotherapy are all re­latively ineffective. Aggressive behavior has also been observed in several histopathologic variants of papillary and follicular cancer and in the context of some familial associations as well.

Part 1 of this two-part article describes in detail the distinct types of thyroid cancer, as well as risk factors, outcomes, and prognostic factors, with a focus on thyroid cancers of follicular cell origin. Part 2, which will appear in next month’s issue, will cover risk assessment and staging, findings that suggest the presence of aggressive tumors, recurrent/metastatic disease, and the value of treatment with chemotherapy and external-beam radiotherapy. Experimental treatments utilizing molecular targets, redifferentiation agents, and gene therapy are covered briefly as well. For a comprehensive review of medullary thyroid cancer the reader will be referred elsewhere.

Epidemiology: Incidence and Prevalence

Thyroid cancer is still relatively rare, accounting for less than 2% of all invasive cancers diagnosed yearly. It accounted for only approximately 25,690 new cancers and 1,490 deaths in the United States in 2005.[1] To put this into perspective, approximately 1.4 million new invasive cancers and 570,000 cancer deaths are estimated to have occurred in the United States during the same time period.[1]

Types of Thyroid Cancer

Thyroid cancers originate from either the follicular cells or the parafollicular C cells. Follicular cells are the largest cellular component of the thyroid. From these cells papillary, follicular, and Hrthle cell cancers arise. Papillary thyroid cancers (PTCs) represent approximately 80%, and follicular thyroid carcinomas (FTCs) approximately 10%, of all thyroid cancers. Medullary thyroid cancer (MTC) arises in the parafollicular C cells and represents approximately 5% of all thyroid cancers. Anaplastic cancers probably arise from follicular cell cancers that have undergone dedifferentiation and represent less than 2% of all thyroid cancers. This article will focus on the identification and treatment of thyroid cancers of follicular cell origin with more aggressive biologic behavior.

Thyroid cancer comprises four principal types that can be further subclassified by histology, genealogy, and/or genotyping. Thyroid cancer is unique in that the biologic behavior and natural history of the types of thyroid cancer vary widely, from the benign incidental subcentimeter PTC, which is probably not clinically significant, to ATC, which is almost uniformly lethal. Less striking is the difference between most differentiated cancers of follicular cell origin. Follicular thyroid cancer, for example, with its approximately 85% 10-year survival, is only somewhat more aggressive than PTC, with an expected 93% to 97% 10-year survival.[2,3] Hrthle cell carcinoma (HCC) is usually classified as a variant of FTC; it is less radioiodine-avid and is associated with more frequent nodal metastases than FTC. Accordingly, the 10-year survival rate is poorer, at approximately 76%.[2]

Medullary thyroid cancer has a poorer prognosis than FTC or PTC, which may in part be due to the ineffectiveness of radioiodine, chemotherapy, or external-beam radiation for this form of thyroid cancer.[4] Overall, 10-year survival is between 50% and 75%.[5] There is variation in the clinical behavior of both the sporadic and inherited forms of MTC. Mutations in the RET proto-oncogene have been demonstrated to be the central event in the oncogenesis of MTC.[6-8] It has been shown that biologic behavior in MTC may be more or less aggressive depending on the specific somatic or genomic codon mutation found in the RET proto-oncogene.[9,10] Medullary thyroid cancer associated with multiple endocrine neoplasia (MEN) 2B has been found to behave in a more aggressive manner than its MEN 2A counterpart, leading some clinicians to recommend prophylactic thyroidectomy as soon as RET mutations are confirmed or prior to 12 months of age in MEN 2B as compared to 5 or 6 years of age in MEN 2A.[4,6,10-12] The treatment of MTC, especially with its syndromic associations, is quite complex and should be performed in referral centers by dedicated specialists. A comprehensive review on the management of MTC is beyond the scope of this article; however, several excellent texts on the subject exist.[13,14]

Risk Factors

The two major risk factors for the development of thyroid cancer of follicular cell origin are exposure to significant amounts of ionizing radiation (especially at a young age) and family history of thyroid cancer. The risk of thyroid cancer also appears to be modulated by dietary iodine intake.

Several reports have described families with a high frequency of thyroid cancer of follicular cell origin,[15-17] and several studies have established that individuals with a close relative with thyroid cancer have an increased risk (five- to ninefold) of developing thyroid cancer themselves.[15,18]

Following exposure to ionizing radiation in childhood (2 to 5 Gy), thyroid nodules may develop at a rate of about 2% per year.[19] Approximately 40% of thyroid nodules found in the setting of prior exposure to ionizing radiation are ultimately found to be malignant. The development of malignancy usually occurs 2 to 3 decades after exposure. Hyperparathyroidism and salivary gland tumors are also more common in these patients. After the Chernobyl reactor meltdown, children living downwind in Belarus developed aggressive thyroid cancers at an alarming rate, some with a lag phase as short as 4 years after exposure.[20] Most of these tumors were more aggressive, with a higher incidence of local recurrence and metastasis. A high incidence of the diffuse sclerosing and solid and trabecular subtypes of PTC were identified in these patients.[20]

Dietary iodine content has not been linked to the incidence of thyroid cancer overall, yet a higher proportion of thyroid cancers in iodine-deficient areas are follicular and anaplastic in nature. In contrast, in areas with adequate dietary iodine there is a higher proportion of the more indolent PTC. Also, iodine supplementation has been associated with a reduction in the development of endemic goiters.[21]

Treatment for Differentiated Thyroid Cancers of Follicular Cell Origin

Although substantial practice variation exists within the United States and abroad, the global treatment strategy for thyroid cancers of follicular cell origin involves a four-step process of surgical resection followed by radioiodine ablation, thyroid-stimulating hormone (TSH) suppression, and surveillance. For differentiated cancers the primary treatment modality is surgical. The goals of surgery are to achieve a complete resection of the primary tumor with appropriate lymph node clearance without causing undue morbidity or any mortality. For undifferentiated cancers the surgical interventions may be more selective. For example, in ATC, airway preservation may be the primary goal. Furthermore, radioiodine ablation is ineffective in ATC and other non-radioiodine-avid tumors, mandating alternative therapies.

There are no controlled prospective studies comparing total thyroidectomy with hemithyroidectomy for differentiated thyroid cancer of follicular cell origin. Controversy still exists as to the optimal surgical approach for small well-differentiated tumors in low-risk patients. For more aggressive tumors or high-risk patients, a more extensive resection such as total or near-total thyroidectomy is recommended by most experts.

There are five main arguments in favor of total thyroidectomy.[22] First, thyroid cancers are commonly multifocal, with studies suggesting that PTCs are multifocal (and potentially bilateral) in 30% to 80% of cases and HCCs are multifocal in 30% of cases.[23-26] However, follicular cancers and sporadic medullary cancers are usually unifocal. Second, total thyroidectomy makes effective radioiodine ablation possible. If substantial residual thyroid tissue is left in situ it will likely be ablated with an initial dose of radioiodine, but a second therapeutic dose of radioiodine will usually be required before metastases can be effectively treated. Third, radioiodine scanning is a more effective tool in those patients with no residual functioning thyroid tissue that might mask uptake in locoregional or distant metastases. Fourth, thyroglobulin can be used as a more sensitive tumor marker during follow-up in those patients with no residual thyroid tissue. Finally, the resection of all thyroid tissue obviates the very small risk of an unresected differentiated cancer eventually dedifferentiating into an incurable anaplastic cancer.

There is also considerable practice variation in the use of radioactive iodine in the postoperative setting. After thyroidectomy, postoperative radioiodine therapy is usually not offered for cancers 1 cm or smaller. In general, radioiodine should only be offered to those patients whose tumors are thought to have the potential for recurrence and are radioiodine-avid. Some clinicians offer radioiodine to all patients with tumors larger than 1.5 or 2.0 cm regardless of other risk factors. Others will reserve radioiodine for tumors 2 cm or larger, or for those patients with other risk factors.

Studies of higher-risk thyroid tumors have shown that radioiodine is associated with fewer recurrences and lower cancer-specific mortality.[27-31] However, most of these studies were done on patients with tumors 1.5 cm or larger. Findings of capsular invasion, local recurrence, or distant metastases are generally agreed upon indications for radioiodine.[32] Radioiodine is also usually given for those cancers that are inoperable or not completely resected. If a patient develops resectable nodal recurrence in the central or lateral neck an attempt should be made to surgically clear the disease before administering radioiodine.

Following surgery, patients are allowed to withdraw from thyroid hormone until such time as the TSH level is elevated to at least 30 µIU/mL.[32] This withdrawal period may take as long as 4 to 6 weeks in many patients because the half-life of endogenous thyroid hormone is about 7 days. During the first few weeks of withdrawal many clinicians administer triiodo­thyronine (T3) in order to avoid the debilitating fatigue that some patients experience. The T3 is then withdrawn for a period of approximately 2 weeks before treatment. Furthermore, for these 2 weeks prior to the predicted radioiodine treatment date the patient is placed on a low-iodine diet. If the patient has received a significant dose of iodine (eg, iodinated contrast for CT scanning) in the prior 6 to 9 months a 24-hour urinary iodine clearance should be measured; it should be less than 200 µg/d per gram of creatinine prior to administering radioiodine.[32] Women of childbearing age must have a negative pregnancy test prior to radioiodine administration.

Once the TSH level is appropriately elevated, a whole-body scan may be performed with a low dose of radioactive iodine. The results of the scan, along with the histologic and intraoperative findings, can assist the clinician in selecting the appropriate treatment dose of radioiodine for each patient. Some physicians use fixed doses of radioiodine based on staging and others use tumor or blood dosimetry to select the appropriate dose.[33] Radioiodine ablation is usually performed shortly after the whole-body scan. After treatment, a second whole-body scan is done to document iodine uptake by the cancer. An added benefit of the posttreatment scan is that in up to 25% of cases, additional uptake is seen after the treatment dose of radioiodine that was not seen with the pretreatment scanning dose. Such findings may lead to upstaging and change clinical management.

Following treatment, the patient is placed back on thyroid hormone. The thyroid hormone dose is titrated to cause suppression of TSH to predetermined values depending on how aggressive the tumor is felt to be. Some studies have shown that lifelong TSH suppression results in fewer tumor recurrences when TSH levels are kept below 0.1 mU/L, and that this may result in improved overall survival.[34-36] It is our practice to recommend suppression of TSH even further (less than 0.05 mU/L) for high-risk patients with more aggressive ­tumors.[37]

The patient subsequently undergoes surveillance with periodic -physical exams, ultrasonography, measurement of TSH-stimulated or TSH-unstimulated thyroglobulin, and possibly thyroid hormone withdrawal or recombinant human TSH (rhTSH)-stimulated scanning. Any sign of possible recurrent disease such as rising thyroglobulin level, palpable or sonographically suspicious adenopathy, or radioiodine uptake signals the need for a metastatic work-up and consideration of reexcision, retreatment with radioiodine, or adjuvant chemoradiotherapy.

The National Comprehensive Cancer Network (NCCN) has made recommendations for the follow-up of PTC and FTC through their Clinical Practice Guidelines in Oncology.[33] Anatomic surveillance by physical exam is recommended every 3 to 6 months for 2 years and then annually. They also recommend that TSH, thyroglobulin, and antithyroglobulin antibodies be checked at 6 and 12 months and then annually if the patient is disease-free. Antithyroglobulin antibodies should always be measured with thyroglobulin because the presence of antibodies makes thyroglobulin measurements unreliable. The NCCN also recommends that if a patient has undergone total thyroidectomy and radioiodine ablation, he or she should undergo radioiodine scanning yearly until negative. The NCCN also recommends considering periodic ultrasound, chest x-ray, and rhTSH-stimulated thyroglobulin measurement. They recommend considering a positron-emission tomography (PET) scan for radio-iodine whole-body-scan-negative, -thyroglobulin-positive tumors when stimulated thyroglobulin is greater than 2 to 5 ng/mL.

For aggressive tumors, we also recommend an ultrasound annually. Findings from the ultrasound can be correlated with functional surveillance data from radioiodine scanning.

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