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.

Outcomes

No randomized prospective clinical trials for the treatment of thyroid cancers exist because of the rarity of cases and the prolonged clinical course. Because of the length of -survival for differentiated thyroid -cancers, measuring quality of survivorship may be as important as measuring overall survival or mortality, but this has rarely been addressed. In one large study from the Mayo Clinic, 2,444 PTC patients were treated between 1940 and 1999 for papillary thyroid cancer; the 25-year cause--specific mortality and recurrence rates were 5% and 14%, respectively.[38] Another large study has shown a 10-year survival of approximately 93% for PTC.[2] For follicular cancers the overall and disease-free survival is poorer, with an approximately 85% 10-year survival rate.[2,39,40] For HCC the 10-year survival is even worse, at approximately 76%.[2] Anaplastic cancers are some of the most aggressive human neoplasms known. Median survival is only between 3 and 6 months in most studies.[41]

Volume/outcome relationships have been examined for many surgical procedures; it has been demonstrated that lower-volume surgeons have poorer outcomes.[42] A low case volume has been associated with higher complication rates and length of stay in thyroid surgery as well.[43] Retrospective review of treatment regimens and follow-up for thyroid cancer patients in one medical center revealed frequent departures from established treatment guidelines when care was given outside of specialized clinics.[44] Studies such as these suggest that optimal care is more likely to be achieved in specialist clinics than in nonspecialist environments. Although overall and disease-free survival have not been correlated with volume of thyroid cancers treated, these studies suggest that there may be a benefit to referring thyroid cancer patients to specialized centers of excellence where complication rates may be lower and treatment protocols exist for managing these relatively rare cancers.

Aggressive Papillary Thyroid Cancer Subtypes

Approximately 10% to 15% of thyroid cancers consist of histologic variants that are believed to display more aggressive biologic behavior.[45] The histologic variants of PTC that may display more aggressive biologic behavior include the tall cell variant, the columnar cell variant, the diffuse sclerosing variant, and the solid and trabecular variant.[45,46] There is debate whether all of these histologic variants truly demonstrate a more aggressive pattern. Unfortunately, due to the rarity of these tumors, treatment has not been studied in a prospective fashion.

The histologic criteria for making the diagnosis of tall cell variant is that at least 30% of the tumor cells are twice as tall as they are wide.[47,48] Tall cell variant cells have an oxy-philic cytoplasm. The tall cell variant has most commonly arisen in the fifth and sixth decades of life. Tall cell variant tumors are generally larger than the common variety of PTC. Extrathyroidal extension and locoregional lymph node involvement are common events. The rate of distant metastases and mortality is higher than standard PTC. RET/PTC3 rearrangements and overexpression of p53 have been demonstrated in a significant percentage of tall cell variant tumors.[48,49] Tumor-related mortality was 16% at 5 years in one review.[45]

The distinction between the co-lumnar cell variant and the tall cell variant is the presence of nuclear pseudostratification.[50] In the columnar cell variant the height of the cells is at least twice the width, as in the tall cell variant, but the height is usually greater than that seen in the tall cell variant. Columnar cell variant patients are younger than tall cell variant patients; the disease usually presents in the fifth decade of life. The columnar cell variant of PTC was originally thought to be associated with a dismal prognosis, but newer studies suggest that when the tumor is encapsulated patients have no poorer a prognosis than those with standard PTC. However, when the tumor is not encapsulated, 67% of patients have died at a mean follow-up of 40 months in one study.[51]

The diffuse sclerosing variant usually occurs in young patients and presents as diffuse thyroid enlargement without a specific nodule. Histologically this tumor usually diffusely involves both lobes, with extensive lymphatic infiltration. This tumor can mimic thyroiditis at presentation because of the lymphocytic infiltrate. The diffuse sclerosing variant has a higher incidence of palpable lympha-denopathy and cervical metastases. The diffuse sclerosing variant usually demonstrates intrathyroidal extension and has a higher rate of locoregional metastases and local and distance recurrence. Interestingly, nearly one-fourth of the cases described in the world literature come from children who developed thyroid cancer after being exposed to nuclear fallout from the Chernobyl disaster.[20,52]

Solid and trabecular variant tumors demonstrate an architectural pattern that is predominately solid and trabecular. There is a strong association between the solid and trabecular variant and radiation exposure, and it was also seen more commonly in Chernobyl victims.[20] Outside of the Chernobyl victims, presentation is usually late in the fifth decade of life. There is little information about recurrence and survival in solid and trabecular variant PTC. One study suggests a recurrence rate of 33% and a 10-year survival of only 72%.[53] Other studies have shown a high rate of extrathyroidal extension and cervical nodal metastases, but no difference in prognosis between solid and trabecular variant and the common variety of PTC.[20,26]

For these aggressive variants of PTC it has been suggested that a more aggressive standard treatment approach, including total thyroidectomy, modified neck dissection, and adjuvant radioiodine therapy, be employed.[45]

Poorly Differentiated Thyroid Cancers

The ability to concentrate iodine, express TSH receptor (TSH-R), and produce thyroglobulin is what distinguishes well-differentiated thyroid cancers from poorly differentiated or undifferentiated thyroid cancers. About 2% to 5% of all thyroid cancers dedifferentiate over time, leading to problems with monitoring disease burden and tumor progression and limiting therapeutic options.[54] Unfortunately, dedifferentiation occurs more frequently in patients with persistent or recurrent thyroid cancer; it is seen in about 30% of these patients.[55] With the loss of iodine ­uptake by the tumor the use of radioiodine scanning and radioiodine ablation is obviated. Suppression of TSH, one of the most powerful weapons against recurrence, is only useful for those tumors that express TSH-R.

Thyroglobulin is a useful tumor marker for those cancers that retain the ability to produce thyroglobulin, but the loss of measurable thyroglobulin in the presence of clinical recurrence suggests that the tumor has undergone dedifferentiation. Unfortunately, there is little effective therapy other than total surgical removal for those tumors that do not concentrate iodine or respond to TSH suppression therapy. External-beam radiotherapy may benefit selected patients, but should be used with caution due to the fact that it often complicates subsequent reoperation as detailed below.

Hrthle Cell Carcinoma

Hrthle cell carcinoma is classified as a variant of follicular carcinoma. Most studies suggest that it is more aggressive than FTC but less aggressive than MTC.[24,56] The HCC variant represents approximately 15% to 20% of all FTC. Hrthle cell carcinomas are defined as encapsulated follicular cancers composed of at least 50% Hrthle cells in a gland that does not have florid thyroiditis.[57] Hrthle cell variants of PTC have also been described, and appear to be more aggressive than standard PTCs.

In contrast to other differentiated cancers of follicular cell origin, HCCs are less radioiodine-avid; only approximately 10% concentrate iodine. Approximately 30% of HCCs are multifocal. Hrthle cell carcinomas are found to have nodal metastases in approximately 30% of cases, in contrast to FTC, which spreads to lymph nodes in only approximately 10% of cases. Some experts feel that HCC should not be classified as a subtype of FTC because of these clinical features.[22] Total thyroidectomy has been recommended based on the higher likelihood of multifocality and the poor avidity for radioiodine. Hrthle cell carcinomas usually secrete thyroglobulin, making it a possible tumor marker following total thyroidectomy. External-beam radiotherapy can be considered for unresectable or residual disease that is not radioiodine-avid, but should be used selectively.

Insular Carcinoma

The insular carcinoma (IC) variant of follicular cancer was formally characterized in 1984. The name insular comes from the histologic features of necrotic tumor with solid clusters or nests of cells, known as insulae, spared from necrosis. The finding of small foci of well-differentiated PTC or FTC is common. Morphologically, IC resembles MTC on fine-needle aspiration (FNA) but has dissimilar immunostaining. Insular carcinoma has a higher rate of regional and distant metastases, with approximately 50% of patients having cervical nodal metastases and 30% to 70% of patients developing distant metastases.[58] Mortality is high in insular carcinoma, with an overall tumor-related mortality of 32% in one review.[45] Presentation is generally in the mid-fourth decade of life. These tumors are usually larger than well-differentiated thyroid cancers. Insular carcinoma represents between 2% and 6% of all thyroid cancers. About 75% to 80% of these cancers are radioiodine-avid.[59,60] Total thyroidectomy, central neck dissection, and modified radical neck dissection followed by radioiodine ablation have been ­recommended.[45] Locoregional recurrences may benefit from external-beam radiotherapy.

Anaplastic Thyroid Cancer

Anaplastic thyroid cancer has the poorest prognosis of all types of thyroid cancer, and in fact is one of the fastest growing, most aggressive ­human malignancies. Survival is measured in months, with an overall median survival of 3 to 4 months.[61,62] Death is usually by asphyxiation. The peak incidence is in the seventh decade of life, and most patients are female.[61] Fortunately, most studies suggest that ATC represents less than 2% of all thyroid cancers, and has an annual age-adjusted incidence of only 2 cases per million people per year.[63] Approximately 20% of patients have a history of thyroid cancer and up to 50% of patients have a history of multinodular goiter. The hallmark of ATC is a large, rapidly growing tumor frequently associated with compressive symptoms and pain. Most of these tumors are 8 cm or larger. Approximately one-third of patients present with vocal cord paralysis.[64] Approximately half of patients have distant metastases at presentation, with the lung being the most common site.[61] Patients presenting with distant metastases have a poorer prognosis.[65]

Most studies show that the extent of operation and completeness of resection do not affect survival,[61,65] but others have shown a benefit of palliative debulking if it is accompanied by adjuvant chemotherapy or radiation.[66] Fine-needle aspiration has an accuracy of approximately 90%, but making the distinction between anaplastic thyroid cancer and other primary thyroid malignancies (eg, IC, MTC, or thyroid lymphoma) or poorly differentiated cancer metastatic to the thyroid can sometimes be difficult.[67] Open biopsy is only rarely required. Once the diagnosis is made or suspected, a computed tomography (CT) scan of the neck, chest, and abdomen is necessary to determine the extent of local and distant disease. Also, if the diagnosis of ATC is in question histologically, a CT scan can demonstrate a primary cancer (eg, renal cell carcinoma) that is likely to be the cause of the poorly differentiated metastasis to the thyroid. Since ATC is not radioiodine-avid, there is no indication for radioiodine scanning. Ultrasound may be essential in the surgical setting in order to identify the location of the trachea, but otherwise adds little to the information from the CT scan.

Multimodality therapy consisting of hyperfractionated radiotherapy, chemotherapy, and surgical resection has emerged as the most promising treatment for ATC.[41] Several small studies have demonstrated a survival benefit to this approach, usually consisting of neoadjuvant chemoradiotherapy followed by surgical resection and postoperative chemotherapy.[68-70] Doxorubicin and paclitaxel are the chemotherapeutic agents that have shown the most promise.[70-73] Gemcitabine (Gemzar) used in combination with cisplatin has been promising in one preclinical study.[74]

Because there is no clearly effective established treatment regimen for ATC, consideration should be given to referring these patients to clinical trials. As of the writing of this article there are seven trials open for recruitment for patients with ATC through the US National Institutes of Health’s www.ClinicalTrials.gov website.[75] Three of these trials are designed specifically for ATC, and the diagnosis of ATC meets enrollment criteria for four others.

Prognostic Factors for Papillary Thyroid Cancer

Well-established independent prognostic factors for papillary thyroid cancer include age at diagnosis, presence of extrathyroidal tumor invasion, distant metastases, and size of primary tumor.[76-78] Most studies show a significant increase in risk of mortality once the age at diagnosis exceeds 45 to 50 years. A tumor size greater than 3 or 4 cm has been shown in most studies to be associated with a poorer prognosis. Less well-established prognostic factors for PTC include gender, incomplete tumor resection, tumor multicentricity, and vascular invasion.[76] Male gender has been historically considered to be a greater risk,[79,80] but many investigators have found that gender is not an independent prognostic factor for PTC.[77,81] Palpable cervical adenopathy and distant metastases found at presentation can herald more advanced disease.

Interestingly, for PTC and FTC the presence of lymph node metastases, unlike almost any other human malignancy, has not been associated with a worse overall survival in most studies,[82-84] although it is associated with poorer disease-free survival. Medullary thyroid cancer, however, does have worse long-term survival when there is lymph node involvement. Signs of local invasion such as recurrent laryngeal nerve palsy, hoarseness, tracheal invasion, hemo-ptysis, or Horner’s syndrome are poor prognostic signs. A history of rapid growth with extension of the tumor into the adjacent tissues should suggest anaplastic cancer.

Family history of two or more first-degree relatives with nonmedullary thyroid cancer should alert the clinician to the possibility of familial nonmedullary thyroid cancer, a syndrome characterized by multifocality, early onset, higher recurrence rates, and greater aggressiveness than nonfamilial thyroid cancers of follicular cell origin. For this reason, the diagnosis should be sought and patients with familial nonmedullary thyroid cancer should be treated more aggressively.[16,85-87]

History of exposure to ionizing radiation (especially during childhood or infancy) should alert the clinician to a greater risk of cancer within an abnormal thyroid gland. Furthermore, some studies have shown a higher incidence of the potentially more aggressive diffuse sclerosing and solid and trabecular subtypes of PTC in those patients.[20,52]

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005.

2. Hundahl SA, Fleming ID, Fremgen AM, et al: A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995. Cancer 83:2638-2648, 1998.

3. Schlumberger MJ: Papillary and follicular thyroid carcinoma. N Engl J Med 338:297-306, 1998.

4. Wells SA, Jr, Franz C: Medullary carcinoma of the thyroid gland. World J Surg 24:952-956, 2000.

5. Saad MF, Ordonez NG, Rashid RK, et al: Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine (Baltimore) 63:319-342, 1984.

6. Wells SA, Jr, Chi DD, Toshima K, et al: Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 220:237-247; discussion 247-250, 1994.

7. Mulligan LM, Kwok JB, Healey CS, et al: Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:458-460, 1993.

8. Donis-Keller H, Dou S, Chi D, et al: Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2:851-856, 1993.

9. Mulligan LM, Eng C, Healey CS, et al: Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 6:70-74, 1994.

10. Machens A, Gimm O, Hinze R, et al: Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: Oncological features and biochemical properties. J Clin Endocrinol Metab 86:1104-1109, 2001.

11. Pacini F, Romei C, Miccoli P, et al: Early treatment of hereditary medullary thyroid carcinoma after attribution of multiple endocrine neoplasia type 2 gene carrier status by screening for ret gene mutations. Surgery 118:1031-1035, 1995.

12. Learoyd DL, Messina M, Zedenius J, et al: Molecular genetics of thyroid tumors and surgical decision-making. World J Surg 24:923-933, 2000.

13. Moley JF: Medullary thyroid carcinoma, in Clark OH, Noguchi S (eds): Thyroid Cancer: Diagnosis and Treatment, pp 279-308. St. Louis, Quality Medical Publishing, 2000.

14. Dralle H, Gimm O, Machens A: Sporadic medullary thyroid carcinoma, in Doherty G, Skogseid B (eds): Surgical Endocrinology, pp 109-126. Philadelphia, Lippincott Williams & Wilkins, 2001.

15. Goldgar DE, Easton DF, Cannon-Albright LA, et al: Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst 86:1600-1608, 1994.

16. Grossman RF, Tu SH, Duh QY, et al: Familial nonmedullary thyroid cancer. An emerging entity that warrants aggressive treatment. Arch Surg 130:892-897; discussion 898-899, 1995.

17. Loh KC: Familial nonmedullary thyroid carcinoma: A meta-review of case series. Thyroid 7:107-113, 1997.

18. Pal T, Vogl FD, Chappuis PO, et al: Increased risk for nonmedullary thyroid cancer in the first degree relatives of prevalent cases of nonmedullary thyroid cancer: A hospital-based study. J Clin Endocrinol Metab 86:5307-5312, 2001.

19. DeGroot LJ: Clinical review 2: Diagnostic approach and management of patients exposed to irradiation to the thyroid. J Clin Endocrinol Metab 69:925-928, 1989.

20. Nikiforov Y, Gnepp DR: Pediatric thyroid cancer after the Chernobyl disaster. Pathomorphologic study of 84 cases (1991-1992) from the Republic of Belarus. Cancer 74:748-766, 1994.

21. Williams ED, Doniach I, Bjarnason O, et al: Thyroid cancer in an iodide rich area: A histopathological study. Cancer 39:215-222, 1977.

22. Clark OH: Papillary thyroid carcinoma: Rationale for total thyroidectomy, in Clark OH, Duh QY, Kebebew E (eds): Textbook of Endocrine Surgery, 2nd ed, pp 110-114. Philadelphia, Elsevier Saunders, 2005.

23. Russell WO, Ibanez ML, Clark RL, et al: Thyroid carcinoma. Classification, intraglandular dissemination, and clinicopathological study based upon whole organ sections of 80 glands. Cancer 16:1425-1460, 1963.

24. Yutan E, Clark OH: Hurthle cell carcinoma. Curr Treat Options Oncol 2:331-335, 2001.

25. Katoh R, Sasaki J, Kurihara H, et al: Multiple thyroid involvement (intraglandular metastasis) in papillary thyroid carcinoma. A clinicopathologic study of 105 consecutive patients. Cancer 70:1585-1590, 1992.

26. Carcangiu ML, Zampi G, Pupi A, et al: Papillary carcinoma of the thyroid. A clinicopathologic study of 241 cases treated at the University of Florence, Italy. Cancer 55:805-828, 1985.

27. Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97:418-428, 1994.

28. Tsang RW, Brierley JD, Simpson WJ, et al: The effects of surgery, radioiodine, and external radiation therapy on the clinical outcome of patients with differentiated thyroid carcinoma. Cancer 82:375-388, 1998.

29. DeGroot LJ, Kaplan EL, Straus FH, et al: Does the method of management of papillary thyroid carcinoma make a difference in outcome? World J Surg 18:123-130, 1994.

30. Mazzaferri EL: Thyroid remnant 131I ablation for papillary and follicular thyroid carcinoma. Thyroid 7:265-271, 1997.

31. Taylor T, Specker B, Robbins J, et al: Outcome after treatment of high-risk papillary and non-Hürthle-cell follicular thyroid carcinoma. Ann Intern Med 129:622-627, 1998.

32. Woodrum DT, Gauger PG: Role of 131I in the treatment of well differentiated thyroid cancer. J Surg Oncol 89:114-121, 2005.

33. Sherman SI, Daniels GH, Kloos RT, et al: NCCN 1.2005 Thyroid Carcinoma Practice Guidelines in Oncology. http://www.nccn.org/professionals/physician_gls/PDF/thyroid.pdf. National Comprehensive Cancer Network, Inc, 2005. Last accessed February 2, 2006.

34. Pujol P, Daures JP, Nsakala N, et al: Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer. J Clin Endocrinol Metab 81:4318-4323, 1996.

35. Mazzaferri EL, Massoll N: Management of papillary and follicular (differentiated) thyroid cancer: New paradigms using recombinant human thyrotropin. Endocr Relat Cancer 9:227-247, 2002.

36. McGriff NJ, Csako G, Gourgiotis L, et al: Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer. Ann Med 34:554-564, 2002.

37. Sturgeon C, Clark OH: Differentiating benign from malignant thyroid nodules: When to operate. Contemp Surg 60:210-216, 2004.

38. Hay ID, Thompson GB, Grant CS, et al: 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 J Surg 26:879-885, 2002.

39. Akslen LA, Haldorsen T, Thoresen SO, et al: Survival and causes of death in thyroid cancer: A population-based study of 2479 cases from Norway. Cancer Res 51:1234-1241, 1991.

40. Hoie J, Stenwig AE: Long-term survival in patients with follicular thyroid carcinoma. The Oslo experience: Variations with encapsulation, growth pattern, time of diagnosis, sex, age, and previous thyroid surgery. J Surg Oncol 49:226-230, 1992.

41. Pasieka JL: Anaplastic thyroid cancer. Curr Opin Oncol 15:78-83, 2003.

42. Birkmeyer JD, Stukel TA, Siewers AE, et al: Surgeon volume and operative mortality in the United States. N Engl J Med 349:2117-2127, 2003.

43. Sosa JA, Bowman HM, Tielsch JM, et al: The importance of surgeon experience for clinical and economic outcomes from thyroidectomy. Ann Surg 228:320-330, 1998.

44. Kumar H, Daykin J, Holder R, et al: An audit of management of differentiated thyroid cancer in specialist and non-specialist clinic settings. Clin Endocrinol (Oxf) 54:719-723, 2001.

45. Sywak M, Pasieka JL, Ogilvie T: A review of thyroid cancer with intermediate differentiation. J Surg Oncol 86:44-54, 2004.

46. Muzaffar M, Nigar E, Mushtaq S, et al: The morphological variants of papillary carcinoma of the thyroid: A clinico-pathological study-AFIP experience. Armed Forces Institute of Pathology. J Pak Med Assoc 48:133-137, 1998.

47. Johnson TL, Lloyd RV, Thompson NW, et al: Prognostic implications of the tall cell variant of papillary thyroid carcinoma. Am J Surg Pathol 12:22-27, 1988.

48. Filie AC, Chiesa A, Bryant BR, et al: The Tall cell variant of papillary carcinoma of the thyroid: Cytologic features and loss of heterozygosity of metastatic and/or recurrent neoplasms and primary neoplasms. Cancer 87:238-242, 1999.

49. Basolo F, Giannini R, Monaco C, et al: Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma. Am J Pathol 160:247-254, 2002.

50. Jayaram G: Cytology of columnar-cell variant of papillary thyroid carcinoma. Diagn Cytopathol 22:227-229, 2000.

51. Yunta PJ, Ponce JL, Prieto M, et al: The importance of a tumor capsule in columnar cell thyroid carcinoma: A report of two cases and review of the literature. Thyroid 9:815-819, 1999.

52. Tronko MD, Bogdanova TI, Komis­sarenko IV, et al: Thyroid carcinoma in children and adolescents in Ukraine after the Chernobyl nuclear accident: statistical data and clinicomorphologic characteristics. Cancer 86:149-156, 1999.

53. Mizukami Y, Noguchi M, Michigishi T, et al: Papillary thyroid carcinoma in Kanazawa, Japan: Prognostic significance of histological subtypes. Histopathology 20:243-250, 1992.

54. Braga-Basaria M, Ringel MD: Clinical review 158: Beyond radioiodine: A review of potential new therapeutic approaches for thyroid cancer. J Clin Endocrinol Metab 88:1947-1960, 2003.

55. Goretzki PE, Simon D, Frilling A, et al: Surgical reintervention for differentiated thyroid cancer. Br J Surg 80:1009-1012, 1993.

56. Kushchayeva Y, Duh QY, Kebebew E, et al: Prognostic indications for Hurthle cell cancer. World J Surg 28:1266-1270, 2004.

57. Chen H, Udelsman R: Hurthle cell adenoma and carcinoma, in Clark OH, Duh QY, Kebebew E (eds): Textbook of Endocrine Surgery, 2nd ed, pp 123-128. Philadelphia, Elsevier Saunders, 2005.

58. Pilotti S, Collini P, Mariani L, et al: Insular carcinoma: A distinct de novo entity among follicular carcinomas of the thyroid gland. Am J Surg Pathol 21:1466-1473, 1997.

59. Flynn SD, Forman BH, Stewart AF, et al: Poorly differentiated (“insular”) carcinoma of the thyroid gland: An aggressive subset of differentiated thyroid neoplasms. Surgery 104:963-970, 1988.

60. Justin EP, Seabold JE, Robinson RA, et al: Insular carcinoma: A distinct thyroid carcinoma with associated iodine-131 localization. J Nucl Med 32:1358-1363, 1991.

61. McIver B, Hay ID, Giuffrida DF, et al: Anaplastic thyroid carcinoma: A 50-year experience at a single institution. Surgery 130:1028-1034, 2001.

62. Haigh PI, Ituarte PH, Wu HS, et al: Completely resected anaplastic thyroid carcinoma combined with adjuvant chemotherapy and irradiation is associated with prolonged survival. Cancer 91:2335-2342, 2001.

63. Ain KB: Anaplastic thyroid carcinoma: A therapeutic challenge. Semin Surg Oncol 16:64-69, 1999.

64. Ain KB: Anaplastic thyroid carcinoma: Behavior, biology, and therapeutic approaches. Thyroid 8:715-726, 1998.

65. Venkatesh YS, Ordonez NG, Schultz PN, et al: Anaplastic carcinoma of the thyroid. A clinicopathologic study of 121 cases. Cancer 66:321-330, 1990.

66. Sugino K, Ito K, Mimura T, et al: The important role of operations in the management of anaplastic thyroid carcinoma. Surgery 131:245-248, 2002.

67. Asa SL and Bedard YC: Fine-needle aspiration cytology and histopathology, in Clark OH, Noguchi S (eds): Thyroid Cancer: Diagnosis and Treatment, pp 105-126. St. Louis, Quality Medical Publishing, 2000.

68. Besic N, Auersperg M, Us-Krasovec M, et al: Effect of primary treatment on survival in anaplastic thyroid carcinoma. Eur J Surg Oncol 27:260-264, 2001.

69. Tennvall J, Lundell G, Hallquist A, et al: Combined doxorubicin, hyperfractionated radiotherapy, and surgery in anaplastic thyroid carcinoma. Report on two protocols. The Swedish Anaplastic Thyroid Cancer Group. Cancer 74:1348-1354, 1994.

70. Nilsson O, Lindeberg J, Zedenius J, et al: Anaplastic giant cell carcinoma of the thyroid gland: Treatment and survival over a 25-year period. World J Surg 22:725-730, 1998.

71. Ain KB, Egorin MJ, DeSimone PA: Treatment of anaplastic thyroid carcinoma with paclitaxel: Phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group. Thyroid 10:587-594, 2000.

72. Haddad R, Mahadevan A, Posner MR, et al: Long term survival with adjuvant carboplatin, paclitaxel, and radiation therapy in anaplastic thyroid cancer. Am J Clin Oncol 28:104, 2005.

73. Heron DE, Karimpour S, Grigsby PW: Anaplastic thyroid carcinoma: comparison of conventional radiotherapy and hyper­fractionation chemoradiotherapy in two groups. Am J Clin Oncol 25:442-446, 2002.

74. Voigt W, Bulankin A, Muller T, et al: Schedule-dependent antagonism of gem­citabine and cisplatin in human anaplastic thyroid cancer cell lines. Clin Cancer Res 6:2087-2093, 2000.

75. www.ClinicalTrials.gov. Bethesda, Md, National Library of Medicine.

76. Kebebew E, Clark OH: Papillary thyroid cancer, in Doherty G, Skogseid B (eds): Surgical Endocrinology, pp 59-73. Philadelphia, Lippincott Williams & Wilkins, 2001.

77. DeGroot LJ, Kaplan EL, McCormick M, et al: Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 71:414-424, 1990.

78. Simpson WJ, McKinney SE, Carruthers JS, et al: Papillary and follicular thyroid cancer. Prognostic factors in 1,578 patients. Am J Med 83:479-488, 1987.

79. Maddox P, Wheeler M: Approach to thyroid nodules, in Clark OH, Duh QY (eds): Textbook of Endocrine Surgery, 1st ed, pp 69-74. Philadelphia, WB Saunders, 1997.

80. Wong C, Sequeira M, Wheeler M: Diagnostic approach to the thyroid nodule, in Doherty G, Skogseid B (eds): Surgical Endocrinology, vol. 1, pp 47-57. Philadelphia, Lippincott Williams & Wilkins, 2001.

81. Moreno-Egea A, Rodriguez-Gonzalez JM, Sola-Perez J, et al: Multivariate analysis of histopathological features as prognostic factors in patients with papillary thyroid carcinoma. Br J Surg 82:1092-1094, 1995.

82. Grebe SK, Hay ID: Follicular cell-derived thyroid carcinomas. Cancer Treat Res 89:91-140, 1997.

83. Sanders LE, Cady B: Differentiated thyroid cancer: Reexamination of risk groups and outcome of treatment. Arch Surg 133:419-425, 1998.

84. McConahey WM, Hay ID, Woolner LB, et al: Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: Initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc 61:978-996, 1986.

85. Alsanea O, Wada N, Ain K, et al: Is familial non-medullary thyroid carcinoma more aggressive than sporadic thyroid cancer? A multicenter series. Surgery 128:1043-1050; discussion 1050-1041, 2000.

86. Uchino S, Noguchi S, Kawamoto H, et al: Familial nonmedullary thyroid carcinoma characterized by multifocality and a high recurrence rate in a large study population. World J Surg 26:897-902, 2002.

87. Sturgeon C, Clark OH: Familial nonmedullary thyroid cancer. Thyroid 15:588-593, 2005.