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(Drug information on 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.
Hürthle Cell Carcinoma
Hürthle 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. Hürthle cell carcinomas are defined as encapsulated follicular cancers composed of at least 50% Hürthle cells in a gland that does not have florid thyroiditis.[57] Hürthle 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. Hürthle 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. Hürthle 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(Drug information on doxorubicin) and paclitaxel(Drug information on paclitaxel) are the chemotherapeutic agents that have shown the most promise.[70-73] Gemcitabine(Drug information on gemcitabine) (Gemzar) used in combination with cisplatin(Drug information on 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.
