The Treatment of Thyroid Cancer
By Fitzgibbons, Shimae C Brams, David M; Wei, John P
THYROID CANCER HAS LONG been recognized as a relatively rare malignancy that, with appropriate treatment, has a good long-term prognosis and cure rate. Historically, patients with thyroid cancer have been divided into low and high-risk subsets in an effort to guide therapeutic decisions and prognostic outlook. Although more aggressive treatment for high-risk patients has generally been accepted as the standard of care, lack of prospective randomized trials has left the selection of definitive treatment, especially amongst low-risk patients, open to considerable debate. This article offers a brief review of thyroid cancer and its medical and surgical treatment. Because controversy still exists regarding certain aspects of management, including screening recommendations, medical therapy, and extent of surgical resection, we review recent data related to these issues and attempt to clarify the current understanding of treatment recommendations.
Epidemiology and Risk Factors
Thyroid cancer is a relatively uncommon cancer, but with over 33,550 new cases of thyroid cancer diagnosed in the United States in 2007; however, it remains the most common endocrine malignancy. The national incidence rate is 8.5 cases per 100,000 people, with a higher rate among women (12.5/100,000) than men (4.3/100,000). The mortality rate varies considerably with the particular type of thyroid cancer. Overall, the estimated total number of deaths related to thyroid cancer in 2007 is 1530. The mortality rate for all thyroid cancer patients between 2000 and 2004 was approximately 0.5 per 100,000 people. The overall five-year survival rate is 96.7 per cent, with a lower rate among men (93.9%) than women (97.5%).1
The incidence of thyroid cancer is associated with levels of iodine within a given population’s diet. FoIlicular and anaplastic cancers occur at higher rates in areas of iodine deficiency. Conversely, populations with diets replete in iodine demonstrate higher percentages of papillary carcinomas.2 Medical follow-up of various populations has revealed that radiation exposure, both therapeutic and accidental, is a significant risk factor for later development of thyroid cancer.3’5 This radiation exposure includes low treatment levels used in childhood radiation for acne, an enlarged thymus, or congenital hemangiomas of the head and neck. It also includes scatter from radiation ports used in the treatment of lymphoma or breast cancer and inadvertent exposure from nuclear radiation fallout, such as at Bikini Atoll in the southern Pacific islands or Chernobyl in the Ukraine. Thyroid cancer that develops in the wake of such radiation exposure is more likely to be multifocal.6
Histology
Thyroid cancer is generally divided into differentiated and undifferentiated types. The category of differentiated thyroid cancer includes the papillary, follicular, and medullary subtypes. Papillary thyroid cancer is by far the most common, constituting approximately 80 per cent of all diagnosed thyroid malignancies. Follicular is the second most common, seen in 15 per cent of cases, with medullary cancer diagnosed in only 4 per cent of cases.7
Papillary and follicular thyroid cancers are often considered together in studies of differentiated thyroid cancer pathology. These two types are responsible for the large majority of thyroid cancer diagnosed on initial biopsy. They are typically diagnosed at an early stage, with low rates of metastatic disease. There are various histological subtypes of the well-differentiated thyroid cancers including columnar, sclerosing, and insular, with variations in prognosis and outcome. The World Health Organization classification of these tumors stands as a useful guide.
An important variant of follicular cell thyroid cancer is Hurthle cell cancer, which has a different biologic course. It has been demonstrated that these tumors are potentially more aggressive than other welldifferentiated thyroid cancers, particularly with respect to metastases to regional lymph nodes or systemic disease.8-10 A recent retrospective review, however, demonstrated considerable variability in Hurthle cell cancer behavior.11 Interestingly, this study suggested categorizing the Hurthle cell cancer based on the presence of the REarranged in Transformation/ Papillary Thyroid Carcinoma Oncogene (RET/PTC) gene rearrangement. In their studies, a polymerase chain reaction based assay of this genetic variation was able to identify the subset of Hurthle cell cancers that behaved more aggressively and would, therefore, require more extensive surgical resection and medical management.
Medullary thyroid cancer is the third general subset of differentiated thyroid cancer and can occur in either a sporadic form or within the setting of a genetically inherited syndrome. The most common syndromes associated with medullary thyroid cancers are multiple endocrine neoplasia (MEN) 2a, MEN 2b, and familial medullary thyroid cancer syndromes. It is more aggressive than papillary and follicular cancers, often presenting with a higher rate of metastatic disease at the time of clinical presentation and diagnosis.7
Diagnosis
Thyroid cancer is often found either on physical exam or incidentally during imaging screens targeted at nearby anatomy, such as the parathyroid glands or vasculature of the neck. A suspicious nodule can also be identified after whole body imaging for disease at other more remote sites. Ultrasonography is often the initial study used to further define the findings and determine a diagnosis. With improved imaging techniques the percentage of micronodules, or nodules less than 1 cm in diameter, seen during these studies has increased. This may have lead to an increase in the incidence of thyroid cancers as well as to a trend towards smaller thyroid cancers with a lower risk profile. This further clouds the issue in current management strategies of small thyroid cancers as our current treatment paradigm, based upon our historical practice involving larger nodules, may not be comparable (Figs. 1 and 2).
Fine-needle aspiration (FNA) is the next step in the diagnostic workup for nodules of the thyroid gland. This technique is widely used and has an accuracy rate of approximately 95 per cent.12 The false-negative rate for a benign FNA biopsy result is 5 per cent whereas the false-positive rate for a malignant result is less than 2 per cent.13,14 It is important to point out that although the cytologic specimens obtained on FNA are sufficient for most varieties of thyroid cancer, follicular and Hurthle cell cancers can only be definitively diagnosed based on permanent histology, with confirmatory evidence of malignancy, such as capsular invasion or lymphatic or vascular spread found after extensive evaluation.15 The concomitant use of ultrasound has provided further refinement of the FNA technique and is essential for the successful biopsy of all nonpalpable nodes. Ultrasound assisted FNA can be used in all cases, however, and results in increased sensitivity and specificity.16 This is particularly useful in the case of micronodules (<1 cm) where the preoperative diagnostic rate of FNA is lower.17 Between 7 and 15 per cent of FNA biopsies result in inadequate or nondiagnostic smears.15,18,19 This rate can be reduced considerably by repeat FNA (Fig. 3).16,19,20
FIG. 1. Ultrasound image of a solid right thyroid nodule.
FIG. 2. Duplex ultrasound image showing vascularity of the same nodule.
Although FNA is the first line step in the diagnosis of a thyroid nodule, controversy remains regarding the best course of treatment in cases of FNA specimens that are suspicious but not diagnostic for carcinoma. The malignancy rate of FNA biopsy specimens resulting in a suspicious result but not diagnostic of thyroid cancer is highly variable.21,22 In a recent retrospective review, 7 per cent of all FNA results were considered suspicious, but not diagnostic of thyroid cancer.18 Reviewing 45 cases of nodules that were nondiagnostic on FNA, investigators found that 40 per cent of final pathological specimens after thyroidectomy contained thyroid cancer. Consequently, they recommend that all cases of FNA biopsies that are read as suspicious for carcinoma be managed with a lobectomy, isthmusectomy, and intraoperative frozen sectioning. In their review, Mittendorf et al. noted that intraoperative frozen sections altered the extent of surgery performed in 56 per cent of cases.18 Specifically, they note that evidence of malignancy on frozen section leads to completion thyroidectomy, whereas evidence of benign disease, even in the setting of bilateral nodules, allowed for a near total thyroidectomy. Leaving residual thyroid tissue around the parathyroids in a near total thyroidectomy decreases the risk of causing significant devascularization or damage to the glands. Because of the variability in ability to interpret fine needle aspiration cytologies and the difficulties inherent in the diagnosis of thyroid carcinoma on frozen-section histology, each surgeon and hospital must settle a priori on their approach and operative strategy, realizing the limitations inherent at their local institutions. The accuracy of papillary carcinoma diagnosis on FNA cytology allows for preoperative and intraoperative stratification, with frozen section confirmation of a diagnosis, before proceeding to the surgical procedure of choice. In the event of FNA cytology with suspicious or indeterminate follicular histology, frequently, the frozen section histology will confirm or refute a diagnosis of malignancy. This then places the therapeutic choice upon the clinical judgment of the surgeon based upon the risk- stratification of the patient and the operative findings. FIG. 3. Ultrasound guided fine-needle biopsy of suspicious thyroid nodule, with the needle seen on the left side as it enters the lesion.
Micronodules
With the increased use of ultrasonography in the diagnostic workup of neck pathology, the incidental finding of a thyroid nodule is increasingly presenting a difficult dilemma. Nodules as small as 1 cm, termed micronodules, are discovered more often.23-26 This relatively new phenomenon of incidentally discovered thyroid micronodules is likely to increase in clinical significance. Future advances in technology and development of imaging and screening techniques will undoubtedly lead to more frequent discovery of early pathology. Already, with the advent of positronemission tomography (PET) scans for the staging of various cancers, incidental thyroid nodules are identified prior to physical or symptomatic presentation. This requires further confirmatory and ultimately, invasive biopsies to exclude or to diagnosis unsuspected thyroid cancer (Fig. 4).
The majority of micronodules, however, will not become clinically significant before the patient dies of other causes. In fact, 50 per cent of all cadavers were found to have previously undetected thyroid nodules.27 Further autopsy reports have demonstrated that of those nodules, between 5.6 per cent and 35.6 per cent are likely to be thyroid microcarcinoma.28-30 The appropriate balance between aggressive surgical therapy and clinical observation for occult thyroid malignancy must allow for the indolent clinical course of those lesions as well as the clinical state of the patient, including risks for progression, metastases, and life-expectancy.
FIG. 4. PET scan demonstrating a hot left thyroid nodule found during staging for colon cancer, confirmed by FNA to be papillary carcinoma.
Despite the fact that microcarcinomas are not associated with significant mortality, the retrospective study by Pellegritti et al.31 of 299 patients with papillary thyroid cancers smaller than 1.5 cm noted interesting clinical trends. Approximately 20 per cent of small cancers had either extrathyroidal invasion and/or bilateral foci at presentation. In addition, 25.7 per cent of these 299 patients had persistent or recurrent dis ease upon follow-up after initial treatment. The most important predictor of recurrence or persistent disease was the presence of metastatic disease in lymph nodes at the time of thyroidectomy. In contrast to this data, a study of 162 patients with FNA-proven papillary microcarcinoma followed without surgical intervention demonstrated that >70 per cent of those tumors did not change in size in over 5 years of follow-up.32
Ideally, a prospective study in which patients agree to undergo randomization to aggressive versus conservative treatment groups would be necessary to resolve this controversy. Given the natural history of papillary and follicular carcinoma, however, the number of patients required to statistically resolve the issue would be clinically unfeasible. Under the current Tumor, Nodes, Metastases by AJCC staging criteria (TNM) staging system which defines microcarcinomas as T1 (less than 2 cm),31,33 Pellegritti et al. found that this updated classification system correctly moved 13 patients from TNM Stage 2 to TNM Stage 1. These 13 patients had outcomes consistent with others in their new stage, reinforcing the perception that the small size of the microcarcinomas portends a less aggressive course.
Classification Systems
Various classification systems have been developed over the past several decades in an attempt to aid clinicians in prognosis and management decisions. One of the earliest prognostic tools was the AMES (Age, Metastasis, Extent of tumor size) criteria developed at the Lahey Clinic.34 The criteria, based upon age, gender, presence of metastasis, extent of disease, and size of tumor, divides the populations into highrisk and low-risk categories. The low-risk patients can be managed with a less aggressive surgical approach whereas still maintaining excellent outcomes.35 Other classification systems have been developed, incorporating tumor grade and the presence of residual disease. The AGES (Age, Grade, Extent of tumor, Size of tumor by Mayo Clinic criteria), TNM, and MACIS (Metastasis, Age, Invasion, Completeness of resection, and Size by Mayo Clinic criteria) systems, integrating other pathologic variables, have all been used to stratify patient’s risk for thyroid cancer mortality, with approximately similar outcomes.36-39
An extensive experience with these classification systems has demonstrated their value in determining a given patient’s prognosis. As expected, the large majority of patients are grouped into low- risk categories (70-80% low-risk vs 11-20% high0 -risk).40,41 Tenyear mortality rates (1-2% vs 28%) and 40-year survival probabilities (95% vs 45%) are also significantly correlated to the low and high-risk groups respectively.40,42,43
Operative Management
Over the past several decades, the operative management of thyroid cancer has come under much scrutiny, with the more conservative but clinically aggressive approach of total thyroidectomy challenged by evidence of excellent survival outcomes in low-risk patients with less extensive resections, including hemilobectomy and subtotal thyroidectomy. Although the surgical management of high-risk patients is well accepted, the lack of prospective clinical trials has left the subject open to debate.
General arguments in favor of less extensive surgery often point to the lack of compelling evidence for survival benefit after total thyroidectomy and/or nodal dissection, and the higher complication rates associated with bilateral surgical dissection. Although surgical complication rates vary depending upon the experience of the surgeon and the institution,44 the rates of hypoparathyroidism and recurrent laryngeal nerve injury have been reported as high as 10 per cent and 4 per cent respectively in patients undergoing total thyroidectomy.
Retrospective reviews, such as that performed by Wanebo et al.,44 failed to demonstrate a survival benefit after total thyroidectomy versus lobectomy or subtotal thyroidectomy in differentiated thyroid cancer. The authors reviewed 347 cases of well-differentiated thyroid cancer, specifically looking at the impact of aggressive resection in patients with risk factors categorizing them as high- risk, including older age (>70) and various pathologic characteristics (components of follicular histology, vascular invasion, or extracapsular extension). They concluded that, in general, no survival benefit could be gleaned from a more extensive operation.
A more recent review by Kirn et al.45 demonstrated that in the majority of cases of papillary thyroid cancer, no significant difference in 20-year survival could be demonstrated after total thyroidectomy in either low or high-risk groups, as defined by the AMES criteria. A noted exception was the subset of patients who were both high-risk and older than 60 years. In this group, the 20-year survival increased from 25 per cent to 54.7 per cent in patients undergoing total versus unilateral hemithyroidectomy.
Although no randomized controlled trials exist, a recent nested case-control study by Lundgren et al.46 conducted on a 5123 patient cohort attempted to define the effect of surgical and postoperative treatment on survival in differentiated thyroid cancer. The specific type of surgery performed affected survival rates only in patients with stage III disease. A subtotal thyroidectomy with subsequent locoregional recurrence was associated with a worse prognosis, favoring more aggressive surgery. These authors could not demonstrate a survival advantage in a comparison of various types of lymph node dissections.
In the presence of conflicting data, several compelling reasons exist for the performance of more aggressive surgery. Recurrent thyroid cancer presents in the contralateral lobe in 4.7 to 24 per cent of cases, and approximately half of patients who develop this recurrence die from the disease.47 Papillary thyroid cancer occurs bilaterally at the relatively high rate of between 30 and 85 per cent.47 Noteworthy is the fact that a subset of these cases are instances of microscopic thyroid cancers of unknown clinical significance. Finally, proponents of total thyroidectomy argue that the benefits of ablative and adjuvant radioactive iodine treatments and thyroglobulin screening are only appreciated after total thyroidectomy.
The importance of nodal dissection has also been a subject of much debate. The value of accurate definition of nodal status has been underscored by the American Joint Committee on Cancer staging guidelines, which redefine certain stage I and II thyroid cancers in patients 45 years or older as stage III dis ease when nodal involvement is confirmed in the central compartment of the neck. The presence of nodal metastasis is stressed in part because of the high correlation between positive nodal disease and future recurrence of cancer.31,48
In a recent retrospective review, Shindo et al.49 demonstrated that 33 per cent of patients with a preoperative diagnosis of papillary thyroid cancer were found to have nodal involvement after central compartment node dissection. They reported only one complication of transient vocal cord paresis in the 100 cases reviewed. Furthermore, Kim et al.45 found that a statistically beneficial effect of lymph node dissection could only be detected in patients with high-risk thyroid cancer who were 60 years or older. The survival improved in these patients from 30.2 per cent to 72.4 per cent over 20 years (Figs. 5 and 6). Locally Advanced Disease
The management of locally advanced thyroid cancer involves extensive surgical resection. The presence of extension of the cancer beyond the thyroid gland is associated with increased incidence of local recurrence, regional spread, and distant metastasis.50 The local structures most commonly involved in advanced disease include the neck strap and pharyngeal muscles, trachea, laryngeal structures, esophagus, carotid artery, jugular vein and vagus, spinal accessory, and phrenic and recurrent laryngeal nerves.51 The guidelines for surgical management dictate that all gross pathology should be resected while preserving the vital structures and functions.52 Surgical resection of involved organs due to invasive carcinoma is predicated upon the structure involved, its function, and the clinical status of the patient. The surgical expertise and ability to perform a reconstruction after resection must be factored in before extensive surgery. High-risk elderly patients may not tolerate the loss of a carotid artery without vascular reconstruction, and tracheal reconstruction may require more technical expertise than generally available.
FIG. 5. Papillary carcinoma of the right thyroid lobe.
FIG. 6. Central compartment after total thyroidectomy and lymph node dissection.
Despite the involvement of these structures, many patients are asymptomatic at presentation, underscoring the need for appropriate preoperative imaging and staging before surgical intervention in high-risk cases.53 This workup should include evaluation for distant metastasis with either radioactive iodine (RAI) screening or the increasingly used positron emission tomography scan.54-55 Postoperatively, radioactive iodine therapy has been used, as well as external beam radiation therapy, although conclusive studies demonstrating survival benefit with these therapies are presently lacking (Fig. 7).56, 57
Recurrence
The recurrence rate of well-differentiated thyroid cancer is reported to be between 8 and 23 per cent. Unfortunately, mortality rates for patients with recurrent disease range as high as 38 per cent to 69 per cent.58 Various methods exist for monitoring patients for recurrence. The management of recurrent well-differentiated cancer has been reviewed by Palme et al.58 in a retrospective review of 73 patients requiring intervention for either recurrent or residual disease. Both patients with a single recurrence and those with multiple recurrences were identified after a median of 7 months. Salvage surgery was performed in 29 per cent of patients with a single recurrence, and in 45 per cent of those with multiple recurrences. The disease-specific 20-year survival was 94 per cent for the first subset and 60 per cent for the second subset of patients, as compared to 100 per cent for those patients with no recurrence. The presence of extrathyroidal spread at the time of the original surgery was the only variable identified on multivariate regression analysis as significant in predicting multiple treatment failure.
FIG. 7. Modified radical neck dissection for recurrent and metastatic papillary carcinoma of the thyroid.
Medullary Thyroid Cancer
Medullary thyroid cancer demonstrates a distinct pathological entity, and is typically considered separately from papillary and follicular thyroid cancer. Medullary cancer constitutes approximately 5 per cent of all thyroid cancers and arises from the parafollicular C cells of the thyroid gland.59 C cells are responsible for the production of calcitonin, a protein which can be measured in cases of possible medullary cancer.
Importantly, approximately 25 per cent of medullary thyroid cancer is seen in the setting of familial syndromes, including MEN 2A, MEN 2B, and familial isolated medullary thyroid cancer.60 It may also be seen in association with other clinical syndromes which are affected by RET (mutation at 10q11.2 on chromosome 10 coding for a cell surface growth factor receptor with tyrosine kinase function) oncogene mutations, such as Hirschsprung’s disease. The association of this disease with hereditary syndromes has led to the discovery of a specific point mutation within the RET oncogene that can be identified in over 90 per cent of affected patients.61, 62 There have been several critical mutations which have been mapped and the genotype linked to the clinical syndromes. The RET gene encodes for a tyrosine kinase which affects cell survival and reproduction, with mutations inducing receptor activation, thus initiating the process down an oncogenic pathway. Certain RET mutations within exons 10 or 11 present with early aggressive medullary thyroid carcinoma, and should induce screening of family members to identify involved kindred prior to development of clinical disease. Childhood or infancy prophylactic thyroidectomy is recommended for certain RET mutations. Other RET mutations, may present with later onset medullary carcinoma but are still just as aggressive. The best hope for cure is the detection of an RET mutation with C-cell hyperplasia in a child prior to the development of medullary thyroid carcinoma. Patients identified with the RET oncogene mutation are recommended for total thyroidectomy and central node dissection, in addition to postoperative monitoring with serum calcitonin levels.59 Those diagnosed with clinical disease may need ipsilateral or bilateral lymph node dissection at the initial surgery. Serum calcitonin levels have proven to be a fairly sensitive marker for the presence of medullary thyroid cancer, allowing for improved long term outcomes secondary to earlier operative intervention.63 Given the association between medullary thyroid cancer and the MEN syndrome, it is important to screen for concurrent pheochromocytomas in these patients. If one were diagnosed by 24-hour urine measurements of catecholamines and breakdown products, the pheochromocytoma would need to be treated pharmacologically and resected prior to treatment of the thyroid cancer.64
Anaplastic Thyroid Carcinoma
The diagnosis of anaplastic thyroid carcinoma has a poor prognosis and usually portends a short overall life expectancy for the patient. Surgical treatment is usually unable to resect the disease and local failure and recurrence and progression is the more common outcome. If a satisfactory diagnosis can be made by FNA, treatment with radiation therapy and chemotherapy should be instituted as rapidly as possible for this aggressive and fast growing malignancy. Of consideration would be the imminent loss of a patent airway, in which case, a tracheostomy as a palliative measure would be warranted. Experimental and clinical trials are underway using antiangiogenesis factors, paclitaxel, and carboplatinum.
Radioactive Iodine Ablation
The use of radioactive iodine in cases of distant metastatic, locally invasive, and nodal disease from papillary or follicular thyroid cancer is very common.65 Ultimately, however, the effects of radioactive iodine therapy on survival outcomes are less compelling.45, 66-70 In a recent meta-analysis investigating the use of RAI in thyroid cancer, some evidence was found indicating that it decreased tumor recurrence, particularly locoregional recurrence.71 The long-term effects on cancer-related mortality was inconclusive, however, with only one of seven studies demonstrating a positive effect. In light of the controversy regarding its use, the side effects of radioactive iodine ablation are often raised. High doses are known to cause chronic sialostasis and sialodenitis, whereas cumulative effects of radioactive iodine may increase a patient’s risk of leukemia and reduce male sperm counts.72
In preparation for radioactive I-131 ablative therapy, thyroid hormone replacement must be withheld for the 4 weeks preceding the use of RAI, allowing serum thyroid stimulating hormone (TSH) levels to rise.59 Alternatively, the patient can be switched to T3 therapy, with a pharmacologically shorter serum half-life, which is discontinued only 14 days before an RAI screening or ablation. Finally, the recent use of recombinant human TSH (rhTSH) has allowed patients to remain on thyroid replacement before the use of RAI interventions. Although rhTSH is more expensive, it is particularly recommended in patients who cannot tolerate the symptoms of thyroid hormone withdrawal.59
Thyroid Suppression
Thyroid suppression therapy with levothyroxine is routinely used. The degree of suppression tends to be guided by the risk stratification of the patient. Low-risk patients are given doses of thyroxine that maintains the serum thyrotropin near normal limits, whereas higher risk patients are administered truly suppressive doses to maintain the serum TSH levels just below the clinical level of hyperthyroidism.64 Thyroid suppression is not entirely without risk; with long-term treatment it increases a patient’s risk of osteoporosis and atrial fibrillation.72
Thyroglobulin Monitoring
Thyroglobulin level monitoring is used as a screen for cancer recurrence in patients with differentiated thyroid cancer after total thyroidectomy and radioactive iodine ablation.73-76 The sensitivity of serum thyroglobulin measurements ranges from 80 to 100 per cent77 with a negative predictive value of 100 per cent.78 A recent study of 256 patients with well-differentiated thyroid cancer, however, demonstrated that, due to the low incidence of recurrence, the positive predictive value of thyroglobulin levels was only 42 to 53 per cent, depending on the cutoff thyroglobulin levels used (5 ng/mL vs 10 ng/mL).79 This study demonstrated that the best positive predictive value was in fact obtained by the slope of the thyroglobulin levels at two consecutive measurements. Furthermore, it has been postulated that the slope may be used as a marker of recurrence in patients with a thyroid remnant.80 It is important to note that 15 to 30 per cent of patients can have antithyroglobulin antibodies which can alter the results of the thyroglobulin assay.80 These antibodies must be screened for in those patients being followed with serial thyroglobulin levels. Future Directions
Various innovations in the field of thyroid cancer treatment have been developed in recent years. The utility of genetic markers such as RET/PTC, BRAF, and RAS (B-rafoncogene, encoding for a serinethreonine kinase, which functions in the protein kinase pathway for signal transduction) combined with the availability of polymerase chain reaction and in-situ hybridization for DNA microarray analysis may lead to their use as a form of screening test or as prognostic indicators.81 Similarly, an oncogene has been identified that may help clinicians differentiate between a benign follicular adenoma and carcinoma.82 Clearly, the realm of genetic analysis is particularly inviting for those interested in thyroid cancer pathology, given the rarity of the disease and the fact that it seems to encompass cancers with highly variable clinical courses.
Post-operatively, long-term follow-up with RAI scans often involves withdrawing the patient’s thyroid hormone treatment for a number of weeks. The use of rhTSH offers a means of performing the RAI scan without subjecting the patient to withdrawal from exogenous hormone.83-86 This is particularly beneficial in patients sensitive to alterations in their metabolism, including those with depression, epilepsy or lupus, and patients with pituitary disease who cannot produce endogenous TSH.83
The development of positron emission tomography scans has also been investigated in the monitoring of postoperative patients. Specifically, false-negative iodine scans pose a problem in patients being followed for recurrence. As many as 13 per cent of patients may be thyroglobulin-positive but iodine-negative.80 In this setting, various alternative isotope imaging techniques have been used. The apparent utility of PET scanning in detection and staging of various other malignancies has prompted investigation into its use as a screen for recurrent thyroid cancer. In a prospective analysis of 24 patients with well-differentiated thyroid cancer, PET proved to have a sensitivity of 94.6 per cent and a diagnostic accuracy of 87.8 per cent.87 Importantly, however, the specificity of PET in this setting was only 25 per cent.
Changes in surgical approaches and development of new instrumentation have altered the standard operative approach to thyroidectomy using Lahey clamps, or Crile hemostats. As surgical techniques have evolved toward minimally invasive or minimally intrusive procedures, equipment such as ultrasonic shears, the video- endoscope, or the surgical robot have driven the evolution of surgery through smaller skin apertures. Concurrent with this has been the application of nerve monitoring equipment to protect recurrent laryngeal nerve function through these less invasive openings. Ultimately as the understanding of thyroid cancer changes, the thyroidectomy procedure itself may give way, following in the footsteps of breast cancer. In that example, the Halsted radical mastectomy has evolved into a localized resection with organ preservation and new adjuvant agents to treat systemic disease (Fig. 8).
Given the concern for higher rates of complications after reoperation for recurrent or persistent thyroid cancer, alternatives to aggressive surgical management have been investigated. Radiofrequency ablation and EtOH (ethanol) injections are minimally invasive techniques presently used as alternatives to surgical resection of malignant liver tumors.88 These techniques have recently been applied to thyroid cancer, both at sites of local recurrence and distant metastasis.89-93 Although the size of the studies have been relatively small, they have been associated with few complications and promising rates of disease free survival.
FIG. 8. Thyroidectomy using the ultrasonic shears.
As molecular genetic research elucidates the pathways of oncogenesis, the possibilities of deriving designer-molecular pharmaco-therapeutic agents increases. As a consequence of the mapping of the RET oncogene and other signaling pathways and an understanding of their functions, inhibiting agents for these transduction pathways, such as ZD6474 (Zactima, Astra-Zeneca, Westborough, MA), are undergoing clinical trials for metastatic medullary thyroid cancer. Other drugs derived from an elucidation of tyrosine kinase and of serine-threonine kinase cell surface receptors are coming to clinical trials and their efficacy should be demonstrable in the near future. Ultimately, future surgical treatment of thyroid cancer may well be predicated upon research in cell biology, leading to less surgery with more of an emphasis on minimally invasive procedures.
REFERENCES
1. Cancer Statistics Review SEER. 1975-2004, National Cancer Institute, Bethesda, MD, http://seer.cancer.gov/csr/ 1975_2003/. Accessed Mar. 3, 2008.
2. Schlumberger MJ. Papillary and follicular thyroid carcinoma. Review. N Engl J Med 1998;338:297-306.
3. Kazakov VS. Thyroid cancer after Chernobyl. Nature 1992; 359:21.
4. Schneider AB. Carcinoma of follicular epithelium: Pathogenesis. In: Braverman LE, Utiger RE, eds. Werner and Ingbar’s The Thyroid, 8th Ed. Philadelphia: Lippincott Williams and Wilkins, 2000, pp 875-86.
5. Sklar C. Abnormalities of the thyroid in survivors of Hodgkin’s disease: Data from the childhood cancer survivor study. J Clin Endocrinol Metab 2000;85:3227-32.
6. Rubino C, Cailleux AF, De Vathaire F., et al. Thyroid cancer after radiation exposure. Eur J Cancer 2002;38:645-7.
7. Hundahl SA. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the US, 1985-1995. Cancer 1998;83:2638-48.
8. Tollefsen HR, Shah JP, Huvos AG. Hurthle cell carcinoma of the thyroid. Am J Surg 1975;130:390-4.
9. Herrera MF, Hay ID, Wu PS, et al. Hurthle cell (oxyphilic) papillary thyroid carcinoma: A variant with more aggressive biologic behavior. World J Surg 1992; 16:669-75.
10. Thompsom NH, Dunn EL, Batsakis JG, Nishiyama RH. Hurthle cell lesions of the thyroid gland. Surg Gynecol Obstet 1974;139:555-60.
11. Maxwell EL, Palme CE, Freeman J. Hurthle cell tumors: Applying molecular markers to define a new management algorithm. Arch Otolaryngol Head Neck Surg 2006; 132:54-8.
12. Gharib H. Fine-needle aspiration biopsy of thyroid nodules: Advantages, limitations and effect. Mayo Clin Proc 1994;69:44-9.
13. Mittendorf EA, McHenry CR. Follow-up evaluation and clinical course of patients with benign nodular thyroid disease. Am Surg 1999;65:653-8.
14. Lowhagen T, Granberg PO, Lundell G, et al. Aspiration biopsy cytology in nodules of the thyroid gland suspected to be malignant. Surg Clin North Am 1979;59:3-18.
15. Gharib H, Goeliner JR. Fine-needle aspiration biopsy of the thyroid: An appraisal. Ann Intern Med 1993;118:282-9.
16. Danese D, Sciacchitano S, Farsetti A, et al. Diagnostic accuracy of conventional versus sonography-guided fine-needle aspiration biopsy of thyroid nodules. Thyroid 1998;8:15-21.
17. Lin JD, Chen ST, Chao TC, et al. Diagnosis and therapeutic strategy for papillary thyroid microcarcinoma. Arch Surg 2005; 140:940-5.
18. Mittendorf EA, Khiyami A, McHenry CR. When fineneedle aspiration biopsy cannot exclude papillary thyroid cancer. Arch Surg 2006;141:961-6.
19. Carmeci C, Jeffrey RB, McDougall IR, et al. Ultrasoundguided fine needle aspiration biopsy of thyroid masses. Thyroid 1998;8:283- 9.
20. Takashima S, Fukuda H, Kobayashi T. Thyroid nodules: Clinical effect of ultrasound-guided fine-needle aspiration biopsy. J Clin Ultrasound 1994;22:535-42.
21. Chen H, Zeiger MA, Clark DP, et al. Papillary carcinoma of the thyroid: Can operative management be based solely on fineneedle aspiration? J Am Coll Surg 1997;184:605-10.
22. Sclabas GM, Staerkel GA, Shapiro SE, et al. Fine-needle aspiration of the thyroid and correlation with histopathology in a contemporary series of 240 patients. Am J Surg 2003;186:702-10.
23. Chow SM, Law SC, Au SK, et al. Changes in clinical presentation, management and outcome in 1348 patients with differentiated thyroid carcinoma: Experience in a single institute in Hong Kong, 1960-2000. Clin Oncol 2003; 15:329-36.
24. Rosen I, Azadian A, Walfish P, et al. Ultrasound-guided fine- needle aspiration biopsy in the management of thyroid disease. Am J Surg 1995;166:346-9.
25. Burguera B, Gharib H. Thyroid incidentalomas: Prevalence, diagnosis, significance, and management. Endocrinol Metab Clin North Am 2000;29:187-203.
26. Papini E, Guglielmi R, Bianchini A, et al. Risk of malignancy in nonpalpable thyroid nodules: Predictive value of ultrasound and color-doppler features. J Clin Endocrinol Metab 2002; 87:1941-6.
27. Mortensen JD, Woolner LB, Bennett WA. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab 1995; 15:1270-80.
28. Neuhold N, Kaiser H, Kaserer K. Latent carcinoma of the thyroid in Austria; a systemic autopsy study. Endocr Pathol 2001; 12:23-31.
29. Ottino A, Pianzola HM, Castelletto RH. Occult papillary thyroid carcinoma at autopsy in La Plata, Argentina. Cancer 1989; 64:547-51.
30. Yamamoto Y, Maeda T, Izumi K, Otsuka H. Occult papillary carcinoma of the thyroid: A study of 408 autopsy cases. Cancer 1990;65:1173-9.
31. Pellegritti G, Scolio C, Lumera G. Clinical behavior and outcome of papillary thyroid cancers smaller than 1.5 cm in diameter: Study of 299 cases. J Clin Endocrinol Metab 2004;89: 3713- 20.
32. Ito Y, Uruno T, Nakamo K, et al. An observational trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid 2003;13:381-7.
33. Shah JP, Kian K, Forastiere A, et al. American Joint Committee on Cancer. Cancer Staging Manual, 6th Ed. New York: Springer-Verlag, 2002, pp 77-87. 34. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988; 104: 947-53.
35. Cady B, Rossi R, Silverman M, et al. Further evidence of the validity of risk group definition in differentiated thyroid carcinoma. Surgery 1985;98:1171-8.
36. Hay ID, Bergstralh EJ, Goellner JR, et al. Predicting outcome in papillary thyroid carcinoma: Development of a reliable prognostic scoring system in a cohort of 1779 patients treated at one institution during 1940 through 1989. Surgery 1993;! 14: 1050-7.
37. Hermanek P, Sobin LH. TNM classification of malignant tumors. In: UICC, International Union Against Cancer. Manual of Clinical Oncology, 4th Ed. Berlin: Springer-Verlag, 1987, p 79.
38. Loh KC, Greenspan FS, Gee L, et al. Pathological tumornode- metastasis (pTNM) staging for papillary and follicular thyroid carcinomas: A retrospective analysis of 700 patients. J CHn Endocrinol Metab 1997;82:3553-62.
39. Jukkola A, Bloigu R, Ebeling T, et al. Prognostic factors in differentiated thyroid carcinomas and their implications for current staging classifications. Endocr Relat Cancer 2004;11:571-9.
40. Gagel RF, Goepfert H, Callender DL. Changing concepts in the pathogenesis and management of thyroid carcinoma. CA Cancer J Clin 1996;46:261-83.
41. Dean DS, Hay ID. Prognostic indicators in differentiated thyroid cancer. Cancer Control 2000;7:229-39.
42. Sanders LE, Cady B. Differentiated thyroid cancer: Reexamination of risk groups and outcome of treatment. Arch Surg 1998;133:419-25.
43. Lo CY, Chan WF, Lam KY. Optimizing the treatment of AMES high- risk papillary thyroid carcinoma. World J Surg 2004; 28:1103-9.
44. Wanebo H, Coburn M, Teates D, Cole B. Total thyroidectomy does not enhance disease control or survival even in high-risk patients with differentiated thyroid cancer. Ann Surg 1998; 227:912- 21.
45. Kim S, Wei JP, Braveman JM, Brams DM. Predicting outcome and directing therapy for papillary thyroid carcinoma. Arch Surg 2004; 139:390-4.
46. Lundgren CI, Hall P, Dickman PW, Zenenius J. Influence of surgical and postoperative treatment on survival in differentiated thyroid cancer. Br J Surg 2007;94:571-7.
47. Clark OH. Total thyroidectomy: The treatment of choice for patients with differentiated thyroid cancer. Ann Surg 1982; 196: 361- 70.
48. Wada N, Duh QY, Sugino K. Lymph node metastasis from 259 papillary thyroid microcarcinomas: Frequency, pattern of occurrence and recurrence and optimal strategy for neck dissection. Ann Surg 2003;237:399-407.
49. Shindo M, Wu JC, Park EE, Tanzella F. The importance of central compartment elective lymph node excision in the staging and treatment of papillary thyroid cancer. Arch Otolaryngol Head Neck Surg 2006; 132:650-4.
50. Falvo L, Catania A, Grilli P, et al. Treatment of “locally advanced” well-differentiated thyroid carcinomas. Ann Ital Chir 2004;75:17-21.
51. McCaffrey TV, Bergstralh EJ, Hay ID. Locally invasive papillary thyroid carcinoma: 1940-1990. Head Neck 1994; 16: 165-72.
52. Patel KN, Shaha AR. Locally advanced thyroid cancer. Curr Opin Otolaryngol Head Neck Surg 2005; 13:112-6.
53. Gillenwater AM, Geopfert H. Surgical management of Iaryngotracheal and esophageal involvement by locally advanced thyroid cancer. Semin Surg Oncol 1999; 16:19-29.
54. Wang W, Macapinlac H, Larson SM, et al. [18F]-2-fluoro-2- deoxy-D-glucose positron emission tomography localizes residual thyroid cancer in patients with negative diagnostic (131)I whole body scans and elevated serum thyroglobulin levels. J Clin Endocrinol Metab 1999;84:2291-302.
55. Larson SM, Robbins R. Positron emission tomography in thyroid cancer management. Semin Roentgenol 2002;37:169-74.
56. Kim TH, Yang DS, Jung KY, et al. Value of external irradiation for locally advanced papillary thyroid cancer. Int J Radiat Oncol Biol Phys 2003;55:1006-12.
57. Philips P, Hanzen C, Andry G, et al. Postoperative irradiation for thyroid cancer. Eur J Surg Oncol 1993;19:399-404.
58. Palme CE, Waseem Z, Raza N, et al. Management and outcome of recurrent well-differentiated thyroid carcinoma. Arch Otolaryngol Head Neck Surg 2004;130:819-24.
59. Harris PE. The management of thyroid cancer in adults: A review of new guidelines. Clinical Medicine. Royal College of Physicians 2002;2:144-6.
60. Castro MR, Gharib H. Continuing controversies in the management of thyroid nodules. Ann Intern Med 2005; 142:926-31.
61. Eng C, Clayton D, Schuffenecker I, Lenoir G. The relationship between specific RET proto-oncogene mutation and disease phenotype in multiple endocrine neoplasia type 2. JAMA 1996; 276:1575-9.
62. Decker RA, Peacock ML. Update on the profile of multiple endocrine neoplasia type 2a RET mutations: Practical issues and implications for genetic testing. Cancer Suppl 1997;80:557-68.
63. Elisei R, Bottici V, Luchetti F, et al. Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: Experience in 10,864 patients with nodular thyroid disorders. J CHn Endo Metab 2004;89:163-8.
64. Singer PA, Cooper DS, Daniels GH, et al. Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. Arch Intern Med 1996;156:2165-72.
65. Dulgeroff AJ, Hershman JM. Medical therapy for differentiated thyroid carcinoma. Endocrinol Rev 1994;15:500-15.
66. Degroot LJ, Kaplan EL, McMormick M, Strauss FH. Natural history, treatment and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 1990;71:414-24.
67. Hay ID. Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 1990; 19:545-76.
68. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97:418-28.
69. Mazzaferri EL, Kloos RT. Clinical review 128: Current approaches to primary therapy for papillary and follicular thyroid cancer. Review. J Clin Endocrinol Metab 2001 ;86:1447-63.
70. Lundgren CI, Hall P, Dickman PW, Zedenius J. Influence of surgical and postoperative treatment on survival in differentiated thyroid cancer. Br J Surg 2007;94:571-7.
71. Sawka AM, Kullathorn T, Brouwers M, et al. A systematic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer. J Clin Endorinol Metab 2004;89:3668-76.
72. Schlumberger M, Challenton C, DeVathaire F. Radioactive iodine treatment and external radiotherapy for lung and bone metastasis from thyroid carcinoma. J Nucl Med 1996;37:598-605.
73. Ashcraft MW, van Herle AJ. The comparative value of serum thyroglobulin measurements and iodine 131 total body scans in the follow-up study of patients with treated differentiated thyroid cancer. Am J Med 1981;71:806-14.
74. Lin JD, Huang MJ, Hsu BR, et al. Significance of postoperative serum thyroglobulin levels in patients with papillary and follicular thyroid carcinomas. J Surg Oncol 2002;80:45-51.
75. Ozata M, Suzuki S, Miyamoto T, et al. Serum thyroglobulin in the follow-up of patients with treated differentiated thyroid cancer. J Clin Endocrinol Metab 1994;79:98-105.
76. Barsano CP, Skosey C, DeGroot LJ, Refetoff S. Serum thyroglobulin in the management of patients with thyroid cancer. Arch Intern Med 1982; 142:763-7.
77. Pacini SI, Lari R, Mazzeo S, et al. Diagnostic value of a single serum thyroglobulin determination on and off thyroid suppressive therapy in the follow-up of patients with differentiated thyroid cancer. Clin Endocrinol (Oxf) 1985;23:405-11.
78. Shlumberger M, Baudin E. Serum thyroglobulin determination in the follow-up of patients with differentiated thyroid carcinoma. Eur J Endocrinol 1998;138:249-52.
79. Baudin E, Do Cao C, Cailleux AF, et al. Positive predictive value of serum thyroglobulin levels, measured during the first year of follow-up after thyroid hormone withdrawal, in thyroid cancer patients. J Clin Endocrinol Metab 2003;88:1107-11.
80. Kinder BK. Well differentiated thyroid cancer. Current Opinion in One 2003;15:71-7.
81. Fagin JA. Perspective: Lessons learned from molecular genetic studies of thyroid cancer: Insights into pathogenesis and tumor- specific therapeutic targets. Endocrinology 2002; 143:2025-8.
82. Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARgammal fusion oncogene in human thyroid carcinoma. Science 2000;289:1357- 60.
83. McDougall IR, Weigel RJ. Recombinant human thyrotropin in the management of thyroid cancer. Curr Opinion in One 2001; 13:39-43.
84. Pacini F, Molinaro E, Lippi F, et al. Prediction of disease status by recombinant human TSH-stimulated serum Tg in the postsurgical follow-up of differentiated thyroid carcinoma. J Clin Endocrinol Metab 2001;86:5686-90.
85. Mazzaferri EL, Kloos RT. Is diagnostic iodine-131 scanning with recombinant human TSH useful in the follow-up of differentiated thyroid cancer after thyroid ablation? J Clin Endocrinol Metab 2002;87:1490-8.
86. Giovanni V, Arianna LG, Antonio C, et al. The use of recombinant human TSH in the follow-up of differentiated thyroid cancer: Experience from a large patient cohort in a single center. Clin Endocrinol (Oxf) 2002;56:247-52.
87. Frilling A, Tecklenborg K, Gorges R, et al. Preoperative diagnostic value of [18F] Fluorodeoxyglucose positron emission tomography in patients with radioiodine-negative recurrent well- differentiated thyroid carcinoma. Ann Surg 2001;234:804-11.
88. Lencioni R, Cioni D, Corcetti L, et al. Percutaneous ablation of hepatocellular carcinoma. Sate of the Art Liver Transpl 2004;10(supp):91-7.
89. Monchik JM, Donatini G, Iannuccilli J, Dupuy DE. Radiofrequency ablation and percutaneous ethanol injection treatment for recurrent local and distant well-differentiated thyroid carcinoma. Ann Surg 2006;244:296-304.
90. Dupuy DE, Monchik JM. Radiofrequency ablation of recurrent thyroid cancer. In: Ellis LM, Curley SA, Tanabe, eds. Textbook Radiofrequency Ablation of Cancer. New York: Springer-Verlag, 2003, pp 213-223.
91. Dupuy DE, Monchik JM, Decrea C, et al. Radiofrequency ablation of regional recurrence from well-differentiated thyroid malignancy. Surgery 2001;130:371-7. 92. Pacini F. Role of percutaneous ethanol injection in management of nodular lesions of the thyroid gland. J Nuc Med 2003; 44:211-2.
93. Charboneau JW, Hay ID, van Heerden JA. Persistent primary hyperparathyroidism: Successful ultrasound-guided percutaneous ethanol ablations of an occult adenoma. Mayo Clin Proc 1988;63:913- 7.
SHIMAE C. FITZGIBBONS, M.D., DAVID M. BRAMS, M.D., JOHN P. WEI, M.D.
From Endocrine Surgery, Lahey Clinic, Burlington, Massachusetts
Editor’s Note: Dr. Wei wishes to dedicate this paper to Arlie Mansberger, Jr., M.D., Chairman emeritus at the Medical College of Georgia, and former President of the Southeastern Surgical Congress, who inspired him and taught him much about the thyroid gland. Dr. Wei is Senior Staff Surgeon at the Lahey Clinic Medical Center, Endocrine Surgery and Department of Surgery at Tufts University School of Medicine. Dr. Wei is a member of The Editorial Board of The American Surgeon.
Address correspondence and reprint requests to John P. Wei, M.D., Lahey Clinic, 41 Mall Road, Burlington, MA 01805. E-mail: john.p.wei@lahey.org.
Copyright Southeastern Surgical Congress May 2008
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