WELL DIFFERENTIATED THYROID CANCER

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1 Scandinavian Journal of Surgery 93: , 2004 WELL DIFFERENTIATED THYROID CANCER N. R. Caron, O. H. Clark Department of Surgery, University of California, San Francisco and UCSF Comprehensive Cancer Center at Mount Zion Hospital, San Francisco, California, U.S.A. Key words: Well differentiated thyroid cancer; papillary thyroid cancer; follicular thyroid cancer; Hurthle cell thyroid cancer INTRODUCTION Differentiated thyroid cancer (DTC) accounts for 98 % of thyroid cancer, with neoplasms arising from the follicular cells (papillary, follicular and Hurthle cell thyroid cancer) and parafollicular cells (medullary thyroid cancer). This paper will focus on the well-differentiated thyroid cancers arising from the follicular epithelial cells. By retaining the differentiated features of normal thyrocytes, these tumors usually retain their ability to produce thyroglobulin and to concentrate and organify iodine. Such features facilitate diagnosis, surveillance and treatment of this disease. There is ongoing debate over the management of DTC with respect to the extent of thyroid resection, indications for radioactive iodine treatment and the extent of thyroid hormone suppression therapy. New elements in cancer screening, diagnosis and treatment continue to evolve with the knowledge gained from ongoing research in thyroid cancer molecular genetics, clinical trials for medical treatments and retrospective studies on recurrence, survival and clinical outcomes of current treatment modalities. EPIDEMIOLOGY AND ETIOLOGY Thyroid cancer is one of the most common endocrine malignancies, second only to ovarian cancer (1). With approximately 20,000 new cases diagnosed per year in the United States, American Cancer Society statistics show that over 200,000 patients are monitored annually for recurrence or progression of their thyroid cancer (2). Although overall prognosis is good, Correspondence: Orlo H. Clark, M.D. University of California, San Francisco and UCSF Comprehensive Cancer Center at Mt. Zion Hospital 1600 Divisadero Street Hellman Bldg. Room C3-47 San Francisco, California , U.S.A. clarko@surgery.ucsf.edu approximately 5 10 % of thyroid carcinoma patients will eventually die of their disease, representing 0.16 % and 0.24 % of all cancer deaths in men and women respectively (3). The median age at diagnosis is 45 to 50 years of age, with a male to female ratio of 1:3 (3). In the pediatric population, DTC is rare, with less than 10 % of all cases found in patients under 21 years of age (4). There is marked geographic and ethnic variation in DTC incidence, with ranges in the literature between 0.5 to 10 cases per 100,000 women per year (3). Papillary thyroid cancer (PTC) has been associated with exposure to various types of radiation: 1) therapeutic radiation for head and neck disease, 2) atomic explosions or nuclear facility releases such as the Chernobyl incident of 1986 and 3) ecological exposure secondary to occupational, geological or altitudinal sources (3). The risk of PTC secondary to radiation exposure is both dose and age dependent. This association is greatest in the pediatric age group, with those exposed over the age of twenty having minimal to no increased risk of thyroid malignancy. The maximal risk of malignancy is at 20 to 30 years post exposure, but the latency period can extend from 4 to 50 years. Most radiation associated thyroid cancers are of similar aggressiveness as sporadic disease but some may be more aggressive. Inadvertent radiation involves the entire thyroid gland, placing it at risk for multicentric or metachronous malignancy. Radiation exposure accounts for less than 10 % of all thyroid cancer. Insufficient and excess dietary iodine have been shown to be associated with different subtypes of DTC although the overall incidence of thyroid cancer has not been conclusively different based on dietary iodine. Papillary thyroid cancer is relatively more common in high iodine intake regions (such as Iceland and Hawaii), while follicular (and anaplastic) thyroid cancer are relatively more common in iodine deficient regions (3). Familial non-medullary thyroid cancer is an uncommon disease, inherited as an autosomal dominant trait, found in a younger age group (mean age of years) and thought to be slightly more clinically aggressive than their sporadic counterparts.

2 262 N. R. Caron, O. H. Clark "Hot"/Hyperfunctionin g follicular adenoma TSH-R, gsp Ras, pten Follicular neoplasm / Follicular adenoma Ras, PAX-8/PPAR-γ PAX-8/PPAR-γ Follicular thyroid carcinoma p53, Rb De novo ras Normal follicular thyroid cell Hurthle cell adenoma ras Hurthle cell carcinoma p53, Rb Anaplastic cancer ret/ptc, BRAF, trk, met, ras Fig. 1. Thyroid tumorigenesis pathway and proposed genetic alterations. Papillary thyroid carcinoma P53, rb, sis Papillary thyroid cancer is the most common familial non-medullary thyroid cancer and it comprises approximately 3%of all PTC (3). Conversely, familial follicular thyroid cancer is extremely rare. Familial thyroid cancer may be associated with familial adenosis polyposis, Gardner s syndrome, Cowden s disease, Carney s syndrome or Multiple Endocrine Neoplasia Type I (3, 5). For reasons that are not clear, the overall incidence of thyroid cancer is rising (2). Despite this, the incidence of follicular thyroid cancer is decreasing in the United States. This is thought to be due to the eradication of iodine deficiency and the more accurate diagnosis of follicular variants of PTC and mixed papillary-follicular thyroid cancer as subtypes of PTC rather than follicular thyroid cancer (6). Genetic abnormalities have now been linked to the pathogenesis of DTC. A model for the oncogenic pathway that determines the progression of normal thyroid epithelial cells into malignant tumors has three proposed elements: signals which stimulate growth (presence of oncogenes), signals which inhibit proliferation (loss of tumor suppressor genes) and signals which regulate cellular immortalization and apoptosis (7). Some key genetic mutations associated with development of DTC have been identified to date (ras, ret/ptc, BRAF, PAX8/PPAR γ, trk, met) and have been incorporated into a proposed multistage progression model of thyroid oncogenesis (Fig. 1). Ras oncogenes are point mutations that result in constitutive activation and subsequent continuous unregulated growth signals. They are most consistently found in follicular adenoma and carcinomas (up to 80 %), but also identified in 12 % of Hurthle cell cancer (HCC) and variably in PTC (up to 50 % in some studies) (3, 7). Activating ras mutations have been associated with DTC in patients exposed to ionizing radiation or an iodine deficient diet (3). RAF proteins are cytoplasmic protein kinases that are regulated by binding to ras proteins and play vital roles in apoptotic and proliferative pathways (7). Mutated BRAF proteins are found in up to 70 % of PTC and are not identified in other thyroid lesions, such as follicular thyroid cancer or follicular variant of PTC. Tyrosine kinase oncogenes (ret, trk, met) are also highly specific for PTC with ret/ptc present in up to 50 % of PTC, trk in % of PTC and met in up to 80 % of PTC (3, 8). The ret/ptc oncogene is associated with pediatric PTC, radiation exposure and PTC microcarcinomas (3). The met oncogene has been shown to be protective against angioinvasiveness (3), associated with an increased prevalence of multicentric disease (3) and the only tyrosine kinase oncogene occasionally detected in follicular thyroid cancer (10 %) (8). Mutations in PAX-8/PPARγ (peroxisome proliferator-activated receptor gamma) genes are potentially the most important genetic abnormalities associated with follicular thyroid cancer to date. With potential clinical applications in diagnosis and treatment, research will continue to elucidate the molecular oncogenic pathway of DTC. PATHOLOGY According to the World Health Organization, welldifferentiated thyroid cancer can be subdivided into two main categories: papillary thyroid cancer and

3 Well differentiated thyroid cancer 263 TABLE 1 Morphologic variants of papillary thyroid cancer (PTC). Morphologic variants of PTC Clinical behavior Salient features compared to typical PTC Follicular Similar Follicles, ground glass empty nucleoli, +/ papillae Micropapillary:occult/minimal Similar < 1.5 cm, Encapsulated Similar Totally surrounded by fibrous capsule, +/ focal invasion Solid/Trabecular Similar Foci of solid/trabecular growth in >50%of tumor (may be confused with poorly differentiated thyroid CA) Tall cell More aggressive Follicular cell height 2x the width, +++ eosinophilic cytoplasm lining glandular and papillary structures, usually >5cm, patients older Diffuse Sclerosing More aggressive Dense intrathyroidal lymphocytic invasion, ++ fibrosis, squamous metaplasia, + psammoma bodies, more frequent in children Columnar More aggressive Epithelial cell height >3x width, marked nuclear stratification within papillary architecture Oxyphil (Hurthle) More aggressive Hurthle cell carcinoma (with marked eosinophilic cytoplasm) that display classic papillary architecture follicular thyroid cancer (FTC). There is a growing opinion that the Hurthle cell carcinoma subtype should be considered a separate entity due to its constellation of molecular biological, histological, epidemiological and tumor characteristics that fail to conform closely to either PTC or FTC. Papillary thyroid cancer accounts for approximately % of DTC in iodine sufficient regions. There are eight recognized morphologic variants of PTC and these are briefly described in Table 1. All are relatively uncommon compared to the typical PTC, except for the occult PTC (< cm) for which the background prevalence is unknown. Autopsy studies have identified occult PTC in 5 36 % of adults (3). This paper will focus on the typical PTC. Papillary thyroid cancer is a firm non-encapsulated nodule with an irregular border and whitish color that ranges in size depending on stage of presentation and virulence of tumor. Approximately % are multicentric, although this has been shown to be as high as 80 % depending on the extent of the gland that was evaluated, whether microscopic evaluation was performed for occult disease and the thickness of histologic sections that were assessed. Histologically, PTC is defined by the presence of papillae (fibrovascular stalks lined with neoplastic epithelial follicular cells) and distinct nuclear features such as grooved nuclei, intranuclear inclusions, hyperchromatic nuclei and absent nucleoli ( orphan Annie bodies ). All PTC variants have some or all of these distinct nuclear features that define this malignancy. Vascular invasion is uncommon, evident in only 2 14 % of cases (9). Lymph node metastases are relatively common with a range of % lymph node involvement, depending on the series and whether a prophylactic lymph node dissection was performed to detect clinically occult and microscopically positive lymph nodes (9). Lymphatic metastases are identified preoperatively in approximately one third of patients (9). Distant metastases to bone or lung are identified in less than 15 % of patients (6). Follicular thyroid cancer accounts for approximately % of thyroid malignancies. This encapsulated tumor has a microscopic follicular pattern that must demonstrate either vascular or capsular invasion in order to distinguish it from its benign counterpart, the follicular adenoma. Although the follicular architecture may vary with level of differentiation, FTC are distinct from PTC by the finding of small follicles with no papillae and by the absence of PTC s specific nuclear features (5, 6). Follicular thyroid carcinoma is classically subdivided into lowrisk and high-risk groups based on capsular, vascular or adjacent thyroid parenchyma/muscle invasion. Minimally invasive FTC may have capsular and/or vascular invasion while widely invasive FTC demonstrates broad area(s) of transcapsular invasion with thyroidal or extrathyroidal invasion (6). D Avanzo et al recently recommended classifying FTC as minimally invasive, moderately invasive or widely invasive since prognosis varied according to these pathological groupings (6). While in only about 10 % of patients FTC will have spread to the lymph nodes, 30 % will demonstrate pulmonary or skeletal metastases (6). A challenging pathologic diagnosis is the follicular variant of papillary thyroid cancer (FVPTC). The general consensus is that FVPTC tumors have at least 80 % pure follicular architecture (10, 11), with some pathologists feeling that the entire tumor should exhibit a follicular pattern (12). These mixed tumors must exhibit the nuclear features of PTC, although whether all such features must be present for the diagnosis or whether as few as two nuclear features typical of PTC are enough to consider it a FVPTC remains controversial. Many studies have demonstrated that FVPTC and mixed papillary-follicular thyroid cancer have a natural history and prognosis similar to the typical PTC. A controversial area within thyroid cancer pathology is the Hurthle cell carcinoma (HCC). HCC is composed of oncocytes with an abundant granular

4 264 N. R. Caron, O. H. Clark cytoplasm due to the large number of mitochondria. Based on criteria set by the World Health Organization, this tumor of follicular cell origin is a subtype of both papillary and follicular thyroid cancer, but it is much more commonly noted as a subtype of FTC. Despite its persistent classification within the realm of FTC, it s histological, epidemiological and tumor characteristics set it apart as a separate entity. Epidemiologic risk factors for HCC are more similar to PTC than FTC; iodine-rich regions, exposure to therapeutic low-dose radiation and familial tendencies. HCC is more likely to involve regional lymph nodes than FTC but not nearly as often as PTC. Where both FTC and PTC usually concentrate radioactive iodine (75 %), only 7%of HCC are found to do so (6). All three types of differentiated thyroid cancer tend to produce thyroglobulin. Many now propose that HCC should be a separate category under the umbrella of differentiated thyroid cancer (6, 13). PROGNOSIS There have been many classification systems proposed for well-differentiated thyroid cancer, with the attempt to estimate prognosis and predict tumor behavior. Options in treatment elements such as extent of thyroid resection, use of RAI and duration and degree of thyroid stimulating hormone (TSH) suppression are assessed with respect to one s underlying prognosis. With careful consideration, each individual patient s risk:benefit ratio is determined for each treatment option. Numerous patient, disease and treatment factors are considered independent prognostic factors that help classify risk in patients with DTC. Important patient factors include gender (male prognosis slightly worse than females with same stage disease), age (improved prognosis if older than 16 and under 45 years of age) and family history (with familial disease considered more aggressive). The disease factors that impact prognosis are similar to other malignancies and include tumor size, evidence of invasion (intra-thyroidal, vascular, extra-thyroidal), aggressive histopathology features and evidence of lymphatic or distant metastases. The treatment factors that impact patient prognosis is completeness of surgical resection and efficacy of RAI treatment. Different scoring systems have used variations of these prognostic risk factors to help predict those with more aggressive disease. AGES (age, histological grade of tumor, extra-thyroidal invasion and distant metastases and tumor size), AMES (age, distant metastases, extra-thyroidal invasion and tumor size) and MACIS (metastases, age, completeness of resection, extra-thyroidal invasion, tumor size) are prognostic classification systems unique to thyroid cancer (1). The TNM (tumor size, nodal status and distant metastases) staging system for DTC incorporates many of the elements of the thyroid specific classifications, including age as those under 45 years are restricted to stage I or II, while those over age 45 have the more classic stage I to IV criteria. Kebebew and Clark found that most retrospective studies in patients classified as low risk by various classification systems reported 10 to 20 year mortality rates of 2%to 5%, while those deemed high risk had mortality rates of 40 % to 50 % (1). Similarly, recurrence rates for low risk patients (10 %) and high risk patients (45 %) differ significantly (1) and the mortality from these recurrences is approximately 33 % to 50 % (1). Two subtypes of DTC that have a particularly excellent prognosis are the occult PTC and the minimally invasive FTC. Fortunately, most differentiated thyroid cancer patients fall into the low risk category and have an excellent overall prognosis. DIAGNOSIS Patients with DTC can present with a thyroid nodule, cervical lymphadenopathy, distant metastases or combinations of these possibilities. Most commonly, initial presentation is a palpable thyroid nodule. Cervical lymph node metastases are palpable in approximately one third of patients with PTC (with microscopic disease estimated in over 50 % of cases) (9) while cervical lymphadenopathy is much less common in FTC (10 %) (1). On the contrary, lung and bone are the most common sites for distant metastases and are more common in FTC (30 %) than in PTC (2 15 %) (6, 9). Patient history, physical examination, serum thyroglobulin levels, RAI scintigraphy and adjuvant radiological investigations facilitate diagnosis. In patients with a thyroid nodule, a history of local or regional symptoms of invasion (voice change, hemoptysis, stridor, dyspnea, dysphagia), rapid nodule growth, history of head or neck irradiation, and personal or family history of previous thyroid cancer or other endocrine malignancy increases the likelihood of thyroid cancer. Physical examination can reveal a firm, potentially fixed, irregular thyroid nodule, palpable cervical lymphadenopathy, or hoarse voice. TSH and serum thyroglobulin (Tg) are useful laboratory investigations but are not diagnostic. Normal or elevated TSH levels can rule out a hyperfunctioning nodule, of which only approximately 1%are associated with malignancy. Tg is a glycoprotein produced only by thyrocytes (normal and differentiated malignant cells). While an elevated serum Tg level may be indicative of metastatic disease if it is unusually high, many benign conditions give rise to modestly elevated levels. The diagnostic test of choice once a thyroid nodule is identified is a fine needle aspiration biopsy (FNAB). There are four possible pathology results from a FNAB: benign, malignant (papillary, medullary, anaplastic thyroid cancer), indeterminant (follicular neoplasm) or an insufficient/non-diagnostic specimen. The diagnostic accuracy of FNAB is greater than 95 % (9) with a false negative rate of 2 6%. FNAB can definitively diagnose PTC, due to the nuclear changes that are well visualized on cytological evaluation. FNAB cannot distinguish between FTC and follicular adenoma. With the absence of distinct cytological features, diagnosis of FTC requires histological evidence of capsular or vascular inva-

5 Well differentiated thyroid cancer 265 sion. If FNAB indicates a follicular neoplasm, the standard recommendation is thyroid lobectomy and/ or isthmusectomy, to permit full histological evaluation, with approximately 20 % ultimately diagnosed as follicular carcinoma. FNAB usually does not require ultrasound guidance to facilitate accurate biopsy but in small or deep-seated nodules it can be helpful. An indeterminant cytology should warrant a repeat FNAB. Clinically palpable or radiologically suspicious lymph nodes may also be evaluated with FNAB and histological staining for thyroglobulin facilitates difficult diagnoses. One must recall that a benign pathology on FNAB should supplement clinical assessment not replace it. Regardless of the FNAB results, rapidly growing nodules, recurrent thyroid cysts and patients at increased risk of thyroid cancer due to a history of head or neck irradiation and/or a significant family history of DTC should have a lobectomy and/or isthmusectomy to definitely rule out malignancy. Preoperative staging of DTC usually consists of the above diagnostic elements of clinical evaluation, FNAB and serum Tg with a chest radiograph to assess for gross pulmonary metastases. Cervical ultrasound (US) is recommended as it may detect lymphadenopathy not clinically evident. It may also identify nodules in the contralateral thyroid lobe. US is well suited for the thyroid gland as its superficial location permits the use of high frequency transducers that emit a high resolution image. The high echogenicity of the gland enhances the US evaluation of the thyroid, which results in a sensitive, cost effective imaging investigation. Other imaging such as magnetic resonance imaging (MRI) or computed tomography (CT) should be used selectively for fixed tumors or substernal goiters. Full staging is completed postoperatively with a RAI whole body scan and histological evaluation of the surgical specimen. TREATMENT The most important treatment for thyroid cancer is complete surgical excision of the tumor. Beyond this, there are many controversies in the management of DTC. The extent of excision (total or near-total thyroidectomy versus lobectomy/isthmusectomy), the use of RAI ablation, and the use of thyroid hormone supplementation to suppress TSH are all debated to some degree, particularly for the low risk patient who appears to have an excellent prognosis regardless of whether a total thyroidectomy is performed or adjuvant treatments are utilized. Most clinicians today use adjuvant RAI ablation and TSH suppression for most patients with DTC. SURGERY Advocates of total or near total thyroidectomy state that this approach permits complete ablation of all remaining thyroid tissue (including potential occult DTC) with RAI so that diagnostic scans can detect regional and distant metastases and radioiodine can be utilized for treatment if necessary. Total or neartotal thyroidectomy with RAI ablation increases the sensitivity of serum Tg as a tumor marker in the long-term follow-up for disease recurrence. Total thyroidectomy removes all sub-clinical multicentric disease in the contralateral lobe (which has been documented in up to 85 % of PTC) and thereby prevents recurrent disease in the contralateral lobe (1). With less extensive resection the recurrence rate in the contralateral lobe is approximately 7%, and 50 % of patients with recurrent DTC will eventually die from this disease(1). Many large retrospective studies with long term follow-up demonstrate decreased recurrence and improved survival in patients who have total thyroidectomy (and RAI ablation) compared to those patients who have less extensive procedures(1). Although this benefit is more significant in those patients in the high-risk group, one must recall that since many elements of these prognostic classification systems are only available postoperatively (age and gender are the only elements one can confirm preoperatively), they are limited in their ability to direct initial surgical treatment. In addition, although rare, even low-risk patients can suffer a recurrence (5 %) and subsequent mortality (50 %) from their well-differentiated thyroid cancer. Advocates of less extensive procedures feel that most patients with thyroid cancer are considered in the low-risk group and have excellent prognosis without extensive surgical resection. Total thyroidectomy places the contralateral parathyroid glands and recurrent laryngeal nerve at risk, where lobectomy and isthmusectomy avoids this increase in the operative complication rate. While the multicentricity of PTC may contribute to an increased local recurrence rate in the contralateral lobe, many studies do not show a significant difference in overall survival and the clinical significance of multicentric disease has been questioned. Indeed, most studies conclude no survival benefit of total or near total thyroidectomy over lobectomy/isthmusectomy in lowrisk patients with occult PTC (< 1.0 cm) or microinvasive FTC. At the University of California, San Francisco (UCSF), we recommend total thyroidectomy for all high-risk and most low-risk patients, as predictions for recurrence or mortality from DTC are not guaranteed. In particular, patients with low risk tumors but the presence of risk factors such as previous head/neck irradiation or family history of thyroid cancer are treated with total thyroidectomy because any remaining tissue is at ongoing risk for malignant transformation. Suggested indications for lobectomy and isthmusectomy (in lieu of more extensive thyroid resections) in the low-risk patient are listed in Table 2. In consideration of the morbidity associated with permanent hypoparathyroidism or recurrent laryngeal nerve injury, total thyroidectomy should be performed by surgeons with experience in this field. The overall surgical complication rate should be less than 2%. Synchronous cervical lymph node metastases may be detected by clinical examination, staging cervical ultrasound or intra-operative identification. If detected preoperatively, formal compartment-based

6 266 N. R. Caron, O. H. Clark therapeutic lymph node dissections (LND) should be performed at the time of the thyroidectomy. Unexpected lymphadenopathy found intraoperatively may be assessed for metastatic disease by frozen section analysis. Positive histology of Delphian, central or lateral cervical lymph nodes should be followed by a central and ipsilateral cervical lymph node dissection. Only if a grossly positive contralateral lymph node is confirmed by biopsy, is a contralateral LND indicated (1). This approach is referred to as a therapeutic lymph node dissection and should be a formal, compartment-based lymphadenectomy as opposed to a berry picking procedure. The modified radical (or functional) LND that is recommended involves excision of fibro-fatty tissue and associated lymph nodes while preserving the sternocleidomastoid muscle, internal jugular vein, and the spinal accessory, vagus and cervical sensory nerves(1). Some centers still consider prophylactic LND (when there is no evidence of lymph node metastases) as part of the surgical treatment of patients with PTC, since the incidence of occult lymph node metastases is so high. This has not been shown to improve patient prognosis and it is associated with a small but increased risk of complications; it therefore is not generally recommended (1). The only scenario in which a prophylactic central LND is recommended is when HCC has been confirmed, because most of these tumors do not concentrate RAI (> 90 %), they have a higher recurrence rate and a significant rate of lymph node metastases (40 %) (1). Indications for LND and type of resection is an ongoing debate, with most studies confirming that therapeutic lymph node dissection at the time of the initial surgery reduces locoregional recurrence but does not usually improve overall survival. The clinical significance of occult cervical metastases is still questioned. RADIOACTIVE IODINE TABLE 2 Potential indications for lobectomy/isthmusectomy in low-risk thyroid cancer patients. Papillary thyroid cancer < 1 cm ( occult PTC ) Minimally invasive (capsular only) follicular thyroid cancer Informed patient choice for lobectomy/isthmusectomy Compliance concerns with post-operative thyroid supplementation medications RLN injury on side ipsilateral to malignant nodule * RLN: recurrent laryngeal nerve A controversial element of DTC treatment is radioactive iodine (RAI) ablation. After a partial or subtotal thyroidectomy, RAI can be used for thyroid remnant ablation. After a total (or near total) thyroidectomy or thyroid remnant RAI ablation, RAI can be used for diagnosis and treatment of recurrent or metastatic DTC. Thyrocytes trap and organify iodine and well-differentiated thyroid cancer cells retain this ability. As normal thyroid cells can trap approximately 100-fold more RAI than DTC cells, the amount of remnant normal thyroid cells remaining post operatively directly impacts the amount of administered RAI available to be trapped by the DTC(1). Post-operative RAI ablation of the thyroid remnant can improve the diagnostic and therapeutic utility of RAI because it will then only be taken up by metastatic or recurrent disease. In addition, with no normal thyroid cells remaining, a subsequent rise in serum Tg level will be a highly sensitive and specific marker of disease recurrence. RAI ablation has been shown by many to reduce recurrences(14) and some believe it may even improve survival in selected patients (1, 15). RAI is a powerful treatment modality specific for thyroid disease. While gross disease is best treated surgically, RAI is the treatment of choice in patients who are suspected of having persistent and/or occult disease. Post-operative RAI treatment is administered to patients with a persistently elevated Tg level post-operatively or a positive initial RAI scan indicating metastatic disease. With no gross disease identified for surgical resection, the diffuse and/or microscopic foci of disease responsible for these elevations in serum Tg can be treated primarily with RAI before they grow to become radiologically evident. This is especially evident with miliary pulmonary metastases. RAI is a vital adjuvant treatment modality used not only to ablate the thyroid remnant, but also to treat patients deemed to be at high risk of recurrence after pathologic review (local invasion, positive margins or aggressive histological subtype). In order to be amenable to treatment with RAI, malignant cells must demonstrate avidity for RAI. Approximately 25 % of patients with recurrent nonresectable PTC will not be able to concentrate RAI(16). Diagnostic RAI scintigraphy utilizes a small dose of RAI that determines the extent and location of metastases or remnant normal thyroid tissue, helps plan subsequent treatment dose, and confirms that the malignant cells concentrate RAI. In some circumstances, patients with persistent or recurrent disease demonstrated by elevated serum thyroglobulin concentrations may have a negative diagnostic RAI scan but convert to a positive scan when treated with the higher therapeutic doses of RAI. The opposite phenomenon may occur during thyroid remnant ablation when an initially positive diagnostic scan loses its uptake intensity. Some centers initially perform a low dose (2 mci) RAI scan to estimate the volume of thyroid remnant and to assess for potential synchronous metastatic disease. While this may help to plan the follow-up ablative dose, there is the risk that the initial RAI dose will stun the thyrocytes (either benign or malignant) and lead to a suboptimal uptake of the therapeutic dose. If small doses of RAI are utilized, this stunning effect is minimized (16). To facilitate uptake of RAI by normal and malignant thyroid cells, high concentrations of TSH are necessary. Until recently, this required withdrawal of thyroid hormone supplementation to achieve a hypothyroid state and subsequent serum TSH level greater than 30 mu/l. Based on hormone half-life,

7 Well differentiated thyroid cancer 267 this target TSH level is achieved when thyroxine is discontinued for 4 to 6 weeks and tri-iodothyronine is discontinued for 2 weeks prior to the RAI administration(2). This preparation is associated with symptomatic hypothyroidism. An alternative method of preparation is the administration of recombinant human (rh) TSH prior to RAI scintigraphy and treatment. This has been shown to be a safe, effective method of stimulating RAI uptake for diagnosis but has not yet been approved for therapeutic RAI indications (2). The choice of rhtsh is of particular interest for patients who cannot withstand the hypothyroid state due to concurrent illness (such as those with brain metastases) or advanced age. The initial RAI scan is performed 4 to 12 weeks postoperatively in order to allow the patient to recover from the neck operation and to permit a hypothyroid state to stimulate TSH levels, if necessary. Additional preparation includes avoidance of iodine containing contrast media during radiological investigations and adherence to a low iodine diet for the preceding two weeks in order to deplete endogenous iodine stores. Although various protocols exist, most patients receive an initial scanning dose (about 2 mci) with the follow-up ablative dose (30 to 100 mci) determined by the percent uptake and approximation of thyroid remnant size. The surgeon should aim for <1%uptake after a total thyroidectomy. If the patient is at high risk of persistent disease, the dose is increased accordingly (150 to 300 mci) and is based on tumor type, disease stage and the extent of residual disease anticipated (2). Repeat treatments may be required to obtain a negative RAI whole body scan (no evidence of remnant thyroid tissue or persistent DTC). After a RAI whole body scan is negative, RAI scintigraphy becomes part of the armamentarium of investigations available to follow a patient for potential recurrence of DTC. This is particularly useful in the event of a rising serum thyroglobulin. RAI is associated with potential side effects and complications. If thyroid hormone withdrawal is utilized, the requirement for TSH >30 mu/l will produce profound symptoms of hypothyroidism in many patients and may exacerbate medical or psychiatric conditions(2). Both endogenous TSH elevation and rhtsh can theoretically stimulate any remaining focus of DTC and rhabdomyolysis and renal failure have been reported. Other adverse reactions and potential complications are rare. These include radiation sialadenitis, xerostomia, hypogeusia, nasolacrimal duct obstruction, transient leucopenia and oligospermia (2). At higher cumulative doses, there have been reports of secondary malignancies including leukemia, small intestine, bladder and possibly breast cancer (2). It is estimated that 0.3 % of patients who receive a cumulative dose of RAI over 500 mci develop these secondary malignancies (2). In patients who develop extensive iodine avid pulmonary metastases, the risk for radiation pneumonitis and fibrosis increases once a total of 80 rads or greater is delivered (2). Women treated with RAI should refrain from breast-feeding as the RAI can be excreted in her milk and concentrated in the lactiferous ducts. These potential complications must be considered on an individual basis when deciding upon a treatment plan. THYROID HORMONE SUPPRESSION OF TSH Thyroid stimulating hormone (TSH) is a growth factor for normal and malignant thyrocytes that has been shown to stimulate tumor growth, invasion and angiogenesis (1) (15, 17). Evidence suggests that by suppressing the endogenous level of this thyroid growth factor by supraphysiologic levels of thyroid hormone, there will be decreased growth of any remaining malignant thyroid tissue (1). Retrospective studies have found that those patients with a history of DTC on TSH suppression therapy have a lower rate of tumor progression, recurrence and possibly an increased overall survival (1, 2, 17). There are, however, no prospective studies confirming the benefit of long-term thyroid hormone suppression therapy. The most effective therapeutic TSH level and duration of suppression are debated. Suppression of TSH requires iatrogenic mild hyperthyroidism, so this must be balanced with each patient s risk of hyperthyroid symptoms, accelerated bone loss, atrial fibrillation, increased left ventricular thickness, and potential precipitation of angina (2, 17). Thyroid hormone suppression to TSH < 0.1 mu/l is the standard therapeutic goal for patients with low and moderate risk thyroid cancers, but should be adjusted if the patient is at increased risk of cardiac or skeletal complications. For high-risk thyroid cancer patients the TSH level should be less than 0.05 mu/l. For patients with low-risk DTC and in remission for several years, the target TSH could be adjusted to a low, but detectable range ( mu/l) (2). At this level of minimal suppression the serum thyroid hormone levels (triiodothyronine and thyroxine) are normal. EXTERNAL BEAM RADIATION External beam radiation is not commonly used in the treatment of DTC and no prospective randomized controlled trials have evaluated its role in this disease. There are limited indications for this treatment modality but it should be considered for patients who have DTC tumors that do not concentrate RAI and who have either residual cervical disease postoperatively or non-resectable tumors (18). Without adequate prospective studies to confirm, it has been suggested that doses of 50 Gy or higher are required to impact local control and there is no consensus on overall time or fractionation (18). The clinical target volume for locoregional disease is limited by the spinal cord. Potential complications include both acute and late reactions. Acute reactions include mucositis, dysphagia, dermatologic reactions and edema. Late reactions include skin fibrosis and tracheal compression. In addition, reoperation becomes much more difficult in patients who have received external beam radiation. Further studies will help to standardize treatment protocols, indications and accurately determine side effect profiles.

8 268 N. R. Caron, O. H. Clark NOVEL AND FUTURE TREATMENTS RAI is a cornerstone of treatment for differentiated thyroid cancer. Although beyond the scope of this review paper, there is ongoing research in the fields of molecular and cellular physiology to develop the ability of non-iodophyllic and de-differentiated thyroid cancer cells to take up RAI. Tumors with a decreased ability to accumulate RAI are associated with a worse prognosis. Approximately 25 % of DTC tumors initially have minimal or no RAI uptake and this increases to 50 % in patients who develop recurrent disease (19). Once a tumor de-differentiates, it loses the thyrocyte-specific ability to uptake iodine, which is made possible by the sodium-iodide symporter (NIS) on the cell s basolateral membrane (19). Some novel therapy options may increase NIS gene expression and subsequent RAI effectiveness (19). Examples include histone deacetylase inhibitors (such as Trichostatin A) (19) and retinoids that bind the retinoic X receptor on the malignant thyrocytes to enhance the expression of the NIS gene (2). Other re-differentiating agents potentially include aromatic fatty acids, peroxisome proliferator-activated receptor gamma agonists (PPAR-gamma agonists), resveratrol and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (20). Current research focusing on therapy that will lead to re-differentiation of thyroid cancer cells and potentially improve the dismal prognosis of this patient population is important. Aggressive tumor behavior, inability to monitor for early tumor recurrence with Tg, and inability to treat with RAI all contribute to the poorer prognosis of patients with de-differentiated tumors. SURVEILLANCE FOR DISEASE RECURRENCE Once a patient with DTC is successfully treated with thyroidectomy, RAI ablation and thyroid hormone suppression, they must continue to be monitored for evidence of disease recurrence. Regular clinical follow-up may elicit signs and symptoms of local, regional or distant disease and patients with a history of DTC should be assessed every 3 to 6 months for 1 to 2 years and then annually if disease free. Monitoring for sub-clinical disease may utilize combinations of serum Tg levels, RAI scintigraphy and other radiological investigations. This diligent surveillance should be life-long, as recurrent DTC has been documented up to 50 years after initial treatment and early detection of recurrence is associated with a longer survival. SERUM THYROGLOBULIN Serum Tg levels can usually accurately determine whether a patient is tumor free after total or near total thyroidectomy and RAI ablation. Elevations of serum Tg in this scenario suggest disease recurrence, as this glycoprotein is thyroid specific. While Tg levels can be assessed on suppressive doses of levothyroxine, the TSH-stimulated Tg levels are most sensitive (2). TSH stimulated serum Tg levels can be obtained by withdrawing hormone supplementation or by administering rhtsh. Thyroid hormone withdrawal to achieve the target stimulated TSH level (> 30 mci/l) provides a greater elevation in Tg than rhtsh, but the overall sensitivity for detecting residual or recurrent disease is similar (21). TSH stimulated serum Tg levels are utilized for postoperative disease surveillance and the best time for determination is when the patient is in a hypothyroid state in preparation for scanning or treatment with RAI. A recent consensus conference concluded that serum Tg levels measured during thyroid hormone suppression although helpful were not sensitive enough to detect all patients with residual disease (21). It suggested that in long-term follow-up, an undetectable stimulated serum Tg level (< 1 microgram/l) is evidence of complete tumor ablation and only after this level of cure is confirmed should annual serum Tg tests be obtained during thyroid hormone suppression. The thresholds at which elevations in serum Tg indicate persistent or recurrent disease differ to some degree between institutions. At UCSF, TSH-stimulated serum Tg levels >5ng/ml or non-stimulated serum Tg level >2ng/ml (in patients on hormone suppression) raise suspicion of disease recurrence and is assessed with further investigations. The National Comprehensive Cancer Network (NCCN) suggests using >10 ng/ml and >5ng/ml, respectively. A recent consensus report recommended a more stringent threshold of 2 ng/ml for stimulated Tg and <1ng/ ml for those on hormone supplementation (21). The quantitative level of Tg reflects not only probability of recurrence, but can be indicative of the extent of disease and its most likely location (distant metastases or locoregional recurrence) (2). The primary limitation of this screening test is the presence of thyroglobulin antibodies (Ab), which make the various serum Tg assays unreliable. While 4 10 % of unselected women and 1 3 % of unselected men have these antibodies, up to 25 % of patients with DTC will have detectable levels (2, 21). Therefore, serum Tg levels must be assessed simultaneously with the serum Tg Ab titer in order to determine if Tg levels will be an accurate and appropriate screening test for each patient with previous DTC. Of interest, serum Tg Ab titers frequently decrease after curative treatment in patients with DTC. RADIOACTIVE IODINE SCINTIGRAPHY: WHOLE BODY SCAN Diagnostic RAI scans are an important component of patient monitoring for recurrent DTC. Disease surveillance begins once complete remission is achieved, which is defined by a negative RAI scan, a serum Tg below the set threshold and no clinical or ultrasound evidence of persistent disease. The role of the RAI scanning in disease surveillance has evolved as the sensitivity of serum Tg has increased. In the past, RAI scintigraphy was a central component of ongoing DTC surveillance. It was performed in conjunction with serum Tg with the anticipation that this com-

9 Well differentiated thyroid cancer 269 bined regimen would increase the ability to detect recurrent disease. With the functional sensitivity of serum Tg assays now at least 1 ng/ml, many investigations have shown that a stimulated serum Tg level in isolation is sufficient to follow low-risk patients who have no clinical evidence of disease and a suppressed serum Tg level while on thyroid hormone suppression therapy (21). It has therefore been suggested that once complete remission is confirmed, RAI surveillance should be left for those low-risk subjects with elevated serum Tg levels (21). For higher risk patients, regular RAI scans may detect additional patients with recurrent disease and could be considered in selected cases (2). As discussed, potential disadvantages of RAI scanning include: 1) the necessity of a biochemical hypothyroid state and the potential associated symptoms, 2) the potential for rapid tumor growth secondary to the elevated TSH level required, and 3) the proposed stunning effect of the low diagnostic dose of RAI that limits the efficacy of higher therapeutic doses, should the diagnostic scan be positive (2). As discussed previously, the biochemical hypothyroid state can be achieved by thyroid hormone withdrawal (with TSH >30 mu/l) or by administration of rhtsh. Although costly, rhtsh provides exogenous stimulation of potential thyroid cancer cells without subjecting the patient to the effects of hypothyroidism. Studies have demonstrated similar sensitivity of RAI scans with thyroid hormone withdrawal and rhtsh. OTHER RADIOLOGICAL IMAGING Cervical ultrasound (US) is considered one of the most sensitive means of detecting neck recurrences. It is an excellent study to employ for low-risk patients; especially those who demonstrate an elevated serum Tg and negative RAI whole body scan. It is a regular surveillance tool for higher-risk patients where it is an adjunct to the traditional serum Tg and RAI scans. Ultrasonography is more important for patients with previous PTC or HCC than for patients with FTC, as lymph node metastases are uncommon in the latter. Sonographic features concerning for metastatic disease include round or bulging lymph nodes which have lost their hilar echoes, punctate calcifications and demonstration of a hyperechoic signal. As with initial diagnosis, cervical US is the most commonly utilized radiological investigation for local or regional disease recurrence. It can locate lesions suspicious for lymph node or soft tissue recurrence and facilitate FNAB to confirm recurrent disease. Well-differentiated thyroid cancer cells retain capacities of their native cell type which includes trapping and organification of iodine and production of thyroglobulin. Such characteristics are capitalized on with specific screening tests of RAI scans and serum thyroglobulin, respectively. Radiological imaging can further define disease detected by elevated serum thyroglobulin or positive RAI scintigraphy by identifying the lesion anatomically, by guiding percutaneous FNAB of the suspicious lesion and by providing important preoperative anatomic information. Local and regional recurrence is well delineated by cervical ultrasound, but may also be demonstrated with computed tomography (CT) or magnetic resonance imaging (MRI) of the region. Mediastinal metastases are best depicted with MRI while CT is excellent for pulmonary metastases. In anticipation for potential treatment with RAI, all imaging must be performed without iodinated contrast. For patients with DTC whose serum Tg levels are low, MRI or CT is not required for routine surveillance and should be utilized on a case-by-case basis. POSITRON EMISSION TOMOGRAPHY While an elevated serum thyroglobulin in an ablated patient is highly suggestive of disease recurrence, defining the extent and location of the disease is necessary in order to plan appropriate treatment. While this is traditionally achieved by the RAI whole body scan, non-iodophyllic disease foci can usually be identified with additional routine radiological imaging. As discussed, these imaging options include ultrasound, CT or MRI. To facilitate identification of occult disease, Positron Emission Tomography (PET) using 18F-fluorodeoxyglucose (FDG) has been shown to identify recurrent disease in 60 % to 94 % of patients with negative RAI scans (22). The sensitivity of PET to identify recurrent DTC has been shown to correlate with two thyroid specific factors: ability to concentrate RAI and TSH level (23). Most RAI negative recurrences demonstrate 18F-FDG-PET uptake in correspondence to its poor differentiation, rapid tumor growth and subsequent increase in metabolic activity and glucose uptake (23). On the contrary, most RAI positive scans (two thirds of DTC recurrences) have negative 18F-FDG-PET scans (23). The sensitivity of PET scans is increased in patients with elevated TSH from thyroid hormone withdrawal and in patients administered rhtsh prior to investigation. This relationship may be explained by the stimulation of benign and malignant thyrocyte metabolism, glucose transport and glycolysis by thyroid stimulating hormone (24). Overall, PET scans facilitate the identification of occult disease recurrence that is marked by an elevated serum thyroglobulin level but not definitely identified by the more standard imaging tests of RAI scan, ultrasound, CT or MRI. TREATMENT OF DISEASE RECURRENCE Disease recurrence can be divided into cervical (locoregional) recurrence or distant metastatic disease. Recurrence generally refers to disease that is detected after a patient with a history of DTC had previously been documented to have a negative clinical examination, an undetectable serum Tg level and a negative RAI scan for at least six months after treatment; disease detected within six months of initial treatment is considered persistent thyroid cancer. Subsequent development of signs or symptoms, rise in serum Tg or positive RAI uptake mandates fur-

10 270 N. R. Caron, O. H. Clark ther investigation to confirm the presence, the extent and the anatomic location of the recurrence. Recurrent rates for DTC range between 10 to 20 %. Although 33 to 50 % of patients who have recurrent disease will ultimately die from their disease, treatment can cure patients and prolong survival in those less fortunate (1). Treatment of recurrence depends on the location and extent of the disease, the possibility of resection and whether avidity for RAI is maintained. If there is any doubt in confirmation of malignancy, any patient with a suspicious lesion should undergo FNAB. Locoregional recurrence defined by clinical examination and/or radiological imaging is best treated by surgical resection with subsequent consideration for adjuvant RAI. RAI treatment is not optimal for macroscopic disease, especially lymph node metastases as these can only infrequently be ablated with RAI. If the disease recurs in the jugular lymph nodes and a formal lateral cervical lymph node dissection has not already been performed, a modified radical lymph node dissection is the recommended procedure. If the recurrence occurs on the background of a previous formal neck dissection, a focused approach to resect the specific lesion in question is the safest, most effective surgical treatment. This applies to the central (level VI) cervical lymph node compartment as well. Post-operative administration of RAI helps to treat any microscopic or gross unresectable residual disease. If surgery is not thought to be safe or feasible, a more experienced thyroid surgeon should be consulted. RAI treatment in isolation could then be considered. Alternatively, external beam radiation or chemotherapy can be considered for patients with non-iodophyllic unresectable disease. The increased difficulty of repeat surgery must not be underestimated. Central lymph node or thyroid bed recurrence will be found within the scar tissue of the total thyroidectomy, and places the ipsilateral recurrent laryngeal nerve and parathyroid glands at risk. There is an increased risk of hypoparathyroidism and recurrent laryngeal nerve injury in repeat surgery, even in the most experienced hands. Preoperative direct or indirect laryngoscopy must be performed to assess the function of the recurrent laryngeal nerves. The operating surgeon should know of documented nerve palsy as it can potentially alter the treatment plan and the patient must know that bilateral recurrent laryngeal nerve injury could lead to the need for a permanent tracheostomy. Similarly, in repeat lateral cervical lymph node dissections, vital structures such as nerves (vagus, phrenic, spinal accessory, cervical sensory, hypoglossal, brachial plexus) and the thoracic duct must be identified and preserved and this is more difficult at reoperation. With the challenging repeat surgery and the need for a multidisciplinary team to identify and optimize treatment of recurrent disease, patients with recurrent DTC should be treated by experienced surgeons in this field. Distant metastases are most commonly detected in the lung. With strict adherence to a surveillance protocol, recurrence is usually detected by serum Tg and RAI scanning before it is evident on chest radiograph or pulmonary CT. This miliary type of pulmonary metastases is best treated with RAI, which achieves remission in approximately 75 % of patients (1). Gross pulmonary metastases detected by chest x-ray, on the other hand are associated with a poor prognosis and are unlikely (4 8 %) to be definitively treated with RAI (1). Treatment of recurrent DTC that is Tg-positive but RAI-negative is a challenging issue. Further imaging (US, CT, MRI, PET) can sometimes identify a cervical recurrence that is resectable, while miliary pulmonary metastases can remain elusive. Some centers advocate empiric treatment of occult recurrence by administering a therapeutic dose of RAI (100 to 150 mci), which is more sensitive in detecting the site of tumor recurrence than the standard scanning doses (2 to 5 mci). This increased dose of I 131 may subsequently disclose the location of the recurrent disease on post treatment scanning as it converts the negative scan to positive and/or this increased dose may achieve the therapeutic result of a decreased or normalization of serum Tg level in about one third of patients (1). If serum Tg levels remain elevated, additional RAI may be administered or surgical resection of subsequently localized disease can be considered. Small malignant foci of disease are more amenable to RAI treatment than larger ones, supporting the role of RAI for occult recurrences. If a RAI scan with a therapeutic dose is negative, no further RAI is indicated. As with treatment of the primary disease, other treatment modalities are available for those who cannot be cured with surgery or I 131 administration. Indications for external beam radiation are similar and chemotherapy remains an uncommon treatment modality. With de-differentiated tumors, the novel and experimental re-differentiating agents should be considered but more clinical data is required. CONCLUSION While differentiated thyroid cancer is renowned for its good prognosis, there are patients who suffer from persistent and recurrent disease both locoregional and distant. Despite a standard repertoire of surgery, nuclear medicine and medical treatment for DTC, there are many controversies on the indications and protocols that accompany these treatment options. 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