Management of Differentiated Thyroid Carcinoma American Thyroid Association Guidelines and Data from Kaohsiung Chang Gung Memorial Hospital

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1 Review Management of Differentiated Thyroid Carcinoma American Thyroid Association Guidelines and Data from Kaohsiung Chang Gung Memorial Hospital Pei-Wen Wang Abstract Background. Most thyroid cancers are differentiated thyroid cancers, which include papillary and follicular carcinomas. Differentiated thyroid cancer, arising from thyroid follicular epithelial cells, is a common malignancy encountered in endocrinology clinics and has increasing incidence in recent years. An overview of the management of differentiated thyroid cancer is provided in this review. Findings. Adequate surgery is the most important initial management of differentiated thyroid cancers. Radioactive iodine treatment, suppression of thyroid-stimulating hormone, and external beam irradiation play the adjunctive roles. Long-term management should provide accurate surveillance for possible recurrence in patients with differentiated thyroid carcinomas. Neck ultrasounds to evaluate the thyroid bed and central and lateral cervical nodal compartments should be performed periodically, depending on the patient's risk for recurrent disease and serum thyroglobulin status. For metastatic or recurrent tumors, several treatment modalities such as watch-and-wait, local therapy, and experimental trials can be considered. Conclusion. The management of well-differentiated thyroid cancer requires a multidisciplinary approach. The majority of patients with differentiated thyroid cancers are alleviated with standard treatments. A small proportion of patients with metastatic or recurrent disease have few treatment options. [Formos J Endocrinol Metab 5: 1-13, 2014] Key words: disease management, practice guideline, thyroid gland, thyroid neoplasms Introduction Differentiated thyroid cancer (DTC) is defined as a carcinoma retaining basic biological characteristics of healthy thyroid tissue. Most thyroid cancers are differentiated thyroid cancers, including papillary and follicular carcinomas. Its incidence rate is noticeably increasing worldwide. The 10-year overall survival rate of DTC is around 85-93%. However, the lifetime recurrence rate of DTC is relatively high, reaching 10-30%. The 10-year overall survival rate in cases of DCT with distant metastasis is about 25-48%. The goals of DTC management are minimizing disease recurrence/metastases, providing accurate long-term surveillance, and performing palliative treatment to prevent complications in Department of Internal Medicine and Nuclear Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan Correspondence to: Dr. Pei-Wen Wang, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Ta-Pei Rd., Niao-Sung District, Kaohsiung City 833, Taiwan Tel: ext Fax: wangpw@adm.cgmh.org.tw 1

2 Pei-Wen Wang targeted organ in patients with incurable disease. An overview of the management of differentiated thyroid cancer is provided in this review. The following text is mainly based on the 2009 American Thyroid Association (ATA) management guidelines and the publications from Kaohsiung Chang Gung Memorial Hospital. Initial management The goals of initial therapy for DTC are listed in Table 1. Adequate surgery is the most important initial management of DTC. Radioactive iodine (RAI) treatment, thyroid-stimulating hormone (TSH) suppression, and external beam irradiation play the adjunctive roles 1. The results of RAI treatment are superior for microscopic or small macroscopic tumors than for larger lesions. An example of a DTC patient who received adequate surgery and subsequent successful RAI ablation is shown in Fig. 1A. Completeness of surgical resection is an important determinant of outcome, while residual metastatic lymph nodes (LNs) represent the most common site of disease persistence and recurrence. A DTC case with LNs and soft tissue involvement is shown in Fig. 1B. This patient's tumor could not be completely removed by surgery and the subsequent RAI ablation was unsuccessful. Preoperative neck ultrasound (US) for the contralateral lobe and cervical LNs (central and especially lateral neck compartments) is recommended before the near-total or total thyroidectomy. DTC, particularly papillary thyroid carcinoma (PTC), involves cervical LNs in 20-50% of patients in most series using standard pathologic techniques, and may be present even when the primary tumor is small and intra-thyroidal. Preoperative US identify suspicious cervical adenopathy in 20-30% of cases, potentially altering the surgical approach. Therapeutic central/ lateral neck LNs dissection should be included if the LNs are clinically involved. The recommendation for prophylactic neck LNs dissection, however, should be interpreted in light of available surgical expertise 1. The sensitivities of computed tomography (CT), magnetic resonance imaging, and positron emission tomography (PET) for the detection of cervical LN metastases are all relatively low (30-40%). These alternative imaging modalities are useful in the assessment of large, rapidly growing, or retrosternal or invasive tumors to assess the involvement of extrathyroidal tissues, such as airway or aerodigestive obstruction 1. The value of CT to detect local tracheal and esophageal invasion is demonstrated in Fig. 2. Both RAI whole-body scanning (WBS) and measurement of serum thyroglobulin (Tg) are affected by residual thyroid tissue. Postoperative RAI remnant ablation can facilitate early detection of tumor recurrence by serum Tg measurement. RAI ablation can decrease risk of recurrence and disease specific mortality as well. Based on the ATA guidelines, RAI ablation is not recommended for patients with unifocal or multifocal cancer with size less than 1 cm and without other higher risk features 1. Nevertheless, by the 2006 European consensus, RAI ablation after thyroidectomy is a standard procedure with the only exception of unifocal papillary thyroid carcinoma 1 cm in diameter and without other higher risk features 2. The ATA guidelines recommended using minimum radioactivity ( mci) to achieve Table 1. The goals of initial therapy for differentiated thyroid carcinoma 1 To remove the primary tumor and the involved cervical lymph nodes To facilitate postoperative treatment with radioactive iodine To permit accurate long-term surveillance for disease recurrence To minimize the risk of disease recurrence and metastatic spread 1 Adapted and modified from reference 1. 2

3 Management of Thyroid Carcinoma (A) (B) Fig. 1 (A) A 35-year woman with T3N0M0 papillary thyroid cancer. She received near-total thyroidectomy in , followed by 100 mci RAI ablation in The first evaluation in revealed undetectable TSH-stimulated Tg and negative diagnostic RAI image. (B) An 8-year boy with T4aN1bM0 papillary thyroid cancer. He received near-total thyroidectomy and neck LN dissection in , followed by 30 mci RAI ablation in A second 30 mci RAI was given in , which revealed persistent local tumor and neck LNs, and high TSH-stimulated Tg level. A third 30 mci RAI was given in , which revealed persistent local tumor, fewer neck LNs, and bilateral lung metastasis. The TSH-stimulated Tg level was still detectable. A forth 80 mci RAI was given in , which revealed radioactivity uptake by local tumor, neck LN, and bilateral lung. The TSH-stimulated Tg level was still detectable. mci, millicurie; RAI, radioactive iodine; TSH, thyroid-stimulating hormone; Tg, thyroglobulin; TgAb, anti-thyroglobulin antibody; LN, lymph node. 3

4 Pei-Wen Wang Fig. 2 A 65-year man with T4aN0M0 papillary thyroid cancer. He received near-total thyroidectomy, 100 mci RAI ablation, external beam irradiation and thyroxine suppression. Five year later, his serum Tg levels became elevated intermittently and neck US did not show significant finding. He then suddenly developed dysphagia. The CT image detected local tracheal and esophageal invasion. mci, millicurie; RAI, radioactive iodine; Tg, thyroglobulin; US, ultrasound; CT, computed tomography. successful remnant ablation 1. Post-therapy WBS (RxWBS) is typically conducted approximately 1 week after the RAI therapy 1. In the presence of a large thyroid remnant, the scan is dominated by uptake within the remnant, potentially masking the presence of extrathyroidal disease, thus reducing the sensitivity of disease detection. Early imaging may be helpful in detection of metastatic lesions, which has shorter time of iodine retention than the thyroid bed 3. For example, in the case displayed in Fig. 3A, the visualization of neck LN metastasis was shown on the 4 th day, but not on the 6 th day image. This metastatic LN was visualized in 18 F-fluorodeoxyglucose PET/CT, indicating its high malignant potential. In another case (Fig. 3B), the visualization of spine metastasis was presented on the image of 4 th day, but not on the 6 th day. The timing of RxWBS seems to be crucial in detecting metastatic lesions. In addition, 131 I single photon emission computed tomography (SPECT)/CT fusion imaging might provide superior lesion localization. Some examples were illustrated in Fig. 4A-4C to show the superiority of 4

5 Management of Thyroid Carcinoma (A) (B) Fig. 3 (A) Early washout of 131 I radioactivity from a metastatic LN of a 41-year-old woman with papillary thyroid cancer. The metastatic left lower neck LN was clearly visible on the 4 th day image, but not on the 6 th day. This metastatic LN was visualized in 18 F-fluorodeoxyglucose PET/CT, indicating its high malignant potential. (B) A 27-year-old woman with papillary thyroid carcinoma developed multiple distant metastases. The spine metastasis was clearly visualized on the 4 th day image, but disappeared on the 6 th day. LN, lymph node; PET-CT, positron emission tomography-computed tomography. 5

6 Pei-Wen Wang (A) (B) (C) Fig. 4 SPECT/CT fusion imaging provides better tumor localization. (A) delineation of extra-thyroidal LN metastatic foci in the neck region. (B) precise localization of fibula bony metastasis from surrounding soft tissue. (C) SPECT/CT detection of tumor invasion to trachea, while planar image only showed faint radioactivity visible within the thyroid bed. 6

7 Management of Thyroid Carcinoma SPECT/CT imaging in tumor localization. Thyroid stunning is a phenomenon in which exposure of a patient to diagnostic amounts of 131 I may influence the efficacy of following RAI therapy. There is an increasing trend to avoid pre-therapy RAI diagnostic scans (DxWBS) because of the concerns of 131 I-induced thyroid stunning. We have compared the results of postoperative RAI remnant ablation between patients who had a 5-mCi DxWBS before 131 I therapy (n=126) and those who had 131 I therapy directly after surgery (n=119) 4. The success ablation rate was 44.4% and 72.2% in patients with and without the preceding DxWBS, respectively (p<0.05). Furthermore, the diagnostic power of Dx- WBS seems to be weaker than that of RxWBS. It has been reported that RxWBS could detected additional metastatic foci in 10-26% of patients receiving high-dose RAI treatment compared with those receiving DxWBS 1. In the case shown in Fig. 5, the 150-mCi RxWBS could detect bilateral lung metastasis, whereas the lesions were not visualized by the 5-mCi DxWBS. In our early experience from 31 patients, about 40% of the metastatic lesions detected by the RxWBS were missed by the 5-mCi DxWBS. Therefore, we recommend that 131 I ablation should be performed directly after thyroidectomy. External Fig. 5 A 40-year man with papillary thyroid cancer developed lung metastasis. The metastatic lung lesions were detected by RxWBS with 150 mci, but not visualized in the 5-mCi DxWBS. mci, millicurie; RxWBS, post-therapy whole body scanning; DxWBS, pre-therapy radioactive iodine diagnostic scanning. 7

8 Pei-Wen Wang beam irradiation should be considered in patients over age 45 years with grossly visible extra-thyroidal extension at the time of surgery and a high likelihood of microscopic residual disease. Initial TSH suppression to < 0.1 mu/l is recommended for high-risk and intermediate-risk thyroid cancer patients, while maintenance of the TSH at or slightly below the lower limit of normal ( mu/l) is appropriate for low-risk patients 1. Six to twelve months after the initial management, the patients are suggested to receive TSH-stimulated DxWBS, Tg measure, and neck US, depending on the clinical condition. The American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) have developed a staging system with respect to DTC to predict risk for cancer death, not for cancer recurrence. For assessment of risk of recurrence/persistence, the experts who developed the ATA guidelines proposed three-level stratification as follows 1 : A. Low-risk: 1) No local or distant metastases; 2) All macroscopic tumors have been resected; 3) No tumor invasion of locoregional tissues or structures; 4) No aggressive histology (tall cell, insular, columnar cell carcinoma) or vascular invasion; 5) No 131 I uptake outside the thyroid bed on the first RxWBS B. Intermediate-risk: 1) Microscopic invasion into the peri-thyroidal soft tissues at initial surgery; 2) Cervical lymph node metastasis or 131 I uptake outside the thyroid bed by RxWBS; 3) Tumor with aggressive histology or vascular invasion C. High-risk: 1) Macroscopic tumor invasion; 2) Incomplete tumor resection; 3) Distant metastases; 4) Thyroglobulinemia out of proportion to what is seen on the RxWBS These staging systems are static representations of the patient's conditions at the time of initial therapy. However, depending on the clinical course of the disease and the response to therapy, the risks of tumor recurrence and death may change over time. The response to initial therapy based on the result of the first evaluation after initial management is a useful tool to predict patients' outcome 5. Excellent response is characterized by a TSH-stimulated Tg < 1ng/mL and a negative neck US examination. Incomplete response is characterized by suppressed Tg 1 ng/ml or stimulated Tg 10 ng/ml, or rising Tg values, or persistent or newly identified disease by imaging studies. Long-term management Long-term management should provide accurate surveillance for possible recurrence in DTC patients. Tests with high negative predictive value allow identification of patients unlikely to experience disease recurrence. Patients with a higher risk of recurrence are monitored more aggressively because early detection of recurrent disease offers the best opportunity for effective treatment. A second goal of long-term follow-up is to monitor thyroxine suppression therapy to avoid under-replacement or overly aggressive therapy 1. A single TSH-stimulated serum Tg < 0.5 ng/ml in the absence of anti-tg antibody (TgAb) has an approximately % likelihood of identifying patients completely free of tumor on follow-up 1,6. The clinical significance of minimally detectable Tg levels is unclear, especially if only detected following TSH stimulation. In these patients, the rising trend 8

9 Management of Thyroid Carcinoma in serum Tg levels is helpful in identifying patients with clinically significant residual disease. We previously followed up a series of 108 patients who had received two consecutive post-therapy evaluations with serum Tg measurement for more than eight years 6. The trend of Tg levels was more informative. The positive predictive value was 62.5% in cases (n = 8) with an increase of serum Tg of > 10 ug/l, 50% in cases (n = 2) with an increase of Tg of 5-10 ug/ L, and 16.6% in cases (n = 18) with an increase < 5 ug/l 6. Of note, an aggressive or poorly differentiated tumor may be present with low levels of basal or stimulated Tg. In the case displayed in Fig. 6, a patient with papillary thyroid carcinoma presented with a very low TSH-stimulated Tg level on the first follow-up evaluation. However, the results of 5-mCi DxWBS and neck US showed positive findings of cervical lymph node metastasis. The presence of TgAb will falsely lower serum Tg determinations in immunometric assays. Even very low concentrations of TgAb may interfere with Tg measurements such that a falsely negative serum Tg value could mask disease progression. Sequential changes of serum TgAb rather than initial TgAb levels are a good predictor of disease activity in patients with papillary thyroid carcinoma and negative Tg. This is supported by our study with a series of 56 such patients who had been followed up for more than 7 years 7. In that study, 66-75% of patients having increasing or persistent TgAb were found to have active disease. Non-diminishing TgAb indicates existence of active tumor and should be interpreted as evidence of tumor persistence or recurrence 7. Cervical US evaluating the thyroid bed and central and lateral cervical nodal compartments should be performed at 6-12 months and then periodically, depending on the patient's risk for recurrent disease and Tg status. Suspicious LNs greater than 5-8mm in the smallest diameter should be biopsied. Suspicious lymph nodes less than 5-8mm in the largest diameter may be followed in caution. If the small LNs are growing or if the node threatens vital structures, intervention should be considered 1. Until techniques could safely remove or destroy small cervical nodal metastases, the clinical significance of interventions on very small (< 0.5 cm) nodal metastases needs to be clarified by more long-term followup studies 1. Fig. 6 A 45-year woman with papillary thyroid cancer. Her first follow-up evaluation after initial management revealed a very low TSH-stimulated Tg level (0.94 ng/ml). However, the 5-mCi DxWBS and neck US showed pictures of cervical node metastasis. mci, millicurie; DxWBS, pre-therapy radioactive iodine diagnostic scanning; US, ultrasound. 9

10 Pei-Wen Wang 18 F-fluorodeoxyglucose PET scanning may be used in initial staging and in follow-up of high-risk patients, especially in those with a negative RxWBS and serum Tg > ng/ml or in those with aggressive histology. 18 F-fluorodeoxyglucose PET is a prognostic tool for identifying patients with known distant metastases and at highest risk for disease-specific mortality 1. In case shown in Fig. 7, one patient with papillary thyroid carcinoma who had negative RxWBS and elevated Tg level underwent an 18 F- fluorodeoxyglucose PET examination. The results revealed multiple metastases in the patients. The patient later on died of the disease. In spite of this, physicians should be aware that inflammatory LNs, suture granulomas, and increased muscle activity all may cause false-positive findings in 18 F-fluorodeoxyglucose PET scanning 1. After the first RxWBS, low-risk patients with an undetectable Tg on thyroid hormone with negative TgAb and a negative US do not require routine DxWBS during the follow-up 1,2. Cases with detectable radioactivity within the thyroid bed in DxWBS, but a TSH-stimulated serum Tg < 0.5 ng/ml and negative TgAb, seldom develop recurrence later on 8. DxWBS may be of value in the follow-up of patients with positive TgAb or high or intermediate risk of persistent disease. The ATA guidelines and the European consensus both suggest that DxWBS should be performed with 123 I or low activity 131 I. In the long-term follow-up, serum TSH in patients with persistent disease should be maintained below 0.1 mu/l in the absence of specific contraindications. In patients free of disease but presenting with high risk for recurrence, serum TSH levels should be maintained at m/l for 5 10 years. In patients free of disease and at low risk for recurrence, the serum TSH may be kept within the lower normal range (0.3-2 mu/l) 1,9. Metastatic or recurrent disease In patients with metastatic disease, the preferred hierarchy of treatment (in order) is: (1) surgical excision of locoregional disease to prevent complications in targeted areas, such as the central nervous system and central neck compartment, (2) 131 I therapy for RAI-avid disease, (3) external beam radiation, (4) watchful waiting in patients with stable Fig. 7 A 55-year man with papillary thyroid cancer had rising Tg levels during the follow-up. The 150- mci RxWBS was negative, while 18 F-fluorodeoxyglucose PET imaging showed multiple metastases. This patient later died of the disease. mci, millicurie; RxWBS, post-therapy whole body scanning; PET, positron emission tomography. 10

11 Management of Thyroid Carcinoma or slowly progressive asymptomatic disease, and (5) experimental trials, especially for patients with significantly progressive macroscopic RAI-refractory disease 1. Patients with RAI refractory metastasis have poor prognosis. Their 10-year overall survival rate is 10% as compared to 60% for those with RAIavid metastasis 10. Recent studies on enhancement of RAI uptake by kinase inhibitor open a window for the development of new therapeutic strategy. Since kinase inhibitor can induce RAI uptake and retention in thyroid tumors, an advantage of this therapeutic strategy is that only a short course of drug therapy is required to elicit a durable clinical effect 11,12. There are currently insufficient outcome data to recommend recombinant human TSH (rhtsh)- mediated RAI therapy for all patients with metastatic disease. This therapy may be indicated in selected patients with comorbidities, for example, those for whom iatrogenic hypothyroidism is potentially risky, those with pituitary disease, and those for who delay in therapy might be deleterious 1. Pulmonary micrometastases should be treated with RAI therapy and repeated every 6 12 months as long as the residual tumor tissue continues to concentrate RAI and respond clinically (Fig. 8). Radioiodine-avid macronodular metastases should be treated with RAI and treatment should be repeated when objective benefit is demonstrated, but complete remission is not likely and survival remains poor (Fig. 9). RAI therapy of iodine-avid bone metastases has been associated with improved survival and should be employed. Complete surgical resection of isolated symptomatic bone metastases has been associated with improved survival and should be considered especially in patients < 45 years old with slowly progressive disease. Complete surgical resection of central nervous system metastases should be considered regardless of RAI avidity, because the intervention is associated with significantly longer survival. Central nervous system lesions that are not amenable to surgery should be considered for targeted external beam irradiation (such as radiosurgery). If metastases in the central nervous system do concentrate RAI, then RAI could be considered and concomitant glucocorticoid therapy are strongly recommended to minimize the effects of a potential TSH-induced increase in tumor size 1. Fig. 8 A 40-year man with papillary thyroid cancer was found to have pulmonary micro-metastases on the RAI 100 mci ablation after thyroidectomy. A 150 mci RAI therapy was given 10 months later. The RxWBS revealed successful ablation of the pulmonary metastasis by the previous radiotherapy. RAI, radioactive iodine; mci, millicurie; RxWBS, post-therapy whole body scanning. 11

12 Pei-Wen Wang Fig. 9 A 30-year man with papillary thyroid cancer developed RAI-avid macronodular metastases. He was treated with repeated doses of RAI. The metastatic lesions responded to the RAI therapy, but could not be eradicated. RAI, radioactive iodine. Fig. 10 Response of metastatic disease to RAI therapy. There is a progressive decrease in remission and resolution rates of RAI-avid disease with increasing accumulated 131 I dose. RAI, radioactive iodine. In our experience of applying RAI therapy in 126 DTC patients with metastasis (followed up for 9.6 ± 5.2 years), most 131 I-avid cases who had disease resolved (79.2%) and disease-free remission (87.5%) after the therapy received a cumulative 131 I dose no greater than 600 mci. The mean cumulative doses of 131 I in both deceased and living patients were similar. It should be noted that resolution of RAI-avid disease does not guarantee tumor elimination. It may be a result from disappearance of 131 I-avid tumor cells. This phenomenon can be observed in the data shown in Fig. 10. Progressive 12

13 Management of Thyroid Carcinoma decrease in disease remission rate occurs with increases in accumulated 131 I dose 13. Therefore, 131 I should be used cautiously in patients who have already received more than 600 mci unless there is a high probability that it would benefit the patient. References 111 Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19: Pacini F, Schlumberger M, Dralle H, et al. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 2006;154: Hung BT, Huang SH, Huang YE, Wang PW. Appropriate time for post-therapeutic I-131 whole body scan. Clin Nucl Med 2009;34: Hu YH, Wang PW, Wang ST, et al. Influence of I-131 diagnostic dose on subsequent ablation in patients with differentiated thyroid carcinoma: Discrepancy between the presence of visually apparent stunning and the impairment of successful ablation. Nucl Med Commun 2004;25: Tuttle RM, Tala H, Shah J, et al. Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: Using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid 2010;20: Huang SH, Wang PW, Huang YE, et al. Sequen- tial follow-up of serum thyroglobulin and whole body scan in thyroid cancer patients without initial metastasis. Thyroid 2006;16: Hsieh CJ, Wang PW. Sequential changes of serum antithyroglobulin antibody levels are a good predictor of disease activity in thyroglobulinnegative patients with papillary thyroid carcinoma. Thyroid 2014;24: Pacini F, Capezzone M, Elisei R, Ceccarelli C, Taddei D, Pinchera A. Diagnostic 131-iodine whole-body scan may be avoided in thyroid cancer patients who have undetectable stimulated serum Tg levels after initial treatment. J Clin Endocrinol Metab 2002;87: Wang PW, Wang ST, Liu RT, et al. Levothyroxine suppression of thyroglobulin in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 1999;84: Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006;91, Chakravarty D, Santos E, Ryder M, et al. Smallmolecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation. J Clin Invest 2011;121: Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013;368: Huang IC, Chou FF, Liu RT, et al. Long-term outcomes of distant metastasis from differentiated thyroid carcinoma. Clin Endocrinol (Oxf) 2012;76: