Abstract
Differentiated Thyroid Cancer (DTC) is increasing in prevalence due to better diagnostic tools and excellent long-term survival. This study is to understand the outcome of twenty-six patients with DTC over a period of 10 years after the initial treatment with surgery and radioiodine therapy. Our study analysis showed no deaths, and indicated that older men were more likely to have persistent disease. Further studies are needed to focus on cost effective long-term management of DTC.
Introduction
Differentiated thyroid cancer (DTC) comprises about 90% of all thyroid cancers in the world1. DTC can be further differentiated to include papillary thyroid cancer (PTC), follicular carcinoma (FC) and Hurthle cell carcinoma (HCC). In the United States, the annual incidence of DTC has increased nearly three-fold over 34 years from 4.9 per 100,000 in 1975 to 14.3 per 100,000 in 20092, mainly attributed to an increase in PTC. DTC has an excellent long-term prognosis, with a five-year survival rate of 97.9%1.
In 1996, the American Thyroid Association (ATA) published guidelines for patients with thyroid nodules and DTC; these guidelines were updated in 2006, 2009 and most recently in 2015, and are widely used for management of patients with DTC. Many patients with DTC undergo total thyroidectomy with radioactive iodine ablation postoperatively. This procedure is followed by appropriate thyroid stimulating hormone (TSH) suppression, as well as long-term follow up2. The increasing incidence and high survival rate of DTC requires long-term monitoring of these patients for recurrence of cancer involving clinical exam, lab studies including TSH and thyroglobulin (Tg) levels, and imaging, if indicated.
The ATA guidelines recommend the monitoring of serum Tg as a tumor marker for DTC due to the high degree of sensitivity and specificity of Tg levels in detecting DTC recurrence or persistence after the initial treatment with total thyroidectomy and remnant ablation with RAI. Serum Tg is also utilized for risk stratification of patients with DTC2. Tg levels of <0.2 ng / mL, with a suppressed TSH or a Tg < 1 ng/dl with TSH stimulation indicate an excellent response to treatment in patients treated with total thyroidectomy and RAI. A Tg greater than 1 ng/ml following thyroidectomy and radioactive iodine indicates an incomplete response to treatment and requires long-term follow up. These patients also require suppressive doses of levothyroxine to maintain a TSH below normal (0.27 – 4.2 mIU/ml). Tg levels should be monitored every 6–12 months2. Imaging, including ultrasound, diagnostic whole body scan, and in certain clinical situations, a neck/chest CT scan, neck MRI or a PET CT scan are performed at varying intervals to identify the focus of DTC. Patients with persistent disease may receive additional doses of adjuvant RAI therapy during the course of their disease.
According to Surveillance, Epidemiology and End Results (SEER) program data there will be an estimated 64,300 new cases of thyroid cancer in the United States in 2016, and an estimated 1,980 people will die of thyroid cancer1. There is an ongoing debate focusing on the increasing incidence of DTC and factors that may be leading to this increase3. Most of this research focuses on low risk DTC, with only a few small studies focusing on patients who have persistent or progressive disease in patients with DTC.
The purpose of this study was to identify patterns in clinical course and management over a period of 10 years in patients with DTC and persistent elevated Tg levels, after initial treatment with surgery and radioactive iodine ablation (RAI) therapy. This study was a retrospective chart review of patients in a clinical setting and as such provides a “real life” picture of patients with thyroid cancer. The study will aid physicians in providing long-term, cost-effective management, focused on individualized care for these complicated cases, which comprise less than 1% of patients diagnosed with DTC.
Material and Methods
A retrospective non-randomized chart review was performed to assess long-term patient management at the University Hospital, Columbia, Mo.
Subjects
Patients receiving medical care from University Hospital, Columbia, Mo., between January 2004 and December 2014 who met the following criteria were included in this study: (a) patients with a diagnosis of DTC, including PTC, papillary thyroid cancer – follicular variant, FC, and HCC presenting to the multidisciplinary clinic during the study period; (b) underwent total thyroidectomy followed by RAI; and (c) at least two Tg measurements, including at least two unstimulated Tg measurements elevated above 0.2 ng/dl or two stimulated Tg measurements above 2 ng/dl. The care of most of the patients was based on ATA guidelines in 2006 and 2009. As a retrospective chart review, no specific protocol for testing or imaging was followed, but patient follow-up was based on “real life clinical management” in a tertiary care hospital. This study was approved by the Institutional Review Board of the University of Missouri School of Medicine. Informed consent requirement was waived because of the retrospective nature of the study.
None of the patients in our study showed secondary primary cancers from other organs. These are usually diagnosed more than 10 years after the primary thyroidectomy3. There were no deaths from thyroid cancer during the study period.
Measures
A retrospective chart review was performed and data collected included clinical history and patient demographics (e.g. age and sex). The clinical history included any known history of radiation to the head and neck area, hypothyroidism, Hashimoto’s thyroiditis, Grave’s disease, uninodular or multinodular goiter, family history of thyroid disease, preoperative laboratory studies including thyroid stimulating hormone (TSH), antithyroglobulin antibody (Tg Ab), and thyroid peroxidase antibodies (TPO), preoperative imaging (ultrasound, CT neck), fine needle aspiration findings, and histopathological findings (tumor size, pathological classification, extrathyroidal extension, intrathyroid multifocality, lymph node metastasis and presence of underlying Hashimoto’s thyroiditis). All studies related to the long-term clinical course after diagnosis and treatment including Tg levels, imaging including CT, MRI, ultrasonography, PET scans were recorded.
Three patients with elevated Tg Abs were excluded from this study. Tg Ab are detected in 25–30% of patients with DTC6. In these patients with elevated Tg antibodies, Tg levels checked utilizing radioimmunoassays are unreliable. Some laboratories measure Tg by Liquid Chromatography-Tandem Mass Spectrography, which is reliable in the presence of Tg Abs2, 4. Some authors have suggested using Tg Abs trends as a surrogate tumor marker in patients with DTC5. However, we preferred to exclude patients with elevated Tg Abs due to lack of reliable data in this setting.
Initial Course
Between 2004 and 2014, 272 patients diagnosed with DTC obtained care at the University Hospital, Columbia, Mo., and were treated with total thyroidectomy. This was followed by radioactive iodine ablation, with I-131 whole body scan (131I WBS) six to twelve months after remnant ablation, as per ATA guidelines2. Patients underwent lymph node dissection if cervical lymph node involvement was noted on preoperative imaging or intraoperatively by the surgeon. Depending on clinical evaluation, imaging studies were performed such as neck ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), and flouro-18-deoxyglucose positron emission tomography (PET). External radiotherapy was performed if clinically indicated for distant metastases. All patients were followed in a multidisciplinary thyroid cancer clinic by the same endocrinologist during the study period (2004 – 2014). During the ten-year follow-up period, TSH and Tg using immunoradiometric assay results were followed at 6 to 12 month intervals. After a 10-year follow-up period, 29 patients had evidence of persistent thyroid cancer, as shown by either two or more unstimulated Tg measurements elevated above 0.2 ng/dL or two stimulated Tg measurements above 2 ng/dL, performed at least 12 months after remnant ablation. Of these 29 patients, 26 patients had at least two detectable Tg measurements with negative Tg antibodies. The long-term outcomes of these 26 patients were further analyzed to determine the clinical course specifically focusing on Tg level, use of imaging modalities and treatment offered including surgery or chemotherapy. The remaining three patients had elevated Tg antibodies and were excluded.
Data Analysis
Due to small sample sizes, only patterns of clinical outcomes and treatment were investigated. Based on at least two detectable Tg measurements with negative Tg antibodies, twenty-six patients of the 272 had evidence of persistent thyroid cancer and were further studied. These participants were followed and categorized into three distinct categories based on Tg levels (e.g. <10 ng/dL, 10ng/dL – 100ng/dL, >100ng/dL). Although primarily a descriptive study, the non-parametric Wilcoxon Rank Sum test was used to determine differences in the age at diagnosis and Tg levels between males and females.
Results
In this cohort of 26, there were 19 females (73%) and seven males (27%) (see Figure 1). Females were 21–58 years old with a mean age of 38.6 years (± 11.9 years). Males were 18–64 years old with a mean age of 54.4 years (± 16.2 years). Most females were between the ages of 20 and 30 years old and most males were between 56 and 65 years old5,6. Male patients were also older at diagnosis, on average, compared to women (p-value = 0.0134). Of the 26 patients, 20 patients had papillary thyroid cancer (PTC). Of these 20 patients, six patients had classical PTC, six patients had multifocal papillary thyroid cancer (MF-PTC), six had papillary thyroid cancer follicular variant (PTC-FV) and two patients had multifocal PTC-FV. Of the six patients that did not have PTC, two patients had follicular thyroid cancer (FTC), three patients had Hurthle cell cancer (HCC) and one patient had struma ovarii with a 1 mm micro PTC. In females, the most common type of DTC was MF-PTC in six females (31%) followed by PTC in four females (26%) and FV-PTC in four females (26%). In males, the most common DTC was PTC in two males (28.5%) and FV-PTC in two males (28.5%). Six patients had a family history of DTC.
Figure 1.
Demographic characteristics for 26 patients with evidence of persistent thyroid cancer.
Seventeen patients (Group 1), three males and fourteen females, had stimulated Tg levels less than 10 ng/dL (see Table 1). In Group 1, one person died of an unrelated cause and four patients were lost to follow-up. Therefore, the survival rate of Group 1 was 94% assuming that those patients who were lost to follow-up are included in the surviving group. Five patients underwent cervical lymph node dissection with postoperative follow-up Tg levels that were less than 1.6 ng/dL.
Table 1.
Group 1: Patient progress for those with TG less than 10ng/dl
| Age at Diagnosis (years) | Sex | Type of Thyroid Cancer | I -131 admin (age) | Imaging (Frequency) | Surgery | Status |
|---|---|---|---|---|---|---|
| 52 | F | Multifocal PTC | 152 mCi (52) | CT neck (1) WBS (1) |
Left neck dissection at age 56, 2 LN + PTC | Doing well at age 60 years, stimulated Tg: 1.5 ng/dL |
| 18 | M | PTC | 33 mCi (18) | WBS (4) | Doing well at age 34, stimulated Tg: 0.4 ng/dL | |
| 205 mCi (18) | CT scan (1) | |||||
| 263 mCi (19) | ||||||
| 255 mCi (22) | ||||||
| 36 | F | PTC | Dose NK (36) | WBS (2) | Lost to follow up at age 40 years, unstimulated Tg : 0.7 ng/dL | |
| 150 mCi (39) | PET (1) | |||||
| 38 | F | PTC FV, Multifocal PTC | 100 mCi (38) | WBS (2) | Left neck dissection age 44 years: 1 LN + PTC | Continues follow up, age 48 years, unstimulated Tg: 0.8 ng/dL |
| 150 mCi (43) | PET (1) | |||||
| MRI neck (1) | ||||||
| 28 | F | FTC | Dose NK (28) | WBS (2) | LN resection at age 29 | Doing well at age 53, unstimulated Tg : 1.1 ng/dL |
| Dose NK (32) | ||||||
| 21 | F | PTC | Dose NK (21) | WBS (1) | Right neck LN dissection at age 31, 2 | Doing well at age 42 years, unstimulated Tg: 1.6 ng/dL |
| Dose NK (27) | CT scan (1) | LN + PTC | ||||
| 58 | F | Struma Ovari_ FTC | Pelvic XRT (58) | WBS (3) | Lost to follow up at age 63, stimulated Tg: 0.5 ng/dL | |
| Thyroid: 1mm PTC | 250 mCi (59) | PET scan (2) | ||||
| CT scan (4) | ||||||
| 26 | F | PTC | 152 mCi (29) | WBS (3) | Being followed at age 38, stable multiple pulmonary nodules, unstimulated Tg: 6.9 ng/dL | |
| 152 mCi (35) | PET scan (3) | |||||
| CT scan (6) | ||||||
| 58 | M | PTC | 104 mCi (58) | WBS (1) | Right neck dissection at age 59, 7 LN + for PTC | Being followed at age 63, unstimulated Tg: < 0.1 ng/dL |
| CT scan (2) | ||||||
| PET scan (1) | ||||||
| 41 | F | PTC | Dose NK (41) | WBS (1) | Deceased age 72, last unstimulated Tg: 1.1 ng/dL | |
| 44 | F | PTC FV | 103 mCi (44) | WBS (1) | Lost to follow up age 54, unstimulated Tg: 0.9 ng/dL | |
| 41 | F | Multifocal PTC | 150 mCi (41) | WBS (3) | Continued follow up, stimulated Tg:3.6 ng/dL | |
| 150 mCi (43) | PET scan (1) | |||||
| 51 | F | Multifocal PTC | 153 mCi (51) | WBS (1) | Lost to follow up at age 56, unstimulated Tg: 2.5 ng/dL | |
| PET scan (1) | ||||||
| CT scan (1) | ||||||
| 30 | F | PTC FV | Dose NK (30) | WBS (1) | Being followed at age 82, unstimulated Tg: 0.6 ng/dL | |
| PET scan (1) | ||||||
| 47 | F | PTC FV | 100 mCi (47) | None | Being followed at age 49 years, unstimulated Tg: 0.2 ng/dL | |
| 31 | F | Multifocal PTC | 154 mCi (31) | WBS (2) | Pulmonary nodules noted at age 34, being followed at age 35, unstimulated Tg: 5.7 ng/dL | |
| 150 mCi (34) | PET scan (2) | |||||
| CT scan (1) | ||||||
| 62 | M | PTC FV, Multifocal PTC | 100 mCi (62) | None | Being followed at age 66 years, unstimulated Tg: 0.4 ng/dL |
Five patients (Group 2) had stimulated Tg levels between 10 and 100 ng/dL, two males and three females (see Table 2). Of these five patients, one patient had cervical vertebral metastases that were removed and was later noted to have pulmonary and brain metastases requiring surgical removal. This surgery was followed by treatment with tyrosine kinase inhibitors (TKI).
Table 2.
Group 2: Patient progress for those with TG 10–100ng/dl
| Age at Diagnosis (years) | Sex | Type of thyroid cancer | I -131 admin (age) | Imaging (Frequency) | Surgery | Status |
|---|---|---|---|---|---|---|
| 35 years | F | Multifocal | 99 mCi (35) | WBS (1) | Continues follow up, age 37, unstimulated Tg: 12 ng/dL | |
| PTC | 150 mCi (37) | PET (1) | ||||
| 29 years | F | Multifocal | 100 mCi (29) | WBS (2) | Lost to follow up age 33 years, stimulated Tg: 13.8 ng/dL | |
| PTC | PET scan (2) | |||||
| CT scan (1) | ||||||
| 58 years | M | FTC | 151 mCi (58) | CT scan (1) | Being followed at age 67 years, unstimulated Tg: 65 ng/dL | |
| 150 mCi (62) | PET scan (3) | |||||
| 57 years | F | HCC | 75 mCi (57) | WBS (1) | Being followed at age 64, unstimulated Tg: 30 ng/dL | |
| 130 mCi (58) | PET scan (1) | |||||
| 151.7 mCi (60) | ||||||
| 59 years | M | PTC FV | 152 mCi (59) | WBS (2) | C-6 vertebral metastasis removed age 61, lung nodules noted age 62, right frontal metastases removed age 64 | TKI started age 64, stable at age 65 years, stable pulmonary metastasis, unstimulated Tg: 59 ng/dL |
| 152 mCi (61) | PET scan (7) | |||||
| CT scan (7) | ||||||
| MRI (6) |
Four patients, two males and two females, had stimulated Tg levels greater than 100 ng/dL (see Table 3). In Group 3, all four patients were noted to have pulmonary metastases; one patient opted for continued surveillance, the other three patients were treated with TKI. Although our sample size was much smaller, we found that more males were in groups 2 and 3, and were also significantly older compared to the females in our cohort (p=.0134).
Table 3.
Group 3: Patient progress for those with TG greater than 100ng/dl
| Age at Diagnosis (years) | Sex | Type of thyroid cancer | I -131 admin (age) | Imaging (Frequency) | Surgery | Status |
|---|---|---|---|---|---|---|
| 64 years | M | HCC | 100 mCi (64) | WBS (2) | Regular follow up, unstimulated Tg: 443 ng/dL, multiple FDG avid lung nodules | |
| PET scan (5) | ||||||
| CT scan (2) | ||||||
| 24 years | F | HCC | 203 mCi (73) | CT scan (5) | Unstimulated Tg: 8981 ng/dL, multiple pulmonary nodules treated with TKI, deceased age 74 years from unrelated renal disease | |
| 54 years | F | PTC FV | 200 mCi (55) | CT scan (1) | Pulmonary and brain metastasis, TKI started age 57 years, being followed at age 58, unstimulated Tg: 2185 ng/dL | |
| 200 mCi (56) | MRI (2) | |||||
| PET (1) | ||||||
| 62 years | M | PTC FV | Dose NK (62) | PET (1) | Right neck LN dissection, 2 + LN for PTC age 65 | Pulmonary metastasis noted in 2014, TKI started age 68, continues follow up at age 69, unstimulated Tg: 2061 ng/dL |
| 151 mCi (65) | CT Scan (2) | |||||
| MRI (1) | ||||||
| WBS (1) |
All patients received radioactive iodine ablation (RAI) and more than half of patients (n=15) received RAI at least twice. The mean dose given was 148.31 mCi, which includes all doses given to all 26 patients. Eleven patients received only a single dose of RAI (42%). The mean doses for Groups 1, 2 and 3 were 151.3 mCi, 131.07 mCi and 170.8 mCi respectively. For three patients, I-131 doses for RAI ablation were not known. All patients had multiple imaging studies during the 10-year study follow-up period. Most patients had two imaging studies in Group 1 (n=6) and Group 2 (n=2). One patient in Group 2 had pulmonary, brain and cervical vertebral metastasis and had 22 imaging studies performed during the 10-year period. In Group 3, most patients had five imaging studies (n=2), one patient had four studies and one patient had nine studies performed for follow-up.
Tyrosine Kinase inhibitors (TKI) treatment was used in four patients, one patient was in group 2 and three patients were in group 3. One patient in group 3 opted for continued clinical surveillance of pulmonary nodules rather than undergoing TKI treatment.
Discussion
This study included patients treated at a single center. It highlights the management of thyroid cancer patients in a “real life clinical situation” outside of the confines of a preset research protocol. Our study shows that the management of thyroid cancer has changed significantly since 2004. Many patients were managed with total thyroidectomy and RAI using previous guidelines in 2006 and 2009. Despite the small size of the sample, we were able to gain some insightful knowledge about patient management. Unlike the prevalence of thyroid nodules and cancer in the general population, where significantly more women are affected compared to men, there was a higher proportion of men with thyroid nodules and cancer in this study. Male gender has been significantly associated with disease-specific mortality in thyroid cancer and males generally show more advanced disease at clinical presentation and have poorer prognosis after therapy 6. Although our study utilized a small sample, there were proportionally more males in Groups 2 and 3 (40% and 50%, respectively), compared to Group 1 although statistical significance was not demonstrated. Male patients were also older at diagnosis, on average, compared to women (p-value = 0.0134). Patient age has been shown to be an independent negative risk factor for survival in DTC6, 7.
There is no consensus for the long-term clinical management of patients with DTC who have an elevated serum Tg8. Tg levels in patients with DTC are reliable indicators to identify recurrence based on elevated Tg levels9. Studies have shown that most patients with PTC and histologically proven lymph node metastases treated with I-131 ablation are rarely free of detectable disease10. Retrospective studies in DTC patients designed to assess the long-term course of Tg positive patients with negative imaging without any therapeutic intervention have shown spontaneous remission in the majority of patients with a minority showing persistent disease11. In patients with persistent disease, therapeutic interventions achieve remission only in some patients, with most patients continuing to harbor persistent disease and a few patients showing progression of the disease leading to their death12. A small case series by Kwong et al. showed that in select patients with PTC and distant metastasis, long-term survival could be achieved by close follow-up without aggressive treatment13. Several recent case series have tried to highlight the clinical course of DTC with distant metastasis. Lin et al. looked at the survival time after diagnosis in patients with DTC and distant metastasis and found a disease-specific mortality of about 70% after a mean follow-up of 10.1 years6. They found that older patients and male patients with distant metastasis needed more aggressive treatment. It is known that recurrent or persistent disease may not be localized and patients undergo different imaging studies to localize the recurrence. In our study, we found that patients had an average of 1.38 imaging studies. We did not analyze the cost of these studies or any anxiety that may have been caused to the patients. The clinical use and cost-effectiveness of different imaging modalities has not been widely studied but may be a question for future research14.
Interestingly, none of the patients in our study showed underlying Hashimoto’s thyroiditis. Some studies have shown an increased prevalence of DTC in patients with Hashimoto’s thyroiditis, especially in the setting of increasing TSH levels10. Some authors have noted that even though the prevalence of DTC has increased, Hashimoto’s thyroiditis may have a protective effect and be associated with better prognostic factors including younger age, smaller tumor size and female sex14, 15. Although some studies have shown increased risk of DTC with hypothyroidism16, none of our study patients had a previous diagnosis of autoimmune hypothyroidism. One patient in Group 1 had been treated for Grave’s disease with RAI ablation six years prior to diagnosis resulting in post ablative hypothyroidism.
Our study has several limitations including a small patient population limited to a single provider in an academic tertiary care setting. The higher percentage of patients with persistent disease in our study may be due to referral bias to the tertiary care center and hence may not be representative of the general population. In addition, a study that assesses mortality and secondary primary cancers in DTC patients will likely need a longer follow-up period, beyond ten years. However, obtaining consistent data for a longer period of time is quite challenging. No specific protocol for long-term treatment of thyroid cancer was followed during the study period. The management of thyroid cancer in a clinical setting may have changed based on thyroid cancer guidelines from the ATA changed in 2006 and revised in 2009. Further, few of our study patients were treated with TKI, a treatment option that has only become available in the last few years. Cellular mutation profile of thyroid cancer was not included in our study. This testing is now included in management of thyroid cancer patients, but was not widely used between 2004 and 2014.
Conclusion
Thyroid cancer is increasing in incidence in the United States and worldwide. Though most patients with DTC have an excellent survival, older men may be more likely to have persistent disease. Patients with persistent disease after initial therapy can be followed long-term with observation and lab tests. Of these patients, a small number will develop progressive disease requiring targeted therapy. All patients with persistent disease should have regular clinic visits, laboratory tests and imaging procedures, and may undergo multiple treatments with RAI and surgeries. Sialadenitis resulting from RAI as well as other side effects resulting from other interventions may add to increased cost and morbidity in these patients. Further studies are needed to better define management in this small group of patients to decrease morbidity during long-term follow-up. Future guidelines for management of persistent thyroid cancer should address the cost of care and encourage providers to review long-term cost effective management, especially in the lower risk groups.
Biography
Sarah Khan is at the University of Missouri School of Medicine. Roopashree Prabhushankar, MD, is at Desert Kidney Associates, Endocrinology, Mesa, Arizona. Emily Leary, PhD, is at the University of Missouri School of Medicine. Uzma Z. Khan, MD, (above), is at the University of Missouri School of Medicine, Department of Internal Medicine.
Contact: khanu@health.missouri.edu
Footnotes
Disclosure
This research was supported by the Ellis Fischel Cancer Center.
Author Contribution Statement
All authors had significant contribution to this manuscript including drafting, revision, and final approval of the manuscript. Sarah Khan contributed with data acquisition and interpretation; Roopashree Prabhushankar contributed with design and concept, data acquisition, and interpretation; Emily Leary contributed with data analysis and interpretation; and Uzma Khan contributed with design and concept, data acquisition, and interpretation.
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