A variation in recurrence patterns of papillary thyroid cancer with disease progression: A long-term follow-up study

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1 ORIGINAL ARTICLE A variation in recurrence patterns of papillary thyroid cancer with disease progression: A long-term follow-up study Joon-Hyop Lee, MD, Yoo Seung Chung, MD, PhD,* Young Don Lee, MD, PhD Thyroid and Endocrine Surgery Section, Department of Surgery, Gachon University Gil Medical Center, Incheon, Republic of Korea. Accepted 17 November 2016 Published online 31 January 2017 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Studies effectively examining temporal patterns of papillary thyroid cancer (PTC) recurrence are currently lacking. The purpose of this study was to examine sites of PTC recurrence, interval from initial treatment to recurrence, and changing patterns of recurrence during long-term follow-up. Methods. Records of 134 patients with PTC recurrence were analyzed retrospectively. Results. The most common site of initial recurrence was the lateral neck. In 6.7% of patients, distant metastases occurred as initial recurrences. In 74%, recurrences occurred within the first 5 years of surgery, whereas in 5.2%, and 1.5%, recurrences occurred between 10 to 20 years and after 20 years of surgery, respectively. Mean time to recurrence and distant metastasis was 48.2 months and 92.5 months, respectively. Male sex (p 5.002), size (p <.001), (p <.001), and recurrence frequency (p 5.049) were prognostic factors for distant recurrence. Conclusion. Men with PTC tumors larger than 2 cm, lateral neck node metastasis, and multiple local recurrences should be scrutinized for distant metastasis even after 10 years. VC 2017 Wiley Periodicals, Inc. Head Neck 39: , 2017 KEY WORDS: papillary thyroid carcinoma, recurrence, temporal pattern, distant metastasis, long-term INTRODUCTION Papillary thyroid carcinoma (PTC) has an excellent prognosis, as evidenced by the extremely low 10-year diseasespecific mortality rate (1.7%) reported in a meta-analysis of 23 studies 1 ; this is the lowest rate among all cancers. The recurrence rate after initial treatment, however, is higher, ranging from 1.4% to 35% 2,3 ; this poses a practical problem for patients and physicians, both in terms of medical costs and the psychological burden associated with long-term follow-up. Considering the longevity of this patient group, a more rational and effective approach to postoperative surveillance is needed. However, this will require a thorough understanding of not only the percentage and time interval to recurrence, but also its pattern and distribution over time. Although several publications have addressed PTC recurrence and behavior, they examined local and distant metastases as separate entities. Few studies have examined the changing pattern of PTC recurrence over time. Therefore, to analyze the temporal patterns of PTC recurrence, we used our institution s 27-year follow-up data on patients with PTC after initial treatment. The primary objective was to examine *Corresponding author: Y. S. Chung, Thyroid and Endocrine Surgery Section, Department of Surgery, Gachon University Gil Medical Center, Gachon University School of Medicine, Gachon University, 1198 Guwol-dong, Namdong-gu, Incheon, , Republic of Korea. dryooseung@gilhospital.com the sites of recurrence, the interval from initial treatment to recurrence, and changes in patterns of recurrence over a long period of time. MATERIALS AND METHODS After obtaining approval from the relevant institutional review board (IRB No: GCIRB ), the medical records of all patients with documented PTC recurrence were analyzed. Among the patients who received initial treatment between 1987 and 2014, only those with documented structural recurrence (in accordance with the 2015 American Thyroid Association guidelines 4 ) from a single tertiary referral center were included. Patients in whom recurrence was detected within 1 year of initial therapy, including patients with synchronous distant metastases, were excluded from this study. The following baseline data were obtained from the cohort: patient demographics, the type and date of the surgical procedure, pathologic characteristics, such as extrathyroidal extension and lymphovascular invasion, and tumor stage. The dose of radioactive iodine ablation (RAI), frequency of RAI, site and time interval to recurrence (recurrences if multiple), and the date of the last check-up were recorded after reviewing the follow-up data. Some items were missing from the pathology report because of the long study period and, therefore, were not included in this analysis. The type of operations undertaken (lobectomy vs total thyroidectomy with routine central and optional lateral HEAD & NECK DOI /HED APRIL

2 LEE ET AL. TABLE 1. Characteristics of 134 recurred patients with papillary thyroid carcinoma. Variables Results Age, y, mean (range) 44.8 (15 83) Sex Female 110 (82.1%) Male 24 (17.9%) Size, cm, mean (range) 2.35 ( ) Extrathyroidal extension (1) 84.0% (100/119) Lymphovascular invasion (1) 22.8% (26/114) Multicentricity (1) 52.6% (61/116) Bilaterality (1) 37.7% (43/114) T1 19 (15.8%) T2 1 (0.8%) T3 87 (72.5%) T4 13 (10.8%) N0 7 (5.9%) N1a 82 (67.5%) N1b 29 (24.6%) I 72 (55.4%) III 35 (26.9%) IV 23 (17.7%) Follow-up duration, mean (range) 96.1 mo (13 345) cervical lymph node dissection) and postoperative RAI protocol were based on our institution s guidelines at the time of presentation. After the first 2 postoperative outpatient department visits (at 2 weeks and 3 months, respectively) and RAI treatments, patients presumed to be recurrence-free were recommended to attend annually for neck ultrasound, thyroid function tests, and basal serum thyroglobulin (Tg) measurement. Those patients with basal serum Tg levels of >10 ng/ml were followed up more frequently (3 6-month intervals), either with or without neck ultrasound or CT. Fine-needle aspiration cytology was performed to confirm recurrence if suspicious radiologic findings were detected in the locoregional neck area. Patients with suspected distant metastases were not subject to biopsy examination. Demographic data are reported as mean values with ranges (for continuous variables) or as percentages (for categorical variables). Intergroup differences were assessed using the t test or Fischer s exact test. The s <.05 were considered significant. All data analyses were performed using SPSS 20.0 (IBM, Armonk, NY). RESULTS Among patients with PTC who received thyroidectomy between January 1987 and March 2014, 134 had documentation of recurrence. The clinicopathologic characteristics are described in Table 1. The mean age was 44.8 years (range, years), and 110 patients (82.1%) were women and 24 (17.9%) were men. Fourteen patients (10.4%) initially underwent lobectomy with central node dissection, 89 (66.4%) underwent total thyroidectomy with central node dissection, and 31 (23.1%) underwent total thyroidectomy with central and lateral lymph node dissection. The mean follow-up period was 96.1 months (range, TABLE 2. Site of first recurrences. Specific recurrence site No. of patients (%) Local 126 (94.0%) Central neck 8 (6.0) Central neck, lateral neck 5 (3.7) Contralateral lobe 7 (5.2) Lateral neck 105 (78.4) Lateral neck, hilar lymph node 1 (0.7) Distant 6 (4.5%) Lungs 4 (3.0) Bones 1 (0.7) Bones, lungs 1 (0.7) Both 2 (1.5%) Lateral neck, lungs 1 (0.7) Central neck, lungs 1 (0.7) Total 134 (100.0) months). None of the patients initially presented with distant metastasis. Regarding TNM classification, 72 patients (55.4%) were stage I, 35 (26.9%) were stage II, and 23 (17.7%) were stage IV. No PTC-related deaths occurred during the study period. The mean time to initial recurrence was 48.2 months (range, months). In the majority of cases (128; 95.5%), the first recurrence was local. The most common site was the lateral neck compartment, which accounted for 112 cases (83.6%), whereas the central neck accounted for 14 cases (10.4%). Distant metastasis, including to the lungs and bones, occurred in 8 cases (6.0%) initially. Two patients (1.5%) presented with concurrent local and distant metastasis (Table 2). The temporal pattern change of recurrence was also noteworthy. Figure 1 shows that 76 (56.7%) and 99 cases (73.9%) of recurrence occurred within the first 3 and 5 years of initial treatment, respectively, whereas 9 (6.7%) and 2 cases (1.5%) occurred 10 and 20 years postsurgery, respectively. The point to notice was the increase in the ratio of distant-to-local recurrence over time. During the first 5 years, the ratio was 5%; however, this increased FIGURE 1. Temporal change in the pattern of the recurrence site. 768 HEAD & NECK DOI /HED APRIL 2017

3 RECURRENCE PATTERN OF PAPILLARY THYROID CANCER TABLE 3. Differences according to recurrence timing. <5y n y n 5 26 >10 y n 5 9 Age, y Female 82 (82.8%) 22 (84.6%) 6 (66.7%).487 Size, cm Extrathyroidal extension 81 (85.3%) 19 (82.6%) 0 (0.0%).166 Lymphovascular invasion 26 (27.7%) 0 (0.0%) 0 (0.0%).007 Multicentricity 53 (56.4%) 8 (38.1%) 0 (0.0%).119 Bilaterality 36 (38.7%) 7 (35.0%) 0 (0.0%).879 Lymph node metastasis 89 (93.7%) 20 (95.2%) 2 (100.0%) T1 15 (15.8%) 3 (13.0%) 1 (50.0%).248 T2 0 (0.0%) 1 (4.3%) 0 (0.0%) T3 68 (71.6%) 18 (78.3%) 1 (50.0%) T4 12 (12.6%) 1 (4.3%) 0 (0.0%) N0 6 (6.3%) 1 (4.8%) 0 (0.0%).804 N1a 67 (70.5%) 14 (66.7%) 1 (50.0%) N1b 22 (23.2%) 6 (28.6%) 1 (50.0%) I 51 (52.6%) 14 (53.8%) 7 (100.0%).271 III 28 (28.9%) 7 (26.9%) 0 (0.0%) IV 18 (18.6%) 5 (19.2%) 0 (0.0%) RAI (1) 85 (95.5%) 20 (95.2%) 3 (100.0%) Frequency of recurrence First recurrence site Local 94 (94.9%) 25 (96.2%) 7 (77.8%).135 Distant 5 (5.1%) 1 (3.8%) 2 (22.2%) Distant recurrences 7 (7.1%) 3 (11.5%) 3 (33.3%).039 Abbreviation: RAI, radioactive iodine ablation. 10-fold (to 50%) at 20 years postsurgery. This point was better demonstrated when the patients are split into 3 groups according to the time of recurrence (Table 3). Distant metastasis accounted for 7 cases (7.1%), 3 cases (11.5%), and 3 cases (33.3%) of recurrence within the first 5 years, between 5 and 10 years, and after 10 years postsurgery, respectively. These differences were significant (p 5.039). Thirteen patients (9.7%) experienced distant metastasis, of which 8 (6.0%) presented with initial recurrence. The mean time to initial distant recurrence was 80.6 months (range, months), whereas the mean time from initial local recurrence to distant recurrence was 47.8 months (range, months; n 5 5). Lung metastasis was found in all 13 patients (100%), and concurrent bone and brain metastasis was present in 2 patients (15.4%). Table 4 shows the difference between patient groups with and without distant recurrence. Univariate analysis revealed male sex, primary tumor size larger than 2 cm, higher, and more frequent recurrences as factors prognostic for distant recurrence. We then performed multivariate analysis after dichotomizing size, N classification, and frequency of recurrence (Table 4). The results identified more than 1 incidence of recurrence (odds ratio, 7.23) as an independent risk factor for distant metastasis. Because this study analyzed patients over a broad time frame, we also analyzed the results by splitting the patients into 3 groups according to time of diagnosis (Table 5) to address lead-time bias issues. We found a pattern of more recently diagnosed patients presenting with smaller tumor sizes, albeit the lack of statistical significance (p 5.218). There were statistically significant differences between the groups, indicating an increase in lymphovascular invasion (p 5.017), a decrease in TNM classification (p 5.043), a shortened mean time to recurrence (p <.001), and less frequent recurrence (p 5.002) for more recently diagnosed patients. There were no differences in other variables. DISCUSSION To the best of our knowledge, this study is the first to examine changes in the pattern of PTC recurrence over time. Our results reveal that, although most incidences of first recurrence occur in the lateral neck lymph nodes, the proportion of distant metastasis increases to 50% in the 20 years postsurgery, especially in those who experience frequent metastasis. According to the results, there is a 94% chance that a patient will experience only local recurrence, and about 80% of these cases will occur first in the lateral neck lymph nodes. The mean time to first recurrence was 48.2 months, suggesting that for the first 5 years (and in the absence of strong clinical suspicion) it may be more efficient to focus surveillance on the neck without the need for a chest CT or whole body positron emission tomography scan. This is consistent with a review published by Grant, 5 which estimates that, in 90% of cases, PTC relapses to the lymph nodes, and that it is typically identified during the first 5 years. HEAD & NECK DOI /HED APRIL

4 LEE ET AL. TABLE 4. Comparison of patients with and without distant recurrences. DM (1), n 5 13 DM ( ), n Multivariate analysis Variables Odds ratio 95% CI Age, y Male 7 (53.8%) 17 (14.0%).002* Male Size, cm <.001* > Extrathyroidal extension 8 (80.0%) 92 (84.4%).660 Lymphovascular invasion 3 (33.3%) 23 (21.9%).424 Multicentricity 3 (33.3%) 58 (54.2%).305 Bilaterality 3 (33.3%) 40 (38.1%) T1 1 (10.0%) 18 (16.4%).678 T2 0 (0.0%) 1 (0.9%) T3 9 (90.0%) 78 (70.9%) T4 0 (0.0%) 13 (11.8%) Lymph node metastasis 8 (80.0%) 103 (95.4%).108 N0 2 (20.0%) 5 (4.6%) <.001* N1b N1a 1 (10.0%) 81 (75.0%) N1b 7 (70.0%) 22 (20.4%) I 7 (58.3%) 65 (55.1%) III 3 (25.0%) 32 (27.1%) IV 2 (16.7%) 21 (17.8%) Frequency of recurrence * Multiple First recurrence site Local 5 (38.5%) 121 (100.0%) <.001* Distant 8 (61.5%) 0 (0.0%) Abbreviations: DM, distant metastasis; CI, confidence interval. * These figures indicate statistical significance. TABLE 5. Differences according to the time of diagnosis. Before 2000 n n 5 74 After 2010 n 5 40 Age, y Sex Female:male 16:4 (80.0%) 63:11 (85.1%) 31:9 (77.5%).577 Size, cm Extrathyroidal extension (1) 6 (85.7%) 61 (84.7%) 33 (82.5%).916 Lymphovascular invasion (1) 0 (0.0%) 11 (15.7%) 15 (38.5%).017 Multicentricity (1) 2 (33.3%) 36 (50.7%) 23 (59.0%).458 Bilaterality (1) 2 (33.3%) 24 (34.8%) 17 (43.6%).685 Lymph node metastasis 8 (100.0%) 67 (95.7%) 36 (90.0%).441 T1 1 (12.5%) 11 (15.3%) 7 (17.5%).977 T2 0 (0.0%) 1 (1.4%) 0 (0.0%) T3 7 (87.5%) 52 (72.2%) 28 (70.0%) T4 0 (0.0%) 8 (11.1%) 5 (12.5%) N0 0 (0.0%) 3 (4.3%) 4 (10.0%).062 N1a 4 (50.0%) 55 (78.6%) 23 (57.5%) N1b 4 (50.0%) 12 (17.1%) 13 (32.5%) I 14 (82.4%) 41 (56.2%) 17 (42.5%).043 III 1 (5.9%) 22 (30.1%) 12 (30.0%) IV 2 (11.8%) 10 (13.7%) 11 (27.5%) Mean time to recurrence, mo <.001 Frequency of recurrence First recurrence site 18 (90.0%) 71 (95.9%) 37 (92.5%).413 Local Distant 2 (10.0%) 3 (4.1%) 3 (7.5%) Distant recurrences 4 (20.0%) 6 (8.1%) 3 (7.5%) HEAD & NECK DOI /HED APRIL 2017

5 RECURRENCE PATTERN OF PAPILLARY THYROID CANCER The cost of postoperative surveillance and the relatively benign nature of PTC means that many clinicians (and sometimes the patients) will stop follow-up visits between 5 and 10 years after initial treatment. Although the risk of recurrence does decrease after this time, the chance of distant metastasis in those who do experience recurrence increases. This is more prominent in male patients with larger tumors, lateral neck node metastasis, and a history of multiple recurrences. Although other studies show that advanced disease tends to predict recurrence, no consensus has been reached. A study by Ito et al 6 reported that age, extrathyroidal extension, tumor size, and were independent factors predictive of recurrence, whereas another group from Korea 7 cited tumor size, bilaterality, extrathyroidal extension,, and vascular invasion were predictive of recurrence. One of the patients examined herein presented with distant metastasis 12 years after the initial recurrence, which emphasizes the importance of a long surveillance period. Ito et al 8 reported a mean follow-up period of 76 months from initial surgery to the detection of distant recurrence, whereas another group from Taiwan 9 reported that it was years. Moreover, Mazzaferri and Jhiang 10 reported that, in 19.3% of cases, recurrence was detected more than 10 years after original treatment, whereas Durante et al 3 reported no recurrences after 8 years. These wide discrepancies can be explained by the characteristics of the different patient groups. For example, the median tumor size reported by Durante et al 3 (15 mm) was smaller than that reported by Mazzaferri and Jhiang 10 (2.5 cm). Likewise, in the former, 25% of patients had lymph node metastasis at presentation compared with 42% in the latter. The patient group in the present study was closer to that of Mazzaferri and Jhiang 10 in terms of mean tumor size (2.35 cm) and percentage of patients with lymph node metastasis at initial presentation (92%), of whom 6.7% experienced a recurrence after 10 years. The findings presented herein (coupled with those of previous reports) suggest that, in many cases, patients with PTC should be followed for longer than 10 years after initial treatment. Tumor stage, lymphovascular invasion, mean time to recurrence, and frequency of recurrence showed statistical significance with respect to the time of initial diagnosis. Before 2000, the pathologic reporting system was less specific and did not contain items such as lymphovascular invasion, which is why there were no such findings in that period. The difference in TNM classification reflects the increase in the mean age of the patient groups, which would inevitably lead to more stage I tumors in the younger groups before Lead-time bias could also affect the mean time and frequency of recurrence, both of which become shorter and lower as patients are diagnosed more recently. Although we were aware of the bias, we thought it was more important to emphasize that, when a patient presents with more than 1 recurrence event, clinicians should always consider the possibility of distant metastasis. Other factors did not differ according to time of diagnosis. This study had several limitations. First, in common with most descriptive and retrospective studies, neither lead-time nor selection bias could be corrected. Although the postoperative surveillance modality, including serum Tg assay, ultrasound, and whole body scan remained constant, there were differences in the resolution of imaging/ assay and the interval of follow-up. The difference in surveillance interval was mostly caused by changes in the national insurance policy, which resulted in higher cost in the earlier study periods and, therefore, longer intervals between surveillances. Second, not all patients received initial treatment at our institution. Consequently, pathologic data for 15 patients were missing and the effectiveness of the initial operation could not be guaranteed. Finally, the relatively small number of subjects in the distant metastasis group means that the results may not be generalizable. Although the majority of patients with PTC do not experience recurrences, it is important to follow the small proportion of patients that do. The findings presented herein may enable clinicians to provide more effective and efficient postoperative follow-up with respect to who, when, and where to focus regarding metastasis. This applies particularly to male patients with a tumor >2 cmatinitial presentation, lateral neck node metastasis, and (most importantly) multiple incidences of local recurrence. While concentrating on detecting local recurrences in this patient group during the early years after initial treatment, the use of diagnostic RAI or positron emission tomography scan to detect distant metastasis should be considered after 10 years of follow-up, with a primary focus on the lungs. To obtain a more generalizable result, however, a prospective study of a large cohort is warranted. REFERENCES 1. Sawka AM, Thephamongkhol K, Brouwers M, Thabane L, Browman G, Gerstein HC. Clinical review 170: a systematic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for welldifferentiated thyroid cancer. J Clin Endocrinol Metab 2004;89: Mazzaferri EL, Kloos RT. Clinical review 128: current approaches to primary therapy for papillary and follicular thyroid cancer. 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