Abstract
Although the outcomes of active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) are generally excellent, some patients undergo conversion surgery for various reasons, including disease progression. We studied the outcomes of PTMC patients who underwent AS, who underwent conversion surgery after AS, and who underwent immediate surgery. Between 2005 and 2019, 4,635 patients were diagnosed with low-risk cT1aN0M0 PTMC at Kuma Hospital: 2,896 opted for AS (AS group) and 1,739 underwent immediate surgery (Surgery group). In the AS group, 242 patients underwent conversion surgery (Conversion group): 72 owing to disease progression (Conversion-prog group) and 170 for other reasons (Conversion-non-prog group). Of the 1,739 patients in the Surgery group, 1,625 had no high-risk features (Surgery-low-risk group). Locoregional recurrence (LRR) occurred in 9, 1, 1, and 0 patient in the Surgery-low-risk group, the Conversion-prog group, the AS group, and the Conversion-non-prog group, respectively. The LRR rate of the AS group was significantly lower than that of the Surgery-low-risk group (0.1% vs. 0.7% at 10 years, p = 0.006). Additionally, the LRR rate of the Conversion group (0.6% at 10 years, p = 0.741) and that of the Conversion-prog group (3.3% at 10 years, p = 0.103) did not significantly differ from the LRR of the Surgery-low-risk group. As the postoperative prognosis of patients with progressive PTMC who underwent conversion surgery did not significantly differ from that of patients who underwent immediate surgery, we think that AS may have resulted in efficient identification of the small proportion of patients with progressive PTMC that require surgical treatment.
SINCE active surveillance (AS) for low-risk papillary thyroid microcarcinoma (cT1aN0M0, PTMC) was started in Kuma Hospital (Kobe, Japan) in 1993 and Cancer Institute Hospital (Tokyo, Japan) in 1995, favorable outcomes of the management have been reported from these two institutions [1-7]. This management for low-risk PTMC was adopted in consensus statements, guidelines, and a position paper by the Japan Association of Endocrine Surgery, Japan Thyroid Association [8, 9], and American Thyroid Association [10]. Thereafter, studies showing promising results were reported also from countries other than Japan [11-17].
During AS, some patients undergo conversion surgery due to disease progression, surgical indication of associated thyroid or parathyroid diseases, and change in patients’ preference, or other reasons [18]. One concern is that conversion surgery may be associated with a higher incidence of complications and poorer oncological outcomes because of slight disease progression at the time of surgery.
In the present study, therefore, we investigated the difference in locoregional recurrence (LRR) rates among patients who underwent AS, those who received conversion surgery after AS, and those who underwent immediate surgery without AS.
Materials and Methods
Patients
Between 2005 and 2019, 4,635 patients were clinically diagnosed with low-risk cT1aN0M0 PTMC by cytology (Bethesda V or VI) and imaging studies. In the present study, the initial tumor diameter was defined as the average of the first two measurements to minimize observer variation. Low-risk PTMC is defined as PTC of ≤10 mm in maximum diameter without invasion to surrounding organs, clinical lymph node metastasis, distant metastasis, or high-grade cytology [8, 9]. Tumor status was evaluated by ultrasound examination, and other imaging studies were added, if indicated. In our study, AS of clinically low-risk PTMC was a management plan of watchful observation, and conversion surgery was performed at an appropriate time, in cases of disease progression. A flowchart demonstrating the management of 4,635 patients with cT1aN0M0 PTMC enrolled in this study is presented in Fig. 1. Of these, 2,896 patients (62.5%) underwent active surveillance for 1 year or longer (AS group) and 1,739 (37.5%) underwent surgery within 1 year after the diagnosis (Surgery group).
The Surgery group was further divided into two categories based on the following explanation. We found 106 patients to have adhesions or cancer invasion of nearby organs at surgery. All of them were suspected of possible tumor invasion to the trachea or the recurrent laryngeal nerve on imaging studies (widely attached to the trachea and lack of normal rim between the tumor and the course of the recurrent laryngeal nerve [19]), although clinical evidences of invasion such as the protrusion to the tracheal lumen or vocal cord paralysis were lacking. Another eight patients were suspected of having lateral node metastasis on ultrasound examination, although not diagnosed on cytology. These 114 patients were still classified as cT1aN0M0, because the evidence for upgrading their TNM stage was lacking; however, the attending physicians recommended immediate surgery. In this study, they were classified as the Surgery-high-risk group and excluded from further analyses. The remaining 1,625 did not have such features, and they were classified as the Surgery-low-risk group. We considered that analyzing these two groups together is not feasible for the scope of the present study. Therefore, we have performed further analyses only on the Surgery-low-risk group.
Of the 2,896 patients in the AS group, 242 underwent surgery more than 1 year after the initiation of AS (Conversion group). Of these 242 patients, 72 underwent conversion surgery for disease progression as described in the next section titled “Evaluation of PTMC progression”, and they were classified as the Conversion-prog group. The remaining 170 underwent conversion surgery for reasons other than disease progression, such as surgical indication of associated thyroid or parathyroid diseases, patients’ change of mind, and physician preference (Conversion-non-prog group).
Evaluation of PTMC progression
PTMC is considered to have grown when the tumor size increased by ≥3 mm. At this point, conversion surgery is discussed with patients. If patients prefer persisting with AS, we continue with AS, possibly until the tumor size reaches ≥13 mm. For patients showing novel suspicious lymph nodes on ultrasound, we perform fine-needle aspiration cytology with measurement of thyroglobulin level in the washout of the needle. If a node is diagnosed with metastasis, surgery is recommended.
Postoperative follow-up
After surgery, patients were advised to have regular check-ups at our outpatient clinic at least once a year, similar to those under AS. Follow-up examinations included blood tests and cervical ultrasound. Locoregional recurrence was defined as cytologically diagnosed recurrence to regional lymph nodes or appearance of PTC in the remnant thyroid. For patients referred to other hospitals, questionnaires were sent once a year to evaluate their conditions. Those with no history of hospital visit for more than 2 years or no response to the questionnaire were considered to be “lost to follow up”.
Study design
This was a retrospective, single-center, cohort study.
Statistical analyses
Stat Flex software (Artec, Osaka, Japan) was used to perform the chi-squared test and Mann–Whitney U test to compare the variables. For time-series analyses, the Kaplan–Meier method and log-rank test were used for univariate analysis. Statistical p-value <0.05 was considered statistically significant.
Statement of human rights
This study was approved by the Ethics Committee of Kuma Hospital (No. 20200709-1).
Results
Follow-up period
The follow-up periods (median and ranges) after PTMC diagnosis in the AS, Conversion-non-prog, Conversion-prog, and Surgery-low-risk groups were 5.6 (1.0–15.7), 8.4 (1.9–15.7), 8.4 (2.6–14.7), and 7.9 (1.0–16.2) years, respectively. The follow-up periods (median and ranges) after surgery in the Conversion-non-prog, Conversion-prog, and Surgery-low-risk groups were 5.4 (0.1–14.5), 4.0 (0.3–12.5), and 7.6 (0.6–16.0) years, respectively. A total of 617 patients (13.6%) were lost to follow up: 404 (13.9%) in the AS group and 213 (13.1%) in the Surgery-low-risk group.
Events
Regarding recurrence of the disease after surgery, six patients had recurrence of PTC in the residual thyroid, which occurred exclusively in the Surgery-low-risk group. In addition, one patient in the Conversion-prog group and three in the Surgery-low-risk group developed lymph node recurrence in the lateral compartment. None of the patients in the Conversion-non-prog group showed PTC recurrence. To date, none of the patients in the present series have shown distant metastasis or died of thyroid carcinoma, however, one patient in the Conversion-non-prog group and 28 patients in the Surgery-low-risk group died of reasons other than thyroid carcinoma.
Comparison of patients between different groups
As shown in Table 1, compared to the patients in the Surgery-low-risk group, those in the AS group were significantly older (median, 58 vs. 55 years; p < 0.01), more frequently had multiple tumors (14.1% vs. 11.1%; p < 0.01), and had smaller-sized tumors (median, 7.0 vs. 8.0 mm; p < 0.01). Compared to the patients in the Surgery-low-risk group, those in the Conversion group had larger-sized tumors (median, 9 vs. 8 mm; p < 0.01) at surgery, more frequently received lateral lymph node dissection (5.8% vs. 0%; p < 0.01), and were more frequently positive for pathological lymph node metastasis (33.9% vs. 27.4%; p < 0.01) (Table 2). Compared to the patients in the Surgery-low-risk group, those in the Conversion-prog group had larger-sized tumors (median, 11.0 vs. 8.0 mm; p < 0.01) at surgery, more frequently received lateral lymph node dissection (19.4% vs. 0%; p < 0.01), and were more frequently positive for lymph node metastasis on pathology (52.7% vs. 27.4%; p < 0.01). Moreover, the tumors of patients in the Conversion-prog group showed higher cell proliferating activity (evaluated by the Ki-67 labeling index [LI] [20, 21]) (26.6% vs. 8.3%; p < 0.01) (Table 3).
Table 1
Clinical features at presentation of the patients in the AS and Surgery-low-risk groups
| Variables |
AS group
(n = 2,896) |
Surgery-low-risk group
(n = 1,625) |
AS vs. Surgery- low-risk
p-value |
| Sex |
Male |
372 (12.8%) |
182 (11.2%) |
p = 0.11 |
| Female |
2,524 (87.2%) |
1,443 (88.8%) |
| Age |
Median
(range) |
58
(20–92) |
55
(20–92) |
p < 0.01 |
| Chronic thyroiditisa |
Yes |
1,025 (35.4%) |
530 (32.6%) |
p = 0.06 |
| Graves’ disease |
Yes |
191 (6.6%) |
129 (7.9%) |
p = 0.09 |
| Family history of PTCb |
Yes |
102 (3.5%) |
60 (3.7%) |
p = 0.77 |
| Multiplicity at diagnosis |
Yes |
408 (14.1%) |
180 (11.1%) |
p < 0.01 |
| Tumor size at the PTC diagnosisc (mm) |
Median
(range) |
7.0
(2.0–10.0) |
8.0
(2.5–11.0) |
p < 0.01 |
Abbreviations: AS, active surveillance; PTC, papillary thyroid carcinoma
Data are expressed as numbers (percentages) or as median (ranges) as indicated.
a Positive for anti-thyroglobulin antibody and/or thyroid peroxidase antibody
b One or more first-degree relatives had PTC.
c Evaluated on imaging studies (mainly ultrasound)
Table 2
Surgical and pathological features in the Conversion and Surgery-low-risk groups
| Variables |
Conversion group
(n = 242) |
Surgery-low-risk group
(n = 1,625) |
Conversion vs. Surgery-low-risk
p-value |
| Age at operation |
Median
(range) |
55
(22–84) |
55
(20–92) |
p = 0.47 |
| Period to surgery |
Median
(range) |
2.8
(1.0–11.3) |
0.3
(0.0–0.9) |
p < 0.01 |
| Tumor size at the operation (mm) |
Median
(range) |
9
(2–19) |
8
(3–18) |
p < 0.01 |
| Extent of thyroidectomy |
Total thyroidectomy |
118 (48.8%) |
716 (44.1%) |
p = 0.17 |
| Lobectomy |
124 (51.2%) |
909 (55.9%) |
| Lymph node dissection |
Central only |
228 (94.2%) |
1,625 (100.0%) |
p < 0.01 |
| Lateral |
14 (5.8%) |
0 (0.0%) |
| Invasion to the trachea |
Partial excision
or window resection |
0 (0.0%) |
0 (0.0%) |
— |
| Invasion to the RLN |
Resection of the RLN |
0 (0.0%) |
0 (0.0%) |
— |
| pN |
pN0 |
160 (66.1%) |
1,179 (72.6%) |
p < 0.01 |
| pN1a |
68 (28.1%) |
446 (27.4%) |
| pN1b |
14 (5.8%) |
0 (0.0%) |
| Ki-67 LIa |
High (>5%) |
25 (11.9%) |
104 (8.3%) |
p = 0.09 |
| Low (≤5%) |
185 (88.1%) |
1,143 (91.7%) |
| Unknown |
32 |
378 |
Abbreviations: Conversion, conversion surgery; Surgery, immediate surgery; Central, central lymph node dissection; Lateral, lateral lymph node dissection; RLN, recurrent laryngeal nerve; LI, labeling index
Data are expressed as numbers (percentages) or as median (ranges) as indicated.
a We performed the immunostaining using surgical specimens.
Following partial resection and window resection of the trachea, the trachea was repaired with direct suture and air-tight tracheocutaneostomy followed by closure with local skin flap later, respectively. Following resection of the RLN, the nerve was reconstructed with ansa cervicalis to RLN anastomosis, free nerve grafting, or direct suture.
Table 3
Surgical and pathological features in the Conversion-prog and Surgery-low-risk groups
| Variables |
Conversion-prog group
(n = 72) |
Surgery-low-risk
(n = 1,625) |
Conversion prog vs. Surgery-low-risk
p-value |
| Age at operation |
Median
(range) |
54
(27–84) |
55
(20–92) |
p = 0.71 |
| Period to surgery |
Median
(range) |
3.6
(1.3–11.3) |
0.3
(0.0–0.9) |
p < 0.01 |
Tumor size at the operation
(mm) |
Median
(range) |
11.0
(4.0–19.0) |
8.0
(3.0–18.0) |
p < 0.01 |
| Extent of thyroidectomy |
Total thyroidectomy |
36 (50.0%) |
716 (44.1%) |
p = 0.32 |
| Lobectomy |
36 (50.0%) |
909 (55.9%) |
| Lymph node dissection |
Central only |
58 (80.6%) |
1,625 (100.0%) |
p < 0.01 |
| Lateral |
14 (19.4%) |
0 (0.0%) |
| Invasion to the trachea |
Partial excision
or window resection |
0 (0.0%) |
0 (0.0%) |
— |
| Invasion to the RLN |
Resection of the RLN |
0 (0.0%) |
0 (0.0%) |
— |
| pN |
pN0 |
34 (47.2%) |
1,179 (72.6%) |
p < 0.01 |
| pN1a |
24 (33.3%) |
446 (27.4%) |
| pN1b |
14 (19.4%) |
0 (0.0%) |
| Ki-67 LIa |
High (>5%) |
17 (26.6%) |
104 (8.3%) |
p < 0.01 |
| Low (≤5%) |
47 (73.4%) |
1,143 (91.7%) |
| Unknown |
8 |
378 |
Abbreviations: Conversion-prog, conversion surgery due to carcinoma progression; Surgery, immediate surgery; Central, central lymph node dissection; Lateral, lateral lymph node dissection; RLN, recurrent laryngeal nerve; LI, labeling index
Data are expressed as numbers (percentages) or as median (ranges) as indicated.
a We performed the immunostaining using surgical specimens.
Fig. 2 indicates the cumulative incidence of locoregional recurrence in patients who opted for AS vs. patients who underwent immediate surgery and had low-risk surgical features. The 10-year LRR rate of patients in the AS group was 0.1%, which was significantly better (p = 0.006) than that of those in the Surgery-low-risk group (0.7%).
Then, we compared the LRR rate between the Surgery-low-risk and the entire Conversion group. As shown in Fig. 3, the 10-year LRR rate of patients in the Conversion group was 0.6%, which did not differ from that of those in the Surgery-low-risk group (0.7%, p = 0.741). Further, the 10-year LRR rate of patients in the Conversion-prog group was 3.3%, which did not significantly differ from that of those in the Surgery-low-risk group (0.7%, p = 0.103) (Fig. 4). Only one of the 72 patients in the Conversion-prog group demonstrated LRR.
Discussion
We initiated AS for low-risk PTMC and reported oncological safety and lower incidences of unfavorable events compared to those of immediate surgery [6, 22, 23]. However, a small proportion of patients on AS underwent conversion surgery for various reasons, including disease progression [6, 18]. Therefore, one concern is the possible poorer outcomes owing to slightly advanced disease in patients with conversion surgery. In the present study, therefore, we investigated whether the prognosis (LRR) of the AS group and the Conversion group (especially, the Conversion-prog group) differed from that of the Surgery-low-risk group.
To date, nine patients in the Surgery-low-risk group and only one in the AS group have shown LRR after surgery (conversion surgery for the AS group). Using the Kaplan-Meier method for analysis, we found that the AS group had a significantly lower LRR rate than that of the Surgery-low-risk group, although both had very low recurrence rates (0.1% vs. 0.7% at 10 years, p = 0.006). In Japan, even for clinical node-negative PTC, surgeons have routinely performed central node dissection (CND) together with thyroidectomy in consideration of the documented rates of the high frequency of pathological lymph node metastasis and to avoid recurrence around resection [24, 25]. In the present series, all operated patients underwent CND, which may have contributed to the low LRR. Conversion surgery was performed for 242 patients: 72 for disease progression and the remaining 170 for other reasons. We compared LRR of the Surgery-low-risk group with that of the entire Conversion group and Conversion-prog group. The 10-year LRR rates of the entire Conversion group and the Conversion-prog group were 0.6% and 3.3%, respectively, and did not significantly differ from that of the Surgery-low-risk group. These findings indicate that delayed surgery of patients after AS do not worsen the LRR of low-risk PTMC patients, even though the surgery was performed due to disease progression. Further, the proportion of patients in the AS group who underwent conversion surgery was low, at 8.3% (242/2,896), indicating that AS (and conversion surgery, if progressed) is a very appropriate strategy for the management of low-risk PTMC patients.
In our series, PTMCs in the AS group were multiple in number more often than those in the Surgery-low-risk group. If patients with multiple PTMCs undergo surgery, total thyroidectomy is performed usually, which increases the risk of adverse events such as recurrent laryngeal nerve paralysis and hypoparathyroidism. However multifocal PTC is not necessarily associated with poorer outcomes compared to unifocal PTC [6]. Therefore, attending physicians may have recommended AS for these patients. Tumors in the Conversion-prog group were larger at surgery and had higher cell proliferation index (evaluated by Ki-67 LI) than those in the Surgery-low-risk group. Hirokawa et al. reported that Ki67-LI was associated with tumor enlargement in low-risk PTMCs [21], which was consistent with our findings. This also indicates AS management resulted in the selection of patients with progressive PTMC, requiring surgery.
Previous reports showed that BRAF mutations affect the prognosis in PTC [26]. However, there are no mature data on whether BRAF mutations are predictive of PTMC enlargement and prognosis. Yabuta et al. reported that, although the number of patients was small, BRAF mutations were not associated with tumor growth in PTMC [27]. Xing et al. demonstrated that PTC having both BRAF and TERT mutations showed a dire prognosis [28], however, for PTMC, previous studies reported that TERT mutations were very rarely detected and did not affect the prognosis of patients with PTMC [27, 29]. To date, therefore, no molecular markers predicting PTMC prognosis have been identified. Fukuoka et al. demonstrated that PTMC with rich vascularity on ultrasound examination had significantly higher rate of tumor enlargement, but the majority of tumor with initially rich vascularity demonstrated decreased blood supply during the follow-up [30], and the authors regarded PTMC with rich vascularity to also be a candidate of AS. Therefore, at least at present, AS is the only strategy to discriminate progressive cases from others.
This study has some limitations. This is a retrospective single-center cohort study, and randomization between the AS and Surgery-low-risk groups was not performed. Although the comparison between patients in the Conversion-prog and those in the Surgery-low-risk was the most important issue in this study, the number of patients in the Conversion-prog group was small (72 patients). Therefore, further analyses using the data of a larger number of patients are desirable. The observation period may not have been sufficiently long for definite conclusions. Also, there are some selection biases in forming the groups in this study, and this may be attributed to the subjective view of attending physicians, which may contribute to some extent in decision-making. Despite the aforementioned limitations, present study clearly demonstrated the safety and relevance of AS in identifying patients with progressive PTMC requiring surgical treatment.
In summary, for low-risk PTMC, the LRR rate was generally low, and the postoperative prognosis of patients who underwent surgery after AS because of disease progression did not differ from that of patients who underwent immediate surgery. Therefore, we can conclude that, when patients with clinically low-risk PTMC are selected to be put under AS, detection of progression is an appropriate management technique. AS may, therefore, be an efficient and practical management plan allowing for the identification of patients with progressive PTMC requiring surgery.
Acknowledgments
We would like to thank Mr. Makoto Kawakami and Masahiko Ota for their contribution to the preparation of this manuscript.
Author Contributions
Makoto Fujishima accumulated data, performed statistical analysis, and contributed in writing the manuscript; Akira Miyauchi proposed and conducted AS management for PTMC patients, constructed the present study plan, and contributed in writing the manuscript; Takumi Kudo extracted data from the electronic medical record system. All of the present authors saw the patients at outpatient clinic and checked the extracted data for the present study. All authors have seen and approved the final version of the manuscript.
Author Disclosure Statement
The authors state that there are no conflicts of interest related to this study.
Funding Statement
No funding was received for this study.
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