Key Points
Question
What are the surgical, pathologic, and oncologic outcomes of patients who underwent conversion surgery (CS) following active surveillance (AS) for low-risk papillary thyroid carcinoma?
Findings
In this cohort study of 55 patients with low-risk papillary thyroid carcinoma, there were no clinically meaningful differences in the rate of surgical complications between patients who underwent CS secondary to disease progression and those who underwent CS for reasons unrelated to disease progression. Additionally, there were no clinically meaningful differences in oncologic outcomes when the disease-progression CS cohort was compared with a matched cohort of patients treated with an upfront initial surgical approach.
Meaning
In this study, CS for patients with disease progression during AS had favorable rates of surgical complications and was associated with excellent survival outcomes and low recurrence rates.
This cohort study examines the surgical, pathologic, and oncologic outcomes of patients with low-risk papillary thyroid carcinoma who underwent conversion surgery after a period of active surveillance.
Abstract
Importance
The outcomes of patients with low-risk thyroid cancer who undergo surgery following a period of active surveillance (AS) are not well-defined.
Objective
To evaluate surgical, pathologic, and oncologic outcomes among patients undergoing conversion surgery (CS) following AS for low-risk papillary thyroid carcinoma.
Design, Setting, and Participants
In this cohort study, patients who underwent CS for disease progression were compared with patients who underwent CS without disease progression and with a propensity score–matched cohort of patients who underwent initial surgery (IS). The median (IQR) postsurgical follow-up time was 40.3 (18.0-59.0) months. Patients were treated at a quaternary cancer referral center in the United States.
Exposures
Surgery.
Main Outcomes and Measures
Surgical complications, pathologic characteristics, overall survival (OS), and recurrence-free survival (RFS).
Results
Of 550 patients who underwent AS, 55 (10.0%) had CS, of whom 39 (7.1%) had surgery due to suspected disease progression (median [IQR] age, 48 [39-56] years; 32 [82.1%] female). There were no clinically meaningful differences in rates of surgical sequalae between the progression CS group (12 of 39 [30.7%]) and the nonprogression CS group (7 of 16 [43.8%]) (Cramer V, 0.2; 95% CI, 0.01-0.5). The 5-year OS was 100% (95% CI, 100%-100%) in both the disease-progression CS cohort and the IS cohort. Although the cohort of patients undergoing CS after disease progression was by definition a subset with more aggressive tumor behavior, no clinically meaningful differences were observed in the rates of regional recurrence (2 of 39 [5.1%] vs 0 of 39 patients with IS), local recurrence (0 patients), distant metastasis (0 patients), or disease-specific mortality (0 patients) when compared with the matched IS group. Five-year RFS rates were similar: 100% in the IS group and 86% (95% CI, 70%-100%) in the CS group.
Conclusions and Relevance
In this cohort study, CS for suspected disease progression was associated with surgical and oncologic outcomes similar to IS, supporting the feasibility and safety of AS for patients with low-risk papillary thyroid carcinoma.
Introduction
The global rise in the incidence of differentiated thyroid cancer is largely attributed to the increased incidental detection of micropapillary thyroid carcinomas (MPTC), many of which are potentially overtreated, as reflected by the unchanged mortality rates.1,2,3 To address this concern, active surveillance (AS) of MPTC lacking high-risk features—such as radiographic nodal metastasis, distant metastasis, and significant extrathyroid extension (ETE)—was introduced in 2 Japanese hospitals during the mid-1990s.4 With favorable outcomes marked by low rates of tumor enlargement and clinically apparent lymph node (LN) involvement, this approach was subsequently integrated into clinical guidelines in Japan in 2010 and in the United States in 2015.5
In the 10% to 20% of patients with low-risk PTC who develop signs of tumor growth during AS, surgery is performed in a delayed fashion. There are limited data describing the outcomes of patients who undergo delayed surgery after a period of AS.6,7 The most recent update from Kuma Hospital in Japan6 highlights the outcomes of 3222 patients who underwent AS, with 394 (12.2%) eventually undergoing conversion surgery (CS). Notably, these patients exhibited low rates of lymph node metastasis and favorable survival outcomes. This study reports the characteristics and oncologic outcomes of patients undergoing CS after AS compared with patients undergoing initial surgery (IS).
Methods
Following institutional review board approval by the Memorial Sloan Kettering Cancer Center (MSKCC) institutional review board, this cohort study examined 550 patients with low-risk PTC who underwent AS at MSKCC followed up between January 2004 and December 2022, with a median time of AS of 3.6 (1.5-5.6) years, using eligibility criteria as previously described by Tuttle et al.8 A waiver of informed consent was approved for this minimal risk retrospective data collection protocol by the MSKCC institutional review board and privacy board. Verifiable data on race and ethnicity were not available and not collected or analyzed. This analysis focuses on patients who underwent conversion surgery (CS) after a period of AS, investigating their indications for surgery, tumor doubling time, intraoperative findings, surgical complications, and pathologic features. Additionally, a comparison was made between patients who underwent CS due to PTC progression and those who chose surgery for reasons unrelated to disease progression.
Next, propensity score matching was used to generate a matched IS cohort from a MSKCC dataset of 8559 patients with differentiated thyroid cancer treated between January 1985 and December 2020.9 Age, gender, tumor size (in centimeters), surgical procedure type, and follow-up time were defined as matching parameters. Follow-up time was defined as time from surgery to date of last known status. Nearest-neighbor matching was used at a 1:1 ratio using the R version 4.2.1 (R Project for Statistical Computing) package MatchIt. Each unit was sequentially matched using the closest propensity score. Standardized mean differences were calculated between groups to assess matching balance, and further adjustments were made after matching. The study was carried out in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.
Statistical Analysis
Statistical analysis was completed using R version 4.2.1. Comparisons between all groups before and after matching were determined using Cramer V for categorical variables. Effect size was interpreted as low (Cramer V, 0.10-0.30), moderate (Cramer V, >0.30-0.50), and high (Cramer V, >0.50). Similarly, associations between continuous variables were measured using η2. Small effect sizes have a value around 0.00, medium 0.06, and strong 0.14. The Kaplan-Meier method was used to estimate overall survival and recurrence-free survival.
Results
AS Cohort: CS
In the cohort of 550 patients being followed up with AS at MSKCC, 55 patients (10.0%) underwent CS after a period of AS. Clinical suspicion for disease progression was the reason for CS in 39 patients (7.1%), while 16 patients (2.9%) elected to have surgery for reasons unrelated to their PTC (Table 1).
Table 1. Patient Characteristics, Preoperative Characteristics, Tumor Staging, Surgical Sequelae.
| Characteristic | Patients by indication for conversion surgery, No. (%) | Effect size (95% CI)a | |
|---|---|---|---|
| Unrelated to disease progression (n = 16) | Disease progression (n = 39) | ||
| Age, median (IQR), y | 52 (42 to 60) | 48 (39 to 56) | 0.01 (−0.02 to 0.11) |
| Gender | |||
| Female | 10 (62.5) | 32 (82.1) | 0.21 (0.01 to 0.49) |
| Male | 6 (37.5) | 7 (17.9) | |
| Indication for surgery | |||
| Disease progressionb | |||
| Tumor growth | 0 | 19 (48.7) | NA |
| Suspicion of ETE | 0 | 18 (46.2) | NA |
| Nodule abutting capsule | 0 | 1 (2.6) | NA |
| Positive LN in lateral neck | 0 | 4 (10.3) | NA |
| Suspicious lateral LN, nonbiopsy proven | 0 | 1 (2.6) | NA |
| Not related to disease progressionb | |||
| Patient preference | 8 (50.0) | 0 | NA |
| Insurance issues | 2 (12.5) | 0 | NA |
| Graves disease | 1 (6.3) | 0 | NA |
| Contralateral parathyroid adenoma | 1 (6.3) | 0 | NA |
| To meet qualifications to be a kidney donor | 1 (6.3) | 0 | NA |
| Planned delayed intervention | 1 (6.3) | 0 | NA |
| To meet qualifications for kidney transplant | 1 (6.3) | 0 | NA |
| Patient planning pregnancyc | 1 (6.3) | 0 | NA |
| Growth of benign nodules | 1 (6.3) | 0 | NA |
| Patients with stable tumor volume during active surveillance | 10 (62.5) | 13 (33.3) | 0.27 (0.03 to 0.53) |
| Maximum diameter at final follow-up prior to surgery, median (IQR), cm | 0.7 (0.5 to 1.2) | 1.0 (0.8 to 1.3) | 0.03 (−0.02 to 0.22) |
| Preoperative imaging | |||
| US | 14 (87.5) | 30 (76.9) | 0.12 (0.00 to 0.32) |
| CT | 2 (12.5) | 9 (23.1) | |
| Procedure | |||
| Lobectomy and isthmusectomy | 9 (56.3) | 25 (64.1) | 0.07 (0.00 to 0.34) |
| Total thyroidectomy | 7 (43.8) | 14 (35.9) | |
| pT stage | |||
| 1a | 12 (75.0) | 21 (53.8) | 0.30 (0.20 to 0.50) |
| 1b | 3 (18.8) | 15 (38.5) | |
| 2 | 0 | 1 (2.6) | |
| 3bd | 1 (6.3) | 1 (2.6) | |
| 4ae | 0 | 1 (2.6) | |
| pN stage | |||
| 0 | 15 (93.8) | 25 (64.1) | 0.30 (0.16 to 0.47) |
| 1a | 1 (6.3) | 9 (23.1) | |
| 1b | 0 | 5 (12.8) | |
| Overall AJCC eighth edition stage | |||
| I | 15 (93.8) | 37 (94.9) | 0.02 (0.00 to 0.30) |
| II | 1 (6.3) | 2 (5.1) | |
| Histology | |||
| Classic PTC | 9 (56.3) | 15 (38.5) | 0.26 (0.19 to 0.53) |
| Classic PTC, infiltrative follicular subtype | 0 | 1 (2.6) | |
| Classic PTC, with oncocytic features | 0 | 1 (2.6) | |
| Classic PTC, with tall cell features | 3 (18.8) | 5 (12.8) | |
| Tall cell subtype | 4 (25.0) | 13 (33.3) | |
| Follicular subtype | 0 | 4 (10.3) | |
| Surgical sequelae | 7 (43.8) | 12 (30.8) | 0.20 (0.01 to 0.50) |
| Sequela typef | |||
| Transient hypocalcemia | 4 (25.0) | 7 (17.9) | 0.08 (0.00 to 0.34) |
| VC permanent paralysisg | 0 | 1 (2.6) | 0.09 (0.06 to 0.17) |
| Seroma | 1 (6.3) | 2 (5.1) | 0.02 (0.00 to 0.31) |
| Wound infection (cellulitis) | 2 (12.5) | 0 | 0.30 (0.18 to 0.51) |
Abbreviations: AJCC, American Joint Commission on Cancer; CT, computed tomography; ETE, extrathyroidal extension; LN, lymph node; PTC, papillary thyroid carcinoma; US, ultrasound; VC, vocal cord.
Age and maximum diameter at final follow-up were assessed with η2; all others were assessed using Cramer V.
Patients may have had more than 1 indication or reason for conversion surgery.
Patient also had increase in nodule size.
Both patients had ETE into strap muscle.
Recurrent laryngeal nerve.
Patients could have more than 1 complication.
In this patient, recurrent laryngeal nerve was not involved by either tumor nor metastatic lymph node.
The median (IQR) age in the disease progression group was 48 (39-56) years, and most patients were women (32 of 39 [82.1%]). The 2 most common indications for surgery were tumor growth, noted in 19 patients (48.7%) and sonographic suspicion of ETE in 18 patients (46.2%). The median (IQR) time of AS for this group was 28.1 (16.2-67.9) months, and the median (IQR) postsurgical follow-up time was 40.3 (18.0-59.0) months.
In the nonprogression CS cohort, the median (IQR) age was 52 (42-60) years, and 10 of 16 patients (62.5%) were female. Half of the patients in this group underwent surgery due to personal preference (8 [50.0%]), 2 more (12.5%) had thyroidectomy due to imminent changes in insurance status, and another 2 patients (12.5%) opted to have surgery because they were preparing for kidney transplant or donation. Other reasons are listed in Table 1.
The median (IQR) maximal tumor diameter prior to surgery was 0.7 (0.5 to 1.2) cm in the nonprogression group and 1.0 (0.8 to 1.3) cm in the disease-progression group (η2 = 0.03; 95% CI, −0.02 to 0.22). Preoperative imaging in both groups relied primarily on ultrasonography (US): 14 patients (87.5%) in the nonprogression group and 30 (76.9%) in the disease progression group (Cramer V, 0.12; 95% CI, 0.00 to 0.32). There were no clinically meaningful differences in the rates of partial vs total thyroidectomies among the 2 groups, as well as T and N stage (T stage: Cramer V, 0.30; 95% CI, 0.20 to 0.50; N stage: Cramer V, 0.30; 95% CI, 0.16 to 0.47) and overall eighth edition of the American Joint Commission on Cancer (AJCC) staging (Cramer V, 0.02; 95% CI, 0.00 to 0.30) (Table 1). There were no clinically meaningful differences in the distribution of histologic subtypes found among the 2 groups (Cramer V, 0.26; 95% CI, 0.19 to 0.53), as can be seen in Table 1.
Gross ETE into overlying strap muscle was detected in 1 patient in the disease progression cohort. This patient has undergone AS for a 1.0 × 0.7 × 0.8–cm posterior upper pole PTC for 3 years. During the AS period, the tumor remained stable in size (approximately 8 mm), yet a sonographic suspicion of posterior thyroid capsule ETE was noted. Upon CS, gross invasion of strap muscle was observed, with no posterior ETE evident clinically or pathologically. The pathology report noted a background of chronic lymphocytic thyroiditis. Another patient from the nonprogression group had gross ETE into strap muscle. This patient, with a 1.2-cm right lower pole PTC that increased 2 mm in maximal diameter over a 6-month follow-up period, elected CS over continued AS. There was no sonographic suspicion of ETE at any point during AS. Intraoperatively, there was adherence of tumor to strap muscle, pathologically confirmed as ETE into muscle.
Table 1 depicts the complications in the nonprogression vs disease-progression groups (7 [43.8%] vs 12 [30.8%]; Cramer V, 0.20; 95% CI, 0.01-0.50). Between the 2 groups, there were no clinically meaningful differences in transient hypocalcemia (Cramer V, 0.08; 95% CI, 0.00-0.34), vocal cord (VC) paresis (Cramer V, 0.09; 95% CI, 0.06-0.17), seroma (Cramer V, 0.02; 95% CI, 0.00-0.31), or wound infection (Cramer V, 0.30; 95% CI, 0.18-0.51) (Table 1).
AS Cohort: Subanalysis of CS for Suspected Disease Progression
In 19 of 39 patients (48.7%) undergoing CS for suspected disease progression, the indication was tumor growth. In 20 of 39 patients (51.2%), the suspected progression event was a sonographically suspicious feature (Table 2). Of 18 patients who had a preoperative suspicion of ETE, 10 (55.6%) had no intraoperative or pathologic evidence of ETE, 5 (27.8%) had microscopic ETE on pathologic examination, and 3 (16.7%) had gross ETE. In 1 patient with a sonographic suspicion of the nodule bulging into the capsule, no ETE was discovered. One patient had sonographically suspicious lateral neck lymph nodes that were later pathologically confirmed to be metastatic PTC.
Table 2. Preoperative Tumor Features Suspicious for Disease Progression vs Actual Surgical Pathology Findings.
| Preoperative suspicion for tumor progression | Patients, No. (% of total) (n = 39) | Operative findings | Suspicious cases, No. (%) |
|---|---|---|---|
| Possible ETE | 18 (46.2) | Micro ETE | 5 (27.8) |
| Gross ETE | 3 (16.7) | ||
| Nodule bulging capsule | 1 (2.6) | No ETE | 1 (100) |
| Suspicious lateral LN, nonbiopsy proven | 1 (2.6) | Neck metastases | 1 (100) |
| Neck metastases, No. | 2 |
Abbreviations: ETE, extrathyroidal extension; LN, lymph node.
Among the disease progression group, 1 patient (2.6%) required dissection of the recurrent laryngeal nerve (RLN) in relation to the index tumor (Table 3). This tumor was located in the left lower pole, in the area of the tracheoesophageal groove. During the surgery, a short segment (2-3 mm) of the RLN was found to be adherent to the tumor and was microdissected free. Nerve electrophysiologic integrity was lost, and hence surgery was staged. Postoperatively, this patient was asymptomatic with normal VC movement. This is the only patient in the cohort who underwent completion thyroidectomy.
Table 3. Surgical Aspects and Outcomes.
| Characteristic | Patients, No. (%) (n = 39)a |
|---|---|
| Index tumor related to RLN | 1 (2.6) |
| RLN dissected off tumor | 1 (2.6) |
| Cases resulted in permanent paresis | 0 |
| Stimulation lost during surgery | 2 (5.1) |
| Transientlyb | 1 (2.6) |
| Through surgery | 1 (2.6) |
| % Cases resulted in permanent paresis | 0 |
| Paralysis ipsilateral to index tumor | 1 (2.6) |
| EBL, median (IQR), mL | 6.5 (5-15) |
| Length of hospital stay, median (IQR), nights | 1 (1-1) |
Abbreviations: EBL, estimated blood loss; RLN, recurrent laryngeal nerve.
Patients are counted in more than 1 category.
Patient had a nonindex contralateral lesion that was initially biopsied as a colloid nodule. They had been receiving active surveillance for 6 years, during which growth was noted in the nonindex lesion and a repeat fine-needle aspiration diagnosed papillary thyroid carcinoma.
The only patient with postoperative VC paralysis transitioned to CS due to diagnosis of positive lateral LN, with a stable 1.1-cm intrathyroidal PTC. Surgery was uneventful, and the RLN was not adherent to the tumor or a metastatic LN yet noted to be of small caliber. Although nerve stimulation was intact at the completion of the procedure, the patient was documented to have VC paralysis postoperatively.
Median (IQR) estimated blood loss was 6.5 (5.0-15.0) mL, and the median (IQR) length of hospitalization was 1 (1-1) night. Total thyroidectomies represented 15 of the 39 operations (38.5%) in this group. The most common indications for performing a total thyroidectomy were the presence of contralateral thyroid nodules (7 of 15 [46.7%]), radiographically suspicious lateral neck LNs (5 of 15 [33.3%]), and sonographic suspicion for ETE (1 of 15 [6.7%]). Three patients (7.7%) underwent thyroid isthmusectomy only.
Central compartment LN dissections were performed in 3 patients with disease progression; only 1 of these procedures (2.6%) was therapeutic, and the rest (2 [5.1%]) were elective. Lateral and central neck dissections, which included the central compartment as well as neck levels II through IV, were performed in 4 patients (10.3%). The median (IQR) time of AS for those undergoing lymphadenectomy was 26.4 (14.9-54.4) months. All lateral neck dissections were unilateral. The median (IQR) number of positive LNs for all neck dissections was 7 (2-12), with a median (IQR) maximal metastatic focus dimension of 0.49 (0.40-0.65) cm. Of the 7 patients (17.9%) who underwent LN dissection, 1 patient (2.5%) was recommended by our multidisciplinary tumor board to be treated with RAI (a patient with 12 involved nodes and 1 focus of extranodal extension).
Propensity-Matched IS Cohort
Propensity score matching was used to match the CS progression group with a group of patients who underwent IS at our institution. Table 4 shows the CS progression and matched IS cohort by matching criteria: age, gender, lesion size on path report, procedure type, and follow-up time. There were no magnitudes of association between any of the criteria.
Table 4. Matched Cohort Criteria.
| Characteristic | Patients, No. (%) | Effect size (95% CI)a | |
|---|---|---|---|
| Initial surgery (n = 39) | Conversion surgery (n = 39) | ||
| Age, median (IQR), y | 51 (43 to 58) | 48 (39 to 56) | 0.00 (−0.01 to 0.09) |
| Gender | |||
| Female | 30 (76.9) | 32 (82.1) | 0.06 (0.00 to 0.28) |
| Male | 9 (22.1) | 7 (17.9) | |
| Size, cm | 0.90 (0.35 to 1.10) | 0.80 (0.70 to 1.10) | 0.01 (−0.01 to 0.06) |
| Procedure | |||
| Less than total thyroidectomy | 26 (66.7) | 25 (64.1) | 0.03 (0.00 to 0.26) |
| Total thyroidectomy | 13 (33.3) | 14 (35.9) | |
| Follow-up time, mo | 40 (9 to 66) | 40 (18 to 58) | 0.01 (−0.01 to 0.05) |
Age, size, and follow-up time assessed with η2; gender and procedure assessed with Cramer V.
Comparison of pathologic characteristics between the CS progression cohort and the matched IS cohort is shown in Table 5. There were no clinically meaningful differences between the groups noted in either gross and microscopic ETE, vascular invasion, positive margins, mitotic activity, and tumor encapsulation (Table 5). The only feature that was not evenly balanced between the 2 cohorts was the PTC histologic subtype, with the disease-progression group having more of the tall cell subtype (13 of 39 [33.3%] vs 2 of 39 [5.1%]; Cramer V, 0.41; 95% CI, 0.27-0.57). Four patients in the IS cohort (10.3%) and 12 in the CS progression cohort (30.8%) were found to have metastatic LNs in the pathologic specimen (η2 = 0.08; 95% CI, 0.00-0.22). There was no clinically meaningful difference in the AJCC staging among the 2 groups: 39 patients in the matched IS group (100%) were stage I compared with 37 of the disease progression group (94.9%) (Cramer V, 0.16; 95% CI, 0.10-0.27).
Table 5. Propensity Score–Matched Cohort Pathologic and Clinical Features.
| Characteristic | Patients, No. (%) | Effect size (95% CI)a | |
|---|---|---|---|
| Immediate surgery (n = 39) | Conversion surgery with disease progression (n = 39) | ||
| Gross ETE | 0 | 4 (10.3) | 0.23 (0.11-0.35) |
| Microscopic ETE | 8 (20.5) | 14 (35.9) | 0.17 (0.01-0.39) |
| Tumor necrosis | 0 | 0 | NA |
| Vascular invasion | 1 (2.6) | 2 (5.1) | 0.07 (0.00-0.24) |
| Positive margins | 1 (2.6) | 2 (5.1) | 0.06 (0.00-0.25) |
| Multifocality | 17 (43.6) | 24 (61.5) | 0.18 (0.02-0.38) |
| Mitotic activity | |||
| Mild to moderate | 0 | 2 (5.1) | 0.17 (0.11-0.29) |
| Not identified | 38 (97.4) | 34 (87.2) | |
| Unknown | 1 (2.6) | 3 (7.7) | |
| Tumor encapsulation | |||
| Completely encapsulated | 11 (28.2) | 4 (10.3) | 0.22 (0.05-0.46) |
| Not identified | 17 (43.6) | 21 (53.8) | |
| Partially encapsulated | 8 (20.5) | 9 (23.1) | |
| Unknown | 3 (7.7) | 6 (15.4) | |
| Neck dissection | |||
| No | 39 (100) | 34 (87.2) | 0.31 (0.20-0.44) |
| Therapeutic central | 0 | 2 (5.1) | |
| Central and lateral | 0 | 3 (7.7) | |
| Regional recurrence | 0 | 2 (5.1) | 0.16 (0.10-0.26) |
| Patients with positive nodes | 4 (10.3) | 13 (33.3) | 0.39 (0.08-0.64) |
| No. of positive nodes, median (IQR) | 1.5 (1.0-2.0) | 4.0 (2.0-11.5) | 0.08 (0.00-0.21) |
| ENE | |||
| No | 38 (97.4) | 37 (94.9) | 0.16 (0.10-0.28) |
| Yes | 0 | 2 (5.1) | |
| Unknown | 1 (2.6) | 0 | |
| pT stage | |||
| 1 | 38 (97.4) | 37 (94.9) | 0.11 (0.10-0.27) |
| 2 | 1 (2.6) | 2 (5.1) | |
| 3 | 0 | 1 (2.6) | |
| pN stage | |||
| N0 | 35 (89.7) | 26 (66.7) | 0.33 (0.20-0.50) |
| N1a | 4 (10.3) | 9 (23.1) | |
| N1b | 0 | 5 (12.8) | |
| Overall AJCC eighth edition stage | |||
| I | 39 (100) | 37 (94.9) | 0.16 (0.10-0.27) |
| II | 0 | 2 (5.1) | |
| Histology | |||
| Classic subtype | 28 (71.8) | 22 (56.4) | 0.41 (0.27-0.57) |
| Follicular subtype | 5 (12.8) | 4 (10.3) | |
| Occult sclerosing subtype | 4 (10.3) | 0 | |
| Tall cell subtype | 2 (5.1) | 13 (33.3) | |
| ATA risk stratification | |||
| Low | 26 (66.7) | 16 (41.0) | 0.31 (0.17-0.50) |
| Intermediate | 13 (33.3) | 19 (48.7) | |
| High | 0 | 4 (10.3) | |
| RAI | |||
| No | 37 (94.9) | 36 (92.3) | 0.05 (0.00-0.24) |
| Yes | 2 (5.1) | 3 (7.7) | |
| Last visit status | |||
| No evidence of disease | 39 (100) | 39 (100) | NA |
Abbreviations: AJCC, American Joint Commission on Cancer; ATA, American Thyroid Association; ENE, extranodal extension; ETE, extrathyroidal extension; NA, not applicable; RAI, radioactive iodine.
Number of positive nodes assessed with η2; all other variables assessed with Cramer V.
There was a moderate magnitude of association in the American Thyroid Association (ATA) risk stratification groupings among the 2 cohorts, with 13 (33.3%) in the matched cohort stratified to the intermediate- and high-risk groups vs 23 (59.0%) in the disease-progression group (Cramer V, 0.31; 95% CI, 0.17-0.50). There was no difference in the rate of RAI treatment among the 2 groups (IS cohort, 2 [5.1%]; CS cohort, 3 [7.7%]; Cramer V, 0.05; 95% CI, 0.00-0.24). All patients in both cohorts were alive with no evidence of disease on their last follow up.
The 5-year OS was 100% in both groups. The median (IQR) follow-up duration was 40.0 (8.9-65.9) months for the matched IS group and 40.3 (18.4-58.5) months for the progression CS group. The disease progression CS group had 2 patients (5.1%) with events of regional recurrence in LNs identified during routine follow-up after thyroid surgery. In 1 patient, this recurrence was treated with an uncomplicated lateral neck dissection, without a completion thyroidectomy, yielding 2 positive nodes, and required no further treatment with RAI. The patient remains without evidence of recurrent disease currently. The other patient underwent completion thyroidectomy and a lateral neck dissection, which yielded 5 of 22 positive nodes, the largest measuring 0.8 cm. The patient was not treated further with RAI and remains without evidence of recurrent disease currently. There were no events of local or distant recurrence. The 5-year RFS was 100% (95% CI, 100%-100%) in the IS group and 86% (95% CI, 70%-100%) in the disease progression CS group, with no clinically meaningful differences between the groups.
Discussion
This study provides additional support to previous observations indicating that, among patients with PTC choosing AS, CS for suspected disease progression is associated with surgical and subsequent oncologic outcomes that are similar to the outcomes seen among patients undergoing upfront IS. In addition, the surgical complexity and sequalae of CS due to disease progression were comparable to those of patients without disease progression. As expected, even when propensity matched for age, gender, tumor size, surgical procedure, and follow-up time, the cohort of patients undergoing CS for disease progression were enriched in features commonly associated with disease progression and structural disease recurrence (tall cell phenotype, histologically confirmed LN metastasis, and intermediate or high ATA risk stratification). Despite the fact that the disease-progression CS group was enriched for those at the highest risk for adverse oncologic outcomes, CS at the time of disease progression was associated with excellent short-term outcomes. These findings are consistent with data from Japanese, Korean, and US centers demonstrating that while disease progression is expected to develop in a small percentage of patients during AS, salvage therapy at the time of disease progression provides oncologic outcomes that are equivalent to the outcomes expected in patients selected for IS.6,10,11,12
In their recent study detailing the application of AS for low-risk PTC, Miyauchi et al6 describe a 3-decade–long experience of 5646 patients who underwent either AS or IS. Their findings reveal an intriguing aspect: 12% of 3222 patients who underwent AS had CS. This figure aligns closely with the 10% of patients in our own cohort who underwent CS for any reason. Furthermore, Miyauchi et al6 reported no cases of nonsalvageable nodal recurrences, no cases of distant metastasis, and no disease-specific deaths.
The clinical impact of detection and resection of subclinical cervical LN metastasis in low-risk papillary carcinoma is questionable given that a very small volume cervical LN metastases are present in more than 60% of patients with papillary microcarcinoma, and yet without prophylactic neck dissections or RAI therapy, the clinical recurrence rate ranges from 2% to 6%.13 In the current study, only 5 patients of the 550 (0.9%) receiving AS developed clinically apparent LN metastasis that required either a central (2 patients) or lateral (3 patients) neck dissection. Miyauchi and colleagues’6 extensive 30-year follow-up period also offers valuable insights into the natural history of low-risk PTC. When compared, the cumulative incidence of nodal metastasis in the IS group was statistically lower than that observed in the AS group (at 10 years, 0.4% vs 1.1%; hazard ratio, 0.42), the risk difference was only 0.7% at 10 years and 1% at 20 years. These data indicate that very-small volume LN metastases are likely to be present in most patients undergoing AS and yet seldom develop into clinically significant disease.
A recent meta-analysis by Cho et al14 delved into the reported indications for CS, a topic sparsely addressed across a handful of publications.10,15 In both the Kuma Hospital and Korean cohorts, CS took place without apparent size increase or LN detection in a substantial proportion of patients: 66.1% in Kuma Hospital and 69% in the Korean group.10,15 In the current study, of the 55 patients who underwent CS, 64% underwent operations for indications other than tumor growth. Setting aside indications unrelated to disease progression, it is intriguing to explore sonographically driven indications for surgery, particularly the suspicion of tumor abutment or infiltration of the thyroid capsule—an observation becoming increasingly common with the enhanced resolution capabilities of modern ultrasound devices. In fact, most cases deemed suspicious for ETE via preoperative sonography did not ultimately show ETE on surgical pathology, revealing the difficulty of diagnosing ETE by ultrasonography in the absence of obvious invasion into surrounding structures.
The Kuma Hospital group7 reported the locoregional recurrence rate of the entire AS group was significantly lower than that of the patients with low-risk PTC who underwent IS (0.1% vs 0.7% at 10 years). Another study compared AS with IS,11 focusing on postoperative complications, and reported that the IS group had significantly higher rates of temporary VC paralysis and temporary hypoparathyroidism than the AS group (VC paralysis: 2.7% vs 0.2%; temporary hypoparathyroidism: 13.6% vs 1.9%). The IS group also had significantly more patients receiving hormone replacement therapy (98.4% vs 10.9%).
Limitations
There are several limitations to this study. With a larger sample size, we could have obtained a more precise estimate of the outcomes following CS. Additionally, the study design has an inherent selection bias, as the disease-progression CS cohort is a highly selected group of patients with PTC that has demonstrated more biologically aggressive behavior. As a result, we did observe that patients in the CS group had higher rates of tall cell subtype histology, ATA intermediate- or high-risk category, neck LN dissections, and nodal metastases than the IS group. These differences are not unexpected, given the selection factors that lead patients with PTC who are receiving AS to eventually go on to CS. Unlike other studies that reported outcomes of CS, our design did not compare the entire AS cohort (550 patients) with a matched similar-size cohort of patients who underwent IS, but rather the highly selected disease progression group to a propensity-matched cohort of the same size, carrying the understandable expectation for somewhat more aggressive tumor behavior in the CS group.
Conclusions
In conclusion, CS for patients with PTC experiencing disease progression during AS demonstrates complication rates akin to patients with no progression. Additionally, undergoing CS did not upstage the patients compared with IS and was associated with excellent survival outcomes and low recurrence rates.
Data Sharing Statement
References
- 1.Cabanillas ME, McFadden DG, Durante C. Thyroid cancer. Lancet. 2016;388(10061):2783-2795. doi: 10.1016/S0140-6736(16)30172-6 [DOI] [PubMed] [Google Scholar]
- 2.McLeod DS, Sawka AM, Cooper DS. Controversies in primary treatment of low-risk papillary thyroid cancer. Lancet. 2013;381(9871):1046-1057. doi: 10.1016/S0140-6736(12)62205-3 [DOI] [PubMed] [Google Scholar]
- 3.Vaccarella S, Franceschi S, Bray F, Wild CP, Plummer M, Dal Maso L. Worldwide thyroid-cancer epidemic? the increasing impact of overdiagnosis. N Engl J Med. 2016;375(7):614-617. doi: 10.1056/NEJMp1604412 [DOI] [PubMed] [Google Scholar]
- 4.Ito Y, Uruno T, Nakano K, et al. An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid. 2003;13(4):381-387. doi: 10.1089/105072503321669875 [DOI] [PubMed] [Google Scholar]
- 5.Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-133. doi: 10.1089/thy.2015.0020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Miyauchi A, Ito Y, Fujishima M, et al. Long-term outcomes of active surveillance and immediate surgery for adult patients with low-risk papillary thyroid microcarcinoma: 30-year experience. Thyroid. 2023;33(7):817-825. doi: 10.1089/thy.2023.0076 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Fujishima M, Miyauchi A, Ito Y, et al. Active surveillance is an excellent management technique for identifying patients with progressive low-risk papillary thyroid microcarcinoma requiring surgical treatment. Endocr J. 2023;70(4):411-418. doi: 10.1507/endocrj.EJ22-0559 [DOI] [PubMed] [Google Scholar]
- 8.Tuttle RM, Fagin J, Minkowitz G, et al. Active surveillance of papillary thyroid cancer: frequency and time course of the six most common tumor volume kinetic patterns. Thyroid. 2022;32(11):1337-1345. doi: 10.1089/thy.2022.0325 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Matsuura D, Yuan A, Harris V, et al. Surgical management of low-/intermediate-risk node negative thyroid cancer: a single-institution study using propensity matching analysis to compare thyroid lobectomy and total thyroidectomy. Thyroid. 2022;32(1):28-36. doi: 10.1089/thy.2021.0356 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Oh HS, Ha J, Kim HI, et al. Active surveillance of low-risk papillary thyroid microcarcinoma: a multi-center cohort study in Korea. Thyroid. 2018;28(12):1587-1594. doi: 10.1089/thy.2018.0263 [DOI] [PubMed] [Google Scholar]
- 11.Liu C, Zhao H, Xia Y, et al. Active surveillance versus immediate surgery: a comparison of clinical and quality of life outcomes among patients with highly suspicious thyroid nodules 1 cm or smaller in China. Eur J Surg Oncol. 2023;49(9):106917. doi: 10.1016/j.ejso.2023.04.016 [DOI] [PubMed] [Google Scholar]
- 12.Lee EK, Moon JH, Hwangbo Y, et al. Progression of low-risk papillary thyroid microcarcinoma during active surveillance: interim analysis of a multicenter prospective cohort study of active surveillance on papillary thyroid microcarcinoma in Korea. Thyroid. 2022;32(11):1328-1336. doi: 10.1089/thy.2021.0614 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Randolph GW, Duh QY, Heller KS, et al. ; American Thyroid Association Surgical Affairs Committee’s Taskforce on Thyroid Cancer Nodal Surgery . The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. Thyroid. 2012;22(11):1144-1152. doi: 10.1089/thy.2012.0043 [DOI] [PubMed] [Google Scholar]
- 14.Cho SJ, Suh CH, Baek JH, et al. Active surveillance for small papillary thyroid cancer: a systematic review and meta-analysis. Thyroid. 2019;29(10):1399-1408. doi: 10.1089/thy.2019.0159 [DOI] [PubMed] [Google Scholar]
- 15.Ito Y, Miyauchi A, Inoue H, et al. An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg. 2010;34(1):28-35. doi: 10.1007/s00268-009-0303-0 [DOI] [PubMed] [Google Scholar]
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Data Sharing Statement