The Definition of Recurrence of Differentiated Thyroid Cancer: A Systematic Review of the Literature

Abstract

Background:

Recurrence is a key outcome to evaluate the treatment effect of differentiated thyroid carcinoma (DTC). However, no consistent definition of recurrence is available in current literature or international guidelines. Therefore, the primary aim of this systematic review was to delineate the definitions of recurrence of DTC, categorized by total thyroidectomy with radioactive iodine ablation (RAI), total thyroidectomy without RAI and lobectomy, to assess if there is a generally accepted definition among these categories.

Methods:

This study adhered to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. In December 2023, a systematic literature search in MEDLINE and EMBASE was performed for studies reporting on the recurrence of DTC, from January 2018 to December 2023. Studies that did not provide a definition were excluded. Primary outcome was the definition of recurrence of DTC. Secondary outcome was whether studies differentiated between recurrence and persistent disease. Two independent investigators screened the titles and abstracts, followed by full-text assessment and data extraction. The study protocol was registered in PROSPERO, CRD42021291753.

Results:

In total, 1450 studies were identified. Seventy studies met the inclusion criteria, including 69 retrospective studies and 1 randomised controlled trial (RCT). Median number of patients in the included studies was 438 (range 25–2297). In total, 17 studies (24.3%) reported on lobectomy, 4 studies (5.7%) on total thyroidectomy without RAI, and 49 studies (70.0%) with RAI. All studies defined recurrence using one or a combination of four diagnostic modalities cytology/pathology, imaging studies, thyroglobulin (-antibodies), and a predetermined minimum tumor-free time span. The most common definition of recurrence following lobectomy was cytology/pathology-proven recurrence (47.1% of this subgroup), following total thyroidectomy with RAI was cytology/pathology-proven recurrence and/or anomalies detected on imaging studies (22.4% of this subgroup). No consistent definition was found following total thyroidectomy without RAI. Nine studies (12.9%) differentiated between recurrence and persistent disease.

Conclusion:

Our main finding is that there is no universally accepted definition for recurrence of DTC in the current studies across any of the treatment categories. The findings of this study will provide the basis for a future, international Delphi-based proposal to establish a universally accepted definition of recurrence of DTC. A uniform definition could facilitate global discussion and enhance the assessment of treatment outcomes regarding recurrence of DTC.

Introduction

Differentiated thyroid carcinoma (DTC) has a very good prognosis, with a 10-year survival rate of more than 95%.^1
–3 Consequently, recurrence is a more prominent outcome to evaluate treatment effect than survival.^1,3
–5 Recurrence rates for DTC vary widely between cohorts from 4% to 42%, mainly due to different inclusion criteria, duration of follow-up, and histological subtypes.^6

–9 Additionally, no consistent definition of recurrence is available in current literature or international guidelines, despite its frequent use as an outcome measure in studies.

International guidelines either do not formulate a definition of recurrence or provide different definitions using various clinical, biochemical, and radiological criteria such as detectable serum Thyroglobulin (Tg) (or Tg antibodies) with different cut-off values, various cross-sectional imaging methods, and/or cytological or histological confirmation.^4,5,10
–12 Alternatively, one guideline established a concept of “complete remission,” which could be considered as part of a definition of recurrence.¹³ All definitions rely on patients undergoing total thyroidectomy with radioactive iodine ablation (RAI). The definitions cannot be applied to patients treated with total thyroidectomy without RAI or lobectomy alone. It is probable that the definition of recurrence for patients treated less extensively differs from that for patients treated with total thyroidectomy and RAI. This has clinical relevance, particularly given the ongoing trend toward de-escalation of treatment for (low-risk) patients with DTC.^14,15

Clearly, there is a need for a universally accepted definition of recurrence following the treatment of DTC. This definition should differentiate between patients treated with total thyroidectomy, with or without RAI, and those treated with lobectomy. Such a definition could facilitate global discussion, streamline research methods, improve the comparability of studies, and enhance the assessment of treatment outcomes regarding the recurrence of DTC. Before establishing a consistent global definition, it is essential to analyze various definitions currently employed in the literature. Therefore, the primary aim of this systematic review was to delineate the definitions of recurrence of DTC, categorized by total thyroidectomy with RAI, total thyroidectomy without RAI and lobectomy, to assess if there is a generally accepted definition among these categories. Additionally, we investigated whether studies differentiated between recurrence and persistent disease.

Materials and Methods

This systematic review was performed according to the latest standard Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.¹⁶ Our protocol was registered in the PROSPERO international Prospective Register of Systematic Reviews database (CRD42021291753)¹⁷ before the study.

Search strategy

A systematic literature search in MEDLINE and EMBASE was performed in March 2023. The search terms were formulated in collaboration with a medical information specialist (F.J.). Publication dates were extended from January 2018 to March 2023. The search was updated on December 20th, 2023. Limitations were set to articles published in English and human studies. Only studies published between 2018 and 2023 were included, as we were only interested in the most recent definitions of recurrence. We excluded systematic reviews and meta-analyses from our search, focusing solely on patient-related reports to identify definitions of recurrence. This choice was made because of its direct clinical relevance to the definition being sought. Conference abstracts were excluded. References lists of identified papers were screened to retrieve additional relevant papers. Unpublished studies were not sought. The full search can be found in Supplementary Table S1.

Study selection

Two investigators (D.B. and P.R.S., both MDs) independently screened the titles and abstracts of all the articles using predetermined inclusion/exclusion criteria. The full-text articles were examined independently by both investigators to determine whether they met the inclusion criteria. Any conflicts were resolved by discussion between D.B. and P.R.S. Disagreement was resolved by a third reviewer (J.D.).

Study inclusion criteria were as follows: Studies regarding DTC and evaluating recurrence after initial treatment were included. Studies involving adult patients, children, or a mixed population were all eligible. Exclusion criteria were as follows: studies that reported on other types of thyroid cancer (i.e., medullary or anaplastic thyroid cancer) or encompassed a mixed population, studies that reported on noninvasive follicular thyroid neoplasm with papillary-like nuclear features and studies that reported on active surveillance as “treatment” for low-risk papillary thyroid carcinoma (PTC). Studies that reported on a mixed treated population (e.g., some patients treated with lobectomy, others with total thyroidectomy with or without RAI) were excluded as our explicit aim was to identify the definitions of recurrence segregated by treatment modality. Studies reporting on patients that were not treated surgically (i.e., laser ablation) were excluded as we expect that the definition of recurrence/persistent disease might be different for this subgroup of patients.

A definition was considered eligible if it explicitly stated that recurrence was “defined as,” “regarded as,” “determined as,” “considered as,” “established as,” or any other synonym. Studies that merely described their clinical activities to diagnose recurrence, but did not state a definition of recurrence, were excluded.

Data extraction

D.B. and P.R.S. independently extracted the data using a predefined data extraction form (see Supplementary Table S2). Data were collected on number of included patients, type of surgical treatment and RAI, definition of recurrence, and whether studies distinguished between recurrence and persistent disease. Data extraction forms were compared and any conflicts were resolved by discussion. Disagreement was resolved by a third reviewer (J.D.).

Data synthesis

In this study, we anticipated much heterogeneity among the identified definitions of recurrence. Therefore, we organized the definitions in multiple tables to clarify their similarities and differences. First, we divided the definitions by treatment modality (i.e., lobectomy, total thyroidectomy without RAI, total thyroidectomy with RAI). Treatment with less-than-total thyroidectomy was clustered under lobectomy. Second, we clustered the definitions according to the diagnostic modalities employed within them, recognizing that recurrence is typically defined using (multiple) diagnostic modalities.

Risk of bias

D.B. and P.R.S. independently assessed the risk of bias using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool to score the overall risk of bias.¹⁸ Any conflicts were resolved by discussion. Disagreement was resolved by a third reviewer (J.D.).

Results

Our literature search yielded 1450 studies. After a review of titles and abstracts, 498 studies were selected for full-text review. Of these, 428 studies (85.9%) were excluded, with 216 studies (43.3%) reporting on recurrence being excluded because they did not provide a definition of recurrence. In total, 70 studies were considered eligible according to the predefined criteria, of which 69 were retrospective studies^{8,19

–86} and 1 RCT.⁸⁷ Among them, nine studies differentiated between recurrence and persistent disease by providing a definition for both terms.^{8,41,49,54,62,67,80,82,86} Figure 1 depicts the PRISMA flowchart of our strategy. The full list of studies and definitions can be found in Supplementary Table S3.

FIG. 1.

PRISMA flowchart search strategy. N = number of studies. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Study characteristics

The median number of patients in the included studies was 438 (range 25–2297). Among the included studies, 17 studies reported on patients treated with lobectomy (24.3%),^{19

–35} 4 studies reported on patients treated with total thyroidectomy without RAI (5.7%),^36

–39 and 49 studies involved a population treated with total thyroidectomy with RAI (70%).^{8,40

–87}

Risk of bias

A detailed overview of the risk of bias in the included studies, evaluated using the ROBINS-I tool, is provided in Supplementary Table S4. The overall risk of bias for these studies was assessed as moderate to serious.

Components of the definition of recurrence

All the included studies defined recurrence using either a singular approach or a combination of the following four diagnostic modalities: cytology/pathology, imaging studies (i.e., ultrasound, I-131 whole body scan), Tg with or without Tg-antibodies, and a predetermined minimum tumor-free time span following initial therapy (Table 1).

Table 1.

Components of the Definition of Recurrence of Differentiated Thyroid Cancer

Components of the definition	Number of studies^a
Cytology/pathology-proven	44
Imaging studies	40
Thyroglobulin	21
Tumor-free time span	9

The overall count in this table surpasses 70 as many studies employ a combination of the above diagnostic modalities in their definition, leading to multiple counts.

Recurrence was defined by cytological/histopathological confirmation in 44 studies.^{19

–28,30,32

–35,38,42
–44,46,50,52,54

–61,63,65,66,68,69,71
–73,75,78,79,81,82} In all of these studies, recurrence was confirmed through either fine-needle aspiration cytology or histopathology.

Imaging techniques were used to identify recurrence in 41 studies.^{8,20,21,27,28,30,34

–37,40,41,43,44,47

–50,55,56,58,60
–62,65,66,69,71

–83,86} Among them, four studies solely relied on structural imaging methods (such as ultrasound or CT-scan) to define recurrence.^28,40,69,83 The remaining 37 studies either used general terms for imaging or included examples of both functional and structural imaging modalities in their definition.^{8,20,21,27,30,34

–37,41,43,44,47

–50,55,56,58,60
–62,65,66,71

–82,86}

Overall, 21 studies incorporated Tg in defining recurrence.^{8,36,37,41,47
–49,52,54,62,65,66,69,73,74,76
–78,80,83,86} Among these, 13 studies employed a cutoff value for Tg to define recurrence.^{8,37,47
–49,54,62,66,74,76,77,80,86} Within this group, nine studies offered a cutoff value for either stimulated and nonstimulated Tg.^{8,37,47
–49,62,66,74,80} These cutoff values varied widely between 0.4 µg/mL–2 ng/mL and 2.0 µg/mL–10 ng/mL for stimulated and non-stimulated Tg, respectively. Moreover, one study further specified a cutoff value for Tg Antibodies (Tg-Ab) in defining no evidence of disease (NED). Llamas-Olier et al. established the cutoff value for Tg-Ab at <60 ng/mL.⁶⁶

The remaining 21 studies characterized recurrence as a rising or abnormal Tg without specifying a cutoff value.^{36,41,52,65,69,73,78} Additionally, one study included rising or abnormal Tg-Ab in their definition of recurrence.⁴¹

Nine studies defined recurrence using a tumor free-time span following initial treatment.^{21,27,43,45,67,68,70,71,82} Among these, seven studies determined recurrence as any reemerging of tumor after 12 months after initial treatment.^{21,27,46,67,68,70,82} Two studies established the recurrence threshold at 6 months.^42,45

Clustering the definitions

The studies were divided based on the treatment types: lobectomy (Table 2), total thyroidectomy without RAI (Table 3), and total thyroidectomy with RAI (Table 4a–e). One study reported on patients treated with isthmectomy²³ and was grouped under lobectomy. The definitions were then clustered according to the (combination of) diagnostic modalities that the authors used to define recurrence.

Table 2.

Definitions of Recurrence of Differentiated Thyroid Cancer Following Lobectomy

Definitions of recurrence after lobectomy	Number of studies, n (% of subgroup)	#
Cytology/pathology-proven	8 (47.1)	1
Imaging studies and cytology/pathology-proven	5 (29.4)	2
Imaging studies and cytology/pathology-proven and tumor-free time span	2 (11.8)	3
General definitions	2 (11.8)	4
Total studies, n (% of total studies)	17 (24.3)

#Refers to the corresponding number aligning with the complete list of definitions found in the supplement.

n, number of studies.

Table 3.

Definitions of Recurrence of Differentiated Thyroid Cancer Following Total Thyroidectomy Without Radioiodine Ablation

Definitions of recurrence after TT without RAI	Number of studies, n (% of subgroup)	#
Cytology/pathology-proven	1 (25.0)	5
Imaging studies and thyroglobulin	1 (25.0)	6
NED: thyroglobulin and imaging studies and cytology/pathology-proven	1 (25.0)	7
Other definitions	1 (25.0)	8
Total studies, n (% of total studies)	4 (5.7)

#Refers to the corresponding number aligning with the complete list of definitions found in the supplement.

n, number of studies; NED, no evidence of disease; RAI, radioactive iodine ablation; TT, total thyroidectomy.

Table 4.

Definitions of Recurrence of Differentiated Thyroid Cancer After Total Thyroidectomy with Radioiodine Ablation

Definitions of recurrence after TT with RAI	Number of studies, n (% of subgroup)	#
4a: Single diagnostic modality
Imaging studies	1 (2.0)	9
Cytology/Pathology-proven	5 (10.2)	10
4b: Multiple diagnostic modalities
Thyroglobulin and imaging studies	5 (10.2)	11
Thyroglobulin and cytology/pathology-proven	2 (4.1)	12
Imaging studies and cytology/pathology-proven	11 (22.4)	13
Thyroglobulin and imaging studies and cytology/pathology-proven	5 (10.2)	14
4c: Tumor-free time span combined with diagnostic modalities
Tumor-free time span	3 (6.1)	15
Tumor-free time span and cytology/pathology-proven	1 (2.0)	16
Tumor-free time span and imaging studies and cytology/pathology-proven	3 (6.1)	17
4d: No evidence of disease
NED: thyroglobulin and imaging studies	7 (14.3)	18
NED: not further specified	2 (4.1)	19
4e: Other definitions
Other definitions	4 (8.2)	20
Total studies, n (% of total studies)	49 (70.0)

#Refers to the corresponding number aligning with the complete list of definitions found in the supplement.

n, number of studies; NED, no evidence of disease; RAI, radioactive iodine ablation; TT, total thyroidectomy.

Definition of recurrence following lobectomy

In total, 17 studies (24.3% of total studies) provided a definition after treatment with lobectomy only (Table 2, see Supplementary Table S3 for the corresponding studies and definitions).^{19

–35} Among these, 8 studies (47.1% of this subgroup) defined recurrence following lobectomy as cytology/pathology-proven recurrence.^{19,22

–26,32,33} Recurrence was defined with both imaging studies and cytology/pathology-proven recurrence in five studies (29.4% of this subgroup).^{20,28,30,34,35} Of these five studies, two studies explicitly stated in their definition that locoregional recurrences were cytology/pathology-proven and distant metastasis were defined as abnormalities on imaging studies.^34,35 The other three studies did not specify such details.^20,28,30

Definition of recurrence following total thyroidectomy without RAI

Four studies (5.7% of total studies) provided a definition after treatment with total thyroidectomy without RAI (Table 3).^36

–39 One study defined recurrence as cytology/pathology-proven recurrence only.³⁸ One study defined recurrence as structural disease detected by imaging (USG/PET-CT/RxWBS/CT) and/or TSH-stimulated serum Tg levels greater than 2 ng/mL.³⁶ One study established criteria for NED, in order to subsequently define recurrence.³⁷ In this study, NED was determined with NED on biochemistry (suppressed Tg <1 ng/mL, stimulated Tg <2 ng/mL, no anti-Tg antibody), on cytology, or imaging (US, CT, iodine 131 whole-body scintigraphy, or PET/CT scan).³⁷

Definition of recurrence following total thyroidectomy with RAI

A definition of recurrence after treatment with total thyroidectomy with RAI was provided in 49 studies (70.0% of total studies; Table 4a–e).^{8,40

–87} These definitions can be subdivided in four types based on the diagnostic modalities.

Recurrence defined using a singular diagnostic modality

In total, six studies (6/49 studies; 12.2%) solely depended on a single diagnostic modality to define recurrence, following treatment with TT and RAI (Table 4a).^{40,42,46,57,59,63} Five of these studies (5/49; studies 10.2%) defined recurrence as cytology/pathology-proven recurrence.^{42,46,57,59,63}

Recurrence defined using multiple diagnostic modalities

Overall, 23 studies (23/49 studies; 46.9%) combined multiple diagnostic modalities in their definition of recurrence, following treatment with TT and RAI (Table 4b).^{44,47,48,50,52,54
–56,58,60,61,65,66,69,72,73,75

–79,81,83} Eleven studies (11/49 studies; 22.4%) defined recurrence with both imaging studies and cytology/pathology.^{44,50,55,56,58,60,61,72,75,79,81} Among these, seven studies stated that structural lesions identified in imaging studies were classified as recurrence only when Tg or Tg-antibodies were also found to be abnormal.^{44,55,56,58,72,79,81} Additionally, one study explicitly stated in their definition that locoregional recurrences were cytology/pathology-proven and distant metastasis was defined as abnormalities on imaging studies.⁷⁵

Recurrence defined using a tumor-free time span combined with diagnostic modalities

In total, seven studies (7/49 studies; 14.3%) defined recurrence by combining one or more diagnostic modalities along with a minimum tumor-free time span following TT and RAI (Table 4c).^{43,45,67,68,70,71,82} Among these, three studies (3/49 studies; 6.1%) established recurrence solely based on a tumor-free time span following TT and RAI.^45,67,70 Within this subgroup, two studies determined recurrence as any reemerging of tumor after 12 months after TT and RAI^67,70 and one study set the time threshold at 6 months.⁴⁵ Three studies (3/49 studies; 6.1%) employed a definition that combined a tumor-free time span with the utilization of both cytology/pathology-confirmation and imaging studies.^43,71,82 Among these, two studies set the minimum time threshold at 12 months,^71,82 one study established it at 6 months.⁴³ Moreover, two studies explicitly defined locoregional recurrence as pathology/cytology-proven and distant metastasis as anomalies identified on imaging studies.^43,71,88

Recurrence defined using no evidence of disease

In total, nine studies (9/49 studies; 18.4%) established criteria for NED to subsequently define recurrence (Table 4d).^{8,41,49,53,62,64,74,80,86} Seven studies (7/49 studies; 14.3%) required a negative Tg (with or without concurrent negative Tg-antibodies) and one or more negative imaging studies to achieve NED.^{8,41,49,62,74,80,86} These studies defined recurrence as any new biochemical, structural, pathological, functional, or metabolic evidence of disease after having achieved NED.

Other definitions

Four studies (4/49 studies; 8.2%) used definitions that could not be grouped within any of the aforementioned categories (Table 4e).^51,84,85,87 Specifically, three of these studies provided general definitions of recurrence without specifying any diagnostic modalities.^51,85,87

Recurrence versus persistent disease

In total, nine studies (12.9% of total studies) differentiated between recurrence and persistent disease by providing a definition for both terms (see Table 5).^{8,41,49,54,62,67,80,82,86} In all studies, patients were treated with TT and RAI. Four studies (4/9 studies; 44.4%) employed a definition of persistent disease that included persistent Tg (-antibodies), persistent structural abnormalities in imaging studies, and cytology/pathology findings.^8,62,80,86 Among these, two studies also mentioned a time frame in their definitions in which such an event is defined as a persistent disease.^80,86 Both studies defined persistent disease as an event within a 12-month timeframe after initial treatment.

Table 5.

Definitions of Recurrence and Persistent Disease of Differentiated Thyroid Cancer

Recurrence vs. persistent disease	Number of studies, n (% of subgroup)	#
Tumor-free time span	2 (22.2)	A
Thyroglobulin and imaging studies	3 (33.3)	B
Thyroglobulin and imaging studies and cytology/pathology-proven	4 (44.4)	C
Total studies, n (% of total studies)	9 (12.9)

#Refers to the corresponding letter aligning with the complete list of definitions found in the supplement.

n, number of studies.

Three studies (3/9 studies; 33.3%) defined persistent disease as persistent Tg or evidence of continued structural disease on imaging studies.^41,49,54 Of these studies, one study additionally specified a time frame of 12 months to classify an event as a persistent disease.⁴¹

Two studies (2/9 studies; 22.2%) exclusively relied on a fixed 12-month period following initial treatment to define persistent disease.^67,82

Discussion

We conducted a systematic review to delineate the definitions of recurrence of DTC in current studies, categorized by total thyroidectomy with RAI, total thyroidectomy without RAI, and lobectomy, to assess if there is a generally accepted definition among these categories. Additionally, we investigated whether studies differentiated between recurrence and persistent disease. Our main finding is that there is no universally accepted definition for recurrence of DTC across any of the treatment categories. Seventeen studies (24.3% of total studies) provided a definition for recurrence following lobectomy.^{19

–35} The most prevalent definition of recurrence following lobectomy is cytology/pathology-proven recurrence (47.1% of this subgroup).^{19,22

–26,32,33} Four studies (5.7% of total studies) provided a definition of recurrence following total thyroidectomy without RAI.^36

–39 No most prevalent definition was identified as the definitions were evenly divided between cytology/pathology-proven recurrence, imaging studies and Tg levels, NED, and other definitions. Overall, 49 studies (70.0% of total studies) provided a definition of recurrence after treatment with total thyroidectomy with RAI.^{8,40

–87} The most common definition of recurrence following total thyroidectomy with RAI is a combination of cytology/pathology-proven recurrence and/or recurrence detected as anomalies on imaging studies (22.4% of this subgroup).^{44,50,55,56,58,60,61,72,75,79,81} Almost all studies (90.0%), define recurrence using one or more diagnostic modalities, including serum Tg levels, imaging studies, cytology/pathology, a tumor-free time span, or a combination of these. In total, nine studies (12.9%) differentiate between recurrence and persistent disease by offering a definition for both.^{8,41,49,54,62,67,80,82,86} Notably, almost half of all the studies reporting on recurrence (216 of 498 studies assessed for eligibility; 43.3%) of lack any definition, resulting in their exclusion from the analysis of this systematic review.

The results of this systematic review give an overview of the extensive variation in the definitions of DTC recurrence and provide insight into the components that make up these definitions. Offering insight into these components can serve as an initial step toward establishing a globally standardized definition of DTC, which could facilitate comparisons of treatment regimens, prognoses, and other research.

Following lobectomy, cytology/pathology serves as a definitive and objective parameter, whereas the use of Tg, for instance, remains a topic of controversy. This is because Tg levels persist after lobectomy, and there’s a lack of consistency in the literature regarding the value of cut-off points to confirm recurrence.^{21,28,89
–91}

For total thyroidectomy without RAI, no consistent definition of recurrence was found. The definitions were evenly divided among cytology/pathology-proven recurrence, recurrence defined by imaging studies and Tg, defining NED, and providing another definition. It’s not feasible to derive conclusions from this as there are only four studies providing definitions of recurrence following total thyroidectomy without RAI.

For total thyroidectomy with RAI, the predominant approach for defining recurrence was the utilization of multiple diagnostic modalities (46.9% of this subgroup).^{44,47,48,50,52,54
–56,58,60,61,65,66,69,72,73,75

–79,81,83} The most common definition of recurrence was to classify it either as cytology/pathology-proven recurrence or as recurrence detected as anomalies on imaging studies (22.4% of this subgroup).^{8,54,59,60,62,64,65,76,79,83,85} Combining both diagnostic modalities to define recurrence is a rational approach. In clinical practice, confirming distant recurrences is not always feasible through cytology/pathology. In such cases, anomalies detected on imaging studies, sometimes in combination with rising Tg or Tg-antibodies, confirm the diagnosis of a distant recurrence. Defining recurrence with cytology/pathology, Tg and/or imaging studies will likely contribute to a more accurate estimate of the true recurrence rate as compared to employing just one of these diagnostic methods in the definition. However, among these studies, only one study explicitly stated in their definition that locoregional recurrences were cytology/pathology-proven and distant metastasis were defined as abnormalities on imaging studies.⁷⁵ The other 10 studies provided fewer or no details on how they defined recurrence through cytology/pathology or imaging studies, which undermines the transparency of the research methods and the credibility of reported recurrence rate.^{44,50,55,56,58,60,61,72,79,81} Additionally, in studies relying solely on cytology/pathology to define recurrence, the rate of distant recurrence often remains unclear. In these studies, the distant recurrence rate is either not clearly reported,^{22,24,33,38,42,46} or it is unclear whether only distant metastases confirmed by cytology/pathology are included.^{19,23,25,26,32,57,59,63} Although cytology/pathology is a definitive and objective endpoint for recurrence, the subsequent lack of clear reporting on distant metastases undermines the credibility of any treatment-related effects.

Extensive variation in the definitions of recurrence of DTC was described in the current studies. Such variability impedes the ability to compare recurrence rates and consequently assess treatment-related effects across studies. The inconsistency in recurrence definitions poses a significant obstacle to advancing care for patients with DTC. Efforts to standardize these definitions are crucial for enhancing research comparability and improving patient outcomes.

The majority of the definitions in this study and statements concerning recurrence and complete remission in international guidelines primarily center around treatment involving total thyroidectomy and RAI.^10,13 These definitions cannot be directly applied for patients treated less extensively with lobectomy or total thyroidectomy without RAI. This is largely because the use of Tg for defining recurrence in patients who undergo less extensive treatment remains a topic of discussion.^{21,28,89
–91} Furthermore, Tg serum levels are not applicable in a small subset of cases where the disease dedifferentiates and no longer produces Tg. Given the ongoing trend toward de-escalation of treatment for patients with (low-risk) DTC, uniform definitions of recurrence should be formulated separately following treatment with total thyroidectomy with RAI, without RAI, and lobectomy. Additionally, definitions of local, regional, and distant recurrence may vary due to differences in the diagnostic modalities used to identify these types of recurrence. The findings of this study serve as the basis of a future Delphi-based proposal of novel and widely accepted definitions of recurrence of DTC, categorized based on treatment protocols. This international Delphi study has already commenced, and the results are expected in 2024.

There are some limitations to this study. First, some definitions could potentially fall into multiple categories/tables, as their interpretation might vary. As a result, there is a possibility that some of the percentages of the categories would undergo slight adjustments. Nevertheless, this pertains only to a limited number of definitions and would have negligible impact to the overall results.

Second, a general limitation of this study is the possibility of subjective bias in the selection and interpretation of the studies as the process of selecting which studies/definitions to include could be subject to interpretation. We have tried to mitigate this limitation, by employing rigorous and stringent in- and exclusion criteria and by using multiple reviewers to independently asses the studies and collect the data.

In conclusion, this systematic review underlines that there is no universally accepted definition of recurrence of DTC in the current studies across any of the treatment categories. The findings of this study illustrate this important knowledge gap and will provide the basis of a future, international Delphi-based proposal aimed at establishing novel and universally accepted definitions of recurrence of DTC, following treatment with total thyroidectomy with RAI, without RAI, and lobectomy. These uniform definitions could facilitate global discussion, streamline research methods, improve the comparability of studies, and enhance the assessment of treatment outcomes regarding recurrence of DTC.

Footnotes

Authors’ Contributions

D.J.B. and P.M.R.S.: Independently screened the titles, abstracts and full text, and extracted and synthesized the data under supervision of J.P.M.D. and A.F.E. D.J.B.: Formulated the search terms in collaboration with F.S.J. D.J.B. and P.M.R.S.: Took the lead in writing the article under supervision of J.P.M.D. and A.F.E. H.M.S., S.C.C., M.R.V., A.S.P.T., C.F.M., E.B., S.K., R.P.P., F.A.V., R.N.-M., E.J.M.N.D.: Critically reviewed and improved the article. All the authors agreed with the publication of the article in the current form.

Institutional Review Board Statement

No formal Institutional Review Board approval was sought as this study did not involve any human subjects or patient data.

Author Disclosure Statement

All authors declare that they have no conflicts of interest.

Funding Statement

This work was supported by Stichting Kinderen Kankervrij (KiKa) grant number 441.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

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