Scoring system for predicting recurrences in patients with papillary thyroid microcarcinoma

in European Journal of Endocrinology

Context

Papillary thyroid microcarcinomas (PMC) defined as tumors ≤10 mm in diameter (including pT1a and pT3 according to the latest pTNM classification) have good prognosis, although recurrence is possible. Clinicians are interested in using a scoring system for predicting recurrences.

Objective

To identify the prognostic factors for recurrence in patients with PMC and to develop a scoring system based on lymph node involvement, multifocality, and sex. To determine the impact of extrathyroidal invasion (ETI) and a threshold value for analyzing multifocality.

Methods

Single-center retrospective study of a cohort of 1669 patients with PMC managed from 1960 to 2007. The Kaplan–Meier survival rate and prognostic factors of events were analyzed using log-rank tests and uni- and multivariate Cox model-based analyses. A scoring system was proposed.

Results

Sixty-eight recurrences were observed. Initial lymph node metastases (P=0.0001), multifocality (P=0.05), and male sex (P=0.01) were significantly associated with recurrence, although there was a period effect (after 1990). PMC size was not a significant variable. Our scoring system allows us to separate patients into three risk groups according to their recurrence-free probability. For PMC Nx patients, total foci size of multifocal tumors >20 mm was significantly associated with recurrence (P<0.0001). Radioiodine (RAI) ablation was associated with better outcome only in PMC with ETI.

Conclusion

Our scoring system classifies recurrence risk. In PMC Nx patients, multifocality is important in planning therapeutic strategies. Recurrence probability of pT3 PMC appears lower if RAI ablation is performed.

Abstract

Context

Papillary thyroid microcarcinomas (PMC) defined as tumors ≤10 mm in diameter (including pT1a and pT3 according to the latest pTNM classification) have good prognosis, although recurrence is possible. Clinicians are interested in using a scoring system for predicting recurrences.

Objective

To identify the prognostic factors for recurrence in patients with PMC and to develop a scoring system based on lymph node involvement, multifocality, and sex. To determine the impact of extrathyroidal invasion (ETI) and a threshold value for analyzing multifocality.

Methods

Single-center retrospective study of a cohort of 1669 patients with PMC managed from 1960 to 2007. The Kaplan–Meier survival rate and prognostic factors of events were analyzed using log-rank tests and uni- and multivariate Cox model-based analyses. A scoring system was proposed.

Results

Sixty-eight recurrences were observed. Initial lymph node metastases (P=0.0001), multifocality (P=0.05), and male sex (P=0.01) were significantly associated with recurrence, although there was a period effect (after 1990). PMC size was not a significant variable. Our scoring system allows us to separate patients into three risk groups according to their recurrence-free probability. For PMC Nx patients, total foci size of multifocal tumors >20 mm was significantly associated with recurrence (P<0.0001). Radioiodine (RAI) ablation was associated with better outcome only in PMC with ETI.

Conclusion

Our scoring system classifies recurrence risk. In PMC Nx patients, multifocality is important in planning therapeutic strategies. Recurrence probability of pT3 PMC appears lower if RAI ablation is performed.

Introduction

Over the past 30 years, there has been a significant rise worldwide in the incidence of papillary thyroid microcarcinoma (PMC) (1), i.e. thyroid carcinoma <10 mm in diameter (2). The last pTNM classification does not recognize PMC as a specific entity. They are included in the pT1a carcinoma category when the tumor is confined to the thyroid and in the pT3 category (called ‘micro pT3’) when minimal extrathyroidal invasion (ETI) is present (i.e. extension to the sternothyroid muscle or perithyroid soft tissues) (3). The overall prognosis of PMC is excellent, although locoregional recurrence (LRR) and the development of distant metastases have been known to occur (3–7 and <1% respectively) (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15).

PMC prognosis depends on the initial clinicopathological presentation. Clinicians are interested in using a scoring system to accurately predict recurrence risk and manage patients accordingly (16). The presence of neck lymph node involvement and multifocality are known to be factors of poor prognosis. In contrast, a unifocal microcarcinoma pT1a presents no cause for concern (16, 17). However, other clinicopathological situations have prognostic significance that is less clearly specified in the guidelines (18, 19), such as Nx PMCs that are incidentally diagnosed after total or partial thyroidectomy for presumably benign disease and therefore have not undergone lymph node dissection. In such cases, the clinician is faced with the issue of multifocality, which is present in up to 48% of cases (20). However, there is no medical data concerning the threshold beyond which multifocality is associated with a higher risk of recurrence. Another unresolved issue is the prognostic impact of small ETI for PMC on the recurrence risk and as a result the relevance of radioiodine (RAI) ablation in such cases.

The aims of this study were to determine recurrence-free probability, identify prognostic factors for recurrence, and develop a simple scoring system enabling the clinician to assess the risk of recurrence. Prognostic factors such as lymph node involvement, ETI, tumor size, sex, multifocality, and RAI treatment were analyzed in a large cohort of 1669 patients with PMC treated at a single institution. Multifocality was studied specifically in pT1a Nx PMCs, which are a common issue for physicians. Prognosis of the pT3 PMC subgroup was also specifically studied. We found that initial lymph node metastases, multifocality, and male sex were the three major prognostic factors for relapse. By assigning scoring points for each factor, patients are divided into three risk groups according to their recurrence-free probability. In patients with multifocal pT1a Nx PMC (pT1a (m) Nx), the sum of all foci >20 mm was a significant predictor of recurrence. RAI ablation was associated with reduced risk of recurrence only in pT3 PMC.

Patients and methods

Patients

Patient information was obtained from a database and from medical records. Of the 6416 patients with differentiated thyroid carcinoma that were treated and followed at the Department of Nuclear Medicine at the Groupe Hospitalier Pitié-Salpêtrière from 1960 to 2007, 1758 patients (308 men and 1450 women) were affected by PMC.

Histological data were obtained from the initial pathology reports. Of the 1758 patients with PMC, 106 were classified initially as having follicular carcinoma. Owing to the rarity and the diagnostic pitfalls of this follicular type, histology slides or reports of the 106 cases were reviewed by a single experienced pathologist: 12 were true, minimally invasive follicular carcinoma (diagnosis based on capsular effraction and/or vascular invasion without typical nuclear features of papillary carcinoma) and were excluded. In the same way, two cases were excluded due to tumor size >10 mm, two cases were a ‘not otherwise specified’ histological type, one case was a medullary carcinoma, and 62 cases did not have slides available. So, finally, of the 106 cases, 27 were papillary PMC, which in most cases were a follicular variant of papillary carcinoma and were kept in our final series.

Furthermore, 10 (0.6%) PMC patients with distant metastases at diagnosis were also excluded. Metastases were located as follows: lung metastases (eight patients), bone metastases (one patient), and mediastinal lymph node involvement (one patient). These metastases were detected by cytological or histological analysis or by abnormal iodine uptake after therapeutic whole-body scan (WBS).

The final series included 1669 patients. Their characteristics are presented in Tables 1 and 2. The mean age of the patients at initial diagnosis was 47.2±13.1 years. The mean size of the initial tumor was 6.2±2.9 mm. Multifocality was accurately assessed in the subgroup of 236 patients with pT1a (m) Nx PMC, with recording data regarding the number of foci, the total foci size, and the bilaterality. In this subgroup, the number of foci ranged from 2 to 11 (mean: 2.6) and the total foci size ranged from 2 to 53 mm (mean: 9.7 mm). The total foci size was between 21 and 53 mm in six patients. Among pT1a (m) Nx carcinomas, 41% were discovered incidentally at the pathological examination.

Table 1

Patients' characteristics according to the initial lymph node status.

N0 (n=418)Nx (n=962)N1 (n=289)Total (n=1669)
Sex, male53 (12.7%)148 (15.6%)88 (30.4%)289 (17.3%)
Age ≥45 years237 (56.7%)596 (15.4%)117 (40.5%)950 (57%)
Total or near-total thyroidectomy411 (98.3%)924 (96%)287 (99.3%)1622 (97.2%)
Lobectomy7 (1.7%)38 (4%)2 (0.7%)47 (2.8%)
Initial cervical node surgerya418 (100%)0261 (90.3%)b679 (40.7%)
Radioiodine ablation of thyroid remnants368 (88%)659 (68.5%)281 (97.2%)1308 (78.4%)
Tumor size ≤5 mm82 (19.6%)369 (38.3%)56 (19.4%)507 (30.4%)
Multifocality141 (33.7%)258 (26.8%)118 (40.8%)517 (31%)
Vascular invasion12 (2.9%)34 (3.5%)26 (9%)72 (4.3%)
ETI (pT3)53 (12.7%)65 (6.7%)57 (19.7%)175 (10.5%)
Period of initial diagnosis earlier than 199096 (23%)199 (20.7%)113 (39.1%)408 (24.4%)

ETI, extrathyroidal invasion.

Includes modified radical lymph node dissection and limited lymph node excision.

Lymph node metastasis discovered incidentally during pathological examination of the thyroid.

Table 2

Patients' characteristics according to the presence of ETI.

pT1 (n=1494)pT3 (n=175)Total (n=1669)
Sex, male257 (17.2%)32 (18.3%)289 (17.3%)
Age ≥45 years848 (56.8%)102 (58.3%)950 (57%)
Total or near-total thyroidectomy1448 (97%)174 (99.4%)1622 (97.2%)
Lobectomy46 (3%)1 (0.6%)47 (2.8%)
Initial cervical node surgerya571 (38.2%)108 (61.7%)679 (40.7%)
Radioiodine ablation of thyroid remnants1137 (76.1%)171 (97.7%)1308 (78.4%)
Tumor size ≤5 mm495 (33.1%)12 (6.8%)507 (30.4%)
Multifocality444 (29.7%)73 (41.7%)517 (31%)
Vascular invasion56 (3.7%)16 (9.1%)72 (4.3%)
Initial cervical lymph node metastases (N1)232 (15.5%)57 (32.6%)289 (17.3%)
Undetermined lymph node status (Nx)897 (60%)65 (37.1%)962 (57.6%)
No lymph node metastases (N0)365 (24.4%)53 (30.3%)418 (25%)
Period of initial diagnosis earlier than 1990386 (25.8%)22 (12.6%)408 (24.4%)

Includes modified radical lymph node dissection and limited lymph node excision.

Initial treatment and follow-up

Patient follow-up data were obtained from the database, medical records, town council registers, and periodic correspondence with patients or their referring physicians. Initial treatment is presented in Tables 1 and 2. Until 1990, the decision to carry out RAI ablation depended on the result of the diagnostic WBS performed 6 weeks after surgery. For the last two decades, the indication for RAI ablation has been discussed on a regular basis in a multidisciplinary staff meeting at our hospital, and iodine therapy has been indicated for tumors with extension beyond the thyroid capsule (pT3 or pT4) and in patients with lymph node involvement (N1) or distant metastases (M1). A suppressive dose of l-thyroxin (l-T4) treatment is initially prescribed only for patients who have received an ablative 131I dose.

Changes in the follow-up of patients with PMC took place during the study period. Ultrasonography and, if necessary, fine-needle aspiration biopsy have been progressively included in follow-up since 1990 in combination with the recombinant human TSH-stimulated thyroglobulin test (21). Currently, the follow-up protocol consists of regular clinical examinations, serum thyroglobulin level measurement, detection of anti-thyroglobulin antibodies (systematically performed since its availability in 1981), and neck ultrasonography. WBS under TSH stimulation (i.e. withdrawal of T4 or, more recently, the use of recombinant human TSH) is no longer performed systematically to check the efficiency of thyroid remnant ablation.

Definition and diagnosis of recurrence

Events were analyzed retrospectively. Events that were considered recurrent included the following:

  • LRR, defined as a thyroid bed, soft tissue, or cervical lymph node recurrence of an initially treated PMC. The diagnosis of LRR was assessed by histological analysis at surgery or by fine-needle aspiration biopsy or by a positive 131I cervical uptake anywhere in the neck after 131I diagnostic (11.1 MBq) or therapeutic (3.7 GBq) dose.
  • Isolated and repeatedly elevated serum thyroglobulin levels (>10 ng/ml after T4 withdrawal) that justified the administration of a second therapeutic dose of 131I.
  • Distant metastases assessed by cytological or histological analysis or by iodine uptake after diagnostic or therapeutic WBS.

Among patients who experienced recurrence, we analyzed the result of the 6-month checkup after initial treatment. We distinguished between patients whose 6-month checkup was normal (i.e. normal clinical examination, undetectable thyroglobulin level, and normal ultrasonography) and those whose 6-month checkup was abnormal (suspicious thyroglobulin level and/or ultrasonography interpreted according to previous RAI ablation).

Residual Tg levels, suspicious neck ultrasonography, or imaging at 6-month checkup after initial treatment, which did not lead to a proven locoregional event or distant metastases or the second administration of 131I therapeutic dose, were not considered as events in the statistical analysis of prognostic factors for recurrence. Patients who were retreated by surgery or 131I within 6 months of the initial treatment were not considered to have a recurrence.

Definition of end point status

At end point, patients were considered as follows:

  • cured if serum thyroglobulin levels (when available) were under 2 ng/ml after withdrawal of l-T4 (or under 2.5 ng/ml before 1984) or, more recently, under 1 ng/ml after the use of recombinant human TSH or undetectable on l-T4 therapy or when there was no iodine uptake after diagnostic WBS and/or normal neck ultrasonography,
  • to have progressive disease if serum thyroglobulin levels increased significantly between two assays or if morphological imaging (CT scan and PET scan) was abnormal,
  • to have a stable disease if they did not match the definition of cured but if serum thyroglobulin levels were stable between the last two assays or if the tumor volume was stable on morphological imaging.

Statistical analysis

The main criterion of the study is the time to recurrence, defined as the difference between the date of recurrence treatment and the date of the treatment. We considered the date of recurrence to be the date of recurrence treatment, with this date corresponding to a standardized reliable proof of recurrence for all patients. Follow-up time was defined as the date of death or the date of the last news from survivors. Patients with no observed recurrence before the end of follow-up were considered as censored at this date. The following potential prognostic factors were studied: age at primary tumor diagnosis, sex, period of initial diagnosis (before or after 1990), initial tumor size (mean >5 or ≤5 mm), invasion of the initial tumor (multifocality, ETI, and vascular invasion), initial lymph node metastases, complete initial surgery (total or near-total thyroidectomy vs lobectomy), initial cervical lymph node surgery (modified radical lymph node dissection or limited lymph node excision vs no lymph node surgery), initial RAI therapy, and RAI dose. For patients with pT1a (m) Nx tumors, the following variables were also studied: number of foci, the sum of the largest sizes of all foci, and bilaterality of the foci. Taking the hypothesis that tumor foci are spherical (volume: 4/3 πr3), the total volume of the tumor foci was calculated and the prognostic value of the total volume was evaluated. The prognostic value of each variable was studied in the total series as well as in pT1a (m) Nx DTMC subset and according to the presence of ETI. The relationships between each potential risk factor and time to recurrence were described using the Kaplan–Meier estimation method and tested first using log-rank tests. In a second step, multivariate Cox models were built using stepwise regressions. Variables with P values <0.20 in univariate analyses were entered into the step-wise regressions, and variables significant with a P value <0.05 with the Wald test were retained in the final models. All tests were two-sided, with a P value <0.05 considered significant. Computations were performed using the SAS V9 statistical package. A simplified prognostic classification was derived from the final Cox model obtained from data with treatment year after 1990. In order to build the classification, Kaplan–Meier recurrence-free probability functions were estimated for each of the eight configurations obtained from the three binary variables defining the final model, and configurations of variables with near recurrence probability functions were grouped into three prognostic classes. Finally, a simple scoring system was built in order to classify the final prognostic groups.

Results

Recurrences and outcome

In our study, the mean follow-up time was 6.5±6.7 years (range: 1 month–37.9 years; median: 4.7 years). Sixty-eight recurrences (4.1%) were observed. Of these 68 recurrences, 16 occurred in patients whose 6-month checkup was normal (i.e. normal clinical examination, undetectable thyroglobulin level, and normal ultrasonography) whereas the other 52 occurred in patients whose 6-month checkup was abnormal. Prognostic factors for recurrence (univariate and multivariate analysis) were analyzed taking into recurrences, 56 (3.3%) were locoregional and two were lung metastases. A second therapeutic dose of 131I was administered in ten cases (0.6%) based on isolated and repeatedly elevated serum thyroglobulin levels. The maximal time period between initial treatment and diagnosis of recurrence was 15 years. The recurrence-free probability at 5, 10, and 20 years was 95.2% (confidence interval (CI): (94%; 96.5%)), 93.5% (CI: (91.9%; 95.5%)), and 92.2% (CI: (91%; 94.4%)) respectively.

At the end point, 1526 patients (91.4%) were cured, 18 patients (1%) had progressive disease, and 42 patients (2.5%) had stable disease. Eighty-three patients (5%) were lost in follow-up, and 38 patients (2.3%) died, although none as a result of their thyroid cancer.

Prognostic factors for recurrence of the 1669 patients

Prognostic factors for recurrence (univariate and multivariate analysis) were analyzed taking into account an interaction period effect. Univariate analysis is shown in Table 3. We chose 1990 as a transitional year as this year is the beginning of the routine use of neck ultrasound for monitoring patients. Significant prognostic factors for recurrence in the multivariate analysis (Table 4) were lymph node metastases, multifocality, and male sex. Considering the interaction period effect, we found an interaction for lymph node metastases, which had more important prognostic significance after 1990 (hazard ratio (HR)=7.5 (1.4–28.9)) than before (HR=3.2 (1.6–6.1)). On the other hand, we found no interaction between multifocality and male sex.

Table 3

Prognostic factors for recurrence (univariate analysis).

Variable10-Year recurrence cumulative incidence probability (s.d.)P value
Age at diagnosis0.024
 ≥45 years0.05 (0.01)
 <45 years0.08 (0.01)
Sex<0.0001
 Male0.12 (0.02)
 Female0.05 (0.01)
Surgical procedure0.29
 Lobectomy0.18 (0.08)
 Near-total thyroidectomy0.04 (0.02)
 Total thyroidectomy0.07 (0.01)
Initial cervical node surgery0.001
 No dissection0.05 (0.01)
 Lymph node dissection0.09 (0.01)
Radioiodine ablation of thyroid remnants0.96
 Yes0.06 (0.01)
 No0.10 (0.04)
Tumor size0.070
 ≥5 mm0.08 (0.01)
 <5 mm0.04 (0.01)
Multifocality0.007
 Yes0.10 (0.02)
 No0.05 (0.01)
Vascular invasion0.46
 Yes0.03 (0.02)
 No0.07 (0.01)
Capsular invasion0.26
 Yes0.08 (0.02)
 No0.06 (0.01)
Initial cervical lymph node metastases<0.0001
 Yes0.19 (0.03)
 No0.04 (0.01)
Initial diagnosis year0.94
 <19900.06 (0.01)
 ≥19900.06 (0.01)

Significant values are in bold.

Table 4

Prognostic factors for recurrence (multivariate analysis).

VariablesHazard ratio (95% CI)P value
Sex
 Female10.010
 Male2.0 (1.2; 3.2)
Multifocality
 No10.051
 Yes1.6 (1.0; 2.6)
Initial cervical lymph node metastases
 No1
 Yes, before 19903.2 (1.6; 6.1)0.001
 Yes, after 19907.5 (4.3; 13.1)<0.0001

ETI did not appear as an independent variable as it was significantly associated with recurrence in the univariate analysis but not in the multivariate analysis. It is notable that ETI and lymph node metastases are interrelated (P<0.0001). Indeed, 57 out of 175 (32.6%) pT3 PMC patients presented with initial lymph node metastases vs 232 out of 1494 (15.5%) pT1a PMC (P<0.0001). Patient age, the size of the PMC, or the RAI ablation appeared to be not significant variables associated with recurrence in the multivariate analysis.

Scoring system

The score was designed to permit risk stratification with available information at initial presentation for patients diagnosed most recently, i.e. 1990 (this year corresponds to the beginning of the regular use of ultrasound).

Points were attributed to three significant prognostic factors: sex (female=0, male=1), multifocality (absent=0, present=1), and lymph node metastasis (absent=0, present=3). Patients were then divided into three risk groups according to their recurrence-free probability (Fig. 1; Table 5).

Figure 1
Figure 1

Time to event stratified by three group score: group 1 (black line), group 2 (gray line), and group 3 (dotted line).

Citation: European Journal of Endocrinology 167, 2; 10.1530/EJE-12-0105

Table 5

Final scoring system for patients diagnosed since 1990.

Recurrence riskPatientspT3 PMCScore10-Year recurrence probability (95% CI)
Low1085105 (9.7%)0, 1, or 22.7% (1.3–4.1%)
Intermediate15339 (25.5%)3 or 424% (13.7–34.3%)
High239 (39.1%)542.6% (12.7–72.5%)

The low-risk group corresponds to the score 0, 1, or 2, i.e.:

  • PMC N0 or Nx, unifocal or multifocal, in a female or
  • PMC N0 or Nx, unifocal or multifocal, in a male.

The intermediate-risk group corresponds to the score 3 or 4, i.e.:

  • PMC N1, unifocal or multifocal in a female or
  • PMC N1, unifocal in a male.

The high-risk group corresponds to the score 5, i.e. PMC N1, multifocal in a male. It is noticeable that in the low-risk group, out of the 29 events observed, 10 (34.5%) occurred in patients whose 6-month checkup was normal (i.e. normal clinical examination, undetectable thyroglobulin level, and normal ultrasonography). In the intermediate-risk group, out of the 31 events observed, 21 (80.6%) occurred in patients whose 6-month checkup was already abnormal. In the high-risk group, the eight events observed occurred after an abnormal 6-month checkup. As expected, pT3 PMC were much more frequent in the high-risk group (Table 5).

Prognostic factors for recurrence in patients presenting with pT1a (m) Nx PMC

In the group of patients with pT1a (m) Nx PMC, the total foci size of a multifocal cancer was a significant predictor for prognosis (P=0.009; HR: 1.2 (1.05–1.4)), with the threshold of a total foci size >20 mm significantly associated with risk of recurrence (P=0.03). Surprisingly, bilaterality, the number of foci, or the threshold of total foci size >10 mm was not significantly associated with an increased risk of recurrence. As shown in Fig. 2, the recurrence-free probability of pT1a (m) Nx PMC with a total foci size >20 mm was worse than for those <20 mm (P=0.03). Moreover, our analysis of the total volume of the tumor foci in patients with pT1a (m) Nx tumors showed that this variable was also significantly linked to prognosis (P<0.0001).

Figure 2
Figure 2

Time to event for pT1a Nx patients for multifocal DTMC with total foci size <10 mm (gray line), between 10 and 20 mm (black line), and >20 mm (dotted line).

Citation: European Journal of Endocrinology 167, 2; 10.1530/EJE-12-0105

Recurrence-free probability and prognostic factors for recurrence depending on the presence of ETI

The recurrence-free probability of patients with pT3 PMC was 89.8% (CI: (83.9%, 95.6%)) at 10 years and was statistically different from those with pT1a PMC (P=0.02). In patients presenting with micro pT3 carcinoma, the only variable significantly associated with absence of recurrence (multivariate analysis) was RAI ablation dose (P<0.002; HR: 0.97 (0.95–0.99)), which averaged 3.2 GBq (range: 0–4.1 GBq).

Discussion

Owing to the dramatic worldwide increase in PMC commonly diagnosed fortuitously after thyroidectomy, clinicians are faced with the challenge of detecting those that are potentially aggressive and managing these efficiently. Although in most cases the outcome is favorable, PMC at diagnosis can present with signs of invasion associated with recurrence risk such as lymph node metastasis (17.3%), ETI (10.7%), multifocality (31%), and even distant metastasis in our series (0.6%). The latest guidelines enable the clinician to stratify the patients according to these factors (18, 19). Nevertheless, frequent incidental detection of PMC implies no neck lymph node dissection, which makes the risk stratification of these patients difficult. Moreover, the evaluation of the degree of multifocality and its management is not sufficiently addressed by the guidelines.

In our retrospective study on a large series of PMC, we started to investigate the predictors for relapse in order to build a scoring system that would accurately predict a patient's postoperative outcome. Most recurrences in papillary thyroid cancer occur within the first 5 years (22, 23). In our work, the median follow-up is 4.7 years. It should be noted that approximately a quarter of our patients (23%) were followed for more than 10 years, which is a reliable period to detect recurrence. Bearing in mind these considerations, our work proposes interesting data that, we feel, will be useful to the clinician.

First, lymph node metastases, multifocality, and male sex were significantly associated with recurrence risk in the multivariate analysis. Overall, our data are consistent with the findings of many others (4, 5, 8, 10, 11, 12, 13, 15, 23, 24, 25, 26, 27).

Secondly, to develop this scoring system, we had to take into account the heterogeneity of the management of patients attending our center over a very long period namely from 1960 to 2007. We chose 1990 as a turning point because this year marks the start of the routine use of cervical ultrasound. The analysis highlighted a period effect that we took into consideration as the time of diagnosis could have an impact on the prognosis. Consequently, on the basis of our Cox step-wise regression analysis, the scoring system was developed solely for patients whose diagnosis of cancer had been made since 1990. Lymph node metastases appeared to have greater prognostic significance after 1990 than before while multifocality and male sex had no interaction with the period. Our data allow classification of patient recurrence risk using simple criteria available at initial presentation, i.e. lymph node status, multifocality, and male sex. Compared with the ETA and ATA guidelines of stratification risk, our scoring system offers additional benefits (18, 19). First, it clarifies the degree of risk of Nx PMC patients. These patients fall into the low-risk group as did most patients in our series. Indeed, the low-risk group represents 65% of our patients with a 10-year recurrence probability of 2.7% (1.3–4.1%) compared with significantly higher risk in the intermediate and high-risk groups: 24 (13.7–34.3%) and 42.6% (12.7–72.5%) respectively. More precisely, the 10-year recurrence probability for patients with N0 DTMC (3.1% (0.9–5.3%)) was statistically not different from those of patients with Nx DTMC (3.9% (2–5.8%)) but both were significantly better than those of the N1 DTMC group (18.7% (13.1–24.2%)). This is naturally reassuring for the patient who has not had neck dissection. Therefore, we focused on the analysis of multifocality in a group of patients with pT1a (m) Nx PMC. We found that multifocality is a prognostic factor for recurrence (HR=1.6) as asserted in other publications (5, 13, 23, 28). Recently published guidelines (18, 19) highlight that PMC patients without lymph node metastasis (N0) presenting with multifocal pT1a with a total foci size ≤10 mm are at low risk and so RAI therapy is not recommended. Data regarding the relevance of this 10 mm threshold are lacking. Our results clearly show that when total foci size reaches 20 mm or more, there is a higher risk for recurrence. However, it is not higher when total foci size is 10 mm. For pT1a (m) Nx PMC, when all foci are <20 mm, our data suggest that RAI ablation may not be recommended (instead of the 10 mm threshold currently recommended). The recommendation remains a hypothesis in the absence of a prospective study comparing the outcome of RAI-treated groups (with total foci tumor size more than 20 mm) vs a nontreated group. Out of caution, we studied the total volume of the tumor foci rather than tumor size. Our results once again showed that there was a close relationship between the total volume of a multifocal pT1a Nx tumor and the risk of recurrence. This result suggested that the total volume is a reliable predictor of recurrence that should be taken into account when evaluating the prognosis of PMC. It further showed that progress remains to be made in creating efficient tools that estimate tumor mass.

Secondly, the model highlights the prognostic significance of the patient's sex. Male sex appeared to be a significant risk factor, although this is attenuated when the tumor is strictly unifocal with no lymph node involvement. In our classification, female patients with N1 PMC fell into the intermediate-risk group, such as in the ATA guidelines (whatever the gender), whereas the ETA guidelines classified them as high risk.

It is noteworthy that in our study, most recurrences occurred in patients whose 6-month checkup after the initial treatment was abnormal (the eight events of the high-risk group and the 25 events out of 31 in the intermediate-risk group). It is difficult to judge how far this may be due to the aggressive behavior of the disease and/or an incomplete initial treatment especially regarding the lymph node dissection procedure. This makes the recent concept based on the delayed risk stratification that integrates the results of the 6- to 12-month control after initial treatment all the more interesting (29, 30, 31, 32). Lastly, we focused on the high-risk group patients. Besides the impact of well-established poor prognosis on the presence of lymph node metastases, we wanted to accurately study the role of ETI whose impact on PMC prognosis has not been well established so far. ETI is recognized as a risk factor for recurrence of carcinoma >10 mm, but this point is still being debated for PMC, as some authors report that ETI is a predictive factor of adverse outcome (33, 34), while others do not (4, 5, 10, 15, 35, 36). One can assume that the minimal ETI of a PMC that is located on the edge of the gland could have a weaker prognostic impact than that of the ETI of a macrocarcinoma developing at the center of the gland and finally invades peripheral soft tissue. In our study, the presence of ETI did not appear to be an independent predictive factor for recurrence in the entire cohort, as it was significantly associated with relapse in the univariate analysis but not in the multivariate one. Surprisingly, in the pT3 PMC group, lymph node metastases were not associated with recurrence. These results are probably due to the fact that ETI and lymph node metastases are interrelated, as suggested both by our statistical analysis and by other authors (26). Furthermore, in this pT3 PMC group, the ablative dose of 131I was the only variable significantly associated with a lower risk of recurrence. Although RAI remnant ablation was not significantly associated with recurrence in our entire series of PMC patients or in several other studies (37, 38), it may be mandatory for patients with pT3 PMC. Ideally, this needs to be confirmed in a prospective study comparing the two therapeutic options (RAI ablation or abstention).

In conclusion, although relapse is rare in patients with PMC, clinicians should pay particular attention to lymph node status, multifocality, male sex, and to a lesser extent to ETI when predicting recurrence. Our scoring system will help physicians accurately predict patients' recurrence risk at initial presentation. This will produce better management decisions tailored on an individual basis, although ideally it needs to be tested on a larger scale. Our study should reassure patients with pT1a Nx PMC regarding the absence of lymph neck dissection. Such patients with multifocality presenting with a total foci size <20 mm may also warrant less aggressive therapeutic and follow-up strategies. Further studies need to be carried out regarding the pathological significance of ETI specifically for pT3 PMC.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Acknowledgements

The authors are grateful to Drs Claudine Guillausseau, Danièle Le Guillouzic, Elodie Le Marois, and Agnès Rouxel for their careful management of patients with differentiated thyroid carcinoma.

References

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    HughesDTHaymartMRMillerBSGaugerPGDohertyGM. The most commonly occurring papillary thyroid cancer in the United States is now a microcarcinoma in a patient older than 45 years. Thyroid201121231236. doi:10.1089/thy.2010.0137.

    • Search Google Scholar
    • Export Citation
  • 2

    HedingerCWilliamsEDSobinLH. The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer198963908911. doi:10.1002/1097-0142(19890301)63:5<908::AID-CNCR2820630520>3.0.CO;2-I.

    • Search Google Scholar
    • Export Citation
  • 3

    Edge SB Byrd DR Compton CC Fritz AG Greene FL & Trotti A. AJCC Cancer Staging Handbook. Springer-Verlag: New York 2010

  • 4

    BesicNPilkoGPetricRHocevarMZgajnarJ. Papillary thyroid microcarcinoma: prognostic factors and treatment. Journal of Surgical Oncology200897221225. doi:10.1002/jso.20935.

    • Search Google Scholar
    • Export Citation
  • 5

    BaudinETravagliJPRopersJMancusiFBruno-BossioGCaillouBCailleuxAFLumbrosoJDParmentierCSchlumbergerM. Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience. Cancer199883553559. doi:10.1002/(SICI)1097-0142(19980801)83:3<553::AID-CNCR25>3.0.CO;2-U.

    • Search Google Scholar
    • Export Citation
  • 6

    RotiERossiRTrasforiniGBertelliFAmbrosioMRBusuttiLPearceENBravermanLEDegli UbertiEC. Clinical and histological characteristics of papillary thyroid microcarcinoma: results of a retrospective study in 243 patients. Journal of Clinical Endocrinology and Metabolism20069121712178. doi:10.1210/jc.2005-2372.

    • Search Google Scholar
    • Export Citation
  • 7

    PelizzoMRBoschinIMToniatoAPiottoABernantePPagettaCRampinLRubelloD. Papillary thyroid microcarcinoma (PTMC): prognostic factors, management and outcome in 403 patients. European Journal of Surgical Oncology20063211441148. doi:10.1016/j.ejso.2006.07.001.

    • Search Google Scholar
    • Export Citation
  • 8

    NoguchiSYamashitaHUchinoSWatanabeS. Papillary microcarcinoma. World Journal of Surgery200832747753. doi:10.1007/s00268-007-9453-0.

  • 9

    NoguchiSYamashitaHMurakamiNNakayamaITodaMKawamotoH. Small carcinomas of the thyroid. A long-term follow-up of 867 patients. Archives of Surgery1996131187191. doi:10.1001/archsurg.1996.01430140077021.

    • Search Google Scholar
    • Export Citation
  • 10

    HayIDGrantCSvan HeerdenJAGoellnerJREbersoldJRBergstralhEJ. Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period. Surgery199211211391147.

    • Search Google Scholar
    • Export Citation
  • 11

    ChowSMLawSCChanJKAuSKYauSLauWH. Papillary microcarcinoma of the thyroid-prognostic significance of lymph node metastasis and multifocality. Cancer2003983140. doi:10.1002/cncr.11442.

    • Search Google Scholar
    • Export Citation
  • 12

    LoCYChanWFLangBHLamKYWanKY. Papillary microcarcinoma: is there any difference between clinically overt and occult tumors?World Journal of Surgery200630759766. doi:10.1007/s00268-005-0363-8.

    • Search Google Scholar
    • Export Citation
  • 13

    HayIDHutchinsonMEGonzalez-LosadaTMcIverBReinaldaMEGrantCSThompsonGBSeboTJGoellnerJR. Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60-year period. Surgery2008144980988. doi:10.1016/j.surg.2008.08.035.

    • Search Google Scholar
    • Export Citation
  • 14

    MercanteGFrasoldatiAPedroniCFormisanoDRennaLPianaSGardiniGValcaviRBarbieriV. Prognostic factors affecting neck lymph node recurrence and distant metastasis in papillary microcarcinoma of the thyroid: results of a study in 445 patients. Thyroid200919707716. doi:10.1089/thy.2008.0270.

    • Search Google Scholar
    • Export Citation
  • 15

    KimTYHongSJKimJMGu KimWGongGRyuJSKimWBYunSCShongYK. Prognostic parameters for recurrence of papillary thyroid microcarcinoma. BMC Cancer20088296doi:10.1186/1471-2407-8-296.

    • Search Google Scholar
    • Export Citation
  • 16

    DuranteCAttardMTorlontanoMRongaGMonzaniFCostanteGFerdeghiniMTuminoSMeringoloDBrunoRDe TomaGCrocettiUMontesanoTDardanoALamartinaLManigliaAGiacomelliLFilettiS. Identification and optimal postsurgical follow-up of patients with very low-risk papillary thyroid microcarcinomas. Journal of Clinical Endocrinology and Metabolism20109548824888. doi:10.1210/jc.2010-0762.

    • Search Google Scholar
    • Export Citation
  • 17

    TorlontanoMCrocettiUAugelloGD'AloisoLBonfittoNVarrasoADicembrinoFModoniSFruscianteVDi GiorgioABrunoRFilettiSTrischittaV. Comparative evaluation of recombinant human thyrotropin-stimulated thyroglobulin levels, 131I whole-body scintigraphy, and neck ultrasonography in the follow-up of patients with papillary thyroid microcarcinoma who have not undergone radioiodine therapy. Journal of Clinical Endocrinology and Metabolism2006916063. doi:10.1210/jc.2005-1185.

    • Search Google Scholar
    • Export Citation
  • 18

    CooperDSDohertyGMHaugenBRKloosRTLeeSLMandelSJMazzaferriELMcIverBPaciniFSchlumbergerMShermanSIStewardDLTuttleRM. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid20091911671214. doi:10.1089/thy.2009.0110.

    • Search Google Scholar
    • Export Citation
  • 19

    PaciniFSchlumbergerMDralleHEliseiRSmitJWWiersingaW. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. European Journal of Endocrinology2006154787803. doi:10.1530/eje.1.02158.

    • Search Google Scholar
    • Export Citation
  • 20

    RotiEDegli UbertiECBondanelliMBravermanLE. Thyroid papillary microcarcinoma: a descriptive and meta-analysis study. European Journal of Endocrinology2008159659673. doi:10.1530/EJE-07-0896.

    • Search Google Scholar
    • Export Citation
  • 21

    FrasoldatiAPesentiMGalloMCaroggioASalvoDValcaviR. Diagnosis of neck recurrences in patients with differentiated thyroid carcinoma. Cancer2003979096. doi:10.1002/cncr.11031.

    • Search Google Scholar
    • Export Citation
  • 22

    PelttariHLaitinenKSchalin-JanttiCValimakiMJ. Long-term outcome of 495 TNM stage I or II patients with differentiated thyroid carcinoma followed up with neck ultrasonography and thyroglobulin measurements on T4 treatment. Clinical Endocrinology200869323331. doi:10.1111/j.1365-2265.2008.03217.x.

    • Search Google Scholar
    • Export Citation
  • 23

    RossDSLitofskyDAinKBBigosTBrierleyJDCooperDSHaugenBRJonklaasJLadensonPWMagnerJRobbinsJSkarulisMCStewardDLMaxonHRShermanSI. Recurrence after treatment of micropapillary thyroid cancer. Thyroid20091910431048. doi:10.1089/thy.2008.0407.

    • Search Google Scholar
    • Export Citation
  • 24

    PisanuARecciaINardelloOUcchedduA. Risk factors for nodal metastasis and recurrence among patients with papillary thyroid microcarcinoma: differences in clinical relevance between nonincidental and incidental tumors. World Journal of Surgery200933460468. doi:10.1007/s00268-008-9870-8.

    • Search Google Scholar
    • Export Citation
  • 25

    ItoYMiyauchiAInoueHFukushimaMKiharaMHigashiyamaTTomodaCTakamuraYKobayashiKMiyaA. An observational trial for papillary thyroid microcarcinoma in Japanese patients. World Journal of Surgery2010342835. doi:10.1007/s00268-009-0303-0.

    • Search Google Scholar
    • Export Citation
  • 26

    LombardiCPBellantoneRDe CreaCPaladinoNCFaddaGSalvatoriMRaffaelliM. Papillary thyroid microcarcinoma: extrathyroidal extension, lymph node metastases, and risk factors for recurrence in a high prevalence of goiter area. World Journal of Surgery20103412141221. doi:10.1007/s00268-009-0375-x.

    • Search Google Scholar
    • Export Citation
  • 27

    TzvetovGHirschDShraga-SlutzkyIWeinsteinRManisterskyYKalmanovichRLapidotMGrozinsky-GlasbergSSingerJSulkesJShimonIBenbassatC. Well-differentiated thyroid carcinoma: comparison of microscopic and macroscopic disease. Thyroid200919487494. doi:10.1089/thy.2008.0228.

    • Search Google Scholar
    • Export Citation
  • 28

    LinJDChaoTCHsuehCKuoSF. High recurrent rate of multicentric papillary thyroid carcinoma. Annals of Surgical Oncology20091626092616. doi:10.1245/s10434-009-0565-7.

    • Search Google Scholar
    • Export Citation
  • 29

    TuttleRMLeboeufR. Follow up approaches in thyroid cancer: a risk adapted paradigm. Endocrinology and Metabolism Clinics of North America200837419435.(ix–x)doi:10.1016/j.ecl.2008.02.008.

    • Search Google Scholar
    • Export Citation
  • 30

    TuttleRM. Risk-adapted management of thyroid cancer. Endocrine Practice200814764774.

  • 31

    TuttleRMTalaHShahJLeboeufRGhosseinRGonenMBrokhinMOmryGFaginJAShahaA. Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid20102013411349. doi:10.1089/thy.2010.0178.

    • Search Google Scholar
    • Export Citation
  • 32

    CastagnaMGMainoFCipriCBelardiniVTheodoropoulouACeveniniGPaciniF. Delayed risk stratification, to include the response to initial treatment (surgery and radioiodine ablation), has better outcome predictivity in differentiated thyroid cancer patients. European Journal of Endocrinology2011165441446. doi:10.1530/EJE-11-0466.

    • Search Google Scholar
    • Export Citation
  • 33

    NeuholdNSchultheisAHermannMKrotlaGKoperekOBirnerP. Incidental papillary microcarcinoma of the thyroid-further evidence of a very low malignant potential: a Retrospective Clinicopathological Study with up to 30 years of follow-up. Annals of Surgical Oncology2011834303436.

    • Search Google Scholar
    • Export Citation
  • 34

    SugitaniITodaKYamadaKYamamotoNIkenagaMFujimotoY. Three distinctly different kinds of papillary thyroid microcarcinoma should be recognized: our treatment strategies and outcomes. World Journal of Surgery20103412221231. doi:10.1007/s00268-009-0359-x.

    • Search Google Scholar
    • Export Citation
  • 35

    RiveraMRicarte-FilhoJTuttleRMGanlyIShahaAKnaufJFaginJGhosseinR. Molecular, morphologic, and outcome analysis of thyroid carcinomas according to degree of extrathyroid extension. Thyroid20102010851093. doi:10.1089/thy.2010.0174.

    • Search Google Scholar
    • Export Citation
  • 36

    MoonHJKimEKChungWYYoonJHKwakJY. Minimal extrathyroidal extension in patients with papillary thyroid microcarcinoma: is it a real prognostic factor?Annals of Surgical Oncology20111819161923.

    • Search Google Scholar
    • Export Citation
  • 37

    SawkaAMBrierleyJDTsangRWThabaneLRotsteinLGafniAStrausSGoldsteinDP. An updated systematic review and commentary examining the effectiveness of radioactive iodine remnant ablation in well-differentiated thyroid cancer. Endocrinology and Metabolism Clinics of North America200837457480. doi:10.1016/j.ecl.2008.02.007.

    • Search Google Scholar
    • Export Citation
  • 38

    SacksWFungCHChangJTWaxmanABraunsteinGD. The effectiveness of radioactive iodine for treatment of low-risk thyroid cancer: a systematic analysis of the peer-reviewed literature from 1966 to April 2008. Thyroid20102012351245. doi:10.1089/thy.2009.0455.

    • Search Google Scholar
    • Export Citation

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  • View in gallery

    Time to event stratified by three group score: group 1 (black line), group 2 (gray line), and group 3 (dotted line).

  • View in gallery

    Time to event for pT1a Nx patients for multifocal DTMC with total foci size <10 mm (gray line), between 10 and 20 mm (black line), and >20 mm (dotted line).

  • 1

    HughesDTHaymartMRMillerBSGaugerPGDohertyGM. The most commonly occurring papillary thyroid cancer in the United States is now a microcarcinoma in a patient older than 45 years. Thyroid201121231236. doi:10.1089/thy.2010.0137.

    • Search Google Scholar
    • Export Citation
  • 2

    HedingerCWilliamsEDSobinLH. The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer198963908911. doi:10.1002/1097-0142(19890301)63:5<908::AID-CNCR2820630520>3.0.CO;2-I.

    • Search Google Scholar
    • Export Citation
  • 3

    Edge SB Byrd DR Compton CC Fritz AG Greene FL & Trotti A. AJCC Cancer Staging Handbook. Springer-Verlag: New York 2010

  • 4

    BesicNPilkoGPetricRHocevarMZgajnarJ. Papillary thyroid microcarcinoma: prognostic factors and treatment. Journal of Surgical Oncology200897221225. doi:10.1002/jso.20935.

    • Search Google Scholar
    • Export Citation
  • 5

    BaudinETravagliJPRopersJMancusiFBruno-BossioGCaillouBCailleuxAFLumbrosoJDParmentierCSchlumbergerM. Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience. Cancer199883553559. doi:10.1002/(SICI)1097-0142(19980801)83:3<553::AID-CNCR25>3.0.CO;2-U.

    • Search Google Scholar
    • Export Citation
  • 6

    RotiERossiRTrasforiniGBertelliFAmbrosioMRBusuttiLPearceENBravermanLEDegli UbertiEC. Clinical and histological characteristics of papillary thyroid microcarcinoma: results of a retrospective study in 243 patients. Journal of Clinical Endocrinology and Metabolism20069121712178. doi:10.1210/jc.2005-2372.

    • Search Google Scholar
    • Export Citation
  • 7

    PelizzoMRBoschinIMToniatoAPiottoABernantePPagettaCRampinLRubelloD. Papillary thyroid microcarcinoma (PTMC): prognostic factors, management and outcome in 403 patients. European Journal of Surgical Oncology20063211441148. doi:10.1016/j.ejso.2006.07.001.

    • Search Google Scholar
    • Export Citation
  • 8

    NoguchiSYamashitaHUchinoSWatanabeS. Papillary microcarcinoma. World Journal of Surgery200832747753. doi:10.1007/s00268-007-9453-0.

  • 9

    NoguchiSYamashitaHMurakamiNNakayamaITodaMKawamotoH. Small carcinomas of the thyroid. A long-term follow-up of 867 patients. Archives of Surgery1996131187191. doi:10.1001/archsurg.1996.01430140077021.

    • Search Google Scholar
    • Export Citation
  • 10

    HayIDGrantCSvan HeerdenJAGoellnerJREbersoldJRBergstralhEJ. Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period. Surgery199211211391147.

    • Search Google Scholar
    • Export Citation
  • 11

    ChowSMLawSCChanJKAuSKYauSLauWH. Papillary microcarcinoma of the thyroid-prognostic significance of lymph node metastasis and multifocality. Cancer2003983140. doi:10.1002/cncr.11442.

    • Search Google Scholar
    • Export Citation
  • 12

    LoCYChanWFLangBHLamKYWanKY. Papillary microcarcinoma: is there any difference between clinically overt and occult tumors?World Journal of Surgery200630759766. doi:10.1007/s00268-005-0363-8.

    • Search Google Scholar
    • Export Citation
  • 13

    HayIDHutchinsonMEGonzalez-LosadaTMcIverBReinaldaMEGrantCSThompsonGBSeboTJGoellnerJR. Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60-year period. Surgery2008144980988. doi:10.1016/j.surg.2008.08.035.

    • Search Google Scholar
    • Export Citation
  • 14

    MercanteGFrasoldatiAPedroniCFormisanoDRennaLPianaSGardiniGValcaviRBarbieriV. Prognostic factors affecting neck lymph node recurrence and distant metastasis in papillary microcarcinoma of the thyroid: results of a study in 445 patients. Thyroid200919707716. doi:10.1089/thy.2008.0270.

    • Search Google Scholar
    • Export Citation
  • 15

    KimTYHongSJKimJMGu KimWGongGRyuJSKimWBYunSCShongYK. Prognostic parameters for recurrence of papillary thyroid microcarcinoma. BMC Cancer20088296doi:10.1186/1471-2407-8-296.

    • Search Google Scholar
    • Export Citation
  • 16

    DuranteCAttardMTorlontanoMRongaGMonzaniFCostanteGFerdeghiniMTuminoSMeringoloDBrunoRDe TomaGCrocettiUMontesanoTDardanoALamartinaLManigliaAGiacomelliLFilettiS. Identification and optimal postsurgical follow-up of patients with very low-risk papillary thyroid microcarcinomas. Journal of Clinical Endocrinology and Metabolism20109548824888. doi:10.1210/jc.2010-0762.

    • Search Google Scholar
    • Export Citation
  • 17

    TorlontanoMCrocettiUAugelloGD'AloisoLBonfittoNVarrasoADicembrinoFModoniSFruscianteVDi GiorgioABrunoRFilettiSTrischittaV. Comparative evaluation of recombinant human thyrotropin-stimulated thyroglobulin levels, 131I whole-body scintigraphy, and neck ultrasonography in the follow-up of patients with papillary thyroid microcarcinoma who have not undergone radioiodine therapy. Journal of Clinical Endocrinology and Metabolism2006916063. doi:10.1210/jc.2005-1185.

    • Search Google Scholar
    • Export Citation
  • 18

    CooperDSDohertyGMHaugenBRKloosRTLeeSLMandelSJMazzaferriELMcIverBPaciniFSchlumbergerMShermanSIStewardDLTuttleRM. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid20091911671214. doi:10.1089/thy.2009.0110.

    • Search Google Scholar
    • Export Citation
  • 19

    PaciniFSchlumbergerMDralleHEliseiRSmitJWWiersingaW. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. European Journal of Endocrinology2006154787803. doi:10.1530/eje.1.02158.

    • Search Google Scholar
    • Export Citation
  • 20

    RotiEDegli UbertiECBondanelliMBravermanLE. Thyroid papillary microcarcinoma: a descriptive and meta-analysis study. European Journal of Endocrinology2008159659673. doi:10.1530/EJE-07-0896.

    • Search Google Scholar
    • Export Citation
  • 21

    FrasoldatiAPesentiMGalloMCaroggioASalvoDValcaviR. Diagnosis of neck recurrences in patients with differentiated thyroid carcinoma. Cancer2003979096. doi:10.1002/cncr.11031.

    • Search Google Scholar
    • Export Citation
  • 22

    PelttariHLaitinenKSchalin-JanttiCValimakiMJ. Long-term outcome of 495 TNM stage I or II patients with differentiated thyroid carcinoma followed up with neck ultrasonography and thyroglobulin measurements on T4 treatment. Clinical Endocrinology200869323331. doi:10.1111/j.1365-2265.2008.03217.x.

    • Search Google Scholar
    • Export Citation
  • 23

    RossDSLitofskyDAinKBBigosTBrierleyJDCooperDSHaugenBRJonklaasJLadensonPWMagnerJRobbinsJSkarulisMCStewardDLMaxonHRShermanSI. Recurrence after treatment of micropapillary thyroid cancer. Thyroid20091910431048. doi:10.1089/thy.2008.0407.

    • Search Google Scholar
    • Export Citation
  • 24

    PisanuARecciaINardelloOUcchedduA. Risk factors for nodal metastasis and recurrence among patients with papillary thyroid microcarcinoma: differences in clinical relevance between nonincidental and incidental tumors. World Journal of Surgery200933460468. doi:10.1007/s00268-008-9870-8.

    • Search Google Scholar
    • Export Citation
  • 25

    ItoYMiyauchiAInoueHFukushimaMKiharaMHigashiyamaTTomodaCTakamuraYKobayashiKMiyaA. An observational trial for papillary thyroid microcarcinoma in Japanese patients. World Journal of Surgery2010342835. doi:10.1007/s00268-009-0303-0.

    • Search Google Scholar
    • Export Citation
  • 26

    LombardiCPBellantoneRDe CreaCPaladinoNCFaddaGSalvatoriMRaffaelliM. Papillary thyroid microcarcinoma: extrathyroidal extension, lymph node metastases, and risk factors for recurrence in a high prevalence of goiter area. World Journal of Surgery20103412141221. doi:10.1007/s00268-009-0375-x.

    • Search Google Scholar
    • Export Citation
  • 27

    TzvetovGHirschDShraga-SlutzkyIWeinsteinRManisterskyYKalmanovichRLapidotMGrozinsky-GlasbergSSingerJSulkesJShimonIBenbassatC. Well-differentiated thyroid carcinoma: comparison of microscopic and macroscopic disease. Thyroid200919487494. doi:10.1089/thy.2008.0228.

    • Search Google Scholar
    • Export Citation
  • 28

    LinJDChaoTCHsuehCKuoSF. High recurrent rate of multicentric papillary thyroid carcinoma. Annals of Surgical Oncology20091626092616. doi:10.1245/s10434-009-0565-7.

    • Search Google Scholar
    • Export Citation
  • 29

    TuttleRMLeboeufR. Follow up approaches in thyroid cancer: a risk adapted paradigm. Endocrinology and Metabolism Clinics of North America200837419435.(ix–x)doi:10.1016/j.ecl.2008.02.008.

    • Search Google Scholar
    • Export Citation
  • 30

    TuttleRM. Risk-adapted management of thyroid cancer. Endocrine Practice200814764774.

  • 31

    TuttleRMTalaHShahJLeboeufRGhosseinRGonenMBrokhinMOmryGFaginJAShahaA. Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid20102013411349. doi:10.1089/thy.2010.0178.

    • Search Google Scholar
    • Export Citation
  • 32

    CastagnaMGMainoFCipriCBelardiniVTheodoropoulouACeveniniGPaciniF. Delayed risk stratification, to include the response to initial treatment (surgery and radioiodine ablation), has better outcome predictivity in differentiated thyroid cancer patients. European Journal of Endocrinology2011165441446. doi:10.1530/EJE-11-0466.

    • Search Google Scholar
    • Export Citation
  • 33

    NeuholdNSchultheisAHermannMKrotlaGKoperekOBirnerP. Incidental papillary microcarcinoma of the thyroid-further evidence of a very low malignant potential: a Retrospective Clinicopathological Study with up to 30 years of follow-up. Annals of Surgical Oncology2011834303436.

    • Search Google Scholar
    • Export Citation
  • 34

    SugitaniITodaKYamadaKYamamotoNIkenagaMFujimotoY. Three distinctly different kinds of papillary thyroid microcarcinoma should be recognized: our treatment strategies and outcomes. World Journal of Surgery20103412221231. doi:10.1007/s00268-009-0359-x.

    • Search Google Scholar
    • Export Citation
  • 35

    RiveraMRicarte-FilhoJTuttleRMGanlyIShahaAKnaufJFaginJGhosseinR. Molecular, morphologic, and outcome analysis of thyroid carcinomas according to degree of extrathyroid extension. Thyroid20102010851093. doi:10.1089/thy.2010.0174.

    • Search Google Scholar
    • Export Citation
  • 36

    MoonHJKimEKChungWYYoonJHKwakJY. Minimal extrathyroidal extension in patients with papillary thyroid microcarcinoma: is it a real prognostic factor?Annals of Surgical Oncology20111819161923.

    • Search Google Scholar
    • Export Citation
  • 37

    SawkaAMBrierleyJDTsangRWThabaneLRotsteinLGafniAStrausSGoldsteinDP. An updated systematic review and commentary examining the effectiveness of radioactive iodine remnant ablation in well-differentiated thyroid cancer. Endocrinology and Metabolism Clinics of North America200837457480. doi:10.1016/j.ecl.2008.02.007.

    • Search Google Scholar
    • Export Citation
  • 38

    SacksWFungCHChangJTWaxmanABraunsteinGD. The effectiveness of radioactive iodine for treatment of low-risk thyroid cancer: a systematic analysis of the peer-reviewed literature from 1966 to April 2008. Thyroid20102012351245. doi:10.1089/thy.2009.0455.

    • Search Google Scholar
    • Export Citation