Ann Surg Oncol (2015) 22:3543–3549 DOI 10.1245/s10434-015-4448-9
ORIGINAL ARTICLE – ENDOCRINE TUMORS
Factors Affecting the Locoregional Recurrence of Conventional Papillary Thyroid Carcinoma After Surgery: A Retrospective Analysis of 3381 Patients Yong Joon Suh, MD1,2, Hyungju Kwon, MD1,2, Su-jin Kim, MD1,2, June Young Choi, MD2,3, Kyu Eun Lee, MD, PhD1,2, Young Joo Park, MD, PhD2,4, Do Joon Park, MD, PhD2,4, and Yeo-Kyu Youn, MD, PhD1,2 Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Korea; 2Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; 3Department of Surgery, Seoul National University Bundang Hospital, Gyeonggi-do, Korea; 4Department of Internal Medicine, Seoul National University Hospital and College of Medicine, Seoul, Korea 1
ABSTRACT Background. Papillary thyroid carcinoma (PTC) does recur, despite its favorable long-term outcome. The incidence of thyroid cancer in South Korea increased during the 1990s, then increased rapidly after the turn of the century. In 2011, the rate of thyroid cancer diagnoses was 15 times that observed in 1993. The present study aimed to identify factors associated with the locoregional recurrence of recently increasing conventional PTC. Methods. The records of 3381 patients with conventional PTC were reviewed for this retrospective cohort study. Between January 2004 and January 2012, these patients underwent ultrasonography, computed tomography, and preoperative and total thyroidectomy with central neck dissection. Disease recurrence was defined as structural evidence of disease following the remission period. Results. Median length of follow-up was 5.6 (range 2.1– 10.1) years. Of 3381 patients, 75 (2.2 %) experienced recurrence. The univariate analysis suggested that locoregional recurrence was associated with tumor size, multifocality, extrathyroidal extension (ETE), lymph node metastasis, lymphatic invasion, vascular invasion, and positive surgical margin. However, multivariate analysis Electronic supplementary material The online version of this article (doi:10.1245/s10434-015-4448-9) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2015 First Received: 31 October 2014; Published Online: 6 March 2015 K. E. Lee, MD, PhD e-mail:
[email protected];
[email protected]
showed that only tumor size (p \ 0.001), bilaterality (p \ 0.001), gross ETE (p = 0.049), lymph node metastasis (p \ 0.001), and vascular invasion (p = 0.013) were independently associated with locoregional recurrence. Conclusions. Tumor size, bilaterality, gross ETE, lymph node metastasis, and vascular invasion were associated with locoregional recurrence. Evaluation of these prognostic factors appears to help identify patients who require close monitoring.
The incidence of thyroid cancer is increasing; papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer.1–4 The recurrence rate of thyroid cancer approaches 30 %, depending on the length of follow-up.5,6 Although more than half of locally recurred patients remain disease-free during the short-term follow-up period, 8 % of patients eventually die of locoregional recurrence.7–9 Studies report that the locoregional recurrence of PTC increased disease-specific mortality, and its effects on survival depended on the type of locoregional recurrence.10–12 Thus, there have been efforts to identify prognostic factors for recurrence and carefully monitor patients with those factors. Several studies investigated factors affecting the recurrence of thyroid cancer; however, there were some limitations, including the heterogeneity of thyroid cancer. Although the prognosis of PTC seems to be similar to that of follicular thyroid carcinoma (FTC), factors affecting the recurrence may be different between the two entities. Even PTC can be subdivided according to aggressiveness, and its prognosis depends on histologic subtype.13,14 Another limitation is the difference of the
3544
surgical extent, including total thyroidectomy or lobectomy. Although continuous measurement of thyroglobulin (Tg) is an important tool in monitoring the potential recurrence, Tg levels are difficult to interpret in patients who undergo lobectomy.15 Furthermore, the extent of surgery itself can affect the recurrence rate. Studies on recurrence need to be conducted in a more uniform cohort of patients with recent PTC. There have been many advances in both the diagnosis and treatment of PTC over the last decade.16 Recently, thyroid-stimulating hormone suppression and radioactive iodine (RAI) ablation are more commonly used to minimize the recurrence of PTC. The current advanced diagnostic techniques and widely-used RAI ablation were not feasible before the 1990s.17 The aim of the present study was to identify the prognostic factors associated with the short-term, disease-specific locoregional recurrence in patients who underwent total thyroidectomy with central lymph node dissection for recent increasing conventional PTC. We created a more restricted, homogeneous cohort to investigate this issue. METHODS Study Design and Patient Selection The records of 3381 patients with conventional PTC were reviewed for this retrospective cohort study. These patients underwent ultrasonography, computed tomography, and preoperative and total thyroidectomy with central neck dissection between January 2004 and January 2012 (electronic supplementary Fig. 1). Additional lateral lymph node dissection was performed in patients who had lateral lymph node metastasis confirmed by preoperative fineneedle aspiration or an intraoperative frozen biopsy. Patients who had distant metastasis before surgery, or patients without remission after surgery, were excluded. Tumors were staged according to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system. Clinicopathologic data were obtained in accordance with the Institutional Review Board (No. 1204-007-403) of Seoul National University Hospital (Seoul, Korea). Subsequent Treatments All patients received thyroid-stimulating hormone suppression therapy as an adjuvant treatment, and 2115 of 3381 (62.6 %) patients received RAI treatment. RAI ablation was performed for all patients with a tumor diameter [4 cm or extrathyroidal extension (ETE) of the tumor, and patients with a 1–4 cm thyroid cancer confined to the thyroid, who had documented lymph node
Y. J. Suh et al.
metastases.16 Depending on the risk group, a dose of 30– 200 mCi of 131I was used for each RAI ablation. Follow-up Monitoring Follow-up evaluations included a physical examination, measurement of serum Tg and anti-Tg antibody levels every 6–12 months, and periodic neck ultrasonography every 1–3 years.18,19 Levothyroxine was administered to suppress serum TSH to undetectable levels during the first 5–10 years after the initial treatment. Once the patients were free of disease, the extent of TSH suppression was reduced to maintain a substitutive level of serum TSH. A whole-body scan, computed tomography, magnetic resonance imaging, or positron emission tomography was performed for those suspected of recurrence. Patients with clinical evidence of recurrence, those with a stimulated Tg level [2 ng/mL with negative Tg antibody (or serial increases in serum Tg) or an imaging abnormality were suspected of recurrence. In such patients, we performed an ultrasonography-guided fine-needle aspiration and measured the Tg level in the needle washout to identify the location and pathology of the recurrence.20 Definitions Remission was defined as no clinical, biochemical, or imaging evidence of tumors. Stimulated Tg level B2 ng/ mL with negative Tg antibodies was used as a criteria to define biochemical remission. Disease recurrence was defined as structural evidence of disease following a remission period of 2 years. Local recurrence was defined as recurrence in the thyroid operative bed. Regional recurrence was defined as recurrence in the regional lymph nodes. Margin-negative resection was defined as having [1 mm of normal tissue at the surgical resection margin. Microscopic ETE was defined as having microscopic disease extending beyond the capsule of thyroid gland. Gross ETE was defined as visually apparent extension of disease beyond the thyroid gland. Statistics The non-recurrence and recurrence groups were compared using the Chi-square test or Fisher’s exact test for categorical data, and Student’s t test or Mann–Whitney U test if the data were not normally distributed for continuous data. Disease-free survival rates were estimated using Kaplan–Meier analysis, including the log-rank test. Disease-free survival intervals were calculated in months from the date of surgery to the date of last follow-up or recurrence. Variables likely to be associated with disease-free survival (p \ 0.2) in a univariate analysis were included in
Recurrence of Conventional PTC: Risk Factors
a multivariate Cox proportional hazards regression model. The adjusted hazard ratio and 95 % confidence intervals (CIs) were calculated from the final multivariate model. In two-tailed tests, a p value\0.05 was considered to indicate statistical significance. Results were analyzed using SAS 9.1 (SAS Institute Inc., Cary, NC, USA). RESULTS Among all 3381 patients, 75 (2.2 %) patients experienced recurrence. The median follow-up period was 5.6 years (range 2.1–10.1) and median time to recurrence was 2.4 years (range 2.1–6.6). No patient experienced distant metastasis during the follow-up period. The clinicopathologic characteristics of the recurrence and nonrecurrence groups are compared in Table 1. More patients in the recurrence group experienced lymph node dissection and RAI ablation. The non-recurrence and recurrence groups showed no significant clinical difference in terms of age, sex, and thyroid function; however, these groups had significant pathological differences in TNM classifications, such as tumor size, ETE, and lymph node metastasis. Between-group differences were also found for multifocality, lymphatic invasion, vascular invasion, and surgical margin. Kaplan–Meier curves showed the effects of variables on the 10-year recurrence-free survival rate, including tumor size, ETE, N classification, vascular invasion, and bilaterality (Fig. 1). Using stepwise selection in a multivariate analysis, tumor size, bilaterality, gross ETE, lymph node metastasis, and vascular invasion were selected. The strength of association of recurrence with these variables was then assessed from the final model. These factors were significantly associated with locoregional recurrence (Table 2). Regional lymph node metastasis at level N1b was more strongly related to recurrence than N1a, even in patients with papillary thyroid microcarcinoma (Table 3). A larger tumor size had a significantly higher risk of recurrence (p \ 0.001). The number of positive lymph nodes that best predicted recurrence was determined using receiver operating characteristic (ROC) curves. ROC curve analysis indicated that the threshold of C2 positive nodes resulted in a sensitivity of 80.7 % and a specificity of 79 % (area under the curve 0.83, 95 % CI 0.77–0.88; p \ 0.001) for predicting recurrence. The recurrence rate was significantly higher in the group with an initial ratio C0.3 (p \ 0.001). DISCUSSION Most patients who ultimately die from PTC suffer from major locoregional complications, such as airway obstruction,
3545 TABLE 1 Comparison of clinicopathologic characteristics by structural recurrence status Characteristic
Nonrecurrence (n = 3306)
Recurrence (n = 75)
p Value
Age (years) Mean
45.6 [12, 93] 43.9 [11, 81]
0.252
\45 [n (%)]
1003 (30)
23 (31)
0.951
C45 [n (%)]
2303 (70)
52 (69)
Female
2776 (84)
58 (77)
Male
530 (16)
17 (23)
Sex [n (%)] 0.123
MRND extent (%) None
74
31
Unilateral
24
49
Bilateral
2
20
\0.001
Tumor size (cm) Mean
0.7 [0.1, 6.5] 1.3 [0.2, 6.4]
\0.001
B1 (%) [1 (%)
69.2 30.8
\0.001
34.7 65.3
Retrieved LN
5 [0, 74]
17 [0, 68]
\0.001
Positive LN
0 [0, 43]
6 [0, 45]
\0.001
LN metastasis (%)
34
83
\0.001
Metastatic LN ratioa Mean
0 [0, 1]
0.31 [0, 1]
\0.001
\0.3 [n (%)]
2727 (82)
38 (51)
\0.001
0.3 [n (%)]
579 (18)
37 (49)
Multifocality (%) \0.001
Yes
36.8
64
Unilateral only
15.2
16
0.101
Bilateral
21.6
48
\0.001 \0.001
ETE [n (%)] No
1511 (46)
15 (20)
Microscopic Gross
1567 (47) 228 (7)
39 (52) 21 (28)
Lymphatic invasion (%)
5
20
\0.001
Vascular invasion (%)
1
8
\0.001
Lymphocytic thyroiditis (%)
35
29
0.350
I/II
2001 (61)
32 (43)
0.003
III/IV
1305 (39)
43 (57)
TNM stage [n (%)]
T classification [n (%)]
1488 (45)
12 (16)
1818 (55)
63 (84)
0 N1a
2193 (66) 812 (25)
13 (17) 14 (19)
N1b
301 (9)
48 (64)
0.3 ± 1.1 [0, 9.9]b
3.4 ± 4.8 [0.1, 22.3]
\0.001
N classification [n (%)]
Suppressed Tg (ng/mL)
\0.001
\0.001
3546
Y. J. Suh et al.
TABLE 1 continued Characteristic
TABLE 2 Multivariate analysis of prognostic factors for locoregional recurrence
Nonrecurrence (n = 3306)
Recurrence (n = 75)
p Value
1.2 ± 2.0 [0, 19.8]c
50.0 ± 106.9 [0.1, 639.0]
\0.001
97
Prognostic factors
Adjusted HR
Age C45 years Stimulated Tg (ng/mL)
\0.001
RAI ablation (%)
62
Total RAI dose, mCi
60 [30, 300] 100 [30, 1050]
\0.001
Median follow-up duration (months)
64.9 [29.9, 121.7]
\0.001
34 [25.4, 80.2]
MRND modified radial neck dissection, LN lymph node, ETE extrathyroidal extension, Tg thyroglobulin, RAI radioactive iodine
b
In 3306 patients, the suppressed Tg level was measured in only 238 (7.2 %) patients because it was undetectable in the remaining 3068 (92.8 %) patients
c
The stimulated Tg level was measured in 2042 patients. The presented value was calculated in 602 (29.5 %) patients because the stimulated Tg level was undetectable in the remaining 1440 (70.5 %) patients
vascular invasion, and hemorrhage, which occur in patients with recurrent differentiated thyroid cancer.21 Severe complications, including recurrent laryngeal nerve injury and persistent hyperparathyroidism, may occur, particularly when reoperation is required due to recurrence in the central
Recurrence-free survival rate
(a)
0.968–1.003
0.115
1.672
1.384–2.019
\0.001
Bilaterality
2.683
1.691–4.256
\0.001
Extrathyroidal extension Microscopic
1.368
0.742–2.52
0.315
Gross
2.061
0.986–4.311
0.049
Lymph node metastasis N1a 2.284
1.057–4.937
N1b Vascular invasion
12.264
6.275–23.969
3.177
1.275–7.615
0.036 \0.001 0.013
HR hazard ratio, CI confidence interval
compartment.4 These complications inspire a need to understand prognostic factors of recurrent PTC and closely monitor for locoregional recurrence. This study described short-term, disease-specific outcomes from a single institution after a median follow-up of 5.6 years. In recent increasing conventional PTC, prognostic factors of locoregional recurrence were only investigated in patients who underwent total thyroidectomy with central lymph node dissection. The reported overall recurrence rate ranged from 1.4 to 29.0 % (Table 4).17,22–34 Different results between studies can originate from a
(b)
(c)
1.0
1.0
1.0
0.8
0.8
p< 0.001
0.8 p< 0.001
0.6
0.6
0.4
0.4
0.6
Tumor size Recurrence rate ≤2 cm
0.2
0.2 10 y: 97.8%
0.0
0.4
p
1.7%
2-4 cm
7.8%
>4 cm
23.3%
0.2
4 cm
20
40
60
80
100
120
(d)
0
20
40
60
80
100
120
(e)
0
20
40
60
80
0.8
0.6
0.6
0.6
0.4
0.4
0.4
0.2
0.2
N0 N1a N1b
0.0 0
20
40
60
80
Months after surgery
100
Bilaterality Negative Positive
Vascular invasion Negative Positive
0.0 120
120
p< 0.001
0.8
0.2
100
1.0 p = 0.003
p< 0.001
0.8
Negative microscopic Gross
(f)
1.0
1.0
ETE
0.0
0.0 0
Recurrence-free survival rate
0.986
p Value
Tumor size [1 cm
a
Ratio was defined as the ratio of the number of positive lymph nodes to the number of retrieved lymph nodes
95 % CI
0.0 0
20
40
60
80
Months after surgery
100
120
0
20
40
60
80
100
120
Months after surgery
FIG. 1 The Kaplan–Meier curves for the 3381 patients show the effects of variables on the 10-year recurrence-free survival rate: a recurrencefree survival rate; b tumor size; c extrathyroidal extension; d N classification; e vascular invasion; and f bilaterality
Recurrence of Conventional PTC: Risk Factors
3547
variety of issues, including demographical features, different histological types, different surgical extent, and different laboratory or imaging techniques. The overall recurrence rate of 7.6 %, which Choi et al. recently reported for the period from 2000 to 2009, is much higher than the rate of 2.2 % observed in the current study for the period from 2004 to 2012.19 This difference resulted primarily from different inclusion criteria. Unlike the previous comprehensive analysis, in the present study we focused only on the structural recurrence of recently increasing conventional PTC after creating a more restricted, homogeneous cohort. The lower recurrence might also suggest that prognosis improved during the late 2000s rather than during the early 2000s. The improved prognosis is consistent with the reduced cause-specific mortality recorded in the Korea Central Cancer Registry.3 In the earlier study, we reported that pathologic characteristics as well as
TABLE 3 Multivariate analysis of prognostic factors for locoregional recurrence in 2314 patients with papillary thyroid microcarcinoma Prognostic factors
Adjusted HR
Age C45 years
95 % CI
p Value
1.392
0.626–3.095
0.417
2.045 2.854
0.766–5.455 1.117–7.287
0.153 0.028
Microscopic
1.297
0.546–3.080
0.556
Gross
2.910
0.720–11.755
0.134
N1a
3.366
1.246–9.099
0.017
N1b
12.579
4.713–33.577
\0.001
2.757
0.362–21.016
0.328
Multifocality Unilateral only Bilateral Extrathyroidal extension
Lymph node metastasis
Vascular invasion
HR hazard ratio, CI confidence interval
TABLE 4 Summary of recent studies that examined the recurrence rate of papillary thyroid cancer Study (year)
No. of Median ORR Disease Surgical extent patients F/U (%) Thyroid (%) (years)
Level Level VI II–V
RAI ablation
Primary endpoint Recurrence
Cancerspecific mortality
Matsuzu et al. 201422
1088
17.6
9.4
cPTC
LTT
?
±
–
Size, ETE, CELNM
Age, size, ETE
Kruijff et al. 201323
1183
2.6
7.9
PTC
TT
±
±
?
Age, sex, size, LN, vascular invasion, ETE
NA
Barczyn´ski et al. 201424
760
5
6.0
PTC
TT
?
–
?
LN, LN ratio
NA
Rogan et al. 201325
269
27
28.0
PTC
TT (66)/LTT (31)/ unknown (3)
±
±
?
Age, FVPTC, TNM stage
Age, TNM stage
Schneider et al. 201326
217
NA
23.2
PTC
TT
?
±
?
LN ratio
NA
Durante et al. 201317
1020
10.4
1.4
PTC
TT
±
±
?
ATA risk
NA
Kim et al. 201327 2095
7
2.1
PTC
TT
±
±
?
Size, LN, distant metastasis, multifocality, cLNDb
NA
Ito et al. 201228
5768
10
7.0
PTC
TT (51)/LTT (49)
±
±
?a
Age, sex, ETE, size, CELNM
NA
Shah et al. 2012
92
2.3
29.0
PTC
NA
±
±
?
CELNM
NA
Tuttle et al. 201030
588
7
1.4
TC
TT
NA
NA
?
ATA risk, response to therapyb
NA
Baek et al. 201031
189
6.8
17.5
PTC
TT (94.2)/LTT (5.8)
±
±
?
N stage
NA
1682
7.7
14.4
PTC
TT (58.9)/LTT (41.1)
±
±
?
Multifocalityb
Multifocality
Kim et al. 2008
293
5.4
5.0
PTMC
TT (56.4)/LTT (43.6)
±
±
?
Sex, N stage
NA
Bilimoria et al. 200734
52,173
10
9.4
PTC
TT (82.9)/LTT (17.1)
NA
NA
?
Size, surgical extent
Size, surgical extent
29
Lin et al. 200932 33
F/U follow-up, ORR overall recurrence rate, cPTC conventional papillary thyroid carcinoma, PTC papillary thyroid carcinoma, TC thyroid carcinoma, PTMC conventional papillary thyroid microcarcinoma, FVPTC follicular variant papillary thyroid carcinoma, LTT less than total, TT total thyroidectomy, ETE extrathyroidal extension, CELNM clinically evident lymph node metastasis, LN lymph node, cLND central lymph node dissection, NA not available, RAI radioactive iodine, ATA American Thyroid Association, ? indicates performed in all patients, - indicates performed in no patients, ± indicates performed in some patients a
Only 84 patients received RAI ablation in this study
b
Persistence was considered in addition to recurrence
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clinical factors, such as age and sex, were prognostic factors. In contrast, in the current study only pathologic characteristics significantly influenced prognosis. The increase in the early detection of patients by regular health examination could have attenuated the clinical factors, or the pathologic details, recently obtained, could have been reflected in the current study.1 We believe that accurate pathologic evaluation is essential to predict prognosis. However, the follow-up duration of the current study was relatively short. Patients included in the present cohort should be followed to ascertain their long-term outcomes. Recurrence was more prevalent at the extremes of age in the present study. Some studies proved that age was a prognostic factor for recurrence;23,25 however, other studies found no association between age and recurrence.22,24,29,31,35 The recurrence risk and rate in each decade could be investigated. The recent recurrence rate tended to be lower overall, whereas the recurrence pattern was very similar to the figure Mazzaferri et al. published in 1994 (electronic supplementary Fig. 2).15 In the present study, lymph node metastasis, especially lateral lymph node metastasis, was the most powerful predictor of recurrence. A similar finding was reported by others.23,25,27,28,31,33 However, there is some controversy as to whether the absolute number or the ratio of lymph node metastasis is more important for recurrence.24,26,36,37 Using ROC curves, metastatic lymph node number of 2 showed the highest accuracy, although the recurrence rate was significantly higher in the group with an initial ratio C0.3 (electronic supplementary Fig. 3). This result suggested that the number of lymph node metastasis was more important in predicting recurrence. Previous studies found that multifocality was a prognostic factor for recurrence.24,27,38 We showed that patients with bilaterality were more likely to experience recurrence. The fact that the recurrence rate was higher in patients with bilaterality may indicate that recurrences occur more frequently in patients with intraglandular metastasis.39,40 Wang et al. found that bilateral, recurrent, and metastatic PTC often occurred in a single clone, and intraglandular metastasis played an important role not only in recurrence but also in the occurrence of bilateral tumors. Their study agreed closely with the current study. However, because some researchers reported no relationship between bilaterality and recurrence, the effects of bilaterality on recurrence is still unclear.41,42 Our study had several limitations. First, because this study focused only on recurrence, patients with distant metastasis and patients with persistent disease were excluded. Therefore, it was difficult to identify diseasespecific mortality. Second, recurrence was defined only as structural recurrence. More patients may have experienced recurrence, considering biochemical recurrence. Third, the duration of follow-up was relatively short, and, lastly, the
Y. J. Suh et al.
present study suffers from the usual limitations of observational studies. CONCLUSIONS The recurrence of conventional PTC was associated with tumor size, gross ETE, lymph node metastasis, vascular invasion, and bilaterality. Evaluation of these prognostic factors in an individual patient appears to help identify patients who require close monitoring. ACKNOWLEDGMENT All statistical analyses were supported by the Medical Research Collaborating Center, Seoul National University and Seoul National University Hospital, Seoul, Korea. The authors are indebted to J. Patrick Barron (Professor Emeritus of Tokyo Medical University and Adjunct Professor of Seoul National University Bundang Hospital) for his editorial work. DISCLOSURES Yong Joon Suh, Hyungju Kwon, Su-jin Kim, June Young Choi, Kyu Eun Lee, Young Joo Park, Do Joon Park, and YeoKyu Youn declare no conflicts of interest and disclose no financial ties.
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