World J Surg DOI 10.1007/s00268-014-2602-3
Papillary Thyroid Microcarcinoma: An Over-Treated Malignancy? Tracy S. Wang • Paolo Goffredo • Julie Ann Sosa Sanziana A. Roman
•
Socie´te´ Internationale de Chirurgie 2014
Abstract Background The clinical importance of papillary thyroid microcarcinoma (PTMC) remains controversial, with current guidelines suggesting that thyroid lobectomy alone is sufficient. The purpose of this study was to identify population-level treatment patterns in the USA for PTMC. Methods Patients with PTMC in SEER (1998–2010) were included; demographic, clinical (extent of surgery, administration of post-operative radioactive iodine [RAI]), and pathologic characteristics were examined. Outcomes of interest were 5- and 10-year overall survival (OS) and disease-specific survival (DSS). Results The cohort consisted of 29,512 patients. Mean age at diagnosis was 48.5 years; mean tumor size was 0.53 cm. Overall, 73.4 % of patients underwent total thyroidectomy, and RAI was administered to 31.3 %. In multivariate analysis, total thyroidectomy was more frequently performed in patients with multifocal (odds ratio [OR] 2.55), ‘regional’, or ‘distant’ PTMC (OR 2.90 and 2.59). Non-operative management was associated with male patients (OR 4.24) and those aged C65 years (OR 6.31). Post-operative RAI was associated with multifocal T. S. Wang (&) Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA e-mail: [email protected] P. Goffredo Department of Surgery, Milano-Bicocca University, Monza, Italy J. A. Sosa S. A. Roman Department of Surgery, Duke University, Durham, NC, USA J. A. Sosa Duke Clinical Research Institute, Durham, NC, USA
PTMC (OR 2.57). Overall, 5- and 10-year DSS was 99.6 and 99.3 %, respectively, with no difference in DSS between patients who underwent partial versus total thyroidectomy. OS of patients with PTMC who underwent any thyroid operation was similar to that of the general population of the USA. Conclusions An increasing number of patients are undergoing total thyroidectomy and RAI for PTMC. While there may be a subset of patients for whom more aggressive therapy is indicated, many patients with PTMC may be over-treated, with no demonstrable benefit to survival.
Introduction Papillary thyroid microcarcinoma (PTMC) is defined as a papillary thyroid cancer (PTC) that measures B10 mm in greatest dimension [1, 2]. Recent studies have suggested that the overall increase in incidence of PTC is partially fueled by the 441 % increase in incidence of PTMC reported between 1983 and 2006 [2–5]. The clinical importance of PTMC remains controversial, given that prognosis of patients with PTC is excellent, and many PTMCs are discovered incidentally after thyroidectomy has been performed for other indications [2, 6–9]. According to the current American Joint Committee on Cancer (AJCC) staging system, differentiated thyroid cancers are separated into B1 cm (T1a) and 1–2 cm (T1b) in order to separate out PTMC [10]. The 2009 guidelines for the management of thyroid nodules and differentiated thyroid cancer issued by the American Thyroid Association (ATA)[1] state that ‘‘thyroid lobectomy alone may be sufficient …’’ for patients with PTMC and did not recommend radioactive iodine (RAI) ‘‘for patients with unifocal cancer \1 cm without other higher risk features.’’
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The National Comprehensive Cancer Network (NCCN) guidelines include similar recommendations [11]. The objectives of this study were to identify populationlevel treatment patterns in the USA for PTMC with respect to extent of surgery and administration of RAI, and factors that are associated with a worse prognosis. We hypothesize that patients with PTMC have equivalent overall survival (OS) regardless of the extent of surgery (lobectomy vs. total thyroidectomy), and that treated patients with PTMC have similar survival when compared with the overall US population.
Materials and methods
Pathologic characteristics were tumor size, aggressive variants, multifocality, regional lymph nodes examined, and SEER stage. Aggressive variants were considered as binary variables: ‘yes’ (diffuse sclerosing and tall cell variants) and ‘no’ (classic PTC, follicular, and oxyphilic variants). ‘Regional lymph nodes examined’ were divided into ‘none’ (no lymph nodes examined), ‘negative’ (lymph nodes examined were negative), and ‘positive’. The SEER staging system is coded as ‘local’ if the malignancy is confined entirely to the thyroid, ‘regional’ if it extends beyond the thyroid into surrounding tissues or has metastasized to regional lymph nodes, and ‘distant’ if metastases to extra-cervical lymph nodes or organs are present [12]. Outcomes of interest were 5- and 10-year OS and disease-specific survival (DSS) as of 31 December 2010.
Data source and study patients The data source for the study was the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, which provides population-based data on cancers from 18 different registries and represents nearly 28 % of the US population [12]. The International Classification of Diseases for Oncology, Third Edition (ICD-O-3) was utilized to identify PTC (codes 8050, 8260, 8350, 8340–8344), and the variables ‘Extent of Disease—Tumor size’ and ‘Clinical Stage—Tumor size’ were combined to select tumors B1 cm in size [13]. We excluded patients \18 years of age, patients with more than one primary malignancy, and those diagnosed before 1988 due to the lack of data on surgery and RAI administration. Demographic variables of interest included patient age at diagnosis, gender, race, Hispanic origin, marital status, year of diagnosis, and geographic areas. Age at diagnosis was divided into three groups: 18–44, 45–64, and C65 years. Race was White, Black, and other (American Indian, Alaska Native, Asian, Pacific Islander, and other unspecified); Hispanic origin was categorized as ‘yes’ or ‘no’. Marital status was recoded into married (married and/ or domestic partner) and single (single, divorced, widowed, or separated). Geographic location was Northeast, South, Midwest, and West. Clinical variables of interest included extent of surgery and administration of post-operative RAI. Surgical treatment was recoded as none, partial thyroidectomy, and total thyroidectomy. RAI administration for adherence analysis was studied as a binary variable: ‘no RAI’ included none and forms of radiation other than RAI (i.e., external beam radiation therapy [EBRT] and radiation—not otherwise specified); ‘yes RAI’ included radioisotopes, radioactive implants, a combination of EBRT and radioactive implants or radioisotopes, and radiotherapy was recommended but the patient or patient’s guardian refused or it was unknown if it was administered.
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Statistical analysis Summary statistics were used to describe baseline characteristics. OS and DSS were analyzed using the Kaplan– Meier method, and the log-rank test. The one sample logrank test was employed to compare survival of patients with PTMC with that of the overall US population. The Chi-squared test was used for univariate analysis. Stepwise binary logistic regression was employed to identify factors independently associated with total thyroidectomy and RAI ablation. Statistical Package for the Social Sciences software (version 21.0; IBM, Armonk, NY, USA) was utilized to perform data analyses; all tests were two-sided, and statistical significance was set at a p value of \0.05. The current study was deemed to be exempt from institutional review board approval.
Results A total of 29,512 patients with PTC B1 cm (PTMC) were identified in the SEER database between 1988 and 2010 (Table 1). PTMCs were more common among White, married females; mean age at diagnosis was 48.5 years (standard deviation [SD] 13.6). Overall, 73.4 % of patients with PTMC underwent total thyroidectomy, 25.2 % partial thyroidectomy, and 1.4 % did not receive any surgical operation; 31.3 % received RAI post-operatively. Mean tumor size was 0.53 cm (SD 0.31); 218 (0.7 %) of PTMCs represented aggressive variants of PTC, and 8,183 (27.8 %) were multifocal. Regional lymph nodes were examined in 38.4 % of patients; 69.7 % had no metastatic lymph nodes identified. SEER stage was ‘local’ in 82.4 % of the cohort, ‘regional’ in 16.6 %, and ‘distant’ in 1.1 %.
World J Surg Table 1 Demographic, clinical, and pathologic characteristics of patients with papillary thyroid microcarcinoma, SEER 1988–2010 (n = 29,512) Patient characteristics
Patient characteristics
Gender 5,130
17.4
Female
24,382
82.6
Age at diagnosis, ya
48.5 ± 13.6
18–44
11,901
40.3
45–64
13,737
46.5
C65
3,873
13.1
24,739
84.8
Black
1,678
5.7
Other
2,773
9.5
Hispanic origin No
26,177
88.7
3,335
11.3
Single
8,603
30.5
Married
19,644
69.5
1988–1999
4,083
13.8
2000–2006
12,545
42.5
2007–2010
12,884
43.7
Northeast
5,519
18.7
South
5,508
18.7
Midwest
3,052
10.3
West
15,433
52.3
None
404
1.4
Partial thyroidectomy Total/near total thyroidectomy
7,424 21,633
25.2 73.4
No
20,113
68.7
Yes
9,170
31.3
Yes Marital status (n = 28,247)
Geographic area
Surgery (n = 29,461)
RAI ablation (n = 29,283)
5-year survival Overall
96.6
Disease-specific
99.6
10-year survival
Pathologic
21,234
72.2
Yes
8,183
27.8
None
18,111
61.6
7,883 3,423
69.7 30.3
Yes Negative Positive SEER stage (n = 29,427) Local
24,237
82.4
Regional
4,881
16.6
Distant
309
1.1
RAI radioactive iodine, SD standard deviation, SEER Surveillance, Epidemiology, and End Results a
Data are presented as mean ± SD
Extent of surgery
Year of diagnosis
Clinical
No
Regional lymph nodes examined (n = 29,417)
Race (n = 29,190) White
%
Multifocality (n = 29,417)
%
Male
PTMC n
PTMC n
Demographic
Table 1 continued
Overall
93.3
Disease-specific
99.3
Tumor size, mma
5.3 ± 3.1
Aggressive variants No
29,294
99.3
Yes
218
0.7
In univariate analysis, fewer total thyroidectomies associated with PTMCs were performed in the earlier time periods analyzed; between 1988 and 1999, a total of 70.5 % of patients underwent total thyroidectomy versus 72.4 % between 2000 and 2006 and 77.7 % between 2007 and 2010 (p \ 0.001). Geographically, total thyroidectomy was more frequently performed in the West (75.9 %) and less frequently in the Northeast (72.2 %, p \ 0.001) and in patients C65 years (p \ 0.001). There was no difference in extent of surgery based on gender, race, marital status, or for aggressive histological variants of PTMC. Once adjusted for confounders, multivariate analysis demonstrated that total thyroidectomy was more frequently performed in patients diagnosed after the year 2000. Patients with multifocal PTMC, those who underwent lymphadenectomy, and those with SEER-classified ‘regional’ or ‘distant’ disease were more likely to have undergone total thyroidectomy (Table 2). Independent factors that were associated with a lower likelihood of undergoing total thyroidectomy were age C65 years and being treated in the Northeast. Compared with those who received either partial or total thyroidectomy, univariate analysis demonstrated that patients who did not undergo surgery for PTMC were more often male (45.2 vs. 17.0 %; p \ 0.001), aged C45 years (77.8 vs. 59.5 %; p \ 0.001), and single (40.2 vs. 30.3 %; p = 0.001). Black patients and other minorities were less likely to undergo surgery than White (21.4 vs. 15.2 %;
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World J Surg Table 2 Multivariate analysis for surgery and administration of radioactive iodine for patients with papillary thyroid microcarcinoma
Reference groups: 18–44 years, age; 1988–1999, time interval; Married, marital status; White, race; West, geographic area; No, multifocality; Not examined, LN status; Local, SEER stage CI confidence interval, LN lymph node, OR odds ratio, PTMC papillary thyroid microcarcinoma, RAI radioactive iodine, SEER Surveillance, Epidemiology, and End Results
Patient characteristics
Surgery, total thyroidectomy
Administration of RAI
OR
OR
p value
95 % CI
p value
Age 45–64 years
0.94
0.89–1.00
0.060
0.89
0.84–0.95
0.001
Age C65 years
0.80
0.73–0.87
\0.001
0.65
0.58–0.72
\0.001
Black race
–
–
–
0.70
0.61–0.81
\0.001
Other races
–
–
–
1.26
1.14–1.40
\0.001
Single status
–
–
–
0.92
0.86–0.99
0.019
Year 2000–2006
1.16
1.07–1.27
0.001
1.16
1.05–1.28
0.003
Year 2007–2010
1.52
1.39–1.65
\0.001
1.05
0.95–1.16
0.349
Northeast
0.79
0.73–0.85
\0.001
0.58
0.53–0.63
\0.001
South
0.93
0.86–1.00
0.052
1.07
0.99–1.17
0.093
Midwest
0.97
0.88–1.07
0.520
0.80
0.71–0.88
\0.001
Multifocal PTMC Lymph nodes negative
2.55 1.86
2.37–2.74 1.74–1.99
\0.001 \0.001
2.57 1.08
2.41–2.74 1.01–1.16
\0.001 0.028
Lymph nodes positive
3.52
2.84–4.36
\0.001
1.47
1.28–1.69
\0.001
SEER regional
2.90
2.52–3.33
\0.001
4.16
3.70–4.67
\0.001
SEER distant
5.19
2.92–9.24
\0.001
4.84
3.62–6.47
\0.001
Table 3 Multivariate analysis for surgical management of patients with papillary thyroid microcarcinoma Characteristics
95 % CI
No surgery OR
95 % CI
p value
Male gender
4.24
3.18–5.65
\0.001
Age 45–64 years
1.98
1.35–2.89
\0.001
Age C65 years
6.31
4.30–9.27
\0.001
Single status
1.83
1.37–2.44
\0.001
Year 2000–2006
0.19
0.13–0.26
\0.001
Year 2007–2010
0.10
0.07–0.15
\0.001
Multifocal
0.38
0.25–0.58
\0.001
SEER regional
0.45
0.28–0.72
\0.001
Reference groups: Female, gender; 18–44 years, age; 1988–1999, time interval; Single, marital status; West, geographic area; No, multifocality; Local, SEER stage CI confidence interval, OR odds ratio, SEER Surveillance, Epidemiology, and End Results
p \ 0.001). Other variables associated with not having surgery for PTMC included those patients diagnosed between 1988 and 1999 and those receiving treatment in the West. After multivariate adjustment, independent factors associated with non-surgical management were male gender, older age, single status, treatment prior to year 2000, and unifocal or localized disease (Table 3).
41.5 % in 2000–2006, respectively; p \ 0.001) and those undergoing treatment in the Northeast (30.7 %); patients in the West had the highest rate of post-operative RAI (43.8 %, p \ 0.001). RAI was administered more frequently in men (44.9 vs. 39.1 %; p \ 0.001) and less frequently in patients who were older (aged C65 years, 31.4 % vs. 18–44 years, 44.2 %; p \ 0.001) and Black (27.5 vs. 40.3 % in Whites; p \ 0.001). Patients of Hispanic origin and those who were married also were more likely to receive RAI (p \ 0.001 and p = 0.018, respectively). The likelihood of receiving RAI after total thyroidectomy was lower in patients with nonaggressive variants of PTC and unifocal PTMC (p = 0.003 and p \ 0.001, respectively). In addition, patients with lymph nodes that were not examined or were negative and those patients with a ‘local’ SEER stage were less likely to receive RAI (both p \ 0.001). In multivariate analysis, factors independently associated with post-operative RAI administration included patients with race designated as ‘other’, those diagnosed between 2000 and 2006, and having multifocal PTMC (Table 2). Compared with patients who did not undergo lymphadenectomy, patients who did were more likely to have post-operative RAI, regardless of whether or not lymph nodes were negative. Older age, Black race, single status, and treatment in the Northeast or Midwest were associated with less RAI utilization.
RAI Ablation
Survival analysis, based on extent of surgery
In univariate analysis, administration of RAI following total thyroidectomy occurred less often in patients with PTMC diagnosed after 2006 (38.4 vs. 41.6 % in 1998–1999 and
Five- and 10-year DSS was 99.6 and 99.3 %, respectively. When comparing patients who underwent partial thyroidectomy with those who underwent total thyroidectomy, there
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Fig. 1 Kaplan–Meier curve of overall survival between patients with papillary thyroid microcarcinoma undergoing surgery compared with the general population of the USA. PTMC papillary thyroid microcarcinoma
was no difference in DSS (hazard ratio [HR] 0.908; 95 % confidence interval [CI] 0.501–1.647; p = 0.752). However, patients who did not undergo surgery for PTMC had compromised survival compared with those undergoing total thyroidectomy (HR 33.783; 95 % CI 14.83–76.99; p \ 0.001). Other factors independently associated with lower DSS were older age, year of diagnosis 1988–1999, SEER stage other than ‘local’, and RAI administration. The OS of patients with ‘local’ SEER stage PTMC was examined; patients who underwent any surgical treatment, irrespective of the extent of surgery, were found to be similar to that of the general population of the USA (Fig. 1). We performed a sub-analysis of patients who did not undergo surgery because it was considered contraindicated or not recommended (n = 270). In this group of patients, 5-year OS was 25.0 % compared with 97.6 % for patients who underwent either partial or total thyroidectomy (p \ 0.001). DSS was reported for 254 patients in the nonoperative group and 28,452 patients in the thyroidectomy group; 9 (3.5 %) and 110 (0.4 %) deaths were reported, respectively (p \ 0.001).
Discussion Variation still remains in the management of patients with PTMC in the USA. The results of this study demonstrate that the majority of patients diagnosed with PTMC have undergone total thyroidectomy, and many also receive post-operative
RAI. These trends have increased in more recent years, despite guidelines recommending a less aggressive management approach. However, a treatment paradox was observed: those patients demonstrating risk factors associated with a higher risk of disease-specific mortality, including older age, were less likely to undergo total thyroidectomy and/or RAI. Existing literature has varied widely in recommendations for extent of therapy in patients with PTMC, ranging from observation to total thyroidectomy and post-operative RAI [2, 6, 7, 9, 14–18]. In two recent studies from a single institution, patients with PTMC were observed without immediate surgery [19, 20]. In the initial study, patients underwent thyroid-stimulating hormone suppression and had serum thyroglobulin and surveillance ultrasonography once or twice annually; tumor enlargement was defined as an increase in tumor size of C3 mm. With a mean followup of 74 months, 31 patients (9.1 %) had enlargement of the primary tumor, and seven patients (2.1 %) developed lymph node metastases [19]. In a follow-up study, when patients were divided by age (\40, 40–59, and C60 years), only younger age was an independent predictor of PTMC progression on multivariate analysis. The authors concluded that older patients with low-risk PTMC may be optimal candidates for observation [20, 21]. In one of the largest series of patients with long-term follow-up, Hay et al [2]. identified 900 patients with PTMC, with a mean follow-up of 17.2 years. Of the 892 patients who underwent surgery, 30- and 40-year recurrence rates were 6 and 8 %, respectively, and the majority of recurrences ([80 %) were locoregional. At 20 years, more recurrences occurred in patients with multifocal tumors (11 vs. 4 %, p = 0.002) and in node-positive patients (16 vs. 0.8 %; p \ 0.001). More extensive surgery and higher rates of post-operative RAI were not shown to affect recurrence, which occurred in 0.8 % of patients with intra-thyroidal, node-negative disease. These findings suggested that the majority of patients with PTMC have an excellent prognosis, and that more extensive surgery and RAI are unnecessary [2]. This was confirmed by our finding that patients with localized PTMC who underwent any surgery and no administration of RAI had a life expectancy similar to that of the general US population. However, several studies have demonstrated that there is a subset of patients with PTMC for whom more extensive surgery and RAI may be indicated [7, 9, 14–17]. In a study utilizing SEER (1988–2009), patients with tall cell (TC) and diffuse sclerosing (DS) variants of PTMC had larger tumors (7.1 [TC] vs. 5.3 mm; p \ 0.001), higher rates of multifocality (47.2 [TC] vs. 34.0 %; p = 0.018), nodal metastases (57.1 [DS] vs. 33.1 %; p = 0.007), and extra-thyroidal extension (27.8 [TC] vs. 13.3 [DS] vs. 6.1 %; p \ 0.001) [22]. There was no difference in OS or DSS between histologies, but given the aggressive characteristics, the authors
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concluded that patients in whom there is pre-operative knowledge of these variants may benefit from total thyroidectomy and central neck dissection [22]. Yu et al. [9] examined 18,445 cases of PTMC in SEER (1988–2007); DSS was 99.5 and 99.3 % at 10 and 15 years, respectively, and lower in patients with two or more risk factors, which included age [45 years, male gender, African-American/ minority race, extra-thyroidal extension, and nodal or distant metastases, suggesting that these patients with PTMC may benefit from total thyroidectomy and RAI [15]. To date, there has been no prospective, randomized, controlled trial to determine if extent of surgery (observation, thyroid lobectomy, or total thyroidectomy) or administration of post-operative RAI leads to improved outcomes in patients with PTMC. The results of our study demonstrate that patients who have localized PTMC and undergo any surgical resection without RAI have survival similar to that of the general US population, suggesting that current ATA recommendations favoring less extensive surgery and treatment are appropriate, with no adverse effects on patient survival. Nonetheless, wide variation remains in the extent of surgery and use of RAI, particularly for patients who are male, older, Black, undergoing treatment in the Northeast, and those who may have other primary malignancies. It is unclear if these variations are related to individual patient characteristics or to issues related to their relative access to care. There are several limitations to this study. In SEER, it is impossible to ascertain which cases of PTMC were incidentally discovered on surgical pathology, which might explain the high percentage of patients undergoing total thyroidectomy. In addition, extent of lymphadenectomy is coded as ‘regional’ and does not differentiate between lymph nodes in the central or lateral compartments. Therefore, it is difficult to separate patients with PTMC and known metastatic disease who underwent planned, therapeutic lymphadenectomy from those who had the incidental removal of lymph nodes at the time of thyroidectomy performed for reasons other than cancer. Lastly, the dataset does not include information on risk factors for thyroid cancer, such as family history and a history of head and neck irradiation, or on surgical complications, such as recurrent laryngeal nerve injury or hypoparathyroidism. The lack of data on the latter precludes the ability to determine if there is increased morbidity as a result of more aggressive surgical management of PTMC.
Conclusions Our findings suggest that an increasing number of patients with PTMC are undergoing total thyroidectomy and RAI despite a lack of evidence that more extensive surgery translates into improved survival. It is important to distinguish patients with risk factors that may predispose to
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recurrent disease; still, it appears that the majority of patients with PTMC are being over-treated. This may have significant implications for patient quality of life and healthcare costs and utilization. Dissemination of these data to endocrinologists and surgeons through institutional multidisciplinary tumor boards, postgraduate conferences, and specialty society meetings is therefore critically important. Disclosures
The authors have no relevant disclosures.
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World J Surg 17. Ogilvie JB, Patel KN, Heller KS (2010) Impact of the 2009 American Thyroid Association guidelines on the choice of operation for well-differentiated thyroid microcarcinomas. Surgery 148:1222–1226 18. Cappelli C, Castellano M, Braga M et al (2007) Aggressiveness and outcome of papillary thyroid carcinoma (PTC) versus microcarcinoma (PMC): a mono-institutional experience. J Surg Oncol 95:555–560 19. Ito Y, Miyauchi A, Inoue H et al (2010) An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg 34:28–35
20. Ito Y, Miyauchi A, Kihara M et al (2014) Patient age is significantly related to the progression of papillary microcarcinoma of the thyroid under observation. Thyroid 24:27–34 21. Ross DS, Tuttle RM (2014) Observing micopapillary thyroid cancers. Thyroid 24:3–6 22. Kuo EJ, Goffredo P, Sosa JA et al (2013) Aggressive variants of papillary thyroid microcarcinoma are associated with extrathyroidal spread and lymph-node metastases: a population-level analysis. Thyroid 23:1305–1311
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Papillary Thyroid Microcarcinoma: An Over-Treated Malignancy? Tracy S. Wang • Paolo Goffredo • Julie Ann Sosa Sanziana A. Roman
•
Socie´te´ Internationale de Chirurgie 2014
Abstract Background The clinical importance of papillary thyroid microcarcinoma (PTMC) remains controversial, with current guidelines suggesting that thyroid lobectomy alone is sufficient. The purpose of this study was to identify population-level treatment patterns in the USA for PTMC. Methods Patients with PTMC in SEER (1998–2010) were included; demographic, clinical (extent of surgery, administration of post-operative radioactive iodine [RAI]), and pathologic characteristics were examined. Outcomes of interest were 5- and 10-year overall survival (OS) and disease-specific survival (DSS). Results The cohort consisted of 29,512 patients. Mean age at diagnosis was 48.5 years; mean tumor size was 0.53 cm. Overall, 73.4 % of patients underwent total thyroidectomy, and RAI was administered to 31.3 %. In multivariate analysis, total thyroidectomy was more frequently performed in patients with multifocal (odds ratio [OR] 2.55), ‘regional’, or ‘distant’ PTMC (OR 2.90 and 2.59). Non-operative management was associated with male patients (OR 4.24) and those aged C65 years (OR 6.31). Post-operative RAI was associated with multifocal T. S. Wang (&) Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA e-mail: [email protected] P. Goffredo Department of Surgery, Milano-Bicocca University, Monza, Italy J. A. Sosa S. A. Roman Department of Surgery, Duke University, Durham, NC, USA J. A. Sosa Duke Clinical Research Institute, Durham, NC, USA
PTMC (OR 2.57). Overall, 5- and 10-year DSS was 99.6 and 99.3 %, respectively, with no difference in DSS between patients who underwent partial versus total thyroidectomy. OS of patients with PTMC who underwent any thyroid operation was similar to that of the general population of the USA. Conclusions An increasing number of patients are undergoing total thyroidectomy and RAI for PTMC. While there may be a subset of patients for whom more aggressive therapy is indicated, many patients with PTMC may be over-treated, with no demonstrable benefit to survival.
Introduction Papillary thyroid microcarcinoma (PTMC) is defined as a papillary thyroid cancer (PTC) that measures B10 mm in greatest dimension [1, 2]. Recent studies have suggested that the overall increase in incidence of PTC is partially fueled by the 441 % increase in incidence of PTMC reported between 1983 and 2006 [2–5]. The clinical importance of PTMC remains controversial, given that prognosis of patients with PTC is excellent, and many PTMCs are discovered incidentally after thyroidectomy has been performed for other indications [2, 6–9]. According to the current American Joint Committee on Cancer (AJCC) staging system, differentiated thyroid cancers are separated into B1 cm (T1a) and 1–2 cm (T1b) in order to separate out PTMC [10]. The 2009 guidelines for the management of thyroid nodules and differentiated thyroid cancer issued by the American Thyroid Association (ATA)[1] state that ‘‘thyroid lobectomy alone may be sufficient …’’ for patients with PTMC and did not recommend radioactive iodine (RAI) ‘‘for patients with unifocal cancer \1 cm without other higher risk features.’’
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The National Comprehensive Cancer Network (NCCN) guidelines include similar recommendations [11]. The objectives of this study were to identify populationlevel treatment patterns in the USA for PTMC with respect to extent of surgery and administration of RAI, and factors that are associated with a worse prognosis. We hypothesize that patients with PTMC have equivalent overall survival (OS) regardless of the extent of surgery (lobectomy vs. total thyroidectomy), and that treated patients with PTMC have similar survival when compared with the overall US population.
Materials and methods
Pathologic characteristics were tumor size, aggressive variants, multifocality, regional lymph nodes examined, and SEER stage. Aggressive variants were considered as binary variables: ‘yes’ (diffuse sclerosing and tall cell variants) and ‘no’ (classic PTC, follicular, and oxyphilic variants). ‘Regional lymph nodes examined’ were divided into ‘none’ (no lymph nodes examined), ‘negative’ (lymph nodes examined were negative), and ‘positive’. The SEER staging system is coded as ‘local’ if the malignancy is confined entirely to the thyroid, ‘regional’ if it extends beyond the thyroid into surrounding tissues or has metastasized to regional lymph nodes, and ‘distant’ if metastases to extra-cervical lymph nodes or organs are present [12]. Outcomes of interest were 5- and 10-year OS and disease-specific survival (DSS) as of 31 December 2010.
Data source and study patients The data source for the study was the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, which provides population-based data on cancers from 18 different registries and represents nearly 28 % of the US population [12]. The International Classification of Diseases for Oncology, Third Edition (ICD-O-3) was utilized to identify PTC (codes 8050, 8260, 8350, 8340–8344), and the variables ‘Extent of Disease—Tumor size’ and ‘Clinical Stage—Tumor size’ were combined to select tumors B1 cm in size [13]. We excluded patients \18 years of age, patients with more than one primary malignancy, and those diagnosed before 1988 due to the lack of data on surgery and RAI administration. Demographic variables of interest included patient age at diagnosis, gender, race, Hispanic origin, marital status, year of diagnosis, and geographic areas. Age at diagnosis was divided into three groups: 18–44, 45–64, and C65 years. Race was White, Black, and other (American Indian, Alaska Native, Asian, Pacific Islander, and other unspecified); Hispanic origin was categorized as ‘yes’ or ‘no’. Marital status was recoded into married (married and/ or domestic partner) and single (single, divorced, widowed, or separated). Geographic location was Northeast, South, Midwest, and West. Clinical variables of interest included extent of surgery and administration of post-operative RAI. Surgical treatment was recoded as none, partial thyroidectomy, and total thyroidectomy. RAI administration for adherence analysis was studied as a binary variable: ‘no RAI’ included none and forms of radiation other than RAI (i.e., external beam radiation therapy [EBRT] and radiation—not otherwise specified); ‘yes RAI’ included radioisotopes, radioactive implants, a combination of EBRT and radioactive implants or radioisotopes, and radiotherapy was recommended but the patient or patient’s guardian refused or it was unknown if it was administered.
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Statistical analysis Summary statistics were used to describe baseline characteristics. OS and DSS were analyzed using the Kaplan– Meier method, and the log-rank test. The one sample logrank test was employed to compare survival of patients with PTMC with that of the overall US population. The Chi-squared test was used for univariate analysis. Stepwise binary logistic regression was employed to identify factors independently associated with total thyroidectomy and RAI ablation. Statistical Package for the Social Sciences software (version 21.0; IBM, Armonk, NY, USA) was utilized to perform data analyses; all tests were two-sided, and statistical significance was set at a p value of \0.05. The current study was deemed to be exempt from institutional review board approval.
Results A total of 29,512 patients with PTC B1 cm (PTMC) were identified in the SEER database between 1988 and 2010 (Table 1). PTMCs were more common among White, married females; mean age at diagnosis was 48.5 years (standard deviation [SD] 13.6). Overall, 73.4 % of patients with PTMC underwent total thyroidectomy, 25.2 % partial thyroidectomy, and 1.4 % did not receive any surgical operation; 31.3 % received RAI post-operatively. Mean tumor size was 0.53 cm (SD 0.31); 218 (0.7 %) of PTMCs represented aggressive variants of PTC, and 8,183 (27.8 %) were multifocal. Regional lymph nodes were examined in 38.4 % of patients; 69.7 % had no metastatic lymph nodes identified. SEER stage was ‘local’ in 82.4 % of the cohort, ‘regional’ in 16.6 %, and ‘distant’ in 1.1 %.
World J Surg Table 1 Demographic, clinical, and pathologic characteristics of patients with papillary thyroid microcarcinoma, SEER 1988–2010 (n = 29,512) Patient characteristics
Patient characteristics
Gender 5,130
17.4
Female
24,382
82.6
Age at diagnosis, ya
48.5 ± 13.6
18–44
11,901
40.3
45–64
13,737
46.5
C65
3,873
13.1
24,739
84.8
Black
1,678
5.7
Other
2,773
9.5
Hispanic origin No
26,177
88.7
3,335
11.3
Single
8,603
30.5
Married
19,644
69.5
1988–1999
4,083
13.8
2000–2006
12,545
42.5
2007–2010
12,884
43.7
Northeast
5,519
18.7
South
5,508
18.7
Midwest
3,052
10.3
West
15,433
52.3
None
404
1.4
Partial thyroidectomy Total/near total thyroidectomy
7,424 21,633
25.2 73.4
No
20,113
68.7
Yes
9,170
31.3
Yes Marital status (n = 28,247)
Geographic area
Surgery (n = 29,461)
RAI ablation (n = 29,283)
5-year survival Overall
96.6
Disease-specific
99.6
10-year survival
Pathologic
21,234
72.2
Yes
8,183
27.8
None
18,111
61.6
7,883 3,423
69.7 30.3
Yes Negative Positive SEER stage (n = 29,427) Local
24,237
82.4
Regional
4,881
16.6
Distant
309
1.1
RAI radioactive iodine, SD standard deviation, SEER Surveillance, Epidemiology, and End Results a
Data are presented as mean ± SD
Extent of surgery
Year of diagnosis
Clinical
No
Regional lymph nodes examined (n = 29,417)
Race (n = 29,190) White
%
Multifocality (n = 29,417)
%
Male
PTMC n
PTMC n
Demographic
Table 1 continued
Overall
93.3
Disease-specific
99.3
Tumor size, mma
5.3 ± 3.1
Aggressive variants No
29,294
99.3
Yes
218
0.7
In univariate analysis, fewer total thyroidectomies associated with PTMCs were performed in the earlier time periods analyzed; between 1988 and 1999, a total of 70.5 % of patients underwent total thyroidectomy versus 72.4 % between 2000 and 2006 and 77.7 % between 2007 and 2010 (p \ 0.001). Geographically, total thyroidectomy was more frequently performed in the West (75.9 %) and less frequently in the Northeast (72.2 %, p \ 0.001) and in patients C65 years (p \ 0.001). There was no difference in extent of surgery based on gender, race, marital status, or for aggressive histological variants of PTMC. Once adjusted for confounders, multivariate analysis demonstrated that total thyroidectomy was more frequently performed in patients diagnosed after the year 2000. Patients with multifocal PTMC, those who underwent lymphadenectomy, and those with SEER-classified ‘regional’ or ‘distant’ disease were more likely to have undergone total thyroidectomy (Table 2). Independent factors that were associated with a lower likelihood of undergoing total thyroidectomy were age C65 years and being treated in the Northeast. Compared with those who received either partial or total thyroidectomy, univariate analysis demonstrated that patients who did not undergo surgery for PTMC were more often male (45.2 vs. 17.0 %; p \ 0.001), aged C45 years (77.8 vs. 59.5 %; p \ 0.001), and single (40.2 vs. 30.3 %; p = 0.001). Black patients and other minorities were less likely to undergo surgery than White (21.4 vs. 15.2 %;
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World J Surg Table 2 Multivariate analysis for surgery and administration of radioactive iodine for patients with papillary thyroid microcarcinoma
Reference groups: 18–44 years, age; 1988–1999, time interval; Married, marital status; White, race; West, geographic area; No, multifocality; Not examined, LN status; Local, SEER stage CI confidence interval, LN lymph node, OR odds ratio, PTMC papillary thyroid microcarcinoma, RAI radioactive iodine, SEER Surveillance, Epidemiology, and End Results
Patient characteristics
Surgery, total thyroidectomy
Administration of RAI
OR
OR
p value
95 % CI
p value
Age 45–64 years
0.94
0.89–1.00
0.060
0.89
0.84–0.95
0.001
Age C65 years
0.80
0.73–0.87
\0.001
0.65
0.58–0.72
\0.001
Black race
–
–
–
0.70
0.61–0.81
\0.001
Other races
–
–
–
1.26
1.14–1.40
\0.001
Single status
–
–
–
0.92
0.86–0.99
0.019
Year 2000–2006
1.16
1.07–1.27
0.001
1.16
1.05–1.28
0.003
Year 2007–2010
1.52
1.39–1.65
\0.001
1.05
0.95–1.16
0.349
Northeast
0.79
0.73–0.85
\0.001
0.58
0.53–0.63
\0.001
South
0.93
0.86–1.00
0.052
1.07
0.99–1.17
0.093
Midwest
0.97
0.88–1.07
0.520
0.80
0.71–0.88
\0.001
Multifocal PTMC Lymph nodes negative
2.55 1.86
2.37–2.74 1.74–1.99
\0.001 \0.001
2.57 1.08
2.41–2.74 1.01–1.16
\0.001 0.028
Lymph nodes positive
3.52
2.84–4.36
\0.001
1.47
1.28–1.69
\0.001
SEER regional
2.90
2.52–3.33
\0.001
4.16
3.70–4.67
\0.001
SEER distant
5.19
2.92–9.24
\0.001
4.84
3.62–6.47
\0.001
Table 3 Multivariate analysis for surgical management of patients with papillary thyroid microcarcinoma Characteristics
95 % CI
No surgery OR
95 % CI
p value
Male gender
4.24
3.18–5.65
\0.001
Age 45–64 years
1.98
1.35–2.89
\0.001
Age C65 years
6.31
4.30–9.27
\0.001
Single status
1.83
1.37–2.44
\0.001
Year 2000–2006
0.19
0.13–0.26
\0.001
Year 2007–2010
0.10
0.07–0.15
\0.001
Multifocal
0.38
0.25–0.58
\0.001
SEER regional
0.45
0.28–0.72
\0.001
Reference groups: Female, gender; 18–44 years, age; 1988–1999, time interval; Single, marital status; West, geographic area; No, multifocality; Local, SEER stage CI confidence interval, OR odds ratio, SEER Surveillance, Epidemiology, and End Results
p \ 0.001). Other variables associated with not having surgery for PTMC included those patients diagnosed between 1988 and 1999 and those receiving treatment in the West. After multivariate adjustment, independent factors associated with non-surgical management were male gender, older age, single status, treatment prior to year 2000, and unifocal or localized disease (Table 3).
41.5 % in 2000–2006, respectively; p \ 0.001) and those undergoing treatment in the Northeast (30.7 %); patients in the West had the highest rate of post-operative RAI (43.8 %, p \ 0.001). RAI was administered more frequently in men (44.9 vs. 39.1 %; p \ 0.001) and less frequently in patients who were older (aged C65 years, 31.4 % vs. 18–44 years, 44.2 %; p \ 0.001) and Black (27.5 vs. 40.3 % in Whites; p \ 0.001). Patients of Hispanic origin and those who were married also were more likely to receive RAI (p \ 0.001 and p = 0.018, respectively). The likelihood of receiving RAI after total thyroidectomy was lower in patients with nonaggressive variants of PTC and unifocal PTMC (p = 0.003 and p \ 0.001, respectively). In addition, patients with lymph nodes that were not examined or were negative and those patients with a ‘local’ SEER stage were less likely to receive RAI (both p \ 0.001). In multivariate analysis, factors independently associated with post-operative RAI administration included patients with race designated as ‘other’, those diagnosed between 2000 and 2006, and having multifocal PTMC (Table 2). Compared with patients who did not undergo lymphadenectomy, patients who did were more likely to have post-operative RAI, regardless of whether or not lymph nodes were negative. Older age, Black race, single status, and treatment in the Northeast or Midwest were associated with less RAI utilization.
RAI Ablation
Survival analysis, based on extent of surgery
In univariate analysis, administration of RAI following total thyroidectomy occurred less often in patients with PTMC diagnosed after 2006 (38.4 vs. 41.6 % in 1998–1999 and
Five- and 10-year DSS was 99.6 and 99.3 %, respectively. When comparing patients who underwent partial thyroidectomy with those who underwent total thyroidectomy, there
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Fig. 1 Kaplan–Meier curve of overall survival between patients with papillary thyroid microcarcinoma undergoing surgery compared with the general population of the USA. PTMC papillary thyroid microcarcinoma
was no difference in DSS (hazard ratio [HR] 0.908; 95 % confidence interval [CI] 0.501–1.647; p = 0.752). However, patients who did not undergo surgery for PTMC had compromised survival compared with those undergoing total thyroidectomy (HR 33.783; 95 % CI 14.83–76.99; p \ 0.001). Other factors independently associated with lower DSS were older age, year of diagnosis 1988–1999, SEER stage other than ‘local’, and RAI administration. The OS of patients with ‘local’ SEER stage PTMC was examined; patients who underwent any surgical treatment, irrespective of the extent of surgery, were found to be similar to that of the general population of the USA (Fig. 1). We performed a sub-analysis of patients who did not undergo surgery because it was considered contraindicated or not recommended (n = 270). In this group of patients, 5-year OS was 25.0 % compared with 97.6 % for patients who underwent either partial or total thyroidectomy (p \ 0.001). DSS was reported for 254 patients in the nonoperative group and 28,452 patients in the thyroidectomy group; 9 (3.5 %) and 110 (0.4 %) deaths were reported, respectively (p \ 0.001).
Discussion Variation still remains in the management of patients with PTMC in the USA. The results of this study demonstrate that the majority of patients diagnosed with PTMC have undergone total thyroidectomy, and many also receive post-operative
RAI. These trends have increased in more recent years, despite guidelines recommending a less aggressive management approach. However, a treatment paradox was observed: those patients demonstrating risk factors associated with a higher risk of disease-specific mortality, including older age, were less likely to undergo total thyroidectomy and/or RAI. Existing literature has varied widely in recommendations for extent of therapy in patients with PTMC, ranging from observation to total thyroidectomy and post-operative RAI [2, 6, 7, 9, 14–18]. In two recent studies from a single institution, patients with PTMC were observed without immediate surgery [19, 20]. In the initial study, patients underwent thyroid-stimulating hormone suppression and had serum thyroglobulin and surveillance ultrasonography once or twice annually; tumor enlargement was defined as an increase in tumor size of C3 mm. With a mean followup of 74 months, 31 patients (9.1 %) had enlargement of the primary tumor, and seven patients (2.1 %) developed lymph node metastases [19]. In a follow-up study, when patients were divided by age (\40, 40–59, and C60 years), only younger age was an independent predictor of PTMC progression on multivariate analysis. The authors concluded that older patients with low-risk PTMC may be optimal candidates for observation [20, 21]. In one of the largest series of patients with long-term follow-up, Hay et al [2]. identified 900 patients with PTMC, with a mean follow-up of 17.2 years. Of the 892 patients who underwent surgery, 30- and 40-year recurrence rates were 6 and 8 %, respectively, and the majority of recurrences ([80 %) were locoregional. At 20 years, more recurrences occurred in patients with multifocal tumors (11 vs. 4 %, p = 0.002) and in node-positive patients (16 vs. 0.8 %; p \ 0.001). More extensive surgery and higher rates of post-operative RAI were not shown to affect recurrence, which occurred in 0.8 % of patients with intra-thyroidal, node-negative disease. These findings suggested that the majority of patients with PTMC have an excellent prognosis, and that more extensive surgery and RAI are unnecessary [2]. This was confirmed by our finding that patients with localized PTMC who underwent any surgery and no administration of RAI had a life expectancy similar to that of the general US population. However, several studies have demonstrated that there is a subset of patients with PTMC for whom more extensive surgery and RAI may be indicated [7, 9, 14–17]. In a study utilizing SEER (1988–2009), patients with tall cell (TC) and diffuse sclerosing (DS) variants of PTMC had larger tumors (7.1 [TC] vs. 5.3 mm; p \ 0.001), higher rates of multifocality (47.2 [TC] vs. 34.0 %; p = 0.018), nodal metastases (57.1 [DS] vs. 33.1 %; p = 0.007), and extra-thyroidal extension (27.8 [TC] vs. 13.3 [DS] vs. 6.1 %; p \ 0.001) [22]. There was no difference in OS or DSS between histologies, but given the aggressive characteristics, the authors
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concluded that patients in whom there is pre-operative knowledge of these variants may benefit from total thyroidectomy and central neck dissection [22]. Yu et al. [9] examined 18,445 cases of PTMC in SEER (1988–2007); DSS was 99.5 and 99.3 % at 10 and 15 years, respectively, and lower in patients with two or more risk factors, which included age [45 years, male gender, African-American/ minority race, extra-thyroidal extension, and nodal or distant metastases, suggesting that these patients with PTMC may benefit from total thyroidectomy and RAI [15]. To date, there has been no prospective, randomized, controlled trial to determine if extent of surgery (observation, thyroid lobectomy, or total thyroidectomy) or administration of post-operative RAI leads to improved outcomes in patients with PTMC. The results of our study demonstrate that patients who have localized PTMC and undergo any surgical resection without RAI have survival similar to that of the general US population, suggesting that current ATA recommendations favoring less extensive surgery and treatment are appropriate, with no adverse effects on patient survival. Nonetheless, wide variation remains in the extent of surgery and use of RAI, particularly for patients who are male, older, Black, undergoing treatment in the Northeast, and those who may have other primary malignancies. It is unclear if these variations are related to individual patient characteristics or to issues related to their relative access to care. There are several limitations to this study. In SEER, it is impossible to ascertain which cases of PTMC were incidentally discovered on surgical pathology, which might explain the high percentage of patients undergoing total thyroidectomy. In addition, extent of lymphadenectomy is coded as ‘regional’ and does not differentiate between lymph nodes in the central or lateral compartments. Therefore, it is difficult to separate patients with PTMC and known metastatic disease who underwent planned, therapeutic lymphadenectomy from those who had the incidental removal of lymph nodes at the time of thyroidectomy performed for reasons other than cancer. Lastly, the dataset does not include information on risk factors for thyroid cancer, such as family history and a history of head and neck irradiation, or on surgical complications, such as recurrent laryngeal nerve injury or hypoparathyroidism. The lack of data on the latter precludes the ability to determine if there is increased morbidity as a result of more aggressive surgical management of PTMC.
Conclusions Our findings suggest that an increasing number of patients with PTMC are undergoing total thyroidectomy and RAI despite a lack of evidence that more extensive surgery translates into improved survival. It is important to distinguish patients with risk factors that may predispose to
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recurrent disease; still, it appears that the majority of patients with PTMC are being over-treated. This may have significant implications for patient quality of life and healthcare costs and utilization. Dissemination of these data to endocrinologists and surgeons through institutional multidisciplinary tumor boards, postgraduate conferences, and specialty society meetings is therefore critically important. Disclosures
The authors have no relevant disclosures.
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