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Pediatric papillary thyroid cancer > 1 cm: is total thyroidectomy necessary?
Journal of Pediatric Surgery xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Pediatric papillary thyroid cancer N 1 cm: is total thyroidectomy necessary? Tate Nice a,⁎, Sebastian Pasara b, Melanie Goldfarb c, John Doski d, Adam Goldin e, Kenneth W. Gow e, Jed G. Nuchtern f, Sanjeev A. Vasudevan f, Monica Langer g, Elizabeth A. Beierle a a
Department of Surgery, Division of Pediatric Surgery, University of Alabama at Birmingham, Children’s Hospital of Alabama, Birmingham, AL School of Public Health, University of Alabama at Birmingham, Birmingham, AL Department of Surgery, John Wayne Cancer Institute/Providence St. John’s Medical Center, Santa Monica, CA d Department of Surgery/Pediatric Surgery Division, University of Texas Health Science Center, San Rosa Children's Hospital, San Antonio, TX e Division of General and Thoracic Surgery, Seattle Children’s Hospital, Seattle, WA f Division of Pediatric Surgery, Baylor College of Medicine, Houston, TX g Division of Pediatric Surgery, Maine Medical Center, Portland, ME b c
a r t i c l e
i n f o
Article history: Received 26 February 2015 Accepted 10 March 2015 Available online xxxx Key words: Pediatric Papillary thyroid cancer Thyroidectomy
a b s t r a c t Purpose: Treatment of pediatric papillary thyroid cancer (p-PTC) often follows adult guidelines, including total thyroidectomy for tumors N1 cm. This study examined the association between operation type and overall survival (OS) for tumors N 1 cm in size in the pediatric population. Methods: Patients ≤21 years of age with primary papillary thyroid cancer N 1 cm were reviewed from the National Cancer Data Base (NCDB) from 1998 to 2011. Kaplan-Meier analysis followed by Cox proportional hazard models estimated the impact of total thyroidectomy (TT) vs. partial thyroidectomy (PT) on overall survival. Models were adjusted for patient, tumor, and treatment factors. Results: 3,861 cases (3474 TT, 387 PT) were included. Estimated 15-year overall survival was 96.10% after TT and 96.18% after PT (p = 0.0855). In multivariate analysis of 3173 patients, only lowest socioeconomic level (HR 4.93, p = 0.001) and unfavorable histology (HR 6.11, p = 0.016) were associated with worse OS. Survival for patients undergoing TT was not statistically improved over those undergoing PT (HR 0.81, p = 0.694). Conclusion: p-PTC N 1 cm has an excellent 15-year overall survival. Treatment with TT did not have an improved OS compared to PT. Lower socioeconomic status and unfavorable histology were associated with decreased OS. © 2015 Published by Elsevier Inc.
Well-differentiated thyroid cancer remains the most common endocrine cancer in the pediatric population, ranging from about 1% of all pediatric malignancies in pre-pubertal children to 7% in adolescents [1]. It affects approximately 0.54 per 100,000 children each year, but the incidence seems to be increasing by 1.1% per year [2,3]. Most pediatric thyroid cancers are either papillary carcinoma or follicular variant of papillary carcinoma (FVPTC) [2]. Treatment of pediatric papillary thyroid cancer (p-PTC) often follows adult guidelines, including total thyroidectomy for tumors N1 cm. However, debate remains over which operation is optimal and whether adult standards should be applied to the pediatric population. This study utilized the National Cancer Data Base to examine the association Abbreviations: FVPTC, follicular variant of papillary carcinoma; NCDB, National Cancer Data Base; OS, overall survival; p-PTC, pediatric papillary thyroid cancer; PT, partial thyroidectomy; TT, total thyroidectomy. ⁎ Corresponding author at: University of Alabama at Birmingham, 1600 7th Avenue South, Lowder Building - Suite 300, Birmingham, AL, 35233. Tel.: +1 205 638 9688; fax: +1 205 975 4972. E-mail address: [email protected] (T. Nice).
of patient, tumor, and treatment characteristics to overall survival for p-PTC tumors N 1 cm in size. A special focus was placed on type of operation in relation to overall survival. 2. Methods 2.1. Data source The National Cancer Data Base (NCDB) is a data repository jointly maintained by the American Cancer Society and the American College of Surgeons Commission on Cancer. With over 1500 participating centers, approximately 70% of all cancer cases in the United States are captured in the database [4,5]. Data from the NCDB has been used in over 350 articles since 1990 [6]. Database records are created through accredited centers by using highly standardized methods and definitions, consistent with specifications by the North American Association of Central Cancer Registries. Records include patient characteristics, cancer properties, treatment administered, and basic outcome information. Data definitions are readily available online [7].
http://dx.doi.org/10.1016/j.jpedsurg.2015.03.031 0022-3468/© 2015 Published by Elsevier Inc.
Please cite this article as: Nice T, et al, Pediatric papillary thyroid cancer N1 cm: is total thyroidectomy necessary?, J Pediatr Surg (2015), http:// dx.doi.org/10.1016/j.jpedsurg.2015.03.031
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T. Nice et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
2.2. Study cohort Institutional review board exemption was obtained (E131009002). All patients ≤21 years of age with primary papillary thyroid cancer N1 cm were examined from the NCDB from 1998 to 2011. Entries with omission of survival data or those that did not undergo a surgical procedure were excluded. 2.3. Categorization All histology codes consistent with papillary thyroid cancer and its subtypes were included: 8050, 8052, 8260, 8337, 8340, 8341, 8342, 8343, 8344, 8350, 8450, 8452, 8503, 8504, and 8507. Separate categories were created for FVPTC (8340) and unfavorable histology, which consisted of papillary squamous cell carcinoma (8052), insular carcinoma (8337), columnar cell (8344), diffuse sclerosing (8350), and solid pseudopapillary tumor (8452). Patient race was classified as white, black, or other. The NCDB uses a second variable for Spanish or Hispanic origins, and this was categorized as either Hispanic or non-Hispanic. Socioeconomic status was estimated by using the average income for the patient’s ZIP code based on 2000 US Census data and classifying into quartiles. Patient comorbidities were recording using Charlson/Deyo Comorbidity Index and were divided into 0, 1, and ≥ 2. The Charlson/Deyo Comorbitity Index is a standardized method of combining a patient’s comorbidities, from 17 different categories, into a single score to help estimate risk from those conditions [8]. Tumor stage was determined by the NCDB analytic stage, which uses pathologic staging when known, otherwise clinical staging is used for the NCDB analytic stage. Clinical and pathological findings were both used to determine metastasis and nodal involvement. Extra-thyroidal extension was based on either a clinical or pathological T stage of 4, 4A, or 4B. Tumor size was based on pathology and categorized into 10–19 mm, 20–29 mm, and ≥30 mm. Type of operation was classified as TT or PT, with PT including sublobar resection, lobectomy, or lobectomy with isthmectomy. 2.4. Statistical analysis chi-Square and pooled variance t-tests were used to compare demographics, tumor characteristics, and treatments between groups. Kaplan-Meier survival estimates were calculated for TT versus PT patients and compared using the log-rank test. Cox proportional hazard models were used to compare survival between these groups adjusting for age, sex, number of comorbidities (Charlson/Deyo Score), race, income quartile, tumor size, unfavorable histology, follicular-variant histology, NCDB analytic stage, multi-focal disease, distant metastasis, extra-thyroidal extension, nodal status, and radioiodine treatment. Due to missing data, not all patients could be utilized for every variable analysis. Comorbidity index, nodal involvement, and multifocality had much lower rates of data completeness. While these variables did undergo univariate analysis, they were dropped from multivariate analysis. Statistical significance was determined at p ≤ 0.05. Statistical analysis utilized SAS software, version 9.3 (Cary, North Carolina). 3. Results A total of 3861 cases of p-PTC N1 cm with a known surgical procedure and known survival status were included in the analysis. Table 1 demonstrates the overall study population. The mean age was 17.6 years with most patients (83.9%) between 15–21 years of age. The majority were white (87.1%), non-Hispanic (79.6%), and female (82.5%). All income levels were represented, with 12.6% in the lowest quartile (b$20,000) and 43.6% in the top income quartile (N$46,000). Only 57 patients (1.5%) had unfavorable papillary histology, and 26.2% had follicular variant of papillary carcinoma. Tumors were most
commonly greater than 3 cm in size (44.6%), while similar numbers of 1–2 cm (28.3%) and 2–3 cm (27.1%) were seen. Lymph node involvement occurred in 44.9% of patients, but extra-thyroid extension was seen in only 12.4%, and only 2.5% of patients had metastatic disease. Multifocal lesions were seen in 34.5%. 3474 (90%) patients underwent total thyroidectomy, while 387 (10%) were treated with partial resections. Of the partial resections, 354 (91.5%) were a lobectomy with or without isthmectomy and 33 (8.5%) were sublobar resections. Radiation, primarily radioactive iodine, was utilized in the treatment regime of 2353 (63.1%). Median follow-up was 83 months with a maximum of 179 months. Table 1 also compares the total thyroidectomy and partial resection subpopulations. The populations had similar demographics, except the partial resection group had slightly higher percentages of non-white patients. Tumor size, stage, and amounts of unfavorable histology were similar between the two groups. Compared to the partial resection group, patients undergoing total thyroidectomy had less follicular variant of papillary cancer (23.5% vs 49.9%) and higher rates of lymph node involvement (47.6% vs 18.8%), extra-thyroid extension (13.2% vs 4.4%), metastasis (2.7% vs 0.5%), and multifocal disease (35.6% vs 22.7%). Patients in the total thyroidectomy group were also more likely to undergo radiation therapy (65.9% vs 37.9%). A total of 48 deaths were recorded, 40 (1.15%) following TT and 8 (2.07%) after PT. Table 2 depicts univariate analysis for overall survival. Due to incomplete data entry, not all patients could be utilized for each variable analysis and the number analyzed for each variable can be seen in the table. NCDB analytic stage, comorbidities, unfavorable histology, and distant metastasis were each associated with lower OS (p b 0.05). Conversely, radioiodine therapy, female gender, and increasing socioeconomic status were associated with increased OS (p b 0.05). Other factors did not significantly impact OS. Specifically, operation type had no statistical association with overall survival in the univariate analysis (p = 0.0911). As seen in Table 2, lymph node status, multi-focal tumors and number of comorbidities were not entered for many of the patients. Therefore, these variables were dropped from the multivariate model due to the requirement for data completeness of all variables and the large drop in patient numbers that would have resulted to include these variables. The multivariate analysis included 3173 cases, and the results are shown in Table 3. Again, survival for patients undergoing total thyroidectomy was not statistically different than those undergoing partial thyroidectomy (p = 0.6939). Only lowest socioeconomic level (HR 4.93, p = 0.001) and unfavorable histology (HR 6.11, p = 0.016) were associated with worse OS. Fig. 1 reveals the results from the Kaplan-Meier analysis of survival by operation type. Survival did not significantly differ between those undergoing TT versus those having PT (p = 0.0855). Estimated 15 year overall survival after TT was 96.10% and 96.18% after PT. 4. Discussion This study encompasses the largest examination of pediatric papillary thyroid cancer to date. OS was excellent for pediatric patients with p-PTC N 1 cm in size, with 15 year OS estimated to be above 96%. These data confirmed the good prognosis normally attributed to children and adults with papillary thyroid cancer. Upon initial review, the 40 deaths after total thyroidectomy may seem significantly higher than the 8 deaths after partial thyroidectomy. However, this difference is actually attributable to the much higher numbers of patients who underwent total thyroidectomy compared to those undergoing partial resection. In this study, univariate and multivariate analysis as well as Kaplan-Meier survival analysis all showed that pediatric patients who underwent TT for tumors N 1 cm did not have an improved OS compared to those patients who received PT. While the TT and PT groups were similar, there were differences in some of the tumor characteristics. Multifocal and lymph node disease were two of the variables that had the most missing information. Still,
Please cite this article as: Nice T, et al, Pediatric papillary thyroid cancer N1 cm: is total thyroidectomy necessary?, J Pediatr Surg (2015), http:// dx.doi.org/10.1016/j.jpedsurg.2015.03.031
T. Nice et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
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Table 1 Study population characteristics. Variable
Demographics
Tumor Characteristics
Treatment
Age (years) Mean [SD] Median Race (n = 3861) White Black Other Hispanic (n = 3861) Yes No Sex (n = 3861) Male Female Income Quartile (n = 3670) b $30,000 $30,000 - $34,999 $35,000 - $45,999 ≥ $46,000 Charlson/Deyo Comorbidity Index (n = 1885) 0 1 ≥2 Histology Favorable Unfavorable Histology: Follicular Variant (n = 3861) Yes No Tumor Size (n = 3681) 10–19 mm 20–29 mm ≥30 mm Lymph Node Involvement (n = 699) Yes No Extra-Thyroid Extension (n = 3861) Yes No Metastasis (n = 3861) Yes No Multifocality (n = 1333) Solitary Multifocal Analytic Stage (n = 3449) 1 2 3 4 Operation Type (n = 3861) Total Thyroidectomy Partial Thyroidectomy Radiation Treatment (n = 3730) Yes No
Total population
Total thyroidectomy
Partial thyroidectomy
N
(%)
N
(%)
N
(%)
17.6 18
[3.3]
17.6
[3.3]
17.6
[3.3]
3364 190 307
(87.1 %) (4.9 %) (8.0 %)
3032 160 282
(87.3%) (4.6%) (8.1%)
332 30 25
(85.8%) (7.7% (6.5%)
0. 0158
788 3073
(20.4 %) (79.6 %)
718 2756
(20.7%) (79.3%)
70 317
(18.1%) (81.9%)
0.2323
676 3185
(17.5 %) (82.5 %)
616 2858
(17.7%) (82.3%)
60 327
(15.5%) (84.5%)
0.2740
462 613 993 1602
(12.6 %) (16.7 %) (27.1 %) (43.6 %)
405 550 906 1446
(12.3%) (16.6%) (27.4%) (43.7%)
57 63 87 156
(15.7%) (17.3%) (24.0%) (43.0%)
0.1976
1787 94 4
(94.8 %) (5.0 %) (0.2%)
1632 88 3
(94.7%) (5.1%) (0.2%)
155 6 1
(95.7%) (3.7%) (0.6%)
0.3734
3804 57
(98.5%) (1.5%)
3419 55
(98.4%) (1.6%)
385 2
(99.5%) (0.5%)
0.0989
1011 2850
(26.2%) (73.8%)
817 2657
(23.5%) (76.5%)
194 193
(49.9%) (50.1%)
b0. 0001
1094 1047 1720
(28.3 %) (27.1 %) (44.6 %)
985 935 1554
(28.4%) (26.9%) (44.7%)
109 112 166
(28.2%) (28.9%) (42.9%)
0.6718
314 385
(44.9 %) (55.1 %)
302 333
(47.6%) (52.4%)
12 52
(18.8%) (81.3%)
b0. 0001
477 3384
(12.4 %) (87.6 %)
460 3014
(13.2%) (86.8%)
17 370
(4.4%) (95.6%)
b0. 0001
95 3766
(2.5 %) (97.5 %)
93 3381
(2.7%) (97.3%)
2 385
(0.5%) (99.5%)
0. 0093
873 460
(65.5 %) (34.5 %)
788 435
(64.4%) (35.6%)
85 25
(77.3%) (22.7%)
0. 0067
2999 214 181 55
(87.0 %) (6.2 %) (5.2 %) (1.6 %)
2697 193 170 51
(86.7%) (6.2%) (5.5%) (1.6%)
302 21 11 4
(89.3%) (6.2%) (3.3%) (1.2%)
0.3230
3474 387
(90.0%) (10.0 %)
3474 -
(100%) -
387
(100%)
-
2353 1377
(63.1 %) (36.9 %)
2211 1144
(65.9%) (34.1%)
142 233
(37.9%) (62.1%)
b0. 0001
a statistical difference was found between the groups. Lymph node involvement, extra-thyroid extension, and multifocal disease may have all been lower in the PT because the extent of resection was lower. Additionally, there may have been some selection bias forcing some patients that were known to be positive for these into the total thyroidectomy group, as is probably the case with metastasis. Given the nature of this large database study, it remains unclear how much this selection bias affects the survival rates of the two groups. Selection bias may account for some of the lack of survival benefit from total thyroidectomy, and therefore, care must be taken in interpreting the two procedures as resulting in equivalent survival for all patients. The univariate analysis identified several variables that may be associated with changes in survival. However, after adjusting for confounding variables, the multivariate analysis showed that only
p-Value
0.9412
socioeconomic status and unfavorable histology were associated with a change in survival. Patients with unfavorable histology suffered a 6-fold decrease in survival. Many of these subtypes have been shown to be more aggressive and result in higher recurrence [9]. Additionally, patients in the lowest income quartile had almost 5 times the risk of death as those in the highest income quartile. Exactly how socioeconomic status increased risk in this cohort is not entirely clear. Certainly, disparities in access to care or treatment differences may have played a role. However, since the outcome was OS, nonthyroid related factors such as nutrition, stress, other medical conditions, or environmental safety may contribute to the difference. Demographically, this study was similar to other reported populations of pediatric thyroid cancer and likely provides a good representation of the overall pediatric population in the United States. As in this
Please cite this article as: Nice T, et al, Pediatric papillary thyroid cancer N1 cm: is total thyroidectomy necessary?, J Pediatr Surg (2015), http:// dx.doi.org/10.1016/j.jpedsurg.2015.03.031
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T. Nice et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
Table 2 Univariate analysis of survival. Variable
N
p-Value
Age Race Hispanic Sex (Female) Income Quartile (increasing) Comorbidity Index Histology-Unfavorable Histology-Follicular Variant Tumor Size Node Involvement Tumor Extension Metastasis Multifocal Analytic Stage Operation Type Radiation
3861 3861 3861 3861 3670 1885 3861 3861 3861 699 3861 3861 1333 3449 3861 3730
0.4539 0.1357 0.1811 0. 0412 0. 0002 0. 0005 0. 0045 0.6073 0.0553 0.3920 0.9628 0. 0167 0.7515 0. 0381 0.0911 0. 0182
HR
Survival
0.523 0.242, 0.373, 0.197 1.674, 60.827 5.496
↑ ↑ ↓ ↓
3.491
↓
2.439, 0.462, 4.478 0.520 0.486
↓ ↑
HR: hazard ratio.
study, previous studies have shown the pediatric population with welldifferentiated thyroid cancer to be N 80% white and have a 4:1 female to male ratio [2]. A study of 1753 patients with thyroid carcinoma from the SEER database had similar rates of regional lymph node involvement (46.4%) and rates of FVPTC. While the SEER database study had a higher rate of metastasis (7.6%), it also included more aggressive tumors such as follicular and medullary cancers [2]. TT has become increasingly common for treatment of p-PTC. A previous study utilizing NCDB data showed TT accounted for 50.6% of pediatric differentiated thyroid cancer treatments in 1985 compared to 84% in 2007 [10]. Although utilization of TT was slightly higher (90%) in the current study, it only included patients with tumors N 1 cm in size. A number of factors have contributed to total thyroidectomy becoming most surgeons’ preference for treating papillary thyroid cancer N1 cm in size. These factors include lower reported recurrence rates, ease in monitoring for recurrence with thyroglobulin, and the ability to ablate residual disease with radioactive iodine [11]. A number of studies support TT for children with thyroid cancer. In one retrospective review of 68 children with all types of thyroid malignancy, 8 of 18 (44%) patients receiving partial thyroid resection required further surgery, compared to only 6 of 50 (12%) of those undergoing TT [12]. Similar findings were seen in a study of 215 patients with papillary carcinoma, where recurrence was seen in 35% of partial resections verses 6% after TT [13]. The high probability of multifocal disease remains another reason to consider TT. Multifocal tumors were found in 34.5% of patients in the current study, but it has been reported in 57% in one retrospective study of 56 pediatric patients with well-differentiated
Table 3 Multivariate analysis of survival. Variable
p-value
Age Race Hispanic Sex (Female) Income Quartile (lowest) Comorbidity Index Histology-Unfavorable Histology-Follicular Variant Tumor Size Node Involvement Tumor Extension Metastasis Multifocal Analytic Stage Operation Type Radiation
0.7351 0.4065 0.4672 0.1621 0. 0010 N/A 0. 0162 0.6647 0.2641 N/A 0.7514 0.5374 N/A 0.4917 0.6939 0.0871
HR: hazard ratio.
HR
Survival
4.93
↓
6.11
↓
thyroid cancer [14]. However, using this argument to justify TT may be flawed since it is not currently clear if recurrence or multifocal disease significantly affects survival given the high survival rate of papillary cancer [11]. PT is often considered due to the concern for increased surgical complications with TT. Reports of surgical complications after TT range from 12-22% [12,15–17]. Complications are likely more common in younger patients. One study reported complications rates of 22% for children less than 6 years old, 15% for children 7 to 12 years old, and 12% for children 12–17 years old [17]. There has been a single pediatric study that reported no statistical difference in complications between operation types, but the study only included 68 patients [12]. However, a recent study of 62,722 adults reported significantly higher complications in patients undergoing TT (20.4%) compared to unilateral thyroidectomy (10.8%) [18]. The most common surgical complications in children are hypoparathyroidism and voice disturbances [17]. Permanent hypothyroidism and bilateral recurrent nerve injury encompass the most severe surgical complications, and although rare, likely result from TT rather than PT. Complication rates have been found to decrease with higher volume surgeons [17–19]. Concerns about appropriate management of thyroid hormone levels and quality of life after TT are commonly overlooked in surgical literature. Extent of surgery for papillary thyroid cancer has also been reexamined in the adult population. Both the SEER and NCDB databases have recently been used for population based studies comparing total thyroidectomy to partial resections [20,21]. Both studies found comparable survival for select populations. One limitation of the current study is that the follow-up may not have been long enough to detect differences in OS since thyroid cancer patients are known to have an excellent OS and live for extended periods of time. Hay and colleagues studied 215 pediatric patients with papillary cancer with a median follow-up of 29 years. Papillary thyroid carcinoma recurred in 32% by 40 years even after complete surgical resection. While survival was on-par with the general population for the first 20 years following surgery, survival was significantly less than expected for patients 30–50 years after treatment. The majority (68%) of the deaths occurred as a result of non-thyroid malignancy, many (73%) of whom had received radioactive iodine as part of their p-PTC treatment. In their study, radioactive iodine did not decrease 25 year regional recurrence compared to total thyroidectomy alone [13]. Other limitations of the current study are those inherent to any large national retrospective database and specifically those of the NCDB. The NCDB does not capture information on tumor recurrence or disease specific survival, both important outcomes for young thyroid cancer patients. Moreover, information regarding surgical complications or disease specific morbidity remains important for both short-term and long-term quality of life in these young patients with very long survivorships, but neither is contained in the NCDB. As a result, associations between these outcomes, type of operation, and the other variables studied could not be examined, and the primary outcome had to be limited to overall survival. Despite these shortcomings, the NCDB provides the opportunity to examine data from a very large number of patients from numerous institutions. 5. Conclusion
0.805
Primary pediatric papillary thyroid cancer has an excellent 15-year overall survival. Patients that underwent total thyroidectomy for tumors N1 cm did not have an improved overall survival compared to partial thyroidectomy. However, both lower socioeconomic status and unfavorable histology were associated with decreased overall survival. Data from this study may be valuable in counseling patients and their families about surgical treatment options. Furthermore, this study highlights the need for a large, multicenter prospective study to reexamine whether total thyroidectomy is necessary for all pediatric papillary thyroid cancers N1 cm, given the potential increased morbidity of total
Please cite this article as: Nice T, et al, Pediatric papillary thyroid cancer N1 cm: is total thyroidectomy necessary?, J Pediatr Surg (2015), http:// dx.doi.org/10.1016/j.jpedsurg.2015.03.031
T. Nice et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
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Fig. 1. Kaplan-Meier Analysis of survival by operation type. Data were evaluated with Kaplan-Meier analysis. Survival of patients who underwent lobectomy was compared to that of patients who had a total thyroidectomy for papillary thyroid cancer. There was no significant difference in survival between the two groups (p = 0.0855).
thyroidectomy over partial thyroidectomy in pediatric patients. Specifically, partial resection may be appropriate for both tumors b1 cm and low-risk tumors N1 cm. Extended long-term follow-up of papillary cancer treatments and the role of radioactive iodine in relation to secondary malignancies should also be examined. Appendix A. Presented by Dr. Tate Nice, Birmingham, AL Discussant DR. BIREN MODI (Boston, MA) Your presentation poses an important question. One facet I'd like to understand before I agree with that conclusion is whether the two groups between total thyroidectomy and partial thyroidectomy were equivalent. So did you actually analyze the potential patient factors between those two groups? Response DR. NICE: Yes. That's how you start off in each study, looking at the two groups. As far as most of the factors, the income levels and age, they were all pretty equivalent across the two groups. But the total thyroidectomy group was a lot larger than the partial resection group, and I think that just kind of reflects current trends. References [1] Wang TS, Roman SA, Sosa JA. Predictors of outcomes following pediatric thyroid and parathyroid surgery. Curr Opin Oncol 2009;21(1):23–8. [2] Hogan AR, Zhuge Y, Perez EA, et al. Pediatric thyroid carcinoma: incidence and outcomes in 1753 patients. J Surg Res 2009;156(1):167–72. [3] Siegel DA, King J, Tai E, et al. Cancer incidence rates and trends among children and adolescents in the United States, 2001–2009. Pediatrics 2014;134(4):e945–55. [4] National Cancer Data Base. Available from: https://www.facs.org/quality-programs/ cancer/ncdb.
[5] Mallin K, Palis BE, Watroba N, et al. Completeness of American Cancer Registry Treatment Data: implications for quality of care research. J Am Coll Surg 2013; 216(3):428–37. [6] Clinical information bibliography. Available from: https://www.facs.org/quality-programs/cancer/ncdb/bilbclin; 2013. [7] National Cancer Data Base On-Line Data Dictionary. Available from: http:// ncdbpufbeta.facs.org/?q=node/259; 2011. [8] Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992;45(6):613–9. [9] Roman S, Sosa JA. Aggressive variants of papillary thyroid cancer. Curr Opin Oncol 2013;25(1):33–8. [10] Raval MV, Bentrem DJ, Stewart AK, et al. Utilization of total thyroidectomy for differentiated thyroid cancer in children. Ann Surg Oncol 2010;17(10):2545–53. [11] Piper H, Skinner M. Childhood diseases of the thyroid and parathyroid glands. In: Coran A, editor. Pediatric surgery. 7th ed. Philadelphia: Elsevier Saunders; 2012. p. 748–50. [12] Bargren AE, Meyer-Rochow GY, Delbridge LW, et al. Outcomes of surgically managed pediatric thyroid cancer. J Surg Res 2009;156(1):70–3. [13] Hay ID, Gonzalez-Losada T, Reinalda MS, et al. Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008. World J Surg 2010;34(6):1192–202. [14] Grigsby PW, Gal-or A, Michalski JM, et al. Childhood and adolescent thyroid carcinoma. Cancer 2002;95(4):724–9. [15] Rosato L, Mondini G, Ginardi A, et al. Incidence of complications of thyroid surgery. Minerva Chir 2000;55(10):693–702. [16] O'Gorman CS, Hamilton J, Rachmiel M, et al. Thyroid cancer in childhood: a retrospective review of childhood course. Thyroid 2010;20(4):375–80. [17] Sosa JA, Tuggle CT, Wang TS, et al. Clinical and economic outcomes of thyroid and parathyroid surgery in children. J Clin Endocrinol Metab 2008;93(8):3058–65. [18] Hauch A, Al-Qurayshi Z, Randolph G, et al. Total thyroidectomy is associated with increased risk of complications for low- and high-volume surgeons. Ann Surg Oncol 2014;21(12):3844–52. [19] Tuggle CT, Roman SA, Wang TS, et al. Pediatric endocrine surgery: who is operating on our children? Surgery 2008;144(6):869–77 [discussion 877]. [20] Mendelsohn AH, Elashoff DA, Abemayor E, et al. Surgery for papillary thyroid carcinoma: is lobectomy enough? Arch Otolaryngol Head Neck Surg 2010;136(11):1055–61. [21] Adam MA, Pura J, Gu L, et al. Extent of surgery for papillary thyroid cancer is not associated with survival: an analysis of 61,775 patients. Ann Surg 2014;260(4): 601–5 [discussion 605–7].
Please cite this article as: Nice T, et al, Pediatric papillary thyroid cancer N1 cm: is total thyroidectomy necessary?, J Pediatr Surg (2015), http:// dx.doi.org/10.1016/j.jpedsurg.2015.03.031
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Pediatric papillary thyroid cancer N 1 cm: is total thyroidectomy necessary? Tate Nice a,⁎, Sebastian Pasara b, Melanie Goldfarb c, John Doski d, Adam Goldin e, Kenneth W. Gow e, Jed G. Nuchtern f, Sanjeev A. Vasudevan f, Monica Langer g, Elizabeth A. Beierle a a
Department of Surgery, Division of Pediatric Surgery, University of Alabama at Birmingham, Children’s Hospital of Alabama, Birmingham, AL School of Public Health, University of Alabama at Birmingham, Birmingham, AL Department of Surgery, John Wayne Cancer Institute/Providence St. John’s Medical Center, Santa Monica, CA d Department of Surgery/Pediatric Surgery Division, University of Texas Health Science Center, San Rosa Children's Hospital, San Antonio, TX e Division of General and Thoracic Surgery, Seattle Children’s Hospital, Seattle, WA f Division of Pediatric Surgery, Baylor College of Medicine, Houston, TX g Division of Pediatric Surgery, Maine Medical Center, Portland, ME b c
a r t i c l e
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Article history: Received 26 February 2015 Accepted 10 March 2015 Available online xxxx Key words: Pediatric Papillary thyroid cancer Thyroidectomy
a b s t r a c t Purpose: Treatment of pediatric papillary thyroid cancer (p-PTC) often follows adult guidelines, including total thyroidectomy for tumors N1 cm. This study examined the association between operation type and overall survival (OS) for tumors N 1 cm in size in the pediatric population. Methods: Patients ≤21 years of age with primary papillary thyroid cancer N 1 cm were reviewed from the National Cancer Data Base (NCDB) from 1998 to 2011. Kaplan-Meier analysis followed by Cox proportional hazard models estimated the impact of total thyroidectomy (TT) vs. partial thyroidectomy (PT) on overall survival. Models were adjusted for patient, tumor, and treatment factors. Results: 3,861 cases (3474 TT, 387 PT) were included. Estimated 15-year overall survival was 96.10% after TT and 96.18% after PT (p = 0.0855). In multivariate analysis of 3173 patients, only lowest socioeconomic level (HR 4.93, p = 0.001) and unfavorable histology (HR 6.11, p = 0.016) were associated with worse OS. Survival for patients undergoing TT was not statistically improved over those undergoing PT (HR 0.81, p = 0.694). Conclusion: p-PTC N 1 cm has an excellent 15-year overall survival. Treatment with TT did not have an improved OS compared to PT. Lower socioeconomic status and unfavorable histology were associated with decreased OS. © 2015 Published by Elsevier Inc.
Well-differentiated thyroid cancer remains the most common endocrine cancer in the pediatric population, ranging from about 1% of all pediatric malignancies in pre-pubertal children to 7% in adolescents [1]. It affects approximately 0.54 per 100,000 children each year, but the incidence seems to be increasing by 1.1% per year [2,3]. Most pediatric thyroid cancers are either papillary carcinoma or follicular variant of papillary carcinoma (FVPTC) [2]. Treatment of pediatric papillary thyroid cancer (p-PTC) often follows adult guidelines, including total thyroidectomy for tumors N1 cm. However, debate remains over which operation is optimal and whether adult standards should be applied to the pediatric population. This study utilized the National Cancer Data Base to examine the association Abbreviations: FVPTC, follicular variant of papillary carcinoma; NCDB, National Cancer Data Base; OS, overall survival; p-PTC, pediatric papillary thyroid cancer; PT, partial thyroidectomy; TT, total thyroidectomy. ⁎ Corresponding author at: University of Alabama at Birmingham, 1600 7th Avenue South, Lowder Building - Suite 300, Birmingham, AL, 35233. Tel.: +1 205 638 9688; fax: +1 205 975 4972. E-mail address: [email protected] (T. Nice).
of patient, tumor, and treatment characteristics to overall survival for p-PTC tumors N 1 cm in size. A special focus was placed on type of operation in relation to overall survival. 2. Methods 2.1. Data source The National Cancer Data Base (NCDB) is a data repository jointly maintained by the American Cancer Society and the American College of Surgeons Commission on Cancer. With over 1500 participating centers, approximately 70% of all cancer cases in the United States are captured in the database [4,5]. Data from the NCDB has been used in over 350 articles since 1990 [6]. Database records are created through accredited centers by using highly standardized methods and definitions, consistent with specifications by the North American Association of Central Cancer Registries. Records include patient characteristics, cancer properties, treatment administered, and basic outcome information. Data definitions are readily available online [7].
http://dx.doi.org/10.1016/j.jpedsurg.2015.03.031 0022-3468/© 2015 Published by Elsevier Inc.
Please cite this article as: Nice T, et al, Pediatric papillary thyroid cancer N1 cm: is total thyroidectomy necessary?, J Pediatr Surg (2015), http:// dx.doi.org/10.1016/j.jpedsurg.2015.03.031
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T. Nice et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
2.2. Study cohort Institutional review board exemption was obtained (E131009002). All patients ≤21 years of age with primary papillary thyroid cancer N1 cm were examined from the NCDB from 1998 to 2011. Entries with omission of survival data or those that did not undergo a surgical procedure were excluded. 2.3. Categorization All histology codes consistent with papillary thyroid cancer and its subtypes were included: 8050, 8052, 8260, 8337, 8340, 8341, 8342, 8343, 8344, 8350, 8450, 8452, 8503, 8504, and 8507. Separate categories were created for FVPTC (8340) and unfavorable histology, which consisted of papillary squamous cell carcinoma (8052), insular carcinoma (8337), columnar cell (8344), diffuse sclerosing (8350), and solid pseudopapillary tumor (8452). Patient race was classified as white, black, or other. The NCDB uses a second variable for Spanish or Hispanic origins, and this was categorized as either Hispanic or non-Hispanic. Socioeconomic status was estimated by using the average income for the patient’s ZIP code based on 2000 US Census data and classifying into quartiles. Patient comorbidities were recording using Charlson/Deyo Comorbidity Index and were divided into 0, 1, and ≥ 2. The Charlson/Deyo Comorbitity Index is a standardized method of combining a patient’s comorbidities, from 17 different categories, into a single score to help estimate risk from those conditions [8]. Tumor stage was determined by the NCDB analytic stage, which uses pathologic staging when known, otherwise clinical staging is used for the NCDB analytic stage. Clinical and pathological findings were both used to determine metastasis and nodal involvement. Extra-thyroidal extension was based on either a clinical or pathological T stage of 4, 4A, or 4B. Tumor size was based on pathology and categorized into 10–19 mm, 20–29 mm, and ≥30 mm. Type of operation was classified as TT or PT, with PT including sublobar resection, lobectomy, or lobectomy with isthmectomy. 2.4. Statistical analysis chi-Square and pooled variance t-tests were used to compare demographics, tumor characteristics, and treatments between groups. Kaplan-Meier survival estimates were calculated for TT versus PT patients and compared using the log-rank test. Cox proportional hazard models were used to compare survival between these groups adjusting for age, sex, number of comorbidities (Charlson/Deyo Score), race, income quartile, tumor size, unfavorable histology, follicular-variant histology, NCDB analytic stage, multi-focal disease, distant metastasis, extra-thyroidal extension, nodal status, and radioiodine treatment. Due to missing data, not all patients could be utilized for every variable analysis. Comorbidity index, nodal involvement, and multifocality had much lower rates of data completeness. While these variables did undergo univariate analysis, they were dropped from multivariate analysis. Statistical significance was determined at p ≤ 0.05. Statistical analysis utilized SAS software, version 9.3 (Cary, North Carolina). 3. Results A total of 3861 cases of p-PTC N1 cm with a known surgical procedure and known survival status were included in the analysis. Table 1 demonstrates the overall study population. The mean age was 17.6 years with most patients (83.9%) between 15–21 years of age. The majority were white (87.1%), non-Hispanic (79.6%), and female (82.5%). All income levels were represented, with 12.6% in the lowest quartile (b$20,000) and 43.6% in the top income quartile (N$46,000). Only 57 patients (1.5%) had unfavorable papillary histology, and 26.2% had follicular variant of papillary carcinoma. Tumors were most
commonly greater than 3 cm in size (44.6%), while similar numbers of 1–2 cm (28.3%) and 2–3 cm (27.1%) were seen. Lymph node involvement occurred in 44.9% of patients, but extra-thyroid extension was seen in only 12.4%, and only 2.5% of patients had metastatic disease. Multifocal lesions were seen in 34.5%. 3474 (90%) patients underwent total thyroidectomy, while 387 (10%) were treated with partial resections. Of the partial resections, 354 (91.5%) were a lobectomy with or without isthmectomy and 33 (8.5%) were sublobar resections. Radiation, primarily radioactive iodine, was utilized in the treatment regime of 2353 (63.1%). Median follow-up was 83 months with a maximum of 179 months. Table 1 also compares the total thyroidectomy and partial resection subpopulations. The populations had similar demographics, except the partial resection group had slightly higher percentages of non-white patients. Tumor size, stage, and amounts of unfavorable histology were similar between the two groups. Compared to the partial resection group, patients undergoing total thyroidectomy had less follicular variant of papillary cancer (23.5% vs 49.9%) and higher rates of lymph node involvement (47.6% vs 18.8%), extra-thyroid extension (13.2% vs 4.4%), metastasis (2.7% vs 0.5%), and multifocal disease (35.6% vs 22.7%). Patients in the total thyroidectomy group were also more likely to undergo radiation therapy (65.9% vs 37.9%). A total of 48 deaths were recorded, 40 (1.15%) following TT and 8 (2.07%) after PT. Table 2 depicts univariate analysis for overall survival. Due to incomplete data entry, not all patients could be utilized for each variable analysis and the number analyzed for each variable can be seen in the table. NCDB analytic stage, comorbidities, unfavorable histology, and distant metastasis were each associated with lower OS (p b 0.05). Conversely, radioiodine therapy, female gender, and increasing socioeconomic status were associated with increased OS (p b 0.05). Other factors did not significantly impact OS. Specifically, operation type had no statistical association with overall survival in the univariate analysis (p = 0.0911). As seen in Table 2, lymph node status, multi-focal tumors and number of comorbidities were not entered for many of the patients. Therefore, these variables were dropped from the multivariate model due to the requirement for data completeness of all variables and the large drop in patient numbers that would have resulted to include these variables. The multivariate analysis included 3173 cases, and the results are shown in Table 3. Again, survival for patients undergoing total thyroidectomy was not statistically different than those undergoing partial thyroidectomy (p = 0.6939). Only lowest socioeconomic level (HR 4.93, p = 0.001) and unfavorable histology (HR 6.11, p = 0.016) were associated with worse OS. Fig. 1 reveals the results from the Kaplan-Meier analysis of survival by operation type. Survival did not significantly differ between those undergoing TT versus those having PT (p = 0.0855). Estimated 15 year overall survival after TT was 96.10% and 96.18% after PT. 4. Discussion This study encompasses the largest examination of pediatric papillary thyroid cancer to date. OS was excellent for pediatric patients with p-PTC N 1 cm in size, with 15 year OS estimated to be above 96%. These data confirmed the good prognosis normally attributed to children and adults with papillary thyroid cancer. Upon initial review, the 40 deaths after total thyroidectomy may seem significantly higher than the 8 deaths after partial thyroidectomy. However, this difference is actually attributable to the much higher numbers of patients who underwent total thyroidectomy compared to those undergoing partial resection. In this study, univariate and multivariate analysis as well as Kaplan-Meier survival analysis all showed that pediatric patients who underwent TT for tumors N 1 cm did not have an improved OS compared to those patients who received PT. While the TT and PT groups were similar, there were differences in some of the tumor characteristics. Multifocal and lymph node disease were two of the variables that had the most missing information. Still,
Please cite this article as: Nice T, et al, Pediatric papillary thyroid cancer N1 cm: is total thyroidectomy necessary?, J Pediatr Surg (2015), http:// dx.doi.org/10.1016/j.jpedsurg.2015.03.031
T. Nice et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
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Table 1 Study population characteristics. Variable
Demographics
Tumor Characteristics
Treatment
Age (years) Mean [SD] Median Race (n = 3861) White Black Other Hispanic (n = 3861) Yes No Sex (n = 3861) Male Female Income Quartile (n = 3670) b $30,000 $30,000 - $34,999 $35,000 - $45,999 ≥ $46,000 Charlson/Deyo Comorbidity Index (n = 1885) 0 1 ≥2 Histology Favorable Unfavorable Histology: Follicular Variant (n = 3861) Yes No Tumor Size (n = 3681) 10–19 mm 20–29 mm ≥30 mm Lymph Node Involvement (n = 699) Yes No Extra-Thyroid Extension (n = 3861) Yes No Metastasis (n = 3861) Yes No Multifocality (n = 1333) Solitary Multifocal Analytic Stage (n = 3449) 1 2 3 4 Operation Type (n = 3861) Total Thyroidectomy Partial Thyroidectomy Radiation Treatment (n = 3730) Yes No
Total population
Total thyroidectomy
Partial thyroidectomy
N
(%)
N
(%)
N
(%)
17.6 18
[3.3]
17.6
[3.3]
17.6
[3.3]
3364 190 307
(87.1 %) (4.9 %) (8.0 %)
3032 160 282
(87.3%) (4.6%) (8.1%)
332 30 25
(85.8%) (7.7% (6.5%)
0. 0158
788 3073
(20.4 %) (79.6 %)
718 2756
(20.7%) (79.3%)
70 317
(18.1%) (81.9%)
0.2323
676 3185
(17.5 %) (82.5 %)
616 2858
(17.7%) (82.3%)
60 327
(15.5%) (84.5%)
0.2740
462 613 993 1602
(12.6 %) (16.7 %) (27.1 %) (43.6 %)
405 550 906 1446
(12.3%) (16.6%) (27.4%) (43.7%)
57 63 87 156
(15.7%) (17.3%) (24.0%) (43.0%)
0.1976
1787 94 4
(94.8 %) (5.0 %) (0.2%)
1632 88 3
(94.7%) (5.1%) (0.2%)
155 6 1
(95.7%) (3.7%) (0.6%)
0.3734
3804 57
(98.5%) (1.5%)
3419 55
(98.4%) (1.6%)
385 2
(99.5%) (0.5%)
0.0989
1011 2850
(26.2%) (73.8%)
817 2657
(23.5%) (76.5%)
194 193
(49.9%) (50.1%)
b0. 0001
1094 1047 1720
(28.3 %) (27.1 %) (44.6 %)
985 935 1554
(28.4%) (26.9%) (44.7%)
109 112 166
(28.2%) (28.9%) (42.9%)
0.6718
314 385
(44.9 %) (55.1 %)
302 333
(47.6%) (52.4%)
12 52
(18.8%) (81.3%)
b0. 0001
477 3384
(12.4 %) (87.6 %)
460 3014
(13.2%) (86.8%)
17 370
(4.4%) (95.6%)
b0. 0001
95 3766
(2.5 %) (97.5 %)
93 3381
(2.7%) (97.3%)
2 385
(0.5%) (99.5%)
0. 0093
873 460
(65.5 %) (34.5 %)
788 435
(64.4%) (35.6%)
85 25
(77.3%) (22.7%)
0. 0067
2999 214 181 55
(87.0 %) (6.2 %) (5.2 %) (1.6 %)
2697 193 170 51
(86.7%) (6.2%) (5.5%) (1.6%)
302 21 11 4
(89.3%) (6.2%) (3.3%) (1.2%)
0.3230
3474 387
(90.0%) (10.0 %)
3474 -
(100%) -
387
(100%)
-
2353 1377
(63.1 %) (36.9 %)
2211 1144
(65.9%) (34.1%)
142 233
(37.9%) (62.1%)
b0. 0001
a statistical difference was found between the groups. Lymph node involvement, extra-thyroid extension, and multifocal disease may have all been lower in the PT because the extent of resection was lower. Additionally, there may have been some selection bias forcing some patients that were known to be positive for these into the total thyroidectomy group, as is probably the case with metastasis. Given the nature of this large database study, it remains unclear how much this selection bias affects the survival rates of the two groups. Selection bias may account for some of the lack of survival benefit from total thyroidectomy, and therefore, care must be taken in interpreting the two procedures as resulting in equivalent survival for all patients. The univariate analysis identified several variables that may be associated with changes in survival. However, after adjusting for confounding variables, the multivariate analysis showed that only
p-Value
0.9412
socioeconomic status and unfavorable histology were associated with a change in survival. Patients with unfavorable histology suffered a 6-fold decrease in survival. Many of these subtypes have been shown to be more aggressive and result in higher recurrence [9]. Additionally, patients in the lowest income quartile had almost 5 times the risk of death as those in the highest income quartile. Exactly how socioeconomic status increased risk in this cohort is not entirely clear. Certainly, disparities in access to care or treatment differences may have played a role. However, since the outcome was OS, nonthyroid related factors such as nutrition, stress, other medical conditions, or environmental safety may contribute to the difference. Demographically, this study was similar to other reported populations of pediatric thyroid cancer and likely provides a good representation of the overall pediatric population in the United States. As in this
Please cite this article as: Nice T, et al, Pediatric papillary thyroid cancer N1 cm: is total thyroidectomy necessary?, J Pediatr Surg (2015), http:// dx.doi.org/10.1016/j.jpedsurg.2015.03.031
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T. Nice et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
Table 2 Univariate analysis of survival. Variable
N
p-Value
Age Race Hispanic Sex (Female) Income Quartile (increasing) Comorbidity Index Histology-Unfavorable Histology-Follicular Variant Tumor Size Node Involvement Tumor Extension Metastasis Multifocal Analytic Stage Operation Type Radiation
3861 3861 3861 3861 3670 1885 3861 3861 3861 699 3861 3861 1333 3449 3861 3730
0.4539 0.1357 0.1811 0. 0412 0. 0002 0. 0005 0. 0045 0.6073 0.0553 0.3920 0.9628 0. 0167 0.7515 0. 0381 0.0911 0. 0182
HR
Survival
0.523 0.242, 0.373, 0.197 1.674, 60.827 5.496
↑ ↑ ↓ ↓
3.491
↓
2.439, 0.462, 4.478 0.520 0.486
↓ ↑
HR: hazard ratio.
study, previous studies have shown the pediatric population with welldifferentiated thyroid cancer to be N 80% white and have a 4:1 female to male ratio [2]. A study of 1753 patients with thyroid carcinoma from the SEER database had similar rates of regional lymph node involvement (46.4%) and rates of FVPTC. While the SEER database study had a higher rate of metastasis (7.6%), it also included more aggressive tumors such as follicular and medullary cancers [2]. TT has become increasingly common for treatment of p-PTC. A previous study utilizing NCDB data showed TT accounted for 50.6% of pediatric differentiated thyroid cancer treatments in 1985 compared to 84% in 2007 [10]. Although utilization of TT was slightly higher (90%) in the current study, it only included patients with tumors N 1 cm in size. A number of factors have contributed to total thyroidectomy becoming most surgeons’ preference for treating papillary thyroid cancer N1 cm in size. These factors include lower reported recurrence rates, ease in monitoring for recurrence with thyroglobulin, and the ability to ablate residual disease with radioactive iodine [11]. A number of studies support TT for children with thyroid cancer. In one retrospective review of 68 children with all types of thyroid malignancy, 8 of 18 (44%) patients receiving partial thyroid resection required further surgery, compared to only 6 of 50 (12%) of those undergoing TT [12]. Similar findings were seen in a study of 215 patients with papillary carcinoma, where recurrence was seen in 35% of partial resections verses 6% after TT [13]. The high probability of multifocal disease remains another reason to consider TT. Multifocal tumors were found in 34.5% of patients in the current study, but it has been reported in 57% in one retrospective study of 56 pediatric patients with well-differentiated
Table 3 Multivariate analysis of survival. Variable
p-value
Age Race Hispanic Sex (Female) Income Quartile (lowest) Comorbidity Index Histology-Unfavorable Histology-Follicular Variant Tumor Size Node Involvement Tumor Extension Metastasis Multifocal Analytic Stage Operation Type Radiation
0.7351 0.4065 0.4672 0.1621 0. 0010 N/A 0. 0162 0.6647 0.2641 N/A 0.7514 0.5374 N/A 0.4917 0.6939 0.0871
HR: hazard ratio.
HR
Survival
4.93
↓
6.11
↓
thyroid cancer [14]. However, using this argument to justify TT may be flawed since it is not currently clear if recurrence or multifocal disease significantly affects survival given the high survival rate of papillary cancer [11]. PT is often considered due to the concern for increased surgical complications with TT. Reports of surgical complications after TT range from 12-22% [12,15–17]. Complications are likely more common in younger patients. One study reported complications rates of 22% for children less than 6 years old, 15% for children 7 to 12 years old, and 12% for children 12–17 years old [17]. There has been a single pediatric study that reported no statistical difference in complications between operation types, but the study only included 68 patients [12]. However, a recent study of 62,722 adults reported significantly higher complications in patients undergoing TT (20.4%) compared to unilateral thyroidectomy (10.8%) [18]. The most common surgical complications in children are hypoparathyroidism and voice disturbances [17]. Permanent hypothyroidism and bilateral recurrent nerve injury encompass the most severe surgical complications, and although rare, likely result from TT rather than PT. Complication rates have been found to decrease with higher volume surgeons [17–19]. Concerns about appropriate management of thyroid hormone levels and quality of life after TT are commonly overlooked in surgical literature. Extent of surgery for papillary thyroid cancer has also been reexamined in the adult population. Both the SEER and NCDB databases have recently been used for population based studies comparing total thyroidectomy to partial resections [20,21]. Both studies found comparable survival for select populations. One limitation of the current study is that the follow-up may not have been long enough to detect differences in OS since thyroid cancer patients are known to have an excellent OS and live for extended periods of time. Hay and colleagues studied 215 pediatric patients with papillary cancer with a median follow-up of 29 years. Papillary thyroid carcinoma recurred in 32% by 40 years even after complete surgical resection. While survival was on-par with the general population for the first 20 years following surgery, survival was significantly less than expected for patients 30–50 years after treatment. The majority (68%) of the deaths occurred as a result of non-thyroid malignancy, many (73%) of whom had received radioactive iodine as part of their p-PTC treatment. In their study, radioactive iodine did not decrease 25 year regional recurrence compared to total thyroidectomy alone [13]. Other limitations of the current study are those inherent to any large national retrospective database and specifically those of the NCDB. The NCDB does not capture information on tumor recurrence or disease specific survival, both important outcomes for young thyroid cancer patients. Moreover, information regarding surgical complications or disease specific morbidity remains important for both short-term and long-term quality of life in these young patients with very long survivorships, but neither is contained in the NCDB. As a result, associations between these outcomes, type of operation, and the other variables studied could not be examined, and the primary outcome had to be limited to overall survival. Despite these shortcomings, the NCDB provides the opportunity to examine data from a very large number of patients from numerous institutions. 5. Conclusion
0.805
Primary pediatric papillary thyroid cancer has an excellent 15-year overall survival. Patients that underwent total thyroidectomy for tumors N1 cm did not have an improved overall survival compared to partial thyroidectomy. However, both lower socioeconomic status and unfavorable histology were associated with decreased overall survival. Data from this study may be valuable in counseling patients and their families about surgical treatment options. Furthermore, this study highlights the need for a large, multicenter prospective study to reexamine whether total thyroidectomy is necessary for all pediatric papillary thyroid cancers N1 cm, given the potential increased morbidity of total
Please cite this article as: Nice T, et al, Pediatric papillary thyroid cancer N1 cm: is total thyroidectomy necessary?, J Pediatr Surg (2015), http:// dx.doi.org/10.1016/j.jpedsurg.2015.03.031
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Fig. 1. Kaplan-Meier Analysis of survival by operation type. Data were evaluated with Kaplan-Meier analysis. Survival of patients who underwent lobectomy was compared to that of patients who had a total thyroidectomy for papillary thyroid cancer. There was no significant difference in survival between the two groups (p = 0.0855).
thyroidectomy over partial thyroidectomy in pediatric patients. Specifically, partial resection may be appropriate for both tumors b1 cm and low-risk tumors N1 cm. Extended long-term follow-up of papillary cancer treatments and the role of radioactive iodine in relation to secondary malignancies should also be examined. Appendix A. Presented by Dr. Tate Nice, Birmingham, AL Discussant DR. BIREN MODI (Boston, MA) Your presentation poses an important question. One facet I'd like to understand before I agree with that conclusion is whether the two groups between total thyroidectomy and partial thyroidectomy were equivalent. So did you actually analyze the potential patient factors between those two groups? Response DR. NICE: Yes. That's how you start off in each study, looking at the two groups. As far as most of the factors, the income levels and age, they were all pretty equivalent across the two groups. But the total thyroidectomy group was a lot larger than the partial resection group, and I think that just kind of reflects current trends. References [1] Wang TS, Roman SA, Sosa JA. Predictors of outcomes following pediatric thyroid and parathyroid surgery. Curr Opin Oncol 2009;21(1):23–8. [2] Hogan AR, Zhuge Y, Perez EA, et al. Pediatric thyroid carcinoma: incidence and outcomes in 1753 patients. J Surg Res 2009;156(1):167–72. [3] Siegel DA, King J, Tai E, et al. Cancer incidence rates and trends among children and adolescents in the United States, 2001–2009. Pediatrics 2014;134(4):e945–55. [4] National Cancer Data Base. Available from: https://www.facs.org/quality-programs/ cancer/ncdb.
[5] Mallin K, Palis BE, Watroba N, et al. Completeness of American Cancer Registry Treatment Data: implications for quality of care research. J Am Coll Surg 2013; 216(3):428–37. [6] Clinical information bibliography. Available from: https://www.facs.org/quality-programs/cancer/ncdb/bilbclin; 2013. [7] National Cancer Data Base On-Line Data Dictionary. Available from: http:// ncdbpufbeta.facs.org/?q=node/259; 2011. [8] Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992;45(6):613–9. [9] Roman S, Sosa JA. Aggressive variants of papillary thyroid cancer. Curr Opin Oncol 2013;25(1):33–8. [10] Raval MV, Bentrem DJ, Stewart AK, et al. Utilization of total thyroidectomy for differentiated thyroid cancer in children. Ann Surg Oncol 2010;17(10):2545–53. [11] Piper H, Skinner M. Childhood diseases of the thyroid and parathyroid glands. In: Coran A, editor. Pediatric surgery. 7th ed. Philadelphia: Elsevier Saunders; 2012. p. 748–50. [12] Bargren AE, Meyer-Rochow GY, Delbridge LW, et al. Outcomes of surgically managed pediatric thyroid cancer. J Surg Res 2009;156(1):70–3. [13] Hay ID, Gonzalez-Losada T, Reinalda MS, et al. Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008. World J Surg 2010;34(6):1192–202. [14] Grigsby PW, Gal-or A, Michalski JM, et al. Childhood and adolescent thyroid carcinoma. Cancer 2002;95(4):724–9. [15] Rosato L, Mondini G, Ginardi A, et al. Incidence of complications of thyroid surgery. Minerva Chir 2000;55(10):693–702. [16] O'Gorman CS, Hamilton J, Rachmiel M, et al. Thyroid cancer in childhood: a retrospective review of childhood course. Thyroid 2010;20(4):375–80. [17] Sosa JA, Tuggle CT, Wang TS, et al. Clinical and economic outcomes of thyroid and parathyroid surgery in children. J Clin Endocrinol Metab 2008;93(8):3058–65. [18] Hauch A, Al-Qurayshi Z, Randolph G, et al. Total thyroidectomy is associated with increased risk of complications for low- and high-volume surgeons. Ann Surg Oncol 2014;21(12):3844–52. [19] Tuggle CT, Roman SA, Wang TS, et al. Pediatric endocrine surgery: who is operating on our children? Surgery 2008;144(6):869–77 [discussion 877]. [20] Mendelsohn AH, Elashoff DA, Abemayor E, et al. Surgery for papillary thyroid carcinoma: is lobectomy enough? Arch Otolaryngol Head Neck Surg 2010;136(11):1055–61. [21] Adam MA, Pura J, Gu L, et al. Extent of surgery for papillary thyroid cancer is not associated with survival: an analysis of 61,775 patients. Ann Surg 2014;260(4): 601–5 [discussion 605–7].
Please cite this article as: Nice T, et al, Pediatric papillary thyroid cancer N1 cm: is total thyroidectomy necessary?, J Pediatr Surg (2015), http:// dx.doi.org/10.1016/j.jpedsurg.2015.03.031