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Changing trends in well differentiated thyroid carcinoma over eight decades
ORIGINAL RESEARCH International Journal of Surgery 10 (2012) 618e623
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Original research
Changing trends in well differentiated thyroid carcinoma over eight decades Iain J. Nixon a, *, Ian Ganly a, Snehal G. Patel a, Frank L. Palmer a, Monica M. Whitcher a, Rony Ghossein b, R. Michael Tuttle c, Ashok R. Shaha a, Jatin P. Shah a a
Head and Neck Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA c Department of Endocrinology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 September 2012 Accepted 21 October 2012 Available online 2 November 2012
Introduction: The incidence of well differentiated thyroid cancer (WDTC) is rising in the USA. The objective of this study is to present the changes in incidence, presentation, management and outcomes of WDTC within our institution over the past 8 decades. Methods: 2797 patients managed between 1932 and 2005 at Memorial Sloan Kettering Cancer Center were identified from our institutional database. Results: There has been an increase in the number of patients managed per decade. Although the median age was 45 years, patients managed post-1985 were more likely to be over 45 years (53% versus 44%, p < 0.001). The percentage of women increased from 68% to 72% (p ¼ 0.026), and the percentage of papillary carcinomas also increased, from 78% to 92%, p < 0.001. An increase in early stage tumors was observed with pT1 lesions increasing from 19% to 48%. Patients in the latter cohort were less likely to have thyroid lobectomy (29% versus 72%, p < 0.001). There was a significant change in the use of RRA, with 8% of the early versus 44% of the latter group receiving post-operative RRA (p < 0.001). Since the introduction of risk group stratification disease specific survival (DSS) has not changed significantly. With a median follow up of 90 months, 10 year DSS rates were below 90% in the cohort managed prior to the 1970s, which rose to >95% thereafter (p < 0.001). Conclusions: Older patients with earlier stage disease present an increasing workload for surgical oncologists. Excellent outcomes remain unchanged despite increasingly aggressive surgical and medical management. Ó 2012 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Thyroid Cancer Well differentiated Papillary thyroid cancer Follicular thyroid cancer Hurthle cell thyroid cancer
1. Introduction Well differentiated thyroid cancer (WDTC) is rising in incidence in the USA and across the world over the past three decades.1e5 Unlike most human malignancies, WDTC has high cure rates when managed appropriately.6e8 Our understanding of the biology of this common disease and the impact of treatment on patient outcome has evolved over the past century. Over this time period, management of thyroid cancer has evolved from a wide spectrum of treatment approaches to a more standardized evidence based approach, due to improved understanding of the biological behavior of this cancer, and supported by national and
* Corresponding author. E-mail addresses: [email protected] (I.J. Nixon), [email protected] (I. Ganly), [email protected] (S.G. Patel), [email protected] (F.L. Palmer), [email protected] (M.M. Whitcher), [email protected] (R. Ghossein), [email protected] (R. Michael Tuttle), [email protected] (A.R. Shaha), shahj@ mskcc.org (J.P. Shah).
international guidelines.9e11 Surgery remains the cornerstone of management of thyroid cancer with post-operative radioactive iodine administered as adjuvant treatment in selected cases based on risk of recurrence and risk of disease specific mortality. The objective of our study is to present the changing trends in the incidence, presentation, management and outcomes of WDTC within our institution over the past 8 decades. 2. Patients and methods Following approval by the Institutional Review Board, 2797 patients who had thyroid surgery for WDTC between 1932 and 2005 at Memorial Sloan Kettering Cancer Center, New York, were identified from our institutional database. Data collection was carried out over two separate time periods, with reports based on the initial cohort (1932e1985, n ¼ 987) published separately from the subsequent group (1986e2005, n ¼ 1810). Both cohorts were combined to produce the data presented in this manuscript. Patients with anaplastic, poorly differentiated and medullary carcinoma, as well as those who were selected as not suitable for surgery were excluded from these studies. Data collected included patient demographics, surgical details including extent of thyroid surgery, histopathological diagnosis at the time of treatment and pTNM status. Data on adjuvant radioactive iodine remnant ablation (RRA) was also
1743-9191/$ e see front matter Ó 2012 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijsu.2012.10.005
ORIGINAL RESEARCH I.J. Nixon et al. / International Journal of Surgery 10 (2012) 618e623 collected. In-depth analysis of recurrence data has been presented previously.12 In this manuscript we present data on 10 year disease specific survival (DSS). Mode of death was determined from case notes and death certificates where available, and cross checked against the social security index for all patients. Patients who were known to have died of disease were coded as cause specific death. Those who died of other causes were censored at the time of death for DSS analysis. Patients who died during follow up, and no cause could be confirmed were considered to have died of disease if there was evidence of disease at last follow up, in order not to underestimate the effect of disease. Our institutional approach to the management of WDTC involves risk stratification using the previously reported GAMES criteria (Table 1).13 These criteria, consider patient and tumor factors in risk stratification. This classification was designed to predict the risk of death from WDTC, rather than the risk of recurrence. Patients are considered at low risk if under the age of 45 years, and high risk if over 45 years. Tumors with more aggressive histology, which are larger than 4 cm, and/or have extrathyroid extension or have distant metastases are considered high risk tumors. In contrast, well differentiated tumors that are less than 4 cm, and are intrathyroidal, and have no evidence of distant metastases are considered low risk tumors. Thus, patients above 45 years of age with high risk tumors are considered in the high risk group. Patients under the age of 45, with low risk tumors are included in the low risk group. All others are included in the intermediate risk group. i.e. young patients with high risk tumors or older patients with low risk tumors. Our philosophy of management has been to advocate ipsilateral lobectomy in low risk patients with a unifocal intraglandular tumor, without any detectable abnormality in the opposite lobe. Assessment of the contralateral lobe is by intraoperative examination. Nowadays, this is supplemented with preoperative ultrasound. These patients do not receive RRA therapy. In the high risk group, a total thyroidectomy or even more extensive resection and post-operative RRA is recommended. Surgical resection of all clinically apparent disease is the mainstay of treatment and to this end extracapsular total thyroidectomy is performed with resection of strap muscles, recurrent nerve and even laryngotracheal or esophageal structures as indicated to ensure macroscopic surgical clearance. For intermediate risk cases, an individualized treatment decision is made based on discussion between the surgeon, endocrinologist and patient and is mainly based on tumor factors. This approach to risk stratification and treatment was adopted during the time period of the initial cohort and has remained our standard of care for subsequent decades. In terms of management of the neck, we do not perform routine elective central or lateral compartment neck dissection. The cervical nodal basins are examined clinically, ultrasonographically (in more recent years) and intra-operatively. For a clinically positive neck, with palpable node in the lateral compartment, an anatomically comprehensive, and oncologically effective selective neck dissection (lymph nodes at levels II, III, IV and V) is carried out. If suspicious nodes are identified during surgery of the primary tumor, frozen section is used to confirm metastatic disease, and appropriate neck dissection is carried out depending on the location of the metastatic nodes. Central compartment dissection is performed only if suspicious nodes are noted during thyroidectomy and confirmed by frozen section. Statistical analysis was carried out using JMP statistical package (SAS Institute Inc. SAS Campus Drive, Cary, NC 27513) and SPSS (IBM Company Headquarters, 233 S. Wacker Drive, 11th Floor, Chicago, Illinois 60606). Variables were compared within groups using Pearson’s Chi squared test. Survival outcomes were determined using the KaplaneMeier method. Univariate analysis was carried out by the log rank test.
3. Results Patient, tumor and treatment characteristics of the group as a whole and stratified by the date of initial surgical management by decade are shown in Table 2. The median follow up for the overall group was 90 months (range 1e811 months). Throughout the time period studied, there has been a steady increase in the number of
Table 1 GAMES risk of cause specific mortality stratification. Risk level
Patient factor
Tumor factor
Low risk High risk
Age <45 y Age >45 y
Low risk case Intermediate risk case High risk case
Papillary Ca Follicular Ca /Hurthle cell Ca Low risk tumor
Low risk patient Low risk patient High risk tumor High risk patient Low risk tumor High risk patient High risk tumor
M0 No ETE Size <4 cm M1 ETE Size >4 cm
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patients managed per decade, with 982 patients managed between 1932 and 1985 in comparison to 1810 patients between 1986 and 2005 (Table 2, Fig. 1). The median age of the whole group was 45 years (range 4e94 years). In comparison with the earlier cohort, patients managed post 1985 were more likely to be over the age of 45 years (53% versus 44%, p < 0.001). The percentage of women in the cohort increased from 68% to 72% in the more recent cohort (p ¼ 0.026), and the percentage of tumors classified as papillary carcinoma also increased from 78% to 92%, p < 0.001. An increase in early stage tumors was observed during the study with pT1 lesions increasing from 19% in the early cohort to 48% in the latter cohort. For pT4 tumors, representing locally advanced tumors, we saw no increase in incidence with 8% in the early cohort and 7% in the latter cohort. Throughout the decades there has been a rise in the percentage of papillary carcinomas presenting with our institution. In the earlier cohort, around 75% of WDTC were classified a papillary carcinoma, which rose to 86% between 1986 and 1995 and 94% between 1996 and 2005. This corresponded with a fall in the percentage of follicular carcinomas from 18% to 3% over the same time period. In part, this change may be explained by changes in the definition of follicular carcinoma, with some patients now being classified as follicular variant of papillary carcinoma. The percentage of patients with pathologically positive neck nodes fell from 48% to 33% (p < 0.001). The incidence of patients with distant metastasis at presentation was similar (4% in the early versus 3% in the later cohort, p ¼ 0.262). The rising age of patients resulted in an increased percentage of intermediate risk cases in the later cohort, and a reduced number of low risk cases. However, the number of cases considered high risk remained relatively constant (Table 4a). Trends in treatment revealed that patients in the later cohort were less likely to have thyroid lobectomy (29% versus 72%, p < 0.001), with a corresponding increase in rates of total thyroidectomy. There was also a significant change in the use of RRA, with 8% of the pre 1985 group versus 44% of the post 1985 group receiving post-operative RRA (p < 0.001). When stratified by decade, the percentage who received RRA rose from 0% in 1932e 1945 to 2%, 8%, 32%, 71%, 48% and 68% by 1996e2005. By the 1970s, evidence had shown that procedures which involved less than unilateral lobectomy resulted in worse outcomes, and therefore for analysis of DSS we considered 3 groups: those managed before 1970, those managed between 1970 and 1986 and those managed between 1986 and 2005. Analysis of DSS by time period shows a significant improvement over time with modern day 10 year survival figures of 96.1% (Table 3). This improvement in outcome is most marked in the high risk group (Table 4b). Since the introduction of risk group stratification, and individualized treatment protocols based on such an approach (around the 1970s) DSS has not changed significantly. 10 year DSS rates were below 90% in the cohort managed prior to the 1970s, which rose to >95% thereafter (p < 0.001). Analysis of factors predictive of poorer outcome for the whole group confirmed non-papillary histology, age over 45 years, the presence of distant metastasis, evidence of extrathyroid extension and size over 4 cm as independent predictors on multivariate analysis (GAMES).14 In contrast, the presence of lymph node metastases was not predictive of DSS (Table 5). 4. Discussion Over the past century there has been a gradual change in the management of thyroid cancer. A number of major centers have
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Table 2 Descriptive statistics of whole group and stratification by decade. Variable
Group
1932e1945
1946e1955
1956e1965
1966e1975
1976e1985
1986e1995
1996e2005
p Value
Age
<45 >45 Female Male Lobe Isthmus Subtotal Total Unresectable Papillary Hurthle cell Follicular T1 T2 T3 T4 <1 cm >1 cm N0 N1 M0 M1 Low Int High No Yes
31 (47%) 35 (53%) 41 (62%) 25 (38%) 52 (79%) 1 (1%) 2 (3%) 11 (17%) 0 (0%) 50 (76%) 4 (6%) 12 (18%) 12 (18%) 29 (44%) 17 (26%) 8 (12%) 9 (14%) 57 (86%) 35 (53%) 31 (47%) 63 (96%) 3 (4%) 19 (29%) 24 (36%) 23 (35%) 66 (100%) 0 (0%)
142 (59%) 100 (41%) 170 (70%) 72 (30%) 180 (74%) 0 (0%) 4 (2%) 58 (24%) 0 (0%) 199 (82%) 14 (6%) 29 (12%) 46 (19%) 136 (56%) 41 (17%) 19 (8%) 41 (17%) 201 (83%) 90 (37%) 152 (63%) 229 (95%) 13 (5%) 118 (49%) 53 (22%) 71 (29%) 241 (>99%) 1 (<1%)
98 (56%) 77 (44%) 119 (68%) 56 (32%) 133 (76%) 0 (0%) 5 (3%) 37 (21%) 0 (0%) 138 (79%) 12 (7%) 25 (14%) 42 (24%) 90 (51%) 27 (15%) 16 (9%) 41 (23%) 134 (77%) 87 (50%) 88 (50%) 168 (96%) 7 (4%) 84 (48%) 44 (25%) 47 (30%) 172 (98%) 3 (2%)
135 (53%) 119 (57%) 177 (70%) 77 (30%) 171 (67%) 0 (0%) 15 (6%) 68 (27%) 0 (0%) 197 (78%) 12 (5%) 45 (18%) 35 (14%) 187 (74%) 24 (9%) 8 (35) 31 (12%) 223 (88%) 155 (61%) 99 (39%) 248 (98%) 6 (2%) 117 (46%) 78 (31%) 59 (23%) 232 (91%) 22 (9%)
143 (57%) 107 (43%) 161 (64%) 89 (36%) 171 (68%) 0 (0%) 6 (2%) 73 (29%) 0 (0%) 191 (76%) 14 (6%) 45 (18%) 52 (21%) 159 (64%) 12 (5%) 26 (10%) 41 (16%) 209 (84%) 146 (58%) 104 (42%) 243 (97%) 7 (3%) 116 (47%) 86 (34%) 47 (19%) 198 (79%) 52 (21%)
242 (53%) 212 (47%) 324 (71%) 130 (29%) 223 (49%) 5 (1%) 24 (5%) 202 (45%) 0 (0%) 391 (86%) 17 (4%) 46 (10%) 191 (43%) 99 (22%) 119 (27%) 35 (8%) 65 (14%) 389 (86%) 270 (60%) 184 (40%) 436 (96%) 18 (4%) 154 (34%) 189 (42%) 111 (24%) 357 (79%) 97 (21%)
605 (45%) 751 (55%) 974 (72%) 382 (28%) 293 (22%) 14 (1%) 13 (1%) 1033 (76%) 3 (<1%) 1277 (94%) 42 (3%) 37 (3%) 664 (49%) 233 (17%) 373 (28%) 86 (6%) 371 (27%) 985 (73%) 936 (69%) 420 (31%) 1322 (98%) 34 (2%) 422 (31%) 628 (46%) 306 (23%) 657 (49%) 699 (51%)
<0.001
Gender Procedure
Histology
pT Stage
Micro Ca pN Stage M Stage GAMES risk group RRA
published the results of institutional series spanning many decades.15,16 The incidence and presenting features of this common disease have undergone significant changes in recent times. It is now recognized that the incidence of papillary thyroid carcinoma is rising at a faster rate than any other malignancy.17 The reasons proposed for this are contentious. There is no doubt that enhanced imaging has resulted in increased rates of detection, particularly of cancers less than 1 cm in size (microcarcinomas).3,17 However, there has also been an increase in tumors greater than 4e6 cm, suggesting that the increasing incidence may be a true increase caused by other yet unknown factors.18 Thyroid cancer is recognized as being more common in females. However, recent reports suggest the incidence in women may be increasing at a higher rate than in males.4 The incidence has also been reported to be increasing at a faster rate in older patients.17 Early reports of deaths from WDTC suggested that less than total thyroidectomy procedures resulted in less favorable oncological outcomes, and that all gross disease should be removed as part of the initial surgical procedure.19e21 Debate about the required extent of initial surgical therapy continues, with an understanding that thyroid lobectomy is a safe and effective option in low risk, unifocal, intraglandular thyroid cancers9e11,22 The management of the contralateral lobe in low risk cases has been long debated with evidence supporting both lobectomy alone23,24 and total thyroidectomy.25,26 In the absence of prospective randomized controlled
Table 3 Analysis of DSS by decade. Decade
Number (n ¼ 2797)
10 yr DSS%
p Value
1932e1945 1946e1955 1956e1965 1966e1975 1976e1985 1986e1995 1996e2005
66 242 175 254 250 454 1356
87.2 87.1 90.9 85.9 95.0 95.8 96.1
<0.001
0.201 <0.001
<0.001
<0.001
<0.001 <0.001 0.224 <0.001
<0.001
trials, this debate is unlikely to be resolved. In high risk cases, the place of total thyroidectomy is widely accepted. Over the past 8 decades at MSKCC there has been an increase in the rate of total thyroidectomy (Fig. 2). High resolution ultrasound imaging in the pre-operative investigation of patients with WDTC has increased the number of contralateral thyroid nodules identified preoperatively. This, previously considered occult disease, now results in total thyroidectomy rather than thyroid lobectomy being adopted, even in low risk patients. Surgical practice has therefore gone full circle, with an initial move away from total thyroidectomy to thyroid lobectomy for selected low risk cases with now a move back towards total thyroidectomy to excise previously occult contralateral nodular disease, regardless of its histological status. The role of RRA also remains unclear in certain situations. For low risk patients, little benefit has been demonstrated,27,28 whereas in high risk cases the benefits are more certain.28 The therapeutic efficacy of RRA in the management of WDTC has led to a large increase in its use, even in low risk patients, at many major centers across the US.29 Our results over the past 73 years reflect the changes described above, with an increasing number of cases managed within our institution over the past 8 decades (Fig. 1). Along with this volume increase, we have also observed a trend towards an older patient group (94% versus 53%, p < 0.001), with a higher percentage of women represented in recent years (72% versus 68%, p ¼ 0.026) (Table 2). These trends may be due to a change in referral patterns with increased access to ultrasound in both primary care and obstetrics and gynecology practice. Analysis of survival of the whole group confirms our earlier reports that non-papillary histology, age over 45 years, the presence of distant metastases, extrathyroid extension, and size over 4 cm are predictive of poorer DSS. The results of analysis of both patient and tumor related factors underscore the importance of risk stratification, to allow for individualization in the management of WDTC (Table 5). In terms of histopathological subtypes of WDTC, papillary thyroid carcinoma remains the most prevalent, with an increasing percentage in recent years (92% versus 78%, p < 0.001). There has
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Fig. 1. Patient numbers managed by decade.
Table 4a GAMES groupings stratified by time period.
Risk group
Low Intermediate High
Number (%)
1932e1969 (n ¼ 564)
1970e1989 (n ¼ 584)
1990e2005 (n ¼ 1648)
p Value
1030 (37%) 1102 (39%) 664 (24%)
254 (45%) 149 (26%) 161 (29%)
251 (43%) 217 (37%) 116 (20%)
525 (32%) 736 (45%) 387 (23%)
<0.001
also been a reduction in the incidence of follicular carcinoma, from 16% to 5% (p < 0.001). This is likely due to the recognition that many primary lesions previously described as follicular carcinoma are now categorized as follicular variant of papillary carcinoma. A further change in histological reporting has resulted in the recognition of poorly differentiated thyroid carcinoma. Towards the end of our study this was recognized as a separate histological entity, and was reported separately. Although we found a relatively constant rate of pT4 disease presented throughout the decades, some more recent pT4 cancers may have been recognized as poorly differentiated and therefore excluded from this analysis. In keeping with other reports, we also noted a significant increase in the number of microcarcinomas (<1 cm). pT1 disease comprised 48% of the recent cohort of patients compared to 19% of the earlier cohort, p < 0.001. Interestingly, nodal disease has decreased in prevalence, from 48% to 33% (p < 0.001). This may be due to the increase in early T stage tumors that we now see. It may also be due to a change in neck dissection policy since our risk stratification system was introduced, with neck dissection only being carried out for clinically palpable neck disease in the past, and more recently for
radiographically detected lymph node metastases. The percentage of patients presenting with evidence of distant metastases has remained constant at less than 5%, suggesting that the percentage of patients presenting with aggressive, high risk disease that is likely to affect survival has not changed dramatically over the 7 decade period. With regards to our risk stratification system (GAMES), we observed a shift of low risk cases to the intermediate risk group category (Table 4a). This is as a result of the older patient age at presentation, despite the increases in low risk tumors. Only 25% of patients in the earlier cohort underwent total thyroidectomy versus 68% in the recent cohort. In our institution, even older patients with intraglandular WDTC are selected for thyroid lobectomy. Therefore a change in overall risk stratification should have a limited effect on rates of total thyroidectomy. This change in practice therefore is likely to be multifactorial in etiology. Along with the change in risk groups, the introduction of preoperative ultrasound over this time period has resulted in more occult nodular disease in the contralateral lobe being detected. As a consequence, there has been an increase in the number of total thyroidectomies. In addition, the
Table 4b 10 Year DSS stratified by GAMES group and by time period.
Risk group
Low Intermediate High
Number (%)
1932e1969 10 Yr DSS (n ¼ 564)
1970e1989 10 Yr DSS (n ¼ 584)
1990e2005 10 Yr DSS (n ¼ 1648)
p Value
1030 (37%) 1102 (39%) 664 (24%)
98.0% 93.0% 63.6%
100.0% 92.5% 81.4%
100.0% 98.3% 86.6%
<0.001
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I.J. Nixon et al. / International Journal of Surgery 10 (2012) 618e623
Table 5 Univariate analysis for disease specific survival for the groups as a whole. Variable
Group
Number
10 Yr DSS
p Value
Multivariate analysis
Age
<45 >45 Female Male Thyroid lobectomy Thyroid isthmusectomy Subtotal thyroidectomy Total thyroidectomy Unresectable thyroid Ca Papillary carcinoma Hurthle cell carcinoma Follicular carcinoma T1 T2 T3 T4 <4 cm >4 cm <1 cm >1 cm Absent Present N0 N1 M0 M1 Low Intermediate High
1396 1401 1966 831 1223 20 69 1482 3 2443 115 239 1042 933 613 198 2228 310 599 2198 2198 598 1719 1078 2709 88 1030 1102 664
98.4% 87.5% 94.8% 89.4% 94.6% 100.0% 90.1% 91.8% 0.0% 94.8% 82.8% 84.4% 97.7% 94.7% 91.5% 68.3% 96.9% 79.3% 98.2% 92.0% 94.9% 85.8% 94.0% 92.1% 95.1% 41.7% 99.4% 96.0% 78.8%
<0.001
Referent 4.987 Referent 1.529
HR
Gender Procedure
Histology
pT Stage
Size of tumor Micro carcinoma Any extrathyroid extension pN Stage M Stage Risk group
(50%) (50%) (70%) (30%) (44%) (1%) (2%) (53%) (0%) (87%) (4%) (9%) (37%) (34%) (22%) (7%) (88%) (12%) (21%) (79%) (79%) (21%) (62%) (38%) (97%) (3%) (37%) (39%) (24%)
increased number of total thyroidectomies may also be accounted for by several international guidelines now recommending total thyroidectomy for intra-thyroid lesions over 1.5 cm.9e11 Post-operative adjuvant RRA was rarely used in the early part of this study, but has become a part of therapy for 44% of cases in recent times (Fig. 2). Over the past few years we have become
<0.001
95% CI
p
2.899e8.272
<0.001
10.47e2.231
0.028
Referent 1.995 2.852
1.172e3.395 1.577e5.156
0.011 0.001
Referent 3.713
2.521e5.469
<0.001
Referent 2.892
1.916e4.266
<0.001
Referent 11.307
7.452e17.157
<0.001
<0.001
<0.001
0.000
0.000 0.000 0.000 0.292 0.000 0.000
increasingly aware of the side effects of RRA as well as the risk of second primaries. As a result, we now carefully consider the risk versus benefit ratio before recommending treatment with RRA. DSS for patients managed during this study has increased significantly from below 90% to over 95% in the later years (Table 3). This improvement is in keeping with other series and demonstrates
Fig. 2. Percentage of patients undergoing total thyroidectomy, receiving RRA and disease specific survival by decade.
ORIGINAL RESEARCH I.J. Nixon et al. / International Journal of Surgery 10 (2012) 618e623
the excellent outcomes that most patients with WDTC now experience. Careful scrutiny of these figures however demonstrates that these improvements were largely achieved prior to the mid-1970s (Table 4b). It was at this time that evidence to support the surgical techniques now routinely employed was starting to appear. This is with particular reference to abandoning the practice of subtotal or near total thyroidectomy and instituting the practice of routine “extracapsular” total thyroidectomy. Around this time the understanding of risk stratification was improving with several investigators presenting their own method for predicting outcome in patients with WDTC.27,30,31 More recently, despite the increase in the rates of total thyroidectomy and RRA, no significant improvement in DSS has been observed for a cancer which already had excellent outcomes (Fig. 2). These figures are affected by the changing trends in presentation. An increased number of intermediate risk cases are now seen (Table 4a). Analysis on a risk group specific level shows improvement in each time period studies (Table 4b) although overall, improved survival was more marked from the mid 1970s. Over the past 8 decades in our institution, the incidence, presentation and management of WDTC has changed considerably. Older patients with earlier stage disease present an increasing workload for our department. It is likely that the incidence of WDTC will continue to rise in the short to medium term at least. Already excellent outcomes are unlikely to be significantly improved with an ever more aggressive approach to treatment. Opportunities to improve standards of care include identifying patient groups most likely to benefit from aggressive contemporary management and at the same time developing new therapeutic strategies. Efforts must also include attempts to identify those patients who will benefit from less invasive treatment, which would reduce the potential lifelong impact that complications of therapy can have, whilst maintaining oncological outcomes and allowing focusing of resources on those patients most likely to benefit. Our efforts in clinical care in future need to be focused to reducing mortality from thyroid cancer, and in the discovery of new treatment modalities, that will create a positive impact on patients with distant metastatic disease, for whom we have little to offer at this time. Ethical approval IRB approval from MSKCC WA 0382-05 (10). Funding No external funding. Author contribution Nixon e data collection and analysis, manuscript preparation. Palmer/Whitcher e Data collection and analysis. Ganly/Patel e Project leads, data analysis and editing. Ghossein/Tuttle e Manuscript editing. Shah/Shaha e Principle investigators, editing of manuscript. Conflict of interest None. References 1. Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid cancer in the United States, 1988e2005. Cancer 2009;115(16):3801e7. Epub 2009/07/15. 2. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973e2002. JAMA 2006;295(18):2164e7. Epub 2006/05/11. 3. Enewold L, Zhu K, Ron E, Marrogi AJ, Stojadinovic A, Peoples GE, et al. Rising thyroid cancer incidence in the United States by demographic and tumor characteristics, 1980e2005. Cancer Epidemiol Biomarkers Prev 2009;18(3):784e 91. Epub 2009/02/26. 4. Elaraj DM, Sturgeon C. Adequate surgery for papillary thyroid cancer. Surgeon 2009;7(5):286e9. Epub 2009/10/24.
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Thyroid 2009;19(11): 1167e214. Epub 2009/10/29. 10. Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW, Wiersinga W. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 2006;154(6):787e803. Epub 2006/05/27. 11. Watkinson JC. The British Thyroid Association guidelines for the management of thyroid cancer in adults. Nucl Med Commun 2004;25(9):897e900. Epub 2004/08/21. 12. Shaha AR, Shah JP, Loree TR. Patterns of failure in differentiated carcinoma of the thyroid based on risk groups. Head Neck 1998;20(1):26e30. Epub 1998/02/17. 13. Shaha AR, Loree TR, Shah JP. Prognostic factors and risk group analysis in follicular carcinoma of the thyroid. Surgery 1995;118(6):1131e6. discussion 6e 8. Epub 1995/12/01. 14. Shaha AR, Shah JP, Loree TR. Risk group stratification and prognostic factors in papillary carcinoma of thyroid. Ann Surg Oncol 1996;3(6):534e8. Epub 1996/ 11/01. 15. Hay ID, Thompson GB, Grant CS, Bergstralh EJ, Dvorak CE, Gorman CA, et al. Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940e1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients. World J Surg 2002;26(8):879e85. Epub 2002/05/23. 16. Sanders LE, Cady B. Differentiated thyroid cancer: reexamination of risk groups and outcome of treatment. Arch Surg 1998;133(4):419e25. Epub 1998/05/23. 17. Hughes DT, Haymart MR, Miller BS, Gauger PG, Doherty GM. The most commonly occurring papillary thyroid cancer in the United States is now a microcarcinoma in a patient older than 45 years. Thyroid 2011;21(3):231e6. Epub 2011/01/28. 18. Morris LG, Myssiorek D. Improved detection does not fully explain the rising incidence of well-differentiated thyroid cancer: a population-based analysis. Am J Surg 2010;200(4):454e61. Epub 2010/06/22. 19. Tollefsen HR, Decosse JJ, Hutter RV. Papillary carcinoma of the thyroid. A clinical and pathological study of 70 fatal cases. Cancer 1964;17:1035e44. Epub 1964/08/01. 20. Cody 3rd HS, Shah JP. Locally invasive, well-differentiated thyroid cancer. 22 years’ experience at Memorial Sloan-Kettering Cancer Center. Am J Surg 1981;142(4):480e3. Epub 1981/10/01. 21. McConahey WM, Hay ID, Woolner LB, van Heerden JA, Taylor WF. Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc 1986;61(12):978e96. Epub 1986/12/01. 22. Nixon IJ, Ganly I, Patel SG, Palmer FL, Whitcher MM, Tuttle RM, et al. Thyroid lobectomy for treatment of well differentiated intrathyroid malignancy. Surgery 2011. Epub 2011/10/18. 23. Shah JP, Loree TR, Dharker D, Strong EW. Lobectomy versus total thyroidectomy for differentiated carcinoma of the thyroid: a matched-pair analysis. Am J Surg 1993;166(4):331e5. Epub 1993/10/01. 24. Hassanain M, Wexler M. Conservative management of well-differentiated thyroid cancer. Can J Surg 2010;53(2):109e18. Epub 2010/03/26. 25. Barney BM, Hitchcock YJ, Sharma P, Shrieve DC, Tward JD. Overall and causespecific survival for patients undergoing lobectomy, near-total, or total thyroidectomy for differentiated thyroid cancer. Head Neck 2011;33(5):645e9. Epub 2010/08/06. 26. Bilimoria KY, Bentrem DJ, Ko CY, Stewart AK, Winchester DP, Talamonti MS, et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg 2007;246(3):375e81. discussion 81-4. Epub 2007/08/25. 27. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988;104(6):947e53. Epub 1988/12/01. 28. Mazzaferri EL. Thyroid remnant 131I ablation for papillary and follicular thyroid carcinoma. Thyroid 1997;7(2):265e71. Epub 1997/04/01. 29. Carcangiu ML, Zampi G, Rosai J. Poorly differentiated (“insular”) thyroid carcinoma. A reinterpretation of Langhans’ “wuchernde Struma”. Am J Surg Pathol 1984;8(9):655e68. Epub 1984/09/01. 30. Shah JP, Loree TR, Dharker D, Strong EW, Begg C, Vlamis V. Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg 1992;164(6):658e61. Epub 1992/12/01. 31. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993;114(6):1050e7. discussion 7e8. Epub 1993/ 12/01.
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Original research
Changing trends in well differentiated thyroid carcinoma over eight decades Iain J. Nixon a, *, Ian Ganly a, Snehal G. Patel a, Frank L. Palmer a, Monica M. Whitcher a, Rony Ghossein b, R. Michael Tuttle c, Ashok R. Shaha a, Jatin P. Shah a a
Head and Neck Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA c Department of Endocrinology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 September 2012 Accepted 21 October 2012 Available online 2 November 2012
Introduction: The incidence of well differentiated thyroid cancer (WDTC) is rising in the USA. The objective of this study is to present the changes in incidence, presentation, management and outcomes of WDTC within our institution over the past 8 decades. Methods: 2797 patients managed between 1932 and 2005 at Memorial Sloan Kettering Cancer Center were identified from our institutional database. Results: There has been an increase in the number of patients managed per decade. Although the median age was 45 years, patients managed post-1985 were more likely to be over 45 years (53% versus 44%, p < 0.001). The percentage of women increased from 68% to 72% (p ¼ 0.026), and the percentage of papillary carcinomas also increased, from 78% to 92%, p < 0.001. An increase in early stage tumors was observed with pT1 lesions increasing from 19% to 48%. Patients in the latter cohort were less likely to have thyroid lobectomy (29% versus 72%, p < 0.001). There was a significant change in the use of RRA, with 8% of the early versus 44% of the latter group receiving post-operative RRA (p < 0.001). Since the introduction of risk group stratification disease specific survival (DSS) has not changed significantly. With a median follow up of 90 months, 10 year DSS rates were below 90% in the cohort managed prior to the 1970s, which rose to >95% thereafter (p < 0.001). Conclusions: Older patients with earlier stage disease present an increasing workload for surgical oncologists. Excellent outcomes remain unchanged despite increasingly aggressive surgical and medical management. Ó 2012 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Thyroid Cancer Well differentiated Papillary thyroid cancer Follicular thyroid cancer Hurthle cell thyroid cancer
1. Introduction Well differentiated thyroid cancer (WDTC) is rising in incidence in the USA and across the world over the past three decades.1e5 Unlike most human malignancies, WDTC has high cure rates when managed appropriately.6e8 Our understanding of the biology of this common disease and the impact of treatment on patient outcome has evolved over the past century. Over this time period, management of thyroid cancer has evolved from a wide spectrum of treatment approaches to a more standardized evidence based approach, due to improved understanding of the biological behavior of this cancer, and supported by national and
* Corresponding author. E-mail addresses: [email protected] (I.J. Nixon), [email protected] (I. Ganly), [email protected] (S.G. Patel), [email protected] (F.L. Palmer), [email protected] (M.M. Whitcher), [email protected] (R. Ghossein), [email protected] (R. Michael Tuttle), [email protected] (A.R. Shaha), shahj@ mskcc.org (J.P. Shah).
international guidelines.9e11 Surgery remains the cornerstone of management of thyroid cancer with post-operative radioactive iodine administered as adjuvant treatment in selected cases based on risk of recurrence and risk of disease specific mortality. The objective of our study is to present the changing trends in the incidence, presentation, management and outcomes of WDTC within our institution over the past 8 decades. 2. Patients and methods Following approval by the Institutional Review Board, 2797 patients who had thyroid surgery for WDTC between 1932 and 2005 at Memorial Sloan Kettering Cancer Center, New York, were identified from our institutional database. Data collection was carried out over two separate time periods, with reports based on the initial cohort (1932e1985, n ¼ 987) published separately from the subsequent group (1986e2005, n ¼ 1810). Both cohorts were combined to produce the data presented in this manuscript. Patients with anaplastic, poorly differentiated and medullary carcinoma, as well as those who were selected as not suitable for surgery were excluded from these studies. Data collected included patient demographics, surgical details including extent of thyroid surgery, histopathological diagnosis at the time of treatment and pTNM status. Data on adjuvant radioactive iodine remnant ablation (RRA) was also
1743-9191/$ e see front matter Ó 2012 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijsu.2012.10.005
ORIGINAL RESEARCH I.J. Nixon et al. / International Journal of Surgery 10 (2012) 618e623 collected. In-depth analysis of recurrence data has been presented previously.12 In this manuscript we present data on 10 year disease specific survival (DSS). Mode of death was determined from case notes and death certificates where available, and cross checked against the social security index for all patients. Patients who were known to have died of disease were coded as cause specific death. Those who died of other causes were censored at the time of death for DSS analysis. Patients who died during follow up, and no cause could be confirmed were considered to have died of disease if there was evidence of disease at last follow up, in order not to underestimate the effect of disease. Our institutional approach to the management of WDTC involves risk stratification using the previously reported GAMES criteria (Table 1).13 These criteria, consider patient and tumor factors in risk stratification. This classification was designed to predict the risk of death from WDTC, rather than the risk of recurrence. Patients are considered at low risk if under the age of 45 years, and high risk if over 45 years. Tumors with more aggressive histology, which are larger than 4 cm, and/or have extrathyroid extension or have distant metastases are considered high risk tumors. In contrast, well differentiated tumors that are less than 4 cm, and are intrathyroidal, and have no evidence of distant metastases are considered low risk tumors. Thus, patients above 45 years of age with high risk tumors are considered in the high risk group. Patients under the age of 45, with low risk tumors are included in the low risk group. All others are included in the intermediate risk group. i.e. young patients with high risk tumors or older patients with low risk tumors. Our philosophy of management has been to advocate ipsilateral lobectomy in low risk patients with a unifocal intraglandular tumor, without any detectable abnormality in the opposite lobe. Assessment of the contralateral lobe is by intraoperative examination. Nowadays, this is supplemented with preoperative ultrasound. These patients do not receive RRA therapy. In the high risk group, a total thyroidectomy or even more extensive resection and post-operative RRA is recommended. Surgical resection of all clinically apparent disease is the mainstay of treatment and to this end extracapsular total thyroidectomy is performed with resection of strap muscles, recurrent nerve and even laryngotracheal or esophageal structures as indicated to ensure macroscopic surgical clearance. For intermediate risk cases, an individualized treatment decision is made based on discussion between the surgeon, endocrinologist and patient and is mainly based on tumor factors. This approach to risk stratification and treatment was adopted during the time period of the initial cohort and has remained our standard of care for subsequent decades. In terms of management of the neck, we do not perform routine elective central or lateral compartment neck dissection. The cervical nodal basins are examined clinically, ultrasonographically (in more recent years) and intra-operatively. For a clinically positive neck, with palpable node in the lateral compartment, an anatomically comprehensive, and oncologically effective selective neck dissection (lymph nodes at levels II, III, IV and V) is carried out. If suspicious nodes are identified during surgery of the primary tumor, frozen section is used to confirm metastatic disease, and appropriate neck dissection is carried out depending on the location of the metastatic nodes. Central compartment dissection is performed only if suspicious nodes are noted during thyroidectomy and confirmed by frozen section. Statistical analysis was carried out using JMP statistical package (SAS Institute Inc. SAS Campus Drive, Cary, NC 27513) and SPSS (IBM Company Headquarters, 233 S. Wacker Drive, 11th Floor, Chicago, Illinois 60606). Variables were compared within groups using Pearson’s Chi squared test. Survival outcomes were determined using the KaplaneMeier method. Univariate analysis was carried out by the log rank test.
3. Results Patient, tumor and treatment characteristics of the group as a whole and stratified by the date of initial surgical management by decade are shown in Table 2. The median follow up for the overall group was 90 months (range 1e811 months). Throughout the time period studied, there has been a steady increase in the number of
Table 1 GAMES risk of cause specific mortality stratification. Risk level
Patient factor
Tumor factor
Low risk High risk
Age <45 y Age >45 y
Low risk case Intermediate risk case High risk case
Papillary Ca Follicular Ca /Hurthle cell Ca Low risk tumor
Low risk patient Low risk patient High risk tumor High risk patient Low risk tumor High risk patient High risk tumor
M0 No ETE Size <4 cm M1 ETE Size >4 cm
619
patients managed per decade, with 982 patients managed between 1932 and 1985 in comparison to 1810 patients between 1986 and 2005 (Table 2, Fig. 1). The median age of the whole group was 45 years (range 4e94 years). In comparison with the earlier cohort, patients managed post 1985 were more likely to be over the age of 45 years (53% versus 44%, p < 0.001). The percentage of women in the cohort increased from 68% to 72% in the more recent cohort (p ¼ 0.026), and the percentage of tumors classified as papillary carcinoma also increased from 78% to 92%, p < 0.001. An increase in early stage tumors was observed during the study with pT1 lesions increasing from 19% in the early cohort to 48% in the latter cohort. For pT4 tumors, representing locally advanced tumors, we saw no increase in incidence with 8% in the early cohort and 7% in the latter cohort. Throughout the decades there has been a rise in the percentage of papillary carcinomas presenting with our institution. In the earlier cohort, around 75% of WDTC were classified a papillary carcinoma, which rose to 86% between 1986 and 1995 and 94% between 1996 and 2005. This corresponded with a fall in the percentage of follicular carcinomas from 18% to 3% over the same time period. In part, this change may be explained by changes in the definition of follicular carcinoma, with some patients now being classified as follicular variant of papillary carcinoma. The percentage of patients with pathologically positive neck nodes fell from 48% to 33% (p < 0.001). The incidence of patients with distant metastasis at presentation was similar (4% in the early versus 3% in the later cohort, p ¼ 0.262). The rising age of patients resulted in an increased percentage of intermediate risk cases in the later cohort, and a reduced number of low risk cases. However, the number of cases considered high risk remained relatively constant (Table 4a). Trends in treatment revealed that patients in the later cohort were less likely to have thyroid lobectomy (29% versus 72%, p < 0.001), with a corresponding increase in rates of total thyroidectomy. There was also a significant change in the use of RRA, with 8% of the pre 1985 group versus 44% of the post 1985 group receiving post-operative RRA (p < 0.001). When stratified by decade, the percentage who received RRA rose from 0% in 1932e 1945 to 2%, 8%, 32%, 71%, 48% and 68% by 1996e2005. By the 1970s, evidence had shown that procedures which involved less than unilateral lobectomy resulted in worse outcomes, and therefore for analysis of DSS we considered 3 groups: those managed before 1970, those managed between 1970 and 1986 and those managed between 1986 and 2005. Analysis of DSS by time period shows a significant improvement over time with modern day 10 year survival figures of 96.1% (Table 3). This improvement in outcome is most marked in the high risk group (Table 4b). Since the introduction of risk group stratification, and individualized treatment protocols based on such an approach (around the 1970s) DSS has not changed significantly. 10 year DSS rates were below 90% in the cohort managed prior to the 1970s, which rose to >95% thereafter (p < 0.001). Analysis of factors predictive of poorer outcome for the whole group confirmed non-papillary histology, age over 45 years, the presence of distant metastasis, evidence of extrathyroid extension and size over 4 cm as independent predictors on multivariate analysis (GAMES).14 In contrast, the presence of lymph node metastases was not predictive of DSS (Table 5). 4. Discussion Over the past century there has been a gradual change in the management of thyroid cancer. A number of major centers have
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Table 2 Descriptive statistics of whole group and stratification by decade. Variable
Group
1932e1945
1946e1955
1956e1965
1966e1975
1976e1985
1986e1995
1996e2005
p Value
Age
<45 >45 Female Male Lobe Isthmus Subtotal Total Unresectable Papillary Hurthle cell Follicular T1 T2 T3 T4 <1 cm >1 cm N0 N1 M0 M1 Low Int High No Yes
31 (47%) 35 (53%) 41 (62%) 25 (38%) 52 (79%) 1 (1%) 2 (3%) 11 (17%) 0 (0%) 50 (76%) 4 (6%) 12 (18%) 12 (18%) 29 (44%) 17 (26%) 8 (12%) 9 (14%) 57 (86%) 35 (53%) 31 (47%) 63 (96%) 3 (4%) 19 (29%) 24 (36%) 23 (35%) 66 (100%) 0 (0%)
142 (59%) 100 (41%) 170 (70%) 72 (30%) 180 (74%) 0 (0%) 4 (2%) 58 (24%) 0 (0%) 199 (82%) 14 (6%) 29 (12%) 46 (19%) 136 (56%) 41 (17%) 19 (8%) 41 (17%) 201 (83%) 90 (37%) 152 (63%) 229 (95%) 13 (5%) 118 (49%) 53 (22%) 71 (29%) 241 (>99%) 1 (<1%)
98 (56%) 77 (44%) 119 (68%) 56 (32%) 133 (76%) 0 (0%) 5 (3%) 37 (21%) 0 (0%) 138 (79%) 12 (7%) 25 (14%) 42 (24%) 90 (51%) 27 (15%) 16 (9%) 41 (23%) 134 (77%) 87 (50%) 88 (50%) 168 (96%) 7 (4%) 84 (48%) 44 (25%) 47 (30%) 172 (98%) 3 (2%)
135 (53%) 119 (57%) 177 (70%) 77 (30%) 171 (67%) 0 (0%) 15 (6%) 68 (27%) 0 (0%) 197 (78%) 12 (5%) 45 (18%) 35 (14%) 187 (74%) 24 (9%) 8 (35) 31 (12%) 223 (88%) 155 (61%) 99 (39%) 248 (98%) 6 (2%) 117 (46%) 78 (31%) 59 (23%) 232 (91%) 22 (9%)
143 (57%) 107 (43%) 161 (64%) 89 (36%) 171 (68%) 0 (0%) 6 (2%) 73 (29%) 0 (0%) 191 (76%) 14 (6%) 45 (18%) 52 (21%) 159 (64%) 12 (5%) 26 (10%) 41 (16%) 209 (84%) 146 (58%) 104 (42%) 243 (97%) 7 (3%) 116 (47%) 86 (34%) 47 (19%) 198 (79%) 52 (21%)
242 (53%) 212 (47%) 324 (71%) 130 (29%) 223 (49%) 5 (1%) 24 (5%) 202 (45%) 0 (0%) 391 (86%) 17 (4%) 46 (10%) 191 (43%) 99 (22%) 119 (27%) 35 (8%) 65 (14%) 389 (86%) 270 (60%) 184 (40%) 436 (96%) 18 (4%) 154 (34%) 189 (42%) 111 (24%) 357 (79%) 97 (21%)
605 (45%) 751 (55%) 974 (72%) 382 (28%) 293 (22%) 14 (1%) 13 (1%) 1033 (76%) 3 (<1%) 1277 (94%) 42 (3%) 37 (3%) 664 (49%) 233 (17%) 373 (28%) 86 (6%) 371 (27%) 985 (73%) 936 (69%) 420 (31%) 1322 (98%) 34 (2%) 422 (31%) 628 (46%) 306 (23%) 657 (49%) 699 (51%)
<0.001
Gender Procedure
Histology
pT Stage
Micro Ca pN Stage M Stage GAMES risk group RRA
published the results of institutional series spanning many decades.15,16 The incidence and presenting features of this common disease have undergone significant changes in recent times. It is now recognized that the incidence of papillary thyroid carcinoma is rising at a faster rate than any other malignancy.17 The reasons proposed for this are contentious. There is no doubt that enhanced imaging has resulted in increased rates of detection, particularly of cancers less than 1 cm in size (microcarcinomas).3,17 However, there has also been an increase in tumors greater than 4e6 cm, suggesting that the increasing incidence may be a true increase caused by other yet unknown factors.18 Thyroid cancer is recognized as being more common in females. However, recent reports suggest the incidence in women may be increasing at a higher rate than in males.4 The incidence has also been reported to be increasing at a faster rate in older patients.17 Early reports of deaths from WDTC suggested that less than total thyroidectomy procedures resulted in less favorable oncological outcomes, and that all gross disease should be removed as part of the initial surgical procedure.19e21 Debate about the required extent of initial surgical therapy continues, with an understanding that thyroid lobectomy is a safe and effective option in low risk, unifocal, intraglandular thyroid cancers9e11,22 The management of the contralateral lobe in low risk cases has been long debated with evidence supporting both lobectomy alone23,24 and total thyroidectomy.25,26 In the absence of prospective randomized controlled
Table 3 Analysis of DSS by decade. Decade
Number (n ¼ 2797)
10 yr DSS%
p Value
1932e1945 1946e1955 1956e1965 1966e1975 1976e1985 1986e1995 1996e2005
66 242 175 254 250 454 1356
87.2 87.1 90.9 85.9 95.0 95.8 96.1
<0.001
0.201 <0.001
<0.001
<0.001
<0.001 <0.001 0.224 <0.001
<0.001
trials, this debate is unlikely to be resolved. In high risk cases, the place of total thyroidectomy is widely accepted. Over the past 8 decades at MSKCC there has been an increase in the rate of total thyroidectomy (Fig. 2). High resolution ultrasound imaging in the pre-operative investigation of patients with WDTC has increased the number of contralateral thyroid nodules identified preoperatively. This, previously considered occult disease, now results in total thyroidectomy rather than thyroid lobectomy being adopted, even in low risk patients. Surgical practice has therefore gone full circle, with an initial move away from total thyroidectomy to thyroid lobectomy for selected low risk cases with now a move back towards total thyroidectomy to excise previously occult contralateral nodular disease, regardless of its histological status. The role of RRA also remains unclear in certain situations. For low risk patients, little benefit has been demonstrated,27,28 whereas in high risk cases the benefits are more certain.28 The therapeutic efficacy of RRA in the management of WDTC has led to a large increase in its use, even in low risk patients, at many major centers across the US.29 Our results over the past 73 years reflect the changes described above, with an increasing number of cases managed within our institution over the past 8 decades (Fig. 1). Along with this volume increase, we have also observed a trend towards an older patient group (94% versus 53%, p < 0.001), with a higher percentage of women represented in recent years (72% versus 68%, p ¼ 0.026) (Table 2). These trends may be due to a change in referral patterns with increased access to ultrasound in both primary care and obstetrics and gynecology practice. Analysis of survival of the whole group confirms our earlier reports that non-papillary histology, age over 45 years, the presence of distant metastases, extrathyroid extension, and size over 4 cm are predictive of poorer DSS. The results of analysis of both patient and tumor related factors underscore the importance of risk stratification, to allow for individualization in the management of WDTC (Table 5). In terms of histopathological subtypes of WDTC, papillary thyroid carcinoma remains the most prevalent, with an increasing percentage in recent years (92% versus 78%, p < 0.001). There has
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621
Fig. 1. Patient numbers managed by decade.
Table 4a GAMES groupings stratified by time period.
Risk group
Low Intermediate High
Number (%)
1932e1969 (n ¼ 564)
1970e1989 (n ¼ 584)
1990e2005 (n ¼ 1648)
p Value
1030 (37%) 1102 (39%) 664 (24%)
254 (45%) 149 (26%) 161 (29%)
251 (43%) 217 (37%) 116 (20%)
525 (32%) 736 (45%) 387 (23%)
<0.001
also been a reduction in the incidence of follicular carcinoma, from 16% to 5% (p < 0.001). This is likely due to the recognition that many primary lesions previously described as follicular carcinoma are now categorized as follicular variant of papillary carcinoma. A further change in histological reporting has resulted in the recognition of poorly differentiated thyroid carcinoma. Towards the end of our study this was recognized as a separate histological entity, and was reported separately. Although we found a relatively constant rate of pT4 disease presented throughout the decades, some more recent pT4 cancers may have been recognized as poorly differentiated and therefore excluded from this analysis. In keeping with other reports, we also noted a significant increase in the number of microcarcinomas (<1 cm). pT1 disease comprised 48% of the recent cohort of patients compared to 19% of the earlier cohort, p < 0.001. Interestingly, nodal disease has decreased in prevalence, from 48% to 33% (p < 0.001). This may be due to the increase in early T stage tumors that we now see. It may also be due to a change in neck dissection policy since our risk stratification system was introduced, with neck dissection only being carried out for clinically palpable neck disease in the past, and more recently for
radiographically detected lymph node metastases. The percentage of patients presenting with evidence of distant metastases has remained constant at less than 5%, suggesting that the percentage of patients presenting with aggressive, high risk disease that is likely to affect survival has not changed dramatically over the 7 decade period. With regards to our risk stratification system (GAMES), we observed a shift of low risk cases to the intermediate risk group category (Table 4a). This is as a result of the older patient age at presentation, despite the increases in low risk tumors. Only 25% of patients in the earlier cohort underwent total thyroidectomy versus 68% in the recent cohort. In our institution, even older patients with intraglandular WDTC are selected for thyroid lobectomy. Therefore a change in overall risk stratification should have a limited effect on rates of total thyroidectomy. This change in practice therefore is likely to be multifactorial in etiology. Along with the change in risk groups, the introduction of preoperative ultrasound over this time period has resulted in more occult nodular disease in the contralateral lobe being detected. As a consequence, there has been an increase in the number of total thyroidectomies. In addition, the
Table 4b 10 Year DSS stratified by GAMES group and by time period.
Risk group
Low Intermediate High
Number (%)
1932e1969 10 Yr DSS (n ¼ 564)
1970e1989 10 Yr DSS (n ¼ 584)
1990e2005 10 Yr DSS (n ¼ 1648)
p Value
1030 (37%) 1102 (39%) 664 (24%)
98.0% 93.0% 63.6%
100.0% 92.5% 81.4%
100.0% 98.3% 86.6%
<0.001
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I.J. Nixon et al. / International Journal of Surgery 10 (2012) 618e623
Table 5 Univariate analysis for disease specific survival for the groups as a whole. Variable
Group
Number
10 Yr DSS
p Value
Multivariate analysis
Age
<45 >45 Female Male Thyroid lobectomy Thyroid isthmusectomy Subtotal thyroidectomy Total thyroidectomy Unresectable thyroid Ca Papillary carcinoma Hurthle cell carcinoma Follicular carcinoma T1 T2 T3 T4 <4 cm >4 cm <1 cm >1 cm Absent Present N0 N1 M0 M1 Low Intermediate High
1396 1401 1966 831 1223 20 69 1482 3 2443 115 239 1042 933 613 198 2228 310 599 2198 2198 598 1719 1078 2709 88 1030 1102 664
98.4% 87.5% 94.8% 89.4% 94.6% 100.0% 90.1% 91.8% 0.0% 94.8% 82.8% 84.4% 97.7% 94.7% 91.5% 68.3% 96.9% 79.3% 98.2% 92.0% 94.9% 85.8% 94.0% 92.1% 95.1% 41.7% 99.4% 96.0% 78.8%
<0.001
Referent 4.987 Referent 1.529
HR
Gender Procedure
Histology
pT Stage
Size of tumor Micro carcinoma Any extrathyroid extension pN Stage M Stage Risk group
(50%) (50%) (70%) (30%) (44%) (1%) (2%) (53%) (0%) (87%) (4%) (9%) (37%) (34%) (22%) (7%) (88%) (12%) (21%) (79%) (79%) (21%) (62%) (38%) (97%) (3%) (37%) (39%) (24%)
increased number of total thyroidectomies may also be accounted for by several international guidelines now recommending total thyroidectomy for intra-thyroid lesions over 1.5 cm.9e11 Post-operative adjuvant RRA was rarely used in the early part of this study, but has become a part of therapy for 44% of cases in recent times (Fig. 2). Over the past few years we have become
<0.001
95% CI
p
2.899e8.272
<0.001
10.47e2.231
0.028
Referent 1.995 2.852
1.172e3.395 1.577e5.156
0.011 0.001
Referent 3.713
2.521e5.469
<0.001
Referent 2.892
1.916e4.266
<0.001
Referent 11.307
7.452e17.157
<0.001
<0.001
<0.001
0.000
0.000 0.000 0.000 0.292 0.000 0.000
increasingly aware of the side effects of RRA as well as the risk of second primaries. As a result, we now carefully consider the risk versus benefit ratio before recommending treatment with RRA. DSS for patients managed during this study has increased significantly from below 90% to over 95% in the later years (Table 3). This improvement is in keeping with other series and demonstrates
Fig. 2. Percentage of patients undergoing total thyroidectomy, receiving RRA and disease specific survival by decade.
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the excellent outcomes that most patients with WDTC now experience. Careful scrutiny of these figures however demonstrates that these improvements were largely achieved prior to the mid-1970s (Table 4b). It was at this time that evidence to support the surgical techniques now routinely employed was starting to appear. This is with particular reference to abandoning the practice of subtotal or near total thyroidectomy and instituting the practice of routine “extracapsular” total thyroidectomy. Around this time the understanding of risk stratification was improving with several investigators presenting their own method for predicting outcome in patients with WDTC.27,30,31 More recently, despite the increase in the rates of total thyroidectomy and RRA, no significant improvement in DSS has been observed for a cancer which already had excellent outcomes (Fig. 2). These figures are affected by the changing trends in presentation. An increased number of intermediate risk cases are now seen (Table 4a). Analysis on a risk group specific level shows improvement in each time period studies (Table 4b) although overall, improved survival was more marked from the mid 1970s. Over the past 8 decades in our institution, the incidence, presentation and management of WDTC has changed considerably. Older patients with earlier stage disease present an increasing workload for our department. It is likely that the incidence of WDTC will continue to rise in the short to medium term at least. Already excellent outcomes are unlikely to be significantly improved with an ever more aggressive approach to treatment. Opportunities to improve standards of care include identifying patient groups most likely to benefit from aggressive contemporary management and at the same time developing new therapeutic strategies. Efforts must also include attempts to identify those patients who will benefit from less invasive treatment, which would reduce the potential lifelong impact that complications of therapy can have, whilst maintaining oncological outcomes and allowing focusing of resources on those patients most likely to benefit. Our efforts in clinical care in future need to be focused to reducing mortality from thyroid cancer, and in the discovery of new treatment modalities, that will create a positive impact on patients with distant metastatic disease, for whom we have little to offer at this time. Ethical approval IRB approval from MSKCC WA 0382-05 (10). Funding No external funding. Author contribution Nixon e data collection and analysis, manuscript preparation. Palmer/Whitcher e Data collection and analysis. Ganly/Patel e Project leads, data analysis and editing. Ghossein/Tuttle e Manuscript editing. Shah/Shaha e Principle investigators, editing of manuscript. Conflict of interest None. References 1. Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid cancer in the United States, 1988e2005. Cancer 2009;115(16):3801e7. Epub 2009/07/15. 2. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973e2002. JAMA 2006;295(18):2164e7. Epub 2006/05/11. 3. Enewold L, Zhu K, Ron E, Marrogi AJ, Stojadinovic A, Peoples GE, et al. Rising thyroid cancer incidence in the United States by demographic and tumor characteristics, 1980e2005. Cancer Epidemiol Biomarkers Prev 2009;18(3):784e 91. Epub 2009/02/26. 4. Elaraj DM, Sturgeon C. Adequate surgery for papillary thyroid cancer. Surgeon 2009;7(5):286e9. Epub 2009/10/24.
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