Significant annual percentage change (APC) was observed for each subtype. A significantly larger APC was also noted in aggressive papillary thyroid carcinoma (PTC) relative to other variants. Pairwise tests of parallelism were performed between aggressive PTC vs well-differentiated papillary thyroid carcinoma (WDPTC), aggressive PTC vs anaplastic variant, and WDPTC vs anaplastic variant. The circles along the dotted lines represent discrete age-adjusted incidence values for a given thyroid variant at a given year.
The T stage data are based on American Joint Committee on Cancer 7th Edition staging. N+ indicates node positivity; PDTC, poorly differentiated thyroid carcinoma; WDPTC, well-differentiated papillary thyroid carcinoma.
Well-differentiated papillary thyroid carcinoma (WDPTC) and anaplastic thyroid carcinoma (ATC) cases were included for reference. Disease-specific survival was calculated using Surveillance, Epidemiology, and End Results data, while overall survival was determined using National Cancer Data Base data. PDTC indicates poorly differentiated thyroid cancer.
eFigure 1. Consolidated Standards of Reporting Trials (CONSORT) diagram detailing the study inclusion criteria.
eFigure 2. Kaplan-Meier curves depicting overall survival (OS) of propensity score-matched cohorts of aggressive PTC variants with WDPTC cases.
eTable 1. Baseline characteristics of all papillary thyroid carcinoma aggressive variants.
eTable 2. Clinicopathologic features and survival outcomes across papillary thyroid carcinoma aggressive variants.
eTable 3. Univariate and multivariable analysis of overall survival in thyroid cancer (unabridged).
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Ho AS, Luu M, Barrios L, et al. Incidence and Mortality Risk Spectrum Across Aggressive Variants of Papillary Thyroid Carcinoma. JAMA Oncol. Published online March 05, 2020. doi:10.1001/jamaoncol.2019.6851
How do aggressive variants of papillary thyroid carcinoma (PTC), typically consolidated as a single intermediate-risk group, differ among histologic subtypes?
This cohort study of 5447 patients found that, between 2000 and 2016, annualized growth in incidence of aggressive PTC variants significantly outpaced that of well-differentiated PTC. Comparative prognostic features and survival outcomes significantly differed between individual variants of PTC as well as relative to well-differentiated and anaplastic subtypes.
Given the disproportionately rising prevalence of aggressive PTC variants and their wide range of outcomes, greater emphasis on tailored treatment approaches is needed for these histologically and prognostically distinct subtypes.
While well-differentiated papillary thyroid carcinoma (WDPTC) outcomes have been well characterized, the prognostic implications of more aggressive variants are far less defined. The rarity of these subtypes has led to their consolidation as intermediate risk for what are in fact likely heterogeneous diseases.
To analyze incidence, clinicopathologic characteristics, and outcomes for aggressive variants of papillary thyroid carcinoma (PTC).
Design, Setting, and Participants
This cohort study used data from 2000 to 2016 from hospital-based and population-based US cancer registries to analyze aggressive PTC variants, including diffuse sclerosing (DSV), tall-cell (TCV), insular, and poorly differentiated (PDTC) subtypes. These variants were compared against WDPTC and anaplastic cases. Data analysis was conducted from January 2019 to October 2019.
Main Outcomes and Measures
Age-adjusted incidence was calculated via annual percentage change (APC) using the weighted least-squares method. Overall survival and disease-specific survival were analyzed via Cox regression. Propensity-score matching was used to adjust survival analyses for clinical and demographic covariates.
Collectively, 5447 aggressive PTC variants were identified (including 415 DSV, 3339 TCV, 362 insular, and 1331 PDTC cases), as well as 35 812 WDPTC and 2249 anaplastic cases. Over the study period, a substantial increase in aggressive variant incidence was observed (APC, 9.1 [95% CI, 7.33-10.89]; P < .001), surpassing the relative increases observed in WDPTC (APC, 5.1 [95% CI, 3.98-6.12]; P < .001) and anaplastic cases (APC, 1.9 [95% CI, 0.75-3.05]; P = .003; parallelism P < .007). Survival varied markedly based on histologic subtype, with a wide spectrum of mortality risk noted; 10-year overall survival was 85.4% (95% CI, 84.6%-86.3%) in WDPTC, 79.2% (95% CI, 73.6%-85.3%) in DSV, 71.9% (95% CI, 68.4%-75.6%) in TCV, 45.1% (95% CI, 40.2%-50.6%) in PDTC, 27.9% (95% CI, 20.0%-38.9%) in the insular variant, and 8.9% (95% CI, 7.5%-10.6%) in anaplastic cases (P < .001). These differences largely persisted even after adjusting for inherent differences in baseline characteristics by multivariable Cox regression and propensity-score matching.
Conclusions and Relevance
An upsurge in aggressive PTC incidence was observed at a rate beyond that seen in WDPTC or anaplastic thyroid carcinoma. Moreover, long-term survival outcomes for aggressive PTC subgroups exhibit heterogeneous clinical behavior and a wide range of mortality risk, suggesting that treatment should be tailored to specific histologic subtypes. Given increasing prevalence and disparate outcomes, further investigation to identify optimal therapeutic strategies is needed in these diverse, understudied populations.
Although well-differentiated papillary thyroid carcinoma (WDPTC) has risen in incidence, it has in turn become increasingly understood on a molecular, diagnostic, and prognostic level.1-3 Evolving staging systems and treatment paradigms have likewise reflected expanded insights into its biologic and clinical behavior.4-6
In contrast, aggressive papillary thyroid carcinoma (PTC) variants remain sparsely defined and largely understudied.7,8 Perhaps because of their rarity, clinicopathologic features remain controversial, as have expected outcomes. Diffuse sclerosing variant (DSV), for instance, has been curiously described as both indolent9,10 and high risk,11,12 depending on the study. Another confounding issue is the lack of precise histologic definitions across both institutions and time. As an example, considerable disagreement exists among investigators regarding the threshold percentage of tall cells (30%-70%) that constitute true tall-cell variant (TCV) PTC.13-15
Aggressive PTC variants represent a unique subset of patients that have been historically underrepresented in clinical trials and large-scale genomic studies, despite appearing to manifest with higher rates of regional spread, distant metastasis, and mortality risk.16 These features may in fact correspond with the progressively undifferentiated state of each variant—yet relative qualities have not been well appraised or compared.
Collectively, aggressive PTC subtypes are often lumped together as intermediate risk4,17: too serious to ignore but too nebulous to separate. This is even though they are morphologically discrete and may harbor a spectrum of mortality risk. Cancer registries offer a valuable opportunity to delineate this spectrum by accruing higher case volumes of rare tumor variants. Here, we analyze shifts in the incidence of aggressive PTC subtypes and characterize their clinicopathologic outcomes in comparison with their conventional and anaplastic counterparts.
Data were extracted from both the Surveillance, Epidemiology, and End Results (SEER)–21 database, as well as the National Cancer Data Base (NCDB). The SEER database is derived from 21 cancer registries and covers more than 28% of incident cases in the United States (https://seer.cancer.gov/). The NCDB is a tumor registry jointly maintained by the American Cancer Society and the Commission on Cancer of the American College of Surgeons and captures 70% of all cancers treated in the United States. Data between the 2 databases were maintained separately because there is likely patient overlap.18,19 The SEER data were used only to assess incidence and disease-specific survival; the remainder of analyses were performed with NCDB data, given the larger cohort size. This study was deemed exempt from formal review because it used publicly available, deidentified data, with a waiver of informed consent granted by the Cedars-Sinai institutional review board.
Cases were selected from International Classification of Diseases for Oncology, Third Revision (ICD-O-3) histology codes, which are based on nomenclature adopted by the World Health Organization International Histological Classification of Tumors (Blue Books). Only cases with topographic code C73 were included. Morphologic subtypes recognized by the World Health Organization and selected for analysis included DSV (8350), TCV (8344), poorly differentiated thyroid cancer (PDTC) (8020), and insular variant (8337). Insular variant was included because of its association with PDTC and the lack of universal agreement on its origin.20 Columnar-cell variant is currently classified together with TCV (https://codes.iarc.fr). Other known, aggressive thyroid cancer subtypes with too few cases for inclusion were solid (8230) and hobnail/micropapillary variants (8265).
For comparison, anaplastic thyroid carcinoma (8021) cases were selected, as were WDPTC cases (papillary carcinoma not otherwise specified , papillary carcinoma of thyroid , follicular variant of PTC , papillary microcarcinoma , and encapsulated papillary carcinoma ). The WDPTC cases designated as poorly differentiated grade or undifferentiated/anaplastic grade were recategorized as PDTC and anaplastic thyroid carcinoma, respectively.
Cases from both the NCDB21 and SEER22 data sets were selected with the described thyroid cancer histologic subtypes. Patients were excluded if they had unknown diagnostic confirmation, missing tumor size, an unknown grade or differentiation, unknown regional lymph-node data, an unknown T stage, an unknown N stage, radiation before surgery or radiation and surgery in an unknown sequence, systemic therapy before surgery or an unknown sequence, an unknown follow-up status, or an unknown vital status. In the NCDB, patients were further excluded if they were missing data on academic facility, income, great circle distance, or Charlson/Deyo comorbidity score. In the SEER database, patients were further excluded if they lacked disease-specific survival data elements.
For annual percentage change (APC), rates were calculated per 100 000 and age adjusted to the 2000 US standard population (19 age groups23); 95% CIs for rates (Tiwari modification24) and trends were calculated. Percentage changes were calculated using 1 year for each end point; APCs were calculated using the weighted least-squares method. Comparison of incidence trends was performed with the Joinpoint Regression Program version 188.8.131.52 (IMS Inc).25 A pairwise test of parallelism was used to compare the APC among each of the PTC subtypes with a Bonferroni-corrected level of P < .02 (0.05/3) for the 3 comparisons considered significant (PTC vs WDPTC, aggressive PTC vs anaplastic PTC, and WDPTC vs anaplastic PTC).
Aggressive-variant PTC cases were described using descriptive statistics such as mean, median, counts, and proportions. The PTC subtypes were then stratified and compared using analysis of variance, Kruskal-Wallis tests, and Pearson χ2 tests for continuous and categorical variables, as appropriate. Overall survival was calculated using the Kaplan-Meier method with survival curves compared using the log-rank test. Disease-specific survival was calculated with the cumulative incidence method and curves compared using the k-sample test. Median follow-up was determined by the reverse Kaplan-Meier method.
Univariate and multivariable survival analyses were performed using the Cox proportional-hazards model. Variable selection was performed using a backward stepwise variable-selection procedure, optimizing for the Akaike information criterion.26 The proportional hazards assumption was assessed by Schoenfeld residuals and the goodness-of-fit test proposed by Grambsch and Therneau.27 Multicollinearity was assessed by the variable inflation factor.
To further adjust for potential bias within our cohorts, propensity scores were used to match each aggressive PTC subtype with the WDPTC subtype.28 Propensity scores were estimated for each individual using a multivariable logistic regression model adjusting for facility, patient, and clinical covariates, such as facility academic status, region, age, sex, race, insurance, income, education, urban, distance from center, comorbidity, lymph node size, number of nodes positive, number of nodes examined, T staging, N staging, M staging, extrathyroidal extension (ETE), whether surgery resection was performed, margin, radiation therapy, and chemotherapy. Propensity scores were then matched among each aggressive PTC subtype cohort with WDPTC using the nearest-neighbor method.29 Quality of the propensity score–matched cohort was assessed visually using density histograms of the propensity scores. All statistical analyses were performed from [month year] to [month year] using R software package version 3.6.1 (R Foundation for Statistical Computing), with a 2-sided test and P values less than .05 considered significant.30
For the primary NCDB analysis, 5447 aggressive-variant PTC cases were reported across 895 institutions (eTable 1 and eFigure 1 in the Supplement), with a median follow-up of 51.2 (95% CI, 50.8-51.6) months. Additionally, 35 812 WDPTC and 2249 anaplastic cases were identified for comparison.
From 2000 to 2016, the age-adjusted incidence of aggressive PTC variants significantly increased (APC, 9.1 [95% CI, 7.33-10.89]; P < .001). This rate of change occurred at a much greater pace compared with anaplastic thyroid cancer (APC, 1.9 [95% CI, 0.75-3.05]; P = .003) or WDPTC (APC, 5.1 [95% CI, 3.98-6.13]; P < .001) (Figure 1). The pairwise test of parallelism between aggressive PTC vs WDPTC (P = .007), aggressive PTC vs anaplastic PTC (P = .001), and WDPTC vs anaplastic PTC (P < .001) all showed significant differences in APC.
Overall, a broad progression of aggressive features was observed across aggressive PTC variants, corresponding to mean age and mean survival (Figure 2; eTable 2 in the Supplement). Relative to WDPTC, each aggressive PTC subtype tended to present in patients older in age (mean [SD] age: WDPTC, 56.3 [10.8] years; DSV, 56.9 [11.8] years; TCV, 58.5 [11.9] years; PDTC, 63.1 [12.8] years; insular variant, 64.7 [12.5] years; anaplastic cases, 69.7 [11.7] years; P < .001), with larger tumor size (mean [SD] size: WDPTC, 1.6 [2.3] cm; DSV, 1.9 [1.7] cm; TCV, 2.4 [2.2] cm; PDTC, 4.3 [4.3] cm; insular variant, 6.1 [4.2] cm; anaplastic cases, 6.5 [6.4] cm; P < .001), with a higher mean metastatic lymph node number (mean [SD] number: WDPTC, 1.6 [3.9] nodes; DSV, 4.5 [7.8] nodes; TCV, 3.5 [5.9] nodes; PDTC, 3.8 [8.0] nodes; insular variant, 2.8 [6.6] nodes; anaplastic cases, 3.4 [6.4] nodes; P < .001), greater rate of ETE (WDPTC, 6032 patients [16.8%]; DSV, 186 patients [44.9%]; TCV, 1860 patients [55.8%]; PDTC, 694 patients [52.3%]; insular variant, 189 patients [52.4%]; anaplastic cases, 1870 patients [85.0%]; P < .001), and greater incidence of M1 disease (WDPTC, 319 patients [0.9%]; DSV, 9 patients [2.3%]; TCV, 126 patients [4.0%]; PDTC, 204 patients [16.1%]; insular variant, 85 patients [24.3%]; anaplastic cases, 851 patients [39.1%]; P < .001). Conversely, these covariates were favorable relative to anaplastic cases (P < .001 for each comparison with the data presented above). Diffuse sclerosing variant and TCV appeared in patients younger in mean (SD) age compared with those with PDTC and insular variants (DSV, 56.9 [11.8] years; TCV, 58.5 [11.9] years; PDTC, 63.1 [12.8] years; insular variants, 64.7 [12.5] years; P < .001). Similar mean (SD) differences were seen in tumor size (DSV, 1.9 [1.7] cm; TCV, 2.4 [2.2] cm; PDTC, 4.3 [4.2] cm; insular variants, 6.1 [4.2] cm; P < .001) and M1 incidence on presentation (DSV, 9 patients [2.3%]; TCV, 126 patients [4.0%]; PDTC, 204 patients [16.1%]; insular variant, 85 patients [24.3%]; P < .001).
On univariate analysis, aggressive PTC subtype (reference) was strongly associated with worsening overall survival compared with other subtypes (hazard ratios: DSV, 1.998 [95% CI, 1.532-2.605]; TCV, 2.163 [95% CI, 1.946-2.404]; PDTC, 6.947 [95% CI, 6.289-7.675]; insular variant, 8.426 [95% CI, 7.189-9.877]; anaplastic cases, 45.741 [95% CI, 42.908-48.76]; P < .001 for all comparisons; Table; eTable 3 in the Supplement). Kaplan-Meier survival plots depicted a wide range of outcomes across aggressive PTC variants. Estimated 10-year overall survival (in the NCDB) was significantly different between subtypes (79.2% [95% CI, 73.6%-85.3%], 71.9% [95% CI, 68.4%-75.6%], 45.1% [95% CI, 40.2%-50.6%], and 27.9% [95% CI, 20.0%-38.9%] for DSV, TCV, PDTC, and insular variants, respectively; P < .001; Figure 3A). Estimated 10-year disease-specific survival (in the SEER database) was also significantly different between subtypes (96.7% [95% CI, 95.0%-98.4%], 89.6% [95% CI, 87.6%-91.7%], 70.0% [95% CI, 67.3%-72.8%], and 59.1% [95% CI, 51.0%-68.4%] for DSV, TCV, PDTC, and insular variants, respectively; P < .001; Figure 3B). On multivariable analysis, all subtypes continued to demonstrate significantly higher hazard ratios relative to WDPTC (hazard ratios: DSV, 1.596 [95% CI, 1.124-2.268]; TCV, 1.413 [95% CI, 1.223-1.632]; PDTC, 2.822 [95% CI, 2.421-3.290]; insular variant, 3.016 [95% CI, 2.366-3.844]; anaplastic cases, 5.719 [95% CI, 4.835-6.765; P < .001 for all comparisons; Table; eTable 3 in the Supplement).
To account for potential confounders, propensity-score analysis was performed to assess for subtype differences in overall survival. On comparison with WDPTC, the difference in overall survival for DSV disappeared (eFigure 2 in the Supplement). The remaining aggressive variants exhibited sustained overall survival differences relative to WDPTC (10-year overall survival: TCV, 72.4% [95% CI, 67.8%-77.3%]; PDTC, 44.3% [95% CI, 37.4%-52.4%]; insular variant, 24.3% [95% CI, 13.8%-42.9%]; P < .001; eFigure 2 in the Supplement).
In this study, we show a rise in aggressive PTC incidence, with a 9.1% increase in incidence each year over the last 2 decades. We further illustrate the wide, heterogeneous range of outcomes among PTC subtypes normally consolidated into a single risk category. Using a multivariable regression model, we observe that histologic subtype is a key independent factor associated with mortality, on a magnitude approximating or surpassing recognized factors, such as extrathyroidal extension and nodal metastasis (Table).
Our results reframe the conventional view regarding the rise in incidence of well-differentiated thyroid cancers.31,32 While the increase documented for WDPTC is substantial, the growth for aggressive PTC variants is even greater over the same period and beyond what might be expected by chance. In addition, although the increase in WDPTC appears to show signs of plateau since 2012, there is no evidence of this for aggressive PTC histologic subtypes. This likewise contrasts with the broader decline in incidence for more common malignant conditions, such as colon, prostate, and lung cancers.33-36
Importantly, the aggressive PTC rise in incidence is less likely to be drawn from incidental diagnosis (ie, the subclinical reservoir), given the high degree of advanced, symptomatic disease inherent in these subtypes (Figure 2; eTable 2 in the Supplement). As such, while the surge in WDPTC incidence has been met with calls for mitigating overdiagnosis and overtreatment because of largely indolent tumor behavior,37-40 the greater rise in aggressive PTC incidence may require markedly different responses for workup and treatment escalation. It is also unclear if the rise is attributable to a fundamental increase in the likelihood of these cancers developing or stems from increasing awareness by pathologists. In either case, optimizing specific therapeutic strategies will become more worthwhile as these variants grow in prevalence.
Our survival analysis builds on prior studies assessing the prognostic importance of histology.9,14,41-43 These reports have debated whether histologic subtype is a surrogate for other unfavorable covariates known to be negatively associated with survival, such as older age or distant metastasis.16 Perhaps because of low numbers and limited follow-up, prior findings may be underpowered to discriminate differences in outcome. Our study design differs in several meaningful ways, including a multifold larger cohort size, a broader array of compared histologic subtypes, and adjustment for potential confounders. Indeed, all aggressive PTC variants demographically exhibited a higher incidence of features that confer poorer prognosis (ie, ETE, older age, larger mean size, nodal metastasis, and distant metastasis; Figure 2; eTable 2 in the Supplement), as others have suggested9,41,43; yet even after correcting for these covariates, each histologic subtype upheld a significant, independent, and negative association with survival.
These PTC subtypes furthermore span a noticeably eclectic spectrum of survival outcomes (Figure 3), which belies current guidelines and clinical management.4,17 Such differences may have noteworthy implications for treatment and counseling. For example, insular and poorly differentiated histologic subtypes have roughly double the risk of death as DSV or TCV, even after adjusting for differences in presentation. Strikingly, the high distant metastasis rate seen on initial presentation (16.1%-24.3%) with PDTC and insular histologic subtypes dwarf that seen in DSV (2.3%) and even TCV subtypes (4.0%): this could alter the management offered to a patient with known insular or PDTC histologic subtypes, whether it be a more aggressive curative approach or scaled-down palliative one if distant metastasis is recognized. In contrast, a patient with DSV or TCV could be comparatively more optimistic regarding prognosis. Knowledge of such histology-specific features and outcomes should enable clinicians to better calibrate management decisions, rather than consider them alike.
A number of caveats may limit this study’s analysis, including its retrospective nature and the scope of ICD-O-3 methodology. Coding errors are inherent within cancer registries, and while annual audits are undertaken, a centralized review of pathology was not performed. Although a number of covariates were corrected for on multivariable analysis, there is an absence of thyroid cancer-specific treatment details, including radioactive iodine dose, thyrotropin suppression targets, and thyroglobulin levels. The lack of precise histologic definitions may also lead to underrepresentation of PTC subtypes, although the diversity of the 895 institutions involved should mitigate any single center’s reporting bias or pathologists’ discretion. Greater appreciation of rarer thyroid cancer variants and the increase in subspecialty thyroid pathologists over time may also bias true incidence. The evolution of histologic definitions may furthermore have affected reported numbers: the Turin criteria for PDTC,44 for instance, was proposed in 2007 but included in World Health Organization classification after our study’s time window. Such reclassification may increase or decrease incidence in multifactorial ways difficult to adjust for.
Finally, it is important to note that individual cancers will contain a blend of variants or tumor grade components that may defy categorization. While NCDB and SEER code only the primary histologic subtype or the highest grade assigned by the pathologist, there exists unavoidable ambiguity for certain cases that we cannot verify. Nonetheless, the divergence noted in incidence and prognosis are intuitively appreciable: the breadth and scale of these results represent convincing evidence backing substratification.
In summary, we describe a disproportionate rise in aggressive PTC incidence and confirm a diverse range of outcomes for a group aggregated as intermediate risk. Such survival differences naturally coincide with heterogeneous disease variants known to be histologically and genomically distinct.8,45-47 Aggressive PTC subtypes deserve deeper understanding and greater vigilance, because they constitute a rising fraction of incidence and a lopsided share of cancer-associated mortality. Our data suggest that broader integration of unique PTC histological characteristics may improve the dynamic risk stratification supported in current treatment guidelines.4,48,49 Such adjustments should better convey prognosis and ultimately advance patient decision-making.
Accepted for Publication: December 11, 2019.
Corresponding Author: Allen S. Ho, MD, Cedars-Sinai Medical Center, 8635 West Third St, Ste 590W, Los Angeles, CA 90048 (firstname.lastname@example.org); Zachary S. Zumsteg, MD, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048 (email@example.com).
Published Online: March 5, 2020. doi:10.1001/jamaoncol.2019.6851
Author Contributions: Drs Ho and Zumsteg had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Ho, Melany, Zumsteg.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Ho, Luu, Barrios, Ali, Y. Chen, Zumsteg.
Critical revision of the manuscript for important intellectual content: Ho, Luu, I. Chen, Melany, Patio, Bose, Fan, Mallen-St. Clair, Braunstein, Sacks.
Statistical analysis: Ho, Luu.
Administrative, technical, or material support: Ho, Barrios, Melany, Patio, Sacks, Zumsteg.
Supervision: Ho, Bose, Mallen-St. Clair, Zumsteg.
Conflict of Interest Disclosures: Dr Zumsteg was on the external advisory board for the Scripps Proton Therapy Center and has been a paid consultant for EMD Serono. No other disclosures were reported.
Funding/Support: This study was supported by the Donna and Jesse Garber Award for Cancer Research (Dr Ho) and the Levy Family Fellowship in Thyroid Cancer (Ms Barrios).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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