Exploring the Relationship Between Patient Age and Cancer-Specific Survival in Papillary Thyroid Cancer: Rethinking Current Staging Systems

Purpose Patient age is considered to play a unique prognostic role in papillary thyroid cancer (PTC), with a distinct staging dichotomization at 45 years of age. This is based on older, limited data demonstrating a marked rise in mortality around the ages of 40 to 50 years. We hypothesized that age is associated with compromised survival from cancer, with no cutoff denoting survival difference. Patients and Methods Patients with PTC who had surgery were identified from the SEER database (1998 to 2012). Multivariable proportional hazards modeling utilizing several flexible smoothing approaches were used to examine the association between age and cancer-specific survival (CSS) and to determine whether there is an age cut point that is associated with CSS decrement. Results A total of 31,802 patients with PTC were included. Median age was 45 years (range, 2 to 105 years). Ten-year CSS according to age was as follows: 2 to 19 years, 99.8%; 20 to 29 years, 99.9%; 30 to 39 years, 99.8%; 40 to 49 years, 99.5%; 50 to 59 years, 98.1%; 60 to 69 years, 94.8%; 70 to 79 years, 91.5%; 80 to 89 years, 79.2%; and ≥ 90 years, 73.9%. After adjustment for patient demographic and clinicopathologic characteristics, increasing age was associated with increasing mortality from the disease in a dose-dependent fashion, without an apparent cut point. Each of the smoothing approaches demonstrated a similar linearity of risk over all ages and provided close measures of goodness of fit to the data. Conclusion Patient age is significantly associated with death from PTC in a linear fashion, without an apparent age cut point demarcating survival difference. These results challenge the appropriateness of a patient age cut point in current staging systems for PTC and argue for considering a revision in how we anticipate prognosis for patients with PTC

T1a Versus T1b Differentiated Thyroid Cancers: Do We Need to Make the Distinction?

BackgroundThe 7th edition of the American Joint Committee on Cancer (AJCC) staging system trialed a subdivision of T1 tumors into T1a (<1 cm) and T1b (1.0-2 cm). The 2009 American Thyroid Association (ATA) guidelines recommended total thyroidectomy for tumors >1 cm, and lobectomy for those ≤1 cm. These AJCC staging parameters remain a focus of debate, and ATA guidelines are in transition. The aim of this study was to determine if the T1 staging subdivision is associated with different treatment strategies and patterns of patient survival.MethodsAll adult patients with AJCC pT1 differentiated thyroid cancer (DTC) from the National Cancer Data Base (NCDB; 1998-2012) and Surveillance, Epidemiology, and End Results (SEER) program (2004-2012) were divided into two groups based on tumor size: T1a versus T1b. Demographic, clinical, and pathologic features were evaluated. Multivariate regression analysis was used to determine factors associated with undergoing total thyroidectomy and radioactive iodine. Cox proportional hazards models were performed to determine factors associated with overall and disease-specific survival.ResultsAmong 149,912 DTC patients, 98,111 (65.4%) were T1a and 51,801 (34.6%) T1b in the NCDB; in SEER, among 18,381 patients, 11,208 (61.0%) had T1a and 7173 (39.0%) T1b tumors. Patients with T1b cancers were younger (48 vs. 51 years T1a) and more likely to have private insurance (76.2% vs. 74.1%), no comorbidities (86.0% vs. 83.8%), and undergo treatment at academic medical centers (41.4% vs. 40.3%; all p < 0.01). They also were more likely to undergo total thyroidectomy (87.7% vs. 74.3%), and had more lymphovascular invasion (10.2% vs. 3.3%), positive surgical margins (7.9% vs. 3.8%), metastatic lymph nodes (35.8% vs. 23.8%), and distant metastases (0.4% vs. 0.3%; all p < 0.01). Factors associated with radioactive-iodine use included younger patient age, lower income, having insurance, positive surgical margins, and T1b stage (p < 0.01). After adjustment, overall (p = 0.23) and disease-specific survival (p = 0.93) were similar among patients with T1a versus T1b tumors.ConclusionThese results illustrate that patients with pT1a versus pT1b tumors undergo different treatment strategies. Based on the newly published 2015 ATA guidelines, whereby either lobectomy or total thyroidectomy can be performed for low-risk tumors, it might be anticipated that treatment differences will diminish over time. Therefore, division of AJCC T1 staging into T1a versus T1b subgroups might become obsolete over time

Transcriptional profiling reveals distinct classes of parathyroid tumors in PHPT

The clinical presentation of primary hyperparathyroidism (PHPT) varies widely, although the underlying mechanistic reasons for this disparity remain unknown. We recently reported that parathyroid tumors can be functionally segregated into two distinct groups on the basis of their relative responsiveness to ambient calcium, and that patients in these groups differ significantly in their likelihood of manifesting bone disability. To examine the molecular basis for this phenotypic variation in PHPT, we compared the global gene expression profiles of calcium-sensitive and calcium-resistant parathyroid tumors. RNAseq and proteomic analysis identified a candidate set of differentially expressed genes highly correlated with calcium-sensing capacity. Subsequent quantitative assessment of the expression levels of these genes in an independent cohort of parathyroid tumors confirmed that calcium-sensitive tumors cluster in a discrete transcriptional profile group. These data indicate that PHPT is not an etiologically monolithic disorder and suggest that divergent molecular mechanisms could drive the observed phenotypic differences in PHPT disease course, provenance, and outcome

T1a Versus T1b Differentiated Thyroid Cancers: Do We Need to Make the Distinction?

Background: The 7th edition of the American Joint Committee on Cancer (AJCC) staging system trialed a subdivision of T1 tumors into T1a (<1 cm) and T1b (1.0–2 cm). The 2009 American Thyroid Association (ATA) guidelines recommended total thyroidectomy for tumors >1 cm, and lobectomy for those ≤1 cm. These AJCC staging parameters remain a focus of debate, and ATA guidelines are in transition. The aim of this study was to determine if the T1 staging subdivision is associated with different treatment strategies and patterns of patient survival. Methods: All adult patients with AJCC pT1 differentiated thyroid cancer (DTC) from the National Cancer Data Base (NCDB; 1998–2012) and Surveillance, Epidemiology, and End Results (SEER) program (2004–2012) were divided into two groups based on tumor size: T1a versus T1b. Demographic, clinical, and pathologic features were evaluated. Multivariate regression analysis was used to determine factors associated with undergoing total thyroidectomy and radioactive iodine. Cox proportional hazards models were performed to determine factors associated with overall and disease-specific survival. Results: Among 149,912 DTC patients, 98,111 (65.4%) were T1a and 51,801 (34.6%) T1b in the NCDB; in SEER, among 18,381 patients, 11,208 (61.0%) had T1a and 7173 (39.0%) T1b tumors. Patients with T1b cancers were younger (48 vs. 51 years T1a) and more likely to have private insurance (76.2% vs. 74.1%), no comorbidities (86.0% vs. 83.8%), and undergo treatment at academic medical centers (41.4% vs. 40.3%; all p < 0.01). They also were more likely to undergo total thyroidectomy (87.7% vs. 74.3%), and had more lymphovascular invasion (10.2% vs. 3.3%), positive surgical margins (7.9% vs. 3.8%), metastatic lymph nodes (35.8% vs. 23.8%), and distant metastases (0.4% vs. 0.3%; all p < 0.01). Factors associated with radioactive-iodine use included younger patient age, lower income, having insurance, positive surgical margins, and T1b stage (p < 0.01). After adjustment, overall (p = 0.23) and disease-specific survival (p = 0.93) were similar among patients with T1a versus T1b tumors. Conclusion: These results illustrate that patients with pT1a versus pT1b tumors undergo different treatment strategies. Based on the newly published 2015 ATA guidelines, whereby either lobectomy or total thyroidectomy can be performed for low-risk tumors, it might be anticipated that treatment differences will diminish over time. Therefore, division of AJCC T1 staging into T1a versus T1b subgroups might become obsolete over time

Low-Risk Thyroid Cancer in Elderly: Total Thyroidectomy/RAI Predominates but Lacks Survival Advantage

BackgroundPapillary thyroid cancer (PTC) is the fastest increasing cancer in the United States; incidence increases with age. It generally has a favorable prognosis but may behave more aggressively in older patients. This study aims to describe national treatment patterns for low-risk PTC in older adults.Materials and methodsThe Surveillance, Epidemiology, and End Results-Medicare database was used to identify patients ≥66&nbsp;y treated for clinical T1N0M0 PTC between 1996 and 2011. Multivariable logistic regression was used to identify factors associated with extent of surgery (total thyroidectomy versus lobectomy) and radioactive iodine (RAI) administration. Cox proportional hazards modeling was used to estimate the effect of treatment type on disease-specific survival (DSS).ResultsThree thousand two hundred and fourteen patients met inclusion criteria; 77.6% were women, median age was 72&nbsp;y, and mean tumor size was 0.7&nbsp;cm. 42.7% had preoperatively diagnosed PTC (versus incidental). 65.4% underwent total thyroidectomy, 29.0% lobectomy, and 5.6% lobectomy followed by completion thyroidectomy; 33.4% received postoperative RAI. Five- and 10-year DSS were 98.9% and 98.3%, respectively. After adjustment, larger tumor size (1.1-2&nbsp;cm), multifocality, and a preoperative PTC diagnosis were associated with greater odds of undergoing more extensive surgery and receiving RAI (P&nbsp;&lt;&nbsp;0.0001). DSS was not associated with extent of surgery or RAI administration (P&nbsp;&gt;&nbsp;0.05).ConclusionsMost older adults with PTC underwent total thyroidectomy and a third received RAI; neither treatment improved DSS. In the growing elderly population, less extensive interventions for PTC may reduce morbidity and improve quality of life while preserving an excellent prognosis

Hazard-rate analysis and patterns of recurrence in early stage melanoma: moving towards a rationally designed surveillance strategy.

While curable at early stages, few treatment options exist for advanced melanoma. Currently, no consensus exists regarding the optimal surveillance strategy for patients after resection. The objectives of this study were to identify patterns of metastatic recurrence, to determine the influence of metastatic site on survival, and to identify high-risk periods for recurrence.A retrospective review of the Duke Melanoma Database from 1970 to 2004 was conducted that focused on patients who were initially diagnosed without metastatic disease. The time to first recurrence was computed from the date of diagnosis, and the associated hazard function was examined to determine the peak risk period of recurrence. Metastatic sites were coded by the American Joint Committee on Cancer (AJCC) system including local skin, distant skin and nodes (M1a), lung (M1b), and other distant (M1c).Of 11,615 patients initially diagnosed without metastatic disease, 4616 (40%) had at least one recurrence. Overall the risk of initial recurrence peaked at 12 months. The risk of initial recurrence at the local skin, distant skin, and nodes peaked at 8 months, and the risk at lung and other distant sites peaked at 24 months. Patients with a cutaneous or nodal recurrence had improved survival compared to other recurrence types.The risk of developing recurrent melanoma peaked at one year, and the site of first recurrence had a significant impact on survival. Defining the timing and expected patterns of recurrence will be important in creating an optimized surveillance strategy for this patient population

Impaired calcium sensing distinguishes primary hyperparathyroidism (PHPT) patients with low bone mineral density

ContextA subset of PHPT patients exhibit a more severe disease phenotype characterized by bone loss, fractures, recurrent nephrolithiasis, and other dysfunctions, but the underlying reasons for this disparity in clinical presentation remain unknown.ObjectiveWe sought to identify new mechanistic indices that could inform more personalized management of PHPT.DesignPre-, peri-, and postoperative data and demographic, clinical, and pathological information from patients undergoing parathyroidectomy for PHPT were collected. Univariate and partial Spearman correlation was used to estimate the association of parathyroid tumor calcium sensing capacity with select variables.Patients or other participantsAn unselected series of 237 patients aged &gt;18years and undergoing parathyroidectomy for PHPT were enrolled.Main outcome measuresCalcium sensing capacity, expressed as the concentration required for half-maximal biochemical response (EC50), was evaluated in parathyroid tumors from an unselected series of 74 patients and assessed for association with clinical parameters. The hypothesis was that greater disease severity would be associated with attenuated calcium sensitivity and biochemically autonomous parathyroid tumor behavior.ResultsParathyroid tumors segregated into two distinct groups of calcium responsiveness (EC50&lt;3.0 and ≥3.0mM). The low EC50 group (n=27) demonstrated a mean calcium EC50 value of 2.49mM [95% confidence interval (CI): 2.43-2.54mM], consistent with reference normal activity. In contrast, the high EC50 group (n=47) displayed attenuated calcium sensitivity with a mean EC50 value of 3.48mM [95% CI: 3.41-3.55mM]. Retrospective analysis of the clinical registry data suggested that high calcium EC50 patients presented with a more significant preoperative bone mineral density (BMD) deficit with a t-score of -2.7, (95% CI: -3.4 to -1.9) versus 0.9, (95% CI: -2.1 to -0.4) in low EC50 patients (p&lt;0.001). After adjusting for gender, age, BMI, 25 OH vitamin D level and preoperative iPTH, lowest t-score and calcium EC50 were inversely correlated, with a partial Spearman correlation coefficient of -0.35 (p=0.02).ConclusionsImpaired calcium sensing in parathyroid tumors is selectively observed in a subset of patients with more severe bone mineral density deficit. Assessment of parathyroid tumor biochemical behavior may be a useful predictor of disease severity as measured by bone mineral density in patients with PHPT

Transcriptional profiling reveals distinct classes of parathyroid tumors in PHPT

The clinical presentation of primary hyperparathyroidism (PHPT) varies widely, although the underlying mechanistic reasons for this disparity remain unknown. We recently reported that parathyroid tumors can be functionally segregated into two distinct groups on the basis of their relative responsiveness to ambient calcium, and that patients in these groups differ significantly in their likelihood of manifesting bone disability. To examine the molecular basis for this phenotypic variation in PHPT, we compared the global gene expression profiles of calcium-sensitive and calcium-resistant parathyroid tumors. RNAseq and proteomic analysis identified a candidate set of differentially expressed genes highly correlated with calcium-sensing capacity. Subsequent quantitative assessment of the expression levels of these genes in an independent cohort of parathyroid tumors confirmed that calcium-sensitive tumors cluster in a discrete transcriptional profile group. These data indicate that PHPT is not an etiologically monolithic disorder and suggest that divergent molecular mechanisms could drive the observed phenotypic differences in PHPT disease course, provenance, and outcome

Extent of surgery for low-risk thyroid cancer in the elderly: Equipoise in survival but not in short-term outcomes

BackgroundTotal thyroidectomy is more common than lobectomy for low-risk papillary thyroid cancer, despite equipoise in survival. Because postoperative morbidity increases with age, we aimed to investigate how the extent of thyroidectomy affects short-term outcomes among older patients.MethodsUsing the Surveillance, Epidemiology, and End Results-Medicare database, we identified patients aged ≥66 years who were treated between 1996 and 2011 for papillary thyroid cancer with tumors ≤2 cm in diameter. We used multivariable logistic regression to evaluate the effect of extent of surgery on complications, emergency-department visits, and unplanned readmissions.ResultsAmong 3,341 selected patients, 77.3% were female, mean age was 72.9 years, and tumors averaged 0.8 cm in diameter. A total of 67.6% of patients underwent total thyroidectomy, and 32.4% underwent lobectomy. Total thyroidectomy was associated with complications (odds ratio&nbsp;= 1.99) and readmissions (odds ratio&nbsp;= 1.59; both P &lt; 0.01). Complications were higher in female patients (odds ratio&nbsp;= 1.34), black patients (versus white patients, odds ratio&nbsp;= 1.65), and those with ≥2 comorbidities (vs 0, odds ratio&nbsp;= 1.43; all P &lt; 0.01). Black patients and those with ≥2 comorbidities had more emergency-department visits (odds ratio&nbsp;= 1.50 and 1.92, respectively) and readmissions (odds ratio&nbsp;= 2.19 and 2.29, respectively; all P &lt; 0.01).ConclusionTotal thyroidectomy for older adults with low-risk papillary thyroid cancer may lead to potentially avoidable complications and readmissions, particularly for black and female patients. In many cases, lobectomy may be a safer and less costly alternative

Projecting Survival in Papillary Thyroid Cancer: A Comparison of the Seventh and Eighth Editions of the American Joint Commission on Cancer/Union for International Cancer Control Staging Systems in Two Contemporary National Patient Cohorts

BackgroundThis study aims to compare the seventh and eighth editions of the American Joint Commission on Cancer/Union for International Cancer Control (AJCC/UICC) tumor, node, metastasis staging system for patients with papillary thyroid cancer (PTC) in two national patient cohorts.MethodsAdult PTC patients undergoing surgery were selected from the Surveillance, Epidemiology and End Results (SEER) program (2004-2012) and the National Cancer Database (2004-2012). Staging criteria for the seventh and eighth AJCC/UICC editions were applied separately to each cohort. Survival probabilities were estimated using the Kaplan-Meier method. Multivariable Cox proportional hazards models were used to estimate the association of stage with survival in both settings. The Akaike information criterion was used to assess model performance.ResultsAbout 23% of patients were downstaged from the seventh to the eighth edition in SEER, while 24% were downstaged in the National Cancer Database. Disease-specific survival (DSS) and overall survival (OS) were significantly related to stage at diagnosis when using both the seventh and eighth editions of the AJCC/UICC staging system (p &lt; 0.001). Patients classified into higher stages (III and IV) in the eighth edition showed a worse prognosis than those classified into similar stages in the seventh edition. After adjustment, PTC stages as defined by both editions were significantly associated with DSS and OS. With respect to both DSS and OS, the eighth edition PTC model appeared to be a better fit to the data (smaller Akaike information criterion values) compared to the seventh edition.ConclusionBased on these large contemporary national cohorts, the eighth edition AJCC/UICC tumor, node, metastasis classification for PTC is superior to the seventh edition for predicting survival