Patient age at diagnosis and biological sex in association with postoperative outcomes of thyroidectomy for low-risk papillary thyroid cancer in the U.S. Military Health System

Introduction

Thyroid cancer incidence, particularly of papillary histology, has increased in the United States (U.S.) between the 1970’s and 2010’s (1-3). Thyroid cancer disproportionally affects younger people (aged 18–49 years) and women (1,2,4,5). However, older patients and men may present with more aggressive disease and may have worse outcomes relative to younger, female patients (5-8). Differences in survival outcomes may be related to the differences in clinicopathologic characteristics or receipt of treatment between groups (5,8). Surgery is the primary treatment for many thyroid tumors, although use of neoadjuvant therapy or surveillance is increasing to improve surgical outcomes or retain thyroid function (9-12).

Short-term postoperative outcomes following thyroid cancer surgery are not well studied. Complications arising from thyroid surgery can negatively impact patient-reported outcomes and delay adjuvant treatment if needed (13,14). Some evidence suggests differences in outcomes by patient sex, with women being more likely to experience hypocalcemia, hypoparathyroidism, or recurrent laryngeal nerve (RLN) injury following thyroid surgery compared to men (7,15,16). Research on potential differences in outcomes of thyroid cancer surgery by age is limited (17-19). One study reported higher complication rates for patients aged 70 years or older undergoing total thyroidectomy for various conditions (18). However, thyroidectomy surgery has been considered safe for both young and elderly patients (17,19). While these earlier studies provide important information on postoperative outcomes of thyroid surgery by sex and age, they are limited in that they include patients with a mix of thyroid conditions and not papillary thyroid cancer explicitly, include patients of certain age ranges (e.g., >65 years), represent geographically isolated areas or single institutions, or include patients with varying access to care. There are unique considerations affecting surgical planning, techniques, and scope for patients with thyroid cancer relative to patients with other benign thyroid conditions (1,10,11). Thus, studies among patients with thyroid cancer covering a wide age range and geographic area and with universal access to care are needed to deepen our understanding of the possible associations between sex and age with postoperative outcomes in this patient population.

Differences in insurance coverage and access to medical care between different demographic groups in the U.S. may explain some of the observed disparities in thyroid cancer diagnosis (e.g., tumor stage), receipt of treatment, and survival between these patient groups in the general population (20-22). The U.S. Department of War (DoW) provides medical insurance and access to care to over 9.6 million beneficiaries of all ages through the Military Health System (MHS) and a network of civilian providers (23). Insurance coverage and access to medical care are provided regardless of a person’s socio-demographic characteristics and care is received at little to no out-of-pocket costs (23,24). The DoW population and MHS enables study of surgical outcomes of thyroid cancer where all beneficiaries have access to care among a wide range of ages and both biological sexes. For this study, we aimed to examine the association between age at diagnosis and biological sex and post-operative outcomes among patients with low-risk papillary thyroid cancer in the MHS to better understand differences previously reported in the literature. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-248/rc) (25).

Methods

Data sources

This retrospective cohort study utilized the Military Cancer Epidemiology (MilCanEpi) database, which links data from the DoW cancer registry to medical encounter data from the MHS and its supporting network of civilian providers and is described in detail elsewhere (26). Briefly, the MilCanEpi data contains detailed information on cancer diagnoses and treatment and information on medical encounters for any condition. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Uniformed Services University of the Health Sciences Institutional Review Board (No. FWA 00001628). Informed consent was waived in this retrospective study.

Study population

Eligible patients included men and women aged 18 years or older who were diagnosed with a single primary malignant papillary thyroid tumor [International Classification of Diseases-Oncology (ICD-O)-3 primary site C739 and ICD-O-3 histology 8050, 8260, 8340, 8341, 8342, 8343, 8344, 8350, 8450, and 8460] between January 1, 2001 and December 31, 2014 who received surgery as primary treatment (4). The study end date was the latest year available in MilCanEpi at the time of the study (27). We included patients with tumor node metastasis (TNM) stage T1-2N0M0 tumors to limit the effects of clinicopathologic features on the results and to account for any differences in tumor staging by age when using the consolidated American Joint Committee on Cancer (AJCC) staging system (28-31). Primary surgery was defined as partial (i.e., lobectomy or hemithyroidectomy) or total thyroidectomy received within 6 months of the cancer diagnosis (see Table S1). Six months was used to limit the effects of periods of active surveillance on surgical outcomes (12,32). Patients with surgery information in the cancer registry only and no information in the medical encounter data were excluded due to missing data on study variables and to minimize the possibility of incomplete follow-up for the study outcomes.

Study variables

Cancer information included the diagnosis date, TNM pathologic T stage, TNM pathologic N stage, and TNM pathologic M stage. When pathologic information was coded as unknown in the data, TNM clinical variables in the cancer registry were used to supplement the data. Tumor grade was not used because papillary tumors are considered well-differentiated (10). Cancer diagnosis date was the pathologic confirmation date from the cancer registry consolidated with information from the medical encounter data (33). Information on surgical treatment including the procedure date, type (partial or total thyroidectomy), surgery admission duration (<24 hours to discharge, i.e., outpatient, or ≥24 hours to discharge, i.e., inpatient), surgery care setting (military or civilian), lymph nodes examined (0–79, unknown), and final surgical margins (negative, positive, unknown) were retained. Time-to-surgery was defined as the number of days between the pathologic cancer diagnosis and thyroid surgery date. For patients with surgical procedures prior to the pathologic diagnosis date, the time interval was negative (−). Time-to-surgery was categorized as −30 to −1, 0, 1 to 30, 31 to 60, and more than 60 days for data presentation. Patient information included age at diagnosis, sex (men, women), self-reported or personnel documented race (Black, White, Asian or Pacific Islander, American Indian or Alaska Native, other) and Hispanic or Latinx ethnicity, marital status (married, single, separated, divorced, widowed), active-duty military status, sponsor’s military service branch (U.S. Air Force, Army, Navy, Marine Corps, other government), U.S. geographic region [Northeast, South, West, outside the continental United States (OCONUS)], and Elixhauser comorbid conditions diagnosed prior to the cancer (34,35). Recent history of myocardial infarction (MI) within 6 months prior to the surgery date and congestive heart failure within 30 days prior to surgery were also captured and patients with these events were excluded from the analysis to limit the effects on the outcomes (27).

Study outcomes

The primary outcomes were 30-day postoperative complications and hospital readmissions. The 30-day period was selected to allow comparison with existing surgical quality databases, such as the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) (27). Postoperative complications included general [blood transfusion, pneumonia, hemorrhage, deep vein thrombosis (DVT), pulmonary embolism (PE), other thrombosis, MI, stroke, urinary tract infection (UTI), systemic inflammatory response syndrome (SIRS), severe sepsis, or septic shock] and local thyroid [surgical site infections (SSIs), hematoma, hypocalcemia, RLN injury, and hypoparathyroidism] conditions identified in the medical encounter data with relevant International Classification of Diseases 9th edition clinical modifier (ICD-9-CM) codes (see Table S2) (9,27,36-43). Hospital readmission was captured as any inpatient record within 30 days of the index surgery, not to include the initial surgical admission.

Statistical analysis

We first compared the frequency and distribution of patient and surgery characteristics between age groups and sex using Chi-squared tests. Then, we examined the association between age at diagnosis and sex with the general and thyroid complications and readmissions using univariable and multivariable Poisson regression models with log link and robust standard errors to estimate risk ratios (RRs) and adjusted risk ratios (ARRs) with 95% confidence intervals (CIs) (44,45). Age at diagnosis was categorized as 18–39, 40–49, and 50 years or older for analysis to correspond to adolescent and young adults, middle aged adults who experience the highest incidence of thyroid cancers, and older adults. The number of patients aged 65 years or older (n=45) or 80 years or older (n<11) was too small in our study to further examine risk of outcomes among subgroups of elderly patients. Sex was binary as men or women. Multivariable models included adjustment for race-ethnicity, marital status, geographic region, active-duty military status, comorbidities, TNM T stage, surgery type (partial or total thyroidectomy), surgery admission (inpatient or outpatient), time-to-surgery, lymph nodes examined (0, 1–9, 10 or more, unknown), final surgical margin, and surgery care setting (military or private). Missing or unknown values were modeled as a separate category for the respective variable. When sample sizes permitted, we also explored associations for individual thyroid complications (e.g., hypocalcemia) using frequency data and Poisson regression models. We further restricted analysis to patients with total thyroidectomy to assess the risk of hypocalcemia and hypoparathyroidism which are more common in total procedures. For all Poisson regression models, results were considered statistically significant at the P<0.05 level when the RR or ARR and 95% CI did not include 1.00. For each main outcome model, we also assessed whether age and sex had modifying effects on each other by testing pairwise interaction terms in the regression model using dummy variables for each level of the variable. Interactions were considered statistically significant when any dummy pair had P<0.05. Analyses were conducted in SAS 9.4 (SAS Inc., Cary, NC, USA).

Results

The study included 2,041 patients with T1-2N0M0 papillary thyroid cancer (Figure 1). The average age at diagnosis was 41.7 (±12.6) years with 77.2% of patients being women. Overall, 39.3% of patients received partial thyroidectomy and 60.7% received total thyroidectomy. The distribution of study variables by age at diagnosis and biological sex are shown in Table 1. Statistically significant (P<0.05) variations in sex, race-ethnicity, marital status, active-duty military status, geographic region, comorbidity, T stage, time-to-surgery, and lymph nodes examined were noted by age at diagnosis (Table 1). Meanwhile, statistically significant variations in race-ethnicity, marital status, active-duty military status, comorbidity, and time-to-surgery were noted by biological sex (Table 1).

Figure 1 Selection of patients with low-risk papillary thyroid cancers who received surgery as primary treatment in the Military Health System, 2001–2014. CHF, congestive heart failure; MI, myocardial infarction; TNM, tumor node metastasis.

Overall, 2.3% of patients had a general complication, 12.1% of patients experienced a thyroid complication, and 13.9% had a readmission within 30 days of surgery. Figure 2 shows the frequency of the outcomes by age at diagnosis (Figure 2A) and sex (Figure 2B). There was a statistically significant difference in the frequency of thyroid complications by age (Chi-squared P=0.04) with the highest frequency among patients aged 40–49 years (14.6%) and the lowest frequency among patients aged 50 years or older (9.7%) (Figure 2A). Also, the highest rates of readmission were observed among patients aged 18–39 years (16.1%) and lowest rates among patients aged 50 years or older (9.5%) (Chi-squared P=0.001) (Figure 2A). Men had relatively lower frequencies of general (1.9% vs. 2.4%) and thyroid (9.9% vs. 12.7%) complications and higher frequencies of readmissions (15.5% vs. 13.4%) relative to women, but the differences were not statistically significant by patient sex (Figure 2B).

Figure 2 Frequency of 30-day general and thyroid specific complications and readmissions following thyroid cancer surgery by patient age at diagnosis (A) and biological sex (B) in the U.S. Military Health System, 2001–2014. (A) Complications and readmissions by patient age at diagnosis. (B) Complications and readmissions by patient sex. General complications include pneumonia, hemorrhage, deep vein thrombosis, pulmonary embolism, other thrombosis, myocardial infarction, stroke, urinary tract infection, blood transfusion, systemic inflammatory response syndrome, severe sepsis, or septic shock; thyroid complications include surgical site infection, hematoma, hypocalcemia, hypoparathyroidism, or recurrent laryngeal nerve injury. U.S., the United States.

Table 2 shows the relative risk of the outcomes by age at diagnosis and biological sex estimated from Poisson regression models. Overall, there were no statistically significant associations between age or sex and risk of general complications. While the frequency of thyroid complications varied by age, the relative risks for patients aged 40–49 and 50 years or older were not statistically different from patients aged 18–39 years when adjusted for potential confounders (Table 2). The risk of thyroid complications was not statistically different for men compared to women (Table 2). Regarding readmission, patients aged 50 years or older had lower risk (ARR =0.68; 95% CI: 0.49–0.93) compared to patients aged 18–39 years and there were no significant differences by sex (Table 2). There were no statistically significant interaction effects between age and sex in the pairwise testing in the multivariable model (all P_interaction>0.05).

Examining specific thyroid complications, the overall frequency of hypocalcemia was 10.1%, hypoparathyroidism was 4.9%, hematoma was 1.0%, RLN injury was 0.7%, and SSI was 0.7%. In the data, 12.2% of hypoparathyroidism events and 16.1% of hypocalcemia events occurred among patients with partial thyroidectomy, while the remaining were observed among patients with total thyroidectomy. Patients aged 50 years or older had significantly lower risks of hypocalcemia (RR =0.69; 95% CI: 0.48–1.00; P=0.049) and hypoparathyroidism (RR =0.39; 95% CI: 0.20–0.74) relative to patients aged 18–39 years in univariable analysis, however only the association for hypoparathyroidism was significant in adjusted models (ARR =0.37; 95% CI: 0.19–0.73) (Table 3). There were no statistically significant differences in hypocalcemia or hypoparathyroidism by sex (Table 3). When restricted to patients with total thyroidectomy, the associations between age and sex with risk of hypocalcemia and hypoparathyroidism were similar to the main results (Table S3). Regarding hematoma, the frequencies among individual age groups were too small to conduct regression analysis (n<11). By sex, men experienced a higher frequency of hematoma (2.2% vs. 0.8%; Chi-squared P=0.01) which was statistically significant in the univariable Poisson regression model (RR =2.82; 95% CI: 1.22–6.48 vs. women; data not shown), but could not be evaluated in a multivariable model. No analysis was conducted for RLN injury or SSI due to low frequency in the study sample.

Discussion

Age has been studied in association with outcomes of thyroid surgery for both benign and malignant diseases in the general U.S. population (15,17-19). To our knowledge, there is little data on age in association with postoperative complications or readmissions specifically for low-risk thyroid cancer. In our study in the MHS, we found similar rates and risk of general complications across age groups of patients with T1-2N0M0 papillary thyroid cancer when adjusted for comorbidity and other potential confounders. This agrees with the literature on age and risk of general cardiac, respiratory, and circulatory complications arising from thyroid surgery and supports the relative safety of these procedures in adults (15,17-19).

Meanwhile, the frequency of thyroid complications varied by age in our study with the highest rates among patients aged 40–49 years and the lowest rates among patients aged 50 years or older. In multivariable analysis, patients aged 50 years or older had a statistically significant lower risk of hypoparathyroidism compared patients aged 18–39 years. Another important consideration is the duration of hypoparathyroidism and whether it resolves relatively quickly with treatment (i.e., transient) or requires long-term management (i.e., definite) (46). Since our study outcome was 30-day complications, additional studies with long-term follow-up are needed to assess whether there are age-based differences in transient or definite hypoparathyroidism following surgery for low-risk papillary thyroid tumors. Nevertheless, one hypothesis for lower rates of postoperative hypoparathyroidism in older patients is that younger patients may have larger tumors requiring bulkier resection and more extensive lymph node dissection which could increase the risk of localized complications (46). However, we included patients with T1-2N0M0 disease and included adjustment for lymph nodes examined in our analysis to limit such effects. Other factors which may influence the risk of postoperative hypoparathyroidism include surgeon volume, intraoperative blood loss, and genetic predisposition which were not available in our study (46). Further research is needed to determine the underlying mechanisms for this observation and the possible role of factors other than access to care such as cognition, health behaviors (e.g., smoking), care seeking behavior, patient-provider communication, and biological features which have been shown to affect thyroid cancer development and response to treatment (47-50).

We also observed differences in the frequency of 30-day hosptial readmission across age groups for patients with low-risk thyroid cancer in our study. The statistically significant 32% lower risk of readmission for older patients relative to those aged 18–39 years may be related to the overall lower rate of thyroid complications among older patients in the study. Readmission may also be related to underlying medical conditions, complication symptoms and severity, their duration, and their impact on patient-reported outcomes such as physical function and health-related quality of life (51). However, we observed no statistical difference in rates of general complications, adjusted for patient comorbidity in regression models, and assessed the outcomes over a short period (i.e., 30 days) which may minimzie the effects of underlying health conditions and complication duration on the results. Nevertheless, we did not have data on complication severity or patient-reported outcomes to determine whether they differed by age and may account for the observation. Future research is needed to confirm the finding of lower readmission rates among patients aged 50 years or older and to elucidate possible reasons for the association.

There is little information on possible sex differences in thyroid surgery or surgical outcomes in U.S. populations (6-8,15). Because of larger or more aggressive tumors in men than those among women (7,8), men may be more likely to have total rather than partial thyroidectomy which may lead to higher rates of some complications (7,9,13). Our study suggests that there were no overall differences in postoperative complications or readmissions between men and women with T1-2N0M0 papillary thyroid cancers after adjustment for surgery extent and other confounding variables. However, there was a possibly higher frequency of neck hematoma among men relative to women although the number of patients affected was low. This is consistent with other studies of thyroid surgery which report sex differences in postoperative outcomes related to anatomy and hormone differences between men and women (15,52). Future research in larger cohorts of patients with low-risk thyroid cancers is needed to identify whether there are sex differences in postoperative outcomes and their contributing factors.

In this study, we used comprehensive cancer registry and medical encounter information to study possible age and sex variations in postoperative outcomes for patients with T1-2N0M0 papillary thyroid cancer. However, there are several limitations to consider. First, the study included cancers diagnosed between 2001 and 2014, which may not reflect current surgical management of thyroid cancer such as increased use of partial thyroidectomy and active surveillance prior to surgery (11,53). Nevertheless, study of surgical outcomes in the available years of data my inform current and future management of papillary thyroid cancer. Second, the MilCanEpi database does not include details such as time in operating room, surgeon volume, or patient baseline performance status which may impact surgical quality. Thus, we cannot rule out the effect of these and other unmeasured confounding factors on the outcomes. Next, we used ICD-9 diagnosis codes to query the data for complications. This method has been used for administrative databases with overall good performance for certain outcomes (40,41,43,54,55). However, the accuracy and validity of using ICD-9 diagnosis codes for thyroid specific complications is unknown. Thus, it may underestimate complications in the study population or misclassify patients on the outcomes. Likewise, errors in coding or reporting could lead to misclassification of surgery or the incorrect estimation of the outcomes. However, the cancer registry and claims data are reviewed for accuracy by registrars and administrators, respectively, and any such errors are not likely to differ between patient groups. Also, the observed complication rates in our study are consistent with those reported in the literature (15,19,56,57). Thus, it is unlikely that any such errors significantly affect our results. Next, our study is limited to outcomes in the 30-day postoperative period which is consistent with the ACS-NSQIP. However, some complications may be transient whereas other complications may persist having different implications for treatment and long-term management. Thus, we cannot draw inference about long-term complications and possible differences by age or sex. Lastly, while the DoW population offers a unique patient pool to study postoperative outcomes of thyroid cancer, the patients treated within the MHS may differ from those in the general population in terms of age, overall health status, or other unmeasured factors. Thus, the results may not be generalizable to the entire U.S. population.

Conclusions

In the MHS, patients aged 50 years or older had lower rates of thyroid complications and readmissions relative to young adult patients with low-risk papillary thyroid cancer. Meanwhile, no overall differences were observed by patient sex. Future research in comprehensive health systems using contemporary datasets is needed to confirm the results and explore the factors contributing to age differences in postoperative outcomes of thyroid cancer surgery.

Acknowledgments

The authors thank the Joint Pathology Center (JPC) for providing the Department of War (DoW) cancer registry data and the Defense Health Agency (DHA) for providing the Military Health System (MHS) data repository (MDR) data. The authors thank ICF International, the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF, Inc.), and the Uniformed Services University of the Health Sciences (USUHS) for data linkage and hosting.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-248/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-248/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-248/prf

Funding: This work was supported by the Murtha Cancer Center Research Program (MCCRP) of the Department of Surgery, Uniformed Services University of the Health Sciences (USUHS) under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF, Inc.), grant numbers HHU0001-16-2-0014 and HU0001-18-2-0032. The funding agency had no role in the study design; in the collection, analysis, and interpretation of data; or in the writing of the report.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-248/coif). Y.L.E., S.D., K.Z. are current employees of the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, assertions, opinions, or policies of the Uniformed Services University of the Health Sciences, the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of War, or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. government. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Uniformed Services University of the Health Sciences Institutional Review Board (No. FWA 00001628). Informed consent was waived in this retrospective study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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