Abstract
Objective
The prognostic role of age in laryngeal squamous cell carcinoma (LSCC) remains unclear, particularly regarding recurrence after total laryngectomy (TL). This study evaluated the impact of age on LSCC outcomes following TL.
Study Design
Retrospective single‐institution cohort study.
Setting
Academic tertiary medical center.
Methods
We reviewed LSCC patients who underwent TL between 1999 and 2024 grouped by age at surgery: <45 versus ≥45 years. Overall survival (OS) and disease‐free survival (DFS) were assessed using Kaplan‐Meier and log‐rank tests. Site‐specific recurrence was analyzed using cumulative incidence functions with Gray's test. Multivariable competing risk regressions with the Fine‐Gray model evaluated the association of age with recurrence.
Results
Among 646 TL patients, 17 were <45 years. Five‐year OS was 82.0% for <45 versus 54.3% for ≥45 (P = .023); 5‐year DFS was 70.2% versus 42.9% (P = .023). There was no significant difference in overall recurrence between age groups. Competing risk analysis showed no significant difference in cumulative incidence of local, regional, or distant recurrence. In multivariable analysis adjusting for T stage, N stage, laryngectomy indication, and adjuvant therapy, younger age was not independently associated with recurrence (sHR 0.55, 95% CI 0.18‐1.63, P = .28).
Conclusions
Younger LSCC TL patients demonstrated improved OS and DFS despite comparable recurrence risk. Age was not independently associated with recurrence, suggesting that improved survival in younger patients does not reflect differences in oncologic control. These findings highlight the importance of distinguishing survival from recurrence outcomes and underscore the need for larger studies evaluating survival differences in younger patients.
Keywords: age factors, laryngeal cancer, recurrence patterns, total laryngectomy, young adults
Laryngeal cancers account for one‐third of all head and neck cancers in the United States, and laryngeal squamous cell carcinoma (LSCC) comprises 90% of laryngeal cancers. 1 , 2 The incidence of LSCC significantly increases with age, with the peak burden of disease occurring after age 65. 3 , 4 , 5 However, the relative incidence of LSCC is rising in young patients. 6 In the case of advanced LSCC, total laryngectomy (TL), or surgical removal of the larynx, is often the curative approach. 7 However, recurrence remains common following TL, with rates as high as 30% to 50%. 2 , 8
Few studies have examined the impact of age on presentation and prognosis of LSCC and there is a lack of consensus as to whether younger patients have similar oncologic outcomes compared to older patients. While some studies report more advanced disease and equal or lower survival rates in young patients, 9 , 10 others have found less aggressive disease and fewer recurrences. 10 , 11 , 12 These incongruent findings likely reflect the rarity of younger LSCC patients, and outcomes following TL remain poorly characterized. 12 , 13
Given evidence that age may influence LSCC outcomes, the current study aims to evaluate survival outcomes and recurrence patterns in young LSCC patients after TL within a single institution over a 25‐year period. Investigating these outcomes is important for informing LSCC management and patient counseling.
Methods
This study was approved by the Vanderbilt University Medical Center Institutional Review Board (IRB #211379). We conducted a retrospective chart review of all patients who underwent TL from January 1999 to December 2024 at Vanderbilt University Medical Center (VUMC). Charts were reviewed through August 2024, and survival outcomes reflect follow‐up available at that time. Patients were excluded if they had non‐SCC laryngeal carcinomas, primary nononcologic laryngeal conditions, and if the purpose of surgery was for a nonfunctional larynx as a consequence of prior oncologic treatment. Patients were also excluded if their primary malignancy originated outside of the larynx (eg, oropharyngeal carcinoma).
LSCC patients were categorized into two groups based on age at time of surgery, <45 and ≥45. Although the National Comprehensive Cancer Network (NCCN) Adolescent and Young Adult (AYA) Oncology Guideline defines young adults as ages 15 to 39 years, 14 prior head and neck cancer literature has shown that oral and oropharyngeal cancers comprise approximately 0.4% to 3.6% of all cancers in patients under 40 and increases to 6.7% under the age of 45. 15 , 16 Given disease rarity and adequate sample size for statistical estimates, we defined younger‐onset disease as <45 years. In addition, multiple prior studies of early‐onset oral cavity cancer have used 45 years of age as a cutoff for young patients. 16 , 17 , 18
Patient, oncologic, treatment, and outcome characteristics were systematically documented. Recorded variables included patient age, race, smoking history, alcohol history, prior treatment history, oncologic subsite, pathologic tumor, node, metastasis (TNM) staging, neck dissection, number of positive lymph nodes, tumor recurrence information, and adjuvant treatment. TNM staging was determined according to the American Joint Committee on Cancer (AJCC) eighth edition criteria. Recurrence sites were classified as local, regional, or distant. Adjuvant treatment was categorized as none, radiotherapy alone, chemoradiotherapy (CRT), or chemotherapy alone. Patients receiving chemotherapy alone as adjuvant therapy were not candidates for radiation due to clinical factors. Patients who received palliative chemotherapy were classified as having received no adjuvant therapy. Key dates including date of surgery and date of recurrence were recorded.
Overall survival (OS) and disease‐free survival (DFS) were estimated using Kaplan‐Meier curves and compared between age groups using log‐rank tests. Recurrence was analyzed using a competing risks framework. Cumulative incidence functions were used to estimate the probability of site‐specific recurrence over time, including local, regional, and distant recurrence, with death without recurrence treated as a competing event. Comparisons between age groups were performed using Gray's test. Exploratory subgroup analyses were performed stratified by laryngectomy indication (primary vs salvage), and results are presented in the supplemental figures. Multivariable competing risk regression was performed using the Fine‐Gray subdistribution hazards model to evaluate whether younger age was independently associated with recurrence. Subdistribution hazard ratios (sHR) with 95% confidence intervals were calculated. Covariates included age group, T stage, N stage, laryngectomy indication, and adjuvant treatment, with reference groups defined as age ≥45 years, T1 stage, N0 stage, primary TL, and no adjuvant therapy. Patients with TX, Tis, or NX disease were excluded from multivariable analyses. All analyses were conducted using R (R Foundation for Statistical Computing).
Results
Patient and Clinical Characteristics
Over the 25‐year study period, 646 patients underwent TL for LSCC. Of these, 17 (2.6%) were under the age of 45 and 629 (97.4%) were ages 45 and older. The mean age of the 2 groups, respectively, were 41.1 ± 3.3 and 62.9 ± 9.0. Table 1 summarizes the patient demographics and prior treatment history. The younger cohort had a significantly higher proportion of non‐white individuals (29.4% vs 10.2%, P = .027). Otherwise, there were no significant differences between age groups with respect to sex, smoking history, alcohol use, or prior treatment with chemotherapy and/or radiotherapy. Importantly, the proportion of patients undergoing primary versus salvage TL was similar between age groups (52.9% vs 34.2% primary TL, P = .124).
Table 1.
Baseline Patient Demographics and Disease History, Stratified by Age Group (<45 vs ≥45)
| Characteristic | Overall cohort | <45 | ≥45 | P a | |
|---|---|---|---|---|---|
| Number of patients, n (%) | 646 | 17 | 629 | ||
| Age, mean ±SD | 62.35 ± 9.58 | 41.12 ± 3.33 | 62.92 ± 9.03 | ||
| Sex, n (%) | .527 | ||||
| Male | 529 (81.9) | 13 (76.5) | 516 (82.0) | ||
| Female | 117 (18.1) | 4 (23.5) | 113 (18.0) | ||
| Race, n (%) | .027 | ||||
| White | 577 (89.3) | 12 (70.6) | 565 (89.8) | ||
| Non‐white | 69 (10.7) | 5 (29.4) | 64 (10.2) | ||
| Smoking history, n (%) | .365 | ||||
| Ever | 584 (90.4) | 15 (88.2) | 569 (90.5) | ||
| Never | 39 (6.0) | 2 (11.8) | 37 (5.9) | ||
| Not reported | 23 (3.6) | 0 (0.0) | 23 (3.7) | ||
| Alcohol history, n (%) | .688 | ||||
| Ever | 358 (55.4) | 11 (64.7) | 347 (55.2) | ||
| Never | 240 (37.2) | 6 (35.3) | 234 (37.2) | ||
| Not reported | 48 (7.4) | 0 (0.0) | 48 (7.6) | ||
| Prior treatment, n (%) | .384 | ||||
| None | 204 (31.6) | 8 (47.1) | 196 (31.2) | ||
| Chemo only | 23 (3.6) | 1 (5.9) | 22 (3.5) | ||
| RT only | 190 (29.4) | 4 (23.5) | 186 (29.6) | ||
| CRT | 229 (35.4) | 4 (23.5) | 225 (35.8) | ||
| TL indication, n (%) | .124 | ||||
| Primary | 224 (34.7) | 9 (52.9) | 215 (34.2) | ||
| Salvage | 422 (65.3) | 8 (47.1) | 414 (65.8) | ||
Abbreviations: CRT, chemoradiation therapy; RT, radiotherapy.
P‐values calculated using Fisher's exact test for categorical variables and Welch's t‐test for age.
Pathological tumor characteristics are detailed in Table 2. Both age groups demonstrated similar tumor subsite distributions, with the majority of patients having transglottic tumors (52.9% for age <45 vs 53.4% for age ≥45, P = .982). Supraglottic tumors are known for high regional metastatic potential due to a rich lymphatic network. 19 , 20 Supraglottic tumors, including transglottic involvement, were present in 70.0% of younger patients compared to 67.9% of older patients; this difference was not statistically significant (Fisher's exact test, P = .88). Additionally, the 2 age groups exhibited comparable tumor and lymph node staging (pT3‐T4: 76.5% vs 78.8%, P = .910; pN0: 52.9% vs 59.5%, P = .745). When reported, there were no significant differences in extranodal extension (ENE) or perineural invasion (PNI) between age groups. No younger patients had reported lymphovascular invasion (LVI, 0.0% vs 22.7%, P = .036), although interpretation is limited by the small cohort and incomplete reporting.
Table 2.
Patient Pathologic Tumor Characteristics, Stratified by Age Group (<45 vs ≥45 Years)
| Characteristic | Overall cohort | <45 | ≥45 | P a | |
|---|---|---|---|---|---|
| Number of patients, n | 646 | 17 | 629 | ||
| Tumor site, n (%) | .982 | ||||
| Glottis | 90 (13.9) | 2 (11.8) | 88 (14.0) | ||
| Supraglottis | 152 (23.5) | 5 (29.4) | 147 (23.4) | ||
| Subglottis | 9 (1.4) | 0 (0.0) | 9 (1.4) | ||
| Hypopharynx | 48 (7.4) | 1 (5.9) | 47 (7.5) | ||
| Transglotticb | 345 (53.4) | 9 (52.9) | 336 (53.4) | ||
| Unspecified | 2 (0.3) | 0 (0.0) | 2 (0.3) | ||
| Tumor stagec, n (%) | .910 | ||||
| T1 | 31 (4.8) | 1 (5.9) | 30 (4.8) | ||
| T2 | 99 (15.3) | 3 (17.6) | 96 (15.3) | ||
| T3 | 202 (31.3) | 5 (29.4) | 197 (31.3) | ||
| T4 | 307 (47.5) | 8 (47.1) | 299 (47.5) | ||
| TX | 6 (0.9) | 0 (0.0) | 6 (1.0) | ||
| Tis | 1 (0.2) | 0 (0.0) | 1 (0.2) | ||
| Lymph node staged, n (%) | .745 | ||||
| N0 | 383 (59.3) | 9 (52.9) | 374 (59.5) | ||
| N1 | 58 (9.0) | 1 (5.9) | 57 (9.1) | ||
| N2 | 102 (15.8) | 4 (23.5) | 98 (15.6) | ||
| N3 | 76 (11.8) | 3 (17.6) | 73 (11.6) | ||
| NX | 27 (4.2) | 0 (0.0) | 27 (4.3) | ||
| Extranodal extensione, n (%) | .762 | ||||
| No | 333 (51.5) | 10 (58.8) | 323 (51.4) | ||
| Yes | 123 (19.0) | 2 (11.8) | 121 (19.2) | ||
| Not reported | 190 (29.4) | 5 (29.4) | 185 (29.4) | ||
| Lymphovascular invasione, n (%) | .036 | ||||
| No | 398 (61.6) | 13 (76.5) | 385 (61.2) | ||
| Yes | 143 (22.1) | 0 (0.0) | 143 (22.7) | ||
| Not reported | 105 (16.3) | 4 (23.5) | 101 (16.1) | ||
| Perineural invasione, n (%) | .273 | ||||
| No | 272 (42.1) | 6 (35.3) | 266 (42.3) | ||
| Yes | 280 (43.3) | 6 (35.3) | 274 (43.6) | ||
| Not reported | 94 (14.6) | 5 (29.4) | 89 (14.1) | ||
P‐values calculated using Fisher's exact test.
Transglottic defined as involvement of more than one laryngeal subsite; may include extension to adjacent structures.
T stage categorized according to AJCC 8th edition; T4 includes T4a and T4b.
N stage categorized according to AJCC 8th edition; N2 includes N2a‐N2c, and N3 includes N3a‐N3b.
Extranodal extension (ENE), lymphovascular invasion (LVI), and perineural invasion (PNI) categorized as present, absent, or not reported. “Not reported” indicates the feature was not explicitly commented on in the pathology report.
Table 3 summarizes surgical and medical management of patients. There were no statistically significant differences in the frequency or laterality of neck dissections (P = .522). These findings suggest comparable surgical management between age groups. Nodal yield analyses were restricted to patients with documented neck dissection and available pathology‐reported lymph node counts. Among patients undergoing neck dissection with documented nodal yield (n = 606), the median number of lymph nodes examined was 40 (IQR 27‐60) in younger patients and 34 (IQR 20‐54) in older patients (P = .315). The proportion of patients with at least one positive lymph node was also similar (47.1% vs 36.1%, P = .444). Adjuvant treatment patterns did not differ significantly by age (P = .210). Most patients in both groups did not receive adjuvant therapy (64.7% vs 80.4%).
Table 3.
Treatment and Surgical Characteristics, Stratified by Age Group (<45 vs ≥45 Years)
| Characteristic | Overall cohort | <45 | ≥45 | P a | |
|---|---|---|---|---|---|
| Number of patients, n (%) | 646 | 17 | 629 | ||
| Neck dissection, n (%) | .522 | ||||
| None | 40 (6.2) | 1 (5.9) | 39 (6.2) | ||
| Unilateral | 113 (17.5) | 1 (5.9) | 112 (17.8) | ||
| Bilateral | 493 (76.3) | 15 (88.2) | 478 (76.0) | ||
| Lymph node yield, median (IQR)b | 34.5 (20‐54) | 40 (27‐60) | 34 (20‐54) | .315 | |
| Patients with ≥1 positive nodes, n (%)b | .444 | ||||
| No | 411 (63.6) | 9 (52.9) | 402 (63.9) | ||
| Yes | 235 (36.4) | 8 (47.1) | 227 (36.1) | ||
| Adjuvant treatment, n (%) | .210 | ||||
| None | 517 (80.0) | 11 (64.7) | 506 (80.4) | ||
| RT only | 58 (9.0) | 3 (17.6) | 55 (8.7) | ||
| Chemo only | 3 (0.5) | 0 (0.0) | 3 (0.5) | ||
| CRT | 68 (10.5) | 3 (17.6) | 65 (10.3) | ||
Abbreviation: IQR, interquartile range.
P‐values calculated using Fisher's exact test for categorical variables and Wilcoxon rank‐sum test for continuous variables.
Nodal yield analyses were restricted to patients with documented neck dissection and available pathology‐reported lymph node counts.
Overall Recurrence and Survival Outcomes
With a median follow‐up of 49 months (IQR 10‐55, maximum 250), 204 patients (31.6%) experienced recurrent disease after TL. When stratified by age group, this included 3 (17.6%) patients under 45 and 201 (32.0%) patients ages 45 and older (Table 4). There was no statistically significant difference in overall recurrence between the 2 groups (P = .293). OS and DFS were assessed by age group using Kaplan‐Meier analyses and log‐rank tests. In the overall cohort, patients under 45 had a significantly improved 5‐year OS of 82.0% compared to 54.3% for those ages 45 and older (log‐rank P = .023, Figure 1A). Younger patients also had significantly improved DFS compared to older patients, with a 5‐year rate of 70.2% to 42.9%, respectively (log‐rank P = .023, Figure 1B). When stratified by primary versus salvage TL, differences in OS between age groups were not statistically significant in either the primary (P = .12) or salvage (P = .09) cohorts. In contrast, DFS differed by age group in the salvage cohort (P = .026) but not in the primary cohort (P = .39) (Figure. S1A‐S1D). However, subgroup sizes in the younger cohort were small (n = 9 primary, n = 8 salvage).
Table 4.
Recurrence Patterns (Overall and by First Site), Stratified by Age Group (<45 vs ≥45 Years)
| Characteristic | Overall cohort | <45 | ≥45 | P a | |
|---|---|---|---|---|---|
| Number of patients, n | 646 | 17 | 629 | ||
| Recurrence, n (%) | .293 | ||||
| No | 442 (68.4) | 14 (82.4) | 428 (68.0) | ||
| Yes | 204 (31.6) | 3 (17.6) | 201 (32.0) | ||
| Recurrence location, n (%) | .018 | ||||
| Local | 109 (16.7%) | 0 (0.0%) | 109 (17.2%) | ||
| Regional | 27 (4.1%) | 2 (11.8%) | 25 (3.9%) | ||
| Distant | 72 (11.0%) | 1 (5.9%) | 71 (11.2%) | ||
P‐values calculated using Fisher's exact test.
Figure 1.
Kaplan‐Meier curves stratified by age group for (A) OS and (B) DFS. Curves are truncated at 120 months for clarity (follow‐up IQR, 10‐55 months; maximum follow‐up, 250 months). DFS, disease‐free survival; OS, overall survival.
Site‐Specific Recurrence Patterns
Recurrence characteristics by age group are summarized in Table 4. Overall recurrence did not differ between age groups (P = .293), while recurrence location differed descriptively (P = .018). In the younger cohort, no patients developed local recurrence, while regional recurrence occurred more frequently (11.8% vs 3.9%). Distant recurrence rates were similar between groups.
Cumulative incidence analyses were conducted to evaluate the time‐dependent risk of site‐specific recurrence, with death without recurrence treated as a competing risk (Figure 2). There were no statistically significant differences in the cumulative incidence of local (P = .061), regional (P = .083), or distant recurrence (P = .490) between age groups. At 5 years, the cumulative incidence of local recurrence was 0.0% in younger patients and 18.3% in older patients, regional recurrence was 13.5% versus 4.1%, and distant recurrence was 10.0% versus 11.9%, respectively. The cumulative incidence of death without recurrence was higher in older patients, although this did not reach statistical significance (P = .118). When stratified by primary versus salvage TL, patterns differed by treatment context (Supplemental Figure S2A‐S2B, available online). In the primary TL cohort, regional recurrence differed significantly by age group (P = .003), whereas no statistically significant differences were observed in the salvage cohort. These exploratory subgroup findings should be interpreted cautiously given the small sample size.
Figure 2.
Cumulative incidence functions for location‐specific recurrence by age group, accounting for death without recurrence as a competing risk. Curves are truncated at 120 months for clarity.
Association Between Age and Recurrence
A multivariable competing risk regression model (Fine‐Gray method) was performed to evaluate whether age was independently associated with recurrence, treating death without recurrence as a competing event (Table 5). Adjusting for T stage, N stage, laryngectomy indication, and adjuvant treatment, younger age was not independently associated with overall recurrence (sHR 0.55, 95% CI 0.18‐1.63, P = .28). Higher N stage was independently associated with increased recurrence risk, with stepwise increases observed for N1 (sHR 1.76, P = .018), N2 (sHR 2.06, P < .001), and N3 disease (sHR 2.53, P < .001). Salvage TL was also associated with increased recurrence risk compared to primary status (sHR 2.26, 95% CI 1.48‐3.43, P < .001). Inclusion of tobacco and alcohol use in a sensitivity analysis did not alter the association between age and recurrence (Supplemental Table S1, available online).
Table 5.
Multivariable Fine–Gray Competing Risks Regression for Overall Recurrence
| Variablea | sHRb (95% CI) | P | |
|---|---|---|---|
| Age group | <45 | 0.55 (0.18‐1.63) | .28 |
| T stagec | |||
| T2 | 1.54 (0.63‐3.78) | .34 | |
| T3 | 1.44 (0.61‐3.42) | 0.41 | |
| T4 | 2.21 (0.95‐5.15) | .067 | |
| N stagec | |||
| N1 | 1.76 (1.10‐2.80) | .018 | |
| N2 | 2.06 (1.38‐3.08) | <.001 | |
| N3 | 2.53 (1.58‐4.06) | <.001 | |
| TL indication | Salvage | 2.26 (1.48‐3.43) | <.001 |
| Adjuvant therapy | RT only | 1.29 (0.71‐2.35) | .41 |
| Chemo only | 9.98 (2.01‐49.50) | .005 | |
| CRT | 1.60 (0.95‐2.68) | .077 |
Reference groups: age ≥45 years, T1, N0, primary TL, and no adjuvant therapy.
sHR = subdistribution hazard ratio from Fine–Gray competing risk regression. Competing event was death without recurrence.
TX, Tis, and NX categories were excluded from the model.
Given the small number of recurrence events in the younger cohort, individual cases are presented to provide clinical context. There were three patients <45 who developed recurrence, including two with regional recurrence and one with distant recurrence. Patient 1 was a 38‐year‐old male with a 1‐month history of supraglottic LSCC. He underwent primary TL with bilateral neck dissection. Final pathology showed pT4aN3b disease with 11/19 positive lymph nodes on the right, 3/23 positive nodes on the left, and negative margins. He was recommended for adjuvant radiation therapy, but developed extensive regional recurrence 2 months after surgery and was transitioned to hospice care. Patient 2 was a 41‐year‐old female with a 3‐month history of transglottic LSCC who underwent primary TL with bilateral neck dissection. Final pathology showed pT4aN2b disease with 2/45 positive lymph nodes on the left and negative margins. She received adjuvant chemoradiation therapy but developed regional recurrence at 14 months, which was treated with a radical right neck dissection. She had a second regional recurrence 13 months later, and was treated with combined immunotherapy and chemotherapy. Patient 3 was a 44‐year‐old male with a 1‐month history of recurrent glottic LSCC previously treated with chemoradiation 2 years prior. He underwent salvage TL with bilateral neck dissection. Final pathology showed pT2N0 disease with no positive lymph nodes retrieved. He did not receive adjuvant therapy. He developed distant mediastinal recurrence 34 months after surgery and subsequently died despite palliative treatment. These individual cases are descriptive and should be interpreted in the context of the overall analyses, which demonstrated no independent association between age and recurrence despite improved survival in younger patients.
Discussion
In this single institution, retrospective study spanning 25 years and including 646 LSCC patients treated with TL, patients under 45 demonstrated significantly improved OS and DFS compared to those 45 and older. Younger age was not independently associated with recurrence, and overall recurrence did not differ between age groups. Although recurrence location differed descriptively, with higher rates of regional recurrence in younger patients, these differences did not persist in cumulative incidence or adjusted analyses. Taken together, these findings suggest that the improved survival observed in younger TL patients is unlikely to be explained by differences in oncologic control.
Young patients make up a small proportion of LSCC cases. 6 , 9 , 10 , 11 , 12 The prevalent primary anatomic tumor site in young head and neck squamous cell carcinoma (HNSCC) patients is the oral cavity; accordingly, much of the age‐focused literature centers on that population. Our series of 646 TL patients represents one of the largest single‐institution studies of LSCC outcomes. Unlike many large database studies, our cohort provides granular recurrence data and relatively consistent surgical management, offering an opportunity to assess age‐related differences in survival and recurrence patterns with long‐term follow‐up. Prior studies have suggested that younger LSCC patients present with more advanced disease or different etiologic profiles. 9 The notion that young HNSCC patients differ in disease etiology is not limited to LSCC; studies on oral squamous cell carcinoma patients have found that young patients without classical risk factors like smoking and alcohol use tend to be younger than 45. 18 In our cohort, we did not find any differences in these risk factors between age groups. Importantly, older patients did not present with more advanced disease based on pathologic T stage or a greater burden of distant recurrence, suggesting that differences in tumor extent or dissemination do not account for the observed survival disadvantage. Notably, our younger cohort had a higher proportion of non‐white patients (29.4% vs 10.2%), which aligns with broader population‐based studies showing that Black patients tend to be diagnosed with LSCC at younger ages than White patients. 21 These patterns warrant further study to assess potential contributions of socioeconomic status, environmental exposures, or biology.
Findings on age as a prognostic factor in LSCC have been mixed, with some studies showing no difference after adjusting for stage and treatment. 11 , 13 In contrast, others have reported improved outcomes in younger patients, consistent with our observed differences in OS and DFS. 10 , 12 Few studies have specifically evaluated the relationship between age and recurrence in LSCC. In a large single‐center study from Norway, patients under 60 years paradoxically had higher recurrence risk despite improved survival. 22 Our results demonstrate that younger LSCC patients do not experience a higher overall burden of recurrence following TL, and age was not independently associated with recurrence after adjustment. Although descriptive differences in recurrence patterns were observed, these did not persist in time‐to‐event or multivariable analyses, suggesting these patterns are unlikely to account for the observed survival differences. The significant association between adjuvant chemotherapy alone and recurrence likely reflects confounding by indication, as patients receiving chemotherapy alone were not candidates for standard adjuvant radiotherapy.
The survival advantage observed in younger LSCC patients in the setting of comparable recurrence should not be interpreted as a function of younger age alone, as TL for advanced LSCC represents a disease state with substantial long‐term morbidity. Rather, these findings suggest that differences in treatment tolerance, recovery, and overall physiologic state may contribute to survival outcomes across age groups. The cumulative incidence of death without recurrence trended higher in older patients and may reduce the observed incidence of recurrence by limiting the time at risk for recurrence. When stratified by primary versus salvage TL, survival outcomes differed from those observed in the overall cohort. Younger patients demonstrated improved DFS in the salvage cohort but not in the primary cohort, while no significant differences in OS were observed within either subgroup. Primary and salvage TL represent distinct clinical contexts with differences in prior treatment exposure and disease characteristics that may influence recurrence and survival outcomes. However, the subgroup analyses in this study were further limited by small sample sizes. Future studies should evaluate age‐related differences in treatment tolerance, functional recovery, and post‐recurrence management.
While these findings provide insight into age‐related recurrence patterns, several limitations merit consideration. As with prior studies examining young LSCC populations, our work is limited by the small number of younger patients and recurrence events. Consequently, confidence intervals were wide, reflecting limited statistical power. Although younger age was not independently associated with recurrence, clinically meaningful differences in recurrence cannot be excluded. Therefore, these findings should be considered hypothesis‐generating rather than definitive evidence of biologically distinct patterns in younger patients. We also recognize that our single‐institution, retrospective study design is subject to bias in patient selection, treatment decisions, and follow‐up. Moreover, with a 25‐year study period, treatment standards and adjuvant therapy protocols may have evolved, confounding associations between age and outcomes. An additional limitation of this study is its restriction to patients who underwent TL. Selection of patients for disease management may differ by age, and cannot be controlled for in this retrospective study design, which could contribute to potential cohort imbalances despite multivariable adjustment. Younger patients may be more likely to undergo surgical management, whereas older patients may be treated non‐operatively or with palliative intent, potentially influencing survival comparisons. We also did not evaluate initial clinical stage or treatment‐selection decisions among patients undergoing salvage TL, which may influence recurrence patterns and should be explored in future studies. Importantly, rates of primary versus salvage laryngectomy did not differ significantly between age groups, suggesting that broad treatment pathway differences may not fully explain the observed findings. However, residual confounding related to age‐based treatment selection cannot be excluded.
Overall, while the etiologies and management of LSCC in young patients require further research, survival outcomes in this population following TL appear favorable despite comparable recurrence risk. These findings suggest that the survival advantage observed in younger patients is unlikely to be explained by differences in oncologic control alone. Continued surveillance remains important across age groups, and larger multi‐institutional studies with detailed recurrence data will be necessary to better define the factors underlying age‐related differences in survival and to inform management of this understudied patient population.
Author Contributions
Clara D. Si, conceptualization, investigation, data analysis, writing—original draft, writing—revision; Whitney Jin, investigation, writing—revision; Brooke Swain, investigation, writing—revision; Jean‐Nicolas Gallant, investigation, writing—revision; Robert J. Sinard, writing—revision; Eben L. Rosenthal, writing—revision; Sarah L. Rohde, writing—revision; Kyle Mannion, writing—revision; Alexander J. Langerman, writing—revision; Michael C. Topf, conceptualization, data analysis, writing—revision, funding acquisition.
Disclosures
Competing interests
None.
Funding source
This work was supported by a National Cancer Institute (NCI) K08 Career Development Award—5K08CA293255‐02.
Supporting information
Supporting File 1.
Supporting File 2.
Supplemental Table 1. Multivariable Fine–Gray competing risks regression for overall recurrence including tobacco and alcohol history.
Acknowledgments
This work was supported by a National Cancer Institute (NCI) K08 Career Development Award−5K08CA293255‐02.
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Associated Data
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Supplementary Materials
Supporting File 1.
Supporting File 2.
Supplemental Table 1. Multivariable Fine–Gray competing risks regression for overall recurrence including tobacco and alcohol history.