Abstract
Objectives:
There has been an increase in young non-smokers (YNS) who develop oral cavity squamous cell carcinomas (OSCC). Oncological outcomes in YNS are controversial and etiology has not been well-defined. We hypothesize that the etiology of cancer development in YNS and their poor outcome is related to an impaired immune system.
Materials and Methods:
From a database of 2073 OSCC patients treated with primary surgery between 1985-2015, 9% were young patients. We categorized patients as: ≤40 years-old/non-smokers (n=100), ≤40 years-old/smokers (n=80), >40 years-old/non-smokers (n=595) and >40 years-old/smokers (n=1298). Patient and tumor variables were used to calculate propensity scores and stabilized inverse probability of treatment weights were calculated. Weighted proportional hazard models were performed. Survival and recurrence outcomes of YNS were compared to the other 3 groups. Host immune status of YNS measured by peripheral blood neutrophil-to-lymphocyte ratio (NLR) was compared to 2 control groups (YNS with thyroid cancer and YNS with benign pathologies).
Results:
After adjusting for tumor and host factors, YNS had a higher probability of death compared to young smokers. This was driven by a higher incidence of regional and distant recurrences. Host factors showed a strong association with outcomes suggesting YNS may have an impaired immune system. Compared to the control cohorts YNS with OSCC had a higher NLR (p=.006).
Conclusion:
When adjusted by relevant covariates, YNS with OSCC have poorer survival than their young smoker counterparts. Our results suggest that an impaired immune system may be partly responsible for OSCC development and poorer outcomes in YNS.
Keywords: Oral cancer, Young patients, Non-smokers, Outcomes, Host, Immune status, NLR
INTRODUCTION
The main risk factor for developing oral cavity squamous cell carcinoma (OSCC) is smoking. OSCC typically occurs in patients over 40 years of age with a predominance in male patients.1 However, epidemiological studies now show that there has been an increase of OSCC in patients that are young, female and who do not report any history of smoking (young non-smokers; YNS).2-7 The etiology and biological behavior in these YNS has not been well-defined. Oncological outcomes are perceived to be worse in YNS with OSCC. However, there is meager data to support this.
We hypothesize that, YNS have poorer survival compared to young smokers and that the development of OSCC in YNS may be related to an impaired host immune status. The lack of evidence in the literature supporting poorer outcomes may be related to inappropriate weighting of prognostic factors and ignoring the host in the equation. An important surrogate marker for the host immune status is the pretreatment peripheral blood neutrophil-to-lymphocyte ratio (NLR), calculated dividing the absolute count of neutrophils by the absolute count of lymphocytes. NLR has been shown to act as a strong independent prognostic factor in patients with OSCC, where higher NLR is associated with worse outcomes.8,9
The primary aim of our study was to analyze outcomes in YNS OSCC patients using adequate weighting of important tumor and host factors and to compare them with their young-smoker and old-smoker/non-smoker counterparts. Our second aim was to study the role of host factors in outcomes and to explore if peripheral blood NLR could explain why YNS develop OSCC and have poor outcome.
METHODS
After Institutional Review Board approval, we performed a retrospective analysis from our departmental database of 2082 OSCC patients treated with primary surgery between 1985-2015. We excluded 9 patients with unknown tobacco history. The final cohort consisted in 2073 patients. We categorized patients into 4 groups according to age and smoking: ≤40 years-old/non-smokers (n=100), ≤40 years-old/smokers (n=80), >40 years-old/non-smokers (n=595) and >40 years-old/smokers (n=1298).
Baseline covariates including patient sex, alcohol use, comorbidities using the Washington University Head and Neck Comorbidity Index (WUHNCI),10 tumor site, pathological overall stage by the American Joint Committee on Cancer (AJCC) 8th Edition,11 and adjuvant treatment were selected to calculate propensity scores. Following propensity score generation, stabilized inverse probability of treatment weights (IPTW) were calculated. The cumulative incidence functions for the outcomes of interest were plotted before and after adjusting by the above mentioned covariates.
Next, we sought to analyze the impact of tumor and host covariates to each outcome of interest. To minimize the impact of missing data, multiple imputation using chained equations (MICE) was performed, and then a weighted Cox proportional hazard model was carried out for overall survival (OS) and disease-specific survival (DSS). The host variables added in the univariate and multivariable analyses were pretreatment peripheral blood neutrophils, monocytes, lymphocytes, albumin and hemoglobin, and body mass index (BMI).
Lastly, we wanted to explore if having a worse peripheral blood leukocyte profile (higher NLR) may partially explain why YNS develop OSCC and have poor outcomes. For this analysis, we only used those patients with available peripheral blood data within 1 month prior to surgery. Out of the 100 YNS, we had NLR available for 88 patients. Using propensity scores and optimal fixed ratio method, we matched this group of patients with 2 control groups: a control cohort of surgical thyroid cancer patients (a more indolent cancer) and a control cohort of surgical benign thyroid and salivary gland patients. Cases were optimally matched using covariates that influence leukocyte counts (age, sex, and smoking status) at a 1:1 ratio with a total absolute difference of 0.07. A total absolute difference <0.10 is considered acceptable. The control cohort of patients with benign pathologies were only included if patients had no past history of cancer. To compare the peripheral blood values between the 3 groups, Kruskal-Wallis test and pairwise two-sided multiple comparison analysis were performed. All statistical analyses were performed in SAS 9.3 (SAS Institute Inc., Cary, NC).
RESULTS
Patient characteristics of the entire cohort (n=2073):
Patient characteristics of the entire cohort are shown in Table 1. Median age was 62 years (IQR 52-72) and 56.5% were males. A total of 66.5% reported tobacco use and 71.7% reported alcohol use. Most patients (72.9%) did not have comorbidities (WUHNCI10 of 0) and the most common site was the tongue (51.4%). The pathological T classifications following AJCC 8th Ed11 were pT1 (29.6%), pT2 (25.9%), pT3 (18.0%) and pT4 (17.6%), and not reported in the remaining cases. Most cases had no regional neck metastases (68.1%). Surgery was followed by adjuvant radiotherapy in 29.4% of the cases and by adjuvant chemoradiotherapy in 6.1%.
Table 1.
Patients’ characteristics
| Characteristics | Overall cohort (n=2073) No. (%) |
Young non-smokers (n=100) No. (%) |
|---|---|---|
| Age Median (IQR) years | 62 (52-72) | 34 (28-37) |
| Sex | ||
| Male | 1171 (56.5) | 44 (44.0) |
| Female | 902 (43.5) | 56 (56.0) |
| Tobacco use | ||
| Never | 695 (33.5) | 100 (100.0) |
| Ever | 1378 (66.5) | 0 (0.0) |
| Alcohol use | ||
| Never | 582 (28.1) | 58 (58.0) |
| Ever | 1486 (71.7) | 42 (42.0) |
| Not reported | 5 (0.2) | 0 (0.0) |
| WUHNCI | ||
| 0 | 1512 (72.9) | 89 (89.0) |
| ≥ 1 | 561 (27.1) | 11 (11.0) |
| Subsite | ||
| Oral Tongue | 1066 (51.4) | 89 (89.0) |
| Lower Gum | 282 (13.6) | 2 (2.0) |
| Floor of Mouth | 299 (14.4) | 2 (2.0) |
| Buccal Mucosa | 139 (6.7) | 5 (0.0) |
| Upper Gum | 128 (6.2) | 0 (0.0) |
| Retromolar Trigone | 116 (5.6) | 2 (2.0) |
| Hard Palate | 43 (2.1) | 0 (0.0) |
| pT classification (AJCC 8th edition) | ||
| pT1 | 613 (29.6) | 35 (35.0) |
| pT2 | 536 (25.9) | 27 (27.0) |
| pT3 | 374 (18.0) | 29 (29.0) |
| pT4 | 365 (17.6) | 5 (5.0) |
| Not recorded | 185 (8.9) | 4 (4.0) |
| pN classification (AJCC 8th edition) | ||
| pNx/pNO | 1411 (68.1) | 64 (64.0) |
| pN1 | 175 (8.4) | 12 (12.0) |
| pN2 | 186 (9.0) | 10 (10.0) |
| pN3 | 224 (10.8) | 8 (8.0) |
| Not recorded | 77 (3.7) | 6 (6.0) |
| pOverall Stage (AJCC 8th edition) | ||
| Stage I | 547 (26.4) | 30 (30.0) |
| Stage II | 369 (17.8) | 17 (17.0) |
| Stage III | 309 (14.9) | 23 (23.0) |
| Stage IV | 643 (31.0) | 22 (22.0) |
| Not recorded | 205 (9.9) | 8 (8.0) |
| Grade | ||
| Well differentiated | 392 (18.9) | 17 (17.0) |
| Moderately differentiated | 1261 (60.8) | 62 (62.0) |
| Poorly differentiated | 275 (13.3) | 16 (16.0) |
| Not recorded | 145 (7.0) | 5 (5.0) |
| Treatment | ||
| Surgery | 1338 (64.5) | 61 (61.0) |
| Surgery and Adjuvant Radiotherapy | 609 (29.4) | 32 (32.0) |
| Surgery and Adjuvant Chemoradiotherapy | 126 (6.1) | 7 (7.0) |
Abbreviations: IQR, Interquartile range; WUHNCI, Washington University Head and Neck Comorbidity Index; AJCC, American Joint Committee on Cancer.
Patient characteristics of the subcohort of young non-smokers (n=100):
Patient characteristics of YNS are shown in Table 1. Median age was 34 years (IQR 28-37), 56.0% were females, and only 42.0% reported alcohol use. Most patients (89.0%) did not have comorbidities and the most common site was the tongue (89.0%). The pT classifications following AJCC 8th Ed11 were pT1 (35.0%), pT2 (27.0%), pT3 (29.0%) and pT4 (5.0%), and not reported in the remaining cases. Most tumors were pNx/pN0 (64.0%). Adjuvant radiotherapy was given in 32.0% of the cases and adjuvant chemoradiotherapy in 7.0%.
Probability of death and death from cancer:
Before adjusting, YNS had a lower probability of death compared to young smokers (Figure 1A). After adjusting by patient sex, alcohol use, comorbidities, tumor site, pathological overall stage, and adjuvant treatment, YNS had a higher probability of death (Figure 1B) than young smokers. When analyzing cancer-specific mortality, YNS had a higher probability of death from cancer compared to young smokers before (Figure 1C) and after adjusting (Figure 1D).
Figure 1.
Probability of death and death of cancer based on age and smoking status before (A and C) and after (B and D) adjusting for sex, alcohol use, comorbidities, tumor site, pathological overall stage (AJCC 8th Ed), and adjuvant treatment
When comparing younger groups vs older groups, both before and after adjusting, the older groups had poorer outcomes than the younger groups. After adjusting, YNS’s risk of death approached the risk of the older groups, while young smokers’ risk did the opposite. For the risk of death from cancer, after adjusting, both young groups had a lower risk than the older groups (Figure 1).
Probability of local, regional, and distant recurrence:
YNS had the lowest local recurrence probability (Figures 2A-B). In contrast, YNS had the highest regional recurrence probability of all groups before adjusting (Figure 2C). After adjusting, YNS still had a higher probability of regional recurrence than young smokers, but lower than those included in the older groups (Figure 2D). For distant recurrence probability, YNS showed the same trends as for regional recurrence. Of all groups, YNS had the highest probability for distant recurrence before adjusting (Figure 2E). After adjusting, YNS still had a higher probability than young smokers, but this was lower than the older groups (Figure 2F).
Figure 2.
Probability of local, regional and distant recurrence based on age and smoking status before (A, C and E) and after (B, D and F) adjusting for sex, alcohol use, comorbidities, tumor site, pathological overall stage (AJCC 8th Ed), and adjuvant treatment
Impact of tumor and host factors on outcomes:
We next performed a multivariable analysis controlling for additional tumor and host factors that were not used in the propensity score generation and therefore have not been used to adjust the groups. YNS maintained the same trend, having worse outcomes than young smokers, for OS (HR=2.02; 95% CI 0.99-4.12; P=.054) and DSS (HR=1.60; 95% CI 0.63-4.02; P=.320). In terms of tumor factors, grade, lymphovascular invasion, perineural invasion and margin status were independent predictors for OS and DSS. As for host factors, BMI, hemoglobin, albumin, and neutrophils were independent predictors for OS and hemoglobin, albumin, neutrophils, and lymphocytes for DSS. The univariate and multivariable analyses for OS and DSS are shown in Table 2 and Table 3, respectively.
Table 2.
Univariable and multivariable analyses including tumor and host factors for overall survival
| Univariate analysis | Multivariable analysis | |||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Group | ||||
| ≤40 years-old/smokers | Reference | Reference | ||
| ≤40 years-old/non-smokers | 1.580 (0.791-3.156) | 0.1948 | 2.017 (0.987-4.123) | 0.0544 |
| >40 years-old/non-smokers | 2.773 (1.545-4.979) | 0.0006 | 2.540 (1.362-4.737) | 0.0034 |
| >40 years-old/smokers | 3.631 (2.043-6.452) | <.0001 | 3.241 (1.754-5.991) | 0.0002 |
| Grade | ||||
| Well differentiated | Reference | Reference | ||
| Moderately differentiated | 1.371 (1.170-1.607) | <.0001 | 1.153 (0.971-1.369) | 0.1035 |
| Poorly differentiated | 2.185 (1.774-2.691) | <.0001 | 1.346 (1.060-1.708) | 0.0148 |
| Lymphovascular invasion | ||||
| Absent | Reference | Reference | ||
| Present | 2.154 (1.808-2.567) | <.0001 | 1.706 (1.406-2.069) | <.0001 |
| Perineural invasion | ||||
| Absent | Reference | Reference | ||
| Present | 2.229 (1.954-2.544) | <.0001 | 1.675 (1.440-1.949) | <.0001 |
| Margins | ||||
| Negative | Reference | Reference | ||
| Close | 1.349 (1.179-1.544) | <.0001 | 1.107 (0.959-1.278) | 0.1661 |
| Positive | 3.258 (2.615-4.058) | <.0001 | 2.400 (1.921-2.997) | <.0001 |
| BMI | 0.965 (0.953-0.978) | <.0001 | 0.981 (0.968-0.993) | 0.0024 |
| Hemoglobin | 0.813 (0.777-0.851) | <.0001 | 0.981 (0.968-0.993) | <.0001 |
| Albumin | 0.336 (0.279-0.405) | <.0001 | 0.481 (0.387-0.598) | <.0001 |
| Neutrophils | 1.097 (1.066-1.129) | <.0001 | 1.077 (1.042-1.113) | <.0001 |
| Monocytes | 2.158 (1.520-3.064) | <.0001 | 1.103 (0.713-1.705) | 0.6607 |
| Lymphocytes | 0.882 (0.791-0.983) | 0.0238 | 0.931 (0.849-1.021) | 0.1284 |
Abbreviations: HR, Hazard ratio; CI, confidence interval; BMI, body mass index.
Table 3.
Univariable and multivariable analyses including tumor and host factors for disease-specific survival
| Univariate analysis | Multivariable analysis | |||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Group | ||||
| ≤40 years smokers | Reference | Reference | ||
| ≤40 years non-smokers | 1.187 (0.478-2.951) | 0.7115 | 1.598 (0.634-4.024) | 0.3203 |
| >40 years non-smokers | 2.099 (0.977-4.511) | 0.0575 | 1.797 (0.806-4.005) | 0.1516 |
| >40 years smokers | 2.259 (1.065-4.791) | 0.0337 | 1.873 (0.853-4.110) | 0.1178 |
| Grade | ||||
| Well differentiated | Reference | Reference | ||
| Moderately differentiated | 1.929 (1.419-2.623) | <.0001 | 1.407 (1.026-1.930) | 0.0341 |
| Poorly differentiated | 3.307 (2.326-4.702) | <.0001 | 1.580 (1.073-2.327) | 0.0206 |
| Lymphovascular invasion | ||||
| Absent | Reference | Reference | ||
| Present | 3.074 (2.440-3.872) | <.0001 | 2.025 (1.549-2.647) | <.0001 |
| Perineural invasion | ||||
| Absent | Reference | Reference | ||
| Present | 3.159 (2.595-3.845) | <.0001 | 2.098 (1.662-2.649) | <.0001 |
| Margins | ||||
| Negative | Reference | Reference | ||
| Close | 1.419 (1.125-1.789) | 0.0031 | 1.088 (0.857-1.382) | 0.4868 |
| Positive | 4.521 (3.383-6.042) | <.0001 | 2.881 (2.116-3.922) | <.0001 |
| BMI | 0.985 (0.965-1.004) | 0.123 | 0.996 (0.977-1.015) | 0.6912 |
| Hemoglobin | 0.830 (0.780-0.884) | <.0001 | 0.872 (0.806-0.945) | 0.0008 |
| Albumin | 0.444 (0.331-0.595) | <.0001 | 0.629 (0.450-0.879) | 0.0065 |
| Neutrophils | 1.139 (1.095-1.185) | <.0001 | 1.107 (1.0545-1.161) | <.0001 |
| Monocytes | 3.075 (1.937-4.880) | <.0001 | 1.436 (0.757-2.724) | 0.2685 |
| Lymphocytes | 0.811 (0.691-0.951) | 0.0098 | 0.861 (0.744-0.997) | 0.0458 |
Abbreviations: HR, Hazard ratio; CI, confidence interval; BMI, body mass index.
NLR as an immune status surrogate marker using matched controlled groups (n = 88):
In Table 4, we compared the peripheral blood NLR between YNS with OSCC to 2 matched control groups (YNS with thyroid cancer and YNS with thyroid or salivary gland benign pathologies) and report that OSCC patients had a higher NLR than the control groups (p=.006). OSCC patients had a significantly higher NLR than patients with thyroid cancer (2.456 vs 2.000; p=.0093) and patients with benign pathologies (2.456 vs 2.158; p=.0343). There were no differences between thyroid cancer patients and patients with benign pathologies (2.000 vs 2.158; p=.7371).
Table 4.
Comparison of the median of neutrophil-to-lymphocyte ratio (NLR) values among 3 matched groups of 88 patients
| Group | Median (SD) | 95% CI | Minimum | Maximum | P |
|---|---|---|---|---|---|
| Oral cavity cancer | 2.456 (2.193) | 2.273-3.000 | 0.667 | 18.500 | 0.006 |
| Thyroid cancer | 2.000 (1.063) | 1.826-2.267 | 0.683 | 7.667 | |
| Benign pathologies | 2.158 (0.945) | 1.937-2.409 | 0.850 | 7.917 |
Abbreviations: SD, Standard deviation; CI, confidence interval.
DISCUSSION
Most OSCC occur in older patients with a smoking and alcohol history.1 However, OSCC also occurs in young patients and even more surprisingly, in young patients without recognized risk factors. The etiology in these young patients who lack risk factors remains unknown. The cutoff used in this study to group patients based on age is arbitrary, although the majority of studies in the literature set this threshold at 40 years.3,6,7,12-15 Other studies have defined young patients as an age less than 45 years.1,2,5,16 In our study we decided to use the lower threshold in order to be stricter in our selection.
When analyzing the YNS cohort’s characteristics, we observed that there were more females. This is in contrast to the overall cohort where there is a higher percentage of males. This trend has also been described by others, with a predominance of females in the group of YNS with OSCC.2-4
Young patients with head and neck cancer tend to have lower rates of tobacco and alcohol use.4 In our study, YNS with OSCC had less alcohol use compared to the overall cohort (42.0% vs 71.7%). This finding might be partially explained by the usual association of smoking and alcohol consumption. In our study, we did not stratify by alcohol use because self-reporting of alcohol consumption is less accurate and has a wide variation in terms of amount of alcohol consumed. In addition, if we only select never-drinkers the filter would be too strict and would not capture all the patients that we believe are part of this different entity.
In terms of oral cavity subsite, a predilection for the oral tongue has been shown for YNS with OSCC,2-4,12,17 which our results also demonstrate. Although oral tongue was the most common site for the entire cohort of 2073 patients with OSCC regardless of age and smoking status (51.4%), the percentage of patients with oral tongue cancer was higher in the YNS group (89.0%).
Multiple studies have recently shown an increase in the incidence of OSCC in young patients, especially those reporting no smoking .2,5-7 A recent study analyzing multi-institutional data reported a significant increase in the incidence OSCC of the tongue in young patients, and reported that the incidence is increasing at a higher rate in females than in males.2 Patel et al also showed that the cohort of patients with an actual increase in the incidence of OSCC was young females.18
YNS are perceived by the treating physicians to have a worse outcome, and several studies have reported this.15,19,20 However, in the literature there is still controversy as several studies have reported superior survival in young OSCC patients than older patients.5,6 Some studies, report a similar disease-free survival but better OS in the young group.12 Other studies report no differences in DSS or OS comparing young vs older patients.14,18 The reason for this heterogeneity in outcomes can be explained by several factors. For example, most studies did not stratify by smoking status, just analyzing the outcomes between young and old patients. This could dilute any differences between the groups. Moreover, many studies include head and neck cancers from all subsites or group together oral cavity and oropharyngeal tumors,13,16 with the possible confounding effect of HPV status. HPV-related tumors are usually seen in younger patients, and they generally have better outcomes.21,22 In our study, we focused on OSCC, and although we do not have HPV status for the entire cohort, most studies report that <5-10% of OSCC are HPV-related.23,24 Nonetheless, if a subset of our OSCC YNS patients were HPV-related, this would actually dilute our results, since HPV-related tumors tend to do better, at least in the oropharynx.
It is reasonable to anticipate that young patients would have a lower likelihood of death compared to older patients partly because YNS tend to have less comorbidities,12 as we observed in our study, indicating a better overall health. To control for this factor, we included comorbidities in the propensity score matching analysis. One would also expect that YNS would have better outcomes than young smokers, since smoking is associated with a poorer immune status and predisposes to other malignancies or other comorbidities that would influence outcomes. However, in our study, after adjusting for these factors, we observed that YNS had a poorer survival than young smokers. Our results match those reported by Schantz et al, who reported a 5-year DFS of 66% vs 86% when comparing YNS to a matched control group of young-smokers.25
In our study, the poorer outcomes we report in YNS compared to young smokers are driven by a higher incidence of regional and distant recurrences. Although multiple studies have found a higher locoregional recurrence rate in young patients compared to older patients with OSCC,14,15 no comparison within the young group has ever been done based on smoking status. It is interesting to observe that after adjusting for tumor and host variables, YNS risk of overall death came closer to the risk of the older groups, when one would expect the opposite to occur, as we observed with the group of young smokers. This finding reflects an inherent worse prognosis in YNS. This could be due to YNS having a biologically more aggressive tumor, or it could also be due to inherent differences in the host. For example, the higher risk of regional and distant recurrence in the YNS could be explained by an impaired immune system which allows for tumor evasion with resultant higher likelihood of tumor spread.
To explore the role of the host we examined multiple peripheral blood markers which have been reported to impact on survival in OSCC patients.26 In our study, host factors such as peripheral blood leukocytes showed a strong association with both OS and DSS suggesting that YNS may have an impaired immune system that led to immune evasion resulting in OSCC development and poor outcomes. Dysregulation of the immune system associated with autoimmune diseases is more frequent in females, and this can possibly explain why we see more females in this YNS group and could support the hypothesis that immune dysregulation is partly responsible for the development and progression of these tumors. Evidence to support this is the observation that OSCC may develop in young patients with immunosuppression either due to HIV or organ transplantation.27,28
There are multiple ways of assessing the host immune status such as analyzing immunoglobulin levels, lymphocytes phenotype, antibody responses or analyzing immune infiltration in the tumor microenvironment. Nonetheless, NLR was chosen in this study as a surrogate of the immune system in YNS due to its easy availability, universal applicability, and reasonable cost. Almost every patient who will undergo surgery will have peripheral blood absolute neutrophil and lymphocyte counts available before the procedure. Higher NLR is described as a worse peripheral blood immune profile associated with worse outcomes.8,9 It is not possible to compare NLR between the 4 groups created in this study based on age and smoking status since NLR is influenced by these two factors. It is well known that NLR increases with age and smoking use, mainly driven by a higher neutrophil count.9,29,30 Therefore, NLR might seem lower in the YNS group compared to older patients and smokers. Because of this, we decided to compare the NLR value of our OSCC YNS cohort with a propensity score matched cohort of patients with a more indolent cancer (thyroid cancer) and a propensity score matched cohort of patients with benign diseases (benign thyroid and salivary). We additionally matched the patients by sex since differences in leukocytes have also been shown between males and females.9,29 We observed a higher NLR in YNS OSCC patients compared to both control groups (p=.006). These results suggest that YNS with OSCC are a different entity, and that dysregulation of their immune system may explain tumor development as well as poorer outcomes. Moreover, the finding that thyroid cancer patients have the same NLR as patients with benign pathologies further support our hypothesis.
It is important to discuss other plausible explanations for the poorer outcomes we observe in YNS. It is possible YNS have OSCC which are biologically more aggressive due to differences in the number and type of genomic alterations. De Paula et al described a higher percentage of patients with positive expression of p53 in the group of young patients compared to the older (80.4% vs 63.6%; p=.04), although they included all head and neck sites and most patients had a smoking history.31 A more comprehensive genomic study on tongue OSCC reported by Pickering et al found similar genomic alterations in young patients and older patients.32 Another study found that younger patients tended to have a smaller mutation burden to typical onset oral tongue cancer though this was not thought to be due to differences in smoking.33 In general, it is thought that there are no major differences in the genomic landscape of OSCC in YNS compared to other patients and it is likely that other factors are responsible. We hypothesize that it is an impairment of the immune system which drives tumor development and poorer outcomes in YNS with a less significant role of the mutational landscape of the tumor itself. Possible environmental changes, diet changes, or even microbiome changes may be important and further research in this area is ongoing.34
This study has inherent limitations due to its retrospective nature and being performed at a single institution. Moreover, although the incidence is increasing for YNS, we still have a limited sample size of young patients with OSCC. In addition, we lack information about HPV status, and although it is less relevant in the setting of oral cavity cancer, we acknowledge this as a limitation of our study.
Lastly, to determine if we are facing a different entity that is mainly driven by differences in the host, we need to analyze data from different geographical areas. Future worldwide collaborative studies to create a larger dataset will help us answer this very important question. Future studies analyzing the tumor microenvironment and the immune profile of these YNS patients with OSCC are warranted.
CONCLUSION
When adjusted by relevant covariates, YNS with OSCC have a poorer survival than their young smoker counterparts due to a higher incidence of regional and distant recurrences. An impaired immune system may be partly responsible for OSCC development and poorer outcomes in YNS, although further studies are needed to confirm our hypothesis.
Highlights:
The incidence of oral cavity cancer in young non-smokers is increasing
Young non-smokers had a higher probability of death compared to young smokers
Young non-smokers had a higher incidence of regional and distant recurrences
Young non-smokers had a higher neutrophil-to-lymphocyte ratio than a control group
An impaired immune system may be partly responsible of these findings
ACKNOWLEDGEMENTS
Funding:
This study was partly funded by Fundación Alfonso Martín Escudero and the NIH/NCI Cancer Center Support Grant P30 CA008748.
Role of the funding source:
The funding source had to role in study design, collection, analysis or interpretation of data, neither in the writing of the manuscript or in the decision to submit the article for publication.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conflict of interest:
The authors declare no conflicts of interest pertinent to this work. Snehal G. Patel has a patent PCT/US2016/026717 Methods of Cancer Detection Using PARPI-FL pending, holds equity in Summit Biomedical Imaging, has a patent US 10,016,238 B2 Apparatus, system and method for providing laser steering and focusing for incision, excision and ablation of tissue in minimally-invasive surgery, holds equity in ColdSteel Laser Inc, has a patent PCT/US2014/073053 Systems, methods, and apparatus for multichannel imaging of fluorescent sources in real time, has a patent PCT/US2015/065816 Cyclic peptides with enhanced nerve-binding selectivity, nanoparticles bound with said cyclic peptides, and use of same for real-time in vivo nerve tissue imaging and has a patent PCT/US2016/066969 Imaging systems and methods for tissue differentiation, e.g., for intraoperative visualization.
Data availability statement:
The data that support the findings of this study are available from the corresponding author upon reasonable request.
REFERENCES
- 1.Warnakulasuriya S Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45(4-5):309–316. doi: 10.1016/j.oraloncology.2008.06.002 [DOI] [PubMed] [Google Scholar]
- 2.Satgunaseelan L, Allanson BM, Asher R, et al. The incidence of squamous cell carcinoma of the oral tongue is rising in young non-smoking women: An international multi-institutional analysis. Oral Oncol. 2020;110:104875. doi: 10.1016/j.oraloncology.2020.104875 [DOI] [PubMed] [Google Scholar]
- 3.Harris SL, Kimple RJ, Hayes DN, Couch ME, Rosenman JG. Never-smokers, never-drinkers: unique clinical subgroup of young patients with head and neck squamous cell cancers. Head Neck. 2010;32(4):499–503. doi: 10.1002/hed.21220 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Toporcov TN, Znaor A, Zhang Z-F, et al. Risk factors for head and neck cancer in young adults: a pooled analysis in the INHANCE consortium. Int J Epidemiol. 2015;44(1):169–185. doi: 10.1093/ije/dyu255 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Shiboski CH, Schmidt BL, Jordan RCK. Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20-44 years. Cancer. 2005;103(9):1843–1849. doi: 10.1002/cncr.20998 [DOI] [PubMed] [Google Scholar]
- 6.Annertz K, Anderson H, Biörklund A, et al. Incidence and survival of squamous cell carcinoma of the tongue in Scandinavia, with special reference to young adults. Int J cancer. 2002;101(1):95–99. doi: 10.1002/ijc.10577 [DOI] [PubMed] [Google Scholar]
- 7.Myers JN, Elkins T, Roberts D, Byers RM. Squamous cell carcinoma of the tongue in young adults: increasing incidence and factors that predict treatment outcomes. Otolaryngol neck Surg Off J Am Acad Otolaryngol Neck Surg. 2000;122(1):44–51. doi: 10.1016/S0194-5998(00)70142-2 [DOI] [PubMed] [Google Scholar]
- 8.Wang Y, Wang P, Andrukhov O, et al. Meta-analysis of the prognostic value of the neutrophil-to-lymphocyte ratio in oral squamous cell carcinoma. J oral Pathol Med Off Publ Int Assoc Oral Pathol Am Acad Oral Pathol. 2018;47(4):353–358. doi: 10.1111/jop.12688 [DOI] [PubMed] [Google Scholar]
- 9.Valero C, Zanoni DK, McGill MR, et al. Pretreatment peripheral blood leukocytes are independent predictors of survival in oral cavity cancer. Cancer. 2020;126(5):994–1003. doi: 10.1002/cncr.32591 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Piccirillo JF, Lacy PD, Basu A, Spitznagel EL. Development of a new head and neck cancer-specific comorbidity index. Arch Otolaryngol Head Neck Surg. 2002;128(10):1172–1179. Accessed February 8, 2019. http://www.ncbi.nlm.nih.gov/pubmed/12365889 [DOI] [PubMed] [Google Scholar]
- 11.Amin MB, Edge SB, Greene FL, et al E. AJCC Cancer Staging Manual. 8th ed. Springer; 2017. [Google Scholar]
- 12.Dougherty MI, Dougherty W, Kain JJ, et al. Non-HPV-Related Head and Neck Squamous Cell Carcinoma in a Young Patient Cohort. Ear Nose Throat J. Published online June 2020:145561320935839. doi: 10.1177/0145561320935839 [DOI] [PubMed] [Google Scholar]
- 13.Verschuur HP, Irish JC, O’Sullivan B, Goh C, Gullane PJ, Pintilie M. A matched control study of treatment outcome in young patients with squamous cell carcinoma of the head and neck. Laryngoscope. 1999;109(2 Pt 1):249–258. doi: 10.1097/00005537-199902000-00015 [DOI] [PubMed] [Google Scholar]
- 14.Friedlander PL, Schantz SP, Shaha AR, Yu G, Shah JP. Squamous cell carcinoma of the tongue in young patients: a matched-pair analysis. Head Neck. 1998;20(5):363–368. doi: [DOI] [PubMed] [Google Scholar]
- 15.Sarkaria JN, Harari PM. Oral tongue cancer in young adults less than 40 years of age: rationale for aggressive therapy. Head Neck. 1994;16(2):107–111. doi: 10.1002/hed.2880160202 [DOI] [PubMed] [Google Scholar]
- 16.Warnakulasuriya S, Mak V, Möller H. Oral cancer survival in young people in South East England. Oral Oncol. 2007;43(10):982–986. doi: 10.1016/j.oraloncology.2006.11.021 [DOI] [PubMed] [Google Scholar]
- 17.Yosefof E, Hilly O, Stern S, Bachar G, Shpitzer T, Mizrachi A. Squamous cell carcinoma of the oral tongue: Distinct epidemiological profile disease. Head Neck. 2020;42(9):2316–2320. doi: 10.1002/hed.26177 [DOI] [PubMed] [Google Scholar]
- 18.Patel SC, Carpenter WR, Tyree S, et al. Increasing incidence of oral tongue squamous cell carcinoma in young white women, age 18 to 44 years. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(11):1488–1494. doi: 10.1200/JCO.2010.31.7883 [DOI] [PubMed] [Google Scholar]
- 19.Amsterdam JT, Strawitz JG. Squamous cell carcinoma of the oral cavity in young adults. J Surg Oncol. 1982;19(2):65–68. doi: 10.1002/jso.2930190202 [DOI] [PubMed] [Google Scholar]
- 20.Brägelmann J, Dagogo-Jack I, El Dinali M, et al. Oral cavity tumors in younger patients show a poor prognosis and do not contain viral RNA. Oral Oncol. 2013;49(6):525–533. doi: 10.1016/j.oraloncology.2013.02.003 [DOI] [PubMed] [Google Scholar]
- 21.Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35. doi: 10.1056/NEJMoa0912217 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100(4):261–269. doi: 10.1093/jnci/djn011 [DOI] [PubMed] [Google Scholar]
- 23.Lopes V, Murray P, Williams H, Woodman C, Watkinson J, Robinson M. Squamous cell carcinoma of the oral cavity rarely harbours oncogenic human papillomavirus. Oral Oncol. 2011;47(8):698–701. doi: 10.1016/j.oraloncology.2011.04.022 [DOI] [PubMed] [Google Scholar]
- 24.Lingen MW, Xiao W, Schmitt A, et al. Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas. Oral Oncol. 2013;49(1):1–8. doi: 10.1016/j.oraloncology.2012.07.002 [DOI] [PubMed] [Google Scholar]
- 25.Schantz SP, Byers RM, Goepfert H, Shallenberger RC, Beddingfield N. The implication of tobacco use in the young adult with head and neck cancer. Cancer. 1988;62(7):1374–1380. doi: [DOI] [PubMed] [Google Scholar]
- 26.Valero C, Zanoni DK, Pillai A, et al. Host Factors Independently Associated With Prognosis in Patients With Oral Cavity Cancer. JAMA Otolaryngol Head Neck Surg. 2020;146(8):699–707. doi: 10.1001/jamaoto.2020.1019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Varga E, Tyldesley WR. Carcinoma arising in cyclosporin-induced gingival hyperplasia. Br Dent J. 1991;171(1):26–27. doi: 10.1038/sj.bdj.4807594 [DOI] [PubMed] [Google Scholar]
- 28.Roland JTJ, Rothstein SG, Mittal KR, Perksy MS. Squamous cell carcinoma in HIV-positive patients under age 45. Laryngoscope. 1993;103(5):509–511. doi: 10.1288/00005537-199305000-00005 [DOI] [PubMed] [Google Scholar]
- 29.Valero C, Pardo L, Lopez M, et al. Pretreatment count of peripheral neutrophils, monocytes, and lymphocytes as independent prognostic factor in patients with head and neck cancer. Head Neck. 2017;39(2):219–226. doi: 10.1002/hed.24561 [DOI] [PubMed] [Google Scholar]
- 30.Valiathan R, Ashman M, Asthana D. Effects of Ageing on the Immune System: Infants to Elderly. Scand J Immunol. 2016;83(4):255–266. doi: 10.1111/sji.12413 [DOI] [PubMed] [Google Scholar]
- 31.De Paula AMB, Souza LR, Farias LC, et al. Analysis of 724 cases of primary head and neck squamous cell carcinoma (HNSCC) with a focus on young patients and p53 immunolocalization. Oral Oncol. 2009;45(9):777–782. doi: 10.1016/j.oraloncology.2008.11.015 [DOI] [PubMed] [Google Scholar]
- 32.Pickering CR, Zhang J, Neskey DM, et al. Squamous cell carcinoma of the oral tongue in young non-smokers is genomically similar to tumors in older smokers. Clin cancer Res an Off J Am Assoc Cancer Res. 2014;20(14):3842–3848. doi: 10.1158/1078-0432.CCR-14-0565 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Campbell BR, Chen Z, Faden DL, et al. The mutational landscape of early- and typical-onset oral tongue squamous cell carcinoma. Cancer. 2021;127(4):544–553. doi: 10.1002/cncr.33309 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Ganly I, Yang L, Giese RA, et al. Periodontal pathogens are a risk factor of oral cavity squamous cell carcinoma, independent of tobacco and alcohol and human papillomavirus. Int J cancer. 2019;145(3):775–784. doi: 10.1002/ijc.32152 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.