- Email: [email protected]
Non-smoking non-drinking elderly females: a clinically distinct subgroup of oral squamous cell carcinoma patients
Int. J. Oral Maxillofac. Surg. 2013; 42: 929–933 http://dx.doi.org/10.1016/j.ijom.2013.04.010, available online at http://www.sciencedirect.com
Clinical Paper Head and Neck Oncology
Non-smoking non-drinking elderly females: a clinically distinct subgroup of oral squamous cell carcinoma patients
K. Koo1, R. Barrowman1,2, M. McCullough1,2, T. Iseli1, D. Wiesenfeld1,2 1 Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia; 2 Melbourne Dental School, The University of Melbourne, Melbourne, Australia
K. Koo, R. Barrowman, M. McCullough, T. Iseli, D. Wiesenfeld: Non-smoking nondrinking elderly females: a clinically distinct subgroup of oral squamous cell carcinoma patients. Int. J. Oral Maxillofac. Surg. 2013; 42: 929–933. # 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Abstract. There is growing interest in non-smoking non-drinking (NSND) patients presenting with oral squamous cell carcinoma (OSCC). There are, however, few published reports of OSCC in the elderly. We describe a subgroup of elderly NSND patients presenting with OSCC. Patients with SCC of the oral cavity were retrospectively assessed from the Head and Neck Oncology Tumour Stream database of the Royal Melbourne Hospital. Epidemiological and clinical data for 169 consecutive patients were reviewed and analysed. NSND patients were more likely to be females with a higher median age at presentation. They were more likely to have maxillary alveolus tumours and oral tongue tumours, with retromolar or mandibular tumours less likely. Second primary tumours for this subgroup were confined to the oral cavity. NSND elderly females experienced a worse diseasespecific mortality. We have identified a distinct subgroup of elderly female patients presenting with OSCC not associated with the traditional risk factors of tobacco and alcohol, who have a worse prognosis. Altered management algorithms may prove beneficial for these patients, and further investigation and genetic analysis are required to delineate the aetiology of these carcinomas.
Oral squamous cell carcinoma (OSCC) is the seventh most prevalent malignancy globally, resulting in significant mortality and morbidity, with severe impairment of quality of life.1 While tobacco and alcohol are well established aetiological agents for the development of OSCC,2 non-smoking, 0901-5027/080929 + 05 $36.00/0
non-drinking patients (NSND) presenting with OSCC have been identified in the literature as a unique and growing subgroup. In contrast to the general predilection for males in OSCC, the NSND group has a female preponderance, younger mean age, and the carcinoma is more
Key words: oral cancer; head and neck cancer; non-smokers; non-drinkers; female; elderly; epidemiology; survival. Accepted for publication 15 April 2013 Available online 20 May 2013
likely to be in the oral cavity than at other sites.3–6 The NSND population currently represents 13–35% of the OSCC population,3,6 although this proportion may increase as tobacco use decreases. There has been considerable interest in young female NSND presenting with
# 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
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Koo et al.
OSCC. The human papillomavirus (HPV), in particular HPV-16, has been implicated in oropharyngeal SCC in young NSND patients. The role of HPV in OSCC and indeed implications for clinical behaviour is uncertain.7,8 There are few published reports of oral cancer in elderly NSND patients. The proportion of elderly patients is increasing alongside life-expectancy, with as many as 24% of head and neck cancers found in patients over 70 years old.9 The aetiology of OSCC in this NSND elderly population is as yet unknown and management algorithms may be different for this age group. This retrospective review was undertaken to compare OSCC disease characteristics between NSND elderly females and the rest of the population. Materials and methods
One hundred and sixty-nine consecutive patients presenting with new or recurrent OSCC between January 2007 and July 2010 were reviewed. Carcinomas of the lip were excluded. Clinical and epidemiological data were obtained from the BioGrid ACCORD head and neck tumour database. This prospectively collected database contains information on risk factors, tumour pathology, subsite, staging, and treatment. Further information was obtained from the clinical history. Patients were classified as NSND or SD (smokers and/or drinkers). Non-smoking status was defined as a negligible history of tobacco use and non-drinking status as nil regular alcohol consumption with no previous history of heavy alcohol intake or abuse. Tumours were classified according to the International Classification of Diseases (ICD) for oral cavity subsites and retrospectively updated to reflect the American Joint Committee on Cancer (AJCC) sixth edition system. Second primary tumours and recurrences were classified as described by Warren and Gates.10 Mortality data were sourced from both the ACCORD and the Victorian Cancer Registry databases, with a minimum follow-up of 18 months (census date 1 January 2012), including disease-specific mortality. Disease-free survival was recorded from the clinical follow-up notes. A statistical analysis was performed to directly compare the NSND and the SD groups using the software package IBM SPSS Statistics 19. x2 Tests were employed for disease characteristics and demographics, while Student’s t-tests were utilized for age analysis. Survival data were plotted on Kaplan–Meier curves
with log-rank tests used for statistical analysis. Statistical significance was set at P < 0.05. Results
A total of 41 patients (24.3%) were identified as NSND from 169 consecutive patients presenting with OSCC between January 2007 and July 2010 (Table 1). The mean age at presentation for all patients was 65.5 years; 72 patients (42.6%) were female. There were no regular users of smokeless tobacco (snus, snuff, etc.) or other oral carcinogens (areca nut, betel quid). Sixty-nine patients (40.8%) were non-smokers and 58 patients (34.3%) were non-drinkers. The NSND group had a mean age of 71 years (median 73 years), and the SD group had a mean age of 63 years (median 63 years) (t-test, P < 0.05). A bimodal age distribution was noted in the NSND group, with peaks at 50–59 years and 70–79 years. In contrast, a single peak at 60– 69 years was seen in the SD group (Fig. 1). Maxillary alveolus tumours were more common in the NSND group than in the SD group (x2 = 4.92, df = 1, P < 0.05), while retromolar tumours were more common in the SD group than in the NSND group (x2 = 5.58, df = 1, P < 0.05). Whilst there were larger numbers of NSND patients with oral tongue tumours, there was a trend towards mandibular alveolus tumours in the SD group (Table 2). There was no statistically significant difference in TNM staging, histological subtype, or differentiation between the two groups (NSND and SD) (Table 3).
Tumours were relatively evenly staged as T1, T2, and T4, with a smaller percentage of tumours staged as T3. Forty-one patients (24.3%) presented with nodal disease. No patients had distant metastatic disease at the time of presentation. Thirteen patients, of whom five were NSND, presented with a second primary tumour during the follow-up period (7.7%), while six patients presented with recurrent disease (3.6%). Two patients (1.2%), both of whom drank heavily and had in excess of a 30 pack-year history of tobacco, presented with synchronous tumours (Table 4). Two of the five NSND patients had multiple presentations with second primary tumours, in contrast to none of the SD patients. Although the proportion of patients presenting with second primary tumours was similar between the NSND (12.2%) and the SD groups (7.8%), none of the NSND patients had a second primary tumour found outside the oral cavity, whereas two of 10 SD patients (20.0%) had nonoral second primary tumours. The mean follow-up time for all patients was 28 months (range 18–65 months). Fifty-one patients had died by the census date, with 14 patients documented as having died of non-cancer causes. Only six out of the 118 surviving patients presented with recurrent disease (5.1%), and there was no difference in recurrence rates amongst surviving patients between the NSND and SD groups. The NSND group (n = 41) was noted to have a higher disease-specific mortality. Tobacco and alcohol use was not a predictor for either disease-specific or non-disease mortality in our cohort.
Table 1. Gender distribution. SD (n = 128) n (% of total SD) Male* (n = 97) Female* (n = 72)
87 (68.0) 41 (32.0)
NSND (n = 41) n (% of total NSND) 10 (24.4) 31 (75.6)
SD, smokers and drinkers; NSND, non-smokers non-drinkers. * P < 0.05 (by Pearson’s x2 test).
Fig. 1. Age distribution of patients; black = smokers and drinkers (SD), red = non-smokers nondrinkers (NSND).
NSND elderly female OSCC patients Table 2. Classification of tumours by subsite.
Table 3. Disease characteristics.
SD, n (% of total SD) Tongue (n = 72) Retromolar (n = 27)* Floor of mouth (n = 22) Maxillary alveolus (n = 20)* Mandibular alveolus (n = 7)y Buccal mucosa (n = 15) Hard palate (n = 6)
51 25 18 12 7 10 5
NSND, n (% of total NSND)
(39.8) (19.5) (14.1) (9.4) (5.5) (7.8) (3.9)
21 2 4 8 0 5 1
(51.2) (4.9) (9.8) (19.5) (0) (12.2) (2.4)
SD, smokers and drinkers; NSND, non-smokers non-drinkers. * P < 0.05 (by Pearson’s x2 test). y P < 0.10 (>0.05).
Furthermore, NSND women (n = 31) and, in particular, elderly NSND women (n = 20), had significantly higher disease-specific mortality than the rest of the patient cohort (log-rank, SPSS package, P < 0.05). There was a non-significant trend of higher disease-specific mortality in the elderly females compared to elderly males. However, there were too few elderly NSND men for a meaningful analysis of this subgroup. No difference was seen in non-disease mortality in any segment of the NSND group compared to the SD group (Fig. 2). Increased age, female gender, and stage III/IV disease were negative predictors for disease-specific mortality (log-rank, SPSS package, P < 0.05). Discussion
NSND patients with OSCC seem to be a distinct clinical subgroup. This group is defined by a bimodal age distribution and is more likely to present with a maxillary alveolus or oral tongue lesion, whereas SD patients are more likely to have tumours in the retromolar trigone or mandibular
931
alveolus. No NSND patient had a second primary tumour outside the oral cavity, compared with 20% of SD patients. There is a trend towards worse outcomes in NSND OSCC patients, with the elderly females having a significantly worse disease-specific mortality. Oral cancer has traditionally been regarded as a disease of male smokers and drinkers. The gender ratio in Australia is approximately 2.4:1 in favour of males,11 whereas we found a ratio of 1.3:1, reflecting a proportionally higher number of female patients in our population. With the declining rates of smoking, the management of OSCC in NSND patients is becoming increasingly relevant. Furthermore, with an ageing population we are likely to see more elderly NSND patients with OSCC, perhaps as a result of the accumulation of genetic mutations in the oral mucosa over a lifetime. The present study is one of the first to focus specifically on this important subgroup. The trend towards worse diseasespecific survival outcomes in the NSND group, as well as worse survival in elderly females, is an important finding.
SD, n (%) Stage I/II Stage III/IV
73 (57.0) 55 (43.0)
NSND, n (%) 25 (61.0) 16 (39.0)
SD, smokers and drinkers; NSND, non-smokers non-drinkers.
Constantinides et al. reported on a cohort of 10 elderly NSND head and neck SCC patients with aggressive local recurrences, nine of whom were female.12 Survival data in elderly patients have to be considered carefully, as they have a shorter lifeexpectancy and more medical co-morbidities. However, the age-related difference in disease-specific mortality is confined to the NSND group, with age in the SD group not a significant predictor of disease-specific mortality. Specific comparison of just the elderly patient population also shows a poorer survival in the NSND group. Together, this suggests that the NSND group does indeed have poorer outcomes independent of co-existing medical morbidities. The finding of worse disease-specific survival in the NSND group is somewhat unexpected. This group would be expected to have better general health as a result of their abstinence from tobacco and alcohol. There might be aetiological as well as genetic differences in tumours between the NSND and SD group, resulting in either more locally aggressive disease or an increased likelihood of nodal and distant spread. Indeed, we observed that two NSND patients presented with multiple second primaries. There are recent data suggesting that the increase in younger NSND patients with OSCC is related to HPV with p16-positive
Table 4. Characteristics of second primary tumours in the SD group vs. the NSND group. Patient* NSND
1 2 3 4 5
SD
6 7 8 9 10 11 12 13 14 15
Original primary site
Second primary site
Interval (years)
Floor of mouth Mandibular alveolus Retromolar trigone Maxillary alveolus Retromolar trigone mandible Retromolar trigone (L) maxillary alveolus
Tongue Mandibular alveolus Hard palate Buccal mucosa
25 11 7 5 From most recent previous primary
(R) maxilla
2 From most recent previous primary
Tongue Mandibular alveolus Maxillary alveolus Tongue Mandibular alveolus Floor of mouth Floor of mouth Tonsil Supraglottic Tonsillar pillar
Mandibular alveolus Mandibular alveolus Tongue Mandibular alveolus Floor of mouth Retromolar trigone Tongue Tongue Retromolar trigone Retromolar trigone
3 9 6 12 16 1 29 3 0 0
SD, smokers and drinkers; NSND, non-smokers non-drinkers. * Patients 1–5 are NSND; patients 6–15 are SD. Patients 4 and 5 had multiple primaries at intervals. Patients 14 and 15 had synchronous tumours.
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Fig. 2. Kaplan–Meier curves. (a) Gender P = 0.027; tobacco P = 0.498; alcohol P = 0.174; age P = 0.007. (b) TNM stage P < 0.001; NSND P = 0.024; NSND women P = 0.020; NSND old women P < 0.001.
tumours.13 Furthermore, HPV may confer a worse prognosis in tumours of the oral tongue.8 The bimodal distribution in our NSND group suggests that the first peak correlates with the recent trend towards HPV-related tumours in younger patients, with the second peak relating to an aetiology that has yet to be elucidated. The results of the present study indicate that OSCC in NSND patients behaves differently to that in SD patients and hence clinicians should be cognizant of their worse survival during assessment, treatment, and follow-up. At this time, there is no significant difference in the treatment of OSCC (e.g. elective neck dissections or adjuvant chemo-radiotherapy) for these patients.14 It has been documented that non-smoking status is a positive predictor of tumour epidermal growth factor receptor (EGFR) expression in head and neck SCC, which is a marker for the response to cetuximab,15 and this is also the case in lung cancers where non-smokers are more likely to respond to erlotinib and gefitinib.16 Altered treatment protocols for NSND patients might therefore provide improved outcomes. The percentage of patients with second primaries was similar in the NSND and SD groups. However, none of the NSND patients had second primaries outside the oral cavity, an area more conveniently assessed than other head and neck sub-
sites. A larger cohort would be needed to elaborate upon this finding, but it suggests a different pattern of second primary cancer development, with field cancerization confined to the oral cavity, as opposed to patients who smoke and the deleterious impact on the entire upper aerodigestive system. If disease is confined to the oral cavity in the NSND group, it would obviate or reduce the need for routine panendoscopies in the initial treatment and follow-up of these patients. There are certain important caveats to our findings. Elderly ‘NSND’ patients in the study cohort were largely from a generation where smoking was a social norm and environmental exposure to secondhand smoke could be a major confounding factor. Accurate information regarding environmental exposures to toxins is inherently difficult to obtain and the role of other environmental toxins driving the development of OSCC in these patients cannot be definitively ruled out. Nevertheless, the different clinical outcomes and different locations of the second primary tumours imply a yet to be identified local carcinogen. The study assessed consecutive patients with oral cancer from a single tertiary referral centre, and therefore it is impossible to know whether the spectrum of patients presenting to our centre is similar to that from the wider Australian commu-
nity. There may therefore be stochastic effects leading to a higher proportion of NSND patients presenting at our centre. In conclusion, this study identified a distinct clinical subgroup of non-smoking and non-drinking patients with oral squamous cell carcinoma. This group has a demographic distribution; different patients only have second primaries within the oral cavity and have worse outcomes with a higher mortality. Analysis of tumour biology in this subgroup may identify an as yet unknown aetiological agent, and may in future guide treatment decisions and provide unique molecular targets. Funding
Funding was provided by the Price Family Foundation. The study sponsors had no involvement in the study design or production of the manuscript. Competing interests
None declared. Ethical approval
This project was approved by the Human Research Ethics Committee of the Office for Research at Melbourne Health (QA2010093).
NSND elderly female OSCC patients Acknowledgements. The authors acknowledge the financial assistance of the Price Family Foundation for this project, as well as Maria Dikeakos and Craig Love for their assistance in data acquisition.
References 1. Garcia M, Jemal A, Ward EM, Center MM, Hao Y, Siegel RL, et al. Global cancer: facts and figures 2007. Atlanta, GA: American Cancer Society; 2007. 2. La Vecchia C, Tavani A, Franceschi S, Levi F, Corrao G, Negri E. Epidemiology and prevention of oral cancer. Oral Oncol 1997;33:302–12. 3. Dahlstrom KR, Little JA, Zafereo ME, Lung M, Wei Q, Sturgis EM. Squamous cell carcinoma of the head and neck in never smoker– never drinkers: a descriptive epidemiologic study. Head Neck 2008;30:75–84. 4. Farshadpour F, Hordijk GJ, Koole R, Slootweg PJ. Non-smoking and non-drinking patients with head and neck squamous cell carcinoma: a distinct population. Oral Dis 2007;13:239–43. 5. Harris SL, Kimple RJ, Hayes DN, Couch ME, Rosenman JG. Never-smokers, neverdrinkers: unique clinical subgroup of young patients with head and neck squamous cell cancers. Head Neck 2010;32:499–503.
6. Wiseman SM, Swede H, Stoler DL, Anderson GR, Rigual NR, Hicks Jr WL et al. Squamous cell carcinoma of the head and neck in nonsmokers and nondrinkers: an analysis of clinicopathologic characteristics and treatment outcomes. Ann Surg Oncol 2003;10:551–7. 7. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005;14:467–75. 8. Duray A, Descamps G, Decaestecker C, Remmelink M, Sirtaine N, Lechien J, et al. Human papillomavirus DNA strongly correlates with a poorer prognosis in oral cavity carcinoma. Laryngoscope 2012;122:1558–65. 9. Kruse AL, Bredell M, Luebbers HT, Gra¨tz KW. Head and neck cancer in the elderly: a retrospective study over 10 years (1999– 2008). Head Neck Oncol 2010;2:25. 10. Warren S, Gates O. Multiple primary malignant tumours. A survey of the literature and a statistical study. Am J Cancer 1932;16:1358. 11. Abreu LP, Kruger E, Tennant M. Oral cancer in Western Australia, 1982–2006: a retrospective epidemiological study. J Oral Pathol Med 2010;39:376–81. 12. Constantinides MS, Rothstein SG, Persky MS. Squamous cell carcinoma in older patients without risk factors. Otolaryngol Head Neck Surg 1992;106:275–7.
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13. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol 2008;26:612–9. 14. Pfister DG, Ang K, Brockstein B, Colevas AD, Ellenhorn J, Goepfert H, et al. National Comprehensive Cancer Network. NCCN practice guidelines for head and neck cancers. Oncology (Williston Park) 2000;14:163–94. 15. Ryott M, Wangsa D, Heselmeyer-Haddad K, Lindholm J, Elmberger G, Auer G, et al. EGFR protein overexpression and gene copy number increases in oral tongue squamous cell carcinoma. Eur J Cancer 2009;45:1700–8. 16. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF receptor gene mutations are common in lung cancers from never smokers and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306–11.
Address: Kendrick Koo Royal Melbourne Hospital Grattan Street Parkville Victoria 3052 Australia Tel: +61 3 93427000 E-mail: [email protected]
Clinical Paper Head and Neck Oncology
Non-smoking non-drinking elderly females: a clinically distinct subgroup of oral squamous cell carcinoma patients
K. Koo1, R. Barrowman1,2, M. McCullough1,2, T. Iseli1, D. Wiesenfeld1,2 1 Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia; 2 Melbourne Dental School, The University of Melbourne, Melbourne, Australia
K. Koo, R. Barrowman, M. McCullough, T. Iseli, D. Wiesenfeld: Non-smoking nondrinking elderly females: a clinically distinct subgroup of oral squamous cell carcinoma patients. Int. J. Oral Maxillofac. Surg. 2013; 42: 929–933. # 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Abstract. There is growing interest in non-smoking non-drinking (NSND) patients presenting with oral squamous cell carcinoma (OSCC). There are, however, few published reports of OSCC in the elderly. We describe a subgroup of elderly NSND patients presenting with OSCC. Patients with SCC of the oral cavity were retrospectively assessed from the Head and Neck Oncology Tumour Stream database of the Royal Melbourne Hospital. Epidemiological and clinical data for 169 consecutive patients were reviewed and analysed. NSND patients were more likely to be females with a higher median age at presentation. They were more likely to have maxillary alveolus tumours and oral tongue tumours, with retromolar or mandibular tumours less likely. Second primary tumours for this subgroup were confined to the oral cavity. NSND elderly females experienced a worse diseasespecific mortality. We have identified a distinct subgroup of elderly female patients presenting with OSCC not associated with the traditional risk factors of tobacco and alcohol, who have a worse prognosis. Altered management algorithms may prove beneficial for these patients, and further investigation and genetic analysis are required to delineate the aetiology of these carcinomas.
Oral squamous cell carcinoma (OSCC) is the seventh most prevalent malignancy globally, resulting in significant mortality and morbidity, with severe impairment of quality of life.1 While tobacco and alcohol are well established aetiological agents for the development of OSCC,2 non-smoking, 0901-5027/080929 + 05 $36.00/0
non-drinking patients (NSND) presenting with OSCC have been identified in the literature as a unique and growing subgroup. In contrast to the general predilection for males in OSCC, the NSND group has a female preponderance, younger mean age, and the carcinoma is more
Key words: oral cancer; head and neck cancer; non-smokers; non-drinkers; female; elderly; epidemiology; survival. Accepted for publication 15 April 2013 Available online 20 May 2013
likely to be in the oral cavity than at other sites.3–6 The NSND population currently represents 13–35% of the OSCC population,3,6 although this proportion may increase as tobacco use decreases. There has been considerable interest in young female NSND presenting with
# 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
930
Koo et al.
OSCC. The human papillomavirus (HPV), in particular HPV-16, has been implicated in oropharyngeal SCC in young NSND patients. The role of HPV in OSCC and indeed implications for clinical behaviour is uncertain.7,8 There are few published reports of oral cancer in elderly NSND patients. The proportion of elderly patients is increasing alongside life-expectancy, with as many as 24% of head and neck cancers found in patients over 70 years old.9 The aetiology of OSCC in this NSND elderly population is as yet unknown and management algorithms may be different for this age group. This retrospective review was undertaken to compare OSCC disease characteristics between NSND elderly females and the rest of the population. Materials and methods
One hundred and sixty-nine consecutive patients presenting with new or recurrent OSCC between January 2007 and July 2010 were reviewed. Carcinomas of the lip were excluded. Clinical and epidemiological data were obtained from the BioGrid ACCORD head and neck tumour database. This prospectively collected database contains information on risk factors, tumour pathology, subsite, staging, and treatment. Further information was obtained from the clinical history. Patients were classified as NSND or SD (smokers and/or drinkers). Non-smoking status was defined as a negligible history of tobacco use and non-drinking status as nil regular alcohol consumption with no previous history of heavy alcohol intake or abuse. Tumours were classified according to the International Classification of Diseases (ICD) for oral cavity subsites and retrospectively updated to reflect the American Joint Committee on Cancer (AJCC) sixth edition system. Second primary tumours and recurrences were classified as described by Warren and Gates.10 Mortality data were sourced from both the ACCORD and the Victorian Cancer Registry databases, with a minimum follow-up of 18 months (census date 1 January 2012), including disease-specific mortality. Disease-free survival was recorded from the clinical follow-up notes. A statistical analysis was performed to directly compare the NSND and the SD groups using the software package IBM SPSS Statistics 19. x2 Tests were employed for disease characteristics and demographics, while Student’s t-tests were utilized for age analysis. Survival data were plotted on Kaplan–Meier curves
with log-rank tests used for statistical analysis. Statistical significance was set at P < 0.05. Results
A total of 41 patients (24.3%) were identified as NSND from 169 consecutive patients presenting with OSCC between January 2007 and July 2010 (Table 1). The mean age at presentation for all patients was 65.5 years; 72 patients (42.6%) were female. There were no regular users of smokeless tobacco (snus, snuff, etc.) or other oral carcinogens (areca nut, betel quid). Sixty-nine patients (40.8%) were non-smokers and 58 patients (34.3%) were non-drinkers. The NSND group had a mean age of 71 years (median 73 years), and the SD group had a mean age of 63 years (median 63 years) (t-test, P < 0.05). A bimodal age distribution was noted in the NSND group, with peaks at 50–59 years and 70–79 years. In contrast, a single peak at 60– 69 years was seen in the SD group (Fig. 1). Maxillary alveolus tumours were more common in the NSND group than in the SD group (x2 = 4.92, df = 1, P < 0.05), while retromolar tumours were more common in the SD group than in the NSND group (x2 = 5.58, df = 1, P < 0.05). Whilst there were larger numbers of NSND patients with oral tongue tumours, there was a trend towards mandibular alveolus tumours in the SD group (Table 2). There was no statistically significant difference in TNM staging, histological subtype, or differentiation between the two groups (NSND and SD) (Table 3).
Tumours were relatively evenly staged as T1, T2, and T4, with a smaller percentage of tumours staged as T3. Forty-one patients (24.3%) presented with nodal disease. No patients had distant metastatic disease at the time of presentation. Thirteen patients, of whom five were NSND, presented with a second primary tumour during the follow-up period (7.7%), while six patients presented with recurrent disease (3.6%). Two patients (1.2%), both of whom drank heavily and had in excess of a 30 pack-year history of tobacco, presented with synchronous tumours (Table 4). Two of the five NSND patients had multiple presentations with second primary tumours, in contrast to none of the SD patients. Although the proportion of patients presenting with second primary tumours was similar between the NSND (12.2%) and the SD groups (7.8%), none of the NSND patients had a second primary tumour found outside the oral cavity, whereas two of 10 SD patients (20.0%) had nonoral second primary tumours. The mean follow-up time for all patients was 28 months (range 18–65 months). Fifty-one patients had died by the census date, with 14 patients documented as having died of non-cancer causes. Only six out of the 118 surviving patients presented with recurrent disease (5.1%), and there was no difference in recurrence rates amongst surviving patients between the NSND and SD groups. The NSND group (n = 41) was noted to have a higher disease-specific mortality. Tobacco and alcohol use was not a predictor for either disease-specific or non-disease mortality in our cohort.
Table 1. Gender distribution. SD (n = 128) n (% of total SD) Male* (n = 97) Female* (n = 72)
87 (68.0) 41 (32.0)
NSND (n = 41) n (% of total NSND) 10 (24.4) 31 (75.6)
SD, smokers and drinkers; NSND, non-smokers non-drinkers. * P < 0.05 (by Pearson’s x2 test).
Fig. 1. Age distribution of patients; black = smokers and drinkers (SD), red = non-smokers nondrinkers (NSND).
NSND elderly female OSCC patients Table 2. Classification of tumours by subsite.
Table 3. Disease characteristics.
SD, n (% of total SD) Tongue (n = 72) Retromolar (n = 27)* Floor of mouth (n = 22) Maxillary alveolus (n = 20)* Mandibular alveolus (n = 7)y Buccal mucosa (n = 15) Hard palate (n = 6)
51 25 18 12 7 10 5
NSND, n (% of total NSND)
(39.8) (19.5) (14.1) (9.4) (5.5) (7.8) (3.9)
21 2 4 8 0 5 1
(51.2) (4.9) (9.8) (19.5) (0) (12.2) (2.4)
SD, smokers and drinkers; NSND, non-smokers non-drinkers. * P < 0.05 (by Pearson’s x2 test). y P < 0.10 (>0.05).
Furthermore, NSND women (n = 31) and, in particular, elderly NSND women (n = 20), had significantly higher disease-specific mortality than the rest of the patient cohort (log-rank, SPSS package, P < 0.05). There was a non-significant trend of higher disease-specific mortality in the elderly females compared to elderly males. However, there were too few elderly NSND men for a meaningful analysis of this subgroup. No difference was seen in non-disease mortality in any segment of the NSND group compared to the SD group (Fig. 2). Increased age, female gender, and stage III/IV disease were negative predictors for disease-specific mortality (log-rank, SPSS package, P < 0.05). Discussion
NSND patients with OSCC seem to be a distinct clinical subgroup. This group is defined by a bimodal age distribution and is more likely to present with a maxillary alveolus or oral tongue lesion, whereas SD patients are more likely to have tumours in the retromolar trigone or mandibular
931
alveolus. No NSND patient had a second primary tumour outside the oral cavity, compared with 20% of SD patients. There is a trend towards worse outcomes in NSND OSCC patients, with the elderly females having a significantly worse disease-specific mortality. Oral cancer has traditionally been regarded as a disease of male smokers and drinkers. The gender ratio in Australia is approximately 2.4:1 in favour of males,11 whereas we found a ratio of 1.3:1, reflecting a proportionally higher number of female patients in our population. With the declining rates of smoking, the management of OSCC in NSND patients is becoming increasingly relevant. Furthermore, with an ageing population we are likely to see more elderly NSND patients with OSCC, perhaps as a result of the accumulation of genetic mutations in the oral mucosa over a lifetime. The present study is one of the first to focus specifically on this important subgroup. The trend towards worse diseasespecific survival outcomes in the NSND group, as well as worse survival in elderly females, is an important finding.
SD, n (%) Stage I/II Stage III/IV
73 (57.0) 55 (43.0)
NSND, n (%) 25 (61.0) 16 (39.0)
SD, smokers and drinkers; NSND, non-smokers non-drinkers.
Constantinides et al. reported on a cohort of 10 elderly NSND head and neck SCC patients with aggressive local recurrences, nine of whom were female.12 Survival data in elderly patients have to be considered carefully, as they have a shorter lifeexpectancy and more medical co-morbidities. However, the age-related difference in disease-specific mortality is confined to the NSND group, with age in the SD group not a significant predictor of disease-specific mortality. Specific comparison of just the elderly patient population also shows a poorer survival in the NSND group. Together, this suggests that the NSND group does indeed have poorer outcomes independent of co-existing medical morbidities. The finding of worse disease-specific survival in the NSND group is somewhat unexpected. This group would be expected to have better general health as a result of their abstinence from tobacco and alcohol. There might be aetiological as well as genetic differences in tumours between the NSND and SD group, resulting in either more locally aggressive disease or an increased likelihood of nodal and distant spread. Indeed, we observed that two NSND patients presented with multiple second primaries. There are recent data suggesting that the increase in younger NSND patients with OSCC is related to HPV with p16-positive
Table 4. Characteristics of second primary tumours in the SD group vs. the NSND group. Patient* NSND
1 2 3 4 5
SD
6 7 8 9 10 11 12 13 14 15
Original primary site
Second primary site
Interval (years)
Floor of mouth Mandibular alveolus Retromolar trigone Maxillary alveolus Retromolar trigone mandible Retromolar trigone (L) maxillary alveolus
Tongue Mandibular alveolus Hard palate Buccal mucosa
25 11 7 5 From most recent previous primary
(R) maxilla
2 From most recent previous primary
Tongue Mandibular alveolus Maxillary alveolus Tongue Mandibular alveolus Floor of mouth Floor of mouth Tonsil Supraglottic Tonsillar pillar
Mandibular alveolus Mandibular alveolus Tongue Mandibular alveolus Floor of mouth Retromolar trigone Tongue Tongue Retromolar trigone Retromolar trigone
3 9 6 12 16 1 29 3 0 0
SD, smokers and drinkers; NSND, non-smokers non-drinkers. * Patients 1–5 are NSND; patients 6–15 are SD. Patients 4 and 5 had multiple primaries at intervals. Patients 14 and 15 had synchronous tumours.
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Fig. 2. Kaplan–Meier curves. (a) Gender P = 0.027; tobacco P = 0.498; alcohol P = 0.174; age P = 0.007. (b) TNM stage P < 0.001; NSND P = 0.024; NSND women P = 0.020; NSND old women P < 0.001.
tumours.13 Furthermore, HPV may confer a worse prognosis in tumours of the oral tongue.8 The bimodal distribution in our NSND group suggests that the first peak correlates with the recent trend towards HPV-related tumours in younger patients, with the second peak relating to an aetiology that has yet to be elucidated. The results of the present study indicate that OSCC in NSND patients behaves differently to that in SD patients and hence clinicians should be cognizant of their worse survival during assessment, treatment, and follow-up. At this time, there is no significant difference in the treatment of OSCC (e.g. elective neck dissections or adjuvant chemo-radiotherapy) for these patients.14 It has been documented that non-smoking status is a positive predictor of tumour epidermal growth factor receptor (EGFR) expression in head and neck SCC, which is a marker for the response to cetuximab,15 and this is also the case in lung cancers where non-smokers are more likely to respond to erlotinib and gefitinib.16 Altered treatment protocols for NSND patients might therefore provide improved outcomes. The percentage of patients with second primaries was similar in the NSND and SD groups. However, none of the NSND patients had second primaries outside the oral cavity, an area more conveniently assessed than other head and neck sub-
sites. A larger cohort would be needed to elaborate upon this finding, but it suggests a different pattern of second primary cancer development, with field cancerization confined to the oral cavity, as opposed to patients who smoke and the deleterious impact on the entire upper aerodigestive system. If disease is confined to the oral cavity in the NSND group, it would obviate or reduce the need for routine panendoscopies in the initial treatment and follow-up of these patients. There are certain important caveats to our findings. Elderly ‘NSND’ patients in the study cohort were largely from a generation where smoking was a social norm and environmental exposure to secondhand smoke could be a major confounding factor. Accurate information regarding environmental exposures to toxins is inherently difficult to obtain and the role of other environmental toxins driving the development of OSCC in these patients cannot be definitively ruled out. Nevertheless, the different clinical outcomes and different locations of the second primary tumours imply a yet to be identified local carcinogen. The study assessed consecutive patients with oral cancer from a single tertiary referral centre, and therefore it is impossible to know whether the spectrum of patients presenting to our centre is similar to that from the wider Australian commu-
nity. There may therefore be stochastic effects leading to a higher proportion of NSND patients presenting at our centre. In conclusion, this study identified a distinct clinical subgroup of non-smoking and non-drinking patients with oral squamous cell carcinoma. This group has a demographic distribution; different patients only have second primaries within the oral cavity and have worse outcomes with a higher mortality. Analysis of tumour biology in this subgroup may identify an as yet unknown aetiological agent, and may in future guide treatment decisions and provide unique molecular targets. Funding
Funding was provided by the Price Family Foundation. The study sponsors had no involvement in the study design or production of the manuscript. Competing interests
None declared. Ethical approval
This project was approved by the Human Research Ethics Committee of the Office for Research at Melbourne Health (QA2010093).
NSND elderly female OSCC patients Acknowledgements. The authors acknowledge the financial assistance of the Price Family Foundation for this project, as well as Maria Dikeakos and Craig Love for their assistance in data acquisition.
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