Abstract
Purpose
There is still debate in literature about the survival outcomes of patients who have cancer of the oral cavity when young. Hence the aims were (1) to estimate disease-free survival, overall survival, and cause-specific survival in patients who developed oral cavity squamous cell carcinoma between 18 and 40 years of age and (2) to assess the clinicopathologic factors including detection of human papillomavirus and epidermal growth factor receptor (EGFR) overexpression in primary lesions affecting recurrence.
Methods
This is a retrospective case-note review and reevaluation of histopathologic slides of patients treated more than 25 years. Descriptive statistics, Cox proportional hazard models, and Kaplan-Meier survival curves were used for statistical analysis.
Results
A total of 62 patients were treated, with mean follow-up of 11.4 years. Forty-five were oral tongue tumors and 43 had stage I or II disease. The 5-year disease-free survival was 73.5%. The 10-year overall survival and cause-specific survival rates were 81.8% and 83.4%, respectively. Smoking and alcohol intake were not seen as risk factors in this population. Multivariate modeling identified only nodal involvement as significantly associated with overall survival and only extracapsular spread as significantly associated with locoregional recurrence. At 5 years after treatment, the cause-specific survival was 100% for patients with low EGFR expression and 81.1% for patients with high EGFR expression (hazard ratio for high vs low, 3.1; 95% confidence interval, 0.4–406.9; P = .46). Human papillomavirus was not detected in all but 2 tumor specimens.
Conclusions
Survival outcomes are quite good in young patients with oral cancer.
1
Introduction
Oral cancer is the eighth most common cancer worldwide, whereas it is the third most common malignancy in South Central Asia . The World Health Organization expects a rising incidence of oral cancer in the coming decades. In the United States, oral cancer contributes to 2% to 4% of yearly incidence of new malignancies, causing about 8000 deaths per year . It typically occurs in older men in the fifth to eighth decades of life. There have been conflicting reports regarding the outcomes of squamous cell carcinoma in the young adult. Many reports suggest that tumors are more aggressive in younger patients and, consequently, need a more aggressive treatment . Others looking specifically into survival outcomes have identified no such difference but noted higher locoregional recurrence rates .
In this scenario, we looked at treatment and survival outcomes of patients 40 years and younger diagnosed as having oral cavity squamous cell cancers at our institution. The aims of our study were to (1) to estimate the overall survival and disease-specific survival for oral cavity squamous cell carcinoma in patients 18 to 40 years of age and (2) to assess the various clinicopathologic factors including human papillomavirus (HPV) presence and epidermal growth factor receptor (EGFR) overexpression affecting recurrence.
2
Materials and methods
After obtaining institutional review board approval (institutional review board number 07-1021), we reviewed the medical records of all patients treated at Mayo Clinic, Rochester, MN, with a diagnosis of squamous cell cancer of oral cavity subsites ( International Classification of Diseases codes 02, 03, 04, 05, and 06) 40 years or older at diagnosis during a 25-year period from 1980 to 2004. The inclusion criteria used were as follows:
• Definitive treatment of cancer at our institution
• Between 18 and 40 years of age at the time of initial diagnosis/treatment
• Minimum follow-up period of 2 years or until death
• Histopathologic diagnosis of squamous cell cancer or its variants
• Patient consent for their medical records to be accessed for research purposes
• Tumors belonging to oral cavity subsites
A recurrence was defined as squamous cell cancer (either of same or of different grade) occurring at the primary site (local recurrence), or in the neck nodes ([regional recurrence] if no further second primary tumors occurred in the intervening period in the head and neck region to account for it) in the first 5 years after treatment. Any tumor that occurred at an anatomically distant subsite to initial tumor or developed after 5 years of recurrence-free period at the original site was taken as a second primary.
The medical records were reviewed, and demographic, clinical, and histopathologic data were abstracted onto a standardized pro forma. All the available hematoxylin and eosin–stained original slides were retrieved and reassessed for uniformity of reporting by a single head and neck histopathologist (D.S.W.). The stored primary tumor specimens were retrieved, fresh slides were prepared, and all cases were tested by immunohistochemistry for EGFR expression and in situ hybridization for high- and low-risk HPV.
In situ hybridization was performed using probes against low-risk HPV family 6 (Ventana Medical Systems, Tucson, AZ; detects types 6 and 11), and separate probes against high-risk HPV family 16 (Ventana Medical Systems; detects types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 66) were performed using the nitroblue tetrazolium/5-bromo-4-chloro-3-indolyl-phosphate chromogen (Roche, Mannheim, Germany). In situ hybridization studies were scored as positive or negative.
Epidermal growth factor receptor immunohistochemical testing was performed using a monoclonal EGFR clone 2-18C9 and a polymer-based detection system (pharmDx Kit K1494 from Dako, Denmark). The EGFR pharmDx assay is a qualitative immunohistochemical kit system used to identify EGFR expression routinely fixed for histologic evaluation. The pharmDx kit specifically detects the EGFR (HER1) protein in EGFR-expressing cells. Both positive and negative controls were used. Positive staining was defined as any staining of tumor cell membranes, and staining intensity was recorded semiquantitatively as low (1+) or high (2+ or 3+) as previously described . A score of 1 would indicate mild levels of staining that will be present inevitably on epithelial tissues, a score of 2 would indicate a moderate degree of overstaining, and a score of 3 would indicate a severe degree of overstaining. The slides were read by the senior author who was blinded to the clinical outcomes.
2.1
Statistics
Standard descriptive statistics were used to summarize the data. Survival free of locoregional recurrence, overall survival (death due to any cause), and cause-specific survival (death due to disease) treatment of oral cavity squamous cell cancer were estimated using the Kaplan-Meier method. Duration of follow-up was calculated from the date of treatment to the date of the outcome of interest (eg, recurrence or death); otherwise, the duration of follow-up was censored at the date of last follow-up. For each outcome, univariate associations were evaluated based on fitting-separate Cox proportional hazard regression models. Multivariable models were evaluated using a stepwise variable selection method. Associations were summarized using hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) calculated using the parameters estimated in the models. All calculated P values were 2 sided, and P values less than .05 were considered statistically significant. Analyses were performed using the SAS software package (version 9.1; SAS Institute, Inc, Cary, NC).
2
Materials and methods
After obtaining institutional review board approval (institutional review board number 07-1021), we reviewed the medical records of all patients treated at Mayo Clinic, Rochester, MN, with a diagnosis of squamous cell cancer of oral cavity subsites ( International Classification of Diseases codes 02, 03, 04, 05, and 06) 40 years or older at diagnosis during a 25-year period from 1980 to 2004. The inclusion criteria used were as follows:
• Definitive treatment of cancer at our institution
• Between 18 and 40 years of age at the time of initial diagnosis/treatment
• Minimum follow-up period of 2 years or until death
• Histopathologic diagnosis of squamous cell cancer or its variants
• Patient consent for their medical records to be accessed for research purposes
• Tumors belonging to oral cavity subsites
A recurrence was defined as squamous cell cancer (either of same or of different grade) occurring at the primary site (local recurrence), or in the neck nodes ([regional recurrence] if no further second primary tumors occurred in the intervening period in the head and neck region to account for it) in the first 5 years after treatment. Any tumor that occurred at an anatomically distant subsite to initial tumor or developed after 5 years of recurrence-free period at the original site was taken as a second primary.
The medical records were reviewed, and demographic, clinical, and histopathologic data were abstracted onto a standardized pro forma. All the available hematoxylin and eosin–stained original slides were retrieved and reassessed for uniformity of reporting by a single head and neck histopathologist (D.S.W.). The stored primary tumor specimens were retrieved, fresh slides were prepared, and all cases were tested by immunohistochemistry for EGFR expression and in situ hybridization for high- and low-risk HPV.
In situ hybridization was performed using probes against low-risk HPV family 6 (Ventana Medical Systems, Tucson, AZ; detects types 6 and 11), and separate probes against high-risk HPV family 16 (Ventana Medical Systems; detects types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 66) were performed using the nitroblue tetrazolium/5-bromo-4-chloro-3-indolyl-phosphate chromogen (Roche, Mannheim, Germany). In situ hybridization studies were scored as positive or negative.
Epidermal growth factor receptor immunohistochemical testing was performed using a monoclonal EGFR clone 2-18C9 and a polymer-based detection system (pharmDx Kit K1494 from Dako, Denmark). The EGFR pharmDx assay is a qualitative immunohistochemical kit system used to identify EGFR expression routinely fixed for histologic evaluation. The pharmDx kit specifically detects the EGFR (HER1) protein in EGFR-expressing cells. Both positive and negative controls were used. Positive staining was defined as any staining of tumor cell membranes, and staining intensity was recorded semiquantitatively as low (1+) or high (2+ or 3+) as previously described . A score of 1 would indicate mild levels of staining that will be present inevitably on epithelial tissues, a score of 2 would indicate a moderate degree of overstaining, and a score of 3 would indicate a severe degree of overstaining. The slides were read by the senior author who was blinded to the clinical outcomes.
2.1
Statistics
Standard descriptive statistics were used to summarize the data. Survival free of locoregional recurrence, overall survival (death due to any cause), and cause-specific survival (death due to disease) treatment of oral cavity squamous cell cancer were estimated using the Kaplan-Meier method. Duration of follow-up was calculated from the date of treatment to the date of the outcome of interest (eg, recurrence or death); otherwise, the duration of follow-up was censored at the date of last follow-up. For each outcome, univariate associations were evaluated based on fitting-separate Cox proportional hazard regression models. Multivariable models were evaluated using a stepwise variable selection method. Associations were summarized using hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) calculated using the parameters estimated in the models. All calculated P values were 2 sided, and P values less than .05 were considered statistically significant. Analyses were performed using the SAS software package (version 9.1; SAS Institute, Inc, Cary, NC).
3
Results
3.1
Demographics and patient characteristics
There were a total of 66 patients who were between 18 and 40 years of age treated for oral cavity squamous cell carcinoma during the 25-year period. This represents 0.5% of the total number of patients treated for oral cavity cancers in the institution for the same period. No patients were excluded due to lack of follow-up, but 4 had not given consent for their medical records to be accessed for research purposes. Thus, 62 patients were included in the study. Relevant patient demographic details are given in Table 1 . Only 2 patients had a Karnofsky performance status of less than 100.
| Characteristics | n = 62 |
|---|---|
| Age at diagnosis (y), mean (SD) | 33.9 (5.2) |
| Sex, n (%) | |
| Male | 37 (59.7) |
| Female | 25 (40.3) |
| Race | |
| White | 55 (88.7) |
| Other/Unknown | 7 (11.3) |
| Smoking history, n (%) | |
| Never | 35 (56.5) |
| Ever | 25 (40.3) |
| Unknown | 2 (3.2) |
| Alcohol use, n (%) | |
| <6 units/wk | 37 (59.7) |
| ≥6 units/wk | 19 (30.6) |
| Unknown | 6 (9.7) |
| Family history of cancer (1st/2nd degree), n (%) | 34 (54.8) |
| Personal history of cancer, n (%) | 4 (6.5) |
| Immunocompromised, n (%) | 3 (4.8) |
The distribution of primary sites was anterior tongue in 45 (72.6%), floor of mouth or alveolar ridge in 8 (12.9%), buccal mucosa in 3 (4.8%), floor of mouth and anterior tongue in 2 (3.2%), and other sites in 4 (6.5%). The final pathologic tumor stage and nodal stage according to 7th American Joint Committee on Cancer (AJCC) staging system is given in Table 2 . The mean (SD) follow-up duration was 11.4 (8.4) years. The median (25th, 75th percentile) follow-up was 10.5 (3.2, 18.7) years. The range was 0.3 to 27.3 years.
| T stage | N stage | Total | |||||
|---|---|---|---|---|---|---|---|
| N 0 | N 1 | N 2a | N 2b | N 2c | N 3 | ||
| T is | – | – | – | – | – | – | 0 |
| T 1 | 29 | 1 | – | 3 | 0 | 0 | 33 |
| T 2 | 14 | 2 | – | 4 | 1 | 0 | 21 |
| T 3 | 1 | 1 | – | 0 | 0 | 0 | 2 |
| T 4a | 1 | 0 | – | 2 | 0 | 0 | 3 |
| T 4b | 0 | 0 | – | 1 | 0 | 2 | 3 |
| Total | 45 | 4 | 0 | 10 | 1 | 2 | 62 |
3.2
Tumor characteristics
The relevant tumor characteristics are given in Table 3 . Only 45 patients had a sufficient primary tumor sample for making new slides for the purposes of EGFR expression and HPV detection. The overall clinical staging and EGFR expression levels are given in Table 4 . All 45 samples that were tested were positive for EGFR expression. Seven (15.6%) had low levels of EGFR expression, whereas 38 (84.4%) had high levels (2+ or 3+) of EGFR expression.
| n (%) | |
|---|---|
| Type | |
| Verrucous ca | 2 (3.2) |
| Well-differentiated SCC ⁎ | 11 (17.7) |
| Moderately differentiated SCC | 25 (40.3) |
| Poorly differentiated SCC | 24 (38.7) |
| Tumor thickness (mm) | |
| <5 | 18 (29.0) |
| 5–10 | 20 (32.3) |
| >10 | 17 (27.4) |
| Unknown | 7 (11.3) |
| Tumor status | |
| Negative | 37 (59.7) |
| Negative after reexcision | 21 (33.9) |
| Close, <2 mm | 2 (3.2) |
| Unknown | 2 (3.2) |
| Dysplasia | 20 (32.3) |
| Desmoplasia in primary | 35 (56.5) |
| Involvement | |
| Muscle | 42 (67.7) |
| Bone | 3 (4.8) |
| Perineural | 16 (25.8) |
| Vascular | 5 (8.1) |
| Lymphatic | 4 (6.5) |
| Moderate-to-severe lymphoid reaction | 37 (59.7) |
| Desmoplasia in nodes | 14 (77.8) ⁎ |
| Extracapsular spread | 10 (16.1) |
| Prominent plasma cells | 26 (41.9) |
| HPV positive | 2 (4.4) † |
| EGFR 2+/3+ | 38 (84.4) † |
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