1

Introduction

Head and neck squamous cell carcinoma (HNSCC) is well known for its relationship with tobacco and alcohol consumption, and more recent studies have established the human papillomavirus (HPV) as another causative factor in certain anatomical subsites of HNSCC . Patients with HPV-positive HNSCC have been demonstrated to have an improved survival over similarly matched patients with HPV-negative disease . This epidemic of virus-related carcinoma has introduced a “new” group of head and neck cancer patients who tend to be young, male, nonsmokers and nondrinkers .

The demographics of patients with HPV-positive and HPV-negative disease have shifted substantially. Within the military veteran population, there remains a large cohort of patients with poorer health status, high use of tobacco and alcohol, increased number of sexual partners, and a tendency towards presentation later in the disease course . A previous analysis from our institution’s VA population has demonstrated that HPV-positive disease is also found among “traditional” head and neck cancer patients who are older with a history of alcohol and tobacco use, and that within these patients it retains its significance as a favorable prognostic indicator .

With the changing trends in HNSCC diagnosis, treatment, and prognosis, it is important to assess the difference in survival among patients with different disease states and to understand the role of various treatment modalities in patients’ outcomes. The appropriate treatment modality remains uncertain in various subsites, and the effect of comorbidities such as smoking on the patients’ outcomes is similarly unknown .

2

Methods

Patients included for analysis were diagnosed with HNSCC between January 1, 2010 and December 31, 2014 at the Veterans Affairs Greater Los Angeles Healthcare System. Patients without available tissue for pathologic analysis were excluded. Demographic and clinical data were retrospectively collected from the electronic medical record. Vital status was determined as death due to HNSCC, death due to other causes, alive, or unknown; patients who were lost to follow up were classified as unknown status and the last available clinical encounter date was used for censoring. Institutional Review Board approval was received for this study.

Tissue samples without HPV and/or p16 (tumor suppressor protein cyclin-dependent kinase inhibitor 2A) testing at the time of initial HNSCC diagnosis were retested. Immunohistochemical stain detection was performed using the DAKO FLEX System, which detects HPV serotypes 6, 11, 16, 18, 31, 33, 42, 51, 52, 56, and 58. Immunohistochemical stain p16 (Ventana) was used. HPV positivity was determined by having either a positive HPV high-risk subtype and/or positive p16 testing of tumor specimens, as over-expression of p16 is highly correlated with oncogenic transformation caused by persistent high-risk HPV infection.

Descriptive analyses were carried out among clinical and pathologic factors, with comparisons performed using the chi-square test for categorical variables and t -test for continuous variables. Univariate analyses were carried out for the impact of individual variables on overall survival using the Kaplan-Meier method and the log rank test. Multivariate analyses were then performed with Cox regression models to determine the effect of treatment modality on mortality after controlling for other predictive factors. Adjusted hazard ratios are presented for analyses among all patients and among only those patients with HPV-positive disease. All tests were two-sided, and P values < 0.05 were considered statistically significant. Statistical analyses were performed using SPSS version 22 and SAS version 9.2.

2

Methods

Patients included for analysis were diagnosed with HNSCC between January 1, 2010 and December 31, 2014 at the Veterans Affairs Greater Los Angeles Healthcare System. Patients without available tissue for pathologic analysis were excluded. Demographic and clinical data were retrospectively collected from the electronic medical record. Vital status was determined as death due to HNSCC, death due to other causes, alive, or unknown; patients who were lost to follow up were classified as unknown status and the last available clinical encounter date was used for censoring. Institutional Review Board approval was received for this study.

Tissue samples without HPV and/or p16 (tumor suppressor protein cyclin-dependent kinase inhibitor 2A) testing at the time of initial HNSCC diagnosis were retested. Immunohistochemical stain detection was performed using the DAKO FLEX System, which detects HPV serotypes 6, 11, 16, 18, 31, 33, 42, 51, 52, 56, and 58. Immunohistochemical stain p16 (Ventana) was used. HPV positivity was determined by having either a positive HPV high-risk subtype and/or positive p16 testing of tumor specimens, as over-expression of p16 is highly correlated with oncogenic transformation caused by persistent high-risk HPV infection.

Descriptive analyses were carried out among clinical and pathologic factors, with comparisons performed using the chi-square test for categorical variables and t -test for continuous variables. Univariate analyses were carried out for the impact of individual variables on overall survival using the Kaplan-Meier method and the log rank test. Multivariate analyses were then performed with Cox regression models to determine the effect of treatment modality on mortality after controlling for other predictive factors. Adjusted hazard ratios are presented for analyses among all patients and among only those patients with HPV-positive disease. All tests were two-sided, and P values < 0.05 were considered statistically significant. Statistical analyses were performed using SPSS version 22 and SAS version 9.2.

3

Results

There were 209 patients with primary tumor sites including larynx (25.4%), oral tongue (19.6%), oral cavity (13.4%), oropharynx (17.2%), tonsil (17.2%), unknown primary (2.9%), nasopharynx (1.9%), and multiple sites (2.4%) ( Table 1 ). The mean age was 65.1 years (± 8.9), with a majority of white patients (66.0%). Patients with HPV-positive disease were statistically significantly younger than those with HPV-negative disease, with mean age of 63.3 years and 66.3 years, respectively ( P = 0.0294). The percentage of white patients was greater in the HPV-positive patients than HPV-negative patients (74.2% and 54.9%, respectively; P = 0.0116). Patients with HPV-positive tumors were more likely to receive chemoradiation (77.5%) than those with HPV-negative tumors (42.7%), and less likely to receive surgery (11.2% and 20.7%, respectively; P < 0.0001). Anatomic subsites also varied by HPV status; tonsil and oropharynx represented 50.6% of the HPV-positive group, while larynx (40.2%) was the most common tumor site in the HPV-negative group ( P < 0.0001). Although there was no difference in T classification between groups, the HPV-positive group was more likely to have N2 (53.9%) or N3 (12.4%) disease compared to the HPV-negative group, which had fewer N2 (39.0%) or N3 (4.9%) patients ( P = 0.0083). Metastatic disease was more common in the HPV-negative group than HPV-positive group (11.0% and 2.2%, respectively; P = 0.0444). Median follow up was 16.2 months (interquartile range 7.7–30.1 months).

Table 1

Demographic and clinical characteristics by HPV status.

	Overall		HPV (−)		HPV (+)		P
	n = 209		n = 82		n = 89
	n	%	n	%	n	%
Race							0.0116
White	138	66.0	45	54.9	66	74.2
Black	52	24.9	25	30.5	18	20.2
Other	18	8.6	12	14.6	4	4.5
Unknown	1	0.5	0	0.0	1	1.1
Smoking							0.1354
Never	33	15.8	9	11.0	18	20.2
Former	80	38.3	30	36.6	35	39.3
Current	95	45.5	43	52.4	35	39.3
Unknown	1	0.5	0	0.0	1	1.1
Alcohol							0.6470
Never	68	32.5	25	30.5	32	36.0
Former	55	26.3	20	24.4	22	24.7
Current	85	40.7	37	45.1	34	38.2
Unknown	1	0.5	0	0.0	1	1.1
Primary treatment							< 0.0001
Chemoradiation	124	59.3	35	42.7	69	77.5
Radiation Therapy	37	17.7	24	29.3	8	9.0
Surgery	39	18.7	17	20.7	10	11.2
None	9	4.3	6	7.3	2	2.2
Anatomic Site							< 0.0001
Nasopharynx	4	1.9	1	1.2	3	3.4
Larynx	53	25.4	33	40.2	6	6.7
Oral Cavity	28	13.4	14	17.1	7	7.9
Tongue	41	19.6	10	12.2	24	27.0
Oropharynx	36	17.2	14	17.1	17	19.1
Tonsil	36	17.2	6	7.3	28	31.5
Unknown Primary	6	2.9	2	2.4	2	2.2
Multiple Sites	5	2.4	2	2.4	2	2.2
T Classification							0.9183
1	54	25.8	23	28.0	22	24.7
2	50	23.9	16	19.5	22	24.7
3	42	20.1	17	20.7	18	20.2
4	53	25.4	22	26.8	24	27.0
Unknown	10	4.8	4	4.9	3	3.4
N Classification							0.0083
0	74	35.4	35	42.7	16	18.0
1	25	12.0	9	11.0	12	13.5
2	89	42.6	32	39.0	48	53.9
3	17	8.1	4	4.9	11	12.4
Unknown	4	1.9	2	2.4	2	2.2
M Classification							0.0444
0	171	81.8	60	73.2	76	85.4
1	13	6.2	9	11.0	2	2.2
Unknown	25	12.0	13	15.9	11	12.4
	mean	SD	mean	SD	mean	SD
Age (years)	65.1	8.9	66.3	9.4	63.3	8.4	0.0294
	median	IQR	median	IQR	median	IQR
Follow up (months)	16.2	7.7, 30.1	17.9	6.0, 29.3	17.3	10.4, 32.2	0.3678

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