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Figure 1.
Frequency of Unknown Primary Squamous Cell Cancer (UPSCC) of the Head and Neck at Presentation Over Time
Frequency of Unknown Primary Squamous Cell Cancer (UPSCC) of the Head and Neck at Presentation Over Time

The frequency of UPSCC cases has increased significantly from 2005 to 2014 (P for trend = .01).

Figure 2.
Mean Annual Number of Cases of Unknown Primary Squamous Cell Cancer (UPSCC) of the Head and Neck at Presentation Over Time
Mean Annual Number of Cases of Unknown Primary Squamous Cell Cancer (UPSCC) of the Head and Neck at Presentation Over Time

In the earliest 4-year calendar period (2005-2008), there were 14 cases. In the later, 3-year calendar period (2009-2011), 30 cases of UPSCC presented. In the most recent and shortest calendar period (2012-2014), 37 UPSCC cases were observed. The mean number of cases in the earlier calendar period compared with the most recent calendar period has significantly increased (P = .03).

Figure 3.
Human Papillomavirus (HPV) Tumor Status Among Unknown Primary Squamous Cell Carcinoma of the Head and Neck at Presentation Over Time
Human Papillomavirus (HPV) Tumor Status Among Unknown Primary Squamous Cell Carcinoma of the Head and Neck at Presentation Over Time

The proportion of unknown primary squamous cell carcinomas of the head and neck that were HPV-positive was similar across calendar periods (100% in 2005-2008, 90.3% in 2009-2011, and 89.7% in 2012-2014; P = .64).

Table 1.  
Clinical Characteristics of the Study Population at Diagnosisa
Clinical Characteristics of the Study Population at Diagnosisa
Table 2.  
UPSCC Detection Rate Over Time and Before and After TORS
UPSCC Detection Rate Over Time and Before and After TORS
1.
Strojan  P, Ferlito  A, Medina  JE,  et al.  Contemporary management of lymph node metastases from an unknown primary to the neck: I. A review of diagnostic approaches.  Head Neck. 2013;35(1):123-132.PubMedGoogle ScholarCrossref
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Koch  WM, Bhatti  N, Williams  MF, Eisele  DW.  Oncologic rationale for bilateral tonsillectomy in head and neck squamous cell carcinoma of unknown primary source.  Otolaryngol Head Neck Surg. 2001;124(3):331-333.PubMedGoogle ScholarCrossref
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McQuone  SJ, Eisele  DW, Lee  DJ, Westra  WH, Koch  WM.  Occult tonsillar carcinoma in the unknown primary.  Laryngoscope. 1998;108(11, pt 1):1605-1610.PubMedGoogle ScholarCrossref
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Park  GC, Lee  M, Roh  J-L,  et al.  Human papillomavirus and p16 detection in cervical lymph node metastases from an unknown primary tumor.  Oral Oncol. 2012;48(12):1250-1256.PubMedGoogle ScholarCrossref
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Vent  J, Haidle  B, Wedemeyer  I,  et al.  p16 expression in carcinoma of unknown primary: diagnostic indicator and prognostic marker.  Head Neck. 2013;35(11):1521-1526.PubMedGoogle ScholarCrossref
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El-Naggar  AK, Westra  WH.  p16 expression as a surrogate marker for HPV-related oropharyngeal carcinoma: a guide for interpretative relevance and consistency.  Head Neck. 2012;34(4):459-461.PubMedGoogle ScholarCrossref
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Desai  PC, Jaglal  MV, Gopal  P,  et al.  Human papillomavirus in metastatic squamous carcinoma from unknown primaries in the head and neck: a retrospective 7 year study.  Exp Mol Pathol. 2009;87(2):94-98.PubMedGoogle ScholarCrossref
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Jensen  DH, Hedback  N, Specht  L,  et al.  Human papillomavirus in head and neck squamous cell carcinoma of unknown primary is a common event and a strong predictor of survival.  PLoS One. 2014;9(11):e110456.PubMedGoogle ScholarCrossref
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Compton  AM, Moore-Medlin  T, Herman-Ferdinandez  L,  et al.  Human papillomavirus in metastatic lymph nodes from unknown primary head and neck squamous cell carcinoma.  Otolaryngol Head Neck Surg. 2011;145(1):51-57.PubMedGoogle ScholarCrossref
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Tribius  S, Hoffmann  AS, Bastrop  S,  et al.  HPV status in patients with head and neck of carcinoma of unknown primary site: HPV, tobacco smoking, and outcome.  Oral Oncol. 2012;48(11):1178-1184.PubMedGoogle ScholarCrossref
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Kobayashi  K, Saito  Y, Omura  G,  et al.  Clinical features of human papilloma virus-related head and neck squamous cell carcinoma of an unknown primary site.  ORL J Otorhinolaryngol Relat Spec. 2014;76(3):137-146.PubMedGoogle ScholarCrossref
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Keller  LM, Galloway  TJ, Holdbrook  T,  et al.  p16 status, pathologic and clinical characteristics, biomolecular signature, and long-term outcomes in head and neck squamous cell carcinomas of unknown primary.  Head Neck. 2014;36(12):1677-1684.PubMedGoogle ScholarCrossref
16.
Durmus  K, Rangarajan  SV, Old  MO, Agrawal  A, Teknos  TN, Ozer  E.  Transoral robotic approach to carcinoma of unknown primary.  Head Neck. 2014;36(6):848-852.PubMedGoogle ScholarCrossref
17.
Mehanna  H, Beech  T, Nicholson  T,  et al.  Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer: systematic review and meta-analysis of trends by time and region.  Head Neck. 2013;35(5):747-755.PubMedGoogle ScholarCrossref
18.
Chaturvedi  AK, Engels  EA, Pfeiffer  RM,  et al.  Human papillomavirus and rising oropharyngeal cancer incidence in the United States.  J Clin Oncol. 2011;29(32):4294-4301.PubMedGoogle ScholarCrossref
19.
Patel  SA, Magnuson  JS, Holsinger  FC,  et al.  Robotic surgery for primary head and neck squamous cell carcinoma of unknown site.  JAMA Otolaryngol Head Neck Surg. 2013;139(11):1203-1211.PubMedGoogle ScholarCrossref
20.
Mehta  V, Johnson  P, Tassler  A,  et al.  A new paradigm for the diagnosis and management of unknown primary tumors of the head and neck: a role for transoral robotic surgery.  Laryngoscope. 2013;123(1):146-151.PubMedGoogle ScholarCrossref
21.
Weiss  D, Koopmann  M, Rudack  C.  Prevalence and impact on clinicopathological characteristics of human papillomavirus-16 DNA in cervical lymph node metastases of head and neck squamous cell carcinoma.  Head Neck. 2011;33(6):856-862.PubMedGoogle ScholarCrossref
22.
Cianchetti  M, Mancuso  AA, Amdur  RJ,  et al.  Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site.  Laryngoscope. 2009;119(12):2348-2354.PubMedGoogle ScholarCrossref
23.
Graboyes  EM, Sinha  P, Thorstad  WL, Rich  JT, Haughey  BH.  Management of human papillomavirus-related unknown primaries of the head and neck with a transoral surgical approach.  Head Neck. 2015;37(11):1603-1611.PubMedGoogle ScholarCrossref
24.
Edge  S, Byrd  D, Compton  C. Thyroid. In:  AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:41-56.
25.
Gillison  ML, D’Souza  G, Westra  W,  et al.  Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers.  J Natl Cancer Inst. 2008;100(6):407-420.PubMedGoogle ScholarCrossref
26.
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(2):467-475.PubMedGoogle ScholarCrossref
27.
Gillison  ML, Chaturvedi  AK, Anderson  WF, Fakhry  C.  Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma.  J Clin Oncol. 2015;33(29):3235-3242.PubMedGoogle ScholarCrossref
28.
Fakhry  C, Gillison  ML.  Clinical implications of human papillomavirus in head and neck cancers.  J Clin Oncol. 2006;24(17):2606-2611.PubMedGoogle ScholarCrossref
29.
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.PubMedGoogle ScholarCrossref
30.
Benson  E, Li  R, Eisele  D, Fakhry  C.  The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas.  Oral Oncol. 2014;50(6):565-574.PubMedGoogle ScholarCrossref
31.
Fakhry  C, Gillison  ML, D’Souza  G.  Tobacco use and oral HPV-16 infection.  JAMA. 2014;312(14):1465-1467.PubMedGoogle ScholarCrossref
32.
D’Souza  G, Gross  ND, Pai  SI,  et al.  Oral human papillomavirus (HPV) infection in HPV-positive patients with oropharyngeal cancer and their partners.  J Clin Oncol. 2014;32(23):2408-2415.PubMedGoogle ScholarCrossref
33.
Rettig  E, Kiess  AP, Fakhry  C.  The role of sexual behavior in head and neck cancer: implications for prevention and therapy.  Expert Rev Anticancer Ther. 2015;15(1):35-49.PubMedGoogle ScholarCrossref
34.
D’Souza  G, Cullen  K, Bowie  J, Thorpe  R, Fakhry  C.  Differences in oral sexual behaviors by gender, age, and race explain observed differences in prevalence of oral human papillomavirus infection.  PLoS One. 2014;9(1):e86023.PubMedGoogle ScholarCrossref
35.
Chaturvedi  AK, Graubard  BI, Broutian  T,  et al.  NHANES 2009-2012 findings: association of sexual behaviors with higher prevalence of oral oncogenic human papillomavirus infections in US men.  Cancer Res. 2015;75(12):2468-2477.PubMedGoogle ScholarCrossref
36.
Fakhry  C, Agrawal  N, Califano  J,  et al.  The use of ultrasound in the search for the primary site of unknown primary head and neck squamous cell cancers.  Oral Oncol. 2014;50(7):640-645.PubMedGoogle ScholarCrossref
37.
Mydlarz  WK, Liu  J, Blanco  R, Fakhry  C.  Transcervical ultrasound identifies primary tumor site of unknown primary head and neck squamous cell carcinoma.  Otolaryngol Head Neck Surg. 2014;151(6):1090-1092.PubMedGoogle ScholarCrossref
38.
Blanco  RGF, Califano  J, Messing  B,  et al.  Transcervical ultrasonography is feasible to visualize and evaluate base of tongue cancers.  PLoS One. 2014;9(1):e87565.PubMedGoogle ScholarCrossref
39.
Coquia  SF, Hamper  UM, Holman  ME,  et al.  Visualization of the oropharynx with transcervical ultrasound.  AJR Am J Roentgenol. 2015;205(6):1288-1294.PubMedGoogle ScholarCrossref
40.
Joseph  AW, Ogawa  T, Bishop  JA,  et al.  Molecular etiology of second primary tumors in contralateral tonsils of human papillomavirus-associated index tonsillar carcinomas.  Oral Oncol. 2013;49(3):244-248.PubMedGoogle ScholarCrossref
41.
Roeser  MM, Alon  EE, Olsen  KD, Moore  EJ, Manduch  M, Wismayer  DJ.  Synchronous bilateral tonsil squamous cell carcinoma.  Laryngoscope. 2010;120(suppl 4):S181.PubMedGoogle ScholarCrossref
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McGovern  SL, Williams  MD, Weber  RS,  et al.  Three synchronous HPV-associated squamous cell carcinomas of Waldeyer’s ring: case report and comparison with Slaughter’s model of field cancerization.  Head Neck. 2010;32(8):1118-1124.PubMedGoogle ScholarCrossref
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Nakahara  S, Yasui  T, Takenaka  Y,  et al.  Synchronous bilateral tonsillar carcinomas associated with human papillomavirus.  Auris Nasus Larynx. 2014;41(1):109-112.PubMedGoogle ScholarCrossref
Original Investigation
March 2016

Changes in Unknown Primary Squamous Cell Carcinoma of the Head and Neck at Initial Presentation in the Era of Human Papillomavirus

Author Affiliations
  • 1Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland
JAMA Otolaryngol Head Neck Surg. 2016;142(3):223-228. doi:10.1001/jamaoto.2015.3228
Abstract

Importance  The presence of human papillomavirus (HPV) in unknown primary squamous cell carcinoma (UPSCC) of the head and neck at initial presentation focuses the investigation for the primary tumor on the oropharynx. The trends, frequency, and detection rate of UPSCCs have not been evaluated in the context of HPV tumor status.

Objectives  To determine the frequency of UPSCC over time and to evaluate the proportion of HPV-positive UPSCCs.

Design, Setting, and Participants  Retrospective, single-institutional case series of patients diagnosed with UPSCC and evaluated at the Johns Hopkins Hospital from January 1, 2005, to June 1, 2014. Human papillomavirus tumor status was determined by p16 immunohistochemical analysis and/or high-risk HPV DNA by in situ hybridization as clinically available.

Main Outcomes and Measures  Number and clinical characteristics of UPSCC cases over time.

Results  Eighty-four UPSCC cases were eligible for analysis. The mean age of the patients was 57.3 years (range 29-80 years), and 88.1% (n = 74) were male. The frequency of UPSCC increased significantly over time (P for trend = .01) and was significantly higher during later calendar periods (14 cases during 2005-2008 vs 39 cases during 2012-2014, P = .03). A total of 69 cases (90.7%) with available HPV tumor status were HPV-positive. The patients with HPV-positive UPSCC were significantly more likely to be male (91% vs 42.9%, P = .005) and younger (56.1 vs 67.7 years, P = .002) than the HPV-negative patients with UPSCC. The overall primary tumor site detection rate was 59.3% (n = 48). There was a nonsignificant increase in the detection rate from calendar periods 2005-2008 to 2012-2014 (50.0% vs 64.9%, P = .38). Since transoral robotic surgery was adopted in the diagnostic evaluation of UPSCC in 2011, a nonsignificant increase in the detection of primary tumors was observed (53.8% vs 64.3%, P = .34).

Conclusions and Relevance  The frequency of UPSCC has increased significantly in recent calendar periods, and most cases are HPV-positive. As expected, patients with HPV-positive UPSCC tend to be male and younger.

Introduction

Unknown primary squamous cell carcinoma (UPSCC) of the head and neck is a rare entity characterized by clinical nodal metastases without an identifiable primary tumor site. Approximately 4% of head and neck SCCs present as UPSCC.1 Diagnostic evaluation of the primary site historically included visualization and directed biopsies of the nasopharynx, larynx, hypopharynx, and oropharynx.2,3 However, contemporary diagnostic evaluation has evolved to include physical examination, endoscopic and radiographic imaging, palatine and lingual tonsillectomy, and human papillomavirus (HPV) and Epstein-Barr virus detection.1 Human papillomavirus–positive tumor status of UPSCC has emerged as an important biomarker for primary disease arising from the oropharynx.4-6 Therefore, the presence of an HPV-positive tumor status in UPSCC permits a focused diagnostic evaluation of the oropharynx.6-8

A disproportionate number of HPV-positive oropharyngeal SCCs compared with HPV-negative oropharyngeal SCCs initially present as UPSCC.9 When these HPV-positive oropharyngeal primary tumors are ultimately discovered, they are commonly found in the cryptic lymphoepithelium of the palatine and lingual tonsils.10 Although UPSCCs are strongly associated with HPV-positive tumor status,4-9 the proportion that are HPV-positive is unknown. Several retrospective series of UPSCC arising from all head and neck sites with sample sizes ranging from 25 to 63 have estimated that 22% to 74% are related to HPV.10-16 One series of 26 cases limited to UPSCCs that were ultimately found to arise exclusively from the oropharynx reported the proportion of HPV-positive tumor status to be as high as 81%.9 With the incidence of HPV-related oropharyngeal cancer increasing in the United States and other countries,17,18 we hypothesized that both the frequency of UPSCCs and the proportion that are HPV-positive are increasing.

Identification of the primary tumor when a patient presents with a UPSCC has important clinical implications. Localization allows for more targeted therapy and potentially decreased morbidity and improved survival.19-21 Considering that treatment outcomes depend on whether the primary tumor is detected, the diagnostic investigation remains paramount for UPSCCs. Estimates of the primary tumor detection rate for UPSCC in the literature are broad and do not account for HPV tumor status.7,20,22 Transoral robotic surgery (TORS) and transoral laser microsurgery are surgical methods touted to increase the detection of primary tumors.23 Whether UPSCC detection rates have improved in the context of these novel surgical tools is unknown. The aims of this study were to determine the changes in frequency of UPSCC evaluated over time, estimate the proportion of UPSCCs that are HPV-positive, and evaluate changes in the detection rate of primary tumors in UPSCC over time.

Methods
Patient Selection

Patients with a clinical diagnosis of UPSCC as determined by a head and neck surgical oncologist at the Johns Hopkins Hospital from January 1, 2005, to June 1, 2014, were eligible for this study. This was a single-institution retrospective review approved by the Johns Hopkins Hospital Institutional Review Board. Patients with recurrent disease or evidence of a primary tumor site determined by previous biopsies or clinical workup were excluded. All records were reviewed to confirm that a Johns Hopkins Hospital head and neck surgeon had provided a clinical diagnosis of UPSCC and documented that there was no clinical evidence or suspicion of a primary lesion on clinical, radiographic, or flexible endoscopic evaluation.

Clinical Data

Medical records of eligible patients were abstracted. Clinical variables of interest included age, sex, race, smoking and alcohol exposure, tumor site, HPV tumor status, TNM classification, and overall stage based on surgical pathologic findings as defined by the American Joint Committee on Cancer.24 Human papillomavirus tumor status was determined by p16 immunohistochemical analysis and/or high-risk HPV DNA in situ hybridization, as clinically available. Patients were considered to be HPV-positive if p16 immunohistochemical analysis and/or in situ hybridization results for high-risk HPV were positive. In addition, receipt of surgical diagnostic interventions, including direct laryngoscopy and palatine and lingual tonsillectomy, was of interest. Of note, TORS was offered for UPSCC detection after 2011 for lingual tonsillectomy in the event that imaging, endoscopy, directed surgical biopsies, and/or palatine tonsillectomy did not identify a primary tumor consistent with previous literature.20

Positron emission tomography (PET) results were reviewed. Patients with equivocal PET scans were eligible for analysis. If a primary tumor was suspected on a PET scan but no primary site was identified after surgical evaluation, these patients were considered to have UPSCC and were therefore eligible for analysis. However, patients with a suspicious lesion on a PET scan, which was pathologically confirmed as the site of the primary tumor, were ineligible. Furthermore, if direct laryngoscopy revealed a visually suspicious lesion, which subsequently tested positive for carcinoma, these patients were also ineligible.

Statistical Analysis

Descriptive statistics were used to summarize frequencies, proportions, means, and ranges. Associations between HPV tumor status and clinical variables of interest were evaluated using Fisher exact tests for categorical variables and 2-sample t tests for continuous variables. Nonparametric tests for trend were performed across periods for the number of UPSCCs evaluated per year and the proportion of cases with primary site detection. Prevalence ratios (PRs) for primary site detection by period were estimated using log-binomial regression. The median number of surgical procedures before and after the potential use of TORS in diagnostic evaluation of UPSCC was compared using a nonparametric Wilcoxon rank sum test. A 2-sided P < .05 was considered statistically significant. Data analysis was performed using STATA statistical software, version 11.2 (StataCorp).

Results
Demographic Characteristics

The characteristics of the study population are summarized in Table 1. In total, 84 cases of UPSCCs were eligible for analysis. The mean age of the patients was 57.3 years (range, 29-80 years). Most of the study population was male (74 of 84 [88.1%]) and had a history of ever smoking (50 of 78 [64.1%]). Human papillomavirus tumor status of metastatic cervical lymph nodes was available for 76 of 84 patients (90.5%). Of the 75 patients with HPV tumor status available, 68 (90.8%) were HPV-positive. The characteristics of patients with and without HPV tumor status were similar (P = .12).

The characteristics of HPV-positive and HPV-negative patients with UPSCCs were compared. A significantly greater proportion of HPV-positive patients with UPSCCs were male than the HPV-negative patients with UPSCCs (91.3% vs 42.9%, P = .005). The HPV-positive patients with UPSCCs were on average significantly younger than the HPV-negative patients with UPSCCs (56.1 vs 67.7 years, P = .002). The HPV-positive patients with UPSCCs were more likely to present with advanced nodal stage compared with the HPV-negative patients with UPSCCs (P = .05). A higher proportion of HPV-positive patients with UPSCCs were never smokers relative to the HPV-negative patients with UPSCCs, although this finding was not statistically significant (37.5% vs 0%, P = .09).

Trends in UPSCC Over Time

The frequency of patients presenting with a clinical diagnosis of UPSCC has significantly increased over time (P for trend = .01; Figure 1). When considering the mean number of UPSCCs per year, an increase was observed by calendar period (Figure 2). The mean number of UPSCCs per year increased significantly from 3.5 cases in the earliest calendar period (2005-2008) to 10.3 cases in 2009-2011 and 15.6 cases in the most recent calendar period (2012-2014) (P = .03). The proportion of UPSCCs that were HPV-positive across calendar periods was similar (P = .64) although most UPSCCs in recent calendar periods were HPV-positive (Figure 3). In the earliest calendar period, there were a substantial number of cases with unknown HPV tumor status (n = 8 [9.5%]; Figure 3).

Trends in Detection

Most UPSCCs underwent diagnostic evaluation in an attempt to localize the primary site (81 of 84 [96.4%]). Therefore, analysis of detection was limited to these 81 patients. Overall, primary tumors were ultimately identified in 48 of 81 UPSCCs (59.3%). Most patients with identified primary tumors were HPV-positive (44 of 46 [95.7%]). All identified primary tumors were found in the oropharynx. Twenty-seven (56.3%) were determined to be primary tumors of the base of tongue, 20 (41.7%) of the palatine tonsils, and 1 (2.1%) that was overlapping the base of tongue and palatine tonsil.

When evaluating changes in detection over time, the proportion of identified primary tumors increased, although nonsignificantly, from 50.0% in 2005-2008 to 64.9% in 2012-2014 (P for trend = .38; PR = 1.3; Table 2). To determine whether the availability of TORS lingual tonsillectomy in 2011 affected the detection rate of primary tumors, the proportion of primary tumors identified before and after TORS was compared. A lower proportion of UPSCCs was identified in the pre-TORS period compared with the post-TORS period, although this finding was nonsignificant (53.8% vs 64.3%; PR = 1.2; P = .34; Table 2). Among HPV-positive UPSCCs, the detection rate over time was similar (P for trend = .14; eTable in the Supplement). Finally, the mean number of surgical procedures per patient with UPSCC before and after TORS was compared. There was no increase in the mean number of surgical procedures performed per patient after the introduction of TORS into the UPSCC diagnostic workup (1.85 vs 1.88; range, 1-4; P = .95).

Among the 48 patients with primary tumors detected, 26 (54.2%) underwent bilateral palatine tonsillectomy or bilateral lingual tonsillectomy. Of those patients, 2 (7.7%) had synchronous primary lesions. In both these cases, the tumor was HPV-positive.

Discussion

This analysis describes an increasing frequency of UPSCCs in recent calendar periods, most of which are HPV-positive. Although the increasing frequency of UPSCCs has not previously been described, it is not unexpected given the evolving epidemiologic features of head and neck cancer.

The increasing incidence of oropharyngeal squamous cell cancers in the United States and abroad is attributable to HPV infection.17,18 Human papillomavirus–positive oropharyngeal cancers are more commonly small primary tumors with advanced nodal disease; consequently, UPSCCs are disproportionately HPV-positive.7,25 In light of these trends, the high proportion of HPV-positive UPSCCs in this series is consistent with the observed epidemiologic features of head and neck cancer. In this large, albeit single-institution series, 91% of contemporary UPSCCs are HPV-positive. Prior estimates varied from 22% to 81%, with most series reporting that less than 50% of cases are HPV-positive by either p16 immunohistochemical analysis or in situ hybridization.10-15 Similar to the epidemiology of oropharyngeal cancer, the variation may be a reflection of geographic heterogeneity26,27 or HPV detection methods.8 The observation that most UPSCCs are HPV-positive suggests that HPV is indeed driving the increased frequency of UPSCCs.

Although the question of greater significance is whether the incidence of UPSCCs is increasing, it is challenging to determine this at a population level. The UPSCCs in the US-based population registry (Surveillance, Epidemiology, and End Results Program of the National Cancer Institute) is not specific to the head and neck but rather captures unknown primary tumors of all anatomical sites, including the abdomen and chest. Given this limitation, we investigated this question at a tertiary medical center and evaluated frequency over time but highlight the inability to provide a rate.

Consistent with the clinicodemographic distinctions between HPV-positive and HPV-negative oropharyngeal cancers, analogous clinicodemographic differences were observed between HPV-positive and HPV-negative UPSCCs.28,29 Human papillomavirus–positive UPSCCs are more commonly found in males, younger patients, and nonsmokers compared with HPV-negative UPSCCs. This finding reinforces the notion that HPV confers a distinct clinicodemographic profile on patients with head and neck malignant neoplasms.28,30 This finding may reflect demographic differences in exposure to oral HPV infection.31-35

Identification of the primary tumor for patients with UPSCC is of prognostic significance and has long been a priority. Bilateral tonsillectomies after negative direct laryngoscopy and directed biopsies have historically been recommended.2,3 However, lingual tonsillectomy has been advocated as a means of further increasing detection rates of unknown primary tumors.20 Small case series with variable selection criteria have reported identification in 72% to 90% of cases.19,20 A large series restricted to HPV-positive UPSCCs reported a detection rate of 89% using a TORS algorithm.23 In this study, there was a nonsignificant increase in the detection rate of primary tumors before vs after TORS. Whether this can be attributed to TORS or the knowledge that HPV-positive UPSCCs are more likely to arise from the oropharynx and therefore increased diagnostic scrutiny of this site remains unknown. Given the potential morbidity of this surgical approach, including bleeding, dysphagia, and strictures, there was not a significant increase in the number of procedures per patient. New strategies, such as transcervical ultrasonography, may help guide primary tumor identification and reduce the breadth of the TORS operative field and therefore potential morbidities.36-39

Of the cases in this study that underwent bilateral palatine or lingual tonsillectomy with the primary lesions ultimately identified, 2 of 26 (7.7%) had synchronous primary lesions. Both these synchronous primary lesions were HPV-positive. Human papillomavirus–positive synchronous primary tumors have been reported, but the pathophysiologic features remain poorly understood.40-43 Groups exploring the molecular causes of synchronous HPV-positive primary tumors hypothesize migration of HPV-infected cells throughout the Waldeyer ring or independent inoculation events by the same virus leading to field cancerization.40 Other studies19,23 investigating the utility of TORS for detecting primary tumors in UPSCCs have also reported synchronous primary tumors; thus, it is important to consider this possibility when evaluating patients with HPV-positive UPSCC. Whether synchronous primary tumors are more or less common in HPV-positive than HPV-negative oropharyngeal cancer is unknown. Determining this and improved estimates of the frequency of synchronous primary tumors will inform the extent of diagnostic interventions at the time of UPSCC evaluation.

Although, to our knowledge, this is the largest single-institution series of UPSCCs in the context of HPV tumor status and describes trends over time, there are important limitations that warrant attention. As previously discussed, changes in frequency, not incidence, are described. Therefore, the frequency changes could be a reflection of institutional referral patterns and marketing, which may affect the total number of patients with head and neck cancer, rather than driven by increasing incidence of this entity. In addition, this is a retrospective single-institution review and therefore has the inherent biases and shortcomings of such a study, including geographic and institutional factors that may influence HPV detection. Of note, HPV detection results are not available for more than half of the earlier calendar period UPSCCs. Human papillomavirus detection results in this calendar period may be biased by physicians ordering HPV tumor detection for UPSCCs with clinical characteristics of patients with oropharyngeal cancer, which could explain why 100% of patients tested in the earliest time point were HPV-positive. Therefore, had all the UPSCCs in the earlier calendar period been appropriately tested, it would be expected that the proportion that were HPV-positive would be commensurate with later calendar periods. Finally, the distribution of calendar years per calendar periods is not equal; therefore, mean number of cases was used to evaluate questions of interest. This was dictated by the number of cases over time and calendar periods.

Conclusions

The findings of this study indicate an increasing frequency of UPSCCs and that most of these cases are HPV-positive. It is likely that the increase in HPV-related tumors is driving the increase in UPSCC. Human papillomavirus–positive UPSCCs differ from HPV-negative UPSCCs by clinicodemographic characteristics.

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Article Information

Submitted for Publication: August 20, 2015; final revision received October 13, 2015; accepted November 15, 2015.

Corresponding Author: Carole Fakhry, MD, MPH, Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins School of Medicine, 601 N Caroline St, Johns Hopkins Outpatient Center, Sixth Floor, Baltimore, MD 21287 (cfakhry@jhmi.edu).

Published Online: January 14, 2016. doi:10.1001/jamaoto.2015.3228.

Author Contributions: Dr Motz and Mr Qualliotine had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Motz, Fakhry.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Motz, Qualliotine, Rettig, Richmon, Fakhry.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Motz, Qualliotine, Rettig, Fakhry.

Obtained funding: Fakhry.

Administrative, technical, or material support: Eisele, Fakhry.

Study supervision: Rettig, Richmon, Eisele, Fakhry.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grant P50DE019032 from the National Institute of Dental and Craniofacial Research and the Oral Cancer Foundation.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Previous Presentation: This study was presented as a poster at the American Head and Neck Society 2015 Translational Research Meeting: April 21-22, 2015; Boston, Massachusetts.

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