929048

research-article2020
AORXXX10.1177/0003489420929048Annals of Otology, Rhinology & LaryngologyAl-Qurayshi et al

Original Article
Annals of Otology, Rhinology & Laryngology

Sinonasal Squamous Cell Carcinoma

1­–7
© The Author(s) 2020
Article reuse guidelines:
Presentation and Outcome: sagepub.com/journals-permissions
DOI: 10.1177/0003489420929048
https://doi.org/10.1177/0003489420929048

A National Perspective journals.sagepub.com/home/aor

Zaid Al-Qurayshi, MBChB, MPH*1 , Ryan Smith, MD*1,

and Jarrett E. Walsh, MD, PhD1

Abstract
Background: examine presentation and outcomes of sinonasal squamous cell carcinoma (SCC).
Methods: A retrospective study utilizing the National Cancer Database, 2004 to 2015. The study population included
adult patients diagnosed with primary sinonasal SCC.
Results: A total of 537 patients were included. The mean age of the study population was 62.6 ± 12.7 years. The median
follow-up time was 35.6 months (interquartile range: 8.6-55.9). The histological variants identified are: (i) 66.7% keratinizing
SCC, (ii) 21.6% non-keratinizing SCC, (iii) 8.0% papillary SCC, and (iv) 3.7% spindle cell carcinoma. Stage at presentation
was: (i) 33.3% T1-2, N0, (ii) 31.8% T3-4a, N0, (iii) 13.8% T1-4a, N+, (iv) 17.0% T4b,N0-3, (v) 4.1% M1. Human papilloma
virus (HPV) status was available for 96 patients and tested positive in 24 (25.0%) patients. By histological variants, 5-year
survival was lowest for spindle cell carcinoma (40.0%), and highest for papillary SCC (70.1%). HPV negative tumors had a
5-year survival of 26.4%, while HPV positive tumors had a 5-year survival of 57.1% (P = <.001). Of the 255 patients with T1-
4a, N0-3, M0 who had surgery of the primary site, 31 (12.2%) patients underwent endoscopic approach. The risk of positive
postsurgical margins was not significantly different comparing endoscopic to open approach (23.8% vs 24.1%, P >.99).
Conclusions: Sinonasal SCC could present at advanced stages in two-thirds of the population and exhibit a variety of
histological subtypes. Like other sites of head and neck, HPV positive tumors are associated with a favorable prognosis.
Endoscopic approach is comparable to open approach in terms of post-surgical margins.

Keywords
sinonasal malignancy, anterior skull base, human papilloma virus, endoscopic surgery, survival

Introduction
Primary sinonasal malignancies are rare, comprising only
3% to 5% of all head and neck cancers and with an annual
incidence rate of 0.6 per 100 000.1-2 Sinonasal squamous
cell carcinoma (SCC) accounts for only 65% of sinonasal
cancer, which is the smallest fraction of any head and neck
subsite.3 Recent reports have indicated that the incidence of
sinonasal SCC has been decreasing in the last years.4
Patients with sinonasal SCC typically present in the 6th
and 7th decades with a 2:1 M:F predominance.3 Common
presenting symptoms noted in the literature are nonspecific
and include nasal obstruction, epistaxis, rhinorrhea, and
facial pain. Primary tumor locations are most commonly the
maxillary sinus and/or nasal cavity.4
Risk of sinonasal SCC has been associated with wood-
working and wood dust exposure, however these are more
strongly linked to nasal adenocarcinoma.5 Other industrial
exposures such as formaldehyde, radium, mustard gas, and
asbestos have also been implicated.6,7 Smoking does increase
the risk by 2-3 fold, but does not seem to be the primary risk
factor like SCC of other head and neck subsites.8
Although sinonasal SCC is uncommon, its histologic pre-
sentation is heterogeneous. Lewis et. al performed a review
of sinonasal SCC subtypes and found that keratinizing
(KSCC) and nonkeratinizing SCC (NKSCC) accounted for
over 83% of sinonasal SCC subtypes, with other variant sub-
types forming the remainder.3 Epithelial immunohistochem-
istry is critical in distinguishing SCC subtypes, often using
p63, p40, and cytokeratin to characterize the variants.9
1
Department of Otolaryngology – Head & Neck Surgery, University of
Iowa Hospitals and Clinics, Iowa City, IA, USA
*Both authors contributed equally to the study.
Corresponding Author:
Jarrett E. Walsh, MD, PhD, Department of Otolaryngology – Head &
Neck Surgery, University of Iowa Hospitals and Clinics, 200 Hawkins
Drive, Iowa City, IA 52242, USA.
Email: jarrett-walsh@uiowa.edu
2 Annals of Otology, Rhinology & Laryngology 00(0)
Though transcriptionally active HPV is strongly impli-
cated in oropharyngeal SCC, its relationship to sinonasal
SCC is less direct. Recent studies have found transcription-
ally active HPV in 40.9% of sinonasal SCC, with a higher
incidence in variants such as basaloid (46.2%), papillary
(80%), and adenosquamous (66.6%).10-13
Our study aims to examine the initial presentation of
sinonasal SCC, prognostic factors, and impact of surgical
approach in the United States.
Methods
The study is a retrospective cohort analysis utilizing the
NCDB, 2004 to 2015.14 The NCDB is a joint program of the
Commission on Cancer of the American College of
Surgeons (ACS) and the American Cancer Society.14 The
ACS has executed a business associate agreement that
includes a data use agreement with each of its Commission
on Cancer accredited hospitals.14 The NCDB, established in
1989, is a nationwide, facility-based, comprehensive clini-
cal surveillance resource oncology data set that currently
captures 70% of all newly diagnosed malignancies in the
US annually.14 The NCDB is a publicly available, de-iden-
tified data that does not meet the criteria of human subject
research.14
The study main objectives were to examine the demo-
graphic, clinical, and histopathological presentation of
patients with sinonasal SCC, and to examine management
types and the associated outcomes in terms of postoperative
surgical margins and overall survival.
The study population included adult patients (age ≥
18 years) who had a primary diagnosis of sinonasal SCC
and no history of previous cancers. The extracted sample
was classified by histopathological types using the
International Classification of Diseases for Oncology third
edition (ICD-O-3) into: (i) keratinizing SCC (ICD-O-3:
8071), (ii) non-keratinizing SCC (ICD-O-3: 8072, 8073),
(iii) basaloid SCC (ICD-O-3: 8084), (iv) papillary SCC
(ICD-O-3: 8052), (v) adenosquamous cell carcinoma (ICD-
O-3: 8075), (vi) spindle cell carcinoma (ICD-O-3: 8074),
and (vii) Schneiderian carcinoma (ICD-O-3: 8121). There
were either no cases or less than 10 patients with basaloid
SCC, adenosquamous cell carcinoma, and Schneiderian
carcinoma. The data-using-agreement prohibit reporting on
such small sample size, thus the aforementioned histopath-
ological categories were not included in the final sample.
Variables considered in the study included: age (18 -
<45, 45 - <65, ≥65), gender (female, male), race (White,
Black, Other), Charlson/Deyo comorbidity index score (0,
1, ≥2),14 site of tumors (nasal cavity, maxillary sinus, eth-
moid sinus), stage classified according to the American
Joint Committee on Cancer and the National Comprehensive
Cancer Network (NCCN) management algorithms of max-
illary sinus tumors (T1-2N0M0, T3-4aN0M0, T1-4aN+M0,
T4bN0-3M0, M1),15 lymphovascular invasion (LVI) status,
human papilloma virus (HPV) status (Negative, Positive for
high-risk for malignancy group according to the NCDB),14
management type (no treatment, surgery only, chemother-
apy and/or radiotherapy, surgery with chemotherapy and/or
radiotherapy), neck dissection (not performed, per-
formed), approach (endoscopic, open), postoperative sur-
gical margins (negative, positive), and overall survival
(the NCDB does not include disease-specific survival).
All factors were checked for completeness, the following
factors had missing value and were analyzed separately as
noted in the results and tables: lymphovascular invasion (n
missing = 256), HPV status (n missing = 441), and
approach (n missing = 282).
Each of the independent factors were tested for its asso-
ciation with overall survival using Log-rank test, factors
that demonstrated significant association were included in
the multivariate Cox Hazard Ratio model that was used to
calculated hazard ratio (HR), 90% confidence interval
(95%CI), and control for time-interaction terms. Fisher’s
exact test was used to compare categorical variables.
Significance level was set as (α = 0.05). All statistical anal-
yses were performed using SAS 9.4 (SAS Institute Inc.,
Cary, NC, USA.).
Results
A total of 537 patients were included (Table 1). The median
follow-up time was 35.6 months (interquartile range: 8.6-55.9).
The mean age of the study population was 62.6 ± 12.7 years.
White and male patients formed the majority of the sample
80.3%, and 63.1%, respectively. The most common site of
sinonasal SCC was the maxillary sinus and the majority
(65.2%) had a T1-4a disease without nodal or distant metas-
tasis. Histopathologically, the sample included: (i) 66.7%
keratinizing SCC, (ii) 21.6% non-keratinizing SCC, (iii)
8.0% papillary SCC, and (iv) 3.7% spindle cell carcinoma.
LVI was reported in 51/281 (18.15%) of the patients. HPV
status was available for 96 patients and it tested positive in
24 (25.0%) patients, and it was most prevalent in patients
with papillary SCC variants (80.0%, p = 0.003) (Figure 1).
In patient who had surgical intervention, the risk of positive
surgical margins was 23.1%.
Figure 2 demonstrates the management type in relation
to NCCN staging.15 Neck dissection was performed in
22.4% of patients who later proved to have T1-2N0M0 and
in 56.1% in patients who later proved to have T3-4aN0M0.
In patients with the surgical approach reported (n = 255),
endoscopic approach was used in 12.2%, with highest use
in patients with T1-4aN+M0 (16.3%), the risk of positive
postsurgical margin was not significantly different com-
paring endoscopic to open approach (23.8% vs 24.1%,
P > .99). In patients with advanced disease, T4b or M1,
approximately 13% refused any treatment in each group.
Al-Qurayshi et al 3

Table 1.  Descriptive Statistics of the Study Population of Discussion

Patients with Sinonasal Squamous Cell Carcinoma. National
Cancer Database, 2004 to 2015. In this study we examined the presentation and outcomes of
sinonasal SCC in the United States. Sinonasal SCC was
Study Population,
more prevalent in patients who are white and/or male, with
n = 537 (%)a
a mean age around 60 years old. The most common histo-
Age (yr.) logical subtype was KSCC. Stage at presentation was most
  18 - <45 41 (7.64) commonly T1-2N0M0 (33.3%), though T3-4N0M0 disease
  45 - <65 250 (46.55) was also prevalent (31.8%). Distant metastatic disease was
  ≥65 246 (45.81) present in only 4.1% of the cohort. Our study showed 5-year
Gender survival of KSCC and NKSCC to be 50.6% and 50.3%,
 Male 339 (63.13) respectively. Papillary SCC showed a trend toward
 Female 198 (36.87) increased 5-year survival at 70%, while spindle cell carci-
Race noma showed a trend toward decreased 5-year survival at
 White 431 (80.26)
40%. The other variants were not represented adequately to
 Black 75 (13.97)
allow for survival data to be determined. These trends con-
 Other 31 (5.77)
tinue to show that SCC variants have strong prognostic
Charlson/Deyo score
associations, though larger cohorts are needed to determine
 0 430 (80.07)
 1 85 (15.83)
statistical significance.
  ≥2 22 (4.1) Multiple prior studies have examined the SEER database
Site for further characterization of sinonasal SCC incidence and
  Nasal cavity 221 (41.15) prognosis. Ansa et al. divided the SEER database by decade
  Maxillary sinus 280 (52.14) and found a similar distribution of disease across sex, race,
  Ethmoid sinus 36 (6.7) and age compared to our data.1 The maxillary sinus was also
Histopathology found to be the most common disease site (76%, n = 5106).1
  Keratinizing SCC 358 (66.67) The Ansa et al. study used the SEER classification of disease
  Non-keratinizing SCC 116 (21.6) extent and found that 8% presented with localized disease
  Papillary SCC 43 (8.01) for the period of 1973 to 2009.1 Our study showed that 33%
  Spindle cell carcinoma 20 (3.72) of the patients presented with T1-2 stage. Another SEER
Stage study by Jain et al. similarly found higher stage to be a nega-
 T1-2,N0,M0 179 (33.33) tive prognostic indicator.16
 T3-4a,N0,M0 171 (31.84) Regarding the influence of the histological subtype in
 T1-4a,N+,M0 74 (13.78) advanced stage disease, a study by Vazquez et al. using the
 T4b,N0-3,M0 91 (16.95) SEER database found that verrucous, papillary, and basa-
 M1 22 (4.1) loid sinonasal SCC conferred increased survival compared
LVI status to conventional KSCC or NKSCC, while adenosquamous
  Not reported 230 (81.85) and spindle cell variants were similar.17 The histological
 Reported 51 (18.15) subtype appeared to be less prognostically influential in
HPV status early stage disease. Our data show a similar favorable prog-
 Negative 72 (75) nosis with the papillary subtype and unfavorable prognosis
 Positive 24 (25)
with the spindle cell subtype.
Postoperative surgical margins
HPV status was only reported in a small subset (n = 96)
 Negative 296 (76.88)
of the cohort, but this data is consistent with previous stud-
 Positive 89 (23.12)
ies in showing a statistically significant increase in 5-year
Abbreviations: HPV, high-risk human papilloma virus; LVI, survival. The HPV negative cohort had an especially poor
lymphovascular invasion; SCC, squamous cell carcinoma. 5-year survival of 26.4%. Of SCC variants, HPV positive
a
Percentage values may not add up to 100% due to rounding. There are
status was most common in the papillary subtype, which is
missing values for LVI (n missing = 256) and HPV status (n missing = 441).
consistent with previous studies. Small cohorts have
recently been examined to determine if sinonasal SCC HPV
Five-year overall survival for the whole sample was status plays a prognostic role similar to HPVs role in the
52.2%. By histological variants, 5-year survival was lowest oropharynx.11-13 Multiple studies have shown a statistically
for spindle cell carcinoma (40.0%), and highest for papil- significant survival increase, while Bishop et al. showed a
lary SCC (70.1%) (Table 2) (Figure 3). HPV negative trend toward improved prognosis.11
tumors had a 5-year survival of 26.4%, while HPV positive Surgery is regarded as the mainstay of sinonasal SCC
tumors had a 5-year survival of 57.1% (P = .002). therapy. Recent surgical investigations have focused on the
4 Annals of Otology, Rhinology & Laryngology 00(0)

Figure 1.  Probability of positive human papilloma virus in relation to histopathological variants of sinonasal squamous cell carcinoma.
[A color scheme described in the Figure].

Figure 2.  Type of management received by patients with sinonasal squamous cell carcinoma based on tumor stage.
[A color scheme described in the Figure].
Al-Qurayshi et al 5

Table 2.  Overall Survival in Patients with Sinonasal Squamous Cell Carcinoma in Relation to Clinical and Pathological Factors.

5-year survival (%) aHRa 95%CI P

Histopathology
  Keratinizing SCC 50.62 Reference  
  Non-keratinizing SCC 50.30 0.90 0.66, 1.24 .52
  Papillary SCC 70.05 0.74 0.44, 1.24 .25
  Spindle cell carcinoma 40.02 1.36 0.74, 2.52 .32
Stage
 T1-2,N0,M0 76.68 Reference  
 T3-4a,N0,M0 58.18 2.638 1.71, 4.07 <.001
 T1-4a,N+,M0 25.33 7.306 4.30, 12.41 <.001
 T4b,N0-3,M0 24.26 4.879 2.08, 11.43 <.001
 M1 0.00 12.754 4.89, 33.24 <.001
HPV status
 Negative 26.37 Reference  
 Positive 57.14 0.05 0.01, 0.23 <.001

Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval.

a
The multivariate model (n = 537) included age, histopathology, stage, margin status, and management type. HPV status was assessed in a separate
model due to missing values, (n = 96).

comparative effectiveness of open versus endoscopic
approaches. Kilic et al. also using the NCDB reviewed
patients with sinonasal SCC (2010-2014) and found no sig-
nificant difference in surgical margins or 5-year overall
survival. The endoscopic approach was associated with a
decreased postoperative hospital stay compared to open
approaches.18 In another study, Kilic et al. found compare-
able outcomes regarding the HPV status impact on sur-
vival.19 Albeit that our study has a longer study period,
employed different stastistical methodology, different clas-
sification of treatment, and the adaptation of the NCCN
staging algorthim; the reproducibility of the outcomes
demonstrated by Kilic et al. in this study ascertains those
observations.
Sinonasal SCC is typically regarded as radiosensitive,
with adjuvant radiotherapy being common in advanced dis-
ease. Though a study by Blanch et al. did not show any
survival benefit with adjuvant radiation versus surgery
alone, this cohort was treated between 1974 and 1995 and
did not account for recent advances in the Radiation
Oncology field.20 Other studies have shown that delays in
beginning adjuvant radiotherapy after surgery lead to
increased mortality.21,22
The subset reporting surgical approach (n = 255) showed
the open surgical approach to be far more common than
endoscopic, though no significant differences was found in
terms of risk of positive margins in association with surgi-
cal approach. The endoscopic approach was reported to be
utilizaed in patients with T1,N0,M0 to T4a,N+,M0 disease.
As 45.3% of these patients received adjuvant radiation,
greater adoption of the endoscopic approach may decrease
time to beginning adjuvant radiation and possibly reduce
mortality.
Chemotherapy in sinonasal SCC has also been a topic of
recent discussion. Neoadjuvant chemotherapy has been
shown to improve overall survival, disease free survival,
and decrease distance metastasis in responders, though only
34.9% of patients showed significant response.23 In our
cohort, systemic therapy with or without radiation was
mostly reserved for T4bN0-3M0 or T1-4N0-3M1 (stage
IVB or IVC) disease.
The study has multiple limitations. The NCDB lacks rel-
evant clinical and surgical details such as type of comorbidi-
ties, imaging studies, lab values, and intraoperative and
postoperative complications that would have explained the
choice of treatment and further eliminated the confounding
effect. Additionally, the NCDB only has overall survival with
no data regarding disease specific survival and recurrence.
Alternatively, the study strength includes the utilization of
large sample size and the availability of histological data.
Conclusion
Review of this NCDB cohort provided several key points that
could be used to guide future care. HPV status is emerging as
a significant prognostic indicator and testing should be done
on all surgical specimens and reported in databases such as
the NCDB and SEER. Sinonasal SCC variants are rare but
continue to have significant prognostic value in late state dis-
ease, and further studies are needed to more precisely define
their impact on survival. Finally, further adoption of the
endoscopic approach shows great promise. Especially in
lower stage disease, increased utilization of the endoscopic
approach could decrease patient morbidity, lower costs,
shortening hospitalizations, and possibly reduce mortality by
shortening time to beginning adjuvant radiation.
6 Annals of Otology, Rhinology & Laryngology 00(0)

ORCID iD
Zaid Al-Qurayshi https://orcid.org/0000-0002-3534-7253

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Figure 3.  Kaplan-Meier curve of overall survival in patients
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Author Note
The study was selected for a poster presentation at the 65th annual
American Rhinologic Society in New Orleans, Louisiana on
September 13 – 14, 2019.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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