The Laryngoscope

C 2013 The American Laryngological,

V
Rhinological and Otological Society, Inc.

Smoking and Malignancy in Sinonasal Inverted Papilloma

Sung-Lyong Hong, MD; Bae-Hyun Kim, MD; Jung-Hoon Lee, MD;

Kyu-Sup Cho, MD; Hwan-Jung Roh, MD

Objectives/Hypothesis: The authors investigated clinical features of squamous cell carcinomas (SCC) arising in sino-
nasal inverted papillomas (IP) and risk factors responsible for their malignant transformation.
Study Design: Retrospective analysis.
Methods: In total, 162 patients diagnosed with sinonasal IP and treated between 1998 and 2009 at Pusan National Uni-
versity Hospital were enrolled. Their demographic data, information about previous surgery, smoking history, treatment
modalities, follow-up duration, recurrence, and presence of malignancy were reviewed retrospectively.
Results: Seventeen patients (10.5%) were diagnosed with SCC arising in sinonasal IPs. Among them, nine (9/162, 5.6%;
9/17, 52.9%) were diagnosed with synchronous malignancies and three (3/162, 1.8%; 3/17, 17.6%) were diagnosed with
metachronous malignancies. In five cases (5/162, 3.1%; 5/17, 29.4%), we could not determine whether their malignancies
were synchronous or metachronous. Among 53 smokers, 14 (26.4%) had malignant transformation, while only three (2.8%)
in 109 nonsmokers had malignant transformation (Odds ratio ¼ 12.7; P < .001). The mean follow-up in the 17 patients with
malignancy was 47.0 months. Three patients did not receive surgical treatment and died of progression of SCC. Among the
other 14 patients who underwent curative surgeries, four (28.6%) had recurrences, and their mean period to cancer recur-
rence was 6.3 months. Two of them died of progression of the cancer. Mean survival of the five patients who died was 14.0
months. They all belonged to T4 stage.
Conclusions: Smoking history is associated with malignant transformation of sinonasal IP. It suggests that close follow-
up be required in smokers with sinonasal IP in order not to overlook the malignant transformation.
Key Words: Inverted papilloma, squamous cell carcinoma, recurrence, neoplasm staging, smoking, synchronous
neoplasm, metachronous neoplasm.
Level of Evidence: 2b.
Laryngoscope, 123:1087–1091, 2013

INTRODUCTION ops at the site of a previously benign IP.4 According to a

Inverted papilloma (IP) is one of the most common
sinonasal tumors. Although it is pathologically benign, it
has destructive or bone-remodeling capacities, tends to
recur after surgical resection, and has a significant ma-
lignant potential.1–3 Therefore, many surgeons regard it
as a malignancy and do not hesitate to use external
approaches to remove it thoroughly.
The rate of malignant association is approximately
10%.4,5 IP with synchronous carcinoma occurs when
there is no history of a previously resected IP.4 The car-
cinoma may arise from the IP itself or be found as a
separate lesion.6 IP with metachronous carcinoma devel-
From the Department of Otorhinolaryngology–Head and Neck
Surgery (S-L.H., J-H.L., K-S.C.) and the Medical Research Institute (S-L.H.),
Pusan National University Hospital, Busan; the Department of
Otorhinolaryngology–Head and Neck Surgery (S-L.H., J-H.L., H-J.R.) and
the Research Institute for Convergence of Biomedical Science and
Technology (S-L.H., H-J.R.), Pusan National University Yangsan Hospital,
Yangsan, Korea.
Editor’s Note: This Manuscript was accepted for publication
October 15, 2012.
The authors have no funding, financial relationships, or conflicts
of interest to disclose.
Send correspondence to Hwan-Jung Roh, MD, PhD, Professor,
Department of Otorhinolaryngology–Head and Neck Surgery, Pusan
National University Yangsan Hospital, Beomeo-ri, Mulgeum-eup, Yang-
san, 626-770, Korea. E-mail: rohhj@pusan.ac.kr
DOI: 10.1002/lary.23876
meta-analysis, the rates of synchronous and metachro-
nous carcinoma are 7.1% and 3.6%, respectively.7
However, the factors responsible for malignant transfor-
mation are not fully elucidated to date.7
Meanwhile, smoking is known to be the most im-
portant risk factor in the development and the
recurrence of various squamous cell carcinomas (SCC) in
the head and neck area, as well as in different organs.
Moreover, a recent study reported that smoking
increases the risk of recurrence of IP.8 However, to the
best of our knowledge, there is no study investigating
the relationship between smoking and the malignant
transformation of sinonasal IPs.
Sinonasal IPs are relatively rare tumors of which
incidence rate is 0.74/100,000/year.9 SCC arising in IPs
are also very rare. For this reason, there have been few
single-center studies for them. We investigated clinical
features of SCC arising in the sinonasal IPs and ana-
lyzed risk factors, including smoking for synchronous or
metachronous malignancies.
MATERIALS AND METHODS
In total, 162 patients who were diagnosed with sinonasal
IPs and treated between April 1998 and December 2009 at
Pusan National University Hospital were enrolled. All of them
underwent complete clinical follow-up. The patient population
comprised of 120 men and 42 women with the mean age of

Laryngoscope 123: May 2013 Hong et al.: Malignant Transformation of Sinonasal Inverted Papilloma
1087
 TABLE I. was 55.4 (range, 24–85) years, which was not signifi-
Demographic Findings Contingent upon Malignant Transformation cantly different from that of 17 patients with
(N 5 162). malignancy (Table I, P ¼ .638 by Student’s t test).
Malignancy (þ) Malignancy ()
n ¼ 17 n ¼ 145 P value

Sex Male 16 (13.1%) 106 (86.9%) .074

Female 1 (2.5%) 39 (97.5%)
Age 55.9 (35–77) 55.4 (24–85)
Smoking (þ) 14 (26.4%) 39 (73.6%)
(-) 3 (2.8%) 106 (97.2%)
55.5 years (range, 24–85 years). Their mean follow-up was 26.8
months (range, 4–128 months).
They had complete information necessary for inclusion in
this study. All patients underwent preoperative computed to-
mography. The pathologic diagnosis was confirmed by a biopsy.
Their demographic data and information about previous sur-
geries; smoking history, including pack-year smoking data;
treatment modalities; follow-up duration; recurrence; and pres-
ence of malignancy were reviewed retrospectively. Patients who
underwent nasal surgeries, including Caldwell-Luc operation
and maxillectomy, previously in other hospitals were excluded.
However, patients with nasal polypectomy or endoscopic sinus
surgery were included in this study.
Smokers were defined as those who had documented ciga-
rette usage in medical records. Nonsmokers were defined as
those who denied a history of cigarette usage during their life-
time. Patients with malignant transformation were categorized
based on the cancer staging distributed by American Joint
Committee on Cancer in 2010.
SPSS 17.0 for Windows software package (SPSS Inc., Chi-
cago, IL) was used for statistical analysis. Univariate analyses
including Student’s t test and Pearson’s chi-square test or Fish-
er’s exact test, were used to compare data between the groups
with and without malignant transformation. The results were
considered statistically significant at P < .05. This study was
performed with the approval of the Institutional Review Board
of Medical Research Institute at Pusan National University
Hospital.
RESULTS
Demographic Data
The patients with SCC arising in IP consisted of 16
men and 1 woman, with a mean age of 55.9 (range, 35–
77) years. The rate of malignant transformation was
higher in men (13.1%, 16/122) than in women (2.5%,
1/40), and odds ratio of sex for malignant transformation
was 5.9. However, it was not statistically significant
(Table I, P ¼ .074 by Fisher’s exact test). Meanwhile,
patients with malignant transformations were evenly
distributed throughout all age groups and their rates in
each age group were similar (Table II). Moreover, the
mean age of the other 145 patients without malignancy
Smoking History and Malignant
.638
Transformation
Among 162 patients, 53 (32.7%) had smoking his-
<.001
tory. In 17 patients with malignancy, 14 (82.3%) had
smoking histories. On the other hand, in the other 145
patients without malignancy, 39 (26.9%) had smoking
histories. The difference between the smoking rates of
the two groups was statistically significant (Table I, P <
.001 by Fisher’s exact test).
To summarize, among 53 smokers, 14 (26.4%) had
malignant transformation (Fig. 1). However, among 109
nonsmokers, only 3 (2.8%) had malignant transforma-
tion. The odds ratio of the smoking history for
malignant transformation was 12.7.
These 14 patients had smoked for an average of
26.9 (611.6; range, 10–50) pack-years and were diag-
nosed with this malignancy at the mean age of 55.0
(612.8; range, 35–77) years. The other 39 patients with-
out malignancy had smoked for an average of 24.2
(69.2; range, 5–45) pack-years and were diagnosed with
sinonasal IP at the mean age of 54.7 (614.5; range, 25–
85) years. The difference in smoking duration was not
statistically significant (P ¼ .712 by Student’s t test).
We divided the 53 smokers into the two groups (
10 pack-years vs. > 10 pack-years). In 14 patients with
malignancy, one (7.1%) belonged to the former and
another 13 (92.9%) to the latter. Meanwhile, in 39
patients without malignancy, 12 (30.8%) belonged to the
former and 27 (69.2%) belonged to the latter. However,
there was no statistically significant relationship
between the total smoking amount and the malignant
transformation of IP (P ¼ .145 by Fisher’s exact test).
Such was the case when we divided the smokers into a
 20-pack-year group and a > 20-pack-year group. Six
(42.9%) patients with malignancy and 22 (56.4%)
patients without malignancy belonged to the  20-pack-
year group, respectively (P ¼ .534 by Pearson’s chi-
square test).
Meanwhile, to rule out the possibility that the
smoking history acted as a confounding factor in the
relationship between sex and malignant transformation,
we stratified them with smoking histories (Table III). In
the smoking group, 13 men (28.9%) of 45 had malignant
transformation and only one woman (12.5%) of eight
women had malignant transformation. However, this dif-
ference was not statistically significant (P ¼ .665 by
Fisher’s exact test) In the patient group without

TABLE II.
Age Distribution of Malignant Transformation (N 5 162).
Age 20–29 30–39 40–49 50–59 60–69 70–79 80–89 Total

Malignancy 0/4 2 /15 3/30 5/46 5 /46 2/18 0/3 17/162

Rate 0% 13.3% 10.0% 10.9% 10.9% 11.1% 0% 10.5%

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 TABLE III.
The Relationship Between Sex and Malignant Transformation in
the Stratification With Smoking Histories (N 5 162).
Sex Malignancy (þ) Malignancy () Total

Smoking (þ) Male 13 (28.9%) 32 (71.1%) 45

Female 1 (12.5%) 7 (87.5%) 8
Smoking (-) Male 3 (3.9%) 74 (96.1%) 77
Female 0 (0%) 32 (100%) 32

tions and were diagnosed with metachronous

Fig. 1. Relationship between smoking history and malignant transfor-
mation. Among 109 patients without smoking histories, only three
(2.8%) had malignant transformation (A). However, among 53 patients
with smoking histories, 14 (26.4%) had malignant transformation (B).
The odds ratio of the smoking history for malignant transformation
was 12.7 (P < .001, Fisher’s exact). [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
smoking histories, three men (3.9%) of 77 had malig-
nancy and zero of 32 women had malignancy.
Synchronous and Metachronous Malignancies
Of 17 patients with malignant transformation, nine
(52.9%) did not have any history of previous nasal sur-
geries; therefore, they were diagnosed with synchronous
malignancies. Among the other eight patients who had
ever undergone nasal surgeries such as nasal polypec-
tomy and endoscopic sinus surgery, three (17.6%) had
pathologic confirmation of IP in their previous opera-
malignancies. However, the remaining five (29.4%)
patients did not have pathologic confirmation of IP in
their previous nasal surgeries. Therefore, we could not
determine whether their malignancies were synchronous
or metachronous.
Data of Patients with Malignant
Transformation
Table IV summarized data of 17 patients with ma-
lignant transformation. Among them, 11 had the
maxillary sinus cancers (1 T2, 7 T3, 2 T4a, and 1 T4b
cancers) and six had the ethmoid sinus cancers or the
nasal cavity cancers (1 T1, 2 T2, 1 T3, and 2 T4a can-
cers). Only one patient (5.9%) had a cervical lymph node
metastasis in the diagnosis.
Three patients did not undergo operations, either
due to their advanced diseases or to their refusal of sur-
geries. Their stages were the maxillary sinus cancer
T4aN0M0, the maxillary sinus cancer T4bN0M0, and
the ethmoid sinus cancer T4aN0M0, respectively. The
patients received chemotherapy and radiation therapy.
The other 14 patients underwent surgeries for their

TABLE IV.
Data of 17 Patients with Malignant Transformation.
Sex Age Malignancy Site Stage Treatment Recurrence Smoking Status

1 M 35 Meta Max T3N0 CTxþSþRT regional 15 PY NED

2 M 38 Syn Max T3N0 SþRT — 15 PY NED
3 M 43 Syn Max T3N2c SþRT local 20 PY NED
4 M 43 ? Max T3N0 S — 10 PY NED
5 M 47 Syn Max T4aN0 CTxþRT — 25 PY DOD
6 M 51 ? Eth T4aN0 SþRT — 30 PY DOD
7 M 54 Syn NC T2N0 SþRT — no NED
8 M 56 Syn Eth T3N0 SþRT — 30 PY NED
9 M 57 Meta Max T3N0 SþRT — 30 PY NED
10 M 58 ? Max T3N0 SþRT — no NED
11 M 61 ? Max T4bN0 CTxþRT — 16 PY DOD
12 M 62 Syn Max T3N0 CTxþSþRT — 40 PY NED
13 M 62 Syn Eth T1N0 SþRT — 40 PY NED
14 M 66 ? Max T4aN0 S local 35 PY DOD
15 F 68 Meta Eth T2N0 SþRT — no NED
16 M 73 Syn Max T2N0 SþRT — 20 PY NED
17 M 77 Syn NC T4aN0 SþRT locoregional 50 PY DOD
?: undetermined; CTx: chemotherapy; DOD: died of disease; Eth: ethmoid sinus; F: female; M: male; Max: maxillary sinus; Meta: metachronous; NC:
nasal cavity; NED: no evidence of disease; PY: pack-year; RT: radiation therapy; S: surgery; Syn: synchronous.

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1089
nasal malignancies. Among them, 10 underwent sur-
geries and postoperative radiation therapy and two
received neoadjuvant chemotherapy and postoperative
radiation therapy as well as surgeries. The remaining
two underwent surgeries only.
The mean follow-up in the 17 patients with malig-
nancy was 47.0 (range, 8–118) months. The three patients
who did not undergo surgeries did not achieve remission
of the diseases and died. Among the other 14 patients,
four (28.6%) had recurrences and their mean period to
cancer recurrence was 6.3 (range, 4–9) months. Two
patients had local recurrences and one had a regional re-
currence. The remaining one patient had both local and
regional recurrences. Three of them had received postop-
erative radiation therapies before their recurrences. Two
of them died of progression of the cancer; and their stages
were the maxillary sinus cancer T4aN0M0 and the nasal
cavity cancer T4aN0M0, respectively.
Mean survival of the five patients who died was
14.0 (range, 5–28) months. It was atypical that they all
belonged to T4 stages. Moreover, among the 17 patients,
those who belonged to T4 stages all died of the disease,
and those who belonged to the lower T stages all
survived.
DISCUSSION
As mentioned above, a meta-analysis reported that
the rates of synchronous and metachronous carcinoma
are 7.1% and 3.6%, respectively.7 Of the 162 patients
that we examined, 17 (10.5%) had SCC arising in their
IPs, among which nine (9/162, 5.6%; 9/17, 52.9%) were
synchronous and three (3/162, 1.8%; 3/17, 17.6%) were
metachronous. In five cases (5/162, 3.1%; 5/17, 29.4%),
we could not determine whether their malignancies
were synchronous or metachronous. However, we think
it reflects the real world of medical practice as in many
cases we cannot know the previous biopsy results of
which patients were informed in other hospitals.
The mean follow-up in the 17 patients with malig-
nancy was 47.0 (range, 8–118) months. Of 14 patients
who underwent the curative surgery, four (28.6%) expe-
rienced recurrences of their malignancies. Two patients
belonged to T4a stage and the other two belonged to T3
stage. Three of them had received postoperative radia-
tion therapies before their recurrences. The mean time
from the end of the treatment to diagnosis of recurrence
was 6.3 (range, 4–9) months. Considering both their tu-
mor extents and the short time to recurrences, their
recurrences might result from incomplete resections of
the malignancies. We presumed that a postoperative
radiation therapy did not lead to the complete remission
of the cancer when it had been incompletely removed.
Among them, two patients who belonged to the T4a
stage finally died of progression of this disease. The
three patients who did not undergo the surgical treat-
ment also died of the disease progression. The mean
survival of these five patients was 14.0 (range, 5–28)
months. Therefore, in the SCC arising in sinonasal IPs,
a thorough surgical resection should be carried out to
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1090
extirpate the malignancies and to prevent their
recurrences.
We think that several factors can increase the risk
of malignant transformation of sinonasal IPs. In this
study, age did not have an influence. However, further
investigation with a larger population should be per-
formed to determine the relationship between sex and
the malignant transformation of sinonasal IP.
The most noticeable result of this study is that
smoking history increased the risk of malignant trans-
formation of sinonasal IP. As discussed earlier, a recent
study reported that smoking increases the risk of recur-
rence of IP.8 Smoking history has been known as a risk
factor for the development and recurrence in other
malignancies, including head and neck cancer.10 More-
over, cigarette smoke contains many well-known
carcinogens that have been identified as initiators or
promoters in carcinogenesis.11 However, there are no
studies regarding the association between smoking and
malignant transformation of sinonasal IP.
In this study, 14 (26.4%) of 53 smokers experienced
malignant transformation, while only three (2.8%) in
109 nonsmokers did (Odds ratio ¼ 12.7; P < .001, Fish-
er’s exact test). However, we did not find any
relationship between the total smoking amount and ma-
lignant transformation. A well-designed, large
population-based prospective study on smoking is a
must for the establishment of that relationship.
Recently, the role of human papilloma virus (HPV)
has been studied in sinonasal IP with SCC.12–14 A clean
inverse relationship of HPV to p53 overexpression was
proved in sinonasal IP with SCC,12 and several studies
reported that HPV infection would be an early event in
the multistep process of the malignant transformation of
sinonasal IP.13,14 Moreover, previous studies identified
that smoking is associated with a significantly higher
incidence and prevalence of HPV infection.15,16 However,
we did not perform the HPV typing in the tumor speci-
mens, which can be one of the limitations of this study.
Further research for the identification of the role of
HPV infection in the malignant transformation of sino-
nasal IP is needed.
CONCLUSION
We presented our results of analyzing clinical fea-
tures and risk factors of SCC arising in sinonasal IP. In
conclusion, smoking is associated with malignant trans-
formation of sinonasal IP, which suggests that close
follow-up be required in smokers with sinonasal IP in
order not to overlook their malignancies. This can be
used as important and convincing data for patient
education and counseling.
Acknowledgment
Authors appreciate the administrative support of
Medical Research Institute at Pusan National University
Hospital.
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