Sinonasal Inverted Papilloma: Risk Factors for Local Recurrence After Surgical Resection

Abstract

Objectives:

Sinonasal inverted papillomas (SIP) present a potential for recurrence years after the surgery, but most studies report short-term follow-up, and risk factors for recurrence are still debated. Furthermore, several classifications are described, and no consensus exists regarding which one should be used. The aims of this study were to report our long-term results, investigate for potential risk factors for recurrence, and compare the existing 8 staging systems.

Methods:

Over a 28-year period, 110 patients with a diagnosis of SIP were enrolled. The median follow-up time was 55.6 months.

Results:

In multivariate Cox regression modeling, history of previous surgery was the only variable associated with recurrence (hazard ratio = 4.91, 95% CI, 1.80-13.39). Recurrences occurred up to 60 months after the surgery. Among the 8 staging systems, none proved to be associated with recurrence.

Conclusion:

The only factor associated with recurrence of SIP was prior surgery, probably corresponding to an incomplete initial resection. Due to late recurrences, an extended follow-up of at least 5 years is mandatory. In the absence of a classification predicting prognosis, Krouse’s staging system should be used to homogenize studies’ report since it is the most widely used.

Keywords

sinonasal inverted papilloma endonasal endoscopic surgery open approach recurrence classification risk factors

Introduction

Sinonasal inverted papilloma (SIP) differs from other benign tumors affecting paranasal sinuses notably by its high recurrence rate, around 10% to 20%.^1,2 Contradictory results have been reported regarding risk factors for local recurrence.^1-13 Furthermore, although the risk of recurrence persists several years after the surgery,¹⁴ most studies report a short-term follow-up, and few use appropriate survival analyses.^1,11,15-18 Another limitation in the existing literature devoted to the analysis of SIP is the fact that numerous staging classification systems are used (detailed in Table S1 available in the online version of the journal),^7,19-25 making for difficult between-studies comparisons as well as systematic reviews and meta-analyses.

This observational study was therefore designed in an effort to improve knowledge regarding risk factors for local recurrence after surgical resection of SIP. More specifically, our study was designed to (1) document recurrence rate in patients with long-term follow-up, (2) explore for potential risk factors for local recurrence, and (3) evaluate the existing 8 classifications systems regarding their capacity to predict an increased risk for local recurrence.

Material and Methods

Study Design

In this observational study, we recruited all consecutives patients over 18 years of age with a diagnosis of SIP confirmed by histology. Recruitment extended from March 1987 until January 2015 in a single institution (tertiary care center and university teaching hospital). According to our national legal regulations and since this study did not interfere with treatment, there was no need to consult our local ethic committee (groupe éthique pour les recherches non CPP – CERHUPO). Report of this study followed the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement.²⁶

Study Population

During the study period, 117 cases of SIP were included. We excluded 7 patients presenting an associated carcinoma (6%) so that the study population consisted of 110 patients. Median age at diagnosis was 56.2 years (range, 23.2-89 years), and 74.5% were men (n = 82).

The preoperative presumption of SIP was based on the evoking clinical aspect of a reddish-gray lobulated tumor noted at the time of clinical examination. All patients underwent a radiological evaluation either with computed tomography scan (CT scan) for patients of the earlier period of the study (before 1992, n = 17) or both CT scan and magnetic resonance imaging (MRI) for patients of the later period (after 1992).

Before 1995, all patients were treated using an external approach: a Caldwell-Luc procedure (n = 3), a lateral rhinotomy (n = 12), or a midfacial degloving approach (n = 8). After 1995, all patients were operated using an endoscopic endonasal procedure. The following criteria were followed: In case of inverted papilloma confined to the nasal septum or nasal floor, an endoscopic removal of the tumor was performed including safe margins. In case of involvement of the ethmoidal sinus, an ipsilateral radical ethmoidectomy was performed. An anterior ethmoidectomy associated with a medial maxillectomy was performed in case of involvement of the maxillary sinus. If the tumor involved the lateral nasal wall or the medial maxillary wall, a radical medial maxillectomy was performed associated with a total ethmoidectomy. If the surgeon had a suspicion regarding the completeness of the resection after the endoscopic approach, a combined procedure was performed. Thus, a purely endoscopic endonasal procedure was performed in 70 patients, and in 17 patients, a combined endoscopic and external approach was performed (Caldwell-Luc in 14 and subciliary incision in 3). The tumor was removed following a subperiosteal plane, and no drilling was performed of the underlying bone.

Follow-up consisted of a regular clinical examination including a nasofibroscopy (3 times a year during the first 5 years after the surgery and 1 time a year after) together with a radiological exam (MRI since 1992) at 1, 2, and 3 years after the surgery. Then, the radiological exam was performed every 2 years until 10 years after the surgery and then every 4 years. Radiological exam was also performed in case of clinical suspicion of recurrence. During the year 2015, all patients were summoned to a medical examination and underwent an MRI to minimize the number of missing data and patients lost to follow-up. Seven patients were excluded due to missing data, so the study population for recurrence analysis consisted of 103 patients. The median follow-up time was 55.6 months (mean = 74.8 months).

Statistical Analyses

First, we explored for potential factors associated with recurrence. We estimated unadjusted hazard ratio (HR) and 95% confidence intervals (CI) using Cox regression modeling. Then, the Kaplan-Meier method was used to generate survival curves, and comparisons were performed using the log-rank test. Finally, multivariate survival analysis using Cox regression modeling was performed, and the assumption of proportional hazards was graphically checked. End points were calculated from the date of surgery until 1 of the following: recurrence date, last consultation date, or loss of follow-up date (censored data).

Second, we investigated for potential associations between staging systems and recurrence rate using survival analyses (log-rank test and Cox regression modeling).

All analyses were 2-sided, and a P value <.05 was considered statistically significant. All analyses were performed using R software version 3.1.3.²⁷

Results

Correlates of Recurrence

Characteristics of the study population according to the existence of a recurrence are presented in Table 1. All recurrences occurred at the same site of origin as the primary tumor, except for 2 patients. Both presented a primary location in the ethmoid sinus, but one presented a recurrence into the frontal sinus and the other one into the sphenoid sinus. In univariate analysis, history of previous surgery, when compared with those who undergone a first resection, was significantly associated with recurrence (HR = 3.79; 95% CI, 1.45-9.89; P = .006).

Table 1.

Characteristics of the Population According to the Existence of a Recurrence.^a

	No Recurrencen = 83	Recurrencen = 20	P Value
Male gender	63 (75.9)	14 (70.0)	.61
Age at diagnosis, y	55.8 ± 13.0	55.7 ± 11.8	.97
Previous surgery	24 (29.6)	14 (70.0)	.002
Site of origin			.99
Ethmoidal sinus	40 (48.2)	11 (55.0)
NS or NF	3 (3.61)	0 (0)
LW	11 (13.3)	3 (15.0)
Maxillary sinus	26 (31.3)	6 (30.0)
Sphenoid sinus	3 (3.61)	0 (0)
Type of surgery			.23
Endoscopic	62 (74.7)	18 (90.0)
Open	21 (25.3)	2 (10.0)

Values are mean ± standard deviation or No. (%).

Abbreviations: LW, lateral wall of the nasal cavity; NF, nasal floor; NS, nasal septum.

Figure 1 illustrates the cumulative incidence rate of recurrence over time (inverted Kaplan-Meier), showing emergence of recurrences up to 60 months. The 3- and 5-year recurrence rates were 19.6% and 21.2%, respectively. Moreover, 2 patients (2.9%) presented a recurrence more than 60 months after the initial surgery. Recurrence-free survival according to prior surgery (yes vs no) is represented in Figure 2. The P value from the log-rank test was .003. No significant differences were found in survival distributions according to gender (P value from log-rank = .81), site of origin (P value = .74), or the type of surgery (open procedure vs endoscopic, P value = .16). In multivariate Cox regression modeling, history of previous surgery was the only variable significantly associated with recurrence (HR = 4.91; 95% CI, 1.80-13.39) after adjusting for gender, age at diagnosis, and type of surgery (see Table 2).

Figure 1.

Cumulative incidence rate for recurrence of inverted papilloma. The shaded area represents the confidence interval.

Figure 2.

Kaplan-Meier representation of recurrence-free rate according to the existence of previous surgery.

Table 2.

Multivariate Cox Regression Modeling for Recurrence of Inverted Papilloma.

	Hazard Ratio (95% CI)n = 97
Gender
Female	1^a
Male	1.48 (0.54-4.10)
Age (per 1 y increase)	1.01 (0.97-1.04)
Previous surgery
No	1^a
Yes	4.91 (1.80-13.39)
Type of surgery
Endoscopic	1^a
Open	0.27 (0.06-1.19)

Reference category.

Classification Systems Comparisons

First, we described the distribution of patients in each group for each classification system, as depicted in Figure 3 and Table 3.

Figure 3.

Proportion of patients in each group of each classification system.

Table 3.

Recurrence Rates According to Classification Systems.^a

Classification	No Recurrence	Recurrence	P Value^b
Krouse			.53
T1	8 (9.64)	1 (5.0)
T2	28 (33.7)	7 (35.0)
T3	46 (55.4)	11 (55.0)
T4	1 (1.20)	1 (5.0)
Cannady			.39
A	36 (43.4)	8 (40.0)
B	46 (55.4)	11 (55.0)
C	1 (1.20)	1 (5.0)
Han			.51
1	35 (42.7)	10 (50.0)
2	37 (45.1)	10 (50.0)
3	10 (12.2)	0 (0.0)
4	0 (0.0)	0 (0.0)
Oikawa			.55
T1	9 (11.0)	1 (5.0)
T2	25 (30.5)	8 (40.0)
T3-A	39 (47.6)	11 (55.0)
T3-B	9 (11.0)	0 (0.0)
T4	0 (0.0)	0 (0.0)
Dragonetti			.69
I	22 (26.8)	6 (30.0)
II	1 (1.22)	0 (0.0)
III	8 (9.76)	2 (10.0)
IVa	22 (26.8)	3 (15.0)
IVb	17 (20.7)	7 (35.0)
V	4 (4.88)	2 (10.0)
VI	8 (9.76)	0 (0.0)
Kamel			.60
I	38 (47.5)	9 (45.0)
II	42 (52.5)	11 (55.0)
Skolnik			.59
T1	6 (7.23)	1 (5.0)
T2	6 (7.23)	1 (5.0)
T3	70 (84.3)	17 (85.0)
T4	1 (1.20)	1 (5.0)
Schneider			.48
1	7 (8.43)	1 (5.0)
2	55 (66.3)	12 (60.0)
3	20 (24.1)	6 (30.0)
4	1 (1.20)	1 (5.0)

Values are No. (%).

P values are from log-rank test.

Second, we explored for potential associations between classification systems and recurrences. None of the classification proved to be associated with recurrence according to each of its stages, as presented in Table 3 (P values from log-rank test range, .39-.69). In multivariate Cox regression modeling adjusted for age and gender, no classification was significantly associated with recurrence (P values range, .17-.99).

Discussion

Risk factors for recurrence of inverted papilloma are still debated, and results are contradictory, as presented in Table 4. Moreover, studies reporting risk factors for recurrence are of uneven quality, with only a few of them employing appropriate survival analyses.¹² In our study, the only factor associated with recurrence was history of previous surgery (ie, patients undergoing a second resection). This finding could suggest that these patients underwent an incomplete initial resection, which leads to an increased likelihood for recurrence after a second resection. Besides, this association has also been reported by other authors.¹² Sciarretta¹² et al hypothesized that these patients were previously operated using limited procedures (eg, polypectomy) leading to incomplete resections and that the scar tissue makes a complete visualization of the boundaries of the recurrent SIP at the time of the revision surgery difficult. No other associations with recurrence were found in our study, and in particular, we found no association between the type of surgery and recurrence, in accordance with other authors.^5-9

Table 4.

Comparison of Risk Factors for Recurrence.^a

Reference (First Author, Year)	Risk Factor for Recurrence
	Krouse Stage	External Approach	Location of the Tumor			Cancer	Previous Surgery
	Krouse Stage	External Approach	Maxillary Sinus	Ethmoid Sinus	Frontal Sinus	Cancer	Previous Surgery
Kim, 2012¹	−	−	+	−	+		−
Busquets, 2006²		+
Jurado-Ramos, 2009³		+
Caparroz, 2013⁴	−	−				−
Mortuaire, 2007⁵		−				−
Percodani, 2006⁶		−	−	−	+		−
Han, 2001⁷		−				−	−
Sautter, 2007⁸	+	−					−
Xiao-Ting, 2013⁹	−	−				−
Katori, 2005¹⁰	−
Lombardi, 2011¹¹	−		−	−	−		−
Sciarretta, 2014¹²	−		−	−	−		+
Katori, 2006¹³					+

– designates an absence of association between studied factor and recurrence; + designates a positive association between studied factor and recurrence.

This lack of clearly identified risk factors for recurrence of inverted papilloma is in line with other studies.^{1,5,7-9,11,12} This may be an argument that no significant risk factors actually exist and that recurrence is essentially, if not entirely, due to an incomplete initial resection. This assumption has been supported by several authors.^{1,11,16,21,28-34} Moreover, recurrences almost always occurred at the same site of origin as the first tumor, as pointed out by several authors, and mostly within the first 3 years following the surgery.^{16,21,29-33,35-38} These characteristics of recurrence support the theory of an incomplete resection of a slow growing tumor. It emphasizes the importance of a complete radical resection of SIP during the first surgery. However, in our cohort, 2 patients presented a recurrence in a different location than the primary tumor. Even if a local recurrence cannot be ruled out due to anatomically closed sites of origin, these 2 cases could indeed represent secondary locations. In the latter case, this could support that SIP arises from a global pathology of the mucosa. This could be in favor of the most widespread theory for the etiology of SIP, which is a viral infection by the human papillomavirus.^39,40

As illustrated in Figure 1, the majority of recurrences occurred within the first 3 years of follow-up but more generally within the first 5 years. This supports an extended follow-up of at least 5 years, beyond the classically 3 years recommended.^15,28 Moreover, few patients (2.9%) presented a recurrence beyond 5 years after the surgery, supporting a prolonged follow-up, at least using nasofibroscopy.

The second main objective of this study was to compare staging systems. The first classification devoted to SIP was proposed by Skolnik in 1966 and was based on the American Joint Committee on Cancer (AJCC) classification.²⁴ A few years later, Schneider²⁵ pointed out that SIP being a benign tumor, a staging system based on the AJCC classification should not be used and proposed a classification based on sinus involvement. In 2000, Krouse²³ proposed a new classification system that aimed to facilitate treatment planning. This staging system was the first proposed since the advent of endoscopic surgery, and it has rapidly spread so that the previous classifications were abandoned. In the following years, other classifications were developed, and there are currently 8 different staging systems proposed for inverted papilloma.^7,19-23 Nevertheless, solely 2 studies compared only 3 of these 8 classifications.^1,41 Using only q classification in the international literature is of primary importance since it would allow between-study comparisons and evaluation of treatment results. Moreover, studies’ reports would be standardized, thus making future systematic reviews and meta-analyses possible.

Given that one of the main goals of a staging system is to provide a prognosis,⁴² we investigated for potential associations between each classification system and recurrence. In our study, none of the classifications were associated with recurrence in multivariate Cox regression. Moreover, survival distributions were not statistically different between stages of each classification. In other words, none of the 8 classifications was able to predict prognosis according to each of its stages. Gras-Cabrerizo⁴¹ et al found an association between recurrence rate and the classification proposed by Cannady. Nevertheless, this association was found only in univariate analysis. Moreover, Kim et al¹ did not highlighted this association in their study. In those 2 studies, no association was found between the other studied classification systems and recurrence rate.^1,41

Keeping in mind that staging systems are not all proposed with the same intent (ie, staging the extent of the disease or guiding surgical procedure), the one proposed by Krouse being the most used in the literature and in the absence of a staging system predicting prognosis, this classification should be used as to homogenize studies’ reports.

Conclusion

In conclusion, our study revealed that history of previous resection was the only factor associated with recurrence. Due to the emergence of recurrences up to 5 years and beyond after the surgery, an extended follow-up is mandatory for these patients. Finally, Krouse’s classification should be widely used to homogenize studies’ reports, thus allowing between-study comparisons and meta-analyses.

Footnotes

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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