Events indicates recurrence cases; OR, odds ratio; and Total, the total number of patients in each Krouse stage for each study.
The Harbord test P values are as follows: P = .16 (A), P = .14 (B), and P = .64 (C).
eFigure 1. Influence Analyses
eFigure 2. Extended Funnel Plots
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Lisan Q, Moya-Plana A, Bonfils P. Association of Krouse Classification for Sinonasal Inverted Papilloma With Recurrence: A Systematic Review and Meta-analysis. JAMA Otolaryngol Head Neck Surg. 2017;143(11):1104–1110. doi:10.1001/jamaoto.2017.1686
Is the Krouse classification for sinonasal inverted papilloma associated with recurrence?
In this systematic review and meta-analysis of 13 studies comprising 1787 unique patients with sinonasal inverted papillomas, stage T3 disease was at significantly higher risk of recurrence when compared with stage T2. No differences in recurrence rates were found between stages T1 and T2 disease or between stages T3 and T4.
Head and neck surgeons must be aware of this higher likelihood of recurrence for stage T3 when planning and performing the surgery for an inverted papilloma.
The risk factors for the recurrence of sinonasal inverted papilloma are still unclear.
To investigate the potential association between the Krouse classification and the recurrence rates of sinonasal inverted papilloma.
The EMBASE and MEDLINE databases were searched for the period January 1, 1964, through September 30, 2016, using the following search strategy: (paranasal sinuses [Medical Subject Headings (MeSH) terms] OR sinonasal [all fields]) AND (inverted papilloma [MeSH terms] OR (inverted [all fields] AND papilloma [all fields]).
The inclusion criteria were (1) studies including sinonasal inverted papilloma only and no other forms of papillomas, such as oncocytic papilloma; (2) minimum follow-up of 1 year after the surgery; and (3) clear report of cases (recurrence) and controls according to the Krouse classification system or deducible from the full-text article. Literature search was performed by 2 reviewers. Of the 625 articles retrieved in the literature, 97 full-text articles were reviewed. Observational cohort studies or randomized controlled trials were included, and the following variables were extracted from full-text articles: authors of the study, publication year, follow-up data, and number of cases (recurrence) and controls (no recurrence) in each of the 4 stages of the Krouse classification system.
Data Extraction and Synthesis
The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. Odds ratios (ORs) and 95% CIs were estimated, and data of included studies were pooled using a random-effects model.
Main Outcomes and Measures
The main outcome was recurrence after surgical removal of sinonasal inverted papilloma according to each stage of the Krouse classification system.
Thirteen studies comprising 1787 patients were analyzed. A significant increased risk of recurrence (51%) was highlighted for Krouse stage T3 disease when compared with stage T2 (pooled OR, 1.51; 95% CI, 1.09-2.09). No significant difference in risk of recurrence was found between Krouse stages T1 and T2 disease (pooled OR, 1.14; 95% CI, 0.63-2.04) or between stages T3 and T4 (pooled OR, 1.27; 95% CI, 0.72-2.26).
Conclusions and Relevance
Inverted papillomas classified as stage T3 according to the Krouse classification system presented a 51% higher likelihood of recurrence. Head and neck surgeons must be aware of this higher likelihood of recurrence when planning and performing surgery for sinonasal inverted papilloma.
Sinonasal inverted papilloma (SIP) is a benign tumor of the nasal cavity and paranasal sinuses. One particularity of SIP is that it presents a potential for recurrence, even several years after surgical resection.1-3 Thus, the risk factors for recurrence have long been investigated, but the results of individual studies are still contradictory.3-7
Kim and Kwon8 recently published a meta-analysis of the existing literature on the risk of SIP recurrence depending on the surgical approach used (ie, open vs endoscopic endonasal). They concluded that the endoscopic approach is safe, resulting in a 44% reduced risk of recurrence when compared with the open approach. Nevertheless, other risk factors for recurrence remain uncertain. Specifically, it is still unclear if the most used classification for SIP, the Krouse classification system,9 is correlated with the risk of recurrence.3,6 Given that a main goal of classification is to estimate prognosis,10 clarifying any potential association between the Krouse classification and recurrence rate is important. Hence, we performed a systematic review and meta-analysis to investigate the potential differences in recurrence rate depending on the Krouse stages.
This report followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines.11 The study protocol was registered on PROSPERO, the international prospective register of systematic reviews (CRD42016041980), on July 14, 2016.
The MEDLINE and EMBASE databases were searched by two of us (Q.L. and A.M.-P.) for articles on cohort studies of SIP. Following are the keywords used for searching both MEDLINE and EMBASE: (paranasal sinuses [Medical Subject Headings (MeSH) terms] OR sinonasal [all fields]) AND (inverted papilloma [MeSH terms] OR (inverted [all fields] AND papilloma [all fields]). The search was conducted for the period January 1, 1964, through September 30, 2016.
After suppressing duplicate publications, we excluded reports of results that were not from observational cohort studies or randomized controlled trials, such as literature review and case series articles. The inclusion criteria were as follows: (1) studies about SIP only and no other forms of papillomas, such as oncocytic papilloma; (2) minimum follow-up of 1 year after the surgery; and (3) clear report of cases (recurrence) and controls according to the Krouse classification or deducible from the full-text article.
A standardized extraction form was used. For each included study, the following variables were extracted from full-text articles: authors of the study, publication year, follow-up data (minimum, maximum, median, and/or mean follow-up time), and number of cases (recurrence) and controls (no recurrence) in each of the 4 stages of the Krouse classification system9:
Stage T1: confined to the nasal cavity
Stage T2: involves ostiomeatal complex region, ethmoid, or medial wall of the maxillary sinus
Stage T3: involves any wall of the maxillary sinus but medial, frontal sinus, or sphenoid sinus
Stage T4: any extranasal or extrasinus extension or presence of a malignant neoplasm
The outcome of this meta-analysis was recurrence after surgery. Because the Krouse classification system is subdivided into 4 stages, 3 primary analyses were performed: (1) recurrence rate after surgery for stage T2 disease when compared with stage T1, (2) recurrence rate for stage T3 disease when compared with stage T2, and (3) recurrence rate for stage T4 disease when compared with stage T3. Hence, we evaluated the likelihood of presenting a recurrence for participants classified in a Krouse stage in comparison with the immediately lower stage. We performed the 3 analyses and not global testing followed by pairwise analyses to avoid multiple comparisons. We estimated the odds ratio (OR) and 95% CI for each study and used a random-effects model to pool estimates for each of the 3 analyses. The I2 statistic was used to assess for potential heterogeneity between studies, and a value of 50% or greater was considered to identify high heterogeneity.12 We performed an influence analysis in which pooled estimates were calculated to omit one study at a time. All statistical analyses were performed with R software, version 3.1.3 (R Foundation for Statistical Computing).13 The meta and metafor packages were used for the meta-analysis.
Risk of publication bias was evaluated using funnel plots, which show the estimate of the influence of each study against its SE. A Harbord test was used to assess any potential asymmetry in funnel plots. Because adding new studies to the existing evidence could lead to new conclusions, evaluating the contribution of a new study to the results is important. Thus, we used extended funnel plots to assess this potential impact.14 Extended funnel plots provide shaded areas, which represent the contribution of a new study to our meta-analysis and allow the exploration of the probability that an additional study would change the current results. We used the extfunnel package in R software to generate extended funnel plots.
As presented in Figure 1, the literature search retrieved 625 articles after duplicate publications were removed, and 97 full-text articles were assessed after irrelevant reports were excluded. We reviewed the bibliography of these articles, but no additional article was included. Overall, 13 articles complied with the inclusion criteria and were therefore included in the meta-analysis.3,6,7,15-24
The 13 included studies comprised 1787 unique patients. Characteristics of studies are summarized in the Table along with the total number of patients and the number of patients with disease at each Krouse stage. The minimum follow-up time was between 12 and 36 months, and the maximum follow-up time ranged from 3.5 to 16 years (although this time was not specified in 8 studies). Overall, 196 patients (11.0%) presented with a SIP classified as stage T1, 695 (38.9%) as stage T2, 800 (44.8%) as stage T3, and 96 (5.4%) as stage T4. There were 13 cases of recurrence for stage T1, 75 for stage T2, 124 for stage T3, and 17 for stage T4. In stage T4, carcinomas were diagnosed in 2% to 7% of patients depending on the study considered. Overall, carcinomas were present in 68 patients (3.8%).
Results of the meta-analysis are presented in Figure 2. No significant difference in risk of recurrence was found between stages T1 and T2 disease as presented in Figure 2A, with a pooled OR of 1.14 (95% CI, 0.63-2.04). A significantly increased risk of recurrence was highlighted for Krouse stage T3 disease compared with stage T2, with a pooled OR of 1.51 (95% CI, 1.09-2.09; Figure 2B). Finally, no significant difference in risk of recurrence was found for Krouse stage T4 disease compared with stage T3, with a pooled OR of 1.27 (95% CI, 0.72-2.26; Figure 2C). In all of these analyses, no between-studies heterogeneity was found (I2 = 0%).
As presented in eFigure 1 in the Supplement, the pooled OR and 95% CI would not have changed by omitting the studies one at a time. For comparison of stages T1 and T2 disease and stages T3 and T4, omitting the studies one at a time did not change the pooled estimate because no significant results were found. For comparison of stages T2 and T3 disease, the pooled estimate stayed significant regardless of the omitted study.
Publication bias was investigated using funnel plots (Figure 3). Visual inspection of funnel plots did not reveal any obvious asymmetry for any of the 3 analyses. In addition, results of the Harbord test were not significant in all cases, showing no significant publication bias (stage T1 vs stage T2 disease, P = .16; stage T2 vs stage T3, P = .14; and stage T3 vs stage T4, P = .64).
We carried out additional analyses using extended funnel plots to assess the potential influence of new studies on the results of our meta-analysis. For the 3 analyses, it appears unlikely that a new study would change our results (eFigure 2 in the Supplement). A new study added to the current evidence would not influence the absence of difference in recurrence rate between stages T1 and T2 disease and between stages T3 and T4 as well as the significant difference in recurrence rate between stages T2 and T3 disease.
A 51% increased risk of recurrence for SIP classified as T3 disease was observed when compared with stage T2. However, no significant difference in risk of recurrence was found between stages T1 and T2 disease or between stages T3 and T4.
Contradictory results have been reported regarding the ability of the Krouse classification system to estimate recurrence. Some studies highlighted an association between recurrence and the Krouse classification,6 but some others did not.3 Only 1 study attempted to evaluate the risk of recurrence according to the Krouse classification system and found no significant difference in recurrence rate at each stage of the classification.8 However, that study was a secondary analysis of a meta-analysis; thus, Kim and Kwon retrieved only 4 articles from the ones they selected for their main analysis. On the other hand, we identified 13 relevant studies. In addition, Kim and Kwon8 gathered the results of different studies and ignored between-study heterogeneity; hence, their results appeared to be statistically invalid.
Our results showed that stage T3 disease is at higher risk of recurrence when compared with stage T2. This finding could indicate that an involvement of the frontal sinus, sphenoid sinus, or any wall of the maxillary sinus but medial represents a higher risk of recurrence. However, keep in mind that stage T3 gathers tumors involving different locations; thus, some heterogeneity may exist in stage T3. All sites included in stage T3 do not represent the same difficulty in achieving a complete removal. For instance, a tumor involving the lateral part of the frontal sinus is more challenging to remove than a tumor limited to the medial part of the posterior wall of the maxillary sinus. Several studies reported an association between the involvement of the frontal sinus and the recurrence rate.3,7,25 These different locations included in the same stage (T3) may result in varying recurrence rates; thus, stage T3 likely gathers tumors with a different prognosis.
In addition, our results indicate that no difference in risk of recurrence exists whether the tumor is classified as stage T1 disease (involving only the nasal cavity) or stage T2 (involving the ethmoid sinus, the medial maxillary wall, or the ostiomeatal complex). Similarly, no difference in recurrence rate was found between stages T3 and T4 disease. Stage T4 gathers tumors extending beyond paranasal sinuses and tumors presenting with a synchronous carcinoma. However, stage T4 may be inappropriate and misleading. Synchronous carcinomas are included in stage T4 regardless of the extension of the tumor or whether it is limited to the nasal cavity or extended to the skull base, for instance. In these situations, the type of surgery largely differs and the risk or recurrence is likely different. Another drawback of stage T4 is that it includes carcinomas, regardless of the type of carcinoma. No differences exist between a focal in situ carcinoma (potentially representing an unexpected discovery on the postoperative histological analysis) and an invasive squamous cell carcinoma. If the diagnosis of a synchronous invasive squamous cell carcinoma is known before the surgery, it will influence the surgical procedure—an open approach is recommended by several authors.26,27 In addition, the diagnosis will lead to a postoperative irradiation therapy,2,26 whereas a simple surveillance is generally required for incidental findings of focal in situ carcinomas. Hence, stage T4 gathers potentially different types of tumors with likely different prognoses, resulting in a heterogeneous stage.
This meta-analysis focused on the Krouse classification system as a potential risk factor for recurrence. Obviously, other factors are associated with recurrence. For instance, in a recent meta-analysis, an endoscopic approach was associated with a 44% reduced risk of recurrence when compared with an open approach.8 Other factors, such as drilling the underlying bone or human papillomavirus infection, are still debated as potential risk factors for recurrence.15,28,29 Future systematic reviews and meta-analyses may be helpful to clarify the potential role of these factors on recurrence rate.
Some limitations should be considered when interpreting our results. As with any meta-analysis, ours may be biased in part because of publication bias. Nevertheless, we assessed publication bias using funnel plots and the Harbord test, and none of our 3 analyses showed a significant small-study effect. In addition, adding results of future studies could modify our results. Thus, to explore for the potential impact of new studies, we used extended funnel plots. Inspecting these funnel plots revealed that an updated result of our meta-analysis would be unlikely to differ from the results presented here.
Our findings could have clinical implications for the management of SIP. Head and neck surgeons must be aware that SIP classified as Krouse stage T3 is at higher risk of recurrence than SIP classified as stage T2. This result must be considered when planning the surgery. In addition, surgeons must be even more thorough in removing such tumors given that several authors suggest that recurrence is largely due to an incomplete initial removal.3,15,19,30,31 Hence, for tumors classified as stage T3 especially, given that they present a higher risk of recurrence, evaluating the association of some surgical techniques with lowered recurrence rate, such as drilling the underlying bone as suggested by some authors, is important.15,19,27
This systematic review and meta-analysis revealed a 51% increased risk of recurrence for SIP classified as Krouse stage T3 disease when compared with stage T2, but no differences in recurrence rate were found between stages T1 and T2 disease or between stages T3 and T4. Head and neck surgeons must be aware of this higher likelihood of recurrence for stage T3 when planning and performing SIP surgery.
Corresponding Author: Quentin Lisan, MD, Department of Otolaryngology–Head and Neck Surgery, European Hospital Georges Pompidou, 20 rue Leblanc, 75015 Paris, France (email@example.com).
Accepted for Publication: July 11, 2017.
Published Online: September 28, 2017. doi:10.1001/jamaoto.2017.1686
Author Contributions: Dr Lisan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: Lisan, Moya-Plana.
Drafting of the manuscript: Lisan.
Critical revision of the manuscript for important intellectual content: Moya-Plana, Bonfils.
Statistical analysis: Lisan.
Administrative, technical, or material support: Moya-Plana, Bonfils.
Study supervision: Moya-Plana, Bonfils.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.