Challenges in the Management of Inverted Papilloma: A Review of 72 Revision Cases

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1 The Laryngoscope VC 2015 The American Laryngological, Rhinological and Otological Society, Inc. Challenges in the Management of Inverted Papilloma: A Review of 72 Revision Cases Gwijde F. J. P. M. Adriaensen, MD; Keng-Hua Lim, MD, MRCS (Edin); Christos Georgalas, MD, PhD FRCS (ORL-HNS); Susanne M. Reinartz, MD, PhD; Wytske J. Fokkens, MD, PhD Objectives/Hypothesis: We report on the treatment outcome of endoscopically managed sinonasal inverted papilloma, focusing on revision cases. Our aim was to identify the properties of revision cases that affect treatment outcome by comparing them to primary cases in a single center. We propose using 5-fluorouracil (5-FU) in the postoperative management of inverted papilloma. Study Design: A retrospective single-center case series. This study met the criteria for approval by the local medical ethics committee. Methods: We performed a retrospective chart review identifying patients operated on between January 2003 and September Data were collected about patient demographics, symptoms, tumor attachment site, imaging, intraoperative and pathological findings, surgical approaches, postoperative treatment, follow-up, and recurrence. Results: One hundred and twenty-one (72 revision and 49 primary) cases were retrieved with a minimum follow-up of 1 year. Revision cases have significantly higher Krouse staging (P ), different distribution of tumor attachment sites, and higher recurrence rates. The recurrence rate was 4.1% for primary cases (mean follow-up 35.5 months) and 18.1% for revision cases (mean follow-up 45 months). Eight of the recurrent cases recurred within the first year. 5-fluorouracil was applied postoperatively in 18 (5 primary and 13 revision) cases, which included one (5.6%) recurrence and one minor complication (transient periorbital swelling). Conclusion: The most important factors in preventing the recurrence of inverted papilloma are the determination of the location of the attachment and the completeness of resection in the primary endoscopic surgery. Revision cases have a higher recurrence rate, and the attachment sites are surgically more challenging. The use of 5-FU might have a place in the postoperative treatment of surgically challenging inverted papilloma. Key Words: Inverted papilloma, revision, recurrence, endoscopic sinus surgery, 5-fluorouracil. Level of Evidence: 4. Laryngoscope, 126: , 2016 INTRODUCTION Inverted papilloma (IP) is a relatively uncommon benign epithelial tumor of the nasal cavity and sinus that is locally aggressive, has a tendency to recur (12% 20%), and is associated with squamous cell carcinoma (SCC) (3% 7%). 1 It accounts for 0.5% to 4% of all neoplasms of the sinonasal tract. 1 Its etiology is unknown. Human papilloma virus DNA has been found in both the IP and cells of adjoining mucosa with normal appearance, implying that this may be a possible cause. 2 Removal of the adjoining predisposed mucosa, with a From the Department of Otorhinolaryngology, Academic Medical Center (G.F.J.P.M.A., C.G., S.M.R., W.J.F.), Amsterdam, The Netherlands; and the Department of Otorhinolaryngology, Tan Tock Seng Hospital (K-H.L.), Singapore Editor s Note: This Manuscript was accepted for publication June 26, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Gwijde F.J.P.M. Adriaensen, Department of Otorhinolaryngology, AMC Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. g.f.adriaensen@amc.uva.nl DOI: /lary normal appearance at the attachment site, may reduce the recurrence rate. 3 Nasal obstruction is the presenting symptom. 4,5 Other symptoms include epistaxis, rhinorrhea, epiphora, headaches, and hyposmia. Inverted papilloma is suspected in anyone with a unilateral nasal polyp, but histology is the gold standard for diagnosis. 6 Most surgeons agree that recurrence is usually the result of incomplete removal of the original tumor, although a field change in mucosa that looks normal at the time of surgery has been suggested. 1 A larger area has to be considered as the potential attachment in recurrent IP because it is often unclear where the original attachment was located. 7 The probability of the malignant deterioration of recurrent disease is up to 11%. 8 Potential contributing factors for recurrence are tumor location, extent, histology, multicentricity, method of removal, and length of follow-up. The completeness of resection at the site of origin is the most important factor. 9,10 The most frequent sites of origin are the ethmoid sinus, lateral nasal wall, and maxillary sinus. Attachment in the sphenoid sinus is less common, and attachment in the frontal sinus or on the nasal septum is rare. 5,11

2 The introduction of endoscopic resection techniques enabled the endonasal removal of IP with good, if not better, results than external approaches. 1,12 Complete resection is possible even in unfavorable sites, such as the anterior wall and floor of the maxillary sinus, the frontal sinus, and the cribriform plate. The main surgical objective is to remove all diseased mucosa and mucoperiosteum, together with a cuff of normal-looking mucosa at the attachment site, followed by drilling and/or coagulation. Endoscopic surgery has become the gold standard for treating the vast majority of IP. 1,4,13 rates tend to be higher after revision surgery (17% 50%) This article compares relevant factors for, and the recurrence of, IP in revision and primary cases in a single institution over a 10-year period. 5-fluorouracil is a structural thymidine analogue that interferes with DNA synthesis and is used to treat epithelial malignancies because it acts on proliferating cells. 18 It is used, for example, to treat actinic keratosis and superficial basal cell carcinoma of the skin, 19 surface squamous neoplasia of the eye, 18 and cervical intraepithelial neoplasm in gynecology. 20 In the nose and sinus, topical 5-FU has been used after the resection of ethmoidal adenocarcinoma in some centers. 21,22 Long-term follow-up of this disease has shown that it is safe and provides longer disease-free survival than primary radiotherapy. Side effects are local irritation reactions, such as burning, crusting, and inflammatory reactions. The literature contains no reports of its use as an adjunct after the resection of inverted papilloma. We evaluated the use of topical 5-FU as a postoperative treatment. This could be a new treatment option for reducing recurrence in cases when drilling and or coagulation is difficult or the surgeon is not absolutely sure that the whole area of attachment has been cleared of diseased mucosa and mucoperiosteum. MATERIALS AND METHODS Study Design A retrospective review of medical records was performed, identifying all patients with IP of the nasal cavity and paranasal sinus who were treated at the Academic Medical Center, Amsterdam, The Netherlands, between January 2003 and September A minimum of 12 months follow-up was selected because most recurrence is found in this period. 23 Patients demographic data, clinical presentation, previous surgeries, tumor attachment site, radiological, intraoperative and pathological findings, surgical approaches, and recurrence rate were collected. Tumor extent was classified using the Krouse staging system. 24 Senior rhinologists of the department performed all surgeries endoscopically. Definitions A primary case is an unoperated case (biopsies excluded). A revision case is a case that has been operated in another institution. A recurrence is a case that has been operated in our institution (either primary or revision) and has recurred. Surgical Method All surgery was performed under general anaesthesia, with local anaesthesia and vasoconstriction achieved using three cotton tips per nasal side soaked in crystalline cocaine (100 mg) dissolved in adrenaline (1 mg/ml). When the size and extent of the tumor permitted, en-block resections were performed. A cuff of mucosa with a normal appearance surrounding the attachment was marked using diathermy and then was excised together with the lesion. Next, the bone underlying the attachment was drilled using a diamond drill. In areas where the bone was too thin, such as the lateral lamella or the cribriform plate, gentle coagulation was used. In revision cases when the attachment site(s) were uncertain or when very large tumors prevented en-block resection, the IP was initially resected piecemeal or debulked using Blakesley forceps and/or a microdebrider. Once the origin was located, resection followed as described above. All operative specimens, including microdebrider contents, were sent for pathological investigation. The surgical cavity was routinely packed with Lomatuell H gauze (Lohmann & Rauscher, Germany) or Merocel pack (Medtronic Xomed Inc, USA) impregnated with either antibiotic hydrocortisone cream or 5-FU cream, ensuring good contact with the resected surfaces for 7 to 10 days. Oral antibiotics were prescribed until the packing was removed in the outpatient clinic. 5-Fluorouracil Topical 5-FU 5% was used in cases when it was difficult to be absolutely sure that all diseased mucoperichondrium or mucoperiosteum had been completely removed, for example, when anatomical locations are hard to reach and/or it is impossible to drill and coagulate without potentially causing serious morbidity, such as attachment to the cribriform plate, lateral lamella, or a far lateral location in the frontal sinus. When applied topically, a Lomatuell H gauze (Lohmann & Rauscher) or Merocel (Medtronic Xomed Inc.) with 5-FU was left in situ for 7 to 10 days. Prior informed consent was obtained for each of the patients receiving 5-FU. Outcome Measurements We compared primary to revision cases on the basis of Krouse staging, the attachment site, and other factors such as pathology and multifocality. We evaluated our recurrences of primary cases, revision cases, and early recurrences with a minimum follow-up of 12 months. Finally, the effect of 5-FU was analyzed. Statistical Analysis We compared recurrences and related factors, such as attachment site; Krouse stage; pathology and focality in primary and revision surgery, and revision cases with and without recurrences. Chi square analysis was the primary approach used for analysis of the categorical data collected. When sample sizes were small (< 5), Fisher s exact test was used. P < 0.05 was considered statistically significant. All calculations were performed using IBM SPSS Statistics for Macintosh, Version 20 (IBM Corp., Armonk, NY). RESULTS Primary Versus Revision Cases Table I shows a comparison of the characteristics of primary and revision cases. 323

3 TABLE I. Characteristics of Primary and Revision Cases. Primary (%) Revision (%) P Value Number of patients Male 35 (71.4) 54 (75.0) P (4.1) 13 (18.1) P P * Krouse P (12.2) 3 (4.2) 2 30 (61.2) 26 (36.1) 3 13 (26.5) 41 (56.9) 4 0 (0) 2 (2.8) Site Ethmoid sinus 33 (67.3) 48 (66.7) P Maxillary sinus 25 (51.0) 36 (50.0) P Frontal recess 7 (14.3) 27 (37.5) P Frontal sinus 3 (6.1) 14 (19.4) P * Sphenoid sinus 0 (0) 3 (4.2) P * Pathology P Dysplasia 1 (2) 5 (6.9) Squamous cell carcinoma 0 (0) 2 (2.8) Focality P Unifocal 46 (93.9) 63 (87.5) Multifocal 1 (2.0) 6 (8.3) *Fisher s exact test. All other P values were calculated using Chi Square analysis. Not mutually exclusive. Bold values are significant. Patient Data One hundred and twenty-three patients were assessed. Two patients were excluded because the data were incomplete, leaving 121 (49 primary and 72 revision cases) for analysis. The mean age at the time of surgery in the Academic Medical Center was 47.8 years (standard deviation [SD] 15.2) for primary IP, as compared to 54.5 years (SD 14.7) for revision cases. Mean follow-up was 35.5 (range ) months for primary IP and 45.1 (range ) months for revision IP. The recurrence rate was 4% for primary IP and 18% for revision cases. Male predominance was a feature of both series (Table I). Krouse Staging The primary cases included a significantly higher proportion of Krouse stage I (12.2%) and stage II (61.2%) disease; the revision cases included more Krouse stage III (56.9%) and stage IV (2.8%; P ) disease (Table I). Tumor Attachment Site Most attachments were found in the ethmoid sinus, followed by the maxillary sinus and frontal recess. The frontal recess and frontal sinus were more involved in the attachment site in revision cases. In five cases, the diagnosis of IP was made after bilateral endoscopic sinus surgery for nasal polyposis, during which material was sent for pathological investigation because IP was suspected. Three cases had been previously operated elsewhere. We do not send material for pathological investigation routinely in nasal polyposis; it is only sent when clinical doubts arise during surgery. In these patients, it was not possible to establish the attachment site (or focality) with certainty (Table I). Other Properties Revision cases had a higher incidence of dysplasia (6.9%) and malignancy (2.8%), as well as multifocality (8.3%). Pathology showed exophytic papilloma in two cases (1 primary, 1 revision) (1.6%), oncocytic papilloma in three revision cases (2.5%), and inverted papilloma in the remainder. Six of seven multifocal IPs were revision cases. We could not ascertain whether they were due to incomplete removal or truly multifocal disease. Table III lists the characteristics of all recurrent cases. See also Figure 2. in Primary Cases Two primary cases (4.1%) recurred at 27 and 11 months, respectively. In the first case, which involved attachment in the ethmoid sinus and to the lateral nasal wall, the bone was coagulated but not drilled to remove mucosa and mucoperiosteum. after 27 months was in the area operated previously: the lateral wall of the posterior ethmoid sinus. During the revision procedure, the bone underlying the attachment was both drilled and coagulated. The second case, which originated in the ethmoid sinus and the agger nasi cell, recurred within a year, at which time it was found to come from the lateral surface of the middle turbinate. A revision Draf 2b was performed. Both patients were disease-free after 7 months and 93 months. From Revision Cases Thirteen (18%) of 72 revision cases recurred. Significantly more revision cases recurred when attachment was in the frontal recess (7/27 [26%]) than when attachment was in the ethmoid sinus (17%), frontal sinus (14%), or maxillary sinus (14%). Three patients developed more than one recurrence after revision. The average time to first recurrence was 26.6 months (range 4 83 months). No statistically significant differences were found between revision cases with and without recurrence in terms of the factors analyzed, such as location or Krouse stage (Table II). Early s Seven of all 15 recurrences (46.7%) occurred within 12 months (Table III). Three recurrences were attached in the frontal sinus (patients 4, 5, and 13). Two recurrences had an IP attached to the medial wall of the maxillary sinus (patients 2 and 7). In consultation with the 324

4 TABLE II. Characteristics of Revision Cases (n 5 72). No. (%)n 5 59 (%)n 5 13 P Value Krouse (3.4) 1 (7.7) 2 23 (30.0) 3 (23.1) 3 32 (54.0) 9 (69.2) 4 2 (3.4) 0 (0) Site* Ethmoid sinus 40 (67.8) 8 (61.5) Maxillary sinus 30 (50.8) 6 (46.2) Frontal recess 20 (33.9) 7 (53.8) Frontal sinus 12 (20.3) 2 (15.4) Sphenoid sinus 3 (4.2) 0 (0) Side 0.94 Bilateral 8 (13.6) 2 (15.4) Number of previous surgeries (81.4) 9 (69.2) 2 6 (10.2) 0 (0) 3 4 (6.8) 3 (23.1) 4 0 (0) 0 (0) 5 1 (1.7) 1 (7.7) *Not mutually exclusive. patient, a slightly higher risk of recurrence was accepted to avoid engaging in an extensive medial maxillectomy with the removal of the nasolacrimal duct. was seen at 4 and 6 months respectively, and endoscopic revision surgery followed. Patient 2 underwent four interventions in total. At the end of the third operation, 5-FU was applied because the attachment area was extensive. Both patients have currently been diseasefree for more than 5 years. Patient 9 had an IP (without dysplasia) for which a Draf 2b was performed initially. The tumor recurred 5 months later at the posterior septum, a completely separate location from the previous attachment sites. An endoscopic resection was performed, and histology showed SCC. The margins were clear, and there has been no recurrence since (at least 36 months) (Table III). 5-Fluorouracil Topical 5-FU was applied after 18 endoscopic procedures: on 12 occasions after the first surgery in our department (4 primary, 8 revision cases) and six times in recurrent cases (1 primary, 5 revision cases). We first tried topical 5-FU in an 11-year-old girl with massive nasal polyposis and mucocele formation but without cystic fibrosis (Fig. 1). Pathology revealed Schneiderian papilloma (inverted and exophytic). A Draf 3 was performed, but the IP rapidly recurred twice after 8 and 5 months despite clinically complete resection including extensive drilling and coagulation of the attachment sites. During the last revision procedure, 5-FU was applied given previous experience with 5-FU in the treatment of adenocarcinoma. 21,22 There has been no recurrence since (at least 82 months). 5-fluorouracil was used in three primary and seven revision cases attached in the frontal sinus because it could not be ascertained that all of the involved mucoperiosteum had been removed after drilling and/or coagulation given that the tumor attachment was in the far lateral section, on the orbital roof, or on the anterior wall. In another primary case, 5-FU was used because of an extensive tumor attachment from the posterior wall of the maxillary sinus to the ethmoid sinus, middle and superior turbinates, frontal recess, and cribriform plate, making complete resection with drilling or coagulation difficult. In two revision cases, the reason for 5-FU application was the rapid recurrence of IP (4 and 5 months) after the first revision. In another revision case, 5-FU was used because of bilateral and multifocal disease. To date, only one patient with a maxillary location of IP (patient 2; described above) (Table III) has suffered a recurrence after the application of 5-FU. Overall, the IP recurrence rate after topical 5-FU in this highly selective series of recurrent or complicated disease was 5.6% (1/18). One patient had transient periorbital swelling. None had any major complications. DISCUSSION We evaluated our treatment outcomes for endoscopic IP surgery in primary and revision cases. We were interested in the recurrence rate and time to recurrence, as well as in identifying specific factors in these groups that might explain these differences. Finally, we used 5-FU in the postoperative treatment period as an adjuvant therapy, with the aim of improving surgical outcome. Most recurrences of IP are thought to be attributable to incomplete resection at the site of origin. 1,10 The attachment is best identified during primary surgery. In revision surgery, finding the attachment can be more challenging because of distorted anatomy, residual disease at different locations, scar tissue, and the absence of bony landmarks. 5 On the basis of a number of small series (14 26 patients), it has been suggested that higher recurrence rates might be found in revision cases In this large series, we did indeed find a significantly higher recurrence rate in revision cases (18.1% [13 of 72]) than in primary cases (4.1% [2 of 49]) (P ). Attachment Site In this series, significantly more recurrences were found when the IP was attached in the frontal recess rather than in another sinus, including the frontal sinus. It is not clear why an IP in the frontal recess seems more difficult to remove, but it can be imagined that the narrow space and delicacy of the surrounding structures make complete removal more difficult. 325

5 TABLE III. Characteristics of Recurrent Cases Case Age (yrs)/ Sex Op Side Origin of Tumor Krouse Surgery 5FU Pathology Time to 1st 2nd 3rd Revision 1 53/M 5 Left FR, FS 3 Draf 2b/Draf 2b No/No No dysplasia 75 FS (post) 2 49/M 1 Right* E, MA (ant), FR 3 EMM, Draf 2b/radical EMM/ revision EMM/endoscopic resection No/No/ Yes/No No dysplasia 4/19/16 MA (lat) MA (med, post, lat, sup) 3 41/M 1 Right MT, E, MA (med) 2 Draf 2a, WMA/EMM No/No No dysplasia 83 E, MA (med) 4 11/F 1 Right# E, FR, FS 3 Draf 3/Draf 3/Draf 3 No/No/Yes No dysplasia 6/5 FS (orbital roof) FS 5 29/F 1 Bilat FR (neostium) 3 Draf 3/Draf 3 No/No No dysplasia 9 E, LP, FR (neostium) 6 72/M 3 Right E, SB 3 Draf 2a/ No/ No dysplasia 33 FR 7 51/F 1 Left MA (ant, lat) 3 EMM/EMM No/No No dysplasia 6 MA (lat, ant, sup) 8 58/F 1 Left E, MA (med) 3 EMM/EMM No/No No dysplasia 37 MA (ant, floor, lat, post) 9 70/F 1 Left E, MT, ST, LC 2 Draf 2b/Draf 2b No/No SCC 8 Septum (post) 10 34/F 2 Left Lachrymal sac 1 DCR/Draf 3, ethmoidectomy, No/Yes No dysplasia 39 FS, orbit orbitotomy 11 64/M 1 Left E, FR 3 Draf 2b/Draf 2b/Draf 2b No/No/No No dysplasia 19/5 E, orbital apex, MT FR 12 61/M 3 Right FR 3 Draf 2b/Draf 2b No/Yes No dysplasia 18 E, MT 13 41/M 1 Left MA, E, FR 3 Draf 3/Draf 3 No/Yes No dysplasia 7 FR Primary 14 40/M 0 Right E, LNW 3 Sphenoidotomy, No/Yes No dysplasia 27 E (post) ethmoidectomy/ ethmoidectomy 15 47/M 0 Left E 2 Draf 2a/Draf 2a No/No No dysplasia 11 E, MT MA (post), FR, LP *Multifocal disease. AEA 5 anterior ethmoidal artery; ant 5 anterior; DCR 5 dacryocystorhinostomy; E 5 ethmoid sinus; EMM 5 endoscopic medial maxillectomy; F 5 female; FR 5 frontal recess; FS 5 frontal sinus; lat 5 lateral; LC 5 lamina cribrosa; LNW 5 lateral nasal wall; LP 5 lamina papyracea; M 5 male; MA 5 maxillary sinus; med 5 medial; MT 5 middle turbinate; Op 5 number of previous operations before referral to the Academic Medical Center, Amsterdam, The Netherlands; SCC 5 squamous cell carcinoma; ST 5 superior turbinate; sup 5 superior; SB 5 skull base; 25 declined reoperation (based on age and size); WMA 5 wide maxillary antrostomy. 326

6 review. 27 Malleable suction diathermy, 28 and probably 5-FU, contributed to these results. Follow-up The literature indicates that the majority of recurrences occur within the first year after surgery, with a small percentage of recurrence possibly being seen at 5 to 6 years after treatment. 10,23,29 Fifty-three percent of our recurrences, however, occurred after the first year, and the longest time to recurrence was 75 months. Furthermore, recurrences were mostly detected during follow-up before symptoms presented. Our department therefore advises lifelong follow-up. The interval between visits can be shorter within the first 1 to 2 years and longer after the second year, with follow-up eventually becoming annual. Fig. 1. T2-weighted, coronal magnetic resonance imaging scan of the first case to receive 5-fluorouracil. Arrow points to a right frontal mucocele that is causing a right orbital roof defect. Frontal sinus IP is rare. 1 The incidence of frontal sinus IP in our series was 19.8% (14 revision and 3 primary cases), probably reflecting the tertiary referral bias rather than the true incidence of frontal IP. An osteoplastic flap, and sometimes a combined endoscopic and external approach, has been recommended for frontal IP involving the anterior and/or lateral and/or superior wall or when the IP is extensive. 4,25,26 Nevertheless, all frontal sinus IPs in this series were accessible endoscopically, and a revision Draf 3 procedure provided adequate access for the resection, with a low recurrence rate (12%) compared to the 22.4% reported in a systemic Fig. 2. T2-weighted, coronal magnetic resonance imaging scan showing hypo-intense convoluted cerebriform pattern of recurrent inverted papilloma. 5-Fluorouracil Based on past experience with 5-FU in adenocarcinoma, 21,22 the last author (W.J.F.) decided to first use topical 5-FU as postoperative treatment in an 11-yearold girl with extensive frontal IP and multiple fast recurrences. There has been no subsequent recurrence (since at least 82 months). This encouraged us to use 5-FU when it was difficult to ascertain complete removal, for example, on the cribriform plate or the orbital roof. Results from this article suggest that 5-FU is a promising topical adjunct in the management of inverted papilloma, with an excellent safety profile. A proposed but not at all proven mechanism of action is that, because the dysplastic and neoplastic cells of the inverted papilloma lesions have a higher DNA requirement than normal epithelial cells, 5-FU acts preferentially to cause apoptosis in inverted papilloma cells. Yet, surgical removal of all attachment site(s) remains the primary therapeutic goal and cannot be replaced by applying 5-FU. We propose its use whenever the surgeon is not certain that the IP has been completely removed due to the anatomical location or the extent of attachment, or when the IP recurs rapidly. We had one minor complication transient periorbital swelling with no residual effect. Using the first 5-FU case as a cutoff point (February 2007), the overall recurrence rate drops from 20% (30 cases) before selective introduction of 5-FU to 9.9% (91 cases) after selective introduction of 5-FU (P ). However, it is not possible to attribute this effect solely to 5-FU. This is a highly subjectively selected subgroup based on clinical characteristics of the IP and the personal decision of the surgeon; thus, no statistical analysis or comparison has been performed, and no treatment effect may be inferred from a retrospective case series. Ideally, a randomized multicenter study should be performed and a larger cohort with clearly defined patient and IP characteristics beforehand, which is followed prospectively will be needed to back our findings. CONCLUSION The most important factor in preventing the recurrence of IP is the completeness of resection, with the 327

7 best opportunity for the achievement of this goal being during primary surgery. The endoscopic resection of IP is also effective in difficult areas of the maxillary sinus and the frontal sinus. The risk of recurrence is significantly higher in surgery for revision cases with a higher Krouse stage and different predilection for attachment sites. Frequent outpatient endoscopic follow-up during the first 2 years is mandatory, but lifelong follow-up is recommended. Topical 5-FU, a chemotherapeutic agent, appears to be promising as an adjuvant therapy in the postoperative treatment of challenging IP. BIBLIOGRAPHY 1. Lund VJ, Stammberger H, Nicolai P, et al. European position paper on endoscopic management of tumours of the nose, paranasal sinuses and skull base. Rhinol Suppl 2010: Vrabec DP. The inverted Schneiderian papilloma: a 25-year study. Laryngoscope 1994;104: Yoon JH, Kim CH, Choi EC. Treatment outcomes of primary and recurrent inverted papilloma: an analysis of 96 cases. J Laryngol Otol 2002;116: Lombardi D, Tomenzoli D, Butta L, et al. Limitations and complications of endoscopic surgery for treatment for sinonasal inverted papilloma: a reassessment after 212 cases. Head Neck 2011;33: Lawson W, Patel ZM. The evolution of management for inverted papilloma: an analysis of 200 cases. Otolaryngol Head Neck Surg 2009;140: Diamantopoulos II, Jones NS, Lowe J. All nasal polyps need histological examination: an audit-based appraisal of clinical practice. J Laryngol Otol 2000;114: Lian F, Juan H. Different endoscopic strategies in the management of recurrent sinonasal inverted papilloma. J Craniofac Surg 2012;23:e44 e Mirza S, Bradley PJ, Acharya A, Stacey M, Jones NS. Sinonasal inverted papillomas: recurrence, and synchronous and metachronous malignancy. J Laryngol Otol 2007;121: Lawson W, Kaufman MR, Biller HF. Treatment outcomes in the management of inverted papilloma: an analysis of 160 cases. Laryngoscope 2003;113: Lawson W, Ho BT, Shaari CM, Biller HF. Inverted papilloma: a report of 112 cases. Laryngoscope 1995;105: Kim DY, Hong SL, Lee CH, et al. Inverted papilloma of the nasal cavity and paranasal sinuses: a Korean multicenter study. Laryngoscope 2012; 122: Busquets JM, Hwang PH. Endoscopic resection of sinonasal inverted papilloma: a meta-analysis. Otolaryngol Head Neck Surg 2006;134: Carta F, Verillaud B, Herman P. Role of endoscopic approach in the management of inverted papilloma. Curr Opin Otolaryngol Head Neck Surg 2011;19: Han JK, Smith TL, Loehrl T, Toohill RJ, Smith MM. An evolution in the management of sinonasal inverting papilloma. Laryngoscope 2001;111: Lee TJ, Huang SF, Lee LA, Huang CC. Endoscopic surgery for recurrent inverted papilloma. Laryngoscope 2004;114: Tufano RP, Thaler ER, Lanza DC, Goldberg AN, Kennedy DW. Endoscopic management of sinonasal inverted papilloma. Am J Rhinol 1999;13: Tomazic PV, Hubmann F, Stammberger H. [The Problem of High Rate in Endoscopic Revision Surgery for Inverted Papilloma]. [Article in German]. Laryngorhinootologie 2014;94: doi: /s Nanji AA, Sayyad FE, Karp CL. Topical chemotherapy for ocular surface squamous neoplasia. Curr Opin Ophthalmol 2013;24: Moore AY. Clinical applications for topical 5-fluorouracil in the treatment of dermatological disorders. J Dermatolog Treat 2009;20: Rahangdale L, Lippmann QK, Garcia K, Budwit D, Smith JS, van Le L. Topical 5-fluorouracil for treatment of cervical intraepithelial neoplasia 2: a randomized controlled trial. Am J Obstet Gynecol 2014;210:314 e311 e Almeyda R, Capper J. Is surgical debridement and topical 5 fluorouracil the optimum treatment for woodworkers adenocarcinoma of the ethmoid sinuses? A case-controlled study of a 20-year experience. Clin Otolaryngol 2008;33: Knegt PP, Ah-See KW, vd Velden LA, Kerrebijn J. Adenocarcinoma of the ethmoidal sinus complex: surgical debulking and topical fluorouracil may be the optimal treatment. Arch Otolaryngol Head Neck Surg 2001; 127: Von Buchwald C, Larsen AS. Endoscopic surgery of inverted papillomas under image guidance a prospective study of 42 consecutive cases at a Danish university clinic. Otolaryngol Head Neck Surg 2005; 132: Krouse JH. Development of a staging system for inverted papilloma. Laryngoscope 2000;110: Zhang L, Han D, Wang C, Ge W, Zhou B. Endoscopic management of the inverted papilloma with attachment to the frontal sinus drainage pathway. Acta Otolaryngol 2008;128: Eweiss A, Al Ansari A, Hassab M. Inverted papilloma involving the frontal sinus: a management plan. Eur Arch Otorhinolaryngol 2009;266: Walgama E, Ahn C, Batra PS. Surgical management of frontal sinus inverted papilloma: a systematic review. Laryngoscope 2012;122: Hughes OR, Skilbeck CJ, Kwame I, Kwa K, Choa DI. Suction diathermy as an adjunct to endoscopic removal of inverted papilloma. Laryngoscope 2011;121: Smith O, Gullane PJ. Inverting papilloma of the nose: analysis of 48 patients. J Otolaryngol 1987;16: