Practical Radiation Oncology (2013) 3, 275–281
www.practicalradonc.org
Original Report
Radiation therapy for sinonasal inverted papilloma Michael Rutenberg MDa , Jessica Kirwan MAa , Christopher G. Morris MSa , John W. Werning MDb , William M. Mendenhall MDa,⁎ a
Department of Radiation Oncology, University of Florida, Gainesville, Florida Department of Otolaryngology, University of Florida, Gainesville, Florida
b
Received 2 May 2012; revised 20 June 2012; accepted 27 July 2012
Abstract Purpose: We retrospectively reviewed long-term outcomes of patients with inverted papilloma (IP) treated with radiation therapy at our institution. Methods and Materials: From 1969 to 2008, 13 patients with advanced or recurrent IP (n = 12) or cylindrical papilloma (n = 1) were treated with radiation therapy. The median age at radiation therapy was 53 years old (range, 32-84). Nine patients received postoperative radiation therapy, 3 received definitive radiation therapy, and 1 received preoperative radiation therapy. Of the 10 patients treated with combined-modality treatment, 1 underwent craniofacial resection and 9 underwent open resection. Eight patients, 4 patients, and 1 patient received once-daily fractionation, twice-daily fractionation, and planned split-course radiation therapy, respectively, to a median dose of 65 Gy (range, 45.3-70.4 Gy). Results: The median follow-up was 16.2 years. Actuarial 15-year overall and cause-specific survival rates were 62% and 82%. Fifteen-year actuarial local and regional control rates were 45% and 73%. Fifteen-year local-regional control rates for IP alone and IP associated with squamous cell carcinoma (IP-SCC) at the time of treatment were 80% and 16%. Fifteen-year overall survival rates for IP alone and IP-SCC were 40% and 50%. The only severe treatment complication was a grade 3 central nervous system radionecrosis. The most common grade 1-2 toxicities were mucositis (61%), pain (46%), conjunctivitis (31%), xerostomia (31%), epiphora (31%), and anorexia (31%). Conclusions: While surgery is the primary treatment for IP, radiation therapy should be considered in patients with SCC, multiply recurrent IPs, and incompletely resectable IP. Radiation therapy is associated with a relatively low risk of severe complications. Despite more aggressive treatment, local failure remains a considerable challenge. © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Introduction Inverted papilloma (IP) of the nasal cavity and paranasal sinuses is a rare, benign neoplasm that typically arises from the lateral wall of the nasal cavity near the middle meatus or Conflicts of interest: None. ⁎ Corresponding author. 2000 SW Archer Rd, PO Box 100385, Gainesville, FL 32610-0385. E-mail address: [email protected]fl.edu (W.M. Mendenhall).
the maxillary sinus. The incidence of these tumors is estimated at 0.2-0.6 per 100,000 individuals per year. IP typically presents as a unilateral polyp, most often occurs in the fifth or sixth decade, and has a 3:1 male to female predominance. 1-4 Patients can present with symptoms including nasal obstruction, nasal drainage, facial pain, epistaxis, headaches, and epiphora. 2-4 The primary treatment for IP is surgery. Historically, more extensive procedures, often involving open resections, have resulted in the best cure rates. However, recent
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use of transnasal endoscopic surgery has been highly successful in achieving total resection with a low recurrence rate. 5,6 Radiation therapy (RT) has been used for the treatment of IP as early as the start of the 20th century. However, despite a long history in its treatment, there are limited long-term outcome studies utilizing RT. 7-9 RT has generally been used in the treatment of IP when associated with malignancy, multiple recurrences, incomplete resections, or inoperable disease. Here we review 13 patients treated at our institute with either RT alone or in combination with surgery. We provide an update of previously published reports and include more extensive follow-up. 8-10
Methods and materials Patient characteristics Thirteen patients with advanced or recurrent sinonasal IP or cylindrical papilloma (CP) of the nasal cavity and paranasal sinuses were treated with external-beam RT at our institute between December 1969 and August 2008. These patients represent all those treated with RT with curative intent at our institution for this disease process during the study period. Twelve patients were treated for IP and 1 was treated for a CP. The median age at RT was 53 years (range, 32-84 years). Nine patients were male (69%) and 4 were female (31%). Ten of 13 patients (77%) were treated for recurrent disease, 6 of whom had 2 or more recurrences before receiving RT. Six patients had concomitant malignancy at the time of RT: carcinoma in situ, 1 patient; invasive squamous cell carcinoma (SCC), 3 patients; both SCC and carcinoma in situ, 1 patient; and transitional cell carcinoma, 1 patient. The primary disease site was the nasal cavity in 12 patients and the maxillary sinus in 1 patient.
Figure 1 Actuarial overall (—) and cause-specific (…) survival in 13 patients treated with radiation therapy for sinonasal papilloma.
Practical Radiation Oncology: October-December 2013
Treatment characteristics Of the 13 patients in our cohort, 9 were treated with surgical resection followed by postoperative RT, 1 received preoperative RT, and 3 received definitive RT. Of the 10 surgical resections performed, 9 were open resections and 1 was a craniofacial resection. RT was delivered using a 2- or 3-field technique with Co60 or 6- to 17-MV photons. Eight patients (62%) received continuous-course irradiation with once-daily fractionation, 1 patient (8%) received once-daily radiation with a planned spit-course, and 4 patients (31%) received twice-daily fractionation. Planned split-course RT has since been abandoned at our institution. Patients treated with oncedaily fractionation received 1.8 Gy per fraction, while twice-daily RT was given at 1.2 Gy per fraction, with a minimum 6-hour interfraction interval. Patients with inverted papilloma did not receive elective neck irradiation; those with concomitant malignancy usually received elective neck irradiation.
Results The median follow-up for our group of patients was 16.2 years (range, 7.2-19.7 years). The 15-year actuarial overall survival and cause-specific survival rates were 62% and 82%, respectively (Fig 1). Fifteen-year actuarial local and regional control rates were 45% and 73%, respectively (Fig 2). Patients and their treatment results are detailed in Table 1. The median follow-up for the 5 living patients at last follow-up was 19.0 years (range, 10.4-19.7 years). Three of these patients (60%) were alive with no evidence of disease. Three of the 8 patients who experienced a recurrence following RT underwent salvage surgery. Two of the 3 patients who underwent salvage surgery following a post-RT failure had active disease at last follow-up. The third patient was alive without
Figure 2 Actuarial local (—) and regional (…) control in 13 patients treated with radiation therapy for sinonasal papilloma.
Practical Radiation Oncology: October-December 2013
evidence of disease 10 years after RT and salvage surgery for a recurrence 9 months following RT. Three patients underwent treatment with definitive RT for unresectable disease to a total dose of 65 Gy at 1.8 Gy per fraction. Two of these patients had a disease recurrence; 1 patient with a recurrence at 13 months died with disease at 14.5 months after RT. A second patient treated with definitive RT for a cylindrical (columnar) papilloma (CP) developed an ethesioneuroblastoma 3.5 years after treatment and experienced a recurrence of the CP 13 years after treatment with RT. He died 15.4 years after RT due to intercurrent disease with persistent CP. One patient underwent preoperative RT for an IP-SCC involving the right nasal cavity, ethmoid sinus, cribriform plate, infratemporal fossa, and right orbital floor. He received 69.2 Gy to the primary tumor and 40.5 Gy to the ipsilateral low neck. He then underwent surgery including a superficial parotidectomy, right maxillectomy, and right orbital exenteration. His pathology indicated a complete pathologic response to RT. He had a local recurrence 13.6 years after RT and received salvage surgery. He died with persistent disease 18.6 years after receiving RT. Patients treated for IP with associated malignancy had worse overall 15-year local-regional control compared with those treated for IP alone; 80% versus 16%, respectively (P = .07). Fifteen-year overall survival rates for IP alone versus IP associated with malignancy were 40% and 50%, respectively (P = .36). Overall, RT in our cohort was relatively well tolerated, with only 1 ≥grade 3 treatment per the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0. 11 One patient treated with open surgical resection and adjuvant twice-daily RT to a dose of 67 Gy developed grade 3 central nervous system radionecrosis (patient 8 in Table 1). This patient had no disease recurrence following RT and at last follow-up was alive and disease-free at 19.4 years after treatment. All patients in our cohort experienced grade 1 or 2 treatment complications, the most common including mucositis (61%), pain (46%), conjunctivitis (31%), xerostomia (31%), epiphora (31%), and anorexia (31%).
Discussion Inverted papilloma is 1 of 3 histologic subtypes of sinonasal papillomas, which also include fungiform (exophytic) papillomas and CPs. 4 IP is distinguished histologically from other sinonasal papillomas by its characteristic endophytic epithelial growth with respect for the underlying basement membrane. All 3 forms of sinonasal papillomas arise from the Schneiderian epithelium of the nasal cavity and paranasal sinuses, which, unlike the endodermal origins of the nasopharynx and upper respiratory tract epithelium, originates from the
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ectodermal germ layer. 1 IP is also distinguished histologically from squamous papillomas and sinonasal polyps, and represents a true neoplastic process rather than inflammation or hyperplasia. 1,12 Although histologically distinct, IP and CP have similar biologic characteristics and treatment approaches. While these benign tumors of the sinonasal tract have virtually no metastatic potential and are associated with low mortality, they demand careful treatment. There are 3 clinical features of IP that weigh heavily in their treatment and indicate a need for an aggressive treatment approach. 3 The first is a tendency for aggressive local invasion. While lymph node or distant metastases are exceedingly rare, IP often shows extensive invasion into the paranasal sinuses and adjacent tissues. Its capacity for bone erosion and normal tissue destruction leads to significant morbidity and occasional mortality. The second important clinical feature of IP is a high incidence of local recurrence after excision. 5 A recent meta-analysis evaluated 1060 cases of IP and reported an average recurrence rate of 15%, with rates as high as 33%. 6 The third clinical feature of IP with important treatment implications is an association with malignancy. IP is associated with SCC in 5% to 15% of cases. 13 While these features indicate the need for aggressive treatment, they explain the difficulty in eradicating these neoplasms. Surgery remains the primary method of treatment for IP, with wide resection offering the best chance for cure. However, their location within the nasal cavity and paranasal sinuses often makes total resection difficult. The extent of tumor invasion and the difficulty of resection lead to surgical procedures that can be disfiguring and often result in tumor recurrence. The high incidence of associated malignancies further complicates the treatment picture. Radiation therapy was successfully used in the treatment of IP as early as 1920, 7 but the indications for its use are still controversial. Adjuvant RT is recommended in cases of concomitant SCC; however, the indications for treatment of pure IP are less established. RT has often been used to treat multiply recurrent disease, postoperative residual disease, and inoperable tumors. 14 There have been several single-institution outcomes studies for IP treated with RT with variable localregional control, disease-free survival, and overall survival rates (Table 2). The most common indication for treating IP with RT in these studies is an association with SCC, with nearly all of the patients reported in these studies receiving postoperative RT. Hug et al 7 reported the largest series to date, describing 25 cases of IP treated with adjuvant RT. Seven patients in their study were treated after subtotal tumor resection or for multiply recurrent disease after prior resections, while 18 patients received RT for IP associated with SCC. With a mean follow-up of 4.8 years, they achieved 88% local-regional control and 82% overall survival; favorable outcomes
278 Table 1
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Practical Radiation Oncology: October-December 2013
Treatment and results in 13 patients with sinonasal papilloma treated with radiation therapy
Patient No.
Age at RT (y), gender
Diagnosis
Krause stage
Primary tumor treatment
Recurrences prior to RT
1
36, male
IP/TCC a
IV
0
2
66, male
IP
III
3
46, male
IP/CIS a SCC c
II
Open resection b Adjuvant RT Unresectable b Definitive RT Open resection
1
4
73, female
IP/SCC c well-diff c
II
Open resection
1
5
47, male
I
53, male
IV
Transnasal resection Open resection
2
6
CCP/ Ethesioneuroblastoma c IP/SCC c well-diff c
3
7
38, male
IP/SCC c
I
Open resection
3
8
56, male
IP
II
Craniofacial resection
2
9
62, male
IP/CIS c
III
1
10
57, male
IP/ CIS/SCC c
II
Endoscopic resection Open resection
2
11
32, female
IP
II
Craniofacial resection
1
12
47, male
IP
III
Open resection b Adjuvant RT
0
13
84, female
IP
I
Transnasal
2
0
b.i.d., two times a day; CIS, carcinoma in situ; CCP, cylindrical cell papilloma; fx, fraction; IP, inverted papilloma; RT, radiation therapy; SCC, squamous cell (Continued) carcinoma; TCC, transitional cell carcinoma. a Denotes carcinoma identified at primary tumor diagnosis; Patient 3 had CIS at primary that progressed to SCC after RT. b Denotes carcinoma that was present at the time of RT. c Carcinoma that was diagnosed at tumor recurrence—not present at primary.
when compared with the current study and prior reports from the University of Michigan (Ann Arbor) and Geisinger Medical Center (Danville, PA). One potential explanation for the difference in outcomes between our study and Hug et al is the difference in follow-up period as many failures occurred well beyond the 5-year mark (Table 2). Our results show a trend toward a difference in localregional control between patients treated with IP only and IP associated with malignancy. The local-regional control and overall survival outcomes in our study for patients with IP associated with malignancy are comparable with prior studies by Vrabec 2 and Lesperance and Escalamado 15 (Table 2). A recent pooled analysis by Tanvetyanon et al 16 reported the results of 10 studies including 76 patients with IP associated with SCC. They show a median overall survival of 126 months and 63%
3-year actuarial overall survival. These studies are similar to our current study with a median overall survival of 180 months and 5-year actuarial survival of 88% in patients with IP with malignancy. Overall these patients are able to achieve long-term survival. However, as shown by our data and others, local-regional control continues to be a long-term challenge (we had a 15-year actuarial local-regional control of 16%). These data support the recommendation that IP associated with cancer requires aggressive treatment with adjuvant RT. In the current study as well as others, it is likely that the incidence of IP recurrence is exaggerated secondary to selection bias in reports from tertiary care centers, where unresectable or difficult-to-manage cases are appropriately referred for RT. Nonetheless, it is those cases of inoperable, incompletely resected, or multiply recurrent IP for which RT should be considered.
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Table 1 (continued) Patient No.
RT course
Post-RT course
Follow-up
1
Open resection w/ adjuvant RT b Co60 70.2Gy 39fx once daily Definitive RT b Co60 65Gy 36fx once daily Open resection w/ adjuvant RT b Co60 65Gy 36fx once daily Craniofacial resection w/ adjuvant RT b 6 MV photons 66Gy 60fx b.i.d. Definitive RT b Co60 65Gy 36fx once daily Preop RT b Co60 69.2Gy in 39fx q.d w/ 40.5 Gy to ipsilateral neck in 15fx w/ open resection, specimen negative c Open resection w/ adjuvant RT b Co60 45.3Gy 32fx once daily Open resection w/ adjuvant RT b 8 MeV and 17 MV photons 67Gy 60fx b.i.d. Open resection w/ adjuvant RT b 6 MeV x-rays 59.4Gy 36fx b.i.d. Open resection w/ adjuvant RT b 8 MV photons 70.4Gy 64fx b.i.d.
Recurrence at 6 mo
Alive with disease at 16.3 y
Complete tumor regression
Died of intercurrent disease at 8 y Died with disease at 8 y
2 3 4 5 6
7 8
9 10
11
12
13
Open resection w/ adjuvant RT8 MV and 17 MV photons 60 Gy 33fx qda Open resection w/ adjuvant RT b Co60 65Gy 32fx once daily, split course Unresectable b Definitive RT b Co60 65Gy 36fx once daily
Recurrence at 6.4 y Recurrence at 9 mo resected c Local recurrence at 13 y nonsurgical candidate c Local recurrence at 11.3 y excision done at 17 y c
Recurrence at 13 y nonsurgical candidate c No recurrence
No recurrence Recurrence at 19 y tx with orbital exenteration and maxillary sinus hemi-resection No recurrence
No recurrence
Recurrence at 13 mo
Alive b with no evidence of disease at 10 y Died with disease at 15.4 y Died with disease at 18.6 y
Died of intercurrent disease at 18.6 y Alive b with no evidence of disease at 19.4 y Died of intercurrent disease at 7.1 y Alive with disease at 19 y Alive b with no evidence of disease at 19.25 y Died of intercurrent disease at 9 y Died with disease at 14.5 mo
b.i.d., two times a day; CIS, carcinoma in situ; CCP, cylindrical cell papilloma; fx, fraction; IP, inverted papilloma; RT, radiation therapy; SCC, squamous cell carcinoma; TCC, transitional cell carcinoma. a Denotes carcinoma identified at primary tumor diagnosis; Patient 3 had CIS at primary that progressed to SCC after RT. b Denotes carcinoma that was present at the time of RT. c Carcinoma that was diagnosed at tumor recurrence—not present at primary.
Ongoing research seeks to identify factors predictive of IP behavior and prognosis. Clinical and pathologic features, including gender, bilateral disease, absence of concomitant nasal polyps, tobacco use, surgical procedures, mitotic index, histologic association with plasma cells, nuclear and cellular atypia, apoptotic pathways, tumor suppressor gene function, cell cycle regulators, and human papilloma virus, have been studied as putative factors predictive for tumor recurrence and/or malignant transformation. 1,14,17,18 However, with the exception of the extent of surgical resection, reliable prognostic factors have been elusive. With advances in the identification of such factors, treatment decision-making will become easier. One long-standing argument against the use of RT in the treatment of pure IP is the suggestion that it might induce a malignant transformation. However, the high rate
of associated malignancies for IP has not been shown to increase following RT. 6,18 In our study, 2 of 13 patients developed new foci of invasive disease following RT. One patient had a diagnosis of synchronous carcinoma in situ associated with IP following resection of his primary tumor. He received 65 Gy of adjuvant RT and developed a recurrence of IP associated with invasive SCC 7.5 years after treatment. The transformation to invasive disease in this case likely represents the natural history of the disease, rather than a radiation-induced second malignancy. A second patient developed an ethesioneuroblastoma 3.5 years after receiving a total dose of 65 Gy for IP. In total, 8 of 13 patients (62%) in our study had malignancies associated with IP; 2 of the malignancies were identified at the time of the initial IP diagnosis (carcinoma in situ and transitional cell carcinoma), 4 were
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Table 2
Practical Radiation Oncology: October-December 2013
Literature review
Institution
No. patients w/ RT
RT delivered
Mean follow-up (y)
Local-regional control
Overall survival
Indications for RT
Phillips et al, 1990 21 Mayo Clinic Hug et al, 1993 7 Massachusetts Eye and Ear Infirmary
6, IP w/ SCC
Adjuvant
6.2
N/A
83% at 5 y
IP w/ SCC
25: 7, IP alone; 18, IP w/ SCC
Adjuvant, 24; Definitive, 1
4.8
Vrabec, 1994 2 Geisinger Medical Center Lesperance and Esclamado, 1995 15 University of Michigan Rutenburg et al, 2012 (present series) University of Florida
7, IP w/ SCC
Adjuvant
9
88% (23/25) IP, 86% (6/7) IP w/ SCC, 89% (16/18) N/A
82% at 10 y IP, 100% IP w/ SCC, 73% DFS, 88% (23/25) 57% (4/7) DFS, 57% (4/7)
Multiply recurrent, inoperable, residual disease, or presence of malignancy IP w/ SCC
10, IP w/ SCC
Adjuvant
4.4
20% (2/10)
30% (3/10) DFS, 20% (2/10)
IP w/ SCC
13: 5, IP alone; 8, IP w/ malignancy
Adjuvant, 9; Neoadjuvant, 1; or Definitive, 3
16.2
45% at 15 years IP alone, 80% IP w/ malignancy, 16%
62% at 15 y IP, 40% IP w/ malignancy, 50% CSS, 82%
Multiply recurrent, inoperable residual disease or presence of malignancy
CSS, cause-specific survival; DFS, disease-free survival; IP, inverted papilloma; N/A, not applicable; RT, radiation therapy; SCC, squamous cell carcinoma.
identified after a recurrence but before RT, and 2 were identified with recurrent disease following RT. We believe that the nature of a retrospective study and the referral patterns of an academic radiation oncology clinic contribute to the overall high incidence of invasive malignancies associated with sinonasal papilloma in our cohort. These data represent one of the largest single-institution series evaluating sinonasal papillomas treated with RT with long-term follow-up. Our results highlight the difficulty in treating these locally destructive and frequently recurrent tumors. Our retrospective data show good overall radiation treatment tolerance, which should only be improved with recent advances in highly conformal RT and improved normal tissue-sparing techniques. Proton beam should be considered to reduce the RT dose to the central nervous system and visual apparatus to further reduce the risk of complications. 19 Surgery with complete excision (open or endoscopically) remains the preferred treatment for sinonasal papilloma. It is generally accepted that adjuvant RT be considered for invasive carcinomas associated with sinonasal papillomas. 7,20 Additionally, we advocate the consideration of RT in the treatment of pure IP in cases of multiple recurrences, incomplete resection, or inoperable disease. 15,21
References 1. Batsakis JG, Suarez P. Schneiderian papillomas and carcinomas: a review. Adv Anat Pathol. 2001;8:53-64.
2. Vrabec DP. The inverted Schneiderian papilloma: a 25-year study. Laryngoscope. 1994;104(5 Pt 1):582-605. 3. Hyams VJ. Papillomas of the nasal cavity and paranasal sinuses. A clinicopathological study of 315 cases. Ann Otol Rhinol Laryngol. 1971;80:192-206. 4. Vrabec DP. The inverted Schneiderian papilloma: a clinical and pathological study. Laryngoscope. 1975;85:186-220. 5. Lawson W, Kaufman MR, Biller HF. Treatment outcomes in the management of inverted papilloma: an analysis of 160 cases. Laryngoscope. 2003;113:1548-1556. 6. Busquets JM, Hwang PH. Endoscopic resection of sinonasal inverted papilloma: a meta-analysis. Otolaryngol Head Neck Surg. 2006;134: 476-482. 7. Hug EB, Wang CC, Montgomery WW, et al. Management of inverted papilloma of the nasal cavity and paranasal sinuses: importance of radiation therapy. Int J Radiat Oncol Biol Phys. 1993;26:67-72. 8. Guedea F, Mendenhall WM, Parsons JT, et al. The role of radiation therapy in inverted papilloma of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys. 1991;20:777-780. 9. Mendenhall WM, Million RR, Cassisi NJ, et al. Biologically aggressive papillomas of the nasal cavity: the role of radiation therapy. Laryngoscope. 1985;95:344-347. 10. Gomez JA, Mendenhall WM, Tannehill SP, et al. Radiation therapy in inverted papillomas of the nasal cavity and paranasal sinuses. Am J Otolaryngol. 2000;21:174-178. 11. Common Terminology Criteria for Adverse Events (CTCAE) v4.0 National Cancer Institute 2010. Available at: http://evs.nci.nih.gov/ ftp1/CTCAE/About.html. Accessed July 28, 2011. 12. Melroy CT, Senior BA. Benign sinonasal neoplasms: a focus on inverting papilloma. Otolaryngol Clin North Am. 2006;39: 601-617, x. 13. Kaufman MR, Brandwein MS, Lawson W. Sinonasal papillomas: clinicopathologic review of 40 patients with inverted and oncocytic Schneiderian papillomas. Laryngoscope. 2002;112(8 Pt 1):1372-1377.
Practical Radiation Oncology: October-December 2013 14. Mendenhall WM, Hinerman RW, Malyapa RS, et al. Inverted papilloma of the nasal cavity and paranasal sinuses. Am J Clin Oncol. 2007;30:560-563. 15. Lesperance MM, Esclamado RM. Squamous cell carcinoma arising in inverted papilloma. Laryngoscope. 1995;105:178-183. 16. Tanvetyanon T, Qin D, Padhya T, et al. Survival outcomes of squamous cell carcinoma arising from sinonasal inverted papilloma: report of 6 cases with systematic review and pooled analysis. Am J Otolaryngol. 2009;30:38-43. 17. Lawson W, Patel ZM. The evolution of management for inverted papilloma: an analysis of 200 cases. Otolaryngol Head Neck Surg. 2009;140:330-335.
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18. Eggers G, Eggers H, Sander N, et al. Histological features and malignant transformation of inverted papilloma. Eur Arch Otorhinolaryngol. 2005;262:263-268. 19. Mendenhall NP, Malyapa RS, Su Z, et al. Proton therapy for head and neck cancer: rationale, potential indications, practical considerations, and current clinical evidence. Acta Oncol. 2011;50: 763-771. 20. Sauter A. Focal malignancy in sinonasal inverted papilloma—Is postoperative radiotherapy recommendable? Oral Oncol. 2011;47:779. 21. Phillips PP, Gustafson RO, Facer GW. The clinical behavior of inverting papilloma of the nose and paranasal sinuses: report of 112 cases and review of the literature. Laryngoscope. 1990;100:463-469.
www.practicalradonc.org
Original Report
Radiation therapy for sinonasal inverted papilloma Michael Rutenberg MDa , Jessica Kirwan MAa , Christopher G. Morris MSa , John W. Werning MDb , William M. Mendenhall MDa,⁎ a
Department of Radiation Oncology, University of Florida, Gainesville, Florida Department of Otolaryngology, University of Florida, Gainesville, Florida
b
Received 2 May 2012; revised 20 June 2012; accepted 27 July 2012
Abstract Purpose: We retrospectively reviewed long-term outcomes of patients with inverted papilloma (IP) treated with radiation therapy at our institution. Methods and Materials: From 1969 to 2008, 13 patients with advanced or recurrent IP (n = 12) or cylindrical papilloma (n = 1) were treated with radiation therapy. The median age at radiation therapy was 53 years old (range, 32-84). Nine patients received postoperative radiation therapy, 3 received definitive radiation therapy, and 1 received preoperative radiation therapy. Of the 10 patients treated with combined-modality treatment, 1 underwent craniofacial resection and 9 underwent open resection. Eight patients, 4 patients, and 1 patient received once-daily fractionation, twice-daily fractionation, and planned split-course radiation therapy, respectively, to a median dose of 65 Gy (range, 45.3-70.4 Gy). Results: The median follow-up was 16.2 years. Actuarial 15-year overall and cause-specific survival rates were 62% and 82%. Fifteen-year actuarial local and regional control rates were 45% and 73%. Fifteen-year local-regional control rates for IP alone and IP associated with squamous cell carcinoma (IP-SCC) at the time of treatment were 80% and 16%. Fifteen-year overall survival rates for IP alone and IP-SCC were 40% and 50%. The only severe treatment complication was a grade 3 central nervous system radionecrosis. The most common grade 1-2 toxicities were mucositis (61%), pain (46%), conjunctivitis (31%), xerostomia (31%), epiphora (31%), and anorexia (31%). Conclusions: While surgery is the primary treatment for IP, radiation therapy should be considered in patients with SCC, multiply recurrent IPs, and incompletely resectable IP. Radiation therapy is associated with a relatively low risk of severe complications. Despite more aggressive treatment, local failure remains a considerable challenge. © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Introduction Inverted papilloma (IP) of the nasal cavity and paranasal sinuses is a rare, benign neoplasm that typically arises from the lateral wall of the nasal cavity near the middle meatus or Conflicts of interest: None. ⁎ Corresponding author. 2000 SW Archer Rd, PO Box 100385, Gainesville, FL 32610-0385. E-mail address: [email protected]fl.edu (W.M. Mendenhall).
the maxillary sinus. The incidence of these tumors is estimated at 0.2-0.6 per 100,000 individuals per year. IP typically presents as a unilateral polyp, most often occurs in the fifth or sixth decade, and has a 3:1 male to female predominance. 1-4 Patients can present with symptoms including nasal obstruction, nasal drainage, facial pain, epistaxis, headaches, and epiphora. 2-4 The primary treatment for IP is surgery. Historically, more extensive procedures, often involving open resections, have resulted in the best cure rates. However, recent
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use of transnasal endoscopic surgery has been highly successful in achieving total resection with a low recurrence rate. 5,6 Radiation therapy (RT) has been used for the treatment of IP as early as the start of the 20th century. However, despite a long history in its treatment, there are limited long-term outcome studies utilizing RT. 7-9 RT has generally been used in the treatment of IP when associated with malignancy, multiple recurrences, incomplete resections, or inoperable disease. Here we review 13 patients treated at our institute with either RT alone or in combination with surgery. We provide an update of previously published reports and include more extensive follow-up. 8-10
Methods and materials Patient characteristics Thirteen patients with advanced or recurrent sinonasal IP or cylindrical papilloma (CP) of the nasal cavity and paranasal sinuses were treated with external-beam RT at our institute between December 1969 and August 2008. These patients represent all those treated with RT with curative intent at our institution for this disease process during the study period. Twelve patients were treated for IP and 1 was treated for a CP. The median age at RT was 53 years (range, 32-84 years). Nine patients were male (69%) and 4 were female (31%). Ten of 13 patients (77%) were treated for recurrent disease, 6 of whom had 2 or more recurrences before receiving RT. Six patients had concomitant malignancy at the time of RT: carcinoma in situ, 1 patient; invasive squamous cell carcinoma (SCC), 3 patients; both SCC and carcinoma in situ, 1 patient; and transitional cell carcinoma, 1 patient. The primary disease site was the nasal cavity in 12 patients and the maxillary sinus in 1 patient.
Figure 1 Actuarial overall (—) and cause-specific (…) survival in 13 patients treated with radiation therapy for sinonasal papilloma.
Practical Radiation Oncology: October-December 2013
Treatment characteristics Of the 13 patients in our cohort, 9 were treated with surgical resection followed by postoperative RT, 1 received preoperative RT, and 3 received definitive RT. Of the 10 surgical resections performed, 9 were open resections and 1 was a craniofacial resection. RT was delivered using a 2- or 3-field technique with Co60 or 6- to 17-MV photons. Eight patients (62%) received continuous-course irradiation with once-daily fractionation, 1 patient (8%) received once-daily radiation with a planned spit-course, and 4 patients (31%) received twice-daily fractionation. Planned split-course RT has since been abandoned at our institution. Patients treated with oncedaily fractionation received 1.8 Gy per fraction, while twice-daily RT was given at 1.2 Gy per fraction, with a minimum 6-hour interfraction interval. Patients with inverted papilloma did not receive elective neck irradiation; those with concomitant malignancy usually received elective neck irradiation.
Results The median follow-up for our group of patients was 16.2 years (range, 7.2-19.7 years). The 15-year actuarial overall survival and cause-specific survival rates were 62% and 82%, respectively (Fig 1). Fifteen-year actuarial local and regional control rates were 45% and 73%, respectively (Fig 2). Patients and their treatment results are detailed in Table 1. The median follow-up for the 5 living patients at last follow-up was 19.0 years (range, 10.4-19.7 years). Three of these patients (60%) were alive with no evidence of disease. Three of the 8 patients who experienced a recurrence following RT underwent salvage surgery. Two of the 3 patients who underwent salvage surgery following a post-RT failure had active disease at last follow-up. The third patient was alive without
Figure 2 Actuarial local (—) and regional (…) control in 13 patients treated with radiation therapy for sinonasal papilloma.
Practical Radiation Oncology: October-December 2013
evidence of disease 10 years after RT and salvage surgery for a recurrence 9 months following RT. Three patients underwent treatment with definitive RT for unresectable disease to a total dose of 65 Gy at 1.8 Gy per fraction. Two of these patients had a disease recurrence; 1 patient with a recurrence at 13 months died with disease at 14.5 months after RT. A second patient treated with definitive RT for a cylindrical (columnar) papilloma (CP) developed an ethesioneuroblastoma 3.5 years after treatment and experienced a recurrence of the CP 13 years after treatment with RT. He died 15.4 years after RT due to intercurrent disease with persistent CP. One patient underwent preoperative RT for an IP-SCC involving the right nasal cavity, ethmoid sinus, cribriform plate, infratemporal fossa, and right orbital floor. He received 69.2 Gy to the primary tumor and 40.5 Gy to the ipsilateral low neck. He then underwent surgery including a superficial parotidectomy, right maxillectomy, and right orbital exenteration. His pathology indicated a complete pathologic response to RT. He had a local recurrence 13.6 years after RT and received salvage surgery. He died with persistent disease 18.6 years after receiving RT. Patients treated for IP with associated malignancy had worse overall 15-year local-regional control compared with those treated for IP alone; 80% versus 16%, respectively (P = .07). Fifteen-year overall survival rates for IP alone versus IP associated with malignancy were 40% and 50%, respectively (P = .36). Overall, RT in our cohort was relatively well tolerated, with only 1 ≥grade 3 treatment per the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0. 11 One patient treated with open surgical resection and adjuvant twice-daily RT to a dose of 67 Gy developed grade 3 central nervous system radionecrosis (patient 8 in Table 1). This patient had no disease recurrence following RT and at last follow-up was alive and disease-free at 19.4 years after treatment. All patients in our cohort experienced grade 1 or 2 treatment complications, the most common including mucositis (61%), pain (46%), conjunctivitis (31%), xerostomia (31%), epiphora (31%), and anorexia (31%).
Discussion Inverted papilloma is 1 of 3 histologic subtypes of sinonasal papillomas, which also include fungiform (exophytic) papillomas and CPs. 4 IP is distinguished histologically from other sinonasal papillomas by its characteristic endophytic epithelial growth with respect for the underlying basement membrane. All 3 forms of sinonasal papillomas arise from the Schneiderian epithelium of the nasal cavity and paranasal sinuses, which, unlike the endodermal origins of the nasopharynx and upper respiratory tract epithelium, originates from the
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ectodermal germ layer. 1 IP is also distinguished histologically from squamous papillomas and sinonasal polyps, and represents a true neoplastic process rather than inflammation or hyperplasia. 1,12 Although histologically distinct, IP and CP have similar biologic characteristics and treatment approaches. While these benign tumors of the sinonasal tract have virtually no metastatic potential and are associated with low mortality, they demand careful treatment. There are 3 clinical features of IP that weigh heavily in their treatment and indicate a need for an aggressive treatment approach. 3 The first is a tendency for aggressive local invasion. While lymph node or distant metastases are exceedingly rare, IP often shows extensive invasion into the paranasal sinuses and adjacent tissues. Its capacity for bone erosion and normal tissue destruction leads to significant morbidity and occasional mortality. The second important clinical feature of IP is a high incidence of local recurrence after excision. 5 A recent meta-analysis evaluated 1060 cases of IP and reported an average recurrence rate of 15%, with rates as high as 33%. 6 The third clinical feature of IP with important treatment implications is an association with malignancy. IP is associated with SCC in 5% to 15% of cases. 13 While these features indicate the need for aggressive treatment, they explain the difficulty in eradicating these neoplasms. Surgery remains the primary method of treatment for IP, with wide resection offering the best chance for cure. However, their location within the nasal cavity and paranasal sinuses often makes total resection difficult. The extent of tumor invasion and the difficulty of resection lead to surgical procedures that can be disfiguring and often result in tumor recurrence. The high incidence of associated malignancies further complicates the treatment picture. Radiation therapy was successfully used in the treatment of IP as early as 1920, 7 but the indications for its use are still controversial. Adjuvant RT is recommended in cases of concomitant SCC; however, the indications for treatment of pure IP are less established. RT has often been used to treat multiply recurrent disease, postoperative residual disease, and inoperable tumors. 14 There have been several single-institution outcomes studies for IP treated with RT with variable localregional control, disease-free survival, and overall survival rates (Table 2). The most common indication for treating IP with RT in these studies is an association with SCC, with nearly all of the patients reported in these studies receiving postoperative RT. Hug et al 7 reported the largest series to date, describing 25 cases of IP treated with adjuvant RT. Seven patients in their study were treated after subtotal tumor resection or for multiply recurrent disease after prior resections, while 18 patients received RT for IP associated with SCC. With a mean follow-up of 4.8 years, they achieved 88% local-regional control and 82% overall survival; favorable outcomes
278 Table 1
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Treatment and results in 13 patients with sinonasal papilloma treated with radiation therapy
Patient No.
Age at RT (y), gender
Diagnosis
Krause stage
Primary tumor treatment
Recurrences prior to RT
1
36, male
IP/TCC a
IV
0
2
66, male
IP
III
3
46, male
IP/CIS a SCC c
II
Open resection b Adjuvant RT Unresectable b Definitive RT Open resection
1
4
73, female
IP/SCC c well-diff c
II
Open resection
1
5
47, male
I
53, male
IV
Transnasal resection Open resection
2
6
CCP/ Ethesioneuroblastoma c IP/SCC c well-diff c
3
7
38, male
IP/SCC c
I
Open resection
3
8
56, male
IP
II
Craniofacial resection
2
9
62, male
IP/CIS c
III
1
10
57, male
IP/ CIS/SCC c
II
Endoscopic resection Open resection
2
11
32, female
IP
II
Craniofacial resection
1
12
47, male
IP
III
Open resection b Adjuvant RT
0
13
84, female
IP
I
Transnasal
2
0
b.i.d., two times a day; CIS, carcinoma in situ; CCP, cylindrical cell papilloma; fx, fraction; IP, inverted papilloma; RT, radiation therapy; SCC, squamous cell (Continued) carcinoma; TCC, transitional cell carcinoma. a Denotes carcinoma identified at primary tumor diagnosis; Patient 3 had CIS at primary that progressed to SCC after RT. b Denotes carcinoma that was present at the time of RT. c Carcinoma that was diagnosed at tumor recurrence—not present at primary.
when compared with the current study and prior reports from the University of Michigan (Ann Arbor) and Geisinger Medical Center (Danville, PA). One potential explanation for the difference in outcomes between our study and Hug et al is the difference in follow-up period as many failures occurred well beyond the 5-year mark (Table 2). Our results show a trend toward a difference in localregional control between patients treated with IP only and IP associated with malignancy. The local-regional control and overall survival outcomes in our study for patients with IP associated with malignancy are comparable with prior studies by Vrabec 2 and Lesperance and Escalamado 15 (Table 2). A recent pooled analysis by Tanvetyanon et al 16 reported the results of 10 studies including 76 patients with IP associated with SCC. They show a median overall survival of 126 months and 63%
3-year actuarial overall survival. These studies are similar to our current study with a median overall survival of 180 months and 5-year actuarial survival of 88% in patients with IP with malignancy. Overall these patients are able to achieve long-term survival. However, as shown by our data and others, local-regional control continues to be a long-term challenge (we had a 15-year actuarial local-regional control of 16%). These data support the recommendation that IP associated with cancer requires aggressive treatment with adjuvant RT. In the current study as well as others, it is likely that the incidence of IP recurrence is exaggerated secondary to selection bias in reports from tertiary care centers, where unresectable or difficult-to-manage cases are appropriately referred for RT. Nonetheless, it is those cases of inoperable, incompletely resected, or multiply recurrent IP for which RT should be considered.
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Table 1 (continued) Patient No.
RT course
Post-RT course
Follow-up
1
Open resection w/ adjuvant RT b Co60 70.2Gy 39fx once daily Definitive RT b Co60 65Gy 36fx once daily Open resection w/ adjuvant RT b Co60 65Gy 36fx once daily Craniofacial resection w/ adjuvant RT b 6 MV photons 66Gy 60fx b.i.d. Definitive RT b Co60 65Gy 36fx once daily Preop RT b Co60 69.2Gy in 39fx q.d w/ 40.5 Gy to ipsilateral neck in 15fx w/ open resection, specimen negative c Open resection w/ adjuvant RT b Co60 45.3Gy 32fx once daily Open resection w/ adjuvant RT b 8 MeV and 17 MV photons 67Gy 60fx b.i.d. Open resection w/ adjuvant RT b 6 MeV x-rays 59.4Gy 36fx b.i.d. Open resection w/ adjuvant RT b 8 MV photons 70.4Gy 64fx b.i.d.
Recurrence at 6 mo
Alive with disease at 16.3 y
Complete tumor regression
Died of intercurrent disease at 8 y Died with disease at 8 y
2 3 4 5 6
7 8
9 10
11
12
13
Open resection w/ adjuvant RT8 MV and 17 MV photons 60 Gy 33fx qda Open resection w/ adjuvant RT b Co60 65Gy 32fx once daily, split course Unresectable b Definitive RT b Co60 65Gy 36fx once daily
Recurrence at 6.4 y Recurrence at 9 mo resected c Local recurrence at 13 y nonsurgical candidate c Local recurrence at 11.3 y excision done at 17 y c
Recurrence at 13 y nonsurgical candidate c No recurrence
No recurrence Recurrence at 19 y tx with orbital exenteration and maxillary sinus hemi-resection No recurrence
No recurrence
Recurrence at 13 mo
Alive b with no evidence of disease at 10 y Died with disease at 15.4 y Died with disease at 18.6 y
Died of intercurrent disease at 18.6 y Alive b with no evidence of disease at 19.4 y Died of intercurrent disease at 7.1 y Alive with disease at 19 y Alive b with no evidence of disease at 19.25 y Died of intercurrent disease at 9 y Died with disease at 14.5 mo
b.i.d., two times a day; CIS, carcinoma in situ; CCP, cylindrical cell papilloma; fx, fraction; IP, inverted papilloma; RT, radiation therapy; SCC, squamous cell carcinoma; TCC, transitional cell carcinoma. a Denotes carcinoma identified at primary tumor diagnosis; Patient 3 had CIS at primary that progressed to SCC after RT. b Denotes carcinoma that was present at the time of RT. c Carcinoma that was diagnosed at tumor recurrence—not present at primary.
Ongoing research seeks to identify factors predictive of IP behavior and prognosis. Clinical and pathologic features, including gender, bilateral disease, absence of concomitant nasal polyps, tobacco use, surgical procedures, mitotic index, histologic association with plasma cells, nuclear and cellular atypia, apoptotic pathways, tumor suppressor gene function, cell cycle regulators, and human papilloma virus, have been studied as putative factors predictive for tumor recurrence and/or malignant transformation. 1,14,17,18 However, with the exception of the extent of surgical resection, reliable prognostic factors have been elusive. With advances in the identification of such factors, treatment decision-making will become easier. One long-standing argument against the use of RT in the treatment of pure IP is the suggestion that it might induce a malignant transformation. However, the high rate
of associated malignancies for IP has not been shown to increase following RT. 6,18 In our study, 2 of 13 patients developed new foci of invasive disease following RT. One patient had a diagnosis of synchronous carcinoma in situ associated with IP following resection of his primary tumor. He received 65 Gy of adjuvant RT and developed a recurrence of IP associated with invasive SCC 7.5 years after treatment. The transformation to invasive disease in this case likely represents the natural history of the disease, rather than a radiation-induced second malignancy. A second patient developed an ethesioneuroblastoma 3.5 years after receiving a total dose of 65 Gy for IP. In total, 8 of 13 patients (62%) in our study had malignancies associated with IP; 2 of the malignancies were identified at the time of the initial IP diagnosis (carcinoma in situ and transitional cell carcinoma), 4 were
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Table 2
Practical Radiation Oncology: October-December 2013
Literature review
Institution
No. patients w/ RT
RT delivered
Mean follow-up (y)
Local-regional control
Overall survival
Indications for RT
Phillips et al, 1990 21 Mayo Clinic Hug et al, 1993 7 Massachusetts Eye and Ear Infirmary
6, IP w/ SCC
Adjuvant
6.2
N/A
83% at 5 y
IP w/ SCC
25: 7, IP alone; 18, IP w/ SCC
Adjuvant, 24; Definitive, 1
4.8
Vrabec, 1994 2 Geisinger Medical Center Lesperance and Esclamado, 1995 15 University of Michigan Rutenburg et al, 2012 (present series) University of Florida
7, IP w/ SCC
Adjuvant
9
88% (23/25) IP, 86% (6/7) IP w/ SCC, 89% (16/18) N/A
82% at 10 y IP, 100% IP w/ SCC, 73% DFS, 88% (23/25) 57% (4/7) DFS, 57% (4/7)
Multiply recurrent, inoperable, residual disease, or presence of malignancy IP w/ SCC
10, IP w/ SCC
Adjuvant
4.4
20% (2/10)
30% (3/10) DFS, 20% (2/10)
IP w/ SCC
13: 5, IP alone; 8, IP w/ malignancy
Adjuvant, 9; Neoadjuvant, 1; or Definitive, 3
16.2
45% at 15 years IP alone, 80% IP w/ malignancy, 16%
62% at 15 y IP, 40% IP w/ malignancy, 50% CSS, 82%
Multiply recurrent, inoperable residual disease or presence of malignancy
CSS, cause-specific survival; DFS, disease-free survival; IP, inverted papilloma; N/A, not applicable; RT, radiation therapy; SCC, squamous cell carcinoma.
identified after a recurrence but before RT, and 2 were identified with recurrent disease following RT. We believe that the nature of a retrospective study and the referral patterns of an academic radiation oncology clinic contribute to the overall high incidence of invasive malignancies associated with sinonasal papilloma in our cohort. These data represent one of the largest single-institution series evaluating sinonasal papillomas treated with RT with long-term follow-up. Our results highlight the difficulty in treating these locally destructive and frequently recurrent tumors. Our retrospective data show good overall radiation treatment tolerance, which should only be improved with recent advances in highly conformal RT and improved normal tissue-sparing techniques. Proton beam should be considered to reduce the RT dose to the central nervous system and visual apparatus to further reduce the risk of complications. 19 Surgery with complete excision (open or endoscopically) remains the preferred treatment for sinonasal papilloma. It is generally accepted that adjuvant RT be considered for invasive carcinomas associated with sinonasal papillomas. 7,20 Additionally, we advocate the consideration of RT in the treatment of pure IP in cases of multiple recurrences, incomplete resection, or inoperable disease. 15,21
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2. Vrabec DP. The inverted Schneiderian papilloma: a 25-year study. Laryngoscope. 1994;104(5 Pt 1):582-605. 3. Hyams VJ. Papillomas of the nasal cavity and paranasal sinuses. A clinicopathological study of 315 cases. Ann Otol Rhinol Laryngol. 1971;80:192-206. 4. Vrabec DP. The inverted Schneiderian papilloma: a clinical and pathological study. Laryngoscope. 1975;85:186-220. 5. Lawson W, Kaufman MR, Biller HF. Treatment outcomes in the management of inverted papilloma: an analysis of 160 cases. Laryngoscope. 2003;113:1548-1556. 6. Busquets JM, Hwang PH. Endoscopic resection of sinonasal inverted papilloma: a meta-analysis. Otolaryngol Head Neck Surg. 2006;134: 476-482. 7. Hug EB, Wang CC, Montgomery WW, et al. Management of inverted papilloma of the nasal cavity and paranasal sinuses: importance of radiation therapy. Int J Radiat Oncol Biol Phys. 1993;26:67-72. 8. Guedea F, Mendenhall WM, Parsons JT, et al. The role of radiation therapy in inverted papilloma of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys. 1991;20:777-780. 9. Mendenhall WM, Million RR, Cassisi NJ, et al. Biologically aggressive papillomas of the nasal cavity: the role of radiation therapy. Laryngoscope. 1985;95:344-347. 10. Gomez JA, Mendenhall WM, Tannehill SP, et al. Radiation therapy in inverted papillomas of the nasal cavity and paranasal sinuses. Am J Otolaryngol. 2000;21:174-178. 11. Common Terminology Criteria for Adverse Events (CTCAE) v4.0 National Cancer Institute 2010. Available at: http://evs.nci.nih.gov/ ftp1/CTCAE/About.html. Accessed July 28, 2011. 12. Melroy CT, Senior BA. Benign sinonasal neoplasms: a focus on inverting papilloma. Otolaryngol Clin North Am. 2006;39: 601-617, x. 13. Kaufman MR, Brandwein MS, Lawson W. Sinonasal papillomas: clinicopathologic review of 40 patients with inverted and oncocytic Schneiderian papillomas. Laryngoscope. 2002;112(8 Pt 1):1372-1377.
Practical Radiation Oncology: October-December 2013 14. Mendenhall WM, Hinerman RW, Malyapa RS, et al. Inverted papilloma of the nasal cavity and paranasal sinuses. Am J Clin Oncol. 2007;30:560-563. 15. Lesperance MM, Esclamado RM. Squamous cell carcinoma arising in inverted papilloma. Laryngoscope. 1995;105:178-183. 16. Tanvetyanon T, Qin D, Padhya T, et al. Survival outcomes of squamous cell carcinoma arising from sinonasal inverted papilloma: report of 6 cases with systematic review and pooled analysis. Am J Otolaryngol. 2009;30:38-43. 17. Lawson W, Patel ZM. The evolution of management for inverted papilloma: an analysis of 200 cases. Otolaryngol Head Neck Surg. 2009;140:330-335.
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18. Eggers G, Eggers H, Sander N, et al. Histological features and malignant transformation of inverted papilloma. Eur Arch Otorhinolaryngol. 2005;262:263-268. 19. Mendenhall NP, Malyapa RS, Su Z, et al. Proton therapy for head and neck cancer: rationale, potential indications, practical considerations, and current clinical evidence. Acta Oncol. 2011;50: 763-771. 20. Sauter A. Focal malignancy in sinonasal inverted papilloma—Is postoperative radiotherapy recommendable? Oral Oncol. 2011;47:779. 21. Phillips PP, Gustafson RO, Facer GW. The clinical behavior of inverting papilloma of the nose and paranasal sinuses: report of 112 cases and review of the literature. Laryngoscope. 1990;100:463-469.
