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Diffuse Intranasal Papillomatosis and its Association with the Human Papilloma Virus. Benjamin S. Bleier, Charles S. Gawthrop, Erica R. Thaler, Duane A. Sewell, Kathleen T. Montone, Alexander G. Chiu University of Pennsylvania School of Medicine, Philadelphia, PA. Abstract Background

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Abstract Background

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  1. Diffuse Intranasal Papillomatosis and its Association with the Human Papilloma Virus Benjamin S. Bleier, Charles S. Gawthrop, Erica R. Thaler, Duane A. Sewell, Kathleen T. Montone, Alexander G. Chiu University of Pennsylvania School of Medicine, Philadelphia, PA Abstract Background Squamous papillomas of the nasal cavity are almost exclusively unilateral and are typically pedicled on the nasal vestibule. We report on two unique cases of bilateral multicentric papillomas mimicking recurrent respiratory papillomatosis (RRP) and discuss their presentation, workup, association with the Human Papilloma Virus (HPV), and treatment. Materials and Methods Case series of two patients presenting at a tertiary care center with diffuse nasal papillomatosis who underwent resection with histopathologic analysis and HPV serotyping using a Quiagen DNeasy Tissue Kit with MYO9/11 anti-HPV primers as well as BLAST analysis of tissue sample PCR products. Results Both patients underwent extensive papilloma resection utilizing a powered microdebrider. Given the extent of disease, one patient underwent intralesional cidofovir injection. Both patients had lesions positive for HPV 6 and both demonstrated focal areas of recurrence at three and six month follow up, respectively. • Case Report Patient #1: • 43 year-old male with a chief complaint of five months of left nasal congestion and a history of right nasal septal papilloma. • Nasal endoscopy revealed multiple right sided exophytic papillomas along the internal nasal valve and nasal floor and a left nasal septal lesion. • The patient underwent excisional biopsy of the right vestibular lesion as well as resection of the remaining bilateral lesions utilizing a powered microdebrider with intralesional injection of cidofovir(5mg/mL). • The final pathology from right septal lesion was read as sinonasal papilloma with focal elements of mild to moderate dysplasia. The contents of the sinus trap were sent which contained specimen from both nares and was read as fragments of sinonasal mucosa with high grade dysplasia, without evidence of definitive invasion and was positive for HPV 6. • The patient was seen at three months post-operatively in follow up and nasal endoscopy revealed focal evidence of recurrence in bilateral nasal cavities. • Pre and Post-Operative endoscopic view of the left nasal cavity (S-septum; MT-middle turbinate; IT-inferior turbinate). Thick arrow – Nasal septal lesion; Thin arrow – Inferior turbinate lesion. • A. Low power view of sinonasal papilloma with exophytic growth pattern (Hematoxylin and Eosin stain; Original magnification x 10). B. Higher power view shows focal squamous dysplasia (Hematoxylin and Eosin stain; Original magnification x 40). • Patient #2 • 59 year-old male a chief complaint of two months of bilateral nasal obstruction following his excision and on nasal endoscopy was found to have a recurrence of the papilloma in the right vestibule and middle turbinate as well as new onset diffuse papillomatosis throughout the left nasal cavity. • The patient was taken to the operating room and underwent resection of papillomas involving the right vestibule and middle turbinate as well as the left septum, middle turbinate, and left nasopharynx utilizing a powered microdebrider. • Final pathology revealed fragments of squamous papilloma with focal inverted features and no dysplasia and was HPV 6 positive. The patient was seen at six month follow-up and also demonstrated focal areas of recurrence. • Discussion • Human Papilloma Virus (HPV) is a double stranded DNA virus which is a member of the papovavirus family. With improved methods of detection, many authors have reported the presence of HPV DNA in several intranasal lesions including schneiderian sinonasal polyps, inverting papillomas, and squamous cell carcinoma(1,2). Recurrent Respiratory Papillomatosis (RRP) is a disease characterized by the recurrent growth of benign papillomas of the upper respiratory tract and has also been linked to an underlying HPV infection(3). Both patients described in our series presented with diffuse bilateral exophytic papillomatosis which is an uncommon clinical entity(4) which departs from the common presentation of nasal squamous papillomas and more closely resembles that of RRP. Given the rarity of nasal papillomatosis, reliable data on natural history and treatment is scarce. The authors therefore sought to further characterize these lesions with histopathology and HPV analysis in an effort to justify a treatment algorthim similar to that for RRP. • The majority of papillomas arise from the glottis, although lesions can be found anywhere that ciliated respiratory epithelium and squamus epithelium are juxtaposed, including the limen vestibuli of the nose(5). • Squamous papillomas of the nose originate from stratified squamous epithelium, most commonly in the nasal vestibule, and are characterized by the growth of multiple papillary fronds, infrequent mitosis, and rare nuclear atypia. In contrast to inverted papilloma, malignant transformation is uncommon and there is generally no adjacent bony destruction or remodeling(4). • While respiratory papillomatosis is characterized by multicentricity, there have only been a few reports of bilateral papillomas occurring in the nasal cavity(4,6). Our HPV analysis showed that both patients were positive for HPV 6. • Surgical resection has classically been the mainstay of treatment for respiratory papillomatosis. In the late 1970’s. the CO2 laser replaced cold steel excision as the primary method of resection, due to improved hemostasis, and decreased post operative scarring. More recently several studies have shown decreased cost and operating time with the surgical microdebrider(1), with anecdotal reports of decreased pain, and decreased incidence of post operative complications. • Cidofovir, an antiviral drug, FDA approved for the treatment of CMV retinitis in AIDS patients, has recently gained favor as an intralesional injection. Several small case series have reported very favorable results. However, the drug is not FDA approved for the treatment of respiratory papillomatosis and there have been no large randomized controlled studies to document its efficacy. • Conclusions • The lesions in our patients were similar to those of glottic papillomatosis and were positive for HPV. We elected to treat them in a conservative manner with local debridement and subsequent intralesional cidofavir injection. Routine follow up is mandatory as recurrence is common and was evident in both of our reported cases. The need for serial debridement is expected and should be discussed with the patient prior to initiating treatment. References • 1. Adi Yoskovitch MD, MSc,  Saul Frenkiel MD, FRCSC,  Eduardo Franco PhD,  François Coutlée MD, FRCPC,  Dan Nachtigal MD,  Louise Rochon MD, FRCPC. Analysis of Human Papillomavirus in Schneiderian Papillomas as Compared to Chronic Sinusitis and Normal Nasal Mucosa. The Journal of Otolaryngology. 2001;30:167-172. • 2. Hoffmann M, Klose N, Gottschlich S. Gorogh T, Fazel A, Lohrey C, Rittgen W, Ambrosch P, Schwarz E, Kahn T. Detection of human papillomavirus DNA in benign and malignant sinonasal neoplasms. Cancer Letters. 2006;239:64-70. • 3. Pasquale K et al. Microdebrider vs. CO2 Laser Removal of Recurrent Respiratory Papillomatosis: A Prospective Analysis Laryngoscope 2003;113:139-143 • 4. Kumagai M. Endo S. Matsunaga E. Kida A. Sakata H. Yamamoto M. Squamous papillomatosis of the bilateral nasal cavities. Tohoku Journal of Experimental Medicine. 206(3):267-70, 2005 Jul. • 5. Derkay CS Recurrent Respiratory Papillomatosis Annals of otology Rhinology and Laryngology 2006;115:1-11 • 6. Perzin KH. Lefkowitch JH. Hui RM. Bilateral nasal squamous carcinoma arising in papillomatosis: report of a case developing after chemotherapy for leukemia. Cancer. 48(11):2375-82, 1981 Dec 1. Conclusion Multicentric nasal papillomatosis represents a distinct clinical entity from a typical unilateral squamous papilloma and may derive from an HPV infection. Their treatment should reflect that of patients with recurrent respiratory papillomatosis with comprehensive debridement, histopathologic characterization, and possible adjunctive intralesional cidofovir injection. These patients may require serial debridement to effect complete eradication of their disease. 2%Agarose Gel demonstrating MYO9/11 HPV6 binding at 450bp (highlighted) for both patients in comparison to a negative control.

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