Pediatric and Developmental Pathology 11, 118–121, 2008 DOI: 10.2350/06-09-0160.1 ª 2008 Society for Pediatric Pathology E6 and E7 Oncogene Expression by Human Papilloma Virus (HPV) and the Aggressive Behavior of Recurrent Laryngeal Papillomatosis (RLP) BAHIG M. SHEHATA, 1,2 KRISTEN J. OTTO, 3 STEVEN E. SOBOL, 3 CHRISTINA A. STOCKWELL, 4 CORA FOULKS, 2 WAYNE LANCASTER, 5 LUCIE GREGOIRE, 5 AND CHARLES E. HILL 2* 1 Department of Pathology, Children’s Healthcare of Atlanta, 1405 Clifton Rd, Atlanta, GA 30322, USA 2 Department of Pathology, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA 3 Department of Otolaryngology/Head and Neck Surgery, Emory University Hospital, 2015 Uppergate Drive, Atlanta, GA 30322, USA 4 Department of Clinical Research, Children’s Healthcare of Atlanta, 1405 Clifton Road, Atlanta, GA 30322, USA 5 Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201, USA Received September 8, 2006; accepted April 20, 2007; published online April 20, 2007. ABSTRACT Recurrent laryngeal papillomatosis (RLP), a chronic disease associated with human papilloma virus (HPV), requires serial surgical procedures for debulking, resulting in debilitating long-term dysphonia, laryngeal scarring, and rarely malignant degeneration. Human papilloma virus 11 tumors have been widely accepted as more aggressive than HPV 6 tumors; however, the clinical course has been difficult to predict at disease onset, and the biologic mediators of proliferation have not been well characterized. A retrospective case review of 43 patients (4 months to 10 years at diagnosis) was performed on children treated for recurrent laryngeal papillomatosis. Patient charts were reviewed for demographic information, age at RLP diagnosis, approximate frequency of surgical intervention, and absolute number of surgical procedures performed. Human papilloma virus subtyping was performed. Expres- sion analysis of the HPV-encoded E6 and E7 oncogenes was performed by reverse-transcriptase polymerase chain reac- tion. Fourteen patients had subtype 11 (33%) and 29 patients had subtype 6 (67%). As expected, HPV 11 patients showed a more aggressive clinical course than HPV 6 patients. However, 38% of patients with subtype 6 (11 patients) followed a clinical course that mirrored the more severe subtype 11 patients. These patients expressed the disease at a younger age (P , 0.0002) and showed higher levels of E6 and E7 oncogenes compared to the patients with the more indolent course. Although HPV subtype and early onset of RLP are well characterized prognostic factors, our study documents the significance of E6 and E7 oncogene expression as potential biologic mediators of proliferation and thereby clinical behavior. Key words: human papilloma virus (HPV), recurrent laryngeal papillomatosis (RLP), RT-PCR INTRODUCTION Recurrent laryngeal papillomatosis (RLP) is associated with the human papilloma virus (HPV), a double-stranded DNA- containing virus of the family Papovaviridae. The epithe- liotropic nature of the virus leads to epithelial cell integration of viral particles and a subsequent epithelial cell proliferation and papilloma formation (Figs. 1,2). The classic clinical presentation of RLP is the presence of multiple papillomas that grow primarily in the larynx and lead to the symptoms of hoarseness and airway obstruction [1,2]. Recurrent laryngeal papillomatosis is most notable in the pediatric population, although it can also occur in adults. There are two clinically recognized variants of the disease: an early-onset, more aggressive form and a late-onset more indolent form [3]. The aggressive form is more common in children. The two most common viral subtypes associated with RLP are HPV 11 and HPV 6. Human papilloma virus 11 is more commonly associated with an aggressive disease course than HPV 6. Although both viruses share the distinct clinical feature of rare malignant transformation, malignan- cy occurs more frequently in patients with HPV 11 [4]. The association between E6 and E7 oncogene expres- sion and malignant transformation has been reported in cervical cancer with high risk HPV subtypes [5]. However, to our knowledge this association has never been reported with RLP, especially with low-risk HPV subtypes. Although malignant transformation is rare in RLP, these proto- oncogenes have been implicated in the escape of cells from cell cycle arrest. There is the distinct possibility that virally derived genes may impart different proliferative capabilities *Corresponding author, e-mail: Cehill@emory.edu