Squamous Cell Carcinoma Arising in Recurrent Respiratory Papillomatosis with Pulmonary Involvement: Emerging Common Pattern of Clinical Features and Human Papillomavirus Serotype Association

Abstract

Squamous papillomas of the lung are an uncommon feature of recurrent respiratory papillomatosis, occurring in fewer than 1% of cases. We describe a 23-year-old patient with pulmonary papillomas who developed a fatal squamous cell carcinoma of the lung. PCR-based human papillomavirus (HPV) typing showed the presence of HPV 11 DNA in both benign papillomas and invasive carcinoma. A review of the literature reveals four reports of malignant transformation of juvenile-onset recurrent respiratory papillomatosis in which HPV typing was performed. Similar clinical features are noted in all of the reports; specifically, each case has arisen in a young adult man with a history of papillomatosis since childhood. In each of the cases, HPV 11 was identified in association with the squamous cell carcinoma. Although HPV 11 is uncommonly associated with the development of invasive carcinoma at other sites, these findings suggest that it is correlated with malignant transformation in the setting of juvenile-onset recurrent respiratory papillomatosis. KEY WORDS: Human papillomavirus 11, Recurrent respiratory papillomatosis, Squamous cell carcinoma. Mod Pathol 2000;13(8):914-918Juvenile-onset recurrent respiratory papillomatosis (RRP) is characterized by numerous squamous papillomas of the respiratory tract secondary to infection with human papillomavirus (HPV) types 6 and 11 (1, 2). HPV is thought to be acquired at the time of vaginal delivery in the presence of genital lesions, and patients typically present with symptoms of hoarseness or respiratory obstruction in childhood or adolescence. In the majority of cases, the papillomas are confined to the larynx; only 5% of patients exhibit more distal involvement of the trachea, and involvement of lung parenchyma occurs in fewer than 1% of cases (1, 2). Pulmonary involvement by RRP is twice as frequent in males than in females and is associated with an aggressive clinical course. Most patients require numerous excisions, frequently require tracheostomy, and ultimately die as a result of respiratory insufficiency or infections (2). Malignant transformation of laryngeal or pulmonary lesions is a very rare event in the absence of prior irradiation; fewer than 20 cases are reported in the English literature (3-6). It remains unclear whether the risk of malignant transformation is dependent on the HPV serotype involved.We describe a patient with pulmonary involvement by RRP who developed a squamous cell carcinoma of the lung. Polymerase chain reaction (PCR) typing performed at postmortem examination showed the presence of HPV 11 DNA in both the papillomas and squamous cell carcinoma. This is the fifth report of an association between HPV 11 and malignant transformation of pulmonary papillomas (3, 4, 6, 7). Together, these five cases suggest a stereotypical clinical setting for the emergence of invasive carcinoma from RRP. CASE REPORTThe patient was a 23-year-old white man with a history of RRP, initially diagnosed at age 5. By age 10, he had developed laryngeal, tracheal, and pulmonary ...

In Situ Hybridization Signal Patterns in Recurrent Laryngeal Squamous Papillomas Indicate that HPV Integration Occurs at an Early Stage

“…The finding that punctate ISH signals are common in both juvenile-onset (7/10) and adult-onset (7/11) patients infected with low-risk HPV genotypes, suggests that HPV integration into the cell genome occurs at an early stage and may be an important factor contributing to the recurrent nature of these lesions. Possibly, if HPV integration occurs in a basal stem cell, HPV is then locked into the cell genome at the site of laryngeal infection and thereafter may support the recurrent papilloma phenotype and eventually the conversion of laryngeal papillomas to carcinomas, especially in juveniles [6,7]. In cervical tumors, high-risk HPV integration is associated with the loss of the HPV E2 gene that regulates the E6 and E7 oncogenes that promote abrogation of cell cycle control and cell division; low-risk HPV integration may support a parallel situation in recurrent papillomas.…”

“…Juvenile-onset RRP (JO-RRP) is generally considered to have a more aggressive clinical course than the adultonset (AO-RRP) [2,4,5]. Also, conversion to laryngeal carcinoma occurs more frequently in juveniles [6,7]. In addition to having a different clinical course, JO-RRP differs in its route of acquisition; while numerous studies have indicated that vertical transmission from maternal genital condylomas is the primary mode of juvenile papillomas, adult papillomas apparently spread secondary to oral-genital contact [8,9].…”

A Case of Multiple Squamous Cell Papillomas of the Trachea

“…Several reports suggested HPV 11 is associated with a transformation to squamous cell carcinoma. 2,3,8) Our patient was female and relatively older than most patients with adult onset papillomas. The route of HPV transmission was unclear.…”

“…In juvenile onset RRP, HPV is thought to be acquired at the time of vaginal delivery. 3) In one case control study, 9) adult onset RRP patients had more sexual partners and oral sex than their controls. HPVs cause latent airway infection, in addition to the active infection, that induces papillomas, and activation of latent HPV DNA, which appears to persist for the life of the patient, is considered to be the cause of recurrent disease.…”

“…According to previous reports, most papillomas are found in the larynx: only 5% of patients had distal involvement of the trachea, and involvement of lung parenchyma is very rare, which is seen in less than 1% of all cases. 3) likely to differ in the juvenile onset and adult onset forms of RRP. In juvenile onset RRP, HPV is thought to be acquired at the time of vaginal delivery.…”