Florid and widespread respiratory papillomatosis is a devastating disorder in a subset of patients with recurrent respiratory papillomatosis, and it poses a major dilemma for the patient and the surgeon. Contrary to common belief, the distribution of papilloma lesions is not random, but follows a predictable pattern, with lesions occurring at anatomic sites in which ciliated and squamous epithelia are juxtaposed. The predominant sites of disease in recurrent respiratory papillomatosis are the limen vestibuli, the nasopharyngeal surface of the soft palate, the midzone of the laryngeal surface of the epiglottis, the upper and lower margins of the ventricle, the undersurface of the vocal folds, the carina, and bronchial spurs. These sites have the common histologic feature of a squamociliary junction. Papillomata also occur at the tracheostomy tract and at the midthoracic trachea in patients with tracheostomies. At the latter sites, abrasion injury to ciliated epithelium heals with metaplastic squamous epithelium and creates an iatrogenic squamociliary junction. The apparent preferential localization of papilloma at squamociliary junctions has at least 2 implications: first, that detection of occult asymptomatic papillomata is enhanced by careful examination of squamociliary junctions, and, second, that iatrogenic papilloma "implantation" is preventable by avoiding injury to nondiseased squamous and ciliated epithelia.

Juvenile-and adult-onset laryngeal papillomas were examined for the presence of a human papillomavirus (HPV) genome and capsid antigens. DNA was isolated from a portion of tissue removed for therapeutic purposes, and the presence of a papillomavirus genome was detected by Southern transfer analysis. The viral DNA found in the 12 juvenile-onset and the 8 adultonset laryngeal papillomas examined was identified as HPV-6 on the basis of size, restriction endonuclease digestion patterns, and homology detected under stringent conditions. Restriction endonuclease analysis of the viral genomes revealed at least four different subtypes, designated HPV-6c through HPV-6f. The most common subtype, HPV-6c, was detected in over half of the papillomas studied, including both juvenile and adult types. The remaining tissue was fixed and processed for immunocytochemistry. The immunoperoxidase technique was used with an antiserum that reacts with capsid antigen(s) common to all HPV serotypes. HPV antigen was found in two of the juvenile-onset papillomas and two of the adult-onset papillomas. The antigen was localized to the nucleus and was distributed in the superficial layers of the epithelium. HPV capsid antigen had not previously been detected in cases of adult-onset papilloma, and the HPV genome in both juvenile-and adult-onset laryngeal papillomas had not been characterized. Despite the absence of detectable viral antigen in most of the specimens examined, the presence of the HPV genome provides strong evidence for the papillomavirus etiology of these tumors.Squamous papillomas ofthe larynx are a serious clinical problem because of their location, their resistance to treatment, their relentless recurrence, and their tendency to spread throughout the respiratory tract (1, 2). The most frequent age of onset is in the first five years oflife, but the disease also occurs in adults.Papillomas of the larynx are tumors of lobulated or papillary form in which each projection has a central core of connective tissue covered with squamous epithelium (3). They histologically resemble cutaneous warts, whose papillomavirus etiology has been established (for review, see ref. 4). Although a papillomavirus etiology has been implicated for laryngeal papillomas, there have been conflicting reports on the presence of virus particles in these tumors when examined by electron microscopy (5-8). More recently, papillomavirus capsid antigen has been detected in juvenile-onset laryngeal papillomas by the immunoperoxidase technique of Sternberger (9), using an antiserum that reacts with genus-specific antigens (10-12). In these studies, papillomavirus antigen was detected in less than half ofthe juvenile-onset laryngeal papillomas. In the positive cases it was not possible to identify the specific viral serotype present in the lesions because the antiserum is crossreactive with capsid antigens of all papillomaviruses. Despite attempts to isolate papillomavirus or detect the papillomavirus genome in juvenile-onset laryngeal papillomas (13-17), ...

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Human papillomavirus (HPV) DNA was identified in the plume produced during CO2 laser vaporization of respiratory tract papillomata. The plume produced from CO2 vaporization was collected on Gelfoam pledgets that were affixed to suction tips evacuating the vapor plume from the operative field. The Gelfoam pledgets were snap frozen in liquid nitrogen, processed, and examined for HPV-6 and HPV-11 DNA by a polymerase chain reaction technique. Tissue and vapor-plume specimens were collected from 22 patients undergoing CO2 laser excision of laryngeal lesions. Seven patients had adult-onset recurrent respiratory laryngeal papillomatosis (RRP), 12 had juvenile-onset RRP, two had laryngeal carcinoma, and one had nonspecific laryngitis. HPV-6 or HPV-11 was identified in 17 of 27 vapor-plume specimens from RRP and in none of three from non-RRP lesions. All but one RRP tissue specimen contained HPV-DNA, and none of the non-RRP tissues contained HPV-DNA. When HPV was present in vapor, the same HPV type was found in the corresponding tissue specimen. Identification of HPV-DNA in the laser plume raises concern regarding potential risks from exposure to the plume--particularly to the endoscopic surgeon and the operating team. The practical concerns and effectiveness of the plume scavenging systems are discussed.

Patients with severe recurrent respiratory papillomatosis may have a sustained or repeated response to treatment with lymphoblastoid interferon alfa-n1. We recommend that patients with recurrent respiratory papillomatosis who require surgery every two to three months be given a six-month trial of interferon alfa-n1.

The relationship of human papillomavirus type 6 (HPV-6) subtypes to the clinical manifestations of respiratory papillomatosis was investigated. DNA was isolated from biopsy specimens of 21 patients and the viral genome analyzed by molecular hybridization. Four subtypes, designated HPV-6c through HPV-6f, were distinguishable by restriction endonuclease cleavage patterns of the viral genome. Patient records were reviewed to identify associations between viral subtype and sex, race, age at onset of papilloma, duration of disease, frequency of operations, history of tracheotomy and anatomical extension of papilloma. HPV-6c was present in 13 cases which were characterized by extensive anatomical spread of disease, higher frequency of operations, and a need for tracheotomy. HPV-6d occurred in 4 black patients with juvenile onset papilloma. HPV-6c was found in 2 white patients--1 with juvenile onset and 1 with adult onset papilloma. HPV-6f was identified in 2 white patients with adult onset disease.

Developing and healing dermal inflammatory lesions were produced in rabbits by the topical application of dilute sulfur mustard (SM), the military vesicant. In tissue sections of such lesions, cells containing the mRNA of important cytokines were identified with in situ hybridization techniques. These cytokines were neutrophil attractant/activation protein-1 (NAP-1 (also called IL-8), monocyte chemoattractant (activating) protein 1 (MCP-1), interleukin 1 (beta) (IL-1 (beta)), and GRO (a growth factor and chemokine). Mononuclear cells (mainly macrophages and activated fibroblasts) contained the mRNA of all four of these cytokines. A higher percentage of cytokine-producing mononuclear cells (macrophages and activated fibroblasts) was present in lesions at 2 days (their peak size) than at 6 days, when they were almost healed. Granulocytes emigrated from the bloodstream, passed through the lesions, and were the major constituent of the protective crust. This sequence correlated with the distribution of cells able to produce NAP-1: At 2 days and 6 days, the mononuclears that contained messenger RNA for this granulocyte chemoattractant were found mainly in the upper part of the dermis. At 2 days and 6 days, cells containing the mRNA of IL-1, a primary cytokine, were also found predominantly in the upper dermis, i.e., nearest the site of injury. In contrast, mononuclears containing the mRNA of MCP-1 (a monocyte chemoattractant), and the mRNA of GRO (a granulocyte chemoattractant) were more equally distributed throughout the dermis. SM stimulated hair follicle epithelial cells to up-regulate GRO mRNA and, to a lesser degree, NAP-1 mRNA. Apparently, the irritation produced by SM directly or indirectly induces such epithelial cells to manufacture these growth factors. In the rabbit, hair follicles are known to be the main source of new epithelial cells after the covering epithelium has been destroyed. Therefore, GRO is probably a major autocrine-paracrine stimulus for such repair. A brief review of the role of cytokines in dermal inflammation is presented.

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