Phoebe Mounts

Sites of Predilection in Recurrent Respiratory Papillomatosis

Florid and widespread respiratory papillomatosis is a devastating disorder occurring 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.

Long-Term Response of Recurrent Respiratory Papillomatosis to Treatment with Lymphoblastoid Interferon Alfa-N1

Abstract Background. We earlier reported that patients with recurrent respiratory papillomatosis responded to six months of treatment with lymphoblastoid interferon alfa-n1. Because another study of patients treated for one year with leukocyte interferon alfa-n3 found that the growth rate of papillomas was slowed in the first six months but returned to base line during months 7 through 12 despite persistent interferon treatment, we now report the long-term results in our original study patients who were followed for a median of four years after the original one-year crossover study. Methods. After the patients in our study had completed the first study year, their physicians could continue or recommence treatment with lymphoblastoid interferon alfa-n1 in a dose of either 2 MU per square meter of body-surface area per day or 4 MU per square meter every other day. The extent of disease was measured by endoscopy when clinically indicated. Results. Data on late-follow-up were obtained for 60 of the 66 patient...

Polymerase chain reaction identification of human papillomavirus DNA in CO2 laser plume from recurrent respiratory papillomatosis.

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.

The cytokines NAP-1 (IL-8), MCP-1, IL-1 beta, and GRO in rabbit inflammatory skin lesions produced by the chemical irritant sulfur mustard

Developing and healing dermal inflammatory lesions were produced in rabbits by the topical application of dilute sulfur mustard (SM),9 the military vesicant. In tissue sections of such lesions, cells containing the mRNA of important cytokines were identified with in situ hydridization 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.

Association of human papillomavirus with nasal neoplasia

Since HPV-57b has been identified by two different techniques in benign, premalignant, and malignant lesions of the nasal cavity, but not in cases of chronic sinusitis, HPV-57 should be recognised as at least a co-factor in the aetiology of nasal neoplasia. Paraffin sections of 22 histologically confirmed nasal tumours were screened by in-situ hybridisation with riboprobes specific for HPV-57b. Virus was demonstrated in 6 of 7 fungiform papillomas, 6 of 8 inverted papillomas, 1 of 3 inverted papillomas with dysplasia, and 2 of 4 inverted papillomas with carcinoma. The presence of HPV-57b was confirmed with the polymerase chain reaction, which identified an additional 4 positive samples, bringing the total to 86% positive specimens. The results underscore the importance of HPVs in the aetiology of cancers at extragenital sites.

Efficacy of human lymphoblastoid interferon in the therapy of resistant condyloma acuminata

The efficacy and tolerance of human lymphoblastoid interferon (Wellferon) were studied in an open label trial of 17 patients with resistant and persistent condyloma acuminata. Patients were treated intramuscularly with 5 X 10(6) U (5 MU)/m2 daily for 28 days followed by thrice weekly injections for two weeks. Sixteen patients were considered evaluable; eight experienced complete clearance, seven had significant reduction (greater than 50%) in lesion size, and one showed no response during the course of this trial. Biologic side effects of interferon occurred in all patients during initial dosing and diminished during thrice weekly therapy. Intramuscular injections and associated side effects were tolerated well. This study shows that systemic human lymphoblastoid interferon is active in treating severe recurrent genital warts in women with a history of recalcitrant disease.

Antibody response to human papillomavirus (HPV) type 11 in children with juvenile-onset recurrent respiratory papillomatosis (RRP)

We previously established, using an ELISA, the presence of specific antibodies directed at human papillomavirus (HPV) type 11 virions in the sera of patients with condylomata acuminata, mostly a disease of young adults that, like recurrent respiratory papillomatosis (RRP), is caused by two closely related HPVs, types 6 and 11. The present study was done to investigate if children with RRP can make viral-specific antibodies to an infection that is acquired at birth. Using the same ELISA, we studied the sera of 32 children with biopsy-documented juvenile-onset RRP and compared them to the sera of 31 control children. The median (and interquartile range) of the OD values in the controls and the cases was 0.078 (0.003, 0.101) and 0.230 (0.063, 0.725), respectively, a statistically significant difference (P = 0.001). Among the cases, there was no difference in seroreactivity between children with HPV-11-induced RRP and those with HPV-6-induced RRP (P = 0.31). Since HPV-11 viral particles do bind to the ELISA plate and remain intact and accessible to antibodies, we conclude that children with RRP, like adults with condylomata acuminata, develop antibodies directed at HPV-11 virions.

Carcinoma ex-papilloma: histologic and virologic studies in whole-organ sections of the larynx.

A patient with adult‐onset recurrent respiratory papillomatosis (RRP), initially diagnosed at age 28 years, was treated with radiation therapy due to the rapid regrowth of lesions. Following 6 years of apparently inhibited growth, papilloma recurred, and squamous carcinoma was diagnosed from a laryngeal biopsy. A spontaneous laryngocutaneous fistula developed, and laryngectomy was performed 14 years after irradiation.

Interferon alfa-n1 (Wellferon) in juvenile onset recurrent respiratory papillomatosis: results of a randomized study in twelve collaborative institutions.

Sixty‐six patients with clinically severe juvenile‐onset recurrent respiratory papillomatosis (RRP) were entered into a 12‐month randomized crossover study to evaluate interferon alpha‐n1 Wellferon® (WFN) as an adjuvant to CO2 laser surgical excision. Eligibility required disease onset to be before age 16, and an endoscopic excision requirement of at least three operations in the 6 months immediately prior to entry. Patients were randomized to Observation versus WFN at a dose of 5 MU/m2 daily for 28 days and three times weekly for 5 months. The patient groups were comparable in extent of disease at entry. Total extent of disease was determined by a composite score derived from the number of diseased anatomic sites and extent of surface area and lumen encroachment present at each site. Standard endoscopic excisions were performed every 2 months and clinical courses compared on a basis of composite scores determined at each endoscopy. Statistically significant improvement occurred in the patient group which received WFN. We conclude that interferon alpha n‐1 is an effective adjuvant to surgery in RRP management.

Coinfection of HPV‐11 and HPV‐16 in a Case of Laryngeal Squamous Papillomas With Severe Dysplasia

Human papillomavirus (HPV) types 6 and 11 have been associated with benign laryngeal papilloma, while HPV‐16 is occasionally associated with laryngeal carcinoma. In this study, a case of laryngeal squamous papillomas with severe dysplasia was evaluated for the presence of HPV infection. The biopsy specimens were taken from a 58‐year‐old female patient at two different time points 3 months apart. Architecturally, the tumor showed papillary configuration reminiscent of squamous papilloma. Cytologically, the lesion showed morphologic features characteristic of severe squamous epithelial dysplasia. HPV infection was determined by DNA in situ hybridization using type‐specific HPV‐DNA probes. HPV‐11 probes demonstrated homogeneous nuclear staining, suggesting productive viral replication. In contrast, HPV‐16 probe produced a speckled pattern, suggesting HPV‐16 DNA integration. Normal laryngeal epithelium did not yield specific hybridization. The presence of HPV‐11 and HPV‐16 was confirmed by PCR using HPV type‐specific primers. Immunocytochemical staining was performed to detect Ki‐67, a proliferation marker, and p53. Ki‐67 expression was demonstrated throughout the whole thickness of epithelium. Staining for p53 was negative. This study suggests that multiple HPV infections can occur in the same lesion and that HPV‐16 infection and its DNA integration may contribute to the occurrence of severe dysplasia in the lesion described.