Case 8--Persistent Lung Mass

Diagnosis: Squamous papilloma of left vocal cord with viropathic (koilocytic) changes. Solitary, cavitary papillomatosis with mixed squamous and glandular epithelium and foci of well-differentiated, papillary squamous carcinoma, left lower lobe of lung. Lymph nodes negative for tumor.

Comment: HPV 11 was identified by PCR in both the laryngeal papilloma and the lung tumor but not in normal lung parenchyma away from tumor. Koilocytic cells (viropathic effect) were also present in the lung lesion. After the diagnosis was made, we obtained a history of excision of a squamous papilloma of the vocal cord when the patient was a teenager. HPV is still present in this patient, and papillomas may recur. Known factors that increase the risk of transformation of papillomas to cancer, such as radiation, chemotherapy, and cigarette smoking, should be avoided.

Discussion: Recurrent Respiratory Papillomatosis (RRP)

Introduction: Recurrent respiratory papillomatosis is caused by the human papillomavirus (HPV), a circular, double-stranded, DNA tumor virus with a 55 nm icosahedral shape [1]. There are more than 70 different papillomavirus strains. Associated diseases include cutaneous warts, genital warts (condyloma* acuminatum), cervical and anal cancers, as well as RRP. In benign conditions, the virus replicates as an extrachromosomal episome in the nucleus of squamous epithelium. In some malignant neoplasms (cervical carcinoma), portions of the viral genome become incorporated into the chromosomes. RRP is similar to giant condylomas (Buschke-Löwenstein tumors) and verrucous carcinomas of the genitalia in its association with HPV types 6 & 11, prolonged infection, invasive behavior of cytologically benign-appearing tumor, and low frequency of metastasis [1].

* condyloma = squamous papilloma with viropathic (koilocytic) cell changes (see microscopic description for image 4)

Landmark studies relating HPV to RRP [2]:

Nomenclature & detection methods: Different viral strains are grouped together if more than 50% of the genome overlaps, e.g., 6/11, 16/18, 31/33/35. The virus cannot be cultured, and diagnosis rests on detection of HPV DNA by immunoperoxidase (IPOX) stains, in situ hybridization (ISH), Southern blotting, or the polymerase chain reaction (PCR). IPOX (sensitivity of several hundred viral particles/cell [4]) and ISH with enzyme-avidin-biotin-labeled probes (sensitivity of <100 copies of DNA/cell [4,5]) may give false positive results because of non-specific adhesion of probes; and PCR, which detects 1 virus particle in 105 cells, may be too sensitive for such a ubiquitous virus. Southern blotting, in which extracted DNA is hybridized to a probe, is the standard for accuracy [4] .

Pathogenesis: Most cases of respiratory papillomatosis occur in children under age 16, but adult onset has also been reported. Because genital warts are caused by HPV 6/11, it has been postulated that respiratory tract infection occurs at birth. However, the infrequency of HPV types 16/18 or 31/33/35, which are frequently found in the cervix, casts some doubt on this type of vertical transmission [4]. Virus can be detected in normal respiratory epithelium away from papillomas [6]. Therefore, it is likely that spread of papillomas to the lower respiratory tract is related more to viral spread than to dropping and implantation of fragments of laryngeal papillomas [7]. One mechanism of oncogenesis may be the binding and inactivation of p53 or the retinoblastoma gene product by HPV E6 or E7 proteins, respectively [1]. Inactivation of these anti-oncoproteins may be a step to neoplasia.

Clinical features: Symptoms include hoarseness, stridor, dyspnea, and cyanosis. Diagnosis is made by laryngoscopy or bronchoscopy and biopsy. Papillomas may be located on the true or false cords, the epiglottis, the tracheobronchial mucosa, or in the lung. More than 90% of patients have lesions that are confined to the larynx. The rest develop tracheobronchial papillomas; less than 1% of patients have lung parenchymal lesions [7]. Tracheobronchial lesions are believed to follow multiple surgical polypectomies and/or tracheostomies. Most, but not all, patients who develop lung lesions have tracheobronchial lesions. One 48-year-old woman had multiple tracheostomies and resections of laryngeal papillomas over 45 years and developed HPV-related lung cancer without any tracheobronchial lesions [5]. Similarly, the patient presented here had only laryngeal and lung lesions. Involvement of the lung is associated with recurrent pneumonias and bronchiectasis [7].

Natural history: The course of papillomas is unpredictable. In most persons with juvenile-onset respiratory papillomatosis caused by HPV, the disease undergoes remission before puberty. Similarly, in most adult-onset cases, the disease remits after 1-3 y [4]. However, chronic disease does occur, and spread to distal airways and lung can lead to death with or without malignant change or metastasis [7]. Factors involved in remission or progression are unknown although in one HPV-related disease, epidermodysplasia verruciformis, an autosomal recessive disease characterized by persistent warts beginning in childhood, defective cell-mediated immunity has been implicated. Patients have impaired natural killer cell activity. The HPV types are unusual (types 5, 8, & 14), and patients are not at risk for other viral diseases [1]. However, no cell-mediated abnormalities have been detected in patients with RRP [8].

Radiographic changes: Airway papillomas can be seen on PA and lateral airway films and on CT scans. In a study of 7 pediatric patients, parenchymal involvement was indicated by round, solid or cystic nodules. Cyst walls were up to 2-3+ mm thick. Small nodules grew and developed cavities. Air-fluid levels occurred. Lesions became confluent, but did not regress. On CT scans, lesions were found both centrally and peripherally with a tendency to be located posteriorly. Atelectasis was not common. Infections were noted [7].

Gross features: The lesions have a cauliflower-like appearance in the air passages. Solid or cystic parenchymal lesions appear granular [7]. If cystic, the luminal surface is lobulated, and if infection is absent, the lumen may contain thick fluid containing sloughed, squamous cells.

Microscopic features: Papillomas are sessile with well-differentiated, non-keratinizing squamous epithelium covering a delicate, fibrovascular core. Viropathic changes (koilocytic cells), when present, suggest the diagnosis. Some papillomas have ciliated or goblet cells mixed with the squamous cells [8,9], and tumors have been classified as squamous or mixed squamous and glandular [10]. (Ordinary bronchogenic carcinomas may also show mixed glandular and squamous differentiation.) Features of malignancy, such as cellular atypia, invasion, keratinization, necrosis, and reactive fibrosis have been described in tumors that had no metastases at autopsy [11]. The term "invasive papillomatosis" has been used for some of these tumors [9], but when atypical cells and/or invasion are present, the lesions have the potential to metastasize and are best considered cancer.

Complications: Cancer is a complication of RRP, and cigarette smoking, radiation, and chemotherapy are considered to be risk factors for it. Nevertheless, lung cancer has been reported in 14 cases of papillomatosis in non-smokers without radiation or chemotherapy. In these patients, the papillomatosis began at an average age of 2.5 y (range 1-6 y), and lung cancer was diagnosed an average of 15 y later (range 4-26 y). Pulmonary extension of papillomatosis was diagnosed premortem in 11 cases, months to 16 y before the cancer was detected. The cancers were well- or moderately-differentiated squamous carcinomas with local extension to other organs, or metastasis. Cancer was multicentric in four. Most died soon after diagnosis [12]. In another study, 7 of 102 patients with RRP developed laryngeal carcinoma and 1 developed lung cancer. Some of the patients with laryngeal cancer were smokers or had been treated with bleomycin. The patient with lung cancer was a non-smoker who had been treated with bleomycin and interferon [13].

In three patients without known risk factors, specific viral types 6 or 11 were identified in tumors that underwent malignant transformation. 1) A 27-y-old man with long-standing RRP and no history of radiation, chemotherapy, or smoking died of metastatic squamous cancer of the lung. The laryngeal papillomas, lung cancer, and liver metastasis all had extrachromosomal HPV type 11. The liver metastasis, which was less differentiated than the respiratory tumors, had a duplication of part of the viral genome [3]. 2) A non-smoking, 26-y-old man developed a poorly- to moderately-differentiated squamous carcinoma of the lung following a 24-year history of papillomatosis. The episomal HPV-6a isolated from the cancer had a duplication that was not present in his benign papillomas [14]. 3) A non-smoking, 35-y-old man with a 33-year history of RRP and no previous radiation died following resection of a well-differentiated squamous carcinoma of the lung. Extrachromosomal HPV 11 was demonstrated in the carcinoma and 2 papillomas. Metastases were confined to 2 peribronchial lymph nodes, and no mutant HPV was noted [12].

Role of virus in carcinogenesis: Two hypotheses have emerged. One is that in RRP a viral mutation is necessary for malignant transformation and metastasis to occur with HPV-6 or 11 [14]. A second hypothesis based on study of solitary bronchial papillomas is that HPV 16/18 is a requisite for malignant transformation [15]. In contrast, in the cervix, malignancy is believed to occur after the virus (16/18) becomes integrated with the chromosome [1]. The role of HPV in common bronchogenic carcinomas is controversial [16].

Therapy: After biopsy for diagnosis, CO2 laser therapy is the usual method for maintaining airway patency. Possible aerosolization of HPV during the procedure apparently does not occur, but eye protection, masks, and gloves are nevertheless advocated [17]. Patients refractory to laser therapy have been treated in addition with interferon alfa [18] or other drugs [19]. Photodynamic therapy is also under investigation. A photosensitizer is activated by light to induce cytotoxic changes in the tumor. Dihematoporphyrin ether, a photosensitizing agent, given intravenously, localizes in the papillomas. Photodynamic therapy with an argon pump dye laser emitting red light is delivered to the lesions some hours later. In one study, therapy produced about a 50% decrease in the rate of laryngeal papilloma regrowth, but did not eradicate virus from the mucosa [20].


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14. DiLorenzo T, Tamsen A, Abramson A, Steinberg B. Human papillomavirus type 6a DNA in the lung carcinoma of a patient with recurrent laryngeal papillomatosis is characterized by a partial duplication. J Gen Virol 1992; 73:423-428.

15. Popper H, El-Shabrawi Y, Wöckel W, Höfler G, Kenner L, Jüttner-Smolle F, Pongratz M. Prognostic importance of human papilloma virus typing in squamous cell papilloma of the bronchus: comparison of in situ hybridization and the polymerase chain reaction. Hum Pathol 1994; 25:1191-1197.

16. Welt A, Hummel M, Niedobitek G, Stein H. Human papillomavirus infection is not associated with bronchial carcinoma: evaluation by in situ hybridization and the polymerase chain reaction. J Pathol 1997; 181:276-280.

17. Abramson A, DiLorenzo T, Steinberg B. Is papillomavirus detectable in the plume of laser-treated laryngeal papilloma? Arch Otolaryngol Head Neck Surg 1990; 116:604-607.

18. Leventhal B, Kashima H, Mounts P, Thurmond L, Chapman S, Buckley S, Wold D. Long-term response of recurrent respiratory papillomatosis to treatment with lymphoblastoid interferon alfa-n1. N Engl J Med 1991; 325:613-617.

19. Avidano M, Singleton G. Adjuvant drug strategies in the treatment of recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg 1995; 112:197-202.

20. Abramson A, Shikowitz M, Mullooly V, Steinberg B, Amella C, Rothstein H. Clinical effects of photodynamic therapy on recurrent laryngeal papillomas. Arch Otolaryngol Head Neck Surg 1992; 118:25-29.

Case 8--Clinical Summary


Table of Contents

Copyright 1997 Martha L. Warnock, M.D.

Last revised 7/17/97