Squamous cell papilloma is a benign tumor consisting of delicate connective tissue fronds with a squamous epithelial surface.^{1,2,3,4,5,6,7,8,9,10,11} Squamous papillomas can be solitary or multiple.¹² In the latter instance, they are frequently associated with respiratory papillomatosis or recurrent laryngeal papillomatosis.

It has been recognized since the 1980s that the lower respiratory tract can be involved with HPV-related papillomas extending from the larynx.¹³ The cause is presumed to be exposure to maternal human papillomavirus (HPV) during vaginal birth. Tracheal involvement in recurrent laryngeal papillomatosis occurs in up to 10% of patients, with pulmonary parenchymal involvement in < 2%.¹⁴ Laryngotracheal papillomatosis is synonymous with “respiratory papillomatosis” or “recurrent respiratory papillomatosis.”^13,14,15 Tracheal and bronchial papillomatoses are defined endoscopically by the presence of papillomas at the level of the first tracheal ring and distally. Pulmonary papillomatosis is diagnosed using chest radiographs or computed tomography scans that show multiple rounded, solid, or cystic nodules.¹⁴

Solitary squamous papilloma is a rare tumor that accounts for <1% of all lung tumors.^1,2,12,16 The tumor has a variety of clinical presentations, including cough, dyspnea, hemoptysis, and recurrent pneumonia.^1,12,16 Solitary squamous papillomas are predominant in male smokers (male-to-female ratio of 3:1) in their sixth decade.^2,16 Bronchial squamous papilloma usually presents as an endobronchial mass in the segmental bronchi with abnormal radiologic findings such as a round tumor shadow, parenchymal infiltrative opacity, atelectasis, and hilar mass on chest x-ray or computed tomography (CT) scan.¹⁶ There are two peculiar features in the clinical history of these lesions: (1) a tendency to spread to multiple sites within the bronchial tree and (2) a substantial potential for malignant transformation.¹¹ These two characteristics strongly implicate an infectious etiology of SSPs. The clinical behavior closely resembles that of recurrent respiratory papillomatosis and natural history of sinonasal papillomas.¹¹ HPV appears to play a pathogenetic role in solitary squamous papilloma.¹ The malignant potential of solitary squamous papilloma ranges from 8% to 40%.¹⁶

Risks for extension of HPV-related papillomas to the lower airways include tracheotomy for laryngeal stenosis, and early onset of disease, with a mean of 20 months of age.¹⁴ Most children develop laryngeal papillomas by the age of 5, and lung lesions may occur as late as age 30.^13,15 Frequently, there are numerous endoscopic procedures and ablations of upper airway lesions before lung lesions appear.¹³ Radiographs and chest computed tomography scans show round or irregular cysts, usually <5 cm diameter, often with air-fluid levels.¹³ These cysts progress to nodules, with a predilection of bilateral lower lobes. Symptoms include respiratory insufficiency and signs of pneumonia, although many lesions are found during screening chest radiographs.¹³ Treatment includes interferon, local injection with cidofovir, and antiproliferative drugs.¹⁵ In the largest study of lower respiratory papillomatosis, 48% of patients achieved remission, 23% had persistence into childhood, 16% had persistence into adulthood, and 13% died from respiratory failure or progression to squamous cell carcinoma.¹⁴

Endobronchial solitary squamous papilloma must be distinguished from more aggressive neoplasms. This distinction is particularly important when one encounters this neoplasm in a peripheral location at frozen section. Solitary squamous papilloma can be exophytic or, less frequently, inverted or plaque-like^16,17 (Fig. 66.1). The histologic examination shows papillary lesions composed of fibrovascular interstitium and proliferation of stratified squamous epithelium with orderly maturation from the base to the superficial layer¹⁶ (Fig. 66.2). Typically, the squamous epithelium is bland; however, cell atypia and increased mitotic activity indicative of dysplasia may be seen and
should be graded accordingly (Fig. 66.3). Endobronchial papillomas, particularly inverted ones, may extend into and replace submucosal glands. This results in small squamous nests in the submucosa and should not be misconstrued as invasion. These squamous nests remain invested of a basal layer. The distinction with a papillary squamous cell carcinoma can be challenging. Papillary squamous cell carcinoma will appear overtly malignant cytologically. Invasion may be difficult to appreciate, but desmoplasia and parenchymal destruction are helpful features when present. Immunohistochemically, p63, p40, CK903, and CK5/6 are diffusely positive, indicative of their squamous differentiation.