Pulmonary Papilloma

Etiology

The etiology of multiple papillomatosis, also known as recurrent respiratory papillomatosis, is primarily associated with human papillomavirus (HPV) infections. This condition is characterized by recurrent benign papillomas in the respiratory tract, particularly in the larynx, trachea, and bronchi. Most papillomatosis cases (over 90%) are caused by HPV subtypes 6 and 11, which do not predispose to malignancy.[3] Variations within HPV types 6 and 11 can predispose individuals to multiple papillomatosis, where the genetics of the responsible virus and the host immune response significantly influence the disease's clinical course. However, other HPV subtypes like 16, 18, and 31 are associated with malignant transformation, particularly in individuals with squamous cell papilloma and TP53 mutations. Smoking, especially in women, is a significant risk factor for malignant transformation in squamous cell papilloma.[4] 

Patients with immune deficiencies, such as those with HIV or other immune disorders, are at an increased risk of developing multiple papillomatosis due to HPV infection. Similarly, pneumatosis related to HPV can be acquired through oral-genital contact or vertically transmitted during perinatal delivery from an infected mother. 

Inflammatory polyps, also known as inflammatory pseudotumors, have distinct inflammation as a unique etiology, unlike other polyps, such as adenomatous polyps, which involve abnormal epithelial cell growth. The inflammatory polyps typically can present as single or multiple papillary lesions in patients with chronic respiratory infections, with some cases being linked to infections themselves.[5] Dysregulation of the immune response may also contribute to the development of inflammatory polyps, as an abnormal immune reaction to stimuli such as infections or environmental factors can lead to chronic inflammation and subsequent polyp formation. Genetic factors may have a role in certain cases associated with specific genetic aberrations.[6] Furthermore, exposure to environmental irritants or toxins can promote chronic inflammation and contribute to polyp development. Solitary polyps, which are rare, are often linked to infections such as HPV or environmental exposure to smoking.[2][7][8]

Epidemiology

The incidence of recurrent respiratory papillomatosis is around 4 per 100,000 in children and 2 per 100,000 in adults, as reported by various studies.[9] These incidence rates can be influenced by the age of onset and socioeconomic status, with higher rates observed in groups with lower socioeconomic status and educational levels.[10][11] However, there is no established relationship between socioeconomic status and the severity of the disease. Concurrently, the prevalence of HPV infection among women has been steadily increasing, with an estimated prevalence of 26.8% in women aged 14 to 59 and 45% in women aged 20 to 24.

Recurrent respiratory papillomatosis is common in adults, predominantly in men (84% of laryngeal papilloma) aged between 40 and  50, with another peak incidence seen in the sixth decade of life.[12] In contrast, lower airway and pulmonary papillomas, especially solitary and inflammatory polyps, represent a rare type of tumor, accounting for less than 1% of all lung neoplasms.[4] About 8% to 9% of patients with HPV-associated recurrent respiratory papillomatosis show pulmonary involvement. Pulmonary manifestations of papilloma primarily occur in children, often due to vaginal delivery from an HPV-infected mother with HPV-6 and HPV-11 in the genital area.[3]

Pathophysiology

Papillomas may manifest as solitary or multiple nodules, which may take the configuration of exophytic, sessile, or pedunculated lesions. Typically, these lesions are confined to the larynx but can commonly affect the vocal cords, ventricular pleats, subglottis, and the laryngeal surface of the epiglottis. Recurrent respiratory papillomatosis can occur throughout the respiratory system, including the tracheobronchial tree and pulmonary parenchyma. In patients with laryngeal papilloma, involvement of the distal airway occurs in only 2% to 5% of cases, while the pulmonary parenchyma is affected in about 1% of cases.[3][13] 

HPV infects the squamous epithelium of the respiratory tract, leading to the development of recurrent papillomas. The virus initially enters the basal layer of epithelial tissue through minor abrasions on mucous or skin surfaces. Subsequently, HPV activates the epidermal growth factor receptor pathway and disrupts various tumor-suppressing proteins, resulting in epithelial cell proliferation and differentiation. This process gives rise to "cauliflower-like" protrusions, a characteristic feature of recalcitrant reticular papillomatosis, typically occurring at the junction of squamous and ciliated columnar epithelia.[14]

The genetic pathogenesis of recalcitrant reticular papillomatosis is associated with mutations in genes such as the tumor protein p53 gene (TP53) and the interferon-beta-1 gene (IFNB1).[15] In addition, this condition has been identified in patients with certain immune-modulated disorders that predispose them to viral infections or immune deficiencies, such as HIV.[16][17][18]

Vascular endothelial growth factor (VEGF) is expressed strongly in the epithelial membrane of the respiratory papilloma and plays a role in the pathogenesis of recurrent respiratory papillomatosis.[19] In addition, VEGF receptors 1 and 2 (VEGFR-1 and VEGFR-2) are expressed abundantly in the endothelial cells of the vessels within the papilloma, making them potential therapeutic targets. The PD-1 T-lymphocyte checkpoint pathway on papilloma cells indicates its contribution to local immunosuppression and its role in papilloma pathogenesis. Blocking this pathway could lead to targeted therapy using monoclonal antibodies.[20]

Histopathology

Pulmonary papillomas can manifest as solitary or multiple nodules. In cases of recurrent respiratory papillomatosis, these nodules can present as exophytic, sessile, or pedunculated lesions, primarily localized to the larynx but commonly affecting surrounding structures such as the vocal cords, ventricular pleats, subglottis, and the laryngeal surface of the epiglottis. Gross features consist of polypoid, tan-white, and friable lesions, ranging in size from 0.7 to 9 cm with a median size of 1.5 cm. They protrude into airway lumens, and involvement may lead to bronchiectasis in distal airways, with the potential for secondary obstructive changes in the distal lung. Histologically, these lesions are typically benign epithelial proliferations that develop at the junctions between ciliated and squamous epithelium. 

Solitary papilloma is a benign tumor that arises from normal bronchial epithelium. Maxwell et al classified this type of papilloma into 2 groups.[21] The first group consisted of solitary papillomas with columnar or cuboidal epithelium, with or without squamous metaplasia, and minimal inflammation. The second group included solitary squamous papillomas characterized by a well-developed connective tissue stroma and stratified squamous epithelium. However, some argue that the distinction is unnecessary, as many papillomas exhibit some degree of squamous metaplasia.[2]

Histological examination of inflammatory polyps shows that the polypoid lesions consist of ciliated columnar epithelium and have a fibrous tissue core with infiltration of inflammatory cells. Microscopic findings in general papilloma have a fibrovascular core with squamous epithelial proliferation lining that shows as lobules of squamous cells surrounding cavitations and necrosis within the alveolar lung tissue. 

The histopathology can, however, vary according to the papilloma's subtype:

• Squamous cell papillomas are characterized by arborizing loose fibrovascular cores covered by stratified squamous epithelium. Exophytic tumors display orderly epithelial maturation with often keratinized cells, along with common features such as acanthosis and parakeratosis. Degeneration into squamous cell carcinoma is rare but can be associated with TP53 mutations. Less than 25% of solitary papillomas show typical features of HPV infection, such as binucleate forms, wrinkled nuclei, and perinuclear haloes. Occasionally, dyskeratotic cells, large atypical cells, and mitotic figures above the basal layer can be observed. Dysplasia is graded based on the current World Health Organization (WHO) classification into discrete, mild, and severe dysplasia. Parenchymal involvement may feature solid intra-alveolar nests of cytologically bland non-keratinizing cells or large cysts lined by similar cells.

• Glandular papillomas are distinguished by a fibrovascular core covered with a pseudostratified or stratified columnar epithelium, which can form micro-papillary tufts. The columnar cells exhibit uniformity, with eosinophilic cytoplasm and regular round nuclei. Although clear cytoplasm is possible, nuclear atypia, necrosis, and abnormal mitoses are typically absent.

• Mixed squamous cells and glandular papilloma are characterized by a combination of both features, with a predominant presence of glandular epithelium and interspersed squamous islands. Glandular atypia and necrosis are typically absent, although squamous atypia may occasionally be observed. Pulmonary papilloma is associated with HPV 11 integration, which is considered tumorigenic and leads to gene duplication and altered innate immunity.[3][12][17][22][23][24][25]   

Distinguishing squamous cell carcinoma in patients with pulmonary papilloma can be challenging with small-size biopsies; therefore, excisional resection is necessary to confirm the diagnosis. 

History and Physical

Clinical symptoms associated with pulmonary papillomas are generally non-specific.[1] Approximately 25% of cases involve asymptomatic tumors discovered incidentally on thoracic imaging. Recently, some centers have categorized pulmonary papillomas into 3 groups—limited, moderate, or severe—based on their level of pulmonary involvement, and are determined by the size and aggressiveness of the tumor. The limited type refers to a single sub-centimeter nodule, whereas moderate and severe types involve several multi-centimeter size cystic lesions.[22] 

In other cases, the most commonly reported symptoms include obstructive symptoms such as coughing or wheezing, similar to those seen in solitary papilloma, which can mimic asthma.[26] Additionally, these lesions may cause hoarseness, stridor, dyspnea, recurrent respiratory infections, and airway compromise.[27] Patients with asthma, especially those using daily inhaled corticosteroids, may experience a more clinically aggressive course.[28]

Hemoptysis and lung abscesses represent the most severe presentations associated with pulmonary papilloma and may necessitate surgical or endoscopic intervention. Hemoptysis related to bronchiectasis might require a bronchial artery embolization procedure. However, when encountering hemoptysis in a patient who smokes, clinicians must rule out lung cancer.[29] In addition, pulmonary resection may be necessary in rare cases of uncontrolled bleeding. 

Evaluation

Solitary papillomas are usually central and endobronchial or, in rare cases, peripheral and endobronchial, such as a plaque lesion.[26] 

Recurrent respiratory papillomatosis can present in various forms, including nodules or masses with smooth or irregular walls, thin or thickened walls, as well as cavities and cysts sharing similar characteristics. These parenchymal lesions are predominantly located in the posterior regions of both lungs. However, the presence of concurrent adenopathy in the hilar or mediastinal regions should raise suspicion of malignant transformation.[30][31] Computed tomography (CT) findings typically include endobronchial plaques, nodules, airway thickening, air-trapping, abscesses, foreign bodies, and bronchiectasis.[27][32][33][34]

Studies have shown that solid and cavitated lung nodules are the most common findings in pulmonary papilloma cases, accounting for more than 80% of cases, often scattered throughout the lungs with distinct patterns such as calcification.[3] Isolated nodular lesions within the parenchyma without airway involvement are rare on chest CT scans.[27] Although positron emission tomography (PET) and chest CT scans are not highly sensitive or specific for detecting pulmonary papilloma, they serve as valuable tools for identifying the appropriate site for biopsy, especially when malignancy is suspected.[35] Changes in the epithelium on the papilloma surface, including metaplastic changes, may be detected by PET scans.[36]

A high index of suspicion should be maintained in specific patient groups, such as individuals with severe uncontrolled asthma who rely on inhaled steroids. Recent reports from a study involving 90 patients with recurrent respiratory papillomatosis (ranging from ages 19 to 86 at first diagnosis) revealed a significant association between asthma and aggressive forms of recurrent respiratory papillomatosis. The study found that 57% of asthma patients had aggressive disease compared to 16% of non-asthma patients (P = .02). Furthermore, a higher prevalence of aggressive recurrent respiratory papillomatosis was observed among corticosteroid users compared to non-users (80% versus 15%; P = .004). Despite this association, the underlying cause remains unclear, and clinical recommendations cannot be formulated solely based on existing data.[28]

Bronchoscopy is a definitive tool for confirming the presence of solitary or recurrent respiratory papillomatosis, revealing endobronchial protuberances or atelectasis during the procedure. Caution is crucial during biopsies of laryngeal and central endobronchial lesions due to the risks of uncontrolled bleeding and airway obstruction. Given the heterogeneity of most pulmonary papilloma lesions, a core biopsy may not suffice, necessitating an excisional biopsy to rule out malignancy or necessitating serial imaging observation.

Similar to other lung tumors, establishing a histopathological diagnosis via biopsy is crucial, followed by staging to determine disease extent and any metastasis. Therefore, endobronchial ultrasonic bronchoscopy (EBUS) is necessary to sample mediastinal and hilar nodes, or in some cases, surgical staging is required. Such staging is essential for planning management with curative intent.[37] 

Treatment / Management

Treatment for pulmonary papilloma depends on various factors such as lesion location, histopathology, lung reserve, and patient age.[38] In cases involving pulmonary parenchyma, such as recurrent respiratory papillomatosis, there is a poorer prognosis and a higher likelihood of requiring a tracheostomy.[39] Due to the significant morbidity associated with recurrent respiratory papillomatosis in adults, including a high rate of malignant transformation and resemblance to non-small cell lung cancer, a treatment approach akin to primary lung squamous cell carcinoma is advisable.[22](B3)

Pulmonary papillomas are typically treated with surgical resection or endoscopic removal in stages 1 or 2 without metastasis.[37] Additional techniques include laryngeal micro-debride therapy, laser treatment, lesion injection of the antiviral drug cidofovir, photodynamic therapy, cryotherapy, and subcutaneous interferon-alpha therapy.[40] (B3)

The novel use of systemic treatment for pulmonary papilloma is emerging. Some reports have indicated an upregulation of programmed cell death protein 1 (PD-1) within pulmonary papillomas, suggesting a potential role for PD-1 targeted anti-PD-1 therapies such as nivolumab and pembrolizumab.[20][41] 

Bevacizumab is a promising treatment for aggressive recurrent respiratory papillomatosis with a safe profile in adults and children.[42][6] Bevacizumab is a monoclonal antibody that targets VEGF.[19] Specifically, the interval between systemic bevacizumab treatment initiation and the need for surgical intervention was significantly prolonged in affected individuals. During the monitoring period of approximately 22 months, over half of the patients did not require intervention.[43] (A1)

Local injection of bevacizumab has shown reduced efficacy, limiting its applicability to many patients and highlighting the need for large-scale clinical trials to further evaluate its effectiveness. Pembrolizumab represents another promising therapy; however, the final results of clinical trials are still pending.[44] Although some reports advocate using medications such as celecoxib to block prostaglandin production and EGER resistance, celecoxib has proven ineffective in treating pulmonary papilloma.[45](B3)

Solitary papillomas that are surgically removed typically do not recur; however, recurrences are observed in about 20% of patients treated with endoscopic removal. The prognosis for completely surgically removed lesions is generally good, with rare recurrences observed in incompletely removed lesions. Malignant transformation is seldom observed in squamous cell papillomas.[1][46] Precautions should be taken during laser therapy to prevent the aerosolization of HPV DNA particles, which could be inhaled by medical staff. The development of the HPV vaccine is promising as it may help prevent the development of respiratory papillomatosis.[38] (B3)

Finally, it is crucial to emphasize the importance of surveillance for patients at risk of pulmonary involvement. Currently, consensus on the best strategy or guidelines for monitoring such patients does not exist. However, it is recommended to consider obtaining early baseline low-dose CT scanning of the chest for individuals with juvenile-onset recurrent respiratory papillomatosis, starting at age 18 or earlier if associated risk factors are present, such as early disease onset, tracheostomy, or the need for multiple surgical interventions.[22] 

Likewise, in adult-onset recurrent respiratory papillomatosis, obtaining a low-dose CT chest as a baseline is advisable, followed by subsequent scans every 5 years if there is no evidence of pulmonary involvement, cysts, or nodules. However, if an incidental nodule is discovered, adhering to the updated Fleischner Society guidelines for managing incidental pulmonary nodules is important.[47]

Differential Diagnosis

Based on clinical findings, major differential diagnoses for pulmonary papillomas include carcinoid tumors and squamous cell carcinoma. Microscopic examination is essential to differentiate between these conditions. Inflammatory polyps and squamous cell carcinoma are the primary diagnostic challenges associated with squamous cell papilloma. Inflammatory polyps lack a true papillary structure despite possible squamous metaplasia.

Squamous cell carcinoma is a malignant epithelial tumor characterized by nests of tumor cells with central squamous pearls and may exhibit dyskeratotic cells. Immunohistochemical studies, particularly using P63 and P40 antibodies, can be valuable in cases where keratinization is not evident.

The differential diagnoses of glandular papilloma include primary and metastatic adenocarcinoma, as well as other adenomas. Carcinomas typically exhibit malignant features such as cytological atypia and invasion of the basal lamina, lacking the basal, ciliated, and mucinous cells characteristic of glandular papilloma.[3][48] Additionally, diagnostic features of adenocarcinomas include glandular structures and/or mucus secretion, which are absent in pulmonary papillomas.

Prognosis

Pulmonary papillomas are typically benign lesions with a favorable prognosis if completely removed. Recurrence is rare but possible when removal is incomplete. Malignant transformations of respiratory papillomas are rare overall but can be increased in certain histopathological types, such as squamous cell papilloma, especially when pulmonary involvement occurs (up to 16% incidence).[39][49] In contrast to isolated upper airway papillomatosis, patients with recurrent respiratory papillomatosis have a significantly higher risk of malignant transformation, estimated to be 32 times greater.[22]

Factors that increase the risk of developing cervical cancer include infection with high-risk HPV subtypes 16 and 18, smoking, previous radiotherapy, use of cytotoxic drugs, p53 gene mutation, and high severity score or high activity of 2'-5'-oligoadenylate synthetase.[14][50] Although considered low risk, HPV subtypes 6 and 11, particularly subtype 11, have also shown potential for malignant transformation.[51] Although the exact mechanism behind this transformation remains unclear, the oncogenic potential of HPV is believed to result from interference with the cell cycle, which alters the regulation of cellular differentiation.

In addition, HPV-associated papillomas, especially subtypes 16, 18, and 31, are recognized for their malignant potential.[52] Laryngotracheal papillomatosis has the potential to spread into the lower respiratory tract in up to 5% of cases.