Introduction
Although in practice the terms “tumor” and “neoplasm” tend to be used interchangeably, there is an important and substantial difference between them. A “tumor” need not be a neoplasm (e.g., a granuloma forms a “tumor”), and “neoplasms” do not always form tumors (e.g., lymphangitic carcinoma or leukemia). Entities discussed in this chapter are all benign neoplasms (generally distinguished from malignant neoplasms by their lack of invasion or metastasis) that form tumors. In general, these benign entities are uncommon, accounting for fewer than 5% of resected lung neoplasms. While many are rare, some benign lung tumors are seen with sufficient frequency to pose periodic diagnostic challenges for primary care providers, pulmonologists, radiologists, surgeons, and pathologists alike. In this chapter, we briefly review the clinical and pathologic features of benign lung neoplasms. Nonneoplastic conditions that may mimic tumors on imaging studies (e.g., granulomas, organizing pneumonia) or certain low-grade but fully malignant neoplasms, such as carcinoid tumors, are not discussed.
Clinical Manifestations
Most benign lung tumors present as asymptomatic solitary pulmonary nodules typically discovered on chest radiographs or computed tomography (CT) scans performed for other purposes. A minority cause symptoms due to airway obstruction, bleeding, or compression of other structures. A preoperative diagnosis may be possible based on a combination of imaging studies and either endoscopic or percutaneous needle biopsies, but most are recognized only after surgical resection of a lesion in which the possibility of malignancy could not be categorically excluded.
A decision to proceed with surgical resection in a patient with an unexplained solitary pulmonary nodule is complex and predicated on analysis of various risk factors. Currently recommended approaches include watchful waiting in selected patients. Prediction models for the likelihood of malignancy and Fleischner guidelines for the management of indeterminate pulmonary nodules are very useful in suggesting watchful waiting for nodules at low risk (<10% probability of malignancy). The approach to the solitary pulmonary nodule is also discussed in Chapter 53 . It is worth noting that many benign lung tumors are discovered as solitary pulmonary nodules. As such, individuals with these entities are often evaluated by 18 F-fluorodeoxyglucose positron emission tomography (PET) scans. Contrary to what one might expect, 18 F-fluorodeoxyglucose (FDG) uptake is quite common among benign lung tumors, and the PET scan cannot therefore reliably discriminate benign from malignant lung tumors.
Benign Epithelial Tumors
Papillomas and Adenomas
Solitary Papillomas
Papilloma refers to exophytic endobronchial lesions with a papillary architecture ( Fig. 56-1 ). Most solitary papillomas arise in central large airways (see eFig. 56-1 ); rarely, they arise in smaller bronchioles and present as peripheral nodules. Flieder and associates divided lung papillomas into three categories based on the lining epithelium: squamous cell, glandular, and mixed types. Squamous lesions account for nearly 70% of reported cases and are seen more frequently in men, and are more often associated with cigarette smoking and human papillomavirus (HPV) infection. Associated foci of squamous cell carcinoma in situ are rare, with only a single well-documented example of invasive carcinoma developing in a patient without respiratory papillomatosis (see later). Most patients with papillomas do well regardless of histologic type. Surgical resection is curative. Local recurrences are rare and limited to patients whose papilloma is not completely resected either because they undergo only biopsy or receive a subtotal bronchoscopic removal. The differential diagnosis includes rare endobronchial papillary variants of squamous cell or adenocarcinoma, a distinction that depends on recognition of cytologic atypia and stromal invasion.
Recurrent respiratory papillomatosis (RRP), also termed juvenile laryngeal or laryngotracheal papillomatosis, is a form of HPV-mediated papillomatosis that presents in early childhood. Presenting symptoms include hoarseness, change or loss of voice, cough, and respiratory distress or stridor. HPV types 11 and 6 have been most commonly implicated and are perinatally acquired from mothers with genital infection. Surgical excision or laser ablation are the mainstays of therapy for patients with symptomatic disease. Recurrences are the rule and often necessitate multiple procedures. Squamous cell carcinoma is an infrequent complication but can affect either the upper or lower respiratory tracts.
The lung parenchyma is involved in about 3% of patients with juvenile onset RRP. HPV-11 is especially prevalent in patients in whom peripheral lung disease develops, accounting for nearly 90% in whom testing was performed. The latent period between diagnosis of RRP and recognition of lung involvement is variable, usually 8 to 10 years. Parenchymal disease presents as multiple asymptomatic nodules that may be cystic or solid ( Figs. 56-2 and 56-3 ; see eFig. 54-29 , eFig. 54-30 , eFig. 54-31 ). Symptomatic patients present with cough and various combinations of hemoptysis, dyspnea, fever, and chest pain. Case reports describing significant uptake of FDG in PET scans suggest that lesions of RRP can be very FDG-avid. The histopathologic findings are unique, demonstrating tufts of benign squamous papillomas emanating from distal bronchioles with polypoid extensions into adjacent alveolar spaces ( Fig. 56-4 ). The involved bronchioles are often ectatic, thus mimicking the appearance of cavitation on imaging studies.
Parenchymal lung involvement in patients with RRP is often associated with an aggressive course. There is currently no effective medical therapy. Interferon and cidofovir, an antiviral agent, show inconsistent results; in addition, cidofovir has been implicated as potentially oncogenic. About 15% of patients with parenchymal disease develop squamous cell carcinoma of the lung, with an average age at carcinoma diagnosis of 23 years (see eFig. 54-32 ). No risk factors clearly identify those patients likely to develop lung carcinoma. Nearly two thirds of reported patients have died of disease, many of squamous cell carcinoma.
Adenomas
Historically the term adenoma was applied to a pathologically heterogeneous group of low-grade endobronchial malignancies that included carcinoid tumors and carcinomas homologous to those arising from salivary glands (i.e., adenoid cystic and mucoepidermoid carcinomas). Today the term is restricted to a group of benign neoplasms with variable clinical presentations and histologic appearances.
Endobronchial adenomas include two entities analogous to salivary gland counterparts. Mucous gland adenomas are rare, presenting as potentially obstructing, sessile, endobronchial masses arising at the level of lobar or segmental bronchi. Average age at diagnosis is 52 to 54 years but with a broad age range that extends to childhood. Most patients are symptomatic at the time of diagnosis. The most frequent complaints are cough, shortness of breath, and wheezing, a combination of findings that can be misconstrued as asthma. Some patients are symptomatic for years before the diagnosis is made. Chest radiographs may be normal but more commonly show a solitary pulmonary nodule and/or postobstructive atelectasis or consolidation. CT scans show discrete nodules that may be accompanied by an air-meniscus sign attesting to an endobronchial location. Histologically, mucous gland adenomas are variably solid and cystic, and composed of cytologically bland columnar mucinous cells ( Fig. 56-5 ). Surgical resection, which is often required for diagnosis, is curative.
Pleomorphic adenomas, also termed benign mixed tumors, are biphasic neoplasms composed of stromal and epithelial elements. They usually arise in major salivary glands; there are fewer than 20 well documented examples of primary lung tumors. Primary pulmonary pleomorphic adenomas have been reported more commonly in women than men (ratio 2 : 1), with an average age at diagnosis of about 51 years. Cough is the most frequent presenting complaint and is sometimes associated with postobstructive pneumonia. One third of patients are asymptomatic when a solitary pulmonary nodule is discovered. Eighty percent are found within the larger central airways as polypoid exophytic tumors. Chest radiographs and CT scans show a solitary well-circumscribed solid mass without distinctive features. PET in a single patient showed high FDG avidity. Complete surgical resection with tumor-free margins is curative. As can happen with their salivary gland counterparts, benign pleomorphic adenomas can undergo transformation to malignant carcinoma (carcinoma ex pleomorphic adenoma) . Primary pleomorphic adenoma must be distinguished from so-called benign metastasizing pleomorphic adenoma, a term that refers to rare patients in whom histologically benign salivary gland tumors inexplicably metastasize to various sites, including lung.
Adenomas involving peripheral lung parenchyma are rare. Alveolar adenoma is the most common variant with just under 30 reported examples. Average age at diagnosis is between 50 and 55 years. Nearly all patients are asymptomatic at the time of diagnosis. Radiologically, alveolar adenomas present as well circumscribed peripheral nodules averaging just over 2 cm in greatest dimension. Magnetic resonance imaging may show a cystic space with central fluid and thin-rim enhancement. Pathologically, alveolar adenomas are partially cystic nodules in which connective tissue septa are lined by cytologically bland epithelial cells ( Fig. 56-6 ). The epithelial cells are derived from pneumocytes while the stromal cells are undifferentiated fibroblasts. Cytogenetic studies performed in a single case demonstrated a clonal translocation supporting the conclusion that these are indeed neoplasms, although their behavior is benign.
Papillary adenomas have been described in fewer than 10 patients. All patients in whom the lesion was discovered during life underwent surgical resection for an asymptomatic solitary peripheral nodule and remained free of disease at follow-up. Histologically, papillary adenomas are circumscribed lesions composed of connective tissue fronds lined by bland type 2 pneumocytes ( Fig. 56-7 ).
Mucinous cystadenoma is a rare lung neoplasm that overlaps with unequivocally malignant mucinous adenocarcinomas. Gao and Urbanski proposed separating them into three histologically defined categories: mucinous cystadenoma, mucinous cystic tumor with atypia, and mucinous cystadenocarcinoma. Histologically, benign tumors without atypia accounted for only 13% of reported patients, further emphasizing that this is an extremely rare neoplasm. Patients typically present with slowly growing, well-demarcated, peripheral lung masses that may or may not appear cystic. All patients with histologically benign cystadenomas have remained free of disease after surgical resection.
Micronodular Pneumocyte Hyperplasia
Micronodular pneumocyte hyperplasia is an unusual proliferation of alveolar epithelium seen almost exclusively in patients with underlying tuberous sclerosis complex and/or lymphangioleiomyomatosis. More than 85% of reported patients were women. Radiologic findings are characterized by scattered nodules that are occasionally numerous and distributed in a miliary fashion, with or without the associated cystic changes typical of lymphangioleiomyomatosis (see eFig. 56-2 ). The radiologic abnormalities correspond to ill-defined pale peripheral nodules that are seen either in isolation or in the setting of lymphangioleiomyomatosis ( Figs. 56-8 and 56-9 ). Histologically, micronodular pneumocyte hyperplasia demonstrates circumscribed proliferations of bland pneumocytes cytologically identical to those seen in papillary adenomas, differing in that they are distributed along intact alveolar septa rather than along papillae ( Fig. 56-10 ).
Sclerosing Hemangioma
Sclerosing hemangiomas (SH) are benign lung neoplasms derived from incompletely differentiated respiratory epithelium. The term hemangioma is a misnomer based on pseudovascular blood-filled spaces seen in some cases. SH presents with a female-to-male predominance of 7 : 1. Mean age at diagnosis is the fifth decade of life, although they have been reported in a wide age range including children. More than three fourths of patients are asymptomatic at the time they are discovered to a have solitary pulmonary nodule. CT scans show a well-circumscribed round or oval subpleural nodule with smooth margins and inhomogeneous enhancement (see eFig. 56-3 ). Associated calcifications are present in about one third of patients. Dynamic contrast CT studies show strong, rapid enhancement that rivals the imaging characteristic of malignancies. PET scanning has been reported in only one patient and was characterized by intermediate FDG avidity. Multiple lesions are seen in about 2% of patients. Deposits in regional lymph nodes are rare and have no impact on the fundamentally benign behavior of these lesions.
Resected SH are well circumscribed subpleural nodules averaging 2 to 3 cm in diameter ( Fig. 56-11 ). The histologic hallmark is a heterogeneous appearance resulting from both a mixture of cell types and highly variable growth patterns. Two populations of epithelial cells are a characteristic feature: (1) surface cuboidal cells derived from pneumocytes or club cell (Clara), and (2) pale interstitial round cells with an incompletely differentiated respiratory epithelial phenotype. Molecular studies using a variety of techniques suggest that both populations of cells are neoplastic, an observation that fits with descriptions of both components in nodal deposits. The cells are arranged in various growth patterns that include a focally conspicuous sclerotic stroma that is often calcified ( Fig. 56-12 ).
Recent molecular studies of SH have demonstrated alterations at P16 and RB that resemble those found in early stage adenocarcinomas, supporting an origin from respiratory epithelial cells and suggesting similarities between the molecular pathogenesis of SH and lung carcinoma. However, a more recent molecular analysis of SH failed to identify alterations in some genes (EGFR, HER2, and KRAS) that are commonly mutated in adenocarcinoma, thereby raising doubts about a common link. Genome-wide approaches will likely be necessary to resolve this controversy.
Benign Nonepithelial Lesions
Hamartoma and Related Lesions
Pulmonary hamartomas are the most common benign neoplasm in adults who undergo surgical resection. They are present in less than 0.5% of consecutively autopsied patients. Although the term hamartoma implies that these are tumor-like malformations rather than true neoplasms, recent studies show consistent and characteristic genetic abnormalities indicating that hamartomas are clonal neoplasms.
Pulmonary hamartomas are discovered in men more often than in women by a ratio of 2 : 1 with an average age at diagnosis in the sixth or seventh decade of life. Most patients present with asymptomatic solitary lung nodules with no lobar predilection. Multiple nodules are present in 2% or less of patients. Endobronchial hamartomas (see eFig. 56-4 and 
), more likely to be associated with cough, are seen in about 10% of patients. CT scans show a characteristic combination of calcifications and/or fat in two thirds of patients ( Fig. 56-13 ; see eFig. 54-23 , eFig. 54-24 , eFig. 54-25 , eFig. 54-26 , eFig. 54-27 ). Resection is nearly always curative with rare reports of recurrence or malignant transformation.
Pulmonary hamartomas usually manifest as well-circumscribed nodules, averaging 1.5 to 2 cm in diameter. A variegated cut surface reflects an admixture of stromal elements ( Fig. 56-14 ). Mature hyaline cartilage is an almost universal component and is typically intermingled with mature fat, fibromyxoid tissue, and rare smooth muscle cells ( Fig. 56-15 ). Any of the stromal components can predominate, however, resulting in a histologic spectrum of neoplasms that includes leiomyomas and lipomas . Entrapped nonneoplastic respiratory epithelium often results in a characteristically biphasic appearance, a phenomenon that contributes to relatively high rates of false-positive diagnoses of carcinoma in fine-needle aspiration biopsies (the most common false-positive diagnoses being carcinoid, adenocarcinoma, and small cell carcinoma).
Pulmonary hamartomas, like other benign mesenchymal tumors such as lipoma and leiomyomas, frequently contain chromosomal rearrangements of genes encoding nonhistone chromosomal high-mobility group family of proteins (HMGA family) with AT-hook DNA-binding motifs. These proteins play a broad role in growth, differentiation, proliferation, and death of mesenchymal cells through a mechanism that involves regulation of transcription via modification of DNA conformation. Two main cytogenetic regions containing abnormalities have been defined in pulmonary hamartoma: 6p21 and 12q14-15. The HMGA1 (also known as HMGIY ) gene maps to 6p21.3, whereas HMGA2 (also known as HMGIC) maps to 12q14-15. Their dual role as regulators of mesenchymal differentiation and of gene expression is provocative, although additional work needs to be done to fully elucidate the role of HMGA fusion genes in pulmonary hamartoma.
Pulmonary chondroma, a related cartilaginous lung tumor, constitutes one component of the triad (i.e., pulmonary chondroma, paraganglioma, gastric stromal tumors) described by Carney in 1977. Pulmonary chondromas develop in about three fourths of patients with Carney syndrome and are multiple in half of these. Chondromas are distinct in being purely cartilaginous without the other stromal and epithelial elements characteristic of hamartoma.
Inflammatory Myofibroblastic Tumor
Inflammatory myofibroblastic tumors (IMTs) of the lung comprise a spectrum of lesions ranging from benign spindle cell tumors to frankly malignant sarcomas. Pulmonary IMTs, also termed plasma cell granulomas by Bahadori and Liebow, are defined in the WHO classification of lung tumors as “a subgroup of the broad category of ‘inflammatory pseudotumours.’” The staggering profusion of synonyms that have been applied to these unusual tumors, which also is seen in multiple extrapulmonary sites, reflects the controversy and confusion regarding their pathogenesis and histogenesis.
IMTs of the lung can arise in any age group but tend to affect children and young adults; more than half of patients are younger than 40 years of age at the time of diagnosis. Most patients present with asymptomatic peripheral lung nodules. Endobronchial tumors (see eFig. 56-5 ) account for around 15% of patients and may be accompanied by symptoms of cough and/or hemoptysis. Chest imaging studies typically show a well-circumscribed mass ranging in size from 0.8 cm to more than 30 cm ( Fig. 56-16 , see eFigs. 54-19 and 54-20 and eFig. 56-6 ), with the majority measuring between 1 and 6 cm in greatest dimension. Most primary pulmonary IMTs are cured with complete surgical resection. Incomplete resection is associated with substantial risk of recurrence and rarely locally aggressive behavior and death. COX-2 inhibitors may have therapeutic value in large unresectable tumors, a treatment strategy for which only limited anecdotal evidence is available.
The long list of competing terms for IMTs attests to its histologic diversity. The most consistent histologic finding is a combination of neoplastic spindle cells and a variably dense infiltrate of polyclonal plasma cells ( Fig. 56-17 ). Immunohistochemical and ultrastructural studies show that the spindle cells have features of myofibroblasts, including expression of smooth muscle–associated proteins. ALK1, a tyrosine kinase receptor, is expressed in between a third and a half of lung tumors, is more frequent in young patients, and reflects the observation that ALK is fused to a variety of constitutively activated genes via balanced translocations (see later). Interestingly, absence of ALK expression may be associated with a greater risk for aggressive behavior.
Although the name suggests a nonneoplastic inflammatory tumor, IMTs are actually low-grade neoplasms. Various techniques have identified a range of genetic abnormalities consistent with the neoplastic nature of IMTs. The most consistent molecular alteration is a balanced translocation of the ALK gene locus (2p23). Fusion of a silent gene ( ALK ) with one of several constitutively expressed genes (e.g., TPM3, TPM4, CLTC ) results in aberrant expression of the silent gene that then typically functions as an oncogene. A similar role for ALK gene fusions is observed in anaplastic large cell lymphomas and lung adenocarcinoma. The ALK inhibitor crizotinib has been used successfully to induce at least a partial response in a patient with IMT bearing an ALK rearrangement. The role of human herpesvirus 8 in the pathogenesis of IMT is controversial and uncertain.
Solitary Fibrous Tumor
Solitary fibrous tumors (SFTs), formerly referred to as localized fibrous mesotheliomas, are mesenchymal neoplasms that frequently arise from the pleura. SFTs are not unique to the pleura, however, and have been described in the parenchyma of the lung (intrapulmonary SFT), in the mediastinum, and in numerous extrathoracic sites.
Pleural and intrapulmonary SFTs affect men and women equally. Mean age at diagnosis is the sixth decade of life. Just more than half of patients are symptomatic with presenting complaints that include chest pain (25%), shortness of breath (15%), and/or cough (12%), attesting to the often large size of these tumors. Clubbing is present in about 2% of patients. A paraneoplastic syndrome of hypoglycemia is rare and results from tumor production of insulin-like growth factor. Imaging studies show large intrathoracic masses with an average maximum diameter of between 8.5 and 10.5 cm. Chest imaging studies show a lobulated and sharply marginated mass with a broad base abutting the chest wall, frequently associated with compression of surrounding structures ( Fig. 56-18 , see eFigs. 56-7 through 56-11 and 
). Heterogeneous attenuation and heterogeneous enhancement are characteristic (see eFig. 56-7 and 56-9 ). Calcifications are rare. Most pleural and intrapulmonary SFTs behave as benign neoplasms. Patients with histologically benign tumors are cured with complete surgical excision. A more aggressive course is seen in just over 10% of patients and is limited to those who either undergo incomplete surgical excision or have histologically malignant tumors ( malignant SFT , see eFigs. 56-12 and 56-13 ).
SFTs are three times more likely to arise from visceral than parietal pleura (see eFig. 56-11 ). Those arising from visceral pleura are frequently pedunculated and attached to the lung surface by a connective tissue pedicle ( Fig. 56-19 ). Occasional examples arise within the fissures, resulting in a radiologic appearance difficult to separate from an intrapulmonary tumor (see eFig. 56-11 ). Parietal pleural lesions are more commonly sessile with a broad base of attachment to chest wall, diaphragm, or mediastinum. Histologically, SFTs are variably cellular spindle cell neoplasms with a collagenous stroma. Malignant variants are larger, more likely to have an invasive growth pattern, and more cellular with associated cytologic atypia, increased mitotic rates, and necrosis.
Recent discovery of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumors provides a genetic signature helpful in separating SFT from other intrathoracic spindle cell neoplasms. Commercially available antibodies for STAT6 provide a useful diagnostic tool for routine clinical practice.
Meningothelial-Like Nodules and Intrapulmonary Meningioma
Pulmonary meningothelial-like nodules (MLNs), historically termed chemodectomas , present in less than 5% of autopsies but are frequently seen as incidental findings in surgical specimens from adults. MLNs are more common in women and are seen with greater frequency in patients with chronic lung diseases, including chronic interstitial pneumonias and thromboembolic disease. A rare syndrome of multiple bilateral MLNs ( diffuse pulmonary meningotheliomatosis ) has been described in women who present in the sixth to eighth decade of life with multiple nodules seen on CT (see eFig. 54-28 ). Half complain of dyspnea and/or cough at presentation. Microscopically, MLNs are composed of nests of epithelioid cells that are histologically and immunophenotypically indistinguishable from meningothelial cells of the central nervous system ( Fig. 56-20 ). Despite this unexplained phenotypic overlap, molecular studies demonstrate significant differences between MLNs and conventional central nervous system meningiomas.
