Neoplastic and Nonneoplastic Benign Mass Lesions of the Lung Open Access

These epithelial proliferations can be divided into those that involve the large airways and those that arise more distally. Squamous papillomas occur in the large airways and are generally exophytic proliferations that can partially occlude the airway. They are associated with human papillomavirus; they can be seen in both pediatric and adult patients but are more frequently encountered in the pediatric population. Involvement of the lower respiratory tract without involvement of the upper tract is unusual. Histologically, these proliferations consist of stratified squamous epithelium with surface koilocytic atypia, growing on fibrovascular cores in an arborizing pattern (Figure 1, A and B). Mixed squamous and glandular papillomas are not associated with human papillomavirus and are lesions of the bronchioles; the fibrous cores are lined by columnar and glandular cells, and in some instances, vaguely resemble transitional-type epithelium (Figure 1, C and D). It is important to recognize the bland lining cells of these distal papillomas, as they can be confused with adenocarcinoma.

The main differential diagnosis of papillomas in the large airways is a tumorlike condition known as a fibroepithelial polyp. While the fibroepithelial polyp also has a fibrous core, the arborizing structures are lined with respiratory epithelium. The fibroepithelial polyp is likely a tumorlike condition, a postinflammatory reactive process.

While this tumor has the historical name of hemangioma, electron microscopy and immunohistochemistry have shown an epithelial origin for this tumor.^2,3  It is most frequently a solitary lung nodule, more common in women. Both radiographically and grossly these are well-circumscribed tumors (Figure 2E). While they can be multiple and can involve lymph nodes, sclerosing hemangioma/pneumocytoma is a benign neoplasm clinically.

There are 4 common patterns seen in these tumors: telangiectatic, epithelial/papillary (Figure 2B), solid, and sclerotic (Figure 2A).⁴  Not all tumors have all 4 patterns. It is the telangiectatic hemorrhagic pattern that led to the morphologic classification of this tumor as a hemangioma. While the sclerotic areas are not usually the predominant pattern, it is the combination of sclerosis in a bland papillary and solid-growing tumor that leads to the consideration of this entity, even on frozen section (Figure 2).

The immunohistochemistry profile of this tumor is distinctive, as the combination of cytokeratin and thyroid transcription factor 1 is generally diagnostic (Figure 2C, D). While cytokeratin shows reactivity in the papillary proliferations, the bland solid areas are negative for this marker. In contrast, thyroid transcription factor 1 shows positivity in both the epithelial/papillary pattern and in the solid pattern. While foci can be positive for neuroendocrine markers (which at one point led to the speculation of a neuroendocrine tumor), these are not diffusely positive as in a carcinoid tumor. In addition, solid-growing areas of a carcinoid tumor are generally strongly cytokeratin positive.

While included among epithelial neoplasms, it is not clear that alveolar adenoma is in fact an epithelial neoplasm. Like sclerosing hemangiomas, alveolar adenomas are usually solitary nodules, seen more commonly in women.⁵  The dilated spaces have been described as resembling a lymphangioma, but they are lined by type II epithelial cells. In contrast to the sclerosing hemangioma, the solid-growing interstitial cells are mesenchymal, not type II epithelial cells, and as a result, only the lining cells are immunoreactive with thyroid transcription factor 1.

While a hamartoma is defined as disordered growth of tissues normally present within the organ, pulmonary hamartomas are clonal proliferations and therefore neoplastic. They contain chromosomal rearrangements of 12p15 and 6p21.⁶  Among the benign neoplasms of lung, which are overall rare, hamartomas are the exception. They can occur in the periphery or endobronchially (Figure 3, A) and can vary in size, although they are usually less than 4 cm. Their distinct radiologic appearance (lobulated, “popcorn” calcification) can be diagnostic, therefore avoiding the need for resection.⁷ 

Pulmonary hamartomas contain at least 2 benign/mature mesenchymal tissues, one of which is often cartilage (Figure 3, B). Adipose tissue is also frequently present, especially in central lesions. The epithelium is thought to be entrapped reactive epithelium. In tumors with only 1 mesenchymal element, a corresponding benign mesenchymal neoplasm, such as a lipoma or chondroma, should be the main diagnostic consideration.

While most commonly a tumor of pleura, intraparenchymal solitary fibrous tumor of lung can also occur. Aside from the location, solitary fibrous tumor of the lung is histologically identical to that of the pleura, with the exception that intrapulmonary solitary fibrous tumor has ingrowth of epithelial cells along clefts in the tumor. This can impart a leaflike growth pattern, which should not cause confusion with other neoplasms (Figure 4, A). The bland spindle cell population of a solitary fibrous tumor, alternating with areas of hyalinized collagen, is fairly distinctive; the addition of strong CD34 positivity is confirmatory (Figure 4, B and C).⁸ 

This rare tumor, thought to be derived from perivascular epithelioid cells, warrants mention since its differential diagnosis includes renal cell carcinoma and clear cell melanoma, both of which are malignant tumors. These are solitary, circumscribed nodules composed of clear cells with a low nuclear grade and without necrosis. They are cytokeratin negative and positive for HMB-45.⁹  Significant cytologic atypia should raise the consideration of metastatic clear cell renal cell carcinoma; this point is of even greater significance given the recognition of a subset of renal cell carcinomas with similar immunohistochemical profile.

While improvements in radiologic evaluation and surveillance of nodules have reduced the number of nonneoplastic lesions requiring surgical excision, a significant proportion of mass-forming tumorlike entities are removed at surgery. The addition of positron emission tomography (PET) scanning into the diagnostic algorithm, while offering another modality of evaluation, has not eliminated the need for histologic assessment. This is partly because the most common resected tumorlike lesion is granulomatous; these lesions are persistent, can show interval growth, and are often PET positive. Infectious necrotizing granulomas are the most common, and when results with special stains are positive, acid-fast bacilli and fungi are the commonly identified causes. Fungal organisms such as Histoplasma, Cryptococcus, Coccidioides, and Blastomyces are found; their relative frequency varies significantly by geographic distribution.¹⁰  Vasculitides, such as Wegener granulomatosis and nodular sarcoid (which can have focal necrosis), are also inflammatory mass lesions in this differential. Among the granulomatous processes, pulmonary rheumatoid nodules can be encountered; these are usually seen in conjunction with articular nodular disease but are, in rare instances, isolated in the lung. A recent report describes rheumatoid nodules in the setting of therapy with anti–tumor necrosis factor α agents.¹¹ 

Pulmonary infarcts can result in a peripheral mass lesion.¹²  When the profile is radiographically classical, and in the correct clinical context of embolic disease, these organize and resolve. However, the fibrous resolution of an infarct can result in a persistent peripheral mass lesion that is sampled to rule out malignancy. While infarcts are not always wedge shaped histologically, their sharp demarcation and association with an abnormal vessel with thrombosis represents strong evidence in favor of the diagnosis (Figure 5, A).

Intraparenchymal lymph nodes are occasionally removed in the setting of a concerning mass lesion. Localized or focal organizing pneumonia, which can have many inciting causes, shows the classic features of organizing pneumonia, that is, intra-alveolar fibroblastic proliferations (Figure 5, B).¹³ 

While these are commonly encountered lesions, as incidental findings in lung tissue resections for other reasons, they are not generally the target lesion of a nodule or mass resection.¹⁴  There are rare cases in which these proliferations exceed 5 mm and are resected for concern of malignancy. They typically expand alveolar walls, imparting a stellate appearance to the lesions (Figure 6, A); the cellular expansion consists of bland cells with indistinct borders in nested and whorled patterns. They are typically positive for epithelial membrane antigen by immunohistochemistry. Despite their name and morphologic similarity, the even rarer true meningioma of the lung appears to harbor different molecular alterations from those of minute meningothelial nodules, raising the question as to whether they actually have related pathogenesis.¹⁵ 

Dense proliferations of lymphocytes in the lung, forming a mass lesion, should be ruled out for lymphoma. With this in mind, areas of lymphoid hyperplasia can form a localized or multinodular mass in lung (Figure 6, B). The inciting trigger for lymphoid hyperplasia has been proposed to be a foreign body/foreign antigen, and this can sometimes be demonstrated. These proliferations are composed of well-formed follicles with organized B-cell and T-cell zones without invasion of pleura or bronchus. Involvement of epithelium can be present, mimicking a lymphoepithelial lesion, but in contrast to B-cell lymphoma, the infiltrating cells are T cells. The plasma cells within the lesion can have Russell bodies but not Dutcher bodies.¹⁶ 

Amyloid¹⁷  can form nodules in lung parenchyma and can be confined to the lung. Amyloid can yield a positive PET signal, and most commonly is of amyloid light chain type. If associated with a cellular infiltrate, plasmacytoma, plasma cell dyscrasia, and plasmacytoid, mucosa-associated lymphoid tissue lymphoma needs to be ruled out. It is unclear whether the neoplastic-associated cases are the PET-positive subset. In addition to the usual stains used to evaluate amyloid (Congo red, crystal violet), a giant cell reaction to the amorphous material, as well as ossification, are often present.

The historical term inflammatory pseudotumor of the lung encompassed 3 entities: (1) focal organizing pneumonia, which we have already discussed; (2) inflammatory myofibroblastic tumor, a true neoplasm with malignant potential; and (3) plasma cell granuloma type. Inflammatory pseudotumor, plasma cell granuloma type, is a description of nodular lesions in the lung, composed of inflammatory cells with a predominance of plasma cells that do not show light-chain class restriction (ie, not a plasmacytoma). It has been proposed that this entity represents a proliferation that is on the spectrum of diseases associated with an increased number of immunoglobulin G4 (IgG4)–positive plasma cells.¹⁸  Originally described in autoimmune pancreatitis, IgG4-positive plasma cells intermixed with fibrosis and obliterative phlebitis characterize these proliferations in several organs including the lung. The spectrum of mass-forming IgG4-related sclerosing disease includes fibroinflammatory masses (some of which resemble pulmonary hyalinizing granuloma, see below); inflammatory pseudotumor, plasma cell granuloma type; and sclerosing mediastinitis.

This is a localized lesion of the lung seen in adults and characterized by a central area of dense, ropy collagen surrounded by a rim of inflammatory cells (Figure 6, C), which are usually lymphocytes.¹⁹  While at low power this can resemble a granuloma, these lesions do not have a rim of histiocytes at the periphery, nor do they have central necrosis or calcification. They are negative for CD34 and therefore do not represent paucicellular solitary fibrous tumor. There is a pleural lesion called calcifying fibrous pseudotumor in which a rim of inflammation is also present, but the center contains dense hyalinized collagen (Figure 6, D) with small calcifications.²⁰  This is seen in young adults and is pleural based, usually visceral pleura.

For bronchial inflammatory polyp (fibroepithelial polyp), see comments in the section discussing papillomas.

This is usually an incidental asymptomatic tracheal and bronchial multinodular growth arising from the cartilaginous components of the airway.²¹  Its distribution along the cartilaginous surfaces of the airway is radiographically and bronchoscopically distinct, sparing the membranous surface of the trachea. Cases that involve the bronchus can cause obstruction necessitating resection. The nodules are composed of cartilage and ossification, with or without adipose tissue. Bone marrow elements can also be seen.

Lesions of nodular fibroelastosis can occur at the apices of the upper lobes of lung as well as the upper portions of the lower lobes. While these lesions yield negative findings on PET scan, their irregular spiculated appearance and their persistence can lead to resection for concern of malignancy.²²  Histologically, apical cap represents a localized area of fibroelastosis that is directly subpleural, extending focally into lung parenchyma. While lesions can be fairly broad and bilateral, multifocality within a given lobe is not generally seen. Fibroelastosis that is associated with multifocality, causing diffuse or multifocal pleural thickening with parenchymal involvement, is outside the spectrum of apical cap/fibroelastosis. In such cases, especially those in which there is a history of pneumothorax, idiopathic pleural parenchymal fibroelastosis needs to be considered,²³  a rare pleural and interstitial lung disease manifested by progressive fibroelastosis.

This is a nonneoplastic lesion of lung tissue that is rolled into or folded into an area of fibrous adhesion between parietal and visceral pleura.²⁴  It is associated with conditions that cause hyalinized parietal pleural plaque with resulting adhesion to the visceral pleura. The lung gets trapped in that adhesion. Asbestos exposure can be the cause of hyalinized plaque. Radiologically, the folded lung shows airways leading into it, with a vaguely radial configuration that has been described as the “comet tail” sign. If the adhesion is removed surgically, the lung can reexpand and the nodule disappears. The histologic profile that remains is often that of relatively normal lung with visceral pleural fibrosis.

A relatively limited number of lung neoplasms are benign, the most common of which is a hamartoma. While pathologists commonly encounter tumorlike conditions, such as granulomas, infarcts, lymph nodes, and organizing pneumonia, a set of unusual proliferations encompassing inflammatory and fibrosing lesions also occur, and their clinical and radiologic overlap with malignant lesions sometimes necessitate resection.