Rare Solitary Benign Tumors of the Lung

James S. Allan
Benign solitary neoplasms of the lung are relatively uncommon but nonetheless must be considered in the differential diagnosis of any solitary pulmonary lesion. Ironically, the advent of improved tomographic imaging and its increasingly broad clinical application have led to a greater recognition of benign solitary pulmonary lesions, presenting the surgeon with a complex management dilemma. Most benign lesions are relatively bland radiographically, making their differentiation from carcinoma difcult. Often, diagnostic certainty can only be achieved with complete resection. Fortunately, advances in minimally invasive thoracic surgery make this prospect less daunting for the patient and surgeon. This article reviews a subset of solitary lesions categorized as rare benign neoplasms from histologic, radiographic, and clinical points of view. 2003 Elsevier Inc. All rights reserved. Key words: Lung, neoplasm, tumor, benign, solitary.

he seemingly straightforward presentation of a patient with a small, asymptomatic solitary lung nodule raises one of the more difcult clinical situations that a thoracic surgeon is likely to encounter. In this scenario, it is incumbent upon the surgeon not only to exclude malignancy with a high degree of certainty but also to do so with a minimum of intervention. Moreover, most patients facing this situation expect a surgeon to provide them with a clear diagnosis, but few are prepared at the outset to undergo a potentially morbid operation simply to rule out a malignancy. This conundrum is further intensied when the lesion is radiographically bland, when the patient has a slightly increased risk for lung cancer, and when comorbidities are present that would make operative intervention less desirable. This article reviews a group of rare pulmonary neoplasms that typically present as solitary lesions. For the most part, these lesions are asymptomatic and radiographically indistinct from many common neoplasms. Because of these traits, the majority of these diagnoses are only obtained after excisional biopsy, which is typically curative. Notably excluded from this review are
From the Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, and the Harvard Medical School, Boston, MA. Address reprint requests to James S. Allan, MD, Massachusetts General Hospital, Blake 1570, 55 Fruit Street Boston, MA 02114. 2003 Elsevier Inc. All rights reserved. 1043-0679/03/1503-$30.00/0 doi:10.1016/S1043-0679(03)

the more common benign pulmonary lesions, including hamartomas, benign brous tumors of the pleura, granulomas, and other inammatory nodules, all of which are considered elsewhere.

Historical Notes
The rst major series addressing the issue of the asymptomatic solitary pulmonary nodule was published in 1963 by Steele.1 Steele compiled histologic data from 882 male patients who underwent pulmonary resection. In this study, he found that 36% of the resected lesions were malignant, while 64% were benign. Granulomas represented the overwhelming majority of the benign lesions. The relatively high incidence of benign granulomas (often tuberculous in etiology) in this series is both a reection of the patient population and the era in which the study was conducted. Also, this study was performed before the advent of computerized tomography (CT), and therefore, it only included asymptomatic lesions that were large enough to be seen on plain chest radiography. If Steeles data set is limited just to true benign solitary neoplasms of the lung and tracheobronchial tree (excluding benign brous tumors of the pleura), these benign neoplasms constitute approximately 10% of the resected neoplasms. Moreover, 94% of these neoplasms were found within the lung parenchyma, with only 6% occurring endobronchially. In a later series from the Mayo Clinic, Arrigoni and colleagues described the relative frequencies of some of the more common, benign 315

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Table 1. Relative Frequencies of Benign Lung Neoplasms2 Hamartoma Benign brous mesothelioma Inammatory pseudotumor Lipoma Leiomyoma Hemangioma Adenoma Mixed tumor Total 100 16 7 2 2 1 1 1 130

lung neoplasms.2 These data are described in Table 1. As seen, the pulmonary hamartoma is the most commonly encountered benign solitary pulmonary neoplasm, accounting for over threefourths of the benign neoplasms resected. The next most common neoplasm reported by Arrigoni et al is the benign mesothelioma, which is now more commonly called a benign brous tumor of the pleura.2 Once these 2 lesions are excluded, only a handful of rare tumors remain. Although there is no recent autopsy series or case study that adequately addresses this issue, it is likely that the apparent prevalence of rare benign tumors will grow as the use of high-resolution CT increases.

They have been subclassied as (1) solitary benign papillomas; (2) multiple benign papillomas; (3) benign combined bronchial mucous gland and surface papillary tumors; and (4) bronchial papillomas. In addition, there is a fth variant, which is in fact malignant, known as the papillary bronchial carcinoma in situ. This subsection will be conned primarily to the solitary benign papilloma. Most commonly, solitary papillomas are seen in the proximal airway. In the pediatric population, these lesions often present in the larynx, while in the adult population, these lesions typically originate in the upper trachea. Only a handful of cases have been seen distal to the carina, and these bronchial papillomas have a high association with subsequent bronchial carcinoma.4 Also, the solitary papilloma appears to be more common in the adult male population, while children tend to present with multiple papillomatous lesions.5 Histologically, the more proximal benign papillomas tend to be pedunculated with a thin central brovascular core covered by a stratied squamous epithelium. The more distal lesions

Table 2. Classication of Benign Lung Tumors

Classication of Benign Lung Tumors

Liebow made the rst attempt at classication of benign lung tumors at Yale University,3 and a modication of Liebows original nosology was adopted by the World Health Organization (Table 2). This classication schema was based primarily on the presumed cell of origin of the neoplasm and has evolved to take advantage of our better understanding of cell ultrastructure with the use of electron microscopy. Also, over the years, several neoplasms originally thought to be benign are now properly recognized as low-grade malignancies and have been reclassied (eg, bronchial adenomas, pulmonary blastoma, tumorlets, hemangiopericytomas, and mucosa-associated lymphoid tumors).

Benign Solitary Neoplasms of Epithelial Origin Papillomas of the Tracheobronchial Tree

Papillomas of the tracheobronchial tree are benign neoplasms of the squamous epithelium.

Epithelial neoplasms Papillomas Benign inammatory polyps Mesodermal Neoplasms Vascular Hemangiomas Lymphangiomas Bronchial Fibromas Chondromas Lipomas Granular cell tumors Sclerosing hemangiomas Leiomyomas Neurogenic tumors Neuromas Neurobromas Neurilemomas Primary pulmonary meningiomas Tumors of developmental or unknown origin Teratomas Chemodectomas Clear cell tumors Intrapulmonary thymomas Inammatory lesions and pseudotumors Inammatory pseudotumors Nodular amyloid

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are typically lined with a mixed epithelium, including glandular elements. It is believed that solitary benign papillomas result from a viral infection with human papilloma virus types 6 and 116 and that there is a small potential for malignant degeneration. The most common presenting symptom of a patient with a solitary papilloma is cough. In addition, patients may present with hemoptysis, wheezing, or recurrent pneumonia. Unless bronchial obstruction has occurred, the chest radiograph is typically normal. Lesions may be identied on CT or plain-lm tomography of the trachea. The diagnosis is readily made on bronchoscopy. Likewise, treatment typically consists of bronchoscopic resection using either conventional rigid bronchoscopic techniques or laser ablation. On a rare occasion, pulmonary resection may be necessary for a distal papilloma.

Benign Inammatory Polyps

Benign inammatory polyps (sometimes termed brous polyps) of the tracheobronchial tree are relatively uncommon and are difcult to differentiate from papillomas. Like tracheobronchial papillomas, benign inammatory polyps have a predilection for the upper respiratory tract. However, they tend to be covered by an epithelium that shows columnar differentiation as well as granulation tissue. Like solitary papillomas, these polyps tend to present with a history of chronic cough and occasional hemoptysis. Signs and symptoms of distal airway obstruction are quite rare. Again, bronchoscopic removal is generally successful.7

Benign Solitary Neoplasms of Mesodermal Origin Hemangiomas

The pulmonary hemangioma is a benign vascular tumor that can be found throughout the respiratory tract. Most commonly, this lesion is seen in the wall of the trachea or a mainstem bronchus. However, it can also be found in the pulmonary parenchyma, usually in a subpleural location. Approximately two-thirds of pulmonary hemangiomas are solitary. When multiple lesions are present, one must suspect the generalized disor-

der of hereditary telangiectasia (Osler-WeberRendu disease). The pulmonary hemangioma is a true neoplasm consisting of a cluster of thin-walled vessels with little supporting stroma. The term cavernous hemangioma is sometimes used to refer to a hemangioma that has a cystic central component, often lled with a serosanguineous uid. The term sclerosing hemangioma is a misnomer and will be considered later in this article. When found in the central airway, the hemangioma is readily identied on bronchoscopy and is seldom obstructing. Some investigators have recommended Nd:YAG laser ablation due to its propensity to bleed with classic bronchoscopic resection techniques.8 Hemangiomas are also known to regress with focal radiation therapy, if surgical ablation is not practical. When located in the pulmonary parenchyma, the solitary hemangioma tends to be a sharply circumscribed rounded lesion with strong contrast enhancement on CT. This result gives the hemangioma a radiographic appearance that is quite similar to that of some contrast-enhancing malignant lesions, such as carcinoid. A conservative wedge resection is the preferred treatment of parenchymal hemangioma. An important distinction must be made between the true hemangioma and arteriovenous malformations (AVM). AVM are not true neoplasms but rather are congenital vascular anomalies.9 Pulmonary AVM are generally asymptomatic solitary nodules typically found in the lower lobes. Contrast-enhanced CT will typically show a vessel providing arterial inow and another vessel providing venous drainage. Because the vascular inow is typically derived from the pulmonary circulation, a large, pulmonary AVM may be associated with signicant right-to-left shunting, creating clinical signs such as cyanosis, clubbing, and polycythemia.9 Like true hemangiomas, there is an association between multiple pulmonary AVM and hereditary telangiectasia.

Lymphangiomas
The lymphangioma is a relatively uncommon thoracic neoplasm that typically presents in the mediastinum or in the trachea of an infant or child.9,10 Only rarely does a lymphangioma present as a solitary pulmonary nodule. Controversy exists in the literature regarding the demo-

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graphics of the patient population that can be affected by this lesion. Shafer et al have reported the presence of thoracic lymphangiomas in patients ranging in age from 6 months to 67 years, with a slight female predominance.11 In contrast, Wilson and colleagues have found a strong male predominance when only parenchymal lesions were surveyed.12 Histologically, the lymphangioma is a benign collection of proliferative, intercommunicating lymphatic vessels that lack systemic lymphatic communication. Cystic and cavernous features can sometimes be seen. It is most commonly found in the neck, where it referred to as a cystic hygroma. This benign lesion appears to be congenitally acquired and is hypothesized to represent the simplest extreme of a spectrum of lymphatic disorders that share a common pathogenesis, including lymphangiomatosis, lypmhangiectasis, and the syndrome of lymphangiomyomatosis. Although tracheal lesions in the pediatric population can result in pneumothorax and respiratory distress, the solitary parenchymal nodule is generally asymptomatic, although hemoptysis has been reported.13 Radiographically, these lesions typically appear as a smooth cystic mass, although spiculation has been described occasionally.12 Wedge resection of solitary pulmonary lesions appears to be curative.

Chondromas
Chondromas (and the related osteochondromas) are the second most common benign pulmonary tumors of mesenchymal origin.14 They are typically found in association with the cartilaginous wall of a large bronchus. Histologically, they are distinct from endobronchial hamartomas in that they lack the other tissue elements that are typically found in a hamartoma. These lesions are generally asymptomatic unless they become obstructing. The treatment of these lesions is similar to that described for benign bromas.

Lipomas
The lipoma is perhaps the rarest of the benign lung neoplasms, and most thoracic surgeons will never encounter this lesion. However, the pulmonary lipoma was ironically one of the rst lung lesions ever reported in the medical literature by Rokitansky in 1854.16 These lesions typically occur in middle-aged males and are slow growing. They arise endobronchially and can either be in a central or peripheral location. Treatment is generally accomplished by either endoscopic resection or parenchymal wedge resection, as appropriate.17,18

Granular Cell Tumors

Granular cell tumors (granular cell myoblastomas) are benign neoplasms composed of large ovoid or polygonal cells that take up periodic acid-Schiff stain. Originally thought to be derived from skeletal muscle tissue, they are now believed to be of Schwann cell origin. Deavers and colleagues reviewed a series of 20 patients, ranging in age from 20 to 57 years, with granular cell tumors.19 There was no sex predilection for this tumor. Also, in approximately half the cases, the tumors were asymptomatic and incidentally discovered. Most of these lesions were solitary and were typically found adjacent to a large bronchus. A parenchymal sparing pulmonary resection is the treatment of choice. However, the surgeon must be attentive to achieving complete resection because the recurrence rate for this lesion is high in the absence of complete excision.20

Fibromas
Pulmonary bromas are benign lesions arising at any level from the walls of the tracheobronchial tree. Fibromas typically account for less than 1/10 of 1% of all resected pulmonary tumors. However, despite its rarity, the benign broma is the most common of the mesenchymal benign tumors.14 Histologically, these lesions are made of benign-appearing spindle cells with an abundance of collagen. Occasionally, these lesions may have a more myxomatous appearance. Peripheral bromas are typically asymptomatic, while those occurring in the more proximal bronchi can present with symptoms of respiratory tract obstruction.15 Because these tumors are relatively avascular, airway lesions are easily treated with bronchoscopic resection, and peripheral lesions can be excised with parenchymal-sparing techniques.

Sclerosing Hemangioma
As mentioned previously, the sclerosing hemangioma is a bit of a misnomer. This lesion was rst

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reported by Liebow and Hubbell in 1974 and has been the subject of some controversy in the eld of pulmonary pathology.21 In particular, some pathologists, on the basis of immunohistochemical studies, have asserted that the sclerosing hemangioma may occur from the type 2 alveolar pneumocyte rather than a vascular mesenchymal cell.22,23 Sclerosing hemangiomas typically present as well-dened rounded masses arising in the periphery of the lung. They most commonly occur in the lower lung elds of middle-aged women. Occasionally, partial calcication may be seen. In a recent series, this neoplasm was identied in approximately 1% of 919 patients who underwent pulmonary resection over a 17-year period, making this lesion second in prevalence to pulmonary hamartomas.22 Sclerosing hemangiomas are easily shelled-out at operation, and there have been no reports of recurrence following parenchymalsparing resection of this lesion.

quite uncommon in the parenchyma of the lung itself.26 The thoracic literature contains scant reports of benign neurogenic tumors occurring centrally and peripherally within the tracheobronchial tree. These tumors have included neuromas, neurobromas, and neurilemomas (schwannomas). Like most other benign tumors of the lung, symptomology depends on the location of the lesion. Therapy is either conservative parenchymal resection or endoscopic removal/ ablation, as appropriate.27,28

Primary Pulmonary Meningiomas

Meningiomas presenting in the pulmonary parenchyma are often metastatic from an intracranial source. Nonetheless, there have been scattered reports of primary pulmonary meningiomas, which typically present in older women. These lesions are usually well-circumscribed nodules and have been reported to be as large as 6 cm. The treatment of pulmonary meningiomas consists of conservative surgical excision, and the prognosis is excellent.29,30 Nonetheless, the nding of a meningioma in the lung mandates careful evaluation to exclude an intracranial lesion.31

Leiomyomas
Leiomyomas are an uncommon benign tumor of mesodermal origin, although the exact incidence is difcult to determine. Originally, leiomyomas were thought to be the fourth most common benign mesodermal tumor of the lung.14 However, more recent series suggest that this lesion may be more common.24 The majority of these lesions present as incidentally found, asymptomatic peripheral solitary pulmonary nodules. Approximately two-thirds of patients who are affected are female.25 It is hypothesized that pulmonary leiomyomas originate from the smooth muscle present in either the bronchial walls or the bronchial arteries. The histologic appearance is quite similar to leiomyoma found elsewhere in the body. The solitary leiomyoma of the lung should not be confused with a clinically distinct entity known as benign metastasizing leiomyomas, which some believe to be of uterine origin, traveling to the lung via a hematogenous route. Because most solitary leiomyomas are asymptomatic, parenchymal-sparing wedge resection is usually sufcient therapy.

Tumors of Unknown or Developmental Origin Teratomas

Teratomas are common anterior mediastinal masses. However, they occur only rarely as a primary lung lesion. It is difcult to determine the exact frequency of pulmonary teratoma because many investigators may have erroneously reported mediastinal teratomas extending into the lung as primary pulmonary lesions.32 Teratomas have the characteristic histologic feature of containing tissue derived from all 3 germ cell layers. Calcication and sebaceous matter are not uncommonly identied in these tumors. The majority of pulmonary teratomas have been found in the anterior segment of the left upper lobe, and resection has proven to be curative.

Neurogenic Tumors
Neurogenic tumors occur with high frequency in the posterior mediastinum. However, they are

Chemodectoma
Tanimura and colleagues have reported a total of 24 cases of primary pulmonary paraganglioma

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(chemodectoma) extant in the literature.33 For the most part, these lesions tend to be solitary and can grow to be quite large.34 When small, these neoplasms are typically asymptomatic. However, compressive symptoms can develop in patients as these tumors grow. Again, conservative pulmonary resection is considered curative. One should also recognize that the solitary chemodectoma is distinct from a related pathologic condition of multiple small tumors, known as minute chemodectoma tumors, described by Torikata and Mukai.35

Inammatory Lesions and Pseudotumors Inammatory Pseudotumors

The term inammatory pseudotumor includes a fairly wide histologic spectrum of diseases that have been variably termed plasma cell granuloma, histiocytoma, xanthoma, xanthobroma, xanthogranuloma, and mast cell granuloma. Various attempts have been made to subclassify these pseudotumors based on their histology. However, the rarity of these lesions makes this effort difcult.42,43 In general, these benign tumors are composed of a mixture of plasma cells, lymphocytes, and varying quantities of brous tissue. They are typically found as solitary pulmonary nodules presenting in children younger than 16 years of age. There is a slight female predominance.44 Although corticosteroids45 and radiation therapy46 have been used to treat those lesions that could not be completely resected, conservative surgical excision is generally sufcient therapy. The pseudolymphoma is not considered here because it is now generally regarded as a low-grade, mucosa-associated lymphoid tumor.

Clear Cell Tumors of the Lung

A total of approximately 35 clear cell tumors of the lung have been reported in the world literature.36-38 Most of these patients were in their fth or sixth decades of life and presented with asymptomatic, peripheral solitary pulmonary nodules. There was no sex predilection among these patients, and these tumors were reported to shellout easily from the surrounding parenchyma. There is a single report of the malignant degeneration of a clear cell tumor in a patient who ultimately died of metastatic disease.39 Histologically, the clear cell neoplasm consists of cells with abundant cytoplasmic glycogen with interspersed neurosecretory granules, suggesting that this unusual tumor may originate from Kulchitsky cells. This tumor has also been given the eponym sugar tumor of the lung.

Nodular Amyloid
Primary amyloidosis of the lung can present as a localized solitary parenchymal lesion or as a sessile endobronchial tumor near the orices of segmental bronchi.1 These parenchymal tumors are commonly identied at thoracotomy for a suspected malignancy, and treatment with conservative surgical resection is generally adequate. The endobronchial lesion can be addressed by endoscopic resection or laser ablation.

Intrapulmonary Thymomas
Thymomas are common tumors of the anterior mediastinum. However, ectopic thymic rests exist in both the lung hila and the peripheral parenchyma.40 Occasionally, these ectopic thymic rests will become thymomatous. The optimal treatment for these rare intrapulmonary thymomas has not been dened. However, a recent histopathological examination of one such case suggests that these lesions can spread through the normal lymphatic drainage of the lung. Therefore, treatment strategies analogous to that of lung cancer, including formal lobectomy and lymph node dissection, have been advocated.41 These tumors are also known to be radiation-sensitive if surgical resection is not possible.

Conclusions
In the United States, approximately 150,000 new solitary pulmonary nodules (dened as lesions less than 3 cm in diameter) are identied each year.47,48 The incidence of malignancy among these nodules is quite variable, ranging from 10% to 70% in published series.49-55 Therefore, it is important for the surgeon to be thoroughly familiar with the differential diagnosis of the solitary pulmonary nodule and to develop strategies for diagnosis that do not rely on excisional biopsy.

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Table 3. Malignancy Likelihood Ratios for Various Clinical and Radiographic Characteristics57 Characteristic Age 60-69 yrs. Nonsmoker 30 Pack/yr. 30-39 Pack/yr. 40 Pack/yr. Hemoptysis Previous malignancy 0-1.0 cm 1.1-2.0 cm 2.1-3.0 cm 3.0 cm Likelihood Ratio 2.64 0.15 0.74 2.00 3.70 5.08 4.95 0.52 0.74 3.67 5.23 Characteristic Lobulated mass Spiculated mass Malignant growth rate Not calcied Benign calcication CT enhancement 15 HU CT enhancement 15 HU PET SUR* 2.5 PET SUR 2.5 PET-positive PET-negative Likelihood Ratio 0.74 5.54 3.40 2.20 0.01 0.04 2.32 0.06 7.10 4.30 0.04

Abbreviations: SUR, standardized uptake ratio.

The rare benign tumors described here collectively account for less than 1% of all solitary pulmonary nodules, with hamartomas, granulomas, and other inammatory lesions comprising the remainder of the benign lesions. Hamartomas and granulomas often have characteristic radiographic features, particularly regarding specic patterns of calcication or fat inclusion.56 These specic ndings may correctly prompt the surgeon to pursue a nonoperative approach in the management of these lesions. Unfortunately, the less common benign lung neoplasms reviewed here all tend to be radiographically bland and will most likely be identied in the course of a resection undertaken to rule out malignant disease. Fluorodeoxyglucose-positron emission tomography (FDG-PET) is the one current modality that holds the promise of limiting the need for surgical excision of solitary nodules of unknown character. Presently, FDG-PET is extremely sensitive and has a strong negative predictive value when applied to nodules more than 1 cm in diameter. The utility of PET in determining a care plan is greatest when the PET data are incorporated into a Bayesian risk analysis model that assesses the risk of malignant disease for a given patient. Table 3 lists a series of likelihood ratios for malignancy derived from one particular case series, considering a variety of clinical and radiographic characteristics, including PET avidity.57 Although Bayesian analysis is imperfect in its application (largely because most risk factors are not statistically independent), this approach begins to quantify and standardize the risk-benet analyses that clinicians have performed subjectively for many years.

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