Tumors of Epithelial Origin
This lesion is usually peripheral in location and appears with approximately equal frequency in both men and women who have a history of heavy smoking. It appears to have a predilection for the right lung. It occurs in the fifth or sixth decade of life and usually is discovered incidentally on a chest radiograph.
This is a unilocular cystic lesion with a fibrous wall and mucinous contents. The relatively bland, cuboidal-to-columnar mucinous epithelium may be sparse or detached. There is no association of cystadenoma with larger airways, and it lacks the ciliated lining, bronchial glands, and cartilage of a bronchogenic cyst. Immunophenotypic and ultrastructural characteristics are nonspecific and of limited utility in the differential diagnosis. A cytokeratin 7-positive, cytokeratin 20-negative phenotype, however, may help to distinguish it from metastatic disease (Fig. 91-7).
Photomicrograph of a mucinous cystadenoma.
On chest radiograph, cystadenomas are well-demarcated singular cystic masses located mostly in the periphery of the lung parenchyma. On CT scan, they appear as homogeneous masses with a smooth margin (Fig. 91-8).
CT image of a mucinous cystadenoma.
Treatment is complete surgical excision with excellent prognosis. Since these lesions may harbor areas of cellular atypia, in situ malignancy, or invasive adenocarcinoma, complete excision is necessary, and careful postoperative histopathologic examination is imperative.26
Alveolar adenomas are very rare, and the largest series reported in the literature consists of only a few patients. These tumors are, on average, 2 cm in diameter, well encapsulated, and can be shelled out easily from the surrounding lung parenchyma. They present more commonly in women between the fifth and seventh decades of life. Usually asymptomatic, most are discovered on routine chest radiograph. Patients can present with chronic, insidious cough, usually nonproductive, but shortness of breath or obstructive symptoms are rare.
These benign lesions arise from a joint proliferation of alveolar epithelium and septal mesenchymal cells. Grossly and microscopically, they are well circumscribed and multicystic. The epithelium is predominantly composed of type II pneumocytes. It is still unclear whether the mechanism of origin involves proliferation of a single primitive cell with dual differentiation or independent proliferation of both cell types. Alveolar adenoma must be distinguished clinicopathologically from atypical adenomatous hyperplasia (a preneoplastic lesion also confusingly called bronchioloalveolar adenoma), lymphangioma, and congenital adenomatoid malformation.
Alveolar adenomas usually are identified on routine chest radiographs as solitary nodules located in the midlung fields. The tumor margins are well demarcated, and they are usually noncalcified. On CT scan, they appear as small, homogeneous nodular areas of ground-glass opacity. A cystic component to the tumor sometimes can be seen on CT scan.
Definitive diagnosis by bronchoscopy is difficult because of the peripheral location of most tumors. Because the radiographic presentation of the tumor is nonspecific, definitive diagnosis requires accurate recognition of the characteristic histologic features of the tumor.
Surgical excision via VATS (preferably) or open thoracotomy appears to be curative. Wedge resection is the procedure of choice, but lobectomy also has been reported (Fig. 91-9).
CT image of an alveolar adenoma.
Tumors of Mesenchymal Origin
These benign tumors of the lung comprise 2% of all benign lung lesions and are found half the time in an endotracheal or endobronchial location and half the time in a parenchymal location. They are more common in females and in young adults.
Most endobronchial leiomyomas cause hemoptysis, which leads to their discovery. The parenchymal ones are usually discovered incidentally on a chest radiograph. The parenchymal lesions are solitary masses that have variable sizes. As in leiomyomas of other organs, pulmonary tumors show sweeping fascicles of bland spindle cells with moderate eosinophilic cytoplasm and cigar-shaped nuclei. They are typically well circumscribed (Fig. 91-10).
Photomicrograph of leiomyoma at 100× magnification. The presence of smooth muscle cells is characteristic.
Occasionally, leiomyomas are observed in young women with uterine leiomyomas, but in these cases, they are considered to be evidence of metastatic disease and can even prove fatal. Recent studies have demonstrated the presence of unique periglandular cells in the stroma of these metastasizing leiomyomas. These cells lack the conventional immunohistochemical characteristics of normal lung smooth muscle cells but stain positively for a variety of unique markers such as CD 10, CD 34, alpha smooth muscle actin, estrogen receptor, and progesterone receptor. It has been speculated that interactions of such cells actually may induce glandular metaplasia in the entrapped pulmonary epithelium seen in these tumors.
Treatment of metastasizing pulmonary leiomyomas requires surgical removal, chemotherapy, and hormonal manipulation. Recent approaches to hormonal manipulation with estrogen-receptor modulators and aromatase inhibitors have proved successful and have obviated the need for oophorectomy. Nonsurgical treatment is preferred if the nodules are multiple and diffuse.
The more common, nonmetastasizing endobronchial lesions are treated with endoscopic laser ablation, simple endoscopic removal, or sleeve bronchoplasty, provided that the distal lung tissue is not destroyed. Parenchymal leiomyomas are treated with complete surgical resection.
Intrapulmonary Fibrous Tumor
This tumor arises from the mesenchymal layer of the visceral pleura and extends into the lung parenchyma. These tumors, however, are not derived from the mesothelium, are not related to asbestos exposure, and do not show mesothelial differentiation. Nonetheless, when an intrapulmonary fibrous tumor is encountered, mesothelioma is the main differential diagnostic consideration.
These intrapulmonary fibrous lesions tend to be well circumscribed, with firm white cut surfaces. Histologic examination reveals that the tumors are composed of spindle cells with oval nuclei and diffuse fine chromatin, surrounded by dense bundles of collagen in less cellular areas. Variable cellularity and branching or “staghorn” blood vessels are common features helpful in the identification of intrapulmonary fibrous tumor. The cells stain for vimentin and CD 34, the latter of which is particularly helpful in excluding mesothelioma from the differential diagnosis.27
The most characteristic radiographic finding of these lesions is the obtuse angle that they make with the chest wall, thus revealing that they arise from the pleura and not the lung. In fact, they have also been reported in the retroperitoneum, mediastinum, and on the parietal surface of the stomach or intestine. They can become quite large, although most are less than 10 cm in diameter.
Treatment is usually surgical resection, which is considered curative. Most commonly, resection is done with VATS because most tumors are pedunculated, and their complete removal is easy. It is important to examine the resected tumor carefully after surgical excision because a malignant variant has been reported.
These are rare lung tumors that are thought to form from pulmonary arteriovenous malformations, and their presence raises suspicion of the possibility of hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu syndrome). MRI is the most accurate way to detect and evaluate them. Solitary lesions are surgically excised. If the lesion is endobronchial, a sleeve resection of the involved bronchus is indicated.
This rare benign lung tumor, most likely of epithelial origin, demonstrates evidence of bronchiolar and alveolar pneumocyte differentiation. The tumor can present between the second and seventh decades of life and has a strong predilection for middle-aged women. It is usually asymptomatic (75% of cases), but symptomatic patients present with chest pain, dyspnea, or hemoptysis. The tumor appears as a solitary nodule on chest radiography and is found most commonly in the lower lobes.
Typically sharply circumscribed, variants of the tumor also may demonstrate multifocality, satellite nodules surrounding a large central lesion, or even nodal metastases. Under the microscope, four basic architectural patterns may be identified: papillary, sclerotic, solid, and hemorrhagic. Round stromal cells and surface lining cells are present, and both may show immunoreactivity to epithelial membrane antigen. Complete surgical resection is curative, and although a minority may metastasize to regional lymph nodes, this does not seem to affect the overall prognosis.
Pulmonary Capillary Hemangiomatosis
This condition represents an aggressive benign tumor of the lung that consists of multiple capillaries proliferating slowly but diffusely in the lung parenchyma, involving the pulmonary vessels and the smaller airways in this proliferation. This results in the development of pulmonary hypertension and eventually in right-sided heart failure. The diagnosis can be made radiographically by observing the typical reticulonodular pattern that characterizes the affected lung. The only treatment available is bilateral lung transplantation because single-lung transplantation has been reported to be inadequate for treating this process.28
Tumors of Inflammatory Origin
Inflammatory Pseudotumor (Inflammatory Myofibroblastic Tumor)
Inflammatory myofibroblastic tumor is an uncommon lesion of borderline malignant potential (low-grade malignancy). It is most likely caused by an excessive inflammatory response to tissue injury and it is frequently preceded by an upper respiratory tract infection. In fact, an organizing pneumonia can function as the nidus for formation of the pseudotumor. The lung is the most common site of occurrence, but it may be seen in the small and large bowel mesentery, omentum, mediastinum, retroperitoneum, and other locations.
Inflammatory myofibroblastic tumor usually presents in children and young adults with no sex or racial predilection. In appearance, it is a firm, nonencapsulated, white or yellow mass. Patients can present with cough, dyspnea, chest pain, wheezing, or hemoptysis. Forty percent of cases are asymptomatic and can be detected by finding solitary nodules on routine chest radiographs or CT scans of the chest.
The mass size varies from 1 to 10 cm, and sometimes it is accompanied by hilar or mediastinal lymphadenopathy, pleural effusion, or distal atelectasis resembling bronchogenic carcinoma. Nevertheless, unlike bronchogenic carcinoma, inflammatory pseudotumors tend to be well circumscribed. Definitive diagnosis usually requires surgical biopsy.
Histologically, they are characterized by a mixture of spindle and inflammatory cells, including plasma cells. Immunohistochemically, the spindle cells express smooth muscle actin, vimentin, and sometimes activin-like kinase receptor 1 (ALK1). The inflammatory cells are polyclonal, which is a critical point in separating these tumors from lymphoma or plasmacytoma (Fig. 91-11).
Photomicrograph of an inflammatory pseudotumor.
The tumors seem to follow two patterns of biologic behavior. One tumor group is aggressive, attains large sizes, has a higher number of inflammatory cells on histologic examination, and tends to invade adjacent structures such as the pulmonary vessels or the diaphragm. The other, more common, group consists of tumors that tend to remain small, do not invade local tissues, and have a smaller number of inflammatory cells.
Treatment is complete surgical excision. Incomplete removal of the tumor may lead to recurrence. Overall prognosis is excellent. For unresectable or multiple lesions, radiation, chemotherapy, or steroids can be used with variable success. Spontaneous regression is seen occasionally in children.
Hyalinizing granuloma is a rare benign pulmonary tumor of dense hyalinized connective tissue that develops in response to inflammation. Most patients have a previous history of fungal or mycobacterial infections that could induce tumor formation or a history of some autoimmune disease. The presence of hyalinizing granulomata also can follow systemic diseases such as multiple sclerosis or systemic idiopathic fibrosis. They can occur at any age from young adults to the elderly, and there is no sex predilection.
Patients either can be asymptomatic or present with a combination of cough, chest pain, dyspnea, and occasionally, weight loss. Lesions can be solitary or multiple but are usually bilateral. The tumor size is also highly variable from a few millimeters to several centimeters. Treatment is usually surgical excision (Fig. 91-12).
CT image of a hyalinizing granuloma.
Tumors of Miscellaneous Origin
Nodular amyloid is part of a spectrum of amyloid lesions associated with the lung that includes a tracheobronchial amyloid type and a diffuse interstitial pulmonary amyloid type. Nodular amyloid is found most commonly in the lower lobes as single or multiple nodules of amyloid surrounded by giant cells and is not associated with systemic amyloidosis. Lesions also can be asymmetric and bilateral. Both sexes are equally affected, and the disease can present at any age, with the sixth and seventh decades of life being most common. The histologic appearance reveals eosinophilic deposits with “apple green” birefringence after staining with Congo Red and examination under polarized light. The nodules may calcify, or metaplastic bone or cartilage formation may occur, and inflammatory cells are often present in the background (Fig. 91-13).
Nodular amyloid (H&E stain; 100×). Nodular deposits of amorphous, eosinophilic amyloid material (right) are surrounded by inflammatory cells, including multinucleate giant cells (bottom left).
Patients are usually asymptomatic, and the nodules are discovered incidentally on chest radiograph. However, the disease is rarely associated with multiple myeloma, and the presence of nodular amyloid always should raise suspicion and induce appropriate diagnostic workup for multiple myeloma (Fig. 91-14).
CT image of a left lower lobe nodular amyloid lesion.
The lesion size can range from 0.4 to 15 cm, with an average size of 3 cm. Diagnosis can be established with bronchoscopic lung biopsy, although these patients do have an increased risk of postbiopsy bleeding.29
Surgical excision is considered curative. Long-term follow-up is necessary because of the reported association of nodular amyloid with macroglobulinemia and lymphoma. Laser therapy also has been used successfully when patients with tracheobronchial amyloidosis present with obstructive symptoms.
Primary Pulmonary Thymoma
Primary pulmonary thymoma is a very rare tumor that arises in the lung of a patient with a normal thymus gland. The tumor most likely arises from embryologic descent of thymic tissue to a position more inferior than normal, but on occasion, it may arise from developmentally immature cells. The tumor exhibits a slight female preponderance and tends to occur in older patients with a mean age of 55 years. There is also some association with myasthenia gravis. Primary pulmonary thymomas can present with fever, retrosternal pain, nonproductive cough, malaise, and hemoptysis, but most patients are asymptomatic, and the tumor is often discovered incidentally on routine chest radiograph.
Intrapulmonary thymoma is identical histologically to a thymoma that arises in the mediastinum. Diagnosis is facilitated by immunohistochemistry, which permits identification of thymic-type T-cell antigens (CD3 and/or CD5) and other markers of immaturity (CD1a, TdT, or CD99). The epithelial component of the thymoma expresses cytokeratin, endomysial antibodies, and sometimes CD5. This epithelial and lymphoid immunophenotype can be critical in distinguishing primary pulmonary thymoma from other tumors in the differential diagnosis, namely, lymphoma or lymphoepithelial-like carcinoma of the lung.
Intrapulmonary thymomas can be located centrally, in a hilar location, or peripherally. The size of the lesion ranges from 1.7 to 12 cm. As in mediastinal thymomas, extension beyond the capsule suggests invasive behavior. Primary pulmonary thymoma has no distinctive radiographic features but appears as a well-circumscribed lesion confined in the lung. They are slow-growing lesions that remain asymptomatic until they cause bronchial obstruction.
Treatment is surgical excision. Prognosis is good in well-circumscribed, encapsulated lesions that are resected completely. The presence of an effusion does not preclude cure unless the pleura is directly involved by the tumor. In the rare case of an extensive, unresectable tumor involving the pleura, radiation therapy can be used with good results.