Detection and Diagnosis

We tend to use the terms tumor and nodule (or mass) synonymously. Benign tumors may also present primarily in the airway versus the lung parenchyma, and certain causes may present in either location or in both locations. Patients presenting with symptoms and found to have tumors on chest x-ray films or computed tomography (CT) imaging studies are more likely to have a lung malignancy.

Incidentally found tumors or nodules in the lung detected at CT screening are more likely to be benign. Studies of CT screening for lung cancer detect one or more nodules in about 25% of participants when CT collimation (slice thickness) is 10 mm and 40% to 60% of participants at 5 mm or less; about 98% of these nodules are benign. Nodule size is generally an excellent guide for determining benign from malignant; less than 1% of nodules 5 mm or less in diameter represent malignancy, even in current or former smokers. This distinction becomes more difficult for larger nodules, with the likelihood of malignancy more than 50% for nodules 2 cm in diameter, and increasing with larger nodule/mass size. A few benign tumors, such as hamartomas and teratomas, may have imaging features such that CT is diagnostic. However, most benign tumors do not have signature characteristics on imaging, and histology is required for diagnosis.

Positron emission tomography (PET) can be helpful in identifying benign from malignant tumors because it is based on the principle that cancer cells have a high rate of glycolysis compared with non-neoplastic cells. False-positive PET scans have been reported with infections, sarcoidosis, and other benign conditions. False-negative PET scans may occur with low-grade tumors, carcinoid tumor, and malignancies less than 1 cm in diameter. PET is now most often performed with integrated CT (PET-CT). Avidity on PET-CT is not the same as tissue, and a biopsy should be obtained rather than assuming a diagnosis or a stage.

Once a nodule is 3 cm or larger, and it is not clearly benign by showing evidence of calcification or fat on CT, the likelihood of malignancy is greater than 90%. Therefore, most benign tumors larger than 3 cm are diagnosed at resection because of the high index of suspicion of malignancy. Although most inflammatory lesions show no evidence of growth in follow-up, many benign tumors will grow and prompt concern for malignancy and subsequent removal for diagnosis. Bronchoscopy or transthoracic needle biopsy may be used to diagnose benign tumors, especially when multifocal or complete resection is not feasible.

Obstruction of the trachea and major bronchi is most often caused by squamous cell and small cell carcinoma or carcinoid tumor, but tracheal obstruction may also be caused by benign tumors. Several benign tumors manifest more frequently in the airways rather than the periphery of the lung. The patients may have symptoms of airway obstruction, such as cough, recurrent infection, wheezing, and dyspnea. The endoscopic appearance of a lesion may suggest a diagnosis, but uniformly, histology is required. If the lesion is polypoid and has a low likelihood of malignant behavior, successful treatment may be achieved with endoscopic techniques. Broad-based lesions and those with greater malignant potential are best treated with surgical excision; lung-sparing procedures such as a bronchoplasty or sleeve resection may be appropriate.

Classification

Benign neoplastic tumors are classified histologically according to the World Health Organization (WHO) classification updated in 2004 (Box 68-1). These histologic distinctions are more helpful to the pathologist than to the clinician approaching a lung tumor and are more likely to be in the “is it malignant or not” mindset. Although typically benign, many of the benign neoplasms have the potential for malignant transformation.

Benign Epithelial Neoplasms

Papillomas

Benign epithelial neoplasms are generally rare, although squamous papilloma is the most common. Histologically, these are identified as papillary tumors with a squamous cell epithelial surface and delicate connective tissue attachments. They may be solitary or multiple and most often occur in the larynx and trachea, with less than 10% having lower airway involvement and only 2% within the lung parenchyma (Figure 68-1). The squamous type of papilloma has an association with human papillomavirus (HPV types 16, 18, 31, 33, and 35). Obstructive symptoms may develop from airway involvement and are an indication for laryngoscopic or bronchoscopic removal. Recurrent papillomas occur in as many as 20%, and some patients require periodic endoscopic debridement. Malignant transformation to squamous cell carcinoma may occur. Compared with squamous cell papillomas, glandular and mixed-cell papillomas are exceedingly rare.

Figure 68-1 A, Chest radiograph in 56-year-old man with history of respiratory papillomatosis diagnosed by wedge resection of one of several masses. At bronchoscopy, obstructing papillomas were seen in the trachea (B) and distal bronchial tree and were removed with rigid bronchoscopy (C). 

Adenomas

Alveolar adenomas are rare and typically occur in the lung periphery. They are recognized as solitary tumors with a network of spaces lined by simple cuboidal epithelium and a spindle cell stroma. Although considered neoplasms, adenomas are not recognized as having malignant potential. Papillary adenomas also typically occur in the periphery of the lung and also appear to have no malignant potential. Mucous gland adenomas more often occur in the central airways and may be difficult to distinguish from low-grade mucoepidermoid carcinomas, although adenomas do not appear to be a malignant precursor. Pleomorphic adenomas have features of both epithelial and connective tissue differentiation; they occur in the airway or the lung periphery and may exhibit malignant behavior. Mucinous cystadenomas are localized cystic masses filled with mucin and lined by columnar mucinous epithelium; they are usually peripheral and are benign, without malignant progression.

Thymoma

Arising from ectopic thymic tissue, intrapulmonary thymomas are epithelial neoplasms and are otherwise identical to those occurring in the mediastinum. Myasthenia is rarely described with intrapulmonary thymoma, and more common symptoms include cough, fever, chest pain, and dyspnea. Resection is the treatment of choice, and invasion and nodal involvement may occur.

Benign Mesenchymal Neoplasms

Chondroma

Chondromas are benign tumors composed of cartilage and are most often found in the patient with Carney triad: pulmonary chondroma, gastric stromal sarcoma, and paraganglioma. Although described as a “triad,” most patients will manifest only two different neoplasms. The appearance of chondromas on chest radiograph is usually diagnostic because these are typically multiple, well-circumscribed, calcified nodules occurring in young women (Figure 68-2). The main differential of the radiographic appearance of a chondroma is a hamartoma, typically singular. Chondromas are benign, and patients with Carney triad will more likely have symptoms from other, extrapulmonary manifestations.

Figure 68-2 Chest radiograph in 25-year-old woman shows multiple calcified pulmonary chondromas. Patient had prior resection of several gastrointestinal stromal tumors (GISTs) and was believed to have Carney triad; she had not demonstrated a paraganglioma.

Inflammatory Myofibroblastic Tumor

Synonyms for inflammatory myofibroblastic tumor (IMT) include inflammatory pseudotumor, plasma cell granuloma, fibrous histiocytoma, and fibroxanthoma. IMT is composed of a mixture of inflammatory cells (with plasma cell predominance), collagen, and spindle cells showing myofibroblastic differentiation. IMTs are the most common benign primary lung tumor in children and usually occur in the airways. In adults these lesions are rare and more often present as solitary parenchymal masses (Figure 68-3). Symptoms may include weight loss and fatigue or pain relating to tumor location; chest wall invasion or angioinvasion can occur. Resection is the only proven treatment, and complete excision is usually curative, although recurrence after excision and metastases or progression to sarcoma can occur.

Figure 68-3 Computed tomography (CT) scans in 40-year-old man, never smoker who developed pain in right side of chest, show a mass anteriorly in A, right upper lobe of lung, and B, mediastinal windows. C, Positron emission tomography (PET)–CT shows lesion with moderate activity. Transthoracic needle biopsy was nondiagnostic. Surgical biopsy showed inflammatory myofibroblastic tumor, and patient underwent complete resection.

Neurofibromas

The neurofibromatoses (NFs) are autosomal dominant disorders and may be associated with benign peripheral nerve sheath tumors in the airway or lung (Figure 68-4). A retrospective study of 156 patients with NF found lung nodules or masses present in 5%, not including those with paraspinal or chest wall masses. Neurofibromas and schwannomas may also be present in the absence of NF, and there is the potential for malignant change. Clinical signs and symptoms typically relate to airway obstruction (cough, wheezing, dyspnea, hemoptysis).

Figure 68-4 A, Chest radiograph in 68-year-old woman with history of asthma presenting with worsening cough and dyspnea shows volume loss. B, CT scan shows obstruction of left main bronchus. C, Bronchoscopy reveals complete obstruction of left main stem by a polypoid tumor. Patient underwent left thoracotomy, with resection of a sleeve of bronchus at takeoff of left upper lobe of lung; pathology revealed a neurofibroma.

Solitary Fibrous Tumor of Pleura

Solitary fibrous tumors of the pleura (SFTPs) are spindle cell mesenchymal tumors. They typically arise in the visceral pleura, but also from lung parenchyma or mediastinum, and may become very large (Figure 68-5). The terminology of “benign mesothelioma” is no longer used. In one retrospective series of 84 patients, 55% were symptomatic (cough, chest pain, dyspnea); 4% had the paraneoplastic manifestations of hypertrophic pulmonary osteoarthropathy (HPO), 6% had HPO and clubbing, and 1% hypoglycemia. Rarely, SFTP can be malignant.

Figure 68-5 A, Chest radiograph identifies a mass in an asymptomatic 61-year-old woman, former smoker. B, CT scan shows mass without adenopathy, and lobectomy showed this to be a 7-cm solitary fibrous tumor with no involvement of the pleura.

Glomus Tumor

Glomus tumors are extremely rare, occur more often in males, and are thought to be of glomus cellular origin, having the appearance of smooth muscle. Based on cellular appearance, they are further classified as classic glomus tumor, glomangioma, and glomangiomyoma. Within the chest, glomus tumors are more likely to be in the trachea, but they have been described in the lung and mediastinum (Figure 68-6). Successful resection has been reported with surgery or bronchoscopy, and malignant behavior has been observed.

Figure 68-6 A, CT chest scan shows a tracheal lesion in 41-year-old man, never smoker, who presented with intermittent hemoptysis for 2 years; chest radiograph was normal. Bronchoscopy showed a broad-based polypoid lesion, and patient underwent tracheal sleeve resection. B, Pathology showed glomus tumor.

Benign Neoplasms: Miscellaneous

Hamartoma

Pulmonary hamartomas are the most common benign neoplasms in the lung, comprising cartilage, fat, connective tissue, and smooth muscle. Hamartomas are rare in children; in adults they are usually in the parenchyma, and approximately 10% present endobronchially (Figure 68-7). Patients with parenchymal hamartoma are usually asymptomatic, and typical features of fat and calcification may be evident on CT images. When lacking classic CT features, parenchymal hamartomas are often diagnosed at resection to exclude malignancy. Rarely, recurrence or sarcomatous transformation has been described.

Figure 68-7 A, CT chest scan shows complete obstruction of right main bronchus and postobstructive pneumonia in 45-year-old man who presented with fever, sweats, and chills; chest radiograph showed right lung opacity and volume loss. B, Bronchoscopy demonstrates a polypoid mass extending into distal trachea.  C, Bronchoscopic resection was performed using polypectomy snare, and pathology showed hamartoma. 

Sclerosing Hemangioma

Histologic features of sclerosing hemangiomas include papillary, solid, sclerotic, and hemorrhagic structures. Sclerosing hemangiomas usually present as asymptomatic radiographic abnormalities, although cough, hemoptysis, and pain may occur. Sclerosing hemangioma behaves benignly. Although spread to regional lymph nodes is described rarely, when present, it appears to have no negative effect on prognosis, and disease-related death has not been reported.

Benign Teratoma

Teratomas are composed of tissues from more than one germ cell line and have mature and immature forms. Mature pulmonary teratomas are benign and more common in the upper lobes of the lung. Immature teratomas may be malignant. Because teratomas are frequently cystic and contain skin, hair, sweat glands, fat, bone, sebaceous material, or toothlike structures, some of these elements may be visible on CT scans. Patients with teratomas may be asymptomatic or may present with chest pain, hemoptysis, or the unusual symptom of trichoptysis, expectorating hair. Surgery is generally recommended, even if the diagnosis is evident from imaging studies (Figure 68-8).

Figure 68-8 A, Chest radiograph shows a right hilar mass in 17-year-old girl who had chest discomfort after a basketball game. B, Resection shows benign, cystic teratoma.

Clear Cell Tumor

The name “clear cell” tumor comes from presence of cells with abundant clear or eosinophilic cytoplasm containing glycogen; it is also called “sugar tumor.” This extremely rare tumor is usually solitary and peripheral, and discovery is incidental. Rarely, malignant features have been described.

Leiomyoma

Leiomyomas are benign smooth muscle tumors occurring in women. When singular, and absent a history of uterine leiomyomas, they most often occur in the airway. Benign leiomyoma may also present in the lung of women with a history of uterine leiomyoma and is termed benign metastasizing leiomyoma (BML). BML is characterized by multiple, slow-growing, smooth muscle tumors (Figure 68-9). Despite the resemblance to malignancy, the number of mitotic indices is low, and there is no evidence of invasion despite multiple distant lesions. Extrauterine leiomyosarcoma must be excluded. The lung involvement in BML is typically evident 10 to 15 years after the removal of the uterine leiomyoma. BML is usually negative on PET imaging. Treatment includes hormonal therapy, surgical resection, and chemotherapy.

Figure 68-9 A 37-year-old former smoker had an abdominal CT done for pain and a lung nodule was seen. CT chest scans A, B, and C showed multiple lung nodules. D, PET-CT scan shows no activity. Patient had no history of malignancy but had a hysterectomy 7 years earlier for fibroid tumors. Needle biopsies of a nodule showed spindle cell neoplasm, consistent with benign metastasizing leiomyoma.

Lipoma

Lipomas are rare, are composed of mature fat cells, and may occur in the airway or less often in the mediastinum. Presenting symptoms depend on the size and location of the lesion, most often dyspnea and cough. CT imaging shows the lesion to be homogeneous and composed of fat (Figure 68-10). Local recurrence has been described after resection.

Figure 68-10 A, Chest radiograph reveals opacification of right side of chest in 24-year-old woman presenting with cough for 6 weeks and mild exertional dyspnea. B, CT scan shows a large, fat-attenuating mass. C, Thoracotomy reveals well-circumscribed benign lipoma (23.0 × 11 cm) with no clonal abnormality. D, Radiograph at 8 weeks postoperatively shows reexpansion of right lung.

Non-Neoplastic Tumors

A variety of conditions cause benign lesions in the lung that are not true neoplasms (Box 68-2). These conditions need to be considered in the differential diagnosis when evaluating a nodule or mass on imaging studies and include nodular lymphoid hyperplasia, organizing pneumonia, endometriosis, rounded atelectasis, and sequestration, as discussed in earlier chapters.

Amyloid Deposits

As an example of a non-neoplastic tumor, amyloid is composed of a group of fibrillar proteins with beta-pleated-sheet formation, which demonstrates birefringence under polarized light on Congo red stain. Pulmonary manifestations of amyloidosis include tracheobronchial infiltration, persistent pleural effusions, parenchymal nodules, and amyloidomas (Figure 68-11). Amyloid deposits in the lung may or may not be associated with systemic amyloidosis.

Figure 68-11 A, CT scan shows mass obstructing right main stem bronchus in 61-year-old man, never smoker, with 12-year history of asthma, presenting with progressing shortness of breath; chest radiograph showed volume loss in right lung. B, Bronchoscopic biopsies show amyloidoma. C, Rigid bronchoscopic resection reestablished patency of right main bronchus.