Bronchial Carcinoids and Benign Neoplasms of the Lung

David H. Kupferberg

Bronchial carcinoids and benign neoplasms of the lung account for less than 10% of all primary pulmonary neoplasms. Many are discovered incidentally due to the increasing use and availability of computed tomography (CT) scanning. The symptoms and diagnosis of these lesions depend very much on their location; most are asymptomatic. When centrally located, they may not be visible on chest radiographs and slowly cause progressive airway obstruction, resulting in focal wheezing, postobstructive pneumonia, or hemoptysis, and even may be confused with chronic airways disease. When peripheral, these tumors are usually clinically silent but still pose the diagnostic challenge typical of any solitary pulmonary nodule. Ultimately, the diagnosis of many of these lesions is obtained at the time of surgery performed to definitively exclude malignancy. Work-up and evaluation relies on clinical suspicion of malignancy, imaging modalities, including positron emission tomography (PET) scanning, and patient’s risk and preference for surgical intervention.

Carcinoid tumors are classified as malignant tumors due their potential for metastases, although “typical” carcinoids have a growth pattern and behavior similar to benign tumors of the lung. Hamartomas are the most common benign pulmonary neoplasms. Leiomyomas, true bronchial adenomas, lipomas, chondromas, inflammatory myofibroblastic tumors, endometriosis, and even teratomas also occur.

BRONCHIAL CARCINOIDS

Bronchial carcinoids comprise the second largest group of lung tumors behind bronchogenic carcinomas and are responsible for approximately 0.5% to 2% of all bronchial tumors. They occur with a small increased frequency in women and at an earlier average age of onset (40–60 years old) compared with noncarcinoid bronchogenic malignancies. Some studies suggest a greater incidence in Caucasians than in African Americans. The link between smoking and the development of carcinoid tumors is unclear and has not been firmly established. While more than 90% of cases are sporadic, there is an association with multiple endocrine neoplasia (MEN type 1) as well as a reported familial non-MEN1 incidence.

Bronchopulmonary carcinoid tumors account for 25% of all carcinoid tumors, which occur primarily in the gastrointestinal tract. The bronchial type tends to develop centrally, in the large airways and can be visualized easily with bronchoscopy. Macroscopically, they can grow primarily either as a polypoid lesion or as a predominantly infiltrative process, with only minimal protrusion into the bronchial lumen (known as iceberg tumor). Growth is largely submucosal, and the surface epithelium is usually intact, although frequently metaplastic. Carcinoids have a wide histologic spectrum; most commonly appearing as clumps of small, uniformly staining cells with a rich vascular stroma. Some form acini and produce mucin; others appear highly malignant and may bear a striking resemblance to small-cell carcinoma. They can be classified along a spectrum as follows: (1) typical carcinoid with the best prognosis and bland-appearing histology; (2) atypical carcinoid with 2 to 10 mitoses per high-power field and necrosis; (3) large-cell neuroendocrine carcinoma with a higher mitotic rate, greater atypia, and necrosis; and (4) small-cell carcinoma, the most aggressive. Immunohistochemistry-identifying synaptophysin, neuron-specific enolase, and chromogranin are often used to support the neuroendocrine origin of cells. The tumor is capable of elaborating a wide spectrum of neuroendocrine products. Atypical carcinoid may be misclassified with bronchoscopic biopsies because of difficulty with mitotic counts on limited sampling.

The clinical manifestations of bronchial carcinoid tumors depend on the site of the tumor. Approximately 80% are central and can produce symptoms and signs of bronchial obstruction, including cough, fever, chest pain, and often a localized wheeze. Hemoptysis is present in approximately 50%, reflecting both their central origin and hypervascularity. Peripheral carcinoids most often are asymptomatic and usually detected fortuitously by radiographic imaging. Regional lymph node metastasis is present in approximately 10% of typical carcinoids at presentation, compared with 30% to 50% of atypical carcinoids.

Rarely, there are associated paraneoplastic findings. The most common is Cushing syndrome, which can even predate visualization of a lung nodule. Acromegaly has also been reported with significantly elevated levels of growth hormone even without overt acromegalic features. The carcinoid syndrome occurs infrequently with an incidence as low as 0% to 3%. Production of high levels of 5-hydroxytryptamine and other substances (e.g., bradykinin, prostaglandins) can enter the systemic circulation causing flushing, wheezing, anxiety, vomiting, and hypotension. In addition, cardiac valvular damage can develop in the left heart in bronchial carcinoid syndrome, as opposed to the right heart with the abdominal variety. This syndrome always reflects metastasis of the carcinoid tumor, usually to the liver. Other neuroendocrine manifestations include the Zollinger–Ellison syndrome, hyperinsulinemia, and an association with MEN type I.

Radiographic findings depend on the site of the tumor. Central tumors may cause bronchial obstruction and result in pneumonitis, atelectasis, bronchiectasis, and collapse. Nonobstructive central and peripheral tumors may appear as a solitary pulmonary nodule, usually 4 cm or less in diameter, and are often slightly lobulated. Atypical carcinoids tend to be larger. Calcification may be present. CT scanning is helpful in identifying endobronchial lesions as well as lymph node enlargement. Because carcinoid tumors tend to be highly vascular, there is marked enhancement with intravenous contrast. Newer localization modalities include radiolabeled somatostatin analog scintigraphy, which has been reported to find up to 85% of all primary and metastatic carcinoid lesions. PET scanning may yield false-negative results because of hypometabolic activity.

Pulmonary function testing is usually normal unless central obstruction occurs, in which case flow obstruction may be demonstrated. Serum or urine hormone levels can be elevated in association with the aforementioned neuroendocrine syndromes.

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