Introduction
Background
Bronchial carcinoid tumors are rare, accounting for up to 2.5% of all pulmonary neoplasms and for 12-15% of carcinoid tumors overall. They originate from the neurosecretory cells of bronchial mucosa and were previously classified as bronchial adenomas, a term no longer used. Bronchial carcinoids are now classed as low-grade malignant neoplasms because of their potential to cause local invasion, their tendency for local recurrence, and their occasional metastases to extrathoracic sites.
Bronchial carcinoids belong to a group of neuroendocrine tumors, which cover tumors ranging from bronchial carcinoid at one end of the spectrum and, at the other end, small cell carcinoma or, possibly, large cell neuroendocrine tumors. They demonstrate a wide range of clinical and biologic behaviors, including the potential to synthesize and secrete peptide hormones and neuroamines, particularly adrenocorticotropic hormone (ACTH), serotonin, somatostatin, and bradykinin.
Large cell neuroendocrine carcinoma of the lung is a newly recognized clinicopathologic entity that is distinct from small cell carcinoma and that is associated with a poor prognosis.1,2,3,4,5,6,7
Bronchial carcinoids are not associated with smoking, whereas small cell lung cancer (neuroendocrine type 3) has a definite relationship to smoking.
For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Bronchial Adenoma.
Lung, carcinoid. Right, Chest radiograph (CXR) in a 45-year-old woman demonstrates complete collapse of the left lower lobe. The cause of collapse is not identified on the image. Left, CT scan of the same patient obtained with soft-tissue window settings shows a hyperattenuating nodule (126 HU) within the left main bronchus. This is a typical bronchial carcinoid and was confirmed on bronchoscopic biopsy.
Lung, carcinoid. Right, CT scan viewed with mediastinal window settings in a 68-year-old man presenting with a productive cough and hemoptysis demonstrates a densely calcified, endobronchial carcinoid tumor in the bronchus intermedius. Left, CT scan obtained with lung window settings reveal severe postobstructive cystic bronchiectasis.
Lung, carcinoid. Indium-111 octreotide scan of the thorax and subdiaphragmatic areas shows a primary lung carcinoid (arrow) and metastases in the liver.
Pathophysiology
Cellular origin
Bronchial carcinoid tumors arise from Kulchitsky cells (argentaffin cells) within the bronchial mucosa. The cells predominantly occur at the bifurcation of the lobar bronchi. These cells are neurosecretory cells, which belong to the amine precursor uptake and decarboxylation (APUD) system. They have the capacity to synthesize serotonin (5-hydroxytryptamine), 5-hydroxytryptophan, ACTH, norepinephrine, bombesin, calcitonin, antidiuretic hormone (ADH), and bradykinin.8,9
Pathologic findings
Gross pathologic examination of specimens usually reveals 3- to 4-cm fingerlike or spherical polypoidal masses. The tumors are usually endobronchial, but they may also involve the adjacent pulmonary parenchyma, producing a collar-button lesion. They may also be predominantly extraluminal, forming an iceberg lesion. Most lesions are confined to the mainstem bronchi. The overlying mucosa is usually intact.
Histologic classification
Histologically, bronchial carcinoids can be categorized into 2 groups: (1) Kulchitsky cell carcinoma (KCC) I, or typical carcinoids, and (2) KCC II, or atypical carcinoids.
KCC I is the classic or typical bronchial carcinoid and the least aggressive. These tumors are usually well defined, smaller than 2.5 cm in diameter, and located centrally within the mainstem bronchi; they are associated with endobronchial growth. These tumors affect relatively young patients, with a marked female predilection. The female-to-male ratio is 10:1. Only 3% of typical carcinoid tumors metastasize to sites other than the regional lymph nodes.
KCC II tumors are atypical carcinoids that account for 25% of lung carcinoid tumors. These lesions are more aggressive than typical carcinoids. They usually affect relatively older patients and have a male preponderance; they are larger than the others at presentation, and they tend to occur in a peripheral location. Regional lymph node metastases are more common, occurring in as many as 50% of patients. Distant metastases to the liver, bone, and brain are reported in one third of patients. Metastases to bone are classically osteoblastic. Multiple tumors are a frequent pathologic finding, but these tumors are usually too small to be recognized radiologically.10
Large cell neuroendocrine carcinoma of the lung is a newly recognized clinicopathologic entity. This disease is distinct from small cell carcinoma and is associated with a poorer prognosis. The clinical features and optimal treatment of a large cell carcinoma have not yet been established.11,12
Histologic findings
Histologically, carcinoid tumors are characterized by uniform nests, cords, and masses of small polygonal cells separated by fine fibrovascular stroma. Cells are usually regular, with uniform and round nuclei, occasional mitoses, and abundant eosinophilic cytoplasm. Pleomorphism with variation in cell or nuclear sizes or shapes is unusual and indicates a more aggressive tumor, as does increased mitotic activity, hyperchromatism, increased cellularity, disorganization, and necrosis.
Electron microscopy reveals a cellular ultrastructure consisting of dense neurosecretory core granules. Immunochemical examination may reveal the presence of serotonin, neurospecific enolase, bombesin, calcitonin, and other peptides. Tumors may also exhibit amyloid deposition, dystrophic calcification, or bone formation.
The 2 types of lung carcinoid tumors may be difficult to differentiate by using small-needle or aspiration biopsy specimens. Furthermore, individual tumors may show different characteristics in different areas.13,14,15
Frequency
United States
Bronchial carcinoid tumors are rare, accounting for up to 2.5% of all pulmonary neoplasms and 12-15% of carcinoid tumors overall. Of all carcinoids, 72% are typical, while the remaining 28% are atypical. Carcinoids account for 1-2% of all malignant lung neoplasms. As many as 20% of carcinoids are of the metastasizing variety. The incidence of carcinoid syndrome is 12% in some series of bronchial carcinoid, especially when the primary is large or liver metastases are present; metastases often occur years after removal of the primary tumor.
International
There are no data to suggest that the frequency of lung carcinoid internationally is any different from that found in the United States.
Mortality/Morbidity
The prognosis is highly dependent on the size of the tumor, the histologic subtype, and the presence of nodal metastases at diagnosis.
- Most tumors follow a benign course and are amenable to surgery. The 5-year survival rate for patients with typical bronchial carcinoid (KCC I) is 94%. Involvement of regional lymph nodes reduces this rate to 71%; however, excellent results may still be achieved with treatment, and the presence of nodal disease does not preclude surgery.
- Patients with atypical carcinoids (KCC II) have a worse prognosis, with a 5-year survival rate of 57%. Approximately 40-50% of these tumors metastasize to the regional lymph nodes. Hepatic metastases occur in approximately 5-10%.
Race
Bronchial carcinoid is rare among blacks.
Sex
For the overall incidence, the male-to-female ratio is 2:1.
Age
Tumors affect individuals in a wide age range, with a peak incidence in the fifth decade.
- Patients with bronchial carcinoid are generally younger than those with the more common primary pulmonary bronchogenic carcinoma.
- Atypical carcinoids occur a decade later in life than typical carcinoids do.
- Approximately 4% of lung carcinoids occur in children and adolescents.16 Bronchial carcinoid is the most common primary pulmonary neoplasm in childhood.
Presentation
The clinical manifestations of bronchial carcinoids may arise because of their endobronchial or central location, their potential for metastatic spread, or their ability to produce vasoactive amines. Hemoptysis is common, occurring in at least 50% of patients. This finding reflects the vascular nature of these lesions. Patients may also present with productive cough; wheezing; chest pain; and recurrent episodes of pneumonitis, bronchiectasis, or postobstructive lung abscess. Some patients present with symptoms that mimic those of asthma.
Alternatively, patients may present with complications resulting from the neurosecretory activity of the tumors. Bronchial carcinoids may secrete ACTH in quantities sufficient to cause Cushing syndrome in 2% of patients. The causative tumors are often small and sometimes are not visible on chest radiographs (CXRs) or CT scans. Carcinoid syndrome due to bronchial carcinoids is rare (2-5%), and when present, it is associated with liver metastases.17 Metastases may also occur in bone, adrenal glands, and the central nervous system (CNS). Approximately 25% of patients are asymptomatic. In such cases, tumors are often located peripherally and are detected incidentally.
Most pediatric patients present with wheezing and atelectasis, though cough, hemoptysis, and pneumonitis are not rare.
On bronchoscopy, endobronchial carcinoids characteristically appear as smooth, polypoid lesions that are cherry red in color.
The histologic diagnosis is usually made on the basis of bronchoscopic biopsy findings.
Preferred Examination
CXR is the first-line imaging investigation in most patients. CXRs are abnormal in 90% of patients with bronchial carcinoid.18
CT is useful for detecting lesions not visible on CXR, for assessing endobronchial lesions, and for characterizing and staging tumors.18
MRI may also be useful for differentiating small tumors from adjacent vessels.9
Nuclear medicine studies hold great promise not only for diagnosing and staging of tumors but also for predicting the potential response to somatostatin analogues and other therapeutic radioligands.19
Limitations of Techniques
Central tumors may not be apparent on CXRs unless an indirect associated finding such as lobar atelectasis, mucus plugging, or bronchiectasis are present.
The differential diagnosis of peripheral lesions includes numerous disorders if the lesion is a solitary pulmonary nodule. On CT scans, carcinoid tumors that do not demonstrate the typical enhancement pattern or that are noncalcified are indistinguishable from endobronchial lesions from other causes and from solitary pulmonary nodules. Intense homogeneous contrast enhancement may mimic a pulmonary varix or pulmonary artery aneurysm, and densely calcified tumors may be mistaken for broncholiths or granulomas. Mediastinal lymphadenopathy has many other causes and may be either reactive or metastatic in etiology.9,18
A proportion of patients are unsuitable for MRI because of contraindications or adverse effects, such as claustrophobia. Positron emission tomography (PET), in particular, is expensive. Somatostatin-analogue scintigraphy is an extremely valuable tool, but its specificity is low; in addition, results of scintigraphy may be positive in patients with other neuroendocrine tumors and in patients with inflammatory conditions.19,20,21
Differential Diagnoses
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References
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Further Reading
Keywords
neuroendocrine carcinoma, Kulchitsky cell carcinoma, KCC, bronchial carcinoid tumors, bronchial adenomas, typical carcinoids, atypical carcinoids, small-cell carcinomas, Kulchitsky cells, argentaffin cells, pulmonary carcinoids, primary pulmonary neoplasms, lung neoplasms, lung cancers, pulmonary cancers
