You are in: eMedicine Specialties > Radiology > CHEST Lung, CarcinoidArticle Last Updated: Apr 11, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 12
  Author: Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR, LRCP, Chairman of Medical Imaging, Professor of Radiology, NGHA, King Fahad National Guard Hospital, King Abdulaziz Medical City, Riyadh, Saudi Arabia Ali Nawaz Khan is a member of the following medical societies: American Institute of Ultrasound in Medicine, Radiological Society of North America, Royal College of Physicians, Royal College of Physicians and Surgeons of the United States, Royal College of Radiologists, and Royal College of Surgeons of England Coauthor(s): Sumaira MacDonald, MBChB, PhD, MRCP, FRCR, Lecturer, Sheffield University Medical School; Endovascular Fellow, Sheffield Vascular Institute; Carolyn M Allen, MB, BCh, MRCP, FRCR, CCST, Consultant Radiologist, Department of Clinical Radiology, North Manchester General Hospital, UK Editors: Kitt Shaffer, MD, PhD, Director of Undergraduate Medical Education, Associate Professor, Department of Radiology, Cambridge Health Alliance; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; W Richard Webb, MD, Chief of Thoracic Imaging, Professor, Department of Radiology, University of California at San Francisco; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Barry H Gross, MD, Professor, Department of Radiology, University of Michigan Medical School; Professor, University of Michigan Cancer Center Author and Editor Disclosure Synonyms and related 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 INTRODUCTIONSection 2 of 12
  BackgroundBronchial 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. PathophysiologyCellular 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 FrequencyUnited StatesBronchial 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. InternationalThere are no data to suggest that the frequency of lung carcinoid internationally is any different from that found in the United States. Mortality/MorbidityThe prognosis is highly dependent on the size of the tumor, the histologic subtype, and the presence of nodal metastases at diagnosis.
RaceBronchial carcinoid is rare among blacks. SexFor the overall incidence, the male-to-female ratio is 2:1. AgeTumors affect individuals in a wide age range, with a peak incidence in the fifth decade.
Clinical DetailsThe 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 ExaminationCXR 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 TechniquesCentral 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 DIFFERENTIALSSection 3 of 12
Aspergillosis, Thoracic Lung Cancer, Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Staging Lung, Arteriovenous Malformation Lung, Metastases Lung, Nontuberculous Mycobacterial Infections Lung, Postprimary Tuberculosis Lung, Primary Tuberculosis Non-Hodgkin Lymphoma, Thoracic Pulmonary Sequestration RADIOGRAPHSection 4 of 12
FindingsKCC I and KCC II (typical and atypical carcinoids) have similar radiographic appearances. CXRs are abnormal in most patients. In approximately 80% of cases, carcinoids arise centrally in the main, lobar, or segmental bronchi without any predilection for a particular bronchus/lobe. Radiographic findings include a hilar or perihilar mass abutting or narrowing a central airway or changes associated with an endobronchial tumor.17 Because the tumors are slow growing, ancillary findings resulting from bronchial obstruction may also be seen. These findings include atelectasis; bronchiectasis; pneumonitis; mucous impaction (bronchocele) of a distal bronchus; and, occasionally, distal abscess formation. However, a collateral drift may maintain aeration of the obstructed segments. The consequent hypoxia of the involved lung is sometimes seen as local vasoconstriction. Mucoid impaction may be the only radiographic finding; impaction appears as a well-defined round, elliptical, or triangular opacity pointing toward the hilum. It is occasionally branching, with an appearance like gloved fingers. As many as 20% of bronchial carcinoids occur as a solitary pulmonary nodule. Overall, the tumors are usually well defined, lobulated, round or oval lesions measuring 2-5 cm. Atypical carcinoids are more likely to be peripheral, and they tend to be larger. Eccentric calcification or ossification is rarely appreciated on CXRs, but it is present in 30% of biopsy specimens. Spiculation is rare, but when it is present, differentiation of this tumor from a bronchogenic carcinoma may be difficult. Multifocal disease is rarely seen. Although rare, sclerotic bone metastases are usually well seen on conventional radiographs. Degree of ConfidenceCXR is usually the first imaging investigation. Approximately 90% of patients with bronchial carcinoid have an abnormal CXR, although appearances are often nonspecific; imaging investigations are not helpful in differentiating the various pathologic types of bronchial carcinoid. False Positives/NegativesCXRs may appear normal in 10% of patients. The differential diagnosis of peripheral carcinoids includes other causes of a solitary pulmonary nodule, such as bronchogenic carcinoma, hamartoma, granuloma, and solitary metastasis. CT SCANSection 5 of 12
FindingsCT provides excellent anatomic detail of both the endobronchial and the extraluminal components of the tumor (see Images 1 to 5). Tumors usually deform or obstruct the adjacent bronchus, and even peripheral tumors are shown to lie in immediate proximity to a recognizable small airway. As on CXRs, lesions usually appear as well-defined, lobulated, round, or oval masses measuring 2-4 cm. Extension into adjacent mediastinal structures is detectable on CT scans with more aggressive tumors.9, 18, 22 Calcification is common, occurring in 30% of cases; it is better appreciated on CT scans than on CXRs. The incidence of calcification is significantly higher in cases involving centrally placed tumors. When present, calcification is usually eccentric and may be curvilinear or nodular. Occasionally, complete calcification of the tumor and, in some cases, frank ossification are recognizable. Lesions are highly vascular and usually demonstrate marked homogeneous enhancement on CT scans obtained after the intravenous administration of contrast material. However, some carcinoid tumors (particularly atypical carcinoids) may show heterogeneous enhancement or no enhancement. Bronchial carcinoids metastasize to the mediastinal lymph nodes in 25% of cases; this feature is more accurately assessed with CT scans than with images of other modalities. Findings related to bronchial obstruction are also well depicted with CT. Large polypoid lesions, which partly obstruct the bronchus, may produce a ball-valve effect, resulting in hyperinflation or expiratory airtrapping. These changes may be demonstrated on CXR (expiratory and inspiratory images), but they are better appreciated on CT scans. Airway obstruction caused by tumor may also result in distal mucous impaction (bronchocele), which is identified on CT scans by the presence of focal fluid-filled, nonenhancing, branching structures with a Y- or V-shaped configuration. This is seen in transversely orientated bronchi with a rounded configuration in craniocaudally orientated airways. Commonly, a peripheral area of emphysema surrounds the mucus impaction. Contrast enhancement may help in differentiating the endobronchial tumor from the peripheral nonenhancing area of mucous impaction. Most endobronchial tumors cause complete obstruction of the bronchus, resulting in distal pulmonary changes of atelectasis and pneumonitis. CT usually shows a loss of volume in the affected segment, which is associated with an air bronchogram. Recurrent infections distal to the obstruction may cause bronchiectasis or a lung abscess. Peripheral carcinoids are usually located distal to the segmental bronchi. As on plain radiographs, these nodules are round or ovoid, with smooth or lobulated borders. Calcification and ossification are more readily seen on CT scans than on conventional radiographs, and these are more common in central (43%) rather than peripheral (10%) tumors. Cavitation is rare. CT is valuable in the assessment of operability of tumors and in monitoring patients for recurrence. When the lesion is confined to the bronchial lumen, endobronchial resection is often feasible. The use of CT bronchography in addition to conventional CT has been described in the detection and characterization of carcinoid tumors, but this approach does not significantly increase sensitivity or specificity. Degree of ConfidenceCT is superior to CXR in the detection, characterization, and staging of tumors. Limitations regarding the specificity apply to CT as with CXR, and bronchoscopic or percutaneous image-guided biopsy may be necessary for definitive diagnosis. False Positives/NegativesUsually, a bronchial carcinoid cannot be distinguished from a carcinoma unless the lesion is demonstrably ossified. Carcinoids may be diffusely calcified and may thereby mimic broncholithiasis. The intense homogeneous contrast enhancement of bronchial carcinoids may mimic a pulmonary varix or pulmonary artery aneurysm. Conversely, atypical carcinoids may demonstrate less-uniform enhancement, overlapping other pathologies. Occasionally, mediastinal lymphadenopathy in association with a bronchial carcinoid may be due to reactive hyperplasia from recurrent pneumonia rather than metastatic disease. A ball-valve effect resulting in overinflation or expiratory airtrapping may result from inhaled foreign bodies, particularly in children. MRISection 6 of 12
FindingsAll bronchial carcinoids have a high signal intensity on T2-weighted and short–inversion time inversion recovery sequences; this characteristic facilitates their distinction from blood vessels. Ultrafast contrast-enhanced MRIs show pronounced rapid increases in signal intensity in bronchial carcinoids.9, 23 Degree of ConfidenceMRI may be useful in distinguishing small bronchial carcinoids from adjacent pulmonary vessels in the central third of the lung if CT findings are nondiagnostic or equivocal. False Positives/NegativesUltrafast contrast-enhanced MRIs that show a pronounced rapid increase in signal intensity in bronchial carcinoids may not be specific because not all carcinoids are vascular, and some bronchial carcinomas may also be enhancing. ULTRASOUNDSection 7 of 12
FindingsUltrasonography has no role in the diagnosis of bronchial carcinoid. NUCLEAR MEDICINESection 8 of 12
FindingsLike other neuroendocrine tumors, carcinoids have somatostatin receptors; therefore, they can be imaged with somatostatin analogues (octreotide, pentetreotide) tagged with an appropriate radioisotope. Single photon emission CT (SPECT) and subtraction techniques improve detection.22, 24, 25 Collateral air drift may maintain aeration despite complete bronchial occlusion; however, the resultant hypoxia may appear as a segmental defect on perfusion scintigraphy. Bronchial carcinoids may take up iodine-123 N-isopropyl-p-iodoamphetamine in sufficient concentration to image a bronchial carcinoid. Fluorodeoxyglucose (FDG) PET uptake is associated with malignancy. However, one small study of FDG PET did not demonstrate sufficient uptake to allow reliable differentiation. Carcinoid tumors show increased uptake and irreversible trapping of another PET tracer, carbon-11–labeled 5-hydroxytryptophan (5-HTP), a serotonin precursor. 11C-labeled 5-HTP has been reported to be more sensitive for the detection of liver and lymph node metastases than FDG imaging, CT, or octreotide scintigraphy. However, high renal excretion of 11C-labeled 5-HTP tracer does produce streak artifact overlying areas of interest in the upper abdomen.26, 27, 28 When the decarboxylase inhibitor carbidopa is given orally as premedication, the renal excretion decreases 6-fold, and tumor uptake increases 3-fold, improving tumor visualization. When 11C-labeled 5-HTP PET scanning is used during the treatment of patients with carcinoid, the correlation of changes in urinary 5-hydroxyindoleacetic acid and changes in the transport rate constant for 5-HTP is higher than 95%. Thus, PET with 11C-labeled 5-HTP can be used to monitor treatment effects. With 11C-labeled 5-HTP, Eriksson et al were able to detect small ACTH-producing bronchial carcinoids that were not detectable with other imaging techniques.29 Iodine-131 meta-iodo-benzylguanidine (MIBG) scintigraphy is a valuable tool in the detection of neuroendocrine tumors. This has been used to detect bronchial carcinoids. Thallium-201 scintigraphy has been used in the diagnosis of a single case of a small (<1 cm), ectopic, ACTH-producing carcinoid tumor.30 CT-SPECT and CT-coincidence fusion images have a potential use in the evaluation of bronchial carcinoids. These techniques combine physiologic information gained from radionuclide imaging with the superior anatomic information derived from CT scans. 111In 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid–lanreotide (111In-DOTA-lanreotide) scintigraphy yields high tumor binding in various lung tumors, including carcinoids (see Image 6). Consequently, radiopeptide therapy may offer a potential new treatment alternative for some lung cancers.31 Both 111In-DOTA-lanreotide and 111In-DOTA-Tyr3-octreotide can be used for the evaluation of somatostatin receptor–mediated radionuclide therapy. The intraoperative identification and localization of a bronchial carcinoid tumor with a radiolabeled somatostatin analogue (111In pentetreotide) and the use of a hand-held intraoperative gamma probe have been described. This approach also allowed scanning of the bed of the tumor after resection and excision of an area of increased isotope uptake that corresponded to residual tumor. Degree of ConfidenceKnown primary and metastatic tumor sites can be imaged with somatostatin analogue scintigraphy, with a sensitivity of 96%. Also, the further detection of previously undiagnosed and unsuspected deposits has been reported by several groups. Octreotide radioisotope uptake facilitates the selection of patients with carcinoids that are likely to respond favorably to octreotide treatment. Patients negative for somatostatin receptors may be treated with agents such as interferon-alpha, 131I MIBG, or chemotherapy. Somatostatin-analogue scintigraphy has been shown to demonstrate tumor in 4 of 12 patients with ectopic ACTH syndrome.32 The inclusion of somatostatin analogue scintigraphy in the staging protocol of small cell lung cancer may lead to upstaging of the disease in patients who are initially thought to have limited disease on the basis of conventional imaging results. False Positives/NegativesFindings from somatostatin analogue scintigraphy may be positive in cases involving other neuroendocrine tumors. Somatostatin receptors have been demonstrated in granulomatous diseases, such as sarcoidosis and other immune-mediated disorders (eg, anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis). ANGIOGRAPHYSection 9 of 12
FindingsBronchial carcinoids are highly vascular tumors that are usually supplied by bronchial arteries, which may appear aberrant and hypertrophied on angiography. Bronchial arborization with abnormal beaded vessels that may extend beyond the tumor into distal pneumonitis has been described as a feature. Despite the neovascularity seen in bronchial carcinoids, bronchial angiography has no role in the diagnosis of these tumors.33 False Positives/NegativesAn aberrant location of a bronchial artery may lead to confusion with pulmonary sequestration. However, bronchial arborization has not been reported as a feature of sequestrated segments. INTERVENTIONSection 10 of 12
Procedures Because these tumors are generally resistant to chemotherapy, complete surgical resection is the primary form of therapy.34 Long-term survival for patients with typical carcinoid is excellent but is decreased in those with the atypical subtype. Complete tumor resection with preservation of uninvolved pulmonary parenchyma remains the primary aim in the surgical treatment of this tumor. Most tumors follow a benign course and are amenable to surgery. Techniques range from radical resection to minimally invasive surgery, including sleeve resection. The treatment of choice is surgical excision. A sleeve resection of part of a bronchus, segmental resection, lobectomy, or pneumonectomy may be required.35, 36 Endoscopic tumor ablation techniques have been used. Thoracotomy may be required in rare cases in which the diagnosis cannot be established by imaging means. Massive hemorrhage after bronchoscopic biopsy has been described and is due to the highly vascular nature of carcinoids. However, the majority of bronchoscopic biopsy procedures are associated with little added morbidity. Percutaneous aspiration or cutting-needle biopsy is indicated for peripheral lung nodules. The procedure may be performed under fluoroscopic or CT guidance. Percutaneous biopsy may also be performed on nodules in patients presenting with Cushing syndrome to analyze the specimen for ACTH. Bronchial lavage results are not usually diagnostic. Relative contraindications to percutaneous lung biopsy include the following: bleeding diathesis, poor respiratory reserve, inability of the patient to cooperate, bullous disease surrounding the lesion, pulmonary hypertension, and previous pneumonectomy. Complications Pneumothorax and hemorrhage are the most common complications. The incidence of pneumothorax is 10-30%. Hemoptysis is usually a self-limiting complication. Medical/Legal Pitfalls
See also the Medscape topic Medical Malpractice and Legal Issues. MULTIMEDIASection 11 of 12
REFERENCESSection 12 of 12
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