Lung Carcinoid Imaging
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 carcinoid tumors appear in the images below.)
Bronchial carcinoids belong to a group of neuroendocrine tumors, which range from bronchial carcinoid tumors at one end of the spectrum to, at the other end, small cell carcinomas 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, 8]
Bronchial carcinoids are not associated with smoking, whereas small cell lung cancer (neuroendocrine type 3) has a definite relationship to smoking.
Chest radiography is the first-line imaging investigation in most patients. Chest radiographs (CXRs) are abnormal in 90% of patients with bronchial carcinoid. 
Computed tomography (CT) scanning is useful for detecting lesions not visible on CXR, for assessing endobronchial lesions, and for characterizing and staging tumors. 
Magnetic resonance imaging (MRI) may also be useful for differentiating small tumors from adjacent vessels. 
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. 
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. [10, 9]
A proportion of patients are unsuitable for MRI because of contraindications or adverse effects, such as claustrophobia. Positron emission tomography (PET) scanning, 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. [11, 12, 13, 14]
KCC 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. A typical bronchial carcinoid and an endobronchial carcinoid are seen in the images below. 
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.
CXR 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. (See the image below.)
CXRs 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 scanning provides excellent anatomic detail of the endobronchial and extraluminal components of the tumor (see the images below). 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. [10, 9, 16]
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 scanning 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.
CT scanning 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.
Usually, 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.
All 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. [10, 17]
MRI may be useful in distinguishing small bronchial carcinoids from adjacent pulmonary vessels in the central third of the lung if CT scan findings are nondiagnostic or equivocal.
Ultrafast, 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.
Like 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) scanning and subtraction techniques improve detection. [16, 18, 19]
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.
Both CT and FDG-PET have limitations in the evaluation of the primary lung tumors and the detection of metastases. These limitations are particularly prominent with primary lung adenocarcinoma that presents as a subsolid nodule and in primary carcinoid tumors of the lung, as these malignancies commonly have low levels of FDG avidity. Misreading of CT and PET imaging can alter the diagnosis and staging when evaluating subsolid nodules and carcinoid tumors, and awareness and knowledge of this limitation is required for appropriate patient management. 
Carcinoid tumors show increased uptake and irreversible trapping of another PET tracer, carbon-11–labeled 5-hydroxytryptophan (5-HTP), a serotonin precursor.11 C-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 of11 C-labeled 5-HTP tracer does produce streak artifact overlying areas of interest in the upper abdomen. [21, 22, 23]
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. When11 C-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 with11 C-labeled 5-HTP can be used to monitor treatment effects. With11 C-labeled 5-HTP, Eriksson et al were able to detect small ACTH-producing bronchial carcinoids that were not detectable with other imaging techniques. 
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. 
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.
111 In 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid–lanreotide (111 In-DOTA-lanreotide) scintigraphy yields high tumor binding in various lung tumors, including carcinoids. Consequently, radiopeptide therapy may offer a potential new treatment alternative for some lung cancers.  Both111 In-DOTA-lanreotide and111 In-DOTA-Tyr3-octreotide can be used for the evaluation of somatostatin receptor–mediated radionuclide therapy. (See the image below.)
The intraoperative identification and localization of a bronchial carcinoid tumor with a radiolabeled somatostatin analogue (111 In 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.
In a Dutch study, 265 patients with inoperable or metastasized gastroenteropancreatic or bronchial neuroendocrine tumors who received [177 Lu-DOTA0,Tyr3]octreotate therapy reported significant improvement in global health status, quality of life, and symptoms of insomnia, appetite loss, and diarrhea. The study also found a decrease in tumor burden and prolongation of overall survival. 
Known 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,131 I MIBG, or chemotherapy. Somatostatin-analogue scintigraphy has been shown to demonstrate tumor in 4 of 12 patients with ectopic ACTH syndrome. 
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.
Findings 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).
Bronchial 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. 
An 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.
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Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR Consultant Radiologist and Honorary Professor, North Manchester General Hospital Pennine Acute NHS Trust, UK
Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR is a member of the following medical societies: American Association for the Advancement of Science, American Institute of Ultrasound in Medicine, British Medical Association, Royal College of Physicians and Surgeons of the United States, British Society of Interventional Radiology, Royal College of Physicians, Royal College of Radiologists, Royal College of Surgeons of England
Disclosure: Nothing to disclose.
Sumaira Macdonald, MBChB, PhD, FRCP, FRCR, EBIR Chief Medical Officer, Silk Road Medical
Sumaira Macdonald, MBChB, PhD, FRCP, FRCR, EBIR is a member of the following medical societies: British Medical Association, Cardiovascular and Interventional Radiological Society of Europe, British Society of Interventional Radiology, International Society for Vascular Surgery, Royal College of Physicians, Royal College of Radiologists, British Society of Endovascular Therapy, Scottish Radiological Society, Vascular Society of Great Britain and Ireland
Disclosure: Received salary from Silk Road Medical for employment.
Carolyn M Allen, MBChB, MRCP, FRCR Consultant Radiologist, Clinical Director, Department of Clinical Radiology, North Manchester General Hospital, UK
Carolyn M Allen, MBChB, MRCP, FRCR is a member of the following medical societies: Society of Thoracic Radiology
Disclosure: Nothing to disclose.
Klaus L Irion, MD, PhD Consulting Staff, The Cardiothoracic Centre Liverpool NHS Trust, The Royal Liverpool University Hospital, UK
Disclosure: Nothing to disclose.
Sarah Al Ghanem, MBBS Consulting Staff, Department of Medical Imaging, King Fahad National Guard Hospital, Saudi Arabia
Disclosure: Nothing to disclose.
Bernard D Coombs, MB, ChB, PhD Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand
Disclosure: Nothing to disclose.
W Richard Webb, MD Professor, Department of Radiology, University of California, San Francisco, School of Medicine
Disclosure: Nothing to disclose.
Kavita Garg, MD Professor, Department of Radiology, University of Colorado School of Medicine
Disclosure: Nothing to disclose.
Kitt Shaffer, MD, PhD
Kitt Shaffer, MD, PhD is a member of the following medical societies: American Roentgen Ray Society
Disclosure: Nothing to disclose.
Lung Carcinoid Imaging
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