Lung, Carcinoid

 

Background: Bronchial carcinoid tumors are rare, accounting for as many as 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 a range of tumors ranging from bronchial carcinoid at one of the spectrum, with a small cell carcinoma, or possibly large cell neuroendocrine tumors at the other end. 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) and serotonin, somatostatin, and bradykinin.

Large-cell neuroendocrine carcinoma of the lung is a newly recognized clinicopathologic entity, which is distinct from small-cell carcinoma and has a poor prognosis.

Bronchial carcinoids are not associated with smoking, whereas small cell lung cancer (neuroendocrine type 3) has a definite relationship to smoking.

 

Pathophysiology:

Cellular origin

Bronchial carcinoid tumors arise from Kulchitsky cells (argentaffin cells) within the bronchial mucosa. The predominant distribution of cells occurs 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.

Pathologic findings

Gross pathologic examination of specimens usually reveals 3-4 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 two groups: Kulchitsky cell carcinoma (KCC) I (typical carcinoids), KCC II, (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, centrally placed within the mainstem bronchi, and 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 and account for one quarter of lung carcinoid tumors. These lesions are much more aggressive than typical carcinoids. They usually affect relatively old patients with a male preponderance, they are larger than the others at presentation, and they tend to occupy 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.

Large-cell neuroendocrine carcinoma of the lung is a newly recognized clinicopathologic entity. This disease is distinct from small-cell carcinoma and has a poorer prognosis. The clinical features and optimal treatment of a large-cell carcinoma has not yet been established.

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.

 

Frequency:

  • In the US: 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 primary large or liver metastases are present, often years after removal of the primary tumor.
  • Internationally: There are no data to suggest that the frequency of lung carcinoid internationally is any different to 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 such that 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 black patients.

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 more-common primary pulmonary bronchogenic carcinoma.
  • Patients with atypical carcinoids are reported to be about a decade older than patients with typical carcinoids.
  • Approximately 4% of lung carcinoids occur in children and adolescents. Bronchial carcinoid is the most common primary pulmonary neoplasm in childhood.

Clinical Details: 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 post-obstructive lung abscess. Some patients present with symptoms that mimic those of asthma.

Alternatively, patients may present with complications due to 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 not visible on chest radiographs (CXR) or CT scans. Carcinoid syndrome due to bronchial carcinoids is rare (2%-5%), and when present, it is associated with liver metastases. 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 detected incidentally.

Most pediatric patients present with wheezing and atelectasis although cough, hemoptysis, and pneumonitis are not rare.

Endobronchial carcinoids have a characteristic bronchoscopic appearance, being seen as smooth, polypoid lesions that appear cherry red. 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.

CT is useful for detecting lesions not visible on CXR, for assessing endobronchial lesions, and also for characterizing and staging of the tumors.

MRI may also be useful for in 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.

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 causes if it 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 other causes of endobronchial lesions and solitary pulmonary nodules. Intense homogenous 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 may also be either reactive or metastatic in etiology.

MRI has somewhat limited availability in the United Kingdom, and a proportion of patients are unsuitable because of contraindications or adverse effects, such as claustrophobia. In particular, the availability of positron emission tomography (PET) is also limited in the United Kingdom, and the technique is expensive. Somatostatin analogue scintigraphy is an extremely valuable tool, but its specificity is low, and its results may be positive in other neuroendocrine tumors and inflammatory conditions.

 

DIFFERENTIALS

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


X-RAY

Findings: 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.

Because the tumors are slow-growing, ancillary findings due to bronchial obstruction may also be seen. These 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, and this is seen as a well-defined round, elliptical, or triangular opacity pointing toward the hilum. It is occasionally branching, looking 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 sized 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 Confidence: CXR is usually the first imaging investigation. Approximately 90% of patients with bronchial carcinoid have an abnormal CXR, although appearances are often nonspecific, and imaging investigations are not helpful in differentiating the various pathologic types of bronchial carcinoid.

False Positives/Negatives: 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.


CAT SCAN

Findings: CT provides excellent anatomic detail of both the endobronchial and the extraluminal components of the tumor. 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 sized 2-4 cm. Extension into adjacent mediastinal structures is detectable on CT scans in more aggressive tumors.

Calcification is common and better appreciated on CT scans than on CXRs, and this is seen in 30%. The incidence of calcification is significantly higher in 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 is 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 or no enhancement.

Bronchial carcinoids metastasize to the mediastinal lymph nodes in 25% of cases; this feature is more accurately assessed on CT scans than other images. Findings related to bronchial obstruction are also well depicted with CT. Large polypoid lesions, which partly obstruct the bronchus, may produce a ball-valve affect, 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 due to 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 is 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 Confidence: CT 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/Negatives: Usually, a bronchial carcinoid cannot be distinguished from a carcinoma unless the lesion is demonstrably ossified. Carcinoids may be diffusely calcified and thereby mimic broncholithiasis. The intense homogenous 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 affect resulting in overinflation or expiratory airtrapping may result from inhaled foreign bodies, particularly in children.

 

MRI

Findings: 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.

Degree of Confidence: MRI 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/Negatives: Ultrafast contrast-enhanced MRI 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.

 

ULTRASOUND

Findings: Ultrasonography has no role in the diagnosis of bronchial carcinoid.

 

NUCLEAR MEDICINE

Findings: 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) and subtraction techniques improve detection.

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.

2-[fluorine 18]-fluoro-2-deoxy-D-glucose (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-hydroxytrytophan (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.

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 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 (Itoh, 2001).

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. Consequently radiopeptide therapy may offer a potential new treatment alternative for some lung cancers. 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 has 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 Confidence: 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, 131I MIBG, or chemotherapy. Somatostatin-analogue scintigraphy has been shown to demonstrate tumor in 4 of 12 patients with ectopic ACTH syndrome (Tabarin, 1999).

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/Negatives: Findings from somatostatin analogue scintigraphy may be positive in other neuroendocrine tumors and inflammatory conditions.

 

ANGIOGRAPHY

Findings: 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 (Mojab, 1974). Despite the neovascularity seen in bronchial carcinoids, bronchial angiography has no role in the diagnosis of these tumors.

False Positives/Negatives: An aberrant location of a bronchial artery may lead to confusion with pulmonary sequestration. However, however bronchial arborization has not been reported as a feature of sequestrated segments.

INTERVENTION

Intervention:

Procedures

The only effective treatment is surgical resection of the primary 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. Recently, 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 pose 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

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:

  • An early histologic diagnosis of a bronchial carcinoid is desirable because its prognosis is more favorable than that of its mimic, bronchogenic carcinoma.
  • FNA of suspected carcinoid tumors can occasionally be misdiagnosed as small cell carcinoma. The editor (Kitt Shaffer) has seen several cases where a nodule was diagnosed as small cell carcinoma based on an FNA, but did not respond to chemotherapy as expected, upon resection were found to be carcinoid tumors. Most small cell carcinomas may initially respond well to chemotherapy while most carcinoids do not.

PICTURES

 

Caption: Picture 1. Lung, carcinoid. Right, Chest radiograph (CXR) in a 45-year-old woman demonstrating 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.
Picture Type: CT
Caption: Picture 2. 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.
Picture Type: CT
Caption: Picture 3. Lung, carcinoid. Abdominal CT scan in a 70-year-old man presenting with liver metastases. Liver biopsy demonstrated a staining pattern typical of a carcinoid tumor.
Picture Type: CT
Caption: Picture 4. Lung, carcinoid. CT scans of the thorax in the same patient as in Image 3 reveals asymmetry of the bronchovascular bundles in the apex of the upper lobe. These are due to a small, subtle, hyperattenuating, peripheral, solitary pulmonary nodule immediately adjacent to the apical segmental bronchus of the right upper lobe. This finding is consistent with a primary bronchial carcinoid tumor. Right, Image with mediastinal window settings. Left, Image with lung window settings.
Picture Type: CT
Caption: Picture 5. Lung, carcinoid. Right, Standard posteroanterior (PA) chest radiograph in a 62-year-old man (a non-smoker) shows a coin lesion at the left lung base. Left, CT scan obtained with lung window settings confirmed the presence of a mass lesion in the left lower lobe. No lymphadenopathy was detectable with the mediastinal window setting. Note thickening of the lesser fissure; this is unrelated to the underlying pathology. Findings from percutaneous needle biopsy confirmed a carcinoid.
Picture Type: CT
Caption: Picture 6. Lung, carcinoid. Indium-111 octreotide scan of the thorax and subdiaphragmatic areas shows a primary lung carcinoid (arrow) and metastases in the liver.
Picture Type: Image