You are in: eMedicine Specialties > Radiology > CHEST Lung Cancer, Small CellArticle Last Updated: Apr 12, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 12
  Author: Abid Irshad, MD, Assistant Professor, Department of Radiology, Medical University of South Carolina Abid Irshad is a member of the following medical societies: Radiological Society of North America and Society of Breast Imaging Coauthor(s): James Ravenel, MD, Assistant Professor of Radiology, Chief of Thoracic Imaging, Clinical Director of Computed Tomography, Assistant Residency Program Director, Department of Radiology, Medical University of South Carolina; Susan Ackerman, MD, Director of Ultrasound, Assistant Professor, Department of Radiology, Medical University of South Carolina 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; Eric J Stern, MD, Director of Thoracic Imaging, Professor of Radiology and Medicine, Departments of Radiology and Internal Medicine, Harborview Medical Center, University of Washington School of Medicine; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Eugene C Lin, MD, Consulting Staff, Department of Radiology, Virginia Mason Medical Center Author and Editor Disclosure Synonyms and related keywords: SCLC, small cell lung cancer, small-cell lung cancer, oat cell cancer, Kulchitsky cell tumor, undifferentiated airway epithelial cell, neuroendocrine tumor, small SCLC, mixed SCLC, combined SCLC, limited SCLC, extensive SCLC INTRODUCTIONSection 2 of 12
  BackgroundCurrently, lung cancer is the leading cause of cancer deaths both in males and females in the US. The incidence of lung cancer is about 60 cases per 100,000 population, and small-cell lung cancer (SCLC) accounts for about 15-25% cases of lung cancer. Historically, the histologic identification of small cell cancer dates back to the 1920s, when the small cell/oat cell tumor was shown to be a carcinoma of the lung and not an oat cell sarcoma of the mediastinum, as thought earlier. This cancer was also noted to occur in patients younger (27-66 y) than those with the other cancers. Since that time, many histologic subtypes of SCLC have been found, and attempts have been made to classify this tumor. However, disagreement regarding the classifications still exists. In 1998, the International Association for the Study of Lung Cancer (IASLC) classified SCLC into 3 general histologic subtypes: small, mixed, and combined. According to this classification, the small-cell subtype includes the previous World Health Organization (WHO) variety of oat cell and intermediate types. The mixed variety encompasses mixed-cell and large-cell cancers. (In the WHO classification, this is considered a combined variety.) The combined variety includes a significant proportion of squamous cell or adenocarcinoma cell cancers in addition to small-cell cancers (1-3% of cases of SCLC). In 1973, the British Medical Research Council reported that patients with SCLC had a poor prognosis and that SCLC was considered a distinct clinicopathologic entity. After that report, different treatment options were considered, and surgery alone was found to be an insufficient method of treatment. A better response was obtained with the addition of chemotherapy and irradiation. Because SCLC is considered a systemic disease, the clinical course, prognosis, and treatment options are clearly different from those of other lung cancers. Clinically, lung cancers are often categorized into SCLCs and non-SCLCs (NSCLCs). SCLC is categorized into 2 stages: limited disease and extensive disease. The disease is termed limited when it is confined to an area of the chest that can be encompassed by a single irradiation port; supraclavicular nodes may be included. The disease is called extensive when metastasis outside the thorax is present or when intrathoracic disease cannot be contained in a single irradiation port. Patients with SCLC are rarely surgical candidates, and they are usually treated with irradiation and/or chemotherapy. On the contrary, patients with NSCLC are usually evaluated for possible surgical excision, and their disease is staged by using the common tumor, nodes, and metastases (TNM) staging system. For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Lung Cancer and Understanding Lung Cancer Medications. PathophysiologySCLC has been found to be strongly associated with cigarette smoking. Studies have also shown that the incidence of SCLC increases in association with radiation exposure. Both smoking and radiation exposure have synergistic effects as risk factors. Exposure to the industrial agent chloromethyl ether (Bis) is also associated with SCLC. The role of dietary, immunologic, genetic, and other factors is not yet clear. SCLC is an aggressive tumor. Despite its neuroendocrine features, whether the origin of this tumor is a neuroendocrine cell (Kulchitsky cell) or an undifferentiated airway epithelial cell is not clear. SCLC mostly originates in the proximal airways such as the lobar bronchi or main bronchi. A small percentage (<5%) originate in the peripheral areas of the lung. The tumor is highly cellular and has a limited fibrotic or inflammatory response. Consequently, the tumor spreads to the submucosal and perivascular connective tissues, to the lymphatics, and to the blood vessels at an early stage, resulting in early nodal and metastatic deposits. Histologically, the oat-cell variety involves small cells (about 2-3 times the size of lymphocytes) with finely stippled chromatin, small or absent nucleoli, and scanty cytoplasm. The intermediate type includes fusiform or polygonal variants with slightly coarser chromatin clumping, variable cell sizes, and nucleoli with relatively abundant cytoplasm. Neurosecretory granules are noted in most of SCLC cells; however, these are fewer and smaller that the cells in carcinoid tumors. Other markers and indicators that have been studied include chromogranin, synaptophysin, Leu-7, carcinoembryonic antigen (CEA), abnormal p53 expression, and a variety of neuropeptides. Many changes have been noted in the cellular genetics of SCLC. Examples of these changes include an abnormal deletion in chromosome 3; alterations in the retinoblastoma gene on chromosome 13; and the presence of BCL2, C-myc, or N-myc oncogenes. However, until now, none of these changes has replaced the traditional morphologic criteria used to diagnose SCLC. FrequencyUnited StatesSCLC represents about 15-25% of all lung cancers. Mortality/MorbidityFor SCLC, the 5-year survival rate is 1-5%, and the overall median survival is about 6-10 months. Some investigators have found a poorer prognosis with mixed small- and large-cell types. About 70% of patients with SCLC present with extensive disease, and only 30% have disease limited to the thorax. One group reported 2-year survival rates of about 10% for limited disease and about 3% for extensive disease. Extensive disease with only brain metastasis may have a survival rate similar to that of limited disease.
Race
SexThe incidence of SCLC has been higher in males than in females. However, because more females are now smoking, the incidence has increased in females, and the difference in the rates has decreased. AgeSCLC generally occurs in a population younger (27-66 y) than that with non-SCLC (44-61 y). AnatomySCLC is generally a disease originating in the central airways. It usually arises from the lobar or main bronchi, and it rarely arises from the trachea. Endobronchial growth frequently occurs. Hilar, paratracheal, and subcarinal groups of lymph nodes are involved early in the course of the disease. Most of the tumoral blood supply is derived from the bronchial arteries, with only a limited supply derived from the pulmonary arteries. Clinical DetailsThe clinical symptoms usually start early, probably because of a central location of the tumor, early invasion, early metastasis, or associated paraneoplastic syndromes. Signs and symptoms may be related to local effects of the tumor. These may include cough, hemoptysis, chest pain, dyspnea, and wheezing. Symptoms due to the involvement of adjacent structures include dysphagia, hoarseness, and superior vena cava (SVC) syndrome. In fact, SCLC is one of the most common causes of SVC syndrome. Nonspecific constitutional signs and symptoms include fever, weight loss, anorexia, fatigue, and malaise, among others. Distant metastasis may cause related symptoms. Metastasis to the brain is more common in SCLC than in NSCLC. The cancer also frequently metastasizes to the bones, liver, and adrenal glands. Extrathoracic non-metastatic manifestations, or the paraneoplastic syndromes (PNS), are more common in SCLC than in NSCLC. Neuromuscular PNSs include Eaton-Lambert myasthenic syndrome (which occurs in 3-6% of SCLCs) and polymyositis. Neuropathy involves peripheral and autonomic nerves and is associated with anti-Hu antibody. Cerebellar degeneration, encephalomyelitis, or limbic encephalitis (rare) has also been associated with SCLC. A more common cause of cerebral symptoms in a patient with SCLC is brain metastasis. Many cutaneous PNS have been described; these include acanthosis nigricans and hypertrichosis lanuginosa, among others. By contrast, hypertrophic pulmonary osteoarthropathy is distinctly uncommon in SCLC, unlike NSCLC. Many endocrine syndromes are associated with SCLC because of the secretion of neuroendocrine hormones. These include Cushing syndrome (which involves adrenocorticotropic hormone [ACTH]), syndrome of inappropriate antidiuretic hormone (ADH) secretion, hyperparathyroidism, carcinoid syndrome, gynecomastia (which involves gonadotropins), hyperpigmentation (which involves melanocyte-stimulating hormone), hypoglycemia (which involves an insulin-like substance), and hypocalcemia (which involves calcitonin). Other features include the following: anemia, thrombocytopenia, migratory thrombophlebitis, leukocytosis, thrombocytosis and glomerulonephritis. Preferred ExaminationThe usefulness of the various imaging examinations largely depends on the clinical findings at the time of presentation and also on the stage of the disease. Many imaging modalities are used to further evaluate the findings seen on the previous imaging and to determine the stage of the disease. Commonly used imaging modalities start with simple ones such as chest radiography and progress to more sophisticated modalities such as CT and/or MRI, and even more sophisticated and costly ones such as positron emission tomography (PET). Conventional radiography is not helpful in finding early disease. When the mass or mass effect is visible on a radiograph, the disease is almost invariably in an advanced stage. Although some institutions use low-dose CT to detect early NSCLC, it is probably not effective in evaluating SCLC. Contrast-enhanced CT is routinely used to further evaluate any suspicious abnormality noted on radiographs. This examination is also routinely used to determine the stage of a known SCLC, to follow up patients after treatment, and to evaluate distant metastatic disease. Although most centers do not routinely use MRI to evaluate the primary lesion in the chest, it may provide useful information in problematic cases of mediastinal invasion. MRI does have a role in ruling out brain metastatic lesions and in differentiating questionable adrenal masses. In pregnant patients, MRI can also be used instead of CT, to avoid the potential effects of ionizing radiation. PET with 2-[fluorine 18]-fluoro-2-deoxy-D-glucose (FDG) has recently received attention, and growing evidence suggests its superiority in the staging of lung cancer. However, PET is more frequently used in evaluating patients with NSCLC to identify surgical candidates. It is less commonly used in patients with SCLC because most of these patients are not candidates for surgery. PET is also useful for evaluating cases in which recurrent disease is questionable. Bone scanning is routinely used to evaluate bony metastatic disease. In nuclear medicine, imaging with technetium-99m–labeled monoclonal antibody has shown some promising results in the evaluation of SCLC; however, this study is not widely used in clinical practice. Limitations of TechniquesSCLC is a histologic diagnosis that is always based on findings in tissue biopsy samples. Imaging only shows suspicious abnormalities that are invariably examined at subsequent biopsy to establish the tissue diagnosis. As mentioned earlier, chest radiography has limited usefulness in detecting early SCLC. In most cases in which an abnormality is visible on a radiograph, the cancer has already metastasized. Radiography has poor sensitivity and specificity, and almost all suspicious abnormalities require further evaluation with other modalities, most often CT. CT shows the anatomic details of the lesion well. CT may have lower sensitivity than MRI in detecting mediastinal invasion. Because CT staging involves criteria based on the size of the lymph nodes, CT has an inherent limitation. Disease may be overstaged if enlarged benign lymph nodes are measured, or disease may be understaged if the microscopically involved normal-sized nodes are classified as being benign. The spatial resolution of MRI is generally considered to be lower than that of CT. For this reason, a group of nodes may sometimes be falsely mistaken as a single large node. Also, because of the inability to detect calcium with MRI, enlarged and calcified benign nodes may be mistaken for pathologic nodes. The cost of MRI and the artifacts due to cardiac and vascular pulsation and respiratory movements limit its usefulness in evaluating primary lung cancer in most cases; however, MRI may be useful in special circumstances. Although PET is emerging as a popular modality for evaluating many cancers, the usefulness of PET is limited because of its cost and unavailability in many clinical practices. Generally, the resolution of PET is not considered good for lesions smaller than 1 cm. The PET results can also overlap with the standard uptake values (SUVs) in some benign lesions and malignant lesions. DIFFERENTIALSSection 3 of 12
Bronchogenic Cyst Other Problems to Be ConsideredThe major differential diagnoses on plain radiographs are other causes of mediastinal and hilar masses. Other causes of mediastinal mass include the following. Lymphadenopathy from other malignant lesions LymphomaLeukemia Metastasis from other cancers Angioimmunoblastic lymphadenopathy Benign lymphadenopathy Inflammatory processes such as tuberculosis (TB), fungal infections, etc Castleman disease Sarcoidosis Other causes Bronchogenic cyst Duplication cyst Neurogenic tumors Teratodermoid tumor Thymoma Vascular aneurysm Esophageal lesions Mesenchymal tumors Mediastinal lipomatosis The causes of hilar mass may similarly include lymphadenopathy due to any other cause, other types of tumors, cysts, and vascular abnormalities, among others. RADIOGRAPHSection 4 of 12
FindingsChest radiographs may show unilateral hilar enlargement, increased hilar opacity, a perihilar mass, mediastinal mass, or a combination of these. Less commonly, SCLC may appear as a solitary pulmonary nodule. Compression of the bronchi is relatively common in SCLC because of the central location of the tumor in most cases. About 30-50% of SCLCs show evidence of obstructive pneumonitis on the initial presentation. SCLC can appear as segmental or lobar atelectasis with or without an obvious hilar mass. The S sign of Golden is seen when a collapsed upper lobe forms a meniscus concave toward the hilum and when an enlarged hilar mass forms the convex meniscus of the S. Occasionally, endobronchial growth or bronchial compression may be appreciated as a bronchial cutoff or filling defect. Thickening of the right paratracheal stripe may be an indication of right paratracheal lymphadenopathy. With massive subcarinal lymphadenopathy, widening of the carinal angle may occasionally be observed. Subtle changes of hilar asymmetry, increased opacity, a convex or lobulated outer hilar border, or any change from a previous radiograph should be viewed with suspicion. Involvement of pleura or pericardium may result in pleural or pericardial effusions. Rarely, involvement of a pulmonary artery may result in compression of the artery with oligemia in the area of distribution. Invasion of pulmonary artery may result in pulmonary metastatic lesions. Large mediastinal masses may lead to lymphatic obstruction, which may result in reticulonodular opacities in the lung. Lateral views are complimentary to the frontal views and help in assessing the mediastinal abnormalities, especially in the retrosternal and hilar regions. Paratracheal masses and thickening of posterior wall of the bronchus intermedius may be seen on the lateral view. Degree of ConfidenceThe degree of confidence is low because a bulky mediastinal mass may also be seen in a variety of conditions other than SCLC (see Differentials). False Positives/NegativesSee above. CT SCANSection 5 of 12
FindingsCT scanning is the modality most commonly used for the evaluation and characterization of an abnormality depicted on a chest radiograph. CT is used to assess the size or volume of the tumor, mediastinal involvement, pathologically enlarged lymph nodes, and vascular invasion. It is also sensitive in detecting pleural and pericardial effusion or thickening. Nodularity of pleura or pericardium is the hallmark of metastatic involvement. Contrast-enhanced CT can sometimes be used to differentiate a tumor mass from the adjacent collapsed lung or pneumonitis, which usually enhances more than the tumor. Sometimes, air bronchograms are observed. Three-dimensional (3D) images reconstructed from thin sections through the mass improved the sensitivity in detecting invasion of adjacent organs. Chest-wall invasion can be demonstrated with evidence of rib destruction (the most specific finding), pleural thickening, and obliteration of the extrapleural fat line. An obtuse angle of the mass with the chest wall may also suggest invasion. Pain in the chest wall is a more specific sign of involvement. Similarly, contact with the mediastinum of more than 3 cm, contact with aorta of more than 90°, invasion of the mediastinal fat, and pleural or pericardial thickening are considered signs of mediastinal invasion. CT scans can also show endobronchial growth and the degree of compression of the bronchi or vessels. The size of lymph nodes is generally estimated for staging purposes by measuring the short axis of the lymph nodes. Compared with the long axis, the short axis is a more accurate predictor of the volume. For practical purposes, a short-axis measurement greater than 1 cm is generally considered abnormal in the chest. However, some have observed different measurements in different groups of patients. CT of the chest routinely includes imaging of the adrenal glands, which are common sites for SCLC metastases. A lesion with an attenuation value less than 10 HU on a nonenhanced CT scan most likely represents an adenoma (90% accuracy). CT of the abdomen and pelvis is also generally indicated in staging SCLC to rule out metastases to the liver, nodes, or other organs. CT of the head helps in ruling out brain metastasis, which is also common in SCLC. CT is also routinely used to follow up patients with SCLC after irradiation and chemotherapy. Degree of ConfidenceCT is reasonably accurate in depicting suspicious or indeterminate masses and for staging SCLCs. False Positives/NegativesWith CT scanning, criteria based on the size of the lymph nodes are used for staging the disease. This method has inherent limitations. False-positive findings are due to enlarged benign reactive nodes, and false-negative findings are due to microscopically involved normal-sized metastatic nodes. MRISection 6 of 12
FindingsMRI is not routinely used for detecting the primary tumor or for staging. However, it may sometimes help in problematic cases because MRI offers improved tissue contrast resolution and a multiplanar imaging capability. In primary tumors, MRI can sometimes help in differentiating tumor from surrounding atelectasis or pneumonitis, which has relatively high signal intensity on T2-weighted images as opposed to the relatively low signal intensity of the tumor. Gadolinium-enhanced MRI may also be helpful because the lung enhances rapidly, whereas the tumor usually enhances relatively slowly. MRI is also good for detecting nodes in the aorto-pulmonary window or for detecting subcarinal nodes because it can provide images in the sagittal and coronal planes. With chemical shift imaging, MRI is reliable in differentiating adrenal adenomas from possible metastasis because it shows decreases in signal intensity on out-of-phase images as compared with in-phase images. Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. As of late December 2006, the FDA had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble movingor straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape. Degree of ConfidenceMRI may be more sensitive than CT for the assessment of mediastinal, vascular, or chest wall invasion. MRI is considered superior to CT for detecting brain metastatic lesions and for evaluating the adrenal masses. False Positives/NegativesBecause of the relatively low spatial resolution of MRI compared with that of CT, a cluster of small lymph nodes may occasionally be mistaken for a single enlarged node. This observation can lead to a false-positive finding. Also, calcifications may be missed on MRIs. ULTRASOUNDSection 7 of 12
FindingsChest ultrasonography has no primary role in the diagnosis or staging of lung cancer. However, abdominal scans sometimes reveal metastatic lesions in the liver, adrenal glands, lymph nodes, or other abdominal or pelvic organs. This finding indicates extensive disease. NUCLEAR MEDICINESection 8 of 12
FindingsBone scanning Bones are the most common sites for metastatic disease in SCLC. Bone scanning is used as one of the tools for staging the SCLC as well as for follow-up. Because an SCLC metastasizes early in its course, bone scanning is an important modality for ruling out bony metastatic disease. Metastatic disease is usually seen as multiple asymmetric areas of increased uptake, mostly in the axial skeleton. A normal bone scan result usually excludes metastatic disease; however, in rare cases, aggressive osteolytic lesions with little bone reaction may not be evident. Similarly, benign conditions such as fractures or degenerative disease may occasionally be confused with metastatic disease. Positron emission tomography PET is one of the most rapidly emerging modalities for the evaluation, staging, and post-therapeutic follow-up of cancer. PET combines the functional and anatomic aspects of the lesions. PET primarily depends on the metabolism of the glucose, which is usually high in tumor cells. By measuring the SUVs within the lesions, the malignant lesions (which usually have values greater than 2.5) can be reliably differentiated from the benign lesions in most cases. However, the values can overlap. PET can be used for staging purposes by determining nodal involvement and distant metastasis. CT is usually used along with PET for anatomic comparison. Some studies have shown that PET is more sensitive than CT for staging purposes. Recently, some studies have also shown that PET has good sensitivity in detecting bony metastasis. The main limitations of PET use are its cost, its limited availability, and the lack of expertise in performing the examination. Ventilation/perfusion scanning Infrequently, when surgery is being considered in the treatment of a peripheral SCLC with limited disease, lung ventilation/perfusion scanning is sometimes helpful for surgical planning to assess the respiratory reserve and perfusion distribution after lobectomy or pneumonectomy. Monoclonal antibody scanning Monoclonal antibody study with technetium-99m NRLU whole-body scanning has been shown to be sensitive in detecting SCLC. However, this study has not been widely used in clinical practice. [Iodine-131]6-beta-iodomethyl-19-norcholesterol nuclear imaging [Iodine-131]6-beta-iodomethyl-19-norcholesterol (NP-59) nuclear imaging is sometimes used to differentiate adrenal metastasis from adrenal adenomas (which take up the agent). Degree of ConfidencePease see the discussion above. False Positives/NegativesPlease see the discussion above. ANGIOGRAPHYSection 9 of 12
FindingsAngiography generally has no primary role in the diagnosis, staging, or follow-up of SCLC. However, in some cases, it may be used to evaluate vascular involvement or to plan surgery. INTERVENTIONSection 10 of 12
CT scanning is generally used to guide biopsy of suspicious lesions. It can be used to guide transbronchial biopsy by demonstrating the location of the lesions, or it can be used for direct CT-guided percutaneous transthoracic biopsy. Similarly, ultrasonographic can also be used to guide biopsy of suspicious intra-abdominal or pelvic lesions. Because SCLC is considered a systemic disease, the clinical course, prognosis, and treatment options are clearly different from those of other lung cancers. Management largely depends on the stage (limited disease vs extensive disease). Imaging helps in staging the disease. Surgery is not routinely indicated. Disease limited to the chest is usually treated with chemotherapy and irradiation, whereas extensive disease with distant metastasis is treated with chemotherapy alone. Patients with SCLC are rarely surgical candidates, and they are usually treated with irradiation and/or chemotherapy. Patients with NSCLC are usually evaluated for possible surgical excision, and their disease is staged by using the common TNM staging system. Because of the high incidence of brain metastasis in SCLC, prophylactic irradiation of brain may help preventing metastatic disease in the brain. MULTIMEDIASection 11 of 12
REFERENCESSection 12 of 12
Lung Cancer, Small Cell excerpt Article Last Updated: Apr 12, 2007 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
