Introduction
Background
Lung cancer is the leading cause of cancer deaths both in males and females in the United States. 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).1
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 SCLC and non-SCLC (NSCLC).
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.
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Lung Cancer, Non-Small Cell
Lung Cancer, Oat Cell (Small Cell)
Lung Cancer, Staging
Lung, Carcinoid
Lung, Metastases
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Pathophysiology
Small cell lung cancer (SCLC) 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. 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 SCLC cells; however, these are fewer and smaller than 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.
Frequency
United States
Small cell lung cancer (SCLC) represents about 15-25% of all lung cancers.
Mortality/Morbidity
For small cell lung cancer (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 cell 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.
- Patients who live longer are at risk of having a second malignancy.
- Generally, the prognosis depends on the stage of the disease, on the histologic type, and on other clinical factors.
Race
- In whites, small cell lung cancer (SCLC) occurs at a rate proportionally higher than that of African Americans.
- White patients typically have a course or outcome worse than that of patients of other races.2
Sex
The incidence of small cell lung cancer (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.
Age
Small cell lung cancer (SCLC) generally occurs in a population younger (27-66 y) than that with non-SCLC (44-61 y).
Anatomy
Small cell lung cancer (SCLC) 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.
Presentation
The clinical symptoms of small cell lung cancer (SCLC) usually start early, probably because of a central location of the tumor, early invasion, early metastasis, or associated paraneoplastic syndromes.
Signs and symptoms of SCLC 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.3
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.4 The cancer also frequently metastasizes to the bones, liver, and adrenal glands.
Extrathoracic nonmetastatic manifestations, or the paraneoplastic syndromes (PNS), are more common in SCLC than in NSCLC. Neuromuscular PNS includes Eaton-Lambert myasthenic syndrome (which occurs in 3-6% of cases of SCLC)5 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 cases of 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 in 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 anemia, thrombocytopenia, migratory thrombophlebitis, leukocytosis, thrombocytosis, and glomerulonephritis.
Preferred Examination
The 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; progress to more sophisticated modalities, such as CT and/or MRI; and then progress to even more sophisticated and costly ones, such as positron emission tomography (PET).6,7,8,9
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 non – small cell lung cancer (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.10
PET with fluorodeoxyglucose (FDG) has received increased attention, and growing evidence suggests its superiority in the staging of lung cancer.7,8,9 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 Techniques
Small cell lung cancer (SCLC) 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.
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.
Differential Diagnoses
Other Problems to Be Considered
The 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
Lymphoma
Leukemia
Metastasis from other cancers
Angioimmunoblastic lymphadenopathy
Benign lymphadenopathy
Inflammatory processes such as tuberculosis (TB), fungal infections
Castleman disease
Sarcoidosis
Other causes
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.
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Further Reading
Keywords
small cell lung cancer, SCLC, small-cell lung cancer, non-small cell lung cancer, NSCLC, oat cell cancer, Kulchitsky cell tumor, undifferentiated airway epithelial cell, neuroendocrine tumor, small SCLC, mixed SCLC, combined SCLC, limited SCLC, extensive SCLC, superior vena cava syndrome
