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    Drugs & Diseases>Oncology

    Small Cell Lung Cancer (SCLC)

    Updated: Dec 18, 2024
    • Author: Winston W Tan, MD, FACP; Chief Editor: Nagla Abdel Karim, MD, PhD  more...
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    Overview

    Practice Essentials

    Small cell lung cancer (SCLC), previously known as oat cell carcinoma, is considered distinct from other lung cancers, which are called non–small cell lung cancers (NSCLCs) because of their clinical and biologic characteristics. See the image below.

    High-power photomicrograph of small cell carcinomaHigh-power photomicrograph of small cell carcinoma on the left side of the image with normal ciliated respiratory epithelium on the right side of the image.
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    SCLC is a neuroendocrine carcinoma that exhibits aggressive behavior, rapid growth, early spread to distant sites, exquisite sensitivity to chemotherapy and radiation, and frequent association with distinct paraneoplastic syndromes, including hypercalcemia, Eaton-lambert syndrome, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, and many others. (See Pathophysiology, Etiology, and Presentation.) [1, 2, 3, 4]

    In patients who present with SCLC, it is important to determine whether the cancer is limited or at an extensive stage. Limited-stage cancer, which is potentially curable, is treated with chemotherapy and radiation, with surgical resection reserved for selected patients with stage I disease. Extensive-stage cancer is incurable; systemic chemotherapy and immune checkpoint inhibitors are used to improve quality of life and prolong survival. [5]  See Treatment and Medication.

    Next: Pathophysiology

    Pathophysiology

    SCLC arises in peribronchial locations and infiltrates the bronchial submucosa. Widespread metastases occur early in the course of the disease, with common spread to the mediastinal lymph nodes, liver, bones, adrenal glands, and brain.

    In addition, production of various peptide hormones leads to a wide range of paraneoplastic syndromes; the most common of these are the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and the syndrome of ectopic adrenocorticotropic hormone (ACTH) production. In addition, autoimmune phenomena may lead to various neurologic syndromes, such as Lambert-Eaton myasthenic syndrome.

    Gay et al identified four subtypes of SCLC, defined largely by differential expression of the transcription factors ASCL1, NEUROD1, and POU2F3. [6] The subtypes are as follows:

    • SCLC-A: Elevated expression of ASCL1
    • SCLC-N: Elevated expression of NEUROD1
    • SCLC-P: Elevated expression of POU2F3
    • SCLC-I: Low expression of all three transcription factor signatures accompanied by an inflamed (I) gene signature

    Each subtype has therapeutic vulnterabilties (eg, to inhibitors of polyadenosine diphosphate-ribose polymerase [PARP] inhibitors, aurora kinases, or BCL-2). In vitro, cisplatin treatment of SCLC-A induces intratumoral shifts toward SCLC-I which supports the hypothesis that subtype switching is a mechanism of acquired platinum resistance.  The addition of immunotherapy to chemotherapy is most beneficial in SCLC-I. [6]

     

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    Etiology

    The predominant cause of SCLC (and non-SCLC) is tobacco smoking. Of all histologic types of lung cancer, SCLC and squamous cell carcinoma have the strongest correlation with tobacco use. [7, 8] Approximately 98% of patients with SCLC have a smoking history. Patients with SCLC should be encouraged to stop smoking, as smoking cessation is associated with improved survival. [9]

    All types of lung cancer occur with increased frequency in uranium miners, but SCLC is the most common. The incidence of lung cancer is increased further in these individuals if they also smoke tobacco.

    Exposure to radon, an inert gas that is a product of uranium decay, has also been reported to cause SCLC.

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    Epidemiology

    Occurrence in the United States

    Lung cancer overall is the second most common malignancy in both sexes in the United States, exceeded in frequency only by prostate cancer in men and breast cancer in women. [10, 11, 12]  In both sexes, lung cancer is the most common cause of cancer death. Although less than half as many new cases of lung cancer than breast cancer are diagnosed in US women each year, almost twice as many US women die of lung cancer each year than from breast cancer.

    The incidence of small cell lung cancer (SCLC) has declined over the last few years, as smoking rates have fallen. [12] SCLC once accounted for 20-25% of all newly diagnosed lung cancers; it now comprises only about 13% of all lung cancers. [13]

    For 2024, the estimates for lung cancer overall in the United States are 234,580 new cases and 125,070 deaths. [14]

    International occurrence

    Globally, lung cancer is the most frequent malignancy in men (in Europe, lung cancer is second only to prostate cancer [15] ) and the fifth most common cancer in women. Although the incidence of lung cancer has been falling in the US, it is increasing at a staggering pace in developing countries due to the rising prevalence of tobacco use. According to World Health Organization (WHO) statistics, about 2.21 million new cases of lung cancer and 1.80 million deaths from lung cancer occurred worldwide in 2020. [16]

    Separate worldwide data for SCLC are not available. The incidence of lung cancer started to decline among men in the early 1980s and has continued to do so over the past 20 years. In contrast, the incidence in women started to increase in the late 1970s and did not begin to decline until the mid-2000s. [10, 12]

    Age- and sex-related demographics

    As with other histopathologic types of lung cancer, most cases of SCLC occur in individuals aged 60-80 years. 

    Over the past two decades, the incidence of lung cancer has generally decreased in both men and women 30 to 54 years of age in all races and ethnic groups. However, the incidence has declined more steeply in men. As a result, lung cancer rates in younger women have become higher than those in younger men. In non-Hispanic whites and Hispanics ages 44 to 49 years, for example, the female-to-male rate ratio for lung cancer incidence rose from 0.88 during 1995-1999 to 1.17 during 2010-2014. [17]

    This reversal can be explained in part by increased rates of cigarette smoking in women born since 1965. However, while the difference in smoking rates in that age group has narrowed, rates in women have generally not exceeded the rates in men, so other factors may be playing a role. For example, women may be more susceptible to the oncogenic effects of smoking. [17]

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    Prognosis

    Approximately 60-70% of patients with small cell lung cancer (SCLC) have clinically disseminated or extensive disease at presentation. Extensive-stage SCLC is incurable. When given combination chemotherapy, patients with extensive-stage disease have a complete response rate of more than 20% and a median survival longer than 7 months; however, only 2% are alive at 5 years. [18] For individuals with limited-stage disease that is treated with combination chemotherapy plus chest radiation, a complete response rate of 80% and survival of 17 months have been reported; 12-15% of patients are alive at 5 years. [19]

    Genome-wide association studies have identified single-nucleotide polymorphisms (eg, within the promoter region of YAP1 on chromosome 11q22) that may affect survival in patients with SCLC. [20, 21]  

    Indicators of poor prognosis include the following:

    • Relapsed disease
    • Weight loss of greater than 10% of baseline body weight
    • Poor performance status
    • Hyponatremia [22]
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    Patient Education

    Because tobacco smoking is the predominant cause of lung cancer, the only means of decreasing the incidence of this disease overall, as well as that of small cell lung cancer (SCLC) specifically, is to decrease the prevalence of smoking. The evidence is clear that the declining incidence of lung cancer in men in the United States has coincided with a decrease in smoking among males.

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