Case-Based Review

Small-Cell Lung Cancer



From the Karmanos Cancer Institute, Detroit, MI (Dr. Mamdani) and the Indiana University School of Medicine, Indianapolis, IN (Dr. Jalal).


  • Objective: To review the clinical aspects and current practices of management of small cell lung cancer (SCLC).
  • Methods: Review of the literature.
  • Results: SCLC is an aggressive cancer of neuroendocrine origin with a very strong association with smoking. Approximately 25% of patients present with limited-stage disease while the remaining majority of patients have extensive-stage disease, defined as disease extending beyond one hemithorax at the time of diagnosis. SCLC is often associated with endocrine or neurologic paraneoplastic syndromes. The treatment of limited-stage disease consists of platinum-based chemotherapy administered concurrently with radiation. Patients with partial or complete response should be offered prophylactic cranial radiation (PCI). Extensive-stage disease is largely treated with platinum-based chemotherapy and the role of PCI is more controversial. The efficacy of second-line chemotherapy after disease progression on platinum based chemotherapy is limited.
  • Conclusion: Despite a number of advances in the treatment of various malignancies over the period of past several years, the prognosis of patients with SCLC remains poor. There have been a number of clinical trials utilizing novel therapeutic agents to improve outcomes of these patients; however, few of them have shown marginal success in a very select subgroup of patients.

Key words: lung cancer; small-cell lung cancer.

Small-cell lung cancer (SCLC) is an aggressive cancer of neuroendocrine origin, accounting for approximately 15% of all lung cancer cases, with approximately 33,000 patients diagnosed annually [1]. The incidence of SCLC in the United States has steadily declined over the past 30 years presumably because of decrease in the percentage of smokers and change to low-tar filter cigarettes [2]. Although the incidence of SCLC has been decreasing, the incidence in women is increasing and the male-to-female incidence ratio is now 1:1 [3]. Nearly all cases of SCLC are associated with heavy tobacco exposure, making it a heterogeneous disease with complex genomic landscape consisting of thousands of mutations [4,5]. Despite a number of advances in the treatment of non-small cell lung cancer over the past decade, the therapeutic landscape of SCLC remains narrow with median overall survival (OS) of 9 months in patients with advanced disease.

Case Study

Initial Presentation

A 61-year-old man presents to the emergency department with progressive shortness of breath and cough over the period of past 6 weeks. He also reports having had 20-lb weight loss over the same period of time. He is a current smoker and has been smoking one pack of cigarettes per day since the age of 18 years. A chest x-ray performed in the emergency department shows a right hilar mass. Computed tomography (CT) scan confirms the presence of a 4.5 cm right hilar mass with presence of enlarged mediastinal lymph nodes bilaterally.

What are the next steps in diagnosis?

SCLC is characterized by rapid growth and early hematogenous metastases. Consequently, only 25% of patients have limited-stage disease at the time of diagnosis. According to the VA staging system, limited-stage disease is defined as tumor that is confined to one hemithorax and can be encompassed within one radiation field. This typically includes mediastinal lymph nodes and ipsilateral supraclavicular lymph nodes. Extensive-stage disease is the presentation in 75% of the patients where the disease extends beyond one hemithorax. Extensive-stage disease includes presence of malignant pleural effusion and/or distant metastasis [6]. The Veterans Administration Lung Study Group (VALG) classification and staging system is more commonly used compared to the AJCC TNM staging system since it is less complex, directs treatment decisions, and correlates closely with prognosis. Given its propensity to metastasize quickly, none of the currently available screening methods have proven to be successful in early detection of SCLC. Eighty-six percent of the 125 patients that were diagnosed with SCLC while undergoing annual low-dose chest CT scans on National Lung Cancer Screening Trial had advanced disease at diagnosis [7,8]. These results highlight the fact that he majority of the SCLC develop in the interval between annual screening imaging.

SCLC frequently presents with a large hilar mass that is symptomatic. In addition, SCLC usually presents with centrally located tumors and bulky mediastinal adenopathy. Common symptoms include shortness of breath and cough. SCLC is commonly located submucosally in the bronchus and therefore hemoptysis is not a very common symptom at the time of presentation. Patients may present with superior vena cava (SVC) syndrome from local compression by the tumor. Not infrequently, SCLC is associated with paraneoplastic syndromes (PNS) owing to the ectopic secretion of hormones or antibodies by the tumor cells. The PNS can be broadly categorized into endocrine and neurologic; and are summarized in Table 1.

The presence of a PNS is often a clue to the potential diagnosis of SCLC in the presence of a hilar mass. Additionally, some PNS, more specifically endocrine PNS, follow the pattern of disease response and relapse, and therefore, can sometimes serve as early marker of disease relapse or progression.

The common sites of metastases include brain, liver, and bone. Therefore, the staging workup should include fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scan. Contrast-enhanced CT scan of chest and abdomen and bone scan can be obtained for staging in lieu of PET scan. Due to the physiologic FDG uptake, cerebral metastases cannot be assessed with sufficient certainty using the PET-CT. Therefore, brain imaging with contrast enhanced CT or MRI is also necessary. Although the incidence of metastasis to bone marrow is less than 10%, bone marrow aspiration and biopsy is warranted in case of unexplained cytopenias, especially when associated with teardrop red cells or nucleated red cells on peripheral blood smear indicative of marrow infiltrative process. The tissue diagnosis is established by obtaining a biopsy of the primary tumor or one of the metastatic sites. In case of localized disease, bronchoscopy (if necessary, with endobronchial ultrasound) with biopsy of centrally located tumor and/or lymph node is required. Histologically, SCLC consists of monomorphic cells, a high nucleus:cytoplasmic ratio, and confluent necrosis. The tumor cells are positive for chromogranin, synaptophysin, and CD56 by immunohistochemistry. Very frequently the cells are also positive for TTF1. Although serum tumor markers, including neuron-specific enolase (NSE) and progastrin-releasing peptide (prGRP), are frequently elevated in patients with SCLC, they are of limited value in clinical practice owing to their lack of sensitivity and specificity.


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