Small Cell Lung Cancer Workup

A thorough history and physical examination usually provide clues to the organ systems involved, and these are used to guide further workup (see Clinical Presentation).

Investigations are performed to identify limited-stage disease (ie, potentially curable and requiring the addition of radiotherapy to its management), as well as to assess organ function before starting therapy.

The purpose of the staging workup for small cell lung cancer (SCLC) is to determine the prognosis and management of this disease. Patients with limited-stage disease are offered combined chemoradiotherapy, whereas those with extensive-stage disease are usually treated with chemotherapy alone. The American College of Chest Physicians (ACCP) 2007 evidence-based clinical practice guideline for management of SCLC supports the staging workup outlined below.^[23]

Staging workup of small cell lung cancer is as follows:

• Complete history and physical examination (see Clinical Presentation)
• Complete blood cell (CBC) count with differential
• Serum electrolytes levels, including calcium
• Liver function tests (LFTs)
• Renal function tests
• Serum lactate dehydrogenase (LDH) level
• Serum alkaline phosphatase (ALP) level
• Chest radiography
• Computed tomography (CT) scanning of the chest and abdomen
• CT scanning/magnetic resonance imaging (MRI) of the brain
• Bone scanning
• Bone marrow aspiration and biopsy if abnormalities are present in the CBC count or peripheral smear

Positron emission tomography (PET) scanning still is under evaluation for lung cancers and, to date, has had its greatest application in non-small-cell lung cancer, in which it is used to more accurately stage patients before anticipated surgery. The 2007 ACCP guidelines do not recommend PET for routine staging of SCLC.^[23] The 2011 NCCN guidelines note that PET is inferior to MRI or CT, that PET-CT is superior to PET alone, and that although PET may improve the accuracy of staging, it still requires confirmation by pathology testing.^[22]

Complete blood cell (CBC) count with differential, serum electrolyte levels, renal function studies, and liver function tests (LFTs) are all part of the routine staging workup, and in some cases they may reveal the site of metastasis (eg, elevated serum calcium level with bone metastasis). These tests are also important to assess organ function before starting therapy.

Serum lactate dehydrogenase (LDH) and sodium levels also provide prognostic information. Increased uric acid levels may indicate the possibility of rapid tumor lysis syndrome with therapy.

CBC count

In 5-10% of patients, the disease may have spread to bone marrow at presentation. Bone marrow examination is not routinely performed unless abnormalities are identified in the CBC count or peripheral smear examination, raising the possibility of bone marrow spread. These may include variable degrees of cytopenias; the presence of immature white and red blood cells (a leukoerythroblastic blood picture) raises the possibility of myelophthisic anemia. Additionally, before instituting initial full-dose combination chemotherapy, the absolute neutrophil count (ANC) should be greater than 1000 x 10³/µL, hemoglobin >10 g/dL and the platelet count greater than 100 x 10³/µL.

Serum chemistries

Elevated serum calcium and alkaline phosphatase (ALP) levels raise the suspicion of bone metastasis, and a bone scan should be ordered even in the absence of symptoms. Serum electrolytes should be obtained to look for paraneoplastic syndromes; the presence of hyponatremia is considered an adverse prognostic indicator.

Elevated serum lactate dehydrogenase (LDH) indicates an increased tumor mass and cell turnover and is also an adverse prognostic indicator. Abnormal liver function findings raise the possibility of hepatic metastasis and may provide a clue to the cause (eg, biliary outflow obstruction vs parenchymal liver metastasis).

Most clinicians recommend bone marrow examination only in patients in whom bone marrow involvement is suspected owing to abnormal findings on a complete blood cell (CBC) count or peripheral smear. Bone marrow examination is necessary in patients in whom myelophthisic anemia (leukoerythroblastic peripheral blood smear) is suspected.

Good posteroanterior and lateral radiographs are useful in identifying the primary tumor as well as concurrent parenchymal abnormalities. Mediastinal widening may be noticed as well.

Evaluation via computed tomography (CT) scan of the thorax (lungs and mediastinum) and commonly involved abdominal viscera (ie, liver, adrenals) is the minimum requirement in standard staging workup of small cell lung cancer. (In the United States, CT scans of the chest and upper abdomen to include the liver and adrenal glands are standard.)

Low-dose CT scanning reduced lung cancer mortality in a randomized trial.^[24]

CT scanning of all common sites of metastasis should be obtained to stage the disease adequately. The 2011 NCCN guidelines recommend using intravenous contrast when possible in performing CTs of the chest, liver, and adrenals.^[22]

Brain metastasis may be present in as many as 10% of patients at diagnosis and may be occult in 5% of patients.

Most clinicians would order a magnetic resonance imaging (MRI) of the brain in asymptomatic or patients with neurologic symptoms. Because MRI is more sensitive than CT scanning with contrast for detection of brain metastasis, it is used as the first-line imaging study in many institutions.

MRI has an increased ability to detect disease in proximity to neurovascular structures and is considered standard in the workup of patients in whom spinal cord compression is suspected.

Although a CT myelogram can establish the diagnosis of vertebral and paraspinal metastases, it is rarely used today. MRI is noninvasive and very sensitive in establishing the diagnosis in almost all cases.

Bone is a common site of metastasis for small cell lung cancer, and a radionuclide bone scan should be obtained to identify bone metastases. Bone metastases from small cell lung cancer are predominantly osteoblastic, and a bone scan is superior to plain radiographs in detecting osteoblastic lesions. However, because some benign etiologies can also cause abnormalities on bone scans, obtaining plain radiographs of abnormal areas for radiographic correlation is important.

Bone scans should be obtained in all patients with small cell lung cancer at diagnosis or during follow-up if new bone symptoms develop or if serum calcium or alkaline phosphatase level is elevated.

Small cell lung cancer is usually centrally located and can be approached easily with a bronchoscope. The advantage of endoscopy is direct visualization of the tumor, allowing for direct biopsy as well as cytologic examination of bronchial washings.

Sputum cytology is a noninvasive test and, if positive, would help the clinician direct his or her attention to further workup of lung cancer and further confirm the exact pathology through biopsy. The highest yield of this test is with large, central tumors. However, because small cell lung cancer cells involve the submucosal layer of the bronchi with little or no exophytic endobronchial extension, sputum cytology may be uncommonly positive. This may be true as well of bronchial washings.

For accessible tumors, transthoracic percutaneous fine-needle aspiration (FNA) is less invasive than bronchoscopy and is carried out under computed tomography (CT) scan guidance.

The presence of malignant pleural effusion upstages the disease to extensive stage. For adequate staging, pleural effusions should be aspirated and examined for malignant cells if no other sites of distant spread are identified.

If a large symptomatic pleural effusion is present, therapeutic thoracentesis provides symptomatic relief. In patients with resistant, relapsed, or nonresponding disease, thoracentesis can be combined with pleurodesis to prevent recurrence. The preferred agent is currently sterilized talc, which can be instilled either as a slurry or as a powder during pleuroscopy. A large randomized study conducted by the Cancer and Leukemia Group B (CALGB) will likely answer the question of whether slurry or poudrage is superior.

Small cell lung cancer is typically centrally located, arising in peribronchial locations. They are thought to arise from Kulchitsky cells. The tumor is composed of sheets of small, round cells with dark nuclei, scant cytoplasm, fine granular nuclear chromatin, and indistinct nucleoli.^[25] Very high rates of cell division are observed, and necrosis, sometimes extensive, may be seen. Because of the central location, the cells exfoliate in sputum and bronchial washings.

Crush artifact leading to nuclear molding is a common finding, but it is not considered diagnostic.

Neurosecretory granules can be identified on electron microscopy, and the neuroendocrine nature of the neoplasm is suggested by its frequent association with paraneoplastic syndromes caused by peptide hormones.

Immunohistochemical stains for chromogranin, neuron-specific enolase, and synaptophysin are usually positive.

Approximately 5% of small cell lung cancers exhibit features of mixed small cell and large cell components and, less frequently, they may exhibit mixed small cell and squamous cell components.

The World Health Organization (WHO) classified small cell lung cancers into 3 subcategories: oat cell carcinoma, intermediate cell type, and combined oat cell carcinoma. However, this subclassification was difficult to reproduce, even by expert lung cancer pathologists, and in 1988, the International Association for the Study of Lung Cancer recommended dropping the intermediate cell type from the classification and adding the category of mixed small cell carcinoma and large cell carcinoma.^[26]