Small Cell Lung Cancer (SCLC) Workup

Lung cancer screening

The American Cancer Society (ACS) and the U.S. Preventive Services Task Force (USPSTF) have issued similar guidelines on lung cancer screening. ^{[25, 26]}  Both recommend annual screening with low-dose computed tomography (LDCT) in patients whose smoking history places them at high risk. 

The ACS recommends LDCT screening in apparently healthy patients 50-80 years of age who have at least a 20 pack-year smoking history and who currently smoke or formerly smoked. The ACS stresses that the decision to initiate lung cancer screening should be shared between the clinician and patient and should involve discussion of the potential benefits, limitations, and harms associated with such screening. ^[25] The ACS guidelines exclude patients from screening if they have any of the following:

• Health conditions that may increase harm or hinder further evaluation, surgery, or other treatment for lung cancer.
• Comorbid conditions that limit life expectancy to less than 5 years
• Unwillingness to accept treatment for cancer detected by screening

The USPSTF recommends annual screening for lung cancer with LDCT in persons aged 50 to 80 years who have at least a 20-pack-year smoking history and either currently smoke or have quit within the past 15 years. The USPSTF recommends discontinuing screening once 15 years have gone by since the patient stopped smoking, or if the patient develops a health problem that "substantially limits life expectancy or the ability or willingness to have curative lung surgery." ^[26]

Lung cancer screening guidelines from the National Comprehensive Cancer Network recommend that along with smoking history, the use of risk calculators may identify additional candidates for screening. ^[27] A study by researchers from the National Cancer Institute (NCI) and the ACS that reviewed nine risk prediction models determined that the following four models were more accurate than the others for predicting lung cancer risk and for selecting patients who had ever-smoked for lung cancer screening:

• Bach model
• Ovarian Cancer Screening Trial Model 2012 (PLCO-M2012)
• Lung Cancer Risk Assessment Tool (LCRAT)
• Lung Cancer Death Risk Assessment Tool (LCDRAT)

Although the researchers concluded that that any of those models could be used to select US smokers who are at the greatest risk for lung cancer incidence or death, all the models have limitations. The Bach model does not account for race/ethnicity, family history of lung cancer, or presence of chronic obstructive pulmonary disease; the PLCO-M2012 model underestimated lung cancer risk in people of Hispanic descent by a factor of 2 to 3, and the LCRAT and LCDRAT models both underestimated risk in the "Asian/other" subgroup. ^[28]

Initial workup

A thorough history and physical examination usually provides clues to the organ systems involved in small cell lung cancer (SCLC), and these are used to guide further workup (see Presentation). Investigations are performed to delineate the extent of disease and to assess organ function before therapy begins. In general, depending on tumor localization, biopsies from the primary tumor should be obtained using bronchoscopy or any of the following techniques ^[14] :

• Mediastinoscopy
• Endobronchial ultrasound (EBUS)
• Endoscopic ultrasound
• Transthoracic needle aspiration
• Thoracoscopy (if necessary)

A metastatic lesion, if easily and safely accessible, may be the preferred option for a biopsy specimen; this will also provide pathological staging. ^[14]

Staging workup

The purpose of a staging workup for small cell lung cancer (SCLC) is to determine the prognosis and management of this disease. Patients with limited-stage disease are usually treated with combined chemoradiotherapy, whereas those with extensive-stage disease are usually treated with chemotherapy alone. Staging workup of SCLC is as follows ^{[29, 30, 14]} :

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

Staging should be adequate before making the diagnosis of limited-stage SCLC. Any pleural effusion should be tested cytologically for malignant cells, and isolated liver or adrenal lesions should be sampled by fine-needle aspiration (FNA) before a diagnosis of limited-stage disease is made. Some authorities suggest a bone marrow examination in the absence of any other evidence of spread.

See Small Cell Lung Cancer Staging for summary tables.

See Lung Cancer Staging -- Radiologic Options, a Critical Images slideshow, to help identify stages of the disease process.

A complete blood cell count (CBC) with differential, serum electrolyte levels, kidney function studies, and liver function tests (LFTs) are all part of the routine staging workup, and in some cases, these studies may reveal the sites of metastasis (eg, elevated serum calcium and/or alkaline phosphatase [ALP] levels 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 and impaired renal function may indicate the potential for tumor lysis syndrome with therapy.

Complete blood cell count

In 5-10% of patients, SCLC may have spread to bone marrow at presentation. Bone marrow examination is not routinely performed in SCLC unless abnormalities are identified in the CBC or peripheral smear examination, raising the possibility of bone marrow spread. These abnormalities may include cytopenia or the presence of immature white and red blood cells (a leukoerythroblastic blood picture), which raises the possibility of myelophthisic anemia.

Additionally, before instituting initial full-dose combination chemotherapy, the CBC should demonstrate the following:

• Absolute neutrophil count (ANC) - Should be greater than 1000 x 10 ³/µL
• Hemoglobin level - Should be above 10 g/dL
• Platelet count - Should be more than 100 x 10 ³/µL

Serum chemistries

The presence of elevated serum calcium and ALP levels raises the suspicion of bone metastasis, and in such cases a bone scan should be ordered even in the absence of symptoms. Serum electrolytes should be obtained to look for paraneoplastic syndromes, such as syndrome of inappropriate antidiuretic hormone (SIADH) secretion. The presence of hyponatremia is considered an adverse prognostic indicator.

Elevated serum LDH indicates an increased tumor mass and high cell turnover; this finding is also an adverse prognostic indicator. Abnormal liver function findings raise the possibility of hepatic metastasis and may require adjustments to planned therapy.

Radiography

Good posteroanterior and lateral radiographs are useful in identifying the primary tumor, as well as concurrent parenchymal abnormalities. Mediastinal widening may indicate mediastinal lymph node involvement.

Computed tomography

Computed tomography (CT) scanning of all common sites of metastasis should be performed to stage the disease adequately. Evaluation via CT scanning of the thorax (lungs and mediastinum) and commonly involved abdominal viscera (ie, liver, adrenals) is the minimum requirement in standard staging workup of SCLC. Intravenous contrast agents should be used whenever possible. ^[29] In the United States, CT scans of the chest and upper abdomen to include the liver and adrenal glands are standard.

Brain metastasis may be present in as many as 10-15% of patients at diagnosis ^[29] and may be occult in 5% of patients. Consequently, magnetic resonance imaging (MRI) of the brain should be ordered in asymptomatic patients as well as in those with neurologic symptoms. ^[29] Because MRI is more sensitive than computed tomography (CT) scanning with contrast for detection of brain metastasis, MRI 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 also 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 currently rarely used. MRI is noninvasive and very sensitive in establishing the diagnosis in almost all cases.

Bone is a common site of metastasis for SCLC. A radionuclide bone scan should therefore be obtained to identify bone metastases.

Bone metastases from SCLC usually contain both osteolytic and osteoblastic components, and a bone scan is superior to plain radiographs in detecting osteoblastic lesions. However, because some benign lesions can also cause abnormalities on bone scans, obtaining plain radiographs of abnormal areas for radiographic correlation is important, particularly in weight-bearing bones at risk for fracture.

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

Positron emission tomography (PET) scanning (see the image below) remains under evaluation for the staging of SCLC. ^{[31, 32]} The American College of Chest Physicians (CHEST) does not recommend PET scanning in the routine staging of SCLC, although the National Comprehensive Cancer Network (NCCN) guidelines recommend combined PET-CT (computed tomography) scanning if limited-stage disease or metastasis is suspected. ^[29] PET-CT imaging is superior to PET scanning alone. (PET scanning is inferior to MRI or CT scanning for the detection of brain metastases.)

This coronal positron emission tomogram shows a large, focal, hypermetabolic area on the right that is consistent with a large mass in the central portion of the right upper pulmonary lobe. Multiple other smaller hypermetabolic areas suggest lymph-node metastatic disease in the chest, abdomen, and right supraclavicular region.

View Media Gallery

In small, uncontrolled studies, PET scanning has shown good accuracy (83-99%) in staging extensive- versus limited-stage SCLC. ^[31] Although PET scanning may improve the accuracy of staging, however, any lesion identified using this modality that would alter staging requires pathologic confirmation due to the possibility of a false-positive finding. ^[33] The full role of PET imaging in this setting remains to be determined. ^{[31, 32]}

SCLC 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.

For tumors that cannot be diagnosed with transbronchial biopsy, transthoracic percutaneous fine-needle aspiration (FNA) carried out under computed tomography (CT) guidance is a reasonable alternative.

Sputum cytology is a noninvasive test and, if positive, can provide an accurate diagnosis of central lung cancers. Although small cell lung cancer (SCLC) usually presents as a large, central tumor, tumor cells frequently involve the submucosal layer of the bronchus with little or no exophytic endobronchial extension. Therefore, sputum cytology is not as useful for diagnosing SCLC as it is for the diagnosis of squamous cell carcinoma.

In small cell lung cancer (SCLC), the presence of malignant pleural effusion upstages the disease to extensive-stage SCLC. 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 of symptomatic effusions. The Cancer and Leukemia Group B (CALGB) reported similar outcomes in patients undergoing pleurodesis via use of talc slurry or poudrage. ^[34] The currently preferred agent for pleurodesis is sterilized talc, which can be instilled either as a slurry or as a powder during pleuroscopy.

Small cell lung cancer (SCLC) is typically centrally located, arising in peribronchial locations. These tumors are thought to develop from neuroendocrine Kulchitsky cells and are composed of sheets of small, round to spindled cells with dark nuclei, scant cytoplasm, and fine, granular (“salt and pepper”) nuclear chromatin with indistinct nucleoli. (See the image below.) ^[35]

High-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.

View Media Gallery

Very high rates of cell division are observed, and necrosis, sometimes extensive, may be seen. Because of the central location, the tumor cells may exfoliate into sputum and bronchial washings. Crush artifact of the relatively fragile tumor cells is a common finding in small biopsies, but this feature is not considered diagnostic in and of itself.

Neurosecretory granules can be identified with the aid of electron microscopy. The neuroendocrine nature of the neoplasm is suggested by its frequent association with neurologic and endocrine paraneoplastic syndromes.

Immunohistochemical stains for chromogranin, neuron-specific enolase, CD56, and synaptophysin are usually positive, but these are not an absolute requirement for the diagnosis.

Approximately 5% of SCLCs exhibit features of mixed small cell and non–small cell components, suggesting phenotypic plasticity and lending support to the cancer stem cell hypothesis. Patients with mixed SCLC/NSCLC histology are managed according to the same guidelines as those for patients with SCLC. ^[29]

SCLC is staged by stage type and staging system.

Types of staging

The American Cancer Society (ACS) uses 2 types of staging—clinical and pathologic—for SCLC. ^[36] Clinical staging involves physical examination, biopsy examinations, and imaging scans; the majority of patients are staged with clinical staging, and this type of staging is usually used to describe SCLC tumor extent.

Pathologic staging is generally more accurate, as it includes clinical staging and adds postsurgical findings. Occasionally, findings between the 2 stages may be different, such as during procedures in which cancer is in an area that is not seen on radiologic studies. The surgical findings may give the cancer a more advanced pathologic stage. ^[37]

Staging systems

VALSG 2-stage system

The staging system most commonly used for SCLC is the Veterans Administration Lung Group (VALSG) 2-stage system, which defines limited-stage and extensive-stage disease. ^[29] Patients with disease confined to one hemithorax, with or without involvement of the mediastinal, contralateral hilar or ipsilateral supraclavicular, or scalene lymph nodes are considered to have limited-stage disease, whereas those with disease involvement at any other location are considered to have extensive-stage disease. ^[29]

The key factor in defining limited-stage disease is the ability to encompass all of the disease within 1 tolerably safe radiation therapy port.

TNM system

Almost all solid tumors, including lung carcinomas, are staged using the tumor, node, metastasis (TNM) system, because it provides important prognostic information and is used to design management plans. However, older literature has stated that the TNM system fails to provide important prognostic information in patients with SCLC and is useful only for the few patients (< 5%) who might be eligible for surgical resection.

IASLC TNM system

The International Association of the Study of Lung Cancer (IASLC) developed a new TNM staging system for lung cancer in 2007; this staging system included non-SCLC (NSCLC) and SCLC. ^[29]

The American Joint Committee on Cancer (AJCC) adopted the new TNM system in 2010. ^[33] In addition, the 2011 National Comprehensive Cancer Network (NCCN) clinical practice guideline for SCLC incorporated TNM staging into its diagnostic and therapeutic algorithms; the NCCN suggested that researchers begin to use the TNM staging system in an effort to more accurately assess prognoses and to more specifically personalize therapeutic options. This recommendation is also reflected in the current NCCN guidelines. ^[29]

For more details, see VALSG and TNM Staging, below.

VALSG staging system

The Veterans Administration Lung Group (VALSG) staged small cell lung cancer (SCLC) into limited- and extensive-stage disease to distinguish between patients who may benefit from more aggressive, potentially curative treatments, such as chemotherapy combined with radiation therapy (limited-stage SCLC), and those individuals whose cancer is not likely to be cured with such therapy (extensive-stage SCLC). ^{[29, 36]}

Limited-stage disease is confined not only to the ipsilateral hemithorax but also to an area that is small enough to be treated with radiation therapy in 1 tolerably safe radiation treatment port. ^{[29, 36]}

AJCC staging system

Under the new tumor, node, metastasis (TNM) staging system, from the American Joint Committee on Cancer (AJCC) (see tables 2 and 3, below), limited-stage SCLC is defined as any T, any N, M0; the exception is T3-4, owing to multiple lung nodules that extend beyond a single radiation field. ^[33]

Extensive-stage disease describes tumors that extend beyond the ipsilateral hemithorax, such as those that reach the contralateral lung and/or contralateral lymph nodes or that find their way to distant organs (eg, bone marrow). ^{[33, 36]} Approximately two thirds of patients with SCLC present with extensive-stage disease at diagnosis. ^[36] The new TNM staging system classifies extensive-stage disease as any T, any N, M1a/b, and T3-4, due to involvement of multiple lung nodules. ^[33]

Table 2, below, summarizes the AJCC lung cancer TNM staging system categories, and Table 3, below, summarizes the lung cancer stage groupings. ^[33] The TNM assignments define the cancer growth and disease extent, and the stage groupings combine cancers with a similar prognosis. ^[29] Generally, lower stage numbers result in a better prognosis. ^[29]

Table 2. AJCC TNM Categories for Lung Cancer (Open Table in a new window)

Table 3. AJCC Stage Groupings for Lung Cancer (Open Table in a new window)