Sections

Workup

Approach Considerations

In a patient with a long history of smoking or other risk factors for lung cancer, the presence of persistent respiratory symptoms should prompt a chest radiograph. Because benign conditions and metastatic malignancies can mimic lung cancer on radiographs, histologic confirmation is necessary. This can be achieved by sputum cytologic studies, bronchoscopy, or computed tomography (CT)-guided transthoracic needle biopsy of the mass, depending on the location of the tumor (see the image below).

Non–small cell lung cancer. Diagnostic approach for possible lung cancer.

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Staging workup

Because of the importance of stage in the therapeutic decision-making process, all patients with non–small cell lung cancer (NSCLC) must be staged adequately. A complete staging workup for NSCLC should be carried out to evaluate the extent of disease. In the United States, the standard staging workup for NSCLC includes 7 main components (see the table below).

Staging workup for non–small cell lung cancer.

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Information obtained from these tests can then be used to guide further testing (eg, imaging studies). Invasive staging procedures such as mediastinoscopy and mediastinotomy may be required to assess mediastinal lymph nodes in patients who are candidates for potentially curative surgical resection. Positron emission tomography (PET) scans may be useful in the detection of involved nodes, the presence of which may influence decisions about operability.

A study by Annema et al determined that among patients with suspected NSCLC, a combination of endosonography and surgical staging had a greater sensitivity for mediastinal nodal metastases than surgical staging alone.^[45]This resulted in fewer unnecessary thoracotomies.

See Non-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.

Other procedures

An electrocardiogram (ECG) is helpful in establishing baseline findings and differentiating clinical symptoms (eg, chest pain, dyspnea). Changing lung hemodynamics often alter ECG wave patterns.

Bedside tests for peak expiratory flow provide good indicators of significant airflow obstruction. Lung cancer is more closely linked to chronic obstructive pulmonary disease with airflow compromise than to the disease without significant airway obstruction.

Laboratory Studies

For staging purposes, a complete blood count (CBC) should be obtained in every patient, especially before instituting chemotherapy. In an emergency setting, a CBC is not helpful in the initial evaluation. Obtain a CBC in patients with widely metastatic disease to aid in determining whether an infiltrate is potentially infectious. Obtain a CBC in patients with fever who have a recent history of chemotherapy to check for neutropenia (absolute neutrophil count < 1000/μL).

Lung cancers have a propensity to cause paraneoplastic syndromes (see the table below). Appropriate studies in such patients may include assays of serum electrolytes, blood urea nitrogen (BUN), creatinine, calcium, and magnesium.

Non–small cell lung cancer. Symptoms and signs of lung cancer.

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The most common metabolic abnormality associated with NSCLC is hypercalcemia, which usually occurs with squamous cell carcinoma and results from secretion of parathyroid hormone–related peptide (PTH-rP) by the tumor. This can be distinguished from hyperparathyroidism by confirmation of normal serum parathyroid hormone (PTH) levels.

Other electrolyte abnormalities can include hyponatremia, in which case the syndrome of inappropriate antidiuretic hormone secretion (SIADH) should be considered. The combination of hyponatremia, serum osmolality < 280 mOsm/kg, and high urine osmolality is the hallmark of SIADH.

Liver function tests (aspirate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transferase [GGT], prothrombin time [PT]/international normalized ratio [INR]) and alkaline phosphatase level are usually not helpful initially. In patients with advanced disease, however, elevated results may be an indication of hepatic metastasis and bone metastasis, respectively.

Arterial blood gas (ABG) levels are useful in the detection of respiratory failure (eg, acidosis, hypercarbia, hypoxia) in sick patients. Obtain ABG levels in patients with active systemic diseases or abnormal labored breathing.

Chest Radiography

A chest radiograph is usually the first test ordered in patients in whom a lung malignancy is suggested. Clues from the chest radiograph may suggest the diagnosis of lung cancer, but may not be helpful in identifying a histologic subtype. If the tumor is clearly visible and measurable, chest radiography can sometimes be used to monitor response to therapy.

Chest radiographs may show the following:

Pulmonary nodule, mass, or infiltrate (see the first image below)
Mediastinal widening
Atelectasis
Hilar enlargement
Pleural effusion (see the second image below)
Non–small cell lung cancer. Bronchoscopy. A large central lesion was diagnosed as non–small cell carcinoma.
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Non–small cell lung cancer. Left pleural effusion and volume loss secondary to non–small cell carcinoma of the left lower lobe. The pleural effusion was sampled and found to be malignant; therefore, the lesion is inoperable.

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Popcorn calcification is usually a radiologic characteristic of benign lesions.

The percentage of patients found to have lung cancer incidentally through chest radiographs has been consistently low. Randomized controlled trials have shown that the use of screening chest radiographs does not reduce lung cancer mortality.^{[46, 47]}

Go to Imaging in Non-Small Cell Lung Cancer for complete information on this topic.

Computed Tomography

A chest CT scan (see the image below) is the standard for staging. The findings of CT scans of the chest and clinical presentation usually allow a presumptive differentiation between NSCLC and small cell lung cancer (SCLC). Massive lymphadenopathy and direct mediastinal invasion are commonly associated with small cell carcinoma. A mass in or adjacent to the hilum is a particular characteristic of SCLC and is seen in about 78% of cases.^[48]

Lung cancer, small cell. Contrast-enhanced CT scan of the chest shows a large left lung and a hilar mass, with invasion of the left pulmonary artery.

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Common sites of spread of NSCLC include the liver and adrenals; hence, CT scanning of the chest and upper abdomen that includes the liver and adrenals is the minimum standard for a staging workup for a person newly diagnosed with NSCLC. Lung nodules incidentally detected on abdominal CT are often benign.^[49]

A CT scan or magnetic resonance imaging (MRI) scan of the brain may be required if neurologic symptoms or signs (eg, mental status change) are present. Most thoracic surgeons perform imaging of the brain before attempting definitive resection of a lung malignancy.

Go to Imaging in Non-Small Cell Lung Cancer for complete information on this topic.

Magnetic Resonance Imaging

MRI is most useful when evaluating a patient in whom spinal cord compression is suggested. In addition, brain MRI has a greater sensitivity than CT scan for detection of central nervous system (CNS) metastasis. MRI may be used when findings of superior sulcus and brachial plexus tumors are equivocal on CT scans.

Go to Imaging in Non-Small Cell Lung Cancer for complete information on this topic.

Bone Scintigraphy

The skeletal system is common site of metastases for lung cancers. If patients report bone pain or if their serum calcium and/or alkaline phosphatase levels are elevated, a bone scan should be obtained to search for bone metastases (see the image below).

Lung cancer, small cell. Whole-body nuclear medicine bone scanning with anterior and posterior images reveal multiple abnormal areas of increased radiotracer activity in the pelvis, spine, ribs, and left scapula. These findings are consistent with bony metastatic disease. The bones are commonly affected in patients with small-cell lung cancer.

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Positron Emission Tomography

PET scanning (see the image below) using fluoro-18–2-deoxyglucose (FDG) has proven to be an excellent modality for evaluating solitary pulmonary nodules and has been approved by the US Food and Drug Administration (FDA) for this indication. The average sensitivity and specificity of FDG-PET scanning for detecting a malignancy was reported to be 0.97 and 0.78, respectively.^[50]However, a meta-analysis by Deppen and colleagues found that FDG-PET had lower specificity for diagnosing malignancies in areas with endemic infectious lung disease compared with areas with nonendemic disease.^[51]

Lung cancer, small cell. Coronal positron emission tomogram shows abnormal areas of increased metabolic activity in the left hilar and left adrenal regions consistent with a hilar tumor with left adrenal metastasis.

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Studies also suggest that PET scanning is useful for searching for systemic spread if other diagnostic modalities cannot clarify an abnormality that may change the treatment of the patient’s condition. However, false-positive and false-negative results occur.

Additional data have emerged that underscore the importance of PET scanning in patients with NSCLC. PET scans appear to be more sensitive, specific, and accurate than CT scans for staging mediastinal disease. Whereas radiographs and CT scans show images of structures, PET scans reveal the nature of the area under study. PET scans often detect abnormalities not demonstrated on CT scans.

Published reports suggest that staging of NSCLC may be influenced by PET scan results in up to 60% of the cases and that as many as 25% of cases may be upstaged after PET scanning.

Caution is required when interpreting the results of PET scans in patients who may be denied potentially curative surgical resection based on PET results.

Go to Imaging in Non-Small Cell Lung Cancer for complete information on this topic.

Sputum Cytologic Studies

Centrally located endobronchial tumors may exfoliate malignant cells into sputum. (This location and tendency to exfoliate are most common in squamous cell carcinomas [SCCs].) Therefore, sputum cytology can be a quick and inexpensive diagnostic test if results are positive. The false-positive rate for sputum cytology is 1%, but the false-negative rate is as high as 40%.

Sputum cytology does not provide reliable distinction between different histologic subtypes. Discordant results are often observed between cytologic and histologic findings of specimens obtained from bronchoscopy or transthoracic biopsy.

The diagnostic accuracy of sputum cytology depends on rigorous specimen sampling (at least 3 specimens) and preservation techniques, as well as on the location (central vs peripheral) and size of the tumor.^[52]The test detects 71% of central tumors but less than 50% of peripheral tumors; therefore, further testing must always follow a negative result.

Several large studies have not revealed that screening with sputum cytology and chest radiography is cost-effective in early detection. In one small study, a cytologic specimen was used to measure EGFR and KRAS mutations; however, this practice still needs to be validated.^[53]

Sputum cytology is suggested for high-risk patients in whom semi-invasive procedures such as bronchoscopy or transthoracic needle aspiration (see below) might pose a higher risk. Currently, however, with the development of advanced x-ray imaging techniques and biopsy procedures, sputum cytology is not commonly employed in the diagnosis of NSCLC.

Bronchoscopy

When a lung cancer is suggested, bronchoscopy provides a means for direct visualization of the tumor, allows determination of the extent of airway obstruction, and allows collection of diagnostic material under direct visualization with direct biopsy of the visualized tumor, bronchial brushings and washing, and transbronchial biopsies.

The decision whether to pursue a diagnostic bronchoscopy for a lesion that is suspected of being lung cancer largely depends on the location of the lesion (central vs peripheral).^[54]Bronchoscopy is the study of choice in patients with central tumors, with a combined sensitivity of 88%. The addition of transbronchial needle aspiration with endobronchial ultrasound to obtain cytology or histology samples when there is submucosal tumor spread or peribronchial tumor causing extrinsic compression further increases the sensitivity of bronchoscopy.^[55]

Biopsy

Transthoracic needle biopsy, guided by CT or fluoroscopy, is preferred for tumors located in the periphery of the lungs because peripheral tumors may not be accessible through a bronchoscope. A positive finding for cancer is reliable; however, the false-negative rate is high at 26%, and, thus, transthoracic biopsy is generally not useful in ruling out cancer.

Diagnostic material can also be obtained from other abnormal sites (eg, enlarged palpable lymph nodes, liver, pleural or pericardial effusions, accessible bone lesions).

Needle Thoracentesis (Ultrasound Guided)

Needle thoracentesis is both diagnostic and therapeutic in patients presenting with respiratory distress. Thoracentesis has a sensitivity of only 80% with a specificity greater than 90%. In patients suspected of having lung cancer who have an accessible pleural effusion, if the pleural fluid cytology finding is negative (after at least 2 thoracenteses), thoracoscopy is recommended as the next step to aid in diagnosis.

Thoracoscopy and Mediastinoscopy

Thoracoscopy is usually reserved for tumors that remain undiagnosed after bronchoscopy or CT-guided biopsy. Thoracoscopy is also an important tool in the management of malignant pleural effusions.

Video-assisted thoracoscopy (VATS) is a newer modality that may be used to sample small peripheral tumors (less than 2 cm in diameter), pleural tumors, or pleural effusions for diagnostic or staging purposes.^[55]It is safe and can provide a definitive diagnosis with a high degree of accuracy and minimal risk to the patient. The reported sensitivity rate ranges between 0.80 and 0.99, the specificity rate ranges between 0.93 and 1, and the negative predictive value ranges between 0.93 and 0.96.^[55]Survival with assisted VATS is comparable to complete VATS and can be cost-effective.^[56]

Mediastinoscopy

Mediastinoscopy may be used to obtain tissue from cancer that has infiltrated into the mediastinum.^[57]It is usually performed to evaluate the status of enlarged mediastinal lymph nodes (seen on CT scan) before attempting definitive surgical resection of lung cancer.

Molecular Testing

Molecular testing forms an important part of the full pathologic evaluation of patients with metastatic non–small cell lung cancer (NSCLC), because very effective, less toxic, targeted treatments have become available for NSCLC with specific molecular abnormalities. Testing should include the following:

Epidermal growth factor receptor ( EGFR) mutation
Anaplastic lymphoma kinase ( ALK) rearrangement
BRAF V600E mutation
RET rearrangement
ROS-1 rearrangement
NTRK 1/2/3 gene fusion
MET exon 14 skipping
KRAS G12C mutation
Programmed death ligand 1 (PD-L1) expression

According to international evidence-based guidelines jointly published by the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP), all lung cancer patients with adenocarcinomas should be tested for the genetic abnormalities that indicate suitability for treatment with targeted agents, irrespective of clinical variables such as sex, ethnicity, or smoking status.^[58] Clinical trial data demonstrate that patients who are tested for these abnormalities and treated with the appropriate targeted therapy have better outcomes.^[58]

Testing for driver mutations (eg, fusion, amplification, deletion) in the above-listed genes can be used to determine whether targeted therapy is appropriate. PD-L1 expression is based on the tumor proportion score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. Certain PD-L1 inhibitors may indicated in cases where the TPS is 1% or greater (eg, pembrolizumab), while others may be indicated in patients with a TPS of 50% or greater (eg, cemiplimab).

In 2013, the US Food and Drug Administration (FDA) approved the cobas EGFR Mutation Test, a companion diagnostic for erlotinib.^[59]This is the first FDA-approved companion diagnostic that can detect EGFR gene mutations. The mutation test allows physicians to identify patients with NSCLC who are candidates for receiving erlotinib as first-line therapy.

The safety and effectiveness of the cobas EGFR Mutation Test was established with clinical data from the EURTAC study and showed progression-free survival in patients with NSCLC who had specific types of EGFR mutations (exon 19 deletions or exon 21 [L858R] substitution mutations) for 10.4 months when they received erlotinib treatment, compared with 5.4 months for those who received standard therapy.^[60]

For more information, see Genetics of Non-Small Cell Lung Cancer.

Histologic Findings

The updated World Health Organization (WHO) classification of lung cancer is widely used. Non–small cell lung cancer (NSCLC) includes squamous cell carcinoma (SCC), adenocarcinoma, and large cell carcinoma. Some lung cancers exhibit two or more histologic patterns. SCC was previously the most common type of NSCLC, but adenocarcinoma appears to be increasing in incidence, especially in women.

SCC has a distinct dose-response relationship to tobacco smoking and usually develops in proximal airways, progressing through stages of squamous metaplasia to carcinoma in situ. Well-differentiated SCCs contain keratin pearls, while poorly differentiated SCCs may stain positive for keratin. Microscopic examination reveals cells with large, irregular nuclei and coarse nuclear chromatin with large nucleoli. Cells are arranged in sheets, and the presence of intercellular bridging is diagnostic.

Histologically, adenocarcinomas form glands and produce mucin. Mucin production can be identified with mucicarmine or periodic acid-Schiff staining. The WHO classification of lung cancer divides adenocarcinomas into (1) acinar, (2) papillary, (3) bronchoalveolar, and (4) mucus-secreting. Bronchoalveolar carcinoma is a distinct clinicopathologic entity that appears to arise from type II pneumocytes and may manifest as a solitary peripheral nodule, multifocal disease, or a pneumonic form, which can spread rapidly from one lobe to another.

Stage for stage, adenocarcinomas are associated with worse prognoses than SCCs, with the exception of T1 N0 M0 tumors.

Large cell carcinoma is the least common of all NSCLCs. It is composed of large cells with prominent nucleoli, and no mucin production or intercellular bridging is identified. Many tumors previously diagnosed as large cell carcinomas are identified as poorly differentiated adenocarcinomas or SCCs after advanced immunohistochemical staining, electron microscopy, and monoclonal antibody studies.

A variant of large cell carcinoma has been identified; it contains neuroendocrine features and is called large cell neuroendocrine carcinoma. Large cell neuroendocrine carcinomas are associated with a worse prognosis than large cell carcinomas.

WHO classification of epithelial lung tumors

WHO divides epithelial lung tumors into preinvasive lesions and invasive malignant lesions. Preinvasive lesions include the following:

Squamous dysplasia/carcinoma in situ
Atypical adenomatous hyperplasia
Diffuse idiopathic pulmonary neuroendocrine hyperplasia

Invasive malignant lesions include the following:

Squamous cell carcinoma – Variants, papillary, clear cell, small cell, basaloid
Small cell carcinoma – Variant, combined small cell carcinoma
Adenocarcinoma – Acinar, papillary, bronchoalveolar, nonmucinous (Clara cell/type II pneumocyte) type, mixed mucinous and nonmucinous (Clara cell/type II pneumocyte and goblet cell) type or intermediate cell type, solid adenocarcinoma with mucin formation, adenocarcinoma with mixed subtypes, variants, well-differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet-ring adenocarcinoma, clear cell adenocarcinoma
Large cell carcinoma – Variants, large cell neuroendocrine carcinoma, combined large cell neuroendocrine carcinoma, basaloid carcinoma, lymphoepitheliomalike carcinoma, clear cell carcinoma, large cell carcinoma with rhabdoid phenotype
Adenosquamous carcinoma
Carcinoma with sarcomatoid, pleomorphic, or sarcomatous elements - Carcinoma with spindle or giant cells, pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, pulmonary blastoma
Carcinoid tumors - Typical carcinoid, atypical carcinoid
Carcinoma of salivary gland type - Mucoepidermoid carcinoma, adenoid cystic carcinoma, others
Unclassified

Staging

The most important prognostic indicator in lung cancer is the extent of disease and lymph node involvement. The American Joint Committee for Cancer Staging and End Results Reporting has developed the TNM (tumor-node-metastasis) staging system, which takes into account the degree of spread of primary tumor, the extent of regional lymph node involvement, and the presence or absence of distant metastases (see the table below).^[61]The TNM system is used for all lung carcinomas except SCLCs.

AJCC TNM staging and grouping system

Primary tumor (T) involvement is as follows:

TX - Primary tumor cannot be assessed
T0 - No evidence of primary tumor
Tis - Carcinoma in situ; squamous cell carcinoma in situ; adenocarcinoma in situ; adenocarcinoma with pure lepidic pattern, 3 cm or less in greatest dimension
T1 - Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (not in the main bronchus)
T1mi - Minimally invasive adenocarcinoma: adenocarcinoma (3 cm or less in greatest dimension) with a predominantly lepidic pattern and 5 mm or less invasion in greatest dimension
T1a - Tumor 1 cm or less in greatest dimension
T1b - Tumor more than 1 cm but 2 cm or less
T1c - Tumor more than 2 cm but 3 cm or less
T2 - Tumor more than 3 cm but 5 cm or less, or one with any of the following features:(1) Involves the main bronchus, regardless of distance to the carina, but without involvement of the carina; (2) Invades visceral pleura (PL1 or PL2); (3) Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung
T2a - Tumor more than 3 cm but 4 cm or less
T2b - Tumor more than 4 cm but 5 cm or less
T3 - Tumor more than 5 cm but 7 cm or less, or one that invades any of the following: : parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary
T4 - Tumor more than 7 cm, or of any size that invades one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary

Lymph node (N) involvement is as follows:

NX - Regional nodes cannot be assessed
N0 - No regional node metastasis
N1 - Metastasis in ipsilateral peribronchial and/or ipsilateral hilar nodes and intrapulmonary nodes, including involvement by direct extension
N2 - Metastasis in ipsilateral mediastinal and/or subcarinal node
N3 - Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene node, or supraclavicular node

Metastatic (M) involvement is as follows:

MX - Distant metastasis cannot be assessed
M0 - No distant metastasis
M1 - Distant metastasis
M1a - Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion
M1b - Single extrathoracic metastasis in a single organ (including involvement of a single nonregional node)
M1c - Multiple extrathoracic metastases in one or more organs

AJCC prognostic groups for NSCLC comprise 4 stages, with further subdivision of stages into subtypes. These stages have important therapeutic and prognostic implications, which are discussed later.

Stage grouping of the TNM system is as follows:

Stage 0 - TisN0M0
Stage IA1- T1miN0M0 / T1aN0M0
Stage IA2 - T1bN0M0
Stage IA3 - T1cN0M0
Stage IB - T2aN0M0
Stage IIA - T2bN0M0
Stage IIB - T1aN1M0 / T1bN1M0 / T1cN1M0 / T2aN1M0 / T2bN1M0 / T3N0M0
Stage IIIA - T1aN2M0 / T1bN2M0 / T1cN2M0 / T2aN2M0 / T2bN2M0 /T3N1M0 / T4N0M0 / T4N1M0
Stage IIIB - T1aN3M0 / T1bN3M0 / T1cN3M0 / T2aN3M0 / T2bN3M0 / T3N2M0 / T4N2M0
Stage IIIC - T3N3M0 / T4N3M0
Stage IVA - Any T, any N, M1a or M1b
Stage IVB - Any T, any N, M1c
M1a designates metastasis within the thoracic cavity
M1b designates a single extrathoracic metastasis
M1c designates multiple extrathoracic metastases

Go to Imaging in Lung Cancer Staging and Non-Small Cell Lung Cancer Staging for complete information on this topic.

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

Workup for Special Populations

Patients with CNS metastasis, immunosuppression, superior vena cava syndrome (SVCS), Pancoast tumor, and/or Ogilvie intestinal pseudo-obstruction may require specific workup, as described below. If no pathologic process is present, discharge the patient with a prescription for continuous analgesic use until follow-up care can be arranged with the patient’s personal physician.^[62]

Patients with CNS metastasis and known cancer

Head CT scanning, with and without contrast enhancement to depict masses, may be indicated. Obtain a neurosurgical consultation. Admit patients for possible whole-brain irradiation or resection.

Headache and brain edema may respond to dexamethasone (10 mg IV). Seizures are treated with anticonvulsants, but patients with brain metastases and no history of seizures do not generally require anticonvulsant therapy.^[63]

Immunosuppressed patients with cancer and infections

Obtain a CBC for evaluation of neutropenia and other blood cell derangements. Assess electrolyte levels for signs of dehydration. The chest radiograph may show only subtle infiltrate. If diarrhea is present, perform urinalysis with a culture, blood cultures with samples from peripheral sites, cultures with samples from any indwelling catheters, and stool cultures for Clostridium difficile.

Administer broad-spectrum empiric antibiotics (eg, piperacillin, gentamicin, second- or third-generation cephalosporin) and an aminoglycoside. If the patient has a penicillin allergy, replace penicillin with carbapenem (if mild penicillin allergy) or aztreonam.

Treatment with granulocyte colony-stimulating factor (G-CSF) may be appropriate for raising neutrophil levels. Consultation with an oncologist is indicated to begin G-CSF therapy.

Patients with Pancoast tumor

An MRI is superior to a CT scan in depicting superior sulcus tumors. Admit the patient for transthoracic needle aspiration. Perform bronchoscopy if endobronchial involvement is present.

Patients with SVCS

Lung cancer accounts for 60-80% of SVCS. Head elevation, cautious administration of fluids, and supplemental oxygen is indicated. Diuretics and glucocorticoids (methylprednisolone 125 mg IV) may help with symptoms, but their roles are unclear. Definitive treatment is usually by radiotherapy or chemotherapy and/or vena caval stenting.

Patients with Ogilvie intestinal pseudo-obstruction

Abdominal radiograph shows massive dilation of the colon and small intestine, with or without air-fluid levels. Check electrolyte levels and correct abnormalities. Place a nasogastric tube and rectal tube.

Admit the patient for possible colonic decompression and treatment of the underlying cause (eg, lung cancer producing autoantibodies to the myenteric neural plexus). For cancer patients with severe pain and advanced disease, administer opioid analgesics. Nasogastric tube and rectal tube placement may help with pain.

Screening

Since the publication of the National Lung Screening Trial results in 2011, which demonstrated that annual low-dose computed tomography (LDCT) allows for early detection and reduces lung cancer mortality by 20%,^[64]screening for lung cancer in patients at high risk has become the standard of care in the United States.^[47]Over time, the trend has been to increase screening eligibility to a larger number of patients, by extending the age range and reducing the smoking history for screening eligibility. Currently, guidelines from the American Cancer Society (ACS), American College of Chest Physicians (CHEST), and U.S. Preventive Services Task Force (USPSTF) recommend offering annual screening with LDCT scanning to patients aged 50 to 80 years who have at least a 20 pack-year smoking history and either continue to smoke or have quit within the past 15 years.^{[65, 47, 66]}

National Comprehensive Cancer Network (NCCN) guidelines include high risk as a criterion, as indicated by the presence of one or more of the following additional risk factors^[65]:

Radon exposure (documented sustained and substantially elevated)
Occupational exposure to carcinogens (eg, silica, cadmium, asbestos, arsenic, beryllium, chromium, diesel fumes, nickel, coal smoke, soot)
Cancer history (eg, lymphomas, head and neck cancer)
Family history of lung cancer in first-degree relatives
Disease history (chronic obstructive pulmonary disease [COPD] or pulmonary fibrosis)
Second-hand smoke exposure

The NCCN notes that evidence from randomized trials supports screening up to age 77 years, but screening beyond age 77 years may be considered as long as patient's functional status and comorbidity allow consideration for curative intent therapy.^[65]

The USPSTF recommends discontinuing screening in patients who either have not smoked for 15 years or who have developed a health condition that will substantially limit their life expectancy, the feasibility of curative lung surgery, or their willingness to undergo such surgery.^[66]

Using data from the National Health Interview Survey, Cheung et al estimated the number of US smokers eligible for screening on the basis of either USPSTF criteria or the Lung Cancer Risk Assessment Tool and the number of lung cancer deaths preventable with each method. They determined that with risk-based screening, more people would be screened and more deaths prevented. In 2015, risk-based screening would have prevented 5000 more lung cancer deaths than USPSTF-based screening.^[67] However, an analysis by Kumar et al concluded that risk-based screening provides only attenuated and modest benefits with respect to life-years, quality-adjusted life-years, and cost-effectiveness.^[68]

A randomized trial designed to assess the value of prolonged lung cancer screening beyond 5 years found LDCT screening benefit improved beyond the 5th year of screening, with a 58% reduced risk of lung cancer mortality (HR 0.42; 95% CI 0.22–0.79), and 32% reduction of overall mortality (HR 0.68; 95% CI 0.49–0.94).^[69]

Limitations of screening

In a 2013 analysis of data on 53,452 individuals at high risk for lung cancer, derived from the National Lung Screening Trial, Patz et al determined that performing lung screens with LDCT scanning carries a 22.5% probability of NSCLC overdiagnosis (ie, detection of indolent cancers), as well as an 18.5% probability of overdiagnosis for lung cancer in general. Patz et al concluded that overdiagnosis—which can lead to increases in treatment costs, anxiety, and treatment-related morbidity—should be a consideration when physicians are discussing the risks of LDCT lung cancer screening.^[70]

Subsequently, in a retrospective cohort analysis of data from the National Lung Screening Trial participants, Patz et al reported that patients whose initial LDCT scan is negative have a lower incidence of lung cancer and lung cancer-specific mortality. These authors proposed that a longer interval between screens might be warranted in patients whose initial LDCT screening scan is negative.^[71]

In this study, lung cancer incidence per 100,000 person-years was 371.88 in the 19,066 participants with a negative LDCT, versus 661.23 in the overall cohort of 26,231 participants. Lung cancer–related mortality rates per 100 000 person-years were 185.82 versus 277.20 for the two cohorts, respectively.^[71]

In a study by Kinsinger et al of lung cancer screening in 2106 patients at Veterans Health Administration medical centers, LDCT identified nodules in 59.7% of screened patients, but just 1.5% of patients had lung cancer diagnosed within 330 days. The rate of false-positive test results was 97.5%. These authors concluded that implementing a lung cancer screening program for Veterans Health Administration patients "would potentially require substantial resources and effort by clinical staff and facilities for an uncertain benefit of reduced mortality from lung cancer."^[72]

Risk models for screening

A study by researchers from the National Cancer Institute (NCI) and the American Cancer Society 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.^[73]

Biomarker screening

A collaborative study has identified and validated a panel of circulating protein biomarkers that may improve lung cancer risk assessment and may be used to define eligibility for CT screening.^[74]Using prediagnostic blood samples from patients at high risk for lung cancer, the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium for Early Detection of Lung Cancer created a risk assessment tool consists of a panel of the following proteins:

Cancer antigen 125
Carcinoembryonic antigen
Cytokeratin-19 fragment
The precursor of surfactant protein B

In the validation study of 63 ever-smoking patients with lung cancer and 90 matched controls, an integrated risk prediction model that combined smoking exposure with the biomarker panel score identified 40 of the 63 lung cancer cases, corresponding to a sensitivity of 0.63. By comparison, the US Preventive Services Task Force screening criteria demonstrated a sensitivity of 0.42 for these cases.^[74]

Treatment & Management

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Non–small cell lung cancer. CT scan shows cavitation and air-fluid level.
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Lung cancer, small cell. Coronal positron emission tomogram shows abnormal areas of increased metabolic activity in the left hilar and left adrenal regions consistent with a hilar tumor with left adrenal metastasis.
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Lung squamous carcinoma 4x: low power magnification of moderately differentiated squamous cell carcinoma showing irregular nests of tumor cells with focal areas of keratinization (pink-orange areas).
Lung squamous carcinoma 20x: higher power magnification of moderately differentiated squamous cell carcinoma showing focal areas of keratinization (pink-orange areas) just to the right of center.
Lung adenocarcinoma 4x: low power magnification of moderately differentiated adenocarcinoma showing rounded nests of pale staining tumor cells with gland lumina within some of the clusters.

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Author

Winston W Tan, MD, FACP Associate Professor of Medicine, Mayo Medical School; Consultant and Person-in-Charge of Genitourinary Oncology-Medical Oncology, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic Jacksonville; Vice Chairman, Division of Hematology/Oncology Education, Chair, Cancer Survivorship Program, Associate Chair, Department of Medicine Faculty Development, Mayo Clinic Florida; Vice President, Florida Society of Clinical Oncology

Winston W Tan, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, Philippine Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Syed Huq, MD Fellow, Division of Hematology-Oncology, Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Ellis Fischel Cancer Center

Syed Huq, MD is a member of the following medical societies: American Medical Informatics Association, American Society of Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Nagla Abdel Karim, MD, PhD Director of Early Therapeutics, Inova Schar Cancer Institute; Professor of Medicine, University of Virginia School of Medicine

Nagla Abdel Karim, MD, PhD is a member of the following medical societies: American Medical Association, American Society of Clinical Oncology, Egyptian American Medical Association, Egyptian Cancer Society, International Association for the Study of Lung Cancer

Disclosure: Nothing to disclose.

Acknowledgements

Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center

Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians