Non-Small Cell Lung Cancer Workup
- Author: Winston W Tan, MD; Chief Editor: Jules E Harris, MD more...
Approach Considerations
Apart from a handful of asymptomatic patients in whom lung cancer is diagnosed incidentally, virtually all patients with lung cancer are symptomatic at presentation. 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. Staging workup
Because of the importance of stage on 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. 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.[30] This resulted in fewer unnecessary thoracotomies.
Although TNM staging is the best prognostic factor for NSCLC, a study by Hofman et al examined the prognostic potential of preoperative detection of circulating tumor cells (CTCs).[31] The study used cytologic analysis after the isolation by size of epithelial tumor cells (ISET method). The results showed that the presence and level of 50 or more circulating nonhematologic cells (CNHC) were associated with worse survival among patients with resectable NSCLC. Although CTCs are potentially interesting, the significance of their presence is still being debated.[32]
A retrospective Surveillance, Epidemiology, and End Results (SEER) analysis found that the number of positive lymph nodes is an independent prognostic factor of survival in patients with N1 NSCLC.[33]
Lab 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 if an infiltrate is potentially infectious. Obtain a CBC in patients with fever with recent history of chemotherapy to check for neutropenia (absolute neutrophil count < 1000).
Because of the propensity of lung cancers to cause paraneoplastic syndromes, serum electrolyte levels should be evaluated. Numerous paraneoplastic syndromes are commonly associated with lung cancer (see the table below).
Non–small cell lung cancer. Symptoms and signs of lung cancer. In an emergency setting, tests for electrolyte, blood urea nitrogen (BUN), creatinine, calcium, and magnesium levels are not helpful, except when specific paraneoplastic syndromes (eg, hypercalcemia, Cushing syndrome, or syndrome of inappropriate antidiuretic hormone secretion [SIADH]) must be considered.
Serum levels of parathyroid hormone (PTH) or parathyroid hormone–related peptide (PTH-rP) can be obtained and checked.
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, but 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.
Electrocardiography
An electrocardiogram (ECG) is helpful in establishing baseline findings and differentiating clinical symptoms (eg, chest pain, dyspnea). Changing lung hemodynamics often alters ECG wave patterns.
Spirometry
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.
Chest Radiography
A chest radiograph is usually the first test ordered in patients in whom a lung malignancy is suggested. 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. 
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.
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. Clues from the chest radiograph may suggest the diagnosis of lung cancer, but may not be helpful in identifying a histologic subtype.
A study by Oken et al found that a screening chest radiograph does not improve detection and survival.[34]
Go to Radiologic Approach to 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%.
A positive finding for malignancy from a cytologic specimen is accurate in as many as 90% of cases, but any distinction between different histologic subtypes is not accurate. Discordant results are often observed between cytologic and histologic findings of specimens obtained from bronchoscopy or transthoracic biopsy.
The diagnostic accuracy of sputum cytology is dependent 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.[35] 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.[36]
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 about 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).[37] This is the study of choice in patients with central tumors, with a combined sensitivity of 88% with this type of tumor.
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.[38]
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).
Thoracoscopy
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.[38] 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.[38] Survival with assisted VATS is comparable to complete VATS and can be cost-effective.[39]
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 small cell cancer and is seen in about 78% of cases.[40]
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. Common sites of spread of a 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.[41]
A CT scan or magnetic resonance imaging (MRI) of the brain may be required if neurological 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.
A 2011 addition to the NCCN Guidelines for Lung Cancer Screening recommends helical low-dose computed tomography (LDCT) screening for select patients at high risk for NSCLC.[42]
Go to Radiologic Approach to 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 Radiologic Approach to Non-Small Cell Lung Cancer for complete information on this topic.
Bone Scintigraphy
The skeletal system is another 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. 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.[43]
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. Recent studies 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 Radiologic Approach to Non-Small Cell Lung Cancer for complete information on this topic.
Mediastinoscopy
Mediastinoscopy may be used to obtain tissue from cancer that has infiltrated into the mediastinum.[44] 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.
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.
Thoracotomy
Thoracotomy is indicated only for diagnosis and treatment of clearly resectable NSCLC.
Histologic Findings
The updated World Health Organization (WHO) classification of lung cancer is widely used. Non-small cell lung cancer includes SCC, adenocarcinoma, and large cell carcinoma. Sometimes, lung cancers can exhibit 2 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.
Go to Radiologic Aspects of Staging Non-Small Cell Lung Cancer for complete information on this topic.
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).[45] The TNM system is used for all lung carcinomas except SCLCs.
AJCC 2010 TNM staging and grouping system
Primary tumor (T) involvement is as follows:
- Tx - Primary tumor cannot be assessed
- T0 - No evidence of tumor
- Tis - Carcinoma in situ
- 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)
- T1a - Tumor 2 cm or less
- T1b - Tumor more than 2 cm but 3 cm or less
- T2 - Tumor more than 3 cm but 7 cm or less
- T2a - Tumor more than 3 cm but 5 cm or less
- T2b - Tumor more than 5 cm but 7 cm or less
- T3 - Tumor more than 7 cm or one that invades any of the following: parietal pleura, chest wall, diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium; or tumor in the main bronchus (< 2 cm distal to carina but without involvement of the carina); or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule in the same lobe
- T4 - Tumor of any size that invades the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor in a different ipsilateral lobe.
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:
- M0 - No metastasis
- M1 - Distant metastasis
- M1a - Separate tumor nodule in a contralateral lobe tumor with pleural nodules or malignant pleural effusion
- M1b - Distant metastasis
For TNM staging, NSCLC is divided into 4 stages, with further subdivision of stages I-III into A and B 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 1A - T1aN0M0 / T1bN0M0
- Stage 1B - T2aN0M0
- Stage IIA - T2bN0M0 / T1aN1M0 / T1bN1M0 / T1bN1M0 / T2aN1M0
- Stage IIB - T2bN1M0 / T3N1M0
- Stage IIIA - T1aN2M0 / T1bN2M0 / T2aN2M0 / T3N1M0 / T3N2M0 / T4N1M0
- Stage IIIB - T1aN3M0 / T1bN3M0 / T2aN3M0 / T2bN3M0 / T3N3M0 / T4N2M0 / T4N3M0
- Stage IV - Any T, any N, M1a / Any T, any N, M1b
- Pleural or pericardial effusion is M1a not T4
- Separate tumor in the contralateral lung is considered M1a
- M1b designates distant metastases
Go to Radiologic Aspects of Staging Non-Small Cell Lung Cancer for complete information on this topic.
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.[46]
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, and contact the patient’s physician. 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.[47]
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.
Consultation with an oncologist is indicated to begin granulocyte colony-stimulating factor
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.
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