Tests
1st tests to order
chest x-ray
Test
A standard posteroanterior chest x-ray is a simple initial step to evaluate cough, chest pain, and/or hemoptysis.
In some centers a lateral chest x-ray may be performed as well. A normal chest x-ray does not exclude a diagnosis of lung cancer.
A new abnormality on chest x-ray needs to be further assessed with contrast-enhanced CT.[48] For symptoms such as persistent hemoptysis, it is common practice to omit the chest x-ray and instead do a CT.
Chest x-rays can be used to track pleural effusions and evaluate for re-expansion of a collapsed lung after an intervention (e.g., endobronchial therapy or radiation therapy).
A chest x-ray is recommended on a routine basis (every 6 months for 2 years and annually thereafter) after definitive treatment of lung cancer.
Result
variable; may detect single or multiple pulmonary nodule(s), mass, pleural effusion, lung collapse, or mediastinal or hilar fullness
contrast-enhanced CT scan of lower neck, thorax, and upper abdomen
Test
Standard and helps to define the primary tumor and evaluate for regional spread.
A new abnormality on chest x-ray needs to be further assessed with contrast-enhanced CT scan, including these areas.[48] For some symptoms, such as persistent hemoptysis, it is common practice to omit the chest x-ray and instead do a CT.
A chest CT should be obtained in patients, especially smokers, with problematic symptoms raising a significant level of suspicion of lung cancer, even if there is a normal chest x-ray. Intravenous contrast is helpful to distinguish lymph nodes from vessels, especially in the hilum.
Treatment recommendations often hinge on whether spread to mediastinal lymph nodes has occurred. CT is noninvasive but has limitations. For mediastinal staging, sensitivity is about 60%, specificity is approximately 80%, positive predictive value is between 50% and 55%, and negative predictive value is about 85%.[88][89]
CT is useful for evaluation of pleural effusions. One study employing a scoring system to predict whether an effusion was malignant or not showed a sensitivity and specificity of 88% and 94%, respectively.[90]
After treatment, follow-up CT scans are occasionally indicated for patients who are in clinical trials or where there is a genuine concern that there is a need to detect early recurrence of disease not easily evaluated on a simple chest x-ray.
Result
shows size, location and extent of primary tumor; evaluates for hilar and/or mediastinal lymphadenopathy and distant metastases
Tests to consider
sputum cytology
Test
A noninvasive and relatively simple diagnostic method. Specificity is high, but the sensitivity is low.[50]
Cytology is more likely to confirm the diagnosis in central lesions than in peripheral lesions.[50]
Sputum cytology cannot accurately determine histology or inform appropriate therapy. Cost may outweigh the usefulness in terms of patient management.[91]
Result
malignant cells in sputum
bronchoscopy
Test
Bronchoscopy, typically performed with a flexible bronchoscope, is an endoscopic procedure in which the proximal bronchial tree can be directly visualized and suspicious areas biopsied.[92] Bronchoscopy is a very safe procedure, with a mortality of <1 in 4000.
Endobronchial masses can be biopsied with forceps. Endobronchial brushings, washings, and alveolar lavage increase the diagnostic yield. Transbronchial needle aspiration biopsy of accessible parenchymal lesions and mediastinal lymph nodes with or without endobronchial ultrasound guidance can be done.[54][55][56][57][68]
Overall, the sensitivity for centrally located lesions is high (about 90%).[92] The sensitivity for peripheral lesions is lower and depends on number of biopsies taken, size of mass, and proximity to the bronchial tree. In general, endobronchial biopsy is more sensitive than brushings or washings.
Detection of small peripheral lesions (<2 cm) is improved by use of endobronchial ultrasound.[50]
Bronchoscopy can be repeated after definitive treatment to assess for recurrent disease is completed.
Autofluorescent or narrow band imaging can improve the detection of early endobronchial lesions and can be used at the time of initial bronchoscopy or follow-up.[58][59]
Result
endobronchial lesions
biopsy
Test
Pathologic confirmation of malignancy is the only widely accepted method to make a definitive diagnosis of lung cancer. Tissue is sampled from bronchoscopy where possible. Transthoracic needle aspiration biopsy, typically using CT guidance, is used to biopsy suspicious peripheral pulmonary lesions that are not accessible with bronchoscopy. Transbronchial needle aspiration biopsy of accessible parenchymal lesions and mediastinal lymph nodes can be carried out with or without endobronchial ultrasound (EBUS) guidance. The use of endobronchial ultrasound expands the number and levels of mediastinal nodes that can be sampled. Endoscopic ultrasound (EUS) can also be used to access other mediastinal nodes plus the left adrenal gland.
Alternatively, lymph node biopsy can provide information about both diagnosis and the stage of disease. Sampling is either of nodes in the supraclavicular fossa or of mediastinal nodes accessed via EBUS, EUS, or surgically via mediastinoscopy, video-assisted thoracoscopic surgery (VATS), or an open surgical procedure.[54][55][56][57][68][93]
All samples should give enough tissue to make typing, subtyping, and mutation testing possible. Multiple biopsies or needle aspirations should be taken.
Result
specimen for pathologic diagnosis
diagnostic thoracentesis and/or pleural biopsy
Test
Many patients present with a pleural effusion, and thoracentesis is indicated, followed by thoracoscopy, if fluid is negative. Thoracentesis involves placing a needle between the ribs and into the chest to sample fluid that has accumulated in the pleural space.
Ultrasound is preferred for all medical pleural procedures and is essential when sampling small pleural effusions.
Video demonstrating how to perform a pleural aspiration
Result
presence of malignant cells in sufficient number to allow full subtyping and mutation testing
sampling of the mediastinal lymph nodes: mediastinoscopy and endobronchial ultrasound (EBUS)
Test
Treatment recommendations often hinge on whether spread to mediastinal lymph nodes has occurred.
Mediastinoscopy has been shown to have the same accuracy as combined endobronchial ultrasound (EBUS) and endoscopic ultrasound, with greater accuracy when all tests are taken together.[68] However, mediastinoscopy is an invasive procedure, and EBUS is increasingly used instead. It has also been shown to be more cost-effective.[94] The standard cervical approach involves a small horizontal incision in the low neck, through which a scope is placed and lymph nodes along the trachea and below the carina are sampled. The procedure is performed under general anesthesia.
Paratracheal and subcarinal lymph nodes can be assessed with cervical mediastinoscopy.
The overall sensitivity of cervical mediastinoscopy is approximately 80% with a negative predictive value of about 90%.[89]
Result
spread to mediastinal lymph nodes
video-assisted thoracoscopic surgery (VATS)
Test
VATS can be used to evaluate aorticopulmonary window lymph nodes.
VATS also allows access to paraesophageal and pulmonary ligament lymph nodes.
Result
spread to other intrathoracic lymph nodes
thoracoscopy
Test
Direct visualization of the pleura using thoracoscopy has a very high degree of specificity for the diagnosis of pleural effusion.
The procedure can be carried out as a "medical" procedure under local anesthetic or as a "surgical" procedure using video-assisted thoracoscopic techniques under a general anesthetic.
Result
direct visualization of pleura; pleural effusion
MRI or CT of brain
Test
Patients with locally advanced non-small-cell lung cancer, especially adenocarcinoma, are at higher risk of harboring brain metastases and should be staged with a head CT or MRI if potentially curative treatment is proposed.
Result
brain metastases appear as enhancing parenchymal masses with surrounding edema
MRI of thoracic inlet
Test
For patients with superior sulcus tumors, MRI of the thoracic inlet may be helpful in assessing resectability.
Result
evaluates brachial plexus involvement, invasion of the subclavian vessels, and/or invasion of adjacent vertebral bodies
CT with contrast and/or fluorodeoxyglucose (FDG)-PET
Test
Can be considered to evaluate progression. FDG-PET/CT is performed from the skull base to mid-thigh. Positive FDG-PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If FDG-PET/CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation.[67]
For patients with known metastatic disease, PET is often unnecessary.
PET accuracy for mediastinal staging is as follows: sensitivity between 80% and 85%, specificity approximately 90%, positive predictive value between 80% and 90%, and negative predictive value approximately 93%.[88][95]
In one Cochrane review the accuracy of PET in distinguishing N2/3 disease was found to be variable and dependent on the make of the scanner, subtype of lung cancer, FDG dose, and country of study origin. Thus, it is important for centers to audit the accuracy of their local practice.[96]
The accuracy of PET for diagnosis of lung cancer in pulmonary nodules shows a sensitivity and specificity of 89% and 77%, respectively, but the latter is reduced to 61% in areas with endemic infectious lung disease.[97]
Result
evaluates location and extent of primary tumor; evaluates for hilar and/or mediastinal lymphadenopathy and distant metastases
bone scan
contrast-enhanced CT liver and adrenals
Test
Important for staging, but usually done in conjunction with CT of chest.
Result
metastatic lesions
pulmonary function tests (PFT)
Test
FEV₁ and diffusion capacity of lung for carbon monoxide (DLCO) should be performed on all patients with lung cancer anticipated to undergo surgery or radical radiation therapy.[80][81] Patients with marginal function can be further assessed with radionuclide studies as needed. Predicted postoperative lung function should be calculated from baseline values and an estimate of the loss of lung function as a result of surgery.
There is debate on the precise criteria for determining fitness for surgery (and also for potentially curative chemoradiation therapy). Some guidelines suggest using formal cardiopulmonary exercise testing.[81] When the predicted postoperative (PPO) FEV₁ and DLCO is <30% of predicted value, if the maximal oxygen uptake is found to be <10mL/kg/minute or <35% predicted, patients are at high risk. For patients with a PPO FEV₁ or DLCO of 30% to 60%, low-technology exercise testing is recommended: for example, stair climbing or shuttle walk testing. Other guideline groups suggest the use of risk prediction scores (e.g., Thorascore) in addition to lung function and exercise testing.[49]
Result
spirometry and lung volumes
CBC
Test
Baseline blood counts are necessary before treatment is initiated or invasive procedures are performed.
Chemotherapy, and to a lesser degree radiation therapy, can decrease hematopoiesis, necessitating baseline and periodic analysis of blood counts.
Result
usually normal but may show anemia
LFTs
Test
May be elevated if hepatic metastases.
Lone elevation of alkaline phosphatase level may indicate bone metastases.
Result
normal or elevated
serum calcium
Test
Elevated in hypercalcemia of malignancy, more commonly in squamous cell carcinomas.
Result
may be elevated
electrolytes and renal function
Test
Recommended as baseline before treatment is initiated.
Hyponatremia may be related to the syndrome of inappropriate ADH secretion (SIADH), although this is more commonly seen in small cell lung cancer.
Result
usually normal, although hyponatremia not uncommon
electrocardiogram and echocardiogram
Test
ECG is always performed preoperatively. Echocardiogram may be done if there is pre-existing cardiac disease or unexpectedly low exercise tolerance.
Result
may show evidence of cardiac disease
epidermal growth factor receptor (EGFR) mutation testing
Test
Testing for mutations of the tyrosine kinase genes that encode EGFR in tumor cells enables targeted therapy to be considered in a subset of patients, particularly those who are ex-light smokers or never-smokers and those with nonsquamous histology (i.e., adenocarcinoma and large cell carcinoma). Patients with sensitizing EGFR-mutations preferentially benefit from EGFR tyrosine kinase inhibitor therapy over chemotherapy.
Result
positive in some tumors, most commonly in adenocarcinomas in never-smokers; it is also more common in Asian populations
anaplastic lymphoma kinase (ALK) testing
Test
Testing for mutations of the tyrosine kinase genes that encode ALK in tumor cells enables targeted therapy to be considered in a subset of patients, particularly those who are ex-light smokers or never-smokers and those with nonsquamous histology (i.e., adenocarcinoma and large cell carcinoma). ALK-positive patients preferentially benefit from ALK-inhibitor therapy over chemotherapy.
Fusions in the ALK gene can facilitate the proliferation of cancer cells. Can be tested by immunohistochemistry or fluorescence in situ hybridization.
Result
positive in some tumors; more prevalent in never-smokers, those with a history of light smoking, and patients with adenocarcinomas
ROS proto-oncogene 1 (ROS1) testing
Test
A receptor tyrosine kinase that may be rearranged in NSCLC. ROS1 fusions are identified in around 1% to 2% of patients and are usually detected by fluorescence in situ hybridization. Testing enables consideration of ROS1-directed therapy with tyrosine kinase inhibitors. ROS1 fusions are more prevalent in younger patients, never-smokers, those with a history of light smoking, and patients with adenocarcinomas.[73]
Result
positive in some tumors
programmed death-ligand 1 (PD-L1) testing
Test
Testing for PD-L1 expression in patients with metastatic non-small-cell lung cancer may identify candidates for PD-L1 inhibitor therapy.[67] PD-L1 status can be evaluated on cytologic samples or biopsies; the SP142 assay has lower sensitivity than the 22C3, 28-8, and SP263 assays, which performed similarly in evaluating PD-L1 expression quantity on tumor cells.[78][79]
Result
positive in the majority of tumors
B-Raf proto-oncogene (BRAF) testing
Test
Presence of the BRAF V600E genotype (found in 1% to 2% of adenocarcinomas) assists decision-making for BRAF inhibitor-directed therapy.[74] One meta-analysis reported a significant association between BRAF mutations and adenocarcinoma in non-small-cell lung cancer (NSCLC) patients; BRAF mutations were more frequent in women. The BRAF V600E mutation was significantly associated with NSCLC in women and nonsmokers.[75]
Result
positive in some tumors
neurotrophin tyrosine receptor kinase (NTRK) fusion testing
Test
Tropomyosin receptor kinase inhibitors are recommended for NTRK fusions.
Result
positive in some tumors
Mesenchymal-epithelial transition factor (MET) exon 14 (METex14) skipping mutations
Test
Should be considered. c-MET inhibitors are recommended.
Result
positive in some tumors
rearranged during transfection (RET) gene mutations testing
Test
The RET gene is a proto-oncogene that may be mutated in patients with NSCLC. RET rearrangements are more common in patients with adenocarcinoma.[76] In European patients, RET rearrangements can occur in both smokers and nonsmokers.[77] RET kinase inhibitors are recommended.
Result
positive in some tumors
KRAS proto-oncogene (KRAS) point mutations testing
Test
Inhibitors of the RAS GTPase family are indicated for the treatment of KRAS G12C-mutated non-small-cell lung cancer.
Result
positive in some tumors
ERBB2 (HER2) mutations testing
Test
ERBB2 encodes for HER2, a receptor tyrosine kinase. Fam-trastuzumab deruxtecan is recommended as subsequent therapy.[67]
Result
positive in some tumors
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