Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer

INTRODUCTION — Most patients with lung cancer present for diagnostic evaluation because of suspicious symptoms or an incidental finding on chest imaging. The goal of the initial evaluation is to obtain sufficient clinical and radiologic information to guide diagnostic tissue biopsy, staging, and treatment.

This review will provide a general overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer. Typically, the approach for those with suspected non-small cell lung cancer (NSCLC) is the same for those with suspected small cell lung cancer, although most of the data are derived from patients with suspected NSCLC. Thus, throughout the text of this topic the term NSCLC is frequently cited. The approach to a patient and modalities used for tissue biopsy and treatment of patients with NSCLC are reviewed elsewhere.

●(See "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer".)

●(See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer".)

●(See "Management of stage I and stage II non-small cell lung cancer".)

●(See "Management of stage III non-small cell lung cancer".)

●(See "Overview of the initial treatment of advanced non-small cell lung cancer".)

●(See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

GENERAL GOALS AND TIMING OF EVALUATION — For the most part, our approach to the initial evaluation and radiologic staging of patients with suspected lung cancer is concordant with several international societies, including the American College of Chest Physicians, the National Comprehensive Cancer Network, and the National Institute for Health and Care Excellence [1-4].

Local expertise and resources, institution and health system factors, and patient preferences all influence the approach taken. Multidisciplinary teams may help facilitate an investigative plan so that therapy can be implemented in a timely fashion. The selection of a biopsy modality, the role of multidisciplinary teams, and the procedures used to obtain tissue are discussed in detail separately. (See "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer" and "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer", section on 'Role of multidisciplinary teams' and "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer".)

Goals — The major goals of the initial evaluation of a patient with suspected lung cancer are to assess the following (figure 1):

●Clinical extent and stage of disease

●Optimal target site and modality for tissue biopsy

●Specific histologic subtype and genotype of the cancer

●Presence of comorbidities, secondary complications, and paraneoplastic syndromes that influence treatment options and outcome

●Patient values and preferences that influence diagnostic and therapeutic choices

When feasible, our goal is to establish diagnosis and staging concurrently by targeting a lesion or site that establishes the most advanced stage (eg, thoracentesis with cytology examination of fluid to establish stage IV disease). However, in practice, patients may require multiple imaging studies and/or invasive tissue sampling for accurate diagnosis and staging.

Timeliness and location of the evaluation

●Timing – Our preference is that the initial evaluation of patients with suspected lung cancer be performed in a timely and efficient manner (eg, within six weeks, although times vary) [3]. This is particularly true for patients in whom there is a suspicion for small cell carcinoma, (eg, large, central tumors or bulky mediastinal disease). This approach is predicated on the relatively slow growth of non-small cell lung cancer (NSCLC), which typically has a doubling time of 90 to 180 days. While some observational series show improved time to therapy with system-driven interventions (eg, multidisciplinary clinic and tumor board, health care- and hospital-associated rapid investigation systems), few studies report improved patient-relevant outcomes due to the intervention [5-7].

For patients who have a delay in completion of evaluation by eight weeks or more from the time of initial imaging, we reimage to evaluate a change in stage since some cases are rapidly growing and can progress during the evaluation period. One case series reported disease progression in 13 percent of patients at four weeks, 31 percent at eight weeks, and 46 percent at 16 weeks, respectively, with distant metastasis newly evident in 3, 13, and 13 percent of cases [8].

A prolonged diagnostic work-up can ultimately delay and complicate definitive cancer therapy [3]. Thus, in patients that present with signs or symptoms of paraneoplastic syndromes, we evaluate the paraneoplastic syndrome in parallel with the evaluation of NSCLC. The evaluation of patients with possible paraneoplastic syndromes is discussed in the following sections:

•Paraneoplastic syndromes of muscle, nerve, and bone – (see "Overview of paraneoplastic syndromes of the nervous system" and "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Association with malignancy').

•Endocrine paraneoplastic syndromes – (see "Diagnostic evaluation of adults with hyponatremia" and "Establishing the diagnosis of Cushing syndrome" and "Diagnostic approach to hypercalcemia").

●Location – We typically investigate most patients in an outpatient setting. However, patient factors may necessitate evaluation in a hospital setting (eg, respiratory failure, hemoptysis, debilitating metastases to the brain or bone).

Racial disparities in stage of lung cancer at presentation exists [9,10]. Further work needs to be done to reduce such disparities.

Patient values and preferences — The initial evaluation of patients with suspected lung cancer requires good communication that adequately assesses patient goals [11]. Patient preferences vary significantly along a spectrum from aggressive investigation aimed at cure to limited investigation directed at symptom management. Establishing and frequently reexamining patient preferences facilitates shared decision-making for diagnostic and therapeutic choices. Priority issues for many patients include life expectancy, daily functioning, side effects, uncertainty about longer-term results, and impact on caregivers [12].

INITIAL EVALUATION — For staging purposes, the eighth edition (table 1) will be used in this topic.

Clinical — Lung cancer may be suspected because the patient has either symptoms suggestive of cancer (eg, cough hemoptysis, dyspnea) or an incidental abnormality on imaging (eg, chest computed tomography [CT] obtained in an asymptomatic patient for another reason), or by screening with low-dose CT. Patients can also present with the manifestations of paraneoplastic syndromes. (See "Clinical manifestations of lung cancer", section on 'Intrathoracic clinical manifestations' and "Diagnostic evaluation of the incidental pulmonary nodule" and "Screening for lung cancer".)

In every patient with suspected lung cancer, we perform a thorough history and physical examination, with particular attention to nonpulmonary symptoms that might suggest metastases. Features that suggest metastases are listed in the table (table 2). (See 'Clinical-directed imaging' below.)

In patients with suspected lung cancer, we review all current chest imaging and compare with prior imaging, since the time course of identified lesions is an important determinant of the likelihood that a nodule or mass represents cancer [13]. (See "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Growth or stable size'.)

The following imaging features should raise the suspicion for lung cancer:

●Lesions larger than 3 cm that are new

●Measurable growth in any nodule or mass

●Pleural nodularity

●Asymmetric or significantly enlarged hilar or paratracheal nodes

●An endobronchial lesion

●An area of consolidation thought to be pneumonia that fails to resolve with medical management

Concerning but less specific findings include the following:

●Pleural effusions

●Non-dependent or substantial atelectasis

●Pleural plaques may indicate significant asbestos exposure [14]

Additional features on chest CT suggestive of malignancy include the following:

●Lesions with an irregular or spiculated border

●Thick-walled cavitary lesions (especially in the absence of findings for active infection)

●Nodules with mixed attenuation, containing a solid component and a less dense ground-glass component

●Pure ground-glass lesions, when persistent or slowly increasing in size over months to years (can be atypical adenomatous hyperplasia, carcinoma in situ, or minimally invasive or frankly invasive adenocarcinoma)

●Multiple nodules (may suggest metastases, though a dominant nodule or mass with additional nodules may be a lung cancer with concurrent benign nodules or metastases)

Estimation of cancer probability — The probability that a lung nodule or mass may represent a malignancy can be estimated by using clinical data (eg, patient's age, sex, family history, and presence of emphysema) and radiologic features. If lung cancer is suspected by chest radiograph, a CT for staging purposes focused on the primary tumor (T- in tumor, node, metastasis staging) and lymph nodes (N) should be obtained. Estimating the probability of cancer for solitary pulmonary nodules is discussed in detail separately. (See "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Assessing the risk of malignancy'.)

Laboratory — When chest imaging is suspicious for lung cancer, we perform the following laboratory studies to identify potential metastases or paraneoplastic syndromes [3,15]:

●Complete blood count

●Electrolytes

●Calcium

●Alkaline phosphatase

●Alanine aminotransferase

●Creatinine

●Albumin and lactate dehydrogenase (not essential)

A detailed clinical examination together with laboratory testing can predict the likelihood of metastases in patients with lung cancer, especially non-small cell lung cancer (NSCLC) [16]. Abnormal testing in these circumstances can prompt additional imaging that guides the clinician in their diagnostic and staging work-up. As examples:

●Liver function test abnormalities should prompt liver-directed imaging. (See 'Clinical-directed imaging' below.)

●Calcium elevation should prompt additional imaging for bone metastasis and/or a work-up for a paraneoplastic manifestation of the primary tumor. (See "Hypercalcemia of malignancy: Mechanisms" and 'Other sites' below.)

●Elevation of alkaline phosphatase could be due to liver or bone metastases and should prompt measurement of gamma glutamyl transpeptidase (GGT). When GGT is normal, an evaluation for bone metastasis is indicated; when abnormal, an evaluation for liver metastases is indicated.

We do not measure serum tumor markers, such as carcinogenic embryonic antigen (CEA), since they have not been shown to have broad clinical utility in patients with NSCLC. (See "Overview of the initial treatment and prognosis of lung cancer", section on 'Prognosis of NSCLC'.)

SUGGESTED APPROACHES TO DIAGNOSTIC EVALUATION AND RADIOGRAPHIC STAGING

Chest computed tomography — Every patient with suspected lung cancer should have contrast-enhanced chest computed tomography (CT).

Intravenous (IV) contrast administration improves the evaluation of mediastinal invasion, lymph node involvement, involvement of the pleura and pericardium, as well as the chest wall, liver, adrenal glands, and soft tissues. For patients at risk for contrast-induced nephropathy, we typically utilize methods to ameliorate the induction of acute kidney injury (eg, IV normal saline) rather than perform non-contrast-enhanced CT [17]. (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management" and "Prevention of contrast-induced acute kidney injury associated with computed tomography" and "Patient evaluation prior to oral or iodinated intravenous contrast for computed tomography".)

Chest CT is generally best performed as a stand-alone test even if whole-body positron emission tomography (PET)/CT is obtained, since PET/CT studies often are done without contrast and with lower-resolution CT images.

Chest CT is useful for the following information:

●Preliminary information on TNM stage (table 1):

•Tumor stage (T) – CT provides anatomic definition of the primary lung tumor including location, size, and invasion, which are the main components of the T stage.

•Lymph nodal stage (N) – Chest CT can also suggest lymph node enlargement, which is an imperfect but informative surrogate for metastases (N stage). When lymph node biopsy is required, chest CT can also be used to guide the selection of biopsy site(s).

•Metastatic stage (M) – Local and regional metastases can also be demonstrated on chest CT, including metastatic involvement of the pleura, pericardium, thoracic spine, chest wall, and soft tissues. Chest CT often includes some coverage of the lower neck, liver, and adrenal glands, which may aid in suggesting extrathoracic metastases.

If, however, a more comprehensive evaluation of the abdomen is required, a dedicated abdominal/pelvic CT or whole-body PET or PET/CT is required. For example, dedicated abdominal or pelvic imaging would be needed in patients with abdominal symptoms, a concerning finding that was incompletely evaluated by chest CT, suspicion for synchronous tumors (eg, lung and colorectal cancer), or metastatic malignancy from another organ (eg, kidney or colorectal cancer) [18-20]. (See 'Clinical-directed imaging' below.)

●Information on associated conditions – Chest CT can assess for conditions associated with lung cancer such as atelectasis (which actually is indicative of T2 disease) and postobstructive pneumonia. Chest CT can also detect coexisting lung disease (eg, emphysema or interstitial lung disease) that may affect biopsy choice, operability, or radiotherapy treatment options. (See "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer", section on 'Assessing patient risk'.)

●Facilitation of additional investigations and biopsy site – CT assessment of the TNM stage facilitates additional investigations (eg, magnetic resonance imaging [MRI] for brachial plexus or bone involvement) and optimal biopsy site. In addition, four major imaging groups defined by CT findings have been suggested that may facilitate further diagnostic or staging investigations [1]. These groups include patients with the following findings on CT scan (table 3):

•A – Patients with bulky tumor encircling/invading mediastinal structures such that isolated lymph nodes cannot be distinguished from primary tumor (image 1).

•B – Patients with discrete lymph node enlargement >1 cm such that an isolated lymph node can be distinguished from the primary tumor (image 2 and image 3).

•C – Patients with central tumor and elevated risk of nodal disease despite normal-sized nodes (ie, high risk for N2/3 disease) (image 4).

•D – Patients with low risk of N2/3 involvement or distant metastatic disease (ie, peripheral T1 tumors) (image 5 and image 6).

The identification of patients in these categories helps guide the clinician to select a target site for tissue biopsy. As an example, patients in group A generally are not candidates for surgical treatment. The focus of biopsy in this setting is on diagnosis of the tumor by the safest method, and imaging may be used as the staging modality. By contrast, for patients with discrete suspicious lymphadenopathy (group B), invasive sampling of the mediastinum and, in particular, the targeted node, is critical for accurate staging. The selection of modality based upon the radiographic findings described above (A through D) and disease stage is discussed in detail separately. (See "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer", section on 'Approach to the patient'.)

●Limitations – The major limitation of CT is its low sensitivity in the identification of lymph node metastases [1,21]. A 2013 systematic review of 43 studies reported the value of CT as a mediastinal staging tool in 7368 patients with suspected non-small cell lung cancer (NSCLC) [1]; a positive scan was defined as lymph nodes measuring >1 cm in short-scanning diameter (prevalence of mediastinal metastasis was 30 percent). CT predicted mediastinal lymph node involvement with a sensitivity of 55 percent, specificity of 81 percent, positive predictive value of 58 percent, and negative predictive value of 83 percent.

Thus, CT scanning is not a reliable modality for accurately staging the mediastinum in patients with lung cancer. With the potential exception of bulky mediastinal disease, this necessitates tissue sampling in most cases to confirm suspected regional lymph node involvement. (See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer" and "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer", section on 'Approach to the patient'.)

Imaging potential metastases

Selecting among the approaches — Experts agree that in patients with suspected lung cancer, imaging potential metastases is important [1-3]. However, the approach to such imaging lacks high-quality evidence, is not standardized, and varies substantially from center to center (and even between the authors of this topic).

Acceptable approaches include either of the following, both of which are targeted at noninvasively assessing the highest radiologic stage and identifying the optimal biopsy site (algorithm 1). In reality, there is some overlap and agreement between them. Ultimately, the sequence of imaging staging obtained may be influenced by clinician preference, institution and regional practices, and patient presentation:

●Comprehensive imaging for potential sites of metastases – This approach uses chest CT and the selective use of whole-body F¹⁸-fluoro-deoxyglucose PET/CT (FDG PET/CT) with or without brain MRI to determine the highest likely radiologic stage and optimal biopsy site. It is in keeping with the National Comprehensive Cancer Network (NCCN) guidelines [4]. (See 'Comprehensive imaging' below.)

Advantages of this approach include the superior sensitivity of PET/CT for detecting occult disease compared with either modality alone and conflicting data that suggest PET/CT may reduce unnecessary thoracotomies by detecting occult stage IV disease.

Limitations of PET or PET/CT are the relatively high false-positive rate, lack of standardized criteria regarding what constitutes a positive result, poor sensitivity for the detection of brain metastases, need for confirmation on tissue sampling, and issues related to cost. (See 'Whole-body FDG PET and PET/CT' below.)

●Clinical-directed imaging – This approach involves using the chest CT and clinical evaluation to determine whether additional imaging needs to be performed to determine potential sites of metastases. (See 'Clinical-directed imaging' below.)

Advantages of this approach include the high negative predictive value of an expanded clinical examination for metastases of the brain, abdomen, and bone. For example, a meta-analysis of 25 studies reported a high negative predictive value of an expanded clinical examination for metastases of the brain (95 percent), abdomen (94 percent), and bone (89 percent) [16].

Limitations include the low sensitivity of chest CT for the detection of lymph node metastases, need for tissue sampling confirmation, and potential for missing occult disease.

The two approaches are largely concordant but are divergent for imaging in patients with small lung cancers for which metastatic likelihood is low; some argue whole-body imaging is not needed in the absence of symptoms and risk factors, whereas others have a low threshold to obtain whole-body FDG PET/CT in this setting. By contrast, when extensive disease is likely, most experts typically obtain whole-body imaging with FDG PET/CT and brain imaging in those with a high likelihood of brain metastases. (See "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Positron emission tomography/computed tomography'.)

Regardless of the extent of imaging, in most cases, tissue confirmation of metastasis is required, unless there is overwhelming evidence of metastatic disease (eg, multiple bony metastases) and adequate tissue from one source has been obtained to guide treatment (immunohistochemical staining and genetic testing).

Comprehensive imaging — This approach selectively uses whole-body FDG PET/CT with or without brain MRI and is determined by the suspected stage of disease on chest CT (see 'Chest computed tomography' above) and the likelihood of cancer (in the event that the diagnosis is unknown) (algorithm 1). It is a commonly practiced approach, particularly in academic centers and in patients in whom the diagnosis is established, and is in keeping with the NCCN guidelines [4]. Once radiologic staging is complete, we proceed with choosing an optimal biopsy site, the details of which are discussed separately. (See "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer".)

General guidance is as follows:

●For patients in whom lung cancer is considered highly likely and in whom mediastinal or distant metastases are suspected (eg, suspected stage III or IV disease on chest CT (table 1)) or in whom a diagnosis of lung cancer has already been made, FDG PET/CT is performed, even if chest CT imaging has already been obtained. When PET or integrated PET/CT is not available, conventional staging with abdominal CT and bone scintigraphy is sufficient, although not as sensitive. The use of PET/CT provides a comprehensive image-based analysis of lymph nodes and is supported by data that suggest that integrated PET/CT is superior to either modality alone at detecting occult disease. These data are discussed below. (See 'Whole-body FDG PET and PET/CT' below.)

●Patients with CT stage III or IV disease also typically undergo routine imaging of the brain with gadolinium-enhanced MRI, or contrast-enhanced CT if MRI is not available. This strategy also allows for the early detection and treatment of brain metastases before development of neurologic deficits or seizures. (See 'Brain, spine, nerve' below.)

●For patients with suspected localized lung cancer that is amenable to curative resection (eg, stage I/II), the timing of imaging with whole body FDG PET/CT is controversial and is dependent upon several factors including radiographic stage, lesion size, and amenability of resection [22-25]. Many experts obtain PET/CT in this group of patients with the expectation that PET/CT will further reduce the risk of unnecessary surgery and guide the optimal biopsy site. Other experts selectively perform PET/CT first in some patients (eg, patients with evidence of hilar nodes) or perform tissue biopsy first without PET/CT (eg, patients with small lesions that are amenable to curative resection) [21,26-30]. In such cases, and particularly in the absence of lymphadenopathy, it may be reasonable to first estimate the probability of malignancy based on the imaging and patient characteristics. This estimate may be useful in determining the sequence of testing and provides necessary information for patient engagement and decision-making for subsequent steps. This calculation is provided separately. (See "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Assessing the risk of malignancy'.)

Both options (ie, using or not using PET/CT) carry risk, specifically the risk of false positives and a small risk from the ionizing radiation exposure (when PET/CT is performed) and the risk of missing occult disease (when PET/CT is not performed). Patient values and preferences may play a key role when making this decision. (See 'Patient values and preferences' above.)

The main advantage of this approach is the superior sensitivity of PET/CT for detecting occult disease, but the main disadvantage is relatively high false-positive rate. In addition, patients with equivocal FDG PET/CT findings may need additional imaging. (See 'Whole-body FDG PET and PET/CT' below.)

Whole-body FDG PET and PET/CT — Whole-body positron emission tomography (PET) can be performed as a stand-alone test or be integrated with computed tomography (CT; ie, integrated PET/CT), although in the United States, the latter has overwhelmingly replaced PET alone (algorithm 1). Choosing between PET and integrated PET/CT is provider-, institution-, and region-specific. However, because integrated PET/CT is more accurate for lymph node staging than CT or PET alone [1,21,31,32], many centers in the United States only offer integrated PET/CT. The role of PET/CT in the evaluation and staging of patients suspected to have lung cancer is discussed here. The role of PET in the evaluation of a solitary pulmonary nodule is discussed separately. (See "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Positron emission tomography/computed tomography'.)

The value and limitations of whole-body PET and integrated PET/CT include the following:

●Information on TNM stage – With the exception of brain metastases, whole-body PET and to a greater degree, PET/CT scanning is more sensitive than CT alone in detecting tumor invasion, occult disease, lymph node involvement, and intra- and extrathoracic metastases [1,21,31-39]. Small randomized studies and case series of PET or PET/CT suggest that, when used for lung cancer staging, unsuspected metastases are discovered between 6 and 36 percent of cases [40-43]. Additionally, their discovery can result in stage migration (up-stage or down-stage) and changes in management in 19 to 22 percent of patients [33,38,39,42,44-46]. However, improved survival due to the discovery of occult metastases has not been conclusively proven.

Integrated PET/CT combines the anatomic resolution of chest CT (see 'Chest computed tomography' above) with information regarding the metabolic activity of the tumor and any local or distant metastases (with the exception of brain metastases). Integrated PET/CT provides information on lymph node size, FDG avidity, shape, proximity to the tumor, location, the presence of other enlarged lymph nodes, and change in lymph node size over serial imaging (if available) [1,47,48]. For example, if metabolic activity is seen in the region of the mediastinum, its relation to vascular, hilar, or endobronchial structures may be unclear by PET imaging alone but can be better appreciated on CT, thereby demonstrating that the mediastinal activity originates from a specific location [31,32].

PET imaging alone, without the use of concurrent CT imaging, has limited anatomic resolution but does provide information on the metabolic activity of the primary tumor, possible mediastinal involvement, and can suggest distant metastases (table 1). PET is more accurate in the evaluation of mediastinal disease (N) when compared with contrast-enhanced chest CT, and sometimes detects occult disease (eg, liver and bone) outside the thoracic cavity (M) that is not evident by CT. With respect to mediastinal staging by PET, one systematic review of 45 studies that included 4105 patients reported that PET had a sensitivity of 80 percent, specificity of 88 percent, positive predictive value of 75 percent, and negative predictive value of 91 percent [1]. Another meta-analysis of 39 studies reported increased sensitivity of PET (100 percent) when lymph nodes were also enlarged (>1 cm) on CT [21].

●Potential reduction in potentially avoidable thoracotomies – Published literature supports the use of PET/CT predominately in the context of avoiding surgery in patients who have disease that does not benefit from surgery. Examples include patients with disease that cannot be fully resected (referred to as "futile thoracotomies" in some papers) or patients with benign disease. However, randomized trials evaluating the association between PET/CT scanning and therapeutic outcome in this population have had conflicting results [22-25,49,50]. While two studies suggested that use of PET/CT reduced the rate of potentially avoidable thoracotomies (7 to 17 percent) [23,25], three studies suggested no difference in similar populations [24,49,50]. In part, thoracotomies are considered potentially avoidable when benign disease or stage III or IV disease was detected or postoperative relapse or death within 12 months of randomization occurred [31,33-39].

●Facilitation of additional investigations – PET assessment of the TNM stage facilitates additional investigations and optimal biopsy site but, unlike chest CT, does not provide information on associated conditions.

●Limitations – PET has several limitations:

•False positives can occur with benign FDG-avid lesions such as infections, inflammation, and granulomatous disease (approximately 10 to 30 percent, depending on the population) [51]. Ideally, positive findings in the mediastinum or outside the thorax should be confirmed pathologically unless imaging reveals overwhelming evidence of metastasis. Conversely, false-negatives typically occur in the setting of microscopic foci of metastasis, and in nonenlarged lymph nodes (eg, <10 mm) [52-54].

•There are no standardized criteria defining what constitutes a positive PET result and no ideal cut-off point for the standardized uptake value. However, we typically consider lymph nodes with FDG uptake greater than that observed in the mediastinal blood pool as more suspicious for metastatic disease than those that are the level of blood pool [55].

•PET is limited in the detection of brain metastases. Thus, for patients with stage III or IV lung cancer, in whom brain metastases are more likely, we typically image the brain with MRI [1]. While isometabolic lesions are particularly hard to identify (ie, lesions of similar FDG avidity to background tissue), intrinsic limitations remain to evaluating hyper- and hypometabolic lesions in the brain [56]. (See 'Brain, spine, nerve' below.)

•Tissue diagnosis is often needed to confirm or reject the possibility of lymph node involvement or extrathoracic metastases [57]. However, in some cases PET/CT is the final assessment for tumor spread to certain areas. For example, widespread metastases to bone are rarely proven by biopsy when malignancy is considered highly likely by imaging.

•FDG PET/CT involves additional radiation exposure compared with CT alone.

Clinical-directed imaging — This approach uses contrast-enhanced chest CT (see 'Chest computed tomography' above) and clinical findings (table 2) to determine further imaging for potential metastases. Once radiologic staging is complete, we proceed with choosing an optimal biopsy site, the details of which are discussed separately. (See "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer".)

Using this approach, we obtain further imaging in the following groups:

●Patients with focal symptoms, signs, or laboratory tests suggestive of metastatic disease (table 2). As examples:

•Hip pain may prompt plain radiographs of the hip or FDG PET/CT (M1b disease)

•Horner syndrome (ipsilateral ptosis, anhidrosis, and miosis) may prompt MRI of the superior sulcus (T3 disease)

•Neurologic symptoms may prompt imaging of the brain or spinal cord with MRI (M1b disease)

•Hypotension with sinus tachycardia and pulsus paradoxus may prompt an echocardiogram to evaluate for malignant pericardial effusion (M1a disease)

●Patients at high risk for brain metastases (eg, stage III or IV disease on chest CT). (See 'Brain, spine, nerve' below.)

●Patients in whom rapid progression is suspected or in whom there is a significant delay between initial imaging and evaluation (eg, eight weeks or more) [1,3]. In this population, we generally start by repeat chest CT imaging. (See 'Timeliness and location of the evaluation' above.)

This approach has a high negative predictive value for the detection of metastases of the brain, abdomen, and bone [16], but has a low sensitivity for the detection of lymph node metastases and has the potential to miss occult disease.

Lymph nodes — Lymph node size >1 cm is typically considered abnormal on contrast-enhanced CT and increases the suspicion for lymph nodal metastases. Enlarged or borderline-sized lymph nodes can be further reevaluated with FDG PET/CT. Endobronchial ultrasound- and/or endoscopic ultrasound-guided biopsy are used to biopsy enlarged nodes and normal-sized lymph nodes that show PET avidity as part of a patient's staging evaluation. (See 'Whole-body FDG PET and PET/CT' above.)

Brain, spine, nerve — Gadolinium-enhanced MRI detects brain lesions as well as spinal bone lesions and can differentiate metastases from other central nervous system lesions with greater sensitivity than nonenhanced MRI [1,58]. Patients in whom we typically obtain brain imaging include those with symptoms suggestive of brain metastases and those with a higher likelihood of having brain metastases (eg, stage III/IV). (See 'Suggested approaches to diagnostic evaluation and radiographic staging' above.)

Gadolinium-enhanced MRI of the brain is the test of choice because it is more sensitive than CT, nonenhanced MRI, FDG PET, and PET/CT [59,60]. If MRI is not available, CT scan of the brain with contrast enhancement is an alternative. FDG PET is poorly sensitive for the identification of brain metastases. (See 'Whole-body FDG PET and PET/CT' above.)

Pleura — Pleural metastases commonly present as a pleural effusion, multiple pleural nodules, and direct extension of the primary tumor to the pleura or chest wall. Other presentations include pleural thickening and pleural puckering. Pleural effusions with no discernable pleural nodularity or thickening may also indicate pleural metastasis, although the specificity of the finding of fluid only is lower than of nodules or direct invasion. Complete evaluation of pleural disease may require multiple imaging modalities (eg, PET, ultrasound, and/or MRI) as well as invasive testing (thoracentesis, thoracoscopy, or pleural biopsy). While imaging is important in the detection of suspected pleural metastases, it generally does not obviate the need to sample the pleura for histologic confirmation. (See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Suspected pleural metastases' and "Imaging of pleural plaques, thickening, and tumors".)

●Contrast-enhanced chest CT – Contrast-enhanced chest CT imaging is particularly important in the evaluation of tumors with extension to the visceral pleura, parietal pleura, or extrapleural fat. Lesions with focal direct invasion through these planes may be operable and need to be distinguished from multifocal or diffuse metastatic disease that has spread throughout the pleural space (M1a), which is inoperable (table 1) [61]. When imaging is insufficient to make this distinction, direct vision at the time of pleuroscopy, thoracoscopy, or thoracotomy may be required. Noteworthy is that CT is of limited value in recognizing invasion of the visceral pleura in T1 adenocarcinomas [62].

●PET – Retrospective studies have shown PET to be an accurate modality in the detection of pleural metastases from NSCLC [63,64]. In one study, FDG PET correctly detected the presence of malignant pleural involvement in 16 of 18 patients with NSCLC and excluded a malignant effusion in 16 of 17 patients with a sensitivity and specificity of 88 and 94 percent, respectively [64]. However, unlike CT, PET is not useful in examining the extent of invasion across tissue planes.

●Pleural ultrasound – Ultrasound has been described in the evaluation of the pleura, although it is generally considered inferior to CT [65].

●Chest MRI – MRI may be useful when evaluating the extent of tumor invasion through muscle, nerve, and bone but has not been formally studied as a staging tool for pleural involvement in NSCLC.

Other sites

●Adrenal gland – In patients with NSCLC, most adrenal nodules are benign. However, all adrenal anomalies in patients with suspected NSCLC require directed evaluation to distinguish benign adrenal lesions from malignant metastases. We biopsy lesions with imaging characteristics suggestive of malignancy. Investigation of adrenal lesions found on imaging is discussed in detail separately. (See "Evaluation and management of the adrenal incidentaloma", section on 'Typical imaging features' and "Evaluation and management of the adrenal incidentaloma", section on 'Adrenal metastases'.)

While most patients are evaluated with CT, PET/CT or MRI may be additionally required for full evaluation:

•CT – Adrenal gland nodules or masses may be found by CT in 3 to 4 percent of patients during the initial evaluation [66-68]. CT scans that use specific adrenal imaging protocols significantly improve the sensitivity and specificity of CT for characterizing adrenal lesions. As an example, in two studies of 288 adrenal masses, CT identified adrenal adenomas with a high sensitivity (98 to 100 percent) and specificity (92 to 95 percent) [69,70].

•PET – In a series of 94 patients with 113 adrenal masses and a prevalence of metastasis of 59 percent, the sensitivity of PET imaging for detection of metastatic disease was 93 percent and the specificity 90 percent [71]. Although PET scans are generally accurate for the detection of adrenal metastases, the detection of small lesions may be limited (<1.5 cm) [72-76].

•MRI – MRI may be helpful in distinguishing benign, fat-containing adrenal adenomas from adrenal metastases [77,78].

Percutaneous biopsy and, rarely, adrenalectomy are considered for isolated lesions involving the adrenal gland. (See "Evaluation and management of the adrenal incidentaloma", section on 'Fine-needle aspiration biopsy' and "Evaluation and management of the adrenal incidentaloma", section on 'Adrenalectomy'.)

●Liver – The liver is rarely the sole site of metastases and occurs in approximately 3 percent of patients with lung cancer. Although most liver lesions in patients with NSCLC are benign cysts or hemangiomas [79], all liver abnormalities in patients with suspected NSCLC require directed evaluation. We typically biopsy liver lesions with characteristics suggestive of malignancy found on CT or PET/CT, particularly if this is the only suspected metastatic site. (See "Approach to the adult patient with an incidental solid liver lesion", section on 'Malignant lesions' and "Approach to the adult patient with an incidental solid liver lesion".)

Data suggest that PET scanning can detect liver metastases with an accuracy of 92 to 100 percent [72,80,81]. Although subgroup analysis in observational case series suggests that PET may be superior to CT for the detection of liver metastases, false-positive and false-negative findings were also reported [72,82].

●Bone – We prefer FDG PET/CT scanning for the detection of bone metastases.

•FDG PET/CT – FDG PET/CT scanning appears to be superior to radionuclide bone scintigraphy for the detection of bone metastases [72,83-87]. Two studies of 158 patients with biopsy-proven bone metastases from NSCLC reported that, compared with bone scintigraphy, PET scanning had similar sensitivity (93 percent) but greater specificity (93 to 96 versus 66 to 73 percent) [83,84]. Like most tests, false-positive and false-negative findings on PET scan have been reported [72,76,88].

•Bone scintigraphy – Bone scintigraphy can be used when PET or PET/CT is not available. The known caveat of bone scintigraphy is that the false-positive rate is high due to the common prevalence of degenerative and traumatic skeletal disease in the general population. One meta-analysis of eight studies suggested that bone scintigraphy has a negative predictive value of >90 percent [1].

•MRI – MRI has comparable accuracy to bone scintigraphy for the diagnosis of bone metastases. In practice, it can be used as a supplementary tool, especially when a suspected lesion crosses tissue planes to involve multiple structures [87,89,90]. For example, apical lesions that invade through the chest wall can involve the shoulder as well as the brachial plexus, and lesions of the posterior mediastinum can involve the vertebra and spinal canal. In these settings, MRI can be used in conjunction with other imaging modalities to distinguish true bony metastases from T3 lesions that are potentially resectable [91].

●Heart and pericardium – The heart and pericardium are initially evaluated by chest CT and whole-body PET/CT. Higher-resolution imaging options that can be considered in targeted situations to better evaluate the pericardium, myocardium, and/or chamber lumens include echocardiography, gated cardiac CT, and cardiac MRI. A complete discussion of the pros and cons of each option is beyond the scope of this summary.

DIAGNOSIS — A diagnosis of lung cancer should not be made without definitive pathology. At a minimum, this involves selecting a biopsy site and obtaining an adequate sample for microscopic examination. Additional consideration needs to be given to obtaining sufficient sample for supplemental immunohistochemical (IHC) and genetic analyses.

Tissue biopsy — Acquiring tissue for microscopic examination is necessary for the diagnosis and staging of patients with suspected lung cancer. Most data are derived from studies of patients with non-small cell lung cancer (NSCLC). Although not absolute, minimally invasive modalities (eg, endoscopic procedures) are typically preferred over more invasive modalities (eg, video-assisted thoracic surgery and mediastinoscopy) for the initial biopsy. However, for patients with suspicious but isolated peripheral pulmonary lesions that are suspected to be localized disease, surgical biopsy is sometimes preferred because diagnosis and curative resection may be achieved simultaneously. (See "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer" and "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Surgical biopsy'.)

Modality — When selecting a modality for biopsy, considerations include the yield for a target lesion in the context of safety and expediency as well as the patient's preferences and values.

●Bronchoscopy with endobronchial ultrasound-directed biopsy has emerged as the most common modality used for diagnosis and staging of suspected NSCLC due to its high diagnostic accuracy for accessing central primary tumors and most mediastinal lymph nodes. Percutaneous computed tomography (CT)-guided biopsy is also commonly used when lesions are less accessible by bronchoscopy (eg, peripheral lesions). Selection of modality is discussed in detail separately. (See "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer" and "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer".)

●If initial tissue sampling provides inconclusive results or is insufficient for essential IHC or molecular characterization, a second biopsy procedure is required. In such cases, we favor modalities with a higher tissue volume (eg, core-tissue sampling by CT-guided biopsy or surgical sampling).

Specimen type — A pathologic diagnosis can be made on cytopathologic or histopathologic (tissue biopsy) samples. In general, if both types of specimens can be obtained with similar feasibility and risks, a tissue biopsy is preferable to a cytologic specimen. This preference is based upon a greater ability to differentiate adenocarcinoma from squamous cell carcinoma and a greater volume of material that facilitates IHC and genetic analysis of the tumor. (See "Pathology of lung malignancies" and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

Cytologic specimens can be obtained from the following sites, the details of which are discussed separately:

●Lung – Sputum, transthoracic needle aspirates, and bronchoscopic washings, brushings, or needle aspirates. (See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Sputum cytology' and "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Endoscopic and percutaneous procedures'.)

●Lymph node – Transthoracic, transbronchial, and transesophageal aspirates. (See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Endoscopic and percutaneous procedures'.)

●Distant metastasis – Pleural fluid, needle aspirates of metastatic tissue (eg, liver). (See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Sampling metastatic disease'.)

Core specimens or biopsy tissue can be obtained from the following, the details of which are discussed separately:

●Lung – Endobronchial biopsy (forceps), transbronchial biopsy (forceps or needle), transthoracic (needle) biopsy, surgical biopsy. (See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Endoscopic and percutaneous procedures' and "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Video-assisted thoracic surgery and robotically assisted thoracic surgery'.)

●Lymph node – Bronchoscopic and transthoracic needle core biopsy, surgical biopsy. (See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Endoscopic and percutaneous procedures' and "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Surgical staging procedures'.)

●Distant metastasis – Core needle aspirates of metastatic tissue (eg, liver, bone, adrenal). (See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Sampling metastatic disease'.)

Histopathology, immunohistochemistry, genetic mutations — Distinguishing among the different histologic subtypes of NSCLC is important to guide subsequent testing for specific mutations and to inform treatment selection, including the identification of patients who are more likely to respond to newer targeted therapies.

Pathologic features of the four major histologic subtypes of NSCLC (adenocarcinoma, squamous carcinoma, adenosquamous carcinoma, and large cell carcinoma) and small cell lung cancer (SCLC) include the following:

●Adenocarcinoma – Neoplastic gland formation or intracytoplasmic mucin (picture 1 and picture 2). (See "Pathology of lung malignancies", section on 'Adenocarcinoma'.)

●Squamous cell carcinoma – The presence of keratin production by tumor cells and/or intercellular desmosomes ("intercellular bridges") (picture 3 and picture 4). (See "Pathology of lung malignancies", section on 'Squamous cell carcinoma'.)

●Adenosquamous carcinoma – Greater than 10 percent malignant glandular and squamous components. (See "Pathology of lung malignancies", section on 'Adenosquamous carcinoma'.)

●Large cell carcinoma – The absence of glandular or squamous differentiation features (ie, poorly differentiated NSCLC).

●Small cell carcinoma – Hyperchromatic appearance, nuclear molding, "salt and pepper" chromatin pattern, small amounts of cytoplasm (ie, high nuclear to cytoplasmic ratio), cohesive sheets of small "blue" cells with rosette formation, crush artifact with necrosis, and cell fragility.

Panels of IHC stains are required to fully classify histologic subtypes and to distinguish NSCLC from other cancers involving the lung (eg, primary lung cancer from secondary metastases) [92]. The major IHC patterns that are commonly used are the following:

●Adenocarcinoma is typically positive for thyroid transcription factor (TTF-1), mucin, napsin-A, surf-A, surf-B, PAS-D, and cytokeratin (CK) 7.

●Squamous cell carcinoma is typically positive for p40, p63, and CK 5/6, and usually negative for CK 7.

●Adenosquamous or large cell carcinoma may have a combination of IHC staining patterns characteristic of both adenocarcinoma and squamous cell carcinoma.

●Poorly differentiated cancers and metastases from distant sites may need to be distinguished from primary NSCLC. As examples, stains that are classically negative in NSCLC are CK 20 (typically positive in adenocarcinoma of the colon) and estrogen and progesterone receptor (typically positive in adenocarcinoma of the breast), thereby distinguishing the tissue of origin for adenocarcinoma found in the lung. Other common staining patterns used to determine the tissue of origin for poorly differentiated neoplasms are described in the table (table 4).

●SCLC can be positive for TTF-1. However, as a neuroendocrine tumor, SCLC should have no other shared IHC staining patterns with NSCLC and is typically positive for synaptophysin, CD 56, chromogranin, or neuron-specific enolase, while NSCLC is negative for these stains.

The common genetic mutations with known targeted therapies include mutations in epithelial growth factor receptor gene (EGFR), rearrangements of the anaplastic lymphoma kinase gene (ALK), and several others listed in the figure (figure 2). Genetic testing for these targetable driver mutations should be obtained in lung adenocarcinomas. These and other driver mutations involved in the pathogenesis of NSCLC are discussed in detail separately. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

NSCLC samples are also typically tested for anti-programmed cell death ligand 1 expression for suitability for immune checkpoint inhibitor therapy. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation".)

The pathology, IHC, and genetic mutations associated with lung malignancies are discussed in detail separately. (See "Pathology of lung malignancies" and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'NSCLC genotypes'.)

Differential diagnosis — The differential diagnosis of NSCLC depends on the presenting symptoms and imaging findings. Biopsy with IHC staining of specimens is required to distinguish NSCLC from other primary thoracic and mediastinal tumors, primary SCLC, metastatic disease arising outside the lung, and other nonmalignant lesions of the lung. Among the malignant etiologies, the major entity that needs to be distinguished from NSCLC is SCLC. This distinction is critical because the prognosis and treatment for NSCLC and SCLC are different.

Although not always present, there are a number of clinical, radiologic, and pathologic features that can help the clinician make this distinction:

●Rapid presentation – Although the common symptoms of lung cancer, cough, dyspnea, hemoptysis, and chest pain, can be encountered in both NSCLC and SCLC, a more rapid presentation over weeks favors SCLC. This may be due to the faster growth rate associated with SCLC. As an example, a rapidly growing lesion on chest imaging (eg, a mass that grows over three to six weeks) is more suggestive of SCLC rather than NSCLC.

●Pancoast syndrome – Benign and malignant lesions of the superior sulcus (ie, the thoracic inlet at the apex of the lung) can cause Pancoast syndrome. Pancoast syndrome is a constellation of one or more clinical signs (eg, weakness and atrophy of the muscles of the hand and/or ipsilateral ptosis, anhidrosis, and miosis [Horner syndrome]) that are due to compression or involvement of the brachial plexus (nerves and vessel) and the cervical sympathetic nerves. Unlike superior vena cava (SVC) syndrome, Pancoast syndrome is overwhelmingly more common in NSCLC and rarely due to SCLC or a benign lesion. Imaging findings of apical masses that have malignant features should always prompt additional evaluation and biopsy for NSCLC involvement of the thoracic outlet. (See "Superior pulmonary sulcus (Pancoast) tumors".)

●Paraneoplastic syndromes – Paraneoplastic manifestations are more commonly observed in SCLC. They are discussed separately in the following sections:

•Paraneoplastic syndromes of muscle, nerve, and bone – (see "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle" and "Clinical manifestations of dermatomyositis and polymyositis in adults").

•Endocrine paraneoplastic syndromes – (see "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Etiology' and "Etiology of hypercalcemia" and "Epidemiology and clinical manifestations of Cushing syndrome", section on 'Frequency and severity of symptoms').

●Pathology – The major histologic feature that distinguishes NSCLC from SCLC is cell size. Typically, the cells in SCLC are roughly twice the size of lymphocytes when subjectively assessed on light microscopy. Additional features that distinguish SCLC from NSCLC are described above (see 'Histopathology, immunohistochemistry, genetic mutations' above). When classic features of SCLC are present, morphologic criteria alone are often diagnostic and supported by high interobserver reliability [93]. By contrast, the classic features of epithelial differentiation (eg, keratin pearls [squamous], gland formation [adenocarcinoma]) are highly suggestive for NSCLC. (See "Pathology of lung malignancies", section on 'Small cell carcinoma' and "Pathology of lung malignancies", section on 'Adenocarcinoma' and 'Histopathology, immunohistochemistry, genetic mutations' above.)

●Immunohistochemical staining – Select patterns of IHC staining are typically used to confirm the tissue of origin in NSCLC. The IHC characteristics of NSCLC and SCLC are discussed separately. (See 'Histopathology, immunohistochemistry, genetic mutations' above.)

●Other – SVC syndrome and metastatic disease were originally thought to be more common in SCLC but due to the higher prevalence of NSCLC, they are commonly encountered in both entities.

•Superior vena cava syndrome – The three most common malignancies associated with SVC syndrome are NSCLC, SCLC, and lymphoma. Unilateral disease may favor SCLC and NSCLC over lymphoma, which is more likely to involve the mediastinum symmetrically. Biopsy is required to distinguish all three entities. (See "Malignancy-related superior vena cava syndrome".)

•Metastatic disease – Clinical manifestations of metastatic disease, particularly bone metastases, are commonly seen in both SCLC and NSCLC. (See "Approach to the adult patient with an incidental solid liver lesion" and "Evaluation and management of the adrenal incidentaloma" and "Epidemiology, clinical manifestations, and diagnosis of brain metastases" and "Bone tumors: Diagnosis and biopsy techniques".)

Importantly, if biopsy demonstrates NSCLC but the clinical presentation or course is more consistent with SCLC (eg, rapid growth, multiple metastases, paraneoplastic syndromes), a second pathologic opinion and, rarely, a repeat biopsy is indicated due to a concern for misdiagnosis.

STAGING — The eighth edition for staging non-small cell lung cancer (NSCLC; (table 1)) is in use. Staging NSCLC determines the appropriate therapy and, when combined with the patient's unique features, provides valuable prognostic information. Four types of staging can be designated in patients with NSCLC:

●The clinical-diagnostic stage is based upon all investigations (clinical, laboratory, radiologic, and pathologic) that are undertaken prior to surgical resection. It is assigned the prefix c (eg, cT3N2M0). A limitation of clinical-diagnostic staging is that the stage is related to the intensity of the preoperative evaluation. Thus, a less aggressively staged patient may be inaccurately staged.

●The surgical-pathologic stage is based on the clinical-diagnostic stage plus histopathologic data from the resected tumor and lymph nodes. It provides confirmation of the T descriptor, N descriptor, and histologic type. In addition, it takes into account the histologic grade, resection margins, and presence or absence of lymphovascular invasion. The surgical-pathologic stage is assigned the prefix p (eg, pT3N2M0).

●A retreatment stage is assigned if there is recurrence of disease, new staging evaluations have been completed, and a new treatment program is planned.

●An autopsy stage is based on a complete postmortem examination.

The tumor, node metastasis (TNM) system for staging NSCLC and the selection of modality for clinical-diagnostic staging are discussed separately (table 1). (See "Tumor, node, metastasis (TNM) staging system for lung cancer" and "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer" and "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer".)

The staging for small cell lung cancer (limited versus extensive and TNM) is also discussed separately. (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Staging'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer" and "Society guideline links: Hemoptysis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Non-small cell lung cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Non-small cell lung cancer treatment; stage I to III cancer (Beyond the Basics)" and "Patient education: Non-small cell lung cancer treatment; stage IV cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Initial evaluation – Lung cancer may be suspected because either the patient has symptoms suggestive of cancer (eg, cough hemoptysis, dyspnea, weight loss) or an abnormality was found incidentally (eg, chest computed tomography [CT] obtained in an asymptomatic patient for another reason) or by lung cancer screening. (See 'Initial evaluation' above and 'Clinical' above.)

During clinical evaluation, we maintain a high index of suspicion for nodal or metastatic disease (table 2). In patients with suspected lung cancer, we generally obtain a complete blood count, electrolytes, calcium, alkaline phosphatase, alanine aminotransferase, creatinine, and albumin. (See 'Estimation of cancer probability' above and 'Laboratory' above.)

●Diagnostic evaluation and staging – The approach to imaging for patients with suspected lung cancer varies from center to center. Acceptable approaches should establish the highest radiologic stage and identify the optimal biopsy site. Once imaging is complete, we proceed with choosing an optimal biopsy site or surgical approach, the details of which are discussed separately. (See "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer".)

•Chest CT – Every patient with suspected lung cancer should have a contrast-enhanced chest CT. Chest CT provides useful preliminary information on the tumor lymph nodal metastases (TNM) stage, associated pulmonary conditions, and potential biopsy targets. (See 'Chest computed tomography' above.)

•Detecting potential metastases – The two approaches to imaging potential metastases are the following (algorithm 1):

Comprehensive imaging approach – This approach uses whole-body F¹⁸-fluorodeoxyglucose positron emission tomography/CT (FDG PET/CT) with or without brain magnetic resonance imaging (MRI) to determine the highest likely radiographic stage and optimal biopsy site. (See 'Comprehensive imaging' above.)

-For patients in whom lung cancer is considered highly likely and in whom mediastinal or distant metastases are suspected (eg, suspected stage III or IV disease (table 1)) or in whom a diagnosis of lung cancer has already been made, FDG PET/CT is performed, even if chest CT imaging has already been obtained. When PET or integrated PET/CT is not available, conventional staging with abdominal CT and bone scintigraphy is sufficient, although not as sensitive. This approach provides a comprehensive image-based analysis of lymph nodes and is supported by data which report that integrated PET/CT is superior to either modality alone at detecting occult disease. (See 'Whole-body FDG PET and PET/CT' above.)

-Patients with CT stage III or IV disease (table 1) also typically undergo routine imaging of the brain with gadolinium-enhanced MRI, or contrast-enhanced CT if MRI is not available. This strategy also allows for the early detection and treatment of brain metastases before development of neurologic deficits or seizures. (See 'Brain, spine, nerve' above.)

-For patients with suspected localized-stage lung cancer (eg, stage I/II), imaging with whole-body FDG PET/CT is controversial and is dependent upon several factors including radiographic stage, lesion size, and amenability of resection. Many experts obtain PET/CT in this group of patients with the expectation that PET/CT will further reduce the risk of unnecessary surgery and guide the optimal biopsy site. Other experts selectively perform PET/CT first in some patients (eg, patients with evidence of hilar nodes) or perform tissue biopsy first without PET/CT (eg, patients with small lesions that are amenable to curative resection)

This approach is supported by the superior ability of PET/CT to detect occult disease compared with either modality alone and conflicting data that suggested a possible reduction in potentially avoidable thoracotomies by the detection of occult stage IV disease. Limitations of PET or PET/CT are the relatively high-false positive rate, lack of standardized criteria regarding what constitutes a positive result, poor sensitivity for the detection of brain metastases, need for confirmation on tissue sampling, and issues related to cost from third-party payers.

Clinical-directed approach – This approach involves using the chest CT and clinical evaluation to determine whether additional imaging needs to be performed to determine potential sites of metastases. (See 'Clinical-directed imaging' above.)

-The initial contrast-enhanced chest CT is evaluated to assess the extent of the primary tumor and potential spread to the mediastinum, liver, thoracic skeleton, and adrenal glands. (See 'Chest computed tomography' above.)

-Additional imaging is performed in patients with focal symptoms, signs, or laboratory tests suggestive of metastatic disease (table 3) and/or patients with a high likelihood of having brain metastases (eg, stage III or IV disease). (See 'Clinical-directed imaging' above.)

-Repeat or additional imaging is performed in patients when new symptoms arise (eg, bone pain or headache), rapid progression is suspected, or when there is a significant delay in initiation of therapy by eight weeks or more. (See 'Timeliness and location of the evaluation' above.)

Advantages of this approach include the minimization of low-value testing. Limitations include the low sensitivity of chest CT for the detection of lymph node metastases, need for tissue sampling confirmation, and potential for missing occult disease.

●Diagnosis and staging

•A diagnosis of lung cancer is made based upon the pathologic evaluation of cytologic (eg, pleural fluid) or histopathologic (eg, tissue biopsy) specimens. Consideration should be given to obtaining a large enough sample to allow supplemental immunohistochemical (IHC) and genetic analysis. (See 'Diagnosis' above and "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer".)

•Adenocarcinoma, squamous carcinoma, adenosquamous carcinoma, and large cell carcinoma are the four major histologic subtypes of non-small cell lung cancer (NSCLC). The main entity on the differential diagnosis of NSCLC is small cell lung cancer (SCLC). While clinical and imaging features can help the clinician distinguish NSCLC from SCLC, histopathologic features and IHC markers are required to make this distinction. (See 'Histopathology, immunohistochemistry, genetic mutations' above and 'Differential diagnosis' above.)

•Using radiologic and pathologic findings, the lung cancer is staged using the eighth edition of the tumor, node metastasis system (table 1). (See 'Staging' above.)