Lung cancer is the leading cause of cancer-related mortality internationally, having been responsible, for example, for approximately 19% of the 8.2 million worldwide deaths linked to cancer in 2012.^[1,2] The main primary types are small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). The first step in the workup of any newly diagnosed lung malignancy is staging, a validated diagnostic tool that involves careful identification of the tumor, lymph node involvement, and metastatic spread.

In this image, SCLC is found in the right mainstem bronchus, adjacent lung parenchyma, and subcarinal lymph nodes, with tumor nodules also situated in the left lung.

Image courtesy of Wikimedia Commons | Yale Rosen from USA.

In the United States, lung cancer is the prevalent cause of cancer-related mortality in men and women. According to the National Cancer Institute, an estimated 224,390 new cases of lung and bronchus cancer (13.3% of all new cancer cases) were diagnosed in 2016, with an estimated 158,080 deaths resulting from this disease.^[3] Nonetheless, the US incidence of lung cancer has been declining, with the rate of new cases of lung and bronchus cancer dropping an average of 1.8% per year, and death rates, between 2003 and 2013, having fallen an average of 2.2% annually.^[3] The most common symptoms of lung cancer are coughing (including hemoptysis), weight loss, shortness of breath, and chest pains.

Image courtesy of the National Cancer Institute (NCI).

Lung cancer staging relies on the tumor-node-metastasis (TNM) system, designed by the American Joint Committee on Cancer (AJCC). The system is based on the spread of the primary tumor (T), the extent of lymph node involvement (N), and the presence or absence of metastases (M). The T, N, and M combination determines the appropriate stage of the cancer, with each stage having specific therapeutic and prognostic implications. Common sites of extrathoracic metastases in lung cancer include the brain, bones, liver, and adrenal glands. The table seen here provides TNM classifications for lung cancer staging.

Table adapted from Medscape.

A host of different imaging options are available for lung cancer staging and are frequently used in combination to provide the most accurate assessment. Conventional chest radiography is the means by which lung cancer is often incidentally first discovered. It allows for a coarse assessment of primary tumor size and may reveal mediastinal lymphadenopathy. Indirect, nonspecific findings associated with a primary mass include pleural effusion, atelectasis, obstructive pneumonitis, and mediastinal widening.

A small cell carcinoma of the left lung (yellow arrow) is seen in this plain chest radiograph.

Image courtesy of Wikimedia Commons | Yale Rosen from USA.

Contrast-enhanced computed tomography (CT) scanning is one of the most useful tools in lung cancer staging. It provides excellent visualization of the primary tumor, allowing accurate measurement of tumor size and the extent of intrathoracic invasion. The National Lung Screening Trial reported that low-dose helical CT scanning has a 94.4% sensitivity, a 72.6% specificity, a 2.4% positive predictive value, and a 99.9% negative predictive value for lung cancer diagnosis.^[4]

Magnetic resonance imaging (MRI) of the chest may be needed for patients with allergies to iodinated contrast or if there is potential involvement of the mediastinal structures that may dictate treatment planning. Unfortunately, the spatial resolution of chest MRI is not as precise as with CT scanning and is limited by respiratory and cardiac motion artifacts because image acquisition time is greater.

This chest CT scan (axial cross section) reveals a peripheral left lung mass.

Image courtesy of Wikimedia Commons | Yale Rosen from USA.

Once a suspicious lung mass is found, the usual next step in the workup is to obtain a biopsy for accurate diagnosis. For peripheral tumors, this can be achieved using radiologic guidance. The most common method is CT-scan–guided percutaneous biopsy. The accuracy of this procedure depends on multiple factors, including the size of the primary tumor; false negative rates of around 10% have been reported.^[5]

A CT-scan–guided percutaneous needle biopsy of a left lung mass is shown.

Images courtesy of Wikimedia Commons | Hellerhoff.

Specimens obtained from any of various biopsy techniques are then histologically analyzed to confirm the type of tumor present and rule out benign causes for the initial findings.

SCLC (hematoxylin and eosin [H&E] stain) is seen in this micrograph of a core biopsy specimen.

Image courtesy of Wikimedia Commons.

To a great extent, the decision to utilize bronchoscopy for diagnosis depends on whether the lesion is central or peripheral.^[6] Bronchoscopic examination is preferred in patients with central tumors, with flexible bronchoscopy reportedly having an overall sensitivity for the diagnosis of central endobrachial lesions of 88%.^[6] The sensitivity of bronchoscopy has been increased with the use of endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA) to obtain samples when there is submucosal tumor spread or when peribronchial tumor causes extrinsic compression.^[7]

This image demonstrates a bronchoscopic view of external compression of the left mainstem bronchus (arrows) caused by a central tumor.

Images courtesy of Wikimedia Commons | JHeuser.

EBUS-TBNA not only permits accurate assessment of central lesions, it also permits all intrathoracic lymph nodes adjacent to the bronchial tree to be sampled in a minimally invasive way.^[8] A pooled analysis of 1299 patients with known or suspected NSCLC undergoing EBUS-TBNA showed that the procedure had a sensitivity of about 90% for the detection of mediastinal nodal metastases.^[9]

This EBUS image shows a central lung mass abutting the aortic arch.

Image courtesy of Wikimedia Commons | Ktg usa.

Bronchoscopy also allows for the collection under direct visualization of diagnostic material for cytologic examination, using either direct biopsy of the visualized tumor, bronchial brushings and washing, or transbronchial biopsy. Cytologic specimens obtained via fine-needle aspiration biopsy are less sensitive than are core biopsy specimens.

This micrograph demonstrates the nuclear molding, salt-and-pepper chromatin, and scant cytoplasm seen in SCLC.

Image courtesy of Wikimedia Commons | Nephron.

Brain imaging is typically done when neurologic signs and symptoms, suggesting the possibility of brain metastases, arise in patients with a known primary lung tumor. MRI with contrast enhancement currently is the procedure of choice in such cases, with other imaging modalities being less sensitive and specific in revealing the presence, location, and number of metastases.^[10,11]

A solitary brain metastasis (arrow) is seen in this image.

Image courtesy of Wikimedia Commons | Marvin 101.

Positron emission tomography (PET) scanning has been used to differentiate benign from malignant pulmonary nodules. PET scans also may be useful in detecting distant metastases when whole-body imaging is performed. Indeed, because tumor cells have a higher than normal metabolism, they are detected on PET scanning by their increased glucose uptake, permitting detection of the extent of metastatic disease, as well as treatment response. However, because PET scans have a high false-positive rate, invasive staging procedures may still be required before potentially curative surgery can be offered to a patient.^[12] The PET scan shown here (left) demonstrates abnormally increased uptake in the left lung hilum and left adrenal gland (yellow arrows), indicating the presence of a primary lung tumor and a metastatic adrenal lesion.

With combined PET/CT scanning, evaluation of metabolic activity and excellent spatial resolution are both possible. In terms of assessing primary tumors and metastases in lung cancer, PET/CT scanning is more accurate than CT scanning alone, PET scanning alone, or visual correlation between PET and CT scanning. The PET/CT fusion image (right) reveals a left lung tumor.

Images courtesy of Medscape.

Whole-body bone scanning allows for the detection of bony metastatic disease, which is usually identified by multiple asymmetrical areas of increased radionuclide uptake. SCLC is well known for the presence of bony metastases; thus, bone scanning is useful in staging and follow-up. It is important to rule out fractures and degenerative diseases in any patient, as these conditions may cause false-positive interpretations on bone scans.

As shown here, whole-body nuclear medicine bone scanning with anterior and posterior images reveals multiple abnormal areas of increased radiotracer activity in the pelvis, spine, ribs, and left scapula. These findings are consistent with bony metastatic disease.

Image courtesy of Medscape.

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 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.^[13,14,15] 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 80% and 99%, the specificity rate ranges between 93% and 100%, and the negative predictive value ranges between 93% and 96%.^[16,17]

The images, of video-assisted thoracoscopic surgery, show the left upper mediastinum before (left) and after (right) lymph node dissection. AL = arterial ligament; LSA = left subclavian artery; PA = pulmonary artery; PN = phrenic nerve; RLN = recurrent laryngeal nerve; VN = vagus nerve

Image courtesy of Wada H, Hida Y, Kaga K, et al. Video-assisted thoracoscopic left lower lobectomy in a patient with lung cancer and a right aortic arch. J Cardiothorac Surg. 2012 Nov 13;7:120. PMID: 23147195.

Once a lung cancer has been appropriately staged, primary and adjuvant therapeutic planning can commence. The treatment options and associated mortality for NSCLC change dramatically with each stage. For SCLC, standard treatment in patients with limited-stage disease includes chemoradiation, combination chemotherapy, and/or surgical resection. Extensive-stage disease is treated with a combination chemotherapy and radiation.

NSCLC (invasive) cases detected while the disease is still localized have a 5-year relative survival rate of 58.7%. (However, only 15% of lung cancer cases receive an early stage diagnosis.) In cases with distant metastases, the 5-year relative survival rate is just 4.7%.^[18,19] For SCLC (invasive), the 5-year relative survival rate for localized disease cases is 27.3%, while for patients with distant metastases, the rate is 2.8%.^[18]

In this image, thoracotomy for lung resection is being performed.

Image courtesy of Wikimedia Commons | Wojciech Filipiak.