Diagnosis

Patients with lung cancer usually present with an abnormal finding on a routine chest radiograph, such as a nodule or effusion. This study is generally followed by a contrast-enhanced chest CT scan, which should include examination of the liver and adrenal glands along with mediastinal lymph node stations. The overall accuracy of CT in mediastinal staging for lung cancer is only 0.75 to 0.80, with 20% to 40% false-negative and 18% to 23% false-positive results. Although integrated PET-CT scanning is more sensitive and specific, yielding up to 98% correct tumor staging compared with final histologic staging, it is not as widely available as CT.

A lymph node is considered malignant when its shortest axis is at least 10 mm. The four most common sites of lung cancer metastases (stage IV disease) are brain, bone, liver, and adrenal glands. Consequently, head CT, brain MRI, and bone scans are often part of the metastatic evaluation. In the absence of central nervous system or bony symptoms in patients presenting with small tumors, the incidence of a true-positive finding is less than 10%. If disease in these sites is excluded, the cancer is confined to the chest (stages I–IIIB).

Positron emission tomography (PET) relies on the uptake and concentration of 2,3-fluorodeoxyglucose (FDG) in lung cancer cells. It is more sensitive and specific (approximately 90% sensitive and specific) for mediastinal nodal metastases compared with CT. PET scan is also fairly sensitive in detecting distant metastatic disease throughout the body exclusive of the brain. PET has an overall sensitivity of 96% (range, 83%–100%), specificity of 79% (range, 52%–100%), and accuracy of 91% (range, 86%–100%). False-negative results can occur with lesions smaller than 1 cm because a critical mass of metabolically active malignant cells is required for PET diagnosis. Lowe and colleagues found a sensitivity of only 80% in lesions smaller than 1.5 cm, compared with 92% in larger lesions.

False-negatives can also occur in tumors with low metabolism, such as carcinoid tumors. False-positive FDG uptake, particularly in pulmonary nodules or mediastinal lymph nodes, is seen in inflammatory conditions such as bacterial pneumonia, pyogenic abscesses, and aspergillosis, and in granulomatous diseases, such as tuberculosis, sarcoidosis, histoplasmosis, Wegener granulomatosis, and coal miner’s lung. Guidelines for obtaining PET scan are shown in Box 1 .

Approximately 70% of lung cancers are diagnosed and staged through small biopsies or cytology rather than using surgical resection specimens, with increasing numbers of transbronchial needle aspirations (TBNA), endobronchial ultrasound–guided needle aspirations (EBUS/TBNA), and esophageal ultrasound–guided needle aspirations being performed each year. Patients with suspected lung cancer who present with a pleural effusion should undergo thoracentesis first to differentiate between a malignant versus paramalignant effusion. When three separate pleural fluid specimens with malignant pleural disease are submitted to an experienced cytologist, a positive diagnosis can be expected in approximately 80% of patients, whereas percutaneous closed pleural biopsy is reported to be diagnostic for malignancy in approximately 50% of patients. Thoracoscopic biopsy of the pleura is safe and can provide a definitive diagnosis with a high degree of accuracy and minimal risk to the patient. In most instances it is performed as an outpatient procedure. The reported sensitivity rate for thoracoscopic biopsy ranges between 0.80 and 0.99, the specificity rate ranges between 0.93 and 1, and the negative predictive value ranges between 0.93 and 0.96. False-negative results are more common with mesothelioma than with primary lung carcinoma. In the case of a small (<3 cm) solitary peripheral lung lesion suspicious for lung cancer, the diagnostic dilemma generally centers on whether to obtain a biopsy specimen to confirm the diagnosis before surgical resection. In the presence of a high index of suspicion for lung cancer, an excisional wedge biopsy performed via video-assisted thoracic surgery has a much higher sensitivity than transthoracic needle aspiration (TTNA) and is the most definitive method of establishing a diagnosis. The diagnostic workup of lung cancer has evolved into a multidisciplinary approach. Patients suspected of having lung cancer require a histologic diagnosis and disease staging before appropriate treatment can be established. In addition, the development and clinical application of so-called targeted therapies require an increasing number of molecular investigations, such as gene amplification or mutation analysis, capable of scutinizing cancer at the nucleic acid level.

The histopathologic typing of lung tumors is performed according to the WHO criteria, but several specific antibodies are useful in establishing or eliminating diagnoses of primary lung cancers. A few examples of proved and reliable markers are available for a few common malignant tumor groups; large cell neuroendocrine carcinoma (chromogranin+, synaptophysin+, NCAM/CD56+, TTF-+/−, CK7+, CK high/lowMW+/−, AE1/AE3), SCLC (TTF-1+, CD56 or other neuroendocrine marker+, CK+, CK lowMW+, AE1/AE3, CK highMW-, LCA-, MIB-1/Ki-67 >50%), typical carcinoid (neuroendocrine marker+, TTF-1-, CK7, MIB1/Ki67<, <2 mitoses/2sqmm (10HPF), and atypical carcinoid (neuroendocrine marker+, TTF-1+/−, CK7+, MIB-1/Ki-67>, 2–10 mitoses/2sqmm and necroses). It also depends on the type of lung cancer, the size and location of the primary tumor, the presence of metastasis , the radiographic appearance of the lesion, and the overall clinical status of the patient .