Lung cancer diagnosis

Lung cancer is usually suspected in individuals who have abnormal chest radiograph findings or have symptoms caused by either local or systemic effects of the tumor. The method of diagnosis of suspected lung cancer depends on the type of lung cancer (ie, small cell lung cancer or non-small cell lung cancer), the size and location of the primary tumor, the presence of metastasis, and the overall clinical status of the patient. Achieving a diagnosis and staging are usually done in concert because the most efficient way to make a diagnosis often is dictated by the stage of the cancer. The best sequence of studies and interventions in a particular patient involves careful judgment of the probable reliability of a number of presumptive diagnostic issues, so as to maximize the sensitivity and to avoid performing multiple or unnecessary invasive procedures. In this article, we consider all manner of clinical presentations of lung cancer in light of currently available diagnostic procedures. Published data supporting a particular diagnostic approach is weighed based on the quality of the benefit as well as the estimated net benefit. Recommendations are graded in terms of strength to provide clinicians with guidance as to the most efficient and approach to the diagnosis of lung cancer in individual patients.

Key words: bronchoscopy; lung neoplasm; sensitivity; specificity; sputum cytology; transthoracic needle aspiration

Abbreviations: FDG = [sup.18]F-2-fluoro-2-deoxy-D-glucose; FN = false negative; FNA = fine needle aspirate; NSCLC = non-small cell lung cancer; PET = positron emission tomography; SCLC = small cell lung cancer; TBNA = transbronchial needle aspiration; TTNA = transthoracic needle aspiration

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The radiographic findings and clinical presentation usually allow a presumptive differentiation between small cell lung cancer (SCLC) and non-SCLC (NSCLC). Massive lymphadenopathy and direct mediastinal invasion are well-recognized phenomena in SCLC. (1,2) A mass in, or adjacent to, the hilum is a particular characteristic of SCLC and is seen in about 78% of cases. (1,2) Not infrequently, patients with SCLC present with paraneoplastic syndromes. (3) These include the syndrome of inappropriate antidiuretic hormone, ectopic adrenocorticotrophic hormone production, and the Lambert-Eaton syndrome. If SCLC is suspected, the diagnosis should be achieved by whatever means is easiest (ie, sputum cytology, thoracentesis if an accessible pleural effusion is present, fine needle aspirate [FNA] of a supraclavicular node or metastatic site, bronchoscopy with or without transbronchial needle aspiration [TBNA] of mediastinal nodes or submucosal process). If the diagnosis of SCLC is established on a biopsy of the primary lesion, the distinction between limited or extensive disease then is made radiographically.

In patients who are suspected of having NSCLC, the method of achieving a diagnosis is usually dictated by the presumed stage of the disease. Patients with suspected lung cancer who present with a pleural effusion should undergo thoracentesis first in order to differentiate between a malignant effusion (ie, one due to malignant involvement of the pleura) and a paramalignant effusion (ie, one due to other factors such as lymphatic blockade, atelectasis, or hypoproteinemia). Distinction between the two is important because the finding of malignant cells in the pleural fluid alters the stage and treatment of the particular patient. Because pleural metastases are more common in the visceral pleura (4) and tend to be focal when there is involvement of the parietal pleura, pleural fluid cytology is a more sensitive diagnostic test than percutaneous pleural biopsy, the latter being a blind sampling procedure. (5-7) When three separate pleural fluid specimens from a patient with malignant pleural disease are submitted to an experienced cytologist, one should expect a positive diagnosis in about 80% of patients. (7,8) Percutaneous, closed pleural biopsy is reported (6) to be diagnostic for malignancy in about 50% of cases. 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. (9,10) The reported sensitivity rate is 0.80 to 1, the specificity rate is 1, and the negative predictive value is 0.93. (9,11-13) False-negative test results are more common with mesothelioma than with primary lung carcinoma. (11)

Patients with metastatic NSCLC (stage IV disease) usually present with constitutional symptoms (ie, fatigue and weight loss), organ-specific symptoms (ie, bone pain and neurologic symptoms), and/or abnormal laboratory findings (ie, anemia, elevated alkaline phosphatase levels, and/or elevated liver enzyme levels). In many of these patients, a FNA or a needle biopsy of a site of metastasis represents the most efficient way both to make a diagnosis and to confirm the stage. In some cases, however, the metastatic site may be technically difficult to biopsy. If metastatic disease can be predicted with a high degree of accuracy on the basis of radiographic findings (ie, multiple brain, liver, or bone lesions), it may be more efficient to achieve a diagnosis of the primary lung lesion by whatever method is easiest for the patient (ie, sputum cytology, bronchoscopy, or transthoracic needle aspiration [TTNA]). This decision must be made by weighing the technical considerations involved in each approach as well as the reliability of diagnosing an extrathoracic lesion as a site of metastasis based on radiographic appearances alone (see the article on clinical/noninvasive staging elsewhere in this supplement). A joint decision among the radiologist, the pulmonologist, and the medical or radiation oncologist is the desirable approach.

NSCLC can present with extensive infiltration of the mediastinum. In such patients, the diagnosis should be achieved by the method that has the most favorable risk/benefit ratio. Bronchoscopy with TBNA for cytologic or histologic examination of mediastinal lymph nodes has been shown to be a safe procedure. (14-17) Technical aspects that are frequently emphasized to be important in achieving a high success rate include accurate preparation of the specimen, rapid on-site evaluation by a cytopathologist, and using the larger 19-gauge needles, which provide better tissue samples for histologic evaluation. (18,19) The overall sensitivity of TBNA is 0.76, and the overall specificity is 0.96. (14-22) (The reader is referred to the article on invasive clinical staging of non-small cell lung cancer elsewhere in this supplement for a more detailed review on the performance characteristics of TBNA for staging the mediastinum.) The negative predictive value of TBNA (0.71) is not high enough to obviate the need for a further confirmation of negative results. Mediastinoscopy is warranted in patients with nondiagnostic results.

CT-guided TTNA of mediastinal masses or nodes (ie, nodes < 1.5 cm in size) can be performed safely. (23) The role of TTNA in patients with extensive mediastinal disease (defined as such extensive invasion of the mediastinum by the tumor that discrete lymph nodes can no longer be discerned) is usually to confirm SCLC, or in patients with NSCLC who are not surgical candidates because of the extent of mediastinal disease.

In the case of a small (ie, < 3 cm), solitary, peripheral lung lesion that is suspicious for lung cancer in a patient who appears to have early-stage disease and is a surgical candidate, the diagnostic dilemma generally centers around whether or not to obtain a biopsy to confirm the diagnosis of cancer before surgical resection is carried out. When the lesion is moderately to highly suspicious for lung cancer, an excisional biopsy performed via thoracoscopy has a much higher sensitivity than TTNA and is the most definitive method of diagnosing a peripheral lung nodule. TTNA has no role in patients with a solitary lesion that is moderately or highly suspicious for lung carcinoma who appear to have early stage-disease and are candidates for surgical resection. (The reader is referred to the article on solitary pulmonary nodules elsewhere in this supplement for a more detailed review on the diagnostic approach to the solitary pulmonary nodule.)

GENERAL APPROACH TO DIAGNOSIS

Recommendations

1. In patients suspected of having SCLC based on the radiographic and clinical findings, the diagnosis should be obtained by whatever method is easiest (ie, sputum cytology, thoracentesis, FNA, or bronchoscopy, including TBNA), as dictated by the patient's presentation. Level of evidence, fair; benefit, moderate; grade of recommendation, B

2. In patients suspected of having lung cancer who have an accessible pleural effusion, a definitive diagnosis of the pleural effusion via thoracentesis should be made first. Level of evidence, fair; benefit, substantial; grade of recommendation, B