Lung Cancer Part 2

Manifestations of Extrathoracic Disease

Extrathoracic manifestations of lung cancer relate to the extent and site of distant spread [see Table 4]. The most common of these are anorexia, weight loss, and fatigue. Bone pain commonly accompanies metastasis to bone, but with the increased use of imaging, asymptomatic bony metastases are commonly found. Liver abnormalities may be detected on clinical examination or on laboratory or imaging studies, but they are generally asymptomatic. The frequency of CNS involvement varies with the extent of other known disease, with a low incidence in patients who have no nodal spread of cancer. However, in patients with other signs of mediastinal or distant involvement, the incidence of occult brain metastases is in the range of 5% to 15%, even in NSCLC.

Occasionally, flank pain will be a presenting feature of adrenal metastases. Although flank pain occurs in fewer than 10% of patients, the adrenal gland is the most frequent site of distant metastatic spread of lung cancer, as detected by CT imaging. Adrenal insufficiency is an unusual but potentially fatal complication of adrenal metastasis from lung cancer, and it is often overlooked because the weight loss and fatigue it causes are common features in lung cancer patients. In selected cases, an adrenal stimulation test may identify patients with limited reserve who may benefit from steroid-replacement therapy.

Patients who have bronchial carcinoid tumors metastatic to liver or other sites may experience the carcinoid syndrome. This dramatic but rare syndrome is characterized by episodic flushing that may be associated with abdominal pain, diarrhea, and wheezing.

Table 5 Common Causes of a Solitary Pulmonary Nodule


Bronchogenic carcinoma


Squamous cell

Large cell

Metastatic cancers


Noninfectious granuloma


Wegener granulomatosis

Infectious granuloma




Nontuberculous mycobacteria

Benign tumors





Arteriovenous malformation

Bronchogenic cyst


Rheumatoid nodule


Pulmonary infarction

Clinical staging

When the results of the clinical examination and chest x-ray indicate early-stage lung cancer, imaging studies may be limited to a chest CT. However, in patients who have clinical, laboratory, or radiologic signs of regional tumor spread, a search for occult bone and CNS metastases is warranted. For patients with suspected metastatic disease, the standard imaging evaluation should include a chest CT with images through the adrenal glands, a bone scan, and a CT or MRI scan of the brain.

The role of PET scanning in the evaluation of lung cancer patients is currently under study. F-18 fluorodeoxyglucose (FDG) uptake is greater in malignant cells than in normal, benign cells. Several series have suggested that FDG-PET imaging can be very useful in determining whether abnormalities seen on CT—particularly in the adrenal gland and bone—likely represent metastatic disease.22 The sensitivity and specificity for me-diastinal lymph node metastases is still being clarified. PET scans are also useful for evaluation of solitary pulmonary nodules, with a sensitivity of 90% to 95% and specificity of 80% to 100% for the detection of cancer. Because PET imaging can detect unsuspected metastatic disease in 11% to 14% of patients and thus help avoid futile surgery in these cases, Medicare in the United States provides coverage for FDG-PET for the staging of NSCLC.23 Meanwhile, PET technology is evolving rapidly, improving its sensitivity for the detection of smaller lesions. Although PET scanning can detect lesions between 0.5 and 1.0 cm, most series have limited the analysis to lesions greater than 1.0 cm. In addition, techniques that incorporate simultaneous CT and PET image analysis are currently being developed.

The diagnostic approach used to confirm the presence of lung cancer and determine the subtype depends on the clinical stage at presentation. In patients with advanced disease, a needle biopsy of a metastatic site (e.g., liver, bone, or a subcutaneous nodule) is often the best choice, providing both confirmation of the diagnosis and identification of the disease stage. In patients with no extrathoracic signs of cancer, the choice of initial diagnostic procedure often depends on whether the patient is likely to be a candidate for surgery. For the surgical population, the primary diagnostic procedure in most patients should be a bronchoscopy and mediastinoscopy by the thoracic surgeon, to determine the type and stage of cancer with respect to mediastinal lymph node involvement, as well as to determine resectability. For patients with more peripheral lung masses or solitary pulmonary nodules, the procedure of choice for confirming the presence of cancer and the prospects for definitive surgery is an initial needle biopsy performed under radiologic guidance or resection by video-assisted thoracoscopic surgery (VATS). In patients with solitary pulmonary nodules, biopsy may show that the cause is not cancer but rather a benign tumor or an inflammatory, infectious, or congenital disorder [see Table 5].

For patients who have evidence of bulky intrathoracic disease but who are not likely to be surgical candidates, the preferred method of evaluation is bronchoscopy. During the bron-choscopy, the surgeon may perform brushings, washings, or transbronchial biopsies of the primary lesion or any associated central mediastinal lymph nodes.

Patients presenting with pleural effusions can be evaluated by diagnostic thoracentesis. In some cases, VATS can provide both definitive diagnosis and management of pleural effusions.

In addition to the clinical stage, the so-called physiologic stage of the patient is also important for determining which diagnostic strategy is best. In patients who are not candidates for surgery because of constraints such as severe comorbid disease or limited pulmonary reserve, transthoracic needle biopsy or bronchoscopy alone may suffice.

Improvements in needle-biopsy techniques have reduced the complications of these procedures, and improvements in cytology have enhanced its diagnostic power. Although these cytologic exams often cannot differentiate subtypes of NSCLC, they are 95% accurate in distinguishing SCLC from NSCLC. Definitive staging is particularly important in patients with NSCLC because of the evolution in treatment strategies for both operable (stage I to IIIA) and inoperable (stage IIIB) cases. Definitive surgical staging with bronchoscopy and medi-astinoscopy remains the preferred approach for most patients with apparent early-stage lung cancer who would be candidates for surgery. If cervical mediastinoscopy is performed, nodal sampling should include the upper paratracheal (level 2), lower paratracheal (level 4), and subcarinal (level 7) stations [see Surgical Staging, below]. For patients with a left upper lobe tumor, an anterior mediastinal approach may also be indicated to sample the AP window lymph nodes (level 5).

Surgical staging

Cancer stage is by far the most important prognostic factor in lung cancer. Histology (i.e., SCLC versus NSCLC) may influence choice of treatment options. Survival rates for patients with the same stage of lung cancer are quite similar, regardless of whether they have SCLC or NSCLC. Other characteristics that can affect outcome are patient characteristics such as performance status, recent weight loss, and significant comorbid conditions. In addition, studies suggest that stage for stage, outcome with both SCLC and NSCLC is better for women than for men. As with other cancers, advanced age may have an adverse effect on outcome, but age per se seems to be less important than the comorbid conditions that are more common in the elderly.

Staging of lung cancer is by the TNM (tumor, node, metas-tases) classification [see Figure 1].24,25 It is based on the size, location, and regional extension of the primary tumor; on the location of regional malignant lymph nodes that drain the region; and on the absence or presence of distant metastases. T1 and T2 tumors are operable tumors differentiated predominantly by size. T1 tumors are 3 cm or less in their greatest dimension, surrounded by lung or visceral pleura, and without bronchoscop-ic evidence of invasion more proximal than the lobar bronchus. T2 tumors have any one of the following characteristics: size greater than 3 cm, main bronchus involvement, location 2 cm or more distal to the carina, invasion of the visceral pleura, or association with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

T3 tumors are tumors of any size that directly invade the chest wall, diaphragm, mediastinal pleura, parietal pleura, or pericardium; are located in the main bronchus less than 2 cm distal to the carina but do not involve the carina; or are associated with atelectasis or obstructive pneumonitis of the entire lung. T3 tumors can be considered marginally operable but require a more extensive operation that may involve removal of the chest wall or pericardium or, for more proximal tumors, a sleeve resection.

T4 tumors are grossly inoperable because they invade the mediastinum, heart, great vessels, trachea, esophagus, a vertebral body, or the carina. Tumors are also classified as T4 if they are associated with a malignant pleural or pericardial effusion or with satellite tumor nodules within the same lobe as the primary tumor.

Lymph node status is determined as N0 (no lymph node involvement), N1 (metastases to the lymph nodes within the confines of the lung), and N2 or N3 (extrapulmonary metastases). N2 represents involvement of ipsilateral mediastinal lymph nodes, whereas N3 represents involvement of contralateral lymph nodes or more distant nodes, including hilar or supraclavicular nodes.

N1 and N2 nodes are further denoted by specific location (station) [see Figure 2].26 Other than level-10 hilar nodes, which may be enlarged on CT, N1 nodal involvement is generally not suspected until it is discovered at the time of surgery. Although N2 and N3 nodes can be suspiciously enlarged on CT, 40% of nodes greater than 2 cm are enlarged because of inflammation, and 10% of normal-sized nodes contain malignancy. Thus, me-diastinoscopy is essential for providing pathologic definition of nodal involvement so that treatment options can be finalized.



The treatment of NSCLC is based on the stage of disease, as determined by the TNM staging system. For stage I or stage II disease, surgical resection is the standard treatment. Stage III disease is treated with definitive radiation therapy and chemotherapy; in addition, a subset of patients with stage IIIA disease have been shown to have improved outcome with the addition of surgical resection. Stage IV disease is treated with chemotherapy, palliative radiation, and supportive care [see Table 6].

An international TNM four-stage system is used in the clinical and surgical evaluation of lung cancer. Definitions of TNM categories are simplified.

Figure 1 An international TNM four-stage system is used in the clinical and surgical evaluation of lung cancer. Definitions of TNM categories are simplified.

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