Lung Cancer

Lung Cancer

Pasquale Ferraro

André Duranceau

Derek Ferguson is a 59-year-old auto mechanic who is admitted to the hospital with a fever, persistent cough, and blood-streaked sputum. He was treated by his family doctor with oral antibiotics for an episode of acute bronchitis 2 weeks ago. He has a 40-pack-year smoking history and his medical history is significant for non-insulin-dependent diabetes mellitus and peptic ulcer disease. Over the years, he has had several episodes of what he calls bronchitis. He is mildly short of breath on exertion but denies any chest pain or wheezing. His weight is stable and he maintains an active 40-hour work week.

What are the possible diagnoses based on this history?

The differential diagnosis at this point includes community-acquired pneumonia, acute bronchitis, exacerbated chronic bronchitis, and lung cancer.

Is fever a common finding with lung cancer?

Fever, which affects only 10% of patients with lung cancer, is usually associated with postobstructive atelectasis or pneumonia. An abscess can develop in a tumor cavity, but this is rare.

What are the clinical manifestations of lung cancer?

More than 90% of patients with lung cancer have symptoms (pulmonary, metastatic, systemic, or paraneoplastic) at the time of diagnosis. Bronchopulmonary symptoms, including coughing, dyspnea, chest pain, and hemoptysis, are found in up to 80% of patients. Some 30% of patients have metastatic disease at presentation, and the usual symptoms are those associated with central nervous system (CNS), bone, or liver metastases. Although common, adrenal gland metastases are rarely symptomatic. Systemic symptoms such as malaise, weight loss, and anorexia are found in 34% of patients. Paraneoplastic syndromes (found in 2% of patients) secondary to lung cancer are among the most varied in clinical presentation. The different types of syndromes include endocrine (hypercalcemia, Cushing’s syndrome, syndrome of inappropriate antidiuretic hormone secretion, gynecomastia), neurologic (encephalopathy, peripheral neuropathy, polymyositis, Eaton-Lambert syndrome), skeletal (clubbing, pulmonary hypertrophic osteoarthropathy), cutaneous (acanthosis nigricans), and hematologic disorders. Only 5% of patients with lung cancer are asymptomatic at the time of diagnosis (1,2).

On physical examination, Mr. Ferguson appears healthy. He is mildly overweight and shows no signs of respiratory distress. His heart rate, blood pressure, and respiratory rate are normal, and his temperature is 38°C. There is no clubbing, and the head and neck examination shows no suspicious lymph nodes. Chest auscultation reveals some crackles over the left lung; the right lung is clear; heart sounds are normal; and the liver is not tender.

Which tests are ordered initially?

Blood tests should include a complete blood count and electrolyte, blood urea nitrogen, and creatinine levels. A chest radiograph and electrocardiogram (ECG) should be ordered as well.

The results of the initial blood tests and ECG are normal. The chest radiograph shows a 4-cm mass in the left upper lung and a clear right lung field.

What is the differential diagnosis on the basis of these findings?

Inflammatory or infectious conditions such as abscess, granuloma, tuberculosis, fungal infection, or pneumonia
Neoplastic disorders, including benign lung tumors and malignant tumors (primary lung cancers and secondary or metastatic lesions)
Congenital lesions
Traumatic lesions

What are other pertinent findings on a simple chest radiograph in a patient suspected of having lung cancer?

Important radiologic findings include a mass with irregular borders, no calcifications, a pleural effusion, an elevated diaphragm, a widened mediastinum, and contralateral nodules. Areas of pneumonitis often surround central tumors with an endobronchial component. When possible, comparison with older radiographs is essential to establish the evolving nature of a nodule or mass.

Which radiologic features characterize a benign lesion in a patient with a solitary pulmonary nodule?

Features of a benign nodule include a smooth border, homogenous appearance, fat within lesion, calcifications in a benign pattern (central, laminated, or diffuse), and stable size over 2 years (3).

What is the likelihood that a radiologically detected mass in a patient such as Mr. Ferguson is cancer?

In a 59-year-old man with a history of heavy smoking and a newly discovered 4-cm mass, the likelihood is greater than 90% that the lesion is a bronchogenic carcinoma. Generally, in the adult population, any new pulmonary nodule carries a 50% risk of being a malignancy if the patient has a significant smoking history (1).

What is the incidence of lung cancer in the United States?

The estimated total number of new cases in 2004 is 173,770, and the estimated number of lung cancer deaths is 160,440. The probability of developing lung cancer is 1 in 12 for men and 1 in 19 for women (4).

What factors have been linked to the development of lung cancer?

Tobacco smoking is undoubtedly the most important causative factor in lung cancer. The lung cancer mortality is 20- to 70-fold higher in smokers than in nonsmokers. Although generally believed to be an important factor, air pollution independent of tobacco use increases the risk of lung cancer only slightly. Exposure to uranium, asbestos, arsenic, nickel, chromium, or beryllium carries proven occupational risk. Certain organic compounds (aromatic hydrocarbons, chlormethyl ether, and isopropyl oils) have also been implicated. The association of dietary factors with lung cancer is less convincing. The consumption of vegetables or fruits containing beta-carotene is considered to be protective, whereas dietary animal fat is believed to promote the development of lung cancer (5).

What additional workup does a patient with probable lung cancer require?

Additional workup is needed to (a) confirm the diagnosis, (b) establish the extent and resectability of the lesion, and (c) assess operability.

How is the diagnosis of lung cancer confirmed?

The diagnosis may be confirmed with sputum cytology, bronchoscopy, or transthoracic needle biopsy. Histologic confirmation may be obtained with a more invasive procedure, such as cervical mediastinoscopy, scalene node biopsy, thoracoscopy, or exploratory thoracotomy.

What is the yield from and the importance of these different diagnostic tests?

Sputum cytology is the most useful test for central hilar lesions, endobronchial tumors, and squamous cell carcinoma, with an overall diagnostic yield of 82% when three early morning specimens are analyzed; with peripheral tumors, the yield is 40% to 50%. The overall rate of false-positive results with sputum cytology is 1% to 3% (6). Bronchoscopy is diagnostic in 25% to 50% of patients with small cell or squamous cell carcinoma. Additional analysis of brushings and washings increases the yield to 90% (2). Bronchoscopy also provides information on tumor location and extent that helps in staging the tumor, and it helps identify a synchronous cancer in another lobe or in the contralateral lung in 1% to 2% of patients. A transthoracic needle biopsy should not be performed as part of the routine workup for lung cancer because the results seldom affect management, it has no value in the staging process, and the procedure is associated with a 30% risk of pneumothorax. Furthermore, the rate of false-negative findings can be as high as 15% to 25% (7). Transthoracic needle biopsy should be limited to patients with a clinically unresectable lesion, to high-risk patients who are inoperable for medical reasons, and to patients who refuse surgery.

How are patients assessed for operability?

Determination of operability necessitates a cardiac workup in patients with symptoms of heart disease, a significant medical history, or risk factors for coronary artery disease. Pulmonary function tests, exercise tolerance, and overall performance status must be assessed in all patients. Renal function and presence of other major systemic diseases also should be evaluated in selected patients.

How is lung cancer classified and staged?

The TNM staging classification is based on a number of specific criteria with respect to the tumor (T) (size, site, local invasion, associated atelectasis), the lymph nodes (N) (hilar, mediastinal, or extrathoracic nodes; ipsilateral or contralateral nodes), and the presence of distant metastases (M). The TNM classification is shown in Table 26.1. The staging of lung tumors according to the TNM classification is shown in Table 26.2.

TABLE 26.1. TNM Classification for Lung Cancer

Primary Tumor (T)
T0	No evidence of primary tumor
TIS	Carcinoma in situ
T1	Tumor 3 cm or smaller, not involving the visceral pleura and not invading proximal to the lobar bronchus
T2	Tumor larger than 3 cm; tumor with invasion of visceral pleura or extending into mainstem bronchus but more than 2 cm from carina; or tumor with lobar atelectasis
T3	Tumor of any size with invasion of parietal pleura, chest wall, pericardium, mediastinal pleura, or diaphragm; tumor in mainstem bronchus within 2 cm of carina but not involving carina; tumor with atelectasis of entire lung; or superior sulcus (Pancoast) tumor
T4	Tumor of any size with invasion of mediastinum, heart, great vessels, esophagus, vertebral body, trachea, or carina; or tumor with malignant pleural effusion
Nodal Involvement (N)
N0	No metastases to regional lymph nodes
N1	Metastases to peribronchial or ipsilateral hilar lymph nodes
N2	Metastases to ipsilateral mediastinal lymph nodes
N3	Metastases to contralateral hilar or mediastinal lymph nodes or to extrathoracic lymph nodes (scalene or supraclavicular)
Distant Metastases (M)
M0	No known distant metastases
M1	Distant metastases present

TABLE 26.2. Staging of Lung Cancer with TNM Classification

Stage	Classification
IA	T1, N0, M0
IB	T2, N0, M0
IIA	T1, N1, M0
IIB	T2, N1, M0, T3, N0, M0
IIIA	T3, N1, M0; T1, N2, M0; T2, N2, M0; T3, N2, M0
IIIB	T4, any N, M0; any T, N3, M0
IV	Any T; any N; M1

Why is the TNM classification important?

The TNM system serves several purposes, such as selecting the most appropriate therapy, establishing the prognosis, and permitting the comparison of data and results.

How are the extent of the lesion and its resectability evaluated?

Bronchoscopy and computed tomography (CT) of the chest are the best techniques for evaluating the local and regional extent of lung cancer. A bronchoscopic finding that suggests unresectability is invasion of the trachea or main carina. On CT of the chest, indications of unresectability include bulky N2 disease (metastatic ipsilateral mediastinal adenopathy), N3 disease (contralateral mediastinal or extrathoracic metastatic adenopathy), or any T4 lesion (invasion of the heart, great vessels, esophagus, trachea, or vertebral body).

Which tests are included in the workup for metastatic disease?

Blood tests consist of liver function tests and determination of the serum calcium level. CT of the chest includes imaging of the liver and adrenal glands, both frequent sites of lung metastases. Unsuspected metastases have been found in the liver or adrenal glands in 3% to 7% of patients (8,9). A bone scan and head CT is obtained in selected cases and in all symptomatic patients.

What is the role of positron-emission tomography (PET) scanning in patients with suspected lung cancer?

PET scanning can be used to characterize pulmonary nodules as malignant or benign, to stage lung cancer both locoregionally and systemically, and to help assess response to treatment in a neoadjuvant or adjuvant setting.

What types of malignant tumors may yield false-negative results with a PET scan?

Bronchoalveolar carcinomas and carcinoid tumors typically have a low metabolic activity and thus a reduced level of FDG accumulation, resulting in a negative PET scan. Also, tumors less than 1 cm in diameter are generally not visualized with PET imaging.

What are the most frequent sites of metastases from a lung cancer?

In descending order of occurrence, the most frequent sites are the mediastinal lymph nodes, the contralateral lung, the adrenal glands, the liver, the brain or CNS, and the bones.

Mr. Ferguson’s blood tests, including liver enzymes, are normal. CT shows a 4-cm mass in the anterior segment of the left upper lobe. The hilar or mediastinal nodes are not enlarged, there is no pleural effusion, and the left lower lobe and the right lung appear normal. Both the liver and the adrenal glands are free of metastases. Bronchoscopy shows a large, friable, irregular mass in the left upper lobe bronchus 2 cm from its origin on the left main stem bronchus. Biopsy of the lesion reveals a squamous cell carcinoma.

What is the clinical stage of Mr. Ferguson’s disease?

According to the TNM classification, the tumor is T2, N0, M0. It is stage IB.

How are malignant tumors of the lung classified histologically?

The histologic classification of lung tumors is presented in Table 26.3.

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