Background: Worldwide, bronchogenic carcinoma is the most common cause of cancer death in both men and in women. In the US, approximately one third of cancer deaths occur as a consequence of lung cancer, and approximately 170,000 new cases of lung cancer occur annually. The 5-year survival rate is 14%, and it has largely remained unchanged for decades. Lung cancer kills more people than colorectal, breast, and prostate cancers combined. Approximately 45% of lung cancer cases occur in women, and, in North America, the number of deaths resulting from lung cancer has recently surpassed the number of deaths resulting from breast cancer.

For the purpose of treatment and prognosis, lung cancer is divided into 2 categories: small-cell lung cancer and non–small cell lung cancer.

Approximately 20% of malignant tumors of the lung are due to small cell carcinoma. At presentation, small cell lung cancer is almost always metastatic to the mediastinal lymph nodes or distantly; therefore, the treatment is combination chemotherapy.

Non–small cell cancer requires meticulous staging, because the treatment and prognosis vary widely depending on the stage. In non–small cell lung cancer, surgical resection offers patients the best chance for survival. Surgery may be curative for stage I and stage II disease; however, these subgroups only a minority of patients (20-25%) have disease at these stages. Patients with stage IIIA disease may be candidates for surgical resection. In patients with stage IIIB disease, the tumors usually are considered unresectable. Patients with stage IV disease have distant metastases and are offered nonsurgical treatment, with the exception of rare cases of resectable solitary metastasis in a patient who also has a resectable primary lesion.

Most patients with stage I and stage II disease require preoperative or intraoperative mediastinal dissection for accurate staging prior to lung resection. The overall surgical mortality rate following lung resection is 3.7%. The mortality rate is higher (6-9%) in patients requiring pneumonectomy and in patients older than 70 years. The overall 5-five year survival rate may depend on whether the tumor is stage T1 or stage T2. The overall 5- and 10-year survival rates are 75% and 67%, respectively, in patients who undergo resection for stage I disease.

Patients with stage IA (T1 N0) disease have a significantly higher survival rate (82% at 5 y) compared with those with stage IB (T2 N0) disease (68% at 5 y and 60% at 10 y) (Martini, 1995). Patients with stage IIA (T1 N1) tumors have a survival rate of approximately 50% at 5 years, whereas patients with stage IIB (T2 N1 and T3 N0) tumors have 40% survival rate. Patients with stage IIIA (T1 or T2 N2) tumors have been reported to have a 5-year survival rate of 29%. The 5-year survival rate in patients with complete resection of stage IIIB tumors is 49% in T3 N0 disease, 27% in T3 N1 disease, and 15% in T3 N2 tumors. For patients with stage IV disease, the median survival is 8.5-21 weeks, and the 1-year survival rate is 10%.

The overall 5-year survival rate is grim because most patients with non–small cell lung cancer present with locally advanced or metastatic disease. Approximately 65-80% of patients present with unresectable disease. At present, the National Cancer Institute and other medical associations and regulatory bodies do not recommend early screening for lung cancer as part of a periodic health examination.

Pathophysiology: Bronchogenic carcinoma is the most common cancer and the most common cause of cancer-related death in both men and women. Risk factors for lung cancer include the following:

• Cigarette smoking: Smoking increases the risk of bronchogenic carcinoma by 4-120 times. In some patients, the risk may return to normal levels 15 years after they stop smoking, but most patients continue to have a lifelong risk than that of individuals who do not smoke.

   

• Exposure to asbestos: Asbestos exposure increases the risk 4- or 5-fold, or as much as 100-fold if the exposed individual is also a smoker.

   

• History of interstitial lung disease: As many as 6-12% of patients with idiopathic pulmonary fibrosis develop bronchogenic carcinoma (adenocarcinoma).

   

• Exposure to toxic agents: Agents such as arsenic, nickel (squamous cell carcinoma), chromium, and chloromethyl ether (small cell carcinoma) increase the risk.

   

• Exposure to uranium or radon: Exposure to breakdown products of uranium increases the risk of non–small cell compared to small-cell moreso than the risk of small-cell carcinoma of the lungs.

   

• Prior lung cancer: Approximately 10-32% of patients who survive resection for lung cancer may develop a second primary lung tumor.

   

• Lung disease: The presence of concomitant chronic obstructive pulmonary disease is a risk factor for lung cancer.

   

• HIV infection: In patients with HIV infection the risk of non–small cell lung carcinoma is increased by 6.5 times. Patients with HIV infection and a history of smoking may develop bronchogenic carcinoma at a relatively young age (<50 y).

Frequency:

• In the US: Lung cancer is the most common cancer in both men and women. In 1999, approximately 171,600 new cases of lung cancer were diagnosed (94,000 new cases in men and 77,600 new cases in women; Landis, 1999). The age-adjusted incidence rates for 1996 were 54.2 cases per 100,000 men and women.

  For the general population, the lifetime risk of developing cancer is 8.1% for men and 5.7% for women. The lifetime risk of lung cancer among male smokers is 14.6%, and among female smokers, it is 8.3%.

  Between 1992 and 1996, the incidence of lung cancer in men decreased by an average of 3.6% per year, and the mortality rates decreased by 1.7% per year. For the same period, the lung cancer incidence among women declined at an average rate of 0.3% per year, but the mortality rates increased at an average rate of 0.9% per year.

• Internationally: Worldwide, lung cancer is the most frequently occurring cancer and the leading cause of cancer mortality. Approximately 1.04 million new cases of lung cancer were diagnosed in 1990, accounting for 12.8% of the worldwide total cancer incidence. The number of new cases is increasing each year; a 16% increase occurred between 1985 and 1990.

Mortality/Morbidity: In 1999, approximately 158,900 lung cancer deaths occurred in the United States. Among men, lung cancer had been the leading cause of death since 1950. Among women, the lung cancer mortality rate exceeded the breast cancer mortality rate in 1987. The 5-year survival rate for all cases of lung cancer from 1989 to 1995 was 14%. Patients with stage I or stage II disease have a 5-year survival rate of approximately 50%; however, only 15% of newly diagnosed cases involve early-stage disease.

Race: In the United States, the highest incidence rates occur among blacks (117 cases per 100,000), and the lowest rate occurs among American Indians (14 cases per 100,000). Hispanics, the Japanese, the Chinese, Philippinos, and Koreans have incidence rates of 42-53 cases per 100,000 population. The Vietnamese, Alaskan natives, Hawaiians, and whites have incidence rates of 71-89 cases per 100,000 population.

Sex: Internationally, trends have shown a marked increase in cancer incidence among women. In 1985-1990, the incidence increased by 4% in men compared with 21% in women.

• Age-adjusted incidence rates for 1996 showed that 68.4 new cases occurred in 100,000 US men, compared with 43.7 cases per 100,000 women. In 1973-1996, the rate in men decreased by 2.5%, but the rate in women increased by 123%.

• Worldwide, lung cancer is more common in men (37.5 new cases per 100,000) than in women (10.8 per 100,000).

Age: Lung cancer is uncommon in those younger than 40 years. The incidence increases with advancing age and peaks between in persons aged 70-80 years. New cases occur in 1.4% of men and 1.1% of women aged 40-44 years, and the incidence is 21.5% for men and 19.8% for women aged 70-74 years.

Anatomy: The relative frequency of lung cancer is 3:2 in the right compared with the left lung and in the upper lobe compared with the lower lobe. Squamous cell carcinomas occur predominantly in a central location, whereas adenocarcinoma presents in approximately 50% of patients as a peripheral lesion. Tumors arising endobronchially are located in segmental or lobar bronchi. Fewer than 4% of cancers arise in the apex of the upper lobes, and fewer than 1% arise from the trachea.

TNM classification

• The primary tumor (T) is classified according to its size and local invasion.

   

  • T1 - A tumor less than or equal to 3 cm in its greatest dimension, surrounded by lung or visceral pleura, without involvement of the main bronchus

     

  • T2 - A tumor with any of the following features:

     

    • Larger than 3 cm in largest dimension

       

    • Involvement of the mainstem bronchus more than 2 cm from the carina

       

    • Invades the visceral pleura

       

    • Associated with atelectasis or postobstructive pneumonitis extending to the hilar region but not involving the entire lung

     

  • T3 - A tumor of any size with any of the following features:

     

    • Tumor (including superior sulcus tumors) directly invading the chest wall, diaphragm, mediastinal pleura, or parietal pericardium

       

    • Tumor in the main bronchus less than 2 cm distal to the carina (but without involvement of the carina)

       

    • Tumor associated with atelectasis or obstructive pneumonitis of the entire lung

     

  • T4 - A tumor of any size with any of the following features:

     

    • Tumor invading the mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or carina

       

    • Any tumor with a malignant pleural or pericardial effusion

       

    • Any tumor with satellite tumor nodules within the ipsilateral primary tumor lobe of the lung

     

  • Additional T descriptions that rarely are used include the following:

     

    • TX - Inability to assess a primary tumor (presence of malignant cells in sputum or bronchial washings but not visualized by imaging studies or bronchoscopy)

       

    • T0 - No evidence of a primary tumor

       

    • TIS - Carcinoma in situ

   

• The regional lymph node status (N) is also used to classify the tumor.

   

  • N0 - No regional lymph node metastasis

     

  • N1 - Ipsilateral peribronchial or hilar nodal metastases or intrapulmonary nodes involved by direct extension of the primary tumor

     

  • N2 - Ipsilateral mediastinal and subcarinal, midline prevascular, and retrotracheal nodes

     

  • N3 - Contralateral mediastinal or contralateral hilar nodal metastases, ipsilateral or contralateral scalene or supraclavicular nodes

     

  • NX - Additional N description rarely used, means regional lymph nodes cannot be assessed

   

• Distant metastasis (M) descriptions classify the tumor according to location of metastases.

   

  • M0 - No distant metastasis

     

  • M1

     

    • Distant metastasis or separate tumor nodules in other lobes of same lung

       

    • Tumor nodules in the contralateral lung (considered M1 if of the same histologic cell type as the primary lesion; tumor of different cell type in contralateral lung is considered a synchronous primary lesion)

     

  • MX - Additional M description in which the presence of distant metastasis cannot be assessed

Staging classification

Clinical staging is shown in Image 10. Preoperative staging is denoted by the prefix c before the TNM designation, whereas prefix p indicates surgical-pathologic staging.

Clinical Details:

Squamous cell carcinoma

Squamous cell carcinoma accounts for 30-40% of cases of bronchogenic carcinoma, and it has a strong association with smoking. The lesion is usually located centrally, and among all bronchogenic carcinomas, it is most likely to cavitate. Squamous cell carcinomas grow intraluminally and are least likely to metastasize distantly (<20% of cases at presentation). The mode of spread is direct extension to the local lymph nodes. Squamous cell carcinomas are commonly associated with clubbing and hypertrophic osteoarthropathy. Hypercalcemia is also commonly observed secondary to a parathormone-like peptide created by the tumor. Tumors of squamous histology can sometimes elicit a sarcoid reaction in nodes, resulting in nodal enlargement without metastatic spread.

Adenocarcinoma

Adenocarcinoma occurs with a frequency of 30-40%, which has surpassed the incidence of squamous cell carcinoma. The lesion is located peripherally in approximately one half of cases, and it is associated with smoking. Adenocarcinoma may arise from a previous scar, it rarely cavitates, and an eccentric pattern of calcification may be evident. An early propensity is noted of metastases to the lymph nodes, pleura, adrenal glands, central nervous system (CNS), and bone.

Bronchoalveolar cell carcinoma

Bronchoalveolar cell carcinoma is a subtype of adenocarcinoma that accounts for as many as 5% of bronchogenic carcinomas. Although an association with smoking has not been established, a substantial percentage of patients have a significant smoking history. The incidence of bronchoalveolar cell carcinoma is increased in patients who have underlying interstitial lung disease, parenchymal scaring, and exogenous lipoid pneumonia.

Bronchoalveolar cell carcinoma is classified as mucinous and nonmucinous on the basis of histopathologic features. The mucinous variety is most common (80%) and arises from columnar mucous containing cells. The mucinous variety is likely to be multicentric, it occasionally appears with bronchorrhea, and it has a worse prognosis. The nonmucinous form arises from type II pneumocytes or Clara cells, it is more likely to be localized, and it has a better prognosis. Bronchoalveolar carcinoma may spread to other sites or the other lung by means of transbronchial spread called aerogenous spread. These tumors can also demonstrate growth along the pulmonary interstitium without destroying lung architecture. This is called lepidic growth. In comparison, both types of growth are associated with a worse prognosis.

Bronchoalveolar carcinoma may appear in a variety of ways, including a solitary pulmonary nodule (45%), multiple nodules (25%), and consolidation (30%). Presentation as a solitary pulmonary nodule is associated with the best prognosis. Nodules can be sharp or poorly defined, and they may be cavitated. In 30% of patients, an associated pleural effusion is noted, as well as hilar or mediastinal lymphadenopathy.

Large cell carcinoma

Large cell carcinomas account for only 5-10% of bronchogenic carcinomas and are strongly associated with cigarette smoking. The lesion occurs peripherally and grows rapidly, with early metastases and a poor outcome. A subtype of large cell carcinoma is giant cell carcinoma. This is highly malignant and associated with a poor prognosis.

Clinical manifestations

The symptoms of non–small cell carcinoma can be secondary to the following:

• Local bronchopulmonary disease – Cough and hemoptysis

   

• Spread of tumor to adjacent structures – Chest pain

   

• Distant metastases - Bone pain, jaundice, seizures, or neurologic symptoms

   

• Constitutional effects – Fatigue, anorexia, and weight loss

   

• Paraneoplastic syndromes

Paraneoplastic syndromes associated with bronchogenic carcinoma

• Hypercalcemia

   

• Ectopic adrenocorticotropic hormone production

   

• Syndrome of inappropriate secretion of antidiuretic hormone

   

• Eaton-Lambert syndrome (peripheral neuropathy with myasthenia-like symptoms)

   

• Acanthosis nigricans

   

• Hypertrophic osteoarthropathy

Superior sulcus or Pancoast tumor may involve the subclavian vein, the phrenic or vagus nerve, the subclavian artery, the recurrent laryngeal nerve, and/or the sympathetic chain. The symptoms may depend on the structure involved and include arm pain, weakness of the shoulder and arm, arm swelling, and Horner syndrome. Constitutional symptoms can include malaise, weakness, fever, and weight loss.

International staging system for lung cancer

The international staging system for lung cancer provides a common framework for treatment options and prognostication in patients with bronchogenic carcinoma. The staging system is derived from the TNM classification scheme in which T indicates the primary tumor, N indicates the regional lymph nodes, and M indicates the distant metastasis; the 4 stage groups I-IV.

Radiologic Findings by Tumor Histologic Type

 

Radiologic Symptom	Squamous Epithelium (%)	Small Cell Carcinoma (%)	Adenocarcinoma (%)	Large Cell Carcinoma (%)
Hilar tumor Peripheral tumor Peripheral tumor >4 cm Apical tumor Multiple tumors Atelectasis Pneumonia Liquefaction Mediastinal lymph nodes	40 27 18 3 0 36 15 7 1	78 29 26 2 1 17 22 0 13	18 71 8 1 2,4 10 15 2 2	32 59 41 4 2 13 23 4 10

Patients with limited chest wall invasion and no evidence of distant metastases are considered potentially curable (stage IIIA). MRI may be slightly more accurate than CT in determining the extent of chest wall invasion. The treatment of choice is radiation therapy followed by surgery or radiation therapy alone for patients with unresectable lesions. The following criteria usually indicate an unresectable lesion:

• Tumor invasion of the great vessels at the thoracic inlet (most commonly the subclavian artery because of its location)

   

• Phrenic or recurrent laryngeal nerve paralysis

   

• Invasion of the vertebral bodies, trachea, or esophagus

Preoperative radiation therapy is used to reduce tumor size 3-6 weeks prior to surgery. Surgery involves en block resection of the chest wall.

Preferred Examination: In a malignancy such as bronchogenic carcinoma, early detection can lead to surgical resection of the lesion and cure. Unfortunately, to date, the use of radiologic modalities has not proven successful in reducing mortality rates. For screening of non–small cell carcinoma of the lung, chest radiography may result in improved survival, although a mortality benefit cannot be demonstrated.

On the basis of results from the Mayo Lung Project and a Czechoslovakian study, the American Cancer Society does not recommend routine mass screening for the detection of lung cancer. However, early stage detection, resectability, and survival improve with chest radiographic screening in high-risk populations. More recently, preliminary studies have shown that low-dose helical CT scan of the thorax may detect lesions at an earlier stage and, therefore, potentially may improve resectability, survival, and mortality rates. A large randomized study is currently underway at the Mayo Clinic.

Radiologic manifestations of bronchogenic carcinoma include obstructive pneumonitis or atelectasis, lung nodule or mass, apical mass, cavitated mass, nodule or mass associated with lymphadenopathy, unilateral hilar, or mediastinal lymphadenopathy alone. Chest radiography is a readily available, inexpensive, and useful imaging modality in the workup of patients with non–small cell carcinoma. Therefore, chest radiography is used most often as an initial investigation.

Invariably, other investigations such as CT scanning are required for better delineation of the abnormality detected on plain radiographs. CT can also be helpful in excluding a benign lesion and in preoperative staging. CT of the chest is an important informative tool that helps in detailed imaging of the primary tumor and its anatomic relationship to other structures, and it provides information with respect to the size of mediastinal lymph nodes and the status of the pleural space. However, CT criteria for adenopathy are based on size alone and do not always accurately reflect the presence or absence of tumor metastases. CT can best be thought of as a technique that provides a roadmap for more accurate surgical staging.

The role of MRI and positron emission tomography (PET) scan are not as well defined, MRI is not used routinely. MRI may be superior to CT in the assessment of the chest wall invasion by apical tumors. The use of PET scanning is expanding rapidly.

PET scanning may be useful in the assessment of solitary pulmonary lung nodules. Several studies indicate that PET scanning appears to be valuable in deciding whether a nodule is benign or malignant as well as in staging locoregional and distant metastatic disease. In some centers, PET/CT scanners are available to allow more precise anatomic localization.

Limitations of Techniques: Chest radiography remains the primary means of radiographic assessment of lung carcinoma. However, 12-30% of lung cancers are missed on chest radiographs (Miller, 1990). A nodule smaller than 2-3 mm may not be detected by using chest radiographs, and overlapping soft tissue opacities may hide small endobronchial lesions. Chest radiographs depict indirect signs of endobronchial lesions such as obstructive pneumonia or atelectasis. These signs may well be secondary to benign tumors or mucus plugging or foreign body. In a solitary lung nodule, probability of malignancy is approximately 40% overall; therefore, a nodule identified on a chest x-ray requires further diagnostic workup to exclude lung cancer.

The advantage of CT scan in non–small cell lung cancer is that it can be used to distinguish tumor from surrounding atelectatic lung. CT scans may be helpful in demonstrating superior vena cava compression, pericardial effusion, and lymphangitic dissemination in several other conditions. A major limitation of CT scan is the inability to distinguish invasion from simple approximation to adjacent structures.

In staging of non–small cell carcinoma, CT has several limitations. Normal-sized mediastinal lymph nodes may contain microscopic metastatic deposits that are subsequently identified on thoracotomy in as many as 20% of patients. Similarly, enlarged inflammatory nodes may be falsely characterized as metastases in as many as 20% of patients.

The sensitivity and specificity of CT in detecting metastatic mediastinal lymph node involvement is in the range of 70-80%. CT scan may have further limitations in distinguishing stage IIIA disease from stage IIIB disease. In a peripheral TI lesion, CT probably does not contribute, because chest radiography appears to be sufficient. CT is also limited in evaluating the extent of endobronchial abnormalities. CT may also be limited in evaluating and staging apical lung tumors.

DIFFERENTIALS

Atelectasis, Lobar
Bronchogenic Cyst
Coccidioidomycosis, Thoracic
Effusion, Pleural
Hamartoma, Lung
Histoplasmosis, Thoracic
Lung Cancer, Small Cell
Lung Cancer, Staging
Lung, Arteriovenous Malformation
Lung, Carcinoid
Lung, Metastases
Lung, Nontuberculous Mycobacterial Infections
Lymphangitic Carcinomatosis

Other Problems to be Considered:

Lung abscess

X-RAY

Findings: On chest radiography, the findings of non–small cell lung carcinomas are varied and considered in the differential diagnosis of many disorders. The most common findings are described below.

• Bronchial stenosis

   

  • Bronchial stenosis and poststenotic changes are commonly because most non–small cell carcinomas demonstrate intraluminal growth. Narrowing of the main bronchi or a complete cutoff can be identified on chest radiographs.

     

  • Endobronchial lesion commonly leads to partial or complete atelectasis and is the most common sign of bronchogenic carcinoma. Complete endobronchial obstruction can sometimes produce distal mucoid impaction, which may be visible on plain radiographs as a tubular or branching opacity.

     

    • Atelectasis of a segment, a lobe, or an entire lung may occur.

       

    • Radiographic signs include patchy irregular or homogeneous opacities in a lobar or segmental distribution.

       

    • A loss of lung volume may be seen, as well as displacement of interlobar fissures, mediastinum, diaphragm, and the ribs.

       

    • Postobstructive pneumonia may be identified in a segmental or lobar distribution. In patients with recurrent pneumonia, bronchogenic carcinoma is suggested unless proven otherwise.

   

• Regional hyperlucency

   

  • An endobronchial lesion reduces the ventilation despite normal or increased air volume.

     

  • As a result, hypoxic vasoconstriction reduces perfusion, and attenuation is seen as hyperlucency on chest radiography. In partially atelectatic areas of the lung, hyperlucency rather than opacity may be evident.

   

• Hilar mass

   

  • Central bronchogenic carcinomas manifest added opacity in the hilar region.

     

  • In the early stage, the tumor may fill the lateral concavity of the hilar shadow, and in the advanced stage, all hilar structures are obliterated.

     

  • Infiltration of lymphatics with bronchogenic carcinomas may be demonstrated as linear opacities radiating from the hilar mass into the lung periphery.

   

• Solitary pulmonary nodule

   

  • A solitary pulmonary nodule may be relatively well marginated and appears as a rounded lung opacity.

     

  • Reportedly, a solitary pulmonary nodule is benign in as many as 60% of patients in some series. All patterns of calcification except eccentric or scattered punctate (stippled) calcification are associated with a benign lesion.

     

  • Procuring and identifying the lesion on previous chest radiographs is extremely important. This may help establish the doubling time interval for the nodule. A doubling time of 30-365 days commonly is associated with a malignancy.

     

  • Other possible signs of malignancy include the following:

     

    • Diameter more than 3 cm

       

    • Ill-defined or spiculated margin

       

    • Rigler notch sign (a notch on the nodule corresponding to the vascular supply)

       

    • Radial striated markings at the nodular margin (termed corona radiata)

       

    • Thick-walled cavity

       

    • Eccentric calcification

   

• Nonresolving pneumonia

   

  • An ill-defined homogeneous or patchy consolidation in a segmental or nonsegmental distribution may be an indication of bronchogenic carcinoma. Patients with these findings often are treated initially for pneumonia; the lack of response to antibiotic therapy suggests the diagnosis of a malignancy.

     

  • The opacity may contain air bronchograms and air alveolograms. This presentation is often seen with adenocarcinoma and bronchoalveolar carcinoma.

   

• Indirect signs of involvement of contiguous structures also may be found. Bronchogenic carcinoma may involve the surrounding thoracic structures, which often indicates that the tumor is not resectable. Findings include the following:

   

  • Osteolytic lesions and pathologic fractures of rib and vertebra

     

  • Phrenic nerve involvement causing diaphragmatic paralysis and exhibiting ipsilateral elevation of involved diaphragm

     

  • Pleural effusion secondary to visceral pleural involvement or lymphatic obstruction (confirm the presence of a malignant effusion using thoracentesis)

   

• Mediastinal lymph node enlargement: Metastases to paratracheal, tracheobronchial, peribronchial, aortopulmonary, and subcarinal lymph nodes may be identified on chest radiographs. The radiographic signs include a widened mediastinum, an increase in the right paratracheal stripe, a convex margin of the mediastinum, an absence of concavity in the aortopulmonary window, and splaying of carina.

Degree of Confidence: Lung cancer screening with chest radiographs has improved the 5-year survival rates, but a mortality benefit has not been demonstrated.