eMedicine Specialties > Radiology > Chest

Lung Cancer, Non-Small Cell

Author: Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital
Coauthor(s): Bruce Maycher, MD, Director of Pulmonary Radiology, St Boniface General Hospital; Associate Professor, Department of Radiology, University of Manitoba
Contributor Information and Disclosures

Updated: May 31, 2009

Introduction

Background

Worldwide, bronchogenic carcinoma is the most common cause of cancer death in both men and 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 surpassed the number of deaths resulting from breast cancer.

Images of non-small cell lung cancer are provided below:

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.^1,2,3,4

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, 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).⁵ 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 a 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.

A number of studies are currently under way to find improved treatments for non-small cell lung cancer.^6,7,8

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Lung Cancer, Bronchoscopy, Understanding Lung Cancer Medications, and Non-Small-Cell Lung Cancer.

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 higher 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 more than 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

United States

In 2005, 20,129 men and 69,078 women in the United States died of lung cancer, and 107,416 men and 89,271 women were diagnosed with lung cancer. Nationally from 1991 to 2005, the incidence of lung cancer decreased 1.8% a year in men but increased 0.5% a year in women.^9,10

Lung cancer accounts for about 15% of all new cancers. During 2009, there will be about 219,440 new cases of lung cancer (116,090 among men and 103,350 among women).¹¹

International

Mortality for women in the US is one of the highest in the world. Compared to men in some other countries, mortality in men in the US is lower than that in men in other countries.⁹

Mortality/Morbidity

In 2005, 20,129 men and 69,078 women in the United States died of lung cancer, and 107,416 men and 89,271 men were diagnosed with lung cancer. From 1991 to 2005, the incidence of lung cancer nationally decreased 1.8% a year in men but increased 0.5% a year in women.^9,10,11

Race

Among men in the United States, lung cancer is the second most common cancer among white, black, Asian/Pacific Islander, American Indian/Alaska Native, and Hispanic men.⁹

Among women in the United States, lung cancer is the second most common cancer among white, black, and American Indian/Alaska Native women, and it is the third most common cancer among Asian/Pacific Islander and Hispanic women.⁹

Sex

Nationally, trends have shown a marked increase in cancer incidence among women.¹² From 1991 to 2005, the incidence of lung cancer decreased 1.8% a year in men but increased 0.5% a year in women. In 2005, 20,129 men and 69,078 women in the United States died of lung cancer, and 107,416 men and 89,271 women were diagnosed with lung cancer.^9,10,11

Age

The percentage of men who will develop lung cancer on the basis of age over the next 10, 20, and 30 years, respectively, has been projected as follows: 30 years of age (0.03%; 0.21%; 1%); 40 years of age (0.19%; 0.99%; 3.15%); 50 years of age (0.83%; 3.07%; 6.22%); 60 years of age (2.43%; 5.84%; 7.72%); 70 years of age (4.08; 6.33; not determined).¹³

The percentage of women who will develop lung cancer on the basis of age over the next 10, 20, and 30 years, respectively, has been projected as follows: 30 years of age (0.03%; 0.21%; 0.83%); 40 years of age (0.18%; 0.81%; 2.47%); 50 years of age (0.64%; 2.33%; 4.70%); 60 years of age (1.78%; 4.26%; 5.69%); 70 years of age (2.80; 4.40; not determined).¹³

Anatomy

The relative frequency of lung cancer is 3:2 in the right lung, as compared with the left lung, and in the upper lobe, as 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 the image below.

Presentation

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 scarring, 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 mucus-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.

Table. Radiologic Findings by Tumor Histologic Type

Open table in new window

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 bloc 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. Studies have shown that low-dose helical CT scan of the thorax may detect lesions at an earlier stage and, therefore, may potentially improve resectability, survival, and mortality rates.

Radiologic manifestations of bronchogenic carcinoma include obstructive pneumonitis or atelectasis, lung nodule or mass, apical mass, cavitated mass, or nodule or mass associated with lymphadenopathy. 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 roles of MRI and positron emission tomography (PET) scan are not as well defined. 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.¹⁴ 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 a 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 scanning 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 scanning 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 scanning 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.

Differential Diagnoses

Other Problems to Be Considered

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