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CANCER PULMONAR (LUNG CANCER)

INTRODUCTION

Lung cancer is the most common cancer worldwide, with an estimated 1,600,000 new cases and 1,380,000 deaths in 2008. In the United States, there will be an estimated 226,000 new cases of lung cancer and 160,000 deaths in 2012.

Both the absolute and relative frequency of lung cancer has risen dramatically. As an example, the age-adjusted death rate from lung cancer is similar to that of pancreatic cancer prior to 1930 for men and prior to 1960 for women. Around 1953, lung cancer became the most common cause of cancer deaths in men, and in 1985, it became the leading cause of cancer deaths in women. Lung cancer deaths have begun to decline in men, reflecting a decrease in smoking . The rise in the death rate in women appears to have reached a plateau, although almost one-half of all lung cancer deaths now occur in women.

The term lung cancer, or bronchogenic carcinoma, refers to malignancies that originate in the airways or pulmonary parenchyma. Approximately 95 percent of all lung cancers are classified as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). This distinction is essential for staging, treatment, and prognosis. Other cell types comprise about 5 percent of malignancies arising in the lung.

This discussion will present an overview of the risk factors, pathology, and clinical manifestations of NSCLC and SCLC. An overview of the initial evaluation, treatment, and prognosis of lung cancer is presented separately.

RISK FACTORS

A number of environmental and life-style factors have been associated with the subsequent development of lung cancer, of which cigarette smoking is the most important. The risk factors associated with the development of lung cancer are discussed in detail separately.

Smoking The primary risk factor for the development of lung cancer is cigarette smoking, which is estimated to account for approximately 90 percent of all lung cancers. The risk of developing lung cancer for a current smoker of one pack per day for 40 years is approximately 20 times that of someone who has never smoked. Factors that increase the risk of developing lung cancer in smokers include the extent of smoking and exposure to other carcinogenic factors, such as asbestos.

Thus, the most important aspects of lung cancer prevention are preventing people from starting to smoke and inducing those who already smoke to stop. In individuals who do quit smoking, the risk of developing lung cancer gradually falls for about 15 years before it levels off and remains about twice that of someone who never smoked.

Radiation therapy — Radiation therapy (RT) can increase the risk of a second primary lung cancer in patients who have been treated for other malignancies.

In women who receive RT following a mastectomy for breast cancer, there appears to be an increased risk of lung cancer among smokers. In a retrospective tumor registry study of 113 breast cancer patients who had a second primary lung cancer and 364 controls, there was an increased risk of a second primary lung cancer among women who had smoked and received postoperative RT. The risk was more pronounced for cancers in the ipsilateral lung. Similarly, RT for Hodgkin lymphoma has been associated with an increased risk of secondary lung cancer.

Improved RT techniques limit the dose of radiation to nonmalignant tissue, and contemporary equipment and dose planning is thought to significantly reduce the risk for secondary lung cancer.

Other factors — A number of other factors may affect the risk of developing lung cancer:

Environmental toxins — Environmental factors have been associated with an increased risk for developing lung cancer. These include exposure to second-hand smoke, asbestos, radon, metals (arsenic, chromium, and nickel), ionizing radiation, and polycyclic aromatic hydrocarbons.

Pulmonary fibrosis — Several studies have shown that the risk for lung cancer is increased about sevenfold patients with pulmonary fibrosis . This increased risk appears to be independent of smoking.

HIV infection — The incidence of lung cancer among individuals infected with HIV appears to be increased compared to that seen in uninfected controls.

Genetic factors — Genetic factors can affect both the risk for and prognosis from lung cancer. Although the genetic basis of lung cancer is still being elucidated, there is a clearly established familial risk.

Dietary factors — Epidemiologic evidence has suggested that various dietary factors (antioxidants, cruciferous vegetables, phytoestrogens ) may reduce the risk of lung cancer, but the role of these factors is not well established. Attempts to confirm these epidemiologic findings and to decrease the incidence of lung cancer in high-risk patients have not been successful. As example, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study actually showed an increase in lung cancer among smokers with dietary supplementation of beta-carotene.

Adenocarcinoma (including bronchioloalveolar carcinoma) — 38 percent (figure 1 and figure 2)

Squamous cell carcinoma — 20 percent (figure 3A-E)

Large cell carcinoma — 5 percent (figure 4A-B)

Small cell carcinoma 13 percent (figure 5A-B)

Other non-small cell carcinomas, which cannot be further classified (18 percent)

Other (6 percent)

Pulmonary function testing may be useful in a patient with dyspnea due to lung cancer, as it may show flattening of the expiratory and/or inspiratory flow-volume loop from presence of tumor in the trachea itself, from extrinsic compression, or from vocal cord paralysis.
Unilateral paralysis of the diaphragm may be due to damage of the phrenic nerve. Patients may be asymptomatic or report shortness of breath. In one series, lung cancer was the most common neoplasm affecting the phrenic nerve, although malignancy accounted for only 4 percent of patients presenting with diaphragmatic paralysis.
Pulmonary function testing may be useful in a patient with dyspnea due to lung cancer, as it may show flattening of the expiratory and/or inspiratory flow-volume loop from presence of tumor in the trachea itself, from extrinsic compression, or from vocal cord paralysis.
Unilateral paralysis of the diaphragm may be due to damage of the phrenic nerve. Patients may be asymptomatic or report shortness of breath. In one series, lung cancer was the most common neoplasm affecting the phrenic nerve, although malignancy accounted for only 4 percent of patients presenting with diaphragmatic paralysis.
Unilateral paralysis of the diaphragm may be due to damage of the phrenic nerve. Patients may be asymptomatic or report shortness of breath. In one series, lung cancer was the most common neoplasm affecting the phrenic nerve, although malignancy accounted for only 4 percent of patients presenting with diaphragmatic paralysis.
These diverse neurologic manifestations include, but are not limited to, Lambert-Eaton myasthenic syndrome (LEMS), cerebellar ataxia, sensory neuropathy, limbic encephalitis, encephalomyelitis, autonomic neuropathy, retinopathy, and opsomyoclonus.

Anemia — Anemia is frequent in patients with lung cancer and can contribute to fatigue and dyspnea. As an example, in one series 40 percent of untreated patients had a hemoglobin ≤12 g/dL, while the incidence of anemia was 80 percent in those on chemotherapy. Anemia may be due to any of a number of causes, including treatment.

Leukocytosis — In one series, tumor-associated leukocytosis was found in 15 percent of patients with lung cancer. Nearly all had NSCLC, and the leukocytosis was thought to be due to overproduction of granulocyte-colony stimulating factor. Leukocytosis in association with lung cancer is associated with a poor prognosis and has also been associated with hypercalcemia.

Thrombocytosis — Thrombocytosis is common and maybe present in as many as 14 percent of patients with lung cancer at presentation. Thrombocytosis at presentation has been identified as an independent predictor of shortened survival.

Eosinophilia — Eosinophilia in tissue or blood is rare, but has been reported in patients with large cell carcinoma.

Hypercoagulable disorders — A variety of hypercoagulable disorders have been associated with lung cancer and other malignancies. These hypercoagulable disorders include:

Trousseau's syndrome (migratory superficial thrombophlebitis)

Deep venous thrombosis and thromboembolism

Disseminated intravascular coagulopathy

Thrombotic microangiopathy

Nonthrombotic microangiopathy

A radiograph of the long bones (ie, tibia and fibula) shows characteristic periosteal new bone formation in patients with HPO. An isotope bone scan or PET typically demonstrates diffuse uptake by the long bones. The symptoms of HPO may resolve after tumor resection. For patients who are not operable, the usual treatment is with nonsteroidal antiinflammatory agents or a bisphosphonate.
A radiograph of the long bones (ie, tibia and fibula) shows characteristic periosteal new bone formation in patients with HPO. An isotope bone scan or PET typically demonstrates diffuse uptake by the long bones. The symptoms of HPO may resolve after tumor resection. For patients who are not operable, the usual treatment is with nonsteroidal antiinflammatory agents or a bisphosphonate.
Cushing's syndrome is relatively common in patients with SCLC and with carcinoid tumors of the lung, as well as extrathoracic malignancies. Patients with Cushing's syndrome and SCLC appear to have a worse prognosis than patients with SCLC without Cushing's syndrome .
Cushing's syndrome is relatively common in patients with SCLC and with carcinoid tumors of the lung, as well as extrathoracic malignancies. Patients with Cushing's syndrome and SCLC appear to have a worse prognosis than patients with SCLC without Cushing's syndrome .

SCREENING

The diagnosis of lung cancer is primarily based upon evaluation of individuals with symptoms. Screening for lung cancer has not been widely used, since chest radiography and sputum cytology have not been shown to reduce mortality from lung cancer.

Prospective, single-arm observational studies have shown that a large percentage of lung cancers detected by CT screening are early stage tumors, which have a favorable prognosis. These findings led to the randomized National Lung Screening Trial that compared CT screening with chest x-ray. This trial demonstrated a 20 percent decrease in lung cancer mortality in heavy smokers who were screened annually for three years.

PATHOLOGY

The World Health Organization classification for primary lung cancer recognizes four major histologic cell types.

Approximate frequencies of these are as follows:

The relative incidence of adenocarcinoma has risen dramatically, and there has been a corresponding decrease in the incidence of other types of NSCLC and SCLC. The increased incidence of adenocarcinoma is thought to be due to the introduction of low-tar filter cigarettes in the 1960s, although this relationship is unproven.

CLINICAL MANIFESTATIONS

The majority of patients with lung cancer have advanced disease at clinical presentation (table 1). This may reflect the aggressive biology of the disease, the frequent absence of symptoms until locally advanced or metastatic disease is present, and the lack of an effective screening test. (See "Screening for lung cancer".)

Symptoms may result from local effects of the tumor, from regional or distant spread, or from distant effects not related to metastases (paraneoplastic syndromes). Approximately three-fourths of patients have one or more symptoms at the time of diagnosis.

Intrathoracic effects of the cancer — There are a wide range of symptoms due to the intrathoracic effects of the cancer, the most common of which are cough, hemoptysis, chest pain, and dyspnea.

Cough — Cough is present in 50 to 75 percent of lung cancer patients at presentation and occurs most frequently in patients with squamous cell and small cell carcinomas, because of their tendency to involve central airways. The new onset of cough in a smoker or former smoker should raise suspicion that lung cancer is present. Bronchorrhea or cough productive of large volumes of thin, mucoid secretions may be a feature of bronchoalveolar cell carcinoma and usually indicates advanced disease. Both NSCLC and SCLC often cause a post-obstructive pneumonia. However, bronchiectasis is uncommon because lung cancer usually progresses too rapidly for bronchiectasis to develop. In contrast, slow-growing neoplasms such as carcinoid tumor or hamartoma are more likely to present with bronchiectasis.

Hemoptysis — Hemoptysis is reported by 25 to 50 percent of patients who are diagnosed with lung cancer, although bronchitis is the most common cause of this symptom. Any amount of hemoptysis can be alarming to the patient, and large volumes of hemoptysis may cause asphyxia. In a patient with hemoptysis, the likelihood of lung cancer varies from 3 to 34 percent in different series depending upon the patient's age and smoking history. In smokers with hemoptysis and a nonsuspicious or normal chest radiograph, bronchoscopy will diagnose lung cancer in about 5 percent of cases.

Chest pain — Chest pain is present in approximately 20 percent of patients presenting with lung cancer. It can be quite variable in character and is more common in younger compared to older patients. Pain is typically present on the same side of the chest as the primary tumor. Dull, aching, persistent pain may occur from mediastinal, pleural, or chest wall extension, but the presence of pain does not necessarily preclude resectability. Although pleuritic pain may be the result of direct pleural involvement, obstructive pneumonitis or a pulmonary embolus related to a hypercoagulable state may also cause chest pain.

Dyspnea — Shortness of breath is a common symptom in patients with lung cancer at the time of diagnosis, occurring in approximately 25 percent of cases. Dyspnea may be due to extrinsic or intraluminal airway obstruction, obstructive pneumonitis or atelectasis, lymphangitic tumor spread, tumor emboli, pneumothorax, pleural effusion, or pericardial effusion with tamponade. Partial obstruction of a bronchus may cause a localized wheeze, heard by the patient or by the clinician on auscultation, while stridor can result from obstruction of larger airways.

Hoarseness — The differential diagnosis of persistent hoarseness in a smoker includes both laryngeal cancer and lung cancer. In patients with lung cancer, this is due to malignancy involving the recurrent laryngeal nerve along its course under the arch of the aorta and back to the larynx.

Pleural involvement — Extension of tumor into the visceral pleura is stage T2 and into the parietal pleura is T3. The presence of carcinoma cells in the pleural fluid classifies the lung cancer as M1a (stage IV) in the seventh edition TNM staging system. Pleural involvement can manifest as pleural thickening without pleural effusion.

Patients with malignant effusions are considered incurable and managed palliatively. Although malignant pleural effusions can cause dyspnea and cough, approximately one-fourth of patients who have lung cancer and pleural metastases are asymptomatic. Although a malignant pleural effusion precludes curative resection, not all pleural effusions in patients with lung cancer are malignant. A benign pleural effusion may occur in a patient with a resectable lung cancer due to lymphatic obstruction, post-obstructive pneumonitis, or atelectasis. In a patient with a pleural effusion, the presence of tumor needs to be confirmed or excluded so that a chance for curative resection is not missed. Series report that 5 to 14 percent of patients with NSCLC and an ipsilateral pleural effusion have resectable disease. Surgical thoracoscopy or medical pleuroscopy should follow two or three negative cytologies to further evaluate the pleural space prior to surgical resection of a primary lesion.

Malignant effusions are typically exudates and may be serous, serosanguineous, or grossly bloody. The yield of pleural fluid cytology after a single thoracentesis in patients with documented pleural involvement is about 60 percent, and the yield rises to 85 percent with three thoracenteses. A prospective series evaluated cytologic yield from pleural fluid aliquots of 10 mL, 60 mL, and ≥150 mL. The sensitivity for diagnosing malignancy in the pleural fluid was lower for volumes of 10 mL compared to the higher volumes. Closed pleural biopsy adds little to the yield of cytologic examination. In a patient with a suspected malignancy, repeat pleural fluid cytology with or without pleural biopsy is appropriate if the initial study is negative.

During the course of their disease, approximately 10 to 15 percent of patients who have lung cancer will have malignant pleural effusions. The management of patients with malignant pleural effusions is discussed separately.

Superior vena cava syndrome — Obstruction of the superior vena cava (SVC) causes symptoms that commonly include a sensation of fullness in the head and dyspnea. Cough, pain, and dysphagia are less frequent. Physical findings include dilated neck veins, a prominent venous pattern on the chest, facial edema, and a plethoric appearance. The chest radiograph typically shows widening of the mediastinum or a right hilar mass. CT can often identify the cause, level of obstruction, and extent of collateral venous drainage.

The SVC syndrome is more common in patients with SCLC than NSCLC. For most patients who have SVC syndrome secondary to lung cancer, the symptoms resolve after treatment of the mediastinal tumor. The pathophysiology and treatment options for the management of patients with SVC syndrome are discussed separately.

Pancoast's syndrome — Lung cancers arising in the superior sulcus cause a characteristic Pancoast's syndrome manifested by pain (usually in the shoulder, and less commonly in the forearm, scapula, and fingers), Horner's syndrome, bony destruction, and atrophy of hand muscles.

Pancoast's syndrome is most commonly caused by NSCLC (typically squamous cell) and only rarely by SCLC. The presentation, diagnosis, and treatment of patients with Pancoast's syndrome due to superior sulcus tumors is discussed in detail elsewhere.

Extrathoracic metastases — Lung cancer can spread to any part of the body tissue. Metastatic spread may result in the presenting symptoms or may occur later in the course of disease.

The staging at presentation of patients with known or suspected lung cancer is reviewed elsewhere.

The most frequent sites of distant metastasis are the liver, adrenal glands, bones, and brain.

Liver — Symptomatic hepatic metastases are uncommon early in the course of disease. Asymptomatic liver metastases may be detected at presentation by liver enzyme abnormalities, CT , or PET. Among patients with otherwise resectable NSCLC in the chest, CT evidence of liver metastasis has been identified in approximately 3 percent of cases. PET or integrated PET-CT identifies unsuspected metastases in the liver or adrenal glands in about 4 percent of patients. The incidence of liver metastases is much higher later in the course of the disease. Autopsy studies have shown that hepatic metastases are present in more than 50 percent of patients with either NSCLC or SCLC.

Bone — Metastasis from lung cancer to bone is frequently symptomatic. Pain in the back, chest, or extremity, and elevated levels of serum alkaline phosphatase are usually present in patients who have bone metastasis. The serum calcium may be elevated due to extensive bone disease. Approximately 20 percent of patients with NSCLC have bone metastases on presentation. An osteolytic radiographic appearance is more frequent than an osteoblastic one, and the most common sites of involvement are the vertebral bodies. Bone metastases are even more frequent in SCLC and can be found in 30 to 40 percent of patients. PET and PET-CT have improved the ability to identify metastases to many organs, including bone, with greater sensitivity than CT or bone scan.

Adrenal — The adrenal glands are a frequent site of metastasis but such metastases are only rarely symptomatic. Concern about adrenal metastasis usually occurs when a unilateral mass is found by staging CT in a patient with a known or suspected lung cancer. Only a fraction of adrenal masses detected on staging scans represent metastasis. This was illustrated by a series of 330 patients with operable NSCLC, in which 32 (10 percent) had an isolated adrenal mass. Only 8 of these 32 (25 percent) were malignant while the remainder had benign lesions (adenomas, nodular hyperplasia, hemorrhagic cysts). Conversely, a negative imaging study does not exclude adrenal metastases. A study of patients with SCLC found that 17 percent of adrenal biopsies showed metastatic involvement despite having a normal CT scan.

The lack of specificity of an initial CT identifying an adrenal mass creates a special problem in patients with an otherwise resectable lung cancer. In this situation, PET may be particularly useful in distinguishing a benign from malignant adrenal mass. Other procedures that may be useful in excluding a metastasis include an MRI consistent with a benign adenoma or a negative needle biopsy.

Involvement of the adrenal glands is more frequent in patients with widely disseminated disease. In autopsy series, adrenal gland metastases have been identified in about 40 percent of patients with lung cancer.

Brain — Neurologic manifestations of lung cancer include metastases and paraneoplastic syndromes. (See 'Paraneoplastic phenomena' below.)

Symptoms from central nervous system metastasis are similar to those with other tumors and include headache, vomiting, visual field loss, hemiparesis, cranial nerve deficit, and seizures.

In patients with NSCLC, the frequency of brain metastasis is greatest with adenocarcinoma and least with squamous cell carcinoma. The risk for brain metastasis increases with larger primary tumor size and the presence of regional node involvement . For carefully selected patients, sequential resection may be feasible in cases that have operable NSCLC in the chest and a solitary brain metastasis.

In patients with SCLC, metastasis to brain is present in approximately 20 to 30 percent of patients at presentation. Without prophylactic irradiation, relapse in the brain occurs in about one-half of patients within two years. Randomized trials have shown that the frequency of brain metastases can be significantly reduced with prophylactic cranial radiation.

Paraneoplastic phenomena — Paraneoplastic effects of tumor are remote effects that are not related to the direct invasion, obstruction, or metastasis.

Hypercalcemia — Hypercalcemia in patients with lung cancer may arise from a bony metastasis or less commonly tumor secretion of a parathyroid hormone-related protein (PTHrP), calcitriol or other cytokines, including osteoclast activating factors.

In one study of 1149 consecutive lung cancers, 6 percent had hypercalcemia. Among those with hypercalcemia, squamous cell carcinoma, adenocarcinoma, and SCLC were responsible in 51, 22, and 15 percent of cases, respectively. Most patients with hypercalcemia have advanced disease (stage III or IV) and a median survival of a few months.

Symptoms of hypercalcemia include anorexia, nausea, vomiting, constipation, lethargy, polyuria, polydipsia, and dehydration. Confusion and coma are late manifestations, as are renal failure and nephrocalcinosis.

Symptomatic patients who have serum calcium of 12 mg/dL (3 mmol/L) or higher require treatment that includes hydration and bisphosphonate. The treatment of hypercalcemia due to malignancy is discussed in detail separately.

SIADH secretion — The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is frequently caused by SCLC and results in hyponatremia. Approximately 10 percent of patients who have SCLC exhibit SIADH. SCLC accounts for approximately 75 percent of all malignancy-related of SIADH.

The severity of symptoms is related to the degree of hyponatremia and the rapidity of the fall in serum sodium. Symptoms include anorexia, nausea, and vomiting. Cerebral edema can occur with the onset of hyponatremia is rapid. Symptoms caused by cerebral edema may include irritability, restlessness, personality changes, confusion, coma, seizures, and respiratory arrest.

The treatment of SIADH focuses on treating the malignancy. In the majority of patients with SCLC, the hyponatremia will resolve within weeks of starting chemotherapy. Chronic hyponatremia or that of unclear duration may be treated with normal saline infusion to euvolemia, fluid restriction and demeclocycline, or a vasopressin-receptor antagonist. Acute and severe hyponatremia may be carefully treated with hypertonic (3 percent) saline infusion for a correction of 1 to 2 mmol per liter per hour with a correction of not more than 8 to 10 mmol per liter in 24 hours .

Neurologic — Lung cancer is the most common cancer with paraneoplastic neurologic syndromes; typically these are associated with SCLC. Paraneoplastic neurologic syndromes are thought to be immune-mediated, and autoantibodies have been identified in a number of instances. The various neurologic paraneoplastic syndromes and their pathophysiology are discussed elsewhere.

The most common of these is LEMS, which may be seen in approximately 3 percent of patients with SCLC. The neurologic symptoms of LEMS precede the diagnosis of SCLC in more than 80 percent of cases, often by months to years.

As many as 70 percent of patients who have SCLC and an associated paraneoplastic neurologic syndrome have limited stage disease. The finding of a paraneoplastic autoantibody in patients presenting with a neurologic syndrome should lead to an evaluation for malignancy. A CT of the chest is indicated in current or former smokers who have a suspected paraneoplastic neurologic syndrome. If the CT chest is negative, then PET may be useful in identifying the location of a neoplasm. Even subtle abnormalities of the lungs or mediastinum require biopsy in this situation.

Paraneoplastic neurologic syndromes generally do not improve with immunosuppressive treatment. However, symptoms may stabilize with response of the underlying neoplasm to treatment.

Hematologic manifestations — A number of hematologic abnormalities are seen in patients with lung cancer. These include the following:

These complications and their management are discussed separately.

Hypertrophic osteoarthropathy — Hypertrophic pulmonary osteoarthropathy (HPO) is defined by the presence of clubbing and periosteal proliferation of the tubular bones associated with lung cancer or other lung disease. Clinically, HPO is characterized by a symmetrical, painful arthropathy that usually involves the ankles, knees, wrists, and elbows. The metacarpal, metatarsal, and phalangeal bones may also be involved.

Dermatomyositis and polymyositis — Dermatomyositis and polymyositis are two distinct forms of inflammatory myopathy, both of which are manifested clinically by muscle weakness. These inflammatory myopathies can be the presenting symptom in patients with lung cancer or can develop later in the course of disease. In addition to lung cancer, other frequent primary sites associated with these disorders include the ovary, cervix, pancreas, bladder, and stomach. The incidence of malignancy and the role of screening for cancer in patients with dermatomyositis or polymyositis is discussed elsewhere.

Cushing's syndrome — Ectopic production of adrenal corticotropin (ACTH) can cause Cushing's syndrome. Patients typically present with muscle weakness, weight loss, hypertension, hirsutism, and osteoporosis. Hypokalemic alkalosis and hyperglycemia are usually present.

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