Neoplasms of the Lung
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[edit] Neoplasms of the Lung
Stephen Dolan
Akira Funahashi
[edit] BENIGN NEOPLASMS
Benign neoplasms of the lung account for about 5% of all lung neoplasms and include hamartoma, fibroma, leiomyoma, and lipoma. Of these, only hamartoma is clinically important.
[edit] Hamartoma
Hamartoma, the most common benign neoplasm of the lung, is believed to be congenital in origin. Histologically, hamartoma contains cartilage, smooth muscle, and mucus-secreting glands. The majority of hamartomas appear as a small, peripheral nodular density on the chest radiograph and may show a popcorn-type calcification. When no clear calcification is seen on the chest radiograph, a computed tomography (CT) scan may reveal a calcification or a characteristic fat density that allows the diagnosis of hamartoma. If no calcification indicates the benign nature of the lesion, a thoracotomy is often necessary for a definitive diagnosis, since commonly applied diagnostic procedures, such as fiberoptic bronchoscopy (FOB) and transthoracic needle aspiration (TNA), often do not yield a definitive diagnosis (see Solitary Pulmonary Nodule). Rarely a hamartoma presents as an endobronchial mass lesion with the clinical and radiographic signs of an obstructive endobronchial lesion, such as a cough, repeated episodes of pneumonia, and atelectasis.
If the radiographic or CT scan appearance confirms the diagnosis of hamartoma, no treatment is necessary. If the diagnosis is uncertain, however, the lesion should be excised. Generally, an endobronchial hamartoma also requires surgical resection because the diagnosis remains uncertain because of small biopsy samples obtained by FOB. If the diagnosis is certain, a local treatment with an yttrium-aluminum-garnet (YAG) laser can be considered.
[edit] Bronchial Adenoma
The term bronchial adenoma was once used to refer to bronchial carcinoid, bronchial cylindroma (adenoid cystic carcinoma), and mucoepidermoid carcinoma, accounting for approximately 90%, 8%, and 2% of cases, respectively. Because these tumors are histologically distinct, however, they are no longer categorized together under the heading of bronchial adenoma. All three are low-grade malignant tumors and should be separated from bronchial adenomas (bronchial cystadenoma and mucoepidermoid adenoma), which are rare, but truly benign, neoplasms.
[edit] Bronchial Carcinoid
The majority of bronchial carcinoids occur in the larger, centrally located bronchi, and only 20% or less originate in the peripheral airways. Bronchial carcinoids are believed to originate in the neurosecretory cells of the bronchial mucosa. Histologically they are composed of small polyhedral cells grouped in nests, trabeculae, or poorly developed tubercles.
The clinical presentation and radiographic findings of bronchial carcinoid differ greatly depending on the tumor's location and size. Centrally located bronchial carcinoids usually grow into the bronchial lumen; thus the patient typically presents with symptoms associated with airway involvement, such as cough and dyspnea. Because bronchial carcinoids are highly vascular, nearly 50% of the patients have hemoptysis. If a tumor obstructs the bronchus, the patient may present with symptoms of pneumonia distal to the obstructed bronchus. Unlike carcinoid tumor of the gastrointestinal (GI) tract, carcinoid syndrome with bronchial carcinoid is very rare. Radiographic findings of bronchial carcinoid also vary greatly. In patients with a centrally located bronchial carcinoid without bronchial obstruction, a chest radiograph often shows a centrally located mass lesion. If bronchial obstruction is present, the film usually shows atelectasis or pneumonic infiltrates distal to the obstruction. If tumor growth is limited within the bronchial lumen with no obstruction, the chest radiograph may be completely normal. When a relatively young individual, particularly a nonsmoker, presents with hemoptysis and a normal chest radiograph, the physician should suspect bronchial carcinoid and have an FOB performed. When bronchial carcinoid originates from a small peripheral airway, the patient is usually asymptomatic, and the lesion is discovered as an incidental finding on the chest radiograph. Establishing the diagnosis of a centrally located bronchial carcinoid is relatively easy once the diagnosis is suspected. In the past a forceps biopsy at bronchoscopy with a rigid bronchoscope was contraindicated because of the potential for massive bleeding. With the advent of FOB and the relatively smaller size of biopsy forceps, a forceps biopsy has been performed safely in some patients, although massive hemoptysis should be considered if a biopsy is performed. A thoracotomy is often required for the definitive diagnosis of a peripherally located carcinoid.
The treatment of bronchial carcinoid is a surgical resection. The prognosis after surgical resection is generally favorable (5-year survival is 90%). Bronchial carcinoids vary in their potential for malignancy, however, and metastases and death occur early in some patients.
[edit] Bronchial Cylindroma (Adenoid Cystic Carcinoma)
Unlike bronchial carcinoid, which arises from neurosecretory cells, bronchial cylindroma arises from the bronchial mucous gland. Microscopically it consists of interlacing cylinders of tumor cells, the centers of which are often canalized to form tubular spaces. Since this tumor grows into bronchial lumen, the clinical and radiographic presentations are those of endobronchial mass lesions that cause cough, dyspnea, and hemoptysis. Treatment is surgical excision, but local recurrence is possible.
[edit] BRONCHOGENIC CARCINOMA
[edit] Epidemiology and Etiology
An estimated 2 million people worldwide develop carcinoma of the lung annually. The highest incidence is found in the industrialized nations of England and Wales, the United States, and Japan. In the United States, although less common than breast and prostate cancer, carcinoma of the lung is the most frequently fatal cancer in men and women, accounting for 28% of all cancer deaths. It ranks second only to ischemic heart disease as the leading cause of death. In 1999 there were an estimated 171,600 new cases of lung cancer. In 1996, 158,900 died of this disease. Lung cancer occurs mainly in males between ages 50 and 80, although the incidence in U.S. women continues to rise, with 40% of all new lung cases involving women.
About 85% to 90% of all lung cancers are the result of cigarette smoking. A clear dose response rate accentuates a genetic predisposition. Male smokers have a 20-fold increased risk of developing lung cancer compared with nonsmokers. Those with chronic obstructive pulmonary disease (COPD) who smoke have an additional twofold to threefold increased risk. Pipe smoking does not carry the same risk as cigarette use, and chewing tobacco is not associated with lung carcinoma but rather malignancies of the upper aerodigestive tract. Passive smoking or environmental tobacco smoke has been demonstrated to be a risk factor for lung carcinoma in lifelong nonsmokers and accounts for an estimated 3000 cancer deaths annually. Other carcinogens linked to lung cancer include asbestos, radon products, polycyclic hydrocarbons, cadmium, chloromethyl ethers, chromium, nickel, and inorganic arsenic. The relative risk of asbestos exposure and tobacco use is multiplicative and estimated to be 100 times that of asbestos workers who do not smoke. Finally, a well-described association exists between bronchoalveolar cell carcinoma and scleroderma and that of adenocarcinoma with fibrocavitary lung disease following granulomatous infections.
[edit] Histopathology
Bronchogenic carcinoma can be classified according to four major cell types: squamous cell carcinoma, adenocarcinoma, large-cell carcinoma, and small-cell carcinoma. Because of the similarities in response to treatment and prognosis, the first three cell types are often grouped together as non–small-cell lung carcinomas (NSCLCs) to distinguish them from small-cell lung carcinomas (SCLCs), which are high-grade malignancies and carry an unfavorable prognosis. A significant number of tumors have more than one cell type in the same specimen and are classified as mixed NSCLCs. Squamous cell carcinoma and small-cell carcinoma are the cell types most closely associated with tobacco use. In recent years, adenocarcinoma has replaced squamous cell carcinoma as the most common presenting cell type.
[edit] Squamous Cell Carcinoma.
Accounting for 30% to 35% of all lung carcinomas, squamous cell carcinomas originate from the respiratory epithelium of the proximal airway (trachea, mainstem bronchi, lobar and segmental bronchi). Typical radiographic features are those of centrally located mass with or without hilar adenopathy. Postobstructive atelectasis or pneumonitis is characteristic given the proximal endobronchial location; cavitation occurs in 5% of cases. Presentation as a small peripheral nodule is less common. Light microscopy features include a stratified layering of polygonal epithelial cells with prominent intercellular bridges and whorls of keratotic debris, the latter being responsible for the term keratin pearls. Doubling time is estimated at 3 months (longer for the more well-differentiated forms), and late distant metastases tend to occur. At presentation, therefore, patients are more often symptomatic from local disease spread than distant metastases.
[edit] Adenocarcinoma.
Accounting for 35% to 40% of all lung carcinomas, adenocarcinomas probably arise from goblet cells in the major bronchi. Despite this, the typical presentation is that of a peripheral tumor in an asymptomatic patient. Adenocarcinoma is the cell type most often associated with lung cancer in nonsmokers or those with preexisting scars (scar carcinoma). Characteristic radiographic features are those of a peripheral mass or nodule in 65% of patients or hilar or mediastinal mass in approximately 40%. Malignant pleural effusion or chest wall involvement is seen in 15%.
Bronchoalveolar cell carcinoma, a subset of adenocarcinoma, presents as a single or multicentric infiltrate with air bronchograms and can mimic an infectious or inflammatory pneumonia. A presenting feature may be that of copious bronchorrhea. Characteristic light microscopy features of all adenocarcinomas include mucin production and gland formation. Bronchoalveolar carcinoma may present as tuftlike proliferation along the alveolar lining. Doubling time is estimated at 6 months, with a predilection to metastasize early to bone, brain, liver and adrenal glands.
[edit] Large-cell Carcinoma.
Accounting for about 10% of all lung cancers, large-cell carcinomas are relatively undifferentiated; they are free of areas of squamous or small cells, gland formation, or carcinoid differentiation. Radiographically, large-cell carcinomas tend to appear as large peripheral mass lesions. Metastatic patterns are similar to adenocarcinoma, and 50% of patients develop brain metastases. Prognosis is poor, with median survival greatly below that of an equivalent stage of the other NSCLC cell types.
Giant-cell carcinoma, a subset of large-cell carcinoma, is an aggressive, highly malignant tumor composed of large, bizarre, multinucleated cells. Tumors are infiltrated with white cells, and peripheral white count can exceed 40,000. An advanced stage is often seen at presentation, and prognosis is very poor.
[edit] Small-cell Carcinoma.
Accounting for 20% to 25% of all lung cancers, small-cell carcinomas are histologically subdivided into oat cell, intermediate, and combined cell types. They show finely distributed nuclear chromatin, inconspicuous nucleoli, and scant cytoplasm. The characteristic radiographic appearance is a rapidly enlarging hilar or perihilar mass with mediastinal adenopathy. A peripheral solitary mass is a rare presentation. Most tumors have extensive spread on presentation. Survival is influenced by stage, histology, and gender, with advanced stage (extensive), classic small-cell histology (absence of large polygonal cells), and male gender being poor prognostic features. Doubling time is estimated at 1 to 2 months, with a predilection for early metastasis to bone, liver, bone marrow, central nervous system (CNS), extrathoracic lymph nodes, and subcutaneous tissue. Median survival is much less than for NSCLC, with a 5-year survival of 27% for limited disease and 7 to 9 months for extensive disease.
[edit] Patient Evaluation
[edit] History.
Most patients with bronchogenic carcinoma are symptomatic at presentation, although the symptomatology may not be specific to lung cancer. Signs and symptoms can be grouped according to those that result from local vs. distant manifestations of the disease.
[edit] Local Manifestations.
Cough resulting from bronchial mucosal irritation is the most common presenting symptom (50% of patients). Airway obstruction presenting as focal wheezing, dyspnea, hoarseness, or even stridor is the result of endobronchial disease or mediastinal extension with involvement of phrenic or recurrent laryngeal nerves. Distal airway obstruction may present as postobstructive atelectasis or pneumonitis with or without cavitation. Hemoptysis, which is usually limited to blood-streaked sputum, suggests endobronchial pathology and warrants a chest radiograph and formal airway examination for smokers over age 40. Chest pain described as a dull ache may result from parietal pleural inflammation. Superior vena cava syndrome occurs in 5% of presenting patients and is caused by compression or invasion of the superior vena cava. Characteristic features include neck vein distention, facial and upper extremity edema, and engorgement of venous collaterals in the anterior chest wall. Patients complain of being unable to wear a necktie or having a tight collar. Tumors of the superior sulcus may involve the brachial plexus, resulting in arm and shoulder pain and weakness (Pancoast's syndrome). Horner's syndrome (ipsilateral miosis, ptosis, and anhydrosis) indicates involvement of the sympathetic stellate ganglia by this same tumor distribution.
[edit] Distant Manifestations.
Extrathoracic manifestations of bronchogenic carcinoma primarily result from metastatic tumor spread or numerous paraneoplastic syndromes (Box 81-1). Bony pain and pathologic fractures associated with bone metastases are the presenting symptoms in 1% of patients. Intracranial metastases occur in up to 6% of patients on presentation. Symptoms include confusion, lethargy, personality changes, a new-onset seizure disorder, or a speech defect. SCLC is the cell type most often associated with the paraneoplastic syndromes; the syndrome of inappropriate antidiuretic hormone (SIADH) is its most common manifestation (10% of patients). Hypercalcemia is primarily associated with squamous cell carcinoma and results from the release of a parathyroid hormone (PTH)–like peptide.
| Box 81-1 - Paraneoplastic Syndromes Associated with Bronchogenic Carcinoma✢ |
| Rights were not granted to include this data in electronic media. Please refer to the printed book. ✢From Matthay RA: Lung neoplasms. In Chest medicine, Baltimore, 1990, Williams & Wilkins. |
[edit] Physical Examination.
Physical examination of patients with lung carcinoma is often unrevealing unless the carcinoma is sufficiently advanced to cause obstruction of major airways, a pleural effusion, or bone or brain metastases. Unilateral or localized wheezing suggests airway narrowing. Diminished breath sounds, egophony, and increased vocal fremitus suggest a postobstructive pneumonia, whereas contralateral tracheal deviation, diminished breath sounds, and diminished vocal fremitus without egophony suggest a massive malignant pleural effusion. Neck vein distention, upper extremity and facial edema, and engorged venous collaterals in the anterior chest wall suggest the superior vena cava syndrome, whereas anhydrosis, miosis, and ptosis suggest Horner's syndrome. A careful nodal examination emphasizing the supraclavicular, scalene, and axillary lymph nodes will identify these important sites of metastases in patients with advanced disease, obviating the need for further invasive evaluation. Digital clubbing of recent onset suggests bronchogenic carcinoma, not COPD. Weakness and fatigability of the proximal muscles, particularly in the legs, suggest Eaton-Lambert syndrome, which is associated with SCLC.
[edit] Diagnosis
[edit] Chest Radiograph.
Because the history, physical examination, and laboratory findings are usually nonspecific, the chest radiograph becomes central to the diagnosis of bronchogenic carcinoma. Chest radiographs should be obtained for the evaluation of unexplained cough, hoarseness, dyspnea, or weight loss, as well as to investigate hemoptysis in a smoker. Typical radiographic features include a central or peripheral masslike lesion with or without hilar or mediastinal adenopathy. Central lesions with proximal endobronchial involvement may lead to lobar collapse as the result of resorptive atelectasis (Fig. 81-1). When this occurs, the chest radiograph reveals increased radiodensity of the collapsed lobe, ipsilateral tracheal and hilar deviation, elevation of the ipsilateral hemidiaphragm, and decreased size of the ipsilateral intercostal spaces. A pneumonia that recurs in the same anatomic location or is slow to resolve radiographically (longer than 12 weeks) similarly suggests bronchial pathology, with either a partial intraluminal obstruction or an extrinsic compressing lesion. Thick-walled cavitary lesions with irregular intraluminal contours suggest squamous cell carcinoma (Fig. 81-2). Small-cell carcinomas tend to present as a rapidly progressing hilar or perihilar mass with mediastinal adenopathy (Fig. 81-3). Other unusual radiographic presentations of bronchogenic carcinoma include multicentric alveolar infiltrates that mimic an infectious or inflammatory process, as seen in bronchoalveolar cell carcinoma (Fig. 81-4).
[edit] Computed Tomography.
A CT scan of the chest complements the radiographic information. For solitary pulmonary nodules, CT may clarify patterns of calcification and delineate border contours, which may assist in the assessment of benignancy. A chest CT scan offers superior visualization of the mediastinum, the site of early local metastases, and therefore can identify a more advanced stage than chest radiography. CT also clearly defines the anatomic location of the suspected lesion, characterizing its relationship to the pleura, chest wall, and mediastinum, which facilitates clinical staging and more invasive evaluation.
[edit] Magnetic Resonance Imaging.
Compared with CT, MRI offers superior contrast resolution and excellent visualization of vascular structures without the need for intravenous contrast. Its major limitations are greater expense, limited availability, and inability to visualize calcium directly. The role of MRI is limited to assessment of vascular or chest wall invasion, as in tumors of the superior sulcus.
Regardless of the findings suggested on imaging studies, the definitive diagnosis of lung carcinoma requires pathologic confirmation.
[edit] Cytopathology.
A sputum cytologic evaluation is an inexpensive and the least invasive means of confirming the diagnosis of lung carcinoma. The examination of five spontaneously collected or induced sputum specimens obtained on consecutive days offers a diagnostic yield of greater than 90% for squamous cell carcinoma histology. The larger and more centrally located the lesion, the more likely the cytology will be positive. Sputum induction can be obtained with aerosolized hypertonic 3% to 5% saline, sterile water, or propylene glycol using an ultrasonic nebulizer. Its major limitation is that it offers no insight into the anatomic location of the offending tumor; thus a positive sputum cytology should be followed by a bronchoscopic airway examination. This applies to all patients except when surgical resection is contraindicated, as in those with prohibitive pulmonary function or active coronary artery disease (CAD).
Pleural fluid in the presence of a suspected lung carcinoma may represent a malignant effusion and requires thoracentesis with cytologic examination. A positive pleural fluid cytology indicates inoperability, thereby providing both diagnosis and staging in a single minimally invasive procedure. Several hundred milliliters should be submitted for each examination. Blind closed-needle pleural biopsy adds little diagnostically to the cytologic evaluation, since pleural metastases are focal and begin near the mediastinum and diaphragm. Costal and cephalad spread occurs late with more advanced disease. Nonmalignant causes of a pleural effusion in the setting of lung carcinoma include parapneumonic effusion from postobstructive pneumonitis, pulmonary embolism from the hypercoagulable state, lymphatic or mediastinal lymph node obstruction from tumor involvement, and transudative effusion from low oncotic pressure associated with the cachexia and catabolic state associated with malignancies.
[edit] Fiberoptic Bronchoscopy.
FOB is an important tool in the diagnosis and evaluation of carcinoma of the lung. It is performed under topical anesthesia with conscious sedation and does not require hospitalization. In skilled hands, FOB can be performed safely even in patients who have limited pulmonary reserve. The diagnostic yield of FOB depends on the tumor's location and size (Table 81-1). With central tumors greater than 2 cm in diameter, diagnosis by FOB approaches 60%. This increases to greater than 90% when the lesion can be directly visualized. In peripheral lesions less than 2 cm, FOB provides a diagnosis in less than 20% of cases. Performing transbronchial biopsies under fluoroscopic guidance increases diagnostic yield when the lesions cannot be directly visualized.
Table 81-1 Transthoracic Needle Aspiration (TNA) vs. Fiberoptic Bronchoscopy (FOB)
| TNA | FOB | |
|---|---|---|
| Lesion size | ≤2 cm | >2 cm |
| Clinical symptoms | None | Cough, blood-tinged sputum |
| Clinical diagnosis | Malignancy | Both malignant and benign processes |
| Airway examination (staging) | Not possible | Routine |
| Pneumothorax | 25%-30% | <5% |
In addition to providing a tissue diagnosis, FOB also offers important staging information. Tumors less than 2 cm from the carina are labeled T3 lesions by the tumor, node, and metastasis (TNM) classification (Box 81-2 and Table 81-2). Positive transbronchial needle aspiration of subcarinal and precarinal lymph nodes confirms N2 nodal status. In 2% to 5% of patients with a unilateral lung mass, a synchronous endobronchial lesion in the contralateral lung is noted on a surveillance airway examination (M1 lesion). All these findings suggest a higher stage with more advanced disease, limiting successful surgical resection and necessitating a different therapeutic intervention.
Table 81-2 Stage Grouping of TNM Subsets in Lung Cancer
| Stage | TNM subset(s) |
|---|---|
| Occult carcinoma | TisN0M0 |
| Ia | T1N0M0 |
| Ib | T2N0M0 |
| IIa | T1N1M0 |
| IIb | T2N1M0, T3N0M0 |
| IIIa | T3N1M0, T1N2M0, T2N2M0, T3N2M0 |
| IIIb | T4N0M0, T4N1M0, T4N2M0, T1N3M0, T2N3M0, T3N3M0, T4N3M0 |
| IV | Any T, any N, M1 |
| Box 81-2 - Tumor, Node, and Metastasis (TNM) Classification† |
Primary Tumor (T)
|
[edit] Transthoracic Needle Aspiration.
Fluoroscopic or CT-directed TNA has a greater positive predictive value than FOB in establishing the diagnosis of malignancy in small (less than 2 cm) peripheral lesions (see Table 81-1). Its major limitations are low negative predictive value (i.e., a negative TNA does not exclude the diagnosis of malignancy) and higher complication rate. The role of TNA in the diagnosis of lung cancer should be limited to (1) patients with multiple pulmonary nodules suggestive of metastatic disease and (2) when a definitive preoperative diagnosis of lung cancer is necessary to warrant the risks of general anesthesia and thoracotomy. An elderly patient with advanced COPD and active CAD is an ideal candidate for TNA. An otherwise healthy, middle-aged smoker with an enlarging peripheral, spiculated, noncalcified nodule should not be subjected to TNA but rather taken directly to surgical resection once the fiberoptic airway examination has excluded synchronous contralateral disease.
[edit] Mediastinoscopy and Thoracoscopy.
Lymph nodes of the mediastinum are the usual sites of early metastases in NSCLC. These include the superior and inferior mediastinal, aortic, and hilar lymph nodes. In the patient with bronchogenic carcinoma, lymph nodes greater than 1 cm in their short axis (as visualized on chest CT scan) have an 80% probability of being malignant. Mediastinoscopy is a surgical technique that allows direct visualization of the superior mediastinum. Subcarinal, aortopulmonary window, and periaortic lymphadenopathy can be better assessed by an anterior mediastinotomy or Chamberlain procedure. Relative contraindications to mediastinoscopy include prior mediastinal radiation and previous tracheostomy. Similar to bronchoscopic attempts at transbronchial needle aspiration (TBNA) of pathologic lymph nodes, the role of mediastinoscopy is to detect advanced disease and therefore exclude patients from futile attempts at thoracotomy and lung resections. Perioperative identification of contralateral lymph node involvement (N3) by mediastinoscopy or transbronchial aspiration is a contraindication to surgical resection (stage IIIb). Perioperative identification of N2 lymph nodes by mediastinoscopy or TBNA (stage IIIa) carries a survival disadvantage (5-year survival of 9% vs. 24% if pathologically negative), and some thoracic surgeons believe this precludes candidacy for surgical resection.
Video-assisted thoracoscopy (VATS) or minimally invasive surgery results in less patient discomfort and shorter hospital stays compared with thoracotomy. The role of VATS in the surgical management of lung carcinoma has been questioned because incomplete visualization and inadequate mediastinal lymph node dissection make it inferior to standard thoracotomy. Staging is therefore inadequate using VATS, and candidates for combined-modality therapy for their advanced disease are missed. The ideal candidate for VATS has a small peripheral tumor and a normal mediastinum on chest CT or has marginal pulmonary function that allows only a wedge resection or segmentectomy. Alternatively, VATS-directed pleural biopsy is superior to pleural fluid cytologic examination obtained by thoracentesis and closed pleural biopsy in the diagnosis of malignant effusions.
[edit] Staging
Once the diagnosis of lung carcinoma has been established, whether by sputum cytology, FOB, or TNA, staging is essential for the treatment planning and prognostication. A standardized staging system also allows comparison of results from multicenter treatment trials. The International Staging System was developed for staging of NSCLCs based on the TNM classification (see Table 81-2 and Box 81-2). Table 81-3 lists a recommended workup for staging both NSCLC and SCLC.
Table 81-3 Recommended Staging Workup for NSCLC and SCLC
| NSCLC | SCLC | |
|---|---|---|
| Initial diagnostic evaluation | H&P, CXR, chest CT, pulmonary function tests | H&P, CXR, chest CT, CBC with review smear, serum chemistry profile |
| Tissue confirmation | Sputum cytology, FOB vs. TNA, thoracentesis if pleural effusion | FOB, thoracentesis if pleural effusion, mediastinoscopy |
| Further studies | As indicated by initial evaluation | As indicated by initial evaluation |
| Neurologic symptoms | Brain MRI | Brain/spine MRI |
| Mediastinal adenopathy | Transbronchial needle aspiration, mediastinoscopy | Transbronchial needle aspiration, mediastinoscopy |
| Palpable lymph node | TNA | TNA |
| Elevated alkaline phosphatase or serum calcium | Bone scan with plain film correlation; biopsy if single lesion to confirm M1 disease | Bone scan with plain film correlation; biopsy if single lesion to confirm extensive disease |
| Leukoerythroblastosis | — | Bone marrow biopsy |
| Elevated transaminases | Liver CT or ultrasound; biopsy if single lesion to confirm M1 disease | Liver CT or ultrasound; biopsy if single lesion to confirm extensive disease |
| NSCLC, Non–small-cell lung carcinoma;SCLC, small-cell lung carcinoma; H&P, history and physical examination; CXR, chest radiograph;CT, computed tomography; CBC, complete blood count; MRI, magnetic resonance imaging; FOB, fiberoptic bronchoscopy; TNA, transthoracic needle aspiration. | ||
Clinical staging must be distinguished from pathologic or surgical staging. Clinical staging relies on the information obtained by noninvasive imaging and often underestimates the extent of disease and therefore survival. Pathologic staging is done at the time of mediastinal lymph node dissection and is more accurate. Table 81-4 shows the percentage of patients surviving 5 years after initial diagnosis and treatment. The cell type of NSCLC also adversely affects prognosis. For a similar stage, survival is least for giant cell and greatest for squamous cell, with large cell and adenocarcinoma interposed. Staging for small-cell carcinoma is much simpler because most patients with this type of carcinoma have distant metastases at diagnosis. Although the TNM staging system is appropriate, most oncologists use a modified staging system for SCLC (Table 81-5). The 5-year survival of patients with limited SCLC is 17% and for extensive disease is 3%.
Table 81-4 Five-year Survival According to Stage in NSCLC
| Stage | TNM subset | 5-year survival (%) |
|---|---|---|
| Ia | T1N0M0 | 67 |
| Ib | T2N0M0 | 57 |
| IIa | T1N1M0 | 55 |
| IIb | T2N1M0 or T3N0M0 | 39 |
| IIIa | T1-3N2M0 | 25 |
| IIIb | T4, any N M0 or any T, N3M0 | 5 |
| IV | Any T, any N, M1 | 1 |
Table 81-5 Modified Staging for SCLC
| Stage | Description | Presenting stage (%) |
|---|---|---|
| Limited | Disease confined to one hemithorax with or without ipsilateral or contralateral mediastinal, supraclavicular lymph node, or ipsilateral pleural effusion | 30-40 |
| Extensive | Any disease at any site beyond limited definition | 60-70 |
[edit] Solitary Pulmonary Nodule
Solitary pulmonary nodule (SPN) is a fairly common radiographic entity. It is usually an incidental finding on a chest radiograph and is defined as a round or oval peripheral density surrounded by aerated lung tissue, with the largest diameter less than 4 cm and without associated hilar or mediastinal lymph node involvement or pleural effusion.
The etiology of an SPN differs greatly depending on geographic location. In developing countries, many SPNs represent infectious processes, particularly tuberculous granuloma. In the United States and other developed countries, approximately 40% of SPNs are the result of bronchogenic carcinoma. When a lung carcinoma presents as an SPN and is resected early, it is potentially curable, as evidenced by a 65% to 75% 5-year survival for T1N0M0 lesions. Therefore the differentiation between a benign and malignant SPN is crucial. The patient's age, smoking history, environmental tobacco exposure, occupational carcinogen exposure, and past residency are important clinical factors. Nonsmoking patients under age 35 have less than a 1% chance that their SPN is malignant. For smokers over 40 with more than 20 pack-years (pack/day) of smoking, the risk of malignancy equals their age.
The chest radiograph provides important findings to differentiate benign from malignant lesions. If the diameter of the lesion is smaller than 1 cm and borders are smooth and nonspiculated, it is most likely benign. If the SPN is larger than 3 cm, it has a 90% chance of being malignant. The presence and pattern of calcification are other important radiographic features. Benign patterns of calcification include central, lamellar, or popcorn calcification, with the latter suggesting a hamartoma, the most common benign neoplasm of the lung. Peripheral calcification suggests malignancy. Previous chest radiographs are essential. If the lesion is stable for more than 2 years, it is probably benign. Similarly, if the SPN doubles its volume in either less than every 20 days or more than 400 days, it is benign. Unfortunately, the smallest size at which a SPN can be reliably identified by chest radiography is a 1-cm nodule. At this size, it has already undergone 20 doubling times and consists of more than 1 million cells. When it has increased from 1 cm in diameter to 2 cm, 50% of patients already have evidence of metastases, increasing their concern when they are assigned to a watch-and-wait algorithm for management of their SPN.
When a standard chest radiograph does not show the characteristic calcifications and no previous chest radiographs are available, a chest CT scan should be obtained. If the CT scan does not demonstrate the benign nature of a lesion, a more invasive approach becomes necessary. FOB or TNA should be the next diagnostic procedure. FOB is useful for patients who have clinical complaints that suggest bronchial involvement, such as increased cough or blood-tinged sputum. TNA should be reserved for peripheral lesions and when a confirmed preoperative diagnosis of lung cancer is necessary to justify the perioperative risks of thoracotomy, as in patients with major surgical risk factors. All others should have thoracotomy. A watch-and-wait approach to an indeterminate SPN should be reserved for patients who have a low probability of cancer, have major surgical risk factors, or who refuse exploratory thoracotomy.
[edit] Management
[edit] Surgery.
For NSCLC, surgery is the best method to achieve long-term survival or cure. All patients in clinical stages I and II should be offered surgery unless they have severely compromised pulmonary function or unstable CAD. Preoperative assessment should include spirometry, an electrocardiogram (ECG), and a thorough cardiac history. Cardiology consultation is necessary for patients with significant cardiac disease, since cardiac problems are the most common complications after lung cancer surgery. Surgical resection offers the best attempt at cure while preserving remaining lung function, thus ensuring a satisfactory quality of life. Determining postoperative pulmonary function is based on the extent of resection, preoperative spirometry, and the contribution of the diseased segment, lobe, or lung to total pulmonary function. An accepted approach is to retain at least 35% of normal pulmonary function values after a lobectomy and 40% after a pneumonectomy. In most patients this would result in a tolerable decrement in exercise tolerance, usually without the requirement of chronic ambulatory oxygen therapy. To determine the predicted postoperative forced expiratory volume in 1 second (FEV1) and diffusing lung capacity for carbon monoxide (DLco), the following equation is used:
Predicted postoperative FEV1=Preoperative FEV1 − [Preoperative FEV1×(Number of segments removed/Total number of segments)× Percent function of that lung]
Of the 19 total lung segments, three are in the right upper lobe, two in the right middle lobe, five in the right lower lobe, four in the left upper lobe, and five in the left lower lobe. A quantitative perfusion scan determines the percentage that the diseased lung contributes to the entire system, since substantial differences can occur in regional ventilation with bullous emphysema or a large mass. When the predicted postoperative FEV1 is less than 40%, postoperative DLco and gas exchange at rest and with exercise are determined. If the predicted postoperative FEV1 is less than 30%, the patient is not a candidate for a lobectomy. If it is greater than 40%, the patient is a candidate for a pneumonectomy. If the predicted postoperative FEV1 is 30% to 40%, candidacy for a lobectomy depends on the predicted postoperative DLco being greater than 40% and a fall in Sao2 being less than 2% at maximal exercise. For selected borderline patients, some centers advocate formal cardiopulmonary exercise testing, with a maximal oxygen consumption (
o2) greater than 20 ml/kg/min determining surgical candidacy.
Limited surgery that includes wedge resection and segmentectomy can be offered to patients with unsatisfactory pulmonary function. These surgical techniques, however, are associated with increased risk of local recurrence and decreased long-term survival, particularly with adenocarcinoma. A number of surgical techniques, such as sleeve resection and bilobectomy, have been developed to preserve nondiseased lung and thus postoperative pulmonary function. Tumor invasion of the intrapulmonary or hilar lymph nodes (N1 disease, stage II NSCLC) decreases survival (67% vs. 55% 5-year survival for T1N0M0 vs. T1N1M0), and adjuvant therapy with radiation and chemotherapy is usually considered at this time. Many patients with clinical stage IIIa disease are potential surgical candidates, although long-term survival for this group is poor, with 5-year survival of 25%. Selected patients may qualify for neoadjuvant chemotherapy and radiation followed by surgical resection in a multicenter study using only the newer chemotherapeutic agents. Patients with stages IIIb and IV NSCLC are not considered surgical candidates. Management of small-cell carcinoma consists of chemotherapy and radiation. The value of surgery followed by chemotherapy in selected patients with limited SCLC has yet to be established.
[edit] Radiation Therapy.
The efficacy of radiation therapy is limited in part by toxicity to the local tissues and adjacent organs. Lower, less toxic doses (and thus less effective therapy) are usually offered when the disease is deemed unresectable at thoracotomy or, regardless of stage, when the patient is deemed inoperable because of comorbid medical problems or when the patient refuses surgery. Postoperative or adjuvant radiation therapy does not increase survival in patients with stage I NSCLC who have complete surgical resection of their lesion. Because they are at risk for a second primary tumor involving their aerodigestive tract (3% to 5% per year), these patients should be followed closely for the first 5 years after resection. Patients with stage I NSCLC who are unwilling or unable to undergo resection should be offered radiation therapy with the intent to cure. A 5-year survival of up to 20% may be achieved for patients with small peripheral lesions. It is important to remember that lung function is lost through surgical resection and radiation-induced fibrotic changes. For patients with intrapulmonary and hilar lymph node metastasis (N1 disease, stage II NSCLC), adjuvant radiation therapy offers improved control of local disease recurrence but has no effect on distant metastases or 5-year survival. Therefore the routine use of postoperative radiation therapy for completely resected stage II NSCLC is not supported.
Preoperative radiation therapy delivered outside a protocol is advocated only for superior sulcus tumors in patients with Pancoast's syndrome. In this setting, benefit is reported only from small, uncontrolled studies. Although patients with stage III disease often receive radiation treatment with a curative dose, long-term survival is seldom achieved. In stage IV disease, radiation therapy is used for palliative purposes, most often to control pain from bone metastases. Other indications include obstruction or narrowing of large airways that causes distal pneumonia or dyspnea and obstruction of a large vessel, as in superior vena cava syndrome. Radiation treatment often provides significant symptomatic relief in these patients. Brachytherapy is a form of local radiation in which a source of radioactivity is placed directly in the involved airway to minimize the effects on the surrounding normal lung tissue.
[edit] Chemotherapy.
Chemotherapy is the preferred treatment in small-cell lung carcinoma. The use of traditional agents (etoposide and cisplatin or cyclophosphamide, doxorubicin and vincristine) has been disappointing, however, with only 17% and 3% 5-year survival for limited and extensive stages, respectively. A current approach uses etoposide and cisplatin with radiotherapy; however, the 5% increase in 2-year survival for those with limited disease is offset by increased pulmonary, bone marrow, and esophageal toxicity. Long-term survival can be achieved in a small percentage of patients with limited disease. Unfortunately, these long-term survivors have a 50% risk for cranial metastases and a 3% to 5% incidence per year of a second primary lung lesion.
The role of chemotherapy in NSCLC is undergoing intensive investigation. Studies have shown promising results for preoperative chemotherapy (neoadjuvant) in carefully selected stage II and IIIa NSCLC. Similarly, treatment of locally advanced or inoperable stage III and IV NSCLC with combined-modality therapy (radiation plus chemotherapy) that includes newer chemotherapeutic agents (e.g., paclitaxel) has shown promising results in patients with good performance status (e.g., Karnofksy, greater than 70%).
[edit] Other Treatment Modalities.
Obstruction of the central airways is a common presenting feature of bronchogenic carcinoma, particularly among squamous cell and small-cell cancers. The proximal location of the lesion often leads to severe dyspnea or a postobstructive pneumonia with possible cavitation. Removal of the obstructing endobronchial component offers immediate palliative symptom control and may improve short-term survival. This can be achieved with a neodynium:YAG laser delivered either through a flexible fiberoptic or rigid bronchoscope under general anesthesia in the operating room by a bronchoscopist. The tissue effects of neodynium:YAG laser include photocoagulation and thermal necrosis, which can penetrate from several millimeters to several centimeters. Endobronchial radiation therapy (brachytherapy), another effective modality to treat centrally obstructing lesions, can be used either with laser bronchoscopy when the lesion has an endobronchial component or alone when there is extrinsic compression only. Bronchoscopically placed endobronchial catheters are afterloaded with radioactive seeds to deliver local radiation with controlled depth of penetration. The use of endobronchial stents to maintain airway patency is best suited for patients with extrinsic compression that is not controlled with brachytherapy.
[edit] Early Detection
Despite the observations that early-stage lung cancer is common, is usually asymptomatic, is amenable to surgical resection, and has the best 5-year survival rate, large-scale cooperative studies designed to detect early-stage lung cancer by chest radiograph and sputum cytology failed to show any benefit in overall mortality. Theories to account for this have included the heterogeneity of the disease itself, the limited sensitivity of radiography for all cell types and of sputum cytology for non–squamous cell carcinomas, and the ineffectiveness of current treatment strategies for advanced disease. Often-cited errors in the study design include biases of selection, lead time, length of time, overdiagnosis, and contamination by poor compliance to screening algorithm. Because of this the National Cancer Institute (NCI) has sponsored the Prostate, Lung, Colon, and Ovary Cancer Screening Trial. The lung cancer arm is designed to look at the usefulness of a yearly chest film in reducing cancer-specific mortality, but results will not be available for about 15 years. In the interim the American Cancer Society, American College of Radiology, NCI, and the U.S. Preventative Services Task Force do not advocate a routine chest radiograph for the mass screening of lung cancer in asymptomatic adults. We advocate annual screening chest radiography in high-risk patients, however, including those with a smoking history of greater than a 40 pack-years and any one or more of the following: COPD, family history of lung cancer, prior history of lung cancer, asbestos, radon or other occupational carcinogen exposure, and chronic fibrotic lung disease of any etiology.
Future developments in the field of lung cancer screening will include the use of serum biomarkers and diagnostic photodynamic therapy. The latter uses a photosensitizing agent and light source delivered through a fiberoptic bronchoscope to detect carcinoma in situ.
[edit] Prevention
Each day, 3000 U.S. teenagers take up the deadly, lifelong habit of cigarette smoking; 1 in 20 will develop lung cancer, and 90% will die from it. Less than 30% of individuals are successful in obtaining long-term smoking cessation, and the risk of developing lung cancer attributable to former cigarette smoking continues beyond 20 years after smoking cessation is complete. These facts emphasize the importance of primary prevention: discouraging those contemplating cigarette smoking from beginning. The physician's efforts at encouraging smoking cessation should not be discounted. The use of tobacco by white males has been declining for the past several decades as the result of intensive antismoking campaigns, and other demographic groups need to be targeted as well.
[edit] METASTATIC CARCINOMA OF THE LUNG
Because of their anatomic location, the lungs are common sites of metastases from malignant neoplasms outside the thorax. Patients with metastatic neoplasm of the lungs often have a known primary site or a recent history of malignancy, although occasionally the metastatic lesion is discovered without an identified site. Metastatic malignancy of the lung usually presents as multiple nodular lesions on the chest radiograph. When it appears as an SPN on the chest radiograph, a CT chest scan often reveals other lesions that are not apparent on the chest radiograph. Careful history, physical examination, and simple laboratory tests (e.g., urinalysis, stool guaiac test) usually suggest the primary site. Common primary sites are the genitourinary system in males (hypernephroma, transitional cell carcinoma of urinary bladder, germ cell tumor of testis) and the breasts and reproductive system in females (breast cancer, cervical cancer, choriocarcinoma). Gastrointestinal (gastric, pancreatic, and colorectal) carcinoma and head and neck carcinoma in smokers are frequent primary sites in both genders. In younger individuals the primary sites include muscle, bone, cartilage, and testes (e.g., leiomyosarcoma, osteosarcoma, synovial cell sarcoma). In some patients the metastasis occurs in the bronchial submucosa and causes an endobronchial lesion with associated symptoms and signs. In patients with endobronchial involvement the diagnosis can be made by FOB, whereas in those with single or multiple peripheral lesions the diagnosis is often made by TNA. Occasionally a thoracotomy is necessary to establish the diagnosis. The treatment of metastatic lesion(s) in the lung depends on the condition of the primary site. Surgery is usually not indicated after the lesions are diagnosed as metastatic neoplasms. Surgical resections have been performed occasionally, however, for select patients when primary tumors have been completely resected, there is no sign of local recurrence, and the lung lesion(s) can be completely resected without serious consequence to pulmonary function.
A less common but clinically important presentation is lymphangitic metastasis. This type of metastatic spread is usually seen in patients with carcinoma of the stomach, the pancreas, and the lung. The patient presents with rapidly progressive dyspnea, and the chest radiograph shows linear and coarse, irregular nodular infiltrates, often in the distribution of a segment or a lobe. Hilar and mediastinal lymph nodes are often enlarged. When a patient with carcinoma of the lung who underwent or is undergoing radiation treatment presents with lymphangitic metastasis, a differential diagnosis for radiation pneumonitis is important because this condition responds to treatment with steroids. Presumptive diagnosis of radiation pneumonitis can often be made on the basis of clinical and radiographic findings, and a trial of steroids may be given. Occasionally a lung biopsy is necessary to confirm the diagnosis.
[edit] LYMPHOMA
Lymphoma is a malignant disease of the lymphatic tissue and frequently involves the intrathoracic lymph node as well as the lung parenchyma. Lymphoma is usually divided into Hodgkin's disease and non-Hodgkin's lymphoma.
[edit] Hodgkin's Disease
Both Hodgkin's disease and non-Hodgkin's lymphoma occur in all age groups; however, Hodgkin's disease is more likely in younger persons. The peak incidence of Hodgkin's disease is the third decade, whereas non-Hodgkin's lymphoma is seen more often in patients over age 50. Involvement of the intrathoracic structures by Hodgkin's disease is usually a part of the generalized disease process, and primary pulmonary Hodgkin's disease is very rare. Patients with Hodgkin's disease usually have constitutional symptoms such as general malaise, easy fatigability, fever, and weight loss at presentation. Physical examination often reveals peripheral lymph node enlargement and anemia. When the disease involves the thorax, it usually presents as mediastinal and hilar lymph node enlargement on chest radiograph. The mediastinal and hilar lymph node enlargement is usually asymmetric but bilateral. The involvement of the lung parenchyma is uncommon and is almost always associated with a mediastinal mass. The lung parenchymal involvement is more often seen in patients with a nodular sclerosis type and is usually the result of direct extension of the mediastinal process. Occasionally it may cause a compression of the airway or actual invasion of the bronchus, resulting in atelectasis or distal pneumonia.
The major differential diagnosis of intrathoracic Hodgkin's disease is sarcoidosis (see Chapter 78 ). Patients with sarcoidosis who have bilateral hilar lymphadenopathy are usually asymptomatic unless there is a significant lung involvement. The diagnosis of sarcoidosis is usually made with FOB and transbronchoscopic lung biopsy, which has a very high diagnostic yield (80% to 85%), even for patients without appreciable lung parenchymal involvement on chest radiograph. The diagnosis of Hodgkin's disease confined in the mediastinum often requires mediastinoscopy.
Treatment of Hodgkin's disease is a combination of radiation and chemotherapy. The response to treatment and the prognosis for patients with Hodgkin's disease are generally better than for patients with non-Hodgkin's lymphoma.
[edit] Non-Hodgkin's Lymphoma
Non-Hodgkin's lymphoma is a heterogenous group of malignant diseases of lymphatic origin and frequently involves the mediastinum and the lungs. Non-Hodgkin's lymphoma is sometimes classified as primary and secondary lymphoma. In primary pulmonary lymphoma, only the lung is involved at diagnosis, with no evidence of extrathoracic dissemination for at least 3 months after the initial diagnosis. In secondary pulmonary lymphoma, patients are known to have disease outside the thorax before the pulmonary involvement. Pathologically the most common cell of primary pulmonary lymphoma is a small lymphocytic type. Radiographically, primary lymphoma manifests as reticulonodular, nodular, or parenchymal consolidation. Clinically, most patients with primary lymphoma are asymptomatic. The histologic diagnosis can be made by examination of FOB specimens but often requires thoracotomy. Secondary pulmonary lymphoma occurs much more frequently than primary pulmonary lymphoma. The most common radiographic manifestation of secondary pulmonary lymphoma is mediastinal and hilar lymph node enlargement. When the lungs are involved, the lesion may present as an SPN or as multiple nodules. Cavitation may occur, but less often than in Hodgkin's disease. The lesion may extend to the large airway and cause an atelectasis or a distal pneumonia. Clinical presentation depends on the extent of extrathoracic disease. Constitutional symptoms, such as fever, anorexia, and weight loss, typically occur.
Treatment of non-Hodgkin's lymphoma is a combination of chemotherapy and radiation. Response to treatment and prognosis are less favorable than for Hodgkin's disease.
[edit] ADDITIONAL READINGS
- MS Bains: Surgical treatment of lung cancer. Chest 1991; 100:826.
- C Boring, TS Squires, T Tong: Cancer statistics. CA Cancer J Clin 1993; 43:7.
- BJ Flehinger, M Kimmel, MR Melmad: The effect of surgical treatment on survival from early lung cancer: implication for screening. Chest 1992; 101:1013.
- DC Ihde: Chemotherapy of lung carcinoma. N Engl J Med 1992; 327:1434.
- J Jett: Pretreatment evaluation of non-small-cell lung cancer. Am J Respir Crit Care Med 1997; 156:320 - 332.
- CF Mountain, SD Greenberg, AE Fraire: Tumor stage in non–small-cell carcinoma of the lung. Chest 1991; 99:1258.
- JR Murren, AC Buzaid: Chemotherapy and radiation for the treatment of non–small-cell lung cancer. Clin Chest Med 1993; 14:161.
