Chapter 66 Lung Cancer
Clinical Evaluation and Staging
Every patient with lung cancer should undergo a timely and thorough clinical evaluation, starting with a comprehensive history and physical examination. The presence or absence of symptoms will influence subsequent imaging and invasive assessment, and decisions relating to future evaluation and treatment will be guided by the patient’s overall health status, including comorbid medical conditions. This general assessment, ultimately leading to the determination of clinical stage, typically will inform further evaluation and will influence the choice of therapy. It is therefore critically important that this process be approached efficiently and comprehensively.
Symptoms and Signs Related to the Primary Tumor
Currently, most patients with lung cancer have advanced disease at the time of presentation and are likely to present with symptoms, particularly if local extension, metastasis to distant sites, or a paraneoplastic syndrome is present. Obtaining a thorough history and a review of systems in patients suspected of having lung cancer constitute an important part of the initial evaluation, because the symptom history will influence the choice of imaging studies, the interpretation of those studies, and the institution of early palliative interventions. Symptoms and signs related to the primary tumor most commonly include cough, dyspnea, chest pain, and hemoptysis. Cough is present in up to 75% of patients with lung cancer and may be related to airway involvement, postobstructive pneumonitis, or bronchorrhea. Dyspnea may be associated with primary site–related problems, such as endobronchial or extrinsic airway obstruction, postobstructive atelectasis, infection, or increased airway secretions, or may be related to metastatic disease, with potential manifestations including pleural effusion, lymphangitic tumor spread, pericardial effusion with tamponade, and pulmonary thromboemboli in the setting of hypercoagulability. Hemoptysis with lung cancer usually manifests as intermittent or persistent bloody streaking of the sputum and rarely can be massive. In up to 9% of patients with hemoptysis and lung cancer, the chest radiograph will be normal in appearance, underscoring the need to include endobronchial tumor as a major consideration in the differential diagnosis in patients presenting with hemoptysis and lung cancer risk factors (Figure 66-1). With the exception of hemoptysis, these pulmonary symptoms may not necessarily prompt a patient with a history of cigarette use, chronic obstructive pulmonary disease, or interstitial lung disease to seek specific medical attention or, conversely, for the clinician to consider an alternative diagnosis. These may be contributing factors to the consistent observation of a delay of several months between the onset of symptoms and a definitive diagnosis of lung cancer.
Symptoms Related to Intrathoracic Spread
Intrathoracic spread of lung cancer may occur by direct extension of the primary tumor or by involvement of lymph nodes and other thoracic structures. Chest pain is reported by up to 50% of patients at presentation and often indicates extension of tumor to the mediastinum, chest wall, or pleura. Hoarseness typically heralds involvement of the left recurrent laryngeal nerve, which in its circuitous course into the chest and under the aortic arch is particularly subject to compromise from left-sided cancers spreading to the ipsilateral mediastinal lymph nodes. Recurrent (inferior) laryngeal nerve palsy also may cause aspiration and coughing related to inadequate apposition of the vocal cords. Superior vena cava syndrome occurs more commonly with lung cancer than any other tumor, with small cell carcinoma the most commonly associated histologic subtype. Patients may present with a sensation of facial fullness, dyspnea, dysphagia, and headache or with actual swelling of the face, neck, and upper chest, and typically exhibit distended neck veins as well as a dilated venous pattern over the upper chest and shoulders. Superior sulcus (Pancoast) tumors are associated with a constellation of symptoms, primarily pain from compression or invasion of the brachial plexus (which, because it typically localizes to the shoulder and scapula, may not immediately prompt a pulmonary evaluation per se), Horner syndrome (ptosis, miosis, anhidrosis) due to involvement of the sympathetic chain and stellate ganglion, and upper extremity muscle wasting and pain related to tumor involvement of the eighth cervical and first and second thoracic nerve roots. Extension of tumor to the pericardium can result in pericardial effusion with or without tamponade, as well as arrhythmias. Bulky mediastinal adenopathy itself causes symptoms uncommonly, although dysphagia may result if the esophagus is compressed.
Symptoms Related to Metastatic Spread
Lung cancer can spread distantly to any organ. The presence of constitutional symptoms, particularly weight loss but also fatigue, weakness, or poor appetite, and new symptoms related to any organ, including musculoskeletal pain, neurologic changes, hoarseness, and abdominal discomfort, should heighten the clinical suspicion for metastatic disease. Laboratory abnormalities, including anemia, abnormalities on liver function tests, and hypercalcemia, also should prompt a search for disease beyond the primary site. Conversely, the absence of any of these symptoms or signs on a thorough initial clinical assessment argues strongly against the presence of metastatic spread. The most common sites of distant spread are lymph glands, liver, bones, adrenal glands, brain and spinal cord, and pleura.
Lymph node metastases typically are seen first in the thorax, in either the ipsilateral hilar area or the mediastinum, and rarely cause symptoms. The supraclavicular fossa should be examined carefully in patients with known or suspected lung cancer, because this is the most common location for palpable malignant adenopathy and offers an easily accessible site for cytologic needle aspiration to establish diagnosis and stage of disease.
Liver metastases may be associated with constitutional symptoms including fever but usually are asymptomatic and often are not associated with any abnormalities on liver function tests. By contrast, bone metastases tend to manifest with pain and may be associated with elevations of alkaline phosphatase or serum calcium levels.
Adrenal metastases typically are unilateral but may be bilateral. Because most adrenal masses actually represent benign adenomas or hyperplasia, a more definitive noninvasive evaluation or biopsy is warranted. Adrenal metastases usually are asymptomatic; adrenal insufficiency related to metastatic invasion of the adrenal glands is rare.
The brain is a common site of spread in patients with lung cancer; conversely, a majority of brain metastases are related to primary sites located in the lung. Overall, intracranial metastasis is present in approximately 10% of all patients with lung cancer at initial diagnosis, with signs and symptoms ranging from headache and confusion to seizures or focal neurologic deficits.
Pleural involvement with tumor may take the form of pleural nodules, direct tumor extension, or malignant pleural effusion. Malignant effusions usually are exudative and may be either serous or bloody. Under the current staging system, the presence of a malignant effusion places the patient in a group with the most advanced stage of clinical disease (stage IV) and establishes nonresectability.
Paraneoplastic syndromes occur in approximately 10% of patients with lung cancer (Table 66-1). Such syndromes may be the initial presenting complaint triggering an evaluation but also can develop late in the course of disease. Paraneoplastic syndromes are unrelated to direct invasion or distant spread of tumor and in and of themselves do not preclude curative-intent therapy. Endocrine syndromes associated with lung cancers often are characterized by tumor production of biologically active hormones. Lung cancer is the most common cause of cancer-associated hypercalcemia, hyponatremia, and syndromes involving ectopic production of adrenal corticotropic hormone (ACTH).
|Endocrine||Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)/hyponatremia; hypercalcemia; ectopic adrenocorticotropic hormone (ACTH) syndrome; Cushing syndrome; hyperglycemia; hypoglycemia; hyperthyroidism; carcinoid syndrome; gynecomastia; elevated growth hormone; elevated follicle-stimulating hormone (FSH); galactorrhea|
|Musculoskeletal||Hypertrophic osteoarthropathy (HOP); clubbing, myopathy; dermatomyositis; polymyositis|
|Neurologic||Lambert-Eaton myasthenic syndrome (LEMS); encephalomyelitis/subacute sensory neuropathy; cerebellar degeneration; opsoclonus-myoclonus; autonomic neuropathy; retinopathy; mononeuritis multiplex; peripheral neuropathy; myopathy|
|Skin||Acanthosis nigricans; pruritus and urticaria, erythema multiforme; erythroderma; exfoliative dermatitis; hyperpigmentation|
|Hematologic||Anemia, thrombocytosis, leukocytosis, hypercoagulable state|
Hypercalcemia of malignancy is the most frequent of these syndromes and is seen most commonly in patients with squamous cell carcinoma. Hypercalcemia in lung cancer patients usually is related to the ectopic production of parathyroid hormone–related peptide (PTHrP), rather than to the osteolytic effects of bone metastases. Early symptoms—thirst, polyuria, fatigue, constipation, nausea—are nonspecific. Mental status changes, lethargy, and even coma may accompany more severe hypercalcemia. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) most commonly occurs in patients with small cell lung cancer (SCLC). In some SCLC series, hyponatremia related to SIADH is present in up to 10% to 15% of patients. As with hypercalcemia, the symptoms—weakness, nausea, headache—often are nonspecific; more severe hyponatremia may have serious consequences, including confusion, seizures, and coma. Ectopic ACTH syndrome is seen most commonly with SCLC. The classic features of Cushing syndrome—truncal obesity, myopathy and muscle weakness, diabetes, hypertension, hirsutism—often are absent. In most cases, tumor cells express a precursor hormone that is cleaved to ACTH. A minority of patients produce corticotropin-releasing hormone, which stimulates ACTH production in the pituitary. The distinction between these two processes can be determined by a dexamethasone suppression test.
Nonendocrinologic extrapulmonary syndromes include musculoskeletal abnormalities, most commonly asymptomatic digital clubbing, which can be seen in isolation or in the setting of hypertrophic pulmonary osteoarthropathy (HPO). The pathogenesis of HPO is unknown, but the disorder consists of a proliferative periostitis characterized by symmetric, painful arthropathy that typically involves the ankles, shins, knees, wrists, and elbows. The diagnosis usually is confirmed by the identification of new periosteal bone formation on plain radiographs of the long bones, or by demonstration of diffuse long bone uptake of radionuclide on bone scan or positron emission tomography (PET) imaging. HPO is more commonly seen with adenocarcinoma. Hematologic dyscrasias commonly occurring in patients with lung cancer include anemia, which may compound fatigue and dyspnea; thrombocytosis; and leukocytosis. Eosinophilia is seen only rarely. Lung cancer is the most common cause of hypercoagulability associated with malignancy, which usually declares itself as deep venous thrombosis or thromboembolism, or with classic Trousseau syndrome (migratory superficial thrombophlebitis). Lung cancer, and specifically SCLC, also is the most common cause of a clinically diverse group of paraneoplastic neurologic syndromes (see Table 66-1).
The commonality with several of these syndromes is that they appear to be driven by autoimmune mechanisms. The most common of these is the Lambert-Eaton myasthenic syndrome (LEMS), which occurs in approximately 2% to 4% of patients with SCLC. LEMS is characterized by proximal muscle weakness, hyporeflexia, dysarthria, blurred vision, and autonomic dysfunction. In contrast with myasthenia gravis, muscle strength typically does not improve with the administration of anticholinesterases, but some recovery of strength may be obtained with treatment of the underlying malignancy. LEMS is associated with an antibody that inhibits acetylcholine release by binding to calcium channels in peripheral cholinergic nerve terminals. The diagnosis usually is based on electromyography demonstrating small amplitude of the resting muscle action potential, which increases with repeated nerve stimulation or exercise. The syndrome of encephalomyelitis–subacute sensory neuropathy is associated with antineuronal nuclear-antibody types 1 and 2 (ANNA-1 and ANNA-2), also called anti-Hu and anti-Ri antibodies, respectively, which react with SCLC tumor cell surface proteins and with neuronal nuclear antigens. Anti-Hu antibodies also are seen in patients with SCLC and cerebellar degeneration as well as opsoclonus-myoclonus. Other paraneoplastic neuropathic syndromes include encephalomyelitis, autonomic neuropathy, and cancer-associated retinopathy.
Approximately 25% of patients with lung cancer present at an early stage of their disease, so only a minority are asymptomatic at the time of diagnosis. The poor overall 5-year survival for patients with lung cancer reflects the disproportionate number of patients who are diagnosed at an advanced stage. Interest in establishing screening for early disease detection in asymptomatic patients has understandably been the focus of many studies. The reasons to develop a reliable lung cancer screening tool are quite evident. Most lung cancers are discovered because of symptom-driven evaluation; a diagnosis of advanced-stage disease unfortunately portends a limited prognosis. By contrast, asymptomatic patients with early-stage cancers are more likely to experience long-term survival with treatment.
Large studies performed since the 1970s evaluating chest radiography, sputum cytologic analysis, and low-radiation-dose chest computed tomography (CT) scanning for lung cancer screening have consistently demonstrated an increase in the number of lung cancers diagnosed and a shift toward identifying earlier-stage disease accompanied by an improvement in survival, but notably without a decrease in lung cancer mortality rates. The National Lung Screening Trial (NLST) is the first large-scale clinical trial to demonstrate a benefit in lung cancer mortality related to screening with low-dose chest CT scanning. The NLST enrolled 53,000 subjects aged 55 to 74 years who were current or former smokers with at least a 30 pack-year history, and who had no previous history of lung cancer. The study compared low-dose chest CT scanning and chest radiography as screening tools, with participants randomized to receiving three annual screens with one or the other modality, with follow-up over another 5 years. The trial was closed in late 2010 when initial results demonstrated that subjects assigned to the CT screening group had 20% less lung cancer deaths than those assigned to chest radiography screening. The disadvantages of screening include a high rate of false-positive findings, which incur additional diagnostic evaluation with the potential for risk or harm related to such evaluation; the anticipated high cost of screening and subsequent evaluation; and the potential consequences of cumulative exposure to radiation from multiple scans. The optimal approach to lung cancer screening inevitably will need to evolve over the coming years, as the results of the NLST are applied to clinical practice, and outcomes related to both benefit and disadvantages can be longitudinally examined.
The Solitary Pulmonary Nodule
The typical presentation of an asymptomatic early stage lung cancer is as a solitary pulmonary nodule (SPN), defined as a solitary lesion 3 cm or less in diameter, surrounded by normal lung and not associated with other thoracic abnormalities such as hilar or mediastinal adenopathy, atelectasis, or pleural effusion. SPNs are common radiographic lesions, frequently identified as incidental findings on chest imaging studies done for issues unrelated to lung cancer. Typical scenarios include routine preoperative evaluation in which a lung nodule or mass is found on the plain chest radiograph, or is identified on a chest CT scan performed for screening purposes or for other reasons unrelated to any chest symptoms, and investigation featuring a CT scan of the abdomen, heart, or spine, in which a portion of the lungs is almost inevitably included.
In evaluating SPNs, it is useful to distinguish small (8 mm or less in diameter) from larger nodules. Small SPNs are very common findings in patients who have participated in CT screening studies for lung cancer, as well as in those undergoing CT scanning for non-lung-related reasons, as noted earlier. In the feasibility study for the NLST performed within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, 21% of subjects had abnormalities identified on the baseline screening CT scan, most of which were small SPNs. Similarly, in the Mayo Clinic lung cancer screening study, 51% of subjects had abnormalities found on the baseline screening study, with an increase to 69% by the second annual screen, the vast majority of which were small SPNs. The enormous number of small SPNs generated by an increased volume of CT scanning prompted a position statement from the Fleischner Society proposing guidelines for the management of small (8 mm or less) SPNs detected on CT scans. The recommendations are outlined in Table 66-2. Appropriately applied, the guidelines outline algorithms for patients based on their risk of lung cancer, providing timelines for follow-up of incidentally discovered nodules that minimize the number of CT scans necessary in the course of evaluation. These practical recommendations will become even more relevant if CT screening for lung cancer becomes the standard of practice. Of note, these recommendations apply only to patients in whom SPNs are discovered incidentally, unrelated to any known underlying disease, and only for solid SPNs 8 mm or less in diameter. Specifically, the guidelines are not intended to apply to patients known to have or suspected of having malignant disease, patients younger than 35 years of age, or patients with unexplained fever. Furthermore, the recommendations are not fully applicable to persons with nonsolid (ground glass appearance) or partially solid nodules, who may require longer follow-up to permit exclusion of biologically indolent cancers with greater confidence.
|Nodule Size*||Low-Risk Patient†||High-Risk Patient‡|
|≤4 mm||No follow-up needed§||Follow-up CT at 12 months; if unchanged, no further follow-up¶|
|>4-6 mm||Follow-up CT at 12 months; if unchanged, no further follow-up¶||Initial follow-up CT at 6-12 months, then at 18-24 months if no change¶|
|>6-8 mm||Initial follow-up CT at 6-12 months, then at 18-24 months if no change||Initial follow-up CT at 3-6 months, then at 9-12 months and 24 months if no change|
|>8 mm||Follow-up CT at around 3, 9, and 24 months, then dynamic contrast-enhanced CT, PET, and/or biopsy||Same as for low-risk patient|
NOTE: Guidelines refer to newly detected indeterminate nodules in persons 35 years of age or older.
PET, positron emission tomography.
* Average of length and width.
† Minimal or absent history of smoking and of other known risk factors.
‡ History of smoking or of other known risk factors.
§ The risk of malignancy in this category (<1%) is substantially less than that determined with a baseline CT scan in an asymptomatic smoker.
¶ Nonsolid (ground glass) or partly solid nodules may require longer follow-up period to exclude indolent adenocarcinoma.
Modified from MacMahon H, Austin JH, Gamsu G, et al: Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society, Radiology 237:395–400, 2005.