21: Lung cancer: Clinical aspects
OUTLINE
Clinical Features, 251
Symptoms Relating to Primary Lung Lesion, 251
Symptoms Relating to Nodal and Distant Metastasis, 252
Paraneoplastic Syndromes, 252
Diagnostic Approach, 253
Macroscopic Evaluation, 253
Microscopic and Molecular Evaluation, 256
Functional Assessment, 257
Screening for Lung Cancer, 257
Principles of Therapy, 257
Treatment of Non–Small-Cell Lung Cancer, 258
Treatment of Small-Cell Lung Cancer, 259
Restoration of Airway Patency, 259
Bronchial Carcinoid Tumors, 259
Solitary Pulmonary Nodule, 260
The goal of this chapter is to extend the discussion of lung cancer into the clinical realm and to relate how the pathologic processes considered in Chapter 20 are encountered in a clinical setting. An outline of the major clinical features of lung cancer is followed by a discussion of the diagnostic approach and general principles of management. The chapter concludes with a brief discussion of bronchial carcinoid tumors and the clinical problem of the solitary pulmonary nodule.
Clinical features
Because lung cancer presumably starts with a single malignant cell, a long period of repetitive divisions and doubling of cell number must occur before the tumor becomes clinically apparent. During this
preclinical period, an estimated 30 divisions take place before the tumor reaches a diameter of 1 cm. This
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process most likely requires several years, during which time the patient and the physician are unaware of the tumor.
The possibility of lung cancer is often raised because of findings on imaging studies such as a chest radiograph or computed tomography (CT) scan, or because of an assortment of symptoms that develop. This section focuses primarily on symptoms; imaging studies and diagnostic sampling are discussed in the section “Diagnostic Approach.” The symptoms at the time of presentation may relate to the primary lung lesion, to metastatic disease (either in intrathoracic lymph nodes or at distant sites), or to what are commonly called “paraneoplastic syndromes.”
Symptoms relating to primary lung lesion
Perhaps the most common symptoms associated with lung cancer are cough and hemoptysis. Because bronchogenic carcinoma generally develops in smokers, these patients often dismiss their symptoms (particularly cough) as routine complications of smoking and chronic bronchitis. With tumors originating in large airways, such as squamous cell carcinoma or small-cell carcinoma, patients may also have problems related to bronchial obstruction, such as pneumonia behind the obstruction or shortness of breath secondary to occlusion of a major bronchus. In contrast, with tumors that arise in the periphery of the lung, including many adenocarcinomas and large-cell carcinomas, patients tend not to have symptoms related to bronchial involvement, and their lesions are often found on imaging obtained for unrelated purposes.
When tumors involve the pleural surface, either by direct extension or by metastatic spread, patients may have chest pain, often pleuritic in nature, or dyspnea resulting from substantial accumulation of pleural fluid. Other adjacent structures, particularly the heart and esophagus, can be involved by direct invasion or extrinsic compression by the tumor. Resulting complications include pericardial effusion, cardiac dysrhythmias, and dysphagia.
Tumors originating in the most apical portion of the lung, which are called superior sulcus or Pancoast tumors, often produce a characteristic constellation of symptoms and physical findings caused by direct extension to adjacent structures. Involvement of the nerves composing the brachial plexus can result in pain and weakness of the shoulder and arm. Involvement of the cervical sympathetic chain produces the typical features of Horner syndrome—ptosis (a drooping upper eyelid), miosis (a constricted pupil), and anhidrosis (loss of sweat) over the forehead and face—all occurring on the same side as the lung mass. Invasion of neighboring bony structures (e.g., ribs and vertebrae) is a common complication.
Potential clinical problems with lung cancer:
1.Symptoms of endobronchial tumor: cough, hemoptysis
2.Problems of bronchial obstruction: postobstructive pneumonia, dyspnea
3.Pleural involvement: chest pain, pleural effusion, dyspnea
4.Involvement of adjacent structures: heart, esophagus
5.Complications of mediastinal involvement: phrenic or recurrent laryngeal nerve paralysis, superior vena cava obstruction
6.Distant metastases: brain, bone or bone marrow, liver, adrenals
7.Ectopic hormone production: ACTH, ADH, parathyroid hormone-related peptide
8.Other paraneoplastic syndromes: neurologic, clubbing, hypertrophic osteoarthropathy
9.Nonspecific systemic effects: anorexia, weight loss
Symptoms relating to nodal and distant metastasis
When a primary lung cancer metastasizes to mediastinal lymph nodes, symptoms often arise from invasion or compression of important structures within the mediastinum, such as the phrenic nerve, recurrent laryngeal nerve, or superior vena cava. As a consequence, the following conditions, respectively, may develop: diaphragmatic paralysis (often with accompanying dyspnea), vocal cord paralysis (with hoarseness), and superior vena cava obstruction (with edema of the face and upper extremities resulting from obstruction to venous return).
Distant metastases, most commonly to the brain, bone or bone marrow, liver, and adrenal gland(s), frequently are asymptomatic. In other cases, symptoms depend on the particular organ system involved, and manifestations such as seizures or bone pain may develop. Small-cell carcinoma is the cell type most likely to generate distant metastases (see Chapter 20). Squamous cell carcinoma is least likely, and both adenocarcinoma and large-cell carcinoma occupy an intermediate position.
Paraneoplastic syndromes
Many lung tumors are associated with clinical syndromes that are not attributable to the space-occupying nature of the tumor or to direct invasion of other structures or organs. These syndromes are called the “paraneoplastic” manifestations of malignancy and frequently are due to either production of a hormone or a hormone-like substance by the tumor or the presence of autoantibodies stimulated by antigens on the tumor.
When a hormone is produced by the lung tumor (or, for that matter, by any type of tumor), the patient is said to have “ectopic” hormone production. Sometimes clinical symptoms result from high circulating levels of the hormone; in other cases, only sensitive techniques of measurement can detect production of the hormone. Why some tumors produce ectopic hormones is not clear. Genetic information coding for the particular hormone is present but not expressed in normal, nonmalignant cells, and it has been hypothesized that in the course of becoming malignant, the cell undergoes a process of gene dysregulation. As a result, the malignant cell regains the ability to express this normally silent genetic material coding for hormone production.
The lung cancer type most frequently associated with ectopic production of humoral substances is small-cell lung cancer (SCLC), presumably because of its neuroendocrine features. Antidiuretic hormone (ADH) and adrenocorticotropic hormone (ACTH) are the most common hormones produced by SCLC. The syndrome of inappropriate ADH (SIADH) causing hyponatremia is seen in approximately 10% of patients with SCLC, and SCLC is the cause of most malignancy-associated cases of SIADH. Ectopic production of ACTH occurs in approximately 1% of patients with SCLC. A paraneoplastic syndrome commonly associated with squamous cell lung cancer, rather than SCLC, is hypercalcemia due to production of parathyroid hormone–related peptide, a peptide with parathyroid hormone-like activity. Production of other hormones, such as calcitonin and human chorionic gonadotropin, also are well described with bronchogenic carcinoma.
SCLC is the most common cause of autoimmune-mediated paraneoplastic syndromes affecting the nervous system. The mechanism is best understood for Lambert-Eaton myasthenic syndrome in which the tumor expresses a voltage-gated calcium channel protein on its surface. This protein is normally present at the neuromuscular junction and is important in calcium regulation. Autoantibodies are stimulated by the protein on the tumor, and these antibodies cross-react with the normal protein at the neuromuscular junction, disrupting neuromuscular transmission and causing skeletal muscle weakness.
The soft tissue and bony manifestations of clubbing and hypertrophic osteoarthropathy (see Chapter 3) are most commonly associated with adenocarcinoma of the lung and may relate to abnormal megakaryocyte fragmentation in the lung in patients with this complication. Nonspecific systemic effects
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of malignancy, such as anorexia, weight loss, and fatigue, are potential consequences of lung cancer, and it has been hypothesized that production of various mediators, such as tumor necrosis factor, may mediate these systemic effects.
Diagnostic approach
A wide variety of diagnostic methods are used in evaluating cases of known or suspected lung cancer. Many of the studies assessing the lung on a macroscopic level aim to demonstrate the presence, location, and probability of spread of bronchogenic carcinoma. Evaluation on a microscopic level is essential for defining the histologic type of lung cancer and analyzing its immunohistochemical and genetic signatures, which are important factors in determining which modalities of therapy are most appropriate. Functional assessment of the patient with lung cancer plays a role primarily in establishing the severity of underlying lung disease, particularly chronic obstructive lung disease resulting from prior heavy smoking. Knowledge of a patient’s functional limitation from lung disease is essential before the clinician can decide whether operative removal of a lung cancer is even feasible without precipitating disabling respiratory insufficiency.
Macroscopic evaluation
The initial test for detection and macroscopic evaluation of bronchogenic carcinoma is typically the posteroanterior and lateral chest radiograph. The presence of a nodule or mass within the lung on a chest radiograph always raises the question of lung cancer, especially when the patient has a significant smoking history. The location of the lesion may give an indirect clue about its histology: peripheral lesions are more likely to be adenocarcinoma or large-cell carcinoma, whereas central lesions are statistically more likely to be squamous cell carcinoma or small-cell carcinoma (Figs. 21.1 and 21.2). The chest radiograph is also useful for determining the presence of additional suspicious lesions, such as a second primary tumor or metastatic spread from the original carcinoma. Involvement of hilar or mediastinal nodes or the pleura (with resulting pleural effusion) may be detected on the chest radiograph, and such a finding will substantially affect the overall approach to therapy.
FIGURE 21.1 Chest radiograph shows small-cell carcinoma of lung manifesting as a left hilar mass.
FIGURE 21.2 A, Posteroanterior (PA) chest radiograph shows adenocarcinoma presenting as a left lower lobe mass. B, Lateral chest radiograph of the same patient shows the mass posterior to the cardiac silhouette (arrows).
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CT of the chest and upper abdomen is a standard part of the diagnostic evaluation of patients with lung cancer (Fig. 21.3). Besides helping to define the location, extent, and spread of tumor within the chest, this technique is particularly useful for the detection of enlarged, potentially malignant, lymph nodes within the mediastinum, which are often not seen with conventional radiography. However, even though CT effectively identifies enlarged mediastinal nodes, it cannot determine whether such nodes simply are hyperplastic or are enlarged because of tumor involvement. Consequently, histologic sampling of enlarged mediastinal nodes is still necessary to confirm tumor involvement of the nodes. CT is also crucial in evaluating the liver and adrenal glands because these are common sites of lung cancer metastasis.
FIGURE 21.3 Chest CT cross-sectional (axial) scan image of the same patient in
Fig. 21.2 demonstrating the appearance of the left lower lobe adenocarcinoma.
Positron emission tomography (PET) scanning (see Chapter 3) is often combined with CT scanning in staging evaluations of lung cancer. Because of their high metabolic activity, malignant lesions typically exhibit high uptake of the tracer 18F-fluorodeoxyglucose (FDG) (see Fig. 3.13). Focal uptake in the region of a parenchymal nodule or mass suggests that the lesion is malignant, and uptake in the mediastinum or at distant sites often reflects spread of the tumor to those sites. However, other metabolically active lesions, such as localized areas of infection, also may show FDG uptake. Thus, a positive PET scan in the appropriate clinical scenario is very suggestive but is not diagnostic of malignancy.
The best way to directly examine the airways of a patient with presumed or known bronchogenic carcinoma is by bronchoscopy with a flexible bronchoscope (see Chapter 3). The location and intrabronchial extent of many tumors can be directly observed, and samples can be obtained from the lesion, either for cytologic or histopathologic examination (Fig. 21.4). In addition, the bronchoscopist can assess whether an intrabronchial carcinoma is impinging significantly on the bronchial lumen and causing either partial or complete airway occlusion. Diagnostic specimens can be obtained in many cases even when the lesion is beyond direct visualization with the bronchoscope. Electromagnetic navigational bronchoscopy, particularly when combined with a robotic platform, is particularly useful in obtaining
specimens that are distal to the visual range of the bronchoscope.
FIGURE 21.4 Bronchoscopic appearance of a large, lobulated lung cancer
obstructing the left mainstem bronchus.
Staging of lung cancer
After a tumor has been documented, evaluation of the extent and spread of the malignancy is formally achieved by staging. Staging uses a TNM classification, which is based on (1) the primary intrathoracic tumor (T)—its size, location, and local complications, such as direct extension to adjacent structures or obstruction of the airway lumen; (2) the presence or absence of tumor within hilar and mediastinal lymph nodes (N); and (3) the distant spread of tumor (i.e., metastasis) beyond the thorax to other tissues or organ systems (M) (Table 21.1). Based on the pattern of T, N, and M characteristics of a particular tumor, a specific tumor stage (I-IV) is assigned (Table 21.2).
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TABLE 21.1
Overview of TNM Classification of Lung Cancera
T Component—Size of Primary Tumor
T1: ≤3 cm
T2: >3 cm but ≤5 cm
T3: >5 cm but ≤7 cm
T4: >7 cm
N Component—Regional Lymph Node Involvement
N0: no regional lymph node involvement
N1: ipsilateral peribronchial and/or hilar nodes
N2: ipsilateral mediastinal and/or subcarinal nodes
N3: contralateral hilar or mediastinal nodes; any scalene or supraclavicular nodes
M Component—Distant Metastasis
M0: no distant metastasis
M1: distant metastasis present
aThe complete classification system has subcategories as well as additional criteria relating to some of the above categories.
Adapted from J Thorac Oncol. 2016;11:39-51.
TABLE 21.2
Overview of Lung Cancer Stages and Prognosis Based on TNM Classificationa
Stage |
T Category |
N Category |
M Category |
5-Year Survival |
I |
T1 or T2 |
N0 |
M0 |
70%–90% |
|
|
|
|
|
II |
T1 or T2 |
N1 |
M0 |
50%–60% |
|
|
|
|
|
|
T3 |
N0 |
M0 |
|
|
|
|
|
|
IIIA |
T1 or T2 |
N2 |
M0 |
35% |
|
|
|
|
|
|
T3 |
N1 |
M0 |
|
|
|
|
|
|
|
T4 |
N0 or N1 |
M0 |
|
|
|
|
|
|
IIIB |
T1 or T2 |
N3 |
M0 |
25% |
|
|
|
|
|
|
T3 or T4 |
N2 |
M0 |
|
|
|
|
|
|
IIIC |
T3 or T4 |
N3 |
M0 |
15% |
|
|
|
|
|
IV |
Any T |
Any N |
M1 |
0%–10% |
|
|
|
|
|
aThe complete staging system also has substages.
Adapted from J Thorac Oncol. 2016;11:39-51.
Basis for formal TNM classification and staging of lung cancer includes the following:
1.Size, location, and local complications of the primary tumor (T)
2.Hilar and mediastinal lymph node involvement (N)
3.Distant metastasis (M)
The first component of staging is defining the characteristics of the primary tumor itself, and it is typically accomplished with a combination of chest imaging and bronchoscopy. The second component, based on involvement of mediastinal lymph nodes by tumor, is typically assessed initially by CT complemented by fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. The FDGPET scan can identify metabolically active tumor (>1 cm in size) in the mediastinum and elsewhere. Superimposing the image of FDG-PET uptake over the corresponding CT image allows precise anatomic localization of the uptake. Definitive evaluation of nodal enlargement and/or FDG uptake requires biopsy and histologic evaluation of the node(s), and this may be accomplished by endobronchial ultrasoundguided transbronchial needle aspiration via a flexible bronchoscope, or by surgical biopsy, either via mediastinoscopy or mediastinotomy. Performed as part of a flexible bronchoscopic procedure, transbronchial needle aspiration is an option for needle sampling of cellular material from lymph nodes adjacent to major airways. In suprasternal mediastinoscopy, the mediastinum is visualized with a scope placed through an incision made just above the sternal notch, and biopsy specimens can be obtained by this technique. In parasternal mediastinotomy, the mediastinum is examined through a small incision made adjacent to the sternum, and samples of suspicious nodes can be taken. Ultrasound-guided biopsy of
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certain mediastinal lymph nodes can be performed via an endoscope introduced into the esophagus rather than the tracheobronchial tree. When available, endobronchial ultrasound-guided transbronchial needle aspiration is preferred to surgical mediastinoscopy to obtain tissue samples because it is less invasive and does not always require general anesthesia.
The third component of staging involves determining whether the tumor has disseminated to distant sites. If available, a total body FDG-PET scan often will indicate sites of distant metastasis in the bones, liver, and adrenal glands. If an FDG-PET scan is not available, metastatic disease in bone can be well demonstrated with radioisotope bone scanning. CT is particularly suitable for detection of metastases to the liver, brain, and adrenal glands. Importantly, FDG-PET scanning is not very useful for assessing intracranial metastasis because brain tissue is so metabolically active at baseline that distinguishing between a metastasis and surrounding normal brain tissue is difficult. Instead, a CT scan or magnetic resonance imaging is best for detecting intracranial metastasis.
Although this formal staging system can be applied to all types of lung cancer, a more simplified system for classifying SCLC is commonly used for treatment purposes. Specifically, SCLC is categorized as limited stage or extensive stage disease. Limited stage disease is defined as tumor that is limited to an ipsilateral thorax and regional lymph nodes. In contrast, extensive stage disease represents spread outside this region.
Microscopic and molecular evaluation
An initial diagnosis of lung cancer can be determined from inspection of cytology specimens obtained from sputum, from washings or brushings obtained through a bronchoscope, or from material aspirated from the tumor with a small-gauge needle. However, full characterization of the tumor requires a larger biopsy specimen, which can be obtained by passing a biopsy forceps through a bronchoscope, by using a cutting needle passed through the chest wall directly into the tumor, or by directly sampling tissue at the time of a surgical procedure.
Over a number of years, there has been a paradigm shift in the evaluation and treatment of lung cancer. Previously, the primary distinction was between SCLC and NSCLC, which includes adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma. Distinguishing among the subtypes of NSCLC was less important because the principles of treatment were generally identical for all patients with NSCLC, that is, based on stage rather than the specific cell type. Although the distinction between SCLC and NSCLC remains critical, the recognition that specific mutations within a NSCLC tumor allow targeted therapy (discussed below) has made more complete molecular analysis of lung tumors an additional component of the diagnostic evaluation. Although histologic examination of a tumor is still performed and is of some value, further immunohistochemical and genetic analysis for specific abnormalities—including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations—is now standard practice in most centers.
In addition to genetic characterization, the tumor may be examined to determine if it is likely to respond to immunotherapy, anticancer medications that stimulate the patient’s immune system to attack the malignancy. Typically, this involves assessing the percentage of tumor cells that express programmed cell death ligand-1 (PD-L1); if greater than 50% of malignant cells express PD-L1, there is a high likelihood of response to a category of drugs called immune checkpoint inhibitors (ICI).
Functional assessment
Functional assessment of the patient with lung cancer provides important information to guide the clinician in the choice of treatment. As discussed in the section “Principles of Therapy,” surgery usually is the procedure of choice if staging has shown that the disease is limited and potentially curable