The segmental bronchial and vascular anatomy of the lungs allows subsegmental and segmental resections, if the clinical situation requires it or if lung tissue can be preserved10 (Fig. 19-7). Note the continuity of the pulmonary parenchyma between adjacent segments of each lobe.
Segmental anatomy of the lungs and bronchi.
Lymph nodes that drain the lungs are divided into two groups according to the tumor-node-metastasis (TNM) staging system for lung cancer: the pulmonary lymph nodes (N1) and the mediastinal nodes (N2) (Fig. 19-8).
The location of regional lymph node stations for lung cancer. (Reproduced with permission from Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest. 1997;111:1718.)
The N1 lymph nodes constitute the following: (a) intrapulmonary or segmental nodes that lie at points of division of segmental bronchi or in the bifurcations of the pulmonary artery; (b) lobar nodes that lie along the upper, middle, and lower lobe bronchi; (c) interlobar nodes located in the angles formed by the main bronchi bifurcating into the lobar bronchi; and (d) hilar nodes along the main bronchi. The interlobar lymph nodes lie in the depths of the interlobar fissure on each side and constitute a lymphatic sump for each lung, referred to as the lymphatic sump of Borrie; all of the pulmonary lobes of the corresponding lung drain into this group of nodes (Fig. 19-9). On the right, the nodes of the lymphatic sump lie around the bronchus intermedius (bounded above by the right upper lobe bronchus and below by the middle lobe and superior segmental bronchi). On the left, the lymphatic sump is confined to the interlobar fissure, with the lymph nodes in the angle between the lingular and lower lobe bronchi and in apposition to the pulmonary artery branches.
The lymphatic sump of Borrie includes the groups of lymph nodes that receive lymphatic drainage from all pulmonary lobes of the corresponding lung.
The N2 lymph nodes consist of four main groups. (a) The anterior mediastinal nodes are located in association with the upper surface of the pericardium, the phrenic nerves, the ligamentum arteriosum, and the left innominate vein. (b) The posterior mediastinal group includes paraesophageal lymph nodes within the inferior pulmonary ligament and, more superiorly, between the esophagus and trachea near the arch of the azygos vein. (c) The tracheobronchial lymph nodes are made up of three subgroups that are located near the bifurcation of the trachea. These include the subcarinal nodes, which lie in the obtuse angle between the trachea and each main stem bronchus, and the nodes that lay anterior to the lower end of the trachea. (d) Paratracheal lymph nodes are located in proximity to the trachea in the superior mediastinum. Those on the right side form a chain with the tracheobronchial nodes inferiorly and with some of the deep cervical nodes above (scalene lymph nodes).
Lymphatic drainage to the mediastinal lymph nodes from the right lung is ipsilateral, except for occasional bilateral drainage to the superior mediastinum. In contrast, in the left lung, particularly the left lower lobe, lymphatic drainage occurs with equal frequency to ipsilateral and contralateral superior mediastinal nodes.
The lung can be conveniently viewed as two linked components: the tracheobronchial tree (or conducting airways component) and the alveolar spaces (or gas exchange component). The tracheobronchial tree consists of approximately 23 airway divisions to the level of the alveoli. It includes the main bronchi, lobar bronchi, segmental bronchi (to designated bronchopulmonary segments), and terminal bronchioles (i.e., the smallest airways still lined by bronchial epithelium and without alveoli). The tracheobronchial tree is normally lined by pseudostratified ciliated columnar cells and mucous (or goblet) cells, which both derive from basal cells (Fig. 19-10). Ciliated cells predominate. Goblet cells, which release mucus, can significantly increase in number in acute bronchial injury, such as exposure to cigarette smoke. The normal bronchial epithelium also contains bronchial submucosal glands, which are mixed salivary-type glands containing mucous cells, serous cells, and neuroendocrine cells called Kulchitsky cells, which are also found within the surface epithelium. The bronchial submucosal glands can give rise to salivary gland–type tumors, including mucoepidermoid carcinomas and adenoid cystic carcinomas.
Normal lung histology. A. Pseudostratified ciliated columnar cells and mucous cells normally line the tracheobronchial tree. B. A Kulchitsky cell is depicted (arrow).
Two cell types, called type I and type II pneumocytes, make up the alveolar epithelium. Type I pneumocytes comprise 40% of the total number of alveolar epithelial cells, but cover 95% of the surface area of the alveolar wall. These cells are not capable of regeneration because they have no mitotic potential. Type II pneumocytes cover only 3% of the alveolar surface, but comprise 60% of the alveolar epithelial cells. In addition, clusters of neuroendocrine cells are seen in the alveolar spaces.
The term “precancerous” does not mean that an inevitable progression to invasive carcinoma will occur, but such lesions, particularly those with high-grade dysplasia,11,12 do constitute a clear marker for potential development of invasive cancer. Three precancerous lesions of the respiratory tract are currently recognized.
Squamous dysplasia and carcinoma in situ. Cigarette smoke can induce a transformation of the tracheobronchial pseudostratified epithelium to metaplastic squamous mucosa, with subsequent evolution to dysplasia as cellular abnormalities accumulate. Dysplastic changes include altered cellular polarity and increased cell size, number of cell layers, nuclear-to-cytoplasmic ratio, and number of mitoses. Gradations are considered mild, moderate, or severe. Carcinoma in situ represents carcinoma still confined by the basement membrane.
Atypical adenomatous hyperplasia (AAH). AAH is a lesion smaller than 5.0 mm, comprising epithelial cells lining the alveoli that are similar to type II pneumocytes. Histologically, AAH is similar to adenocarcinoma in situ; it represents the beginning stage of a stepwise evolution to adenocarcinoma in situ and then to adenocarcinoma. With the availability of thin-section CT, it is possible to detect preinvasive adenocarcinoma lesions as early as AAH. These lesions can be multiple, are typically small (5 mm or less), and have a ground-glass appearance.
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. This rare lesion represents a diffuse proliferation of neuroendocrine cells, but without invasion of the basement membrane. It can exist as a diffuse increase in the number of single neuroendocrine cells, or as small lesions less than 5.0 mm in diameter. Lesions over 5.0 mm in size or that breach the basement membrane are carcinoid tumors.
Invasive or Malignant Lesions
The pathologic diagnosis of lung cancer is currently based on light microscopic criteria and is broadly divided into two main groups: non–small cell lung carcinoma and neuroendocrine tumors.13 Immunohistochemical staining and electron microscopy are used as adjuncts in diagnosis, particularly in the assessment of potential neuroendocrine tumors.
Non–Small Cell Lung Carcinoma
The term non–small cell lung carcinoma (NSCLC) includes many tumor cell types, including large cell, squamous cell, and adenocarcinoma. Historically, these subtypes were considered to be a uniform group based on limited understanding of the distinct clinical behaviors of the subtypes as well as the fact that there were few treatment options available. With increasing understanding of the molecular biology underlying these tumor subtypes, however, the approach to diagnosis and management and the terminology used in describing these tumors are evolving rapidly.
The incidence of adenocarcinoma has increased over the last several decades, and it is now the most common lung cancer, accounting for 30% of lung cancers in male smokers and 40% of lung cancers in female smokers. Adenocarcinoma is the histologic subtype for 80% and 60% of lung cancers in nonsmoking females and males, respectively. It occurs more frequently in females than in males. It is the most frequent histologic subtype in women, patients who are under 45 years of age, and Asian populations.14
Histologic Subtyping of Adenocarcinoma
Increasing understanding of lung adenocarcinoma, such as important clinical, radiologic, pathologic, and genetic differences between mucinous and nonmucinous adenocarcinomas, prompted multiple changes in the classification system in 2011.15 Based on consensus, the international working group proposed a multidisciplinary approach, with standardized criteria and terminology for diagnosis in cytologic and small biopsy specimens, and routine molecular testing for known mutations, such as EGFR and KRAS mutations (Table 19-1). The new classification system delineated a stepwise pathlogic progression, from AAH to invasive adenocarcinoma based on the predominant histologic growth patterns; the terms bronchioloalveolar carcinoma and mixed subtype adenocarcinoma were eliminated in favor of more biologically driven classification (Table 19-2).
Table 19-1Difference between invasive mucinous adenocarcinoma and nonmucinous adenocarcinoma in situ/minimally invasive adenocarcinoma/lepidic predominant adenocarcinoma ||Download (.pdf) Table 19-1 Difference between invasive mucinous adenocarcinoma and nonmucinous adenocarcinoma in situ/minimally invasive adenocarcinoma/lepidic predominant adenocarcinoma
| ||INVASIVE MUCINOUS ADENOCARCINOMA (FORMERLY MUCINOUS BAC) ||NONMUCINOUS AIS/MIA/LPA (FORMERLY NONMUCINOUS BAC) |
|Female ||49/84 (58%)52,120,121,123 ||101/140 (72%)52,120,121,123 |
|Smoker ||39/87 (45%)52,120,121,123,124 ||75/164 (46%)52,120,121,122,124 |
|Radiographic appearance ||Majority consolidation; air bronchogram125 ||Majority ground-glass attenuation23,56,58,103,129,130,131,132,133,134 |
| ||Frequent multifocal and multilobar presentation56,125,126,127,128 || |
|Cell type ||Mucin-filled, columnar, and/or goblet50,51,52,125,135 ||Type II pneumocyte and/or Clara cell50,51,52,125,135 |
|Phenotype || || |
| CK7 ||Mostly positive (~88%)a54,55,136,137,138,139 ||Positive (~98%)a54,55,136,137,138,139 |
| CK20 ||Positive (~54%)a54,55,136,137,138,139 ||Negative (~5%)a54,55,136,137,138,139 |
| TTF-1 ||Mostly negative (~17%)1 a54,55,120,137,138,139 ||Positive (~67%)a54,55,120,137,138,139 |
|Genotype || || |
| KRAS mutation ||Frequent (~76%)a55,94,121,127,140,141,142,143,144 ||Some (~13%)a55,121,127,140,141,142,143,144 |
| EGFR mutation ||Almost none (~3)a55,121,127,140,141,142 ||Frequent (~45%)a55,121,127,140,141,142 |
Table 19-2New classification system for lung adenocarcinoma ||Download (.pdf) Table 19-2 New classification system for lung adenocarcinoma
Atypical adenomatous hyperplasia
Adenocarcinoma in situ (≤3 cm formerly BAC)
Minimally invasive adenocarcinoma (≤3 cm lepidic predominant tumor with ≤5 mm invasion)
Lepidic predominant (formerly nonmucinous BAC pattern, with >5 mm invasion)
Solid predominant with mucin production
Variants of invasive adenocarcinoma
Invasive mucinous adenocarcinoma (formerly mucinous BAC)
Fetal (low and high grade)
Adenocarcinoma in situ (AIS). AISs are small (≤3 cm) solitary adenocarcinomas that have pure lepidic growth; lepidic growth is characterized by tumor growth within the alveolar spaces. These lesions are not invasive into the stroma, vascular system, or pleura and do not have papillary or micropapillary patterns or intra-alveolar tumor cells. They are very rarely mucinous, consisting of type II pneumocytes or Clara cells. These patients are expected to have 100% disease-specific survival with complete surgical resection. On CT scan, AIS can appear as a pure ground-glass neoplasm, but occasionally will present as part of a solid or part-solid nodule. Mucinous AIS is more likely to appear solid or to have the appearance of consolidation. As with AAH, the lesions can be single or multiple; the ground-glass changes in AIS, however, tend to have a higher attenuation compared to AAH.
Minimally invasive adenocarcinoma (MIA). In the same size solitary lesion, if less than 5 mm of invasion are noted within a predominantly lepidic growth pattern, the lesion is termed minimally invasive adenocarcinoma (MIA) to indicate a patient group with near 100% survival when the lesion is completely resected. This differentiates patients with AIS, but recognizes the fact that the presence of invasion becomes prognostically significant when the size of the invasive component reaches 5 mm or greater in size.16 If multiple areas of microscopic invasion are found within the lepidic growth, the size of the largest invasive area, measured in the largest dimension, is used; this area must be ≤5 mm to be considered MIA. As with AIS, MIA is very rarely mucinous. The invasive component histologically is acinar, papillary, micropapillary, and/or solid and shows tumor cells infiltrating into the surrounding myofibroblastic stroma. On CT scan, the appearance of MIA is often a part-solid nodule (≤5 mm) with a predominant ground-glass component, but can be highly variable.
Lepidic predominant adenocarcinoma (LPA). If lymphovascular invasion, pleural invasion, tumor necrosis, or more than 5 mm of invasion are noted in a lesion that has lepidic growth as its predominant component, MIA is excluded and the lesion is called lepidic predominant adenocarcinoma (LPA), and the size of the invasive component is recorded for the T stage.
Invasive adenocarcinoma. The new classification system now recommends classifying invasive adenocarcinoma by the most predominant subtype after histologic evaluation of the resection specimen. To determine the predominant subtype, histologic sections are evaluated and the patterns are determined, in 5% increments, throughout the specimen. This semiquantitative method encourages the viewer to identify and quantify all patterns present, rather than focusing on a single pattern. In the pathology report, the tumor is classified by the predominant pattern, with percentages of the subtypes also reported (Fig. 19-11).Subtypes include:
Adenocarcinoma is often peripherally located and frequently discovered incidentally on routine chest radiographs, unlike squamous cell cancers. When symptoms occur, they are due to pleural or chest wall invasion (pleuritic or chest wall pain) or pleural seeding with malignant pleural effusion. Invasive adenocarcinoma is usually solid by CT scan, but can also be part-solid and even a ground-glass nodule. Occasionally, a lobar ground-glass opacification may be present, which is often associated with significant respiratory compromise and can be mistaken for lobar pneumonia. Bubble-like or cystic lucencies on CT scan in small (≤2 cm) adenocarcinomas or extensive associated ground-glass components correlate with slow growth and well-differentiated tumors and a more favorable prognosis. Intratumoral air bronchograms are usually indicative of well-differentiated tumor, whereas spiculations that are coarse and thick (≥2 mm) portend vascular invasion and nodal metastasis and are associated with decreased survival following complete surgical resection. Pleural retraction is also a poor prognostic indicator.
Additional histologic variants include colloid adenocarcinoma (formerly mucinous cystadenocarcinoma), fetal adenocarcinoma, and enteric adenocarcinoma. Clear cell and signet ring cell types are no longer considered to be distinct subtypes as they are found in association with most of the five dominant histologic patterns (lepidic, acinar, papillary, micropapillary, and solid). However, they are still notable, as they can signal clinically relevant molecular changes, such as the presence of the EML4-ALK fusion gene in solid tumors with signet ring features.
Major histologic patterns of invasive adenocarcinoma. A. Lepidic predominant pattern with mostly lepidic growth (right) and a smaller area of invasive acinar adenocarcinoma (left). B. Lepidic pattern consists of a proliferation type II pneumocytes and Clara cells along the surface alveolar walls. C. Area of invasive acinar adenocarcinoma (same tumor as in A and B). D. Acinar adenocarcinoma consists of round to oval-shaped malignant glands invading a fibrous stroma. E. Papillary adenocarcinoma consists of malignant cuboidal to columnar tumor cells growing on the surface of fibrovascular cores. F. Micropapillary adenocarcinoma consists of small papillary clusters of glandular cells growing within this airspace, most of which do not show fibrovascular cores. G. Solid adenocarcinoma with mucin consisting of sheets of tumor cells with abundant cytoplasm and mostly vesicular nuclei with several conspicuous nucleoli. No acinar, papillary, or lepidic patterns are seen, but multiple cells have intracytoplasmic basophilic globules that suggest intracytoplasmic mucin. H. Solid adenocarcinoma with mucin. Numerous intracytoplasmic droplets of mucin are highlighted with this diastase-periodic acid Schiff stain. (Reproduced with permission from Travis W, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: International multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244.)
Representing 30% to 40% of lung cancers, squamous cell carcinoma is the most frequent cancer in men and highly correlated with cigarette smoking. They arise primarily in the main, lobar, or first segmental bronchi, which are collectively referred to as the central airways. Symptoms of airway irritation or obstruction are common, and include cough, hemoptysis, wheezing (due to high-grade airway obstruction), dyspnea (due to bronchial obstruction with or without postobstructive atelectasis), and pneumonia (caused by airway obstruction with secretion retention and atelectasis).
Occasionally a more peripherally based squamous cell carcinoma will develop in a tuberculosis scar or in the wall of a bronchiectatic cavity. Histologically, cells develop a pattern of clusters with intracellular bridges and keratin pearls. Central necrosis is frequent and may lead to the radiographic findings of a cavity (possibly with an air-fluid level). Such cavities may become infected, with resultant abscess formation.
Large cell carcinoma accounts for 10% to 20% of lung cancers and may be located centrally or peripherally. These tumors have cell diameters of 30 to 50 μm, which are often admixed with various other malignant cell types. Large cell carcinoma can be confused with a large cell variant of neuroendocrine carcinoma, but can be differentiated by special immunohistochemical stains.
Salivary Gland–Type Neoplasms
Salivary-type submucosal bronchial glands throughout the tracheobronchial tree can give rise to tumors that are histologically identical to those seen in the salivary glands. The two most common are adenoid cystic carcinoma and mucoepidermoid carcinoma. Both tumors occur centrally due to their site of origin. Adenoid cystic carcinoma is a slow-growing tumor that is locally and systemically invasive, growing submucosally and infiltrating along perineural sheaths. Mucoepidermoid carcinoma consists of squamous and mucous cells and is graded as low or high grade, depending on the mitotic rate and degree of necrosis.
Neuroendocrine lung tumors are classified into neuroendocrine hyperplasia and three separate grades of neuroendocrine carcinoma (NEC). Immunohistochemical staining for neuroendocrine markers (including chromogranins, synaptophysin, CD57, and neuron-specific enolase) is essential to accurately diagnose most tumors.17
Grade I NEC (classic or typical carcinoid) is a low-grade NEC; 80% arise in the epithelium of the central airways. It occurs primarily in younger patients. Because of the central location, it classically presents with hemoptysis, with or without airway obstruction and pneumonia. Histologically, tumor cells are arranged in cords and clusters with a rich vascular stroma. This vascularity can lead to life-threatening hemorrhage with even simple bronchoscopic biopsy maneuvers. Regional lymph node metastases are seen in 15% of patients, but rarely spread systemically or cause death.
Grade II NECs (atypical carcinoid) have a much higher malignant potential and, unlike grade I NEC, are etiologically linked to cigarette smoking and are more likely to be peripherally located. Histologic findings may include areas of necrosis, nuclear pleomorphism, and higher mitotic rates. Lymph node metastases are found in 30% to 50% of patients. At diagnosis, 25% of patients already have remote metastases.
Grade III NEC large cell–type tumors occur primarily in heavy smokers and in the mid to peripheral lung fields. They are often large with central necrosis and a high mitotic rate. Their neuroendocrine nature is revealed by positive immunohistochemical staining for at least one neuroendocrine marker.
Grade IV NEC (small cell lung carcinoma [SCLC]) is the most malignant NEC and accounts for 25% of all lung cancers; these NECs often have early, widespread metastases. These cancers also arise primarily in the central airways. As with squamous cell cancers, symptoms include cough, hemoptysis, wheezing (due to high-grade airway obstruction), dyspnea (due to bronchial obstruction with or without postobstructive atelectasis), and pneumonia (caused by airway obstruction with secretion retention and atelectasis). Evaluation includes expert pathology review and comprehensive evaluation for metastatic disease. Three groups of grade IV NEC are recognized: pure small cell carcinoma (sometimes referred to as oat cell carcinoma), small cell carcinoma with a large cell component, and combined (mixed) tumors.
Grade IV NECs consist of smaller cells (diameter 10 to 20 μm) with little cytoplasm and very dark nuclei; they can be difficult to distinguish from lymphoproliferative lesions and atypical carcinoid tumors. Histologically, a high mitotic rate with easily visualized multiple mitoses and areas of extensive necrosis are characteristic. Importantly, very small bronchoscopic biopsies can distinguish NSCLC from SCLC, but crush artifact may make NSCLC appear similar to SCLC. If uncertainty exists, special immunohistochemical stains or rebiopsy (or both) will be necessary. These tumors are the leading producer of paraneoplastic syndromes.
Lung cancer is the leading cancer killer and second most frequently diagnosed cancer in the United States, accounting for nearly 28% of all cancer deaths—more than cancers of the breast, prostate, ovary, and colon and rectum combined (Fig. 19-12). In 2008, it was estimated that 1 in 13 men and 1 in 16 women would develop lung cancer in their lifetime. The overall 5-year survival for all patients with lung cancer is 16%, making lung cancer the most lethal of the leading four cancers (Fig. 19-13A, B) It is encouraging, however, that the average annual death rate declined by 2.8% per year for men and 1.1% per year for women from 2005 to 2009.18 Unfortunately, most patients are still diagnosed at an advanced stage of disease, so therapy is rarely curative.
Leading new cancer cases and deaths: 2012 estimates. *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. (Modified with permission from John Wiley and Sons: Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2012;62:10. © 2012 American Cancer Society, Inc.)
Age-adjusted cancer death rates. A. Males by site, United States, 1930 to 2008. B. Females by site, United States, 1930 to 2008. *Per 100,000, age adjusted to the 2000 U.S. standard population. (Modified with permission from John Wiley and Sons: Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2012;62:10. © 2012 American Cancer Society, Inc.)
Prognostic markers for lung cancer survival include female sex (5-year survival of 18.3% for women vs. 13.8% for men), younger age (5-year survival of 22.8% for those <45 years vs. 13.7% for those >65 years), and white race (5-year survival of 16.1% for whites vs. 12.2% for blacks). When access to advanced medical care is unrestricted, as for the military population, the racial difference in survival disappears, suggesting that, at least in part, differences in survival may be explained by less access to advanced medical care and later diagnosis.19
Risk Factors for Lung Cancer
Cigarette smoking was implicated as a causal factor in approximately 75% of all lung cancers worldwide in 2007. According to the U.S. Surgeon General’s report in 2004, 90% of lung cancers in men and nearly 80% in women can be attributed to cigarette smoking or secondhand cigarette smoke exposure. Two lung cancer types—squamous cell and small cell carcinoma—are extraordinarily rare in the absence of cigarette smoking. The risk of developing lung cancer escalates with the number of cigarettes smoked, the number of years of smoking, and the use of unfiltered cigarettes. Conversely, the risk of lung cancer declines with smoking cessation, but never drops to that of never smokers, regardless of the length of abstinence (Table 19-3).20 Radon exposure accounts for the vast majority of the remaining cancers. Approximately 25% of all lung cancers worldwide and 53% of cancers in women are not related to smoking, and most of them (62%) are adenocarcinomas. Table 19-4 summarizes the existing data regarding the etiology of lung cancer in nonsmokers.21
Table 19-3Relative risk of lung cancer in smokers ||Download (.pdf) Table 19-3 Relative risk of lung cancer in smokers
|SMOKING CATEGORY ||RELATIVE RISK |
|Never smoked ||1.0 |
|Currently smoke ||15.8–16.3 |
|Formerly smoked || |
| Years of abstinence || |
| 1–9 ||5.9–19.5 |
| 10–19 ||2.0–6.1 |
| >20 ||1.9–3.7 |
Table 19-4Summary of selected studies of risk factors for lung cancer in individuals who never smoked ||Download (.pdf) Table 19-4 Summary of selected studies of risk factors for lung cancer in individuals who never smoked
|RISK FACTOR ||RISK ESTIMATE (95% CI) ||COMMENTS ||REFERENCE |
|Environmental tobacco smoke || |
1.19 (90% CI: 1.04–1.35)
Meta-analysis of 11 U.S. studies of spousal exposure (females only)
Meta-analysis of 44 case-control studies worldwide of spousal exposure
Meta-analysis of 25 studies worldwide of workplace exposure
Meta-analysis of 22 studies worldwide of workplace exposure
|Residential radon || |
8.4% (3.0%–15.8%) per 100 Bq m3 increase in measured radon
11% (0%–28%) per 100 Bq m3
Meta-analysis of 13 European studies
Meta-analysis of 7 North American studies
|Cooking oil vapors ||2.12 (1.81–2.47) ||Meta-analysis of 7 studies from China and Taiwan (females who never smoked) ||230 |
|Indoor coal and wood burning || |
Meta-analysis of 7 studies from China and Taiwan (both sexes)
Large case-control study (2861 cases and 3118 controls) from Eastern and Central Europe (both sexes)
Large case-control study (1205 cases and 1541 controls) from Canada (significant for women only)
|Genetic factors: family history, CYP1A1 Ile462Val polymorphism, XRCC1 variants || |
No association overall; reduced risk 0.65 (0.46–0.83) with Arg194Trp polymorphism and 0.56 (0.36–0.86) with Arg280His for heavy smokers
Increased risk for never smokers 1.3 (1.0–1.8) and decreased risk for heavy smokers 0.5 (0.3–1.0) with Arg299Gln
Meta-analysis of 28 case-control, 17 cohort, and 7 twin studies
Meta-analysis of 14 case-control studies of Caucasian never smokers
Meta-analysis of 21 case-control studies of Caucasian and Asian never smokers (significant for Caucasians only)
Meta-analysis of 13 case-control studies
Large case-control study from Europe (2188 cases and 2198 controls)
Large case-control study from the United States (1091 cases and 1240 controls)
|Viral factors: HPV 16 and 18 ||10.12 (3.88–26.4) for never smoking women >60 y ||Case-control study (141 cases, 60 controls) from Taiwan of never smoking women ||239 |
Nearly 3500 deaths from lung cancer each year are attributable to secondhand (environmental) smoke exposure, which confers an excess risk for lung cancer of 24% when a nonsmoker lives with a smoker.22 Risk is conferred by exposure to any burning tobacco, including cigars. The amount of secondhand exposure from one large cigar is equivalent to the exposure from 21 cigarettes. As with active smoking, risk of developing lung cancer increases with longer duration and higher level of exposure to environmental tobacco.
Over 7000 chemicals have been identified in tobacco smoke, and more than 70 of the compounds are known to be carcinogens. The main chemical carcinogens are polycyclic aromatic hydrocarbons, which are actively or passively inhaled in the tobacco smoke and absorbed; these compounds are activated by specific enzymes and become mutagenic, bind to macromolecules such as deoxyribonucleic acid (DNA), and induce genetic mutations. In treating any patient with a previous smoking history, it is important to remember that there has been field cancerization of the entire aerodigestive tract. The patient’s risk is increased for cancers of the oral cavity, pharynx, larynx, tracheobronchial tree and lung, and esophagus. In examining such patients, a detailed history and physical examination of these organ systems must be performed.
Other causes of lung cancer include exposure to a number of industrial compounds, including asbestos, arsenic, and chromium compounds. In fact, the combination of asbestos and cigarette smoke exposure has a multiplicative effect on risk. Pre-existing lung disease confers an increased risk of lung cancer—up to 13%—for individuals who have never smoked. Patients with chronic obstructive pulmonary disease are at higher risk for lung cancer than would be predicted based on smoking risk alone. Patients with secondary scar formation related to a history of tuberculosis also have a higher risk of primary lung carcinoma. This increase is thought to be related to poor clearance of inhaled carcinogens and/or to the effects of chronic inflammation.
Screening for Lung Cancer in High-Risk Populations
In 2002, the National Lung Screening Trial (NLST) was launched to determine whether screening with CT in high-risk populations would reduce mortality from lung cancer. The study randomized 53,353 eligible patients age 55 to 74 years to either three annual low-dose helical CT scans (LDCT; aka spiral CT) or posteroanterior view chest radiograph. Patients were eligible for the trial if they had a greater than 30 pack-year history of cigarette smoking; had smoked within the past 15 years if a former smoker; had no prior history of lung cancer; had no history of other life-threatening cancers in the prior 5 years; did not have symptoms suggestive of an undiagnosed lung cancer (such as hemoptysis or weight loss); and had not had a chest CT scan in the prior 18 months. Accrual to the study was excellent, and the primary endpoint of a 20% relative reduction in mortality was achieved in 2010. An absolute risk reduction of lung cancer death of four per 1000 individuals screened by LDCT was realized. Interestingly, all-cause mortality was also reduced by nearly 7% in the LDCT group, further emphasizing the impact of lung cancer on the mortality of smokers and former smokers.23 An estimated 320 individuals need to be screened to save one life from lung cancer. Additional considerations require further evaluation before widespread LDCT screening will become reality. First, there was a 7% false-positive rate in this trial. False-positive scans lead to patient anxiety, invasive testing, and potentially morbid procedures to further evaluate the finding. The impact of these issues on patient quality of life and cost-effectiveness has yet to be elucidated. It is also critical that regulatory guidelines for patient eligibility, frequency of screening, interpretation of the scans, processes for further evaluation and management of positive findings, and dose of radiation are well established and well accepted to ensure the generalizability of the results for patients who will be screened in the general medical community rather than in the specialized centers that performed the trial.
Solitary Pulmonary Nodule
A solitary pulmonary nodule is typically described as a single, well-circumscribed, spherical lesion that is 3 cm or less in diameter and completely surrounded by normal aerated lung parenchyma.24 Lung atelectasis, hilar enlargement, and pleural effusion are absent. The majority are detected incidentally on chest radiographs (CXRs) or CT scans obtained for some other purpose. About 150,000 solitary nodules are found incidentally each year. The clinical significance of such a lesion depends on whether or not it represents a malignancy.
The differential diagnosis of a solitary pulmonary nodule should include a broad variety of congenital, neoplastic, inflammatory, vascular, and traumatic disorders. The probability of cancer in a solitary pulmonary nodule increases if the patient has a history of smoking (50% or higher for smokers compared to 20%–40% in never smokers). It is also more likely to be malignant if it is symptomatic or the patient is older, male, or has had occupational exposures.
Solitary pulmonary nodules were defined by findings on CXR, but with the increased sensitivity of low-dose screening CT, up to 50% of solitary lesions are found to be associated with multiple (one to six) other, usually subcentimeter, nodules. In the Early Lung Cancer Action project, almost 7% of healthy volunteers were found to have between one and three nodules and 25% had up to six nodules. CT scanning is necessary to characterize nodule number, location, size, margin morphology, calcification pattern, and growth rate.25 Spiral (helical) CT allows continuous scanning as the patient is moved through a scanning gantry, allowing the entire thorax to be imaged during a single breath hold (Fig. 19-14). Compared to conventional CT, this provides a superior image quality, because motion artifacts are eliminated, and improves detection of pulmonary nodules and central airway abnormalities.26 The shorter acquisition time of spiral CT also allows for consistent contrast filling of the great vessels, resulting in markedly improved visualization of pathologic states and anatomic variation contiguous to vascular structures. In addition, three-dimensional spiral CT images can be reconstructed for enhanced visualization of spatial anatomic relationships.27 Thin sections (1–2 mm collimation) at 1-cm intervals should be used to evaluate pulmonary parenchyma and peripheral bronchi. If the goal is to find any pulmonary metastases, thin sections at intervals of 5 to 7 mm collimation are recommended. For assessing the trachea and central bronchi, collimation of 3 to 5 mm is recommended. Providing accurate clinical history and data is of paramount importance to obtaining appropriate imaging.
Spiral computed tomography scan showing normal transverse chest anatomy at four levels. A. At the level of the tracheal bifurcation, the aorticopulmonary window can be seen. B. The origin of the left pulmonary artery can be seen at a level 1 cm inferior to A. C. The origin and course of the right pulmonary artery can be seen at this next most cephalad level. The left upper lobe bronchus can be seen at its origin from the left main bronchus. D. Cardiac chambers and pulmonary veins are seen in the lower thorax. AA = ascending aorta; APW = aorticopulmonary window; DA = descending aorta; LA = left ventricle; LMB = left main bronchus; LPA = left pulmonary artery; MPA = main pulmonary artery; RA = right atrium; RPA = right pulmonary artery; RV = right ventricle; SVC = superior vena cava; T = trachea.
CT findings characteristic of benign lesions include small size, calcification within the nodule, and stability over time. Four patterns of benign calcification are common: diffuse, solid, central, and laminated or “popcorn.” Granulomatous infections such as tuberculosis can demonstrate the first three patterns, whereas the popcorn pattern is most common in hamartomas. In areas of endemic granulomatous disease, differentiating benign versus malignant can be challenging. Infectious granulomas arising from a variety of organisms account for 70% to 80% of this type of benign solitary nodules; hamartomas are the next most common single cause, accounting for about 10%.
CT findings characteristic of malignancy include growth over time; increasing density on CT scan (40%–50% of partial solid lesions are malignant compared to only 15% of subcentimeter solid or nonsolid nodules); size >3 cm; irregular, lobulated, or spiculated edges; and the finding of the corona radiata sign (consisting of fine linear strands extending 4–5 mm outward and appearing spiculated on radiographs) (Fig. 19-15). Calcification that is stippled, amorphous, or eccentric is usually associated with cancer.
Computed tomography scan images of solitary pulmonary nodules. A. The corona radiata sign demonstrated by a solitary nodule. Multiple fine striations extend perpendicularly from the surface of the nodule like the spokes of a wheel. B. A biopsy-proven adenocarcinoma demonstrating spiculation. C. A lesion with a scalloped border, an indeterminate finding suggesting an intermediate probability for malignancy.
Growth over time is an important characteristic for differentiating benign and malignant lesions. Lung cancers have volume-doubling times from 20 to 400 days; lesions with shorter doubling times are likely due to infection, and longer doubling times suggest benign tumors, but can represent slower-growing lung cancer. Positron emission tomography (PET) scanning can differentiate benign from malignant nodules28; most lung tumors have increased signatures of glucose uptake, as compared with healthy tissues and, thus, glucose metabolism can be measured using radio-labeled 18F-fluorodeoxyglucose (FDG). Meta-analysis estimates 97% sensitivity and 78% specificity for predicting malignancy in a nodule. False-negative results can occur (especially in patients who have AIS, MIA, or LPA, carcinoids, and tumors <1 cm in diameter), as well as false-positive results (because of confusion with other infectious or inflammatory processes).
Metastatic Lesions to the Lung
The cause of a new pulmonary nodule(s) in a patient with a previous malignancy can be difficult to discern.29 Features suggestive of metastatic disease are multiplicity; smooth, round borders on CT scan; and temporal proximity to the original primary lesion. One must always entertain the possibility that a single new lesion is a primary lung cancer. The probability of a new primary cancer vs. metastasis in patients presenting with solitary lesions depends on the type of initial neoplasm. The highest likelihood of a new primary lung cancer is in patients with a history of uterine (74%), bladder (89%), lung (92%), and head and neck (94%) carcinomas.
Surgical resection of pulmonary metastases has a role in properly selected patients.30 The best data regarding outcomes of resection of pulmonary metastases come from the International Registry of Lung Metastases (IRLM). The registry was established in 1991 by 18 thoracic surgery departments in Europe, the United States, and Canada, and included data on 5206 patients. About 88% of patients underwent complete resection. Survival analysis at 5, 10, and 15 years (grouping all primary tumor types) was performed (Table 19-5). Multivariate analysis showed a better prognosis for patients with germ cell tumors, osteosarcomas, a disease-free interval over 36 months, and a single metastasis.31 Depicted in Fig. 19-16, survival after metastasectomy in a variety of cancers is optimal when metastatic disease is resectable, solitary, and identified 36 or more months after initial treatment. When any or all of these optimal characteristics are absent, survival progressively declines.
The actuarial survival after metastasectomy is depicted for patients with various tumor types further categorized into four groups according to resectability, solitary or multiple, the interval between primary resection and metastesectomy, and a combination of factors known in our work and in others, as follows: (1) resectable, solitary, and disease-free interval (DFI) greater than or equal to 36 months; (2) resectable, solitary, or DFI 36+ months; (3) resectable, multiple metastases, and DFI <36 months; and (4) unresectable. (Reprinted with permission from Pastorino, U. (2010). The Development of an International Registry. J Thorac Oncol. 5(6): S196-S197)
Table 19-5Actuarial survival data from the International Registry of Lung Metastases ||Download (.pdf) Table 19-5 Actuarial survival data from the International Registry of Lung Metastases
|SURVIVAL ||COMPLETE RESECTION (%) ||INCOMPLETE RESECTION (%) |
|5 years ||36 ||13 |
|10 years ||26 ||7 |
|15 years ||22 ||— |
The general principles of patient selection for metastasectomy are listed in Table 19-6. The technical aim of pulmonary metastasectomy is complete resection of all macroscopic tumors. In addition, any involved adjacent structures should be resected en bloc (i.e., chest wall, diaphragm, and pericardium). Multiple lesions and/or hilar lesions may require lobectomy. Pneumonectomy is rarely justified or employed.
Table 19-6General principles governing appropriate selection of patients for pulmonary metastasectomy ||Download (.pdf) Table 19-6 General principles governing appropriate selection of patients for pulmonary metastasectomy
1. Primary tumor must already be controlled.
2. Patient must be able to tolerate general anesthesia, potential single-lung ventilation, and the planned pulmonary resection.
3. Metastases must be completely resectable based on computed tomographic imaging.
4. There is no evidence of extrapulmonary tumor burden.
5. Alternative superior therapy must not be available.
Pulmonary metastasectomy can be approached through a thoracotomy or via video-assisted thoracic surgery (VATS) techniques. McCormack and colleagues reported their experience at Memorial Sloan-Kettering in a prospective study of 18 patients who presented with no more than two pulmonary metastatic lesions and underwent VATS resection.32 A thoracotomy was performed during the same operation; if palpation identified any additional lesions, they were resected. The study concluded that the probability that a metastatic lesion will be missed by VATS excision is 56%. Patients in the Memorial study were evaluated before the advent of spiral CT scanning, however, and it remains controversial whether metastasis resection should be performed via VATS. Proponents of VATS argue that the resolution of spiral CT scanning is so superior that prior studies using standard CT scanners are no longer relevant. Indeed, a recent study suggested that only 18% of malignant nodules would be missed using a VATS approach in the current era while another study from the United Kingdom found equivalent outcomes with regard to missed lesions and pulmonary progression comparing open and VATS approaches. To date, no prospective study using spiral CT scan has been performed to resolve this clinical dilemma.
Primary Lung Cancer-Associated Signs and Symptoms
Lung cancer displays one of the most diverse presentation patterns of all human maladies (Table 19-7). The wide range of symptoms and signs is related to (a) histologic features, which often help determine the anatomic site of origin in the lung; (b) the specific tumor location in the lung and its relationship to surrounding structures; (c) biologic features and the production of a variety of paraneoplastic syndromes; and (d) the presence or absence of metastatic disease. Symptoms related to the local intrathoracic effect of the primary tumor can be conveniently divided into two groups: pulmonary and nonpulmonary thoracic.
Table 19-7Clinical presentation of lung cancer ||Download (.pdf) Table 19-7 Clinical presentation of lung cancer
|CATEGORY ||SYMPTOM ||CAUSE |
|Pulmonary symptoms ||Cough ||Bronchus irritation or compression |
| ||Dyspnea ||Airway obstruction or compression |
| ||Wheezing ||>50% airway obstruction |
| ||Hemoptysis ||Tumor erosion or irritation |
| ||Pneumonia ||Airway obstruction |
|Nonpulmonary thoracic symptoms ||Pleuritic pain ||Parietal pleural irritation or invasion |
| ||Local chest wall pain ||Rib and/or muscle involvement |
| ||Radicular chest pain ||Intercostal nerve involvement |
| ||Pancoast’s syndrome ||Stellate ganglion, chest wall, brachial plexus involvement |
| ||Hoarseness ||Recurrent laryngeal nerve involvement |
| ||Swelling of head and arms ||Bulky involved mediastinal lymph nodes |
| || ||Medially based right upper lobe tumor |
Pulmonary symptoms result from the direct effect of the tumor on the bronchus or lung tissue. Symptoms (in order of frequency) include cough (secondary to irritation or compression of a bronchus), dyspnea (usually due to central airway obstruction or compression, with or without atelectasis), wheezing (with narrowing of a central airway of >50%), hemoptysis (typically, blood streaking of mucus that is rarely massive; indicates a central airway location), pneumonia (usually due to airway obstruction by the tumor), and lung abscess (due to necrosis and cavitation, with subsequent infection).
Nonpulmonary Thoracic Symptoms
Nonpulmonary thoracic symptoms result from invasion of the primary tumor directly into a contiguous structure (e.g., chest wall, diaphragm, pericardium, phrenic nerve, recurrent laryngeal nerve, superior vena cava, and esophagus), or from mechanical compression of a structure (e.g., esophagus or superior vena cava) by enlarged tumor-bearing lymph nodes.
Peripherally located tumors (often adenocarcinomas) extending through the visceral pleura lead to irritation or growth into the parietal pleura and potentially to continued growth into the chest wall structures. Three types of symptoms, depending on the extent of chest wall involvement, are possible: (a) pleuritic pain, from noninvasive contact of the parietal pleura with inflammatory irritation or direct parietal pleural invasion; (b) localized chest wall pain, from deeper invasion and involvement of the rib and/or intercostal muscles; and (c) radicular pain, from involvement of the intercostal nerve(s). Radicular pain may be mistaken for renal colic in the case of tumors invading the inferoposterior chest wall.
Other specific nonpulmonary thoracic symptoms include:
Pancoast’s syndrome. Tumors originating in the superior sulcus (posterior apex) elicit: apical chest wall and/or shoulder pain (from involvement of the first rib and chest wall); Horner’s syndrome (unilateral enophthalmos, ptosis, miosis, and facial anhidrosis from invasion of the stellate sympathetic ganglion); and radicular arm pain (from invasion of T1, and occasionally C8, brachial plexus nerve roots).
Phrenic nerve palsy. The phrenic nerve traverses the hemithorax along the mediastinum, parallel and posterior to the superior vena cava and anterior to the pulmonary hilum. Tumors at the medial lung surface or anterior hilum can directly invade the nerve; symptoms include shoulder pain (referred), hiccups, and dyspnea with exertion because of diaphragm paralysis. Radiographically, unilateral diaphragm elevation on CXR is present; the diagnosis is confirmed by fluoroscopic examination of the diaphragm with breathing and sniffing (the “sniff” test).
Recurrent laryngeal nerve palsy. Recurrent laryngeal nerve (RLN) involvement most commonly occurs on the left side, given the hilar location of the left RLN as it passes under the aortic arch. Paralysis results from: (a) invasion of the vagus nerve above the aortic arch by a medially based left upper lobe tumor; or (b) direct invasion of the RLN by hilar tumor and/or hilar or aortopulmonary lymph node metastases. Symptoms include voice change, often referred to as hoarseness, but more typically a loss of tone associated with a breathy quality, and coughing, particularly when drinking liquids.
Superior vena cava (SVC) syndrome. As a result of bulky enlargement of involved mediastinal lymph nodes compressing or a medially based right upper lobe tumor invading the SVC, SVC syndrome symptoms include variable degrees of swelling of the head, neck, and arms; headache; and conjunctival edema. It is seen most commonly with NEC grade IV (small cell) lung cancer.
Pericardial tamponade. Pericardial effusions (benign or malignant), associated with increasing levels of dyspnea and/or arrhythmias, and pericardial tamponade occur with direct pericardial invasion. Diagnosis requires a high index of suspicion in the setting of a medially based tumor with symptoms of dyspnea and is confirmed by CT scan or echocardiography.
Back pain. Results from direct invasion of a vertebral body and is often localized and severe. If the neural foramina are involved, radicular pain may also be present.
Other local symptoms. Dysphagia is usually secondary to external esophageal compression by enlarged lymph nodes involved with metastatic disease, usually with lower lobe tumors. Finally, dyspnea, pleural effusion, or referred shoulder pain can result from invasion of the diaphragm by a tumor at the base of a lower lobe.
Associated Paraneoplastic Syndromes
All lung cancer histologies are capable of producing a variety of paraneoplastic syndromes, most often from systemic release of tumor-derived biologically active materials (Table 19-8). Paraneoplastic syndromes may produce symptoms even before any local symptoms are produced by the primary tumor, thereby aiding in early diagnosis. Their presence does not influence resectability or treatment options. Symptoms often abate with successful treatment; paraneoplastic symptom recurrence may herald tumor recurrence. The majority of such syndromes are associated with grade IV NEC (small cell carcinoma), including many endocrinopathies.
Table 19-8Paraneoplastic syndromes in patients with lung cancer ||Download (.pdf) Table 19-8 Paraneoplastic syndromes in patients with lung cancer
Hypercalcemia (ectopic parathyroid hormone)
Syndrome of inappropriate secretion of antidiuretic hormone
Elevated growth hormone level
Elevated levels of prolactin, follicle-stimulating hormone, luteinizing hormone
Subacute cerebellar degeneration
Progressive multifocal leukoencephalopathy
Pulmonary hypertrophic osteoarthropathy
Pure red cell aplasia
Disseminated intravascular coagulation
Erythema gyratum repens
Hypertrichosis lanuginosa acquista
Secretion of vasoactive intestinal peptide with diarrhea
Anorexia or cachexia
Hypertrophic pulmonary osteoarthropathy (HPO). Often severely debilitating, symptoms of HPO may antedate the diagnosis of cancer by months. Clinically, ankle, feet, forearm, and hand tenderness and swelling are characteristic, resulting from periostitis of the fibula, tibia, radius, metacarpals, and metatarsals. Clubbing of the digits may occur in up to 30% of patients with grade IV NEC (Fig. 19-17). Plain radiographs show periosteal inflammation and elevation, while bone scans demonstrate intense but symmetric uptake in the long bones. Aspirin or nonsteroidal anti-inflammatory agents provide temporary relief; treatment requires successful surgical or medical tumor eradication.
Hypercalcemia. Up to 10% of patients with lung cancer will have hypercalcemia, most often due to metastatic disease. Ectopic parathyroid hormone secretion by the tumor, most often squamous cell carcinoma, is causative in up to 15%, however, and should be suspected if metastatic bone disease is not present. Symptoms of hypercalcemia include lethargy, depressed level of consciousness, nausea, vomiting, and dehydration. Most patients have resectable tumors, and, following complete resection, the calcium level will normalize. Unfortunately, tumor recurrence is extremely common and may manifest as recurrent hypercalcemia.
Hyponatremia. Characterized by confusion, lethargy, and possible seizures, hyponatremia can result from the inappropriate secretion of antidiuretic hormone from the tumor into the systemic circulation (syndrome of inappropriate secretion of antidiuretic hormone [SIADH]) in 10% to 45% of patients with grade IV NEC (small cell). It is diagnosed by the presence of hyponatremia, low serum osmolality, and high urinary sodium and osmolality. Another cause of hyponatremia can be the ectopic secretion of atrial natriuretic peptide (ANP).
Cushing’s syndrome. Autonomous tumor production of an adrenocorticotropic hormone (ACTH)-like molecule leads to rapid serum elevation of ACTH and subsequent severe hypokalemia, metabolic alkalosis, and hyperglycemia. Symptoms are primarily related to the metabolic changes while the physical signs of Cushing’s syndrome (e.g., truncal obesity, buffalo hump, striae) are unusual due to the rapidity of ACTH elevation. Diagnosis is made by demonstrating hypokalemia (<3.0 mmol/L); nonsuppressible elevated plasma cortisol levels that lack the normal diurnal variation; elevated blood ACTH levels; or elevated urinary 17-hydroxycorticosteroids, all of which are not suppressible by administration of exogenous dexamethasone. Immunoreactive ACTH is present in nearly all extracts of SCLC, and a high percentage of patients with SCLC have elevated ACTH levels by radioimmunoassay, yet fewer than 5% have symptoms of Cushing’s syndrome.
Peripheral and central neuropathies. Unlike other paraneoplastic syndromes, which are usually due to ectopic secretion of an active substance, these syndromes are felt to be immune mediated. Cancer cells are thought to secrete antigens normally expressed only by the nervous system, generating antibodies leading either to interference with neurologic function or to immune neurologic destruction. Up to 16% of lung cancer patients have neuromuscular disability, and, of these, half have grade IV NEC (small cell) and 25% have squamous cell carcinomas. In patients with neurologic or muscular symptoms, central nervous system (CNS) metastases must be ruled out with CT or magnetic resonance imaging (MRI) of the head. Other metastatic disease leading to disability must also be excluded.
Lambert-Eaton syndrome. This myasthenia-like syndrome is caused by tumor secretion of immunoglobulin G (IgG) antibodies targeting voltage-gated calcium channels, which causes a neuromuscular conduction defect by decreasing the amount of acetylcholine released from presynaptic sites at the motor end plate. Symptoms, including gait abnormalities from proximal muscle weakness and impaired coordination, may actually precede radiographic evidence of the tumor. Therapy is directed at the primary tumor with resection, radiation, and/or chemotherapy. Many patients have dramatic improvement after successful therapy. For patients with refractory symptoms, treatment consists of guanidine hydrochloride, immunosuppressive agents such as prednisone and azathioprine, and occasionally plasma exchange. Unlike with myasthenia gravis patients, neostigmine is usually ineffective.
Hypertrophic pulmonary osteoarthropathy associated with small cell carcinoma. A. Painful clubbing of the fingers. B. Painful clubbing of the toes (close-up). C. The arrows point to new bone formation on the femur.
Symptoms Associated with Metastatic Lung Cancer
Lung cancer metastasizes most commonly to the CNS, vertebral bodies, bone, liver, adrenal glands, lungs, skin, and soft tissues. CNS metastases are present at diagnosis in 10% of patients; another 10% to 15% will develop CNS metastases following diagnosis. Focal symptoms, including headache, nausea, vomiting, seizures, hemiplegia, and dysarthria, are common. Lung cancer is the most common cause of spinal cord compression, either by primary tumor invasion of an intervertebral foramen or direct extension of vertebral metastases. Bony metastases are identified in 25% of all patients with lung cancer. They are primarily lytic and produce pain locally; thus any new and localized skeletal symptoms must be evaluated radiographically. Liver metastases are most often an incidental finding on CT scan. Adrenal metastases are also typically asymptomatic and are usually discovered by routine CT scan. They may lead to adrenal hypofunction. Skin and soft tissue metastases occur in 8% of patients dying of lung cancer and generally present as painless subcutaneous or intramuscular masses. Occasionally, the tumor erodes through the overlying skin, with necrosis and creation of a chronic wound; excision may then be necessary for both mental and physical palliation.
Nonspecific Cancer-Related Symptoms
Lung cancer often produces a variety of nonspecific symptoms such as anorexia, weight loss, fatigue, and malaise. The cause of these symptoms is often unclear, but should raise concern about possible metastatic disease.
Role of Histologic Diagnosis and Molecular Testing
Establishing a clear histologic diagnosis early in the evaluation and management of lung cancer is critical to effective treatment. Molecular signatures are also key determinants of treatment algorithms for adenocarcinoma and will likely become important for squamous cell carcinoma as well. Currently, differentiation between adenocarcinoma and squamous cell carcinoma in cytologic specimens or small biopsy specimens is imperative in patients with advanced stage disease, as treatment with pemetrexed or bevacizumab-based chemotherapy is associated with improved progression-free survival in patients with adenocarcinoma but not squamous cell cancer. Furthermore, life-threatening hemorrhage has occurred in patients with squamous cell carcinoma who were treated with bevacizumab. Finally, EGFR mutation predicts response to EGFR tumor kinase inhibitors and is now recommended as first-line therapy in advanced adenocarcinoma. Because adequate tissue is required for histologic assessment and molecular testing, each institution should have a clear, multidisciplinary approach to patient evaluation, tissue acquisition, tissue handling/processing, and tissue analysis (Fig. 19-18). In many cases, tumor morphology differentiates adenocarcinoma from the other histologic subtypes. If no clear morphology can be identified, then additional testing for one immunohistochemistry marker for adenocarcinoma and one for squamous cell carcinoma will usually enable differentiation. Immunohistochemistry for neuroendocrine markers is reserved for lesions exhibiting neuroendocrine morphology. Additional molecular testing should be performed on all adenocarcinoma specimens for known predictive and prognostic tumor markers (e.g. EGFR, KRAS, and EML4-ALK fusion gene). Ideally, use of tissue sections and cell block material is limited to the minimum necessary at each decision point. This emphasizes the importance of a multidisciplinary approach; surgeons and radiologists must work in direct cooperation with the cytopathologist to ensure that tissue samples are adequate for morphologic diagnosis as well as providing sufficient cellular material to enable molecular testing. With adoption of endobronchial and endoscopic ultrasound, electromagnetic navigational bronchoscopy, VATS, and even transthoracic image-guided fine-needle and core-needle biopsy, surgeons are increasingly involved in the acquisition of diagnostic tissue for primary, metastatic, and recurrent intrathoracic disease, and a thorough understanding of key issues is necessary to ensure optimal treatment and patient outcomes.
Algorithm for adenocarcinoma diagnosis in small biopsies and/or cytology. Step 1: When positive biopsies (fiberoptic bronchoscopy [FOB], transbronchial [TBBx], core, or surgical lung biopsy [SLBx]) or cytology (effusion, aspirate, washings, and brushings) show clear adenocarcinoma (ADC) or squamous cell carcinoma (SQCC) morphology, the diagnosis can be firmly established. If there is neuroendocrine (NE) morphology, the tumor may be classified as small cell carcinoma (SCLC) or non–small cell lung carcinoma (NSCLC), probably large cell neuroendocrine carcinoma (LCNEC) according to standard criteria (+ = positive, – = negative, and ± = positive or negative). If there is no clear ADC or SQCC morphology, the tumor is regarded as NSCLC–not otherwise specified (NOS). Step 2: NSCLC-NOS can be further classified based on (a) immunohistochemical stains, (b) mucin (DPAS or mucicarmine) stains, or (c) molecular data. If the stains all favor ADC-positive ADC marker(s) (i.e., TTF-1 and/or mucin positive) with negative SQCC markers, then the tumor is classified as NSCLC, favor ADC. If SQCC markers (i.e., p63 and/or CK5/6) are positive with negative ADC markers, the tumor is classified as NSCLC, favor SQCC. If the ADC and SQCC markers are both strongly positive in different populations of tumor cells, the tumor is classified as NSCLC-NOS, with a comment it may represent adenosquamous carcinoma. If all markers are negative, the tumor is classified as NSCLC-NOS. †EGFR mutation testing should be performed in (1) classic ADC, (2) NSCLC, favor ADC, (3) NSCLC-NOS, and (4) NSCLC-NOS, possible adenosquamous carcinoma. In NSCLC-NOS, if EGFR mutation is positive, the tumor is more likely to be ADC than SQCC. Step 3: If clinical management requires a more specific diagnosis than NSCLC-NOS, additional biopsies may be indicated. CD = cluster designation; CK = cytokeratin; DPAS = diastase-periodic acid Schiff; DPAS +ve = periodic-acid Schiff with diastase; EGFR = epidermal growth factor receptor; IHC = immunohistochemistry; NB = of note; TTF-1 = thyroid transcription factor-1; –ve = negative; +ve = positive. (Reproduced with permission from Travis W, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: International multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244.
Evaluation prior to treatment encompasses three areas: diagnosis and assessment of the primary tumor, assessment for metastatic disease, and determination of functional status (the patient’s ability to tolerate the prescribed treatment regimen). A discrete approach to each area allows the surgeon to systematically evaluate the patient, perform accurate clinical staging, and enable assessment of the patient’s functional suitability for therapy, including pulmonary resection (Table 19-9).
Table 19-9Evaluation of patients with lung cancer ||Download (.pdf) Table 19-9 Evaluation of patients with lung cancer
| ||PRIMARY TUMOR ||METASTATIC DISEASE ||FUNCTIONAL ASSESSMENT |
|History ||Pulmonary ||Weight loss ||Ability to walk up two flights of stairs |
| ||Nonpulmonary thoracic ||Malaise ||Ability to walk on a flat surface indefinitely |
| ||Paraneoplastic ||New bone pain || |
| || ||Neurologic signs or symptoms || |
| || ||Skin lesions || |
|Physical examination ||Voice ||Supraclavicular node palpation ||Accessory muscle usage |
| || ||Skin examination ||Air flow by auscultation |
| || ||Neurologic examination ||Force of cough |
|Radiographic examination ||Chest CT ||Chest CT, PET ||Chest CT: tumor anatomy, atelectasis |
|Tissue analysis ||Bronchoscopy ||Bone scan, head MRI, abdominal CT ||Quantitative perfusion scan |
| ||Transthoracic needle aspiration and biopsy ||Bronchoscopic lymph node FNA || |
| || ||Endoscopic ultrasound || |
| || ||Mediastinoscopy || |
| || ||Biopsy of suspected metastasis || |
|Other ||Thoracoscopy ||— ||Pulmonary function tests (FEV1, Dlco, O2 consumption) |
Assessment of the Primary Tumor
Assessment of the primary tumor begins with the history and directed questions regarding the presence or absence of pulmonary, nonpulmonary, thoracic, and paraneoplastic symptoms. Because patients often present to the surgeon with a CXR or CT scan demonstrating the lesion, the location of the tumor can help direct the clinician in performing the history and physical examination.
If the patient does not already have a chest CT scan, this should be performed expeditiously as the next stage in evaluating a new patient. A routine chest CT scan should include intravenous contrast material to enable assessment of the primary tumor, delineation of mediastinal lymph nodes relative to normal mediastinal structures, and the tumor’s relationship to surrounding and contiguous structures. Recommendations for treatment and options for obtaining tissue diagnosis require a thorough understanding and assessment of CT findings.
Concern for contiguous invasion of adjacent structures often is raised in response to a combination of symptom history, location of the primary tumor, and CT imaging. It is common to see the primary tumor abutting the chest wall without clear radiographic evidence of rib destruction. In this circumstance, a history of pain in the area is an accurate guide to the likelihood of parietal pleural, rib, or intercostal nerve involvement. Similar observations apply to tumors abutting the recurrent laryngeal nerve, phrenic nerve, diaphragm, vertebral bodies, and chest apex. Thoracotomy should not be denied because of presumptive evidence of invasion of the chest wall, vertebral body, or mediastinal structures; proof of invasion may require thoracoscopy or even thoracotomy.
MRI of pulmonary lesions and mediastinal nodes, overall, offers no real improvement over CT scanning. It is an excellent modality, however, for defining a tumor’s relationship to a major vessel, given its excellent imaging of vascular structures. This is especially true if the use of iodine contrast material is contraindicated. Thus, use of MRI in lung cancer patients is reserved for those with contrast allergies or with suspected mediastinal, vascular, or vertebral body invasion.
Options for Tissue Acquistion
The surgeon must have an evidence-based algorithm for approaching the diagnosis and treatment of a pulmonary nodule and masses (Fig. 19-19).24 Depending on nodule size, proximity to the bronchial tree, and the prevalence of cancer in the population being sampled, bronchoscopy has 20% to 80% sensitivity for detecting neoplastic processes within a pulmonary lesion. Diagnostic tissue from bronchoscopy can be obtained by one of four methods:
Recommended management algorithm for patients with solitary pulmonary nodules (SPNs) measuring 8 mm to 30 mm in diameter. CT = computed tomography; CXR = chest radiograph; PET = positron emission tomography; XRT = radiotherapy. (Reproduced with permission from the American College of Chest Physicians from Gould MK, et al. Evaluation of patients with pulmonary nodules: when is it lung cancer?: ACCP Evidence-based Clinical Practice Guidelines. (2nd edition) Chest. 2007;132:108S.)
Brushings and washings for cytology
Direct forceps biopsy of a visualized lesion
Endobronchial ultrasound-guided fine-needle aspiration (FNA) of an externally compressing lesion without visualized endobronchial tumor
Transbronchial biopsy with fluoroscopy to guide forceps to the lesion or electromagnetic navigational bronchoscopy
Electromagnetic navigation bronchoscopy is a recent addition to the surgeon’s armamentarium for transbronchial biopsy of peripheral lung lesions. Using electromagnetic markers that create a three-dimensional image and align the recorded CT images to the patient’s true anatomy, a catheter is advanced transbronchially and brushings, FNA, cup biopsy, and washings can be performed. Diagnostic yield using electromagnetic navigation bronchoscopy as an adjunct to standard bronchoscopy is reported as high as 80%. The approach can also be used for placement of fiducial markers for subsequent stereotactic body radiation therapy and for tattooing the perilesional region to guide subsequent video-assisted thoracoscopic resection. Pneumothorax rates with this approach are approximately 1% in larger series and up to 3.5% in reports of early experience.
For peripheral lesions (roughly the outer half of the lung), transbronchial biopsy is performed first, followed by brushings and washings. This improves diagnostic yield by disrupting the lesion with the biopsy forceps and mobilizing additional cells. For central lesions, direct forceps biopsy by bronchoscopic visualization is often possible. For central lesions with external airway compression but no visible endobronchial lesions, endobronchial ultrasound (EBUS) is highly accurate and safe for transbronchial biopsies of both the primary tumor (when it abuts the central airways) as well as the mediastinal lymph nodes.33
Image-guided transthoracic FNA (ultrasound or CT FNA) biopsy can accurately diagnose appropriately selected peripheral pulmonary lesions in up to 95% of patients. Three biopsy results are possible after image-guided biopsy procedures: malignant, a specific benign process, or indeterminate. Because false-negative rates range from 3% to 29%, further diagnostic efforts are warranted in the absence of a specific benign diagnosis (such as granulomatous inflammation or hamartoma) because malignancy is not ruled out.34 The primary complication is pneumothorax in as many as 30% of cases. Intrapulmonary bleeding occurs, but rarely causes clinically significant hemoptysis or respiratory compromise.
Some groups advocate use of video-assisted thoracoscopic biopsy as the first option for diagnosis, citing superior diagnostic accuracy and low surgical risk. With VATS, the nodule can be excised with a wedge or segmental resection, if less than 3 cm, or a core-needle biopsy can be performed under direct vision for larger lesions. VATS can also provide valuable staging information, including sampling/dissection of mediastinal lymph nodes and assessing whether the primary tumor has invaded a contiguous structure (such as the chest wall or mediastinum). Lesions most suitable for VATS are those that are located in the outer one third of the lung. The surgeon should avoid direct manipulation of the nodule or violation of the visceral pleura overlying the nodule. In addition, the excised nodule must be extracted from the chest within a bag to prevent seeding of the chest wall. If the patient’s pulmonary reserve is adequate, the surgeon can proceed to lobectomy (either VATS or open) after frozen section diagnosis.
A thoracotomy is occasionally necessary to diagnose and stage a primary tumor. Although this occurs rarely, two circumstances may require such an approach: (a) a deep-seated lesion that yielded an indeterminate needle biopsy result or that could not be biopsied for technical reasons; or (b) inability to determine invasion of a mediastinal structure by any method short of palpation. In the circumstance of a deep-seated lesion without a diagnosis, tissue can be obtained via thoracotomy using FNA, core-needle biopsy, or excisional biopsy. Intraoperative frozen-section analysis is required; if the open biopsy frozen-section result is indeterminate, a lobectomy may be necessary in extremely rare situations. If a pneumonectomy is required to remove the lesion, a tissue diagnosis of cancer must be made before proceeding.
Assessment for Metastatic Disease
Distant metastases are found in approximately 40% of patients with newly diagnosed lung cancer. The presence of lymph node or systemic metastases may imply inoperability. As with the primary tumor, assessment for the presence of metastatic disease should begin with the history and physical examination, focusing on the presence or absence of new bone pain, neurologic symptoms, and new skin lesions. In addition, constitutional symptoms (e.g., anorexia, malaise, and unintentional weight loss of >5% of body weight) suggest either a large tumor burden or the presence of metastases. Physical examination should focus on the patient’s overall appearance, noting any evidence of weight loss such as redundant skin or muscle wasting, and a complete examination of the head and neck, including evaluation of cervical and supraclavicular lymph nodes and the oropharynx. This is particularly true for patients with a significant tobacco history. The skin should be thoroughly examined. Routine laboratory studies include serum levels of hepatic enzymes (e.g., serum glutamic oxaloacetic transaminase and alkaline phosphatase), as well as those of serum calcium (to detect bone metastases or the ectopic parathyroid syndrome). Elevation of either hepatic enzymes or serum calcium levels typically occurs with extensive metastases.
Chest CT scanning permits assessment of possible metastatic spread to the mediastinal lymph nodes. It continues to be the most effective noninvasive method available to assess the mediastinal and hilar nodes for enlargement. However, a positive CT result (i.e., nodal diameter >1.0 cm) predicts actual metastatic involvement in only about 70% of lung cancer patients. Thus even with enlarged mediastinal lymph nodes on a CT scan, up to 30% of such nodes are enlarged from noncancerous reactive causes such as inflammation due to atelectasis or pneumonia secondary to the tumor. Therefore, no patient should be denied an attempt at curative resection just because of a positive CT result for mediastinal lymph node enlargement. Any CT finding of metastatic nodal involvement must be confirmed histologically. The negative predictive value of normal-appearing lymph nodes by CT (lymph nodes <1.0 cm) is better than the positive predictive value of a suspicious-appearing lymph node, particularly with small squamous cell tumors. With normal-size lymph nodes and a T1 tumor, the false-negative rate is less than 10%, leading many surgeons to omit mediastinoscopy. However, the false-negative rate increases to nearly 30% with centrally located and T3 tumors. It has also been demonstrated that T1 adenocarcinomas or large cell carcinomas have a higher rate of early micrometastasis. Therefore, all such patients should undergo mediastinoscopy.
Mediastinal lymph node staging by PET scanning appears to have greater accuracy than CT scanning. PET staging of mediastinal lymph nodes has been evaluated in two meta-analyses. The overall sensitivity for mediastinal lymph node metastasis was 79% (95% confidence interval 76%–82%), with a specificity of 91% (95% CI 89%–93%) and an accuracy of 92% (95% CI 90%–94%).35
In comparing PET with CT scans in patients who also underwent lymph node biopsies, PET had a sensitivity of 88% and a specificity of 91%, whereas CT scanning had a sensitivity of 63% and a specificity of 76%. Combining CT and PET scanning may lead to even greater accuracy.36 In one study of CT, PET, and mediastinoscopy in 68 patients with potentially operable NSCLC, CT correctly identified the nodal stage in 40 patients (59%). It understaged the tumor in 12 patients and overstaged it in 16 patients. PET correctly identified the nodal stage in 59 patients (87%). It understaged the tumor in five patients and overstaged it in four. For detecting N2 and N3 disease, the combination of PET and CT scanning yielded a sensitivity, specificity, and accuracy of 93%, 95%, and 94%, respectively. CT scan alone yielded 75%, 63%, and 68%, respectively. Studies examining combined PET-CT consistently show improved accuracy compared to PET or CT alone; accuracy for PET-CT nodal positivity confirmed by mediastinoscopy is approximately 75%, with a negative predictive value of approximately 90%. Right upper lobe lesions were more likely to have occult N2 disease than other lobes of the lung.37,38,39,40 PET-positive mediastinal lymph nodes require histologic verification of node positivity, either by EBUS-guided FNA/core-needle biopsy or mediastinoscopy, to minimize the risk of undertreatment. Assuming node positivity without histologic confirmation relegates the patient to, at a minimum, induction chemotherapy. If there is a suggestion of N3 disease, the patient would be incorrectly staged as having IIIB disease and would not be considered a candidate for potentially curative surgical resection.
It is important for surgeons who are managing patients with lung cancer to have a clear algorithm for invasive mediastinal staging. In general, invasive staging is underused, placing many patients at risk for over- or understaging and, thus, inappropriate treatment. An absolute indication for obtaining a tissue diagnosis is mediastinal lymph node enlargement greater than 1.0 cm by CT scan. There are several options for invasive mediastinal staging:
Less invasive than mediastinoscopy, EBUS enables image-guided transtracheal and transbronchial FNA cytologic samples from hilar masses and lymph nodes from level 4R and 4L, level 7, level 10, and level 11. A core-needle biopsy device recently became available for the EBUS and will improve the diagnostic yield when sampling mediastinal lymphadenopathy. Rapid onsite pathologic evaluation with expert cytopathologist evaluation greatly increases the diagnostic accuracy of the procedure; importantly, the intraoperative evaluation will confirm whether the target lesion is being sampled and greatly facilitates acquisition of satisfactory samples for determining the morphologic diagnosis as well as sufficient material for cell block for immunohistochemistry and molecular testing. Like mediastinoscopy, EBUS does not allow assessment of level 3, 5, or 6 nodal stations.
Endoscopic ultrasound (EUS) can accurately visualize mediastinal paratracheal lymph nodes (stations 4R, 7, and 4L) and other lymph node stations (stations 8 and 9) and is able to visualize primary lung lesions contiguous with or near the esophagus (see Fig. 19-8). Using FNA or core-needle biopsy, samples of lymph nodes or primary lesions can be obtained. Diagnostic yield is improved with intraoperative cytologic evaluation, which can be performed with the cytopathologist in the operating room. Limitations of EUS include the inability to visualize the anterior (pretracheal) mediastinum; thus, EUS does not replace mediastinoscopy for complete mediastinal nodal staging. However, it may not be necessary to perform mediastinoscopy if findings on EUS are positive for N2 nodal disease, particularly if more than one station is found to harbor metastases.
Cervical mediastinoscopy provides tissue sampling of all paratracheal and subcarinal lymph nodes and permits visual determination of the presence of extracapsular extension of nodal metastasis (Fig. 19-20). With complex hilar or right paratracheal primary tumors, it allows direct biopsies and assessment of invasion into the mediastinum. When the size of mediastinal lymph nodes is normal, mediastinoscopy is generally recommended for centrally located tumors, for T2 and T3 primary tumors, and occasionally for T1 adenocarcinomas or large cell carcinomas (due to their higher rate of metastatic spread). Some surgeons perform mediastinoscopy in all lung cancer patients because of the poor survival associated with surgical resection of N2 disease.
It is important to note that EBUS or EUS can be used for initial diagnosis in enlarged lymph nodes, but the predictive value of a negative EBUS in a patient with radiographically suspicious mediastinal disease is not sufficient to accurately guide treatment. At the authors’ institutions, it is standard to begin mediastinal lymph node staging with EBUS-guided FNA of clinically suspicious mediastinal lymphadenopathy. If the FNA is negative by intraoperative rapid onsite cytologic evaluation, cervical video mediastinoscopy is performed in the same operative setting to ensure accurate staging of the mediastinal nodes. However, if the FNA is positive, mediastinoscopy is not performed and the patient is referred to medical oncology for induction chemotherapy; avoiding a pretreatment mediastinoscopy in this manner facilitates the safe performance of a postinduction mediastinoscopy for restaging of the mediastinum in patients who respond favorably to induction therapy.
Left video-assisted thoracoscopic lymph node sampling may be needed for patients with left upper lobe tumors who have localized regional spread to station 5 and 6 lymph nodes, without mediastinal paratracheal involvement (see Fig. 19-8). If there is a low index of suspicion for nodal metastasis, the patient can be schedule for VATS biopsy and lobectomy under the same anesthesia; the procedure begins by sampling the level 5 and 6 nodes for frozen section, and if the nodes are negative, the anatomic lung resection is performed. If the index of suspicion is high, the VATS biopsy is performed as a separate procedure. Cervical mediastinoscopy should precede VATS biopsy, even if patients have normal paratracheal lymph nodes. Additional diagnostic evaluation of the lymph nodes in station 5 and 6 may be unnecessary if the mediastinal lymph nodes are proven to be benign with biopsy during cervical mediastinoscopy and the preoperative CT scan suggests complete respectability of the tumor. There are, however, several indications for prethoracotomy biopsy of station 5 and 6 lymph nodes, which are listed in Table 19-10. It is particularly important to prove that mediastinal lymph nodes are pathologically involved and not just radiographically suspicious for nodal metastasis prior to deciding that the patient is not a candidate for resection.
Cervical mediastinoscopy. Paratracheal and subcarinal lymph node tissues (within the pretracheal space) can be sampled using a mediastinoscope introduced through a suprasternal skin incision.
Table 19-10Indications for prethoracotomy biopsy of station 5 and 6 lymph nodes ||Download (.pdf) Table 19-10 Indications for prethoracotomy biopsy of station 5 and 6 lymph nodes
1. Enrollment criteria for induction therapy protocol require pathologic confirmation of N2 disease.
2. Computed tomographic scan shows evidence of bulky nodal metastases or extracapsular spread that could prevent complete resection.
3. Tissue diagnosis of a hilar mass or of lymph nodes causing recurrent laryngeal nerve paralysis is needed.
The presence of pleural effusion on radiographic imaging should not be assumed to be malignant. Pleural effusion may be secondary to atelectasis or consolidation, seen with central tumors, reactive, or secondary to cardiac dysfunction. Pleural effusion associated with a peripherally based tumor, particularly one that abuts the visceral or parietal pleural surface, does have a higher probability of being malignant, which would alter the pathologic stage of the disease to stage IV by the American Joint Committee on Cancer (AJCC) 7th edition TNM staging criteria. If this is the only site concerning for metastatic disease, pathologic confirmation is mandatory. Cytology reveals malignant cells in 50% of malignant effusions. Thoracoscopy, performed as part of a separate staging procedure, often with mediastinoscopy or immediately before a planned thoracotomy, may be needed to rule out pleural metastases in select patients.
Currently, chest CT and PET are routine in the evaluation of patients with lung cancer. Integrated PET-CT scanners have become standard and have substantially improved accuracy of detection and localization of lymph node and distant metastases, as compared with independently performed PET and CT scans (Fig. 19-21). This technology overcomes the imprecise information on the exact location of focal abnormalities seen on PET and has become the standard imaging modality for lung cancer. Compared to routine chest or abdominal CT and bone scans, PET scanning detects 10% to 15% more distant metastases, but should be confirmed with MRI and/or biopsies if the patient otherwise has early-stage disease. Brain MRI should be performed when the suspicion or risk of brain metastases is increased, such as in patients with clinical stage III disease. In the absence of neurologic symptoms or signs, the probability of a negative head CT scan is 95%. Liver abnormalities that are not clearly simple cysts or hemangiomas and adrenal enlargement, nodules, or masses are further evaluated by MRI scanning and, occasionally, by needle biopsy. Adrenal adenomas have a high lipid content (secondary to steroid production), but metastases and most primary adrenal malignancies contain little if any lipid; thus MRI is usually able to distinguish the two.
Imaging of non–small cell lung cancer by integrated positron emission tomography (PET)-computed tomography (CT) scan. A. CT of the chest showing a tumor in the left upper lobe. B. PET scan of the chest at the identical cross-sectional level. C. Coregistered PET-CT scan clearly showing tumor invasion (confirmed intraoperatively). (Reprinted with permission from Lardinois D, Weder W, Hany TF, et al. Staging of non-small–cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med. 2003;348:2504. Copyright © 2003 Massachusetts Medical Society.)
Tumor, Node, and Metastasis: Lung Cancer Staging
The staging of any tumor is an attempt to estimate the extent of disease and determine the patient’s prognosis; in a given patient, tumors are typically classified into a clinical stage and a pathologic stage. Clinical staging information includes the history and physical examination, radiographic test results, and diagnostic biopsy information. Therapeutic plans are generated based on clinical stage. After surgical resection of the tumor and lymph nodes, a postoperative pathologic stage (pTNM) is determined, providing further prognostic information.
The staging of solid epithelial tumors is based on the TNM staging system. The primary tumor “T” status provides information about tumor size and relationship to surrounding structures; the “N” status provides information about regional lymph nodes; and the “M” status provides information about the presence or absence of metastatic disease. The designation of lymph nodes as N1, N2, or N3 requires familiarity with the lymph node mapping system41 (see Fig. 19-8). Based on clearly delineated anatomic boundaries, accurate and reproducible localization of thoracic lymph nodes is possible, which facilitates detailed nodal staging for individual patients and standardization of nodal assessment between surgeons.
Pathologic staging criteria are based on the predicted survival relative to each combination of tumor, node, and metastasis status. In 2010, the AJCC 7th edition incorporated multiple changes into the staging system for NSCLC based on analysis of survival predictors from more than 100,000 patients worldwide. Table 19-11 shows the clinical and pathologic criteria for each of the TNM descriptors currently used in staging NSCLC and the overall stage classifications. In addition to the TNM stage, it is recommended that histologic grade, presence or absence of pleural/elastic layer invasion, separate tumor nodules, lymphovascular invasion, and residual tumor after treatment also be recorded into cancer registries to facilitate evaluation of these potential predictors in future analysis of staging criteria.
Table 19-11American Joint Committee on Cancer Seventh Edition Staging of Non–Small Cell Lung Cancer ||Download (.pdf) Table 19-11 American Joint Committee on Cancer Seventh Edition Staging of Non–Small Cell Lung Cancer
|CLINICAL Extent of disease before any treatment ||Stage Category Definitions ||PATHOLOGIC Extent of disease through completion of definitive surgery |
|❏ y clinical–staging completed after neoadjuvant therapy but before subsequent surgery ||TUMOR SIZE: ———— ||LATERALITY:❏ left ❏ right ❏ bilateral ||❏ y pathologic–staging completed after neoadjuvant therapy AND subsequent surgery |
Primary Tumor (T)
Primary tumor cannot be assessed
No evidence of primary tumor
Tis Carcinoma in situ
Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)*
Tumor ≤2 cm in greatest dimension
Tumor > 2 cm but ≤3 cm in greatest dimension
Tumor > 3 cm but ≤7 cm or tumor with any of the following features (T2 tumors with these features are classified T2a if ≤5 cm)
Involves main bronchus, ≥2 cm distal to the carina
Invades visceral pleura (PL1 or PL2)
Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung
Tumor > 3 cm but ≤5 cm in greatest dimension
Tumor > 5 cm but ≤7 cm in greatest dimension
Tumor > 7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor in the main bronchus (< 2 cm distal to the carina* but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe
Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumor nodule(s) in a different ipsilateral lobe
* The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.
Regional Lymph Nodes (N)
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
Metastasis in ipsilateral mediastinal and/or subcarinal llymph node(s)
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
Distant Metastasis (M)
No distant metastasis (no pathologic MO; use clinical M to complete stage group)
Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural (or pericardial) effusion**
**Most pleural (and pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple cytopathologic examinations of pleural (pencardial) fluid are negative for tumor, and the fluid is nonbloody and is not an exudate. Where these elements and clinical judgement dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be classified as MO.
|ANATOMIC STAGE · PROGNOSTIC GROUPS |
|CLINICAL ||PATHOLOGIC |
|GROUP ||T ||N ||M ||GROUP ||T ||N ||M |
|❏ Stage unknown ||❏ Stage unknown |
PROGNOSTIC FACTORS (SITE-SPECIFIC FACTORS)
REQUIRED FOR STAGING: None
Pleural/Elastic Layer Invasion (based on H&E and elastic stains) _________
Separate Tumor Nodules ____________________________
For identification of special cases of TNM or pTNM classifications, the “m” suffix and “y,” “r,” and “a” prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate analysis.
Staging for small cell lung cancer (SCLC) is typically based on the extent of disease. SCLC presenting with bulky locoregional disease confined to the ipsilateral hemithorax, with no evidence for distant metastatic disease, is termed “limited” SCLC. Limited disease must be treatable within a tolerable field of radiation. Using AJCC descriptors, this includes any T stage, any N stage, without metastatic disease (M0). The only exception is when multiple lung nodules are widely spread throughout the ipsilateral lung in the same hemithorax; in these patients, the size of the involved area would preclude a “safe” radiation field. In contrast, in “disseminated” disease, tumor is beyond the ipsilateral hemithorax or widely spread within the ipsilateral lung and to distant sites. Metastases to the pleura and pericardium, with resultant effusions, are considered disseminated disease. Metastases to brain, bone, bone marrow, and the pleural and pericardial spaces are common.
Assessment of Functional Status
Patients with potentially resectable tumors require careful assessment of their functional status and ability to tolerate either lobectomy or pneumonectomy. The surgeon should first estimate the likelihood of pneumonectomy, lobectomy, or possibly sleeve resection, based on the CT images. A sequential process of evaluation then unfolds.
A patient’s history is the most important tool for gauging risk. Specific questions regarding performance status should be routinely asked. If the patient can walk on a flat surface indefinitely, without oxygen and without having to stop and rest secondary to dyspnea, he will be very likely to tolerate lobectomy. If the patient can walk up two flights of stairs (up two standard levels), without having to stop and rest secondary to dyspnea, she will likely tolerate pneumonectomy. Finally, nearly all patients, except those with carbon dioxide (CO2) retention on arterial blood gas analysis, will be able to tolerate periods of single-lung ventilation and wedge resection.
Current smoking status and sputum production are also pertinent. Current smokers and patients with a greater than 60 pack-year history of smoking have a significantly increased risk of postoperative pulmonary complications; heavy smokers are 2.5 times more likely to develop pulmonary complications and three times more likely to develop pneumonia compared to patients with a ≤60 pack-year history (odds ratio [OR] 2.54; 95% CI 1.28–5.04; P = .0008). Impaired exchange of CO2 is also predictive of increased risk, independent of the smoking history. For every 10% decline in percent carbon monoxide diffusion capacity (%Dlco), the risk of any pulmonary complication increased by 42% (OR 1.42; 95% CI 1.16–1.75; P = .008).42 Risk reduction requires smoking cessation at least 8 weeks preoperatively, a requirement that is often not feasible in a cancer patient. Nevertheless, abstinence for at least 2 weeks before surgery should be encouraged. Smoking cessation on the day of surgery leads to increased sputum production and potential secretion retention postoperatively, and some authors have reported increased rates of pulmonary complications in this group.43 Patients with chronic daily sputum production will have more problems postoperatively with retention and atelectasis; they are also at higher risk for pneumonia. Sputum culture, antibiotic administration, and bronchodilators may be warranted preoperatively.
Pulmonary function studies are routinely performed when any resection greater than a wedge resection will be performed. Of all the measurements available, the two most valuable are forced expiratory volume in 1 second (FEV1) and carbon monoxide diffusion capacity (Dlco). General guidelines for the use of FEV1 in assessing the patient’s ability to tolerate pulmonary resection are as follows: greater than 2.0 L can tolerate pneumonectomy, and greater than 1.5 L can tolerate lobectomy. It must be emphasized that these are guidelines only. It is also important to note that the raw value is often imprecise because normal values are reported as “percent predicted” based on corrections made for age, height, and gender. For example, a raw FEV1 value of 1.3 L in a 62-year-old, 75-inch male has a percent predicted value of 30% (because the normal expected value is 4.31 L); in a 62-year-old, 62-inch female, the predicted value is 59% (normal expected value 2.21 L). The male patient is at high risk for lobectomy, while the female could potentially tolerate pneumonectomy.
To calculate the predicted postoperative value for FEV1 or Dlco, the percent predicted value of FEV1 or Dlco is multiplied by the fraction of remaining lung after the proposed surgery. For example, with a planned right upper lobectomy, a total of three segments will be removed. Therefore, three of a total 20 segments will leave the patient with (20 – 3/20) × 100 = 85% of their original lung capacity. In the two patients mentioned earlier, the man will have a predicted postoperative FEV1 of 30% × 0.85 = 25%, whereas the woman will have a predicted postoperative FEV1 of 50%. Percent predicted value of less than 50% for either FEV1 or Dlco correlates with risk for postoperative complications, particularly pulmonary complications; the risk of complications increases in a stepwise fashion for each 10% decline. Figure 19-22 shows the relationship between predicted postoperative Dlco and estimated operative mortality.
Operative mortality after major pulmonary resection for non–small cell lung cancer (334 patients) as a function of percent predicted postoperative carbon monoxide diffusion capacity (ppoDlco%). Solid line indicates logistic regression model; dashed lines indicate 95% confidence limits. (Adapted with permission from Wang J, Olak K, Ferguson M. Diffusing capacity predicts operative mortality but not long-term survival after resection for lung cancer. J Thorac Cardiovasc Surg. 1999;117:582. Copyright Elsevier.)
Quantitative perfusion scanning is used in select circumstances to help estimate the functional contribution of a lobe or whole lung. Such perfusion scanning is most useful when the impact of a tumor on pulmonary physiology is difficult to discern. With complete collapse of a lobe or whole lung, the impact is apparent, and perfusion scanning is usually unnecessary. Figure 19-23 shows a tumor with significant right main stem airway obstruction with associated atelectasis and volume loss of the right lung. At presentation, the patient was dyspneic with ambulation, and the FEV1 was 1.38 L. Six months prior, this patient could walk up two flights of stairs without dyspnea. The surgeon can anticipate that the patient will tolerate pneumonectomy because the lung is already not functioning due to main stem airway obstruction, and may, in fact, be contributing to a shunt. However, with centrally located tumors associated with partial obstruction of a lobar or main bronchus or of the pulmonary artery, perfusion scanning may be valuable in predicting the postoperative result of resection. For example, if the quantitative perfusion to the right lung is measured to be 21% (normal is 55%) and the patient’s percent predicted FEV1 is 60%, the predicted postoperative FEV1 after a right pneumonectomy would be 60% × 0.79 = 47%, indicating the ability to tolerate pneumonectomy. If the perfusion value is 55%, the predicted postoperative value would be 27%, and pneumonectomy would pose a significantly higher risk.
Chest computed tomography scan of an obstructing right main stem lung tumor. Arrow indicates location of right main bronchus. The right lung volume is much less than the left lung volume.
It is not uncommon to encounter patients with significant reductions in their percent predicted FEV1 and Dlco whose history shows a functional status that is inconsistent with the pulmonary function tests. In these circumstances, exercise testing that yields maximal oxygen consumption (V.o2 max) has emerged as a valuable decision-making technique to help patients with abnormal FEV1 and Dlco (Table 19-12). Values of less than 10 mL/kg/min are associated with a 26% mortality after major pulmonary resection compared to only 8.3% with V.o2 max ≥10 mL/kg/min. Values greater than 15 mL/kg/min generally indicate the patient’s ability to tolerate pneumonectomy.
Table 19-12Relation between maximum oxygen consumption (V.o2 max) as determined by preoperative exercise testing and perioperative mortality ||Download (.pdf) Table 19-12 Relation between maximum oxygen consumption (V.o2 max) as determined by preoperative exercise testing and perioperative mortality
|STUDY ||DEATHS/TOTAL |
|V.o2 max 10–15 mL/kg per minute || |
| Smith et al196 ||1/6 (33%) |
| Bechard and Wetstein197 ||0/15 (0%) |
| Olsen et al198 ||1/14 (7.1%) |
| Walsh et al199 ||1/5 (20%) |
| Bolliger et al200 ||2/17 (11.7%) |
| Markos et al201 ||1/11 (9.1%) |
| Wang et al202 ||0/12 (0%) |
| Win et al203 ||2/16 (12.5%) |
| Total ||8/96 (8.3%) |
|V.o2 max <10 mL/kg per minute || |
| Bechard and Wetstein197 ||2/7 (29%) |
| Olsen et al198 ||3/11 (27%) |
| Holden et al204 ||2/4 (50%) |
| Markos et al201 ||0/5 (0%) |
| Total ||7/27 (26%) |
The risk assessment of a patient is an amalgam of clinical judgment and data. The risk assessment described earlier must be integrated with the experienced clinician’s sense of the patient and with the patient’s attitude toward the disease and toward life. Figure 19-24 provides a useful algorithm for determining suitability for lung resection.44
Algorithm for preoperative evaluation of pulmonary function and reserve prior to resectional lung surgery. CPET = cardiopulmonary exercise test; CT = computed tomographic scan; CXR = chest radiograph; Dlco = carbon monoxide diffusion capacity; FEV1 = forced expiratory volume in 1 second; %ppo = percent predicted postoperative lung function; V.o2 max = maximum oxygen consumption. (Reproduced with permission from the American College of Chest Physicians from Colice GL, et al: Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP Evidence-based Clinical Practice Guidelines. (2nd edition) Chest. 2007;132:161S.)
Grade IV NEC (Small Cell) Lung Carcinoma
In rare circumstances where SCLC presents as an isolated lung lesion, lobectomy followed by chemotherapy is warranted after surgical mediastinal staging has confirmed the absence of N2 disease. Often, ultrasound-guided FNA provides a definitive positive diagnosis and more invasive approaches are not needed. However, less than 5% are stage I, and there is no benefit from surgical resection for more advanced-stage disease; treatment is chemotherapy with or without radiation therapy depending on the extent of disease and the patient performance status.
Early-Stage Non–Small Cell Lung Cancer
Early-stage disease includes T1 and T2 tumors (with or without N1 nodal involvement) and T3 tumors (without N1 nodal involvement). This group represents a small but increasing proportion of the total number of patients diagnosed with lung cancer each year (approximately 20% of 101,844 patients from 1989 to 2003).45 Surgical resection is the current standard, ideally accomplished by video-assisted lobectomy or pneumonectomy, depending on the tumor location.
Despite the term “early-stage,” the overall 5-year survival rate for stage I is 65% and only 41% for stage II. Median survival for untreated patients with stage IA NSCLC is 14 months, and 5-year survival rate is 22%.46 After surgical resection of postoperative pathologic stage IA disease, 5-year survival is better than with no treatment, but still only 67%.41 Survival declines with higher stages. Advanced age at diagnosis, male sex, low socioeconomic status, nonsurgical treatment, and poor histologic grade are associated with increased mortality risk on multivariate analysis.45
Depending on tumor size and location, lobectomy, sleeve lobectomy, and occasionally pneumonectomy, with mediastinal lymph node dissection or sampling, are appropriate for patients with clinical early-stage disease. Sleeve resection is performed for tumors located at airway bifurcations when an adequate bronchial margin cannot be obtained by standard lobectomy. Pneumonectomy is rarely performed; primary indications for pneumonectomy in early-stage disease include large central tumors involving the distal main stem bronchus and inability to completely resect involved N1 lymph nodes. The latter circumstance occurs with bulky adenopathy or with extracapsular nodal spread.
Management of Early-Stage Lung Cancer in the High-Risk Patient
Lobectomy may not be an option for some patients with early-stage disease, due to poor cardiopulmonary function or other comorbid illnesses. The ultimate decision that a patient is not operable, both with regard to the ability of the patient to tolerate surgery and the likelihood of successful resection, should be accepted only after evaluation by an expert surgeon. Surgeons with limited expertise, when faced with a complicated patient, should refer the patient to a high-volume center for further evaluation if they are unable to offer the patient surgical resection in their own center.
Rationale for Limited Resection in Early-Stage Lung Cancer
Limited resection, defined as segmentectomy or wedge resection, is a viable option for achieving local control in high-risk patients. Historically, limited resection with wedge or segmentectomy has been considered a compromise operation due to unacceptably high rates of local recurrence and concerns for worse survival.47,48 Subsequent meta-analysis of the literature shows that the difference in death rate is likely negligible49 (Table 19-13). The high rates of local recurrence demonstrated by Ginsberg and others, however, remain a significant concern and continue to restrict the use of limited resection for early-stage lung cancer to the high-risk patient.
Table 19-13Summary of studies comparing limited resection and lobectomy ||Download (.pdf) Table 19-13 Summary of studies comparing limited resection and lobectomy
|STUDY ||STUDY DESIGN ||STAGE ||NO. OF LIMITED RESECTIONS ||NO. OF LOBECTOMIES ||REASONS FOR LIMITED RESECTION ||SURVIVAL DIFFERENCE |
|Hoffman and Ransdell (1980)70 ||RS ||IA ||33 (W) ||40a ||Poor cardiopulmonary function and smaller lesions ||NS |
|Read et al (1990)71 ||RS ||IA ||113 (107 S + 6 W) ||131 ||ND ||NS (CSS) |
|Date et al (1994)72 ||MPS ||IA ||16 (6 S + 10 W) ||16 ||Poor pulmonary function ||Lobectomy better |
|Warren and Faber (1994)48 ||RS ||IA + IB ||66 (S) ||103 ||Poor cardiopulmonary function and smaller lesions ||Lobectomy better |
|Harpole et al (1995)73 ||RS ||IA + IB ||75 (W) ||193 ||Poor cardiopulmonary function and smaller lesions ||NS (CSS) |
|LCSG (1996)47,74 ||RCT ||IA ||122 (82 S + 40 W) ||125 ||Randomization ||NS |
|Kodama et al (1997)75 ||RS ||IA ||46b (W) ||77 ||Intentional resection for small lesions ||NS |
|Landreneau et al (1997)76 ||RS ||IA ||102 (W) ||117 ||Poor cardiopulmonary function ||NS |
|Pastorino et al (1997)77 ||RS ||IA + IB ||53 (S + W) ||367 ||ND ||NS |
|Kwiatkowski et al (1998)78 ||RS ||IA + IB ||58 (S + W) ||186c ||ND ||Lobectomy better |
|Okada et al (2001)79 ||RS ||IA ≤2 cm ||70 (S) ||139 ||Intentional resection for small lesions ≤2 cm ||NS |
|Koike et al (2003)80 ||RS ||IA ≤2 cm ||74 (60 S + 14 W) ||159 ||Intentional resection for small lesions ≤2 cm ||NS |
|Campione et al (2004)81 ||RS ||IA ||21 (S) ||100 ||Poor cardiopulmonary function ||NS |
|Keenan et al (2004)82 ||RS ||IA + IB ||54 (S) ||147 ||Poor pulmonary function ||NS |
With the recent publication of a 20% reduction in lung cancer mortality with screening CT scans in high-risk populations, the topic of limited resection is again the subject of intensive review. Studies investigating anatomic segmentectomy (or extended wedge resection) with hilar and mediastinal lymph node dissection suggest that close attention to the ratio of surgical margin to tumor diameter and a careful assessment of the lymph nodes substantially reduce local recurrence.50,51,52 Recurrence rates were 6.2%, comparable to rates associated with lobectomy, when the margin-to-tumor diameter ratio exceeded 1, compared to 25% if the margin-to-tumor diameter ratio was less than 1.50 In most centers, this requires use of a thoracotomy, although increasing experience with VATS in high-volume centers shows that limited resection is safe and feasible, with perioperative adverse outcomes that are comparable to lobectomy.52,53,54,55
Rationale for Tumor Ablation in the Management of Primary Lung Cancer
Limited resection, by definition, requires that the patient has sufficient cardiopulmonary reserve to undergo a general anesthesia and loss of at least one pulmonary segment. For the high-risk or nonoperable patient, as determined by experience pulmonary surgeons, tumor ablation techniques have been developed for treatment of early-stage lung cancers.
Current limitations of this approach include the absence of nodal staging, lack of tissue for molecular profiling, chemoresistance, or sensitivity testing, concerns about definitions of locoregional recurrence, and a lack of uniformity across centers. Surgeons typically define locoregional recurrence as tumor growth within the operative field, including resectable lymph nodes, whereas local recurrence after ablation is most commonly defined as tumor growth within the field of treatment. Despite the fact that in-transit or lymph node metastases are present in up to 27% of clinically stage I NSCLCs at resection, any tumor growth outside the field of ablative treatment is not be considered treatment failure.56
Despite these limitations, tumor ablative strategies are increasingly proposed as viable alternatives to surgical resection, even in potentially operable patients.56,58,59,60,61,62 While premature, ablative techniques may ultimately be shown to have efficacy equivalent to lobectomy for the primary treatment of very small peripheral early-stage lung cancers. Multidisciplinary collaboration between thoracic surgery, interventional radiology/pulmonology, and radiation oncology is required to ensure that development of these ablative techniques occurs through properly designed and well-controlled prospective studies and will ensure that patients receive the best available therapy, regardless of whether it is surgical resection or ablative therapy.
The two most commonly applied ablation techniques are radiofrequency ablation and stereotactic body radiotherapy.
Radiofrequency ablation. Radiofrequency ablation is performed using either monopolar or bipolar delivery of electrical current to electrodes placed within the tumor tissue. In lung tumors, the electrodes are typically inserted into the tumor mass under CT guidance. An electrical current is delivered; the current is converted by means of friction into heat, which quickly leads to immediate and irreparable tissue destruction in the tissue surrounding the electrode. The efficacy of radiofrequency ablation for controlling the primary tumor and improving survival in poor operative candidates (either due to significant comorbid diseases precluding general anesthesia or poor pulmonary function excluding lung resection) is safe and feasible for peripheral lung nodules. In tumors <3.5 cm, the rate of radiographic resolution of tumor is up to 80% and cancer-specific survival at 2 years was approximately 90%, indicating excellent local control of the primary site.57,58,59,63 It has become the preferred modality for small peripheral tumors over standard external-beam radiation in centers where the technique is available.
Radiofrequency ablation is an excellent modality for the patient at risk for adverse outcomes with pulmonary resection or for patients who refuse surgery, and surgeons should have an algorithm for determining which patients are optimal for this modality.64,65,66,68,69 (see Fig. 19-24). Target lesions larger than 5 cm, tumor abutting the hilum, associated malignant pleural or pericardial effusion, greater than three lesions in one lung, and the presence of pulmonary hypertension are all contraindications to radiofrequency ablation.64 Proximity to a large vessel is a contraindication not only due to the risk of massive bleeding, but also because large blood vessels act as a heat sink and lethal cellular temperatures are less likely to be achieved. For these patients, stereotactic body radiotherapy may provide local tumor control with less risk of major complications. Combination therapy with either external-beam radiation or stereotactic body radiotherapy is also under investigation.
Stereotactic body radiotherapy. Stereotactic body radiotherapy applies highly focused, high-intensity, three-dimensional conformal radiation to the target lesion over a few sessions. Tumor motion quantification and image guidance technologies have significantly improved the delivery of radiation with high levels of precision to the target lesion. This accuracy is important because the lung is extremely sensitive to radiation injury and the majority of patients with early-stage lung cancer who are currently considered candidates for ablative therapy have marginal lung function; excessive injury to normal surrounding lung tissue is not desirable. Importantly, these techniques allow the safe delivery of up to 66 Gy of radiation to the target tumors without exceeding the maximum-tolerated dose.62,83 A phase II North American multicenter study recently demonstrated the safety and efficacy of this approach in 59 nonoperable patients.62 Patients with biopsy-proven, node-negative peripheral NSCLCs less than 5 cm in diameter (T1 or T2) were treated with stereotactic body radiotherapy after they were deemed inoperable, based on coexisting medical conditions, by a thoracic surgeon and/or pulmonologist. Primary tumor control was excellent; at 3 years, 97.6% were deemed to have primary tumor control by the authors and 90.6% had local control. However, it is important to note that primary tumor failure was defined specifically as at least a 20% increase in the longest diameter of the gross tumor volume by CT scan and evidence of tumor viability either by biopsy confirming carcinoma or by demonstration of FDG avidity on PET scan. For viability to be confirmed with PET scan, the uptake was required to be of similar intensity to the pretreatment staging PET scan. Failure beyond a 1.5- to 2-cm margin around the primary tumor volume was considered local failure. Failure in regional node basins was seen in two patients. When compared to locoregional control rates of approximately 6.5% with limited resection, the 3-year locoregional recurrence was higher at 12.8%.
Patient selection for stereotactic body radiotherapy, as with limited resection and radiofrequency ablation, is important. Because the radiation field is so precise, patients with severe emphysema and chronic obstructive pulmonary disease can be safely treated without significant concern for worsening lung function. However, patients with central tumors near the mediastinum and hilum have increased incidence of significant hypoxia, hemoptysis, atelectasis, pneumonitis, and reduced pulmonary function.83 In the multicenter trial detailed earlier, treated tumors were required to be greater than 2 cm from the proximal bronchial tree in all directions (which they defined as the distal 2 cm of the trachea, carina, and named major lobar bronchi up to their first bifurcation).62
Rationale for Chemotherapy in the Management of Early-Stage NSCLC
The role of chemotherapy in early-stage (stage I and II) NSCLC is evolving, with several prospective phase II studies having shown a potential benefit.84,85 Initial concerns that induction chemotherapy may result in increased perioperative morbidity or mortality appear to be unwarranted, as the incidence of perioperative morbidity and mortality is not different between the two groups, except in patients undergoing right-sided pneumonectomy after induction chemotherapy.86 As shown in Table 19-14, an absolute survival benefit of 4% to 7% can be realized using induction for all stages of lung cancer, and in situations where use of adjuvant chemotherapy is anticipated, induction chemotherapy is an acceptable alternative.
Table 19-14Five-year stage-specific survival after induction chemotherapy followed by surgery ||Download (.pdf) Table 19-14 Five-year stage-specific survival after induction chemotherapy followed by surgery
|STAGE ||5-YEAR SURVIVAL (%) ||ABSOLUTE BENEFIT (%) ||NEW 5-YEAR SURVIVAL (%) |
|IA ||75 ||4 ||79 |
|IB ||55 ||6 ||61 |
|IIA ||50 ||7 ||57 |
|IIB ||40 ||7 ||47 |
|IIIA ||15–35 ||6–7 ||21–42 |
|IIIB ||5–10 ||3–5 ||8–15 |
National Comprehensive Cancer Network guidelines currently recommend observation for T1a (≤2 cm) and T1b (>2–≤3 cm), node-negative, completely resected NSCLCs (T1abN0M0). For patients with larger tumors (T2a tumor >3 cm but ≤5 cm; T2b tumor >5 cm but ≤7 cm) that are node-negative, it is recommended that chemotherapy be considered in high-risk patients, ideally in the setting of a clinical trial. High-risk tumor characteristics include poorly differentiated tumors, moderately to poorly differentiated lung neuroendocrine tumors, vascular invasion, resection limited to wedge resection only, tumors >4 cm in size, visceral pleural involvement, and when lymph node sampling at the time of resection was incomplete (Nx).
Evaluation and Management of Locally Advanced NSCLC
Five-year relative survival in patients with locoregional disease is 25%, but there is significant heterogeneity within the group. Stage III disease includes patients with small tumors that have metastasized to the mediastinal lymph nodes as well as large tumors invading unresectable structures or the major carina with no nodal metastasis at all. Patients with clinically evident N2 disease (i.e., bulky adenopathy present on CT scan or mediastinoscopy, with lymph nodes often replaced by tumor) have a 5-year survival rate of 5% to 10% with surgery alone. In contrast, patients with microscopic N2 disease discovered incidentally in one lymph node station after surgical resection have a 5-year survival rate that may be as high as 30%. As a result, many surgeons and oncologists differentiate between microscopic and bulky N2 lymphadenopathy and the number of involved N2 nodal stations in determining whether to proceed with resection following induction therapy. It is generally accepted that surgical resection is appropriate for patients with a single-station metastasis with a single lymph node smaller than 3 cm, although randomized trials specifically investigating resection following induction therapy for patients with single-station microscopic disease have not yet been performed.
Histologic confirmation of N2 nodal metastases is imperative; false-positive findings on PET scan are unacceptably high, and reliance on this modality will lead to significant undertreatment of patients with earlier stage cancers. This is particularly true in regions with high incidence of granulomatous diseases. When N2 nodes are found, incidentally, to harbor metastasis at the time of planned anatomic lung resection, the decision to proceed with resection varies depending on surgeon preference; it is acceptable to either proceed with anatomic resection and mediastinal lymph node sampling/dissection or to stop the procedure, refer the patient for induction therapy, and re-evaluate for resection after induction therapy is completed. When histologically confirmed metastases are found during preoperative staging evaluation, patients should be referred for induction chemotherapy; patients in whom the mediastinal nodes are sterilized by induction therapy have a better prognosis, and surgical resection is generally warranted as part of a multimodal approach. As with preinduction evaluation, histologic confirmation of persistent N2 disease after induction therapy is imperative; patients should not be denied surgical resection following induction chemotherapy based on radiographic evidence for N2 disease because the survival for resected NSCLC is significantly better than with definitive chemotherapy.
Surgery in T4 and Stage IV Disease
Surgery is occasionally appropriate for highly selected patients with tumors invading the SVC, carinal or vertebral body involvement, or satellite nodules in the same lobe (T3, N0-1, M0) or in T4, N0-1 tumors with limited invasion into the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina through direct extension. Surgery generally does not have a role in the care of patients with any tumor with N3 disease or T4 tumors with N2 disease. Survival rates remain extremely low for these patients. Simlarly, the treatment of patients with stage IV disease is chemotherapy. However, on occasion, patients with a single site of metastasis are encountered, particularly with adenocarcinomas presenting with a solitary brain metastasis. In this highly select group, 5-year survival rates of 10% to 15% can be achieved with surgical excision of the brain metastasis and the primary tumor, assuming it is early stage.
Surgery for Management of Pancoast’s Tumor
Carcinoma arising in the extreme apex of the chest with associated arm and shoulder pain, atrophy of the muscles of the hand, and Horner’s syndrome presents a unique challenge to the surgeon. Any tumor of the superior sulcus, including tumors without evidence for involvement of the neurovascular bundle, is now commonly known as Pancoast’s tumors, after Henry Pancoast who described the syndrome in 1932. The designation is reserved for tumors involving the parietal pleura or deeper structures overlying the first rib. Chest wall involvement at or below the second rib is not a Pancoast’s tumor.74 Treatment is multidisciplinary; due to the location of the tumor and involvement of the neurovascular bundle that supplies the ipsilateral extremity, preserving postoperative function of the extremity is critical. For this reason, resection should only be performed in patients who are proven negative for mediastinal lymph node involvement. Survival with N2 positive nodes is poor, and the morbidity and mortality associated with surgical resection are high. If bulky lymphadenopathy is present, EBUS- or EUS-guided FNA/core-needle biopsy may prove nodal involvement. However, a negative FNA is not sufficient for proving the absence of mediastinal involvement and should be followed by mediastinoscopy to ensure accurate and complete evaluation of the mediastinum.
Because Pancoast’s tumors have high rates of local recurrence and incomplete resection, induction chemoradiotherapy followed by surgery is recommended. This treatment regimen was well tolerated in a study performed by the Southwest Oncology Group, with 95% of patients completing induction treatment. Complete resection was achieved in 76%. Five-year survival was 44% overall and 54% when complete resection was achieved. Disease progression with this regimen was predominantly at distant sites, with the brain being the most common.75 The current treatment algorithm for Pancoast’s tumors is presented in Fig. 19-25.
Treatment algorithm for Pancoast’s tumors. CT = computed tomography; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; NSCLC = non–small cell lung cancer; PET = positron emission tomography.
Surgical excision is performed via thoracotomy with en bloc resection of the chest wall and vascular structures and anatomic lobectomy. A portion of the lower trunk of the brachial plexus and the stellate ganglion are also typically resected. With chest wall involvement, en bloc chest wall resection, along with lobectomy, is performed, with or without chest wall reconstruction. For small rib resections or those posterior to the scapula, chest wall reconstruction is usually unnecessary. Larger defects (two rib segments or more) are usually reconstructed with Gore-Tex to provide chest wall contour and stability. En bloc resection is also used for other locally advanced tumors (T3) with direct invasion of the adjacent chest wall, diaphragm, or pericardium. If a large portion of the pericardium is removed, reconstruction with thin Gore-Tex membrane will be required to prevent cardiac herniation and venous obstruction.
Preoperative (Induction) Chemotherapy for NSCLC
The use of chemotherapy before anatomic surgical resection has a number of potential advantages:
The tumor’s blood supply is still intact, allowing better chemotherapy delivery and avoiding tumor cell hypoxia (in any residual microscopic tumor remaining postoperatively), which would increase radioresistance.
The primary tumor may be downstaged, enhancing resectability.
Patients are better able to tolerate chemotherapy before surgery and are more likely to complete the prescribed regimen than after surgery.
It functions as an in vivo test of the primary tumor’s sensitivity to chemotherapy.
Response to chemotherapy can be monitored and used to guide decisions about additional therapy.
Systemic micrometastases are treated.
It identifies patients with progressive disease/non-responders and spares them a pulmonary resection.
Potential disadvantages include:
There is a possible increase in the perioperative complication rate in patients requiring right pneumonectomy after induction chemotherapy.
While the patient is receiving chemotherapy, potentially curative resection is delayed; if the patient does not respond, this delay could result in tumor spread.
In stage IIIA N2 disease, the response rates to induction chemotherapy are high, in the range of 70%. The treatment is generally safe, as it does not cause a significant increase in perioperative morbidity. Two randomized trials have now compared surgery alone for patients with N2 disease to preoperative chemotherapy followed by surgery. Both trials were stopped before complete accrual because of a significant increase in survival for the chemotherapy arm. The initially observed survival differences have been maintained for up to 3 years and beyond (5-year data not shown). Given these results, induction chemotherapy with cisplatin-based regimens (two to three cycles) has become standard for patients with N2 disease. Table 19-15 summarizes the findings of a systematic review and meta-analysis reporting response rates, progression-free survival, and overall survival after induction chemotherapy followed by surgical resection.
Table 19-15Selected randomized trials of neoadjuvant chemotherapy for stage III non–small cell lung cancer ||Download (.pdf) Table 19-15 Selected randomized trials of neoadjuvant chemotherapy for stage III non–small cell lung cancer
|TRIAL (REFERENCE) ||NO. OF PATIENTS (STAGE III) ||CHEMOTHERAPY ||RESPONSE RATE (%) ||PCR (%) ||COMPLETE RESECTION ||PFS ||OS ||5-YEAR SURVIVAL |
|Rosell et al85 ||60 (60) || |
|60 ||4 ||85% ||12 vs. 5 mo (DFS; P = .006) ||22 vs. 10 mo (P = .005) ||16% vs. 0% |
|Roth et al90 ||60 (60) || |
|35 ||NR ||39% vs. 31% ||Not reached vs. 9 mo (P = .006) ||64 vs. 11 mo (P = .008) ||56% vs. 15%a |
|Pass et al91 ||27 (27) || |
|62 ||8 ||85% vs. 86% ||12.7 vs. 5.8 mo (P = .083) ||28.7 vs. 15.6 mo (P = .095) ||NR |
|Nagai et al92 ||62 (62) || |
|28 ||0 ||65% vs. 77% ||NR ||17 vs. 16 mo (P = .5274) ||10% vs. 22% |
|Gilligan et al93 ||519 (80) ||Platinum basedb ||49 ||4 ||82% vs. 80% ||NR ||54 vs. 55 mo (P = .86) ||44% vs. 45% |
|Depierre et al94 ||355 (167) || |
|64 ||11 ||92% vs. 86% ||26.7 vs. 12.9 mo (P = .033) ||37 vs. 26 mo (P = .15) ||43.9% vs. 35.3%c |
|Pisters et al95 ||354 (113)d || |
|41 ||NR ||94% vs. 89% ||33 vs. 21 mo (P = .07) ||75 vs. 46 mo (P = .19) ||50% vs. 43% |
|Sorensen et al96 ||90 (NR) || |
|46 ||0 ||79% vs. 70% ||NR ||34.4 vs. 22.5 mo (NS) ||36% vs. 24% (NS) |
|Mattson et al97 ||274 (274) ||Docetaxel ||28 ||NR ||77% vs. 76%e ||9 vs. 7.6 mo (NS) ||14.8 vs. 12.6 mo (NS) ||NR |
Postoperative (Adjuvant) Chemotherapy for NSCLC
Postoperative adjuvant chemotherapy was previously thought to confer no benefit based on multiple prospective randomized trials, in part because patients who had undergone thoracotomy and lung resection had difficulty tolerating the adjuvant regimens. More recently, however, newer, more effective agents have shown promise and adjuvant therapy is better tolerated after minimally invasive lung resection (i.e., VATS or robotic anatomic resection). Targeted therapies, which have been shown to be beneficial in advanced-stage lung cancer, are of particular interest.
Any patient with nodal metastasis (N1 or N2) or with T3 tumors (defined as tumors >7 cm; invading chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, or main bronchus tumor <2 cm distal to the carina; causing atelectasis or obstructive pneumonitis; or with separate nodules in the same lobe of the lung) should receive adjuvant chemotherapy if they are able to tolerate the regimens. In the situation where the margins of resection are positive, re-resection is recommended. If not possible, concurrent chemoradiation is recommended for macroscopic residual tumor and sequential chemoradiation for microscopic residual tumor.
Definitive Nonsurgical Treatment for NSCLC
Recent advances in targeted therapies have changed the management of advanced NSCLC from a generalized, platinum-based approach to one in which molecular analysis and targeted, personalized therapies are now standard of care. It is now mandatory that the pathologist clearly differentiate between squamous cell carcinoma and adenocarcinoma because the therapeutic options are different and use of bevacizumab, while beneficial in patients with adenocarcinoma, has been found to cause excessive pulmonary hemorrhage in patients with squamous histology. For the surgeon, this requirement translates into a much more aggressive approach to tissue diagnosis. At our institution, the cytopathologist provides onsite rapid assessment of the fine-needle aspirate to determine whether tumor cells are present and confirm that sufficient tumor cells are present to enable molecular testing. This has increased the number of passes performed during an EBUS-guided FNA or during CT-guided aspiration of a pulmonary or intrathoracic lesion; typically, an additional two passes are made for cell block material after confirming the presence of tumor cells in the target area. When insufficient cells are obtained for molecular testing, despite having a diagnosis, additional sampling is warranted; this is mandatory in patients with adenocarcinoma and likely to become necessary for other non–small cell histologic types as advances in targeted therapies become available for clinical use. Acquiring adequate tissue for diagnosis may require mediastinoscopy or VATS; close communication between the oncologist, surgeon, pathologist, and patient is needed to ensure that the benefits to the patient clearly outweigh the risks and that results obtained through more aggressive diagnostic measures are needed to direct subsequent care.
Once a treatment plan has been devised, two strategies for delivery are available. “Sequential” chemoradiation involves full-dose systemic chemotherapy (i.e., cisplatin combined with a second agent) followed by standard radiotherapy (approximately 60 Gy). The combination of chemotherapy followed by radiation has improved 5-year survival from 6% with radiotherapy alone to 17%.89 An alternative approach, referred to as “concurrent chemoradiation,” administers chemotherapy and radiation at the same time. Certain chemotherapeutic agents sensitize tumor cells to radiation and, thus, enhance the radiation effect. The advantages of this approach are improved primary tumor and locoregional lymph node control and elimination of the delay in administering radiotherapy that occurs with sequential treatment. A disadvantage, however, is the necessary reduction in chemotherapy dosage in order to diminish overlapping toxicities; this can potentially lead to undertreatment of systemic micrometastases. Randomized trials have shown a modest 5-year survival benefit as compared with chemotherapy. In a systematic review of 47 trials and six meta-analyses, an absolute survival benefit of 4% at 2 years was seen when concurrent platinum-based chemoradiation was given compared to sequential radiation.98
Definitive radiotherapy is predominantly used for palliation of symptoms in patients with poor performance status; cure rates with radiation as a single modality in patients with N2 or N3 disease is less than 7%. Recent improvement has been seen with three-dimensional conformal radiotherapy and altered fractionation. Such poor results for patients with stage III lung cancer reflect the limitations of locoregional treatment in a disease where death results from systemic metastatic spread.
Options for Thoracic Surgical Approaches
Thoracic surgical approaches have changed over recent years with advancements in minimally invasive surgery. A surgeon trained in advanced minimally invasive techniques can now perform pleural-based, pulmonary and mediastinal procedures through multiple thoracoscopic ports without the need for a substantial, rib-spreading incision. Subjective measures of quality of life after VATS, such as pain (Fig. 19-26) and perceived functional recovery, consistently and reproducibly favor VATS over thoracotomy. Objective measures such as functional status as measured by 6-minute walk, return to work, and ability to tolerate chemotherapy also favor VATS over thoracotomy. Finally, recovery of respiratory function occurs earlier in VATS patients. These findings are pronounced in patients with chronic obstructive pulmonary disease and in the elderly—populations whose quality of life can be dramatically impacted by changes in their respiratory symptoms and function, thoracic pain, and physical performance. Table 19-16 provides a summary of populations that may benefit from VATS approaches.
Table 19-16Special circumstances under which lobectomy by video-assisted thoracic surgery may be preferable ||Download (.pdf) Table 19-16 Special circumstances under which lobectomy by video-assisted thoracic surgery may be preferable
|CONDITION ||EXAMPLES |
|Pulmonary compromise ||Poor FEV1/Dlco, heavy smoking, sleep apnea, recent pneumonia |
|Cardiac dysfunction ||Congestive heart failure, severe coronary artery disease, recent myocardial infarction, valvular disease |
|Extrathoracic malignancy ||Solitary brain metastasis from lung cancer, deep pulmonary metastases requiring lobectomy |
|Poor physical performance ||Performance status equivalent to a Zubrod score of 2 or 3, morbid obesity |
|Rheumatologic/orthopedic condition ||Spinal disease, severe rheumatoid arthritis, severe kyphosis, lupus erythematosus, osteomyelitis |
|Advanced age ||Age >70 years |
|Vascular problems ||Aneurysm, severe peripheral vascular disease |
|Recent or impending major operation ||Urgent abdominal operation, joint replacement requiring use of crutches, need for contralateral thoracotomy |
|Psychological/neurologic conditions ||Substance abuse, poor command following, pain syndromes |
|Immunosuppression/ impaired wound healing ||Recent transplantation, diabetes |
Pie chart comparison of pain control at 3 weeks after lobectomy by standard thoracotomy or video-assisted thoracic surgery (VATS). The pie charts show that patients undergoing VATS have significantly less pain (P < .01) as measured by the most potent analgesic still required: severe—schedule II narcotic; moderate—schedule III or lower narcotic; mild—nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen. (Reproduced with permission from Demmy TL, Nwogu C. Is video-assisted thoracic surgery lobectomy better? Quality of life considerations. Ann Thorac Surg. 2008;85:S719. Copyright Elsevier.)
Video-Assisted Thoracoscopic Surgery
VATS has become the recommended approach to diagnosis and treatment of pleural effusions, recurrent pneumothoraces, lung biopsies, lobectomy or segmental resection, resection of bronchogenic and mediastinal cysts, and intrathoracic esophageal mobilization for esophagectomy.99 It is also utilized for pneumonectomy in some centers of excellence with very high volumes of VATS lung resection. VATS is performed via two to four incisions measuring 0.5 to 1.2 cm in length to allow insertion of the thoracoscope and instruments. An access incision, typically in the fourth or fifth intercostal space in the anterior axillary line, is used for dissection of the hilum during lung resection. The incision location varies according to the procedure. With respect to VATS lobectomy, port placement varies according to the lobe being resected and is highly variable among surgeons.100 The basic principle is to position the ports high enough on the thoracic cage to have access to the hilar structures Endoscopic staplers are used to divide the major vascular structures and bronchus (Fig. 19-27).
Selected video-assisted thoracic surgery lobectomy maneuvers. All the maneuvers are shown with the patient positioned in the left lateral decubitus position. The same maneuvers can be performed in mirror image for left-sided work. A. Medial viewing and inferior holding of lung to allow dissection through the access incision. Example shows dissection of the apical hilum. B. Medial viewing and access holding of lung to allow stapling of hilar structures from below. Example shows division of the apical pulmonary artery trunk to the right upper lobe (upper lobe branch of vein divided and reflected away). C. Standard viewing and use of working port to dissect and divide structures while lung is retracted through access incision. Example shows use of stapler to divide pulmonary artery to right lower lobe. D. Standard viewing and use of working port to retract lung and access incision to dissect structures. This method is commonly used to dissect the pulmonary artery in the major fissure. Example shows inferior pulmonary vein after the pulmonary ligament was divided using this maneuver. E. Standard viewing and use of access incision to deliver stapler to divide fissures. Example shows division of the posterior fissure between the right lower lobe and the upper lobe. (Reproduced with permission from Demmy et al.100 Copyright Elsevier.)
Open approaches to Thoracic Surgery
When video-assisted thoracoscopic approach is not possible, an open approach, most frequently the posterolateral thoracotomy, is used to gain access to the intrathoracic space.101,102 The posterolateral thoracotomy incision can be used for most pulmonary resections, esophageal operations, and operations in the posterior mediastinum and vertebral column (Fig. 19-28). The anterolateral thoracotomy has traditionally been used in trauma victims. This approach allows quick entry into the chest with the patient supine. In the face of hemodynamic instability, the lateral decubitus position significantly compromises control over the patient’s cardiopulmonary system and resuscitation efforts, whereas the supine position allows the anesthesiologist full access to the patient. A bilateral anterior thoracotomy incision with a transverse sternotomy (“clamshell” thoracotomy) is a standard operative approach to the heart and mediastinum in certain elective circumstances. It is the preferred incision for double-lung transplantation in many centers. A partial median sternotomy can also be added to an anterior thoracotomy (“trap-door” or “hemiclamshell” thoracotomy) for access to mediastinal structures. A hypesthetic nipple is a frequent complication of this approach. The median sternotomy incision allows exposure of anterior mediastinal structures and is principally used for cardiac operations. Although the surgeon has access to both pleural cavities, incision into the pleural cavity can be avoided if entry is unnecessary (Fig. 19-29).
The posterolateral thoracotomy incision. A. Skin incision from the anterior axillary line to the lower extent of the scapula tip. B and C. Division of the latissimus dorsi and shoulder girdle musculature. D. The pleural cavity is entered after dividing the intercostal muscles along the lower margin of the interspace, taking care not to injure the neurovascular bundle lying below each rib.
The median sternotomy incision. A. Skin incision from the suprasternal notch to the xiphoid process. B. Exposure of the pleural space. a. = artery; v. = vein.
At the conclusion of most thoracic operations, the pleural cavity is drained with a chest tube(s). If the visceral pleura has not been violated and there is no concern for pneumo- or hemothorax (e.g., after VATS sympathectomy), a chest tube is unnecessary. After chest tube placement, the lung is re-expanded with positive-pressure ventilation. There are two reasons for the use of pleural tubes in this setting: first, the tube allows evacuation of air if an air leak is present; second, blood and pleural fluid can be drained, thereby preventing accumulation within the pleural space that would compromise the patient’s respiratory status. The tube is removed when the air leak is resolved and when the volume of drainage decreases below an acceptable level over 24 hours.
Historically, many surgeons have somewhat arbitrarily required less than 150 mL of drainage volume over 24 hours prior to removing a chest tube to minimize risk of reaccumulation. The pleural lymphatics, however, can absorb up to 0.40 mL/kg per hour in a healthy individual, which may be as much as 500 mL over a 24-hour period. In fact, studies have shown that pleural tubes can be removed after VATS lobectomy or thoracotomy with 24-hour drainage volumes as high as 400 mL, without subsequent development of pleural effusions.103 It is our current practice to remove chest tubes with 24-hour outputs of 400 mL or less after lobectomy or lesser pulmonary resections. In settings where normal pleural fluid dynamics have been altered, such as malignant pleural effusion, pleural space infections or inflammation, and pleurodesis, strict adherence to a volume requirement before tube removal is appropriate (typically 100–150 mL over 24 hours).
For operations involving lung resection or parenchymal injury, suction levels of –20 cm H2O are routinely used to eradicate residual air spaces and to control postoperative parenchymal air leaks for the first 12 to 24 hours. The following day, however, the decision to continue suction or place the patient to water seal (off suction) must be made. Applying suction to an air leak has been shown to prolong the duration of the air leak and extend the time frame during which tube thoracostomy is needed.104 The main guidelines for the continued use of suction if an air leak is present depend on the expansion of the remaining lung as determined by CXR. If the lung is well-expanded, the chest tube can remain to water seal drainage. If an undrained pneumothorax is present on CXR, the chest tube and its attached tubing should be examined to ensure that the chest tube is patent and the attached tubing is not kinked or mechanically obstructed, such as occurs when the patient is lying on the tube. If the tube is a small caliber tube (aka pigtail catheter), it should be flushed with sterile saline through a three-way stopcock that has been cleaned with alcohol because these tubes tend to become clogged with fibrin. These catheters are also prone to kinking at the insertion site into the skin. Once the surgeon has confirmed that the chest tube is patent, the patient is asked to voluntarily cough or perform the Valsalva maneuver. This maneuver increases the intrathoracic pressure and will push air that is contained within the hemithorax out of the chest tube. During the voluntary cough, the fluid level in the water seal chamber should move up and down with the cough and with deep respiration, reflecting the pleural pressure changes occurring with these maneuvers. A stationary fluid level implies either a mechanical blockage (e.g., due to external tube compression or to a clot/debris within the tube) or pleurodesis of the pleural space. If bubbles pass through the water seal chamber, an air leak is presumed. If the leak is significant enough to induce atelectasis or collapse of the lung during use of water seal, suction should be used to achieve lung re-expansion.
Good pain control after intrathoracic procedures is critical; it permits the patient to actively clear and manage secretions and promotes ambulation and a feeling of well-being. The most common techniques of pain management are epidural, paravertebral, and intravenous. Epidural catheters are commonly used, although we prefer to use paravertebral catheters in our center. To maximize efficacy, epidural catheters should be inserted at about the T6 level, roughly at the level of the scapular tip. Lower placement risks inadequate pain control, and higher placement may provoke hand and arm numbness. Typically, combinations of fentanyl at 0.3 μg/mL with either bupivacaine (0.125%) or ropivacaine (0.1%) are used. Ropivacaine has less cardiotoxicity than bupivacaine; thus, the potential for refractory complete heart block, in the case of inadvertent intravenous injection, is significantly less with ropivacaine. Paravertebral blocks can be placed using the same epidural catheter kit 2.5 cm lateral to the spinous process at T4 to T6. Combinations of narcotic and topical analgesia are then infused as with the epidural catheter.
When properly placed, a well-managed epidural can provide outstanding pain control without significant systemic sedation.105 Thoracic epidurals do not commonly cause urinary retention, although a low thoracic epidural may block the sensory fibers to the bladder. Motor function, however, remains intact. In some patients who are having difficulty voiding, it may be possible to avoid Foley catheterization by simply reminding the patient to void on a regular basis. In male patients with voiding difficulty prior to surgery, urinary catheterization may be required. In addition, the use of local anesthetics may cause sympathetic outflow blockade, leading to vasodilation and hypotension often requiring intravenous vasoconstrictors (an α-agonist such as phenylephrine) and/or fluid administration. In such circumstances, fluid administration for hypotension may be undesirable in pulmonary surgery patients, particularly after pneumonectomy. Paravertebral catheters provide equivalent pain control with less effect on hemodynamics.106
Alternatively, intravenous narcotics via patient-controlled analgesia can be used, often in conjunction with ketorolac and intravenous Tylenol. Dosing must be titrated to balance the degree of pain relief with the degree of sedation. Oversedated patients are as ominous as patients without adequate pain control, because of the significant risk of secretion retention, atelectasis/pneumonia, and pulmonary aspiration. These concerns are particularly relevant in elderly patients who should be carefully assessed for aspiration risk when ordered for dietary advancement. Proper pain control with intravenous narcotics requires a carefully regulated balance between pain relief and sedation; maximizing the benefits of pain control while minimizing these very real and potentially life-threatening complications.
Whether on epidural, paravertebral, or intravenous pain control, the patient is typically transitioned to oral pain medication on the third or fourth postoperative day. During both the parenteral and oral phase of pain management, a standardized regimen of stool softeners and laxatives is advisable in order to prevent severe constipation.
The best respiratory care is achieved when the patient is able to deliver an effective cough to clear secretions and results from the commitment and proper training of all involved healthcare providers. The process begins preoperatively, with clear instructions on using pillows (or other support techniques) over the wound and then applying pressure. Postoperatively, proper pain control (as outlined earlier) is essential, without oversedation. Daily morning rounds should include a careful assessment of the patient’s pulmonary status, reminders to the patient and family about the importance of coughing and deep breathing, including use of adjunctive respiratory equipment if ordered, and mobilization of the patient. Early transition to a chair and to ambulation is the best respiratory therapy and should be strongly encouraged. When available, physical and/or cardiopulmonary rehabilitation services are vital additional members of the care team.
In patients whose pulmonary function is significantly impaired preoperatively, generating an effective cough postoperatively may be nearly impossible. In this setting, routine nasotracheal suctioning can be employed, but is uncomfortable for the patient. A better alternative is placement of a percutaneous transtracheal suction catheter at the time of surgery. This catheter is well-tolerated by most patients and allows regular and convenient suctioning.
Postoperative complications after pulmonary resection range from minor to life-threatening. Strict attention to volume status, early and aggressive pulmonary toilet, and good pain control can reduce the risk of most complications, but does not completely eliminate them, even in centers of excellence. The most devastating complication after pulmonary resection is postpneumonectomy pulmonary edema, which occurs in 1% to 5% of patients undergoing pneumonectomy and more often after right compared to left pneumonectomy. Clinically, symptoms of respiratory distress manifest hours to days after surgery. Radiographically, diffuse interstitial infiltration or frank alveolar edema is seen. The pathophysiologic causes are related to factors that increase permeability and filtration pressure and decrease lymphatic drainage from the affected lung. Judicious use of intravenous fluids perioperatively, including use of vasopressors rather than fluid boluses for hypotension intraoperatively and postoperatively, is critical to minimizing the risk of this syndrome. Treatment consists of ventilatory support, fluid restriction, and diuretics. Extracorporeal membrane oxygenation may be life-saving in centers where this option is available. The syndrome reportedly has a nearly 100% mortality rate despite aggressive therapy.
Other postoperative complications include air leak and bronchopleural fistula. Although these are two very different problems, distinguishing between them may be difficult. Postoperative air leaks are common after pulmonary resection, particularly in patients with emphysematous lung, because the fibrosis and destroyed blood supply impairs healing of surface injuries. Prolonged air leaks (i.e., those lasting >5 days) may be treated by diminishing or discontinuing suction (if used), by continuing chest drainage, or by instilling a pleurodesis agent, usually doxycycline or talcum powder, which will cause pleurodesis of the lung within the chest cavity and minimize the possible collapse of the lung due to persistent air leak. This is useful only in patients in whom full lung expansion is achieved, either with suction or on water seal, as patients with a persistent pneumothorax on CXR will not have adequate lung-to-parietal pleural apposition to achieve adequate pleurodesis.
If the leak is moderate to large, a high index of suspicion for bronchopleural fistula from the resected bronchial stump should be maintained, particularly if the patient is immunocompromised or had induction chemotherapy and/or radiation therapy. If a bronchopleural fistula is suspected, flexible bronchoscopy is performed to evaluate the bronchial stump. Management options include continued prolonged chest tube drainage, reoperation, and reclosure (with stump reinforcement with an intercostal muscle flap or a pedicled serratus muscle flap). If the fistula is very small (<4 mm), bronchoscopic fibrin glue application has been used successfully to seal the hole in some patients. Patients often have concomitant empyema, and open drainage may be necessary.
Spontaneous pneumothorax is secondary to intrinsic abnormalities of the lung and can be classified as primary and secondary. Primary spontaneous pneumothorax is defined as a spontaneous pneumothorax without underlying lung disease. The most common cause is rupture of an apical subpleural bleb. The cause of these blebs is unknown, but they occur more frequently in smokers and males, and they tend to predominate in young postadolescent males with a tall thin body habitus. Treatment is generally chest tube insertion with water seal. If a leak is present and persists for greater than 3 days, thoracoscopic management (i.e., bleb resection with pleurodesis by talc or pleural abrasion) is performed. Recurrences or complete lung collapse with the first episode are generally indications for thoracoscopic intervention.107 Additional indications for intervention on the first episode include occupational hazards such as air travel, deep-sea diving, or travel to remote locations. CT findings of multiple small bullae or a large bleb are associated with an increased risk of recurrent pneumothorax.108 Many surgeons are now using screening CT scan to recommend VATS bleb resection with pleurodesis for first-episode spontaneous pneumothorax.
Secondary spontaneous pneumothorax occurs in the setting of underlying lung disease, such as emphysema (rupture of a bleb or bulla), cystic fibrosis, acquired immunodeficiency syndrome (AIDS), metastatic cancer (especially sarcoma), asthma, lung abscess, and occasionally primary lung cancer. Catamenial pneumothorax, a rare but interesting cause of spontaneous pneumothorax in women in their second and third decades, occurs within 72 hours of the onset of menses and is possibility related to endometriosis. Management of pneumothorax in these circumstances is similar to that of primary spontaneous pneumothorax in that drainage and lung re-expansion are required. Additional therapy, however, is often tied to therapy of the specific disease process and may involve lung resection, thoracoscopic pleurectomy, or talc pleurodesis.
A lung abscess is a localized area of pulmonary parenchymal necrosis caused by an infectious organism; tissue destruction results in a solitary or dominant cavity measuring at least 2 cm in diameter. Less often, there may be multiple, smaller cavities (<2 cm). In that case, the infection is typically referred to as a necrotizing pneumonia. An abscess that is present for more than 6 weeks is considered chronic.
Based on the etiology (Table 19-17), lung abscesses are further classified as primary or secondary. A primary lung abscess occurs, for example, in immunocompromised patients, as a result of highly virulent organisms inciting a necrotizing pulmonary infection, or in patients who have a predisposition to aspirate oropharyngeal or gastrointestinal secretions. A secondary lung abscess occurs in patients with an underlying condition such as a partial bronchial obstruction, a lung infarct, or adjacent suppurative infections (subphrenic or hepatic abscesses).109
Table 19-17Causes of lung abscess ||Download (.pdf) Table 19-17 Causes of lung abscess
A. Necrotizing pneumonia
1. Staphylococcus aureus, Klebsiella, Pseudomonas, Mycobacterium
2. Bacteroides, Fusobacterium, Actinomyces
3. Entamoeba, Echinococcus
B. Aspiration pneumonia
3. Drugs or alcohol
C. Esophageal disease
1. Achalasia, Zenker’s diverticulum, gastroesophageal reflux
1. Cancer (and chemotherapy)
3. Organ transplantation
4. Steroid therapy
A. Bronchial obstruction
2. Foreign body
B. Systemic sepsis
1. Septic pulmonary emboli
2. Seeding of pulmonary infarct
C. Complication of pulmonary trauma
1. Infection of hematoma or contusion
2. Contaminated foreign body or penetrating injury
D. Direct extension from extraparenchymal infection
1. Pleural empyema
2. Mediastinal, hepatic, subphrenic abscess
Lung abscesses result when necrotizing microorganisms infect the lower respiratory tract via inhalation of aerosolized particles, aspiration of oropharyngeal secretions, or hematogenous spread from distant sites. Direct extension from a contiguous site is less frequent. Most primary lung abscesses are suppurative bacterial infections secondary to aspiration. Risk factors for pulmonary aspiration include advanced age, conditions of impaired consciousness, suppressed cough reflex, dysfunctional esophageal motility, laryngopharygeal reflux disease, and centrally acting neurologic diseases (e.g., stroke). At the time of aspiration, the composition of the oropharyngeal flora determines the etiologic organisms. With increasing use of proton pump inhibitors to suppress acid secretion in the stomach, the oropharyngeal flora has shifted and the risk of developing bacterial lung infections after an aspiration event has increased.110 Secondary lung abscesses occur most often distal to an obstructing bronchial carcinoma. Infected cysts or bullae are not considered true abscesses.
Normal oropharyngeal secretions contain many more Streptococcus species and more anaerobes (approximately 1 × 108 organisms/mL) than aerobes (approximately 1 × 107 organisms/mL). Pneumonia that follows from aspiration, with or without abscess development, is typically polymicrobial. An average of two to four isolates present in large numbers have been cultured from lung abscesses sampled percutaneously. Overall, at least 50% of these infections are caused by purely anaerobic bacteria, 25% are caused by mixed aerobes and anaerobes, and 25% or fewer are caused by aerobes only. In nosocomial pneumonia, 60% to 70% of the organisms are gram-negative bacteria, including Klebsiella pneumoniae, Haemophilus influenzae, Proteus species, Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, and Eikenella corrodens. Immunosuppressed patients may develop abscesses because of the usual pathogens as well as less virulent and opportunistic organisms such as Salmonella species, Legionella species, Pneumocystis carinii, atypical mycobacteria, and fungi.
Clinical Features and Diagnosis
The typical presentation may include productive cough, fever (>38.9°C), chills, leukocytosis (>15,000 cells/mm3), weight loss, fatigue, malaise, pleuritic chest pain, and dyspnea. Lung abscesses may also present in a more indolent fashion, with weeks to months of cough, malaise, weight loss, low-grade fever, night sweats, leukocytosis, and anemia. After aspiration pneumonia, 1 to 2 weeks typically elapse before cavitation occurs; 40% to 75% of such patients produce putrid, foul-smelling sputum. Severe complications such as massive hemoptysis, endobronchial spread to other portions of the lungs, rupture into the pleural space and development of pyopneumothorax, or septic shock and respiratory failure are rare in the modern antibiotic era. The mortality rate is about 5% to 10%, except in the presence of immunosuppression, where rates range from 9% to 28%.
The CXR is the primary tool for diagnosing a lung abscess (Fig. 19-30). Its distinguishing characteristic is a density or mass with a relatively thin-walled cavity. An air-fluid level observed within the abscess indicates communication with the tracheobronchial tree. CT scan of the chest clarifies the diagnosis when CXR is equivocal and identifies endobronchial obstruction and/or an associated mass and other pathologic anomalies. A cavitating lung carcinoma is frequently mistaken for a lung abscess. Differential diagnosis also includes loculated or interlobar empyema, infected lung cysts or bullae, tuberculosis, bronchiectasis, fungal infections, and noninfectious inflammatory conditions (e.g., Wegener’s granulomatosis).
Lung abscess resulting from emesis and aspiration after an alcoholic binge. A. Chest x-ray showing an abscess cavity in the left upper lobe. B. A coronal tomogram highlights the thin wall of the abscess. C. Healing of the abscess cavity after 4 weeks of antibiotic therapy and postural drainage.
Ideally, the specific etiologic organism is identified before antibiotic administration. Bronchoscopy, which is essential to rule out endobronchial obstruction due to tumor or foreign body, is ideal for obtaining uncontaminated cultures using bronchoalveolar lavage. Culture samples can also be obtained by percutaneous, transthoracic FNA under ultrasound or CT guidance. Routine sputum cultures are often of limited usefulness because of contamination with upper respiratory tract flora.
Actinomycosis and nocardiosis, although rare, are particularly virulent infections associated with lung abscess, and diagnosis can be difficult.111 Both frequently masquerade as other clinical syndromes; thus, it is important for the surgeon to keep these bacteria in mind when considering the differential diagnosis for cavitary lung lesions. Actinomyces, a normal oropharyngeal bacterium, causes extensive pulmonary damage as the result of aspiration. Actinomycosis lung infection typically begins as acute pneumonitis after an aspiration. The symptoms mimic pulmonary tuberculosis, including chronic cough, night sweats, weight loss, and hemoptysis. Ongoing infection leads to chronic inflammation and fibrosis; cavitation occurs due to destruction of the pulmonary tissues. Without treatment, the infection continues to destroy surrounding structures, which can result in fistula formation into the adjacent structures, including the adjacent lung, interlobar fissures, pleural space, chest wall, and mediastinum. Actinomyces israelii is the most common cause of disease among the Actinomyces species. Nocardiosis is also a rare opportunistic infection that usually occurs in an immunocompromised host (human immunodeficiency virus [HIV] or cancer patients) and causes both local and systemic suppurative infections. The most common site is pulmonary, caused by Nocardia asteroides in 90% of cases; one series, however, reported a high prevalence of the particularly virulent species, Nocardia farcinica. Similar to actinomycosis, infection is slowly progressive, with weight loss, fatigue, cough, and hemoptysis. An acute pulmonary infection is common, with necrotizing pneumonia and cavitation or slowly enlarging pulmonary nodule(s). In some cases, empyema also develops.
Management of Lung Abscess
Systemic antibiotics directed against the causative organism represent the mainstay of therapy. The duration of antimicrobial therapy varies from 3 to 12 weeks for necrotizing pneumonia and lung abscess. It is likely best to treat until the cavity is resolved or until serial radiographs show significant improvement. Parenteral therapy is generally used until the patient is afebrile and able to demonstrate consistent enteral intake. Oral therapy can then be used to complete the course of therapy. For community-acquired infections secondary to aspiration, likely pathogens are oropharyngeal streptococci and anaerobes. Penicillin G, ampicillin, and amoxicillin are the main therapeutic agents, but a β-lactamase inhibitor or metronidazole should be added to cover the increasing prevalence of gram-negative anaerobes that produce β-lactamase. Clindamycin is also a primary therapeutic agent. For hospital-acquired infections, Staphylococcus aureus and aerobic gram-negative bacilli are common organisms of the oropharyngeal flora. Piperacillin or ticarcillin with a β-lactamase inhibitor (or equivalent alternatives) provide better coverage of likely pathogens.
Surgical drainage of lung abscesses is uncommon since drainage usually occurs spontaneously via the tracheobronchial tree. Indications for intervention are listed in Table 19-18. Drainage and resection may be required for actinomycosis and nocardiosis; diagnosis is often delayed because the bacteria are difficult to culture; invasion of the infection into surrounding structures is, therefore, common. Once identified, long-term antibiotics (months to years) are typically required along with drainage, debridement, and resection as needed. While penicillin derivatives are effective against most Actinomyces species, the infections are typically polymicrobial, and broad-spectrum parenteral antibiotics may be required. Nocardia species, in contrast, are highly variable; specific identification of the infecting species with antibiotic sensitivities is needed to direct appropriate therapy. Evaluation for malignant spread, particularly to the brain, is also required in the management of nocardiosis, as systemic dissemination occurs early and frequently.
Table 19-18Indications for surgical drainage procedures for lung abscesses ||Download (.pdf) Table 19-18 Indications for surgical drainage procedures for lung abscesses
1. Failure of medical therapy
2. Abscess under tension
3. Abscess increasing in size during appropriate treatment
4. Contralateral lung contamination
5. Abscess >4–6 cm in diameter
6. Necrotizing infection with multiple abscesses, hemoptysis, abscess rupture, or pyopneumothorax
7. Inability to exclude a cavitating carcinoma
External drainage may be accomplished with tube thoracostomy, percutaneous drainage, or surgical cavernostomy. The choice between tube thoracostomy versus radiographically guided catheter placement depends on the treating physician’s preference and the availability of interventional radiology. Surgical resection is required in fewer than 10% of lung abscess patients. Lobectomy is the preferred intervention for bleeding from a lung abscess or pyopneumothorax. An important intraoperative consideration is to protect the contralateral lung with a double-lumen tube, bronchial blocker, or contralateral main stem intubation. Surgical treatment has a 90% success rate, with an associated mortality of 1% to 13%.
Bronchiectasis is defined as a pathologic and permanent dilation of bronchi with bronchial wall thickening. This condition may be localized to certain bronchial segments, or it may be diffuse throughout the bronchial tree, typically affecting the medium-sized airways. Overall, this is a rare clinical entity in the United States with a prevalence of less than 1 in 10,000, although the incidence has increased in recent years and noncystic fibrosis–related bronchiectasis is now thought to affect 27.5 out of every 10,000 persons over age 75.
Development of bronchiectasis can be attributed to either congenital or acquired causes. The principal congenital diseases that lead to bronchiectasis include cystic fibrosis, primary ciliary dyskinesia, and immunoglobulin deficiencies (e.g., selective IgA deficiency). Congenital causes tend to produce a diffuse pattern of bronchial involvement. Acquired causes are categorized broadly as infectious and inflammatory. Bronchial obstruction from cancer, inhaled objects, extrinsic airway compression, or inspissated sputum promotes localized infection and subsequent medium airway destruction. Diffuse pneumonic processes from pathogens including necrotizing bacterial pneumonia, pertussis and measles pneumonia, severe influenza, or varicella pneumonia can lead to widespread bronchiectasis. Chronic granulomatous disease, immunodeficiency disorders, and hypersensitivity disorders can also lead to diffuse bronchiectasis.
Noninfectious causes of bronchiectasis include inhalation of toxic gases such as ammonia, which results in severe and destructive airway inflammatory responses. Allergic bronchopulmonary aspergillosis, Sjögren’s syndrome, and α1-antitrypsin deficiency are some additional examples of presumed immunologic disorders that may be accompanied by bronchiectasis.
In addition, recent studies have suggested an association between chronic gastroesophageal reflux disease, acid suppression, and nontuberculous mycobacterial infection with bronchiectasis.112,113 This interaction is thought to be related to chronic aspiration of colonized gastric secretions in the setting of acid suppression; while not proven to be causative, these findings suggest a role for gastroesophageal reflux disease in the pathogenesis of bronchiectasis.
The process shared by all causes of bronchiectasis is impairment of airway defenses or deficits in immunologic mechanisms, which permit bacterial colonization and chronic infection. Common organisms include Haemophilus species (55%), Pseudomonas species (26%), and Streptococcus pneumoniae (12%).114 Both the bacterial organisms and the inflammatory cells recruited to thwart the bacteria elaborate proteolytic and oxidative molecules, which progressively destroy the muscular and elastic components of the airway walls; those components are then replaced by fibrous tissue. Thus chronic airway inflammation is the essential pathologic feature of bronchiectasis. The dilated airways are usually filled with thick purulent material; more distal airways are often occluded by secretions or obliterated by fibrous tissue. Bronchial wall vascularity increases, bronchial arteries become hypertrophied, and abnormal anastomoses form between the bronchial and pulmonary arterial circulation.
There are three principal types of bronchiectasis, based on pathologic morphology: cylindrical—uniformly dilated bronchi; varicose—an irregular or beaded pattern of dilated bronchi; and saccular (cystic)—peripheral balloon-type bronchial dilation. The saccular type is the most common after bronchial obstruction or infection (Fig. 19-31).
Multiple cystic-type bronchiectatic cavities can be seen on a cut section of right lower lobe lung.
Clinical Manifestations and Diagnosis
Typical symptoms are a daily persistent cough and purulent sputum production; the quantity of daily sputum production (10 mL to >150 mL) correlates with disease extent and severity. Other patients may appear asymptomatic or have a dry nonproductive cough (“dry bronchiectasis”). These patients are prone to have involvement of the upper lobes. The clinical course is characterized by progressive symptoms and respiratory impairment. Increasing resting and exertional dyspnea are the result of progressive airway obstruction. Acute exacerbations may be triggered by viral or bacterial pathogens. Bleeding attributable to chronically inflamed, friable airway mucosa causes increasingly more frequent hemoptysis with disease progression. Massive bleeding may result from erosion of the hypertrophied bronchial arteries.
Both mild and severe forms of bronchiectasis are readily demonstrated with chest CT scanning because it provides a highly detailed, cross-sectional view of bronchial architecture. CXRs, although less sensitive, may reveal characteristic signs of bronchiectasis such as lung hyperinflation, bronchiectatic cysts, and dilated, thick-walled bronchi forming track-like patterns radiating from the lung hila. Sputum culture may identify characteristic pathogens. Sputum acid-fast bacillus smears and cultures should be performed to evaluate for the presence of nontuberculous mycobacteria, which is common in this setting. Spirometry provides an assessment of the severity of airway obstruction and can be followed to track the course of disease.
Management of Bronchiectasis
Standard therapy includes optimizing airway clearance, use of bronchodilators to reverse any airflow limitation, and correction of reversible underlying causes whenever possible.115 Chest physiotherapy based on vibration, percussion, and postural drainage is widely accepted, although randomized trials demonstrating efficacy are lacking. Acute exacerbations should be treated with a 2- to 3-week course of broad-spectrum intravenous antibiotics tailored to culture and sensitivity profiles, followed by an oral regimen; this will result in a longer-lasting remission.
Macrolide antibiotics have been shown to decrease sputum production, inhibit cytokine release, and inhibit neutrophil adhesion and formation of reactive oxygen species. They also inhibit migration of Pseudomonas, disrupt biofilm, and prevent release of virulence factors.116 While macrolide therapy does appear to be efficacious, it is important to remember that macrolides have significant activity against nontuberculous mycobacteria, and widespread prophylactic use for patients with bronchiectasis may lead to multidrug-resistant nontuberculous mycobacterial species. It has also been suggested that inhaled antibiotics, such as tobramycin and colistin, improve rates of bacterial clearance and slow the decline in pulmonary function associated with bronchiectasis, but large, randomized trials showing overall clinical benefit have not yet been published.117,118
In addition to antibiotics, daily nebulized hypertonic saline appears to be effective. A recent randomized crossover study comparing lung function and quality of life has shown that 7% normal saline, compared to isotonic saline, results in a statistically significant 15% increase in FEV1 and an 11% increase in forced vital capacity (compared to 1.8% and 0.7%, respectively, with isotonic saline). Antibiotic use and emergency room utilization were significantly decreased; from this, hypertonic saline appears to be a reasonable adjunct to maintaining quality of life and decreasing exacerbations by reducing sputum volume, improving mucociliary clearance, and slowing the decline in lung function.119 Studies supporting mucolytics such as DNase and N-acetylcysteine for non-cystic fibrosis bronchiectasis have shown either no change or a worsening of pulmonary status and require further study in the non-cystic fibrosis population.
Surgical resection of a localized bronchiectatic segment or lobe, preserving as much functional lung as possible, may benefit patients with refractory symptoms while on maximal medical therapy. Multifocal disease must be excluded before any attempt at surgery; any uncorrectable predisposing factor (e.g., ciliary dyskinesia) must also be excluded. Patients with end-stage lung disease from bronchiectasis may be potential candidates for a bilateral lung transplant. Surgical resection is also indicated in patients with significant hemoptysis, although bronchial artery embolization is the preferred first option. Antireflux surgery may also prove beneficial in patients with chronic aspiration, but further studies are required. It is particularly important to recognize that antireflux surgery in patients with severe underlying pulmonary dysfunction has higher risk for perioperative adverse outcomes than in the general population. It should be undertaken only by very experienced surgeons with direct involvement of the pulmonary medicine physicians to minimize postoperative pulmonary compromise.
Tuberculosis is a widespread problem that affects nearly one third of the world’s population. Between 8.3 and 9 million new cases of tuberculosis and 12 million prevalent cases (range 10–13 million) were estimated worldwide in 2011 according to the World Health Organization. Only 10,521 new cases were reported to the World Health Organization in the United States in 2011. HIV infection is the strongest risk factor for developing active tuberculosis. The elderly, minorities, and recent immigrants are the most common populations to have clinical manifestations of infection, yet no age group, sex, or race is exempt from infection. In most large urban centers, reported cases of tuberculosis are more numerous among the homeless, prisoners, and drug-addicted populations. Immunocompromised patients additionally contribute to an increased incidence of tuberculosis infection, often developing unusual systemic as well as pulmonary manifestations.120 As compared with past decades, presently surgical intervention is required more frequently in patients with multidrug-resistant tuberculosis organisms (MDRTB) who do not respond to medical treatment and in selected patients with nontuberculous mycobacterial infections (NTM).
Mycobacterial species are obligate aerobes. They are primarily intracellular parasites with slow rates of growth. Their defining characteristic is the property of acid-fastness, which is the ability to withstand decolorization by an acid-alcohol mixture after being stained. Mycobacterium tuberculosis is the highly virulent bacillus of this species that produces invasive infection among humans, principally pulmonary tuberculosis.121 Infections with M. tuberculosis are primary when they are the first infection in a previously unsensitized host and secondary or postprimary when reactivation of a previous infection occurs.
Because of improper application of antimycobacterial drugs and multifactorial interactions, MDRTB organisms, defined by their resistance to at least two of the first-line antimycobacterial drugs (isoniazid and rifampin), have emerged. It is estimated that 1.4% of new tuberculosis cases and 7.6% of retreatment cases in the United States in 2011 are from MDRTB organisms. In addition, there is another rare variant termed extensively drug-resistant tuberculosis, which is resistant to isoniazid and rifampin, all fluoroquinolones, and at least one of the injectable second-line drugs (e.g., capreomycin, amikacin, kanamycin). It is estimated that 9% of all MDRTB cases are extensively drug resistant.
The more important NTM organisms include Mycobacterium kansasii, M. avium and M. intracellulare complex (MAC), and M. fortuitum. The highest incidence of M. kansasii infection is in midwestern U.S. cities among middle-aged males from good socioeconomic surroundings. MAC organisms are important infections in elderly and immunocompromised patient groups. M. fortuitum infections are common complications of underlying severe debilitating disease. None of these organisms are as contagious as M. tuberculosis.
Pathogenesis and Pathology
The main route of transmission is via airborne inhalation of viable mycobacteria. Three stages of primary infection have been described. In the first stage, alveolar macrophages become infected through ingesting the bacilli. In the second stage, from days 7 to 21, the patient typically remains asymptomatic while the bacteria multiply within the infected macrophages. The third stage is characterized by the onset of cell-mediated immunity (CD4+ helper T cells) and delayed-type hypersensitivity. Activated macrophages acquire an increased capacity for bacterial killing. Macrophage death increases, resulting in the formation of a granuloma, the characteristic lesion found on pathologic examination.
Tuberculous granulomas are composed of blood-derived macrophages, degenerating macrophages or epithelioid cells, and multinucleated giant cells (fused macrophages with nuclei around the periphery; also known as Langerhans cells). The low oxygen content of this environment inhibits macrophage function and bacillary growth, with subsequent central caseation as macrophage death occurs. A Ghon complex is a single, small lung lesion that is often the only remaining trace of a primary infection. The primary infection is usually located in the peripheral portion of the middle zone of the lungs.
Reactivation tuberculosis may occur after hydrolytic enzymes liquefy the caseum. Typically, the apical and posterior segments of the upper lobes and the superior segments of the lower lobes are involved. Edema, hemorrhage, and mononuclear cell infiltration are also present. The tuberculous cavity may become secondarily infected with other bacteria, fungi, or yeasts, all of which may contribute to enhanced tissue destruction.
The pathologic changes caused by NTM organisms are similar to those produced by M. tuberculosis. M. intracellulare complex infections commonly occur, not only in immunocompromised patients, but also in patients with previously damaged lungs. Caseous necrosis is uncommon and is characterized by clusters of tissue macrophages filled with mycobacteria. It has a poor granulomatous response and confinement of immune cell infiltration to the interstitium and alveolar walls. Cavitary disease is infrequent, although nodules may be noted.
Clinical Presentation and Diagnosis
The clinical course of infection and the presentation of symptoms are influenced by many factors, including the site of primary infection, the stage of disease, and the degree of cell-mediated immunity. About 80% to 90% of tuberculosis patients present with clinical disease in the lungs. In 85% to 90% of these patients, involution and healing occur, leading to a dormant phase that may last a lifetime. The only evidence of tuberculosis infection may be a positive skin reaction to tuberculin challenge or a Ghon complex observed on CXR. Within the first 2 years of primary infection, reactivation may occur in up to 10% to 15% of infected patients. In 80%, reactivation occurs in the lungs; other reactivation sites include the lymph nodes, pleura, and the musculoskeletal system.
After primary infection, pulmonary tuberculosis is frequently asymptomatic. Systemic symptoms of low-grade fever, malaise, and weight loss are subtle and may go unnoticed. A productive cough may develop, usually after tubercle cavitation. Many radiographic patterns can be identified at this stage, including local exudative lesions, local fibrotic lesions, cavitation, bronchial wall involvement, acute tuberculous pneumonia, bronchiectasis, bronchostenosis, and tuberculous granulomas. Hemoptysis often develops from complications of disease such as bronchiectasis or erosion into vascular malformations associated with cavitation. Extrapulmonary involvement is due to hematogenous or lymphatic spread from pulmonary lesions. Virtually any organ can become infected, giving rise to the protean manifestations of tuberculosis. The pleura, chest wall, and mediastinal organs may all be involved. More than one third of immunocompromised patients have disseminated disease, with hepatomegaly, diarrhea, splenomegaly, and abdominal pain.
The definitive diagnosis of tuberculosis requires identification of the mycobacterium in a patient’s bodily fluids or involved tissues. Skin testing using purified protein derivative is important for epidemiologic purposes and can help exclude infection in uncomplicated cases. For pulmonary tuberculosis, sputum examination is inexpensive and has a high diagnostic yield. Bronchoscopy with alveolar lavage may also be a useful diagnostic adjunct and has high diagnostic accuracy. Chest CT scan can delineate the extent of parenchymal disease.
Medical therapy is the primary treatment of pulmonary tuberculosis and is often initiated before a mycobacterial pathogen is definitively identified. Combinations of two or more drugs are routinely used in order to minimize resistance, which inevitably develops with only single-agent therapy. A current treatment algorithm is outlined in Fig. 19-32. Generally, therapy lasts about 18 months. The overall response rate is satisfactory in 70% to 80% of patients with M. kansasii infection. Surgical intervention is rarely required in the 20% to 30% of patients who are not responsive to medical therapy. In contrast, pulmonary M. intracellulare complex infections respond poorly, even to combinations of four or more drugs, and most of the patients will eventually require surgical intervention. Overall, sputum conversion is achieved in only 50% to 80% of NTM infections, and relapses occur in up to 20% of patients.
Treatment algorithm for tuberculosis. Patients in whom tuberculosis is proven or strongly suspected should have treatment initiated with isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) for the initial 2 months. A repeat smear and culture should be performed when 2 months of treatment has been completed. If cavities were seen on the initial chest radiograph (CXR) or the acid-fast bacillus (AFB) smear results are positive at completion of 2 months of treatment, the continuation phase of treatment should consist of INH and RIF daily or twice daily for 4 months to complete a total of 6 months of treatment. If cavitation was present on the initial CXR and the culture results at the time of completion of 2 months of therapy are positive, the continuation phase should be lengthened to 7 months (total of 9 months of treatment). If the patient has HIV infection and the CD4+ cell count is <100/μL, the continuation phase should consist of daily or three times weekly INH and RIF. In HIV-uninfected patients with no cavitation on CXR and negative results on AFB smears at completion of 2 months of treatment, the continuation phase may consist of either once weekly INH and rifapentine (RPT) or daily or twice weekly INH and RIF to complete a total of 6 months of treatment (bottom). For patients receiving INH and RPT whose 2-month culture results are positive, treatment should be extended by an additional 3 months (total of 9 months). *EMB may be discontinued when results of drug susceptibility testing indicate no drug resistance. †PZA may be discontinued after it has been taken for 2 months (56 doses). ‡RPT should not be used in HIV-infected patients with tuberculosis or in patients with extrapulmonary tuberculosis. §Therapy should be extended to 9 months if results of 2-month culture are positive. (Reproduced with permission of the American Thoracic Society. Copyright © American Thoracic Society. Blumberg HM, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167:603.)
In the United States, surgical intervention is most often required in order to treat patients with MDRTB organisms whose lungs have been destroyed and who have persistent thick-walled cavitation.122 The indications for surgery related to mycobacterial pulmonary infections are presented in Table 19-19. The governing principle of mycobacterial surgery is to remove all gross disease while preserving any uninvolved lung tissue. Scattered nodular disease may be left intact, given its low mycobacterial burden. Antimycobacterial medications should be given preoperatively (for about 3 months) and continued postoperatively for 12 to 24 months. Overall, more than 90% of patients who were deemed good surgical candidates are cured when appropriate medical and surgical therapy is used.
Table 19-19Indications for surgery to treat mycobacterial pulmonary infections ||Download (.pdf) Table 19-19 Indications for surgery to treat mycobacterial pulmonary infections
1. Complications resulting from previous thoracic surgery to treat tuberculosis
2. Failure of optimized medical therapy (e.g., progressive disease, lung gangrene, or intracavitary aspergillosis superinfection)
3. Need for tissue acquisition for definitive diagnosis
4. Complications of pulmonary scarring (e.g., massive hemoptysis, cavernomas, bronchiectasis, or bronchostenosis)
5. Extrapulmonary thoracic involvement
6. Pleural tuberculosis
7. Nontuberculous mycobacterial infection
Pulmonary Fungal Infections
The incidence of fungal infections has increased significantly, with many new opportunistic fungi emerging. This increase is attributed to the growing population of immunocompromised patients (e.g., organ transplant recipients, cancer patients undergoing chemotherapy, HIV patients, and young and elderly patients) who are more likely to become infected with fungi.123 Clinically significant examples include species of Aspergillus, Cryptococcus, Candida, and Mucor. Other at-risk patient populations include those who are malnourished, severely debilitated, or diabetic or who have hematologic disorders. Patients receiving high-dose, intensive antibiotic therapies are also susceptible. There are, however, some fungi that are primary or true pathogens, able to cause infections in otherwise healthy patients. Some endemic examples in the United States include species of Histoplasma, Coccidioides, and Blastomyces.124
Direct identification of the organism in body exudates or tissues, preferably as growth in culture, provides definitive diagnosis. Serologic testing to identify mycotic-specific antibodies may also be useful. Several new classes of antifungal agents have proven effective against many life-threatening fungi and are less toxic than older agents. In addition, thoracic surgery may be a useful therapeutic adjunct for patients with pulmonary mycoses.
The genus Aspergillus comprises over 150 species and is the most common cause of mortality due to invasive mycoses in the United States. It is typically acute in onset and life-threatening and occurs in the setting of neutropenia, chronic steroid therapy, or cytotoxic chemotherapy. It can also occur in the general intensive care unit population of critically ill patients, including patients with underlying chronic obstructive pulmonary disease (COPD), postoperative patients, patients with cirrhosis or alcoholism, and postinfluenza patients, without any of these factors present. The species most commonly responsible for clinical disease include A. fumigatus, A. flavus, A. niger, and A. terreus. Aspergillus is a saprophytic, filamentous fungus with septate hyphae. Spores (2.5–3 μm in diameter) are released and easily inhaled by susceptible patients; because the spores are microns in size, they are able to reach the distal bronchi and alveoli.
Aspergillosis can manifest as one of three clinical syndromes: Aspergillus hypersensitivity lung disease, aspergilloma, or invasive pulmonary aspergillosis. Overlap occurs between these syndromes, depending on the patient’s immune status.125 Aspergillus hypersensitivity manifests as a productive cough, fever, wheezing, pulmonary infiltrates, eosinophilia, and elevation of IgE antibodies to Aspergillus, whereas aspergilloma (fungal ball) is a matted sphere of hyphae, fibrin, and inflammatory cells that tends to colonize pre-existing intrapulmonary cavities. Grossly, aspergilloma appears as a round or oval, friable, gray (or red, brown, or even yellow), necrotic-looking mass (Fig. 19-33). This form is the most common presentation of noninvasive pulmonary aspergillosis. The most common symptoms are hemoptysis, chronic and productive cough, clubbing, malaise, or weight loss. CXR can suggest the diagnosis by the finding of a crescentic radiolucency above a rounded radiopaque lesion (Monad sign).
Pulmonary aspergilloma. A. The chest x-ray shows a solid mass within a cavity surrounded by a rim of air between the mass and cavity wall (Monad sign, arrows). B. A cut section shows the “fungus ball” occupying an old, fibrotic cavity. C. Histologic stain reveals characteristic Aspergillus hyphae invading the wall of the cavity.
The natural history varies greatly between patients and, therefore, treatment is individualized. Factors associated with poor prognosis include severe underlying pulmonary disease, growth in the number or size of the aspergilloma(s) during observation, immunosuppression or HIV infection, history of lung transplantation, chronic pulmonary sarcoidosis, and increasing Aspergillus-specific IgG titers. Asymptomatic patients can be observed without any additional therapy. Antifungals have limited utility due to the poor blood supply to the aspergilloma. Amphotericin B is the drug of choice, although voriconazole has recently been used for treatment of aspergillosis, with fewer side effects and equivalent efficacy. Hemoptysis is a harbinger of erosion of the disease into adjacent bronchial arteries and typically requires intervention. In the setting of very mild hemoptysis (e.g., blood-streaked sputum), cough suppression is warranted while further therapeutic evaluation is performed.
Bronchial artery embolization is the first-line therapy for massive hemoptysis and may be definitive therapy.126 This is particularly important to consider for patients with severely impaired pulmonary function who may not have sufficient reserve to tolerate even a very small pulmonary resection. Operative intervention may be required for recurrent hemoptysis, particularly after bronchial artery embolization, chronic cough with systemic symptoms, progressive infiltrate around the mycetoma, and a pulmonary mass of unknown cause.127
When operative intervention is indicated, the surgeon must remain cognizant of the goals of the procedure. As this disease typically occurs in patients with significantly impaired pulmonary function, attempts should be made to excise all diseased tissue with as limited a resection as possible. Once resection is completed, the postresection space in the hemithorax should be obliterated with a pleural tent, pneumoperitoneum, decortication of the remaining lung, intrathoracic rotation of a muscle or omental flap, or thoracoplasty. Long-term follow-up is necessary, given that the recurrence rate after surgery is about 7%.
Invasive pulmonary aspergillosis typically affects immunocompromised patients who have dysfunctional cellular immunity, namely defective polymorphonuclear leukocytes. Invasion of pulmonary parenchyma and blood vessels by a necrotizing bronchopneumonia may be complicated by thrombosis, hemorrhage, and then dissemination. Patients present with fever that is nonresponsive to antibiotic therapy in the setting of neutropenia. They may also have pleuritic chest pain, cough, dyspnea, or hemoptysis. Characteristic signs on CT scan include the halo sign and cavitary lesions. Treatment with voriconazole must be prompt and aggressive, including reversal of neutropenia, if there is to be any chance for recovery. Mortality ranges from 93% to 100% in bone marrow transplant recipients, to approximately 38% in kidney transplant recipients, although this improves to approximately 60% at 12 weeks with voriconazole therapy. Several other advances in diagnosis and treatment, including CT scans in high-risk populations and development of additional triazoles and echinocandins, have improved the early identification and response to therapy in this patient population. Additional treatment considerations include the use of hematopoietic growth factors to minimize the neutropenic period, which contributes to uncontrolled disease. Surgical removal of the infectious nidus is advocated by some groups because medical treatment has such poor outcomes. Treatment continues until microbiologic clearance is achieved and clinical signs and radiographic imaging indicate resolution of disease. In addition, the patient should no longer be immunosuppressed. If continuation of immunosuppressive medications is required, antifungal therapy should also continue to prevent recurrence of invasive disease.
Cryptococcosis is a subacute or chronic infection caused by Cryptococcus neoformans, a round, budding yeast (5–20 μm in diameter) that is sometimes surrounded by a characteristic wide gelatinous capsule. Cryptococci are typically present in soil and dust contaminated by pigeon droppings. When inhaled, such droppings can cause a nonfatal disease primarily affecting the pulmonary and central nervous systems. At present, cryptococcosis is the fourth most common opportunistic infection in patients with HIV infection, affecting 6% to 10% of that population. Four basic pathologic patterns are seen in the lungs of infected patients: granulomas; granulomatous pneumonia; diffuse alveolar or interstitial involvement; and proliferation of fungi in alveoli and lung vasculature. Symptoms are nonspecific, as are the radiographic findings. Cryptococcus may be isolated from sputum, bronchial washings, percutaneous needle aspiration of the lung, or cerebrospinal fluid. If disease is suspected, serum cryptococcal antigen titers should be obtained; if positive or if the patient has persistent fever, evidence of progression, physiologic compromise, or dissemination, treatment should be promptly initiated. Multiple antifungal agents are effective against C. neoformans, including amphotericin B and the azoles. The choice of antifungal and duration of treatment depend on the severity of disease. Duration of therapy is longer in patients who are immunocompromised.
Candida organisms are oval, budding cells (with or without mycelial elements) that colonize the oropharynx of many healthy individuals. The fungi of this genus are common hospital and laboratory contaminants. Usually, Candida albicans causes disease in the oral or bronchial mucosa, among other anatomic sites. Other potentially pathogenic Candida species include C. tropicalis, C. glabrata, and C. krusei. Historically, C. albicans was the most common pathogen to cause invasive candidal infection. However, more recent reports suggest that other Candida species, particularly C. glabrata and C. krusei, are becoming more prevalent and now account for between 40% and 50% of all cases. These species are relatively resistant to fluconazole, and the shift is likely related to the widespread use of this antifungal agent.128
The incidence of Candida infections has increased and is no longer confined to immunocompromised patients. Increasing incidence of infection has been identified in patients with any of the following risk factors: critical illness of long duration; use of long-term antibiotics, particularly multiple; indwelling urinary or vascular catheter; gastrointestinal perforation; or burn wounds.129 With respect to the thorax, such patients commonly have candidal pneumonia, pulmonary abscess, esophagitis, and mediastinitis. Pulmonary candidal infections typically result in an acute or chronic granulomatous reaction. Because Candida can invade blood vessel walls and a variety of tissues, systemic or disseminated infections can occur, but are less common.
Treatment for candidal infection includes both fungicidal and fungistatic agents. The fungicidal medications include polyenes (amphotericin B deoxycholate [AmB-D] and various lipid-associated amphotericin B preparations) and the echinocandins (caspofungin, micafungin, and anidulafungin). Fungistatic drugs include the triazoles (fluconazole, itraconazole, voriconazole, and posaconazole).128 The availability of multiple effective therapies allows for specific tailoring of treatment, including combination regimens, based on the patient’s ability to tolerate associated toxicities, the microbiologic information for the specific candidal species, and the route of administration. While demonstrated efficacy is similar, the triazoles and echinocandins appear to have fewer side effects and are better tolerated than the other classes of antifungal drugs.
In addition to prompt institution of antifungal therapy, it is advisable to remove all central venous catheters. For fungemia, an eye examination should be performed. Treatment should continue for at least 2 weeks after the last positive blood culture. For patients with Candida mediastinitis (which has a mortality rate of >50%), surgical intervention to debride all infected tissues is required, in addition to prolonged administration of antifungal drugs.
The Mucor species, rare members of the class Zygomycetes, are responsible for rapidly fatal disease in immunocompromised patients. Other disease-causing species of the class Zygomycetes include Absidia, Rhizopus, and Mortierella.130 Characteristic of these fungi are nonseptate, branching hyphae that are difficult to culture. Infection occurs via inhalation of spores. Immunocompromised patients, including patients with neutropenia, acidosis, diabetes, and hematologic malignancy all predispose to clinical susceptibility. In the lungs, disease consists of blood vessel invasion, thrombosis, and infarction of infected organs. Tissue destruction is significant, along with cavitation and abscess formation. Initial treatment is to correct underlying risk factors and administer antifungal therapies, although the optimal duration and optimal total dose are unknown. Lipid formulations of amphotericin B are recommended at this time. Surgical resection of any localized disease should be performed after initial medical treatment attempts fail.
Histoplasma capsulatum is a dimorphic fungus existing in mycelial form in soil contaminated by fowl or bat excreta and in yeast form in human hosts. The most common of all fungal pulmonary infections, histoplasmosis primarily affects the respiratory system after spores are inhaled. It is endemic in the Midwest and Mississippi River Valley of the United States, where about 500,000 new cases arise each year. In immunocompromised patients, the infection becomes systemic and more virulent; because cell-mediated immunity is impaired, uninhibited fungal proliferation occurs within pulmonary macrophages and then spreads. Acute forms of the disease present as primary or disseminated pulmonary histoplasmosis; chronic forms present as pulmonary granulomas (histoplasmomas), chronic cavitary histoplasmosis, mediastinal granulomas, fibrosing mediastinitis, or bronchiolithiasis. Histoplasmosis is definitively diagnosed by fungal smear, culture, direct biopsy of infected tissues, or serologic testing.
The clinical presentation depends on the inoculum size and on host factors. Symptoms of acute pulmonary histoplasmosis are fever, chills, headache, chest pain, musculoskeletal pain, and nonproductive cough. CXRs may be normal or may show mediastinal lymphadenopathy and patchy parenchymal infiltrates. Most patients improve in a few weeks; mild to moderate disease can be treated with itraconazole. Amphotericin B is the treatment of choice if moderate symptoms persist for 2 to 4 weeks or if the illness is extensive, including dyspnea and hypoxia, and if patients are immunosuppressed.131
As the pulmonary infiltrates from acute histoplasmosis heal, consolidation into an asymptomatic solitary nodule or histoplasmoma may occur and is usually seen incidentally on radiographs as a coin-shaped lesion. Central and concentric calcification may occur; if so, no further treatment is required. Noncalcification of the lesion requires further diagnostic workup including chest CT scan, needle biopsy, or surgical excision to rule out a malignancy. Figure 19-34 demonstrates the differences in pathologic findings between infections in normal and immunocompromised hosts.132
Pathologic findings of infection in normal and immunocompromised hosts. Histopathologic preparations are shown contrasting acute diffuse pulmonary involvement in a lung segment of a normal host with a probable primary infection (A through D) with pulmonary granulomas from an immunocompromised patient who had an opportunistic reinfection with Histoplasma capsulatum (E, F). A. Diffuse interstitial pneumonitis in an adult (normal host) with recent heavy environmental exposure and subsequent development of progressive pulmonary disease. There is an inflammatory cell infiltrate primarily involving the interalveolar interstitial spaces but present within many alveolar spaces as well. The exudate consists mostly of mononuclear phagocytes, lymphocytes, and occasional plasma cells. Many of the alveolar walls are markedly thickened (hematoxylin and eosin stain [H&E], ×50). B. Another area from the same lung as in A showing focal vasculitis with an infiltrate of lymphocytes and macrophages (H&E, ×25). C. Relatively large alveolar macrophages packed with single and budding yeasts 2 to 4 μm in diameter (same lung as in A and B). The basophilic cytoplasm of these yeasts is retracted from their thin outer cell walls, leaving halo-like clear areas that can be confused with capsules (H&E, ×500). D. Intracellular and extracellular yeasts, 2 to 4 μm in diameter, some of which are single, budding, or in short chains (Gomori methenamine silver stain, ×500). E. Nonnecrotizing (sometimes called epithelioid cell or noncaseating) granuloma from a patient who had recently received chemotherapy for a germ cell tumor (different patient than in A through D). This lesion consists of a focal collection of macrophages (sometimes referred to as histiocytes or epithelioid cells) plus lymphocytes and occasional plasma cells. A few multinucleated macrophages are present. A thin layer of fibroblasts circumscribes the lesion. Yeasts of H. capsulatum, probably present within macrophages of this lesion at an earlier stage, were not identified in this granuloma or in any of several other nonnecrotizing granulomas within the specimen. Lesions of this type often undergo necrosis to become necrotizing granulomas (H&E, ×50). F. Necrotizing (sometimes referred to as caseating) granuloma from the same lung as in E. This lesion has a necrotic center surrounded by macrophages, encapsulating fibroblasts, fibrous connective tissue in the periphery, and scattered lymphocytes. A prominent giant cell is present in the lower left of the granuloma (at approximately 8 o’clock). Microorganisms are usually present only in relatively small numbers in these types of lesions. They are most frequently detected within the most central necrotic material in these granulomas (H&E, ×25). (Reproduced with permission from Hage et al.132)
When lymph nodes and pulmonary granulomas calcify over time, pressure atrophy on the bronchial wall may result in erosion and migration of the granulomatous mass into the bronchus, causing bronchiolithiasis. Typical symptoms include cough, hemoptysis, and dyspnea. Life-threatening complications include massive hemoptysis or bronchoesophageal fistula. In addition to radiography, bronchoscopy should be performed to aid in diagnosis. Definitive treatment requires surgical excision of the bronchial mass and repair of the airway and contiguous structures. Endobronchial debridement is not advised as this can result in massive, fatal bleeding.
Fibrosing mediastinitis is an uncommon manifestation of histoplasmosis but can be fatal due to progressive distortion and compression of the major vessels and central airways. Diagnosis can be difficult and symptoms may be present for extended periods, even years, before the diagnosis is made. The differential diagnosis for the disease process includes granulomatous mediastinitis related to recent infection, malignancy, and chronic pulmonary thromboembolism. A trial of itraconazole is worthwhile, although it is not proven to be effective. In cases where radiographic or physiologic improvement is achieved after a trial of 12 week of therapy, continuation of therapy is considered for a full 12 months. In the majority of patients, however, antifungal therapy has not been proven effective. There is no role for corticosteroids at this time or for antifibrotics. Occasionally, intravascular stents have been helpful for severe vascular compromise. Balloon dilatation and endobronchial silicone stents may be needed for airway compromise, although this should be directed by a surgeon with expertise in mediastinal and airway disease management.
Chronic pulmonary histoplasmosis occurs in about 10% of patients who become symptomatic after infection. Most such patients have pre-existing lung pathology, particularly emphysema, which becomes colonized. Subsequent pneumonitis and necrosis, cavity enlargement, new cavity formation, and pulmonary dissemination occur. Nonspecific symptoms, such as cough, sputum production, fever, weight loss, weakness, and hemoptysis are common. Chest radiography may reveal intrapulmonary cavitation and scarring. Occasionally, partial resolution of the inflammatory changes may be observed. Itraconazole provides effective therapy, but must be given for 12 to 24 months. It is superior to ketoconazole and fluconazole; these should only be used if itraconazole is not tolerated. Voriconazole and posaconazole have been found to be useful for salvage therapy. Serum itraconazole levels should be monitored to ensure that the drug is being absorbed. Occasionally, lipid-associated amphotericin B is necessary for more severe infections. Surgical excision should be considered in patients with adequate pulmonary reserve and localized, thick-walled cavities that have been unresponsive to antifungal therapy.
Disseminated histoplasmosis occurs most frequently in patients who are severely immunocompromised, such as posttransplantation patients, patients with HIV, and patients using immunosuppressive medications. Presentation ranges from nonspecific signs of fever, weight loss, and malaise, to shock, respiratory distress, and multiorgan failure. Diagnosis can be made with a combination of Histoplasma urine antigen, serologic assay, and fungal culture and should be suspected in patients with the above symptoms in any endemic area, particularly if the patient is immunosuppressed.133 Any of the antifungal therapies can be used in treatment of disseminated histoplasmosis. Use of amphotericin B has decreased the mortality rate to less than 25% in this type of serious infection.
Coccidioides immitis is an endemic fungus found in soil and dust of the southwestern United States. Agricultural workers, military personnel, and other occupations with extensive exposure to soil, especially in areas of endemic growth, are at highest risk, as are immunocompromised individuals.134 Spores (arthroconidia) are inhaled, swell into spherules, and subdivide into endospores, and subsequent infection develops. Diagnosis can be achieved through serum analysis for anticoccidioidal antibody, spherule identification in tissue, or by isolating the fungus in cultures from sputum, other body fluid, or tissue.
Inhalation of the fungus causes pulmonary involvement in 95% of patients with symptomatic disease. Three main categories of pulmonary involvement, based on the associated signs and symptoms, are possible: primary; complicated; and residual pulmonary coccidioidomycosis. Primary pulmonary coccidioidomycosis occurs in about 40% of people who inhale spores. The other 60% will remain asymptomatic and develop life-long immunity. The constellation of symptoms of “valley fever,” including fever, chills, headache, erythema multiforme, erythema nodosum, polyarthralgias, nonproductive cough, and chest pain, and a CXR showing hilar and paratracheal adenopathy are highly suggestive of pulmonary coccidioidomycosis. In many patients, initial diagnosis is community-acquired pneumonia, and it is only when the patient fails to respond to appropriate antibiotic therapy that pulmonary coccidioidomycosis is considered. The disease is self-limited in the majority of patients, and treatment is not required in these cases.
Therapy should be considered for (a) patients with impaired cellular immunity; (b) comorbid illnesses that are adversely impacted by the infection, including chronic pulmonary dysfunction, renal failure, and congestive heart failure; and (c) when symptoms and radiographic findings persist for more than 6 to 8 weeks, at which time the disease is considered to be persistent coccidioidal pneumonia and occurs in approximately 1% of patients. Progression to caseous nodules, cavities, and calcified, fibrotic, or ossified lesions indicates complicated or residual stages of coccidioidomycosis.
There are several relative indications for surgery in pulmonary coccidioidomycosis. A rapidly expanding (>4 cm) cavity that is close to the visceral pleura is a high risk for rupture into the pleural space and subsequent empyema. Other indications for operative intervention include life-threatening hemoptysis; hemoptysis that is persistent despite medical therapy; symptomatic fungus ball; bronchopleural fistula; cavitary lesions with persistent positive sputum; and pulmonary nodules that degenerate over time. Finally, any nodule with signs that are concerning for malignancy should undergo further evaluation, including biopsy or resection, to determine the underlying etiology.
Diagnosis of coccidioidomycosis is confirmed by histopathologic, mycologic, and serologic evaluation. Extrapulmonary disease may develop in approximately 0.5% of infected patients, with involvement of meninges, bones, joints, skin, or soft tissues. Immunocompromised patients are especially susceptible to disseminated coccidioidomycosis, which carries a mortality rate over 40%. Treatment options for this disease vary depending on the severity of the disease as well as the stage. Amphotericin B deoxycholate or the triazoles continue to be the primary antifungal medications. If meningeal involvement is identified, fluconazole or itraconazole therapy is required for the remainder of the patient’s life. Intrathecal amphotericin B can also be administered in some cases.
Blastomyces dermatitidis is a round, single-budding yeast with a characteristic thick, refractile cell wall. It resides in the soil as a nonmotile spore called conidia. Exposure occurs when contaminated soil is disturbed and the conidia are aerosolized. The spore is inhaled and transforms into a yeast phase at body temperature.135 Infection is typically self-limited. A small minority of patients will develop chronic pulmonary infection or disseminated disease, including cutaneous, osteoarticular, and genitourinary involvement. B. dermatitidis has a worldwide distribution; in the United States, it is endemic in the central states.136 With chronic infection, the organism induces a granulomatous and pyogenic reaction with microabscesses and giant cells; caseation, cavitation, and fibrosis may also occur. Symptoms are nonspecific and consistent with chronic pneumonia in 60% to 90% of patients. They include cough, mucoid sputum production, chest pain, fever, malaise, weight loss, and, uncommonly, hemoptysis. In acute disease, radiographs are either completely negative or have nonspecific findings; in chronic disease, fibronodular lesions (with or without cavitation) similar to tuberculosis are noted. Pulmonary parenchymal abnormalities in the upper lobe(s) may be noted. Mass lesions similar to carcinoma are frequent, and lung biopsy is frequently used. Over 50% of patients with chronic blastomycosis also have extrapulmonary manifestations, but less than 10% of patients present with severe clinical manifestation.135
Once a patient manifests symptoms of chronic blastomycosis, antifungal treatment is required to achieve resolution. Mortality approaches 60% if untreated.135 While controversial, a short course of triazole therapy (oral itraconazole 200 mg daily) for 6 months is the treatment of choice for most patients with mild to moderate forms of the disease. Because itraconazole has poor CNS penetration, the most common site of recurrence after apparently successful therapy is in the CNS. In the absence of therapy, close follow-up is warranted for evidence of progression to chronic or extrapulmonary disease. Amphotericin B is warranted for patients with severe or life-threatening disease, CNS involvement, disseminated disease, or extensive lung involvement and in immunocompromised patients. After adequate drug therapy, surgical resection of known cavitary lesions should be considered because viable organisms are known to persist in such lesions.
Massive hemoptysis is generally defined as expectoration of over 600 mL of blood within a 24-hour period. It is a medical emergency associated with a mortality rate of 30% to 50%. Most clinicians would agree that losing over a liter of blood via the airway within 1 day is significant, yet use of an absolute volume criterion presents difficulties. First, it is difficult for the patient or caregivers to quantify the volume of blood being lost. Second, and most relevant, the rate of bleeding necessary to incite respiratory compromise is highly dependent on the individual’s prior respiratory status. For example, the loss of 100 mL of blood over 24 hours in a 40-year-old male with normal pulmonary function would be of little immediate consequence, because his normal cough would ensure his ability to clear the blood and secretions. In contrast, the same amount of bleeding in a 69-year-old male with severe COPD, chronic bronchitis, and an FEV1 of 1.1 L may be life-threatening.
The lungs have two sources of blood supply: the pulmonary and bronchial arterial systems. The pulmonary system is a high-compliance, low-pressure system, and the walls of the pulmonary arteries are very thin and delicate. The bronchial arteries, part of the systemic circulation, have systemic pressures and thick walls; most branches originate from the proximal thoracic aorta. Most cases of massive hemoptysis involve bleeding from the bronchial artery circulation or from the pulmonary circulation pathologically exposed to the high pressures of the bronchial circulation. In many cases of hemoptysis, particularly those due to inflammatory disorders, the bronchial arterial tree becomes hyperplastic and tortuous. The systemic pressures within these arteries, combined with a disease process within the airway and erosion, lead to bleeding.
Significant hemoptysis occurs as a result of pulmonary, extrapulmonary, and iatrogenic causes. Table 19-20 summarizes the most common causes of hemoptysis. Most are secondary to inflammatory processes. Aneurysms of the pulmonary artery (referred to as Rasmussen’s aneurysm) can develop within pulmonary cavities and can result in massive bleeding. Hemoptysis due to lung cancer is usually mild, resulting in blood-streaked sputum. Massive hemoptysis in patients with lung cancer is typically caused by malignant invasion of pulmonary artery vessels by large central tumors. Although rare, it is often a terminal event.
Table 19-20Pulmonary and extrapulmonary causes of massive hemoptysis ||Download (.pdf) Table 19-20 Pulmonary and extrapulmonary causes of massive hemoptysis
|PULMONARY ||EXTRAPULMONARY ||IATROGENIC |
Pulmonary parenchymal disease
Cavitary fungal infection (e.g., aspergilloma)
Lung parasitic infection (ascariasis, schistosomiasis, paragonimiasis)
Pulmonary infarction or embolism
Congestive heart failure
|Intrapulmonary catheter |
Life-threatening hemoptysis is best managed by a multidisciplinary team of intensive care physicians, interventional radiologists, and thoracic surgeons. Treatment priorities begin with respiratory stabilization; intubation with isolation of the bleeding lung may be required to prevent asphyxiation. This can be done with main-stem intubation into the nonbleeding lung, endobronchial blockers into the bleeding lung, or double-lumen endotracheal intubation, depending on the urgency of the situation and the expertise of the providers. Once adequate ventilation has been achieved, the bleeding site should be localized; bronchoscopy can often provide direct visualization of blood coming from a specific area of the tracheobronchial anatomy. Control of the hemorrhage is then achieved endobronchially with laser or bronchial occlusion, endovascularly with bronchial and/or pulmonary artery embolization, or surgically with resection of the involved area.137 The order of priorities in management is detailed in Table 19-21.
Table 19-21Treatment priorities in the management of massive hemoptysis ||Download (.pdf) Table 19-21 Treatment priorities in the management of massive hemoptysis
1. Achieve respiratory stabilization and prevent asphyxiation.
2. Localize the bleeding site.
3. Control the hemorrhage.
4. Determine the cause.
5. Definitively prevent recurrence.
The clinically pragmatic definition of massive hemoptysis is a degree of bleeding that threatens respiratory stability. Therefore, clinical judgment of respiratory compromise is the first step in evaluating a patient.138,139 Two scenarios are possible: (1) bleeding is significant and persistent, but its rate allows a rapid, sequential diagnostic and therapeutic approach, or (2) bleeding is so rapid that emergency airway control and therapy are necessary.
Scenario 1: Significant, Persistent, but Nonmassive Bleeding
Although bleeding is brisk in scenario 1, the patient may be able to maintain clearance of the blood and secretions with his or her own respiratory reflexes. Immediate measures are admission to an intensive care unit; strict bed rest; Trendelenburg positioning with the affected side down (if known); administration of humidified oxygen; cough suppression; monitoring of oxygen saturation and arterial blood gases; and insertion of large-bore intravenous catheters. Strict bed rest with sedation may lead to slowing or cessation of bleeding, and the judicious use of intravenous narcotics or other relaxants to mildly sedate the patient and diminish some of the reflexive airway activity is often necessary. Also recommended are administration of aerosolized adrenaline, intravenous antibiotic therapy if needed, and correction of abnormal blood coagulation study results. Finally, unless contraindicated, intravenous vasopressin (20 U over 15 minutes, followed by an infusion of 0.2 U/min) can be given.
A CXR is the first test and often proves to be the most revealing. Localized lesions may be seen, but the effects of blood soiling of other areas of the lungs may predominate, obscuring the area of pathology. Chest CT scan provides more detail and is nearly always performed if the patient is stable. Pathologic areas may be obscured by blood soiling.
Flexible bronchoscopy is the next step in evaluating the patient’s condition. Some clinicians argue that rigid bronchoscopy should always be performed. However, if the patient is clinically stable and the ongoing bleeding is not imminently threatening, flexible bronchoscopy is appropriate. It allows diagnosis of airway abnormalities and will usually permit localization of the bleeding site to either a lobe or even a segment. The person performing the bronchoscopy must be prepared with excellent suction and must be able to perform saline lavage with a dilute solution of epinephrine.
Most cases of massive hemoptysis arise from the bronchial arterial tree; therefore, the next therapeutic option frequently is selective bronchial arteriography and embolization. Bronchoscopy prior to arteriogram is extremely useful to direct the angiographer. However, if bronchoscopy fails to localize the bleeding site, then bilateral bronchial arteriograms can be performed. More recently, use of multidetector CT angiography in patients with hemoptysis that is not immediately life-threatening has been shown to facilitate endovascular intervention; reformatting of the images in multiple projections allows clear delineation of the pulmonary vascular anatomy.126 With this approach, abnormal bronchial and nonbronchial arteries can be visualized and subsequently targeted for therapeutic arterial embolization.140 Once the targeted arterial system has been embolized, immediate control and cessation of the hemoptysis is achieved in more than 80% of patients. If bleeding persists after bronchial artery embolization, a pulmonary artery source should be suspected and a pulmonary angiogram performed at the same setting.
Recurrence is seen in 30% to 60% of cases and is very common in the setting of invasive fungal infections such as aspergilloma. Recurrence after bronchial artery embolization is less common in the setting of malignancy and active tuberculosis but does occur and can ultimately result in patient death.141 Repeat embolization can be effective and is warranted for initial management of recurrent hemoptysis, but early surgical intervention should be considered, particularly in the setting of aspergilloma or other cavitary lesions.126
If respiratory compromise is impending, orotracheal intubation should be performed. After intubation, flexible bronchoscopy should be performed to clear blood and secretions and to attempt localization of the bleeding site. Depending on the possible causes of the bleeding, bronchial artery embolization or (if appropriate) surgery can be considered.
Scenario 2: Significant, Persistent, and Massive Bleeding
Life-threatening bleeding requires emergency airway control and preparation for potential surgery. Such patients are best cared for in an operating room equipped with rigid bronchoscopy. Immediate orotracheal intubation may be necessary to gain control of ventilation and suctioning. However, rapid transport to the operating room with rigid bronchoscopy should be facilitated. Rigid bronchoscopy allows adequate suctioning of bleeding with visualization of the bleeding site; the nonbleeding side can be cannulated with the rigid scope and the patient ventilated. After stabilization, ice-saline lavage of the bleeding site can then be performed (up to 1 L in 50-mL aliquots); bleeding stops in up to 90% of patients.142
Alternatively, blockade of the main stem bronchus of the affected side can be accomplished with a double-lumen endotracheal tube, with a bronchial blocker, or by intubation of the nonaffected side by an uncut standard endotracheal tube. Placement of a double-lumen endotracheal tube is challenging in these circumstances, given the bleeding and secretions. Proper placement and suctioning may be difficult, and attempts could compromise the patient’s ventilation. The best option is to place a bronchial blocker in the affected bronchus with inflation. Endovascular embolization can be performed to stop the bleeding after control has been achieved with the bronchial blocker. The blocker is left in place for 24 hours; after 24 hours, the area is re-examined bronchoscopically.
In most patients, bleeding can be stopped, recovery can occur, and plans to definitively treat the underlying cause can be made. In scenario 1 (significant, persistent, but nonmassive bleeding), the patient may undergo further evaluation as an inpatient or outpatient. A chest CT scan and pulmonary function studies should be obtained preoperatively. In scenario 2 (patients with significant, persistent, and massive bleeding), surgery, if appropriate, will usually be performed during the same hospitalization as the rigid bronchoscopy or main stem bronchus blockade. In a small number of patients (<10%), immediate surgery will be necessary due to the extent of bleeding. The bleeding site in these patients is localized using rigid bronchoscopy with immediate thoracotomy or sternotomy to follow.
Surgical treatment is individualized according to the source of bleeding and the patient’s medical condition, prognosis, and pulmonary reserve. General indications for urgent surgery are presented in Table 19-22. In patients with significant cavitary disease or with fungus balls, the walls of the cavities are eroded and necrotic; rebleeding will likely ensue. In addition, bleeding from cavitary lesions may be due to pulmonary artery erosion, which requires surgery for control.
Table 19-22General indications for urgent operative intervention for massive hemoptysis ||Download (.pdf) Table 19-22 General indications for urgent operative intervention for massive hemoptysis
1. Presence of a fungus ball
2. Presence of a lung abscess
3. Presence of significant cavitary disease
4. Failure to control the bleeding
Lung Volume Reduction Surgery
The ideal patient for lung volume reduction surgery (LVRS) has heterogeneous emphysema with apical predominance, meaning the worst emphysematous changes are in the apex (seen on chest CT scan) of the lungs. The physiologic lack of function of these areas is demonstrated by quantitative perfusion scan, which shows minimal or no perfusion. By surgically excising these nonfunctional areas, the volume of the lung is reduced, theoretically restoring respiratory mechanics. Diaphragm position and function are improved, and there may be an improvement in the dynamic small airway collapse in the remaining lung.
Operative mortality in the initial experience was 16.9%, with a 1-year mortality of 23%. In response, the National Emphysema Treatment Trial (NETT) performed a randomized trial of 1218 patients in a noncrossover design to medical vs. surgical management after a 10-week pretreatment pulmonary rehabilitation program. Subgroup analysis demonstrated that in patients with the anatomic changes delineated by Cooper and colleagues, LVRS significantly improved exercise capacity, lung function, quality of life, and dyspnea compared to medical therapy. After 2 years, functional improvements began to decline toward baseline. Similar parameters in medically treated patients steadily decline below baseline. LVRS was associated with increased short-term morbidity and mortality and did not confer a survival benefit over medical therapy.143
The most common indications for lung transplant are COPD and idiopathic pulmonary fibrosis (IPF). Most patients with IPF and older patients with COPD are offered a single-lung transplant. Younger COPD patients and patients with α1-antitrypsin deficiency and severe hyperinflation of the native lungs are offered a bilateral-lung transplant. Most patients with primary pulmonary hypertension and almost all patients with cystic fibrosis are treated with a bilateral-lung transplant. A heart-lung transplant is reserved for patients with irreversible ventricular failure or uncorrectable congenital cardiac disease.
Patients with COPD are considered for placement on the transplant waiting list when their FEV1 has fallen to below 25% of its predicted value. Patients with significant pulmonary hypertension should be listed earlier. IPF patients should be referred when their forced vital capacity has fallen to less than 60% or their Dlco has fallen to less than 50% of their predicted values.
In the past, patients with primary pulmonary hypertension and New York Heart Association (NYHA) class III or IV symptoms were listed for a lung transplant. However, treatment of such patients with intravenous prostacyclin and other pulmonary vasodilators has now markedly altered that strategy. Virtually all patients with primary pulmonary hypertension are now treated with intravenous epoprostenol. Several of these patients have experienced a marked improvement in their symptoms associated with a decrease in their pulmonary arterial pressures and an increase in exercise capacity. Listing of these patients is deferred until they develop NYHA class III or IV symptoms or until their mean pulmonary artery pressure rises above 75 mmHg.
Medium-term and bronchiolitis obliterans syndrome (BOS)-free survival rates of patients who underwent a lung transplant during a recent 5-year period at the University of Minnesota are shown in Figs. 19-35 and 19-36. The mortality of patients while waiting for transplants is about 10%. In an effort to expand the number of lung donors, many transplant groups have liberalized their criteria for donor selection. Still, the partial pressure of arterial oxygen (Pao2) should be greater than 300 mmHg on a fraction of inspired oxygen (Fio2) of 100%. In special circumstances, lungs may be used from donors with a smoking history; from donors older than 50 years of age; and from donors with positive Gram stains or infiltrates on CXR.144,145 The use of two living donors, each donating a single lower lobe, is another strategy for increasing the donor pool. Recipient outcomes are similar to those with cadaver donors in carefully selected patients.
The overall survival rate after lung transplantation at the University of Minnesota.
The survival rate after lung transplantation in the absence of bronchiolitis obliterans syndrome (BOS) at the University of Minnesota.
Most of the early mortality after lung transplant is related to primary graft failure resulting from a severe ischemia-reperfusion injury to the lung(s) (Fig. 19-37). Reperfusion injury is characterized radiographically by interstitial and alveolar edema and clinically by hypoxia and ventilation-perfusion mismatch. Donor neutrophils and recipient lymphocytes probably play an important role in the pathogenesis of reperfusion injury. The most important impediment to longer-term survival after a lung transplant is the development of BOS, a manifestation of chronic rejection. Episodes of acute rejection are the major risk factors for developing BOS. Other injuries to the lung (including early reperfusion injury and chronic gastroesophageal reflux disease) may also adversely affect long-term outcomes of patients.146,147
The survival rate after lung transplantation at the University of Minnesota as a function of primary graft failure (PGF).