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Surgery_Schwartz. t-stage for AIS is tumor in situ (Tis).2. 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 com-ponent 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 larg-est dimension, is used; this area must be ≤5 mm to be con-sidered MIA. As with AIS, MIA is very rarely mucinous. The invasive component histologically is acinar, papillary, micropapillary, and/or solid and shows tumor cells infil-trating into the surrounding myofibroblastic stroma. On CT scan, the


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Surgery_Schwartz. mucinous. The invasive component histologically is acinar, papillary, micropapillary, and/or solid and shows tumor cells infil-trating 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. The 8th edition American Joint Committee on Cancer (AJCC) staging manual t-stage for MIA is T1mi.3. Lepidic predominant adenocarcinoma (LPA). If lympho-vascular 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, the lesion is called lepidic predominant adenocarcinoma (LPA), and the size of the invasive component is recorded for the T stage.4. 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


Surgery_Schwartz

Surgery_Schwartz. 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 speci-men. This semiquantitative method encourages the viewer to identify and quantify all patterns present, rather than focus-ing 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:a. Lepidic predominantb. Acinar predominantc. Papillary predominantd. Micropapillary predominante. Solid predominantAdenocarcinoma 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


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Surgery_Schwartz. 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 lucency 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 favor-able 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 sur-vival following complete surgical resection. Pleural


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Surgery_Schwartz. tumor, whereas spiculations that are coarse and thick (≥2 mm) portend vascular invasion and nodal metastasis and are associated with decreased sur-vival following complete surgical resection. Pleural retraction is also a poor prognostic indicator.5. Additional histologic variants include colloid adenocarci-noma (formerly mucinous cystadenocarcinoma), fetal ade-nocarcinoma, 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.Squamous Cell Carcinoma 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


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Surgery_Schwartz. ring features.Squamous Cell Carcinoma 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, Brunicardi_Ch19_p0661-p0750.indd 67101/03/19 7:00 PM 672SPECIFIC CONSIDERATIONSPART IIFigure 19-11. 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 pneumo-cytes and Clara cells along the surface alveolar walls. C. Area of invasive acinar adenocarcinoma (same tumor as in A and B). D. Acinar adenocarcinoma con-sists of round to oval-shaped malignant glands invad-ing a fibrous stroma. E. Papillary adenocarcinoma


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Surgery_Schwartz. Area of invasive acinar adenocarcinoma (same tumor as in A and B). D. Acinar adenocarcinoma con-sists of round to oval-shaped malignant glands invad-ing 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 consist-ing 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 baso-philic globules that suggest intracytoplasmic mucin. H. Solid adenocarcinoma with mucin. Numerous intracytoplasmic droplets of mucin are highlighted with this diastase-periodic acid Schiff stain. (Repro-duced with permission from Travis WD, Brambilla E, Noguchi M, et al:


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Surgery_Schwartz. with mucin. Numerous intracytoplasmic droplets of mucin are highlighted with this diastase-periodic acid Schiff stain. (Repro-duced with permission from Travis WD, Brambilla E, Noguchi M, et al: International association for the study of lung cancer/american thoracic society/european respiratory society international multidisci-plinary classification of lung adenocarcinoma, J Thorac Oncol. 2011 Feb;6(2):244-285.)hemoptysis, wheezing (due to high-grade airway obstruction), dyspnea (due to bronchial obstruction with or without postob-structive atelectasis), and pneumonia (caused by airway obstruc-tion 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


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Surgery_Schwartz. 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 Large cell carcinoma accounts for 10% to 20% of lung cancers and may be located centrally or periph-erally. 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 neu-roendocrine 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 occur cen-trally due to


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Surgery_Schwartz. 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 occur cen-trally 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 mitotic rate and degree of necrosis.Neuroendocrine Neoplasms. Neuroendocrine lung tumors are classified into neuroendocrine hyperplasia and three grades of neuroendocrine carcinoma (NEC). Immunohistochemical staining for neuroendocrine markers (including chromogranins, synaptophysin, CD57, and neuron-specific enolase) is essential to accurate diagnosis.17Grade I NEC (classic or typical carcinoid) is a low-grade NEC; 80% arise in the central airway epithelium and occur primarily in younger patients.


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Surgery_Schwartz. enolase) is essential to accurate diagnosis.17Grade I NEC (classic or typical carcinoid) is a low-grade NEC; 80% arise in the central airway epithelium and occur primarily in younger patients. Because it is a central lesion, hemoptysis, with or without airway obstruction and pneumonia is the most common presentation. Histologically, tumor cells Brunicardi_Ch19_p0661-p0750.indd 67201/03/19 7:00 PM


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Surgery_Schwartz. CHAPTER 19673CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAare arranged in cords and clusters with a rich vascular stroma, which can lead to life-threatening hemorrhage with even simple bronchoscopic biopsy maneuvers. Regional lymph node metas-tases are seen in 15% of patients, but systemic spread and death from Grade I NEC is rare.Grade II NECs (atypical carcinoid) have a much higher malignant potential and, unlike grade I NEC, are etiologically linked to cigarette smoking and 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. Often large with central necrosis and a high mitotic rate, their neuro-endocrine nature is revealed by positive immunohistochemical staining for at


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Surgery_Schwartz. smokers and in the mid to peripheral lung fields. Often large with central necrosis and a high mitotic rate, their neuro-endocrine 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 atel-ectasis), 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 (previously referred to as oat cell carci-noma), small cell carcinoma with a large


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Surgery_Schwartz. evaluation for metastatic disease. Three groups of grade IV NEC are recognized: pure small cell carcinoma (previously referred to as oat cell carci-noma), 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 EpidemiologyLung cancer is the leading cancer killer and second most frequently diagnosed cancer in the United


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Surgery_Schwartz. necessary. These tumors are the leading producer of paraneoplastic syndromes.Lung Cancer EpidemiologyLung cancer is the leading cancer killer and second most frequently diagnosed cancer in the United States, account-ing for 26% of all cancer deaths in 2017—more than cancers of the breast, prostate, ovary, and colon and rectum com-bined (Fig. 19-12).18 Lung cancer incidence continues to decline, though at twice the rate for men compared to women (Fig. 19-13A, B). It is encouraging, however, that the average annual death rate declined by 3.5% per year for men and 2% per year for women from 2010 to 2014, representing a 43% decline in mortality for men and a 17% decline for women from 1990 MalesFemalesBreastLung & bronchusColon & rectumUterine corpusNon-Hodgkin lymphomaThyroidMelanoma of the skinPancreasLeukemiaKidney & renal pelvisAll Sites252,710105,51064,01061,38042,47034,94032,16025,84025,70023,380852,63030%12%8%7%5%4%4%3%3%3%100%MalesFemalesLung & bronchusProstateColon &


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Surgery_Schwartz. of the skinPancreasLeukemiaKidney & renal pelvisAll Sites252,710105,51064,01061,38042,47034,94032,16025,84025,70023,380852,63030%12%8%7%5%4%4%3%3%3%100%MalesFemalesLung & bronchusProstateColon & rectumPancreasLiver & intrahepatic bile ductLeukemiaEsophagusUrinary bladderNon-Hodgkin lymphomaBrain & other nervous systemAll SitesLung & bronchusBreastColon & rectumPancreasOvaryLeukemiaNon-Hodgkin lymphomaUterine corpusLiver & intrahepatic bile ductBrain & other nervous systemAll Sites71,28040,61023,11020,79014,08010,92010,2009,3108,6907,080282,50025%14%8%7%5%4%4%3%3%3%100%84,59027,15026,73022,30019,61014,30012,72012,24011,4509,620318,42027%9%8%7%6%4%4%4%4%3%100%ProstateLung & bronchusColon & rectumUrinary bladderMelanoma of the skinNon-Hodgkin lymphomaKidney & renal pelvisOral cavity & pharynxLeukemiaLiver & intrahepatic bile ductAll Sites161,360116,99071,42060,49052,17040,61040,08036,29035,72029,200836,15019%14%9%7%6%5%5%4%4%3%100%Estimated new casesEstimated deathsFigure 19-12. Leading


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Surgery_Schwartz. & intrahepatic bile ductAll Sites161,360116,99071,42060,49052,17040,61040,08036,29035,72029,200836,15019%14%9%7%6%5%5%4%4%3%100%Estimated new casesEstimated deathsFigure 19-12. Leading new cancer cases and deaths: 2017 estimates. *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. (Reproduced with permission from Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2017, CA Cancer J Clin. 2017 Jan;67(1):7-30.)Brunicardi_Ch19_p0661-p0750.indd 67301/03/19 7:00 PM 674SPECIFIC CONSIDERATIONSPART IIFigure 19-13. Trends in death rates by sex for select cancers, United States, 1930 to 2014. A. Males. B. Female rates are age-adjusted to the 2000 U.S. standard population. Due to improvements in International Classification of Diseases (ICD) coding over time, numerator data for cancers of the lung and bronchus, colon and rectum, liver, and uterus differ from the contemporary time period. For example, rates for lung and bronchus include pleura, trachea,


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Surgery_Schwartz. numerator data for cancers of the lung and bronchus, colon and rectum, liver, and uterus differ from the contemporary time period. For example, rates for lung and bronchus include pleura, trachea, mediastinum, and other respiratory organs. (Adapted with permission from Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2017, CA Cancer J Clin. 2017 Jan;67(1):7-30.)0102030405060708090100Pancreas†StomachLung and BronchusColon and RectumProstateLiver†LeukemiaTrends in Age-Adjusted Cancer Death Rates* by Site, Males, US, 1930-2014*Per 100,000, age adjusted to the 2000 US standard population.†Mortality rates for pancreatic and liver cancers are increasing.1930193419381942194619501954195819621966197019741978198219861990199419982002200620102014Trends in Age-Adjusted Cancer Death Rates* by Site, Females, US, 1930-2014*Per 100,000, age adjusted to the 2000 US standard population.†Uterus refers to uterine cervix and uterine corpus combined.‡Mortality rates for liver cancer are


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Surgery_Schwartz. Rates* by Site, Females, US, 1930-2014*Per 100,000, age adjusted to the 2000 US standard population.†Uterus refers to uterine cervix and uterine corpus combined.‡Mortality rates for liver cancer are increasing.010203040505152535451930193419381942194619501954195819621966197019741978198219861990199419982002200620102014StomachColon and RectumPancreas‡Lung and BronchusBreastUterus†Liver‡Brunicardi_Ch19_p0661-p0750.indd 67401/03/19 7:00 PM


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Surgery_Schwartz. CHAPTER 19675CHEST WALL, LUNG, MEDIASTINUM, AND PLEURATable 19-3Relative risk of lung cancer in smokersSMOKING CATEGORYRELATIVE RISKNever smoked1.0Currently smoke15.8–16.3Formerly smoked Years of abstinence 1–95.9–19.5 10–192.0–6.1 >201.9–3.7Data from Samet JM. Health benefits of smoking cessation, Clin Chest Med. 1991;12(4):669-679.to 2014.18 Unfortunately, most patients are still diagnosed at an advanced stage of disease (22% with regional metastasis and 57% with distant metastasis), so therapy is rarely curative.18Prognostic 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 pop-ulation, the racial difference in survival disappears, suggesting that, at least in part, differences in


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Surgery_Schwartz. for blacks). When access to advanced medical care is unrestricted, as for the military pop-ulation, 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.19Risk Factors for Lung Cancer. Cigarette smoking is the leading preventable cause of cancer death, accounting for 29% of the popu-lation attributable fraction in 2010, and is implicated as a causal factor in approximately 90% of lung cancers in men and nearly 80% in women. 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


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Surgery_Schwartz. 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.21Nearly 3500 deaths from lung cancer each year are attrib-utable to secondhand (environmental) smoke exposure, which confers an excess risk for lung cancer of 24% when a non-smoker lives with a smoker.22 Risk is conferred by exposure to any burning tobacco, including cigars. The amount of second-hand 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


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Surgery_Schwartz. of second-hand 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 acti-vated by specific enzymes and become mutagenic, bind to mac-romolecules such as deoxyribonucleic acid (DNA), and induce genetic mutations. In treating any patient with a previous smok-ing 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, tra-cheobronchial tree and lung, and esophagus. In examining such patients, a detailed


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Surgery_Schwartz. the entire aerodigestive tract. The patient’s risk is increased for cancers of the oral cavity, pharynx, larynx, tra-cheobronchial 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 num-ber 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 his-tory of tuberculosis or other lung infections also have a higher risk of primary lung carcinoma. This increase is thought to be related to poor clearance of inhaled


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Surgery_Schwartz. scar formation related to a his-tory of tuberculosis or other lung infections 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 PopulationsIn 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 posteroante-rior 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


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Surgery_Schwartz. 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% rela-tive 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 empha-sizing the impact of lung cancer on the mortality of smokers and former smokers.23 The U.S. Preventive Services Task Force (USPSTF) now recommends annual screening for lung cancer with low-dose computed tomography screening in high risk patients. Annual screening averted 14% of lung cancer deaths when applied to a population of asymptomatic adults age 55 to 80 years who have a 30


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Surgery_Schwartz. low-dose computed tomography screening in high risk patients. Annual screening averted 14% of lung cancer deaths when applied to a population of asymptomatic adults age 55 to 80 years who have a 30 pack-year smoking history and are either currently smoking or have quit within the past 15 years. Patients should be healthy enough to tolerate curative treatment, specifically surgery per guidelines, and screening should be dis-continued once the patient has not smoked for 15 years or develops a life-limiting health condition, becomes unable to tolerate lung surgery or is unwilling to undergo curative lung resection. Require-ments for coverage differ between Medicare and private insurers, with private insurers following the USPSTF guidelines, while Medicare uses age 55 to 77 years with the same smoking history but does not define comorbid conditions. Use of standardized reporting with criteria for lung nodule identification and classifica-tion is required by the Center for Medicaid &


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Surgery_Schwartz. same smoking history but does not define comorbid conditions. Use of standardized reporting with criteria for lung nodule identification and classifica-tion is required by the Center for Medicaid & Medicare Services (CMS) but is only recommended by private insurers. Shared deci-sion-making is also required by Medicare, but it is only recom-mended by private insurers. Medicare also differs from private 4Brunicardi_Ch19_p0661-p0750.indd 67501/03/19 7:00 PM 676SPECIFIC CONSIDERATIONSPART IITable 19-4Summary of selected studies of risk factors for lung cancer in individuals who never smokedRISK FACTORRISK ESTIMATE (95% CI)COMMENTSREFERENCEEnvironmental tobacco smoke1.19 (90% CI: 1.04–1.35)Meta-analysis of 11 U.S. studies of spousal exposure (females only)2251.21 (1.13–1.30)Meta-analysis of 44 case-control studies worldwide of spousal exposure2261.22 (1.13–1.33)Meta-analysis of 25 studies worldwide of workplace exposure2261.24 (1.18–1.29)Meta-analysis of 22 studies worldwide of


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Surgery_Schwartz. of 44 case-control studies worldwide of spousal exposure2261.22 (1.13–1.33)Meta-analysis of 25 studies worldwide of workplace exposure2261.24 (1.18–1.29)Meta-analysis of 22 studies worldwide of workplace exposure227Residential radon8.4% (3.0%–15.8%) per 100 Bq m3 increase in measured radonMeta-analysis of 13 European studies22811% (0%–28%) per 100 Bq m3Meta-analysis of 7 North American studies229Cooking oil vapors2.12 (1.81–2.47)Meta-analysis of 7 studies from China and Taiwan (females who never smoked)230Indoor coal and wood burning2.66 (1.39–5.07)Meta-analysis of 7 studies from China and Taiwan (both sexes)2301.22 (1.04–1.44)Large case-control study (2861 cases and 3118 controls) from Eastern and Central Europe (both sexes)2312.5 (1.5–3.6)Large case-control study (1205 cases and 1541 controls) from Canada (significant for women only)232Genetic factors: family history, CYP1A1 Ile462Val polymorphism, XRCC1 variants1.51 (1.11–2.06)Meta-analysis of 28 case-control, 17 cohort, and 7 twin


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Surgery_Schwartz. from Canada (significant for women only)232Genetic factors: family history, CYP1A1 Ile462Val polymorphism, XRCC1 variants1.51 (1.11–2.06)Meta-analysis of 28 case-control, 17 cohort, and 7 twin studies2332.99 (1.51–5.91)Meta-analysis of 14 case-control studies of Caucasian never smokers2342.04 (1.17–3.54)Meta-analysis of 21 case-control studies of Caucasian and Asian never smokers (significant for Caucasians only)235No associationMeta-analysis of 13 case-control studies236No association overall; reduced risk 0.65 (0.46–0.83) with Arg194Trp polymorphism and 0.56 (0.36–0.86) with Arg280His for heavy smokersLarge case-control study from Europe (2188 cases and 2198 controls)237Increased risk for never smokers 1.3 (1.0–1.8) and decreased risk for heavy smokers 0.5 (0.3–1.0) with Arg299GlnLarge case-control study from the United States (1091 cases and 1240 controls)238Viral factors: HPV 16 and 1810.12 (3.88–26.4) for never smoking women >60 yCase-control study (141 cases, 60 controls) from


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Surgery_Schwartz. study from the United States (1091 cases and 1240 controls)238Viral factors: HPV 16 and 1810.12 (3.88–26.4) for never smoking women >60 yCase-control study (141 cases, 60 controls) from Taiwan of never smoking women239Abbreviations: Bq = becquerels; CI = confidence interval; CYP1A1 = cytochrome P450 enzyme 1A1; HPV = human papilloma virus.Reproduced with permission from Sun S, Schiller JH, Gazdar AF: Lung cancer in never smokers—a different disease, Nat Rev Cancer. 2007 Oct; 7(10):778-790.insurers in that it requires accreditation of the imaging center and submission of all low-dose CT data to a CMS-approved national registry, among other specifications. With this approach, it is expected that 50% of diagnosed cancers will be early stage. Screening of patients age 50 years or older with a 20 pack-year or greater history and additional risk factors (as determined by the Tammemagi lung cancer risk calculator or other validated risk scores) that increase the risk of lung cancer to 1.3%


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Surgery_Schwartz. a 20 pack-year or greater history and additional risk factors (as determined by the Tammemagi lung cancer risk calculator or other validated risk scores) that increase the risk of lung cancer to 1.3% or greater should also be considered as part of lung cancer screening pro-grams. In all cases, patient–physician shared decision-making should be undertaken, with a discussion of the risks and benefits of screening. It is important to note that there was a 7% false-positive rate in NLST trial, which can 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 requires further study, particularly as screening programs are implemented outside of the controlled set-ting of a clinical trial. It is also critical that regulatory guidelines for patient eligibility, frequency of screening, interpretation of the scans, processes for further evaluation and management of


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Surgery_Schwartz. of a clinical trial. It is also critical that regulatory guidelines for patient eligibility, frequency of screening, interpretation of the scans, processes for further evaluation and management of posi-tive 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.Brunicardi_Ch19_p0661-p0750.indd 67601/03/19 7:00 PM


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Surgery_Schwartz. CHAPTER 19677CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAABCDFigure 19-14. 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.Solitary Pulmonary NoduleA solitary pulmonary nodule is typically described as a single, well-circumscribed, spherical


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Surgery_Schwartz. pulmonary artery; RV = right ventricle; SVC = superior vena cava; T = trachea.Solitary Pulmonary NoduleA solitary pulmonary nodule is typically described as a single, well-circumscribed, spherical lesion that is 3 cm or less cm 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 inciden-tally each year, with increasing numbers as low-dose computed tomography screening in high-risk populations is adopted. 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, inflam-matory, vascular, and traumatic disorders. The probability of cancer in a solitary pulmonary nodule increases if the patient


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Surgery_Schwartz. nodule should include a broad variety of congenital, neoplastic, inflam-matory, 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% to 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 morphol-ogy, calcification pattern, and growth rate.25 Spiral (helical) CT allows continuous scanning as


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Surgery_Schwartz. to six nodules. CT scanning is necessary to characterize nodule number, location, size, margin morphol-ogy, 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 to 2 mm collimation) at 1-cm intervals should be used to evaluate pulmonary parenchyma and


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Surgery_Schwartz. images can be reconstructed for enhanced visualization of spatial anatomic relationships.27 Thin sections (1 to 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 metas-tases, 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.CT findings characteristic of benign lesions include small size, calcification within the nodule, and stability over time. Brunicardi_Ch19_p0661-p0750.indd 67701/03/19 7:00 PM 678SPECIFIC CONSIDERATIONSPART IIABCFigure 19-15. 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


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Surgery_Schwartz. 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.Table 19-5Actuarial survival data from the International Registry of Lung MetastasesSURVIVALCOMPLETE RESECTION (%)INCOMPLETE RESECTION (%)5 years361310 years26715 years22—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


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Surgery_Schwartz. 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% to 50% of partial solid lesions are malignant compared to only 15% of subcenti-meter solid or nonsolid nodules); size >3 cm; irregular, lobu-lated, or spiculated edges; and the finding of the corona radiata sign (consisting of fine linear strands extending 4 to 5 mm out-ward and appearing spiculated on radiographs) (Fig. 19-15). Calcification that is stippled, amorphous, or eccentric is usually associated with cancer.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


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Surgery_Schwartz. with cancer.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) scan-ning 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% spec-ificity 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 LungThe cause of a new


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Surgery_Schwartz. 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 LungThe cause of a new pulmonary nodule(s) in a patient with a previous malignancy can be difficult to discern.29 Features sug-gestive of metastatic disease are multiplicity; smooth, round borders on CT scan; and temporal proximity to the original pri-mary 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


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Surgery_Schwartz. 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 Interna-tional 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 meta-static disease is resectable, solitary, and identified 36 or more months after initial treatment. When any or all of these optimal characteristics are absent, survival


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Surgery_Schwartz. of cancers is optimal when meta-static 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.Brunicardi_Ch19_p0661-p0750.indd 67801/03/19 7:00 PM


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Surgery_Schwartz. CHAPTER 19679CHEST WALL, LUNG, MEDIASTINUM, AND PLEURA10080604020002448All Sites7296120Soft Tissue Sarcomas100806040200024487296120Breast Cancer100806040200024487296120Osteosarcoma1001234806040200024487296120Colon Cancer100806040200024487296120Melanoma100806040200024487296120ABCDEFFigure 19-16. The actuarial survival after metastasectomy is depicted for patients with various tumor types (A-F) further categorized into four groups according to resectabil-ity, solitary or multiple, the inter-val between primary resection and metastesectomy, and a combination of factors known in our work and in others, as follows: (1) resectable, soli-tary, and disease-free interval (DFI) greater than or equal to 36 months; (2) resectable, solitary, and DFI 36+ months; (3) resectable, multiple metastases, and DFI <36 months; and (4) unresectable. (Reproduced with permission from Pastorino U: The development of an international registry, J Thorac Oncol. 2010 Jun; 5(6 Suppl 2):S196-S197.)The general


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Surgery_Schwartz. and DFI <36 months; and (4) unresectable. (Reproduced with permission from Pastorino U: The development of an international registry, J Thorac Oncol. 2010 Jun; 5(6 Suppl 2):S196-S197.)The general principles of patient selection for metasta-sectomy are listed in Table 19-6. The technical aim of pulmo-nary 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.Pulmonary metastasectomy can be approached through a thoracotomy or via video-assisted thoracic surgery (VATS) techniques. McCormack and colleagues reported their expe-rience 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 thora-cotomy was performed during the same operation; if


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Surgery_Schwartz. in a prospective study of 18 patients who presented with no more than two pulmonary metastatic lesions and underwent VATS resection.32 A thora-cotomy was performed during the same operation; if palpation Brunicardi_Ch19_p0661-p0750.indd 67901/03/19 7:00 PM 680SPECIFIC CONSIDERATIONSPART IITable 19-7Clinical presentation of lung cancerCATEGORYSYMPTOMCAUSEPulmonary symptomsCoughBronchus irritation or compressionDyspneaAirway obstruction or compressionWheezing>50% airway obstructionHemoptysisTumor erosion or irritationPneumoniaAirway obstructionNonpulmonary thoracic symptoms Pleuritic painParietal pleural irritation or invasionLocal chest wall painRib and/or muscle involvementRadicular chest painIntercostal nerve involvementPancoast’s syndromeStellate ganglion, chest wall, brachial plexus involvementHoarsenessRecurrent laryngeal nerve involvementSwelling of head and armsBulky involved mediastinal lymph nodes Medially based right upper lobe tumorTable 19-6General principles governing


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Surgery_Schwartz. involvementHoarsenessRecurrent laryngeal nerve involvementSwelling of head and armsBulky involved mediastinal lymph nodes Medially based right upper lobe tumorTable 19-6General principles governing appropriate selection of patients for pulmonary metastasectomy1. 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.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 resec-tion should be performed via VATS. Proponents of VATS argue that


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Surgery_Schwartz. Memorial study were evaluated before the advent of spiral CT scanning, however, and it remains controversial whether metastasis resec-tion 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 equiv-alent 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 SymptomsLung cancer displays one of the most diverse presentation pat-terns 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


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Surgery_Schwartz. presentation pat-terns 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 pro-duction 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 nonpul-monary thoracic.Pulmonary Symptoms. 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


Surgery_Schwartz

Surgery_Schwartz. 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), pneu-monia (usually due to airway obstruction by the tumor), and lung abscess (due to necrosis and cavitation, with subsequent infection).Nonpulmonary Thoracic Symptoms. Nonpulmonary tho-racic 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.


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Surgery_Schwartz. 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, depend-ing 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:1. Pancoast’s syndrome. Tumors originating in the supe-rior sulcus (posterior apex) elicit: apical chest wall and/or shoulder pain (from involvement of the first rib and chest wall); Horner’s syndrome (unilateral enophthal-mos,


Surgery_Schwartz

Surgery_Schwartz. originating in the supe-rior sulcus (posterior apex) elicit: apical chest wall and/or shoulder pain (from involvement of the first rib and chest wall); Horner’s syndrome (unilateral enophthal-mos, 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).2. Phrenic nerve palsy. The phrenic nerve traverses the hemi-thorax 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 Brunicardi_Ch19_p0661-p0750.indd 68001/03/19 7:00 PM


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Surgery_Schwartz. CHAPTER 19681CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAdiaphragm paralysis. Radiographically, unilateral diaphragm elevation on chest radiograph is present; the diagnosis is confirmed by fluoroscopic examination of the diaphragm with paradoxical motion with breathing and sniffing (the “sniff” test).3. 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 associ-ated with a breathy quality, and coughing, particularly when drinking liquids.4. Superior vena cava (SVC) syndrome. As a result of bulky enlargement of involved mediastinal


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Surgery_Schwartz. a loss of tone associ-ated with a breathy quality, and coughing, particularly when drinking liquids.4. Superior vena cava (SVC) syndrome. As a result of bulky enlargement of involved mediastinal lymph nodes com-pressing or a medially based right upper lobe tumor invad-ing 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.5. 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.6. 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


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Surgery_Schwartz. by CT scan or echocardiography.6. 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.7. 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 his-tologies are capable of producing a variety of paraneoplastic syndromes, most often from systemic release of tumor-derived biologically active materials (Table 19-8). Paraneoplastic syn-dromes may produce symptoms even before any local symp-toms are produced by the primary tumor, thereby aiding in early diagnosis. Their presence does not influence resectabil-ity or treatment options. Symptoms often abate with


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Surgery_Schwartz. even before any local symp-toms are produced by the primary tumor, thereby aiding in early diagnosis. Their presence does not influence resectabil-ity or treatment options. Symptoms often abate with success-ful treatment; paraneoplastic symptom recurrence may herald tumor recurrence. The majority of such syndromes are associ-ated with grade IV NEC (small cell carcinoma), including many endocrinopathies.1. Hypertrophic pulmonary osteoarthropathy (HPO). Often severely debilitating, symptoms of HPO may antedate the diagnosis of cancer by months. Clinically, ankle, feet, fore-arm, and hand tenderness and swelling are characteristic, resulting from periostitis of the fibula, tibia, radius, meta-carpals, 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 Table 19-8Paraneoplastic syndromes in patients with lung


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Surgery_Schwartz. with grade IV NEC (Fig. 19-17). Plain radiographs show periosteal inflammation and elevation, while bone scans demonstrate intense but Table 19-8Paraneoplastic syndromes in patients with lung cancerEndocrineHypercalcemia (ectopic parathyroid hormone)Cushing’s syndromeSyndrome of inappropriate secretion of antidiuretic hormoneCarcinoid syndromeGynecomastiaHypercalcitoninemiaElevated growth hormone levelElevated levels of prolactin, follicle-stimulating hormone, luteinizing hormoneHypoglycemiaHyperthyroidismNeurologicEncephalopathySubacute cerebellar degenerationProgressive multifocal leukoencephalopathyPeripheral neuropathyPolymyositisAutonomic neuropathyEaton-Lambert syndromeOptic neuritisSkeletalClubbingPulmonary hypertrophic osteoarthropathyHematologicAnemiaLeukemoid reactionsThrombocytosisThrombocytopeniaEosinophiliaPure red cell aplasiaLeukoerythroblastosisDisseminated intravascular coagulationCutaneousHyperkeratosisDermatomyositisAcanthosis nigricansHyperpigmentationErythema


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Surgery_Schwartz. red cell aplasiaLeukoerythroblastosisDisseminated intravascular coagulationCutaneousHyperkeratosisDermatomyositisAcanthosis nigricansHyperpigmentationErythema gyratum repensHypertrichosis lanuginosa acquistaOtherNephrotic syndromeHypouricemiaSecretion of vasoactive intestinal peptide with diarrheaHyperamylasemiaAnorexia or cachexiasymmetric uptake in the long bones. Aspirin or nonsteroidal anti-inflammatory agents provide temporary relief; treat-ment requires successful tumor eradication.2. 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 leth-argy, depressed level of consciousness, nausea, vomiting, Brunicardi_Ch19_p0661-p0750.indd 68101/03/19 7:00 PM 682SPECIFIC


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Surgery_Schwartz. bone disease is not present. Symptoms of hypercalcemia include leth-argy, depressed level of consciousness, nausea, vomiting, Brunicardi_Ch19_p0661-p0750.indd 68101/03/19 7:00 PM 682SPECIFIC CONSIDERATIONSPART IIABCFigure 19-17. 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.and dehydration. Following complete tumor eradication, the calcium level will normalize. Unfortunately, tumor recur-rence is extremely common and may manifest as recurrent hypercalcemia.3. Hyponatremia. Characterized by confusion, lethargy, and possible seizures, hyponatremia can result from the inappro-priate 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 pres-ence


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Surgery_Schwartz. 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 pres-ence 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).4. 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., trun-cal obesity, buffalo hump, striae) are unusual due to the rapidity of ACTH elevation. Diagnosis is made by dem-onstrating hypokalemia (<3.0 mmol/L); nonsuppressible elevated plasma cortisol levels that lack the normal diurnal variation; elevated blood ACTH levels; or elevated urinary


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Surgery_Schwartz. Diagnosis is made by dem-onstrating 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. Immuno-reactive 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.5. Peripheral and central neuropathies. Unlike other para-neoplastic 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 dis-ability, and, of these,


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Surgery_Schwartz. generating antibodies leading either to interference with neurologic function or to immune neurologic destruction. Up to 16% of lung cancer patients have neuromuscular dis-ability, 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 dis-ease leading to disability must also be excluded.6. 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 abnormali-ties from proximal muscle weakness and impaired coordi-nation, may actually precede radiographic evidence of the tumor. Therapy is directed at the


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Surgery_Schwartz. motor end plate. Symptoms, including gait abnormali-ties from proximal muscle weakness and impaired coordi-nation, may actually precede radiographic evidence of the tumor. Therapy is directed at the primary tumor with resec-tion, radiation, and/or chemotherapy. Many patients have dramatic improvement after successful therapy. For patients with refractory symptoms, treatment consists of guanidine Brunicardi_Ch19_p0661-p0750.indd 68201/03/19 7:00 PM


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Surgery_Schwartz. CHAPTER 19683CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAhydrochloride, immunosuppressive agents such as predni-sone and azathioprine, and occasionally plasma exchange. Unlike with myasthenia gravis patients, neostigmine is usu-ally ineffective.Symptoms Associated with Metastatic Lung Cancer. Lung cancer metastasizes most commonly to the CNS, vertebral bod-ies, 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, vom-iting, 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 lung cancer patients. They are primar-ily lytic and produce pain locally; thus, any new and localized skeletal symptoms must be


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Surgery_Schwartz. of vertebral metastases. Bony metastases are identified in 25% of lung cancer patients. They are primar-ily lytic and produce pain locally; thus, any new and localized skeletal symptoms must be evaluated radiographically. Liver metastases and adrenal metastases are typically asymptomatic and usually discovered by routine CT scan. Adrenal metastasis may lead to adrenal hypofunction. Skin and soft tissue metas-tases occur in 8% of patients dying of lung cancer and gener-ally present as painless subcutaneous or intramuscular masses. Occasionally, tumor erodes through overlying skin; 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 and their presence raises con-cern for metastatic disease.Lung Cancer ManagementRole of Histologic Diagnosis and Molecular Testing. Establishing a clear histologic diagnosis early in the


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Surgery_Schwartz. and malaise and their presence raises con-cern for metastatic disease.Lung Cancer ManagementRole of Histologic Diagnosis and Molecular Testing. Establishing a clear histologic diagnosis early in the evaluation and management of lung cancer is critical to effective treat-ment. Molecular signatures are also key determinants of treat-ment 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 treat-ment with pemetrexed or bevacizumab-based chemotherapy is associated with improved progression-free survival in patients with adenocarcinoma but not squamous cell cancer. Further-more, 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


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Surgery_Schwartz. Further-more, 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 evalu-ation, tissue acquisition, tissue handling/processing, and tissue analysis (Fig. 19-18). In many cases, tumor morphology differ-entiates 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


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Surgery_Schwartz. 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 mark-ers (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 cytopa-thologist to ensure that tissue samples are adequate for morpho-logic diagnosis as well as providing sufficient cellular material to enable molecular testing. With adoption of endobronchial and endoscopic ultrasound, electromagnetic navigational bronchos-copy, VATS, and even transthoracic image-guided fine-needle and core-needle biopsy, surgeons are increasingly involved in the acquisition of diagnostic tissue for


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Surgery_Schwartz. navigational bronchos-copy, 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.Patient Evaluation. Pretreatment evaluation encompasses three areas: diagnosis and assessment of the primary tumor, assessment for metastatic disease, and determination of func-tional 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 determine the patient’s functional suitabil-ity for therapy (Table 19-9).Assessment of the Primary Tumor Primary tumor assessment begins with directed history questions regarding the presence or absence of pulmonary, nonpulmonary, thoracic, and


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Surgery_Schwartz. for therapy (Table 19-9).Assessment of the Primary Tumor Primary tumor assessment begins with directed history questions regarding the presence or absence of pulmonary, nonpulmonary, thoracic, and paraneo-plastic symptoms. Because patients often present to the surgeon with a CXR or CT scan demonstrating the lesion, tumor location can guide the history and physical examination.A routine chest CT scan should be performed; this should include intravenous contrast to enable assessment of the pri-mary 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 is often raised in response to a combination of symptom history, location of the primary tumor, and CT imaging. It is common to see the primary


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Surgery_Schwartz. for contiguous invasion of adjacent structures is often 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, localized pain can indicate parietal pleural, rib, or intercostal nerve involvement. Similar observations apply to tumors abut-ting 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, over-all, offers no real advantages over CT scanning. It is an excel-lent modality, however, for defining a tumor’s relationship to a major vessel, given its excellent imaging of vascular structures. This is especially true if


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Surgery_Schwartz. over CT scanning. It is an excel-lent 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 suspected mediasti-nal, vascular, or vertebral body invasion.Options for Tissue Acquisition The surgeon must have an evidence-based algorithm for diagnosis and treatment of a pul-monary nodule and masses (Fig. 19-19).24 Depending on nodule size, bronchial tree proximity, and the population prevalence of lung cancer, bronchoscopy has a 20% to 80% sensitivity for detecting neoplastic processes within a pulmonary lesion. Brunicardi_Ch19_p0661-p0750.indd 68301/03/19 7:00 PM 684SPECIFIC CONSIDERATIONSPART IISTEP 1STEP 2POSITIVE BIOPSY (FOB,TBBx, Core, SLBx)POSITIVE CYTOLOGY(effusion, aspirate, washings,brushings)Histology: Lepidic, papillary, and/oracinar


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Surgery_Schwartz. 7:00 PM 684SPECIFIC CONSIDERATIONSPART IISTEP 1STEP 2POSITIVE BIOPSY (FOB,TBBx, Core, SLBx)POSITIVE CYTOLOGY(effusion, aspirate, washings,brushings)Histology: Lepidic, papillary, and/oracinar architecture(s)Cytology: 3-D arrangements, delicatefoamy/vacuolated (translucent)cytoplasm,Fine nuclear chromatin and oftenprominent nucleoliNuclei are often eccentrically situatedClassic morphology:ADCADC markerand/orMucin +ve;SQCCmarker –ve(or weak insame cells)NSCLC, favor ADCNE morphology, large cells,NE IHC+No clear ADC orSQCC morphology:NSCLC-NOSNSCLC, favor SQCCSQCC marker +veADC marker –ve/orMucin –veApply ancillary panel ofOne SQCC and one ADC marker+/OR MucinIHC –ve andMucin –veNSCLC NOSADC marker or Mucin +ve;as well as SQCC marker +vein different cellsMolecular analysis:e.g., EGFR mutation†NSCLC, NOS,possibleadenosquamous caIf tumor tissue inadequate for molecular testing,discuss need for further sampling — back to Step 1NE morphology, small cells, nonucleoli, NE IHC+, TTF-1


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Surgery_Schwartz. mutation†NSCLC, NOS,possibleadenosquamous caIf tumor tissue inadequate for molecular testing,discuss need for further sampling — back to Step 1NE morphology, small cells, nonucleoli, NE IHC+, TTF-1 +/–,CK+Keratinization, pearlsand/or intercellular bridgesNSCLC,LCNECClassic Morphology:SQCCSCLCSTEP 3Figure 19-18. Algorithm for adenocarcinoma diagnosis in small biopsies and/or cytology. Step 1: When positive biopsies (fiberoptic bronchos-copy [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


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Surgery_Schwartz. 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


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Surgery_Schwartz. 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 WD, Brambilla E, Noguchi M, et al: Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International


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Surgery_Schwartz. = negative; +ve = positive. (Reproduced with permission from Travis WD, Brambilla E, Noguchi M, et al: Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, Arch Pathol Lab Med. 2013 May;137(5):668-684.)Brunicardi_Ch19_p0661-p0750.indd 68401/03/19 7:00 PM


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Surgery_Schwartz. CHAPTER 19685CHEST WALL, LUNG, MEDIASTINUM, AND PLEURATable 19-9Evaluation of patients with lung cancer PRIMARY TUMORMETASTATIC DISEASEFUNCTIONAL ASSESSMENTHistoryPulmonaryWeight lossAbility to walk up two flights of stairsNonpulmonary thoracicMalaiseAbility to walk on a flat surface indefinitelyParaneoplastic New bone painNeurologic signs or symptomsSkin lesionsPhysical examination VoiceSupraclavicular node palpationAccessory muscle usage Skin examinationAir flow by auscultation Neurologic examinationForce of coughRadiographic examinationChest CTChest CT, PETChest CT: tumor anatomy, atelectasisTissue analysisBronchoscopyBone scan, head MRI, abdominal CTQuantitative perfusion scanTransthoracic needle aspiration and biopsy Bronchoscopic lymph node FNAEndoscopic ultrasoundMediastinoscopyBiopsy of suspected metastasisOtherThoracoscopy—Pulmonary function tests (FEV1, Dlco, O2 consumption)Abbreviations: CT = computed tomography; Dlco = carbon monoxide diffusion capacity; FEV1 = forced


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Surgery_Schwartz. of suspected metastasisOtherThoracoscopy—Pulmonary function tests (FEV1, Dlco, O2 consumption)Abbreviations: CT = computed tomography; Dlco = carbon monoxide diffusion capacity; FEV1 = forced expiratory volume in 1 second; FNA = fine-needle aspiration; MRI = magnetic resonance imaging; O2 = oxygen; PET = positron emission tomography.Diagnostic tissue from bronchoscopy can be obtained by one of four methods:1. Brushings and washings for cytology2. Direct forceps biopsy of a visualized lesion3. Endobronchial ultrasound-guided fine-needle aspiration (FNA) of an externally compressing lesion without visual-ized endobronchial tumor4. Transbronchial biopsy with fluoroscopy to guide forceps to the lesion or electromagnetic navigational bronchoscopyElectromagnetic navigation bronchoscopy is a recent addi-tion 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


Surgery_Schwartz

Surgery_Schwartz. addi-tion 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 transbronchial catheter is advanced, and brushings, FNA, cup biopsy, and washings can be performed. Diagnostic yield using electromagnetic naviga-tion 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 are approximately 1% to 3.5%.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,


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Surgery_Schwartz. 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 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.33Image-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 falsenegative 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)


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Surgery_Schwartz. Because falsenegative 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 malig-nancy is not ruled out.34 The primary complication is pneumo-thorax in as many as 30% of cases. Intrapulmonary bleeding occurs, but it 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 informa-tion, including sampling/dissection of mediastinal lymph nodes and assessing whether the primary tumor has invaded a contigu-ous structure (such as the chest wall or mediastinum).Lesions most suitable for VATS


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Surgery_Schwartz. sampling/dissection of mediastinal lymph nodes and assessing whether the primary tumor has invaded a contigu-ous 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.Brunicardi_Ch19_p0661-p0750.indd 68501/03/19 7:00 PM 686SPECIFIC CONSIDERATIONSPART IIA thoracotomy is occasionally necessary to diagnose and stage a primary tumor. Although this occurs rarely, two circum-stances 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


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Surgery_Schwartz. Although this occurs rarely, two circum-stances 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 inva-sion 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 indetermi-nate, a lobectomy may be necessary in extremely rare situations. If a pneumonectomy is required to remove the lesion, a tissue diag-nosis of cancer must be made before proceeding.Assessment for Metastatic Disease Approximately 40% of patients with newly diagnosed lung cancer present with distant metastasis. The presence of lymph node or systemic metastases may imply inoperability. As with the primary tumor, assess-ment for


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Surgery_Schwartz. 40% of patients with newly diagnosed lung cancer present with distant metastasis. The presence of lymph node or systemic metastases may imply inoperability. As with the primary tumor, assess-ment for the presence of metastatic disease should begin with the history and physical examination, focusing on new bone pain, neurologic symptoms, and new skin lesions. In addition, constitutional symptoms (e.g., anorexia, malaise, and unin-tentional weight loss of >5% of body weight) suggest either a large tumor burden or the presence of metastases. Physical examination focuses on overall appearance, noting any evi-dence of weight loss such as redundant skin or muscle wasting, and a complete examination of the head and neck, including NegativetestsPositivetestsNoNoNew SPN (8 mm to 30 mm)identified on CXR orCT scanBenign calcificationpresent or 2-year stabilitydemonstrated?Surgical risk acceptable?Assess clinicalprobability of cancer Low probabilityof cancer(<5%)Intermediateprobability of


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Surgery_Schwartz. on CXR orCT scanBenign calcificationpresent or 2-year stabilitydemonstrated?Surgical risk acceptable?Assess clinicalprobability of cancer Low probabilityof cancer(<5%)Intermediateprobability of cancer(>5%–60%)High probabilityof cancer(>60%)Establish diagnosis bybiopsy when possible.Consider XRT or monitorfor symptoms andpalliate as necessarySerial high-resolutionCT at 3, 6, 12 and24 monthsAdditional testing• PET imaging, if available• Contrast-enhanced CT, depending on institutional expertise• Transthoracic fine-needle aspiration biopsy, if nodule is peripherally located• Bronchoscopy, if airbronchogram present or if operator has expertise with newer guided techniques Video-assistedthoracoscopic surgery:examination of a frozensection, followed byresection if nodule ismalignantYesYesNo further interventionrequired except forpatients with pure groundglass opacities, in whomlonger annual follow-upshould be consideredFigure 19-19. Recommended management algorithm for patients with


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Surgery_Schwartz. further interventionrequired except forpatients with pure groundglass opacities, in whomlonger annual follow-upshould be consideredFigure 19-19. 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. (Adapted with permission from Gould MK, Fletcher J, Iannettoni MD, et al: Evaluation of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition), Chest. 2007 Sep;132(3 Suppl):108S-130S.24)Brunicardi_Ch19_p0661-p0750.indd 68601/03/19 7:01 PM


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Surgery_Schwartz. CHAPTER 19687CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAevaluation of cervical and supraclavicular lymph nodes and the oropharynx. This is particularly true for patients with a sig-nificant tobacco history. The skin should be thoroughly exam-ined. Routine laboratory studies include serum levels of hepatic enzymes (e.g., serum glutamic oxaloacetic transaminase and alkaline phosphatase), and serum calcium (to detect bone metas-tases or the ectopic parathyroid syndrome). Elevation of either hepatic enzymes or serum calcium levels typically occurs with extensive metastases.Mediastinal Lymph Nodes. Chest CT scanning facilitates assessment of mediastinal and hilar nodes for enlargement. How-ever, a positive CT result (i.e., nodal diameter >1.0 cm) predicts actual metastatic involvement in only about 70% of lung cancer patients. Thus, up to 30% of such nodes are enlarged from non-cancerous reactive causes (e.g., inflammation due to atelectasis or pneumonia secondary to the tumor). Patients


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Surgery_Schwartz. about 70% of lung cancer patients. Thus, up to 30% of such nodes are enlarged from non-cancerous reactive causes (e.g., inflammation due to atelectasis or pneumonia secondary to the tumor). Patients should not be denied an attempt at curative resection just because of a posi-tive CT result for mediastinal lymph node enlargement; any CT finding of metastatic nodal involvement must be confirmed his-tologically. 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. How-ever, the false-negative rate increases to nearly 30% with cen-trally located and T3 tumors. It has also been demonstrated that T1 adenocarcinomas or large cell carcinomas have a higher rate of early micrometastasis. Therefore,


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Surgery_Schwartz. increases to nearly 30% with cen-trally 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 [CI] 76%–82%), with a specificity of 91% (95% CI 89%–93%) and an accuracy of 92% (95% CI 90%–94%).35In 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 scan-ning may lead to even greater accuracy.36 In one study of CT, PET, and mediastinoscopy in 68 patients with potentially opera-ble NSCLC, CT


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Surgery_Schwartz. of 63% and a specificity of 76%. Combining CT and PET scan-ning may lead to even greater accuracy.36 In one study of CT, PET, and mediastinoscopy in 68 patients with potentially opera-ble 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 medi-astinoscopy 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


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Surgery_Schwartz. positivity confirmed by medi-astinoscopy 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.37-40 PET-positive mediastinal lymph nodes require histologic verifica-tion of node positivity, either by EBUS-guided FNA or mediasti-noscopy, 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 TABLE 19-10Techniques for invasive mediastinal stagingEndoscopicEndobronchial ultrasound with transbronchial needle aspirationEndoscopic ultrasound with needle aspirationTransbronchial needle aspirationComputed tomography–guided transthoracic needle aspirationSurgicalVideo-assisted mediastinoscopyTranscervical extended mediastinal lymphadenectomy (TEMLA)Video-assisted mediastinal lymphadenectomy (VAMLA)Thoracoscopic transthoracic


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Surgery_Schwartz. needle aspirationSurgicalVideo-assisted mediastinoscopyTranscervical extended mediastinal lymphadenectomy (TEMLA)Video-assisted mediastinal lymphadenectomy (VAMLA)Thoracoscopic transthoracic lymphadenectomyIndications for invasive mediastinal staging in lung cancer1. Radiographically enlarged mediastinal lymph nodes2. Centrally located tumors3. N1 nodal enlargement4. Tumor size >3 cm5. Peripheral clinical stage I tumor with nonenlarged but FDG-avid mediastinal lymph nodesIndications for prethoracotomy/thoracoscopy biopsy of stations 5 and 6 lymph nodes1. Criteria for invasive staging met and other mediastinal lymph node stations are negative (assuming patient would have induction therapy if any nodal station positive)2. Enrollment criteria for induction therapy protocol require pathologic confirmation of N2 disease3. Computed tomography scan shows evidence of bulky nodal metastasis or extracapsular spread that could prevent complete resection4. Tissue diagnosis of a hilar mass or of


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Surgery_Schwartz. confirmation of N2 disease3. Computed tomography scan shows evidence of bulky nodal metastasis or extracapsular spread that could prevent complete resection4. Tissue diagnosis of a hilar mass or of lymph nodes causing recurrent laryngeal nerve paralysis is neededN3 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 medias-tinal staging. In general, invasive staging is underutilized, plac-ing many patients at risk for overor 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 (Table 19-10):1. Endobronchial Ultrasound (EBUS)-guided transbron-chial needle aspiration. Less invasive than


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Surgery_Schwartz. than 1.0 cm by CT scan. There are several options for invasive mediastinal staging (Table 19-10):1. Endobronchial Ultrasound (EBUS)-guided transbron-chial needle aspiration. Less invasive than mediasti-noscopy, 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. Rapid onsite pathologic evaluation with expert cytopathology 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 Brunicardi_Ch19_p0661-p0750.indd 68701/03/19 7:01 PM 688SPECIFIC CONSIDERATIONSPART IIFigure 19-20. Cervical mediastinoscopy. Paratracheal and sub-carinal lymph node tissues (within the pretracheal space) can


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Surgery_Schwartz. 68701/03/19 7:01 PM 688SPECIFIC CONSIDERATIONSPART IIFigure 19-20. Cervical mediastinoscopy. Paratracheal and sub-carinal lymph node tissues (within the pretracheal space) can be sampled using a mediastinoscope introduced through a suprasternal skin incision.and molecular testing. EBUS does not allow assessment of level 3, 5, or 6 nodal stations.2. Endoscopic ultrasound (EUS). EUS can accurately visual-ize mediastinal paratracheal lymph nodes (stations 4R, 7, and 4L), paraesophageal (station 8) and inferior pulmonary ligament (station 9) lymph nodes and 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. Diagnos-tic yield is improved with intraoperative cytologic evalua-tion, 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


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Surgery_Schwartz. evalua-tion, 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/EBUS for complete medi-astinal 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.3. Cervical video-assisted mediastinoscopy. Mediastinos-copy provides tissue sampling of all paratracheal and sub-carinal 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. Mediastinoscopy is recommended for centrally located tumors, T2 and T3 primary tumors, and occasionally for T1 adenocarcinomas or large cell carcinomas (due to their higher


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Surgery_Schwartz. into the mediastinum. Mediastinoscopy is recommended for centrally located tumors, 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 surgi-cal resection of N2 disease.4. 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 intraoperative rapid onsite cytologic evaluation is nega-tive, mediastinoscopy is performed in the same operative setting to ensure accurate mediastinal staging. However, if the FNA is positive,


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Surgery_Schwartz. If intraoperative rapid onsite cytologic evaluation is nega-tive, mediastinoscopy is performed in the same operative setting to ensure accurate mediastinal staging. However, if the FNA is positive, mediastinoscopy is not performed, and the patient is referred to medical oncology for induc-tion therapy; avoiding a pretreatment mediastinoscopy in this manner facilitates the safe performance of a postinduc-tion mediastinoscopy for restaging of the mediastinum in patients who respond favorably to induction therapy.5. Left video-assisted thoracoscopic lymph node sampling may be needed for patients with left upper lobe tumors who have localized regional spread to stations 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