58. Pita-Gutierrez F, Pertega-Diaz S, Pita-Fernandez S, et al. Place of preoperative treatment of

acromegaly with somatostatin analog on surgical outcome: a systematic review and meta-analysis.

PLoS One 2013;8(4):e61523.

59. Ben-Shlomo A, Melmed S. Clinical review 154: the role of pharmacotherapy in perioperative

management of patients with acromegaly. J Clin Endocrinol Metab 2003;88(3):963–968.

60. Newman CB, Melmed S, Snyder PJ, et al. Safety and efficacy of long-term octreotide therapy of

acromegaly: results of a multicenter trial in 103 patients–a clinical research center study. J Clin

Endocrinol Metab 1995; 80(9):2768–2775.

61. Karavitaki N, Turner HE, Adams CB, et al. Surgical debulking of pituitary macroadenomas causing

acromegaly improves control by lanreotide. Clin Endocrinol (Oxf) 2008;68(6):970–975.

62. Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing’s disease: is it worth a try? J Clin

Endocrinol Metab 2014;99(5):1623–1630.

63. Colao A, Petersenn S, Newell-Price J, et al; Pasireotide B2305 Study Group. A 12-month phase 3

study of pasireotide in Cushing’s disease. N Engl J Med 2012;366(10):914–924. Erratum in: N Engl J

Med. 2012 Aug 23;367(8):780.

64. Godbout A, Manavela M, Danilowicz K, et al. Cabergoline monotherapy in the long-term treatment

of Cushing’s disease. Eur J Endocrinol 2010; 163(5):709–716.

65. Fleseriu M, Biller BM, Findling JW, et al; SEISMIC Study Investigators. Mifepristone, a

glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with

Cushing’s syndrome. J Clin Endocrinol Metab 2012;97(6):2039–2049.

66. Feelders RA, de Bruin C, Pereira AM, et al. Pasireotide alone or with cabergoline and ketoconazole

in Cushing’s disease. N Engl J Med 2010; 362(19):1846–1848.

67. Assié G, Bahurel H, Coste J, et al. Corticotroph tumor progression after adrenalectomy in Cushing’s

Disease: a reappraisal of Nelson’s Syndrome. J Clin Endocrinol Metab 2007;92(1):172–179.

68. Wattson DA, Tanguturi SK, Spiegel DY, et al. Outcomes of proton therapy for patients with

functional pituitary adenomas. Int J Radiat Oncol Biol Phys 2014;90(3):532–539.

69. Sheehan JP, Xu Z, Salvetti DJ, et al. Results of gamma knife surgery for Cushing’s disease. J

Neurosurg 2013;119(6):1486–1492.

70. Patil CG, Prevedello DM, Lad SP, et al. Late recurrences of Cushing’s disease after initial successful

transsphenoidal surgery. J Clin Endocrinol Metab. 2008;93(2):358–362.

71. Hofmann BM, Hlavac M, Kreutzer J, et al. Surgical treatment of recurrent Cushing’s disease.

Neurosurgery 2006;58(6):1108–1118; discussion 1108–1118.

72. Patil CG, Veeravagu A, Prevedello DM, et al. Outcomes after repeat transsphenoidal surgery for

recurrent Cushing’s disease. Neurosurgery 2008;63(2):266–270; discussion 270–271.

73. Freda PU, Beckers AM, Katznelson L, et al. Endocrine Society. Pituitary incidentaloma: an

endocrine society clinical practice guideline. J Clin Endocrinol Metab 2011;96(4):894–904.

74. Gittoes NJ, Sheppard MC, Johnson AP, et al. Outcome of surgery for acromegaly- the experience of

a dedicated pituitary surgeon. QJM 1999;92:741–745.

75. Ciric I, Ragin A, Baumgartner C, et al. Complications of transsphenoidal surgery: results of a

national survey, review of the literature, and personal experience. Neurosurgery 1997;40:225–236.

76. Barker FG 2nd, Klibanski A, Swearingen B. Transsphenoidal surgery for pituitary tumors in the

United States 1996–2000: mortality, morbidity, and the effects of hospital and surgeon volume. J

Clin Endocrinol Metab 2003;88:4709–4719.

77. Biermasz NR, Roelfsma F, Pereira AM, et al. Cost-effectiveness of lanreotide Autogel in treatment

algorithms of acromegaly. Expert Rev Pharmacoecon Outcomes Res 2009;9:223–234.

78. Swearingen B, Wu N, Chen SY, et al. Health care resource use and costs among patients with

Cushing disease. Endocr Pract 2011;17:681–690.

2229

SECTION L: LUNG

2230

Chapter 79

Lung Neoplasms

Andrew C. Chang and Jules Lin

Key Points

1 Lung cancer remains the leading cause of cancer-related death in the United States.

2 Advances in molecular biology including genomic and proteomic techniques constitute promising

methodologies for the diagnosis and patient-tailored management of non–small cell lung cancer

(NSCLC), but to-date these strategies have not been validated for broad clinical implementation.

3 Low-dose screening chest CT can reduce lung cancer–related mortality in “at-risk” patients.

4 Common sites of distant metastases are bone, liver, adrenal glands and the central nervous system;

therefore, the metastatic evaluation includes a PET scan and CT of the chest and upper abdomen,

and a brain MRI.

5 Resection remains the mainstay in the treatment of lung cancer, yet only about 20% of all patients

diagnosed with lung cancer are considered resectable (stages I to IIIA). VATS/robotic approaches

have changed the landscape for operation although the principles of oncologic resection remain

unchanged.

6 In addition to new chemotherapeutic agents, new radiation techniques, such as hyperfractionated or

accelerated schedules, also merit further exploration in neoadjuvant trials with concurrent

chemotherapy.

7 Taken as a whole, neoadjuvant therapy trials have demonstrated the feasibility of induction

chemotherapy and radiation followed by resection for the treatment of selected stage IIIA NSCLC.

Most studies show improved rates of resectability and survival in comparison with the historical

experience for surgical resection or radiation alone.

8 Generally, a solitary lesion is more likely to be a metastasis if the primary tumor was a sarcoma or a

melanoma. If the primary tumor originated in the head, neck, or breast, it is more likely to be a new

primary lung cancer.

INTRODUCTION

1 Although population estimates of both the incidence and mortality of lung cancer have begun to

decline, lung cancer remains second only to heart disease among all causes of mortality. With 224,210

new cases and 159,260 deaths projected for 2014, lung cancer is the leading cause of cancer-related

death in the United States. Lung cancer is second in cancer prevalence only to prostate cancer among

men and breast cancer among women, and remains the leading cause of cancer-related death for both

sexes. Since 2005, both the annual incidence and mortality rates due to lung cancer have started to

decrease in the United States, reflecting improvements in cancer control and prevention, particularly

efforts to reduce the prevalence of smoking.1 There is also significant regional variation in both lung

cancer incidence and mortality. Among men, lung cancer mortality has decreased from 1996 through

2005 in over 80% of the 50 states and the District of Columbia, whereas among women over the same

period, mortality decreased in only three states (California, New Jersey, and Texas) and has increased in

13 other states, primarily in the Midwest and South,2 although more recently consistent rates of decline

have been noted for both men and women.

The best predictor of survival for patients with lung cancer is still tumor stage. Resection remains the

mainstay in the treatment of lung cancer, yet only approximately 37% of all patients diagnosed with

lung cancer are considered resectable (with either local or regional disease, that is, stages I to IIIA).

Even among patients who have undergone complete resection with curative intent for early-stage

disease, as determined using pathologic Tumor–Node–Metastasis (TNM) criteria, a substantial number

will have recurrence of their cancer.3

2231

Clinical trials continue to demonstrate that adjuvant chemotherapy can improve survival over surgery

alone for early-stage lung cancer.4–6 Importantly, screening low-dose chest computed tomography (CT)

appears to improve early detection of resectable lung cancer, with an improvement in overall

survival,7,8 albeit with a possible risk of overdiagnosis.9 As understanding of the molecular changes

occurring in lung cancer evolves, new strategies that allow for early detection and classification of lung

cancer will provide valuable information for the treatment of patients.

HISTORY

Ferdinand Sauerbruch, whose interests included the physiology of pneumothorax and is considered one

of the pioneers of thoracic surgery, reported the first successful lobectomy for lung carcinoma in 1920.

At that time, it was believed that only total pneumonectomy would provide a cure for lung cancer. Dr.

Evarts A. Graham performed the first successful single-stage pneumonectomy for a left upper lobe

bronchogenic carcinoma in 1933,10 although this was neither the first pulmonary resection nor

pneumonectomy, establishing the modern era of thoracic surgery for lung cancer. Ultimately, Dr.

Graham succumbed to lung cancer himself in 1957, and was outlived by his patient, Dr. James L.

Gilmore, who had continued to smoke.11

EPIDEMIOLOGY

Recently, population studies have demonstrated sustained declines in lung cancer incidence among both

men (80.0 cases per 100,000), and women (55.1 per 100,000) as of 2010. African-American men

continue to have the greatest incidence of lung cancer, in excess of nearly 20% (94.7 per 100,000) over

the cases reported for all men.12,13 The decline in incidence as well as mortality may be due in part to

public health efforts to promote smoking cessation.14 In a follow-up to the Seven Countries Study of

smoking-related mortality, follow-up analysis of the initial cohorts studied from Europe, the United

States and Japan confirmed that cigarette smoking increased the risk for death due to lung cancer with a

hazard ratio of 4.2 per pack of cigarettes smoked. Furthermore, the death rates due to lung cancer

decreased to that of never-smokers after 10 years of smoking cessation.15 Exposure to environmental

“second-hand” cigarette smoke or other particulate matter air pollution can also contribute to an

increased risk of lung cancer,16,17 particularly adenocarcinoma.17,18

PATHOLOGIC CLASSIFICATION

Uniform classification of lung cancer is important both to provide consistent treatment for patients and

to allow standardization in reports of epidemiologic, clinical, and basic scientific studies. Currently, the

classification is largely histologic and is based on light microscopy findings determined from specimens

obtained by resection or needle biopsy, permitting its wide application by surgical pathology

laboratories where more advanced techniques might not be readily available. Nevertheless,

immunohistochemical and electron microscopy analyses are important, particularly in the diagnosis of

neuroendocrine tumors, or for distinguishing between primary bronchogenic adenocarcinoma and

metastatic lesions. The most recent revision of the World Health Organization (WHO) classification

(Table 79-79) was published in 200419 but is largely unchanged from the previous revision in 1999.20

Guidelines for defining preinvasive lesions such as squamous dysplasia and carcinoma in situ are

provided. Recognition and definition of the heterogeneity among adenocarcinomas is reflected in the

subclassification of this group, including more restrictive definitions for bronchioloalveolar carcinoma

(BAC), which has been redesignated as “adenocarcinoma in situ.20a Definitions for the spectrum of

neuroendocrine tumors, ranging from typical and atypical carcinoid, to small cell lung cancer (SCLC)

and large cell neuroendocrine carcinomas are provided.

TUMOR BIOLOGY

Genetic alterations in several regulatory pathways including apoptosis, cell cycle and mitogenic

signaling have been identified in tumors of patients with non–small cell lung cancer (NSCLC).

Chromosomal loss of heterozygosity (LOH) or allelic gain appears to occur more frequently among

2232

patients with adenocarcinoma and history of tobacco exposure than among patients without any

smoking history. Mutations among the Ras oncogenes, particularly K-ras, are characterized by the

accumulation of DNA adducts within these genes, predominantly among patients with a history of

tobacco use.21 This has been attributed to the exposure to tobacco carcinogens such as benzo[a]pyrene

(BaP), its activated form, benzo[a]pyrene diol epoxide (BPDE), and N-nitrosamines. These genes encode

GTP-binding proteins which participate in cellular signal transduction; their mutation results in constant

Ras activation. Another family of oncogenes, Myc, encoding several transcription factors, is activated by

gene amplification, primarily in SCLC.21

The tumor suppressor gene, p53, is the most frequently mutated gene in human cancer. Among

patients with a history of tobacco use, mutations within p53 were identified in over 50% of patients

with NSCLC, particularly squamous cell carcinoma (SCC) and non–AIS adenocarcinoma.22,23 Among

patients with stage I tumors, those with mutations, particularly truncating, structural, or those that

abolished DNA binding, demonstrated significantly worse actuarial survival in comparison with patients

who had wild-type p53. In contrast those patients with missense mutations did not demonstrate

significantly different survival than those with wild-type p53. In several clinical trials demonstrating the

benefit of adjuvant chemotherapy among patients with resected NSCLC, the presence of p53 mutations

was not associated with any significant survival difference among patients assigned to treatment or

observation arms.24,25 Among patients found to have mutations in the p53 gene, those treated with

adjuvant chemotherapy had worse outcomes than untreated patients.25 Investigators have also identified

p53 protein expression, determined by immunohistochemical analysis, as a predictor of poor outcome in

patients with stage I NSCLC.26 Furthermore, p53 expression is associated with tumors more likely to

demonstrate distant metastases.27 Notably, patients with p53 expression detectable by

immunohistochemistry appear to have improved survival following adjuvant chemotherapy compared

to patients without IHC-detected p53 expression.24

CLASSIFICATION

Table 79-1 Histologic Classification of Lung Tumors

2233

Epigenetic mechanisms of gene regulation also appear to participate in the tumorigenesis of lung

cancer. In particular gene promoter inactivation by hypermethylation may be an important mechanism

in the inactivation of tumor suppressor genes such as p16INK4a (p16), an inhibitory regulator in the

cyclin D-retinoblastoma cell cycle pathway. In patients with premalignant lesions such as squamous

dysplasia and carcinoma in situ, both allelic loss and hypermethylation of p16 have been identified, with

associated decreases in p16 protein expression,28 suggesting that loss of p16 may be an important early

event in NSCLC tumorigenesis.29

Over the past decade genome-wide studies have revolutionized the study of complex disease processes

including NSCLC. Efforts by groups comprising The Cancer Genome Atlas have yielded detailed and

comprehensive characterization of mutational events across the entire cancer genome.30,31

Distinguishing those genes that appear to be involved causally in lung cancer tumorigenesis from those

genes that are regulated secondarily is critical for our understanding of this disease and for the

identification of potential targets for therapeutic intervention.

CLASSIFICATION

Table 79-2 TNM Classification for Staging System of Non–Small Cell Lung Cancer

(6th ed.)

2234

2 Targeted molecular therapy has been shown to have clinical benefit notably for patients with

advanced NSCLC. For example, among patients whose tumors are shown to carry specific mutations in

the epidermal growth factor receptor (EGFR) gene, treatment with small molecule tyrosine–kinase

inhibitors targeting EGFR has been associated with improved progression-free survival as demonstrated

by several randomized trials.32 Whether such treatment regimens might be effective in the adjuvant

setting for patients with earlier stage NSCLC who have undergone curative-intent lung resection has yet

to be established, but is the focus of a recently initiated cooperative group trial. The Adjuvant Lung

Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST) will evaluate patients

with resected lung adenocarcinomas (stage IB to stage IIIA). Those subjects found to have tumors

carrying activating EGFR mutations or the ALK-echinoderm microtubule-associated protein-like 4 (EML4)

fusion gene will be randomized for “maintenance” treatment with either erlotinib (EGFR) or crizotonib

(ALK fusion), respectively, following completion of standard-of-care adjuvant chemotherapy with or

without radiation therapy. Enrolled patients found to have neither of the targeted mutations will be

followed in an observational study until tumor recurrence. These studies represent an exciting potential

application of gene expression studies for use in determining patient prognosis, as well as guiding the

2235

clinical management of lung cancer and preventing over- or undertreatment of patients.

NON–SMALL CELL LUNG CANCER

Diagnosis

The diagnosis of lung cancer should be directed by the presumed stage of disease at patient

presentation. Accurate and reproducible TNM staging of lung cancer allows clinicians to provide

consistent treatment of lung cancer and provides the basis for uniform reporting of clinical research

across institutions and study groups. In 1997, revisions in the International System for Staging Lung

Cancer (Table 79-2) were adopted by the American Joint Committee on Cancer (AJCC) and the Union

Internationale Contre le Cancer (UICC), based on 5,319 cases of lung cancer.3 Revisions implemented

for the most recent iteration of the TNM classification schema arose from evaluation of 67,725 cases of

NSCLC with broad geographic diversity including subjects from Asia, Australia, Europe, and North

America33,34 and addressed both T35 and M36 designations (Table 79-3), with no changes implemented

for the current nodal designations (Table 79-4).37 Stratification of patient survival, particularly among

subjects with pathologic stage IB and IIA cancers, was more distinct with application of the 7th edition

criteria (Table 79-5).

Guidelines for surveillance of the incidentally detected subcentimeter nodule (<8 to 10 mm) or

larger solitary pulmonary nodule (8 to 10 mm or larger) have been published by the Fleischner Society

for Thoracic Imaging and Diagnosis,38 the American College of Chest Physicians

39 and others

40 and are

incorporated in a suggested algorithm (Algorithm 79-1) for evaluation of these common incidental chest

findings. As with any algorithm, assessment of patient risk factors (pretest probability) for cancer39 as

well as comorbidities

38 should be taken into consideration before following these guidelines in one’s

practice.

3 One recent goal in the diagnosis of lung cancer has been the early detection of tumors arising in

asymptomatic high prevalence populations, for example, older patients with a history of tobacco use.

Low-dose chest CT screening appears to reduce lung cancer–related mortality as demonstrated by two

modern clinical trials,7,8 while remaining cost-effective.41

4 The aims of the initial evaluation of a patient with NSCLC are to determine whether distant

metastatic disease is present and to assess the extent of intrathoracic disease. A multidisciplinary

approach, involving input from pulmonary medicine, chest radiology, medical and radiation oncology,

and thoracic surgery, should be undertaken in the selection of the most suitable testing for any

individual patient. One general algorithm is provided (Algorithm 79-2). A thorough history and physical

examination, combined with a plain chest radiograph and baseline laboratory data (complete blood cell

count and measurement of serum sodium, calcium, alkaline phosphatase, and lactate dehydrogenase

levels), can suggest the presence of metastatic disease. Common metastatic sites include the brain,

supraclavicular lymph nodes, contralateral lung, bones, liver, and adrenal glands. Chest CT and FDG–

PET body scans are obtained for noninvasive evaluation and metabolic characterization of suspected

lung tumors and evidence of mediastinal or extrathoracic involvement. If necessary, biopsy by needle

aspiration or operation can be performed to obtain confirmation of malignancy and to determine the

extent of disease.

If the initial clinical evaluation does not suggest the presence of distant disease, the extent of further

evaluation by various scans is controversial. Some physicians always perform a complete metastatic

workup with CT of the chest and abdomen, CT or MRI of the brain, and FDG–PET scan. CT scan of the

chest and upper abdomen as well as FDG–PET scan have become standard, as much to evaluate the

extent of the primary tumor and the status of the mediastinal lymph nodes as to detect metastases in the

ipsilateral or contralateral lung, liver, or adrenals. Additional scans in asymptomatic patients may detect

the 5% to 10% of metastases that are occult, but these scans are not clearly cost-effective in patients

with clinical stage IA tumors. In patients who are suitable candidates for operation, who have a

suspicious solitary pulmonary nodule that is of indeterminate origin despite appropriate evaluation,

excisional biopsy and subsequent lobectomy for resectable lung cancer should be pursued.42

Multi-institutional studies have indicated a benefit for a combined modality approach in the treatment

of stage IIIA NSCLC, consisting of neoadjuvant chemotherapy and radiation followed by resection.43

Therefore tissue confirmation of mediastinal nodal involvement (Table 79-4) has implications not only

for the staging but the management of patients who are otherwise candidates for resection of

locoregionally advanced NSCLC.44

2236