Handbook of Thoracic Malignancies and Esophageal Related Cancer

By Tian Yulong, Liu Guohao, Qu Xiaohan and 2 more

"Handbook of Thoracic Malignancies and Esophageal Related Cancer" is a practical guide to management of lung cancer and other cancers of the thoracic cavity. The book focuses on evidence-based conventional and novel treatment strategies that have been transforming the landscape of lung cancer, esophageal cancer, gastric cancer, and related tumors. It includes guidance on video-assisted thoracoscopic surgery, adjuvant chemotherapy, combined-modality therapy, and site- directed treatment of oligometastatic disease. The book has included a renowned group of expert authors from three well-known Chinese hospitals: The First Hospital of China Medical University, Shengjing Hospital of China Medical University and Affiliated Hospital of Jilin Medical University. Authors are also from a variety of disciplines,including interventional medicine, imaging, thoracic, gastroenterology and oncology nursing.

• Language: English
• Publisher: American Harmony Medical Academic Publisher
• Release date: Sep 8, 2021
• ISBN: 9781737781028

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Handbook of Thoracic Malignancies

and Esophageal related Cancer

Authors:

Tian Yulong, M.D.

Postdoctoral, Attending Physician and Lecturer in the Intervention Department of the First Hospital of China Medical University

Liu Guohao, M.D.

Postdoctoral, Director and Associate Professor of the Department of Medical Imaging of Jilin Medical University, Deputy Director and Associate Chief Physician of Affiliated Hospital of Jilin Medical University, Department of Radiology

Qu Xiaohan, M.D.

Master Supervisor, Associate Chief Physician and Associate Professor of the First Hospital of China Medical University, Thoracic Surgery Department

Shao Hua

Associate Chief Physician and Associate Professor of

Gastrointestinal/Nutrition Surgery Department of Shengjing Hospital of China Medical University

Liu Wei

Supervisor Nurse and Trainer of the First Hospital of China Medical University, Oncology Department

Series Editor: Simon Zhang

Preface:

How do I care for my patients? is always the question that drove the development of the Handbook of Thoracic Malignancies and Esophageal related Cancer. Over the past few years, we have witnessed a quantum leap of new knowledge and novel therapeutic options that have positioned lung cancer, esophageal cancer, and gastric cancer at forefront of the personalized medicine revolution in oncology.

The management of our patients now requires the understanding and utilization of numerous multidisciplinary modalities, including minimally invasive surgical procedures, adjuvant chemotherapy, stereotactic radiotherapy, radiofrequency ablation, combined-modality therapy, maintenance, therapy, etc. However, despite the fact that this plethora of therapeutic options provides our patients with an increased potential for cure and improved life quality, it makes increasingly more difficult for busy clinicians to keep up with the essential knowledge required to provide state-of-the-art care. Driven by these concerns, we endeavored to create a practical guide to the management of Thoracic Malignancies and Esophageal related Cancer for practicing oncologists, trainees, and other healthcare providers.

Handbook of Thoracic Malignancies and Esophageal Related Cancer is a practical guide to management of lung cancer and other cancers of the thoracic cavity. The book focuses on evidence-based conventional and novel treatment strategies that have been transforming the landscape of lung cancer, esophageal cancer, gastric cancer, and related tumors. It includes guidance on video-assisted thoracoscopic surgery, adjuvant chemotherapy, combined-modality therapy, and site-directed treatment of oligometastatic disease. The book has included a renowned group of expert authors from three well-known Chinese hospitals: The First Hospital of China Medical University, Shengjing Hospital of China Medical University and Affiliated Hospital of Jilin Medical University. Authors are also from a variety of disciplines,

including interventional medicine, imaging, thoracic, gastroenterology and oncology nursing.

We acknowledge the time and efforts of all the authors who contributed outstanding content for this handbook and thank American Harmony Medical Academic Publisher for believing in this project and bringing our concept to final work.

Tian Yulong

Liu Guohao

Qu Xiaohan

Shao Hua

Liu Wei

American Harmony Medical Academic Publisher

© 2021 American Harmony Medical Academic Publisher (Zhang & Ding, LLC). All rights reserved.

First Edition July 2021

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Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein.

Because of rapid advances in the medical sciences, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by the authors, editors or contributors of this book for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

ISBN: 978-1-7377810-1-1

E-book ISBN: 978-1-7377810-2-8

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Table of Contents

Part I Lung Cancer

Chapter 1 Epidemiology and Etiology of Lung Cancer

Qu Xiaohan, M.D.

Chapter 2 Lung Cancer Screening

Liu Guohao, M.D. / Qu Xiaohan, M.D.

Chapter 3 Diagnosis and Staging of Lung Cancer

Liu Guohao, M.D. / Qu Xiaohan, M.D.

Chapter 4: Early-Stage Non-Small Cell Lung Cancer Management

Tian Yulong, M.D. / Qu Xiaohan, M.D.

Chapter 5 Locally Advanced Non-Small-Cell Lung Cancer Management

Tian Yulong, M.D. / Qu Xiaohan, M.D.

Chapter 6 Management of Advanced-Stage Non-small-cell Lung Cancer

Tian Yulong, M.D.

Chapter 7 Management of Limited and Extensive Stage Small Cell Lung Cancer

Tian Yulong, M.D. / Qu Xiaohan, M.D.

PART II Thoracic Malignancies Related Cancer

Chapter 8 Management of Pulmonary Neuroendocrine Tumors:

Tian Yulong, M.D. / Qu Xiaohan, M.D.

Chapter 9 Management of Pleural Mesothelioma

Qu Xiaohan, M.D. / Tian Yulong, M.D.

Chapter 10: Management of Thymic Tumor

Tian Yulong, M.D. / Liu Guohao, M.D. / Qu Xiaohan, M.D.

Chapter 11: Palliative Care in Thoracic Oncology

Qu Xiaohan, M.D.

Chapter 12 Percutaneous Transthoracic Needle Biopsy

Tian Yulong, M.D.

Chapter 13 Surgical Resection of Lung Cancer for the Elderly

Qu Xiaohan, M.D.

PART III Esophageal Cancer and Gastric Cancer

Chapter 14: The Role of Endoscopic Ultrasound in Esophageal and Gastric Cancer

Shao Hua

Chapter 15 Radiation Treatment for Early Esophageal and Gastric Cancer

Shao Hua / Tian Yulong, M.D.

Chapter 16 Endoscopic Resection for Gastric and Esophageal Cancer

Shao Hua

Chapter 17 Endoscopic Submucosal Dissection

Shao Hua

Chapter 18 Surgical Therapy of Early Esophageal and Gastric Cancer

Shao Hua

Chapter 19 Combined Modality Therapy in Locally Advanced Esophageal and Gastric Cancer

Shao Hua / Tian Yulong, M.D.

Chapter 20 Preoperative Assisted Localization Technique for Small Pulmonary Nodules

Tian Yulong, M.D.

PART IV Nursing

Chapter 21: Preoperative and Postoperative Nursing Care of Lung Cancer

Liu Wei

Part I Lung Cancer

Chapter 1 Epidemiology and Etiology of Lung Cancer

Qu Xiaohan, M.D.

a.Incidence and Mortality

In 2015, lung cancer was the second most common cancer diagnosed in men and women in the United States, accounting for 14% of all newly diagnosed cancers in men and 13% in women. However, lung cancer remains the leading cause of cancer-related deaths, accounting for 28% of male cancer deaths and 26% of female cancer deaths. In 2015, there were 221,000 new lung cancer diagnoses and 158,000 deaths in the United States. The median age at diagnosis was 70 years, and there was little gender difference. Among men, as smoking rates declined, morbidity and mortality rose steadily until the early 1980s and early 1990s, respectively. Among women, morbidity and mortality did not decline until the mid-2000s. The annual average age-adjusted incidence rate (2008-2012) is 70.1 cases per 100,000 men (about 30% lower than the peak) and 50.2 per 100,000 women (about 5% lower than the peak); the mortality rate for men and women is 59.8, respectively /100,000 and 37.8/100,000.

Globally, lung cancer caused approximately 1.6 million deaths in 2012, making it the leading cause of cancer deaths worldwide. Mortality rates vary depending on the prevalence of smoking, with males having the highest mortality rates in Central Europe, Eastern Europe, and East Asia, while females in North America and Northern Europe have the highest mortality rates.

b.Risk Factors for Lung Cancer

i.Tobacco and Inhaled Smoke Exposure:

The association between cigarette smoking and lung cancer is well known, with a landmark report on smoking and health released by the Surgeon General of the U.S. Public Health Service in 1964. At the time of this report, the risk for lung cancer in smoking men was estimated to be approximately 10-fold higher than in never-smoking men, with lower risk among women. Risk was shown to increase with greater amount smoked and decline with cessation of smoking. This report resulted in a steep decline in smoking among men, driving a decline in lung cancer incidence beginning in the mid-1980s. A somewhat slower decline in cigarette use has been reported among women, with incidence rates beginning to decline in the mid-2000s. The incidence rates for lung cancer reflect the change in the use of tobacco, with women now smoking at rates comparable to men and both sexes starting in their teens.

The National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study provides some of the most current data on smoking habits with follow-up for lung cancer in a cohort of 186,057 women and 266,074 men born between 1924 and 1945, who were enrolled in 1995 and followed for 11 years. Among women, 17% were current smokers and 44% were never smokers; among men, 13% were current smokers and 26% were never smokers, with most beginning to smoke between ages 15 and 19. Lung cancer incidence rates increased with amount smoked, with rates similar in men and women within comparable cigarette per day categories. In women, smoking 1 to 10, 11 to 20, 21 to 40, and greater than 40 cigarettes per day was associated with relative risks of 12.2, 19.8, 28.4, and 44.2, respectively. Among men in the same cigarette per day categories, relative risks were 17.3, 27.9, 37.3, and 53.0, respectively. Smokers of menthol cigarettes in this study, while at increased risk of lung cancer compared with never smokers, had lower rates of lung cancer than smokers of nonmenthol cigarettes. Other tobacco exposures in the form of cigar and pipe use are associated with a two to fivefold increase in lung cancer risk. This risk is lower than that seen for cigarette smoking since exposures are typically lower and smoke inhalation is not as deep.

ii.Environmental Exposures:

(1) Asbestos

One of the strongest environmental risk factors for lung cancer is asbestos. Asbestos includes a variety of natural mineral fibers that have been widely used in industry. Usage peaked in the 1970s, and then due to the Consumer Product Safety Commission’s ban on certain products in 1977 and the reduction in Occupational Safety and Health Administration (OSHA) guidelines for allowable exposure limits, industrial usage in the United States subsequently declined. In multiple studies, asbestos exposure is associated with an increased risk of lung cancer, with an incubation period of 20 to 40 years. The risk is related to both the dose and the size and composition of the inhaled fiber. Smoking has a synergistic effect on lung cancer risk.

(2) Radon

Radon gas is first associated with lung cancer in highly exposed underground miners. Outside the occupational environment, personal exposure may occur when radon appears as an indoor air pollutant. Residential exposure is associated with an approximately 10% increase in lung cancer risk for every 100 Bq/m³ increase in radon measured, showing a linear dose-response relationship. The synergistic effect with smoking causes the risk of smokers to be 25 times higher than that of non-smokers. It is estimated that 20,000 lung cancers diagnosed in the United States each year can be attributed to radon exposure, which prompted the U.S. Environmental Protection Agency in 2011 to develop a plan to raise awareness and reduce risks.

(3) Ionizing Radiation

In studies of atomic bomb survivors in Hiroshima and Nagasaki, ionizing radiation was associated with an increased risk of lung cancer in a linear dose-response relationship. Much lower doses of ionizing radiation, such as those received in diagnostic medical procedures, are generally not associated with an increased risk of lung cancer. As low-dose CT screening for lung cancer becomes more common. However, the risks and benefits associated with repeated medical screening and diagnostic procedures should be weighed.

iii.Generic Susceptibility

(1) Family Risk:

A hallmark of genetic susceptibility to cancer is family aggregation. Given that smoking is clustered in the family and is an important risk factor for the disease, it is challenging to study the clustering of lung cancer in the family. Even with these challenges, there is consistent evidence that the risk of lung cancer in first-degree relatives increases by 2 to 4 times after considering other risk factors (including smoking amount and duration), and risk estimates vary depending on lung age. Cancer diagnosis, Smoking status and ethnicity. The meta-analysis showed consistent findings that the risk of lung cancer associated with family history increased approximately 1.5 to 2 times. Risk estimates vary by race and age at diagnosis (2.0 for onset <50 years).

The level of risk associated with family history is similar to that seen for breast, colon, and prostate cancer, suggesting an under- lying genetic contribution to lung cancer susceptibility. Family studies to identify rare, highly penetrant, inherited mutations have been limited to one study that reported the first evidence of a lung cancer susceptibility locus on chromosome 6q23-25 segregating in high-risk lung cancer families. As the number of relatives and generations affected with lung cancer increased, so did the significance of this finding. Most importantly, putative carriers of risk in this locus were at higher risk even if they were never smokers or had light smoking histories, suggesting that any level of tobacco exposure increases risk among those with inherited lung cancer susceptibility. A germline mutation in PARK2 in this region was linked to lung cancer risk in one family with eight affected members. Additional evidence of linkage was found for regions on chromosomes 1q, 8q, 9p, 12q, 5q, 14q, and 16q. A two-stage genome-wide association study (GWAS) that focused on variants associated with a family history of lung cancer, identified SNPs on chromosomes 4p15.2 and 10q23.33. GWAS data have also been used to estimate overall heritability and the proportion of heritability associated with smoking. It is estimated that 24% of the heritability of lung cancer is attributable to genetic determinants of smoking.

(2) Genome-Wide Association Studies

In addition to rare, highly penetrative genetic mutations that lead to lung cancer risk, there is also evidence that the more common, low penetrance genetic changes found in GWAS lead to susceptibility (Table 1.1). Several early GWAS identified a region on chromosome 15q25 that is more common in lung cancer cases than in controls. The neuronal nicotinic acetylcholine receptor gene cluster containing CHRNA3 and CHRNA5 subunits is in this region. The genetic variation here is associated with an approximately 30% increase in the risk of lung cancer in individuals with heterozygous mutations, while individuals who are homozygous for the mutation have an approximately 80% increase in lung cancer risk. A meta-analysis of smokers with or without lung cancer and/or chronic obstructive pulmonary disease (COPD) reported that multiple loci within this region are associated with cigarettes smoked per day and at least one locus is associated with lung cancer independent of amount smoked.

Table Description automatically generated

Table 1.1 Genome-wide association study results in lung cancer

Additional regions of interest have been identified on chromosomes 6p21 and 5p15. A large meta-analysis of 14,900 lung cancer cases and 29,485 controls of European ancestry from 16 GWAS validated associations between lung cancer risk and genetic variation at 5p15, 6p21, and 15q25. Imputation has been used to expand the data available from GWAS, resulting in the identification and validation of associations between squamous cell carcinoma of the lung and rare variants of BRCA2- K3326X (odds ratio [OR] 2.5, P = 4.7 × 10−20) and CHEK2-I157T (OR 0.38, P = 1.27 × 10−13).

The largest GWAS have included only individuals of European ancestry. The varied genetic architecture and smoking histories of different race/ethnic groups make GWAS in other populations necessary for the eventual identification of lung cancer susceptibility genes. The findings among whites on 15q25, 5p15, and 6p21 have been replicated in African Americans. In the Han Chinese population, GWAS identified lung cancer risk associations on 5p15, 3q28, 13q12, and 22q12, and 10p14, 5q32, and 20q13. In the Japanese population, the findings on 5p15, 3q28, and 6p21 were also replicated. GWAS in never smokers has been limited. In never-smoking Asian women, the 6p21, 5p15, and 3q28 findings were replicated and regions on 10q25 and 6q22 were also identified as being associated with lung cancer. A large GWAS in never smokers of European ancestry is underway.

These studies have the potential to uncover mechanisms of carcinogenesis and to identify high-risk individuals to target for prevention and screening efforts.

iv.Chronic Obstructive Pulmonary Disease (COPD)

(1) COPD and Lung Cancer Incidence:

A large amount of evidence has suggested that there is a link between COPD and lung cancer. These diseases have a common risk factor, that is, smoking. However, studies have also shown that a history of COPD is associated with a two to three-fold increase in the risk of lung cancer, not smoking. Even among people who have never smoked, the link between COPD and lung cancer is obvious. COPD represents a disease with multiple phenotypes, including emphysema and chronic bronchitis, and it is not clear how the risk of lung cancer varies depending on the COPD phenotype. Epidemiological data that relies on COPD self-reports show some differences in the risk of COPD phenotype. The largest meta-analysis reported that lung cancer was associated with previous COPD (OR 2.2, 95% CI 1.7-3.0), chronic bronchitis (OR 1.5, 95% CI 1.3-1.8), and emphysema (OR 2.0, 95% CI 1.7 –2.4).

Clinical studies use CT evidence of emphysema and/or airflow obstruction measurements defined by spirometry to assess the risk of subsequent lung cancer and reduce the possibility of disease misclassification and recall bias. The increased risk of lung cancer is associated with a decrease in forced expiratory volume (FEV1) in one second, even among smokers with a small decrease in FEV1. Several studies have reported that in the presence of CT evidence of emphysema, the risk of lung cancer increases by two to four times, while the risk associated with airflow obstruction is no or lower. In the study using quantitative CT image analysis (qCT), the CT measurements of emphysema were not related to lung cancer and were not related to other COPD measurements. In a meta-analysis of seven studies by Dr. Smith, visual emphysema increased the risk of lung cancer three-fold (95% CI 2.71, 4.51), but a nonsignificant 1.16-fold (95% CI 0.48, 2.81) increased risk of lung cancer with qCT-defined emphysema. These studies demonstrate the need to consistently define COPD to better understand the relationship between COPD and lung cancer.

(2) COPD and Genetic Risk

Candidate gene studies in COPD and lung cancer have identified common and shared genetic variation in inflammation, extracellular matrix proteolysis, and oxidative stress pathways, including SNPs in epoxide hydrolase 1 (EPHX1), matrix metalloproteinases, and interleukin 1b (IL1B). Inflammatory pathway gene SNPs in IL7R, IL15, TNF, TNFRSF10A, IL1RN, and IL1A have been associated with lung cancer risk differentially by self-reported history of COPD. SNPs in IL1A have also been reported to be more strongly associated with lung cancer risk in those with emphysema. Genetic variation on 15q25.1, as reported from GWAS in lung cancer, has been reported in GWAS for COPD-related phenotypes as well. Summary data show that the 15q25 locus is associated with risk of both diseases, genetic variants on 4q31 and 4q22 are associated with reduced risk of both diseases, loci on 6p21 are most strongly associated with lung cancer risk in smokers with COPD, and variants on 5p15 and 1q23 alter lung cancer risk when COPD is not present.

v.Infectious Agents:

(1) Tuberculosis

Lung cancer risk has been associated with several infectious diseases, including tuberculosis (TB). In a meta-analysis of 37 case-control studies and four cohort studies, TB was associated with a 70% increased risk of lung cancer (95% CI 1.5–2.0), adjusting for smoking. Similar risk is observed among never smokers and the highest risk is seen within 5 years of a TB diagnosis.

(2) Human Papillomavirus

Human papillomavirus (HPV) prevalence in lung tumor tissue ranges from 0% to 100%, with differences by geographic regions, histology subtype of lung cancer, sex, and HPV subtype, but little is known about HPV-lung cancer risk profiles.

(3) Human Immunodeficiency Virus

HIV infection has been associated with a 1.5- to 5.0-fold increased risk of lung cancer. In a review of 65 studies, lung cancer risk in HIV-positive populations varied by geographic region. Standardized incidence ratios or incidence rate ratios were 1.5 to 3.4 in Europe, 0.7 to 6.9 in the United States, and 5.0 in Africa. Lung cancer risk among HIV-infected patients receiving highly active antiretroviral therapy (HAART) is similar to that among patients not receiving HAART. The cumulative incidence of lung cancer by age 75 is 3.4% among those with HIV and 2.8% among those without HIV.

c.Conclusion:

Lung cancer is the leading cause of cancer-related deaths worldwide. Although morbidity and mortality have declined with the decline in smoking rates, the 5-year survival rate is still less than 20%. Although the main risk factors for this disease are well known (smoking), progress in prevention and early diagnosis has been slow. In addition to smoking, lung cancer is also related to asbestos, radon, ionizing radiation and indoor air pollution. Both family-based studies and GWAS describe the contribution to genetic susceptibility well. It is necessary to continue to explore the effects of COPD, infection, and exposure to smoke from marijuana, water pipes and e-cigarettes to further determine lung cancer risk. The best target population for lung cancer prevention and screening needs to be based not only on smoking history, but also on clearly defined high-risk populations.

REFERENCES:

Chapter 2 Lung Cancer Screening

Liu Guohao, M.D. / Qu Xiaohan, M.D.

a.Introduction:

Lung cancer is the leading cause of cancer-related death worldwide. The association between tobacco use and lung cancer has been reported since the 1950s, and smoking cessation is the key intervention for preventing lung cancer. However, tobacco cessation is difficult to achieve. The wide use of tobacco is the main reason that lung cancer continues to burden society. At the time of diagnosis, most patients with lung cancer have stage III or IV disease, and over half have distant metastases. Since most early-stage lung tumors are asymptomatic, only 15% of lung cancers are localized at the time of detection. Due to the high frequency of late stage at diagnosis, the 5-year survival rate for lung cancer is only 16%, with little recent improvement. The high prevalence and mortality of lung cancer highlights the great impact that successful screening could have on this disease.

b.Biologic Basis of Lung Cancer:

i.Exposure and Susceptibility:

Tobacco smoking is the major cause of lung cancer. Individuals with predisposition to nicotine addiction are more prone to continue smoking, and thus, be exposed to high doses of tobacco-associated carcinogens, including the polycyclic aromatic hydrocarbon (PAH) benzo-[a]-pyrene and the key nicotine metabolite nicotine-derived nitrosamine ketone (NNK) (Figure 2.1). These carcinogens can be activated or eliminated through endogenous enzyme systems whose activity is determined by specific genetic polymorphisms. For example, the glutathione- S-transferase (GST) system detoxifies carcinogens by adding a glucuronide metabolite to PAHs. Individuals with a GST-Mu 1 (GSTM1) genotype are deficient in this process, so GSTM1 smokers will have an increased risk of lung cancer. Conversely, the cytochrome P450 system metabolically activates carcinogens, such as PAHs, by adding an epoxide metabolite. Individuals with a P450 CYP1A1 genotype have increased activity of this enzyme, so CYP1A1 smokers have an increased risk for lung cancer. Thus, individual genetic differences can confer susceptibility to lung cancer upon specific carcinogen exposure.

Activated PAHs can covalently bind to DNA to form specific DNA adducts, an early sign of lung carcinogenesis. These adducts can be repaired by endogenous DNA repair enzymes, which have differential activity conferred by genetic variation. If not repaired, damaged DNA can induce cell death. However, if these alterations persist, they can lead to oncogenic, somatic alterations of tumor suppressor genes (e.g., p53, Rb) or oncogenes (e.g., KRAS1, BRAF2), or to DNA instability as indicated by loss of heterozygosity. These alterations are commonly found in the bronchial epithelium of cigarette smokers leading to field carcinogenesis. In some individuals, this process gives rise to a cell that undergoes clonal transformation and develops into a tumor. The full series of events that facilitate cellular transformation remain unclear, but likely includes a stochastic process of mutation accumulation, transformation of key pluripotent cells or stem cells, and cooperation between mutations in epithelial cells and a permissive immune environment that allows the proliferation of cells bearing foreign neoantigens.

Figure 2.1 Mechanistic Framework for Understanding How Cigarette Smoking Causes Lung Cancer. All Events Can Occur Chronically Since a Smoker Typically Uses Multiple Cigarettes per Day for Many Years Source: From Ref. (1). Hecht SS. Lung carcinogenesis by tobacco smoke. Int J Cancer. 2012.

ii.Field Carcinogenesis

Recent studies of bronchial field carcinogenesis provide insight into the molecular pathogenesis of lung cancer and may directly impact the care of those at risk for lung cancer by providing novel strategies for early detection and targeted chemoprevention. Two multicenter trials demonstrated that a gene expression classifier from normal-appearing bronchial epithelial cells was a sensitive biomarker for diagnosing lung cancer among smokers undergoing bronchoscopy for suspected disease. Other studies have identified spatial and temporal variations in cellular alterations within field of cancerization in smokers, including transcriptional dysregulation of AKT and ERK1/2, epigenetic alterations of micro-RNAs (miRNAs) such as miR4423, and somatic chromosomal alterations. These aberrations can have a significant impact on the entire bronchial epithelial field, including basal cells that may serve as progenitors for lung carcinoma.

Many interactions between epithelial cells and stromal cells during lung cancer are similar to those necessary for normal lung development. The pathways involved in normal lung development and differentiation are also important for tumor occurrence, progression, and histological differentiation. The current paradigm shows that lung cancer originates from pluripotent stem cells and progenitor cells that can differentiate into multiple histological cell types. The hypothesis that lung cancer is caused by the abnormal expression of genes involved in lung development is supported by gene expression studies, which proved the difference between the genetic characteristics obtained from human lung tumors and the characteristics observed during normal lung development. Similarity. These studies show that the molecular profile of high-grade tumors (for example, large cell carcinoma) indicates that genes involved in the regulation of the cell cycle and transcription are disrupted, leading to arrest of development at a stage close to undifferentiated progenitor cells. However, the molecular features of low-grade tumors (such as adenocarcinoma) consist of genes involved in the terminal differentiation pathway. This link between poorly differentiated tumors and molecular parameters of early development suggests that these genetic features are important for lung cancer progression and are potential biomarkers of clinical outcome.

The clinical significance of the developmental regulation of histologic differentiation is highlighted by recent clinical trials showing the differential efficacy of selected lung cancer therapies within specific histological and molecular subtypes. These findings have helped transform the clinical management of non–small-cell lung cancer (NSCLC) from a one-size-fits-all approach to a strategy based on personalized medical care.

In the most recent World Health Organization (WHO) lung cancer classification scheme, the major subtypes of lung cancer have been reorganized and renamed based upon seminal clinical and biological studies. The major changes include grouping all neuroendocrine tumors together, restricting the designation of large-cell carcinoma to tumors that lack differentiation by both morphologic and immunohistochemical criteria, and the adoption of the IASLC/ATS/ERS Lung Adenocarcinoma Classification scheme. These modifications are supported by biological studies that demonstrated that specific molecular signatures are associated with clinically relevant histological subtypes. More in detail, the chemotherapeutic agent pemetrexed has activity in non-squamous NSCLC, but not squamous cell carcinoma, while necitumumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, may augment the activity of standard chemotherapy in some patients with squamous cell carcinoma, but not non-squamous NSCLC.

For early-stage lung adenocarcinoma, the revised classification scheme captures distinct histological and biological subtypes with prognostic significance. For example, tumors with a preinvasive histology, such as adenocarcinoma in situ (AIS) or microinvasive adenocarcinoma (MIA), have 5-year survival rates of 95% to 100% after completing surgical resection. The histologic classification is also supported by the biological data demonstrating unique molecular properties of specific subtypes. Gene expression profiling studies from North America, Asia, and Europe have reproducibly demonstrated that early-stage lung adenocarcinomas cluster into three major genomic subgroups that correlate with histology (Figure 2.2). These studies have led to incorporation of these subgroups into the new WHO classification scheme and the revised lung cancer TNM staging system, with annotations for AIS and MIA now included for T1 tumors. It will be important to prospectively validate the prognostic accuracy of the revised staging system for preinvasive cancers and to evaluate the clinical significance of specific subtypes of invasive adenocarcinoma. For example, recent studies indicate that the micropapillary and solid variants are associated with a poorer prognosis after resection than other subtypes, such as lepid-ic-predominant adenocarcinoma.

Figure 2.3 Adenocarcinoma Molecular Profiles Correlate With Histological Subtype Class

Independent studies (A–C) with different genomics analysis platforms all show that early-stage lung adenocarcinomas cluster into three major genomic subgroups that correlate with three major adenocarcinoma pathological subtypes (preinvasive adenocarcinoma in-situ and minimally invasive; lepidic predominant adenocarcinoma; solid adenocarcinoma). Source: Panel A, American Thoracic Society, copyright © 2016 American Thoracic Society. Panel B, Macmillan Publishers Ltd. Panel.

iii.Histologic Subtyping of Lung Cancer

Clinical treatment options were traditionally based on the distinction between SCLC and NSCLC, without major therapeutic interest in further subclassification. However, the advent of molecular profiling and targeted therapy renewed interest in the distinguishing between the major subtypes of NSCLC: adenocarcinoma (ADC, 39%) (2), squamous cell carcinoma (SqCC; 20%), and large cell lung carcinoma (LCLC, 3%) (Figure 2.4). LCLC occurs throughout the lung and usually grows and spreads at a rapid rate. Other subtypes, including sarcomatous carcinoma and neuroendocrine large cell carcinoma, represent a very small proportion of all NSCLC cases.

Figure 2.4 Microphotographs of H&E Stained