Malignant Pleural Mesothelioma: A Guide for Clinicians

Malignant Pleural Mesothelioma: A Guide for Clinicians is a practical book developed to assist clinicians, pathologist and molecular biologist in the management of malignant pleural mesothelioma (MPM). MPM represents a challenge in terms of diagnosis, staging and treatment, and to date, the optimal management of MPM patients has not yet been clearly defined – and this book is intended to be an efficient tool for these cases.

The book encompasses topics such as epidemiology and surveillance evidence, multimodality imaging assessment of MPM, pathology, molecular mechanisms and treatment of such disease. Additionally, it discusses the standard operative procedures and the future directions for the management of MPM from experts’ experiences. Malignant Pleural Mesothelioma: A Guide for Clinicians is a valuable source for oncologists, pathologist, cancer researchers, thoracic specialists and several members of biomedical field who needs to learn more from experts about the diagnosis, operative procedures and treatment of malignant pleural mesothelioma.

• Offers operative procedure sections in each chapter
• Brings updated information on epidemiology, molecular mechanism, diagnosis and treatment of MPM from experts of the field
• Provides innovative and prospective approaches for the management of mesotheliomas

• Language: English
• Publisher: Academic Press
• Release date: Feb 21, 2019
• ISBN: 9780128127254

Book preview

States

Preface

Malignant mesothelioma (MM), a rapidly growing cancer resulting from unregulated proliferation of the mesothelial cells lining the pleural, peritoneal, and pericardial cavities, continues to be an epidemiologic problem in many developed countries, affecting nearly 2500 Americans and 5000 Western Europeans annually and adding an estimated 85,000 total new cases (88% male, 12% female) in the United States by the year 2054. MM is considered an aggressive disease with very poor survival times and limited treatment options regardless of stage or subtype, while the disease is, in general, clinically resistant to chemotherapy and radiation, and surgical benefit is minimal at best. However, through the convergence of public policy efforts as a result of epidemiologic study, and in combination with omics-based research to ascertain cancer-driver genes, advances in biotechnology, and our improved understanding of cancer etiology, we are starting to see a pathway toward improvements in overall incidence and survival rates for MM.

MM is also a unique disease from an environmental exposure perspective as occupational exposure and environmental exposure to asbestos, in discrete regions of Italy and Turkey, have been linked with increased incidence of this particular form of cancer. In fact, unlike many other carcinogens, asbestos is specifically linked to mesothelioma. In addition epidemiologic studies have revealed some gender-specific differences. Although male incidence of pleural mesothelioma in the United States, Sweden, and Norway has decreased significantly after peak asbestos use, incidence of pleural mesothelioma in females has remained constant since the 1980s, with an estimated 0.4/100,000 new cases of pleural mesothelioma per year in the United States and apparently not related to occupational or environmental asbestos exposure.

It has been suggested a genetic component may increase risk for development of mesothelioma after asbestos exposure. Recently, a genome wide association study (GWAS), conducted with high statistical power and separate case–control cohorts in Italy (407 MPM cases: 389 controls) and Australia (428 MPM cases: 1269 controls) to determine genetic risk factors associated with development of MPM, detected multiple SNPs located within regions of chromosomal aberrations that correlated to MPM incidence. It is noted that asbestos exposure results in genotoxicity in rodent studies as well as evidence of chromosomal aberrations in exposed populations, such as increased incidence of sister chromatid exchange, DNA double strand breaks, and inactivation of multiple tumor suppressor pathways. Multiple studies have suggested the potentially important mechanistic roles for a number of nuclear regulatory proteins, oncogenes, proto-oncogenes, and second messenger proteins such as p53, TGF-B, NF-KB, and numerous tyrosine kinases.

Although numerous potential therapeutic targets for MPM have been suggested from genomic screenings, limited clinical success has been achieved in translating these findings to the clinic. To this effect, targeted therapies toward receptor kinases, whose clinical activity is correlated to receptor kinase mutational status, have failed in the clinic. Also, a large body of evidence suggests a significant epigenetic component to the development of MPM. Numerous genes have been shown to be downregulated in mesothelioma cells by epigenetic regulation such as DNA methylation of their transcriptional promoters.

Intraoperative molecular imaging, use of molecular fluorescent probes to demarcate tumor boundaries and identify residual disease during surgical removal of MPM, is a new tool in the arsenal available to the surgical oncologist. Use of probes such as indocyanine green and fluorescently tagged folate receptor alpha have shown utility in identifying intrathoracic malignancies during surgical procedures and ultimately resulting in more favorable postsurgical outcomes as a result of improved resection of the tumor. And as a result of the findings from omics studies, the identification and validation of panels of biomarkers for MM will aid in the development of new cancer-specific markers/probes, useful not only in intraoperative molecular imaging but also postoperative tumor monitoring, such as from liquid biopsy.

This book highlights some of the recent trends and discoveries in MM research, diagnosis, and treatment, with particular attention how new technological and informatics advancements have ushered in paradigm shifts in how we think about cancer. This book is not meant to be a didactic textbook on therapy and surgical guidelines for MM but represents a conversation and unique perspectives on the disease from a diverse panel of experts from multiple oncology-related disciplines to benefit the understanding and discourse among surgical oncologists with respect to this deadly disease. Therefore the reader is asked to understand how the convergence of public health policy, basic and translational efforts, the advancement of omics, bioinformatics, and high-performance computing are being translated to current breakthrough discoveries, in association with the basic biological knowledge we have amassed through diligent research and how these principles and the latest research can be used by the next generation of cancer scientists and oncologists to provide future breakthroughs. In the past basic research had provided a new platform for the era of genomics in oncology; now it is up to this next generation of scientists and oncologists to provide the basic research for the next platform, which will create the future breakthroughs to combat this still deadly disease.

Chapter 1

Evidence From Epidemiology and Health Surveillance

Roberto G. Lucchini¹,², Dana Hashim¹, Luca Lambertini¹ and Donatella Placidi²,    ¹Icahn School of Medicine at Mount Sinai, New York, NY, United States,    ²University of Brescia, Brescia, Italy

Abstract

Asbestos exposure is still relevant across the world and increases the risk of malignant mesothelioma through known and less known occupational exposure, as well as nonoccupational exposure. Cumulative exposure increases the risk of mesothelioma even at low doses of less than 0.1 (fiber/mL) years. Therefore, current legal standards are not protective for prolonged exposure and incremental exposure at any concentration can increase the risk of the disease. Individuals with previous exposure should not be further exposed even at low levels to avoid increased risk. Even after 40–50 years after the exposure, the risk of mesothelioma increases and it is not clear whether it may reduce afterwards.

Keywords

Malignant mesothelioma; asbestos fibers; occupational and environmental exposure

Highlights

• The risk of malignant mesothelioma (MM) is still high and will peak in the next decades, especially in the low and middle income countries, where it was introduced more recently than in Europe, Australia, the United States, and Japan

• The risk of MM increases at levels lower than current international legal standards, and is proportional to cumulative exposure

• Cumulative exposure increases the risk of MM

• Data on occupational and nonoccupational exposures to asbestos need to focus on unknown sources to allow preventive intervention

• Asbestos usage and frequency of MM are underreported globally and especially in the low and middle income countries, where training and research needs to be intensified

Introduction

MM is a cancer arising from alterations of normal mesothelial cell linings of the serous membranes, most commonly in the pleural and peritoneal spaces. Malignant pleural mesothelioma is the most frequent, with a high mortality rate and limited therapeutic options. In this chapter the main current usage and exposure sources to asbestos are reviewed, with updated prevalence and incidence data, and future projections.

Current Usage of Asbestos

Asbestos is the collective name given to six naturally occurring fibrous minerals that exist in two physical configurations: serpentine and amphibole. Chrysotile, also known as white asbestos, is originated from serpentine minerals, accounts for 95% of the asbestos ever used, and is the only type of asbestos still in commercial use. Amphibole asbestos species are amosite, crocidolite, tremolite, anthophyllite, and actinolite. The two forms of amphibole asbestos that were most commercially important in the past—amosite (or brown asbestos) and crocidolite (or blue asbestos)—are no longer in use. Asbestos fibers can withstand fire, heat, and acid; have great tensile strength; and provide thermal and acoustic insulation. For these reasons, asbestos came into wide commercial use and gave rise to a burgeoning industry many years before its detrimental health effects became known [1,2].

All forms of asbestos, including chrysotile, crocidolite, amosite, anthophyllite, tremolite, and actinolite, cause MM. This statement is based on epidemiological, experimental, and mechanistic studies and reflects a broad consensus of views in the scientific, public health, and regulatory communities [3–8]. Asbestos was declared a proven human carcinogen by the US Environmental Protection Agency (EPA), the International Agency for Research on Cancer (IARC), of the World Health Organization (WHO) and the National Toxicology Program (NTP) more than 20 years ago. There is overwhelming agreement that there is no safe level of exposure to asbestos [9] and no evidence of a threshold level below which there is no risk of mesothelioma [10]. Despite these concerns, based on scientific evidence, the global use of chrysotile has remained at around two million metric tons per year in recent years, mostly in the low- and middle-income countries, and is likely to remain stable for the near future owing to continued demand [11]. The WHO has estimated, in 2014, that there are approximately 125 million people in the world who are exposed to asbestos in the workplace [12]. Vast development projects in Asia are largely responsible for maintaining the chrysotile asbestos market [13] and India’s asbestos industry [14]. The Chemical Review Committee of the Rotterdam Convention has recommended that chrysotile asbestos be put on the Convention’s list of hazardous substances, thus requiring exporting countries to obtain prior informed consent (PIC) from the importing countries. A handful of countries have opposed that recommendation, thus preventing this basic safety protection from coming into effect [15,16].

Nonoccupational Exposure Sources

Mesothelioma and other asbestos-related diseases (ARD) are commonly attributed to occupational exposure. Even in countries that no longer extract asbestos and where commercial uses have declined, past occupational exposures remain the predominant impetus for mesothelioma mortality. However, since mesothelioma has been found also in cases with no known previous occupational exposure, numerous studies have focused on environmental sources [17].

Paraoccupational Exposure

Paraoccupational, or take-home exposures from asbestos workers, occur via a variety of situations. Laundering work clothes, cleaning, and ambient asbestos-containing dust that was transported by the worker to the home and/or the worker’s vehicle are potential exposures to household members that can be integrated into exposure assessments if individual-level data are collected on contact frequency with these routes [18]. Not only spouses but also sons, daughters, parents, and siblings are at risk from asbestos brought home by exposed workers [19]. Donovan et al. [20] reviewed the literature on paraoccupational asbestos exposure and found that over half of the reported cases were pleural mesothelioma confirmed at autopsy, and over 65% of them occurred in persons who lived with workers classified as miners, shipyard workers, insulators, or others involved in the manufacturing of asbestos-containing products, with nearly all remaining workers identified as craftsmen. A population-based, case–control study in Casale Monferrato in northwest Italy found that family members who lived with an occupationally exposed worker, the majority of whom brought work clothes home for cleaning, had an increased risk of mesothelioma (OR = 2.2; 95% CI: 1.2–4.0) [21]. Exposure was assessed based on residential proximity to asbestos industrial or natural sources and domestic/occupational pathways. Four exposure categories were based on standardized fiber/milliliter-year (fiber/mL-years), ranging from <0.1 to ≥10. The analysis showed a dose–response relationship OR = 23.3 (2.9–187) for the highest quartile, relative to the lowest. A meta-analysis yielded a summary OR of 5.0 (2.5–10) for paraoccupational exposure and mesothelioma [22]. Thus, despite the uncertainty with respect to quantifiable exposure levels to household members, and despite the difficulty in distinguishing neighborhood exposure from an asbestos industry point source, the evidence that paraoccupational exposures are associated with mesothelioma is quite strong.

Community Exposure From Industrial Operations

Environmental exposures to communities with large, asbestos-related industrial operations can occur via airborne emissions arising from loading, processing, ventilation, or waste disposal activities, or via the local use of waste products from the facility (e.g., mine tailings) for roads, soil amendments, or other purposes. In the United States, mesothelioma incidence and mortality was described in 70 separate communities receiving or processing asbestos-contaminated vermiculite materials from Libby, Montana [23]. Elevated standardized mortality ratios (SMRs) were identified in seven sites, at the city level, among male cases only, and were limited by a small female case number. The Italian National Registry of Malignant Mesothelioma (ReNaM) provides one of the most comprehensive characterizations of individual-level exposure via occupational, paraoccupational, or environmental pathways [24]. A spatial evaluation by ReNaM of incident mesothelioma cases detected the exposure clusters localized to areas with large asbestos cement plants or shipyards [25]. Among three communities with large, asbestos cement manufacturing facilities, 38% (467/1217) of the cases were women and 20% (198/1006) of all cases with characterized exposure sources were attributed to environmental exposures. However, a distinction could not be made between paraoccupational exposure and exposure attributed to residential proximity to an asbestos plant. Mesothelioma case clusters with dose–response associations were also identified in communities with large shipbuilding industries, but only a small proportion of these clusters were attributed to environmental exposures. Thus, despite the confluence of occupational, paraoccupational, and environmental exposures in these communities with asbestos industry point sources, the evidence most clearly supports an increased risk for mesothelioma among people exposed environmentally, presumably via airborne