Pathologist s Discussion of Plaintiffs Latest Theories

Transcription

1 Pathologist s Discussion of Plaintiffs Latest Theories Mary Beth Beasley, MD Mt. Sinai Medical Center Annenberg Building 15th Floor Room Madison Avenue New York, NY (212) [email protected]

2 Mary Beth Beasley, MD, is currently Associate Professor of Pathology and Head of Pulmonary Pathology at Mt. Sinai Medical Center in New York City. Dr. Beasley did her pathology residency at Duke University and at Tulane University, followed by a fellowship in Pulmonary and Mediastinal Pathology at the Armed Forces Institute of Pathology where she subsequently served as a staff pathologist. Dr. Beasley is the author or co-author of over 75 peer-reviewed articles and book chapters on various aspects of pulmonary pathology and is a co-editor of three pulmonary pathology textbooks. Dr. Beasley serves on multiple national and international pathology committees, the editorial board of Archives of Pathology, and has given numerous presentations at national and international pathology meetings.

3 Pathologist s Discussion of Plaintiffs Latest Theories Table of Contents I. Issue: Plaintiff contention regarding the significance of asbestos bodies in lymph node tissue and equating such findings as evidence causality of mesothelioma II. Issue: Plaintiff contention that molecular medicine supports that chrysotile causes mesothelioma Pathologist s Discussion of Plaintiffs Latest Theories Beasley 473

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5 Pathologist s Discussion of Plaintiffs Latest Theories I. Issue: Plaintiff contention regarding the significance of asbestos bodies in lymph node tissue and equating such findings as evidence causality of mesothelioma Background: It has long been recognized that asbestos fibers may be found in tissue samples other than the lung. Indeed, asbestos bodies were described in pulmonary lymph nodes as early as In contrast to digestion studies of lung tissue, the significance of asbestos fibers in lymph nodes and other sites is not known. Digestion studies examining lymph node tissue have found asbestos concentrations in lymph node tissue that may be higher, lower, or similar to those found in matched lung samples. It has been suggested, most notably by Dodson, et al, that the lymph node concentration may be a better indicator of life long exposure than lung tissue given that in their study the concentration was typically higher in the lymph nodes than lung tissue. Plaintiff hypotheses and contentions: A poster presentation by Gordon and Dikman at an annual meeting of the American Thoracic Society generated several conclusions regarding the significance of asbestos in lymph node samples. The authors performed digestion studies on 100 paratracheal and/or peribronchial lymph nodes from patients with malignant mesothelioma and compared the results to matched lung parenchymal samples. The authors further correlate the findings with known occupational history and duration of exposure. Based on their results, the authors conclude that it is close to impossible to consider the mesotheliomas idiopathic when it is possible to identify a causative agent in the lungs, peribronchial and [para]tracheal lymph nodes, or both, asbestos regardless of the amount. Discussion points: In fairness, the data from this study has been presented in abstract/poster format only and, to date, has not been published in a peer-reviewed journal. As such, criticisms potentially may be ultimately be clarified in a final subsequent version. The abstract and poster have numerous typographical errors. That aside, several issues warrant comment: Regarding the control samples, the controls and patient sample levels were counted using different methods. Additionally, mean fiber counts per gram of wet lung for amphiboles and chrysotile fibers combined in the control samples are less than or equal to the mean fiber counts for each fiber type individually. As such, it is difficult to interpret the results of the patient samples in the absence of consistent methodology between patient and population control groups. Looking at the results of the provided patient results, in attempt to correlate the findings with those of known laboratory controls, it should be noted that of the 100 patient samples tested, 45 had asbestos body counts less than or equal to 20 per gram of wet lung, the control range for some laboratories. The vast majority of patients did have higher asbestos fiber counts in the lymph nodes than the lung; however, again, it is unclear what these numbers mean, particularly in light of the disparity with the control methodology and further, as discussed below, finding fibers in the lymph nodes does not equate with causation. While the authors correctly conclude what is already generally known i.e. that lung digestion studies are not necessarily reflective of past chrysotile exposure- they have not demonstrated that, while the lymph node asbestos fiber counts were generally higher than those of the lung samples, they are necessarily more Pathologist s Discussion of Plaintiffs Latest Theories Beasley 475

6 significant. Most importantly, the authors erroneously conclude that the finding of asbestos equates with causality, particularly in regard to chrysotile. II. Issue: Plaintiff contention that molecular medicine supports that chrysotile causes mesothelioma Background: The precise mechanism by which asbestos causes the development of mesothelioma is not known and is likely to be multifactorial. Several theories exist, primarily involving either direct toxic action of asbestos fibers on mesothelial cells or initiation of inflammation, activation of cytokines or other mediators such as reactive oxygen species and free radicals which damage mesothelial cells, or a combination of factors. Animal studies have demonstrated that inhalation or injection of chrysotile fibers may result in the development of mesothelioma. Cell culture studies have also shown that mesothelial cells may engulf chrysotile fibers and long fibers have been observed to intertwine with the DNA structure. Plaintiff contention: Some experts contend that the above animal and cell culture studies definitively prove that chrysotile as well as amphiboles can produce cellular abnormalities which can result in the development of abnormal cell clones which ultimately develop into malignant mesothelioma. Some have referred to this as a gold standard Discussion points: While animal studies do provide certain valuable information, the results cannot necessarily be extrapolated to humans and must be interpreted with caution. This is particularly true when the conditions under which an animal experiment is conducted differ significantly from what an individual may encounter in a work environment. Further, carcinogensis is a complex process and a cell with DNA damage does not necessarily evolve into a malignant cell. In regard to molecular studies, molecular analysis of neoplasia in general has provided insight into the genetic abnormalities that underlie the biology of carcinomas, but identification of the abnormality alone does not necessarily provide insight into how the abnormality came about. Thus far, a single consistent molecular abnormality has not been identified in mesothelioma although deletion of p16/cdkn2a is reported most frequently, and was found in 80% of mesotheliomas in one study. Other reported mutations include mutations of BAP1 and NF-2. Other mutations have been reported inconsistently in variably numbers of cases. A few studies have suggested that certain mutations are more frequent in asbestos associated mesotheliomas than those which are not. While these mutations provide insight into the tumor biology and may ultimately be a guide for targeted therapy, they do not currently distinguish an asbestos related mesothelioma from one that is not. The major issue common to both of these contentions is the erroneous leap to a definitive association with causality. In addition to the above points, additional issues will be covered. 476 Asbestos Medicine Seminar November 2012