Abstract
Malignant mesothelioma is a rare aggressive malignancy of serosal surfaces that is strongly associated with exposure to asbestos. The pathological diagnosis of malignant mesothelioma can be difficult to distinguish from reactive benign hyperplasia. Mutations in BAP-1 and CDKN2a distinguish mesothelioma from reactive hyperplasia. An in situ growth phase of mesothelioma until recently was difficult to ascertain due to limits of histological assessment and because mesothelioma tends to spread diffusely along serosal surfaces making sampling for invasion impossible without extensive resection. The current WHO classification of thoracic tumors recognizes mesothelioma in situ as a distinct entity based on histological, genetic, and clinical features. This chapter reviews the topic and concludes that the diagnosis of malignant mesothelioma in situ should be limited to patients eligible for radical resection to confirm the putative diagnosis.
Keywords
- mesothelioma
- in situ
- invasion
- BAP-1
- CDKN2A
1. Introduction
Malignant tumors result from dysregulated clonal cell proliferations. Malignant tumors can potentially invade local tissues and metastasize to distant sites. There are many pathways leading to malignant transformation and the spread of tumor. Most solid epithelial tumors pass through a stage of
Malignant mesothelioma is a rare malignancy of serosal-lined surfaces [1]. Most mesotheliomas occur in the pleura (85%), with the remainder in peritoneum (~10%), pericardium and tunica vaginalis (each less than 2.5%). Mesothelioma was rarely described in the medical literature prior to 1960, when Wagner described a large cohort of cases in South African asbestos miners and those living in proximity to the mines. Subsequently, a large percentage of mesotheliomas have been demonstrated to be causally linked to prior exposure to asbestos, the latter a naturally occurring fibrous magnesium silicate that was used extensively as an insulating material in the construction and other trades in the twentieth century. There is a prolonged latency for the development of malignant mesothelioma, on average greater than 30 years following first exposures to asbestos. Other recognized causes of mesothelioma are rare and include therapeutic radiation and the mineral erionite that was used in the construction of homes in the Cappadocia region of Turkey [2].
Mesothelial cells line normal serosal surfaces. They secrete acid mucins and regulate cavitary fluid accumulation of lubricant fluid. In response to inflammation, normal mesothelial cells proliferate and show enhanced fluid secretion, leading to exudative effusions that bring patients to clinical attention. Reactive mesothelial proliferation can be difficult to differentiate histologically from mesothelial malignancy. Mesothelial cells are pluripotential cells; and under neoplastic conditions, they may give rise to tumors with epithelioid, sarcomatoid, or mixed (biphasic) histologies. Until recently, unequivocal evidence of soft tissue invasion was required to distinguish malignancy from benign reactive mesothelial proliferations. Unfortunately, the propensity of malignant mesothelioma to spread diffusely along serosal surfaces and to invade adjacent structures makes curative surgical excision virtually impossible. Consequently, nearly all patients with malignant mesothelioma die from their disease.
2. Genetics of mesothelial malignancy
Malignant mesothelioma are heterogeneous with complex genetic, chromosomal, and epigenetic changes. Mesotheliomas are often polyclonal neoplasms, likely reflecting a “field effect” induced by asbestos. They also display relatively low mutation burdens, compared to most adult solid tumors [3].
The Cancer Genome Atlas program studied 74 mesotheliomas for genetic alterations using next-generation sequencing (NGS), whole-exome sequencing (WES), messenger RNA expression, methylation analysis, microRNA expression, exomes, reverse-phase protein array, and transcription factor analyses. They observed frequent characteristic mutations in
Roughly, half of all cases of malignant mesothelioma show biallelic mutations in
Biallelic acquired deletions of
3. Invasion and metastasis
Malignant transformation can occur without tumor invasion and metastasis and may precede it in many cases. The steps leading to tumor invasion and spread are complex and include both genetic and epigenetic changes. The mammalian organism is divided into tissue compartments separated by extracellular matrix, i.e. basement membrane, and interstitial stroma [10]. Basal epithelial cells normally attach to basement membrane, or as in the case of mesothelial cells, directly to subjacent interstitial matrix. In normal tissues, these cell populations do not intermix.
On the “other” side of the basement membrane, the interstitial stroma includes an array of cells, including fibroblasts, myofibroblasts, and their secreted matrix. Like epithelium, nerve cells, muscle cells, and blood vessels are surrounded by a continuous extracellular matrix. During tissue remodeling, benign proliferative disorders, and carcinoma
Tumor invasion by malignant cells is an active process [10]. Interactions of the tumor cell with basement membrane and interstitial matrix require initial attachment, the dissolution of matrix, and cellular migration. In this regard, tumor cells secrete lytic enzymes or induce the host to elaborate proteinases that degrade matrix adhesion molecules. Locomotion propels the tumor cell across the basement membrane and stroma through a zone of proteolyzed matrix. Directional movement is regulated by cell surface ligand binding and mobilization of cytoskeletal elements that interact with the cell membrane surface. Tumor cell motility is modulated by cytokines, and direction of movement is influenced by local chemoattractants.
Little is known about the specific pathways that promote tissue invasion and metastasis in malignant mesothelioma. Malignant mesothelioma cells produce collagens, and the prognosis of mesothelioma may be related to the expression of matrix metalloproteinases. Malignant mesothelioma tumors also induce immune responses from their hosts. Chronic inflammation is manifested by the presence of tumor inflammatory cells and the local release of cytokines. Mesothelioma cell growth also requires neoangiogenesis to provide nutrients to proliferating cells and supportive matrix. Growth signals and loss of tumor-suppressor genes may provide the growth advantage that leads to tumor cell proliferation.
4. Distinguishing malignant mesothelioma in situ
The existence of an
In 2018, Churg et al. described 10 patients with mesothelioma
Elliott et al. [13] reported a case of malignant peritoneal mesothelioma that had apparently progressed from mesothelioma
5. The WHO classification of mesothelioma in situ
The most recent WHO classification of thoracic malignancies includes malignant mesothelioma
Although the diagnosis of mesothelioma
To date, only a handful of cases of malignant mesothelioma
Serious problems apparently persist with respect to the confidence in which this diagnosis is made, as well as in with how to approach this “entity” therapeutically. It may be premature to accept mesothelioma
Accurate sampling to exclude microscopic foci of invasion is virtually impossible to achieve in the absence of complete tumor excision with detailed pathological examination. The WHO criteria do not include validated criteria for how extensively to sample serosal surfaces, although it recognizes that limited sampling will lead to overdiagnosis of this entity.
Although having molecular markers of mesothelial malignancy is a substantial scientific advance, enthusiasm should be balanced by consideration of the clinical implications of the diagnosis of mesothelioma
For this reason, it is argued that a diagnosis of mesothelioma
6. Conclusion
Malignant mesothelioma is a rare and deadly malignancy. Five-year survival rates are negligible, even following surgical and chemo/immunotherapeutic interventions. For this reason, the possibility of defining a preinvasive stage of malignant mesothelioma theoretically offers the possibility of therapeutic cure. However, the diffuse nature of the disease and the advanced age of most patients with mesothelioma
Acknowledgments
The author would like to thank Dr. Siobhan Cashman for her assistance in the preparation of the manuscript.
Conflict of interest
Dr. Kradin has testified as an expert witness in cases of mesothelioma attributed to asbestos.
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