Chromosomal alterations in early stages of malignant mesotheliomas

Abstract

In a case of a 67-year-old man with two different early stages of a predominantly epithelioid mesothelioma ("mesothelioma in situ", "early-stage mesothelioma"), chromosomal imbalances were determined by comparative genomic hybridisation (CGH), a molecular cytogenetic technique to detect chromosomal gains and losses in tumour cells. In the case of the mesothelioma in situ cells, nine different chromosomal alterations could be detected (losses on 3p, 5q, 6q, 8p, 9p, 15q, 22q, Y; gain on 7q), whereas the early-stage mesothelioma showed the same defects except for the gain on 7q. The simultaneous losses of 6q, 9p and 22q, as well as other chromosomal regions, correlate well with the most common defects previously found in 90 cases of more-advanced-stage mesotheliomas using CGH. These data demonstrate that initial chromosomal defects in early stages of mesotheliomas can be detected by conventional CGH in combination with laser microdissection. The molecular cytogenetic findings support the histological diagnosis of a pleural mesothelioma. The surprisingly high number and extent of genomic alterations found in the examined case probably reflects the genomic instability in the tumour cells and indicates a "genetic chaos" even in earlier stages of malignant mesotheliomas.

Malignant mesothelioma in situ

“…As noted in the Introduction, the diagnosis of MIS is considered unreliable by routine histological examination, and most of the cases that have been claimed to show MIS have been in the setting of a co-existing invasive mesothelioma. To our knowledge, the only study that has attempted to look at genomic events in a case of possible MIS is that of Simon et al, 9 who used comparative genomic hybridisation and reported an almost identical set of chromosomal losses in both the surface and invasive component of a mesothelioma. However, the problem with all these studies is that there is no proof that the surface proliferation really represents primary in-situ disease rather than surface spread of invasive disease.…”

Facts and fiction: premalignant lesions of lung tissues

“…Overlap exists between the different categories, and there is some argument that CIS is different at a molecular level from high grade dysplasia and may clinically behave differently, but this may need confirmation by further studies. 17,20,40,47 In addition, telomerase dysregulation and hypermethylation are intermediate steps, whilst p53 and KRAS mutations occur later in the development of invasive lesions (reviewed in 13,15,16). Others have found that the degree of dysplasia at baseline-assessment was not predictive of patient outcome, and indeed, molecular signature of the lesion may be more predictive of its behaviour than histological grade.…”

“…6) and reliable and early diagnosis of mesothelioma in situ would in theory facilitate curative therapy. 17 Features that have been proposed as criteria for diagnosis of in situ mesothelioma include a single layer of atypical mesothelial cells along the pleural surface, as well as complex multilayered collections of mesothelial cells along the pleural surface, either as solid sheets or papillary structures. However, Simon et al did report a single case of mesothelioma in situ in association with focal early-stage invasive mesothelioma and both the in situ lesion and the invasive mesothelioma showed a very similar though not identical profile of chromosomal abnormalities, and we commonly see foci of in situ mesothelial atypia in sections that also contain invasive tumour.…”

“…5 These include squamous metaplasia with dysplasia and carcinoma in situ as precursors for squamous cell carcinoma (SCC), and AAH as a presumed precursor for adenocarcinoma, as well as diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) as a potential precursor for carcinoid tumour. [13][14][15][16][17] These observations may reflect anatomically and functionally distinct compartments of the respiratory tree. 6 Other lesions that are likely to represent bona fide pre-invasive lesions that may progress directly to invasive malignancies, but which are not currently WHO-listed, include HPV-related respiratory (laryngotracheobronchial) papillomatosis with squamous epithelial atypia as an albeit uncommon precursor for invasive SCC, and mesothelioma in situ as a precursor for diffuse malignant mesothelioma.…”

“…17 However, not all precursor lesions may be detected, since morphologically unremarkable epithelium may harbour significant molecular abnormalities. 17 However, not all precursor lesions may be detected, since morphologically unremarkable epithelium may harbour significant molecular abnormalities.…”