p16 FISH Deletion in Surface Epithelial Mesothelial Proliferations Is Predictive of Underlying Invasive Mesothelioma

Abstract

An atypical mesothelial proliferation along the pleural or peritoneal surface without evidence of invasive tumor poses a diagnostic challenge. Homozygous deletion of p16 (CDKN2A) by fluorescence in situ hybridization (FISH) has been shown to be a good marker of malignancy in mesothelial proliferations, but correlations of p16 status between atypical surface proliferations and underlying mesothelioma have not been described. We used p16 FISH to investigate 11 pleural and 7 peritoneal mesotheliomas that had both an invasive component and a separate surface mesothelial proliferation. In 5/11 pleural samples and 1/7 peritoneal samples, the invasive mesotheliomas showed homozygous deletion of p16 (all cases in excess of 90% of cells deleted); the surface proliferation in all 6 cases with deletion in the invasive tumor was also p16 deleted. Conversely, the 12 tumors that did not show p16 deletion in the invasive compartment also did not have deletion in the surface component. We conclude that (1) surface mesothelial proliferations near invasive mesotheliomas show the same pattern of p16 by FISH as the underlying tumor and may represent in situ disease or growth of the underlying mesothelioma along the serosal surface; (2) p16 deletion in mesothelial surface proliferations is strongly associated with p16 deletion in underlying mesotheliomas, and biopsies consisting of pure surface mesothelial proliferations that are p16 deleted allow a diagnosis of mesothelioma without an additional biopsy if there is clinical (thoracosopic/laparoscopic) or radiologic evidence of diffuse pleural or peritoneal tumor; (3) however, the absence of p16 deletion in surface proliferations does not rule out underlying invasive mesothelioma.

Malignant mesothelioma in situ

“…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. Indeed, we have reported previously 18 cases of invasive mesothelioma that had an accompanying surface growth (mainly multilayered rather than single mesothelial cells) and showed that CDKN2A FISH give identical fractions of deleted cells in the invasive and surface components, supporting the idea that such proliferations were probably surface spread of the underlying tumour. Further, none of these reports provides morphological criteria that allow separation of (putative) MIS from reactive mesothelial proliferations.…”

Characterization of preneoplastic and neoplastic rat mesothelial cell lines: the involvement of TETs, DNMTs, and 5-hydroxymethylcytosine

“…A recent study confirmed that p16 deletion is a good marker of malignancy, both in pleural and peritoneal mesotheliomas with invasive components [53]. A common chromosomal deletion was detected at 5q32, containing the Cdkn2a gene, and a homozygous deletion was observed in the majority of cases from epithelioid to sarcomatoid and biphasic mesotheliomas [54].…”

Deletion status of p16 in effusion smear preparation correlates with that of underlying malignant pleural mesothelioma tissue

“…The overall sensitivity of p16 FISH has been reported to be between 56% and 79%, and, notably, the positive predictive value and specificity are both 100% . Detection of homozygous p16 deletion by FISH seems to be feasible and helpful in confirming a diagnosis of mesothelioma in cytologic and surgical specimens …”

“…By using an appropriate panel of IHC/ICC markers, cells of mesothelial origin can be readily distinguished from pleural metastases of other primary carcinomas in most cases. However, there is still no reliable marker separating benign from malignant mesothelial proliferations with sufficient sensitivity and specificity …”

“…Biopsy specimens are sometimes too small to detect invasion for diagnostic purposes. However, Hwang et al . showed that an MPM diagnosis may be made with only small surface tissue by demonstrating the correlation of p16 FISH status between the surface mesothelial proliferation and the underlying invasive mesothelioma.…”