P16 Loss and Mitotic Activity Predict Poor Survival in Patients with Peritoneal Malignant Mesothelioma

Abstract

Purpose: Peritoneal malignant mesothelioma is an aggressive neoplasm for which intensive therapy improves survival in a subset of patients. We hypothesized that pathologic variables would stratify patients into favorable and unfavorable survival subgroups. Experimental Design: Fifty-four patients with peritoneal malignant mesothelioma were evaluated for trimodal therapy from 1995 to 2003. Two pathologists evaluated pathologic variables independently, and p16 status was analyzed by immunohistochemistry. Results: Patients not receiving trimodal therapy had a significantly increased risk of death [hazard ratio (HR), 9.6; 4.3-21.6; P < 0.0001]. Biphasic histology was also associated with increased risk of death (HR, 8.5;; P < 0.0001). In multivariate analysis adjusting for treatment modality and histologic type, high mitotic rate and p16 loss were associated with increasedriskof death (HR, 3.074;1.05-9.0; P <0.04andHR,3.65;1.3-10.2;P <0.014,respectively).Conclusions: Biphasic histology, increased mitotic rate, and p16 loss were independently associated with poorer survival in peritoneal malignant mesothelioma. Among the trimodal treated patients, increased mitotic rate was associated with increased risk of death.

Diagnostic importance of 9p21 homozygous deletion in malignant mesotheliomas

“…It is known that chromosome 9p represents a chromosomal region that is more prone to DNA damage by asbestos. 36 It is interesting that in our study only 5 of 20 cases of peritoneal mesotheliomas displayed the 9p21 deletion and 2 of these cases had documented asbestos exposure. In the other cases, the exposure history was either negative or unknown.…”

Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin–proteasome pathway as a therapeutic target in poor prognosis tumors

“…biphasic tumors, similar to P16 loss in mesothelioma (Borczuk et al, 2005b). To identify biologically important differentially expressed genes and pathways, we examined the functional annotation of mesothelioma histologic subtype classifiers using The Pathway Comparison tool of BRBArray Tools.…”

“…Understanding the biological basis of mesothelioma clinical behavior may facilitate a personalized treatment approach that will identify poor prognostic parameters early, reducing the heterogeneity of clinical response. Previously, we and others identified molecular characteristics associated with histology and outcome, including loss of expression of P16 in biphasic tumors (Borczuk et al, 2005b;Lopez-Rios et al, 2006). In this study, we use global molecular profiling with DNA microarrays to identify pathways associated with histologic subtype of malignant peritoneal mesothelioma.…”

Guidelines for Pathologic Diagnosis of Malignant Mesothelioma: 2012 Update of the Consensus Statement from the International Mesothelioma Interest Group

“…It remains unclear whether identification of any component of malignant spindled histology portends a poor prognosis in PMM. 55 Multiple mesothelial-lined cysts, also known as benign multicystic mesothelioma, represent a rare but welldescribed entity that may enter the differential diagnosis of mesothelial neoplasia. This lesion is nearly always encountered in the peritoneum, although rare cases with pleural involvement have been described.…”

“…85,90,91 There is also a correlation between p16 protein loss, as demonstrated by immunohistochemistry, and a poor prognosis with increased risk of death in peritoneal mesothelioma, but the association is not as strong. 55,90 There are no molecular markers to help distinguish malignant mesotheliomas from carcinomas or sarcomas on formalin-fixed, paraffin embedded tissue.…”