Pathogenesis of malignant pleural mesothelioma and the role of environmental and genetic factors.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor for which no effective therapy exists despite the discovery of many possible molecular and genetic targets. The late stage of MPM diagnosis and the long latency that exist between some exposures and diagnosis have made it difficult to comprehensively evaluate the role of risk factors and their downstream molecular effects. METHODS: This manuscript is a review of current literature about the pathogenesis of malignant mesothelioma. In this overview, current published studies concerning pathogenesis of malignant mesothelioma are reviewed, with insights into its etiology and pathogenesis. We searched pubmed using the following subjects: mesothelioma, radiation, genetics, pediatric malignant mesothelioma, SV40 virus, and growth factors. We selected 350 valuable articles of which 152 sources were used to complete this review. CONCLUSION: Many risk factors for MPM development have been recognized including environmental exposures, genetic susceptibility, viral contamination, and radiation. In this review, we discuss the current molecular and genetic contributors to MPM pathogenesis and the risk factors associated with these carcinogenic

Abdominal computed tomography scans in the selection of patients with malignant peritoneal mesothelioma for comprehensive treatment with cytoreductive

BACKGROUND: Malignant peritoneal mesothelioma is a rare and fatal disease. Until recently, the treatment options were very limited and ineffective. The new comprehensive approach of cytoreductive surgery with perioperative intraperitoneal chemotherapy offers improved survival rates at a cost of considerable morbidity and mortality as in other peritoneal surface malignancies. The outcome after these treatments is predominantly dependent on adequate cytoreduction. The aim of the current study was to identify computed tomography (CT) scan images that are useful in patient selection for this comprehensive approach. METHODS: An analysis of the preoperative CT scans of 30 patients with peritoneal mesothelioma treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy at a single institution was performed. Based on the size of residual tumor nodules after cytoreductive surgery, patients were divided into 2 groups: those with residual lesions2.5 cm (suboptimal cytoreduction). The CT scans for each patient were evaluated by a standardized scoring system with the reader blinded to the operative findings. Thirty-nine CT scan parameters were obtained and statistically analyzed to determine their association with the study outcome variables, namely, adequacy of cytoreduction. RESULTS: Seven patients (64%) in the suboptimal cytoreduction group and 2 patients (11%) in the adequate cytoreduction group had a >5-cm tumor mass in the epigastric region (P=0.004). Nine patients (82%) in the suboptimal group and 2 patients (11%) in the adequate cytoreduction group had CT scans that showed loss of normal architecture of the small bowel and its mesentery (P<0.001). In a composite analysis of these 2 radiologic features, none of the patients with a >5-cm tumor mass in the epigastric region and loss of normal architecture of the small bowel and its mesentery had an adequate cytoreduction. Patients who lacked these two preoperative CT scan findings had a 94% probability of an adequate cytoreduction. CONCLUSIONS: CT scans effectively identified large peritoneal mesothelioma tumors at crucial anatomic sites. Because adequate cytoreduction is necessary to achieve prolonged survival, CT scans became an accurate prognostic radiologic test for patient selection for comprehensive treatment. Copyright (c) 2005 American Cancer Society.

Peritoneal mesothelioma.

Peritoneal mesothelioma is usually a rapidly fatal primary peritoneal surface malignancy with a median survival time of less than 1 year, mainly because of lack of effective treatment. The incidence is approximately one per 1,000,000; approximately one fifth to one third of all mesotheliomas are peritoneal. Because of its unusual nature, the disease has not been clearly defined in terms of its natural history, diagnosis, or management. Treatment options with intravenous chemotherapy are far from satisfactory. However, because malignant peritoneal mesothelioma usually remains confined to the peritoneal cavity for most of its natural history, regional chemotherapy is an attractive option. From a theoretic perspective, the treatments are most likely to succeed in selected patients with small-volume residual disease after cytoreductive surgery. Advantages of intraperitoneal chemotherapy include greatly enhanced drug concentrations in the peritoneal cavity and decreased systemic toxicity. In designing an intraperitoneal treatment strategy for the management of peritoneal mesothelioma, the limited number of active cytotoxic drugs and the timing of drug delivery pose problems. Prognosis as determined by clinical presentation, the completeness of cytoreduction, and gender (female patients survive longer than male patients) appears to be improved by the use of intraperitoneal chemotherapy. Over the past decade, the management of these patients has evolved similarly to ovarian cancer treatment and now involves cytoreductive surgery, heated intraoperative intraperitoneal chemotherapy with cisplatin and doxorubicin, and early postoperative intraperitoneal paclitaxel. These perioperative treatments are followed by adjuvant intraperitoneal paclitaxel and second-look cytoreduction. Prolonged disease-free survival and reduced adverse symptoms with the current management strategy are documented by a high complete response rate as assessed by a negative second look. This multimodality treatment approach with debulking surgery and intraperitoneal chemotherapy has resulted in a median survival of 50 to 60 months. Peritoneal mesothelioma is an orphan disease that is treatable, with expectations for "potential" cure in a small number of patients diagnosed and treated early with definitive local/regional treatments. A prolonged high quality of life is possible in the majority of patients.

Diagnosis and treatment of peritoneal mesothelioma: The Washington Cancer Institute experience.

Peritoneal mesothelioma is a rare disease, but increasing in frequency. The incidence is approximately one per 1,000,000 and about one fifth to one third of all mesotheliomas are peritoneal. Because of its unusual nature, the disease has not been clearly defined either in terms of its natural history, diagnosis, or management. This article reviews a single institution's experience with 51 patients prospectively treated over the past decade with increasingly aggressive local/regional protocols. Peritoneal mesothelioma patients generally present with two types of symptoms and signs; those with abdominal pain, usually localized and related to a dominant tumor mass with little or no ascites and those without abdominal pain, but with ascites and abdominal distention. Pathologically, a positive immunostain for calretinin has markedly increased the accuracy of diagnosis. Prognosis as determined by clinical presentation, the completeness of cytoreduction, and gender (females survive longer than males) appears to be improved by the use of intraperitoneal chemotherapy. Over the past decade, the management of these patients has evolved similarly to ovarian cancer treatment and now involves cytoreductive surgery, heated intraoperative intraperitoneal chemotherapy (HIIC) with cisplatin and doxorubicin, and early postoperative intraperitoneal paclitaxel. These perioperative treatments are followed by adjuvant intraperitoneal paclitaxel and second-look cytoreduction. Prolonged disease-free survival and reduced adverse symptoms with the current management strategy are documented by a high complete response rate as assessed by a negative second-look. This multimodality treatment approach with cytoreductive surgery and intraperitoneal chemotherapy has resulted in a median survival of 50 to 60 months. Peritoneal mesothelioma is an orphan disease that is treatable with expectations for "potential" cure in a small number of patients if diagnosed and treated early with definitive local/regional treatments. A prolonged high quality of life is possible in the majority of patients. Copyright 2002 by W.B. Saunders Company.

The immunohistochemical diagnosis of mesothelioma. Differentiation of mesothelioma and lung adenocarcinoma

Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston 77030.

Despite numerous histochemical, ultrastructural, and immunohistochemical studies, differentiation between malignant epithelial pleural mesothelioma and adenocarcinoma of the lung remains extremely difficult. Although there is general agreement that immunohistochemical methods can aid in this distinction, some studies have produced conflicting results with some of the proposed markers for mesothelioma. To obtain comparable and reproducible results, 19 unequivocal epithelial mesotheliomas and 23 unequivocal primary lung adenocarcinomas were studied by the avidin-biotin-peroxidase complex method on formalin-fixed, paraffin-embedded tissue specimens. Well-characterized, commercially available antibodies to carcinoembryonic antigen (CEA), a high- and low-molecular-weight keratin, vimentin, epithelial membrane antigen, human milk fat globule, Leu-M1, TAG-72 (identified by monoclonal antibody B72.3), beta 1 pregnancy-specific glycoprotein (SP1), human placental lactogen, secretory component (SC), CA19-9, and S-100 protein were used. Twenty-one adenocarcinomas (91.3%) reacted for CEA, 14 (60.9%) for Leu-M1, 14 (60.9%) for SC, nine (39.1%) for CA19-9, and eight (34.8%) for SP1; no mesotheliomas stained for any of these markers. Nineteen adenocarcinomas (82.6%) and one mesothelioma (5.3%) reacted with B72.3. Adenocarcinomas and mesotheliomas did not significantly vary in reaction to the remaining antibodies. None of the antibodies used was specific for mesothelioma, but CEA was the single most useful marker. One of the two adenocarcinomas negative for CEA was positive for TAG-72, Leu-M1, and SC, and the only B72.3-positive mesothelioma was negative for CEA, Leu-M1, SC, CA19-9, and SP1. These findings indicate that greater sensitivity in differentiating mesothelioma and adenocarcinoma can be achieved by immunostaining for both CEA and one or more of the markers TAG-72 (B72.3), Leu-M1, SC (these three have the highest sensitivity and specificity after CEA), CA19-9, and SP1.