Introduction.

Pleural mesothelioma with metastasis to the subcutaneous tissue of the abdominal wall at first diagnosis and without penetration into the peritoneum is an extremely rare clinical presentation. Methods. Patients with pleural mesothelioma have low survival rate. Usually, the disease at presentation is confined to its site of origin (most often the pleural cavity). A 55-year-old man was referred to our center due to increasing dyspnea and a painful periumbilical mass in the anterior abdominal wall. CT scan revealed both advanced mesothelioma of the pleura and a tumor mass confined to the subcutaneous fatty tissue without penetration through the peritoneum.

Results.

Video-assisted thoracoscopy confirmed the diagnosis of epithelioid pleural mesothelioma, which was also confirmed by a biopsy of the periumbilical mass. Systemic chemotherapy with cisplatin and pemetrexed was initiated. Under the ongoing systemic chemotherapy, the evaluation revealed partial remission of pleura mesothelioma and its subcutaneous manifestation of the abdominal wall.

Conclusion.

Mesothelioma of the pleura with a simultaneous metastasis to the subcutaneous fatty tissue of the abdominal wall at presentation without penetration of peritoneum is a rare clinical presentation of mesothelioma disease. The knowledge of its natural history is very limited. This is the first ever clinical documentation of a patient with pleura mesothelioma and simultaneous subcutaneous manifestation of abdominal wall.

Mesothelioma is the most common malignant primary tumor of the pleura and usually associated with inhalation of asbestos fibers. In contrast, peritoneal mesothelioma is a rare entity whose pathomechanism is not yet fully understood. The coexistence of pleural mesothelioma with secondary involvement of the abdominal cavity has not been addressed in the literature. In this case report, we describe secondary malignant mesothelioma of the greater omentum. A 69-year-old man with histologically proven pleural mesothelioma on the right side and no past medical history of asbestos exposure received palliative treatment consisting of a talc pleurodesis. After a 6-month interval of stable disease, a local progressive tumor of the right pleura was seen on a CT scan. Eleven months later, during follow-up, the patient presented at our emergency department with a sudden onset of diffuse abdominal pain. Abdominal ultrasound revealed a mass within the greater omentum and the coexistence of free fluid. Subsequent abdominal CT scans demonstrated tumor infiltration from the right pleura by a transdiaphragmatic route into the abdomen, where diffuse infiltration of the greater omentum was observed. Aspiration of the ascites and the biopsy of the greater omentum confirmed the diagnosis of secondary malignant mesothelioma of the peritoneum. In conclusion, we present the extremely rare diagnosis of secondary malignant mesothelioma of the abdomen, which arose as a result of local progression from the right pleura into the abdomen.

BACKGROUND::

Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to cytoreductive surgery along with intraperitoneal chemotherapy. Therefore, early diagnosis of DMPM is very important. Some researchers have previously reported that high-mobility group box 1 (HMGB1) was correlated with pulmonary fibrosis. DMPM involves the malignant transformation of mesothelial cells, which originate from mesenchymal cells, similar to lung fibroblasts. Here, we investigated serum levels of HMGB1 in patients with MPM and compared them with those of a population that had been exposed to asbestos without developing MPM. STUDY:: The serum concentrations of HMGB1 were measured in 13 DMPM patients and 45 individuals with benign asbestos-related diseases.

RESULT:

: We demonstrated that the patients with DMPM had significantly higher serum levels of HMGB1 compared with the population who had been exposed to asbestos but did not develop DMPM.

CONCLUSION:

: Our data suggest that serum HMGB1 concentration is a useful serum marker for DMPM.

Malignant mesothelioma (MM) is an aggressive tumor arising primarily from the pleural or peritoneal cavities. It develops by asbestos exposure after a long latency, which is characterized by insidious growth and clinical presentation at an advanced stage of disease. MM is highly refractory to conventional therapies even with a combination of aggressive surgical intervention and multimodality strategies, with cure remaining elusive. Molecular genetic analysis has revealed several key genetic alterations which are responsible for the development and progression of MM. The CDKN2A/ ARF, NF2, and BAP1 genes are the most frequently mutated tumor suppressor genes detected in MM cells; the alterations of the latter two are relatively characteristic of MM. Merlin, which is encoded by NF2, regulates multiple cell signaling cascades including the Hippo and mTOR pathways which regulate cell proliferation and growth. BAP1 is involved in histone modification and its inactivation induces the disturbance of global gene expression profiling. The discovery of a new familial cancer syndrome with germline mutation of BAP1 also indicates the importance of genetic factors in MM susceptibility. Meanwhile, although frequent expression and functional activations of oncogene products such as receptor tyrosine kinases are observed in MM cells, activating mutations of these genes are rare. With further comprehensive genome analyses, new genetic and epigenetic alterations in MM cells are expected to be revealed more precisely, and the new knowledge based on them will be applied for developing new diagnostic tools and new target therapies against MMs.

Malignant serous effusions are a common manifestation of advanced cancer, associated with significant morbidity and mortality. The aim of this study was to identify the metabolic differences between ovarian serous carcinoma effusions obtained pre- and post-chemotherapy, as well as to compare ovarian carcinoma (OC) effusions with breast carcinoma and malignant mesothelioma specimens. The supernatants of 115 effusion samples were analyzed by high-resolution magnetic resonance spectroscopy in vitro and multivariate analysis. The samples comprised pleural and peritoneal effusions from 95 OC, 10 breast carcinomas, and 10 malignant mesotheliomas. Among the OC, 8 were paired peritoneal specimens obtained pre- and post-chemotherapy from the same patient. OC had elevated levels of ketones (aceto-acetate and β-hydroxybutyrate) and lactate compared to malignant mesotheliomas and breast carcinomas, whereas the latter had more glucose, alanine, and pyruvate. Multivariate analysis of paired effusions in OC showed a significant increase in glucose and lipid levels in the post-treatment spectra (P = .039). Magnetic resonance spectroscopy is a promising technique for comprehensive and comparative studies of metabolites in malignant serous effusions, and our study shows that small metabolites associated with effusions might improve our understanding of tumor biology and disease progression and has diagnostic potential in this differential diagnosis.

Mesothelioma is a slow-growing insidious lesion of neoplastic aetiology arising from the pleural, peritoneal or pericardial mesothelium. It shows a predilection for the surfaces of the pelvic viscera and has a high rate of recurrence after excision. Cystic mesotheliomas are not associated with asbestos exposure. We report a case of cystic mesothelioma of the peritoneum encasing the ovary, which presented as a cystic adnexal mass. As highlighted in this case and other recent reports, a cystic mesothelioma should not be referred to as a benign cystic mesothelioma, as it has potential for locoregional invasion, as well as distant nodal and serosal metastases. This tumour should be treated with aggressive cytoreductive surgery and appropriate chemotherapy. We review the differential diagnosis of this rare entity and suggest guidelines for its differentiation.

Malignant mesothelioma (MM), which is associated with asbestos exposure, is one of the most deadly tumors in humans. Early MM is concealed in the serosal cavities and lacks specific clinical symptoms. For the better treatment, early detection and prognostic markers are necessary. Recently, CD146 and IMP3 (insulin-like growth factor 2 mRNA-binding protein 3) were reported as possible positive markers of MM to distinguish from reactive mesothelia in humans. However, their application on MM of different species and its impact on survival remain elucidated. To disclose the utility of these molecules as early detection and prognostic markers of MM, we injected chrysotile or crocidolite intraperitoneally to rats, thus obtaining 26 peritoneal MMs and establishing 11 cell lines. We immunostained CD146 and IMP3 using the paraffin-embedded tissues and cell blocks and found CD146 and IMP3 expression in 58% (15/26) and 65% (17/26) of MMs, respectively, but not in reactive mesothelia. There was no significant difference in both immunostainings for overexpression among the three histological subtypes of MM, and the expression of CD146 and IMP3 was proportionally associated. Furthermore, the overexpression of CD146 and/or IMP3 was proportionally correlated with shortened survival. These results suggest that CD146 and IMP3 are useful diagnostic and prognostic markers of MM. This article is protected by copyright. All rights reserved.

Vascular endothelial growth factor (VEGF) is up-regulated during mesothelial to mesenchymal transition (MMT) and has been associated with peritoneal membrane dysfunction in peritoneal dialysis (PD) patients. It has been shown that normal and malignant mesothelial cells (MCs) express VEGF receptors (VEGFRs) and co-receptors and that VEGF is an autocrine growth factor for mesothelioma. Hence, we evaluated the expression patterns and the functional relevance of the VEGF/VEGFRs/co-receptors axis during the mesenchymal conversion of MCs induced by peritoneal dialysis. Omentum-derived MCs treated with TGF-β1 plus IL-1β (in vitro MMT) and PD effluent-derived MCs with non-epithelioid phenotype (ex vivo MMT) showed down-regulated expression of the two main receptors Flt-1/VEGFR-1 and KDR/VEGFR-2, whereas the co-receptor neuropilin-1 (Nrp-1) was up-regulated. The expression of the Nrp-1 ligand semaphorin-3A (Sema-3A), a functional VEGF competitor, was repressed throughout the MMT process. These expression pattern changes were accompanied by a reduction of the proliferation capacity and by a parallel induction of the invasive capacity of MCs that had undergone an in vitro or ex vivo MMT. Treatment with neutralizing anti-VEGF or anti-Nrp-1 antibodies showed that these molecules played a relevant role in cellular proliferation only in naïve omentum-derived MCs. Conversely, treatment with these blocking antibodies, as well as with recombinant Sema-3A, indicated that the switched VEGF/VEGFRs/co-receptors axis drove the enhanced invasion capacity of MCs undergoing MMT. In conclusion, the expression patterns of VEGFRs and co-receptors change in MCs during MMT, which in turn would determine their behaviour in terms of proliferation and invasion in response to VEGF.

BACKGROUND:

Well-differentiated papillary mesothelioma (WDPM) is a rare variant of epithelioid mesothelioma and is considered to be associated with good prognosis due to its clinically indolent behavior and long survival. Most reported cases involve the peritoneum of women at reproductive age with no history of exposure to asbestos, with pleural involvement being less common. The optimal management, including the role of chemotherapy in the treatment of WDPM, remains unsettled.

PATIENTS AND METHODS:

The authors describe two cases of WDPM in women of the same family (siblings); the elder with WDPM of the pleura and peritoneum with a 12-year survival period and the younger with a WDPM of the peritoneum diagnosed in 2011 and uveal melanoma diagnosed in 2012. Neither patient had any known exposure to asbestos fibers or any other mineral carcinogens.

RESULTS:

After the concurrent diagnosis of WDPM and uveal melanoma, genetic diagnosis was carried out taking into consideration that these two malignancies were recently associated with hereditary BAP1 gene mutations and it was positive for both the patients.

CONCLUSIONS:

To our knowledge, this is the first description of WDPM in two siblings who also presented with a germline BAP1 mutation. This article provides evidence of the wide clinical spectrum of cancer susceptibility associated with a BAP1 germline mutation.

Standard chemotherapy does not lead to long-term survival in patients with malignant pleural mesothelioma. Malignant pleural mesothelioma is strongly dependent on vasculature with high vessel counts and high concentrations of serum vascular growth factors. Thalidomide has shown antiangiogenic activity, and we hypothesised that its use in the maintenance setting could improve outcomes.In this open-label, multicentre, randomised phase 3 study, eligible patients had proven malignant pleural or peritoneal mesothelioma and had received a minimum of four cycles of first-line treatment containing at least pemetrexed, with or without cisplatin or carboplatin, and had not progressed on this treatment. Patients were randomly assigned (in a 1:1 ratio, stratified by previous first-line chemotherapy, histological subtype, and recruiting hospital) to receive thalidomide 200 mg per day (including a 2 week run in of 100 mg per day) plus active supportive care or active supportive care alone until disease progression. Patients were required to be registered and to start treatment with thalidomide within 10 weeks after the end of the first-line chemotherapy. Thalidomide was given for a maximum of 1 year or until unacceptable toxicity. The primary endpoint was time to progression. The primary analyses were by intention to treat. The study is registered, ISRCTN13632914.Between May 11, 2004, and Dec 23, 2009, we randomly assigned 222 patients, 111 in each group (one patient on active supportive care later withdrew consent and was excluded from analyses). At the time of this final analysis, median follow-up was 33·1 months (IQR 22·3-66·8), and physician-reported disease progression had occurred in 104 patients in the thalidomide group and 107 in the active supportive care group; 92 patients in the thalidomide group and 93 in the active supportive care group had died. Median time to progression in the thalidomide group was 3·6 months (95% CI 3·2-4·1) compared with 3·5 months (2·3-4·8) in the active supportive care group (hazard ratio 0·95, 95% CI 0·73-1·20, p=0·72). 43 (39%) grade 3 or 4 adverse events were reported in the thalidomide group and 31 (28%) in the active supportive care group; neurosensory events were reported by two (2%) patients on thalidomide and none on active supportive care, cardiac events by two (2%) patients on thalidomide and three (3%) on active supportive care, and thromboembolic events by three (3%) patients on thalidomide and none on active supportive care.No benefit was noted in time to progression with the addition of thalidomide maintenance to first-line chemotherapy. Different treatment strategies are needed to improve outcomes in patients with malignant mesothelioma.Dutch Cancer Society (KWF), Eli Lilly, NSW Dust Disease Compensation Board, University of Sydney, and Cancer Australia.