Malignant Peritoneal Mesothelioma Research Articles

Cytoreductive Surgery and HIPEC for Malignant Peritoneal Mesothelioma: Outcomes and Survival From an Australian Centre

The aim of the study was to determine outcomes and overall survival (OS) in patients undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) for malignant peritoneal mesothelioma (MPM). This was a retrospective cohort study from a prospectively maintained database of patients that underwent CRS/HIPEC for MPM from April 1999 to December 2021. A total of 81 patients were identified with MPM. Median OS was 53 months with a 1-, 3- and 5-year OS of 76%, 55% and 49% respectively. Multivariate analysis identified lymph node status, PCI and CC score as statistically significant prognostic factors that impact survival. Median OS for PCI 0-20 was 103 months vs. 33 months for PCI 21-39 (p=0.005). Median OS for CC0, CC1 and CC2 were 104, 30 and 2.7 months respectively (p<0.001). Hazard ratio for node-positive disease over node-negative was 2.14 (95% CI=1.07-4.31, p<0.033). Grade III/IV complication rate was 43.2% and mortality 4.9%. CRS/HIPEC remains the gold standard for treating patients with MPM with excellent patient OS. Lymph node status, PCI and CC score were independent prognostic factors that affect OS.

5-hmC loss is another useful tool in addition to BAP1 and MTAP immunostains to distinguish diffuse malignant peritoneal mesothelioma from reactive mesothelial hyperplasia in peritoneal cytology cell-blocks and biopsies.

The differentiation between reactive mesothelial hyperplasia (RMH) and diffuse malignant peritoneal mesothelioma (DMPM) is challenging especially when applied on peritoneal small samples. The use of BRCA-associated protein 1 (BAP1) and methylthioadenosine phosphorylase (MTAP) immunostains is familiar to identify malignant mesothelial proliferation. Recently, nuclear 5-hydroxymethylcytosine (5-hmC) was reported to be a new recognition tool of pleural mesothelial malignancy on surgical specimens. However, application of 5-hmC immunostaining has not yet studied in peritoneal specimens from small biopsies or cytology cell-blocks. The aim was to assess the diagnostic accuracy of this new marker combination to distinguish DMPM from RMH in biopsies and cell-blocks. Seventy-five cases were analyzed; among which, 38 were of cytological specimens including 6 RMH and 32 DMPM, and 37 tissue biopsies with 7 RMH and 30 DMPM. BAP1, MTAP, and 5-hmC immunostains were performed on all cases. RMH cases exhibited a retained staining with all immunostains. Among DMPM, BAP1 was lost in 71.8% of cytology cell-blocks and 66.7% of biopsies. MTAP was lost in 40.6% of cytology cell-blocks and 33.3% of biopsies. 5-hmC was lost in 40.6% of cytology cell-blocks and 30% of biopsies. The combination of BAP1, MTAP, and 5-hmC showed the best accuracy in differential diagnosis between RMH and DMPM (sensitivity = 0.84, specificity = 1 in cytology cell-blocks; sensitivity = 0.90, specificity = 1 in biopsy). The best diagnostic combination in peritoneal cytology effusion fluids and biopsies samples provided by BAP1, MTAP, and 5-hmC should be applied on a diagnostic step-wise algorithm by pathologists involved into the management of DMPM, because of their therapeutic implications.

Immunohistochemical Pitfalls in Malignant Peritoneal Mesothelioma: A Case Report and Review for the General Pathologist

Abstract Malignant peritoneal mesothelioma is an aggressive malignancy that often mimics carcinomatosis both clinically and histologically, making definitive diagnosis challenging for the general pathologist. Many of the common immunohistochemical stains used to narrow the differential diagnosis show a lack of specificity, requiring a panel approach to ensure correct categorization. We report a case of epithelioid malignant peritoneal mesothelioma with diffuse and strong Ber-EP4 positivity and review some of the most commonly encountered pitfalls associated with immunohistochemical staining.

Key factors for successful cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy to treat diffuse malignant peritoneal mesothelioma: results from specialized peritoneal cancer center in China

Objectives To investigate independent factors for the efficacy and safety of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of diffuse malignant peritoneal mesothelioma (DMPM). Methods The clinical database of 110 DMPM patients treated with CRS + HIPEC at our hospital was retrospectively analyzed. Independent prognostic factors were screened using univariate and multivariate analyses and the safety of the perioperative period was evaluated based on adverse events. Results Among the 110 patients with DMPM, 34 (30.9%) had a peritoneal cancer index (PCI) < 20 and 76 (69.1%) had PCI ≥20; 59 (53.6%) patients achieved completeness of cytoreduction (CC) 0/1 and 51 (46.4%) cases achieved CC 2/3. At the median follow-up of 43.3 (95%CI: 37.3–49.4) months, 48 (43.6%) patients were still alive and 62 (56.4%) patients died. The median overall survival was 32.6 months. Serious adverse events (SAEs) occurred in 41 patients (37.3%) and the perioperative mortality rate was 2.7%. Univariate analysis identified nine prognostic factors: Karnofsky performance status score, perioperative tumor markers, PCI, red blood cell infusion, pathological type, vascular tumor emboli, lymphatic metastasis, Ki-67 index, and perioperative SAEs (all p < 0.05). Multivariate analysis identified four independent prognostic factors: pathological type (p = 0.007), vascular tumor emboli (p = 0.044), Ki-67 index (p = 0.044), and SAEs (p = 0.004). Conclusions CRS + HIPEC for DMPM treatment resulted in prolonged survival with acceptable safety. Tumor pathology and SAEs are key factors for successful CRS + HIPEC.

Primary malignant peritoneal mesothelioma mimicking tuberculous peritonitis: A case report

BACKGROUNDMalignant peritoneal mesothelioma (MPM) is a rare malignancy arising in mesothelial cells in the peritoneum. It can be mistaken for many other diseases, such as peritoneal carcinomatosis and tuberculous peritonitis (TBP), because its clinical manifestations are often nonspecific. Therefore, the diagnosis of MPM is often challenging and delayed.CASE SUMMARYA 42-year-old man was referred to our hospital with lower abdominal pain for 1 wk and ascites observed under abdominal sonography. His laboratory findings revealed an isolated elevated tumor marker of carcinoma antigen 125 (167.4 U/mL; normal, < 35 U/mL), and contrast enhanced computed tomography showed peritoneal thickening. Thus, differential diagnoses of TBP, carcinomatosis of an unknown nature, and primary peritoneal malignancy were considered. After both esophagogastroduodenoscopy and colonoscopy produced negative findings, laparoscopic intervention was performed. The histopathological results revealed mesothelioma invasion into soft tissue composed of a papillary, tubular, single-cell arrangement of epithelioid cells. In addition, immunohistochemical staining was positive for mesothelioma markers and negative for adenocarcinoma markers. Based on the above findings, TBP was excluded, and the patient was diagnosed with MPM.CONCLUSIONIt is important to distinguish MPM from TBP because they have similar symptoms and blood test findings.

Treatment of Patients with Malignant Peritoneal Mesothelioma.

Malignant peritoneal mesothelioma is a rare malignancy arising from the serosa of the peritoneal cavity. It is diagnosed based on suspicious findings on cross sectional imaging and a tissue biopsy showing confirmatory histologic and immunohistochemical features. The disease is hallmarked by its propensity to progress mainly in the peritoneal cavity. In selected patients, surgical cytoreduction and hyperthermic intra-operative peritoneal chemotherapy has become the initial preferred treatment and is associated with provide prolonged in many patients. Systemic chemotherapy using a couplet of cisplatin or gemcitabine with pemetrexed has modest response rates and duration of response. Expression of PD-L1 has been demonstrated in peritoneal mesothelioma tumors and there has been significant interest in the use of check point blockade targeted against PD-L1 in this clinical setting. Future clinical research using a combination of check point blockade with surgical cytoreduction is a high clinical priority.

MiR-550a-3p is a prognostic biomarker and exerts tumor-suppressive functions by targeting HSP90AA1 in diffuse malignant peritoneal mesothelioma

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and rapidly lethal tumor, poorly responsive to conventional treatments. In this regards, the identification of molecular alterations underlying DMPM onset and progression might be exploited to develop novel therapeutic strategies. Here, we focused on miR-550a-3p, which we found downregulated in 45 DMPM clinical samples compared to normal tissues and whose expression levels were associated with patient outcome. Through a gain-of-function approach using miRNA mimics in 3 DMPM cell lines, we demonstrated the tumor-suppressive role of miR-550a-3p. Specifically, miRNA ectopic expression impaired cell proliferation and invasiveness, enhanced the apoptotic response, and reduced the growth of DMPM xenografts in mice. Antiproliferative and proapoptotic effects were also observed in prostate and ovarian cancer cell lines following miR-550a-3p ectopic expression. miR-550a-3p effects were mediated, at least in part, by the direct inhibition of HSP90AA1 and the consequent downregulation of its target proteins, the levels of which were rescued upon disruption of miRNA-HSP90AA1 mRNA pairing, partially abrogating miR-550a-3p-induced cellular effects. Our results show that miR-550a-3p reconstitution affects several tumor traits, thus suggesting this approach as a potential novel therapeutic strategy for DMPM.

The role of imaging in diagnosis and management of malignant peritoneal mesothelioma: a systematic review.

Imaging of the peritoneum and related pathology is a challenge. Among peritoneal diseases, malignant peritoneal mesothelioma (MPeM) is an uncommon tumor with poor prognosis. To date, there are no specific guidelines or imaging protocols dedicated for the peritoneum and MPeM. The objective of this study was to analyze the literature describing imaging modalities used for MPeM to determine their relative clinical efficacy and review commonly reported imaging features of MPeM to promote standardized reporting. We performed a systematic review of original research articles discussing imaging modalities in MPeM from 1999 to 2020. Effectiveness measures and common findings were compared across imaging modalities. Among 582 studies analyzed, the most-used imaging modality was CT (54.3%). In the differentiation of MPeM from peritoneal carcinomatosis, one study found CT had a diagnostic sensitivity of 53%, specificity of 100%, and accuracy of 68%. Two studies found fluorodeoxyglucose positron emission tomography (FDG-PET) had sensitivity of 86-92%, specificity of 83-89%, and accuracy of 87-89%. Another study found magnetic resonance imaging (MRI) was the best predictor of the peritoneal carcinomatosis index. Characteristics shown to best differentiate MPeM from other diseases included ascites, peritoneal thickening, mesenteric thickening, pleural plaques, maximum tumor dimension, and number of masses. Most published MPeM imaging studies utilized CT. PET/CT or MRI appear promising, and future studies should compare effectiveness of these modalities. MPeM imaging reports should highlight ascites, number of and maximum tumor dimension, peritoneal/mesenteric thickening, and associated pleural plaques, allowing for better aggregation of MPeM imaging data across studies.

Incidence, treatment and survival of malignant pleural and peritoneal mesothelioma: a population-based study

IntroductionMalignant mesothelioma (MM) is an aggressive cancer that primarily arises from the pleura (MPM) or peritoneum (MPeM), mostly due to asbestos exposure. This study reviewed the Dutch population-based incidence, treatment...

Impact of Centralization of Care for Malignant Peritoneal Mesothelioma: A historical cohort study from two Dutch expert centers

Background: Malignant peritoneal mesothelioma (MPM) is a rare and aggressive cancer that has a poor prognosis. Currently, available treatments are cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), and systemic chemotherapy. However, an earlier population based study showed that in the Netherlands the majority of patients does not receive anti-cancer treatment. In 2015, Dutch Malignant Mesothelioma care was centralized in to two expert centers. Moreover, initiation of a phase-2 clinical trial in 2018 caused a boost in patients being referred.

Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) for diffuse malignant peritoneal mesothelioma is associated with promising oncological outcomes

Background: Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a novel intraperitoneal drug delivery method, implemented for peritoneal metastasis (PM) of various origins, particularly in the absence of disease control with systemic chemotherapy. Diffuse malignant peritoneal mesothelioma (DMPM) is associated with high survival rates if cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is feasible but has ominous prognosis if the disease is unresectable. We aimed to analyse oncological outcomes after PIPAC for DMPM.

Management of Patients with Malignant Peritoneal Mesothelioma: The Evolving Role of Surgery and Immunotherapy

Malignant peritoneal mesothelioma, a neoplastic process that arises from the peritoneal membranes and presents as a diffuse malignant process, has an incidence of approximately 400-600 new cases annually in the United States. Systemic chemotherapy regimens, like the combination of cisplatin and pemetrexed, have response rates of approximately 25% in peritoneal mesothelioma. Due to chemotherapy’s poor response rates, the first line approach to treating malignant peritoneal mesothelioma over the last 30 years has been surgical resection with regional intra-peritoneal chemotherapy in appropriately selected patients. Hyperthermic intraoperative intraperitoneal perfusion with chemotherapy with cisplatin or mitomycin c for 90 to 120 minutes is the most commonly reported type of regional chemotherapy that is administered during surgical cytoreduction. Favorable prognostic factors for patient outcomes after cytoreduction and hyperthermic intraperitoneal perfusion with chemotherapy tend to be favorable operative characteristics (lower peritoneal cancer index, better complete cytoreduction score), less aggressive tumor characteristics (epithelioid histology, low Ki-67, well-differentiated), and other patient characteristics (young, female, fewer comorbidities). Recently, there has been considerable interest in the utility of immune checkpoint inhibitors either alone or in combination with chemotherapy for patients with mesothelioma. Data demonstrate that programmed death-ligand 1 may be highly expressed in a large proportion of malignant peritoneal mesothelioma tumors and therefore the evaluation of checkpoint blockade in this patient population is a high clinical priority.

Solid papillary mesothelial tumor

We report nine examples of a previously undescribed type of peritoneal circumscribed nodular mesothelial tumor characterized by nests or sheets of mesothelial cells with sharp cell borders and extremely bland, sometimes grooved, nuclei. In some cases, nests were separated by fibrous bands. All patients were women, age range 30–72 years (median 52 years). All tumors were incidental findings during surgery and grossly were either solitary nodules or a few small nodules on the peritoneal surface. Referring pathologic diagnoses included diffuse malignant mesothelioma, localized malignant mesothelioma, well-differentiated papillary mesothelioma, and adenomatoid tumor. No tumor showed BAP1 loss by immunohistochemistry nor deletion of CDKN2A by FISH. RNA-seq revealed that these tumors clustered together and were distinct from peritoneal diffuse malignant mesotheliomas. Very few mutations or translocations were found, none of them recurrent from tumor to tumor, and no tumor showed an abnormality in any of the genes typically mutated/deleted in diffuse malignant mesothelioma. Array CGH on three cases revealed two with a completely flat profile and one with a small deletion at 3q26–3q28. On follow-up (range 5–60, median 34 months), there were no deaths, no recurrences, and no evidence of metastatic disease nor local spread; one case that initially had scattered nodules on the pelvic peritoneum had the same pattern of nodules at a second look operation 2 years later. We propose the name solid papillary mesothelial tumor for these lesions. These appear to be either benign or very low-grade tumors that need to be separated from malignant mesotheliomas.

A rare presentation of malignant peritoneal mesothelioma in a 22-year-old man

A rare presentation of malignant peritoneal mesothelioma in a 22-year-old man

Hepatic bridge and round ligament of the liver during cytoreductive surgery: a retrospective cohort.

The hepatic bridge as an anatomical variation may lead to recurrence and treatment failure in cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) by constituting an obscure region during surgery. This report aimed to highlight the relationship between the hepatic bridge and various prognostic factors in peritoneal carcinomatosis. Data of 101 patients who underwent CRS/HIPEC for peritoneal carcinomatosis in a single centre were retrospectively reviewed. Demographic characteristics, primary origin of peritoneal carcinomatosis, classification of hepatic bridge, Peritoneal Cancer Index (PCI) score, and completeness of cytoreduction (CC) score were analysed. The tumour was proven histopathologically in 18 (28.6%) of 63 patients who underwent distal round ligament (DRL) resection. The PCI score was found to be significantly higher in patients with tumour in DRL compared to the ones without tumour (p < 0.001). The median PCI score of patients with implant positive DRL was 18 (12-20) and this score was 3 (2-6) for patients with implant negative DRL (p < 0.001). The ROC curve concerning the risk of an implant penetrating the round ligament revealed the optimal cut-off value of PCI at 10 with 88.9% sensitivity and 79.3% specificity. The round ligament should be removed, regardless of the PCI score, as a standard in mucinous adenocarcinoma of the appendix and malignant peritoneal mesothelioma. DRL should be removed when PCI is equal or higher than 10 for PC due to colorectal and ovarian cancers.

ASO Visual Abstract: Non-resectable Malignant Peritoneal Mesothelioma Treated with Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Plus Systemic Chemotherapy Could Lead to Secondary Complete Cytoreductive Surgery: A Cohort Study

ASO Visual Abstract: Non-resectable Malignant Peritoneal Mesothelioma Treated with Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Plus Systemic Chemotherapy Could Lead to Secondary Complete Cytoreductive Surgery: A Cohort Study

Treatment of Platinum Nonresponsive Metastatic Malignant Peritoneal Mesothelioma With Combination Chemoimmunotherapy.

Malignant peritoneal mesothelioma is a rare cancer associated with minimal durable disease control with chemotherapy and poor overall survival. The efficacy of combined cytotoxic chemotherapy and immune checkpoint inhibitors (ICIs) in malignant peritoneal mesothelioma has not previously been studied. We describe the clinical course of 2 patients with metastatic peritoneal mesothelioma who both relapsed with platinum nonresponsive disease after initial cytoreductive surgery and chemotherapy. In both cases, addition of pembrolizumab to platinum and pemetrexed treatment resulted in a substantial partial and a near complete disease response. Notably, both patients possessed tumors without validated biomarkers of ICI response, including low tumor mutational burden and negative programmed death ligand-1. The unique genomic landscape of each patient may have enabled increased tumor immunorecognition and ICI efficacy. In addition, chemotherapy priming of the tumor microenvironment may have improved ICI response. This report supports future research to characterize the benefit of combination chemotherapy and ICI in peritoneal mesothelioma.

In This Issue

In This Issue

New Immunotherapy Combinations Enter the Battlefield of Malignant Mesothelioma.

Chimeric antigen receptor (CAR) T cells targeting mesothelin plus pembrolizumab, and atezolizumab plus bevacizumab, have recently shown clinical efficacy in phase I trials in malignant pleural and peritoneal mesothelioma. Despite being tested in a highly selected patient population and requiring a complex engineering that can hardly be upscaled, CAR T cells combined with pembrolizumab bring the first proof of efficacy in cold solid tumors with low genomic heterogeneity, while atezolizumab-bevacizumab offers an easy-to-use combination of antiangiogenics and immunotherapy in an orphan disease.See related article by Raghav et al., p. 2738.See related article by Adusumilli et al., p. 2748.

Non-resectable Malignant Peritoneal Mesothelioma Treated with Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Plus Systemic Chemotherapy Could Lead to Secondary Complete Cytoreductive Surgery: A Cohort Study.

Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive primary peritoneal neoplasia. At diagnosis, few patients are eligible for a recommended cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Among neoadjuvant strategies, pressurized intraperitoneal aerosol chemotherapy (PIPAC) combined with systemic chemotherapy has been recently proposed. This study evaluated this strategy in a cohort of DMPM patients. Patients with DMPM and primary or recurrent non-resectable diseases who received at least one PIPAC procedure in alternation with systemic chemotherapy were included in this retrospective study to analyze oncologic outcomes. Overall, 26 DMPM patients were treated with at least one PIPAC, including 20 patients with no previous CRS. Of 22 patients (85%) who had symptoms, 9 had perceptible ascites. Overall, 79 PIPAC procedures were performed, with half of the patients receiving three PIPAC procedures or more. Among eight patients (31%), 10 adverse events (13% of procedures) were reported, including two severe complications, both corresponding to digestive perforations. Improvement of symptoms was reported for 32% of the patients, whereas control of ascites was noted in 46%. All but one procedure among 14 patients (54%) secondarily treated by CRS-HIPEC were considered complete resections. After a median follow-up period of 29.6 months (95% confidence interval [CI], 17.6-not reached [NR]), the median overall survival period was 12 months (95% CI 11.1-NR). The median progression-free survival (PFS) was significantly better among the patients who underwent resection than among those who did not (33.5 vs 7.4 months; hazard ratio [HR], 0.18; 95% CI 0.06-0.755; p < 0.001). For patients with initially non-resectable DMPM, PIPAC is feasible for treatment with neoadjuvant intent and could facilitate complete secondary resection.