Current Management and Future Opportunities for Peritoneal Metastases: Peritoneal Mesothelioma

Purpose

Diffuse malignant peritoneal mesothelioma (MPM) is a rare and ultimately fatal cancer that was first described just over a century ago. It is a diffuse malignancy arising from the mesothelial lining of the peritoneum; morbidity and mortality from MPM is due to its propensity to progress locoregionally within the abdominal cavity.

Methods

The purpose of this article is to review the current state-of-the-science related to the diagnosis, staging, and treatment of MPM.

Results

The condition afflicts men and women equally and the peak incidence is between 55 and 60 years of age although it can arise in the young and elderly. Patients afflicted with MPM most commonly present with nonspecific abdominal symptoms that usually lead to diagnosis when the condition is relatively advanced. Historically, median overall survival for MPM patients without treatment is < 1 year. The couplet of systemic pemetrexed and cisplatin has an overall response rate of approximately 25% and a median overall survival of approximately 1 year.

Conclusion

The available data, almost all retrospective in nature, have shown that in selected patients, operative cytoreduction (CRS) and regional chemotherapy administered as hyperthermic intraoperative peritoneal chemotherapy (HIPEC) or early postoperative intraperitoneal chemotherapy (EPIC) is associated with long-term survival. Studies on the molecular biology of MPM have yielded new insights relating to the potentially important role of the phosphoinsitide-3-kinase/mammalian target of rapamycin (PI3 K/mTOR) pathways and immune checkpoint inhibitors that may translate into new therapeutic options for patients with diffuse MPM.

     

Malignant Peritoneal Mesothelioma: a Case Report

In this paper we report a case of malignant peritoneal mesothelioma, a rare abdominal tumour. A 72-year-old male with a medical history of heart disease presented to our Clinic because of pain in the right half of the abdomen. Diagnostic procedures, including clinical and laboratory examination, X-ray, ultrasonography and computed tomography, revealed a tumour in the right lower quadrant of the abdomen. The approximate size of the tumour size at initial detection was 7 cm. During the pre-operative procedure an evident growth of the tumour was noticed, indicating exploratory laparotomy. Intra-operative findings revealed a large tumour of the anterolateral abdominal wall, involving the greater omentum. Tumour resection was performed, as well as resection of the portion of the anterolateral abdominal wall and omentectomy. Postoperative immunohistochemical analysis revealed malignant peritoneal mesothelioma.     

Lymph Node Metastases in Diffuse Malignant Peritoneal Mesothelioma

Background  

Improved survival has been reported for diffuse malignant peritoneal mesothelioma (DMPM) treated by surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). The significance of lymph node involvement in this disease is still poorly understood.     

Surgical Management of Malignant Mesothelioma

The surgical management of 18 patients diagnosed as having malignant mesothelioma is reviewed. Of these patients, 7 received limited treatment—pleurectomy or biopsy. The mean survival was 10 months, and no patient was disease-free at time of death. The other 11 patients were treated by radical extrapleural pneumonectomy. There were 2 long-term, disease-free survivors at 2 and 4 years. Mean survival for the entire group was 15 months, but most patients received good palliation following tumor removal.Surgical procedures for removal of malignant mesothelioma can be accomplished safely and without major morbidity. When possible, radical extrapleural pneumonectomy affords the best palliation and the only opportunity for cure.     

我国165例腹膜恶性间皮瘤临床特点

目的：总结我国腹膜恶性间皮瘤的临床表现及诊治方法。方法：以腹膜恶性间皮瘤为检索词,分别对中国期刊网全文数据库、维普资讯网中文科技期刊数据库在2000—2010年期间发表的中文临床报道进行检索。结果：共检出腹膜恶性间皮瘤165例,男性多于女性。临床症状以腹痛、腹胀为最常见,出现率约为77.8%及63.9%。腹水是最常见的体征,出现率约为96%。剖腹及腹腔镜下探查是确诊的最常见手段。腹膜恶性间皮瘤预后较差,综合治疗后中位生存期约1.5年。结论：腹膜恶性间皮瘤是临床罕见病,误诊率高,应充分认识其特点,提高早期诊治腹膜恶性间皮瘤的水平。积极的综合治疗可以延长病人的生存期。     

Malignant Peritoneal Mesothelioma: Prognostic Factors and Oncologic Outcome Analysis

Background

Most patients with malignant peritoneal mesothelioma (MPM) present with late-stage, unresectable disease that responds poorly to systemic chemotherapy while, at the same time, effective targeted therapies are lacking. We assessed the efficacy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) in MPM.

Methods

We prospectively analyzed 65 patients with MPM undergoing CRS/HIPEC between 2001 and 2010. Kaplan–Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting oncologic outcomes.

Results

Adequate CRS was achieved in 56 patients (CC-0 = 35; CC-1 = 21), and median simplified peritoneal cancer index (SPCI) was 12. Pathologic assessment revealed predominantly epithelioid histology (81 %) and biphasic histology (8 %), while lymph node involvement was uncommon (8 %). Major postoperative morbidity (grade III/IV) occurred in 23 patients (35 %), and 60-day mortality rate was 6 %. With median follow-up of 37 months, median overall survival was 46.2 months, with 1-, 2-, and 5-year overall survival probability of 77, 57, and 39 %, respectively. Median progression-free survival was 13.9 months, with 1-, 2-, and 5-year disease failure probability of 47, 68, and 83 %, respectively. In a multivariate Cox-regression model, age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), aggressive histology (epithelioid, biphasic), and postoperative sepsis were joint significant predictors of poor survival (chi square = 42.8; p = 0.00001), while age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), and aggressive histology (epithelioid, biphasic) were joint significant predictors of disease progression (Chi square = 30.6; p = 0.00001).

Conclusions

Tumor histology, disease burden, and the ability to achieve adequate surgical cytoreduction are essential prognostic factors in MPM patients undergoing CRS/HIPEC.     

Laparoscopy and Primary Diffuse Malignant Peritoneal Mesothelioma: a Diagnostic Challenge

Primary diffuse malignant peritoneal mesothelioma is a rare malignancy with an estimated incidence of 200 to 400 new cases annually in the USA. We describe a case of diffuse malignant peritoneal mesothelioma arising in a 65-year old man who presented ascites of unknown origin. The importance of laparoscopy with subsequent histology of biopsy specimens in the diagnosis of this disease is emphasized. Because of his poor general condition, the patient had no further treatment. Update of treatment is briefly described with particular attention to multimodality approach.     

Quantitative X-ray Computed Tomography Peritoneography in Malignant Peritoneal Mesothelioma Patients Receiving Intraperitoneal Chemotherapy

Background

Intraperitoneal chemotherapy is used to treat peritoneal surface-spreading malignancies. We sought to determine whether volume and surface area of the intraperitoneal chemotherapy compartments are associated with overall survival and posttreatment glomerular filtration rate (GFR) in malignant peritoneal mesothelioma (MPM) patients.

Methods

Thirty-eight MPM patients underwent X-ray computed tomography peritoneograms during outpatient intraperitoneal chemotherapy. We calculated volume and surface area of contrast-filled compartments by semiautomated computer algorithm. We tested whether these were associated with overall survival and posttreatment GFR.

Results

Decreased likelihood of mortality was associated with larger surface areas (p = 0.0201) and smaller contrast-filled compartment volumes (p = 0.0341), controlling for age, sex, histologic subtype, and presence of residual disease >0.5 cm postoperatively. Larger volumes were associated with higher posttreatment GFR, controlling for pretreatment GFR, body surface area, surface area, and the interaction between body surface area and volume (p = 0.0167).

Discussion

Computed tomography peritoneography is an appropriate modality to assess for maldistribution of intraperitoneal chemotherapy. In addition to identifying catheter failure and frank loculation, quantitative analysis of the contrast-filled compartment’s surface area and volume may predict overall survival and cisplatin-induced nephrotoxicity. Prospective studies should be undertaken to confirm and extend these findings to other diseases, including advanced ovarian carcinoma.

     

Parasternal Lymph Node Metastasis of Malignant Peritoneal Mesothelioma: Report of a Case

We report a case of malignant peritoneal mesothelioma with parasternal lymph node metastasis. The patient was a 34-year-old man who presented with a history of several years of abdominal pain and ascites of unknown origin. Exploratory laparoscopic biopsies yielded histological findings of malignancy, but a final diagnosis was not able to be made. A chest computed tomographic scan done the following year showed a parasternal nodule, and thoracoscopically obtained biopsied material was positive for calretinin. These findings led to a pathological diagnosis of metastasis to the parasternal lymph node from peritoneal mesothelioma.     

Primary Malignant Peritoneal Mesothelioma in an Incarcerated Groin Hernia: Report of a Case

Malignant peritoneal mesothelioma arising from the inguinal hernia sac is rare. We report the case of a 71-year-old man examined in our emergency department for a bilateral inguinoscrotal hernia, which was recurrent in the right groin, and primary and incarcerated in the left groin. An emergency exploratory operation revealed a firm mass, 10cm in diameter, in the left inguinal hernia sac. The remaining peritoneal surface appeared macroscopically normal. Therefore, we resected the mass and performed a Rutkow hernioplasty. The patient was discharged after a short, uneventful recovery, and was referred to the oncology department for adjuvant therapy. He is now well and asymptomatic with no evidence of ascites, 26 months after his operation. A mesothelioma of the hernial sac peritoneum was the final histological diagnosis.     

Benign Peritoneal Cystic Mesothelioma

Background Benign peritoneal cystic mesothelioma (BPCM) is a rare tumor of unknown origin, most frequently encountered in women of reproductive age. Etiology is unknown; definitions and terminology are confusing, and preoperative diagnosis is difficult. Several differential diagnoses must be considered. Methods Based on our own clinical experience and a review of the relevant literature, we address clinical challenges and controversies of importance. Results Current literature on BPCM is mostly based on small case reports. Complete surgical resection is recommended if possible. Nevertheless, recurrent disease is not uncommon. Clinical positive effects of various adjuvant medical treatments remain to be shown. Conclusions Lack of consistent definitions, various treatment approaches, and mostly short follow-up times make it difficult to draw any firm conclusions from published reports. The natural history of this rare disease is less than well clarified. When possible, in an individual patient, surgical resection with curative intent seems to be the treatment of choice.     

Treatment of Malignant Mesothelioma

Malignant pleural mesothelioma (MPM) is a rare tumor that predominantly afflicts men over 50 years of age. Nearly 3000 MPMs are reported annually in the United States with the incidence expected to rise into the new millenium. Over the past 40 years, MPM has been unequivocally linked to asbestos exposure worldwide. Recently, however, a new theory on the carcinogenesis of this tumor has been proposed with the isolation of a simian virus (SV 40)-like gene sequence in mesothelioma tumor cells. The clinical presentation of MPM is variable, although most patients typically present with dyspnea, chest pain, or pleural effusion. Obtaining a diagnosis of MPM has been greatly assisted by video-assisted surgery and the use of immunohistochemistry and electron microscopic techniques, which help distinguish MPM from other tumor pathologies such as adenocarcinoma. Computed tomography and magnetic resonance imaging have been also useful for determining tumor burden and resectability. Traditionally, strategies for the treatment of MPM have included supportive care, surgery, radiotherapy, and chemotherapy. Survival with supportive care alone ranges between 4 and 12 months. Single-modality therapy using traditional approaches (surgery, radiotherapy, chemotherapy) alone has failed to improve patient survival significantly. Recently, results using a multimodality approach have been favorable. In particular, cytoreductive surgery (pleuropneumonectomy) followed by sequential chemotherapy and radiotherapy have demonstrated improved survival, especially for patients with epithelial histology, negative resection margins, and no metastases to extrapleural lymph nodes. Innovative therapies such as the use of photodynamic, targeted cytokines and gene therapy are currently being investigated for management of MPM.     

Peritoneal Biphasic Mesothelioma in a Dog

A 10‐year‐old German shepherd dog was presented with a severe abdominal distension. At necropsy, whitish and firm mass was observed in the mesentery with metastases in the pericardium and pleura. The intestinal serosa was thickened and stiff. Histologically, the tumours were composed of a biphasic population of cells, which reacted with cytokeratin, vimentin and Wilms’ tumour 1 protein antibody. Ultrastructural examination revealed numerous microvilli, abundant rough endoplasmic reticulum, numerous desmosomes and bundles of microfilament. The tumour was classified as biphasic mesothelioma of peritoneal origin.     

Oncolytic Vaccinia Virus as an Adjuvant Treatment to Cytoreductive Surgery for Malignant Peritoneal Mesothelioma

Background

Malignant peritoneal mesothelioma (MPM) is an aggressive cancer with a dismal prognosis. Oncolytic viruses are a promising new therapy for cancer because of their ability to kill tumor cells with minimal toxicity to normal tissues. This experimental study aimed to examine the potential of modified vaccinia virus (VV) to treat MPM when administered alone or as an adjuvant treatment to surgery.

Methods

Two aggressive murine mesothelioma cell lines (AC29, AB12), were used. Cell viability and viral cytopathic effects were assessed using MTS and crystal violet assays. Immunocompetent mice were injected intraperitoneally with MPM cells and treated with intraperitoneal VV. Tumor-bearing mice also underwent cytoreductive surgery (CRS) followed by VV (or control) therapy.

Results

The cytotoxic effects of VV on MPM cell lines was significantly increased compared with the control non-cancer cell line. In both orthotopic models, VV induced tumor regression, prolonging median and long-term survival. VV treatment after incomplete CRS was not superior to VV alone; however, when mice with microscopic disease were treated with VV, further prolongation of median and long-term survivals was observed.

Conclusions

VV selectively kills MPM cells in vitro and leads to improved survival and cures in immunocompetent murine models. Higher efficacy of the virus in the microscopic disease context suggests the use of the virus as an adjuvant treatment to complete surgical resection. These promising results justify further studies of VV in humans as a novel treatment for MPM.