Peritoneal mesothelioma is a rare malignancy where life expectancy with systemic chemotherapy remains poor. Most patients with this disease are diagnosed late with extensive peritoneal disease burden leading to nausea, pain, and abdominal distention as a result of ascites and a partial bowel obstruction. A newly proposed staging system comprising elements of the tumor burden measured by the peritoneal cancer index, abdominal nodal status, and extra-abdominal metastases has been demonstrated to reliably stratify patient outcomes based on staging subgroups after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. This new staging system may form the basis of selecting patients for radical surgery and improve survival outcomes.
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Peritoneal mesothelioma remains a rare primary disease of the peritoneum where survival advantage may be achieved through cytoreductive surgery and hyperthermic intraperitoneal chemotherapy over systemic treatment alone.
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Recognition of the histopathologic subtype of a malignant peritoneal mesothelioma is essential in treatment planning.
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Future diagnostic and treatment outcomes should be mapped and staged against the new staging criteria for future validation.
Introduction
Peritoneal mesothelioma is a rare and fatal cancer. Studies indicate an incidence that is demonstrating a rising trend and a global 15-year cumulative mortality rate of 213,200 cases. Malignant mesothelioma affects the pleura, peritoneum, pericardium, and tunica vaginalis with each site-specific cancer surprisingly showing some epidemiologic differences. Disease affecting the pleura accounts for 70% and peritoneum accounts for 30% of all mesothelioma. Instead of the male predominance and approximate mean age of mortality at 70 years seen in the other types of mesothelioma, peritoneal mesothelioma is more commonly seen in females and occurs earlier in life with a younger mean age at mortality of 66 years. This disease is mostly seen in higher income countries because of the historical use of asbestos and the availability of expertise and technology that allow identification of this disease. This article focuses on peritoneal mesothelioma and describes the current knowledge and recent clinical research findings in this disease entity.
Pathophysiology
Asbestos is recognized as an etiologic factor in the formation of mesothelioma. Risk increases throughout life after asbestos exposure despite removal of the offending agent. The evolution of mesothelial cells into cancer has been widely studied and several hypotheses have been put forward. It is theorized that the asbestos is inhaled, expectorated, and subsequently swallowed. Its favorable physical characteristics allow the mineral to penetrate the bowel lumen and enter into the lymphatics and splanchnic circulation. The foreign body reaction triggered by asbestos fibers results in a series of host inflammatory response. In a study of immortalized human pleural mesothelial cells, ferritin heavy chain present within asbestos leads to production of reactive oxygen species and reactive nitrogen species. The phagocytotic process by alveolar macrophages also results in the production of these proinflammatory cytokines. Overall, these processes lead to disruption of the genetic makeup of the mesothelial cells. Direct disruption of the normal mitotic activity by asbestos fibers has also been recognized to cause aneuploidy and other abnormal chromosomal arrangements. This carcinogenic process occurs with incessant activation of kinases and early expression of the proto-oncogene (FOS or JUN or activated protein 1 family members) in mesothelial cells that confers the neoplastic mesothelial cell a persistent proliferating capacity. Results from clinical studies have indicated that patients with malignant mesothelioma are observed to have higher levels of interleukin-10, a cytokine that drives further production of transforming growth factor-β. Interleukin-10 and transforming growth factor-β are postulated to play a role in asbestos-related carcinogenesis. In some cases, whereby there is an absence of asbestos exposure, the role of other etiologic agents, such as the simian vacuolating virus (SV 40), has been implicated to contribute to the formation of the malignancy but the role of this oncogenic virus remains a postulate because there are conflicting studies that seem to suggest otherwise.
Pathophysiology
Asbestos is recognized as an etiologic factor in the formation of mesothelioma. Risk increases throughout life after asbestos exposure despite removal of the offending agent. The evolution of mesothelial cells into cancer has been widely studied and several hypotheses have been put forward. It is theorized that the asbestos is inhaled, expectorated, and subsequently swallowed. Its favorable physical characteristics allow the mineral to penetrate the bowel lumen and enter into the lymphatics and splanchnic circulation. The foreign body reaction triggered by asbestos fibers results in a series of host inflammatory response. In a study of immortalized human pleural mesothelial cells, ferritin heavy chain present within asbestos leads to production of reactive oxygen species and reactive nitrogen species. The phagocytotic process by alveolar macrophages also results in the production of these proinflammatory cytokines. Overall, these processes lead to disruption of the genetic makeup of the mesothelial cells. Direct disruption of the normal mitotic activity by asbestos fibers has also been recognized to cause aneuploidy and other abnormal chromosomal arrangements. This carcinogenic process occurs with incessant activation of kinases and early expression of the proto-oncogene (FOS or JUN or activated protein 1 family members) in mesothelial cells that confers the neoplastic mesothelial cell a persistent proliferating capacity. Results from clinical studies have indicated that patients with malignant mesothelioma are observed to have higher levels of interleukin-10, a cytokine that drives further production of transforming growth factor-β. Interleukin-10 and transforming growth factor-β are postulated to play a role in asbestos-related carcinogenesis. In some cases, whereby there is an absence of asbestos exposure, the role of other etiologic agents, such as the simian vacuolating virus (SV 40), has been implicated to contribute to the formation of the malignancy but the role of this oncogenic virus remains a postulate because there are conflicting studies that seem to suggest otherwise.
Clinical presentation and examination
Patients typically present with an account of prolonged symptoms including complaints of abdominal pain (33%), increase in abdominal girth (31%), or both (10%). Other findings also include new onset of hernia, weight loss, dyspnea, fever, or night sweats and further history may reveal the absence of menstruation or complaints of infertility. Attempts to classify the presenting complaints into three groups, namely classical (73%), surgical (16%), and medical (11%), are described in Table 1 . Although it is useful to have a clinical structure in approaching this malignancy, it may not be applicable at all times because some cases may not necessarily have the entire constellation of symptoms or fit into any of the three groups. At times, rarer instances of peritoneal mesothelioma may present with the development of subcutaneous swelling, oral gingivitis, or paraneoplastic syndrome.
| Classical | Medical | Surgical |
|---|---|---|
| Abdominal pain Ascites Abdominal mass | Abdominal pain Weight loss Fever Diarrhea Vomiting Asthenia Anorexia | Hernia Ileus Abdominal perforation |
Diagnostic investigations
The entire diagnostic work-up to arrive at a confirmatory diagnosis of peritoneal mesothelioma is lengthy and involves a series of serologic, imaging, and histopathologic tests. This is comprised of common blood tests including full blood count; erythrocyte sedimentation rate; C-reactive protein; and tumor markers (CEA, CA199, CA125, and mesothelin). Tumor markers CA-125 and mesothelin are known to be elevated in peritoneal mesothelioma but are not entirely specific because these proteins are also observed to be elevated in other malignancies, such as ovarian cancer, and infective processes, such as tuberculosis. CA-125 has a sensitivity of 53.3% and is more useful in supporting a diagnosis and for disease monitoring during the follow-up period. Mesothelin, which is detected in pleural and peritoneal effusions, may be a valuable diagnostic marker because its serum level is shown to progressively increase in patients with a history of asbestos exposure who were later diagnosed with the mesothelioma. Creaney and colleagues adopted a logistic regression model combining the two index markers, CA-125 and mesothelin, and examined its sensitivity for detecting mesothelioma but found that using both biomarkers did not improve the sensitivity of mesothelioma diagnosis over a single biomarker alone. Other tumor markers, including CA 15.3, have been reported to have a baseline diagnostic sensitivity of 48.5%, whereas CEA and CA 19.9 have not been found to be helpful. Recent studies have discovered a redox-active protein known as the “serum thioredoxin-1” and tenascin-X in effusions, which may act as diagnostic markers; however, this remains experimental and further research is required. Hence, tumor markers have only a supportive role in arriving at the diagnosis and do not have sufficient sensitivity and specificity that is required of a diagnostic tool.
CT scan may detect overt peritoneal lesions by demonstrating well-defined masses, omental thickening, and modularity present within the mesentery. Yan and colleagues examined the CT scans of a series of 33 patients with peritoneal mesothelioma and described the presence of pleural abnormalities in 8 (24%) of 33 patients, 91% of patients having involvement of the greater omentum, 97% of patients having vesico, rectal, or uterine pouches, and 66% of patients having ascites. This predominant central abdominal and pelvic disease burden observed may seem to be a characteristic pattern in the presentation of this disease. Park and colleagues used the terminology of “dry” and “wet” as descriptors of the CT features of peritoneal mesothelioma, with the dry appearance consisting of peritoneal-based lesions and the wet appearance consisting of ascites, irregular or nodular thickening of the peritoneum, and an omental mass that may scallop or directly invade adjacent abdominal viscera. After these imaging findings, it is important to exclude the presence of any intestinal primaries as cause of these peritoneal lesions. Commonly, an esophagogastroduodenoscopy and colonoscopy are required. After this, the diagnosis of peritoneal lesions arising from mesothelioma and not an intestinal primary is confirmed through a histologic assessment of biopsies obtained during laparoscopy. Macroscopically, peritoneal mesothelioma appear as multiple whitish nodules that may coalesce to form plaques or masses or layers out evenly to cover the peritoneal surface partially or completely. The diagnostic laparoscopy procedure could also provide an opportunity to evaluate the peritoneal disease burden and assess the potential for cytoreduction. Laterza and colleagues reported 33 patients with peritoneal mesothelioma who underwent diagnostic laparoscopy and judged 30 patients to be amendable to complete cytoreduction, for which 29 patients eventually underwent cytoreduction with complete cytoreduction attained.
Histopathologic examination of pathologic specimens for the diagnosis of mesothelioma requires hematoxylin and eosin stain, which typically reveals an epithelioid type (79%) or sarcomatoid and biphasic type (12%). Epithelioid mesothelioma has a prominent papilla-tubular structure and this must be differentiated from an adenocarcinoma of other origins. Sarcomatoid mesothelioma depicts proliferation of spindle cells and must be differentiated from sarcoma of the abdominal wall or retroperitoneum. Biphasic mesothelioma consists of dedifferentiated cells comprising epithelioid and sarcomatoid variant in varying proportions. A rare form of low malignant potential mesothelioma, multicystic variant, is also recognized and accounts for approximately 6.4% of all mesothelioma. Immunohistochemical stains are then used to confirm the diagnosis after histomorphologic assessment with mesothelial cell markers including calretinin, WT1, thrombomodulin, mesothelin, and D2-40. These are tested against a panel of marks that are expressed in other malignancies to serve as a negative predictor to support the diagnosis (ie, CEA, CD15, Ber-EP4, MOC-31, ER). For sarcomatoid tumors, cytokeratins (AE1/AE3 or CAM5.2) are highly specific and are useful in arriving at a diagnosis.
Staging of peritoneal mesothelioma
The peritoneal disease burden of mesothelioma is typically assessed systematically using Sugarbaker’s peritoneal cancer index (PCI). The PCI is comprised of a score ranging between 0 and 3 assessed based on lesion size and computed in total out of a score ranging from 1 to 39 by a summation of specific scores from 13 abdominopelvic regions. The Peritoneal Surface Oncology Group International (PSOGI) has collaborated to combine their experiences of managing patients with peritoneal mesothelioma to enroll patients collectively into a multi-institutional registry database to formulate a clinicopathologic staging system through prognostic parameters identified from patients treated uniformly with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) at eight international institutions. The staging system adopts the common nomenclature of the tumor-node-metastasis (TNM) system comprised of tumor burden (T) assessed by the PCI subgrouped into four categories: T1 being PCI 1–10, T2 being PCI 11–20, T3 being PCI 21–30, and T4 being PCI 30–39. Abdominal nodal disease commonly affected by peritoneal mesothelioma includes the iliac chain, para-aortic, celiac axis, mesenteric, and the portocaval lymph nodes; any involvement of nodes is classified as N1. The M element refers to the presence or absence of extra-abdominal metastases. Formal stage-wise classification was done in a reverse fashion after analysis of the prognostic impact of the PCI, lymph node, and metastasis status before arriving at four clinical stages ( Table 2 ). Patients with T1N0M0 were designated as stage I; T2–3N0M0 as stage II; and stage III was comprised of patients with T4, N1, or M1 disease. From the complete clinicopathologic data of the 294 patients that formed the cohort used to derive this staging system, stratification of stage-based survival was achieved with 5-year survival associated with stage I, II, and III disease being 87%, 53%, and 29%, respectively. This proposed TNM staging system is being evaluated in further prospective studies and it is hoped it will be formally endorsed by the American Joint Committee on Cancer.
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