Incidence, Survival Analysis and Future Perspective of Primary Peritoneal Mesothelioma (PPM): A Population-Based Study from SEER Database

Simple Summary Mesotheliomas arising from the lining of the mesothelial cells of the peritoneum are rare. However, they are strongly linked to asbestos exposure, similar to the relatively well-known pleural mesotheliomas. It is slightly more common in men than in women, with the majority of cases seen in Caucasians older than 50 years. Distant spread of tumor, size > 4 cm, and negative lymph node status were observed in our study among the patients with evaluable data. Optimal outcomes are achieved when patients are treated in specialized centers with surgical debulking followed by heated chemotherapy administered intraoperatively. Systemic chemotherapy and radiation are options for the selected patient groups. Patients with poorly differentiated large tumors (>4 cm), Caucasian race, and distant spread of disease outside the abdominal cavity have worse prognosis. Abstract Background: Primary peritoneal mesothelioma (PPM) is a rare and aggressive tumor arising from the visceral and parietal peritoneum. The diagnosis and treatment of PPM are often delayed because of non-specific clinical presentation, and the prognosis is worse. The current study investigated the demographic, clinical, and pathological factors affecting patient prognosis and survival in PPM. Methods: Demographic and clinical data of 1998 patients with PPM were extracted from the Surveillance Epidemiology and End Results (SEER) database (1975–2016). The chi-square test, paired t-test, and multivariate analysis were used to analyze the data. Results: The majority of PPM patients were male (56.2%, p < 0.005) and Caucasian (90.4%, p < 0.005, with a mean age of diagnosis was 69 ± 13 years. The grading, histological, and tumor size information were classified as “Unknown” in most of the cases, but when available, poorly differentiated tumors (8.7%), malignant mesothelioma, not otherwise specified (63.4%) and tumors > 4 cm in size (8%), respectively, were most common, p < 0.005. Chemotherapy was administered to 50.6% of patients, followed by resection (29.2%) and radiation (1.5%), p < 0.001. The cohort of PPM had a five-year overall survival of 20.3% (±1.1), compared to 43.5% (±5.9), 25.9% (± 8.4), and 18.7% (±1.6) for those with surgery, radiation, or chemotherapy alone, respectively. Poor differentiation (OR = 4.2, CI = 3.3–4.9), tumor size > 4 cm (OR = 3.9, CI = 3.2–4.5), Caucasian race (OR = 2.9, CI = 2.6–4.4), and distant SEER stage (OR = 2.5, CI = 1.1–3.2) were all linked with increased mortality (p < 0.001). Conclusion: An extremely rare and aggressive peritoneal tumor, PPM may be difficult to identify at the time of diagnosis. Radiation therapy likely to have a limited function in the treatment of this condition, with surgery and chemotherapy being the primary choices. All PPM patients should be enrolled in a nationwide registry to improve our understanding of the pathogenesis and identify factors affecting survival.


Introduction
Malignant mesothelioma (MM) is an aggressive and lethal disease. It affects pleural and peritoneal membranes and is associated with asbestos exposure [1,2]. PPM comprises 30% of all mesotheliomas, second to pleural mesothelioma [3,4]. Approximately 85% of all mesotheliomas are associated with asbestos exposure in males [5].
Due to nonspecific clinical features and an indolent course, diagnosis is often delayed; if an adequate tumor specimen is not available, such as that obtained by ascitic fluid sampling, it may be mistaken for other benign or malignant abdominal processes [6].
Suspected cases were mostly advanced. PPM presents with ascites, significant weight loss, fatigue, anorexia, palpable abdominal mass, and signs of intestinal obstruction [7]. Likewise, PPM has different variants, and the precise diagnosis of PPM with the subtype can only be made with tissue biopsy using special stains [8]. Although no specific imaging has been beneficial in diagnosing PPM, abdominal imaging, particularly multidetector computed tomography (MDCT), helps in further evaluation and extent of the tumor [9,10].
Additionally, no specific guidelines exist for PPM management; however, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are recommended in most eligible patients [11]. The role of systemic chemotherapy is limited to patients who are not good candidates for cytoreductive surgery and HIPEC [11]. Even with optimum treatment, the overall survival of PPM is dismal [11]. So far, most data regarding PPM are based on a few case reports and case series. To better understand this rare entity, we conducted an updated population-based outcome study using data from the SEER database.
Moreover, patients without histological confirmation and those diagnosed with in situ cancer were excluded. The current study looked at overall survival, mortality, and 1-, 2-, and 5-year cancer survival. For categorical variables, the chi-square test was utilized, while for continuous variables, the paired t-test and ANOVA were used. Statistical significance was defined at p < 0.05 for multivariable analysis.

Results
Data from 1998 patients were extracted. Patient's tumor and survival characteristics were observed in the entire cohort.

Discussion
The World Health Organization (WHO) classifies mesothelioma into three histologic subtypes; epithelioid, sarcomatoid, and biphasic. The epithelioid type is further divided into papillary, tubulopapillary, acinar, adenomatoid, and solid types. The epithelioid type resembles normal mesothelial cells with papillary and tubolopapillary architectures with minimal cellular atypia. The sarcomatoid subtype comprises of spindle cells with malignant osteoid and, chondroid elements. The biphasic subtype of mesothelioma contains both epithelioid and sarcomatoid components [10]. Along with tumor node metastasis (TNM), the staging peritoneal cancer index (PCI) is a measure of disease spread. PCI was scored in 13 abdominal regions for tumor size and distribution. PCI for peritoneal spread of the disease is evaluated using either laparotomy or computed tomography. A high PCI score is associated with a worse prognosis [12]. However, the subclassification of epithelioid mesothelioma and data on the peritoneal cancer index are not available in the SEER registry.
Peritoneal mesotheliomas are fatal neoplasms, with a median survival of 6-12 months [13]. Due to variability and vague presentation, a deeper characterization of the disease is indispensable to advance our understanding. In addition to describing epidemiological characteristics, we investigated contributing factors, such as pathological and clinical factors, that impact the prognosis and survival of patients with PPM through this population-based study from 1975 to 2016 using the SEER database.
PPM primarily affects male patients in their seventh decade of life. To better analyze the age-adjusted incidence rate of PPM in both men and women, Moolgavkar et al. conducted a SEER database study from 1973-2005 [14]. They reported an age-adjusted PPM rate in men to be 1.2 per million person-years and 0.8 per million person-years in women [14]. Consistent with these findings, we report that 56.2% of patients diagnosed with PPM were men, with an average age of 69 years at the time of diagnosis. Moreover, similar to our extensive database study, age at diagnosis has been shown to be a predictor of survival in previous studies, with patients older than 65 years having poor median overall survival [15].
Although a few non-asbestos-related mesothelioma cases have been reported, prolonged asbestos exposure has been linked to PPM development [8,16,17]. Asbestos toxicity generates reactive oxygen species via oxidative stress, causing genomic instability and DNA damage [18]. The molecular changes in PPM have not been well established; however, in 40-70% of PPM patients, loss of 9p, including cyclin-dependent kinase inhibitor 2A (CDKN2A), or 22q, including neurofibromatosis type 2 (NF2), has been established [19]. Studies have shown that the epithelioid subtype confers a more favorable overall survival (OS) compared to sarcomatoid and biphasic subtypes [20].
Moreover, owing to the insidious nature of the disease, it is difficult to reliably suspect PPM clinically at the initial stages [23]. When the disease progresses to an advanced stage, the most common clinical presentation of PPM includes increased abdominal girth, abdominal pain, nausea, weight loss, and bowel obstruction [7]. Similar to clinical presentation, suspecting PPM on abdominal imaging in isolation is exceptionally challenging. Abdominal compute tomography (CT) findings are nonspecific, ranging from peritoneumbased masses to ascites with associated peritoneal thickening and scalloping of adjacent abdominal organs. Unlike pleural mesotheliomas, calcified peritoneal plaques are rare [24].
Nonetheless, abdominal CT has traditionally been used more frequently than any other imaging modality for disease extent determination in patients with PPM [9].
Ultimately, the gold standard method for PPM diagnosis is tissue biopsy using immunohistochemical staining [25]. The initial panel usually contains two mesothelial markers (cytokeratin 5/6, calretinin, Wilms tumor 1 (WT-1), and D2-40) and two epithelial markers (MOC-31 and claudin-4). After confirmation of the mesothelial lineage, BAP1 loss, CDKN2A homozygous deletion, and MTAP loss were the most specific markers for the diagnosis of malignant mesothelioma. 5-hmC loss and increased EZH2 expression are novel markers for the diagnosis of malignant mesothelioma but are not widely used yet [26][27][28].
The type of therapy employed is determined by the patient clinical status and spread of the disease [29]. Cytoreductive surgery with HIPEC remains the gold standard for suitable candidates, and for those who cannot tolerate surgical resection, systemic chemotherapy alone can be considered [11,29,30]. However, the long-term benefits of systemic chemotherapy alone are not well understood. To the best of our knowledge, no uniformly accepted guidelines are available for radical resection in PPM patients; however, surgical resection is considered in most PPM patients, with no extraperitoneal spread [31]. Likewise, adjuvant radiation therapy is unlikely to provide survival benefits in PPM patients [31,32]. PPM develops in the anatomical region amidst several vital organs, and radiation therapy may add to additional organ damage in these patients [33]. Our study showed that patients receiving surgical intervention had a more favorable five-year survival rate than those receiving either chemotherapy or radiation therapy alone; however, no statistical significance was observed after analyzing the data.
Optimal cytoreductive surgery (CRS) followed by HIPEC is the gold standard for fitting patients without extraperitoenal spread. For patients who are not candidates for CRS/HIPEC, debulking surgery is not routinely performed and systemic chemotherapy is preferred. Pemetrexed in combination with cisplatin, carboplatin, or gemcitabine is preferred for systemic use. No targeted agents or immunotherapies have been specifically approved for PPM treatment. Based on preclinical models, pharmacological inhibition of the PI3K-PTEN-AKT-mTOR pathway has been tested in phase I/II trials [34]. Agents targeting novel molecular pathways and targets, such as mesothelin, vascular endothelial growth factor, histone deacetylase, focal adhesion kinase, and anaplastic lymphoma kinase, are being actively explored [34]. Although immune checkpoint inhibitors are approved for pleural mesothelioma, trials with these agents do not include patients with PPM. Many clinicians use checkpoint inhibitors off-label for MPM, especially PD-1/PDL-1 antibodies, based on responses in single-arm phase I/II trials. A randomized phase IIb trial with tremelimumab, a CTLA4 antibody (DETERMINE), in PPM was negative [35]. While whole abdominal radiation is part of the traditional treatment paradigm for diffuse MPM, radiation has been vanishingly rare in modern times due to its increased toxicity and dubious survival benefit, as evident in our study. Owing to the lack of specific genomic data and treatment details, we were unable to discuss the use of novel or experimental agents in our group of patients.

Limitations
Despite these findings, our study has limitations that are applicable to most databasebased studies. Information regarding the timing of chemotherapy relative to surgical resection (adjuvant vs. neoadjuvant), type of chemotherapy (HIPEC vs. systemic chemotherapy), specific agents used for each modality, extent and nature of surgical resection, and radiotherapy dosing schedule were not provided in the SEER database, limiting our interpretation of the results. The outcome data of our study is divided into subgroups of patients who received each modality of treatment, but we do not know whether each treatment modality was used alone or in combination. Some of the critical clinical factors, such as socioeconomic factors, performance status, comorbidities, sub-classification of epithelioid mesothelioma, peritoneal cancer index, mitotic tumor index, and other associated pathologies that might affect the interpretation of the results, are not coded correctly in the SEER database. Finally, the side-effects and complications of surgery, chemotherapy, and radiation therapy were not available in the SEER database. Despite these limitations, our study attempts to adequately describe the clinical and demographic aspects of PPM patients.

Conclusions
PPM is an aggressive malignancy of the peritoneal surface, where tumor size, Caucasian race, and advanced SEER stage of the disease correlated with poor survival in our study. Surgical resection and HIPEC offers optimum management, with systemic chemotherapy being an option for nonsurgical candidates, and radiation therapy has a limited role in treating patients with PPM. To the best of our knowledge, the current cohort is the most extensive database study of this rare entity. Although the disease is rare; we were able to use a national registry to obtain a substantial number of cases. With the advent of novel agents, further analysis is required to account for changes in the prognosis of various histopathologic subtypes. We strongly suggest that an international registry enrolling all patients with PPM should be introduced to better understand this rare disease. Institutional Review Board Statement: All data is publicly available and no IRB required.
Informed Consent Statement: Patient consent was waived due to this article is from SEER database, which is publicly available deidentified patients data from National Cancer Institute (NCI), USA.
Data Availability Statement: All data is publicly available. The data of this manuscript was presented at Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), Los Vegas, Nevada, 31 August-3 September 2021.