Peritoneal mesothelioma and Pseudomyxoma peritonei

Diffuse mesothelioma is a tumor originating from the mesothelial or submesothelial cells of the pleura, peritoneum, or very rarely the pericardium. Under 20% of mesotheliomas originate in the peritoneum. Advanced peritoneal mesotheliomas show a wide variation in prognosis with a median overall survival of 5-30 months [1, 2].

The highly differentiated papillary mesothelial tumor (WDPMT) represents a special clinical and prognostic disease. It occurs predominantly in women of childbearing age and is usually diagnosed as an incidental finding during surgery for another reason. There is not always a connection to asbestos exposure. After complete resection, patients mostly have a good prognosis [3, 4].

Pseudomyxoma peritonei is a clinical diagnosis characterized by disseminated abdominal mucinous deposits. The most common site of origin is a mucinous neoplasm of the appendix (low grade appendiceal mucinous neoplasm, LAMN). In perforated LAMN, approximately 65% of patients develop Pseudomyxoma peritonei. If non-perforated LAMN is present, PMP develops in approximately 17% of patients within 50 months [5].

The incidence rate for peritoneal mesothelioma in industrialized countries is reported to be 0.5 to 3 per 1,000,000 in men and 0.2 to 2 per 1,000,000 cases in women [1]. In the United States, the reported incidence is approximately 200 peritoneal mesotheliomas for a total of 2000 mesotheliomas per year.

Currently, about 150 cases of the disease are diagnosed in Germany each year. Men are diagnosed about twice as often as women. In both sexes, mesothelioma of the peritoneum accounts for less than 0.5 per thousand of all cancers.

Given such small numbers of cases and the associated annual fluctuations, it is difficult to assess changes over time. The age-standardized incidence rates (Figure 1) in the joinpoint regression model show a slight slope (0.9% per year since 2003) in men and virtually constant disease rates in women (model 0.3% per year since 2003). Both values are not statistically significant.

To a similar extent as the disease rates, the number of cases naturally also shows strong fluctuations (Figure 2). In men, the numbers vary between 52 and 120 cases, in women between 23 and 59 cases. The joinpoint regression model [6] shows a larger increase in the number of cases than in the number of cases (+2.8% in men, +2.3% in women per year since 2003). Again, both values are not statistically significant.

Given the low number of cases, mortality is also low. The official causes-of-death statistics show an average of 28 deaths in men and 19 deaths in women per year for the period 2003-2016. A presentation in diagrams has been omitted here.

Source: Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V., special evaluation.

Source: Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V., special evaluation.

With a median age of onset of 72 years (men) and 70 years (women), peritoneal mesothelioma is a disease of older age. The median age of onset is two years and one year higher than the median age of onset of cancer overall. Most cases occur in both sexes in the age group 75 to 79 years Figure 3 (bars). This age group also shows the highest disease rates, i.e., the number of cases relative to the underlying population Figure 3 (lines). Up to the age of 60, the risk of disease is almost equal in both sexes. It starts at about age 30 and increases steadily until age 60. Thereafter, the risk in women continues to rise steadily until the age of 80, while in men the probability of disease increases significantly from the age of 60. From the age of 80, the rates decrease again in both sexes.

Source: Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V., special evaluation.

Based on the current incidence of the disease and the 14th coordinated population projection of the Federal Statistical Office (G2L2W2, moderate development), an increase in the number of cases to 170 new cases (2040) can be expected in the next 25 years, solely due to the shift in age structures in the population.

The actual incidence rate is not known because no uniform classification systems are available. Thus, in Germany, it may be recorded under ICD 10 C48.1, C48.2, and C48.8, but these also include other diseases. The estimated incidence is approximately 2 per 1,000,000 inhabitants per year [7].

Data from the Netherlands [8] show an incidence of mucinous neoplasia of the appendix of 0.3%, of which again 20% progress to PMP.

Mesotheliomas arise from mesothelial cells. Less than 20% of mesotheliomas are of peritoneal origin; the majority arise in the pleura. Peritoneal mesotheliomas, like pleural mesotheliomas, may be associated with past exposure to asbestos. Despite the ban on asbestos use, the incidence of asbestos-related disease continues to rise. This can be explained by the long latency period after asbestos exposure of 15 to 60 years [9]. Therefore, the main age of manifestation is in the 6th decade of life [10].

Simian virus 40 (SV40) infection is considered another risk factor.

In non-asbestos-associated cases of peritoneal mesothelioma, rearrangements in the anaplastic lymphoma kinase (ALK) gene have been described as the underlying pathomechanism [11].

Germline mutation of BAP1 is a rare predisposing factor for peritoneal mesothelioma [12, 13].

PMP are characterized by mucinous biliary ascites, usually following perforation of a mucinous neoplasm of the appendix, leading to the appearance of a so-called "biliary abdomen/carcinoma". This term is a purely macroscopic, i.e., clinical, description. Here, a mucinous neoplasia of the appendix is the most frequent site of origin; in principle, an origin in the entire gastrointestinal tract or also in the area of the ovary is possible. A typical pathomechanism is the occurrence of a "redistribution phenomenon" in which the pseudomyxoma cells distribute and proliferate freely in the peritoneal fluid to predilection sites in the abdominal cavity. Typical predilection sites include the omentum majus and minus and the underside of the diaphragm, especially on the right side [7] or the paracolic gutters, the omentum majus, the right subdiaphragmatic and subhepatic spaces, and the lesser pelvis [14].

Exposure to asbestos is considered a recognized risk factor for the development of peritoneal mesothelioma. Thus, peritoneal mesothelioma caused by asbestos is accepted as an occupational disease under section 4105 of the Occupational Diseases Ordinance.

Specific risk factors are not known.

Peritoneal mesothelioma (MPM) has no pathognomonic symptoms, so diagnosis may be difficult.

Clinically, 3 subgroups can be distinguished

• Patients with abdominal circumferential proliferation: massive ascites formation and large tumor nodules, weight loss, and abdominal pain

• Patients with acute problems who require emergency surgical therapy

• Patients with unclear fever, weight loss, and a picture of inflammatory bowel disease

In early stages, there may be non-specific general symptoms such as fatigue, loss of appetite, weight loss, and unexplained fever (B symptoms).

Malignant ascites is present in up to 90% of advanced MPM. In advanced stages of disease, there may be constriction or infiltration of the bowel, resulting in obstruction with ileus. Dyspnea, abdominal pain, nausea, vomiting, diarrhea, and increasing abdominal circumference with a feeling of tightness (ascites) indicate an already advanced stage, as do non-specific tumor signs such as anemia, thrombocytosis, or eosinophilia [15].

Spread of tumor cells into subcutaneous adipose tissue along incisions is common, so the resection of incision or puncture sites should be part of the surgical treatment.

Approximately 10% of patients are diagnosed with MPM during umbilical hernia repair.

The diagnosis is often made as an incidental finding in the case of an unclear tumorous mass in the region of the ovary, in connection with an inguinal hernia, appendicitis or an etiologically unclear ileus, as well as in the context of an extended diagnosis in the case of unclear abdominal complaints.

In 30-50% of cases, there is an increase in abdominal circumference (so-called "jelly belly"). Less common symptoms are abdominal pain, weight loss, micturition problems, constipation, vomiting and dyspnea [7].

The main problem of all scores is that all mentioned classifications are semiquantitative and above all subjective. In addition, the scores can only be determined intraoperatively, whereas for optimal patient selection the precisely defined tumor burden should ideally already be known prior to laparotomy. This is not always possible, not even by staging laparoscopy.

TNM classification is currently available only for pleural mesotheliomas.

The most widely used score is the so-called peritoneal carcinomatosis index (PCI) according to Sugarbaker et al., see Chapter 5.3.2.1. and Figure 4.

A treatment algorithm for malignant peritoneal mesothelioma is shown in Figure 5.

Therapy of choice for resectable tumors is a combination of cytoreductive surgery (CRS) and intraperitoneal therapy, usually applied as hyperthermic intraperitoneal chemotherapy (HIPEC). Due to the complexity of the disease and the required interventions, patients should be treated in specialized and certified (see also DGAV homepage) high-volume centers. Therapeutic decisions must be made in a multidisciplinary board.

Surgical treatment aims to achieve a complete peritonectomy if possible. This may not be feasible in cases of multiple small bowel involvement. In these cases, serial debulking may also be useful.

Adnexa in young patients are a special problem. In general, bilateral adnectomy is usually also recommended with hysterectomy for peritoneal tumors, due to frequent involvement to achieve complete cytoreduction, and must be discussed individually.

Splenectomy is often necessary in case of extensive tumors. It may therefore be useful to perform vaccinations preoperatively, when imaging or laparoscopy show extensive involvement of the left upper quadrant.

The value of neoadjuvant and/or adjuvant systemic treatment has not been clarified. The proliferation index (determined with the immunohistochemical marker Ki67) allows the identification of high-risk patients and can be used for further differential therapeutic considerations. Data from retrospective evaluations indicate a potential benefit of adjuvant chemotherapy with an improvement in 5-year overall survival (OS) to 67% from 56% without systemic therapy [32].

Patients with rapidly proliferating tumors (Ki67 > 9%), increased PCI (> 17), and a biphasic/sarcomatoid histologic subtype (compared with an epithelioid) were identified as a high-risk population in a retrospective evaluation of 117 patients, with a median OS after surgery and HIPEC of 10.3 months. In these patients, primary preoperative/neoadjuvant systemic chemotherapy with a platinum derivative plus pemetrexed may be considered [33]. Resectability should be re-evaluated after 2-3 cycles. However, other retrospective evaluations did not show a benefit from perioperative chemotherapy [34] or even described a disadvantage with neoadjuvant chemotherapy [32].

In locally advanced and/or metastatic tumors, systemic therapy with a combination of pemetrexed and a platinum derivative is standard, analogous to pleural mesothelioma. The value of an additional administration of bevacizumab [35] as well as that of a second-line therapy has not been conclusively explored.

A treatment algorithm for pseudomyxoma peritonei (PMP) is shown in Figure 6.

Therapy of choice is a combination of cytoreductive surgery (CRS) with aspiration of mucinous ascites in combination with intraabdominal chemotherapy (IP). This can be given directly during surgery as HIPEC (hyperthermic intraperitoneal chemotherapy) or as postoperative EPIC (early postoperative intraperitoneal chemotherapy), which aims to improve both overall survival and progression-free survival.

The goal here is to achieve complete macroscopic cytoreduction/tumor removal, which is assessed and documented using the Completeness of Cytoreduction (CCR), see Table 2. CCR is a prognostically relevant factor.

The procedures performed can be extremely complex and time consuming, with median operation times of approximately 9 hours [38].

In locally advanced PMP, tumor debulking may also improve prognosis [39].

Postoperative systemic therapy may help to improve prognosis in high-grade PMP or may be used in unresectable tumors [40]. However, the available data are sparse. Here, most data are available for combination therapies in analogy to systemic treatment for metastatic colorectal carcinoma.

The adnexa are a special problem in young patients. Due to the usually high tumor burden in the minor pelvis, a complete resection can only be achieved by including the ovaries, the uterus and the rectum up to the fold as an extraperitoneal anterior rectum resection en bloc with hysterectomy and salpingoovarectomy. In low-grade PMP with low tumor burden, leaving the left adnexa in place may be considered in individual cases.

Cytoreductive surgery (CRS) is an essential component of multimodal therapy and is recognized as the standard surgical procedure for peritoneal mesothelioma. The most important goal is to remove all tumor nodules as completely as possible. Due to the frequent distribution of tumor nodules over a large area and due to the origin of the primary in the area of the peritoneum itself, a complete peritonectomy should therefore be aimed for.

The largely extraperitoneal dissection and tumor distribution across all quadrants of the abdomen requires special visceral surgical expertise for the operation. Cytoreductive surgery is usually a time-consuming procedure associated with large wound areas. In addition to peritonectomy, which is usually (sub)total, multivisceral resection may be necessary.

Free tumor cells spread in the peritoneal fluid across the abdomen and lead to peritoneal carcinomatosis (complete redistribution phenomenon, CRP) predominantly at the typical predilection sites, so that a complete parietal peritonectomy usually has to be performed [41].

The selection of the surgical approach depends on the localization:

• Upper abdominal peritonectomy

• Lower abdominal peritonectomy

• Interenteric peritonectomy

For both entities, no conclusive data on radiotherapy are available. Possible indications for palliative radiotherapy are (rare) bone metastases or local complications that cannot be treated surgically and/or with medication.

In patients with peritoneal mesothelioma, irradiation of the trocar sites and puncture sites may be considered postoperatively.

Pseudomyxoma peritonei is hardly sensitive to radiation.