Prof. Yusuf Yıldırım

CAUSES & RISK FACTORS

Comprised of a single layer of mesothelial cells, the peritoneum is the largest and most complex serous membrane of the human body. The visceral peritoneum that covers the abdominal organs and mesentery, is followed by the parietal peritoneum covering the abdominal wall and pelvic cavities. The peritoneal cavity is the (virtual) space between the parietal and visceral layers of the peritoneum and normally contains a small amount of serous fluid (peritoneum produces approximately 50 ml of fluid per day). As a large sac covering the abdominal organs, the peritoneum is connected to many points within the abdomen but still maintains significant mobility. Adults peritoneal surface area is approximately 1.7–1.8 m2, equivalent to the individual's body area however, given the enormous microvilli structure (≥300 per mesothelial cell), the total area is likely much larger. This large surface area is involved in the exchange of nutrients, metabolites and gases, forms a mechanical barrier against infectious agents and acts as a line of defense through the transfer of innate and adaptive immune cells, cytokines and chemokines. The greater omentum, which has a prominent peritoneal fold and also known as the “gastrocolic ligament,” has been referred to by some as the “policeman of the abdomen” for its role in limiting the spread of infection or tumor in the abdominopelvic space. Due to this unique nature, the omentum is often at risk of disease through local spread of any abdominal malignancy.

Peritoneal cancers (aka peritoneal surface malignancies-PSM) comprise a heterogeneous group of tumors. These may be in the form of tumors originating from the peritoneum itself (primary) or intraperitoneal (digestive and female reproductive system) and extraperitoneal tumors that have spread to the peritoneum from other organ tumors (secondary). The second group known as peritoneal metastasis accounts for 97% of "peritoneal carcinomatosis (PC)" cases (3% of the cases are primary). The term PC, which actually means “disseminated peritoneal cancer” was first used by Sampson in 1931 for detailed description of metastatic involvement of the peritoneal stromal surface by ovarian cancer cells, is now generally utilised to express secondary (metastatic) involvement of the peritoneum. If peritoneal dissemination is due to a sarcoma, it is referred more specifically as "peritoneal sarcomatosis" instead of carcinomatosis or if it is due to a lymphoma, it is called "peritoneal lymphomatosis". Peritoneal sarcomatosis (PS) may arise from an intra-abdominal sarcoma or metastasize from extra-abdominal sarcomas. The most frequent tumors that give rise to PS are gastrointestinal stromal tumors (GISTs), liposarcomas, leiomyosarcomas and angiosarcomas. Another distinctive type of PC is Pseudomyxoma Peritonei (PMP), a condition that mostly develops concurrently with mucinous appendage tumors.

Ovarian cancer is the cause for approximately 45% of peritoneal metastasis cases due to the anatomical location of the ovaries and close contact with the peritoneum and the embryological developmental continuity of ovarian epithelial cells with peritoneal mesothelial cells. Reported relative incidence of peritoneal metastases from ovarian cancer is around 70%. This rate is below 10% for other gynecological malignancies. For gastrointestinal malignancies, the relative incidence of peritoneal metastases is highest for gastric cancer at 15–43% (for both synchronous and metachronous metastases). For colorectal cancer, the relative incidence of synchronous (simultaneous) peritoneal metastases is 5-15% and metachronous (subsequent) malignant proliferation is 20-50%. Approximately 25% of patients with recurrent colorectal cancer develop metastatic disease confined to peritoneal surfaces. PMP is detected in nearly half of appendiceal mucinous tumor cases (with a higher rate in those presenting with a clinical appearance other than appendicitis). PC is detected during diagnosis in 9% of non-endocrine pancreatic cancers and 6% of GI-NETs. The most common non-abdominal cancers that develop peritoneal metastasis are breast cancer, lung cancer and melanoma. However, the actual incidence of peritoneal metastases from these cancers is low: for example, patients with breast cancer is 0.7% (and metastases from other sites in 82% of cases). The primary source cannot be found in 3-4% of peritoneal metastases, which is referred as peritoneal metastasis of unknown primary origin. However, prior reaching to a conclusion, a comprehensive evaluation should be made. Sugarbaker et al. reported occult (hidden) appendiceal adenocarcinoma during laparotomy in 36% of cases initially with unknown primary source (preoperative period). Sources of peritoneal metastasis:

1.Peritoneal metastasis of intraperitoneal organ origin (87%)

• Ovary or tube (45%)
• Uterus
• Colo-rectal
• Stomach
• Pancreas (non-endocrine)
• Small intestine
• Appendix (the most common origin of PMP cases)
• Cholangiocarcinoma
• Gall bladder
• GI-NETs (Neuroendocrine tumors)
• Bladder
• Sarcomas (GI, Gynecological)

2.Peritoneal metastasis of extraperitoneal organ origin (10%)

• Breast (most common: ~40%)
• Lung
• Melanoma
• Kidney (Renal cell carcinoma)
• Lymphoma (NHL)
• Sarcoma (retroperitoneal, extremity, etc.)

3.Peritoneal metastasis/carcinomatosis from an unknown primary site (3%).

The GLOBOCAN registry, which provides estimates of global cancer incidence based on data from 185 countries, does not separately record the incidence of peritoneal cancers. Therefore, we do not have global data on the incidence of peritoneal metastasis. Instead, we only have data from cohort studies that report the incidence or prevalence of peritoneal metastases in patients with specific tumor types (for example, the incidence of peritoneal metastases due to colorectal cancer in the United States is 2-3 per hundred thousand). Nevertheless, data on the general incidence of peritoneal cancers are presented from some countries. For example, in the Czech Republic, between 2012 and 2016, the annual age-adjusted incidence of primary peritoneal malignancies was reported as 4.36 per 1,000,000 persons and the incidence of synchronous peritoneal metastases as 99.0 per 1,000,000 persons

Generally, peritoneal metastasis occurs when the primary tumor is at an advanced stage. Advanced “T” stage of the primary tumor, regional lymph node involvement, unfavorable histological subtype and positive peritoneal fluid cytology are common risk factors for peritoneal metastasis in most underlying primary tumors.

SYMPTOMS, DIAGNOSIS & STAGES

Patients with peritoneal carcinomatosis may have symptoms characteristic of the underlying primary tumor and nonspecific symptoms. Sometimes, peritoneal metastasis may be detected incidentally during an elective or unrelated surgery or during imaging tests performed for other indications.

Secondary metastatic deposits can range from microscopic involvement to nodules to bulky disease and the degree as well as location of this involvement determine symptoms. In the early stages, there may be no symptoms or vague symptoms that resemble other conditions. In later stages, cancer often causes symptoms such as:

• Diarrhea or constipation
• Nausea and/or vomiting
• Abdominal pain
• Bloating
• Weight loss
• Excessive urination
• Loss of appetite or feeling of satiation quickly
• Intestinal obstruction
• Ascite-related symptoms: swelling of the abdomen or ankles, breathing problems, extreme fatigue, unusual weight gain due to fluid accumulation, etc.

The two most important clinical features associated with peritoneal carcinomatosis are ascites (accumulation of fluid in the peritoneum) and intestinal obstruction. However, these are clinically found in less than 50% of patients.

If peritoneal carcinomatosis has been suspected, a blood test, imaging tests or biopsy can be done for confirmational purpose. Sometimes, tumors in the peritoneum are noticed during surgery for primary cancer and peritoneal carcinomatosis is diagnosed.

• Imaging Tests: Cancerous lesions involving the peritoneum can sometimes (but not always) be seen with ultrasound (including transvaginal in women), CT (CT), MRI and 18F-fluorodeoxyglucose (FDG) PET/CT.
• Tumor markers: CEA, Ca19.9, Ca125 and Ca15.3 are frequently studied tumor markers. All these tumor markers can also be produced from normal epithelial cells thus, elevations can also be detected in certain non-cancerous (benign) conditions. CYFRA (cytokeratin fragments) is the sole tumor marker that is found in high quantities only in malignant conditions.
• Gastrointestinal (GI) endoscopy: Colonoscopy is required to investigate colorectal origin while gastroscopy to investigate stomach origin. Biopsy or polypectomy is performed if a tumor, polyp or suspicious area is detected during these procedures.
• Ascites fluid examination: Tumor cells can be investigated in ascites fluid. Most often, results are given as “positive”, “negative” or “suspicious”. In “positive” cases, sometimes cytological findings indicating primary organ origin can be obtained. Some researchers have also reported that measuring the levels of tumor markers in ascitic fluid to be useful for diagnosis.
• Diagnostic/staging laparoscopy: More evidence and comprehensive studies are needed for routine practice. It is reasonable to assume maximum impact of staging laparoscopy will be in colorectal, gastric and ovarian peritoneal carcinomatosis, where PCI is an important criterion for deciding on CRS and HIPEC. Laparoscopy will have less effect in PMP (especially the “diffuse peritoneal adenomucinosis” variant) and peritoneal mesothelioma (PM), where CRS and HIPEC may be possible even when PCI is high, and in recurrent colorectal cancer, where involvement of retroperitoneal structures may be difficult to detect.
• Biopsy: The definitive diagnosis of peritoneal metastasis is made by histopathological examination of biopsy samples obtained percutaneously (fine needle or tru-cut) or laparoscopically (or during laparotomy) from tumoral formations on the peritoneal surfaces (usually in the omentum). Occasionally, if it can be detected and accessed, diagnosis can be made from tissue samples obtained from the primary tumor via endoscopy (colonoscopy or gastroscopy). It is essential to use the specific immunohistochemical (IHC) stains for the correct tumor differentiation, grading, and providing appropriate treatment. Primary peritoneal serous carcinoma (PPSC) is positive for BerEP4 (indicating epithelial origin). The malignant mesothelioma stains negative for BerEP4 and positive for calretinin (indicating mesothelial origin), cytokeratin (CK)-5/6, and podoplanin. The metastatic adenocarcinomas show no nuclear staining for calretinin and cytokeratins. The tumors from the upper gastrointestinal tract are positive for CK-7. In contrast, tumors from lower gastrointestinal tract are negative for CK-7 and positive for CK-20 and CDX2.

Peritoneal metastasis can sometimes be confused with primary peritoneal cancers and various granulomatous and non-granulomatous tumor-like lesions. Differential diagnosis includes:

• Primary peritoneal serous carcinoma (PPSC)
• Malign peritoneal mesothelioma (MPM)
• Benign mesothelial lesions (benign cystic mesothelioma, mesothelial hyperplasia, peritoneal inclusion cysts, etc.): Benign cystic peritoneal mesotheliomas are rare and found predominantly in young women. It tends to recur even after aggressive surgery; However, no related deaths have been reported.
• Peritoneal tuberculosis
• Peritoneal sarcoidosis
• Peritoneal histoplasmosis
• Peritoneal melanosis and other histiocytic lesions
• Gliomatosis peritonei
• Sclerosing peritonitis
• Peritoneal fibrosis nodules
• Granulomatous peritonitis secondary to foreign material
• Peritoneal hemangiomatosis
• Disseminated peritoneal leiomyomatosis (or Leiomyomatosis peritonealis disseminate).

The traditionally used system for staging secondary peritoneal cancers is the Gilly classification (staging).Today, Sugarbaker’s “Peritoneal Cancer Index (PCI)” scoring and its modifications are commonly used. In all systems, stages/categories/groups/scores can be calculated in two ways as pre-operative (radiological) and intra-operative (surgical) and the main purpose is to help guide the treatment decision and predict “prognosis”/ “future outcome”.

Gilly Classification/Staging 

• Stage 0: No macroscopic disease
• Stage I: Malignant lesion/implant/nodule of size < 5mm localized to one part of the abdomen.
• Stage II: Lesion is < 5mm but diffuses to the whole abdomen.
• Stage III: Malignant lesions/implants/nodules are >5mm but <2cm
• Stage IV: Large malignant nodules – greater than 2 cm

Peritoneal Cancer Index (PCI) Score

Peritoneal cancer/carcinomatosis index (PCI) is determined by assigning a LSS (lesion size score) to each of the 13 peritoneal regions and summing the scores. The maximum possible score is 39. (Lesion sites: 0-central,1-right upper, 2-epigastrium, 3-left upper, 4-left flank, 5-left lower, 6-pelvis, 7-right lower, 8-right flank, 9-upper jejunum, 10-lower jejunum, 11-upper ileum, 12-lower ileum). Some studies use PCI categories of:

• PCI 0-10: “very limited” peritoneal disease
• PCI 10-20: “limited” peritoneal disease
• PCI 20-30: “moderate” peritoneal disease
• PCI over 30: “extensive” peritoneal disease.

Although the “cut-off” PCI score for resectability has been taken as 15, 17, 20 or 25 in various studies, “20” is generally accepted. One study showed that the radiological PCI score had 76% sensitivity, 69% specificity, 85% positive predictive value, and 56% negative predictive value compared to the surgical PCI score. In addition, adequate cytoreduction was still achieved in 46% of patients with a radiological PCI score ≥20. Therefore, a better assessment of resectability may sometimes require a staging/diagnostic laparoscopy.

Peritoneal Surface Disease Severity Score (PSDSS)

The American Society of Peritoneal Surface Malignancies (ASPSM) defined the “Peritoneal Surface Disease Severity Score (PSDSS)” by combining PCI with clinical and pathological data. According to this PSDSS Stages (Groups):

• Stage/Group I: 2-3 points
• Stage/Group II: 4-7 points
• Stage/Group III: 8-10 points (or 2-10 points with mutated RAS)
• Stage/Group IV: >10 points.

Another scoring system is the Dutch Simplified Peritoneal Cancer Index (SPCI), where the number of affected regions (out of a total of 7 regions) is taken as a criterion in addition to the total score to decide whether to continue with the CRS-HIPEC or not. The number of affected regions is:

• ≤2: “limited” peritoneal disease
• 3-5: “moderate” peritoneal disease
• >5: “extensive” peritoneal disease (CRS-HIPEC is not continued).

Lastly, a group of researchers defined the Simplified Peritoneal Sarcomatosis Score (SPSS), specifically for peritoneal sarcomatosis, by adapting it from the Peritoneal Surface Disease Severity Score (PSDSS) defined by the American Society of Peritoneal Surface Malignancies. SPSS groups:

• Low SPSS (SPSS-L): total score 0-1
• High SPSS (SPSS-H): total score 2-3

TREATMENT & PROGNOSIS

Historically, the presence of metastatic deposits in the peritoneal cavity meant an incurable fatal disease for which curative surgical treatment was no longer a reasonable option. Newer surgical techniques and innovative approaches in medical management strategies, have significantly changed course of the disease in recent years and improved the state of being disease-free and overall survival.

Management strategies may differ depending on the underlying primary malignancy causing peritoneal metastasis. The multidisciplinary tumor board usually evaluates treatment options of perioperative (neoadjuvant and/or adjuvant) chemotherapy, surgery and intraperitoneal chemotherapy and whether the treatment is intended to be curative or palliative.

Cytoreductive Surgery (CRS) and Hyperthermic (Heated) Intraperitoneal Chemotherapy (HIPEC) along with peritonectomy form the basis of treatment. In cytoreductive surgery, the surgeon removes tumors from the peritoneum and in some cases nearby abdominal organs. Peritonectomy is a surgery performed to remove the peritoneum. Generally, done immediately after cytoreductive surgery, HIPEC bathes the peritoneal surfaces (inside the abdomen) with heated chemotherapy drugs to kill any remaining cancer cells.

CRS involves removing the organ from which the tumor originates, surgical removal of the peritoneum (peritonectomy), which is the covering of the abdominal and pelvic cavities, and all adjacent organs where the tumor has spread. Removal of the omentum (the fatty tissue that covers front abdomen), ovaries, fallopian tubes and uterus (hysterectomy and bilateral salpingo-oophorectomy: TH-BSO), and sections of the small and/or large intestine are common procedures. Sometimes bowel resection will also require an ostomy, which may be permanent or temporary. Depending upon the spread of the tumor, other organs might also be removed, including but not limited to the gallbladder (cholecystectomy), spleen (splenectomy), and stomach (gastrectomy). For organs that cannot be removed safely (like the liver), the surgeon strips off the tumor from the surface (for example, liver capsulectomy). The goal of CRS is to remove all visible tumors. Resection (cytoreduction) is considered “complete” if no masses larger than 2.5 mm are left. Completeness of Cytoreduction Score (CCS):

·         CCS-0: No visible tumor nodules.

·         CCS-1: Tumor nodules remaining after cytoreduction are less than 2.5 mm in diameter.

·         CCS-2: The remaining nodules are between 2.5 mm and 2.5 cm in diameter.

·         CCS-3: Tumor nodules remaining after cytoreduction are greater than 2.5 cm in diameter.

HIPEC is only useful when complete macroscopic cytoreduction is achieved. HIPEC is a regional cancer treatment that is groundbreaking in the curative and palliative treatment of peritoneal malignancies and has become increasingly common in the last 30 years. It aims to eliminate invisible or small cancer foci by combining heat and chemotherapy. In order to administer HIPEC, a patient’s medical/surgical performance must be suitable, and the post-surgical disease burden should be "minimal residual disease" (largest residue ≤2.5 mm diameter) or "microscopic". The procedure is generally performed by circulating various chemotherapy drugs in the abdomen for 30-120 minutes in a closed environment at an average temperature of 42°C, with 2-4 liters of fluid, over 2 inlet and 2 outlet cannulas. Although HIPEC has certain complications and risks (15-20% serious complications and 1-5% mortality), it provides long-term survival rate in selected cases. The most commonly used HIPEC regimens are Cisplatin-based, Mitomycin C-based and Oxaliplatin-based regimens. For example, “American Society of Peritoneal Surface Malignancies-ASPSM” Low Dose Mitomycin C Regimen:

• Mitomycin C dose for 90-minute HIPEC treatment is 40 mg/3 L
• Add Mitomycin C to 3 L of 1.5% dextrose peritoneal dialysis solution
• Add Mitomycin C to 1.5% peritoneal dialysis solution at a dose of 30 mg/3 L followed by 10 mg over 60 minutes.

Peritoneal metastasis is an advanced form of invasive cancer that spreads from another tumor, which can be difficult to be treated. Most tumors that cannot be operated on or cannot be adequately reduced via surgery, either do not shrink much or does not shrink at all with chemotherapy and other systemic treatments. That is the reason doctors focus on palliative care to manage symptoms, relieve pain and improve quality of life. The following clinical presentations and complications develop in cases that cannot be treated or do not respond to treatment:

• Refractory/intractable ascites 
• Intestinal obstruction
• Urinary tract obstruction
• Shortness of breath due to malignant pleural effusion
• Gastrointestinal dysmotility
• Pulmonary thromboembolism
• Peritonitis
• Complications related to portal hypertension including upper GI bleeding (due to esophageal varices), hepatic encephalopathy, and refractory/intactable ascites.
• Enteric fistula.

Treatment Success and Prognosis (outcome)

Survival rate depends on many factors including the type, extent and biologic activity of tumor. Prognostic indicators currently used for PC are the following: 

• The type of primary cancer: Peritoneal metastasis from an unknown primary tumor has a poor prognosis. Therefore, efforts should focus on detecting and identifying the primary tumor, potentially increasing the prognostic benefits from treatment. Survival rates of PC also differ according to the location of the primary tumor; pancreatic origin has worst (an average of 2.9 months), followed by gastric, colorectal, and ovarian origin. 
• Histologic subtype: Unfavorable histologic subtypes have poor prognosis.
• The concomitant presence of ascites and hepatic metastasis are negative survival factors.
• Patient's clinical symptoms: severe symptoms are related to unfavorable outcome.
• Gilly stage
• Peritoneal cancer/carcinomatosis index (PCI) score : PCI is the best indicator for survival. PCI score of >20 in colorectal and ovarian cancers and >10 in gastric cancers has been identified as an independent poor prognostic factor in patients undergoing CRS and HIPEC.
• The achievement of cytoreduction based on completeness of cytoreduction score (CCS): A CCS of 0/1 has been shown to be an independent prognostic factor.
• Whether to apply HIPEC treatment or not. 

*You can visit our current website “oncosurgery.com.tr” for further information about peritoneal metastasis/carcinomatosis and its surgery.

**You can visit our current website “oncosurgery.com.tr” for further information about HIPEC (Heated Chemotherapy).