Peritoneal Surface Malignancies

Etiology

Peritoneal surface malignancies form a heterogeneous group of neoplasms, and their etiology varies depending on the type of tumor. Primary peritoneal malignancies, eg, malignant peritoneal mesothelioma, are closely associated with asbestos exposure and genetic alterations, including mutations in tumor suppressor genes like BAP1.[3] Secondary peritoneal malignancies result from the transcoelomic spread of tumor cells from a primary lesion. The etiology of primary tumors is varied, and a detailed discussion of each is beyond the scope of this chapter.

Epidemiology

Accurate population-based incidence data for PSMs remain elusive because these malignancies arise from a diverse range of primary tumors and typically present at advanced stages. Approximately 30% of patients with colorectal cancer develop peritoneal metastases during their disease course, and 5% to 10% present with synchronous peritoneal disease at the time of diagnosis. Moreover, 25% of patients with peritoneal carcinomatosis from colorectal cancer show the peritoneum as the sole site of metastatic spread, emphasizing the unique dissemination pattern of these tumors.[4]

Epidemiological studies indicate that the incidence of appendiceal neoplasms ranges from 0.12 to 2 cases per million people per year. When left untreated, a significant proportion of these neoplasms progress to pseudomyxoma peritonei, a condition characterized by the accumulation of mucinous ascites and widespread peritoneal implants. Primary peritoneal mesothelioma is more common in men, and represents about 7% to 18% of all mesothelioma cases, with an annual incidence of 1 in 100,000.[5] 

Although each subset of PSMs—whether arising from appendiceal, colorectal, ovarian, or primary peritoneal origins—remains individually rare, these malignancies collectively contribute to a substantial fraction of advanced intra-abdominal cancers. Advances in diagnostic imaging and cytoreductive surgical techniques have improved detection and management, yet the heterogeneous nature of these diseases continues to challenge both epidemiological assessments and treatment strategies.

Pathophysiology

Peritoneal Cavity Anatomy

The anatomy of the peritoneal cavity plays a crucial role in determining the distribution of disease and selecting treatment approaches. The peritoneum is a layer of simple squamous epithelium that lines the abdominal cavity's visceral and parietal surfaces. This lining secretes peritoneal fluid, which continuously moves among the organs and through potential spaces created by mesenteric attachments and other supporting ligaments, eg, the gastrohepatic and coronary ligaments.[6][7]

The constant movement of peritoneal fluid, driven partly by diaphragmatic contractions and gravity, influences where malignant cells may implant within the abdomen (see Image. Pathways of Peritoneal Fluid Movement). This explains why certain areas, including the subphrenic spaces due to diaphragmatic "pull" forces, paracolic gutters, and the pelvis, which is gravity-dependent, are more commonly involved in peritoneal disease.[3]

Peritoneal Surface Malignancy Pathophysiology

PSMs primarily spread through transcoelomic dissemination, a process in which tumor cells detach from the primary tumor and migrate within the peritoneal cavity. Tumor cells actively breach the basement membrane and subsequently adhere to and infiltrate the mesothelial lining of the peritoneum. As the peritoneal cavity is a large, serous surface with constantly moving peritoneal fluid, malignant cells spread throughout the cavity, evading immune cells and utilizing local growth factors to multiply.

Tumor cells employ several strategies to promote their dissemination. They secrete proteolytic enzymes, eg, matrix metalloproteinases, that degrade extracellular matrix components, easing their passage through tissue barriers and preparing the peritoneal surfaces for subsequent implantation. In addition, malignant cells overexpress adhesion molecules, including integrins and CD44, which enhance their ability to attach firmly to the mesothelial lining and increase the likelihood of successful implantation and subsequent growth on the peritoneal surface.[6][8]

Moreover, the peritoneal cavity itself actively participates in the metastatic process. The peritoneal fluid circulates continuously within the cavity, disseminating tumor cells throughout the abdomen. The mesothelial cells lining the peritoneum release cytokines and growth factors in response to the presence of tumor cells, which may inadvertently create a supportive microenvironment that promotes tumor cell survival and proliferation.[6][9]

In some cases, tumor cells can also exploit the lymphatic channels present in the peritoneal lining. These channels facilitate the absorption of peritoneal fluid, and when occupied by malignant cells, they provide an additional pathway for the spread of disease. Although hematogenous dissemination plays a lesser role in PSMs than other metastatic routes, it can still contribute to the disease's complexity by allowing isolated tumor cells to reach distant sites beyond the peritoneum.[6] 

History and Physical

Clinical Presentations

Peritoneal carcinomatosis may manifest in a synchronous or metachronous fashion, often depending on the primary malignancy and extent of the disease. In one retrospective series of patients with nongynecologic peritoneal carcinomatosis, 57% presented with synchronous peritoneal disease, with ascites in 34% and bowel obstruction in 19% as the most common presenting symptoms. By contrast, those with a low tumor burden may remain asymptomatic or report only nonspecific complaints such as mild abdominal pain or early satiety.

When peritoneal carcinomatosis arises synchronously, patients often present with symptoms attributable to the underlying primary tumor (eg, hematochezia in colorectal cancer or pelvic pain in ovarian cancer) after which further staging investigations reveal peritoneal involvement. If imaging fails to capture small-volume disease, intraoperative findings may provide the first indication of peritoneal carcinomatosis. In a metachronous setting, patients typically have a known history of malignancy, including colorectal, appendiceal, or ovarian cancers, and they are diagnosed with peritoneal carcinomatosis either during routine surveillance or when new, often vague symptoms (eg, fatigue), unintended weight loss, or altered bowel habits warrant additional investigation. In advanced disease or when the tumor burden is high, progressive ascites, bowel obstruction, and significant weight changes commonly occur, reflecting extensive intraperitoneal seeding.[1][10]

Physical Examination

On examination, abdominal distension is often observed, and fluid waves or shifting dullness may indicate the presence of ascites. Ovarian cancer, which commonly presents at stage III when involving the peritoneum, can cause pelvic or low back pain, urinary frequency, and an increase in abdominal girth. Patients with pseudomyxoma peritonei, often due to appendiceal mucinous neoplasms, may notice a gradual increase in abdominal size, sometimes accompanied by hernias. Approximately 23% report progressive girth and 14% develop new hernias.

Peritoneal mesothelioma, which accounts for 10% to 30% of mesothelioma cases, may present with diffuse abdominal pain, distension, and early satiety. Approximately 30% to 50% of patients experience these symptoms at their initial evaluation. Physical examination may reveal palpable masses, localized tenderness, or signs of malnutrition and cachexia, all of which are attributable to chronic intra-abdominal pressure and diminished oral intake.[10][1]

Evaluation

The evaluation of PSMs involves identifying the malignancy site and tissue of origin, staging to assess for extraperitoneal disease, and quantifying the amount and distribution of peritoneal disease. 

Laboratory Studies

Tumor markers

Tumor markers can be of value and depend on the site of tumor origin. They are not diagnostic, but provide prognostic information and help in surveillance, including:

• Carcinoembryonic antigen (CEA) is elevated in colorectal and gastric cancer-related peritoneal carcinomatosis.
• Cancer antigen 125 (CA-125) is particularly useful in ovarian and primary peritoneal carcinomas, with high sensitivity but low specificity.
• Cancer antigen 19-9 (CA 19-9) is suggestive of peritoneal involvement in pancreatic and gastrointestinal malignancies.
• Alpha-fetoprotein (AFP) is elevated in hepatocellular carcinoma and yolk sac tumors with peritoneal spread.
• Human epididymis protein 4 (HE4) is often elevated in peritoneal carcinomatosis of ovarian origin.[11][12]

Cytokine and inflammatory biomarkers

Inflammatory biomarkers help in assessing tumor burden and the peritoneal inflammatory response, including:

• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are elevated in advanced-stage peritoneal carcinomatosis.
• Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) correlate with disease progression, particularly in ovarian cancer-related PSM.[13]
• Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are predictive of prognosis in peritoneal carcinomatosis [13][12][13]

Peritoneal fluid cytology and biomarker analysis

The following peritoneal fluid analysis tests can provide direct evidence of malignancy in cases with ascites:

• Cytology: This study is the gold standard for detecting malignant cells in peritoneal carcinomatosis, though sensitivity varies based on tumor type and burden.
• Lactate dehydrogenase (LDH): Increased levels of LDH in peritoneal fluid are associated with malignancy.
• CEA and CA-125 in peritoneal fluid: Elevated levels of these markers suggest malignancy over benign etiologies, eg, cirrhosis-related ascites.[13]

Molecular and Genetic Testing

Molecular testing is increasingly used to help assess prognosis and determine suitability for targeted treatment. Tests that may be utilized for PSMs include:

• KRAS, BRAF, and MSI testing are essential in colorectal cancer-related peritoneal carcinomatosis for therapy selection.
• BRCA1/2 and homologous recombination deficiency (HRD) testing guide the use of PARP inhibitors in ovarian cancer with peritoneal spread.
• Next-generation sequencing (NGS) enables identifying actionable mutations for targeted therapies in peritoneal mesothelioma and other PSMs.

Liquid Biopsy 

Circulating tumor DNA and cells (ctDNA and CTCs) are increasingly used in certain tumors, such as colorectal cancer, and are likely to be more widely used in the coming years.

Imaging Studies

Several imaging studies may be utilized to evaluate patients with suspected or known PSMs.[14] 

Computed tomography

A contrast-enhanced computed tomography (CT) scan of the abdomen and pelvis is the primary imaging modality for evaluating patients with suspected or known PSMs.[15] It provides detailed anatomic information suggesting tumor deposits along peritoneal reflections, the greater and lesser omentum, mesentery, and serosal surfaces of abdominal organs. Features that raise suspicion for PSMs include soft-tissue nodules on the peritoneal surfaces, focal or diffuse peritoneal thickening, omental caking, and ascites. CT can also help identify mucinous components by revealing low-attenuation masses, characteristic of pseudomyxoma peritonei (see Image. Pseudomyxoma Peritonei) secondary to appendiceal or ovarian neoplasms. However, sensitivity may be limited for detecting smaller lesions (<5 mm), and the disease burden in the small bowel or mesentery is frequently underestimated due to overlapping loops of bowel and variable bowel distension.[16]

Several radiologic signs can predict a high likelihood of nonresectability, eg, a large solitary mass in the upper abdomen (often >5 cm), diffuse small bowel wall thickening, or the “smudge” sign where small bowel loops appear matted together, findings sometimes referred to collectively as “Sugarbaker’s Criteria.” Although CT is routinely used to approximate the peritoneal cancer index (PCI), studies suggest it can either underestimate or overestimate the true extent of disease by up to 20% to 30%.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) plays an increasingly vital role in evaluating PSMs, offering superior soft-tissue contrast and multi-planar capabilities without the risks associated with ionizing radiation. In particular, diffusion-weighted imaging enhances the detection of small peritoneal deposits and mucinous lesions, critical for assessing conditions, eg, pseudomyxoma peritonei. When combined with contrast-enhanced sequences, MRI further refines staging by clearly delineating the extent of disease, a key factor in planning cytoreductive surgery and intraperitoneal chemotherapy.[17]

Recent studies have demonstrated that MRI can achieve sensitivity values of approximately 90% to 95% and specificity values of around 85% to 92% for detecting peritoneal metastases, particularly for lesions >5 mm.[18]

Positron emission tomography

Fluorodeoxyglucose positron emission tomography (FDG-PET), typically combined with computed tomography (PET/CT), can reveal hypermetabolic foci within peritoneal surface malignancies and detect extraperitoneal metastases that may alter therapeutic decision-making. Its sensitivity, however, is limited in low-cellularity mucinous neoplasms, including pseudomyxoma peritonei, where radiotracer uptake can be insufficient for accurate detection. Moreover, inflammatory changes or surgical manipulation can yield false-positive signals. Thus, PET/CT is generally regarded as an adjunct to contrast-enhanced CT or MRI, most valuable for ruling out distant metastatic disease or clarifying equivocal findings rather than serving as the principal staging modality.[19][20]

Diagnostic Laparoscopy

Diagnostic laparoscopy provides the most accurate assessment of peritoneal disease burden and distribution, while also allowing for biopsies. It should be performed in all patients for whom cytoreduction and intraperitoneal chemotherapy are considered, and is often also performed in cases where imaging is equivocal. By permitting real-time assessment of tumor distribution and burden, particularly in areas prone to underestimation on CT or MRI, laparoscopy enables a more precise estimation of the PCI and aids in evaluating resectability (see Image. Peritoneal Cancer Index).[21][22][23]

PCI is a standardized quantitative tool for estimating the extent and distribution of PSMs. It partitions the abdominal cavity into 13 discrete anatomical regions (0 through 12) and assigns each region a lesion size (LS) score ranging from 0 to 3. The PCI is then calculated by summing the lesion size scores across all areas, with a maximum possible value of 39 reflecting extensive disease. Notably, lesion size 3 (>5 cm or confluence of disease) is associated with a poor prognosis.[24][25]

In clinical practice, the PCI is a robust surrogate for tumor burden, correlates strongly with both resectability and survival outcomes, and often dictates eligibility for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). While radiologic estimates of the PCI using CT or MRI can guide patient selection for surgery, definitive scoring typically occurs intraoperatively via either laparotomy or, in selected centers, laparoscopic exploration. Accurate scoring is paramount, as patients with a PCI exceeding a certain threshold—commonly 20 for high-grade appendiceal or colorectal cancer, for example—are more likely to have incomplete cytoreduction and diminished survival benefits from aggressive surgical intervention. Consequently, the PCI is integral to risk stratification, surgical planning, and counseling regarding prognosis in the interprofessional management of PSMs.[24]

Treatment / Management

Peritoneal Surface Malignancy Management

The management of peritoneal surface malignancies is predicated on disease extent, tumor biology, and patient fitness. In general, complete cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) offers a chance of long-term survival in well-selected patients, particularly those with low- to moderate-volume disease and favorable histologies. Adjunctive systemic chemotherapy, early postoperative intraperitoneal chemotherapy (EPIC), or emerging techniques like pressurized intraperitoneal aerosol chemotherapy (PIPAC) may further refine treatment outcomes, while targeted therapies and immunotherapies hold promise in specific molecular subsets. Given the complexity of care, patients benefit from coordinated, interprofessional care at high-volume institutions.

Cytoreductive surgery

Cytoreductive surgery (CRS) focuses on excising all macroscopically visible tumors, often involving peritonectomy and resection of involved visceral structures (eg, the omentum, spleen, segments of small or large bowel) and occasionally other organs (eg, liver wedge resections, hysterectomy, bilateral salpingo-oophorectomy in select cases). The goal is to achieve a completeness of cytoreduction (CC) score of 0 or 1 (ie, no visible disease or residual nodules <2.5 mm) because intraperitoneal chemotherapy penetrates only a few millimeters into tissue. Achieving a CC-0/1 resection is strongly associated with improved survival.[3][26][27]

Patient selection for CRS hinges on tumor and patient-related factors. Tumor burden is classically quantified using the PCI. Most centers discourage CRS if the PCI substantially exceeds 20 for high-grade appendiceal or colorectal etiologies, due to the lower likelihood of complete cytoreduction and diminished survival benefits. Favorable histopathologic subtypes (eg, low-grade mucinous appendiceal neoplasms and epithelial mesothelioma) are typically more amenable to CRS than high-grade or signet ring cell carcinomas. Additional considerations include performance status (ECOG/WHO) and comorbidities, as well as prior response to systemic therapies.

Hyperthermic intraperitoneal chemotherapy

Immediately following CRS, HIPEC is administered to eliminate microscopic residual disease. Heat (40 °C to 43 °C) enhances the cytotoxic effect of chemotherapy and improves tissue penetration, theoretically increasing cell kill in areas that are not resectable by surgery alone. Commonly used agents include mitomycin C, oxaliplatin, or cisplatin, which may be combined with doxorubicin.

Drug choice is guided by histology (eg, oxaliplatin and mitomycin C in colorectal PSM, cisplatin-based regimens in peritoneal mesothelioma).[28][29][30] CRS plus HIPEC has shown robust survival benefits for carefully selected patients, especially those with low- or intermediate-volume disease and favorable tumor biology. However, morbidity can be significant, including hematologic toxicity (neutropenia, thrombocytopenia), anastomotic leaks, abscesses, and organ-specific complications (eg, renal dysfunction with cisplatin).[28][29][30] Please see StatPearls' companion resource, "Cytoreduction CRS and Hyperthermic Intraperitoneal Chemotherapy HIPEC", for further information. (A1)

Systemic chemotherapy

Systemic therapy can be used preoperatively to stabilize or downstage disease and assess tumor biology in high-grade malignancies, eg, colorectal or gastric primary tumors. Postoperative therapy may be considered to eradicate microscopic disease, especially in high-risk features (eg, nodal involvement or high-grade histology). However, data on its precise efficacy in the CRS plus HIPEC setting remains evolving.

Standard regimens mirror those used in metastatic gastrointestinal cancers, eg, FOLFOX (5-FU, leucovorin, and oxaliplatin) or FOLFIRI (5-FU, leucovorin, and irinotecan), often combined with targeted agents (bevacizumab or anti-EGFR therapies) or immunotherapies in select settings. Pemetrexed-based regimens, with cisplatin or carboplatin, remain the mainstay of treatment for peritoneal mesothelioma. For low-grade appendiceal tumors, some centers use capecitabine or 5-FU/mitomycin regimens. The optimal sequence, duration, and combination of systemic therapy with CRS plus HIPEC remain areas of active clinical investigation.[31][32][33](A1)

Palliative Care and Symptomatic Management

Noncurative surgical intervention, eg, diverting stomas or debulking without HIPEC, may be warranted to relieve obstructive symptoms, mitigate pain, and improve quality of life in individuals with advanced, unresectable PSMs. Repeated paracentesis can provide temporary symptomatic relief for refractory malignant ascites, and indwelling peritoneal catheters may improve outpatient symptom control. Nutritional assessments, often involving dietitians and supplements, are essential, as reduced oral intake and high metabolic demands frequently lead to malnutrition.[34][35]

Follow-Up and Surveillance

Patients who undergo CRS and HIPEC require regular imaging (CT or MRI) and clinical evaluation at intervals determined by the type of tumor, such as every 3 to 6 months for 2 years, then every 6 to 12 months. Tumor markers (eg, CEA, CA 19-9, or CA-125) may be monitored if they are initially elevated. Recurrence patterns can include new deposits or progression in unresected sites, and some centers consider repeat CRS plus HIPEC for highly selected patients with limited recurrence.

Many PSM patients experience prolonged survival after successful CRS and HIPEC, especially those with low-grade appendiceal or mesothelioma histology. Nonetheless, vigilant surveillance for late recurrences, comorbidities, and complications of extensive surgery (eg, adhesions and incisional hernias) is vital to optimize outcomes.

Differential Diagnosis

The differential diagnoses for peritoneal metastasis include:

• Primary peritoneal malignancy
• Peritoneal mesothelioma
• Peritoneal tuberculosis
• Peritonitis

Prognosis

Quantitative prognostic indicators currently used for peritoneal carcinomatosis include:

• Tumor histology
• Intraoperative assessment of the extent of carcinomatosis at the time of surgical exploration, which can be determined by different scoring systems as described earlier. They include:
  • Gilly staging
  • PCI scoring system
  • Staging by the Japanese Cancer Society for gastric cancer
  • Dutch simplified peritoneal carcinomatosis index (SPCI)
• Completeness of cytoreduction (CC)
• Patient's clinical symptoms [36]

The primary outcome parameters, eg, overall survival, disease-free survival, and 5-year survival rate, depend on the type of primary cancer, achieving cytoreduction (based on CC scoring), HIPEC treatment, and/or the cancer's biological activity. Peritoneal metastasis from an unknown primary tumor has a poor prognosis, with survival as low as 3 months. Although specific histologic subtypes have shown favorable survival, efforts should focus on detecting and identifying the primary tumor, potentially increasing the prognostic benefits of treatment.[37]

Complications

Complications related to untreated or inoperable peritoneal carcinomatosis include:

• Refractory ascites 
• Intestinal obstruction
• Gastrointestinal dysmotility
• Pulmonary thromboembolism
• Peritonitis
• Complications related to portal hypertension (eg, upper GI bleed related to esophageal varices, splenomegaly, hepatic encephalopathy, and ascites)
• Enteric fistula [35]

Postoperative complications related to CRS include bleeding, infection, bowel obstruction, hemorrhage, or peritonitis. Complications associated with HIPEC agents include oxaliplatin, which is used with dextrose solutions, that can potentially contribute to postoperative acidosis and hyperglycemia, and mitomycin C, which can cause neutropenia in about one-third of patients and other gastrointestinal adverse effects.