Peritoneal carcinomatosis implies metastatic dissemination of malignant diseases, most commonly colorectal and pancreatic cancer to the peritoneum. It carries a very poor prognosis, and clinical presentation may include ascites, pain, nausea, and other constitutional symptoms. The diagnosis is made by using various imaging techniques, and treatment, when possible, includes cytoreductive surgery and intraperitoneal administration of chemotherapy.
The clinical presentation of patients with peritoneal carcinomatosis is nonspecific, and most common symptoms are constitutional, such as weight loss, fatigue, while abdominal discomfort and nausea are also commonly reported . Bowel obstruction may occur, resulting in symptoms such as constipation, abdominal pain, cramping and bloating. In general, symptoms are seen only in advanced stages of peritoneal dissemination, as the majority of patients are initially asymptomatic. Development of ascites is also noted in patients and carries a worse prognosis. In any case, patients with such nonspecific symptoms without an apparent cause require a thorough diagnostic workup, to identify the cause and to start prompt treatment. This principle is particularly important for peritoneal carcinomatosis, but for malignant diseases in general, because an early diagnosis may significantly provide better outcomes and survival rates.
Entire Body System
Cancer Chemistry, Hunt Hedi, Lorena Simón-Gracia, Allan Tobi, Kazuki N. [cancerres.aacrjournals.org]
Ikemoto H 1, Lingasamy P 1, Anton Willmore AM 1, Hunt H 1, Kurm K 1, Tammik O 2, Scodeller P 1, Simón-Gracia L 1, Kotamraju VR 3, Lowy AM 4, Sugahara KN 3, 5, Teesalu T 1, 3, 6. [ncbi.nlm.nih.gov]
- Generalized Lymphadenopathy
Computed tomography images showed extensive peritoneal and mesenteric mass associated generalized lymphadenopathy. Core biopsy of the mass confirmed Burkitt's lymphoma. [ncbi.nlm.nih.gov]
- Lower Abdominal Pain
We describe a 26-year-old woman with peritoneal TB presenting with lower abdominal pain and distention, weight loss, and night sweats. There are no pathognomonic clinical, laboratory, or radiologic findings for peritoneal TB. [ncbi.nlm.nih.gov]
Metastatic NET management is often focused solely on liver metastases, and specific PC treatment is either neglected or relegated to a secondary plan. [karger.com]
- Testicular Pain
Twenty months following surgery and intraperitoneal therapy, the patient presented with testicular pain and swelling. [ncbi.nlm.nih.gov]
The initial diagnosis of peritoneal carcinomatosis is achieved primarily by different imaging techniques, while a definite diagnosis is made by tissue biopsy.
Several imaging studies may be used to establish metastatic dissemination of abdominal tumors into the peritoneum. CT scanning and MRI can be used to assess the grade and scope of dissemination and provide significant information in the evaluation of therapeutic principles. These techniques may also reveal metastasis of other sites. Alternatively, an abdominal ultrasound may be performed. PET scanning, using 18F-Fluorodeoxyglucose, is one of the most specific diagnostic procedures, but it is one of the most expensive as well. PET scan can identify very small metastatic deposits in the peritoneum, and also identify the site of the primary tumor with greater sensitivity than CT scan or MRI.
A definite diagnosis can be made by performing laparotomy or laparoscopy with biopsy of the peritoneum, and subsequent histopathological examination. Once peritoneal dissemination of cancer has been established, treatment should be initiated.
Treatment of patients with peritoneal carcinomatosis is very difficult, as long-term survival rates are very low. Nevertheless, significant improvements have been made in the last few decades regarding treatment strategies in patients with this phenomenon.
Because metastatic deposits from the peritoneum cannot be fully removed, and because conservative chemotherapy shows poor results, current approaches in therapy include cytoreductive surgery together with hyperthermic intraperitoneal chemotherapy . Surgery comprises removal of all visible metastases from the surface. Optimal results are achieved when no visible tumor remains after this procedure, but sometimes not all tumors may be resected and removed. Cytoreduction score (CCR) is used to indicate the presence of remaining tumor tissue, and after surgery, HIPEC is administered in the attempt to eliminate remaining cancer cells. In some cases, intraperitoneal chemotherapy is administered right after surgery is performed, or within a few days. Most common chemotherapeutic agents include oxaliplatin, cisplatin, and mitomycin C, but other agents have been used as well. Hyperthermia, which is induced by administration of chemotherapy, is hypothesized to increase the permeability of malignant cells to chemotherapy, and this approach has been shown better results in terms of survival rates .
However, treatment of patients using these modalities may be extremely difficult, and pose significant risks, as the procedure may take up to 14 hours . Complications related to the procedure, drug toxicity, and numerous post-operative risks are present, which illustrates the complexity of treating patients with this form of metastatic malignant disease.
The prognosis of patients with peritoneal carcinomatosis is not good, as this finding implies advanced metastatic disease which is unlikely treatable. Initially, survival rates were extremely poor with conventional chemotherapy , but some advances have been made with the introduction of novel strategies in managing patients with this form of metastatic cancer. Unfortunately, survival rates are still low, ranging from a few months to a year  . Patients who develop malignant ascites have a very poor prognosis, with survival rates below 30 days according to certain studies.
Peritoneal carcinomatosis stems from the invasion of malignant cells of the primary tumor into the peritoneum. The most common primary tumors that have been identified include colorectal, pancreatic, gastric, and ovarian cancers, while other primary tumors that give peritoneal metastasis include sarcomas and breast cancer . Routes of dissemination include direct invasion from the primary tumor or hematogenous and lymphatic spread. The omentum , mesentery, diaphragm, and bowel surface are all peritoneal sites where cells from the primary tumor may be shed .
The exact rates of peritoneal carcinomatosis are unknown, primarily because of underdiagnosis and very scattered reports that are primarily single-center experiences. According to certain studies, approximately one in seven patients will develop peritoneal carcinomatosis , while some larger cohorts have established prevalence rates of between 8-15% among patients with colorectal cancer  . Postoperative development of peritoneal carcinomatosis in patients with gastrointestinal malignancies ranges between 4-19%, while more than 40% of patients with recurrent colorectal cancer develop metastatic dissemination of the tumor into the peritoneum . Neither gender nor ethnic predilections have been established.
The pathogenesis of peritoneal carcinomatosis includes several steps :
- Detachment of cells from the primary tumor - through down-regulation of E-cadherin, a transmembrane glycoprotein that serves as the adhesion molecule, malignant cells are able to break out and spread into other tissues. E-cadherin down-regulation has been confirmed in various tumors, including those that give rise to peritoneal carcinomatosis. Additionally, exfoliation of malignant cells that have reached and invaded the serosa from its primary site is an additional factor in the initial steps of peritoneal dissemination of tumors. Mechanical forces, such as those exerted during resection of the tumor and surrounding lymphatics, may directly introduce tumor cells into the peritoneum as well .
- Binding of malignant cells to the peritoneum - numerous factors have been determined to play a role in the process of adhesion, including various cytokines such as epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), interleukins, adhesion molecules such as integrins and selectins .
- Attachment and proliferation - Once malignant cells have attached to the peritoneum, various proliferative mechanisms are triggered. Through autocrine and paracrine signaling, EGF and VEGF activation results in angiogenesis and cellular proliferation.
Additional mechanisms described in the pathogenesis model of peritoneal carcinomatosis include dissemination of cancer cells through milky spots - organs that are similar to lymph nodes, but devoid of the capsule and contain lymphatic cells, primarily macrophages . The cancer cells pass through these structures on their way to the peritoneum, which is supported by the fact that they are more widely present around anatomical sites through which metastatic dissemination occurs - the greater omentum, Douglas pouch, mesentery of the small bowel, and other.
Prevention of peritoneal carcinomatosis can be achieved by an early diagnosis of malignant diseases that may predispose patients to this disease. However, symptoms may not be apparent until advanced stages of the disease, which significantly contributes to poor outcomes that are established in these patients. Surgical procedures have shown to be a potential factor in the dissemination of malignant cells into the peritoneum, and their indications should be closely inspected prior to their conduction, especially in patients previously diagnosed with colorectal cancer.
Peritoneal carcinomatosis is considered to be a terminal manifestation of cancers originating from the abdomen. Most commonly, tumors of colorectal, gastric, pancreatic and ovarian origin are those in which metastatic dissemination to the peritoneum is observed , and this finding carries a poor prognosis in the majority of patients. The pathogenesis model of peritoneal carcinomatosis includes detachment of cells from the primary tumor that either reaches the peritoneum by direct invasion through the peritoneal layers, or by the hematologic and lymphatic spread. Surgical procedures also pose a risk of disseminating malignant cells into the peritoneum. The clinical presentation of patients with peritoneal carcinomatosis may be nonspecific, and even asymptomatic. Constitutional symptoms, which are related to the metastasis, include malaise, fatigue, nausea, vomiting, weight loss, pain and other symptoms depending on the site. Ascites can also be encountered, and in these patients, the term "malignant ascites" is used. The diagnosis is made by imaging studies, including computed tomography (CT scan) and magnetic resonance imaging (MRI), which can identify other metastatic deposits as well. However, the most specific and most sensitive, but also most expensive technique that can be used in identifying peritoneal metastases is positron emission tomography (PET scan). By using fluorodeoxyglucose (FDG-PET scan), lesions in the peritoneum can be identified, while a definite diagnosis may be obtained by performing laparoscopy with biopsy, and subsequent histopathologic examination. Because survival rates are very low in these patients, very aggressive forms of treatment are used, including surgery and chemotherapy when possible. Because tumors cannot be excised completely, cytoreductive surgery is performed, which implies removal of as much tumor tissue as possible. Intraperitoneal administration of one or more chemotherapeutic agents, such as cisplatin, mitomycin C, doxorubicin, have shown superior result compared to conventional chemotherapy because greater concentrations reach malignant cells without a substantial increase in serum concentrations, thus limiting toxicity and maximizing the effect . Moreover, hyperthermic intraperitoneal chemotherapy (HIPEC) has shown better results, presumably because hyperthermia additionally increases the permeability of malignant cells to cytotoxic drugs. Despite these aggressive approaches, however, survival rates are still measured in months in the majority of patients, which illustrates the importance of recognizing and diagnosing malignant diseases in their early stages.
Peritoneal carcinomatosis (PC) is one of the terminal features that is seen in patients with colon, stomach, ovarian, or pancreatic cancer. The term implies the presence of metastases in the peritoneum, which is a large membrane that encloses the abdominal organs. The function of the peritoneum is to provide structural support and it contains blood and lymphatic vessels which provide nutritional support throughout the abdomen. In patients with cancers that develop in the abdomen, malignant cells may detach and reach the peritoneum, either by direct invasion or by spreading through blood and lymphatic vessels. Because symptoms are not commonly present, the diagnosis of peritoneal carcinomatosis may be difficult. Symptoms that are reported include abdominal discomfort, malaise, weight loss, fatigue, pain, nausea, vomiting, and other non-specific symptoms that may be seen in the majority of patients with malignant disease. The diagnosis of peritoneal carcinomatosis is made by performing certain imaging techniques, such as computed tomography or magnetic resonance imaging, which can show the presence of peritoneal metastases. Positron emission tomography is expensive, but the most successful diagnostic procedure, which comprises injection of labeled molecules which bind to malignant cells, and this technique is superior to CT or MRI. A definite diagnosis can be made by performing a biopsy. The prognosis of patients with peritoneal carcinomatosis is very poor, and the majority of patients are able to survive only a few months, and rarely a year, but significant therapeutic advances have been made in the past decades. Currently, the therapy comprises surgery that has a goal to eliminate as much tumor tissue as possible (called cytoreductive surgery), which is combined with administration of chemotherapy directly into the peritoneum, because higher concentrations are achieved in that way. Additionally, it was established that if the temperature inside the peritoneum is increased, chemotherapy will be more successful, presumably because cancer cells become more susceptible to the drugs, which is why the term hyperthermic intraperitoneal chemotherapy (HIPEC) is used. Although significant advances have been made in therapy, long-term survival of patients peritoneal carcinomatosis is minimal, which is why an early diagnosis of patients with malignant diseases is essential.
- Sugarbaker PH, Schellinx ME, Chang D, et al. Peritoneal carcinomatosis from adenocarcinoma of the colon. World J Surg. 1996;20:585–591.
- Arjona-Sánchez A, Medina-Fernández FJ, Muñoz-Casares FC, et al. Peritoneal metastases of colorectal origin treated by cytoreduction and HIPEC: An overview. World J Gastrointest Oncol. 2014;6(10):407-412.
- Chu DZ, Lang NP, Thompson C, et al. Peritoneal carcinomatosis in nongynecologic malignancy. A prospective study of prognostic factors. Cancer. 1989;63:364–367.
- Gerber SA, Rybalko VY, Bigelow CE, et al. Preferential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth. Am J Pathol. 2006;169:1739–1752.
- Meyers MA. Distribution of intra-abdominal malignant seeding: dependency on dynamics of flow of ascitic fluid. Am J Roentgenol Radium Ther Nucl Med. 1973;119:198–206.
- Ceelen WP, Bracke ME. Peritoneal minimal residual disease in colorectal cancer: mechanisms, prevention, and treatment. Lancet Oncol. 2009;10(1):72-79.
- Jayne DG, Fook S, Loi C, Seow-Choen F. Peritoneal carcinomatosis from colorectal cancer. Br J Surg. 2002;89:1545–1550.
- Golfinopoulos V, Salanti G, Pavlidis N, Ioannidis JP. Survival and disease-progression benefits with treatment regimens for advanced colorectal cancer: a meta-analysis. Lancet Oncol. 2007;8:898–911.
- Koppe MJ, Boerman OC, Oyen WJG, Bleichrodt RP. Peritoneal Carcinomatosis of Colorectal Origin: Incidence and Current Treatment Strategies. Annals of Surgery. 2006;243(2):212-222.
- Kusamura S, Baratti D, Zaffaroni N, et al. Pathophysiology and biology of peritoneal carcinomatosis. World Journal of Gastrointestinal Oncology. 2010;2(1):12-18.
- Kostić Z, Cuk V, Bokun R, et al. Detection of free cancer cells in peritoneal cavity in patients surgically treated for gastric adenocarcinoma Vojnosanit Pregl. 2006;63:349–356.
- Jayne DG. The molecular biology of peritoneal carcinomatosis from gastrointestinal cancer. Ann Acad Med Singapore. 2003;32:219–225.
- Sacchi G, Di Paolo N, Venezia F, et al. Possible role of milky spots in mesothelial transplantation. Int J Artif Organs. 2007;30:520–526.
- Bloemendaal AL, Verwaal VJ, van Ruth S, Boot H, Zoetmulder FA. Conventional surgery and systemic chemotherapy for peritoneal carcinomatosis of colorectal origin: a prospective study. Eur J Surg Oncol. 2005;31:1145–1151.
- Sadeghi B, Arvieux C, Glehen O, et al. Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer. 2000;88:358–363.
- Köhne CH, Cunningham D, Di Costanzo F, et al. Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients. Ann Oncol. 2002;13:308–317.
- Levy AD, Shaw JC, Sobin LH. Secondary tumors and tumorlike lesions of the peritoneal cavity: imaging features with pathologic correlation. Radiographics. 2009;29(2):347-73.
- Klaver YL, Lemmens VE, Nienhuijs SW, et al. Peritoneal carcinomatosis of colorectal origin: Incidence, prognosis and treatment options. World Journal of Gastroenterology : WJG. 2012;18(39):5489-5494.
- Chua TC, Yan TD, Morris DL. Outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma: the Australian experience. J Surg Oncol. 2009;99:109–113.
- Brücher BL, Piso P, Verwaal V, et al. Peritoneal carcinomatosis: cytoreductive surgery and HIPEC--overview and basics. Cancer Invest. 2012;30(3):209-24.