Peritoneal Cancer

Synonyms and related keywords: primary peritoneal cancer, peritoneal malignancy, peritoneum, peritoneal carcinoma, peritoneal carcinoma, malignant mesothelioma, benign papillary mesothelioma, desmoplastic small round cell tumor, peritoneal angiosarcoma, leiomyomatosis peritonealis disseminata, LPD, peritoneal hemangiomatosis, abdominal therapeutic radiation, radiation therapy, asbestos exposure


INTRODUCTION

Background: Since the early years of the last century, the peritoneum has been a topic of considerable interest. Initially, the major focus was on peritoneal infections; however, with the subsequent introduction of antibiotics, the focus of gynecological and nongynecological pathologists shifted to neoplastic and nonneoplastic peritoneal conditions.

Currently, a number of primary cancers have been described to originate from the peritoneum. Knowledge of primary peritoneal cancers is important because these entities have been implicated in many cases of carcinomas of unknown primary origin when no clear explanation for peritoneal carcinomatosis can be documented. The existence of this phenomenon also explains the occurrence of ovarian cancer in women several years after bilateral oophorectomy, as is observed with primary peritoneal carcinoma. Other described primary peritoneal cancers and tumorlike lesions include malignant mesothelioma, benign papillary mesothelioma, desmoplastic small round cell tumors, peritoneal angiosarcoma, leiomyomatosis peritonealis disseminata (LPD), and peritoneal hemangiomatosis.

Pathophysiology: The peritoneum is a serous lining of mesothelial cells with a rich vascular and lymphatic capillary network.

Peritoneal mesothelioma is a primary tumor of the mesothelial lining of the peritoneum. The tumor can be classified as benign, borderline malignant, or malignant. Benign mesothelioma is a circumscribed papillary tumor of considerable firmness, while malignant mesothelioma covers the surface of the mesentery and can obliterate the entire peritoneal cavity.

Both mesotheliomas (solitary and diffuse forms) have a similar growth pattern and are composed of strands of connective tissue covered by cells that react positively to periodic acid-Schiff staining in the cytoplasm. These cells grow in multiple layers, forming papillary or tubular formations. In most instances, the tumor is dominated by growth of cells, but very rarely, abundant production of collagen fibers can occur, leading to the fibrous type of peritoneal mesothelioma. Microscopic findings in malignant mesothelioma include extensive cell vacuolization, rare psammoma bodies, the presence of hyaluronic acid, and a lack of mucin.

This tumor tends to spread into the pleural space, leading to pleural plaques observed on chest x-ray films in 50% of patients with primary peritoneal cancer, compared to 20% of patients with primary pleural mesothelioma, which suggests a higher level of asbestos exposure in patients with peritoneal disease. The incidence of asbestos exposure in patients with benign mesothelioma approximates the incidence rate of exposure in the general population, while the association of malignant peritoneal mesothelioma and asbestos exposure has been reported to be as high as 83%. Malignant peritoneal mesothelioma has also been associated with abdominal therapeutic radiation.

A rare syndrome of recurrent peritoneal mesothelial cysts (also termed benign cystic peritoneal mesothelioma) consisting of multiloculated inclusion cysts has been described. Some authors advocate classifying this lesion as reactive proliferation rather than malignancy.

Primary peritoneal carcinoma (also termed serous surface papillary carcinoma) is a malignancy that arises primarily from peritoneal cells. The mesothelium of the peritoneum and the germinal epithelium of the ovary arise from the same embryologic origin; therefore, the peritoneum may retain the multipotentiality of the müllerian system, allowing the development of a primary carcinoma.

A desmoplastic small round cell tumor can sometimes be difficult to differentiate from a malignant peritoneal mesothelioma. This tumor demonstrates extensive involvement of the peritoneal surfaces, with rapid multifocal growth and hematogenous metastasis to the liver, lungs, and lymph nodes.

LPD is a condition of small, firm, white-to-gray nodules studding and covering the peritoneal surface. Histologically, these nodules are composed mainly of smooth muscle cells with variable amounts of decidualization and hyalinization. Minimal mitotic activity is observed, with no evidence of atypia or nuclear pleomorphism. The histogenesis of LPD has been a point of debate because of the discrepancy of ultrastructural studies. Regardless of whether the cellular content is decidual cells or smooth muscle cells, embryogenesis involves multipotential mesenchymal stem cells. Excessive hormonal stimulation with estrogen or progesterone has been recognized as a potential stimulus for LPD development. Although once believed to be an unquestionably benign process, cases have been reported of patients with LPD that subsequently evolved into aggressive leiomyosarcomas.

Peritoneal angiosarcomas are rare tumors that appear benign histologically but usually act aggressively. They may arise following previous radiation treatment to the serous membranes. Hemangiomatoses of the peritoneum are rare and are usually associated with hemangiomas of the GI tract or cutaneous hemangiomas.

Frequency:

• In the US: Primary peritoneal carcinoma is a rare tumor occurring almost exclusively in women. Peritoneal mesotheliomas are also rare, with 2 cases per 1 million population reported each year. However, the incidence appears to be increasing. Based on the prior use of asbestos, more than 8 million persons in the United States are exposed and at risk. Benign cystic peritoneal mesotheliomas are rare.

Mortality/Morbidity:

• Survival rates are poor for patients with primary peritoneal carcinoma, with 100% mortality; the median survival reported is from 12-25 months, even with extensive surgery and chemotherapy.

• Benign cystic peritoneal mesotheliomas are associated with prolonged survival despite bulky disease.

• Desmoplastic small round cell tumors are associated with a reported median survival of 17 months.

Sex:

• Primary peritoneal carcinoma is a rare tumor occurring almost exclusively in women.

• Malignant mesotheliomas show extreme male predominance (93% in one series).

Age: Patients with primary peritoneal carcinoma are older compared to those with epithelial ovarian cancers.

• Desmoplastic small round cell tumors occur in adolescent persons and young men.

• Benign cystic peritoneal mesotheliomas are rare and are found predominantly in younger women.

• Most cases of LPD have been discovered in reproductive-aged women (mean age 37 y), in young pregnant women, and in women who have hormonal excess for any other reason. In most reported cases, nodules either regress or exhibit growth once the hormonal stimulation has been removed.

CLINICAL

History:

• Primary peritoneal carcinoma usually manifests with abdominal distention and diffuse nonspecific abdominal pain secondary to ascites. This tumor is described almost exclusively in women. Atypical presentations of primary peritoneal carcinoma have been described, including a case of severe glandular dysplasia on a screening Papanicolaou test (Pap smear), which, after ectocervical biopsy, revealed evidence of moderately differentiated adenocarcinoma, later confirmed to be metastasis of primary peritoneal carcinoma.

• Malignant peritoneal mesothelioma usually manifests with symptoms and signs of advanced disease, including pain, ascites, weight loss, or an abdominal mass.

• These tumors tend to manifest with diffuse involvement of the peritoneal cavity, including omental caking and diaphragmatic and pelvic tumor deposits.

• Thrombocytosis is common and is associated with a poor prognosis.

• Other common clotting abnormalities include phlebitis, emboli, hemolytic anemia, and disseminated intravascular coagulation.

• Esophageal achalasia, secondary amyloidosis, and dermatomyositis have been reported.

• Most patients die without metastasis or involvement of the chest.

• Desmoplastic small round cell tumors are rare, typically occurring in adolescent persons and young men and manifesting with extensive involvement of the peritoneal surfaces. Rapid multifocal growth and hematogenous metastasis to the liver, lungs, and lymph nodes are common.

• LPD is found most commonly in women of reproductive age who are pregnant; these patients are usually asymptomatic, have a long-term history of oral contraceptive use, or have uterine leiomyomas at the time of diagnosis. All cases of this disease have been discovered intraoperatively during obstetric and gynecologic surgical procedures.

• Peritoneal hemangiomas are usually associated with hemangiomas of the GI tract. They are rare and can manifest with ascites, anemia (from chronic blood loss), thrombocytopenia, and coagulopathy.

Causes:

• A chromosomal translocation, which results in the fusion of the Ewing sarcoma gene with the Wilms tumor gene, has been identified and implicated in desmoplastic small round cell tumors.

• Hereditary predisposition may play a role in primary peritoneal carcinoma because patients with the BRCA1 mutation have an increased risk.

• Although conventional wisdom dictates that asbestos is the environmental factor most commonly associated with mesothelioma, asbestos does not transform human mesothelial cells in tissue culture. This suggests that additional carcinogens act in concert with asbestos to cause mesothelioma.

DIFFERENTIALS

Ovarian Cysts

Other Problems to be Considered:

The differential diagnosis of primary peritoneal cancers includes peritoneal metastasis (ie, peritoneal carcinomatosis) from primary sites including the GI tract, ovaries, or breast or as part of the syndrome of adenocarcinomas of unknown primary site. Although the primary histology findings dictate the clinical course, important concepts of diagnosis and treatment are common to all forms. The most important risk factor for developing peritoneal carcinomatosis is the depth of invasion of the primary tumor.

Reactive tumorlike lesions of the peritoneum have been described and should be included in the differential diagnosis of primary peritoneal cancers, as follows:

• Granulomatous lesions
  
  
  • Vernix caseosa and meconium peritonitis
    
    
  • Granulomatous peritonitis secondary to foreign material, including keratin
    
    
  • Necrotic pseudoxanthomatous nodules
    
    
  • Postcautery granulomas
  
  
• Nongranulomatous histiocytic lesions
  
  
  • Ceroid-rich histiocytic infiltrates
    
    
  • Peritoneal melanosis
    
    
  • Mucicarminophilic histiocytosis
    
    
  • Other histiocytic infiltrates
  
  
• Fibrosing lesions
  
  
  • Sclerosing peritonitis
    
    
  • Peritoneal fibrosis nodules
  
  
• Mesothelial lesions
  
  
  • Mesothelial hyperplasia
    
    
  • Peritoneal inclusion cysts

Pseudomyxoma peritonei typically includes any low-grade or benign tumor within the abdominal cavity that produces copious amounts of mucinous ascites. This condition includes peritoneal spread from well-differentiated adenocarcinomas of the GI tract and benign mucin-secreting adenomas of the appendix.


WORKUP

Lab Studies:

• Malignant peritoneal mesothelioma: Findings from cytologic examination of ascites can suggest the diagnosis, and findings from percutaneous biopsy of the omentum can help verify the diagnosis. This condition is usually confined to the abdomen at the time of diagnosis.

Imaging Studies:

• Standard imaging tests, including ultrasonography and helical CT scans, are notably insensitive for the detection of peritoneal tumors.

• The sensitivity of CT scans for peritoneal nodules measuring smaller than 1 cm is approximately 15-30%.

• Ultrasonography is similarly insensitive; therefore, considering findings, rather than solid tumor detection, that may suggest the presence of peritoneal lesions is important. These include the presence of ascites, fixing together of bowel loops, thickening of mesentery, and omental matting.

• CT scan findings are nonspecific in primary papillary serous carcinoma of the peritoneum. Consider this diagnosis when findings include ascites, omental caking, and diffuse enhancement with nodular thickening of the parietal peritoneum of the pelvis observed with normal-sized ovaries, with or without a fine enhancing surface nodularity of the ovary.

• Some studies show that MRI is superior to helical CT scan for the detection of peritoneal and bowel wall abnormalities.

• Positron emission tomography imaging has not been shown to be sensitive for lesions smaller than 1 cm in the abdominal cavity.

• Findings from radionuclide scan studies can help confirm the diagnosis of peritoneal hemangiomas; the isotope concentrates in the area where platelets are being sequestered. A CT scan and ultrasound also may detect larger hemangiomas. Angiographic evaluation is a more precise, although invasive, procedure when radionuclide scans, CT scan, and ultrasound findings are negative.

Procedures:

• Procedures for the workup of peritoneal lesions include peritoneal lavage cytology. This can be performed using a cutaneous closed technique or at the time of laparoscopy or laparotomy. The sensitivity of the test results depends on the ability to completely lavage all regions of the peritoneal cavity and the ability to detect cancer cells being shed into the peritoneal cavity by the tumor.

• Direct visualization of the peritoneal surfaces along with palpation of the abdominal contents is by far the most sensitive modality for detecting peritoneal cancer. This can be accomplished with a minimally invasive approach (ie, laparoscopy), which allows for safe, directed peritoneal lavage for cytology and with open abdominal exploration and palpation of the peritoneal surfaces. Open abdominal exploration and palpation are extremely sensitive for 1- to 2-mm peritoneal nodules.

Histologic Findings: Primary peritoneal carcinoma is histologically indistinguishable from primary epithelial ovarian carcinoma; however, primary ovarian cancer can be excluded based on certain criteria. First, both ovaries must be of normal in size. Second, the extraovarian involvement must be greater than the involvement on the surface of the ovary. Third, the ovarian component must be smaller than 5 by 5 mm within the ovary or confined to the ovarian surface. Finally, the cytologic characteristics must be of the serous type.


TREATMENT

Medical Care:

• In general, primary peritoneal carcinoma is treated similar to ovarian cancer, with cytoreduction and adjuvant therapy with platinum-based chemotherapeutic regimens. Treatment consists of total abdominal hysterectomy and bilateral salpingo-oophorectomy as needed, with debulking of the tumor and follow-up chemotherapy. Carboplatin or cisplatin therapy, in combination with paclitaxel, is associated with a high response rate and improvement of median survival.

• Chemotherapy and radiation therapy are used sometimes and may cause a partial response. Intraperitoneal instillation of radioactive colloidal gold Au 198 has been reported to improve symptoms of peritoneal mesothelioma. In one study, intraperitoneal chemotherapy using cisplatin with intravenous thiosulphate protection resulted in a 59% complete response rate. Other agents used intraperitoneally include mitomycin C, doxorubicin, and epidoxorubicin.

• Benign papillary mesothelioma is believed to require only follow-up care after excisional biopsy because no malignant potential has been reported.

• Excessive hormonal stimulation appears to correlate with LPD development because it is commonly associated with pregnancy. Conservative management, with removal of the source of excessive hormones where applicable, and long-term follow-up care are recommended because of the general indolent clinical course of LPD.

• Treatment of peritoneal and GI hemangiomas has involved surgical removal. Radiation therapy has also been reported effective in some cases but applies mostly to single, large hemangiomas. Corticosteroids have also been successful in many cases; recently, trials with the fibrinolytic inhibitor epsilon-aminocaproic acid, which promotes local thrombosis within the hemangioma, have been reported. Chemotherapy with cyclophosphamide has also been used in children with hemangiomas, with variable success. The use of a carbon dioxide laser may be a useful adjunct to surgery when diffuse capillary hemangiomas are present and not amenable to surgical extirpation.

Surgical Care:

• Treatment of primary peritoneal carcinoma consists of total abdominal hysterectomy and bilateral salpingo-oophorectomy as needed, with debulking of tumor and follow-up chemotherapy

• Treatment of malignant peritoneal mesothelioma consists primarily of surgical palliation. Complete surgical resection is rarely, if ever, feasible and has not been shown to afford a survival benefit in the absence of additional therapy. If laparoscopy is used to help make the initial diagnosis, confine port sites to the abdominal midline because port site recurrence has been described, requiring extensive abdominal wall resection.

• Benign cystic mesothelioma tends to recur even with aggressive surgical removal; however, among recorded cases, no deaths have been attributable to this process.

• A combination of aggressive surgical debulking and systemic chemotherapy with cyclophosphamide, doxorubicin, and vincristine interspersed with ifosfamide, etoposide, and mesna (P6 protocol) appears to lead to an improved outcome in patients with desmoplastic small cell tumors.

• Treatment of peritoneal and GI hemangiomas has involved surgical removal.

MEDICATION

The goals of pharmacotherapy are to induce remission, to prevent complications, and to reduce morbidity.

Drug Category: Chemotherapeutic agents -- Inhibit cell growth and proliferation. Agents used include cisplatin, doxorubicin, cyclophosphamide, carboplatin, and paclitaxel.

Drug Name	Cisplatin (Platinol) -- Inhibits DNA synthesis and thus cell proliferation by causing DNA cross-links and denaturation of double helix.
Adult Dose	75-100 mg/m2 q3wk IV; 90-270 mg/m2 IP; retain 4 h before draining with systemic sodium thiosulphate
Pediatric Dose	30-100 mg/m2 q2-3wk
Contraindications	Documented hypersensitivity; preexisting renal insufficiency, myelosuppression, and hearing impairment
Interactions	Increases toxicity of bleomycin and ethacrynic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	Administer adequate hydration before and 24 h after dosing to reduce risk of nephrotoxicity; hyperuricemia, nausea and vomiting, myelosuppression, anemia, peripheral neuropathy, ototoxicity, nephrotoxicity, acute renal failure, bradycardia, arrhythmia, mild alopecia, SIADH, hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia, mouth sores, elevated liver enzymes, phlebitis, optic neuritis, blurred vision, and papilledema may occur; symptoms of overdosage include severe myelosuppression, intractable nausea and vomiting, kidney and liver failure, deafness, ocular toxicity, and neuritis; use proper handling and disposal

Drug Name	Doxorubicin (Adriamycin, Rubex) -- Inhibits topoisomerase II and produces free radicals, which may cause the destruction of DNA. Combination of these events can, in turn, inhibit the growth of neoplastic cells.
Adult Dose	60-75 mg/m2 as a single dose, repeat q21d; 20-30 mg/m2/d for 2-3 d, repeat in 4 wk; or 20 mg/m2 once wk
Pediatric Dose	35-75 mg/m2 as a single dose, repeat q21d; 20-30 mg/m2 once weekly; or 60-90 mg/m2 continuous infusion over 96 h q3-4wk
Contraindications	Documented hypersensitivity; severe heart failure; cardiomyopathy; impaired cardiac function; preexisting myelosuppression
Interactions	May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Extravasation may result in severe local tissue necrosis; reduce dose in patients with impaired hepatic function; use proper handling and disposal; total dose not to exceed 550 mg/m2 or 400 mg/m2 in patients with previous or concomitant treatment (ie, with daunorubicin, cyclophosphamide, or irradiation of the cardiac region); alopecia, nausea and vomiting, mucositis, ulceration and necrosis of the colon, anorexia and diarrhea, stomatitis, esophagitis, red discoloration of urine, myelosuppression, and cardiac toxicity may occur Acute arrhythmia, heart block, pericarditis-myocarditis, and chronic cardiac toxicity as congestive cardiac failure may occur; facial flushing, hyperpigmentation of nail beds, erythematous streaking along the vein if administered too rapidly, hyperuricemia, fever, chills, urticaria, conjunctivitis, allergic reaction, and anaphylaxis may occur; radiation recall noticed in patients who have had prior irradiation; symptoms of overdosage include myelosuppression, nausea, vomiting, and myocardial toxicity

Drug Name	Carboplatin (Paraplatin) -- Analog of cisplatin. Has same efficacy as cisplatin but with better toxicity profile. Dose is based on following formula: Total dose (mg) = (target AUC) X (GFR = 25), where AUC (area under plasma concentration-time curve) is expressed in mg/mL/min and GFR (glomerular filtration rate) is expressed in mL/min.
Adult Dose	360 mg/m2 IV q3wk as monotherapy or 300 mg/m2 q4wk as combination therapy
Pediatric Dose	300-600 mg/m2 IV q4wk
Contraindications	Documented hypersensitivity; bone marrow suppression
Interactions	Nephrotoxicity increases with aminoglycosides and other nephrotoxic drugs
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor bone marrow function; use proper handling and disposal; high doses have resulted in severe LFT abnormalities; increased risk of allergic reactions if previously exposed to platinum therapy; hypocalcemia, hypomagnesemia, hyponatremia, hypokalemia, nausea, vomiting, stomatitis, myelosuppression, asthenia, alopecia, diarrhea, anorexia, peripheral neuropathy, and ototoxicity may occur; symptoms of overdosage include bone marrow suppression and hepatic toxicity

Drug Name	Cyclophosphamide (Neosar, Cytoxan) -- Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Adult Dose	50-100 mg/m2/d PO continuous therapy or 400-1000 mg/m2 PO in divided doses 4-5 d intermittent therapy
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate cyclophosphamide-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; use proper handling and disposal Adverse effects include alopecia, sterility, nausea and vomiting, diarrhea, stomatitis, mucositis, jaundice, headache, skin rash, facial flushing, myelosuppression, cardiac dysfunction, dizziness, darkening of skin/fingernails, hyperglycemia, hypokalemia, hyperuricemia, SIADH, acute hemorrhagic cystitis, hepatic toxicity, renal tubular necrosis, nasal congestion, interstitial pulmonary fibrosis, and secondary malignancy (alone or in combination with other antineoplastics) Both bladder carcinoma and acute leukemia are well documented; symptoms of overdosage include myelosuppression, alopecia, nausea, and vomiting

Drug Name	Paclitaxel (Taxol) -- Mechanisms of action are tubulin polymerization and microtubule stabilization.
Adult Dose	175 mg/m2 IV over 3 h q3wk; alternatively, 135 mg/m2 IV over 24 h q3wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to paclitaxel or polyoxyethylated castor oil; peripheral neuropathy; bone marrow suppression; liver failure; severe cardiac disease
Interactions	Coadministration with cisplatin may further increase myelosuppression
Pregnancy	D - Unsafe in pregnancy
Precautions	Premedicate with steroids, H1 blockers, and H2 blockers to decrease risk of hypersensitivity reactions; current evidence indicates that prolongation of infusion >6 h plus premedication may minimize this effect; adverse reactions include hypotension, abnormal ECG tracings, alopecia, nausea and vomiting, diarrhea, mucositis, bleeding anemia neutropenia, thrombocytopenia, abnormal LFT results, peripheral neuropathy, myalgia, bradycardia, and radiation pneumonitis in patients receiving concurrent radiotherapy

FOLLOW-UP

Further Inpatient Care:

• Follow up to evaluate patients for complications of the cancer, spread of the cancer, and possible complications of therapy.

• Screening is also essential to help rule out known associated cancers and cancer syndromes.

Prognosis:

• Patients with peritoneal mesothelioma generally have a better prognosis compared to those with pleural mesothelioma. Original reports suggest a median survival of less than 1 year from the time of diagnosis; however, multiple varied treatment approaches may prolong long-term survival.

• See Mortality/Morbidity.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Failure to diagnose and appropriately treat cancers and precancerous lesions

• Failure to monitor to detect cancer recurrence and complications

• Failure to detect adverse effects and complications of therapy