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How to differentiate peritoneal cancer from other diseasesNonspecific abdominal and GI complaints often lead to misdiagnosis—or to a missed diagnosis. Be especially alert for symptoms that are new, severe, or more frequent.Dawanda R. Pesicka, PA-CDawanda Pesicka practices with Group Health Permanente, Seattle, Washington. She has indicated no relationships to disclose relating to the content of this article.Primary peritoneal cancer (PPC) is a disease in which carcinomatosis—defined as widespread dissemination of carcinoma1—is present within the abdominopelvic peritoneum. The histologic appearance of PPC, its clinical manifestations, and the response to treatment closely parallel those for papillary serous ovarian carcinoma.2,3 In PPC, however, involvement of the ovaries is either minimal or nonexistent. PPC was first reported in the literature by Dr. Martin Swerdlow in 1959.4 Dr. Swerdlow discussed the case of a 27-year-old female who presented with an 8-year history of pelvic pain, lower abdominal heaviness, and urinary urgency and frequency. Exploratory laparotomy revealed an 8.5-cm granular tumor that histologically resembled ovarian papillary cystadenocarcinoma, except that both ovaries and the right fallopian tube were free of disease.4 A greater understanding of PPC revealed that the tumor was a derivative of the müllerian system, including the tubal, endometrial, and endocervical epithelium,5 and constituted a separate entity from ovarian carcinoma. EPIDEMIOLOGY AND ETIOLOGYTwo theories propose to explain the similarity between PPC—also referred to as papillary serous carcinoma of the peritoneum—and papillary serous ovarian carcinoma. One theory says that the tumor develops from remnants of ovarian tissue left in the peritoneum during embryonic development. The second hypothesis suggests that the tumor originates from the mesoderm.6 Although PPC is seen almost exclusively in women, two cases have been reported in men,7,8 which supports the second theory. However, researchers have not conclusively agreed with either theory. Exact incidence rates of PPC are unknown. An estimated 10% of ovarian cancer cases are, in fact, PPC; this translates to approximately 2,000 cases of PPC annually in the United States.2,3,9 Better recognition in recent years has resulted in an apparent increase in occurrence. In fact, as many as 18% of laparotomies performed for ovarian carcinoma yield a diagnosis of PPC on pathology.3,10 Average age at diagnosis is 57 to 66 years.2,11,12 PPC is not specific to any demographic population defined by race, socioeconomic status, smoking history, or use of birth control or hormones. Data on age at menarche, family history of gynecologic malignancies, and number of births have been compared with data for epithelial ovarian cancer. However, much of this information is conflicting. Because the numbers of participants in these studies have been low, the study findings lack any significant conclusions.3,10,13 SYMPTOMS Patients with PPC commonly report the presence of several nonspecific abdominal symptoms (see Table 1). Other symptoms reported include feeling full after small meals, back pain, fatigue, and dyspnea.3,6 The presence of two or more symptoms is common in patients with PPC. Only 6% of patients with PPC are asymptomatic.3 Several presenting symptoms are somewhat vague in nature and may occur in women without malignancy. They are also complaints women commonly mention to their primary care providers. However, new-onset symptoms or those that occur with greater severity or increased frequency should be deemed suspicious, particularly when the symptoms persist for more than 2 to 4 weeks.14 Abdominopelvic CT scans should be obtained even if pelvic examination findings are normal. DIAGNOSTIC CRITERIAPPC can be diagnosed only via pathologic evaluation, but several earlier steps can be taken toward making the diagnosis. A complete history that includes as much information about the patient’s family history as possible may be helpful. A complete physical examination, including thorough abdominal and rectovaginal examinations, should be performed. The Gynecologic Oncology Group established criteria that define PPC11 (see Table 2). Ascites is the most common physical examination finding in patients with PPC. Ascites is reported in 50% to 85% of cases.2,3 An important consideration is that pelvic examination findings may be normal because the ovaries are either minimally or not involved. Abdominal or extraovarian pelvic masses are palpable in only 30% of cases.3 Laboratory studies include a baseline CBC and measurement of the cancer antigen 125 (CA-125) tumor marker. CA-125 level is elevated (more than 35 μg/mL) in more than 90% of patients with PPC.15 In Eltabbakh and colleagues’ study, which included 75 women with PPC, the median CA-125 level was 1,320 μg/mL.15  Radiography plays a key role in diagnosing PPC and in determining the extent of disease. Common CT findings include ascites; omental caking; lymph node enlargement; and irregular, nodular peritoneal thickening6 (see Figure 1). Pap smear results that reveal the presence of psammoma bodies are occasionally associated with PPC.16 Despite this finding, a Pap smear should not be considered a diagnostic tool for PPC. Cytologic evaluation of abdominopelvic fluid may be useful in pinpointing cellular etiology; however, paracentesis can cause additional seeding of the tumor at the fluid withdrawal site. This procedure is more commonly used for symptomatic relief of the abdominal distention, decreased satiety, nausea/vomiting, and dyspnea that are associated with abundant ascites fluid. Cellular sampling can rule out malignant pleural effusions and determine if chest imaging is needed to further evaluate extent of disease. Unlike most gynecologic cancers, PPC does not follow a specific staging system. Diffuse peritoneal carcinoma spread is typical in about three fourths of all cases of PPC. In the remaining cases, more distant metastases usually manifest as malignant pleural effusions or liver lesions. If a staging system was followed, these would be stages III and IV, respectively, with no possibility of early-stage cases. PPC is rarely limited to the pelvis.3 A prompt diagnosis and initiation of proper treatment can prevent further disease spread, particularly distant metastases, ultimately resulting in symptom relief, improved quality of life, and longer life expectancy. CASE PRESENTATIONThe patient is a 69-year-old, G2P2 female who presented to her primary care physician (PCP) with a 3-month history of vague abdominal pain and fatigue; the patient also complained of long-standing constipation. She denied bloating, changes in her abdominal girth, nausea or vomiting, or unintentional weight loss. Her medical history included hypertension, osteoarthritis, depression, sleep disturbance, irritable bowel syndrome, and newly diagnosed hypothyroidism. The surgical history included appendectomy at age 17 years; abdominal hysterectomy for menorrhagia at age 30 years; and a right breast biopsy at age 67 years, the results of which were benign. Her medications included triamterene/hydrochlorothiazide, 37.5/25 mg daily for hypertension; zolpidem (Ambien), 5 mg as needed at bedtime for sleep disturbance; temazepam (Restoril), 50 mg as needed at bedtime for sleep disturbance; melatonin as needed; sertraline (Zoloft), 50 mg daily for depression; and levothyroxine, 150 mcg daily for hypothyroidism. She was allergic to tricyclic antidepressants. The patient had two sisters, both of whom had colon cancer and heart disease. Both of her parents succumbed to heart disease, her mother at age 79 years and her father at age 65 years. Her brother had a fatal MI at age 39 years. She had no known family history of breast or ovarian cancer. The patient was retired and recently divorced after 50 years of marriage. She was a lifetime nonsmoker and rarely used alcohol. Referral to a gastroenterologist for a colonoscopy was the next step. No intrinsic masses were found; however, ascites was suspected, and a 2.8-cm22.2-cm, fluid-filled projection from the right side of the colon was noted. Abdominal and pelvic ultrasounds confirmed the diagnosis of ascites, but no obvious mass was visualized. The patient was then referred to our gynecologic oncology clinic for further evaluation. Repeat pelvic and transvaginal ultrasounds showed approximately 1 L of echogenic ascites. In addition, the right ovary had increased vascularity on color flow Doppler. There was no ovarian enlargement, cysts, or nodularity. The left ovary was not conclusively visualized. Cancer antigen 125 (CA-125) tumor marker was elevated (473 mg/mL; normal range, 0-30 mg/mL). No abnormalities were found on physical examination. No palpable disease was noted on rectovaginal examination. The patient underwent an exploratory laparotomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic fluid sampling. Results of pathology tests revealed poorly differentiated papillary serous carcinoma. Intraoperative findings included small ovaries (right, 3.5 cm22.0 cm20.8 cm; left, 2.0 cm22.0 cm20.8 cm) without masses, but the surfaces of the ovaries were studded with tumor. Diffuse serosal implants were found. Most of the implants were less than 3 mm in size, none measured more than 1 cm. The right and left hemidiaphragms were covered with miliary implants, with more implants on the right side than on the left. Postsurgical treatment included six cycles of carboplatin (Paraplatin) and paclitaxel (Taxol). The patient’s CA-125 level was 171 mg/mL postoperatively and dropped to 5.3 mg/mL after she completed chemotherapy. Her CA-125 level remained between 5.9 and 16.3 mg/mL for 14 months, at which time her CA-125 level increased to 35.3 mg/mL. CT showed no abnormalities. However, a repeat CT obtained 3 months later revealed multiple abdominopelvic peritoneal nodules highly suspicious for recurrent disease. The patient received another six cycles of carboplatin and paclitaxel. After completing the second chemotherapy regimen, the patient returned quarterly for physical examinations, including measurements of her CA-125 levels. At the time of this writing, the patient appeared to be in remission, her last known CA-125 level being 8.0 mg/mL. TREATMENTWhen a diagnosis of PPC is suspected, the patient should be referred to a gynecologic oncologist immediately. Because treatment of PPC often includes surgical exploration and tumor cytoreduction or debulking, prompt referral is essential. Debulking typically includes a total abdominal hysterectomy, bilateral salpingo-oophorectomy, excision of bulking pelvic and para-aortic lymph nodes, and omentectomy. Appendectomy and bowel resections may also be necessary, depending on intraoperative findings. In most cases, chemotherapy is initiated shortly after surgery. Although many agents may be used, a common starting point is six cycles of carboplatin (Paraplatin) and paclitaxel (Abraxane, Onxol, Taxol). If disease is extensive, surgery is delayed and neoadjuvant chemotherapy is initiated, which allows for a greater chance of optimal cytoreduction. Another option is heated intraperitoneal localized chemotherapy either combined with or independent of systemic chemotherapy. Essentially, treatment is individualized according to the extent of disease, the general health of the patient and her ability to tolerate treatment, and the likely benefit of treatment. The rate of recurrence for PPC is 70% to 80%, and recurrence is typical within 2 years of treatment.3 Close surveillance is warranted, with quarterly physical examinations, including pelvic and rectovaginal evaluations. CA-125 levels typically trend with the presence of PPC or a response to chemotherapy. Therefore, as in cases of advanced epithelial ovarian cancer, laboratory studies are an important part of follow-up and posttreatment care. Radiographic studies are indicated by increasing symptoms or rising CA-125 levels.3 The Case Presentation illustrates the presentation, diagnosis, and treatment course of a patient with PPC. PPC AND GENETICSThe BRCA gene mutations that increase the risk of some breast and ovarian cancers are also a factor with PPC. Women with the BRCA1 mutation have an increased risk of developing PPC; Bandera and associates reported this risk to be 11%.17 One might think that prophylactic bilateral oophorectomy would protect patients against developing PPC. However, two research teams reported a 0.8% to 1% risk of developing PPC despite prophylactic surgery.18,19 Notably, in both studies the women were known to have either BRCA1 or BRCA2 germline mutations. Other research teams estimated that BRCA1 carriers who had bilateral prophylactic oophorectomy have a 5% to 10% risk of developing PPC.3,20,21 IMPROVED SURVIVAL RATESAdvances in treatment regimens are improving survival rates in patients with PPC. In a 1990 study of 74 women with PPC, the overall median survival time was 24.0 months.12 The women had undergone both surgery and some form of chemotherapy. Those treated with combination chemotherapy fared better than those who received single-agent regimens (survival of 29.5 months vs 16.5 months).12 More recently, data from a 2004 study of 32 women revealed an overall median survival of 38.5 months; 29 women had radical cytoreduction surgery, and all 32 women received neoadjuvant or early postoperative chemotherapy.22 Of note, these women had either advanced ovarian cancer or PPC; both diseases have similar prognoses. Similarly, in a study of 28 women with advanced ovarian cancer or PPC, overall medical survival had increased.23 Twenty-five women had optimal cytoreduction, and all 28 received either intraoperative or early postoperative intraperitoneal chemotherapy, as opposed to systemic treatment by vein. Overall median survival in this group was 45.8 months.23 This finding has prompted gynecologic oncologists to consider using intraperitoneal treatment for improved survival time, especially in women whose tumor was optimally debulked with little residual disease.
SUMMARYPPC is a malignancy with potentially devastating effects. Symptoms of PPC are nonspecific and common, and several are particularly vague in nature. PAs must understand the disease process in order to avoid misdiagnosis. Prompt initiation of proper treatment is important for improved outcomes. Treatment regimens are continuing to improve with a better understanding of this disease. REFERENCES
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