Document oeb33O5MD35MGQ70qL3Xn07GE

' Volume 54, Number 5 Obstetrical and Gynecologic^ Survey Copyright 1999 CME REVIEWARTICLEbyLippgpcon WWtams &WtkJns, Inc. MW Chef Edttor's Note This article is the 13th of 36 that will be published in 1999 for which a total of up to 36 Category 1 CME credits can be earned. Instructions for how credits can be earned appear on the last page of the Table of Contents. This CME activity is supported by an unrestricted educational grant fern Procter & Gamble. <;} NOTICE: THIS MATERIAL MAY BE PROTECTED ^ bv r-Pi^vKu-t-iT i AW (TITLE 17 (J.S. CODE) Primary Peritoneal Carcinoma: A Review of the Literature Christina S. Chu, Andrew W. Menzin, Debra G.B. Leonard, Stephen C. Rubin and James E. Wheeler Departments of Obstetrics and Gynecology (C.S.C., S.C.R.) and Pathology and Laboratory Medicine (D.G.B.L., J.E.W.), University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; and Department of Obstetrics and Gynecology, North Shore University Hospital (A.W.M.), Manhasset, New York Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader will be able to understand the similarities and differences between primary peritoneal carcinoma and epithelial ovarian cancer, the criteria used to define primary peritoneal carcinomas, and the differences in presentation between a low malignant potential tumor of the peritoneum and an ovarian low malignant potential tumor. In 1959, Swerdlow (1) reported a case of a 27-yearold woman with a tumor of the pelvic peritoneum, histologically resembling papillary serous carcinoma of the ovary. Since Swerdlow's report, primary peri toneal carcinoma (PPC) has been called by many names , including mesothelioma, papillary carcinoma of the peritoneum, serous surface papillary carci noma, and extraovarian papillary serous carcinoma, reflecting the controversy surrounding its histogene sis and clinical behavior. Initially, these tumors were classified as mesotheliomas because of their pur ported common ancestry (2), despite the apparent epidemiological differences. PPC is a tumor that diffusely involves the perito neal surface while sparing or only minimally involv ing the ovaries. It is histologically indistinguishable from primary epithelial ovarian carcinoma (EOC), and is diagnosed in the absence of another identifi able primary. Upon retrospective review, approxi mately 10 percent of the patients initially felt to have Reprint requests to: Christina S. Chu, MD, 106 Dulles, 3400 Spruce Street, University of Pennsylvania Medical Center, Phila delphia, PA 19104. E-mail: chuc9mail.med.upenn.edu The authors have disclosed no significant financial or other relationship with any commercial entity. They also have affirmed that this activity Includes no discussion of investigational or unla beled use of products. EOC are reclassified instead as PPC (196 of 1958 patients in five different series) (3-7). With its in creased recognition and subsequent studies, it seems timely to review the past and current literature per taining to PPC. EPIDEMIOLOGY PPC was initially distinguished from malignant mesothelioma (MM) on the basis of differing epide miologic profiles. Approximately 63 percent of pa tients diagnosed with peritoneal MM are men and up to 83 percent involve a history of asbestos exposure (8-11). In contrast, PPC has been described exclu sively in women, with a single recent exception (12). No association with asbestos exposure has been re ported in PPC. Patients with PPC are older at diagnosis than those with EOC, with weighted mean ages at presentation of 61 and 56, respectively, calculated from multiple series (3-6, 9, 10, 13-21 for PPC; 20, 22 for EOC). MM usually develops at a median age of 50 to 60 (23). Eltabbakh et al. (20) examined over 40 epide miologic features of 50 women with PPC and 503 women with EOC. The authors concluded that the mean age at diagnosis is significantly older (63.8 vs. 323 324 Obstetrical and Gynecological Survey TABLE 1 A comparison of primary epithelial ovarian carcinoma (EOC), primary peritoneal carcinoma (PPC), and malignant mesothelioma (MM) - EOC' PPC' Single reported case of PPC `m a male (Ref. 74) MM of the Peritoneum* % Female Mean age at - diagnosis Age range Mean age at menarche Median parity Asbestos expo- sure Talc exposure Median survival (months) 100 56 14-92 12.8 2 % 48% 27-30 >99 61 4-92 13.3 3-4 * 26% 12-24 NAf 74 NA NA NA none t 3 37-46 53 38-82 t t 50-83% t 4-18 ' The numbers in parentheses Indicate the oiled references for each. EOC (20,22,24,25). PPC (3-4,9,10,13-19,21,2294-27), and BIM (8-11,23,28,29). t NA, not applicable. % Data not available. Survival for patients with peritoneal and/or pleural mesothe lioma. 55.0 years, respectively, P < .001), menarche later (13.3 vs. 12.8 years, P = .024), and talc use less (26 vs. 48.1 percent, P = ,003) in patients with PPC, The use of hormone replacement therapy and oral contra ceptives was similar, as was parity. Table 1 summarizes selected epidemiologic features ofPPC, EOC, and MM. The racial distribution of PPC has rarely been reported. Fromm et al. (5) reviewed all referrals to the M, D. Anderson Cancer Center (MDACC) and identified 74 patients with PPC: 91 percent white, 5 percent African American, 3 percent Hispanic, and 1 percent Asian. In comparison, Morgan et al. (30) reviewed 221 patients diagnosed with EOC at the Hospital of the University of Pennsylvania and found patients to be 91 percent white and 9 percent African American. CLINICAL PRESENTATION Patients with PPC, as with EOC, usually present with abdominal distention, pain, or pressure often associated with ascites (3,6,10,13,14,17, 31). The symptoms may be vague and mild until the disease is advanced. Fromm et al. (5) categorized the symp toms of women with PPC presenting to the MDACC: 55 percent reported abdominal pain, 52 percent dis tention, and 19 percent gastrointestinal symptoms (i.e., nausea, vomiting, loss of appetite). Only 6 per cent of patients were asymptomatic. Ransom et al. (17) noted that although 76 percent of wpmen com plained of pain, distention, or palpable abdominal mass, 21 percent of their 33 patients had normal pelvic examinations at the time of initial presenta tion. Occasionally, PPC is detected after the identi fication of psammoma bodies on routine Pap smear (9) or during exploratory surgery for other reasons (17). PRESURGICAL EVALUATION Because the symptoms of PPC are similar to those of EOC, the preoperative assessment is the same as that of a woman suspected of having ovarian cancer. This should include a thorough history and physical examination, as well as radiologic and laboratory studies. A chest radiograph is usually obtained as part of presurgical assessment, to rule out metastases or pleural effusion as well as potential anesthetic risks. Additional studies are obtained as dictated by the review of systems, particularly those referable to the gastrointestinal tract Although PPC cannot reli ably be distinguished from EOC by preoperative testing, an ultrasound revealing normal-sized ovaries with evidence of carcinomatosis may raise suspicion. A computed tomography (CT) scan provides an as sessment of peritonea] disease, retroperitoneal and hepatic lesion, and may identify obstructive uropathy. Laboratory studies should include an evaluation of hematologic, renal, hepatic, and electrolyte param eters. With any suspicion of ovarian or peritoneal cancer, serum CA-125 determination should be per formed. In any patient presenting with diffuse abdominal tumor, preoperative assessment should be directed at identifying potential primary sites in addition to the ovary, including mammary, pancreatic, and gastroin testinal lesions. Identification of the correct primary site is critical because the surgical management of PPC is vastly different from that of carcinomatosis associated with other malignancies. Although PPC may be considered in the differential, it is not a diagnosis made preoperatively. The diagnosis of PPC is typically made by exclusion after both operative assessment and pathologic study. Paracentesis may provide short-term relief of symptoms caused by massive ascites. Although the positive predictive value of cytologic evaluation of ascitic fluid is quite high, the sensitivity is rather low (32); furthermore, even when cytologic evidence of malignancy is present, a definitive identification of the primary lesion is typically not possible. Unless the information will alter the management of an Primary Peritoneal Carcinoma CME Review Article 325 individual patient, diagnostic paracentesis is not war ranted. Thoracentesis may also provide short-term relief of pulmonary symptoms in a woman with a pleural effusion. Cytologic evaluation of the effusion is important because it changes the stage, and to some degree, the prognosis of the patient. PATHOLOGY The central problem in diagnosis is separation of PPC with some ovarian involvement from primary EOC. The Gynecologic Oncology Group (GOG) de fined "extraovarian peritoneal serous papillary carci noma" according to the following criteria: 1. Both ovaries must be either physiologically normal in size or enlarged by a benign process. 2. The involvement in the extraovarian sites must be greater than the involvement on the surface of either ovary. 3. Microscopically, the ovarian component must be one of the following: nonexistent confined to ovarian surface epithelium with no evidence of cortical invasion, involving ovarian surface epithelium and un derlying cortical stroma but with any given tumor size less than 5X5 mm, tumor less than 5X5 mm within ovarian substance associated with or without surface disease 4. The histological and cytological characteristics of the tumor must be predominantly pf the serous type that is similar or identical to ovar ian serous papillary adenocarcinoma, any grade. In 1994, Mulhollan et al. (24) defined a "serous surface papillary carcinoma" (PPC) characterized by tumors on the ovary of 5.0 mm or less in greatest dimension with only surface ovarian in volvement or minimal superficial invasion of the ovarian cortex (maximum depth of invasion 3.0 mm). Mills et al. (25) rejected the diagnosis of PPC in any patient with ovaries greater than 3.0 cm in largest dimension, whereas Fromm et al. (5) allowed a maximum ovarian diameter of 4.0 cm. A comparison of various definitions is presented in Table 2. We recommend use of the GOG's defi nition of PPC, expanding it to include nonserous types of PPC with a histological appearance iden tical to other subtypes of EOC (i.e., mucinous, clear cell, etc.). We also propose that even a large implant on the surface of an otherwise normal ovary be recognized as PPC if histologic exami nation reveals invasion less than 5X5 mm. Grossly, the tumor often appears gritty and hard, diffusely studding pelvic and abdominal peritoneal surfaces. PPC demonstrates light microscopic, histochemical, and immunohistochemical features similar to EOC (Table 3) (9, 13, 15). Whereas papillary serous differentiation is the overwhelm- TABLE 2 Different criteria for the diagnosis of PPC Author Name Mills et at. (25) 1988 Serous surface papillarycarcinoma Fromm et al. (5) 1990 Gynecologic Oncology Group, 1993* Papillary serous carcinoma of the peritoneum Extraovarian peritoneal serous papillary carcinoma Mulhollan et at (24) 1994 Serous surface papillary carcinoma (small type) AS specified in GOG Protocol #138. Criteria 1. Grossly normal ovaries, 3.0 cm 2. No ovarian Involvement, or involvement con fined to the surface, or only minimally inva sive tumor 1. Ovaries 4.0 cm 2. Ovarian involvement minimal with only 1-15 mm Implants 1. Ovaries normal in size, or enlarged by benign process 2. Involvement in extraovarian sites greater than ovarian involvement 3. No ovarian Involvement, or surface involve ment without microscopic invasion, or In volving ovarian surface and stroma with tumor <5x5 mm in size 4. Histology must be predominantly'serous 1. Ovaries 3.0 cm in greatest dimension 2. Tumor 5.0 mm in greatest dimension 3. Only surface ovarian Involvement, or super ficial invasion 3.0 mm i I 326 Obstetrical and Gynecological Survey 4 TABLE 3 A comparison of the staining properties of primary EOC, PPC, and MM (Refs. 9,10,13,27,33-36) tribution of grade among 100 cases of E>C (6,52, and 42 percent, respectively). Hyperplasia of the EOC PP MM ovarian surface epithelium may be present, and a PAS-D {%) 90 75 0-5 transition may sometimes be seen from normal to EMA 100 100 80-100 atypical to frankly malignant epithelium (13, 14, Cytokeratin 100 100 LeuMl 73 45 B72.3 91 85 CEA 54 14-25 100 19). Histochemical studies reveal the almost uni 11* 0 versal presence of neutral or acidic mucin either in 0 the cytoplasm or on the cell surface. Immunohis- S100 100 100 0-11 tochemical studies show characteristic positive PLAP CA-125 Lewis Y 29-45 100 71 38 75 88 0 staining for cytokeratin and epithelial membrane 0-14 antigen (EMA). Wick et al. (43) concluded that the 0 lesions they termed "serous surface papillary car * Denotes only minute foci of staining. cinoma" and "serous ovarian papillary carcinoma" are virtually identical morphologically and immu- ingly predominant histology (99 vs. 36 percent for nophenotypically based on analysis of cytokeratin, EOC) (37), other varieties of miillerian differenti EMA, B72.3, CEA, Leu Ml, CA-125, LN1, LN2, ation have been reported including clear cell, en MB2, SI00, PLAP, and amylase staining (see Ta dometrioid, mucinous, and mixed miillerian meso ble 3). dermal tumor. A review of 21 series with a total of Although MM of the peritoneum is grossly in 530 patients revealed only 5 cases of nonserous distinguishable from carcinomatosis peritonei, his histology (1, 3-7, 9, 10, 13-19, 24, 31, 38-41). tologically, the tumor may present with a wide Microscopically, the tumor may demonstrate spectrum of appearances. The epithelial type is solid, cribriform, or cystic growth patterns. Papil characterized by papillary structures lined by uni lary structures and epithelial tufting with areas of form, cuboidal cells with pink cytoplasm and gland formation may also be prominent. Psam round, bland nuclei displaying infrequent mitotic moma bodies, a desmoplastic reaction, and necro figures and nucleoli. A spindle cell or sarcomatoid sis are common features. Cytologic features are component is common, and psammoma bodies are often high grade with markedly atypical cells dis usually absent (detected in only 3.5 percent) (8). A playing prominent nucleoli, crowded irregular nu variant of MM, termed well-differentiated papil clei, high N:C ratio, and mitoses ranging from 20 lary mesothelioma, may develop in the peritoneum to 60/10 high power field (hpf) (Fig. 1) (5). Dal- of women most commonly during the third and rymple et al. (4) reviewed 31 cases of PPC and fourth decades (44). This type of MM may also noted the distribution of low-, moderate-, and occur in the pericardium and pleura, grossly ap high-grade tumors to be 13, 45, and 42 percent, pearing as multiple peritoneal nodules covering respectively, using standard criteria (42). In com the omentum, mesentery, and pelvic peritoneum, parison, Dvoretsky et al. (22) noted a similar dis- with occasional involvement of the ovarian sur face. Psammoma bodies may be present in approx imately 5 percent (8). Because of similarities in the gross and micro scopic appearance of PPC and MM (especially the well-differentiated papillary subtype), the use of histochemical and immunohistochemical stains may aid in the characterization of these tumors. Unlike PPC, MM virtually never stains for mucin (9,13). Immunohistochemical stains for EMA and keratin are positive in both. PPC, however, dis plays staining for many other markers which tend to be negative in MM: S100, CEA, LeuMl, B72.3, placenta] alkaline phosphatase, CA-125, and Lewis Y. Staining for either Si00 and placental alkaline phosphatase, or Si00 and B72.3 charac Flg. 1. Primary peritoneal carcinoma invading omentum. The terizes the majority of serous PPC and EOC (45). Ovaries were not involved. Others have reported that if at least two of the i * k Primary Peritoneal Carcinoma CME Review Article 327 markers, S100, B72.3, and BerEP4 are positive with the appropriate histologic appearance, serous carcinoma can be assumed (46). Positive staining for carrinoembryonic antigen (CEA), placental al kaline phosphatase, or B72.3 effectively excludes peritoneal mesothelioma (47). Histochemical properties are summarized in Table 3. Electron microscopy has also been utilized to further char acterize the differences between PPC and MM: the PPCs possess taller, ciliated cells, but lack tonofilaments; MMs have long microvilli (14, 19,48). INTRAOPERATIVE ASSESSMENT AND STAGING Surgical abdominal exploration provides the means for both diagnosis and staging evaluation of patients with PPC. The procedure should parallel that de scribed for EOC (Table 4). A vertical incision pro vides adequate exposure to the upper abdomen for exploration and sampling. If ovaries seem normal with widespread disease elsewhere in the abdomen, PPC becomes a leading diagnostic possibility. How ever, because surface involvement of the ovaries is present in approximately 96 percent of the cases, the distinction between PPC and EOC may only be made after histologic examination to evaluate the extent of ovarian invasion by tumor. The International Federation of Gynecology and Obstetrics (FIGO) has not yet adopted a specific staging system for PPC. The surgical staging classi fication scheme as outlined for ovarian carcinoma is typically applied to women found to have PPC (al though, by definition, there can be no stage I disease) (3,4,6,19,21,41). PPC tends to present in advanced stages. The distribution by stage of PPC and EOC, for multiple series and FIGO data, respectively, is summarized in Table 5. . When disease seems confined to the pelvis (appar ent stage II), sampling the omentum, abdominal peri- TABLE 4 Surgical staging tor PPC* Vertical Incision Thorough abdominal and pelvic examination ' BSO TAH Omentectorny Sampling of gross lesions in the abdomen and pelvis Peritoneal biopsies of the paracolic gutters and sub- diapgragmatic regions, bilaterally Retroperitoneal tymph node sampling In the pelvis and paraaortic regions, bilaterally 'Adapted from GOB Surgical Staging Procedure, Specifica tions Protocol G0G#157. TABLE 5 Distribution by stage of PPC and EOC Stage PPC* {%) EOCTW 1 II . III IV s 73 25 23 13 47 16 * References 3,4,6,14,16,17,21,25,41 (weighted average), t Reference 49. toneal surfaces, and retroperitoneal lymph nodes is advocated to rule out occult abdominal disease (stage El). In cases of small volume disease (<2 cm nod ules) abdominal and pelvic lymph node sampling is also recommended. The majority of patients will present with diffuse abdominal disease (>2 cm nod ules), and the extent of disease will be determined by inspection rather than surgical sampling. Of patients with stage IV disease, common sites of extraperitoneal involvement include malignant pleu ral effusions and parenchymal liver metastases. More rare sites include the pleura, the axillary lymph nodes, the anterior abdominal wall, the vagina, and the skin (4, 5, 40, 50). An autopsy study of 57 patients with PPC conducted by Rothacker and Mobius (7) revealed blood-borne metastases to the lung parenchyma in two cases and to the brain in one case. CYTOREDUCTION Surgery remains critically important for both the diagnosis and the therapy of PPC. Once the diagnosis is established and the extent of disease documented, maximal cytoreduction becomes the primary goal of the procedure. Excision of all visible implants is the hallmark of cytoreductive efforts. The omentum con tains evidence of tumor in 89 to 100 percent of patients (5, 6,13) and should be resected if possible. Grossly enlarged lymph nodes should be excised, even when a diagnostic sampling is not needed, and bowel resection or splenectomy may be indicated for a maximal surgical excision, or to prevent obstruc tion or control hemorrhage. EOC is unusual among solid tumors in having a survival benefit associated with cytoreduction in the setting of carcinomatosis. The first quantitative evi dence of the importance of "residual disease" on the outcome of women with EOC came from Griffiths in 1975 (51). He demonstrated that the diameter of the largest remaining nodule after tumor resection cor related with survival. This phenomenon has been supported by numerous retrospective series, although cytoreduction, per se, has never been studied in a randomized, prospective trial 1 328 Obstetrical and Gynecological Survey The terms "optimal" and "suboptimal" used to characterized the burden of disease after cytoreduction in women with EOC have also been applied to PPC. Criteria defining optimal residual disease have varied widely among authors (from 0-3 cm of largest remaining implant). A widely accepted cutoff is that used by the GOG: less than a 1-cm diameter of the largest residual nodule. There is also evidence that the number of residual lesions may have prognostic significance, particularly in the setting of optimal disease status among women with EOC (52); it is advisable, therefore, to include this information in the operative record. In light of the pathological and clinical similarity between EOC and PPC, it is inferred that a similar or equivalent benefit might be seen in women with PPC. The feasibility of cytoreduction of PPC has been addressed in several retrospective series. The ability to achieve significant cytoreduction may vary widely from surgeon to surgeon, but available data suggest that PPC may be debulked as well as EOC (6, 21) with one exception (53). Factors that may preclude optimal debulking include extensive nodu lar infiltration of mesenteric, visceral, and peritoneal surfaces (6) and higher paraaortic lymph node dis ease, involvement of the liver, porta-hepatis, and the mesentery of the small bowel and stomach (21). The only case-control study (53) that demonstrates PPC to be significantly (P < .0001) more difficult to debulk than EOC should be confirmed by additional studies. Several studies suggest that approximately 40 percent of patients with either PPC (5) or EOC (54, 55) may be optimally debulked. ADJUVANT THERAPY Given the similarities between PPC and EOC, phy sicians have used therapies for PPC that have proven effective in EOC. In the past two decades, chemo therapy has predominantly consisted of platinumbased regimens. Fromm et al. (5) documented a significant increase (P = .02) in median survival in patients treated with platinum-based combination chemotherapy (31.5 months) versus patients treated with nonplatinum-based regimens (19.5 months). First-line agents for PPC have resulted in an overall clinical response rate of 60 percent (5, 15), which is comparable to the response rates for EOC to similar regimes (56,57). A recent phase H GOG trial directly compared response rates after cisplatin/cyclophosphamide therapy for groups of women with PPC and EOC (58). The authors found similar clinical re sponse rates (65 vs. 59 percent, respectively), and identical complete surgical response rates of 20 per cent. More recently, therapy for EOC has evolved to include use of paclitaxel, an antimicrotubule agent, in combination with platinum analogues. In 1992, Wall et al. (38) reported the effectiveness of paclitaxel as a single agent salvage therapy in a young woman with relapsed PPC, and in 1996, Menzin et al. (31) first documented surgically confirmed responses to the combination of paclitaxel and cisplatin. Among four patients with suboptimal residual disease, one complete and three partial (but marked) responses were noted after six courses of therapy. Recent evi dence (59) suggests that regimens of pacljtaxel/cisplatinol and cyclophosphamide/cisplatinol may have similar efficacy as first-line therapy in women with suboptimal residual PPC after primary debulking sur gery. In patients known to be sensitive to paclitaxel/ platinum as a first-line regimen, paclitaxel/caiboplatinum has been shown to be an effective secondline regimen after disease recurrence (60). With new GOG protocols that previously included only women with EOC now often also open to patients with PPC, more data regarding the efficacy of various regimens should become available in the coming years. CLINICAL FOLLOW-UP Considering the relapse rates following remission after platinum-based therapy among women with EOC, continued surveillance of those with PPC is warranted. Serial CA-125 determination may assist in follow-up if levels were elevated at the time of diagnosis. The vast majority of women will indeed have elevated values, and the regression usually par allels response to therapy (25, 31). Routine imaging studies in asymptomatic patients with normal exam inations and normal CA-125 levels are not war ranted. A schedule of periodic examinations is deter mined on an individual basis, with most clinicians favoring visits at 3-month intervals during the early years after initial therapy, during which recurrence rates are highest. When symptoms, examination, or CA-125 levels arouse suspicion, radiologic evalua tion is indicated. SURVIVAL Median survival among women with PPC has been reported to range from 12 to 25 months (5,6,24,25). Multiple studies, including a retrospective case-con trol study with close matching of clinical character istics (53), have suggested that PPC and EOC have Primary Peritoneal Carcinoma CME Review Article 329 similar survival rates (4-6, 17, 21, 61). However, others have concluded survival for patients with PPC is worse, (24, 25), although it is difficult to interpret these studies inasmuch as the authors did not con sider variables such as age and residual disease in one study (24), and the analysis in the second in cluded only 10 patients with RPC (25). The preponderance of evidence in women with EOC suggests that residual disease burden is in versely correlated with response rates, progressionfree interval, survival, and the likelihood of achiev ing a negative surgical reassessment (21,54, 55,62). Similar statistics of women with PPC also indicates a trend toward unproved survival with optimal cytoreduction (21, 63-65). Ben-Baruch et al. (21) noted a median survival of 20.5 months for suboptimally debulked patients as opposed to 46.0 months for those optimally debulked, although the study was too small to show statistical significance. Similarly, Fowler et al. (64), Stmad et al. (65), and Tans et al. (27) demonstrated prolonged survival in patients af ter optimal cytoreduction, but again, their results were not statistically significant. Fromm et al. (5) reported the largest series with 74 patients treated with surgery and adjuvant therapy at a single insti tution and found no difference in survival (25.5 months for those suboptimally debulked and 26.0 months for those optimally debulked, P = ,51). Of note, Eltabbakh et al. (63) studied 75 patients with PPC and on multivariate analysis noted a significant survival advantage for those with residual disease < 1 cm (P = .03) and for those with performance status := 1 (P < .001). A comparison of survival rates for EOC and PPC stratified by presence of residual disease is presented in Table 6. Some authors have considered a number of poten tial prognostic factors on survival. Mulhollan et al. (24) noted that the use of multiagent versus single- TABLE 6 Survival for EOC and PPC fay volume of residual disease Author Residual disease (cm) EOC Conte et al. (66) (W = 125) Redman et al. (67) (W 86) Vogl at al. (68) <N = 38) Wharton and Hereon (69) (N ^ 104) Plver et al. (70) (N = 40) Neijtetal. (71) (W = 179) Delgado at al. (72) (N = 75) 0 <2 2-5 >5 <10 cm3 10-60 cm3 >60 cm3 ;s2 >2 2 >2 2 cm >2 cm Microscopic si 1-2 2-5 >5 0 PPC Ben-Baruch et al. (21) (N = 22) Fowler et al. (64) (N - 34) Stmad at al. (65) (N = 18) Fromm et al. (5) (N = 74) Eftafabakh et al. (63) (N = 75) ' NS, not significant, P > .05. <2 >2 <2 >2 <1.5 >1.5 <3 >3 =2 >2 1 >1 Median survival (months) ' >42 >42 17 15 38 36 19 >40 15 28 15 . 48 21 >36 42 22 20 18 (Mean survival) 45 45 16 46 20 16 17 31 11 25 26 40 16.6 P value .001 .00085 .003 ,0057 Not stated .0001 Not stated NS* NS Not stated NS 0-03 330 Obstetrical and Gynecological Survey agent chemotherapy, the use of platinum- versus nonplatmum-based regimens, and the absence of mi toses predicted an improved survival in women with PPC. Age (age greater than or less than 50), die presence of residual disease (as mentioned above), the percent of papillary component (more than or less than 10 percent), and the presence of vascular inva sion did not correlate significantly with differences in survival. Although the authors did not cite data re garding flow cytometric analysis, they did comment that their preliminary results suggest "a greater di versity of ploidy" in cases of PPC, In contrast, Ko walski et al. (73) noted no significant difference in aneuploidy between 44 patients with PPC and 44 patients with EOC matched for age, stage, histology, grade, cytoreduction, and survival. LOW MALIGNANT POTENTIAL TUMORS OF THE PERITONEUM In 1979, a tumor with diffuse peritoneal involve ment and a histologic appearance similar to EOC of low malignant potential (LMP) was reported and termed "atypical endosalpingiosis" (74). In 1987, the term "serous papillary borderline tumor" was used to describe similar lesions (75). Only three large series of patients with LMP tumors of the peritoneum have been reported (76-78)- TABLE 7 A comparison of LMP tumors of the peritoneum [76-78) and the ovary (78-89) (weighted means) Peritoneal LMP Ovarian LMP Mean age (years) Presenting complaint (%) Pain Distension Infertility Abnormal bleeding No symptoms 5-Year survival (%) Serous histology (%) Stage at presentation (%) 1 II III IV Elevated serum CA-125 (%) Presence of ascites (%) 34 26 0 13 7 35-50 95 100 0 54 41 0 Unknown 0 43 31 52 1 10 12 95-100 42 (52% mucinous, 4% endometri oid, 2% mixed) 74 8 17 1 22 37-43% of pa tients with stage III dis ease Peritoneal tumors of LMP present in ysung women (mean age 34) (76-78). Many patients are asymp tomatic at the time of diagnosis, with the tumor incidentally found either at the time of surgery (36 percent) or by the presence of psammoma bodies on routine Pap tests (10 percent) (76-78). Of the re maining patients, infertility and abdominal pain are the most common presenting complaints (Table 7). Peritoneal LMP tumors display serous histology identical to noninvasive implants of ovarian serous borderline tumors, and show minimal or no ovarian surface involvement (76). Reported involvement has been either focal or diffuse. Grossly, the disease process may resemble miliary granules or peritoneal carcinomatosis, or appear as small nodules, diffuse adhesions, irregular peritoneal blebs, or solitary cys tic and solid lesions (77). Histologically, well-differ entiated papillary structures may be seen lined by tall pseudostratified columnar cells often demonstrating epithelial tufting. Mitoses are rare and invasion is not evident (Fig. 2), Hie differential diagnosis may in clude endosalpingiosis, mesothelial hyperplasia, lowgrade mesothelioma, or adenocarcinoma, either pri mary or metastatic. Because patients with peritoneal tumors of LMP present at a younger age and often with infertility, conservative treatment may be advocated until child bearing is complete. At surgery, an LMP lesion can not reliably be distinguished from its invasive coun terpart by gross examination alone. As with ovarian LMP tumors, definitive treatment may await perma nent section diagnosis, because frozen-section diag nosis of an LMP tumor may not be representative. Fig. 2. Low malignant potential peritoneal tumor on peritoneal surface. Papillary groups of cells with a serous histology lie on the surface surrounded by scattered chronic inflammatory cells and a few fibroblasts. No invasion is present. Primary Peritoneal Carcinoma CME Review Article 331 Overall survival is excellent. Bell and Scully (76) reported a 95 percent survival rate among 25 patients followed for a mean of 8 years. Similarly, Biscotti and Hart (77) reported on 14 patients with long-term follow up: 12 were alive with a mean survival of 7.5 years, 1 patient died of an intercunent illness, and the remaining patient died 7 weeks postoperatively of suspected complications of therapy. Weir et al, (78) identified 14 patients, all alive at a mean of 3 years of follow up: 10 were without evidence of disease, 2 were alive with minimal residual disease, and 2 were subsequently diagnosed with PPC. Of these two pa tients, one was near death secondary to bowel ob struction. But this patient's diagnosis of peritoneal LMP tumor was based on biopsy only. PPC may have been diagnosed if tumor sampling had been adequate. Adjuvant chemotherapy and/or radiation (with their attendant complications) are not recom mended by the authors of these studies. suspicion that PPC may occur with 10-fold increased frequency in women with hereditary ovarian cancer. Furthermore, study is needed to better define the risks for this population of women and their relatives. Approximately 5 to -10 percent of all cases of EOC are thought to occur on the basis of a hereditary predisposition (55, 93-97). Although germline mu tations in BRCAl are felt to be responsible in 90 percent of these cases, (98) mutations in this gene have been reported to occur in only 3 to 6 percent of all patients with epithelial ovarian carcinoma (99, 100). Bandera et al. (101) screened 17 patients with PPC using single strand conformation polymorphism analysis with sequencing of shifted bands, and iden tified two patients (11 percent) with germline muta tions in BRCAL This preliminary work suggests that hereditary predisposition may play a role in the de velopment of PPC with a frequency similar to that in EOC. FAMILIAL PREDISPOSITION AND BRCA STATUS In 1982, Tobacman et al. (39) from the National Cancer Institute reported three cases of intraabdomi nal carcinomatosis resembling metastatic ovarian cancer among 28 women who had undergone pro phylactic oophorectomy from 16 families at high risk of ovarian carcinoma. These authors noted the sim ilarity between their cases and those described as primary peritoneal carcinoma by Foyle et al. (90). The authors recommend a thorough exploration at the time of prophylactic surgery to rule out the pres ence of an occult malignancy. Inadequate examina tion of the patient or the pathologic specimens may be responsible for the apparent diagnosis of PPC shortly after removal of the ovaries. The occurrence of PPC itself suggests that the protection afforded women from prophylactic surgery may not be com plete. Piver et al. (91) reporting on data from the Gilda Radner Familial Ovarian Cancer Registry identified six cases of PPC in 324 women who had undergone prophylactic oophorectomy based on a family history of ovarian cancer. These cases developed 1 to 27 years after prophylactic surgery. Although the au thors state that the incidence of PPC in this high-risk population cannot be inferred, 1.85 percent of these women in this series developed PPC. In comparison, the lifetime incidence of PPC is calculated to be approximately 0.14 percent (1 in 70 women develop EOC, (92) and approximately 10 percent of these cases may actually be PPC). These figures raise the PATHOGENESIS The pathogenesis of PPC is not well characterized. In 1972, Lauchlan (102) pointed out that the female peritoneum should be considered a part of what he termed the "secondary miillerian system," noting (as did Swerdlow) that both the germinal (surface) epi thelium of the ovary and the mesothelium of the peritoneum arise from the same embryologic origin and retain the multipotentiality of the miillerian sys tem. Multipotentiality supports the hypothesis that metaplasia of the peritoneum may account for con ditions such as squamous metaplasia, endometriosis, and endosalpingiosis. Based on the epidemiological findings and concerns over potential differences in biologic behavior coupled with this concept of miil lerian multipotentiality, in 1977 Kannerstein et al. (16) proposed a distinction between mesothelioma and papillary tumors of the peritoneum. Additional information acquired since then strengthens the case for PPC as a separate clinical, histologic, immunohistochemical, and ultrastructural entity (9,10,13,41). Although PPC is not always a predominant pelvic tumor, and because simultaneous carcinomas of the endosalpinx and endometrium have been docu mented, Truong et al. (13) hypothesized that a "field effect" involving the entire miillerian system may play a role in the pathogenesis of PPC. Because PPC occurs almost exclusively in women, hormonal in fluences on the susceptible miillerian system have been speculated to play a role. However, although LH and hCG receptors have been demonstrated in one case report of PPC (103), estrogen (ER) and 332 Obstetrical and Gynecological Survey progesterone (PR) receptors are not a common find ing in cases of PPC. Unpublished data by Chu and co-workers on 14 cases of PPC have demonstrated positive staining for ER and PR in only 21 and 36 percent of tumors, respectively. Eltabbakh et al. (63) demonstrated staining in 50 percent for ER and 6 percent for PR. Rates of iinmunohistochemical stain ing for ER and PR in cases of PPC is similar to those for EOC with 38 and 32 percent of cases of HOC exhibiting positive staining, respectively (104, 105). Others have suggested that irritants such as talc ascending through the female genital tract may con tribute to carcinogenesis. Although talc use has been documented to be significantly increased in women with PPC when compared with those with EOC (20), talc has not been a notable finding upon histologic review of pathologic specimens (106), and a causal relationship has not yet been proven. MOLECULAR GENETICS Although EOC has been demonstrated to be a monoclonal expansion of tumor cells (107-112), the clonality of PPC is debated: some propose that the tumor arises from the ovarian surface epithelium and then spreads throughout the peritoneum whereas oth ers propose a multifocal malignant transformation process. Only Kupryjanczyk et al. (107) have con cluded that PPC is a monoclonal entity, although their conclusions are based on the examination of p53 gene mutations in only two cases of PPC. The remainder of the literature supports a multifocal or igin in at least some cases of PPC (41, 113-116). Mutations in the p53 tumor suppressor gene on chromosome 17 are demonstrated both in EOC (44-57 percent) (115, 117) and in PPC (75 percent) (115). Overexpression of the protein results in ma lignant transformation in several human cancers (118-120). Frequent nuclear accumulation may cor relate with more aggressive biologic behavior and poorer clinical prognosis (121,122). Marchenko and Moll (123) have concluded that PPC is one of a growing number of tumors which demonstrates pS3 nuclear accumulation in the absence of a p53 gene mutation. This phenomenon is also observed in other tumors, including head and neck squamous cell car cinoma, endometrial carcinoma, uterine papillary se rous carcinoma, and acute myelogenous leukemia (123). The mechanism underlying this observation is not understood, although hypotheses include inacti vation and nuclear accumulation of p53 by interac tion with a second abnormal protein, or the ability of the cell to transiently increase and decrease nuclear p53 with levels of DNA damage (123). Additional molecular studies have reported similar rates of expression of HER-2/neu, BCL-2, and nm23-Hl for cases of PPC and EOC (73,124). LOH at 17q also seems similar (97, 114, 125-130). CONCLUSIONS Primary peritoneal carcinoma (PPC) is a tumor of the peritoneum, distinct from malignant mesotheli oma (MM), but similar in many ways to primary epithelial ovarian carcinoma (EOC). PPC seems his tologically identical to EOC and is differentiated from EOC based on the extent of gross ovarian involvement and microscopic invasion of the cortex. Currently, PPC is evaluated, staged and treated in the same fashion as EOC, with GOG trials for the treat ment of EOC now open to patients with PPC. PPC is currently managed surgically in the same way as EOC with the shared goal of optimal cytoreduction. Although the preponderance of evidence supports the benefit of maximal cytoreductive efforts for EOC, only limited data are available for debulking in PPC. On a molecular level, other differences between PPC and POC are becoming apparent as well: although EOC is a clonal proliferation, PPC seems to be mul tifocal in many patients. PPC and EOC seem to share similar hereditary risks, with the rates of BRCA1 germline mutations comparable in both entities. The clinician should keep in mind that PPC may develop after bilateral salpingo-oophorectomy for either be nign disease or ovarian cancer prophylaxis. Women at risk for hereditary EOC may, in fact, still be at an elevated risk of developing PPC over the baseline population. REFERENCES 1. Swerdlow M. Mesothelioma of the pelvic peritoneum resem bling papillary cystadenocarcinoma of the ovary. Am J Obstet Gynecol 1959:77:197. 2. Farmley TH, Woodruff JD. The ovarian mesothelioma. Am J Obstet Gynecol 1974;120234. 3. Attains MM, Avtaam R, Cohen I et al. Primary peritoneal papillary serous adenocarcinoma: Clinical and management aspects, Gynecol Oncol 1991:40:230. 4. Daliymple JC, Bannatyne P, Russell P et al. Extraovarien peritoneal serous papillary carcinoma: A clinicopathologlc study of 31 cases. Cancer 1989;64:110. 5. Fromm G-L, Gershenson DM, Silva EG. Papillary serous carcinoma of the peritoneum. Obstet Gynecol 1990;75:89. 6. Killackey MA, Davis AR. Papillary serous carcinoma of the peritoneal surface: Matched-case comparison with papillary serous ovarian carcinoma. Gynecol Oncol 1993:51;171. 7. Rothacker D, Mobius G. Varieties of serous surface papillary Primary Peritoneal Carcinoma CME Review Article 333 carcinoma ofthe peritoneum in Northern Germany: A 30-year autopsy study. Int J Gynecol Pathol 1995;14:310. 3. Kannerstein M, Churg J. Peritoneal mesothelioma. Hum Pathol 1977;8:83. 9: Raju U, Fine G, Greenawald KAet al. Primary papillary serous neoplasia of the peritoneum: A clintcopathologic and ultra- structural study of eight cases. Hum Pathol 1989:20:426. 10. Zhou J, Iwasa Y, Konishi I et al. Papillary serous carcinoma of the peritoneum in women. Cancer 1995:76:429. 11. Battlfora H, McCaughey WTH. Alias of Tumor Pathology: Tumors of the Serosal Membranes. Washington, DC: Armed Foroes Institute of Pathology, 1995; pp 17-66. 12. Shah IA, Jayram L, Gani OS et al, Papillary serous carcinoma of the peritoneum in a man: A case report. Cancer 1998:82: B60. 13. Truong LD, Maccato ML Await H et al. Serous surface carcinoma of the pertoneum: A ciinlcopathologic study of 22 cases. Hum Pathol 1990:21:99. 14. White PF, Merino MJ, Berwick KW. Serous surface papillary carcinoma of the ovary: A clinical, pathologic, ultrastructurat, and Immunohlstochemical study of 11 cases. Pathol Ann 1985^0:403. 15. Leie SB, Piver MS, Matharu J et al. Peritoneal papillary carcinoma. Gynecol Oncol 1988:31:315. 16. Kannerstein M, Churg J, McCaughey WTE et al. Papillary tumors of the peritoneum in women: Mesothelioma or pap illary carcinoma. Am J Obstet Gynecol 1977;127;306. 17. Ransom DT, Pate! SR, Keeney GL et al. Papillary serous carcinoma of the peritoneum: A review of 33 cases treated with platin-based chemotherapy. Cancer 1990:66:1091. 18. August CA, Murad TM, Newton M. Multiple focal extraovar- ian serous carcinoma. Inrt J Gynecol Pathol 1985;4:11. 19. Gooneratne S, Sassone M, Blaustein A et al. Serous surface papillary carcinoma of the ovary: A clinicopathologic study of 16 cases. Int J Gynecol Pathol 1982:1:258, 20. Eltabbakh G.H, Piver MS, Natarajan N et al. Epidemiologic differences between women with extraovarian primary peri toneal carcinoma and women with epithelial ovarian cancer. Obstet Gynecol 199B;91:254. 21. Ben-Baruch Q, Sivan E, Moran O et at. Primary peritoneal serous papillary carcinoma: A study of 25 cases and com parison with stage III-IV ovarian papillary serous carcinoma Gynecol Oncol 1996;60:393. 22. Dvoretsky PM, Richards KA, Angel C et al. Distribution of disease at autopsy in 100 women with ovarian cancer. Hum Pathol 1988;19:67. 23. Legha SS, Muggia FM. Pleural mesotheliomas, clinical fea tures and therapeutic Implications. Ann Intern Med 1977;B7: 613. 24. Mulholtan TJ, Silva EG, Tomos C et al. Ovarian Involvement by serous surface papillary carcinoma. Int J Gynecol Pathol 1994;13:120. 25. Mills SE, Andersen WA, Fechner RE et al. Serous surface papillary carcinoma: A clinicopathologic study of 10 cases and comparison with stage III-IV ovarian serous carcinoma. ' Am J Surg Pathol 1988:12:827. . 26. Greco FA, Halnsworth JD. Cancer: Principles & Practice of Onoology. Philadelphia: Lippincott-Raven Publishers, 1997, pp 2423-2427, 27. Taus P, Petru E, Gucer F et af. Primary serous papillary carcinoma of the peritoneum: A report of 18 patients. Eur J Gynaecol Oncol 1997:18:171. 28. Antman KH, Blum RH, Greenberger JS et al. Multimodality therapy for mesothelioma based on a study of natural his tory. Am J Med 1980:68:356. 29. Antman KH, Schlff PB, Pass Hi. Cancer: Principles & Prac tice of Oncology. Philadelphia: Uppincott-Raven PuWishers, 1997, pp 1053-1858. 30. Morgan MA, Behbakht K, Benjamin I et al. Racial differences in survival from gynecologic cancer. Obstet Gyrjpcol 1996; 88:914. 31. Menzln AW, Alldns JK, Wheeler JE et al. Surgically docu mented responses to paclltaxel and dsplatin in patients with primary peritoneal carcinoma, GynBcol Oncol 1996:62:55. 32. Rubin SC, Dulaney ED, Markman M et al. Peritonea! cytology as an Indicator of disease in patients with residual ovarian carcinoma. Obstet Gynecol 1986:71:851. 33. Petru E, Heydarfadai M, Picket H et al. Primary, papillary serous carcinoma of the perttonlunr A report of experiences. GeburtshiHe Frauenheilkd 1992;52:533. 34. Silcocks PB, Herbert A Wright DH. Evaluation of PASdiastase and carcinoembryonlc antigen staining in the differ ential diagnosis of malignant mesothelioma and papillary serous carcinoma of the ovary. J Pathol 1986:149:133. 35. Kannerstein M, Churg J, Manger D. Biological Effects of Asbestos. Lyon: IARC Scientific Publications Service No, 8, 1973; pp 62-64. 36. Khoury N, Raju U, Crissman JD et al. A comparative immunohistochemical study of peritoneal and ovarian serous tu mors, and mesotheliomas. Hum Pathol 1990:21:811. 37. Weiss NS, Hononchuk T, Young JL Jr. Incidence of the histologic types of ovarian cancer. The U.S. Third National Cancer Survey, 1969-1971. Gynecol Oncol 1977;5:161, 38. Wall JE, Mandrel! SN, Jenkins JJ et al. Effectiveness Df paclltaxel in treating papillary serous carcinoma of the peri toneum In an adolescent. Am J Obstet Gynecol 1995; 172: 1049. 39. Tobacman JK, Green MH, Tucker MA et al. Intraabdominal carcinomatosis after prophylactic oophorectomy in ovariancancer-prone families, Lancet 1962:2:795. 40. Cowan LI, Roller Jf, Connelly PJ et al. Extraovarian stage IV peritoneal serous papillary carcinoma presenting as an asymptomatic skin lesion--A case report and literature re view, Gynecol Oncol 1995:57:433. 41. Moll UM, Valea F, Chumas J. Role of p53 alteration In pri mary peritoneal carcinoma. Int J Gynecol Pathol 1997:16: 156. 42. Russell P. Haines and Taylor Obstetric and Gynaecological Pathology. Edinburgh: Churchill Livingstone, 1987; pp 556 662. . . 43. Wick MR, Mills SE, Dehner LP et al. Serous papillary carci nomas arising from the peritoneum and ovaries: A clinico pathologic and immunohlstochemical comparison. Int J Gy necol Pathol 19B9;B:179. 44. Daya D, McCaughey WT. Well-differentiated papillary me sothelioma of the peritoneum: A clinicopathologic study of 22 cases. Cancer 1990;65:292. 45. Bollinger DJ, Wick MR, Dehner LP et al. Peritoneal malignant mesothelioma versus serous papillary adenocarcinoma: A histochemteal and immunohlstochemical comparison. Am J Surg Pathol 1989;13:659. 46. Gitsch Gt Tabery U, Feigl W et al. The differential diagnosis of primary peritoneal papillary tumors. Arch Gynecol Obstet 1992:251:139. 47. Bollinger DJ, Wick MR, Manlvel JC et al. Peritonea! malignant mesothelioma vs. serous papillary adenocarcinoma: An lmmunohistochemical comparison (Abstr). Lab invest 1968:53: 11A. 48. Warhol MJ, Hunter NJ, Corson JM. An ultrastructural com parison of mesotheliomas and adencarcinomas of the ovary and endometrium, Int J Gynecol Pathol 1982; 1:125. 49. Pettersson F. international Federation of Gynecology and Obstetrics Report. Stockholm: FIGO, 1991, pp 246. 50. Chen KTK, Flam MS. Peritoneal papillary serous carcinoma with long-term survival. Cancer 1986;58:1371. 51. Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian cancer. Natl Cancer Inst Monogr 1975: 42:101, 52. Haskins WJ, Bundy BN, Thigpen JT et al. The influence of 334 Obstetrical and Gynecological Survey cytoreductive surgery on recurrence-free interval and sur vival in small-vDlume stage III epithelial ovarian carcinoma: A Gynecology Oncology Group Study. Gynecol Oncol 1992; 47:150. . 53. Valea FA, Bakshi S, Pearl ML et al. A comparison of disease- free and overall survival in primary peritoneal and ovarian cancers: A case-control study (Abstr 208). Gynecol Oncol 1998,-68:123. 54. Hoskins WJ. Ovarian Cancer. New York: McGraw-Hill, Inc, 1993; pp 241-253. 55. Ozols RF, Rubin SC. Thomas G et al. Principles and Practice of Gynecologic Oncology. Philadelphia: Lippincott-Raven, 1997, pp 919-986, 56. McGuire WP, Hoskins WJ, Brady MF et al. Cyclophospha mide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian carcinoma N Engl J Med 1996:334:1. 57. Omura G, Blessing JA, Ehrlich CE et al. A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma. Cancer 1987;56:1725. 58. Bioss JD, Brady M, Rocereto T et al. A phase II trial of cisplatin and cyclophosphamide In the treatment of extrao- varian peritoneal serous papillary carcinoma with compari son to papillary serous ovarian carcinoma: A Gynecologic Oncology Group study (Abstr 150). Gynecol Oncol 1998:68: 109. . 59. Aiklns JK, Paulson J, Arnold G et al. Comparison of pacii- taxel/cisplatinol to cyclophosphamide/cisplatinol in incom pletely resected papillary serous peritoneal cancer (Abstr 143). Gynecof Oncol 1998;68:107, 60. Rose PG, Fusco N, Fuellen L et al. Second-line therapy with paclitaxel and carboplatin for recurrent disease following first-line therapy with paclitaxel and platinum In ovarian or peritoneal carcinoma. J Clin Oncol 1998:68:199. 61. Bioss JD, Liao S-Y, Buller RE et al. Extraovarian peritoneal serous papillary carcinoma: A case-control retrospective comparison to papillary adenocarcinoma of the ovary. Gy necol Oncol 1993:60:347. 62. Hoskins WJ. Cancer of the Ovary. New York: Raven Press, 1993; pp 163-173. 63. Eltabbakh GH, Wemess BA, Plver S et al. Prognostic factors in extraovarian primary peritoneal carcinoma. Gynecol Oncol 1998:71.230-239. 64. Fowler JM, Nieberg RK, Schooler TA et al. Peritoneal ade nocarcinoma (serous) of Mullerian type: A subgroup of women presenting with peritoneal carcinomatosis. Int J Gy necol Canoer 1994;4:43. 65. Stmad CM, Grosh WW, Baxter J et al. Peritoneal carcino matosis of unknown primary site in women. A distinctive subset of adenocarcinoma. Ann Intern Med 1989;111:213. 66. Conte PF, Bruzzonp M, Chiara S et al. A randomized trial comparing cisplatin plus cyclophosphamide versus cisplatin, doxorubicin, and cyclophosphamide in advanced ovarian cancer. J Clin Oncol 1986;4;965. 67. RedmanJR, Petroni GR, Saigo PE et al. Prognostic factors In advanced ovarian cancer. J Clin Oncol 1986;4:515. 68. Vogl SE, Pagano M, Kaplan BH et al. Cisplatin-based com bination chemotherapy for advanced ovarian cancer High overall response rate with curative potential only in women with small tumor burdens, Cancer 1983;51:2024. 69. Wharton JT, Hereon J. Surgery for common epithelial tumors of the ovary. Cancer 1981;48:582. 70. Plver MS, Lele SB, Marchetti DL et al. The impact of aggres sive debulking surgery and cisplatin-based chemotherapy on progression-free survival in stage III and IV ovarian car cinoma. J Clin Oncoi 1988:6:983. 71. Neijt JP, ten Bokket Hutriink WW, van der Burg ME et al. Randomized trial comparing two combination chemotherapy regims (CHAP-5 vs. CP) in advanced ovarian carcinoma. JCfin Oncol 1987;5:1157. 72. Delgado G, Oram DH, Petriili ES. Stage III epithelial ovarian cancer. The role of maximum surgical reduction. Gynecol Oncol 1984:18:293. 73. Kowalski LD, Kanbour Al, Price FB et al. A case-matched molecular comparison of extraovarian versus primary ovar ian adenocarcinoma. Cancer 1997',79:1587. 74. Russell P. The pathological assessment of ovarian neo plasms. I: Introduction to the common "epithelial" tumours and analysis of benign "epithelial" tumours. Pathology 1979; 11:5. . 75. Dailenbach-HelJweg G. Atypical endosalplngiosls: A case report with consideration of the differential diagnosis of glan dular subperitoneai inclusions. Pathol Res Pract 1987;1B2: 180. ' 76. Bell DA, Scully RE. Serous borderline tumors of the perito neum. Am J Surg Pathol 1990:14:230. 77. Biscottl GV. Hart WR. Peritoneal serous micropapillomatosis of low malignant potential (serous borderline tumors of the peritoneum): A clinlcopathologic study of 17 cases. Am J Surg Pathol 1992;16:467. 78. Weir MM, Bell DA, Young RH. Grade 1 peritoneal serous carcinomas. A report of 14 cases and comparison with 7 peritoneal serous psammocardnomas and 19 peritoneal se rous borderline tumors. Am J Surg Pathol 1998;22:649-862. 79. Buttini M, Nicklln JL, Crandon A. Low malignant potential ovarian tumors: A review of 175 consecutive cases. Aust N Z J Obstet Gynaecol 1997:37:100. 80. Kliman L, Rome HM, Fortune DW. Low malignant potential tumors of the ovary: A study of 76 cases. Obstet Gynecol 1986^8:336. . 81. Nakashima N, Nagasaka T, Oiwa N et al. Ovarian epithelial tumors of borderline malignancy in Japan. Gynecol Oncol 1990:38:90. 82. O'Qufnn AB, Hannigan EV. Epithelial ovarian neoplasms of low malignant potential. Gynecol Oncol 1985:21:177. 83. Carter J, Atkinson K, Coppleson M et al. A comparative study of proliferating (borderline) and invasive epithelial ovar ian tumors in young women. Aust N 2 j Obstet Gynaecol 1989:29:245. 84. Seldman JD, Kutman RJ, Subclassification of serous border line tumors of the ovary into benign and malignant types: A clinicopathologic study of 65 advanced stage cases. Am J Surg Pathol 1996:20:1331. 85. Kennedy AW, Hart WR. Ovarian papillary serous tumors of low malignant potential (serous borderline tumors): A long term follow-up study, including patients with microinvasion, lymph node metastasis, and transformation to invasive se rous carcinoma. Cancer 1996;78:278, 86. Trimble EL, Trimble CL Cancer of the Ovary. New York, 1993; pp 415-427. 87. Sutton GP, Bundy BN, Omura GA et al. Stage III ovarian tumors of low malignant potential treated with cisplatin com bination therapy (a Gynecologic Oncology Group study). Gy necol Oncol 1991:41:230. 88. Gershenson DM, Silva EG. Serous ovarian tumors of low malignant potential with peritoneal Implants. Cancer 1990; 65:578. 89. Chambers JT, Merino MJ, Kohom El et al. Borderline ovarian tumors. Am J Obstet Gynecol 19SB;159:1088. - . 90. Foyle A, Al-Jabf M, McCaughey WTE. Papillary peritoneal tumors in women. Am J Surg Pathol 1981,-5:241. 91. Plver MS, Jlshi MF, Tsukada Y et al. Primary peritoneal carcinoma after prophylactic oophorectomy In women with a family history of ovarian cancer. Cancer 1993;71:2751. 92. Mills GB, May C, McGill M et al. A putative new growth factor In ascitic fluid from ovarian cancer patients: Identification, characterization, and mechanism of action. Cancer Res 1988,-48:1066. 93. Boyd J, Rubin SC. Hereditary ovarian carcinoma: molecular Primary Peritoneal Carcinoma CME Review Article 335 genetics and clinical Implications. Gynecol Oncol 1997;54: 196. 94. Lynch HT, Lynch JF, Conway TA Ovarian Cancer. New York: McGraw-Hill, Inc, 1993; pp 189-217. 95. Schildkraut JM, flisch N, Thompson WD. Evaluating genetic association among ovarian, breast, and endometiral cancer Evidence for a breast/ovarian cancer relationship. Am J Hum Genet 1989:45:521. 96. Houlston RS, Colling A, Slack J et al. Genetic epidemiology of ovarian cancer Segregation analysis. Ann Hum Genet 1991:55:291. 97. Bewtra C, Watson P, Conway T et al. Hereditary ovarian cancer A cliriicopathologlcal study, int J Gynecol Pathol 1992:11:1BO. 98. Berchuk A Cirisano F, Lancaster JM et al. Role of BRCA1 mutation screening in the management of familial ovarian cancer. Am J Obstet Gynecol 1998:175:738. 99. Takahastii H, Behbakht K, McGovern PE et al. Mutation analysis of the BRCA1 gene in ovarian cancers. Cancer Res 1995:55:2998. 100. Stratton JF, Gayther SA, Russell P et al. Contribution of BFtCAl mutation to ovarian cancer. N Engl J Med 1997;336: 1125. 101. Bandera GA Muto MM, Schorge J et al. BBCA1 gene mu tations in women with papillary serous carcinoma of the peritoneum. Obstet Gynecol 1998;92:596-600. 102. Lauchlan SC. The secondary Mullerian system. Obstet Gy necol Surv 1972:27:133,. 103. Komatsu T, Konlshl I, Mandal M et al. Peritoneal papillary serous carcinoma arising In an infertile woman during ovu lation-induction therapy: Immunohistochemical expression of LH/hCG receptors. Gynecol Oncol 1995;56:470. 104. Kitawaki J, Noguchi T, Yamamoto T et al. Immunohisto chemical localisation of aromotase and Its correlation with progesterone receptors in ovarian epithelial tumours. Anti cancer Res 1996:16:91. 105. Kommoss F, Pfisterer J, Thome M et al. Steroid receptors in ovarian carcinoma: Immunohistochemical determination may lead to new aspects. Gynecol Oncol 1992:47:317, 106. Longo DL, Young RC. Cosmetic talc and ovarian carcinoma. Lancet 1979,-2:1011. 107. Kupryjanczyk J, Thor AD, Beauchamp R et al. Ovarian, peri toneal, and endometrial serous carcinoma: Clonal origin of multifocal disease. Mod Pathol 1996:9:166. 108. Pejovic T, Heim S, Mandahl N et al. Bilateral ovarian carci noma: Cytogenetic evidence of unicentric origin, int J Can cer 1B91;47:358. 109. Mok C-H, TBao S-W, Knapp RC et al. Unifocal origin of advanced human epithelial ovarian cancers. Cancer Res 1992:52:5119. 110. Jacobs IJ, Kohler MF, Wiseman RW et al. J Natl Cancer Inst 1992:84:1793. 111. US. Han H, Resnik E et al. Advanced ovarian carcinoma: Molecular evidence of unifocal origin. Gynecol Oncol 1993: 51:21. 112. Tsao SW. Mok CH, Knapp RC et al. Molecular genetic evi dence of a unifocal origin for human serous ovarian carcino mas. Gynecol Oncol 1993;48:5. * 113. Muto MG, Welch WR, Mok SC et al. Evidence for a multifocal origin of papillary serous carcinoma of the peritoneum. Can cer Res 1995:55:490. 114. Schorge JO, Muto MG, Welch WR et al. Molecular evidence ter multifocal papillary serous carcinoma of the peritoneum in patients with germline BRCA1 mutations. J Natl Cancer Inst 1998;90:841-5. 115. Bandera CA Muto MG, Welch WR et aJ. Genetic imbalance on chromosome 17 In papillary serous carcinoma of the peritoneum. Oncogene 1998;16:3455-3459. 116- Schorge JO, Muto MG, Welch WR et al. Androgen receptor genetic analysis of the X-chromosome inactivation pattern in patients with papillary serous carcinoma of the peritoneum (Abstr 67). Gynecol Oncol 1998;68:B9. 117. Greenblatt MS, Bennett WP, Hollstein M et al.'Mutations In the p53 tumor suppressor gene; Clues to cancer etiology and molecular pathogenesis. Cancer Res 1994:54:4855. 118. Slamon DJ, Godoiphln W, Jones LA et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989:244:707.' 119. Hudziak RM, Schlessinger J, Ullrich A Increased expression of the putative growth factor receptor p1B5HR2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc Natl Acad Set USA 1987:84:7159. 120. DiFtore PP, Pierce JH, Fleming TP et al. Overexpression of the human EGF receptor confers an EGF-dependent trans formed phenotype to NIH 3T3 cells. Cell 1987:51:1063. 121. Geisler JP, Geisler HE, Wiemann MC et al. Quantification of p53 In.epithelial ovarian cancer. Gynecol Oncol 1997:66:435. 122. Buttttta F, Marchetti A, Gadduccl A et al. p53 alterations are predictive of chemoresistance and aggressiveness in ovar ian carcinomas: A molecular and immunohistochemical study. Br J Cancer 1997;75230. 123. Marchenko ND, Moli UM, Nuclear overexpression of p53 protein does not correlate with gene mutation in primary peritoneal carcinoma. Hum Pathol 1997:28:1002. 124. Chen L-M, Yamada SD, Ru YS et al. Molecular similarity of primary peritoneal and primary ovarian carcinomas {Abstr 15). Gynecol Oncol 1998;68;76. 125. Pieretti M, Powell DE, Galllon HH et al. Genetic alterations on chromosome 17 distinguish different types of epithelial ovar ian tumors. Hum Pathol 1995:26:393. 126. Russell SEH, Hickey Gl, Lowry WS et al. Allele loss from chromosome 17 in ovarian cancer. Oncogene 1990;5:1581. 127. Sato T, Saito H, Morita R et al. Allelotype of human ovarian cancer. Cancer Res 1991 ;51:5118. 128. Eccles DM, Russell SEH, Haites NE at al. Early loss of heterozygosity on 17q in ovarian cancer. Oncogene 1992:7: 2069. .129- Cllby W, Ritiand S, Hartmann L et al. Human epithelial ovar ian cancer allelotype. Cancer Res 1993:53:2393. 130. Yang-Fertg TL, Han H. Chen KC et al. Allelic loss in ovarian cancer. Int J Cancer 1993;54:546. i 4