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Clear-cell and papillary serous cancer: treatment options
Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 15, No. 3, pp. 433±446, 2001
doi:10.1053/beog.2000.0187, available online at http://www.idealibrary.com on
8 Clear-cell and papillary serous cancer: treatment options Claes TropeÂ
MD PhD
Professor
Gunnar Balle Kristensen
MD PhD
Assistant Professor Department of Gynecologic Oncology, The University Clinic, The Norwegian Radium Hospital, Montebello, N-0310, Oslo, Norway
Vera Maria Abeler
MD PhD
Senior Consultant Department of Pathology, The University Clinic, The Norwegian Radium Hospital, Montebello, N-0310, Oslo, Norway
Clear-cell carcinoma (CCC) and serous papillary carcinoma of the endometrium (UPSC) are rare subtypes of endometrial carcinoma (10%). The histological diagnosis can be made on the dilation and curettage specimens in both types in a very high percentage of the cases. This is important in the planning of treatment. CCC and UPSC are associated with about 50% of all relapses occurring in endometrial carcinoma, and the 5-year survival rate is, on average, 42% and 27% respectively. Surgico-pathological stage, age, and vessel invasion are independent prognostic factors for both groups. The recurrence rate is extremely high, and the most frequent extra-pelvic sites of relapse are the upper abdomen, lungs and liver. Stage Ia patients treated with complete surgical staging alone have a low risk of relapse and need not be oered adjuvant systemic therapy or pelvic radiation. The treatment of patients with CCC and UPSC stage Ib, Ic, II and III should include radical debulking surgery and some form of adjuvant therapy, but it is not clear which type is most eective. Adjuvant pelvic radiotherapy plus intracavitary radiotherapy is usually given in early-stage disease and pelvic radio therapy/or whole abdomen irradiation plus adjuvant systemic chemotherapy (PAC) in advanced disease. However, we are urgently waiting for a large prospective randomized study to compare both modalities. Paclitaxel, alone or in combination, is currently being tested in phase II studies. Key words: endometrioid carcinoma; carcinoma; uterine papillary serous carcinoma (UPSC); clear-cell adenocarcinoma (CCC); prognosis; nuclear grade; ¯ow cytometry; DNA ploidy; p53 immunohistochemistry; surgery; chemotherapy; pelvic; abdominal irradiation.
A continuous increase in the incidence of endometrial carcinoma has been reported in western countries during the past 30 years. Endometrial cancer is the commonest female genital tract cancer in Scandinavia with age-adjusted (European standard population) incidence rate of 17±21/105 women and age-adjusted death rates of 1521±6934/01/03043314 $35.00/00
c 2001 Harcourt Publishers Ltd. *
434 C. TropeÂ, G. B. Kristensen and V. M. Abeler
100 Expected Adenoacanthoma
Survival (%)
80
Adenocarcinoma Total Material Adenosquamous Undifferentiated
60
40 Clear Cell 20
0
Serous Papillary
0
30
60
90
120
Months Figure 1. Ten-year crude survival for the entire population of 1974 patients treated at the NRH between 1970 and 1977.
4±5/105.1,2 Because it generally presents as early-stage disease (stage I in 75% of cases) and can be treated without radical surgery, endometrial carcinoma has frequently been regarded as a relatively benign type of cancer with a fairly good overall 5-year survival rate of approximately 75%. However, a more critical evaluation of survival data indicates that this concept is partly misleading.3 It is well known that endometrial carcinoma is a morphological heterogeneous group of malignancies. The majority (480%) of endometrial carcinomas are of endometric type with/without squamous dierentiation and carry a good prognosis. Patients with endometrioid tumours with squamous dierentiation have the most favourable prognosis, with a 5-year crude survival rate of 91.2%. This contrasts with patients with clear-cell and serous papillary carcinoma, which make up about 10% of endometrial carcinomas but which are associated with about 50% of all relapses occurring in endometrial cancer patients whose 5-year survival rate averages only 42 and 27% respectively (Figure 1). Patients in these groups are almost all post-menopausal, tend to be elderly and are generally neither obese nor diabetic.3 The challenge in treating patients with these subtypes continues to be careful identi®cation of high-risk prognostic features and a critical evaluation of treatment. HISTOLOGICAL TYPES AND PROGNOSTIC VARIABLES Clear-cell carcinoma The concept of clear-cell carcinoma as being of mesonephric origin and designated as `mesonephroma' was introduced in 1939 by Schiller4 to describe a subtype of ovarian tumour which resembles renal carcinoma and tumours originating from the mesonephric duct system. Scully and Barlow5 related the origin of the latter group of tumours to the MuÈllerian epithelium rather than the mesonephros and proposed in 1967 the descriptive term `clear-cell carcinoma' (CCC). CCC of the female genital
Clear-cell and papillary serous cancer 435
tract is now a well-established histopathological entity and comprises about 1±6% of endometrial carcinomas.6,7 The prognostic implication of CCC was not recognized until 1976 when Kurman and Scully8 reported a series of 21 cases with an unfavourable clinical course. In the early literature, survival for CCC is usually given for clinically staged patients with an overall survival ranging from 21 to 60%.8 This aggressive clinical behaviour was con®rmed by Abeler et al in 19966 in the largest single institution study from The Norwegian Radium Hospital (NRH) (181 patients), who demonstrated a 5- and 10-year actuarial disease-free survival rate of 43 and 39% respectively (for all stages). The 5-year survival for pathological stage I CCC of 54% and for stage II of 27% was lower than that reported by Carcangiu and Chambers9 of 72 and 59% respectively. Surgico-pathological stage, clinical stage, age, vessel invasion and myometrial invasion were the only signi®cant prognostic variables in the univariate analyses.6 In the multivariate analysis surgico-pathological stage and age were the sole independent prognostic factors. Twothirds of the patients with relapse did so outside of the pelvis, with the most frequent extra-pelvic sites of relapse being the upper abdomen, lungs and liver. Only patients with intramucosal tumours had a prognosis comparable to those with endometrioid adenocarcinomas. Ninety percent of the patients with intramucosal tumours survived 5 years in contrast to 15% of the patients with deep myometrial in®ltration.6 Uterine papillary serous carcinoma Uterine papillary serous carcinoma (UPSC) is an uncommon aggressive type of endometrioid adenocarcinoma that was delineated by Hendrickson et al in 198210 as a clinico-pathological entity distinct from endometrioid carcinoma. Attention was drawn primarily to the presence of psammoma bodies and predominantly papillary architecture, although solid areas can be present focally in the dilation and curettage material (D & C). Kovalev et al11 suggested that, apart from distinct clinicopathological features, a unique molecular pathogenesis that diers from endometrioid carcinoma exists. Moll et al12 and others13±16 have shown that p53 inactivation plays a key role in the molecular carcinogenesis and progression of UPSC. Several studies have found a high rate (80%) of p53 overexpression in UPSC, which is in sharp contrast to the low rate (10±25%) found in high-grade endometrioid carcinoma.12,16 Moll et al12 and Sherman et al16 suggested that UPSC is a p53-driven neoplasm that is biologically related to other serous papillary malignancies of the ovaries and peritoneum and, according to this hypothesis, UPSC bypasses the slow hormone-dependent pathway of tumour genesis, but instead undergoes early p53 alterations which lead to rapid highly aggressive tumour development. UPSC accounts for 1±10%17±20 of all cases of endometrial carcinoma. UPSC is frequently mixed with foci of CCC10,17 and in some tumours it is impossible to dierentiate between the two. Christopherson21 suggested that there are two distinct types of papillary carcinoma: the papillary clear-cell carcinoma and the papillary nonclear-cell carcinoma where the latter appears to correspond to UPSC. Unlike typical endometrioid adenocarcinoma, UPSC is an aggressive malignancy, often associated with deep myometrial and lymphatic invasion, and with widespread peritoneal disease simulating the behaviour of ovarian carcinoma.22 Unlike endometrioid tumours, depth of invasion is not a prognostic factor in UPSC. In a study by Go et al23 50 patients with UPSC were surgically staged. Thirty-three patients had pure UPSC and 17 had UPSC admixed with other histology. Extra-uterine disease was found in 36 women (72%).
436 C. TropeÂ, G. B. Kristensen and V. M. Abeler
Lymph node metastases were present in 36% of the women without myometrial invasion, in 50% with inner half invasion, and in 40% with outer one-half invasion. Similarly, the presence of intraperitoneal diseases and positive washings did not correlate with increasing myometrial invasion. These ®ndings have also been shown by Sherman et al17 and Carcangiu and Chambers9, who found no dierence in survival based upon myometrial invasion. In contrast Gallion et al24 found that no patient had recurrent disease in the absence of myometrial invasion. Grade and histology (mixed versus pure) are also not predictive of extrauterine disease.9,17,23 Go et al23 found that lymphatic/vascular space invasion was associated with extra-uterine disease, but even in cases without lymphatic/vascular space invasion they saw a high incidence of extra-uterine disease. The survival rate is dismal even when UPSC is only a component of the tumour.17 The overall 5-year survival is approximately 30% for all stages.20,25 Patients with surgical stage I and II tumours had a 5-year overall survival rate in the NRH series of 54 and 27% respectively, and there were no 5-year survivors among those with stage III and IV disease.19 These ®gures are in contrast to those of Kato et al25 who reported a 5-year survival rate of 79% in patients with early-stage disease and 25% in those with advanced disease. Widespread metastases and death can occur even in those cases in which tumour is con®ned to the endometrium or to an endometrioid polyp.9,25,26 MOLECULAR BIOLOGICAL PROGNOSTIC FACTORS Studies of the tumour biology of UPSC and CCC are in their infancy. Most of these tumours are not surprisingly DNA aneuploid and have a high S phase.27,28 Nordstrom et al22 have studied the prognostic impact of UPSC and CCC in relation to nuclear grade, DNA ploidy and p53 expression. In a histopathological review of 266 women with stage I±IV endometrial carcinoma, UPSC and CCC were diagnosed in 31 (12%) and six (2%) of the patients respectively. Strong expression of the mutated p53 gene product was signi®cantly more common in the UPSC plus CCC group than in the reference group (64 versus 19%). In a Cox multivariate analysis, including histopathological and clinical variables, UPSC and CCC were still signi®cant predictors of survival. When nuclear grade and ploidy were added to the analysis, histological type as well as degree of dierentiation lost most of their prognostic impact. DNA ploidy was found to be the strongest independent predictor of outcome besides age and stage, in contrast to the study of Kato et al25 who did not ®nd DNA ploidy to have a signi®cant impact on survival. p53 overexpression as a prognostic factor has also been studied by King et al (in 22 patients)15 and Bancher-Todesca et al (23 patients).29 Seventy-three percent and 45% of the tumours, respectively, were scored as having p53 overexpression, with patients whose tumour-overexpressed p53 having a statistically shorter survival. It should be noted, however, that a comparative analysis with other prognostic factors has not been studied and patient numbers are small. FUTURE DIRECTIONS What staging surgery should be performed in patients with clear-cell carcinoma and with uterine papillary serous carcinoma? Several studies have demonstrated signi®cant understaging when patients with endometrial cancer are subjected to thorough surgical evaluation.30±32 The discrepancy
Clear-cell and papillary serous cancer 437
between clinical and surgical staging is most clearly seen in stages I and II, with about 50% of the patients being clinically understaged.33,34 The inaccuracy of the previous clinical staging system has been shown, as in the endometrioid carcinoma, to be inadequate in assessing patients with CCC and UPSC.19,22,23,35±38 For instance, in one study 68% of the patients with clinical stage I and II tumours were upstaged at the time of surgery.25 Although more accurate information should be obtained if thorough surgical staging is carried out on all patients this is unfortunately unlikely to happen and interpretation of the literature will be dicult. Routine lymphadenectomy is unlikely to be performed for a number of reasons, including the fact that many patients with CCC and UPSC are treated in the community where the necessary surgical skills may not be available to perform lymphadenectomy, many patients are obese and not suitable for extensive nodal resection and some tumours may not always justify routine lymphadenectomy. In addition, the extent of the lymphadenectomy has not been de®ned (random sampling of pelvic and para-aortic nodes versus complete pelvic and or para-aortic lymphadenectomy versus resection of any enlarged nodes).34 Surgical stage has, in many studies, been the strongest independent prognostic factor6,25,39 and supports routine extended surgical staging in women with a preoperative or intra-operative diagnosis of CCC and UPSC. Certainly in our institution the ®ndings of CCC and UPSC on an endometrial sampling is sucient to stage the tumours surgically whether or not there is pre-operative or intra-operative evidence of myometrial invasion or cervical involvement. The same staging procedure as for epithelial ovarian carcinoma is used and includes total abdominal hysterectomy omentectom and bilateral salpingo-oophorectomy, peritoneal washings, peritoneal biopsies and pelvic and para-aortic lymphadenectomy. The same strategy is accepted by many other centres.23,36,38±42 It is an important observation that CCC and UPSC have such characteristic histological patterns that a correct diagnosis can be made on the dilation and curettage specimen alone in 87% of the patients with CCC and in 100% of the patients with UPSC.6,20 A clinical dilemma may arise when the curettage specimen is positive for CCC or UPSC but where no such pathological features are seen in the hysterectomy specimen. Aquino-Parson et al treated eight such patients expectantly with none recurring within a median follow-up of 3 years.43
REMAINING PROBLEMS The appropriate therapy for patients with early surgical stage CCC and UPSC is controversial, with as yet no prospective randomized study which could help to decide which patients might bene®t from adjuvant post-operative therapy. We know, however, that stage Ia cases treated with complete staging surgery alone have a low risk of relapse, and we agree with Craighead et al36, Geisler et al38, Grice et al41 and Aquino-Parson et al43 that these patients do not need to be oered adjuvant systemic therapy or pelvic radiation. The treatment of patients with CCC and UPSC stage Ib, Ic, II and III, should probably include radical debulking surgery and some form of adjuvant therapy, but it is not clear which type is most eective.42 By and large, adjuvant pelvic radiotherapy plus intracavitary radiotherapy is usually given in early-stage disease and pelvic radiotherapy/or whole abdomen irradiation plus adjuvant systemic chemotherapy in advanced disease.36
438 C. TropeÂ, G. B. Kristensen and V. M. Abeler
Chemotherapy With the proven poor prognosis associated with CCC and UPSC the necessity for eective adjuvant and salvage therapies has become evident. Multiple modalities have been evaluated with variable success. Unfortunately, most of these studies are in patients with clinically staged disease and are therefore of limited value in establishing the overall eectiveness of a speci®c treatment modality. The rationale behind the use of post-operative chemotherapy in CCC includes the considerable histopathological similarity between CCC and ovarian clear-cell carcinoma. Furthermore, a response rate of up to 60% has been reported in patients with recurrent and advanced endometrioid carcinoma and CCC with cisplatin and doxorubicin.6,44 The regimen in adjuvant (or advanced and recurrent) CCC tumour we use at the NRH consists of four courses of cisplatin at 75 mg/m2 combined with doxorubicin 50 mg/m2. The response duration is, however, short lasting and the use of paclitaxel, which has shown promising results in clear-cell carcinoma of the ovary45 is planned. Systemic therapy with progestational agents has no impact on survival of CCC patients. In fact the cardiovascular side-eects of progestational therapy may make routine treatment dangerous.6 The use of chemotherapy in UPSC also seems rational because there is considerable histopathological similarity between UPSC and ovarian serous papillary carcinoma (75% response rate to cisplatin-based combination regimens), and most relapses occur outside the pelvis. However, the high response rates seen in ovarian cancer have not been observed in UPSC46 and the eect of chemotherapy on the outcome of patients with UPSC has been controversial.47 Some studies on adjuvant chemotherapy in patients with UPSC with a high risk of recurrence indicate a prolonged relapse-free survival.46,48,49 For instance, Price et al48 used cisplatin, doxorubicin and cyclophosphamide (PAC) in 19 patients radically operated on without any residual tumour. Eight stage I patients were alive without evidence of disease after a median follow-up of 24 months. Of the remaining 11 patients who had extrauterine disease at diagnosis, eight were dead of disease at a median of 14 months. Levenback et al49 reported on 20 UPSC patients treated with PAC of whom 13 had advanced or recurrent disease and six had no residual tumour. The patients received a mean of ®ve cycles of PAC. Only two of 11 patients with evaluable disease achieved complete responses (of 12 and 31 months duration). The median survival for the entire group was 24 months. Turner et al50 have also shown that in six stage I UPSC patients with complete surgical staging with adjuvant PAC chemotherapy there were no recurrences at a median follow-up of 31 months. Hamaguchi et al51 used ifosphamide instead of cyclophosphamide in the PAC combination in seven patients in an adjuvant setting. Two patients had tumour recurrences within 6 months. Another approach using the PAC regimen in UPSC patients has been reported by Chambers et al.52 Sixteen patients with UPSC underwent complete surgical staging and at the same time an intraperitoneal port was placed. Post-operatively they received cisplatin 100 mg/m2 given intraperitoneally (i.p.) and doxorubicin 50 mg/m2 intravenously (i.v.) and cyclophosphamide 600 mg/m2 i.v. every 4 weeks for six cycles. In three cases the i.p. port did not work. All patients except one had no gross residual at the end of surgery, yet despite this seven patients have died, one patient is alive with disease and ®ve patients are alive with no evidence of disease. Five of the seven patients with extra-uterine disease died of their disease. The median survival was
Clear-cell and papillary serous cancer 439
34 months with an overall 3-year survival of only 24%. There was no advantage of this regimen over the same PAC regimen given i.v. at the same institution. It is apparent that platinum/doxorubicin-based combination chemotherapy has a response rate of about 20±25%46,49 and that patients with recurrent or advanced disease should be part of clinical trials of therapy with taxanes. Paclitaxel has recently been shown to be active in endometrioid carcinoma, and the ultimate role of paclitaxel alone or in combination with cisplatin or carboplatin in the management of UPSC awaits further investigation.45 The ®rst report on the use of paclitaxel in UPSC was a case report by Resnik and Taxy53 who described a dramatic response in an advanced UPSC tumour after three cycles of paclitaxel and carboplatinum given as neoadjuvant therapy. Zanotti et al54 treated 24 patients with UPSC with paclitaxel (175 mg/m2) alone or paclitaxel (175 mg/m2) combined with carboplatin alea under curve (AUC 5) or cisplatin (75 mg/m2). Eighteen patients received the regimens in the adjuvant setting. Eleven patients received one or more courses of this combination for recurrent disease. A median progression-free survival (PDS) of 30 months (range 8±61) was seen in patients treated in the adjuvant setting. An objective response indicated by normalisation of CA 125 was seen in eight of nine patients treated for residual disease after initial surgery (median PFS of 13 months, range 5±38), while an objective response was seen in seven out of eleven patients with recurrent disease (median PFS of 9 months, range 4±18). Zanotti et al also re-treated six patients with paclitaxel and four of these six patients responded a second time.54 As in CCC, hormonal therapy is not indicated because no responses have been reported with medroxyprogesterone, megestrol or tamoxifen.46 Radiotherapy Patients with high-risk endometrial carcinoma are traditionally oered adjuvant treatment with pelvic radiation, although the ecacy of this treatment is a matter of debate (60% relapse outside irradiated area).55±57 It is still reasonable to expect some bene®t with this modality in the management of CCC and UPSC because the majority of the recurrences are located in the upper abdomen; however, it is more logical to suggest that the whole abdomen should be treated to obtain the greatest advantage. Several retrospective studies have recommended the use of whole abdominal pelvic radiation therapy (WAPT) in early UPSC but have not provided sucient data to determine whether this can be safely or eectively applied.36 Frank et al58 treated nine patients with stage Ic-IIIa UPSC with WAPT on an adjuvant basis after cytoreductive surgery. All patients were treated with megavoltage photons to an abdominal pelvic ®eld to a median dose of 2500 cGy with continued treatment to the whole pelvic ®eld to a median dose of 4500 cGy. At a median follow-up time of 25 months, six patients had recurrent disease at 5 to 20 months (median 7.5 months), with four of these patients dead of disease. Mallipedd et al59 treated ten patients with UPSC with WAPT as adjuvant therapy following staging laparotomy and debulking surgery. The pelvic dose varied from 4750 to 5100 cGy (median 5010 cGy) and the median dose administered to the upper abdomen was 2975 cGy. WAPT was administered over 42±80 days. Nine patients had clinical stage I disease, but the tumour in eight of these was upstaged on the basis of laparotomy ®ndings. Five patients were alive with no evidence of disease at 102±103 months, while four patients died. All recurrences were observed within 30 months of the initial diagnosis. In contrast to Frank et al58, Mallipeddi et al59 concluded that the treatment of UPSC should
440 C. TropeÂ, G. B. Kristensen and V. M. Abeler
include WAPT because they had ®ve long-term survivors after WAPT and failures who responded to local irradiation. Combined therapies Rosenberg et al 199360 introduced a new treatment approach to a series of 24 clinical stage I patients with UPSC; the treatment consisted of radical hysterectomy and staging followed by external pelvic irradiation to 44±45 Gy by two opposing pelvic ®elds delivered in 22±25 fractions and ®nally four courses of cisplatin 50 mg/m2, epirubicin 50 mg/m2 at 28-day intervals. Fourteen patients (58%) did not start or complete the protocol for reasons of age, concomitant disease and treatment of toxicity. None of the ten high-intensity treated UPSC patients died of relapse during a median observation time of 32 months, whereas 16 of 30 (53%) of UPSC control patients died of their disease during a median observation period of 38 months (Figure 2). Eleven of seventeen patients (64%) in an historical control group who were given adjuvant pelvic irradiation in addition to radical surgery and intracavitary treatment, but did not receive any chemotherapy, died of their disease. Rosenberg et al concluded that the most eective component of the combination of surgery, radiation, and chemotherapy was the administration of cisplatin/epirubicin. The median follow-up in this study is currently 60 months and the majority of the patients are still recurrence-free (Rosenberg personal communication, 2000). Bancher-Todesca et al47 studied the prognostic signi®cance of various types of postoperative treatment in 23 surgically staged patients with UPSC. After surgery, nineteen women were macroscopically free of disease. The other four had residual tumours of more than 2 cm. Eight patients had FIGO stage I/II, whereas ®fteen patients showed stage III/IV tumours. Five women underwent adjuvant irradiation alone, consisting of vault irradiation and external beam irradiation (dose to the whole pelvic region 45±50 Gy). Five women received chemotherapy and eight women received a combination of both irradiation and chemotherapy (carboplatinum alone or cisplatin and cyclophosphamide). The median duration of follow-up was 39.4 months. The median overall survival was 43.3 months. Three of ten patients who received only 1.0
Survival
0.8 0.6 0.4 0.2 0.0
0
12
24
36 48 Months
60
72
84
Figure 2. Patients with stage I UPSC: corrected survival. high-intensity treated (n 10); adequately treated (n 30). P 0.021. Reproduced from Rosenberg et al (1993, Gynecologic Oncology 48: 32±37) with permission.
Clear-cell and papillary serous cancer 441
chemotherapy or radiotherapy are alive, whereas seven of eight patients who received a combination of both are alive with no evidence of disease. The 5-year overall survival was 80% in those who received radiotherapy and chemotherapy and only 30% in those who were treated with radiotherapy alone compared to 0% in those who were treated with chemotherapy alone (P 0.05). Craighead et al36 studied 92 patients (stage I±IV) with CCC31 and UPSC.61 Forty-nine percent of all cases underwent surgery alone, 39% underwent post-operative treatment, which included pelvic radiation (45 Gy in 25 daily fractions), and 7% underwent postoperative treatment, which included PAC chemotherapy. Pelvic recurrence was signi®cantly reduced by post-operative radiotherapy in stage Ib, Ic, II and III (19% recurrence with no radiotherapy versus 7% recurrence with radiotherapy). Chemotherapy improved overall survival but made little dierence to distant relapse rates. There was only an 11% recurrence rate in stage Ia where the patients had no post-operative treatment, with all of these being either vault or pelvic in nature. Several others have reported excellent results for observation in stage I UPSC.41,43 The results for intermediate risk cases (stage Ib, Ic and II) support the use of radiotherapy post-operatively but show that distant relapses remain a problem (44% stage I and 35% in stage II). Craighead et al36 concluded that stage Ic and II cases with lymphovascular space involvement and all stage III cases should be treated with systemic treatment plus pelvic radiation. Turner et al61 studied the outcome in 38 stage I UPSC treated with high-dose-rate (HDR) vaginal apex radiation (192Ir) to a total dose of 21 Gy in three fractions together with ®ve courses of PAC. They found that the 5-year actuarial overall survival for patients with complete surgical staging and adjuvant HDR vaginal apex brachytherapy and systemic PAC was 100% (15 patients). CONCLUSION It is suggested that although stage I CCC patients have a signi®cantly better survival than stage I UPSC patients, these tumours have similar clinical and pathological pro®les, demonstrating the need for an aggressive approach, including a staging laparotomy and similar post-operative therapy. The high risk of recurrence in CCC and UPSC, and the strong correlation between lymphatic/vascular space involvement, and extra-uterine disease, suggest that the current FIGO staging scheme for endometrioid carcinoma of the usual type may not be entirely relevant and that surgical staging, as employed in epithelial ovarian carcinoma, may be more appropriate. The need for, and the extent of, lymphadenectomy as a part of the surgical staging continues to be debated, and it is clear that the more extensive the lymphadenectomy the greater the incidence of lymph node metastases identi®ed. Unfortunately, terms such as `partial', `selective' and `simple' to describe the extent of lymphadenectomy have crept into the literature without de®nition. It is also clear that only adequate surgical staging will optimally de®ne the extent of disease in CCC and UPSC, and that risks and bene®ts as well as clinical judgement need to be considered in determining the extent of surgery. The results of PAC chemotherapy as a treatment for recurrent disease have been disappointing, with response rates in the order of 20±25%. There are sucient grounds to test paclitaxel, and several phase II studies are ongoing to test the drug alone or in combination in CCC and UPSC. The use of chemotherapy as a post-operative adjuvant treatment for CCC and UPSC has been extensively studied but remains controversial.
442 C. TropeÂ, G. B. Kristensen and V. M. Abeler Table 1. The Norwegian Radium Hospital's recommendations for treatment of clear-cell carcinoma and serous papillary carcinoma of the endometrium (outside research protocols). Stage Ia Total abdominal inspection, omentectomy, bilateral salpingo-oophorectomy, peritoneal washings. Peritoneal biopsies and pelvic and para-aortic lymphadenectomy similar to an ovarian cancer staging No adjuvant systemic or pelvic radiation Stages Ib, Ic, II and III Surgical staging as above Pelvic irradiation 45 Gy plus cisplatin 75 mg/m2 i.v. combined with doxorubicin 50 mg/m2 or epirubicin 75 mg/m2 i.v., and cyclophosphamide 650 mg/m2 (PAC) (to be repeated every 3±4 weeks) Stage IV Aggressive debulking surgery upfront followed by PAC Recurrent disease Platinum sensitive: Paclitaxel 135 mg/m2 combined with carboplatin AUC5 Platinum resistant: Paclitaxel 175 mg/m2
Table 2. A randomised trial of adjuvant treatment with radiation plus chemotherapy versus radiation in high-risk endometrioid carcinoma.a Study design Open labelled randomized, two-armed study Surgical stage I ! External pelvic radiation ! External pelvic radiation followed or preceded by chemotherapy Surgery For CCC and UPSC surgical staging as described in the text Radiation treatment Pelvic irradiation with four-®eld technique. Total dose: 44 Gy 29 Gy/fraction ®ve times per week Chemotherapy Cisplatin 75 mg/m2 i.v. plus doxorubicin 50 mg/m2 i.v. as bolus. Both drugs are given on the same day and the treatment to be repeated every 3±4 weeks An intergroup study: Nordic Society of Gynecological Oncology and EORTC Gynecological Cancer Cooperative Group.
The PAC regimen is still considered standard chemotherapy when given outside protocol (Table 1). This literature review indicates that surgically staged CCC and UPSC post-operative treatment consisting of chemotherapy and radiation therapy increases the survival rate in patients with stage Ib, Ic, II and III. However, further prospective randomized studies using both treatment regimens simultaneously will be needed to con®rm this. Multiple claims of success have been published in small uncontrolled studies. Management has ranged from observation to adjuvant pelvic radiation in stage I disease and from WAPT to chemotherapy in stage II and III disease. In Europe a prospective randomized study aimed at addressing this problem has recently been commenced (Table 2).
Clear-cell and papillary serous cancer 443
Practice points . CCC is of MuÈllerian and not mesonephric origin. Pathological stage and age are the two most important independent prognostic factors in CCC. Two-thirds of patients have tumours which relapse outside the pelvis . p53 alterations are common in UPSC and are probably responsible for its aggressive biological behaviour . UPSC is often associated with deep myometrial invasion, with lymphatic invasion and with widespread peritoneal disease, simulating the behaviour of ovarian carcinoma . the true extent of disease must be known to ascertain the ecacy of optimal adjuvant therapy . patients with CCC and UPSC should undergo a staging laparotomy similar to the procedure undertaken for patients with ovarian carcinoma . the use of chemotherapy as a post-operative adjuvant treatment for CCC and UPSC has been extensively studied but still remains controversial . the treatment results of CCC and UPSC recurrences with chemotherapy are still very poor . the challenge in treating these diseases continues to be the careful identi®cation of high-risk prognostic features and the initial evaluation of patients
Research agenda . the role of molecular biological and other prognostic factors in upfront treatment decisions needs to be tested in prospective randomized studies . to prevent over- and under-treatment, methods for separating patients who need no post-operative treatment and those who might bene®t from multi-modal therapy are necessary . prospective randomized studies are required to de®ne optimal treatment (the role of chemotherapy and/or both radiation) for women with stage Ib, Ic, II, III and IV tumours
REFERENCES 1. Engeland A, Haldorsen T, Tretli S et al. Prediction of cancer incidence in the Nordic countries up to the years 2000 and 2010. A collaborative study of the ®ve Nordic Cancer Registries. APMIS suppl 1993; 38: 1±124. 2. Engeland A, Haldorsen T, Tretli S et al. Prediction of cancer mortality in the Nordic countries up to the years 2000 and 2010, on the basis of relative survival analysis. A collaborative study of the ®ve Nordic Cancer Registries. APMIS suppl 1995; 49: 1±161. 3. Abeler VM, Kjorstad KE & Berle E. Carcinoma of the endometrium in Norway: a histopathological and prognostic survey of a total population. International Journal of Gynecologic Cancer 1992; 2: 9±22. 4. Schiller W. Mesonephroma ovarii. American Journal of Cancer 1939; 35: 1±21. 5. Scully RE & Barlow JF. `Mesonephroma' of ovary. Tumor of Mullerian nature related to the endometrioid carcinoma. Cancer 1967; 20: 1405±1417. 6. Abeler VM, Vergote IB, Kjorstad KE et al. Clear cell carcinoma of the endometrium. Prognosis and metastatic pattern. Cancer 1996; 78: 1740±1747.
444 C. TropeÂ, G. B. Kristensen and V. M. Abeler 7. Christopherson WM, Alberhasky RC & Connelly PJ. Carcinoma of the endometrium: I. A clinicopathologic study of clear-cell carcinoma and secretory carcinoma. Cancer 1982; 49: 1511±1523. 8. Kurman RJ & Scully RE. Clear cell carcinoma of the endometrium: an analysis of 21 cases. Cancer 1976; 37: 872±882. 9. Carcangiu ML & Chambers JT. Uterine papillary serous carcinoma: a study on 108 cases with emphasis on the prognostic signi®cance of associated endometrioid carcinoma, absence of invasion, and concomitant ovarian carcinoma. Gynecologic Oncology 1992; 47: 298±305. 10. Hendrickson M, Ross J, Eifel P et al. Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. American Journal of Surgical Pathology 1982; 6: 93±108. 11. Kovalev S, Marchenko ND, Gugliotta BG et al. Loss of p53 function in uterine papillary serous carcinoma. Human Pathology 1998; 29: 613±619. 12. Moll UM, Chalas E, Auguste M et al. Uterine papillary serous carcinoma evolves via a p53-driven pathway. Human Pathology 1996; 27: 1295±1300. 13. Reinartz JJ, George E, Lindgren BR et al. Expression of p53, transforming growth factor alpha, epidermal growth factor receptor, and c-erbB-2 in endometrial carcinoma and correlation with survival and known predictors of survival. Human Pathology 1994; 25: 1075±1083. 14. Prat J, Oliva E, Lerma E et al. Uterine papillary serous adenocarcinoma. A 10-case study of p53 and cerbB-2 expression and DNA content. Cancer 1994; 74: 1778±1783. 15. King SA, Adas AA, LiVolsi VA et al. Expression and mutation analysis of the p53 gene in uterine papillary serous carcinoma. Cancer 1995; 75: 2700±2705. 16. Sherman ME, Bur ME & Kurman RJ. p53 in endometrial cancer and its putative precursors: evidence for diverse pathways of tumorigenesis. Human Pathology 1995; 26: 1268±1274. 17. Sherman ME, Bitterman P, Rosenshein NB et al. Uterine serous carcinoma. A morphologically diverse neoplasm with unifying clinicopathologic features. American Journal of Surgical Pathology 1992; 16: 600±610. 18. Rosenberg P, Blom R, Hogberg T et al. Death rate and recurrence pattern among 841 clinical stage I endometrial cancer patients with special reference to uterine papillary serous carcinoma. Gynecologic Oncology 1993; 51: 311±315. 19. Christopherson WM, Alberhasky RC & Connelly PJ. Carcinoma of the endometrium. II. Papillary adenocarcinoma: a clinical pathological study, 46 cases. American Journal of Clinical Pathology 1982; 77: 534±540. 20. Abeler VM & Kjorstad KE. Serous papillary carcinoma of the endometrium: a histopathological study of 22 cases. Gynecologic Oncology 1990; 39: 266±271. 21. Christopherson W. The signi®cance of pathologic ®ndings in endometrial cancer. Obstetrics and Gynecology 1986; 13: 673±693. 22. Nordstrom B, Strang P, Lindgren A et al. Endometrial carcinoma: the prognostic impact of papillary serous carcinoma (UPSC) in relation to nuclear grade, DNA ploidy and p53 expression. Anticancer Research 1996; 16: 899±904. 23. Go BA, Kato D, Schmidt RA et al. Uterine papillary serous carcinoma: patterns of metastatic spread. Gynecologic Oncology 1994; 54: 264±268. 24. Gallion HH, van-Nagell-JR J, Powell DF et al. Stage I serous papillary carcinoma of the endometrium. Cancer 1989; 63: 2224±2228. 25. Kato DT, Ferry JA, Goodman A et al. Uterine papillary serous carcinoma (UPSC): A clinicopathologic study of 30 cases. Gynecologic Oncology 1995; 59: 384±389. 26. Silva EG & Jenkins R. Serous carcinoma in endometrial polyps. Modern Pathology 1990; 3: 120±128. 27. Rosenberg P, Wingren S, Simonsen E et al. Flow cytometric measurements of DNA index and S-phase on paran-embedded early stage endometrial cancer: an important prognostic indicator. Gynecologic Oncology 1989; 35: 50±54. 28. Sorbe B, Risberg B & Frankendal B. DNA ploidy, morphometry, and nuclear grade as prognostic factors in endometrial carcinoma. Gynecologic Oncology 1990; 38: 22±27. 29. Bancher-Todesca TD, Gitsch G, Williams KE et al. p53 protein overexpression: a strong prognostic factor in uterine papillary serous carcinoma. Gynecologic Oncology 1998; 71: 59±63. 30. Tiitinen A, Forss M, Aho I et al. Endometrial adenocarcinoma: clinical outcome in 881 patients and analysis of 146 patients whose deaths were due to endometrial cancer. Gynecologic Oncology 1986; 25: 11±19. 31. Boronow RC, Morrow CP, Creasman WT et al. Surgical staging in endometrial cancer: clinical-pathologic ®ndings of a prospective study. Obstetrics and Gynecology 1984; 63: 825±832. 32. Creasman WT, Morrow CP, Bundy BN et al. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987; 60: 2035±2041. 33. Abeler VM. Endometrial carcinoma in Norway: morphology and prognosis. University of Oslo, Oslo, 1982.
Clear-cell and papillary serous cancer 445 34. Hacker NF. Uterine cancer. In Berek J & Hacker NF (eds) Practical Gynecologic Oncology, 2nd edn, pp 285±326. Baltimore: Williams and Wilkins, 1994. 35. Jerey JF, Krepart GV & Lotocki RJ. Papillary serous adenocarcinoma of the endometrium. Obstetrics and Gynecology 1986; 67: 670±674. 36. Craighead PS, Sait K, Stuart GC et al. Management of aggressive histologic variants of endometrial carcinoma at the Tom Baker Cancer Centre between 1984 and 1994. Gynecologic Oncology 2000; 77: 248±253. 37. Malpica A, Tornos C, Burke TW et al. Low-stage clear-cell carcinoma of the endometrium. American Journal of Surgical Pathology 1995; 19: 769±774. 38. Geisler JP, Geisler HE, Melton ME et al. What staging surgery should be performed on patients with uterine papillary serous carcinoma? Gynecologic Oncology 1999; 74: 465±467. 39. Cirisano-FD J, Robboy SJ, Dodge RK et al. Epidemiologic and surgicopathologic ®ndings of papillary serous and clear cell endometrial cancers when compared to endometrioid carcinoma. Gynecologic Oncology 1999; 74: 385±394. 40. Mallipeddi P, Kapp DS & Teng NN. Long-term survival with adjuvant whole abdominopelvic irradiation for uterine papillary serous carcinoma. Cancer 1993; 71: 3076±3081. 41. Grice J, Ek M, Greer B et al. Uterine papillary serous carcinoma: evaluation of long-term survival in surgically staged patients. Gynecologic Oncology 1998; 69: 69±73. 42. Hendrickson MR, Longacre TA & Kempson RL. Uterine papillary serous carcinoma revisited. Editorial. Gynecologic Oncology 1994; 54: 261±263. 43. Aquino-Parson PC, Lim P, Wong F et al. Papillary serous and clear cell carcinoma limited to endometrial curettings in FIGO stage 1a and 1b endometrial adenocarcinoma: treatment implications. Gynecology Oncology 1998; 71: 83±86. 44. Trope C, Johnsson JE, Simonsen E et al. Treatment of recurrent endometrial adenocarcinoma with a combination of doxorubicin and cisplatin. American Journal of Obstetrics and Gynecology 1984; 149: 379±381. 45. Thigpen T, Vance RB & Khansur T. The platinum compounds and paclitaxel in the management of carcinomas of the endometrium and uterine cervix. Seminars in Oncology 1995; 22: 67±75. 46. Nicklin JL & Copeland LJ. Endometrial papillary serous carcinoma: patterns of spread and treatment. Clinical Obstetrics and Gynecology 1996; 39: 686±695. 47. Bancher-Todesca TD, Neunteufel W, Williams KE et al. In¯uence of postoperative treatment on survival in patients with uterine papillary serous carcinoma. Gynecologic Oncology 1998; 71: 344±347. 48. Price FV, Chambers SK, Carcangiu ML et al. Intravenous cisplatin, doxorubicin, and cyclophosphamide in the treatment of uterine papillary serous carcinoma (UPSC). Gynecologic Oncology 1993; 51: 383±389. 49. Levenback C, Burke TW, Silva E et al. Uterine papillary serous carcinoma (UPSC) treated with cisplatin, doxorubicin, and cyclophosphamide (PAC). Gynecologic Oncology 1992; 46: 317±321. 50. Turner BC, Knisely JP, Kacinski BM et al. Eective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy. International Journal of Radiation Oncology Biology and Physics 1998; 40: 77±84. 51. Hamaguchi K, Komai K, Sakihama H et al. Chemotherapeutic approach to uterine papillary serous carcinoma. Asia Oceania Journal of Obstetrics and Gynaecology 1990; 16: 367±372. 52. Chambers JT, Chambers SK, Kohorn EI et al. Uterine papillary serous carcinoma treated with intraperitoneal cisplatin and intravenous doxorubicin and cyclophosphamide. Gynecologic Oncology 1996; 60: 438±442. 53. Resnik E & Taxy JB. Neoadjuvant chemotherapy in uterine papillary serous carcinoma. Gynecologic Oncology 1996; 62: 123±127. 54. Zanotti KM, Belinson JL, Kennedy AW et al. The use of paclitaxel and platinum-based chemotherapy in uterine papillary serous carcinoma. Gynecologic Oncology 1999; 74: 272±277. 55. Onsrud M, Kolstad P & Normann T. Postoperative external pelvic irradiation in carcinoma of the corpus stage I: a controlled clinical trial. Gynecologic Oncology 1976; 4: 222±231. 56. Aalders J, Abeler V, Kolstad P et al. Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstetrics and Gynecology 1980; 56: 419±427. 57. Creutzberg CL, van-Putten WL, Koper PC et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 2000; 355: 1404±1411. 58. Frank AH, Tseng PC, Haty BG et al. Adjuvant whole-abdominal radiation therapy in uterine papillary serous carcinoma. Cancer 1991; 68: 1516±1519. 59. Mallipeddi P, Kapp DS & Teng NN. Long-term survival with adjuvant whole abdominopelvic irradiation for uterine papillary serous carcinoma. Cancer 1993; 71: 3076±3081.
446 C. TropeÂ, G. B. Kristensen and V. M. Abeler 60. Rosenberg P, Boeryd B & Simonsen E. A new aggressive treatment approach to high-grade endometrial cancer of possible bene®t to patients with stage I uterine papillary cancer. Gynecologic Oncology 1993; 48: 32±37. 61. Turner BC, Knisely JP, Kacinski BM et al. Eective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy. International Journal of Radiation Oncology Biology and Physics 1998; 40: 77±84.
doi:10.1053/beog.2000.0187, available online at http://www.idealibrary.com on
8 Clear-cell and papillary serous cancer: treatment options Claes TropeÂ
MD PhD
Professor
Gunnar Balle Kristensen
MD PhD
Assistant Professor Department of Gynecologic Oncology, The University Clinic, The Norwegian Radium Hospital, Montebello, N-0310, Oslo, Norway
Vera Maria Abeler
MD PhD
Senior Consultant Department of Pathology, The University Clinic, The Norwegian Radium Hospital, Montebello, N-0310, Oslo, Norway
Clear-cell carcinoma (CCC) and serous papillary carcinoma of the endometrium (UPSC) are rare subtypes of endometrial carcinoma (10%). The histological diagnosis can be made on the dilation and curettage specimens in both types in a very high percentage of the cases. This is important in the planning of treatment. CCC and UPSC are associated with about 50% of all relapses occurring in endometrial carcinoma, and the 5-year survival rate is, on average, 42% and 27% respectively. Surgico-pathological stage, age, and vessel invasion are independent prognostic factors for both groups. The recurrence rate is extremely high, and the most frequent extra-pelvic sites of relapse are the upper abdomen, lungs and liver. Stage Ia patients treated with complete surgical staging alone have a low risk of relapse and need not be oered adjuvant systemic therapy or pelvic radiation. The treatment of patients with CCC and UPSC stage Ib, Ic, II and III should include radical debulking surgery and some form of adjuvant therapy, but it is not clear which type is most eective. Adjuvant pelvic radiotherapy plus intracavitary radiotherapy is usually given in early-stage disease and pelvic radio therapy/or whole abdomen irradiation plus adjuvant systemic chemotherapy (PAC) in advanced disease. However, we are urgently waiting for a large prospective randomized study to compare both modalities. Paclitaxel, alone or in combination, is currently being tested in phase II studies. Key words: endometrioid carcinoma; carcinoma; uterine papillary serous carcinoma (UPSC); clear-cell adenocarcinoma (CCC); prognosis; nuclear grade; ¯ow cytometry; DNA ploidy; p53 immunohistochemistry; surgery; chemotherapy; pelvic; abdominal irradiation.
A continuous increase in the incidence of endometrial carcinoma has been reported in western countries during the past 30 years. Endometrial cancer is the commonest female genital tract cancer in Scandinavia with age-adjusted (European standard population) incidence rate of 17±21/105 women and age-adjusted death rates of 1521±6934/01/03043314 $35.00/00
c 2001 Harcourt Publishers Ltd. *
434 C. TropeÂ, G. B. Kristensen and V. M. Abeler
100 Expected Adenoacanthoma
Survival (%)
80
Adenocarcinoma Total Material Adenosquamous Undifferentiated
60
40 Clear Cell 20
0
Serous Papillary
0
30
60
90
120
Months Figure 1. Ten-year crude survival for the entire population of 1974 patients treated at the NRH between 1970 and 1977.
4±5/105.1,2 Because it generally presents as early-stage disease (stage I in 75% of cases) and can be treated without radical surgery, endometrial carcinoma has frequently been regarded as a relatively benign type of cancer with a fairly good overall 5-year survival rate of approximately 75%. However, a more critical evaluation of survival data indicates that this concept is partly misleading.3 It is well known that endometrial carcinoma is a morphological heterogeneous group of malignancies. The majority (480%) of endometrial carcinomas are of endometric type with/without squamous dierentiation and carry a good prognosis. Patients with endometrioid tumours with squamous dierentiation have the most favourable prognosis, with a 5-year crude survival rate of 91.2%. This contrasts with patients with clear-cell and serous papillary carcinoma, which make up about 10% of endometrial carcinomas but which are associated with about 50% of all relapses occurring in endometrial cancer patients whose 5-year survival rate averages only 42 and 27% respectively (Figure 1). Patients in these groups are almost all post-menopausal, tend to be elderly and are generally neither obese nor diabetic.3 The challenge in treating patients with these subtypes continues to be careful identi®cation of high-risk prognostic features and a critical evaluation of treatment. HISTOLOGICAL TYPES AND PROGNOSTIC VARIABLES Clear-cell carcinoma The concept of clear-cell carcinoma as being of mesonephric origin and designated as `mesonephroma' was introduced in 1939 by Schiller4 to describe a subtype of ovarian tumour which resembles renal carcinoma and tumours originating from the mesonephric duct system. Scully and Barlow5 related the origin of the latter group of tumours to the MuÈllerian epithelium rather than the mesonephros and proposed in 1967 the descriptive term `clear-cell carcinoma' (CCC). CCC of the female genital
Clear-cell and papillary serous cancer 435
tract is now a well-established histopathological entity and comprises about 1±6% of endometrial carcinomas.6,7 The prognostic implication of CCC was not recognized until 1976 when Kurman and Scully8 reported a series of 21 cases with an unfavourable clinical course. In the early literature, survival for CCC is usually given for clinically staged patients with an overall survival ranging from 21 to 60%.8 This aggressive clinical behaviour was con®rmed by Abeler et al in 19966 in the largest single institution study from The Norwegian Radium Hospital (NRH) (181 patients), who demonstrated a 5- and 10-year actuarial disease-free survival rate of 43 and 39% respectively (for all stages). The 5-year survival for pathological stage I CCC of 54% and for stage II of 27% was lower than that reported by Carcangiu and Chambers9 of 72 and 59% respectively. Surgico-pathological stage, clinical stage, age, vessel invasion and myometrial invasion were the only signi®cant prognostic variables in the univariate analyses.6 In the multivariate analysis surgico-pathological stage and age were the sole independent prognostic factors. Twothirds of the patients with relapse did so outside of the pelvis, with the most frequent extra-pelvic sites of relapse being the upper abdomen, lungs and liver. Only patients with intramucosal tumours had a prognosis comparable to those with endometrioid adenocarcinomas. Ninety percent of the patients with intramucosal tumours survived 5 years in contrast to 15% of the patients with deep myometrial in®ltration.6 Uterine papillary serous carcinoma Uterine papillary serous carcinoma (UPSC) is an uncommon aggressive type of endometrioid adenocarcinoma that was delineated by Hendrickson et al in 198210 as a clinico-pathological entity distinct from endometrioid carcinoma. Attention was drawn primarily to the presence of psammoma bodies and predominantly papillary architecture, although solid areas can be present focally in the dilation and curettage material (D & C). Kovalev et al11 suggested that, apart from distinct clinicopathological features, a unique molecular pathogenesis that diers from endometrioid carcinoma exists. Moll et al12 and others13±16 have shown that p53 inactivation plays a key role in the molecular carcinogenesis and progression of UPSC. Several studies have found a high rate (80%) of p53 overexpression in UPSC, which is in sharp contrast to the low rate (10±25%) found in high-grade endometrioid carcinoma.12,16 Moll et al12 and Sherman et al16 suggested that UPSC is a p53-driven neoplasm that is biologically related to other serous papillary malignancies of the ovaries and peritoneum and, according to this hypothesis, UPSC bypasses the slow hormone-dependent pathway of tumour genesis, but instead undergoes early p53 alterations which lead to rapid highly aggressive tumour development. UPSC accounts for 1±10%17±20 of all cases of endometrial carcinoma. UPSC is frequently mixed with foci of CCC10,17 and in some tumours it is impossible to dierentiate between the two. Christopherson21 suggested that there are two distinct types of papillary carcinoma: the papillary clear-cell carcinoma and the papillary nonclear-cell carcinoma where the latter appears to correspond to UPSC. Unlike typical endometrioid adenocarcinoma, UPSC is an aggressive malignancy, often associated with deep myometrial and lymphatic invasion, and with widespread peritoneal disease simulating the behaviour of ovarian carcinoma.22 Unlike endometrioid tumours, depth of invasion is not a prognostic factor in UPSC. In a study by Go et al23 50 patients with UPSC were surgically staged. Thirty-three patients had pure UPSC and 17 had UPSC admixed with other histology. Extra-uterine disease was found in 36 women (72%).
436 C. TropeÂ, G. B. Kristensen and V. M. Abeler
Lymph node metastases were present in 36% of the women without myometrial invasion, in 50% with inner half invasion, and in 40% with outer one-half invasion. Similarly, the presence of intraperitoneal diseases and positive washings did not correlate with increasing myometrial invasion. These ®ndings have also been shown by Sherman et al17 and Carcangiu and Chambers9, who found no dierence in survival based upon myometrial invasion. In contrast Gallion et al24 found that no patient had recurrent disease in the absence of myometrial invasion. Grade and histology (mixed versus pure) are also not predictive of extrauterine disease.9,17,23 Go et al23 found that lymphatic/vascular space invasion was associated with extra-uterine disease, but even in cases without lymphatic/vascular space invasion they saw a high incidence of extra-uterine disease. The survival rate is dismal even when UPSC is only a component of the tumour.17 The overall 5-year survival is approximately 30% for all stages.20,25 Patients with surgical stage I and II tumours had a 5-year overall survival rate in the NRH series of 54 and 27% respectively, and there were no 5-year survivors among those with stage III and IV disease.19 These ®gures are in contrast to those of Kato et al25 who reported a 5-year survival rate of 79% in patients with early-stage disease and 25% in those with advanced disease. Widespread metastases and death can occur even in those cases in which tumour is con®ned to the endometrium or to an endometrioid polyp.9,25,26 MOLECULAR BIOLOGICAL PROGNOSTIC FACTORS Studies of the tumour biology of UPSC and CCC are in their infancy. Most of these tumours are not surprisingly DNA aneuploid and have a high S phase.27,28 Nordstrom et al22 have studied the prognostic impact of UPSC and CCC in relation to nuclear grade, DNA ploidy and p53 expression. In a histopathological review of 266 women with stage I±IV endometrial carcinoma, UPSC and CCC were diagnosed in 31 (12%) and six (2%) of the patients respectively. Strong expression of the mutated p53 gene product was signi®cantly more common in the UPSC plus CCC group than in the reference group (64 versus 19%). In a Cox multivariate analysis, including histopathological and clinical variables, UPSC and CCC were still signi®cant predictors of survival. When nuclear grade and ploidy were added to the analysis, histological type as well as degree of dierentiation lost most of their prognostic impact. DNA ploidy was found to be the strongest independent predictor of outcome besides age and stage, in contrast to the study of Kato et al25 who did not ®nd DNA ploidy to have a signi®cant impact on survival. p53 overexpression as a prognostic factor has also been studied by King et al (in 22 patients)15 and Bancher-Todesca et al (23 patients).29 Seventy-three percent and 45% of the tumours, respectively, were scored as having p53 overexpression, with patients whose tumour-overexpressed p53 having a statistically shorter survival. It should be noted, however, that a comparative analysis with other prognostic factors has not been studied and patient numbers are small. FUTURE DIRECTIONS What staging surgery should be performed in patients with clear-cell carcinoma and with uterine papillary serous carcinoma? Several studies have demonstrated signi®cant understaging when patients with endometrial cancer are subjected to thorough surgical evaluation.30±32 The discrepancy
Clear-cell and papillary serous cancer 437
between clinical and surgical staging is most clearly seen in stages I and II, with about 50% of the patients being clinically understaged.33,34 The inaccuracy of the previous clinical staging system has been shown, as in the endometrioid carcinoma, to be inadequate in assessing patients with CCC and UPSC.19,22,23,35±38 For instance, in one study 68% of the patients with clinical stage I and II tumours were upstaged at the time of surgery.25 Although more accurate information should be obtained if thorough surgical staging is carried out on all patients this is unfortunately unlikely to happen and interpretation of the literature will be dicult. Routine lymphadenectomy is unlikely to be performed for a number of reasons, including the fact that many patients with CCC and UPSC are treated in the community where the necessary surgical skills may not be available to perform lymphadenectomy, many patients are obese and not suitable for extensive nodal resection and some tumours may not always justify routine lymphadenectomy. In addition, the extent of the lymphadenectomy has not been de®ned (random sampling of pelvic and para-aortic nodes versus complete pelvic and or para-aortic lymphadenectomy versus resection of any enlarged nodes).34 Surgical stage has, in many studies, been the strongest independent prognostic factor6,25,39 and supports routine extended surgical staging in women with a preoperative or intra-operative diagnosis of CCC and UPSC. Certainly in our institution the ®ndings of CCC and UPSC on an endometrial sampling is sucient to stage the tumours surgically whether or not there is pre-operative or intra-operative evidence of myometrial invasion or cervical involvement. The same staging procedure as for epithelial ovarian carcinoma is used and includes total abdominal hysterectomy omentectom and bilateral salpingo-oophorectomy, peritoneal washings, peritoneal biopsies and pelvic and para-aortic lymphadenectomy. The same strategy is accepted by many other centres.23,36,38±42 It is an important observation that CCC and UPSC have such characteristic histological patterns that a correct diagnosis can be made on the dilation and curettage specimen alone in 87% of the patients with CCC and in 100% of the patients with UPSC.6,20 A clinical dilemma may arise when the curettage specimen is positive for CCC or UPSC but where no such pathological features are seen in the hysterectomy specimen. Aquino-Parson et al treated eight such patients expectantly with none recurring within a median follow-up of 3 years.43
REMAINING PROBLEMS The appropriate therapy for patients with early surgical stage CCC and UPSC is controversial, with as yet no prospective randomized study which could help to decide which patients might bene®t from adjuvant post-operative therapy. We know, however, that stage Ia cases treated with complete staging surgery alone have a low risk of relapse, and we agree with Craighead et al36, Geisler et al38, Grice et al41 and Aquino-Parson et al43 that these patients do not need to be oered adjuvant systemic therapy or pelvic radiation. The treatment of patients with CCC and UPSC stage Ib, Ic, II and III, should probably include radical debulking surgery and some form of adjuvant therapy, but it is not clear which type is most eective.42 By and large, adjuvant pelvic radiotherapy plus intracavitary radiotherapy is usually given in early-stage disease and pelvic radiotherapy/or whole abdomen irradiation plus adjuvant systemic chemotherapy in advanced disease.36
438 C. TropeÂ, G. B. Kristensen and V. M. Abeler
Chemotherapy With the proven poor prognosis associated with CCC and UPSC the necessity for eective adjuvant and salvage therapies has become evident. Multiple modalities have been evaluated with variable success. Unfortunately, most of these studies are in patients with clinically staged disease and are therefore of limited value in establishing the overall eectiveness of a speci®c treatment modality. The rationale behind the use of post-operative chemotherapy in CCC includes the considerable histopathological similarity between CCC and ovarian clear-cell carcinoma. Furthermore, a response rate of up to 60% has been reported in patients with recurrent and advanced endometrioid carcinoma and CCC with cisplatin and doxorubicin.6,44 The regimen in adjuvant (or advanced and recurrent) CCC tumour we use at the NRH consists of four courses of cisplatin at 75 mg/m2 combined with doxorubicin 50 mg/m2. The response duration is, however, short lasting and the use of paclitaxel, which has shown promising results in clear-cell carcinoma of the ovary45 is planned. Systemic therapy with progestational agents has no impact on survival of CCC patients. In fact the cardiovascular side-eects of progestational therapy may make routine treatment dangerous.6 The use of chemotherapy in UPSC also seems rational because there is considerable histopathological similarity between UPSC and ovarian serous papillary carcinoma (75% response rate to cisplatin-based combination regimens), and most relapses occur outside the pelvis. However, the high response rates seen in ovarian cancer have not been observed in UPSC46 and the eect of chemotherapy on the outcome of patients with UPSC has been controversial.47 Some studies on adjuvant chemotherapy in patients with UPSC with a high risk of recurrence indicate a prolonged relapse-free survival.46,48,49 For instance, Price et al48 used cisplatin, doxorubicin and cyclophosphamide (PAC) in 19 patients radically operated on without any residual tumour. Eight stage I patients were alive without evidence of disease after a median follow-up of 24 months. Of the remaining 11 patients who had extrauterine disease at diagnosis, eight were dead of disease at a median of 14 months. Levenback et al49 reported on 20 UPSC patients treated with PAC of whom 13 had advanced or recurrent disease and six had no residual tumour. The patients received a mean of ®ve cycles of PAC. Only two of 11 patients with evaluable disease achieved complete responses (of 12 and 31 months duration). The median survival for the entire group was 24 months. Turner et al50 have also shown that in six stage I UPSC patients with complete surgical staging with adjuvant PAC chemotherapy there were no recurrences at a median follow-up of 31 months. Hamaguchi et al51 used ifosphamide instead of cyclophosphamide in the PAC combination in seven patients in an adjuvant setting. Two patients had tumour recurrences within 6 months. Another approach using the PAC regimen in UPSC patients has been reported by Chambers et al.52 Sixteen patients with UPSC underwent complete surgical staging and at the same time an intraperitoneal port was placed. Post-operatively they received cisplatin 100 mg/m2 given intraperitoneally (i.p.) and doxorubicin 50 mg/m2 intravenously (i.v.) and cyclophosphamide 600 mg/m2 i.v. every 4 weeks for six cycles. In three cases the i.p. port did not work. All patients except one had no gross residual at the end of surgery, yet despite this seven patients have died, one patient is alive with disease and ®ve patients are alive with no evidence of disease. Five of the seven patients with extra-uterine disease died of their disease. The median survival was
Clear-cell and papillary serous cancer 439
34 months with an overall 3-year survival of only 24%. There was no advantage of this regimen over the same PAC regimen given i.v. at the same institution. It is apparent that platinum/doxorubicin-based combination chemotherapy has a response rate of about 20±25%46,49 and that patients with recurrent or advanced disease should be part of clinical trials of therapy with taxanes. Paclitaxel has recently been shown to be active in endometrioid carcinoma, and the ultimate role of paclitaxel alone or in combination with cisplatin or carboplatin in the management of UPSC awaits further investigation.45 The ®rst report on the use of paclitaxel in UPSC was a case report by Resnik and Taxy53 who described a dramatic response in an advanced UPSC tumour after three cycles of paclitaxel and carboplatinum given as neoadjuvant therapy. Zanotti et al54 treated 24 patients with UPSC with paclitaxel (175 mg/m2) alone or paclitaxel (175 mg/m2) combined with carboplatin alea under curve (AUC 5) or cisplatin (75 mg/m2). Eighteen patients received the regimens in the adjuvant setting. Eleven patients received one or more courses of this combination for recurrent disease. A median progression-free survival (PDS) of 30 months (range 8±61) was seen in patients treated in the adjuvant setting. An objective response indicated by normalisation of CA 125 was seen in eight of nine patients treated for residual disease after initial surgery (median PFS of 13 months, range 5±38), while an objective response was seen in seven out of eleven patients with recurrent disease (median PFS of 9 months, range 4±18). Zanotti et al also re-treated six patients with paclitaxel and four of these six patients responded a second time.54 As in CCC, hormonal therapy is not indicated because no responses have been reported with medroxyprogesterone, megestrol or tamoxifen.46 Radiotherapy Patients with high-risk endometrial carcinoma are traditionally oered adjuvant treatment with pelvic radiation, although the ecacy of this treatment is a matter of debate (60% relapse outside irradiated area).55±57 It is still reasonable to expect some bene®t with this modality in the management of CCC and UPSC because the majority of the recurrences are located in the upper abdomen; however, it is more logical to suggest that the whole abdomen should be treated to obtain the greatest advantage. Several retrospective studies have recommended the use of whole abdominal pelvic radiation therapy (WAPT) in early UPSC but have not provided sucient data to determine whether this can be safely or eectively applied.36 Frank et al58 treated nine patients with stage Ic-IIIa UPSC with WAPT on an adjuvant basis after cytoreductive surgery. All patients were treated with megavoltage photons to an abdominal pelvic ®eld to a median dose of 2500 cGy with continued treatment to the whole pelvic ®eld to a median dose of 4500 cGy. At a median follow-up time of 25 months, six patients had recurrent disease at 5 to 20 months (median 7.5 months), with four of these patients dead of disease. Mallipedd et al59 treated ten patients with UPSC with WAPT as adjuvant therapy following staging laparotomy and debulking surgery. The pelvic dose varied from 4750 to 5100 cGy (median 5010 cGy) and the median dose administered to the upper abdomen was 2975 cGy. WAPT was administered over 42±80 days. Nine patients had clinical stage I disease, but the tumour in eight of these was upstaged on the basis of laparotomy ®ndings. Five patients were alive with no evidence of disease at 102±103 months, while four patients died. All recurrences were observed within 30 months of the initial diagnosis. In contrast to Frank et al58, Mallipeddi et al59 concluded that the treatment of UPSC should
440 C. TropeÂ, G. B. Kristensen and V. M. Abeler
include WAPT because they had ®ve long-term survivors after WAPT and failures who responded to local irradiation. Combined therapies Rosenberg et al 199360 introduced a new treatment approach to a series of 24 clinical stage I patients with UPSC; the treatment consisted of radical hysterectomy and staging followed by external pelvic irradiation to 44±45 Gy by two opposing pelvic ®elds delivered in 22±25 fractions and ®nally four courses of cisplatin 50 mg/m2, epirubicin 50 mg/m2 at 28-day intervals. Fourteen patients (58%) did not start or complete the protocol for reasons of age, concomitant disease and treatment of toxicity. None of the ten high-intensity treated UPSC patients died of relapse during a median observation time of 32 months, whereas 16 of 30 (53%) of UPSC control patients died of their disease during a median observation period of 38 months (Figure 2). Eleven of seventeen patients (64%) in an historical control group who were given adjuvant pelvic irradiation in addition to radical surgery and intracavitary treatment, but did not receive any chemotherapy, died of their disease. Rosenberg et al concluded that the most eective component of the combination of surgery, radiation, and chemotherapy was the administration of cisplatin/epirubicin. The median follow-up in this study is currently 60 months and the majority of the patients are still recurrence-free (Rosenberg personal communication, 2000). Bancher-Todesca et al47 studied the prognostic signi®cance of various types of postoperative treatment in 23 surgically staged patients with UPSC. After surgery, nineteen women were macroscopically free of disease. The other four had residual tumours of more than 2 cm. Eight patients had FIGO stage I/II, whereas ®fteen patients showed stage III/IV tumours. Five women underwent adjuvant irradiation alone, consisting of vault irradiation and external beam irradiation (dose to the whole pelvic region 45±50 Gy). Five women received chemotherapy and eight women received a combination of both irradiation and chemotherapy (carboplatinum alone or cisplatin and cyclophosphamide). The median duration of follow-up was 39.4 months. The median overall survival was 43.3 months. Three of ten patients who received only 1.0
Survival
0.8 0.6 0.4 0.2 0.0
0
12
24
36 48 Months
60
72
84
Figure 2. Patients with stage I UPSC: corrected survival. high-intensity treated (n 10); adequately treated (n 30). P 0.021. Reproduced from Rosenberg et al (1993, Gynecologic Oncology 48: 32±37) with permission.
Clear-cell and papillary serous cancer 441
chemotherapy or radiotherapy are alive, whereas seven of eight patients who received a combination of both are alive with no evidence of disease. The 5-year overall survival was 80% in those who received radiotherapy and chemotherapy and only 30% in those who were treated with radiotherapy alone compared to 0% in those who were treated with chemotherapy alone (P 0.05). Craighead et al36 studied 92 patients (stage I±IV) with CCC31 and UPSC.61 Forty-nine percent of all cases underwent surgery alone, 39% underwent post-operative treatment, which included pelvic radiation (45 Gy in 25 daily fractions), and 7% underwent postoperative treatment, which included PAC chemotherapy. Pelvic recurrence was signi®cantly reduced by post-operative radiotherapy in stage Ib, Ic, II and III (19% recurrence with no radiotherapy versus 7% recurrence with radiotherapy). Chemotherapy improved overall survival but made little dierence to distant relapse rates. There was only an 11% recurrence rate in stage Ia where the patients had no post-operative treatment, with all of these being either vault or pelvic in nature. Several others have reported excellent results for observation in stage I UPSC.41,43 The results for intermediate risk cases (stage Ib, Ic and II) support the use of radiotherapy post-operatively but show that distant relapses remain a problem (44% stage I and 35% in stage II). Craighead et al36 concluded that stage Ic and II cases with lymphovascular space involvement and all stage III cases should be treated with systemic treatment plus pelvic radiation. Turner et al61 studied the outcome in 38 stage I UPSC treated with high-dose-rate (HDR) vaginal apex radiation (192Ir) to a total dose of 21 Gy in three fractions together with ®ve courses of PAC. They found that the 5-year actuarial overall survival for patients with complete surgical staging and adjuvant HDR vaginal apex brachytherapy and systemic PAC was 100% (15 patients). CONCLUSION It is suggested that although stage I CCC patients have a signi®cantly better survival than stage I UPSC patients, these tumours have similar clinical and pathological pro®les, demonstrating the need for an aggressive approach, including a staging laparotomy and similar post-operative therapy. The high risk of recurrence in CCC and UPSC, and the strong correlation between lymphatic/vascular space involvement, and extra-uterine disease, suggest that the current FIGO staging scheme for endometrioid carcinoma of the usual type may not be entirely relevant and that surgical staging, as employed in epithelial ovarian carcinoma, may be more appropriate. The need for, and the extent of, lymphadenectomy as a part of the surgical staging continues to be debated, and it is clear that the more extensive the lymphadenectomy the greater the incidence of lymph node metastases identi®ed. Unfortunately, terms such as `partial', `selective' and `simple' to describe the extent of lymphadenectomy have crept into the literature without de®nition. It is also clear that only adequate surgical staging will optimally de®ne the extent of disease in CCC and UPSC, and that risks and bene®ts as well as clinical judgement need to be considered in determining the extent of surgery. The results of PAC chemotherapy as a treatment for recurrent disease have been disappointing, with response rates in the order of 20±25%. There are sucient grounds to test paclitaxel, and several phase II studies are ongoing to test the drug alone or in combination in CCC and UPSC. The use of chemotherapy as a post-operative adjuvant treatment for CCC and UPSC has been extensively studied but remains controversial.
442 C. TropeÂ, G. B. Kristensen and V. M. Abeler Table 1. The Norwegian Radium Hospital's recommendations for treatment of clear-cell carcinoma and serous papillary carcinoma of the endometrium (outside research protocols). Stage Ia Total abdominal inspection, omentectomy, bilateral salpingo-oophorectomy, peritoneal washings. Peritoneal biopsies and pelvic and para-aortic lymphadenectomy similar to an ovarian cancer staging No adjuvant systemic or pelvic radiation Stages Ib, Ic, II and III Surgical staging as above Pelvic irradiation 45 Gy plus cisplatin 75 mg/m2 i.v. combined with doxorubicin 50 mg/m2 or epirubicin 75 mg/m2 i.v., and cyclophosphamide 650 mg/m2 (PAC) (to be repeated every 3±4 weeks) Stage IV Aggressive debulking surgery upfront followed by PAC Recurrent disease Platinum sensitive: Paclitaxel 135 mg/m2 combined with carboplatin AUC5 Platinum resistant: Paclitaxel 175 mg/m2
Table 2. A randomised trial of adjuvant treatment with radiation plus chemotherapy versus radiation in high-risk endometrioid carcinoma.a Study design Open labelled randomized, two-armed study Surgical stage I ! External pelvic radiation ! External pelvic radiation followed or preceded by chemotherapy Surgery For CCC and UPSC surgical staging as described in the text Radiation treatment Pelvic irradiation with four-®eld technique. Total dose: 44 Gy 29 Gy/fraction ®ve times per week Chemotherapy Cisplatin 75 mg/m2 i.v. plus doxorubicin 50 mg/m2 i.v. as bolus. Both drugs are given on the same day and the treatment to be repeated every 3±4 weeks An intergroup study: Nordic Society of Gynecological Oncology and EORTC Gynecological Cancer Cooperative Group.
The PAC regimen is still considered standard chemotherapy when given outside protocol (Table 1). This literature review indicates that surgically staged CCC and UPSC post-operative treatment consisting of chemotherapy and radiation therapy increases the survival rate in patients with stage Ib, Ic, II and III. However, further prospective randomized studies using both treatment regimens simultaneously will be needed to con®rm this. Multiple claims of success have been published in small uncontrolled studies. Management has ranged from observation to adjuvant pelvic radiation in stage I disease and from WAPT to chemotherapy in stage II and III disease. In Europe a prospective randomized study aimed at addressing this problem has recently been commenced (Table 2).
Clear-cell and papillary serous cancer 443
Practice points . CCC is of MuÈllerian and not mesonephric origin. Pathological stage and age are the two most important independent prognostic factors in CCC. Two-thirds of patients have tumours which relapse outside the pelvis . p53 alterations are common in UPSC and are probably responsible for its aggressive biological behaviour . UPSC is often associated with deep myometrial invasion, with lymphatic invasion and with widespread peritoneal disease, simulating the behaviour of ovarian carcinoma . the true extent of disease must be known to ascertain the ecacy of optimal adjuvant therapy . patients with CCC and UPSC should undergo a staging laparotomy similar to the procedure undertaken for patients with ovarian carcinoma . the use of chemotherapy as a post-operative adjuvant treatment for CCC and UPSC has been extensively studied but still remains controversial . the treatment results of CCC and UPSC recurrences with chemotherapy are still very poor . the challenge in treating these diseases continues to be the careful identi®cation of high-risk prognostic features and the initial evaluation of patients
Research agenda . the role of molecular biological and other prognostic factors in upfront treatment decisions needs to be tested in prospective randomized studies . to prevent over- and under-treatment, methods for separating patients who need no post-operative treatment and those who might bene®t from multi-modal therapy are necessary . prospective randomized studies are required to de®ne optimal treatment (the role of chemotherapy and/or both radiation) for women with stage Ib, Ic, II, III and IV tumours
REFERENCES 1. Engeland A, Haldorsen T, Tretli S et al. Prediction of cancer incidence in the Nordic countries up to the years 2000 and 2010. A collaborative study of the ®ve Nordic Cancer Registries. APMIS suppl 1993; 38: 1±124. 2. Engeland A, Haldorsen T, Tretli S et al. Prediction of cancer mortality in the Nordic countries up to the years 2000 and 2010, on the basis of relative survival analysis. A collaborative study of the ®ve Nordic Cancer Registries. APMIS suppl 1995; 49: 1±161. 3. Abeler VM, Kjorstad KE & Berle E. Carcinoma of the endometrium in Norway: a histopathological and prognostic survey of a total population. International Journal of Gynecologic Cancer 1992; 2: 9±22. 4. Schiller W. Mesonephroma ovarii. American Journal of Cancer 1939; 35: 1±21. 5. Scully RE & Barlow JF. `Mesonephroma' of ovary. Tumor of Mullerian nature related to the endometrioid carcinoma. Cancer 1967; 20: 1405±1417. 6. Abeler VM, Vergote IB, Kjorstad KE et al. Clear cell carcinoma of the endometrium. Prognosis and metastatic pattern. Cancer 1996; 78: 1740±1747.
444 C. TropeÂ, G. B. Kristensen and V. M. Abeler 7. Christopherson WM, Alberhasky RC & Connelly PJ. Carcinoma of the endometrium: I. A clinicopathologic study of clear-cell carcinoma and secretory carcinoma. Cancer 1982; 49: 1511±1523. 8. Kurman RJ & Scully RE. Clear cell carcinoma of the endometrium: an analysis of 21 cases. Cancer 1976; 37: 872±882. 9. Carcangiu ML & Chambers JT. Uterine papillary serous carcinoma: a study on 108 cases with emphasis on the prognostic signi®cance of associated endometrioid carcinoma, absence of invasion, and concomitant ovarian carcinoma. Gynecologic Oncology 1992; 47: 298±305. 10. Hendrickson M, Ross J, Eifel P et al. Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. American Journal of Surgical Pathology 1982; 6: 93±108. 11. Kovalev S, Marchenko ND, Gugliotta BG et al. Loss of p53 function in uterine papillary serous carcinoma. Human Pathology 1998; 29: 613±619. 12. Moll UM, Chalas E, Auguste M et al. Uterine papillary serous carcinoma evolves via a p53-driven pathway. Human Pathology 1996; 27: 1295±1300. 13. Reinartz JJ, George E, Lindgren BR et al. Expression of p53, transforming growth factor alpha, epidermal growth factor receptor, and c-erbB-2 in endometrial carcinoma and correlation with survival and known predictors of survival. Human Pathology 1994; 25: 1075±1083. 14. Prat J, Oliva E, Lerma E et al. Uterine papillary serous adenocarcinoma. A 10-case study of p53 and cerbB-2 expression and DNA content. Cancer 1994; 74: 1778±1783. 15. King SA, Adas AA, LiVolsi VA et al. Expression and mutation analysis of the p53 gene in uterine papillary serous carcinoma. Cancer 1995; 75: 2700±2705. 16. Sherman ME, Bur ME & Kurman RJ. p53 in endometrial cancer and its putative precursors: evidence for diverse pathways of tumorigenesis. Human Pathology 1995; 26: 1268±1274. 17. Sherman ME, Bitterman P, Rosenshein NB et al. Uterine serous carcinoma. A morphologically diverse neoplasm with unifying clinicopathologic features. American Journal of Surgical Pathology 1992; 16: 600±610. 18. Rosenberg P, Blom R, Hogberg T et al. Death rate and recurrence pattern among 841 clinical stage I endometrial cancer patients with special reference to uterine papillary serous carcinoma. Gynecologic Oncology 1993; 51: 311±315. 19. Christopherson WM, Alberhasky RC & Connelly PJ. Carcinoma of the endometrium. II. Papillary adenocarcinoma: a clinical pathological study, 46 cases. American Journal of Clinical Pathology 1982; 77: 534±540. 20. Abeler VM & Kjorstad KE. Serous papillary carcinoma of the endometrium: a histopathological study of 22 cases. Gynecologic Oncology 1990; 39: 266±271. 21. Christopherson W. The signi®cance of pathologic ®ndings in endometrial cancer. Obstetrics and Gynecology 1986; 13: 673±693. 22. Nordstrom B, Strang P, Lindgren A et al. Endometrial carcinoma: the prognostic impact of papillary serous carcinoma (UPSC) in relation to nuclear grade, DNA ploidy and p53 expression. Anticancer Research 1996; 16: 899±904. 23. Go BA, Kato D, Schmidt RA et al. Uterine papillary serous carcinoma: patterns of metastatic spread. Gynecologic Oncology 1994; 54: 264±268. 24. Gallion HH, van-Nagell-JR J, Powell DF et al. Stage I serous papillary carcinoma of the endometrium. Cancer 1989; 63: 2224±2228. 25. Kato DT, Ferry JA, Goodman A et al. Uterine papillary serous carcinoma (UPSC): A clinicopathologic study of 30 cases. Gynecologic Oncology 1995; 59: 384±389. 26. Silva EG & Jenkins R. Serous carcinoma in endometrial polyps. Modern Pathology 1990; 3: 120±128. 27. Rosenberg P, Wingren S, Simonsen E et al. Flow cytometric measurements of DNA index and S-phase on paran-embedded early stage endometrial cancer: an important prognostic indicator. Gynecologic Oncology 1989; 35: 50±54. 28. Sorbe B, Risberg B & Frankendal B. DNA ploidy, morphometry, and nuclear grade as prognostic factors in endometrial carcinoma. Gynecologic Oncology 1990; 38: 22±27. 29. Bancher-Todesca TD, Gitsch G, Williams KE et al. p53 protein overexpression: a strong prognostic factor in uterine papillary serous carcinoma. Gynecologic Oncology 1998; 71: 59±63. 30. Tiitinen A, Forss M, Aho I et al. Endometrial adenocarcinoma: clinical outcome in 881 patients and analysis of 146 patients whose deaths were due to endometrial cancer. Gynecologic Oncology 1986; 25: 11±19. 31. Boronow RC, Morrow CP, Creasman WT et al. Surgical staging in endometrial cancer: clinical-pathologic ®ndings of a prospective study. Obstetrics and Gynecology 1984; 63: 825±832. 32. Creasman WT, Morrow CP, Bundy BN et al. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987; 60: 2035±2041. 33. Abeler VM. Endometrial carcinoma in Norway: morphology and prognosis. University of Oslo, Oslo, 1982.
Clear-cell and papillary serous cancer 445 34. Hacker NF. Uterine cancer. In Berek J & Hacker NF (eds) Practical Gynecologic Oncology, 2nd edn, pp 285±326. Baltimore: Williams and Wilkins, 1994. 35. Jerey JF, Krepart GV & Lotocki RJ. Papillary serous adenocarcinoma of the endometrium. Obstetrics and Gynecology 1986; 67: 670±674. 36. Craighead PS, Sait K, Stuart GC et al. Management of aggressive histologic variants of endometrial carcinoma at the Tom Baker Cancer Centre between 1984 and 1994. Gynecologic Oncology 2000; 77: 248±253. 37. Malpica A, Tornos C, Burke TW et al. Low-stage clear-cell carcinoma of the endometrium. American Journal of Surgical Pathology 1995; 19: 769±774. 38. Geisler JP, Geisler HE, Melton ME et al. What staging surgery should be performed on patients with uterine papillary serous carcinoma? Gynecologic Oncology 1999; 74: 465±467. 39. Cirisano-FD J, Robboy SJ, Dodge RK et al. Epidemiologic and surgicopathologic ®ndings of papillary serous and clear cell endometrial cancers when compared to endometrioid carcinoma. Gynecologic Oncology 1999; 74: 385±394. 40. Mallipeddi P, Kapp DS & Teng NN. Long-term survival with adjuvant whole abdominopelvic irradiation for uterine papillary serous carcinoma. Cancer 1993; 71: 3076±3081. 41. Grice J, Ek M, Greer B et al. Uterine papillary serous carcinoma: evaluation of long-term survival in surgically staged patients. Gynecologic Oncology 1998; 69: 69±73. 42. Hendrickson MR, Longacre TA & Kempson RL. Uterine papillary serous carcinoma revisited. Editorial. Gynecologic Oncology 1994; 54: 261±263. 43. Aquino-Parson PC, Lim P, Wong F et al. Papillary serous and clear cell carcinoma limited to endometrial curettings in FIGO stage 1a and 1b endometrial adenocarcinoma: treatment implications. Gynecology Oncology 1998; 71: 83±86. 44. Trope C, Johnsson JE, Simonsen E et al. Treatment of recurrent endometrial adenocarcinoma with a combination of doxorubicin and cisplatin. American Journal of Obstetrics and Gynecology 1984; 149: 379±381. 45. Thigpen T, Vance RB & Khansur T. The platinum compounds and paclitaxel in the management of carcinomas of the endometrium and uterine cervix. Seminars in Oncology 1995; 22: 67±75. 46. Nicklin JL & Copeland LJ. Endometrial papillary serous carcinoma: patterns of spread and treatment. Clinical Obstetrics and Gynecology 1996; 39: 686±695. 47. Bancher-Todesca TD, Neunteufel W, Williams KE et al. In¯uence of postoperative treatment on survival in patients with uterine papillary serous carcinoma. Gynecologic Oncology 1998; 71: 344±347. 48. Price FV, Chambers SK, Carcangiu ML et al. Intravenous cisplatin, doxorubicin, and cyclophosphamide in the treatment of uterine papillary serous carcinoma (UPSC). Gynecologic Oncology 1993; 51: 383±389. 49. Levenback C, Burke TW, Silva E et al. Uterine papillary serous carcinoma (UPSC) treated with cisplatin, doxorubicin, and cyclophosphamide (PAC). Gynecologic Oncology 1992; 46: 317±321. 50. Turner BC, Knisely JP, Kacinski BM et al. Eective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy. International Journal of Radiation Oncology Biology and Physics 1998; 40: 77±84. 51. Hamaguchi K, Komai K, Sakihama H et al. Chemotherapeutic approach to uterine papillary serous carcinoma. Asia Oceania Journal of Obstetrics and Gynaecology 1990; 16: 367±372. 52. Chambers JT, Chambers SK, Kohorn EI et al. Uterine papillary serous carcinoma treated with intraperitoneal cisplatin and intravenous doxorubicin and cyclophosphamide. Gynecologic Oncology 1996; 60: 438±442. 53. Resnik E & Taxy JB. Neoadjuvant chemotherapy in uterine papillary serous carcinoma. Gynecologic Oncology 1996; 62: 123±127. 54. Zanotti KM, Belinson JL, Kennedy AW et al. The use of paclitaxel and platinum-based chemotherapy in uterine papillary serous carcinoma. Gynecologic Oncology 1999; 74: 272±277. 55. Onsrud M, Kolstad P & Normann T. Postoperative external pelvic irradiation in carcinoma of the corpus stage I: a controlled clinical trial. Gynecologic Oncology 1976; 4: 222±231. 56. Aalders J, Abeler V, Kolstad P et al. Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstetrics and Gynecology 1980; 56: 419±427. 57. Creutzberg CL, van-Putten WL, Koper PC et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 2000; 355: 1404±1411. 58. Frank AH, Tseng PC, Haty BG et al. Adjuvant whole-abdominal radiation therapy in uterine papillary serous carcinoma. Cancer 1991; 68: 1516±1519. 59. Mallipeddi P, Kapp DS & Teng NN. Long-term survival with adjuvant whole abdominopelvic irradiation for uterine papillary serous carcinoma. Cancer 1993; 71: 3076±3081.
446 C. TropeÂ, G. B. Kristensen and V. M. Abeler 60. Rosenberg P, Boeryd B & Simonsen E. A new aggressive treatment approach to high-grade endometrial cancer of possible bene®t to patients with stage I uterine papillary cancer. Gynecologic Oncology 1993; 48: 32±37. 61. Turner BC, Knisely JP, Kacinski BM et al. Eective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy. International Journal of Radiation Oncology Biology and Physics 1998; 40: 77±84.