Endometrial carcinoma, the most common gynecologic malignancy in the United States, accounts for 6% of all new cancer cases. Whereas endometrioid adenocarcinoma has relatively good cure rates, other uncommon histologic types, such as papillary serous carcinoma and clear cell adenocarcinoma, which account for 1–10% of endometrial carcinomas, have a much poorer prognosis, even in early stage disease.1–10 In a review study of uterine papillary serous carcinoma, women with stage I disease had a 5-year survival rate of 60%, compared with an 85–90% 5-year survival rate in those with stage I endometrioid adenocarcinoma.1
Papillary serous carcinoma was first described by Hendrickson et al in 1982.11 In their series, uterine papillary serous carcinoma was histologically similar to ovarian carcinoma and often had associated psammoma bodies, which can be present in up to 33% of uterine papillary serous carcinoma cases, compared with 60–70% of well-differentiated ovarian serous carcinomas.12 In addition to a similar histology, uterine papillary serous carcinoma and ovarian carcinoma have similar patterns of spread, with a propensity for upper abdominal involvement. Before description as a distinct entity in 1982, many uterine papillary serous carcinomas were believed to be sites of metastasis from ovarian malignancies.
Papillary serous cell type is a poor prognostic factor, and the significance of prognostic factors for endometrioid adenocarcinomas (depth of myometrial invasion, lymphovascular space invasion, and tumor grade) is not known for serous histology. Lymphovascular space invasion and depth of myometrial invasion have been described as prognostic factors in uterine papillary serous carcinoma by some authors2,10–13 but not others.6,14–17 The significance of myometrial invasion in papillary serous carcinoma is not fully appreciated. Tumor recurrence and death have been reported in women with papillary serous carcinoma in whom tumors were confined to the endometrium.4,10,11,15 In one review, up to 60% of cases initially thought to be early stage uterine papillary serous carcinoma by clinical criteria were of higher stage at surgery.1 Surgical staging for women with known uterine papillary serous carcinoma is important because those lesions frequently are associated with metastatic disease despite minimal uterine disease. This study was done to determine the clinical course of noninvasive papillary serous carcinoma and whether it indicates advanced metastasis.
Materials and Methods
Between January 1990 and February 2000, 595 women with endometrial carcinoma, 69 of whom had papillary serous carcinoma, were treated at the University of North Carolina at Chapel Hill School of Medicine. Those 69 women's charts were reviewed and clinical information was extracted. This study met the exemption criteria set forth by the Institutional Review Board at the University of North Carolina at Chapel Hill. Women without gross evidence of metastatic disease were staged surgically, which included washings, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and lymph node sampling. Omental sampling was done in eight cases, six of which had total omentectomies and two of which had omental biopsies. Women with advanced disease also had cytoreductive surgery. Staging was based on the 1988 International Federation of Gynecology and Obstetrics criteria.
The diagnosis of papillary serous carcinoma was based on criteria described by Hendrickson et al,11 which included complex papillary architecture with tufted stratification of lining epithelium, marked nuclear pleomorphism, high nuclear-to-cytoplasmic ratio, macronuclei, and a high mitotic rate. Presence of psammoma bodies was not necessary for the diagnosis of papillary serous carcinoma. In the current study, we reviewed an average of eight endometrial-myometrial sections per case to evaluate myometrial and lympho-vascular space invasion. Ovarian tissue was examined to exclude either primary metastatic ovarian carcinomas or synchronous primary endometrial and ovarian tumors. All histologic specimens were reviewed by the study pathologist (P.G.) at the University of North Carolina at Chapel Hill to confirm diagnoses of uterine papillary serous carcinoma.
Pathologic review of hysterectomy specimens found that 16 of 69 women had serous lesions in the uterus that did not invade the myometrium. Those 16 comprise the study group for our investigation. Age at diagnosis, surgical procedure, surgical staging, postoperative therapy, disease-free interval, recurrence site, and length of follow-up were recorded from medical records.
The median patient age was 70.6 years (range 60–86 years). All women were postmenopausal at diagnosis. Median follow-up time was 22.5 months (range 0–73 months); however, one woman died on postoperative day 10 of a pulmonary embolism. Excluding her, median follow-up time was 24 months. Among papillary serous carcinomas identified, eight were mixed with other histologic types and eight were pure papillary serous tumors. The eight mixed tumors were admixed with either grade 2–3 endometrioid adenocarcinoma or clear cell adenocarcinoma. Examples of typical serous histology found in the hysterectomy specimens are shown in Figures 1 and 2.
The tumors were similar histologically to ovarian serous carcinomas, with complex papillary architecture composed of pleomorphic high-grade nuclei. The malignant cells formed papillary tufts and irregular slitlike glandular spaces (Figures 1 and 2). Psammoma bodies were found in some cases. A clear transition between neoplastic endometrial glands and uninvolved myometrium was evident in all cases (Figure 1). Myometrial invasion was not seen. Similar morphology was seen in tumor foci outside the uterus (Figure 3). Ovaries were examined in all cases and were uninvolved in 14. In the other two cases, there were microscopic metastatic foci on ovarian cortical surfaces.
After laparotomy and complete surgical staging, six of 16 women with noninvasive lesions had no other sites of metastasis and stage IA was diagnosed (Table 1). However, ten had metastases at surgical staging. Five of six women with stage IA disease had no evidence of lymphovascular space invasion, but six of ten with stages II–IV disease had evidence of lympho-vascular space invasion. Three women had stage IIA disease with tumor that involved the cervical mucosa with no stromal involvement. Among those with stage III disease, one woman had disease limited to the right fallopian tube (IIIA) and four had disease limited to pelvic lymph nodes (IIIC). Two women had stage IV disease with macroscopic omental disease (Figure 3).
Treatment for women with advanced disease was varied and included radiotherapy or platinum-based chemotherapy. Eligible women were offered treatment according to the Gynecologic Oncology Group protocol. Two women with stage IIIC and one with stage IVB disease received adjuvant chemotherapy with paclitaxel and carboplatin (Table 1).
The six women with stage IA disease were followed up for a median of 24 months (range 2–73 months), and two had disease recurrence at 5 and 48 months. Both recurrences were confined to the vagina and were treated with radiation therapy. The woman whose disease recurred at 5 months had whole abdominal radiation with a pelvic boost and had no evidence of disease at 73 months. The woman whose disease recurred after 48 months was treated with external beam radiation and brachytherapy and was lost to follow-up. Except for the woman who died, those with stages II–IV carcinoma were followed up for a median of 24 months (0–61 months). Two women with stage III disease had recurrence, one with vaginal metastasis at 11 months and the other with a pelvic mass at 46 months. Neither pursued additional therapy. The remaining seven were free of disease at a median follow-up time of 22.5 months (range 0–61 months).
Papillary serous carcinoma is an aggressive uterine adenocarcinoma. Papillary serous carcinoma and ovarian serous papillary carcinomas are histologically similar and are characterized by papillary fronds lined with markedly pleomorphic cells. They are so similar histologically and behaviorally that many uterine papillary serous carcinomas were believed to be metastases of ovarian malignancies.
In our study, 69 of 595 women with endometrial adenocarcinoma had papillary serous carcinoma, a rate similar to that of Carcangiu and Chambers,10 but much higher than reviews that reported frequencies of 1–8%.1–9,16 The higher frequency of papillary serous histology in our study might indicate changing referral patterns. When specimens obtained during preoperative evaluation suggested a more aggressive histology or grade, women in our area were referred to a university center. Endometrioid adenocarcinomas are often treated by community physicians. Among the 16 women with noninvasive papillary serous carcinoma in our study, ten had evidence of metastasis at surgical staging. Dunton et al1 also noted that 20–63% of patients were staged higher surgically. Lack of complete surgical staging of those women would have resulted in inadequate diagnosis and treatment.
The prognostic significance of myometrial invasion and lymphovascular space invasion in patients with papillary serous carcinoma is debatable. Several authors suggested that they are important negative prognostic factors and that the propensity for deep myometrial invasion and lymphovascular space invasion is partly responsible for poor prognoses.2,10–13,17 In a study of 52 patients with papillary serous carcinoma of all stages, Goff et al14 found that the absence of myometrial invasion or lymphovascular space invasion did not predict the presence of extrauterine disease. In their study, 14 women had no evidence of uterine invasion, but lymph node metastases and intraperitoneal disease were found in 36% and 43% of patients, respectively. In a recent study by Cirisano et al,16 only one of eight noninvasive papillary serous carcinoma patients had associated extrauterine disease at staging. In our study, ten of 16 patients had extrauterine disease at surgical staging, and among those ten, six had evidence of lymphovascular space invasion. Among the women with stage IA disease in our study, two had disease recurrence despite absence of lymphovascular space invasion or lower uterine segment disease, which contrasts with several studies that reported no recurrences when there was no myometrial invasion.5,11,13
Postoperatively, there was no standard recommendation for adjuvant therapy; the most prescribed regimen was whole abdominal radiotherapy in women with stages IIA–IVB disease. Several authors recommend some form of additional treatment, including postoperative radiation therapy, chemotherapy, or a combination.1,8,9,18,20–23 Price et al24 also reported that three patients with radiographic evidence of metastatic papillary serous carcinoma showed significant partial responses with neoadjuvant chemotherapy comprising paclitaxel and carboplatin. Our study was too small to make a definitive statement about adjuvant therapy for advanced stage uterine papillary serous carcinoma.
Papillary serous carcinoma should be treated differently because traditional prognostic factors do not necessarily apply to it and typical patterns of spread are not predictable. When preoperative evaluation indicates serous histology, patients should have full surgical staging to determine the extent of metastasis.
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© 2001 The American College of Obstetricians and Gynecologists
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