Conservative management of early endometrial adenocarcinoma with ...

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Conservative management of early endometrial adenocarcinoma with repeat curettage and hormone therapy under assistance of hysteroscopy and laparoscopy.
Human Reproduction vol.12 no.8 pp.1649–1653, 1997

Conservative management of early endometrial adenocarcinoma with repeat curettage and hormone therapy under assistance of hysteroscopy and laparoscopy Fu-Tsai Kung1,4, Wei-Jen Chen2, Hung-Hsueh Chou1, Sheung-Fat Ko3 and Shiuh-Young Chang1 Departments of 1Obstetrics and Gynecology, 2Pathology and 3Radiology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan 4To

whom correspondence should be addressed at : Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, 123, Ta Pei Road, Niao Sung Hsiang, Kaohsiung Hsien, Taiwan

We report a rare case of early-stage endometrial adenocarcinoma in a 22 year old nullipara with polycystic ovaries undergoing conservative treatment. Pretreatment evaluation including tumour grade, depth of myometrial invasion, tumour size, hormone receptor status and flow cytometric analysis indicated a favourable prognosis. The patient underwent repeat endometrial curettage and a 6 month period of therapy with megestrol acetate and tamoxifen. A combination contraceptive pill was then prescribed to ensure withdrawal of the menstrual cycle thereafter. Now, 1 year after the last curettage, there is no evidence of disease. During the treatment period, hysteroscopy allowed for a more precise approach in panoramically examining the tumour nest in the endometrial cavity, and the subsequent endometrial response to hormone therapy. Laparoscopy using bulldog clamps applied to the isthmic portion of the Fallopian tubes prevented i.p. spread of endometrial tissue from retrograde regurgitation during hysteroscopy. Laparoscopic ovarian electrocautery resulted in the reduction of abnormal hypervascularization on the surface of polycystic ovaries postoperatively but caused a peri-ovarian adhesion complication. It is interesting that this case posed a unique opportunity to demonstrate the tumour regression under the assistance of laparoscopy and hysteroscopy. Key words: conservative treatment/endometrial carcinoma/ hysteroscopy/laparoscopy

Introduction The life-time probability of developing endometrial cancer is 1% from ages 0–74 in the UK (European Menopause Society, 1996). Endometrial cancer occurs primarily in postmenopausal women. Endometrial carcinoma in young adolescence is rare and, if it presents, is often associated with polycystic ovarian syndrome complicated by long-term unopposed oestrogen exposure (McDonald et al., 1977; Farhi et al., 1986; Lee and Scully, 1989). Conventionally, the primary treatment method for endometrial cancer has been total hysterectomy and bilateral salpingo–oophorectomy. This procedure, without the need for © European Society for Human Reproduction and Embryology

adjuvant therapy, almost always results in a good prognosis in patients with stage Ia, grade 1 endometrial carcinoma (International Federation of Obstetrics and Gynecology, 1989), but with unavoidable sterilization and premature ageing in reproductive age women. For the younger patient desiring a family, removal of uterus and ovaries by castration was thought to be too radical in some cases. We report the case of a young woman with endometrial adenocarcinoma with typical polycystic ovaries, and a favourable prognosis according to pretreatment evaluation, who received a combination of repeat endometrial curettage and hormone therapy in an effort to preserve her uterus. During the period of treatment, the application of hysteroscopy and laparoscopy also proved to be clinically significant. Case report A 22 year old female student, body mass index 27.1 kg/ m2, with no experience of sexual activity, complained of progressively excessive and prolonged vaginal bleeding at irregular intervals for 3 years. Progestin/oestrogen, vasoconstrictors and iron-supplemented drugs were prescribed as needed by a local gynaecologist, who found that the patient’s ultrasound scans always showed a ‘thicker endometrium pattern’ and bilateral enlarged ovaries. The patient was referred to our hospital because of the persistent and recently exaggerated symptoms. Laboratory analysis yielded the following data: haemoglobin 9.0 g%, follicle stimulating hormone (FSH) 4.52 mIU/ml, luteinizing hormone (LH) 1.53 mIU/ml, prolactin 11.0 ng/ml, and CA-125 16.7 IU/ml. Informed consent for a hysteroscopic examination and endometrial curettage associated with possible hymen laceration was obtained. The endometrial cavity was distended by using 10% dextrose solution and keeping infusion pressure at ~100 mmHg. Panoramic hysteroscopy before dilatation and curettage (D&C) showed a cluster of multiple polypoid projections on the right lower quarter of the uterine corpus, about 332.5 cm in area (Figure 1A). Vigorous curettage was performed to try to eradicate the lesion en bloc under the impression that it represented endometrial polyps. However, the pathological diagnosis was well differentiated adenocarcinoma. Both oestrogen and progesterone receptors were positive on immunoperoxidase staining. Flow cytometry and DNA analysis disclosed diploid content with a low S-phase fraction (5.73%). Magnetic resonance imaging (MRI) revealed no obvious myometrium invasion by the tumour and multiple small follicles along the periphery of the ovaries. Computerized tomography (CT) of the abdomen and pelvis demonstrated no evidence of pelvic or para-aortic lymph node enlargement. The patient and her parents strongly 1649

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Figure 1. Hysteroscopy and laparoscopy show serial gross changes of the endometrium and the ovary in the case of endometrial adenocarcinoma with polycystic ovaries during conservative treatment. (A) An original feature of endometrial adenocarcinoma: a cluster of polypoid projections. (B) Bulldog clamps on bilateral Fallopian tubes to block tubal reflux during hysteroscopy. (C) Multifocal translucent polypoids on the endometrium during 3 month hormone therapy, which were histologically confirmed to be a marked decidual reaction. (D) Sclerosing ovarian cortex with tiny vessels crossing over the surface. (E) Adhesion bands and tiny vessels along the previous location of endometrial carcinoma during 6 month hormone therapy. (F) The ovary has reduced vascularization on the surface but adheres densely to the pelvic sidewall during 3 month interval second-look laparoscopy.

requested that the uterus be preserved, and were committed to receiving the experimental method of conservative management. A hormone therapy regimen of tamoxifen (30 mg) and megestrol acetate (160 mg) daily, according to the report of 1650

Lai et al. (1994) of one case at our hospital, was initiated 10 days after D&C. Subsequently, menometrorrhagia did not occur and haemoglobin concentration gradually increased to 13.1 g%.

Early endometrial adenocarcinoma

Three months after the first hysteroscopy and D&C, laparoscopy was performed to examine the abdomino–pelvic cavity, and a second hysteroscopy to check the endometrium. In order to block the retrograde passage of endometrial tissue during hysteroscopy and vigorous curettage of the endometrium, both Fallopian tubes were temporarily clamped by two atraumatic bulldog clamps (titanium 30-0995, 4 cm; Lawton GmbH & Co., Tuttlingen, Germany) via laparoscope before attempting the second hysteroscopy (Figure 1B). Cytological and cell block analysis of the washing peritoneal fluid, obtained before hysteroscopy, showed no malignant cells and, when obtained after hysteroscopy, was negative for endometrial tissue. There were multifocal cotton-like polypoids with a translucent appearance on the endometrium (Figure 1C). The endometrial specimen, obtained by D&C, histologically disclosed marked decidual change and without residual tumour. Bilateral enlarged whitish smooth ovaries with a prominent reticular vascular network of overlying capsules (Figure 1D) were found, as well as a whole peritoneal cavity grossly free of tumour implant. In an attempt to diminish both the abnormal vascularization on the surface and the size of enlarged ovaries, laparoscopic drilling was performed, using a fine 400 W monopolar electrode for 3 s and 15 punctures per ovary, concomitant with desiccating the tiny vessels on the ovarian surfaces. In concluding the operative procedures, the surgical fields of the pelvis were vigorously irrigated and washed with normal saline, removing the bulldog clips, and lactate Ringer’s solution 1000 ml was instilled into the peritoneal cavity. Three months after the second curettage, another MRI revealed a thin endometrial thickening with a clear junction between the endometrium and myometrium. We repeated the same laparoscopic and hysteroscopic procedures and D&C as before. A cotton-yarn looking endometrium interlaced with a moderate degree of filmy adhesion bands (Figure 1E) in the uterine cavity was found. The ovaries had reduced vascular distribution on the surfaces but densely adhered to the pelvic sidewall and cul-de-sac (Figure 1F). The total adnexal adhesion score, according to the American Fertility Society, 1998 classification, was 16. The peri-ovarian adhesions were removed by laparoscopic scissor dissection and intrauterine adhesions were cut by hysteroscopic-guided scissors. Peritoneal washing cytology was again negative for malignant cells, and pathological examination confirmed the third D&C specimen to be a decidual reaction. Subsequently, the 6 month hormone regimen with tamoxifen and megestrol acetate was discontinued and changed to a combination contraceptive pill (0.25 mg levonorgestrel, 0.05 mg ethinyl oestradiol). At the time of writing, 1 year after the last D&C, the patient has a predictable menstrual flow, and normal endometrial thickness as indicated by transabdominal ultrasound. All of the image features taken during each set of operative procedures were displayed on a video camera monitor and stored in a record system for subsequent analysis and comparison. Discussion A number of variables are associated with a better prognosis of endometrial cancer: early clinical staging (Marziale et al.,

1989), younger age, well-differentiated adenocarcinoma with oestrogen dependence, limited depth of myometrial invasion, absence of lymph node metastasis (Morrow et al., 1991; Gusberg, 1994), association with unopposed oestrogen exposure (European Menopause Society, 1996), small tumour size (Schink et al., 1991), presence of tumour hormone receptor (Palmer et al., 1988), diploid DNA content, and a low proliferative index (Stendahl et al., 1991). In addition to welldifferentiated histological differentiation and absent myometrial invasion, both of which are of the utmost importance, other favourable variables also suggest the possibility of a good outcome. The oncological assessment using an intensive survey for our patient met all of the favourable prognostic variables. With advances in the predictability of the prognosis of endometrial carcinoma by using retrospective analyses of clinical and surgical–pathological variables as above, conservative treatment of early-stage adenocarcinoma in selected young women who wish to remain fertile can be considered a permissible alternative. Also, reports from Bokhman et al. (1985), Thornton et al. (1985), Farhi et al. (1986), Lai et al. (1994), and Kimmig et al. (1995) have stated that the effectiveness of conservative treatment with curettage of the endometrium and progestogen therapy in selected young patients with well-differentiated carcinoma limited to the endometrium might preserve fertility. Based on the abovementioned observations and experiences, we took a conservative, although experimental, approach in treating this patient with early endometrial cancer. Happily, she is now well, and free of clinical evidence of disease. Contrary to the conventional method of blunt curettage in treating endometrial lesions, panoramic visualization of the exact location of the endometrial carcinoma in the uterine cavity under the guidance of hysteroscopy provides a better way to eradicate as much of the tumour foci as possible. The surgeon is able to confirm the completion of operative procedures in eliminating the gross residual tumour by comparative assessment of preoperative and postoperative hysteroscopies. During the period of our patient’s hormone therapy, the endometrium of the previous tumour location on the second hysteroscopy appeared to have marked polypoid decidual formation but, on the third hysteroscopy, this appearance was less prominent, with interlaced adhesion bands crossed over by tiny vessels. The intrauterine adhesion formation, as we saw on the third hysteroscopy, resulted from both the lack of optimal oestrogen stimulation of the endometrium and the repeat vigorous curettage. The possible i.p. spread of endometrial tissue through tubal reflux when using a distention medium during hysteroscopy has been a major concern (Ranta et al., 1990). Romano et al. (1992) suggested that irrigation of the endometrial cavity during hysteroscopy might disseminate the adenocarcinoma to the abdominal cavity, thereby changing the course and the prognosis of treatment. Our patient opted to receive repeat vigorous curettage as a conservative mode of surgical treatment, so the risk of retrograde dissemination of tumour cells into the peritoneal cavity had to be avoided as much as possible. We performed a temporary tubal clamp using bulldog clamps to block the reflux of endometrial tissue. Although we know 1651

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the optimal time to use tubal blockage is during the initial attempt at diagnostic hysteroscopy and D&C, it is impossible to make the diagnosis of endometrial cancer without obtaining a D&C specimen. The efficacy of tubal blockage was proved by histological confirmation of the absence of endometrial decidual tissue in the peritoneal fluid after hysteroscopic and curettage procedures. We found that abnormal hypervascularization on the ovarian cortex decreased after laparoscopic electrocautery based on the 3 month interval second-look laparoscopy. This obvious change of gross appearance is interesting and almost certainly resulted from the ovarian electrodrilling and desiccating procedures. On the other hand, concerning the postoperative adhesion complication of laparoscopic electrothermal treatment, our experience was compatible with previous results. That is, various extents of adhesion formation occur in patients with polycystic ovarian syndrome who fail to respond to medical induction of ovulation, and receive laparoscopic ovarian drilling as an alternative method to help with ovulation (Gu¨rgan et al. 1991; Naether and Fischer, 1993). The greater the extent of damage to the surface of the ovary (we performed 15 punctures in each ovary), the greater the potential for postoperative peri-ovarian adhesion formation. Neither meticulous haemostasis of drilled holes nor i.p. instillation of a large volume of isotonic fluid can satisfactorily prevent the manipulated ovaries from developing adhesions. Current concepts of staging in endometrial cancer require an extirpative uterine specimen for surgical–pathological study. Although we did not obtain uterine and lymph node specimens in our case, initial imaging studies including MRI and CT showed that the tumour was confined to the endometrial layer only and there was no evidence of node enlargement. Gordon et al. (1989) have stated that MRI could be used preoperatively to assess myometrial invasion with a fairly high degree of accuracy. Besides, in our case, later laparoscopic direct visualization and washing cytology yielded no evidence of gross ovarian or peritoneal metastasis. Creasman et al. (in a gynaecological oncology group study, 1987) reported that no patients with grade 1 endometrium-only tumours in their study had pelvic or para-aortic node metastasis from the surgical– pathological examination and the prognosis for a patient with the absence of nodal involvement appeared to be excellent. We therefore speculated that the extent of tumour involvement in our patient was limited to a localized small endometrial area, free of macroscopic lymph node metastasis outside the uterus; and the prognosis would be favourable. Hormone therapy with progestogens for early-stage endometrial carcinoma patients undergoing conservative treatment has been used for a long time (Bokhman et al., 1985; Thornton et al., 1985; Farhi et al., 1986; Lee and Scully, 1989). Tamoxifen, a non-steroidal anti-oestrogen, was prescribed in our case in addition to megestrol acetate because of (i) its use in inhibiting the binding of oestradiol to the oestrogen receptors and increasing progesterone receptors, which in turn enhanced the effect of the progestational agent on the endometrium; (ii) the possibility of intra-abdominal spread of tumour cells carried by either direct tumour invasion or the distention medium in the first hysteroscopy, and then underestimation of the tumour 1652

stage without an extirpated pathological specimen, and (iii) a favourable experience based on the report of Lai et al. (1994) from our hospital. In contrast, according to recent studies of prolonged hormone therapy in breast carcinoma, tamoxifen treatment may be associated with an increased incidence of proliferative and neoplastic changes in the endometrium (Daniel et al. 1996). Therefore, whether a combination regimen of anti-oestrogen and progestogen is appropriate or more effective than the traditional treatment of progestogen alone in such an early-stage endometrial adenocarcinoma remains to be determined. After our patient underwent potent hormone therapy for 6 months, which caused amenorrhoea, a combination oral pill was used to ensure the withdrawal of menstruation. Therefore, the risk of re-induction of the endometrial neoplasm as an effect of unopposed oestrogen stimulation was hopefully minimized. Conservative treatment without hysterectomy for a welldifferentiated endometrial adenocarcinoma limited to the endometrial layer only may be relevant to such a young nulliparous woman as our patient. A combination of initial vigorous endometrial curettage and aggressive hormone therapy with megestrol acetate and tamoxifen for 6 months as a primary treatment modality would have eradicated the existing tumour nests in the endometrial layer. Repeat curettage on two occasions, 3 months apart, confirmed the endometrium was free of residual tumour during the period of aggressive hormone therapy. Following the primary treatment course, it is important to ensure both predictable regularity of withdrawal bleeding induced by oral contraceptive pills and normal appearance of the endometrium demonstrated by ultrasound. However, in the future, the possibility of recurrence of malignant tumour should never be neglected and therefore elective hysterectomy was advised if and when she no longer desired to maintain fertility. Our case presented a unique opportunity to demonstrate the course of conservative treatment of an early endometrial carcinoma with the assistance of laparoscopy and hysteroscopy. The following significant implications for the use of endoscopy were confirmed: (i) hysteroscopic panoramic visualization of the gross-appearing endometrial adenocarcinoma, the tumour location and extent, and the endometrial response to hormone therapy; (ii) bilateral tubal blockade, effectively preventing the retrograde spread of endometrial tissue during hysteroscopy and then avoiding the possibility of subsequent i.p. tumour implant; (iii) extensive laparoscopic ovarian electrodrilling therapy reducing hypervascularization on the ovarian surface, although resulting in peri-ovarian adhesion formation.

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