Endometrial cancer in patients with preoperative diagnosis of atypical endometrial hyperplasia

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1 European Journal of Obstetrics & Gynecology and Reproductive Biology 122 (2005) Endometrial cancer in patients with preoperative diagnosis of atypical endometrial hyperplasia Carla Merisio a, Roberto Berretta a, Andrea De Ioris a, D. Caterina Pultrone a, Martino Rolla a, Giovanna Giordano b, Saverio Tateo c, Mauro Melpignano a, * a Maternal and Infant Care Department, University of Parma, Via Gramsci 14, Parma, Italy b Department of Pathology and Laboratory Medicine, Section of Anatomy and Pathological Histology, University of Parma, Parma, Italy c Obstetrics and Gynaecology Unit, Policlinico San Matteo Hospital, Pavia, Italy Received 22 September 2004; received in revised form 30 November 2004; accepted 10 January 2005 Abstract Objective: Atypical endometrial hyperplasia (AEH) has been associated with the presence of concomitant endometrial carcinoma (EC). The aim of this study is to examine the frequency of coexisting endometrial carcinoma when atypical endometrium hyperplasia was found upon biopsy. We also evaluated the influence of preoperative diagnostic techniques (pipelle and dilation and curettage (D&C)), and the value of transvaginal ultrasound in detecting unexpected tumor invasion. Study design: Between January 1992 and December 2003, at the Department of Obstetrics and Gynecology, University of Parma, and Policlinico S. Matteo, Pavia, 70 consecutive patients subjected to total hysterectomy with a histological diagnosis of AEH were retrospectively selected. 52/70 patients underwent vaginal hysterectomy, with bilateral salpingo-oophorectomy (BSO) whereas 18/70 had abdominal hysterectomy with BSO within 8 weeks since the diagnosis of AEH. Results: We found in 30 of the 70 patients with atypical endometrial hyperplasia in the biopsy coexisting endometrial carcinoma (43%). No differences in diagnostic accuracy between the pipelle method and D&C were found. Conclusion: Transvaginal ultrasound was not a feasible method for predicting EC. After a follow-up of an average of 5 years there was, neither in the abdominal operated patients nor in the vaginal operated patients, a recurrence of disease. # 2005 Published by Elsevier Ireland Ltd. Keywords: Endometrial cancer; Atypical hyperplasia; Vaginal versus abdominal hysterectomy 1. Introduction As early as 1900, Cullen observed the presence of atypical endometrium in the areas adjacent to endometrial adenocarcinoma (EC) [1]. Only half a century later, adenomatous hyperplasia was identified and described by Gusberg as a precursor of endometrial cancer [2]. A variety of terms have been used to define the different form of hyperplasia. The lack of consistency in diagnostic criteria has often resulted in conflicting literature reports. The classification of the International Society of Gynecological Pathologists (ISGYP), adopted also by the * Corresponding author. Tel.: ; fax: address: mmelpignano@ao.pr.it (M. Melpignano). WHO and FIGO, divides endometrial hyperplasia into the two groups of hyperplasia with and without cytologic atypia; these are further divided into the two subgroups of simple and complex hyperplasia [3]. In spite of the terminology limitations resulting from the adoption of different diagnostic criteria, there is no doubt that atypical hyperplasia carries a greater risk of cancer progression compared with hyperplasia without cytologic atypia [4 6]. The literature reports a 15 50% rate of concomitant endometrial carcinoma in patients undergoing hysterectomy a few weeks after being diagnosed with atypical endometrial hyperplasia (AEH) by pipelle biopsy or dilation and curettage (D&C). The purpose of this prospective study was to investigate the presence of EC in patients undergoing hysterectomy for /$ see front matter # 2005 Published by Elsevier Ireland Ltd. doi: /j.ejogrb

2 108 C. Merisio et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 122 (2005) AEH and to determine cancer histology, grading and staging, when present. We also evaluated the biopsy technique, the surgical procedure, i.e. vaginal hysterectomy versus abdominal hysterectomy and the diagnostic value of transvaginal ultrasound in detecting unexpected EC. 2. Patients and methods Seventy patients undergoing hysterectomy for AEH at the University of Parma, Department of Obstetrics and Gynecology, and at the Pavia-based Policlinico S. Matteo were studied between January 1992 and December Preoperative histological diagnosis was made by D&C in 39 patients (55%) and by pipelle biopsie in 31 (45%); we preferred D&C in nulliparus patients and in case of profuse metrorrhagia. The histological criteria used for AEH diagnosis at both centers were those recommended by the ISGYP [7], namely: increased number of endometrial glands (with or without architectural alterations, e.g. glandular complexity) lined by atypical epithelium and occupying at least half of a histological preparation under medium magnification, absence of desmoplastic stromal changes, confluent glandular aggregates, complex papillary patterns and/or squamous metaplasia. The following clinical variables were investigated in each patient: age, parity, past history of cardiovascular disease, diabetes, obesity and estrogen intake (Table 1). In addition to routine clinical examinations (chest X-ray and blood tests), a preoperative ultrasound examination was performed in all patients to measure the endometrial thickness. All patients underwent hysterectomy with bilateral salpingo-oophorectomy (BSO) [8] within 8 weeks of pipelle biopsy or D&C (range, 2 8 weeks). The uterus was removed intact and sent to the pathologist for the final histological examination, with no intraoperative gross examination. The surgical procedure of choice was vaginal hysterectomy (52 patients out of 70, 74%). In the presence of contraindications to hysterectomy by the vaginal route (significant uterine Table 1 Characteristics of patients with preoperative diagnosis of atypical endometrial hyperplasia (n = 70) Mean S.D. (range) Age (38 80) Parity (0 6) Weight (kg) (50 118) Height (cm) ( ) n (%) Menopausal status 25 (35.7) BMI > 30 kg/m 2 16 (22.8) Hypertension 18 (25.7) Diabetes mellitus 4 (5.7) Hormone therapy 8 (11.4) enlargement, restricted uterine mobility, vaginal tightness, possible adhesions resulting from endometriosis or inflammation), abdominal hysterectomy was performed (18/70, 26%). The histopathologic criteria used to determine stromal invasion and consequently to establish the diagnosis of carcinoma in the surgically removed samples were those recommended by Silverberg [9], namely: disappearance of endometrial stroma; desmoplastic reaction and stromal necrosis. Based on the WHO classification, endometrial carcinoma was graded as well differentiated (G I), moderately differentiated (G II) or poorly differentiated (G III). The patients were divided into two groups, depending on whether or not cancer was found in the surgically removed uterus on the histological examination (cancer group versus no-cancer group). The patients with endometrial cancer were followed up by general physical examination, vagino-rectal exploration, CA-125 and CA-15.3 assay every 6 months, and diagnostic imaging (chest X-ray and abdominal/pelvic ultrasound once a year). Adjuvant pelvic radiotherapy was given only to those patients with deep myometrial invasion who tested negative on the abdominal/pelvic CT scan performed postoperatively to detect metastatic sites. Statistical analysis was carried out using the x 2 -test and the logistic regression test. 3. Results We found the coexistence rate of EC with AEH was 43% (30 patients out of 70). Among the 30 patients with final diagnosis of EC, myometrial invasion was present in 90% of cases (27/30): the invasion was superficial in 92% (25/27) and deep in 8% (2/27). In the remaining 10% of cases (3/30), cancer was confined to the endometrium (see Table 2). The tumor was well differentiated (G I) in 19 cases (64%) and moderately differentiated (G II) in 11 (36%). None of our patients had a poorly differentiated tumor (G III) or a tumor of non-endometrioid histology. The histological sections obtained preoperatively in the patients with final diagnosis of EC were re-examined by the pathologist. The initial diagnosis of complex AEH was confirmed in all patients. Table 2 Myometrial invasion and grade distribution of patients with endometrial cancer (n = 30) Myometrial invasion Total M0 M1 M2 Grade I Grade II Grade III Total M, myometrial invasion; M0, no myometrial invasion; M1, superficial invasion <50%; M2, deep myometrial invasion >50%.

3 C. Merisio et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 122 (2005) The statistical analyses carried out in the two cancer and no-cancer groups to evaluate age, parity, obesity (BMI > 30 kg/m 2 ), arterial hypertension, diabetes, menopausal status and estrogen replacement therapy, did not show statistically significant differences ( p > 0.05) between the two groups (see Table 3). The technique used for preoperative diagnosis, i.e. pipelle biopsy in 55% of cases and D&C in 45%, did not prove to be different in not detecting the adjacent existing cancer; EC was detected in 16 of 39 patients (41%) undergoing D&C, and in 14 of 31 patients (45%) undergoing the pipelle method ( p > 0.05). About endometrial thickness measured by transvaginal ultrasonography we found in EC group a mean thickness of (range 3 21 mm) and in AEH group a mean of (range 2 21 mm). The difference is not statistically significant ( p > 0.05). Simple hysterectomy with bilateral salpingooophorectomy was performed by the vaginal route in 74% of cases (52/70) and by laparotomy in the remaining cases. In no case was vaginal hysterectomy laparoscopically assisted or converted to abdominal hysterectomy. Final histological evidence pointed to a diagnosis of EC in 20 of the patients undergoing vaginal hysterectomy and in 10 of the patients undergoing abdominal hysterectomy. Final cancer staging was based only on the results of the final histological examination. Patients with cancer confined to the endometrium (3 cases) or with superficial myometrial invasion (25 cases, including 15 G I and 10 G II) were included in a follow-up program of at least 5 years. Patients with myometrial invasion >50% (two cases, one G I and one G II) received adjuvant pelvic radiotherapy after a CT-scan performed for exclusion of pathological iliac and/ or paraaortic lymph nodes. All women were alive with no evidence of recurrence disease (follow-up range, 1 11 years; mean, 5.3 years). Table 3 Characteristics of two groups Group I (n = 40) Mean age (range) (38 80) Mean parity (range) (0 6) Weight (kg) (range) (50 100) Height (cm) (range) ( ) Group II (n = 30) (42 72) (0 3) (55 118) ( ) Menopausal status 14 (35%) 11 (36.7%) BMI > 30 kg/m 2 8 (20%) 8 (26.6%) Hypertension 11 (27.5%) 7 (23.3%) Diabetes mellitus 2 (5%) 2 (7.7%) Hormone therapy 6 (15%) 2 (7.7%) Group I, patients with AEH; Group II, patients with further diagnosis of EC. P Table 4 Literature survey of coexisting EC in patients with a preoperative diagnosis of AEH Authors 4. Comment Atypical endometriale hyperplasia Coexisting endometriale cancer Gusberg and Kaplan [2] (22%) Kurman and Norris [10] (17%) King et al. [11] (15%) Janicek and Rosenshein [12] (43%) Hunter et al. [13] (35%) Lambert et al. [14] 29 6 (21%) Liapis et al. [15] (36%) Widra et al. [16] (50%) Xie et al. [17] (38%) Bilgin et al. [18] (24%) Merisio et al. (present study) (43%) Total (29%) From a review of the literature (Table 4) it appears that the coexistence rate of EC with AEH varies according to the different authors: while Kurman reported a 17% rate, Widra found an association between the two conditions in 50% of cases [2,10 18]. A recent study conducted by Bilgin et al. on 46 patients indicated a coexistence of EC with AEH in 11 cases (24%). In our case series, the coexistence rate of EC and AEH was 43% (30 patients out of 70). The higher coexistence rate that we found in our study (43%) compared with Bilgin s (21%) might be explained by the older age of our patient sample (55 year) compared with Bilgin s study (52 year). The 30 tumors found at the final histological examination were all of endometrioid histology: in 10% of cases, the tumor was confined to the endometrial mucosa, while in 90% it invaded the myometrium; in 92% of cases with myometrial invasion, tumor infiltration was confined to the inner half of the myometrium and only in 8% did it exceed 50%. No tumors were graded as poorly differentiated. Our findings seem to confirm previous literature reports [7], indicating that AEH is primarily associated with welland moderately-differentiated tumors that mostly infiltrate the myometrium only superficially. Use of preoperative instrumental tests, ultrasound and MRI has been proposed to detect the depth of any possible myometrial invasion [19,20]. In this study, we performed only transvaginal ultrasonography. The statistical analysis conducted on the efficacy of preoperative ultrasound sonography (endometrial thickness) in our two study groups did not yield statistically significant results, suggesting that this technique is of no use as a routine diagnostic tool in detecting EC prior to hysterectomy. By contrast, intraoperative frozen section examination of the surgically removed uterus may provide useful indications both on the presence of EC and on the depth of tumor infiltration.

4 110 C. Merisio et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 122 (2005) However, frozen section examination may fail to detect up to 50% of EC cases associated with AEH [18]. If there is no grossly apparent tumor, the frozen section examination is usually performed on one or two sections at the most; the tumor may not be found on these sections and therefore be detected only at the final histological examination. In cases of endometrial EC with deep myometrial invasion, both intraoperative gross examination and frozen section examination have an accurate detection rate of about 90% [21]. On the other hand, Shim et al. reported that in 45% of cases with no apparent myometrial invasion on frozen section examination, the final histological examination did reveal the presence of tumor infiltration into the myometrium [22]. Therefore, frozen section examination cannot rule out with certainty the presence of EC, especially in those cases with no or little myometrial invasion. The identification of molecular markers for early detection of concomitant EC in AEH cases has not yet produced unambiguous results or given definite indications for their possible use in routine clinical practice [23 26]. Preoperative histological diagnosis was made by D&C or pipelle biopsy. Literature reports point to a greater accuracy of pipelle biopsy compared with D&C in menopausal women [27]. As our study population was mostly composed of postmenopausal women (mean age for the two study groups: 55 years versus 56 years), and also in consideration of the possible coexistence of EC with AEH, all patients were surgically treated by hysterectomy with BSO, vaginal in 74% of cases and abdominal in 26%. The final histological examination evidenced endometrial EC in 38.4% (20/ 52) of women undergoing vaginal hysterectomy versus 55% (10/18) of women undergoing abdominal hysterectomy. All patients with final diagnosis of EC were included in a 6-monthly follow-up scheme (range, 1 11 years; mean, 5.3 years). At the time being, no patient has shown any signs of relapse. The fact that the patients in our case series had G I or G II endometrial carcinoma, confined to the endometrium or to the inner half of the myometrium in 93.4% of cases (28/30), with 100% disease-free survival, explains why hysterectomy alone with bilateral salpingo-oophorectomy was considered the best treatment option in peri- or post-menopausal women. Where possible, vaginal hysterectomy was preferred over abdominal hysterectomy, thanks to its wellknown advantages in reducing morbidity and length of hospital stay. 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