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Hysteroscopic view in atypical endometrial hyperplasias: A correlation with pathologic findings on hysterectomy specimens
Journal of Minimally Invasive Gynecology (2006) 13, 325–330
Hysteroscopic view in atypical endometrial hyperplasias: A correlation with pathologic findings on hysterectomy specimens Giancarlo Garuti, MD, Maurizio Mirra, MD, and Massimo Luerti, MD From the Obstetrics and Gynecology Department (Drs. Garuti and Luerti) and the Department of Pathology (Dr. Mirra), Lodi Hospital, Lodi, Italy. KEYWORDS: Endometrial atypical hyperplasia; Endometrial hyperplasia; Endometrial carcinoma; Endometrial biopsy; Hysteroscopy
Abstract: STUDY OBJECTIVE: To evaluate whether hysteroscopic imaging can contribute to decrease the rate of undetected endometrial carcinomas concurrent with atypical hyperplasia diagnosed by endometrial biopsy. DESIGN: Retrospective study. DESIGN CLASSIFICATION: Canadian Task Force Classification II-3. SETTING: Public hospital. PATIENTS: Hysteroscopic reports of 25 menopausal patients undergoing endometrial biopsy yielding a diagnosis of atypical hyperplasia were reviewed. On the basis of this diagnosis, all patients were treated by hysterectomy, and the pathologic findings on the uterine specimen were correlated with the diagnoses obtained by hysteroscopic view. INTERVENTIONS: Hysteroscopy was video-assisted and carried out with normal saline solution used as liquid distension medium; a 5-mm sheathed hysteroscope, with a working channel, was used for each examination. After hysteroscopic inspection, an endometrial sampling targeted under vision was performed by mechanical or electrosurgical instrumentation. When extensive features of hyperplastic or neoplastic growth were observed, we combined a blind sampling procedure with Vabracurettage. We calculated the sensitivity, specificity, and negative and positive predictive values of hysteroscopic inspection to foresee the diagnosis of endometrial cancer incidentally detected on hysterectomy specimen. MEASUREMENTS AND MAIN RESULTS: On the basis of histopathologic study of uterine specimens, non atypical hyperplasias were detected in 3 patients, the diagnosis of complex atypical hyperplasia was confirmed in 11 patients, whereas a concurrent infiltrating endometrial adenocarcinoma was detected in 11 patients (44.0%). In the 14 patients with diagnosis of endometrial hyperplasia, no feature suggesting endometrial malignancy was reported by hysteroscopic inspection. In the 11 cases showing infiltrating carcinomas, hysteroscopic view was consistent with endometrial malignancy in 9 patients and with endometrial hyperplasia in 2 patients. An intramucous endometrial carcinoma without evidence of myometrial invasion was found on hysterectomy specimens of these two latter patients. From these figures, sensitivity, specificity, and negative and positive predictive values of hysteroscopy to foresee a diagnosis of infiltrating carcinoma were 84.6%, 100%, 87.5%, and 100%, respectively. CONCLUSIONS: Hysteroscopic view is a sensitive and specific method to identify among patients with a diagnosis of atypical hyperplasia on endometrial biopsy those with a coexisting infiltrating carcinoma. © 2006 AAGL. All rights reserved.
1553-4650/$ -see front matter © 2006 AAGL. All rights reserved. doi:10.1016/j.jmig.2006.03.010
326
Journal of Minimally Invasive Gynecology, Vol 13, No 4, July/August 2006
The diagnosis of atypical endometrial hyperplasia, resulting from an endometrial biopsy specimen obtained by uterine dilation and curettage, poses a therapeutic challenge to the gynecologist because of the frequent underestimation of concurrent infiltrating carcinoma found in the hysterectomy specimens in 40% to 60% of patients.1–5 Simple hysterectomy, with or without bilateral adnexectomy, is considered an adequate treatment for atypical hyperplasia diagnosed in menopausal patients,6 and endocrine therapy can be safely administered to treat atypical hyperplasia in patients of fertile age7 or in menopausal patients with high surgical risk.8 On the other side, a full surgical staging, according to International Federation of Gynecology and Obstetrics (FIGO) current guidelines,9 is recommended to treat endometrial cancer, even in early-stage and low-grade carcinomas,10 and an extended pelvic surgery is advisable in the treatment of second-stage disease.11 Appropriate surgery for endometrial carcinoma leads to more rational, effective, and cost-saving selection of patients scheduled to undergo adjuvant therapy. Therefore a differential diagnosis between endometrial atypical hyperplasia and carcinoma is of great clinical relevance, but, as referenced above, a poor sensitivity endometrial sampling technique, such as dilation and curettage, cannot be considered reliable. The current standard procedure for investigation of endometrial pathologies is based on hysteroscopy with endometrial biopsy.12 The visual assessment of the endometrial cavity, coupled with “oriented” or “targeted” tissue collection, improves the accuracy of blind sampling procedures in the diagnosis of submucosal fibroids,13 polyps,14 focal hyperplasias or carcinomas,12,15 and endometrial atrophy.16 The sensitivity and the positive predictive value of the hysteroscopic view to detect endometrial hyperplasia have been reported as low, mainly because of the unreliable visual criteria currently used for this diagnosis.15,17 Nevertheless, a higher diagnostic accuracy of hysteroscopic view to detect endometrial carcinoma is generally reported,15,18 on the basis of a more substantial and specific disruption of endouterine architecture associated with malignant endometrial growth.19,20 The purpose of this retrospective study is to estimate the accuracy of hysteroscopic imaging to predict concurrent infiltrating carcinomas in menopausal patients with atypical hyperplasia diagnosed by endometrial biopsy.
Patients and methods Patient selection
per year. We reviewed all hysteroscopic reports from January 2002 to October 2005 of patients in whom endometrial atypical hyperplasia was diagnosed, on the basis of the biopsy specimen sampled at the end of the hysteroscopic inspection. Twenty-five of 28 patients with this diagnosis underwent hysterectomy at our gynecology department; the histopathologic findings on uterine specimens of these 25 patients were compared with the diagnoses on the basis of the hysteroscopic view. Twelve patients selected in this series were also included in previously published studies.17,21
Hysteroscopy All patients underwent outpatient hysteroscopy with a 5 mm-sheathed hysteroscope tipped with a 30-degree lens with a 1.5 mm working channel (Karl Storz, Tuttlingen, Germany). Normal saline solution was used as a liquid distension medium, and it was delivered by an irrigating suction device, setting endouterine pressure below 120 mm Hg and endouterine flow below 100 mL/min; all examinations were video assisted. As a rule, no systemic analgesia or local anesthetic was administered, and the vaginoscopic technique was used.22 At the patient’s request, in case of anxiety or when a cervical inspection suggested that a cervical stenosis too difficult to overcome without inducing significant pelvic pain, anesthetic paracervical block was performed before the procedure was started.
Hysteroscopic classification Hysteroscopic-view diagnosis was reported according to previously published criteria.18 Briefly, the following hysteroscopic findings were considered normal: an evenly thin, atrophic endometrium; an atrophic endometrium with focal mucous-containing cysts covered by a thin endometrium; or a functional, proliferative or secretory endometrium with no focal features of endometrial hyperplasia (see below). The following findings were considered abnormal: endometrial polyp, diagnosed as broad-based or pedunculated focal mucosal projection measuring more than 0.5 cm, with no associated features suggesting endometrial hyperplasia or carcinoma; endometrial hyperplasia, defined as focal or extensive, polypoid or papillary mucosal thickening with or without finding of gland cysts, abnormal vascular network, crowded or abnormally-spaced gland openings; endometrial carcinoma, classified according to Sugimoto, in papillary, polypoid, nodular or mixed endometrial growth,19 showing a friable consistency, focal necrosis, and atypical vessels.
In the outpatient hysteroscopy department at Lodi Hospital (Italy), we perform about 250 diagnostic procedures
Endometrial sampling and pathologic assessment
Corresponding author: Giancarlo Garuti, MD, Obstetrics and Gynecology Department, Lodi Hospital, via Savoia no. 1, 26900-Lodi, Italy. [email protected] Submitted December 17, 2005. Accepted for publication March 12, 2006.
Endometrial tissue sampling was carried out in all cases following Loffer’s recommendations16; accordingly, we avoided tissue sampling only when a good visualization was obtained, and a normal uterine shape associated with a
Garuti et al
Atypical endometrial hyperplasias
uniform thin endometrium was found. Focal lesions were sampled under visual guidance by hysteroscopic mechanical instrumentation (scissors for fashioning the tissue sample and grasping forceps for its extraction) through the working channel of hysteroscope. “Excisional” biopsy was attempted for small lesions, generally suspected of focal hyperplasias, whereas an “incisional” biopsy was fashioned for larger endometrial polypoid protrusions suggesting an endometrial cancer. During the same outpatient procedure, polyps were removed by mechanical or bipolar electrosurgical (Versapoint, Menlo Park, Calif) resection of the pedicle at the endometrial-myometrial junction.23 When extensive features of abnormal endometrial thickening were found, we targeted the hysteroscopically-guided biopsy specimens to the most “suspicious” mucosal abnormality suggesting an underlying endometrial hyperplasia or neoplasia, but in these cases we also performed a blind sampling by Vabra suction-curettage or by Novak’s curette. Endometrial biopsy specimens were sent to the pathologist in 1 or more vials, depending on the number of collected tissue specimens, and classified with the method described by Buckley and Fox.24
Results Age, parity, and body mass index of the 25 patients forming the group of study, expressed as mean ⫾ standard deviation were 61.0 ⫾ 6.1 years, 1.7 ⫾ 0.8, and 29.5 ⫾ 5.2, respectively. All patients were menopausal; in 24 of them menopause occurred physiologically and in a 39-year-old woman the menopausal status was chemotherapy-induced because of a previous treatment for breast cancer. Three patients were symptom free: in one of them hysteroscopy was indicated as a scheduled follow-up of simple endometrial hyperplasia, and in the other 2 patients it was due to an increased endometrial thickness incidentally found at transvaginal ultrasonography. In the other 22 patients, hysteroscopy was indicated because of abnormal uterine bleeding and an endometrial thickness measured above 4 mm by transvaginal ultrasonography. Six women were affected by breast cancer, and 4 of them were treated with tamoxifen. Severe morbidities such as obesity, diabetes, and hypertension were found in 9 patients (36.0%). Hysteroscopic view diagnosis, endometrial sampling methods, pathologic findings on endometrial biopsy, type of hysterectomy accomplished and definitive pathology on the uterine specimen obtained in each patient are specified in Table 1. In all patients hysteroscopic inspection showed an abnormal endometrium; endometrial hyperplasia, endometrial polyp, and endometrial carcinoma were diagnosed by hysteroscopic view in 8, 8, and 9 cases, respectively. A diagnosis of simple atypical hyperplasia was given in 1 patient with a hysteroscopic report of endometrial polyp, whereas complex atypical hyperplasias were found in the remaining 24 patients. On the uterine specimens non-atypical simple and
327 complex hyperplasias were found in 1 and 2 patients, respectively, whereas complex atypical hyperplasia was confirmed on hysterectomy specimens of 11 patients. In all 14 patients with endometrial hyperplasia on hysterectomy specimen, hysteroscopy reported no suspected findings of malignancy, and it was consistent with endometrial polyps (8 cases) or hyperplasias (6 cases). Infiltrating endometrial adenocarcinomas, all of endometrioid histotype, were found on the uterine specimens of 11 patients (44.0%). In 9 of them (81.8%) hysteroscopy correctly predicted the diagnosis of malignancy. Among the 16 patients not suspected of having cancer under hysteroscopy, an infiltrating endometrial carcinoma was found in 2 cases (12.5%). Endometrial hyperplasia was recorded by hysteroscopy in these 2 patients, whereas a pathologic diagnosis of well-differentiated, intramucous carcinoma was found in both uterine specimens (Table 1). Both patients underwent hysteroscopy because of intervening vaginal bleeding during tamoxifen administration for breast cancer, lasting 12 months and 8 months from a previous normal endometrial ultrasonographic work-up, carried out for routine endometrial surveillance. Three patients with endometrial carcinoma spreading to endocervical stroma (2 patients) and showing a moderately differentiated carcinoma with myometrial invasion of more than 50% (1 patient) underwent adjuvant radiotherapy (Table 1). According to these figures, to foresee the diagnosis of carcinomas underestimated as atypical hyperplasias by endometrial biopsy, hysteroscopic inspection provides specificity, sensitivity, positive predictive value, and negative predictive value of 100%, 84.6%, 100%, and 87.5%, respectively.
Discussion In agreement with the high false-negative rates reported by other authors,1–5 in this series we found that endometrial biopsy resulting in a diagnosis of atypical hyperplasia failed to sample a concurrent infiltrating carcinoma in 44.0% of patients. In spite of the performance of hysteroscopically targeted biopsy, our results did not improve the high rates of carcinomas undetected by using blind tissue collection.1–5 On biopsy specimens, the distinction between well-differentiated carcinomas and atypical hyperplasias, on the basis of distortion of glands architecture and cytologic atypia, is neither simple nor reproducible even by experienced pathologists,25 and the detection of stromal or myometrial invasion might be the sole finding suggesting an infiltrating disease.6,26 In several patients with endometrial cancer, myometrial tissue but also endometrial stromal tissue can be unavailable or poorly represented in curettage or biopsy specimens24; in addition, atypical hyperplasia is often found beside type I infiltrating endometrial carcinoma.27 Probably, the high rates of undetected carcinomas in patients showing atypical hyperplasia on endometrial biopsy specimens are
328
Journal of Minimally Invasive Gynecology, Vol 13, No 4, July/August 2006
Table 1 Hysteroscopic-view diagnoses, tissue sampling modalities, pathologic findings on endometrial biopsy, type of hysterectomy, and histopathologic study on the hysterectomy specimens are detailed for all 25 patients showing atypical hyperplasia on endometrial biopsy
Patients
Hysteroscopic-view diagnosis
Tissue sampling
1
Focal hyperplasia
Targeted biopsy
2
Polyp
Polypectomy
3
Polyp
Polypectomy
4
Focal hyperplasia
Targeted biopsy
5
Polyp
Polypectomy
6
Polyp
Polypectomy
7
Polyp
Polypectomy
8
Polyp
Polypectomy
9
Focal hyperplasia
Targeted biopsy
10
Polyp
Polypectomy
11
Extensive hyperplasia
12
Polyp
Targeted biopsy-Vabra Polypectomy
13
Focal hyperplasia
Targeted biopsy
14
Extensive hyperplasia
15
Polypoid carcinoma
Targeted biopsy - Vabra Targeted biopsy
16
Focal hyperplasia
Targeted biopsy
17
Extensive hyperplasia
18
Focal nodular carcinoma
Targeted biopsy-Vabra Targeted biopsy
19 20
Mixed papillary-polypoid carcinoma Polypoid carcinoma
21
Polypoid carcinoma
22
Papillary carcinoma
23 (BER)
Papillary carcinoma
24 (BER-BRT)
Polypoid carcinoma with isthmus extension Polypoid carcinoma with endocervical extension
25 (BER-BRT)
Targeted biopsy-Vabra Targeted biopsy-Novak Targeted biopsy-Vabra Targeted biopsy-Vabra Targeted biopsy Targeted biopsy-Vabra Targeted biopsy-Vabra
Pathologic study on endometrial biopsy Complex atypical hyperplasia Simple atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia
Type of hysterectomy
Pathologic study on uterine specimen
VH-BA
Complex atypical hyperplasia
VH
Simple hyperplasia
VH
Complex hyperplasia
LAVH-BA
Complex atypical hyperplasia
VH-BA
Complex atypical hyperplasia
VH-BA
Complex atypical hyperplasia
VH-BA
Complex atypical hyperplasia
LAVH-BA
Complex atypical hyperplasia
VH
Complex atypical hyperplasia
VH-BA
Complex atypical hyperplasia
VH-BA
Complex atypical hyperplasia
VH-BA
Complex hyperplasia
VH-BA
Complex atypical hyperplasia
VH
Complex atypical hyperplasia
LAVH-BA
Adenocarcinoma I°A/G2/Nx
VH-BA
Adenocarcinoma I°A/G1/Nx
VH
Adenocarcinoma I°A/G1/Nx
LAVH-BA
Adenocarcinoma I°B/G1/Nx
VH
Adenocarcinoma I°B/G1/Nx
TAH-BA
Adenocarcinoma I°B/G2/Nx
TAH-BA
Adenocarcinoma I°B/G2/Nx
TAH-BA
Adenocarcinoma I°B/G2/Nx
VH-BA
Adenocarcinoma I°C/G2/Nx
LAVH-BA
Adenocarcinoma II°B/G2/Nx
VH
Adenocarcinoma II°B/G2/Nx
The stages of 11 endometrial carcinomas incidentally found on hysterectomy specimens are arbitrarily assigned on the basis of the depth of myometrial infiltration and spreading to the endocervix. BER ⫽ adjuvant beam external radiotherapy; BRT ⫽ adjuvant brachytherapy; VH ⫽ vaginal hysterectomy; VH-BA ⫽ vaginal hysterectomy with bilateral adnexectomy; TAH-BA ⫽ total abdominal hysterectomy with bilateral adnexectomy; LAVH-BA ⫽ laparoscopically-assisted vaginal hysterectomy with bilateral adnexectomy.
Garuti et al
Atypical endometrial hyperplasias
based on these technical and biologic reasons. The high rate of undetected carcinomas found also by hysteroscopicallyguided biopsy specimens can be mainly related to our common practice of targeting the sampling at the most superficial layers of a mass protruding within the uterine cavity, because of an easier and quicker fashioning of the specimen, but possibly causing a poor sampling of the underlying stromal tissue. In addition, the mechanical handling of a friable neoplastic tissue causes its fragmentation, particularly by use of grasping hysteroscopic forceps for specimen’s extraction, leading to suboptimal quality of tissue samples examined by the pathologist. Furthermore, the easy bleeding of a neoplastic mass caused by the hysteroscopic instrumentation is often responsible for obscured hysteroscopic vision, even with liquid distension medium, and it can consequently lead, mainly in an outpatient setting, to suboptimal specimen collection. The hysteroscopic appearance of an endometrial carcinoma is quite typical, and this visual diagnosis is generally based on the presence of a gross distortion of endometrial cavity, because of focal or extensive nodular, polypoid, papillary or mixed patterns of neoplastic growth.19 Focal necrosis, friable consistency, and atypical vessels are other features almost invariably associated with endometrial cancer and easily detected by hysteroscopic inspection.18,20 By using these visual criteria, we found a 100% positive predictive value and 100% specificity of hysteroscopic view to diagnose endometrial carcinomas underestimated by biopsy finding of atypical hyperplasia. By hysteroscopic inspection, we underestimated 2 intramucous carcinomas as endometrial hyperplasia. This finding might be related to the early stage of neoplasias, influencing the lack of gross endometrial distortion associated with more advanced carcinomas and showing hysteroscopic features possibly overlapping on some ones considered specific of hyperplasia. These underestimated diagnoses led negative predictive values (87.5%) and sensitivity (84.6%) of hysteroscopy to be less than optimal in excluding an endometrial carcinoma when the visual findings are consistent with endometrial hyperplasia. To our knowledge, there is only 1 report in the current literature evaluating the prevalence of malignancy among patients with hysteroscopic view evocative of benign pathologic condition and resulting in a diagnosis of atypical hyperplasias on endometrial biopsy. Similar to our 12.5% false-negative findings, Agostini et al,28 in a series of 17 patients, found a 5.9% rate of cancer when atypical hyperplasia was incidentally diagnosed on hysteroscopic resection products, when no hysteroscopic features suggested an endometrial cancer. The presented findings suggest that when appropriate hysteroscopic facilities are available, an inspective diagnosis of endometrial cancer should be considered by the pelvic surgeon as highly predictive of malignancy, in spite of a pathologic finding of atypical hyperplasia previously obtained by endometrial biopsy. We believe that in these cases a repeat endometrial sampling should be considered, partic-
329 ularly in patients with hysteroscopic imaging consistent with neoplastic endocervical spread or for which a conservative surgical or medical treatment is planned. In patients who are candidates for hysterectomy, intraoperative frozen sections of uterine specimen are recommended, and the type of surgery should be planned to allow adequate modulation, faced with a highly probable concurrent infiltrating carcinoma.
References 1. Karamursel BS, Guven S, Tulunay G, Kucukali T, Ayhan A. Which surgical procedure for patients with atypical endometrial hyperplasia? Int J Gynecol Cancer. 2005;15;127–131. 2. Trimble CL, Kauderer J, Zaino R, Silverberg S, Lim PC, Burke JJ 2nd, et al. Concurrent endometrial carcinoma in women with biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer. 2006;106: 812– 819. 3. Widra EA, Dunton CJ, McHugh M, Palazzo JP. Endometrial hyperplasia and the risk of carcinoma. Int J Gynecol Cancer. 1995;5:233– 235. 4. Janicek MF, Rosenshein NB. Invasive endometrial cancer in uteri resected for atypical endometrial hyperplasia. Gynecol Oncol. 1994; 52:373–378. 5. Shutter J, Wright TC. Prevalence of underlying adenocarcinoma in women with atypical endometrial hyperplasia. Int J Gynecol Pathol. 2005;24:313–318 6. Wells M. Hyperplasias of the endometrium. In: Gershenson DM, McGuire WP, Gore M, Quinn MA, Thomas G, editors. Gynecologic cancer, controversies in management. Philadelphia: Elsevier; 2004. p. 249 –257. 7. Jadoul P, Donnez J. Conservative treatment may be beneficial for young women with atypical endometrial hyperplasia or endometrial adenocarcinoma. Fertil Steril. 2003;80:1315–1324. 8. Agorastos T, Vaitsi V, Pantazis K, Efstathiadis E, Vavilis D, Bontis JN. Aromatase inhibitor anastrozole for treating endometrial hyperplasia in obese postmenopausal women. Eur J Obstet Gynecol Reprod Biol. 2005;118:239 –240. 9. Creasman WT. Announcement: FIGO stages-1988 revision. Gynecol Oncol. 1989;35:125–127. 10. Ben-Shachar I, Pavelka J, Cohn DE, et al. Surgical staging for patients presenting with grade 1 endometrial carcinoma. Obstet Gynecol. 2005; 105:487– 493. 11. Cornelison TI, Trimble EL, Kosary CL. SEER data, corpus uteri cancer: treatment trends versus survival for FIGO stage II, 1988-1994. Gynecol Oncol. 1999;74:350 –355. 12. Gimpelson RJ, Rappold HO. A comparative study between panoramic hysteroscopy with directed biopsies and dilatation and curettage, a review of 276 cases. Am J Obstet Gynecol. 1988;152:489 – 492. 13. Nagele F, O’Connor H, Davies A, Badawy A, Mohamed H, Magos A. 2500 outpatient diagnostic hysteroscopies. Obstet Gynecol. 1996;88: 87–92. 14. Gebauer G, Hafner A, Siebzehnrubl E, Lang N. Role of hysteroscopy in detection and extraction of endometrial polyps: results of a prospective study. Am J Obstet Gynecol. 2001;184:59 – 63. 15. Clark TJ, Voit D, Gupta JK, Hyde C, Song F, Khan KS. Accuracy of hysteroscopy in the diagnosis of endometrial cancer and hyperplasia. JAMA. 2002;288:1610 –1621. 16. Loffer FD. Hysteroscopy with selective endometrial sampling compared with dilatation and curettage for abnormal uterine bleeding: the value of a negative hysteroscopic view. Obstet Gynecol. 1989;73:16 – 20.
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17. Garuti G, Cellani F, Garzia D, Colonnelli M, Luerti M. Accuracy of hysteroscopic diagnosis of endometrial hyperplasia: a retrospective study on 323 patients. J Min Inv Gynecol. 2005;12:247–253. 18. Garuti G, Sambruni I, Colonnelli M, Luerti M. Accuracy of hysteroscopy in predicting histopathology of endometrium in 1500 women. J Am Assoc Gynecol Laparosc. 2001;8:207–213. 19. Sugimoto O. Hysteroscopic diagnosis of endometrial carcinoma. A report of fifty-three cases examined at the women’s clinic of Kyoto University Hospital. Am J Obstet Gynecol. 1975;121:105–113. 20. Triolo O, Antico F, Palmara V, Benedetto V, Panama S, Nicotina PA. Hysteroscopic findings of endometrial carcinoma. Evaluation of 104 cases. Eur J Gynaecol Oncol. 2005;26:434 – 436. 21. Garuti G, Cellani F, Centinaio G, Sita G, Nalli G, Luerti M. Histopathologic behavior of endometrial hyperplasia during tamoxifen therapy for breast cancer. Gynecol Oncol. 2005: Nov 16. 22. Bettocchi S, Selvaggi L. A vaginoscopic approach to reduce the pain of hysteroscopy. J Am Assoc Gynecol Laparosc. 1997;4:255–258. 23. Garuti G, Cellani F, Colonnelli M, Grossi F, Luerti M. Outpatient hysteroscopic polypectomy in 237 patients: feasibility of a one-stop
24.
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26.
27.
28.
“see and treat” procedure. J Am Assoc Gynecol Laparosc. 2004;11:500 –504. Buckley CH, Fox H. Biopsy pathology of the endometrium. In: Gattlieb LS, Neville AM, Walker F, editors. Biopsy pathology series. London: Chapman & Hall, 1989. Kendall BS, Ronnett BM, Isacson C, Cho KR, Hedrick L, Diener-West M, et al. Reproducibility of the diagnosis of endometrial hyperplasia, atypical hyperplasia, and well differentiated carcinoma. Am J Surg Pathol. 1998;22:1012–1017. Mutter GL and the Endometrial Collaborative Group. Endometrial Intraepithelial Neoplasia (EIN): will it bring order to chaos? Gynecol Oncol. 2000;76:287–290. Kaku T, Tsukamoto N, Hachisuga T, Tsuruchi N, Sakai K, Hirakawa T, et al. Endometrial carcinoma associated with hyperplasia. Gynecol Oncol. 1996;60:22–25. Agostini A, Cravello L, Shojai R, Schaeffer V, Bretelle F, Roger V, et al. Risk of finding an endometrial cancer when atypical hyperplasia was incidentally diagnosed on hysteroscopic resection products. Eur J Obstet Gynecol Reprod Biol. 2002;103;58 –59.
Hysteroscopic view in atypical endometrial hyperplasias: A correlation with pathologic findings on hysterectomy specimens Giancarlo Garuti, MD, Maurizio Mirra, MD, and Massimo Luerti, MD From the Obstetrics and Gynecology Department (Drs. Garuti and Luerti) and the Department of Pathology (Dr. Mirra), Lodi Hospital, Lodi, Italy. KEYWORDS: Endometrial atypical hyperplasia; Endometrial hyperplasia; Endometrial carcinoma; Endometrial biopsy; Hysteroscopy
Abstract: STUDY OBJECTIVE: To evaluate whether hysteroscopic imaging can contribute to decrease the rate of undetected endometrial carcinomas concurrent with atypical hyperplasia diagnosed by endometrial biopsy. DESIGN: Retrospective study. DESIGN CLASSIFICATION: Canadian Task Force Classification II-3. SETTING: Public hospital. PATIENTS: Hysteroscopic reports of 25 menopausal patients undergoing endometrial biopsy yielding a diagnosis of atypical hyperplasia were reviewed. On the basis of this diagnosis, all patients were treated by hysterectomy, and the pathologic findings on the uterine specimen were correlated with the diagnoses obtained by hysteroscopic view. INTERVENTIONS: Hysteroscopy was video-assisted and carried out with normal saline solution used as liquid distension medium; a 5-mm sheathed hysteroscope, with a working channel, was used for each examination. After hysteroscopic inspection, an endometrial sampling targeted under vision was performed by mechanical or electrosurgical instrumentation. When extensive features of hyperplastic or neoplastic growth were observed, we combined a blind sampling procedure with Vabracurettage. We calculated the sensitivity, specificity, and negative and positive predictive values of hysteroscopic inspection to foresee the diagnosis of endometrial cancer incidentally detected on hysterectomy specimen. MEASUREMENTS AND MAIN RESULTS: On the basis of histopathologic study of uterine specimens, non atypical hyperplasias were detected in 3 patients, the diagnosis of complex atypical hyperplasia was confirmed in 11 patients, whereas a concurrent infiltrating endometrial adenocarcinoma was detected in 11 patients (44.0%). In the 14 patients with diagnosis of endometrial hyperplasia, no feature suggesting endometrial malignancy was reported by hysteroscopic inspection. In the 11 cases showing infiltrating carcinomas, hysteroscopic view was consistent with endometrial malignancy in 9 patients and with endometrial hyperplasia in 2 patients. An intramucous endometrial carcinoma without evidence of myometrial invasion was found on hysterectomy specimens of these two latter patients. From these figures, sensitivity, specificity, and negative and positive predictive values of hysteroscopy to foresee a diagnosis of infiltrating carcinoma were 84.6%, 100%, 87.5%, and 100%, respectively. CONCLUSIONS: Hysteroscopic view is a sensitive and specific method to identify among patients with a diagnosis of atypical hyperplasia on endometrial biopsy those with a coexisting infiltrating carcinoma. © 2006 AAGL. All rights reserved.
1553-4650/$ -see front matter © 2006 AAGL. All rights reserved. doi:10.1016/j.jmig.2006.03.010
326
Journal of Minimally Invasive Gynecology, Vol 13, No 4, July/August 2006
The diagnosis of atypical endometrial hyperplasia, resulting from an endometrial biopsy specimen obtained by uterine dilation and curettage, poses a therapeutic challenge to the gynecologist because of the frequent underestimation of concurrent infiltrating carcinoma found in the hysterectomy specimens in 40% to 60% of patients.1–5 Simple hysterectomy, with or without bilateral adnexectomy, is considered an adequate treatment for atypical hyperplasia diagnosed in menopausal patients,6 and endocrine therapy can be safely administered to treat atypical hyperplasia in patients of fertile age7 or in menopausal patients with high surgical risk.8 On the other side, a full surgical staging, according to International Federation of Gynecology and Obstetrics (FIGO) current guidelines,9 is recommended to treat endometrial cancer, even in early-stage and low-grade carcinomas,10 and an extended pelvic surgery is advisable in the treatment of second-stage disease.11 Appropriate surgery for endometrial carcinoma leads to more rational, effective, and cost-saving selection of patients scheduled to undergo adjuvant therapy. Therefore a differential diagnosis between endometrial atypical hyperplasia and carcinoma is of great clinical relevance, but, as referenced above, a poor sensitivity endometrial sampling technique, such as dilation and curettage, cannot be considered reliable. The current standard procedure for investigation of endometrial pathologies is based on hysteroscopy with endometrial biopsy.12 The visual assessment of the endometrial cavity, coupled with “oriented” or “targeted” tissue collection, improves the accuracy of blind sampling procedures in the diagnosis of submucosal fibroids,13 polyps,14 focal hyperplasias or carcinomas,12,15 and endometrial atrophy.16 The sensitivity and the positive predictive value of the hysteroscopic view to detect endometrial hyperplasia have been reported as low, mainly because of the unreliable visual criteria currently used for this diagnosis.15,17 Nevertheless, a higher diagnostic accuracy of hysteroscopic view to detect endometrial carcinoma is generally reported,15,18 on the basis of a more substantial and specific disruption of endouterine architecture associated with malignant endometrial growth.19,20 The purpose of this retrospective study is to estimate the accuracy of hysteroscopic imaging to predict concurrent infiltrating carcinomas in menopausal patients with atypical hyperplasia diagnosed by endometrial biopsy.
Patients and methods Patient selection
per year. We reviewed all hysteroscopic reports from January 2002 to October 2005 of patients in whom endometrial atypical hyperplasia was diagnosed, on the basis of the biopsy specimen sampled at the end of the hysteroscopic inspection. Twenty-five of 28 patients with this diagnosis underwent hysterectomy at our gynecology department; the histopathologic findings on uterine specimens of these 25 patients were compared with the diagnoses on the basis of the hysteroscopic view. Twelve patients selected in this series were also included in previously published studies.17,21
Hysteroscopy All patients underwent outpatient hysteroscopy with a 5 mm-sheathed hysteroscope tipped with a 30-degree lens with a 1.5 mm working channel (Karl Storz, Tuttlingen, Germany). Normal saline solution was used as a liquid distension medium, and it was delivered by an irrigating suction device, setting endouterine pressure below 120 mm Hg and endouterine flow below 100 mL/min; all examinations were video assisted. As a rule, no systemic analgesia or local anesthetic was administered, and the vaginoscopic technique was used.22 At the patient’s request, in case of anxiety or when a cervical inspection suggested that a cervical stenosis too difficult to overcome without inducing significant pelvic pain, anesthetic paracervical block was performed before the procedure was started.
Hysteroscopic classification Hysteroscopic-view diagnosis was reported according to previously published criteria.18 Briefly, the following hysteroscopic findings were considered normal: an evenly thin, atrophic endometrium; an atrophic endometrium with focal mucous-containing cysts covered by a thin endometrium; or a functional, proliferative or secretory endometrium with no focal features of endometrial hyperplasia (see below). The following findings were considered abnormal: endometrial polyp, diagnosed as broad-based or pedunculated focal mucosal projection measuring more than 0.5 cm, with no associated features suggesting endometrial hyperplasia or carcinoma; endometrial hyperplasia, defined as focal or extensive, polypoid or papillary mucosal thickening with or without finding of gland cysts, abnormal vascular network, crowded or abnormally-spaced gland openings; endometrial carcinoma, classified according to Sugimoto, in papillary, polypoid, nodular or mixed endometrial growth,19 showing a friable consistency, focal necrosis, and atypical vessels.
In the outpatient hysteroscopy department at Lodi Hospital (Italy), we perform about 250 diagnostic procedures
Endometrial sampling and pathologic assessment
Corresponding author: Giancarlo Garuti, MD, Obstetrics and Gynecology Department, Lodi Hospital, via Savoia no. 1, 26900-Lodi, Italy. [email protected] Submitted December 17, 2005. Accepted for publication March 12, 2006.
Endometrial tissue sampling was carried out in all cases following Loffer’s recommendations16; accordingly, we avoided tissue sampling only when a good visualization was obtained, and a normal uterine shape associated with a
Garuti et al
Atypical endometrial hyperplasias
uniform thin endometrium was found. Focal lesions were sampled under visual guidance by hysteroscopic mechanical instrumentation (scissors for fashioning the tissue sample and grasping forceps for its extraction) through the working channel of hysteroscope. “Excisional” biopsy was attempted for small lesions, generally suspected of focal hyperplasias, whereas an “incisional” biopsy was fashioned for larger endometrial polypoid protrusions suggesting an endometrial cancer. During the same outpatient procedure, polyps were removed by mechanical or bipolar electrosurgical (Versapoint, Menlo Park, Calif) resection of the pedicle at the endometrial-myometrial junction.23 When extensive features of abnormal endometrial thickening were found, we targeted the hysteroscopically-guided biopsy specimens to the most “suspicious” mucosal abnormality suggesting an underlying endometrial hyperplasia or neoplasia, but in these cases we also performed a blind sampling by Vabra suction-curettage or by Novak’s curette. Endometrial biopsy specimens were sent to the pathologist in 1 or more vials, depending on the number of collected tissue specimens, and classified with the method described by Buckley and Fox.24
Results Age, parity, and body mass index of the 25 patients forming the group of study, expressed as mean ⫾ standard deviation were 61.0 ⫾ 6.1 years, 1.7 ⫾ 0.8, and 29.5 ⫾ 5.2, respectively. All patients were menopausal; in 24 of them menopause occurred physiologically and in a 39-year-old woman the menopausal status was chemotherapy-induced because of a previous treatment for breast cancer. Three patients were symptom free: in one of them hysteroscopy was indicated as a scheduled follow-up of simple endometrial hyperplasia, and in the other 2 patients it was due to an increased endometrial thickness incidentally found at transvaginal ultrasonography. In the other 22 patients, hysteroscopy was indicated because of abnormal uterine bleeding and an endometrial thickness measured above 4 mm by transvaginal ultrasonography. Six women were affected by breast cancer, and 4 of them were treated with tamoxifen. Severe morbidities such as obesity, diabetes, and hypertension were found in 9 patients (36.0%). Hysteroscopic view diagnosis, endometrial sampling methods, pathologic findings on endometrial biopsy, type of hysterectomy accomplished and definitive pathology on the uterine specimen obtained in each patient are specified in Table 1. In all patients hysteroscopic inspection showed an abnormal endometrium; endometrial hyperplasia, endometrial polyp, and endometrial carcinoma were diagnosed by hysteroscopic view in 8, 8, and 9 cases, respectively. A diagnosis of simple atypical hyperplasia was given in 1 patient with a hysteroscopic report of endometrial polyp, whereas complex atypical hyperplasias were found in the remaining 24 patients. On the uterine specimens non-atypical simple and
327 complex hyperplasias were found in 1 and 2 patients, respectively, whereas complex atypical hyperplasia was confirmed on hysterectomy specimens of 11 patients. In all 14 patients with endometrial hyperplasia on hysterectomy specimen, hysteroscopy reported no suspected findings of malignancy, and it was consistent with endometrial polyps (8 cases) or hyperplasias (6 cases). Infiltrating endometrial adenocarcinomas, all of endometrioid histotype, were found on the uterine specimens of 11 patients (44.0%). In 9 of them (81.8%) hysteroscopy correctly predicted the diagnosis of malignancy. Among the 16 patients not suspected of having cancer under hysteroscopy, an infiltrating endometrial carcinoma was found in 2 cases (12.5%). Endometrial hyperplasia was recorded by hysteroscopy in these 2 patients, whereas a pathologic diagnosis of well-differentiated, intramucous carcinoma was found in both uterine specimens (Table 1). Both patients underwent hysteroscopy because of intervening vaginal bleeding during tamoxifen administration for breast cancer, lasting 12 months and 8 months from a previous normal endometrial ultrasonographic work-up, carried out for routine endometrial surveillance. Three patients with endometrial carcinoma spreading to endocervical stroma (2 patients) and showing a moderately differentiated carcinoma with myometrial invasion of more than 50% (1 patient) underwent adjuvant radiotherapy (Table 1). According to these figures, to foresee the diagnosis of carcinomas underestimated as atypical hyperplasias by endometrial biopsy, hysteroscopic inspection provides specificity, sensitivity, positive predictive value, and negative predictive value of 100%, 84.6%, 100%, and 87.5%, respectively.
Discussion In agreement with the high false-negative rates reported by other authors,1–5 in this series we found that endometrial biopsy resulting in a diagnosis of atypical hyperplasia failed to sample a concurrent infiltrating carcinoma in 44.0% of patients. In spite of the performance of hysteroscopically targeted biopsy, our results did not improve the high rates of carcinomas undetected by using blind tissue collection.1–5 On biopsy specimens, the distinction between well-differentiated carcinomas and atypical hyperplasias, on the basis of distortion of glands architecture and cytologic atypia, is neither simple nor reproducible even by experienced pathologists,25 and the detection of stromal or myometrial invasion might be the sole finding suggesting an infiltrating disease.6,26 In several patients with endometrial cancer, myometrial tissue but also endometrial stromal tissue can be unavailable or poorly represented in curettage or biopsy specimens24; in addition, atypical hyperplasia is often found beside type I infiltrating endometrial carcinoma.27 Probably, the high rates of undetected carcinomas in patients showing atypical hyperplasia on endometrial biopsy specimens are
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Table 1 Hysteroscopic-view diagnoses, tissue sampling modalities, pathologic findings on endometrial biopsy, type of hysterectomy, and histopathologic study on the hysterectomy specimens are detailed for all 25 patients showing atypical hyperplasia on endometrial biopsy
Patients
Hysteroscopic-view diagnosis
Tissue sampling
1
Focal hyperplasia
Targeted biopsy
2
Polyp
Polypectomy
3
Polyp
Polypectomy
4
Focal hyperplasia
Targeted biopsy
5
Polyp
Polypectomy
6
Polyp
Polypectomy
7
Polyp
Polypectomy
8
Polyp
Polypectomy
9
Focal hyperplasia
Targeted biopsy
10
Polyp
Polypectomy
11
Extensive hyperplasia
12
Polyp
Targeted biopsy-Vabra Polypectomy
13
Focal hyperplasia
Targeted biopsy
14
Extensive hyperplasia
15
Polypoid carcinoma
Targeted biopsy - Vabra Targeted biopsy
16
Focal hyperplasia
Targeted biopsy
17
Extensive hyperplasia
18
Focal nodular carcinoma
Targeted biopsy-Vabra Targeted biopsy
19 20
Mixed papillary-polypoid carcinoma Polypoid carcinoma
21
Polypoid carcinoma
22
Papillary carcinoma
23 (BER)
Papillary carcinoma
24 (BER-BRT)
Polypoid carcinoma with isthmus extension Polypoid carcinoma with endocervical extension
25 (BER-BRT)
Targeted biopsy-Vabra Targeted biopsy-Novak Targeted biopsy-Vabra Targeted biopsy-Vabra Targeted biopsy Targeted biopsy-Vabra Targeted biopsy-Vabra
Pathologic study on endometrial biopsy Complex atypical hyperplasia Simple atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia Complex atypical hyperplasia
Type of hysterectomy
Pathologic study on uterine specimen
VH-BA
Complex atypical hyperplasia
VH
Simple hyperplasia
VH
Complex hyperplasia
LAVH-BA
Complex atypical hyperplasia
VH-BA
Complex atypical hyperplasia
VH-BA
Complex atypical hyperplasia
VH-BA
Complex atypical hyperplasia
LAVH-BA
Complex atypical hyperplasia
VH
Complex atypical hyperplasia
VH-BA
Complex atypical hyperplasia
VH-BA
Complex atypical hyperplasia
VH-BA
Complex hyperplasia
VH-BA
Complex atypical hyperplasia
VH
Complex atypical hyperplasia
LAVH-BA
Adenocarcinoma I°A/G2/Nx
VH-BA
Adenocarcinoma I°A/G1/Nx
VH
Adenocarcinoma I°A/G1/Nx
LAVH-BA
Adenocarcinoma I°B/G1/Nx
VH
Adenocarcinoma I°B/G1/Nx
TAH-BA
Adenocarcinoma I°B/G2/Nx
TAH-BA
Adenocarcinoma I°B/G2/Nx
TAH-BA
Adenocarcinoma I°B/G2/Nx
VH-BA
Adenocarcinoma I°C/G2/Nx
LAVH-BA
Adenocarcinoma II°B/G2/Nx
VH
Adenocarcinoma II°B/G2/Nx
The stages of 11 endometrial carcinomas incidentally found on hysterectomy specimens are arbitrarily assigned on the basis of the depth of myometrial infiltration and spreading to the endocervix. BER ⫽ adjuvant beam external radiotherapy; BRT ⫽ adjuvant brachytherapy; VH ⫽ vaginal hysterectomy; VH-BA ⫽ vaginal hysterectomy with bilateral adnexectomy; TAH-BA ⫽ total abdominal hysterectomy with bilateral adnexectomy; LAVH-BA ⫽ laparoscopically-assisted vaginal hysterectomy with bilateral adnexectomy.
Garuti et al
Atypical endometrial hyperplasias
based on these technical and biologic reasons. The high rate of undetected carcinomas found also by hysteroscopicallyguided biopsy specimens can be mainly related to our common practice of targeting the sampling at the most superficial layers of a mass protruding within the uterine cavity, because of an easier and quicker fashioning of the specimen, but possibly causing a poor sampling of the underlying stromal tissue. In addition, the mechanical handling of a friable neoplastic tissue causes its fragmentation, particularly by use of grasping hysteroscopic forceps for specimen’s extraction, leading to suboptimal quality of tissue samples examined by the pathologist. Furthermore, the easy bleeding of a neoplastic mass caused by the hysteroscopic instrumentation is often responsible for obscured hysteroscopic vision, even with liquid distension medium, and it can consequently lead, mainly in an outpatient setting, to suboptimal specimen collection. The hysteroscopic appearance of an endometrial carcinoma is quite typical, and this visual diagnosis is generally based on the presence of a gross distortion of endometrial cavity, because of focal or extensive nodular, polypoid, papillary or mixed patterns of neoplastic growth.19 Focal necrosis, friable consistency, and atypical vessels are other features almost invariably associated with endometrial cancer and easily detected by hysteroscopic inspection.18,20 By using these visual criteria, we found a 100% positive predictive value and 100% specificity of hysteroscopic view to diagnose endometrial carcinomas underestimated by biopsy finding of atypical hyperplasia. By hysteroscopic inspection, we underestimated 2 intramucous carcinomas as endometrial hyperplasia. This finding might be related to the early stage of neoplasias, influencing the lack of gross endometrial distortion associated with more advanced carcinomas and showing hysteroscopic features possibly overlapping on some ones considered specific of hyperplasia. These underestimated diagnoses led negative predictive values (87.5%) and sensitivity (84.6%) of hysteroscopy to be less than optimal in excluding an endometrial carcinoma when the visual findings are consistent with endometrial hyperplasia. To our knowledge, there is only 1 report in the current literature evaluating the prevalence of malignancy among patients with hysteroscopic view evocative of benign pathologic condition and resulting in a diagnosis of atypical hyperplasias on endometrial biopsy. Similar to our 12.5% false-negative findings, Agostini et al,28 in a series of 17 patients, found a 5.9% rate of cancer when atypical hyperplasia was incidentally diagnosed on hysteroscopic resection products, when no hysteroscopic features suggested an endometrial cancer. The presented findings suggest that when appropriate hysteroscopic facilities are available, an inspective diagnosis of endometrial cancer should be considered by the pelvic surgeon as highly predictive of malignancy, in spite of a pathologic finding of atypical hyperplasia previously obtained by endometrial biopsy. We believe that in these cases a repeat endometrial sampling should be considered, partic-
329 ularly in patients with hysteroscopic imaging consistent with neoplastic endocervical spread or for which a conservative surgical or medical treatment is planned. In patients who are candidates for hysterectomy, intraoperative frozen sections of uterine specimen are recommended, and the type of surgery should be planned to allow adequate modulation, faced with a highly probable concurrent infiltrating carcinoma.
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