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Embolic Vascular Seeding of Endometrial Adenocarcinoma, a Complication of Hysteroscopic Endometrial Biopsy
Gynecologic Oncology 72, 261–264 (1999) Article ID gyno.1998.5249, available online at http://www.idealibrary.com on
CASE REPORT Embolic Vascular Seeding of Endometrial Adenocarcinoma, a Complication of Hysteroscopic Endometrial Biopsy Ronald D. Workman, M.D.,* Douglas S. Wong, M.D.,† and William C. Pitts, M.D.‡ *Department of Pathology and Laboratory Medicine, St. Francis Health System, 400 45th Street, Pittsburgh, Pennsylvania 15201; and †Department of Radiation Oncology and ‡Department of Pathology/Clinical Laboratories, Community Health System, Fresno, California 93721 Received September 21, 1998
Objective. A case of embolic vascular seeding of endometrial adenocarcinoma following hysteroscopy is reported. Methods. This phenomenon was recognized in the uterus specimen from a hysterectomy performed 1 week after hysteroscopic endometrial biopsy. Tissue processing artifact was excluded. Results. Since the patient was otherwise low risk, treatment was limited to hysterectomy. The patient was not given adjuvant therapy. Two years later she remains alive and well with no evidence of disease. The surgical, morphologic, and clinical features of this case are presented and illustrated. Conclusion. Previous reports of peritoneal tumor seeding associated with hysteroscopy are reviewed. Tumor embolization during hysteroscopic endometrial biopsy was not followed by tumor recurrence in this case. © 1999 Academic Press Key Words: hysteroscopy; neoplasm seeding; neoplasm staging; endometrial neoplasms; adenocarcinoma.
expected to have pelvic or periaortic node metastasis [1], they and other low-risk patients with Stage I cancer are generally treated by simple hysterectomy. Stage I neoplasms predominate in most series of endometrial cancer. Although hysteroscopy is an attractive technique, uterine perforation [2] or reflux of endometrial tissue [3] may rarely accompany it. Therefore, procedure-related spread of malignant cells in otherwise lowrisk patients is a potential source of concern. We report a case of intravascular endometrial cancer in a patient that was apparently due to tumor embolism during hysteroscopy. The relationship of this and other posthysteroscopy findings to cancer recurrence and survival is discussed. It is hoped this report may lead to wider recognition of this phenomenon to avoid confusion with true vascular invasion. CASE REPORT
INTRODUCTION Endometrial adenocarcinoma is the most common gynecologic malignancy. The disease often presents with abnormal uterine bleeding. Fractional dilatation and curettage has long been employed as a means of obtaining diagnostic endometrial tissue. Hysteroscopy is a newer endometrial biopsy technique using continuous saline irrigation or CO 2, wherein the uterus is dilated under pressure and the endometrium examined with direct visualization. This approach enables the surgeon to biopsy any suspicious areas directly. Hysteroscopy represents a possible improvement in diagnostic accuracy over traditional dilatation and curettage. Although curettage is meant to provide a thorough examination of the endometrial tissue, in practice there may be limitations of sampling due to individual variations in anatomy or location of neoplastic tissue, myomata, difficulties of dilatation, or other factors. Thus, hysteroscopy is being increasingly employed to assure the sampling of diagnostic areas of the endometrium and offers the potential to improve early diagnosis of endometrial cancer. Since patients with grade I endometrial-only cancer are not
A 52-year-old woman presented to her gynecologist with menstrual irregularities, having recently relocated to the area. She related a 10-year history of irregular menstrual flow with hot flashes and mood swings. Past estrogen and progesterone therapies were poorly tolerated and only taken intermittently. She reported several prior difficult endometrial biopsies showing “hyperplasia.” Her intolerance of exogenous medication had led her to seek alternative health care maintenance, including acupuncture. Physical examination revealed no abnormalities, and the uterus was not enlarged on pelvic examination. The vaginal examination was unremarkable. Her gynecologist recommended hysteroscopy with dilatation and curettage. This procedure was carried out on 10/23/95 with endometrial biopsy. No complications or unusual aspects of the hysteroscopy procedure were described. The pathology specimen received in the laboratory consisted of 4 –5 cc of gray–red tissue fragments and blood. The specimen was submitted in its entirety for histologic examination. Microscopically, the endometrium showed several foci of cribriform, back-to-back glandular growth pattern, with stratification of the nuclei and minimal
261
0090-8258/99 $30.00 Copyright © 1999 by Academic Press All rights of reproduction in any form reserved.
262
WORKMAN, WONG, AND PITTS
FIG. 1. Left uterine cornua. There are enlarged, angular glands with a complex growth pattern. Nuclear stratification and morphologic variability are present. Cytologic atypia is mild. These findings are interpreted as endometrioid adenocarcinoma, grade I.
cytologic atypia. The diagnosis given was endometrial adenocarcinoma, well-differentiated, grade I. Abdominal/pelvic magnetic resonance imaging was performed on 10/25/95; no retroperitoneal adenopathy was described but an 8-mm nodule was noted within the endometrial cavity. The uterus was not enlarged and there was no radiologic evidence of myometrial invasion. On 10/30/95, she underwent laparoscopic-assisted total abdominal hysterectomy and bilateral salpingo-oophorectomy. No extrauterine disease was identified at the time of surgery. The hysterectomy specimen received in the laboratory consisted of a grossly unremarkable uterus, with attached fallopian tubes and ovaries. After the adnexal structures were removed, the uterus weighed 84 g. It had a normal pyriform shape. The endometrial cavity measured 5.0 cm in length. In the left cornual region, the endometrium was slightly thickened and friable. The remainder of the endometrium was generally smooth. The myometrium showed a somewhat indurated region in the left cornual area and a gray nodular area in the right cornual area, resembling adenomyosis. There was no gross evidence of myometrial tumor invasion. The fallopian tubes were unremarkable. The left and right ovaries measured 2.5 and 3.0 cm, respectively, and showed tiny serous cysts. The microscopic sections of the uterus showed focal endometrioid adenocarcinoma with mild cytologic atypia (Fig. 1), correlating with the endometrial biopsy. There were multiple foci of adenomyosis. There was no evidence of myometrial invasion. However, there were numerous, larger myometrial blood vessels containing tumor epithelium (Fig. 2). This was observed on several microscopic sections as well as on deeper levels cut from the paraffin blocks. The fragments of intravas-
cular tumor tissue were sometimes wedged into involved vessels and apparently adherent to the vessel wall. Some showed areas of cellular degeneration resembling autolysis (Fig. 3). Most intravascular fragments showed relatively abundant inflammatory cells. The intravascular tumor tissue did not have significant cytologic atypia. Initially thought to represent vascular invasion of the carcinoma, these findings resulted in referral of the patient for oncology evaluation. The patient was referred to radiation oncology for consideration of adjuvant radiation therapy. The case history and clinical, radiologic, and pathologic findings were reviewed by the authors. Angioinvasion of endometrial carcinoma was considered to be distinctly unusual in a grade I endometrial adenocarcinoma without deep myometrial invasion. Moreover, in this case the endometrial adenocarcinoma did not appear to be extensive within the endometrium and the uterus was not enlarged. The microscopic appearance of the intravascular tumor, described above, resembled what one might expect in an embolic phenomenon; it did not show the tight, compact clusters of atypical cells usually seen in true angioinvasion. After consultation with the patient’s gynecologist, conservative follow-up was recommended. No adjuvant therapy was given. She subsequently recovered to her usual state of health, had no further vaginal bleeding, and has been followed by periodic examinations. She remains alive 2 years after diagnosis of endometrial adenocarcinoma, with no evidence of disease. DISCUSSION To our knowledge, this is the first reported case of hysteroscopy-related embolization of endometrial carcinoma. The
CASE REPORT
263
FIG. 2. Intravascular tumor embolus. Several myometrial blood vessels contain fragments of neoplastic glandular tissue. Some tumor fragments are wedged into vascular clefts. Note accompanying inflammatory cells.
nature of the abnormality was recognized primarily by its microscopic appearance. There were larger fragments of endometrioid glandular tissue in the vessels, not small clusters of epithelial cells as expected in true angioinvasion. All were
located exclusively within vessels. Some were wedged into involved vessels and adherent to the vessel wall. The embolic tissue also showed cellular degeneration and increased inflammatory cells, consistent with the approximately 1-week inter-
FIG. 3. Intramural uterine vessel. There are fragments of glandular tumor tissue within a uterine vessel. One such fragment is adherent to the vessel wall. There is autolysis of the neoplastic cells.
264
WORKMAN, WONG, AND PITTS
val between the hysteroscopic endometrial biopsy and subsequent hysterectomy. The presence of the abnormality in multiple sections from several paraffin-embedded tissue blocks excludes tissue processing artifact. With true lymphatic/vascular space invasion, there is a relationship to depth of myometrial involvement and the stage of the disease [4]. There is a significant correlation of such invasion with tumor recurrence [5]. The finding of vascular invasion should be considered, along with other tumor-related risk factors, in planning the treatment of individual patients [6]. In 1992, Romano et al. reported a case of positive peritoneal cytology following hysteroscopic diagnosis of papillary adenocarcinoma of the endometrium with minimal stromal invasion [7]. This patient developed recurrence of adenocarcinoma in the vaginal stump 1 year later. In 1994, Schmitz and Nahhas reported a patient with peritoneal cytology positive for endometrial carcinoma at hysterectomy, 3 weeks after hysteroscopic diagnosis [8]. In 1996, Egarter et al. reported a negative peritoneal cytology examination before, and positive cytology after, hysteroscopy [9]. Their samples were obtained by washing the peritoneal cavity with saline. All these authors expressed concern that these events may change the patient’s prognosis. All questioned whether hysteroscopy should be recommended in cases of suspected endometrial cancer. Neis et al. [10] published a longitudinal study of the effect of hysteroscopy on prognosis of patients with endometrial carcinoma in 1994. These authors studied 154 endometrial carcinoma patients diagnosed by CO 2 hysteroscopy in Germany. For 118 of these patients, the subsequently resected fallopian tubes were subjected to thorough histologic examination. In 1 such patient, a single tumor cell complex was detected inside the ampullar part of a fallopian tube. The patients in this study showed the same 5-year survival rates and frequency of relapse as those in other literature reports. This study was interpreted by the authors as proving that the prognosis of endometrial carcinoma is not worsened by hysteroscopy. Pathologic findings of vascular invasion appropriately lead to the consideration of adjuvant therapy. However, oncologists should be cautious about a diagnosis of angioinvasion in otherwise low-risk endometrial cancer when discovered after re-
cent hysteroscopic biopsy. For pathologists, this case illustrates a potential pitfall of histologic diagnosis. Apparent angioinvasion associated with localized, low-grade endometrial carcinoma should prompt a thorough evaluation of the microscopic findings. Recognition of procedure-related tumor involvement of vessels may potentially spare patients with low-risk endometrial carcinoma from unnecessary postoperative therapy. Although concerns have been raised, there is at present no adverse prognostic implication associated with hysteroscopic biopsy of endometrial carcinoma. Our case with 2-year follow-up indicates that tumor embolization during hysteroscopic endometrial biopsy may not lead to tumor recurrence. The long-term prognosis of such patients may be more confidently understood if additional cases are identified. REFERENCES 1. Creasman WT, Morrow CP, Bundy BN, et al.: Surgical pathologic spread patterns of endometrial cancer, a Gynecologic Oncology Group study. Cancer 60:2035–2041, 1987 2. Cayuela E, Cos It, Onbargi L, et al.: Complications of operative hysteroscopy. J Am Assoc Gynecol Laparosc 3:(4, Suppl):S6, 1996 3. Nagel TC, Kopher RA, Tagate GE, et al.: Tubal Reflux of Endometrial Tissue During Hysteroscopy. in Sigler AM, Lindemann HI (eds): Hysteroscopy: Principles and Practice. Philadelphia, Lippincott, 1984, p 45 4. Sivridis E, Buckley CH, Fox H: The prognostic significance of lymphatic vascular space invasion in endometrial adenocarcinoma. Brit J Obstet Gynecol 94:991–994, 1987 5. Hanson MB, Van Nagell JR, Powell DE, et al.: The prognostic significance of lymph–vascular space invasion in stage I endometrial cancer. Cancer 55:1753–1757, 1985 6. Kadar N, Malfefano IH, Homesley RD: Determinants of survival of surgically staged patients with endometrial carcinoma histologically confined to the uterus: implications for therapy. Obstet Gynecol 80:655– 659, 1992 7. Romano S, Shimoni Y, Muralee D, Shalev E: Retrograde seeding of endometrial carcinoma during hysteroscopy. Gynecol Oncol 44:116 –118, 1992 8. Schmitz MJ, Nahhas WA: Hysteroscopy may transport malignant cells into the peritoneal cavity. Eur J Gynecol Oncol 15:121–124, 1994 9. Egarter C, Krestan C, Kurz C: Abdominal dissemination of malignant cells with hysteroscopy. Gynecol Oncol 63:143–144, 1996 10. Neis KJ, Brandner P, Keppeler U: Tumor cell seeding caused by hysteroscopy. Geburtshilfe Frauenheilkd 12:651– 655, 1994
CASE REPORT Embolic Vascular Seeding of Endometrial Adenocarcinoma, a Complication of Hysteroscopic Endometrial Biopsy Ronald D. Workman, M.D.,* Douglas S. Wong, M.D.,† and William C. Pitts, M.D.‡ *Department of Pathology and Laboratory Medicine, St. Francis Health System, 400 45th Street, Pittsburgh, Pennsylvania 15201; and †Department of Radiation Oncology and ‡Department of Pathology/Clinical Laboratories, Community Health System, Fresno, California 93721 Received September 21, 1998
Objective. A case of embolic vascular seeding of endometrial adenocarcinoma following hysteroscopy is reported. Methods. This phenomenon was recognized in the uterus specimen from a hysterectomy performed 1 week after hysteroscopic endometrial biopsy. Tissue processing artifact was excluded. Results. Since the patient was otherwise low risk, treatment was limited to hysterectomy. The patient was not given adjuvant therapy. Two years later she remains alive and well with no evidence of disease. The surgical, morphologic, and clinical features of this case are presented and illustrated. Conclusion. Previous reports of peritoneal tumor seeding associated with hysteroscopy are reviewed. Tumor embolization during hysteroscopic endometrial biopsy was not followed by tumor recurrence in this case. © 1999 Academic Press Key Words: hysteroscopy; neoplasm seeding; neoplasm staging; endometrial neoplasms; adenocarcinoma.
expected to have pelvic or periaortic node metastasis [1], they and other low-risk patients with Stage I cancer are generally treated by simple hysterectomy. Stage I neoplasms predominate in most series of endometrial cancer. Although hysteroscopy is an attractive technique, uterine perforation [2] or reflux of endometrial tissue [3] may rarely accompany it. Therefore, procedure-related spread of malignant cells in otherwise lowrisk patients is a potential source of concern. We report a case of intravascular endometrial cancer in a patient that was apparently due to tumor embolism during hysteroscopy. The relationship of this and other posthysteroscopy findings to cancer recurrence and survival is discussed. It is hoped this report may lead to wider recognition of this phenomenon to avoid confusion with true vascular invasion. CASE REPORT
INTRODUCTION Endometrial adenocarcinoma is the most common gynecologic malignancy. The disease often presents with abnormal uterine bleeding. Fractional dilatation and curettage has long been employed as a means of obtaining diagnostic endometrial tissue. Hysteroscopy is a newer endometrial biopsy technique using continuous saline irrigation or CO 2, wherein the uterus is dilated under pressure and the endometrium examined with direct visualization. This approach enables the surgeon to biopsy any suspicious areas directly. Hysteroscopy represents a possible improvement in diagnostic accuracy over traditional dilatation and curettage. Although curettage is meant to provide a thorough examination of the endometrial tissue, in practice there may be limitations of sampling due to individual variations in anatomy or location of neoplastic tissue, myomata, difficulties of dilatation, or other factors. Thus, hysteroscopy is being increasingly employed to assure the sampling of diagnostic areas of the endometrium and offers the potential to improve early diagnosis of endometrial cancer. Since patients with grade I endometrial-only cancer are not
A 52-year-old woman presented to her gynecologist with menstrual irregularities, having recently relocated to the area. She related a 10-year history of irregular menstrual flow with hot flashes and mood swings. Past estrogen and progesterone therapies were poorly tolerated and only taken intermittently. She reported several prior difficult endometrial biopsies showing “hyperplasia.” Her intolerance of exogenous medication had led her to seek alternative health care maintenance, including acupuncture. Physical examination revealed no abnormalities, and the uterus was not enlarged on pelvic examination. The vaginal examination was unremarkable. Her gynecologist recommended hysteroscopy with dilatation and curettage. This procedure was carried out on 10/23/95 with endometrial biopsy. No complications or unusual aspects of the hysteroscopy procedure were described. The pathology specimen received in the laboratory consisted of 4 –5 cc of gray–red tissue fragments and blood. The specimen was submitted in its entirety for histologic examination. Microscopically, the endometrium showed several foci of cribriform, back-to-back glandular growth pattern, with stratification of the nuclei and minimal
261
0090-8258/99 $30.00 Copyright © 1999 by Academic Press All rights of reproduction in any form reserved.
262
WORKMAN, WONG, AND PITTS
FIG. 1. Left uterine cornua. There are enlarged, angular glands with a complex growth pattern. Nuclear stratification and morphologic variability are present. Cytologic atypia is mild. These findings are interpreted as endometrioid adenocarcinoma, grade I.
cytologic atypia. The diagnosis given was endometrial adenocarcinoma, well-differentiated, grade I. Abdominal/pelvic magnetic resonance imaging was performed on 10/25/95; no retroperitoneal adenopathy was described but an 8-mm nodule was noted within the endometrial cavity. The uterus was not enlarged and there was no radiologic evidence of myometrial invasion. On 10/30/95, she underwent laparoscopic-assisted total abdominal hysterectomy and bilateral salpingo-oophorectomy. No extrauterine disease was identified at the time of surgery. The hysterectomy specimen received in the laboratory consisted of a grossly unremarkable uterus, with attached fallopian tubes and ovaries. After the adnexal structures were removed, the uterus weighed 84 g. It had a normal pyriform shape. The endometrial cavity measured 5.0 cm in length. In the left cornual region, the endometrium was slightly thickened and friable. The remainder of the endometrium was generally smooth. The myometrium showed a somewhat indurated region in the left cornual area and a gray nodular area in the right cornual area, resembling adenomyosis. There was no gross evidence of myometrial tumor invasion. The fallopian tubes were unremarkable. The left and right ovaries measured 2.5 and 3.0 cm, respectively, and showed tiny serous cysts. The microscopic sections of the uterus showed focal endometrioid adenocarcinoma with mild cytologic atypia (Fig. 1), correlating with the endometrial biopsy. There were multiple foci of adenomyosis. There was no evidence of myometrial invasion. However, there were numerous, larger myometrial blood vessels containing tumor epithelium (Fig. 2). This was observed on several microscopic sections as well as on deeper levels cut from the paraffin blocks. The fragments of intravas-
cular tumor tissue were sometimes wedged into involved vessels and apparently adherent to the vessel wall. Some showed areas of cellular degeneration resembling autolysis (Fig. 3). Most intravascular fragments showed relatively abundant inflammatory cells. The intravascular tumor tissue did not have significant cytologic atypia. Initially thought to represent vascular invasion of the carcinoma, these findings resulted in referral of the patient for oncology evaluation. The patient was referred to radiation oncology for consideration of adjuvant radiation therapy. The case history and clinical, radiologic, and pathologic findings were reviewed by the authors. Angioinvasion of endometrial carcinoma was considered to be distinctly unusual in a grade I endometrial adenocarcinoma without deep myometrial invasion. Moreover, in this case the endometrial adenocarcinoma did not appear to be extensive within the endometrium and the uterus was not enlarged. The microscopic appearance of the intravascular tumor, described above, resembled what one might expect in an embolic phenomenon; it did not show the tight, compact clusters of atypical cells usually seen in true angioinvasion. After consultation with the patient’s gynecologist, conservative follow-up was recommended. No adjuvant therapy was given. She subsequently recovered to her usual state of health, had no further vaginal bleeding, and has been followed by periodic examinations. She remains alive 2 years after diagnosis of endometrial adenocarcinoma, with no evidence of disease. DISCUSSION To our knowledge, this is the first reported case of hysteroscopy-related embolization of endometrial carcinoma. The
CASE REPORT
263
FIG. 2. Intravascular tumor embolus. Several myometrial blood vessels contain fragments of neoplastic glandular tissue. Some tumor fragments are wedged into vascular clefts. Note accompanying inflammatory cells.
nature of the abnormality was recognized primarily by its microscopic appearance. There were larger fragments of endometrioid glandular tissue in the vessels, not small clusters of epithelial cells as expected in true angioinvasion. All were
located exclusively within vessels. Some were wedged into involved vessels and adherent to the vessel wall. The embolic tissue also showed cellular degeneration and increased inflammatory cells, consistent with the approximately 1-week inter-
FIG. 3. Intramural uterine vessel. There are fragments of glandular tumor tissue within a uterine vessel. One such fragment is adherent to the vessel wall. There is autolysis of the neoplastic cells.
264
WORKMAN, WONG, AND PITTS
val between the hysteroscopic endometrial biopsy and subsequent hysterectomy. The presence of the abnormality in multiple sections from several paraffin-embedded tissue blocks excludes tissue processing artifact. With true lymphatic/vascular space invasion, there is a relationship to depth of myometrial involvement and the stage of the disease [4]. There is a significant correlation of such invasion with tumor recurrence [5]. The finding of vascular invasion should be considered, along with other tumor-related risk factors, in planning the treatment of individual patients [6]. In 1992, Romano et al. reported a case of positive peritoneal cytology following hysteroscopic diagnosis of papillary adenocarcinoma of the endometrium with minimal stromal invasion [7]. This patient developed recurrence of adenocarcinoma in the vaginal stump 1 year later. In 1994, Schmitz and Nahhas reported a patient with peritoneal cytology positive for endometrial carcinoma at hysterectomy, 3 weeks after hysteroscopic diagnosis [8]. In 1996, Egarter et al. reported a negative peritoneal cytology examination before, and positive cytology after, hysteroscopy [9]. Their samples were obtained by washing the peritoneal cavity with saline. All these authors expressed concern that these events may change the patient’s prognosis. All questioned whether hysteroscopy should be recommended in cases of suspected endometrial cancer. Neis et al. [10] published a longitudinal study of the effect of hysteroscopy on prognosis of patients with endometrial carcinoma in 1994. These authors studied 154 endometrial carcinoma patients diagnosed by CO 2 hysteroscopy in Germany. For 118 of these patients, the subsequently resected fallopian tubes were subjected to thorough histologic examination. In 1 such patient, a single tumor cell complex was detected inside the ampullar part of a fallopian tube. The patients in this study showed the same 5-year survival rates and frequency of relapse as those in other literature reports. This study was interpreted by the authors as proving that the prognosis of endometrial carcinoma is not worsened by hysteroscopy. Pathologic findings of vascular invasion appropriately lead to the consideration of adjuvant therapy. However, oncologists should be cautious about a diagnosis of angioinvasion in otherwise low-risk endometrial cancer when discovered after re-
cent hysteroscopic biopsy. For pathologists, this case illustrates a potential pitfall of histologic diagnosis. Apparent angioinvasion associated with localized, low-grade endometrial carcinoma should prompt a thorough evaluation of the microscopic findings. Recognition of procedure-related tumor involvement of vessels may potentially spare patients with low-risk endometrial carcinoma from unnecessary postoperative therapy. Although concerns have been raised, there is at present no adverse prognostic implication associated with hysteroscopic biopsy of endometrial carcinoma. Our case with 2-year follow-up indicates that tumor embolization during hysteroscopic endometrial biopsy may not lead to tumor recurrence. The long-term prognosis of such patients may be more confidently understood if additional cases are identified. REFERENCES 1. Creasman WT, Morrow CP, Bundy BN, et al.: Surgical pathologic spread patterns of endometrial cancer, a Gynecologic Oncology Group study. Cancer 60:2035–2041, 1987 2. Cayuela E, Cos It, Onbargi L, et al.: Complications of operative hysteroscopy. J Am Assoc Gynecol Laparosc 3:(4, Suppl):S6, 1996 3. Nagel TC, Kopher RA, Tagate GE, et al.: Tubal Reflux of Endometrial Tissue During Hysteroscopy. in Sigler AM, Lindemann HI (eds): Hysteroscopy: Principles and Practice. Philadelphia, Lippincott, 1984, p 45 4. Sivridis E, Buckley CH, Fox H: The prognostic significance of lymphatic vascular space invasion in endometrial adenocarcinoma. Brit J Obstet Gynecol 94:991–994, 1987 5. Hanson MB, Van Nagell JR, Powell DE, et al.: The prognostic significance of lymph–vascular space invasion in stage I endometrial cancer. Cancer 55:1753–1757, 1985 6. Kadar N, Malfefano IH, Homesley RD: Determinants of survival of surgically staged patients with endometrial carcinoma histologically confined to the uterus: implications for therapy. Obstet Gynecol 80:655– 659, 1992 7. Romano S, Shimoni Y, Muralee D, Shalev E: Retrograde seeding of endometrial carcinoma during hysteroscopy. Gynecol Oncol 44:116 –118, 1992 8. Schmitz MJ, Nahhas WA: Hysteroscopy may transport malignant cells into the peritoneal cavity. Eur J Gynecol Oncol 15:121–124, 1994 9. Egarter C, Krestan C, Kurz C: Abdominal dissemination of malignant cells with hysteroscopy. Gynecol Oncol 63:143–144, 1996 10. Neis KJ, Brandner P, Keppeler U: Tumor cell seeding caused by hysteroscopy. Geburtshilfe Frauenheilkd 12:651– 655, 1994