高强度聚焦超声消融联合GnRHa治疗子宫腺肌病的临床研究

目的：将高强度聚焦超声（HIFU）消融与促性腺激素释放激素激动剂（GnRHa）联合用于子宫腺肌病患者的治疗,并结合临床实际探讨其应用价值。方法：将石家庄市第一医院妇产科2015年1月—2018年1月诊治的89例子宫腺肌病患者作为研究对象。将入组病例分为2组：HIFU联合GnRHa组（41例）和单纯HIFU组（48例）,比较2组患者治疗后随访1年的疗效指标。结果：HIFU联合GnRHa组病灶体积缩小率和子宫体积缩小率均大于单纯HIFU组,差异有统计学意义（均P＜0.05）。HIFU联合GnRHa组血红蛋白水平高于单纯HIFU组,差异有统计学意义（P=0.044）。HIFU联合GnRHa组痛经VRS评分亦优于单纯HIFU组,差异有统计学意义（P=0.018）。2组患者血清CA125水平和不良反应发生率比较,差异无统计学意义（均P＞0.05）。结论：与仅采用HIFU消融比较,HIFU联合GnRHa治疗子宫腺肌病能更有效地缩小病灶体积和子宫体积,同时改善血红蛋白水平和痛经症状。     

Evaluating prognostic parameters in women with uterine leiomyosarcoma. A clinicopathologic study

OBJECTIVE: To evaluate the prognostic impact of different clinicopathologic parameters in patients with uterine leiomyosarcoma. STUDY DESIGN: Twenty-one patients with histologically proven uterine leiomyosarcoma were included in the analysis. Leiomyosarcomas were defined as uterine smooth muscle tumors with > or = 5 mitoses per 10 high-power fields and nuclear atypia and/or necrosis. RESULTS: The median follow-up time was 47 months; 5-year overall survival was 41%. A univariate Cox model revealed that early tumor stage (P = .00001), age at diagnosis < 50 years (P = .02), absence of vascular space involvement (P = .04), low myometrial invasion (P = .006) and low histologic grade (P = .04) were associated with lengthened overall survival. Adjuvant radiotherapy and/or chemotherapy (P = .1) did not influence overall survival. CONCLUSION: Early tumor stage, age at diagnosis < 50 years, absence of vascular space invasion, low myometrial invasion and low histologic grade were parameters of a good prognosis in women with uterine leiomyosarcoma. Adjuvant chemotherapy and/or radiotherapy showed no benefit in these patients.     

Unexpected uterine leiomyosarcoma in a woman with multiple myomas treated with ulipristal acetate: case report and literature review

Ulipristal acetate (UPA) has been recognized as an alternative strategy to surgery in the management of symptomatic women with uterine fibroids. We present a case report on a woman with hereditary fibrinogen deficiency exclusively treated with UPA for myoma-related menorrhagia and abdominal pain, who subsequently underwent a hysterectomy because of clinical worsening. A FIGO IB uterine leiomyosarcoma was found among multiple myomas. A review of the literature found two other cases of uterine leiomyosarcoma in patients treated with UPA: clinical data are reported. The aim of this case report is to increase clinicians' awareness that, although rare, leiomyosarcoma can develop in a uterus with multiple myomas and no reliable diagnostic tools exist yet. Thus, a clinical and instrumental careful reevaluation and patient counseling should be a priority when planning to repeat UPA treatment cycles.     

Tumor angiogenic activity of gynecologic tumor cell lines on the chorioallantoic membrane

Tumor angiogenic activity (TAA) from tumor angiogenesis factor (TAF), produced by 24 cell lines of various kinds of gynecologic tumors, was assayed onto chorioallantoic membranes (CAMs) of chick embryos. Methylcellulose (1%) pellets containing 1 x 10(7) cells were placed on 8-day-old postfertilized CAMs, and the grade of neovascularization was assayed 3 days after inoculation. Neovascularization occurred prominently in such cell lines, as HTBOA (poorly differentiated ovarian carcinoma), HUOCA-II (poorly differentiated clear cell adenocarcinoma), HWUA (poorly differentiated endometrial adenocarcinoma), and in HKUS (uterine cervical small cell carcinoma); however, neovascularization did not occur in SNK (uterine leiomyosarcoma line). The cell lines which secreted TAF showed high heterotransplantability in the nude mice and produced rapidly growing tumors which were rich in blood vessels. However, the SKN line which did not secret TAF was not transplantable. These results suggested that there was a close relationship among TAA, transplantability, and tumor growth rate.     

裸大鼠人子宫内膜癌模型的建立和评价

目的:建立裸大鼠人子宫内膜癌皮下瘤和宫腔原位移植瘤模型,初步观察其生物学特性。方法:体外培养子宫内膜癌细胞株Ishikawa,注射于8只雌性裸大鼠皮下,2周后处死2只成瘤裸大鼠,将皮下瘤修剪成2mm3的组织块移植入10只同种雌性裸大鼠左侧子宫内。4周后牺牲10只裸大鼠,取出左侧子宫。通过巨检、镜检、免疫组化、流式细胞仪等初步观察肿瘤的生物学特性。结果:8只雌性裸大鼠皮下均成瘤,10只雌性裸大鼠中7只左侧子宫内成瘤,免疫组化证实雌激素受体和孕激素受体在皮下瘤均有表达。流式细胞分析早期裸大鼠人子宫内膜癌的S期细胞含量为37.83%。结论:人子宫内膜癌裸大鼠皮下瘤和宫腔原位移植瘤模型成功建立,为子宫内膜癌的体内实验和新型治疗提供了较理想的动物模型。     

Activity of trabectedin (ET-743, Yondelis) in metastatic uterine leiomyosarcoma

BACKGROUND: The ongoing search for more effective agents in the treatment of uterine leiomyosarcomas is warranted because of the poor prognosis related to these tumors. CASE: A case of advanced, recurrent and refractory uterine leiomyosarcoma is presented that responded to trabectedin (ET-743) 1.2 mg/m2 intravenously over 24 h every 3 weeks after failing four prior regimens. A durable objective response lasting at least 8 months was documented. CONCLUSION: Trabectedin (ET-743) has activity in uterine leiomyosarcoma and warrants further investigation.     

Microsatellite instability in uterine sarcomas

Abstract. Amant F, Dorfling CM, Dreyer L, Vergote I, Lindeque BG, Van Rensburg EJ. Microsatellite instability in uterine sarcomas.
Studies have shown a 15–30% frequency of microsatellite instability in endometrial cancer. In addition, we found a 21% frequency of microsatellite instability in endometrial cancer. Our aim was to investigate the presence of microsatellite instability and loss of heterozygosity in uterine sarcomas. The records of 69 women referred to Kalafong Academic and Pretoria Academic Hospital with a primary diagnosis of uterine sarcoma were reviewed. At histological review of 43 cases with a primary diagnosis of leiomyosarcoma, diagnosis of mitotically active leiomyoma was made in 21. Diagnosis of carcinosarcoma was made in 21 cases and endometrial stromal sarcoma in five. In all cases, genomic DNA was extracted from normal myometrium and tumor and analyzed for microsatellite instability and loss of heterozygosity. High-frequency microsatellite instability was absent in leiomyosarcoma, endometrial stromal sarcoma, and mitotically active leiomyomas and was observed in 1 (5%) carcinosarcoma. Loss of heterozygosity for chromosome 11 was present in 8/48 (17%) of uterine sarcomas, equally distributed between leiomyosarcomas (4/22 = 18%) and carcinosarcomas (4/21 = 19%). There was no loss of alleles in endometrial stromal sarcoma nor mitotically active leiomyomas. In conclusion, it is suggested that tumor suppressor genes may play a role in the tumorigenesis of uterine mesenchymal cells, whereas mismatch repair genes contribute to the carcinogenesis of endometrial cancer.     

Characterization of an estradiol-independent but estradiol-responsive growth phenotype in a human endometrial adenocarcinoma heterotransplanted into nude mice

The tumor growth phenotype was characterized in relation to concentration of circulating estradiol, estradiol receptor (ER) activation and progesterone receptor (PgR) induction. Ten tumor pieces from an ER and PgR positive human endometrial adenocarcinoma grown in non-oophorectomized nude mice for one year were randomly selected to grow during a preparation phase of 4 weeks either in oophorectomized nude mice — to adapt tumor growth to the absence of estradiol (group A), or in non-oophorectomized nude mice (group B). For the experimental phase, tumor pieces from each group were again randomly assigned to either of two subgroups (i.e., 4 subgroups in all): with estradiol treatment (subgroups A+ and B+), or without (subgroups A− and B−) as control subgroups. There were no differences in take rate or tumor growth rate between the control subgroups (A− vs. B−), indicating tumor growth to be estradiol-independent. The tumor was estradiol-sensitive, however, as tumor growth could be stimulated by estradiol. Despite its estradiol-independence of growth, the tumor's estradiol-binding capacity varied according to whether the host animals were oophorectomized or not; and despite the similar growth patterns during the experimental phase, the values of high affinty bound ER (ER activation) were greater for tumors grown in non-oophorectomized mice during the preparation phase than for those grown in oophorectomized mice. Thus, our findings show that an ovarain (estradiol) independent but responsive phenotype of tumor growth is present in human endometrial adenocarcinomas growing in nude mice. This growth phenotype may represent an intermediate state of tumor progression to hormone independence and resistance, which has hitherto been observed only in rodent tumors.     

Photodynamic therapy of human ovarian epithelial carcinoma, OVCAR-3, heterotransplanted in the nude mouse.

OBJECTIVE: Our objective was to develop an animal model for the study of photodynamic therapy in the treatment of human ovarian epithelial carcinoma. STUDY DESIGN: The human ovarian carcinoma OVCAR-3 was heterotransplanted into nude, athymic mice and treated with photodynamic therapy consisting of the hematoporphyrin derivative Photofrin II 10 ng/kg and argon-pumped dye laser light at 630 nm (200 J/cm2). Growth of tumors on one side of seven mice (treated tumors, n = 7) was compared with contralateral tumors (control tumors, n = 8) not exposed to laser. Hematoporphyrin derivative uptake was determined in tumor and other tissues. RESULTS: Photodynamically treated tumors were completely ablated, and all remained absent. Hematoporphyrin derivative uptake was nonselective for tumor compared with other tissues. CONCLUSION: This model provides reproducible parameters for the study of photodynamic therapy in the treatment of gynecologic malignancies and demonstrates the need for methods to increase selective uptake of hematoporphyrin derivatives.     

Apoptotic and cell cycle regulatory markers in uterine leiomyosarcoma

OBJECTIVES: The primary aim of this study was to investigate the expression of apoptotic and cell cycle regulators p53, p21, p27, bax, and bcl-2 in uterine leiomyosarcoma in order to identify molecular pathways that possibly could be important in the development of leiomyosarcoma. A secondary aim was to examine if the apoptotic and cell cycle regulatory protein expression profile of uterine leiomyosarcoma is potentially useful for clinical prognostic purposes. METHODS: A tissue microarray representing 36 uterine leiomyosarcomas and 19 uterine leiomyomas was created with 3 representative cores from each tumor. Immunohistochemical staining was performed for bcl-2, bax, p21, p27, and p53 using standard techniques. Staining was scored 0-12 for each marker, 0-3 being negative and 4-12 positive. Outcome analyses were performed only for leiomyosarcomas. First recurrence was determined from the time of initial diagnosis. Survival was determined from the time of initial diagnosis to last follow-up. RESULTS: Associations were found between disease type (leiomyosarcoma vs. leiomyoma) and the positivity status of p21 (43% vs. 0%, P < 0.001), p53 (54% vs. 0%, P < 0.001), and bax (34% vs. 94%, P < 0.001). bcl-2-positive leiomyosarcoma was associated with a longer time to recurrence (P = 0.02) in a univariate analysis. In a multivariate analysis, tumor stage was the only independent significant prognostic factor (P = 0.002). CONCLUSION: The significant differential expression of apoptotic and cell cycle regulatory proteins in uterine leiomyosarcoma as compared to benign smooth muscle tumors suggests that pathways involving these proteins may be important in the development of malignant disease and, therefore, could be potential targets for molecular therapies.     

The prognostic relevance of histological type in uterine sarcomas: a Cooperation Task Force (CTF) multivariate analysis of 249 cases

PURPOSE OF INVESTIGATION: The objective of this retrospective multicenter study was to assess the prognostic relevance of histologic type in uterine sarcomas. METHODS: The hospital reports of 249 patients with uterine sarcomas were reviewed. Surgery was the initial therapy for all patients. Histologic type was leiomyosarcoma in 95 cases, low-grade endometrial stromal sarcoma (ESS) in 19, high-grade ESS in 34, and carcinosarcoma in 101. Postoperative treatment was given without well-defined protocols. Median follow-up of survivors was 97 months. RESULTS: In the whole series 2-year, 5-year, and 10-year survival rates were 53.5%, 41.6%, and 35.8%, respectively, and median survival was 31 months. At univariate analysis survival was significantly related to stage (p = 0.0001), mitotic count (p = 0.0001), and histologic type (low-grade ESS vs leiomyosarcoma vs carcinosarcoma vs high-grade ESS, median: not reached vs 27 months vs 21 months vs 16.5 months, p = 0.0011), but not to postoperative therapy and patient age. The Cox model revealed that tumor stage, mitotic count and histologic type were independent prognostic variables for survival. In detail, the risk of death was significantly lower for low-grade ESS (risk ratio [RR] = 0.257; 95% confidence interval [CI] = 0.071-0.931) and carcinosarcoma (RR = 0.509; 955 CI = 0.324-0.799) when compared to leiomyosarcoma. Conversely, no significant difference in survival was found between leiomyosarcoma and high-grade ESS. CONCLUSIONS: Histologic type is an independent prognostic variable for survival in uterine sarcomas. Low-grade ESS has the best clinical outcome, whereas leiomyosarcoma has the poorest one. It is noteworthy that, when adjusting for stage and mitotic count, leiomyosarcoma has a significantly worse prognosis than carcinosarcoma.     

Myxoid leiomyosarcoma of the uterus with subsequent pregnancy and delivery

BACKGROUND: Myxoid leiomyosarcoma of the uterus is an extremely rare neoplasm. In young women with this disease, fertility should be considered in the treatment protocol. CASE: A 20-year-old woman presented with a huge pelvic mass originating from the uterine wall and showing a histopathology of myxoid leiomyosarcoma. Five and one-half years after laparotomy, the recurrent tumor was found and removed. Two years after the second operation, she became pregnant, and delivered a healthy baby by cesarean section. Multiple recurrent masses were evident and removed at cesarean section. She is alive and well without evidence of recurrence 1 year after delivery. CONCLUSION: The best treatment for this tumor is not established. In young women with a desire to bear children, the management is more controversial.     

A human ovarian carcinoma murine xenograft model useful for preclinical trials

OBJECTIVE: To establish a murine xenograft model of human ovarian carcinoma. METHODS: A slurry of fresh human tumor from patients with intraperitoneal malignancies was heterotransplanted intraperitoneally into nude (nu/nu) and severely combined immunodeficient mice (CB-17, SCID). Xenograft growth was assessed by serial examination and necropsy. The xenografts were passaged to new animals when tumors were palpably greater than 1 cm(3). Histopathologic analysis of the xenografts was performed at each passage as well as immunohistochemical staining for p53 mutations. Persistent expression of human genes by the xenografts at higher passages was assessed by RT-PCR amplification of the human beta-globin gene. This xenograft model was used in the preclinical evaluation of an adenoviral vector containing a beta-galactosidase reporter gene and a wild-type p53 gene. RESULTS: Tumor growth was not established in any of the nude mice heterotransplanted with tissue from six different ovarian cancer patients. Eleven of 13 specimens established xenograft growth when injected in SCID mice. Nine xenografts have been subsequently passaged between 6 and 24 animal generations to date. All xenografts retained histopathologic similarities to their original human tumors and the p53 expression patterns remained stable through higher passages. Within 24 h after intraperitoneal administration of an adenoviral vector, transduction of the reporter gene was evident in the xenografts. In addition, administration of an adenoviral vector containing a wild-type p53 gene significantly decreased the tumor burden compared to controls (P < 0.04). CONCLUSIONS: This murine xenograft model of human ovarian carcinoma appears to be reliable and reproducible and has utility for the study of novel therapeutics.     

Antitumor effects of high-dose cisplatin in hypertonic saline against human ovarian tumors heterotransplanted in nude mice

To overcome the dose limiting toxicity of cisplatin we administered high-dose (12 mg/kg) cisplatin together with hypertonic (3%) saline to tumor-bearing nude mice three times at four day intervals. The heterotransplanted human ovarian tumors consisted of a mucinous cystadenocarcinoma (designated as OVA-1), a poorly differentiated adenocarcinoma (OVA-2), an endometrioid adenocarcinoma (OVA-3) and three yolk sac tumors (YST-1,-2,-3). The mean volumes of the tumors in animals treated with a standard dose 6 mg/kg of cisplatin in 0.9% NaCl or 12 mg/kg of cisplatin in 3% NaCl were, as a percentage of the mean tumor volume in untreated animals: 51 and 26 for OVA-1, 28 and 15 for OVA-2, 11 and 7 for OVA-3, 7 and 14 for YST-1, 3 and 12 for YST-2, and 11 and 10 for YST-3, respectively. The most interesting result was that a high dose (12 mg/kg) of cisplatin succeeded in producing a strong antitumor effect on mucinous cystadenocarcinoma (OVA-1), which was resistant to standard dose cisplatin (6 mg/kg). A comparison of the body weight of tumor-bearing nude mice before and on Day 30 of treatment did not show any appreciable treatment-related changes.     

Biological characteristics of a human uterine leiomyosarcoma cell line,particularly its heterotransplantability and effect on the proliferation of vascular endothelial cells

Human uterine cervical leiomyosarcoma cell line SKN has been proliferating stably for 11 years since establishment, while there has been no change in the cytobiological properties such as morphology (fibrous and long spindle), proliferating ability [doubling time (DT) = 30 hours, plating efficiency (PE) = 25%], or chromosome (mode: hyper tetraploid, large telocentric marker chromosome), etc. A part of the large telocentric marker chromosomes is found to be 2q as a result of G-band karyotyping, and the marker chromosome was recognized in all of the cells. Transplantation to nude mice was unsuccessful. 1 X 10(7) cells were planted on the chorioallantoic membrane (CAM) of chick embryo, but neovascularization was not evident. The conditioned medium of SKN cells slightly suppressed the proliferation of vascular endothelial cells. The reason for the unsuccessful heterotransplantation to nude mouse seems to be that neovascularization and proliferation of vascular endothelial cells do not take place.     

Uterine smooth-muscle tumor of uncertain malignant potential metastasizing to the humerus as a high-grade leiomyosarcoma

BACKGROUND: Smooth-muscle tumors of uncertain malignant potential represent a variant of uterine leiomyoma and remain a dilemma due to their uncertain clinical behavior. Most of these tumors have a benign clinical course, and coagulative tumor cell necrosis has usually been associated with worse outcome. CASE: We present a case of a uterine smooth-muscle tumor (SMT) of uncertain malignant potential without coagulative tumor cell necrosis that has metastasized to the humerus. The metastatic lesion was a high-grade leiomyosarcoma consistent with uterine origin. CONCLUSIONS: Smooth-muscle tumors of uncertain malignant potential that demonstrate a lack of coagulative tumor cell necrosis do not necessarily insure benign clinical outcome. These lesions can recur and metastasize to distant sites, thus requiring long-term follow-up.     

Leiomyosarcoma of the uterus: a clinicopathologic study of 21 cases

BACKGROUND: The purpose of the present study was to identify the prognostic factors of and to determine the most appropriate mode of treatment for uterine leiomyosarcoma. METHODS: We reviewed the hospital records, including surgical notes and pathologic reports, of 21 patients with uterine leiomyosarcoma treated at Chang Gung Memorial Hospital, Kaohsiung, Taiwan, between 1987 and 1997. Univariate analysis was performed using the log-rank test. Cox regression was used to identify independent prognostic factors. RESULTS: The mean follow-up time was 30 months, and the 5-year disease-free survival rate was 55%. Evaluating the correlation between clinicopathologic parameters and survival, early stage (p = 0.0002), tumor cells without necrosis (p = 0.0026), low-grade tumor (p = 0.015), absence of vascular space involvement (p = 0.006), and tumor without atypia (p = 0.016) were associated with good prognosis. However, in a multivariate analysis using the Cox model, only advanced stage (p = 0.032) and tumor necrosis (p = 0.032) were found to be independent poor prognostic factors. The 5-year disease-free survival was only 21% in patients with the presence of any one or both of these two factors. Five of 11 patients in this group had received aggressive adjuvant therapy after surgery, and none of them survived more than 19 months. CONCLUSIONS: We found that patients with advanced stage or presence of tumor necrosis had an extremely poor prognosis. Adjuvant therapy seemed to play a limited role, and provided no survival benefit. Treatment for these patients should be palliative until effective therapeutic modalities prove otherwise.     

Reclassification of a tubal leiomyosarcoma as an eGIST by molecular evaluation of c-KIT

BACKGROUND: Extragastrointestinal stromal tumors (eGISTs) are rare mesenchymal-derived tumors arising outside of the GI tract. eGISTs are often histologically confused with leiomyosarcoma. Distinction between eGIST and leiomyosarcoma is critical because of the unique responsiveness of eGISTs to the molecularly targeted agent imatinib. CASE: A woman presented with a history of tubal spindle cell tumor that was initially diagnosed and treated as a leiomyosarcoma. Because of minimal response to sarcoma directed chemotherapy, the possibility that the tumor was in fact an eGIST was investigated and supported by immunohistochemical and mutational analyses of the c-Kit receptor tyrosine kinase. The patient currently has stable disease control on imatinib for the last 18 months. CONCLUSIONS: The possibility of eGIST should be considered in the differential diagnosis of tumors with a spindle cell morphology in the gynecologic tract especially when involving the ovary, fallopian tube, or uterine serosa.     

A huge abdominal mass mimicking ovarian cancer: p53-negative but aneuploid myxoid leiomyosarcoma of the uterus.

OBJECTIVE: Less than 20 myxoid leiomyosarcoma cases were reported in literature. Since, these tumors are very rare and may exhibit highly malignant behavior despite their low mitotic index, clinical course and optimum type of therapy of myxoid variant of leiomyosarcoma were not well understood. The goal of this report is to contribute the better understanding of this rare type of tumor. METHODS: A 39-year-old woman presented with a huge abdominal cystic mass. Laparotomy was performed and frozen section diagnosis was low-grade uterine leiomyosarcoma. TAH-BSO, omentectomy, pelvic lymph node and peritoneal samplings were carried out. No chemotherapy was performed after surgical therapy. RESULTS: Final histopathological diagnosis was uterine myxoid leiomyosarcoma. The tumor was p53-negative and had aneuploid DNA content. The patient tolerated well the operation and she is alive and free of disease after 24 months of primary surgical treatment. CONCLUSION: Uterine myxoid leiomyosarcoma may present a huge abdominal cystic mass and can be treated successfully with surgery alone.     

子宫肉瘤临床特点及预后相关因素101例分析

目的 探讨子宫肉瘤的临床特点及预后相关因素,以改善其生存率。方法 对辽宁省肿瘤医院1984年2月至2008年8月收治的101例子宫肉瘤的组织学类型、临床特点、治疗方法及预后进行回顾性分析。结果 101例子宫肉瘤患者5年总生存率为46.5%。单因素分析显示:年龄≤52岁组的5年生存率为57.1%,>52岁组为36.5%,差异有统计学意义(χ2=5.915,P=0.003）。绝经前患者5年生存率为57.6%,绝经后患者为25.7%(χ2=9.332,P=0.002 )。子宫平滑肌肉瘤5年生存率34.3%,恶性中胚叶混合瘤为16.7%,子宫内膜间质肉瘤为73.8%,三者比较差异有统计学意义(χ2=23.274,P<0.001)。Ⅰ期与Ⅱ、Ⅲ、Ⅳ期的5年生存率分别为61.1%、36.4%、18.2%、0%,差异有统计学意义(χ2=9.428,P=0.009)。当子宫体积<妊娠3个月子宫时,5年生存率为65.2%,而≥3个月时为41.0%(χ2=4.178,P=0.041 )。手术、手术+放疗+化疗、手术+化疗、手术+放疗者5年生存率分别为41.7%、62.5%、45.9%、44.4%,差异无统计学意义(χ2=4.390,P=0.375)。多因素分析显示:仅绝经状态、手术分期和病理类型3个因素与患者的预后有关,其中手术分期是影响患者预后的最重要因素（P=0.001）。结论 绝经状态、手术分期、病理类型是影响子宫肉瘤患者预后的独立因素。