摘要
第一部分宫颈恶性肿瘤患者保留生育功能的腹式根治性宫颈切除术
1.1、宫颈癌保留生育功能的腹式根治性宫颈切除术——一项潜在获益人群的研究
目的：研究早期宫颈癌患者中,适合行保留生育功能的腹式根治性宫颈切除术(ART)的患者比例。
方法：我们回顾性地查阅了2000年1月到2007年12月,腹式根治性宫颈切除术尚未在复旦大学附属肿瘤医院广泛开展前,因浸润性宫颈癌在我院行根治性子宫切除术的患者病历。根据我院行根治性宫颈切除术的指征,研究适合行腹式根治性宫颈切除术的潜在患者人群。
结果：经筛选,2000年1月到2007年12月期间共有3220名患者因为浸润性宫颈癌在我院行根治性子宫切除术。其中1638名患者年龄不大于45岁。根据我院行根治性宫颈切除术的标准,653(39.87%)名患者初步符合行腹式根治性宫颈切除术的FIGO分期、肿瘤大小和病理类型,但其中49名患者因最终病理提示肿瘤播散可能需要放弃保留生育功能的手术。我们的研究最终确定604名(36.87%)患者可能适合接受ART手术。
结论：不大于45岁的宫颈癌患者中,有相当一定比例的人群符合腹式根治性宫颈切除术的指征。这部分患者如能在术前充分告知手术的风险和利益,将有可能接受腹式根治性宫颈切除术,在治疗肿瘤的同时保留生育功能。
1.2、宫颈恶性肿瘤保留生育功能的腹式根治性宫颈切除术：107名患者的手术学、肿瘤学和生育结果
目的：报道在宫颈恶性肿瘤患者中开展保留生育功能的腹式根治性宫颈切除术的经验,探讨患者接受这一手术后的肿瘤学、手术学结果,研究影响患者生育结果的因素。
方法：从2004年4月到2012年3月,前瞻性地入组因“宫颈恶性肿瘤”在复旦大学附属肿瘤医院妇科行保留生育功能的腹式根治性宫颈切除术的患者。研究组患者的临床病理资料予以详细记录和分析。术后对患者进行长期随访。为明确影响患者生育结果的因素,术后定期向患者进行电话及信件形式的问卷调查。
结果：107名宫颈恶性肿瘤患者计划行保留生育功能的腹式根治性宫颈切除术。三名患者因术中快速冰冻提示病理高危因素而转行根治性子宫切除术。研究组患者平均年龄28.3岁(范围：11-42岁)。患者肿瘤的组织病理类型包括：11例(10.58%)腺癌、83例(79.81%)鳞癌、4例(3.85%)腺鳞癌以及6例(5.77%)宫颈横纹肌葡萄簇肉瘤。平均淋巴结切除数目为25枚(范围：12-53枚)。18名(17.31%)患者因病理高危因素接受术后辅助治疗。66名IB1期宫颈癌患者中26例肿瘤最大径>2cm。研究组患者随访至今仅一例复发,中位随访时间26.2个月(0.5-94个月)。唯一的复发病例为一名IB1期肿瘤2cm的宫颈鳞癌患者,术中冰冻病理提示淋巴结阴性,最终石蜡病理提示右盆腔淋巴结一枚转移,肿瘤侵犯深肌层及淋巴脉管间隙。患者术后拒绝接受辅助放疗,仅接受四疗程辅助化疗。术后5个月随访CT发现肝脏多发转移结节。手术开展初期5名(4.81%)患者在术后出现宫颈管狭窄。改良手术、向患者宫腔置入带尾丝的T型宫内节育器后,没有患者出现术后宫颈管狭窄。48名患者完成了生育结果影响因素调查。基于各种原因,手术患者中仅12人尝试怀孕,其中四人成功受孕(三名自然受孕,一名借助辅助生育技术受孕)。三名患者在孕39周经剖宫产顺利产下健康婴儿,另一名患者尚在怀孕中。
结论：我们的研究显示,对于宫颈肿瘤不大于4cm的患者,由有经验的妇科肿瘤专科医师实施腹式根治性宫颈切除术是一项切实可行的治疗选择。这一手术最主要的围手术期并发症为术后宫颈管狭窄。术中向患者宫腔置入带尾丝的T型宫内节育器能有效预防术后宫颈管狭窄的发生。社会因素、家庭因素以及生理因素均在很大程度上影响了患者的生育结果。术后患者的生活质量和生育问题值得进一步深入研究。
1.3儿童及青少年宫颈葡萄簇横纹肌肉瘤保留生育功能的手术治疗
背景：宫颈横纹肌肉瘤多发生于儿童和青少年,是一种非常少见的恶性肿瘤。以往多采用盆腔除脏术和化放疗结合的激进的治疗方法进行治疗。
目的：探讨这类患者接受保育手术的适应证以及合适的手术方法,观察患者治疗后的预后和发育情况,为这一罕见肿瘤的治疗提供我们的经验
方法：自2006年8月至2012年3月,所有至复旦大学附属肿瘤医院妇科就诊的“宫颈葡萄簇横纹肌肉瘤”患者治疗前经过全面的妇科体检及常规检查。用于初次诊断的肿瘤活检或肿瘤切除组织均经专科病理医师进一步复片确诊。每位患者根据IRS的横纹肌肉瘤分类分期标准进行分期。患者术前行胸部、盆腔以及腹腔MRI和/或CT检查以评估是否适合接受保留生育功能的手术。选择合适的“宫颈葡萄簇横纹肌肉瘤”病例行保留生育功能的手术。所有研究组患者的临床病理资料予以详细记录和分析。术后对患者进行长期随访。
结果：共有七例儿童及青少年宫颈葡萄簇横纹肌肉瘤患者接受了保留生育功能的手术。除第一例患者接受宫颈锥切+子宫内膜诊刮+处女膜修补手术之外,其余六例患者均接受腹式根治性宫颈切除术+盆腔淋巴结活检术。研究组中患者平均年龄14.1岁(范围：11-19岁),平均随访时间28.7个月(范围：7-67个月)。至今7名患者无一例复发,均在治疗后获得正常月经周期并发育良好。
结论：选择合适的宫颈葡萄簇横纹肌肉瘤病例接受保留生育功能的手术,可以获得较好的治疗效果。腹式根治性宫颈切除术+盆腔淋巴结活检术作为保育手术的一种,与单纯的息肉切除术等其他微创性保育手术相比,具备更好的肿瘤局控率。由有经验的妇科肿瘤医师开展腹式根治性宫颈切除术,术中保留子宫动脉,可以保证子宫卵巢获得足够的血供,从而有利于儿童和青少年患者的生理发育。
第二部分宫颈癌患者术前淋巴结转移相关microRNA的研究
目的：筛查宫颈癌淋巴结转移相关的microRNA,在宫颈癌细胞株中验证microRNA与细胞侵袭转移能力间的关系。为进一步深入研究宫颈癌淋巴结转移的调控机制,最终采用microRNA作为宫颈癌淋巴结转移的标志物打下基础。
方法：选择“有淋巴结转移的宫颈癌原发灶新鲜冻存组织标本8例”和“无淋巴结转移的宫颈癌原发灶新鲜冻存组织标本9例”,使用Ambion mirVana RNA isolation kit提取样本的RNA,采用基因芯片比较筛选两组标本的差异microRNA。为排除生物个体背景差异,另取7名有淋巴结转移患者的宫颈原发灶以及同一患者的转移淋巴结标本(共7对14例标本),Ambion mirVana RNA isolation kit提取样本的RNA,采用基因芯片比较筛选两组标本的差异microRNA。在宫颈鳞癌细胞株中转染筛选出的差异nicroRNA的mimic, transwell实验比较转染前后肿瘤细胞转移能力变化。
结果：8例“伴有淋巴结转移的宫颈癌原发灶新鲜冻存组织标本”和9例“无淋巴结转移的宫颈癌原发灶新鲜冻存组织”经Ambion mirVana RNA isolation kit提取RNA, Agilent2100Bioanalyzer电泳检测提取RNA合格；Agilent miRNA Complete Labeling and Hyb Kit分析miRNA表达谱,采用配对t检验统计分析。统计分析后获得7个共同的差异基因：has-miR-142-3p, has-miR-196b, has-miR-320b, has-miR-424, has-miR-550a, has-miR-652, has-miR-H18。7名自身对照研究患者的“宫颈原发灶”和“自身转移淋巴结”标本经基因芯片筛选、配对t检验分析差异基因后,发现三个共同的差异表达的miRNA (has-miR-630, has-miR-223和has-miR-451)具统计意义。将has-miR-652的mimic转染宫颈癌Caski细胞株,transwell转移实验显示Caski细胞株的转移能力较转染前显著增强。
结论：“伴有淋巴结转移的宫颈癌原发灶标本”和“无淋巴结转移的宫颈癌原发灶标本”中has-miR-142-3p, has-miR-196b, has-miR-320b, has-miR-424, has-miR-550a, has-miR-652, has-miR-H18的表达具有统计学差别,体外细胞实验初步提示两组标本中has-miR-652的表达差异具有功能学意义。进一步的研究需要扩大样本量检验上述结果,并通过体外细胞株实验和小鼠动物实验来深入了解microRNA如何通过作用于靶向mRNA和下游功能蛋白以调节宫颈癌的淋巴结转移,最终采用microRNA作为宫颈癌淋巴结转移的标志物。
Part1. Abdominal Radical Trachelectomy for Cervical Malignancies
1.1Abdominal radical trachelectomy (ART) for cervical cancer: how many patients may be eligible for fertility preservation?
Objective:To determine the percentage of patients with early-stage cervical cancer who may be eligible for fertility preservation with abdominal radical trachelectomy (ART).
Methods:We retrospectively reviewed the records of patients who underwent a radical hysterectomy for invasive cervical cancer at our institution from01/2000to12/2007, before ART was widely conducted at Cancer Hospital of Fudan University. Institutional eligibility criteria for ART were applied.
Results:We identified3220patients who had undergone radical hysterectomy for cervical cancer;1638were age≤45at surgery. Six hundred and fifty-three (39.87%) patients may have been eligible by FIGO stage, tumor size and histology. In49patients, ART may have been aborted or altered because of unfavorable pathological factors. Six hundred and four (36.87%) patients were identified as eligible for ART in our study.
Conclusion:A significant number of patients≤45with early-stage cervical cancer may be pathologically eligible for ART and should be counseled on this preoperatively.
1.2Abdominal radical trachelectomy for cervical malignancies: surgical, oncological and fertility outcomes in107patients
Objective:To report our experience of radical abdominal trachelectomy for patients with cervical malignancies.
Methods:We conducted a retrospective review of a prospectively maintained database of patients undergoing fertility-sparing radical abdominal trachelectomy for cervical malignancies at our institution from04/2004to03/2012.
Results:One hundred and seven patients with cervical malignancies underwent laparotomy for planned radical abdominal trachelectomy. Three patients needed immediate completion of radical hysterectomy due to unfavorable intraoperative findings. Median age was28.3years (range,11-42). Histology included11(10.58%) with adenocarcinoma,83(79.81%) with squamous carcinoma,4(3.85%) with adenosquamous carcinoma and6(5.77%) with botryoid sarcoma. Median number of nodes evaluated was25(range,12-53); Eighteen(17.31%) patients with pathologic risk factors received adjuvant therapy. Twenty-six of66IB1cases had tumor size>2cm. One recurrence was observed at a median follow-up of26.2months (range,0.5-94months). The recurrent case was a patient with2cm IB1squamous carcinoma. Frozen section evaluation for pelvic lymph nodes was negtive during the operation. However, final pathological results revealed one positive lymph node in right pelvis and the tumor was deep myometrial invasion and lymphvascular space invasion. The patient refused radiation and underwent four cycles of adjuvant chemotherapy. Five months after radical abdominal trachelectomy, upper abdominal CT scan revealed mutiple recurrent nodals in her liver. Five(4.81%) patients developed postoperative cervical stenosis-all occurred before we started to routinely install T-IUDs during the procedure. Only48patients completed the survey which aimed to understand what factors influenced these patients'reproductive outcomes. For various reasons, only12patients attempted to conceive and4of them succeeded (1employed assisted reproductive techniques). Three of them delivered by cesarean section after39weeks and one patient is currently pregnant.
Conclusion:Radical abdominal trachelectomy seems to be a reasonable option for selected patients whose tumors are no larger than4cm when conducted by experienced gynecologic oncologists. The main perioperative complication is postoperative cervical stenosis, which could be effectively prevented by installation of a tailed T-IUD during the surgery. Social, familial and physical factors can largely influence the patients' reproductive outcomes. The issues of reproductive concerns and quality of life require further investigation.
1.3Fertility-sparing surgery for pediatric (adolescent) patients with botryoid rhabdomyosarcoma involving the uterine cervix
Background:Botryoid rhabdomyosarcoma of the uterine cervix, which is most often seen arising in the adolescents, is extremely rare. In the past, this tumor was best treated with pelvic exenteration and chemoradiation.
Objective:To report our experience on fertility-sparing treatment with this disease. To discuss proper selective criteria and type of surgery for fertility-sparing treatment with this disease.
Methods:We conducted a retrospective review of a prospectively maintained database of patients undergoing fertility-sparing surgery for cervical botryoid rhabdomyosarcoma at our institution from08/2006to03/2012.
Results:We presented here seven pediatric (adolescent) patients with botryoid rhabdomyosarcoma involving the uterine cervix. All these cases were offered fertility-sparing surgery. The first patient was offered cervical conization while other six patients underwent radical abdominal trachelectomy and pelvic lymph node biopsy. They all accepted multiagent chemotherapy and presented with favorable outcomes.
Conclusion:In properly selected cases of cervical botryoid rhabdomyosarcoma, conservative surgeries should attempt to preserve reproductive function without compromising in survival. Radical abdominal trachelectomy and pelvic lymph node biopsy have appeared to secure local disease control. Radical abdominal trachelectomy with skills preserving uterine arteries may allow sufficient blood supply to maintain uterine viability and achieve future fertility, and thus benefit the adolescent patients.
Part2. Exploratory Research on Lymph Node metastasis-related microRNA in Patients with Cervical Cancer
Objective:To screen microRNAs associated likely with lymph node metastasis in cervical cancer, and verify the relationship between microRNAs'regulation and tumor metastasis in cervical cancer cell lines. This study was aimed at finding certain microRNA to regulate lymph node metastasis, showing regulatory network, offering experimental evidence for further investigation and finally utilizing microRNAs as markers for predicting lymph nodes metastasis in cervical cancer
Methods and Materials:We hypothesize that miRNAs interconnect with mRNA involved in lymph node metastasis, which influence intrinsic metastasis ability of tumor. We obtain the miRNAs associated likely with lymph node metastasis through screening miRNAs expression profiling in primary cervical cancers with and without positive lymph node using microarray. Furthermore, we try to obtain lymph node metastasis-related miRNAs by screening miRNAs expression profiling in the same patient's 'primary lesion' and 'metastatic lymph node'. Those differentially expressed miRNAs come from the same ecological background and may have direct relationship with lymph node metastasis. In order to test the result of microarray, Real-time Polymerase Chain Reaction is performed. Transwell experiment in cell strains would be employed to verify the relationship between miRNAs expression and lymph node metastasis. Furthermore, prediction algorithms TargetScan will be used to analyze the possible trget gene.
Results:MiRNA microarray showed that four miRNAs (has-miR-142-3p, has-miR-550a, has-miR-652and has-miR-H18) were overexpressed in cervical cancer samples with positive lymph nodes, when compared to the cervical cancer samples without positive lymph nodes, while three miRNAs (has-miR-320b, has-miR-196b and has-miR-424) were underexpressed. Three miRNAs'expression (has-miR-630, has-miR-223and has-miR-451) were found statistically different by screening miRNAs expression profiling in seven patients''primary lesion' and 'metastatic lymph node'. Squamous cancer cell line Caski was transfected by has-miR-652-mimic. Transwell experiment in Caski cell strain revealed the metastatic ability of tumor cell was significantly improved after miR-652-mimic's transfection. Furthermore, prediction algorithm TargetScan was used to analyze the possible target gene. Eight genes, ISL1included, became the candidates.
Conclusions:The preliminary results of our exploratory research showed that differently expressed microRNAs detected from cervical cancer samples with and without lymph node metastasis had functional meaning. Further study, either in vitro or in vivo, is needed to to figure out the mechanism of microRNA-regulated lymph node metastasis, and establish an microRNA model to predict lymph node metastasis in cervical cancer, thus offer evidence for personalized treatment and possible gene therapy.
引文
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