History and Perspectives of Hyperradical, Laterally Extended Parametrectomy (LEP).

Cervical cancer has been and still is a major global health problem and a major treatment challenge for which surgical interventions have played a key role throughout the past century. In early stages (I/A2-II/B), where high-risk factors are not present, the efficacy of surgical and radiotherapy treatment has been considered equivalent with different (treatment modality specific) complications and quality of life consequences. Negative prognostic factors in early stages of the disease (pelvic lymph-node positivity) and in more advanced stages (parametrial and/or surgical margins' tumor involvement) forecast the deterioration of outlooks for good life expectancy. In these high-risk cases, when radio- or chemoradiotherapy is contraindicated, we investigated the potential role of a more radical surgical approach than the traditional radical hysterectomy. Twenty-five years ago, a hyperradical surgical procedure for the treatment of high-risk cervical cancer patients was introduced in Budapest. The procedure was named as laterally extended parametrectomy (LEP) in Budapest Hungary. The surgical intention was the complete removal of the fibro-fatty tissue content of the pelvis, which contains the lymphatic vessels, lymph nodes, and tumor-affected pelvic side wall structures. We initiated observational studies on the primary treatment in parametrium and/or lymph-node tumor-positive early-stage cases and on second-line surgical therapy of pelvic side wall recurrent tumors following radiotherapy. Promising results of our observational studies propose that prospective randomized trials are worth to be initiated to clarify the potential of this treatment modality in this poor prognosis cohort of patients.

[The need, potential and unresolved issues of fertility preservation in the early stages of cervical cancer]. / A méhnyakrák korai stádiumaiban a fertilitás megtartásának igénye, lehetoségei és lezáratlan kérdései.

In the choice of a planned fertility preservation procedure for stage IA1 and IB1 cervical cancer, optimal oncological safety is the main focus of virtually all protocols. The surgeon should remove the appropriate proportion of the cervix for oncological safety, ensuring an adequate tumour-free surgical margin. However, some of the literature on fertility preservation, referring to histological parameters, still considers conisation with excellent fertility results to be optimal for the treatment of tumours with a diameter of 2 cm. With regard to fertility preservation in the case of radical trachelectomy versus simple conisation, we are aware of several ongoing studies, the results of which may provide an answer as to whether a more conservative surgical therapy for smaller tumours (less than 2 cm in diameter) represents an acceptable oncological safety.

Laterally extended parametrectomy.

OBJECTIVE: To describe the laterally extended parametrectomy (LEP) surgical technique, emphasizing the main challenges of the procedure. METHODS: LEP was designed as a more radical surgical procedure aiming to remove the entire parametrial tissue from the pelvic sidewall. Its initial indications were for lymph node positive Stage Ib (current International Federation of Gynecology and Obstetrics 2018 Stage IIIc) and Stage IIb cervical cancer. Currently, with most guidelines recommending definitive radiochemotherapy for these cases, initial LEP indications have become debatable. LEP is now mainly indicated for removing tumors involving the soft structures of the pelvic sidewall during a pelvic exenteration, aiming to obtain lateral free margins. This expands the lateral borders of the dissection to not only the medial surface of internal iliac vessels, but also to the true limits of the pelvic sidewall. RESULTS: During LEP, the parietal and visceral branches of the hypogastric vessels are divided at the entry and exit level of the pelvis. Consequently, the entire internal iliac system is excised, and no connective or lymphatic tissue remain on the pelvic sidewall. The main technical challenges of LEP are caused by the difficulty in ligating large caliber vessels (internal iliac artery and vein) and the variable anatomic distribution of pelvic sidewall veins. CONCLUSION: LEP is a feasible technique for removing pelvic sidewall recurrences, aiming to obtain surgical free margins.

Use of abdominal radical trachelectomy to treat cervical cancer greater than 2 cm in diameter.

OBJECTIVE: Invasive cervical cancer is one of the most common cancers, with 500,000 new cases diagnosed annually. Fertility preservation has become an important component of the overall quality of life of many cancer survivors. Expert opinion has suggested that fertility-sparing surgery should be limited to those patients diagnosed with cervical cancer less than 2 cm in diameter. Our objective was to report our abdominal radical trachelectomy (ART) experience in the opposite group of patients-those with a cervical cancer more than 2 cm in diameter. METHODS: Between 1999 and 2006, a total of 45 patients with cervical carcinoma at International Federation of Gynecology and Obstetrics stage IB1-IB2 measuring more than 2 cm in diameter underwent fertility-sparing ART and pelvic lymphadenectomy at the 3 institutions where the authors are based (Budapest, Hungary; London, United Kingdom; New York, United States). They were followed up for more than 5 years. RESULTS: For 69% of patients (n = 31), completed ART was considered to have been curative, and no adjuvant treatment was advised. Of those patients, 93.5% (n = 29) were alive at the time of follow-up. Thirty-one percent of patients (n = 14) underwent immediate completion of radical hysterectomy. Three of 8 patients who wished to fall pregnant delivered healthy neonates. CONCLUSIONS: The 5-year survival rate (93.5%) for this case series is equal (or better) to rates reported in the literature for patient treated with radical hysterectomy. Our survival data seem to support the hypothesis that ART is a safe treatment option for patients with invasive cervical cancer lesions of more than 2 cm.

Surgical treatment of stage IB cervical cancer.

INTRODUCTION: Recurrence originating from the pelvic lymph node containing fibro-fatty tissue has consistently been identified as the most frequent pattern of treatment failure in early-stage cervical cancer. A surgical technique for the complete removal of the connective tissue content of the pelvis was introduced at St. Stephen Hospital in 1993 to improve oncological outcome by reducing the risk of recurrence from the pelvis. Efficacy and toxicity of the procedure were studied in 563 patients with stage IB cervical cancer with a completed 5-year follow-up. METHODS: Final pathology in 492 (87.4%) of 563 consecutive completed radical hysterectomies suggested that all tissue, which could contain tumor dissemination, was removed from the pelvis; thus, no adjuvant treatment was applied. Adjuvant chemoradiotherapy was advised in 71 cases (12.6%), where pathologic finding alluded tumor spread beyond the study criteria. FINDING: At completed 5-year follow-up, the overall survival of 492 patients who had surgery without adjuvant therapy was 94.0%. Pathologic stage, lymphovascular space involvement, pelvic lymph node metastases, histology classification, and grade had no significant influence on prognosis. The only factor that influenced the overall survival was International Federation of Gynecology and Obstetrics stage (IB1 or IB2). Five-year overall survival of 71 patients to whom adjuvant therapy was recommended was 56.3%. Five-year overall survival of the whole cohort (n = 563) was 88.8%. The complication rate did not seem to be different from the published data on traditional radical surgery in cervical cancer. CONCLUSIONS: Our results (in accordance with other recent publications) suggest that complete excision of the connective tissue content of the pelvis provides equal or better survival chances without any adjuvant treatment for almost 90% of operable patients with stage IB cervical cancer than less radical surgery with or without adjuvant treatment. We suggest this strategy to be mentioned as one alternative in future treatment protocols.

Immunology of uterine transplantation: a review.

The idea of using organ transplantation to solve quality-of-life issues was first introduced a century ago, with cornea transplants and thrusted before the world again in 1998, following a controversial hand transplant. Uterus transplantation (UTn) has been proposed as another quality-of-life transplant for the cure of permanent uterine factor infertility. In order to proceed in humans, a greater appreciation of the immunological mechanisms that underlie UTn is desirable. Allogeneic UTn (animal model) was first described by 2 studies in 1969. The first and only human UTn, performed in 2000, was an early attempt with limited use of animal model experiments prior to moving onto the human setting. Since then, work using rat, mouse, ovine, goat, and nonhuman primate models has demonstrated that the uterus is a very different but manageable organ immunologically compared to other transplanted organs. Therefore, specifically exploring immunological issues relating to UTn is a valuable and necessary part of the inevitable scientific process leading to successful human UTn.

Surgical treatment of lymph node metastases in stage IB cervical cancer. The laterally extended parametrectomy (LEP) procedure: experience with a 5 year follow-up.

INTRODUCTION: In 2003, we published our preliminary experience with the use of an operative technique (laterally extended parametrectomy, the LEP procedure) without adjuvant therapy, in the treatment of 29 stage IB, cervical cancer patients with pelvic lymph node metastases. In our present paper, by an extended recruiting period, with a completed 5 year follow up, we studied the outcome of LEP operations, used with the same indications. METHODS: In 70 out of 106 LEP-Wertheim operated patients, no adjuvant treatment was used. In 36 patients, where histology suggested tumor spread beyond the threshold of our surgery, adjuvant chemo-radiotherapy was advised. 5 year follow up was completed (without any patient lost for follow up) for the whole cohort of patients. RESULTS: In 70 patients treated by LEP procedure alone, the overall 5-year survival was 91.4%. For those 36 patients, who were excluded due to disease spread above study criteria, 5 year survival was 44%. Complications in 10% of the cases necessitated a second operation. Apart from transient hyper continence and one case of permanent incontinence, no severe quality of life consequence of the operation was observed. CONCLUSIONS: Our results suggest that in two-thirds of pelvic lymph node positive, stage IB cervical cancer cases surgery alone could provide equal or better survival (without the toxicity of chemo-radiotherapy), than any kind of multimodality treatment alternatives. LEP procedure should be considered a treatment option for stage IB cervical cancer patients with pelvic lymph node metastases.

Rescue radical trachelectomy for preservation of fertility in benign disease.

OBJECTIVES: To report a series of patients treated with modified radical abdominal trachelectomy to preserve fertility in benign disease that would normally result in hysterectomy. DESIGN: We reviewed all cases of radical abdominal trachelectomy performed for nonneoplastic indications. PATIENT(S): Of the >160 radical abdominal trachelectomies we performed, four cases were performed for benign indications. One patient had a 10-year history of progressive endometriosis with worsening hydronephrosis, failed medical therapy, and infertility. Two myomectomy patients had intraoperative consultation and a third had preoperative consultation for large lower segment/cervical myomas with conversion to trachelectomy rather than hysterectomy. INTERVENTION(S): Modified radical trachelectomy was successfully completed in all patients. MAIN OUTCOME MEASURE(S): We measured the successful completion of the surgery without hysterectomy, complications, and follow-up. RESULT(S): Hysterectomy was avoided in all patients, and all resumed normal menses. There were no intraoperative or postoperative complications. One required hysterectomy for recurrence 1 year later, and the remainder were symptom free at 1-5 years of follow-up. CONCLUSION(S): Although traditionally performed with cervical cancer, radical abdominal trachelectomy can be modified to preserve fertility for benign indications that would otherwise require hysterectomy.

Gynecologic cancers in pregnancy: guidelines of an international consensus meeting.

BACKGROUND: Gynecologic cancer during pregnancy is a special challenge because cancer or its treatment may affect not only the pregnant women in general but directly involve the reproductive tract and fetus. Currently, there are no guidelines on how to deal with this special coincidence. METHODS: An international consensus meeting on staging and treatment of gynecological malignancies during pregnancy was organised including a systematic literature search, and interpretation followed by a physical meeting of all participants with intensive discussion. In the absence of large trials and randomized studies, recommendations were based on available literature data and personal experience thus representing a low but best achievable level of evidence. FINDINGS: Randomized trials and prospective studies on cancer treatment during pregnancy are lacking. Gynecological cancer during pregnancy is a demanding problem, and multidisciplinary expertise should be available. Counseling both parents on the maternal prognosis and fetal risk is needed. When there is a firm desire to continue the pregnancy, gynecological cancer can be treated in selected cases. The staging and treatment should follow the standard approach as much as possible. Guidelines for safe pelvic surgery during pregnancy are presented. Mainly in cervical and ovarian cancer, chemotherapy and an alternative surgical approach need to be considered. Administration of chemotherapy during the second or third trimester may probably not increase the incidence of congenital malformations. Until now, the long-term outcome of children in utero exposed to oncological treatment modalities is poorly documented, but preterm birth on its own is associated with cognitive impairment. Delivery should be postponed preferably until after a gestational age of 35 weeks. INTERPRETATION: Further research including international registries for gynecologic cancer in pregnancy is urgently needed. The gathering of both available literature and personal experience allowed only suggesting models for treatment of gynecologic cancer in pregnancy.

Primary pelvic exenteration in cervical cancer patients.

Despite the reports of a number of leading institutions concerning the use of primary exenteration, there are differences in regard to definition, indications, and interpretation of results of this treatment approach to cervical cancer. In this paper we present our own experience with 41 cervical cancer patients treated with primary exenteration at St. Stephen Hospital Budapest. We explore some important unsettled aspects (definition, indications, and quality of life consequences) of this treatment modality in view of our own experience and the literature. Between January 1993 and June 2006, 2540 invasive cervical cancer patients were seen at the gynecologic oncology service of the St. Stephens Hospital Budapest. Two hundred twelve (8%) of these patients were surgically explored with the plan of an exenterative surgery. Exenteration was the primary treatment in 41 (25%) of 166 completed exenterations; these 41 cases included 2 cases of supralevator total exenteration, 9 cases of supralevator anterior exenteration, and 30 cases of partial supralevator anterior exenteration. In the 2 total exenteration patients, anal function was restored with a low rectal anastomosis, with a temporary defunctioning colostomy in 1 patient. Urethral function was restored in 9 out of 11 supralevator exenteration cases with the Budapest pouch bladder replacement technique. In the remaining 2 cases, a Bricker conduit was used for urinary diversion. There was no operation-related mortality in this cohort of patients. An external fecal or urinary stoma was avoided in 38 (93%) out of the 41 primary exenteration patients; in 1 patient a temporary defunctioning colostomy was used; and in 2 patients a permanent ileal conduit was created. In 9 patients (22%), complications (ileus and peritonitis, occlusion of the femoral artery, stricture of the implanted ureter, and postoperative ureterovaginal fistula) necessitated surgical intervention. A quality of life study revealed the need for prolonged self-catheterization, partial (mainly night time) incontinence, and lymphedema in 7 patients. We consider and suggest that an en bloc resection of part(s) of the urinary bladder and/or the rectum with the uterine cervix should be considered an exenteration (partial exenteration). A 50% survival rate of a select group of stage IVA cervical cancer patients treated with primary exenteration can be considered significant, but cannot be considered superior to that of chemoradiation therapy. The same applies when considering treatment-related mortality and complications that require operative interventions. Low rectal anastomosis and orthotopic bladder replacement with a relative low risk of fistula formation in non-irradiated patients constitute a strong quality of life argument in favor of primary exenteration in a select group of stage IVA cervical cancer patients.

Cold ischaemic preservation of human uterine tissue.

Uterine transplantation may be a possible treatment option in the future for absolute uterine infertility. The tolerance of human uterine tissue to cold ischemic preservation is one of the issues that need to be resolved. The objective of this study was to assess the morphological changes in human uterine tissue after cold ischemic preservation in a transplant solution. Small tissue samples of human uteri were subjected to cold ischemia (2-8 degrees C for up to 48 hours) in Celsior transplant solution. Histological analysis by light and electron microscopy was used to assess evidence of cold ischemic injury. Histological examination did not show any major changes of the uterine tissue after 48-hour cold preservation; whereas, electron microscopy after 24 hours confirmed unchanged structural integrity of the uterine myoendometrium. The human uterus is morphologically resistant toward cold ischemia in Celsior preservation solution for up to 24 hours and may be suitable for transplantation purposes.

Human uterus retrieval from a multi-organ donor.

OBJECTIVE: To determine if a uterus can be retrieved for reproductive organ transplantation and to describe the surgical technique. METHODS: We participated in a local organ donor network retrieval team for over 6 months. Heart-beating, brain-dead multi-organ donors were identified through an existing donor network following routine protocols. RESULTS: After institutional review board and organ donor network approval of the uterus transplantation project, approximately 1,800 eligible organ donors were identified as required by legislation. Multi-organ procurement surgery took place in approximate 150 of these, with nine specifically consented for the uterus retrieval. Regularly performed multi-organ transplantation retrievals included the uterus without complications in eight donors. Pedicles used included the ovarian, uterine, or internal iliac vessels. After retrieval, serial histology sections throughout the period of cold ischemia, taken every 15-30 minutes, showed no signs of change over 12 hours of cold ischemia. CONCLUSION: The human uterus can be obtained from local organ donor networks using existing protocols. LEVEL OF EVIDENCE: III.

Abdominal radical trachelectomy during pregnancy to preserve pregnancy and fertility.

BACKGROUND: For 10,000-40,000 women each year, cervical cancer complicates pregnancy. Current therapy usually terminates the pregnancy and results in the loss of future fertility. Abdominal radical trachelectomy is a fertility-preserving alternative to radical hysterectomy for young women with cervical cancer. CASES: We report five pregnancies complicated by cervical cancer treated by abdominal radical trachelectomy with preservation of the concurrent pregnancy and the birth of two healthy term infants. CONCLUSION: Pregnancy complicated by concurrent cervical cancer can be managed with abdominal radical trachelectomy during pregnancy while preserving future fertility.

Pelvic vascular prospects for uterine transplantation.

While developing the technique of abdominal radical trachelectomy for conservative cervical cancer management, the vascular supply of the uterus was thoroughly examined. This was a prelude to study the possibility of uterine transplantation where initial concerns were about how uterine artery anastomosis might be achieved and the subsequent function of these vessels in pregnancy. In experiment 1, the uterine arteries in two sows were divided and reanastomosed. At 6 weeks, all sows including control were inseminated. After weaning 3 months after delivery, the sows were killed, and postmortem studies were undertaken. Successful reanastomoses of the uterine arteries were accomplished in both study sows. After insemination, pregnancy proceeded uneventfully, and both sows farrowed normally with average litter sizes. Histopathology of the uterine arteries revealed minimal intimal fibrosis across all anastomotic sites. Uterine artery anastomosis in the porcine model is feasible with subsequent normal vascular function in pregnancy of the anastomosed vessels.

Pulse oximetry and perfusion index measurement to assess uterine perfusion and viability.

This study was designed to establish if pulse oximetry (O2Sat) and perfusion index (PI) could be used to assess the contribution that uterine and ovarian vessels make to the overall perfusion of the uterus. During routine hysterectomies, the O2Sat and PI were measured over the right and left uterine cornu. These measurements were taken before any vessels were ligated (baseline), after only the ovarian vessels were clamped and then after the uterine vessels were clamped. Clamping the ovarian vessels alone decreased the uterine O2Sat and PI by a statistically significant amount. Subsequent clamping of the uterine vessels produced further significant decreases in O2Sat and PI. We concluded that both pairs of vessels contribute almost equally to uterine perfusion and that there may be a role, particularly for O2Sat and possibly for PI variables, in determining the success of uterine and ovarian vessel reanastomosis in uterine transplantation.

Complications after fertility-preserving radical trachelectomy.

OBJECTIVE: We report a case of cervical cancer treated by radical trachelectomy complicated by pelvic inflammatory disease, tubo-ovarian complex, and infertility. DESIGN: Case report. SETTING: Tertiary referral university hospital. PATIENT(S): A 35-year-old with stage IB1 cervical cancer underwent an uneventful radical vaginal trachelectomy. Three years later she presented with pelvic pain and fever after a new partner. Cervical chlamydia was positive, and sonography showed bilateral complex adnexal masses. Her symptoms resolved with prolonged IV, followed by oral, antibiotics. Temperature, cultures, and blood tests have all normalized but her sonogram demonstrates persistent bilateral hydrosalpinx. She has not conceived and underwent laparoscopic salpingectomy prior to IVF. She remains cancer free. INTERVENTION(S): Radical vaginal trachelectomy, salpingectomy and assisted reproductive techniques. MAIN OUTCOME MEASURE(S): Cancer disease status and fertility preservation. RESULT(S): Three years later, the patient remains cancer free but has been unable to conceive or carry a pregnancy. CONCLUSION(S): Fertility-preserving cancer treatments are relatively new. Complications may be encountered that must be reported, collected, and analyzed to maximize cancer cure and fertility preservation.