Cervical cancer is the second commonest female malignancy worldwide.1 Although the overall incidence has decreased in countries with effective screening programs, in these countries cervical cancer is being detected at an earlier stage and this coupled with the tendency to delay pregnancy has led to the dilemma of fertility conservation in those with early cervical cancer.
In Scotland, despite an established screening program since 1988, there are approximately 280 cases of cervical cancer diagnosed per year. The West of Scotland Cancer Network (WoSCAN) serves a population of 2.5 million. There are several colposcopy units within the region which all feed into the network/multidisciplinary team (MDT) based in Glasgow. Within WoSCAN, 30% of cases of cervical cancer are diagnosed through our screening program. The most recent data have revealed that, in 2011, there were 134 cases of cervical cancer diagnosed.2
The gold standard surgical treatment of early cervical cancer remains a radical hysterectomy with pelvic node dissection (RHND) as described by Wertheim3 in the 1900s. Current practice is simple hysterectomy with or without bilateral pelvic lymph node dissection (BPND) for stage I [International Federation of Gynaecology and Obstetrics (FIGO) 2009] and RHND for stages IB1 and IIA (FIGO 2009). For those wishing to conserve their fertility, there is the option of radical trachelectomy (RT). This was first described by Dargent et al4 in 1994. Although successful, this procedure is associated with significant obstetric morbidity including preterm labor and midtrimester pregnancy loss.5–8 It also requires the surgeon to obtain specialist surgical skills and is associated with 10% to 15% morbidity.9 However, there is ongoing uncertainty and debate within the Gynaecological Oncology community that such radical surgery may be over treating cases of early cervical cancer.10
The SHAPE Trial, a Gynecologic Cancer Intergroup trial led by the NCIC Clinical Trials Group, has been proposed to address this issue.11 This randomized controlled trial (RCT) will compare RHND with simple hysterectomy and BPLND for stage IA2 and stage IB1 cancers which are less than 2 cm. The hypothesis of this trial is that omitting excision of the parametrium with its associated nodal tissue and the upper 2 cm of vagina is oncologically safe in the management of early cervical cancer. In early stage cervical cancer, the recurrence risk is low and the risk of parametrial involvement is consistently less than 1%.12–15 These data support the theory that involvement of the pelvic lymph nodes is the most important prognostic factor in early cervical cancer. In early cervical cancer, measuring less than 2 cm, if the lymphatics are negative the likelihood of parametrial involvement is 0.6% to 1%.15 This forms the basis of the hypothesis that the pelvic lymph nodes are a surrogate marker of parametrial involvement; hence, radical excision of the parametrium can be omitted if they are negative.
Presently, there is no proposal for a trial of a less radical alternative to RT in those patients with early cervical cancer who wish to conserve their fertility. We proposed that repeat large loop excision of the transformation zone (LLETZ) and laparoscopic pelvic BPND is an oncologically safe alternative to RHND and RT, in early stage disease where the tumor is less than 2 cm.
Using the theater logbooks of Glasgow Royal Infirmary, all cases of BPND (laparotomy and laparoscopy) between 2004 and November 2011 were manually identified. We then excluded cases which had endometrial or ovarian cancer. Paper and electronic case notes and the Scottish cervical cytology recall system (SCCRS) were used to obtain the clinical and pathological information required.
The following data were collected on a pro forma sheet: age, parity, smoking status, detection (screen-detected cancer/symptomatic cancer presentation/both), smear history, histological subtype and grade, presence of lymphovascular space invasion (LVSI), FIGO stage, planned and actual procedure, reason for deviation, any intraoperative/postoperative or long-term complications, lymph node count, duration of follow-up, subsequent obstetric history, and recurrence of cervical cancer.
The cases included in our study were initially managed within their local colposcopy clinic. They had undergone LLETZ/punch biopsy for suspected high-grade cervical intraepithelial neoplasia (CIN) but were diagnosed with microscopic cervical cancers on pathological analysis. After this diagnosis, the cases within WoSCAN were discussed at our weekly MDT after assessment at a colposcopy clinic. Patients who had an early cervical cancer and who expressed a desire to conserve their fertility were discussed and offered fertility conserving management if appropriate. Before 2004, all patients who were offered fertility conservation were referred onto supraregional services for consideration of RT and BPND. In 2004, we began to offer repeat LLETZ with laparoscopic BPND to early cervical cancer cases, stages IA2 and 1B1 less than 2 cm, instead of RT. As part of the preoperative workup, it was recommended that a magnetic resonance imaging (MRI) of the pelvis be performed.
Patients were seen pre operatively by a Consultant Gynaecological Oncologist and counseled appropriately regarding the risks and benefits of their management options. All women were offered the gold standard treatment of RHND if fertility was not an issue, referral for RT and BPND, or the possibility of a repeat LLETZ with laparoscopic BPND. Patients were counseled that repeat LLETZ with laparoscopic BPND was not the “gold standard” treatment. If significant residual invasive disease was found at the time of colposcopic assessment including repeat LLETZ, then they were offered referral for consideration of RT with BPND or RHND. If the pelvic lymph nodes were positive, then they were offered chemoradiotherapy.
Pelvic lymphadenectomy was defined anatomically. The lateral boundary was the midportion of the psoas muscle, the medial border of the obliterated umbilical artery, the superior border was the bifurcation of common iliac artery, inferior border was the circumflex iliac artery, and deep margin was the obturator nerve. All fatty tissue within these boundaries was removed to completely expose the external iliac vessels and the obturator nerve.
Pathology was reviewed by 2 gynecological pathologists and all cases were then rediscussed postoperatively at the MDT. The FIGO staging was used. Where there was multifocal disease, this was not summated; the staging was based on the dimensions of the single largest focus. Within our network, we have specialist gynecological pathologists to ensure that no microinvasive case was unnecessary upstaged and that there was consistency with regards grading and presence of LVSI.
Patients were reviewed long-term within the colpos copy setting. This involved colposcopic assessment and cervical cytology. Human papillomavirus (HPV) testing was not performed as this has only been widely available within our service during the last 12 months before submitting this study.
Subsequent obstetric care was provided by obstetricians in the region where the patient lived, with information being provided to them with respect to the cervical procedures undertaken. Management was thereafter guided by the protocols in the respective obstetric departments. The Gynaecological Oncology team had no input into the subsequent obstetric management including the decision to perform transvaginal ultrasound scans for the measurement of cervical length or the placement of sutures.
Forty-three patients underwent fertility conserving management of early cervical cancer between 2004 and 2011. Forty (93%) cancers were screen detected. Three (7%) patients presented with symptoms and after onward referral to Gynaecology Department were subsequently diagnosed with a cervical cancer.
Mean age was 29 years (range, 22–38 years); 28 (65.1%) were nulliparous, 7 (16.3%) para 1, 4 (9.3%) para 2, 1 (2.3%) para 4, and it was not recorded in 3 (7%). Twelve (27.9%) were smokers, 23 (53.5%) nonsmokers, and 2 (4.7%) ex-smokers. Smoking status was not recorded in 6 (14%). Thirty-nine (90.7%) cases were screen-detected (Table 1).
There were 28 (65.1%) squamous carcinoma, 11 (25.6%) adenocarcinoma, and 4 (9.3%) adenosquamous carcinoma.
Only 1 cancer measured more than 2 cm (26 mm). There were 2 (4.7%) cases of stage IA1 with LVSI, 4 (9.3%) were stage IA2, and 37 (86%) were stage IB1. The pathological characteristics are illustrated in Table 1.
In the LLETZ excision performed for diagnosis of cancer, there was coexisting high-grade CIN in 32 (74.4%), 12 (27.9%) high-grade cervical glandular intraepithelial neoplasia, and 6 (14%) had both present. This was completely excised in 5 (11.6%), incompletely excised in 28 (65.1%), and not recorded in 8 (18.6%).
Forty-two patients underwent a second LLETZ. In those cases who had a second LLETZs, 29 had no residual disease, 8 had residual carcinoma, and 5 had residual high-grade CIN or cervical glandular intraepithelial neoplasia (Table 2). Three patients who had residual carcinoma in the second LLETZ were counseled and opted for a third LLETZ which did not contain any evidence of tumor or dysplasia. One patient had a single LLETZ as the grade 2 stage IA1 squamous cell cancer with LVSI and HGCIN were both completely excised.
Seven hundred ninety-five lymph nodes were retrieved from all 43 patients. The mean nodal count was 18.5 (median, 18; range, 5–46) from 43 patients. Two positive nodes were retrieved from a single patient (1 from right and 1 from the left side of the pelvis).
Management and Complications
The laparoscopy was converted to laparotomy in 3 patients due to intraoperative bleeding.
There were 3 immediate postoperative complications; infected LLETZ site, bilateral infected pelvic lymphocysts requiring admission and intravenous antibiotics, and secondary hemorrhage from LLETZ site.
Six patients report long-term problems; 2 lymphoedema, 1 abdominal pain, 1 lymphocyst, and 2 thigh paraesthesia.
Three patients were excluded from our follow-up analysis.
Patient 1 is a 36-year-old woman with a screen-detected single foci of grade 1 squamous cell carcinoma stage IB1 had residual tumor within her repeat LLETZ but 12 negative pelvic nodes. After counseling, she opted for completion radical hysterectomy.
Patient 2 is a 22-year-old woman presented with a moderately dyskaryotic smear and a single foci of G2 SCC stage IB1 with no LVSI but with perineural invasion. On her repeat LLETZ, she had residual G2 squamous cell carcinoma with LVSI and had 22 negative pelvic lymph nodes. She opted for completion RH and after MDT discussion also received postoperative chemoradiotherapy.
Patient 3 is a 29-year-old woman presented with a high-grade screening smear to colposcopy. She was diagnosed with a multifocal grade 3 adenosquamous cancer with LVSI. On her repeat LLETZ, the invasive component was incompletely excised and she had 2 positive pelvic lymph nodes. She was counseled and subsequently received chemoradiotherapy. This patient subsequently died of radiation peritonitis. These patients are excluded from the follow-up analysis and follow-up data are therefore presented for 40 patients.
The mean follow-up for 40 patients is 42 months; median, 44; and with a range of 0 to 91 months. However, 2 patients emigrated within the immediate postoperative period.
Two (4.7%) patients developed recurrent carcinoma. No deaths are recorded within those that had fertility conserving management as their sole treatment.
Recurrence 1—Patient with initial G1 squamous cell cervical cancer stage IA2 whose second LLETZ had shown residual HGCIN which extended to the endocervical margin but no residual carcinoma and 25 pelvic lymph nodes were negative. She was diagnosed with recurrence at 33 months after a smear which was suspicious of invasion at colposcopic follow-up. The MRI showed recurrence on the posterior cervix and onto lower 1/3 of vagina. The patient received induction chemotherapy followed by standard pelvic irradiation with 45 Gy in 25 fractions and HDR Brachytherapy (24 Gy in 4 fractions). This patient is well with no further recurrent disease at 36 months.
Recurrence 2—A second patient was diagnosed with recurrence at 25 months. Her initial pathology reported a stage IB1 cancer that had been a single focus of G2 Adenocarcinoma with LVSI and coexisting HGCIN both of which were incompletely excised on her initial LLETZ. Her preoperative MRI was normal and repeat LLETZ showed no preinvasive or invasive disease and 14 pelvic nodes were negative. This patient presented at 25 months with irregular menstrual bleeding and underwent an abdominal hysterectomy at which time an endocervical G3 adenocarci noma was diagnosed. She received concomitant chemoradiotherapy and HDR brachytherapy and is well with no further recurrence at 9 months.
One patient opted for total laparoscopic hysterectomy for abdominal pain and final histology revealed residual CIN2. One patient opted for completion total abdominal hysterectomy when her family was complete and final pathology was negative. One patient had TAH for persistent high-grade smear but pathology of uterus and cervix was negative.
Sixteen (41.9%) patients have subsequently become pregnant, 4 of these are currently pregnant. There have been 15 live children to 12 women so far. One patient had a preterm singleton abdominal delivery at 36 + 4 weeks gestation followed by preterm abdominal delivery of monochorionic diamniotic twins at 32 weeks gestation. Another patient had 2 cesarean sections at term with an abdominal suture in situ. This patient subsequently opted for completion hysterectomy. There have been 4 (9.3%) preterm deliveries in total with the earliest gestation at 32 weeks. Six (14%) patients had a cervical suture inserted. One (2.3%) patient had a first trimester miscarriage and another a first trimester termination of pregnancy. The Gynaecological Oncology team had no input into the obstetric management.
There are a number of publications supporting RT as a safe oncological procedure with comparable recurrence rates, morbidity, and mortality as the gold standard RHND.4–8,16,17 However, there remain concerns regarding the obstetric sequelae of RT. The SHAPE RCT can be extrapolated to the management of those desiring fertility conservation and we believe that LLETZ is a safe alternative to RT in selected cases of early cervical cancer.
A review by Rob et al suggests that less radical fertility conserving procedures may be comparable to RT.17 Our proposal was to offer repeat LLETZ and laparoscopic BPND to selected cases of early cervical cancer who were requesting fertility conservation on the basis that if the nodes were negative, the risk of parametrial disease would be less than 1%.15 Although there have been no RCTs assessing the safety of the less radical management of early cervical cancer in those wishing to conserve their fertility, there have been a number of case series within the literature. These describe cases ranging from stage IA1 with LVSI up to stage IB1 and report a 0% to 6% incidence of lymph node metastasis with a low rate of both central and side wall recurrence.18–25 As in previously published papers, we have included cases of 1A1 with LVSI as they are at increased risk of nodal metastasis. 18,23
In our series, we had no recurrence within the pelvic side wall. Although the nodal count varies within our group, the same anatomical boundaries described previously are adhered to when carrying out the procedure. There have not been any side wall recurrences which would be a marker of suboptimal lymphadenectomy technique. A recent cadaveric study confirmed that there is a large variation in nodal count between individuals and supports our varied nodal count.26 We currently do not perform sentinel lymph node assessment in cases of cervical cancer. There are a number of publications which support its feasibility and safety in early cervical cancer.17,27–30 This technique would identify the sentinel node which is not always located within the boundaries of a pelvic lymphadenectomy and detect micrometastasis of which there is emerging evidence that this is an important prognostic factor in early cervical cancer.30,31 We therefore recognize that this is an interesting development which would further limit the morbidity in this select group of patients.
Our series predated the availability of posttreatment HPV-DNA test of cure within the health service in Scotland. A number of published studies have described the use of this in the follow-up early cervical cancer treated with less radical procedures.18,23 Using HPV-DNA testing as an adjunct to cytological and colposcopic follow-up may have altered the clinical course of the 2 patients with central recurrence of their cervical cancer if they were HPV-DNA positive after treatment. We plan to assess the feasibility of incorporating this into the follow-up of newly diagnosed patients who have their cervical cancer managed conservatively.
Most of our cancers were screen-detected cancers which were referred to colposcopy with high-grade cervical cytology. There was a suspicion of invasion noted in the referral cytology in 1 patient only. We feel that this explains why most of our group had the diagnosis of cancer made on LLETZ as in the majority these were not clinically obvious cancers. Some cases were treated under a “see and treat” policy by those performing colposcopy. If a clinically obvious lesion were apparent, then we would anticipate that a punch biopsy would be performed and the patient would be referred to a gynecological oncologist urgently to allow more accurate assessment of the tumor. In our opinion, it is lesions which are not clinically obvious cancers that are suitable for less radical management as they are small and have potentially lower risk. This series highlights one of the strengths of the national cervical screening program within Scotland.
In our series, 42 patients had at least 1 repeat LLETZ procedure. It is interesting, however, that 29 (67%) had no residual carcinoma or preinvasive disease within their second LLETZ. In the remainder, there was invasive disease within 8 (18.6%) and preinvasive disease within 5 (11.6%). Three patients required a third LLETZ and this had no residual disease within it. This substantiates our belief that more radical treatments are overtreating cases of early cervical cancer.
There have, however, been concerns that, although fertility can be conserved with both LLETZ and RT, they may be detrimental to fertility particularly with regard to first and second trimester miscarriages and also preterm labor and its neonatal sequelae. A large case-control study in 1995 by Cruickshank et al reported that when socioepidemiological factors associated with CIN were controlled for, then LLETZ did not have an adverse effect on subsequent pregnancy outcome.32 Subsequent publications have confirmed this.33 However, there are publications which describe a statistically significant risk of preterm labor and delivery in those who had previously had an LLETZ, although there is no significant increase in admissions to the neonatal intensive care unit.35,37 This is in contrast with publications reporting up to a 25% risk of preterm labor post-RT including 10% significant prematurity rate below 32 weeks.5–8 Therefore, although both LLETZ and RT are associated with cervical shortening, this is less marked and less clinically significant in those post-LLETZ.36,38 Our data support this proposition. It is interesting to note that, so far, only 18 patients have become pregnant. It is unclear from this current study whether this is due to patient choice or subfertility.
To our knowledge, this is the largest case series described in the literature of cases of early cervical cancer managed by repeat LLETZ and BPND. It confirms the low morbidity and mortality of this procedure. We have a higher pregnancy rate than previously described studies with 18 (42%) of our patients achieving pregnancy. Although a weakness is that our denominator is unknown. In our group, the preterm labor rate is low with 9% (4 patients) and the earliest gestation was 32 weeks.
In conclusion, even within our highly select group, we have had 2 cases of central recurrent disease. These cases are described previously. We are aware that our numbers are small and therefore are urging caution in the global adoption of this technique in the treatment of early cervical cancer. Ideally, a multicenter, multinational prospective RCT would evaluate the role of repeat LLETZ and laparoscopic nodes in the management of those with early cervical cancer who wish to conserve their fertility to objectively assess its role and minimize bias.
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11. The SHAPE Trial NCIC CTG Protocol Number: CX.5
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