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Abstract
Objective There has been a contemporary shift in clinical practice towards tailoring treatment in patients with early cervical cancer and low-risk features to non-radical surgery. The objective of this study was to evaluate the oncologic, fertility, and obstetric outcomes after cervical conization and sentinel lymph node (SLN) biopsy in patients with early stage low-risk cervical cancer.
Methods We conducted a retrospective review in patients with early cervical cancer treated with cervical conization and lymph node assessment between November 2008 and February 2020. Eligibility criteria included patients with a histologic diagnosis of invasive squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma, International Federation of Gynecology and Obstetrics 2009 stage IA1 with positive lymphovascular space invasion (LVSI), stage IA2, or stage IB1 (≤2 cm) with less than two-thirds (<10 mm) cervical stromal invasion.
Results A total of 44 patients were included in the analysis. The median age was 31 years (range 19–61) and 20 patients (45%) were nulliparous. One patient had a 25 mm tumor while the remaining patients had tumors smaller than 20 mm. Eighteen (41%) patients had LVSI. Median follow-up was 44 months (range 6–137). A total of 17 (39%) patients had negative margins on the diagnostic excisional procedure, and none had residual disease on the repeat cone biopsy. Three (6.8%) patients had micrometastases detected in the SLNs and underwent ipsilateral lymphadenectomy; all remaining non-SLN lymph nodes were negative. Six (13.6%) patients required more definitive surgical or adjuvant treatment due to high-risk pathologic features. There were no recurrences documented. Three patients developed cervical stenosis. The live birth rate was 85% and 16 (94%) of 17 patients had live births at term.
Conclusion Cervical conization with SLN biopsy appears to be a safe treatment option in selected patients with early cervical cancer. Future results of prospective trials may shed definitive light on fertility-sparing options in this group of patients.
- cervix uteri
- surgical procedures
- operative
- uterine cervical neoplasms
- gynecologic surgical procedures
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HIGHLIGHTS
Cervical conization with lymph node assessment by sentinel lymph node mapping is feasible in patients with low-risk early cervical cancer.
In patients with negative margins on diagnostic loop electrosurgical excision procedure or cone biopsy, a repeat cone biopsy may not be necessary.
A total of 13.6% of patients required definitive surgery or adjuvant treatment after cervical conization.
Introduction
Ever since the publication of a large case series of surgical management of cervical cancer by Wertheim and co-workers,1 numerous alterations have been proposed to the radical hysterectomy. Some have led to the development of ultraradical surgery2 and some have incorporated modifications to limit the radicality of resection by extending or reducing the excision margins, respectively.3 Based on knowledge regarding high-risk features, probability and location of metastatic spread, there has been a gradual shift towards tailoring treatment and an interest in less radical surgery for patients with early stage disease and low-risk pathologic features.4
For patients who wish to preserve fertility, the standard of care is a radical trachelectomy.5 In patients with small tumors (<2 cm), recurrence ranges from 4% to 6%,6 similar to patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB1 treated with radical hysterectomy.7 Despite excellent oncologic outcomes, rates of infertility and obstetric complications are relatively high after radical trachelectomy.8 9 In a retrospective review of 360 patients treated with abdominal radical trachelectomy, 58% of patients had a diagnosis of infertility, mostly related to cervical stenosis and fallopian tube obstruction.10 A recent systematic review found that the rate of premature delivery was 39–57%.9 Routine use of a prophylactic cerclage can decrease prematurity rates by almost 50%, but it is associated with a higher incidence of cervical stenosis.11
In comparison, pre-term delivery occurred in only 15% of patients treated with non-radical surgery (cone biopsy or simple trachelectomy).9 Non-radical surgery has emerged as a treatment option given that the risk of parametrial invasion in pre-selected patients with early cervical cancer and low-risk pathologic features is less than 1%.12–14 Despite the lack of a rigid definition of low-risk disease, it is generally accepted that this includes patients with tumors <2 cm in size, limited depth of invasion to the inner half or two-thirds of the cervical stroma, and negative pelvic lymph nodes. Results from GOG278 and SHAPE, two prospective trials evaluating quality of life and oncologic outcomes after conservative surgery in patients with FIGO stage I cervical cancer, are currently pending. Preliminary results from the ConCerv trial, a prospective multicenter cohort trial, reported two (4.5%) of 44 patients who underwent cervical conization with lymph node assessment had recurrences at a median follow-up of 25 months.15
There have been fewer than 250 cases reported in the literature across multiple retrospective series of patients with early cervical cancer treated with a cone biopsy and lymph node assessment.16 The relatively uncommon incidence of the disease in developed countries, strict eligibility criteria, and widely varying surgical options indicate that randomized trials of cervical conization or simple trachelectomy may not be feasible and that, similar to radical trachelectomy, adoption into accepted clinical practice may be predominantly based on data from cohort and retrospective studies. The purpose of our study is to evaluate oncologic and obstetric outcomes in patients with early cervical cancer who underwent a cone biopsy and lymph node assessment.
Methods
Patient selection
This was a retrospective cohort study of prospectively collected data in patients with early cervical cancer treated with a cone biopsy and lymph node assessment. Approval from the institutional ethics review board was obtained. Patients treated by members of our division between January 2008 and April 2020 with a diagnosis of cervical cancer FIGO 2009 stages IA1–IB1 were identified. Eligibility criteria included patients with a histologic diagnosis of invasive squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma, stage IA1 with positive lymphovascular space invasion (LVSI), stage IA2 or stage IB1 (≤2 cm) with less than two-thirds (<10 mm) cervical stromal invasion. Diagnostic and surgical specimens were reviewed by a gynecologic pathologist. Patient electronic and paper medical records were reviewed and detailed pathologic data as well as oncologic and obstetric outcomes were recorded.
Surgical procedure and histopathology
Surgery included a cone biopsy and lymph node assessment by laparoscopic sentinel lymph node (SLN) biopsy. The protocols for the SLN procedure using technetium sulfur colloid or indocyanine green and for the histopathologic assessment have been previously published.17 18 Confirmatory pelvic lymphadenectomy was not performed if the SLN was negative on frozen section. If the SLN was not identified, an ipsilateral pelvic lymphadenectomy was completed.
Patients who were found to have nodal macrometastasis were treated with primary chemoradiation. Patients with nodal micrometastasis underwent completion ipsilateral lymphadenectomy to rule out the presence of other positive lymph nodes. Two patients with one lymph node micrometastasis received no further adjuvant treatment based on the nodal micrometastasis alone, while one patient with two lymph nodes positive for micrometastasis received adjuvant chemoradiation.
Results
Patient and tumor characteristics
A total of 44 patients met the inclusion criteria and were included in the study. Patient and tumor characteristics are summarized in Table 1. The median age was 31 years (range 19–61) and 20 patients (45%) were nulliparous. One patient had a 25 mm tumor, while the remaining patients had tumors <20 mm; 18 (41%) patients had lymphovascular invasion.
Patient and treatment characteristics
Surgical and adjuvant treatment
The majority of patients in the study were referred for management after a diagnostic excisional procedure: loop electrosurgical excision procedure (LEEP; 18/44, 41%) or cone biopsy (21/44, 48%), while four patients (9%) had a cervical biopsy only (one patient did not have documentation on the type of initial diagnostic procedure). Seventeen (39%) patients had negative margins on the diagnostic specimen and 31 (70%) patients did not have any residual disease on the repeat cone biopsy (1/17 patients with negative margins did not have a repeat cone biopsy). All 44 patients had lymph node assessment with SLN biopsy. Three (6.8%) patients had micrometastatic nodal disease; two patients were recognized intra-operatively and complete ipsilateral pelvic and para-aortic lymphadenectomy was performed, while the third underwent a second surgery for an ipsilateral complete pelvic lymphadenectomy. There were no other positive non-sentinel lymph nodes, although one of three patients had two positive SLNs on the same side, both with micrometastasis.
A small number of patients (6/44, 13.6%) required further treatment post-operatively due to high-risk pathological factors; four patients required additional surgery while two patients received pelvic radiation with concurrent chemotherapy. Details of the six patients are shown in Table 2. An additional four patients underwent a simple hysterectomy for non-oncologic reasons at a later date, three for cervical stenosis (after unsuccessful attempts at dilatation with laminaria tents) and one for recurrent persistent high grade squamous intra-epithelial lesion. Median follow-up was 44 months (range 6–137) and no recurrences were noted in any patients.
Characteristics of patients who did not complete non-radical fertility-sparing treatment
Fertility and obstetric outcomes
Of the 38 patients who retained fertility, at least eight (21%) had not attempted to get pregnant. A total of 20 clinical pregnancies and 16 term deliveries were achieved by 13 of 30 patients who attempted pregnancy. One patient underwent two therapeutic abortions and subsequently delivered at term, while another had an ectopic pregnancy and a subsequent pre-term delivery. Five patients underwent in vitro fertilization, one of whom did not achieve a successful pregnancy. Six patients actively tried to get pregnant during the follow-up period and were unsuccessful (6/30, 20% infertility rate). The live birth rate was 85% (17/20) and 16 of the 17 live births (94%) were at term.
Discussion
Our study shows that cervical conization with lymph node assessment by SLN mapping is feasible in patients with low-risk cervical cancer. Despite a proportion of patients who initially met the criteria for conservative management needing to undergo more definitive treatment due to high-risk pathologic criteria, we found no recurrences after a median follow-up of 44 months. A systematic review,6 contemporary retrospective studies,16 19–22 and prospective data from ConCerv15 have similarly found low recurrence rates after cone biopsy, simple trachelectomy, or simple hysterectomy and lymph node assessment in carefully selected patients. Most recently, a group from China reported their outcomes in a case series of 40 patients and reviewed the literature.16 The authors documented one recurrence in their original study and a 5.4% recurrence rate in a pooled analysis of all previously published reports of non-radical fertility-sparing surgery in patients with negative lymph nodes (19/353 reported recurrences).
A substantial proportion of our patients had negative margins on the diagnostic LEEP or cone biopsy (17/44, 39%). The majority (16/17, 94%) had a repeat cone biopsy; no residual invasive carcinoma was detected in any of the repeat cone specimens in these patients, raising the question of the value of a repeat cone biopsy when margins are negative. Similar to previous reports, we found that half (12/24, 50%) of those with positive margins on the diagnostic specimen did not have any residual disease on the repeat cone biopsy.22 However, 25% (6/24) of patients who had positive margins on the diagnostic specimen required more definitive treatment due to positive margins and other high-risk pathologic features after the repeat conization, highlighting the importance of pre-operative patient counseling of potentially needing radical surgery or adjuvant treatment in this population.
In comparison to previously published literature, our study reports outcomes in patients with early cervical cancer after cone biopsy and lymph node assessment with SLN biopsy alone, where all patients did not undergo confirmatory bilateral lymphadenectomy. Two of three patients who had a positive single lymph node with micrometastasis with all other lymph nodes negative did not receive any adjuvant treatment, while the third had two SLNs with micrometastases and received adjuvant chemoradiation. Our group has recently reported on the outcomes of patients treated at our center with early cervical cancer and small volume nodal metastatic disease.18 Receipt of adjuvant treatment was variable and largely based on other pathologic risk factors, making it difficult to draw definite conclusions regarding the most appropriate treatment in this scenario. A recent case series of patients who underwent simple trachelectomy similarly reported that 8% (4/50) of patients had nodal metastatic disease, and they were all small volume disease (micrometastases or isolated tumor cells). In that study, three patients with isolated tumor cells did not receive adjuvant treatment, while the one patient with micrometastases received adjuvant chemotherapy alone. It would be of interest for future studies to consider looking at the role of adjuvant chemotherapy after fertility-sparing surgery in node positive patients to decrease the risk of recurrence while preserving ovarian and uterine function. While platinum-based chemotherapy has also been associated with some ovarian toxicity,23 adjuvant pelvic radiation would significantly impair the goal of preserving fertility, especially if ovarian transposition or oocyte/embryo cryopreservation were not performed.
Two systematic reviews have analyzed the available data on fertility and obstetric outcomes after fertility-preserving surgery in early cervical cancer. In the review by Bentivegna et al in 20168 it was challenging to calculate overall pregnancy rates for the patients who had undergone non-radical surgery (cone biopsy or simple trachelectomy) due to the data available. An updated review by Nezhat et al9 reported the highest live birth rate with cervical conization or simple trachelectomy at 86.4% compared with radical fertility-sparing surgery. These findings compare favorably with our calculated live birth rate of 85%. Importantly, 16 of the 17 live births we observed occurred at term without the use of a prophylactic cerclage, while the prematurity rate in the literature ranges from 30% to 50% with radical trachelectomy.8 9 Six patients (20%) tried to become pregnant during the follow-up period but experienced infertility. In the USA the incidence of primary infertility in the general population is reported at 7–9% in women younger than 34 and 25% in the 34–39 years age group.24
There were no major peri-operative complications in our cohort, but three patients developed cervical stenosis and eventually required a simple hysterectomy for symptomatic control. Similar findings have been reported by others with cervical stenosis in 4–16% of patients9 16 22 after cone biopsy or simple trachelectomy compared with 10–30% after radical trachelectomy.8 9 25 Procedures to prevent stenosis of the cervix have not been well studied in non-radical surgery for cervical cancer, but a review by Li et al25 showed that the use of intra-uterine devices, catheters, or Smit sleeves may help decrease the risk of cervical stenosis after radical trachelectomy. A recent randomized study showed benefit of timed cervical dilation in post-menopausal women after LEEP for cervical dysplasia.25
Our results suggest that, in patients with negative margins on diagnostic LEEP or cone biopsy, a repeat cone biopsy may not be necessary. Similar to other studies, our group has had excellent oncologic outcomes without any recurrences to date with appropriate pre-operative patient selection and use of radical surgery or chemoradiation when high-risk features are detected. Moreover, most live births occurred at term, circumventing one of the main drawbacks of radical trachelectomy—namely, prematurity. Cervical stenosis was the most commonly encountered complication in this case series. Future studies are needed to assess the utility of tools to prevent stenosis in this population to further improve fertility and obstetric outcomes. The limitations of our study include the small number of patients and retrospective study design, leading to inherent selection, measurement, and attrition bias. Larger prospective studies are needed in order to confirm the oncologic safety, as well as the obstetric and fertility advantages of cervical conization compared with radical trachelectomy in a defined low-risk group of patients, but are unlikely to occur. Cervical conization with lymph node assessment appears to be a safe alternative to radical trachelectomy in patients with small cervical tumors without deep stromal invasion and no metastatic spread, while also reducing fertility, obstetric, and peri-operative complications.
References
Footnotes
Contributors AN performed data collection, analysis and wrote the manuscript. ZM performed data collection. LTG, RK, and DV were involved in the surgical treatment of patients and manuscript editing. AC is the senior author, involved in the surgical treatment of patients, and also responsible for the study idea, and for supervising data collection, analysis, and manuscript editing.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. In accordance with the journal’s guidelines, we will provide our data for the reproducibility of this study in other centers if such is requested.