The World Health Organization ranks cervical cancer as the second most common cause of death in women worldwide. Because of better screening methods, the conditions of an increasing number of patients of reproductive age are diagnosed with early-stage microinvasive cervical cancer, and there is a strong trend to delay childbearing. It is beneficial for these women to establish confidence in the fertility-sparing treatment and to improve their quality of life. Fertility-sparing treatments have been hot topics in the gynecologic oncology field.
Cervical cancer is often treated with hysterectomy for routine operation. The traditional operation has obvious shortcomings. In 1987, Dargent proposed radical trachelectomy (RT)21, which has now become the fertility-sparing treatment in microinvasive cervical cancer clinical stage IA2 to IB1 and stage IA1 with lymph vascular space invasion (LVSI). However, the operation has a certain degree of difficulty and complexity, it can only be carried out in a certain range, and the pathology inspection requirements are high; there are high risks of infertility, miscarriage, and preterm birth.1 Cervical cold knife conization (CKC) is the conventional operation used for the treatment of cervical intraepithelial neoplasia 2–3 (CIN2-3). Considering that most patients are diagnosed with microinvasive cervical squamous cell cancer (SCC) at asymptomatic that originates from CIN, the purpose of this study is to explore the feasibility and curative effects of CKC for microinvasive cervical SCC (clinical stage IA1).
MATERIALS AND METHODS
The patients enrolled in this retrospective study were examined in the outpatient clinic of the Beijing Obstetrics and Gynecology Hospital, Capital Medical University, between June 2009 and July 2012. The study was approved by the hospital ethics committee, and informed consents on all procedures were obtained from all patients before examination. All the patients enrolled underwent routine cervical cancer screening. The conditions of all the patients were diagnosed with microinvasive cervical SCC clinical stage IA1 (invasion depth <3 mm, width ≤7 mm) by pathology. All patients were followed up 1 year after the surgery. Exclusion criteria were as follows: cervical lesions and transvaginal operation history, previous chemotherapy, and radiation history. Individual profiles were set up for enrolled patients. Profiles included general conditions (age, menarche, sex age, childbearing, family cancer history, smoking history, menopause, human papillomavirus [HPV] infection), TCT (Thinprep Cytologic Test) screening results, colposcopy, pathological diagnosis, and clinicopathological characteristics (final therapy, LVSI, pelvic lymph node dissection [PLND], cell grade, and resection margin status after CKC).
TCT screening carried out using a ThinPrep 2000 Processor (USA), an automated slide preparation unit that performs liquid-based cytology tests. The slide was examined by specialists with at least 10 years of experience. The cervical cytological diagnostic criteria were adopted from The Bethesda System 2001.2 High-grade atypical squamous cells, low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, and SCC were regarded as the abnormal TCT results, which were needed in performing further colposcopy and cervical biopsy. Patients with atypical squamous cells (ASCUS) underwent a second TCT screening 8 weeks later; TCT was recommended 6 to 12 month if the second result was cervicitis. Colposcopy and cervical biopsy were performed if the second TCT confirmed ASCUS, high-grade atypical squamous cells, low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, or SCC.
Colposcopy was performed by 2 attending physicians using a Leica MZ6 stereomicroscope (Leica Camera AG, Barnack, Germany). The physicians had at least 5 years of experience with colposcopy examination, performing 500 procedures each year. A standard colposcopy protocol was adopted in the current study, including the acetic acid test and Lugol’s iodine experiment.3 The classification and initial diagnosis of abnormal colposcopy were described according to 2003 International Federation for Cervical Pathology and Colposcopy terminology.
Cervical biopsies were analyzed by 2 consultant pathologists, and 5% of the total number of slides were reviewed and double-checked every 3 to 6 months. The WHO Classification of Tumors Pathology and Genetic Tumors of the Breast and Female Genital Organs was used for pathological diagnosis.4 All the biopsies were carried out in suspected cervical lesions.
CKC and Hysterectomy
Cold Knife Conization
Using spinal anesthesia or intravenous anesthesia at lithotomy position, the cervix was exposed and 1/200000 10 mL epinephrine was injected at 3 and 9 points of the cervix to prevent bleeding. The cervical surface was coated with iodine. Observing the iodine stain on the location and scope, circular cone resection was made with cold knife on the cervical surface 0.5 cm outside the area with no iodine coloring (cone height, 2.5–3.0 cm). Cervical suture was subsequently performed for hemostasis.
In this study, 83 patients underwent further hysterectomy, including extrafascial hysterectomy (EFH), extensive hysterectomy (EH), and radical hysterectomy (RH), concrete steps to see gynecology and obstetrics operation.5
All specimens were send to pathology diagnosis if a cone biopsy was performed preoperatively (usually 4–6 weeks before surgery), and if a tumor was found on the hysterectomy specimen, the maximum depth of invasion was defined as the sum of the depth of invasion found on hysterectomy specimen and the depth of invasion found on cone biopsy. If CKC was performed as the final therapy, the maximum depth of invasion found on cone bioscopy was defined as the sum of the depth. Cervical cancer clinical stage was assigned according to the criteria set by the International Federation of Gynecology and Obstetrics.6 Squamous cell cancer cases were graded using a modified Broders7 system (1–3 numerical) grades (grade 1 [G1] indicates well; grade 2 [G2], moderately; grade 3 [G3], poorly differentiated).
A database was established by EpiData software; SPSS 13.0 software was used to perform statistical analysis. Continuous data were expressed as mean (SD). Count data were expressed as percentage (%). The Fisher exact test, t test, or the χ2 was used appropriately in the statistical analysis. P values < 0.05 were considered statistically significant.
General Conditions of Patients With Microinvasive Cervical SCC (Stage IA1)
A total of 108 patients were enrolled finally; CKC were performed in all the patients. Of the total 108 patients, 83 patients (76.9%) underwent further hysterectomy. The mean age of women who underwent CKC as final therapy was obviously younger than the age of women who underwent hysterectomy (P = 0.000). There were no significant differences of other conditions between the 2 groups (Table 1).
Clinicopathological Characteristics of Patients With Microinvasive Cervical SCC
Of the 108 patients, 104 patients were graded G1 (96.3%), and 4 cases were graded G2 (3.7%), but no one was graded G3. Of the 83 patients who underwent further hysterectomy, 48 cases (57.8%) underwent EFH, 30 cases (36.1%) underwent EH, and 5 cases (6.1%) underwent RH. A total of 19 patients underwent PLND; there were 357 lymph node dissections without any lymph node metastasis. A total of 5 patients (4.6%) had LVSI without 1 positive PLND, and all of them underwent further hysterectomy (Table 2).
Cervical Residual Lesion and Prognosis of Microinvasive Cervical SCC
Of the 83 patients who performed further hysterectomy and were followed up 1 year after the operation, 18 patients with positive resection margins indicating cervical residual lesions (CIN1-3) have greater likelihood than 65 patients with clear resection margins, the former was 77.8% (14/18) and the latter was 33.8% (22/65), respectively, but there were no statistic differences (Table 3); Of 18 patients with positive resection margins, LVSI was present in 1 patient with a diagnosis of CIN1 by pathology after further hysterectomy; Of 65 patients with negative resection margins, LVSI was present in 4 patients of whom 2 cases were diagnosed with cervicitis, one was diagnosed with CIN1, and the other one was diagnosed with stage IA1 microinvasive cervical SCC by pathology after further hysterectomy. All pathology showed clear resection margins after hysterectomy. No one presented with metastasis and progression within 1 year of followed-up.
Of the 25 patients who performed CKC as final therapy and were followed up for 1 year, 2 patients with positive resection margins had the second CKC surgery, one was diagnosed with CIN1, and the other one was diagnosed with cervicitis by pathology; 23 had clear resection margins, 2 patients underwent the second CKC 3 months after the first CKC because of the abnormal TCT result, and they were both diagnosed with stage IA1 microinvasive cervical SCC by pathology with clear resection margins. No one presented metastasis and progression within 1 year of follow-up.
Microinvasive cervical SCC refers to the occurrence of early interstitial microinvasive SCC through the basement membrane on cervix (microinvasive width ≤0.7 cm and depth <0.3 cm). Most scholars believe that the incidence is related with early marriage, childbearing, fertility, cervical erosion, frequency of sexual intercourse, sex hormone imbalance, social economic status, and mental factors. In recent years, the link between microinvasive cervical SCC and HPV infection is well established,8 especially HPV16; 18 infections play an important role in microinvasive cervical SCC. Sexually active young women have the high rate of HPV infection, the infection peak is at the age of 18 to 28 years. With the popularization of cervical cancer screening, more young women with microinvasive cervical SCC are diagnosed at an early stage and treated immediately. Fertility-sparing treatments for cervical cancer operation can satisfy the majority of patients’ desire.
Microinvasive cervical SCC treatments included operation, radiotherapy, chemotherapy, and comprehensive treatment. Operation treatment with hysterectomy is still the main treatment for early-stage cervical cancer.9 Aged women who have given birth were recommended with hysterectomy to prevent the recurrence and metastasis of the cancer, and patients with positive LVSI and positive resection margins after CKC who are afraid of progression are also recommended with hysterectomy. Over the past few decades, the fertility-sparing operation of microinvasive cervical SCC has been a hot topic issue in gynecology, varied from cervical CKC to RT with PLND. The various operation selections depend on the various diagnosis standards and were determined by pathological interstitial microinvasive depth and width, LVSI, and tumor size.10 Microinvasive cervical SCC patients who underwent hysterectomy may cause bladder, rectum, and ureteral injury. In addition, hysterectomy weakens the lubrication of cervical secretions, destroys vaginal structural integrity, and causes vaginal shortening, which may be resulted in uncomfortable, painful sexual intercourse, thus affecting the quality of women’s life.11 After hysterectomy, patients with infertility have anxiety and fear, or even severe mental disorders. Of course, there are also some specific problems related to RT such as deep dyspareunia, excessive vaginal discharge, and recurrent candidiasis; these problems seem to be related to the cervical cerclage. Cervical stenosis is not an uncommon problem and may require dilation under anesthesia. It also has been reported that only 63% of all pregnancies after RT resulted in a more or less normal term delivery, usually by cesarean section,12 so there are many reasons to avoid an RT if there is a safe alternative. Cold knife conization causes less injury and bleeding compared with hysterectomy and RT; the data for pregnancy results and operation complications after CKC for early-stage microinvasive cervical cancer show better results than RT, which is important to preserve fertility.13 Patients who had CKC have better quality of life and sex than patients who had hysterectomy and RT as treatment of microinvasive cervical SCC.14
It has been reported that important prognostic factors with early-stage cervical SCC are tumor volume, LVSI, and PLND. Most patients with clinical stage IA1 have small tumor, negative PLND, and negative LVSI. There were reports that the lymph nodes metastasis were found 1.5% to 4.2% in microinvasive cervical SCC stage IA1,15 and others reported that the incidence of lymph nodes metastasis in patients with microinvasive cancer (stage IA1) was 0.1% to 0.8%. Lymph vascular space invasion represents the most controversial issue at presents; the difficulties in assessing LVSI have been expressed in several publications and reflected in a wide range of incidences reported from 0.9% to 10.2%,15 but there were no obvious correlations between LVSI and PLND. Because the risk of recurrence was lower than 1%, the low incidence of LVSI and PLND in stage IA1 cervical cancer could be cured 100% by CKC. Our study showed that 19 patients underwent PLND without 1 positive, and the incidence of positive LVSI was 4.6% (5/108); there was no significant correlation between positive PLND and positive LVSI, which were consistent with those reported previously. As long as it fulfilled the requirements of fertility sparing, CKC could be the preferred surgery under close follow-up, and hysterectomy and PLND may not be required.14,16 The National Comprehensive Cancer Network (NCCN) clinical practice guidelines on early-stage cervical SCC treatment recommendations were as following: the patients without lymph node invasion who have fertility requirements or were not suitable for hysterectomy should undergo fertility-sparing surgery (including CKC); and patients who have no fertility requirements could undergo hysterectomy.17 We found that some young and nulliparous patients who had stage IA1 microinvasive cervical SCC with clear resection margins after CKC considered CKC operation as the final therapy. However, with more desire about the preservation of fertility and increasing childbearing age, aged females who have given birth should get more attention from obstetrics and gynecology doctors to consider fertility-sparing treatment.
Positive resection margins after CKC have been reported,18 which were generally considered to be a risk factor for cervical microinvasive SCC recurrence or persistence, but for subsequent treatment methods, the conclusions were not consistent. The most conservative treatment is close follow-up with TCT, high-risk HPV monitoring, and regular colposcopy.19 The treatments for positive resection margins after CKC vary from merely follow-up to RH with PLND because the various operation types bring patients and physicians difficulty in choosing. Conservative treatment may increase disease recurrence or persistence, and large operation may bring patients unnecessary trauma and complications. Ghaem-Maghami et al20 performed a meta-analysis in patients who underwent CKC from 1966 to 2007 around the world among the 66 results; they indicated that the cervical lesion recurrence risk in positive resection margins after CKC was 5.47 times more than the clear resection margins; the recurrence risk of the lesion advanced than CIN2 was 6.09. The positive resection margins indicate residual lesion possibility up to 38.3% in patients with early-stage cervical cancer.18 Another report showed that a handful of patients with CIN would progress after treatment; therefore, some experts did not suggest using complete clear resection for the final therapy.20 A positive resection margin after CKC was not a hysterectomy operation indication. We found that of the 108 patients diagnosed with cervical microinvasive SCC by pathology after CKC, 83 patients (76.9%) underwent further hysterectomy, and the CIN1 to CIN3 residual lesion rate 77.8% (14/18) in positive resection margins after CKC group was higher than 33.8% (22/65) in the clear resection margins after CKC group, but there were no significant differences (P = 0.917). In addition, there were no obvious correlations among resection margins, PLND, and LVSI. Taking into account, both positive resection margins and clear resection margins after CKC may cause the cervical residual lesion, especially the CIN lesion. Because of the low incidence of positive LVSI and positive PLND in stage IA1 microinvasive cervical SCC, the patients with stage IA1 microinvasive cervical SCC who are eager to preserve fertility can be recommended close surveillance and follow-up with colposcopy after CKC. If necessary, we suggest a second CKC for further fertility-sparing treatment. Because of the short-time follow-up, we will conduct further long-time follow-up.
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© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.