INTRODUCTION
Lymphatic metastasis is the primary metastatic mode of cervical cancer .[ 1 ] The rate of inguinal lymph node metastasis is low. The lymphatic drainage of the lower one-third of the vagina is similar to that of vulvar carcinoma, which is drained to the inguinal lymph nodes through the inguinal pathway.[ 2 ] Inguinal lymph node metastasis primarily occurs in patients with vulvar cancer and patients with vaginal cancer with invasion of the lower one-third of the vagina. According to the National Comprehensive Cancer Network (NCCN) guidelines version 1.2021 for cervical cancer , patients with cervical cancer with invasion of the lower one-third of the vagina require bilateral inguinal lymphatic area preventive irradiation. This treatment principle is based on the radiotherapy regimen for patients with vaginal cancer with invasion of the lower one-third of the vagina.[ 3 ] Reportedly, the incidence of inguinal lymph node metastasis in patients with stage I–II vulvar cancer is only 10–26%,[ 4 ] indicating that most patients with early vulvar cancer do not have inguinal lymph node metastasis . Therefore, patients with cervical cancer with invasion of the lower one-third of the vagina have a lower incidence of inguinal lymph node metastasis than patients with vulvar cancer.
Currently, sentinel lymph node biopsy is used in vulvar cancer to avoid systematic lymph node dissection, reduce the injury and postoperative complications of surgery in patients, and improve the quality of life of patients.[ 5 , 6 ] Similarly, we also intended to reduce complications after treatment in patients with cervical cancer .[ 7 ] To reduce the side effects of treatment in patients with cervical cancer with invasion of the lower one-third of the vagina, we proposed that due to the different sites of cervical and vaginal cancer foci, which lead to different metastasis modes, it is not necessary to administer preventive radiation in the inguinal lymphatic region. Some studies have reported a significantly higher rate of 22% of inguinal lymph node metastasis of vaginal cancer[ 8 ] than that of cervical cancer , which was 8%.[ 9 ] However, there is no report on the incidence of inguinal lymph node metastasis in patients with cervical cancer with invasion of the lower one-third of the vagina. Therefore, we conducted this study to investigate the incidence of inguinal lymph node metastasis in patients with cervical cancer with invasion of the lower one-third of the vagina and the necessity of bilateral inguinal lymph node preventive irradiation in patients without pathological metastases of the inguinal lymph nodes .
MATERIALS AND METHODS
Patients
This retrospective cohort study selected 558 patients with International Federation of Gynecology and Obstetrics (2009) stage III cervical cancer who visited the Department of Gynecology Oncology of our hospital from January 2014 to December 2019. The inclusion criteria were pathologically confirmed cervical cancer , invasion of the lower one-third of the vagina, fully exercised the right to know and having normal communication and cognitive skills, and undergoing radiotherapy. The exclusive criteria were a previous history of pelvic and abdominal surgery or radiotherapy, complicated with basic diseases of the gastrointestinal tract or bladder, complicated with diseases of the hematological system or severe basic medical diseases, and severe mental disorders. We speculated that cervical cancer would not recur. The procedures were conducted according to the ethical standards of the responsible committee on human experimentation (institutional or regional) and the Helsinki Declaration of 1975, as revised in 2000. The Medical Ethics Committee of our hospital approved the study (KY2021-14). Informed consent was obtained from the patients and their family members.
Detection of inguinal lymph node metastasis
All patients were subjected to computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), PET-CT, and ultrasound (US) to detect lymph node enlargement in the inguinal region. The enlarged inguinal lymph nodes were then examined pathologically by ultrasound-guided fine-needle aspiration (USgFNAC), and results were reviewed by two independent pathologists blinded to clinical information.
Treatment
As the primary focus of this study was on preventing irradiation and recurrence in the inguinal lymph nodes , we do not describe the treatment plan and recurrence in other sites. All patients received concurrent chemoradiation therapy, including weekly carboplatin (Qilu Pharmaceutical Co. Ltd, Ji Nan, China) or weekly cisplatin (Qilu Pharmaceutical). We designed and optimized image-guided intensity-modulated radiation therapy to treat the pelvic cavity and the inguinal area using the Varian Eclipse Planning System. The prescribed dose in the inguinal region was 2.0 Gy/F × 25 F, with a total of 50 Gy, five times a week for five weeks.
Follow-up
The clinical records of the patients were obtained from the departments providing follow-up care of our hospital. All patients with cervical cancer included in this study were followed up periodically by telephone to evaluate recurrence in the inguinal lymph nodes , inguinal skin damage, lower extremity edema, and femoral head necrosis. This information from discharge to December 2020 was followed up for 12–84 months. The follow-up was performed every 3 months for 2 years, at 6-month intervals for 3–5 years, and annually thereafter. The recurrence in the inguinal lymph nodes was defined as the interval from the end of the treatment to death due to any cause or to the date of the last contact.
Data analysis and statistical methods
The occurrence of inguinal skin damage, lower extremity edema, and femoral head necrosis was observed during and after treatment according to the Radiation Therapy Oncology Group criteria for the classification of radiation injuries. Statistical analysis was conducted using the SAS 9.4 software (SAS Institute Inc., USA). The measurement data were expressed as mean ± standard deviation, and comparison between groups was performed using t-test. Data were enumerated using frequency (percentage), and comparison between groups was performed using a Chi-square test. A test level of α = 0.05 and P < 0.05 indicated statistically significant differences.
RESULTS
Clinical characteristics of patients and inguinal lymph node metastasis rate
The study subjects included 184 patients with cervical cancer with invasion of the lower one-third of the vagina. Of the 184 patients, 13 (7.07%) showed inguinal lymph node enlargement on imaging examination, and only four cases (2.17%) were further confirmed by pathology.
The remaining 180 patients without inguinal lymph node metastasis were divided into two groups, preventive radiotherapy (109 patients) and nonpreventive radiotherapy (71 patients), on the basis of whether the inguinal lymph node was irradiated. The age, pathological type, invasion of the vaginal wall, and pelvic lymph node metastasis of the two groups showed no statistically significant differences (P > 0.05) [Table 1 ]. Details regarding the vaginal invasion in the 184 patients with cervical cancer with invasion of the lower one-third of the vagina are shown in Table 2 . A total of 13 types of vaginal invasion have been reported. The front vaginal wall was invaded in 133 (72.28%) patients, and the back vaginal wall was invaded in 19 (10.33%) patients. Both the anterior–posterior vaginal wall and the four vaginal walls were invaded in seven (3.8%) patients.
Table 1: Clinical characteristics of the two groups of patients
Table 2: List of vaginal invasion in 184 patients with cervical cancer
Comparison of the incidence of local adverse events and recurrence in the inguinal lymph nodes between the two groups
In the group without inguinal region prophylaxis irradiation, only three patients had skin reactions, such as congestion and redness, dry desquamation, and wet peeling, in the inguinal region. In the inguinal area prophylaxis irradiation group, 26 patients had adverse events, among whom three had both local skin damage and lower limb edema. The incidence of adverse events was significantly different between the two groups (p = 0.0004) [Table 3 ]. In the follow-up of the two groups after treatment, no recurrence was detected in the inguinal lymph nodes .
Table 3: Comparison of local radiation injury in the inguinal region between the two groups
DISCUSSION
Lymphatic metastasis is the primary dissemination route of cervical cancer .[ 10 ] The NCCN guidelines recommend that patients with definite inguinal lymph node metastasis and those with invasion of the lower one-third of the vagina should receive inguinal region irradiation. However, irradiation in the inguinal region might cause skin damage, rupture, and local contracture, edema of lower extremities, and femoral head necrosis, which might result in physical and mental harm to the patients.[ 11 ] Moreover, an increase in the dose and range of radiotherapy results in worsening of the side effects. Although radiotherapy is essential for patients with inguinal lymph node metastasis , it is not clear whether patients with cervical cancer with invasion of the lower one-third of the vagina without lymph node metastasis require preventive inguinal area irradiation.
This study was aimed at investigating the rate of inguinal lymph node metastasis in patients with cervical cancer with invasion in the lower one-third of the vagina. Imaging examination methods are often used to evaluate the metastasis of lymph nodes, wherein the common methods include CT,[ 12 , 13 ] MRI,[ 14 , 15 ] PET,[ 16 ] PET-CT,[ 17–19 ] and US[ 20 ] for inguinal lymph node examination with high accuracy. Subsequently, USgFNAC is essential for pathological examination.[ 13 , 20 , 21 ] Stecklein et al . reported that 33/407 (8%) patients with stage III–IV vulvar cancer showed inguinal lymph node enlargement on imaging examination, but only 8 (2%) patients had tumor metastasis after biopsy. All the 33 patients underwent radiotherapy and chemotherapy, after 3 years, four patients showed lymph node recurrence in the inguinal region, including three patients with simultaneous vulvar region recurrence. Therefore, lymph node recurrence in the inguinal region might be related to vulvar region recurrence.[ 22 ] Henriksen et al .[ 9 ] reported that the rate of inguinal lymph node metastasis of cervical cancer was 8%, but the clinical estimate was >25% when compared with autopsy results, and lymph nodes with inflammation and sclerosis were mistaken for malignant metastasis. In the present study, 13 (7.07%) of 184 patients with cervical cancer showed inguinal lymph node enlargement, but only four cases (2.17%) were pathologically confirmed to have inguinal lymph node metastasis , indicating a significant difference between imaging and pathological diagnosis. We also found that two of the four patients with inguinal lymph node metastasis had stage IV cervical cancer , with multiple metastases in the entire body, including supraclavicular lymph nodes. Inguinal lymph node metastasis may be associated with the strong invasion and metastasis ability of cancer cells and the late stage of the disease. Currently, there is no clear evidence to prove that patients with cervical cancer with invasion of the lower one-third of the vagina are susceptible to inguinal lymph node metastasis , especially those confirmed by pathology.
We next compared the rates of local secondary injury and local recurrence in the groin of 180 patients with cervical cancer with invasion the lower one-third of the vagina. No recurrence was detected in the inguinal lymph nodes in the nonpreventive irradiation group, except for the local side damage that was less than that in the preventive irradiation group. It has been reported that the rate of inguinal lymph node metastasis in patients with cervical cancer recurrence was 9.8%. Even if there is inguinal lymph node recurrence, the prognosis is better after the active treatment of enlarged lymph nodes.[ 23 ] Fagundes et al .[ 24 ] conducted a follow-up of patients with cervical cancer after treatment for 10 years and found that 199 of 312 patients with stage III–IVA cervical cancer developed recurrence and metastasis, among whom eight patients (4%) had inguinal lymph node metastasis . Hence, it could be deduced that the rate of inguinal lymph node recurrence and metastasis is not high after the treatment of advanced cervical cancer . In the present study, we found that the vaginal wall of two patients with inguinal lymph node metastasis was deeply invaded, reaching the vaginal opening. Therefore, preventive radiotherapy may be essential for patients with deep vaginal wall invasion. This was a single-centre retrospective study, requiring a large dataset from multiple centers and abundant cases.
To summarize, the rate of inguinal lymph node metastasis in patients with cervical cancer with invasion of the lower one-third of the vagina is 2.17%, as evaluated by pathological examination. Node needle aspiration biopsy is a simple method and recommended as a preferred alternative to imaging in the diagnosis of inguinal lymph node metastases. Prophylactic irradiation of inguinal lymph nodes in patients with cervical cancer with invasion in the lower one-third of the vagina, but without pathological metastasis, did not reduce the recurrence rate of inguinal lymph nodes , and rather increased the incidence of local collateral injuries. Therefore, prophylactic inguinal lymph node irradiation is not essential for these patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Haiyan Foundation of Harbin Medical University Cancer Hospital JJZD2021-16.
Conflicts of interest
There are no conflicts of interest.
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