The cervical and uterine neoplasms involve standardized treatments, decided by a multidisciplinary team, according to disease staging. The surgeries performed whenever possible involve, in cervical cancer cases, trachelectomies or radical hysterectomies with bilateral salpingo-oophorectomy, along with obturator fossa, common iliac and interaortocaval lymph node dissection (Wertheim surgery/NCCN Guidelines Version 1.2021)(1). For uterine cancer cases, the most common surgical intervention is total hysterectomy with bilateral salpingo-oophorectomy, along with lymph node sampling (mainly pelvic lymphadenectomy) (NCCN Guidelines Version 2.2020)(2).
The tumor grade (G), the postoperative (pTNM) and the post-neoadjuvant treatment (chemotherapy, radiotherapy, chemoradiotherapy) (ypTNM) the HP examination, associated to immunocytochemistry (cytokeratin AE1/AE3) for detecting micrometastases (pN1mi – pN0 [i+]) may indicate tumor aggressiveness through the presence or absence of neoplastic cells on the surgical specimen and in the obturator lymph nodes(3).
In the genital area neoplasms, the presence or absence of lymph node metastases is a major prognosis factor, representing an important criterion for adjuvant treatment. The CT, MR or PET-CT scans proposed for lymph node staging in uterine cancers provide less accurate outcomes, and the diagnosis is to be clarified by lymph node dissection. However, systematic lymphadenectomy is not lacking complications, some with a substantial impact on the patient’s subsequent evolution. This is why the minimally invasive surgical procedures, such as sentinel lymph node biopsy (SLN), have become more important lately. This technique was successfully used in 1990 in the USA by Giuliano for axillary lymph nodes in breast cancer, and in 1992 by Morton in malignant melanoma, with methyl blue dye. After this technique (credited with low morbidity) was validated, it was applied to vulva, cervix and uterine corpus cancers. Dargent published, in 2000, the first studies for laparoscopic SLN technique. At this moment, studies on SLN in ovarian cancer are underway(4).
Materials and method
Between 2019 and 2020, we registered 123 female patients at the General Surgery and Surgical Oncology Clinic I of the “Prof. Dr Alexandru Trestioreanu” Institute of Oncology, Bucharest. The patients were subjected to cervical and uterine neoplasm surgeries. The excised surgical specimen and obturator lymph nodes HP exam were correlated to the stage and aggressiveness of disease, from an anatomy and pathology perspective. Forty-six patients (37.39%) had uterine corpus neoplasms, and the remaining 77 patients (62.62%) had cervix neoplasms. Their ages varied between 35 and 81 years old, with a mean age of 58.47 years old.
The stage I and II FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) patients, carefully selected subsequently to their neoadjuvant treatment, were subjected to surgery (Wertheim surgery), post-radiotherapy ± chemotherapy ± brachytherapy. The uterine body tumor surgery patients were stage I-II FIGO. They were subjected to total hysterectomy with bilateral salpingo-oophorectomy, obturator fossa and, occasionally, paraaortic lymph node sampling (depending on the CT or MRI result or the intraoperative findings of paraaortic lymph node chain palpation). The treatment was chosen following a multidisciplinary decision of the surgeon, medical oncologist and radiotherapist.
The analyzed lymph node groups were: level I, including the external iliac lymph nodes and the obturator lymph nodes (as described by T. Ionescu and Leveuf-Godard), the hypogastric lymph nodes (as defined by Cunéo and Marcille), and the uterine artery lymph nodes (Lucas Championnière). There are one or more lymph nodes at the obturator fossa level that might be involved in a neoplastic process. The next pelvic lymph nodes level with a potential neoplastic invasion is level II, including the primitive iliac, promontory and latero-sacral lymph nodes. Level III is extra-pelvic and includes the lower lateral aortic, lumbar aortic and paracaval lymph nodes. These lymph nodes are subjected to neoplastic invasion in advanced stages. Sometimes, in advanced cancers, a neoplastic invasion of left supraclavicular lymph nodes (Virchow-Troisier lymph node) may be detected(4).
Obturator and paraaortic lymph node metastases were detected in 9 patients (7.31% of the 123 total). Obturator lymph node metastases were detected in 6 patients (4.87%) and paraaortic lymph node metastases were detected in 3 patients. Out of the six patients with obturator lymph node metastases, five had cervical tumors.
Twenty-five patients (32.46%) with cervical tumors had residual cervical tumors (marked as pT in the anatomy and pathology exam) post-radiotherapy ± chemotherapy (15 patients were subjected to chemotherapy associated with radiotherapy) and Wertheim surgery.
The five patients (4% of 123) with obturator lymph node metastases also had residual cervical tumors post-radiotherapy and had ypT1-2 ypN1 Mx staging. The five patients with obturator lymph node metastases represented 6.49% of the 77 cervical tumor patients subjected to radiotherapy.
Two of them were also subjected to adjuvant chemotherapy with cisplatin. Two patients out of the five had a G3 (poorly differentiated) grade, with high aggressivity from an anatomy and pathology perspective. One patient out of the 25 with residual tumor on the surgical specimen had an endocervical adenocarcinoma (ADK), deemed more aggressive than the squamous carcinoma.
Four patients (8.69%) out of the 46 with uterine corpus tumors had lymph node metastases: two with a G2 (moderately differentiated) tumor grade and obturator lymph node metastases and two with a G3 (poorly differentiated) tumor grade and paraaortic lymph node metastases, where lymph node metastases skipped the pelvic lymph node levels.
The inner iliac lymph node chain is situated under the lower edge of the external iliac vein, and it is linked to the obturator lymph nodes. Thus, the “main” obturator lymph node described by Thoma Ionescu in 1900 and later by Leveuf-Godard (1919-1923) is situated in the anterior part of the lymph node fatty tissue. There are cases where the neoplastic invasion process does not follow the lymph node levels order precisely, skipping from level I to the level II or III lymph node groups. Extensive lymph node dissection is not curative per se. Still, it is necessary when the abdomen and pelvis RMN/CT scans or the intraoperative palpation reveal lymph nodes increased in volume, helping identify the upward expansion of the neoplastic invasion, and thus allowing for a more precise prognosis for the patient. The neoplastic invasion of these lymph nodes determines the appropriate treatment, using adjuvant chemotherapy and/or targeted radiotherapy.
As previously described, the genital neoplasms involve extensive lymph node dissection that may carry additional risks and complications, in addition to high anaesthesia-related and surgery-related risks (obesity, hypertension, diabetes etc.). The pelvic lymphadenectomy complications(5) are:
Internal/external iliac, obturator fossa, corona mortis damage-induced haemorrhages.
Postoperative pelvic lymphocele, lymphorrhagia or pelvic limb lymphoedema or cellulitis.
Deep vein thrombosis, pulmonary embolism.
Obturator or genital-femoral nerve injury.
These complications lead to longer hospitalization and higher costs, therefore the current surgical treatment protocols recommend the sentinel lymph node biopsy technique in stages I-II for gynecologic oncology surgery. It is used for tumors of up to 4 cm in diameter (best results in tumors <2 cm). The cervix is injected with a dye ± Tc 99 (Technetium 99 radiolabelled colloid). The sentinel lymph node is visualized and/or detected with a Tc99 gamma camera during laparoscopic or open surgery. A near infrared camera can visualize the indocyanine green-dyed lymph nodes. The detection rate is 89-92%, with an 89-90% sensitivity (NCCN 1, 2).
The studies indicate that in stage I cervical cancers, the lymph node metastases are present in 0-17% of the cases, meaning that 80% of the cases don’t require lymphadenectomy. In our patients, only 6.49% of those with cervical tumors had obturator lymph node metastases. However, the SLN technique allows for avoiding the bilateral pelvic lymphadenectomy complications(4).
The sentinel lymph node may be detected in one of the following locations: medial from the external iliac blood vessels, anterior from the hypogastric blood vessels, in the upper part of the obturator fossa space. After being detected in the obturator fossa, the lymph node is excised and sent to frozen section pathologic examination. The sentinel lymph node metastases identified on HP examination using serial cross-sectioning and immunohistochemistry change the patient’s postoperative treatment, without decreasing the survival potential, but improving the staging accuracy. Detecting the lymph node metastases determine the use of adjuvant chemotherapy, extending the external radiation ± brachytherapy ± IMRT (Intensity-Modulated Radiation Therapy) for the suspicious lymph nodes. Therefore, any suspicious lymph node needs to be excised and, if the sentinel lymph node mapping is impossible, it is recommended to perform a lymphadenectomy. In the cervical tumors, the lymph node metastases presence (marked as r for radiology or as p for postoperative detection) is correlated with the advanced stages of disease (stage III C, C1 for pelvic lymph nodes, C2 for paraaortic lymph nodes)(1). The 2018 FIGO classification also includes lymph node invasion(1). Endocervical adenocarcinomas are deemed more aggressive than the squamous carcinomas (often in the presence of lymph node metastases), which is important in selecting the adjuvant treatment.
As for the endometrial tumors we recorded (46 patients), we noticed lymph node metastases in 8.69% of the patients (two with obturator lymph node metastases and two with paraaortic lymph node metastases, skipping the first lymph node station). The literature indicates that the lymph node metastasis may be identified in 6% to 9% of the patients, with 2% to 3% in patients with well-differentiated tumors; delimitated endometrial tumors have a low risk of metastasis, of 1%(5). Thus, the stage II FIGO and G3 histology stages in a uterine corpus adenocarcinoma require, in addition to the total hysterectomy and the bilateral adnexectomy, lymph node sampling, as well as external radiation ± brachytherapy ± systemic chemotherapy. The lymph node metastases presence in uterine tumors upgrade the staging to IIIC (NCCN 2.5). Such cases require external radiotherapy and chemotherapy. The SLN technique allows for better endometrial cancer staging, and if positive pelvic lymph nodes are identified, lumbo-aortic lymph node dissection is required. The sentinel lymph node technique is not to be recommended in uterine sarcoma(4-6).
The lymph node status is an important factor in the staging and prognosis of genital neoplasms. The good outcomes of malignant melanoma and breast cancer treatments allowed for expanding the SLN determination to the pelvic neoplasms. At present, the SLN technique is deemed feasible, and performing it using laparoscopy provides new benefits in the curative treatment of uterine cancer, while also being useful in neoplasm staging and in determining the adjuvant/neoadjuvant treatment(6,7). The technique was also successfully applied in treating vulvar cancer(8,9) and multicentric studies are used for ovarian cancer(10). This therapeutic approach for genital cancer is included in the “personalized medicine” concept.
The tumor cells present in the obturator lymph nodes are correlated with advanced disease stages and with aggressive histology and pathology.
Radiotherapy may not always provide the expected outcomes.
It is important to associate chemotherapy to radiotherapy in the cervical tumors.
Lately, the sentinel lymph node detection has become more important in the pelvic oncological surgery (cervix, uterus etc.), thus avoiding the pelvic lymphadenectomy complications. Studies are currently underway for ovarian cancer.
Sentinel lymph node metastases lead to recommending adjuvant chemotherapy ± radiotherapy.
The authors wish to thank Professor Johanna Mäenpää, MD, PhD, Professor (Emer.) of Obstetrics and Gynecology at the Tampere University, Finland, Deputy Medical Director, Clinical Trial Unit of NSGO, for this article.
Conflicts of interests: The authors declare no conflict of interests.