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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 6  |  Page : 1231-1234

Preoperative predictors of pelvic and para-aortic lymph node metastases in cervical cancer


1 Department of Obstetrics and Gynecology, Kaman State Hospital, Kırşehir, Turkey
2 Department of Gynecologic Oncology, Tepecik Education and Research Hospital, Izmir, Turkey
3 Department of Gynecologic Oncology, Mugla Sitki Kocman University, Education and Research Hospital, Mugla, Turkey
4 Department of Gynecology and Oncology, Bakirkoy Sadi Konuk Research and Training Hospital, Istanbul, Turkey

Date of Submission02-Jun-2017
Date of Decision20-Aug-2017
Date of Acceptance25-Feb-2018
Date of Web Publication24-Dec-2019

Correspondence Address:
Dr. Varol Gulseren
Department of Obstetrics and Gynecology, Kaman State Hospital, Kirsehir
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_467_17

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 > Abstract 


Aim: This study investigated potential preoperative predictors of pelvic lymph node (PLN) and para-aortic LN (PaLN) involvement in cervical cancer (CC).
Materials and Methods: This study retrospectively analyzed 283 patients diagnosed with early (stage IA1–IIA) CC who underwent retroperitoneal LN dissection between January 1992 and February 2015. Several risk factors that are believed to influence PLN and PaLN involvement in CC were analyzed as follows: age >50 years, lymphovascular space invasion (LVSI), tumor size ≥2 cm, hemoglobin <12 g/dL, and nonsquamous cell histologic type.
Results: LVSI (odds ratio [OR] = 11.3, 95% confidence interval [CI] = 5.2–24.3) and tumor size (OR = 3.2, 95% CI = 1.4–7.2) were independent predictors of PLN involvement. None of the factors predicted PaLN involvement in a regression analysis. However, all nine patients who had PaLN involvement also had PLN involvement.
Conclusion: LVSI and tumor size independently increase the risk of PLN involvement.

Keywords: Cervical cancer, lymphovascular space invasion, para-aortic lymph node, pelvic lymph node


How to cite this article:
Gulseren V, Kocaer M, Gungorduk O, Ozdemir IA, Gokcu M, Mart EM, Sanci M, Gungorduk K. Preoperative predictors of pelvic and para-aortic lymph node metastases in cervical cancer. J Can Res Ther 2019;15:1231-4

How to cite this URL:
Gulseren V, Kocaer M, Gungorduk O, Ozdemir IA, Gokcu M, Mart EM, Sanci M, Gungorduk K. Preoperative predictors of pelvic and para-aortic lymph node metastases in cervical cancer. J Can Res Ther [serial online] 2019 [cited 2020 Apr 1];15:1231-4. Available from: http://www.cancerjournal.net/text.asp?2019/15/6/1231/231454




 > Introduction Top


Cervical cancer (CC) is the second most common cancer in women and the third leading cause of death due to a gynecological malignancy.[1] With screening programs, the detection of early-stage CC has increased gradually. Treatment options for early-stage CC include radical surgery or primary radiotherapy (RT) or combined therapy.[1] Prognostic factors in early CC are the clinical stage, tumor histology, size of the primary tumor, depth of invasion, presence of tumor cells at the surgical margins, tumor grade, parametrium metastasis, lymph node (LN) metastasis, and lymphovascular space invasion (LVSI).

The International Federation of Gynecology and Obstetrics (FIGO) published a clinical staging system for CC. The most important prognostic factor in CC is LN status.[2],[3] The 5-year survival rate decreases from 85% to 50% with LN involvement.[4] An extended lymphadenectomy may have unfavorable adverse effects. The possibility of detecting LN involvement in early-stage CC patients is <10%.[5] To reduce the morbidity of lymphadenectomy, treatment should be individualized, and the extent of lymphadenectomy should be specified. Unfortunately, the sensitivity of the imaging modalities used to evaluate LNs in CC patients is low as follows: 67%, 38%, and 84% for computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET), respectively.[5],[6] The false-negative rate of PET is 16%–32%.[6] Prognostic factors for early-stage CCs that are identified preoperatively, excluding stage, can help to determine the LN involvement rate preoperatively and plan for or extend lymphadenectomy.

This study investigated the potential roles of risk factors that are identified preoperatively in predicting pelvic LN (PLN) and para-aortic LN (PaLN) involvement.


 > Materials and Methods Top


This study retrospectively evaluated 283 patients diagnosed with early (stage IA1–IIA) CC who underwent retroperitoneal LN dissection at the Tepecik Research and Teaching Hospital Gynecologic Oncology Clinic between January 1992 and February 2015. This study was approved by the Local Ethics Committee. Clinical staging (FIGO 2009) was performed under general anesthesia. Blood was drawn at the initial diagnosis and patients were evaluated using MRI. The existence of metastasis, disease-free survival (DFS), overall survival (OS), type and dosage of chemotherapy, and dosage of RT were analyzed.

The following risk factors believed to influence PLN and PaLN involvement in CC were analyzed: LVSI, tumor size ≥2 cm, age >50 years, hemoglobin <12 g/dL, and nonsquamous cell carcinoma histologic type.

Postoperatively, the women were evaluated every 3 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter. CT or MRI was performed annually. The criterion for ending follow-up was death of the patient. The effects of LVSI, tumor size, hemoglobin level, age, and histological type on prognosis, PLN and PaLN involvement, recurrence, and survival were assessed.

Survival analysis was performed using the Kaplan–Meier method, and the results were compared using the log-rank test. DFS was defined as the time from the date of primary surgery to the detection of recurrence or last observation. OS was defined as the time from the date of primary surgery to death or the last observation. The Chi-Square test and Student's t-test for unpaired data were used for the statistical analysis. A Cox regression analysis was used to determine factors affecting survival; the results are presented as hazard ratios. All statistical analyses were performed using MedCalc version 11.5 for Windows (MedCalc Software, Mariakerke, Belgium). A value of P < 0.05 was considered to indicate statistical significance.


 > Results Top


During the study period, a total of 844 patients with CC were investigated. A total of 435 patients with early-stage CC were investigated of whom 283 (65%) underwent retroperitoneal LN dissection. [Table 1] summarizes the patients' demographic data and clinical features. The mean DFS and OS times were 82 ± 61 and 85 ± 60 months, respectively.
Table 1: Clinical characteristics of the study population

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The complications during surgery were urinary bladder laceration in two patients (0.7%), rectum laceration in one patient (0.4%), and pulmonary emboli in one patient (0.4%). Complications of chemoradiotherapy (CRT) included leukopenia in three patients (1.4%), and allergy, vesicovaginal fistula, ileus, and secondary tuberculosis in one patient each (each 0.5%).

[Table 2] and [Table 3] show the relationships between prognostic factors and PLN and PaLN involvement according to a multivariate and univariate regression analysis. LVSI (odds ratio [OR] = 11.3, 95% confidence interval [CI] = 5.2–24.3) and tumor size (OR = 3.2, 95% CI = 1.4–7.2) were independent risk factors for PLN involvement. There were no significant predictors of PaLN involvement. However, all nine patients who had PaLN involvement also had PLN involvement.
Table 2: The relationship between prognostic factors and pelvic lymph node and para-aortic lymph node involvement with P values from the multivariate regression analysis of early-stage cervical cancer

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Table 3: The relationship between prognostic factors and pelvic lymph node and para-aortic lymph node involvement with P values from the univariate regression analysis of early-stage cervical cancer

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 > Discussion Top


This study investigated the preoperative predictors of LN involvement because imaging modalities have low sensitivity for determining LN involvement, and sentinel LN dissection has high false-negative rates for confirming micrometastasis using frozen sections.[5],[6],[7] The reported frequency of PLN involvement is 19%–20.2%.[8],[9] In this study, the PLN and PaLN involvement rates were 23% and 3.9%, respectively.

The most frequent long-term complication of pelvic lymphadenectomy is lymphedema (4%–20%).[8],[10] Lymphocysts, a short-term complication, can cause pain and infection and are seen in 10%–25% of cases.[9],[10] Low-molecular-weight heparin treatment can decrease the occurrence of lymphocysts.[11] PLN involvement and postoperative RT do not increase the risk of lymphocysts or lymphedema.[9],[11] The most common nerve injured during PLN dissection is the obturator nerve (1%).[10] The most frequent intravascular complication is hemorrhage due to vascular damage.[10] Most such hemorrhages are venous.[10] Deep vein thrombosis is observed in 2.3% of cases and can cause pulmonary embolism.[10] Although external iliac artery thrombosis is rare (0.5%), it is a serious complication.[10] In a study of 393 stage, IB1 CC cases without LN involvement who underwent radical hysterectomy and LN dissection, 4.1% of the patients developed a Grade 4 morbidity, and 0.7% of the patients died.[12] Acute and chronic complications of lymphadenectomy can cause mortality or affect the quality of life. Lymphadenectomy should be performed only in patients who need it based on prognostic factors, and the extent of the procedure should be considered carefully.

A study of 50 patients that evaluated recurrence and PLN involvement according to LVSI and tumor size found that LVSI (P = 0.02) and tumor size (>500 to ≤ 500 mm 3) (P < 0.001) were significant predictors of PLN involvement.[13] A study of 251 stage IB–IIA CC patients identified stage IB2–IIA, tumor size >2 cm, and the existence of LVSI as risk factors for PLN involvement.[14] A significant relationship between LVSI and PLN involvement has been reported.[3],[15] In a study of 201 stage IA2–IB CC patients, PLN involvement was found in 9.52% and 20.37% (P = 0.039) of patients with a tumor size of ≤2 cm and >2 cm, respectively.[16] The PLN involvement rates for patients with no early-stage risk factor, with a single risk factor (except LVSI), with only LVSI, and with two or three risk factors were 0%, 2.3%, 9.1%, 29.1%, and 58.8%, respectively.[14] In this study, LVSI (OR = 11.3, 95% CI = 5.2–24.3) and tumor size (OR = 3.2, 95% CI = 1.4–7.2) were significant predictors of PLN involvement in the multivariate regression analysis. Primary CRT may be preferred over surgery in the treatment of CC patients with LN involvement. The complication rates were higher in patients treated with adjuvant therapy after surgery compared with patients receiving primary CRT, while the recurrence rates and survival outcomes were similar.[17]

The limitations of this study include its retrospective character and the fact that some of the patients were treated by nongynecological oncology surgeons over a period of 23 years that were reviewed. Moreover, during 23 years, significant improvements in the surgical approach may have affected the results. Retrospective cohort studies are open to selection bias, recall bias, and unknown confounding variables, which may negatively influence the accuracy of the results. Despite these restrictions, our study included a large number of cases with similar demographic characteristics, and high-quality follow-up data were available. In addition, squamous cell antigen screening was not available at our center, and the pathologists did not specify deep invasion in some cases.


 > Conclusion Top


This study found that the presence of LVSI and tumor size independently increased the risk of PLN involvement. Well-designed randomized controlled studies are required to confirm our results.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Herr D, König J, Heilmann V, Koretz K, Kreienberg R, Kurzeder C, et al. Prognostic impact of satellite-lymphovascular space involvement in early-stage cervical cancer. Ann Surg Oncol 2009;16:128-32.  Back to cited text no. 1
    
2.
Chittithaworn S, Hanprasertpong J, Tungsinmunkong K, Geater A. Association between prognostic factors and disease-free survival of cervical cancer stage IB1 patients undergoing radical hysterectomy. Asian Pac J Cancer Prev 2007;8:530-4.  Back to cited text no. 2
    
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Yan M, Zhang YN, He JH, Sun JR, Sun XM. Influence of lymph vascular space invasion on prognosis of patients with early-stage cervical squamous cell carcinoma. Chin J Cancer 2010;29:425-30.  Back to cited text no. 3
    
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Delgado G, Bundy B, Zaino R, Sevin BU, Creasman WT, Major F, et al. Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: A Gynecologic oncology group study. Gynecol Oncol 1990;38:352-7.  Back to cited text no. 4
    
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Scheidler J, Hricak H, Yu KK, Subak L, Segal MR. Radiological evaluation of lymph node metastases in patients with cervical cancer. A meta-analysis. JAMA 1997;278:1096-101.  Back to cited text no. 5
    
6.
Havrilesky LJ, Kulasingam SL, Matchar DB, Myers ER. FDG-PET for management of cervical and ovarian cancer. Gynecol Oncol 2005;97:183-91.  Back to cited text no. 6
    
7.
Slama J, Dundr P, Dusek L, Cibula D. High false negative rate of frozen section examination of sentinel lymph nodes in patients with cervical cancer. Gynecol Oncol 2013;129:384-8.  Back to cited text no. 7
    
8.
Ditto A, Martinelli F, Lo Vullo S, Reato C, Solima E, Carcangiu M, et al. The role of lymphadenectomy in cervical cancer patients: The significance of the number and the status of lymph nodes removed in 526 cases treated in a single institution. Ann Surg Oncol 2013;20:3948-54.  Back to cited text no. 8
    
9.
Liu Y, Zhao LJ, Li MZ, Li MX, Wang JL, Wei LH, et al. The number of positive pelvic lymph nodes and multiple groups of pelvic lymph node metastasis influence prognosis in stage IA-IIB cervical squamous cell carcinoma. Chin Med J (Engl) 2015;128:2084-9.  Back to cited text no. 9
    
10.
Sivanesaratnam V, Sen DK, Jayalakshmi P, Ong G. Radical hysterectomy and pelvic lymphadenectomy for early invasive cancer of the cervix – 14-year experience. Int J Gynecol Cancer 1993;3:231-8.  Back to cited text no. 10
    
11.
Sahbaz A, Gungorduk K, Gulseren V, Ozdemir IA, Harma M, Harma M, et al. What are the risk factors for lymphocyst formation apart from lymphnode dissection and lymphnode count in gynecologic malignancy? Geburtshilfe Frauenheilkd 2016;76:403-7.  Back to cited text no. 11
    
12.
Ayhan A, Al RA, Baykal C, Demirtas E, Ayhan A, Yüce K, et al. Prognostic factors in FIGO stage IB cervical cancer without lymph node metastasis and the role of adjuvant radiotherapy after radical hysterectomy. Int J Gynecol Cancer 2004;14:286-92.  Back to cited text no. 12
    
13.
Murakami I, Fujii T, Kameyama K, Iwata T, Saito M, Kubushiro K, et al. Tumor volume and lymphovascular space invasion as a prognostic factor in early invasive adenocarcinoma of the cervix. J Gynecol Oncol 2012;23:153-8.  Back to cited text no. 13
    
14.
Yanaranop M, Sathapornteera N, Nakrangsee S. Risk factors of pelvic lymph node metastasis in cervical adenocarcinoma following radical hysterectomy and pelvic lymphadenectomy. J Med Assoc Thai 2014;97 Suppl 11:S87-95.  Back to cited text no. 14
    
15.
Chandacham A, Charoenkwan K, Siriaunkgul S, Srisomboon J, Suprasert P, Phongnarisorn C, et al. Extent of lymphovascular space invasion and risk of pelvic lymph node metastases in stage IB1 cervical cancer. J Med Assoc Thai 2005;88 Suppl 2:S31-6.  Back to cited text no. 15
    
16.
Liu Q, Yang JX, Cao DY, Shen K, Wu M, Pan LY, et al. Identification of low-risk indicators of early stage cervical cancer. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2012;34:580-4.  Back to cited text no. 16
    
17.
Fanfani F, Vizza E, Landoni F, de Iaco P, Ferrandina G, Corrado G, et al. Radical hysterectomy after chemoradiation in FIGO stage III cervical cancer patients versus chemoradiation and brachytherapy: Complications and 3-years survival. Eur J Surg Oncol 2016;42:1519-25.  Back to cited text no. 17
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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