ORIGINAL STUDY
Can Pelvic Lymphadenectomy be Omitted in Stage IA2 to IIB Uterine Cervical Cancer? Shinichi Togami, MD, PhD, Masaki Kamio, MD, PhD, Shintaro Yanazume, MD, PhD, Mitsuhiro Yoshinaga, PhD, MD, and Tsutomu Douchi, MD, PhD
Objectives: The aims of this study were to predict pelvic lymph node metastasis in uterine cervical cancer before surgery and to evaluate the potential efficacy of omitting pelvic lymphadenectomy. Materials and Methods: A total of 163 patients with invasive uterine cervical cancer in FIGO stage IA2 to IIB, all of whom underwent primary radical hysterectomy with pelvic lymphadenectomy, participated in this study. Results: The incidences of pelvic lymph node metastasis in stage IA2, stage IB1, stage IB2, stage IIA, and stage IIB cervical cancer were 0% (0/12), 17% (13/76), 22% (6/27), 33% (8/24), and 63% (15/24), respectively. A significant difference was observed in overall survival with nodal metastasis status (P G 0.0001). Univariate analysis revealed that parametrial invasion (P G 0.0001), tumor markers (P = 0.0006), tumor size greater than 2 cm (P G 0.0001), tumor size less than 3 cm (P = 0.0009), and tumor size greater than 4 cm (P = 0.0024) were correlated with pelvic lymph node metastasis. However, multivariate analysis revealed that parametrial invasion (P = 0.01; odds ratio, 3.37; 95% confidence interval, 1.31Y9.0) and tumor size greater than 2 cm (P = 0.005; odds ratio, 4.93; 95% confidence interval, 1.54Y22.01) were independently associated with nodal metastasis. Conclusions: Pelvic lymphadenectomy may be avoided in patients with negative parametrial invasion and a tumor size less than 2 cm, thereby minimizing postoperative complications. Key Words: Uterine cervical cancer, Pelvic lymphadenectomy, Parametrial invasion, Tumor marker, Tumor size Received February 4, 2014, and in revised form March 30, 2014. Accepted for publication April 1, 2014. (Int J Gynecol Cancer 2014;24: 1072Y1076)
uterine cervical cancer is curable with definitive A lthough treatment, it is still the major cause of cancer-related death in women worldwide. Early-stage invasive cervical cancers have been routinely treated over the past 6 decades by radical hysterectomy including pelvic lymphadenectomy. The
Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan. Address correspondence and reprint requests to Shinichi Togami, MD, PhD, Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. E-mail: [email protected]. The authors declare no conflicts of interest. Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000163
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single most important prognostic factor for patients with cervical cancer is the presence of lymph node metastasis, which is associated with recurrence and survival. However, the occurrence of lymphoceles and lymphedema in the lower limbs is a well-recognized complication in gynecological cancer patients after pelvic lymphadenectomy.1 Lymphedema is a chronic, incurable condition; the effects of which include limb swelling and feelings of heaviness, tightness, and pain.2 This can take a psychological toll, with patients exhibiting symptoms such as anxiety, depression, and adjustment problems.3 Several groups recently demonstrated that the detection of sentinel lymph nodes was a feasible and promising technique in patients with uterine cervical cancer.4,5 However, the detection of sentinel lymph nodes requires an injection of technetium or blue dye and frozen section analysis. These techniques cannot be performed everywhere.
International Journal of Gynecological Cancer
& Volume 24, Number 6, July 2014
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number 6, July 2014
The purpose of the present study was to retrospectively evaluate the risk factors for pathological pelvic lymph node metastasis after radical hysterectomy, including pelvic lymphadenectomy, and also to evaluate the possibility of avoiding pelvic lymphadenectomy without compromising the oncological outcome.
METHODS Patients We reviewed the medical records and pathological materials obtained from 180 patients with invasive carcinoma of the uterine cervix, FIGO stage IA2 to IIB, who had been treated at the Department of Obstetrics and Gynecology, Kagoshima University Hospital between 1998 and 2009. This study included patients who met the following criteria: patients with FIGO stage IA2 to IIB disease and patients who underwent primary surgery consisting of radical hysterectomy with pelvic lymphadenectomy. FIGO staging was based on clinical examination and the preoperative use of computed tomography and magnetic resonance imaging. Radical hysterectomy has been a standard treatment option for patients with FIGO stage IA2 to IIB disease in our institute. The radicality of hysterectomy in this study corresponded to class III of the Piver-Rutledge classification. Adjuvant postoperative irradiation to the whole pelvis was administered to patients with a tumor size greater than 4 cm, depth of invasion greater than 10 mm (approximately equivalent to the middleouter one third of the cervical stroma), parametrial involvement, and positive pelvic lymph node metastases proven by a pathological examination after surgery. Patients who received preoperative anticancer chemotherapy or radiotherapy were excluded. Five patients were lost to the follow-up. Postoperative pathological classification was performed according to the Union for International Cancer Control TNM classification of malignant tumors. The histological type was evaluated according to the criteria of the World Health Organization International Histological Classification of Tumors. The histological evaluation revealed 100 cases of squamous cell carcinomas (SCCs), 13 adenosquamous cell carcinomas, and 50 adenocarcinomas. Patients who had other histological types were excluded. Tumor measurements were estimated based on preoperative magnetic resonance imaging, excluding microscopic cancers that were obtained from conized pathological materials. Blood samples were collected from patients before surgery for SCC antigen, cancer antigens CA125, CA19-9, and CEA analysis. Twelve patients had no tumor marker data. All blood samples were immediately transferred to the laboratory for testing. The upper limits of 1.5 ng/mL for SCC, 35 U/mL for CA125, 37 U/mL for CA19-9, and 5.0 ng/mL for CEA were used to define reference values as recommended by the manufacturers.
Statistical Analysis The primary outcome measurement in this study was the presence of lymph node metastasis. Relapse-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and the differences were analyzed by the
Pelvic Lymphadenectomy Omission
log-rank test. The relationship between clinical and pathological variables and lymph node metastasis was examined with univariate analysis using the W2 test. The independent effects of the clinical and pathological variables on lymph node metastasis were determined by multiple logistic regression analysis. A P value of 0.05 was considered significant for both univariate and multivariate analyses. JMP software (SAS Institute Inc, Cary, NC) was used for statistical analysis.
RESULTS A total of 163 patients with uterine cervical cancer met the study criteria. After radical hysterectomy, 106 patients received adjuvant therapy. All patients received primary radiotherapy with or without concurrent cisplatin-containing chemotherapy. One hundred three patients received concomitant chemoradiotherapy, and 2 patients received brachytherapy. All 163 patients were followed-up for 8 to 159 months, and the mean follow-up period was 65 months. The mean age of the patients was 47 years (range, 22Y76 years). Forty-two patients (26%) had positive pelvic lymph nodes. The incidences of pelvic lymph node metastasis in stage IA2, stage IB1, stage IB2, stage IIA, and stage IIB cervical cancer were 0% (0/12), 17% (13/76), 22% (6/27), 33% (8/24), and 63% (15/24), respectively. In the preoperative evaluation, parametrial invasion was present in 25 patients (15%), and elevated tumor markers were observed in 69 patients (46%). In the preoperative evaluation, the tumor size was less than or equal to 2 cm in 50 patients and greater than 2 cm in 113 patients. None of the patients with less than or equal to 2 cm tumors had parametrial invasion. Figure 1 shows Kaplan-Meier curves for RFS and OS stratified by pelvic lymph node status. The 5-year RFS rates for negative lymph nodes and positive lymph nodes were 92% and 46%, respectively. A significant difference was observed in RFS among the lymph node statuses (P G 0.0001). The 5-year OS rates for negative lymph nodes and positive lymph nodes were 94% and 61%, respectively. A significant difference was observed in OS among the nodal metastasis statuses (P G 0.0001). Table 1 shows the clinicopathological characteristics of 163 patients with uterine cervical cancer as they relate to the pelvic lymph node status in the preoperative evaluation. Univariate analysis revealed that parametrial invasion (P G 0.0001), tumor markers (P = 0.0006), tumor size greater than 2 cm (P G 0.0001), tumor size less than 3 cm (P = 0.0009), and tumor size greater than 4 cm (P = 0.0024) were correlated with a positive lymph node status. No significant differences were observed in age at diagnosis (P = 0.52) and the distribution of the histological subtype (P = 0.65) with the nodal metastasis status. We analyzed whether positive markers can be used to predict lymph node involvement in histological subgroups. There was a significant difference between tumor markers and adenocarcinoma (P = 0.0003), but there was no significant difference in SCC and adenosquamous cell carcinoma (data not shown). Table 2 shows multivariate analysis of the clinicopathological variables associated with the pelvic lymph node status
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& Volume 24, Number 6, July 2014
pelvic lymph node metastasis. Pelvic lymph node metastasis is an independent predictive factor for poor survival and the relapse of cervical cancer.13Y15 In the present study, 5-year OS rates for negative lymph nodes and positive lymph nodes were 94% and 61%, respectively. The 5-year survival of pelvic lymph nodeYpositive patients with stage IB to IIB cervical cancer was previously shown to be between 64% and 68.2%.16Y18 Our results suggest that cervical cancer patients with lymph node metastasis have a poor prognosis. We evaluated the risk factors for pathological pelvic lymph node metastasis. Parametrial invasion, tumor markers, and the tumor size were identified as risk factors for pelvic lymph node metastasis by univariate analysis (P G 0.05). Takeda et al19 reported that tumor markers (a doubleYtumor marker index based on serum SCC and CA125 measurements) and tumor diameter (e2 vs Q2 cm) were independently related to lymph node metastasis. Previous studies demonstrated the usefulness of a combination assay of serum SCC and CA125 levels in predicting lymph node TABLE 1. Clinicopathological characteristics of 163 patients with uterine cervical cancer in relation to the pelvic lymph node status Lymph Lymph Node Node Metastasis Metastasis Negative, Positive, Total n (%) n (%)
FIGURE 1. Kaplan-Meier survival curves of patients with cervical cancer stratified by pelvic lymph node status (negative lymph nodes and positive lymph nodes). A, Relapse-free survival. B, Overall survival. Significant differences were observed in both (P G 0.0001 and P G 0.0001, by the log-rank test). using 3 models. Parametrial invasion (model 1 [P = 0.01; odds ratio (OR), 3.37; 95% confidence interval (CI), 1.31Y9.0], model 2 [P = 0.007; OR, 3.8; 95% CI, 1.45Y10.23], model 3 [P = 0.003; OR, 4.34; 95% CI, 1.66-11.7]) and tumor size greater than 2 cm (P = 0.005; OR, 4.93; 95% CI, 1.54Y22.01) were independently associated with lymph node metastasis.
DISCUSSION Radical hysterectomy including pelvic lymphadenectomy for invasive uterine cervical cancer remains the criterion standard of treatment in most international guidelines. However, pelvic lymphadenectomy is associated with the potential risk of massive blood loss, blood transfusion, nerve or vascular injury, ileus, lymphoceles, and lymphedema.6Y11 The risk of lymph node metastasis is accepted to be low in certain cases of early-stage cervical cancer. Therefore, the omission of lymphadenectomy is desirable when no metastasis is detected in the pelvic lymph nodes. In the present study, the incidences of pelvic lymph node metastasis in stage IA2, stage IB1, stage IB2, stage IIA, and stage IIB cervical cancer were 0% (0/12), 17% (13/76), 22% (6/27), 33% (8/24), and 63% (15/24), respectively. Sakuragi et al12 reported that the incidences of pelvic lymph node metastasis in stage IB, stage IIA, and stage IIB cervical cancer were 11.5%, 26.7%, and 39.2%, respectively. Patients with advanced cervical cancer are at high risk of
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Age G40 Q40 Histological subtype SCC Adenocarcinoma /adenosquamous carcinoma Parametrial invasion Negative Positive Tumor marker Negative Positive Tumor size e2 cm 92 cm Tumor size e3 cm 93 cm Tumor size e4 cm 94 cm
P
121 (74)
42 (26)
45 118
35 (29) 86 (71)
10 (24) 32 (76)
0.52
100 63
73 (60) 48 (40)
27 (64) 15 (35)
0.65
139 24
112 (93) 9 (7)
27 (66) 15 (34)
G0.0001
82 69
70 (63) 42 (37)
12 (31) 27 (69)
0.0006
49 114
46 (38) 75 (62)
3 (7) 39 (93)
G0.0001
81 82
70 (58) 51 (42)
11 (26) 31 (74)
0.0003
100 63
82 (68) 39 (32)
18 (43) 24 (57)
0.0047
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International Journal of Gynecological Cancer
& Volume 24, Number 6, July 2014
TABLE 2. Multivariate analysis of the clinicopathological variables associated with the pelvic lymph node status using 3 models Variables Model 1 Parametrial invasion Tumor marker Tumor size (92 cm) Model 2 Parametrial invasion Tumor marker Tumor size (93 cm) Model 3 Parametrial invasion Tumor marker Tumor size (94 cm)
OR
95% CI
P
3.6 1.9 4.7
1.4Y9.9 0.8Y4.3 1.4Y20.9
0.01 0.13 0.008
3.8 2.0 2.3
1.4Y10.6 0.8Y4.6 0.96Y5.6
0.009 0.11 0.06
4.2 2.2 1.9
1.6Y11.7 0.95Y5.0 0.8Y4.2
0.004 0.07 0.14
status, and the prognostic significance of pretreatment tumor marker determination in cervical carcinoma is also controversial.20,21 Multivariate logistic regression analysis including parametrial invasion, tumor marker, and tumor size was performed to evaluate the clinical significance of these parameters in predicting pelvic lymph node metastasis further. We found that parametrial invasion and tumor size (92 cm) correlated with pelvic lymph node metastasis in multiple logistic regression analysis. None of the patients with tumor size less than or equal to 2 cm had parametrial invasion; therefore, tumor size (e2 cm) had a significant effect on pelvic lymph node metastasis, which is very important for survival. Turan et al22 reported that the cutoff value (4 cm) for tumor size in FIGO stage IB cervical cancer was associated with pelvic lymph node metastasis. However, Delgado et al23 found that cutoff values of 20 mm and 30 mm were not significantly associated with pelvic lymph node metastasis in patients without para-aortic lymph node metastasis. They performed multivariate analysis and included lymphovascular space invasion. We did not include lymphovascular space invasion in this analysis because it cannot be evaluated precisely before surgery. Similar to other disease sites, sentinel lymph node biopsy (SLNB) has been extensively described for the assessment of pelvic lymph nodes in patients with cervical cancer.24 If the sentinel node is free of metastatic disease, the other lymph nodes in the regional basin will also be negative for metastasis, and full lymphadenectomy can be avoided.24 Van de Lande et al25 reported that the sensitivity of SLNB in early cervical cancer was 92% (95% CI, 84%Y98%), and the detection rate was 97% (95% CI, 95%Y98%) when the combined technique of technetium-99 radiotracer and blue dye was used. Altgassen et al26 showed that the sensitivity of SLNB was better in small tumors measuring 2 cm or less than in larger tumors. Thus, pelvic lymphadenectomy may be avoided by adding sentinel node navigation surgery.
Pelvic Lymphadenectomy Omission
In conclusion, we demonstrated that pelvic lymph node metastasis was associated with parametrial invasion and tumor sizes in IA2 to IIB uterine cervical cancer. We propose that pelvic lymphadenectomy may be avoided on the basis of negative parametrial invasion and a tumor size less than 2 cm, thereby minimizing postoperative complications associated with systemic pelvic lymphadenectomy, which are of high medical risk. A future prospective study is needed to investigate whether parametrial invasion and tumor size before surgery have diagnostic significance in predicting lymph node metastasis in cervical cancer.
REFERENCES 1. Tada H, Teramukai S, Fukushima M, et al. Risk factors for lower limb lymphedema after lymph node dissection in patients with ovarian and uterine carcinoma. BMC Cancer. 2009;9:47. 2. Newman ML, Brennan M, Passik S. Lymphedema complicated by pain and psychological distress: a case with complex treatment needs. J Pain Symptom Manage. 1996;12:376Y379. 3. Rockson SG. Lymphedema. Am J Med. 2001;110:288Y295. 4. Okamoto S, Niikura H, Nakabayashi K, et al. Detection of sentinel lymph node metastases in cervical cancer: assessment of KRT19 mRNA in the one-step nucleic acid amplification (OSNA) method. Gynecol Oncol. 2013;130:530Y536. 5. Martinez A, Mery E, Filleron T, et al. Accuracy of intraoperative pathological examination of SLN in cervical cancer. Gynecol Oncol. 2013;130:525Y529. 6. Abu-Rustum NR, Alektiar K, Iasonos A, et al. The incidence of symptomatic lower-extremity lymphedema following treatment of uterine corpus malignancies: a 12-year experience at Memorial Sloan-Kettering Cancer Center. Gynecol Oncol. 2006;103:714Y718. 7. Alexander-Sefre F, Chee N, Spencer C, et al. Surgical morbidity associated with radical trachelectomy and radical hysterectomy. Gynecol Oncol. 2006;101:450Y454. 8. Bergmark K, Avall-Lundqvist E, Dickman PW, et al. Vaginal changes and sexuality in women with a history of cervical cancer. N Engl J Med. 1999;340:1383Y1389. 9. Bergmark K, Avall-Lundqvist E, Dickman PW, et al. Lymphedema and bladder-emptying difficulties after radical hysterectomy for early cervical cancer and among population controls. Int J Gynecol Cancer. 2006;16:1130Y1139. 10. Covens A, Rosen B, Murphy J, et al. Changes in the demographics and perioperative care of stage IA(2)/IB(1) cervical cancer over the past 16 years. Gynecol Oncol. 2001;81:133Y137. 11. Pieterse QD, Maas CP, ter Kuile MM, et al. An observational longitudinal study to evaluate miction, defecation, and sexual function after radical hysterectomy with pelvic lymphadenectomy for early-stage cervical cancer. Int J Gynecol Cancer. 2006;16:1119Y1129. 12. Sakuragi N, Satoh C, Takeda N, et al. Incidence and distribution pattern of pelvic and paraaortic lymph node metastasis in patients with stages IB, IIA, and IIB cervical carcinoma treated with radical hysterectomy. Cancer. 1999;85:1547Y1554. 13. Kasamatsu T, Onda T, Sawada M, et al. Radical hysterectomy for FIGO stage I-IIB adenocarcinoma of the uterine cervix. Br J Cancer. 2009;100:1400Y1405. 14. Takeda N, Sakuragi N, Takeda M, et al. Multivariate analysis of histopathologic prognostic factors for invasive cervical cancer treated with radical hysterectomy and systematic retroperitoneal
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lymphadenectomy. Acta Obstet Gynecol Scand. 2002;81: 1144Y1151. Hosaka M, Watari H, Mitamura T, et al. Survival and prognosticators of node-positive cervical cancer patients treated with radical hysterectomy and systematic lymphadenectomy. Int J Clin Oncol. 2011;16:33Y38. Garipagaoglu M, Tulunay G, Kose MF, et al. Prognostic factors in stage IB-IIA cervical carcinomas treated with postoperative radiotherapy. Eur J Gynaecol Oncol. 1999;20:131Y135. Morice P, Castaigne D, Pautier P, et al. Interest of pelvic and paraaortic lymphadenectomy in patients with stage IB and II cervical carcinoma. Gynecol Oncol. 1999;73:106Y110. Lai CH, Hong JH, Hsueh S, et al. Preoperative prognostic variables and the impact of postoperative adjuvant therapy on the outcomes of stage IB or II cervical carcinoma patients with or without pelvic lymph node metastases: an analysis of 891 cases. Cancer. 1999;85:1537Y1546. Takeda M, Sakuragi N, Okamoto K, et al. Preoperative serum SCC, CA125, and CA19-9 levels and lymph node status in squamous cell carcinoma of the uterine cervix. Acta Obstet Gynecol Scand. 2002;81:451Y457. Duk JM, Groenier KH, de Bruijn HW, et al. Pretreatment serum squamous cell carcinoma antigen: a newly identified prognostic
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factor in early-stage cervical carcinoma. J Clin Oncol. 1996;14:111Y118. Gaarenstroom KN, Kenter GG, Bonfrer JM, et al. Can initial serum cyfra 21-1, SCC antigen, and TPA levels in squamous cell cervical cancer predict lymph node metastases or prognosis? Gynecol Oncol. 2000;77:164Y170. Tulunay G, Yildirim BA, Tulany G, et al. Prognostic effect of different cut-off values (20mm, 30mm and 40mm) for clinical tumor size in FIGO stage IB cervical cancer. Surg Oncol. 2010;19:106Y113. Delgado G, Bundy BN, Fowler WC Jr, et al. A prospective surgical pathological study of stage I squamous carcinoma of the cervix: a Gynecologic Oncology Group Study. Gynecol Oncol. 1989;35:314Y320. Eiriksson LR, Covens A. Sentinel lymph node mapping in cervical cancer: the future? BJOG. 2012;119:129Y133. van de Lande J, Torrenga B, Raijmakers PG, et al. Sentinel lymph node detection in early stage uterine cervix carcinoma: a systematic review. Gynecol Oncol. 2007;106:604Y613. Altgassen C, Hertel H, Brandstadt A, et al. Multicenter validation study of the sentinel lymph node concept in cervical cancer: AGO Study Group. J Clin Oncol. 2008;26:2943Y2951.
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Can Pelvic Lymphadenectomy be Omitted in Stage IA2 to IIB Uterine Cervical Cancer? Shinichi Togami, MD, PhD, Masaki Kamio, MD, PhD, Shintaro Yanazume, MD, PhD, Mitsuhiro Yoshinaga, PhD, MD, and Tsutomu Douchi, MD, PhD
Objectives: The aims of this study were to predict pelvic lymph node metastasis in uterine cervical cancer before surgery and to evaluate the potential efficacy of omitting pelvic lymphadenectomy. Materials and Methods: A total of 163 patients with invasive uterine cervical cancer in FIGO stage IA2 to IIB, all of whom underwent primary radical hysterectomy with pelvic lymphadenectomy, participated in this study. Results: The incidences of pelvic lymph node metastasis in stage IA2, stage IB1, stage IB2, stage IIA, and stage IIB cervical cancer were 0% (0/12), 17% (13/76), 22% (6/27), 33% (8/24), and 63% (15/24), respectively. A significant difference was observed in overall survival with nodal metastasis status (P G 0.0001). Univariate analysis revealed that parametrial invasion (P G 0.0001), tumor markers (P = 0.0006), tumor size greater than 2 cm (P G 0.0001), tumor size less than 3 cm (P = 0.0009), and tumor size greater than 4 cm (P = 0.0024) were correlated with pelvic lymph node metastasis. However, multivariate analysis revealed that parametrial invasion (P = 0.01; odds ratio, 3.37; 95% confidence interval, 1.31Y9.0) and tumor size greater than 2 cm (P = 0.005; odds ratio, 4.93; 95% confidence interval, 1.54Y22.01) were independently associated with nodal metastasis. Conclusions: Pelvic lymphadenectomy may be avoided in patients with negative parametrial invasion and a tumor size less than 2 cm, thereby minimizing postoperative complications. Key Words: Uterine cervical cancer, Pelvic lymphadenectomy, Parametrial invasion, Tumor marker, Tumor size Received February 4, 2014, and in revised form March 30, 2014. Accepted for publication April 1, 2014. (Int J Gynecol Cancer 2014;24: 1072Y1076)
uterine cervical cancer is curable with definitive A lthough treatment, it is still the major cause of cancer-related death in women worldwide. Early-stage invasive cervical cancers have been routinely treated over the past 6 decades by radical hysterectomy including pelvic lymphadenectomy. The
Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan. Address correspondence and reprint requests to Shinichi Togami, MD, PhD, Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. E-mail: [email protected]. The authors declare no conflicts of interest. Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000163
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single most important prognostic factor for patients with cervical cancer is the presence of lymph node metastasis, which is associated with recurrence and survival. However, the occurrence of lymphoceles and lymphedema in the lower limbs is a well-recognized complication in gynecological cancer patients after pelvic lymphadenectomy.1 Lymphedema is a chronic, incurable condition; the effects of which include limb swelling and feelings of heaviness, tightness, and pain.2 This can take a psychological toll, with patients exhibiting symptoms such as anxiety, depression, and adjustment problems.3 Several groups recently demonstrated that the detection of sentinel lymph nodes was a feasible and promising technique in patients with uterine cervical cancer.4,5 However, the detection of sentinel lymph nodes requires an injection of technetium or blue dye and frozen section analysis. These techniques cannot be performed everywhere.
International Journal of Gynecological Cancer
& Volume 24, Number 6, July 2014
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number 6, July 2014
The purpose of the present study was to retrospectively evaluate the risk factors for pathological pelvic lymph node metastasis after radical hysterectomy, including pelvic lymphadenectomy, and also to evaluate the possibility of avoiding pelvic lymphadenectomy without compromising the oncological outcome.
METHODS Patients We reviewed the medical records and pathological materials obtained from 180 patients with invasive carcinoma of the uterine cervix, FIGO stage IA2 to IIB, who had been treated at the Department of Obstetrics and Gynecology, Kagoshima University Hospital between 1998 and 2009. This study included patients who met the following criteria: patients with FIGO stage IA2 to IIB disease and patients who underwent primary surgery consisting of radical hysterectomy with pelvic lymphadenectomy. FIGO staging was based on clinical examination and the preoperative use of computed tomography and magnetic resonance imaging. Radical hysterectomy has been a standard treatment option for patients with FIGO stage IA2 to IIB disease in our institute. The radicality of hysterectomy in this study corresponded to class III of the Piver-Rutledge classification. Adjuvant postoperative irradiation to the whole pelvis was administered to patients with a tumor size greater than 4 cm, depth of invasion greater than 10 mm (approximately equivalent to the middleouter one third of the cervical stroma), parametrial involvement, and positive pelvic lymph node metastases proven by a pathological examination after surgery. Patients who received preoperative anticancer chemotherapy or radiotherapy were excluded. Five patients were lost to the follow-up. Postoperative pathological classification was performed according to the Union for International Cancer Control TNM classification of malignant tumors. The histological type was evaluated according to the criteria of the World Health Organization International Histological Classification of Tumors. The histological evaluation revealed 100 cases of squamous cell carcinomas (SCCs), 13 adenosquamous cell carcinomas, and 50 adenocarcinomas. Patients who had other histological types were excluded. Tumor measurements were estimated based on preoperative magnetic resonance imaging, excluding microscopic cancers that were obtained from conized pathological materials. Blood samples were collected from patients before surgery for SCC antigen, cancer antigens CA125, CA19-9, and CEA analysis. Twelve patients had no tumor marker data. All blood samples were immediately transferred to the laboratory for testing. The upper limits of 1.5 ng/mL for SCC, 35 U/mL for CA125, 37 U/mL for CA19-9, and 5.0 ng/mL for CEA were used to define reference values as recommended by the manufacturers.
Statistical Analysis The primary outcome measurement in this study was the presence of lymph node metastasis. Relapse-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and the differences were analyzed by the
Pelvic Lymphadenectomy Omission
log-rank test. The relationship between clinical and pathological variables and lymph node metastasis was examined with univariate analysis using the W2 test. The independent effects of the clinical and pathological variables on lymph node metastasis were determined by multiple logistic regression analysis. A P value of 0.05 was considered significant for both univariate and multivariate analyses. JMP software (SAS Institute Inc, Cary, NC) was used for statistical analysis.
RESULTS A total of 163 patients with uterine cervical cancer met the study criteria. After radical hysterectomy, 106 patients received adjuvant therapy. All patients received primary radiotherapy with or without concurrent cisplatin-containing chemotherapy. One hundred three patients received concomitant chemoradiotherapy, and 2 patients received brachytherapy. All 163 patients were followed-up for 8 to 159 months, and the mean follow-up period was 65 months. The mean age of the patients was 47 years (range, 22Y76 years). Forty-two patients (26%) had positive pelvic lymph nodes. The incidences of pelvic lymph node metastasis in stage IA2, stage IB1, stage IB2, stage IIA, and stage IIB cervical cancer were 0% (0/12), 17% (13/76), 22% (6/27), 33% (8/24), and 63% (15/24), respectively. In the preoperative evaluation, parametrial invasion was present in 25 patients (15%), and elevated tumor markers were observed in 69 patients (46%). In the preoperative evaluation, the tumor size was less than or equal to 2 cm in 50 patients and greater than 2 cm in 113 patients. None of the patients with less than or equal to 2 cm tumors had parametrial invasion. Figure 1 shows Kaplan-Meier curves for RFS and OS stratified by pelvic lymph node status. The 5-year RFS rates for negative lymph nodes and positive lymph nodes were 92% and 46%, respectively. A significant difference was observed in RFS among the lymph node statuses (P G 0.0001). The 5-year OS rates for negative lymph nodes and positive lymph nodes were 94% and 61%, respectively. A significant difference was observed in OS among the nodal metastasis statuses (P G 0.0001). Table 1 shows the clinicopathological characteristics of 163 patients with uterine cervical cancer as they relate to the pelvic lymph node status in the preoperative evaluation. Univariate analysis revealed that parametrial invasion (P G 0.0001), tumor markers (P = 0.0006), tumor size greater than 2 cm (P G 0.0001), tumor size less than 3 cm (P = 0.0009), and tumor size greater than 4 cm (P = 0.0024) were correlated with a positive lymph node status. No significant differences were observed in age at diagnosis (P = 0.52) and the distribution of the histological subtype (P = 0.65) with the nodal metastasis status. We analyzed whether positive markers can be used to predict lymph node involvement in histological subgroups. There was a significant difference between tumor markers and adenocarcinoma (P = 0.0003), but there was no significant difference in SCC and adenosquamous cell carcinoma (data not shown). Table 2 shows multivariate analysis of the clinicopathological variables associated with the pelvic lymph node status
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& Volume 24, Number 6, July 2014
pelvic lymph node metastasis. Pelvic lymph node metastasis is an independent predictive factor for poor survival and the relapse of cervical cancer.13Y15 In the present study, 5-year OS rates for negative lymph nodes and positive lymph nodes were 94% and 61%, respectively. The 5-year survival of pelvic lymph nodeYpositive patients with stage IB to IIB cervical cancer was previously shown to be between 64% and 68.2%.16Y18 Our results suggest that cervical cancer patients with lymph node metastasis have a poor prognosis. We evaluated the risk factors for pathological pelvic lymph node metastasis. Parametrial invasion, tumor markers, and the tumor size were identified as risk factors for pelvic lymph node metastasis by univariate analysis (P G 0.05). Takeda et al19 reported that tumor markers (a doubleYtumor marker index based on serum SCC and CA125 measurements) and tumor diameter (e2 vs Q2 cm) were independently related to lymph node metastasis. Previous studies demonstrated the usefulness of a combination assay of serum SCC and CA125 levels in predicting lymph node TABLE 1. Clinicopathological characteristics of 163 patients with uterine cervical cancer in relation to the pelvic lymph node status Lymph Lymph Node Node Metastasis Metastasis Negative, Positive, Total n (%) n (%)
FIGURE 1. Kaplan-Meier survival curves of patients with cervical cancer stratified by pelvic lymph node status (negative lymph nodes and positive lymph nodes). A, Relapse-free survival. B, Overall survival. Significant differences were observed in both (P G 0.0001 and P G 0.0001, by the log-rank test). using 3 models. Parametrial invasion (model 1 [P = 0.01; odds ratio (OR), 3.37; 95% confidence interval (CI), 1.31Y9.0], model 2 [P = 0.007; OR, 3.8; 95% CI, 1.45Y10.23], model 3 [P = 0.003; OR, 4.34; 95% CI, 1.66-11.7]) and tumor size greater than 2 cm (P = 0.005; OR, 4.93; 95% CI, 1.54Y22.01) were independently associated with lymph node metastasis.
DISCUSSION Radical hysterectomy including pelvic lymphadenectomy for invasive uterine cervical cancer remains the criterion standard of treatment in most international guidelines. However, pelvic lymphadenectomy is associated with the potential risk of massive blood loss, blood transfusion, nerve or vascular injury, ileus, lymphoceles, and lymphedema.6Y11 The risk of lymph node metastasis is accepted to be low in certain cases of early-stage cervical cancer. Therefore, the omission of lymphadenectomy is desirable when no metastasis is detected in the pelvic lymph nodes. In the present study, the incidences of pelvic lymph node metastasis in stage IA2, stage IB1, stage IB2, stage IIA, and stage IIB cervical cancer were 0% (0/12), 17% (13/76), 22% (6/27), 33% (8/24), and 63% (15/24), respectively. Sakuragi et al12 reported that the incidences of pelvic lymph node metastasis in stage IB, stage IIA, and stage IIB cervical cancer were 11.5%, 26.7%, and 39.2%, respectively. Patients with advanced cervical cancer are at high risk of
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Age G40 Q40 Histological subtype SCC Adenocarcinoma /adenosquamous carcinoma Parametrial invasion Negative Positive Tumor marker Negative Positive Tumor size e2 cm 92 cm Tumor size e3 cm 93 cm Tumor size e4 cm 94 cm
P
121 (74)
42 (26)
45 118
35 (29) 86 (71)
10 (24) 32 (76)
0.52
100 63
73 (60) 48 (40)
27 (64) 15 (35)
0.65
139 24
112 (93) 9 (7)
27 (66) 15 (34)
G0.0001
82 69
70 (63) 42 (37)
12 (31) 27 (69)
0.0006
49 114
46 (38) 75 (62)
3 (7) 39 (93)
G0.0001
81 82
70 (58) 51 (42)
11 (26) 31 (74)
0.0003
100 63
82 (68) 39 (32)
18 (43) 24 (57)
0.0047
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International Journal of Gynecological Cancer
& Volume 24, Number 6, July 2014
TABLE 2. Multivariate analysis of the clinicopathological variables associated with the pelvic lymph node status using 3 models Variables Model 1 Parametrial invasion Tumor marker Tumor size (92 cm) Model 2 Parametrial invasion Tumor marker Tumor size (93 cm) Model 3 Parametrial invasion Tumor marker Tumor size (94 cm)
OR
95% CI
P
3.6 1.9 4.7
1.4Y9.9 0.8Y4.3 1.4Y20.9
0.01 0.13 0.008
3.8 2.0 2.3
1.4Y10.6 0.8Y4.6 0.96Y5.6
0.009 0.11 0.06
4.2 2.2 1.9
1.6Y11.7 0.95Y5.0 0.8Y4.2
0.004 0.07 0.14
status, and the prognostic significance of pretreatment tumor marker determination in cervical carcinoma is also controversial.20,21 Multivariate logistic regression analysis including parametrial invasion, tumor marker, and tumor size was performed to evaluate the clinical significance of these parameters in predicting pelvic lymph node metastasis further. We found that parametrial invasion and tumor size (92 cm) correlated with pelvic lymph node metastasis in multiple logistic regression analysis. None of the patients with tumor size less than or equal to 2 cm had parametrial invasion; therefore, tumor size (e2 cm) had a significant effect on pelvic lymph node metastasis, which is very important for survival. Turan et al22 reported that the cutoff value (4 cm) for tumor size in FIGO stage IB cervical cancer was associated with pelvic lymph node metastasis. However, Delgado et al23 found that cutoff values of 20 mm and 30 mm were not significantly associated with pelvic lymph node metastasis in patients without para-aortic lymph node metastasis. They performed multivariate analysis and included lymphovascular space invasion. We did not include lymphovascular space invasion in this analysis because it cannot be evaluated precisely before surgery. Similar to other disease sites, sentinel lymph node biopsy (SLNB) has been extensively described for the assessment of pelvic lymph nodes in patients with cervical cancer.24 If the sentinel node is free of metastatic disease, the other lymph nodes in the regional basin will also be negative for metastasis, and full lymphadenectomy can be avoided.24 Van de Lande et al25 reported that the sensitivity of SLNB in early cervical cancer was 92% (95% CI, 84%Y98%), and the detection rate was 97% (95% CI, 95%Y98%) when the combined technique of technetium-99 radiotracer and blue dye was used. Altgassen et al26 showed that the sensitivity of SLNB was better in small tumors measuring 2 cm or less than in larger tumors. Thus, pelvic lymphadenectomy may be avoided by adding sentinel node navigation surgery.
Pelvic Lymphadenectomy Omission
In conclusion, we demonstrated that pelvic lymph node metastasis was associated with parametrial invasion and tumor sizes in IA2 to IIB uterine cervical cancer. We propose that pelvic lymphadenectomy may be avoided on the basis of negative parametrial invasion and a tumor size less than 2 cm, thereby minimizing postoperative complications associated with systemic pelvic lymphadenectomy, which are of high medical risk. A future prospective study is needed to investigate whether parametrial invasion and tumor size before surgery have diagnostic significance in predicting lymph node metastasis in cervical cancer.
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