Gynecologic Oncology 135 (2014) 462–467
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Comparison of adenocarcinoma and adenosquamous carcinoma in patients with early-stage cervical cancer after radical surgery Min-Hyun Baek, Jeong-Yeol Park ⁎, Daeyeon Kim, Dae-Shik Suh, Jong-Hyeok Kim, Yong-Man Kim, Young-Tak Kim, Joo-Hyun Nam Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
H I G H L I G H T S • Outcomes of adenocarcinoma and adenosquamous carcinoma of the cervix were compared. • The clinicopathologic characteristics of the two histologic types were similar. • Histologic type had no impact on patterns of recurrence and survival outcomes.
a r t i c l e
i n f o
Article history: Received 26 June 2014 Accepted 2 October 2014 Available online 12 October 2014 Keywords: Early-stage cervical cancer Adenocarcinoma Adenosquamous carcinoma
a b s t r a c t Objective. To compare outcomes after radical hysterectomy in patients with stage IB1 adenocarcinoma (AdCa) and adenosquamous carcinoma (AdSCCa) of the uterine cervix. Methods. We performed a retrospective analysis of 265 patients with AdCa and 72 patients with AdSCCa. Demographic, clinicopathologic, surgical, and follow-up data were compared. Results. There were no differences in demographic and clinicopathologic characteristics between the two histologic types (AdCa vs. AdSCCa). Only mean size of tumor and lymphovascular space invasion was larger and more frequent in AdSCCa (2.7 cm vs 2.3 cm, P = 0.019 & 29.2% vs 14.7%, P = 0.008). After a median follow-up time of 68 months, 39 (14.7%) and 13 (18.1%) AdCa and AdSCCa patients, respectively, had recurrent disease (P = 0.467), and 33 (12.5%) and 11 (15.3%) patients, respectively, died of their disease (P = 0.555). 5-year RFS rates were 89% and 85% (P = 0.582), respectively, and 5-year OS rates were 93% and 89% (P = 0.787). Histologic type had no clinical impact on RFS and OS in multivariate analysis adjusting for significant prognostic factors. There were no differences in pattern of recurrence and time to recurrence between the two histologic types. When patients were stratified into three risk groups according to the criteria of GOG protocols 92 and 109, histologic type had no clinical impact on RFS and OS in any of the risk groups. Conclusion. There are no differences in clinicopathologic factors, patterns of recurrence, time to recurrence, RFS and OS between patients with AdCa and AdSCCa. © 2014 Elsevier Inc. All rights reserved.
Introduction Cervical cancer is the second most common cancer and the most common cause of cancer deaths in women worldwide [1]. In Korea, it is the seventh most common cancer and the ninth most common cause of cancer deaths in women, and 3728 new cases and 989 deaths from cervical cancer were recorded in 2011 [2,3]. Although the incidence of cervical cancer is decreasing owing to the introduction of nation-wide organized screening programs in developed countries, it ⁎ Corresponding author at: Department of Obstetrics and Gynecology, College of Medicine, University of Ulsan, Asan Medical Center, #388-1 Poongnap-2 dong, Songpagu, Seoul, 138-736, Republic of Korea. Fax: +82 2 476 7331. E-mail address: [email protected] (J.-Y. Park).
http://dx.doi.org/10.1016/j.ygyno.2014.10.004 0090-8258/© 2014 Elsevier Inc. All rights reserved.
remains an important health problem for women. Squamous cell carcinoma (SCCa), although varying in frequency between populations, is the most common histologic type of cervical cancer; it accounts for approximately 75% of all cases [4], although its incidence is decreasing [5]. Adenocarcinoma (AdCa) is the second most common histologic type of cervical cancer, accounting for 15% of all cases [4], but its absolute and relative incidences are increasing, especially in women aged 20–40 [5]. In older reports, 5% of all cervical cancers were AdCa [6], whereas in more recent reports the incidence was as high as 18.5–27% [7,8]. Adenosquamous carcinoma (AdSCCa) is a mixture of malignant glandular and squamous components consisting of intermingled AdCa and SCCa. It occurs in 2–3% of patients with cervical cancer, and its incidence is increasing, along with that of AdCa [5]. Many studies have suggested that patients with early-stage AdCa and AdSCCa have poorer
M.-H. Baek et al. / Gynecologic Oncology 135 (2014) 462–467
463
Table 1 Clinicopathologic factors in the adenocarcinoma and adenosquamous carcinoma groups (n = 337). Characteristic Age (years), mean (range)
Parity, n (%)
≤47 years, n (%) N47 years, n (%) ≤2 N2
2
BMI (kg/m ), mean (range) ≤24 kg/m2, n (%) N24 kg/m2, n (%) Size of tumor (cm), mean (range)
LVSI, n (%) DOI, n (%) Parametrium, n (%) Resection margin, n (%) Lymph node, n (%) Adjuvant therapy, n (%)
≤2 cm, n (%) N2 cm, n (%) Negative Positive ≤1/2 N1/2 Negative Positive Negative Positive Negative Positive Not done Chemotherapy Radiotherapy CCRT
Total (n = 337)
Adenocarcinoma (n = 265)
Adenosquamous carcinoma (n = 72)
P-value
46.2 (25–76) 197 (58.5) 140 (41.5) 236 (70) 101 (30) 23.8 (17.1–42.2) 195 (57.9) 142 (42.1) 2.4 (0.2–7.3) 163 (48.4) 174 (51.6) 277 (82.2) 60 (17.8) 190 (56.4) 147 (43.6) 302 (89.6) 35 (10.4) 332 (98.5) 5 (1.5) 285 (84.6) 52 (15.4) 225 (66.8) 26 (7.7) 37 (11) 49 (14.5)
46.1 (27–73) 159 (60) 106 (40) 184 (69.4) 81 (30.6) 23.6 (17.1–35.2) 159 (60) 106 (40) 2.3 (0.2–7.3) 134 (50.6) 131 (49.4) 226 (85.3) 39 (14.7) 156 (58.9) 109 (41.1) 240 (90.6) 25 (9.4) 261 (98.5) 4 (1.5) 229 (86.4) 36 (13.6) 186 (70.2) 19 (7.2) 27 (10.2) 33 (12.5)
46.7 (25–76) 38 (52.8) 34 (47.2) 52 (72.2) 20 (27.8) 24.4 (17.5–42.2) 36 (50) 36 (50) 2.7 (0.2–8.0) 29 (40.3) 43 (59.7) 51 (70.8) 21 (29.2) 34 (47.2) 38 (52.8) 62 (86.1) 10 (13.9) 71 (98.6) 1 (1.4) 56 (77.8) 16 (22.2) 39 (54.2) 7 (9.7) 10 (13.9) 16 (22.2)
0.633 0.283 0.772 0.086 0.140 0.019 0.144 0.008 0.083 0.279 1.000 0.096 0.069
BMI, body mass index; FIGO, International Federation of Obstetrics and Gynecology; LVSI, lymphovascular space invasion; and DOI, depth of cervical stromal invasion.
prognoses than those with SCCa after radical hysterectomy [8–12] although contrary results have been reported [13–15]. Due to the relative rarity of AdCA and AdSCCa, however, the optimal management and prognostic factors for early-stage patients have not been clearly established. It is also unclear whether AdCa and AdSCCa have different prognoses because many studies did not distinguish between them, and only a few have directly compared outcomes between patients with AdCa and those with AdSCCa [16–18]. We therefore evaluated outcomes and prognostic factors in patients with FIGO stage IB1 AdCa and AdSCCa of the uterine cervix after radical hysterectomy followed by tailored adjuvant therapy.
We retrospectively reviewed the medical records of each patient to collect demographic data, including age, parity, and body mass index (BMI); clinical data, including preoperative imaging, pelvic examination, neoadjuvant chemotherapy, surgery, and adjuvant therapy; pathologic data, including histologic type of the tumor, grade of differentiation, tumor size, depth of cervical stromal invasion (DOI), lymphovascular space invasion (LVSI), parametrial invasion, resection margin status, and lymph node status; and follow-up data, including date of recurrence, treatment at recurrence, date of last follow-up, patient status at last follow-up, and cause of death. Statistical analysis
Materials and methods With the approval of the Institutional Review Board of Asan Medical Center, we searched the cancer registry and computerized database of the institution to identify patients with early-stage AdCa and AdSCCa of the uterine cervix who underwent radical hysterectomy. Patients were included if they had: 1) previously untreated cervical cancer; 2) had AdCa or AdSCCa histologic types; 3) had FIGO stage IB1; and 4) had undergone radical hysterectomy by the Rutledge and Piver classification with pelvic and/or para-aortic lymphadenectomy [19]. We excluded patients who received neoadjuvant chemotherapy, radiotherapy (RT) or concurrent chemoradiation therapy (CCRT) before radical hysterectomy, patients with occult cervical cancer identified after simple hysterectomy, and patients with additional malignancies. In our center the preferred treatment for patients with FIGO stages IA2–IIA cervical cancer is radical hysterectomy; thus, almost all the patients with FIGO stage IB1 cervical cancer undergo radical hysterectomy and only a small number who are not eligible for radical surgery receive RT or CCRT. If positive pelvic or para-aortic lymph node involvement is confirmed by frozen section, our policy is to complete radical hysterectomy. Tumors were reviewed by one pathologist at our hospital who specializes in gynecologic oncology full time. Occasionally, an assistant pathologist also reviewed the findings. However, the final diagnosis was only made following agreement between both pathologists.
Clinicopathologic factors, recurrence-free survival (RFS) and overall survival (OS) were compared between the AdCa and AdSCCa groups to identify any differences between the two histologic subtypes. The correlations between RFS and OS and clinicopathologic factors were examined to identify factors prognostic for RFS and OS. To determine the prognostic role of histologic type in each risk group, we stratified patients into three risk groups (low, intermediate and high) according to the criteria of two randomized controlled trials of adjuvant therapy in early-stage cervical cancer, the Gynecologic Oncologic Group (GOG) protocols 92 [20] and 109 [21]. RFS was calculated as the number of months from the date of surgery to either the date of recurrence or the date of censoring. OS was calculated as the number of months from the date of surgery to either the date of death or the date of censoring. Survival curves and rates were calculated using the Kaplan–Meier method [22]. Differences in survival were assessed using the log-rank test for categorical factors [23] and Cox's proportional hazards model for continuous factors in univariate analysis [24]. A multivariate analysis was performed using Cox's proportional hazards model to determine risk factors after adjustment for known prognostic variables. Frequency distributions were compared using Chi-squared and Fisher's exact tests, and mean and median values in the groups were compared using the Student's t-test and the Mann–Whitney U-test. A two-sided P-value less than 0.05 indicated statistical significance. Data were analyzed using SPSS software for Windows (version 11.0; SPSS Inc., Chicago, IL).
464
M.-H. Baek et al. / Gynecologic Oncology 135 (2014) 462–467
Fig. 1. a) Recurrence-free survival (left) and overall survival (right) of patients with adenocarcinoma (AdCa) and adenosquamous carcinoma (AdSCCa) of the cervix (univariate analysis, the Kaplan–Meier method). b) Recurrence-free survival (left) and overall survival (right) by risk group (univariate analysis, the Kaplan–Meier method).
Results We identified 337 patients from 1989 to 2011 who met the eligibility criteria of this study. Of these, 265 (78.6%) had AdCa and 72 (21.4%) had AdSCCa. After surgery, 112 (33.2%) patients received adjuvant therapy, with 26 (7.7%) receiving chemotherapy, 37 (11%) receiving RT, and 49 (14.5%) receiving CCRT. Patient characteristics are listed in Table 1. There were no differences between the AdCa group and AdSCCa group in age, parity, BMI, FIGO stage, depth of stromal invasion, parametrial involvement, resection margin involvement, lymph node metastasis, and adjuvant therapy. However, mean tumor size of the AdSCCa group was larger than AdCa group (2.3 cm vs 2.7 cm, P = 0.019). Also, LVSI was more common (29.2% vs 14.7%, P = 0.008) in the AdSCCa than in the AdCa group. The mean and median follow-up times were 79 and 68 months (range, 4.4–256 months), respectively, for all patients; 76 and 65 months (range, 4.4–225 months), respectively, for the AdCa group; and 90 and 72 months (range, 4.4–256 months), respectively, for the
AdSCCa group. The 5- and 10-year RFS rates were 88% and 85%, respectively, and the 5- and 10-year OS rates were 92% and 88%, respectively. At the time of this analysis, 39 (14.7%) patients in the AdCa group and 13 (18.1%) in the AdSCCa group had recurrent disease (P = 0.467). Of these patients, 33 (12.5%) in the AdCa group and 11 (15.3%) in the AdSCCa group died of disease (P = 0.555). The 5- and 10-year RFS rates were 89% and 86%, respectively, for the AdCa group and 85% and 82%, respectively, for the AdSCCa group (P = 0.582) (Fig. 1A). The 5- and 10-year OS rates were 93% and 88%, respectively, for the AdCa group and 89% and 86%, respectively, for the AdSCCa group (P = 0.787) (Fig. 1A). Univariate analysis showed that tumor size, LVSI, DOI, parametrial involvement, and lymph node metastasis were significantly associated with RFS and OS, whereas age, parity, BMI, resection margin involvement, and histologic type were not (Table 2). In multivariate analysis, after adjusting for factors that were significant in univariate analysis, LVSI, DOI, and lymph node metastasis were significantly associated with RFS, while LVSI and lymph node metastasis were significantly associated with OS (Table 2). After adjusting for factors that
M.-H. Baek et al. / Gynecologic Oncology 135 (2014) 462–467
465
Table 2 Factors associated with recurrence-free survival and overall survival. Characteristics
N
Recurrence free survival
Overall survival
Univariate analysis 5- & 10-year rate (%) Age Parity BMI Size of tumor LVSI DOI Parametrium Resection margin Lymph node Histology
≤47 y N47 y ≤2 N2 ≤24 kg/m2 N24 kg/m2 ≤2 cm N2 cm Negative Positive ≤1/2 N1/2 Negative Positive Negative Positive Negative Positive AdCa AdSCCa
197 (58.5) 140 (41.5) 236 (70) 101 (30) 195 (57.9) 142 (42.1) 163 (48.4) 174 (51.6) 277 (82.2) 60 (17.8) 190 (56.4) 147 (43.6) 302 (89.6) 35 (10.4) 332 (98.5) 5 (1.5) 285 (84.6) 52 (15.4) 265 (78.6) 72 (21.4)
87 & 86 89 & 84 89 & 86 86 & 81 90 & 88 85 & 81 92 & 90 83 & 80 92 & 91 67 & 58 95 & 93 79 & 74 91 & 88 63 & 57 88 & 85 80 & 80 92 & 90 65 & 58 89 & 86 85 & 82
P-value
Multivariate analysis
Univariate analysis
OR (95% CI)
5- & 10-year rate (%)
P-value
0.574 0.359 0.090 0.014 b0.001 b0.001 b0.001
1 1.0 (0.6–1.9) 1 2.6 (1.4–5.0) 1 2.2 (1.1–4.3) 1 1.7 (0.8–3.5)
0.906 0.004 0.027 0.138
0.619 b0.001
1 2.2 (1.2–4.1)
0.015
0.583
92 & 89 93 & 86 92 & 89 92 & 84 93 & 90 91 & 85 96 & 92 89 & 84 96 & 93 73 & 65 97 & 94 86 & 80 95 & 91 71 & 63 93 & 88 80 & 80 96 & 92 73 & 64 93 & 88 89 & 86
Multivariate analysis P-value
OR (95% CI)
P-value
0.306 0.314 0.050 0.039 b0.001 b0.001 b0.001
1 1.0 (0.5–1.9) 1 2.7 (1.3–5.5) 1 2.0 (0.9–4.2) 1 1.8 (0.8–3.9)
0.884 0.006 0.072 0.156
0.382 b0.001
1 2.3 (1.1–4.6)
0.020
0.787
OR, Odds ratio; CI, confidence interval; BMI, body mass index; FIGO, International Federation of Obstetrics and Gynecology; NR, not reported; LVSI, lymphovascular space invasion; DOI, depth of cervical stromal invasion; AdCa, adenocarcinoma; and AdSCCa, adenosquamous carcinoma.
were significant in univariate analysis, the risks of recurrence (odds ratio [OR], 0.8; 95% confidence interval [CI], 0.4–1.5; P-value, 0.533) and death (OR, 0.8; 95% CI, 0.4–1.5; P-value, 0.454) did not differ between the AdCa and AdSCCa groups. Using the criteria of GOG protocols 92 and 109, 236 (70%), 32 (9.5%), and 69 (20.5%) patients were assigned to low-, intermediate- or highrisk groups, respectively (Table 3). The 5- and 10-year RFS rates of the low-, intermediate-, and high risk groups were 93% and 92%, 88% and 84%, and 70% and 62%, respectively (low vs intermediate, P = 0.240; low vs high, P b 0.001; intermediate vs high, P = 0.026) (Fig. 1B). The 5- and 10-year OS rates of the low-, intermediate-, and high-risk groups were 97% and 94%, 94% and 91%, and 75% and 67%, respectively (low vs intermediate, P = 0.733; low vs high, P b 0.001; intermediate vs high, P = 0.009) (Fig. 1B). When each risk group was analyzed separately, we found that adjuvant therapy, recurrence rate, death rate, and 5- and 10-year RFS and OS rates did not differ between the AdCa and AdSCCa groups (Table 3). The mean time from diagnosis to recurrence was 32 months (range, 4.0–128 months) in the AdCa group and 31 months (range, 5.5–97 months) in the AdSCCa group (P = 0.935). Fifteen (38.5%) patients in the AdCa group and 4 (30.8%) in the AdSCCa group had isolated pelvic recurrences (P = 0.746). Among the AdCa group patients, 10 did not undergo adjuvant therapy, two underwent radiotherapy, and three
underwent concurrent chemoradiation therapy following radical hysterectomy. In the AdSCCa group, one patient did not undergo adjuvant therapy, one underwent radiotherapy, and two underwent concurrent chemoradiation therapy following radical hysterectomy. Twenty-four (61.5%) patients in the AdCa group and nine (69.2%) in the AdSCCa group had recurrences outside of the pelvis. In the AdCa group, eight patients did not undergo adjuvant therapy, two underwent chemotherapy, three underwent radiotherapy, and 11 underwent concurrent chemoradiation therapy after radical hysterectomy. In the AdSCCa group, three patients did not undergo adjuvant therapy, two underwent chemotherapy, one underwent radiotherapy, and three underwent concurrent chemoradiation therapy after radical hysterectomy. The locations of recurrent disease at the time of first recurrence did not differ according to the type of adjuvant therapy in the AdCa group (P = 0.059) or in the AdSCCa group (P = 0.831). Discussion There were no differences in demographic and clinicopathologic characteristics between the two histologic types (AdCa vs. AdSCCa) of early-stage cervical cancer. Only mean size of tumor and LVSI were larger and more frequent in AdSCCa than AdCa. Histologic type (AdCa vs AdSCCa) had no clinical impact on RFS and OS, in either univariate
Table 3 Survival analysis by histologic type and risk group. Risk group and histology
Low Risk Group AdCa AdSCCa Intermediate risk group AdCa AdSCCa High risk group AdCa AdSCCa
Total n, (%)
236 (100) 194 (100) 42 (100) 32 (100) 23 (100) 9 (100) 69 (100) 48 (100) 21 (100)
Adjuvant therapy, n (%)
Recurrence-free survival
None
CTx
RT
CCRT
200 (84.7) 167 (86.1) 33 (78.6) 20 (62.5) 15 (65.2) 5 (55.6) 5 (7.2) 4 (8.3) 1 (4.8)
12 (5.1) 8 (4.1) 4 (9.5) 5 (15.6) 4 (17.4) 1 (11.1) 9 (13.0) 7 (14.6) 2 (9.5)
16 (6.8) 12 (6.2) 4 (9.5) 5 (15.6) 2 (8.7) 3 (33.3) 16 (23.2) 13 (27.1) 3 (14.3)
8 (3.4) 7 (3.6) 1 (2.4) 2 (6.3) 2 (8.7) 0 (0) 39 (56.5) 24 (50.0) 15 (71.4)
P-value
0.402
0.314
0.430
Recur n, (%)
5- & 10-year rate (%)
21 (8.9) 17 (8.8)⁎ 4 (9.5) 5 (15.6) 4 (17.4)⁎ 1 (11.1) 26 (37.7) 18 (37.5)⁎ 8 (38.1)
93 & 92 94 & 92 91 & 91 88 & 84 87 & 83 89 & 89 70 & 62 69 & 63 71 & 62
Overall survival P-value
0.773
1.000
1.000
Death n, (%)
5-& 10-year rate (%)
17 (7.2) 13 (6.7)⁎ 4 (9.5) 3 (9.4) 3 (13.0)⁎ 0 (0) 24 (34.8) 17 (35.4)⁎ 7 (33.3)
97 & 94 99 & 94 91 & 91 94 & 91 91 & 87 100 & 100 75 & 67 73 & 65 81 & 71
CTx, chemotherapy; RT, radiotherapy; CCRT, concurrent chemoradiation therapy; AdCa, adenocarcinoma; and AdSCCa, adenosquamous carcinoma. ⁎ P N 0.05 compared with the AdSCCa group.
P-value
0.514
0.541
1.000
466
M.-H. Baek et al. / Gynecologic Oncology 135 (2014) 462–467
or multivariate analysis. There was also no difference in the pattern of recurrence and the time to recurrence after treatment between the two histologic types. When patients were stratified into three risk groups according to the criteria of GOG protocols 92 and 109, histologic type (AdCa vs AdSCCa) had no clinical impact on RFS and OS in any of the risk groups. Because the incidence of AdCa and AdSCCa is increasing and most patients are diagnosed at an early stage, making them amenable to radical hysterectomy [5,8,17,25,26], it is important to establish the optimal management strategy and identify prognostic factors. We found that 5- and 10-year RFS rates were 88% and 85%, respectively, and 5- and 10-year OS rates were 92% and 88%, respectively, suggesting that our treatment strategy, consisting of radical hysterectomy followed by tailored adjuvant therapy, is appropriate for patients with these histologic varieties. Multivariate analysis showed that LVSI, DOI, and lymph node metastasis were independent risk factors for recurrence, and LVSI and lymph node metastasis were independent risk factors for death. Previous studies have reported similar 5-year survival rates after radical hysterectomy to those reported here in patients with early-stage AdCa and AdSCCa, ranging from 74% to 88% [10,15,27]. Those studies also found that FIGO stage, tumor size, and lymph node metastasis were independent prognostic factors for survival [10,15,28]. Although several studies have indicated that after radical hysterectomy patients with early-stage AdCa and AdSCCa have a poorer prognosis than those with SCCa [8–12], other studies have reported contrary results [13–15]. Few studies, however, have directly compared clinicopathologic factors, patterns of recurrence, time interval to recurrence, RFS and OS in patients with AdCa and AdSCCa [16–18]. There are several reports that clinicopathologic factors do not differ between patients with AdCa and AdSCCa [10,16,29], although other studies have found that grade 3 histology and LVSI were more common in patients with AdSCCa [18]. In our series, patients with AdSCCa had larger tumors and more frequent involvement of the outer one-third of the cervical stroma than patients with AdCa, but the differences were small. Other clinicopathologic factors were similar in the two histologic types. In agreement with others, we found that the pattern of recurrence did not depend on the histologic type [10,29]. It is important to classify recurrent disease as inside or outside the pelvis because patients with isolated pelvic recurrence can undergo treatment with curative intent by surgery or RT/CCRT and these patients are expected to survive longer. In our series, 38.5% and 30.8% of patients in AdCa and AdSCCa groups, respectively, had isolated pelvic recurrences (P = 0.746). The locations of recurrent disease also did not differ between the two groups when analyzed according to the type of adjuvant therapy. Although several groups found that times to recurrence did not differ [10,28], others found earlier recurrence in patients with AdSCCa than in those with AdCa [18]. We detected no difference, in agreement with a large scale and multi-centered study [30]. Most investigators have reported that RFS and OS are similar in patients with AdCa and AdSCCa, as reported here. However, some workers found that patients with AdSCCa had poorer OS than those with AdCa [28] or that advanced-stage but not early-stage AdSCCa was associated with poorer outcomes [17]. In addition, some authors have suggested that after radical hysterectomy AdSCCa is associated with poorer RFS and OS in low-risk patients than AdCa [31]. However, in our multivariate analysis we noted no differences in RFS and OS rates between the AdCa and AdSCCa groups after adjusting for factors significant in univariate analysis. When we analyzed the low-, intermediate-, and high-risk groups separately, we also found that survival outcomes did not differ significantly between patients with AdCa and AdSCCa. Among the limitations of our study is its retrospective design. Adjuvant therapy differed somewhat over time, and was at the discretion of the attending physicians after discussion with the patient. As far as we know, however, this is the largest study to date to directly compare outcomes of patients with AdCa and AdSCCa with its long follow-up period.
In conclusion, survival outcomes after radical hysterectomy followed by tailored adjuvant therapy are excellent, and justify the use of this treatment strategy in patients with FIGO stage IB1 AdCa and AdSCCa of the uterine cervix. LVSI, DOI, and lymph node metastasis are independent prognostic factors after treatment. Clinicopathologic factors, recurrence patterns and time to recurrence are similar in patients with the two histologic types. There are no differences in RFS and OS rates between AdCa and AdSCCa, even after stratification by risk. Conflict of interest statement The authors declare that there are no conflicts of interest.
References [1] Waggoner SE. Cervical cancer. Lancet 2003;361:2217–25. [2] Jung KW, Won YJ, Kong HJ, Oh CM, Lee DH, Lee JS. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2011. Cancer Res Treat 2014;46: 109–23. [3] Jung KW, Won YJ, Kong HJ, Oh CM, Lee DH, Lee JS. Prediction of cancer incidence and mortality in Korea, 2014. Cancer Res Treat 2014;46:124–30. [4] Kosary CL. FIGO stage, histology, histologic grade, age and race as prognostic factors in determining survival for cancers of the female gynecological system: an analysis of 1973–87 SEER cases of cancers of the endometrium, cervix, ovary, vulva, and vagina. Semin Surg Oncol 1994;10:31–46. [5] Vinh-Hung V, Bourgain C, Vlastos G, Cserni G, De Ridder M, Storme G, et al. Prognostic value of histopathology and trends in cervical cancer: a SEER population study. BMC Cancer 2007;7:164. [6] Kjorstad KE. Adenocarcinoma of the uterine cervix. Gynecol Oncol 1977;5:219–23. [7] Berek JS, Hacker NF, Fu YS, Sokale JR, Leuchter RC, Lagasse LD. Adenocarcinoma of the uterine cervix: histologic variables associated with lymph node metastasis and survival. Obstet Gynecol 1985;65:46–52. [8] Hopkins MP, Morley GW. A comparison of adenocarcinoma and squamous cell carcinoma of the cervix. Obstet Gynecol 1991;77:912–7. [9] Eifel PJ, Burke TW, Morris M, Smith TL. Adenocarcinoma as an independent risk factor for disease recurrence in patients with stage IB cervical carcinoma. Gynecol Oncol 1995;59:38–44. [10] Lai CH, Hsueh S, Hong JH, Chang TC, Tseng CJ, Chou HH, et al. Are adenocarcinomas and adenosquamous carcinomas different from squamous carcinomas in stage IB and II cervical cancer patients undergoing primary radical surgery? Int J Gynecol Cancer 1999;9:28–36. [11] Nakanishi T, Ishikawa H, Suzuki Y, Inoue T, Nakamura S, Kuzuya K. A comparison of prognoses of pathologic stage Ib adenocarcinoma and squamous cell carcinoma of the uterine cervix. Gynecol Oncol 2000;79:289–93. [12] Samlal RA, van der Velden J, Ten Kate FJ, Schilthuis MS, Hart AA, Lammes FB. Surgical pathologic factors that predict recurrence in stage IB and IIA cervical carcinoma patients with negative pelvic lymph nodes. Cancer 1997;80:1234–40. [13] Anton-Culver H, Bloss JD, Bringman D, Lee-Feldstein A, DiSaia P, Manetta A. Comparison of adenocarcinoma and squamous cell carcinoma of the uterine cervix: a population-based epidemiologic study. Am J Obstet Gynecol 1992;166:1507–14. [14] Grisaru D, Covens A, Chapman B, Shaw P, Colgan T, Murphy J, et al. Does histology influence prognosis in patients with early-stage cervical carcinoma? Cancer 2001; 92:2999–3004. [15] Kasamatsu T, Onda T, Sawada M, Kato T, Ikeda S, Sasajima Y, et al. Radical hysterectomy for FIGO stage I–IIB adenocarcinoma of the uterine cervix. Br J Cancer 2009; 100:1400–5. [16] Harrison TA, Sevin BU, Koechli O, Nguyen HN, Averette HE, Penalver M, et al. Adenosquamous carcinoma of the cervix: prognosis in early stage disease treated by radical hysterectomy. Gynecol Oncol 1993;50:310–5. [17] Farley JH, Hickey KW, Carlson JW, Rose GS, Kost ER, Harrison TA. Adenosquamous histology predicts a poor outcome for patients with advanced-stage, but not earlystage, cervical carcinoma. Cancer 2003;97:2196–202. [18] dos Reis R, Frumovitz M, Milam MR, Capp E, Sun CC, Coleman RL, et al. Adenosquamous carcinoma versus adenocarcinoma in early-stage cervical cancer patients undergoing radical hysterectomy: an outcomes analysis. Gynecol Oncol 2007;107:458–63. [19] Piver MS, Rutledge F, Smith JP. Five classes of extended hysterectomy for women with cervical cancer. Obstet Gynecol 1974;44:265–72. [20] Sedlis A, Bundy BN, Rotman MZ, Lentz SS, Muderspach LI, Zaino RJ. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: a Gynecologic Oncology Group Study. Gynecol Oncol 1999;73:177–83. [21] Peters III WA, Liu PY, Barrett II RJ, Stock RJ, Monk BJ, Berek JS, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18:1606–13. [22] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–81. [23] Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163–70. [24] Cox DR. Regression models and life tables. R Stat Soc B 1972;34:187–220. [25] Chen RJ, Chang DY, Yen ML, Lee EF, Huang SC, Chow SN, et al. Prognostic factors of primary adenocarcinoma of the uterine cervix. Gynecol Oncol 1998;69:157–64.
M.-H. Baek et al. / Gynecologic Oncology 135 (2014) 462–467 [26] Chargui R, Damak T, Khomsi F, Ben Hassouna J, Chaieb W, Hechiche M, et al. Prognostic factors and clinicopathologic characteristics of invasive adenocarcinoma of the uterine cervix. Am J Obstet Gynecol 2006;194:43–8. [27] Ayhan A, Al RA, Baykal C, Demirtas E, Yuce K, Ayhan A. A comparison of prognoses of FIGO stage IB adenocarcinoma and squamous cell carcinoma. Int J Gynecol Cancer 2004;14:279–85. [28] Look KY, Brunetto VL, Clarke-Pearson DL, Averette HE, Major FJ, Alvarez RD, et al. An analysis of cell type in patients with surgically staged stage IB carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 1996;63:304–11.
467
[29] Chen JL, Cheng JC, Kuo SH, Chen CA, Lin MC, Huang CY. Outcome analysis of cervical adenosquamous carcinoma compared with adenocarcinoma. Acta Obstet Gynecol Scand 2012;91:1158–66. [30] Shingleton HM, Bell MC, Fremgen A, Chmiel JS, Russell AH, Jones WB, et al. Is there really a difference in survival of women with squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma of the cervix? Cancer 1995;76:1948–55. [31] Lea JS, Coleman RL, Garner EO, Duska LR, Miller DS, Schorge JO. Adenosquamous histology predicts poor outcome in low-risk stage IB1 cervical adenocarcinoma. Gynecol Oncol 2003;91:558–62.
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Comparison of adenocarcinoma and adenosquamous carcinoma in patients with early-stage cervical cancer after radical surgery Min-Hyun Baek, Jeong-Yeol Park ⁎, Daeyeon Kim, Dae-Shik Suh, Jong-Hyeok Kim, Yong-Man Kim, Young-Tak Kim, Joo-Hyun Nam Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
H I G H L I G H T S • Outcomes of adenocarcinoma and adenosquamous carcinoma of the cervix were compared. • The clinicopathologic characteristics of the two histologic types were similar. • Histologic type had no impact on patterns of recurrence and survival outcomes.
a r t i c l e
i n f o
Article history: Received 26 June 2014 Accepted 2 October 2014 Available online 12 October 2014 Keywords: Early-stage cervical cancer Adenocarcinoma Adenosquamous carcinoma
a b s t r a c t Objective. To compare outcomes after radical hysterectomy in patients with stage IB1 adenocarcinoma (AdCa) and adenosquamous carcinoma (AdSCCa) of the uterine cervix. Methods. We performed a retrospective analysis of 265 patients with AdCa and 72 patients with AdSCCa. Demographic, clinicopathologic, surgical, and follow-up data were compared. Results. There were no differences in demographic and clinicopathologic characteristics between the two histologic types (AdCa vs. AdSCCa). Only mean size of tumor and lymphovascular space invasion was larger and more frequent in AdSCCa (2.7 cm vs 2.3 cm, P = 0.019 & 29.2% vs 14.7%, P = 0.008). After a median follow-up time of 68 months, 39 (14.7%) and 13 (18.1%) AdCa and AdSCCa patients, respectively, had recurrent disease (P = 0.467), and 33 (12.5%) and 11 (15.3%) patients, respectively, died of their disease (P = 0.555). 5-year RFS rates were 89% and 85% (P = 0.582), respectively, and 5-year OS rates were 93% and 89% (P = 0.787). Histologic type had no clinical impact on RFS and OS in multivariate analysis adjusting for significant prognostic factors. There were no differences in pattern of recurrence and time to recurrence between the two histologic types. When patients were stratified into three risk groups according to the criteria of GOG protocols 92 and 109, histologic type had no clinical impact on RFS and OS in any of the risk groups. Conclusion. There are no differences in clinicopathologic factors, patterns of recurrence, time to recurrence, RFS and OS between patients with AdCa and AdSCCa. © 2014 Elsevier Inc. All rights reserved.
Introduction Cervical cancer is the second most common cancer and the most common cause of cancer deaths in women worldwide [1]. In Korea, it is the seventh most common cancer and the ninth most common cause of cancer deaths in women, and 3728 new cases and 989 deaths from cervical cancer were recorded in 2011 [2,3]. Although the incidence of cervical cancer is decreasing owing to the introduction of nation-wide organized screening programs in developed countries, it ⁎ Corresponding author at: Department of Obstetrics and Gynecology, College of Medicine, University of Ulsan, Asan Medical Center, #388-1 Poongnap-2 dong, Songpagu, Seoul, 138-736, Republic of Korea. Fax: +82 2 476 7331. E-mail address: [email protected] (J.-Y. Park).
http://dx.doi.org/10.1016/j.ygyno.2014.10.004 0090-8258/© 2014 Elsevier Inc. All rights reserved.
remains an important health problem for women. Squamous cell carcinoma (SCCa), although varying in frequency between populations, is the most common histologic type of cervical cancer; it accounts for approximately 75% of all cases [4], although its incidence is decreasing [5]. Adenocarcinoma (AdCa) is the second most common histologic type of cervical cancer, accounting for 15% of all cases [4], but its absolute and relative incidences are increasing, especially in women aged 20–40 [5]. In older reports, 5% of all cervical cancers were AdCa [6], whereas in more recent reports the incidence was as high as 18.5–27% [7,8]. Adenosquamous carcinoma (AdSCCa) is a mixture of malignant glandular and squamous components consisting of intermingled AdCa and SCCa. It occurs in 2–3% of patients with cervical cancer, and its incidence is increasing, along with that of AdCa [5]. Many studies have suggested that patients with early-stage AdCa and AdSCCa have poorer
M.-H. Baek et al. / Gynecologic Oncology 135 (2014) 462–467
463
Table 1 Clinicopathologic factors in the adenocarcinoma and adenosquamous carcinoma groups (n = 337). Characteristic Age (years), mean (range)
Parity, n (%)
≤47 years, n (%) N47 years, n (%) ≤2 N2
2
BMI (kg/m ), mean (range) ≤24 kg/m2, n (%) N24 kg/m2, n (%) Size of tumor (cm), mean (range)
LVSI, n (%) DOI, n (%) Parametrium, n (%) Resection margin, n (%) Lymph node, n (%) Adjuvant therapy, n (%)
≤2 cm, n (%) N2 cm, n (%) Negative Positive ≤1/2 N1/2 Negative Positive Negative Positive Negative Positive Not done Chemotherapy Radiotherapy CCRT
Total (n = 337)
Adenocarcinoma (n = 265)
Adenosquamous carcinoma (n = 72)
P-value
46.2 (25–76) 197 (58.5) 140 (41.5) 236 (70) 101 (30) 23.8 (17.1–42.2) 195 (57.9) 142 (42.1) 2.4 (0.2–7.3) 163 (48.4) 174 (51.6) 277 (82.2) 60 (17.8) 190 (56.4) 147 (43.6) 302 (89.6) 35 (10.4) 332 (98.5) 5 (1.5) 285 (84.6) 52 (15.4) 225 (66.8) 26 (7.7) 37 (11) 49 (14.5)
46.1 (27–73) 159 (60) 106 (40) 184 (69.4) 81 (30.6) 23.6 (17.1–35.2) 159 (60) 106 (40) 2.3 (0.2–7.3) 134 (50.6) 131 (49.4) 226 (85.3) 39 (14.7) 156 (58.9) 109 (41.1) 240 (90.6) 25 (9.4) 261 (98.5) 4 (1.5) 229 (86.4) 36 (13.6) 186 (70.2) 19 (7.2) 27 (10.2) 33 (12.5)
46.7 (25–76) 38 (52.8) 34 (47.2) 52 (72.2) 20 (27.8) 24.4 (17.5–42.2) 36 (50) 36 (50) 2.7 (0.2–8.0) 29 (40.3) 43 (59.7) 51 (70.8) 21 (29.2) 34 (47.2) 38 (52.8) 62 (86.1) 10 (13.9) 71 (98.6) 1 (1.4) 56 (77.8) 16 (22.2) 39 (54.2) 7 (9.7) 10 (13.9) 16 (22.2)
0.633 0.283 0.772 0.086 0.140 0.019 0.144 0.008 0.083 0.279 1.000 0.096 0.069
BMI, body mass index; FIGO, International Federation of Obstetrics and Gynecology; LVSI, lymphovascular space invasion; and DOI, depth of cervical stromal invasion.
prognoses than those with SCCa after radical hysterectomy [8–12] although contrary results have been reported [13–15]. Due to the relative rarity of AdCA and AdSCCa, however, the optimal management and prognostic factors for early-stage patients have not been clearly established. It is also unclear whether AdCa and AdSCCa have different prognoses because many studies did not distinguish between them, and only a few have directly compared outcomes between patients with AdCa and those with AdSCCa [16–18]. We therefore evaluated outcomes and prognostic factors in patients with FIGO stage IB1 AdCa and AdSCCa of the uterine cervix after radical hysterectomy followed by tailored adjuvant therapy.
We retrospectively reviewed the medical records of each patient to collect demographic data, including age, parity, and body mass index (BMI); clinical data, including preoperative imaging, pelvic examination, neoadjuvant chemotherapy, surgery, and adjuvant therapy; pathologic data, including histologic type of the tumor, grade of differentiation, tumor size, depth of cervical stromal invasion (DOI), lymphovascular space invasion (LVSI), parametrial invasion, resection margin status, and lymph node status; and follow-up data, including date of recurrence, treatment at recurrence, date of last follow-up, patient status at last follow-up, and cause of death. Statistical analysis
Materials and methods With the approval of the Institutional Review Board of Asan Medical Center, we searched the cancer registry and computerized database of the institution to identify patients with early-stage AdCa and AdSCCa of the uterine cervix who underwent radical hysterectomy. Patients were included if they had: 1) previously untreated cervical cancer; 2) had AdCa or AdSCCa histologic types; 3) had FIGO stage IB1; and 4) had undergone radical hysterectomy by the Rutledge and Piver classification with pelvic and/or para-aortic lymphadenectomy [19]. We excluded patients who received neoadjuvant chemotherapy, radiotherapy (RT) or concurrent chemoradiation therapy (CCRT) before radical hysterectomy, patients with occult cervical cancer identified after simple hysterectomy, and patients with additional malignancies. In our center the preferred treatment for patients with FIGO stages IA2–IIA cervical cancer is radical hysterectomy; thus, almost all the patients with FIGO stage IB1 cervical cancer undergo radical hysterectomy and only a small number who are not eligible for radical surgery receive RT or CCRT. If positive pelvic or para-aortic lymph node involvement is confirmed by frozen section, our policy is to complete radical hysterectomy. Tumors were reviewed by one pathologist at our hospital who specializes in gynecologic oncology full time. Occasionally, an assistant pathologist also reviewed the findings. However, the final diagnosis was only made following agreement between both pathologists.
Clinicopathologic factors, recurrence-free survival (RFS) and overall survival (OS) were compared between the AdCa and AdSCCa groups to identify any differences between the two histologic subtypes. The correlations between RFS and OS and clinicopathologic factors were examined to identify factors prognostic for RFS and OS. To determine the prognostic role of histologic type in each risk group, we stratified patients into three risk groups (low, intermediate and high) according to the criteria of two randomized controlled trials of adjuvant therapy in early-stage cervical cancer, the Gynecologic Oncologic Group (GOG) protocols 92 [20] and 109 [21]. RFS was calculated as the number of months from the date of surgery to either the date of recurrence or the date of censoring. OS was calculated as the number of months from the date of surgery to either the date of death or the date of censoring. Survival curves and rates were calculated using the Kaplan–Meier method [22]. Differences in survival were assessed using the log-rank test for categorical factors [23] and Cox's proportional hazards model for continuous factors in univariate analysis [24]. A multivariate analysis was performed using Cox's proportional hazards model to determine risk factors after adjustment for known prognostic variables. Frequency distributions were compared using Chi-squared and Fisher's exact tests, and mean and median values in the groups were compared using the Student's t-test and the Mann–Whitney U-test. A two-sided P-value less than 0.05 indicated statistical significance. Data were analyzed using SPSS software for Windows (version 11.0; SPSS Inc., Chicago, IL).
464
M.-H. Baek et al. / Gynecologic Oncology 135 (2014) 462–467
Fig. 1. a) Recurrence-free survival (left) and overall survival (right) of patients with adenocarcinoma (AdCa) and adenosquamous carcinoma (AdSCCa) of the cervix (univariate analysis, the Kaplan–Meier method). b) Recurrence-free survival (left) and overall survival (right) by risk group (univariate analysis, the Kaplan–Meier method).
Results We identified 337 patients from 1989 to 2011 who met the eligibility criteria of this study. Of these, 265 (78.6%) had AdCa and 72 (21.4%) had AdSCCa. After surgery, 112 (33.2%) patients received adjuvant therapy, with 26 (7.7%) receiving chemotherapy, 37 (11%) receiving RT, and 49 (14.5%) receiving CCRT. Patient characteristics are listed in Table 1. There were no differences between the AdCa group and AdSCCa group in age, parity, BMI, FIGO stage, depth of stromal invasion, parametrial involvement, resection margin involvement, lymph node metastasis, and adjuvant therapy. However, mean tumor size of the AdSCCa group was larger than AdCa group (2.3 cm vs 2.7 cm, P = 0.019). Also, LVSI was more common (29.2% vs 14.7%, P = 0.008) in the AdSCCa than in the AdCa group. The mean and median follow-up times were 79 and 68 months (range, 4.4–256 months), respectively, for all patients; 76 and 65 months (range, 4.4–225 months), respectively, for the AdCa group; and 90 and 72 months (range, 4.4–256 months), respectively, for the
AdSCCa group. The 5- and 10-year RFS rates were 88% and 85%, respectively, and the 5- and 10-year OS rates were 92% and 88%, respectively. At the time of this analysis, 39 (14.7%) patients in the AdCa group and 13 (18.1%) in the AdSCCa group had recurrent disease (P = 0.467). Of these patients, 33 (12.5%) in the AdCa group and 11 (15.3%) in the AdSCCa group died of disease (P = 0.555). The 5- and 10-year RFS rates were 89% and 86%, respectively, for the AdCa group and 85% and 82%, respectively, for the AdSCCa group (P = 0.582) (Fig. 1A). The 5- and 10-year OS rates were 93% and 88%, respectively, for the AdCa group and 89% and 86%, respectively, for the AdSCCa group (P = 0.787) (Fig. 1A). Univariate analysis showed that tumor size, LVSI, DOI, parametrial involvement, and lymph node metastasis were significantly associated with RFS and OS, whereas age, parity, BMI, resection margin involvement, and histologic type were not (Table 2). In multivariate analysis, after adjusting for factors that were significant in univariate analysis, LVSI, DOI, and lymph node metastasis were significantly associated with RFS, while LVSI and lymph node metastasis were significantly associated with OS (Table 2). After adjusting for factors that
M.-H. Baek et al. / Gynecologic Oncology 135 (2014) 462–467
465
Table 2 Factors associated with recurrence-free survival and overall survival. Characteristics
N
Recurrence free survival
Overall survival
Univariate analysis 5- & 10-year rate (%) Age Parity BMI Size of tumor LVSI DOI Parametrium Resection margin Lymph node Histology
≤47 y N47 y ≤2 N2 ≤24 kg/m2 N24 kg/m2 ≤2 cm N2 cm Negative Positive ≤1/2 N1/2 Negative Positive Negative Positive Negative Positive AdCa AdSCCa
197 (58.5) 140 (41.5) 236 (70) 101 (30) 195 (57.9) 142 (42.1) 163 (48.4) 174 (51.6) 277 (82.2) 60 (17.8) 190 (56.4) 147 (43.6) 302 (89.6) 35 (10.4) 332 (98.5) 5 (1.5) 285 (84.6) 52 (15.4) 265 (78.6) 72 (21.4)
87 & 86 89 & 84 89 & 86 86 & 81 90 & 88 85 & 81 92 & 90 83 & 80 92 & 91 67 & 58 95 & 93 79 & 74 91 & 88 63 & 57 88 & 85 80 & 80 92 & 90 65 & 58 89 & 86 85 & 82
P-value
Multivariate analysis
Univariate analysis
OR (95% CI)
5- & 10-year rate (%)
P-value
0.574 0.359 0.090 0.014 b0.001 b0.001 b0.001
1 1.0 (0.6–1.9) 1 2.6 (1.4–5.0) 1 2.2 (1.1–4.3) 1 1.7 (0.8–3.5)
0.906 0.004 0.027 0.138
0.619 b0.001
1 2.2 (1.2–4.1)
0.015
0.583
92 & 89 93 & 86 92 & 89 92 & 84 93 & 90 91 & 85 96 & 92 89 & 84 96 & 93 73 & 65 97 & 94 86 & 80 95 & 91 71 & 63 93 & 88 80 & 80 96 & 92 73 & 64 93 & 88 89 & 86
Multivariate analysis P-value
OR (95% CI)
P-value
0.306 0.314 0.050 0.039 b0.001 b0.001 b0.001
1 1.0 (0.5–1.9) 1 2.7 (1.3–5.5) 1 2.0 (0.9–4.2) 1 1.8 (0.8–3.9)
0.884 0.006 0.072 0.156
0.382 b0.001
1 2.3 (1.1–4.6)
0.020
0.787
OR, Odds ratio; CI, confidence interval; BMI, body mass index; FIGO, International Federation of Obstetrics and Gynecology; NR, not reported; LVSI, lymphovascular space invasion; DOI, depth of cervical stromal invasion; AdCa, adenocarcinoma; and AdSCCa, adenosquamous carcinoma.
were significant in univariate analysis, the risks of recurrence (odds ratio [OR], 0.8; 95% confidence interval [CI], 0.4–1.5; P-value, 0.533) and death (OR, 0.8; 95% CI, 0.4–1.5; P-value, 0.454) did not differ between the AdCa and AdSCCa groups. Using the criteria of GOG protocols 92 and 109, 236 (70%), 32 (9.5%), and 69 (20.5%) patients were assigned to low-, intermediate- or highrisk groups, respectively (Table 3). The 5- and 10-year RFS rates of the low-, intermediate-, and high risk groups were 93% and 92%, 88% and 84%, and 70% and 62%, respectively (low vs intermediate, P = 0.240; low vs high, P b 0.001; intermediate vs high, P = 0.026) (Fig. 1B). The 5- and 10-year OS rates of the low-, intermediate-, and high-risk groups were 97% and 94%, 94% and 91%, and 75% and 67%, respectively (low vs intermediate, P = 0.733; low vs high, P b 0.001; intermediate vs high, P = 0.009) (Fig. 1B). When each risk group was analyzed separately, we found that adjuvant therapy, recurrence rate, death rate, and 5- and 10-year RFS and OS rates did not differ between the AdCa and AdSCCa groups (Table 3). The mean time from diagnosis to recurrence was 32 months (range, 4.0–128 months) in the AdCa group and 31 months (range, 5.5–97 months) in the AdSCCa group (P = 0.935). Fifteen (38.5%) patients in the AdCa group and 4 (30.8%) in the AdSCCa group had isolated pelvic recurrences (P = 0.746). Among the AdCa group patients, 10 did not undergo adjuvant therapy, two underwent radiotherapy, and three
underwent concurrent chemoradiation therapy following radical hysterectomy. In the AdSCCa group, one patient did not undergo adjuvant therapy, one underwent radiotherapy, and two underwent concurrent chemoradiation therapy following radical hysterectomy. Twenty-four (61.5%) patients in the AdCa group and nine (69.2%) in the AdSCCa group had recurrences outside of the pelvis. In the AdCa group, eight patients did not undergo adjuvant therapy, two underwent chemotherapy, three underwent radiotherapy, and 11 underwent concurrent chemoradiation therapy after radical hysterectomy. In the AdSCCa group, three patients did not undergo adjuvant therapy, two underwent chemotherapy, one underwent radiotherapy, and three underwent concurrent chemoradiation therapy after radical hysterectomy. The locations of recurrent disease at the time of first recurrence did not differ according to the type of adjuvant therapy in the AdCa group (P = 0.059) or in the AdSCCa group (P = 0.831). Discussion There were no differences in demographic and clinicopathologic characteristics between the two histologic types (AdCa vs. AdSCCa) of early-stage cervical cancer. Only mean size of tumor and LVSI were larger and more frequent in AdSCCa than AdCa. Histologic type (AdCa vs AdSCCa) had no clinical impact on RFS and OS, in either univariate
Table 3 Survival analysis by histologic type and risk group. Risk group and histology
Low Risk Group AdCa AdSCCa Intermediate risk group AdCa AdSCCa High risk group AdCa AdSCCa
Total n, (%)
236 (100) 194 (100) 42 (100) 32 (100) 23 (100) 9 (100) 69 (100) 48 (100) 21 (100)
Adjuvant therapy, n (%)
Recurrence-free survival
None
CTx
RT
CCRT
200 (84.7) 167 (86.1) 33 (78.6) 20 (62.5) 15 (65.2) 5 (55.6) 5 (7.2) 4 (8.3) 1 (4.8)
12 (5.1) 8 (4.1) 4 (9.5) 5 (15.6) 4 (17.4) 1 (11.1) 9 (13.0) 7 (14.6) 2 (9.5)
16 (6.8) 12 (6.2) 4 (9.5) 5 (15.6) 2 (8.7) 3 (33.3) 16 (23.2) 13 (27.1) 3 (14.3)
8 (3.4) 7 (3.6) 1 (2.4) 2 (6.3) 2 (8.7) 0 (0) 39 (56.5) 24 (50.0) 15 (71.4)
P-value
0.402
0.314
0.430
Recur n, (%)
5- & 10-year rate (%)
21 (8.9) 17 (8.8)⁎ 4 (9.5) 5 (15.6) 4 (17.4)⁎ 1 (11.1) 26 (37.7) 18 (37.5)⁎ 8 (38.1)
93 & 92 94 & 92 91 & 91 88 & 84 87 & 83 89 & 89 70 & 62 69 & 63 71 & 62
Overall survival P-value
0.773
1.000
1.000
Death n, (%)
5-& 10-year rate (%)
17 (7.2) 13 (6.7)⁎ 4 (9.5) 3 (9.4) 3 (13.0)⁎ 0 (0) 24 (34.8) 17 (35.4)⁎ 7 (33.3)
97 & 94 99 & 94 91 & 91 94 & 91 91 & 87 100 & 100 75 & 67 73 & 65 81 & 71
CTx, chemotherapy; RT, radiotherapy; CCRT, concurrent chemoradiation therapy; AdCa, adenocarcinoma; and AdSCCa, adenosquamous carcinoma. ⁎ P N 0.05 compared with the AdSCCa group.
P-value
0.514
0.541
1.000
466
M.-H. Baek et al. / Gynecologic Oncology 135 (2014) 462–467
or multivariate analysis. There was also no difference in the pattern of recurrence and the time to recurrence after treatment between the two histologic types. When patients were stratified into three risk groups according to the criteria of GOG protocols 92 and 109, histologic type (AdCa vs AdSCCa) had no clinical impact on RFS and OS in any of the risk groups. Because the incidence of AdCa and AdSCCa is increasing and most patients are diagnosed at an early stage, making them amenable to radical hysterectomy [5,8,17,25,26], it is important to establish the optimal management strategy and identify prognostic factors. We found that 5- and 10-year RFS rates were 88% and 85%, respectively, and 5- and 10-year OS rates were 92% and 88%, respectively, suggesting that our treatment strategy, consisting of radical hysterectomy followed by tailored adjuvant therapy, is appropriate for patients with these histologic varieties. Multivariate analysis showed that LVSI, DOI, and lymph node metastasis were independent risk factors for recurrence, and LVSI and lymph node metastasis were independent risk factors for death. Previous studies have reported similar 5-year survival rates after radical hysterectomy to those reported here in patients with early-stage AdCa and AdSCCa, ranging from 74% to 88% [10,15,27]. Those studies also found that FIGO stage, tumor size, and lymph node metastasis were independent prognostic factors for survival [10,15,28]. Although several studies have indicated that after radical hysterectomy patients with early-stage AdCa and AdSCCa have a poorer prognosis than those with SCCa [8–12], other studies have reported contrary results [13–15]. Few studies, however, have directly compared clinicopathologic factors, patterns of recurrence, time interval to recurrence, RFS and OS in patients with AdCa and AdSCCa [16–18]. There are several reports that clinicopathologic factors do not differ between patients with AdCa and AdSCCa [10,16,29], although other studies have found that grade 3 histology and LVSI were more common in patients with AdSCCa [18]. In our series, patients with AdSCCa had larger tumors and more frequent involvement of the outer one-third of the cervical stroma than patients with AdCa, but the differences were small. Other clinicopathologic factors were similar in the two histologic types. In agreement with others, we found that the pattern of recurrence did not depend on the histologic type [10,29]. It is important to classify recurrent disease as inside or outside the pelvis because patients with isolated pelvic recurrence can undergo treatment with curative intent by surgery or RT/CCRT and these patients are expected to survive longer. In our series, 38.5% and 30.8% of patients in AdCa and AdSCCa groups, respectively, had isolated pelvic recurrences (P = 0.746). The locations of recurrent disease also did not differ between the two groups when analyzed according to the type of adjuvant therapy. Although several groups found that times to recurrence did not differ [10,28], others found earlier recurrence in patients with AdSCCa than in those with AdCa [18]. We detected no difference, in agreement with a large scale and multi-centered study [30]. Most investigators have reported that RFS and OS are similar in patients with AdCa and AdSCCa, as reported here. However, some workers found that patients with AdSCCa had poorer OS than those with AdCa [28] or that advanced-stage but not early-stage AdSCCa was associated with poorer outcomes [17]. In addition, some authors have suggested that after radical hysterectomy AdSCCa is associated with poorer RFS and OS in low-risk patients than AdCa [31]. However, in our multivariate analysis we noted no differences in RFS and OS rates between the AdCa and AdSCCa groups after adjusting for factors significant in univariate analysis. When we analyzed the low-, intermediate-, and high-risk groups separately, we also found that survival outcomes did not differ significantly between patients with AdCa and AdSCCa. Among the limitations of our study is its retrospective design. Adjuvant therapy differed somewhat over time, and was at the discretion of the attending physicians after discussion with the patient. As far as we know, however, this is the largest study to date to directly compare outcomes of patients with AdCa and AdSCCa with its long follow-up period.
In conclusion, survival outcomes after radical hysterectomy followed by tailored adjuvant therapy are excellent, and justify the use of this treatment strategy in patients with FIGO stage IB1 AdCa and AdSCCa of the uterine cervix. LVSI, DOI, and lymph node metastasis are independent prognostic factors after treatment. Clinicopathologic factors, recurrence patterns and time to recurrence are similar in patients with the two histologic types. There are no differences in RFS and OS rates between AdCa and AdSCCa, even after stratification by risk. Conflict of interest statement The authors declare that there are no conflicts of interest.
References [1] Waggoner SE. Cervical cancer. Lancet 2003;361:2217–25. [2] Jung KW, Won YJ, Kong HJ, Oh CM, Lee DH, Lee JS. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2011. Cancer Res Treat 2014;46: 109–23. [3] Jung KW, Won YJ, Kong HJ, Oh CM, Lee DH, Lee JS. Prediction of cancer incidence and mortality in Korea, 2014. Cancer Res Treat 2014;46:124–30. [4] Kosary CL. FIGO stage, histology, histologic grade, age and race as prognostic factors in determining survival for cancers of the female gynecological system: an analysis of 1973–87 SEER cases of cancers of the endometrium, cervix, ovary, vulva, and vagina. Semin Surg Oncol 1994;10:31–46. [5] Vinh-Hung V, Bourgain C, Vlastos G, Cserni G, De Ridder M, Storme G, et al. Prognostic value of histopathology and trends in cervical cancer: a SEER population study. BMC Cancer 2007;7:164. [6] Kjorstad KE. Adenocarcinoma of the uterine cervix. Gynecol Oncol 1977;5:219–23. [7] Berek JS, Hacker NF, Fu YS, Sokale JR, Leuchter RC, Lagasse LD. Adenocarcinoma of the uterine cervix: histologic variables associated with lymph node metastasis and survival. Obstet Gynecol 1985;65:46–52. [8] Hopkins MP, Morley GW. A comparison of adenocarcinoma and squamous cell carcinoma of the cervix. Obstet Gynecol 1991;77:912–7. [9] Eifel PJ, Burke TW, Morris M, Smith TL. Adenocarcinoma as an independent risk factor for disease recurrence in patients with stage IB cervical carcinoma. Gynecol Oncol 1995;59:38–44. [10] Lai CH, Hsueh S, Hong JH, Chang TC, Tseng CJ, Chou HH, et al. Are adenocarcinomas and adenosquamous carcinomas different from squamous carcinomas in stage IB and II cervical cancer patients undergoing primary radical surgery? Int J Gynecol Cancer 1999;9:28–36. [11] Nakanishi T, Ishikawa H, Suzuki Y, Inoue T, Nakamura S, Kuzuya K. A comparison of prognoses of pathologic stage Ib adenocarcinoma and squamous cell carcinoma of the uterine cervix. Gynecol Oncol 2000;79:289–93. [12] Samlal RA, van der Velden J, Ten Kate FJ, Schilthuis MS, Hart AA, Lammes FB. Surgical pathologic factors that predict recurrence in stage IB and IIA cervical carcinoma patients with negative pelvic lymph nodes. Cancer 1997;80:1234–40. [13] Anton-Culver H, Bloss JD, Bringman D, Lee-Feldstein A, DiSaia P, Manetta A. Comparison of adenocarcinoma and squamous cell carcinoma of the uterine cervix: a population-based epidemiologic study. Am J Obstet Gynecol 1992;166:1507–14. [14] Grisaru D, Covens A, Chapman B, Shaw P, Colgan T, Murphy J, et al. Does histology influence prognosis in patients with early-stage cervical carcinoma? Cancer 2001; 92:2999–3004. [15] Kasamatsu T, Onda T, Sawada M, Kato T, Ikeda S, Sasajima Y, et al. Radical hysterectomy for FIGO stage I–IIB adenocarcinoma of the uterine cervix. Br J Cancer 2009; 100:1400–5. [16] Harrison TA, Sevin BU, Koechli O, Nguyen HN, Averette HE, Penalver M, et al. Adenosquamous carcinoma of the cervix: prognosis in early stage disease treated by radical hysterectomy. Gynecol Oncol 1993;50:310–5. [17] Farley JH, Hickey KW, Carlson JW, Rose GS, Kost ER, Harrison TA. Adenosquamous histology predicts a poor outcome for patients with advanced-stage, but not earlystage, cervical carcinoma. Cancer 2003;97:2196–202. [18] dos Reis R, Frumovitz M, Milam MR, Capp E, Sun CC, Coleman RL, et al. Adenosquamous carcinoma versus adenocarcinoma in early-stage cervical cancer patients undergoing radical hysterectomy: an outcomes analysis. Gynecol Oncol 2007;107:458–63. [19] Piver MS, Rutledge F, Smith JP. Five classes of extended hysterectomy for women with cervical cancer. Obstet Gynecol 1974;44:265–72. [20] Sedlis A, Bundy BN, Rotman MZ, Lentz SS, Muderspach LI, Zaino RJ. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: a Gynecologic Oncology Group Study. Gynecol Oncol 1999;73:177–83. [21] Peters III WA, Liu PY, Barrett II RJ, Stock RJ, Monk BJ, Berek JS, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18:1606–13. [22] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–81. [23] Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163–70. [24] Cox DR. Regression models and life tables. R Stat Soc B 1972;34:187–220. [25] Chen RJ, Chang DY, Yen ML, Lee EF, Huang SC, Chow SN, et al. Prognostic factors of primary adenocarcinoma of the uterine cervix. Gynecol Oncol 1998;69:157–64.
M.-H. Baek et al. / Gynecologic Oncology 135 (2014) 462–467 [26] Chargui R, Damak T, Khomsi F, Ben Hassouna J, Chaieb W, Hechiche M, et al. Prognostic factors and clinicopathologic characteristics of invasive adenocarcinoma of the uterine cervix. Am J Obstet Gynecol 2006;194:43–8. [27] Ayhan A, Al RA, Baykal C, Demirtas E, Yuce K, Ayhan A. A comparison of prognoses of FIGO stage IB adenocarcinoma and squamous cell carcinoma. Int J Gynecol Cancer 2004;14:279–85. [28] Look KY, Brunetto VL, Clarke-Pearson DL, Averette HE, Major FJ, Alvarez RD, et al. An analysis of cell type in patients with surgically staged stage IB carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 1996;63:304–11.
467
[29] Chen JL, Cheng JC, Kuo SH, Chen CA, Lin MC, Huang CY. Outcome analysis of cervical adenosquamous carcinoma compared with adenocarcinoma. Acta Obstet Gynecol Scand 2012;91:1158–66. [30] Shingleton HM, Bell MC, Fremgen A, Chmiel JS, Russell AH, Jones WB, et al. Is there really a difference in survival of women with squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma of the cervix? Cancer 1995;76:1948–55. [31] Lea JS, Coleman RL, Garner EO, Duska LR, Miller DS, Schorge JO. Adenosquamous histology predicts poor outcome in low-risk stage IB1 cervical adenocarcinoma. Gynecol Oncol 2003;91:558–62.
