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Impact of histology on prognosis of patients with early-stage cervical cancer treated with radical surgery
International Journal of Gynecology and Obstetrics 115 (2011) 183–187
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j g o
CLINICAL ARTICLE
Impact of histology on prognosis of patients with early-stage cervical cancer treated with radical surgery Korapin Rudtanasudjatum a, Kittipat Charoenkwan a,⁎, Surapan Khunamornpong b, Sumalee Siriaunkgul b a b
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
a r t i c l e
i n f o
Article history: Received 1 February 2011 Received in revised form 16 June 2011 Accepted 28 July 2011 Keywords: Adenocarcinoma Cervical cancer Histology Radical hysterectomy Squamous cell carcinoma
a b s t r a c t Objective: To examine the effect of carcinoma cell type on tumor characteristics, tumor spread, tumor recurrence, and survival of patients with early-stage cervical cancer who had radical hysterectomy and pelvic lymphadenectomy. Method: Data from 499 patients with stage IA to IIA cervical carcinoma who received primary surgical treatment from 2003 to 2005 at Chiang Mai University were retrospectively reviewed with regard to 3 histologic types; squamous cell carcinoma (SCC), adenocarcinoma (AC), and adenosquamous carcinoma (AS). Results: Among the 499 patients, 71.1% had SCC, 23.4% had AC, and 5.4% had AS. There was no significant difference in stage, tumor size, tumor characteristics, or rate of loco-regional spread. A higher proportion of women with SCC needed adjuvant radiation (P = 0.001). Five-year recurrence-free survival (RFS) and overall survival (OS) were comparable among the groups. Among patients with pelvic node metastasis, 5-year RFS and OS were significantly lower in those with AC than in those with SCC (RFS, 66.1% versus 86.4%, P = 0.02; OS, 68.2% versus 88.2%, P = 0.05). Conclusion: There was no difference among SCC, AC, and AS in most tumor characteristics, spread, recurrence, and survival in patients with early-stage cervical cancer. Among patients with pelvic lymph node metastasis, AC was associated with less favorable outcomes than SCC. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Cervical cancer is the most common female cancer in low-income countries, and the second most common cancer in women worldwide. In 2002, the global incidence of cervical cancer was 493 243, and the annual death was 273 505 [1,2]. Although the incidence of cervical cancer has decreased in past decades, the relative proportion of cervical adenocarcinoma (AC) and adenosquamous carcinoma (AS), as compared with squamous cell carcinoma (SCC), has increased [3–8]. It remains unclear whether or not patients with AC have a worse prognosis. Although some studies have reported that there are no differences in survival between AC and SCC [9–13], others have found that AC is associated with a worse prognosis [3,14–18]. This discrepancy in outcome may be due to the inclusion of high-risk subtypes, especially AS to AC. The aim of the present study was to examine the effects of histologic cell type on tumor characteristics, tumor spread, tumor recurrence, and
⁎ Corresponding author at: Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Tel.: + 66 81 9920845; fax: + 66 53 946112. E-mail addresses: [email protected], [email protected] (K. Charoenkwan).
patient survival among women with early-stage cervical cancer who had radical hysterectomy and pelvic lymphadenectomy. 2. Materials and methods In a retrospective study, data from patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA to IIA cervical carcinoma who underwent radical hysterectomy and pelvic lymphadenectomy as a primary treatment at the Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, from January 1, 2003, to December 31, 2005, were reviewed. Patients with undifferentiated carcinoma, small cell carcinoma, and mixed mesodermal tumor of the cervix were excluded from the study. The Institutional Review Board of the Faculty of Medicine approved the study. Because the study was performed via retrospective chart review, with strict preservation of patient anonymity, informed consent was not required. Patients with positive pelvic lymph nodes, parametrial extension, or positive vaginal margins received postoperative adjuvant chemoradiation according to the Intergroup Trial 0107 [19]. Patients with 2 or more of the following factors—a tumor size of 4 centimeters or more, extensive lymph-vascular space invasion (LVSI; ≥10 spaces), and deep stromal invasion (distance from tumor to outermost cervical stroma of ≤ 3 millimeters)—also received adjuvant pelvic radiation. Follow-up after treatment was every 3 months in the first year, every
0020-7292/$ – see front matter © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2011.06.011
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K. Rudtanasudjatum et al. / International Journal of Gynecology and Obstetrics 115 (2011) 183–187
Table 1 Clinical and tumor characteristics by cell type.a Patient characteristics
Number of Patients Age, years Parity Tumor grade 1 2 3 FIGO stage IA1 IA2 IB1 IB2 IIA Tumor size, cm Tumor characteristics Exophytic Infiltrative Ulcerative Microscopic Mixed No residual tumor (post LEEP) Adjuvant radiation therapy
Overall
Histology
P value
Squamous cell carcinoma
Adenocarcinoma
Adenosquamous carcinoma
499 (100) 45 (25–69) 2 (0–13)
355 (71.1) 45 (25–69) 2 (0–13)
117 (23.4) 44 (28–62) 2 (0–6)
27 (5.4) 43 (30–59) 2 (0–5)
106 (21.2) 218 (43.7) 65 (13.0)
42 (15.2) 192 (69.3) 43 (15.5)
63 (64.9) 16 (16.5) 18 (18.6)
1 (6.7) 10 (66.7) 4 (26.7)
b 0.001
28 (5.6) 26 (5.2) 343 (68.7) 56 (11.2) 46 (9.2) 2.0 (0–7.0)
19 21 234 46 35 2.0
(5.4) (5.9) (65.9) (13) (9.9) (0–7.0)
9 (7.7) 5 (4.3) 86 (73.5) 8 (6.8) 9 (7.7) 1.7 (0–6.5)
0 0 23 (85.2) 2 (7.4) 2 (7.4) 2.3 (0–6.0)
0.42
152 170 19 89 13 56 200
103 118 18 68 8 40 160
(29.0) (33.2) (5.1) (19.2) (2.3) (11.3) (45.1)
39 (33.3) 42 (35.9) 1 (0.9) 18 (15.4) 4 (3.4) 13 (11.1) 31 (26.5)
10 (37.0) 10 (37.0) 0 3 (11.1) 1 (3.7) 3 (11.1) 9 (33.3)
(30.5) (34.1) (3.8) (17.8) (2.6) (11.2) (40.1)
0.04 0.92
0.43 0.59
0.001
Abbreviation: LEEP, loop electrosurgical excision procedure. a Values are given as median (range) or number (percentage) unless stated otherwise.
4 months in the second year, every 6 months in the third to fifth years, and annually thereafter. The following clinical data were collected: age, parity, clinical stage, greatest tumor dimension, tumor characteristics, date of surgery, postoperative adjuvant treatment, date of diagnosis of recurrence, recurrence pattern, salvage therapy, and date of death. Pathologic data including histology, histologic grade, depth of cervical stromal invasion, distance from tumor to outermost cervical stroma, LVSI, uterine extension, adnexal metastasis, parametrial extension, lymph node metastasis, and vaginal margin status were collected. The greatest tumor dimension was measured from pathology specimens. Tumor characteristics were classified as microscopic, infiltrative, ulcerative, exophytic, and no residual tumor. The depth of tumor invasion was measured from the base of the surface epithelium to the deepest malignant cells. Pelvic recurrence was detected by pelvic examination and confirmed by computerized tomography (CT) of the whole abdomen. Distant recurrence was diagnosed from physical examination and chest X-ray. If the findings of lung metastasis on chest X-ray were equivocal, chest CT was performed to confirm the diagnosis.
Statistical analysis was performed by using SPSS software (SPSS, Chicago, IL, USA). Categoric variables were analyzed via the χ 2 or Fischer exact test, as appropriate. For continuous variables with skewed distribution, the Wilcoxon rank test was employed. Survival curves were generated via Kaplan–Meier methods. Overall survival (OS) and recurrence-free survival (RFS) associated with histologic type were compared by using the log-rank test. P b 0.05 was considered statistically significant. 3. Results During 2003–2005, 519 patients with early-stage cervical cancer had radical hysterectomy and pelvic lymphadenectomy at the Department of Obstetrics and Gynecology, Chiang Mai University, Chiang Mai, Thailand. Twenty patients were excluded owing to a neuroendocrine cell type. Among the remaining 499 patients, 355 (71.1%) had SCC, 117 (23.4%) had AC, and 27 (5.4%) had AS. Tables 1 and 2 show clinical and pathologic characteristics according to histologic cell type. Women with AC had significantly
Table 2 Pathologic characteristics by cell type.a Characteristics
Depth of invasion Inner third Middle third Outer third Distance to outermost serosa of cervix, mm LVSI positive No. of LVSIs Pelvic LN metastasis Para-aortic LN metastasis Parametrial metastasis Uterine metastasis Vaginal metastasis Positive vaginal margin Adnexal metastasis
Overall
75 65 214 2.5 298 1 128 7 39 40 44 11 4
(15.0) (13.0) (42.9) (0–15.6) (59.7) (0–100) (25.7) (1.4) (8.6) (8.0) (8.8) (2.4) (0.8)
Cell type
P value
SCC (n = 355)
AC (n = 117)
AS (n = 27)
49 (19.9) 40 (16.3) 157 (63.8) 2.0 (0–14.0) 228 (64.2) 1 (0–70) 97 (27.3) 4 (1.1) 31 (9.7) 23 (7.2) 33 (10.4) 9 (2.8) 1 (0.3)
22 (25.9) 20 (23.5) 43 (50.6) 4.0 (0–15.0) 53 (45.3) 0 (0–100) 25 (21.4) 3 (2.6) 5 (4.5) 13 (11.8) 9 (8.2) 2 (1.8) 3 (2.6)
4 (17.4) 5 (21.7) 14 (60.9) 3.3 (0–12.0) 17 (63.0) 1 (0–30) 6 (22.2) 0 (0.0) 3 (11.1) 4 (14.8) 2 (7.4) 0 (0.0) 0 (0.0)
Abbreviations: AC, adenocarcinoma; AS, adenosquamous carcinoma; SCC, squamous cell carcinoma; LVSI, lymph-vascular space invasion. a Values are given as median (range) or number (percentage) unless stated otherwise.
0.28
0.03 0.001 0.02 0.39 0.37 0.22 0.18 0.82 0.87 0.19
K. Rudtanasudjatum et al. / International Journal of Gynecology and Obstetrics 115 (2011) 183–187
more favorable disease characteristics, including a lower proportion of grade 2 and 3 tumor, a greater distance to the outermost serosa of the cervix, a lower rate of LVSI, and a lower LVSI count, as compared with those who had SCC or AS. There was no significant difference in the following factors: parity, FIGO stage, tumor size, tumor characteristics, rate of cancer metastasis to pelvic and/or para-aortic lymph nodes, uterine cavity, vagina, parametrium, or adnexa. After surgery, a higher proportion of women with SCC needed adjuvant radiation therapy as compared with those who had AC or AS (P = 0.001). The 5-year RFS and OS for the whole cohort was 90.2% and 91.2%, respectively. Five-year RFS was comparable among the study groups: 91.1% for SCC, 88.1% for AC, and 88.6% for AS (P = 0.62) (Fig. 1). Similarly, there was no significant difference in OS among the different histologic types identified (SCC, 91.8%; AC, 88.1%; AS, 96.3%; P = 0.88) (Fig. 2). Data from women with pelvic lymph node metastasis were analyzed to compare the survival of patients who had SCC with that of women who had AC among this subgroup. Fiveyear RFS (Fig. 3) and OS (Fig. 4) were significantly lower among patients with AC than among those with SCC for this subgroup (RFS, 66.1% versus 86.4%, P = 0.02; OS, 68.2% versus 88.2%, P = 0.05). No significant differences in 5-year RFS or OS were seen between SCC and AC patients without pelvic lymph node metastasis (RFS, 92.8% versus 94.2%, P = 0.62; and OS, 93.2% versus 95.6%, P = 0.46). Among patients with parametrial invasion, by contrast, RFS was comparable between SCC and AC (84.7% versus 80%; P = 0.55). Regarding patterns of recurrence, the SCC group had comparable numbers of patients who had local and distant recurrence. In the AC group, recurrence was more likely to recur locally than distantly. By contrast, most of the recurrence in the AS group occurred at distant sites (Table 3).
Fig. 1. Recurrence-free survival among patients with squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma types of early-stage cervical cancer (months).
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Fig. 2. Overall survival among patients with squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma types of early-stage cervical cancer (months).
Fig. 3. Recurrence-free survival among women with SCC and AC with pelvic lymph nodes metastasis (months).
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Fig. 4. Overall survival among women with SCC and AC with pelvic lymph nodes metastasis (months).
shown that for small tumors similar to those in the present study (median tumor size 2 centimeters) the difference in survival associated with histology may be negligible, which in turn might be due to the good prognosis related to early-stage cervical cancer regardless of histologic type [3,15,20–22]. Among the subgroup of patients who had pelvic node metastasis in the present study, those with AC had significantly decreased 5-year RFS and OS as compared with those with SCC, whose 5-year survival rates were unchanged from the whole SCC cohort. The difference in survival between AC and SCC in this subgroup was approximately 20% for both RFS and OS. Other studies have reported a 22%–43% better survival in the SCC group than in the AC group when only patients with pelvic metastasis were taken into account [9,15,16,21,23,24]. The present findings confirm the prognostic significance of extrauterine pelvic spread in patients with AC histology. The strength of the study include an adequate sample size for the main outcomes, with a uniform treatment plan for all study participants as a result of data collection within a single large institution. We were able to collect data from a considerable number of cases in a short duration, and therefore could avoid the diversion of treatment techniques over time. Moreover, all pathologic specimens were interpreted by 3 experienced gynecologic pathologists. There were, however, some limitations. There is the possibility of recall bias associated with the retrospective nature of the study. In addition, the small number of patients with AS made it difficult to reach a meaningful conclusion for some aspects related to this histologic type. In conclusion, there was no significant difference among SCC, AC, and AS histologic subtypes in term of most tumor characteristics, tumor spread, tumor recurrence, and patient survival. Among patients with tumor spread to the pelvic lymph nodes, however, AC was associated with less favorable outcomes as compared with SCC. Acknowledgments
4. Discussion Among patients with early-stage cervical cancer treated by primary surgery, the prognosis of AC and AS seemed to be poorer than that of SCC in some studies [3,14–18]. By contrast, a previous GOG study showed no difference in survival between patients with AC and those with SCC, but a shorter survival for those with AS [10]. Recently, dos Reis et al. [20] reported that there was no difference in survival between patients with AS and those with AC, but the time to recurrence was shorter for patients with AS. The present study demonstrated comparable tumor characteristics (i.e. stage, tumor size, tumor appearance, and loco-regional metastasis), tumor recurrence, and patient survival among all histologic types. These results are in line with those of some other studies [10–13]. A possible explanation for the present findings might be that women with AC had a significantly higher number of favorable disease characteristics, including lower tumor grade, lesser depth of stromal invasion, lower rate of LVSI, and smaller LVSI count, as compared with women with SCC or AS. One could, however, consider that these favorable characteristics might be natural to AC, leading to a good outcome. Indeed, a higher proportion of patients in the SCC group needed adjuvant radiation as compared with those in the AC and AS groups. It should also be noted that data from previous studies have Table 3 Pattern of recurrence by cell type. Pattern of recurrence
Squamous cell Adenocarcinoma Adenosquamous P value carcinoma carcinoma
Pelvic Distant Pelvic and distant Total
11 (36.7) 13 (43.3) 6 (20.0) 30 (100)
7 (53.8) 5 (38.5) 1 (7.7) 13 (100)
Values are given as number (percentage).
1 (25.0) 3 (75.0) 0 (0.0) 4 (100)
0.49
The National Research University Project, under Thailand's Office of the Higher Education Commission, provided financial support. Conflict of interest The authors have no conflicts of interest. References [1] Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55(2):74–108. [2] Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24(14):2137–50. [3] Eifel PJ, Morris M, Oswald MJ, Wharton JT, Delclos L. Adenocarcinoma of the uterine cervix. Prognosis and patterns of failure in 367 cases. Cancer 1990;65(11): 2507–14. [4] 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(1):28–36. [5] Smith HO, Tiffany MF, Qualls CR, Key CR. The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States—a 24-year population-based study. Gynecol Oncol 2000;78(2):97–105. [6] Sasieni P, Adams J. Changing rates of adenocarcinoma and adenosquamous carcinoma of the cervix in England. Lancet 2001;357(9267):1490–3. [7] Sherman ME, Wang SS, Carreon J, Devesa SS. Mortality trends for cervical squamous and adenocarcinoma in the United States. Relation to incidence and survival. Cancer 2005;103(6):1258–64. [8] Bray F, Carstensen B, Møller H, Zappa M, Zakelj MP, Lawrence G, et al. Incidence trends of adenocarcinoma of the cervix in 13 European countries. Cancer Epidemiol Biomarkers Prev 2005;14(9):2191–9. [9] 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(10 Suppl):1948–55. [10] 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(3):304–11.
K. Rudtanasudjatum et al. / International Journal of Gynecology and Obstetrics 115 (2011) 183–187 [11] Kilgore LC, Soong SJ, Gore H, Shingleton HM, Hatch KD, Partridge EE. Analysis of prognostic features in adenocarcinoma of the cervix. Gynecol Oncol 1988;31(1): 137–53. [12] Alfsen GC, Kristensen GB, Skovlund E, Pettersen EO, Abeler VM. Histologic subtype has minor importance for overall survival in patients with adenocarcinoma of the uterine cervix: a population-based study of prognostic factors in 505 patients with nonsquamous cell carcinomas of the cervix. Cancer 2001;92(9):2471–83. [13] Lee KB, Lee JM, Park CY, Lee KB, Cho HY, Ha SY. What is the difference between squamous cell carcinoma and adenocarcinoma of the cervix? A matched casecontrol study. Int J Gynecol Cancer 2006;16(4):1569–73. [14] Chen RJ, Lin YH, Chen CA, Huang SC, Chow SN, Hsieh CY. Influence of histologic type and age on survival rates for invasive cervical carcinoma in Taiwan. Gynecol Oncol 1999;73(2):184–90. [15] 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(2):289–93. [16] Irie T, Kigawa J, Minagawa Y, Itamochi H, Sato S, Akeshima R, et al. Prognosis and clinicopathological characteristics of Ib–IIb adenocarcinoma of the uterine cervix in patients who have had radical hysterectomy. Eur J Surg Oncol 2000;26(5): 464–7. [17] Takeda N, Sakuragi N, Takeda M, Okamoto K, Kuwabara M, Negishi H, et al. Multivariate analysis of histopathologic prognostic factors for invasive cervical cancer treated with radical hysterectomy and systematic retroperitoneal lymphadenectomy. Acta Obstet Gynecol Scand 2002;81(12):1144–51.
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[18] Davy ML, Dodd TJ, Luke CG, Roder DM. Cervical cancer: effect of glandular cell type on prognosis, treatment, and survival. Obstet Gynecol 2003;101(1):38–45. [19] 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(8):1606–13. [20] dos Reis R, Frumovitz M, Milam MR, Capp E, Sun CC, Coleman RL. Adenosquamous carcinoma versus adenocarcinoma in early-stage cervical cancer patients undergoing radical hysterectomy: an outcomes analysis. Gynecol Oncol 2007;107(3): 458–63. [21] 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(1):46–52. [22] 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(1):38–44. [23] Baalbergen A, Ewing-Graham PC, Hop WC, Struijk P, Helmerhorst TJ. Prognostic factors in adenocarcinoma of the uterine cervix. Gynecol Oncol 2004;92(1): 262–7. [24] Macdonald OK, Chen J, Dodson M, Lee CM, Gaffney DK. Prognostic significance of histology and positive lymph node involvement following radical hysterectomy in carcinoma of the cervix. Am J Clin Oncol 2009;32(4):411–6.
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j g o
CLINICAL ARTICLE
Impact of histology on prognosis of patients with early-stage cervical cancer treated with radical surgery Korapin Rudtanasudjatum a, Kittipat Charoenkwan a,⁎, Surapan Khunamornpong b, Sumalee Siriaunkgul b a b
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
a r t i c l e
i n f o
Article history: Received 1 February 2011 Received in revised form 16 June 2011 Accepted 28 July 2011 Keywords: Adenocarcinoma Cervical cancer Histology Radical hysterectomy Squamous cell carcinoma
a b s t r a c t Objective: To examine the effect of carcinoma cell type on tumor characteristics, tumor spread, tumor recurrence, and survival of patients with early-stage cervical cancer who had radical hysterectomy and pelvic lymphadenectomy. Method: Data from 499 patients with stage IA to IIA cervical carcinoma who received primary surgical treatment from 2003 to 2005 at Chiang Mai University were retrospectively reviewed with regard to 3 histologic types; squamous cell carcinoma (SCC), adenocarcinoma (AC), and adenosquamous carcinoma (AS). Results: Among the 499 patients, 71.1% had SCC, 23.4% had AC, and 5.4% had AS. There was no significant difference in stage, tumor size, tumor characteristics, or rate of loco-regional spread. A higher proportion of women with SCC needed adjuvant radiation (P = 0.001). Five-year recurrence-free survival (RFS) and overall survival (OS) were comparable among the groups. Among patients with pelvic node metastasis, 5-year RFS and OS were significantly lower in those with AC than in those with SCC (RFS, 66.1% versus 86.4%, P = 0.02; OS, 68.2% versus 88.2%, P = 0.05). Conclusion: There was no difference among SCC, AC, and AS in most tumor characteristics, spread, recurrence, and survival in patients with early-stage cervical cancer. Among patients with pelvic lymph node metastasis, AC was associated with less favorable outcomes than SCC. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Cervical cancer is the most common female cancer in low-income countries, and the second most common cancer in women worldwide. In 2002, the global incidence of cervical cancer was 493 243, and the annual death was 273 505 [1,2]. Although the incidence of cervical cancer has decreased in past decades, the relative proportion of cervical adenocarcinoma (AC) and adenosquamous carcinoma (AS), as compared with squamous cell carcinoma (SCC), has increased [3–8]. It remains unclear whether or not patients with AC have a worse prognosis. Although some studies have reported that there are no differences in survival between AC and SCC [9–13], others have found that AC is associated with a worse prognosis [3,14–18]. This discrepancy in outcome may be due to the inclusion of high-risk subtypes, especially AS to AC. The aim of the present study was to examine the effects of histologic cell type on tumor characteristics, tumor spread, tumor recurrence, and
⁎ Corresponding author at: Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Tel.: + 66 81 9920845; fax: + 66 53 946112. E-mail addresses: [email protected], [email protected] (K. Charoenkwan).
patient survival among women with early-stage cervical cancer who had radical hysterectomy and pelvic lymphadenectomy. 2. Materials and methods In a retrospective study, data from patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA to IIA cervical carcinoma who underwent radical hysterectomy and pelvic lymphadenectomy as a primary treatment at the Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, from January 1, 2003, to December 31, 2005, were reviewed. Patients with undifferentiated carcinoma, small cell carcinoma, and mixed mesodermal tumor of the cervix were excluded from the study. The Institutional Review Board of the Faculty of Medicine approved the study. Because the study was performed via retrospective chart review, with strict preservation of patient anonymity, informed consent was not required. Patients with positive pelvic lymph nodes, parametrial extension, or positive vaginal margins received postoperative adjuvant chemoradiation according to the Intergroup Trial 0107 [19]. Patients with 2 or more of the following factors—a tumor size of 4 centimeters or more, extensive lymph-vascular space invasion (LVSI; ≥10 spaces), and deep stromal invasion (distance from tumor to outermost cervical stroma of ≤ 3 millimeters)—also received adjuvant pelvic radiation. Follow-up after treatment was every 3 months in the first year, every
0020-7292/$ – see front matter © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2011.06.011
184
K. Rudtanasudjatum et al. / International Journal of Gynecology and Obstetrics 115 (2011) 183–187
Table 1 Clinical and tumor characteristics by cell type.a Patient characteristics
Number of Patients Age, years Parity Tumor grade 1 2 3 FIGO stage IA1 IA2 IB1 IB2 IIA Tumor size, cm Tumor characteristics Exophytic Infiltrative Ulcerative Microscopic Mixed No residual tumor (post LEEP) Adjuvant radiation therapy
Overall
Histology
P value
Squamous cell carcinoma
Adenocarcinoma
Adenosquamous carcinoma
499 (100) 45 (25–69) 2 (0–13)
355 (71.1) 45 (25–69) 2 (0–13)
117 (23.4) 44 (28–62) 2 (0–6)
27 (5.4) 43 (30–59) 2 (0–5)
106 (21.2) 218 (43.7) 65 (13.0)
42 (15.2) 192 (69.3) 43 (15.5)
63 (64.9) 16 (16.5) 18 (18.6)
1 (6.7) 10 (66.7) 4 (26.7)
b 0.001
28 (5.6) 26 (5.2) 343 (68.7) 56 (11.2) 46 (9.2) 2.0 (0–7.0)
19 21 234 46 35 2.0
(5.4) (5.9) (65.9) (13) (9.9) (0–7.0)
9 (7.7) 5 (4.3) 86 (73.5) 8 (6.8) 9 (7.7) 1.7 (0–6.5)
0 0 23 (85.2) 2 (7.4) 2 (7.4) 2.3 (0–6.0)
0.42
152 170 19 89 13 56 200
103 118 18 68 8 40 160
(29.0) (33.2) (5.1) (19.2) (2.3) (11.3) (45.1)
39 (33.3) 42 (35.9) 1 (0.9) 18 (15.4) 4 (3.4) 13 (11.1) 31 (26.5)
10 (37.0) 10 (37.0) 0 3 (11.1) 1 (3.7) 3 (11.1) 9 (33.3)
(30.5) (34.1) (3.8) (17.8) (2.6) (11.2) (40.1)
0.04 0.92
0.43 0.59
0.001
Abbreviation: LEEP, loop electrosurgical excision procedure. a Values are given as median (range) or number (percentage) unless stated otherwise.
4 months in the second year, every 6 months in the third to fifth years, and annually thereafter. The following clinical data were collected: age, parity, clinical stage, greatest tumor dimension, tumor characteristics, date of surgery, postoperative adjuvant treatment, date of diagnosis of recurrence, recurrence pattern, salvage therapy, and date of death. Pathologic data including histology, histologic grade, depth of cervical stromal invasion, distance from tumor to outermost cervical stroma, LVSI, uterine extension, adnexal metastasis, parametrial extension, lymph node metastasis, and vaginal margin status were collected. The greatest tumor dimension was measured from pathology specimens. Tumor characteristics were classified as microscopic, infiltrative, ulcerative, exophytic, and no residual tumor. The depth of tumor invasion was measured from the base of the surface epithelium to the deepest malignant cells. Pelvic recurrence was detected by pelvic examination and confirmed by computerized tomography (CT) of the whole abdomen. Distant recurrence was diagnosed from physical examination and chest X-ray. If the findings of lung metastasis on chest X-ray were equivocal, chest CT was performed to confirm the diagnosis.
Statistical analysis was performed by using SPSS software (SPSS, Chicago, IL, USA). Categoric variables were analyzed via the χ 2 or Fischer exact test, as appropriate. For continuous variables with skewed distribution, the Wilcoxon rank test was employed. Survival curves were generated via Kaplan–Meier methods. Overall survival (OS) and recurrence-free survival (RFS) associated with histologic type were compared by using the log-rank test. P b 0.05 was considered statistically significant. 3. Results During 2003–2005, 519 patients with early-stage cervical cancer had radical hysterectomy and pelvic lymphadenectomy at the Department of Obstetrics and Gynecology, Chiang Mai University, Chiang Mai, Thailand. Twenty patients were excluded owing to a neuroendocrine cell type. Among the remaining 499 patients, 355 (71.1%) had SCC, 117 (23.4%) had AC, and 27 (5.4%) had AS. Tables 1 and 2 show clinical and pathologic characteristics according to histologic cell type. Women with AC had significantly
Table 2 Pathologic characteristics by cell type.a Characteristics
Depth of invasion Inner third Middle third Outer third Distance to outermost serosa of cervix, mm LVSI positive No. of LVSIs Pelvic LN metastasis Para-aortic LN metastasis Parametrial metastasis Uterine metastasis Vaginal metastasis Positive vaginal margin Adnexal metastasis
Overall
75 65 214 2.5 298 1 128 7 39 40 44 11 4
(15.0) (13.0) (42.9) (0–15.6) (59.7) (0–100) (25.7) (1.4) (8.6) (8.0) (8.8) (2.4) (0.8)
Cell type
P value
SCC (n = 355)
AC (n = 117)
AS (n = 27)
49 (19.9) 40 (16.3) 157 (63.8) 2.0 (0–14.0) 228 (64.2) 1 (0–70) 97 (27.3) 4 (1.1) 31 (9.7) 23 (7.2) 33 (10.4) 9 (2.8) 1 (0.3)
22 (25.9) 20 (23.5) 43 (50.6) 4.0 (0–15.0) 53 (45.3) 0 (0–100) 25 (21.4) 3 (2.6) 5 (4.5) 13 (11.8) 9 (8.2) 2 (1.8) 3 (2.6)
4 (17.4) 5 (21.7) 14 (60.9) 3.3 (0–12.0) 17 (63.0) 1 (0–30) 6 (22.2) 0 (0.0) 3 (11.1) 4 (14.8) 2 (7.4) 0 (0.0) 0 (0.0)
Abbreviations: AC, adenocarcinoma; AS, adenosquamous carcinoma; SCC, squamous cell carcinoma; LVSI, lymph-vascular space invasion. a Values are given as median (range) or number (percentage) unless stated otherwise.
0.28
0.03 0.001 0.02 0.39 0.37 0.22 0.18 0.82 0.87 0.19
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more favorable disease characteristics, including a lower proportion of grade 2 and 3 tumor, a greater distance to the outermost serosa of the cervix, a lower rate of LVSI, and a lower LVSI count, as compared with those who had SCC or AS. There was no significant difference in the following factors: parity, FIGO stage, tumor size, tumor characteristics, rate of cancer metastasis to pelvic and/or para-aortic lymph nodes, uterine cavity, vagina, parametrium, or adnexa. After surgery, a higher proportion of women with SCC needed adjuvant radiation therapy as compared with those who had AC or AS (P = 0.001). The 5-year RFS and OS for the whole cohort was 90.2% and 91.2%, respectively. Five-year RFS was comparable among the study groups: 91.1% for SCC, 88.1% for AC, and 88.6% for AS (P = 0.62) (Fig. 1). Similarly, there was no significant difference in OS among the different histologic types identified (SCC, 91.8%; AC, 88.1%; AS, 96.3%; P = 0.88) (Fig. 2). Data from women with pelvic lymph node metastasis were analyzed to compare the survival of patients who had SCC with that of women who had AC among this subgroup. Fiveyear RFS (Fig. 3) and OS (Fig. 4) were significantly lower among patients with AC than among those with SCC for this subgroup (RFS, 66.1% versus 86.4%, P = 0.02; OS, 68.2% versus 88.2%, P = 0.05). No significant differences in 5-year RFS or OS were seen between SCC and AC patients without pelvic lymph node metastasis (RFS, 92.8% versus 94.2%, P = 0.62; and OS, 93.2% versus 95.6%, P = 0.46). Among patients with parametrial invasion, by contrast, RFS was comparable between SCC and AC (84.7% versus 80%; P = 0.55). Regarding patterns of recurrence, the SCC group had comparable numbers of patients who had local and distant recurrence. In the AC group, recurrence was more likely to recur locally than distantly. By contrast, most of the recurrence in the AS group occurred at distant sites (Table 3).
Fig. 1. Recurrence-free survival among patients with squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma types of early-stage cervical cancer (months).
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Fig. 2. Overall survival among patients with squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma types of early-stage cervical cancer (months).
Fig. 3. Recurrence-free survival among women with SCC and AC with pelvic lymph nodes metastasis (months).
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Fig. 4. Overall survival among women with SCC and AC with pelvic lymph nodes metastasis (months).
shown that for small tumors similar to those in the present study (median tumor size 2 centimeters) the difference in survival associated with histology may be negligible, which in turn might be due to the good prognosis related to early-stage cervical cancer regardless of histologic type [3,15,20–22]. Among the subgroup of patients who had pelvic node metastasis in the present study, those with AC had significantly decreased 5-year RFS and OS as compared with those with SCC, whose 5-year survival rates were unchanged from the whole SCC cohort. The difference in survival between AC and SCC in this subgroup was approximately 20% for both RFS and OS. Other studies have reported a 22%–43% better survival in the SCC group than in the AC group when only patients with pelvic metastasis were taken into account [9,15,16,21,23,24]. The present findings confirm the prognostic significance of extrauterine pelvic spread in patients with AC histology. The strength of the study include an adequate sample size for the main outcomes, with a uniform treatment plan for all study participants as a result of data collection within a single large institution. We were able to collect data from a considerable number of cases in a short duration, and therefore could avoid the diversion of treatment techniques over time. Moreover, all pathologic specimens were interpreted by 3 experienced gynecologic pathologists. There were, however, some limitations. There is the possibility of recall bias associated with the retrospective nature of the study. In addition, the small number of patients with AS made it difficult to reach a meaningful conclusion for some aspects related to this histologic type. In conclusion, there was no significant difference among SCC, AC, and AS histologic subtypes in term of most tumor characteristics, tumor spread, tumor recurrence, and patient survival. Among patients with tumor spread to the pelvic lymph nodes, however, AC was associated with less favorable outcomes as compared with SCC. Acknowledgments
4. Discussion Among patients with early-stage cervical cancer treated by primary surgery, the prognosis of AC and AS seemed to be poorer than that of SCC in some studies [3,14–18]. By contrast, a previous GOG study showed no difference in survival between patients with AC and those with SCC, but a shorter survival for those with AS [10]. Recently, dos Reis et al. [20] reported that there was no difference in survival between patients with AS and those with AC, but the time to recurrence was shorter for patients with AS. The present study demonstrated comparable tumor characteristics (i.e. stage, tumor size, tumor appearance, and loco-regional metastasis), tumor recurrence, and patient survival among all histologic types. These results are in line with those of some other studies [10–13]. A possible explanation for the present findings might be that women with AC had a significantly higher number of favorable disease characteristics, including lower tumor grade, lesser depth of stromal invasion, lower rate of LVSI, and smaller LVSI count, as compared with women with SCC or AS. One could, however, consider that these favorable characteristics might be natural to AC, leading to a good outcome. Indeed, a higher proportion of patients in the SCC group needed adjuvant radiation as compared with those in the AC and AS groups. It should also be noted that data from previous studies have Table 3 Pattern of recurrence by cell type. Pattern of recurrence
Squamous cell Adenocarcinoma Adenosquamous P value carcinoma carcinoma
Pelvic Distant Pelvic and distant Total
11 (36.7) 13 (43.3) 6 (20.0) 30 (100)
7 (53.8) 5 (38.5) 1 (7.7) 13 (100)
Values are given as number (percentage).
1 (25.0) 3 (75.0) 0 (0.0) 4 (100)
0.49
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