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Treatment and outcome of stage Ia1 squamous cell carcinoma of the uterine cervix
International Journal of Gynecology and Obstetrics 113 (2011) 72–75
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
Treatment and outcome of stage Ia1 squamous cell carcinoma of the uterine cervix Herman Haller a, Maja Krašević b,⁎, Ozren Mamula a, Alemka Brnčić-Fischer a, Senija Eminović b, Miljenko Manestar a a b
Department of Obstetrics and Gynecology, Clinical Hospital Centre, School of Medicine, University of Rijeka, Rijeka, Croatia Department of Pathology, School of Medicine, University of Rijeka, Rijeka, Croatia
a r t i c l e
i n f o
Article history: Received 2 June 2010 Received in revised form 8 October 2010 Accepted 23 December 2010 Keywords: Cervical squamous cell carcinoma Clinicopathologic study Conization FIGO stage IA1
a b s t r a c t Objective: To evaluate the treatment and clinical outcome of patients with FIGO stage IA1 cervical squamous cell carcinoma (SCC). Methods: Medical records, including 5-year follow-up, were reviewed for 276 patients with stage IA1 SCC. Results: As definitive surgery, 152 (55.1%), 72 (26.1%), 40 (14.5%), and 12 (4.3%) patients underwent conization, hysterectomy, hysterectomy with pelvic lymphadenectomy (PL), and radical hysterectomy with PL, respectively. Among these groups, the 5-year recurrence-free rate was 94.1%, 98.6%, 95%, and 100%, respectively, and the survival rate was 98.7%, 98.6%, 100%, and 100%, respectively. Recurrent disease was identified among 12 (4.3%) patients, and was related to the depth of invasion (P b 0.001). Eleven (4.0%) of 276 patients were found to have lymph vascular space invasion (LVSI). There were no positive lymph nodes among 52 patients who underwent PL, including those with LVSI. Conization was followed by hysterectomy in 49 patients. In these patients, residual intraepithelial neoplasia was found in 18 women, 3 of whom had no involved margins on previous conization. In the group of patients treated by conization, recurrence correlated with the status of the endocervical and lateral cone margin (P b 0.001). Conclusion: As a conservative approach, conization is an effective and reasonable treatment option for stage IA1 SCC, especially in actively reproductive women. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction The concept of “microinvasive carcinoma of the cervix” (MIC) has been a subject of continual discussion since its introduction by Mestwerdt in 1947 [1]. There has been no agreement about its pathologic definition or subsequent implications for its treatment. The original definition of MIC was proposed by Burghardt in 1973 [2], and applied to neoplastic lesions with a maximum depth of invasion of 5 mm, measured from the basement membrane. In 1974, the Committee on Nomenclature of the Society of Gynecologic Oncologist recommended more restrictive criteria for MIC: namely, a lesion with stromal invasion of 3 mm or less, but without lymph vascular space invasion (LVSI). Since then, several histopathologic criteria have been advocated, including horizontal tumor spread, tumor volume, and LVSI. In the most recent FIGO revision of stage IA cervical carcinoma in 1994, this stage was subdivided into IA1 and IA2 as lesions with a depth of stromal invasion of 3 mm or less and 5 mm or less, respectively, both with a horizontal spread of 7 mm or less. Diagnosis of stage IA disease should be based exclusively on microscopic
⁎ Corresponding author. Department of Pathology, School of Medicine, Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia. Tel.: + 385 51325811. E-mail address: [email protected] (M. Krašević).
examination of the surgical material. LVSI does not alter the stage, and its significance as a risk factor for lymph node metastasis or recurrence of the disease has not been completely defined [3]. The most recent and significant FIGO statistics showed a very satisfactory patient outcome for stage IA1 cervical carcinoma with a 5-year survival of 97.5% [4]. The treatment policy of early stage disease remains controversial. In the past, radical methods have been applied to cases of cervical carcinoma stage IA1 [5,6]. There is, however, an obvious move toward a conservative approach, where simple hysterectomy is the method of choice, although conization is a feasible treatment for patients who desire to preserve their fertility [7]. The aim of the present study was to assess the risk of recurrence and 5-year survival among patients with microinvasive stage IA1 cervical squamous cell carcinoma (SCC) with a particular focus on conization as an effective and adequate surgical procedure. 2. Materials and methods In the present retrospective study, the hospital records including pathologic reports were reviewed for all patients with cervical carcinoma treated from January 1, 1990, to December 31, 2004, at the Department of Obstetrics and Gynecology University Hospital of Rijeka. A total of 276 patients with cervical SCC with a maximum depth of stromal invasion of 3 mm or less and a horizontal spread of 7 mm or less were identified from the records. Glandular lesions were
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H. Haller et al. / International Journal of Gynecology and Obstetrics 113 (2011) 72–75
not considered. The tumors in 83 patients treated before 1995 were retrospectively staged after 1995 according to the 1994 FIGO nomenclature. The research was approved by the ethical committee of the Clinical Hospital Centre of Rijeka. Patients gave informed consent for participation in the study. Diagnostic workup began with cervical cytology screening. The patients had at least 1 additional Pap smear on 3 separate slides (vaginal fornix, ectocervix, and endocervix) before colposcopy. Cervical biopsy and endocervical curettage were the diagnostic procedure in 181 out of the 276 patients, and subsequent conization was carried in 110 women. In the other 95 patients, owing to positive endocervical cytology or unsatisfactory colposcopy, conization was the primary diagnostic procedure. In all patients with cervical SCC staged as IA1, definitive diagnosis was made after analysis of the conization, hysterectomy, or radical hysterectomy specimens. Conization, hysterectomy, hysterectomy with pelvic lymphadenectomy (PL), and radical hysterectomy with PL were the definitive treatments in 152, 72, 40, and 12, patients, respectively. In all patients undergoing conization, cold-knife conization and sharp conical excision of the cervix by scalpel were performed. The cervical orifice was reconstructed by 2 separate sutures knotted together on the ectocervix on 3 and 9 o'clock. According to the local findings, hysterectomy was performed abdominally. Radical hysterectomies were performed as Piver class II, including resection of the medial half of the lateral parametrium, the minimal part of the uterosacral ligaments (posterior parametrium), and approximately 2 cm of vaginal cuff. Ovaries were usually preserved in patients younger than 45 years when hysterectomy or radical hysterectomy was performed. During the study period, the surgical protocol became less radical. Before 1997, for patients with invasion of less than 3 mm and LVSI, radical hysterectomy was performed as the definitive treatment. From 1997 onward, a reduction in parametrial radicality was considered as acceptable. The definitive treatment included pelvic PL and (simple) hysterectomy with or without ovaries. The surgical margins of each cone specimen were marked with ink and bisected along the axis of the endocervical canal. Each half was cut at additional 4–5-mm intervals in a plane parallel to the axis of the canal. Each block was serially sectioned. Six levels from each block— and additional levels if stromal invasion had been found—were examined routinely. According to the dimensions, 40–90 sections were obtained from each cone. The cervices of the extirpated uteri were opened longitudinally and sectioned along the axis at 3–4-mm intervals in separate blocks. Four sections were cut from each block. Histologic evaluation comprised the depth of invasion and horizontal spread of the tumor, LVSI, and involvement of the surgical margins. Both stromal invasion and horizontal spread of the tumor were measured by means of a calibrated ocular micrometer. The depth of invasion was defined as the distance from the epithelial– stromal junction of the adjacent dysplastic epithelium, surface, or cryptal, and the deepest point of invasion. Horizontal spread was evaluated depending on the pattern of microinvasion (unifocal or multifocal), as previously described [8]. LVSI was considered to be present when tumor cells were found within capillary spaces lined by endothelial cells. The clinical data analyzed included patient age, type of definitive surgical procedure, and treatment. Residual disease after conization was considered as cervical intraepithelial neoplasia II–III (CIN II–III) or microinvasive disease in the hysterectomy specimens. Recurrence was defined by cytology and/or histology. Distant recurrence was defined by the presence of positive findings on imaging techniques associated with clinical findings. The patients were followed-up by means of clinical examination and Pap smear. The mean duration of follow-up was 80 months (range 36–205 months). The incidence of recurrence and death, in addition to the total disease-free interval and the 5-year survival rate, were examined.
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Data were stored in an apposite database and analyzed via MedCalc version 9.5.2.0 (MedCalc, Mariakerke, Belgium). Statistical significance was calculated by t test, correlation matrices, χ2 test or two-tailored Fisher exact test where appropriate, and the Mann– Whitney U test. The Kaplan–Meyer product limit method was applied in the analysis of recurrence and survival rate. A P value of less than 0.05 was considered to be significant.
3. Results The mean age of the 276 patients was 39.4 years (range 21– 82 years). Seventy-five (27.2%) patients were postmenopausal. Most tumors (221, 80.1%) had a depth of stromal invasion of 1 mm or less (Table 1). The depth of invasion correlated with patient age (r = 0.223, P b 0.0002; 95% confidence interval [CI] 0.11–0.33). LVSI was detected in 11 (4.0%) cases. Increasing depth of stromal invasion also correlated with incidence of LVSI (r = 0.22, P = 0.0002; CI 0.11–0.33). Of the 276 patients with stage IA1 SCC, 201 underwent conization, either as part of a diagnostic surgical procedure or as a definitive treatment (Table 2). Positive cone margins (endocervical and/or lateral) for high-grade CIN (II–III) or LVSI were found in 35 (17.4%) and 6 (2.9%) cases, respectively. In 152 patients, conization remained the definitive treatment, although 15 and 1 of these women had positive surgical margins for CIN and LVSI, respectively. In 49 (24.4%) patients, conization was followed by more extensive treatment (simple or radical hysterectomy) for several reasons (Table 2). In hysterectomy specimens, residual intraepithelial neoplasia was found in 18 patients: namely, 15 out of 20 (75%) who had a hysterectomy because of positive surgical margins; and 3 out of 24 (12.5%) who elected to have a hysterectomy but had no involvement of the margins on previous conization. During the 5-year follow up period, recurrent disease was identified among 12 (4.3%) patients with stage IA1 cervical SCC, resulting in a 5-year recurrence-free survival of 95.7%. Recurrence significantly correlated with the depth of invasion (P b 0.05). Recurrence occurred in 7 (3.2%) and 5 (18.5%) patients who had tumors Table 1 Age, depth of stromal invasion, and LVSI in patients with stage IA1 cervical cancer.a Depth of invasion, mm
No. of patients
Age, years
Patients with LVSI
≤1 N 1 and ≤ 2 N 2 and ≤ 3 Total
221 (80.1) 28 (10.1) 27 (9.8) 276 (100)
38.4 ± 8.2 42.2 ± 13.1 44.8 ± 11.8 39.7 ± 9.5
4 (1.8) 3 (10.7) 4 (14.8) 11 (4.0)
Abbreviation: LVSI, lymph vascular space invasion. a Values are given as number (percentage) or mean ± SD.
Table 2 Conization in 201 patients with stage IA1 cervical cancer.a Conization
No. of patients
Residual disease
As definitive treatment b,c Followed by hysterectomy owing to LVSI Followed by hysterectomy owing to positive margins for CIN Followed by hysterectomy owing to LVSI and positive margins for CIN Followed by hysterectomy owing to patients choice, with negative margins for CIN and no LVSI
152 (75.6) 5 (2.5) 20 (10.0)
− 0 15 (75.0)
0 24 (11.9)
0 3 (12.5)
Abbreviations: CIN, cervical intraepithelial neoplasia; LVSI, lymph vascular space invasion. a Values are given as number (percentage). b Among 152 patients for whom conization was the definitive treatment; 15 had positive margin(s) and in LVSI was found in 1 patient. c Residual disease was not assessed in this group. The group was followed-up, and results are presented in Table 5.
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H. Haller et al. / International Journal of Gynecology and Obstetrics 113 (2011) 72–75
Table 3 Type of recurrence during follow-up in patients with stage IA1 cervical cancer.a Conization HY Total no. of patients 152 Recurrence based on cytology 3 (2.0) Cervical or vaginal intraepithelial recurrence 3 (2.0) (CIN/VaIN) Cervical or vaginal microinvasive recurrence 1 (0.7) Pelvic invasive recurrence 2 (1.3) Distant recurrence 0
HY, LY
RHY, LY
72 40 12 0 1 (2.5) 0 1 (1.4) 0 0 0 0 0
0 1 (2.5) 0
0 0 0
Abbreviations: CIN, cervical intraepithelial neoplasia; HY, hysterectomy; LY, lymphadenectomy; RHY, radical hysterectomy; VaIN, vaginal intraepithelial neoplasia. a Values are given as number (percentage) unless otherwise indicated.
4. Discussion
Table 4 Type of definitive surgery in 276 patients with stage IA1 cervical cancer.a Type of surgery
No. of patients
Age, years
5-year recurrence free
5-year survival rate
Conization Hysterectomy Hysterectomy + pelvic lymphadenectomy Radical hysterectomy + pelvic lymphadenectomy
152 (55.1) 72 (26.1) 40 (14.5)
35.4 ± 6.3 45.3 ± 9.6 42.2 ± 10.9
143 (94.1) 71 (98.6) 38 (95.0)
150 (98.7) 71 (98.6) 40 (100)
12 (4.3)
45.2 ± 12.0
12 (100)
12 (100)
a
Values are given as number (percentage) or mean ± SD.
with 1 mm or less invasion, and more than 2–3 mm of invasion, respectively (χ2, P b 0.001). In the group of patients who had tumors with more than 1–2 mm of invasion, no recurrence was found. Types of recurrence are detailed in Table 3. Three patients died because of disease, resulting in a 5-year survival rate of 98.9%. Similar 5-year recurrence-free and survival rates were observed when the patients with stage IA1 cervical SCC were classified according to the surgery performed (Table 4). In the group of patients treated by conization, 2 patients with a tumor invasion depth of 1 and 2.8 mm showed local (pelvic) invasive recurrence after 4 and 38 months, respectively. In the first case, however, the recurrence might have been a remnant from the multifocal disease. Both patients were treated by radio- and chemotherapy, and died 6 and 12 months after recurrence was noted. In the hysterectomy group, 1 patient had local recurrence after 28 months; she was treated by brachytherapy and died 12 months later. In the group of hysterectomy and lymphadenectomy, 2 patients had recurrence 26 and 42 months after surgical treatment; they received radiotherapy and are still alive. In the same group, a 37-year-old patient died owing to pulmonary thromboembolism, with no evidence of cervical SCC disease.
Table 5 Relation of marginal status and LVSI to 5-year recurrence and survival among 152 patients with stage IA1 cervical cancer treated by conization. Risk factors on conization specimen
No. of patients
Recurrence
Negative margin, no LVSI Positive lateral margin for CIN Positive endocervical margin for CIN Positive lateral/endocervical margin for CIN LVSI
136 4 10 1 1
3 (2.2) 1 (25.0) 4 (40.0) 1 (100) –
a,b
All patients treated by radical hysterectomy were alive without signs of disease at the 5-year follow-up. As an adjuvant surgical procedure, PL was performed in 52 patients. The mean ± SD number of lymph nodes removed was 18 ± 10.2 (range 6–47). Lymph nodes were negative for disease in all cases. The correlation was assessed between histologic findings in cone specimens, and recurrence and survival in patients treated only by conization (Table 5). Recurrence was identified in 6 out of 15 patients with cone margins positive for CIN II–III, and 3 out of 136 patients with negative cone margins, resulting in 40% and 2.2% recurrence, respectively. This difference was highly significant (χ2 = 28.0, P b 0.0001). Patient age was not found to have an influence on recurrence rate.
Death
a,c
1 (0.7) – 1 (10.0) – –
Abbreviations: CIN, cervical intraepithelial neoplasia; LVSI, lymph vascular space invasion. a Values are given as number (percentage). b Recurrence included atypical Pap smear without histologic confirmation, histology of cervical intraepithelial neoplasia, microinvasive and invasive disease. c Two patients died: 1 without risk factors 50 months after conization with pelvic invasive recurrence, and 1 with positive intraepithelial lesion (CIN) on the cone tip 10 months after conization with pelvic invasive recurrence and venous thromboembolism of the leg.
Patients with stage IA cervical SCC comprise about 40.0% of all patients with cervical SCC [9] currently treated in our institution, and more than two-thirds have stromal invasion of less than 1 mm. The present results show a relatively higher incidence of microinvasive cervical cancer as compared with FIGO statistics [4]. This finding might be partly attributed to the high number of serial sections (40–90)—cut through the paraffin blocks of cone specimens—that are routinely obtained and analyzed in our laboratory. In the present study, 152 (55.1%) patients with stage IA1 cervical SCC were treated by conization alone. Historically, stage IA1 disease has been managed by various procedures, including radical ones [6]. The actual incidence of parametrial invasion [10] and lymph node involvement is negligible, and patients can be adequately treated by simple hysterectomy without lymphadenectomy. As a surgical procedure in patients with stage IA1 cervical SCC, conization is still recommended. In previous studies, approximately 96% of patients with stage IA1 cervical cancer who were treated conservatively were found to be alive and disease-free after 5 years of follow-up, and the recurrence rate ranged from 2.7% to 9% [11,12]. In the present conservatively managed group of patients, the disease-free rate was 94.1% and the 5-year survival rate was 98.7%. The actual guidelines for conservative treatment of patients with cervical cancer indicate that only the histologic characteristics of the tumor should be considered [12]. The significance of increasing age [13], positive endocervical curettage, positive cone margins, and increasing neoplastic severity [14] has been attributed to the presence of residual disease on hysterectomy specimens after conization. The results of some studies [13] have indicated that menopausal status could be a risk factor for residual disease, owing to difficulties in eradicating the lesions of the retracted transformation zone in older patients. In the present study, endocervical curettage after conization was not performed routinely and menopausal status was not taken into account. As a therapeutic approach, however, conization was not used in postmenopausal women. Only 4 out of 152 women older than 50 years were treated by conization (data not shown). A cooperative study by Gadducci et al. [15] showed that, among northern Italian institutions, conization was performed in 30 (21%) out of 143 patients with stage IA1 SCC, a considerably smaller proportion than in our study. In the same study, hysterectomy and radical hysterectomy with PL were applied more frequently. In the present study, hysterectomy was carried out in postmenopausal patients. The 5-year survival and recurrence-free interval were similar to those of the conization group (χ2 = 2.29, P = 0.1302). A positive resection margin for CIN (lateral and endocervical) should be considered as a risk factor for predicting post-conization residual disease and further conservative management [16]. Furthermore, apical and lateral clearance, defined as the distance between the tumor margin, and the apex and lateral margin of the cone could be used as additional parameter in optimizing the conservative management of patients with stage IA1 cervical cancer [12]. Despite several reports
H. Haller et al. / International Journal of Gynecology and Obstetrics 113 (2011) 72–75
showing that dysplastic lesions on the resection margins are responsible for recurrence, a histologically defined cervical lesion was previously found in only 40% of cases of hysterectomy after conization [17]. In the present study, the hysterectomy specimens obtained after conization with positive margins showed a high rate of residual CIN: namely 15 (75%) out of 20. Among the group of women followed-up after conization with positive margins, a recurrence rate of 40% was found. The present results emphasize the importance of marginal status in patients treated by conization, and we support the necessity of prompt surgical re-intervention if marginal status is positive for CIN. Exceptions should be closely monitored. Patients with negative marginal status are, however, not excluded from the risk of recurrence. Residual lesions were previously found in 8–24% of patients with negative margins, precluding politopic disease development in the uterine cervix [18]. In the present study, residual lesions were found in 12.5% of hysterectomy specimens obtained after conization with negative margins for CIN. The detection of human papillomavirus status after loop electrosurgical conization, combined with “classical” surgical margin status in patients with CIN, could be used to subdivide patients with different risks of recurrence. This would require new, tailored, surveillance procedures [19], and further studies are needed to evaluate the precise role of such testing. A low risk of lymph node metastasis, recurrence and death has been found in microinvasive cervical carcinoma [6,10]. In the present study, no positive lymph nodes were found among 52 patients with stage IA1 disease. The incidence of lymph node metastasis in stage IA1 disease has been reported to vary from 0% to 2% [20,21]. There is no consensus regarding the significance of LVSI in predicting lymph node metastasis. A risk of lymph node metastasis was previously found in 0.3% of patients with microinvasive cervical cancer with less than 3 mm of stromal invasion and no LVSI, as compared with 2.6% of patients with LVSI [22]. Other investigators found a higher incidence of pelvic lymph node metastasis (1.7% in patients with stage IA1 disease), but without correlation with LVSI [23]. The prognostic meaning of LVSI remains unresolved, and further evaluations would clarify its precise prognostic significance. Involvement of the parametrium has not been extensively reported. Similarly, in the present study, no parametrial involvement was detected among 12 patients who underwent radical treatment. In conclusion, the present results indicate that a conservative surgical approach—namely, conization—is an effective and reasonable treatment option for patients with stage IA1 cervical cancer, especially those patients who are still of reproduction age. The status of the surgical margins is a crucial histologic parameter. If the endocervical and lateral resection margins are positive for highgrade CIN, further surgical treatment should be promptly applied to minimize the risk of recurrence. Conflict of interest The authors have no conflicts of interest.
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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
Treatment and outcome of stage Ia1 squamous cell carcinoma of the uterine cervix Herman Haller a, Maja Krašević b,⁎, Ozren Mamula a, Alemka Brnčić-Fischer a, Senija Eminović b, Miljenko Manestar a a b
Department of Obstetrics and Gynecology, Clinical Hospital Centre, School of Medicine, University of Rijeka, Rijeka, Croatia Department of Pathology, School of Medicine, University of Rijeka, Rijeka, Croatia
a r t i c l e
i n f o
Article history: Received 2 June 2010 Received in revised form 8 October 2010 Accepted 23 December 2010 Keywords: Cervical squamous cell carcinoma Clinicopathologic study Conization FIGO stage IA1
a b s t r a c t Objective: To evaluate the treatment and clinical outcome of patients with FIGO stage IA1 cervical squamous cell carcinoma (SCC). Methods: Medical records, including 5-year follow-up, were reviewed for 276 patients with stage IA1 SCC. Results: As definitive surgery, 152 (55.1%), 72 (26.1%), 40 (14.5%), and 12 (4.3%) patients underwent conization, hysterectomy, hysterectomy with pelvic lymphadenectomy (PL), and radical hysterectomy with PL, respectively. Among these groups, the 5-year recurrence-free rate was 94.1%, 98.6%, 95%, and 100%, respectively, and the survival rate was 98.7%, 98.6%, 100%, and 100%, respectively. Recurrent disease was identified among 12 (4.3%) patients, and was related to the depth of invasion (P b 0.001). Eleven (4.0%) of 276 patients were found to have lymph vascular space invasion (LVSI). There were no positive lymph nodes among 52 patients who underwent PL, including those with LVSI. Conization was followed by hysterectomy in 49 patients. In these patients, residual intraepithelial neoplasia was found in 18 women, 3 of whom had no involved margins on previous conization. In the group of patients treated by conization, recurrence correlated with the status of the endocervical and lateral cone margin (P b 0.001). Conclusion: As a conservative approach, conization is an effective and reasonable treatment option for stage IA1 SCC, especially in actively reproductive women. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction The concept of “microinvasive carcinoma of the cervix” (MIC) has been a subject of continual discussion since its introduction by Mestwerdt in 1947 [1]. There has been no agreement about its pathologic definition or subsequent implications for its treatment. The original definition of MIC was proposed by Burghardt in 1973 [2], and applied to neoplastic lesions with a maximum depth of invasion of 5 mm, measured from the basement membrane. In 1974, the Committee on Nomenclature of the Society of Gynecologic Oncologist recommended more restrictive criteria for MIC: namely, a lesion with stromal invasion of 3 mm or less, but without lymph vascular space invasion (LVSI). Since then, several histopathologic criteria have been advocated, including horizontal tumor spread, tumor volume, and LVSI. In the most recent FIGO revision of stage IA cervical carcinoma in 1994, this stage was subdivided into IA1 and IA2 as lesions with a depth of stromal invasion of 3 mm or less and 5 mm or less, respectively, both with a horizontal spread of 7 mm or less. Diagnosis of stage IA disease should be based exclusively on microscopic
⁎ Corresponding author. Department of Pathology, School of Medicine, Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia. Tel.: + 385 51325811. E-mail address: [email protected] (M. Krašević).
examination of the surgical material. LVSI does not alter the stage, and its significance as a risk factor for lymph node metastasis or recurrence of the disease has not been completely defined [3]. The most recent and significant FIGO statistics showed a very satisfactory patient outcome for stage IA1 cervical carcinoma with a 5-year survival of 97.5% [4]. The treatment policy of early stage disease remains controversial. In the past, radical methods have been applied to cases of cervical carcinoma stage IA1 [5,6]. There is, however, an obvious move toward a conservative approach, where simple hysterectomy is the method of choice, although conization is a feasible treatment for patients who desire to preserve their fertility [7]. The aim of the present study was to assess the risk of recurrence and 5-year survival among patients with microinvasive stage IA1 cervical squamous cell carcinoma (SCC) with a particular focus on conization as an effective and adequate surgical procedure. 2. Materials and methods In the present retrospective study, the hospital records including pathologic reports were reviewed for all patients with cervical carcinoma treated from January 1, 1990, to December 31, 2004, at the Department of Obstetrics and Gynecology University Hospital of Rijeka. A total of 276 patients with cervical SCC with a maximum depth of stromal invasion of 3 mm or less and a horizontal spread of 7 mm or less were identified from the records. Glandular lesions were
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H. Haller et al. / International Journal of Gynecology and Obstetrics 113 (2011) 72–75
not considered. The tumors in 83 patients treated before 1995 were retrospectively staged after 1995 according to the 1994 FIGO nomenclature. The research was approved by the ethical committee of the Clinical Hospital Centre of Rijeka. Patients gave informed consent for participation in the study. Diagnostic workup began with cervical cytology screening. The patients had at least 1 additional Pap smear on 3 separate slides (vaginal fornix, ectocervix, and endocervix) before colposcopy. Cervical biopsy and endocervical curettage were the diagnostic procedure in 181 out of the 276 patients, and subsequent conization was carried in 110 women. In the other 95 patients, owing to positive endocervical cytology or unsatisfactory colposcopy, conization was the primary diagnostic procedure. In all patients with cervical SCC staged as IA1, definitive diagnosis was made after analysis of the conization, hysterectomy, or radical hysterectomy specimens. Conization, hysterectomy, hysterectomy with pelvic lymphadenectomy (PL), and radical hysterectomy with PL were the definitive treatments in 152, 72, 40, and 12, patients, respectively. In all patients undergoing conization, cold-knife conization and sharp conical excision of the cervix by scalpel were performed. The cervical orifice was reconstructed by 2 separate sutures knotted together on the ectocervix on 3 and 9 o'clock. According to the local findings, hysterectomy was performed abdominally. Radical hysterectomies were performed as Piver class II, including resection of the medial half of the lateral parametrium, the minimal part of the uterosacral ligaments (posterior parametrium), and approximately 2 cm of vaginal cuff. Ovaries were usually preserved in patients younger than 45 years when hysterectomy or radical hysterectomy was performed. During the study period, the surgical protocol became less radical. Before 1997, for patients with invasion of less than 3 mm and LVSI, radical hysterectomy was performed as the definitive treatment. From 1997 onward, a reduction in parametrial radicality was considered as acceptable. The definitive treatment included pelvic PL and (simple) hysterectomy with or without ovaries. The surgical margins of each cone specimen were marked with ink and bisected along the axis of the endocervical canal. Each half was cut at additional 4–5-mm intervals in a plane parallel to the axis of the canal. Each block was serially sectioned. Six levels from each block— and additional levels if stromal invasion had been found—were examined routinely. According to the dimensions, 40–90 sections were obtained from each cone. The cervices of the extirpated uteri were opened longitudinally and sectioned along the axis at 3–4-mm intervals in separate blocks. Four sections were cut from each block. Histologic evaluation comprised the depth of invasion and horizontal spread of the tumor, LVSI, and involvement of the surgical margins. Both stromal invasion and horizontal spread of the tumor were measured by means of a calibrated ocular micrometer. The depth of invasion was defined as the distance from the epithelial– stromal junction of the adjacent dysplastic epithelium, surface, or cryptal, and the deepest point of invasion. Horizontal spread was evaluated depending on the pattern of microinvasion (unifocal or multifocal), as previously described [8]. LVSI was considered to be present when tumor cells were found within capillary spaces lined by endothelial cells. The clinical data analyzed included patient age, type of definitive surgical procedure, and treatment. Residual disease after conization was considered as cervical intraepithelial neoplasia II–III (CIN II–III) or microinvasive disease in the hysterectomy specimens. Recurrence was defined by cytology and/or histology. Distant recurrence was defined by the presence of positive findings on imaging techniques associated with clinical findings. The patients were followed-up by means of clinical examination and Pap smear. The mean duration of follow-up was 80 months (range 36–205 months). The incidence of recurrence and death, in addition to the total disease-free interval and the 5-year survival rate, were examined.
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Data were stored in an apposite database and analyzed via MedCalc version 9.5.2.0 (MedCalc, Mariakerke, Belgium). Statistical significance was calculated by t test, correlation matrices, χ2 test or two-tailored Fisher exact test where appropriate, and the Mann– Whitney U test. The Kaplan–Meyer product limit method was applied in the analysis of recurrence and survival rate. A P value of less than 0.05 was considered to be significant.
3. Results The mean age of the 276 patients was 39.4 years (range 21– 82 years). Seventy-five (27.2%) patients were postmenopausal. Most tumors (221, 80.1%) had a depth of stromal invasion of 1 mm or less (Table 1). The depth of invasion correlated with patient age (r = 0.223, P b 0.0002; 95% confidence interval [CI] 0.11–0.33). LVSI was detected in 11 (4.0%) cases. Increasing depth of stromal invasion also correlated with incidence of LVSI (r = 0.22, P = 0.0002; CI 0.11–0.33). Of the 276 patients with stage IA1 SCC, 201 underwent conization, either as part of a diagnostic surgical procedure or as a definitive treatment (Table 2). Positive cone margins (endocervical and/or lateral) for high-grade CIN (II–III) or LVSI were found in 35 (17.4%) and 6 (2.9%) cases, respectively. In 152 patients, conization remained the definitive treatment, although 15 and 1 of these women had positive surgical margins for CIN and LVSI, respectively. In 49 (24.4%) patients, conization was followed by more extensive treatment (simple or radical hysterectomy) for several reasons (Table 2). In hysterectomy specimens, residual intraepithelial neoplasia was found in 18 patients: namely, 15 out of 20 (75%) who had a hysterectomy because of positive surgical margins; and 3 out of 24 (12.5%) who elected to have a hysterectomy but had no involvement of the margins on previous conization. During the 5-year follow up period, recurrent disease was identified among 12 (4.3%) patients with stage IA1 cervical SCC, resulting in a 5-year recurrence-free survival of 95.7%. Recurrence significantly correlated with the depth of invasion (P b 0.05). Recurrence occurred in 7 (3.2%) and 5 (18.5%) patients who had tumors Table 1 Age, depth of stromal invasion, and LVSI in patients with stage IA1 cervical cancer.a Depth of invasion, mm
No. of patients
Age, years
Patients with LVSI
≤1 N 1 and ≤ 2 N 2 and ≤ 3 Total
221 (80.1) 28 (10.1) 27 (9.8) 276 (100)
38.4 ± 8.2 42.2 ± 13.1 44.8 ± 11.8 39.7 ± 9.5
4 (1.8) 3 (10.7) 4 (14.8) 11 (4.0)
Abbreviation: LVSI, lymph vascular space invasion. a Values are given as number (percentage) or mean ± SD.
Table 2 Conization in 201 patients with stage IA1 cervical cancer.a Conization
No. of patients
Residual disease
As definitive treatment b,c Followed by hysterectomy owing to LVSI Followed by hysterectomy owing to positive margins for CIN Followed by hysterectomy owing to LVSI and positive margins for CIN Followed by hysterectomy owing to patients choice, with negative margins for CIN and no LVSI
152 (75.6) 5 (2.5) 20 (10.0)
− 0 15 (75.0)
0 24 (11.9)
0 3 (12.5)
Abbreviations: CIN, cervical intraepithelial neoplasia; LVSI, lymph vascular space invasion. a Values are given as number (percentage). b Among 152 patients for whom conization was the definitive treatment; 15 had positive margin(s) and in LVSI was found in 1 patient. c Residual disease was not assessed in this group. The group was followed-up, and results are presented in Table 5.
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Table 3 Type of recurrence during follow-up in patients with stage IA1 cervical cancer.a Conization HY Total no. of patients 152 Recurrence based on cytology 3 (2.0) Cervical or vaginal intraepithelial recurrence 3 (2.0) (CIN/VaIN) Cervical or vaginal microinvasive recurrence 1 (0.7) Pelvic invasive recurrence 2 (1.3) Distant recurrence 0
HY, LY
RHY, LY
72 40 12 0 1 (2.5) 0 1 (1.4) 0 0 0 0 0
0 1 (2.5) 0
0 0 0
Abbreviations: CIN, cervical intraepithelial neoplasia; HY, hysterectomy; LY, lymphadenectomy; RHY, radical hysterectomy; VaIN, vaginal intraepithelial neoplasia. a Values are given as number (percentage) unless otherwise indicated.
4. Discussion
Table 4 Type of definitive surgery in 276 patients with stage IA1 cervical cancer.a Type of surgery
No. of patients
Age, years
5-year recurrence free
5-year survival rate
Conization Hysterectomy Hysterectomy + pelvic lymphadenectomy Radical hysterectomy + pelvic lymphadenectomy
152 (55.1) 72 (26.1) 40 (14.5)
35.4 ± 6.3 45.3 ± 9.6 42.2 ± 10.9
143 (94.1) 71 (98.6) 38 (95.0)
150 (98.7) 71 (98.6) 40 (100)
12 (4.3)
45.2 ± 12.0
12 (100)
12 (100)
a
Values are given as number (percentage) or mean ± SD.
with 1 mm or less invasion, and more than 2–3 mm of invasion, respectively (χ2, P b 0.001). In the group of patients who had tumors with more than 1–2 mm of invasion, no recurrence was found. Types of recurrence are detailed in Table 3. Three patients died because of disease, resulting in a 5-year survival rate of 98.9%. Similar 5-year recurrence-free and survival rates were observed when the patients with stage IA1 cervical SCC were classified according to the surgery performed (Table 4). In the group of patients treated by conization, 2 patients with a tumor invasion depth of 1 and 2.8 mm showed local (pelvic) invasive recurrence after 4 and 38 months, respectively. In the first case, however, the recurrence might have been a remnant from the multifocal disease. Both patients were treated by radio- and chemotherapy, and died 6 and 12 months after recurrence was noted. In the hysterectomy group, 1 patient had local recurrence after 28 months; she was treated by brachytherapy and died 12 months later. In the group of hysterectomy and lymphadenectomy, 2 patients had recurrence 26 and 42 months after surgical treatment; they received radiotherapy and are still alive. In the same group, a 37-year-old patient died owing to pulmonary thromboembolism, with no evidence of cervical SCC disease.
Table 5 Relation of marginal status and LVSI to 5-year recurrence and survival among 152 patients with stage IA1 cervical cancer treated by conization. Risk factors on conization specimen
No. of patients
Recurrence
Negative margin, no LVSI Positive lateral margin for CIN Positive endocervical margin for CIN Positive lateral/endocervical margin for CIN LVSI
136 4 10 1 1
3 (2.2) 1 (25.0) 4 (40.0) 1 (100) –
a,b
All patients treated by radical hysterectomy were alive without signs of disease at the 5-year follow-up. As an adjuvant surgical procedure, PL was performed in 52 patients. The mean ± SD number of lymph nodes removed was 18 ± 10.2 (range 6–47). Lymph nodes were negative for disease in all cases. The correlation was assessed between histologic findings in cone specimens, and recurrence and survival in patients treated only by conization (Table 5). Recurrence was identified in 6 out of 15 patients with cone margins positive for CIN II–III, and 3 out of 136 patients with negative cone margins, resulting in 40% and 2.2% recurrence, respectively. This difference was highly significant (χ2 = 28.0, P b 0.0001). Patient age was not found to have an influence on recurrence rate.
Death
a,c
1 (0.7) – 1 (10.0) – –
Abbreviations: CIN, cervical intraepithelial neoplasia; LVSI, lymph vascular space invasion. a Values are given as number (percentage). b Recurrence included atypical Pap smear without histologic confirmation, histology of cervical intraepithelial neoplasia, microinvasive and invasive disease. c Two patients died: 1 without risk factors 50 months after conization with pelvic invasive recurrence, and 1 with positive intraepithelial lesion (CIN) on the cone tip 10 months after conization with pelvic invasive recurrence and venous thromboembolism of the leg.
Patients with stage IA cervical SCC comprise about 40.0% of all patients with cervical SCC [9] currently treated in our institution, and more than two-thirds have stromal invasion of less than 1 mm. The present results show a relatively higher incidence of microinvasive cervical cancer as compared with FIGO statistics [4]. This finding might be partly attributed to the high number of serial sections (40–90)—cut through the paraffin blocks of cone specimens—that are routinely obtained and analyzed in our laboratory. In the present study, 152 (55.1%) patients with stage IA1 cervical SCC were treated by conization alone. Historically, stage IA1 disease has been managed by various procedures, including radical ones [6]. The actual incidence of parametrial invasion [10] and lymph node involvement is negligible, and patients can be adequately treated by simple hysterectomy without lymphadenectomy. As a surgical procedure in patients with stage IA1 cervical SCC, conization is still recommended. In previous studies, approximately 96% of patients with stage IA1 cervical cancer who were treated conservatively were found to be alive and disease-free after 5 years of follow-up, and the recurrence rate ranged from 2.7% to 9% [11,12]. In the present conservatively managed group of patients, the disease-free rate was 94.1% and the 5-year survival rate was 98.7%. The actual guidelines for conservative treatment of patients with cervical cancer indicate that only the histologic characteristics of the tumor should be considered [12]. The significance of increasing age [13], positive endocervical curettage, positive cone margins, and increasing neoplastic severity [14] has been attributed to the presence of residual disease on hysterectomy specimens after conization. The results of some studies [13] have indicated that menopausal status could be a risk factor for residual disease, owing to difficulties in eradicating the lesions of the retracted transformation zone in older patients. In the present study, endocervical curettage after conization was not performed routinely and menopausal status was not taken into account. As a therapeutic approach, however, conization was not used in postmenopausal women. Only 4 out of 152 women older than 50 years were treated by conization (data not shown). A cooperative study by Gadducci et al. [15] showed that, among northern Italian institutions, conization was performed in 30 (21%) out of 143 patients with stage IA1 SCC, a considerably smaller proportion than in our study. In the same study, hysterectomy and radical hysterectomy with PL were applied more frequently. In the present study, hysterectomy was carried out in postmenopausal patients. The 5-year survival and recurrence-free interval were similar to those of the conization group (χ2 = 2.29, P = 0.1302). A positive resection margin for CIN (lateral and endocervical) should be considered as a risk factor for predicting post-conization residual disease and further conservative management [16]. Furthermore, apical and lateral clearance, defined as the distance between the tumor margin, and the apex and lateral margin of the cone could be used as additional parameter in optimizing the conservative management of patients with stage IA1 cervical cancer [12]. Despite several reports
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showing that dysplastic lesions on the resection margins are responsible for recurrence, a histologically defined cervical lesion was previously found in only 40% of cases of hysterectomy after conization [17]. In the present study, the hysterectomy specimens obtained after conization with positive margins showed a high rate of residual CIN: namely 15 (75%) out of 20. Among the group of women followed-up after conization with positive margins, a recurrence rate of 40% was found. The present results emphasize the importance of marginal status in patients treated by conization, and we support the necessity of prompt surgical re-intervention if marginal status is positive for CIN. Exceptions should be closely monitored. Patients with negative marginal status are, however, not excluded from the risk of recurrence. Residual lesions were previously found in 8–24% of patients with negative margins, precluding politopic disease development in the uterine cervix [18]. In the present study, residual lesions were found in 12.5% of hysterectomy specimens obtained after conization with negative margins for CIN. The detection of human papillomavirus status after loop electrosurgical conization, combined with “classical” surgical margin status in patients with CIN, could be used to subdivide patients with different risks of recurrence. This would require new, tailored, surveillance procedures [19], and further studies are needed to evaluate the precise role of such testing. A low risk of lymph node metastasis, recurrence and death has been found in microinvasive cervical carcinoma [6,10]. In the present study, no positive lymph nodes were found among 52 patients with stage IA1 disease. The incidence of lymph node metastasis in stage IA1 disease has been reported to vary from 0% to 2% [20,21]. There is no consensus regarding the significance of LVSI in predicting lymph node metastasis. A risk of lymph node metastasis was previously found in 0.3% of patients with microinvasive cervical cancer with less than 3 mm of stromal invasion and no LVSI, as compared with 2.6% of patients with LVSI [22]. Other investigators found a higher incidence of pelvic lymph node metastasis (1.7% in patients with stage IA1 disease), but without correlation with LVSI [23]. The prognostic meaning of LVSI remains unresolved, and further evaluations would clarify its precise prognostic significance. Involvement of the parametrium has not been extensively reported. Similarly, in the present study, no parametrial involvement was detected among 12 patients who underwent radical treatment. In conclusion, the present results indicate that a conservative surgical approach—namely, conization—is an effective and reasonable treatment option for patients with stage IA1 cervical cancer, especially those patients who are still of reproduction age. The status of the surgical margins is a crucial histologic parameter. If the endocervical and lateral resection margins are positive for highgrade CIN, further surgical treatment should be promptly applied to minimize the risk of recurrence. Conflict of interest The authors have no conflicts of interest.
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