Aggressive characteristics of cervical cancer in young women in Taiwan

International Journal of Gynecology and Obstetrics 107 (2009) 220–223

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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

Aggressive characteristics of cervical cancer in young women in Taiwan Hei-Yu Lau a, Chi-Mou Juang a,b, Yi-Jen Chen a, Nae-Fang Twu a, Ming-Shyen Yen a, Kuan-Chong Chao a,⁎ a b

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan Institute of Public Health, National Yang-Ming University, Taipei, Taiwan

a r t i c l e

i n f o

Article history: Received 6 May 2009 Received in revised form 5 June 2009 Accepted 20 July 2009 Keywords: Cervical adenocarcinoma Cervical cancer Non-squamous cell carcinoma Young women

a b s t r a c t Objective: To compare the characteristics and prognosis of cervical cancer in young women (under 30 years) with those of older women (over 30 years). Methods: A retrospective study of 2443 patients diagnosed with FIGO stage IA–IIA cervical cancer who underwent surgical procedures between January 1983 and December 2007. Results: Thirty patients (1.2%) were 30 years or younger. The proportion of non-squamous cell carcinoma was higher in patients 30 years or younger compared with in patients over 30 years (14/30, 46.7% vs 10/30, 33.3%; P = 0.001). A higher rate of parametrial involvement was found in the younger group of patients compared with those over 30 years (10/30, 33.3% vs 289/2413, 12.0%; P = 0.001). Patients under 30 years had a higher rate of distant metastases compared with older patients (60% vs 49.7%; P = 0.036). Conclusions: Non-squamous histology, parametrial involvement, a higher rate of distant metastases, and poorer prognosis are more common in women aged 30 or younger with cervical cancer than in older women with the disease. Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.

1. Introduction Cervical cancer is the second most common cancer (after breast cancer) and the third most common cause of cancer-related mortality (after lung and breast cancer) among women worldwide [1]. However, population-based cervical cancer screening has reduced its incidence by 40%–50% and mortality by 60% in many countries. The incidence of invasive cervical cancer and squamous cell carcinoma (SCC) has declined over time, while the incidence of non-SCC, particularly adenocarcinoma, has shown no change or sometimes even an increase, especially in young women [2]. Controversy surrounds whether these different histologic types have any bearing on prognosis [1]; moreover, in recent studies [3,4] conflicting prognosis and survival rates have been reported for young women with cervical cancer. According to the data of the Department of Health in Taiwan, the proportion of non-SCC relative to SCC and to all cervical cancers doubled between 1995 and 2005, mostly in young women. The incidence of adenocarcinoma and the other types of non-SCC that have increased may be explained by changes in sexual behavior, HPV infection, or an insufficient ability to detect a substantial proportion of adenocarcinoma precursor lesions in current screening practices [5]. Moreover, women who have never had sexual intercourse are at low risk of SCC, but other histologic types of cervical cancer can occur in

⁎ Corresponding author. Department of Gynecology and Obstetrics, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. Tel.: +886 2 28735423; fax: +886 2 28734101. E-mail address: [email protected] (K.-C. Chao).

women with no previous history of sexual activity [6]. Patients with adenocarcinomas of the cervix are considered to have lower survival rates compared with patients with SCC, which are associated with higher stages of the disease [7]. The disease pattern of the nonsquamous cell type is unclear from previous reports. The proportion and prognosis of cervical cancer in young women varies in different studies [3,4,8], from 7%–14% in Scandinavia to 25% in a small series from the USA. These variations presumably reflect different referral, demographic, geographic, racial, and social patterns. In review studies [8], an increased incidence of non-squamous cell types of cervical cancer with a poor prognosis and progressive disease were also reported in young women. Screening for cervical lesions by cytology is performed in women older than 30 years in Taiwan; however, the number of patients younger than 30 years with cervical cancer has increased. The aim of the present study was to examine retrospectively the records of women with invasive cervical cancers who were treated at Taipei Veterans General Hospital from January 1983 to December 2007. We examined the incidence, histologic and stage distribution, survival and recurrence rates, and disease pattern of cervical cancer in 2 age groups of women: 30 years or younger and over 30 years. 2. Materials and methods The study retrospectively reviewed 2443 eligible patients categorized with International Federation of Gynecology and Obstetrics (FIGO) cervical cancer stage IA to IIA who had undergone surgical procedures (including conization, modified radical hysterectomy, or radical hysterectomy) at Taipei Veterans General Hospital from January

0020-7292/$ – see front matter. Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics. doi:10.1016/j.ijgo.2009.07.029

H.-Y. Lau et al. / International Journal of Gynecology and Obstetrics 107 (2009) 220–223

1983 to December 2007. All eligible patients had given informed consent before undergoing surgical procedures. The retrospective study was approved by the Institutional Review Board of the hospital. Age, tumor histology, stage, prognostic factors, overall survival, and progression-free survival of patients with cervical cancer were examined. Histologic examination of the surgical specimens was performed by a single pathologist. Patients were divided into 2 groups: aged 30 years or younger and older than 30 years. Surgical procedures included conization or class II Rutledge technique [8,9] for FIGO stage IA1, class II Rutledge technique for FIGO stage IA2, and class III Rutledge technique [8,9] for FIGO stage IB1 to IIA. The uterus, along with the lateral parametrium, uterosacral and uterovesical ligaments, and vaginal cuff with adjacent tissue in the paravagina, was extirpated. The National Comprehensive Cancer Network (NCCN) cervical cancer treatment guidelines call for adjuvant radiotherapy after surgery with surgical stage pT2b or more extensive disease, less than 3 mm of uninvolved cervical stroma, bulky tumor size, lymphatic vessel invasion and cut-through, or combined chemotherapy for a positive node. Follow-up includes an interval history and a physical examination, and a Pap test every 3 months for 2 years, every 6 months for another 3 years, and then annually. Statistical analyses were performed using univariate analysis of differences, χ2 test, and Fisher exact test. Overall and progression-free Table 1 Demographic and histologic parameters of the study groups.a Patients aged ≤ 30 years (n = 30) Age, y Median Range BMI b18.5 18.5–24.9 ≥25 Smoking Never Former Current Stage IA1 IA2 IB1 IB2 IIA Histotype Squamous Non-squamous Adenocarcinoma Leiomyosarcoma Adenosquamous cell MMMT Adenosarcoma Small cell Clear cell Others LVSI Negative Positive DSI Negative Positive Parametrial involvement Negative Positive LN metastasis Negative Positive

27.2 16–30

Patients aged N30 years (n = 2413)

P value

66.7 31–89 0.88

2 (6.7) 24 (80) 4 (13)

193 (8.0) 1834 (76) 386 (16)

22 (73) 6 (20) 2 (6.7)

1617 (67) 531 (22) 265 (11)

4 (13) 2 (6.7) 16 (53) 0 (0) 8 (27)

242 (10) 169 (7.0) 1110 (46) 289 (12) 603 (25)

16 (53) 14 (47) 2 (14) 2 (14) 2 (14) 2 (14) 2 (14) 2 (14) 2 (14) 0 (0)

2114 (88) 299 (12) 170 (57) 10 (3.3) 47 (16) 20 (6.7) 3 (1.0) 25 (8.4) 4 (1.3) 20 (6.7)

24 (80) 6 (20)

1762 (73) 651 (27)

20 (67) 10 (33)

2076 (86) 337 (14)

20 (67) 10 (33)

2124 (88) 289 (12)

24 (80) 6 (20)

2052 (85) 361 (15)

0.69

0.37

b0.001

221

Table 2 Recurrence pattern in the study groups. Age, y

Central recurrence

≤ 30

P value

4/20

Distant metastases 12/20

0.08 N 30

123/314

P value

P value

4/20 0.036

156/314

0.046 35/314

survival was analyzed by log rank test. Prognostic factors were evaluated in Cox proportional hazards models by stepwise selection using the Akaike information criteria. P b 0.05 was considered statistically significant. 3. Results Between January 1983 and December 2007, 2443 patients with FIGO cervical cancer stages IA to IIA were treated by primary surgery. A total of 30 patients (1.2%) were 30 years or younger. The characteristics of the 2 groups are summarized in Table 1. There was no difference between patients aged 30 years or younger and patients aged over 30 years for body mass index (calculated as weight in kilograms divided by the square of the height in meters), smoking habits, and staging distribution. However, there was a higher proportion of nonSCC in patients aged 30 years or younger compared with in patients aged over 30 years (14/30, 46.7% vs 299/2413, 12.4%; P b 0.001). Non-squamous histologic types included adenocarcinoma, leiomyosarcoma, adenosquamous cell carcinoma, malignant mixed mullerian tumor, adenosarcoma, small cell carcinoma, clear cell carcinoma, and other classified carcinomas. A higher rate of parametrial involvement was found in patients aged 30 years or younger compared with patients aged over 30 years (10/30, 33.3% vs 289/2413, 12.0%; P = 0.001). Frequency of upstaging was higher among patients aged 30 years or younger than among patients aged over 30 years (32.3% vs 19.6%; P = 0.03 by χ2 test). Patients aged 30 years or younger had a higher rate of distant metastases compared with patients aged over 30 years (60% vs 49.7%; P = 0.036) (Table 2). Patients aged 30 years or younger had significantly shorter overall survival (P = 0.013) (Fig.1) and progression-free survival (P = 0.011) (Fig. 2) than did patients aged over 30 years. The Cox proportional hazard model revealed that the prognostic factors of age, parametrial invasion, pelvic lymph node metastases, tumor size, deep stromal invasion and adenosquamous carcinoma were statistically significant (Table 3).

0.52

0.007

0.001

0.61

Abbreviations: BMI: body mass index (calculated as weight in kilograms divided by the square of the height in meters); MMMT, malignant mixed mullerian tumor; LVSI, lymphovascular space involvement; DSI, deep stromal invasion; lymph node. a Values are given as number (percentage) unless otherwise indicated.

Combined

Fig. 1. Overall survival stratified by age.

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Fig. 2. Progression-free survival stratified by age.

4. Discussion Cervical cancer is the most prevalent cancer in Taiwan. Many epidemiological reports have suggested that the incidence of invasive cervical cancer in young women is rising [4,8,10,11]. This could be explained by changes in sexual behavior related to HPV infection and smoking, which causes some abnormal cell changes in young people [12–14]. Moreover, there have been conflicting reports on the prognosis of cervical cancer in young women. In some studies, young women have appeared to have a poorer prognosis than older women [3], while others report that younger women have a better prognosis [4]. Some authors have reported that age has no bearing on survival rates [10]. More than 90% of women with cancer of the cervix are infected with HPV, which is a strong risk factor for cervical cancer [15–17]. HPV types 16 and 18 are related to the development of squamous, adenoand small cell carcinoma of the cervix, and advanced metastasis of cervical cancer. In Taiwan, the HPV infection rate is 6.6% at 20–30 years of age, and most common among those aged 20–24 years. HPV types 52 and 58 are other prevalent types. Conventional cervical cytology is performed in women aged over 30 years in Taiwan. However, trends toward patients presenting with cervical cancer at a younger age and having a poorer prognosis are commonly noted in our setting. Therefore, the present review was performed to analyze the clinical and histologic characteristics of younger (under 30 years) and older (over 30 years) women with cervical cancer; our results confirm the clinical impression that the disease is changing in both character and behavior in younger women. The histologic types of cervical cancer are also different from those in older women. Most invasive cancers are still SCC [18], but a greater prevalence of non-squamous cell types has been reported.

Table 3 Multivariable Cox proportional hazards model for survival. Risk factor

Hazard ratio

95% CI

P value

Age (≤30 years vs N30 years) Parametrial invasion (+ vs –) PLN metastases (+ vs –) Tumor size (N 4 cm vs ≤ 4 cm) DSI (+ vs –) Adenosquamous carcinoma

1.69 2.29 3.78 2.12 1.46 1.38

1.02–2.49 1.49–3.15 2.67–4.63 1.67–2.61 1.15–3.17 1.07–1.73

0.02 0.01 b0.001 0.02 0.03 0.04

Abbreviations: CI, confidence interval; PLN, pelvic lymph node; DSI, deep stromal invasion.

Clinical stage is an important prognostic factor and the state of the pelvic lymph nodes provides additional prognostic information. However, the disease is changing and histologic characteristics have changed in younger women [8]. Our results showed there was no difference between the 2 groups in staging distribution; close to 70% were stage I and the majority were stage IB1. However, a worrying development has been the apparent worsening of the prognosis in young women with more parametrial involvement and deep stromal invasion. Therefore, a higher frequency of upstaging was noted, and shorter progression-free and overall survival was found in the younger women. Bulk et al. [2] reported that the survival of patients with SCC increased during 1988–2000, while the survival of patients with adenocarcinomas did not change significantly. Moreover, patients with cervical adenocarcinoma were slightly younger and had a worse prognosis than did patients with SCC. There are substantial differences in the exact type of high-risk HPV and the histologic diagnosis. Adenocarcinoma of the uterine cervix is associated more often with HPV type 18 than is SCC [19], and HPV 18 has been shown to be associated with a worse prognosis than are other HPV types [20]. The primary infection site of HPV is at the squamous–columnar (S–C) junction of the cervical epithelium, where the cells actively proliferate. The S–C junction of a teenage girl is more exposed at the exocervix, and the cells within are more vulnerable to HPV infection if she has an early sexual experience. Other estrogen-excess statuses that lead to cervical ectropion and vulnerability include pregnancy and the use of oral contraceptives. The HPV-positive rate was strongly associated with age: it was highest in the 20–29 years age group and declined to the lowest level in woman aged about 35 years, as found in other investigations [15,21,22]. This finding can be explained by acquired immunity to HPV from past exposure [23,24]. In reviewing the SEER population study [1], histologic type was found to be an important independent prognostic factor in cervical cancer. The histologic types associated with the poorest survival were small cell carcinoma, adenosquamous carcinoma, and several subtypes of adenocarcinoma (mucinous and clear cell). The influence of age on the prognosis for cervical cancer remains controversial. In the present study, the proportion of non-squamous cell carcinoma was significantly higher in the younger women, and a higher rate of distant metastases was also significant in this group. After analysis, our results also showed that age, parametrial involvement, deep stromal invasion, and histologic type (adenosquamous carcinoma) are independent prognostic factors. This finding may be explained by the significant changes in the diseasespreading pattern in young women. Although the number of patients in the young age group is small, this development prompted us to consider the use of adjuvant treatment (radiation or chemotherapy, or both) for all young patients regardless of pelvic node state [8]. In conclusion, we demonstrated a significant difference in prognosis and survival rates for cervical cancer between younger and older women. The relational factors in this change are still unclear and could not be explained by HPV infection alone. Aggressive characteristics and disease pattern were also significant. Non-squamous histologic tumors and common parametrial involvement were observed in the younger patients. This specific group of patients tended to have a higher rate of distant metastases and poorer overall survival, so optimal adjuvant treatment with closer follow-up is mandatory. Moreover, the age of this group trends progressively younger. We would re-emphasize the importance of screening programs for all sexually active women. The introduction of HPV vaccination will not remove the need of cervical screening. However, most women who acquire genital HPV infections are asymptomatic [25]. HPV vaccination provides a new and promising strategy for primary prevention of precursor lesions and cervical cancer and should be beneficial to young women. 5. Conflict of interest No conflicts of interest to declare.

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