SERUM CEA IN PATIENTS WITH ENDOMETRIAL CANCER, Hashiguchi et al. ORIGINAL ARTICLE
Serum carcinoembryonic antigen as a tumour marker in patients with endometrial cancer Y. Hashiguchi md,* M. Kasai md,* T. Fukuda md,* T. Ichimura md,* T. Yasui md,* and T. Sumi md* ABSTRACT Background No potential tumour markers have been validated for prognosis in endometrial cancer. However, carcinoembryonic antigen (cea) is one of the most widely used tumour markers in various types of cancer. Although cea expression in endometrial cancer has been investigated, its prognostic value remains controversial, and no studies have investigated serum cea levels in large case series. In the present study, we investigated diagnostic and prognostic applications of serum cea for endometrial cancer.
Methods This prospective study was approved by our Institutional Review Board. Between January 2006 and December 2012, serum cea was measured prospectively in 215 patients with endometrial cancer and was subsequently measured during treatment and at scheduled follow-up examinations in patients with elevated baseline serum cea. Results During the study period, 215 patients (142 stage i, 19 stage ii, 32 stage iii, 22 stage iv) were treated for endometrial cancer. By the time of last follow-up, 52 had relapsed (24.2%), and the median follow-up duration was 45 months (range: 1–95 months). Elevated serum cea was identified in 25 patients (11.6%) and was associated with histologic type (p = 0.04), histologic grade (p = 0.03), and myometrial invasion depth (p = 0.01). Elevated serum cea was not related to clinical stage, lymph node metastasis, distant metastasis, age, menopausal status, or body mass index. Relapse of disease was related to elevated serum cea (p = 0.006). Conclusions Serum cea is a potential prognostic indicator for endometrial cancer. Key Words Serum cea, endometrial cancer, tumour markers Curr Oncol. 2016 Oct;23(5):e439-e442
INTRODUCTION Endometrial cancer is the most common cancer of the female genital tract, and its incidence is increasing globally. Although several biomarkers have been associated with clinical characteristics and prognosis in endometrial cancer1–6, none have been implemented in clinical practice. Novel biomarkers for endometrial cancer are therefore required. Carcinoembryonic antigen (cea) is a 200-kDa glycoprotein, described first in 1965 by Gold and Freedman7, when they identified the antigen that was present in both fatal colon and colon adenocarcinoma, but that appeared to be absent from healthy adult colon. Serum cea is one of the most widely used tumour markers, having been reported to be elevated in many cancers, such as those of
www.current-oncology.com
colon and rectum, breast, lung, pancreas, liver, stomach, thyroid, prostate, bladder, and ovary 8–10. Although cea expression has been investigated in endometrial cancer, controversy continues to revolve around its associations with that malignancy. Neunteufel et al.11 and Duk et al.12 reported that cea was expressed in 58% and 62.5% of endometrial carcinoma patients respectively. A few reports that investigated serum cea levels revealed that serum cea was elevated in endometrial cancer patients in 22% of cases13,14. Only those few small studies have investigated serum cea in patients with endometrial cancer; no large studies of endometrial cancer have reported cea levels. In the present work, we investigated the diagnostic and prognostic value of serum cea in patients with endometrial cancer.
Correspondence to: Yasunori Hashiguchi, Department of Obstetrics and Gynecology, Osaka City University, Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585 Japan. E-mail: [email protected] n DOI: http://dx.doi.org/10.3747/co.23.3153 Current Oncology, Vol. 23, No. 5, October 2016 © 2016 Multimed Inc.
e439
SERUM CEA IN PATIENTS WITH ENDOMETRIAL CANCER, Hashiguchi et al.
METHODS This prospective study was approved by the Osaka City University Graduate School of Medicine Institutional Review Board. Available electronic medical records for January 2006 to December 2012 were reviewed, and serum cea and clinicopathologic features in patients with endometrial cancer were analyzed. Patients with a co-existing malignant disease were excluded from the analyses. Clinical management of endometrial cancer in our institution is performed by gynecologic oncologists and diagnoses are established by curettage. All patients are clinically or surgically classified according to the International Federation of Gynaecology and Obstetrics surgical staging system (2008 version)15. Histologic diagnoses were confirmed by microscopy examination of hematoxylin- and eosin-stained sections according to World Health Organization criteria. In operable cases, patients received total abdominal or radical hysterectomy plus bilateral salpingo- oophorectomy. Peritoneal fluid samples were obtained for cytology testing, and systemic pelvic lymphadenectomy was performed in most cases. Para-aortic lymph node sampling was performed in patients with intermediate- or high-risk disease. In patients without lymph node ade nectomy, lymph nodes larger than 1 cm were detected by computed tomography or magnetic resonance imaging (or both) and were considered positive. After surgery, adjuvant chemotherapy was provided for patients with intermediate- or high-risk disease. No hormonal therapies or targeted treatments such as monoclonal antibodies or tyrosine kinase inhibitors were administered. Treatment was followed by gynecologic examinations, including transvaginal or abdominal ultrasonography (or both) and cytology testing of vaginal cut edges, and by laboratory examinations, including assessments of tumour marker expression. Further computed tomography or magnetic resonance imaging exams were performed for patients with clinically suspicious symptoms or elevated tumour marker levels. Recurrent disease was diagnosed by biopsy or imaging methods. Serum cea was measured before therapy, during the pre-treatment examinations. A lower level of 5.0 ng/mL was used as the cut-off for normal serum cea. In patients with elevated baseline serum cea, cea was measured again during treatment and at scheduled follow-up examinations. The intervals between follow-up appointments were every 2 months during years 1–3 after treatment, every 6 months during years 4–5 after treatment, and annually from year 6 after treatment.
Statistical Analyses Relationships between clinical groups were analyzed using the Fisher exact probability test. In the analyses of disease relapse, survival distributions were calculated using the Kaplan–Meier method, and relapse-free patients included those with no evidence of disease recurrence and those who died from unrelated causes. Univariate and multivariate Cox regression analyses were used to identify variables associated with relapse-free survival (histologic type, histologic grade, clinical stage, myometrial invasion depth, lymph node metastasis, distant metastasis, age,
e440
menopausal status, and body mass index), and associations were considered significant at p < 0.05.
RESULTS Clinical Characteristics of Patients with Endometrial Cancer Table i shows the clinical characteristics of the patients with endometrial cancer. During the study period, 215 patients were treated (142 stage I, 19 stage ii, 32 stage iii, 22 stage iv). Median age in the cohort was 60 years (range: 28–85 years), and the histologic types included 191 endometrioid adenocarcinomas, 7 carcinosarcomas, 5 serous adenocarcinomas, 5 adenosquamous carcinomas, 3 mucinous adenocarcinomas, 2 clear cell adenocarcinomas, 1 small-cell carcinoma, and 1 undifferentiated carcinoma. Histologic grade was grade 1 in 71 patients, grade 2 in 83 patients, and grade 3 in 61 patients. Surgery was the primary therapy in 212 patients (98.6%), and chemotherapy was given in 3 patients with inoperable disease (1.4%). Surgery included total abdominal or radical hysterectomy plus bilateral salpingo-oophorectomy in 210 patients (97.7%); lymphadenectomy was additionally performed in 194 patients (90.2%). Para-aortic lymph node biopsies were performed in 24 patients (11.2%), and tumour biopsies were obtained in 2 patients (0.9%) with advanced disease. After surgery, adjuvant chemotherapy was given in 101 patients (47.0%) with intermediate- or high-risk disease, including paclitaxel–carboplatin therapy in 86 patients, docetaxel– carboplatin therapy in 10 patients, and docetaxel–cisplatin
TABLE I Patient characteristics Characteristic
Value
Age (years) Median Range
60 (28–85)
Histology (n) Endometrioid
191
Carcinosarcoma
7
Serous adenocarcinoma
5
Adenosquamous carcinoma
5
Mucinous adenocarcinoma
3
Clear-cell adenocarcinoma
2
Small-cell adenocarcinoma
1
Undifferentiated carcinoma
1
Stage (n) I
142
II
19
III
32
IV
22
Histologic grade (n) 1
71
2
83
3
61
Current Oncology, Vol. 23, No. 5, October 2016 © 2016 Multimed Inc.
SERUM CEA IN PATIENTS WITH ENDOMETRIAL CANCER, Hashiguchi et al.
therapy in 5 patients. Paclitaxel–carboplatin therapy was given in the 3 inoperable cases. At the time of last follow-up, 52 patients (24.2%) had experienced disease relapse. Median follow-up duration for all patients was 45 months (range: 1–95 months).
TABLE II Clinicopathologic characteristics of the study cohort by serum carcinoembryonic antigen (CEA) status
Serum CEA in Patients with Endometrial Cancer Table ii shows serum cea measurements and clinical characteristics for the patients. Elevated serum cea was detected in 25 patients (11.6%). Compared with patients having endometrioid adenocarcinoma, those with other histologic disease types had significantly more elevated serum cea measurements (25.0% vs. 9.9%, p = 0.04); similarly, serum cea was significantly elevated in patients with histologic grade 3 disease than in those with grade 1 or 2 disease (19.7% vs. 8.4%, p = 0.03). Serum cea was also significantly elevated in patients with a myometrial invasion depth exceeding 1/2 (19.5%) than in those with a myometrial invasion depth less than 1/2 (7.2%, p = 0.01). Elevated serum cea was not associated with clinical stage, lymph node metastasis, distant metastasis, age, menopausal status, or body mass index. Of the 25 patients with elevated serum cea, 17 (68.0%) achieved remission. Although serum cea fell to within the defined normal range in 11 of those patients, it did not fall in 6 patients. However, 12 of the 25 patients (48.0%) relapsed, with a concomitant increase in serum cea in every case. Of the 6 patients whose serum cea did not fall into the defined normal range, none experienced disease recurrence. In the patients with elevated serum cea, relapse of disease was significantly more frequent than it was in the patients with normal serum cea (23.1% vs. 8.0%, p = 0.006).
DISCUSSION Numerous studies have investigated biomarkers for endometrial cancer1–6. In particular, measurement of cancer antigen 125 (CA125) in serum has been investigated as a tumour marker in patients with endometrial cancer. Duk et al.12 reported that CA125 is a useful marker in endometrial carcinoma, and Patsner et al.15 demonstrated its utility as a marker for monitoring treatment effects in patients with advanced endometrial cancer. However, the precise role of CA125 in preoperative evaluations of endometrial cancer patients remains uncharacterized and controversial16. Nonetheless, no other potential tumour markers have been validated for predicting prognosis and classifying endometrial cancers, warranting identification of tumour markers that can inform the management of patients with endometrial cancer. On the other hand, serum cea, one of the most widely used tumour markers, is reported to be elevated in many cancers, such as those of colon and rectum, breast, lung, pancreas, liver, stomach, thyroid, prostate, bladder, and ovary 8–10. The identification of abnormal pre- and postoperative serum cea could be a useful auxiliary for prognosis or postoperative surveillance in colorectal cancer patients10. Although some publications have investigated cea expression or serum cea level, they included only small numbers of patients with endometrial cancer11–14. One report investigated serum cea for detection of recurrent
Current Oncology, Vol. 23, No. 5, October 2016 © 2016 Multimed Inc.
Variable
Serum CEA group [n (%a)]
p Value
Elevated
Normal
Age
Serum carcinoembryonic antigen as a tumour marker in patients with endometrial cancer Y. Hashiguchi md,* M. Kasai md,* T. Fukuda md,* T. Ichimura md,* T. Yasui md,* and T. Sumi md* ABSTRACT Background No potential tumour markers have been validated for prognosis in endometrial cancer. However, carcinoembryonic antigen (cea) is one of the most widely used tumour markers in various types of cancer. Although cea expression in endometrial cancer has been investigated, its prognostic value remains controversial, and no studies have investigated serum cea levels in large case series. In the present study, we investigated diagnostic and prognostic applications of serum cea for endometrial cancer.
Methods This prospective study was approved by our Institutional Review Board. Between January 2006 and December 2012, serum cea was measured prospectively in 215 patients with endometrial cancer and was subsequently measured during treatment and at scheduled follow-up examinations in patients with elevated baseline serum cea. Results During the study period, 215 patients (142 stage i, 19 stage ii, 32 stage iii, 22 stage iv) were treated for endometrial cancer. By the time of last follow-up, 52 had relapsed (24.2%), and the median follow-up duration was 45 months (range: 1–95 months). Elevated serum cea was identified in 25 patients (11.6%) and was associated with histologic type (p = 0.04), histologic grade (p = 0.03), and myometrial invasion depth (p = 0.01). Elevated serum cea was not related to clinical stage, lymph node metastasis, distant metastasis, age, menopausal status, or body mass index. Relapse of disease was related to elevated serum cea (p = 0.006). Conclusions Serum cea is a potential prognostic indicator for endometrial cancer. Key Words Serum cea, endometrial cancer, tumour markers Curr Oncol. 2016 Oct;23(5):e439-e442
INTRODUCTION Endometrial cancer is the most common cancer of the female genital tract, and its incidence is increasing globally. Although several biomarkers have been associated with clinical characteristics and prognosis in endometrial cancer1–6, none have been implemented in clinical practice. Novel biomarkers for endometrial cancer are therefore required. Carcinoembryonic antigen (cea) is a 200-kDa glycoprotein, described first in 1965 by Gold and Freedman7, when they identified the antigen that was present in both fatal colon and colon adenocarcinoma, but that appeared to be absent from healthy adult colon. Serum cea is one of the most widely used tumour markers, having been reported to be elevated in many cancers, such as those of
www.current-oncology.com
colon and rectum, breast, lung, pancreas, liver, stomach, thyroid, prostate, bladder, and ovary 8–10. Although cea expression has been investigated in endometrial cancer, controversy continues to revolve around its associations with that malignancy. Neunteufel et al.11 and Duk et al.12 reported that cea was expressed in 58% and 62.5% of endometrial carcinoma patients respectively. A few reports that investigated serum cea levels revealed that serum cea was elevated in endometrial cancer patients in 22% of cases13,14. Only those few small studies have investigated serum cea in patients with endometrial cancer; no large studies of endometrial cancer have reported cea levels. In the present work, we investigated the diagnostic and prognostic value of serum cea in patients with endometrial cancer.
Correspondence to: Yasunori Hashiguchi, Department of Obstetrics and Gynecology, Osaka City University, Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585 Japan. E-mail: [email protected] n DOI: http://dx.doi.org/10.3747/co.23.3153 Current Oncology, Vol. 23, No. 5, October 2016 © 2016 Multimed Inc.
e439
SERUM CEA IN PATIENTS WITH ENDOMETRIAL CANCER, Hashiguchi et al.
METHODS This prospective study was approved by the Osaka City University Graduate School of Medicine Institutional Review Board. Available electronic medical records for January 2006 to December 2012 were reviewed, and serum cea and clinicopathologic features in patients with endometrial cancer were analyzed. Patients with a co-existing malignant disease were excluded from the analyses. Clinical management of endometrial cancer in our institution is performed by gynecologic oncologists and diagnoses are established by curettage. All patients are clinically or surgically classified according to the International Federation of Gynaecology and Obstetrics surgical staging system (2008 version)15. Histologic diagnoses were confirmed by microscopy examination of hematoxylin- and eosin-stained sections according to World Health Organization criteria. In operable cases, patients received total abdominal or radical hysterectomy plus bilateral salpingo- oophorectomy. Peritoneal fluid samples were obtained for cytology testing, and systemic pelvic lymphadenectomy was performed in most cases. Para-aortic lymph node sampling was performed in patients with intermediate- or high-risk disease. In patients without lymph node ade nectomy, lymph nodes larger than 1 cm were detected by computed tomography or magnetic resonance imaging (or both) and were considered positive. After surgery, adjuvant chemotherapy was provided for patients with intermediate- or high-risk disease. No hormonal therapies or targeted treatments such as monoclonal antibodies or tyrosine kinase inhibitors were administered. Treatment was followed by gynecologic examinations, including transvaginal or abdominal ultrasonography (or both) and cytology testing of vaginal cut edges, and by laboratory examinations, including assessments of tumour marker expression. Further computed tomography or magnetic resonance imaging exams were performed for patients with clinically suspicious symptoms or elevated tumour marker levels. Recurrent disease was diagnosed by biopsy or imaging methods. Serum cea was measured before therapy, during the pre-treatment examinations. A lower level of 5.0 ng/mL was used as the cut-off for normal serum cea. In patients with elevated baseline serum cea, cea was measured again during treatment and at scheduled follow-up examinations. The intervals between follow-up appointments were every 2 months during years 1–3 after treatment, every 6 months during years 4–5 after treatment, and annually from year 6 after treatment.
Statistical Analyses Relationships between clinical groups were analyzed using the Fisher exact probability test. In the analyses of disease relapse, survival distributions were calculated using the Kaplan–Meier method, and relapse-free patients included those with no evidence of disease recurrence and those who died from unrelated causes. Univariate and multivariate Cox regression analyses were used to identify variables associated with relapse-free survival (histologic type, histologic grade, clinical stage, myometrial invasion depth, lymph node metastasis, distant metastasis, age,
e440
menopausal status, and body mass index), and associations were considered significant at p < 0.05.
RESULTS Clinical Characteristics of Patients with Endometrial Cancer Table i shows the clinical characteristics of the patients with endometrial cancer. During the study period, 215 patients were treated (142 stage I, 19 stage ii, 32 stage iii, 22 stage iv). Median age in the cohort was 60 years (range: 28–85 years), and the histologic types included 191 endometrioid adenocarcinomas, 7 carcinosarcomas, 5 serous adenocarcinomas, 5 adenosquamous carcinomas, 3 mucinous adenocarcinomas, 2 clear cell adenocarcinomas, 1 small-cell carcinoma, and 1 undifferentiated carcinoma. Histologic grade was grade 1 in 71 patients, grade 2 in 83 patients, and grade 3 in 61 patients. Surgery was the primary therapy in 212 patients (98.6%), and chemotherapy was given in 3 patients with inoperable disease (1.4%). Surgery included total abdominal or radical hysterectomy plus bilateral salpingo-oophorectomy in 210 patients (97.7%); lymphadenectomy was additionally performed in 194 patients (90.2%). Para-aortic lymph node biopsies were performed in 24 patients (11.2%), and tumour biopsies were obtained in 2 patients (0.9%) with advanced disease. After surgery, adjuvant chemotherapy was given in 101 patients (47.0%) with intermediate- or high-risk disease, including paclitaxel–carboplatin therapy in 86 patients, docetaxel– carboplatin therapy in 10 patients, and docetaxel–cisplatin
TABLE I Patient characteristics Characteristic
Value
Age (years) Median Range
60 (28–85)
Histology (n) Endometrioid
191
Carcinosarcoma
7
Serous adenocarcinoma
5
Adenosquamous carcinoma
5
Mucinous adenocarcinoma
3
Clear-cell adenocarcinoma
2
Small-cell adenocarcinoma
1
Undifferentiated carcinoma
1
Stage (n) I
142
II
19
III
32
IV
22
Histologic grade (n) 1
71
2
83
3
61
Current Oncology, Vol. 23, No. 5, October 2016 © 2016 Multimed Inc.
SERUM CEA IN PATIENTS WITH ENDOMETRIAL CANCER, Hashiguchi et al.
therapy in 5 patients. Paclitaxel–carboplatin therapy was given in the 3 inoperable cases. At the time of last follow-up, 52 patients (24.2%) had experienced disease relapse. Median follow-up duration for all patients was 45 months (range: 1–95 months).
TABLE II Clinicopathologic characteristics of the study cohort by serum carcinoembryonic antigen (CEA) status
Serum CEA in Patients with Endometrial Cancer Table ii shows serum cea measurements and clinical characteristics for the patients. Elevated serum cea was detected in 25 patients (11.6%). Compared with patients having endometrioid adenocarcinoma, those with other histologic disease types had significantly more elevated serum cea measurements (25.0% vs. 9.9%, p = 0.04); similarly, serum cea was significantly elevated in patients with histologic grade 3 disease than in those with grade 1 or 2 disease (19.7% vs. 8.4%, p = 0.03). Serum cea was also significantly elevated in patients with a myometrial invasion depth exceeding 1/2 (19.5%) than in those with a myometrial invasion depth less than 1/2 (7.2%, p = 0.01). Elevated serum cea was not associated with clinical stage, lymph node metastasis, distant metastasis, age, menopausal status, or body mass index. Of the 25 patients with elevated serum cea, 17 (68.0%) achieved remission. Although serum cea fell to within the defined normal range in 11 of those patients, it did not fall in 6 patients. However, 12 of the 25 patients (48.0%) relapsed, with a concomitant increase in serum cea in every case. Of the 6 patients whose serum cea did not fall into the defined normal range, none experienced disease recurrence. In the patients with elevated serum cea, relapse of disease was significantly more frequent than it was in the patients with normal serum cea (23.1% vs. 8.0%, p = 0.006).
DISCUSSION Numerous studies have investigated biomarkers for endometrial cancer1–6. In particular, measurement of cancer antigen 125 (CA125) in serum has been investigated as a tumour marker in patients with endometrial cancer. Duk et al.12 reported that CA125 is a useful marker in endometrial carcinoma, and Patsner et al.15 demonstrated its utility as a marker for monitoring treatment effects in patients with advanced endometrial cancer. However, the precise role of CA125 in preoperative evaluations of endometrial cancer patients remains uncharacterized and controversial16. Nonetheless, no other potential tumour markers have been validated for predicting prognosis and classifying endometrial cancers, warranting identification of tumour markers that can inform the management of patients with endometrial cancer. On the other hand, serum cea, one of the most widely used tumour markers, is reported to be elevated in many cancers, such as those of colon and rectum, breast, lung, pancreas, liver, stomach, thyroid, prostate, bladder, and ovary 8–10. The identification of abnormal pre- and postoperative serum cea could be a useful auxiliary for prognosis or postoperative surveillance in colorectal cancer patients10. Although some publications have investigated cea expression or serum cea level, they included only small numbers of patients with endometrial cancer11–14. One report investigated serum cea for detection of recurrent
Current Oncology, Vol. 23, No. 5, October 2016 © 2016 Multimed Inc.
Variable
Serum CEA group [n (%a)]
p Value
Elevated
Normal
Age
