A Comparison of Prognoses of Pathologic Stage Ib Adenocarcinoma and Squamous Cell Carcinoma of the Uterine Cervix

Gynecologic Oncology 79, 289 –293 (2000) doi:10.1006/gyno.2000.5935, available online at http://www.idealibrary.com on

A Comparison of Prognoses of Pathologic Stage Ib Adenocarcinoma and Squamous Cell Carcinoma of the Uterine Cervix Toru Nakanishi, M.D., 1 Hisatake Ishikawa, M.D., Yuka Suzuki, M.D., Takeo Inoue, M.D., Shigeo Nakamura, M.D.,* and Kazuo Kuzuya, M.D. Department of Gynecology and *Department of Pathology and Clinical Laboratory, Aichi Cancer Center Hospital, Nagoya, Japan Received March 22, 2000

Objectives. The influence of the histology of adenocarcinoma on recurrence and survival for patients treated with radical hysterectomy and diagnosed as having pathologic stage Ib cervical cancer was investigated. Methods. Five hundred and nine patients (405 squamous cell carcinomas, 104 adenocarcinomas) with pathologic stage Ib cervical cancer treated initially at the Aichi Cancer Center between 1976 and 1995 were studied. Results. Multivariate analysis identified the prognostic variables as histology of adenocarcinoma, number of lymph nodes involved, and tumor size beyond 4 cm. Five-year overall survival and disease-free survival of patients with adenocarcinoma in the presence of lymph node metastasis were 63.2 and 47.4%, respectively, significantly poorer than for squamous cell carcinoma (83.6 and 80.6%; P < 0.001 and P ⴝ 0.002, respectively). These were not different in the absence of lymph node metastasis (adenocarcinoma, 93.9 and 92.7%; squamous cell carcinoma, 97.9% and 96.1%; P ⴝ 0.067 and P ⴝ 0.250, respectively). Conclusions. The independent significant risk factors for the recurrence and survival of pathologic stage Ib cervical cancer were the presence of lymph node metastasis, large tumor size beyond 4 cm, and histology of adenocarcinoma. The prognosis of patients with adenocarcinoma was poorer than of patients with squamous cell carcinoma in the presence of lymph node metastasis, while the prognosis of pathologic stage Ib cervical cancer was equivalent when there was no metastasis. © 2000 Academic Press Key Words: cervical cancer; adenocarcinoma; squamous cell carcinoma; lymph node metastasis.

INTRODUCTION Interest in adenocarcinoma of the uterine cervix has grown as a result of its increasing incidence and its possible impact on the overall cervical cancer mortality rate [1–3]. In particular, it remains controversial whether or not the histology of adenocarcinoma influences the prognosis in patients with stage Ib cervical cancer [2–14]. Recently, the Gynecologic Oncology 1 To whom all correspondence should be addressed at Department of Gynecology, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku, Nagoya 4648681, Japan. Fax: 81-52-764-2963.

Group reported that survival was equivalent for patients with squamous cell carcinoma and adenocarcinoma of the uterine cervix [5, 6]. Our previous study revealed that the 5-year survival of stage Ib adenocarcinoma was 87.7%, which was no worse than that of squamous cell carcinoma [15, 16]. But there are several studies that have reported a poorer prognosis for adenocarcinoma [3, 11–14]. The current study focuses on the recurrences and survivals of 405 patients with squamous cell carcinoma of pathologic stage Ib cervical cancer and 104 with adenocarcinoma. We hoped to determine whether the histology of adenocarcinoma influences the recurrence and survival of these patients. PATIENTS AND METHODS In this retrospective study, the clinical and pathologic records were reviewed for all patients seen at the Aichi Cancer Center between 1976 and 1995 with a diagnosis of pathologically confirmed stage Ib cervical cancer. Patients qualified who had received primary surgical treatment including radical hysterectomy and pelvic lymphadenectomy, and if a primary cervical lesion was diagnosed as squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, or any variant thereof (e.g., clear cell adenocarcinoma). Three patients who were diagnosed pathologically as undifferentiated carcinoma, two as malignant mixed mesodermal tumor, and one as small cell carcinoma were excluded from this study. Finally, 509 patients who were treated initially at the Aichi Cancer Center formed the basis of this study. Informed consent was obtained from each patient regarding the use of clinicopathologic variables before the primary treatment. The clinicopathologic characteristics of the patients are summarized in Table 1. Obesity was defined according to the criteria of the Japan Society of Obesity, i.e., a body mass index greater than 26.4. During our study, pathologic slides were reviewed by one of the authors (S. Nakamura), and the histologic variables were confirmed. The presence of endometrial invasion was defined pathologically as a tumor extending over the histologic internal os and invading the endometrium and/or

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TABLE 1 Comparison of Clinicopathologic Variables of Pathologic Stage Ib Cervical Cancer between Squamous Cell Carcinoma and Adenocarcinoma Squamous a

Total Age

Postmenopausal state Obesity Number of lymph nodes involved

Endometrial invasion Lymph-vascular space invasion Pathological tumor size (mm) Depth of invasion (mm) Year

a

ⱕ40 40–50 50–60 ⱖ60 No Yes No Yes 0 1 ⬎2 No Yes No Yes ⱕ40 ⱖ41 ⬍5 ⬎5 1976–1985 1986–1995

Adeno

Total N

n

%

N

%

509 83 199 159 68 303 206 444 65 422 38 49 484 25 254 255 455 54 126 383 318 191

405 58 159 135 53 233 172 354 51 337 31 37 390 15 200 205 363 42 97 308 277 128

14.3 39.3 33.3 13.1 57.5 42.5 87.4 12.6 83.2 7.7 9.1 96.3 3.7 49.4 50.6 89.6 10.4 24.0 76.0 68.4 31.6

104 25 40 24 15 70 34 90 14 85 7 12 94 10 54 50 92 12 29 75 41 63

24.0 38.5 23.1 14.4 67.3 32.7 86.5 13.5 81.7 6.7 11.5 90.4 9.6 51.9 48.1 88.5 11.5 27.9 72.1 39.4 60.6

P

0.053

0.070 0.728 0.736

0.013 0.644 0.073 0.407 ⬍0.001

Squamous, squamous cell carcinoma; Adeno, adenocarcinoma.

myometrium of the uterine body. Tumor size was determined from the pathologic slides. For patients with gross tumors, the maximum diameter was noted. Lymph-vascular space invasion was considered to be present only if viable tumor cells were present inside an endothelium-lined space within an area of stroma of the uterine cervix. Depth of invasion of all patients was measured from the base of the surface epithelium to the deepest malignant cells. All patients were treated with radical hysterectomy and pelvic lymphadenectomy. The relationship between treatment and histologic diagnosis is summarized in Table 2. While paraaortic lymphadenectomy was performed on 17 patients with squamous cell carcinoma and 16 with adenocarcinoma, the pathologic lymph node metastasis was found on one with squamous cell carcinoma and three with adenocarcinoma. Eighty-seven patients with lymph node metastases received adjuvant irradiation according to hospital policy [16]. Thirtythree patients with deep stromal invasion and/or severe lymphvascular space invasion received whole-pelvis irradiation, while lymph node metastases were not found pathologically. Whole-pelvis irradiation of 40 – 45 Gy and paraaortic node irradiation of 40 – 45 Gy were performed using the conformation radiotherapy technique, as described previously [16, 17]. Four patients with squamous carcinoma and four with adeno-

carcinoma with lymph node metastases chose mitomycin Cbased chemotherapy instead of irradiation. Comparison of age of patients was tested with Student’s t-test analysis. Pearson’s ␹ 2 test was used to examine the TABLE 2 Comparison of Treatment of Pathologic Stage Ib Cervical Cancer between Squamous Cell Carcinoma and Adenocarcinoma Squamous a

Total Paraaortic lymphadenectomy radiation Whole pelvis Paraaorta chemotherapy Patients without lymph node metastasis, radiation, whole pelvis Patients with lymph node metastasis, radiation Whole pelvis Paraaorta a

Total n

n

509

405

29 109 41 8 422 33 87

17 95 33 4 337 31 68

4.2 23.5 8.1 1.0

76 41

64 33

94.1 48.5

Adeno

%

n

%

104

9.2

Squamous, squamous cell carcinoma; Adeno, adenocarcinoma.

12 14 8 4 85 2 19

11.5 13.5 7.7 3.8

12 8

63.2 42.1

2.4

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ADENOCARCINOMA AND SCC OF UTERINE CERVIX

TABLE 3 Multivariate Analysis of Pathologic Stage Ib Cervical Cancer Overall survival Odds ratio Histology Number of lymph nodes involved

Pathologic tumor size (mm)

a

Squamous Adeno 0 1 ⱖ2 ⱕ40 ⱖ41

1 2.86 1 0.78 6.58 1 2.09

95% CI a

Disease-free survival P

Odds ratio

⬍0.001

1 2.33 1 0.66 7.07 1 2.16

1.60–5.09 ⬍0.001 0.18–3.29 3.48–12.45 0.031 1.67–4.09

95% CI

P 0.003

1.34–4.05 ⬍0.001 0.16–2.76 3.93–12.70 0.015 1.16–4.03

95% CI, 95% confidence interval; Squamous, squamous cell carcinoma; Adeno, adenocarcinoma.

significance of variables in relation to the histology of adenocarcinoma. Survival of patients was calculated by the method of Kaplan and Meier. The relationship between each of the variables and survival was assessed by the log-rank test. Multivariate results were confirmed using Cox proportional hazards regression. The stability of the model was certified by using a likelihood ratio step-forward and step-backward fitting procedure. The level of significance was taken from the last step of the regression analysis. All variables were assessed according to the categories listed in Table 1. Statistical analysis was performed with SPSS software Version 6.1J, and a P value ⬍0.05 was considered to be statistically significant. RESULTS All patients included in this study were Japanese. The median follow-up time of surviving patients was 111 months. Histologic diagnosis of squamous cell carcinoma included both keratinizing and nonkeratinizing types (78 and 327 cases, respectively). Histologic diagnosis of adenocarcinoma included both the 54 patients with endocervical and 12 with endometrial types as well as the 36 with adenosquamous carcinoma and 2 with clear cell adenocarcinoma. The mean age of patients at presentation was 49.3 years (range, 24 –73 years). While the mean age of patients with adenocarcinoma was 47.9 years and that of those with squamous cell carcinoma was 49.7 years, these were not different significantly (P ⫽ 0.087). The mean age of patients treated before 1985 was 50.0 years, which was significantly older than that after 1986 (48.2 years, P ⫽ 0.044). While it seemed that adenocarcinoma attacked young patients under 40 (Table 1), we considered that it would be caused by the increase in adenocarcinoma after 1986 (Table 1). Endometrial invasion was observed more frequently in patients with adenocarcinoma (Table 1). The incidence of patients in a postmenopausal state, number of lymph nodes involved, tumor size beyond 4 cm, and depth of invasion beyond 5 mm did not significantly differ between adenocarcinoma and squamous cell carcinoma (Table 1). Multivariate analysis performed on 509 cases with complete

pathologic data identified the prognostic variables as histology of adenocarcinoma, number of lymph nodes involved, and tumor size beyond 4 cm (Table 3). Although the estimated odds ratios for overall survival and disease-free survival were not different for patients with one positive node and those without node metastasis, the ratio increased in patients with two or more positive nodes. Age, postmenopausal state, presence of obesity, endometrial invasion, lymph-vascular space invasion, whole-pelvis irradiation, paraaortic node irradiation, and year of treatment were not significant variables in the multivariate analysis. To investigate why adenocarcinoma was a prognostic variable in the current study, we compared the recurrence and survival of patients with adenocarcinoma with those of patients with squamous cell carcinoma using univariate analysis. While the prognosis of patients with adenocarcinoma was significantly poorer than that of patients with squamous cell carcinoma in the presence of positive nodes, there was no difference between the prognoses of adenocarcinoma and squamous cell carcinoma in patients in the absence of lymph node metastasis (Table 4). Although we compared the prognoses of patients by age, postmenopausal state, presence of obesity, endometrial invasion, lymph-vascular space invasion, tumor size, wholepelvis irradiation, paraaortic node irradiation, and year of treatment in each group, the prognoses for adenocarcinoma were significantly poorer than those for squamous cell carcinoma (data not shown). Because the incidence of patients with adenocarcinoma receiving irradiation was much less than that of patients squamous cell carcinoma (Table 2), we also compared the prognoses of 12 patients with adenocarcinoma and 64 patients with squamous cell carcinoma who received irradiation with lymph node metastasis. These 76 patients did not receive chemotherapy in the primary treatment. The prognosis of adenocarcinoma (5-year overall survival, 58.3%; 5-year disease-free survival, 41.7%) was also significantly poorer than that of squamous cell carcinoma (84.1%, P ⫽ 0.002, and 81.0%, P ⫽ 0.003, respectively). While we analyzed the prognoses of 8

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TABLE 4 Comparison of Overall Survival and Disease-Free Survival of Pathologic Stage Ib Cervical Cancer between Squamous Cell Carcinoma and Adenocarcinoma Squamous a

Total

Overall survival Total Number of lymph nodes involved

Pathologic tumor size (mm) Disease-free survival Total Number of lymph nodes involved

Pathologic tumor size (mm)

n

5 years

0 1 ⱖ2 ⱕ40 ⱖ41

509 422 38 49 455 54

94.0 97.1 97.3 65.3 95.7 78.6

0 1 ⱖ2 ⱕ40 ⱖ41

509 422 38 49 455 54

91.6 95.4 97.3 55.1 94.2 68.6

Pb

⬍0.001 ⬍0.001

⬍0.001 ⬍0.001

Adeno

n

5 years

n

5 years

Pc

405 337 31 37 363 42

95.5 97.9 100 70.3 97.2 80.4

104 85 7 12 92 12

88.0 93.9 85.7 50.0 90.0 71.6

⬍0.001 0.067 ⬍0.001 0.028 ⬍0.001 0.448

405 337 31 37 363 42

93.5 96.1 100 64.9 96.1 70.5

104 85 7 12 92 12

84.0 92.7 85.7 25.0 86.6 62.9

0.005 0.250 0.001 0.027 0.002 0.620

a

Squamous, squamous cell carcinoma; Adeno, adenocarcinoma. P value was calculated comparing difference between the variables. c P value was calculated comparing difference between squamous cell carcinoma and adenocarcinoma. b

patients with adenocarcinoma and 35 with squamous cell carcinoma who received irradiation with multiple lymph node metastases, the prognosis of adenocarcinoma (25.0 and 25.0%, respectively) was also significantly poorer than that of squamous cell carcinoma (71.4%, P ⫽ 0.042, and 65.7%, P ⫽ 0.034, respectively). DISCUSSION Adenocarcinoma is the second most common carcinoma of the uterine cervix, and the relative proportion of such adenocarcinomas has increased in recent years [2, 3]. Although some studies have reported that the prognosis of adenocarcinoma is poorer compared with squamous cell carcinoma [3, 11–14], the Gynecologic Oncology Group reported that histologic type had no significant effect on survival in clinical stage Ib disease [5, 6]. McLellan et al. also found that radical abdominal hysterectomy and pelvic lymphadenectomy was an appropriate treatment for stage I adenocarcinoma of the uterine cervix [18]. In our recent study, the 5-year survival of stage Ib adenocarcinoma was 87.7%, which was no worse than that of squamous cell carcinoma, in our previous study [15, 16]. To confirm these results, we compared the prognosis of adenocarcinoma of the uterine cervix with that of squamous cell carcinoma in this study. As multivariate analysis revealed, the results were quite the reverse of what we expected; adenocarcinoma was a significant prognostic factor in this study, though analyzed only in pathologic stage Ib. To investigate the reason for these results, we compared the incidence of clinicopathologic variables and the

prognosis of adenocarcinoma with that of squamous cell carcinoma. There was no difference in the incidence of lymph node metastases, number of lymph nodes involved, lymphvascular space invasion, tumor size, depth of invasion, or other variables that might influence the prognosis. Although the incidence of endometrial invasion in adenocarcinoma was higher than that in squamous cell carcinoma, this difference did not influence the other factors or the prognosis. However, in the examination of prognosis where lymph node metastasis was a prognostic variable, the difference was clear. The presence of lymph node metastasis worsened the prognoses of adenocarcinoma of the uterine cervix, although there was no difference between the prognosis of patients with adenocarcinoma and squamous cell carcinoma in the absence of lymph node metastasis. These results suggested that the difference in prognosis between adenocarcinoma and squamous cell carcinoma was caused by the distinction between the prognoses of the patients with lymph node metastasis. The poor prognosis associated with lymph node metastasis in early cervical cancer is consistent throughout the literature [3, 5–9, 11–16, 18], and adjuvant whole-pelvis irradiation has been performed for patients with metastasis in our hospital. But in the current study, the prognosis of patients with adenocarcinoma with lymph node metastasis was significantly poorer than that of patients with squamous cell carcinoma, though only those who received adjuvant irradiation were analyzed. These results suggest that adjuvant irradiation might be inadequate in improving the prognosis of patients with adenocarcinoma with lymph node metastasis. Although some studies

ADENOCARCINOMA AND SCC OF UTERINE CERVIX

have reported irradiation therapy as an effective treatment for adenocarcinoma [12, 19], recent studies have reported longer survival for patients with early-stage adenocarcinoma who are treated with radical surgery compared with radiation alone [5, 6, 13], suggesting the radioresistance and/or the frequency of distant metastasis of adenocarcinoma more than of squamous cell carcinoma. These characteristics of adenocarcinoma correspond well with the results of the poor prognosis of adenocarcinoma with lymph node metastasis, and the presence of lymph node metastasis was important in analyzing the prognosis of adenocarcinoma of the uterine cervix. Although some previous studies reported no significant difference in 5-year survival among squamous cell carcinoma and adenocarcinoma in clinical/pathologic stage Ib, the incidence of lymph node metastasis was less than that in the current study; Shingleton et al. [5] found that the incidence of metastasis with adenocarcinoma (including adenosquamous carcinoma) was 9.5%, Look et al. [6] reported 10.7%, and the current study reported 18.3%. Although Shingleton et al. [5] found that there was no difference in 5-year survival among patients with squamous cell carcinoma and adenocarcinomas, they stated that lymph node metastasis reduced the survival of adenocarcinoma. These findings suggest that differences in the incidence of lymph node metastasis caused the discrepancy in results. Thus, we considered that the prognosis of adenocarcinoma was poorer than that of squamous cell carcinoma in the presence of lymph node metastasis. CONCLUSION The independent significant risk factors for the recurrence and survival of pathologic stage Ib cervical cancer were the presence of lymph node metastasis, large tumor size beyond 4 cm, and histology of adenocarcinoma. Although the prognosis of patients with adenocarcinoma in the absence of lymph node metastasis was not different from that of patients with squamous cell carcinoma, the prognosis for adenocarcinoma was poor in the presence of lymph node metastasis. REFERENCES 1. Zheng T, Holford TR, Ma Z, Chen Y, Liu W, Ward BA, Boyle P: The continuing increase in adenocarcinoma of the uterine cervix: A birth cohort phenomenon. Int J Epidemiol 25:252–258, 1996 2. Miller BE, Flax SD, Arheart K, Photopulos G: The presentation of adenocarcinoma of the uterine cervix. Cancer 72:1281–1285, 1993 3. Hopkins MP, Morley GW: A comparison of adenocarcinoma and squamous cell carcinoma of the cervix. Obstet Gynecol 77:912–917, 1991

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