OBJECTIVE: To evaluate the detailed clinicopathologic characteristics of parametrial spread in uterine endometrial cancer.
METHODS: We retrospectively identified 334 individuals with uterine endometrial cancer who had undergone radical hysterectomy between 1988 and 2007. Parametrial spread was determined by histopathological analysis of surgically resected specimens.
RESULTS: Twenty-eight (8.4%) individuals had histopathologically confirmed parametrial spread, and lymphatic or blood vessel invasion (22 cases) was the most frequently observed type of parametrial spread; direct invasion to parametrial connective tissue (five cases) or cardinal lymph node metastasis (four cases) were less frequently observed. Parametrial spread occurred not only in individuals with cervical involvement but also in individuals with more than half myometrial invasion, retroperitoneal (pelvic, paraaortic, or both), lymph node metastasis, ovarian metastasis, positive peritoneal cytology results, and lymphovascular space invasion. Twenty-six individuals (92.9%) with parametrial spread showed more than one of these histopathological factors (median number of factors 3, range 1–6); the other two individuals had lymphovascular space invasion alone. In 10 individuals with parametrial spread (35.7%), the condition recurred during the median follow-up period of 49 months, and initial recurrence was observed in the lung in six individuals (60.0%). Although the long-term prognosis for those with parametrial spread was significantly poorer than that of those without parametrial spread, both among all individuals (P<.001) and among individuals with International Federation of Gynecology and Obstetrics stage III (P<.05), multivariate analysis showed that parametrial spread was not an independent prognostic factor for uterine endometrial cancer.
CONCLUSION: Parametrial spread cannot be predicted by cervical involvement alone but may be predicted by various lymphovascular space invasion-related histopathologic factors. Further, parametrial spread may not be an independent prognostic factor in individuals with uterine endometrial cancer.
LEVEL OF EVIDENCE: III
Parametrial spread in endometrial cancer may not be predicted by cervical involvement alone, but by various risk factors related to lymphovascular space invasion.
From the Departments of Obstetrics and Gynecology and Pathology, Kinki University School of Medicine, Osaka, Japan.
See related editorial on page 1016 and related articles on pages 1035 and 1141.
The authors thank Dr. K. Noda, honorary president of Japanese Gynecologic Oncology Group, honorary president of Kinki University, for his suggestions on the histopathologic characteristics of parametrial spread.
Corresponding author: Yoh Watanabe, MD, PhD, Department of Obstetrics and Gynecology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osakasayama, Osaka 589-8511, Japan; e-mail: email@example.com.
Financial Disclosure The authors did not report any potential conflicts of interest.
Parametrial spread in uterine endometrial cancer has been thought to be predicted by cervical involvement; therefore, both the National Comprehensive Cancer Network Practice Guidelines in Oncology (version 2, 2009)1 and the Endometrial Cancer Treatment Guidelines of Japan Society of Gynecologic Oncology2 recommend radical hysterectomy when the individuals show uterine endometrial cancer with cervical involvement. However, a recent survey among members of the Japanese Gynecologic Oncology Group regarding the status of surgical treatment procedures for endometrial cancer3 has revealed that 35.5% of the member institutions of the Japanese Gynecologic Oncology Group performed only simple total hysterectomy, and 70.5% never performed radical hysterectomy in the cases of endometrial cancer. Although detailed investigation of the clinicopathologic characteristics of parametrial spread in uterine endometrial cancer should be performed to safely omit radical hysterectomy, only four studies on parametrial spread in uterine endometrial cancer have been found in the English literature.4–7 Moreover, the actual incidence and detailed clinicopathologic characteristics of uterine endometrial cancer with parametrial spread are still unknown, because the previous studies had assessed only individuals with International Federation of Gynecology and Obstetrics (FIGO) stage II disease or included individuals who were treated using modified radical hysterectomy. Therefore, although recent studies have reported that minimally invasive surgeries, such as laparoscopic surgery, can be safely performed in gynecologic malignancies, especially in individuals with uterine endometrial cancers,8–11 radical hysterectomy should still be performed as a standard surgery in individuals with uterine endometrial cancer with cervical involvement.
In this regard, we were able to examine the detailed characteristics of parametrial spread in individuals with uterine endometrial cancer because we have been routinely performing pelvic nerve-sparing radical hysterectomy12,13 as a standard surgical procedure for individuals with endometrial cancer, except those with endometrioid adenocarcinoma without myometrial invasion, aged older than 80 years, uncontrollable complications such as diabetes mellitus or cardiac disease, peritoneal macroscopic tumor spread, or stage IV disease. We performed a retrospective study to evaluate the clinicopathologic characteristics and histopathological predictive factors of parametrial spread in individuals with uterine endometrial cancer who were treated using radical hysterectomy.
MATERIALS AND METHODS
We used clinical records to retrospectively review 334 individuals with endometrial cancer who were treated by pelvic nerve-sparing radical hysterectomy at Kinki University Hospital from January 1988 to December 2007. Further, histopathologic specimens of surgically resected tissues were independently rediagnosed by two pathologists who were completely blinded to the clinical information of the individuals. For accurate diagnosis, we had obtained routine histopathologic specimens of parametrial spread by performing the following procedures when the individuals underwent radical hysterectomy: bilateral parametrial tissues were removed immediately after radical hysterectomy and fixed separately; and paraffin-embedded specimens of the surgically resected parametrial tissues were used to prepare three to five serial histopathological sections stained with hematoxylin and eosin.
Pelvic lymph node dissection was performed in all cases, and the pelvic lymph node dissection included the common iliac, external iliac, internal iliac, obturator, supra-inguinal, sacral, and cardinal lymph nodes. Paraaortic lymph node (paraaortic lymph node) dissection was selectively performed in the cases in which preoperative magnetic resonance imaging or intraoperative macroscopic findings indicated more than 50% myometrial invasion and the cases in which pelvic lymph node or paraaortic lymph node swelling was diagnosed by preoperative computed tomography, magnetic resonance imaging, or intraoperative direct palpation. Paraaortic lymph node dissection was performed in the region inferior to the inferior mesenteric artery, up to the renal artery, or both of these.
Furthermore, postoperative adjuvant therapy was indicated in the individuals, except for those with International Federation of Gynecology and Obstetrics (1988) stage Ia disease or stage Ib disease without lymphovascular space invasion.
A standardized computer software package was used for statistical analysis. We used χ2 test and considered P<.05 as statistically significant. Further, we used the logistic regression test (stepwise, backward selection, conditional method) for multivariate analysis. This study was approved as a retrospective study by Ethical Committee of Kinki University Faculty of Medicine.
The clinicopathologic characteristics of the 334 individuals are shown in Table 1. All individuals underwent pelvic nerve-sparing radical hysterectomy, pelvic lymph node dissection, and analysis of peritoneal cytology. Paraaortic lymph node dissection was performed in 170 (50.9%) individuals, and one individual did not undergo oophorectomy. The histological subtype, histological grade, depth of myometrial invasion, presence of cervical involvement, parametrial spread, and lymphovascular space invasion were determined in all the individuals. On the basis of the histopathological analysis, 308 (92.2%) individuals had endometrioid adenocarcinoma diagnosed; among these, 226 (67.7%) cases were grade 1, 72 were grade 2, and 36 were grade 3. On the basis of FIGO surgical staging, 224 cases (67.1%) were stage 1, 16 were stage 2, and 94 were stage 3. Postoperative adjuvant therapies were performed in 173 (51.8%) cases, and adjuvant chemotherapy was the most frequently performed treatment.
Table 2 shows the histopathologic characteristics of the patients. Parametrial spread was observed in 28 (8.4%) individuals. Further, myometrial invasion, pelvic lymph node metastasis, ovarian metastasis, cervical involvement, positive peritoneal cytology results, and lymphovascular space invasion were observed in 317 (94.9%), 40 (12.0%), 21 (6.4%), 46 (14.1%), 54 (16.6%), and 110 (33.7%) individuals, respectively. Although paraaortic lymph node dissection was performed in 170 individuals, paraaortic lymph node metastasis was observed in only 16 (4.8%) individuals.
On the basis of histopathological assessments, parametrial spread was classified into lymphatic and blood vessel involvement (Fig. 1A), direct invasion to parametrial connective tissue (Fig. 1B), and cardinal lymph node metastasis (Fig. 1C), and these forms of parametrial spread were observed in 22 cases (78.6%), five cases, and four cases, respectively.
Table 3 shows the correlation between histopathologic factors and parametrial spread in the 28 individuals with parametrial spread. Parametrial spread was significantly correlated with FIGO stage III, more than 50% myometrial invasion, retroperitoneal lymph node metastasis, ovarian metastasis, cervical involvement, positive peritoneal cytology results, and lymphovascular space invasion, whereas parametrial spread did not show any significant correlation with the histologic grade.
Figure 2 shows the detailed histopathologic characteristics of individuals with parametrial spread. The frequencies of each histopathologic factor in individuals with parametrial spread were as follows: tumor with grade 2 or higher, 35.7% (13 cases); more than 50% myometrial invasion, 67.9% (19 cases); pelvic lymph node or paraaortic lymph node metastasis, 50.0% (14 cases); ovarian metastasis, 17.9% (five cases); cervical involvement, 39.3% (11 cases); positive peritoneal cytology, 39.3% (11 cases); and lymphovascular space invasion, 100% (28 cases). Twenty-six individuals (92.9%) had multiple histopathologic factors; the median number of histopathologic factors was three (range 1–6). Two individuals (cases 4 and 26) had only lymphovascular space invasion. One individual (case 17) showed direct invasion to parametrial tissue and cardinal lymph node metastasis and one individual (case 25) showed direct invasion to parametrial tissue, cardinal lymph node metastasis, and lymphatic and blood vessel involvement. We observed seven parametrial spread-positive cases even among individuals with stage I. Although four cases had more than 50% myometrial invasion and lymphovascular space invasion, the other three cases showed only lymphovascular space invasion. Furthermore, in the histopathological analysis, none of the individuals with stage I showed the direct-invasion form of parametrial spread.
The outcomes are as follows: 26 individuals died because of disease progression, 13 died because of another cause, and four were alive with recurrent disease. The outcomes of patients with parametrial spread during the median follow-up period of 49 months (range 6–216 months) are shown in Table 4. All the individuals with parametrial spread received postoperative adjuvant therapy and 10 (35.7%) individuals showed recurrence. The most frequent site of recurrence was the lung (six individuals), and the median time to progression was 7 months (range 2–42 months). Long-term prognosis of parametrial spread by Kaplan-Meier analysis is shown in Figure 3. Individuals with parametrial spread had significantly poorer prognoses, among both all individuals (Fig. 3A; P<.001) and individuals with FIGO stage III (Fig. 3B, P<.05). However, multivariate analysis showed that, although individual age and pelvic lymph node metastasis predicted outcome, parametrial spread was not an independent prognostic factor in individuals with uterine endometrial cancer who had undergone radical hysterectomy (Table 5).
Individuals with uterine endometrial cancer with cervical involvement have been undergoing radical hysterectomy for sufficient excision of the vaginal wall and the effective cardinal ligament to prevent vaginal stump and parametrial recurrences.14–17 Furthermore, several studies18–22 have reported the superiority of radical hysterectomy in the treatment of FIGO stage II uterine endometrial cancer with cervical involvement. However, the detailed clinicopathologic features of parametrial spread in uterine endometrial cancer were still unknown. Parametrial spread was predicted only by cervical involvement, and radical hysterectomy should be performed only for uterine endometrial cancer with cervical involvement. On the basis of the results of these previous studies, the understanding of parametrial spread in uterine endometrial cancer can be summarized. First, parametrial spread in uterine endometrial cancer occurs as a result of causes similar to those of uterine cervical adenocarcinoma with endometrial invasion. Second, radical hysterectomy should be performed only for FIGO stage II because parametrial spread is predicted by cervical involvement. Third, parametrial spread is not observed in individuals with FIGO stage I disease. However, our present study has revealed that although parametrial spread was associated with cervical involvement in 21.3% of the individuals, none of the individuals with stage II had parametrial spread. Furthermore, although parametrial spread occurred even in stage I, histopathologic assessments in these individuals revealed lymphovascular space invasion or cardinal lymph node metastasis.
Table 6 summarizes the results of four previous retrospective studies,4–7 including our present study on parametrial spread in uterine endometrial cancer. Interestingly, although the reported frequency of cervical involvement ranged from 39.3% to 75.0%, the dominant histopathologic type of parametrial spread was not direct invasion but lymphatic involvement or lymph node metastasis. Moreover, Gadducci et al23 studied individuals with FIGO stage I-II endometrioid type of uterine endometrial cancer and showed that lymphovascular space invasion and outer one-third myometrial invasion were independent predictive variables for the risk of distant hematogenous failure.
These results suggest that parametrial spread in uterine endometrial cancer may occur because of different processes associated with uterine cervical cancer. These results also elucidated why parametrial spread was a prognostic factor in univariate analysis but did not show any significant correlation in multivariable analysis. Moreover, radical hysterectomy for stage II uterine endometrial cancer may not improve individual prognosis if parametrial spread in uterine endometrial cancer is a type of multiple spread caused by disease progression. Therefore, parametrial spread in uterine endometrial cancer would be predicted not by cervical involvement but by clinical factors related to lymphovascular space invasion, which is known as a predictive factor of tumor spread and prognosis for uterine endometrial cancer,24–27 such as deep myometrial invasion. Furthermore, parametrial spread was observed only in endometrioid histology in the present study. In this regard, additional studies are required to determine the correlation between histologic subtypes and parametrial spread in uterine endometrial cancer, because only 7.8% of the individuals showed nonendometrioid histology in our study. However, previous studies have reported that the histological type is not a significant predictive factor of parametrial spread4 in uterine endometrial cancer.
Although several previous studies28–31 have reported that radical hysterectomy improved the prognosis for uterine endometrial cancer with positive parametrial spread (surgical stage II), the accuracy of preoperative examination to determine cervical involvement has remained within 29.6%32 to 45%.33 Therefore, the majority of individuals with clinical stage II uterine endometrial cancer have undergone surgical overtreatment.
Our results imply that radical hysterectomy should not be performed for individuals with cervical involvement alone, except when the preoperative inner pelvic examination shows obvious parametrial invasion. However, parametrial lymph node dissection should be considered if parametrial lymph node swelling or deep myometrial invasion is suspected by preoperative magnetic resonance imaging findings.
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