Ayhan, Ali MD*; Gultekin, Murat MD*; Taskiran, Cagatay MD*; Salman, Mehmet Coskun MD*; Celik, Nilufer Yigit MD*; Yuce, Kunter MD*; Usubutun, Alp MD*; Kucukali, Turkan MD†
The purpose of initial surgical treatment in epithelial ovarian cancers is correct detection of intraperitoneal and retroperitoneal metastatic involvement.1–5 The appendix is an intraperitoneal organ in 95% of the cases and prone to metastatic involvement by epithelial ovarian cancers.6 Both the location, which is close to the paracolic spaces where the ascitic fluid is drained, and proximity to the right ovary may contribute to its invasion by the tumor. Although some authors emphasize the importance of appendectomy in patients with mucinous ovarian cancers, debate is continuing on whether to perform routine appendectomy in all patients.2–16 In the published literature, only a few studies evaluated the role of appendiceal involvement in epithelial ovarian cancers, all of which had many important limitations in assessing the exact role of appendectomy. This lack of data prompted us to analyze the importance of appendectomy in patients with epithelial ovarian cancers to demonstrate the possible relationship with the clinicopathologic variables and also to assess the role of appendiceal involvement for both the upstaging of early stage disease and to accomplish optimal cytoreduction.
MATERIALS AND METHODS
The patients treated for epithelial ovarian cancers including appendectomy as part of their surgery in Hacettepe University Hospital between 1981 and 2001 were retrospectively evaluated. Data were obtained from hospital records, special gynecologic oncology files, and medical and pathologic reports. Patients with concomitant tumors or a past history of cancer were excluded from the study group. Overall, 314 patients had appendectomy as a part of surgery. Ten patients who had appendectomy in a second-look procedure and 19 patients who received preoperative chemotherapy at another center were also excluded, leaving 285 patients meeting inclusion criteria. Patients who did not have an appendectomy for other reasons (prior appendectomy, personal preference of the surgeons) and the patients with incomplete clinicopathologic data were all excluded from the final analysis. All patients were subjected to initial surgical staging procedure according to the recommendations of the International Federation of Gynecology and Obstetrics. Of the 285 patients, 278 (97.5%) were treated with total abdominal hysterectomy, bilateral salpingo-oophorectomy, total omentectomy, and bilateral pelvic para-aortic lymphadenectomy. The remaining 7 (2.5%) patients with early stage disease were subjected to fertility-saving surgery.
Appendiceal involvement was divided into 2 groups: gross and microscopic. As prognostic factors, age at diagnosis, stage, histologic cell type, grade, peritoneal cytology (negative compared with positive), ascites (absent, < 1,000 mL, and ≥ 1,000 mL), Ca-125 levels (< 35, 35–500, and > 500 U/mL), maximal primary tumor diameter (<10 cm compared with ≥ 10 cm), site of the tumor (bilateral or right- or left-sided tumoral involvement), and the cytoreductive success (optimal if residual tumor volume < 1 cm) were tested for significance. Because one of the important points is microscopic metastasis, after excluding the patients with gross involvement the same comparisons were made to define a subset of patients who are at risk of microscopic appendiceal metastasis and so could benefit from an appendectomy as a part of cytoreductive effort. Patients with microscopic appendiceal involvement without any evidence of other gross or microscopic metastasis were considered to be upstaged due to the isolated appendiceal metastasis. All the paraffin blocks were reviewed by a single pathologist.
Statistical analyses were performed with SPSS 10.0 (SPSS Inc., Chicago, IL) software. Categorical data were compared by χ2 and Fisher exact tests. Continuous variables were tested for significance by Student t test. Multivariate analysis was performed by logistic regression in a forward stepwise fashion. Significance was accepted when the P value was < .05.
Overall, 106 (37%) patients had appendiceal involvement. Of these patients, 27 (25.4%) had only microscopic metastasis, whereas 79 patients (74.6%) had gross involvement. Clinicopathologic characteristics of the patients are listed in Table 1. The mean age at the time of diagnosis was 52 (range 19–88) years, without a significant difference between the groups (53.4 ± 13.5 years compared with. 51.2 ± 13.5 years, P = .18). The patients were distributed by stage as follows: 25.3% stage I, 10.5% stage II, 57.2% stage III, and 7.0% stage IV. Appendiceal metastasis was detected in 2.8% of patients with apparent stage I disease (no gross intra-abdominal metastasis other than appendix). This rate increased to 26.7% in apparently stage II disease, 54.0% in stage III, and 40.0% in stage IV disease (P < .001).
Of these 285 patients, 150 (52.6%) had serous, 53 (18.6%) had mucinous, 25 (8.8%) had endometrioid, 13 (4.5%) had undifferentiated, 10 (3.5%) had Brenner, 10 (3.5%) had clear cell, and 24 (8.5%) had mixed tumors. With respect to histopathologic diagnosis, there was no significant difference with appendiceal involvement (P = .39). Appendiceal involvement was found in 18.2%, 33.8%, and 48.2% of patients with grade I, II, and III tumors, respectively (P < .001). There was no significant difference in patients without ascites or ascites less than 1,000 mL (31.9%, and 31.3%, respectively). However, in patients with ascites of 1,000 mL or more, the appendiceal metastasis incidence increased to 50.6%, and this difference was statistically significant (P = .01). Presence of malignant washings or ascites were associated with 46.8% appendiceal metastasis, whereas the patients with negative cytology had 29.3% appendiceal involvement (P = .006). Appendiceal metastasis was seen in 20.0% of patients with Ca-125 levels of less than 35 U/mL. This rate increased to 33.7% in patients with Ca-125 level between 35 and 500 U/mL (P = .02), and further increased to 50.5% in patients who had Ca-125 level greater than 500 U/mL (P < .001). Optimal cytoreduction was accomplished in 211 patients (74%). Appendiceal metastasis rate almost doubled in suboptimal group (58.1% compared with 29.9%; P < .001). Maximal primary tumor diameter was less than 10 cm in 158 patients (55.4%), and 10 cm or greater in 127 patients (44.6%). The appendiceal involvement rates in the former and latter groups were 43% and 29.9%, respectively (P = .023). Appendiceal involvement was 46.9% in 192 bilateral tumors, 19.2% in 52 right-, and 14.6% in 41 left-sided tumors. Only bilateral involvement affected appendiceal involvement significantly (P < .001). In multivariate analysis, where the factors found to be significant on univariate analysis (stage, grade, ascites ≥ 1,000 mL, positive cytologic washings, Ca-125 levels, cytoreductive success, maximal tumoral diameter, and the laterality of the tumors) were evaluated, stage was the only factor to be significant for the appendiceal metastasis (P = .02, odds ratio [OR] 12.7, 95% confidence interval [CI] 2.5–64.4 for stage II compared with. Stage I, P < .001, OR 41.0, 95% CI 9.7–173.0 for stage III compared with. Stage II and P < .001, OR 23.3, 95% CI4.4–123.4 for Stage IV compared with. Stage III).
To explore the importance of microscopic appendiceal metastasis, a second analysis was performed excluding the patients with gross involvement. In univariate analysis, stage, grade, ascites, cytology, Ca-125 level, and site of the tumor were found to be significantly related with the microscopic appendiceal metastasis (Table 2). In multivariate analysis of these significant factors, only the presence of ascites was found to be an independent predictor of microscopic involvement (P = .03, OR 2.5, 95% CI 1.1–5.9).
Of the 7 patients with microscopic appendiceal involvement in stage I-II disease, 1 had microscopic omental metastasis, and 1 had microscopic lymph node involvement in addition. Therefore, the remaining 5 patients were upstaged only due to isolated microscopic appendiceal involvement (5/102; 4.9%).
Comprehensive surgical staging and the optimal or maximal cytoreduction are the most important objectives of treatment in epithelial ovarian cancers. Ovarian cancer has a well-established widespread peritoneal dissemination.1–3 Although the surface of the appendix constitutes less than 1% of the peritoneal cavity, it is suggested as a frequent metastatic site. In this study, 37.0% of patients had appendiceal involvement. In patients with stage III-IV disease, this figure increased to 40–54%. This was in close accordance with our previous study,8 which included 65 patients with stage III-IV. epithelial ovarian cancer with a 49.2% appendiceal involvement rate. Sonnendocker,17 who was the first to demonstrate the high frequency of appendiceal involvement in epithelial ovarian cancers, reported an 83.3% metastatic rate in his small study of 12 stage III-IV patients. In subsequent reports by Rose et al,5 Malfetano,6 and Takaç,18 similar high rates were also reported in stage III-IV disease (69.7%, 69–75%, and 54.2%, respectively).
Gross involvement of the appendix was seen in 74.8% (80/107) of the patients with metastasis, and this finding was parallel to the 68% gross involvement rate reported by Rose et al.5 In the study of Fontanelli et al7 this rate was 88.3%. Removal of such appendices were thought to aid in the cytoreductive effort by many authors. Such an approach is mandatory to resect all tumoral implants optimally and to enhance the response of the tumor to chemotherapy.3,5,6,19
One of the main purposes of this study was to detect the rate of microscopic appendiceal involvement and also to evaluate a possible relation with clinicopathologic variables. Previous reports had focused on the presence or absence of appendiceal metastasis rather than stratifying the data for microscopic metastasis. Because gross metastasis may usually be visible intraoperatively and managed accordingly, defining the risks for the microscopic metastasis will bring more useful practical information for clinicians. Overall, 27 patients (25.4%) had microscopic metastasis. Stage, grade, presence of ascites, positive cytology, high Ca-125 level, and tumor laterality were found to be significant predictors of microscopic appendiceal involvement. In the multivariate analysis, only the presence of ascites was found to be independently related to appendiceal metastasis. This may be explained by the close relationship of the appendix to the drainage pathway of the ascitic fluid through the paracolic space.
The role of microscopic involvement in upstaging is another topic that should be discussed. Malfetano6 and Fontanelli et al7 reported 5% and 11.7% microscopic appendiceal involvement, respectively. However, none of these patients was upstaged in either of these studies, because all had gross metastatic intra-abdominal involvement. Rose et al5 found 33.3% microscopic involvement, but the patients who were assumed to be upstaged also had microscopic omental metastases. Likewise, Bese et al19 observed microscopic involvement in 8% of patients; however, all had intra-abdominal metastatic spread, therefore none of these patients was upstaged. In our previous report, the patients with epithelial and nonepithelial ovarian tumors were analyzed together; and 7.3% of patients were upstaged due to appendiceal involvement.8 In the current study, only the patients with epithelial ovarian cancer were considered, and 6% (7/102) of 102 stage I-II patients were found to have microscopic appendiceal involvement. Of these patients, 5 (4.9%) had no metastasis at another localization and were upstaged only because of appendiceal involvement. This finding may justify appendectomy in early stage patients, to provide effective therapy.
In this study, there was no significant relationship between appendiceal metastasis and histopathologic subgroup. On the contrary; Fontanelli et al7 and Rose et al5 reported significantly more appendiceal involvement in patients with serous histology. A significant upward tendency for appendiceal involvement was found in our study by grade. Although the grade was shown as a significant determinant of appendiceal involvement in some studies, this relationship was not observed in others.5,7,18,19 Malignant ascites was found to be associated with appendiceal metastases in 2 previous reports.7,19 In our study, positive peritoneal cytology and ascites of more than 1,000 mL were found to be significantly related to appendiceal involvement in univariate analysis (P = .006, and P = .01 respectively). Presence of ascites was also a significant determinant in multivariate analysis for microscopic metastasis. In this report, a Ca-125 level higher than 500 U/mL was also found to be significantly related to appendiceal metastasis (P < .001).
Bilaterality of the tumor was found to be a significant determinant of appendiceal involvement (P < .001). There was no significant difference between the patients with unilateral right and left tumors (P = 0.56). Although it did not reach a significant value, Fontanelli et al7 reported a higher prevalence of appendiceal involvement in patients with right-sided tumors (16.1% compared with 7.6%).
This study includes a relatively larger number of patients compared with the previous reports where a multivariate analysis was performed. Stage was found to be the single most significant factor determining the appendiceal metastasis in the multivariate analysis.
Additionally, appendectomy per se may have some mild benefits in staging procedures by giving a chance to detect some other incidental pathologies.12–14 In our previous report8 4 patients were found to have primary appendiceal carcinoma. Appendicitis secondary to the metastatic cancer has also been reported.11 Besides the detection of incidental pathologies, appendectomy has also a prophylactic value for possible acute appendicitis, which has a high morbidity and mortality in these elderly patients.20 This will also help clinicians in the discrimination of appendicitis-related acute abdomen from intestinal obstruction, which is the one of the most common events in the follow-up period of patients with epithelial ovarian cancers.
In conclusion, according to our findings, routine appendectomy may be justified in all epithelial ovarian cancer patients as part of the initial surgical staging procedure because of a considerable rate of upstaging in early stage disease and for an optimal cytoreduction in advanced stages. More studies dealing with this subject are needed for definite recommendations, especially evaluations of the prognostic and therapeutic role of appendectomy.
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