Clinicopathological analysis of giant ovarian tumors.

Renata Alya Ulhaq: Writing – review & editing, Project administration. Hanif Ardiansyah Sulistya: Writing – review & editing. Brahmana Askandar Tjokroprawiro: Writing – original draft, Supervision, Methodology, Conceptualization. Khoirunnisa Novitasari: Writing – original draft, Formal analysis, Data curation.

The authors declare no funding for this study.

Sixty-three patients with ovarian tumors > 20 cm in size were included in this study. The patients underwent surgery at Dr. Soetomo Academic Hospital, Surabaya, Indonesia. The average patient age was 38 years (11–66 years). The histopathological tumor type in the youngest patient was embryonal cell carcinoma, and that in the oldest patient was granulosa cell tumor. The average tumor size was 25.9 cm (20–41 cm). The average tumor sizes were 26.61 and 24.91 cm for malignant and benign tumors, respectively. There was no significant difference in tumor size between benign and malignant giant ovarian tumors (p = 0.261; Table 1 ). Table 1 Bivariate analysis between malignancy and tumor size. Table 1 Malignant (Mean + SD) Benign (Mean + SD) P value Tumor size 26.61 + 5.74 24.91 + 6.1 0.261 * Patient's age 38.17 + 14.39 37.29 + 12.03 0.841 * * Independent t-test Bivariate analysis between malignancy and tumor size. Independent t-test Based on histopathological results, among the 63 giant ovarian tumors, 42 were malignant (66.67 %), 17 were benign (26.98 %), and four were borderline (6.35 %). Among the 13 patients with non-epithelial malignant ovarian tumors, the most dominant type was granulosa cell tumors in five patients (38.5 %), followed by yolk sac tumors in four patients (30.8 %), and an immature teratoma, dysgerminoma, embryonal cell tumor, and mixed tumor in only one patient for each type (7.7 %) ( Table 2 ). Table 2 Descriptive data of giant ovarian tumors. Table 2 Variable N (%) of all Patient's age 10-20 y.o 7 (11.11 %) 21-30 y.o 13 (20.63 %) 31-40 y.o 16 (25.40 %) 41-50 y.o 13 (20.63 %) 51-60 y.o 10 (15.87 %) > 60 y.o 4 (6.36 %) Malignancy Benign Borderline Malignant 17 (26.98 %) 4 (6.35 %) 42 (66.67 %) Endometriosis (7) Mucinous (4) Serous (3) Mature teratoma (3) Serous (2) Mucinous (2) Epithelial (29) Non-Epithelial (13) Tumor type Epithelial 47 (74.60 %) Non-epithelial 16 (25.40 %) Involved adnexa Left adnexa 43 (68.25 %) Right adnexa 20 (31.75 %) Descriptive data of giant ovarian tumors. We used FIGO ( The International Federation of Gynecology and Obstetrics ) staging type for classification. Among the 42 patients with malignant giant ovarian tumors, 28 were in stage I (66.7 %), 10 in stage II (23.8 %), 3 in stage IV (7.14 %), and 1 in stage II (2.38 %). Based on histopathological types, among the 42 patients with malignant ovarian tumors, 29 (69.05 %) had epithelial malignant ovarian tumors, and 13 of them were non-epithelial type (30.95 %). Seventeen patients had malignant ovarian tumors that were mucinous type (40.48 %) ( Table 3 ). Table 3 Descriptive data of malignant giant ovarian tumors. Table 3 Variable N (%) of all % of each histopathological type Stage Stage I 28 (66.67 %) Stage II 1 (2.38 %) Stage III 10 (23.81 %) Stage IV 3 (7.14 %) Histopathological type Epithelial (29) Serous 5 (11.90 %) (17.24 %) Mucinous 17 (40.48 %) (58.62 %) Endometrioid 2 (4.77 %) (6.9 %) Clear cell 5 (11.90 %) (17.24 %) Non-Epithelial (13) Immature Teratoma 1 (2.38 %) (7.7 %) Granulosa cell tumor 5 (11.90 %) (38.5 %) Dysgerminoma 1 (2.38 %) (7.7 %) Yolk Sac Embryonal cell 4 (9.53 %) 1 (2.38 %) (30.8 %) (7.7 %) Mixed tumor 1 (2.38 %) (7.7 %) Descriptive data of malignant giant ovarian tumors. Of the 63 giant ovarian tumors, 43 originated from the left (68.2 %) and 20 originated from the right (31.8 %) adnexa. There were no significant differences in patient age (p = 0.511), tumor size (p = 0.168), malignancy (p = 0.303), or histopathological type (p = 0.232) between either adnexal side ( Table 4 ). Table 4 Analysis between involved adnexal side, patient's age, and tumor characteristics. Table 4 Type Right Left P-value Patient's age 40.55 + 14.07 37.60 + 14.04 0.511 * Tumor size 25 (20-40) 25 (20-41) 0.168 ** Malignancy • Benign • Malignant • Borderline 3 (4.8 %) 16 (25.4 %) 1 (1.6 %) 14 (22.2 %) 26 (41.3 %) 3 (4.8 %) 0.303 # Histopathological type • Epithelial 13 (20.6 %) 7 (11.1 %) 34 (54 %) 9 (14.3 %) 0.232 ## • Non-Epithelial * Independent t-test ** Man-whitney # Kruskal-wallis test ## Chi-square test Analysis between involved adnexal side, patient's age, and tumor characteristics. Benign Malignant Borderline Epithelial Non-Epithelial Independent t-test Man-whitney Kruskal-wallis test Chi-square test Only patients under 30 years old were assessed for all tumor markers, including CA125, CEA, LDH, beta-hCG, and AFP, among all the study samples. Due to cost constraints, patients over 30 years old are only tested for the tumor marker CA125, not for any additional tumor markers ( Table 5 ; Table 6 ). Table 5 Characteristic of tumor markers level giant ovarian tumor under 30 years old. Table 5 No. Histopathology CA125 CEA LDH Beta-hCG AFP 1. clear cell carcinoma 78,50 1,97 248,00 0,59 1,30 2. endometrioma 33140,00 2,59 165,00 0,30 1,60 3. mixed germ cell 431,50 < 0,5 1906,00 0,50 27,60 4. mucinous carcinoma 71,70 0,05 168,00 0,20 1,40 5. mucinous carcinoma 50,70 3,72 551,00 0,20 1,30 6. endometrioma 291,00 1,07 225,00 0,30 0,90 7. endometrioma 366,40 1,64 207,00 0,40 0,40 8. mucinous carcinoma 116,50 5,24 208,00 0,30 1,66 9. dysgerminoma 230,00 < 0,5 6185,00 190,40 1,30 10. mucinous borderline 104,60 2,00 160,00 0,30 1,40 11. yolk sac tumor 125,00 0,50 405,00 3307,00 78019.2 12. immature teratoma 170,50 12,52 185,00 0,30 21,80 13. mucinous carcinoma 136,80 10,10 194,00 0,20 1,40 14. yolk sac tumor 341,10 1,18 541,00 0,20 3467,90 15. yolk sac tumor 282,65 1,00 187,00 0,30 23813,50 16. mature teratoma 14,60 8,24 162,00 0,20 20,60 Table 6 Statistic distribution of tumor markers level giant ovarian tumor under 30 years old. Table 6 Mean Median Minimum Maximum SD CA125 2246,97 153,65 14,6 33140 8239,07 CEA 3,30 1,80 0,05 12,52 3,79 LDH 731,06 207,50 160 6185 1516,76 Beta- hCG 218,86 0,3 0,2 3307 824,87 AFP 6586,45 1,5 0,4 78019,20 19953,29 Characteristic of tumor markers level giant ovarian tumor under 30 years old. Statistic distribution of tumor markers level giant ovarian tumor under 30 years old. Non-epithelial type ovarian tumors had increased levels of beta-hCG, AFP, and LDH. Epithelial and non-epithelial ovarian cancers significantly differ in AFP levels ( Table 7 ). Table 7 Bivariate analysis between histopathology and tumor markers. Table 7 Epithelial Median (min-max) Non Epithelial Median (min-max) P value CA125 116,5 (50,7-33140) 230 (14,6-431,5) 0536 CEA 2,0 (0,05-10,10) 1,0 (0,5-12,52) 0408 Beta-hCG 0,3 (0,2-0,59) 0,3 (0,2-3307) 0470 AFP 1,4 (0,4-1,66) 27,6 (1,3-78019,2) 0005 LDH 207 (160-551) 405 (162-6185) 0351 *Man-Whitney test Bivariate analysis between histopathology and tumor markers. *Man-Whitney test Due to the lack of comprehensive tumor marker data, we decided to concentrate on a study of CA125 values. The average CA125 level was 864.98 units/mL (13.86–33140 units/mL). CA125 levels did not differ significantly between malignant and benign giant ovarian tumors (p = 0.604). There was no correlation between tumor size and CA125 levels in giant ovarian tumors (p = 0.308). A significant difference was observed between CA125 levels and the involved adnexal side (p = 0.010). Right adnexal involvement showed higher CA125 levels in the tumor (mean: 1871.95 unit/mL) compared to those with left adnexal involvement (mean: 396.62 unit/mL) ( Table 8 ). Table 8 Analysis between Ca125 level and tumor characteristics. Table 8 Malignant Median (Min-Max) Benign Median (Min-Max) P-value CA125 level 138.5 (23.57-6554.3) 71.9 (13.86–33140) 0.604 * Right Left CA125 level 147.35 (13.86-33140) 128.94 (14.6-6554.30) 0.010 * Tumor size of malignant tumor Median (Min-Max) CA125 level 138.5 (23.57-6554.3) 0.308 ** * Man-Whitney test ** Pearson correlation test Analysis between Ca125 level and tumor characteristics. Man-Whitney test Pearson correlation test

This study was an observational study of all patients with giant ovarian tumors at Dr. Soetomo Hospital Surabaya in Indonesia between January 2020 and June 2022. We observed several clinical parameters, including patient age, tumor size, involved adnexal side, CA125 level, tumor stage, and histopathological type. Data were collected from the medical records of patients diagnosed with giant ovarian tumors who underwent surgery in 2020–2022 at Dr. Soetomo Hospital in Surabaya, Indonesia. Only tumors with a diameter > 20 cm were considered giant and included in this study. All statistical analyses were performed using the Statistical Package for Social Scientists (SPSS) version 25 to assess the frequency distribution and bivariate analysis with an independent t-test. In accordance with the journal's guidelines, we will provide our data for independent analysis by a team selected by the Editorial Team for additional data analysis or the reproducibility of this study in other centers if requested. This study was approved by the ethics committee of Dr. Soetomo General Academic Hospital in Surabaya, Indonesia (registration number: 1635/104/4/IX/2022). The ethics committee of Dr. Soetomo General Academic Hospital waived the need for informed consent because of the study's retrospective nature. Patient confidentiality was guaranteed.

Clinical and pathological mapping of giant ovarian tumors is important for analyzing the incidence and prevalence among all patients with ovarian tumors, the clinical characteristics and size, side of adnexal involvement, and histopathological type. Understanding clinical trends and histopathology can provide an overview of the management and prognosis of patients with giant ovarian tumors. This study shows that most giant ovarian tumors are malignant and diagnosed at an early stage. They are commonly epithelial types and mostly involve the left adnexa. CA125 levels did not correlate with the size of malignant ovarian tumors.

Based on our findings, the majority of giant ovarian tumors are malignant and diagnosed at an early stage (stage I). Most lesions were epithelial and mucinous, with left adnexal involvement. There were no statistically significant differences between malignant and benign giant ovarian tumors in terms of tumor size, patient age, or CA125 levels. CA125 levels were also unrelated to tumor size. There were no significant differences in patient age, tumor size, histopathological type, or malignancy between left and right adnexal involvement; however, right adnexal involvement was associated with higher CA125 levels. There are no publications on the analysis of giant ovarian tumors at a specific age. Several case reports of giant ovarian tumors have been published, and the ages of patients in these reports varied from children to older women [11] , [16] . Based on this study, giant ovarian tumors may occur at any age from 11–66 years. The youngest patient's histopathological type was embryonal cell carcinoma, and the oldest was a granulosa cell tumor. The histopathological types in several reports of giant ovarian tumors in women > 60 years old were ovarian cystadenocarcinoma, benign serous cystadenoma, and metastatic adenocarcinoma from rectal cancer [16] , [17] . The mean age of patients with giant ovarian tumors in this study was 38 years. There have been no publications on the average age of patients with giant ovarian tumors. The size of an ovarian tumor does not determine its malignancy. Several tools for estimating the malignancy of ovarian cancer, such as the risk malignancy index and risk of ovarian malignancy algorithm, do not include tumor size as a parameter for predicting whether ovarian tumors are malignant [19] . The International Ovarian Tumor Analysis group's 10 Simple Rules for evaluation of adnexal lesions include tumor size as one of the parameters determining malignancy; however, in this calculation, size is not purely a determinant, but other parameters include size, namely the presence or absence of solid parts and unilocular or multilocular tumors [20] . Most giant ovarian tumors exhibit benign characteristics, with only a minority demonstrating malignant properties. To the best of our knowledge, only a limited number of studies have reported the presence of large malignant ovarian tumors [11] . Our findings showed that giant ovarian tumors can be benign or malignant, and most giant ovarian tumors in this study were malignant (67 %). In cases of ovarian cancer in younger patients, the symptoms that a patient encounters are impacted by the size of the tumor as well as its pathology. On the other hand, symptoms alone are not sufficient to determine the malignancy of the ovarian tumor. There is a high probability that a malignant ovarian tumor would be significantly larger than 10 centimeters, will be bilateral, and not well circumscribed [18] . Our study showed that most malignant giant ovarian tumors were stage I (66.7 %). Women with early-stage ovarian cancer have larger ovarian tumors than those with advanced-stage ovarian cancer [12] . One possible theory regarding this is that advanced-stage tumors spread when the tumor is still relatively small. In contrast, early-stage tumors develop locally and continue to grow in size without spreading to other tissues. Advanced ovarian cancer may produce substances that cause metastasis, whereas early-stage ovarian cancer may not secrete these substances. In this study, malignant ovarian tumors were primarily epithelial type (69 %), and only 31 % were non-epithelial. Epithelial ovarian cancer is more common than the non-epithelial type, and 95 % of ovarian malignancies are epithelial type [21] . To the best of our knowledge, no published studies have compared the proportion of epithelial and non-epithelial types among giant ovarian tumors. According to our study, both epithelial and non-epithelial ovarian cancers can develop into giant ovarian tumors. Our study showed that mucinous ovarian tumors were the most common type of giant malignant ovarian tumors (40.48 %), which is in accordance with the literature showing that mucinous ovarian tumors are usually large, with an average size of 18 cm [22] . The size of mucinous ovarian tumors can be used as an early indicator of whether the mucinous ovarian cancer is primary or metastatic. Most primary ovarian cancers are unilateral tumors of > 10 cm [22] . Our study confirms that mucinous ovarian tumors tend to be large, even if malignant. Molecular research has provided insights into several features of ovarian cancer, resulting in the categorization of epithelial-type ovarian cancer into two distinct types: type I ovarian cancer and type II ovarian cancer [23] . The subtypes of ovarian cancer classified as type I are low-grade serous, mucinous, endometrioid, and clear cell carcinoma. From a clinical perspective, Type I tumors are believed to manifest as large tumors, one-sided cystics that are limited to the ovary. These tumors are often considered low-grade, exhibiting less aggressive clinical behavior and a more favorable prognosis. There is a hypothesis suggesting that Type I neoplasms originate from non-cancerous lesions outside the ovaries, which then become embedded in the ovaries and eventually evolve into malignant tumors [24] . Type II epithelial ovarian cancer encompasses high-grade serous carcinomas, undifferentiated carcinomas, and carcinosarcomas [23] . Type II tumors have a higher level of aggressiveness, are typically detected at more advanced stages, and display a significant degree of genetic instability. Most of these tumors include mutations in the TP53 gene, and nearly half of the cases show mutations, hypermethylation, or malfunction in the breast cancer gene BRCA1/2 [23] . There is a widely held belief that certain Type II epithelial ovarian cancers (EOC) originate from aberrant cells in the fallopian tube lining known as serous tubal intra-epithelial lesions (STIL), which then evolve into serous tubal intra-epithelial carcinomas (STIC) [24] . In this study, type I were found in 60,31 % of giant ovarian cancers, and type II were counted in 14,28 % cases. Among giant non-epithelial ovarian tumors, granulosa cell tumors were the most common type (38.5 %). One study showed that the mean size of ovarian granulosa cell tumors was 11.8 cm (range: 5–27 cm) [25] . The second most common giant malignant ovarian tumor in our study was an endodermal sinus tumor. Another type of giant ovarian tumor is ovarian dysgerminoma, which can grow very rapidly and is very large, up to 50 cm in size, as shown in our study [26] . Borderline ovarian tumors can also be very large, and a case report showed a mucinous borderline ovarian tumor measuring 60 × 50 × 40 cm [27] . In our study, there were four borderline ovarian tumors (6 %), which is consistent with a systematic review by Grigore et al. that showed the proportion of borderline ovarian tumors was approximately 3.4 % of all ovarian tumors > 10 cm [13] . The laterality (right or left) of giant ovarian tumors has not been well studied. Several case reports have shown that giant ovarian tumors originate on the left side [11] , [28] , while other publications have reported that giant ovarian tumors originate from the right side [16] , [27] . Our study showed that most giant ovarian tumors (68.2 %) originated in the left ovary. From our findings, the origin of the tumor, whether from the right or left ovary, was not related to the malignancy of giant ovarian tumors. Furthermore, our findings showed that tumor size was unrelated to laterality or histopathological type. Our study showed that CA125 levels did not correlate with the size of giant malignant ovarian tumors. Prior research has not investigated the correlation between the size of malignant ovarian tumors and CA125 levels, as our study did. Only one study showed that a higher CA125 level was associated with larger borderline ovarian tumors [29] . Studies showed that CA125 levels are more strongly related to the prediction of successful cytoreductive surgery, metastasis, and survival [30] . Our study's comparative analysis of CA125 levels between benign and malignant giant ovarian tumors showed no significant differences. However, CA125 levels in malignant ovarian tumors tended to be higher than those in benign ovarian tumors. Another study on borderline ovarian tumors showed that tumor size positively correlated with CA125 levels [29] . This study analyzed only borderline tumors and did not include other histopathological types. In our study, CA125 levels do not correlate or predict tumor size but can be a predictor of treatment responses and survival. Due to financial constraints, our study could not analyze tumor markers other than Ca125. Consequently, tests for markers other than Ca125 were only conducted on patients under 30. Examination of tumor markers in individuals below the age of 30 revealed a notable disparity in AFP levels across epithelial and non-epithelial tumor types. High-grade serous ovarian cancer is the predominant form of epithelial ovarian cancer, accounting for 70 % of cases. Additionally, 90 % of all ovarian cancer cases are of the epithelial type [31] . Alterations in the fallopian tubes are a contributing factor to the development of high-grade serous ovarian cancer, beginning with the presence of serous tubal intra-epithelial carcinomas (STIC). Salpingectomy has been linked to a significant reduction in the risk of ovarian cancer, estimated to be over 80 % [32] . Research has shown that salpingectomy is a safe and cost-effective procedure that does not lead to an earlier onset of menopause. Additional research is required to determine if salpingectomy can effectively prevent particularly big ovarian cancer. Our study included all cases of giant ovarian tumors with a minimum diameter of 20 cm, providing a summary of the characteristics and features of giant ovarian tumors. Our study also evaluated the role of CA125 in giant ovarian tumors. The obvious limitation was that our study did not include survival as a parameter. Survival parameters were difficult to analyze because many patients lost follow-up and changed addresses/phone numbers during study periods. However, this did not significantly impact the study because we focused on clinical characteristics, not survival. In clinical practice, the findings of this study have immediate and tangible implications for the diagnosis and management of giant ovarian tumors. By examining these clinicopathological characteristics, practitioners can make more precise and individualized treatment decisions. This may improve patient outcomes and optimize therapeutic strategies. The findings of this study may also influence surgical techniques and postoperative care protocols. Given the complexity of ovarian tumors, a multidisciplinary approach represents the most effective way to care for patients. In particular, a medical oncologist must collaborate with a gynecologic oncologist, radiologist, pathologist, and other specialists, as it allows for the development of personalized care plans and prescriptions for each patient. Moreover, multidisciplinary team meetings and continuous patient experience discussions enable accurate diagnosis and treatment options [33] .

In 2020, 313,959 new cases of ovarian cancer were diagnosed worldwide, with an age-standardized incidence of 6.6 per 100,000 [1] . Of all ovarian malignancies, 88.4 % are epithelial cancers, and the most prevalent histological categories are mucinous (15 %) and serous (65.9 %) carcinomas [2] . Adnexal masses can be benign, borderline, or malignant, originating from the ovary and fallopian tubes [3] . Among the benign ovarian tumors, serous ovarian cystadenoma is the most common, followed by mucinous ovarian cystadenoma and dermoid [4] . Malignant ovarian tumors can be divided into epithelial ovarian cancer, germ cell tumors, sex cord-stromal tumors, and metastatic tumors [3] . Bloating, an enlarged abdomen, weariness, urinary tract problems, and pelvic or abdominal discomfort are the most common ovarian cancer symptoms [5] . Localized ovarian malignancies have few or no symptoms, which may delay the application of appropriate diagnostic imaging techniques [6] . The diagnosis of ovarian tumors can be confirmed by physical examination, ultrasonography, computed tomography, or magnetic resonance imaging. Suspicion of ovarian tumor malignancy can be assessed from radiological imaging of the tumor and elevated tumor markers such as cancer antigen 125 (CA125), carcinoembryonic antigen (CEA), beta human chorionic gonadotropin (Beta-hCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH) [3] , [7] . Surgery is the cornerstone of ovarian tumor management. Surgical staging is crucial for accurately determining the disease stage, the extent of surgery, and the need for adjuvant treatment [7] . An important objective of surgery for early-stage ovarian tumors is to determine the disease stage definitively. In contrast, an important aim of surgery for advanced-stage ovarian tumors is complete resection [8] . Tumor size is an important factor to consider when deciding on clinical treatment. Tumors with a diameter > 10 cm that cause complaints can be indicated for surgical treatment. Tumor size as a predictor of malignancy in ovarian tumors remains debatable. One study showed that including tumor size in the risk of malignancy index calculation did not increase performance, but another study showed otherwise [9] , [10] . Large ovarian tumors can be benign or malignant [11] . One study showed that early-stage ovarian cancer had a larger tumor size than advanced-stage ovarian cancer [12] . To date, there is no standard definition or parameter for large ovarian tumors. The ovarian tumor is considered large if the size is > 10 cm or above the umbilicus [13] . Another publication considered an ovarian mass between 5 and 15 cm as large, and if the diameter was > 20 cm, it was considered giant [14] . Histopathological analysis of large ovarian tumors showed that the most common type was a mature teratoma, followed by mucinous and serous cystadenomas. In contrast, another study showed that the most common type of larger ovarian tumor was a benign teratoma, followed by serous cystadenoma and endometriotic cysts [13] , [15] . Other case reports of large ovarian tumors have shown other histopathological types, including fibromas, seromucinous adenocarcinomas, and low-grade mucinous papillary cystadenocarcinomas [11] . Clinical and pathological mapping of giant ovarian tumors is important for analyzing the incidence and prevalence among all patients with ovarian tumors, the clinical characteristics and size, side of adnexal involvement, and histopathological type. Understanding clinical trends and histopathology can provide an overview of the management and prognosis of patients with giant ovarian tumors.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.