Clinical Features of Borderline Ovarian Seromucinous Tumor

T hirty-two patients with ovarian BSM T were included. T he patients’ median age was 45 years (range= 22-72 years), and 25 out of 32 patients (78%) were premenopausal (Table I). Lower abdominal pain was the most common symptom (13 patients, 40.6%), but about one-third of patients were asymptomatic (n= 11, 34.4%) and were diagnosed during a medical check-up. In five patients (15.6%), malignant tumor was suspected based on ultrasound during follow-up for endometriosis. O ne patient presented with abnormal genital bleeding. In two patients, the chief complaint was unknown. Twenty-two patients (68.8%) had no history of pregnancy. Preoperative serum carbohydrate antigen 19-9 (CA19-9) levels were elevated in 19 cases (59%), and serum CA125 was elevated in 15 (47%) cases. Twelve patients (37.5%) had elevated levels of both CA19-9 and CA125, whereas in 10 patients (31.3%), both tumor markers were within normal limits. Endometriosis was diagnosed in 25 cases (78.1%) based on preoperative transvaginal ultrasonography and imaging studies. O perative details and results are shown in Table II. O f 32 patients, 12 (37.5%) underwent staging laparotomy (bilateral salpingo-oophorectomy, total abdominal hysterectomy, and omentectomy), followed by lymph node biopsy or dissection. Four patients underwent bilateral salpingo-oophorectomy, total abdominal hysterectomy, and omentectomy. Sixteen patients underwent tumorectomy or unilateral salpingo- oophorectomy to preserve their fertility. Intraoperative consultation was performed in 28 patients; 26 were diagnosed with borderline tumor, and two were borderline tumors or carcinoma. T he tumors varied in size, ranging from 2.5 to 20 cm, with a median of 6.4 cm. Tumor was unilateral in most cases (78.1%). H istological examination confirmed coexistent endometriosis in 30 patients (93.7%); it was in the ipsilateral ovary in 24 (80%) and in the contralateral ovary and pelvic peritoneum in addition to the ipsilateral ovary in six (20%). T hirty cases were stage I, and only two cases were diagnosed as stage II. Follow-up information was available for all 32 patients, with a range of 1-211 months (median= 71 months). O nly two (6.3%) had recurrences; one only underwent tumorectomy initially, and unilateral salpingo-oophorectomy and omentectomy were performed when BSM T recurred in the ipsilateral ovary 8 years later. In another patient, the initial surgery was staging laparotomy to prove stage IIB BSM T with noninvasive peritoneal implants and a concurrent endometrial endometrioid carcinoma grade 1 (pT 1apN 0). H er ovarian BSM T had both exophytic and intracystic growth, with the latter having a micropapillary component. She also had a mesenteric mass and enlarged para-aortic lymph nodes found intraoperatively; these were pathologically proven to be follicular lymphoma. Fifteen months after the initial surgery, another mesenteric tumor was found, and the resected tumor was grade 1 endometrioid carcinoma with an BSM T component. Paclitaxel/carboplatin chemotherapy regimen was unsuccessful, and the patient died 2 years and 7 months after the initial surgery.

Although histological and genetic characteristics of BSM T have been reported, there are few characteristic biomarkers, and it is not easy to estimate BSM T clinically. T herefore, it is important for the surgeon to know the clinical characteristics such as fluctuating tumor markers and frequent complications of endometriosis, as well as the gross appearance of the explanted specimen. Regarding tumor markers, this study showed that the serum CA19-9 level is often elevated in patients with BSM T (59.4%); this finding was only given limited attention in previous reports. Indeed, in 19 out of 32 patients with elevated serum CA19-9 level in this study, in five it exceeded 1,000 U/ml, and the highest was 3,471 U/ml. CA19-9 is best known as a useful marker for mucinous tumors of the pancreas and biliary tract, with a relatively high sensitivity and specificity. It is localized in the pancreatic and biliary parenchyma (6). CA19-9 is also elevated in various diseases, including mucinous ovarian tumors, teratoma, endometriosis, benign hepatic and pulmonary diseases, thyroiditis, diabetes mellitus, and autoimmune diseases (6). Its elevation is explained by inflammation and proliferation of non-tumorous tissues or metabolic malfunction. BSM T is histologically characterized by neutrophilic infiltration into the stroma and epithelium, and these inflammatory findings in tumors may be associated with an elevated serum CA19-9 level. Regarding the relationship of serum CA19-9 to the histological subtypes of ovarian tumors, N akagawa et al. reported that the serum CA19-9 levels in patients with borderline ovarian mucinous tumors and endometriotic cysts were significantly elevated compared with those in control individuals and that CA19-9 can be useful for preoperative evaluation (7). It is CANCER DIAGNOSIS & PROGNOSIS 3: 360-364 (2023) 361 particularly interesting that serum CA19-9 levels were higher in those with endocervical type tumors, which corresponds to the current definition of BSM T, than in the intestinal type. BSM T is frequently associated with endometriosis, as shown in literature (3, 4, 8) and in the present study, and is usually accompanied by prominent neutrophil infiltration, thus it may be responsible for CA19-9 elevation. H owever, in some cases in this study, serum CA19-9 was not elevated despite the presence of endometriosis or neutrophil infiltration in tumors. T he mechanism of this elevation requires further investigation. BSM T is included in endometriosis-related ovarian neoplasms, along with clear-cell carcinoma and endometrioid carcinoma (8). In this study, 25 patients (78.1%), including five who had endometriotic cysts, had preoperative imaging studies indicating the presence of endometriosis. In 93% (30/32) of patients with surgically removed ovaries, a histological diagnosis of coexistent endometriosis was found; this was more frequent than what was previously reported. O f the 30 patients with endometriosis, six (20%) had endometriosis in the contralateral ovary or pelvic peritoneum. O ne possible reason for the higher frequency of coexisting endometriosis in this study is the number of tissue sections taken at our institution, which was at least one section per 1 cm of tumor diameter. In this study, two patients (6.3%) had recurrence. While the recurrence rate of borderline ovarian tumors is 5-33% generally (9), H ada et al. reported a rate of 18% for BSM T, suggesting that the association with endometriosis may be a factor that increases recurrence (10). Ren et al. reported that conservative surgical procedures, cyst rupture, advanced International Federation of O bstetrics and G ynecology stage, microinvasion, and peritoneal implants are risk factors for N agayoshi et al : Clinicopathological Factors of BSM T 362 Table I. Characteristics of patients in this study (n=32 patients). Characteristics N (%) Age, years M edian (range) 45 (22-72) <40 Years 10 (31.2%) ≥40 Years 22 (68.8%) M enopausal status Premenopausal 25 (78.1%) Postmenopausal 7 (21.9%) Chief complaint Abdominal pain 13 (40.6%) N o symptoms 11 (34.4%) Endometriosis* 5 (15.6%) O ther 1 (3.1%) Unknown 2 (6.3%) Parity 0 22 (68.8%) ≥1 10 (31.2%) Preoperative serum tumor markers CA19-9 ≤37.0 U/ml 13 (40.6%) > 37.0 U/ml 19 (59.4%) M edian (range), U/ml 169 (42-3,471) CA125 ≤35.0 U/ml 17 (53%) > 35.0 U/ml 15 (47%) M edian (range), U/ml 198 (38-10,035) CA19-9/CA125 Positive for both 12 (37.5%) N egative for both 10 (31.3%) Endometriosis* Yes 25 (78.1%) N o 4 (12.5%) Unknown 3 (9.4%) Recurrence Yes 2 (6.3%) N o 30 (93.7%) *H istory, ultrasound/magnetic resonance imaging findings. Table II.Operative details and results. N (%) Surgical procedure, n (%) Staging laparotomy a 12 (37.5%) Standard laparotomy b 4 (12.5%) Fertility-sparing staging laparotomy c 16 (50%) Intraoperative diagnosis, n (%) Benign 0 Borderline 26 (81.3%) Carcinoma 0 Borderline/carcinoma 2 (6.2%) N ot made 4 (12.5%) Tumor size, cm M edian (range) 6.4 (2.8-20) Site of tumor, n (%) Unilateral 25 (78.1%) Bilateral 7 (21.9%) Yes 30 (93.7%) Endometriosis*, n (%) Ipsilateral 24 (80%) Contralateral or pelvis 6 (20%) N o 2 (6.3%) Stage, n (%) I 30 (93.8%) IA 18 (56.3%) IB 3 (9.4%) IC d 9 (28.1%) II 2 (6.2%) III-IV 0 *H istologically confirmed in the surgical specimens. aBilateral salpingo- oophorectomy with hysterectomy, omentectomy, lymph node biopsy or lymphadenectomy. bBilateral salpingo-oophorectomy with hysterectomy, omentectomy. cUnilateral salphingo-oophorectomy and tumorectomy or bilateral tumorectomy with or without omentectomy. dN on-invasive implant present. recurrence of BSM T (11). Another report showed a recurrence rate of 14-20.5% with conservative surgery compared to 0-7% with radical surgery (12). In fact, one of the patients with recurrence in the present study only underwent tumorectomy initially. It is noteworthy that one patient in our study whose initial surgery was staging laparotomy to prove stage IIB BSM T with non-invasive peritoneal implants and pT 1apN 0 developed peritoneal carcinoma at the time of recurrence. It is possible that the non-invasive peritoneal implant progressed to cancer; another possibility is that ovarian or peritoneal diseases had a carcinoma component, which was not pathologically detectable. Koskas et al. reported that three cases of endocervical-like borderline mucinous tumors and mixed- epithelial borderline tumors, which are currently called BSM T, recurred during a 10-year follow-up, with two recurring as invasive carcinomas (13). It is known that 2-3% of borderline ovarian tumors develop as invasive carcinoma at the time of recurrence (14, 15). In a review of 130 cases of borderline malignancies, including those who underwent conservative surgery, O h et al. reported 11 (8.5%) recurrences; four cases recurred as borderline malignancies, while seven cases had a histological diagnosis of carcinoma (9). Based on these reports, it is more likely that the non- invasive peritoneal implant progressed to cancer in our patient. Although borderline ovarian tumors are generally considered to have a favorable prognosis and survival rates, which do not differ significantly among histological types (16), it should be noted that rare BSM Ts of advanced stages may develop as cancer in the peritoneum and result in a poor prognosis. When only performing tumorectomy or unilateral salpingo-oophorectomy in a patient with BSM T for fertility sparing, it is essential to understand that BSM T is often associated with endometriosis in the ipsilateral ovary or other foci in the pelvis; this may result in tumor recurrence, either as borderline tumor or carcinoma. T his study has several limitations. O ne is that the follow- up period (median= 6 years) is not long enough for borderline tumors given that one patient had recurrence 8 years after the initial surgery. A larger study of BSM T with a longer follow-up should be carried out. T he accumulation of such studies will help elucidate the exact clinical features of this disease. Secondly, as mentioned previously, it was not possible to identify the mechanism of CA19-9 elevation. Finally, we only focused on clinical features of patients with BSM T, and no molecular analysis was performed. In previous studies, gene mutations of cancer-related genes, such as of KRAS proto-oncogene, G T Pase (KRAS), AT-rich interaction domain 1A (ARID1A), and phosphatidylinositol- 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, were reported in BSM T, suggesting that molecular analysis may clarify the biological characteristics, development, and progression of this entity (4, 17, 18). In summary, BSM T can occur in a wide range of age groups (19, 20), and it can be identified based on symptoms associated with pelvic masses or discovered incidentally without any symptoms (21, 22). T he preoperative diagnosis of BSM T is often difficult because of variable clinical findings, but a history of endometriosis and elevated serum CA19-9 level may aid in some cases. Conflicts of Interest T he Authors have no conflicts of interest to declare. Authors’ Contributions Yoko N agayoshi and Kyosuke Yamada designed this study. Yoko N agayoshi wrote the initial draft of the article. Takafumi Kuroda and Daito N oguchi collected the data. N ei Fukasawa and Takako Kiyokawa reviewed hematoxylin and eosin-stained slides to confirm the histological type of tumors based on WH O 2020 criteria. Yoko N agayoshi contributed to the analysis and interpretation of data and assisted in the preparation of the article. Aikou O kamoto critically reviewed the article and made revisions. All other Authors have contributed to data collection and interpretation and critically reviewed the article. All Authors approved the final version of the article and agreed to be accountable for all aspects of the work by ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

T he article was edited by Enago (www.enago.jp) for English language review. T he Authors would like to thank the staff of the Department of O bstetrics and G ynecology and Department of Pathology, T he Jikei University School of M edicine H ospital for their support and cooperation.

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Cancer 61(3) : 546-554, 1988. PM ID: 3338022. DO I: 10.1002/1097-0142(19880201)61:3 3.0.co;2-i Received February 19, 2023 Revised March 4, 2023 Accepted March 6, 2023 N agayoshi et al : Clinicopathological Factors of BSM T 364