Clinical characteristics of the patients with ovarian strumal diseases
A total of 275 (2.14%) patients with ovarian strumal diseases were identified in 12,864 patients diagnosed with ovarian teratomas. The median age of the patients was 43 years (range: 17–92). Two hundred and twenty-nine patients (83.3%) were diagnosed with SO, being the most predominant pathologic subtype. Notably, OSC was less common, occupying 12.0% (33 cases) and MSO was rarely seen in only 4.7% (13 cases) in this cohort (Table 1).
Combined imaging examinations, including ultrasound, CT and MRI, and serum tumor markers, were examined preoperatively to determine the nature of tumor. Most patients were considered as benign diseases, while only 6 cases manifested obvious malignant features. The median tumor size was 6.4 cm. Two patients (0.7%) had bilateral ovarian strumal diseases and 6 cases (2.2%) presented metastatic diseases at initial diagnosis. Ascites and elevated tumor markers were observed in 16.0% and 26.2% of cases, respectively. Some patients had more than one abnormal tumor marker. In this cohort, CA125 and CA19-9 were the two most frequently elevated tumor markers found in 59 (21.5%) and 22 (8.0%) patients, respectively. One-way ANOVA and χ2/Fisher’s exact test showed no statistical differences in terms of age, tumor sizes, the proportion of preoperatively suspected malignant, elevated tumor markers, and ascites.
The details of the surgery and adjuvant therapy were described in subsequent subgroup analyses. During a median follow-up time of 5.3 years (range: 0.25–32.2), 9 patients had disease relapse. Of them, four patients underwent surgery, while the other five patients chose to follow up. At the final follow-up, 94.6% of the patients were alive with no evidence of disease (NED), 2.5% of them were alive with the disease (AWD), and 2.5% of them died of other diseases. Only one tumor-related death related to tumors occurred (DOD) (Fig. 1f).
Patients with SO
The median age was 43.0 years (range: 17–92), and predominantly affected patients were aged between 30 and 59 years (152 cases, 66.4%), but it was almost equally distributed in a 10-year interval. A large tumor size (≥ 10.0 cm) was detected in 39 (17.03%) patients, and a tumor size of over 15 cm was noted in 10 (4.37%) patients. Moreover, an 18-year-old girl had the largest tumor of 50 cm, originating from the right ovary. Only 5 patients were successfully preoperatively diagnosed with SO by imaging study, of which three patients were examined by ultrasound and the rest were by MRI (Table 1).
Although SO presented a right ovarian predominance (57.2% originated in right ovary), there were two patients had bilateral SO and one presented metastatic SO at their initial presentation. Elevated tumor markers were noted in approximately one-fourth of patients. Furthermore, the values of both CA125 and CA19-9 could be remarkably high that up to 2263.5 U/ml and 480.0 U/ml, respectively. Importantly, SO in 141 patients (61.6%) was pure without any other teratoma components. However, SO with adenomatous proliferation was noted in 15 cases (6.6%) in the overall cohort, including 3 cases of local adenomatous hyperplasia. Co-existence of other non-teratoma tumors in the ipsilateral ovary was rare and only found in 10 cases (4.4%), where endometrioma and cystadenoma were the most common pathology (Fig. 1a). However, SO with synchronous contralateral tumors was more frequent that found in 29 patients, of which mature teratoma (18 cases) was the most predominant (Fig. 1b). Besides, the mean Ki-67 index was nearly 2% in 26 patients who reported this item, with the highest value of only 8% and 92.3% (24/26) of patients had a Ki-67 index not more than 3%. However, no significant correlation could be found between a higher Ki-67 index and aggressive behavior of SO, such as metastasis.
Ovarian cystectomy was the most common treatment option administered in 40.6% of patients, followed by H/BSO (29.3%), USO (21.8%), and BSO (4.4%) (Fig. 1c; Table 1). Nonetheless, nine (3.9%) patients underwent comprehensive staging surgery, of which four were due to coexisting gynecologic cancer, and one due to a recurrent bilateral mucinous borderline ovarian tumor, and the rest four patients because of the uncertain intraoperative frozen pathology. Intraoperative frozen pathology was administered in 79 (34.5%) patients, of whom 61 (77.2%) was diagnosed with SO, and benign teratoma was identified in other 12 cases, but the rest 6 cases reported undetermined results or could not exclude malignancy. Two patients received postoperative adjuvant therapy due to coexisting rectal cancer.
Recurrence was suspected in 6 patients, but 4 patients presented ovarian cysts and chose to follow up without intervention. The other two patients developed metastatic SO at the peritoneum 11 years after the first surgery and at the anterior mesorectum 14 years after initial treatment, respectively. Surgical excision was then conducted, and they both achieved NED. After a median follow-up of 5.6 years (range: 0.4–32.2), all patients were alive, except seven patients who died of other diseases.
Patients with OSC
In this cohort, OSC mostly affected women aged in the fourth decade (10 cases, 30.3%), followed by patients aged over 50 years (9 cases, 27.3%). Most OSC (78.8%) patients were preoperatively diagnosed with benign tumors. However, the mean carcinoid size (0.44 cm) was much smaller compared with the mass size (6.7 cm). All OSCs were unilateral diseases confined to the ovary and no carcinoid syndrome was noted (Table 1). Furthermore, 48.5% of the OSC contained only SO and carcinoid componence (pure OSC), and none coexisted with the ipsilateral or contralateral non-teratoma component. The Ki-67 index was reported in 18 patients, showing an extremely low value that the mean value was 2% and only three patients had a Ki-67 index of 5%.
USO was the most common surgical option administered in 39.4% of patients, followed by H/BSO (24.3%), ovarian cystectomy (21.2%), and comprehensive staging surgery (12.1%). Only 1 case (3.0%) underwent BSO (Fig. 1d). Notably, four patients received USO after a previous ovarian cystectomy that confirmed the diagnosis of OSC. Two patients were treated with platinum-based chemotherapy postoperatively, of whom one was due to coexisting ovarian adenocarcinoma.
The survival outcomes were excellent in the OSC patients. They all obtained NED and none experienced recurrences a median follow-up period of 3.1 years (range: 0.25–25.9).
Patients with MSO (thyroid cancer arising in SO)
Imaging examinations had poor diagnostic efficiency in MSO patients, such that 11 (84.6%) patients were initially diagnosed with benign tumors, and the other two patients were suspected of epithelial ovarian carcinoma. Asymptomatic pelvic mass or ovarian cyst was the most common manifestation in these patients. The thyroid function test was within normal range.
The thyroid cancer components only occupied a small portion (0.6 cm) of the ovarian mass (mean size of 7.1 cm). At primary diagnosis, elevated thyroglobulin (TG) level was noted in one patient (7.7%) who had metastatic disease. However, three patients who had recurrent diseases showed remarkable higher TG levels, of whom two had TG > 1000 ng/ml. Conversely, the TG levels in these three patients were normal at primary diagnosis. Ten patients had MSO confined to the ovary at initial diagnosis, whereas the other three patients had metastatic diseases. Papillary thyroid carcinoma (PTC) was the most common pathologic subtype (6 cases, 46.2%), followed by follicular thyroid carcinoma (FTC) (5 cases, 38.5%). Follicular variants of PTC (FVPTC), mixed PTC and FTC were two less common subtypes that were identified in each patient. The mean Ki-67 index was about 5% in 7 reported cases, of which six patients exhibited no more than 5%, and one patient had the highest value of 15%. A genetic test was conducted inone patient with extensive metastatic disease and NRAS mutation was detected. Coexisted PTC in the neck was also found in one patient.
In patients with MSO, USO remained the most common surgical option administered in 61.5% (8 cases) of patients, including three patients who underwent USO after ovarian cystectomy. One patient who had multiple metastases in the peritoneum and left acetabulum underwent ovarian cystectomy, metastasectomy, and bone biopsy without adjuvant therapy to preserve fertility. One patient was treated with H/BSO. Staging/cytoreductive surgery was applied to three patients, of which one received USO followed by staging surgery (Fig. 1e). However, no intraoperative frozen pathology was applied in MSO patients and they all established the diagnosis by paraffin pathology. Lymphadenectomy was conducted in four patients, but all were negative. At initial treatment, adjuvant therapy was administered in 6 patients, including platinum-based chemotherapy in 5 patients and total thyroidectomy (TT) followed by radioiodine therapy (RAI) in another patient.
Eleven patients achieved NED after initial treatment and two were AWD. The patient who preserving fertility had successfully conceived and delivered at full term. In this patient, regular monitoring of serum TG showed a normal level, and imaging examinations of the thyroid and abdominopelvic cavity revealed stable disease. The patient with NRAS mutation metastasized to the liver and lung but maintained stable after receiving four courses of RAI. During the follow-up, three patients relapsed, with a 5-year and 10-year RFS rate of 88.9% and 71.1%, respectively, and the median RFS was 17.0 years. Repeat optimal cytoreductive surgery was administered in two patients who had multiple peritoneal metastases but showed a poor response to chemotherapy. One patient who developed multiple seedings in the peritoneum, liver, lung, and mediastinum eventually succumbed to the disease. The other patient received TT followed by RAI at 4 years after ceasing chemotherapy but showed only a partial response. The third patient who had disease recurrence in the lung 17 years after the first surgery, she achieved NED for more than 10 years after administered four courses of RAI.
After a median follow-up of 6.2 years (range: 0.8–29.0), the 10-year OS and DSS rates were both 75.0%, with only one death occurring 9.5 years after the diagnosis (Figure S2). Other nine patients achieved NED and three were AWD.