The incidence of ONETs is extremely low, and the result of this study is consistent with the fact which is 0.49%. The patients were mainly in productive ages with the mean age being 38.4 years. Previous studies have reported that ovarian neuroendocrine carcinoma could also occur after menopause[6, 7]. Abdominal pain and a pelvic mass are the most common symptoms, which concurs with the findings of previous studies, suggesting these tumors lacked specific clinical manifestations. Patients have no symptoms in the early stage of the disease. Like other ovarian malignant tumors, early detection is difficult. ONETs tend to be solid and cystic, bilateral, and large. Most patients (6/10) presented with advance disease at the time of diagnosis, which was consistent with the literature. It suggested the tumors have an aggressive clinical behavior with a high tendency to metastasize distant organs. However, none of the cases had retroperitoneal lymph node metastasis, which seemed to imply a low rate of lymph node metastasis in ONETs. There has been no reported on the rate of lymph node metastasis in the published literature.
US and CT usually lack specific findings in ONETs cases. A research suggested different morphological features on the magnetic resonance imaging (MRI) may indicate these rare malignant tumors. However, it is far from enough to make a diagnosis by imaging test alone. In this study, serum CA-125 levels were elevated in most cases (8/10) at the time of diagnosis. It seemed to indicate a link between CA-125 and these tumors. Studies have confirmed that CA-125 level is closely related to epithelial ovarian cancers and can be used for the monitoring and diagnosis of epithelial ovarian cancers[10, 11]. Therefore, further study is needed to analyzed the relationship between CA-125 and ONETs. Ascitic fluid cytology was also performed, and only two cases found malignant cells in ascites or peritoneal lavage fluid, suggesting that it may be difficult to identify malignant cells derived from ONETs in ascitic fluid. Therefore, histopathological analysis of tissue specimens is crucial for the diagnosis of ONETs.
While most ONETs can be recognized on H༆E staining, immunohistochemistry is required to confirmed the diagnosis. The results of immunohistochemistry showed tumors expressed at less one neuroendocrine marker such as Cg-A, CD56 or Syn. These markers were commonly used in most practices[12, 13]. In our study, CD56 seemed to be the most sensitive marker in demonstrating neuroendocrine nature of these tumors and was expressed in all cases. But CD56 lacked specificity because it was also expressed by nonendocrine tissues such as renal tubules, ovarian sex cord-stromal, and thyroid follicular cells[14–16]. Therefore, some authors did not recommend using CD56 alone to demonstrate neuroendocrine components[12, 14]. Syn seem to be more sensitive than Cg-A. As seen in our cases, Syn was either wore widely expressed than Cg-A or was positive when Cg-A was negative. Some cases also expressed cytokeratin, which might be useful to confirm the epithelial nature of the tumors. According to the previous study, immunohistochemical markers were useful for the differential diagnosis of ONETs. Organ related markers used for this such as thyroid transcription factor-1 (TTF-1) for the thyroid and lung, islet-1 (ISL-1) for pancreas, PAX-8 for the thyroid, and CDX-2 for the gastrointestinal tract.
At present, the primary treatment for ONETs is usually surgical resection with adjuvant chemotherapy, but there is still no standard guideline. The purpose of surgical resection is to obtain negative margins. A recent study indicated surgery significantly improved survival rates and complete surgical resection should be recommended as the primary modality. In previous stage III/IV cases, most patients firstly underwent open surgery for diagnosis and treatment, and sometimes it was difficult to perform satisfactory primary debulking surgery (PDS), resulting in deterioration of patients′ general condition and worse prognosis[6, 9, 12]. In our study, one case accepted diagnostic laparoscopy, finding that complete PDS cannot be performed. The patient received neoadjuvant chemotherapy followed by internal debulking surgery (NACT-IDS). The role of diagnosis laparoscopy for patients with advanced-stage ovarian cancer have been reported[19, 20], and these studies will be helpful in offering a similar method for ONETs. Some patients diagnosed with ONETs are of childbearing age and are willing to undergo fertility-sparing surgery. However, fertility-sparing surgery has been controversial. Small case series have reported patients undergoing USO and adjuvant chemotherapy achieved good result[21, 22]. Another study reported 26 patients underwent USO and none of the patients had a subsequent successful pregnancy. In our study, two patients accepted fertility-sparing surgery. One patient who underwent BSO relapsed after 5 months of treatment and died 10 months later, and the other patient who underwent USO recurred 12 months after the end of treatment. The result was terrible. In addition, postoperative chemotherapy may also affect their ovarian function. Therefore, further research is needed to determine whether fertility-sparing surgery is reasonable for patients with ovarian neuroendocrine carcinoma.
Present adjuvant therapies are based on data arising from pulmonary or ovarian literature, including chemotherapy and radiation. In this study, 60% of patients who treated with EP recurred, and 80% patients who received PT relapsed. 50% recurred within 6 months of chemotherapy, which suggested that these tumors might respond poorly to chemotherapy. Yang et al reviewed sporadic case reports, and their study did not confirm survival benefits from chemotherapy. Two patients who received EP have been followed up for 24 and 27 months, without disease. The paucity of data suggests that EP chemotherapy may benefit patients. Due to the limited data, the efficacy of the two chemotherapy regimens cannot be statistically analyzed, and there is also no relevant research in the literature. In this study, only one patient received radiation therapy, which may be partly due to the low rate of radiation use to treat ovarian carcinoma histology. The patient has been followed up for 48 years, and there is no imaging evidence that the tumor has recurred. The role of radiotherapy in the treatment of ONETs is largely unknown, but several reports have suggested a potential benefit[25, 26]. Radiotherapy is worthy being further explored in ONETs. At present, there were few studies on targeted therapy in ONEETs. In this study, one patient with BRCA2 germline mutation was maintained with PARP inhibitors (Olaparib). The patient did not benefit from Olaparib and recurred after 4 months.