The incidence of ONETs is extremely low, and the result here complied with the fact of 0.49%. The cases were largely in productive ages with the mean age of 38.4 years. As reported by existing studies have reported that ovarian neuroendocrine carcinoma could also occur after menopause[6, 7]. Abdominal pain and pelvic mass refer to the main symptoms, complying the findings of existing studies, which suggested the mentioned tumors lack specific clinical manifestations. Cases have no symptoms at the early stage of the disease. Like other ovarian malignant tumors, early detection is difficult. O-NETs are progressively solid and cystic, bilateral, and large. Most cases (6/10) presented advanced-stage diseases during the diagnosis, which was consistent with the literature. It was therefore 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 O-NETs. The rate of lymph node metastasis has been rarely reported in the published literature.
On the whole, US and CT usually lack specific findings in ONETs cases. A research suggested that different morphological features on the magnetic resonance imaging (MRI) may indicate the mentioned rare malignant tumors. However, it is insufficient to make a diagnosis by imaging test alone. In this study, serum CA-125 levels increased in most cases (8/10) during the diagnosis. It seemed to indicate a link between CA-125 and these tumors. Existing studies confirmed that CA-125 level is closely related to epithelial ovarian cancers and can be exploited for the monitoring and diagnosis of epithelial ovarian cancers[10, 11]. Accordingly, further studies are required to analyze 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, which demonstrated that it may be difficult to identify malignant cells derived from O-NETs in ascitic fluid. Thus, histopathological analysis of tissue specimens is critical to the diagnosis of O-NETs.
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 least one neuroendocrine marker (e.g., Cg-A, CD56 or Syn). The mentioned markers have been applied in practices[12, 13]. In this study, CD56 was suggested as the most sensitive marker to demonstrate the neuroendocrine nature of the mentioned tumors, and it was expressed in all cases. However, CD56 lacked specificity since it was also expressed by nonendocrine tissues (e.g., renal tubules, ovarian sex cord-stromal, and thyroid follicular cells)[14–16]. For this reason, some authors did not recommend the use of CD56 alone to demonstrate neuroendocrine components[12, 14]. Syn seem to be more sensitive than Cg-A. According to the cases of this study, Syn was either wore widely expressed than Cg-A or was positive when Cg-A was negative. Besides, some cases expressed cytokeratin, which might help to confirm the epithelial nature of the tumors. Given the existing study, immunohistochemical markers could contribute to the differential diagnosis of O-NETs. 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 generally surgical resection with adjuvant chemotherapy, but there is still no standard guideline. Surgical resection aims to obtain negative margins. A recent study indicated that surgeries could significantly improve survival rates, and complete surgical resection should be recommended as the primary modality. In this study, one case accepted the diagnostic laparoscopy, which suggested that complete primary debulking surgery (PDS) could not be performed. The case received neoadjuvant chemotherapy followed by internal debulking surgery (NACT-IDS). The role of diagnosis laparoscopy for patients with advanced-stage ovarian cancer was reported[19, 20], and the mentioned studies will be help present a similar method for ONETs. Some patients diagnosed with O-NETs are of childbearing ages and 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 results[21, 22]. Another study reported 26 cases undergoing USO, and none of the cases had a subsequent successful pregnancy. In this study, two cases accepted fertility-sparing surgery. One case who underwent BSO relapsed after 5 months of treatment and died 10 months later, and the other case who underwent USO recurred 12 months after the end of the treatment. The result was not ideal. In addition, postoperative chemotherapy may affect their ovarian function. Accordingly, in-depth studies should be conducted to determine whether fertility-sparing surgery is reasonable for patients with ovarian neuroendocrine carcinoma.
Present adjuvant therapies refer to data from pulmonary literature, including chemotherapy and radiation. In this study, 60% of cases (3/5) who treated with EP recurred, and 80% of cases (4/5) who received paclitaxel/platinum relapsed. 50% recurred in 6 months of chemotherapy, which suggested that these tumors might respond poorly to the chemotherapy. Yang et al. reviewed sporadic case reports, and their study failed to confirm survival benefits from chemotherapy. Two cases who received EP have been followed up for 24 and 27 months, without any diseases. The paucity of data revealed 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 case received the radiation therapy, which might be partly due to the low rate of radiation use to treat ovarian carcinoma histology. The case has been followed up for 48 months, and it was not evidenced that the tumor recurred. The role of radiotherapy in the treatment of O-NETs remains largely unclear, whereas several reports have suggested a potential benefit[25, 26]. Radiotherapy is worth further exploring in O-NETs. At present, there have been few studies on targeted therapy in O-NETs. In this study, one case with BRCA2 germline mutation was maintained with PARP inhibitor (Olaparib). The case was not improved from Olaparib and recurred after 4 months. More cases are required to be recruited to study the role of PARP inhibitors in O-NETs.