The pathogenesis of primary O-NECs is not well understood. These tumors are primarily classified into three histological types: SCCs (hypercalcemic, pulmonary types), carcinoid (insular, trabecular, goiter, mucinous carcinoid, mixed types), and large cell NEC [1]. At present, there is limited clinical understanding regarding the incidence, histogenesis, treatment, and prognosis of this disease. In this report, we have described the various pathological features observed in patients with different pathological stages. We analyzed clinical history data, imaging data, and IHC results to summarize the prognosis of clinical treatment for these patients. Additionally, we analyzed long-term follow-up results to provide a reference for future clinical work and to improve patient prognosis.
Ovarian SCC is an extremely uncommon malignant tumor of the ovary. SCC (pulmonary type) is a subtype of ovarian SCC with neuroendocrine features. Patients with this type of cancer vary widely in age. The incidence of unilateral and bilateral ovarian tumors is almost equal. The tumor is predominantly solid, with a microscopic distribution of tumor cells arranged in nests or patches. The cells are smaller, have less cytoplasm, darkly stained nuclei, and inconspicuous nucleoli. The origin of the tumor is unclear, and its prognosis is poorly documented. Taraszewski et al. observed a postoperative survival time of approximately 18 months [2].
Patient 1 in this study was an elderly female with ovarian SCC (pulmonary type) who had already developed extra-ovarian involvement at the time of presentation. The microscopic pathological structural features were similar to the existing reports. The sample tested positive for CD56 and negative for Syn and CgA. Post-surgery, the patient received TC therapy (Taxol injection of 240 mg and Carboplatin 0.5 g) every 3 weeks for a total of 8 courses. The patient passed away 21 months after the surgery due to lymph node metastasis that occurred during the 16-month follow-up period. Ovarian SCC (pulmonary type) is a highly malignant tumor, and it is common to find extra-ovarian spread at the time of detection. Despite undergoing extensive surgical resection and receiving regular postoperative chemotherapy, the patient experienced rapid recurrence and extensive metastasis, ultimately resulting in death.
Most existing studies pertaining to O-NEC are primarily case reports. Cai et al. [3] reported a case of primary small cell O-NEC (pulmonary type) in a 65-year-old patient. A mass of approximately 20 cm in diameter was found in the pelvis. The tumor cells appeared lymphocyte-like, with scant cytoplasm and numerous mitotic figures under microscopy. IHC results: NSE (+), Syn (+), CgA (+), CD99 (+), Ki67 (70% +), Vimentin (-), LCA (-), CK (-), S-100 (-), CD10 (-), inhibin (-), CK7 (-), and EMA (-). Cancer infiltration was observed in the perimetrium, myometrium, endometrium, and serosal surface of both fallopian tubes, and it accumulated in the posterior wall of the bladder. The ultrasound revealed tumor recurrence during the 3-month postoperative follow-up.
Guo et al. [4] reported a case of a high-grade O-NEC (primary ovarian SCC, pulmonary type) in a 30-year-old patient. A 15 cm × 11 cm × 5 cm solid mass was found above the uterus. The tumor cells were arranged in an insular pattern. IHC results: CD56 (+), Syn (+), EMA (+), CgA (partially positive), Ki67 (70% +), CD99 (-), CK (-), Vimentin (-), Calretinin (-), α-inhibin (-), ER (-), and PR (-). The patient passed away four months after the surgery.
Niu et al. [5] reported a case of ovarian clear cell carcinoma with concomitant localized NEC in a 43-year-old patient. The patient had a cauliflower-like mass of approximately 13 cm in diameter with a poor and brittle texture, which was found in the right adnexa. IHC results: ER (focal +), PR (-), CgA (focal +), Syn (focal +), CD56 (+), Ki67 (30% +), CDX2 (+), CK (AE1/AE3) (punctate +), CK20 (focal +), CK7 (+). The final diagnosis was clear cell adenocarcinoma of the right ovary with an intestinal-type borderline mucinous tumor containing localized small cell NEC (probably pulmonary type). After the surgery, the patient underwent chemotherapy but passed away 12 months later during the postoperative follow-up period.
Primary ovarian SCC (pulmonary type) must be distinguished from metastatic SCC, granulosa cell tumors of the ovary, and primary or metastatic carcinoid tumors of the ovary. Metastatic SCC is morphologically identical to primary ovarian SCC. As a result, detecting the primary lesion mainly relies on medical history and relevant examinations. Ovarian granulosa cell tumors typically affect women of reproductive age and are usually encapsulated. The nuclei of the tumor cells exhibit folding or furrowing, resulting in a “coffee bean” appearance or the formation of Call-Exner vesicles under microscopy. Symptoms of hyperestrogenism related to the endocrine system are often observed in clinical practice. The immunophenotype expresses Vimentin, SMA, actin, and S-100 proteins but does not express EMA or NSE. In primary or metastatic carcinoid tumors, the morphology typically exhibits a rosette-like structure with atypical nuclei, few mitotic figures, and no evidence of tumor necrosis.
Primary ovarian carcinoid tumors are rare NECs that are often associated with teratomas. The tumors exhibit slow growth, low malignancy, and a low potential for recurrence [6]. Most patients with ovarian carcinoid tumors are typically asymptomatic, although some may present with carcinoid syndrome, which can include symptoms such as flushing, bronchospasm, abdominal distention, and constipation [7]. Tumors often develop unilaterally, vary in diameter, and can be yellow or yellow-brown in color. They may be either solid or cystic. Microscopically, tumor cells can have an insular, goiter, trabecular, mucinous, or mixed distribution. The most common types are insular and goiter-type ovarian carcinoid tumors. IHC testing for neuroendocrine markers, such as Syn, NSE, CgA, and AE1/AE3, can be helpful in making a diagnosis.
The two patients with primary ovarian carcinoid tumors in this study varied greatly in age. The tumors exhibited small acinar, trabecular, stripe, and nest-like distributions. The cells had a polygonal shape and were morphologically consistent, with less cytoplasm and hyperchromatic nuclei. The nuclei were either round or ovoid in shape and had finely speckled chromatin. There were few mitotic figures, and no foci of necrosis were observed. The cells were CD56 (+), Syn (+), and CgA (+). The systemic examination did not reveal any other abnormalities. The diagnosis of a primary ovarian carcinoid was made based on clinical, morphological, and IHC findings. The patients had a positive prognosis and were still alive as of the date of the follow-up period.
Zhao et al. [8] reported six cases of primary ovarian carcinoid tumors. The age of onset for the patients ranged from 28 to 54 years old, and the tumors occurred on the left and right sides of the ovary in three cases each. Microscopically, there were three cases of the trabecular type, two cases of the goiter type, and one case of the insular type. They had a low-grade malignancy with a favorable prognosis.
In the two cases of primary ovarian carcinoid tumors reported by Yu et al., [9] the age of onset for the patients was 35 and 48 years, respectively. There was one case each of the insular and trabecular types under microscopy. The tumor cells had a round or polygonal shape, and there was no evidence of recurrence observed during the 45- and 63-month postoperative follow-up periods, respectively. IHC showed that the tumor cells were Syn (+) and CK (+) to varying degrees, but α-inhibin (-), CD99 (-), TTF-1 (-), ER (-), and PR (-). The Ki-67 proliferation index was less than 1%. They had a good prognosis.
Nicolas et al. [10] reported a case of an ovarian carcinoid tumor combined with a teratoma. The patient was a 65-year-old woman with an enlarged right adnexa measuring 13 cm × 13 cm × 8.5 cm. Microscopic examination revealed nest and trabecular-type tumor cells with pleomorphic nuclei. IHC showed that the tumor cells were Syn (+), CD56 (+), chromogranin (-), and Ki67 (10–12% +). The patient had a positive postoperative recovery and was discharged after seven days of follow-up.
Two cases of ovarian carcinoid tumors were reported by Vora et al [11]. The age of onset for the patients was 40 and 26 years, respectively, and both had unilateral onset of symptoms. One of them also had a mixed teratoma as well. Under microscopy, the tumor cells had a nest or trabecular type with eosinophilic cytoplasm and finely speckled chromatin. IHC results showed that the tumor cells were Syn (+) and chromogranin (+) in two cases. The post-surgery disease-free survival ranged from 10 months to 12 years.
Primary ovarian carcinoid must be distinguished from metastatic carcinoid, small cell carcinoma, and granulosa cell tumor. The primary lesion of metastatic ovarian carcinoid is mostly in the small intestine, particularly in the ileum. Additionally, both ovaries may be involved. The microscopic appearance of the tumor is similar to that of a primary carcinoid tumor. However, it is not associated with ovarian teratomas. A thorough systemic examination can help identify the primary lesion. Although SCCs share similarities with carcinoid tumors in terms of cell morphology and arrangement, they can be distinguished by numerous mitotic figures and common necrosis. The nuclei of the ovarian granulosa tumor cells exhibit furrowing, resulting in a “coffee bean” appearance or the formation of Call-Exner vesicles under microscopy. Symptoms of hyperestrogenism related to the endocrine system are often observed in clinical practice. The immunophenotype expresses Vimentin, SMA, actin, and S-100 proteins but does not express EMA or NSE.
Treatment options for various types of primary O-NECs can vary. The current standard of care for patients with early-stage SCC is a total hysterectomy and bilateral adnexal resection. Patients in advanced stages undergo tumor cytoreduction, followed by postoperative adjuvant chemotherapy [12]. There are various chemotherapy regimens, such as PAC (cisplatin, adriamycin, and cyclophosphamide), VAC (vincristine, actinomycin D, and cyclophosphamide), and PVB (cisplatin, vincristine, and bleomycin), among others. The disease is highly aggressive, and the prognosis is poor even for patients diagnosed in the early stages.
The primary treatment for carcinoid tumors is surgical resection, particularly for stage I patients, which is highly effective in nearly 100% of cases. In contrast, the 5-year survival rate for patients with advanced carcinoid tumors is 33% [13]. Pathological results are crucial for assessing the nature and extent of tumors. Through pathological analysis, doctors can determine the grade of the tumor and whether there is cellular infiltration or metastasis. These results help in deciding whether adjuvant therapies such as chemotherapy or radiation therapy are needed and can provide a more precise evaluation of the scope and method of surgery. Laparoscopic surgery is a minimally invasive surgical approach commonly used in the treatment of ovarian neuroendocrine tumors. Compared to traditional open surgery, laparoscopic surgery offers significant advantages [14]. Firstly, it involves smaller incisions and the use of laparoscopic instruments, which helps reduce surgical trauma, postoperative pain, and shortens hospitalization and recovery time. Additionally, laparoscopic surgery provides better cosmetic outcomes, leaving smaller and more aesthetically pleasing scars. However, laparoscopic surgery also has limitations, including the requirement of high surgical skills and dependence on equipment. Compared to other treatment methods, laparoscopic surgery is generally considered a more direct and thorough treatment option, but the specific treatment plan should be determined based on the patient’s condition and the advice of the physician.
O-NECs are largely reported as isolated cases both in China and internationally, with no relevant treatment guidelines. However, SCC of the ovary is a rapidly progressing, highly malignant disease with a high mortality rate and a poor prognosis. Therefore, clinicians and researchers should pay particular attention to this disease. With the advent of new chemotherapeutic drugs, immunological breakthroughs, molecular biology, and biological and gene treatments, the therapeutic outcomes for this type of cancer are expected to improve significantly, leading to a better prognosis. Exploring the pathogenesis of the disease is an important aspect of future research on this tumor, as it can provide a basis for adjuvant therapy for patients with advanced disease.
In conclusion, there are several clinical types of O-NECs. The prognosis and survival of each type are determined by its diagnosis. Ovarian SCC is a highly malignant and invasive cancer that is prone to recurrence. In contrast, primary ovarian carcinoid is less malignant, less likely to metastasize, and patients have a better prognosis. Therefore, accurate pathological staging and early detection of primary O-NECs are crucial for improving patient survival [15, 16].
