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A 21-year-old virgin presented with abdominal discomfort and pelvic mass. Laparotomy revealed non-ruptured right ovarian tumour about 5 cm in diameter with no ascites. No extra-ovarian disease was noted intraoperatively. She underwent right salpingo-oophorectomy at a local hospital. Pathological diagnosis was right ovarian Sertoli–Leydig cell tumour with heterogeneous components. Subsequently, she received three courses of combined chemotherapy composed of bleomycin, etoposide and cisplatin, but the disease had been progressing.
At the time of admission to our hospital just 4 months later from the initial operation, her serum β subunit of human chorionic gonadotropin (β-HCG) was 258.6 mIU/ml, and other tumour markers were normal. Her serum parathyroid hormone (PTH) was 88.6 pg/ml (normal 5∼70 pg/ml), but serum calcium level was normal.
The pathology slides from her first operation were reviewed. The tumour was composed of two different components, most of which consisted of poorly differentiated medium to large tumour cells with enlarged round or oval nuclei arranged in solid cords and nests. On higher magnification, the tumours had abundant eosinophilic and granular cytoplasm, and the nuclei had coarse chromatin and prominent nucleoli (figure 1). The smaller component consisted of a strip of mucinous borderline tumour and some sarcomatous area (figure 2). Immunohistochemical stains revealed that the larger component of the tumour were diffusely positive for chromogranin (CgA) (figure 3) and synaptophysin, and focally positive for neuron-specific enolase and epithelial membrane antigen, whereas the cells of the smaller component were negative. The morphological and immunohistochemical features of the larger component were compatible with those of non-small cell neuroendocrine carcinoma (NSCNEC) of the lung. Therefore, a diagnosis of ovarian neuroendocrine carcinoma, non-small cell type, with an admixture of mucinous borderline tumours was made.
High-power view of neuroendocrine carcinoma. The tumour cells arranged in solid cords and nests had abundant eosinophilic and granular cytoplasm and the nuclei had coarse chromatin and prominent nucleoli (magnification ×200, HE stain).
A strip of mucinous borderline tumour and some sarcomatous area (magnification ×100, HE stain).
Immunochemical staining of the neuroendocrine tumour cells for chromogranin (CgA) (magnification ×200).
She was treated with a weekly taxol and carboplatin regimen of chemotherapy, but the treatment was ineffective. Serum β-HCG continued to rise up to 445.5 mIU/ml. Five months after the first operation, the patient died of respiratory failure due to progressive and disseminated tumours.
The autopsy provided further clues to the patient's disease. Massive tumours were present in the lungs and mediastinum. The main trachea was circumferentially involved, composed of necrotic tissue (figure 4). The liver and kidneys were involved but not infiltrated by tumours. The pelvic cavity and retroperitoneum were filled with tumours. The histological findings were consistent with metastasis of NSCNEC without mucinous component as described above, and tumour cells were positive for CgA and synaptophysin but negative for carcinoembryonic antigen, β-HCG, placental alkaline phosphatase and CD117.
The main trachea was wholly involved by the yellowish necrotic mass (blue arrow).
Ovarian neuroendocrine carcinoma of non-small cell type is a rare, recently established entity characterised by medium-sized to large tumour cells expressing various neuroendocrine antigens. Twenty-seven cases of ovarian NSCNEC in total have been reported in literatures.1–3 Except for 4 cases, 23 cases have been reported to be admixed with surface epithelial ovarian tumours, among which 16 cases were mucinous neoplasm. The behaviour of these tumours has been described as aggressive, as evidenced by the fact that 11 cases died of the disease within 1 year of diagnosis.
It was reported previously that one patient of NSCNEC had an elevated serum PTH level with hypercalcaemia.4 The elevated PTH is considered to be secreted by the cells of the neuroendocrine carcinoma. Our patient had a lightly high level of PTH but a normal level of serum calcium. In this case, the PTH produced by the tumour cells may have poor functions. This patient also had a high level of β-HCG, which increased with the progression of the disease. Although we thought that the tumour had choriocarcinoma components which produced β-HCG, surprisingly, we did not find any evidence of choriocarcinoma components in the tissue samples taken during initial surgery or at autopsy. However, we could not assure if the overall tumour had any choriocarcinoma cells because we could not review all tumour tissues from her first operation. It is the first such tumour to be associated with a high level of β-HCG. Previously, we had known that an elevated serum level of β-HCG confers poor prognosis in ovarian carcinoma.5
The differential diagnosis of ovarian NSCNEC includes primary or metastatic carcinoid tumours. These neoplasms can be distinguished from NSCNEC by their low mitotic activity, cytological uniformity, organoid architectural patterns and absence of necrosis. Clinical history will be of paramount importance in ruling out a metastatic tumour. In our case, no mass lesion was detected in other organs including lungs during the first surgery, so metastatic ovarian NSCNEC could be excluded. Immunohistochemical stains for placental alkaline phosphatase and CD117 were negative; germ cell tumours such as dysgerminnoma were not considered. In our case, we made the diagnosis because the components of the tumour tissues were mostly of neuroendocrine carcinoma tissues but little mucinous borderline tumour and some sarcomatous area from the first surgical sample slides; therefore, we excluded the anaplastic carcinoma with neuroendocrine differentiated in mural nodules of mucinous neoplasms.
The histogenesis of ovarian neuroendocrine carcinomas remains unclear.6 Autopsy findings suggest that the metastasis occurred mainly through lymphatic spread, but haematologic spread was likely given the patient's advanced stage of disease. In fact, in three patients' autopsy or follow-up biopsies previously reported, metastases were shown to be exclusively composed of neuroendocrine components.7 These findings were consistent with our results in that metastatic lesions showed only the neuroendocrine carcinoma components.
Because of the rarity of this disease, a general consensus for optimal treatment has yet to emerge. More cases should be collected and studied to establish optimal therapeutic guidelines.
Take-home messages
NSCNEC of the ovary is a rare and aggressive tumour, which can be associated with a surface epithelial tumour.
This is the 28th case and the first such tumour to be associated with an elevated serum level of β-HCG.
Footnotes
Competing interests None.
Patient consent Obtained.
Ethics approval The Ethics Committee of Peking Union Medical College Hospital has approved publication of the case.
Provenance and peer review Not commissioned; externally peer reviewed.