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 Table of Contents  
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 90-93

Clinical and histological features of primary pure large-cell neuroendocrine carcinoma of the ovary

1 Department of Medical Oncology, CHU Habib Bourguiba, University of Sfax, Sfax, Tunisia
2 Department of Pathology, CHU Habib Bourguiba, University of Sfax, Sfax, Tunisia
3 Department of General Surgery, CHU Habib Bourguiba, University of Sfax, Sfax, Tunisia

Date of Submission12-Jan-2020
Date of Acceptance23-Mar-2020
Date of Web Publication22-May-2020

Correspondence Address:
Dr. Sana Ennouri
Department of Medical Oncology, CHU Habib Bourguiba, University of Sfax, Sfax
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/LJMS.LJMS_1_20

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Primary pure large-cell neuroendocrine carcinoma (LCNEC) of the ovary is a rare entity which has been reported only through few cases. It is described as an aggressive tumor with the tendency to present at advanced stages and to cause death after a short postoperative time. Until nowadays, there is no standard therapeutic protocol that helps to guide the treatment of this malignancy. In this article, we report two cases of pure LCNEC of the ovary to make physicians aware of this entity and to show its clinical and pathological features in order to put emphasis on its aggressiveness. The first case was a 38-year-old patient diagnosed in 2015. The ovarian LCNEC was classified according to the International Federation of Gynecology and Obstetrics (FIGO) staging classification as FIGO Stage IV and was treated by surgery and chemotherapy. The second case was a 67-year-old patient diagnosed in 2017. The ovarian LCNEC was classified as Stage IIIB and not resectable and was treated by paclitaxel–carboplatin chemotherapy.

Keywords: Cancer treatment protocol, large-cell carcinoma, neuroendocrine carcinoma, ovary neoplasm, pathology

How to cite this article:
Feki J, Sghaier S, Ennouri S, Mellouli M, Boudawara T, Mzali R, Khanfir A. Clinical and histological features of primary pure large-cell neuroendocrine carcinoma of the ovary. Libyan J Med Sci 2020;4:90-3

How to cite this URL:
Feki J, Sghaier S, Ennouri S, Mellouli M, Boudawara T, Mzali R, Khanfir A. Clinical and histological features of primary pure large-cell neuroendocrine carcinoma of the ovary. Libyan J Med Sci [serial online] 2020 [cited 2023 Mar 28];4:90-3. Available from: https://www.ljmsonline.com/text.asp?2020/4/2/90/284683

  Introduction Top

Neuroendocrine tumors (NETs) frequently occur in the lungs or the gastrointestinal tract.[1] They are uncommon in the genital tract and constitute < 2% of all gynecologic malignancies.[2] In female genital tract, the spectrum of NETs comprises carcinoid tumors, small-cell neuroendocrine carcinoma, and large-cell neuroendocrine carcinoma (LCNEC).[2],[3] In the ovary, carcinoid tumors are the most common NET.[4] Primary pure LCNEC of the ovary is a rare primary malignant tumor of the ovary that was recently included in the latest World Health Organization (WHO) classification of ovarian tumors.[5] LCNEC is a high-grade carcinoma with aggressive behavior and poor prognosis.[6]

Most of the reported LCNECs are associated with teratoma or surface epithelial stromal tumors.[7] Since its original description by Collins et al., in 1991, 34 cases of LCENC have been reported so far in literature, of which 29 cases were associated with other epithelial cancers.[8] This entity was only described through case report in the literature.[8],[9],[10],[11] In many reported cases, it has been noticed that LCNEC has a very aggressive behavior and a poor prognosis even when it is diagnosed at early stages.[12] Herein, we report two cases of primary pure LCNEC of the ovary, and we describe its clinical and histological features.

  Case Reports Top

Case 1

A 38-year-old woman was referred to our oncology department for abdominal distension and polyuria. She denied having any symptoms of the flush syndrome. Physical examination had shown abdominal distension, a palpable firm mass in the abdomen with a splenomegaly. Ultrasonography and abdominal computed tomography (CT) revealed a 20 cm pelvic mass with a cystic and solid component encompassing the bladder, the uterus, and the rectum with intraabdominal nodes, diffuse peritoneal carcinomatosis, a 5 cm spleen lesion, and hepatic metastasis. There was no parietal lesion in the digestive tract. Colonoscopy, gastroscopy, and CT-chest were normal. The carbohydrate antigen 125 (CA 125) level was at a high level (140 U/ml), and the neuron-specific enolase (NSE) was at 90 ng/ml. The human chorionic gonadotropin and alpha feto-protein levels were normal. Taken together, the ovary was considered as the original site of tumor. A CT-guided peritoneal biopsy with pathologic diagnosis concluded to LCNEC [Figure 1]. There was a cribriform formation composed of large tumor cells, oval to round in shape with coarse chromatin. Immunohistochemical staining was positive for chromogranin, synaptophysin, and CK7. The Ki 67 was at 50%. The LCNEC of the ovary was classified as Stage IV according to the International Federation of Gynecology and Obstetrics (FIGO) staging classification. The patient received nine courses of chemotherapy based on etoposide 100 mg/m2 day 1–3 + cisplatin 100 mg/m2 day 1, every 21 days. Radiological evaluation showed a 55% decrease of the pelvic mass according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria with a total regression of peritoneal nodes and hepatic metastases. Therefore, the patient underwent surgery. She had splenectomy, hysterectomy, bilateral salpingo-oophorectomy, appendectomy, omentectomy, pelvic, and para-aortic lymphadenectomy. Microscopically, viable cancer cells were found in both ovaries, in spleen metastases, and in four metastatic para-aortic nodes [Figure 2]. She received three courses of carboplatin with the area under the curve (AUC) at 5 at day 1 and Paclitaxel 175 mg/m2 at day 1 every 21 days. Six months after the completion of chemotherapy, CA-125 level increased again with no detectable lesion on CT-scan imaging. Nine months later, the CT scan revealed the presence of perirectal lymph node with rectal wall thickening. A third-line chemotherapy cyclophosphamide/doxorubicin/vincristine (CAV) was then delivered. The CT scan showed a progressive disease after eight cycles of CAV chemotherapy. The patient received irinotecan 150 mg/m2 and carboplatin AUC 4. After six courses, the CT scan showed a stable disease, and the NSE level decreased to 23 ng/ml. Now at 50 months from initial diagnosis, the patient is still alive and stable in spite of mild peripheral neuropathy Grade 2.
Figure 1: Peritoneal biopsy/Large-cell neuroendocrine carcinoma: (a) cells proliferate in a nesting pattern with rosette-like structures (H and E, ×200). Tumor cell expression of chromogranin (b) (×400), synaptophysin (c) (×400), and thyroid transcription factor-1 (d) (×200)

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Figure 2: (a) Infiltration of the ovarian parenchyma (*) by a large-cell neuroendocrine carcinoma (H and E, ×100). (b) Tumor cells have eosinophilic cytoplasm and large nuclei with necrosis (H and E, ×400). (c and d) Therapeutic response to chemotherapy: Note the presence of foamy histiocytes (H and E, ×200)

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Case 2

A 67-year-old woman was referred to our oncology department because of continuous abdominal pain with no palpable mass. Ultrasound and CT examinations revealed an 8 cm bilateral cystic ovarian tumor and no distant lesions. CA-125 test was at a high level (196 U/ml). Exploratory laparoscopy with bilateral biopsy was performed. Histopathologically, the tumor was diagnosed as LCNEC. Peritoneal washing cytology was negative. Although we planned an optimal surgery, the patient had been out of sight. Two months later, she reconsulted for a genital bleeding. At pelvic examination, a 2 cm mass was found prolapsed from the uterine cervix. CT scan showed a 5-cm uterine mass involving the cervix as well as two ovarian tumors and a disseminated carcinomatosis. The tumor was classified as FIGO Stage IIIB, and consequently, we initiated paclitaxel/carboplatin in the neoadjuvant setting. After six courses of chemotherapy, radiological evaluation showed a 35% progression of the pelvic mass according to RECIST criteria. In regards of the altered performance status, no further chemotherapy was administered. Few days later, she developed a massive pulmonary embolism and died from respiratory failure.

  Discussion Top

Primary pure LCNEC of the ovary is a rare tumor which was included in the WHO tumor classification.[13] It is defined as a poorly differentiated carcinoma of nonsmall cell neuroendocrine type with large cells that show neuroendocrine differentiation.[10] The most common neuroendocrine (NE) tumors of the ovary are typical carcinoid tumors. Atypical carcinoids and poorly differentiated NE carcinomas are very rare.[14] Neuroendocrine carcinoma originates from the endocrine cells of the diffuse neuroendocrine system that includes several endocrine organs such as the ovary.[15] It has been also shown that this type of ovarian cancer may develop from nonneuroendocrine cells through the activation of neuroendocrine differentiation promoting genes.[8] The majority of the published cases (58 cases in 2019) of LCNEC were associated with surface epithelial and germ cell tumors[15],[16] and only 15 cases of pure ovary LCNEC were published until 2019.[16]

Primary poor LCNEC presents different epidemiological, clinical, and histological features. In a review about 58 women with ovary LCNEC,[16] Yang et al. found that 43.1% of patients were of a childbearing age and that age of patients ranged between 18 and 80 years.

The presentation of LCNEC of the ovary is similar to the usual presentation of epithelial ovarian cancer with abdominal pain, abdominal distension, a palpable mass in the abdomen or pelvis, and pollakiuria due to compression of the bladder by the ovarian mass.[17],[18]

The CA-125 is a tumor antigen found in 80% of all epithelial ovarian cancers, and its serum level correlates with cancer stages and response to treatment. However, in pure LCNEC, C-125 levels are not specific to clinical courses.[19] The first case had an increased C-125 serum level but not increased enough regarding to the size of the tumor and the different metastasis. Some authors have reported other tumor markers such as NSE which is a tumor marker for neuroectodermic and neuroendocrine cancers.

When making the diagnosis, primary pure LCNEC should be distinguished from other primary or secondary NETs and non-NETs. Metastatic neuroendocrine cancer cells are usually not found in the epithelial layer of the ovary. Yet, a pulmonary or a gastro-intestinal primary tumor has to be excluded before concluding to a primary LCNEC of the ovary. Several non-NETs, such as teratoma sex cord stromal tumors, and epithelial cancer may show neuroendocrine differentiation. These biphasic tumors can be distinguished from pure LCNEC by identifying nonneuroendocrine components.[17]

Macroscopically, most of primary LCNEC have double components which are a solid and a cystic part, with a size ranging from 9 to 30 cm.[10] In this report, the ovarian mass was also partially solid and cystic, and it measured 20 cm. Microscopically, pure primary LCNEC is characterized by large tumor cells, oval or round in shape, which are usually arranged in solid nests, sheets, or a trabecular pattern.[20],[21] The cribriform formation is less frequently observed, and yet, it was found in the first case. The tumor has large vesicular nucleoli or coarse chromatin, and sometimes, it has extensive necrosis and numerous mitoses.[17],[22] Neuroendocrine differentiation can be confirmed by immunohistochemical analysis due to the neuroendocrine nature of the cell, as they express at least one neuroendocrine marker such as CD56, chromogranin A, synaptophysin, or NSE. Our two specimens were positive for chromogranin, synaptophysin, and CK7. These two cases fulfilled the structure and immunohistochemical criteria for a primary pure ovarian LCNEC.

Because of the rarity of this condition, there is no standard treatment of ovarian LCNEC. Only limited data are available to guide treatment. Most patients undergo primary surgery to obtain the definitive diagnosis and to get a tumor debulking surgery. After that, chemotherapy is administrated to the majority of the reported cases. Various combinations of chemotherapy had been tried, including cisplatin/cyclophosphamide, followed by etoposide/cisplatin or paclitaxel/carboplatin protocols.[20] As for the two cases reported in this article, we used different regimens: etoposid/cisplatin, paclitaxel/carboplatin, CAV, and irinotecan/carboplatin.

The prognosis of pure ovarian LCNEC is recognized to be exceedingly poor. In fact, 5-year survival rate was 34.9% and still only 35.3% for Stage I cases, even though in over 95% of these cases, optimal surgery was performed. In addition, this entity has a high incidence of recurrence, including unusual metastatic sites that differ from those of other ovarian cancers. Even though it has known poor prognosis, it is noteworthy that primary LCNEC of the ovary may have a certain chemosensitivity and a relatively good outcome, as shown in some published cases.[11],[23] As for the first case, the drug combination we used (etoposide/cisplatin) led to a decrease of 55% of the tumor mass and the disappearance of metastatic lesions. Veras et al. conducted a study at the MD Anderson Cancer Center and reported that Stage I cases of LCNEC acquired long-term survival for 22–68 months and that even Stage III and IV cases had similar prognosis with surgery, followed by adjuvant platinum-based chemotherapy.[22]

  Conclusion Top

Primary LCNEC of the ovary is a rare tumor that is usually described as very aggressive. It is typically associated with surface epithelial or germ cell tumors. Only few reported cases, including these two cases, occurred in a pure form. Due to its rarity, consensus on the standard therapy has not been established yet. Generally, the prognosis of LCNEC is recognized as being poor, owing to its biologically aggressive behavior. However, some ovarian LCNECs revealed more favorable prognosis because of their chemosensitivity. Thus, prospective clinical studies to evaluate the efficacy of treatment modalities are crucial.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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Chun YK. Neuroendocrine Tumors of the Female Reproductive Tract: A Literature Review. J Pathol Transl Med 2015;49:450-61.  Back to cited text no. 2
Travis WD, Linnoila RI, Tsokos MG, Hitchcock CL, Cutler GB Jr, Nieman L, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 1991;15:529-53.  Back to cited text no. 3
Kaiho-Sakuma M, Toyoshima M, Watanabe M, Toki A, Kameda S, Minato T, et al. Aggressive neuroendocrine tumor of the ovary with multiple metastases treated with everolimus: A case report. Gynecol Oncol Rep 2018;23:20-3.  Back to cited text no. 4
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Lopes Dias J, Cunha TM, Gomes FV, Callé C, Félix A. Neuroendocrine tumours of the female genital tract: A case-based imaging review with pathological correlation. Insights Imaging 2015;6:43-52.  Back to cited text no. 14
Neuroendocrine Tumors of the Gynecologic Tract: Select Topics. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=Neuroendocrine+tumors+of+the+gynecologic+ tract%3A+Select+topics. [Last accessed on 2019 Jul 20].  Back to cited text no. 15
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  [Figure 1], [Figure 2]


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