Large cell neuroendocrine carcinoma (LCNEC) of the ovary: A case report and review of the literature

Neuroendocrine tumors consist of a spectrum of malignancies that arise from the neuroendocrine cell system. This group of tumors can be divided into well-differentiated (i.e. carcinoid) and poorly differentiated neuroendocrine neoplasms (i.e. small cell and large cell) [1]. Neuroendocrine carcinomas of the female genital tract are uncommon. More specifically, large cell neuroendocrine carcinoma (LCNEC) of the ovary is an exceedingly rare diagnosis. These malignant tumors are associated with an aggressive clinical course with a short survival, even when diagnosed at an early stage. The majority of LCNECs of the ovary are associated with surface epithelial ovarian tumors. We have identified 37 documented cases in the literature. Eight cases of primary LCNEC of the ovary have been described without any concomitant epithelial ovarian component [1,2]. In this report, we present a case of a primary LCNEC of the ovary without an epithelial component with a relatively prolonged survival. Additionally, we summarize the current literature regarding the management of this rare tumor.


Introduction
Neuroendocrine tumors consist of a spectrum of malignancies that arise from the neuroendocrine cell system. This group of tumors can be divided into well-differentiated (i.e. carcinoid) and poorly differentiated neuroendocrine neoplasms (i.e. small cell and large cell) [1]. Neuroendocrine carcinomas of the female genital tract are uncommon. More specifically, large cell neuroendocrine carcinoma (LCNEC) of the ovary is an exceedingly rare diagnosis. These malignant tumors are associated with an aggressive clinical course with a short survival, even when diagnosed at an early stage. The majority of LCNECs of the ovary are associated with surface epithelial ovarian tumors. We have identified 37 documented cases in the literature. Eight cases of primary LCNEC of the ovary have been described without any concomitant epithelial ovarian component [1,2]. In this report, we present a case of a primary LCNEC of the ovary without an epithelial component with a relatively prolonged survival. Additionally, we summarize the current literature regarding the management of this rare tumor.

Materials and methods
For this original and updated review, we performed a keyword search within PubMed, Ovid, and Cochrane Library for "large cell neuroendocrine tumor" and "ovary". This case report was exempt from approval by the institutional review board.

Case report
A 62 year old woman presented with a two-week history of nausea, emesis, diarrhea, and malaise. On physical exam a pelvic mass was palpated. Laboratory evaluation revealed an elevated white blood cell count (24.28 K/uL) and CA-125 (176.8 units/mL). A CT scan demonstrated a 12 cm complex pelvic mass. A pelvic abscess versus neoplasm was suspected. Her leukocytosis resolved with antibiotics, but the mass persisted. She underwent an exploratory laparotomy. She was noted to have a mass adherent to the rectosigmoid colon and the left adnexa. Intraoperative pathologic examination was consistent with a poorly differentiated carcinoma. A hysterectomy, bilateral salpingooophorectomy, including resection of pelvic mass, lymphadenectomy and omentectomy was performed. The patient recovered appropriately postoperatively.
Gross pathologic inspection of her surgical specimen demonstrated a 7 cm left ovary with a smooth, pink serosal surface. Final histopathologic examination was consistent with a large cell neuroendocrine carcinoma (Figures 1 and 2). Metastases to the uterine serosa, colonic serosa, and right fallopian tube were identified, and as   pelvic lymph node was detected on PET CT. She underwent a roboticassisted laparoscopic resection of this lymph node. There was no evidence of recurrence on histologic examination of this resected tissue.
However, approximately 10 months later, she was found to have a pelvic mass suspicious for recurrence. The mass measured 9 x 7 cm, encompassed and narrowed the sigmoid colon and was intimately involved with the common and external iliac vessels. A combination of carboplatin and etoposide chemotherapy was administered with the hopes of improving the resectability of the tumor. Following therapy, the mass did decrease in size to 7 x 5 cm. The patient then underwent a radical en bloc tumor resection, including vaginectomy, left colectomy, left nephrectomy, right distal ureterectomy and reimplantation, and resection of para-aortic lymph nodes. At the completion of this surgery, there was no grossly visible residual disease. She recovered well postoperatively. Pathologic examination was again consistent with recurrent large cell neuroendocrine tumor. She was treated with additional cycles of carboplatin plus etoposide. A post-treatment follow-up CT showed no evidence of recurrent or metastatic disease.

Discussion
Large cell neuroendocrine carcinomas of the ovary are extremely rare with a historically poor survival [2][3][4][5]. The precise histiogenesis of LCNEC of the ovary remains unknown. A number of theories have been proposed. As neuroendocrine cells are present in normal epithelium of the female genital tract, these may serve as the origin of neuroendocrine tumors of the ovary. Primitive endodermal cells have the ability to differentiate into endocrine and other cell types. Also, ovarian neuroendocrine tumors may arise from non-neuroendocrine cells, in which activated genes promote neuroendocrine differentiation [5,7].
Secondary to its rarity, there is no standard treatment for LCNEC. Previous studies have reported chemotherapy platinum-based regimens combined with agents such as paclitaxel, etoposide, and bleomycin. Some reports have proposed that in mixed LCENC with epithelial components, optimal first line treatment should be targeted against the epithelial component [8]. For pure LCNEC, platinum agents have been used in combination with etoposide or paclitaxel (Table 1). Although most reported patients were treated with paclitaxel and carboplatin, they showed a wide range of responses from death within 3-4 months of surgery to remaining disease free for up to 10 months [2,4,[9][10][11]. The two patients treated with etoposide and platinum therapy showed no evidence of disease after 9 months and 1 year [12,13]. The relatively prolonged disease free interval lends support to the combination of platinum and etoposide in the management of pure LCNEC.
Herein we have presented a case of woman with Stage IIB LCNEC tumor of the ovary treated with a surgical resections and combination chemotherapy of a platinum agent with etoposide associated with a relatively long survival. This case supports a potential role for secondary surgical cytoreduction which should be considered in appropriately selected patients. Ki et al reported the only other case of secondary cytoreduction; this in a 58-year-old woman with a recurrence in a para-aortic lymph node after initially being diagnosed with stage IA disease treated with cisplatin and paclitaxel. Unfortunately, she died of multiorgan failure 17 months after initial diagnosis [5].
In summary, LCNEC of the ovary is a rare entity. These cases have historically had an aggressive clinical course, despite surgical resection and adjuvant chemotherapy. We have presented a case of a woman with pure LCNEC responding to surgical resections and platinum plus etoposide combination chemotherapy, for a relatively prolonged overall survival (33 months). While there is no standard of care regarding this rare entity, this approach should be considered in appropriately selected patients. Secondary to their rarity, an international tumor registry for ovarian LCNEC and other rare histologic subtypes would be helpful. With the knowledge gained therein, treatment approaches could be optimized.