Cervical Neuroendocrine Carcinoma Presenting as Isolated Large Ovarian Metastasis: A Case Report

Introduction

Neuroendocrine carcinoma (NEC) of the cervix is uncommon, accounting for less than 2% of all cervical cancers [1]. Histologically, cervical NECs are categorized as low-grade (typical and atypical carcinoid) or high-grade (small- and large-cell) NEC [2]. The most prevalent histological type is small-cell NEC (SCNEC), which accounts for 80% of all cases, followed by large-cell NEC (LCNEC) [3,4]. In contrast to the squamous and adenocarcinoma (ADC) subtypes, high-grade NEC has a strong tendency to spread through the lymphatic system and bloodstream, even when confined to the cervix [2].

Currently, evidence regarding the occurrence of ovarian metastasis in patients with NEC is limited. Cases of NEC with clinical manifestations of an isolated large ovarian metastasis are rare. Recent studies have shown that the incidence of ovarian metastasis in early-stage cervical cancer is only 3.61% in endocervical ADCs and 1.46% in squamous cell carcinomas (SCCs) [5,6]. A 10-year study revealed no incidence of ovarian metastasis from NEC [7]. Here, we describe a case involving a 42-year-old woman with cervical NEC accompanied by an isolated large ovarian metastasis.

Case Report

A 42-year-old woman with 2 living children experienced stomach pain over the course of 4 months, which had progressively worsened in the past month. She also reported weight loss and an enlarged abdomen over the past 3 months. Physical examination indicated a 15-cm abdominal lump and gynecological examination revealed a smooth cervix with no visible ectocervical mass. Subsequently, laboratory examination showed that she had a hemoglobin level of 10.7 g/dl, a white blood cell count of 11.3×103/µL, a platelet count of 455×103/µL, and serum albumin of 3.97 g/dl, along with increases in the tumor markers cancer antigen 125 (803.9 U/mL) and carcinoembryonic antigen (241.9 ng/ml). The liver and renal function and electrolyte levels were normal. A preoperative Pap test for cervical cancer screening was not performed because the initial examinations were focused on the patient’s ovarian tumor.

To confirm the presence of a suspected ovarian tumor, computed tomography (CT) was used to reveal a hypoattenuating solid mass with a calcified component and indistinct borders. The mass extended from the pelvis through the abdomen with postcontrast enhancement, measuring 16.6×15.5 cm. It significantly effaced the bowel loops and bladder and was adherent to the posterior uterus. No abnormalities were observed in the uterus, cervix, or other abdominal organs, and lymph node enlargement was not detected (Figure 1).

Based on these preoperative findings, we diagnosed the patient with a probable malignant solid ovarian tumor without any suspicion of cervical cancer and planned a primary debulking surgery.

During the procedure, the tumor was found to have arisen from the left adnexa, measuring approximately 25×20 cm, and was attached to the peritoneal wall and sigmoid rectum (Figure 2A). Other organs, such as the uterus, right adnexa, and liver, appeared normal; however, several nodules were identified in the omentum and peritoneum. The adhesions were released, and we decided to perform primary debulking surgery, which included total abdominal hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and biopsy of several nodules in the peritoneum and omentum.

A malignant ovarian tumor was still suspected after the intra-operative findings. Histopathological examination revealed a large amount of tumor tissue in the left ovary, along with a smooth cervical portion (Figure 2B, 2C). Excision of the cervix revealed an endocervical mass measuring 2.5×1.5×1.5 cm, with uncertain borders, irregular edges, and a dense consistency (Figure 2D). Microscopically, tissue slices consisting of normal ectocervix lined with squamous epithelium showed tumor growth in the endocervix. It also consisted of round, oval, pleomorphic, hyperchromatic cells, prominent nuclei, and a thin solid cytoplasm (Figure 3A). The left ovary showed tumor growth arranged in a solid pattern with central necrotic areas. The tumor consisted of proliferating oval-round nucleated anaplastic cells, coarse to hyperchromatic chromatin, multiple prominent nucleoli, and a narrow cytoplasm (Figure 3B). The tumor grew invasively into the fibrous connective tissue stroma and penetrated the capsule, exhibiting lymphovascular invasion. No perineural invasion or tumor infiltration of the ectocervix, parametrium, uterus, right adnexa, left fallopian tube, omentum, or peritoneal nodes was observed. These results led to the diagnosis of a poorly differentiated carcinoma expressing a neuroendocrine tumor in the left ovary and cervix. Immunohistochemistry (IHC) was performed on cervical and left ovarian tumor specimens to identify the origin of the primary organ. IHC of the cervical tumor showed CD56 (+) on the tumor cell membrane (Figure 4A), synaptophysin (+) in the cytoplasm of tumor cells (Figure 4B), chromogranin A (+) focally in the cytoplasm of tumor cells (Figure 4C), P16 (+) in the nucleus of tumor cells (Figure 4D). The Ki-67 proliferation index was found to be 90%. We also performed IHC for the left ovarian tumor. We found similar features, including synaptophysin (+) and chromogranin A (+) in the tumor cell cytoplasm (Figure 5A, 5B), P16 (+) in the tumor cell nucleus (Figure 5C), and CD56 (+) in the tumor cell membrane. Positivity for CD56, synaptophysin, chromogranin A, p16, and Ki67 index >20% in both tumors confirmed that the tumor was a human papilloma virus (HPV)-associated small-cell NEC of the cervix that had metastasized to the left ovary.

Finally, the patient was diagnosed with stage IB2 NEC of the cervix and ovarian metastasis. An adjuvant chemotherapy regimen of cisplatin (75 mg/m2 on day 1) and etoposide (100 mg/m2 on days 1, 2, and 3) was administered every 21 days for 6 cycles. The patient’s condition was favorable following the completion of chemotherapy. At the last follow-up visit (12 months after treatment), the patient was in good condition, and no residual malignancies were detected on physical and pelvic ultrasound examinations. Postoperative magnetic resonance imaging (MRI) was not performed for surveillance owing to limited resources.

Discussion

This case report describes a woman in her early 40s, diagnosed with cervical NEC, clinically manifesting as a very large ovarian tumor, without signs of metastasis to any other organs. Cervical NEC is an uncommon yet aggressive cancer that affects younger individuals more than other prevalent types of cervical cancer [7,8]. The survival rate decreases with age >60 years, even in patients with early-stage disease. In advanced-stage disease, age at diagnosis <50 years is associated with longer overall survival [9].

Primary gynecological neuroendocrine neoplasms account for approximately 2% of all female reproductive tumors [8]. Crane et al found that more than 50% of these neoplasms originate in the cervix, followed by 24% in the uterine corpus [10]. Low-grade neuroendocrine tumors are most commonly found in the ovaries of the genital tract. In contrast, the cervix is the most prevalent location of aggressive, poorly differentiated NECs [9]. The symptoms of cervical NEC are similar to those of other cervical malignancies, including abnormal bleeding, unexplained pain in the pelvis, whitish vaginal discharge, and systemic symptoms such as ectopic neuroendocrine secretion, hypoglycemia, syndrome of inappropriate antidiuretic hormone secretion, and hypercalcemia [11,12]. Unlike in our patient, NEC of the cervix usually appears as erosive, cauliflower-shaped, or ulcer-like cervical tumors. This tumor can reach the cervix, become barrel-shaped like squamous or ADC, and present a gray-white or gray-yellow color [11,12]. Variance in symptoms may be due to the location of the cervical tumor within the endocervix.

The patient’s major concern was abdominal discomfort with an enlarged abdomen and an atypical presentation of cervical cancer. Therefore, ovarian malignancy was suspected on the basis of other preoperative assessments. Ovarian metastasis is rarely observed in cervical NECs, and limited evidence regarding its overall incidence is available [11,13]. Previous studies have shown conflicting results, with some reporting that very few metastatic cases occur in the ovarium [11,13]. Notably, a study conducted by Castaneda et al over 10 years found no cases of ovarian metastasis [7]. Another study revealed that only 2 of 133 patients with cervical NEC developed ovarian metastasis [5].

Histopathological examination revealed small-cell carcinoma and an HPV-associated tumor. According to several reports, the most common histological type of cervical NEC is SCNEC [11,14]. SCNEC in the cervix is characterized by small, spherical, or fusiform cells with little cytoplasm, hyperchromatic nuclei, coarse granular chromatin, and no nucleoli. Several mitotic figures, nuclear molding, and apoptotic entities were observed, and IHC was required to confirm neuroendocrine differentiation [15]. The importance of IHC staining for CD56, synaptophysin, chromogranin A, Ki-67, and P16 in cervical NEC cannot be overstated because they are essential for precise diagnosis and treatment [16]. These markers are used to detect neuroendocrine differentiation in tumors and are crucial for differentiating cervical NECs from other forms of cervical cancer [16]. Cervical NEC was diagnosed using IHC staining for chromogranin, CD56, and synaptophysin. Notably, all of these markers were positive in our patient. In cervical SCNEC, Ki67 is relatively sensitive and can help in the diagnosis and prognosis of the disease. According to World Health Organization criteria, the Ki67 proliferative index should be >20% in SCNEC [9,12,17]. Regarding the ovaries, small-cell carcinomas and hypercalcemic types have been sequenced and confirmed to be malignant rhabdoid tumors by virtue of consistent deleterious mutations in SMARCA4, a chromatin-remodeling gene encoding protein BRG1. Although these morphologically resemble high-grade neuroendocrine tumors, they are now recognized as distinct clinical and pathological entities [9,12,18].

The indicators of cervical origin and HPV-related tumors in our patient were positive for p16 IHC staining. P16 is a protein that suppresses tumor growth and is frequently observed at high levels in cervical NECs. Overexpression is associated with the presence of oncogenic HPV. This p16 antibody aids in identifying the differences between cervical NECs and other types of cervical cancers, as well as in diagnosing epithelial tumors that are linked to HPV [19]. More than 90% of NEC cases in women are associated with high-risk HPV infection, with type 18 being the most common. IHC staining for p16 was consistently positive for cervical NEC because of its association with HPVs. Together with LCNEC, SCNEC is categorized as a high-grade NEC. High-grade NEC of the cervix is predominantly caused by HPV, with HPV 16 and 18 being the most prevalent. Although some studies detected HPV18 more frequently than HPV16, this trend is not universal. Approximately 85% of cervical SCNEC cases are attributed to oncogenic HPV infections, with HPV18 being the most common genotype, followed by HPV16 and HPV35 [14,12,20].

Regarding preoperative screening, the use of MRI or positron emission tomography-computed tomography (PET-CT) for diagnosis and staging, as well as the Pap test for cervical cancer screening, requires attention. According to Khalbuss et al, the Pap test can be used to diagnose small-cell carcinoma. These tests consist of small-cell carcinoma tumor cells, which can be either scattered as individual cells or organized into loosely cohesive sheets or gland-like clusters [21]. Another study determined that small-cell carcinoma could be primarily detected in liquid-based cytology specimens using a panel of immunocytochemical stains [22]. A preoperative Pap test, along with an MRI or PET-CT examination, can help plan the surgical approach more accurately. While MRI is superior for assessing local tumor extent, PET-CT is considered more reliable for evaluating lymph node status and distant metastases [23]. However, our institution does not have PET-CT facilities.

The patient in this study was diagnosed with NEC of the cervix at an early stage (1B2), and in a study by Xiang et al, 61.2% of patients were diagnosed at an early stage, according to the International Federation of Gynecology and Obstetrics 2018 classification [8]. Another retrospective study demonstrated that cervical SCNEC is commonly diagnosed at stages I and II (approximately 85%) [13]. However, other studies have reported that NEC of the cervix exhibits markedly elevated rates of metastasis to the bone, brain, and liver compared with non-NEC of the cervix, such as SCC and ADC [1,11]. Nevertheless, a significant proportion (40–50%) of SCNEC originating from the genital tract shows early-stage lymph node metastases. It manifests as a systemic disease affecting various organs, such as the liver, lung, bone, brain, and skin. Given the aggressive nature of SCNECs, their tendency to spread to nearby and distant areas at an early stage, and their tendency to be diagnosed at advanced stages, CT or PET-CT is recommended to accurately determine the degree of metastasis [11].

The management strategy for small-cell carcinoma of the cervix was published by the Society of Gynecologic Oncology and Gynecologic Cancer InterGroup, using a multimodal therapy approach. Surgery is an option for the early stages of the disease, and studies have included radical hysterectomy with regional lymphadenectomy as a component of primary management. For tumors <4 cm, management includes radical hysterectomy and lymphadenectomy, followed by adjuvant etoposide/platinum-based therapy [24,25]. However, radical hysterectomy and pelvic lymph node dissection were not performed because prior suspicion and intraoperative findings suggested an ovarian malignancy. Therefore, our patient underwent cisplatin-etoposide chemotherapy following the surgical procedure.

We expected her prognosis to be favorable because patients aged <50 years and in the early stages of the disease have a longer overall survival [9,26].

Conclusions

The findings from the present case indicate that a large ovarian metastasis is an uncommon clinical characteristic of cervical NEC. It can manifest without the classic symptoms of cervical cancer and may clinically appear as a large ovarian tumor without metastases.