Small Cell Neuroendocrine Carcinoma of the Uterine Cervix Mimicking Cervical Lymphoma: A Case Report

Small cell neuroendocrine carcinoma of the uterine cervix (SCNCC) is a rare primary neoplasm of the uterine cervix that accounts for < 1% of all gynecological malignancies [1]. SCNCC is more aggressive than squamous cell carcinoma or adenocarcinoma of the cervix and has a high propensity for lymphatic and hematogenous spread, even in its early stages [1]. Along with its poor prognosis, SCNCC has different treatment strategies from other cervical cancers; therefore, early and accurate diagnosis of SCNCC is essential. However, because of its rarity, there are limited data on its diagnosis in the radiological literature. We present a case of SCNCC mimicking cervical lymphoma and review its radiological findings, with a focus on magnetic resonance imaging (MRI).

A 50-year-old woman presented to Konyang University Hospital with vaginal bleeding for three weeks. The patient was menopausal with no relevant medical history. All laboratory results, including tumor markers such as squamous cell carcinoma-related antigen and cancer antigen 125, were within the normal ranges. Colposcopy revealed an irregular exophytic mass replacing the uterine cervix; therefore, an immediate punch biopsy was performed, followed by abdominal and pelvic computed tomography (CT) and pelvic MRI for tumor evaluation in the cervix. CT showed an irregular enhancing mass in the uterine cervix and multiple enlarged lymph nodes along the bilateral common, external and internal iliac chain, and para-aortic and aortocaval areas. Additionally, a 5.2 × 5.2 cm heterogeneous enhancing mass was found in segment 4 of the liver, which was highly suggestive of metastasis (Fig. 1). MRI also revealed a lobulated, expansile solid mass measuring 6 × 5.5 cm. Although the mass was not infiltrative in the uterine cervix, it extended into the uterus and upper third of the vagina, which were hypointense on T1- and T2-weighted images.

Fig. 1
Abdominal and pelvic CT images of the patient. A: Contrast-enhanced axial CT images show an irregular heterogeneously enhancing mass in the uterine cervix (thick arrow). B-D: Axial and coronal CT images demonstrate multiple enlarged lymph nodes along the bilateral common, external and internal iliac chain, and paraaortic and aortocaval areas (thin arrows in B-D). Two huge subserosal myomas (asterisks) are located in the uterine fundus (C, D). In segment 4 of the liver, a 5.2 × 5.2 cm heterogeneously enhancing mass (empty arrow) is present, highly suggestive of metastasis (E). CT, computed tomography.

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Despite the bulky mass, the cervical epithelium was relatively preserved, and there was no evidence of parametrial invasion. The tumor showed marked heterogeneous enhancement. Axial diffusion-weighted imaging (DWI) (b = 800 sec/mm²) and apparent diffusion coefficient (ADC) showed marked restricted diffusion within the tumor with an ADC value of 0.91 × mm²/s. CT and MRI showed huge uterine subserosal myomas in the uterine fundus without interfacing with the cervical mass (Fig. 2). Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) was also conducted and revealed avid FDG uptake in the uterine cervix, liver, and multiple retroperitoneal and pelvic lymph nodes. Given the numerous enlarged retroperitoneal and pelvic lymph nodes, the tumor's magnetic resonance (MR) signal intensity, and the preserved cervical epithelium, the initial diagnosis was uterine cervical lymphoma with extensive lymph node and liver metastases rather than conventional squamous cervical cancer. The pathological specimen from the punch biopsy showed a marked proliferation of small hyperchromatic neuroendocrine cells. Immunohistochemical staining showed strong positivity of the tumor cells for synaptophysin, a neuroendocrine marker (Fig. 3). These findings were consistent with those of small cell neuroendocrine carcinoma (NEC) of the cervix. The patient began combination chemotherapy with paclitaxel-cisplatin-bevacizumab.

Fig. 2
Pelvic MRI images of the patient. Axial and sagittal T2-weighted images (A, D), axial T1-weighted image (B), and axial fat-suppressed T2-weighted image (C) show a lobulated, expansile, and hypointense solid mass (thick arrows) in the uterine cervix that extends into the uterus and upper third portion of the vagina. The cervical epithelium (arrowheads) is relatively preserved despite the bulky mass. The tumor (thick arrow) shows marked enhancement on a sagittal T1-weighted contrast-enhanced image with fat suppression (E). Axial DWI (b = 800 sec/mm²) (F) and ADC (G) show marked restricted diffusion within the tumor (thick arrows) with an ADC value of 0.91 × mm²/s and no evidence of parametrial invasion. An enlarged left obturator lymph node with restricted diffusion is highly suggestive of lymph node metastasis (thin arrows), and the huge uterine subserosal myoma (asterisks) in the uterine fundus does not interface with the cervical mass. MRI, magnetic resonance imaging; DWI, diffusion-weighted imaging; ADC, apparent diffusion coefficient.

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Fig. 3
Histopathological findings of the SCNCC. Photomicrography (hematoxylin-eosin, ×400) (A) shows a marked proliferation of small hyperchromatic neuroendocrine cells. The tumor cells are strongly positive for the neuroendocrine marker, synaptophysin (×40) (B). The immunohistochemical stain with cytokeratin (×40) reveals a negative reaction (C), which rules out squamous cell carcinoma. SCNCC, small cell neuroendocrine carcinoma of the uterine cervix.

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Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors of epithelial or neuronal/neuroectodermal origin that can arise in any organ. NENs of the neuronal type are represented as paragangliomas. According to the classification proposed by the World Health Organization and the International Agency for Research on Cancer (WHO/IARC) in 2018, epithelial NENs are classified as well-differentiated neuroendocrine tumors (NETs) or poorly differentiated NECs [2]. NECs are further subdivided into small neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC). SCNECs commonly affect the lungs. Extrapulmonary SCNECs are rare, accounting for only 2.5%–5.0% of all SCNECs. The cervix is considered a common site for extrapulmonary SCNECs, but this accounts for fewer than 3% of all cervical cancers [3].

Patients with SCNCC range in age from 21 to 88 years, with the peak incidence occurring in the fourth decade of life. SCNCC is reportedly associated with high-risk human papillomavirus (HPV) infections, predominantly types 16 and 18 [1]. Symptoms are similar to those of other cervical tumors, including abnormal vaginal bleeding, postcoital bleeding, vaginal discharge, and pelvic pain/pressure; however, some patients are asymptomatic. Occasionally, paraneoplastic syndromes manifest, including Cushing syndrome, syndrome of inappropriate antidiuretic hormone, hypercalcemia, and hypoglycemia, which are common in patients with NET of the lung [4].

SCNCC is a highly aggressive neoplasm compared with non-neuroendocrine cervical tumors. Even patients diagnosed at an early stage present with frequent lymph node involvement, vascular invasion, and hematogenous metastases [3]. Similar to small cell lung cancer, the prognosis of SCNCC is related to disease extent. The clinical staging system of SCNCC, established by the International Federation of Gynecology and Obstetrics (FIGO) for uterine cervical cancer, was revised in 2018 to include pelvic and/or paraaortic lymph node metastases as stage IIIC, irrespective of primary tumor size or local pelvic spread. Therefore, radiologists should precisely evaluate the extent of the tumor and determine the presence of distant nodal metastases.

The Papanicolaou smear, a widespread screening method for uterine cervical cancer, is not sensitive enough to diagnose SCNCC [5]. Although the treatment strategies for SCNCC differ from those for other carcinomas, some patients are misdiagnosed as having non-small cell carcinoma based solely on Papanicolaou smear results, leading to inadequate treatment. Hence, another crucial role of radiological imaging is to detect small cell carcinoma for adequate patient treatment.

Owing to its high soft tissue resolution, MRI is considered the gold standard modality for the imaging evaluation of uterine cervical cancer. The MR imaging features of SCNCC are nonspecific. Most tumors are voluminous, exceed 6 cm in size, and show variable morphological patterns, including expansile solid, invasive solid, and diffuse infiltrative patterns [6]. In previous reports, SCNCC demonstrated high signal intensity on T2-weighted images, iso- or low-signal intensity on T1-weighted images, and intense enhancement, which is also seen in non-SCNCC cervical malignancies [5]. Compared with other cervical carcinomas, it tends to show homogeneous signal intensity on T2-weighted images and homogeneous enhancement [5, 7]. DWI and ADC can also help to differentiate between SCNCC and non-SCNCC cervical tumors. According to Duan et al. [7], an ADC cutoff value of 0.90 × mm²/s allows for differentiation between SCNCC and other cervical cancers, with a sensitivity of 63.3% and a specificity of 95%. Other imaging features that distinguish SCNCC from other carcinomas of the uterine cervix include frequent extensive lymphadenopathy and parametrial invasion, even in small tumors [6]. MRI is a valuable imaging modality for detecting parametrial invasion, with a sensitivity of 69% and specificity of 93% [4]. Preoperative assessment of nodal metastases is based on size criteria (greater than 1 cm in the short diameter); however, normal-sized nodes may also contain metastases. MRI can provide improved accuracy using DWI, based on differences in cellularity and histopathology [4]. The lesion homogeneity, low ADC values, and frequent nodal metastases observed in cervical lymphoma can confuse the diagnosis of SCNCC. An important clue for differentiating lymphoma from other cervical tumors is the preservation of the cervical epithelium in the presence of extensive involvement of the cervical stroma [8]. However, this patient had a preserved cervical epithelium; therefore, differentiation between SCNCC and lymphoma was challenging.

In addition to pure SCNCC, there are also cases of SCNCC mixed with other histological types, such as LCNEC, squamous carcinoma, adenocarcinoma, serous carcinoma, adenosquamous cell carcinoma, or carcinoma in situ. In particular, due to the association of high-risk HPV infection with SCNCCs, SCNCC concordance with squamous cells and adenocarcinomas is sometimes reported [9, 10]. The incidence of non-small cell carcinoma differentiation has been documented in 25% of SCNCCs, ranging from 8.7% to 42.3% [10]. Similar to the challenge of distinguishing between squamous cell carcinoma and adenocarcinoma of the uterine cervix using MRI, differentiating between pure and mixed SCNCCs is also difficult, and these diverse histological types of SCNCCs contribute to various MRI findings.

Although SCNCC shows enhancement on contrast-enhanced CT, this modality plays a limited role in the preoperative assessment of SCNCC. However, it can also detect distant metastases and extent of nodal metastases. In addition, chest CT is required to exclude metastasis from small-cell lung cancer. PET/CT is also an essential imaging modality for evaluating distant metastasis and metabolic response to treatment before observing any morphological changes [4].

Treatment of SCNCC is based on the consensus guidelines established by the Society of Gynecologic Oncology in 2011 and the Gynecologic Cancer InterGroup in 2014. Early-stage SCNCC (FIGO stage I–IIA), measuring < 4 cm, is treated with radical hysterectomy and pelvic lymphadenectomy, followed by adjuvant chemotherapy with etoposide and cisplatin or vincristine, Adriamycin, and cyclophosphamide. Large early-stage SCNCC (FIGO I–IIA), measuring > 4 cm, is treated with neoadjuvant chemotherapy. Late-stage SCNCCs with locally advanced disease (IIB–IVA) are treated with chemoradiation followed by systemic chemotherapy, while patients with distant metastasis (IVB) are managed with chemotherapy and palliative radiotherapy [5].

In conclusion, SCNCC is a rare form of cervical carcinoma with a poor prognosis. The role of the radiologist is to suggest the possibility of SCNCC when the cervical tumor is visible on imaging and to evaluate the extent of the tumor and the presence of nodal and distant metastases for accurate staging. MR features that suggest SCNCC include lesion homogeneity, low ADC value, and frequent nodal metastases. The patient in this report showed preserved cervical epithelium in addition to all of these features, which mimics lymphoma. Despite the rarity of SCNCC, it shares imaging features with lymphoma. A broader differential diagnosis is needed when a cervical mass presents with a homogenous texture, restricted diffusion, and extensive nodal metastasis.