Introduction
Small cell neuroendocrine carcinoma (SCNEC) is a highly aggressive malignancy. Although it most commonly arises in the lungs, its occurrence in the gynaecological tract is rare (1). When SCNEC does affect gynaecological organs, the uterine cervix is the most frequently involved site (1). Cervical SCNEC accounts for <1% of all gynaecological malignancies and <5% of all cervical cancers (2,3). Compared to cervical squamous cell carcinoma (SCC) and adenocarcinoma, cervical SCNEC has a significantly worse prognosis (1–4). Therefore, early detection and multimodal therapy are crucial for improving patient outcomes.
Cytological examination is one of the gold standards for detecting cervical lesions because it is convenient, minimally invasive, and cost-effective (5). Thus, cytological diagnosis plays a crucial role in the early detection of cervical SCNEC. However, due to its rarity, diagnosing SCNEC cytologically can be challenging. In one study, only one out of 13 patients was suspected of having cervical SCNEC based on cytological findings (6). In another cytological series, none of the patients were accurately diagnosed with cervical SCNEC (7). Instead, patients were often misdiagnosed with squamous lesions, which are far more common (6,7). The cytological features of cervical SCNEC are similar to those of other organs, such as the lungs. These features include loose cohesive clusters and/or single small, round neoplastic cells with a high nuclear-to-cytoplasmic ratio, oval-to-round nuclei with finely granular chromatin and inconspicuous nucleoli, nuclear moulding in a necrotic background (6–10). Moreover, cervical SCNEC may coexist with other histological types of non-neuroendocrine neoplasms, including squamous intraepithelial lesions (SIL), SCC, and adenocarcinoma (11–15). The presence of these additional components may lead to a misdiagnosis of SCNEC components in cytological specimens, as SIL, SCC, or adenocarcinoma components can overshadow the SCNEC features (16–19).
This study retrospectively analysed the cytological features of cervical SCNEC, including combined SCNEC, and discussed the clinicocytological features of this rare tumour, with a focus on identifying coexisting carcinoma components.
Discussion
This study described the cytological features of six patients with cervical SCNEC. To our knowledge, this is the second cytological series on cervical SCNEC to include combined SCNEC. The cytological features of SCNEC are consistent across various organs, including the lungs, bile duct, uterine cervix, endometrium, and urinary bladder (6–10). Thus, the cytological diagnosis of SCNEC using cervical smears should not be particularly challenging. However, due to the rarity of cervical SCNEC, the rate of accurate cytodiagnosis remains low (6,7). For instance, Liu et al (7) retrospectively analysed cytological cases of cervical SCNEC, including combined SCNEC. Their study comprised seven pure SCNEC cases and four combined SCNEC, and none of the patients were correctly diagnosed with SCNEC based on the initial cytological examination. Instead, three cases were suspected to have high-grade SIL, while two were misdiagnosed as atypical glandular cells. Additionally, only one cytological specimen contained high-grade SIL, but no adenocarcinoma and SCC components were present by retrospective review of combined SCNEC (7). Cervical SCNEC is mainly missed or misdiagnosed as SIL or SCC (6,7,20–22). In the present series, five of six patients were initially diagnosed with SCNEC, and the remaining patients were diagnosed with SCC. Liu et al summarised the causes of misdiagnosis of SCNEC by the cervical cytological examination as follows: i) the rarity of this type of carcinoma, ii) SCNEC can be overlooked in the presence of squamous and/or glandular lesions, iii) SCNEC can be mimicked by the other neoplasms, such as SIL and SCC (cytological differential diagnostic considerations are discussed later), iv) SCNEC is not present in the cytological specimens because this carcinoma component can be present in the submucosal region or necrosis and/or heavy inflammatory may result in insufficient sampling (7). Interestingly, the present series included two patients with combined SCNEC and one patient with carcinosarcoma. Retrospective cytological analysis revealed that the adenocarcinoma component was present in the cytological specimen of one of the two patients with combined SCNEC, and both the sarcomatous component and SCNEC were present in the cytological specimen of the carcinosarcoma. Previous reports have suggested that SCNEC, as well as combined adenocarcinoma and/or SIL components, can be detected in cervical cytological specimens (16,17). According to these results, careful observation of cervical cytological specimens may lead to the correct diagnosis of SCNEC as well as combined tumour lesions.
Carcinosarcomas are rare biphasic malignant tumours composed of carcinomatous and sarcomatous components. Although rare, SCNEC can serve as the carcinomatous component in cervical carcinoma (23), as seen in our study (Patient 6). The sarcomatous component is often homologous (e.g., fibrosarcoma, endometrioid stromal sarcoma) but can also exhibit heterologous differentiation (e.g., osteosarcoma and rhabdomyosarcoma) (23). The accuracy of initial cytological diagnosis for cervical carcinosarcoma is generally low. A previous study reported that only two of 23 cases (21 endometrial and two cervical carcinosarcomas) were correctly identified as carcinosarcoma through cytological examination, while 14 cases were misdiagnosed as carcinoma (24). The detection of sarcomatous components in endometrial and cervical cytological specimens is notably more challenging (24,25). In Patient 6 (carcinosarcoma), the SCNEC component was identified by initial cytological examination. However, retrospective cytological analysis was able to detect both SCNEC and sarcomatous components. These findings emphasise the importance of meticulous cytological evaluation for achieving an accurate diagnosis.
It is well-recognised that HPV is associated with the development of a large proportion of cervical neoplasms, including SIL, SCC, and adenocarcinoma (5). Infection with HPV, particularly HPV18, a common high-risk strain, is correlated with cervical SCNEC (1,7). Consequently, cervical SCNEC may contain SIL, SCC, and/or adenocarcinoma components, although their precise incidence remains unknown. Immunohistochemical staining for p16 is widely used as a surrogate marker for detecting high-risk HPV, and most cervical SCNECs exhibit positive immunoreactivity for this marker (1,7). Additionally, it has been reported that combined SIL, SCC, and adenocarcinoma components exhibit positive immunoreactivity for p16 (11,16,17). In the present study, all SCNEC showed positive immunoreactivity for p16. Although HPV testing results were not available for all patients in the present cohort, all likely had a high-risk HPV infection, particularly HPV18 (1,7).
The primary differential cytological diagnoses for cervical SCNEC are SIL and SCC. A small proportion of patients with cervical SCNEC are misdiagnosed with SIL and SCC (6,7,20–22), and one of the six patients in the present cohort was initially diagnosed with SCC. Key distinguishing features of SCNEC include finely granular (salt-and-pepper) chromatin, inconspicuous nucleoli, and nuclear moulding (6,7,20–22). In contrast, SIL and SCC typically exhibit richer and denser cytoplasm, clearer cell boundaries, and a lack of definitive nuclear moulding (6,7,20–22). These cytological features may help in differential diagnosis. In one patient initially diagnosed with SCC in the present study, nuclear moulding was not apparent; therefore, SCC was initially considered. Positive immunocytochemical staining for CD56 may aid in the cytodiagnosis of SCNEC (20); however, immunocytochemical staining for neuroendocrine markers was not performed in the present study.
The present study had some limitations. First, this study included relatively few patients with SCNEC, although this type of carcinoma is relatively rare. Second, HPV testing results were not available for all patients in the present cohort. Further studies are needed to clarify the clinicocytological and molecular features of cervical SCNEC.
In conclusion, the results of the present study demonstrated that most SCNEC could be detected in cervical cytological specimens. Moreover, other combined carcinoma components, as well as sarcomatous components, could be identified in cervical cytological specimens. Thus, cervical cytological examination may be helpful in SCNEC diagnosis. The detection of SCNEC in cervical cytological specimens is crucial for accurate and early diagnosis and timely treatment of this aggressive carcinoma.