Basaloid Squamous Cell Carcinoma of the Uterine Cervix: An Often Aggressive Subtype Frequently Underestimated by Cytology

ABSTRACT

Basaloid squamous cell carcinoma of the cervix (BSCC) is an extremely rare subtype. In the 2020 WHO classification, BSCC is considered a subtype within HPV‐associated squamous cell carcinoma. We report a case wherein liquid‐based cytology (LBC) initially suggested a high‐grade squamous intraepithelial lesion (HSIL). Retrospective review, prompted by the histologic diagnosis of BSCC, revealed diffuse sheets of monotonous basaloid and parabasaloid cells. Key cytologic features included three‐dimensional clusters with occasional papillary architecture, palisading, and cord‐like arrangements—findings that can be misleading. This case underscored that BSCC's deceptively bland cytology often overlaps with HSIL, contributing to diagnostic under‐call. Increased awareness of these subtle yet distinctive patterns is crucial for accurate identification and appropriate clinical management of this rare variant.

1. Introduction

In the 2020 World Health Organization (WHO) classification of female genital tumors, Basaloid squamous cell carcinoma of the cervix (BSCC) is considered a subtype within HPV‐associated squamous cell carcinoma. It is a distinct, rare variant of squamous cell carcinoma. Compared to conventional squamous cell carcinoma, it has been reported to exhibit more aggressive clinical behavior, including deeper stromal invasion and higher metastatic potential. Despite its clinical significance, preoperative diagnosis by cytology is challenging due to scant literature on its cytomorphologic features. There is only one detailed prior report in English literature focusing on cytology. This frequently leads to misinterpretation as a high‐grade intraepithelial lesion (HSIL) or other entities, delaying recognition of its invasive nature. We present a case with comprehensive cytologic, histologic, and immunohistochemical correlation to elucidate the overlapping and distinctive features of cervical BSCC, aiming to enhance diagnostic accuracy in cytology practice.

2. Case Report

2.1. Clinical History

A 46‐year‐old woman presented with postcoital bleeding and increased vaginal discharge. HPV testing was positive. Cervical ultrasound revealed a 3.9 cm hypoechoic mass (Figure 1A). Initial LBC diagnosis was HSIL. Cervical biopsy confirmed invasive squamous cell carcinoma, basaloid subtype. The patient underwent radical hysterectomy with lymphadenectomy. Final pathology confirmed poorly differentiated BSCC with deep stromal invasion and lymphovascular space invasion. All resected lymph nodes were negative. The patient received adjuvant chemoradiotherapy and remained disease‐free after 22 months of follow‐up, with subsequent negative cervical cytology.

FIGURE 1.

Clinical and cytological features of cervical basaloid squamous cell carcinoma (BSCC).

2.2. Cytologic Features (Liquid‐Based Preparation)

Retrospective review of the LBC slides, following the histologic diagnosis, revealed characteristic yet deceptive findings:

The smear was hypercellular, dominated by diffuse, monotonous sheets of small to medium‐sized cells resembling basaloid and parabasaloid cells (Figure 1B).

Cells were present in flat, cohesive sheets with a “cobblestone” appearance, in crowded three‐dimensional clusters, and as scattered single cells (Figure 1C,D).

The cell size was uniform, similar to parabasal cells, with a high nuclear‐to‐cytoplasmic ratio. The cytoplasm was scant and cyanophilic.

Nuclei were round to oval with smooth contours, coarsely granular but evenly distributed chromatin, and frequent single prominent nucleoli—a feature less common in typical HSIL (Figure 1E).

Architectural clues included peripheral palisading in cell balls, cord‐like structures, and, notably, occasional papillary and pseudoglandular formations (Figure 1F). These complex architectural patterns, though not pathognomonic, are an unusual and helpful clue distinguishing it from simple HSIL.

Background was clean, lacking tumor diathesis.

2.3. Histologic and Immunohistochemical Features

Histology showed tumor nests with peripheral palisading, lobulated, cribriform, and cord‐like patterns (Figure 2A). Tumor cells were monomorphic with scant cytoplasm, hyperchromatic nuclei, and frequent mitoses. Immunohistochemistry was positive for p40, p63, CK5/6, and p16 (block‐type), supporting squamous differentiation and HPV association. Ki‐67 index was high (~80%). Focal positivity for CK7 and CK8/18 was noted. Tumor cells do not express BCL‐2.

FIGURE 2.

Histopathological and immunohistochemical features (H&E and IHC).

Figure 1A Transvaginal ultrasound showing a hypoechoic cervical mass. B: Low‐power view of LBC smear demonstrating hypercellularity with diffuse sheets of monotonous basaloid cells (Papanicolaou stain, × 100). C: Flat sheet of tumor cells with a characteristic “cobblestone” appearance (× 200). D: Three‐dimensional cluster exhibiting a cord‐like structure and peripheral palisading (arrows) (× 200). E: High‐power cytologic view revealing key details: uniform round nuclei, coarsely granular chromatin, and conspicuous nucleoli. These features are central to the diagnosis and differential (× 400). F: Cell cluster with a complex papillary‐like architecture, an uncommon but helpful diagnostic clue (× 200).

Figure 2A Histology (H&E, × 10): Invasive tumor nests showing a lobulated growth pattern with peripheral palisading. B: immunohistochemistry for p16 (× 10): Strong and diffuse block‐type positivity, confirming HPV‐associated carcinoma. C: Immunohistochemistry for p63 (× 10): Diffuse nuclear positivity, confirming squamous differentiation. D: Immunohistochemistry for CK8/18 (× 10): Focal positivity in tumor cells.

3. Discussion

This case highlights the critical diagnostic challenge posed by cervical BSCC in cytology. The predominant finding—a monotonous population of basaloid cells—creates significant overlap with HSIL, often leading to an invasive carcinoma being undercalled as a high‐grade lesion.

3.1. Unique Cytomorphologic Features

Our case exhibited several features that, while not entirely exclusive, serve as valuable diagnostic clues: (1) striking uniformity of basaloid cells throughout the smear; (2) presence of conspicuous nucleoli in many cells, which are atypical for classic HSIL; and (3) formation of complex architectures such as papillary and pseudoglandular structures within cell clusters. These findings supplement the limited prior descriptions [1] and should raise suspicion for a basaloid variant.

3.2. Overlap With HSIL and Diagnostic Pitfalls

The morphologic mimicry of HSIL is the primary confounding factor. Martínez‐Girón et al. described BSCC smears as showing syncytial groups of small, hyperchromatic cells [1], a feature easily misinterpreted as HSIL. Major pitfalls leading to underestimation include: (a) lack of pronounced pleomorphism compared with usual squamous cell carcinoma; (b) smooth nuclear contours and evenly distributed chromatin that may appear less malignant [1]; and (c) insufficient experience with this rare entity. A review by Wang Liqun et al. of cases with prior cytology found diagnoses ranging from normal to ASC‐H/HSIL, confirming a high rate of under‐call or misdiagnosis [2]. Other reports also noted cytologic interpretations as reactive changes or ASCUS [3, 4], underscoring the diagnostic difficulty.

3.3. Differential Diagnosis From Other Basaloid Tumors

The main differential diagnoses of BSCC include adenoid cystic carcinoma (ACC), small cell carcinoma, large cell neuroendocrine carcinoma, and adenoid basal cell carcinoma (ABC). Positive immunostaining for epithelial markers (Figure 2B–D) in our case ruled out neuroendocrine carcinomas, leaving ACC and ABC as the primary considerations. An increasing number of studies suggest that BSCC shares a common origin with ACC and ABC [5]. However, unlike ABC (which is generally indolent), BSCC and ACC are considered high‐grade malignancies with invasive potential [6].

Differentiation from ACC: Cytologically, ACC smears show abundant globular, amorphous material with lesional cells forming three‐dimensional rosette‐like structures around it. The nuclei are usually round or oval, monomorphic, with few nucleoli. In contrast, BSCC has larger nucleoli and lacks semi‐transparent mucinous globules. Histologically, ACC displays three‐dimensional clusters with a small acini pattern; the solid variant shows mainly solid sheets of small basaloid tumor cells with focal cribriform areas and basement membrane‐like material (positive for collagen IV and laminin). BSCC exhibits peripheral palisading without an acini pattern. Immunohistochemically, ACC is generally positive for broad‐spectrum CK, EMA, CD117, and CK7 [7], whereas BSCC stains strongly and positively for p63 (Figure 2C) and p40, with ACC being generally negative for these markers.

Differentiation from ABC: In the 2020 WHO classification, cervical ABC is categorized as another type of epithelial tumor, and its relationship with HPV infection remains unclear. Cytologically, ABC and BSCC are relatively difficult to distinguish, but nucleoli are less commonly seen in ABC. Histologically, ABC consists of uniform, small basaloid cells arranged in round or lobular configurations, with peripheral palisading and occasional glandular or cribriform architecture. The tumor nests are smaller with bland cytomorphology and minimal stromal reaction. In contrast, BSCC shows irregular tumor nest contours, frequent central necrosis, marked cellular atypia, and readily identifiable mitotic figures. Immunohistochemically, both are diffusely positive for broad‐spectrum cytokeratin, p63, and p16 (Figure 2C). However, a low Ki‐67 proliferation index in the basaloid cell component favors ABC over BSCC.

3.4. Molecular Features

Because of the rarity of BSCC, knowledge of its molecular background is limited. Only isolated cases have been reported, including the case reported by Munkhdelger et al. where both PIK3CA mutation and NTRK2 fusion coexisted [8]. Therefore, the specific driving mechanisms of BSCC remain incompletely understood.

3.5. Clinical Implications and Prognostic Context

The perceived aggressive behavior of BSCC requires careful contextualization. Early case reports and small series have described features such as deeper stromal invasion, lymphovascular space involvement, and anecdotal reports of rapid progression even in young patients [4, 9]. However, the largest population‐based study to date [9], using propensity score matching and multivariate adjustment, found that BSCC does not differ significantly from conventional squamous cell carcinoma in disease‐specific or overall survival. Therefore, while historical literature has suggested a poorer prognosis with higher rates of recurrence and distant metastasis, more recent evidence indicates that such assumptions may not hold when accounting for confounders.

3.6. Emerging Molecular Landscape and Future Directions

Beyond the morphologic and immunohistochemical framework, emerging molecular data are beginning to define the genomic and epigenetic landscape of BSCC, offering opportunities to deepen biologic understanding and extend clinical relevance. While the molecular pathology of cervical BSCC remains largely uncharted, the literature on BSCC arising in other anatomic sites—particularly the esophagus—provides important insights. In esophageal BSCC, studies have demonstrated a distinct genetic profile characterized by a low frequency of PIK3CA mutations compared with conventional esophageal SCC (23% in SCC vs. 0% in BSCC), along with significantly lower LINE‐1 methylation levels, suggesting that BSCC and SCC of the same organ represent biologically distinct entities with different cellular phenotypes [10]. Epigenetic dysregulation has been further implicated in BSCC pathogenesis through hypermethylation‐mediated silencing of sFRP‐2, leading to activation of the Wnt/β‐catenin signaling pathway [11]. In the lung, pure basaloid squamous cell carcinomas exhibit a specific mRNA expression signature characterized by upregulation of genes involved in cell cycle control, transcription, chromatin remodeling, and splicing—with prevalent expression in germline and stem cells—while genes related to squamous differentiation are markedly underexpressed, indicating a primitive cellular phenotype [12]. For cervical BSCC specifically, a clinicopathological and molecular analysis by Shi et al. demonstrated that high‐risk HPV oncogenes likely play a pathogenic role in cervical carcinomas with basaloid features [13]. Future studies employing next‐generation sequencing on larger cohorts of cervical BSCC are urgently needed to clarify whether the molecular features observed in esophageal and pulmonary BSCC are recapitulated in cervical tumors, and to identify potential targetable alterations that could inform personalized treatment strategies.

From a clinical standpoint, accurate preoperative identification of BSCC remains valuable, primarily to avoid misdiagnosis with its histologic mimics (e.g., ABC, HSIL). Given the morphologic overlap, raising the possibility of BSCC when cytology shows a monotonous HSIL‐like picture can guide appropriate diagnostic workup and surgical planning. However, statements implying an inherently more aggressive tumor than conventional squamous cell carcinoma should be tempered, as the best available evidence does not support a meaningful difference in overall prognosis after risk adjustment.

4. Conclusion

Cervical BSCC is a rare but potentially aggressive tumor frequently misclassified as HSIL in cytology due to deceptively bland and overlapping morphologic features. Awareness of its characteristic monotony, nucleolar prominence, and distinctive architectural patterns is essential to avoid diagnostic pitfall. Correlation with clinical presentation and a low threshold for recommending biopsy in such “atypical” HSIL cases are crucial. Inclusion of BSCC in the differential diagnosis of monotonous HSIL‐like lesions will improve preoperative detection and optimize patient management for this rare variant.

Funding

This work was supported by the Shenzhen Health Economy Project (No. 202520) and the Sanming Project of Medicine in Shenzhen Grant No. (SZSM 202211032).

Ethics Statement

This case report was reviewed and approved by the Institutional Review Board/Ethics Committee of Shenzhen Maternity and Child Healthcare Hospital. The committee granted a formal waiver for the requirement of obtaining individual patient informed consent for the publication of this de‐identified case report, as it involved retrospective analysis of existing medical records and posed minimal risk to the patient.

Consent

In accordance with the approval from the Ethics Committee of Shenzhen Maternity and Child Healthcare Hospital, the requirement for written informed consent from the patient for the publication of this de‐identified case report has been formally waived. All patient identifiers have been removed to protect privacy.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this case report are not publicly available due to patient privacy and ethical restrictions. De‐identified data may be made available from the corresponding author upon reasonable request and with permission from the Ethics Committee of Shenzhen Maternity and Child Healthcare Hospital.