Basosquamous Carcinoma: Beyond the High-Risk Label—Does Histotype Alone Define Prognosis?

1. Introduction

Basosquamous carcinoma (BSC), also referred to as metatypical basal cell carcinoma, represents an uncommon keratinocyte malignancy characterized by the coexistence of basaloid and squamous differentiation within the same tumor. Although basal cell carcinoma (BCC) is typically associated with an indolent clinical course and an exceptionally low metastatic risk, BSC has long been regarded as a problematic “borderline” entity, raising relevant diagnostic and prognostic concerns [1,2]. In the current World Health Organization framework [3], BSC is included within the spectrum of basal cell carcinomas and is characterized by squamous differentiation, a definition that supports the notion of phenotypic evolution within a primarily basaloid tumor rather than a true “collision” of two independent neoplasms [1,2]. Nevertheless, terminology and classification remain debated, and the lack of uniform diagnostic criteria continues to complicate comparisons across published series [4].

Clinically, BSCs may present as relatively inconspicuous erythematous or keratotic lesions, particularly when small and non-ulcerated. In such lesions, dermoscopy may reveal a heterogeneous combination of BCC-like vascular features and whitish or keratotic SCC-associated structures, reflecting the dual morphological phenotype of the tumor [4]. In small or superficial biopsies, histopathological diagnosis may be challenging In small or superficial biopsies, histopathological diagnosis may be challenging because limited sampling may fail to capture squamous differentiation located elsewhere or deeper within the tumor [1,5]. Ancillary techniques, including immunohistochemistry, may help support the diagnosis, yet the biological meaning of transitional areas and the relationship between basaloid and squamous compartments remain incompletely clarified [6]. In recent years, genomic and transcriptomic data have provided important insights into tumor plasticity, suggesting that BSC shares key driver alterations with BCC and may acquire additional pathways associated with squamatization, supporting a model of dynamic differentiation rather than a de novo SCC [7]. Even with these advances, the mechanisms that trigger and maintain the squamous phenotype, as well as their clinical correlates, are still under investigation.

The central unresolved question concerns prognosis. Historically, BSC has been described as more aggressive than conventional BCC, with higher local recurrence rates and a non-negligible risk of nodal or distant metastasis, leading some authors to consider its clinical behavior closer to cutaneous squamous cell carcinoma [6,8]. However, reported recurrence and metastasis rates are highly heterogeneous and likely influenced by case-mix, anatomical site, tumor stage, margin status, and other adverse histological features [6,8]. Contemporary series largely composed of early-stage tumors have documented low event rates, challenging the traditional view of BSC as intrinsically more aggressive than conventional BCC [1,9].

These uncertainties have practical implications for management and follow-up strategies. Current clinical practice typically treats BSC as a high-risk keratinocyte carcinoma, emphasizing complete excision, careful margin assessment, and consideration of micrographically controlled surgery in anatomically critical locations, in line with broader recommendations for difficult-to-treat or high-risk BCC [2,10]. Nonetheless, dedicated evidence-based guidelines specifically addressing BSC remain limited, and the intensity of follow-up is often decided empirically, reflecting the persisting gap between biological concepts and robust prognostic stratification [9].

On this background, the present study aims to characterize the clinicopathological features and clinical course of basosquamous carcinoma in a real-world institutional cohort, with particular attention to clinical outcomes in the context of established histopathological high-risk features.

2. Materials and Methods

We conducted a retrospective, observational case-series study at the Dermatologic Clinic, Fondazione IRCCS Policlinico San Matteo, University of Pavia (Italy). Consecutive patients with a pathology-record diagnosis of BSC between January 2018 and December 2023 were retrieved from institutional records. All specimens had been diagnosed on hematoxylin and eosin-stained sections as part of routine clinical practice, and all cases were re-examined by a board-certified dermatopathologist (CT) according to the morphological criteria detailed below. Immunohistochemistry, including BerEP4 and EMA, was reviewed, when available.

According to the WHO classification, BSC was defined as a malignant epithelial tumor showing, within the same lesion, unequivocal basaloid areas consistent with BCC and areas of true squamous differentiation [3]. Squamous differentiation was identified by the presence of larger polygonal cells with eosinophilic cytoplasm, cytoplasmic keratinization and/or dyskeratosis, intercellular bridges, and, when present, keratin pearl formation. A morphological transition between the basaloid and squamous components was considered a key feature supporting the interpretation of a unified neoplasm, whereas collision tumors consisting of spatially distinct BCC and SCC components without morphological transition were excluded.

Particular attention was paid to distinguishing BSC from BCC with follicular (trichoid) differentiation, as both may display prominent keratinization. In BCC with follicular differentiation, keratinization occurs within well-organized follicular-like structures or horn cysts, while the surrounding tumor cells retain a predominantly basaloid phenotype. In contrast, BSC shows true squamous differentiation, with progressive transition from basaloid cells to larger eosinophilic keratinizing cells, often accompanied by keratin pearl formation.

Variables were recorded at three levels. Sex, age at excision, follow-up duration and outcome were recorded per patient; anatomical site, maximum tumor diameter and primary treatment per tumor; histopathological features per specimen. Anatomical sites were grouped as face, scalp, ear, neck, upper limb and lower limb. Maximum tumor diameter was taken as the major axis of the lesion recorded in the macroscopic description of the pathology report; a 2-cm threshold was applied descriptively, as a conventional size threshold in the BCC literature, without formal tumor staging.

The growth pattern of the BCC component was classified as nodular, superficial, infiltrative, or micronodular according to the classification used by Raasch et al. [11] Tumors displaying two or more growth patterns were categorized as mixed. This classification was applied exclusively to the BCC component of the tumors.

The squamous component was recorded as focal or diffuse, and its extent was estimated semiquantitatively and dichotomized as <50% versus ≥50% of the tumor area.

Invasion depth was measured as for cutaneous squamous cell carcinoma, from the granular layer of the adjacent epidermis or from the base of the ulcer when present [12], to the deepest invasive tumor focus. Ulceration, lateral and deep margin status with minimum clearance in millimeters, perineural invasion and lymphovascular invasion were also recorded. Margins were classified as involved or clear according to the statement in the pathology report, and the minimum clearance was recorded in millimeters.

Follow-up time was calculated from the date of the surgical procedure to the last documented clinical evaluation; for the patient who underwent two procedures, follow-up was calculated from the date of the first procedure. Primary outcome measures were local recurrence and metastatic spread. Regional or distant metastasis was defined as disease identified clinically and/or radiologically, with histopathological confirmation when available. Analyses were descriptive, with continuous variables summarized as mean values and categorical variables reported as absolute counts and percentages. Given the descriptive nature of the study and the absence of a comparative cohort, no inferential statistical analyses were performed.

3. Results

Overall, 32 patients with histologically confirmed BSC were included, corresponding to 32 tumors and 33 histological specimens (Table 1); one patient with involved margins underwent margin-revision surgery and is therefore represented by two sequential specimens. The cohort comprised 19 males (59.4%) and 13 females (40.6%). Mean age at excision was 78.2 years (median 80, range 51–95), with most patients in the 8th–9th decades of life. Twenty-five tumors (78.1%) arose in the head and neck region, with the face representing the most frequent individual site (19/32, 59.4%), followed by the lower limbs (6/32, 18.8%) and the upper limb (1/32, 3.1%); no lesions were observed on the trunk.

The anatomical distribution differed descriptively between the sexes: facial tumors accounted for 14/19 tumors in men (73.7%), whereas lower-limb tumors accounted for 6/13 tumors in women (46.2%).

Tumor size was available for 29/32 tumors. Most tumors were small, measuring <1 cm in 7/29 cases (24.1%) and 1.0–1.9 cm in 16/29 cases (55.2%). Lesions measuring 2.0–2.9 cm accounted for 4/29 cases (13.8%), while lesions measuring 3.0–3.9 cm accounted for 2/29 cases (6.9%). Overall, 23/29 tumors (79.3%) were <2 cm. Invasion depth was available for all 32 tumors and averaged 2.5 mm (SD 1.26; range 0.3–5.0), with a median of 2.0 mm. The deepest anatomical plane, recorded in 31/32 tumors, was the reticular dermis in 21/31 (67.7%), the subcutis in 6/31 (19.4%) (Figure 1A), the papillary dermis in 2/31 (6.5%) and skeletal muscle in 2/31 (6.5%). Perineural invasion was documented in 3/32 tumors (9.4%) and lymphovascular invasion in 1/31 assessable tumors (3.2%).

The BCC growth pattern was micronodular in 11/32 tumors (34.4%), mixed in 11/32 (34.4%), nodular in 7/32 (21.9%), and superficial in 3/32 (9.4%). Among tumors with a mixed growth pattern, the micronodular–infiltrative combination was the most frequent (5/11, 45.5%). A micronodular component, either as the sole pattern or as part of a mixed pattern, was present in 21/32 tumors (65.6%).

The squamous component was diffusely distributed in 28/32 tumors (87.5%) and focal in 4/32 (12.5%), and accounted for at least 50% of the tumor area in 21/32 (65.6%) (Figure 1B–D). Ulceration was present in 24/31 assessable specimens (77.4%) (Figure 1 and Figure 2) .

Immunohistochemistry was available in 7/33 specimens (21.2%). In these cases, BerEP4 preferentially highlighted the basaloid component, with reduced or absent staining in areas of squamous differentiation, whereas EMA showed the opposite distribution (Figure 1E,F).

Surgical margins were assessed in the 31 tumors treated by primary excision; the remaining tumor had been sampled by incisional biopsy and treated with cryotherapy. Both margins were clear in 27/31 excisions (87.1%). The lateral margin was involved in 3/31 (9.7%) and the deep margin in 2/31 (6.5%): the lateral margin alone in two excisions, the deep margin alone in one, and both margins in one (1/31, 3.2%), so that at least one margin was involved in 4/31 excisions (12.9%). Where the margin was clear, the mean lateral clearance was 2.5 mm (median 2.0; range 1.0–5.0) and the mean deep clearance 2.8 mm (median 2.0; range 0.2–6.0). The patient with both margins involved underwent margin-revision surgery; in the re-excision specimen the lateral margin remained focally involved while the deep margin was clear. Two further patients underwent subsequent wide re-excision, one for an involved lateral margin and one for a deep clearance below 1 mm; both re-excision specimens were free of residual tumor and were therefore not included among the study specimens.

Follow-up was documented in 28/32 patients (87.5%), with an observation time of 1.0 to 7.0 years (mean 3.9, median 3.7). No histologically confirmed local recurrence of BSC was observed and no regional or distant metastases occurred. Two patients developed a further cutaneous malignancy at the site of the previous excision: an invasive squamous cell carcinoma one year after surgery, and a Merkel cell carcinoma six months after surgery in a patient with a previous bone-marrow transplant. Neither lesion was reported as showing basosquamous morphology, and both were therefore recorded as second tumors arising at a previously treated site rather than as proven BSC recurrences. Four patients died during the observation period; no disease-specific deaths occurred.

4. Discussion

Basosquamous carcinoma (BSC) has occupied an unsettled position within the spectrum of keratinocyte carcinomas since its earliest formal descriptions, beginning with the classic concept of “basal squamous cell epithelioma” [13,14], and subsequent debates on whether these lesions represent true collision tumors or, more plausibly, a basal cell carcinoma undergoing squamous differentiation [15,16]. This historical and diagnostic uncertainty may partly explain why BSC has traditionally been regarded as more aggressive than conventional BCC. However, much of the earlier literature was generated before standardized diagnostic criteria were established and included heterogeneous methods of case ascertainment, potentially introducing definitional variability, referral bias, and incomplete pathological assessment. BSC may also be underdiagnosed on partial or superficial biopsies, which may sample predominantly basaloid areas while failing to capture squamous differentiation located elsewhere or deeper within the tumor. In several studies, tumors ultimately diagnosed as BSC had initially been classified clinically or histologically as BCC before complete excision or margin-controlled assessment revealed squamous differentiation [17,18,19,20]. These diagnostic limitations should be considered when interpreting the heterogeneous clinical outcomes reported across BSC series.

In the present clinicopathological series of 32 BSCs, most tumors were small and predominantly located in the head and neck region. Despite the presence of adverse histopathological features in a subset of cases, including perineural invasion and deep extension, no histologically confirmed local recurrences or regional or distant metastases were documented during the available follow-up. From a morphological standpoint, one of the most notable findings was the high prevalence of a micronodular BCC component, while squamous differentiation occupied at least 50% of the tumor area in approximately two thirds of cases.

Overall, these findings provide the basis for discussing the morphological characteristics of BSC and their possible relationship with the relatively favorable clinical course observed in our predominantly small-tumor cohort. The high prevalence of the micronodular component was particularly noteworthy: it occurred as a pure growth pattern in 11/32 tumors (34.4%) and, either alone or within a mixed pattern, was documented in 21/32 tumors (65.6%). This proportion is higher than the frequency of micronodular BCC reported in unselected institutional and population-based series [11,21,22,23].

Because our cohort was selected for the presence of squamous differentiation, direct comparison with unselected BCC cohorts should be interpreted cautiously. Nevertheless, the high prevalence of a micronodular component raises the possibility of an association between squamous differentiation and high-risk basaloid growth patterns [2].

A possible biological framework is provided by molecular evidence suggesting that squamous transformation may arise through ARID1A-dependent epigenetic plasticity within a Hedgehog-driven basaloid clone [7]. This model provides a potential mechanistic context for the co-occurrence of micronodular growth and squamous differentiation observed in our series.

The extent of squamous differentiation represents another potentially relevant morphological observation. A squamous component involving ≥50% of the tumor was recorded in 21/32 tumors (65.6%). To our knowledge, no dedicated study has systematically graded BSC according to the quantitative proportion of squamous differentiation or correlated this parameter with growth pattern or outcome; therefore, this finding should be regarded as descriptive and hypothesis-generating.

The proportion of lower-limb tumors in our cohort is also noteworthy. Although BSC is predominantly reported at head-and-neck sites, lower-limb involvement has also been documented in contemporary real-world series [1,9]. The predominance of lower-limb lesions among women in our small cohort is descriptive and requires confirmation in larger epidemiological series.

The principal clinical question, however, remains whether BSC histology itself confers an adverse prognosis or whether the outcomes reported in different series primarily reflect the distribution of established clinicopathological risk factors. Although the cohort was small and predominantly composed of tumors measuring <2 cm, it was not devoid of adverse pathological findings, including perineural invasion in 3/32 (9.4%). Nevertheless, no disease progression was documented during a median follow-up of 3.7 years, even though adverse pathological features were present in a subset of tumors.

A large single-center clinicopathological cohort similarly reported no recurrences or metastases in a population largely restricted to small, limited-stage tumors, suggesting that the absence of advanced-stage tumors may substantially contribute to the favorable outcomes observed in contemporary series [9]. These observations should not, however, be interpreted as evidence that margin involvement, perineural invasion, incomplete excision, or non-surgical treatment lack prognostic relevance.

In contrast, historical series that contributed substantially to the perception of BSC as an intrinsically aggressive tumor reported considerably higher event rates, with local recurrence approaching one third of cases and clinically relevant nodal or distant metastases [8,24]. However, these cohorts often included selected high-risk tumors and were characterized by heterogeneous pathological definitions and treatment approaches, making it difficult to separate the prognostic contribution of BSC histology from that of other adverse clinicopathological factors. Importantly, even in more contemporary head-and-neck series where measurable rates of local relapse and nodal metastasis are documented, progression clusters in tumors with advanced T classification, deep infiltration, incomplete resection and high-risk subsites, suggesting that established clinicopathological risk factors may contribute substantially to the adverse outcomes historically attributed to BSC [6].

This conclusion gains further plausibility when benchmarked against conventional BCC and cutaneous SCC literature: in BCC, large diameter and deeper invasion are recognized predictors of recurrence and adverse outcomes, and cohorts restricted to tumors ≥2 cm demonstrate materially worse courses than typical low-risk BCC populations [25]. In cutaneous SCC, size and depth-related parameters, including diameter above 2 cm and increasing thickness, consistently correlate with higher rates of recurrence and metastasis [26,27]. Therefore, the characterization of BSC as uniformly more aggressive than other BCC subtypes should account for tumor size, depth, anatomical site, margin status, growth pattern, and other established high-risk features before attributing differences in outcome to histotype itself.

An additional issue when comparing recurrence rates across BSC series is the definition of local recurrence. Two patients in our cohort developed histologically distinct cutaneous malignancies at previously treated sites. Neither showed basosquamous morphology, and both were therefore considered second primary tumors rather than BSC recurrences. This observation underscores the importance of histological confirmation when assessing suspected local recurrence, particularly in retrospective series, in which misclassification may influence reported recurrence rates.

Finally, follow-up duration requires explicit contextualization. Although the median follow-up of 3.7 years provides clinically relevant observation time, incomplete ascertainment of late events remains an inherent limitation. The literature demonstrates substantial heterogeneity in follow-up, ranging from short mean surveillance windows in low-event series to longer follow-up distributions in historical datasets that captured late progression in selected high-risk cases, highlighting the importance of follow-up duration when comparing event rates across different BSC series [6,8,9]. Follow-up information was unavailable for four patients, preventing complete outcome ascertainment. Other limitations of the present study include its single-centre retrospective design, the small cohort, the absence of a comparator group of conventional BCC subtypes, and the lack of formal site-specific staging or adjusted prognostic analyses. Conversely, the consistent pathological review, the separation of patient-, tumor-, and specimen-level denominators, and the detailed characterization of the basaloid and squamous components strengthen the internal consistency of the series.

Taken together, the comparison between our cohort and the broader literature supports a pragmatic conclusion: BSC should be managed as a potentially high-risk keratinocyte carcinoma, yet prognosis appears heterogeneous and should be interpreted in the context of established clinicopathological risk factors. Consequently, it is more appropriate to tailor surgical planning and follow-up intensity to individual risk profiles, rather than to infer prognosis solely from the basosquamous histological label.

5. Conclusion

In this single-center series of 32 basosquamous carcinomas, most tumors were small and located in the head and neck region, and no histologically confirmed local recurrence or metastasis occurred during the available follow-up, despite perineural invasion, deep extension, and margin involvement in a subset of cases. The most notable morphological finding was the high prevalence of a micronodular component, documented in approximately two thirds of tumors. BSC should continue to be regarded as a potentially high-risk keratinocyte carcinoma; however, our findings support interpreting prognosis in the context of the individual clinicopathological risk profile—including tumor size, depth, site, growth pattern, and margin status—rather than from the histological label alone.