Introduction
The clinical diagnosis of inflammatory dermatoses presents a significant challenge, as numerous diseases share similar macroscopic features [1–3]. These conditions encompass a broad spectrum, ranging from simple allergic reactions like urticaria and allergic contact dermatitis to severe pathologies such as systemic lupus erythematosus, vasculitis, and early-stage malignancies. In diagnostically complex cases where a definitive diagnosis is not established by standard methods, patients may be exposed to unnecessary treatment trials and a subsequent increased risk of morbidity or mortality [4]. Within these complex clinical scenarios, skin biopsy serves as an essential tool in the diagnostic process; clinicopathological correlation (CPC) contributes to the determination of correct treatment strategies [3, 5, 6]. Furthermore, dermatology consultations have been reported to shorten hospital stays and reduce the probability of readmission [7].
In patients presenting with a suspected allergic skin lesion, the clinical appearance may be deceptive and mask different underlying pathologies. For example, common conditions such as acute urticaria can be confused with more serious entities, including urticarial vasculitis, erythema multiforme, or autoimmune bullous diseases [1, 2, 8]. Urticarial vasculitis is often associated with drugs, infections, or autoimmune diseases, and histopathology may reveal findings such as leukocytoclastic vasculitis and fibrin deposits [2, 8]. Similarly, differentiating between viral and drug-related etiologies in maculopapular eruptions is not always feasible through clinical, hematological, or biochemical tests alone [9, 10]. In such lesions, the presence of moderate spongiosis, extensive vacuolar alteration of the basal layer, necrotic keratinocytes, and a dermal infiltrate rich in eosinophils or lymphocytes increases the likelihood of a drug-induced etiology [9, 10]. Early-stage cutaneous T-cell lymphomas, particularly mycosis fungoides, can exhibit clinical and histological similarities to common inflammatory dermatoses like dermatitis and psoriasis, which may lead to a delay in diagnosis [4, 11–13]. Such diagnostic difficulties underscore the potential importance of skin biopsy and CPC in reaching an accurate diagnosis [3, 6, 14].
The current literature predominantly focuses on biopsy outcomes in general patient populations or examines specific disease mimics individually [3, 5, 7]. However, comprehensive data on the final diagnostic distribution within a unique patient cohort – those referred with a preliminary diagnosis of an allergic skin lesion, found to have no primary allergic pathology, and who subsequently undergo a diagnostic skin biopsy – remain limited. In patients undergoing this diagnostic journey, the frequency of different underlying causes despite an initial “allergic” suspicion is not well-established.
Aim
This study tested the hypothesis that in this specific patient group, who underwent a two-stage specialist evaluation, the initial suspicion of “allergy” represents a non-primary allergic pathology in many cases. In this context, the primary aim of the study was to describe the histopathological diagnostic distribution in patients who underwent a diagnostic skin biopsy after being referred to for a suspected allergic skin lesion but did not receive a diagnosis of a primary allergic pathology. Secondary aims were to report the demographic characteristics of this cohort and to compare age and gender distributions among the main histopathological diagnostic groups.
Material and methods
Study design
This single-center, observational, retrospective study was designed as an archival review. The study data comprised records collected between January 2016 and August 2025.
Study population and sample
The study population consisted of patients who were evaluated for a suspected allergic skin lesion at the Allergy and Immunology outpatient clinic of the Necmettin Erbakan University Medical Faculty during the specified period. This group included adult patients who either presented directly or were referred to from other clinics, in whom a primary allergic pathology was not identified, and who subsequently underwent a diagnostic skin biopsy at the Dermatology clinic.
Inclusion criteria
Having presented to or been referred to the Allergy and Immunology clinic with at least one of the following preliminary diagnoses: “chronic urticaria”, “suspected drug eruption”, “atopic/eczematous dermatitis exacerbation”, or “unclassified rash”.
Not having received a diagnosis of a primary allergic pathology (e.g., type I hypersensitivity, allergic contact dermatitis) following evaluation at the Allergy and Immunology clinic, which included skin prick tests, specific IgE measurements, or patch tests where appropriate.
Having undergone a diagnostic skin biopsy at the Dermatology clinic due to an uncertain diagnosis after history, physical examination, and, when necessary, dermoscopic or native preparation evaluations.
Age ≥ 18 years.
Sample size
Given the retrospective nature of the study, a priori power analysis for sample size was not performed. The records of 314 patients who met the inclusion criteria within the specified date range were identified. According to the exclusion criteria, 35 patients with insufficient clinical or pathological data were excluded. The final analysis included all 279 patients with complete data.
Study procedures and data collection
Data were retrieved from the hospital’s electronic health record system (Hospital Information Management System, HIMS) and the digital archive of the Pathology department. Demographic information (age, gender) was retrieved from outpatient clinic records. The various pathological diagnoses were independently classified by two researchers into 11 predefined major diagnostic categories based on commonly used histopathological pattern-based classification approaches in the dermatopathology literature [3, 5, 14]. These categories included eczematous dermatitis, papulosquamous diseases, vascular diseases, urticaria/prurigo, drug reactions, infectious dermatoses, connective tissue diseases, autoimmune bullous diseases, neoplastic/lymphoproliferative disorders, granulomatous diseases, and non-specific inflammatory findings. In cases with overlapping or borderline histopathological features, classification was performed according to the dominant histopathological pattern reported in the pathology assessment, with discrepancies resolved by consensus with a third researcher. All data were recorded on a standardized data collection form.
Statistical analysis
All statistical analyses were performed using SPSS Statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY, USA). The normality of distribution for the continuous variable (age) was assessed using the Shapiro-Wilk test. As the data were normally distributed across all groups, descriptive statistics were presented as mean ± standard deviation (SD) for continuous variables and as numbers (n) and percentages (%) for categorical variables.
One-way ANOVA was used to compare mean ages across the diagnostic groups. Differences in gender distribution were examined using Pearson’s χ2 test. For significant χ2 results, a post-hoc analysis using standardized residuals was conducted to identify which groups contributed to the difference, with a |residual| > 1.96 considered statistically significant. The level of statistical significance for all analyses was set at p < 0.05. Given the descriptive and exploratory nature of the study, advanced modeling such as multivariable regression analysis to evaluate the relationship between the main diagnostic groups and demographic variables was not performed.
Results
Study population and demographics
The records of 314 patients who met the inclusion criteria within the specified period were identified. As detailed in the Methods section, 35 patients were excluded due to incomplete data. The final analysis included 279 patients with complete data.
Of the study population, 63.1% (n = 176) were female and 36.9% (n = 103) were male, and the mean age was 50.64 ±16.72 years. Detailed demographic characteristics by diagnostic group are presented in Table 1.
TABLE 1
Patient numbers, gender distribution, mean age, and prevalence estimates by diagnostic category
[i] Data are presented as number (n), percentage (%), or mean ± standard deviation (SD). Gender percentages within each diagnostic category indicate the proportion of females or males within that group. Percentages in the “Total N (%)” column represent the proportion of each category within the total study population (N = 279). 95% CI indicates the confidence interval for the population proportion. SD – standard deviation, CI – confidence interval.
Primary endpoint: distribution of histopathological diagnoses
The final diagnoses were classified into 11 main histopathological groups. The most frequently identified diagnostic group was eczematous dermatitis, accounting for 23.7% (95% CI: 18.8–29.1; n = 66) of the total population. This was followed by papulosquamous diseases (16.1%, 95% CI: 12.0–21.0; n = 45) and vascular diseases (12.5%, 95% CI: 8.9–17.1; n = 35), respectively (Table 1).
Secondary endpoints: age and gender comparisons
No statistically significant difference was found in mean age among the diagnostic groups (ANOVA, F = 0.693, p = 0.723) (Table 2).
TABLE 2
Comparative analysis of age and gender distribution among diagnostic groups
[i] The table summarizes the comparative statistical analysis of age and gender across the 11 diagnostic groups. The statistical significance level was set at p < 0.05, and statistically significant p-values are presented in bold. Post-hoc comparisons following a significant χ2 test were evaluated using standardized residuals, with |residual| > 1.96 considered statistically significant. d f – degrees of freedom, χ2 – chi-square statistic, F – ANOVA F statistic.
In contrast, a statistically significant difference in gender distribution was observed among the groups (Pearson’s chi-square, χ2 = 30.43, p = 0.001). Post-hoc analyses indicated that this difference was primarily driven by two groups. The proportion of female patients in the urticaria/prurigo group was significantly higher than expected (93.3%, 95% CI: 77.9–99.2; n = 28/30) (std. residual = +2.7). Similarly, the proportion of female patients in the vascular diseases group was also significantly higher than expected (77.1%, 95% CI: 60.1–89.2; n = 27/35) (std. residual = +2.0).
Discussion
The primary finding of this study is that in patients with persistent diagnostic uncertainty despite a two-stage specialist evaluation (allergy and dermatology), skin biopsy reveals an exceptionally broad and unexpected diagnostic spectrum. Our findings demonstrate that many skin lesions clinically evaluated as “allergic” may be manifestations of very different pathologies, highlighting the critical role of histopathological examination in reaching an accurate diagnosis. This is consistent with the consensus that clinicopathological correlation is indispensable in dermatological diagnosis and that biopsy is a tool that significantly enhances diagnostic accuracy.
The predominance of eczematous dermatitis (23.7%), the most common group in our study, parallels results reporting that eczematous reactions are frequent among patients presenting to allergy clinics [13, 15]. The fact that papulosquamous diseases ranked second (16.1%) indicates how frequently psoriasiform and lichenoid patterns can be clinically misdiagnosed as eczema or drug reactions [11]. A particularly noteworthy finding was the high rate of vascular diseases at 12.5%; this rate quantitatively supports studies emphasizing that underlying systemic conditions, such as urticarial vasculitis, should not be overlooked in cases of atypical or treatment-resistant urticaria [2, 8]. Indeed, it is stressed that urticaria mimics include vasculitis, autoinflammatory syndromes, and even angioedema, and that querying lesion duration, residual hyperpigmentation, and systemic symptoms is crucial for their differentiation [1].
Concordance rates between clinical and histopathological diagnoses reported in the literature range widely from 54% to 87% [6, 7]. Our study, however, illuminates a different aspect of the diagnostic process rather than evaluating it based on a “concordance rate”. We demonstrate that the initial general suspicion of “allergy” leads to a significant diagnostic redirection, evolving into a specific histopathological diagnosis in most cases. In fact, when diagnostic categories more closely related to allergic conditions, namely urticaria/prurigo (10.8%) and drug reactions (7.5%), were excluded, the remaining diagnostic groups accounted for approximately 82% of the cohort, representing predominantly non-primary allergic inflammatory or vascular dermatoses. This high conversion rate strongly emphasizes the role of biopsy in diagnostic clarification and transformation within this patient group, far more than a simple concordance rate would.
These findings are indirectly related to studies indicating that clinicopathological concordance increases in populations with high diagnostic value, such as patients referred by dermatologists [7]. Our patient group represents a diagnostically challenging population, having been filtered through two specialty clinics (allergy and dermatology). Therefore, this high rate of diagnostic redirection we observed demonstrates how critical the clinicopathological correlation process is and how biopsy can fundamentally alter the diagnostic algorithm, especially in atypical presentations. Our results provide tangible evidence for the maxim “biopsy clarifies the diagnosis” within a challenging and specific patient group of “allergy mimics” [3, 14].
Our study aligns with findings showing that more than 50% of diagnoses change after biopsy in hospitalized patients who receive a dermatology consultation [5]. Although our cohort consisted of outpatients, the similarly high diagnostic diversity we identified suggests that the diagnostic impact of biopsy is not limited to inpatients. However, comparing with concordance rates in the literature helps to contextualize our findings. For instance, the reported concordance rates of 54.5% in general populations or the high rate of 85% when referred by dermatologists typically reflect situations with less diagnostic uncertainty [6, 7]. Our patient cohort, in contrast, represents the very cases where this 85% concordance could not be achieved, meaning the diagnosis remained uncertain despite a specialist dermatologist’s evaluation. This supports the notion that diagnostic accuracy increases when sufficient clinical information is provided to the pathologist and the CPC process is utilized; indeed, the adequacy of clinical information on the biopsy request form is known to be a key factor in diagnostic agreement [14].
From a demographic perspective, the male predominance (60%) observed in the neoplastic/lymphoproliferative lesions group is consistent with literature data reporting that cutaneous T-cell lymphomas are more common in men [16]. It should be noted that early-stage mycosis fungoides can mimic chronic dermatitis with non-specific histological findings, which may lead to diagnostic delays in male patients. In the drug reactions group, the mean age (54.7 years) was notably one of the highest in our cohort, although the age difference among groups was not statistically significant (p = 0.723). This finding supports the literature suggesting that serious drug reactions are not confined to younger individuals but can occur across a wide age range and may pose a diagnostic challenge by mimicking other dermatoses in older patients with polypharmacy [17, 18]. The female predominance observed in the vascular diseases group is consistent with previous reports indicating a higher prevalence of immune-mediated vascular dermatoses, including urticarial vasculitis, among women [1, 2].
This diagnostic diversity may be explained by common immunological mechanisms that cause different dermatoses to present with similar clinical patterns. For example, in eczematous conditions such as allergic contact dermatitis and atopic dermatitis, T-cell-mediated inflammation, epidermal barrier dysfunction, and specific cytokine profiles (IL-4, IL-13, IFN-γ) play a role [19]. Similarly, the interface dermatitis and eosinophilic infiltrate seen in the histopathology of maculopapular drug reactions can share features with viral exanthems, which is the core mechanism complicating the differentiation between these two entities [9].
Strengths of our study include its relatively large sample size for a single center, the systematic performance of CPC in all cases, and its focus on a unique patient cohort that underwent a two-stage specialist evaluation. These features support the internal validity of our findings. However, despite these strengths, certain important limitations must be considered when interpreting the generalizability of our results.
The retrospective design carries an inherent risk of information bias; for example, variations in the level of detail in clinical notes may have influenced the decision to perform a biopsy. This could have led to an over-representation of more atypical or treatment-resistant cases in our sample (selection bias). Second, as a single-center study at a tertiary referral hospital, the generalizability of our results is limited. Our center likely attracts more complex cases, which could mean that the frequency of rarer conditions in our findings, such as vasculitis (12.5%) or neoplastic diseases (3.6%), may be higher than in primary care or general dermatology settings. Finally, the grouping of diagnoses into broad categories may have obscured important clinical differences between subtypes (e.g., different variants of lupus erythematosus). Furthermore, the lack of standardization in biopsy techniques (e.g., punch, excisional) and sampling depth, reviewed retrospectively, is another factor that could have affected diagnostic accuracy. These limitations prevent a more granular understanding of the diagnostic spectrum.
Conclusions
These findings encourage allergy and dermatology clinicians to consider biopsy early in cases of chronic or treatment-resistant urticaria-like lesions. In cases biopsied with a preliminary diagnosis of urticaria or allergic dermatitis, histopathological examination reveals a wide diagnostic range, predominantly featuring eczematous, papulosquamous, and vascular dermatoses. This once again confirms that clinicopathological correlation is an indispensable tool in the diagnostic process. To address the limitations of the current study, future research should be designed prospectively with larger, multicenter cohorts and supported by advanced techniques such as immunophenotyping and molecular analysis to further enhance diagnostic accuracy.
