Characteristics and differential diagnosis of common verrucous proliferative skin diseases under dermoscopy and reflectance confocal microscopy

Abstract

Objective

Verrucous epidermal nevus (VEN), seborrheic keratosis (SK), verruca plana (VP), verruca vulgaris (VV), and nevus sebaceous (NS) are common verrucous proliferative skin diseases with similar clinical appearances, often posing diagnostic challenges. Dermoscopy and reflectance confocal microscopy (RCM) can aid in their differentiation, yet their specific features under these tools have not been systematically described. This study aims to summarize and analyze the dermoscopic and RCM features of VEN, SK, VP, VV, and NS.

Methods

A total of 121 patients with histopathologically confirmed verrucous proliferative skin diseases were enrolled. Dermoscopy and RCM imaging was used to observe and analyze the microscopic features of these conditions.

Results

Under dermoscopy, the 5 diseases displayed distinct characteristics: VEN typically showed gyriform structures; SK was characterized by gyriform structures, comedo-like openings, and milia-like cysts; VP and VV featured dotted vessels and frogspawn-like structures; NS presented as brownish-yellow globules. RCM revealed shared features such as hyperkeratosis and acanthosis across all 5 diseases. Specific features included gyriform structures and elongated rete ridges in VEN; pseudocysts and gyriform structures in SK; evenly distributed ring-like structures in VP; vacuolated cells and papillomatous proliferation in VV; and frogspawn-like structures in NS.

Conclusion

These 5 verrucous proliferative skin conditions exhibit distinguishable features under both dermoscopy and RCM. The combination of these 2 noninvasive imaging modalities holds significant clinical value for the differential diagnosis of verrucous proliferative skin diseases.

Common verrucous hyperplasia dermatoses in clinic include verrucous epidermal nevus (VEN), seborrheic keratosis (SK), verruca plana (VP), verruca vulgaris (VV), and nevus sebaceous (NS). Patients are often referred to the hospital due to the appearance of impairment. All 5 diseases appear as skin-colored or yellowish papules early which is easy to misdiagnose. Therefore, some clinical tests are often needed to aid in the differential diagnosis. Pathological biopsy, dermoscopy, and reflectance confocal microscopy (RCM) are 3 commonly used identification methods.

Dermatopathology was always considered as “golden standard” of the skin diseases, but it is an invasive test, it is not clinically acceptable for the identification of verrucous hyperplasia dermatoses. Dermatoscopy mainly focuses on the observation of structure in superficial pigmented lesions, blood vessels, and hair follicles. It is non-invasive and widely used in clinical practice, but it does not achieve good sensitivity for inspecting deep skin structures and cytomorphological details^[1]. RCM allows for non-invasively and real-time in vivo visualization of the epidermis and the upper parts of the dermis at the cellular level to assist in the diagnosis of skin diseases^[2-3]. Clinical dermoscopy and RCM can reflect the imaging features of the skin in non-invasive and real-time, and their application can largely replace pathological examination. However, the features of verrucous hyperplasia dermatoses under dermoscopy and RCM have not been systematically described and distinguished. In this study, we will analyze and describe the basic characteristics of these 5 common verrucous hyperplasia dermatoses under dermoscopy and RCM, and provide evidence for clinical differentiation and diagnosis.

1. Subjects and methods

1.2. Patients

Patients with verrucous hyperplasia dermatoses treated at the Department of Dermatology, the Third Xiangya Hospital of Central South University between January 2021 and December 2023 were included in this retrospective study. A total of 121 patients (65 males and 56 females) with typical skin lesions were randomly enrolled, of which 14 had VEN, 39 had SK, 34 had VP, 19 had VV, and 15 had NS (Figure 1), and the mean age was 35.8 (3-60) years. The patients were referred for pathological examination, dermoscopy, and RCM examination.

Figure 1. Clinical presentations (A, D, G, J, M), histopathological examination (B, E, H, K, N), and dermoscopy (C, F, I, L, O) characteristics of VEN, SK, VP, VV, NS.

A: VEN; B: Papillary hyperplasia and predominantly lymphocytic infiltration in VEN tissues (HE staining); C: Gyroid structure and light pink background (red circle) in VEN skin (×50); D: SK; E: False horn cyst (red circle) of SK (HE staining); F: Fissures and ridges (red circle), comedo-like openings (red arrow), and milia-like cysts (yellow arrow) in SK skin (×50); G: VP; H: Acanthosis cell layer thickening of VP (HE staining); I: A number of punctate hemorrhages (yellow arrow) and frogspawn-like structure (red arrow) of VP skin (×50); J: VV; K: Papillary hyperplasia of VV tissues (HE staining); L: Frogspawn-like structure (red circle) and punctate hemorrhages (red arrow) of VV skin (×50); M: NS, N: Frogspawn-like structures (red circle) of NS tissues (HE staining); O: Brown and orange globules (red arrow) and gyroid structure (red circle) of NS skin (×50). VEN: Verrucous epidermal nevus; SK: Seborrheic keratosis; VP: Verruca plana; VV: Verruca vulgaris; NS: Nevus sebaceous.

The inclusion criteria were as follows: 1) solitary papule dermatosis with a definitive diagnosis made by 2 independent dermatologists with more than 10 years of clinical experience according to clinical presentations and dermoscopic findings; 2) no topical or systemic treatment before dermoscopy and RCM examination; and 3) consent to participate in the study.

1.3. Instrument

1.3.1. Dermoscopy

Dermoscopic images were taken using Dermlite DL4 Equipment (San Juan Capistrano, CA, USA) at 10-fold magnification. All the dermoscopic images were acquired before therapy.

1.3.2. RCM imaging

All patients included in the study were examined using a commercially available RCM system, a VivaScope 1500 (Lucid Inc, Rochester, NY, USA). The system used an infrared 830 nm diode laser operating at a power of less than 35 mV at the tissue level. The probe was routinely disinfected with 75% alcohol before and after each examination. The best angle and image definition were adjusted, and the dermoscopic and RCM images of the skin lesion were collected. All images were collected by the same staff.

2. Results

2.1. Dermatoscopic image characteristics of the 5 verrucous proliferative dermatoses

The majority of the VEN was characterized by light red/pink background and gyroid structure (14/14, 100%; Figure 1C, red circle). SK was characterized by gyroid structure (39/39, 100%), comedo-like openings (39/39, 100%) and milia-like cysts (27/39, 69.23%; Figure 1F). VP was characterized by a number of punctate hemorrhages scattered against a light-red background (20/34, 58.82%) and frogspawn-like structure (18/34, 52.94%; Figure 1I). VV was characterized by frogspawn-like structure (19/19, 100%) and a small amount of irregularly distributed red, brown, or black punctate hemorrhages (8/19, 42.11%; Figure 1L). NS was characterized by gyroid structure (10/15, 66.67%) and brown and orange globules (15/15, 100%; Figure 1O). Descriptive results of the dermoscopic analyses are shown in Table 1.

Table 1.

Key demoscopic features of verrucous epidermal nevus, seborrheic keratosis, verruca plana, verruca vulgaris, and nevus sebaceous

Groups	n	Brown circular ring/%	Punctate hemorrhages/%	Papillary hyperplasia		Comedo-like openings/%	Milia-like cysts/%	Brown and orange globules/%
				Gyroid structure/%	Frogspawn-like structure/%
Verrucous epidermalnevus	14	0	0	100	0	0	0	0
Seborrheic keratosis	39	0	0	100	0	100	69.23	0
Verruca plana	34	8.82	58.82	0	52.94	0	0	0
Verruca vulgaris	19	0	42.11	0	100	0	0	0
Nevus sebaceous	15	0	0	66.67	0	0	0	100

2.2. RCM image characteristics of the 5 verrucous hyperplastic dermatoses

The 5 verrucous hyperplastic dermatoses exhibited the following non-characteristic RCM features: The stratum corneum demonstrated hyperkeratosis with high refractivity and acanthosis when compared to adjacent normal skin.

Descriptive results of the RCM analyses are shown in Table 2. The characteristic RCM manifestations of the 5 verrucous hyperplastic dermatoses are as follows:

Table 2.

Key reflectance confocal microscopy features of verrucous epidermal nevus, seborrheic keratosis, verruca plana, verruca vulgaris, and nevus sebaceous

Groups	n	Hyperkeratosis/%	Acanthosis/%	Gyrus hyperplasia/ Papillomatous hyperplasia/%	Epidermal elongation/%
Verrucous epidermal nevus	14	71.43	100	100	100
Seborrheic keratosis	39	100	100	100	100
Verruca plana	34	73.53	100	0	0
Verruca vulgaris	19	100	100	26.32	0
Nevus sebaceous	15	33.33	100	0	0

Groups	False horn cyst/%	Vacuolar cell/%	Frogspawn-like structures/%	Inflammatory cell infiltration/%	Petal-like structures/%
Verrucous epidermal nevus	0	0	0	92.86	0
Seborrheic keratosis	100	0	0	76.92	0
Verruca plana	0	100	0	88.24	100
Verruca vulgaris	0	100	0	100	0
Nevus sebaceous	0	0	100	66.67	0

2.2.1. VEN

VEN was characterized by gyrus hyperplasia in the granulosa layer (14/14, 100%), the upper spine layer, epidermal elongation (14/14, 100%), and inflammatory cell infiltration in the dermal papilla (13/14, 92.86%; Figure 2A, 2B).

Figure 2. Classic reflectance confocal microscopy characteristics of VEN, SK, VP, VV, and NS.

A: Gyrus hyperplasia (red arrow) and the pigment content of basal layer increased (yellow arrow) of VEN; B: Inflammatory cell infiltration (red arrow) of VEN; C: False horn cysts (red arrow) and cobblestone structure (red circle) of SK; D: False horn cysts (red circle) of SK; E: Reticular appearance in the stratum corneum of VP; F: Petal-like structures of VP (red circle); G: Frogspawn-like structures of VV; H: papillomatous hyperplasia of VV; I: Frogspawn-like structures (red circle) and no dermal papillary ring (red arrow) of NS; J: Frogspawn-like structures of NS.

2.2.2. SK

SK was characterized by gyrus hyperplasia in the granulosa layer (39/39, 100%), the upper spine layer, false horn cysts in the epidermis (39/39, 100%), and inflammatory cell infiltration in the dermal papilla (30/39, 76.92%; Figure 2C, 2D).

2.2.3. VP

VP was characterized by petal-like structures (34/34, 100%; Figure 2F), prolongation of epidermal process in the deep dermis, inflammatory cell infiltration in the dermal papilla (30/34, 88.24%), and vacuolar cells in the spine (34/34, 100%; Figure 2E). No gyrus hyperplasia were found.

2.2.4. VV

VV was characterized by papillomatous hyperplasia (5/19, 26.32%), inflammatory cell infiltration in the dermal papilla (19/19, 100%), and vacuolar cells in the spine (19/19, 100%; Figure 2G, 2H).

2.2.5. NS

NS was characterized by lymphocyte infiltration in the superficial dermis and frogspawn-like structures (15/15, 100%; Figure 2I, 2J).

3. Discussion

Verrucous hyperplastic dermatoses, such as VEN, SK, VP, VV, and NS, are clinically manifest as similar skin-colored or yellowish papules, which are usually difficult to identify with the naked eye^[4-5]. SK is usually roundish or oval in shape, but irregular lesions also occur. The degree of pigmentation can vary, from skin-colored or yellowish to light brown and even black^[6]. And this can happen with VEN, VP, and VV. NS may be considered an SK simulator, especially when it is small in size and first observed during adulthood, because of its cerebriform surface, well-defined borders and brownish color^[7-8]. Previous studies^{[6, 8]} often focused on the features of one or two verrucous hyperplastic dermatoses under dermoscopy or RCM without detailed description, comparison, and analysis. In this study, the 5 similar verrucous hyperplastic dermatoses were systematically summarized and compared, and the characteristics of them in dermoscopy and RCM were quantitatively analyzed. This will provide an important reference value for the differential diagnosis of clinical verrucous hyperplastic dermatoses. Pathological diagnosis is the gold standard for diagnosis of these diseases. However, it is very unfortunate that some enrolled patients refused pathological examination because their lesions occurred on the face and they were concerned that the pathological examination might bring about a disfiguring manifestation. Therefore, not all enrolled patients had pathological results for comparison. In the rare cases where clinical history, visual identification, dermoscopy and RCM fail to differentiate, histopathological examination may still be necessary.

In our study, we analyzed and calculated the frequency of characteristic structures of 5 verrucous hyperplastic dermatoses under dermoscopy, and made a list of comparative analyses: All 5 kinds of diseases can observe the papillomatous appearance and vascular structure. The papillomatous appearance and brown globules are characteristic of NS. The papillomatous appearance accompanied by comedo-like openings or milia-like openings is SK. Normally, the papillomatous structure of VEN appears as gyroid structures. VP usually has a mild papillomatous appearance on a brown-yellow background with punctate vessels. VV is more obvious papillomatous appearance of punctate or looped vessels. The above characteristics are complex and sometimes not obvious. Dermoscopy alone hardly provides strong auxiliary diagnostic value, so their diagnosis is often made in combination with clinical features or with the help of RCM. The imaging characteristics of VEN were rarely described in the past. Guo, et al^[9] described the RCM images of VEN as hyperkeratosis, acanthosis, gyrus hyperplasia, epidermal elongation, and inflammatory cell infiltration.The result in our research is consistent with their results. Considering that RCM manifests as gyrus hyperplasia, epidermal elongation and inflammatory cell infiltration are not characteristic, VEN is more likely to be confused with SK. But SK is characterized by false horn cysts. Hanlon, et al^[10] described it as the white round structure showed high refraction because of the false horn cysts. We also observed this structure in SK tissues, which is helpful in diagnosis and differentiation with other verrucous hyperplasia dermatoses. In this study, we observed petal-like structures in VP tissues, which is consistent with Lu, et al^[11] findings that the RCM characteristics of VP is as rose-like concentric structures. At present, there are no relevant RCM reports on VV, but the changes we found in RCM are consistent with the pathological results. The vacuolar cells observed in RCM imaging of VP and VV, characterized by hyper-refractivity, correlated with pathological findings of vacuolar cells, rendering their identification under RCM challenging. The histopathological features of NS are sebaceous hyperplasia^[12]. RCM imaging of NS revealed frogspawn-like structures corresponding to pathological findings of sebaceous hyperplasia, with our observations aligning with histopathological features.

We have summarized clinical experiences using dermoscopy and RCM to distinguish 5 verrucous hyperplastic dermatoses. The presence of gyroid structures on dermoscopy should prompt dermatologists to include VEN, SK, and NS in the differential diagnosis. However, these conditions can be further distinguished by their distinct dermoscopic features: SK typically presents with comedo-like openings and milia-like cysts, and NS is characterized by brown and orange globules. Under RCM VEN is more likely to be confused with SK. False horn cysts are a typical feature of SK. It is difficult to distinguish VP from VV by dermoscopy or RCM alone. VP can presents brown circular ring under dermoscopy, and VV can reveal gyrus hyperplasia under RCM. Integrated dermoscopic and RCM examination may enhance diagnostic accuracy for skin lesions. However, since VP and VV share identical treatment protocols, precise differentiation between these entities is not clinically imperative for therapeutic decision-making. VP and VV are easily distinguishable from VEN, SK, and NS by dermoscopy or RCM. The features of VEN, VP, and NS under the dermoscopy and RCM are relatively stable at all stages of the disease. Early-stage SK and VV may present with similar clinical features that challenge visual differentiation, though microscopic examination enables reliable distinction. In advanced-stage lesions, severe hyperkeratosis may occasionally obscure the microscopic differentiation between SK and VV. Histopathological evaluation becomes essential for definitive diagnosis in such exceptional cases.

In our follow-up study, we will further expand the sample size (more than 100 enrolled patients/each disease) and extend the follow-up time, so as to statistically and analytically characterize the features of the above 5 verrucous proliferative dermatoses at different disease stages under dermoscopy and RCM, and compare them with the pathological results. Accurate diagnosis is important for guiding optimal treatment in these 5 verrucous hyperplastic dermatoses. However, each examination method has limitations. In conclusion, we suggest that RCM combined with dermoscopy could provide more diagnostic basis of the diseases, significantly improving the success rate of non-invasive diagnosis of verrucous hyperplastic dermatoses.

Funding Statement

This work was supported by the Project of Health Committee of Hunan Province (D202304128868), China.Open access: This is an open access article under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Conflict of Interest

The authors declare that they have no conflicts of interest to disclose.

AUTHORS’CONTRIBUTIONS

ZHOU Lu, FU Yule, and WANG Jia Experimental operation and paper writing; HUANG Jian and TANG Zhen Data collecting and analysis; LU Jianyun, TAN Lina, WANG Dan, and ZENG Jinrong Data collecting, paper supervision and revision; GAO Lihua Research design, paper supervision and revision. The final version of the manuscript has been approved and read by all authors.

Ethical approval

for this investigation was obtained from the Ethics Committee of the Third Xiangya Hospital, Central South University (No. 24579).

Note

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202503358.pdf