Investigation of using very high‐frequency ultrasound in the differential diagnosis of early‐stage pemphigus vulgaris vs seborrheic dermatitis

Abstract Background Early‐stage pemphigus vulgaris (PV) often manifests as erythema alone. We hypothesized that very high‐frequency ultrasonography (VHFUS) features could simplify the differential diagnosis of early‐stage pemphigus vulgaris versus seborrheic dermatitis (SD). Materials and Methods Fourteen patients with SD or early‐stage PV were recruited from our outpatient clinic during 2016‐2019. We used 50‐MHz VHFUS to image the erythema on the patients’ scalp, face, chest, and back and retrospectively evaluated their ultrasonographic features. Results Very high‐frequency ultrasonography images of early‐stage PV showed enhanced epidermal echo (8/14, 57%), linear or oval intra‐epidermal hypoechoic/anechoic areas (12/14, 86%), linear anechoic areas at the dermal‐epidermal junction (14/14, 100%), reduced echo of superficial to whole dermis (9/14, 64%), and slightly increased dermal thickness (14/14, 100%). The intra‐epidermal hypoechoic/anechoic bands (100%) showed the greatest specificity. VHFUS images of SD showed enhanced epidermal echo (7/14, 50%), epidermal unevenness (7/14, 50%), linear anechoic bands at the dermal‐epidermal junction (8/14, 57%), reduced middle dermis echo (10/14, 71%), and slightly increased dermal thickness (10/14, 71%). The epidermal unevenness (100%) had the greatest specificity. There was a significant difference (P < .05) between early‐stage PV and SD regarding the proportion of linear intraepithelial hypoechoic/anechoic bands and linear anechoic areas at the dermal‐epidermal junction. Conclusions Early‐stage PV and SD have relatively specific VHFUS erythematous manifestations. Intra‐epidermal hypoechoic/anechoic bands for early‐stage PV and epidermal unevenness for SD were most specific. VHFUS contributes to the differential diagnosis of PV and SD by highlighting their features, that is, intra‐epidermal hypoechoic/anechoic bands and linear anechoic areas at the dermal‐epidermal junction.

Early clinical manifestations of the disease, characterized by multiple erythematous areas, erosion, and scabs on the head, face, chest, and back, are easily misdiagnosed before the appearance of the typical blisters, bullae, and mucosal damage. Seborrheic dermatitis (SD) is characterized by multiple erythematous areas and greasy scales or crusts on the head and face, chest, and back, similar to the clinical manifestations of PV in its early stage. Hence, the two are often confused in clinical practice and must be differentiated by histopathological and/or direct immunofluorescence examinations and other invasive tests, which are often difficult to implement.
Very high-frequency ultrasound (VHFUS) is a high-resolution, noninvasive, objective examination that has been used as an auxiliary means to evaluate superficial tumors and internal organs in the past. In recent years, VHFUS has proved to have unique value in the identification of inflammatory lesions of the skin and subcutaneous tissues, such as scleroderma 1 and psoriasis. 2 The use of VHFUS for evaluating autoimmune bullous skin diseases has rarely been reported. We therefore used VHFUS to study the characteristics of erythema in patients with PV at an early stage and those with SD and then explored the value of VHFUS in their differential diagnosis.

| Patients
This retrospective study was conducted from June 2016 to April 2019, during which time we enrolled 14 patients with early-stage PV and 14 with SD who were recruited from the outpatient clinic of Peking Union Medical College Hospital. The diagnosis was confirmed in each case based on their clinical manifestations and histopathological or immunofluorescence examination. Patients with PV were all in the early stage of the disease course and mainly presented with erythema, erosion, and scabs on the head, face, and/ or chest and back. None had yet developed the typical blisters or bullae. The patients with SD presented with erythema and greasy scales on the head, face, and/or chest and back.
For the PV patients, the male:female ratio was 1:1.8, and the age range was 27-73 years (mean 50 ± 14 years). Samples of the lesions were collected from the head and face in three cases and the trunk in 11 cases. For SD patients, the male:female ratio was 1:2.5, and the age range was 22-54 years (mean 44 ± 10 years). Samples from their lesions were collected from the head and face in nine cases and the trunk in five cases.

| Acquisition and evaluation of ultrasonic images
The VHFUS instrument was produced by Tianjin Minda Company.
Ultrasonic images of patients with new erythematous areas were scanned with a 50-MHz frequency probe. The images were compared with those from normal skin at a contralateral site or at the lesion's margin. The ultrasonic images were collected by the same staff to avoid differences in the procedure.

| Statistical analysis
Percentages of the classification data were used for statistical descriptions, and Fisher's exact test was used to determine whether there was significant difference in the ultrasonographic characteristics of the two diseases. A value of P < .05 indicated statistical significance. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, and Jordan index were calculated. All statistics were processed by SPSS 20.0 software (IBM).

| Analysis of the differences and the diagnostic value of the ultrasonographic features
The VHFUS characteristics identified in the early-stage PV patients were linear or oval intra-epidermal hypoechoic or anechoic regions (86%), linear anechoic areas at the dermal-epidermal junction (100%), and slightly increased dermal thickness (100%) ( Table 3). The characteristic with highest specificity was the linear intra-epidermal hypoechoic or anechoic bands (100%), which was significantly different from that in the SD patients (P < .05). In contrast, the SD patients' most specific VHFUS erythematous characteristic of SD patients was uneven epidermis, but this characteristic was not significantly different between that found in the early-stage PV patients (P > .05).
Linear anechoic areas at the dermal-epidermal junction were apparent in the erythematous areas of patients with early-stage PV (100%) and those with SD (57%), although there was a significant difference between the two groups (P < .05).   epidermis can be used as a basis for differentiating early-stage PV and SD. Epidermal unevenness can be used as a VHFUS feature to diagnose SD, but it cannot be used as the basis of a differential diagnosis. However, 100% of patients with early PV and only 57% of patients with SD in this study had the ultrasonic characteristic of a linear anechoic region at the dermal-epidermal junction, and the difference between the two groups was significant.

| CON CLUS ION
VHFUS is an important noninvasive diagnostic tool that can assist in the differential diagnosis of early-stage PV and SD, thereby reducing the number of clinical misdiagnoses. The application of HFUS in the diagnosis and differential diagnosis of more skin diseases requires further study.

ACK N OWLED G EM ENT
We thank Nancy Schatken BS, MT(ASCP), from Liwen Bianji, Edanz Group China (www.liwen bianji.cn/ac), for editing the English text of a draft of this manuscript.

CO N FLI C T O F I NTE R E S T
None reported.