Author details:
Shu Ding, Email: dingshu68@163.com
Lingxue Hu, Email: hlx_0302@163.com
Yu Rao, Email: 2323268559@qq.com
Ruijian Ren, Email: 516731642@qq.com
Xiaoliang Tong, Email: 601630@scu.edu.cn
Aiyuan Guo, Email: aiyuan_derm @126.com
Jian Huang, Email: 45406162@qq.com
Correspondence: Zhen Tang, Department of Dermatology, the Third Xiangya
Hospital, Central South University, #138 Tongzipo Road, Changsha 410013
Hunan, China, Email: 1264297232@qq.com
Funding information : National Natural Science Foundation of
China (No. 81972921), Natural Science Foundation of Hunan Province (No.
2023JJ20090,2020JJ5849), the Science and Technology Innovation Program
of Hunan Province(No.2023RC3086), the Hunan Provincial Health
Commission(No. 202304129002),Innovation-Driven Research Programme
Funds for the Central Universities of Central South University (No.
2023CXQD074),and the Wisdom Accumulation and Talent Cultivation Project
of the Third Xiangya Hospital of Central South University (No.
YX202101).
Data availability statement : The data that support the findings
of this study are available on request from authors.
Conflict of interest disclosure : The authors declare no
conflict of interest.
Permission to reproduce material from other sources: The
article didn’t reproduce material from other sources.
Ethics approval statement : The study was approved by the
insititutional review board (IRB) of Third Xiangya Hospital, Central
South University.
Patient consent statement: All patients obtained informed
consent before undergoing the examination.
Research Highlights:
1. A retrospective study of reflectance confocal microscopy (RCM) and
histological diagnosis in patients with clinical diagnosis of Bowen’s
disease (BD).
2. Analyze the RCM characteristics of skin lesions verified by biopsy.
3. RCM has great value in the diagnosis and differentiation of BD.
Abstract
Bowen’s disease (BD) is a relatively rare early-stage squamous cell
carcinoma in situ, most commonly affecting the middle-aged and elderly,
and occurring on the skin or mucous membranes of various parts of the
body. Its onset is concealed, the course of the disease is chronic, and
some patients are accompanied by malignant tumors outside the skin, so
it is necessary to diagnose and evaluate the disease in its early
stage. This study aims to investigate the application of reflectance
confocal microscopy (RCM) in diagnosing Bowen’s disease. We performed
RCM imaging on the lesion site of 113 patients initially diagnosed with
Bowen’s disease in clinic, of which 92 patients underwent skin biopsy
for histological diagnosis. A retrospective analysis of the RCM result
as well as the histological examination revealed that after analyzing
RCM images, 69 out of 113 patients were diagnosed with Bowen’s
disease; out of 92 biopsy lesions, 61 were Bowen’s disease, of which 54
were consistent with RCM diagnosis. Among 59 cases diagnosed with
Bowen’s disease by RCM, 54 cases were consistent with histological
diagnosis. Afterwards, we analyzed the RCM characteristics in patients
with Bowen’s disease verified by biopsy, and compared the RCM images of
two different lesions, Classic Bowen’s Disease (CBD) and Pigmented
Bowen’s Disease (PBD), and further summarized the key points of Bowen’s
disease under RCM. Finally, we focused on the differential
characteristics between Bowen’s disease and other skin diseases under
RCM. It is found that RCM is of great value in diagnosing Bowen’s
disease.
KEYWORDS
diagnosis; Bowen’s disease; reflectance confocal microscopy;
histopathology
1 | INTRODUCTION
Bowen’s Disease (BD) is a comparatively rare early-stage non-melanocytic
intraepithelial malignant tumor. It is estimated that approximately 3%
-5% of BD cases in the general population transform into invasive
squamous cell carcinoma(Morton et al., 2014). The typical manifestation
is chronic, asymptomatic, and scaly plaques. Its incidence rate is as
low as 76.8 per 100,000 annually(Jansen et al., 2019). In general, the
rate is slightly higher for women. For instance, the incidence rate for
males and females in the Netherlands in 2017 was 68 and 72 per 100,000
annually respectively(Jansen et al., 2019). However, due to the
concealed onset of Bowen’s disease and the general lack of obvious
symptoms, patients often delay seeking medical treatment. Skin lesions
of Bowen’s disease lack obvious specificity in appearance and may be
similar to other benign skin diseases clinically including eczema,
seborrheic keratosis(SK), and superficial mycosis, which are easily
misdiagnosed by clinical physicians(Mohandas et al., 2020).
Currently, the gold standard for diagnosing BD is biopsy confirmed by
histology. Typical histopathology includes hyperkeratosis and
parakeratosis or accompanied by scabs, disordered arrangement of cells
in various layers of the epidermis, atypical cell morphology and size,
large and deeply stained nuclei, some dyskeratotic cells, elongated and
widened skin processes, and intact basal cell layer(Palaniappan &
Karthikeyan, 2022). Since biopsy is an invasive method and most lesions
of patients with BD occur in such exposed areas as the face and the
head, many patients are reluctant to undergo such examinations. Besides,
its incidence rate is low, clinicians often do not like to consider this
diagnosis first. Therefore, a non-invasive examination technique is
quite needed.
At present, there are several non-invasive examination techniques used
for skin diseases, including dermatoscopy, reflectance confocal
microscopy (RCM) and optical coherence tomography, and so on(Pellacani
& Argenziano, 2022). Among which dermatoscopy is widely used.
Dermatoscopy can magnify the surface of the skin and observe its
submicroscopic structure and pathological changes simply and
conveniently(Mazzilli et al., 2020). Researchers have probed into the
value of dermatoscopy in diagnosing Bowen’s disease, but its diagnostic
value is limited since many skin diseases, such as actinic
keratosis(AK), psoriasis, melanoma, contact dermatitis, may be similar
to Bowen’s disease in clinical practice and under dermatoscopy(Namiki et
al., 2017; Wozniak-Rito & Rudnicka, 2018).
Compared to dermatoscopy, RCM is based on the principle of optical
confocal imaging, which utilizes a system to focus on the reflected
light of a low energy laser light source at a specific skin level. RCM
can achieve a scanning depth of 150-250㎛ from the epidermis to the
superficial dermis to capture cell level resolution images, enabling in
vitro, non-invasive, real-time, and dynamic imaging (Lboukili et al.,
2022; Shahriari et al., 2021), which offers more proofs for diagnosis
and differential diagnosis. Some case reports discovered that RCM can
assist in the diagnosis of Bowen’s disease without considering the
differential diagnosis(Shahriari et al., 2018; Yamanaka-Takaichi et al.,
2019). In addition, it has been reported that RCM is capable of
diagnosing and differentiating between neoplastic and inflammatory skin
diseases(Ianoși et al., 2019; Tang et al., 2020). Some studies have
discovered that RCM can be applied to distinguish Bowen’s disease from
some other diseases, including basal cell carcinoma(BCC) (Chen et al.,
2023), and actinic keratosis(AK)(Zhou & Mistry, 2017). However, due to
the low incidence of Bowen’s disease, there are only a few case reports
and small studies. Thus, no specific guidelines were formulated due to
limited cases and inadequate evidence.
The study aims to probe into the application of RCM in the diagnosis and
differential diagnosis of Bowen’s disease, and to explore the complete
scheme of BD diagnosis by RCM on the basis of clinical experience.
2 | MATERIALS AND METHODS
2.1 | Patients
The study focused on 113 patients (39 males and 74 females) initially
diagnosed with Bowen’s disease in clinic by Department of Dermatology,
the Third Xiangya Hospital of Central South University from March 2016
to August 2023, with an average age of 51.3 (25-87 years old) and a
course of disease ranging from 3 months to more than 10 years. The skin
lesions include the face, limbs, back, lower abdomen, vulva, buttocks,
scalp, and other parts. All patients obtained informed consent before
undergoing the examination. This study was carried out on the principle
of the Helsinki Declaration and received ethical approval.
2.2 | RCM imaging
RCM imaging was carried out on all selected cases using the VivaScope
1500 device produced by Lucid. The laser of the light source has a
wavelength of 830nm and a power of less than 35㎽ at the tissue level.
The obtained images measure 500㎛*500㎛. The best images were obtained
by dermatologists at the junction of the epidermis and dermis, as well
as at the dermal papilla, and dermatologists diagnosed the patients
according to RCM images.
2.3 | Histopathological examination
After RCM examination, 92 patients (29 males and 63 females) underwent
skin biopsy. The biopsy tissue was fixed in formaldehyde, embedded in
paraffin, sliced, stained with hematoxylin -eosin for routine treatment,
and finally stored at room temperature. Dermatopathologists reviewed the
images and conducted histological diagnosis.
2.4 | Analysis
A comprehensive data and descriptive analysis was conducted on the
results of RCM and histopathological examination.
3.RESULTS
3.1 | Diagnosis by RCM
Based on RCM image analysis, 69 out of 113 patients (61.1%) were
diagnosed with BD. 11 patients were diagnosed with AK, four with BCC,
two with squamous cell carcinoma(SCC), five with SK, one with
superficial fungal infection, two with eczema, three with bowenoid
papulosis(BP), and one with extramammary Paget’s disease (EMPD). Out of
113 patients, 15 (13.3%) couldn’t be diagnosed by RCM, and were
considered as undiagnosed. (Table 1)
3.2 | RCM diagnosis compared with histopathological diagnosis
Out of 113 patients, 92 underwent biopsy. Among these 92 cases, based on
histopathological standard, 54 out of 59 cases were diagnosed with BD by
RCM, which was consistent with histological diagnosis. Of the other five
cases, two were diagnosed with AK, one with SK, and two with SCC. Five
cases of AK, three cases of BCC, two cases of SCC, three cases of SK,
two cases of BP, and one case of EMPD were diagnosed by RCM, which were
consistent with the histological diagnosis. Two cases of BD were
misdiagnosed as AK by RCM, and one case was misdiagnosed as BCC. After
histopathological diagnosis of the 12 undiagnosed cases, one were
diagnosed with BD, three with AK, two with BCC, two with SK, and one
with discoid lupus erythematosus (DLE) (Table 2).
As shown in Table 2, the sensitivity and specificity of RCM in the
diagnosis of BD were calculated as 88.5% and 86.8%, respectively.
3.3 | RCM characteristics in 54 patients of BD
3.3.1 | Skin lesions of Classic Bowen’s Disease (CBD)
52 skin lesions were featured by red or dark red patches or plaques,
often with scales, scabs, or exudates on the surface. Removing the
scales and scabs can reveal a dark red granular or granulation-like
moist surface, with almost no bleeding (Fig. 1a). In the
histopathological images, the red or dark red patches or plaques show
hyperkeratosis and parakeratosis, atypia in epidermal cell accompanied
by dyskeratotic cells, and more obvious inflammation in the dermis (Fig.
1b). RCM shows five microscopic characteristics, including (1)
scale/parakeratosis (Fig. 1c), (2) disarranged cells manifested as
irregular honeycomb pattern in the spinous layer, (Fig. 1d), (3) target
cells in the spinous layer (Fig. 1e), (4) enlargement of interpapillary
spaces in some cases, (5) vessels in tortuous morphology inside the
dermal papilla and infiltration of inflammatory cells in the dermis
(Fig. 1f).
3.3.2 | Skin lesions of Pigmented Bowen’s Disease (PBD)
9 skin lesions were pigmentary, manifested as black or brown scale
patches or plaques with clear boundaries (Fig. 2a). In histopathology,
the lesions were characterized by atypia of keratinized cells in the
entire layer of the epidermis with scattered abnormal keratinized cells
and basilar hyperpigmentation(Fig. 2b). Under RCM, the following were
observed: (1) varying degrees of hyperkeratosis and parakeratosis, (2)
irregular honeycomb pattern and target cells in the spinous layer (Fig.
2c), (3) spindle-shaped cells with dendritic processes at the spinous
layer (Fig. 2d), (4) edged papillae (Fig. 2e) and enlargement of
interpapillary spaces, (5) Vessels in tortuous morphology inside the
dermal papilla, with visible melanophages and inflammatory cells (Fig.
2f).
In summary, target cells and irregular honeycomb patterns are important
RCM features of BD, while the presence of dendritic cells was not stable
in different categories of lesions. Abnormal keratinization of the
stratum corneum, irregular hyperplasia of the dermal papillae, and
infiltration of inflammatory cells might all be present, but edged
papillae and melanophages in the dermis were typical manifestations of
pigmented BD. (Table 3).
3.4 | Differential diagnosis of Bowen’s disease from other skin
diseases
In order to further improve the accuracy of RCM in diagnosing BD and
better differentiate it from other skin diseases, we listed the main
manifestations of BD, AK, BCC, SK, and SCC (Table. 4).
4 | DISCUSSION
BD, also known as squamous cell carcinoma in situ, is a rare skin tumor
characterized by being asymptomatic and slow growth. It is prone to the
chronically exposed skin of the elderly. BD usually has no pigmentation,
but occasionally pigmentary changes can be seen, known as PBD. PBD is an
uncommon variant of BD, accounting for no more than 2% of all BD cases
(Zhou & Mistry, 2017). Due to the atypical clinical manifestations, CBD
is difficult to be distinguished from such diseases as AK, SK,tinea and
eczema while PBD is difficult to be distinguished from diseases like SK,
BCC and melanoma(Zhou & Mistry, 2017). The current gold standard for
diagnosing Bowen’s disease is still biopsy (Palaniappan & Karthikeyan,
2022). However, since the skin lesions often occur at the exposed part,
and the diagnostic method for it is invasive and time-consuming,
compliance of patients is poor. As a result, there are certain
difficulties in conducting tissue biopsy, which often delays diagnosing.
RCM is an optical microscope that utilizes various refractive indices of
light in different tissues or cells to present images of varying
brightness levels under the microscope, forming in vivo
three-dimensional images (Lboukili et al., 2022). RCM can intuitively
observe the morphology and arrangement of cells, which is consistent
with histopathology. Therefore, RCM could be used to identify atypical
cells in vivo to a certain extent. Currently, RCM has been used to
assist in the diagnosis of various neoplastic dermatoses. In some case
reports and small studies, RCM has been utilized to assist in the
diagnosis of BCC, Paget’s disease, and SCC(Chen et al., 2023; Ozdemir et
al., 2017; Shahriari et al., 2018; Tan et al., 2022).
At present, in some case reports or small studies, RCM has been reported
as a diagnostic aid for BD (Ianoși et al., 2019; Lacarrubba et al.,
2021; Mazzilli et al., 2020; Namiki et al., 2017; Rstom et al., 2022;
Shahriari et al., 2018). According to existing studies, the easily
accepted diagnostic points of RCM for BD include irregular honeycomb
patterns in the epidermis, atypical cellular structures in the spinous
layer, vessels in tortuous morphology inside the dermal papilla, and
infiltration of inflammatory cells. In the RCM observation of this
study, BD cases exhibited the above findings. Researches have found that
for atypical cells, some of them can be recognized as target cell and
are considered as manifestations of dyskeratosis cells(Ianoși et al.,
2019; Karaarslan et al., 2018; Lacarrubba et al., 2021). It was observed
in our study that target cells often appeared in the spinous layer, and
in some cases, they might involve the entire layer of the epidermis,
manifesting as an increase in cell volume, irregular morphology, low
nuclear refraction, large nucleus, enhanced peripheral cytoplasmic
refraction, and target-like structures with dark nuclei and bright
cytoplasm. These cells are considered as dyskeratosis cells. Target cell
were observed by RCM in BD cases in this study with high specificity,
indicating that the appearance of target cells was a typical
manifestation of BD. We also found dendritic phenomenon in some spinous
layer cells in PBD, and found high refractive index melanophages in the
dermal papilla. Therefore, we speculated that this might be a typical
manifestation of PBD. The study found that dendritic cells (43%) with
spindle-shaped spines were confirmed as lccs by immunostaining (Rstom et
al., 2022), which might be due to the observed high reflectivity under
RCM mirrors after uptaking of melanosomes by LCs. In addition, we found
that the reduced dermal papilla contained a majority of highly
refractive pigment structures, which might represent melanocytes, and
might be another feature of PBD. The characteristics observed in the
lesions of BD cases, such as the disappearance of normal honeycomb
pattern in the epidermis, disarranged cells, vascular proliferation in
the dermal papilla, and infiltration of inflammatory cells, might also
occur in other skin tumors, which might be an important reason for
misdiagnosis with diseases including highly malignant SCC, AK, and BCC.
Because of its low incidence, atypical clinical manifestations, and the
need for invasive biopsy for diagnosis, physicians usually do not like
to diagnose it as BD at the initial diagnosis. The application of
non-invasive technology makes it easier for patients to accept the
advice of physicians for examination, and also makes it easier for
physicians to include BD in clinical diagnosis and differential
diagnosis.
Both BD and AK clinically manifest as erythema accompanied by scales,
which can cause bleeding after being scraped off. After analysis of
their RCM characteristics, it was found that both BD and AK exhibited
hyperkeratosis, irregular honeycomb pattern and target cells in the
epidermis, which made the two diseases easily confused. The
proliferation of dermal papilla and superficial blood vessels, as well
as the degree of inflammatory cell infiltration, cannot effectively
distinguish between the two. Therefore, based on histopathology, we
reanalyzed their RCM characteristics and found some subtle differences.
AK showed more hyperkeratosis and parakeratosis in the stratum corneum,
while BD showed more obvious hyperkeratosis. Besides, epidermal cells in
BD were disarranged, with target cells appearing in the spinous layer or
even the entire epidermis. In comparison, target cells for AK were
mostly in the basal layer, and there were normal honeycomb patterns in
the spinous layer. This manifestation may be a feature of gradual
progression from AK to BD. SCC is a tumor that occurs in epithelial
cells and is more malignant than AK and BD, with a wide invasion range.
An early manifestation of SCC is infiltrative erythema, which gradually
develops into plaques or warty lesions, often accompanied by ulcers and
scabs on the surface. In this study, two cases of SCC were diagnosed as
SCC after RCM and pathological examination. After analyzing the RCM
characteristics, it was found that SCC had more severe hyperkeratosis in
the stratum corneum, with keratin rupture, disordered arrangement of
epidermal cells, and target cells throughout the entire layer of the
epidermis. The difference was that in the dermis, atypical proliferation
and aggregation of keratinocytes were displayed, and the cell volume was
larger than that of surrounding inflammatory cells. This is an important
distinguishing feature for identifying SCC with AK and BD.
SK is the benign epidermal proliferative tumor most commonly affecting
the elderly, with a slow course and early manifestation of brown flat
papules or patches with clear boundaries. Due to the long course of the
disease, the lesion may gradually change after exposure to sunlight and
scratching. At present, the commonly recognized points for diagnosing SK
by RCM include hyperkeratosis, papillary hyperplasia of the epidermis,
increased pigmentation in basal layer, formation of keratin-filled
cystic inclusions, and cerebriform architecture of the epidermis(Guo et
al., 2018). In this study, one patient was diagnosed with BD through
RCM, but ultimately diagnosed with SK through pathology. Analysis of RCM
characteristics revealed that SK and BD couldn’t be accurately
distinguished by hyperkeratosis, epidermal hyperplasia and dendritic
cells in the basal layer. The presence of melanophages in the dermis was
a factor that made it difficult to distinguish between SK and PBD.
BCC is the most common skin tumor with diverse and complex clinical
manifestations. Superficial BCC is characterized by erythema with or
without scales, which is easily confused with non-pigmented BD. Skin
lesions of pigmented BCC is often black or brown, making it easy to be
misdiagnosed as PBD. Therefore, exploring the RCM characteristics of BD
has profound significance for the diagnosis of BD and BCC. The RCM
characteristics of BCC include: disarranged epidermal cells, loss of
normal honeycomb patterns, proliferation of dermal cells, elongated
tumor masses in the form of palisade or spindle-shaped cells, numerous
high refractive pigmented masses in the middle, dendritic cell
structures, and aggregation of melanophages and inflammatory
cells(Niculet et al., 2022). Our study found that the spindle-shaped
cell structure of BD was mistakenly believed to be a tumor mass of BCC
extending into the dermis, accompanied by melanophages, and was
misdiagnosed as pigmented BCC. The spindle-shaped structure within the
epidermis was a typical manifestation of PBD, and the position of the
tumor nest at different skin layers might affect the diagnosis of
disease. Moreover, the structure and cell morphology of the blood
vessels within the dermal papilla also require detailed analysis and
observation.
It was found in our study that brown patches or plaques that occurred in
the external genitalia also made it difficult to distinguish BP and PBD
in clinical practice. Therefore, we analyzed the RCM characteristics of
BP: papillomatous proliferation in the epidermis, disarranged spinous
cells, irregular cell structures with high refractive and large nuclei,
dendritic cells in the basal layer, and a small amount of melanophages
and inflammatory cells in the dermis. These highly refractive
heteromorphic cells with large nuclei were easily considered as target
cells. Whether there is a certain association between BD and BP may
require further exploration.
Due to the fact that in clinical practice, BD is more likely to be
overlooked, we have posted clinical experience using RCM to distinguish
BD from other diseases. (1) AK, BD and SCC are tumors derived from
epithelial cells, with clinical manifestations of erythema accompanied
by scales, ulcers, and scabs. RCM is featured by target cells, and we
can differentiate diagnosis based on the presence of atypical
keratinocytes in different layers of the skin. (2) When the clinical
manifestation is black or brown skin lesions, dermatologists cannot
ignore the possibility of BD. PBD is more likely to be confused with SK
and pigmented BCC. The pattern of epidermal hyperplasia can be used to
determine BD and SK, and palisade-like tumor masses in the dermis are
the typical manifestations of BCC. (3) It is difficult to distinguish
between superficial BCC and BD with clinical manifestations of erythema.
RCM can find target cells throughout the epidermis and there is no
pigmentation, which can serve as a clue for CBD and BCC. (4) Bowenoid
papulosis is usually associated with HPV infection, and RCM can detect
large vacuolar-like cells (with large nuclei and low refraction) in the
spinous layer, which may be a feature that could exclude BP.
In addition to diagnosing and distinguishing BD, RCM can also be used to
evaluate and delineate the boundaries of BD surgery, monitor the
treatment process of laser therapy, topical imiquimod, photodynamic
therapy and 5-fluorouracil, and identify BD recurrence after treatment.
(Combalia & Carrera, 2020)
Limitations still exist in our research. To begin with, the study was
carried out in a retrospective way. In addition, the majority of
patients undergoing histopathological examination were patients with
atypical clinical manifestations and RCM characteristics that require
further diagnosis, so the biopsy samples were not randomly selected. In
addition, the number of patients in this study was limited.
In summary, RCM exhibits high sensitivity and specificity in diagnosing
BD, indicating that RCM is of great value in the diagnosis and
differential diagnosis of BD, though more researches are required to
testify it. The goal of our further efforts is to perfect the diagnostic
standards for RCM and improve the consistency between RCM and histology.
ACKNOWLEDGMENTS
This work was supported by grants from the National Natural Science
Foundation of China (No. 81972921), Natural Science Foundation of Hunan
Province (No. 2023JJ20090,2020JJ5849), the Science and Technology
Innovation Program of Hunan Province(No.2023RC3086), the Hunan
Provincial Health Commission(No. 202304129002),Innovation-Driven
Research Programme Funds for the Central Universities of Central South
University (No. 2023CXQD074),and the Wisdom Accumulation and Talent
Cultivation Project of the Third Xiangya Hospital of Central South
University (No. YX202101).
AUTHOR CONTRIBUTIONS
Shu Ding and Zhen Tang designed the study. Shu Ding, Zhen Tang, Lingxue
Hu, Yu Rao analyzed the data and wrote the manuscript. Shu Ding, Lingxue
Hu, Yu Rao collected patients’ clinical and examination data. Ruijian
Ren, Xiaoliang Tong, Aiyuan Guo designed the graphics. Shu Ding,Zhen
Tang, Lingxue Hu ,Aiyuan Guo, Jian Huang performed the examination. All
authors critically reviewed the manuscript.
ORCID
Shu Ding , https://orcid.org/0000-0002-7078-108X
Zhen Tang , https://orcid.org/0000-0003-2354-5041
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