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Citation: Cuomo, R.; Rozen, W.M.;
Pentangelo, P.; Ceccaroni, A.; Alfano,
C.; Seth, I. Human Papillomavirus-
Associated Giant Clear Cell
Acanthoma and Squamous Cell
Carcinoma: A Rare Case Report and
Literature Review. J. Clin. Med. 2024,
13, 2482. https://doi.org/10.3390/
jcm13092482
Academic Editor: Dennis Paul Orgill
Received: 26 March 2024
Revised: 13 April 2024
Accepted: 21 April 2024
Published: 24 April 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Journal of
Clinical Medicine
Review
Human Papillomavirus-Associated Giant Clear Cell Acanthoma
and Squamous Cell Carcinoma: A Rare Case Report and
Literature Review
Roberto Cuomo 1, * , Warren M. Rozen 2, Paola Pentangelo 3, Alessandra Ceccaroni 3, Carmine Alfano 3
and Ishith Seth 2
1Plastic Surgery Unit, Department of Medicine, Surgery and Neuroscience, University of Siena,
53100 Siena, Italy
2Department of Plastic Surgery, Peninsula Health, Melbourne, VIC 3199, Australia
3Plastic Surgery Unit, Department of Medicine, Surgery and Dentistry, University of Salerno,
84081 Baronissi, Italy
*Correspondence: robertocuomo@outlook.com
Abstract: Clear cell acanthoma (CCA) and squamous cell carcinoma (SCC) represent distinct entities
within dermatological oncology, each posing unique diagnostic and therapeutic challenges. CCA is a
rare, benign epidermal growth, often not associated with human papillomavirus (HPV) infection,
whereas SCC, a more aggressive form of skin cancer, has been linked to both ultraviolet (UV) exposure
and HPV. Understanding the co-occurrence of these conditions in a single patient can enhance
diagnostic accuracy and therapeutic outcomes. We report a 64-year-old male who underwent an
operation for a verruciform lesion in the right groin, which was diagnosed as HPV-positive CCA
alongside keratinised SCC. A literature search across January 2024 revealed limited evidence directly
linking HPV to CCA, suggesting a need for further investigation. The speculative association
between HPV and CCA warrants deeper exploration, especially considering the potential for HPV to
contribute to lesion development through indirect mechanisms. The coexistence of CCA and SCC in
an elderly patient presents a unique clinical scenario. This emphasises the need for vigilant diagnosis
and tailored treatment strategies, highlighting the gap in understanding the pathogenesis of CCA,
particularly its potential association with HPV. Further research is crucial for elucidating the complex
interactions governing these conditions and for developing targeted interventions.
Keywords: clear cell acanthoma; squamous cell carcinoma; inguinal; human papillomavirus; HPV
1. Introduction
Clear cell acanthoma (CCA) and squamous cell carcinoma (SCC) pose distinct chal-
lenges in dermatological oncology, highlighted by their rarity, varied aetiologies, and
aggressive behaviour, particularly in the older male demographic [
1
]. SCC stands as the
second most prevalent skin cancer, primarily driven by excessive ultraviolet (UV) light
exposure, with risk factors including immunosuppression, arsenic exposure, and chronic
irritation contributing to its development [
2
,
3
]. In contrast, CCA is a rare, benign tumour
originating from keratinocytes, mainly occurring on the lower limbs but also seen in the
inguinal region, trunk, forearms, face, and occasionally the nipple–areola complex [
3
]. The
aetiology of CCA is not well understood, with some proposing it inflammatory dermatosis,
evidenced by its psoriasis-like cytokeratin expression [
4
]. This condition shows a slight
male predilection. CCA typically ranges from 0.5 to 2 cm in diameter, though lesions up to
5.5 cm have been reported [
5
]. The primary treatment is surgical excision, with alternatives
like electrocoagulation, cryotherapy, curettage, or carbon dioxide laser excision for multiple
lesions or those previously confirmed histologically [5].
The diagnosis of CCA and SCC relies on histopathological analysis, with SCC charac-
terised by keratin pearls and clear cell differentiation, while CCA is identified through its
J. Clin. Med. 2024,13, 2482. https://doi.org/10.3390/jcm13092482 https://www.mdpi.com/journal/jcm
J. Clin. Med. 2024,13, 2482 2 of 13
glycogen-rich clear cells and positive periodic acid-Schiff staining [
4
]. Treatment strategies
vary according to the stage of cancer and overall patient health, predominantly involving
surgical measures. SCC treatment protocols suggest variable margins based on lesion
characteristics, whereas CCA management might include less invasive methods such as
cryotherapy, demonstrating the diverse approaches required for these distinct dermatologi-
cal conditions [6].
Moreover, the prognosis for SCC patients remains guarded, with survival rates signifi-
cantly influenced by the stage at diagnosis, tumour grade, and differentiation level. The
rarity of GCCA and its non-regressive nature further complicate the clinical landscape,
necessitating ongoing research and case studies to refine understanding and treatment
approaches. This juxtaposition of GCCA and SCC within the dermatological oncology field
highlights the importance of tailored diagnostic and therapeutic strategies to effectively
manage these complex conditions.
2. Methodology
2.1. Literature Search
A comprehensive literature search was executed across PubMed, Web of Science,
Embase and Scopus databases from their inception to January 2024. The search strat-
egy incorporated an array of keywords and terms, including “human papillomavirus”,
“HPV”, “clear cell acanthoma”, “squamous cell carcinoma”, “skin cancer”, “HPV-associated
skin lesions”, “clear cell acanthoma”, “clear cell acanthosis”, “Degos acanthoma”, and
“glycogen-rich acanthoma.” (See Table 1). The intent was to encapsulate a broad spectrum
of the literature addressing the nexus between HPV and these specific dermatological
conditions, ensuring a comprehensive review that integrates varied nomenclatures and
terminologies used in the field. Only articles published in English were considered for
inclusion. (Table 2summarises the most relevant).
Table 1. Literature research strategy.
Search Terms Databases Inclusions Criteria Exclusion Criteria
human papillomavirus PubMed English manuscript Non-English manuscript
clear cell acanthoma Web of Science other keywords used
squamous cell carcinoma Embase
skin cancer Scopus
HPV-associated skin lesions
clear cell acanthoma
clear cell acanthosi
Degos acanthoma
glycogen-rich acanthoma
Table 2. Analysed manuscripts.
Author Year Keypoints
Ramoz [7] 2002 Some mutations can bring verruciformis lesions
Forslund [8] 2003 New strategies to detect HPV
Rohwedder [9] 2008 HPV is linked to acanthoma and other “fields of cancerisation”
Chahoud [2] 2015 HPV genus linked to cutaneous squamous cell carcinoma
Harwood [10] 2004 Increased risk of skin cancer linked to HPV
Kuma [11] 2015 HPV and skin cancer are linked in immunosuppressed patients
J. Clin. Med. 2024,13, 2482 3 of 13
Table 2. Cont.
Author Year Keypoints
Kombe, Kombe [2] 2020 Epidemiology of HPV diseases
Chesson [12] 2014 Prevalence of HPV in the USA
Mahal [13] 2019 Incidence of cancers in HPV patients
Forman [14] 2012 Global burden of HPV and related disease
Roden [2] 2018 HPV vaccination and cancer
Lecher [2] 2022 HPV and oral cancer
Szymonowicz [2] 2020 Analysis of molecular aspects of HPV-related cancer
Moody [2] 2010 HPV oncoproteins
Symer [15] 2018 HPV and anal cancer
Shamseddine [16] 2021 New therapies for HPV-related cancer
Chera [17] 2019 Chemo-radiotherapy for HPV-associated squamous cell carcinoma
Rusan [18] 2015 Genomic aspects of HPV-associated cancer
Kim [19] 2014 P16 immunohistomchemistry expression mlinked to HPV infection in bladder cancer with
squamous differentiation
Eich [20] 2020 HPV linked to squamous cell carcinoma of the penis
Gao [21] 2019 Genome sequencing reveals HPV integration in oropharyngea squamous cell carcinomas
Neagu [22] 2023 HPV has a role in skin cancer
Nindl [23] 2007 Description of the role of HPV in non-melanoma skin cancer
Waterboer [24] 2008 Different types of HPV are linked to different types of squamous cell carcinoma of the skin
Farzan [25] 2013 Different types of HPV are linked to different types of squamous cell carcinoma of the skin
Svajdler [26] 2016 HPV has a role in p16 expression in Bowen’s disease
Conforti [27] 2019 HPV can also be linked to keratoacanthoma
Conforti [28] 2019 New concepts of cancerisation of HPV
Parson [29] 1997 SCC can be linked to clear cell acanthoma
D’Antonio [30] 2011 Clinical aspects of rare skin cancers
Bandolin [31] 2020 HPV beta can be linked to tumorigenesis in the skin
Galloway [32] 2015 Describes pathogenesis pathways of HPVs
Balaji [33] 2022 Describes the role of HPV proteins in carcinogenesis
Bouwes [2] 2010 Beta-HPV infection and cutaneous squamous cell carcinoma analogies
2.2. Ethical Considerations
Written informed consent was obtained from the patient for the use of his clinical
information and images for the purposes of research and publication, ensuring respect
for his autonomy and privacy. The confidentiality of the patient’s identity and medical
information was rigorously protected throughout the study, aligning with ethical guidelines
and principles of patient care and research integrity.
2.3. Case Presentation
A 64-year-old male patient was referred to the plastic surgery outpatient clinic, pre-
senting with a verruciform lesion in the right groin that had progressively enlarged and
darkened over five months. The primary concerns associated with this lesion included
pruritus and localised pain. The patient’s medical history was significant for chronic lym-
phocytic leukaemia and hypertension, which are pertinent given their potential impact on
his dermatological health.
J. Clin. Med. 2024,13, 2482 4 of 13
Clinically, the lesion was observed as a raised verruciform and mamillated cutaneous
neoformation, measuring 12 cm in length, 6 cm in width, and 5 cm in height (Figures 1–3).
It was characterised by a broad base of implantation and exhibited a taut elastic consis-
tency. Additionally, two minor satellite neoformations were identified at the 3 o’clock and
11 o’clock positions relative to the primary lesion, each measuring 1.5 cm by 1.5 cm and
displaying similar morphological features.
J. Clin. Med. 2024, 13, x FOR PEER REVIEW 4 of 14
and 11 o’clock positions relative to the primary lesion, each measuring 1.5 cm by 1.5 cm
and displaying similar morphological features.
Figure 1. Pre operative picture.
Figure 2. Intra operative picture after acanthoma remotion.
Figure 3. Raised verruciform and mamillated cutaneous neoformation lesion measuring 12 cm in
length, 6 cm in width, and 5 cm in height.
Figure 1. Pre operative picture.
J. Clin. Med. 2024, 13, x FOR PEER REVIEW 4 of 14
and 11 o’clock positions relative to the primary lesion, each measuring 1.5 cm by 1.5 cm
and displaying similar morphological features.
Figure 1. Pre operative picture.
Figure 2. Intra operative picture after acanthoma remotion.
Figure 3. Raised verruciform and mamillated cutaneous neoformation lesion measuring 12 cm in
length, 6 cm in width, and 5 cm in height.
Figure 2. Intra operative picture after acanthoma remotion.
J. Clin. Med. 2024, 13, x FOR PEER REVIEW 4 of 14
and 11 o’clock positions relative to the primary lesion, each measuring 1.5 cm by 1.5 cm
and displaying similar morphological features.
Figure 1. Pre operative picture.
Figure 2. Intra operative picture after acanthoma remotion.
Figure 3. Raised verruciform and mamillated cutaneous neoformation lesion measuring 12 cm in
length, 6 cm in width, and 5 cm in height.
Figure 3. Raised verruciform and mamillated cutaneous neoformation lesion measuring 12 cm in
length, 6 cm in width, and 5 cm in height.
J. Clin. Med. 2024,13, 2482 5 of 13
Histopathological evaluation of the lesion revealed significant findings, including an
accumulation of intracytoplasmic glycogen and a predominant presence of eosinophilic
granulocytes within the intraepidermal micro-abscesses. Further pathological features
included dyskeratosis and coilocytotic-like changes. Immunohistochemical staining demon-
strated positivity for p16, which is a marker often associated with human papillomavirus
(HPV) infection (Figure 4). These findings led to a diagnosis of HPV-positive clear cell
acanthoma in conjunction with keratinised squamous cell carcinoma. Additionally, a
melanocytic nevus exhibiting severe atypia was identified within the lesion’s composition.
The patient underwent surgical treatment involving complete excision of the skin’s neofor-
mation, resulting in a satisfactory functional and cosmetic outcome in the inguinal region
at the two-month follow-up and no reoccurrence at the 12-month follow-up (Figure 5).
This case highlights the efficacy of surgical intervention in managing extensive dermato-
logical neoformations, emphasising the potential for positive post-operative results both
functionally and aesthetically.
J. Clin. Med. 2024, 13, x FOR PEER REVIEW 5 of 14
Histopathological evaluation of the lesion revealed significant findings, including an
accumulation of intracytoplasmic glycogen and a predominant presence of eosinophilic
granulocytes within the intraepidermal micro-abscesses. Further pathological features in-
cluded dyskeratosis and coilocytotic-like changes. Immunohistochemical staining
demonstrated positivity for p16, which is a marker often associated with human papillo-
mavirus (HPV) infection (Figure 4). These findings led to a diagnosis of HPV-positive clear
cell acanthoma in conjunction with keratinised squamous cell carcinoma. Additionally, a
melanocytic nevus exhibiting severe atypia was identified within the lesion’s composition.
The patient underwent surgical treatment involving complete excision of the skin’s
neoformation, resulting in a satisfactory functional and cosmetic outcome in the inguinal
region at the two-month follow-up and no reoccurrence at the 12-month follow-up (Figure
5). This case highlights the efficacy of surgical intervention in managing extensive derma-
tological neoformations, emphasising the potential for positive post-operative results both
functionally and aesthetically.
Figure 4. Histopathological evaluation of the lesion with an accumulation of intracytoplasmic gly-
cogen and a predominant presence of eosinophilic granulocytes within intraepidermal micro-ab-
scesses; Immunohistochemical staining demonstrated positivity for p16 indicative of human papil-
lomavirus (HPV) infection.
Figure 5. Post-operative picture.
3. Discussion
This case report and literature review highlight a rare clinical encounter of a 79-year-
old male patient presenting with a concurrent diagnosis of inguinal clear CCA devoid of
HPV infection and SCC, highlighting the complexity and diagnostic challenges in derma-
tological oncology. CCA, a benign epithelial tumour of keratinocyte origin, is commonly
localised to the lower limbs but can also manifest in regions such as the inguinal area,
showcasing its variable clinical presentation. This case is particularly intriguing due to the
simultaneous occurrence of CCA and SCC, a common skin cancer known for its aggres-
sive behaviour and association with UV light exposure, in a single patient [29]. This case
Figure 4. Histopathological evaluation of the lesion with an accumulation of intracytoplasmic
glycogen and a predominant presence of eosinophilic granulocytes within intraepidermal micro-
abscesses; Immunohistochemical staining demonstrated positivity for p16 indicative of human
papillomavirus (HPV) infection.
J. Clin. Med. 2024, 13, x FOR PEER REVIEW 5 of 14
Histopathological evaluation of the lesion revealed significant findings, including an
accumulation of intracytoplasmic glycogen and a predominant presence of eosinophilic
granulocytes within the intraepidermal micro-abscesses. Further pathological features in-
cluded dyskeratosis and coilocytotic-like changes. Immunohistochemical staining
demonstrated positivity for p16, which is a marker often associated with human papillo-
mavirus (HPV) infection (Figure 4). These findings led to a diagnosis of HPV-positive clear
cell acanthoma in conjunction with keratinised squamous cell carcinoma. Additionally, a
melanocytic nevus exhibiting severe atypia was identified within the lesion’s composition.
The patient underwent surgical treatment involving complete excision of the skin’s
neoformation, resulting in a satisfactory functional and cosmetic outcome in the inguinal
region at the two-month follow-up and no reoccurrence at the 12-month follow-up (Figure
5). This case highlights the efficacy of surgical intervention in managing extensive derma-
tological neoformations, emphasising the potential for positive post-operative results both
functionally and aesthetically.
Figure 4. Histopathological evaluation of the lesion with an accumulation of intracytoplasmic gly-
cogen and a predominant presence of eosinophilic granulocytes within intraepidermal micro-ab-
scesses; Immunohistochemical staining demonstrated positivity for p16 indicative of human papil-
lomavirus (HPV) infection.
Figure 5. Post-operative picture.
3. Discussion
This case report and literature review highlight a rare clinical encounter of a 79-year-
old male patient presenting with a concurrent diagnosis of inguinal clear CCA devoid of
HPV infection and SCC, highlighting the complexity and diagnostic challenges in derma-
tological oncology. CCA, a benign epithelial tumour of keratinocyte origin, is commonly
localised to the lower limbs but can also manifest in regions such as the inguinal area,
showcasing its variable clinical presentation. This case is particularly intriguing due to the
simultaneous occurrence of CCA and SCC, a common skin cancer known for its aggres-
sive behaviour and association with UV light exposure, in a single patient [29]. This case
Figure 5. Post-operative picture.
3. Discussion
This case report and literature review highlight a rare clinical encounter of a 79-year-
old male patient presenting with a concurrent diagnosis of inguinal clear CCA devoid of
HPV infection and SCC, highlighting the complexity and diagnostic challenges in derma-
tological oncology. CCA, a benign epithelial tumour of keratinocyte origin, is commonly
localised to the lower limbs but can also manifest in regions such as the inguinal area,
showcasing its variable clinical presentation. This case is particularly intriguing due to the
simultaneous occurrence of CCA and SCC, a common skin cancer known for its aggressive
behaviour and association with UV light exposure, in a single patient [
29
]. This case also
J. Clin. Med. 2024,13, 2482 6 of 13
underlines the importance of comprehensive histopathological evaluation and the use of
ancillary histochemical and immunohistochemical studies in accurately diagnosing and
distinguishing between cutaneous malignancies and benign conditions like CCA. The
differentiation is crucial for prognostication and selecting an appropriate treatment strategy
to ensure optimal patient outcomes.
CCA’s aetiology remains largely speculative, with the recent literature suggesting it to
be a reactive and localised psoriasiform dermatitis rather than a true neoplastic entity. This
assertion is supported by its clinicopathologic and immunohistochemical profile, which
includes psoriasiform acanthosis, glycogen-rich clear or pale-staining epithelial cells, and a
strong immunopositivity for cytokeratin markers akin to those found in psoriasis. Notably,
the absence of HPV in the CCA lesion, as indicated by PCR analysis, emphasises the non-
viral pathogenesis of CCA, distinguishing it from other HPV-associated dermatoses and
neoplasms.
The association between HPV and clear cell acanthoma CCA remains speculative, with
limited direct evidence linking the two. However, a theoretical framework can be proposed
based on HPV’s known mechanisms of action in other cutaneous and mucosal pathologies.
HPV, particularly its oncogenic strains, possesses the ability to integrate its DNA into
the host cell genome, leading to the overexpression of viral oncogenes E6 and E7 [
34
–
36
].
These oncogenes are known to disrupt the function of tumour suppressor proteins p53
and retinoblastoma, respectively, thereby promoting uncontrolled cell proliferation and
potentially leading to neoplastic transformation [
35
,
37
–
39
]. In the context of CCA, a benign
lesion characterised by glycogen-rich, clear keratinocytes, it is conceivable that HPV could
contribute to lesion development through indirect mechanisms [
29
,
40
]. For instance, the
virus might induce localised inflammatory responses or alter keratinocyte differentiation,
creating a microenvironment conducive to the accumulation of glycogen within cells. This
process could be facilitated by the disruption of cellular regulatory pathways involved
in glycogen metabolism, potentially as a side effect of the host’s attempt to combat viral
infection [
29
,
30
,
41
]. Additionally, HPV’s role in modulating immune surveillance could
permit the persistence of aberrant keratinocytes, allowing for the manifestation of clear
cell pathology observed in CCA. While this hypothesis integrates known aspects of HPV
pathogenicity, it is essential to acknowledge the current lack of empirical evidence directly
linking HPV to CCA development. Further research, particularly studies exploring the
presence of HPV DNA within CCA lesions and investigating the virus’s impact on cellular
metabolism and immune response in the skin, is crucial to elucidate any potential causal
relationship [42–45].
The coexistence of CCA and SCC in this patient raises important considerations
regarding the differential diagnosis and management of complex skin lesions, especially
in elderly patients with significant sun exposure history or other carcinogenic risk factors.
SCC, characterised by its potential for aggressive growth and metastasis, necessitates
prompt and effective treatment, typically involving surgical excision with adequate margins.
In contrast, the treatment approach for CCA, given its benign nature, may involve less
invasive options such as cryotherapy or CO2 laser excision, highlighting the need for
individualised treatment planning based on the lesion’s nature and the patient’s overall
health status [46–48].
Patients with immunosuppression are at a heightened risk for developing cutaneous
malignancies, including SCC, with evidence suggesting roles for both UV radiation and
HPV in their pathogenesis [
49
,
50
]. Beta-HPVs, in particular, are hypothesised to con-
tribute to cancer development through a ‘hit-and-run’ mechanism, initiating malignant
transformation early and becoming less critical as cancer progresses, likely by enabling
the accumulation of UV-induced DNA mutations [
51
]. The World Health Organization
has updated its classification for head and neck tumours to include specific sections for
HPV-associated dysplasia, acknowledging their distinct clinical attributes from traditional
SCCs, yet it stops short of directly associating CCA with HPV infection [
52
–
54
]. The stan-
dardisation of pathology terminology, such as low-grade squamous intraepithelial lesion
J. Clin. Med. 2024,13, 2482 7 of 13
(LSIL) and high-grade squamous intraepithelial lesion (HSIL), aims to enhance diagnos-
tic accuracy and treatment efficacy, though direct links between HPV and CCA remain
unestablished. Epidemiologically, cutaneous HPVs are widespread across healthy skin,
possibly constituting part of the normal skin flora, and their role in non-melanoma skin
cancer, especially in immunocompromised individuals like organ transplant recipients who
are more prone to
β
-HPV infections, warrants further study [
31
,
55
–
58
]. A case report on
hyaline inclusion acanthoma revealing intracytoplasmic eosinophilic hyaline inclusions in
keratinocytes, without association with low- or high-risk HPVs, suggests that alternative
oncogenic pathways may be at play [
47
,
59
,
60
]. Advancements in the understanding of
the immunopathogenesis of persistent oncogenic HPVs, which may contribute to chronic
inflammation and subsequent carcinogenesis, highlight the importance of exploring new
diagnostic and therapeutic strategies, including vaccines targeting these viruses. Such
advancements offer hope for future management options against the cancers they cause,
including skin cancers [61].
The relationship between HPV infection and skin cancer, particularly non-melanoma
skin cancer (NMSC), such as squamous cell carcinoma (SCC) and keratoacanthoma, has
been a subject of considerable scientific inquiry. The systematic review by Neagu et al. (2022)
included 2284 patients and found a significant presence of beta and gamma HPV subtypes
in various forms of NMSC, suggesting the potential etiological role of HPV in keratinocyte
skin cancers [
22
,
62
–
64
]. Ramezani et al. in 2020 conducted a meta-analysis specifically
examining the association of
β
-HPV with SCC in immunosuppressed individuals, finding
a high prevalence of
β
-HPVs in cutaneous SCC patients, which supports the hypothesis of
β
-HPV contributing to SCC development in those with compromised immune systems [
65
].
Nindl et al. in 2007 and Galloway and Laimins in 2015 discussed the basic virology and
clinical manifestations of HPV in relation to NMSC, highlighting the transforming proper-
ties of some HPV types and their potential co-factor role in SCC pathogenesis, especially in
the context of UV-radiation and immune system interactions
[23–28,32].
Waterboer et al.
in 2008 and Farzan et al. in 2013 provided serological evidence linking beta and gamma
HPV types to SCC risk, suggesting a specific association between these HPV genera and
skin SCC [
24
,
25
]. Conversely, Švajdler et al. in 2016 examined the presence of
α
-HPV and
β
-HPV in extragenital/extraungual Bowen’s disease, finding a considerable proportion
of lesions positive for high-risk HPV types, which could imply the etiological role of HPV
in these precancerous conditions [
26
]. The literature also discusses the potential benefits
of HPV vaccination in preventing NMSC, with some evidence suggesting that a beta-
HPV vaccine could serve as an adjuvant treatment measure for patients with recalcitrant
NMSC [
22
,
66
,
67
]. The role of HPV proteins in cancer development was explored by Balaji
et al. in 2022, who reviewed the mechanisms through which HPV proteins, especially E6
and E7 oncoproteins, contribute to carcinogenesis [68].
The presented data from the literature support the association between HPV, par-
ticularly beta and gamma HPV genera, and the development of skin cancer, including
SCC and potentially keratoacanthoma. This association is particularly pronounced in
immunosuppressed individuals, where the prevalence of
β
-HPV is significantly higher.
The evidence suggests that specific HPV types play a co-factor role in the pathogenesis of
skin cancer, potentially through mechanisms involving the suppression of DNA repair and
the promotion of oncogenic transformation in the context of UV-induced DNA damage.
Despite these associations, the exact causative role of HPV in skin cancer development
remains to be fully elucidated, and further research is warranted to understand the complex
interplay between HPV infection, immune response, UV exposure, and skin carcinogene-
sis [
33
,
69
]. The potential protective role of HPV vaccination against NMSC also requires
additional investigation to determine its efficacy and feasibility as a preventive or adjuvant
treatment strategy.
Many authors focused on the relationship between HPV infection and skin cancer,
acknowledging its complex and multifaceted nature. HPV is a ubiquitous pathogen with
over 200 types, categorised into high risk and low risk based on their oncogenic potential,
J. Clin. Med. 2024,13, 2482 8 of 13
as described by Kombe Kombe et al. in 2021 [
70
]. Epidemiological evidence strongly
supports the association of specific HPV types, particularly from the beta-genus, with skin
cancers such as cSCC in both immunocompetent and immunocompromised individuals,
according to Chahoud et al. in 2016 [
71
–
73
]. The meta-analysis by Chahoud et al. in 2016
provides compelling evidence of a significant association between
β
-genus HPV and cSCC,
with an adjusted pooled odds ratio indicating a moderate but statistically significant risk.
Epidermodysplasia verruciformis (EV), a rare genodermatosis caused by mutations in the
EVER1 and EVER2 genes, exemplifies the role of HPV in skin carcinogenesis [
71
,
74
,
75
].
Individuals with EV exhibit an abnormal susceptibility to specific HPV types, leading to a
high risk of skin carcinoma. This condition highlights the genetic and virological interplay
in the pathogenesis of HPV-related skin cancers [
7
]. Improved detection methods have
enhanced our understanding of the prevalence and diversity of cutaneous HPV types in
skin tumours, as described by Forslund et al. in 2003 [
8
]. The presence of multiple HPV
types in skin lesions, including those not traditionally associated with high oncogenic
risk, suggests the broader involvement of HPV in skin carcinogenesis than previously
recognised. Moreover, the concept of “field of cancerisation”, wherein areas of skin exposed
to HPV exhibit a predisposition to cancer development, further supports the role of HPV in
the aetiology of skin cancers [
9
,
73
,
76
,
77
]. The presence of EV HPV types in normal skin
has been associated with an increased risk of nonmelanoma skin cancer (NMSC), offering
a potential predictive value for skin cancer risk [Harwood et al., 2004]. The burden of
HPV-associated diseases extends beyond cervical cancer to include a significant impact
on skin cancers, particularly in immunosuppressed patients. The high lifetime probability
of acquiring HPV underscores the pervasive nature of this infection and its potential to
contribute to skin carcinogenesis in a substantial portion of the population [10–14].
This evidence collectively substantiates a significant association between HPV infec-
tion and the development of skin cancer, particularly cSCC. The critical roles of specific HPV
types, genetic susceptibility (as seen in EV), and immune status in modulating this risk are
evident. Given the high prevalence of HPV and the considerable burden of HPV-associated
skin cancers, particularly in immunocompromised individuals, these findings underscore
the importance of HPV vaccination and targeted prevention efforts for at-risk populations.
While the direct causality in some instances remains to be fully elucidated, the aggregate
evidence strongly supports the oncogenic potential of HPV in skin carcinogenesis.
The relationship between human papillomavirus (HPV) and acanthoma, particularly
epidermolytic acanthoma and its variants, presents a complex and multifaceted area of
dermatologic pathology. The role of HPV in the pathogenesis of various skin lesions,
including acanthomas, has been a subject of investigation, with some studies identifying
HPV DNA in lesions typically associated with epidermolytic changes [
78
,
79
]. The term
“EV acanthoma” has been coined to describe lesions with histopathological features of
epidermodysplasia verruciformis (EV) in the absence of clinical signs of EV, where EV-
HPV types have been detected [
79
–
81
]. This suggests the potential etiological role of HPV
in the development of these acanthomas. Notably, a case of HPV-14 and -21-positive
EV acanthoma arising in association with condyloma has been reported, highlighting the
coexistence of condyloma with EV acanthoma and suggesting a link between HPV infection
and the development of these skin lesions. The literature also discusses the utility of in situ
hybridisation for detecting genital HPV types in solitary epidermolytic acanthomas, with
findings indicating the absence of genital HPV types in these lesions [
81
–
83
]. This suggests
that while HPV may be implicated in the pathogenesis of some acanthomas, its role is
not ubiquitous across all types or locations of acanthoma. Moreover, the classification
and nomenclature of the oral cavity and mobile tongue tumours have evolved, with
the introduction of new entities and the separation of previously grouped conditions
reflecting advancements in our understanding of their clinical, histological, and molecular
characteristics. This reclassification underscores the importance of precise diagnostic
criteria and the need for ongoing research into etiological factors, including the potential
role of HPV in these lesions. The evidence presents a dichotomy regarding the association
J. Clin. Med. 2024,13, 2482 9 of 13
of HPV with acanthomas. While some studies have found HPV DNA in lesions with
epidermolytic changes, others have reported negative results for HPV infection in similar
cases [
84
]. This discrepancy may be attributed to differences in lesion types, anatomical
locations, HPV detection methods, or the specific HPV subtypes examined.
Many data suggest a correlation between HPV and acanthoma, particularly epider-
molytic variants. While HPV DNA has been detected in certain cases, suggesting its
possible etiological role, the absence of HPV in other similar lesions indicates that the
relationship is not straightforward and may be influenced by multiple factors. Therefore, it
is premature to definitively conclude that HPV is a primary causative agent in the develop-
ment of acanthomas. Further research employing standardised methods for HPV detection
across a broader spectrum of acanthoma types and locations is necessary to elucidate the
role of HPV in the pathogenesis of these lesions.
The literature on HPV’s role in oncogenesis, particularly in relation to skin cancer,
delineates a complex interplay between viral infection and host cellular mechanisms. The
oncogenic potential of HPV, primarily high-risk subtypes, has been well established in the
pathogenesis of cervical, oropharyngeal, anal, and vulvar cancers [
15
,
16
]. This relationship
hinges on the ability of HPV to modulate the immune microenvironment towards a pro-
tumorigenic state, facilitating immune evasion and suppression. The integration of HPV
DNA into the host genome emerges as a pivotal event in tumorigenesis, leading to the en-
hanced expression of viral oncoproteins and alterations in critical cellular genes [
18
,
85
,
86
].
This may include the disruption of tumour suppressor genes, the amplification of onco-
genes, and impairment of DNA repair mechanisms. Notably, recurrent integrations in
genes such as RAD51B, NR4A2, and TP63 have been observed, which could result in
aberrant protein functions contributing to malignant progression. In the context of skin
cancer, specifically squamous cell carcinoma (SCC), the role of HPV is nuanced and less
clearly defined. By contrast, HPV infection has been associated with urothelial carcinoma
exhibiting squamous differentiation [
19
,
81
,
84
]. New evidence for a direct causative role in
skin SCC is less conclusive. However, the expression of p16, a surrogate marker for HPV
infection, has been utilised to infer viral involvement in various SCCs, including those of
the penis and potentially the skin [
20
]. This is corroborated by findings that HPV-positive
SCCs may exhibit distinct clinical and molecular profiles, including a higher prevalence
of non-smokers in HPV-positive cases, suggesting the potential etiologic role of the virus
independent of tobacco exposure [
19
]. The complexity of HPV sequences and integration
events, as revealed by whole genome sequencing, further complicates the landscape. In
HPV-positive oropharyngeal squamous cell carcinomas, for example, a wide range of HPV
copy numbers and disruptive HPV integration events have been observed, leading to
significant genomic instability [
17
,
21
,
87
–
89
]. While this study focused on oropharyngeal
cancer, the mechanisms of HPV-mediated genomic alteration could plausibly extend to
skin SCC, given the commonality in squamous epithelial origin.
This evidence suggests the multifaceted role of HPV in the oncogenesis of various
cancers, with specific mechanisms such as viral integration and immune modulation play-
ing pivotal roles. While the direct causative link between HPV infection and skin cancer,
particularly squamous cell carcinoma, is less clear and warrants further investigation, the
existing literature underscores the potential for HPV to contribute to skin carcinogenesis
through similar genomic and immunological pathways observed in other HPV-related ma-
lignancies. Targeted therapeutic strategies, including vaccination and immunotherapy, hold
promise for the prevention and treatment of HPV-associated cancers, including potential
implications for skin cancer management [33,90–93] (See Supplementary Materials).
4. Conclusions
While the current literature provides limited evidence of a direct link between HPV
infections and the causation of CCA, there exists a broader connection to skin carcinogenesis
in immunocompromised populations, where viruses alongside environmental factors like
UV exposure play contributory roles. This underscores the need for further investigation
J. Clin. Med. 2024,13, 2482 10 of 13
into the intricate interactions that govern these processes and the potential for improved
interventions through targeted immunotherapy against oncogenic HPV strains.
Furthermore, the excellent prognosis associated with CCA contrasts with the poten-
tially unfavourable outcome of SCC, depending on its stage at diagnosis. This dichotomy
emphasises the necessity for vigilant follow-up and management strategies tailored to the
patient’s specific diagnoses, ensuring that the benign nature of CCA does not overshadow
the need for the aggressive management of coexistent SCC. In conclusion, the simultaneous
occurrence of HPV-clear CCA and SCC in an elderly patient presents a unique clinical
scenario that challenges the diagnostic and therapeutic paradigms in dermatology. This
case underscores the significance of a thorough clinical and pathological assessment in
the management of complex skin lesions, advocating for a multidisciplinary approach to
ensure comprehensive care and favourable patient outcomes.
Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/jcm13092482/s1, Table S1. Literature research strategy. Table S2.
Analysed manuscripts—NR = not registered; pts = patients.
Author Contributions: Conceptualisation, R.C. and I.S. Methodology, R.C. and W.M.R. Validation,
C.A. and W.M.R. Formal analysis, P.P. and A.C. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Due to nature of this study’s design, no institutional ethical
approval was required.
Informed Consent Statement: Written informed consent for the publication and procedures was be
obtained from participating patients.
Data Availability Statement: The data that support the findings of the review are available in
PubMed, Scopus, EMBASE, and Cochrane Library. No other data are available about the participants
of this study.
Conflicts of Interest: The authors declare no conflicts of interest.
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