Tumor Keratinocytes Research Articles

Clinicopathological study of skin tumors

Background: The diagnosis of skin tumors can cause difficulties due to their wide variety of overlapping differentiation and complicated nomenclature. Histopathological study is the most valuable means of diagnosis. Keeping in view these facts, an attempt is made to study the different varieties of tumors of the skin. Aims and Objectives: (1) The aim of this study was to study the histomorphology of different skin tumors with ancillary technique necessary and to correlate with the clinical features. (2) To find the proportion of various skin tumors. (3) To classify and identify various skin tumors and study its variation according to age, sex, site, etc., which will bear an impact on patient management and prognosis. Materials and Methods: This observational study included all cases of skin tumors received in the Department of Pathology, Kottayam Medical College, during a period of 1 year. Biopsy samples were collected, fixed in 10% formalin, processed and embedded in paraffin blocks, and stained with hematoxylin and eosin (H and E). The stained sections were studied under a microscope and histopathological diagnosis was correlated with clinical diagnosis. Results: Out of the 227 cases of skin tumors, 102 (44.9%) were male and 125 (55.1%) were female. The incidence of skin tumors peaks in individuals older than 60 years of age. The most common sites affected were face (40%). Keratinocytic tumors constituted the largest proportion of tumors (43%), followed by melanocytic tumors (31%), soft-tissue tumors (13%), appendage tumors (11%), neural (1%), and hematolymphoid tumors (1%). Conclusion: Out of the 227 cases in the present study, the clinical diagnosis of only 169 cases was correlating with the histopathological diagnosis. This emphasizes the role of microscopy in the correct diagnosis of skin tumors.

Photodynamic Therapy for the Treatment of Bowen's Disease: A Review on Efficacy, Non-Invasive Treatment Monitoring, Tolerability, and Cosmetic Outcome.

Bowen's disease represents the in situ form of cutaneous squamous cell carcinoma; although it has an excellent prognosis, 3-5% of lesions progress to invasive cutaneous squamous cell carcinoma, with a higher risk in immunocompromised patients. Treatment is therefore always necessary, and conventional photodynamic therapy is a first-line option. The aim of this review is to provide an overview of the clinical response, recurrence rates, safety, and cosmetic outcome of photodynamic therapy in the treatment of Bowen's disease, considering different protocols in terms of photosensitizers, light source, and combination treatments. Photodynamic therapy is a valuable option for tumors at sites where wound healing is poor/delayed, in the case of multiple and/or large tumors, and where surgery would be difficult or invasive. Dermoscopy and reflectance confocal microscopy can be used as valuable tools for monitoring the therapeutic response. The treatment is generally well tolerated, with mild side effects, and is associated with a good/excellent cosmetic outcome. Periodic follow-up after photodynamic therapy is essential because of the risk of recurrence and progression to cSCC. As the incidence of keratinocyte tumors increases, the therapeutic space for photodynamic therapy will further increase.

Cutaneous Malignancies: A Prospective Study of Demographic Patterns, Risk Factors, and Clinical Spectrum at a Tertiary Care Center in South India

Background and Objectives: The incidence of skin cancer is increasing worldwide and is causing a massive burden to the health-care system. It arises as a result of interplay between various predisposing factors. We intend to study the various clinical presentations of cutaneous malignancies and the demographic pattern and risk factors associated with them. Methodology: The study was done over a period of 7 years, 181 patients were diagnosed with cutaneous malignancy in the department of dermatology of our tertiary care hospital. A diagnosis was done based on history, clinical and histopathological examination. Results: Of 181 patients, majority of the patients belonged to 7th decade (n = 56, 31%) with the mean age being 55 years. The study group had 105 males (58%) and 76 (42%) females. The most common site was the head-and-neck region (n = 105, 58%). The most important associated condition/predisposing factor was ultraviolet (UV) radiation exposure (n = 79, 44%). Keratinocytic tumors formed the largest group (n = 131, 72%) in which basal cell carcinoma (BCC) was the most common (n = 75, 41%). Surgical excision was the main modality of treatment and was done in 111 (61%) patients. Conclusion: BCC was the most common skin cancer with head-and-neck region being the most common location in our study. Important risk factors were increasing age, male sex, and prolonged exposure to UV radiation. Early diagnosis helps in planning effective management strategies.

Abstract 5415: Fibroblast mediated head and neck tumor cell invasion in 3D culture is independent of partial epithelial to mesenchymal transition

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with a five-year-survival of 61-64%. Recent studies have demonstrated tumor keratinocytes with features of a partial transition from epithelial to a mesenchymal phenotype, also known as partial-EMT (pEMT), at the edge of invading tumor islands associates with metastatic disease. As such, pEMT likely results from direct interactions between tumor cells and their surrounding microenvironment. To test if specific secreted factors or cell interactions drive the acquisition of pEMT, we first analyzed a series of primary and established HNSCC cell populations to determine TGF-β1 responsiveness since TGF-β1 is a known driver of pEMT. Of the eight populations tested, six displayed an increased level of pSMAD3 upon incubation with 5 ng/mL of TGF-β1 (p < 0.0001). To determine if this TGF-β1 response leads to an increase in pEMT phenotype, a pEMT-score (derived from mRNA expression of 9 pEMT markers) for each HNSCC population was determined following TGF-β1 treatment. As expected, the two non-responsive HNSCC populations showed no increase in pEMT-score, whilst five of the six TGF-β1-responsive HNSCC populations demonstrated a significant increase in pEMT-score (p = 0.006). To assess if TGF-β induced pEMT phenotype correlates with increased invasive potential, we produced 3D skin equivalent models using the eight HNSCC keratinocyte populations, in the presence or absence of primary fibroblasts and/or TGF-β1 treatment. TGF-β1 treatment alone caused a significant increase in invasion of all five TGF-β1-induced pEMT HNSCC populations (r2 = 0.449, p = 0.0045), whilst the three populations previously shown to be pEMT unresponsive to TGF-β1 treatment showed no increase. Interestingly, addition of primary fibroblasts without TGF-β1 treatment caused a universal dramatic increase in invasion in 3D organ culture (p = 0.0064, 34-fold increase), regardless of the previously determined TGF-β1-induced pEMT status. Unexpectedly, TGF-β1 treatment in the presence of fibroblasts caused no significant increase in invasion in 3D cultures (r2 = 0.00001, p = 0.9906). We next compared levels of pEMT markers in 3D cultures using immunofluorescence and observed a significant increase in PDPN in six of the eight HNSCC populations (p = 0.0136) with the addition of fibroblasts suggesting that factors independent of TGF-β1 contributes to pEMT marker expression and invasion in 3D culture. Overall, these data demonstrate fibroblasts induce HNSCC keratinocyte invasion regardless of the population’s ability to respond to TGF-β1-induced pEMT and that pEMT may be driven by factors independent of TGF-β1 in 3D culture. Citation Format: Pyung Hun Park, Michael M. Alexander, Joseph M. Curry, Adam J. Luginbuhl, Andrew P. South. Fibroblast mediated head and neck tumor cell invasion in 3D culture is independent of partial epithelial to mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5415.

Histopathological spectrum of skin lesions in a tertiary health care centre – A retrospective study

Skin is the body’s largest and most complex organ, performing a wide range of functions. Environmental factors, genetics, cleanliness standards and social norms all influence the type of skin lesions that exist in different countries and regions. The skin lesions can vary from inflammatory to neoplastic. In clinically alike dermatoses, skin biopsy is used to provide significant information to the pathologist and dermatologist. The aim of the study is to identify and discuss the histopathology of different types of skin lesions, as well as their prevalence, age, sex distribution and location of lesions among hospital patients and compare the results with other relevant studies. The study was a retrospective observational study undertaken for the duration of three years in the Pathology Department of a tertiary health care center. Skin biopsy slides stained with hematoxylin and eosin were studied and classified after a detailed histopathological study under light microscope. 178 cases of skin lesions in total were evaluated having a 1.5:1 male to female ratio. Nonneoplastic lesions constituted 30.33% of skin lesions, while benign and malignant tumors constituted 55.05% and 14.6% of skin lesions respectively. In neoplastic lesions, keratinocytic tumors were the most common tumor type. The most common malignant tumor was squamous cell carcinoma, whereas epidermal inclusion cyst was the most prevalent benign tumor. The head and neck were the most prevalent sites for skin lesions. Most of the skin lesions can be accurately diagnosed by histopathological evaluation of biopsy of lesions in combination with clinical findings.

Dermoscopy of Cutaneous Neoplasms in Skin of Color - A Systematic review by the International Dermoscopy Society "Imaging in Skin of Color" Task Force.

Over the last few decades, dermoscopy has been showed to facilitate the non-invasive diagnosis of both benign and malignant skin tumors, yet literature data mainly comes from studies on light photo-types. However, there is growing evidence that skin neoplasms may benefit from dermoscopic assessment even for skin of color. This systematic literature review evaluated published data in dark-skinned patients (dermoscopic features, used setting, pathological correlation, and level of evidence of studies), also providing a standardized and homogeneous terminology for reported dermoscopic findings. A total of 20 articles describing 46 different tumors (four melanocytic neoplasms, eight keratinocytic tumors, 15 adnexal cutaneous neoplasms, seven vascular tumors, four connective tissue tumors, and eight cystic neoplasms/others) for a total of 1724 instances were included in the analysis. Most of them showed a level of evidence of V (12 single case reports and six case series), with only two studies featuring a level of evidence of IV (case-control analysis). Additionally, this review also underlined that some neoplasms and phototypes are underrepresented in published analyses as they included only small samples and mainly certain tones of "dark skin" spectrum (especially phototype IV). Therefore, further studies considering such limitations are required for a better characterization.

Surgical Excision Margins in Primary Care and Plastic Surgery for Keratinocytic Cancers Diagnosed via Teledermatology: Retrospective Observational Cross-Sectional Study

Background The incidence of keratinocytic cancers is increasing. In New Zealand, surgical treatment of skin cancers is often undertaken in primary care. In the Waikato district, general practitioners (GPs) are encouraged to confirm diagnoses via teledermatology. Histological examination should confirm clear surgical margins to reduce tumor recurrence. International guidelines recommend a lateral margin of ≥3 mm for basal cell carcinomas (BCCs) and ≥4 mm for squamous cell carcinomas (SCCs). Objective This study aimed to determine lateral and deep margins in keratinocytic cancer excisions performed by GPs (in a private setting) and plastic surgeons (in a private or public setting) after a teledermatologist had confirmed that excision was necessary. Demographic, clinical, and histological features were recorded. Methods A retrospective observational cross-sectional study was conducted. The sample in the electronic dermatology referral database included keratinocyte cancers recommended for excision from March to May 2022. Results Histological reports revealed that excision was complete in 186 of 201 confirmed cases of keratinocyte cancer. The lateral margins of resection were considered in 10 tumors and deep margins in 8 tumors. All incomplete excisions were carried out by GPs, 11 of which were on the head and neck. There were 133 BCCs, 100 of which were excised by a GP, 3 by a private plastic surgeon, and 30 by a public hospital surgeon. In total, 52 BCCs were present on the head and neck (25 excised by GPs, 25 by hospital plastic surgeons, and 2 by private plastic surgeons) and 81 were present on other sites (75 excised by GPs, 5 by hospital plastic surgeons, and 1 by a private plastic surgeon). Lateral margins were considered in 9 cases (of which 5 cases involved head and neck tumors). The minimum distance from the tumor to the lateral margin was <3 mm in 80 tumors: 64 were excised by a GP, 2 by private plastic surgeons, and 14 by hospital plastic surgeons. This distance was ≥3 mm in 44 tumors (27 excised by GPs, 1 by a private plastic surgeon, and 16 by hospital plastic surgeons). These data show significant adherence to surgical margin recommendations among plastic surgeons compared to that among GPs (odds ratio 2.873, CI 1.274-6.477; P=.009). There were 68 SCCs: 57 were excised by a GP, 2 by a private plastic surgeon, and 9 by a public hospital surgeon. In total, 21 SCCs were on the head and neck (14 excised by GPs, 6 by hospital plastic surgeons, and 1 by a private plastic surgeon) and 47 were on other sites (43 excised by GPs, 3 by hospital plastic surgeons, and 1 by a private plastic surgeon). Lateral margins were considered in 1 head and neck SCC case and were not reported in others. The minimum distance from the tumor to the lateral margin was <4 mm in 35 cases: 31 were excised by a GP, 1 by a private plastic surgeon, and 3 by a hospital plastic surgeon. This distance was ≥4 mm in 31 cases (24 excised by GPs, 1 by a private plastic surgeon, and 6 by hospital plastic surgeons). These data do not show significant difference in adherence to surgical margin recommendations between GPs and plastic surgeons (P>.05). Conclusions Complete resection reduces the risk of recurrence of keratinocytic tumors. GPs in our study were less likely than specialist surgeons to respect surgical margin recommendations established in international guidelines for managing keratinocytic cancer. Conflicts of Interest None declared.

Acantholytic Nodular Basal Cell Carcinoma.

Acantholysis is a microscopic finding describing the breakdown of desmosomes of keratinocytes and the formation of intraepithelial clefts after the loss of cohesion of keratinocytes. It can be observed in keratinocytic neoplasms, typically actinic keratoses and squamous cell carcinomas, and defines the acantholytic variants of these entities. Acantholysis has so far been reported in only 4 cases of basal cell carcinomas (BCCs), mainly of the superficial type. A case of an otherwise typical nodular BCC showing features of acantholysis is presented here. Because BCCs are keratinocytic neoplasms, the finding of acantholysis in them is not totally surprising; however, the reason why it is only very exceptionally observed in BCCs is unclear.

MiR-22 promotes immunosuppression via activating JAK/STAT3 signaling in cutaneous squamous cell carcinoma.

Immunotherapy is the only approved systemic therapy for advanced cutaneous squamous cell carcinoma (cSCC), however, roughly 50% of patients do not respond to the therapy and resistance often occurs over time to those who initially respond. Immunosuppression could have a critical role in developing treatment resistance, thus, understanding the mechanisms of how immunosuppression is developed and regulated may be the key to improving clinical diagnosis and treatment strategies for cSCC. Here, through using a series of immunocompetent genetically engineered mouse models, we demonstrate that miR-22 promotes cSCC development by establishing regulatory T cells (Tregs)-mediated immunosuppressive tumor microenvironment (TME) in a tumor cell autonomous manner. Mechanism investigation revealed that miR-22 elicits the constitutive activation of JAK/STAT3 signaling by directly targeting its suppressor SOCS3, which augments cancer cell-derived chemokine secretion and Tregs recruitment. Epithelial-specific and global knockouts of miR-22 repress papilloma and cSCC development and progression, manifested with reduced Tregs infiltration and elevated CD8+ T cell activation. Transcriptomic analysis and functional rescue study confirmed CCL17, CCL20 and CCL22 as the main affected chemokines that mediate the chemotaxis between miR-22 highly expressing keratinocyte tumor cells and Tregs. Conversely, overexpression of SOCS3 reversed miR-22-induced Tregs recruitment toward tumor cells. Clinically, gradually increasing Tregs infiltration during cSCC progression was negatively correlated with SOCS3 abundance, supported by previously documented elevated miR-22 levels. Thus, our study uncovers a novel miR-22-SOCS3-JAK/STAT3-chemokines regulatory mechanism in defining the immunosuppressive TME and highlights the promising clinical application value of miR-22 as a common targeting molecule against JAK/STAT3 signaling and immune escape in cSCC.

Distinguishing Keratoacanthoma from Well-Differentiated Cutaneous Squamous Cell Carcinoma Using Single-Cell Spatial Pathology

Keratoacanthoma (KA) is a common keratinocyte neoplasm that is regularly classified as a type of cutaneous squamous cell carcinoma (cSCC) despite demonstrating benign behavior. Differentiating KA from well-differentiated cSCC is difficult in many cases due to the substantial overlap of clinical and histological features. Currently, no reliable discriminating markers have been defined, and consequently, KAs are often treated similarly to cSCC, creating unnecessary surgical morbidity and healthcare costs. In this study, we used RNA sequencing to identify key differences in transcriptomes between KA and cSCC, which suggested divergent keratinocyte populations between each tumor. Imaging mass cytometry was then used to identify single-cell tissue characteristics, including cellular phenotype, frequency, topography, functional status, and interactions between KA and well-differentiated cSCC. We found that cSCC had significantly increased proportions of Ki67+ keratinocytes among tumor keratinocytes, which were dispersed significantly throughout non-basal keratinocyte communities. In cSCC, regulatory T-cells were more prevalent and held greater suppressive capacity. Furthermore, cSCC regulatory T-cells, tumor-associated macrophages, and fibroblasts had significant associations with Ki67+ keratinocytes as opposed to avoidances with KA, indicating a more immunosuppressive environment. Our data suggest that multicellular spatial features can serve as a foundation to enhance the histological discrimination of ambiguous KA and cSCC lesions.

DS07 (P22) Clinicopathologic characteristics of metastatic cutaneous squamous cell carcinoma: a cohort study

Abstract Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte tumour with excellent prognosis following early-stage surgical treatment. Nevertheless, cSCC possesses an inherent potential for locoregional and distant metastasis in ∼4% of cases, contributing to disease-specific mortality. Recent guidance on cSCC management risk stratifies patients based on clinicopathological factors to identify those patients most at risk of metastasis. A retrospective cohort study identified 3455 cSCCs arising in 2522 patients, via review of histopathological diagnoses of cSCC at a tertiary hospital in Dublin, Ireland, between the years of 2009 and 2019. The aim of the study was to describe adequately a large cohort of patients with metastatic cSCC and investigate factors associated with metastasis. Metastatic disease was identified by histopathological and/or radiological confirmation in 116 patients, with complete data available in 105 cases. Twenty-two (21%) were female. Mean age at primary tumour diagnosis was 74.8 years, and mean time to first metastasis was 0.8 years. Twenty-six (25%) patients were immunosuppressed, the commonest reason for which was haematological malignancy. Median (SD) size of the primary tumour was 36 (21.65) mm, and median depth was 10 (7.43) mm. Eighty-six (82%) tumours were located on the head and neck. Seventeen (16%) of the tumours were recurrent, 58 (55%) were > 20 mm, 38 (36%) demonstrated extension beyond subcutaneous fat, 22 (21%) demonstrated lymphovascular invasion, 24 (23%) demonstrated perineural invasion of nerves > 0.1 mm in diameter, and 41 (39%) tumours were poorly differentiated. Twenty-six patients developed distant metastatic disease in addition to nodal metastasis. In most patients in our cohort, AJCC 8th Edition histopathological high-risk cSCC features were absent, apart from size > 20 mm. Conversely, most patients exhibited at least one clinical high-risk cSCC feature as per the British Association of Dermatologists guidelines for the management of cutaneous squamous cell carcinoma, including advanced age and tumour location (Keohane SG, Botting J, Budny PG et al. British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma 2020. Br J Dermatol 2021; 184:401–14). All patients were discussed at a specialist skin multidisciplinary team meeting, with significant variability noted in preoperative imaging, depending on the primary treating specialty. This cohort illustrates the importance of risk stratification of cSCC on clinicopathological features. This facilitates management decisions and ongoing patient surveillance with a view to preventing disease-specific morbidity and mortality.

DS16 Clinicopathological features of metastatic squamous cell carcinoma treated with Mohs micrographic surgery: a case series

Abstract Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte tumour with inherent metastatic potential. Approximately 4% of cSCCs metastasize locoregionally and/or distally. Mohs micrographic surgery (MMS) is efficacious, with cure rates in selected cases of 95–99%. Diagnoses of cSCC treated at St James’s Hospital between the years 2010 and 2019 were identified via histopathology reports. Clinicopathological and treatment data in cases with metastatic disease were collected. Nodal metastasis was defined as biopsy-confirmed cSCC in locoregional lymph nodes and/or supporting radiological evidence. During the timeframe, 3455 cSCCs occurred in 2522 patients. Metastatic disease was identified in 116 patients, with complete data available in 105 cases. Six patients had undergone MMS to the primary tumour. Mean age at time of surgery was 75.6 years (range 65–85); five patients were male. Tumours were located on the cheek (n = 2), ear (n = 2), lower eyelid and nasal tip. Mean time to first metastasis was 6.67 months (range 2–16). Two patients were immunosuppressed at time of metastasis. All patients demonstrated high-risk cSCC features, with four patients demonstrating very-high-risk features as defined by the British Association of Dermatologists. One patient received adjuvant radiotherapy prior to detectable metastasis. All patients were discussed at either skin or head and neck multidisciplinary team (MDT) meetings. No patient received preoperative imaging. This series highlights the importance of risk stratification in cSCC management, irrespective of treatment modality. Consideration should be given to patient age and relative immune status, with dedicated locoregional imaging being guided by MDT discussion.

P22 Clinicopathologic characteristics of metastatic cutaneous squamous cell carcinoma: a cohort study

Abstract Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte tumour with excellent prognosis following early-stage surgical treatment. Nevertheless, cSCC possesses an inherent potential for locoregional and distant metastasis in approximately 4% of cases, contributing to disease-specific mortality. Recent guidance on cSCC management risk stratifies patients based on clinicopathological factors to identify those patients most at risk of metastasis. A retrospective cohort study identified 3455 cSCCs arising in 2522 patients, via review of histopathological diagnoses of cSCC at a tertiary hospital in Dublin, Ireland, between the years of 2009 and 2019. The aim of the study was to describe adequately a large cohort of patients with metastatic cSCC and investigate factors associated with metastasis. Metastatic disease was identified by histopathological and/or radiological confirmation in 116 patients, with complete data available in 105 cases. Twenty-two (21%) were female. Mean age at primary tumour diagnosis was 74.8 years and mean time to first metastasis was 0.8 years. Twenty-six (25%) patients were immunosuppressed, the commonest reason for which was haematological malignancy. Median (SD) size of the primary tumour was 36 (21.65) mm and median depth was 10 (7.43) mm. Eighty-six (82%) tumours were located on the head and neck. Seventeen (16%) of the tumours were recurrent, 58 (55%) were > 20 mm, 38 (36%) demonstrated extension beyond subcutaneous fat, 22 (21%) demonstrated lymphovascular invasion, 24 (23%) demonstrated perineural invasion of nerves > 0.1 mm in diameter and 41 (39%) tumours were poorly differentiated. Twenty-six patients developed distant metastatic disease in addition to nodal metastasis. In most patients in our cohort, AJCC 8th Edition histopathological high-risk cSCC features were absent, apart from size > 20 mm. Conversely, most patients exhibited at least one clinical high-risk cSCC feature as per the British Association of Dermatologists’ guidelines for the management of cutaneous squamous cell carcinoma, including advanced age and tumour location (Keohane SG, Botting J, Budny PG et al. British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma 2020. Br J Dermatol 2021; 184:401–14). All patients were discussed at a specialist skin multidisciplinary team meeting, with significant variability noted in preoperative imaging, depending on the primary treating specialty. This cohort illustrates the importance of risk stratification of cSCC on clinicopathological features. This facilitates management decisions and ongoing patient surveillance with a view to preventing disease-specific morbidity and mortality.

Histomorphological Study of Skin Lesions in a Specialized Tertiary Care Hospital: A Descriptive Study

Introduction: The skin is the largest organ of the integumentary system in human. Dermatological lesions are commonly encountered in all countries and it encompasses a wide spectrum, varies from country to country and various regions within a country. Skin diseases are much common in developing countries. The spectrum varies according to geographic distribution, gender, age, and coexisting disorder. We conducted this study to find out the prevalence of different skin lesions and to evaluate their frequency and site of distribution. Aim of the Study: The aim of this study was to find out the prevalence of different skin lesions and to evaluate their frequency and site of distribution. Methods: This was a descriptive study and was conducted in the Department of Histopathology of Bangladesh Specialized Hospital, Dhaka, Bangladesh during the period from January 2019 to December 2021.We included 133 skin biopsies in our study. Result: Among 133 skin biopsies examined, non-infectious vesicobullous and vesicopustular disease were found in 53 (48.18%) cases followed by microbial disease in 20 (18.18%) and non-infectious erythematous papular and squamous disease in 28 (21.05%) cases. Lichen simplex chronicus was the most common vesicobullous disease seen in 08 (15.09%) cases. Dermatophytes were the commonest microbial disease found in 10 (50%) cases. The commonest non- infectious erythematous papular and squamous disease was lichen planus and psoriasis 08 (15.09%) cases. The commonest neoplastic lesion was keratinocytic tumor seen in 13 (56.53%) cases. The commonest tumor of the skin was seborrheic keratosis and squamous cell carcinoma in 13 (56.53 %) cases. Upper extremities were the most frequently involved site by skin lesions. Conclusion: In our study prevalence of lichen simplex chronicus was higher. We observed a wide spectrum of skin lesions ranging from dermatitis to malignant neoplasm. The importance of specific histomorphological features lies in distinguishing various skin lesions and play a major role in making the final diagnosis of these diverse skin lesions. This highlights the role of histopathological examination for the proper management of patient.

Abstract LB111: Epigenetic mechanism underlying pathogenesis of skin photo-damage and actinic keratoses

Abstract Chronic skin exposure to solar ultraviolet B (UVB) radiation causes cutaneous inflammation, sun-burns and pre-malignant lesions known as Actinic Keratosis (AK). About 20% of AKs may progress to highly invasive malignant lesions known as Squamous Cell Carcinoma (SCC). These lesions carry multiple mutations in oncogenes and/or tumor suppressor genes. However, the molecular mechanism underlying AK is not incompletely defined. Here, we demonstrate that cutaneous UVB exposure leads to activation of bromodomain-4 (BRD4), an epigenetic modifier. We observed enhanced expression of BRD4 and its hyper-acetylation marks, H3K18ac and H3K27ac in AK, accompanied by elevated transcription of BRD4-target genes: MMP13, CXCL9, IL33, Apol19b, IL19 and Oasl2. Using confocal microscopy, we observed enhanced nuclear accumulation of BRD4 and H3K27ac in the sun-exposed lesional skin, AK and in SCC tissues from patients. Ptch+/−/SKH1 mice irradiated with to chronic UVB manifest similar molecular alterations in highly photo-damaged skin. By manipulating BRD4 expression in human skin SCC A431 cells, we identified two important BRD4-regulated signaling pathways, which may be involved in the molecular pathogenesis of AKs and SCCs. BRD4-mediated inflammatory cytokine signaling is regulated by EZH2-SOCS3-NFkB/STAT3 axis while Myc-Survivin-CDK4-E2F1 axis drives tumor cell hyper-proliferation. Co-localization of BRD4/H3K27ac and Survivin-E2F1 was contiguous from sun-burn skin to AK and SCC. We observed enhanced copy number of Myc in human AK lesional skin and associated SCCs. We also show that Myc-Survivin-CDK4-E2F1 axis is critical in driving the progression of tumor keratinocytes to highly invasive and fast growing SCCs. This signaling acts by enhancing the expression epithelial-mesenchymal transition transcription factors and other proteins involved in UVB-induced SCC development. 9cUAB30, a RXR agonist developed by us blocked BRD4 activation and its downstream signaling in A431 and SCC13 cells. Oral administration of 9cUAB30 abrogates UVB-induced inflammation and keratinocyte hyper-proliferation in murine skin in BRD4 dependent manner. 9cUAB30 treatment attenuates growth of human SCC xenograft tumors in highly immune-suppressed mice, a response which was significantly more profound when the drug was administered with a survivin inhibitor, LQZ-7I. These translational studies demonstrate that UVB-induced cutaneous BRD4 drives AK pathogenesis and their progression to invasive SCCs. Citation Format: Mahendra P. Kashyap, Rajesh Sinha, Rubina Shafi, Venkatram R. Atigadda, Craig A. Elmets, Mohammad Athar. Epigenetic mechanism underlying pathogenesis of skin photo-damage and actinic keratoses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB111.

Matrix Metalloproteinase-1 Expression in Fibroblasts Accelerates Dermal Aging and Promotes Papilloma Development in Mouse Skin

Fragmentation, disorganization, and depletion of the collagen-rich dermal extracellular matrix are hallmarks of aged human skin. These deleterious alterations are thought to critically mediate many of the prominent clinical attributes of aged skin, including thinning, fragility, impaired wound healing, and a propensity for carcinoma. Matrix metalloproteinase-1 (MMP1) initiates the cleavage of collagen fibrils and is significantly increased in dermal fibroblasts in aged human skin. To investigate the role of elevated MMP1 in skin aging, we generated a conditional bitransgenic mouse (type I collagen alpha chain 2; human MMP1 [Col1a2;hMMP1]) that expresses full-length, catalytically active hMMP1 in dermal fibroblasts. hMMP1 expression is activated by a tamoxifen-inducible Cre recombinase that is driven by the Col1a2 promoter and upstream enhancer. Tamoxifen induced hMMP1 expression and activity throughout the dermis Col1a2:hMMP1 mice. At 6 months of age, Col1a2;hMMP1 mice displayed loss and fragmentation of dermal collagen fibrils, which was accompanied by many of the features of aged human skin, such as contracted fibroblast morphology, reduced collagen production, increased expression of multiple endogenous MMPs, and proinflammatory mediators. Interestingly, Col1a2;hMMP1 mice displayed substantially increased susceptibility to skin papilloma development. These data demonstrate that fibroblast expression of hMMP1 is a critical mediator of dermal aging and creates a dermal microenvironment that promotes keratinocyte tumor development.

Giant basal cell carcinoma of the scalp: rotation advancement flap as a successful dermatosurgical approach.

Giant keratinocyte tumors, in particular basal cell carcinomas of the scalp area, are a serious challenge for dermatosurgeons, oncologists, and maxillofacial and reconstructive surgeons. The scalp area is limited in terms of skin mobility, and its elasticity decreases with age. The size of the tumors in this area and the degree of infiltration of the underlying tissues are important for the therapeutic choice, from surgical removal, waiting for granulations to form, and placing a split skin mesh graft (at a later stage) to performing complex rotational/transpositional or advancement flaps. Achieving an optimal aesthetic result is often the consequence of interventions carried out or based on the decisions of multidisciplinary teams. Alternatives, such as radiotherapy and targeted therapy with vismodegib, could be administered both preoperatively and postoperatively or as first-line therapy, depending on the tumor board decisions. We present the case of a 69-year-old female patient with a histopathologically proven preoperative giant basal cell carcinoma of the scalp that did not infiltrate the tabula externa. A preoperative ultrasound was performed to preserve the feeding flap arteries. Surgical treatment under general anesthesia was planned and subsequently carried out. During surgery, the surgical resection lines were in close proximity to the arterial vessels, but they remained preserved and ensured a subsequently unproblematic healing process. After the application of the rotational advancement flap technique under general anesthesia, an optimal cosmetic effect was achieved.

A pilot study using immunohistochemical staining to characterize dihydropyrimidine dehydrogenase expression in keratinocyte neoplasms

To the Editor: Topical 5-fluorouracil (5-FU) is a chemotherapeutic agent used to treat actinic keratoses (AK), superficial basal cell carcinoma, and squamous cell carcinoma in situ (SCCis). 5-FU is metabolized and inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD), which is highly active in the liver but can be expressed in tumors as well. In several visceral malignancies, tumor DPD expression predicts response to systemic 5-FU: tumors with lower DPD expression correlate with higher 5-FU reactivity and better clinical response.1Horiguchi J. Yoshida T. Koibuchi Y. et al.DPD activity and immunohistochemical DPD expression in human breast cancer.Oncol Rep. 2004; 11: 65-72PubMed Google Scholar, 2Oi K. Makino M. Ozaki M. et al.Immunohistochemical dihydropyrimidine dehydrogenase expression is a good prognostic indicator for patients with Dukes' C colorectal cancer.Anticancer Res. 2004; 24: 273-279PubMed Google Scholar, 3Fukuda H. Takiguchi N. Koda K. Oda K. Seike K. Miyazaki M. Thymidylate synthase and dihydropyrimidine dehydrogenase are related to histological effects of 5-fluorouracil and cisplatin neoadjuvant chemotherapy for primary gastric cancer patients.Cancer Invest. 2006; 24: 235-241https://doi.org/10.1080/07357900600632082Crossref PubMed Scopus (18) Google Scholar Although this association has been studied in visceral tumors, the expression of DPD in keratinocyte neoplasms is not known. In this pilot study, we assessed DPD expression in benign, premalignant, and malignant keratinocyte neoplasms to assess the range and level of DPD activity. We performed DPD immunohistochemistry (IHC) staining of 26 superficial and nodular basal cell carcinomas (BCCs), 10 SCCis, 16 AKs, and 8 seborrheic keratoses from formalin-fixed paraffin-embedded specimens collected within the past 3 years. Diagnoses were confirmed by dermatopathologists (B.H., B.D.). DPD IHC was performed with anti-DPD antibody (Abcam #134922, 1:500 dilution). DPD expression was scored by intensity ranging from 0 to 3 by 2 authors (O.I. and B.D.), with hepatic staining as a positive control (Table I). Fisher’s exact test was used to compare DPD scores between classes of keratinocyte neoplasms (R software, version 4.0.3, https://www.r-project.org).Table IDihydropyrimidine dehydrogenase immunohistochemistry intensity score in patient samples (n = 60)DPD IHC intensity score0123Seborrheic keratosis0422Actinic keratosis1960SCC in situ0442Basal cell carcinoma21410Basal cell carcinoma includes both superficial and nodular subtypes. DPD IHC intensity was scored from 0 to 3 (0: no expression, 1: weak expression, 2: moderate expression, 3: strong expression). Fisher’s exact test P value = 3.95 × 10−9.DPD, Dihydropyrimidine dehydrogenase; IHC, immunohistochemistry; SCC, squamous cell carcinoma. Open table in a new tab Basal cell carcinoma includes both superficial and nodular subtypes. DPD IHC intensity was scored from 0 to 3 (0: no expression, 1: weak expression, 2: moderate expression, 3: strong expression). Fisher’s exact test P value = 3.95 × 10−9. DPD, Dihydropyrimidine dehydrogenase; IHC, immunohistochemistry; SCC, squamous cell carcinoma. The results showed a significantly enriched proportion of BCCs (81%, 21/26) displaying no DPD expression (DPD IHC intensity score of 0), compared to 0% (0/10) of SCCis and 6% (1/16) of AKs (P = 3.95 × 10−9, Table I). By contrast, 15% of BCC, 40% of SCCis, and 56% of AK had an intensity score of 1; 3% of BCC, 40% of SCCis, and 37.5% of AK had an intensity score of 2; and 0% of BCC, 20% of SCCis, and 0% of AK had an intensity score of 3 (Table I). The DPD intensity scores of seborrheic keratoses, a noncancerous keratinocyte neoplasm control, were distributed between 1 and 3. Our results suggest that DPD expression varies both within and across different keratinocyte neoplasms, and that a substantial fraction of BCC may have lower DPD expression compared to AK, squamous cell carcinoma (SCC), and seborrheic keratoses. Clinical studies have reported a wide range of efficacy in the use of topical 5-FU treatment for early-stage BCC and SCC, with success rates in SCC ranging from 27% to 93%.4Love W.E. Bernhard J.D. Bordeaux J. Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma.Arch Dermatol. 2009; 145: 1431-1438Crossref PubMed Scopus (191) Google Scholar,5Neale H. Michelon M. Jacob S. et al.Topical 5% 5-fluorouracil versus procedural modalities for squamous cell carcinoma in situ and superficial basal cell carcinoma: a retrospective cohort analysis.J Am Acad Dermatol. 2022; 87: 423-425https://doi.org/10.1016/j.jaad.2021.08.045Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar While differences in treatment regimens and study design are likely to contribute to this variability, our results raise the possibility that differences in keratinocyte tumor DPD expression could also play a role in topical 5-FU treatment efficacy. The results of this pilot study support the value of a larger prospective study to investigate if DPD expression predicts clinical response of low-grade BCC and SCC to topical 5-FU. If true, then DPD IHC staining could be performed by pathology services to identify keratinocyte neoplasms that are more likely to respond favorably to topical 5-FU, reducing the uncertainty of treatment efficacy to this useful therapeutic option. None disclosed.

A Histopathological Study on Primary Cutaneous Malignancies of Surface Epidermis

Introduction: Skin is a complex organ, it’s intricacy allows for a wide range of malignancies. Skin types, geographical latitudes, occupational exposure, sun exposure, and skin protection behaviors may all contribute to skin cancer trends and rates. Some cancers are easily recognised clinically, whereas others require a combination of clinical and histopathological correlation. Aim: To determine the spectrum and frequency of various primary cutaneous malignancies of the surface epidermis based on histomorphological characteristics, Guntur, Andhra Pradesh, India. Materials and Methods: The present retrospective study was conducted in the Department of Pathology at Katuri Medical College and Hospital, Guntur, Andhra Pradesh, India. The study covered a total of 30 cases of primary cutaneous malignancies of surface epidermis with histopathological confirmation. The study samples included from January 2019 to June 2021 over a 30-month period and the data was collected and analysed in the month of August 2021 and September 2021 from the histopathology records. Typing of these tumours was done by using Haematoxylin and Eosin (H&E) stained sections. All the cases were analysed and divided according to the patient’s age, gender, and tumour location, as well as the tumour’s histological characteristics. Descriptive statistics were used and data was tabulated in frequency and percentages. Results: A total of 30 cases of primary cutaneous malignancies of surface epidermis, were studied, of which 21 (70%) cases were keratinocyte derived cancers and 6 (20%) cases were melanocyte derived cancers. The most frequent keratinocyte tumour was squamous cell carcinoma followed by Basal cell carcinomas. Present study documented three cases of melanocarcinomas, of which two were basomelanocytic tumors and one case was squamomelanocytic tumors. There was slight male preponderance with male to female was 3:2. Most cases distributed in the age group of 61-80 years, followed by 41-60 years. The most frequently involved anatomical site was the head and neck region followed by the trunk region. Conclusion: Skin cancers, at times, may be difficult to diagnose clinically. Hence, histopathological examination is a must for definitive diagnosis. This study highlighted the critical role of histopathology in accurately classifying tumours into distinct morphological types which enables the clinician to make the correct diagnosis and formulate appropriate treatment plan.

Lobulated red nodule on right lower back.

A 60-year-old man with a history of basal cell carcinoma (BCC) on his forehead excised 10 years ago presented to the dermatology clinic with an enlarging red bump on his back for the past few months. He had no other personal or family history of malignancy and no known radiation exposure (Fig. 1). Physical examination revealed a 2 cm lobulated red nodule with multiple serpiginous vessels coursing through it located on the right lower back. There was no regional lymphadenopathy clinically. Histopathology showed lobules of basaloid tumor cells displaying vesicular, overlapping nuclei, and prominent nucleoli. Admixed aggregates of mature sebocytes, scattered foci of necrosis, and easily identifiable mitotic figures were seen (Fig. 2). Sebaceous carcinoma. This is sebaceous carcinoma, with an estimated incidence of 1–2 cases per 1,000,000 person-years.1, 2 Most cases of sebaceous carcinoma are ocular, and extraocular sites are usually in the head and neck area as a yellowish or red nodule with ulceration.1, 3 Histopathology shows sheets of basaloid and sebaceous cells sheets or asymmetric sebaceous lobules and other signs of malignancy like necrosis, pleomorphism, hyperchromatism, and numerous mitotic figures.1 Mohs surgery is considered first-line for removal of nodules suspicious for sebaceous carcinoma, as is wide-local excision with frozen sections.1 Further studies should include margin assessment of both peripheral and deep tissue edges, with regional lymph node biopsy if there is clinical suspicion of lymphatic involvement.1 As this patient had no clinical lymphadenopathy, no lymph node biopsy was indicated. However, the further pathological analysis showed negative nuclear staining for MSH2 and MSH6, concerning for Muir–Torre syndrome. Muir–Torre syndrome is an autosomal dominant phenotypic variant of Lynch syndrome, and typical findings include a constellation of sebaceous cutaneous neoplasms and visceral malignancies, most commonly colon cancer.4 Immunohistochemistry can be conducted on sebaceous neoplasms to identify mismatch repair gene mutations, and a thorough review of family and personal history of neoplasms as well as personal history of radiation exposure and immunosuppression is indicated. With this patient's multiple sebaceous nodules and DNA mismatch mutation on histology, extensive malignancy workup was started. To date, computed tomography (CT) revealed a multicystic pancreatic tail lesion and multiple metastatic lesions to the liver, with plans to conduct further colonoscopy and upper gastrointestinal (GI) imaging. This case is an excellent example of how dermatologic evaluation can help identify unsuspected internal disease. Sebaceous hyperplasia is incorrect. This is common in older adults and can often be confused with nodular BCC.3 Clinically, these appear as smooth yellow soft umbilicated papules and may elicit sebum with lateral compression, and histopathology would show enlarged sebaceous glands with normal morphology. Typical MCC includes a cutaneous or subcutaneous pink to violet dome-shaped rapidly growing papule or nodule with intact overlying skin in an immunosuppressed patient.3 Histopathology reveals aggregated, deeply blue staining small basaloid or lymphoma-like cells in sheets with CK20 positivity. SCC is incorrect, as these lesions are often plaques or nodules and can be differentiated (hard, keratinized) or undifferentiated (soft, no keratinization).3 These are tumors of pleomorphic keratinocytes that extend into the dermis, and histopathology yields keratinocyte anaplasia, multiple mitoses, and varying degrees of keratinization. FeP is considered a rare variant of BCC characterized by a skin-colored, firm, sessile, fleshy papule, or plaque which often develops in patients with a history of BCC.5 Histopathology is definitive with thin anastomosing basaloid or squamous strands of keratinocytes in a fibrous stroma projecting down from the epidermis, resembling a honeycomb.