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Histopathology and Pathogenesis of Skin Cancer
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Histopathology and Pathogenesis of Skin Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: 20 June 2026 | Viewed by 9162

Special Issue Editors

Prof. Dr. Carlos Torres-Cabala

E-Mail Website
Guest Editor
The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: cutaneous tumors; lymphomas; melanoma; pathology
Special Issues, Collections and Topics in MDPI journals
Dr. Alessio Giubellino

E-Mail Website
Guest Editor
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
Interests: dermatopathology; melanoma; receptor tyrosine kinase; MET; HGF; histopathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cutaneous malignant neoplasms comprise a wide and varied group of tumors that often represent a challenge for both clinicians and researchers. The spectrum of tumors involving the skin encompasses indolent and very aggressive neoplasms arising from distinct lineages and with very different clinical presentations and therapeutic approaches.

This Special Issue will focus on the pathological features of tumors involving skin. Histopathological, immunohistochemical, and molecular aspects used in the diagnosis, prognosis, and prediction of these entities, along with research on the mechanisms of pathogenesis, will be covered. Original research and review topics on dermatopathology and basic, and translational research of cutaneous neoplasms (squamous, adnexal, melanocytic, hematolymphoid, mesenchymal, neural) will be included in a broad but also deep showcase of what is current and novel in cutaneous neoplasms.

We look forward to receiving your contributions.

Prof. Dr. Carlos Torres-Cabala
Dr. Alessio Giubellino
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • skin
  • tumor
  • cancer
  • histopathology
  • pathogenesis
  • molecular
  • immunohistochemistry
  • pathway
  • pathology

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Published Papers (6 papers)

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Research

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19 pages, 6210 KB  
Article
Nestin as a Vascular Marker of Angiogenesis in Non-Melanoma Skin Cancer
by Katarzyna Nowogrodzka, Maciej Tota, Aleksandra Piotrowska, Andrzej Bieniek, Piotr Dzięgiel and Alina Jankowska-Konsur
Cancers 2026, 18(9), 1495; https://doi.org/10.3390/cancers18091495 - 6 May 2026
Viewed by 595
Abstract
Background: Angiogenesis is critical for tumor progression. Microvessel density (MVD) is commonly assessed using CD31 and CD34, which detect both mature and newly formed vessels and therefore cannot distinguish active neoangiogenesis from stable, quiescent vasculature. Nestin, an intermediate filament protein expressed preferentially in [...] Read more.
Background: Angiogenesis is critical for tumor progression. Microvessel density (MVD) is commonly assessed using CD31 and CD34, which detect both mature and newly formed vessels and therefore cannot distinguish active neoangiogenesis from stable, quiescent vasculature. Nestin, an intermediate filament protein expressed preferentially in proliferating endothelial cells, has been proposed as a complementary marker of active angiogenesis and has been investigated in several solid tumor types, including pancreatic, colorectal, and breast carcinomas. However, no studies have quantitatively compared nestin-positive MVD across AK, BCC, and SCC using standardized methods. Methods: Immunohistochemistry for nestin, CD31, and CD34 was performed on 118 patient samples collected in 2015–2019 and diagnosed with AK, BCC, or SCC. MVD was quantified by averaging vessel counts in three representative “hot spot” areas. Results: Nestin-positive MVD was significantly lower in patients with AK compared to patients with BCC and SCC (p < 0.001). The mean MVD of nestin-positive vessels was significantly lower in AK than in BCC and SCC (p < 0.0001). In all three groups, nestin-positive MVD demonstrated a strong, positive correlation with both CD34 and CD31. Conclusions: Nestin-positive MVD was significantly elevated in BCC and SCC compared to AK lesions and demonstrated strong correlations with standard angiogenic markers. These findings suggest that nestin may warrant further investigation as a complementary marker of angiogenesis in non-melanoma skin cancer. Whether nestin-positive MVD offers independent diagnostic or prognostic value in this context remains to be determined in larger, prospective, multicentre studies. Full article
(This article belongs to the Special Issue Histopathology and Pathogenesis of Skin Cancer)
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15 pages, 804 KB  
Article
Selecting Representative Tumour Bed Slices May Allow Reduced Embedding Without Loss of Accuracy in Response Evaluation to Neoadjuvant Immunotherapy in Stage IIIB/C Cutaneous Melanoma
by Anders Bergström, Axel Nelson, Anne Huibers, Emel Cicek, Åse Silverdal, Martin E. Johansson, Katarzyna Lundmark, Jonas Selling, Anders Muszta and Iva Johansson
Cancers 2026, 18(9), 1400; https://doi.org/10.3390/cancers18091400 - 28 Apr 2026
Viewed by 465
Abstract
Background/Objectives: Histological assessment of the response to neoadjuvant immunotherapy in stage IIIB/C cutaneous melanoma is commonly performed using the INMC recommendations, which advocate embedding the entire tumour bed. However, this approach is highly resource-intensive. The original Swedish National Clinical Cancer Care Guidelines for [...] Read more.
Background/Objectives: Histological assessment of the response to neoadjuvant immunotherapy in stage IIIB/C cutaneous melanoma is commonly performed using the INMC recommendations, which advocate embedding the entire tumour bed. However, this approach is highly resource-intensive. The original Swedish National Clinical Cancer Care Guidelines for Melanoma recommend a reduced embedding strategy, but its diagnostic performance in comparison with full embedding has not been systematically evaluated. We aimed to assess whether a reduced sampling approach based on selecting representative tumour bed slices provides comparable response classification to comprehensive embedding according to the INMC protocol. Methods: Ten consecutive patients with stage IIIB/C melanoma treated with neoadjuvant immunotherapy and subsequent lymph node dissection were included. All lymph node material was completely embedded, and the pathological response was evaluated using INMC criteria. Response classification based on the full embedding of the tumour bed was compared with reduced-sampling approaches that simulate the Swedish National Clinical Cancer Care Guidelines for Melanoma. Agreement between sampling methods was analyzed. Results: Targeted reduced sampling of two slices per lymph node demonstrated complete agreement with the full embedding for the INMC response category. Conclusions: In our study, a targeted reduced-embedding strategy focusing on slices with the largest area of tumour bed enables accurate histological assessment of response to neoadjuvant immunotherapy in stage IIIB/C melanoma while substantially reducing workload. These findings support the feasibility of targeted reduced embedding of instructions in the Swedish National Clinical Cancer Care Guidelines for Melanoma as an efficient alternative to full embedding of the lymphadenectomy specimens. Full article
(This article belongs to the Special Issue Histopathology and Pathogenesis of Skin Cancer)
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13 pages, 2873 KB  
Article
Gene Expression Profile (GEP) Comparison of Atypical Fibroxanthoma (AFX) and Pleomorphic Dermal Sarcoma (PDS)
by Alessio Giubellino, Gerardo Cazzato, Mario Della Mura, Giuseppe Broggi, Alessandro Rizzo, Nehaaluddin Azmi, Carlos A. Torres-Cabala, Sarah Munro and Faqian Li
Cancers 2026, 18(6), 934; https://doi.org/10.3390/cancers18060934 - 13 Mar 2026
Viewed by 1175
Abstract
Background/Objectives: Atypical fibroxanthoma (AFX) and cutaneous undifferentiated pleomorphic sarcoma (cUPS)/pleomorphic dermal sarcoma (PDS) are related dermal neoplasms of uncertain histogenesis that occupy opposite ends of a shared clinical and histopathologic spectrum, with AFX displaying typically low-grade behavior and PDS representing its more [...] Read more.
Background/Objectives: Atypical fibroxanthoma (AFX) and cutaneous undifferentiated pleomorphic sarcoma (cUPS)/pleomorphic dermal sarcoma (PDS) are related dermal neoplasms of uncertain histogenesis that occupy opposite ends of a shared clinical and histopathologic spectrum, with AFX displaying typically low-grade behavior and PDS representing its more aggressive counterpart. The recent literature has confirmed that AFX and PDS also overlap at the molecular and genomic levels; however, little is known about their gene-expression profiles. Methods: We performed gene-expression profiling using RNA sequencing with a Pan-Cancer RNA Panel on a small series of AFX and PDS samples. Results: Unsupervised cluster analysis showed a clear separation between the two groups. We confirmed a TP53 UV-radiation signature in both. However, while AFX and PDS share common DNA mutation profiles in our cohort, RNA sequencing reveals distinct gene-expression signatures that may aid in differentiating these related tumors. In particular, the MAPK pathway, cell adhesion, DNA repair, EMT-like signatures and inflammatory responses play key roles in distinguishing the two groups, at least in our limited cohort, consistent with their differing biological behavior. Differences in the expression of receptor tyrosine kinases were also observed. Conclusions: Gene-expression profiling have the potential to be a valuable tool for distinguishing AFX from PDS, clarifying their positions at opposite ends of a spectrum and providing deeper insight into the biology of these neoplasms. Full article
(This article belongs to the Special Issue Histopathology and Pathogenesis of Skin Cancer)
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17 pages, 2901 KB  
Article
Diagnostic Algorithm for Secondary Extramammary Paget Disease from Institutional Cases and Literature Review
by Salin Kiratikanon, Ayaka Fukui, Masahiro Hirata, Jakob M. T. Moran, Masakazu Fujimoto and Mai P. Hoang
Cancers 2025, 17(24), 4014; https://doi.org/10.3390/cancers17244014 - 17 Dec 2025
Cited by 1 | Viewed by 1276
Abstract
Background/Objectives: Although clinicopathologic correlation with integration of clinical and radiographic data is the gold standard in distinguishing primary extramammary Paget disease (EMPD) from secondary EMPD, immunoprofiling of EMPD tumors enables distinction between primary and secondary EMPD. Methods: We evaluated the immunoprofiles [...] Read more.
Background/Objectives: Although clinicopathologic correlation with integration of clinical and radiographic data is the gold standard in distinguishing primary extramammary Paget disease (EMPD) from secondary EMPD, immunoprofiling of EMPD tumors enables distinction between primary and secondary EMPD. Methods: We evaluated the immunoprofiles of previously published cases in the literature as well as 12 secondary EMPD cases from our archives in order to construct a diagnostic algorithm that enables the distinction between primary and secondary EMPD. Results: Immunoprofiles of 480 primary (published cases) and 132 secondary (120 published cases and 12 institutional cases) EMPD cases were compared. CK7, CK20, CDX2, GATA3, GCDFP15, TRPS1, and SATB2 expression was significantly different in primary EMPD versus colonic secondary EMPD (p < 0.001 for all except SATB2, p = 0.036). CK20, GCDFP15, TRPS1, p63 and uroplakin II/III expression was significantly different in primary EMPD versus urothelial secondary EMPD (p < 0.001). CK7, CDX2, SATB2, GATA3 and p63 expression was significantly different in colonic versus urothelial secondary EMPD. CK20, CDX2, and GCDFP15 expression was significantly different in colonic versus prostatic secondary EMPD. CK20 expression was significantly different in colonic versus prostatic secondary EMPD (p = 0.018). CK20, GCDFP15 and TRPS1 are helpful in the distinction of primary EMPD versus colonic and urothelial secondary EMPD (p < 0.001). Conclusions: We propose that the initial IHC panel should include TRPS1, CK7 and CK20. In TRPS1-negative cases, additional immunostains should be performed: CDX2 and SATB2 for colonic; p63, GATA3 and uroplakin II/III for urothelial; and PSA and NKX3.1 for prostatic secondary EMPD. Full article
(This article belongs to the Special Issue Histopathology and Pathogenesis of Skin Cancer)
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Review

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17 pages, 5703 KB  
Review
IFN γ and the IFN γ Signaling Pathways in Merkel Cell Carcinoma
by Lina Song, Jinye Guan, Qunmei Zhou, Wenshang Liu, Jürgen C. Becker and Dan Deng
Cancers 2025, 17(15), 2547; https://doi.org/10.3390/cancers17152547 - 1 Aug 2025
Cited by 1 | Viewed by 1953
Abstract
Recent preclinical and clinical studies have confirmed the essential role of interferons in the host’s immune response against malignant cells. Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer strongly associated with Merkel cell polyomavirus (MCPyV). Despite progress in understanding MCC pathogenesis, [...] Read more.
Recent preclinical and clinical studies have confirmed the essential role of interferons in the host’s immune response against malignant cells. Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer strongly associated with Merkel cell polyomavirus (MCPyV). Despite progress in understanding MCC pathogenesis, the role of innate immune signaling, particularly interferon-γ (IFN γ) and its downstream pathways, remains underexplored. This review summarizes recent findings on IFN-γ in MCC, highlighting its dual role in promoting both antitumor immunity and immune evasion. IFN-γ enhances cytotoxic T cell responses, upregulates MHC class I/II expression, and induces tumor cell apoptosis. Transcriptomic studies have shown that IFN-γ treatment upregulates immune-regulatory genes including PD-L1, HLA-A/B/C, and IDO1 by over threefold; it also activates APOBEC3B and 3G, contributing to antiviral defense and tumor editing. Clinically, immune checkpoint inhibitors (ICIs) such as pembrolizumab and avelumab yield objective response rates of 30–56% and two-year overall survival rates exceeding 60% in advanced MCC. However, approximately 50% of patients do not respond, in part due to IFN-γ signaling deficiencies. This review further discusses IFN-γ’s crosstalk with the STAT1/3/5 pathways and emerging combination strategies aimed at restoring immune sensitivity. Understanding these mechanisms may inform personalized immunotherapeutic approaches and guide the development of IFN-γ–based interventions in MCC. Full article
(This article belongs to the Special Issue Histopathology and Pathogenesis of Skin Cancer)
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16 pages, 3665 KB  
Review
Squamous Cell Carcinoma and Its Rare Variant, Carcinoma Cuniculatum: Insights and Case Studies
by Klaudia Knecht-Gurwin, Aleksandra A. Stefaniak, Iwona Chlebicka, Lukasz Matusiak, Zdzisław Woźniak and Jacek C. Szepietowski
Cancers 2025, 17(7), 1217; https://doi.org/10.3390/cancers17071217 - 3 Apr 2025
Cited by 1 | Viewed by 2706
Abstract
Background: Squamous cell carcinoma (SCC) presents a significant challenge in dermatological pathology, necessitating comprehensive insights for effective management. This review highlights SCC’s broad aspects and focuses particularly on carcinoma cuniculatum (CC), a rare variant that warrants special attention due to its unique diagnostic [...] Read more.
Background: Squamous cell carcinoma (SCC) presents a significant challenge in dermatological pathology, necessitating comprehensive insights for effective management. This review highlights SCC’s broad aspects and focuses particularly on carcinoma cuniculatum (CC), a rare variant that warrants special attention due to its unique diagnostic and therapeutic challenges. Methods:
We conducted a narrative review of current literature on SCC and CC, supplemented by illustrative clinical case presentations. The analysis emphasized epidemiology, pathogenesis, clinical presentation, diagnostic pitfalls, and treatment modalities. Results:
The key findings from our analysis indicate that CC, although locally aggressive, exhibits a lower metastatic potential and requires distinct management strategies, primarily surgical, due to its poor responsiveness to radiotherapy. Conclusions:
The review also includes illustrative clinical cases to highlight the diverse presentations and underscore the necessity for multidisciplinary approaches and heightened clinical vigilance in diagnosing and managing CC. By consolidating current knowledge and clinical experiences, this review aims to enhance awareness, facilitate early recognition, and optimize therapeutic strategies for SCC, particularly CC, thereby improving patient outcomes and prognosis. Full article
(This article belongs to the Special Issue Histopathology and Pathogenesis of Skin Cancer)
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