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Balan K, Cicek K, Karaduman A, Gokoz O. Red nodule on the lateral trunk. JAAD Case Rep 2025; 57:25-27. [PMID: 39936158 PMCID: PMC11810644 DOI: 10.1016/j.jdcr.2024.11.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Affiliation(s)
- Kerem Balan
- Department of Dermatology and Venereology, Hacettepe University, School of Medicine, Ankara, Turkey
| | - Kübra Cicek
- Department of Dermatology and Venereology, Hacettepe University, School of Medicine, Ankara, Turkey
| | - Aysen Karaduman
- Department of Dermatology and Venereology, Hacettepe University, School of Medicine, Ankara, Turkey
| | - Ozay Gokoz
- Department of Pathology, Hacettepe University, School of Medicine, Ankara, Turkey
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2
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Vygovska M, Hoyt D, Snyder AM, Jonmundsson T, Khouri A, Sahni DR, Ungar J, Lewin JM, Gulati N, Phelps RG, Sahni VN, Grant-Kels JM, Sigurdsson H, Jonasson JG, Adalsteinsson JA. Incidence and outcomes of Merkel cell carcinoma related to Merkel cell polyomavirus status in Iceland in 1981-2023. JAAD Int 2024; 17:192-199. [PMID: 39525848 PMCID: PMC11549985 DOI: 10.1016/j.jdin.2024.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2024] [Indexed: 11/16/2024] Open
Abstract
Background Impact of Merkel cell polyomavirus (MCPyV) associated Merkel cell carcinoma (MCC) has not been assessed in the Icelandic population, nor in a whole population elsewhere. Objectives The primary objective was to assess trends in the incidence of MCC in Iceland and the association with MCPyV. Secondary objectives aimed to analyze MCC outcomes. Methods In this retrospective cohort study, patients diagnosed with MCC between 1981 and 2021 were identified from the Icelandic Cancer Registry. Patients were separated into 2 groups based on MCPyV immunochemistry staining. Age-standardized incidence was calculated and Joinpoint analysis was used to assess incidence trends. A Cox proportional hazards model was used to assess survival differences between the 2 groups. Results Overall incidence of MCC increased from 0.015 to 0.26 per 100,000 persons, though the incidence of MCPyV positive cases recently decreased while negative cases increased. MCPyV negative tumors were associated with sun exposure (P < .01), a history of keratinocyte carcinoma, smaller tumor size, and lower overall survival. Limitations Even with population-level data, comprehensively investigating associations with MCC is difficult due to its rarity. Conclusion MCPyV negative MCC tumors were associated with lower survival despite smaller tumor size. Thus, MCPyV status could be an important prognostic biomarker.
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Affiliation(s)
- Maria Vygovska
- Division of Pathology, Landspitali-University Hospital, Reykjavik, Iceland
| | - David Hoyt
- Division of Dermatology, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, Utah
| | - Ashley M. Snyder
- Department of Dermatology, University of Utah, Salt Lake City, Utah
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
- Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Thorarinn Jonmundsson
- Faculty of Medicine, Division of Oncology, University of Iceland, Reykjavik, Iceland
| | - Ashley Khouri
- Division of Dermatology, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, Utah
| | - Dev Ram Sahni
- Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Jonathan Ungar
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jesse M. Lewin
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Nicholas Gulati
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Robert G. Phelps
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York
- Department of Dermatopathology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Vikram N. Sahni
- Department of Dermatology, University of Utah, Salt Lake City, Utah
| | - Jane M. Grant-Kels
- Department of Dermatology, University of Connecticut School of Medicine, Farmington, Connecticut
- Department of Dermatology, University of Florida College of Medicine, Gainesville, Florida
| | - Helgi Sigurdsson
- Faculty of Medicine, Division of Oncology, University of Iceland, Reykjavik, Iceland
| | - Jon Gunnlaugur Jonasson
- Division of Pathology, Landspitali-University Hospital, Reykjavik, Iceland
- Faculty of Medicine, Division of Oncology, University of Iceland, Reykjavik, Iceland
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Li Z, Hu B, Kang L, Zeng S, Xiao Y, Yu N, Huang J, Long X. Different prognosis in cutaneous early-onset and late-onset Merkel cell carcinoma: a population-based retrospective study. Int J Dermatol 2024; 63:1575-1583. [PMID: 38863308 DOI: 10.1111/ijd.17297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 05/12/2024] [Accepted: 05/17/2024] [Indexed: 06/13/2024]
Abstract
BACKGROUND Merkel cell carcinoma (MCC) is a rare and highly aggressive form of skin cancer. However, there is limited research on the clinicopathological features of early-onset MCC (EOMCC) and the differences between EOMCC and late-onset MCC (LOMCC). Our objective was to evaluate the clinicopathological features and cancer-specific survival (CSS) of EOMCC. METHODS Our cohort study analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2018, to December 31, 2020. Data from 1941 patients who were diagnosed with primary cutaneous MCC were included. We then divided the patients with MCC into two groups: those with EOMCC (526 patients) and those with LOMCC (1415 patients). CSS is used as the primary outcome. RESULTS The EOMCC group exhibited trends toward advanced tumor progression, an expanded surgical scope, increased lymph node retrieval, intensified radiotherapy, greater utilization of systemic therapy, and a better prognosis. Multivariate analysis revealed that LOMCC (HR 3.305 [2.002-5.456], P < 0.001), advanced T stage (HR 1.430 [1.139-1.797], P = 0.002), advanced N stage (HR 1.522 [1.221-1.897], P < 0.001), M1 stage (HR 2.587 [1.480-4.521], P < 0.001), and radiation (HR 0.586 [0.410-0.837], P = 0.003) were significantly associated with CSS. Among these factors, EOMCC/LOMCC was most strongly associated with CSS, indicating that LOMCC is an independent risk factor for CSS. Interestingly, we found that regional EOMCC and localized or in situ LOMCC had almost completely overlapping survival curves (Plog-rank = 0.620). Additionally, we observed that the TNM staging + age model was a more accurate predictor of CSS among MCC patients than using TNM staging alone. CONCLUSIONS We found that EOMCC has distinct clinicopathological features compared to LOMCC. EOMCC is associated with better CSS. The combination of TNM staging and age was more accurate for predicting patient outcomes than TNM staging alone.
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Affiliation(s)
- Zhujun Li
- Department of Plastic and Reconstructive Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Bozhi Hu
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China
| | - Lin Kang
- Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Songlu Zeng
- Department of Plastic and Reconstructive Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yiding Xiao
- Department of Plastic and Reconstructive Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Nanze Yu
- Department of Plastic and Reconstructive Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jiuzuo Huang
- Department of Plastic and Reconstructive Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao Long
- Department of Plastic and Reconstructive Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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4
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Martins AC, Oshiro MY, Albericio F, de la Torre BG. Food and Drug Administration (FDA) Approvals of Biological Drugs in 2023. Biomedicines 2024; 12:1992. [PMID: 39335511 PMCID: PMC11428688 DOI: 10.3390/biomedicines12091992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/26/2024] [Accepted: 08/20/2024] [Indexed: 09/30/2024] Open
Abstract
An increase in total drug (small molecules and biologics) approvals by the Food and Drug Administration (FDA) was seen in 2023 compared with the previous year. Cancer remained the disease most targeted by monoclonal antibodies (mAbs), followed by autoimmune conditions. Our data reveal the prevalence of approvals for biologics even during years when the total number of authorizations was low, such as in 2022. Over half the drugs that received the green light in 2023 benefited from expedited programs, as the incidence of many diseases increased. In addition, over half of the biologics approved received Orphan Drug Designation from the FDA. This narrative review delves into details of the most significant approvals in 2023, including mAbs, enzymes, and proteins, explaining their mechanisms of action, differences from previous drugs, placebo, and standards of care, and outcomes in clinical trials. Given the varying number of drugs authorized annually by the U.S. health authority, this review also examines the limits of external influences over the FDA's decisions and independence regarding drug approvals and withdrawals.
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Affiliation(s)
- Alexander C Martins
- School of Health Sciences, UAM, Universidade Anhembi-Morumbi, São Paulo 03101-001, Brazil
- Medical Information Department, Thermo Fisher Scientific, São Paulo 4542011, Brazil
| | - Mariana Y Oshiro
- School of Health Sciences, UAM, Universidade Anhembi-Morumbi, São Paulo 03101-001, Brazil
| | - Fernando Albericio
- School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa
- CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain
| | - Beatriz G de la Torre
- KRISP, College of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
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Gupta P, Venuti A, Savoldy M, Harold A, Zito FA, Taverniti V, Romero-Medina MC, Galati L, Sirand C, Shahzad N, Shuda M, Gheit T, Accardi R, Tommasino M. Merkel Cell Polyomavirus targets SET/PP2A complex to promote cellular proliferation and migration. Virology 2024; 597:110143. [PMID: 38917692 PMCID: PMC11552451 DOI: 10.1016/j.virol.2024.110143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 05/28/2024] [Accepted: 06/14/2024] [Indexed: 06/27/2024]
Abstract
Merkel Cell Carcinoma (MCC) is a rare neuroendocrine skin cancer. In our previous work, we decoded genes specifically deregulated by MCPyV early genes as opposed to other polyomaviruses and established functional importance of NDRG1 in inhibiting cellular proliferation and migration in MCC. In the present work, we found the SET protein, (I2PP2A, intrinsic inhibitor of PP2A) upstream of NDRG1 which was modulated by MCPyV early genes, both in hTERT-HK-MCPyV and MCPyV-positive (+) MCC cell lines. Additionally, MCC dermal tumour nodule tissues showed strong SET expression. Inhibition of the SET-PP2A interaction in hTERT-HK-MCPyV using the small molecule inhibitor, FTY720, increased NDRG1 expression and inhibited cell cycle regulators, cyclinD1 and CDK2. SET inhibition by shRNA and FTY720 also decreased cell proliferation and colony formation in MCPyV(+) MCC cells. Overall, these results pave a path for use of drugs targeting SET protein for the treatment of MCC.
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Affiliation(s)
- Purnima Gupta
- International Agency for Research on Cancer, Lyon, France.
| | - Assunta Venuti
- International Agency for Research on Cancer, Lyon, France
| | - Michelle Savoldy
- Cancer Virology Program, University of Pittsburgh, Pittsburgh, PA, USA
| | - Alexis Harold
- Cancer Virology Program, University of Pittsburgh, Pittsburgh, PA, USA
| | - Francesco A Zito
- Bari Dipartimento dei Servizi, U.O.C. di Anatomia Patologica, Istituto Tumori IRCCS "Giovanni Paolo II", Italy
| | | | | | - Luisa Galati
- International Agency for Research on Cancer, Lyon, France
| | - Cecilia Sirand
- International Agency for Research on Cancer, Lyon, France
| | - Naveed Shahzad
- School of Biological Sciences, University of the Punjab, Lahore, Pakistan
| | - Masahiro Shuda
- Cancer Virology Program, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Tarik Gheit
- International Agency for Research on Cancer, Lyon, France.
| | - Rosita Accardi
- International Agency for Research on Cancer, Lyon, France
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Pozzi V, Molinelli E, Campagna R, Serritelli EN, Cecati M, De Simoni E, Sartini D, Goteri G, Martin NI, van Haren MJ, Salvolini E, Simonetti O, Offidani A, Emanuelli M. Knockdown of nicotinamide N-methyltransferase suppresses proliferation, migration, and chemoresistance of Merkel cell carcinoma cells in vitro. Hum Cell 2024; 37:729-738. [PMID: 38504052 PMCID: PMC11016511 DOI: 10.1007/s13577-024-01047-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 02/21/2024] [Indexed: 03/21/2024]
Abstract
Merkel cell carcinoma (MCC) is an aggressive skin cancer, with a propensity for early metastasis. Therefore, early diagnosis and the identification of novel targets become fundamental. The enzyme nicotinamide N-methyltransferase (NNMT) catalyzes the reaction of N-methylation of nicotinamide and other analogous compounds. Although NNMT overexpression was reported in many malignancies, the significance of its dysregulation in cancer cell phenotype was partly clarified. Several works demonstrated that NNMT promotes cancer cell proliferation, migration, and chemoresistance. In this study, we investigated the possible involvement of this enzyme in MCC. Preliminary immunohistochemical analyses were performed to evaluate NNMT expression in MCC tissue specimens. To explore the enzyme function in tumor cell metabolism, MCC cell lines have been transfected with plasmids encoding for short hairpin RNAs (shRNAs) targeting NNMT mRNA. Preliminary immunohistochemical analyses showed elevated NNMT expression in MCC tissue specimens. The effect of enzyme downregulation on cell proliferation, migration, and chemosensitivity was then evaluated through MTT, trypan blue, and wound healing assays. Data obtained clearly demonstrated that NNMT knockdown is associated with a decrease of cell proliferation, viability, and migration, as well as with enhanced sensitivity to treatment with chemotherapeutic drugs. Taken together, these results suggest that NNMT could represent an interesting MCC biomarker and a promising target for targeted anti-cancer therapy.
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Affiliation(s)
- Valentina Pozzi
- Department of Clinical Sciences, Polytechnic University of Marche, 60020, Ancona, Italy
| | - Elisa Molinelli
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, 60020, Ancona, Italy
| | - Roberto Campagna
- Department of Clinical Sciences, Polytechnic University of Marche, 60020, Ancona, Italy.
| | - Emma N Serritelli
- Department of Clinical Sciences, Polytechnic University of Marche, 60020, Ancona, Italy
| | - Monia Cecati
- Department of Clinical Sciences, Polytechnic University of Marche, 60020, Ancona, Italy
| | - Edoardo De Simoni
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, 60020, Ancona, Italy
| | - Davide Sartini
- Department of Clinical Sciences, Polytechnic University of Marche, 60020, Ancona, Italy.
| | - Gaia Goteri
- Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, 60020, Ancona, Italy
| | - Nathaniel I Martin
- Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE, Leiden, The Netherlands
| | - Matthijs J van Haren
- Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE, Leiden, The Netherlands
| | - Eleonora Salvolini
- Department of Clinical Sciences, Polytechnic University of Marche, 60020, Ancona, Italy
| | - Oriana Simonetti
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, 60020, Ancona, Italy
| | - Annamaria Offidani
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, 60020, Ancona, Italy
| | - Monica Emanuelli
- Department of Clinical Sciences, Polytechnic University of Marche, 60020, Ancona, Italy
- New York-Marche Structural Biology Center (NY-MaSBiC), Polytechnic University of Marche, 60131, Ancona, Italy
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7
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Zhang J, Xiang Y, Chen J, Liu L, Jin J, Zhu S. Conditional survival analysis and dynamic prediction of long-term survival in Merkel cell carcinoma patients. Front Med (Lausanne) 2024; 11:1354439. [PMID: 38390567 PMCID: PMC10881824 DOI: 10.3389/fmed.2024.1354439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 01/23/2024] [Indexed: 02/24/2024] Open
Abstract
Background Merkel cell carcinoma (MCC) is a rare type of invasive neuroendocrine skin malignancy with high mortality. However, with years of follow-up, what is the actual survival rate and how can we continually assess an individual's prognosis? The purpose of this study was to estimate conditional survival (CS) for MCC patients and establish a novel CS-based nomogram model. Methods This study collected MCC patients from the Surveillance, Epidemiology, and End Results (SEER) database and divided these patients into training and validation groups at the ratio of 7:3. CS refers to the probability of survival for a specific timeframe (y years), based on the patient's survival after the initial diagnosis (x years). Then, we attempted to describe the CS pattern of MCCs. The Least absolute shrinkage and selection operator (LASSO) regression was employed to screen predictive factors. The Multivariate Cox regression analysis was applied to demonstrate these predictors' effect on overall survival and establish a novel CS-based nomogram. Results A total of 3,843 MCC patients were extracted from the SEER database. Analysis of the CS revealed that the 7-year survival rate of MCC patients progressively increased with each subsequent year of survival. The rates progressed from an initial 41-50%, 61, 70, 78, 85%, and finally to 93%. And the improvement of survival rate was nonlinear. The LASSO regression identified five predictors including patient age, sex, AJCC stage, surgery and radiotherapy as predictors for CS-nomogram development. And this novel survival prediction model was successfully validated with good predictive performance. Conclusion CS of MCC patients was dynamic and increased with time since the initial diagnosis. Our newly established CS-based nomogram can provide a dynamic estimate of survival, which has implications for follow-up guidelines and survivorship planning, enabling clinicians to guide treatment for these patients better.
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Affiliation(s)
- Jin Zhang
- The First Affiliated Hospital of the Naval Medical University, Shanghai, China
- Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yang Xiang
- The First Affiliated Hospital of the Naval Medical University, Shanghai, China
| | - Jiqiu Chen
- The First Affiliated Hospital of the Naval Medical University, Shanghai, China
| | - Lei Liu
- The First Affiliated Hospital of the Naval Medical University, Shanghai, China
- Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jian Jin
- The First Affiliated Hospital of the Naval Medical University, Shanghai, China
| | - Shihui Zhu
- The First Affiliated Hospital of the Naval Medical University, Shanghai, China
- Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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8
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Al-Noshokaty TM, Elballal MS, Helal GK, Abulsoud AI, Elshaer SS, El-Husseiny AA, Fathi D, Abdelmaksoud NM, Abdel Mageed SS, Midan HM, Zaki MB, Abd-Elmawla MA, Rizk NI, Elrebehy MA, Zewail MB, Mohammed OA, Doghish AS. miRNAs driving diagnosis, prognosis and progression in Merkel cell carcinoma. Pathol Res Pract 2023; 249:154763. [PMID: 37595447 DOI: 10.1016/j.prp.2023.154763] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 08/09/2023] [Accepted: 08/12/2023] [Indexed: 08/20/2023]
Abstract
Merkel cell carcinoma (MCC) is a rare, aggressive form of skin malignancy with a high recurrence commonly within two to three years of initial diagnosis. The incidence of MCC has nearly doubled in the past few decades. Options for diagnosing, assessing, and treating MCC are limited. MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules that play an important role in controlling many different aspects of cell biology. Many miRNAs are aberrantly expressed in distinct types of cancer, with some serving as tumor suppressors and others as oncomiRs. Therefore, the future holds great promise for the utilization of miRNAs in enhancing diagnostic, prognostic, and therapeutic approaches for MCC. Accordingly, the goal of this article is to compile, summarize, and discuss the latest research on miRNAs in MCC, highlighting their potential clinical utility as diagnostic and prognostic biomarkers.
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Affiliation(s)
- Tohada M Al-Noshokaty
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Gouda Kamel Helal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11231, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Shereen Saeid Elshaer
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Department of Biochemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11823, Egypt
| | - Ahmed A El-Husseiny
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City 11829 Cairo, Egypt
| | - Doaa Fathi
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | | | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mohamed Bakr Zaki
- Biochemistry, Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt
| | - Mai A Abd-Elmawla
- Biochemistry, Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Nehal I Rizk
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Moataz B Zewail
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Osama A Mohammed
- Department of Clinical Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
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9
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Rizk NI, Midan HM, Helal GK, Abulsoud AI, Elshaer SS, El-Husseiny AA, Fathi D, Abdelmaksoud NM, Abdel Mageed SS, Elballal MS, Zaki MB, Abd-Elmawla MA, Al-Noshokaty TM, Elrebehy MA, El-Dakroury WA, Abulsoud LA, Doghish AS. The emerging role of miRNAs in Merkel cell carcinoma pathogenesis: Signaling pathway crosstalk. Pathol Res Pract 2023; 249:154771. [PMID: 37611429 DOI: 10.1016/j.prp.2023.154771] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/08/2023] [Accepted: 08/15/2023] [Indexed: 08/25/2023]
Abstract
Merkel cell carcinoma (MCC) is an uncommon invasive form of skin cancer that typically manifests as a nodule on the face, head, or neck that is flesh-colored or bluish-red in appearance. Rapid growth and metastasis are hallmarks of MCC. MCC has the second-greatest mortality rate among skin cancers after melanoma. Despite the recent cascade of molecular investigations, no universal molecular signature has been identified as responsible for MCC's pathogenesis. The microRNAs (miRNAs) play a critical role in the post-transcriptional regulation of gene expression. Variations in the expression of these short, non-coding RNAs have been associated with various malignancies, including MCC. Although the incidence of MCC is very low, a significant amount of study has focused on the interaction of miRNAs in MCC. As such, the current survey is a speedy intensive route revealing the potential involvement of miRNAs in the pathogenesis of MCC beyond their association with survival in MCC.
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Affiliation(s)
- Nehal I Rizk
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Gouda Kamel Helal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11231, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt.
| | - Shereen Saeid Elshaer
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Department of Biochemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11823, Egypt
| | - Ahmed A El-Husseiny
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, 11829 Cairo, Egypt
| | - Doaa Fathi
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | | | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mohamed Bakr Zaki
- Biochemistry, Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt
| | - Mai A Abd-Elmawla
- Biochemistry, Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Tohada M Al-Noshokaty
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Logyna A Abulsoud
- Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt.
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10
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Orfanoudaki M, Smith EA, Hill NT, Garman KA, Brownell I, Copp BR, Grkovic T, Henrich CJ. An Investigation of Structure-Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells. Mar Drugs 2023; 21:474. [PMID: 37755087 PMCID: PMC10532587 DOI: 10.3390/md21090474] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/23/2023] [Accepted: 08/25/2023] [Indexed: 09/28/2023] Open
Abstract
A library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) cell viability. The set included five new natural products and semi-synthetic compounds whose structures were elucidated with NMR, HRMS, and ECD techniques. Several discorhabdins averaged sub-micromolar potency against the MCC cell lines tested and most of the active compounds showed selectivity towards virus-positive MCC cell lines. An investigation of structure-activity relationships resulted in an expanded understanding of the crucial structural features of the discorhabdin scaffold. Mechanistic cell death assays suggested that discorhabdins, unlike many other MCC-active small molecules, do not induce apoptosis, as shown by the lack of caspase activation, annexin V staining, and response to caspase inhibition. Similarly, discorhabdin treatment failed to increase MCC intracellular calcium and ROS levels. In contrast, the rapid loss of cellular reducing potential and mitochondrial membrane potential suggested that discorhabdins induce mitochondrial dysfunction leading to non-apoptotic cell death.
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Affiliation(s)
- Maria Orfanoudaki
- Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; (M.O.); (E.A.S.)
| | - Emily A. Smith
- Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; (M.O.); (E.A.S.)
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Natasha T. Hill
- Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20891, USA; (N.T.H.); (K.A.G.); (I.B.)
| | - Khalid A. Garman
- Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20891, USA; (N.T.H.); (K.A.G.); (I.B.)
| | - Isaac Brownell
- Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20891, USA; (N.T.H.); (K.A.G.); (I.B.)
| | - Brent R. Copp
- School of Chemical Sciences, University of Auckland, Auckland 1142, New Zealand;
| | - Tanja Grkovic
- Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; (M.O.); (E.A.S.)
- Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, MD 21702, USA
| | - Curtis J. Henrich
- Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; (M.O.); (E.A.S.)
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
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11
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Omar A, Alassil H, Alloush D. Multiple Merkel cell carcinoma: a case report. Oxf Med Case Reports 2023; 2023:omad081. [PMID: 37637369 PMCID: PMC10451116 DOI: 10.1093/omcr/omad081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/13/2023] [Accepted: 07/06/2023] [Indexed: 08/29/2023] Open
Abstract
Merkel cell carcinoma (MCC) is an uncommon, fast-growing tumour, classified as a neuroendocrine neoplasm that affects the skin and spreads quickly to other parts of the body. It often affects aged, immunosuppressed people with a history of sun exposure and has a slight tendency to affect men. This report represents a case of multiple MCC nodules distributed on the chest and head of a 65-year-old Syrian male. The lesions occurred 1 year before presentation. The excisional biopsy confirmed the diagnosis of MCC. Further investigations indicated to assess metastasis, but the patient passed away before completing our recommendation. In this report, we aim to confirm the vital role of early detection when dealing with an aggressive tumour such as MCC, with a 50% chance of survival for 5 years. Otherwise, more lesions will worsen the prognosis, precisely like what occurred with our patient.
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Affiliation(s)
- Abdullah Omar
- Department of Dermatology and Venerology, Damascus Hospital, Damascus, Syria
- Faculty of Medicine Syrian Private University, Damascus, Syria
| | - Houda Alassil
- Department of Dermatology and Venerology, Damascus Hospital, Damascus, Syria
| | - Duha Alloush
- Department of Dermatology and Venerology, Damascus Hospital, Damascus, Syria
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12
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Ren MY, Shi YJ, Lu W, Fan SS, Tao XH, Ding Y. Facial Merkel cell carcinoma in a patient with diabetes and hepatitis B: A case report. World J Clin Cases 2023; 11:4179-4186. [PMID: 37388796 PMCID: PMC10303596 DOI: 10.12998/wjcc.v11.i17.4179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/06/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Patients with chronic inflammatory disorders are at a higher risk of developing aggressive Merkel cell carcinoma (MCC). Diabetes is a common chronic inflammatory disease that is possibly associated with MCC; however, there are still no reports on the association between hepatitis B virus (HBV) infection and MCC. Whether there is an association between these three diseases and the specific mechanisms behind their effects is worth further research in the future.
CASE SUMMARY We herein report a rare case of MCC with extracutaneous and nodal invasion in an Asian individual with type 2 diabetes mellitus and chronic HBV infection, but no immunosuppression or other malignancies. Such cases are uncommon and have rarely been reported in the literature. A 56-year-old Asian male presented with a significant mass on his right cheek and underwent extensive resection combined with parotidectomy, neck lymphadenectomy, and split-thickness skin grafting. Based on the histopathological findings, a diagnosis of MCC involving the adipose tissue, muscle, nerve, and parotid gland with lymphovascular invasion was made. Subsequently, he received radiotherapy with no adverse reactions.
CONCLUSION MCC is a rare, aggressive skin cancer with frequent local recurrence, nodal invasion, and metastasis, which usually arises in older people of the white race. Patients with chronic inflammatory disorders are at a higher risk of developing aggressive MCC. The diagnosis can be confirmed with histology and immunohistochemistry. For localized MCC, surgery is the preferred treatment option. However, for advanced MCC, radiotherapy and chemotherapy have proven to be effective. In cases where chemotherapy is not effective or in the advanced stages of MCC, immune therapy plays an important role in treatment. As with any rare disease, the management of MCC remains an enormous challenge for clinicians; thus, follow-up should be individualized and future progress needs multidisciplinary collaborative efforts. Furthermore, physicians should include MCC in their list of possible diagnoses when they come across painless, rapidly growing lesions, particularly in patients with chronic HBV infection or diabetes, as these patients are more susceptible to the development of this condition and it tends to be more aggressive in them.
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Affiliation(s)
- Ming-Yang Ren
- School of Medicine, Graduate School of Bengbu Medical College, Bengbu 233030, Anhui Province, China
| | - Yun-Juan Shi
- School of Medicine, Graduate School of Bengbu Medical College, Bengbu 233030, Anhui Province, China
| | - Wei Lu
- Center for Plastic and Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Hangzhou 310014, Zhejiang Province, China
| | - Sha-Sha Fan
- Center for Plastic and Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Hangzhou 310014, Zhejiang Province, China
| | - Xiao-Hua Tao
- Center for Plastic and Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Hangzhou 310014, Zhejiang Province, China
| | - Yang Ding
- Center for Plastic and Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Hangzhou 310014, Zhejiang Province, China
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13
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Dennis LK, Brown HE, Arrington AK. Comparison of Prognostic Factors for Merkel Cell Carcinoma, Mucosal Melanoma and Cutaneous Malignant Melanoma: Insights into Their Etiologies. Curr Oncol 2023; 30:3974-3988. [PMID: 37185414 PMCID: PMC10136436 DOI: 10.3390/curroncol30040301] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/26/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Little is known about the epidemiology of Merkel cell carcinoma (MCC) and mucosal melanoma (MM). Using the United States (US) National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program data, we compared MCC and MM with cutaneous malignant melanoma (CMM) with respect to incidence rates and prognostic factors to better understand disease etiologies. We describe the proportional incidences of the three cancers along with their survival rates based on 20 years of national data. The incidence rates in 2000–2019 were 203.7 per 1,000,000 people for CMM, 5.9 per 1,000,000 people for MCC and 0.1 per 1,000,000 people for MM. The rates of these cancers increased over time, with the rate of MM tripling between 2000–2009 and 2010–2019. The incidences of these cancers increased with age and rates were highest among non-Hispanic Whites. Fewer MCCs and MMS were diagnosed at the local stage compared with CMM. The cases in the 22 SEER registries in California were not proportional to the 2020 population census but instead were higher than expected for CMM and MCC and lower than expected for MM. Conversely, MM rates were higher than expected in Texas and New York. These analyses highlight similarities in the incidence rates of CMM and MCC—and differences between them and MM rates—by state. Understanding more about MCC and MM is important because of their higher potential for late diagnosis and metastasis, which lead to poor survival.
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Affiliation(s)
- Leslie K. Dennis
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA
| | - Heidi E. Brown
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA
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14
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Ouyang K, Zheng DX, Agak GW. T-Cell Mediated Immunity in Merkel Cell Carcinoma. Cancers (Basel) 2022; 14:cancers14246058. [PMID: 36551547 PMCID: PMC9775569 DOI: 10.3390/cancers14246058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/01/2022] [Accepted: 12/04/2022] [Indexed: 12/13/2022] Open
Abstract
Merkel cell carcinoma (MCC) is a rare and frequently lethal skin cancer with neuroendocrine characteristics. MCC can originate from either the presence of MCC polyomavirus (MCPyV) DNA or chronic ultraviolet (UV) exposure that can cause DNA mutations. MCC is predominant in sun-exposed regions of the body and can metastasize to regional lymph nodes, liver, lungs, bone, and brain. Older, light-skinned individuals with a history of significant sun exposure are at the highest risk. Previous studies have shown that tumors containing a high number of tumor-infiltrating T-cells have favorable survival, even in the absence of MCPyV DNA, suggesting that MCPyV infection enhances T-cell infiltration. However, other factors may also play a role in the host antitumor response. Herein, we review the impact of tumor infiltrating lymphocytes (TILs), mainly the CD4+, CD8+, and regulatory T-cell (Tregs) responses on the course of MCC, including their role in initiating MCPyV-specific immune responses. Furthermore, potential research avenues related to T-cell biology in MCC, as well as relevant immunotherapies are discussed.
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Affiliation(s)
- Kelsey Ouyang
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
| | - David X. Zheng
- Department of Dermatology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - George W. Agak
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
- Correspondence:
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15
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Dimitraki MG, Sourvinos G. Merkel Cell Polyomavirus (MCPyV) and Cancers: Emergency Bell or False Alarm? Cancers (Basel) 2022; 14:cancers14225548. [PMID: 36428641 PMCID: PMC9688650 DOI: 10.3390/cancers14225548] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 11/06/2022] [Accepted: 11/08/2022] [Indexed: 11/15/2022] Open
Abstract
Merkel cell polyomavirus (MCPyV), the sole member of Polyomavirus associated with oncogenesis in humans, is the major causative factor of Merkel cell carcinoma (MCC), a rare, neuroendocrine neoplasia of the skin. Many aspects of MCPyV biology and oncogenic mechanisms remain poorly understood. However, it has been established that oncogenic transformation is the outcome of the integration of the viral genome into the host DNA. The high prevalence of MCPyV in the population, along with the detection of the virus in various human tissue samples and the strong association of MCPyV with the emergence of MCC, have prompted researchers to further investigate the role of MCPyV in malignancies other than MCC. MCPyV DNA has been detected in several different non-MCC tumour tissues but with significantly lower prevalence, viral load and protein expression. Moreover, the two hallmarks of MCPyV MCC have rarely been investigated and the studies have produced generally inconsistent results. Therefore, the outcomes of the studies are inadequate and unable to clearly demonstrate a direct correlation between cellular transformation and MCPyV. This review aims to present a comprehensive recapitulation of the available literature regarding the association of MCPyV with oncogenesis (MCC and non-MCC tumours).
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16
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Roberto M, Botticelli A, Caggiati A, Chiriatti A, Della Rocca C, Ferraresi V, Musicco F, Pellacani G, Marchetti P. A Regional Survey on Merkel Cell Carcinoma: A Plea for Uniform Patient Journey Modeling and Diagnostic-Therapeutic Pathway. Curr Oncol 2022; 29:7229-7244. [PMID: 36290847 PMCID: PMC9600681 DOI: 10.3390/curroncol29100570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 09/16/2022] [Accepted: 09/27/2022] [Indexed: 11/20/2022] Open
Abstract
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine cancer that usually affects the elderly and immunosuppressed in sun-exposed areas. Due to its rarity, it is frequently unrecognized, and its management is not standardized across medical centers, despite the more recent availability of immunotherapy, with avelumab as first-line treatment improving the prognosis even in advanced stages of disease. We conducted a purpose-designed survey of a selected sample of physicians working in the Lazio region, in Italy, to assess their awareness and knowledge of MCC as well as their perspective on assisted diagnostic and therapeutic pathways. The Lazio region, and in particular Rome, is one of the most important academic and non- academic center in Italy dedicated to the diagnosis and treatment of skin cancer. A total of 368 doctors (including 100 general practitioners, 72 oncologists, 87 dermatologists, 59 surgeons, and 50 anatomopathologists) agreed to be part of this survey. Surgeons, oncologists, and dermatologists thought themselves significantly more updated on MCC than primary care physicians, but more than half of the interviewees are interested in CCM training courses and training with clearer and more standardized care pathways. Significant differences have been reported from survey participants in terms of multidisciplinary team set up for MCC management. The identification of specialized centers and the improvement of communication pathways among different specialties, as well as between patients and physicians, could be very beneficial in improving patients' journey modeling and starting a uniform diagnostic and therapeutic pathway for MCC patients in the new era of immunotherapies.
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Affiliation(s)
- Michela Roberto
- Medical Oncology Unit A, Umberto I University Hospital, Sapienza University, 00100 Rome, Italy
- Correspondence:
| | - Andrea Botticelli
- Department of Radiological, Oncological and Anatomopathological Science, Umberto I University Hospital, 00161 Rome, Italy
| | | | - Alberto Chiriatti
- Primary Care Physician Azienda Sanitaria Locale (ASL) Roma 3, 00125 Rome, Italy
| | - Carlo Della Rocca
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University, Pathology Service, Umberto I University Hospital, 00185 Rome, Italy
| | - Virginia Ferraresi
- Sarcomas and Rare Tumors Departmental Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Felice Musicco
- IRCCS IFO Regina Elena and San Gallicano Institute, 00144 Rome, Italy
| | - Giovanni Pellacani
- Dermatology Clinic, Department of Clinical, Internal, Anesthesiological and Cardiovascular Science, University of Rome, 00185 La Sapienza, Italy
| | - Paolo Marchetti
- Department of Radiological, Oncological and Anatomopathological Science, Umberto I University Hospital, 00161 Rome, Italy
- Istituto Dermopatico dell’Immacolata IRCCS, 00167 Rome, Italy
- Oncology Unit, Department of Clinical and Molecular Medicine, Sapienza University, Sant’Andrea Hospital, 00187 Rome, Italy
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17
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Papaccio F, D′Arino A, Caputo S, Bellei B. Focus on the Contribution of Oxidative Stress in Skin Aging. Antioxidants (Basel) 2022; 11:1121. [PMID: 35740018 PMCID: PMC9220264 DOI: 10.3390/antiox11061121] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/31/2022] [Accepted: 06/03/2022] [Indexed: 02/04/2023] Open
Abstract
Skin aging is one of the most evident signs of human aging. Modification of the skin during the life span is characterized by fine lines and wrinkling, loss of elasticity and volume, laxity, rough-textured appearance, and pallor. In contrast, photoaged skin is associated with uneven pigmentation (age spot) and is markedly wrinkled. At the cellular and molecular level, it consists of multiple interconnected processes based on biochemical reactions, genetic programs, and occurrence of external stimulation. The principal cellular perturbation in the skin driving senescence is the alteration of oxidative balance. In chronological aging, reactive oxygen species (ROS) are produced mainly through cellular oxidative metabolism during adenosine triphosphate (ATP) generation from glucose and mitochondrial dysfunction, whereas in extrinsic aging, loss of redox equilibrium is caused by environmental factors, such as ultraviolet radiation, pollution, cigarette smoking, and inadequate nutrition. During the aging process, oxidative stress is attributed to both augmented ROS production and reduced levels of enzymatic and non-enzymatic protectors. Apart from the evident appearance of structural change, throughout aging, the skin gradually loses its natural functional characteristics and regenerative potential. With aging, the skin immune system also undergoes functional senescence manifested as a reduced ability to counteract infections and augmented frequency of autoimmune and neoplastic diseases. This review proposes an update on the role of oxidative stress in the appearance of the clinical manifestation of skin aging, as well as of the molecular mechanisms that underline this natural phenomenon sometimes accelerated by external factors.
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Affiliation(s)
| | | | | | - Barbara Bellei
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (F.P.); (S.C.)
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18
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Spada F, Bossi P, Caracò C, Sileni VC, Dei Tos AP, Fazio N, Grignani G, Maio M, Quaglino P, Queirolo P, Ascierto PA. Nationwide multidisciplinary consensus on the clinical management of Merkel cell carcinoma: a Delphi panel. J Immunother Cancer 2022; 10:e004742. [PMID: 35701070 PMCID: PMC9198700 DOI: 10.1136/jitc-2022-004742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2022] [Indexed: 11/04/2022] Open
Abstract
Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine carcinoma. The MCC incidence rate has rapidly grown over the last years, with Italy showing the highest increase among European countries. This malignancy has been the focus of active scientific research over the last years, focusing mainly on pathogenesis, new therapeutic trials and diagnosis. A national expert board developed 28 consensus statements that delineated the evolution of disease management and highlighted the paradigm shift towards the use of immunological strategies, which were then presented to a national MCC specialists panel for review. Sixty-five panelists answered both rounds of the questionnaire. The statements were divided into five areas: a high level of agreement was reached in the area of guidelines and multidisciplinary management, even if in real life the multidisciplinary team was not always represented by all the specialists. In the diagnostic pathway area, imaging played a crucial role in diagnosis and initial staging, planning for surgery or radiation therapy, assessment of treatment response and surveillance of recurrence and metastases. Concerning diagnosis, the usefulness of Merkel cell polyomavirus is recognized, but the agreement and consensus regarding the need for cytokeratin evaluation appears greater. Regarding the areas of clinical management and follow-up, patients with MCC require customized treatment. There was a wide dispersion of results and the suggestion to increase awareness about the adjuvant radiation therapy. The panelists unanimously agreed that the information concerning avelumab provided by the JAVELIN Merkel 200 study is adequate and reliable and that the expanded access program data could have concrete clinical implications. An immunocompromised patient with advanced MCC can be treated with immunotherapy after multidisciplinary risk/benefit assessment, as evidenced by real-world analysis and highlighted in the guidelines. A very high consensus regarding the addition of radiotherapy to treat the ongoing focal progression of immunotherapy was observed. This paper emphasizes the importance of collaboration and communication among the interprofessional team members and encourages managing patients with MCC within dedicated multidisciplinary teams. New insights in the treatment of this challenging cancer needs the contribution of many and different experts.
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Affiliation(s)
- Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, Milano, Italy
| | - Paolo Bossi
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health-Medical Oncology, University of Brescia, ASST-Spedali Civili, Brescia, Italy
| | - Corrado Caracò
- Melanoma and Skin Cancers Surgery Unit, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Napoli, Italy
| | | | | | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, Milano, Italy
| | - Giovanni Grignani
- Division of Medical Oncology, Candiolo Cancer Institute FPO IRCCS, Candiolo, Italy
| | - Michele Maio
- Center for Immuno-Oncology, Department of Oncology, University Hospital of Siena, Siena, Italy
| | - Pietro Quaglino
- Dermatologic Clinic, Department of Medical Sciences, University of Turin, Torino, Italy
| | - Paola Queirolo
- Melanoma and Sarcoma Medical Treatment, European Institute of Oncology (IEO), Milano, Italy
| | - Paolo Antonio Ascierto
- Melanoma Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione "G.Pascale", Napoli, Italy
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19
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Rastrelli M, Del Fiore P, Russo I, Tartaglia J, Dal Monico A, Cappellesso R, Nicolè L, Piccin L, Fabozzi A, Biffoli B, Di Prata C, Ferrazzi B, Dall’Olmo L, Vecchiato A, Spina R, Russano F, Bezzon E, Cingarlini S, Mazzarotto R, Parisi A, Scarzello G, Pigozzo J, Brambullo T, Tropea S, Vindigni V, Bassetto F, Bertin D, Gregianin M, Dei Tos AP, Cavallin F, Alaibac M, Chiarion-Sileni V, Mocellin S. Merkel Cell Carcinoma: Evaluation of the Clinico-Pathological Characteristics, Treatment Strategies and Prognostic Factors in a Monocentric Retrospective Series (n=143). Front Oncol 2021; 11:737842. [PMID: 34976795 PMCID: PMC8718393 DOI: 10.3389/fonc.2021.737842] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 12/02/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin. The incidence of the disease has undergone a significant increase in recent years, which is caused by an increase in the average age of the population and in the use of immunosuppressive therapies. MCC is an aggressive pathology, which metastasizes early to the lymph nodes. These characteristics impose an accurate diagnostic analysis of the regional lymph node district with radiography, clinical examination and sentinel node biopsy. In recent years, there has been a breakthrough in the treatment of the advanced pathology thanks to the introduction of monoclonal antibodies acting on the PD-1/PD-L1 axis. This study aimed to describe the clinico-pathological characteristics, treatment strategies and prognostic factors of MCC. METHODS A retrospective cohort study was conducted involving 143 consecutive patients who were diagnosed and/or treated for MCC. These patients were referred to the Veneto Institute of Oncology IOV-IRCCS and to the University Hospital of Padua (a third-level center) in the period between December 1991 and January 2020. In the majority of cases, diagnosis took place at the IOV. However, some patients were diagnosed elsewhere and subsequently referred to the IOV for a review of the diagnosis or to begin specific therapeutic regimens. RESULTS 143 patients, with an average age of 71 years, were affected mainly with autoimmune and neoplastic comorbidities. Our analysis has shown that age, autoimmune comorbidities and the use of therapy with immunomodulating drugs (which include corticosteroids, statins and beta-blockers) are associated with a negative prognosis. In this sense, male sex is also a negative prognostic factor. CONCLUSIONS Autoimmune and neoplastic comorbidities were frequent in the studied population. The use of drugs with immunomodulatory effects was also found to be a common feature of the population under examination. The use of this type of medication is considered a negative prognostic factor. The relevance of a multidisciplinary approach to the patient with MCC is confirmed, with the aim of assessing the risks and benefits related to the use of immunomodulating therapy in the individual patient.
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Affiliation(s)
- Marco Rastrelli
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, Italy
| | - Paolo Del Fiore
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
| | - Irene Russo
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
- Division of Dermatology, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Jacopo Tartaglia
- Division of Dermatology, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Alessandro Dal Monico
- Division of Dermatology, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Rocco Cappellesso
- Pathological Anatomy Unit, University Hospital of Padua, Padua, Italy
| | - Lorenzo Nicolè
- Department of Medicine, University of Padua School of Medicine and Surgery, Padua, Italy
- Unit of Surgical Pathology & Cytopathology, Ospedale dell’Angelo, Mestre, Italy
| | - Luisa Piccin
- Melanoma Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
| | - Alessio Fabozzi
- Oncology Unit 3, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
| | - Bernardo Biffoli
- Clinic of Plastic Surgery, Department of Neuroscience, Padua University Hospital, University of Padua, Padua, Italy
| | - Claudia Di Prata
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
| | - Beatrice Ferrazzi
- Postgraduate School of Occupational Medicine, University of Verona, Verona, Italy
| | - Luigi Dall’Olmo
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, Italy
| | - Antonella Vecchiato
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
| | - Romina Spina
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
| | - Francesco Russano
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
| | - Elisabetta Bezzon
- Radiology Unit, Department of Imaging and Medical Physics, Istituto Oncologico Veneto (IOV) IRCSS, Padua, Italy
| | - Sara Cingarlini
- Oncology Section, Department of Oncology, Verona University and Hospital Trust, Verona, Italy
| | - Renzo Mazzarotto
- Department of Radiotherapy, Ospedale Civile Maggiore, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Alessandro Parisi
- Radiotherapy Unit, Veneto Institute of Oncology, Istituto Oncologico Veneto (IOV)-IRCCS, Padua, Italy
| | - Giovanni Scarzello
- Radiotherapy Unit, Veneto Institute of Oncology, Istituto Oncologico Veneto (IOV)-IRCCS, Padua, Italy
| | - Jacopo Pigozzo
- Melanoma Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
| | - Tito Brambullo
- Clinic of Plastic Surgery, Department of Neuroscience, Padua University Hospital, University of Padua, Padua, Italy
| | - Saveria Tropea
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
| | - Vincenzo Vindigni
- Clinic of Plastic Surgery, Department of Neuroscience, Padua University Hospital, University of Padua, Padua, Italy
| | - Franco Bassetto
- Clinic of Plastic Surgery, Department of Neuroscience, Padua University Hospital, University of Padua, Padua, Italy
| | - Daniele Bertin
- Radiotherapy and Nuclear Medicine Unit, Oncological Institute of Veneto IOV-IRCCS, Padua, Italy
| | - Michele Gregianin
- Radiotherapy and Nuclear Medicine Unit, Oncological Institute of Veneto IOV-IRCCS, Padua, Italy
| | - Angelo Paolo Dei Tos
- Pathological Anatomy Unit, University Hospital of Padua, Padua, Italy
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy
| | | | - Mauro Alaibac
- Division of Dermatology, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | | | - Simone Mocellin
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, Italy
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Merkel Cell Carcinoma: From Pathobiology to Clinical Management. BIOLOGY 2021; 10:biology10121293. [PMID: 34943208 PMCID: PMC8698953 DOI: 10.3390/biology10121293] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/24/2021] [Accepted: 12/01/2021] [Indexed: 12/12/2022]
Abstract
Simple Summary Merkel cell carcinoma (MCC) is an uncommon type of skin cancer that carries a poor prognosis. It is seen predominantly in old age in sun-exposed body parts. Racial and geographical differences are seen in its occurrence. Viral infection and radiation exposure are the two leading factors implicated in its causation. Small, firm to hard nodule (usually in sun-exposed areas), red with a history of a rapid increase in size is a common personation of the disease. Other body parts such as upper limbs, trunk, and even lower limbs may be also involved. The disease is diagnosed by taking a tissue sample (biopsy) for examination, and other radiological investigations are needed to reach a proper diagnosis with the staging of the disease. There are various treatment options including surgery, radiotherapy, and chemotherapy. Surgery is the primary treatment option though some patients may not be the candidates for operation where other treatment options come into play. Abstract Merkel cell carcinoma (MCC) is an infrequent, rapidly growing skin neoplasm that carries a greater probability of regional lymph node involvement, and a grim prognosis in advanced cases. While it is seen predominantly in old age in sun-exposed body parts, the prevalence varies among different races and geographical regions. Merkel cell polyomavirus and UV radiation-induced mutations contribute to its etiopathogenesis. The clinical presentation of MCC lacks pathognomonic features and is rarely considered highly at the time of presentation. Histopathological examination frequently reveals hyperchromatic nuclei with high mitotic activity, but immunohistochemistry is required to confirm the diagnosis. Sentinel lymph node biopsy (SLNB) and imaging are advised for effective staging of the disease. Multimodal management including surgery, radiation therapy, and/or immunotherapy are deployed. Traditional cytotoxic chemotherapies may result in an initial response, but do not result in a significant survival benefit. Checkpoint inhibitors have dramatically improved the prognosis of patients with metastatic MCC, and are recommended first-line in advanced cases. There is a need for well-tolerated agents with good safety profiles in patients who have failed immunotherapies.
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21
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Liu CY, Lai FJ, Chang ST, Chuang SS. Diagnostic clues for differentiating Merkel cell carcinoma from lymphoma in fine-needle aspiration cytology. Diagn Cytopathol 2021; 50:E23-E27. [PMID: 34491618 DOI: 10.1002/dc.24872] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/23/2021] [Accepted: 08/30/2021] [Indexed: 11/09/2022]
Abstract
Nodal fine needle aspiration (FNA) is usually the first procedure in the work-up of malignancy of unknown primary. Merkel cell carcinoma (MCC) is an aggressive cutaneous cancer more common in Caucasians but rare among Asians. It is a diagnostic challenge in evaluating FNA from a metastatic MCC without the knowledge of a current or prior history of skin cancer. We report the case of a Taiwanese male with cervical and axillary masses. The diagnosis of the FNA from the axillary lymph node was lymphoproliferative lesion suspicious for lymphoma. The histopathological evaluation of nodal biopsy revealed a metastatic neuroendocrine carcinoma and the subsequent excision of the right palm tumor confirmed MCC. Retrospective review of the FNA and imprint cytology smears of the nodal biopsy showed nuclear molding, Indian filing and rare cytoplasmic pale bodies, but no lymphoglandular bodies. Cytologically metastatic MCC may mimic small round cell tumor including lymphoma, we consider these three cytological features as additional diagnostic clues for metastatic MCC. In this report, we present the cytologic and pathological features of this metastatic MCC and discuss the differential diagnosis of the cytologic mimickers.
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Affiliation(s)
- Chih-Yi Liu
- Division of Pathology, Sijhih Cathay General Hospital, New Taipei City, Taiwan.,College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Feng-Jie Lai
- Department of Dermatology, Chi-Mei Medical Center, Tainan, Taiwan
| | - Sheng-Tsung Chang
- Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.,Department of Nursing, National Tainan Institute of Nursing, Tainan, Taiwan
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22
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Slater DN. Merkel cell carcinoma staging. Clin Exp Dermatol 2021; 47:418-419. [PMID: 34427001 DOI: 10.1111/ced.14911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 08/23/2021] [Indexed: 11/26/2022]
Affiliation(s)
- D N Slater
- Department of Histopathology, Royal Hallamshire Hospital, Sheffield, UK.,Department of Histopathology, Chesterfield Royal Hospital, Chesterfield, UK
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T-Cell Responses in Merkel Cell Carcinoma: Implications for Improved Immune Checkpoint Blockade and Other Therapeutic Options. Int J Mol Sci 2021; 22:ijms22168679. [PMID: 34445385 PMCID: PMC8395396 DOI: 10.3390/ijms22168679] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/02/2021] [Accepted: 08/05/2021] [Indexed: 02/06/2023] Open
Abstract
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with rising incidence and high mortality. Approximately 80% of the cases are caused by the human Merkel cell polyomavirus, while the remaining 20% are induced by UV light leading to mutations. The standard treatment of metastatic MCC is the use of anti-PD-1/-PD-L1-immune checkpoint inhibitors (ICI) such as Pembrolizumab or Avelumab, which in comparison with conventional chemotherapy show better overall response rates and longer duration of responses in patients. Nevertheless, 50% of the patients do not respond or develop ICI-induced, immune-related adverse events (irAEs), due to diverse mechanisms, such as down-regulation of MHC complexes or the induction of anti-inflammatory cytokines. Other immunotherapeutic options such as cytokines and pro-inflammatory agents or the use of therapeutic vaccination offer great ameliorations to ICI. Cytotoxic T-cells play a major role in the effectiveness of ICI, and tumour-infiltrating CD8+ T-cells and their phenotype contribute to the clinical outcome. This literature review presents a summary of current and future checkpoint inhibitor therapies in MCC and demonstrates alternative therapeutic options. Moreover, the importance of T-cell responses and their beneficial role in MCC treatment is discussed.
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24
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Díaz-Flores L, Gutiérrez R, García MP, González-Gómez M, Rodríguez-Rodriguez R, Hernández-León N, Díaz-Flores L, Carrasco JL. Cd34+ Stromal Cells/Telocytes in Normal and Pathological Skin. Int J Mol Sci 2021; 22:ijms22147342. [PMID: 34298962 PMCID: PMC8307573 DOI: 10.3390/ijms22147342] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 11/25/2022] Open
Abstract
We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other authors in the normal dermis regarding CD34+SC/TC characteristics and distribution around vessels, nerves and cutaneous annexes, highlighting their practical absence in the papillary dermis and presence in the bulge region of perifollicular groups of very small CD34+ stromal cells. In non-tumoral skin pathology, we studied examples of the principal histologic patterns in which CD34+SCs/TCs have (1) a fundamental pathophysiological role, including (a) fibrosing/sclerosing diseases, such as systemic sclerosis, with loss of CD34+SCs/TCs and presence of stromal cells co-expressing CD34 and αSMA, and (b) metabolic degenerative processes, including basophilic degeneration of collagen, with stromal cells/telocytes in close association with degenerative fibrils, and cutaneous myxoid cysts with spindle-shaped, stellate and bulky vacuolated CD34+ stromal cells, and (2) a secondary reactive role, encompassing dermatitis—e.g., interface (erythema multiforme), acantholytic (pemphigus, Hailey–Hailey disease), lichenoid (lichen planus), subepidermal vesicular (bullous pemphigoid), psoriasiform (psoriasis), granulomatous (granuloma annulare)—vasculitis (leukocytoclastic and lymphocytic vasculitis), folliculitis, perifolliculitis and inflammation of the sweat and sebaceous glands (perifolliculitis and rosacea) and infectious dermatitis (verruca vulgaris). In skin tumor and tumor-like conditions, we studied examples of those in which CD34+ stromal cells are (1) the neoplastic component (dermatofibrosarcoma protuberans, sclerotic fibroma and solitary fibrous tumor), (2) a neoplastic component with varying presentation (fibroepithelial polyp and superficial myxofibrosarcoma) and (3) a reactive component in other tumor/tumor-like cell lines, such as those deriving from vessel periendothelial cells (myopericytoma), epithelial cells (trichoepithelioma, nevus sebaceous of Jadassohn and seborrheic keratosis), Merkel cells (Merkel cell carcinoma), melanocytes (dermal melanocytic nevi) and Schwann cells (neurofibroma and granular cell tumor).
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Affiliation(s)
- Lucio Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (R.R.-R.); (N.H.-L.); (L.D.-F.J.); (J.L.C.)
- Correspondence: ; Tel.: +34-922-319-317; Fax: +34-922-319-279
| | - Ricardo Gutiérrez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (R.R.-R.); (N.H.-L.); (L.D.-F.J.); (J.L.C.)
| | - Maria Pino García
- Department of Pathology, Eurofins Megalab–Hospiten Hospitals, 38100 Tenerife, Spain;
| | - Miriam González-Gómez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (R.R.-R.); (N.H.-L.); (L.D.-F.J.); (J.L.C.)
| | - Rosa Rodríguez-Rodriguez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (R.R.-R.); (N.H.-L.); (L.D.-F.J.); (J.L.C.)
| | - Nieves Hernández-León
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (R.R.-R.); (N.H.-L.); (L.D.-F.J.); (J.L.C.)
| | - Lucio Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (R.R.-R.); (N.H.-L.); (L.D.-F.J.); (J.L.C.)
| | - José Luís Carrasco
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (R.R.-R.); (N.H.-L.); (L.D.-F.J.); (J.L.C.)
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Dellambra E, Carbone ML, Ricci F, Ricci F, Di Pietro FR, Moretta G, Verkoskaia S, Feudi E, Failla CM, Abeni D, Fania L. Merkel Cell Carcinoma. Biomedicines 2021; 9:718. [PMID: 34201709 PMCID: PMC8301416 DOI: 10.3390/biomedicines9070718] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/10/2021] [Accepted: 06/21/2021] [Indexed: 12/20/2022] Open
Abstract
Merkel cell carcinoma (MCC) is a rare and extremely aggressive neuroendocrine carcinoma of the skin, with increasing incidence worldwide. This review intends to propose a comprehensive evaluation of MCC epidemiology, clinical features, pathogenetic mechanisms, diagnosis, and therapies. A section is dedicated to immunological aspects and another to the involvement of angiogenesis and angiogenic growth factors in MCC progression, proposing novel diagnostic and therapeutic approaches. Advanced MCC tumors have been treated with immune checkpoint inhibitors with effective results. Therefore, the state of art of this immunotherapy is also examined, reporting on the most recent clinical trials in the field. We conclude by underlining the achievements in the understanding of MCC pathology and indicating the present needs for effective diagnosis and therapeutic management of the disease.
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Affiliation(s)
- Elena Dellambra
- Molecular and Cell Biology Laboratory, IDI-IRCCS, 00167 Rome, Italy;
| | - Maria Luigia Carbone
- Experimental Immunology Laboratory, IDI-IRCCS, 00167 Rome, Italy; (E.F.); (C.M.F.)
| | | | - Francesco Ricci
- Dermatology Department, IDI-IRCCS, 00167 Rome, Italy; (F.R.); (G.M.); (L.F.)
| | | | - Gaia Moretta
- Dermatology Department, IDI-IRCCS, 00167 Rome, Italy; (F.R.); (G.M.); (L.F.)
| | - Sofia Verkoskaia
- Oncology Department, IDI-IRCCS, 00167 Rome, Italy; (F.R.D.P.); (S.V.)
| | - Elisa Feudi
- Experimental Immunology Laboratory, IDI-IRCCS, 00167 Rome, Italy; (E.F.); (C.M.F.)
| | - Cristina M. Failla
- Experimental Immunology Laboratory, IDI-IRCCS, 00167 Rome, Italy; (E.F.); (C.M.F.)
| | - Damiano Abeni
- Clinical Epidemiology Unit, IDI-IRCCS, 00167 Rome, Italy;
| | - Luca Fania
- Dermatology Department, IDI-IRCCS, 00167 Rome, Italy; (F.R.); (G.M.); (L.F.)
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