Loss of p16 Immunoexpression and Deletions of CDKN2A in the Progression of Extramammary Paget Disease: An Immunohistochemical and Genetic Study of 24 Invasive/Metastatic Cases.
Journal
The American Journal of dermatopathology
ISSN: 1533-0311
Titre abrégé: Am J Dermatopathol
Pays: United States
ID NLM: 7911005
Informations de publication
Date de publication:
23 Apr 2024
23 Apr 2024
Historique:
medline:
22
4
2024
pubmed:
22
4
2024
entrez:
22
4
2024
Statut:
aheadofprint
Résumé
Information regarding the genetic alterations in extramammary Paget disease (EMPD) is scarce. This study investigated the significance of CDKN2A and MTAP alterations in EMPD progression using immunohistochemistry and panel DNA sequencing. In total, 24 invasive/metastatic EMPD cases were included in this study. The immunoexpression of p16 and MTAP in the primary in situ, primary invasive, and metastatic tumor components was evaluated. Panel DNA sequencing was performed for metastatic tumor components in 5 of the 24 cases. Immunoexpression of p16 in the in situ tumor component was at least partially preserved in all 19 tested cases (100%). By contrast, the invasive tumor component was diffusely or partially lost in 18 (81.8%) of 22 tested cases. Regarding the foci of lymph node metastasis, 13 (81.2%) of the 16 patients showed a significant loss of p16 expression. Loss of MTAP immunoexpression was observed less frequently compared with the loss of p16 expression. CDKN2A homozygous deletions were confirmed in all 5 tested cases by sequencing, whereas MTAP deletions were detected in only 2 cases. In conclusion, p16 expression loss and CDKN2A deletions can be frequently seen in invasive/metastatic cases of EMPD.
Identifiants
pubmed: 38648029
doi: 10.1097/DAD.0000000000002726
pii: 00000372-990000000-00340
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Kaken Pharmaceutical
ID : JP22K06994
Informations de copyright
Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
Références
Prieto VG, McCluggage WG, Michal M, et al. Extramammary Paget disease. In: WHO Classification Of Tumours Editorial Board, ed. WHO Classification of Skin Tumours. 5th ed (β version). Lyon: International Agency for Research on Cancer Press 2023. https://tumourclassification.iarc.who.int/home
Mazoujian G, Pinkus GS, Haagensen DE Jr. Extramammary Paget's disease--evidence for an apocrine origin. An immunoperoxidase study of gross cystic disease fluid protein-15, carcinoembryonic antigen, and keratin proteins. Am J Surg Pathol. 1984;8:43–50.
Willman JH, Golitz LE, Fitzpatrick JE. Vulvar clear cells of Toker: precursors of extramammary Paget's disease. Am J Dermatopathol. 2005;27:185–188.
Konstantinova AM, Spagnolo DV, Stewart CJR, et al. Spectrum of changes in anogenital mammary-like glands in primary extramammary (anogenital) Paget disease and their possible role in the pathogenesis of the disease. Am J Surg Pathol. 2017;41:1053–1058.
Hatta N, Yamada M, Hirano T, et al. Extramammary Paget's disease: treatment, prognostic factors and outcome in 76 patients. Br J Dermatol. 2008;158:313–318.
Shu B, Shen XX, Chen P, et al. Primary invasive extramammary Paget disease on penoscrotum: a clinicopathological analysis of 41 cases. Hum Pathol. 2016;47:70–77.
Kang Z, Xu F, Zhang QA, et al. Oncogenic mutations in extramammary Paget's disease and their clinical relevance. Int J Cancer. 2013;132:824–831.
Kiniwa Y, Yasuda J, Saito S, et al. Identification of genetic alterations in extramammary Paget disease using whole exome analysis. J Dermatol Sci. 2019;94:229–235.
Plaza JA, Torres-Cabala C, Ivan D, et al. HER-2/neu expression in extramammary Paget disease: a clinicopathologic and immunohistochemistry study of 47 cases with and without underlying malignancy. J Cutan Pathol. 2009;36:729–733.
Ishida Y, Kakiuchi N, Yoshida K, et al. Unbiased detection of driver mutations in extramammary Paget disease. Clin Cancer Res. 2021;27:1756–1765.
Shain AH, Yeh I, Kovalyshyn I, et al. The genetic evolution of melanoma from precursor lesions. N Engl J Med. 2015;373:1926–1936.
Hayward NK, Wilmott JS, Waddell N, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545:175–180.
Zeng H, Jorapur A, Shain AH, et al. Bi-allelic loss of CDKN2A initiates melanoma invasion via BRN2 activation. Cancer Cell. 2018;34:56–68.e9.
Hustinx SR, Leoni LM, Yeo CJ, et al. Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion. Mod Pathol. 2005;18:959–963.
Vij M, Cho BB, Yokoda RT, et al. p16 immunohistochemistry is a sensitive and specific surrogate marker for CDKN2A homozygous deletion in gliomas. Acta Neuropathol Commun. 2023;11:73.
Maragkou T, Reinhard S, Jungo P, et al. Evaluation of MTAP and p16 immunohistochemical deficiency as surrogate marker for CDKN2A/B homozygous deletion in gliomas. Pathology. 2023;55:466–477.
Geyer L, Wolf T, Chenard MP, et al. p16 immunohistochemical expression as a surrogate assessment of CDKN2A alteration in gliomas leading to prognostic significances. Cancers (Basel). 2023;15:1512.
Vrugt B, Kirschner MB, Meerang M, et al. Deletions of CDKN2A and MTAP detected by copy-number variation array are associated with loss of p16 and MTAP protein in pleural mesothelioma. Cancers (Basel). 2023;15:4978.
Zschernack V, Andreiuolo F, Dörner E, et al. p16 immunohistochemistry as a screening tool for homozygous CDKN2A deletions in CNS tumors. Am J Surg Pathol. 2024;48:46–53.
Uguen A, Talagas M, Costa S, et al. A p16-Ki-67-HMB45 immunohistochemistry scoring system as an ancillary diagnostic tool in the diagnosis of melanoma. Diagn Pathol. 2015;10:195.
Uguen A, Uguen M, Guibourg B, et al. The p16-Ki-67-HMB45 immunohistochemistry scoring system is highly concordant with the fluorescent in situ hybridization test to differentiate between melanocytic nevi and melanomas. Appl Immunohistochem Mol Morphol. 2018;26:361–367.
Koh SS, Roehmholdt BF, Cassarino DS. Immunohistochemistry of p16 in nevi of pregnancy and nevoid melanomas. J Cutan Pathol. 2018;45:891–896.
Koh SS, Cassarino DS. Immunohistochemical expression of p16 in melanocytic lesions: an updated review and meta-analysis. Arch Pathol Lab Med. 2018;142:815–828.
Oaxaca G, Billings SD, Ko JS. p16 Range of expression in dermal predominant benign epithelioid and spindled nevi and melanoma. J Cutan Pathol. 2020;47:815–823.
Bahmad HF, Oh KS, Alexis J. Potential diagnostic utility of PRAME and p16 immunohistochemistry in melanocytic nevi and malignant melanoma. J Cutan Pathol. 2023;50:763–772.
Brcic L, Le Stang N, Gallob F, et al. A combination of MTAP and p16 immunohistochemistry can substitute for CDKN2A fluorescence in situ hybridization in diagnosis and prognosis of pleural mesotheliomas. Arch Pathol Lab Med. 2023;147:313–322.
Powell EL, Leoni LM, Canto MI, et al. Concordant loss of MTAP and p16/CDKN2A expression in gastroesophageal carcinogenesis: evidence of homozygous deletion in esophageal noninvasive precursor lesions and therapeutic implications. Am J Surg Pathol. 2005;29:1497–1504.
Bertin R, Acquaviva C, Mirebeau D, et al. CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono- and bi-allelic 9p21 deletions in childhood acute lymphoblastic leukemia. Genes Chromosomes Cancer. 2003;37:44–57.
Illei PB, Ladanyi M, Rusch VW, et al. The use of CDKN2A deletion as a diagnostic marker for malignant mesothelioma in body cavity effusions. Cancer. 2003;99:51–56.
Illei PB, Rusch VW, Zakowski MF, et al. Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas. Clin Cancer Res. 2003;9:2108–2113.
Kreuger IZM, Slieker RC, van Groningen T, et al. Therapeutic strategies for targeting CDKN2A loss in melanoma. J Invest Dermatol. 2023;143:18–25.e1.
Fennell DA, King A, Mohammed S, et al. Abemaciclib in patients with p16ink4A-deficient mesothelioma (MiST2): a single-arm, open-label, phase 2 trial. Lancet Oncol. 2022;23:374–381.
Sasaki Y, Goto K, Sugino T, et al. Characteristic clinicopathological features of secondary extramammary Paget disease with underlying anorectal adenocarcinoma: evenly circumferential perianal distribution, fibroepithelioma of Pinkus-like changes, and subepidermal mucin deposits without invasive tumor cells. Am J Dermatopathol. 2021;43:721–726.
Nobori T, Miura K, Wu DJ, et al. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 1994;368:753–756.
Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366:704–707.
Li J, Poi MJ, Tsai MD. Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. Biochemistry. 2011;50:5566–5582.
De Wispelaere N, Rico SD, Bauer M, et al. High prevalence of p16 staining in malignant tumors. PLoS One. 2022;17:e0262877.
Sah SP, McCluggage WG. Florid vulval Paget disease exhibiting p16 immunoreactivity and mimicking classic VIN. Int J Gynecol Pathol. 2013;32:221–227.
Al-Obaidy KI, Kao CS, Idrees MT. P16 expression in extramammary Paget's disease of the vulva and scrotum is not human papillomavirus related. Int J Surg Pathol. 2018;26:617–620.
Zhang G, Zhou S, Zhong W, et al. Whole-exome sequencing reveals frequent mutations in chromatin remodeling genes in mammary and extramammary Paget's diseases. J Invest Dermatol. 2019;139:789–795.
Kitamura S, Yanagi T, Maeda T, et al. Cyclin-dependent kinase 4/6 inhibitors suppress tumor growth in extramammary Paget's disease. Cancer Sci. 2022;113:802–807.
Hashimoto H, Kaku-Ito Y, Oda Y, et al. CDK4: a novel therapeutic target for extramammary Paget's disease. Front Oncol. 2021;11:710378.
Urata K, Kajihara I, Myangat TM, et al. Overexpression of cyclin-dependent kinase 4 protein in extramammary Paget's disease. J Dermatol. 2019;46:444–448.
Infante JR, Cassier PA, Gerecitano JF, et al. A phase I study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas. Clin Cancer Res. 2016;22:5696–5705.