{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:17:05Z","timestamp":1783592225596,"version":"3.55.0"},"reference-count":26,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Cutaneous metastases are an uncommon but clinically significant manifestation of internal malignancy, occurring in approximately 0.7\u201310.4% of patients with cancer. In some cases, they represent the first clinical manifestation of an otherwise occult malignancy, making accurate diagnosis critical for timely patient management. Distinguishing cutaneous metastases from primary cutaneous neoplasms, particularly malignant adnexal tumors, remains one of the most challenging problems in dermatopathology because of their substantial clinical, histopathologic, and immunophenotypic overlap. This review summarizes the epidemiology and biology of cutaneous metastasis and the clinical presentation of cutaneous metastases and emphasizes the central role of clinicopathologic correlation in diagnosis. Histologic features such as a purely dermal or subcutaneous location, intravascular tumor emboli, and a \u201cbottom-heavy\u201d growth pattern favor metastasis, whereas the presence of an in situ component or transition from a benign precursor lesion strongly supports a primary cutaneous neoplasm. We review the diagnostic utility of optimized immunohistochemical panels, highlighting the complementary roles of p63, cytokeratin 15, calretinin, and D2-40 (podoplanin) in establishing primary adnexal lineage, together with emerging markers including SOX10, androgen receptor, TRPS1, adipophilin, INSM1, SATB2, and BerEP4 for diagnostically challenging cases. We also discuss recent advances in molecular biology and comprehensive genomic profiling, including recurrent gene fusions (e.g., MYB::NFIB, CRTC1::MAML2, and YAP1 fusions) and characteristic mutational signatures that provide increasingly robust diagnostic evidence of tumor lineage. Finally, we provide a comprehensive, practical diagnostic algorithm for differentiating primary cutaneous adnexal carcinomas from cutaneous metastases of adenocarcinomas. By integrating traditional histopathologic techniques with modern immunohistochemical and molecular techniques, pathologists and clinicians can successfully navigate this complex differential diagnosis and thereby facilitate appropriate patient management and therapeutic intervention.<\/jats:p>","DOI":"10.3390\/biology15141108","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T08:50:56Z","timestamp":1783587056000},"page":"1108","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["When the Skin Tells a Bigger Story: Distinguishing Cutaneous Metastases from Primary Adnexal Carcinomas in Dermatopathology"],"prefix":"10.3390","volume":"15","author":[{"given":"Elsayed","family":"Ibrahim","sequence":"first","affiliation":[{"name":"Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3398-0573","authenticated-orcid":false,"given":"Phyu P.","family":"Aung","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"943","DOI":"10.5858\/arpa.2018-0051-RA","article-title":"Cutaneous Metastases: A Review and Diagnostic Approach to Tumors of Unknown Origin","volume":"143","author":"Habermehl","year":"2019","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tinca, A.C., Lazar, B.A., Cozac-Sz\u0151ke, A.R., Radu, G.N., Simion, S.P., Chiorean, D.M., Kosovski, I.B., Sab\u0103u, A.H., Niculescu, R., and Cocuz, I.G. (2025). Cutaneous Metastases\u2014Histological Particularities of Multifaceted Entities. Dermatopathology, 12.","DOI":"10.3390\/dermatopathology12020014"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Starace, M., Cedirian, S., and Rapparini, L. (2025). Clinical Aspects of Cutaneous Metastasis from Non-Cutaneous Primary Tumors. Cancers, 17.","DOI":"10.3390\/cancers17193126"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1097\/01.pcr.0000258738.38970.b1","article-title":"Primary Cutaneous Adnexal Neoplasms and Their Metastatic Look-Alikes","volume":"12","author":"Perna","year":"2007","journal-title":"Pathol. Case Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1136\/jclinpath-2015-203228","article-title":"Challenges in the Diagnosis of Cutaneous Adnexal Tumours","volume":"68","author":"Danialan","year":"2015","journal-title":"J. Clin. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Macagno, N., Sohier, P., Kervarrec, T., Pissaloux, D., Jullie, M.-L., Cribier, B., and Battistella, M. (2022). Recent Advances on Immunohistochemistry and Molecular Biology for the Diagnosis of Adnexal Sweat Gland Tumors. Cancers, 14.","DOI":"10.3390\/cancers14030476"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bou Zerdan, M., Jamouss, K.T., Maalouf, A., Moukarzel, R., Chhabra, T., Zaccarini, D.J., Pavlick, D., Danziger, N., and Ross, J. (2026). Comprehensive Genomic Profiling of Cutaneous Adnexal Carcinomas: A Genomic Landscape Study. Dermatopathology, 13.","DOI":"10.3390\/dermatopathology13020015"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41392-021-00817-8","article-title":"Circulating tumor cells: Biology and clinical significance","volume":"6","author":"Lin","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ghafoor, S., Garcia, E., Jay, D.J., and Persad, S. (2025). Molecular mechanisms regulating epithelial mesenchymal transition (EMT) to promote cancer progression. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26094364"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.cell.2010.03.015","article-title":"Matrix metalloproteinases: Regulators of the tumor microenvironment","volume":"141","author":"Kessenbrock","year":"2010","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1002\/ijc.26031","article-title":"The seed and soil hypothesis revisited\u2014The role of tumor-stroma interactions in metastasis to different organs","volume":"128","author":"Langley","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/s41392-024-01937-7","article-title":"Pre-metastatic niche: Formation, characteristics and therapeutic implication","volume":"9","author":"Wang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1097\/DAD.0b013e31823069cf","article-title":"Cutaneous Metastases From Internal Malignancies: A Clinicopathologic and Immunohistochemical Review","volume":"34","author":"Alcaraz","year":"2012","journal-title":"Am. J. Dermatopathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1001\/jamadermatol.2013.8502","article-title":"Dermoscopic Findings in Cutaneous Metastases","volume":"150","author":"Chernoff","year":"2014","journal-title":"JAMA Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/0190-9622(93)70228-L","article-title":"Microcystic Adnexal Carcinoma of the Skin: A Reappraisal of the Differentiation and Differential Diagnosis of an Underrecognized Neoplasm","volume":"29","author":"LeBoit","year":"1993","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/modpathol.2011.3","article-title":"PAX 8 Expression in Non-Neoplastic Tissues, Primary Tumors, and Metastatic Tumors: A Comprehensive Immunohistochemical Study","volume":"24","author":"Ozcan","year":"2011","journal-title":"Mod. Pathol."},{"key":"ref_17","first-page":"13233","article-title":"Clinical and pathological characteristics of extramammary Paget disease: Report of 246 Chinese male patients","volume":"8","author":"Kang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/modpathol.2010.46","article-title":"The Diagnostic Utility of Immunohistochemistry in Distinguishing Primary Skin Adnexal Carcinomas from Metastatic Adenocarcinoma to Skin: An Immunohistochemical Reappraisal Using Cytokeratin 15, Nestin, p63, D2-40, and Calretinin","volume":"23","author":"Mahalingam","year":"2010","journal-title":"Mod. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1016\/j.humpath.2014.01.006","article-title":"p40 Exhibits Better Specificity than p63 in Distinguishing Primary Skin Adnexal Carcinomas from Cutaneous Metastases","volume":"45","author":"Lee","year":"2014","journal-title":"Hum. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1097\/01.pas.0000213388.47913.f1","article-title":"Podoplanin Is a Highly Sensitive and Specific Marker to Distinguish Primary Skin Adnexal Carcinomas from Adenocarcinomas Metastatic to Skin","volume":"31","author":"Liang","year":"2007","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_21","first-page":"433","article-title":"Immunohistochemical Study of Calretinin in Normal Hair Follicles and Tumors with Follicular Differentiation","volume":"30","author":"Kutzner","year":"2008","journal-title":"Am. J. Dermatopathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1001\/archderm.143.5.613","article-title":"Clinicopathologic Correlation of Cutaneous Metastases: Experience from a Cancer Center","volume":"143","author":"Sariya","year":"2007","journal-title":"Arch. Dermatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/cup.13927","article-title":"Distant Cutaneous Metastasis of Malignant Epithelioid Mesothelioma","volume":"48","author":"Collins","year":"2021","journal-title":"J. Cutan. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1309\/AJCP2N1AFXEFOVYE","article-title":"Immunohistochemical Distinction of Primary Sweat Gland Carcinoma and Metastatic Breast Carcinoma: Can It always be accomplished reliably?","volume":"143","author":"Mentrikoski","year":"2015","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1097\/PAI.0b013e318205b059","article-title":"Combination of Napsin A and TTF-1 Immunohistochemistry Helps in Differentiating Primary Lung Adenocarcinoma from Metastatic Carcinoma in the Lung","volume":"19","author":"Ye","year":"2011","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/gim.2014.19","article-title":"A Clinical Scoring System to Identify Patients with Sebaceous Neoplasms at Risk for the Muir-Torre Variant of Lynch Syndrome","volume":"16","author":"Roberts","year":"2014","journal-title":"Genet. Med."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/14\/1108\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T09:18:15Z","timestamp":1783588695000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/14\/1108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":26,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["biology15141108"],"URL":"https:\/\/doi.org\/10.3390\/biology15141108","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]}}}