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      Current Diagnosis and Treatment Options for Cutaneous Adnexal Neoplasms with Apocrine and Eccrine Differentiation

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          Abstract

          Adnexal tumors of the skin are a rare group of benign and malignant neoplasms that exhibit morphological differentiation toward one or more of the adnexal epithelium types present in normal skin. Tumors deriving from apocrine or eccrine glands are highly heterogeneous and represent various histological entities. Macroscopic and dermatoscopic features of these tumors are unspecific; therefore, a specialized pathological examination is required to correctly diagnose patients. Limited treatment guidelines of adnexal tumor cases are available; thus, therapy is still challenging. Patients should be referred to high-volume skin cancer centers to receive an appropriate multidisciplinary treatment, affecting their outcome. The purpose of this review is to summarize currently available data on pathogenesis, diagnosis, and treatment approach for apocrine and eccrine tumors.

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          Most cited references323

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          The Mutational Landscape of Adenoid Cystic Carcinoma

          Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here, we determined the ACC mutational landscape and report the exome or whole genome sequences of 60 ACC tumor/normal pairs. These analyses revealed a low exonic somatic mutation rate (0.31 non-silent events/megabase) and wide mutational diversity. Interestingly, mutations selectively involved chromatin state regulators, such as SMARCA2, CREBBP, and KDM6A, suggesting aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to DNA damage and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying these aberrations as critical events. Lastly, we identified recurrent mutations in the FGF/IGF/PI3K pathway that may potentially offer new avenues for therapy (30%). Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.
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            Eccrine porocarcinoma (malignant eccrine poroma): a clinicopathologic study of 69 cases.

            The clinicopathologic characteristics of 69 cases of eccrine porocarcinoma (EP) have been studied. Seven cases of purely in situ disease are included. Forty patients were female, 29 male with ages ranging from 29 to 91 years (mean 73 years). The lower extremity represented the single most common site (44%). Other common sites were the trunk (15 cases, 24%) and head (11 cases, 18%). The histologic diagnosis of EP was predicated on the basis of an irregular tumor at least partly formed of characteristic poromatous basaloid epithelial cells displaying ductal differentiation, and significant cytologic atypia. Forty-seven tumors (68%) contained mature well-formed eccrine ducts having an eosinophilic luminal cuticle, with the remaining tumors containing small ill-formed ducts and/or intracytoplasmic lumina. All ducts were discernible via light microscopy and in 49 cases were highlighted with DPAS stain and/or CEA/EMA immunocytochemistry. A variant with a broad pushing tumor margin and marked nuclear pleomorphism showed some resemblance to proliferative bowenoid dysplasia. In 11 cases (18%) the tumors appeared to arise in continuity with a benign preexistent poroma. A variety of histologic patterns were displayed including clear, squamous, and spindle cell differentiation, mucus cell metaplasia, and colonization by melanocytes. Lymphovascular invasion was present in 9 cases (15%). Three cases showed pagetoid extension of malignant cells (epidermotropism) and appeared to be multifocal. Follow-up was available in 54 patients (78%) with 9 (17%) experiencing local recurrence, 10 developing lymph node metastases (19%), and 6 (11%) experiencing distant metastases or death. Mitoses, the presence of lymphovascular invasion, and tumor depth >7 mm were associated with a poorer prognosis. Dividing tumors into those with a "pushing" or "infiltrating" advancing margin was also predictive of outcome with the latter having an increased risk of local recurrence. This report, the largest series of EP to date, suggests that the incidence of aggressive behavior is less than popularly believed. Furthermore, EP can display a wide variety of histologic patterns that may lead to diagnostic error in the unwary. The large number of cases in this series enables a reliable evaluation of prognostic parameters. A more aggressive clinical course may be indicated by more than 14 mitoses per high power field (hazard ratio [HR] for death 17.0, 95% confidence interval [CI] 2.71-107), lymphovascular invasion by tumor (HR 4.41, CI 1.13-17.2), and depth >7 mm (HR 5.49, CI 1.0-30.3). Thus, mitoses, lymphovascular invasion, and tumor depth should be evaluated in these tumors. We also suggest that tumors presenting an "infiltrative" advancing margin are particularly prone to local recurrence and require wide excision with close attention to the surgical margins by the reporting pathologist.
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              Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.

              Nevus sebaceous is a common congenital cutaneous malformation. Affected individuals may develop benign and malignant secondary tumors in the nevi during life. Schimmelpenning syndrome is characterized by the association of nevus sebaceous with extracutaneous abnormalities. We report that of 65 sebaceous nevi studied, 62 (95%) had mutations in the HRAS gene and 3 (5%) had mutations in the KRAS gene. The HRAS c.37G>C mutation, which results in a p.Gly13Arg substitution, was present in 91% of lesions. Nonlesional tissues from 18 individuals had a wild-type sequence, confirming genetic mosaicism. The HRAS c.37G>C mutation was also found in 8 of 8 associated secondary tumors. Mosaicism for HRAS c.37G>C and KRAS c.35G>A mutations was found in two individuals with Schimmelpenning syndrome. Functional analysis of HRAS c.37G>C mutant cells showed constitutive activation of the MAPK and PI3K-Akt signaling pathways. Our results indicate that nevus sebaceous and Schimmelpenning syndrome are caused by postzygotic HRAS and KRAS mutations. These mutations may predispose individuals to the development of secondary tumors in nevus sebaceous.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                11 May 2021
                May 2021
                : 22
                : 10
                : 5077
                Affiliations
                [1 ]Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; iplachta@ 123456outlook.com (I.P.); marcin.kleibert@ 123456interia.pl (M.K.); mateusz@ 123456spalek.co (M.S.); piotr.rutkowski@ 123456pib-nio.pl (P.R.)
                [2 ]Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
                [3 ]Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; szumann@ 123456gmail.com
                [4 ]Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, 00-791 Warsaw, Poland
                Author notes
                [†]

                Equally contributed to the work.

                Author information
                https://orcid.org/0000-0002-0830-2711
                https://orcid.org/0000-0003-1562-8450
                https://orcid.org/0000-0002-2107-3810
                https://orcid.org/0000-0002-3960-7673
                https://orcid.org/0000-0002-8920-5429
                Article
                ijms-22-05077
                10.3390/ijms22105077
                8151110
                34064849
                fe9d59e0-db28-4252-b782-200c6dd01f40
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 14 March 2021
                : 02 May 2021
                Categories
                Review

                Molecular biology
                apocrine,eccrine,neoplasms,tumors,treatment
                Molecular biology
                apocrine, eccrine, neoplasms, tumors, treatment

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