Abstract
Simple SummaryCutaneous sweat gland tumors form an extremely diverse and heterogeneous group of neoplasms that show histological differentiation to the sweat apparatus. Due to their rarity, wide diagnostic range, and significant morphological overlap between entities, their accurate diagnosis remains challenging for pathologists. Until recently, little was known about the molecular pathogenesis of adnexal tumors. Recent findings have revealed a wide range of gene fusions and other oncogenic factors that can be used for diagnostic purposes and, for some, can be detected by immunohistochemistry. Among other organs containing exocrine glands, such as salivary glands, breasts, and bronchi, most of these biomarkers have been reported in homologous neoplasms that share morphological features with their cutaneous counterparts. This review aims to describe these recent molecular and immunohistochemical biomarkers in the field of sweat gland tumors.Cutaneous sweat gland tumors are a subset of adnexal neoplasms that derive or differentiate into the sweat apparatus. Their great diversity, rarity, and complex terminology make their pathological diagnosis challenging. Recent findings have revealed a wide spectrum of oncogenic drivers, several of which are of diagnostic interest for pathologists. Most of these molecular alterations are represented by gene fusions, which are shared with other homologous neoplasms occurring in organs containing exocrine glands, such as salivary and breast glands, which show similarities to the sweat apparatus. This review aims to provide a synthesis of the most recent immunohistochemical and molecular markers used for the diagnosis of sweat gland tumors and to highlight their relationship with similar tumors in other organs. It will cover adenoid cystic carcinoma (NFIB, MYB, and MYBL1 fusion), cutaneous mixed tumor (PLAG1 fusion), cylindroma and spiradenoma and their carcinomas thereof (NF-κB activation through CYLD inactivation or ALKP1 hotspot mutation), hidradenoma and hidradenocarcinoma (MAML2 fusion), myoepithelioma (EWSR1 and FUS fusion), poroma and porocarcinoma (YAP1, MAML2, and NUTM1 fusion), secretory carcinoma (ETV6, NTRK3 fusion), tubular adenoma and syringo-cystadenoma papilliferum (HRAS and BRAF activating mutations). Sweat gland tumors for which there are no known molecular abnormalities will also be briefly discussed, as well as potential future developments.
Highlights
Benign and malignant cutaneous adnexal tumors are rare [1]
Molecular biology: Fusions of MYB or MYB proto-oncogene like 1 (MYBL1) with NFIB are detected in 40–97% of adenoid cystic carcinomas with very high specificity [5,6,12,16,19,20]
Poroid cells compared to the adjacent epidermis, which suggest a YAP1-fusion (×200); (d) NUT immunohistochemistry demonstrates diffuse nuclear staining when a NUTM1 gene fusion is involved, which is more frequent in the poroid hidradenoma variant (×200)
Summary
Benign and malignant cutaneous adnexal tumors are rare [1]. They span a wide variety of different diagnoses, classified according to their apocrine, eccrine, follicular, and sebaceous differentiation. In salivary glands, the term “cylindroma” has been used as a synonym of adenoid cystic carcinoma and, while adenoid cystic carcinoma cases of the skin are analogous to their salivary counterparts, with recurrent fusion involving the MYB gene, skin cylindromas represent a distinct tumor entity with frequent CYLD mutation. Some of these biomarkers are related to a whole group of adnexal neoplasms since they are detected in benign and malignant cases, while some evidence suggests a multistep progression from a benign precursor with a specific molecular background to their malignant counterpart. Sweat gland tumors lacking known recurrent molecular abnormalities will be briefly discussed in the last paragraph of this review
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