Abstract

Hidradenocarcinoma (HCa) is a rare cutaneous adnexal neoplasm which represents the malignant counterpart of hidradenoma (HA). Although the majority of HA harbor MAML2 gene fusions, the genetic alterations that underlie progression to HCa are poorly understood. We present 4 cases of pure HCa and 4 cases of HCa arising in association with HA (HCa ex HA), in which next generation sequencing (NGS), MAML2 fluorescence in situ hybridization (FISH) or Archer RNA sequencing, and p53 immunohistochemistry (IHC) were performed. Clinical characteristics include 5 male:3 female patients with an average age of 61 (range: 25-82). Tumors occurred on the distal extremities (4, 50%), trunk (3, 37.5%), and neck (1, 12.5%). p53 IHC showed aberrant diffuse positive staining in the carcinoma component in 5 cases (71%; 4 HCa ex HA, 1 pure HCa) and showed a wild-type pattern in HA components and in 2 pure HCa cases (29%). Archer RNA sequencing was performed on 1 pure HCA, which revealed a CRCT1::MAML2 gene fusion. MAML2 FISH was performed on 5 cases and showed positive gene rearrangement in both components in one case (1, 20%). The remaining cases suggested monosomy of chromosome 11 by FISH (4, 80%), the chromosome on which the MAML2 gene is located. Capture-based NGS performed on the malignant and benign components of 3 HCa ex HA and on 1 pure HCa demonstrated distinct, recurrent chromosomal copy number changes in the HCa component compared to the HA component in 3/3 cases and also in the pure HCa (100%). Chromosomal alterations in HCa included loss of distal 11q (50%); gains of chromosome 1q (25%), 5q (25%), proximal 7p and 7q (25%), 8 (25%), 18q (25%); and copy neutral loss of heterozygosity of chr 9 (25%). Additionally, somatic mutations identified include recurrent CDKN2A mutations (3/4, 75%) and a p53 mutation in one HCa (1/4, 25%). Our study shows that aberrant diffusely positive p53 staining and chromosomal copy number changes correlate with malignant transformation of HCa from HA.

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