NUT Is a Specific Immunohistochemical Marker for the Diagnosis of YAP1-NUTM1-rearranged Cutaneous Poroid Neoplasms

Abstract

YAP1-NUTM1 fusion transcripts have been recently reported in poroma and porocarcinoma. NUTM1 translocation can be screened by nuclear protein in testis (NUT) immunohistochemistry in various malignancies, but its diagnostic performance has not been thoroughly validated on a large cohort of cutaneous epithelial neoplasms. We have evaluated NUT immunohistochemical expression in a large cohort encompassing 835 cases of various cutaneous epidermal or adnexal epithelial neoplasms. NUT expression was specific to eccrine poromas and porocarcinoma, with 32% of cases showing NUT expression. All other cutaneous tumors tested lacked NUT expression, including mimickers such as seborrheic keratosis, Bowen disease, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, nodular hidradenoma, and all other adnexal tumors tested. Remarkably, NUT expression was more frequent in a distinct morphologic subgroup. Indeed, 93% of poroid hidradenoma (dermal/subcutaneous nodular poroma, 13/14) and 80% of poroid hidradenocarcinoma cases (malignant poroid hidradenoma, 4/5) showed NUT expression, in contrast to 17% and 11% of classic poroma (4/23) and porocarcinoma cases (4/35), respectively. RNA sequencing of 12 NUT-positive neoplasms further confirmed the presence of a YAP1-NUTM1 fusion transcript in all cases, and also an EMC7-NUTM1 gene fusion in a single case. In the setting of a cutaneous adnexal neoplasm, nuclear expression of NUT accurately and specifically diagnosed a specific subgroup of benign and malignant poroid tumors, all associated with a NUTM1 fusion, which frequently harbored a poroid hidradenoma morphology.

Skin adnexal carcinoma with BRD3‐NUTM2B fusion

“…Recent studies have shown that NUTM1 can have a wider range of fusion partners and associated histopathologic phenotypes than previously thought 26‐33 . These observations include the association of YAP1‐NUTM1 fusions in cutaneous poroid neoplasms 26‐32 …”

NUTM1-Rearranged Neoplasms: A Heterogeneous Group of Primitive Tumors with Expanding Spectrum of Histology and Molecular Alterations: An Updated Review

“…On the order of 17% and 11% of classic poroma and porocarcinoma cases, respectively, show NUT expression. In addition, amongst all other subtypes of cutaneous adnexal tumors tested, NUT expression is only found in a subset of poroid skin tumors 100 . Figures 2C and 2D show a porocarcinoma that harbored a YAP1-NUTM1 fusion and its corresponding NUT immunostain.…”

“…The majority of fusion transcripts in poroid tumors detected were YAP-NUTM1, YAP-MAML2, and/or MAML2-YAP fusion 14,68,100 . Rare tumors harbor WWTR1-NUTM1 14 and EMC7-NUTM1 100 fusions.…”

“…Rare tumors harbor WWTR1-NUTM1 14 and EMC7-NUTM1 100 fusions. The simultaneous presence of these transcripts was common except WWTR1-NUT1, which was mutually exclusive with YAP1-NUTM1 14 (YAP-NUTM1 and EMC7-NUTM1 are not mutually exclusive and have been detected in the same tumor 100 ). Fusions are all in-frame with preserved transcriptional enhancer factor domain TEA DNA binding domain (TEAD)-binding and p-300-binding domain 14,68 .…”

“…Similarly, NUT fusion is involved in the pathogenesis of a subset of poromas and porocarcinomas with additional events likely required for a porocarcinoma to develop. Secondary events such as KRAS, SETD2, TP53, and RB1 mutations are required for progression to malignancy 89 . Studying non-fusion factors is also essential in understanding the clinical heterogeneity and differential drug responses.…”