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.
Aims
Recently, YAP1 fusion genes have been demonstrated in eccrine poroma and porocarcinoma, and the diagnostic use of YAP1 immunohistochemistry has been highlighted in this setting. In other ...organs, loss of YAP1 expression can reflect YAP1 rearrangement or transcriptional repression, notably through RB1 inactivation. In this context, our objective was to re‐evaluate the performance of YAP1 immunohistochemistry for the diagnosis of poroma and porocarcinoma.
Methods and results
The expression of the C‐terminal part of the YAP1 protein was evaluated by immunohistochemistry in 543 cutaneous epithelial tumours, including 27 poromas, 14 porocarcinomas and 502 other cutaneous tumours. Tumours that showed a lack of expression of YAP1 were further investigated for Rb by immunohistochemistry and for fusion transcripts by real‐time PCR (YAP1::MAML2 and YAP1::NUTM1). The absence of YAP1 expression was observed in 24 cases of poroma (89%), 10 porocarcinoma (72%), 162 Merkel cell carcinoma (98%), 14 squamous cell carcinoma (SCC) (15%), one trichoblastoma and one sebaceoma. Fusions of YAP1 were detected in only 16 cases of poroma (n = 66%), 10 porocarcinoma (71%) all lacking YAP1 expression, and in one sebaceoma. The loss of Rb expression was detected in all cases except one of YAP1‐deficient SCC (n = 14), such tumours showing significant morphological overlap with porocarcinoma. In‐vitro experiments in HaCat cells showed that RB1 knockdown resulted in repression of YAP1 protein expression.
Conclusion
In addition to gene fusion, we report that transcriptional repression of YAP1 can be observed in skin tumours with RB1 inactivation, including MCC and a subset of SCC.
Recently, YAP1 fusion genes have been demonstrated in eccrine poroma and porocarcinoma, resulting in YAP1 expression loss detectable by immunohistochemistry. In the present study, in addition to gene fusion mechanisms, we report that transcriptional repression of YAP1 can be observed in skin tumours with RB1 inactivation, including the majority of MCC and a subset of SCC, a morphological mimicker of porocarcinoma.
Aims
Porocarcinoma is a malignant sweat gland tumour differentiated toward the upper part of the sweat duct and may arise from the transformation of a preexisting benign poroma. In 2019, Sekine ...et al. demonstrated the presence of YAP1::MAML2 and YAP1::NUTM1 fusions in most poromas and porocarcinomas. Recently, our group identified PAK2‐fusions in a subset of benign poromas. Herein we report a series of 12 porocarcinoma cases harbouring PAK1/2/3 fusions.
Methods and Results
Five patients were male and the median age was 79 years (ranges: 59–95). Tumours were located on the trunk (n = 7), on the thigh (n = 3), neck (n = 1), or groin area (n = 1). Four patients developed distant metastases. Microscopically, seven cases harboured a benign poroma component and a malignant invasive part. Ductal formations were observed in all, while infundibular/horn cysts and cells with vacuolated cytoplasm were detected in seven and six tumours, respectively. In three cases, the invasive component consisted of a proliferation of elongated cells, some of which formed pseudovascular spaces, whereas the others harboured a predominant solid or trabecular growth pattern. Immunohistochemical staining for CEA and EMA confirmed the presence of ducts. Focal androgen receptor expression was detected in three specimens. Whole RNA sequencing evidenced LAMTOR1::PAK1 (n = 2), ZDHHC5::PAK1 (n = 2), DLG1::PAK2, CTDSP1::PAK1, CTNND1::PAK1, SSR1::PAK3, CTNNA1::PAK2, RNF13::PAK2, ROBO1::PAK2, and CD47::PAK2. Activating mutation of HRAS (G13V, n = 3, G13R, n = 1, Q61L, n = 2) was present in six cases.
Conclusion
Our study suggests that PAK1/2/3 fusions is the oncogenic driver of a subset of porocarcinomas lacking YAP1 rearrangement.
Recurrent PAK1/2/3 fusions are detected in a subset of porocarcinomas with frequent follicular and sebaceous differentiation.
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