Squamoid Eccrine Ductal Carcinoma Displays Ultraviolet Mutations and Intermediate Gene Expression Relative to Squamous Cell Carcinoma, Microcystic Adnexal Carcinoma, and Porocarcinoma.

Squamoid eccrine ductal carcinoma is a rare infiltrative tumor with morphologic features intermediate between squamous cell carcinoma (SCC) and sweat gland carcinomas such as microcystic adnexal carcinoma. Although currently classified as a sweat gland carcinoma, it has been debated whether squamoid eccrine ductal carcinoma is better classified as a variant of SCC. Furthermore, therapeutic options for patients with advanced disease are lacking. Here, we describe clinicopathologic features of a cohort of 15 squamoid eccrine ductal carcinomas from 14 unique patients, with next-generation sequencing DNA profiling for 12 cases. UV signature mutations were the dominant signature in the majority of cases. TP53 mutations were the most highly recurrent specific gene alteration, followed by mutations in NOTCH genes. Recurrent mutations in driver oncogenes were not identified. By unsupervised comparison of global transcriptome profiles in squamoid eccrine ductal carcinoma (n = 7) to SCC (n = 10), porocarcinoma (n = 4), and microcystic adnexal carcinoma (n = 4), squamoid eccrine ductal carcinomas displayed an intermediate phenotype between SCC and sweat gland tumors. Squamoid eccrine ductal carcinoma displayed significantly higher expression of 364 genes (including certain eccrine markers) and significantly lower expression of 525 genes compared with other groups. Our findings support the classification of squamoid eccrine ductal carcinoma as a carcinoma with intermediate features between SCC and sweat gland carcinoma.

Gene fusions in poroma, porocarcinoma and related adnexal skin tumours: An update.

Poroma is a benign sweat gland tumour showing morphological features recapitulating the superficial portion of the eccrine sweat coil. A subset of poromas may transform into porocarcinoma, its malignant counterpart. Poroma and porocarcinoma are characterised by recurrent gene fusions involving YAP1, a transcriptional co-activator, which is controlled by the Hippo signalling pathway. The fusion genes frequently involve MAML2 and NUTM1, which are also rearranged in other cutaneous and extracutaneous neoplasms. We aimed to review the clinical, morphological and molecular features of this category of adnexal neoplasms with a special focus upon emerging differential diagnoses, and discuss how their systematic molecular characterisation may contribute to a standardisation of diagnosis, more accurate classification and, ultimately, refinement of their prognosis and therapeutic modalities.

Spindle cell porocarcinoma with a novel YAP1::MAML3 fusion.

Porocarcinomas are rare sweat gland cancers representing the malignant counterpart to benign poromas. Their diagnosis can be challenging, especially in the absence of an associated poroma or when the tumor is poorly differentiated. Since recurrent YAP1::MAML2 and YAP1::NUTM1 fusions have been identified in poroid tumors, molecular studies provide an opportunity to support the diagnosis in challenging cases. We describe a case of a female patient in her early 90s, with a polypoid mass of the hip. Histopathologically, there was a poorly differentiated malignant spindle cell tumor adjacent to a poroma. Because of the close association with a poroma and immunoreactivity for p40, a diagnosis of spindle cell porocarcinoma was rendered, which was further supported by YAP1 immunohistochemical studies. Antibodies targeting both the N-terminus and C-terminus confirmed YAP1 rearrangement in both the poroma and the spindle cell neoplasm. Subsequent targeted RNA sequencing revealed a YAP1::MAML3 gene fusion. MAML3 has previously not yet been reported as a YAP1 fusion partner in porocarcinoma. With the illustration of a rare spindle cell variant of porocarcinoma and the identification of a novel gene fusion, this case report expands the spectrum of morphologic and genomic aberrations associated with porocarcinoma.

Porocarcinoma: Clinical and Histological Features, Immunohistochemistry and Outcomes: A Systematic Review.

Porocarcinoma (PC) is a rare adnexal tumor, mainly found in the elderly. The tumor arises from the acrosyringium of eccrine sweat glands. The risk of lymph node and distant metastasis is high. Differential diagnosis with squamous cell carcinoma is difficult, although NUT expression and YAP1 fusion products can be very useful for diagnosis. Currently, wide local excision is the main surgical treatment, although Mohs micrographic surgery is promising. To date, there is no consensus regarding the role of sentinel lymph node biopsy and consequential lymph node dissection. No guidelines exist for radiotherapy, which is mostly performed based on tumor characteristics and excision margins. Only a few studies report systemic treatment for advanced PC, although therapy with pembrolizumab and EGFR inhibitors show promise. In this review, we discuss epidemiology, clinical features, histopathological features, immunohistochemistry and fusion products, surgical management and survival outcomes according to stage, surgical management, radiotherapy and systemic therapy.

Gene expression profiling in porocarcinoma indicates heterogeneous tumor development and substantiates poromas as precursor lesions.

BACKGROUND AND OBJECTIVES: Malignant sweat gland tumors are rare, with the most common being eccrine porocarcinoma (EP). Approximately 18% of benign eccrine poroma (EPO) transit to EP. Previous research has provided first insights into the mutational landscape of EP. However, only few studies have performed gene expression analyses. This leaves a gap in the understanding of EP biology and potential drivers of malignant transformation from EPO to EP. METHODS: Transcriptome profiling of 23 samples of primary EP and normal skin (NS). Findings from the EP samples were then tested in 17 samples of EPO. RESULTS: Transcriptome profiling revealed diversity in gene expression and indicated biologically heterogeneous sub-entities as well as widespread gene downregulation in EP. Downregulated genes included CD74, NDGR1, SRRM2, CDC42, ANXA2, KFL9 and NOP53. Expression levels of CD74, NDGR1, SRRM2, ANXA2, and NOP53 showed a stepwise-reduction in expression from NS via EPO to EP, thus supporting the hypothesis that EPO represents a transitional state in EP development. CONCLUSIONS: We demonstrated that EP is molecularly complex and that evolutionary trajectories correspond to tumor initiation and progression. Our results provide further evidence implicating the p53 axis and the EGFR pathway. Larger samples are warranted to confirm our findings.

Distinct regulations driving YAP1 expression loss in poroma, porocarcinoma and RB1-deficient skin carcinoma.

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.

Porocarcinoma with YAP1-NUTM1 fusion presenting as a NUT immunohistochemistry-positive lymph node metastasis.

INTRODUCTION: Porocarcinoma is a rare, malignant adnexal tumor that recently has been shown to contain YAP1-NUTM1 and YAP1-MAML2 fusion transcripts, with nuclear protein in testis (NUT) immunohistochemistry (IHC) positivity in a subset of these tumors. Consequently, NUT IHC may either aid in the differential diagnosis, or represent a confounding factor depending on the clinical scenario. Here, we present a case of NUTM1-rearranged sarcomatoid porocarcinoma of the scalp presenting as a NUT IHC-positive lymph node metastasis. CASE REPORT: A mass was excised from the right neck level 2 region with a lymph node initially diagnosed as metastatic NUT carcinoma with unknown primary site. An enlarging scalp mass was identified 4 months later, excised and diagnosed as NUT-positive carcinoma. Additional molecular testing was performed to detect the fusion partner in the NUTM1 rearrangement, confirming a YAP1-NUTM1 fusion. Given this molecular data along with the histopathologic characteristics, the clinicopathologic picture was retrospectively determined to be most consistent with a primary sarcomatoid porocarcinoma of the scalp with metastasis to a right neck lymph node and the right parotid. DISCUSSION: Porocarcinoma is a rare entity, and typically only enters the differential diagnosis when the clinical consideration is a cutaneous neoplasm. In an alternative clinical scenario such as the approach to tumors of the head and neck, porocarcinoma is not typically a consideration. In the latter scenario, as seen in our case, positivity with NUT IHC led to the initial misdiagnosis of NUT carcinoma. This case represents an important presentation of porocarcinoma that will occur not infrequently, and pathologists must be aware of this presentation to avoid this pitfall.

Fusion-positive skin/adnexal carcinomas.

Gene fusions have been increasingly identified as central events driving oncogenesis in a variety of benign and malignant neoplasms of different histogenesis originating in diverse organs. While some fusion-driven neoplasms may occur at any body site, certain genotypes and their associated phenotypic entities cluster to specific body site/organ, albeit with variable frequencies among anatomic locations. In the last two decades, several skin adnexal entities driven by specific fusions have been described; some of them represent new entities (eg, secretory carcinoma harboring NTRK fusions), while others are old established entities with newly discovered underlying gene fusions (eg, poroid neoplasms harboring NUTM1, YAP1, and WWTR1 fusions). While limited availability of next generation sequencing tools in routine practice has largely limited and delayed discovery of fusions in old entities, the increasing availability of novel immunoantibodies as surrogates to recognize gene fusions (such as NUT and YAP1 immunohistochemistry) represents a relatively cheap, quick, and reliable routine tool for their proper recognition and appropriate classification. This review highlights the main, recently defined skin adnexal carcinomas carrying gene fusions.

Porocarcinoma with orbital metastasis, a case report with review of literature.

We present a patient who presented with an orbital mass lesion which was a metastatic lesion from a porocarcinoma of the scalp with progressive deterioration of the patient.A 78-year-old male presented with functional decline and a rapidly growing scalp lesion of 3 months duration. In addition to the scalp lesion, Computed Tomography showed an incidental finding of a left lateral orbital wall tumour. Fine-needle aspiration of the two lesions revealed malignant cells with similar morphologies. Punch biopsy of the scalp lesion showed histological features suggestive of a porocarcinoma. Patient underwent palliative radiotherapy and immunotherapy and subsequently succumbed to the disease.

Molecular analysis of NUT-positive poromas and porocarcinomas identifies novel break points of YAP1::NUTM1 fusions.

BACKGROUND: Poromas, and their malignant counterparts, porocarcinomas, harbor recurrent translocations involving YAP1-MAML2, YAP1-NUTM1, and infrequently WWTR1-NUTM1; YAP1-NUTM1 being the most common in porocarcinomas. NUT immunohistochemistry (IHC) can be used to identify NUTM1-translocated tumors. This study sought to investigate potential novel NUTM1-fusion partners among NUT IHC-positive poromas and porocarcinomas. METHODS: Thirteen NUT IHC-positive poroid tumors (four poromas and nine porocarcinomas) were identified within a multi-institutional international cohort. Next-generation sequencing (NGS) assessed for NUTM1 fusion partners. RESULTS: NGS detected a NUTM1 fusion in 12 of 13 cases: YAP1-NUTM1 (11/12 cases) and WWTR1-NUTM1 (1/12 cases). Two of the cases (2/12) with NUTM1 fusion were not called by the NGS algorithm but had at least one read-spanning YAP1-NUTM1 break point upon manual review. A NUTM1 fusion was not identified in one case; however, the sample had low RNA quality. The following fusion events were identified: YAP1 exon 4::NUTM1 exon 3 in six cases, YAP1 exon 6::NUTM1 exon 2 in one case, YAP1 exon 3::NUTM1 exon 3 in three cases, WWTR1 exon 3::NUTM1 exon 3 in one case, and YAP1 exon 8::NUTM1 exon 3 fusion in one case. CONCLUSION: While no novel NUTM1 fusion partners were identified within our cohort, 12 of 13 cases had discoverable NUTM1 fusions; YAP1-NUTM1 fusion was detected in 11 cases (92%) and WWTR1-NUTM1 in 1 case (8%). These data corroborate findings from other recent investigations and further substantiate the utility of NUT IHC in diagnosing a subset of poroid neoplasms. In addition, two of our cases harbored fusions of YAP1 exon 6 to NUTM1 exon 3 and YAP1 exon 8 to NUTM1 exon 2, which have not been reported before in poroid neoplasms and indicate novel break points of YAP1.

Merkel cell polyomavirus is a passenger virus in both poroma and porocarcinoma.

BACKGROUND: Merkel cell polyomavirus (MCPyV) has been studied in several malignant and nonmalignant tissues. However, only in Merkel cell carcinoma (MCC) has the connection to tumorigenesis been established. Previously, eccrine porocarcinoma samples were shown to express MCPyV in the majority of samples. We aimed to examine MCPyV in porocarcinoma and poroma samples using MCC as the reference material. METHODS: We analyzed 17 porocarcinoma and 50 poroma samples for the presence of MCPyV using LT antigen immunostaining and DNA detection methods. In addition, 180 MCC samples served as controls. RESULTS: MCPyV LT antigen immunostaining was detected in 10% of poroma and 18% of porocarcinoma samples; on the other hand, it was present in 65% of MCC samples. MCPyV DNA was detected in only 10% of poroma and porocarcinoma samples compared with 96% of MCC samples. The viral DNA copy number in all MCPyV DNA-positive MCCs was at least 25 times higher than that in porocarcinoma or poroma samples with the highest MCPyV DNA-to-PTPRG ratio. CONCLUSIONS: The low number of viral DNA copies in poroma and porocarcinoma samples, together with the negative LT expression of MCPyV DNA-positive tumors, indicates that MCPyV is simply a passenger virus rather than an oncogenic driver of porocarcinoma.

A case of YAP1 and NUTM1 rearranged porocarcinoma with corresponding immunohistochemical expression: Review of recent advances in poroma and porocarcinoma pathogenesis with potential diagnostic utility.

Porocarcinoma is a rare malignant adnexal tumor with predilection for the lower extremities and the head and neck region of older adults. This entity may arise de novo or in association with a benign poroma. Porocarcinoma's non-specific clinical appearance, immunohistochemical profile, and divergent differentiation may occasionally be diagnostically challenging. Recently, highly recurrent YAP1 and NUTM1 gene rearrangements have been described in cases of poroma and porocarcinoma. In this report, we present a case of porocarcinoma with squamous differentiation in an 81-year-old woman which harbored rearrangement of the YAP1 and NUTM1 loci and was diffusely immunoreactive for NUTM1. We discuss the recent advancements in the pathogenesis of poromas and porocarcinomas with emphasis on the clinical utility of the NUTM1 antibody.

Utility of YAP1 and NUT immunohistochemistry in the diagnosis of porocarcinoma.

BACKGROUND: Porocarcinoma is the malignant counterpart of poroma, a benign tumor derived from the eccrine or apocrine units. In contrast to poroma, porocarcinoma is rare and its diagnosis may be challenging. Recent work has identified YAP1-associated gene fusions in most poromas, and a subset of porocarcinomas. These included YAP1-MAML2 and YAP1-NUTM1, the latter being enriched in porocarcinomas over poromas. METHODS: We studied YAP1 C-terminus and NUT immunohistochemistry in a cohort of 12 porocarcinomas, 10 poromas, 10 squamous cell carcinomas, and 6 hidradenocarcinomas. RESULTS: Seven of 12 (58%) porocarcinomas showed loss of YAP1 C-terminus expression, consistent with a YAP1 fusion. Of these seven, five showed NUT positivity, implying the presence of the YAP1-NUTM1 fusion. One of 12 (8%) cases showed NUT positivity, but retention of YAP1 C-terminus expression, consistent with a non-YAP1 NUT-associated fusion. Eight of 10 (80%) poromas showed loss of YAP1 C-terminus expression and negative NUT staining, consistent with non-NUT YAP1 fusions. All squamous cell carcinomas and hidradenocarcinomas retained YAP1 C-terminus expression and were negative for NUT. CONCLUSION: YAP1 C-terminus and NUT immunohistochemistry may be helpful in the diagnosis of porocarcinoma, with the combination of YAP1 C-terminus loss and NUT positivity being particularly informative.

Poroid adnexal skin tumors with YAP1 fusions exhibit similar histopathologic features: A series of six YAP1-rearranged adnexal skin tumors.

BACKGROUND: Adnexal skin tumors are diagnostically challenging with few known molecular signatures. Recently, however, YAP1-MAML2 and YAP1-NUTM1 fusions were identified in poroid adnexal skin tumors. METHODS: Herein, we subjected eight poroid adnexal skin tumors (three poromas and five porocarcinomas) to fusion gene analysis by whole transcriptome sequencing and next-generation DNA sequencing analysis. RESULTS: YAP1 fusions were identified in six cases. YAP1-NUTM1 fusions were identified in two poromas and three porocarcinomas. A single case of porocarcinoma harbored a YAP1-MAML2 fusion. Two cases were negative for gene fusion. All cases that harbored YAP1-NUTM1 fusions showed nuclear protein in testis (NUT) expression by immunohistochemistry, with NUT being negative in the YAP1-MAML2-positive case. In this case series, we provide a detailed histopathologic description of six YAP1-fused poroid skin tumors, which we show harbor reproducible histopathologic features, to include broad, bulbous tumor tongues with admixtures of basaloid, poroid cells punctuated by squamatized cuticles and ductules, with uniform tumor nuclei featuring frequent grooves and pseudonuclear inclusions. CONCLUSIONS: Awareness of the characteristic histopathologic features of YAP1-fused poroid adnexal skin tumor is a step toward a more reproducible classification of adnexal skin tumors as well as a step toward targeted therapy for metastatic and/or unresectable examples of this poroid group of neoplasms.

Porocarcinoma with areas of mucinous differentiation suggesting multilineage differentiation.

Porocarcinoma is an infrequent malignant adnexal carcinoma, with some histopathological variants described, such as the clear cell, the sarcomatoid or the pigmented porocarcinoma. We report an invasive porocarcinoma showing areas of tumor cells floating in prominent dermal mucin, simulating mucinous carcinoma, that we consider a new histopathological variant of porocarcinoma. We report a 74-year-old male with previous history of multiple basal cell carcinomas that presented a nodule on his left temple. Histopathologic study showed a large ulcerated multilobular tumor composed of thickened cords of cells emanating from a hyperplastic epidermis and showing a mixed infiltrative and pushing pattern in the dermis. Poroid differentiation was observed in most of the neoplasm, both in intraepidermal and dermal invasive component. Within the neoplasm a prominent area where these small nests with clear formation of ducts were floating in mucinous pools with few septa intermingled was observed, simulating a primary cutaneous mucinous carcinoma. Cytology, immunohistochemistry and the presence of both neoplastic areas as closely related and with multiple points of connectivity favors the consideration of a composite tumor in this peculiar case. Other differentials are discussed.

Malignant Eccrine Porocarcinoma in Finland During 2007 to 2017.

Malignant eccrine porocarcinoma is a rare skin adnexal cancer arising from the sweat glands. Little is known about the epidemiology and incidence of eccrine porocarcinoma. This registry-based study examined the epidemiology and incidence data for eccrine porocarcinoma from the Finnish Cancer Registry. The study included all persons diagnosed with eccrine porocarcinoma in 2007 to 2017. There were 69 cases in the study period; 34 (49%) male and 35 (51%) female patients. Mean age at diagnosis was 75.5 years. Incidence for men was 0.06 per 100,000 person-years and for women 0.04 per 100,000 person-years adjusted for age according to the World Standard Population. Incidence increased with age. There was one eccrine porocarcinoma-specific death among the 69 patients. The incidence of eccrine porocarcinoma in Finland is therefore low. The mean age at time of diagnosis and the location of eccrine porocarcinoma are consistent with previous reports. The survival of patients with eccrine porocarcinoma is high.

[Management of malignant adnexal neoplasms of the skin]. / Management von malignen Adnextumoren der Haut.

Malignant adnexal neoplasms of the skin are a heterogeneous group of rare malignancies with eccrine, apocrine, sebaceous and follicular differentiation. Essential clinical practice recommendations for the overall management of these cancers are presented. Moreover, specific evidence-based findings according to diagnosis, therapy and follow-up of porocarcinoma, sebaceous carcinoma and microcystic adnexcarcinoma will be explained.

Eccrine poroma of the eyelid.

Clinical and histopathologic case of an eyelid eccrine poroma, a benign adnexal neoplasm rarely found on the periorbital skin.

Rare case of large eccrine poroma of the eyelid.

Eccrine poroma is a rare tumor arising from sweat glands with common location being soles and palms. We are reporting a case of 70-year male patient with large lower lid mass lesion. Owing to its location and history of growth, malignancy was suspected. Biopsy proved it to be eccrine poroma which is a benign lesion. Complete excision with lid reconstruction was done. Eccrine poroma, though rare, should be kept in the differential diagnosis of eyelid tumors. Owing to the risk of malignant transformation and difficulty in clinical differentiation between poroma and porocarcinoma, wide excision should be done.

Altered Rb, p16, and p53 expression is specific for porocarcinoma relative to poroma.

BACKGROUND: Porocarcinomas are rare aggressive carcinomas that harbor tumor suppressor mutations and must be distinguished from benign entities such as poromas. METHODS: To determine whether altered expression of these genes was diagnostically informative, we examined p53, Rb, and p16 staining patterns in 15 poromas and 16 porocarcinomas. RESULTS: Poromas consistently displayed diffuse strong expression of Rb in all but one case that displayed focal loss (1/15, 7%), and no evidence of aberrancy in p53 or p16. Porocarcinomas displayed diffuse or focal loss of Rb expression in 9/16 (56%) cases, diffuse loss or overexpression of p53 in 8/15 (53%), and diffuse loss or overexpression of p16 in 6/14 (43%). Diffuse aberrancy in p53 and Rb expression correlated with tumor mutations in TP53 and RB1, respectively, whereas focal Rb loss was associated with wild type RB1. Diffuse p16 overexpression correlated with Rb loss rather than CDKN2A mutation. For porocarcinomas with all three stains evaluable, 10/13 (77%) displayed aberrancy in at least one marker. CONCLUSIONS: Our findings suggest that altered p53, p16, and/or Rb expression is relatively specific to porocarcinoma in comparison with poroma. Technical limitations of this panel, including possible focal Rb loss, must be kept in mind, especially in limited samples.