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.

Porocarcinomas with PAK1/2/3 fusions: a series of 12 cases.

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.

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.

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.

Porocarcinoma of the Left Foot: A Case Review.

Eccrine porocarcinoma is a rare malignant tumor of the eccrine sweat gland. This malignancy occurs most commonly in the lower extremities. It tends to occur in patients aged 60 to 80 years, affecting men and women equally. We present the case of a 62-year-old man with a lesion on the left foot. The diagnosis of the initial biopsy was squamous cell carcinoma. Six months later, the lesion reoccurred, and a second biopsy confirmed it to be eccrine porocarcinoma.

Eccrine Porocarcinoma: Clinical and Histopathological Study of 14 Patients with Special Emphasis on Sentinel Lymph Node Biopsy.

Eccrine porocarcinoma is a rare skin adnexal tumour that affects elderly people. Most eccrine porocarcinomas are stage I or II according to the American Joint Committee on Cancer. The prognosis is good in early stages, but worsens when advanced. Since information on the use of sentinel lymph node biopsy in these patients is scarce, this study examined the records of all patients with eccrine porocarcinoma treated at Helsinki University Hospital during a 17-year period and focused on sentinel lymph node biopsy patients. The study identified 14 patients (9 male, 5 female). There were 2 metastases to the lymph nodes and 2 recurrences at initial referral to our institution. All primary tumours had wide local excision and 6 patients also had sentinel lymph node biopsy, of whom none had positive lymph nodes. There were no new metastases or recurrences during follow-up. Three patients died of causes other than eccrine porocarcinoma. When comparing the wide local excision only and wide local excision with sentinel lymph node biopsy groups, no parameters reached statistical significance. The decision process of the multidisciplinary tumour board meeting on whether to perform sentinel lymph node biopsy was not clear, perhaps due to the limited knowledge of eccrine porocarcinoma. Further studies and international collaboration are warranted.

Cuticular Poroma: A Rare Poroma Variant Simulating a Malignant Neoplasm That Often Harbors YAP1::NUTM1 Fusions Similar to Their Conventional Counterparts.

ABSTRACT: Cuticular poroma is a rare variant of poroma composed of exclusively or predominantly cuticular cells, namely of large cells with ample eosinophilic cytoplasm. We report 7 cases of this rare tumor identified among 426 neoplasms diagnosed as poroma or porocarcinoma. The patients were 4 males and 3 females, ranging in age from 18 to 88 years. All presented with a solitary asymptomatic nodule. The location included knee (2 cases), shoulder, thigh, shin, lower arm, and neck (each 1). All lesions were surgically removed. No evidence of disease was observed in 5 patients with available follow-up (range 12-124 months).Microscopically, all neoplasms were composed of variably sized, focally closed packed, or interconnecting nodules constituted mostly of cuticular cells. Small poroid cells were a focal feature in 5 tumors, whereas in the remaining 2 cases, poroid cells with conspicuous but still in minority. Five neoplasms were somewhat asymmetric, with irregular outlines. Ductal differentiation and intracytoplasmic vacuoles were seen in 6 tumors. Other features variably encountered were conspicuous intranuclear pseudoinclusions, cystic change, occasional multinucleated cells, increased mitoses, and stromal desmoplasia. Four of the 5 tumors analyzed with next-generation sequencing yielded YAP1::NUTM1 fusions. In addition, various mutations, mostly of unknown significance were identified in one neoplasm.

Wide Local Excision for Eccrine Porocarcinoma of the Forearm.

Eccrine porocarcinoma is a rare and aggressive cutaneous malignancy that develops in the seventh and eight decades of life. We present a 76-year-old male with eccrine porocarcinoma developing from a long standing previously benign lesion who underwent successful treatment with wide local excision. It can also develop de novo, presenting most commonly as a mass or nodule. Tissue biopsy with histopathology is required to confirm the diagnosis. Wide local excision is recommended for local disease. Radiation and chemotherapy can be used as adjuncts in advanced and metastatic disease. Given its rarity, there are no guidelines to direct therapy for locally advance or metastatic disease and for follow-up. Further studies are needed to better understand and guide management of this entity.

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.

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.

An Unusual Case of a Scrotal Porocarcinoma and Review of the Literature.

ABSTRACT: Porocarcinomas are rare tumors derived from the acrosyringium and eccrine ducts, which most commonly occur on the lower extremities or head and neck region in older adults. Microscopically, they invariably demonstrate continuity with the epithelium, showing downgrowth of broad anastomosing bands with more infiltrative intradermal cords and nests of pleomorphic tumor cells with ductal lumina; an associated poroma may also be seen. We report an unusual case of a porocarcinoma arising on the scrotum of a 55-year-old man. Because of the extraordinary location and the presence of keratinizing squamous differentiation, distinction from a squamous cell carcinoma was particularly challenging. Close examination revealed the presence of a co-existing poroma, and immunohistochemistry revealed loss of YAP1 with diffuse nuclear expression of NUT in both the porocarcinoma and poroma components. This finding is particularly suggestive of a YAP1::NUTM1 fusion which has been reported to be highly specific for poroid neoplasms. Distinction of porocarcinoma from its mimics is important due to the frequent aggressive behavior of this neoplasm.

Seborrheic Keratosis With Malignant Transformation (Invasive or Noninvasive Squamous Cell Carcinoma Arising in Seborrheic Keratosis): A Clinicopathologic and Immunohistochemical Study of 11 Cases.

ABSTRACT: Seborrheic keratosis is a common benign neoplasm composed of basaloid keratinocytes. However, little is known about the malignant transformation of the tumor. Eleven cases of seborrheic keratosis with malignant transformation were analyzed. The 11 patients included 5 male patients and 6 female patients with a median age of 75 years at diagnosis (68-90 years). The tumors arose at various sites from the scalp (n = 3) to the lower leg (n = 2). The median tumor size was 12 (10-32) and 40 (20-75) mm in 7 noninvasive and 4 invasive cases, respectively. One patient exhibited in-transit skin metastasis. Histopathology of the malignant components resembled porocarcinoma or inverted follicular keratosis. Bowenoid and pagetoid spreading was frequently observed. The malignant components expressed cytokeratin 5/6 (100%) and GATA3 (73%), but not cytokeratin 7 (0%), cytokeratin 19 (9%), BerEP4 (0%), c-kit (0%), and NUT (0%). No significant immunoreactivity of YAP1 was observed in any of the cases. Mutant-type immunostaining of p53 and PTEN was observed in 91% and 82% of the cases, respectively. An increase in p16 expression was seen in 6 (86%) of the 7 cases with noninvasive carcinoma, although a loss of p16 immunoexpression was seen in the invasive carcinoma component in 3 (75%) of the 4 cases. This study demonstrated that seborrheic keratosis can undergo malignant transformation, particularly in large-sized lesions in elderly patients. Malignant components mimic porocarcinoma or inverted follicular keratosis. Malignant transformation induced by TP53 and PTEN mutations and tumor invasion by CDKN2A inactivating mutations are suggested in this study.

Pigmented eccrine poroma in an atypical location.

Eccrine poroma is the term that includes benign neoplasms of the terminal duct of the eccrine sweat glands, which may clinically and dermoscopically resemble other melanoma and non-melanoma skin tumors. They are often located on the extremities (especially palms and soles), presenting as normochromic or erythematous papules and nodules, measuring up to 2 cm. Pigmented variants are uncommon, accounting for less than 20% of cases. This report describes a 37-year-old man who developed a large pigmented eccrine poroma on his right shoulder, causing diagnostic difficulty. Histopathological examination revealed a nodular neoplasm consisting of small, monomorphic, cuboidal cells, with ample, eosinophilic cytoplasm and well-defined borders, in addition to conspicuous intercellular bridges, with melanin deposits diffusely distributed inside them. The absence of cytological atypia, cellular pleomorphism, increased mitotic activity, and necrosis foci corroborated the diagnostic exclusion of porocarcinoma, which can develop from eccrine poroma.