Primary cutaneous apocrine carcinoma with RARA::NPEPPS fusion.

Gene fusions have emerged as crucial molecular drivers of oncogenesis in a subset of cutaneous adnexal neoplasms, including poroid neoplasms and hidradenomas. We present a unique case of primary cutaneous apocrine carcinoma harboring RARA::NPEPPS fusion, broadening the spectrum of fusion-associated cutaneous adnexal neoplasms. A 77-year-old African American male presented with an ulcerated thigh nodule. Histopathologically, the predominantly dermal-based adenocarcinoma exhibited papillary, micropapillary, cribriform, and solid growth patterns with central comedonecrosis, set in a fibrotic/desmoplastic stroma. Immunophenotypically, the neoplastic cells were positive for CK7, CK19, GATA3, TRPS1, HER2, CK5/6, calretinin, p63, and DPC4 (no loss), while lacking immunoreactivity for CK20, CDX2, TTF1, napsin-A, PAX8, arginase-1, adipophilin, NKX3.1, uroplakin II, and D2-40. The immunoprofile and clinical and radiographic absence of any internal malignancy, including breast carcinoma, except for multiple lymphadenopathy, supported the diagnosis of primary cutaneous apocrine carcinoma. Next-generation sequencing unveiled the novel RARA::NPEPPS fusion, concurrent ERBB2 amplification, and multiple somatic mutations involving TP53, CDKN2A, BRCA2, PIK3CA, PIK3R1, and others. The patient developed widespread metastases within a year after the initial diagnosis, indicating the tumor's aggressive behavior. This novel fusion, unprecedented in any human malignancies including primary cutaneous adnexal carcinomas, may suggest a potential new subtype within primary cutaneous adnexal carcinoma.

NUT Expression Is of Diagnostic Utility in the Distinction of Digital Papillary Carcinoma From Poroid Hidradenoma.

ABSTRACT: The distinction between digital papillary adenocarcinoma (DPAC) and benign cutaneous adnexal tumors is clinically important and can be challenging. Poroid hidradenoma frequently occurs at acral sites and can show a number of histological features, which overlap with digital papillary adenocarcinoma. Recent work has shown that YAP1-NUTM1 fusions are frequent in poroid hidradenoma and are associated with nuclear protein in testis (NUT) expression by immunohistochemistry. We evaluated the expression of NUT-1 by immunohistochemistry in 4 cases of DPAC and 4 cases of poroid hidradenoma. Three of 4 cases of poroid hidradenoma showed strong NUT-1 expression, with no staining in any of the cases of DPAC. These results suggest that NUT-1 immunohistochemistry may be a useful additional tool in evaluating this differential diagnosis.

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.

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.

Value of Immunohistochemistry to Differentiate Digital Papillary Adenocarcinoma From Acral Hidradenoma With Papillary Structures.

ABSTRACT: Digital papillary adenocarcinoma is a malignant adnexal tumor with a predilection for acral sites. Hidradenoma is a benign solid and cystic sweat gland neoplasm with focal ductal and glandular differentiation and good outcomes. Hidradenomas can occur at acral sites and show papillary structures; for this reason, they are included in the differential diagnosis of digital papillary adenocarcinoma, and immunohistochemistry is a valuable tool in this scenario. We described a case of a 43-year-old man with an epithelial tumor showing papillary structures in the intermediate phalanx of the fourth finger. There was diffuse positivity for p63 and negativity for S100 protein, suggesting that this tumor was an acral hidradenoma with papillary structures.

Comparison of Immunohistochemical Expression of Cytokeratin 19, c-KIT, BerEP4, GATA3, and NUTM1 Between Porocarcinoma and Squamous Cell Carcinoma.

ABSTRACT: Distinguishing porocarcinoma from squamous cell carcinoma (SCC) is clinically significant; however, differential diagnosis can often be challenging. This study sought to confirm the diagnostic utility of cytokeratin 19, c-KIT, BerEP4, GATA3, and NUTM1 immunohistochemistry in distinguishing porocarcinoma from SCC. Immunohistochemical analysis of cytokeratin 19, c-KIT, BerEP4, GATA3, and NUTM1 in 14 porocarcinomas and 22 SCCs was performed; the extents and intensities of expression of these markers were recorded. The statistical associations of the immunoexpression between porocarcinoma and SCC were analyzed using the Pearson χ2 test. Cytokeratin 19 was positive in 13 (92.9%) of 14 porocarcinomas, and for all the positive cases, staining was strong and evident in >20% of the tumor cells. By contrast, 9 (40.9%) of 22 SCCs expressed cytokeratin 19 (P = 0.0018), of which 6 showed extremely focal (≤10% of the tumor cells) expression. Of the 14 porocarcinomas, 11 (78.6%) cases showed c-KIT positivity, whereas only 3 of 22 SCCs (13.6%) expressed c-KIT focally (P = 0.0001). In addition, BerEP4 immunostaining differed between porocarcinomas and SCCs (57.1% vs. 9.1%, respectively; P = 0.0017). However, no significant difference between the groups was reported in terms of GATA3 expression (57.1% vs. 72.7%, respectively; P = 0.3336). NUTM1 was expressed in 4/14 (28.6%) porocarcinomas but not in the SCCs. Immunohistochemistry for cytokeratin 19, c-KIT, and BerEP4 could be helpful in distinguishing porocarcinomas from SCCs. In addition, NUTM1 immunoexpression is highly specific, although not sensitive, to porocarcinomas. GATA3 immunohistochemistry has no meaningful implications in the differential diagnosis of porocarcinoma and SCC.

Glioma-Associated Oncogene-1 Expression in Basal Cell Carcinoma and Its Histologic Mimics.

ABSTRACT: Basal cell carcinoma (BCC) is the most common skin cancer, and it has numerous histologic mimics with variable prognoses and treatments. Although some immunohistochemical stains can be used for the differential diagnosis of BCC, variability and overlap in results can complicate their interpretation. Immunohistochemical staining for glioma-associated oncogene-1 (Gli-1) was performed on 26 nodular BCCs, 22 infiltrative BCCs, 9 basaloid squamous cell carcinomas, 12 desmoplastic trichoepitheliomas, 19 Merkel cell carcinomas, 11 sebaceous carcinomas, 10 cylindromas, 14 spiradenomas, 12 adenoid cystic carcinomas (AdCC), and 1 solitary trichoepithelioma. Strength of staining was scored as 0, 1+, 2+, or 3+, and distribution of staining was categorized as diffuse, multifocal, or focal. Strong, diffuse Gli-1 expression was seen in all tumors with basal epidermal-type differentiation, including BCC, trichoepithelioma, and basaloid squamous cell carcinoma. All examples of Merkel cell carcinoma were negative for cytoplasmic expression. Seven out of 11 sebaceous carcinomas were negative for Gli-1, and the remaining 4 showed 1+ expression. Cylindroma, spiradenoma, and AdCC, each an adnexal skin tumor, showed the most variable staining, but with cylindroma and spiradenoma demonstrating comparable labeling patterns. Overall, although Gli-1 may not distinguish between basal epidermal-type tumors, it may have a role in separating that group from lesions with adnexal differentiation, particularly sebaceous carcinoma, but also cylindroma, spiradenoma, and AdCC. Any cytoplasmic staining seems to exclude the diagnosis of Merkel cell carcinoma.

Clear Cell Proliferations of the Skin: A Histopathologic Review.

ABSTRACT: Cutaneous clear cell proliferations encompass a heterogenous group of several primary cutaneous neoplasms and metastatic tumors with different histogenesis. Many of these clear cell proliferations may seem strikingly similar under the microscope resulting in challenging diagnosis. In many of these clear cell lesions, the reason for the clear or pale appearance of proliferating cells is unknown, whereas in other ones, this clear cell appearance is due to intracytoplasmic accumulation of glycogen, mucin, or lipid. Artifacts of tissue processing and degenerative phenomenon may also be responsible for the clear cell appearance of proliferating cells. Awareness of the histopathologic findings as well as histochemical and immunohistochemical techniques are crucial to the accurate diagnosis. This review details the histopathologic features of clear cell cutaneous proliferations, classifying them according their type of differentiation and paying special attention to the histopathologic differential diagnosis among them.

Next-generation sequencing implicates oncogenic roles for p53 and JAK/STAT signaling in microcystic adnexal carcinomas.

Microcystic adnexal carcinoma is a locally aggressive sweat gland carcinoma characterized by its infiltrative growth and histopathologic overlap with benign adnexal tumors, often posing challenges to both diagnosis and management. Understanding the molecular underpinnings of microcystic adnexal carcinoma may allow for more accurate diagnosis and identify potential targetable oncogenic drivers. We characterized 18 microcystic adnexal carcinomas by targeted, multiplexed PCR-based DNA next-generation sequencing of the coding sequence of over 400 cancer-relevant genes. The majority of cases had relatively few (<8) prioritized somatic mutations, and lacked an ultraviolet (UV) signature. The most recurrent mutation was TP53 inactivation in four (22%) tumors. Frame-preserving insertions affecting the kinase domain of JAK1 were detected in three (17%) cases, and were nonoverlapping with TP53 mutations. Seven (39%) cases demonstrated copy number gain of at least one oncogene. By immunohistochemistry, p53 expression was significantly higher in microcystic adnexal carcinomas with TP53 mutations compared with those without such mutations and syringomas. Similarly, phospho-STAT3 expression was significantly higher in microcystic adnexal carcinomas harboring JAK1 kinase insertions compared with those with wild-type JAK1 and syringomas. In conclusion, microcystic adnexal carcinomas are molecularly heterogeneous tumors, with inactivated p53 or activated JAK/STAT signaling in a subset. Unlike most other nonmelanoma skin cancers involving sun-exposed areas, most microcystic adnexal carcinomas lack evidence of UV damage, and hence likely originate from a relatively photo-protected progenitor population in the dermis. These findings have implications for the biology, diagnosis, and treatment of microcystic adnexal carcinomas, including potential for therapeutic targeting of p53 or the JAK/STAT pathway in advanced tumors.

Syringocystadenoma papilliferum associated with verrucous carcinoma of the skin in the same lesion: Report of four cases.

The association of syringocystadenoma papilliferum (SCAP) with verrucous carcinoma (VC) of the skin in the same lesion is a rare, but well-documented event. Although human papillomaviruses (HPV) have been proposed to have an etiologic role in the development of the verrucous proliferations associated with SCAP, most of the immunohistochemical and molecular studies have failed to show the presence of their genomic material in these lesions. We report a series of four cases of SCAP associated with VC in anogenital lesions. In two of the cases, we demonstrated the presence of the BRAF V600E mutation by polymerase chain reaction and immunohistochemistry, both in the glandular and in the squamous component. No HPV-related histopathologic changes were found, nor could the presence of viral DNA be showed.

Bowen disease with invasive mucin-secreting sweat gland differentiation: Report of a case and review of the literature.

Bowen disease (BD) with divergent adnexal differentiation is a rare composite cutaneous tumor featuring different phenotypic elements. Sebaceous, poroid and trichilemmal invasive components have been described in this setting and very infrequent reports of mucinous glandular differentiation are extant. Clinically, these tumors are not sufficiently distinctive to enable recognition without histopathological evaluation. From a microscopic perspective, care must be taken to exclude a collision tumor as well as other combined cutaneous neoplasms featuring squamous and glandular differentiation. Direct continuity between the two epithelial phenotypes helps to establish the correct diagnosis and generates interesting speculation about the pathogenesis of these and other epithelial skin tumors. We describe a case of BD in continuity with an invasive adenocarcinoma exhibiting mucinous sweat gland differentiation on the face of an elderly man. Details of the case are outlined with the objective of adding to a scant literature on this topic.

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.

Mixed pleomorphic lobular and apocrine carcinoma of the breast: A case report suggesting pathogenesis.

Pleomorphic lobular carcinoma (PLC) of the breast is a variant of lobular carcinoma, characterized by loss of E-cadherin expression and high-grade morphologies. Whether the pathogenesis of PLC is in the ductal or the lobular lineage has been discussed. In this report, a case of PLC combined with apocrine carcinoma is presented. Histologically, the tumor showed two distinct carcinoma components: one was a typical apocrine carcinoma, and the other was a pleomorphic invasive lobular carcinoma. The former showed complete membranous expression of E-cadherin, whereas the latter aberrantly expressed it not on the cell membrane, but in the cytoplasm. Both components were triple-negative and strongly positive for GCDFP-15, suggesting apocrine differentiation. The intraductal component showed only a feature of apocrine ductal carcinoma in situ. This case suggests that apocrine carcinoma could be an origin of PLC.

Homeobox transcriptional factor engrailed homeobox 1 is expressed specifically in normal and neoplastic sweat gland cells.

AIMS: A number of homeobox transcriptional factors are utilised as organ-specific markers in the histopathological diagnosis of neoplasms. We have screened a homeobox gene that is expressed specifically in normal sweat gland cells and is useful for the histopathological diagnosis of sweat gland neoplasms. METHODS AND RESULTS: By screening an open database resource of The Human Protein Atlas, 37 genes among the 235 homeobox transcriptional factors were found to be expressed specifically in the skin. Among those 37 genes, the engrailed homeobox 1 (En1) was expressed in normal eccrine glands but not in the epidermal keratinocytes. Expression of En1 was found throughout the eccrine glands, but not in the apocrine secretory coils, sebaceous glands or hair follicles. Expression of En1 was examined immunohistochemically in 111 cases of cutaneous epithelial neoplasms. All nine cases of poroma, seven cases of spiradenoma and six cases of syringoma, which are considered to differentiate towards eccrine glands, showed positive nuclear staining in most of the tumour cells. Sebaceous gland and hair follicle tumours were immunonegative. En1 was expressed focally in the epidermal neoplasms of seborrheic keratosis and squamous cell carcinoma. CONCLUSION: Engrailed homeobox 1 was expressed specifically in normal eccrine glands and was expressed in most of the tumour cells of sweat gland neoplasms with eccrine gland differentiation. En1 was expressed focally in epidermal neoplasms; however, it was absent in sebaceous or hair follicle neoplasms. These findings will help in the histopathological diagnosis as well as understanding of the histogenesis of sweat gland neoplasms.

Microcystic adnexal carcinoma of the orbit mimicking pagetoid sebaceous gland carcinoma.

Microcystic adnexal carcinoma (MAC) is a rare malignancy of sweat glands that has been reported most often on the face in the form of a cutaneous lesion, with the potential for deeper invasion. The synonyms of MAC include sclerosing sweat duct carcinoma, syringomatous carcinoma, and malignant syringoma. Clinically, MAC in the periocular area has been misdiagnosed as basal cell carcinoma, squamous cell carcinoma, or even chalazia. We report a case of MAC presenting clinically as sebaceous gland carcinoma with pagetoid spread for the first time in literature.

A case report of a primary apocrine adenocarcinoma of the eyelid with literature review.

INTRODUCTION: Primary Apocrine adenocarcinomas (PAA) are very infrequent tumors that are often confused initially with benign lesions. Little is known about this disease and there is still much to be clarified. We present a case of PAA on the eyelid successfully treated with surgery alone and a literature review regarding what is currently described about this disease. METHODS: Noncomparative, retrospective case report of a patient with PAA on the eyelid succesfully treated with surgery alone and a literautre review. RESULTS: A 91-year-old man with a 2 months lesion on the upper left eyelid was treated with surgery alone with oncological margins of 5mm. The Hystopathology diagnosis was a PAA of the eyelid and free margins were obtained. After 12 months of follow-up, the patient does not show any signs of local recurrence or distant metastasis. A review of the literature suggests these tumors are located more frequently in the axilla (50%) and secondly in the head and neck (35%), with similar distribution in the upper (41%) and lower eyelid (45%). The most commonly used treatment is surgical excision, but radiotherapy and chemotherapy have also been used with variable results. CONCLUSIONS: PAA is a very rare and aggressive tumor. Because it is so infrequent, treatments are based on the sporadic cases encountered in the literature. As more cases are reported, more can be elucidated about the characteristics of this tumor, its behavior and best treatment choice and this may allow progress in the understanding and management of this disease.

Polarizable crystals in apocrine sweat gland tumors: A series of 3 cases.

Polarizable calcium oxalate (CaOx) crystals have been well documented in breast biopsies, generally associated with benign apocrine metaplasia. In contrast, polarizable crystals are only rarely reported in skin adnexal neoplasms. We report 3 different cases of sweat gland tumors with polarizable crystals morphologically suggestive of CaOx: 1 apocrine hidrocystoma and 2 tubular apocrine adenomas. The histologic features were examined in 3 cases. Clinical presentation summary included 2 males and 1 female, ages 53 to 74 years, with lesions located on the left cheek, inferior vertex scalp and the left eyebrow. All 3 cases showed polarizable, geometric, plate-like and fractured, colorless crystals within the lumens of the neoplasm. Of note, these crystals were seen only on the toluidine blue-stained section of Case #1, but were not present on the corresponding permanent section. We hypothesize that polarizable crystals may be present in sweat gland neoplasms more often than previously documented, but that they may often dissolve with routine processing, accounting for their rare visibility. We highlight this rare finding, and suggest that it may be underreported. We only noted this finding in benign apocrine tumors; further investigation would be necessary to determine whether these crystals are also seen in other cutaneous adnexal neoplasms.

SOX10 immunohistochemistry in sweat ductal/glandular neoplasms.

BACKGROUND: SOX10 is a newer Schwannian and melanocytic marker that has generated great interest for its relative sensitivity and specificity in the diagnosis of neural crest-derived tumors. Previous studies with SOX10 have shown positive immunohistochemical expression in cutaneous eccrine glands and negative expression in eccrine ducts, apocrine glands and hair follicles. Thus, we hypothesized that some sweat gland tumors of presumed eccrine origin would be positive for SOX10, whereas apocrine-derived sweat gland tumors would not. METHODS: A mouse monoclonal anti-SOX10 (clone BC34: Biocare Medical; Concord, California) immunohistochemical antibody was performed on various sweat gland tumors and basal cell carcinoma. RESULTS: SOX10 showed positivity in spiradenomas (13/13), cylindromas (9/10), hidradenoma papilliferum (10/10), syringocystadenoma papilliferum (8/10), apocrine adenomas (8/10), and negativity in poromas (0/12), syringomas (0/10), and basal cell carcinomas (0/13). There was mixed staining of hidradenomas (6/15). CONCLUSIONS: SOX10 immunohistochemistry may be of utility in distinguishing some of the varying adnexal tumors from each other, and from basal cell carcinoma (BCC), but given the staining of both apocrine and eccrine tumors, does not seem to provide information as to their origins as either eccrine or apocrine tumors.