Immunohistochemical Study of Non-Epithelial Cells in Spiradenoma.

BACKGROUND: Intratumoral lymphocytes are a defining feature of spiradenoma; however, there have only been a few reports on the phenotypic features of non-epithelial cells. Spiradenomas also contain numerous cells positive for S-100 protein and the nature of these cells is still controversial. METHODS: We performed a clinicopathological and immunohistochemical study of ten cases of spiradenoma. RESULTS: The study included seven men and three women. On histopathological examination, spiradenoma could be divided into two types: the vascular proliferating (VP) type (five cases) that featured granulation tissue with edema, vascular proliferation, and inflammatory cell infiltration into the stroma, and the common type (five cases), which did not include any of the aforementioned features. Immunohistochemical staining demonstrated a large number of cells positive for S-100 protein. These included cells with large pale nuclei, dendritic cells, and a few cells with small dark nuclei that were also positive for α-smooth muscle actin. Most of the cells infiltrating the parenchymata of these lesions were CD3-positive. The proportions of CD4-positive and CD8-positive cells were almost equal or CD8-positive cells were predominant. CD20+ cells were observed in five spiradenomas. In painful lesions, there were numerous nerve fibers near the tumor. CONCLUSIONS: In spiradenoma, CD3+ T cells were mainly seen in the parenchyma and CD8+ cells were predominant over CD4+ cells in most cases. CD20+ cells showed focal infiltration of the parenchyma and stroma, especially in VP-type lesions. S-100 protein-positive cells in spiradenoma contained not only Langerhans cells, but also cells with myoepithelial differentiation.

Perineural growth of benign cutaneous sweat gland tumors: a hitherto unrecognized phenomenon unassociated with malignancy.

BACKGROUND: Cutaneous intraneural reactive epithelial proliferations mimicking malignancy include epithelial sheath neuroma, re-excision perineural invasion and reactive neuroepithelial aggregates. Nevertheless, intraneural growth of benign sweat gland tumors has not been reported before. AIMS: To report a predominantly intraneural proliferation of morphologically bland sweat gland tumors, describe their clinicopathological features and correlate them with survival. RESULTS: We analyzed a spiradenoma and a hidradenoma with a prominent intraneural growth, occurring on the back of the 19-year-old woman and on the arm of the 53-year-old woman. Both lesions presented as a painful and slightly raised papule. After complete excision, an uneventful clinical course was observed during the follow-up period of 52 and 54 months. Pathologically, the most striking feature was an almost exclusive intraneural growth within the peripheral nerves of the deep dermis and subcutis. CONCLUSION: We report for the first time the predominantly intraneural growth of benign sweat gland tumors. Although their histogenesis is unknown, perineural displacement due to previous surgery or trauma, as well as development from intraneural embryological epithelial remnants remains possibilities. Long-term follow-up of our patients suggests that intraneural growth of otherwise bland sweat gland tumors does not signify malignancy. Complete excision appears to be sufficient treatment procedure.

Painful eccrine spiradenoma containing nerve fibers: a case report.

An eccrine spiradenoma is a rare benign tumor most often seen in the head, neck and upper trunk of young adults. Although spontaneous pain or tenderness is a typical symptom of eccrine spiradenomas, the underlying mechanism has not been fully elucidated. Here, we report the case of a 47- year-old woman who had a spiradenoma in the subcutaneous tissue of her posterior neck accompanied by agonizing pain which was triggered by pressure. Multiple nodular lesions were excised and the typical histopathological findings of spiradenoma were seen. The histopathological architecture of a disorganized nerve fiber encasing the tumor nodules appeared to correlate with the unique clinical symptom of pain.

Hidradenoma papilliferum with mixed histopathologic features of syringocystadenoma papilliferum and anogenital mammary-like glands: report of a case and review of the literature.

Hidradenoma papilliferum of the anogenital region was previously believed to originate from apocrine glands but has recently been accepted as originating from anogenital mammary-like glands. We describe a case of hidradenoma papilliferum with mixed features of syringocystadenoma papilliferum and mammary-like glands from the left labia majora of a 25-year-old woman. Histopathologically, the lesion showed an epithelial lining with apocrine secretion, and like syringocystadenoma papilliferum, the lesion extended from the epithelium as invaginations into the dermis. Adjacent to this lesion were ductal and glandular structures resembling normal mammary tissue. This review of the literature highlights the heterogeneity and complexity of lesions arising from anogenital mammary-like glands, and this case serves as further documentation of the association between anogenital mammary-like glands and hidradenoma papilliferum.

Syringoid eccrine carcinoma: a clinicopathological and immunohistochemical study of four cases.

BACKGROUND: Syringoid eccrine carcinoma (SEC) is a rare malignant adnexal tumour with variable presentations. AIM: To examine the clinicopathological and immunohistochemical features of SEC. METHODS: Four cases were reviewed by three dermatopathologists and the immunohistochemical profile was examined using antibodies against CK5/6, CK7, CK14, CK20, LMWK, HMWK, EMA, mCEA, p63, ER, PR, AR, S-100 and Ber-EP4. RESULTS: The cases occurred in two men and two women, ranging in age from 61 to 87 years (mean 68.5). Two of the lesions were from the face and two from the trunk. All four lesions were composed of an atypical infiltrative mass with syringoma-like tadpole morphology with ductular differentiation and prominent desmoplasia. Three cases demonstrated perineural invasion and two had positive lymph node metastases. Immunostaining was variable. Immunohistochemistry positivity was as follows: three out of four cases were positive for CK5/6, CK7 (2/4), CK14 (1/3), CK20 (0/2), HMWK (0/2), LMWK (1/2), EMA (3/4), mCEA (4/4), p63 (2/3), ER (2/3), PR (1/2), AR (0/3), S-100 (0/3) and Ber-EP4 (2/2). CONCLUSION: SEC can present on the trunk and are not limited to the head and neck region. In addition to syringoma-like tadpole structures and glandular differentiation, these tumours can also exhibit squamoid and cribriform growth patterns. Immunostaining in SEC is variable and this variability is believed to stem from this tumour's ability to differentiate along multiple routes, including sweat secretory and/or ductal differentiation.

Transition from cylindroma to spiradenoma in CYLD-defective tumours is associated with reduced DKK2 expression.

Patients carrying heterozygous germline truncating mutations in the CYLD gene develop multiple primary hair follicle-related tumours. A highly patterned tumour, termed cylindroma, and a highly disorganized tumour, termed spiradenoma, may both develop in the same patient. Furthermore, histological features of both tumour types have been described within the same tumour specimen. We used three-dimensional computer-aided reconstruction of these tumours to demonstrate contiguous growth of cylindromas into spiradenomas, thus suggesting a transition between the two tumour types. To explore factors that may influence cutaneous tumour patterning, genome-wide transcriptomic analysis of 32 CYLD-defective tumours was performed. Overexpression of the Wnt/ß-catenin signalling pathway was observed relative to normal perilesional tissue. Morphometric analysis was used to investigate the relationship between Wnt pathway-related gene expression and tumour organization. This revealed an association between reduced Dickkopf 2 (DKK2-a negative regulator of the Wnt/ß-catenin signalling pathway) expression and loss of tumour patterning. Reduced DKK2 expression was associated with methylation of the DKK2 gene promoter in the majority of tumour samples assayed. RNA interference-mediated silencing of DKK2 expression in cylindroma primary cell cultures caused an increase in colony formation, cell viability, and anchorage-independent growth. Using these data, we propose a model where epigenetic programming may influence tumour patterning in patients with CYLD mutations.

Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours.

Individuals with germline mutations in the tumour-suppressor gene CYLD are at high risk of developing disfiguring cutaneous appendageal tumours, the defining tumour being the highly organised cylindroma. Here, we analysed CYLD mutant tumour genomes by array comparative genomic hybridisation and gene expression microarray analysis. CYLD mutant tumours were characterised by an absence of copy-number aberrations apart from LOH chromosome 16q, the genomic location of the CYLD gene. Gene expression profiling of CYLD mutant tumours showed dysregulated tropomyosin kinase (TRK) signalling, with overexpression of TRKB and TRKC in tumours when compared with perilesional skin. Immunohistochemical analysis of a tumour microarray showed strong membranous TRKB and TRKC staining in cylindromas, as well as elevated levels of ERK phosphorylation and BCL2 expression. Membranous TRKC overexpression was also observed in 70% of sporadic BCCs. RNA interference-mediated silencing of TRKB and TRKC, as well as treatment with the small-molecule TRK inhibitor lestaurtinib, reduced colony formation and proliferation in 3D primary cell cultures established from CYLD mutant tumours. These results suggest that TRK inhibition could be used as a strategy to treat tumours with loss of functional CYLD.

Alteration of the ß-catenin pathway in spiradenoma.

BACKGROUND: Although skin carcinogenesis has been widely investigated, only limited information is available for epidermal tumors, while even less is known about other skin structures. Alterations in the ß-catenin pathway have been reported in several epidermal tumors, while little is known about in adnexal tumors. This study was performed to assess alterations in the ß-catenin pathway associated with adnexal tumors, and to investigate the mechanisms underlying these alterations. METHODS: ß-Catenin expression in 48 adnexal tumors (trichoepithelioma, trichofolliculoma, pilomatricoma, syringoma, eccrine poroma, spiradenoma, sebaceous hyperplasia and nevus sebaceus) was assessed using immunohistochemistry. The tumors showing intense nuclear reactivity for ß-catenin were further evaluated by immunohistochemistry for ß-catenin degradation complex such as adenomatosis polyposis coli (APC), Axin and glycogen synthase kinase 3ß (GSK-3ß). RESULTS: Intense nuclear immunoreactivity for ß-catenin was observed in pilomatricoma and spiradenoma. Among 12 eccrine spiradenomas, APC was downregulated in 2 (16.7%) cases, and Axin and GSK-3ß were downregulated in 11 (91.7%) and 10 (83.3%) cases, respectively. CONCLUSIONS: This is the first reported analysis of the role of alterations in the ß-catenin pathway in spiradenoma. We suggest that downregulation of Axin and GSK-3ß in the ß-catenin pathway may be an important signaling alteration in the development of spiradenoma.

Diminished number or complete loss of myoepithelial cells associated with metaplastic and neoplastic apocrine lesions of the breast.

The presence of myoepithelial (ME) cells is considered an important feature in the vast majority of benign breast lesions. Recently, a case showing the absence of myoepithelium in a mammary duct with apocrine metaplasia was reported. To investigate the status of ME cells associated with apocrine metaplasia, the distribution of ME cells in 59 metaplastic and intraductal proliferative apocrine lesions was evaluated using immunohistochemical expression of p63 and Calponin. p63 showed a diminished number of ME cells and increased intermyoepithelial nuclear distance in ducts with all variants of apocrine metaplasia and proliferation compared with normal glands. In the majority of cases, Calponin showed a continuous ME layer. In 6 cases, including an apocrine papilloma, there were definitive ME gaps confirmed by both markers, in the absence of atypia and with preservation of the basement membrane. In all cases, there was frequent heterogeneity in the distribution of ME cells in ducts harboring apocrine cells and even in various papillae within papillary lesions. In summary, benign and noninvasive apocrine lesions can show reduction and occasional complete loss of ME cells. This observation is particularly important when evaluating apocrine papillary proliferations, in which the absence of ME cells may lead to overdiagnosis of atypia and/or malignancy. The observation suggests that at least 2 ME markers should be used when evaluating apocrine lesions, and that a malignant diagnosis should be based on features of the proliferating cells until more data become available on the significance, if any, of the absence of ME cells in apocrine lesions.

Cytologic features of hidradenoma in fine needle aspiration biopsies.

OBJECTIVE: To review the cytologic features of hidradenoma to describe criteria that may aid in identification of these tumors at the time of aspiration and allow for a more specific diagnosis than the umbrella term of benign skin adnexal tumor. STUDY DESIGN: Three patients aged 10-23 years presented with mass lesions in the region of the head. Fine needle aspiration (FNA) of these lesions showed the presence of benign skin adnexal tumors. Subsequent histology showed the presence of hidradenomas. A retrospective analysis of the cytology was performed. RESULTS: The following cytomorphologic findings are consistent with the diagnosis of hidradenoma: a cystic component to the aspirate as represented by amorphous background material with or without foam cells and epithelial duct-like cells and tubular structures. In addition, a biphasic cytoplasmic staining pattern with both eosinophilic and clear to basophilic cells may be seen with the Papanicolaou stain in hidradenomas. CONCLUSION: Knowledge of the cytologic features of hidradenoma will allow for correct management of the patient and prevent misdiagnosis as a malignant tumor.

Atypical and malignant hidradenomas: a histological and immunohistochemical study.

The histological features of atypical hidradenoma are worrisome for increased risk of recurrence and possible malignant potential; however, earlier studies with immunohistochemistry or patient follow-up have not been reported. In addition, immunohistochemical analysis of hidradenocarcinoma exists in the literature mainly as case reports and as a single series of six cases. We compare the histological features and Ki-67, phosphorylated histone H3, epidermal growth factor receptor, and Her2/neu expression profiles of 15 atypical and 15 malignant hidradenomas with those of benign hidradenoma and metastasizing adnexal carcinomas. Infiltrative growth pattern, deep extension, necrosis, nuclear pleomorphism, and > or =4 mitoses per 10 high-power fields are specific features of hidradenocarcinomas. Significant difference in mean Ki-67% was observed between benign and malignant hidradenomas (P<0.001), benign and metastasizing adnexal carcinomas (0.002), atypical and malignant hidradenomas (P<0.001), and between atypical hidradenomas and metastasizing adnexal carcinomas (0.002). Significant difference in mean phosphorylated histone H3% was observed between benign and malignant hidradenomas (P<0.001), benign and metastasizing adnexal carcinomas (0.003), atypical and malignant hidradenomas (P<0.001), and between atypical hidradenomas and metastasizing adnexal carcinomas (P<0.001). Mean epidermal growth factor receptor total score was significantly different in benign and atypical hidradenoma when compared with that in metastasizing adnexal carcinoma (P=0.014 and 0.019, respectively). Equivocal or 2+ Her2/neu positivity was observed in one hidradenocarcinoma and in two metastasizing adnexal carcinomas. Receiver operating characteristic curve analysis for Ki-67 and phosphorylated histone H3% positivity reveals statistically significant criterion values of >11.425 and >0.7, respectively, for distinguishing malignant hidradenomas from atypical hidradenomas. Despite the presence of some worrisome histological features, the significantly different immunoprofile from the malignant counterpart suggests that atypical hidradenomas are likely to recur but are unlikely to metastasize. A tumor with Ki-67>11% and/or phosphorylated histone H3>0.7% would likely be a malignant rather than an atypical hidradenoma. The infrequent Her2/neu overexpression in hidradenocarcinoma suggests its limited therapeutic role.

Immunohistochemical differentiation of four benign eccrine tumors.

BACKGROUND: The histogenesis and differentiation of eccrine tumors, including cylindroma, poroma, spiradenoma and syringoma, remains controversial. This controversy may be because of sporadic and incomplete studies of these neoplasms. METHODS: Ten examples each of normal eccrine structures and of four benign eccrine tumors are analyzed with antibodies to cytokeratin (CK) 7, CD34, CK6, CK10, smooth muscle actin (SMA) and CD10. These markers represent two different immunohistochemical stains for each part of the eccrine structure; CK7 and CD34 stain the secretory coil, CK6 and CK10 stain the straight duct and SMA and CD10 stain the myoepithelial cells. This redundancy in staining is performed on four benign eccrine tumors to better interpret the existing literature. RESULTS: We find that CK7 is a sensitive marker for the secretory coil; both cylindromas and spiradenomas express CK7. We also find that CK6 is a marker for the inner ductal cells, while CK10 is a marker for the middle ductal cells; syringomas express both these markers. SMA appears to be a more specific marker for myoepithelial cells surrounding normal eccrine coils, and none of the studied tumors express SMA or CD10. CONCLUSIONS: Our studies suggest that syringomas are tumors of the eccrine duct, while cylindromas and spiradenomas are tumors of the secretory coil.

Hidradenoma papilliferum with a ductal carcinoma in situ component: case report and review of the literature.

Hidradenoma papilliferum (HP) is a benign cutaneous adnexal neoplasm occurring mainly in the anogenital region of adult women and has features analogous to intraductal papilloma of the breast. Malignant change in HP is extremely rare. Only a single case of ductal carcinoma in situ arising in HP has been previously reported. We present a new case of HP which, in addition to the typical appearance of HP, contained a focus of ductal carcinoma in situ that appeared as enlarged pleomorphic epithelial cells having a "blastic" appearance, exhibiting atypical mitotic figures and surrounded by myoepithelial cells. Molecular biological study identified human papillomavirus (HPV)-16, which, it may be argued, may have played a role in the development of the carcinoma.

A case of sebaceoma with extensive apocrine differentiation.

Apocrine differentiation is a rare event in sebaceoma, and only 3 cases have been reported. We report a case of sebaceoma with extensive apocrine differentiation on the scalp in a 73-year-old Japanese woman. The resected tumor was located entirely within the dermis and subcutis as a well-circumscribed, lobulated, solid, and partially cystic mass, measuring 35 mm at the largest diameter. Histopathologically, it was composed of uniform basaloid cells with clusters of sebocytes, squamous islands of ductal structures, and apocrine cells with apparent decapitation secretion. Nuclear atypia of all types of cells was inconspicuous, and mitotic figures were infrequent. We considered the lesion to be a sebaceoma with apocrine differentiation.

POU5F1, encoding a key regulator of stem cell pluripotency, is fused to EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands.

The EWSR1 gene is known to play a crucial role in the development of a number of different bone and soft tissue tumours, notably Ewing's sarcoma. POU5F1 is expressed during early development to maintain the totipotent status of embryonic stem and germ cells. In the present study, we report the fusion of EWSR1 and POU5F1 in two types of epithelial tumours: hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands. This finding not only broadens considerably the spectrum of neoplasms associated with EWSR1 fusion genes but also strengthens the evidence for shared pathogenetic mechanisms in the development of adnexal and salivary gland tumours. Reminiscent of the previously reported fusion genes involving EWSR1, the identified transcript is predicted to encode a chimeric protein consisting of the EWSR1 amino-terminal domain and the POU5F1 carboxy-terminal domain. We assessed the transcriptional activation potential of the chimera compared to the wild-type proteins, as well as activation of transcription through the oct/sox composite element known to bind POU5F1. Among other POU5F1 target genes, this element is present in the promoter of NANOG and in the distal enhancer of POU5F1 itself. Our results show that although the chimera is capable of significant transcriptional activation, it may in fact convey a negative regulatory effect on target genes.

Syringocystadenoma papilliferum with sebaceous differentiation in an intradermal tubular apocrine component. Report of a case.

Syringocystadenoma papilliferum is a benign tumor most commonly located on the scalp or face, and it often arises within a nevus sebaceus of Jadassohn. We describe a 61-year-old man with syringocystadenoma papilliferum developing within a nevus sebaceus with sebaceous differentiation in an intradermal tubular apocrine component of the syringocystadenoma papilliferum. Although some adnexal neoplasms that develop in association with a nevus sebaceus may exhibit conjoint sebaceous, follicular, or apocrine differentiation, reflecting close embryological relations of the folliculosebaceous-apocrine unit, the feature we report on has not previously been described to the best of our knowledge.