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Hidradenoma papilliferum (HP) is a benign epithelial tumor most commonly seen in the vulva. It is proposed to be derived from the anogenital mammary-like glands and is histologically very similar to the mammary intraductal papilloma (IP). Approximately 60% of mammary IPs have activating mutations in either PIK3CA or AKT1, with each gene accounting for 30% of cases. In this study, we screened the mutation statuses of PIK3CA, AKT1, RAS, and BRAF in 30 HPs. The results showed that activating mutations in either PIK3CA or AKT1 were identified in 20 tumors (67%); 19 tumors had PIK3CA mutations (63%; 13 in exon 20 and 6 in exon 9), and 1 had an AKT1 E17K mutation (3%). BRAF V600E mutation was found in an HP that also had a PIK3CA H1047R mutation. No RAS mutation was found. The mutation status was not correlated with the degree of epithelial cell hyperplasia. We conclude that although there might be site-related variations in the mutation frequencies of PIK3CA and AKT1 genes, HP is histologically and also genetically very similar to the mammary IP, suggesting that HP can be viewed as the extramammary counterpart of mammary IP., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: High expression of carbonic anhydrase IX (CA IX) has been reported in clear cell renal cell carcinoma (ccRCC); few studies have reported CA IX expression in other tumours with predominantly clear cell morphology. The aim of study was to examine the expression and diagnostic implications of CA IX in these latter tumours., Methods and Results: An immunohistochemical study was performed of 159 tumours with predominantly clear cell morphology. The results showed that, in addition to primary (25/25) and metastatic (10/11) ccRCC, CA IX was also expressed in breast (2/2), pulmonary (3/5) and hepatic (1/4) clear cell carcinoma, urothelial carcinoma with clear cell change (3/6), clear cell meningioma (4/6) and ependymoma (2/3), haemangioblastoma (10/10), and clear cell hidradenoma (5/6). However, while strong and diffuse positivity for CA IX was observed in ccRCC, clear cell breast carcinoma, haemangioblastoma, and clear cell hidradenoma, the other cases showed predominantly focal positivity for CA IX. In particular, CA IX staining was often seen at the periphery of necrotic areas., Conclusions: Our results indicate that strong and diffuse CA IX expression may be useful for differentiating ccRCC from several clear cell tumours, with the exception of clear cell breast carcinoma, haemangioblastoma, and clear cell hidradenoma., (© 2014 John Wiley & Sons Ltd.)

Adnexal tumours are a rare heterogeneous group of neoplasms, most commonly found in the head and neck region. Although most are benign, malignant adnexal tumours often behave aggressively, resulting in early metastasis. There is increasing interest in the role that nitric oxide (NO) plays in the behaviour of many cancers. It is thought that NO, produced by the enzyme inducible NO synthase (iNOS), facilitates tumour growth and dissemination. iNOS has been studied in the common skin cancers, where its expression correlates with tumour behaviour, but it has not been previously investigated in cutaneous adnexal tumours. An immunhistochemical study was performed using a monoclonal antibody to iNOS in 37 cases of adnexal tumours (19 benign, 18 malignant). iNOS expression was weakly expressed by basal keratinocytes of adjacent skin in all cases and it was variably expressed in the tumours. Malignant tumours had significantly increased iNOS expression when compared to both adjacent skin (P<0.001) and the benign tumour group (P<0.001). No significant difference was found between iNOS expression in benign tumour and adjacent skin (P=0.5). The role of iNOS in this rare group of tumours and the possibility of pharmacologically inhibiting it in the clinical setting warrants further investigation.

Twenty-eight cases of mixed tumour of the skin were studied and subclassified into three types: eccrine (1 case), indeterminate (7), and apocrine type (20). The indeterminate type was defined as mixed tumours having tubuloalveolar patterns with two layers of epithelium, ut without apocrine secretion or pilosebaceous differentiation. Enzyme-histochemical studies were performed on four cases (one indeterminate, three apocrine): in the indeterminate type the tubular epithelial cells showed eccrine differentiation while in the apocrine type tubules were found showing the direction of differentiation to be toward the apocrine gland, but tubules with eccrine differentiation were intermingled in all three. Immunohistochemically, no differences were observed between the indeterminate and the apocrine type: hints of eccrine features were observed in both groups. Thus, the indeterminate type could be an eccrine tumour and the apocrine type showed direction of differentiation toward both eccrine and apocrine glands. It is concluded that mixed tumours of the skin are fundamentally eccrine neoplasmas, and that the apocrine features may represent apocrine metaplasia.

Matrix-degrading metalloproteinases play a major role in tissue remodeling. Recent studies have shown that enzymes of this class are constitutively expressed primarily by stromal cells and not by epithelium. Here we present immunohistochemical evidence that matrilysin is localized within epidermal cells in developing skin and in tumor cells of cutaneous malignancies. The expression of matrilysin protein in developing fetal skin (6-15 weeks) is localized primarily to the germinative basal cell layer of fetal epidermis and early appendageal buds. The buds continue to express matrilysin during mesenchymal invasion. As development progresses (15-19 weeks) matrilysin is concentrated only in cells at the distal portion of the invading follicular and sweat gland appendageal cords. In adult skin, matrilysin was localized specifically to the outer root sheath of the hair follicles and the secretory cells of the eccrine glands but was absent in the epidermis. Nodulocystic, keratotic, adenoid basal cell carcinomas (BCCs) did not express matrilysin. In contrast, in the more aggressive morpheaform (infiltrative) BCCs and recurrent BCCs, matrilysin was localized at the tumor-stromal interface. In squamous cell carcinomas matrilysin was present in tumor cells at the stromal interface surrounding the tumor nests. The demonstration of matrilysin protein in germinal basal cells during fetal skin development and its presence in tumor cells at the stromal junction suggests that this enzyme may contribute to the proteolytic activity associated with cell-extracellular matrix interactions during appendageal development and tumor invasion.

We report a rare case of mucinous carcinoma of the skin with mammary infiltrating carcinoma-like patterns. An 82-year-old Japanese male had a gourd-shaped tumor on his scalp. Histopathologically, the posterior portion of the tumor showed small lobules of cuboidal tumor cells with no atypia floating in mucinous lakes. In the anterior portion, there were solid lobules, cords, and strands of anaplastic tumor cells infiltrating into the surrounding stroma. Enzyme- and immunohistochemistry and electron microscopy confirmed the eccrine origin of this tumor. It is suggested that mucinous carcinoma of the skin can occur in association with diverse histological patterns, analogous to mucinous carcinoma of the breast.

We investigated the existence of lysozyme in various sweat apparatus tumors by adopting the avidin-biotin-peroxidase complex method. Positive reactions for lysozyme were found in four cases of apocrine cystadenoma, hidradenoma papilliferum, and an apocrine sweat apparatus benign tumor resembling "apocrine spiradenoma", all of which derive from apocrine sweat apparatus. On the other hand, in ten cases of syringoma, eccrine hidrocystoma, clear cell hidradenoma, eccrine spiradenoma, and eccrine poroma, which derive from eccrine sweat apparatus, no positive stainings for lysozyme were obtained. In four out of five cases of mixed tumor of the skin, the apocrine type exhibited positive results. Two cases of syringocystadenoma papilliferum were negative for lysozyme. The investigation of lysozyme in various sweat apparatus tumors is useful in determining the direction of differentiation in these tumors.

A case of papillary eccrine adenoma was analysed with immunohistochemical and ultrastructural methods regarding their direction of differentiation. It was found that the majority of the structures show either eccrine ductal or glandular differentiation. There were some segments, particularly in those exhibiting papillary growth, where cells similar to eccrine secretory (clear) cells or cells with characteristics of both ductal basal cells and glandular myoepithelial cells were present.

Immunohistochemical distribution of carbonic anhydrase isoenzyme I and II was studied in mixed tumours of major salivary glands and skin. The normal salivary glands displayed strong carbonic anhydrase activity in both ductal epithelium and serous acinar cells and the serous demilune cells in the submandibular glands, including the eccrine ducts. Pleomorphic adenoma salivary gland origin exhibited positive staining in the inner-layer of epithelial cells of tubular, duct-like and glandular structures. No enzymatic staining was noted in the outer layer of tumour cells in these structures. Spindle tumour cells or the fibroblast-like cells with long cytoplasmic processes identified in the adjacent hyalin and myxomatous stroma were rarely positive, while chondroidal and osteo-chondroidal cells were highly reactive. Mixed tumours of eccrine gland origin showed the most reactive staining cells scattered throughout neoplastic epithelium in all tissues examined. Immunohistochemical stainability was usually higher for carbonic anhydrase II than I for both normal and tumour tissues. The biological roles of the distribution profiles of carbonic anhydrase are discussed.

Tubular apocrine adenoma is a rare, benign apocrine tumour of the skin, histologically distinct from other epithelial proliferations, showing apocrine differentiation. A new case of this uncommon lesion is reported herein and a review of the literature concerning this tumour is made.

Little has been written about eccrine hidrocystomas since the condition was first described in 1893. This paper presents a "classic" case of this disorder, and reviews current knowledge about clinical and histologic features. New information concerning the etiology, histochemistry, and electron microscopy of eccrine hidrocystomas is presented, as well as the first description of an effective, safe, and rational method of treatment.

Immunohistochemical distribution of carbonic anhydrase II (CA) in mixed tumours and adenomas of sweat gland origin and in sebaceous adenomas was demonstrated by the PAP method. Normal sweat glands, both eccrine and apocrine, clear cells of the secretory coils, and ductal epithelial cells all showed conspicuous staining for CA, and sebaceous glands were also positive. Mixed tumours of the skin indicated strongly positive staining for CA in the luminal cells of tubular and duct-like or cystic structures, while most of the other tumour cells were negative. In solid or massive foci, CA positive cells were found scattered among the cellular mass. Sebaceous adenomas were usually moderately positive for CA throughout the tumour.

The histochemical and electron microscopic findings in seven cases of dermal duct tumor are described. All seven of the patients were elderly, and five were women. The tumors were small flesh-colored or red papules located most often on the head and neck region. Intense phosphorylase and moderate respiratory enzymes characterized the histochemical reaction of the tumors. The following three types of tumor cells were recognized ultrastructurally: clear, dark, and luminal. The tumor was principally composed of clear cell proliferation around a regular ductal lumen. In addition, melanocytes, Langerhans' cells, and lymphocytes were occasionally seen within the tumor masses. An intact basal lamina and few hemidesmosomes with no detectable actin-like microfilaments were the features of the tumor-stroma interface. Our study results showed that the dermal duct tumor is a benign tumor with eccrine dermal ductal differentiation.

Only one case of clear-cell syringoma has been reported in the United States, whereas six cases have already been reported in Japan, and ours described herein constitute an eighth and ninth. Eight of the total of nine cases of clear-cell syringoma were associated with diabetes mellitus. In this report, we summarize these nine cases and emphasize the close relationship between clear-cell syringoma and diabetes mellitus.