Yutaka Narisawa

Periostin promotes chronic allergic inflammation in response to Th2 cytokines

Allergic inflammation triggered by exposure of an allergen frequently leads to the onset of chronic inflammatory diseases such as atopic dermatitis (AD) and bronchial asthma. The mechanisms underlying chronicity in allergic inflammation remain unresolved. Periostin, a recently characterized matricellular protein, interacts with several cell surface integrin molecules, providing signals for tissue development and remodeling. Here we show that periostin is a critical mediator for the amplification and persistence of allergic inflammation using a mouse model of skin inflammation. Th2 cytokines IL-4 and IL-13 stimulated fibroblasts to produce periostin, which interacted with αv integrin, a functional periostin receptor on keratinocytes, inducing production of proinflammatory cytokines, which consequently accelerated Th2-type immune responses. Accordingly, inhibition of periostin or αv integrin prevented the development or progression of allergen-induced skin inflammation. Thus, periostin sets up a vicious circle that links Th2-type immune responses to keratinocyte activation and plays a critical role in the amplification and chronicity of allergic skin inflammation.

Sebaceoma and related neoplasms with sebaceous differentiation : a clinicopathologic study of 30 cases

The classification of benign sebaceous neoplasms has been challenged both by the assertion that sebaceous adenomas are really carcinomas and by difficulties in drawing the boundaries between sebaceomas and other lesions. We performed a clinicopathologic study of 30 cases of basaloid neoplasms with sebaceous differentiation, excluding cases of definite sebaceous carcinoma with severe nuclear atypia invading deep within the subcutaneous tissue and those of ocular sebaceous carcinoma. We tried to classify sebaceous neoplasms in six categories with defined histopathologic criteria. All the neoplasms were characterized by aggregations of basaloid cells admixed with sebocytes and sebaceous duct-like structures located in the dermis with or without connection to the epidermis. The categories were 1) sebaceoma (14 cases); 2) trichoblastoma with sebaceous differentiation (3 cases); 3) apocrine poroma with sebaceous differentiation (2 cases); 4) low-grade sebaceous carcinoma (6 cases); 5) sebaceous carcinoma (4 cases); and 6) basal cell carcinoma with sebaceous differentiation (1 case). The sebaceoma was further subclassified as classic type (12 cases) or verruca/seborrheic keratosis type (2 cases). Although most sebaceomas can be distinguished from other lesions, there are problematic cases. We discuss the histopathologic diagnostic problems associated with sebaceoma and also argue in favor of the concept of sebaceous adenoma.

Periostin, a matricellular protein, accelerates cutaneous wound repair by activating dermal fibroblasts

Abstract:  Cutaneous wound repair is a highly ordered and well‐coordinated process involving various cell lineages and many molecular effectors. Cell–matrix interactions through integrin molecules provide key signals important for wound repair. Periostin is a matricellular protein that may provide signals important during tissue development and remodelling by interacting with several integrin molecules, via the phosphatidylinositol 3‐kinase/Akt and MAP kinase pathways. In this study, we examined the role of periostin in the process of cutaneous wound repair using periostin‐deficient mice and by analysing the effects of periostin on dermal fibroblasts. We first determined the expression profile and localization of periostin in a well‐characterized wound repair model mice. Periostin was robustly deposited in the granulation tissues beneath the extended epidermal wound edges and at the dermal–epidermal junctions in wounded mice. Moreover, periostin‐deficient mice exhibited delayed in vivo wound repair, which could be improved by direct administration of exogenous periostin. In vitro analyses revealed that loss of periostin impaired proliferation and migration of dermal fibroblasts, but exogenous supplementation or enforced periostin expression enhanced their proliferation. Combined, these results demonstrate that periostin accelerates the process of cutaneous wound repair by activating fibroblasts.

Epithelial skirt and bulge of human facial vellus hair follicles and and associated Merkel cell-nerve complex

Many morphological variations of bulge areas, such as knob-like swellings, were found in extracted human facial vellus hairs. In anagen vellus hair of the face bulge areas including these knobs had a band-like dense aggregation of CAM5.2 (K8, 52.5 kDa) reactive Merkel cells. In telogen hair the bulge became indistinguishable from the clubbed or regressed end of the follicle but Merkel cells continued to be abundant. The epithelial hood at sebaceous gland level showed most commonly a skirt-like structure but variations were also observed; these were bamboo joints, tulip flower, and long apron configurations. Merkel cells were found sparsely in these structures. Palisading stockade-like nerve endings were observed surrounding the follicular epithelium under the skirt and around the bulge areas including the knobs. Merkel cells were sparse in the follicular segment corresponding to the attachment of stockade nerve endings.

Sebaceous neoplasms in Muir-Torre syndrome.

A 59-year-old Japanese woman presented with two sebaceous neoplasms on the chest wall and on the left cheek. The patient had a history of ascending colon cancer, and her mother had died of gastric cancer. The histopathologic features of both sebaceous neoplasms were vaguely in accordance with those of sebaceous adenoma and sebaceoma. Based on these findings, we diagnosed the patient as having Muir-Torre syndrome. The sebaceous neoplasm on the chest wall exhibited features of a sebaceous adenoma with a unique cystic appearance, namely cystic sebaceous adenoma, which has been reported as a specific marker for Muir-Torre syndrome (MTS). However, histopathologically, both the sebaceous adenoma and sebaceoma had relatively large, vesicular or heterochromous and crowded nuclei with some pleomorphism and distinct nucleoli associated with some mitotic figures, casting doubt on their benignancy. We show that some or most benign sebaceous neoplasms in MTS might have a high potential for malignant transformation or may be well-differentiated sebaceous carcinomas with low-grade malignancy, mimicking sebaceous adenoma/sebaceoma. This results in difficulties in classification regarding sebaceous neoplasms in MTS.

A high concentration of Merkel cells in the bulge prior to the attachment of the arrector pili muscle and the formation of the perifollicular nerve plexus in human fetal skin

The distribution of Merkel cells in human fetal hair follicles was studied using whole mounts of separated epidermis with attached hair follicles. The technique had the advantage of enabling the elucidation of the spatial relationships of Merkel cells with other cells in the skin. In a 16-week-old fetus the hair anlagen had formed one or two epithelial swellings of variable size. In a 17-week-old fetus sebaceous glands and the bulge of the hair follicle were recognizable and immunoreactive Merkel cells were present in the bulge and surrounding the acrotrichium (intraepidermal follicular canal). In a 20-week-old fetus the sebaceous gland and bulge were well formed and immunoreactive Merkel cells were concentrated in the bulge and infundibulum. In vertical sections of a 20-week-old fetus immunoreactive Merkel cells were also situated in the vicinity of the bulge. Arrector pili muscles were first observable in a 24-week-old fetus being weakly stained with anti-desmin antibody. In a 24-week-old fetus, nerves were also stained within the arrector pili muscles with S-100 protein antibody. In the presumptive arrector pili muscle immunoreactivity for S-100 protein developed before or at the same time as immunoreactivity for desmin. Merkel cells or their products in the bulge may serve as attractants for the growing arrector pili muscle which contain peripheral nerves. Following our report that dermal Merkel cells influence the formation of the dermal nerve plexus, perifollicular Merkel cells near the bulge may also play an inductive and growth-stimulative role for the perifollicular nerve plexus.

Basal cell carcinoma with sebaceous differentiation.

Some authors have used sebaceous epithelioma as a synonym for basal cell carcinoma (BCC) with sebaceous differentiation. However, our review of the literature revealed that definite cases of BCC with sebaceous differentiation that provide adequate clinical and histopathologic information are scarce. We present the case of a 72-year-old woman with a pigmented nodular lesion on her right ala nasi region, clinically diagnosed as pigmented BCC. Histopathologically, this nodular lesion, which was completely excised, showed typical features of BCC. It was noteworthy that within one aggregation of the presented BCC, tiny and small duct-like structures lined by cornified layers with a crenulated inner surface were seen. Vacuolated cells were scattered within a few aggregations, and they had foamy, bubbly cytoplasm and starry nuclei. The vacuolated cells were immunohistochemically positive for epithelial membrane antigen (EMA). These histopathologic findings demonstrated unquestionable sebaceous differentiation in this BCC, namely BCC with sebaceous differentiation, which should be distinguishable from both sebaceoma and sebaceous carcinoma. The small duct-like structures lined by eosinophilic cuticle, indicating apocrine differentiation, were also observed in this BCC.

Rippled-pattern sebaceoma.

A 71-year-old woman had a dome-shaped, slightly erythematous nodule on the anterior scalp. The nodule histopathologically revealed sebaceoma based on the silhouette and cytology. A notable and unique finding was often observed in the aggregations of sebaceoma; an arrangement of small, monomorphous, cigar-shaped basaloid cells in linear rows parallel to one another, resembling the palisading of nuclei of Verocay bodies, namely a rippled-pattern. Although we are not certain that sebaceoma can be clearly separated from trichoblastoma with sebaceous differentiation in all cases, in the present case, the absence of an abundant and densely fibrotic stroma, of follicular differentiation, and of a palisading border in the neoplastic aggregations as well as the presence of many vacuolated cells and tiny duct-like spaces favors the diagnosis of sebaceoma rather than trichoblastoma with sebaceous differentiation. Based on the expression patterns of CKs as well as similar cytological features between germinative cells in our case and immature cells in the mantles of normal vellus follicles, we believe that rippled-pattern sebaceoma is composed of immature sebaceous germinative cells with some foci of advanced sebaceous differentiation (toward the sebaceous duct and sebaceous lobule).

Sebaceous carcinoma with apocrine differentiation.

A 54-year-old male had a dome-shaped and skin-colored nodule on his nose. Histopathologically, we diagnosed this neoplasm as a low-grade sebaceous carcinoma rather than a sebaceoma based on the scanning magnification and cytology. This low-grade sebaceous carcinoma was associated with glandular structures. We regarded the glandular structures as those of apocrine glandular differentiation based on 1) the histopathologic features of the glandular structures formed by columnar luminal cells with evidence of decapitation secretion; 2) the expression of cytokeratin (CK) 19, CK8, CK8/18, and CK7 in the luminal cells; 3) the positive reaction of carcinoembryonic antigen and epithelial membrane antigen on the luminal surface and in the cytoplasm of the luminal cells; and 4) the common embryologic origin of the folliculosebaceous-apocrine unit. We found CK15 expression in undifferentiated cells within the mantles of normal hair follicles, suggesting that sebaceous stem cells might exist in mantles as follicular stem cells exist in bulge areas. Pluripotent stem cells in the folliculosebaceous-apocrine unit can give rise to follicular stem cells, sebaceous stem cells, and apocrine stem cells. Our patients neoplasm showed apocrine glandular differentiation and partial immunohistochemical positivity for CK15 in the neoplastic aggregations. We believe this neoplasm originated from pluripotent stem cells destined to become sebaceous stem cells or from sebaceous stem cells, which also have the ability to differentiate within apocrine glands.

Infundibular (follicular) and infundibulocystic squamous cell carcinoma: a clinicopathological and immunohistochemical study.

Two types of squamous cell carcinoma (SCC), which are considered to show infundibular differentiation, have been described so far; namely, follicular SCC and infundibulocystic SCC. The latter includes (1) a well-differentiated form, (2) a less-differentiated form, and (3) an infiltrative variant. This study examined the clinicopathological features of 8 cases of SCC with infundibular differentiation, which included follicular SCCs and infundibulocystic SCCs (a less-differentiated form and an infiltrative variant). The present study confirmed that these SCCs with follicular differentiation are clinicopathologically distinct from keratoacanthoma. However, one example of infundibulocystic SCC (less-differentiated form) proved to be difficult to distinguish from keratoacanthoma. The relationship between the follicular SCC and the less-differentiated form of infundibulocystic SCC was investigated. At the periphery of the latter lesions, a focus corresponding to the follicular SCC or advanced follicular SCC lesions was seen. Therefore, these 2 types of SCCs are considered to be similar and thus represent the same neoplastic disease. The less-differentiated form of infundibulocystic SCC is considered to be a more aggressive condition. A unified term, infundibular (follicular) SCC, was used to describe these 2 conditions in this study. The clinicopathological features of the infiltrative variant of infundibulocystic SCCs were unique and distinct from the other 2 types of SCCs. This variant of infundibulocystic SCC is therefore considered to be a distinct entity and therefore has been simply called infundibulocystic SCC in this study. Infundibulocystic SCC may therefore be related to either a microcystic adnexal carcinoma or a malignant counterpart of the trichoadenoma of Nikolowski.