Myocardial Vasculitis Associated With the Immune Checkpoint Inhibitor Pembrolizumab.

Recent developments in immune checkpoint inhibitors (ICIs) have provided new treatment strategies for advanced cancer. However, ICIs lead to an imbalance between T cell-mediated inflammatory responses and immune tolerance in the myocardium. Here we report the first case that implicates the contribution of ICI-induced vasculitis to myocardial injury. (Level of Difficulty: Intermediate.).

Cutaneous mucinous nodule in a patient with rheumatoid arthritis.

We report a cutaneous mucinous nodule on the inflamed elbow joint in a patient with rheumatoid arthritis (RA). The lesion is clinically characterized by a continuous flow of mucinous exudates from the nodule, and histologically by an extensive mucin deposition and proliferations of the fibroblastic cells and mononuclear cells. The histological findings suggest the histogenesis of this unique nodule is related to extralesional proliferation of synovial lining cells consisting of monocyte-macrophage lineage cells and fibroblast-like cells which potentially produce synovial fluid. Four patients have been hitherto reported in the published work and all of them have been associated with RA. The condition may be one of the characteristic skin manifestations of RA.

Proliferation of HSP47-positive skin fibroblasts in dermatofibroma.

BACKGROUND: The cell origin of dermatofibroma (DF) has not been clarified satisfactorily. This study was undertaken to assess the distribution of fibroblasts and the relationship between fibroblasts and other constituent cells in DF by 47-kDa heat-shock protein (HSP47), a cell marker for skin fibroblast. METHODS: Immunohistochemistry was performed to evaluate the expression of HSP47 and other cell markers in histological variants of DF. RESULTS: Almost all spindle-shaped cells showed strong immunoreactivity for HSP47 in DF. In the fibrocollagenous type, a common type of DF, HSP47-positive fibroblasts were the major constituent cells. In the cellular and atypical types, many constituent cells were positive for HSP47. Huge cells with bizarre nuclei, which are distinctive of the atypical type, showed immunoreactivity for HSP47, not for CD68 or factor XIIIa (FXIIIa). In the histiocytic and angiomatous types, CD68-positive histiocytes were the major constituent cells, but many scattered spindle cells were positive for HSP47. FXIIIa-positive dermal dendritic cells were increased, irrespective of DF variants, whereas the cell number varied from case to case. CONCLUSIONS: Skin fibroblast is one of the major constituent cells in DF, and DF may be composed chiefly of two types of cell lineages, fibroblasts and bone marrow-derived monocyte/macrophages (dermal dendritic cells and/or histiocytes).

Accumulation of elafin in actinic elastosis of sun-damaged skin: elafin binds to elastin and prevents elastolytic degradation.

Elafin has a primary structure with two functional domains; a transglutaminase substrate domain at the N-terminus and a protease inhibitor domain at the C-terminus. Elafin expression has so far been reported only for epithelial tissues. Accumulation of elafin was immunohistochemically detected in the actinic elastosis of sun-damaged skin. Exposure of normal skin to UVA induced elafin expression that colocalized with elastic fibers. Incubation of synthetic transglutaminase substrate domain of elafin and elastin molecules in the presence of tissue transglutaminase in vitro resulted in the formation of a higher molecular complex on SDS-PAGE. Elafin expression was not detected in normal cultured skin fibroblasts, but was induced by UVA irradiation at both messenger RNA and protein levels. When radiolabeled insoluble elastin was incubated with recombinant full-length elafin and tissue transglutaminase, insoluble elastin became more resistant to neutrophil elastase digestion. These results indicate that (1) dermal fibroblasts potentially express elafin on UV irradiation, (2) UV-mediated elafin interacts with elastin, and (3) the elafin-elastin complex protects elastic fibers from elastolytic degradation, leading to the accumulation of elastic fibers in the actinic elastosis of sun-damaged skin. The transglutaminase substrate moiety of elafin plays an important role in anchoring elafin at its proper sites of action during UV-induced aging processes.

Bone morphogenetic protein-mediated type II collagen expression in pilomatricoma and cutaneous mixed tumor.

BACKGROUND: We have previously reported that type II collagen deposition in overlying dermo-epidermal junction (DEJ) of pilomatricoma is mediated by bone morphogenetic protein 2/4 (BMP 2/4) expressed by shadow cells (SCs) of pilomatricoma. OBJECTIVE: This time, we studied the expression of type II collagen and BMP in a large number of cases of pilomatricoma and extended our study to cutaneous mixed tumor (CMT). RESULTS: We found type II collagen deposition in the overlying DEJ (16 of 50 cases) and in the SCs (19/50) of pilomatricoma. The number of case of type II collagen deposition in DEJ (DEJ(+)) and in SCs (SC(+)) of pilomatricoma correlated to the chronological stage of pilomatricoma. We also found type II collagen deposition in overlying DEJ (two of 11) and in the stromal chondroid tissue (four of 11) of CMT. BMP 2 was expressed in most cases of pilomatricoma (37/50) and CMT (seven of 11). CONCLUSIONS: The expression of type II collagen in pilomatricoma is dependent upon the chronological stage of pilomatricoma. Type II collagen expression in the overlying DEJ and chondroid matrix in CMT may be induced by BMP via the same mechanism as in pilomatricoma.

Abnormal accumulation of inter-alpha-trypsin inhibitor and hyaluronic acid in lichen sclerosus.

Inter-alpha-trypsin inhibitor (ITI) is a recently identified extracellular hyaluronic acid (HA)-binding protein which greatly improves extracellular HA stability. In lichen sclerosus (LS), a broad hyalinized zone of superficial dermis is the most prominent pathological change. To assess the pathogenic role of ITI in accumulation of HA in a broad hyalinized zone in LS, we examined the expression and localization of ITI and HA immunohistochemically. In LS lesional skin sections, ITI staining revealed a strong, diffuse immunoreactivity predominantly in the upper dermis, whereas no staining was detected in normal skin sections. HA staining clearly showed positive reactivity in the superficial dermis, the epidermis, and occasionally the perivascular inflammatory infiltrate in LS skin sections. In normal skin, HA was present only in the epidermis. Double staining for ITI and HA demonstrated that ITI was localized in the areas where HA was abnormally deposited in the superficial dermis of LS. Other HA-binding proteins, CD44 and versican, did not show enhanced staining in the upper dermis of LS compared to normal skin specimens. These findings strongly suggest that ITI is closely implicated in the accumulation of HA in a broad hyalinized zone of the superficial dermis of LS.

Treatment of eosinophilic pustular folliculitis with tacrolimus ointment.

We describe a patient with eosinophilic pustular folliculitis who partially responded to oral indomethacin, but intermittently experienced new eosinophilic pustular folliculitis lesions. Treatment with tacrolimus ointment 0.1% resulted in the rapid improvement of each recurred lesion and allowed withdrawal of indomethacin. To our knowledge, this is the first report of the use of topical tacrolimus in the treatment of eosinophilic pustular folliculitis.

Lichen amyloidosus with subepidermal blister formation.

We report a 74-year-old man who presented with multiple, itchy keratotic papules or plaques on the trunk and extremities. Erosions and vesicles were also intermingled on keratotic lesions. Histopathologic examination of biopsy specimens taken from three different lesions showed a subepidermal blister with amyloid deposits in the dermal papillae. No systemic disease or involvement of other organs was detected. The clinical and histological findings were compatible with a bullous variant of lichen amyloidosus. Although bullous amyloidosis has been reported in systemic amyloidosis, bullous lesions associated with lichen amyloidosus are very rare.

Punctate palmoplantar keratoderma with pigmentary lesions on the dorsa of feet and ankles: successful treatment with a combination of low-dose oral etretinate and topical calcipotriol.

We describe a patient with typical keratotic lesions of punctate palmoplantar keratoderma on the hands and feet and unique pigmentary lesions on the dorsa of the feet and ankles. A combination of low-dose oral etretinate (10 mg/day) and calcipotriol ointment 0.005% resulted in a complete regression, whereas pigmentary lesions on the dorsa of the feet and ankles did not change during the treatment.

Subcutaneous granuloma pyogenicum in patients with antiphospholipid antibodies.

We describe 2 cases of subcutaneous granuloma pyogenicum occurring in patients with antiphospholipid antibodies. The 2 patients had asymptomatic nodules with histopathological findings of a typical subcutaneous granuloma pyogenicum. In addition, case 1 was diagnosed as primary antiphospholipid syndrome with livedo reticularis, superficial thrombophlebitis, thrombocytopenia, cerebral and pulmonary infarcts and renal involvement. Case 2 had no clinical manifestations of vascular occlusive diseases, although anticardiolipin antibody levels were highly positive. To our knowledge, these are the first reported cases of subcutaneous granuloma pyogenicum associated with antiphospholipid antibodies. Antiphospholipid-antibody-mediated thrombosis or immunological mechanisms may be involved in subcutaneous granuloma pyogenicum in our cases.

Type II collagen accumulation in overlying dermo-epidermal junction of pilomatricoma is mediated by bone morphogenetic protein 2 and 4.

Pilomatricoma consists of the cells differentiating towards hair matrix cells. Immunohistochemical study revealed the deposition of type II collagen in the overlying dermo-epidermal junction (DEJ) of this benign tumor. Proalpha(1)(II) mRNA was detected by RT-PCR in the overlying epidermal layer but not in the dermal layer prepared from the lesional skin of pilomatricoma. The neutral salt-soluble proteins extracted from the tumor of pilomatricoma induced proalpha(1)(II) mRNA in the cultured human keratinocytes but not in the cultured dermal fibroblasts. Bone morphogenetic protein 2 or 4 (BMP2 or 4) was immunohistochemically detected in some shadow cells of pilomatricoma. Recombinant BMP2 and BMP4 were found to induce proalpha(1)(II) mRNA concentration dependently in the cultured human keratinocytes but not in the cultured fibroblasts. Proalpha(1)(II) mRNA induced by BMP2 and in cultured keratinocytes contained exon 2, indicating that the mRNA species is non-chondrogenic type IIA form. The results strongly suggest that BMP2 or 4 expressed in pilomatricoma is responsible for the induction of proalpha(1)(II) collagen mRNA in the overlying epidermal cells resulting in the deposition of type II collagen in the DEJ. When human keratinocytes were cultured on type II collagen substratum in vitro, the cell proliferation was accelerated at the early period of culture but was inhibited at the late period of culture, whereas the cell proliferation was persistently accelerated by type I or IV collagen substratum. Type II collagen deposition in the DEJ may potentially exert profound effects on keratinocyte proliferation and differentiation.

Coexistence of spindle cell lipoma and ordinary lipoma.

We report a patient with a spindle cell lipoma on the nape and three ordinary lipomas on the abdomen and extremities. The coexistence of spindle cell lipoma and ordinary lipoma in a single patient is rare. Abundant CD34-positive spindle cells and mast cells were found in the spindle cell lipoma, but in the ordinary lipomas, only a small number of CD34-positive spindle cells were found in the interstitial connective tissue and no mast cells were seen. Because mast cells are known to stimulate mesenchymal cell proliferation and collagen production, mast cell infiltration may be a trigger for the proliferation of CD34-positive spindle cells, leading to the conversion of ordinary lipoma into spindle cell lipoma.

The diagnosis of lichen-planus-like contact dermatitis to chlorpheniramine maleate.

In spite of the common use of the diagnostic category of lichen-planus-like contact dermatitis, we were unable to find established criteria for such a condition. An atypical distribution of otherwise typical lichen planus lesions is usually considered as a feature of a lichenoid eruption. When facing unusual or unexpected clinical features, it is always advisable to consider an adverse reaction to a medical intervention as a potential option. We report a lichen-planus-like eruption occurring after contact with a topical agent containing chlorpheniramine maleate. To our knowledge, this is the first reported case of lichen-planus-like contact dermatitis associated with chlorpheniramine maleate.