Thrombomodulin expression by human keratinocytes. Induction of cofactor activity during epidermal differentiation.

Thrombomodulin is an endothelial cell surface glycoprotein that inhibits the procoagulant activities of thrombin and accelerates activation of the anticoagulant protein C. Because protein C deficiency is associated with cutaneous thrombosis, we investigated the expression of thrombomodulin in human skin. Thrombomodulin was detected by immunohistochemical staining both in dermal endothelial cells and in epidermal keratinocytes. Within the epidermis, thrombomodulin staining was limited to keratinocytes of the spinous layer, suggesting that thrombomodulin is induced when basal keratinocytes begin to terminally differentiate. Thrombomodulin expression also correlated with squamous differentiation in epidermal malignancies; little or no thrombomodulin staining was seen in five basal cell carcinomas, whereas strong thrombomodulin staining was observed in each of five squamous cell carcinomas. Human foreskin keratinocytes cultured in medium containing 0.07 mM calcium chloride synthesized functional thrombomodulin with cofactor activity comparable to thrombomodulin in human umbilical vein endothelial cells. Stimulation of keratinocyte differentiation with 1.4 mM calcium chloride for 48 h produced 3.5-, 3.2-, and 5.6-fold increases in thrombomodulin cofactor activity, antigen, and mRNA, respectively. These observations suggest that thrombin is regulated by keratinocyte thrombomodulin at sites of cutaneous injury, and indicate a potential role for thrombomodulin in epidermal differentiation.

A cutaneous sign of IgA-associated small dermal vessel leukocytoclastic vasculitis in adults (Henoch-Schönlein purpura).

A series of patients shared the distinctive cutaneous findings of palpable purpuric plaques with multifocal areas of hemorrhage or superficial necrosis within individual lesions and a retiform pattern of hemorrhage, superficial necrosis, or lesional margins. This pattern was looked for in every patient presenting with palpable purpura, but it was seen exclusively in the seven patients described herein. Each patient was found to have an IgA-associated small dermal vessel vasculitis that was proved to be leukocytoclastic in six of the seven patients. These distinctive cutaneous findings may be evidence of the presence of IgA deposition in patients with small-vessel leukocytoclastic vasculitis and may infer a different pathogenesis for lesion formation in some patients with IgA-associated vasculitis.

Myeloma, paraproteinemias, and the skin.

This review focuses on those systemic diseases or syndromes associated with monoclonal plasma cell disorders that may present with important cutaneous manifestations. Amyloidosis, POEMS syndrome, cutaneous plasmacytoma, xanthomas, benign hypergammaglobulinemic purpura of Waldenström, and scleromyxedema are emphasized.

Cutaneous manifestations of systemic diseases.

Many aspects of dermatologic diagnosis are either of importance or interest to the nondermatologist, and there are many excellent textbooks available for guidance. This article focuses on four categories of conditions that are the source of frequent queries from the primary care setting: (1) common skin diseases that frequently mimic systemic illness, (2) common skin diseases that have important systemic associations, (3) common systemic diseases that have prominent cutaneous findings, and (4) the seldom seen but frequently raised concerns regarding cutaneous signs of internal malignancy.

The differential diagnosis of purpura from a morphologic perspective.

Diseases associated with purpura range from the most common and trivial of human afflictions to some of the most devastating and rapidly fatal syndromes known. In order to sort the simple from the sinister, it is necessary to use not only the history and general physical examination, but also various morphologic components of the purpuric lesions themselves to suggest likely pathophysiologies of hemorrhage. Findings such as erythema, livedo reticularis, size of hemorrhage, presence or absence of palpability, symmetry or retiform patterning of lesions, and presence and extent of necrosis or eschar formation all can serve as clues to the likely etiologies of hemorrhage. Effective communication about purpuric syndromes requires information regarding the likely age of lesions described clinically or histologically and a precise description of the individual elements of the lesion. Such communication would be enhanced by eliminating the ambiguity inherent in the current usage of many of the terms employed to describe such lesions. This paper presents one possible approach to better use of the information that the morphology of purpuric lesions can provide.

An approach to cutaneous changes caused by hematologic malignancies.

Most hematologic malignancies can present with or later develop cutaneous lesions. The proper diagnosis of such patients through the evaluation of their cutaneous lesions is complicated both by the confusing variety of clinical findings and by the shifting classifications of hematologic malignancies in the face of evolving knowledge. The spectrum of T-cell malignancies continues to increase and now includes several disorders formerly attributed to B-cells or macrophages. The cutaneous findings of malignant and malignant behaving hematologic disorders are grouped by the presumed cellular etiology and by the clinical subset of tumor. Clinical and histopathologic features unique to individual disorders are emphasized, as well as those features that may be shared by otherwise quite dissimilar malignancies.

Antimalarials.

Antimalarial medications have become the parenteral drugs of choice for treating the cutaneous manifestations of lupus erythematosus. The immune-modulating activity of these agents makes them useful in a variety of other dermatoses. With prudent dosage and monitoring, these agents can be used safely and effectively in the treatment and management of dermatologic disease.

The incidence of second malignancies in subsets of Kaposi's sarcoma.

There is strong evidence linking Kaposi's sarcoma with an increased risk of developing a second primary malignancy. This risk of a second malignancy appears to depend in part on the clinical setting in which Kaposi's sarcoma develops. This paper examines these risks by relating them to specific subsets of Kaposi's sarcoma and to specific types of second malignancies.

Successful treatment of hypertrophic lupus erythematosus with isotretinoin.

A patient with systemic lupus erythematosus had the additional finding of hypertrophic lupus erythematosus. The lesions cleared with an 11-week course of isotretinoin alone. She has remained without recurrence for 9 months. This is the first reported case of total resolution of hypertrophic lupus erythematosus with a short course of isotretinoin.

Clinical and serologic expression of localized scleroderma. Case report and review of the literature.

A patient is presented in whom both linear scleroderma and eosinophilic fasciitis developed. The latter is rare in childhood. A positive antinuclear antibody, a positive rheumatoid factor, and seizures also developed. In reviewing the literature, we concluded that the clinical and histologic pattern of cutaneous sclerosis may be more valuable than serologic findings in predicting both the likelihood of, and the expected sites for, systemic involvement. The literature also suggests that central nervous system (CNS) involvement is rare in most sclerosing syndromes but that linear scleroderma may be associated with CNS or spinal disease. The ipsilateral association of linear scleroderma and seizure focus in this patient, as well as the focal onset of these seizures, is unusual and suggests an association between the seizure disorder and the linear cutaneous sclerosis.

Morphea after bromocriptine therapy.

A 57-year-old man developed morphea while taking bromocriptine. This drug is a semisynthetic ergot alkaloid, one of a class of drugs that is associated with fibrotic disorders. Other agents known for such association are serotonin (5-hydroxytryptamine) and beta-adrenergic blockers. A common pathogenesis to link these agents to fibrosis remains uncertain.

Cutaneous angiomyolipoma. A light-microscopic, immunohistochemical, and electron-microscopic study.

We report a case of cutaneous angiomyolipoma found on the helix of a 67-year-old man. The lesion was studied by routine light microscopy, special stains, immunohistochemical methods, and electron microscopy. Histologic examination showed a well-circumscribed nodule in the dermis composed of an intimate mixture of blood vessels, smooth muscle, and mature fat. These components were confirmed by special stains, immunohistochemistry, and electron microscopy. We concluded that the unique features of this lesion distinguish it from other lesions such as angiomyoma, angiolipoma, and other mixed mesenchymal tumors. This report demonstrates that the features considered diagnostic of angiomyolipoma can occur in extrarenal sites and, therefore, this diagnosis cannot be excluded on the basis of site alone.

Erythematous plaques due to platelet plugging: a clue to underlying myeloproliferative disorder.

We report a syndrome in a middle-aged woman characterized by tender erythematous plaques with histologic evidence of dramatic dermal vessel occlusion. These cutaneous findings occurred in association with progressive inferior vena cava and portal vein thrombosis while on coumarin anticoagulation, following hepatic transplantation for Budd-Chiari syndrome. The material occluding dermal vessels was proven by immunohistochemical staining to be platelet plugs. These findings led to the diagnosis of an underlying myeloproliferative disorder explaining both her cutaneous and liver abnormalities and institution of appropriate platelet directed anticoagulation with aspirin.

Xanthoma disseminatum and Waldenström's macroglobulinemia.

A 71-year-old woman had a 7-month history of multiple asymptomatic papules on the upper part of the body. The clinical picture and histopathologic findings confirmed the diagnosis of xanthoma disseminatum. Further studies revealed Waldenström's macroglobulinemia. Treatment with chlorambucil and prednisone led to a dramatic reduction in her paraprotein level. In addition, cutaneous lesions improved and new lesions stopped appearing. Treatment of selected papules by cryotherapy or intralesional corticosteroid injection provided further improvement. This case is notable because (1) it is the first report of xanthoma disseminatum in a patient with Waldenström's macroglobulinemia and (2) there was an unusually good response to therapy.