Glutathione S-transferases in human and rodent skin: multiple forms and species-specific expression.

The glutathione S-transferases (GST) are a family of widely distributed multifunctional detoxification enzymes that catalyze the reaction between reduced glutathione and a variety of electrophiles. Of interest is the fact that several extracutaneous tissues exhibit a distinct spectrum of isozymes that are expressed in a highly controlled fashion. Despite the fact that the skin is continuously exposed to numerous injurious agents, little is known about the expression of GST isozymes and their role in metabolism of physiologic and xenobiotic substrates in cutaneous tissue. Using specific polyclonal antibodies to the Alpha, Mu, and Pi classes of GST, we identified their expression in rat, mouse, and human skin cytosol. In each species, GST isozymes expressed activities towards 1-chloro-2,4-dinitrobenzene, benzo(a)pyrene 4,5-oxide, styrene 7,8-oxide, leukotriene A4, and ethacrynic acid, but not towards bromosulfophthalein and cumene hydroperoxide. Western blot analysis indicated the predominant expression of Pi isozyme in all three species. Alpha class of isozyme(s) was present only in human skin, whereas Mu class of isozyme(s) was detected only in rat and mouse skin. Similarly, in normal and transformed cultured human keratinocytes Pi was the predominant isozyme. In situ localization studies using immunohistochemical techniques confirmed the observations of Western blotting. In mouse skin, Pi and Mu isozyme(s) were found to be predominantly localized in sebaceous glands, whereas no reactivity was observed with the Alpha class of isozymes. Our data show that multiple forms of GST exist in rodent and human skin and that GST Pi is the predominant isozyme in each species. Furthermore, cutaneous GST can metabolize both endogenous substrates and foreign compounds.

Neutrophilic eccrine hidradenitis simulating orbital cellulitis.

Orbital swelling in patients with cancer can reflect neoplastic or infectious processes. Accurate diagnosis can be especially difficult in the face of associated fever and neutropenia. We treated a 30-year-old man undergoing induction chemotherapy for acute myelogenous leukemia, who had fever of unknown origin and periorbital swelling suggestive of orbital cellulitis. However, the periorbital findings were more compatible with passive swelling and hemorrhage. A skin biopsy specimen demonstrated isolated neutrophilic inflammation and necrosis of the eccrine glands. Cultures of the tissue for bacteria and fungi were negative. Pertinent literature regarding eccrine-gland inflammatory disease was reviewed. This unusual entity, termed neutrophilic eccrine hidradenitis, is most common in patients undergoing induction chemotherapy. Cases with infectious causes and cases in neutropenic patients have also been reported. No other patients, to our knowledge, with periocular involvement by neutrophilic eccrine hidradenitis have been described. Neutrophilic eccrine hidradenitis should be added to the differential diagnosis of cases of periocular hemorrhage and swelling in patients with cancer who receive chemotherapy.

Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alfa and zinc.

BACKGROUND: Necrolytic acral erythema is a recently described necrolytic erythema that is unique in its exclusive acral location and strong association with hepatitis C. OBSERVATION: We report the first case of necrolytic acral erythema in the United States. The patient is a 43-year-old black woman who presented with a 4-year history of tender, flaccid blisters localized to the dorsal aspect of her feet. Serum zinc and glucagon levels were normal. Serum antibodies were positive for hepatitis C, and a liver biopsy specimen showed chronic hepatitis. She was successfully treated with interferon alfa-2b and zinc. We review all previously reported cases. CONCLUSIONS: Necrolytic acral erythema is a distinct entity. In a review of the literature, most patients were between 35 and 55 years of age, although 1 patient was 12 years old. Five of 8 patients were female. Four of 7 patients described previously were treated with variable success using oral zinc sulfate and amino acids, whereas 2 were successfully treated with interferon alfa. All patients were infected with hepatitis C. Necrolytic acral erythema appears to be a skin disorder linked to infection with hepatitis C virus that responds to treatment with interferon alfa and oral zinc.

Apoptosis during photodynamic therapy-induced ablation of RIF-1 tumors in C3H mice: electron microscopic, histopathologic and biochemical evidence.

Very little is known about the applicability of the metabolic and biochemical events observed in cell culture systems to in vivo tumor shrinkage following photodynamic therapy (PDT). The purpose of this study was to assess whether PDT induces apoptosis during tumor ablation in vivo. We treated radiation-induced fibrosarcoma (RIF-1) tumors grown in C3H/HeN mice with PDT employing three photosensitizers, Photofrin-II, chloroaluminum phthalocyanine tetrasulfonate, or Pc IV (a promising phthalocyanine developed in this laboratory). Each photosensitizer was injected intraperitoneally and 24 h later the tumors were irradiated with an appropriate wavelength of red light using an argon-pumped dye laser. During the course of tumor shrinkage, the tumors were removed at 1, 2, 4 and 10 h post-PDT for DNA fragmentation, histopathologic, and electron microscopic studies. Markers of apoptosis, viz. the ladder of nucleosome-size DNA fragments, increased apoptotic bodies, and condensation of chromatin material around the periphery of the nucleus, were evident in tumor tissue even 1 h post-PDT; the extent of these changes increased during the later stages of tumor ablation. No changes were observed in tumors given photosensitizer alone or irradiation alone. Our data suggest that the damage produced by in vivo PDT may activate endonucleolysis and chromatin condensation, and that apoptosis is an early event in tumor shrinkage following PDT.

Apoptosis is an early event during phthalocyanine photodynamic therapy-induced ablation of chemically induced squamous papillomas in mouse skin.

Photodynamic therapy (PDT) is a promising new modality to treat malignant neoplasms including superficial skin cancers. In our search for an ideal photosensitizer for PDT, Pc 4, a silicon phthalocyanine, has shown promising results both in in vitro assays and in implanted tumors. In this study we assessed the efficacy of Pc 4 PDT in the ablation of murine skin tumors; and the evidence for apoptosis during tumor ablation was also obtained. The Pc 4 was administered through tail vein injection to SENCAR mice bearing chemically induced squamous papillomas, and 24 h later the lesions were illuminated with an argon ion-pumped dye laser tuned at 675 nm for a total light dose of 135 J/cm2. Within 72-96 h, almost complete tumor shrinkage occurred; no tumor regrowth was observed up to 90 days post-PDT. As evident by nucleosome-size DNA fragmentation, appearance of apoptotic bodies in hematoxylin and eosin staining and direct immunoperoxidase detection of digoxigenin-labeled genomic DNA in sections, apoptosis was clearly evident 6 h post-PDT at which time tumor shrinkage was less than 30%. The apoptotic bodies, as evident by the condensation of chromatin material around the periphery of the nucleus and increased vacuolization of the cytoplasm, were also observed in electron microscopic studies of the tumor tissues following Pc 4 PDT. The extent of apoptosis was greater at 15 h than at 6 and 10 h post-PDT. Taken together, our results clearly show that Pc 4 may be an effective photosensitizer for PDT of nonmelanoma skin cancer, and that apoptosis is an early event during this process.

Sebocrine adenoma. An adnexal adenoma with sebaceous and apocrine poroma-like differentiation.

Sebocrine adenoma is a benign cutaneous adnexal neoplasm differentiating in the direction of sebaceous and apocrine glands. The sebaceous differentiation is characterized by solitary instances or clusters of sebocytes and sebaceous ducts. The apocrine differentiation is characterized by eccrine poroma-like histology. Reported herein are three such cases.

Mycosis fungoides: cutaneous T-cell lymphoma.

Most patients with mycosis fungoides are between 40 and 60 years of age. The disease has three clinical stages: (1) the premycotic, or patch, stage, consisting of macular, scaling, faint pink to red pruritic patches, usually on unexposed surfaces; (2) the mycotic, or plaque, stage, consisting of reddish, purple-brown plaques, often annular in shape and symmetric in distribution, and (3) the tumor stage, consisting of red-brown to violaceous, dome-shaped, firm tumors with a predilection for the face and body folds. The Sézary syndrome is a leukemic variant. Treatment depends on the extent of disease and includes topical or systemic chemotherapy, radiotherapy and psoralen plus long-wave ultraviolet light therapy.

Signet-ring clear-cell basal cell carcinoma.

Basal cell carcinoma displays a myriad of histopathologic variants, some of which are related to the different lines of differentiation, vis-a-vis, squamous, pilar, eccrine, or sebaceous. We herein report an example of a rare signet-ring, clear-cell variant. Our diagnosis is primarily based on the histopathologic features of the tumor, namely, the dermal nests of tumor cells with peripheral palisading and focally retracted fibroblastic stroma. Several nests are folliculocentric. The tumor cells are glycogen-rich, mucin-negative, pankeratin-positive, cytokeratin-negative, S100 protein-negative, and carcinoembryonic antigen-negative. Based on the histopathology and the results of the special stains we propose that the signet-ring clear-cell variant of basal cell carcinoma is differentiating in the direction of the outer root sheath cells of the pilar structure.

A clinicopathologic approach to granulomatous dermatoses.

Reaching a diagnosis or formulating a differential diagnosis in dermatopathology involves combining information from clinical and pathological sources. Traditionally, this process is presented as a chronologic progression from the patient's complaint, through the evaluation of findings, terminating in the microscopic examination of the biopsy specimen. However, dermatopathologists often find the sequence reversed. They must first form an impression of the diagnosis from the slide and then supplement it with clinical information. The purpose of this article is to present the spectrum of granulomatous dermatoses from a pathologic perspective. The dermatoses are categorized into five groups on the basis of histologic patterns.

Natural history of melanocytic nevi.

The natural history of common acquired nevi begins with junctional nevi, which first evolve into compound nevi and then intradermal nevi. The clinical appearance and histopathology of these lesions permit precise identification. Spitz nevi, blue nevi, congenital nevi and dysplastic nevi represent subcategories that also have easily identifiable features. An understanding of the nature of benign nevi makes it easier to identify potentially life-threatening melanomas.

Protection against N-nitrosodiethylamine and benzo[a]pyrene-induced forestomach and lung tumorigenesis in A/J mice by green tea.

In recent years we and others have shown the cancer chemopreventive effects of green tea in several animal tumor models. In this study we assessed the cancer chemopreventive effects of water extract of green tea (WEGT) and the polyphenolic fraction (GTP) isolated from WEGT against N-nitrosodiethylamine (DEN)- and benzo[a]pyrene (BP)-induced forestomach and lung tumorigenesis in A/J mice. The protective effects, both in forestomach and lungs, were evident by a decrease in number of tumors and the percentage of mice with tumors when WEGT and GTP were fed to animals during initiation, post-initiation and entire period of tumorigenesis protocols. Oral feeding of 0.2% GTP in drinking water to mice afforded 68-82 and 39-66% protection against DEN- and BP-induced forestomach tumorigenesis respectively. In case of pulmonary tumor multiplicity caused by DEN and BP, the protective effects of GTP were between 38-43 and 25-46% respectively. Similarly, oral feeding of 2.5% WEGT to mice also afforded 80-85 and 61-71% protection against DEN- and BP-induced forestomach tumorigenesis respectively. In case of lung tumorigenesis, the protective effects of WEGT were 43-62 and 25-51% respectively. Histological studies of forestomach tumors showed significantly lower squamous cell carcinoma counts in GTP- and WEGT-fed groups of mice compared to carcinogen alone treated control group of mice. When pulmonary tumors were examined histologically, no adenocarcinomas were observed in GTP- and WEGT-fed groups of mice compared to 20% mice with adenocarcinomas in carcinogen alone treated control group. Oral feeding of GTP and WEGT in drinking water also showed significant enhancement in the activities of glutathione S-transferase and NADP(H): quinone reductase in liver, small bowel, stomach and lung. The results of this study suggest that green tea possesses chemopreventive effects against carcinogen-induced tumorigenesis in internal body organs, and that the mechanism of such effects may involve the enhancement of phase II and anti-oxidant enzyme systems.

Congenital miliaria crystallina: case report and literature review.

Generalized congenital miliaria crystallina occurred in a black newborn boy. Although miliaria crystallina occurring in infancy and beyond is well established, congenital occurrence is very rare. The pathogenesis of the disorder is not well understood. We discuss some hypotheses of pathogenesis in the context of our patient, as well as a differential diagnosis and a comparison with a previously reported case. Miliaria crystallina should be considered in the differential diagnosis of vesiculobullous eruptions in newborns.

Transient blueberry muffin appearance of a newborn with congenital monoblastic leukemia.

A full-term male infant was born with skin findings suggesting a blueberry muffin appearance. Biopsy of a cutaneous nodule was consistent with monoblastic leukemia cutis, and bone marrow examination confirmed the diagnosis of leukemia. The infant has remained well 2 years after spontaneous resolution of the cutaneous eruption. Infiltrative neoplasms should be considered along with congenital infections and hematologic disorders in the differential diagnosis of a newborn with a blueberry muffin appearance.

Terminal hepatic failure in erythropoietic protoporphyria.

Erythropoietic protoporphyria is an inherited disorder characterized biochemically by a deficiency of ferrochelatase, the enzyme that catalyzes the incorporation of ferrous iron into protoporphyrin to form heme. We describe a patient who illustrates the unpredictability of the course of liver disease in erythropoietic protoporphyria. She remained stable for several years after her first evidence of liver function abnormalities. Then, in a period of weeks, hepatic failure developed and she died. Findings of serial liver biopsy specimens showed extensive hepatocellular degeneration and inflammation that appeared in a 10-day period. The factors that cause this rapid deterioration in hepatic function remain unknown. Reported cases of fatal hepatic failure in patients with erythropoietic protoporphyria are reviewed.

In situ evidence for the involvement of superoxide anions in cutaneous porphyrin photosensitization.

Dihematoporphyrin ether, also known as Photofrin-II (Pf-II) is currently used in the diagnosis and management of a variety of epithelial neoplasms, in a modality known as photodynamic therapy (PDT). A major drawback of these porphyrins for PDT is their ability to evoke prolonged cutaneous photosensitization. The mechanism of tumor ablation and cutaneous photosensitization by these photosensitizers is thought to relate to the generation of one or more reactive oxygen species such as superoxide anion, singlet oxygen and hydroxyl radical. However, the role of these oxygen species has not been established unequivocally. In this study, the mechanism of Pf-II-mediated cutaneous photosensitization was examined using murine ear swelling as a marker. The mice treated with Pf-II and light demonstrated two-fold enhancement of ear swelling whereas animals treated with the SOD mimic, beta-carotene and dimethyl sulfoxide (DMSO) had considerably less ear swelling (p less than 0.01). The observed protective effect was dependent on the dose of each quencher and followed the pattern SOD mimic DMSO beta-carotene. The histopathologic alterations caused by Pf-II photosensitization were significantly alleviated by pretreatment with SOD mimic whereas beta-carotene and (DMSO) were less effective. Inhibitors of superoxide dismutase (sodium diethyldithiocarbamate) and catalase (hydroxyl amine and 3, amino 1,2,4-triazole) augmented Pf-II-mediated cutaneous photosensitization. These data provide the first in vivo evidence for the involvement of superoxide anion in cutaneous porphyrin photosensitization.

Carbon dioxide laserabrasion: a new approach to management of familial benign chronic pemphigus (Hailey-Hailey disease).

Familial benign chronic pemphigus (FBCP), or Hailey-Hailey disease, can be a debilitating condition. Treatment is palliative and only excision of lesional skin followed by split-thickness grafting may be curative. The success of surgery is attributed to the removal of adnexal structures and a decrease in sweating and maceration. This is the first report of successful carbon dioxide (CO2) laserabrasion of a patient with FBCP. The procedure spared the underlying adnexae which contributed to the reepithelialization of the epidermis. The selective destructive property of the CO2 laser may contribute to understanding the pathophysiology of FBCP.

An immunopathological study of herpes-associated erythema multiforme.

Any pathogenetic mechanism proposed for erythema multiforme (EM) must account for the prominent mononuclear cell infiltrate in the skin lesions. The purpose of this study was to characterize immunopathologically, with monoclonal antibodies to human leukocyte antigens, the inflammatory cells in early target lesions of recurrent herpes-associated EM. Cryostat sections of snap-frozen skin biopsies were studied by the avidin-biotin immunoperoxidase technique with use of the following monoclonal antibodies: anti-HLA-DR, anti-Leu M5, anti-Leu 4 + 5b, anti-Leu 3a + 3b, anti-Leu 2a, anti-Leu 14, and anti-Leu 6. The dermal mononuclear inflammatory infiltrate in the EM biopsies consisted of monocyte-macrophages and T-lymphocytes, with both helper and suppressor T cells present. Both the dermal inflammatory infiltrate and the overlying keratinocytes were strongly HLA-DR positive. No definite alteration of Langerhans cell number or distribution was noted. These findings are consistent with the characteristics seen in cell-mediated immune reactions in the skin and point to this as a likely immune mechanism for the tissue damage of EM.