Biomedical subjects
Publications and source records attributed to J Bhawan.
Widespread melanocytic nevi may rarely appear suddenly after a severe bullous disease. We describe two patients in whom eruptive melanocytic nevi developed 3 weeks after a severe episode of Stevens-Johnson syndrome. Benign melanocytic proliferation may develop after a bullous dermatosis and should not be confused with malignant or metastatic melanoma.
Communication between the nervous system and epidermal melanocytes has been suspected on the basis of their common embryologic origin and apparent parallel involvement in several disease processes, but never proven. In this study, confocal microscopic analysis of human skin sections stained with antibodies specific for melanocytes and nerve fibers showed intraepidermal nerve endings in contact with melanocytes. This intimate contact was confirmed by electron microscopy, which further demonstrated thickening of apposing plasma membranes between melanocytes and nerve fibers, similar to synaptic contacts seen in nervous tissue. Since many intraepidermal nerve fibers are afferent nerves that act in a "neurosecretory" fashion through their terminals, cultured human melanocytes were stimulated with calcitonin gene-related peptide (CGRP), substance P, or vasoactive intestinal peptide, neuropeptides known to be present in cutaneous nerves, to examine their possible functions in the epidermal melanin unit. CGRP increased DNA synthesis rate of melanocytes in a concentration- and time-dependent manner. Cell yields after 5 d were increased 25% compared with controls maintained in an otherwise optimized medium. Furthermore, stimulation by CGRP induced rapid and dose-dependent accumulation of intracellular cAMP, suggesting that the mitogenic effect is mediated by the cAMP pathway. These studies confirm and expand a single earlier report in an animal model of physical contact between melanocytes and cutaneous nerves and for the first time strongly suggest that the nervous system may exert a tonic effect on melanocytes in normal or diseased human skin.
Sustained improvement with prolonged topical tretinoin for photodamaged skin has been well documented for up to 22 months of continuous treatment. We now report long-term (4 years) histologic effects of topical tretinoin in photodamaged skin of 27 patients, the longest study to date. The observed decreases in dermal elastin content and perivascular inflammation and increase in epidermal mucin in facial biopsies obtained after up to 4 years of treatment may be partly responsible for the continued clinical improvement. Furthermore, the study shows that there are no untoward effects on keratinocytes or melanocytes during long-term use of topical tretinoin.
Epithelioid vascular tumors are a heterogeneous group characterized by epithelioid-appearing endothelial cells. Included are benign vascular tumors (epithelioid hemangioma), borderline tumors (epithelioid hemangioendothelioma), and malignant tumors (epithelioid angiosarcoma). We describe a case of multiple epithelioid hemangiomas.
To determine the factors associated with the duration of wheals in urticaria, we carried out a quantitative study of mast cells and eosinophils in both peripheral bloods and skin lesions. The percentage of cytoplasmic vacuolation, indicating a result of eosinophil degranulation of all types of specific granules of circulating eosinophils was significantly increased in the long-duration group compared with the short-duration group. Many extracellular free eosinophil granules were observed in the vicinity of disrupted eosinophils in the long-duration wheals. On the other hand, the short-duration wheals had few free eosinophil granules. The number of free eosinophil granules and the percentage of free eosinophil granules to eosinophils were significantly different between the long-and the short-duration wheals, whereas there was no significant difference between the early stage and the late stage of the long-duration wheals. The numbers of all inflammatory cells, eosinophils, and activated mast cells were increased in the late stage of the long-duration wheals. These findings suggest that free eosinophil granules liberated from infiltrating eosinophils by some stimulus may provoke the persistent activation of mast cells, and the mast-cell-derived mediators may induce the persistent state of inflammation in the long-duration wheals.
We describe four cases of unusual superficial cutaneous cysts that have a lining epithelium composed of apocrine cells immediately adjacent to keratinizing squamous epithelium with an intact granular layer. Two of the cysts were on the nipple of the breast and two of the cysts were on the face. The lumina of all four cysts contained keratin. Immunoperoxidase staining for carcinoembryonic antigen in the facial cysts showed positive staining within the apocrine cells of the lining epithelium in one case. The pathogenesis of these lesions is uncertain. We suggest that these unusual cysts be called hybrid epidermoid and apocrine cysts.
The capacity of the skin to be stretched and to return to its resting position is correlated to the quantity and to the quality of the elastic fiber network. Although elastic fibers have been demonstrated in scars, the time course of their appearance in scars and their role in scar elasticity has not been elucidated. A study was therefore undertaken to evaluate the elastic fiber network in scars. The scars studied were from re-excision specimens following a biopsy performed for a benign or a malignant process. A total of 182 scars were evaluated in patients of different age groups. Miller's elastic tissue stain, considered to be superior to Verhoeff's van Giesen stain, was used. No elastic fibers were detected in any of 116 scars which were of less than 3 months' duration. In 66 scars present for over 3 months, a progressive increase in elastic fibers was present, first as focal and thin fibers, then as diffuse and thicker fibers. For scars of the same duration, a regional difference was noted in that scars from the back contained more and thicker elastic fibers than those from the cheek. When patients were stratified according to age, no appreciable difference was noted in the density of elastic fibers in both new and old scars between the different age groups. These results show that the synthesis of elastic tissue fibers in scars is a function of duration and site of the scar.
Melanoma is a malignant tumor with a varied histologic appearance. Melanoma composed of spindle cells may include desmoplastic and neurotropic melanoma. The histologic diagnosis of desmoplastic and neurotropic melanoma can be difficult. Although S100 protein stains a majority of these melanomas, the staining may be weak or focal. HMB-45, a more specific marker of melanoma, is frequently negative in desmoplastic and neurotropic melanoma. In order to aid the identification of desmoplastic and neurotropic melanoma, we stained 13 spindle cell melanomas (5 neurotropic melanomas, 5 desmoplastic melanomas, 3 spindle cell melanomas without either desmoplasia or neurotropism) with p75 NGF-R and compared the staining results with S100 and HMB-45. p75 NGF-R is the low affinity nerve growth factor receptor reported to be present on the surface of neural-crest-derived cells. Conventional melanoma as well as neurotized nevi, neurofibroma, spindle squamous carcinoma, atypical fibroxanthoma, dermatofibroma and scars were also stained with p75 NGF-R. p75 NGF-R stained all of the desmoplastic and neurotropic melanomas tested. In each of these cases, negative HMB-45 staining of the spindle cells was seen. In many cases the number and intensity of the spindle cells staining with p75 NGF-R was greater than with S100. Neurofibroma, neurotized nevi and focal cells in round cell melanoma also were stained with p75 NGF-R. All the squamous cell carcinomas, atypical fibroxanthomas, dermatofibromas and scars were negative for p75 NGF-R. Based on our results, p75 NGF-R may be useful as an additional confirmatory antibody in a melanoma panel, especially in differentiating desmoplastic and neurotropic melanomas from non-neural-crest-derived spindle cell lesions. We feel it also can be helpful in better identifying margins of excision of these melanomas. p75 NGF-R, like S100 protein, will not differentiate desmoplastic and neurotropic melanomas from other neural-crest-derived lesions.
Intraepidermal nerve fibers were studied by electron microscopy in chronically photodamaged preauricular skin and in paired sun-protected postauricular sites of 20 Caucasian women aged 56-70 years. As previously reported, basal keratinocytes in the sun-exposed skin showed various degrees of degenerative changes including intracellular vacuolar structures and widened intercellular spaces. Neurites were frequently closely apposed to basal keratinocytes in preauricular sun-exposed skin, but were observed less than 10% as often in sun-protected postauricular skin. When degree of epidermal photodamage was quantified by means of the number of degenerated keratinocytes per 100 keratinocytes in the basal layer, the number of intraepidermal nerve fibers was significantly correlated by linear regression analysis to the severity of epidermal photodamage (r = 0.913) independent of anatomical sites. These results demonstrate for the first time a correlation between degree of epidermal innervation and chronic photodamage and suggest the possibility of neural involvement in the pathophysiology and/or repair of photodamaged skin.
Plaque-type psoriasis has been successfully treated with topical calcitriol, but there has been no long-term follow-up study of the safety and efficacy of this calciotropic hormone. In a single-centre study, patients with plaque or erythrodermic psoriasis were enrolled in a double-blind, right/left comparison, placebo-controlled study, and received 1.5 micrograms of calcitriol (15 micrograms/g of Vaseline) per day, or a placebo consisting of Vaseline alone. A subset of these patients (n = 22), with at least 25% involvement, applied 0.1 g of calcitriol ointment/50 cm2 on an area of from 2,500 to 5,000 cm2. Of the 84 patients enrolled in the double-blind control study, 96.5% responded to topical calcitriol therapy, compared with 15.5% whose lesions improved with Vaseline alone, after 2.4 months. After completion of the double-blind study, 22 patients applied calcitriol ointment (15 micrograms/g Vaseline) to all of their lesions (up to 10 g of calcitriol ointment; 150 micrograms calcitriol lesions showed either excellent or moderate clearing in 90.9% of all cases. The remaining 9.1% of cases showed slight improvement of their lesions. No abnormalities in calcium metabolism were noted in any of the patients using topical calcitriol. None of the patients experienced any local cutaneous side-effects, including six patients who applied calcitriol ointment to the face. Topical calcitriol is safe and effective for the treatment of psoriasis.
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The small proline-rich protein 1 (SPRR1) gene encodes a precursor of the keratinocyte cornified envelope. To understand SPRR1 regulation we investigated its expression and modulation in keratinocytes in vivo and in vitro. SPRR1 was strongly expressed in suprabasal layers of the epidermis in newborn skin but only weakly expressed in adult skin. Both in vivo and in vitro, SPRR1 was not expressed in undifferentiated cells of basal or squamous carcinomas. However, within the same tumors and in premalignant lesions of squamous cell origin, cells with histologic evidence of differentiation showed a relative increase in SPRR1 transcript level. Within 24 h physiologic doses of uv irradiation induced SPRR1 mRNA in vivo. To investigate the possibility that SPRR1 expression is regulated by uv-induced cytokines, keratinocytes were stimulated with interleukin-1 (IL-1) and interleukin-3 (IL-3). Both significantly induced SPRR1 mRNA, while TGF-beta, known to lower IL-1 receptor in keratinocytes, down-regulated it. Moreover, proximity to inflammatory cells in vivo was associated with SPRR1 induction in anaplastic tumor cells. Our data suggest that SPRR1 is induced early in differentiation of normal keratinocytes but is not expressed in anaplastic cells of keratinocyte origin. Further, its regulation in skin appears to be modulated at least in part through cytokine release.
Disorders affecting the maturation of the epidermis are regarded as incidental findings in normal skin and otherwise unrelated benign lesions. These include epidermolytic hyperkeratosis, focal acantholytic dyskeratosis, and pagetoid dyskeratosis. The former two entities also occur as primary pathologic lesions. We report a hyperkeratotic lesion with a specific histologic pattern consisting of dyskeratotic cells throughout the epidermis and a parakeratotic horn, with large, rounded cells at all levels of the stratum corneum. Because we believe it to be a variant of the solitary, acquired lesions characterized by abnormal epidermal maturation, such as epidermolytic acanthomas, we suggest the term "dyskeratotic acanthoma" for this lesion.
A 25-year-old man had a 5-year history of multiple tender lesions of both extremities and trunk. Biopsy found an encapsulated subcutaneous nodule composed of numerous small, well-formed blood vessels, some filled with fibrin thrombi. This lesion was made up > 99.9% of blood vessels with only a minimal amount of adipose tissue. We believe our case is in the spectrum of angiolipoma even though it is made up almost entirely of a vascular component. These tumors may be confused with other multiple or eruptive vascular lesions that have a more ominous clinical course. This case is being reported to stress that multiple or eruptive "vascular" lesions do not always reflect an underlying immunosuppression or malignancy.
A 39-year-old white man presented with four discrete dermal nodules in his right upper arm. Biopsy revealed superficial dermal well-circumscribed nodules composed of solid areas and vascular spaces lined by epithelioid endothelial cells and a similar nodule composed of spindle and epithelioid cells. A moderate mitotic count of 3-4 mitoses/10 hpf was present. Multiple lesions erupted 1 month later distally and proximally to the original lesions. Magnetic resonance imaging of the right arm demonstrated a lesion in the humerus. Biopsy of the humerus showed a vascular tumor with similar histologic features to the overlying skin lesions. The differential diagnosis included epithelioid vascular tumors, bacillary angiomatosis, pyogenic granuloma, and Kaposi sarcoma. Vascular lesions containing epithelioid and spindle cells span a spectrum from benign to malignant. We believe these tumors belong in the category of hemangioendothelioma and propose the name eruptive epithelioid hemangioendothelioma with spindle cells. Our case emphasizes that eruptive cutaneous vascular lesions do not always suggest immunosuppression or malignancy. Additionally, it highlights the association between epithelioid vascular lesions of the skin and bone.
Histologic studies have become increasingly important in recognizing morphologic differences in photoaged versus intrinsically aged skin. Earlier histologic studies have attempted to evaluate these changes by examining anatomical sites which are not comparable, such as face and buttocks. As part of a multicenter study, we have quantitatively examined a panel of 16 histologic features in baseline facial skin biopsies from 158 women with moderate to severe photodamage. When compared to the postauricular area (photo protected), biopsies of the crow's feet area (photo exposed) had a twofold increase in melanocytes and a statistically significant increase in melanocytic atypia (p < .0001) and epidermal melanin (p < .0001). Other epidermal changes included reduced epidermal thickness (p < .01), more compact stratum corneum (p < .0001) and increased granular layer thickness (p < .0001) in the crow's feet skin. There was increased solar elastosis (p < .0001), dermal elastic tissue (p < .0001), melanophages (p < .0001), perivascular inflammation (p < .05) and perifollicular fibrosis (p < .01) but no change in the number of mast cells or dermal mucin in the photo exposed skin. Our data document quantitative differences in photoaged versus intrinsically aged facial skin and provides the groundwork for future studies to evaluate the efficacy of new treatments for photoaged skin.
A 36-year-old Caucasian man presented with chronic, slightly erythematous, scaly plaques of 6 years duration. Some improvement was noticed after treatment with topical steroids. Differential clinical diagnoses included psoriasis and eczema. A biopsy revealed psoriasiform changes with "fatty vacuoles" replacing the papillary dermis. The histogenesis of these findings is unknown. Even though small foci of fatty vacuolization have been observed in association with heavy inflammatory infiltrates in skin, this is the first reported case of massive fatty infiltrates in a non-neoplastic disorder of the skin associated with only sparse inflammatory infiltrate.