Biomedical subjects
Publications and source records attributed to M J Trotter.
Pseudopelade is a rare self-limited hair disorder, resulting in cicatricial alopecia. It presents with skin-colored alopecic patches primarily involving the parietal and vertex portions of the scalp. This is a case report of a patient with pseudopelade that involves both his scalp and beard area.
BACKGROUND: Numerous modalities may be used for skin resurfacing, including chemical peels, dermabrasion, and lasers. Each of these methods is associated with significant disadvantages. OBJECTIVE: The purpose of these initial studies was to determine the efficacy and safety of a new electrosurgical resurfacing system. Depth of cutaneous injury was also evaluated. METHODS: Postoperative scar resurfacing was performed on six patients in the initial feasibility study. Patients were evaluated with questionnaires, physician observations, and photographs. The histologic investigation evaluated depth of injury after resurfacing at various power settings and number of passes. RESULTS: Appearance of postoperative scars in all 6 patients was improved by electrosurgical resurfacing. The overall injury, residual thermal damage plus ablation, for all power levels and passes was 114.1 micrometer (mean) with a standard deviation of 60.7 micrometer. CONCLUSION: Electrosurgical resurfacing may become an effective and safe alternative to current resurfacing modalities.
We postulate that genes involved in the control of cell proliferation are important determinants of melanoma growth and/or transformation. Using Western blot analysis, we compared the expression of nine key cell cycle regulators in metastatic melanomas with that in benign acquired naevi. Among the cyclin-dependent kinases (CDKs) examined, CDK2 was consistently and significantly overexpressed (three- to eight-fold) in metastatic melanomas compared with naevi. CDK1 and CDK4 exhibited no significant difference in expression between benign naevi and metastatic melanomas. CDK6 expression was variable, with four out of 10 metastatic melanomas showing higher expression than naevi. All the cyclins examined, especially cyclins A and D, were expressed more in metastatic melanomas than in naevi. Cyclin E was not detected in benign naevi, but was easily detectable in most of the metastatic melanomas. In addition, there was significantly greater expression of CDC25A, a tyrosine phosphatase that activates CDK kinases, in the metastatic melanomas. Over-expression of CDK2, CDK6, CDC25A and cyclin A was confirmed in melanoma cell lines. These cell cycle regulators may play an important role in melanoma growth and/or transformation.
BACKGROUND: Human T-cell lymphotropic virus I (HTLV- 1) infection can lead to myelopathy/tropical spastic paresis and adult T-cell leukemia/lymphoma (ATLL). Infection with HTLV-1 has also been associated with clinically significant immunosuppression. Crusted scabies, also known as Norwegian scabies, is an uncommon presentation of scabies that may occur in conjunction with immunosuppression. Although crusted scabies has been reported in association with HTLV-1 infection, to our knowledge it has never been described in association with HTLV-1 associated myelopathy. OBJECTIVE: The aim is to describe a case of HTLV-1 associated myelopathy and concomitant crusted scabies. METHODS: This article includes a case report and a literature review. CONCLUSIONS: Crusted scabies is reported in association with HTLV-1 infection with or without concomitant ATLL. Crusted scabies should be considered in the differential diagnosis of a generalized cutaneous eruption in an HTLV-1 positive patient. Patients with crusted scabies from an HTLV-1 endemic population should be rested for a possible HTLV-1 infection. These patients may be at increased risk of progressing to ATLL.
BACKGROUND: The tumour suppressor, p53, is recognized as a crucial molecule in regulating cellular responses to various DNA-damaging agents. Very early on in the development of nonmelanoma cancers p53 is mutated or lost, suggesting that p53 is crucial in protecting normal keratinocytes from the harmful effects of ultraviolet (UV) radiation. OBJECTIVE: Using two mouse models, one with multiple copies of mutant p53 and the other a p53 "knockout," our laboratory has examined a role for p53 in UV-induced DNA damage and determined if these effects are differentiation dependent. CONCLUSION: We outline in this review a proposed model reflecting differentiation-dependent p53 regulation of UV-induced responses in keratinocytes. After exposure to UV, basal keratinocytes repair damaged DNA, whereas differentiating keratinocytes undergo cell death, both processes are regulated by p53.
BACKGROUND: Epithelial elements, such as trichoepithelioma, are occasionally associated with melanocytic nevi. OBJECTIVE: A case of trichoepithelioma in association with cellular blue nevus is reported. METHODS AND RESULTS: A solitary, pigmented nodule was removed from the scalp of a middle-aged woman. Histopathologic examination demonstrated a circumscribed cellular blue nevus within which were embedded epithelial strands and cystic structures consistent with trichoepithelioma. CONCLUSION: Trichoepitheliomas have been described in relation to common acquired nevi, but an association with a blue nevus is rare. The intimate admixture of trichoepithelioma within the nodule of a nevus supports the concept of epithelial induction by melanocytic nevi.
Previous studies from our laboratory, using p53 transgenic mice, have suggested that ultraviolet (UV) light-induced keratinocyte apoptosis in the skin is not affected by overexpression of mutant p53 protein. To further elucidate a possible role for p53 in UV-induced keratinocyte cell death, we now examine apoptosis in skin and isolated keratinocytes from p53 null (-/-) mice and assess the influence of cell differentiation on this process. In vivo, using this knockout model, epidermal keratinocytes in p53-/- mice exhibited only a 5.2-fold increase in apoptosis after 2000 J/m2 UVB irradiation compared with a 26.3-fold increase in normal control animals. If this p53-dependent apoptosis is important in elimination of precancerous, UV-damaged keratinocytes, then it should be active in the undifferentiated cells of the epidermal basal layer. To test this hypothesis, we examined the effect of differentiation on UV-induced apoptosis in primary cultures of murine and human keratinocytes. Apoptosis was p53-independent in undifferentiated murine keratinocytes, which exhibited relative resistance to UVB-induced killing with only a 1.5-fold increase in apoptosis in p53+/+ cells and a 1.4-fold increase in p53-/- cells. Differentiated keratinocytes, in contrast, showed a 9.4-fold UVB induction of apoptosis in p53+/+ cells, almost three times the induction observed in p53-/- cells. This UV-induced difference in apoptosis was observed when keratinocytes were cultured on type IV collagen substrate, but not on plastic alone. Western blotting of UV-irradiated, differentiated keratinocytes did not support a role for either Bax or Bcl-2 in this process. In support of these findings in mice, cell death in human cultured keratinocytes also occurred in a differentiation-associated fashion. We conclude that p53-induced apoptosis eliminates damaged keratinocytes in the differentiated cell compartment, but this mechanism is not active in the basal, undifferentiated cells and is therefore of questionable significance in protection against skin cancer induction.
In response to ultraviolet radiation (UVR), skin keratinocytes increase expression of heat shock proteins that can protect cells from stress-induced damage. This heat shock response is known to be transcriptionally regulated in eukaryotic cells exposed to certain forms of environmental stress. In the skin, absorption of ultraviolet B light occurs primarily in the epidermis, and therefore, using primary cultures of normal human epidermal keratinocytes, we have examined whether transcriptional activation of the hsp72 gene occurs following UVB irradiation. Cultured keratinocytes were exposed to UVB (290-320 nm, 300 J per m2) and then incubated at 37 degrees C for various intervals before harvesting. Immediately following UV exposure, the heat shock transcription factor 1 (HSF1) dissociated from HSP72-HSF1 complexes, underwent trimerization and phosphorylation, and demonstrated DNA binding activity to the heat shock element in the promoter region of the hsp72 gene. UVB also increased hsp72 mRNA, with peak levels observed 1-3 h post-UVR. HSP72 protein was constitutively expressed in keratinocytes, and its expression was increased by UVB, with maximum levels at 6 h post-UVR. The stress response may be extremely important in the protection of human skin from UVB radiation, and modulation of heat shock protein expression and/or function offers a potential therapeutic target in the prevention of photoaging and skin cancer.
Empty spaces within the dermis of paraffin-embedded sections of skin have been attributed to fatty infiltration and postulated to originate from topical steroid administration or sebaceous gland rupture. We examined skin biopsy specimens exhibiting dermal vacuolation to determine whether this phenomenon was associated with specific skin diseases and to attempt to illuminate its etiology. Routine hematoxylin-eosin-stained sections from 26 formalin-fixed, paraffin-embedded biopsy specimens were examined. Histochemical stains for mucin and immunohistochemical staining for S100 protein and vascular markers were performed. Dermal vacuolation was characterized by empty spaces, 15-120 microm in diameter, in the superficial dermis, associated with either fibrosis/sclerosis or a lymphocytic infiltrate. There was no relationship to clinical findings, topical steroid treatment, or histologic diagnosis. There was no evidence of true adipocyte differentiation, and vascular markers were negative. Transmission electron microscopy showed nonmembrane-bound irregular spaces in the dermis. Dermal vacuoles likely represent an artifact of tissue fixation or processing and are unrelated to the underlying pathologic process. We propose the name pseudolipomatosis cutis, analogous to insufflation-induced colonic vacuolation, to distinguish this phenomenon from true dermal fatty infiltration and to emphasize its incidental, likely artifactual nature.
BACKGROUND: p53 protects the integrity of the genome by inducing programed cell death or by promoting DNA repair. We have previously shown that loss or mutation of p53 leads to reduced DNA repair in keratinocytes. OBJECTIVE: The hypothesis that p53 regulates repair of ultraviolet light-induced epidermal DNA damage in vivo was tested in mice. METHODS: An immunohistochemical assay for pyrimidine dimers and 6-4 photoproducts was performed on ultraviolet-irradiated skin from p53 null (-/-) and wild type (+/+) mice. Immunostaining for photoproducts was quantified using computer-assisted imaging. The level of DNA repair was then expressed as the percentage of positive cells remaining as compared to the zero hour time point. RESULTS: p53+/+ mouse skin exposed to 1000 J/m2 retained ' 25% of epidermal cyclobutane dimers at 48 h, whereas approximately 50% remained in p53-/- cells. Using the same UV dose, p53+/+ mice retained 20% of detectable 6-4 photoproducts by 24 h, whereas about 50% remained in epidermal cells of p53-deficient mice. CONCLUSION: Using in situ labelling of UV-damaged cells, we confirm our earlier conclusion that p53 regulates DNA repair within the epidermis after exposure to UV light.
BACKGROUND: Multinucleate cell angiohistiocytoma (MCAH) is a rare cutaneous disorder that usually presents as papules or nodules. OBJECTIVE: This article reports a case of MCAH that appeared clinically as a large cutaneous plaque. METHODS AND RESULTS: A 74-year-old woman presented with a large painless, dusky red, indurated plaque measuring 12 x 6 cm on the trunk that was found on histopathologic examination to be a MCAH. Based on a literature review, this is the first reported case of MCAH presenting as a plaque rather than a papule or nodule. CONCLUSION: Multinucleate cell angiohistiocytoma may manifest clinically as a solitary cutaneous plaque.
Metastatic malignant melanoma (MM) is usually incurable and responds poorly to chemotherapy. Because many cytotoxic drugs cause cell death by inducing apoptosis, an imbalance of apoptosis regulatory proteins may contribute to MM treatment resistance. We have previously shown reduced expression of Bcl-2 protein, a negative regulator of apoptosis, in MM as compared with benign nevi. It is hypothesized that other apoptosis regulators may be involved in survival of MM cells. We examined the expression of Bax, Bcl-2, Bcl-X, and Mcl-1 in human benign nevi, primary MM, and metastatic MM using immunohistochemistry. Results were confirmed with Western blotting. The proapoptotic protein, Bax, was surprisingly overexpressed in all MM samples compared with benign nevi. Interestingly, in most MM samples there was overexpression of Mcl-1 or Bcl-XL, both negative regulators of apoptosis. Increased expression of Mcl-1 and Bcl-XL was first observed in thin primary melanomas, suggesting that up-regulation of these proteins represents a relatively early event associated with malignant transformation in MM. As published previously, the majority of primary and metastatic MM exhibited reduced Bcl-2 levels. We conclude that the apoptosis inhibitors Bcl-XL or Mcl-1, alone or in combination, may circumvent the normal cell death pathway, contributing to the pathogenesis and treatment resistance in metastatic MM.
p21(WAF1/CIP1) (p21) is an inhibitor of cyclin-dependent kinases recently identified as the downstream effector of wild-type p53-mediated cell cycle arrest. The gene coding for p21 may function as a negative regulator of melanoma growth, progression, and metastasis. Using immunohistochemistry and Western blotting, we investigated the expression of p21 in human melanocytic proliferations. Immunohistochemical staining was performed on 13 common acquired nevi, 12 dysplastic nevi, 23 primary malignant melanomas, and 12 metastatic melanomas. Common acquired nevi showed minimal p21 staining (1.8+/-0.3%, mean+/-SEM). The percentage of positive nuclei was slightly elevated in dysplastic nevi (8.9+/-1.7%). Both primary malignant melanoma (29+/-3%) and metastatic melanoma (33+/-5%) demonstrated a significantly increased number of p21-positive nuclei compared to benign lesions (p<0.001). p21 was strongly expressed even in actively proliferating lesions as confirmed by MIB-1 labelling, and although the majority of p21-positive cells likely represent a non-proliferating population, staining was occasionally observed in cells undergoing mitosis, suggesting abnormal function of this cell cycle inhibitor in malignant melanoma. Overexpression of p21 in metastatic melanoma compared to common acquired nevi was confirmed by Western blot analysis of human tumor samples. These findings suggest that increased p21 expression relative to benign nevi is not sufficient to control melanoma growth in vivo.
Sezary syndrome is an uncommon variant of cutaneous T-cell lymphoma (CTCL) characterized by erythroderma, pruritus, adenopathy, and circulating atypical T-lymphocytes with cerebriform nuclei. The definition of Sezary syndrome can be further refined by including only patients with a circulating peripheral blood population of clonal T-cells. We have evaluated 79 skin biopsies from such a group of 41 erythrodermic patients with circulating Sezary cells and a clonal population of T-cells detected by T-cell receptor-beta gene rearrangement on Southern analysis of peripheral blood mononuclear cells. Histopathologic features consistent with chronic dermatitis were observed in 26/79 (33%) skin biopsy specimens, emphasizing that a non-specific histologic appearance is common. Evidence of CTCL was lacking in 11/41 patients on biopsy of their erythrodermic skin. The survival of these patients was not significantly different from 30/41 patients in whom skin biopsies revealed changes diagnostic of CTCL, such as a dermal lymphocytic band with atypical lymphocytes (18/79, 23%) or a mycosis fungoides-like infiltrate (30/79, 38%). This study confirms that non-specific cutaneous histopathologic findings are common in Sezary syndrome, even when a circulating T-cell clone is present. This stresses the need for peripheral blood genetic analysis and for multiple or repeat skin biopsies in erythrodermic patients when there is high clinical suspicion of CTCL.
The role of the tumor suppressor p53 in repair of ultraviolet light (UV)-induced DNA damage was evaluated using a host-cell reactivation (HCR) assay. HCR determines a cell's ability to repair UV-damaged DNA through reactivation of a transfected CAT reported plasmid. Most UV damage is removed through nucleotide excision repair (NER). Primary murine keratinocytes isolated from p53-deficient and wild-type p53 mice were used in the HCR assay. The NER was reduced in p53-/- keratinocytes as compared with p53+/+ keratinocytes. The reduced DNA repair in p53-/- mice was confirmed with a radioimmunoassay comparing cyclobutane dimers (CPDs) and (6-4) photoproducts in p53+/+ and p53-/- keratinocytes after the cells were exposed to UV irradiation. Our results demonstrate that wildtype p53 plays a significant role in regulating NER. Furthermore, as there is evidence that p53 protein levels decrease after keratinocytes become differentiated, we sought to determine whether p53 plays a role in NER in differentiated keratinocytes. Differentiation of the keratinocytes by increasing the Ca2+ concentration in the culture media resulted in a marked reduction in NER equally in both p53+/+ and p53-/- groups. This finding suggests that reduced DNA repair after differentiation is p53 independent. A similar reduction in HCR was confirmed in differentiated human keratinocytes. These data, taken together, indicate that p53 or p53-regulated proteins enhance NER in basal undifferentiated keratinocytes but not in differentiated cells. As nonmelanoma skin cancers originate from the basal keratinocytes, our findings suggest that loss of p53 may contribute to the pathogenesis of this common skin cancer.
Dermatomyofibroma is a rare, plaque-like, cutaneous myofibroblastic proliferation that usually presents as a 1-2 cm, firm, dermal plaque, often with brown-red discoloration. We report an example of dermatomyofibroma presenting as a poorly defined, linear, indurated area, 8 cm in length, on the posterior aspect of the neck of a 20-year-old female. This lesion is the largest dermatomyofibroma reported to date and the first to demonstrate a linear distribution.
The finding of mitotic figures in granuloma annulare (GA) has not been emphasized in the literature. We describe 20 cases of a cellular, mitotically active variant of GA; we defined this group as cases having > or = 1 mitosis per 10 hpf. Clinically, the lesions could not be distinguished from typical, localized GA: there were 9 males and 11 females with a mean patient age of 49 +/- 15 years (mean +/- SD), compared to 45 +/- 20 years in a randomly selected control group of 60 patients with GA, and no unusual sites of predilection were noted. Histologically, a classic, palisading granuloma pattern predominated (18/20 cases). Lesions were located in the mid-dermis and tended to be more cellular than typical GA. The histiocytes comprising the lesion often had enlarged nuclei and prominent nucleoli. The number of mitoses per 10 hpf was 3.0 +/- 1.5 (range 1.0-7.2), control group 0.3 +/- 0.5; occasional atypical mitotic figures were observed. The proliferative nature of these lesions was confirmed using MIB-1 staining; the percentage of MIB-1 positive cells ranged from 5%-29% (mean 15 +/- 6%). Mitotic GA must be distinguished histologically from neoplastic processes, in particular epithelioid sarcoma. We conclude that histiocytes in clinically typical GA can exhibit an increased mitotic rate. Recognition of this variant is important in order to avoid overdiagnosis of a malignant condition.
Pemphigus herpetiformis is a rare pemphigus variant with light microscopic features that have historically been described as either "acantholytic dermatitis herpetiformis" or as "eosinophilic spongiosis in pemphigus". The clinical features of this form of pemphigus are reminiscent of dermatitis herpetiformis; however, the direct immunofluorescence finding of epidermal inter-cellular IgG deposition is that of the pemphigus group. We report two patients with clinical presentations suggestive of dermatitis herpetiformis in whom the histopathologic features were those of a neutrophilic intraepidermal blistering disorder. Biopsies showed marked epidermal spongiosis with midepidermal acantholytic vesicles containing predominantly neutrophils and a few eosinophils. Direct immunofluorescence was positive for epidermal intercellular IgG; IgA deposition was not present. Neutrophilic spongiosis, in the absence of a prominent eosinophilic infiltrate, should be recognized as an early finding in some cases of pemphigus, and immunofluorescence studies are justified when this histologic feature is encountered in a skin biopsy.