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Background: Classic Kaposi sarcoma (CKS) is a relatively rare vascular disease primarily affecting human immunodeficiency virus (HIV)-uninfected elderly men. The infection with Kaposi sarcoma-associated herpesvirus (KSHV) is necessary for the establishment of Kaposi sarcoma (KS), although it is not sufficient. Thus, only a small fraction of KSHV-infected individuals develops KS. The cofactors that influence risk of KS among HIV-uninfected individuals are yet to be determined. The objective of the current study was to assess potential risk factors for CKS in the KSHV-infected Jewish population in Israel., Methods: A case-control study involved 35 CKS cases and 48 matched KSHV-infected controls. Lifestyle and medical history data from case patients and controls were compared by logistic regression analysis., Results: In a multivariate analysis, the authors identified an age-related small increased risk for CKS in subjects originating from Asia and Africa. The risk for CKS increased, although not significantly statistically, in subjects who reported alcohol consumption, diabetes mellitus, herpes simplex, and asthma. No relation was found with cigarette smoking, family size, number of lifetime sexual partners, or sexually transmitted disease., Conclusions: A borderline increase in CKS risk among elderly subjects originating from Africa or Asia was identified. These results need to be further evaluated by larger studies. The authors believe that genetic and immunologic parameters may alter risk for CKS and, therefore, should also be investigated.

Background: Classic Kaposi's sarcoma (CKS) primarily affects elderly Mediterranean or Eastern European men. Incidence rates of CKS in Israel are among the world's highest. In practically all cases, antibodies against Kaposi's sarcoma-associated herpesvirus (KSHV) can be detected. A relatively high seroprevalence rate of KSHV in Israel generally correlates with the incidence of CKS. A sexual mode of virus transmission is recognized among homosexual men, whereas the precise transmission routes in the heterosexual population and those with CKS are still unclear., Objective: To better assess the transmission routes of KSHV in Israeli patients with CKS and their first-degree relatives as compared with a control group., Design: Serum was collected from all study participants and tested for KSHV antibodies by means of latent and lytic immunofluorescence assays. An open reading frame 65 (ORF65) Western blot assay was applied as a confirmatory tool., Setting: Three dermatological departments in Israel., Patients: Sixty-four Jewish patients with CKS, 143 of their first-degree relatives, and 186 hospital-based control subjects., Results: Seropositivity to KSHV was detected in 62 (96.9%) of the patients with CKS, in 56 (39.2%) of their first-degree relatives, and in only 21 (11.3%) of the hospital controls (P<.001). The specific relationship with the index patient (spouse, offspring, or sibling) had no significant effect on the prevalence of serpositivity in the family members., Conclusion: Our serologic evidence of familial clustering of KSHV infection suggests a predominantly nonsexual horizontal transmission route of the virus.

It is widely accepted that there is a causal association between Kaposi sarcoma-associated herpesvirus (KSHV) and Kaposi sarcoma (KS). However, the majority of individuals infected with KSHV never develop KS. Here, we present a unique familial case of classic KS, in which the disease occurs in 4 siblings who have no recognized underlying immunodeficiency. We examine risk factors that could play a role in this condition, including KSHV infection, KSHV DNA load, genetic variants of KSHV, infection with additional viruses, interleukin-6-promoter polymorphism, and HLA genotype. We hypothesize that a genetic susceptibility to KS, in combination with KSHV infection, may play an important role in the presented familial case.

Aim: Familial cases of Kaposi's sarcoma (KS) are rare, and have all been described in patients with the classical variant of the disease. The predisposition of classical Kaposi's sarcoma among Jews is well known. We herein describe five families, all Jews, in which two members have Kaposi's sarcoma. To our knowledge, this has been the largest reported series of familial Kaposi's sarcoma., Patients and Methods: The clinical course, management and response to therapy were described and compared with other published cases., Results: No similarity was found in any of the families in time and age of onset of the disease, or in the severity and course of the disease among the members of the same family. There was a high incidence of second neoplasms among these familial cases., Conclusions: We discuss the potential implications of second neoplasms based on our understanding of the pathogenesis of the disease, as well as the influence or predisposal of some genetic mechanisms to the development of Kaposi's sarcoma.

Trends in the incidence of classic Kaposi's sarcoma in the Jewish population in Israel for the period between 1960 and 1998 were analysed. World standardised incidence rates of 20.7 and 7.5 per million among men and women, respectively, were calculated. The highest incidence rates were displayed by men originated from Africa and by Asian-born women.

Background: Classical Kaposi sarcoma (CKS) is a rare indolent neoplasm that is particularly prevalent among Jews of Ashkenazi and Mediterranean origin. Data regarding prognostic factors for CKS are scarce. The aim of the current retrospective analysis was to better define prognostic subgroups among patients with CKS., Methods: Between 1960 and 1995, 248 consecutive patients with CKS were treated at the Rambam and Rabin Medical Centers in Israel. Although treatment options included local excision, radiotherapy, and chemotherapy, observation alone was used for 31% of patients. For prognostic factor analysis, disease progression was classified as any progression and dissemination, and progression-free survival was calculated for each., Results: At a median follow-up of 20 months, four patients (1.6%) died of CKS. Of the patients eligible for analysis, 94 of 220 (39%) had any progression and 23 of 120 (18%) had dissemination. Only 8 of 202 (4%) had visceral spread. On univariate analysis, age was a statistically significant prognostic factor for any progression (P = 0.04), whereas immunosuppression and visceral involvement at presentation had only borderline significance. Immunosuppression was the only prognostic factor for dissemination (P = 0.003). On multivariate analysis, both age and immunosuppression were significant prognostic factors for any progression (P = 0.001 and 0.01, respectively). Immunosuppression was also predictive of dissemination (P = 0.006)., Conclusions: Immunosuppression and older age (50 years and older) are strongly associated with poorer outcome among CKS patients. The two end points used in this study may be used for future prognostic factor analyses., (Copyright 2002 American Cancer Society.)

A previous study demonstrated that, in generalized granuloma annulare in the epidermis, the Langerhans' cell section area and the number of Langerhans' cell granules or Birbeck granules per cell section were increased, suggesting an active state of these Langerhans' cells. Reexamination by transmission electron microscopy of the same tissue, but in samples also containing dermal tissue, from the same subjects revealed endothelial cells with rod-shaped bodies resembling Birbeck granules or Birbeck granule-like structures. This finding has not been previously described in blood vessels of human skin and is described here.

Background: Androgenetic alopecia is considered to be genetically determined. Recently, a rare autosomal recessive form of hereditary alopecia, termed atrichia with papular lesions (APL), was found to result from mutations in the human hairless gene., Objective: Our aim was to assess the pattern of androgenetic alopecia in heterozygous carriers of a deleterious mutation in the human hairless gene., Methods: Healthy male second-degree relatives (n = 31) of patients affected with APL and belonging to a large consanguineous kindred were interviewed and given a Hamilton score of baldness. DNA was obtained from each subject and analyzed for the presence of a mutation in the human hairless gene known to affect this family. The age at onset and extent of baldness were compared in healthy homozygotes and heterozygous carriers of the mutation., Results: Statistical analysis of the results revealed no differences in age at onset and extent of androgenetic alopecia between the two groups of subjects., Conclusion: The present study reports the first attempt to characterize the phenotype of heterozygous carriers of a mutation in the human hairless gene. It indicates that the presence of a deleterious mutation in one allele of the hairless gene does not affect the pattern of androgenetic hair loss.

Background: The histopathologic differential diagnosis of Spitz nevus (SN) from malignant melanoma (MM) may be difficult., Objective: We attempted to elucidate the pattern of expression of a newly recognized melanocyte-specific melanosomal protein MART-1 in routinely processed specimens of SNs, MMs, and ordinary melanocytic nevi (MNs) and to see whether it can help to differentiate between them., Methods: Twenty SN, 22 MM, and 27 ordinary MN were immunostained with anti-MART-1 monoclonal antibody (clone A103)., Results: All SNs, MNs, and MMs demonstrated cytoplasmic staining for MART-1 in some of their tumor cells, of which 17 of 20 (85%) and 24 of 27 (89%) of SN and MN, respectively, demonstrated positive stainings in more than half of their tumor cells, as compared with only 10 of 22 (45%) of the MM (P <.05). The majority of lesions in all 3 types of tumors showed a homogeneous mode of staining, although MM tended to show a more heterogeneous pattern. A consistent pattern of stratification of staining with progressive descent into the dermis was not demonstrated in these tumors., Conclusion: MART-1 does not differentiate between SN, MM, and ordinary MN in a consistent pattern, but it may be used as a marker for these tumors.

Background: The morphology of Kaposi's sarcoma is clinically and histologically the same in all clinical forms of the disease. However, there is a difference in the clinical and biological behaviour of the different forms of the disease. The behaviour also differs among individuals with the same form. The factors involved in the initiation and prognosis of the disease are still unknown. The classical form is more common in middle-aged Jews of East European or Mediterranean origin, people of Italian and southern Greek origin. Classic Kaposi's Sarcoma is seen relatively more frequently in Israel than in many other countries., Objective: The aim of this study was to examine risk factors that influence the development and course of the disease., Methods: This retrospective study includes 125 patients with Kaposi's sarcoma, all diagnosed and followed in the Department of Dermatology at Rambam Medical Center in Haifa., Results: The group included 85 (68%) men and 40 (32%) women. Fourteen subjects received corticosteroid therapy and three were kidney transplant recipients. Age at onset of the disease was 21-87 years, with a mean age of 67. A total of 121 patients (96.8%) were Jews and four (3.2%) were non-Jews. A majority (61.6%) were of East European origin. The number of new cases each year was constant in relation to the general population, except for two peaks, one in 1970 and another in 1986-89. The lower limbs were involved in most patients. Extracutaneous involvement was present in 18.4%. Of all the subjects, 28 (22.4%) had diabetes mellitus and 21 (16.8%) had a second primary malignancy. The malignancies were of lymphoreticular origin in 10 patients, four in the urinary bladder, three had carcinoma of the large bowel and one of the pancreas., Conclusion: Our study shows similar clinical findings to those described in other series. The relatively high frequency of carcinomas of the colon and urinary bladder was not reported elsewhere. We observed a consistent rate of new cases each year with two peaks in 1970 and 1986-1989, the cause of which deserves explanation. Of interest is the relative rise in the number of females with Kaposi's sarcoma. A relative high risk for developing Kaposi's sarcoma has been found among Jews of Ashkenazi origin compared to those of other ethnic groups. Israeli-born subjects presented a relatively more aggressive course of disease than others.

Atrichia with papular lesions is a rare autosomal recessive form of alopecia characterized by hair loss soon after birth and the development during childhood of a diffuse papular rash. We have previously shown that this disorder results from a deleterious mutation in the human hairless gene, a gene also involved in the pathogenesis of a related but clinically distinct form of congenital alopecia, termed alopecia universalis congenita. In this report, we describe a novel nonsense mutation in exon 4 of the human hairless gene in a consanguineous kindred affected with atrichia with papular lesions. This report provides additional evidence for phenotypic heterogeneity among inherited atrichias and for an association between the papular rash of atrichia with papular lesions and nonsense mutations in the human hairless gene.

Recently, we showed that atrichia with papular lesions (APL), a rare inherited form of alopecia, is transmitted as an autosomal recessive trait in a large inbred kindred of Israeli-Arab origin. Furthermore, we mapped the APL locus to a 5-cM region of chromosome 8p12 in this family. The human "hairless" gene is a candidate target gene for the disease mutation because it maps to the APL locus and because it was recently found to be mutated in a related but clinically distinct form of alopecia known as "alopecia universalis" or "congenital alopecia." In the present study, the coding sequence of the hairless gene was compared by reverse transcription-PCR in fibroblast cell lines derived from an affected patient and an unrelated individual. We identified a single-base deletion (3434delC) in the hairless gene that cosegregated with the disease phenotype in the family. This deletion is predicted to cause a frameshift mutation in the highly conserved C-terminal part of the hairless protein, a region putatively involved in the transcription factor activity of the hairless gene product. The present results are indicative of phenotypic heterogeneity in inherited atrichias caused by mutations in the hairless gene, suggesting different roles for the regions mutated in APL and in other forms of congenital atrichia during hair development.

Impaired regulation of apoptosis is known to be associated with the development of various forms of cancer. Fas binding to its ligand, Fas ligand (Fas-L), has been shown to trigger apoptosis in various cell types. Fas-L is expressed by melanoma cells and has been suggested to play a role in melanoma escape from immune surveillance. In the present study, we assessed apoptotic activity and examined Fas and Fas-L expression in malignant melanomas, Spitz nevi and ordinary melanocytic nevi. We evaluated apoptotic activity using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling. Apoptotic activity was found to be minimal in melanomas and moderate in Spitz nevi. In contrast, common nevi demonstrated significant levels of apoptosis in the deep parts of the tumor. Fas was found to be expressed by all Spitz nevi, most melanocytic nevi and approximately half of the malignant melanoma specimens. Fas expression was also significantly more pronounced in Spitz nevus cells as compared with the two other tumors. The anti-Fas-L antibody was found to stain all three melanocytic tumors. Staining was shown to be stronger and more frequent in melanoma cells as compared to the nevus cells. Using the Spearman test, no significant correlation between Fas-L expression in melanoma cells and apoptosis in MM-infiltrating mononuclear cells was found, suggesting that Fas-L expression in melanoma cells may not be instrumental in their ability to escape immune mechanisms of defense. In contrast, increased levels of apoptosis in the deep parts of melanocytic nevi may reflect and possibly contribute to their benign nature.

Atrichia with papular lesions (APL) (OMIM 209500) is a hereditary form of alopecia. Hair loss occurs soon after birth and is followed years later by the development of a diffuse papular eruption. Its mode of transmission is still uncertain. A related but clinically distinct form of alopecia, known as alopecia universalis (OMIM 203655), has recently been found to be associated with a mutation in the human hairless gene. The present report describes the largest consanguineous kindred of APL reported to date and provides strong evidence for autosomal recessive inheritance of this rare disorder. On the basis of a linkage analysis of this kindred using six microsatellite markers spanning the human hairless gene region, we found that the APL locus maps to chromosome region 8p12 in a 5 cM interval between marker D8S560 and marker D8S1739. A maximum lodscore of 3.7 was obtained with marker D8S1786, at a recombination fraction of 0. Our results suggest phenotypic variability at the hairless locus although they do not rule out the existence of a gene cluster associated with hair disorders in the same region.

Methotrexate is widely used in the treatment of severe psoriasis. However, little is currently known about the mechanisms underlying its therapeutic activity in the skin. Methotrexate has been shown to be carried into cells through the reduced folate carrier (RFC-1). The recent cloning and characterization of the human gene encoding this transmembranal carrier enabled us to investigate RFC-1 gene expression in human skin. Biopsies were obtained from the skin of healthy and psoriatic volunteers. RNA extracted from these biopsies was analyzed by the reverse transcriptase-polymerase chain reaction technique. While RFC-1 gene expression was barely detectable in the uninvolved skin of psoriatic patients and in the skin of healthy volunteers, high levels of RFC-1 transcripts were found in biopsies obtained from psoriatic plaques. To further investigate this pattern of gene expression, we studied skin biopsies by in situ hybridization with a labeled antisense riboprobe specific for the RFC-1 gene. The RFC-1 gene was found to be weakly expressed in the epidermis, in biopsies obtained from the skin of healthy subjects as well as in those from the uninvolved skin of psoriatic patients. In contrast, in biopsies obtained from psoriatic plaques, high levels of RFC-1 gene transcripts were found mostly in the spinous layer of the epidermis. These results suggest the existence of a specific methotrexate carrier in the human epidermis, and may bear relevance to the cutaneous manifestations of methotrexate toxicity.

Background: The histopathologic diagnosis of mycosis fungoides (MF) may be difficult., Objective: Our purpose was to evaluate the role of immunophenotyping and T-cell receptor (TCR) gene rearrangement studies as an adjunct to the histopathologic diagnosis of MF., Methods: Immunohistochemical studies with antibodies to CD4, CD5, CD7, and CD8 and TCR gamma gene rearrangement analysis with a polymerase chain reaction were performed on fresh-frozen material of patients with "classic" histology of MF, "inconclusive" histology, and benign inflammatory dermatoses., Results: Clonal TCR gamma gene rearrangements were found in 11 of 16 (69%) of classic MF cases, in 3 of 19 (16%) of inconclusive cases, and in none of the 12 inflammatory dermatoses cases (P < .05 and P < .001, respectively). Only the mean CD7 counts were statistically significantly different between these 3 groups (MF < inconclusive < inflammatory)., Conclusion: Inconclusive histology is probably a heterogeneous group in which CD7 counts and TCR gamma gene rearrangement studies might help to differentiate the MF cases from the benign cases.

The expression of c-fos protein was studied in formalin-fixed, paraffin-embedded sections of 11 compound Spitz nevi (SNs), 16 ordinary compound melanocytic nevi (MNs), and 17 malignant melanomas (MMs) using monoclonal antibody MAB1283 and an immunoperoxidase technique. Eleven (100%) SNs, 15 (94%) MNs, and 16 (94%) MMs showed positive reactions in some of the tumor cells (p = nonsignificant). In the majority of the tumors the staining was located in nuclei and graded as moderate to strong in intensity. The percentages of positively stained cells did not differentiate the three types of tumor, although they were higher in the melanocytic nevi. Most of the lesions with a significant dermal component did not show stratification of staining with progressive descent into the dermis. Positive staining for c-fos was also frequently found in the normal skin constituents within and adjacent to the melanocytic tumors. In conclusion, the pattern of expression of c-fos in routinely processed specimens does not differentiate between SNs, MNs, and MMs.

Background: Diabetic dermopathy is the most common cutaneous marker of diabetes mellitus. The relationship of diabetic dermopathy to internal complications of diabetes mellitus, such as nephropathy, retinopathy, and neuropathy, is still unknown., Methods: The possible role of diabetic dermopathy as a clinical sign of internal complications in diabetes mellitus was investigated. One hundred and seventy-three patients with diabetes mellitus, of whom 125 (72%) had insulin-dependent diabetes mellitus and 48 (28%) had non-insulin-dependent diabetes mellitus, were studied., Results: Diabetic dermopathy was present in 69 (40%) of patients, statistically more significant in patients 50 years of age and older. The mean diabetic duration was significantly higher in patients with diabetic dermopathy than in those without. The associations of diabetic dermopathy with retinopathy, nephropathy, and neuropathy were each statistically significant, and the increased frequency of diabetic dermopathy correlated with an increased number of these three complications in each patient., Conclusions: Some of the factors that affect the development of internal complications in diabetes mellitus may play a role in the development of diabetic dermopathy, and diabetic dermopathy may serve as a clinical sign of an increased likelihood of these internal complications in diabetic patients.

This study was performed in an attempt to further elucidate the pathogenesis of delayed postburn blistering. Two cases were studied ultrastructurally and immunohistochemically, 1 with blisters on the recipient site of autologous split-thickness skin grafts and the other on the donor site. Ultrastructurally, the basement membrane was on the roof of the blisters in both cases, except for a single small blister in the first case where it was on the dermal floor. In the blister roofs, the basement membrane showed small or marked segments of discontinuity. In the adjacent non-blistered healed skin, the basement membrane was usually continuous, and anchoring fibrils were present. Immunoperoxidase staining on frozen sections, using antibodies to laminin, laminin 5, collagen IV, and collagen VII, showed a mostly continuous linear pattern in the adjacent non-blistered skin, which often became discontinuous near the blisters and markedly discontinuous in the blister roofs. In the blister floors, weakly stained linear or granular deposits of some of these components were sometimes also present. The results of this study support discontinuity of the basement membrane as the main anomaly in delayed postburn blistering. Disturbance in the reassembly or local breakdown of the basement membrane components might be the underlying defect.

Livedo reticularis is associated with collagen vascular diseases and other vaso-occlusive disorders in a substantial number of cases. In the remaining cases the cause of livedo reticularis is still unknown. (i.e., idiopathic). We sought to determine a possible causal relationship between idiopathic livedo reticularis and autoimmune factors associated with the coagulation system, including antiendothelial cell antibodies. Nine patients with idiopathic livedo reticularis were studied. All patients were found to have normal platelet count, fibrinogen levels, and prothrombin and activated partial thromboplastin times, as well as negative results for Venereal Disease Research Laboratory and D-timer tests. Anticoagulant activity was detected in 2 patients: one had positive results of thromboplastin titration index and Russell's viper venom test, as well as increased levels of anticardiolipin antibodies and anti-endothelial cell antibodies; the other has positive thromboplastin titration index, mildly increased levels of anti-endothelial cell antibodies, and markedly increased levels of antinuclear antibodies. A third patient had mildly increased levels of anti-endothelial cell antibodies alone, and a fourth patient had mildly increased levels of antinuclear antibodies only. The clinical outcome was uneventful in all of the patients during an 18-month follow-up period. These findings suggest involvement of autoimmune factors associated with the coagulation system in some patients with idiopathic livedo reticularis, whose clinical significance remains to be determined.

The expression of c-myc protein was studied in formalin-fixed, paraffin-embedded sections of 16 compound Spitz nevi (SNs), 20 ordinary compound melanocytic nevi (MNs) and 30 malignant melanomas (MMs), using monoclonal antibody 9E10 and an immunoperoxidase technique. Nine (56%) SNs, 16 (80%) MNs and 23 (77%) MMs showed positive reactions in some of the tumor cells (P = non-significant). The staining reactions were mostly cytoplasmic, and moderate to strong in intensity. The frequencies of positively stained cells were higher in the MN and SN groups. Most of the lesions with a significant dermal component did not show stratification of staining with progressive descent into the dermis. Therefore, the mode of expression of c-myc in routinely processed specimens does not differentiate between SNs, MNs and MMs. One possible reason is that the increased expression of the c-myc protein is not sufficient alone to promote proliferation and malignant transformation in these types of tumors.

A parallel-group double-blind study was carried out which compared the efficacy of chemical avulsion of affected nail by urea 40% and bifonazole 1% cream alone with that of the same local therapy combined with short-term oral griseofulvin in onychomycosis. A total of 120 patients were included in the study. Patients' characteristics were comparable in both treatment groups. Of the 98 patients fully evaluated, 91 had toenail involvement and only seven had fingernail involvement. Forty-six of the patients were men and 51 were women. The mean age of the patients was 47.14 +/- 13.84 years (range 17-80 years). The duration of onychomycosis was for more than 1 year in 96 patients and for 3 months duration in only one patient, who was in the placebo group. Forty patients had received different previous therapies. All topical treatments were discontinued for at least 2 weeks and oral therapy for at least 2 months prior to the beginning of the study. The diagnosis was confirmed by positive mycologic cultures. Trychophyton rubrum was identified as the pathogen in 90 patients, 45 in each group, T. tonsurans in four patients, two in each group, and T. mentagrophytes in three patients, two in the griseofulvin treated group, and one in the placebo group. The first phase of treatment given to all patients consisted of occlusive dressing every 24 h with urea 40% and bifonazole 1% ointment until the infected nail became completely detached. Subsequently, in the second phase bifonazole 1% cream was applied to the nail ped every 24 h for 4 weeks. In addition, concomitantly with the bifonazole cream the patients were randomly allocated to a daily oral double-blind treatment with griseofulvin 500 mg or placebo, for 4 weeks. Clinical and mycologic evaluations were carried out at baseline, immediately after removal of the nail, and at 3 days, 4 weeks, and 4 months after the end of treatment with bifonazole cream and griseofulvin/placebo tablets. Mycologic examination included identification of fungi by KOH preparation and culture on potato dextrose agar. Positive cultures were transfered for identification on Sabouraud's. Criteria for evaluation of efficacy comprised: "cure" defined as clinical and mycologic cure (fresh specimen and culture negative) at both investigation times after the end of treatment; "late cure" defined as mycologic cure at both investigation times after the end of treatment, clinical clearing of the nail only 4 months after the end of treatment; "improvement" defined as mycologic cure and only partial clinical improvement at both times after the end of treatment; "failure" indicating no mycologic cure (fresh specimen and/or culture positive); and "relapse" signifying a change from negative findings 1 month after the end of treatment to positive findings 4 months after the end of treatment. Adverse reactions were evaluated on each visit. Only those patients who had completed clinical and mycologic evaluation during the entire study were included in the final statistical analysis. Those patients with partial evaluation were included only in the evaluation of adverse events. Based on the assumptions of a failure rate (failure and relapse) of 30% with bifonazole cream alone and of 10% with bifonazole cream and griseofulvin tables, a = 0.05 and b = 0.2 the required sample size was at least 58 patients for each treatment group (Casagrande formula, one-sided test). The primary efficacy variable "assessment of treatment" (cure and improvement versus failure and relapse) was tested for treatment differences by Fisher's exact test (a = 0.05, one-sided test; Ho, no advantage with additional systemic therapy of griseofulvin). Additionally, the relapse rates of both treatments were tested exploratively in the same way as the primary efficacy variable. All other data were analyzed descriptively.

Mucinous syringometaplasia (MS) is an unusual skin lesion of unknown etiology, characterized histologically by epidermal invaginations lined by mucin-laden goblet-like cells and by nonkeratinized squamous cells. The present case study was performed to elucidate further the characteristics of this lesion using immunohistochemistry and electron microscopy. The mucin-laden cells in the MS lesion stained positively for carcinoembryonic antigen, epithelial membrane antigen, and low molecular weight keratins. The ultrastructural examination, which was performed on deparaffined sections, revealed two morphological variants of mucous granules. Electron-dense mucous granules predominated in the mucus-containing cells, which were situated among the keratinocytes adjacent to the epidermal invaginations, mostly in the lower parts of the epidermis. Larger, electron-lucent granules containing flocculent material were found more abundantly in the cells lining the epidermal invaginations. Also, some of the mucus-containing cells showed bundles of tonofilaments; structures that appeared to be isolated short, stubby microvilli; and attachments to adjacent mucus-containing cells and keratinocytes by desmosomes. The ultrastructural and immunohistochemical findings in our case suggest that the mucinous changes occurred as a metaplastic process in the resident epidermal cells and were accompanied by changes in cellular antigen expression resembling those of simple secretory epithelium.

The present study was performed to determine the frequency of p53 protein immunoreactivity in classical Kaposi's sarcoma (KS) as a whole and in relation to the histological subtypes which are considered to correspond to the developmental stages of the tumor. The accumulation of p53 protein was studied immunohistochemically using monoclonal antibody BP53-12 on formalin-fixed paraffin-embedded sections of 36 KS lesions, of which 14 were classified histologically as early type and 22 as spindle-cell or mixed type. No positive immunoreactivity was detected in any of the 14 early-type lesions. Among the 22 spindle-cell and mixed variants, positive staining was detected in 5-10% of the tumor cells in one lesion, 1-5% of the cells in six lesions, and in < 1% of the cells in two lesions. These very small percentages of positively stained cells in less than half of the cases of the spindle-cell and mixed variants do not support a significant role for p53 in tumor progression and evolution in KS.

The lipid compositions of 8 normolipidemic xanthelasma palpebrarum (XP) lesions were analyzed using thin-layer chromatography, with the adjacent uninvolved skin used as control. The lesions were found to be composed predominantly of cholesterol, mostly cholesteryl ester, whereas in the control specimens phospholipids predominated. The degradation rates of 125I-low-density lipoprotein (LDL), oxidized LDL, and acetyl LDL, and the rates of intracellular cholesterol synthesis from 1,2-(14)C-acetate, in blood monocyte-derived macrophages (MDM) from 3 normolipidemic patients, were similar to those of MDM from 3 normal control subjects. The mean levels of lipid peroxides and conjugated dienes under basal conditions, as well as following the addition of a free radical-generating compound (2,2-azobis-2-amidinopropane hydrochloride) to the plasma of 14 normolipidemic XP patients were significantly higher than those of 14 age- and sex-matched normal controls. We conclude that the predominant lipid accumulated in normolipidemic XP lesions is cholesteryl ester, but there is no evidence for intrinsic cellular cholesterol metabolism derangement in blood MDM from patients which could account for this. Since macrophage cholesterol accumulation can also result from enhanced uptake of increased levels of oxidized LDL, the increased plasma lipid peroxidation (derived from oxidized LDL) might lead to accumulation of cholesterol in macrophages and formation of foam cells via this mechanism.

The accumulation of p53 protein was studied immunohistochemically on paraffin-embedded sections of 26 Spitz nevi (SNs), 26 primary invasive cutaneous malignant melanomas (MMs), 20 metastases of MM, and 17 ordinary compound nevi (CNs), using monoclonal antibody BP53-12. Positive reactivity was detected in some of the tumor cells in seven (35%) metastatic MMs, all exhibiting strong nuclear staining; eight (31%) primary MMs, of which seven showed strong nuclear staining; two (7%) SNs, of which only one showed strong nuclear staining; and none of the CNs. The frequencies of the positively stained lesions in general, and the strongly positively stained lesions in particular, in the MM and metastatic MM groups were each statistically significantly higher than the respective frequencies in the SN and CN groups. We believe that the immunohistochemical detection of p53 protein with the use of monoclonal antibodies such as BP53-12 on paraffin sections, especially when strong nuclear reactivity is demonstrated, may prove to be an adjunctive tool in the histopathologic differentiation of MM from SN.

Several of the methods of treating plaque-stage mycosis fungoides (MF) advocate treatment of the whole skin, although relatively little information exists on the histologic appearance of clinically uninvolved MF skin. Our study was performed to elucidate the histologic appearance of the clinically uninvolved skin of plaque-stage MF patients. Biopsies were taken from the clinically uninvolved skin of 18 untreated patients with plaque-stage MF, 1 cm (near) and > or = 10 cm (far) from the MF plaques, and from 23 normal, healthy controls. Eight to 12 serial sections from each specimen were examined. The most common histologic finding, which was observed in six (33%) biopsies of near skin and four (22%) biopsies of far skin compared with only one (4%) biopsy of normal control (p = 0.02 and 0.1, respectively), consisted of mononuclear-cell infiltrate around a blood vessel in the papillary dermis, with extension of some of these cells into the overlying epidermis. More diffuse and epidermotropic mononuclear cell infiltrates were seen in an additional three (17%) biopsies of near skin, whereas mild nonepidermotropic superficial perivascular or perifollicular mononuclear cell infiltrates were observed in an additional four (17%) biopsies of the normal controls. In conclusion, the most common histologic finding in our study, which was observed predominantly in the MF group, might represent an earlier stage and clinically undetectable involvement of the normal-looking skin in MF patients.

Sixty-three patients (mean age 54 +/- 9 years) who were treated for a basal cell carcinoma (BCC) and 54 control subjects (mean age 51 +/- 11 years) filled out detailed questionnaires on their sun exposure and sun protection habits. Patients were given the questionnaires at least 1 year after their skin tumors had been excised. Differences between patients and controls in mean age, gender, Fitzpatrick's skin type and eye and hair color were statistically nonsignificant. The level of education was high in both patients and controls (mean of 13.4 +/- 3.1 school years). Differences in education were statistically nonsignificant. We found that both patients and controls were knowledgeable about the role of sunscreens in preventing skin tumors (79% and 83% respectively) and in preventing sun-induced aging (90% and 85% respectively). Significantly more patients used sunscreens regularly (64%) compared with controls (36%). Nevertheless, our data show no statistically significant differences between the sun exposure habits of the patients previously treated for BCC and controls. Moreover, we found that, although 82% of the patients declared that they tried to avoid sun, only 49% regularly wore hats or shirts with long sleeves in the summer (19%). Sixty-two percent of the patients used two or fewer bottles of sunscreens per year, which is inadequate for effective year-round sun protection. In addition, we found that many patients, as well as the controls, applied sunscreens only once a day (57% and 46% respectively), did not reapply after swimming (58%, 74% respectively), and did not use sunscreens in the winter (49%, 61%). Our data show that, although patients after BCC removal have a significantly higher sunscreen use compared with controls, the amount and methods of application are less than adequate. Moreover, other simpler methods to prevent photodamage, such as simple sun avoidance or the use of protective clothing, are often neglected.

Because of the abundance of the classical form of Kaposi sarcoma (CKS) among Jews and people of Mediterranean origin, studies have been conducted to find an association between CKS and HLA antigens. No conclusive results have been drawn, although in a number of these investigations an increased incidence of HLA-DR5 was reported. In our study 49 CKS patients of Jewish origin were serologically analyzed for HLA class I and class II antigens. We found no significant deviation in serologically defined HLA antigens frequencies between patients and 99 ethnically matched controls. However, a nonsignificant decrease in the frequencies of HLA-DR4, HLA-DR12, and the combination of DR4/DR11 was observed. Then we determined in these patients HLA-DRB1, HLA-DQA1, and DQB1 allelic polymorphism by oligotyping on PCR-amplified DNA. In this molecular analysis the only notable finding was a decreased frequency of the combination HLA-DQA1*0301/DQB1*0301, which appeared in one (2%) patient compared to 13 (13%) of the controls. However, the decrease was not statistically significant. On the basis of both serological and molecular analysis done on a relatively large group of CKS patients, we conclude that there is no significant linkage between HLA antigens and CKS in Jewish population.

Adult xanthogranulomatosis is an uncommon disorder in which dermal macrophages accumulate cholesterol intracellularly despite normal plasma cholesterol levels. In an attempt to elucidate an underlying biochemical abnormality in this disorder, we studied the rates of 125I-labeled low-density lipoprotein degradation, and intracellular cholesterol synthesis, in human monocyte-derived macrophages of three patients with adult xanthogranulomatosis. In all three patients, the rates of cellular 125I-low-density lipoprotein degradation and of cholesterol synthesis were 22-37% and 14-84% higher than those of the respective normal controls (p < 0.01). These findings suggest that in MDM of adult xanthogranulomatosis patients, the uptake and degradation of low-density lipoprotein-derived cholesterol and intracellular cholesterol biosynthesis are enhanced. Because dermal macrophages are derived from blood monocytes, it is possible that such an enhancement might play a role in the accumulation of cholesteryl esters in the macrophages that form the xanthogranulomatosis lesions.

The histological findings in the first diagnostic biopsy of 50 patients with Kaposi's sarcoma (KS) were classified and were related to the clinical course. Forty-one patients had the "classic KS," of whom 31 had a benign course and 10 an aggressive disease. Nine patients had iatrogenically induced KS. Histologically the following subtypes were found: mixed type in 18 patients, spindle type in 16, early type in 14, and hemangiomatous and lymphangiomatous types in one each. We did not find any statistical relationship between the histological subtypes, degree of nuclear atypia, number of mitoses, and density of the inflammatory cell infiltrates in the KS lesions, and the clinical types and course of the disease. The results of this study do not support the possibility of a prognostic importance regarding the histological features of the early lesions in patients with classic or iatrogenic Kaposi's sarcoma.

We studied 10 biopsies of early (< 1 week) localized granuloma annulare (LGA) lesions and 10 specimens of the normal-looking skin adjacent to actively spreading LGA lesions for signs of vasculitis, using histological and direct immunofluorescent (DIF) techniques. In the early LGA lesions, the collagen fibers showed various forms of alterations, with hyalinization and fragmentation being the most common; in half of these lesions, neutrophils and nuclear fragments in various numbers and densities were found among the altered collagen fibers. Some of the small blood vessels in the areas of granulomatous inflammation showed endothelial cell hypertrophy in four cases, and in one case also endothelial cell proliferation and luminal occlusion. In only one case, a single small blood vessel, which was situated in the center of a palisading granuloma, showed fibrinoid necrosis of its walls. The DIF study of all 20 specimens and the histological study of the 10 specimens of normal-looking adjacent skin did not reveal immune deposits in the vessels' walls, or histological evidence of vasculitis, respectively. We believe that these findings do not support a role of vasculitis in the formation of LGA lesions, but suggest that neutrophils might play a primary or secondary role in their pathogenesis.

We describe a patient who, 2 1/2 years after injection with Zyderm I collagen, developed large erythematous indurated nodules and plaques at the facial injection sites. This occurred despite a prior negative skin test with the injectable material. Histopathologically, a sarcoid-like foreign-body reaction was present in the dermis and subcutaneous fat and muscles. Retesting with Zyderm I collagen on the forearm produced a positive reaction that showed, histologically, a sarcoid-like reaction similar to that which was found in the face. Various modes of therapy have failed to clear the facial lesions and disfigurement.

Dermatofibrosarcoma protuberans is an uncommon skin tumor with a high potential for local recurrence if not adequately excised. There are only two reports in the literature describing dermatofibrosarcoma protuberans that enlarged considerably during pregnancy. On the other hand, the new development or enlargement of dermatofibromas in pregnancy is well documented. We present 2 additional patients in whom a dermatofibrosarcoma protuberans appeared and grew rapidly during pregnancy. Immunohistochemical studies were negative for estrogen and progesterone receptors. The possible pathophysiology and surgical management are presented and discussed.

Pseudoainhum is an infrequent complication in the autosomal-recessive keratodermas. We describe two related families in which the diagnosis of mal de Meleda keratoderma has been confirmed by mode of inheritance and ultrastructural findings. One family member, a 9-year-old girl, developed pseudoainhum which threatened the viability of her little fingers. This responded to treatment with etretinate. The treatment dilemma posed by keratoderma-induced pseudoainhum in children, i.e. the concern over the possible skeletal toxic effects of long-term etretinate treatment vs. the risks and outcome of surgery, is discussed.

Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) has been said to represent a widely dilated, keratin-plugged acrosyringium and dermal duct. We have observed in a case of congenital PEODDN a normal-appearing, acrosyringium-like duct that traverses vertically the entire length of the parakeratotic column. Also, in its lower course, it stained positively for carcinoembryonic antigen, while the inner borders of the invagination from which the parakeratotic column arose stained negatively. This leads us to suggest that the epithelial structure in PEODDN is an abnormally keratinizing epidermal invagination through which an acrosyringium-like duct traverses, rather than an abnormally dilated, parakeratotically plugged acrosyringium and dermal duct.

Background: Conflicting evidence exists on the relation between sun exposure and the number of common acquired nevi. The increase in the number of common acquired nevi until early adulthood and their greater concentration on sun-exposed areas suggested that the growth of common acquired nevi is promoted by UV radiation. Nevertheless, it was noticed that although solar exposure accumulates with age, the number of common acquired nevi decreases after the third decade., Objective: Our purpose was to examine the relation between the prevalence of common acquired nevi and accumulative sun exposure., Methods: The number of common acquired nevi on 128 patients with multiple solar keratoses (SK) was compared with their number on 82 control subjects. The existence of SK served as a biologic marker for long-term solar effects., Results: On patients with SK we counted 1285 nevi (mean 10.0 nevi per person) and on control subjects, 1521 nevi (mean 18.5 nevi) (p = 0.0046; Kruskal-Wallis test). The finding that persons exhibiting signs of accumulating sun effects have fewer nevi was maintained irrespective to differences of gender, occupation, and complexion., Conclusion: Our data suggest that accumulating solar effects may contribute to the natural maturation and elimination of common acquired nevi in late adulthood.

Background: Malignant melanomas (MMs) with a small diameter (less than 6 mm) are rarely removed surgically; therefore there is a need for more data to characterize them., Objective: The purpose of this study was to further elucidate the clinical and histopathologic features of small melanomas., Methods: The greatest diameters of 112 consecutively submitted MMs were measured histologically. Those lesions with diameters of less than 6 mm were further studied clinically and histopathologically., Results: Four MMs (3.5%) were found to have small histologic diameters. Their clinical features differed from the classic clinical ABCD's, although their histopathologic features resembled those of large MMs. Their depth of dermal invasion was relatively superficial, and their clinical outcome was favorable., Conclusion: Histopathologically, small MMs tend to resemble large MMs, but clinically they may require other diagnostic criteria. Because they tend to show a relatively superficial depth of invasion, their increased recognition and removal may have an impact on overall mortality from MM.

We studied keratin expression in the involved and uninvolved skin of six benign familial chronic pemphigus (BFCP) patients, using monoclonal antibodies specific for various keratin polypeptides and immunohistopathologic techniques. Normal and psoriatic (i.e., hyperproliferative) skin specimens served as controls. The uninvolved BFCP epidermis showed keratin profiles identical to that of normal epidermis. In the acantholytic epidermal segments of the involved BFCP skin, some of the lower suprabasal acantholytic cells failed to express keratin polypeptides 10 and 11 (Moll's catalog). This delay in expression of suprabasal keratins was not accompanied by an expression of hyperproliferative keratin polypeptide 16. Also, some of the lower suprabasal acantholytic cells of the involved BFCP epidermis retained staining by the antikeratin KS-1A3 antibody, which in the normal, psoriatic, and uninvolved epidermis was limited to the basal cell layer. Staining for keratin polypeptide 18 was negative in the epidermis of all four types of specimens. We believe that the delay in suprabasal keratin expression in the involved BFCP epidermis was more likely secondary to the acantholysis (i.e., "arrest of differentiation" due to acantholysis) rather than due to a primary defect in keratin expression.

Lymphocyte function as expressed by T-lymphocyte subsets and natural killer cell activity was evaluated in a group of Israeli patients with classic Kaposi's sarcoma. T-cell subsets were examined in 28 patients, 14 with lesions limited to the lower extremities and 14 with diffuse cutaneous or systemic involvement. CD4 and CD8 lymphocytes and CD4/CD8 ratio were in the normal range in all patients, and mean values of the entire group were similar to a control group. However, CD8 was in the upper limits of the normal range in some patients with diffuse cutaneous or systemic involvement. This factor led to a significantly decreased CD4/CD8 ratio in that group as compared with the group of patients with the disease limited to the lower extremities. Mean values of natural killer cell activity in three effector/target cell ratios were significantly decreased in 13 of the patients with Kaposi's sarcoma with lesions limited to the lower extremities and in all of the patients with normal T-cell subsets and CD4/CD8 ratios.

We performed an immunohistochemical study that compared a primary adenoid cystic carcinoma (ACC) of the skin with two salivary gland ACC. All three tumors stained positively and in identical fashion for epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), broad-spectrum keratins, and low-molecular-weight keratins. Both EMA and CEA were localized to the luminal surfaces and the secreted contents of the tubular structures and the ductlike structures of the cribriform formations. The staining reactions for both types of keratin were more intense in the cells lining the tubular structures and the ductlike structures of the cribriform formations. One of the two salivary ACCs stained positively for S-100 protein; the other was positive for vimentin. The cutaneous ACC was negative for both antigens. Leu-7 antigen was not detected in either type of ACC. These results show that primary cutaneous ACC and salivary ACC have similar immunohistochemical staining patterns for a number of antigens. We believe this similarity is due to the fact that these antigens are shared by the sweat glands and salivary glands, which are considered to be the respective sites of origin for these two types of tumors.

Neutral lipid storage disease with ichthyosis (NLSDI) is an inherited metabolic disorder characterized by accumulation of neutral lipids, in a wide variety of cells, by a still unknown mechanism. Previous studies have shown normal cholesterol content in NLSDI granulocytes, fibroblasts and skin cells. Monocyte-derived macrophages possess an additional pathway of cholesterol uptake, which is not shared by these cells and which is not regulated by intracellular cholesterol levels. This pathway is thought to play a rôle in the process of atherosclerosis. Three NLSDI patients were studied. The serum levels of triglycerides, cholesterol, high-density lipoprotein cholesterol, and apolipoproteins A-I and B were within normal limits in all three patients. The intracellular levels of free and esterified cholesterol were measured in the monocyte-derived macrophages of one patient and found to be normal, while the triglyceride concentrations were twice as high as normal. The cholesterol esterification rates, which serve as a sensitive indicator of intracellular changes in cholesteryl ester levels, were normal in the monocyte-derived macrophages of all three patients. These findings provide further evidence that cholesterol metabolism is not disturbed in NLSDI, and it may be inferred that in this respect these patients are not at increased risk for atherosclerosis.

This study was conducted in order to evaluate a possible protective role of seborrheic complexion and a history of acne on the development of basal cell epithelioma (BCE). For this purpose, 77 patients with this tumor were examined and asked to fill out a questionnaire. The questionnaire included demographic data and questions about skin type, eye and hair colors, sun exposure habits and a past history of acne. The nature, number and location of tumors, the texture of skin and acne scars were noted by a physician. A group of 93 age-, sex- and skin-color-matched patients served as controls. The results show a clear relationship between seborrheic features and a lower risk of developing BCE, after controlling for solar exposure using the Mantel-Haenszel summary measure. The same trend was found in patients with a history of acne. Whether ultraviolet light absorption by sebum, an anticancer activity of Propionibacterium acnes or other factors play a protective role against the development of BCE is as yet unclear.