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The article discusses the progress in skin cancer prevention and treatment in Great Britain as of 2014. Topics covered include the predicted increase in the cost of skin cancer treatment by 2020, the debate over whether sun protection recommendations should be changed to accommodate the need to raise vitamin D levels, and the role of genomics in skin cancer therapeutics.

A patient is described with features of both bullous ichthyosiform erythroderma (BIE) and ichthyosis bullosa -- a separate entity first described in 1937 by Siemens. This combination of characteristics has not been previously reported. Bullous ichthyosiform erythroderma and ichthyosis bullosa of Siemens, occurring together in this patient may best be regarded as varying expressions of a single genodermatosis. [ABSTRACT FROM AUTHOR]

Atypical mycobacterial infections of the skin have increased in frequency in immunocompromised individuals in recent years. Such patients may follow a different clinical pattern from immunocompetent patients, often lacking a history of preceding trauma and presenting with multiple suppurating subcutaneous nodules. A sporotrichoid pattern of spread may occur with the species Mycobacterium kansasii and M. marinum but is rare with M. chelonei. [ABSTRACT FROM AUTHOR]

To establish why the lateral border of tongue is the site of predilection for the development of hairy leukoplakia (HL) and to understand its likely behavior, the pattern of keratin expression was compared in 8HL lesions with matched controls in an immunocytochemical study. Keratins 7, 8, 18 were absent in HL and normals; uniform basal keratin 19 was present in normals but much reduced in HL. Loss of conformationally sensitive epitopes of keratin 14 in lower epithelial layers was seen in HL. Overall expression of non-cornifying keratins 4/13 was reduced in HL and completely lost in the parakeratin zone. Expression of the high-turnover keratins 6/16 was reduced in HL. The HL keratin phenotype suggests that no dysplastic change is likely, but in contrast there is enhanced differentiation, which suggests a benign course for the condition. [ABSTRACT FROM AUTHOR]

: BackgroundAmniotic fluid embolism is a rare yet often lethal peripartum complication resulting from rapid cardiovascular collapse. Progress toward a better understanding of this entity has failed to identify either the underlying hemodynamic pathophysiology or an effective evidence-based treatment.: CaseA 45-year-old woman with a documented placenta previa experienced an amniotic fluid embolism during scheduled cesarean delivery. Transesophageal echocardiogram examination revealed catastrophic pulmonary vasoconstriction. The use of cardiopulmonary bypass, heparin, epinephrine, and high-dose steroids resulted in a successful outcome.: ConclusionTimely placement of transesophageal echocardiogram revealed catastrophic pulmonary vasoconstriction as the cause of circulatory collapse in a patient with amniotic fluid embolism, supporting the use of cardiopulmonary bypass as an effective intervention. [Copyright &y& Elsevier]

The article reports on the use of cultured skin in the grafting of an elderly patient with stasis ulceration. In-patient treatment had failed to produce any reduction in size of accurate maps traced on a used x-ray plate over 6 weeks. These ulcers were extremely painful. Cultured skin taken from a 5-mm punch biopsy of the thigh was applied to leg ulcers and dressed with chlorhexidine impregnated gauze. After application of grafts the ulcer base could be seen through the translucent skin but when the dressing was removed, at 5 days, an opaque intact epidermis could be seen to cover the ulcer site. These grafts became very hyperkeratotic by 10 days post grafting but appeared normal after 21 days. The pain was relieved within 24 hours of the grafting procedure.

The article focuses on the case of an old lady with cutaneous T-cell lymphoma involving skin and tonsil. Erythematous filtrated plaques were found on the patient's chin, legs and abdomen. It shows that the patient had enlarged right tonsil and swollen uvula. It states the medical treatment given to the patient.

We present a patient with multiple leiomyomas confined to the left cheek, giving rise to an unusual clinical presentation of this condition. The lesions were cosmetically disfiguring and, because of their exposed location, were particularly painful in the winter months. The treatment of this condition is discussed. [ABSTRACT FROM AUTHOR]

The article focuses on the case of a 74-year-old retired instrument manufacturer presented with a widespread rash and malaise. The result of the histochemical stains for lysozyme, alpha-1-antitrypsin and acid phosphatase were positive, indicating that the malignant cells are macrophage cell line. It cites the definition of malignant histiocytosis.

Germline heterozygous loss-of-function mutations of fumarate hydratase ( FH) predispose to the autosomal dominant syndrome of multiple cutaneous and uterine leiomyomatosis (MCUL). Forty-five distinct FH mutations have been identified in 76 of 89 (85%) reported probands with skin leiomyomas. This suggests that MCUL is a genetically homogeneous condition and that most patients presenting with skin leiomyomas will have underlying FH mutations. FH mutations identified include 26/45 (58%) missense; 12/45 (27%) frameshift, 4/45 (9%) nonsense changes and 3/45 (7%) different whole gene deletions. In MCUL kindreds, the majority of females with FH mutations have both skin and uterine leiomyomas. A proportion of individuals with FH mutations have associated renal cancer, a variant known as hereditary leiomyomatosis and renal cell cancer (HLRCC). If selection bias is removed, the prevalence of renal cancer in MCUL lies between one of 46 (2%) families who were not radiologically screened, and two of 32 (6%) families who were radiologically screened. Truncating, particularly frameshift, mutations appear to be significantly associated with renal cancer ( P = 0·003), suggesting a possible basis for selective screening. There may also be a significantly increased rate of renal cancer in females ( P = 0·004), suggesting a possible role for hormonal factors. Review of the literature suggests that, unlike most individuals presenting with skin leiomyomas, the majority of patients presenting with uterine leiomyomas or renal cancer will not have underlying FH mutations. [ABSTRACT FROM AUTHOR]

The article presents a report on woolly hair naevi with systematized linear epidermal naevus. Woolly hair naevus is a rare abnormality of scalp hair which is frequently found in association with a linear epidermal naevus. In this article, a case where woolly hair naevi has been discussed which is associated with a systemized linear epidermal naevus, a previously undescribed combination. Under the light microscope, no morphological difference between the woolly hair and normal hair is evident. Scanning electron micrographs of normal and abnormal hair are identical.

21 lesions from 16 patients with discoid lupus erylhematosus (DLE) were examined immunohistologically using monoclonal antibodies to keratins (K). Markers of basal epithelial cells (the keratin conformarion specific basal markers LH6 and LH8), differentiating keralinocytes (K1 and K10), hyperproliferating keralinocytes (K16) and panepidermal keratin (K14), were used. A monoclonal antibody to type VII collagen was used as a guided the state of the basement membrane zone (BMZ). Keratin distribution in DLE differed from controls. Suprabasal cells were tabelled by LH6 in 95% of specimens t19/20) and LH8 in 79% (l5/19) in contrast to the basal distribution in normal skin Reduction of suprabasal LL017 (K1) expression was seen in 59% (10/17) of lesions, An increase of LL025 (K16) expression was seen in 33% (5/15) of specimens. Where LL025 (K16) expression wax increased, LL017 (K1) expression was reduced in 80% (4/5). Dermal colloid bodies expressed both basal and suprabasal keratins and were present at sites of maximal basement membrane disruption. These findings are consistent with a mode of DLE in which there is an increase in the proliferative basal compartment. This compartment and the associated BMZ suffer fragmentation and loss of colloid bodies to /he dermis which ex press a range of keratins not uniformaly associated with basal keratinocytes. [ABSTRACT FROM AUTHOR]

The tissue labelling of a panel of monoclonal antikeratin antibodies (LL001, LL003, LP2K, BA17, LP34, CAM5.2, and LH1) recognising keratins 1, 5, 8, 10, 14, 18, and 19 were investigated in frozen and formalin-fixed normal skin. Antibodies LL001, LL003, BA17, LP34, CAM5.2, and LH1 were found to be reactive in formalin-fixed material and were used to study 23 basal cell carcinomas, 8 squamous cell carcinomas, 5 keratoacanthomas, 5 Bowen's disease, and 6 clear cell acanthomas. All these tumours demonstrated a loss of keratin 10 expression as demonstrated by loss of labelling with LH001, was reduced but present in all the tumours except squamous cell carcinomas and keratoacanthomas where increased labelling was observed in the more differentiated areas of these tumours, Simple epithelial keratin expression was demonstrated by positive labelling with CAM5.2 and keratin 19 by BA17 in a third of basal cell carcinomas and squamous cell carcinomas. Three of the five keratoacanthomas labelled with BA17, indicating the presence of keratin 19 in these lesions. These results support eh concept that keratin expression is a phenotypic marker of the state of differentiation or malignant transformation and that patterns of keratin expression are not specific to any particular premalignant or malignant disorder. [ABSTRACT FROM AUTHOR]

A patient with scieredema of Buschke in association with α-heavy chain multiple myeloma (MM) is described with improvement in the skin following treatment of the myeloma with cyclophosphamide. Scleredema of Buschke is a rare skin condition in which the skin is symmetrically indurated and tethered with a tendency to affect the face and upper trunk in particular. There are several reports of an association of scleredema with benign manoclonal gammopathies,[sup1-4] but only two other reports of an associatin with MM.[sup3.5] [ABSTRACT FROM AUTHOR]

Non-Hodgkin's lymphoma developed in a 32-year-old woman with dermatomyositis, and in a 51-year-old man with psoriasis, following treatment with azathioprine for 10 years and 5 years, respectively. [ABSTRACT FROM AUTHOR]

Background:Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in fair-skinned populations worldwide and its incidence is increasing. Despite previous observations of multiple genetic abnormalities in cSCC, the oncogenic process remains elusive. The purpose of this study was to elucidate key molecular events associated with progression from premalignant actinic keratoses (AKs) to invasive cSCC by transcriptome profiling.Methods:We combined laser capture microdissection with the Affymetrix HGU133 Plus 2.0 microarrays to profile 30 cSCC and 10 AKs.Results:We identified a core set of 196 genes that are differentially expressed between AK and cSCC, and are enriched for processes including epidermal differentiation, cell migration, cell-cycle regulation and metabolism. Gene set enrichment analysis highlighted a key role for the mitogen activated protein kinase (MAPK) pathway in cSCC compared with AK. Furthermore, the histological subtype of the tumour was shown to influence the expression profile.Conclusion:These data indicate that the MAPK pathway may be pivotal to the transition from AK to cSCC, thus representing a potential target for cSCC prevention. In addition, transcriptome differences identified between cSCC subtypes have important implications for future development of targeted therapies for this malignancy. [ABSTRACT FROM AUTHOR]

Plasmacytoid dendritic cells (pDCs) fulfil multiple roles in immunity, and can secrete large amounts of interferon (IFN)-α. However, the available evidence suggests that they may actually counteract efficient antitumour immunity. Thus in melanoma, pDCs are abundant, but they are anergic and deficient in IFN-α secretion. pDC anergy is thought to be caused by immunosuppressive factors secreted by melanoma cells. One factor strongly expressed by melanoma is Wnt5a, which is implicated in cancer tissue invasion. In this paper, we show that Wnt5a is able to block the upregulation of the activation markers CD80 and CD86 on naive human pDCs stimulated by CpG oligodeoxynucleotide, and CpG-triggered secretion of IFN-α by pDCs. Our results suggest that Wnt5a may not only initiate cancer invasion, but could also regulate activation of pDC. These data provide a clear rationale to investigate a role for Wnt5a in immune regulation. [ABSTRACT FROM AUTHOR]

Background:Novel prognostic biomarkers and therapeutic strategies are urgently required for malignant melanoma. Ecto-5-prime-nucleotidase (NT5E; CD73) overexpression has been reported in several human cancers. The mechanism(s) underlying deregulated expression and the clinical consequences of changes in expression are not known.Methods:We used RT-PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse expression and regulation of NT5E in malignant melanoma cell lines and primary and metastatic melanomas.Results:NT5E is subject to epigenetic regulation in melanoma. NT5E mRNA is downregulated by methylation-dependent transcriptional silencing in the melanoma cell lines SKMel2, SKMel23, WM35, Mel501, Mel505 and C81-61 and expression is reactivated by azacytidine. In contrast, the CpG island is unmethylated and the gene expressed in cultured normal melanocytes. In clinical cases of melanoma, methylation in the NT5E CpG island occurs in both primary and metastatic melanomas and correlates with transcriptional downregulation of NT5E mRNA. Relapse with metastatic disease, particularly to the visceral sites and brain, is more common in primary melanomas lacking NT5E methylation. Primary melanomas with methylation in NT5E show limited metastatic potential or more commonly metastasise predominantly to nodal sites rather than viscera and brain (P=0.01).Conclusion:Deregulation of NT5E expression in melanoma occurs via epigenetic changes in the NT5E CpG island. Confirmation of our results in larger clinical series would support the candidacy of NT5E as a clinical biomarker in melanoma, which could be applied in both primary and relapsed disease. Inhibition of NT5E may have therapeutic potential in melanoma, particularly in patients with more aggressive disease metastatic to viscera or the brain. [ABSTRACT FROM AUTHOR]

Identifying therapeutic targets for cancer treatment relies on consistent changes within particular types or sub-types of malignancy. The ability to define either consistent changes or sub-types of malignancy is often masked by tumor heterogeneity. To elucidate therapeutic targets in cutaneous squamous cell carcinoma (cSCC), the most frequent skin neoplasm with malignant potential, we have developed an integrated approach to gene expression profiling beginning with primary keratinocytes in culture. Candidate drivers of cSCC development were derived by first defining a set of in vitro cancer genes and then comparing their expression in a range of clinical data sets containing normal skin, cSCC and the benign hyper-proliferative condition psoriasis. A small interfering RNA (siRNA) screen of the resulting 21 upregulated genes has yielded targets capable of reducing xenograft tumor volume in vivo. Small-molecule inhibitors for one target, Polo-like kinase-1 (PLK1), are already in clinical trials for other malignancies, and our data show efficacy in cSCC. Another target, C20orf20, is identified as being overexpressed in cSCC, and siRNA-mediated knockdown induces apoptosis in vitro and reduces tumor growth in vivo. Thus, our approach has shown established and uncharacterized drivers of tumorigenesis with potent efficacy as therapeutic targets for the treatment of cSCC. [ABSTRACT FROM AUTHOR]

Background: The incidence of human papillomavirus-associated vulval neoplasia is increasing worldwide; yet the associated genetic changes remain poorly understood.Methods: We have used single-nucleotide polymorphism microarray analysis to perform the first high-resolution investigation of genome-wide allelic imbalance in vulval neoplasia. Our sample series comprised 21 high-grade vulval intraepithelial neoplasia and 6 vulval squamous cell carcinomas, with paired non-lesional samples used to adjust for normal copy number variation.Results: Overall the most common recurrent aberrations were gains at 1p and 20, with the most frequent deletions observed at 2q, 3p and 10. Copy-neutral loss of heterozygosity at 6p was a recurrent event in vulval intraepithelial neoplasia. The pattern of genetic alterations differed from the characteristic changes we previously identified in cutaneous squamous cell carcinomas. Vulval neoplasia samples did not exhibit gain at 5p, a frequent recurrent aberration in a series of cervical tumours analysed elsewhere using an identical protocol.Conclusion: This series of 27 vulval samples comprises the largest systematic genome-wide analysis of vulval neoplasia performed to date. Despite shared papillomavirus status and regional proximity, our data suggest that the frequency of certain genetic alterations may differ in vulval and cervical tumours. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) infection is associated with genital malignancy and specific cutaneous malignancies. We report a case of an HPV-associated concurrent vulval intraepithelial neoplasia and periungual Bowen's disease in a young immunocompetent Afro-Caribbean woman with no known risk factors for either disease. HPV genotyping studies detected multiple α and β papillomaviruses with concordance for HPV-34 [a high-risk (HR) mucosal type], and HPV-21 [an epidermodyslasia verruciformis (EV) type] in both vulval and finger tissue. Although the HR-mucosal viruses detected are likely to have a pathogenic role in vulval intraepithelial neoplasia, this is the first report of concordance for EV HPV types in both genital and nongenital skin premalignancies. This case, in the context of accumulating epidemiological and experimental data in cutaneous SCC, raises the question of whether EV HPV may contribute to vulval malignancy, and further study is merited. [ABSTRACT FROM AUTHOR]

Background Organ transplant recipients (OTR) are at high risk of developing nonmelanoma skin cancer and premalignant epidermal dysplasia (carcinoma in situ/ Bowen's disease and actinic keratoses). Epidermal dysplasia is often widespread and there are few comparative studies of available treatments. Objectives To compare topical methylaminolaevulinate (MAL) photodynamic therapy (PDT) with topical 5% fluorouracil (5-FU) cream in the treatment of post-transplant epidermal dysplasia. Methods Eight OTRs with epidermal dysplasia were recruited to an open-label, single-centre, randomized, intrapatient comparative study. Treatment with two cycles of topical MAL PDT 1 week apart was randomly assigned to one area of epidermal dysplasia, and 5-FU cream was applied twice daily for 3 weeks to a clinically and histologically comparable area. Patients were reviewed at 1, 3 and 6 months after treatment. The main outcome measures were complete resolution rate (CRR), overall reduction in lesional area, treatment-associated pain and erythema, cosmetic outcome and global patient preference. Results At all time points evaluated after completion of treatment, PDT was more effective than 5-FU in achieving complete resolution: eight of nine lesional areas cleared with PDT (CRR 89%, 95% CI: 0·52–0·99), compared with one of nine lesional areas treated with 5-FU (CRR 11%, 95% CI: 0·003–0·48) ( P = 0·02). The mean lesional area reduction was also proportionately greater with PDT than with 5-FU (100% vs. 79% respectively). Cosmetic outcome and patient preference were also superior in the PDT-treated group. Conclusions Compared with topical 5-FU, MAL PDT was a more effective and cosmetically acceptable treatment for epidermal dysplasia in OTRs and was preferred by patients. Further studies are now required to confirm these results and to examine the effect of treating epidermal dysplasia with PDT on subsequent development of squamous cell carcinoma in this high risk population. [ABSTRACT FROM AUTHOR]

The molecular mechanisms that underlie the development of squamous cell skin cancers (SSC) are poorly understood. We have used oligonucleotide microarrays to compare the differences in cellular gene expression between a series of keratinocyte cell that mimic disease progression with the aim of identifying genes that may potentially contribute towards squamous cell carcinoma (SCC) progression in vivo, and in particular to identify markers that may serve as potential therapeutic targets for SCC treatment. Gene expression differences were corroborated by polymerase chain reaction and Western blotting. We identified Axl, a receptor tyrosine kinase with transforming potential that has also been shown to have a role in cell survival, adhesion and chemotaxis, was upregulated in vitro in SCC-derived cells compared to premalignant cells. Extending the investigation to tumour biopsies showed that the Axl protein was overexpressed in vivo in a series of SCCs. [ABSTRACT FROM AUTHOR]

Viral warts may cause significant morbidity in individuals unable to mount an adequate T-helper 1 cell-mediated immune response to human papillomavirus. Imiquimod is a potent inducer of antiviral cytokine activity which has shown significant efficacy in the treatment of genital warts. Similar efficacy in cutaneous warts is not yet established. To assess the response of persistent cutaneous warts to 5% imiquimod cream in immunosuppressed individuals.Fifteen immunosuppressed patients with warts on the hands and/or feet present for more than 18 months, which had failed to respond to a minimum of 12 weeks of topical salicylic acid and four cycles of cryotherapy, were recruited. Imiquimod 5% cream was applied in an open label, right vs. left comparison study for 24 weeks (three times weekly for 8 weeks, daily for 8 weeks, then daily with occlusion for 8 weeks).Twelve (80%) patients completed the study protocol. Benefit was seen in five patients[36% in the intent-to-treat analysis (14 patients)], including more than 30% clearance of warts in three patients and reduction in overall size of warts in two further cases. Local skin reactions occurred in four (29%) patients and were usually mild. A transient rise in creatinine (11–29% above baseline) was measured in three renal transplant recipients, but we did not consider that this was related to imiquimod exposure.This is the first controlled study to assess therapeutic efficacy of topical 5% imiquimod cream in persistent warts associated with immunosuppression. It provides preliminary evidence that topical imiquimod may benefit a subgroup of immunosuppressed patients with recalcitrant cutaneous warts. [ABSTRACT FROM AUTHOR]

Hereditary subtotal leuconychia is a rare nail disease. The gene(s) underlying this phenotype is (are) not known. Immunohistochemical and ultrastructural studies of nails are performed infrequently. To perform genetic linkage analysis and to assess ultrastructure and soft/hard keratin expression in hereditary white nails. We have analysed microscopically and ultrastructurally the white nails of a patient from a family in which the trait is inherited in an autosomal dominant manner as an isolated symptom. No skin lesions or hair abnormalities could be detected. Genetic linkage studies were performed on DNA samples obtained from several members of the affected family. A longitudinal surgical biopsy of the nail from a great toe was split in two parts. One part was fixed in formalin and processed for histopathology. Another part was further subdivided and embedded either in Epon, following fixation in 2% glutaraldehyde, or in Lowicryl K4M, after fixation in 3% paraformaldehyde. Dewaxed nail sections and Lowicryl ultrathin sections were also stained with various antikeratin antibodies. Genetic linkage studies of the family pointed to the disease gene mapping to the chromosomal 12q13 region. Genes mapping within this chromosomal region include the genes coding for type II (basic) cytokeratins and hard keratins. The nail matrix presented an abnormal hypergranulosis. The upper part of the nail plate, originating from the proximal nail matrix, had a nonhomogeneous lamellar appearance, with numerous intracellular ‘lipidic’ vacuoles and ‘empty’ spaces separating keratin filament bundles. These cells were progressively shed at the nail surface. The cell loss was compensated by hyperproliferation of the distal matrix and of the nail bed keratinocytes, with persistent marked parakeratosis and loose arrangement of keratin bundles. The distal matrix and the nail bed contributed equally to formation of the lower plate. This presented the characteristics of a tissue composed of soft keratins. Accordingly, there was virtually no labelling with the Hb1 antibody to a basic hard keratin in the white nail, whereas the labelling with AE3 antibody to all type II keratins and with KL1 recognizing suprabasal soft keratins was normal or even enhanced. Genetic linkage indicates that the gene defect underlying the leuconychia in the family studied resides on chromosome 12q13. As the type II keratins map within this chromosomal interval, it is possible that a mutation in one of these keratin genes may be a cause of the hereditary leuconychia. The white appearance of nails in this disease seems to be due to an abnormal keratinization of cells originating from the proximal nail matrix, leading to the presence of abundant intracellular vacuoles and to a lesser compactness of keratins. [ABSTRACT FROM AUTHOR]

Human papillomaviruses (HPVs) are found in normal skin and in benign and malignant skin conditions. Epidermodysplasia verruciformis (EV) HPV types are those most plausibly linked to the development of squamous cell carcinomas of the skin. To assess the risk of nonmelanoma skin cancer (NMSC) associated with the presence of EV HPV in normal skin in immunocompetent (IC) individuals and renal transplant recipients (RTRs). Using a degenerate and nested polymerase chain reaction technique, HPV DNA was sought in 124 normal skin samples from sun-exposed and nonsun-exposed sites, from 39 IC individuals and 38 RTRs, both with and without NMSC. Data were analysed using the Mantel–Haenszel test and by logistic regression analysis. HPV DNA was detected in 58/67 (87%) and 20/57 (35%) samples from renal transplant and IC patients, respectively. There was no difference in either the prevalence or spectrum of HPV types found in sun-exposed and nonsun-exposed normal skin. However, there was significant association between NMSC and the presence of EV HPV DNA. Multivariate analysis provided an odds ratio of 6·41 (95% confidence interval 1·79–22·9) for the association of EV HPV DNA in normal skin (irrespective of site) and NMSC status, even after stratifying for patient group and adjusting for the clustering effect of multiple sampling. Conversely, there was no association between skin cancer status and the presence of cutaneous or mucosal HPV types in either sun-exposed or nonsun-exposed skin. HPV DNA is widespread in normal adult skin, particularly in transplant patients. In our study, the presence of EV but not cutaneous HPV DNA in normal skin was significantly associated with NMSC status and may prove to be of predictive value for skin cancer risk. These data provide reason to focus on EV HPV types as causal agents in skin cancer. [ABSTRACT FROM AUTHOR]

The few studies published on angiogenesis in lymphoma have raised the question of whether or not microvessel density (MVD) is associated with more aggressive disease and have reported the observation that in follicular lymphomas, vessels are mature rather than immature. We investigated MVD and the vascular phenotype within follicular or diffuse large B-cell lymphomas, reactive nodes and tonsils. Vascular phenotype was defined by the expression or loss of reactivity to the antibody LH39 (detecting the LH39 laminin epitope of the basement membrane in mature vessels) and by detection of alpha V beta 3 (expressed on immature vessels). In reactive nodes and in follicular lymphomas, MVD was higher in the paracortex than in germinal centres or in neoplastic follicles. However, in neoplastic follicles an increase in alpha V beta 3-positive endothelium suggested the activation of an angiogenic pathway different from that present in the reactive follicles. In large B-cell lymphomas, MVD was higher than in reactive and neoplastic follicles but lower than in the reactive paracortex. The number of immature vessels (LH39 negative) and of alpha V beta 3-positive vessels was higher than in reactive lymph nodes and follicular lymphoma suggesting that a switch to a different angiogenic pathway has occurred. Finally, we have demonstrated that within reactive and neoplastic follicles vascular regression is occurring, perhaps constraining the growth of reactive follicles alongside other phenomena such as apoptosis. Vascular regression was previously believed to occur in adults only in ovarian and endometrial tissue. We conclude that different types of angiogenesis are present in follicular lymphomas and large B-cell lymphomas. This has implications for possible future therapies. [ABSTRACT FROM AUTHOR]

We have previously described a group of non-small cell lung carcinomas without morphological evidence of neo-angiogenesis. In these tumours neoplastic cells fill up the alveoli and the only vessels present appear to belong to the trapped alveolar septa. In the present study we have characterised the phenotype of the vessels present in these non-angiogenic tumours, in normal lung and in angiogenic non-small cell lung carcinomas. The vessels, identified by the expression of CD31, were scored as mature when expressing the epitope LH39 in the basal membrane and as newly formed when expressing alphaVbeta3 on the endothelial cells and/or lacking LH39 expression. In the nine putative non-angiogenic cases examined, the vascular phenotype of all the vessels was the same as that of alveolar vessels in normal lung: LH39 positive and alphaVbeta3 variable or negative. Instead in 104 angiogenic tumours examined, only a minority of vessels (mean 13.1%; range 0--60%) expressed LH39, while alphaVbeta3 (in 45 cases) was strongly expressed on many vessels (mean 55.5%; range 5--90%). We conclude that in putative non-angiogenic tumours the vascular phenotype is that of normal vessels and there is no neo-angiogenesis. This type of cancer may be resistant to some anti-angiogenic therapy and different strategies need to be developed. [ABSTRACT FROM AUTHOR]

Presents a study which undertook a genomewide screen of 11 families segregating multiple leiomyomatosis (ML) to detect the localization of the ML gene. Subjects and methods; Results; Discussion.

A unique series of epidermal cell lines representing different stages of malignant transformation were spontaneously derived from a single adult immunosuppressed individual. Four keratinocyte lines (PM1–4) established from forehead skin are here compared with 4 squamous cell carcinoma (SCC) lines (MET1–4) derived respectively from a primary cutaneous tumour, two local recurrences and a distant metastasis of invasive SCC. Despite altered growth properties, the PM lines retained many features of normal keratinocytes including keratin phenotype, differentiation capacity and non-tumorigenicity in athymic mice. In contrast, from early passage, the MET lines displayed markedly reduced growth requirements, abnormal differentiation, aberrant K18 expression and tumorigenicity in athymic mice. The abnormal keratin profile of individual MET lines closely reflected the keratin phenotype of the tumour of origin. Although unusual HPV types were identified in the original tissue, there was no evidence of persistent virus within any cell line and it appears that HPV is not critical for maintenance of the immortal phenotype. The PM lines were distinctly different from invasive SCC lines and are likely to be useful for studies of mutations important early in neoplastic progression. The SCC series represent primary, recurrent and metastatic carcinoma. Availability of such a series from the same individual will facilitate genetic analysis of the malignant process. [ABSTRACT FROM AUTHOR]

Angiogenesis, the formation of new vessels, has been demonstrated to be an indicator of prognosis in breast cancer patients. The extent of differentiation of the tumour vessels may affect access of peripheral white cells and egress or invasion of tumour cells. This has not been assessed in relation to tumour microvessel density or other variables and may be a marker of vascular remodelling. LH39 is a monoclonal antibody recognizing an epitope located at the lamina lucida of mature small veins and capillaries but not in newly formed vessels. To study vascular differentiation in breast tumours, we examined the vascular maturation index (VMI) in 12 normal and 50 breast carcinomas and this was correlated with different clinicopathological variables including angiogenesis. Mature vessels were defined by staining with antibodies to both LH39 and to CD31, using double immunohistochemistry, whereas immature vessels stained only for CD31. VMI was defined as the % fraction of mature vessels (LH39-positive) / total number of vessels (CD31-positive). The VMI was significantly higher in normal (54-68.5%; median 66.5%) than in tumours (0-47%; median 8.8%) (P = 0.0005). There was a significant inverse correlation between the tumour VMI and nodal status (Fisher's exact test,P = 0.01) and between high VMI and low thymidine phosphorylase (TP) expression (Mann-WhitneyU-test,P = 0.01). No significant association between VMI and tumour size, oestrogen receptor, epidermal growth factor receptor, grade, angiogenesis, patient age, or E-selectin was seen. There was a significant reduction in relapse-free survival (P = 0.01) with high angiogenesis. These findings show that the VMI gives new information on the mechanism of tumour angiogenesis independently from microvessel quantitation, there is a wide variation in the differentiation of tumour vasculature but the degree of capillary differentiation is not associated with quantitative angiogenesis. The VMI identifies a subset of patients... [ABSTRACT FROM AUTHOR]

Diffuse non-epidermolytic palmoplantar keratoderma (NEPPK) belongs to the heterogeneous group of skin diseases characterized by thickening of the stratum corneum of the palms and soles (1). This autosomal dominant PPK is characterized by a diffuse pattern of palmar and plantar hyperkeratosis giving the affected areas a thickened yellowish appearance with a marked erythematous edge. Linkage of diffuse NEPPK to chromosome 12q11-q13 has been demonstrated in two independent reports (2, 3). In this study, we describe detailed haplotyping with microsatellite markers mapping to this chromosomal region in three diffuse NEPPK pedigrees from the south of England. Fine mapping of a previously identified recombination event and the identification of a common disease haplotype segregating in the three pedigrees places the diffuse NEPPK locus proximal to the type II keratin gene cluster. [ABSTRACT FROM AUTHOR]

Bullous congenital ichthyosiform erythroderma (BCIE) is a dominantly inherited keratinizing disorder characterized by erythroderma and blistering in neonates and generalized epidermolytic hyperkeratosis (EH) in adulthood. Previously, it has been shown that BCIE can be caused by mutations in either of the genes encoding K1 or K10, the keratins predominantly expressed in suprabasal layers of the epidermis. Using direct sequencing of genomic PCR fragments, we have analyzed 4 British families with BCIE, all of whom were found to carry mutations in K10. In 1 family, the affected person was found to have an unusual dinucleotide transversion mutation, 2138CC ??? AA, causing two amino acid substitutions, D155E and R156S, also in the 1A domain of the K10 polypeptide. In 2 further kindreds, the previously reported "hotspot" mutations 2139C ??? T and 2140G ??? A were found. These mutations predict amino acid substitutions in the helix 1A domain of K10, designated R156C and R156H respectively. The proband in the fourth family was found to carry a novel mutation 4724T ??? C, predicting the amino acid change L452P in the helix 2B domain of K10. All mutations were confirmed in the affected persons and were excluded from a population of 50 normal, unrelated individuals by restriction enzyme analysis. The location of these mutations in the highly conserved helix boundary motif sequences of K10 are consistent with previously reported dominant negative mutations in K10 and other keratins. Despite the unusual nature of two of these mutations, in particular the double missense mutation, the phenotypes of the affected individuals in these 4 families were entirely typical of BCIE. [ABSTRACT FROM AUTHOR]

Although there are clear parallels between apoptosis and epidermal terminal differentiation it is unclear whether terminal differentiation of keratinocytes is a form of apoptosis. We found that apoptosis was rare in adherent cultures of normal keratinocytes, even when growth factors were removed. When keratinocytes were placed in suspension for 24-96 h the majority of cells were induced to undergo terminal differentiation, as assessed by involucrin expression and cornified envelope assembly, but few cells underwent apoptosis, as assessed by morphological examination, TUNEL labelling and by DNA laddering. Withdrawal of serum and growth factors stimulated apoptosis of suspended keratinocytes but led to some reduction in the number of cells that underwent terminal differentiation. At 96 h the majority of cells retained their nuclei in the presence or absence of serum and growth factors. In normal epidermis only occasional cells within the granular layer had apoptotic nuclei, determined by TUNEL labelling and light and electron microscopy. In affected epidermis of psoriasis, Darier's disease and pityriasis rubra pilaris, diseases characterized by perturbation of growth, differentiation or adhesion, light microscopy revealed no higher proportion of apoptotic nuclei than in normal epidermis. However, the majority of viable epidermal layers in diseased skin were positive by TUNEL labelling, suggesting that TUNEL is not always a specific marker of apoptosis in keratinocytes. We conclude that in vivo and in culture keratinocyte terminal differentiation and apoptosis are distinct cellular events, subject to different stimuli. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify a sterilization technique for the preparation of human allodermis which could be used as a dermal component in wound healing and as the dermal base for production of dermal–epidermal composites for one-stage grafting in patients. We report that it is possible to produce dermal–epidermal composites which perform well in vitro and in vivo using a standard ethylene oxide sterilization methodology. Prevention of ethylene oxide-induced damage to the dermis was achieved using gentle dehydration of the skin prior to ethylene oxide sterilization. The issue of whether viable fibroblasts are required for composite production was examined in comparative studies using glycerol vs. ethylene oxide sterilized dermis. Where good collagen IV retention was achieved following preparation of acellular de-epidermized dermis there was no advantage to having fibroblasts present in vitro or in vivo; however, where collagen IV retention was poor or where keratinocytes were initially expanded in culture then there was a significant advantage to introducing fibroblasts to the composites during their preparative 10-day period in vitro. The requirement for fibroblasts became less evident when composites were grafted on to nude mice. In conclusion, we report a protocol for the successful sterilization of human allodermis to achieve an acellular dermis with good retention of collagen IV. This acellular dermis would be appropriate for clinical use as a dermal replacement material. It can also be used for the production of dermal–epidermal composites using autologous keratinocytes (with or without fibroblasts). [ABSTRACT FROM AUTHOR]

Fifty-two patients with discoid lupus erythematosus were examined with reference to systemic symptoms and the presence and titre of antinuclear antibody and anticardiolipin antibody were determined. Serological abnormalities were found in 62%. Antinuclear antibody was detected using epithelial derived cell lines in 56%, which is much higher than in previous series using mouse liver as the substrate. There was a definite association between positive antinuclear antibody and systemic symptoms. Anticardiolipin antibodies were found in low titre and were not associated with a thrombotic tendency, but were associated with antinuclear antibody. [ABSTRACT FROM AUTHOR]

In dyskeratosis congenita, the hyperkeratotic lesions affecting the mucous membranes have a propensity to undergo malignant change. Unfortunately there is presently no reliable method for predicting such an outcome. Oral mucosal biopsies were obtained from a case of dyskeratosis congenita and keratin expression identified using a panel of antikeratin antibodies. Marked changes were found from keratin profiles established for normal oral mucosa. In particular coexpression of three separate type 1 keratins (K16, K10 and K13) were observed in the ventral tongue lesion. The keratin pattern found in the tissue biopsies examined is suggestive of an unusually immature or disturbed state of tissue differentiation, and as such may be indicative of future malignant change. [ABSTRACT FROM AUTHOR]

The patterns of cytokeratin expression in the epithelium of 5 dental follicles, 7 dentigerous cysts, 5 odontogenic keratocysts, 3 nasopalatine cysts and an epidermoid cyst have been studies using a panel of monoclonal antibodies. The epithelium of dental follicles and of developmental odontogenic cysts strongly expressed keratins 5 and 19 and showed weaker expression of keratins typical of stratified non-cornified and of simple epithelia. Staining with mAbs against the latter keratins varied with the degree of epitehlial differentiation. Nasopalatine cysts strongly expressed simple epithelial keratins and the epidermoid cyst strongly expressed a marker of cornification. Odontogenic cysts thus appear to differ in their pattern of keratin expression from other oral developmental cysts and all derivatives of odontogenic epithelia appear to share similar basic patterns of cytokeratin expression. [ABSTRACT FROM AUTHOR]

The localization of fetal antigen 2 (FA2), a recently described basement membrane (BM) associated antigen, was studied by immunohistochemical techniques in 21 basal cell carcinomas (BCC). In both superficial and infiltrating BCC, FA2 was located in a broad diffuse band around the tumour elements and in close contact with the BM. Compared to normal skin, a more extensive distribution of FA2 was seen in BCC. In the infiltrating BCC, FA2 staining was also present in the interstital stroma between the tumour islands. FA2 was absent in areas with inflammatory cell infiltrates and elastoid degeneration. Epithelial and tumour cells were FA2 negative. The distribution of FA2 was clearly different from that of laminin and collagen type 4. Collgen type 4 and laminin were present as a continuous linear band corresponding to the BM surrounding the tumors. The close contact to the BM and the increased content of Fa2 in the reactive stroma around BCC suggest that FA2 is involved in the matrix and/or BM changes place during tumour growth and invasion. [ABSTRACT FROM AUTHOR]

Using immunocytochemistry and a panel of monoclonal antibodies directed against various keratin polypeptides we examined specimens of normal periodontal ligament. periapical granulomas and inflammatory dental cysts. Epithelial elements with the appearance of rests of Malassez were identified in 6 specimens of normal periodontium and 10 periapical granulomas. Altered epithelium was present in 16 periapical granulomas and a lining epithelium in 10 inflammatory dental cysts. The patterns of binding of antibodies by these epithelia indicated that (a) keratin 19 was expressed by all epithelia, and (b) rests of Malassez also expressed keratin 5 but not large amounts of other keratins and (c) epithelial proliferation in periapical lesions was associated with increased expression of keratin 14, a marker of stratifying epithelia, new expression of keratins 4 and 13, differentiation markers for non-cornifying epithelia and variable, low levels of keratins 8 and 18, markers of simple epithelia. Proliferation of the epithelial rests of Malassez to form the lining of inflammatory dental cysts thus appears to be associated with a change from an unusual epithelial phenotype to that of a stratified non-cornifying epithelium in which some simple epithelial keratins are coexpressed. [ABSTRACT FROM AUTHOR]

Erythema multiforme may be recurrent and the oral cavity is often affected. A series of 82 patients with unequivocal recurrent cutaneous erythema multiforme were examined to determine the incidence and nature of oral lesions. Seventy per cent of patients had oral lesions, comprising multiple, large, shallow, extremely painful and debilitating ulcers, which affected the entire oral mucosa in over 20%. The buccal mucosa and tongue were the most frequently affected sites in the remainder and the lips were affected in 13% of patients. Lesions generally lasted for 1-3 weeks. In over 60% of cases these attacks followed an episode of herpes simplex virus infection during the preceding fortnight. Recurrent attacks showed a different site distribution from the initial attacks, with a greater proportion having genital as well as skin and oral mucosal involvement. Detailed case histories of five patients are presented to illustrate the role of azathioprine in treating oral lesions and to document a familial case of recurrent erythema multiforme, with severe mucosal involvement. [ABSTRACT FROM AUTHOR]

Pili annulati is a rare autosomal inherited hair shaft abnormality of unknown pathogenesis in which clinical examination reveals alternating light and dark bands leading to a shiny appearance of the hair due to cavities within the cortex of the hair shaft. This is the first investigation of the proposed cytokeratin defect in pili annulati hair follicles. Four cryopreserved pili annulati and four control scalp specimens were analysed using immunohistochemistry for different‘hard’ trichocytic and‘soft’ epithelial cytokeratins including K1, K6, K10, K14, K16, K17, K18, K19, Ha1 and Hb1. There was no difference in staining intensity and quality of staining pattern seen in pili annulati and control scalp specimens. These results suggest that pili annulati is not caused by a defect of the cytokeratins investigated in this study. [ABSTRACT FROM AUTHOR]