Cytokine alterations in lichen sclerosus: an immunohistochemical study.

BACKGROUND: Although the histology of lichen sclerosus is characteristic, the precise nature of the inflammatory changes and the signals provoking them is uncertain. OBJECTIVES: To delineate the inflammatory changes in lichen sclerosus more accurately by studying cytokine changes. METHODS: An immunohistochemical study of 12 specimens of genital lichen sclerosus and one specimen of extragenital lichen sclerosus was undertaken using monoclonal antibodies to interferon (IFN)-gamma, IFN-gamma receptor, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, IL-2 receptor (CD25), intercellular adhesion molecule-1 (ICAM-1) and its ligand CD11a. Control specimens were seven specimens of normal vulva obtained during gynaecological procedures, three specimens of normal skin, adjacent uninvolved thigh from three of the patients with lichen sclerosus, five specimens of nonvulval psoriasis, four specimens of nonvulval lichen planus and two specimens from chronic wounds. RESULTS: The lichen sclerosus specimens demonstrated slightly increased staining for IFN-gamma within the epidermis compared with the normal vulva and nonvulval skin. There was increased dermal staining for IFN-gamma both within the pale zone of the upper dermis and within the inflammatory zone below this. We confirmed our previous demonstration that in lichen sclerosus HLA-DR immunostaining is increased in association with vascular endothelium, the inflammatory cell infiltrate and around the keratinocytes. The areas of the epidermis with the strongest immunostaining for HLA-DR generally also had the strongest staining for IFN-gamma. In the lichen sclerosus specimens the zone of inflammation also demonstrated increased immunostaining for TNF-alpha, IL-1alpha, IFN-gamma receptor, CD25, CD11a and ICAM-1 while the zone of sclerosus demonstrated a smaller increase in immunostaining for IFN-gamma receptor, TNF-alpha, CD11a and ICAM-1, and the epidermis demonstrated increased staining for ICAM-1. CONCLUSIONS: The increased staining for IFN-gamma, TNF-alpha, IL-1alpha, IFN-gamma receptor, CD25, CD11a and ICAM-1 suggest that the cytokine response in lichen sclerosus shares characteristics of the cytokine response in lichen planus and chronic wounds.

Skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate.

BACKGROUND: Renal-transplant recipients are at increased risk of developing skin cancers, especially squamous cell carcinoma. We have carried out a comprehensive epidemiologic review of skin cancers occurring in a population receiving transplants in Oxford over a 21-year period, where nearly all patients have remained under the care of the Oxford Transplant Centre. METHODS: Between 1975 and 1996, 1,360 renal transplants were performed in 1,115 patients. Skin cancer data were reviewed in 979 patients from this group who remained under the care of the Oxford Transplant Centre. The lesions included in the analysis were histologically confirmed basal cell carcinoma, Bowen's disease, squamous cell carcinoma, keratoacanthoma, malignant melanoma, Merkel cell tumor, and sebaceous carcinoma. RESULTS: One hundred eighty-seven (19.1%) transplant patients developed at least one skin malignancy. The rate of skin cancer was 141 per 1,000 person years at risk. Sixty-four percent of patients with skin cancer had multiple lesions (maximum 50). Squamous cell carcinoma was the most common skin cancer to develop and the most common first skin cancer to present. The mean time to presentation of the first skin cancer was 8 years. Six patients developed nodal metastases, and two patients died secondary to skin cancer. Risk factors identified were increasing age at transplantation, recipient sex, total time of exposure to immunosuppression, increased creatinine levels at 1 year, and graft relation. The cumulative incidence of skin cancer reached 61% at 20 years after transplantation. CONCLUSION: The data from this study suggest that more patients develop skin malignancies than previously reported from Europe. It is important to advise patients before transplantation in regard to skin complications, provide regular dermatological follow-up, and tailor immunosuppressive regimen to minimum doses to be compatible with good graft function.

Effects of clinical service reorganisation on cellular pathology workload.

AIMS: To assess changes in volume and complexity of cellular pathology workload after clinical service reorganisation and alterations in pathology reporting practices, and to identify objective measures of change applicable to all cellular pathology departments. The ear, nose, and throat (ENT), head and neck (HN) specialty was chosen for assessment. METHODS: Cellular pathology workload from the ENT-HN surgical specialty was assessed numerically and the complexity in examination of cancer resection specimens was evaluated. Medical and technical time inputs in the reporting of ENT-HN cancer resections were measured prospectively, and the histological and cytological workload arising from the management of such cases was obtained. RESULTS: The 88.83% increase in ENT-HN specimens contrasted with a 13.53% increase in total surgical workload. Substantial increases in work complexity were found when measured as blocks/slides for each case and number of histochemical/immunohistochemical requests. On average, examination of one ENT-HN cancer case consumed 55% of one pathologist's work session and over one 10th of a technician's working week. On average, each cancer generated 3.3 histological and 1.06 cytological specimens. CONCLUSIONS: Evidence is provided of the increase in cellular pathology workload and in its complexity. This study lists objective measures of complexity applicable to all pathology subspecialties. Given the workforce crisis and expanding clinical needs, realistic workload calculations should include measurement of complexity and not just volumes.

Giant lichenification of the scalp.

Lichenification is characterized clinically by thickening of areas of skin as a result of the itch-scratch cycle and therefore is seen in conditions associated with chronic pruritus. The characteristic feature of giant lichenification is the occurrence of tumour-like growths with a warty cribriform surface. We describe a renal transplant patient presenting with giant lichenification of the scalp following an attack of herpes zoster at the same site. Chronic pruritus following scalp dysaethesia secondary to herpes zoster was considered the most likely explanation for the occurrence of these lesions.

Alterations in fibrillin as well as collagens I and III and elastin occur in vulval lichen sclerosus.

BACKGROUND: The clinical features of lichen sclerosus, which include atrophy, scarring, fragility and tendency to form ecchymoses with only slight trauma, suggest that there is an alteration in the extracellular matrix fibres that are responsible for the tensile strength of the dermis. However, the precise nature of these changes is poorly understood. METHODS: Biopsies from 16 patients with untreated, histologically confirmed, vulval lichen sclerosus were examined immunohistochemically using polyclonal antibodies to collagens I and III and a monoclonal antibody to elastin. Twelve of the lichen sclerosus specimens were also stained with a monoclonal antibody to fibrillin. Normal vulva tissue and patients' uninvolved thigh were used as controls. RESULTS: In the lichen sclerosus specimens, collagens I and III stained with a more homogeneous pattern than in the control tissues. Reduced numbers of elastin fibres were seen in the zone of sclerosus in 15 of the 16 lichen sclerosus specimens. In the control tissue fibrillin fibres were seen as a fine network of fibres in the upper dermis arranged at right angles to and inserting into the basement membrane and forming a fine network throughout the dermis. In the lichen sclerosus specimens, although fibrillin microfibrils were still seen inserting at right angles into the basement membrane, below this the fibrillin staining was reduced in the upper dermis in 11 of the 12 lichen sclerosus specimens. The zone of reduced fibrillin staining was greatest in those specimens where the band of inflammation was deep in the dermis. CONCLUSIONS: The distribution of collagens I and III, elastin and fibrillin are altered in lichen sclerosus and this is likely to contribute to the fragility, scarring and atrophy seen clinically in lichen sclerosus.

An infective aetiology for vulval lichen sclerosus re-addressed.

Although there is evidence to support an autoimmune basis for lichen sclerosus, there have also been some studies which suggest an infective aetiology. These include reports of the presence of spirochaetal forms with Steiner silver stains and purplish coccoid forms with Fite stains. We have repeated these studies on vulval biopsies obtained from 16 patients with vulval lichen sclerosus. Using the Steiner silver method we found no evidence of spirochaetal forms in any of the specimens. With the Fite stain we observed purple-staining coccoid forms within the dermis of 13 of the 16 lichen sclerosus specimens. However, these coccoid forms also stained strongly positive with toluidine blue, suggesting they were mast cell granules rather than micro-organisms. We were therefore unable to demonstrate evidence for an infective aetiology in vulval lichen sclerosus, although this cannot yet be excluded. Further work is also needed to understand the significance of mast cells in lichen sclerosus.

Paget's disease of the vulva associated with local adenocarcinoma and previous breast adenocarcinoma: report of two cases.

We report two women in whom vulval Paget's disease occurred in association with local adenocarcinoma and previous breast adenocarcinoma. The first patient presented at the age of 83 years with moist erythematous changes over the perineum and an indurated area near the anus. Biopsy of the indurated area showed Paget's cells throughout the epidermis and, below, adenocarcinoma infiltrating the dermis. Ten years previously, she had undergone a left mastectomy for infiltrating ductal carcinoma of the breast. The second patient was diagnosed as having Paget's disease at the age of 74 years. A vulval biopsy showed Paget's cells in the epidermis but, in addition, there were changes suggestive of adenocarcinoma of the sweat glands. Her symptoms of vulval itching had started at the age of 45 years and had led to a simple vulvectomy at the age of 57 years. Retrospective review of this vulvectomy specimen showed Paget's disease. She had also previously been treated for infiltrating ductal adenocarcinoma of the breast and adenocarcinoma of the rectum. The management of Paget's disease is difficult because of its high recurrence rate and, as illustrated by our two cases, treatment is difficult if the patients are elderly and in poor general health.

The localization of the target antigens and antibodies in linear IgA disease is heterogeneous, and dependent on the methods used.

Fifty-nine patients with linear IgA disease, 24 with onset in childhood and 35 with adult onset, were studied. Sera from all patients were tested by indirect immunofluorescence, using as substrates intact normal skin and normal skin which had been split through the lamina lucida region of the basement membrane zone by suction and by prolonged incubation with molar NaCl. This enabled the site of the target antigen for the circulating IgA antibodies to be determined. The sites of deposition of the IgA antibodies in vivo were detected by raising a suction blister in eight patients, and splitting seven patients' biopsies by prolonged incubation with molar NaCl. Eighteen sera were positive with intact skin, and 34 with split skin. Twenty-nine sera were positive with suction blisters as substrate; 14 bound to the epidermal aspect of the split skin, seven in a combined pattern (binding to the epidermis and dermis) and six to the dermal aspect. Thirty-one sera bound to salt-split skin, 24 to the epidermal side and seven on the dermal side. There was discordance between the two methods of skin splitting in 15 sera. Seven sera gave a combined pattern with suction but with salt-split skin, five of these bound epidermally, one was dermal, and one negative. Five sera showed epidermal binding on salt-split skin and were negative on suction blisters, and the reverse was seen with one serum. Two sera gave variable results on suction blisters. Direct immunofluorescence studies showed dermal binding on all eight patients with suction blisters, and epidermal binding in four and dermal binding in three patients with salt splitting.(ABSTRACT TRUNCATED AT 250 WORDS)

Suction-induced basal cell cytolysis in the Weber-Cockayne variant of epidermolysis bullosa simplex.

In the Weber-Cockayne form of epidermolysis bullosa simplex (EBS-WC), trauma induces blisters which are confined to the palms and soles. Histologically, basal cell cytolysis is seen. We studied 6 patients with EBS-WC to determine the ultrastructural level at which artificially-induced suction blisters form. Blisters were raised by application of a suction blister cup to uninvolved forearm skin, the cup being connected to a negative pressure of 200 mm of mercury. The blisters were biopsied and examined by light and electron microscopy. On light microscopy, all biopsies showed marked vacuolization of keratinocytes in the lower two-thirds of the epidermis, and in all but one there was a cleavage plane through the basal keratinocytes. These findings were confirmed by electron microscopy in 4 patients. The separation through the basal cells is in contrast to the situation in normal individuals in whom cleavage occurs below the level of the basal cells, within the lamina lucida. Thus, even apparently normal skin from non-acral sites has the same structural abnormality as the affected acral sites in EBS-WC.

A clinicopathological study of scarring alopecia.

We have studied 10 cases of scarring alopecia, and investigated the diagnostic reliability of immunofluorescence and histopathology in lichen planopilaris and pseudopelade. In the light of our findings, we discuss the possible pathomechanisms of both disease processes.

Serum anti-Helicobacter pylori IgG antibodies and pepsinogens A and C as serological markers of chronic atrophic gastritis.

This study was designed to test the sensitivity and specificity of serum anti-Helicobacter pylori IgG antibodies and the ratio of serum pepsinogen A to pepsinogen C (PGA:PGC) in detecting chronic atrophic gastritis (CAG) and intestinal metaplasia. Parallel gastric biopsies and a serum sample were collected from a series of 87 patients aged 20-69 years attending a routine upper endoscopy clinic. The seroprevalence (> 10 micrograms IgG/ml) of anti-H. pylori antibodies was 42.7%, and of a low PGA:PGC ratio (< 1.5) was 17.7%. A positive H. pylori IgG antibody level was more sensitive than the level of PGA:PGC in diagnosing CAG (71.4% and 25.0%, respectively), moderate CAG (86.7% and 26.7%, respectively), and intestinal metaplasia (90.9% and 50.0%, respectively). Anti-H. pylori IgG antibody levels were less specific than PGA:PGC levels in diagnosing CAG (90.9% and 93.9%, respectively), moderate CAG (78.3% and 89.1%, respectively), and intestinal metaplasia (72.6% and 92.2%, respectively). A combination of anti-H. pylori antibodies and a low PGA:PGC ratio for the detection of CAG resulted in a specificity of 100%, but the sensitivity was 21.4%.

Sensory and sympathetic ganglia in HIV-1 infection: immunocytochemical demonstration of HIV-1 viral antigens, increased MHC class II antigen expression and mild reactive inflammation.

Sensory and sympathetic ganglia from 12 cases of human immunodeficiency virus type 1 (HIV-1) infection, all but one without clinical evidence of peripheral nerve disease, were studied immunocytochemically for their content of lymphocytes, macrophages, MHC Class II antigens and HIV-1 and cytomegalovirus antigens. They were compared with ganglia from 7 normal and peripheral nerve disease control cases. Compared with normal controls, many of the ganglia from the majority of HIV-1-infected subjects contained more T lymphocytes and macrophages and enhanced MHC class II expression. A few also showed occasional neuronal degeneration which was not present in the normal controls. In 7 cases HIV-1 gp41 envelope protein and/or p24 core protein antigens were detected in intraganglionic macrophages. Sensory ganglia contained more gp41 HIV-1 antigen than sympathetic ganglia. There was no clear correlation between detection of HIV-1 antigens in ganglia and in the CNS. Detection of HIV-1 antigens in ganglia was more common in cases of HIV-1 infection that had progressed to clinical AIDS by the time of death (71%) than in those that had not done so (40%). It is concluded that there is commonly a mild ganglionitis which is asymptomatic in the absence of detailed clinical testing and frequently associated with local presence of HIV-1 antigens in sensory and sympathetic ganglia in AIDS.

Variation in the deposition of the antibodies at different anatomical sites in linear IgA disease of adults and chronic bullous disease of childhood.

The diagnosis of linear IgA disease of adults (LAD) and chronic bullous disease of childhood (CBDC) relies upon finding a linear band of IgA at the basement membrane zone on direct immunofluorescence. This study examines the regional variation in antigen expression in the skin of affected individuals. Direct immunofluorescence was performed on biopsies from four different sites in 17 patients with these diseases. In two patients a biopsy from the volar surface of the forearm was negative, but other sites were positive; in the remaining patients there was no variation in antibody expression with site. It is therefore recommended that, if a single diagnostic biopsy is to be taken, the volar surface of the forearm is avoided.

Nasal mucosal involvement in lupus erythematosus.

The involvement of oral, conjunctival and genital mucosa in lupus erythematosus (LE) has recently been described. Reports of nasal involvement have been sporadic. A prospective study was performed to assess the prevalence of nasal symptoms and signs in LE and to identify the incidence of deposition of immunoreactants in the nasal mucosa of patients with LE. Thirty-six patients with LE were studied; 21 had non-specific nasal symptoms and 12 had evidence of chronic inflammatory changes in the mucosa of the nasal cavity or in the vestibule (septal perforation, inflamed mucosa, vestibulitis). Immunoreactants were found in only 4 patients and did not correlate well with clinical evidence of disease. Nasal mucosal involvement in LE is underestimated and often overlooked in the assessment of such patients.

A search for Pneumocystis carinii in post-mortem lungs by DNA amplification.

DNA amplification of specific sequences and subsequent oligonucleotide hybridization were used to search for Pneumocystis carinii in post-mortem lung samplings from non-immunosuppressed individuals ranging from 15 to 70 years of age. No P. carinii-specific DNA was detected in 45 DNA amplification reactions from 15 lungs.

The effect of immediately preoperative adjuvant radiotherapy in the surgical treatment of primary cutaneous malignant melanoma.

A historical series of patients with primary cutaneous malignant melanoma is reviewed. These patients had been treated with a single therapeutic dose of irradiation to the tumour and surrounding skin immediately before surgical excision. Some patients had also received a single necrotising dose of radiotherapy to the tumour itself. Recurrence and survival rates have been examined retrospectively in the light of reviewed histology, and compared with other published series. Preoperative radiotherapy was found to have no significant influence on the outcome of surgical treatment of primary malignant melanoma.