Penile intraepithelial neoplasia: histopathological evaluation, HPV typing, clinical presentation and treatment.

BACKGROUND: Genital human papillomavirus (HPV) infection in male patients can cause great variety of lesions, most of which are benign, but some are categorised as penile intraepithelial neoplasia (PIN). OBJECTIVES: The aims of the present work were to: (i) perform HPV testing and correlate to histopathology from genital HPV-induced lesions in men; and (ii) determine the clinical presentation and treatment of PIN. METHODS: Men attending the venereological clinic at Karolinska Hospital for surgical treatment of genital HPV infection were included. Two biopsies were taken from each patient, one for histopathology and one for HPV typing using PCR. Patients exhibiting PIN were selected for further analysis. Lesions were described, and treatment and follow-up data were recorded. RESULTS: Forty-seven of 303 (16%) male HPV patients exhibited PIN lesions. Nineteen were afflicted with lesions denominated as PIN I, 13 had PIN II lesions and 15 had PIN III lesions. Macular lesions were most common (n = 27). Ninety-three percent of the analysed PIN lesions were HPV-positive. Three of twelve (25%) HPV-positive PIN III lesions contained only low-risk HPV types compared to 13 of 19 (68%) PIN I lesions. In addition, 9 of 12 (75%) HPV-positive PIN III lesions contained high-risk HPV types compared to 6 of 19 (32%) PIN I lesions (P = 0.029). HPV 6 and HPV 16 were the most prevalent genotypes. A mean of four surgical treatment sessions was performed during a treatment period of mean 27 months. CONCLUSIONS: PIN is highly HPV-positive, can show differing clinical pictures and is difficult to treat.

MicroRNA-203 functions as a tumor suppressor in basal cell carcinoma.

Basal cell carcinoma (BCC) of the skin represents the most common malignancy in humans. MicroRNAs (miRNAs), small regulatory RNAs with pleiotropic function, are commonly misregulated in cancer. Here we identify miR-203, a miRNA abundantly and preferentially expressed in skin, to be downregulated in BCCs. We show that activation of the Hedgehog (HH) pathway, critically involved in the pathogenesis of BCCs, as well as the EGFR/MEK/ERK/c-JUN signaling pathway suppresses miR-203. We identify c-JUN, a key effector of the HH pathway, as a novel direct target for miR-203 in vivo. Further supporting the role of miR-203 as a tumor suppressor, in vivo delivery of miR-203 mimics in a BCC mouse model results in the reduction of tumor growth. Our results identify a regulatory circuit involving miR-203 and c-JUN, which provides functional control over basal cell proliferation and differentiation. We propose that miR-203 functions as a 'bona fide' tumor suppressor in BCC, whose suppressed expression contributes to oncogenic transformation via derepression of multiple stemness- and proliferation-related genes, and its overexpression could be of therapeutic value.

Clinical and genetic studies of Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant cancer syndrome characterised by benign skin tumours, renal tumours, and spontaneous pneumothorax. The gene has been mapped to chromosome 17p11.2 and recently identified, expressing a novel protein called folliculin. We report the clinical and genetic studies of four sporadic BHD cases and four families with a total of 23 affected subjects. Haplotype analysis of these families using BHD linked markers showed they did not share the same affected alleles, excluding common ancestry. Mutation analysis of the BHD gene identified two germline mutations on exon 11 (c.1733insC and c.1733delC) in three of four families as well as two of four sporadic cases. A novel somatic mutation, c.1732delTCinsAC, was detected in a BHD related chromophobe renal carcinoma. Our results confirmed the (C)8 tract in exon 11 as a mutational hot spot in BHD and should always be considered for future genetic testing. Our observation also indicated that the second hit (of Knudson's two hit theory) in some BHD related tumours is in the form of somatic mutation rather than LOH. In a large French family in which eight affected subjects carry the c.1733delC mutation, a phenocopy who has multiple episodes of spontaneous pneumothorax was identified. A total of five mutation carriers (aged between 37 to 66) did not have any evidence of BHD features, suggesting either reduced penetrance or late age of onset of the disease. In addition, six out of eight affected subjects who have positive germline mutation have confirmed neoplastic colonic polyps, indicating that colorectal neoplasia is an associated feature of BHD in some families. Our studies have observed several interesting genetic features in BHD: (1) the poly (C) tract in exon 11 as a mutational hot spot; (2) the existence of phenocopy; (3) reduced penetrance or late age of onset of disease; (4) association with colorectal neoplasia in some families; and (5) somatic mutation instead of LOH as the second hit in BHD tumours.

Flashlamp pulsed dye laser and argon-pumped dye laser in the treatment of port-wine stains: a clinical and histological comparison.

BACKGROUND: Port-wine stains (PWS) are congenital vascular malformations occurring in 0.3% of children. The pulsed dye laser is a well established treatment for PWS. OBJECTIVES: To compare, clinically and histologically, the effects of the flashlamp pulsed dye laser with the argon-pumped dye laser in the treatment of PWS. METHODS: Thirty patients were treated on two to four test areas with both laser types using different energy fluences. A flashlamp pulsed dye laser with 0.45 ms pulse duration and a spot size of 5 mm was compared with an argon-pumped dye laser, with a spot size of 1 mm delivered with a robotic scanning laser handpiece (Hexascan) and 70-190 ms pulse duration. Both were tuned to 585 nm. Twelve weeks later the degree of lightening was evaluated and biopsies were taken. To count the vessels the skin sections were stained with CD34 using an immunohistochemical technique. The vessels were divided into three groups by diameter (d): d < 10 microm, 10 < or = d < 20 microm, d > or = 20 microm. RESULTS: The clinical results showed a significantly better lightening using the flashlamp pulsed dye laser than with the argon-pumped dye laser. The histological results showed a significant decrease in the number of vessels of diameter larger than 20 microm in treated compared with untreated lesions. We found no histological difference in the number of vessels between the two laser treatments. However, there was a tendency towards more small vessels (diameter < 10 microm) after one treatment with the flashlamp pulsed dye laser compared with untreated PWS. CONCLUSIONS: The flashlamp pulsed dye laser is clinically superior to the argon-pumped dye laser in the treatment of PWS.

Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant neoplasia syndrome characterized mainly by benign skin tumors, and to a lesser extent, renal tumors and spontaneous pneumothorax. To map the BHD locus, we performed a genome-wide linkage analysis using polymorphic microsatellite markers on a large Swedish BHD family. Evidence of linkage was identified on chromosome 17p12-q11.2, with a maximum LOD score of 3.58 for marker D17S1852. Further haplotype analysis defined a approximately 35 cM candidate interval between the two flanking markers, D17S1791 and D17S798. This information will facilitate the identification of the BHD gene, leading to the understanding of its underlying molecular etiology.

[Botryomycosis--peculiar bacterial granuloma]. / Botryomykos--besynnerligt bakteriellt granulom.

Botryomycosis is a chronic granulomatous infection, usually of skin or mucous membranes in predisposed individuals. Infection in internal organs may occur in immunosuppressed persons and is serious but uncommon. Trauma or foreign bodies and defective immune defense mechanisms predispose for the disease, which is mainly caused by Staphylococcus aureus, but also by other bacteria. The histopathological picture is diagnostic and biopsy is encouraged in granulomatous infections. Differential diagnoses may be mycobacteriosis, mycosis and parasitosis. If excision, the preferred treatment, is not radical, prolonged antibiotic treatment is required. The disease may become more widespread in connection with the common use of piercing in young immunocompetent persons.

Squamous cell carcinoma complicating chronic venous leg ulceration: a study of the histopathology, course and survival in 25 patients.

We have studied 25 cases of squamous cell carcinoma in chronic venous leg ulcers. Twenty-three of the patients were dead and two were alive. The mean age at cancer diagnosis was 78.5 years. The median survival was 1 year. Eleven tumours were well-differentiated, 10 moderately and four poorly. All patients with a poorly differentiated tumour died within a year. Metastases were certain in eight cases. The disease was lethal in 10 cases which included all poorly differentiated tumours. The survival of the study group was significantly shortened compared with a control group of patients with lower limb non-melanoma skin cancer (n = 433) from the Swedish Cancer Registry (P = 0.0084). When diagnosed, squamous cell carcinoma in chronic leg ulcers merits a thorough investigation of the degree of differentiation and spread. Assertive treatment is indicated as poorly differentiated tumours and some moderately differentiated tumours may be fatal.

Penile lichen sclerosus et atrophicus treated with clobetasol dipropionate 0.05% cream: a retrospective clinical and histopathological study.

BACKGROUND: Treatment with clobetasol propionate 0.05% cream is effective against lichen sclerosus et atrophicus (LSA) of the vulva. OBJECTIVE: The purpose of this study was to retrospectively evaluate whether clinical and histologic responses to topical clobetasol can be accomplished in penile LSA. METHODS: A self-assessment questionnaire was obtained from 22 men with LSA, and a clinical examination was performed in 21 of them. Biopsy specimens from 15 cases were compared before and after treatment. RESULTS: Itching, burning, pain, dyspareunia, phimosis, and dysuria decreased significantly (P < .001 to .05) after 1 to 2 daily applications, for a mean of 7.1 weeks (2-16 weeks). Additional operation for phimosis was required in 6 of the 22 men. All histologic LSA criteria were significantly (P < .01 to .05) reduced after treatment. CONCLUSION: Topical treatment of penile LSA with clobetasol propionate represents a safe and effective therapy with no risk of epidermal atrophy but with some potential for triggering latent infections, most importantly human papillomavirus.

Melanocytic naevus or malignant melanoma? A large-scale epidemiological study of diagnostic accuracy.

While the early detection of malignant melanoma is important and has been emphasized widely in the past few years, it is difficult to accomplish. The purpose of this study is to assess how well dermatologists recognize malignant melanomas in patients with naevi. Information from 9,121 patients visiting two dermatological clinics in Stockholm and diagnosed melanocytic naevi was linked with the Swedish Cancer Registry to identify individuals with records of malignant melanoma. One-hundred-and-thirteen cases of malignant melanoma were detected in the study population. Sixty patients were diagnosed malignant melanoma prior to the naevus diagnosis and most of them were under continuous follow-up. A further 35 patients were diagnosed malignant melanoma and naevus at the same time. The remaining 18 were given the diagnoses malignant melanoma after the naevus diagnosis and, of these, 6 cases were detected more than 6 years after examination and malignant melanoma was considered not present at the time of consultation. Three cases can be considered as missed (6%) and four others as partially missed or delayed. Thus, of 47 cases of probable recognizable malignant melanoma, there was insufficient management of 7 (15%). Six cases were detected during dermatological examination for other conditions and five through general examination of naevi. Although a few possibly detectable malignant melanomas were not discovered, the results of this study reflect a high clinical detection rate. In addition, a number of cases were discovered by chance during examinations for other dermatological conditions.

Late skin-prick-test reactions to malted wheat. Clinical observations and immunohistochemical characterization.

This study reports late skin-prick-test (SPT) reactions in seven bakers and seven control subjects to malted wheat appearing after 6-10 h, and not preceded by an immediate-phase reaction. Two subjects in each group had a history of atopic symptoms and were Phadiatope positive. Serologic IgE analysis (RAST) of normal wheat flour and of malted wheat grain was negative in all subjects. Skin biopsy specimens were obtained 16-18 h after SPT to malted wheat grain and to histamine and from untested skin. The late SPT reactions in all participants had an urticarial appearance, clinically and in routine histology. Immunohistologically mild to moderate perivascular dermal cell infiltrates were observed in both groups, consisting mainly of CD4+ and HLA-DR+ cells. The number of CD1a+ epidermal cells was statistically significantly higher (P < 0.01) in the bakers' prick-tested skin compared to that of the controls, a fact which might reflect preparedness to react upon challenge. There were no statistical differences between the two groups in IgE+ epidermal cells or epidermal cells expressing the high-affinity IgE receptor (Fc epsilon RI). However, there was a correlation between serum-IgE levels and the number of IgE+ epidermal cells. The late skin reactions observed in both bakers and controls were probably more of an irritant or toxic than immune-mediated nature, but they raise the question of whether skin contact with malted flour contributes to an unfavorable prognosis of hand eczema in bakers.

Immunohistochemical markers for distinguishing Spitz nevi from malignant melanomas.

In this study, we demonstrate that immunostaining with MIB-1 and anti-bcl-2 is a useful tool to distinguish compound Spitz nevi from malignant melanomas. Forty-six cases of Spitz nevi and 50 cases of vertical growth-phase melanomas (Clark III-V) were compared for the immunoreactivity of MIB-1 and bcl-2 in the intradermal component of the lesions. As many as 76% of the Spitz nevus cases showed a low percentage (0-2%) of MIB-1 immunoreactivity. In the malignant melanomas, such a low MIB-1 index was shown in only 2% of the cases. The average MIB-1 index in malignant melanomas and Spitz nevi was 29.7 and 4.0%, respectively. bcl-2 was negative in only 4% of the melanoma cases, whereas the corresponding value was 72% in Spitz nevi. Statistical analyses using Students t test showed that the differences were highly significant (P < 0.001). By considering the immunoreactivity for MIB-1 and bcl-2 in the individual cases, we found that as many as 96% of the melanomas both expressed a bcl-2 positivity and exhibited a MIB-1 index exceeding 2% in the dermal component. The corresponding value was as low as 6% in the Spitz nevi.

Metastatic Crohn's disease. Report of 3 cases with special reference to histopathologic findings.

BACKGROUND: Metastatic Crohn's disease is a rare, often unrecognized cutaneous disorder lacking definite histopathologic criteria. The purpose of this study was to document clinicopathologic and immunologic findings in 3 patients with metastatic Crohn's disease. The histopathologic findings are evaluated in correlation to those reported in the literature in an attempt to better define the histopathologic features. OBSERVATIONS: None of the patients showed signs of depressed cell-mediated immune response as evaluated with skin tests and T-cell subtyping of blood samples. One of the patients had antineutrophil cytoplasmic antibodies. Polymerase chain reaction, a highly efficient method of amplifying low levels of specific DNA sequences, did not show mycobacterial DNA in the samples studied. Granulomas of the sarcoid type with numerous foreign body and Langhans giant cells were the dominating features. In accordance with previous results, we found vascular involvement in 2 cases, manifested as granulomatous perivasculitis in both. We also found necrobiotic areas in all 3 cases. CONCLUSIONS: We propose that both necrobiosis and granulomatous perivasculitis be added to the histopathologic characteristics of metastatic Crohn's disease. Patients may even have a positive antineutrophil cytoplasmic antibody test result.

Psoriasis response to the pulsed dye laser.

BACKGROUND AND OBJECTIVE: In psoriasis the blood vessels are enlarged and dilated. These vessels, the psoriatic microvasculature, have been implicated as participating in the pathogenesis of psoriasis. The purpose of this preliminary study was to use the flash-lamp-pumped pulsed dye laser, which selectively damages dermal vessels, to treat psoriatic plaques and to evaluate the role of the vasculature in the therapeutic response. MATERIALS AND METHODS: Ten patients with psoriasis were treated with the pulsed dye laser on single, stable psoriasis plaques. Treatments varied between one and three times, and the lesional response was graded using a scale for erythema, scaling, and infiltration. RESULTS: Six of 10 patients experienced a beneficial clinical effect after therapy. The psoriasis severity scale in these patients was reduced to 2.2 +/- 1.3 compared with a 7.2 +/- 1.7 grade for control areas. The plaques readily developed crusting with therapy, with one leg lesion healing with atrophy. Histopathology in three patients immediately after therapy showed no epidermal damage. One week after laser therapy, the necrotic former epidermis was apparent in superficial crusting. Epidermal thinning and regeneration was seen without any signs of psoriasis. CONCLUSIONS: Pulsed dye laser therapy may improve plaque psoriasis. This improvement may be related to the role the microvasculature plays in psoriasis.

Accuracy in the clinical diagnosis and pattern of malignant melanoma at a dermatological clinic.

The diagnostic pattern of malignant melanoma and clinical suspicion rate has been investigated at a dermatological university clinic. Of 174 histologically proven malignant melanomas, 60 (34%) were not clinically suspected as melanomas. The accuracy of clinical diagnosis increased with level of experience. Physicians with < 1 year experience in dermatology were able to detect malignant melanoma as the first diagnosis in 31% of the cases in contrast to 63% for those with > 10 years experience. Of 50 patients immediately referred from the dermatologic clinic to surgery departments, 12 did not have melanoma.

Genetic instability of microsatellite markers in region q22.3-q31 of chromosome 9 in skin squamous cell carcinomas.

Microsatellite markers assigned to chromosome 9q22.3-q31 were used in order to analyze squamous cell carcinomas from human skin. From the informative samples examined, one showed loss of heterozygosity with both microsatellite markers D9S109 and D9S180. Furthermore, in four cases with D9S109 and in one case with both microsatellite markers, genetic instability was observed in the tumors. These results are interpreted as suggestive of two distinct genetic changes associated with skin squamous cell carcinomas: Loss of a tumor suppressor gene that might relate to the observed frequent loss of a co-localized gene in basal cell carcinomas and alteration of replication/mismatch-repair factors, in similarity to the ones thought to be involved in the genetic instability detected in hereditary nonpolyposis colorectal cancer.

Papillomavirus-associated balanoposthitis.

OBJECTIVE: To assess whether there might be an association between genital papillomavirus infection (GPVI) and balanoposthitis. DESIGN: Retrospective HPV DNA examination of biopsy specimens from 23 men suffering from balanoposthitis and exhibiting acetowhite lesions that were penoscopically and histologically concurrent with HPV infection. SETTING: The STD clinics at Karolinska Hospital and South Hospital, Stockholm, Sweden. PARTICIPANTS: Randomly selected men attending with long-lasting and/or recurrent penile symptoms and exhibiting a clinical picture of balanoposthitis, who revealed a penoscopical and histopathological picture of epidermal lesions that were concordant with accepted criteria for typical or conspicuous GPVI. Asymptomatic controls were selected retrospectively on the basis of identical penoscopy and histology criteria. RESULTS: A history of previous condylomata was obtained in eight (35%) of 23 men. At penoscopic evaluation tiny condylomatous lesions were observed in five (22%) patients. The in situ hybridisation (ISH) assay using specific probes for the HPV types 6/11, 16/18, 31/33 and 42 was positive in 13/23 (56%) of the patient samples, but in only 26% of the 19 control samples. In patient biopsies the oncogenic HPV types 16/18 and/or 31/33 were found in 7/13 samples, whereas HPV 6/11 and/or 42 were present in another six cases. PCR performed on the ten ISH negative patient biopsies, were negative in all cases. CONCLUSION: Symptoms included redness, itching, burning, tenderness, dyspareunia, fissuring and in two cases penile oedema and inguinal adenopathy. All patients fulfilled penoscopical and histopathological criteria for HPV infection. We demonstrate some tentative evidence that HPV might be associated with long-lasting balanoposthitis, although our data still are circumstantial for a causative association. The results also elucidate the diversity in clinical presentation of GPVI.