Nevus-associated Lentigo Maligna and Lentigo Maligna Melanoma, Clinicopathological Features.

Nevus-associated lentigo maligna and lentigo maligna melanoma (NALMM) are rarely described in the literature and are considered an incidental finding. This study aimed to evaluate the frequency of NALMM and its clinicopathological features. A total of 201 histopathology reports were reviewed and among them 20% of the samples corresponded to NALMM, with females overrepresented in this group (p = 0.02). A significant association was also observed between NALMM with the presence of multiple nevi (p = 0.01), and dysplastic nevi (p = 0.04). Moreover, the risk of developing a second melanoma of nevus-associated type was 4.3 times higher in patients with NALMM. These results indicate that NALMM is more frequent than previously reported, suggesting that the associated nevus could interact or even act as a precursor for LM/LMM. Future studies with larger samples allied to techniques like confocal microscopy and molecular analysis are essential to determine this biological link between nevus and LM/LMM.

Human papillomavirus-associated balanoposthitis--a marker for penile intraepithelial neoplasia?

The purpose of this study was to analyse, among men treated with diathermy, whether there was a difference in balanoposthitis between men with histopathologically benign human papillomavirus-associated lesions and those with penile intraepithelial neoplasia. Data were derived from patient material from a previously published study. Two clinically identical lesions from the same genital site were collected for analysis with routine histopathology and with nested PCR. In total, 292 men were included, of which 47 (16%) had penile intraepithelial neoplasia. Of those with penile intraepithelial neoplasia, 19/47 (40%) reported problems consistent with balanoposthitis, compared with only 15/245 (6%) patients with benign lesions (p < 0.0001). A statistical difference in percentage distribution was also seen regarding morphology (p = 0.001) and location (p = 0.0003) of the lesions among the men having benign lesions with and without balanoposthitis. It is not possible to take biopsies from patients with genital warts, but this study suggests that one probably should be more observant for genital dysplasia among those men with warts with a history of balanoposthitis than those with no such history.

Interobserver variability of histopathological prognostic parameters in cutaneous malignant melanoma: impact on patient management.

Clinical management of primary cutaneous melanomas is based on histopathological staging of the tumour. The aim of this study was to investigate, in a non-selected population in clinical practice, the agreement rate between general pathologists and pathologists experienced in melanoma in terms of the evaluation of histopathological prognostic parameters in cutaneous malignant melanomas, and to what extent the putative variability affected clinical management. A total of 234 cases of invasive cutaneous malignant melanoma were included in the study from the Stockholm-Gotland Healthcare Region in Sweden. Overall interobserver variability between a general pathologist and an expert review was 68.8-84.8%. Approximately 15.5% of melanomas ≤1 mm were re-classified either as melanoma in situ or melanomas >1 mm after review. In conclusion, review by a pathologist experienced in melanoma resulted in a change in recommendations about surgical excision margins and/or sentinel node biopsy in subgroups of T1 melanomas.

The spectrum of genital human papillomavirus infection among men attending a Swedish sexually-transmitted infections clinic: human papillomavirus typing and clinical presentation of histopathologically benign lesions.

There have been a number of Swedish studies on human papillomavirus (HPV) typing in men, most of which have used less sensitive HPV-typing techniques. The present study included male patients with genital HPV-induced lesions planned for surgery. Samples were prepared for histopathology and PCR. HPV was detected in 233/253 (92%) and HPV 6 or 11 in 89% of the HPV-positive lesions. There were statistically significant differences regarding morphology (p=0.002), location (p=0.000001) and colour (p=0.005) of the lesions for low- vs. mixed or high-risk HPV types. For example, acuminate lesions were mostly found among men with low-risk HPV types, whereas macular lesions were over-represented among them with mixed or high-risk types. The HPV type distribution is similar to that in earlier studies, but we also found correlations with some clinical parameters.

Serotonin and its 5-HT1 receptor in human mastocytosis.

CONTEXT: Human mastocytosis is a rare disease, in which the serotonergic system may be involved. OBJECTIVE: The objective of the present study was to examine the possible presence of serotonin (5-HT) and its 5-HT1A receptor (R) in the skin of patients with mastocytosis. In addition, the effect of the 5-HT1AR was tested on human mastocytosis cells, cultured in vitro. MATERIALS AND METHODS: The expression of 5-HT and 5-HT1AR in patients with urticaria pigmentosa and mastocytoma was studied using immunohistochemistry. The effects of 8-OH-DPAT, an agonist of 5-HT1AR, on the proliferation (cell number), viability, apoptosis, spontaneous release of histamine, as well as a possible 5-HT metabolism, in the human HMC-1 mast cell line, were investigated. RESULTS: Both 5-HT and 5-HT1AR were expressed in the mast cells in biopsies of mastocytoma and urticaria pigmentosa, as well as in HMC-1 cells. However, no metabolism of 5-HT by the cell line could be detected by the methodology used. The 5-HT1AR agonist had no significant effect on the viability and number of HMC-1 cells, and was without effect on the apoptosis. At concentrations of 10⁻6 mol/L and 10⁻8-10⁻¹° mol/L (i.e. also at physiological concentrations), the agonist inhibited histamine release by these cells by as much as 30%. CONCLUSION: These findings indicate that 5-HT and its 5-HT1AR are expressed in human mastocytosis and that an agonist of the 5-HT1AR might be of value in the treatment of these patients.

Grenz ray treatment of lentigo maligna and early lentigo maligna melanoma.

BACKGROUND: Lentigo maligna (LM) is the in situ phase of lentigo maligna melanoma (LMM). A wide variety of modalities has been used to manage LM, including conventional surgery, staged excision, Mohs micrographic surgery, cryotherapy, radiotherapy, laser therapy, and, recently, imiquimod. OBJECTIVES: Soft x-radiation is an accepted treatment for LM/LMM. The aim of the present study was to evaluate the efficacy and safety of ultra-soft x-ray/grenz-ray (GR) treatment in patients with LM and early LMM. METHODS: Five hundred ninety-three patients were treated with GR (primary therapy, n = 350; partial excision followed by GR, n = 71; radical excision followed by GR as recurrence-prophylactic treatment, n = 172) at the Department of Dermatology, Karolinska University Hospital, Stockholm, Sweden between 1990 and 2009. The treatment was given twice a week over 3 consecutive weeks in total doses of 100 to 160 Gy. Dosage depended on the stage of LM and the depth of periadnexal atypical melanocytic extension in histologically examined materials before treatment. Four hundred twenty-five patients have been followed up for at least 2 years; of these, 241 for 5 years. RESULTS: Overall, 520 of 593 patients (88%) showed complete clearance after one fractionated treatment. Residual lesions were seen in 15 patients, and 58 relapsed, 53 of whom (72%) within 2 years. LIMITATION: Woods light examination was not used in the clinical diagnosis of lentigo maligna. CONCLUSIONS: GR is an efficient and safe treatment in LM and early LMM when administered according to the recommendations presented herein. Moreover, GR offers an excellent cosmetic result.

Analyte flux at a biomaterial-tissue interface over time: implications for sensors for type 1 and 2 diabetes mellitus.

OBJECTIVE: The very presence of an implanted sensor (a foreign body) causes changes in the adjacent tissue that may alter the analytes being sensed. The objective of this study was to investigate changes in glucose availability and local tissue metabolism at the sensor-tissue interface in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). METHOD: Microdialysis was used to model implanted sensors. Capillary glucose and subcutaneous (sc) microdialysate analytes were monitored in five T1DM and five T2DM patients. Analytes included glucose, glycolysis metabolites (lactate, pyruvate), a lipolysis metabolite (glycerol), and a protein degradation byproduct (urea). On eight consecutive days, four measurements were taken during a period of steady state blood glucose. RESULTS: Microdialysate glucose and microdialysate-to-blood-glucose ratio increased over the first several days in all patients. Although glucose recovery eventually stabilized, the lactate levels continued to rise. These trends were explained by local inflammatory and microvascular changes observed in histological analysis of biopsy samples. Urea concentrations mirrored glucose trends. Urea is neither produced nor consumed in sc tissue, and so the initially increasing urea trend is explained by increased local capillary presence during the inflammatory process. Pyruvate in T2DM microdialysate was significantly higher than in T1DM, an observation that is possibly explained by mitochondrial dysfunction in T2DM. Glycerol in T2DM microdialysate (but not in T1DM) was higher than in healthy volunteers, which is likely explained by sc insulin resistance (insulin is a potent antilipolytic hormone). Urea was also higher in microdialysate of patients with diabetes mellitus compared to healthy volunteers. Urea is a byproduct of protein degradation, which is known to be inhibited by insulin. Therefore, insulin deficiency or resistance may explain the higher urea levels. To our knowledge, this is the first histological evaluation of a human tissue biopsy containing an implanted glucose monitoring device. CONCLUSIONS: Monitoring metabolic changes at a material-tissue interface combined with biopsy histology helped to formulate an understanding of physiological changes adjacent to implanted glucose sensors. Microdialysate glucose trends were similar over 1-week in T1DM and T2DM; however, differences in other analytes indicated wound healing and metabolic activities in the two patient groups differ. We propose explanations for the specific observed differences based on differential insulin insufficiency/resistance and mitochondrial dysfunction in T1DM versus T2DM.

Different serotonergic expression in nevomelanocytic tumors.

The neuromediator serotonin (5-hydroxytryptamine; 5-HT) has been proposed to play a role in tumor progression. Thus, the aim of the present investigation was to determine whether alterations in the serotonergic system occur in nevomelanocytic tumors. For this purpose, paraffin-embedded biopsies of superficial spreading malignant melanoma (SSM), dysplastic compound nevi (DN) and benign compound nevi (BCN) were characterized with regard to their expression of 5-HT, the 5-HT1A and 5-HT2A receptors, and the serotonin transporter protein (SERT), by immunohistochemical analysis. Melanocytes in the region surrounding the tumor were found to express both the 5-HT1A and 5-HT2A receptors. Tumor cells that immunostained positively for the different serotonergic markers were observed in the suprabasal epidermis of DN tissue and, to an even greater extent, in the case of SSM. Furthermore, some of these latter cells expressed both 5-HT1AR and 5-HT2AR. The level of expression of 5-HT1AR at the junctional area was lower for SSM than for DN or BCN. As the degree of atypia increased, the intensity of tumor cell staining in the dermis for 5-HT1AR and SERT declined. Vessel immunoreactivity for 5-HT2A was more intense in SSM than in BCN tissue. Round-to-dendritic cells that expressed both SERT and 5-HT1AR were seen to infiltrate into the dermal region of the tumor, this infiltration being more evident in the case of DN and SSM. These latter cells were also tryptase-positive, indicating that they are mast cells. Thus, alterations in serotonergic system may be involved in nevomelanocytic tumors and mast cells may play an important role in this connection.

Mortality and clinicopathological features of cutaneous squamous cell carcinoma in organ transplant recipients: a study of the Swedish cohort.

Solid organ transplant recipients have a high incidence of cutaneous squamous cell carcinoma and often develop multiple and aggressive tumours. This retrospective study based on the Swedish organ transplant cohort, focuses on the deaths caused by cutaneous squamous cell carcinoma and aims to elucidate the clinicopathological features of these tumours. The cohort comprised 5931 patients who underwent organ transplantation during the period 1970 to 1997 and were registered in the Swedish In-patient Registry, Cancer Registry and Causes-of-Death Registry. A total of 544 cutaneous squamous cell carcinomas in 201 patients were re-examined. The dominating size of the tumours was 5-10 mm and one-third of the tumours were removed by methods other than excision surgery. Well-differentiated tumours and Clark level IV were predominant. Seven patients died from their tumours, all of which were localized on the head. The principal site of metastasis was the parotid gland. The mean duration between date of transplantation and death was 10.4 years (range 6-17 years). Mortality from cutaneous cell carcinoma was compared with that of the general population. There was a highly increased risk; standardized mortality ratio 52.2; 95% confidence interval 21.0-107.6. However, the mortality rate in the Swedish cohort appears to be lower than what has been reported previously from other countries.

Concomitant late soft tissue infections by Cladophialophora bantiana and Mycobacterium abscessus following tsunami injuries.

A Swedish man and woman sustained severe soft tissue injuries during the tsunami catastrophe in Thailand in December 2004, and subsequently received partial thickness skin grafts after multiple surgical revisions. Four to six weeks post trauma they displayed signs of purulent infections in the non-traumatized, virtually intact skin outside the resection margins. Skin biopsies revealed granulomatous reactions and pigmented fungal hyphae were observed in specimens from the male patient. Cladophialophora bantiana and Mycobacterium abscessus were recovered concomitantly from samples obtained from both patients. Antifungal treatment was given with voriconazole for one month, after which no fungal growth was detected on biopsies. Antimycobacterial treatment was given with clarithromycin and amikacin. The symptoms gradually subsided in the male patient, but recurrent abscesses were noted with the female patient, from which M. abscessus was recovered despite prolonged antibiotic therapy.

The contribution of the Fas/FasL apoptotic pathway in ulcer formation during Leishmania major-induced cutaneous Leishmaniasis.

Cutaneous leishmaniasis (CL), caused by the intracellular protozoan Leishmania major, is characterized by lesion formation and ulceration at the site of infection. The mechanism of ulcer formation during CL is not fully understood. The expression of Fas and FasL and the levels of apoptosis in skin biopsies and in restimulated blood mononuclear cells from patients with 1 to 7 months of L. major-induced CL were analyzed using immunohistochemistry and fluorescence-activated cell sorting analysis. The levels of soluble Fas and FasL were also analyzed by enzyme-linked immunosorbent assay. A substantial number of apoptotic keratinocytes were observed mainly in the superficial epidermis of morphologically active and healing CL skin samples. Fas expression was increased on epidermis in active CL, whereas Fas expression was similar in healing and healthy epidermis. FasL-expressing macrophages and T cells were found in subepidermal infiltrate, mainly in active disease. When CL peripheral blood mononuclear cells were restimulated with L. major, Fas was up-regulated on effector T cells, and high levels of sFasL were secreted. Supernatants from restimulated cultures induced apoptosis in human keratinocytes (HaCaT), possibly through Fas/FasL interactions. Our results indicate that FasL-expressing effector T cells and macrophages may act to induce apoptosis and ulcer formation in Fas-expressing keratinocytes during L. major infection.