Melanoma incidence and Breslow tumour thickness development in the central Alpine region of South Tyrol from 1998 to 2012: a population-based study.

BACKGROUND: Cutaneous melanoma incidence is increasing worldwide, especially for in situ and thin (<1 mm) lesions, while thick (≥1 mm) lesions have been generally stable in many studies; although epidemiological data on melanoma is readily available, population-based studies, especially on mountain regions, are rare. OBJECTIVE: The aim of this study was to analyse cutaneous melanoma incidence and Breslow tumour thickness in the central Alpine mountain region of South Tyrol, northern Italy. METHODS: All newly diagnosed cutaneous in situ and invasive melanomas in the resident population from 1998 to 2012 were taken from the Pathology Unit, Bolzano Hospital and South Tyrol Cancer Registry. Incidence and Breslow tumour thickness were analyzed. Statistical analyses included Mann-Whitney and Kruskal-Wallis tests. RESULTS: A total of 784 in situ melanomas and 1663 invasive melanomas were collected. In situ melanomas showed the highest increase: European age-standardized incidence rose from 2.44 per 100,000 inhabitants in 1998-2002 to 16.01 in 2008-2012. Invasive melanoma incidence increased from 12.69 in 1998-2002, to 22.88 in 2008-2012. The incidence rise was observed in thin melanomas (from 8.39 to 16.18) and in thick melanomas (from 4.30 to 6.70). Breslow distribution revealed a median value of 0.62 mm (mean 1.34; SD 2.24; range 0.09-30.0) and did not change significantly over time (P = 0.286). Higher Breslow values were observed at advanced age (P < 0.001), among males (P = 0.017), in nodular melanomas (P < 0.001) and at higher Clark levels (P < 0.001). Significant differences were also found in urban hospitals compared to rural hospitals during the whole period (P = 0.004), but not in the last 5 years (P = 0.053). CONCLUSION: Incidence of cutaneous melanoma is increasing in South Tyrol, especially for in situ and thin lesions, but also for thick lesions; no reduction in median tumour thickness is observed. Rural areas and elevated altitudes may contribute to this effect.

Comparative analysis of immunohistochemistry, polymerase chain reaction and focus-floating microscopy for the detection of Treponema pallidum in mucocutaneous lesions of primary, secondary and tertiary syphilis.

BACKGROUND: The incidence of syphilis is increasing in many parts of the world including a re-emergence in Western Europe and North America. Depending on the disease stage, direct detection of Treponema pallidum in mucocutaneous lesions of syphilis may be difficult and histopathological findings are not always straightforward. Thus, the correct histological diagnosis may be challenging. OBJECTIVES: Comparatively to evaluate the evidence for infection with T. pallidum by immunohistochemistry (IHC), polymerase chain reaction (PCR) and focus-floating microscopy (FFM). METHODS: A series of 86 paraffin-embedded skin biopsy samples from patients with primary, secondary or tertiary syphilis was assessed for detection of T. pallidum by IHC and FFM; 45 specimens were also investigated by a T. pallidum-specific PCR analysis. Histopathological reaction patterns and number and distribution of treponemes were studied, and all data were re-evaluated by clinicopathological correlation. RESULTS: Using a polyclonal antibody directed against T. pallidum, we detected the presence of T. pallidum by IHC in 42/86 (49%) samples [6/9 (67%) primary, 34/62 (55%) secondary and 2/15 (13%) tertiary syphilis]. T. pallidum-specific DNA was detected in 31/45 (69%) specimens [4/4 (100%) primary, 26/34 (76%) secondary and 1/7 (14%) tertiary syphilis]. In comparison, FFM analysis resulted in an overall detection rate of 82/86 (95%) [9/9 (100%) primary, 60/62 (97%) secondary and 13/15 (87%) tertiary syphilis]. Significant differences were observed concerning amount and distribution of organisms (epitheliotropic vs. endotheliotropic) in correlation to the three disease stages and to histopathological reaction patterns. CONCLUSIONS: FFM is a highly sensitive and specific method to detect T. pallidum in tissue from mucocutaneous syphilis lesions. Our results indicate that a combination of PCR and FFM, as the most sensitive approach, could provide an additional benefit for the histopathological diagnosis of (late) secondary and tertiary syphilis and may be helpful in cases where serological testing of T. pallidum antibodies has failed, but the clinical suspicion for syphilis remains.

The expanding spectrum of cutaneous borreliosis.

The known spectrum of skin manifestations in cutaneous Lyme disease is continuously expanding and can not be regarded as completed. Besides the classical manifestations of cutaneous borreliosis like erythema (chronicum) migrans, borrelial lymphocytoma and acrodermatitis chronica atrophicans evidence is growing that at least in part also other skin manifestations, especially morphea, lichen sclerosus and cases of cutaneous B-cell lymphoma are causally related to infections with Borrelia. Also granuloma annulare and interstitial granulomatous dermatitis might be partly caused by Borrelia burgdorferi or similar strains. There are also single reports of other skin manifestations to be associated with borrelial infections like cutaneous sarcoidosis, necrobiosis lipoidica and necrobiotic xanthogranuloma. In addition, as the modern chameleon of dermatology, cutaneous borreliosis, especially borrelial lymphocytoma, mimics other skin conditions, as has been shown for erythema annulare centrifugum or lymphocytic infiltration (Jessner Kanof) of the skin.

Comparison of metallothionein-overexpression with sentinel lymph node biopsy as prognostic factors in melanoma.

BACKGROUND: Metallothioneins (MT) are ubiquitous, intracellular small proteins with high affinity for heavy metal ions. Immunohistochemical MT overexpression in paraffin-embedded tissues of patients with primary melanoma is associated with poor prognosis. While sentinel lymph node (SLN) biopsy is an established surgical technique for high-risk melanoma patients with predictive value for progression, the benefit of this procedure for the individual patient's overall survival remains unclear. AIM AND METHODS: We examined the role of MT overexpression in comparison with SLN biopsy in melanoma patients as a prognostic marker for progression and survival. One hundred and fifty-eight (158) patients underwent SLN biopsy due to high-risk melanoma. Primary melanoma specimens were investigated by using a monoclonal antibody against MT on routinely fixed, paraffin-embedded tissues. The patients were followed up (median 37 months); the data of disease free survival and overall survival were calculated with a broad panel of statistical analyses. RESULTS: Twenty-eight (18%) out of 158 recruited melanoma patients developed metastases, 17 (11%) patients died due to widespread disease. Kaplan-Meier curves gave significant disadvantages for the MT-positive as well as the SLN-positive group for progression and survival. In the Fisher's exact test and Pearson's chi(2)-test MT overexpression was highly significant for progression, whereas SLN biopsy failed significance. In univariate as well as multivariate Cox regression analysis MT overexpression proved an excellent marker for progression (P=0.007 and P=0.009), although the P-values for survival were not significant. In contrast, while in the univariate analysis SLN biopsy did not show significant results for progression it did for survival, and in the multivariate analysis reached a P-value < 0.05 for both measured endpoints. CONCLUSION: Results corroborate the validity of MT overexpression in primary melanoma as a useful prognostic marker in melanoma patients. Accuracy is comparable and to some degree supplementary to the results of SLN biopsy.

Sentinel lymph node status in melanoma: a valuable prognostic factor?

BACKGROUND: Sentinel lymph node (SLN) biopsy is advocated as the standard of care for patients with primary melanoma. It is a procedure with few side-effects and provides valuable staging information about the regional lymphatics. OBJECTIVES: To investigate the prognostic value of SLN biopsy and to compare it with that of other known risk factors in primary melanoma. METHODS: One hundred and forty-nine patients with primary melanomas (tumour thickness >1.0 mm) underwent SLN biopsy between May 1998 and April 2004 at our department. This report summarizes the follow-up data of this cohort until October 2004. RESULTS: SLN biopsies of 49 of 149 patients (33%) revealed micrometastatic disease. Of all clinical and histological criteria, only the clinical type of primary melanoma (11 of 19 patients with acrolentiginous melanomas) and the Clark level were predictive for SLN positivity. Progression was observed in 22 patients (15%). It was significantly associated with ulceration of the primary tumour, tumour thickness, clinical type and localization of the primary tumour, female sex and older age. In contrast, SLN positivity was not significantly associated with a higher risk of progression (eight of 49 SLN-positive vs. 14 of 100 SLN-negative patients; P = 0.807). Twelve of 149 patients (8%) died because of melanoma in the follow-up period. Significant criteria for death were ulceration of the tumour, clinical type and localization of the primary tumour, but not SLN positivity. CONCLUSIONS: A high percentage of positive SLNs was observed in the patients with melanoma in our study (33%). The fractions of patients both with progressive disease and with tumour-related death were not significantly higher in patients with positive SLN than in those with negative SLN. We therefore conclude that the SLN status is not a reliable prognostic factor for progression of melanoma.

[Xanthoma disseminatum: a rare case involving the upper extremity]. / Xanthoma disseminatum -- ein seltener Befall an der oberen Extremität.

We describe a dramatic case of class II non-Langerhans cell histiocytosis, xanthoma disseminatum, in a 30-year-old male patient with progressive involvement of the skin, vocal cords, eyes, bones and nerves in spite of chemotherapy with Vespesid and immunotherapy with interferon-gamma. At the age of 43 years, the patient required surgical clearance of airways, eyelids and peripheral nerves, but at present exhibits stable disease on a combination of lipid-lowering drugs including thiazolidinedione.

Metallothionein - overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients.

Metallothioneins (MT) are ubiquitous, intracellular small proteins with high affinity for heavy metal ions. In the last decades, it was shown that MT overexpression in a variety of cancers is associated with resistance to anticancer drugs and is combined with a poor prognosis. In this prospective study, we examined the role of MT overexpression in melanoma patients as a prognostic factor for progression and survival. Between 1993 and 2004, 3386 patients with primary cutaneous melanoma were investigated by using a monoclonal antibody against MT on routinely fixed, paraffin-embedded tissues. In all, 1270 patients could be followed up for further statistical analysis (Fisher's exact test, Mantel-Haenszel chi2 test, Kaplan-Meier curves). The MT data of disease-free interval and overall survival were compared univariately and multivariately in Cox regression analysis. Immunohistochemical overexpression of MT in tumour cells of patients with primary melanoma (310 of 1270; 24.4%) was associated with a higher risk for progression (117 of 167; 70.1%) and reduced survival (80 of 110; 72.7%) of the disease (P<0.0001). Similarly, Kaplan-Meier curves gave highly significant disadvantages for the MT-positive group. Univariate analysis (relative risk 7.4; 95% confidence interval (CI) 5.2-10.2; P<0.0001 for progression; relative risk 7.1; 95% CI 4.7-10.9; P<0.0001 for survival), as well as multivariate analysis with other prognostic markers resulted in MT overexpression as a highly significant and independent factor for prognosis in primary melanoma.

Suppression of natural killer cells in the presence of CD34+ blood progenitor cells and peripheral blood lymphocytes.

Abstract Mobilization of CD34 + peripheral blood progenitor cells (PBPCs) with granulocyte-colony stimulating factor (G-CSF) may induce functional alterations in peripheral blood lymphocyte (PBL) subsets. We and others have shown that natural killer (NK) cells from PBPC collections are less expandable in vitro than those obtained during steady-state hematopoiesis. We show here that the extent of this proliferation deficit is related to the number of circulating CD34 + cells in vivo at the time of PBPC apheresis. Likewise, addition of autologous CD34 + cells to unseparated PBL reduced the expansion of the NK-cell subset by 22.2% +/- 6.0% (n = 10; P <.005). In contrast, when using purified NK cells, their proliferation remained unimpaired by autologous CD34 + cells. Supernatants from CD34 + cells cultured with autologous PBLs had an inhibitory effect on proliferation of purified NK cells (n = 16; P =.03), indicating that an interaction between CD34 + cells and lymphocytes is essential for the suppressive effect on NK cells. To investigate the role of T cells in this interaction, intracellular cytokines were determined in T cells cultured for 7 days with or without autologous CD34 + cells. When cultured with CD34 + cells, the frequency of IL-2-producing CD4 + and CD8 + T cells was reduced by 19% and 24%, respectively, compared with T cells cultured alone (n = 7; P =.016). Interferon-gamma-producing T cells were slightly reduced ( P = not statistically significant [ns]). Finally, the influence of T cells and NK cells on the recovery of myeloid colony-forming cells (CFU-GMs) from purified CD34 + cells was examined. In the presence of T cells, 16% +/- 6% of the input CFU-GM recovered after 7 days, compared with 5% +/- 4% in the presence of NK cells (n = 5; P = ns). Our findings point to an inhibition of NK-cell proliferation mediated by an interaction of CD34 + cells and T cells occurring during PBPC mobilization with G-CSF.