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Cancer evolves from a combination of genetic and epigenetic abnormalities resulting in aberrant gene expression profiles as well as altered epigenomic patterns. Epigenetic alterations such as DNA methylation and histone modification play an important role in tumorigenesis. While in the pathobiology of uveal melanoma (UM) genetic changes have been well characterized, there is growing evidence suggesting that epigenetic changes are also involved. We investigated whether epigenetic modifications (global levels of histone acetylation, DNA methylation, ubiquitination) are detectable in UM tissues compared to healthy controls with respect to inter- and intratumoral heterogeneity. Formalin-fixed paraffin-embedded tissues of primary UM (n = 15), UM metastasis (n = 13), and control choroid (n = 12) were immunohistochemically investigated by two ophthalmic pathologists for global levels of histone acetylation (Histone 3 acetylation, H3Ac; Histone 4 acetylation, H4Ac), DNA methylation (5-methylcytosine, 5-MeC; 5'-hydroxymethylcytosine, 5-hMeC), global ubiquitination (UBC) as well as Ubiquityl-Histone H2A (H2Aub). The nuclear staining intensity of primary tumors, metastases and control choroids was evaluated using a score from 0 to 3, which was multiplied with the percentage of stained cells (score from 0 to 4). The control choroid and the choroid next to the tumor showed a more intense nuclear staining than the primary tumor tissue. The choroid next to the tumor was stained less than the control choroid. The nuclear staining intensity in the tumor was comparable to that in the metastases. The tumor tissue itself often exhibited a heterogeneous staining pattern, as nuclei in the tumor center were less intensely stained than in the periphery. Cells with a presumed invasive potential (extraocular extension, growth along emissary canals) showed also an intense staining reaction. Although no prognostically relevant pattern of global epigentic markers could be identified, our results suggest that epigenetic changes play a role in UM pathogenesis and metastasis. In particular the staining reaction of tumor cell subtypes with a presumed invasive potential warrants further attention. The role of epigenetically relevant interactions with the tumor micromilieu should be further investigated as immune cells are predominantly located in the tumor periphery which showed a different staining intensity than the tumor center. However, as considerable epigenetic diversity exists in primary tumors, studies on biopsy tissue are not recommended for the immunohistochemical investigation of epigenetic markers., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Assessing whether an association exists between drainage to multiple basins and lymphatic metastasis in patients with truncal melanoma (TM)., Methods: The study included 260 patients with primary TM (163 men; median age 56.5 y/o) with a cN0 M0, who underwent a sentinel lymph node scintigraphy and biopsy. The median tumor thickness (TT) was 1.51 mm., Results: One hundred and three patients showed more than one basin; of these, 95 patients had 2 basins, 6 had 3 basins, and 2 had 4 basins of drainage. Nodal histology was positive for metastatic disease in 65 patients, of whom, 40 had 1 basin, 24 had 2 basins and 1 had 3 basins of drainage. Of the 195 node-negative patients, 116 had 1 basin, 70 had 2 basins, 5 had 3 basins, and 2 had 4 basins of drainage (P=0.89). In a median follow-up of 36 months, 26 patients showed progressive disease, of whom 15 had 1 basin and 11 had 2 basins (P=0.76). Twenty patients died, of whom 11 had 1 basin and 9 had 2 basins (P=0.8)., Conclusions: There is no significant association between the number of drainage basins and sentinel node positivity or further progress of the disease in patients with TM.

Macrophages have been found to be negative predictors of outcome in patients with uveal melanoma. In particular, recent studies point toward a disease-progressing role of proangiogenic M2 macrophages in melanomas with monosomy 3. Although most studies implicate a protective effect of PPAR-gamma activation in tumors, PPAR-gamma has also been shown to promote the polarization of M1 macrophages toward the M2 phenotype. The purpose of this investigation was first, to characterize the phenotype of tumor infiltrating macrophages and second, to study PPAR-gamma expression in uveal melanomas with molecular gene expression profile as prognostic predictors for patients' outcome. Twenty specimens from patients with uveal melanoma were analyzed for clinical and histologic tumor characteristics. The molecular RNA profile (class 1 or class 2) was commercially determined. Using immunohistochemical techniques, the specimens were dual labeled for CD68 and CD163. CD68 + CD163- M1 macrophages and CD68 + CD163+ M2 macrophages were analyzed in ten high power fields sparing macrophage-poor areas and a mean value was calculated for each tumor. The tumors were immunostained for von Willebrand factor and the micro vascular density (MVD) was analyzed according to Foss. To assess the proliferative rate of each tumor, Ki67 expression was evaluated in ten high power fields followed by calculation of a mean value. Expression of PPAR-gamma was evaluated using a score from 0 (no staining) to 3 (tumor entirely stained). Statistical analysis and a respective correlation were made between histologic characteristics, molecular profile, type of tumor infiltrating macrophages (M1 vs. M2), MVD, proliferative rate, and PPAR-gamma expression. Our results showed a correlation between the ratio of M2/M1 macrophages and the molecular profile with a ratio of approximately 1 corresponding to molecular class 1 and a ratio of approximately 2 corresponding to molecular class 2 (p = 0.01). The ratio of M2/M1 macrophages was higher in tumors with extraocular extension (p = 0.01). PPAR-gamma was predominantly expressed in the cytoplasm of tumor cells. Its expression showed no association with the molecular RNA profile (p = 0.83). This study confirmed that the ratio of M2/M1 macrophages is another prognostic factor in uveal melanoma. Thus, polarization of macrophages plays an important role for patients' outcome. PPAR-gamma is expressed in uveal melanoma tumor cells and further studies are warranted to determine its role in tumor biology., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: Sentinel lymph node biopsy (SLNB) is a widely accepted procedure to accurately stage melanomas with a thickness ≥1 mm. The value of SLNB in thin melanomas is still controversial, especially because long-term observations of these patients are rare. The purpose of the current study was to identify the positive sentinel lymph node (SLN) ratio in low-risk patients with cutaneous melanoma (CM) of thickness less than 1 mm and its possible prognostic value, focusing on long-term follow-up data., Methods: In a retrospective single-centre study performed at the Department of Dermatology and Allergy, University of Bonn, 121 patients who had received SLNB were identified out of 621 patients with a diagnosis of CM of <1.00 mm thickness presenting between September 2000 and February 2009 (mean follow-up time, 50.9 months)., Results: Of the 121 patients, 5 (4.1%) had a positive SLN. All positive SLNs were found in patients with a tumour thickness between 0.90 mm and 1.00 mm. There were no significant differences in the presence of positive SLNs according to Clark level and ulceration status (Clark levels II and III and no ulceration vs. Clark levels IV and V or ulceration), regression, gender or age. Disease-free survival was 100% in the SLN-positive patients. On the other hand, five SLN-negative patients (4.1%) developed disease progression. One of these five progressive patients showed recurrence in the former negative SLN basin (16.7% false-negative rate)., Conclusion: A positive SLN in thin melanomas is uncommon with a prevalence of 4.1% in our study population. We could not identify reliable clinicopathological risk factors which could predict results of SLNB in thin melanomas. Based on our results, SLNB may be considered in patients with a melanoma of thickness in the range 0.90-0.99 mm, because all SLN-positive patients belonged to this subgroup.