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Targeting immune cells instead of cancer cells is a new and successful therapeutic approach in patients with a variety of advanced cancers. Blocking antibodies bind to specific immune-checkpoint molecules namely cytotoxic T-lymphocyte-associated antigen 4, programmed cell death protein-1, and programmed cell death-ligand 1. However, their mechanism of action can lead to immune-related adverse events. In particular, neurological immune-related adverse events present, currently, a problem, as they are rare, difficult to diagnose, and are often high grade or even fatal. Here, we describe four cases with metastatic melanoma who developed symptoms of acute progressive weakness 3-9 weeks after therapy onset with immune-checkpoint inhibitors (ICIs) nivolumab and ipilimumab. Neurological examination and diagnostic procedures revealed results partly consistent with neurological disorders such as neuropathy, myositis, and myasthenia. This suggests an overlap of these known diseases indicating a new ICI-induced neuropathy-myositis-myasthenia-like syndrome. Here, we give recommendations for a structured and focused diagnostic assessment in patients presenting with neurological deficits during ICI therapy. This might improve the understanding, management, and ultimately the outcome of ICI-induced neurological adverse events.

Background: PD-1 inhibition (PD-1i) is the standard of care in melanoma and other malignancies. In patients with bone metastases of solid tumors, the monoclonal antibody denosumab directed against RANKL is approved for the prevention of skeletal-related events. However, RANKL is not only relevant in osteoclastogenesis, but also has immunological effects. Hence, we aimed at investigating, whether the combination of PD-1i and denosumab produces synergistic effects in metastatic melanoma treatment., Methods: We retrospectively collected and analyzed clinical data of metastatic melanoma patients with bone metastases, who received PD-1i and denosumab therapy., Results: 29 patients were identified with a median age of 60.7 years: 20 were male and 9 were female. 20 patients (69%) were in stage IV M1c and 9 (31%) in stage IV M1d; 52% had an increased serum LDH. 24 patients (83%) received PD-1i as first-line therapy and five patients (17%) as second- or third-line therapy. 13 patients received the triple combination nivolumab, ipilimumab and denosumab (N + I+D), 16 patients received PD-1i and denosumab (PD-1i + D). Within a median follow-up time of 19.8 months, 17 patients progressed with a median time to progression of 6 months. The objective response rate was 54% in the N + I + D group and 50% in the PD-1i + D group. Recalcification of bone metastases was radiologically observed in 18 (62%) patients. No unexpected treatment-related adverse events emerged., Conclusions: The combination therapy of metastatic melanoma with PD-1i and denosumab was feasible without unexpected safety issues and showed a promising efficacy signal. Further investigation in prospective studies is needed.

Background: Nonmelanoma skin cancer (NSMC) is the most common malignancy after organ transplantation. Lung transplant recipients (LTRs) are particularly prone to develop NMSC as compared to renal or hepatic transplant recipients due to higher dosages of immunosuppression needed. Everolimus, an immunosuppressant used in organ transplant recipients, is thought to inherit a lower risk for NMSC than calcineurin inhibitors, especially in renal transplant recipients. It is currently unknown whether this also applies to LTRs., Objectives: To determine risk factors for NMSC and precancerous lesions after lung transplantation (LTx) and to characterize the effect of everolimus-based regimens regarding this risk., Materials and Methods: 90 LTRs and former participants of the interventional trial "Immunosuppressive Therapy with Everolimus after Lung Transplantation", who were randomized to receive either an everolimus- or mycophenolate mofetil- (MMF-) based regimen, were enrolled and screened in this retrospective, single-center cohort study., Results: After a median follow-up of 101 months, we observed a prevalence of 38% for NMSC or precancerous lesions. 33% of the patients continuously receiving everolimus from LTx to dermatologic examination compared to 39% of all other patients, predominantly receiving an MMF-based regimen, were diagnosed with at least one NMSC or precancerous lesion ( P= .66). Independent risk factors for NMSC or precancerous lesions after LTx were male sex and duration of voriconazole therapy., Conclusion: NMSC or precancerous lesions were very common after LTx, and risk factors were similar to previous reports on LTRs. Everolimus did not decrease this risk under the given circumstances of this study. Patients should be counseled regarding their risk, perform vigorous sunscreen, and undergo regular dermatological controls, regardless of their immunosuppressive regimen.

Background: Due to their immunosuppressive therapy, organtransplant recipients (OTRs) exhibit a high incidence for the development of cutaneous squamous cell carcinoma (cSCC). Randomized studies of kidney-transplanted patients indicate a significant lower susceptibility for cSCC among patients receiving the mTOR-inhibitor Sirolimus, compared to patients without mTOR-regimen. The exact mechanism, how mTOR inhibition affects keratinocyte carcinogenesis remains unclear., Objective: Our aim was to investigate the impact of Sirolimus on the expression level of the oncogene ATF3, which is involved in the development and progression of cSCC., Methods: We incubated human keratinocytes, cSSC cell lines and 3D skin equivalents with Sirolimus, exposed the cells to calcineurin inhibitors (CNI) and UVA-radiation and measured the expression level of ATF3 by real-time PCR and western blot., Results: We show that Sirolimus downregulates the expression of ATF3 induced by cyclosporine or cyclosporine plus UV-radiation in keratinocytes. In line with this we demonstrate a decrease in ATF3 expression, by incubating 3D skin equivalents with Sirolimus prior to cyclosporine and UV-light. However, Sirolimus has no significant impact on the ATF3 expression levels of cyclosporine stimulated cSCC cell lines., Conclusion: Taken together, our study demonstrates that Sirolimus downregulates the CNI or UV-induced ATF3 expression in human keratinocytes, which could be a potential molecular mechanism how Sirolimus reduces cSCC in OTRs. The lack of ATF3 suppression by Sirolimus in cSCC cell lines fits to observations from clinical studies which demonstrated a clinical benefit from the switch to a mTOR-regimen in patients with low tumor burden in early stage of disease., (Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Targeted therapies with BRAF plus MEK inhibitors (BRAFi; MEKi) represent the major treatment strategy for patients with BRAF-mutated metastatic melanoma (MM). Previous analyses suggested a correlation between programmed death-ligand 1 (PD-L1) expression in tumour tissues and the outcome of targeted therapies. This study investigated PD-L1 as a potential predictive biomarker of BRAFi-based targeted therapies in MM patients., Patients and Methods: We analysed two independent cohorts of BRAF V600-mutated MM patients undergoing BRAFi-based therapies for PD-L1 expression in pre-treatment tumour tissues. The oligocentre cohort 1 included 83 patients whose tumour tissues were analysed retrospectively with the anti-PD-L1 antibody clone E1L3N. The multicentre cohort 2 included 58 patients whose tumour tissues were analysed prospectively within the framework of the "Registry of the Arbeitsgemeinschaft Dermatologische Onkologie" (ADOREG) and "Tissue Registry in Melanoma" (TRIM) project using the anti-PD-L1 antibody clone 28-8., Results: PD-L1 expression in pre-treatment tumour tissue did not correlate with response or survival to BRAFi-based therapies in both MM patient cohorts. This finding was not influenced by retrospective versus prospective immunohistochemistry analyses, oligocentre versus multicentre cohorts or the different anti-PD-L1 antibody clones used. In cohort 1, PD-L1 positivity was detected in tumour tissue of 41.0% and 18.1% of patients (cut-off 1% and 5%, respectively). In cohort 2, 58.6% and 39.7% of patients showed PD-L1 positivity (cut-off 1% and 5%, respectively)., Conclusion: In two independent cohorts including a total of 141 MM patients, PD-L1 expression in tumour tissue did not correlate with the outcome of BRAFi-based treatment. Therefore, PD-L1 cannot be recommended for the use as a predictive biomarker of BRAFi-based therapy in BRAF V600-mutated MM., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Mucosal melanoma (MM) is a rare but diverse cancer entity. Prognostic factors are not well established for Caucasians with MM., Patients and Methods: We analysed the disease course of 444 patients from 15 German skin cancer centres. Disease progression was determined with the cumulative incidence function. Survival times were estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariate Cox regression analysis., Results: Common anatomic sites of primary tumours were head and neck (MMHN, 37.2%), female genital tract (MMFG, 30.4%) and anorectal region (MMAN, 21.8%). MMAN patients showed the highest vertical tumour thickness (p = 0.001), had a more advanced nodal status (p = 0.014) and a higher percentage of metastatic disease (p = 0.001) at diagnosis. Mutations of NRAS (13.8%), KIT (8.6%) and BRAF (6.4%) were evenly distributed across all tumour site groups. Local relapses were observed in 32.4% and most commonly occurred in the MMHN group (p = 0.016). Male gender (p = 0.047), advanced tumour stage (p = 0.001), nodal disease (p = 0.001) and incomplete resection status (p = 0.001) were independent risk factors for disease progression. Overall survival (OS) was highest in the MMFG group (p = 0.030) and in patients without ulceration (p = 0.004). Multivariate risk factors for OS were M stage at diagnosis (p = 0.002) and incomplete resection of the primary tumour (p = 0.001)., Conclusion: In this large series of MM patients in a European population, anorectal MM was associated with the poorest prognosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Significant progress has been made in the treatment of metastatic melanoma during the last years. Approval of immune-checkpoint inhibitors and targeted therapies has been achieved recently. The sequencing of these therapies is an important issue. Here, we report our experience with the treatment and retreatment with PD1-inhibitors (PD1i) in eight patients. The patients (two female and seven male with a median age of 70 years, all melanoma stage IV, M1c) underwent a first treatment period with PD1i for a median of 5.5 months. Three (37.5%) patients had a stable disease as best response, two (25%) showed progression, two (25%) showed partial response, and one (12.5%) achieved complete remission. PD1i was discontinued due to disease progression in seven patients and due to side effects (pancreatitis) in one patient. Patients were subsequently treated with ipilimumab (n=2), or chemotherapy (n=4), or no other medical treatment (n=2). All eight patients were subsequently retreated with PD1i for a median of 2.5 months. One (12.5%) developed a partial response, whereas in three patients (37.5%) the disease was stabilized. PD1i have shown a high and durable response rate in the first-line treatment of metastatic melanoma. Our study suggests PD1i retreatment as a reasonable option for selected patients. Further investigations are needed to verify the value of PD1i re-exposure and to identify subgroups of patients who can benefit.

Aim: Programmed cell death protein 1 (PD-1) inhibitors are a common treatment strategy for metastatic melanoma and other tumour entities. Clinical trials usually exclude patients with preexisting autoimmune diseases, thus experience with PD-1 inhibitor (PD-1i) in this patient population is limited., Patients and Methods: Metastatic melanoma patients with preexisting autoimmune disorders or previous ipilimumab-triggered immune-related adverse events (irAE) undergoing treatment with PD-1i from seven German skin cancer centres were evaluated retrospectively with regard to flare of the preexisting autoimmunity and development of new, not preexisting irAE as well as response to PD-1i therapy., Results: In total, 41 patients had either preexisting autoimmunity (n=19, group A, including two patients with additional ipilimumab-triggered autoimmune colitis) or ipilimumab-triggered irAE (n=22, group B). At PD-1i therapy initiation, six patients in group A and two patients in group B required immunosuppressive therapy. In group A, a flare of preexisting autoimmune disorders was seen in 42% of patients, new irAE in 16%. In group B, 4.5% of patients showed a flare of ipilimumab-triggered irAE and 23% new irAE. All flares of preexisting autoimmune disorders or irAE were managed by immunosuppressive and/or symptomatic therapy and did not require termination of PD-1i therapy. tumour responses (32% in group A and 45% in group B) were unrelated to occurrence of autoimmunity., Conclusion: While preexisting autoimmunity commonly showed a flare during PD-1i therapy, a flare of ipilimumab-triggered irAE was rare. Response rates were above 30% and unrelated to irAE. PD-1i therapy can be considered in patients with autoimmune disorders depending on severity and activity of autoimmunity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Mucosal melanomas represent a rare entity with different risk factors and molecular features compared to cutaneous melanomas. They arise most commonly from mucosal surfaces in the head/neck region, the female genital tract (FGT) and the anorectal region. The aim of this study was to evaluate clinics, prognosis, and treatment options of patients with mucosal melanoma, in particular with regard to different primary sites.We retrospectively analyzed 75 patients with mucosal melanomas diagnosed in the years 1993 to 2015 in our department. The primary melanomas were located in the head/neck region (n = 32), the FGT (n = 24), and the anorectal region (n = 19).The median age of the patients was 66 years. At initial diagnosis the primary melanoma was not completely resectable in 11 (15%) patients, 18 (24%) patients had regional lymph node metastases, and 7 (9%) patients distant metastases. During follow-up, 22 (29%) patients suffered from a local recurrence, in particular patients with primary melanoma in the head/neck region without postoperative radiotherapy. By multivariate analysis location of the primary melanoma in the head/neck area or anorectal region and presence of metastases at time of diagnosis represented poor prognostic factors for recurrence-free survival. In 62 tested individuals 7 KIT mutations were found, 2 BRAF mutations in 57 tested patients. Four patients received targeted therapies, 14 checkpoint inhibitors, 4 (1/1 on vemurafenib, 1/7 on ipilimumab, and 2/7 on PD-1 inhibitors) patients showed responses of more than 100 days duration.Mucosal melanomas are often locally advanced or metastatic at initial diagnosis, thus they require extensive staging procedures. The high rate of local recurrences in the head/neck region can be significantly reduced by postoperative radiotherapy. For the potential use of medical treatment a mutation analysis for KIT and BRAF genes should be performed. The use of new immunologic and targeted therapies has to be further evaluated., Competing Interests: The authors have no conflicts of interest to disclose.

Risk factors for the development of cutaneous squamous cell carcinoma (cSCC) include ultraviolet radiation and immunosuppression. In particular, solid organ transplant recipients show a high incidence of cSCC, depending on the immunosuppressive regimen. While azathioprine or calcineurin inhibitors increase the risk of cSCC development, mammalian target of rapamycin (mTOR) inhibitors decreases this risk. At the moment, the mechanisms behind this protective effect of mTOR inhibitors are not fully understood. We evaluated effects of the mTOR inhibitors sirolimus and everolimus on keratinocytes, cSCC cell lines and an organotypic skin model in vitro in regard to proliferation, cytokine secretion and differentiation. We show that mTOR inhibitors block keratinocyte proliferation and alter cytokine and cytokeratin production: in particular, mTOR inhibition leads to upregulation of interleukin-6 and downregulation of cytokeratin 10. Therefore, mTOR inhibitors have effects on keratinocytes, which could play a role in the pathogenesis of cSCC., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Around 5% of all cutaneous squamous cell carcinoma (cSCC) metastasise. Metastases usually locate in regional skin and lymph nodes, suggesting collective cancer invasion. The cellular level of tumour invasion and prognostic parameters remain to be characterised., Methods: We performed immunohistochemical analyses of E-cadherin (marker for collective cancer invasion) and podoplanin (marker for epithelial-mesenchymal transition [EMT], single-cell invasion) expression in 102 samples of metastatic and non-metastatic cSCC and 18 corresponding skin and lymph node metastases to characterise the invasion of cSCC. Immunohistochemical results were retrospectively correlated with clinical data., Results: E-cadherin was highly expressed in metastatic and non-metastatic cSCC and skin metastases. This suggests collective cancer invasion. However, E-cadherin was downregulated in poorly differentiated cSCC and lymph node metastases, suggesting partial EMT. Podoplanin was significantly upregulated in metastatic (p = 0.002) and poorly differentiated (p = 0.003) cSCC. Overexpression of podoplanin represented a statistically independent prognostic factor for disease-free survival (p = 0.014)., Conclusion: Collective cancer invasion is likely in cSCC. In lymph node metastases and poorly differentiated cSCC, partial EMT is possible. Podoplanin is an independent prognostic parameter for metastasis., (© 2016 S. Karger AG, Basel.)

Background: The detection of BRAFV600 mutations in patients with metastatic melanoma is important because of the availability of BRAF inhibitor therapy. However, the clinical relevance of the frequency of BRAFV600 mutant alleles is unclear., Patients and Methods: Allele frequencies of BRAFV600 mutations were analyzed by ultra-deep next-generation sequencing in formalin-fixed, paraffin-embedded melanoma tissue (75 primary melanomas and 88 matched metastases). In a second study, pretreatment specimens from 76 patients who received BRAF inhibitors were retrospectively analyzed, and BRAFV600 allele frequencies were correlated with therapeutic results., Results: Thirty-five patients had concordantly BRAF-positive and 36 (48%) patients had concordantly BRAF-negative primary melanomas and matched metastases, and four patients had discordant samples with low allele frequencies (3.4-5.2%). Twenty-six of 35 patients with concordant samples had BRAFV600E mutations, three of whom had additional mutations (V600K in two patients and V600R in one) and nine patients had exclusively non-V600E mutations (V600K in eight patients and V600E -c.1799_1800TG > AA- in one patient). The frequency of mutated BRAFV600 alleles was similar in the primary melanoma and matched metastasis in 27/35 patients, but differed by >3-fold in 8/35 of samples. BRAFV600E allele frequencies in pretreatment tumor specimens were not significantly correlated with treatment outcomes in 76 patients with metastatic melanoma who were treated with BRAF inhibitors., Conclusions: BRAFV600 mutation status and allele frequency is consistent in the majority of primary melanomas and matched metastases. A small subgroup of patients has double mutations. BRAFV600 allele frequencies are not correlated with the response to BRAF inhibitors.

Unlabelled: The objective of this study was to analyze different types of nodal basin recurrence after sentinel lymph node biopsy (SLNB) for melanoma., Patients and Methods: Kaplan-Meier estimates and the Cox proportional hazards model were used to study 2653 patients from 3 German melanoma centers retrospectively.The estimated 5-year negative predictive value of SLNB was 96.4%. The estimated false-negative (FN) rates after 1, 2, 3, 5, and 10 years were 2.5%, 4.6%, 6.4%, 8.7%, and 12.6%, respectively. Independent factors associated with false negativity were older age, fewer SLNs excised, and head or neck location of the primary tumor. Compared with SLN-positive patients, the FNs had a significantly lower survival. In SLN-positive patients undergoing completion lymphadenectomy (CLND), the 5-year nodal basin recurrence rate was 18.3%. The recurrence rates for axilla, groin, and neck were 17.2%, 15.5%, and 44.1%, respectively. Significant factors predicting local relapse after CLND were older age, head, or neck location of the primary tumor, ulceration, deeper penetration of the metastasis into the SLN, tumor-positive CLND, and >2 lymph node metastases. All kinds of nodal relapse were associated with a higher prevalence of in-transit metastases.The FN rate after SLNB steadily increases over the observation period and should, therefore, be estimated by the Kaplan-Meier method. False-negativity is associated with fewer SLNs excised. The beneficial effect of CLND on nodal basin disease control varies considerably across different risk groups. This should be kept in mind about SLN-positive patients when individual decisions on prophylactic CLND are taken.

Treatment with BRAF inhibitors (BRAFi) leads to complete remissions (CR) in 3-6% of patients with BRAF mutant metastatic melanoma. In cases of CR, it is unclear whether BRAFi therapy should be continued. We retrospectively analyzed the clinical course of patients with metastatic melanoma who discontinued BRAFi therapy after achieving a CR. In 12 patients, CR of metastatic melanoma was diagnosed after a median BRAFi treatment duration of 13 (range 0.3-32) months. Reasons for discontinuation were side effects in seven patients and patient demand in five patients. Six patients are still in CR after a median of 17 (range 2-26) months after discontinuation of BRAF inhibition. Six patients developed a melanoma recurrence after a median of 3 (range 2-17) months of discontinuation of BRAFi therapy. Subsequently, these patients were again treated with a BRAFi, which resulted in three CR, one stable disease, and one progressive disease; one patient could not be assessed. Melanoma patients achieving CR during BRAFi therapy represent a heterogeneous group. Discontinuation of BRAFi therapy after a CR has to be balanced carefully with the potential risk of nonresponding to BRAFi retreatment in the case of relapse., (Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.)

In the case of a positive sentinel lymph node (SLN), melanoma patients are recommended to proceed to complete lymph node dissection (CLND). However, CLND for SLN-positive patients - especially with minimal tumor burden in SLN - is becoming more controversial. We analyzed the clinical course of 305 SLN-positive patients with a mean follow-up of 51.1 months by Kaplan-Meier analyses. Overall, 58/305 (17%) patients did not undergo CLND. These were compared with a matched selection of 58 comparable patients who underwent CLND. Moreover, 106/305 patients with minimal tumor burden in SLN (<0.1 mm diameter of the largest tumor deposit) were analyzed separately. Of these 106 patients, 34 did not undergo CLND, whereas 72/106 patients were treated by CLND. In the matched groups, the CLND group and the non-CLND group did not differ significantly with respect to clinical characteristics, characteristics of the primary melanoma, and histopathological parameters of SLN. There were no differences in recurrence-free survival (P=0.765) and overall survival (P=0.844). The total number of regional lymph node metastases and time to regional lymph node metastases were not significantly higher for non-CLND patients. The subgroup of patients with minimal tumor burden in SLN also did not benefit significantly from CLND. In our analyses from a single German center, we could not find any evidence for a therapeutic survival benefit for CLND after positive SLN. However, future prospective randomized trials should confirm these data.

Background: Organ transplant recipients are prone to the development of non-melanoma skin cancer. Organ transplant recipients often develop multiple non-melanoma skin cancers and the tumors show an aggressive growth pattern, therefore surgical therapy can be difficult. Switch of the immunosuppressive regimen to mTOR-inhibitors such as everolimus or sirolimus can have an antitumor effect., Patients and Methods: In a monocentric retrospective study we evaluated organ transplant recipients who presented with non-melanoma skin cancer in the years 2008-2010. Experience with patients who were switched to an mTOR-inhibitor due to non-melanoma skin cancer are reported in detail, and recent clinical studies are reviewed., Results: 60 organ transplant recipients with non-melanoma skin cancer were evaluated. Due to the development of multiple non-melanoma skin cancer within a few years, the immunosuppressive regimen was switched to everolimus in 7 patients and to sirolimus in 5 patients. Eight patients were evaluable for the effect of mTOR-inhibitors on the development of non-melanoma skin cancer; 4 patients had to discontinue the medication with mTOR-inhibitors early due to various side effects. In the year before the switch to mTOR-inhibitors, 8 patients developed 16 squamous cell carcinomas, 3 Basal cell carcinomas and 22 cases of Bowen's disease. All tumors were histologically confirmed. In the year after switch of immunosuppression, the rate of squamous cell carcinomas (n = 2) and Bowen's disease (n = 3), but not of basal cell carcinomas (n = 2) was significantly reduced. Moreover, 5 prospective randomized trials recently have demonstrated a reduced number of non-melanoma skin cancers in organ transplant recipients after switch of the immunosuppressive regimen to mTOR-inhibitors., Conclusion: Switch of the immunosuppressive regimen to mTOR-inhibitors should be considered for organ transplant recipients suffering from multiple non-melanoma skin cancers., (© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Head or neck location of primary cutaneous melanomas has been described as an adverse prognostic factor, but this has to be reassessed after the introduction of sentinel lymph node (SLN) excision (SLNE). Descriptive statistics, Kaplan-Meier estimates and Cox proportional hazard models were used to study retrospectively a population of 2302 consecutive melanoma patients from three German melanoma centres undergoing SLNE. Approximately 10% of the patients (N=237) had a primary melanoma located at the head or neck (HNM). In both the SLN-positive and SLN-negative subpopulation, patients with HNM were significantly older, more frequently men and had thicker primaries compared with patients with tumours in other locations. The proportion of positive SLNs was lower in HNM compared with other locations of the primary (20 vs. 26%, P=0.048). The false-negative rate was higher in HNM (17.5 vs. 8.4%, P=0.05). In patients with HNM, the SLN status was a significant factor for recurrence-free survival but not for overall survival. SLN-negative HNM patients had a significantly worse overall survival than the SLN negatives with primaries at other sites, whereas the prognosis of the SLN-positive patients was similar in both groups. The prevalence of lymph node metastases after SLNE is lower in patients with HNM compared with other melanoma locations. As a result, the prognostic information provided by the SLN for HNM seems less important. Decision making for SLNE in HNM should be carefully balanced considering the potential morbidity of the procedure.

Background: We have shown previously that T cells from atopic dermatitis (AD) patients produce more IL-22 upon staphylococcal exotoxin stimulation compared to psoriasis patients and healthy controls. The role of staphylococcal exotoxins on polarized memory T helper (Th)22 cells which are enriched in inflamed AD skin remains elusive. Our aim was to investigate IL-22 production in response to staphylococcal enterotoxin B (SEB) and α-toxin stimulation in human memory T cells and polarized Th22 cells., Methods: IL-22 induction was investigated in human peripheral blood-derived CD4+CD45RO+CD45RA- T cells and polarized Th22 cells after SEB and sublytic α-toxin stimulation in a time-dependent manner at the mRNA and protein (ELISA) levels., Results: Th22 cells secreted more IL-22 compared to freshly isolated peripheral blood-derived memory T cells. SEB and α-toxin induced IL-22 in memory T cells as well as in Th22 cells. More IL-22 was induced by SEB and α-toxin in freshly isolated peripheral blood memory T cells compared to Th22 cells derived from memory T cells in long-term cell culture without polarization and Th22 cells under Th22-promoting conditions with IL-6 and TNF-α. No differences in IL-22 induction by staphylococcal exotoxins were observed between cells from AD compared to psoriasis patients and healthy controls., Conclusions: Increased IL-22 secretion can promptly be induced by staphylococcal exotoxins in skin infiltrating CD4+CD45RO+CD45RA- memory T cells and can potentially amplify chronic skin inflammation in AD in the context of bacterial colonization and infection. This should be investigated further in detail in lesional skin of AD and psoriasis patients., (© 2014 S. Karger AG, Basel.)

This first German evidence-based guideline for cutaneous melanoma was developed under the auspices of the German Dermatological Society (DDG) and the Dermatologic Cooperative Oncology Group (DeCOG) and funded by the German Guideline Program in Oncology. The recommendations are based on a systematic literature search, and on the consensus of 32 medical societies, working groups and patient representatives. This guideline contains recommendations concerning diagnosis, therapy and follow-up of melanoma. The diagnosis of primary melanoma based on clinical features and dermoscopic criteria. It is confirmed by histopathologic examination after complete excision with a small margin. For the staging of melanoma, the AJCC classification of 2009 is used. The definitive excision margins are 0.5 cm for in situ melanomas, 1 cm for melanomas with up to 2 mm tumor thickness and 2 cm for thicker melanomas, they are reached in a secondary excision. From 1 mm tumor thickness, sentinel lymph node biopsy is recommended. For stages II and III, adjuvant therapy with interferon-alpha should be considered after careful analysis of the benefits and possible risks. In the stage of locoregional metastasis surgical treatment with complete lymphadenectomy is the treatment of choice. In the presence of distant metastasis mutational screening should be performed for BRAF mutation, and eventually for CKIT and NRAS mutations. In the presence of mutations in case of inoperable metastases targeted therapies should be applied. Furthermore, in addition to standard chemotherapies, new immunotherapies such as the CTLA-4 antibody ipilimumab are available. Regular follow-up examinations are recommended for a period of 10 years, with an intensified schedule for the first three years.

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers., Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment., Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.

Overexpression of microRNA-21 (miR-21) has been observed in various cancer types, but little is known about the role of miR-21 in melanoma. In this study, we demonstrate that levels of miR-21 are significantly increased in primary melanoma tissues as compared to benign nevi and in human melanoma cell lines as compared to melanocytic cell preparations. We show that downregulation of miR-21 in melanoma cell lines with high endogenous miR-21 expression induced apoptosis, whereas proliferation was not significantly altered. Upregulation of miR-21 in melanocytes resulted in increased proliferation and decreased apoptosis. However, in the MEWO melanoma cells with low endogenous miR-21 expression, upregulation of miR-21 had no functional effects. These findings indicate a potential pathogenetic role of miR-21 upregulation in a subgroup of melanomas., (© 2012 John Wiley & Sons A/S.)

In our study, we investigated the impact of the constitutional factor age on the clinical courses of melanoma patients with sentinel lymph node (SLN) biopsy. Descriptive statistics, Kaplan-Meier estimates, logistic regression analysis and the Cox proportional hazards model were used to study a population of 2,268 consecutive patients from three German melanoma centers. Younger age was significantly related to less advanced primary tumors. Nevertheless, patients younger than 40 years of age had a twofold risk of being SLN-positive (p < 0.000001). Of the young patients with primary melanomas with a thickness of 0.76 mm to 1.0 mm, 19.7% were SLN-positive. Using multivariate analysis, younger age, increasing Breslow thickness, ulceration and male sex were significantly related to a higher probability of SLN-metastasis. During follow-up, older patients displayed a significantly increased risk of in-transit recurrences (p = 0.000002) and lymph node recurrences (p = 0.0004). With respect to melanoma specific overall survival the patient's age was highly significant in the multivariate analysis. The unfavorable effect of being older was significant in the subgroups with positive and negative SLNs. Age remained also significant for the survival after the onset of distant metastases (p = 0.002). In conclusion, the patient's age is a strong and independent predictor of melanoma-specific survival in patients with localized melanomas, in patients with positive SLNs and after the onset of distant metastases. Younger patients have a better prognosis despite their higher probability of SLN metastasis. Older patients are less frequently SLN-positive but have a higher risk of loco-regional recurrence., (Copyright © 2011 UICC.)

In many patients with atopic dermatitis (AD), the disease is complicated by their enhanced susceptibility to bacterial skin infections, especially with Staphylococcus aureus (S. aureus). Resistance to bacterial skin infections, e.g. S. aureus, is based on the function of intact innate immune mechanisms in the epidermis, mainly provided by keratinocytes. Toll-like receptor (TLR)-2 recognizes components of S. aureus and is known to be expressed on keratinocytes. The aim of this study was to investigate intrinsic TLR-2 expression and cytokine secretion upon TLR-2 stimulation with peptidoglycan (PGN), lipoteichoic acid (LTA) and N-palmitoyl-S-[2,3-bis(palmitoyl)-(2RS)-propyl]-(R)cysteinyl-alanyl-glycine (Pam3Cys) in keratinocytes from patients with AD compared to healthy controls. Human primary keratinocytes (HPKs) were cultivated from hair follicles of patients with AD and non-atopic healthy controls and stimulated with Pam3Cys, LTA and PGN. TLR-2, TLR-1 and TLR-6 expression were investigated at the mRNA level. IL-6, IL-8, chemokine C-C motif ligand (CCL)-20 and MMP-9 production were studied at the protein level. TLR-2, TLR-1 and TLR-6 were expressed on both HPKs from patients with AD as well as healthy controls without significant differences between these groups. HPKs from patients with AD had an intrinsically reduced capacity to produce IL-6, IL-8, CCL-20 and MMP-9 and responded less to TLR-2 stimulation compared to HPKs from healthy controls. Our findings show evidence for intrinsic alterations in HPKs from patients with AD compared to healthy controls and diminished responses upon TLR-2 stimulation that might contribute to the enhanced susceptibility to skin infections with S. aureus., (© 2011 John Wiley & Sons A/S.)

Background: Patients with atopic dermatitis (AD) are frequently colonized with α-toxin-producing Staphylococcus aureus which is in turn positively correlated with the severity of eczema., Methods: IN this study we addressed T cell proliferation and T cell as well as monocyte cytokine secretion upon α-toxin stimulation in peripheral blood mononuclear cells (PBMCs) from AD patients compared to healthy controls., Results: We found that α-toxin stimulation of PBMCs markedly enhanced T cell proliferation both in patients with AD and healthy controls and was significantly increased in AD patients compared to healthy controls. PBMCs of AD patients secreted significantly more IL-31 compared to those of healthy controls upon α-toxin and SEB stimulation. Moreover, α-toxin stimulation yielded an increase in T cell (IL-2, IL-9, IL-10 and IFN-γ) as well as monocyte (IL-1β and TNF-α) cytokine secretion., Conclusion: Our results could partly explain how skin colonization and infection with S. aureus can contribute to chronic skin inflammation and pruritus in AD., (Copyright © 2011 S. Karger AG, Basel.)

The hand-foot-syndrome (HFS, palmoplantar erythrodysesthesia, chemotherapy-associated acral erythema) is characterized by painful predominantly palmo-plantar lesions. The association with different chemotherapeutic agents has been known for over 20 years. More recently, HFS has been reported in association with regimens using targeted agents, in particular the multikinase inhibitors (MKI) sorafenib and sunitinib. The HFS associated with MKI has a different distribution and clinical appearance than the traditional disorder. In this review, similarities and differences between chemotherapy- and MKI-associated HFS are discussed and current recommendations for their prophylaxis and management are summarized.

Background: In melanoma, different classification systems have been proposed that predict overall survival (OS) and recurrence-free survival (RFS) based on findings in the sentinel lymph node (SLN). The authors of this report compared the RFS and OS of 697 melanoma patients as predicted by various classification systems., Methods: The Rotterdam system (based on the greatest dimension of the largest tumor cell deposit), the Augsburg S-classification (based on tumor penetrative depth [TPD]), and the Hannover system (based on a combination of tumor load, TPD, and invasion of the capsule) were studied in 697 consecutive melanoma patients who underwent SLN biopsy at the authors' center., Results: In univariate analyses, the Rotterdam and Hannover systems (but not the S-classification) identified 1 group of SLN-positive patients that had OS and RFS similar to the OS and RFS of SLN-negative patients. The intermediate groups from all classification systems did not differ significantly with regard to RFS and/or OS from the adjacent groups. In multivariate analysis using a Cox model, the greatest dimension of the largest tumor cell deposit (cutoff point, <0.1 mm vs > or = 0.1 mm), the TPD (cutoff point, < or = 2 mm vs > 2 mm), and capsular involvement represented independent parameters for RFS; and TPD and capsular involvement also were independent parameters for OS. On the basis of these 3 parameters, a new scoring system for risk assessment in patients with melanoma is proposed that can distinguish 3 separate groups of patients that differed significantly in OS and RFS., Conclusions: Different parameters of independent prognostic significance were identified in SLNs from patients with melanoma. Combining these parameters, the prognosis of patients with melanoma was predicted more precisely by the new scoring system than by currently published classification systems.

MicroRNAs (miRNAs) are small noncoding RNAs ( approximately 22 bp) that posttranscriptionally regulate gene expression. MiRNAs possess oncogenic or tumor suppressor activity in various tumors but little is known about miRNA expression pattern in malignant melanoma. We determined the expression level of 16 potentially relevant miRNAs (miR-15a, miR-15b, miR-16, miR-34a, miR-210, let-7I, miR-23a, miR-23b, miR-24, miR-27a, miR-27b, miR-100, miR-137, miR-222, miR-373-1, miR-373*) by real-time PCR in 6 preparations of normal melanocytes vs. 10 melanoma cell lines and in formalin fixed paraffin embedded tissue of 11 melanocytic nevi versus 16 melanomas. MiR-15b and miR-210 were significantly upregulated, miR-34a was significantly downregulated in melanomas compared with melanocytic nevi. These 3 miRNAs were analyzed in a total of 128 primary melanomas from patients with detailed clinical follow-up information. High expression of miR-15b (but not miR-210 upregulation and miR-34a downregulation) was significantly associated with poor recurrence free survival and overall survival by univariate Kaplan-Meier and multivariate Cox analyses. Downregulation of miR-15b in two melanoma cell lines with high miR-15b expression by transfection with anti-miR-15b siRNA was associated with reduced tumor cell proliferation, whereas apoptosis was increased. In summary, miRNA expression levels show distinct differences comparing benign and malignant melanocytic cell proliferations and can provide independent prognostic informations. MiR-15b appears to represent a particular important miRNA in melanoma that is associated with poor prognosis and tumorigenesis.

Introduction: The cyclic adenosine monophosphate-dependent protein kinase (cAK) is considered a key protein in the control of smooth muscle tone in the cardiovascular system. There is evidence that erectile dysfunction might be linked to systemic vascular disorders and arterial insufficiency, subsequently resulting in structural changes in the penile tissue. The expression and significance of cAK in human cavernous arteries (HCA) have not been evaluated., Aims: To evaluate the expression of cAK isoforms in HCA and examine the role of cAK in the cyclic adenosine monophosphate (cAMP)- and cyclic guanosine monophosphate (cGMP)-mediated control of penile vascular smooth muscle., Methods: The expression and distribution of phosphodiesterase type 4 (PDE4) and cAK isoforms in sections of HCA were investigated by means of immunohistochemistry and Western blot analysis. The effects of the cAK inhibitor Rp-8-CPT-cAMPS on the relaxation of isolated preparations of HCA (diameter > 100 µm) induced by rolipram, sildenafil, tadalafil, and vardenafil were studied using the organ bath technique., Main Outcome Measures: Investigate the expression of cAK in relation to α-actin and PDE4 in HCA and evaluate the effects of an inhibition of cAK on the relaxation induced by inhibitors of PDE4 and PDE5 of isolated penile arteries., Results: Immunosignals specific for cAKIα, IIα, and IIβ were observed within the wall of HCA. Double stainings revealed colocalization of cAK with α-actin and PDE4. The expression of cAK isoforms was confirmed by Western blot analysis. The reversion of tension induced by inhibitors of PDE4 and PDE5 of isolated penile vascular tissue were attenuated significantly by Rp-8-CPT-cAMPS., Conclusions: Our results demonstrate the expression of cAK isoforms in the smooth musculature of HCA and its colocalization with PDE4. A significant role for cAK in the regulation mediated by cAMP and cGMP of vascular smooth muscle tone in HCA can also be assumed.

The aim of this study was to evaluate the hypothesis that interstitial cells might play a role in controlling and synchronizing via gap junctions the electrical activity of smooth muscle cells. The expression and distribution of interstitial cells in human penile erectile tissue was evaluated to determine whether or not cavernous interstitial cells express the gap junction protein connexin 43. Specimens of human corpus cavernosum were excised from full preparations of human penises. Cryostat sections (10 microm to 15 microm) of formaldehyde-fixated tissue segments were incubated using a double-labelling technique with antibodies directed against smooth muscle alpha-actin, c-kit, and connexin 43. Then, sections were exposed to secondary antibodies. Visualization was commenced by means of laser fluorescence microscopy. Double-staining techniques revealed immunosignals specific for c-kit (transmembrane receptor protein) and connexin 43 (gap junction protein) in multipolar cells located adjacent to smooth muscle cells. The number of c-kit-positive cells was significantly lower within the smooth musculature than within bundles of connective tissue surrounding smooth muscle cells of corpus cavernosum or cavernous arteries. Our findings demonstrate the distribution of c-kit- and connexin 43-positive interstitial cells in the connective tissue and smooth musculature of the corpus cavernosum. Additional studies are needed in order to evaluate further the ultrastructure of human penile erectile tissue and enable the identification of gap junctions mediating direct cell-to-cell communication.

Previously an increased frequency of KIT aberrations in mucosal melanomas was reported, whereas c-KIT in most types of cutaneous melanomas does not appear to be of pathogenetic importance. Imatinib has become the standard of care in other cancers with KIT mutations such as gastrointestinal stromal tumors. Recently 12 cases of metastatic melanoma and KIT-activating mutations have been published to be successfully treated with c-KIT blockers such as imatinib, sunitinib, dasatinib or sorafenib. We report here on one of our patients with KIT-activating mutation in metastatic anal mucosal melanoma, who showed a response to imatinib therapy and summarize the available literature regarding this new therapeutic option., (Copyright 2009 S. Karger AG, Basel.)

Sentinel node (SN) biopsy in melanoma patients is an accurate and minimally invasive method of staging and determining prognosis in patients with early-stage disease, and of identifying those patients who may benefit from complete regional lymph node dissection. Careful identification, removal and pathological assessment of SNs is critical to the accuracy of the technique and deficiencies in any of these steps may result in a false-negative biopsy. Pathologists should examine multiple sections from each SN, stained routinely with haematoxylin-eosin and immunohistochemically for melanoma-associated antigens. However, the most appropriate staining and sectioning protocol is not clear from the available evidence. While it appears that more extensive sectioning protocols detect more melanoma, failure rates and false-negative rates of the procedure do not appear to be significantly worse than with less extensive sampling protocols. Micromorphometrical parameters of melanoma deposits in SNs (such as their size, maximal tumour penetrative depth, microanatomical location and percentage nodal cross-sectional area) have been shown to be predictive of regional non-SN involvement and of clinical outcome. Classifying and measuring these parameters can be difficult, depending on the nature and distribution of the tumour deposits in the SN. Because the positive SNs have been removed in all patients included in studies assessing the clinical significance of tiny SN melanoma micrometastases, the likely therapeutic effect of the SN biopsy itself and/or any complete lymph node dissection, as well as lead time bias, are important confounding factors that must be considered when interpreting these studies. Limited data from some retrospective studies with relatively short follow-up suggest that some melanoma metastases may not be clinically relevant, but other studies imply a likely clinical significance of even very small SN metastases. Until there is unequivocal evidence from prospective randomised clinical trials with long term follow-up for the prognostic significance (or lack thereof) of very small SN tumour deposits, it is probably prudent to treat patients with such deposits as SN-positive.

Background: Previous studies described various criteria in sentinel lymph nodes (SLN) of melanoma patients that predict the involvement of further, nonsentinel lymph nodes (NSLN). Such criteria may facilitate the selection of patients who might benefit from a completion lymph node dissection (CLND). However, it is currently unclear which parameters are most important., Methods: A total of 180 melanoma patients with positive SLNB and subsequent CLND were investigated. Histopathologic parameters in the SLN were systematically evaluated and compared with regard to NSLN positivity. Twenty-eight of these patients (16.0%) had positive NSLN., Results: By univariate analysis several criteria with regard to tumor burden and location of melanoma cells in the SLN correlated with NSLN involvement, such as positivity by hematoxylin-eosin (H&E) staining (P < .001), largest diameter of clusters (P < .001), capsular involvement (P = .001), extranodal extension (P < .001), and tumor penetrative depth (P < .001). Multivariate analysis revealed three independent parameters: (1) positivity of the SLN by H&E staining (versus by immunohistochemistry alone), (2) relative tumor burden > 10% of total lymph node tissue, and (3) perinodal intralymphatic tumor. In 23 of 28 patients with positive NSLN the SLN was positive by H&E staining, in 15 of 28 patients the relative tumor burden was > 10%, and 13 of 28 showed perinodal intralymphatic tumor. In 5 of 28 patients with NSLN involvement, these three parameters were negative., Conclusions: Histopathologic examination of the SLN can identify patients at risk for NSLN positivity.

Background: The value of the status of the sentinel lymph node (SLN) in patients with thick melanomas (Breslow thickness > or = 4 mm) is controversial., Patients and Methods: Using Kaplan-Meier estimates and Cox regression models, we studied 152 patients with primary melanomas > or = 4 mm thickness who underwent sentinel lymph node excision (SLNE) at the university hospitals of Hannover and Göttingen, Germany, between 1998 and 2006., Results: The median tumor thickness was 5.2 (4-18) mm; 58.5% of primary melanomas were ulcerated. Micrometastasis to a SLN was found in 48.7%. The patients with positive SLNs were significantly younger than those with negative SLN (p = 0.01). Of the complete lymph node dissections, 32% contained positive non-SLN. The estimated 5 year recurrence-free survival was 42.5 +/- 5% (+/- standard error) (26.3 +/- 6.6% after positive SLNE, 58.7 +/- 7.1% after negative SLNE). The 5 year overall survival rate was 53.2 +/- 5.4% (37.5 +/- 8.1% after positive SLNE, 67.6 +/- 6.7% after negative SLNE). By multivariate analysis, the SLN was a highly significant predictor for overall survival (p = 0.007, relative risk 2.3, 95%, confidence interval 1.2-4.2). The overall survival was significantly associated with penetration of nodal metastases into the SLN > 0.3 mm (p = 0.001). Other parameters such as tumor thickness, ulceration, age and sex were not significant. In the subgroup of patients with negative SLN, neither tumor thickness nor ulceration was significant., Conclusions: The status of the SLN represents the most important prognostic parameter in patients with thick melanomas, whereas other parameters such as tumor thickness and ulceration loose their prognostic value.

Interferon alpha is used for the adjuvant treatment of malignant melanoma at different dosages (high-, intermediate-, low-dose therapy). Only a minority of patients might benefit from this therapy, and markers to identify such patients are missing. A recent study suggested that melanoma patients developing autoantibodies or clinical manifestations of autoimmunity during adjuvant high-dose interferon alpha treatment had a significant survival benefit. We retrospectively reviewed 134 melanoma patients from our institution treated with adjuvant low-dose interferon alpha therapy and correlated the development of autoimmune diseases with prognosis. Interferon (IFN) therapy was routinely monitored by history, physical examination and laboratory tests before, after the first month and then after every 3 months of therapy. During a median follow up of 46.0 months (8.5-79.0 months) 28 patients (20.9%) suffered from recurrences and melanoma related deaths occurred in 16 patients (11.9%). In 20 patients (14.9%) autoimmune thyroiditis (AIT) was diagnosed during IFN therapy, one of these 20 patients developed rheumatoid arthritis later while continuing IFN therapy. Other autoimmune diseases were not observed. In 2 patients (one with AIT and one with arthritis) the autoimmune disease led to discontinuation of IFN therapy, in the other patients AIT remained subclinical or responded well to treatment while IFN therapy was continued. Kaplan-Meier analyses revealed a significant better recurrence free survival and a trend for a better overall survival for patients with AIT. Thus, autoimmunity triggered by low-dose IFN therapy appears to indicate an improved prognosis and should encourage continuation of IFN therapy., ((c) 2007 Wiley-Liss, Inc.)

The detection of micrometastases (defined as groups of malignant cells) in the sentinel lymph node (SLN) is an important prognostic tool in melanoma. The use of immunohistochemistry with melanocytic markers such as HMB45 and Melan A increases the detection rate of micrometastases but there are also cases with isolated immunohistochemically positive cells (IPC). To determine the prognostic significance of isolated HMB45 and/or Melan A positive cells in melanoma SLN, we compared the clinical course of 47 patients with IPC to 308 patients with negative SLN and to 122 patients with micrometastases. The mean follow-up was 38.1 months. By Kaplan-Meier analyses, relapse free survival and overall survival of patients with IPC were similar to SLN negative patients, whereas patients with micrometastases had a significantly worse relapse free survival and overall survival. In the 47 patients with IPC, 6 relapses (12.8%) and 3 melanoma-related death (6.4%) occurred, in the SLN negative patients 36 relapses (11.7%) and 17 melanoma-related deaths (5.5%), in the patients with micrometastases 46 relapses (37.7%) and 29 melanoma-related deaths (23.8%). Prognosis of patients with IPC in SLN did not correlate with type of positive staining (HMB45, Melan A, or both), capsular involvement, number of cells, presence of cytologic atypias of IPC, or tumor penetrative depth. In conclusion, with short-term follow-up IPC in melanoma SLN are without prognostic significance.

Erythropoietin has been successfully used in Europe since 1997 in the treatment of anemia induced by chemotherapy of solid tumors. There is only limited experience with regard to its use when treating dermatologic tumors such as metastatic melanoma. We review here current guidelines on the use of erythropoietin in cancer patients and report on our own melanoma patients treated with erythropoietin for chemotherapy-induced anemia.

Tumoral or nodular melanosis is characterized by a clinical lesion suspicious for malignant melanoma, the histopathological correlate is a nodular accumulation of melanophages in the dermis. We present a patient with nodular melanosis involving also the sentinel lymph nodes and discuss possible differential diagnoses as well as prognostic and therapeutic implications.