G protein-coupled estrogen receptor 1 and collagen XVII endodomain expression in human cutaneous melanomas: can they serve as prognostic factors?

Melanoma incidence is increasing globally. Although novel therapies have improved the survival of primary melanoma patients over the past decade, the overall survival rate for metastatic melanoma remains low. In addition to traditional prognostic factors such as Breslow thickness, ulceration, and mitotic rate, novel genetic and molecular markers have been investigated. In our study, we analyzed the expression of G-protein coupled estrogen receptor 1 (GPER1) and the endodomain of collagen XVII (COL17) in relation to clinicopathological factors in primary cutaneous melanomas with known lymph node status in both sexes, using immunohistochemistry. We found, that GPER1 expression correlated with favorable clinicopathological factors, including lower Breslow thickness, lower mitotic rate and absence of ulceration. In contrast, COL17 expression was associated with poor prognostic features, such as higher tumor thickness, higher mitotic rate, presence of ulceration and presence of regression. Melanomas positive for both GPER1 and COL17 had significantly lower mean Breslow thickness and mitotic rate compared to cases positive for COL17 only. Our data indicate that GPER1 and COL17 proteins may be of potential prognostic value in primary cutaneous melanomas.

SARS-CoV-2 Infection in Pemphigus Vulgaris Two Weeks after Rituximab Therapy with Total Recovery: A Case Report.

The mortality risk factors for Corona Virus Disease-19 (COVID-19) infection (caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)) include advanced age, male sex, certain comorbidities, and immunosuppression (1). Pemphigus vulgaris is a rare mucocutaneous autoimmune disease with autoantibodies against desmosomal desmoglein-1 and desmoglein-3, resulting in acantholysis and blister formation. This epithelial barrier defect increases susceptibility to infections, which may lead to relapses (2). Additionally, therapy-associated immunosuppression can lead to severe infections. Corticosteroids are the mainstay therapy. For moderate and severe pemphigus, rituximab is recommended in first-line treatment along with other immunosuppressants, and it may also be added in refractory cases. It is a monoclonal antibody against CD20 with long-lasting B-cell depletion potency. Recovery of B-cell function may last from one to seven years. Consequently, patients receiving rituximab cannot produce enough COVID-19 specific plasma cells, leading to a severe course of COVID-19 (2). Shashidi-Dadras et al. reported five mild COVID-19 cases among 167 patients with pemphigus who had received rituximab one to five years earlier. The authors presumed rituximab use within five years increases COVID-19 susceptibility regardless the number of courses received (3). Among 48 patients with pemphigus treated with rituximab within five years, Uzuncakmak et al. reported one mild case of COVID-19 (in a patient who had received a single course seven months earlier) (4). In another study, high titers of SARS-CoV-2 antibodies and high counts of antibody-secreting cells were associated with severe COVID-19 (5), which may be the consequence of antibody-dependent enhancement (6). Mahmoudi et al. concluded that B-cells may not be necessary for recovery in COVID-19, but they may protect from reinfection (7). Considering these data, rituximab should be postponed during the pandemic (8). In exceptional cases, it may be applied with careful consideration of the risk-benefit ratio (2,4). Patients should be monitored for signs of COVID-19 before and during treatment. A 63-year-old woman with pemphigus vulgaris presented at our department with widespread skin lesions. Comorbidities included hypertension, hypothyroidism, and glaucoma. Diagnosis was established based on histology and direct and indirect immunofluorescent microscopy results. Both desmoglein-1 and desmoglein-3 autoantibodies were detectable by ELISA. The patient was initially treated with low-dose systemic methylprednisolone (8 mg/day), because glaucoma contraindicated a higher dose. Azathioprine was subsequently started (gradually increased from 0.6 to 2.5 mg/kg/day). Continuous mucocutaneous progression 4 weeks later led to the decision to add rituximab therapy. The patient was confirmed as SARS-CoV-2 negative and received 1000 mg 12 weeks after starting glucocorticoid treatment. Two weeks later, she developed fever and became SARS-CoV-2 positive, and therefore the second rituximab treatment had to be cancelled. The patient had fever for six weeks without any other complaints, hospitalization was not required, and immunosuppression was continued with 8 mg methylprednisolone and 2.5 mg/kg azathioprine. Two weeks after recovery, she was diagnosed with pulmonary embolism, but recovered completely. Pulmonary embolism is a relatively common complication of COVID-19 which may be triggered by inactivity, loss of body fluids due to fever, a hypercoagulable state, and direct toxic venous endothelial damage caused by the virus (9). At a follow-up 4 months later, minimal skin lesions and significantly decreased desmoglein-1 and desmoglein-3 titers were observed. Azathioprine and methylprednisolone therapy were continued, and a second dosage of rituximab was given 7 months from the first one without any side-effects. We conclude that rituximab is a highly effective therapy in pemphigus, but the risk-benefit ratio should be carefully considered during the COVID-19 pandemic. We have not observed irreversible or permanent consequences of its administration, but our patient had a potentially lethal complication, pulmonary embolism, which may be associated with a more severe COVID-19 course due to immunosuppression. Total recovery was observed despite COVID-19 shortly after the initiation of rituximab.

Hairy cell leukaemia diagnosed in a polysensitized patient with atypical haemorrhagic skin lesions / Atípusos haemorrhagiás bortünetek hátterében igazolt hajas sejtes leukaemia poliszenzibilizált betegen.

As the topical use of non-steroidal anti-inflammatory drugs (NSAIDs) has gained popularity recently, adverse reactions related to their application have also become more common. The authors present the case of a 49-year-old man, who used etofenamate gel to treat leg pain. Following sun exposure, haemorrhagic, atypical lesions appeared and after rapid spread of the symptoms, the patient was hospitalized. In the area of the etofenamate application as well as on both legs, arms, trunk and face, confluent, erythematous sero-papules and macules were found, along with petechiae on the oral mucosa. Splenomegaly and thrombocytopenia accompanied the skin symptoms, which prompted an oncohematological workup, and the patient was diagnosed with hairy cell leukaemia. Epicutaneous testing (ET) was performed and found a positive reaction to etofenamate gel as well wood tar, propylen glycol, fragrance mix I, methylisothiazolinone, benzoic acid and balsam of Peru. The lymphocyte transformation test (LTT) and CD69 expression were negative for etofenamate. Orv Hetil. 2020; 161(38): 1646-1651.

[Role of cancer stem cells in the progression and heterogeneity of melanoma]. / Tumorossejtek szerepe a melanoma progressziójában és heterogenitásában.

Over the past decade a rare cell population called cancer stem cells has been identified in both solid tumors and hematologic cancers. These cells are reminiscent of somatic and embryonic stem cells and play a critical role in the initiation and progression of malignancies. As all stem cells, they are able to undergo asymmetric cell division and hence renew themselves and create various other progenies with heterogenous phenotypes. A growing body of literature suggested that stem cell subpopulations contribute significantly to the growth and metastatic properties of melanoma. This review gives a comprehensive overview of the current literature on melanoma stem cells, with a special emphasis on the signaling pathways responsible for the homeostatic growth of melanocytes and the uncontrolled proliferation of melanoma cells. The importance of the local microenvironment are demonstrated through summarizing the role of various cell types, soluble factors and cell adhesion molecules in the progression of melanoma and the creation of treatment resistant cancer cell clones. Last but not least, the models of melanoma progression will be introduced and a variety of cellular markers will be presented that may be used to identify and therapeutically target melanoma. Orv. Hetil., 2016, 157(34), 1339-1348.

Retrospective Analysis of Clinicopathological Characteristics of Pregnancy Associated Melanoma.

Pregnancy associated melanoma (PAM) by definition appears during pregnancy or within 1 year after delivery. In this retrospective study we analysed the pathological characteristics and survival rate of PAM and matched the data with non-pregnant age- and stage-matched control patients. Between 2003 and 2014, 34 pregnant women (aged 32.5 ± 5.6 years) were diagnosed with melanoma at the Department of Dermatology, Venereology and Dermatooncology of the Semmelweis University. During the pathological process histologic subtype, Breslow thickness and Clark level, tumor cell type, mitotic rate, peritumoral inflammation, as well as ulceration, regression, necrosis, vascular invasion and presence of satellite were analyzed and related to clinical data. Primary tumor location and clinical staging, disease course, local recurrence and metastases, 5-year survival rate, other tumor development before or after the diagnosis of melanoma have also been documented. We found no difference in all parameters between pregnant and non-pregnant melanoma cases except peritumoral inflammation which was higher in PAM group, moreover the presence of mild inflammation was significantly higher in PAM group compared to non-pregnancy associated melanoma (NPAM) women group.