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Pemphigus vulgaris (PV) is a severe autoimmune blistering disease affecting both skin and mucous membranes. Its pathogenesis is related to IgG autoantibodies primarily targeting the cellular adhesion protein desmoglein (Dsg) 3, one of the major desmosome components. Impaired redox regulation is considered a major player in the pathogenesis of autoimmune diseases such as pemphigus by enhancing inflammation and breakdown of immunological tolerance by structural protein modifications. Despite many recent advances, local and systemic redox profiles that characterize the immune response in pemphigus are virtually unknown but potentially crucial in further advancing our understanding of redox-dependent modifications that eventually lead to clinical manifestation. Here, we have analyzed the individual expression pattern of four major redox enzymes that are members of the thioredoxin (Trx) fold superfamily (peroxiredoxins (Prxs) 1 and 4, glutaredoxin (Grx) 2, and Trx1) in serum and PBMCs as well as their distribution in the skin of pemphigus patients compared to healthy controls. We show that in groups of five pemphigus patients, Prx1 is upregulated in both serum and PBMCs, while its epithelial distribution remains within the spinous epithelial layer. Expression of Grx2 and Prx4 is both reduced in serum and PBMCs, while their distinct and similar expression in the skin changes from an even distribution throughout the basal layer (healthy) to ubiquitous nuclear localization in pemphigus patients. In PV patients, Trx1 is secreted into serum, and cellular distribution appears membrane-bound and cytosolic compared to healthy controls. We furthermore showed that a 3D ex vivo human skin model can indeed be used to reproduce similar changes in the protein levels and distribution of redox enzymes by application of cold atmospheric plasma. Deciphering the relationship between redox enzyme expression and autoimmunity in the context of pemphigus could be critical in elucidating key pathogenic mechanisms and developing novel interventions for clinical management.

Dear Editor, Reticulate pigmentary disorders (RPD) is a term used to classify a spectrum of several acquired and congenital disorders. Different clinical features can be present, including a reticular pattern and a freckle-like pattern with hyper- or hypo-pigmented macules (1). Dowling-Degos disease (DDD), an autosomal dominant genodermatosis, is the main type of RPD (2). Clinically, DDD presents with pigmented, reticulate, flexural macules and comedo-like papules on the back and neck. Galli-Galli disease (GGD) is a very rare variant of DDD, from which is clinically indistinguishable (3). A 65-year-old Caucasian male patient presented to our Department with a 6-year history of diffuse maculopapular lesions involving the trunk and the extensor and flexor regions of the upper and lower extremities (Figure 1). These lesions were small, monomorphous, erythematous macules and papules, some covered by discrete scales. Numerous brown lentiginous macules were also observed. The patients did not present with comedo-like lesions, reticulate pigmentation, pitted acneiform facial scars, palmar pits, or nail changes. Furthermore, the oral mucosa showed no lesions. The patient's familial history was negative for dermatoses. Laboratory routine tests were all negative. Topical and oral steroids as well as systemic retinoids were unsuccessful. Therefore, a punch biopsy was performed. Histologic examination showed a digitate elongations of rete ridges, with small foci of acantholysis (Figure 2, a). The epidermis showed a finger-like projections extending into the papillary dermis with increased melanin pigment. The epidermis was atrophic above the digitate proliferations and above the acantholytic foci, where necrotic and dyskeratotic keratinocytes also were found (Figure 2, b). In the papillary dermis, a lymphohistiocytic infiltrate with perivascular distribution was detected (Figure 2, a). According to the clinical and histological findings, a final diagnosis of Galli-Galli disease with lentigo-like macular lesions was established. The patients started 25 mg/day acitretin with only partial improvement. GGD is now considered a variant of DDD, from which is clinically indistinguishable (2,3). Several differential diagnosis can be considered, including Darier's and Groover's disease (2-9) (Table 1). Because of the absence of digitate proliferation of the rete ridges and the presence of yellow or brown macules, Darier's disease can be distinguished from GGD. In our patient, the involvement of the lower legs and the presence of unusual brown, lentigo-like macules were accurately evaluated, because of the major diagnostic pitfall with an extensive kind of Grover's-like eruption with lentiginous freckling (6). However, the involvement of sun-shielded areas and the histological presence of a lentiginous elongation of rete ridges led us to a final diagnosis of GGD. Regarding the pathogenesis, the alteration of the keratine 5 gene (12q13.13) may be the main factor in GGD. In GGD, a reduced amount of functional keratin 5 impairs the structure of keratin intermediate filaments (10). As a result, the structure of the epidermis is affected, leading to alterations in desmosomes and hemidesmosomes (2). Regarding the lentigo-like pattern of our patient, the additional diffusion of lentigos over shield-sites and the absence of extreme sun exposure in the patient's history ruled out the ultraviolet radiation as the main etiopathogenetic factor. In this regard, as reported by Girard et al., lentigos could represent a post-inflammatory pigmentation of the papular acantholytic lesions (10). However, as emphasized by Coper et al. (6), the persistence of lentigos for several years would contrast with this hypothesis. It is indeed known that a failure of keratin 5 may disrupt the movement of pigment-carrying melanosomes into keratinocytes. The disruption of melanosome transport is thought to be the cause of the pigmentation abnormalities seen in DDD as well as in GGD. These aspects could explain the elongated rete ridges and the altered pigmentation clinically and pathologically observed in GGD and DDD.

Mastocytosis can be associated with other clonal or non-clonal hematologic diseases as well as a variety of non-hematologic malignancies. A 75-year-old Caucasian male patient was referred to us with a 5-month history of neutrophilic leukocytosis and mild splenomegaly. He had developed a cutaneous melanoma sixteen years ago. According to the clinical and pathological features, a final diagnosis of systemic mastocytosis was established. The patient started treatment with interferon-α at a dose of 3 MIU/day, combined with low doses of prednisone. We observed a rapid disappearance of symptoms. Unfortunately, after 3 months a diagnosis of pancreatic adenocarcinoma was established. A review of the literature suggests that mastocytes could have a pivotal role in several malignancies. Different chemokines, mitogenic factors, chemical mediators of inflammation, and specific gene mutations could explain the association between mastocytosis and other hematologic and non-hematologic disorders.

Agminated blue nevus (ABN) is a melanocytic nevus rarely mentioned in the literature and not well known. The term agminated is used when many blue nevi are clustered together in a sharply demarcated area ≤10 cm. Specific dermatoscopic features have not currently been clearly defined. We describe two cases of ABN and provide a review of the literature, reporting the main points in order to facilitate the diagnosis of this rare entity.

Extracutaneous melanoma (ECM) is a very rare malignancy and its biology differs from that of cutaneous melanoma. Residential studies can offer an important contribution to the study of this disease.We characterized the distribution of ECM according to residential and demographic baseline characteristics. We computer-searched patients that removed an ECM, and we analyzed all demographic and residential parameters. Disease free survival (DFS), date of death or last follow-ups were evaluated. The same parameters were analyzed using hazards-regression. Finally, we used the multiple regressions between DFS and the predictors.A total of 44 ECM patients were included in our analysis. Median DFS was of 10 months; at Log-Rank Test and Cox-hazard regression, the variable age (P0.01; P0.004) and latitude (P0.02; P0.006) reached a statistical significance; at multiple logistic regression, the significance was instead maintained only for the variable age. General OS was of 42 months at Log-Rank Test age (P0.001), as well as latitude (P0.006) maintained its significance at hazard-regression.Demographic and residential aspects can play an important role in the study of this rare disease, supporting the assumption that ECM are generated by processes actually unknown, as demonstrated in our results compared with those of the literature.

Dear Editor, Cutaneous metastases (CM) are detected in about 0.6-10.4% of patients with an internal malignancy (1-3). Excluding melanoma, breast and lung carcinomas are the main source of CM in women and men, respectively (1,4,5). CM can have different clinical features, and a diagnosis of CM is usually suspected before performing a biopsy. However, this can be a pitfall for clinicians when the clinical presentation is not the typical inflammatory nodule or mass. Herein we report 2 cases of cutaneous metastases of breast carcinoma, initially treated as a common skin infection. Case 1 A 51-year-old Caucasian woman presented to our Institute with a four-month history of diffuse and erythematous pustular, lesions on the right arm that were painless and non pruritic (Figure 1). The patient had undergone excision for a breast adenocarcinoma (stage IIIA) 5 years earlier. An initial diagnosis of folliculitis was established, and the patient started systemic and topical antibiotics without any improvement. Based on the clinical features and the patient medical history, we performed a skin biopsy. Pathologically dermal nests of tumor cells, arranged in a glandular-like pattern and involving the perifollicular and follicular areas (Figure 2, Figure 3), were highlighted. The tumor cells were positive to cytokeratin (CK) 7, CK19, and carcinoembryonic antigen (CEA) and negative for CK20, CK5/6, CD10, and thyroid transcription factor-1 (TTF-1) (Figure 4). According to the clinical history and pathology, a final diagnosis of folliculotropic metastatic breast carcinoma was established. Unfortunately, the patient died after 10 months. Case 2 A 61-year old Caucasian woman presented to our Department with a two-month history of pink/violet macular lesions with diffuse telangiectasia on the left breast and arm (Figure 5, Figure 6). Five years earlier she had undergone excision for a breast adenocarcinoma (stage II A). A previous diagnosis of cellulitis had been made, and systemic antibiotic therapy had been started without any improvement. Based on the clinical features and the patient medical history, a punch biopsy was performed. Examination of skin biopsy showed a diffuse, sclerotic, and mixoid stroma with several dense ectatic lymphatic vessels (Figure 7, Figure 8). The dermal and hypodermal lymphatic lumens were filled with neoplastic cells. Thus, a diagnosis of cutaneous lymphangitis carcinomatosa (CLC) was established. Unfortunately, the patient died after 8 months. Discussion CM are present after breast carcinoma in about 23.9% of patients, often involving the chest and abdomen and manifesting on average 5 years after surgical removal of the first malignancy (1,6). CM of breast cancer are usually solitary or multiple nodular pinkish lesions (ranging between 1 and 3 cm) (1). However, several clinical features have been reported in the literature, including telangiectatic carcinoma, erythema-like, erythema annulare centrifugum-like, morphea-like, erysipelas-like, dermatofibroma-like, herpes-zoster-like, and alopecia-like lesions (1,7-10). Clinical and pathological images of folliculitis-like metastases are rarely reported in the literature, especially after breast cancer (11,13) Clinically, folliculitis-like metastases could resemble a zosteriform-like metastatic lesion (7,14,15) although they do not follow a dermatome and are pustular lesions rather than violaceous indurate papules and/or nodules (13,14) Pathologically, our cases showed an infiltration of the dermis and pilosebaceous units growing through the pilosebaceous unit in a "pseudo-eruptive way". In this regard, folliculitis-like CM could be similar to alopecia neoplastica, where the metastatic process involves and destroys the pilosebaceous units completely, leading to scarring alopecia (9,10). However, in our case, the pilosebaceous unit was still slightly recognizable, and clinically there were no scar-like features. The mechanism of folliculitis-like metastasis formation is currently unknown. As reported in zosteriform-like metastases, the lymphatic and hematogenous spread of malignant cells or the koebnerization at the site of a previous viral and/or bacterial infection could lead to metastasis (7,14-16). However, unlike zosteriform-like metastases, the spread of neoplastic cells from the dorsal root ganglia was not a plausible mechanism of metastasization in our cases because of the absence of dermatome involvement. Furthermore, there were no signs of possible koebnerization in a previous bacterial and/or viral infection site (7,13) In our opinion, folliculitis-like metastasis may be a result of the skin extruding malignant cells through the pilosebaceous unit to limit the neopalstic proliferation. This could explain the clinical and pathological features of folliculitis-like metastasis. Alternatively, the adnexotropic behavior of malignant cells may be explained by homing mechanisms, involving the up-regulation of the intercellular adhesion molecule 1 (ICAM-1) on the follicular epithelium, such as folliculotropic mycosis fungoides (17). In our patient, the folliculitis-like eruption was the first sign of recurrence after 5 years of disease-free survival. It is evident that the unusual folliculitis-like eruption of CM led to a delay in the diagnosis. CLC is a rare presentation of skin metastasis, characterized by an occlusion of dermic lymphatic vessels by neoplastic cells (18). CLC has been reported in the literature in association with several malignancies, including lung, breast, and ovarian cancer (19). CLC shows pink/violet macular lesions with diffuse telangiectasias, often associated with itching and burning sensation. The main differential diagnoses are erysipelas and cellulitis. However, CLC is not associated with fever, chills, and leukocytosis. Furthermore, CLC shows no response to antibiotic therapies. Several clinicopathological types of cutaneous metastasis have been reported in the literature, including telangiectatic metastatic breast carcinoma (TMBC) and carcinoma erysipelatous (CE). TMBC is characterized by yellowish/reddish or violaceous papulo-vesicular lesions. CE usually shows blistering erythematous eruptions resembling erysipelas. However, CLC, TMBC, and CE are different clinical expressions of the same metastatic process, pathologically characterized by edema of the dermis and ectatic lymphatic vessels. Positivity to CD31 and podoplanin in the endothelial cells shows that the tumor metastatises predominantly via lymphatic vessels (20). In conclusion, we stress that every cutaneous lesion should be studied and examined carefully in patients with a personal history of cancer. Indeed, a correct diagnosis remains the pivotal point for a better management of these patients.

Cumulative exposure of the skin to ultraviolet radiation promotes mutation in keratinocytes and their abnormal growth led to the formation of scaly lesions, called actinic keratoses (AKs). Its incidence is growing at an emerging rate, becoming a worldwide problem especially for occupational ultraviolet (UV) rays exposure. Detectable lesions are often associated with field changes, where the surrounding skin is altered and subclinical lesions may be present. Thus, a field-directed therapy, such as topical treatment, should be preferred for the prevention of invasive cancer development. A retrospective analysis was made, evaluating the efficacy of ingenol-mebutate gel, using a novel device the 3D in vivo optical skin Imaging (Antera 3D, Miravex, Ireland).We included all patients with multiple non-hypertrophic Aks, to whom it was prescribed ingenol-mebutate gel, applied at the dosages of 0.015 for lesions in the scalp/face (for 3 consecutive days) and at the dosage of 0.05% for lesions in the trunk and/or extremities (for 2 consecutive days).A reduction of the lesions and of median hemoglobin levels, after a follow-up of 60 days, was observed in 100% of patients.Ingenol mebutate gel, the last topical molecule appeared in the Italian market showed its efficacy using Antera 3D also in terms of hemoglobin reduction. Therefore, this camera could be considered an useful tool for the identification of the area to be treated and for therapeutic follow-up.