Pigmented epithelioid melanocytoma: report of a case with favourable outcome after a 4-year follow-up period.

BACKGROUND: Pigmented epitheliod melanocytoma (PEM) is a uncommon melanocytoma with unique histopathological features and possibly with a favourable prognosis, because, although sentinel lymph-node metastases may occur, in the great majority of cases described up to now there is no spread beyond regional lymph-nodes. The nature of PEM, its biologic behaviour and its relationships to naevi and melanoma, however, remain to be clearly established, and several Authors suggest that further cases of PEM with long follow-up should be published, in order to better assess the biologic/prognostic characteristics of PEM. METHODS AND RESULTS: We report a new case of PEM, dealing with an oval, regularly marginated, darkly pigmented, asymptomatic nodule. The dermoscopic pattern showed a homogeneous blue-black pigmentation, without any other dermoscopic sign. The histopathologic analysis showed both isolated and nested oval melanocytes at the junctional level, and a mixture of epitheliod and spindle melanocytes, heavily pigmented, together with numerous melanophages in the dermis, with tendency to periadnexal distribution; cellular atypia was pronounced, but only occasional mitoses were identified in the superficial dermis. After a 4-year follow-up period after excision, no persistent lesion or metastases occurred. CONCLUSIONS: The present case suggests that PEM has a distinct histopathologic/diagnostic identity among melanocytic tumours. Although the up-to-now favourable outcome, however, our patient needs a large period of observation, and further studies with long follow-up are needed to better define the biologic/prognostic identity of PEM.

Unusual form of cutaneous infiltration by cancer.

Breast cancer is the most common visceral neoplasm which metastatizes in skin. Skin infiltration by breast cancer may appear as various types of neoplastic/inflammatory lesions, including plaques, pigskin-like areas, scirrhous morphea-like lesions, nodules, zosteriform lesions, and papulovescicles. An unusual form of cutaneous infiltration involving a mammary region bearing a post-mastectomy surgical skin scar is herein described: interestingly, such a cutaneous cancer involvement could not be included in the above classification, because it merely consisted of red-purple areas dealing with small telangiectasias, without any sign of inflammation.

Unknown: Papules on the knees. Elastosis perforans serpiginosa (EPS).

Elastosis perforans serpiginosa (EPS) can occur in patients with an underlying connective tissue disorder. Down syndrome, osteogenesis imperfecta, acrogeria, Ehlers-Danlos syndrome type IV, Marfan syndrome, pseudoxanthoma elasticum, Rothmund-Thomson syndrome, and scleroderma have all been associated with EPS. The clinical appearance exhibits umbilicated papules arranged in a typical serpiginous pattern, usually located around the neck. Less frequently, lesions may be seen on the face, abdomen, and extremities with a symmetrical distribution, as in our case. The clinical course may be variable with a spontaneous resolution in a few months or years, but frequently new lesions develop leading to persistence and progression of the disorder. We describe a 12-year-old girl affected by Down syndrome who presented a localized form of EPS, which involved only the extremities. Strangely, it resolved spontaneously after biopsy with no recurrence, without therapy.

Hydrogen sulfide inhibits IL-8 expression in human keratinocytes via MAP kinase signaling.

Sulfur is able to penetrate the skin, and a sulfur-rich balneotherapy has been suggested to be effective in the treatment of psoriasis. Psoriasis is now considered a genetically programmed, immune-mediated, inflammatory disease, in which intralesional T lymphocytes trigger keratinocytes to proliferate and perpetuate the disease process. Interleukin (IL)-17 and IL-22 produced by Th1/Th17 lymphocytes induce IL-8 secretion by keratinocytes, a key event in the pathogenesis of the disease. It is now clear that mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinases (ERK) 1 and 2) activity is required for IL-17-induced IL-8 synthesis by keratinocytes, and, in fact, MAPK activity is increased in lesional psoriatic skin. Here, we demonstrate both in vitro and in vivo on primary psoriatic lesions that pharmacological inhibitors of ERKs as well as hydrogen sulfide not only reduce the basal expression and secretion of IL-8, but also interfere with IL-17- and IL-22-induced IL-8 production. These observations, together with the known anti-inflammatory activity of H2S, are relevant to understanding some previously unexplained biological effects exerted by sulfur therapy.

The vast majority of lymphocytes infiltrating primary cutaneous melanoma express the CD27 costimulatory receptor: implications for melanoma progression.

Melanoma progression is favoured by prevalence, within the micro-environment of primary cutaneous melanoma, of suppressive forces, e.g. exerted by CD4(+) CD25(+) FOXP3(+) regulatory T lymphocytes, over anti-melanoma immunity, e.g. exerted by CD8(+) cytolytic T lymphocytes. The CD27 glycoprotein is crucial because it is able to identify regulatory T cells endowed with strong suppressive ability, whilst CD8(+) T cells endowed with actual cytolytic ability become CD27(-). The present in situ quantitative immunohistochemical study, including a series of double labelling experiments and morphometrical cell analyses, shows that the vast majority of lymphocytes infiltrating primary cutaneous melanoma express CD27. Specifically, virtually the entire CD4(+) CD25(+) FOXP3(+) T subset infiltrating primary cutaneous melanoma also co-expressed CD27; CD27 was, moreover, co-expressed even by the vast majority of the CD8(+) T cells, and, conversely, effector/cytotoxic CD8(+)CD27(-) cells were very scarcely represented. The overwhelming CD27 co-expression may confer on the CD4(+)CD25(+)FOXP3(+) T subset a consistent capacity to suppress anti-melanoma immunity, whereas the too low CD8(+) CD27(-) cell proportion may presumably be insufficient to confer on the CD8(+) T subset a satisfactory anti-melanoma cytotoxic activity. We therefore propose that these CD27-discriminated pathways may trigger a functional imbalance within the microenvironment of primary cutaneous melanoma, thus favouring melanoma progression.

Congenital systematized basaloid follicular hamartoma with microphthalmia and hemimegalencephaly.

The lines of Blaschko are a cutaneous pattern of mosaicism present in a variety of skin disorders. Developmental abnormalities affecting other tissues derived from the embryonic ectoderm and mesoderm are sometimes associated. Here, we describe a 5-year-old boy with basaloid follicular hamartoma affecting the left side of the body in linear multiple bands, following Blaschko lines. Lesions were predominantly hypopigmented macules and streaks, but among these, we could observe brownish atrophic patches and brown papules. Furthermore, ipsilateral hemimegaloencephaly and microphthalmia were present. These findings suggest a neurocutaneous condition recently described by Happle and Tinschert. Its nosologic classification will be discussed.

Chronic urticaria is usually associated with fibromyalgia syndrome.

Although the pathophysiology of chronic urticaria is not fully understood, it is possible that dysfunctioning of peripheral cutaneous nerve fibres may be involved. It has also been suggested that fibromyalgia syndrome, a multi-symptomatic chronic pain condition, may be associated with alterations and dysfunctioning of peripheral cutaneous nerve fibres. The aim of this study was to determine whether patients with chronic urticaria are also affected by fibromyalgia syndrome. A total of 126 patients with chronic urticaria were investigated for fibromyalgia syndrome. An unexpectedly high proportion (over 70%) had fibromyalgia syndrome. The corresponding proportion for 50 control dermatological patients was 16%, which is higher than previously published data for the Italian general population (2.2%). It is possible that dysfunctional cutaneous nerve fibres of patients with fibromyalgia syndrome may release neuropeptides, which, in turn, may induce dermal microvessel dilatation and plasma extravasation. Furthermore, some neuropeptides may favour mast cell degranulation, which stimulates nerve endings, thus providing positive feedback. Chronic urticaria may thus be viewed in many patients, as a consequence of fibromyalgia syndrome; in fact, skin neuropathy (fibromyalgia syndrome) may trigger neurogenic skin inflammation (chronic urticaria).

Densities, distribution and phenotypic expression of T cells in human fetal skin.

T cells are present in normal adult human skin, but their occurrence in fetal skin is unknown. T cell and Langerhans cell (LC) populations were studied using single or double immunohistochemical staining on cryostat-section. Skin samples taken from different body regions of 17 fetuses ranging from 18 to 30 weeks estimated gestational-age (w-EGA), were examined. In all specimens but one, we did not find any epidermal T cell. In contrast, dermal CD3(+) T cells occurred at all w-EGA. The density of these cells increased with increasing age. Double staining showed that CD3(+) T cells were predominantly CD4(+)/CD45RA(+). On the other hand, LC, as assessed by CD1a expression, was evenly distributed within the interfollicular epidermis and papillary dermis at all gestational ages. Analysis of T cell and LC density in different body regions did not show significant topographic differences. We suggest that lack of epidermal T cells, although the LC network was fully represented, might reflect the scarce opportunity of fetal LC to contact foreign antigens in utero.

Density and proportions of the epidermal T cell population in human sun-exposed skin differ from those in sun-protected skin: preliminary immunohistochemical study.

Epidermal T cells, which are found in clinically normal human skin, show topographic differences in density and proportions; however, the mechanisms and the biological consequences of such differences are still unknown. In a previous work, we showed that epidermal T cells are altered in number and composition after a single exposure to solar-simulated radiation (SSR). The purposes of the present investigation were, first, to compare the density of epidermal T cells and the proportion of T cell subpopulations in habitually sun-exposed versus sun-protected sites; second, to determine the effects of repetitive exposures to SSR on the latter cell populations. Biopsies from habitually sun-exposed, sun-protected and solar-simulated-exposed skin of 28 healthy volunteers were taken and immunohistochemistry was performed on cryostat sections. Compared with sun-protected sites, epidermal CD3(+) T cell numbers of habitually sun-exposed sites were significantly lower. Double staining showed that the number of CD3(+)CD8(+) T cells was significantly lower in sun-exposed than in sun-protected skin, whereas the numbers of CD3(+)CD4(+) T cells were similar in both sites. Therefore, the CD4/CD8 ratio was markedly higher in sun-exposed compared to sun-protected sites. Moreover, repeated exposures of sun-protected skin to SSR induced a significant reduction in number of epidermal CD3(+) T cells. The mean number of epidermal CD3(+)CD8(+) double stained cells significantly decreased after such exposures, while the epidermal CD3(+)CD4(+) T cell subpopulation was not significantly changed. In conclusion, both chronically sun-exposed skin and repeatedly SSR-exposed skin show a decrease in density of epidermal CD3(+) and CD3(+)CD8(+) T cells. We hypothesize that such sun-induced changes may weaken the immunosurveillance capacity of the skin and therefore increase the occurrence of skin cancer.

Treatment of chronic venous leg ulcers by platelet gel.

Chronic venous leg ulcers (CVLU) are chronic wounds, associated with long-standing venous hypertension, which have a poor prognosis for healing. In the process of wound healing the first step is represented by platelet aggregation and subsequent release of growth factors and other mediators, which play a key role in the repair response. Platelet gel (PG), a hemocomponent obtained by mixing platelets, thrombin, and calcium, is able, when applied topically, to release platelet mediators that likely favor CVLU healing. However, unstandardized protocols have been described in studies utilizing PG for the regeneration of a number of tissues, including CVLU; the relative clinical outcomes were hence highly variable. In our experience the topical use of PG, together with the strict adherence to the principles of good wound care, quickly promoted increased granulation tissue, followed by a complete CVLU epithelization. Although further studies and trials are needed to establish the major outcome affecting rules for optimal indications, preparation, and use of PG for CVLU treatment, PG can be undoubtedly considered a useful tool, able to improve the management of CVLU.

Therapeutic restoration of cytolytic and suicidal cell molecular machineries favours disease healing.

BACKGROUND/OBJECTIVE: Several drugs have recently been demonstrated to successfully treat diseases by activating cytolytic or suicidal cell molecular machineries. On the other hand, in healthy subjects cytolytic and suicidal machineries are able to maintain tissue homeostasis, thus preventing the onset of a number of diseases. These machineries include both the cytolysis, exerted by cytotoxic T lymphocytes, of cells 'altered' by infectious or neoplastic antigens (altered cell cytolysis [AlCC]), and the suicide of antigen-activated T cells when in antigen-excess (activated cell suicide [AcCS]). RESULTS/CONCLUSIONS: These drugs may therefore, in our opinion, restore AlCC or AcCS, and, as aconsequence, favour disease healing. Thus, such a restoration could prove helpful for treating disorders caused by failure of such machineries.

Phase- and stage-related proportions of T cells bearing the transcription factor FOXP3 infiltrate primary melanoma.

Although tumor-infiltrating lymphocytes (TILs) of primary cutaneous melanoma (PCM) include cytolytic T cells able to exert anti-PCM immunity, progression of PCM most frequently occurs, raising the hypothesis that the PCM microenvironment may also exert suppressive forces, for example, possibly developed by regulatory T (T(REG)) lymphocytes. The aim of this study was to investigate whether TILs of PCMs include lymphocytes bearing the transcription factor forkhead box protein P3 (FOXP3), which is the T(REG) lineage specification molecule in mice, and is debated to have a similar role in humans. Fourteen patients with PCM were selected, of which four had radial growth phase (RGP) stage I melanoma, five had vertical growth phase (VGP) stage I melanoma, and five had VGP stage III-IV melanoma. Formalin-fixed, paraffin-embedded sections were utilized for immunohistochemical single and double stainings. TILs of PCMs included FOXP3-bearing lymphocytes, which predominantly were CD20- and CD8-negative, but CD3-, CD4-, and CD25-positive, thus consistent with the standard immunophenotypical characteristics of "natural" T(REG) cells. Further, the proportions of FOXP3-bearing lymphocytes were higher in vertical than in RGP (P=0.001), as well as in late than in early melanoma stages (P<0.001). Should these FOXP3-bearing lymphocytes actually exert regulatory capabilities within the PCM microenvironment, they may suppress "in vivo" the local anti-PCM immune response, thus favoring melanoma progression.

Exacerbation of paranoid schizophrenia in a psoriatic patient after treatment with cyclosporine A, but not with etanercept.

Psoriasis may be frequently associated with psychiatric diseases. We present a 44-year-old man undergoing cyclosporine therapy for treatment of generalized plaque psoriasis which exacerbated his symptoms of paranoid schizophrenia, and disappeared a few days after discontinuation of cyclosporine. Replacement therapy with etanercept achieved clinical remission of psoriasis without any psychiatric side effects. Systemic medications, such as cyclosporine and etanercept, induce modifications of the cytokine network. This is pathogenetically significant in both psoriasis and psychiatric disorders. This case report suggests that dermatologists need to become more familiar with the risk-benefit of drug-induced cytokines dysregulation in psoriatic patients with comorbid psychiatric disorders.

Dermatopathological indicators of poor melanoma prognosis are significantly inversely correlated with the expression of NM23 protein in primary cutaneous melanoma.

BACKGROUND: Some dermatopathological parameters are recognized as dominant indicators of high metastatic potential in melanoma, especially Breslow thickness, ulceration, Clark's level of invasion and mitotic rate. Because NM23 protein is the product of a melanoma metastasis suppressor gene, the aim of this study was to compare such dermatopathological indicators of melanoma prognosis with NM23 protein expression in primary cutaneous melanoma. METHODS: The immunohistochemical NM23 expression was semiquantitatively assessed in 30 primary cutaneous melanomas. Ten dermatopathological parameters were evaluated and compared with NM23 expression. RESULTS: A significant inverse correlation was found for NM23 expression in comparison with Breslow thickness (p < 0.01), ulceration (p < 0.05), Clark's level (p < 0.01), mitotic rate (p < 0.05), and vertical growth phase (p < 0.05). By contrast, no significant correlation was found for NM23 expression in comparison with cell morphology, presence of adjacent nevus, pigmentation, tumor-infiltrating lymphocytes, and regression was impossible to evaluate. CONCLUSIONS: The expression of NM23 protein in primary cutaneous melanoma is significantly inversely correlated with dermatopathological parameters currently recognized as powerful indicators of melanoma prognosis. NM23 may be therefore considered in the dermatopathological evaluation of primary cutaneous melanoma.

Exogenous hydrogen sulfide induces functional inhibition and cell death of cytotoxic lymphocytes subsets.

The toxic effects of exogenous hydrogen sulfide on peripheral blood lymphocytes have been investigated in detail. Hydrogen sulfide is now considered as a gasotransmitter with specific functional roles in different cell types, like neurons and vascular smooth muscle. Here we show that exogenous hydrogen sulfide induces a caspase-independent cell death of peripheral blood lymphocytes that depends on their intracellular glutathione levels, with a physiologically relevant subset specificity for CD8+ T cells and NK cells. Although lymphocyte activation does not modify their sensitivity to HS-, after 24 h exposure to hydrogen sulfide surviving lymphocyte subsets show a dramatically decreased proliferation in response to mitogens and a reduced IL-2 production. Overall, our data demonstrate that HS- reduces the cellular cytotoxic response of peripheral blood lymphocytes as well as their production of IL-2, therefore de-activating the major players of local inflammatory responses, adding new basic knowledge to the clinically well known anti-inflammatory effects of sulfur compounds.