Vincenzo Ruocco

Clinically equivocal melanocytic skin lesions with features of regression: a dermoscopic-pathological study.

Background  Benign melanocytic skin lesions may be difficult to differentiate from melanoma both clinically and dermoscopically. One of the most confounding dermoscopic features, commonly seen in melanoma but in our experience also in melanocytic naevi, is represented by the so‐called blue–white structures (BWS).

Bullous pemphigoid: Etiology, pathogenesis, and inducing factors: Facts and controversies

The term pemphigoids includes a group of autoimmune bullous diseases characterized by subepidermal blistering. Bullous pemphigoid (BP) is not only the most common disorder within the pemphigoid group, but also represents the most frequent autoimmune blistering disease in general. The onset and course of BP depend on a variable interaction between predisposing and inducing factors. HLA genes are the most significant genetic predisposition factor to autoimmunity mechanisms. Many studies show an association between HLA-DQβ1*0301 and distinct clinical pemphigoid variants. Imbalance between autoreactive T helper (Th) and T regulatory cells, toll-like receptor activation, and Th17/IL-17 pathway are the three possible autoimmunity triggers underlying BP. The pathomechanism of BP hinges on an autoantibody response toward structural components of the hemidesmosome (BP180 and BP230). The binding of autoantibodies leads to complement activation, recruitment of inflammatory cells, and release of proteolytic enzymes. The inflammatory cascade also may be directly triggered by activation of Th17 cells with no intervention of autoantibodies. The intervention of inducing factors in BP can be identified in no more than 15% of patients. Facilitating factors in genetically predisposed individuals are various (drug intake, physical agents, and viral infections). Drugs may act as triggers by either modifying the immune response or altering the antigenic properties of the epidermal basement membrane. Cases of induction of BP by physical agents (eg, radiation therapy, ultraviolet radiation, thermal or electrical burns, surgical procedures, transplants) are rare, but well-documented events. A contributing role in inducing BP has been suggested for infections, in particular human herpes virus (HHV) infections (cytomegalovirus, Epstein-Barr virus, and HHV-6), but also hepatitis B and C viruses, Helicobacter pylori, and Toxoplasma gondii. Unlike pemphigus, no dietary triggers have been suspected of being involved in the induction of BP. In all patients who have a diagnosis of BP, an environmental agent as a potential cause should always be considered, because the prompt discontinuation of it might result in rapid improvement or even cure of the disease.

Pemphigus Provoked by D(-)Penicillamine

We present the results of our experiments with in vitro tissue cultures of normal human skin, carried out in order to clarify the mechanism(s) by which D(-) penicillamine provokes pemphigus. Various concentrations of D(-) penicillamine were added to the culture medium and produced acantholytic splitting, closely similar to control lesions produced by pemphigus serum, whereas no lesions occurred in controls cultured without the drug. This suggests to us that the pemphigus of D(-)penicillamine is due to biochemical mechanisms and is not mediated by antibodies. Integrating our data with those of previous clinical and experimental studies on idiopathic pemphigus vulgaris leads us to think that the pemphigus antigen(s) might be present in certain structures of the cell membrane of epithelial cells, which are linked with the initial phases of keratin differentiation.

Vitamin E: the radical protector

Since its discovery and isolation the importance of vitamin E in maintaining normal physiologic processes and its value in treating various disease states have been the subject of much controversy. It was our intention to review and highlight some of the arguments and problems regarding the usefulness of vitamin E and to try to put them into proper perspective. The major area of interest concerning vitamin E lies essentially in its role in preventing damage caused by free radicals. The latter are now known to play an important role in radiation induced carcinogenesis, photoaging and photosensitization. The chemistry of vitamin E, its physiological function as a major antioxidant and its interaction with other antioxidants are described by the sum of animal studies, in vitro research and epidemiological investigations. In preparing the current data, it appeared that despite the controversy and conflicting results the body of literature as a whole judges vitamin E to be useful as an antioxidant. Although, in principle, the use of vitamin E can be quite advantageous, the manner of its administration, especially regarding topical application, remains unclear.

Detection of herpesvirus DNA in peripheral blood mononuclear cells and skin lesions of patients with pemphigus by polymerase chain reaction

Pemphigus is an autoimmune disease where both endogenous (genetic) and exogenous (environmental) factors play a part. Viral infections, in particular herpesvirus infections, have been identified as a possible triggering factor for pemphigus. In this study, using the polymerase chain reaction, we studied peripheral blood mononuclear cells (PBMC) and skin biopsies from patients with pemphigus, and in some of these were able to demonstrate the presence of DNA sequences of herpes simplex virus 1/2 (50% in PBMC and 71% in skin biopsies), Epstein–Barr virus (15% in PBMC and 5% in skin biopsies) and human herpesvirus 6 (20% in PBMC only). However, the inability to detect herpesvirus DNA consistently in these cases suggests that viral infection may only be an occasional factor triggering the outbreak or exacerbation of the disease. The possible role of interferons and interleukins in the pathogenesis of virus‐induced pemphigus is discussed.

Kaposi's sarcoma: aetiopathogenesis, histology and clinical features

Kaposis sarcoma (KS) represents today one of the most common skin cancers in transplanted Mediterranean subjects and, since the epidemic of human immunodeficiency virus/acquired immune deficiency syndrome, in young unmarried single men. The disease has been associated with the recent identified human herpesvirus (HHV)‐8 or KS herpesvirus and its incidence in the general population shows a north to south gradient that parallels the HHV‐8 increasing prevalence from Nordic countries to sub‐Saharan regions. The identification of the aetiopathogenetic mechanisms (viral agents and immunodeficiency) involved in the pathogenesis of KS, are relevant for identifying susceptible subjects (HHV‐8 seropositive subjects), monitoring the immune levels in iatrogenic immune suppressed patients, and developing new therapeutic approaches based on antiviral and immune modulators.

Kaposi's sarcoma on a lymphedematous immunocompromised limb.

ABSTRACT: Kaposis sarcoma appeared on a chronically lymphedematous leg oi a 75‐year‐old man. lmrnunologic investigations revealed a lack of cellular immune response confined to the involved lower limb. Regional disorders of immune surveillance are thought to play an important role in the early stages of Kaposis sarcoma.

Pemphigus: Associations and management guidelines: Facts and controversies

Pemphigus, a prototypical organ-specific human autoimmune disease, may be associated with other immunity-related disorders, viral infections, and different types of tumors. Coexistence with immune diseases is fairly frequent and, for some of them (eg, myasthenia gravis, Basedows disease, rheumatoid arthritis, or lupus erythematosus), common pathogenic mechanisms can be considered. The association with viral infections (mainly herpesvirus infections) raises the question of whether the virus triggers the outbreak of the disease or simply complicates its clinical course. Neoplastic proliferations coexisting with pemphigus have a different histogenesis and the pathogenic link may vary according to the associated tumor (thymoma, lymphoma, carcinoma, or sarcoma). A subset of pemphigus-neoplasia association is represented by Anhalts paraneoplastic pemphigus, with peculiar clinical, histologic, and immunologic features characterizing it. Coexistence of pemphigus with Kaposis sarcoma, albeit not frequent, offers an intriguing speculative interest. The cornerstone of management in pemphigus is the combination of systemic corticosteroids and immunosuppressants. The conventional treatment used in most cases is based on oral administration of deflazacort and azathioprine. In selected cases, mycophenolate mofetil is preferred to azathioprine. Severe forms of pemphigus require intravenous pulse therapy with dexamethasone (or methylprednisolone) and cyclophosphamide. In the recent years, the use of high-dose intravenous immunoglobulin therapy has gained several consents. Rituximab, a monoclonal anti-CD 20 antibody, which affects both the humoral and cell-mediated responses, has proved to give a good clinical response, often paralleled by decrease of pathogenic autoantibodies. The combination with intravenous immunoglobulin offers the double advantage of better clinical results and a reduced incidence of infection. Interventional treatments, such as plasmapheresis and extracorporeal immunoadsorption, are aimed at patients with life-threatening forms of pemphigus and high levels of circulating autoantibodies, a circumstance where the medical therapy alone risks failing. Second-line treatments include gold salts (which we do not favor because of the acantholytic potential inherent in thiol structure) and the association of oral tetracyclines with nicotinamide, which is rather safe. Local treatments, supplementary to the systemic therapy, are aimed at preventing infections and stimulating reepithelialization of eroded areas. Innovative topical treatments are epidermal growth factor, nicotinamide gel, pimecrolimus, and a proteomics-derived desmoglein peptide. Pemphigus patients should be warned against over-indulging in unnecessary drug intake, prolonged exposure to ultraviolet rays, intense emotional stress, and too spiced or too hot foods. Cigarette smoking is not contraindicated in pemphigus patients because of the nicotine anti-acantholytic properties.

Oral pemphigus : Clinical significance of esophageal involvement: Report of eight cases

The extension of the blisters of pemphigus to the esophagus is relatively uncommon, especially in patients treated with corticosteroids who appear to be in clinical remission. The aim of this study was to evaluate the esophagus in eight patients affected by oral pemphigus in various stages of the disease. Upper gastrointestinal endoscopy revealed esophageal involvement in five patients (two men and three women); three had blisters or erosions in the upper esophagus, whereas two showed red longitudinal lines along the entire organ. Direct immunofluorescence was positive in all eight patients. It is suggested that endoscopic examination of esophageal mucosa is an objective criterion by which to judge the success of therapy of pemphigus vulgaris.

Kaposi’s sarcoma: Etiology and pathogenesis, inducing factors, causal associations, and treatments: Facts and controversies

Abstract Kaposis sarcoma (KS), an angioproliferative disorder, has a viral etiology and a multifactorial pathogenesis hinged on an immune dysfunction. The disease is multifocal, with a course ranging from indolent, with only skin manifestations to fulminant, with extensive visceral involvement. In the current view, all forms of KS have a common etiology in human herpesvirus (HHV)-8 infection, and the differences among them are due to the involvement of various cofactors. In fact, HHV-8 infection can be considered a necessary but not sufficient condition for the development of KS, because further factors (genetic, immunologic, and environmental) are required. The role of cofactors can be attributed to their ability to interact with HHV-8, to affect the immune system, or to act as vasoactive agents. In this contribution, a survey of the current state of knowledge on many and various factors involved in KS pathogenesis is carried out, in particular by highlighting the facts and controversies about the role of some drugs (quinine analogues and angiotensin-converting enzyme inhibitors) in the onset of the disease. Based on these assessments, it is possible to hypothesize that the role of cofactors in KS pathogenesis can move toward an effect either favoring or inhibiting the onset of the disease, depending on the presence of other agents modulating the pathogenesis itself, such as genetic predisposition, environmental factors, drug intake, or lymph flow disorders. It is possible that the same agents may act as either stimulating or inhibiting cofactors according to the patient’s genetic background and variable interactions. Treatment guidelines for each form of KS are outlined, because a unique standard therapy for all of them cannot be considered due to KS heterogeneity. In most cases, therapeutic options, both local and systemic, should be tailored to the patient’s peculiar clinical conditions.