The Granulated Sweetener Packet Sign.

The last two decades have seen a continuing shift from visual and tactile diagnoses in dermatology towards novel, state-of-the-art, and noninvasive instrumental technologies. Against the current tide toward replacing classical physical examinations with sophisticated high-tech ones, the present article will describe an easy-to-use and practical clinical sign to differentiate between metastases of malignant lesions and apparently benign inflamed/infected dermoid cysts. Epidermoid cysts (sometimes erroneously called "sebaceous cysts") are subcutaneous nodules containing keratin and encapsulated by an epidermoid wall. They are mobile nodules, smooth to the touch, variable in size, and most commonly located on the face, neck, and trunk. They may rupture or become infected and inflamed, red, painful, or purulent. Diagnosis is usually clear-cut, and uncomplicated cysts may not require treatment. Patients usually seek advice and request excision for esthetic or medical reasons (inflammation/infection). A 48-year-old otherwise healthy woman presented for a consultation because of a small cyst on her forehead (Figure 1). Two-finger palpation of the cyst revealed that it did not have the gelatinous fluctuant consistency of an ordinary cyst, but rather felt like a packet of granulated sweetener. The histological diagnosis of the cyst was small-to-medium-sized T-cell lymphoma. The diagnostic challenge of this case was to distinguish between metastases and an ordinary innocent-appearing cyst. The impression of a packet containing granular material upon palpitation of a cyst can be the definitive clue to detecting metastases of malignant lesions among what appear to be uncomplicated dermoid cysts. We have seen several such cases of subcutaneous nodules that turned out to be metastases of sarcomas and carcinomas, all of them with the same impression of a packet of granulated material upon palpation. We propose the term "granulated sweetener packet sign" for this diagnostic sign.

Drug eruptions in the mature patient.

The world's population is now ageing at an unprecedented rate. Declining fertility and improved health and longevity have generated rising numbers and proportions of the older population in most parts of the world. With advancing age, however, comes an increasing incidence of disease (comorbidity or multimorbidity), an increasing use of medications (polypharmacy), and consequently an increase in adverse drug reactions (ADRs). Age-related changes in pharmacodynamics and pharmacokinetics (eg, volumes of drug distribution, metabolism and clearance, altered drug responsiveness and toxicity) and greater vulnerability to ADRs are other reasons for the higher incidence of ADRs in the elderly compared with young adults. Because the clinical patterns of ADRs are very similar for all age groups, including the elderly, the present review will deal mainly with statistics and numbers, rather than the clinical and/or disease patterns.

Acral manifestations of Sweet syndrome (neutrophilic dermatosis of the hands).

Neutrophilic dermatosis of the hand (NDH) is a rare localized variant of the syndrome, originally described two decades ago by Strutton et al. The lesions of NDH and Sweet syndrome are similar, as indicated in the first report of NDH. Both diagnoses are characterized by an acute onset of fever, leukocytosis, and tender, erythematous infiltrated plaques. There are also bullae and ulceration in NDH, in contrast to Sweet syndrome, in which bullae are quite uncommon, especially at the early stages. Similar to Sweet syndrome, the majority of NDH patients are women (69%). Patients with NDH present with fever, peripheral neutrophilia, leukocytosis, and/or an elevated erythrocyte sedimentation rate or C-reactive protein level, but at a significantly lower rate than those in Sweet syndrome (33%). Similar to Sweet syndrome, NDH has been associated with the following conditions: Malignancies (particularly hematological [21%], most common of which is acute myelogenous leukemia, but many other malignancies as well), inflammatory bowel disease (19%), medication and vaccination-related eruptions, bacterial and viral infections, rheumatologic diseases, and others. The clues to the diagnosis of NDH are the same as for Sweet syndrome. Awareness of this diagnosis is important not only to avoid unnecessary medical and surgical therapy and to expediently initiate the administration of steroids for this highly responsive dermatosis, but also to conduct an appropriate workup to exclude associated diseases, especially malignancies.

Baboon syndrome and toxic erythema of chemotherapy: Fold (intertriginous) dermatoses.

Three decades ago, researchers described an eruption with a very characteristic distribution pattern that was confined to the buttocks and the intertriginous and flexor areas. They gave this reaction pattern one of the most unforgettable names in dermatology, baboon syndrome (BS), due to the characteristic, bright-red, well-demarcated eruption predominantly on the buttocks and genital area, reminiscent of the red bottom of a baboon. The authors described three cases provoked by ampicillin, nickel, and mercury. They were convinced that BS represented a special form of hematogenous or systemic contact-type dermatitis, but several important papers that appeared during the past decade disagreed and suggested that BS should be distinguished from hematogenous or systemic contact-type dermatitis. A new acronym, SDRIFE (symmetrical drug-related intertriginous and flexoral exanthema), was proposed along with five diagnostic criteria: (1) exposure to a systemically administered drug at the time of first or repeated doses (contact allergens excluded), (2) sharply demarcated erythema of the gluteal/perianal area and/or V-shaped erythema of the inguinal/perigenital area, (3) involvement of at least one other intertriginous/flexural fold, (4) symmetry of affected areas, and (5) absence of systemic symptoms and signs. Although there are merits to the arguments in favor of SDRIFE, many of us still prefer to use the wittier name baboon syndrome, and even more authors use both terms. We confess that we find it difficult to relinquish the term BS, which has served us so well for years; however, recognition, familiarity, and knowledge of the characteristics of this form of drug eruption must supersede sentimental attachment to a certain nomenclature and so, however reluctantly, we must embrace change. Another intertriginous drug eruption is the one induced by chemotherapy. Toxic erythema of chemotherapy (TEC) is a useful clinical term that recently has been introduced to describe this group of chemotherapy-induced eruptions. This group of overlapping toxic reactions is characterized by areas of painful erythema often accompanied by edema usually involving the hands and feet, intertriginous zones (eg, axilla, groin), and, less often, the elbows, knees, and ears. Toxic erythema of chemotherapy is briefly discussed.

Diaper (napkin) dermatitis: A fold (intertriginous) dermatosis.

Diaper (napkin) dermatitis is an acutely presenting inflammatory irritant contact dermatitis of the diaper region. It is one of the most common dermatologic diseases in infants and children. In the past, the disease was thought to be caused by ammonia; however, a number of factors, such as friction, wetness, inappropriate skin care, microorganisms, antibiotics, and nutritional defects, are important. Diaper dermatitis commonly affects the lower parts of the abdomen, thighs, and diaper area. Involvement of skin fold regions is typical with diaper dermatitis. At the early stages of the disease, only dryness is observed in the affected area. At later stages, erythematous maceration and edema can be seen. Secondary candidal and bacterial infections can complicate the dermatitis. In the differential diagnosis of the disease, allergic contact dermatitis, intertrigo, psoriasis, atopic and seborrheic dermatitis, and the other diseases should be considered. Causes of the disease should be determined and eliminated primarily. Families need to be informed about the importance of a clean, dry diaper area and the frequency of diaper changes. The use of superabsorbent disposable diapers has decreased the incidence of the disease. Soap and alcohol-containing products should be avoided in cleaning the area. In some cases, corticosteroids and antifungal agents can be administered. If necessary, antibacterial agents and calcineurin inhibitors can also be beneficial.

Psychologic factors in the development of facial dermatoses.

In medical literature, as well as in daily practice, some common facial dermatoses are considered to be influenced or triggered by emotional factors. The main damager is stress, but depression and anxiety may play a role, among other factors. Some patients may experience a vicious cycle: Their facial dermatosis is triggered or worsened by stress, and in turn, the exacerbation itself is a major stressogenic stimulus. It appears that clinical wisdom and experience preceded clinical investigation in this field. Although patients testify that their emotional state may sometimes influence their facial condition, only limited experimental data exist so far, and only a few facial dermatoses were investigated.

Wolf's post-herpetic isotopic response: Infections, tumors, and immune disorders arising on the site of healed herpetic infection.

Herpes simplex viruses (HSV-1/HSV-2) and varicella-zoster virus (VZV) have several characteristics in common. Both are epidermoneurotropic, cause skin eruptions accompanied by sensory symptoms (itch, pain), damage peripheral sensory nerve fibers and cutaneous nerve endings, and interfere with neuromediator release, which can alter local mechanisms of immune control. For this reason, herpes-infected areas may become a preferential location for the subsequent onset of immunity-related skin disorders (infections, tumors, and dysimmune reactions), an event first reported by a neurologist and focused on by two brothers, a dermatologist and a pediatrician. The phenomenon therefore named Wolf's post-herpetic isotopic response (PHIR) refers to the occurrence of a new skin disorder at the site of a previous and already healed herpetic eruption (herpes zoster in most cases). Until now, we have been able to gather 189 well-documented cases of PHIR (all reported in the reference section), but our list is far from being complete. Some of the most emblematic cases are briefly described here. In some circumstances, the opposite of PHIR occurs, with diffuse skin disorders or eruptions that selectively spare herpes-infected areas (Wolf's post-herpetic isotopic nonresponse). Experimental investigations with patch testing have been performed in seven patients who were sensitized to nickel and had had herpes zoster in the past years. The tests were carried out bilaterally on the affected dermatomes and on the unaffected contralateral ones. The uneven immune responses we obtained have shown that the immune behavior of an herpes zoster-affected dermatome can be different from that of the corresponding contralateral dermatome, thus supporting the existence of immune dysregulation in herpes-infected areas.

The immunocompromised district in dermatology: A unifying pathogenic view of the regional immune dysregulation.

Besides the systemic immune deficiency, a sectorial default in immune control may occur in immunocompetent subjects. This regional immune defect can appear and remain confined to differently damaged skin areas, lately labeled immunocompromised districts (ICDs). An ICD is a skin area more vulnerable than the rest of the body for genetic or acquired reasons. Its vulnerability mainly consists in a local dysregulation of the immune control, which often facilitates (but sometimes hinders) the local onset of immunity-related eruptions or skin disorders. The factors responsible for localized immune dysregulation are multifarious, being represented by chronic lymphatic stasis, herpetic infections, ionizing or ultraviolet (UV) radiations, burns, all sorts of trauma (especially amputation), tattooing, intradermal vaccinations, and others of disparate nature (eg, paralytic stroke, poliomyelitis). Whatever the cause, in time an ICD may become a vulnerable site, prone to developing opportunistic infections, tumors, or dysimmune reactions (often of granulomatous type), strictly confined to the district itself; however, the opposite may also occur with systemic immune disorders or malignancies that selectively spare the district. In any case, the immunologic behavior of an ICD is different from that of the rest of the body. The pathomechanisms involved in this sectorial immune destabilization may reside in locally hampered lymph drainage that hinders the normal trafficking of immunocompetent cells (eg, chronic lymphedema, posttraumatic lymph stasis) or in a damage to sensory nerve fibers that release immunity-related peptides (eg, herpetic infections, carpal tunnel syndrome), or in both conditions (eg, amputation stump, radiation dermatitis). The ICD is a conceptual entity with no definite shape or dimension. It may take an extremely variable form and extent depending on the causative agent, ranging from a minimal area (eg, intradermal vaccination) or a small area (eg, herpes simplex infection), through a wide area (eg, radiotherapy), a bandlike segment (eg, skin mosaicism, herpes zoster infection), or an acral area (eg, carpal tunnel syndrome), up to a whole limb (eg, Stewart-Treves syndrome) or even an entire half body (eg, brain stroke). Varied newly coined terminology can be used to indicate the specific cause each time that it is responsible for a regional immune dysregulation. The advantage of the umbrella term ICD is that it encompasses all the possible causes involved in a local immune destabilization. An ICD may have a congenital or a postnatal origin, and interesting similarities between the two forms exist. An ICD may also take place in patients with a preexisting systemic immune deficiency, thus creating a more vulnerable site in an already vulnerable patient. Identifying a cutaneous ICD in a given patient is an important standpoint for both diagnostic and prevention purposes. This can be proven by the educative clinical examples that are reported here.

Rosacea and rhinophyma.

Rosacea is a common and chronic inflammatory cutaneous disease with unknown etiology. The pathophysiology of rosacea is still poorly understood. Epidemiological studies indicate a genetic component, but a rosacea gene has not been detected yet. Recent molecular studies propose that an altered innate immune response is involved in the pathogenesis of the rosacea disease. Signs of rosacea are indicated by the presence of characteristic facial or ocular inflammation involving both the vascular and tissue stroma. A wide range of drug options is available for the treatment of rosacea, including several topical ones (metronidazole, antibiotics, azelaic acid, benzoyl peroxide, sulfacetamide/sulfur, retinoids) and oral ones (mainly tetracyclines, metronidazole, macrolides, isotretinoin). This review highlights the recent clinical and pathophysiological developments concerning rosacea.

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, Basedow's 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 Anhalt's paraneoplastic pemphigus, with peculiar clinical, histologic, and immunologic features characterizing it. Coexistence of pemphigus with Kaposi's 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.

Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies.

Pemphigus includes a group of autoimmune bullous diseases with intraepithelial lesions involving the skin and Malpighian mucous membranes. Pemphigus vulgaris (PV), the most frequent and representative form of the group, is a prototypical organ-specific human autoimmune disorder with a poor prognosis in the absence of medical treatment. The pathomechanism of PV hinges on autoantibodies damaging cell-cell cohesion and leading to cell-cell detachment (acantholysis) of the epidermis and Malpighian mucosae (mainly oral mucosa). A controversy exists about which subset of autoantibodies is primarily pathogenic: the desmoglein-reactive antibodies or those directed against the acetylcholine receptors of the keratinocyte membrane. The onset and course of PV depend on a variable interaction between predisposing and inducing factors. Genetic predisposition has a complex polygenic basis, involving multiple genetic loci; however, the genetic background alone ("the soil"), although essential, is not by itself sufficient to initiate the autoimmune mechanism, as proven by the reports of PV in only one of two monozygotic twins and in only two of three siblings with an identical PV-prone haplotype. The intervention of inducing or triggering environmental factors ("the seed") seems to be crucial to set off the disease. The precipitating factors are many and various, most of them directly originating from the environment (eg, drug intake, viral infections, physical agents, contact allergens, diet), others being endogenous (eg, emotional stress, hormonal disorders) but somehow linked with the subject's lifestyle. As to certain drugs, their potential of provoking acantholysis may be implemented by their interfering with the keratinocyte membrane biochemistry (biochemical acantholysis) and/or with the immune balance (immunologic acantholysis). Viral infections, especially the herpetic ones, may trigger the outbreak of PV or simply complicate its clinical course. The precipitating effect might be due to interferons and other cytokines released by the host as a consequence of the viral attack, which overactivate the immune response. Inductions of PV by physical agents (ultraviolet or ionizing radiation, thermal or electrical burns, surgery and cosmetic procedures), contact allergens (in particular, organophosphate pesticides), dietary factors (eg, garlic, leek, onion, black pepper, red chili pepper, red wine, tea), and emotional stress are rare, but well-documented events. The possible intervention of the environment in the outbreak of PV has been overlooked in the past, but nowadays clinicians perceive it more frequently. The assumption that genetic factors alone are not sufficient to cause the outbreak of the disease, inevitably instills the idea that PV may not occur spontaneously, but always results from an interaction between an individual predisposing genetic background and environmental precipitating factors, often concealed or apparently harmless.

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-DQß1*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.

RETRACTED: Bullous pemphigoid: associations and management guidelines: facts and controversies.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor following the discovery that the text overlaps significantly with sections of several articles that are cited in the reference section, including the following: Culton DA, Diaz LA. Treatment of subepidermal immunobullous diseases. Clin Dermatol 2012;30:95­102. Meurer M. Immunosuppressive therapy for autoimmune bullous diseases. Clin Dermatol 2012;30:78­83. Ljubojevic S, Lipozencic J. Autoimmune bullous diseases associations. Clin Dermatol 2012;30:17­33. Sehgal VN, Verma. Leflunomide: dermatologic perspective. J Dermatolog Treat 2013;24:89­95. Gürcan HM, Ahmed AR. Analysis of current data on the use of methotrexate in the treatment of pemphigus and pemphigoid. Br J Dermatol 2009;16:723­31. Chen YJ, Wu CY, Lin MW, et al. Comorbidity profiles among patients with bullous pemphigoid: a nationwide population-based study. Br J Dermatol 2011;165:593­9

Phacomatosis pigmento-pigmentaria: should we add a new type of phacomatosis? Fact and controversies.

There are currently five types of recognized phacomatosis pigmentovascularis plus one more, phacomatosis pigmentokeratotica, making six types altogether. Should we stop here and consider the classification as being complete? Or, do we leave room to add more types or, alternatively, lump the ones we have together and shorten the list? We present our reasons for adding one or two new types of phacomatoses to the current classification, in full recognition that it is already complicated and somewhat cumbersome. We consider that the benefits of doing so outweigh any additional strain on the already complicated classification. We expect that this might not sit well with some of our colleagues, but we are prepared to do battle.

Kaposi's sarcoma: etiology and pathogenesis, inducing factors, causal associations, and treatments: facts and controversies.

Kaposi's 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.