Relapse of pemphigus vulgaris after topical application of ingenol mebutate.

Ingenol mebutate is a recently approved topical agent for the treatment of actinic keratosis. Its most common adverse effects are transient local skin reactions. We report a 63-year-old white man who presented with a red-brownish crusted plaque involving the dorsum of his nose and an eroded area on his lower lip, which appeared soon after topical application of ingenol mebutate gel. Clinical, histological and immunopathological features were consistent with a diagnosis of pemphigus vulgaris (PV). To our knowledge, this is the first report of relapse of PV after topical application of ingenol mebutate gel. The temporal relationship between the application of the drug and the outbreak of PV supports the involvement of this agent in triggering the disease. It is plausible that ingenol mebutate may have induced the disease by its action on the production of proinflammatory cytokines.

Chaperone patterns in vernal keratoconjunctivitis are distinctive of cell and Hsp type and are modified by inflammatory stimuli.

BACKGROUND: Vernal keratoconjunctivitis (VKC) is a severe ocular allergy with pathogenic mechanism poorly understood and no efficacious treatment. The aims of the study were to determine quantities and distribution of Hsp chaperones in the conjunctiva of VKC patients and assess their levels in conjunctival epithelial and fibroblast cultures exposed to inflammatory stimuli. METHODS: Hsp10, Hsp27, Hsp40, Hsp60, Hsp70, Hsp90, Hsp105, and Hsp110 were determined in conjunctiva biopsies from nine patients and nine healthy age-matched normal subjects, using immunomorphology and qPCR. Conjunctival epithelial cells and fibroblasts were cultured and stimulated with IL-1ß, histamine, IL-4, TNF-α, or UV-B irradiation, and changes in Hsp levels were determined by Western blotting. RESULTS: Hsp27, Hsp40, Hsp70, and Hsp90 levels increased in the patients' conjunctiva, whereas Hsp10, Hsp60, Hsp100, and Hsp105 did not. Double immunofluorescence demonstrated colocalization of Hsp27, Hsp40, Hsp70, and Hsp90 with CD68 and tryptase. Testing of cultured conjunctival cells revealed an increase in the levels of Hsp27 in fibroblasts stimulated with IL-4; Hsp40 in epithelial cells stimulated with IL-4 and TNF-α and in fibroblasts stimulated with IL-4, TNF-α, and IL-1ß; Hsp70 in epithelial cells stimulated with histamine and IL-4; and Hsp90 in fibroblasts stimulated with IL-1ß, TNF-α, and IL-4. UV-B did not induce changes. CONCLUSIONS: VKC conjunctiva displays distinctive quantitative patterns of Hsps as compared with healthy controls. Cultured conjunctival cells respond to cytokines and inflammatory stimuli with changes in the Hsps quantitative patterns. The data suggest that interaction between the chaperoning and the immune systems drives disease progression.

Differences in clinicopathological features and distribution of risk factors in Italian melanoma patients.

BACKGROUND: No studies are available in the literature on the distribution of different melanoma features and risk factors in the Italian geographical areas. OBJECTIVE: To identify the differences in clinical-pathological features of melanoma, the distribution of risk factors and sun exposure in various Italian macro-areas. METHODS: Multicentric-observational study involving 1,472 melanoma cases (713 north, 345 centre, 414 south) from 26 referral centres belonging to the Italian Multidisciplinary Group for Melanoma. RESULTS: Melanoma patients in northern regions are younger, with thinner melanoma, multiple primaries, lower-intermediate phototype and higher counts of naevi with respect to southern patients; detection of a primary was mostly connected with a physician examination, while relatives were more involved in the south. Northern patients reported a more frequent use of sunbeds and occurrence of sunburns before melanoma despite sunscreen use and a lower sun exposure during the central hours of the day. CONCLUSIONS: The understanding of differences in risk factors distribution could represent the basis for tailored prevention programmes.

Cutaneous melanoma in solid organ transplant patients.

Solid organ transplant patients are at greatly increased risk of developing a wide variety of skin cancers, particularly epithelial skin cancers. On the other hand, it is well known that an intact immune system limits the development of benign melanocytic lesions. The eruptive nevi phenomenon, which we can observe in solid organ transplant recipients, is indicative of the relationship between melanocyte proliferation and immune system. Regression of melanocytic nevi after restoration of complete immune responsiveness is a further clinical example the role of immunosurveillance on melanocyte proliferation. However, melanoma incidence in organ transplant recipients appears only 2-3 folds higher than in general population. To this regard, organ transplant recipients who develop de novo melanomas thicker than 2mm seem to have a significantly worse outcome with a greatly increased risk of dying of metastatic melanoma, whereas those who develop a ≤2 mm thickness melanoma seem to have a prognosis similar to that of the general population. Furthermore, there is no evidence supporting an increased risk of melanoma recurrences after transplant in patients with a history of low-risk melanoma. Melanoma is also one of the most frequent and lethal donor-derived malignancies suggesting that a history of invasive melanoma should be considered an absolute contraindication to donation. The aim of this review is to investigate the relationship between immunosuppression and melanoma and to discuss its clinical implications for the management of transplant-associated melanoma.

Kaposi's sarcoma and other rare skin cancers in organ transplant patients.

Kaposi's sarcoma and Merkel cell carcinoma represent potentially lethal cutaneous complications in organ transplanted patients. These neoplasms can severely complicate the clinical outcome of transplanted patient. Moreover, as the diagnosis is mainly clinical, a knowledge of these clinical entities may be fundamental in the daily management of this group of patients. In this review we will discuss these neoplasms in relation to the role of immunosuppression in their onset and progression.

Histopathological characteristics of subsequent melanomas in patients with multiple primary melanomas.

BACKGROUND: Multiple primary melanomas (MPM) occur in up to 20% of melanoma patients, and subsequent tumours seem to have a favourable histopathological pattern. OBJECTIVE: A prospectively collected cohort of 194 patients with MPM was retrospectively reviewed to investigate clinical and histopathological features of first and subsequent melanomas. METHODS: Patients with MPM who were diagnosed at our Department (1985-2011) and who attended at least a follow-up control yearly were identified. RESULTS: The number of nevi was <10, 10-50 and >50 in 8.7%, 41% and 50.3% of patients respectively. Histopathological dysplastic nevi have been diagnosed in 105 patients. During a median follow-up of 58 months, 159 (81.9%), 24 (12.3%), 7 (3.6%) and 4 (2%) patients developed 2, 3, 4 and ≥ 5 melanomas, respectively. The median time to second primary melanoma was 45 months. The second primary melanoma was diagnosed within 1-year and after 5-year from the first melanoma in 36.6% and 17.3% of patients respectively. First and second primary melanomas were in situ in 41 (21%) and 104 (54%) patients respectively (P < 0.001). Among patients with ≥ 2 invasive melanomas (N = 80), median tumour thickness and ulceration of first and second primaries were 0.91 and 0.44 mm (P <0.001), and 32% and 7.7% (P = 0.001) respectively. CONCLUSIONS: Subsequent melanomas occurred within 1-year from the appearance of the first melanoma in 36% of patients with MPM, while a late melanoma diagnosis was detected in 17% of cases. Second primary melanoma had favourable histopathological features. Our findings support long-term skin surveillance to detect subsequent melanomas at an early stage.

Verrucous sarcoidosis of the skin simulating squamous cell carcinoma.

Here, we report a case of a 38-year-old woman with a history of systemic sarcoidosis who developed cutaneous verrucous sarcoidosis simulating a squamous cell carcinoma. This modality of presentation is unusual in both caucasic patients and in woman and may represent a diagnostic challenge for dermatologists.

TLR7 Gln11Leu single nucleotide polymorphism in patients with sarcoidosis.

Sarcoidosis is a multi-factorial systemic disease with increased activity of the cellular immune components which is responsible of the formation of non-caseating granulomas in involved organs. Recent views on the etiology indicate interactions between inherited susceptibility and environmental or lifestyle factors. Concerning genes that may influence susceptibility to sarcoidosis Toll-like receptors (TLRs) may represent plausible candidates. In this present study, we investigated the X-linked TLR7 rs179008/Gln11Leu polymorphism situated on exon 3. SNP genotyping of the TLR7 exon polymorphism was performed by TaqMan allelic discrimination using the StepOnePlus™ Real-Time PCR System (Applied Biosystems). In females, the incidence of the AT genotypes of the polymorphism was significantly lower in sarcoidosis patients compared to control subjects  (P=0.0001). We could observe in control subjects a significant preponderance of the T allele of the TLR7 rs179008/Gln11Leu polymorphism compared to sarcoidosis female patients (P=0.008). In males, no significant differences between patients and controls emerged in allele frequencies of the TLR7 rs179008/Gln11Leu polymorphism. The presence of the TLR7 rs179008/Gln11Leu polymorphism in sarcoidosis may determine an alteration of TLR7 function hampering the signaling pathway involved in the onset of both cellular and humoral autoimmunity. This is consistent with the view that in some circumstances genetic mutations affecting components of the immune system can prevent systemic autoimmunity.

Primary cutaneous posttransplant lymphoproliferative disorders in solid organ transplant recipients: a multicenter European case series.

Primary cutaneous posttransplant lymphoproliferative disorders (PTLD) are rare. This retrospective, multicenter study of 35 cases aimed to better describe this entity. Cases were (re)-classified according to the WHO-EORTC or the WHO 2008 classifications of lymphomas. Median interval between first transplantation and diagnosis was 85 months. Fifty-seven percent of patients had a kidney transplant. Twenty-four cases (68.6%) were classified as primary cutaneous T cell lymphoma (CTCL) and 11 (31.4%) as primary cutaneous B cell PTLD. Mycosis fungoides (MF) was the most common (50%) CTCL subtype. Ten (90.9%) cutaneous B cell PTLD cases were classified as EBV-associated B cell lymphoproliferations (including one plasmablastic lymphoma and one lymphomatoid granulomatosis) and one as diffuse large B cell lymphoma, other, that was EBV-negative. Sixteen (45.7%) patients died after a median follow-up of 19.5 months (11 [68.8%] with CTCL [6 of whom had CD30(+) lymphoproliferative disorders (LPD)] and 5 [31.2%] with cutaneous B cell PTLD. Median survival times for all patients, CTCL and cutaneous B cell PTLD subgroups were 93, 93, and 112 months, respectively. Survival rates for MF were higher than those for CD30(+) LPD. The spectrum of primary CTCL in organ transplant recipients (OTR) is similar to that in the general population. The prognosis of posttransplant primary cutaneous CD30(+) LPD is worse than posttransplant MF and than its counterpart in the immunocompetent population. EBV-associated cutaneous B cell LPD predominates in OTR.

Mycosis fungoides: disease evolution of the "lion queen" revisited.

Mycosis fungoides (MF), which represents the most common subtype of primary cutaneous T-cell lymphoma (CTCL), is an epidermotropic lymphoma included as an indolent form in the recent WHO/EORTC classification. From a clinical point of view, the classic disease progression usually is slow and takes over years or even decades, and characterized by the evolution from patches to more infiltrated plaques and eventually to tumours or erythroderma. However, the analysis of the MF disease course has been greatly impaired by the rarity of the disease, thus data about the time course of disease progression and pattern of relapse during time are not well known. In this review, a summary of published data on MF large patients cohorts will be presented, together with the results obtained by a retrospective analysis of clinical features and follow-up data of 1,422 MF patients diagnosed and followed-up from 1975 to 2010 in 27 Italian Centres (Italian Study Group for Cutaneous Lymphoma). From a clinical perspective, the amount of data support the relevance of a stage-tailored, differentiated follow-up strategy, in as much as the TNMB staging appears not only to be associated with different progression rates, but also shows as a new finding a relationship with different patterns of disease progression. From a biological point of view, there is the need to understand the molecular basis of the different clinical pathways of disease progression, to be able to potentially identify at an earlier phase of disease evolution, the patients who are more likely to develop erythroderma or tumour-stage progression. In conclusion, if MF is indeed a true "lion queen", as dermatologists we need to be expert and wise tamers to keep it under control.

CD30+ lymphoproliferative disorders of the skin: still an open question.

CD30+ lymphoproliferative disorders of the skin represent a well-defined spectrum of primary cutaneous T-cell lymphomas. They include lymphomatoid papulosis and cutaneous anaplastic large-cell lymphoma which are characterized by the common expression of the CD30 antigen, but different clinical, histological and molecular features. Recent progress in the pathobiology and identification of therapeutic targets has contributed to our current understanding of this peculiar group of cutaneous lymphoproliferative disorders. The characteristic features of this group of cutaneous lymphoproliferative disorders are reviewed with particular emphasis to their diagnosis and treatment strategies.

The liver: another organ involved in Muir Torre syndrome?

Muir Torre syndrome is a rare autosomal dominant cancer-predisposing syndrome characterized by the occurrence of sebaceous gland neoplasms and/or keratoacanthomas associated with visceral malignancies that belong to the spectrum of hereditary non polyposis colorectal cancer (HNPCC), i.e., tumors of gastrointestinal and genitourinary tracts. Hepatobiliary malignancy in association with Muir Torre syndrome has rarely been reported. Here, we describe a case of Muir Torre syndrome associated with an hepatocellular-carcinoma in a patient with a non-cirrhotic liver and an HNPCC-family with multiple cases of hepatocellular carcinoma.

Anetoderma in cutaneous marginal-zone B-cell lymphoma.

Anetoderma is a rare condition, consisting of well-circumscribed areas of slack skin, in which dermal elastic fibres are destroyed or deficient. We present the case of a 45-year-old man with a 25-year history of deep nodules and plaques gradually progressing to areas of anetoderma. Histological examination found an infiltrate composed of neoplastic cells with lymphoplasmocytoid morphology. The cells were positive for CD20, CD38 and CD138, and there was a monoclonal kappa light chain gene rearrangement of plasma cells. A diagnosis of cutaneous marginal-zone B-cell lymphoma was made. The pathogenesis of anetoderma remains unknown, but it is possible that cytokines or other soluble factors produced by the infiltrating lymphocytes have a role in this process.

[A case of Kaposi's sarcoma in the rapamycin era]. / Un caso di sarcoma di Kaposi nell'era della Rapamicina.

We report a case of Kaposi's sarcoma in a patient who received a double kidney transplant in 2005. Immunosuppression was induced with rapamycin and antilymphocyte serum while maintenance therapy consisted of rapamycin, corticosteroids and mycophenolic acid. The patient developed delayed graft function but no rejection. In November 2006 and March 2007 two graft biopsies were taken because of a significant rise in serum creatinine; they revealed chronic allograft nephropathy and polyomavirus infection. Meanwhile a skin biopsy of the leg was performed to determine the nature of a discolored lesion. The morphohistological diagnosis was Kaposi's sarcoma. For this reason rapamycin was stopped and steroid treatment gradually reduced. Specific therapy with doxorubicin was started; radiological and endoscopic examination excluded disseminated disease while serological tests were positive for antibodies to HHV-8, a virus known to cause Kaposi's sarcoma. Unfortunately, withdrawal of antirejection therapy caused loss of the graft, so the patient had to start dialysis. In this report we stress the possible development of malignancy in transplanted patients who are given rapamycin. Rapamycin is known to be an antirejection drug and to have antineoplastic activity; the major risk of malignancy is probably related to immunosuppression rather than the type of drugs used to obtain it.

Topical photodynamic therapy of actinic keratosis in renal transplant recipients.

Organ transplant recipients (OTRs) show an increased risk of precancerous (mostly actinic keratosis [AK]) and cancerous (mostly squamous cell carcinomas [SCC] and basal cell carcinomas [BCC]) cutaneous lesions. Their frequency increases with time after transplantation. AKs seem to progress more often and faster to invasive SCC in OTRs compared with the general population. The steady increase of risk of cutaneous premalignancies and malignancies with time after transplantation is an alarming figure because the number of organ allograft recipients who live for many years after transplantion is rapidly growing. This points out the need to devote more resources to skin cancer prevention, detection, and management. Various therapies, including cryotherapy, topical 5-fluorouracil, imiquimod, topical diclofenac, curettage, electrosurgery, carbon dioxide laser, and surgical excision, are available for AKs. However, most of these are limited by frequent relapses and the presence of multiple lesions over a wide area. Topical photodynamic therapy (PDT) represents an innovative therapeutic approach for nonsurgical treatment of cutaneous precancerous lesions and skin cancers. In this study we confirmed the usefulness of PDT in the treatment of AKs in OTRs, even in lesions relapsing or unresponsive to conventional treatment. We showed a complete response rate of 71%, after 2 treatments sessions that were 2 weeks apart. The response rate of scalp/facial lesions (72%) was higher compared with acral lesions (40%). Topical PDT could represent a useful therapeutic alternative for AKs in OTRs because large lesions can be treated with excellent cosmetic outcome.