Multiple genetic copy number alterations in oral squamous cell carcinoma: study of MYC, TP53, CCDN1, EGFR and ERBB2 status in primary and metastatic tumours.

BACKGROUND: Oncogenesis in the oral cavity is believed to result from genetic alterations that cause a stepwise transformation of the mucosa to invasive carcinoma. In oral squamous cell carcinoma (OSCC) multiple cytogenetic abnormalities have been reported, but their practical significance remains uncertain. OBJECTIVE: To evaluate the usefulness of the assessment of CCND1, MYC, EGFR, ERBB2 and TP53 in OSCC and lymph node metastases. METHODS: Fifty-one consecutive samples of OSCC, nine lymph node biopsies showing metastatic spread from OSCC, 16 biopsies diagnosed as oral leucoplakia (OLK), 13 samples corresponding to oral lichen planus (OLP) and 14 samples from normal oral mucosa were included in the study. Clinical and histopathological characteristics were reviewed. The genetic and protein status of the CCND1, MYC, EGFR, ERBB2 oncogenes and the TP53 tumour suppressor gene were assessed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). The obtained results were compared with the clinical characteristics and the outcome of the OSCCs. RESULTS: TP53 gene losses and MYC, ERBB2, CCND1 and EGFR copy number gains and amplifications were detected in a higher proportion in OSCC and lymph node samples than in OLK and OLP samples (P < 0·005). Overexpression of p53, Myc, Cyclin D1, c-erbB-2 and epidermal growth factor receptor (EGFR) was more prevalent in malignant samples than benign samples (P < 0·05). Correlation between FISH and IHC results was demonstrated in MYC, EGFR and CCND1 studies. The presence of two or more genetic abnormalities in the studied loci was exclusively detected in primary and metastatic OSCC. CONCLUSIONS: In our series, genetic abnormalities in TP53, MYC, CCND1, ERBB2 and EGFR detected by FISH were absent in inflammatory lesions, infrequent in precursor lesions and common in tumoral lesions. Evaluation of the genetic status of TP53, MYC, CCND1, ERBB2 and EGFR may be an additional diagnostic tool in distinguishing benign from malignant oral lesions in histopathologically challenging cases.

MYC gene numerical aberrations in actinic keratosis and cutaneous squamous cell carcinoma.

BACKGROUND: The genetic alterations that drive the transition from actinic keratoses (AKs) to cutaneous squamous cell carcinomas (SCCs) have not been defined precisely. Amplification and/or overexpression of the MYC proto-oncogene have been demonstrated in several human, malignant tumours including head and neck SCCs. OBJECTIVES: To evaluate the presence of MYC genomic aberrations in both AKs and SCCs. METHODS: Skin biopsy specimens corresponding to AKs, SCCs and control samples were included in two paraffin-embedded tissue microarrays. MYC cytogenetic profile was evaluated by fluorescence in situ hybridization (FISH). The results obtained were compared with MYC immunohistochemical expression. RESULTS: Twenty-three AKs and 30 SCCs were evaluated. MYC numerical aberrations were observed in eight of 23 (35%) AKs and 19 of 30 (63%) SCCs (P = 0.05). MYC numerical aberrations were more frequent in moderately to poorly differentiated SCCs (77%) when compared with well-differentiated SCCs (25%; P = 0.027). A significant association between copy number gains of MYC by FISH analysis and MYC protein expression was demonstrated. CONCLUSIONS: MYC gains and amplifications are frequent cytogenetic abnormalities in SCCs and may play a relevant role in promoting SCC undifferentiation and tumoral progression.

Clinical characteristics and psychopathological profile of patients with vulvodynia: an observational and descriptive study.

BACKGROUND: Vulvodynia is a fairly common dermatological symptom that often interferes with the personal, social and working activities of affected women and results in a significant loss of their quality of life. It is a persistent and tedious clinical disorder which is often resistant to conventional treatments. OBJECTIVES: The aim of this study is to evaluate the main clinical signs, associated psychopathological disorders and outcome after antidepressant treatment of patients with vulvodynia. METHODS: Eighty patients were included. Clinical characteristics and psychopathological profiles were determined by appropriate instruments. The improvement of clinical symptoms after combined antidepressant drug therapy was also evaluated. RESULTS: Pain (70%), burning (63.7%), dyspareunia (57.5%) and stinging (56.2%) were the most commonly reported symptoms. Most patients (56.5%) showed anxiety, and 52.2% of them were reported as having a depression disorder. When evaluated by psychometric tools, 81.4% of patients scored >150 on the Life Event Scale, which means a risk >50% of suffering an illness in the near future, and patients' scores in the Dermatology Life Quality Index showed higher values than the mean of the Spanish validation group. After 6 months of combined treatment with escitalopram (10-20 mg/day), perfenazine (2-4 mg/day) and amytriptiline (10 mg/day), a complete remission of the clinical symptoms was achieved in 41% of patients. In contrast, only 12% of patients who did not follow drug treatment reported a complete resolution of the clinical symptoms. CONCLUSIONS: Our results seem to confirm that vulvodynia is associated with psychiatric co-morbidity such as stress and depression. The study highlights that the psychiatric treatment may be a useful option to improve clinical symptoms. Whether these patients should be evaluated for depression or be referred to a psychiatrist, remains to be investigated.

Review of 26 cases of classical pyoderma gangrenosum: clinical and therapeutic features.

BACKGROUND: Classical pyoderma gangrenosum (CPG) is an uncommon, idiopathic, neutrophilic skin disease, generally associated with other skin conditions and systemic diseases, and with several treatment options. OBJECTIVE: The objective of this review was to know the clinical and therapeutic features of our cases of CPG. METHODS: Twenty-six cases of CPG were included; 65 episodes of PG and 120 treatment courses were analysed; and the mean follow-up was 4.6 years. RESULTS: 21 cases (80%) had lesions on the lower extremities, 16 (61%) had recurrences, 22 (84%) had some disease associated, and 13 (50%) had autoimmune inflammatory conditions. Cyclosporin A (CSA) was used in 22 (84%) patients and 51 (78%) episodes, and prednisone (PDN) was used in 15 (57%) patients and 26 (40%) episodes. CONCLUSIONS: CSA efficacy was excellent, with an early response and acceptable toxicity, although it did not seem to have any impact on the incidence of PG recurrences.

Impact of climate and land use change on water availability and reservoir management: scenarios in the Upper Aragón River, Spanish Pyrenees.

Streamflows in a Mediterranean mountain basin in the central Spanish Pyrenees were projected under various climate and land use change scenarios. Streamflow series projected for 2021-2050 were used to simulate the management of the Yesa reservoir, which is critical to the downstream supply of irrigation and domestic water. Streamflows were simulated using the Regional Hydro-Ecologic Simulation System (RHESSys). The results show that increased forest cover in the basin could decrease annual streamflow by 16%, mainly in early spring, summer and autumn. Regional climate models (RCMs) project a trend of warming and drying in the basin for the period 2021-2050, which will cause a 13.8% decrease in annual streamflow, mainly in late spring and summer. The combined effects of forest regeneration and climate change are expected to reduce annual streamflows by 29.6%, with marked decreases affecting all months with the exception of January and February, when the decline will be moderate. Under these streamflow reduction scenarios it is expected that it will be difficult for the Yesa reservoir to meet the current water demand, based on its current storage capacity (476 hm(3)). If the current project to enlarge the reservoir to a capacity of 1059 hm(3) is completed, the potential to apply multi-annual streamflow management, which will increase the feasibility of maintaining the current water supply. However, under future climate and land cover scenarios, reservoir storage will rarely exceed half of the expected capacity, and the river flows downstream of the reservoir is projected to be dramatically reduced.

Nodular lymphangitic subcutaneous dissemination after intralesional antimonial treatment for localized cutaneous leishmaniasis.

Human leishmaniases are protozoan diseases with diverse clinical features. They are transmitted by the bites of the Phlebotomus sand fly, and the reservoirs are usually wild and domestic animals, particularly dogs. In Spain, Leishmania infantum is the causative agent of both cutaneous and visceral leishmaniasis. Cutaneous leishmaniasis is a parasitic disease occurring throughout the Americas and in the Old World, particularly the Middle East and North Africa. It is spread by the female sandfly. We report a 33-year-old man who presented with a solitary plaque on the right elbow, which was found to contain Leishmania bodies. He was treated with intralesional meglumine antimoniate, but 2 weeks later, several subcutaneous nodules were noted on the inner right arm. PCR identified the organism as L. infantum. The patient was treated with itraconazole (200 mg/day) for 6 weeks was prescribed, which resulted in marked clinical improvement in the elbow plaque. However, because of the persistence and lack of response of the other lesions, systemic treatment with meglumine antimoniate (20 mg/kg/day) intravenously for 7 days and intramuscularly for 13 days was administered. A progressive improvement in both cutaneous and subcutaneous lesions was achieved, and the lesions resolved completely after 2 months.

Recurrent and self-healing cutaneous monoclonal plasmablastic infiltrates in a patient with AIDS and Kaposi sarcoma.

Infection with human immunodeficiency virus (HIV) increases the risk of developing non-Hodgkin lymphoma. Plasmablastic lymphoma (PBL) is a rare variant of diffuse large cell lymphoma that often involves the oral cavity of HIV+ patients. It is characterized by immunoblastic morphology and plasma cell phenotype. Cutaneous involvement in PBL appears to be rare. We report a 44-year-old man with AIDS and Kaposi sarcoma (KS) previously treated with doxorubicin who, following treatment with highly active antiretroviral therapy, developed an erythematous infiltrated nodule on the right arm. Histology showed subcutaneous fat necrosis and clusters of atypical large plasma cells (plasmablastic cells). Immunohistochemistry revealed lambda light chain restriction. Epstein-Barr virus (EBV) mRNA was detected by in situ hybridization within the plasmablastic cells. Polymerase chain reaction amplification with specific primers for human herpesvirus 8 (HHV-8) performed on the skin biopsy specimen detected a specific band. A complete screening (bone marrow biopsy, computed tomographic scan, radiological survey) disclosed no abnormalities. The lesion resolved spontaneously after 3 months. Two years later an infiltrated plaque developed on the abdominal wall. The clinical and histopathological features of this new lesion were similar to those observed 2 years previously. No evidence of extracutaneous involvement was detected. The lesion again resolved spontaneously after 25 days. PBL may be seen in patients with transplants or receiving chemotherapy, but is usually observed in patients with advanced AIDS. The observation of recurrent self-healing EBV- and HHV-8-associated cutaneous monoclonal plasmablastic infiltrates, in a patient with AIDS and KS, expands the clinical spectrum of AIDS-associated plasmablastic lymphoproliferative disorders.

Erythrokeratoderma variabilis-like ichthyosis in Chanarin-Dorfman syndrome.

Neutral lipid storage disease (Chanarin-Dorfman syndrome) is an autosomal recessive metabolic disorder associated with congenital ichthyosis and a multisystemic accumulation of neutral lipids (lipid droplets) in various types of cells. The clinical presentation has been reported to correspond to that of nonbullous congenital ichthyosiform erythroderma. We report a 4-year-old boy presenting a generalized ichthyosiform disorder manifested by migrating scaly plaques alternating with areas of normal-looking skin, showing erythematous borders with sharp margins, clinically suggestive of erythrokeratoderma variabilis (EKV). A peripheral blood smear revealed cytoplasmic vacuoles in most granulocytes. Genetic studies from the patient and his parents revealed that the patient carried two different and novel mutations of the ABHD5 gene: a nonsense mutation in exon 6 (transmitted by the father) and an insertion/deletion in exon 4 (transmitted by the mother). Our observation demonstrates the clinical heterogeneity of the ichthyosiform dermatoses observed in Chanarin-Dorfman syndrome and widens the clinical range of conditions presenting migrating scaly plaques mimicking EKV.

Aggressive multifocal Buruli ulcer with associated osteomyelitis in an HIV-positive patient.

Mycobacterium ulcerans infection causes a skin disease known as Buruli ulcer (BU), a disorder manifested usually as a solitary and painless nodule or papule that progresses to massive necrotizing destruction and cutaneous ulceration. When healing occurs, it often results in disabling deformities. Buruli ulcer is considered the third most common mycobacterial disease in immunocompetent people, after tuberculosis and leprosy. Although the emergence of Buruli ulcer in Western African countries over the past decade has been dramatic, it has been scarcely reported in industrialized countries. We report a patient from Equatorial Guinea who was human immunodeficiency virus-positive, presenting aggressive and multifocal BU associated with an underlying destructive osteomyelitis, in which only an aggressive surgical approach yielded to a resolution of the disease. In a global world, with increasing migratory population fluxes, an increased awareness of dermatologists regarding the clinical, histopathological and microbiological features of BU is important in order to avoid significant delays in diagnosis and treatment.

Prognostic significance of p27Kip1, p45Skp2 and Ki67 expression profiles in Merkel cell carcinoma, extracutaneous small cell carcinoma, and cutaneous squamous cell carcinoma.

AIMS: To compare the immunohistochemical expression of prognostic markers p27(Kip1), p45(Skp2) and Ki67 in Merkel cell carcinoma (primary neuroendocrine carcinoma of the skin, MCC), small cell neuroendocrine carcinoma of lung and urinary bladder (SNC), and cutaneous squamous cell carcinoma (SCC). METHODS AND RESULTS: Immunohistochemistry was performed using antibodies directed against p27(Kip1), p45(Skp2) and Ki67 on 72 tumour cases: 24 MCC, 25 SCC, and 23 SNC (15 from the lung and eight from the urinary bladder). Percentages of positive cells were determined for each marker and statistically analysed. Expression profiles on MCC and SCC were significantly different for all three markers. MCC and SNC exhibited significant similarities in their p27(Kip1) and p45(Skp2) expression profiles. In contrast, MCC and SNC differed significantly in their Ki67 proliferation indices, which were much higher in SNC. Additionally, MCC cases showed an association between increased proliferation indices and the appearance of local recurrence(s) and/or metastases. CONCLUSION: The immunohistochemical profile of MCC differs from that of SCC, in spite of their common oncogenesis and the supposed metaplastic origin of MCC, and resembles that of SNC, except for Ki67 levels, which were higher in the latter (characterized by greater biological aggressiveness). High levels of Ki67 also appear to be a prognostic factor in MCC.

Acantholytic dyskeratotic naevi following Blaschko's lines: a mosaic form of Darier's disease.

Darier's disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells and abnormal keratinization. Several patients with unilateral, linear, 'zosteriform' or localized lesions have been reported. We report three cases of DD in a localized pattern corresponding to mosaicism type 1 according to Happle's classification and review the literature about the genetic cause of DD and DD in a 'zosteriform' pattern.

Kikuchi's disease (necrotizing lymphadenitis) with cutaneous involvement associated with subacute cutaneous lupus erythematosus.

Necrotizing histiocytic lymphadenopathy (Kikuchi's disease) is a rarely observed clinical entity characterized by fever, and solitary or multiple lymphadenopathy predominantly in the posterior cervical region. Kikuchi's disease has been reported to precede, coexist with or follow the diagnosis of systemic lupus erythematosus. In only rare instances has its association with cutaneous lupus erythematosus without systemic involvement been reported. We report a 45-year-old woman who presented characteristic systemic and cutaneous manifestations of Kikuchi's disease. Several months later, after sun exposure, she developed lesions of subacute cutaneous lupus erythematosus. The American Rheumatism Association criteria for systemic lupus erythematosus were not fulfilled. The possible pathogenic relationships between the two processes are discussed.