Hedgehog- and mTOR-targeted therapies for advanced basal cell carcinomas.

Basal cell carcinomas (BCCs) are the most frequent human cancer. Over 90% of all BCCs have a mutation in PTCH1 or smoothened, two conducting proteins of the Hedgehog pathway. They rarely progress deeply and metastasize; however, if they do, these advanced basal cell carcinoma become amenable to treatment by inhibiting the Hedgehog and the P13K-mTOR pathways. Such innovative drugs include vismodegib, cyclopamine, itraconazole, everolimus and a few other agents that are in early clinical development.

Protomyofibroblast Pathway in Early Thermal Burn Healing.

Wound healing following partial thickness thermal burns is commonly hampered by the risk of hypertrophic scarring. Skin myofibroblast (MF) density is commonly increased in postburn healing. The transition between fibroblast-like cells and α-smooth muscle actin (SMA)+ MF possibly begins with CD14+ monocytes, evolving to CD14+ CD34+ fibrocytes, followed by ß-SMA+ protomyofibroblast (PMF) maturation. Skin biopsies from 25 burn patients were collected about 1 and 4 weeks after injury. Immunohistochemistry was performed using monoclonal antibodies to α-SMA, ß-SMA, factor XIIIa, lysozyme, Mac 387, CD14, CD117 and Ulex europaeus agglutinin-1 (UEA-1). The set of Mac 387+ and CD14+ monocytes was accompanied by both CD34+ fibrocytes and factor XIIIa+ dendrocytes. By contrast, ß-SMA+ PMF were rare. Of note, α-SMA+ MF were more abundant at week 4 than at week 1 (p < 0.01). The UEA-1+ endothelial cells showed marked variations in their dermal distribution, irrespective of the densities in the other scrutinized cells. In conclusion, healing of partial thickness thermal burns involves a diversity of cell types including PMF. In the present samples, the PMF density remained low. © 2015 S. Karger AG, Basel.

Simulants of Malignant Melanoma.

During the recent period, dermoscopy has yielded improvement in the early disclosure of various atypical melanocytic neoplasms (AMN) of the skin. Beyond this clinical procedure, AMN histopathology remains mandatory for establishing their precise diagnosis. Of note, panels of experts in AMN merely report moderate agreement in various puzzling cases. Divergences in opinion and misdiagnosis are likely increased when histopathological criteria are not fine-tuned and when facing a diversity of AMN types. Furthermore, some AMN have been differently named in the literature including atypical Spitz tumor, metastasizing Spitz tumor, borderline and intermediate melanocytic tumor, malignant Spitz nevus, pigmented epithelioid melanocytoma or animal-type melanoma. Some acronyms have been further suggested such as MELTUMP (after melanocytic tumor of uncertain malignant potential) and STUMP (after Spitzoid melanocytic tumor of uncertain malignant potential). In this review, such AMN at the exclusion of cutaneous malignant melanoma (MM) variants, are grouped under the tentative broad heading skin melanocytoma. Such set of AMN frequently follows an indolent course, although they exhibit atypical and sometimes worrisome patterns or cytological atypia. Rare cases of skin melanocytomas progress to loco regional clusters of lesions (agminate melanocytomas), and even to regional lymph nodes. At times, the distinction between a skin melanocytoma and MM remains puzzling. However, multipronged immunohistochemistry and emerging molecular biology help profiling any malignancy risk if present.

In vivo skin fluorescence imaging in young Caucasian adults with early malignant melanomas.

BACKGROUND: Human cutaneous malignant melanoma (CMM) is an aggressive cancer showing a dramatic worldwide increase in incidence over the past few decades. The most prominent relative epidemiological increase has been disclosed in young women. The aim of the study was to assess the effects of chronic sun exposures in order to rate the extend of melanocytic stimulations in the vicinity of CMM. METHODS: The study was designed to evaluate the melanin distribution and density using ultraviolet light illumination. The present study was performed on surgical excision specimens of thin CMM lesion removed from the upper limbs of 55 Caucasian adults (37 women and 18 men). Two control groups comprised 23 men and 21 women of similar ages who had medium-size congenital melanocytic nevi, also present on the upper limbs. The peritumoral skin was scrutinized using a Visioscan(®) VC98 device, revealing the faint mosaic melanoderma (FMM) pattern that grossly indicates early signs of chronic photodamage in epidermal melanin units. RESULTS: The median extent of relative FMM was significantly higher in the CMM male group. By contrast, the CMM female group showed a reverse bimodal distribution in FMM size. Only 12/37 (32.5%) of the CMM female group had an increased FMM size, whereas 25/37 (67.5%) of females with CMM had a global FMM extent in the normal range, relative to the controls. CONCLUSION: Thin CMM supervening in young women appear unrelated to repeat photoexposure. Other mechanisms are possibly involved.

Cyanoacrylate skin surface stripping and the 3S-Biokit advent in tropical dermatology: a look from Liège.

In the dermatopathology field, some simple available laboratory tests require minimum equipment for establishing a diagnosis. Among them, the cyanoacrylate skin surface stripping (CSSS), formerly named skin surface biopsy or follicular biopsy, represents a convenient low cost procedure. It is a minimally invasive method collecting a continuous sheet of stratum corneum and horny follicular casts. In the vast majority of cases, it is painless and is unassociated with adverse events. CSSS can be performed in subjects of any age. The method has a number of applications in diagnostic dermatopathology and cosmetology, as well as in experimental dermatology settings. A series of derived analytic procedures include xerosis grading, comedometry, corneofungimetry, corneodynamics of stratum corneum renewal, corneomelametry, corneosurfametry, and corneoxenometry.

Dermal ultrastructure in collagen VI myopathy.

The COL VI mutations are responsible for a spectrum of myopathies. The authors report cutaneous ultrastructural alterations in a patient with COL6A2 myopathy. The changes include variations in size of collagen fibrils, flower-like sections of collagen fibrils, as well as thickening of vessel and nerve basement membranes. Electron microscopy of a skin biopsy contributes to the diagnosis of COL VI myopathies.

Dormancy of growth-stunted malignant melanoma: sustainable and smoldering patterns.

The presentations of primary and metastatic cutaneous malignant melanoma (CMM) are very diverse. Evidence increasingly indicates that single CMM cells spread to distant sites quite early during cancer progression and are soon eliminated before they become clinically detectable. However bulky metastases which appear at a later stage might derive from some of these early neoplastic cells. It seems that local CMM single cell micro-metastases commonly predict sentinel lymph node involvement without overtly reflecting CMM progression to bulky visceral metastases. This study is intended to review the current understanding of the mechanisms underlying two CMM presentations. The first is the long interval, apparently disease-free, with persistent CMM dormancy, which may precede overt metastatic growth. Immunosurveillance may induce dormancy in single CMM cells disseminated in the body by blocking their proliferation cycle. The second is the so-called CMM smoldering phenomenon, which is marked by an alternate progression and regression of CMM locally with metastases that wax and wane for long periods of time over restricted skin areas. These very diverse patterns of CMM progression are likely to be ascribable to a number of biological factors, including the activation of CMM stem cells, and the combined phenotypic heterogeneity and variability in proliferative amplification in CMM cell clusters. Furthermore an adequate stimulation of CMM immune-surveillance and the induction of a specific stromal structure and vascular response are required. In this context, most early CMM tumors are in part controlled by lymphocyte-mediated responses before they become clinically detectable. However both the role of immune-surveillance and the mechanisms underlying both persistent and smoldering CMM dormancy remain unclear.

Immunohistochemical sweat gland profiles.

BACKGROUND: Human sweat glands are heterogeneous in their structures and functions. Accordingly, eccrine, apocrine, and apoeccrine glands are distinguished. AIMS: Some immunohistochemical markers are expected to distinguish the sweat gland types in their secretory and excretory parts. METHODS: This study used two sets of antibodies. The first panel was composed of antibodies directed to well-defined sweat gland structures. The molecular targets included the low-molecular-weight cytokeratins CAM 5.2, the S100-B protein, the epithelial membrane antigen (EMA), the carcinoembryonic antigen (CEA), and the lectin Ulex europaeus agglutinin-1 (UEA-1). A second exploratory panel of antibodies targeted syndecan-1 (CD138), NKI-C3 (CD63), and CD68. They were used to disclose some undescribed antigen expressions in human sweat glands. RESULTS: The first set of antibodies confirmed previous findings. The immunoreactivities of the three sweat gland types were similar in the excretory ducts. By contrast, they were distinguished in the deeper coiled secretory portions of the glands. CONCLUSION: Clues supporting their distinction and probably their functional activity were obtained by immunohistochemistry using the S100-B protein, CEA and CD63 antibodies. The immunoreactivity to the S100-B protein, CEA and CD63 possibly help identifying apoeccrine sweat glands or a peculiar functional activity of eccrine sweat glands.

Scrutinizing skinfield melanin patterns in young Caucasian women.

INTRODUCTION: When using adequate wavelength illumination and high resolution recordings, Caucasian skin color appears uneven. The patterns of faint mosaic melanoderma (FMM) are diverse and possibly related to the risk of skin cancer development. AREAS COVERED: The current peer-reviewed publications about objective methods quantifying FMM are revisited. The images from the Visioscan® and Visioface® Quick devices are computerized in order to record the ultraviolet light-enhanced visualization (ULEV) and the color-enhanced visualization (CEV) of the skin. Previously published data regarding the FMM are gathered in 20 odd Caucasian women. Seven FMM patterns are distinguished. They appear expressed differently according to body regions, but the mean gray level appears more uniform. EXPERT OPINION: The combination of larger subclinical melanotic macules and ivory spots during early adulthood is apparently associated with an increased risk for non-melanoma skin cancers.

Immunohistochemical patterns in the interfollicular Caucasian scalps: influences of age, gender, and alopecia.

Skin ageing and gender influences on the scalp have been seldom studied. We revisited the changes in the interfollicular scalp. The study was performed on a population of 650 volunteers (300 women and 350 men) for over 7 years. Three age groups were selected in both genders, namely, subjects aged 20-35, 50-60, and 60-70 years. The hair status was further considered according to nonalopecic and alopecic patterns and severity (discrete, moderate, and severe). Biopsies from the parietal area were processed for immunohistochemistry. Stromal cells were distinguished according to the presence of vimentin, Factor XIIIa, CD117, and versican. Blood and lymphatic vessels were highlighted by Ulex europaeus agglutinin-1 and human podoplanin immunoreactivities, respectively. Actinic elastosis was identified by the lysozyme coating of elastic fibres. The epidermis was explored using the CD44 variant 3 and Ki67 immunolabellings. Biplot analyses were performed. Immunohistochemistry revealed a prominent gender effect in young adults. Both Factor XIIIa+ dermal dendrocytes and the microvasculature size decreased with scalp ageing. Alopecia changes mimicked stress-induced premature senescence.

Revisiting the cutaneous impact of oral hormone replacement therapy.

Menopause is a key point moment in the specific aging process of women. It represents a universal evolution in life. Its initiation is defined by a 12-month amenorrhea following the ultimate menstrual period. It encompasses a series of different biologic and physiologic characteristics. This period of life appears to spot a decline in a series of skin functional performances initiating tissue atrophy, withering, and slackness. Any part of the skin is possibly altered, including the epidermis, dermis, hypodermis, and hair follicles. Hormone replacement therapy (oral and nonoral) and transdermal estrogen therapy represent possible specific managements for women engaged in the climacteric phase. All the current reports indicate that chronologic aging, climacteric estrogen deficiency, and adequate hormone therapy exert profound effects on various parts of the skin.

Chronicle of a pigmented superficial Basal cell carcinoma.

Dermoscopic patterns of basal cell carcinoma (BCC) are well defined, but the dynamics of dermoscopic changes in time were apparently never described so far. In this paper, prominent changes were observed over a 8-week period, allowing to establish a close connection between spoke wheel areas and maple leaf-like aspects, through progressive thickening of the former ones. A chronobiological phenomenon ruling synchronous apoptosis in some of the most superficial BCC nests is suggested, leading to a wax and wane process of millimetric crusts, taking part in the spontaneous BCC regression/progression process.

HOX Gene Aberrant Expression in Skin Melanoma: A Review.

The homeobox family and its subset of HOX gene products represent a family of transcription factors directing DNA-protein and protein-protein interactions. In the embryo, they are central regulators in cell differentiation during morphogenesis. A series of genes of the four HOX gene clusters A, B, C, and D were reported to show aberrant expressions in oncogenesis, particularly in cutaneous malignant melanoma (CMM). They are involved in cell proliferation and progression in the CMM metastatic path. We present relevant peer-reviewed literature findings about the aberrant expression of HOX genes in CMM. The number of CMM cell nuclei exhibiting aberrant HOX protein expression appears correlated with tumour progression.

Malignant melanoma and its stromal nonimmune microecosystem.

In recent years, rapid advances were reached in the understanding of a series of biologic signals influencing cutaneous malignant melanoma (CMM) cells. CMM is in close contact with a peculiar dermal extracellular matrix (ECM). Stromal cells store and release various structural ECM components. The impact on CMM growth and progression is mediated through strong and long-lasting effects of ECM products. This paper summarizes some peculiar aspects of the peri-CMM stroma showing intracytoplasmic loads in Factor XIIIa, CD34, versican, and α (IV) collagen chains. The restricted peri-CMM skin territory exhibiting such changes corresponds to the area showing neoangiogenesis and extravascular unicellular metastatic spread. The latter inconspicuous migratory CMM cells possibly correspond to CMM stem cells or to CMM cells with aberrant HOX gene expression. Their presence is associated with an increased risk for metastases in the regional sentinel lymph nodes. In conclusion, the CMM-stroma connection appears crucial to the growth regulation, invasiveness and initial metastatic spread of CMM cells. Although much remains to be learned in this field, the active intervention of the peri-CMM stroma is likely involved in the inconspicuous early metastatic migration of CMM cells.

Autoimmunity-related granulomatous dermatitis in association with hepatitis.

AIM: Both interstitial granulomatous dermatitis (IGD) and palisaded neutrophilic granulomatous dermatitis (PNGD) are rare disorders typically associated with systemic autoimmune conditions. They probably represent different aspects of a disease spectrum encompassing the concept of autoimmunity-related granulomatous dermatitis (ARGD). CASE REPORT: A 61-year-old woman presented with ARGD and autoimmune hepatitis. The clinical presentation suggested PNGD, while histopathology was consistent with IGD. DISCUSSION: The association of ARGD with autoimmune hepatitis is apparently a rare event. The present case shows that the clinicopathological correlation in ARGD does not always clearly fit with the classical presentations of IGD or PNGD.

The skin ivory spot. A possible indicator for skinfield photo-carcinogenesis in recreational sunbed addicts.

INTRODUCTION: For a decade or so, artificial sources of restricted light wavelengths, particularly sunbeds, have progressively gained popularity among adolescents and young adults. Warnings were raised focusing on the risk of accelerated photoaging and photocarcinogenesis. The ULEV (ultraviolet light-enhanced visualization) method is a convenient noninvasive way identifying subtle pigmentary changes presenting as a mottled subclinical melanoderma (MSM). Of note, rare spotty amelanotic macules presenting as skin ivory spots (SIS) was reported on any part of the body. SUBJECTS AND METHOD: This work is the first attempt at evaluating the changes in the MSM and SIS spots developed on the skin of 33 phototype III young women designated as avid users involved in frequent exposures to sunshine and sunbeds for lifestyle purposes for a duration of at least 120 months. RESULTS: MSM was markedly heterogeneous and was distinctly obvious in the majority of adepts of frequent natural and artificial photoexposures. SIS was particularly developed in subjects presenting with severe MSM patterns. DISCUSSION: MSM and SIS are more severe in subjects frequently exposed to sunbeds and sun exposures. These signs possibly represent a risk marker for field photocarcinogenesis.

Smouldering malignant melanoma and metastatic dormancy: an update and review.

The fund of knowledge regarding the versatility of presentation of MM metastases is still quite incomplete. The recent literature pertaining to the current understanding of the mechanisms underlying two special features of MM metastasis is reviewed. On the one hand, a long disease-free interval (MM dormancy) may occur before the surge of overt metastases. On the other hand, the so-called MM smouldering phenomenon refers to the condition where regional metastases wax and wane for long periods of time on restricted skin regions. It is important to emphasize that local micrometastases often predict sentinel lymph node involvement but may not reflect progression of the primary MM to full-blown visceral metastatic competence. It is likely that a combination of factors impacts the versatile MM metastasic progression. Among the main factors, one has to mention the phenotypic heterogeneity and variability in the phenotype of MM cells, the presence of MM stem cells and MM cells engaged in an amplification proliferation pool, as well as the host immune response, and possibly the induction of a particular stromal structure and vascularity.

Molecular dermatopathology in malignant melanoma.

At present, immunohistochemistry is taken for granted in the establishment of malignant melanoma (MM) diagnosis. In recent years, molecular diagnosis in dermatopathology has benefited from a vast array of advances in the fields of genomics and proteomics. Sensitive techniques are available for detecting specific DNA and RNA sequences by molecular hybridization. This paper intends to update methods of molecular cytogenetics available as diagnostic adjuncts in the field of MM. Cytogenetics has highlighted the pathogenesis of atypical melanocytic neoplasms with emphasis on the activation of the mitogen-activated protein kinase (MAPK) signalling pathway during the initiation step of the neoplasms. 20 to 40% of MM families have mutations in the tumour suppressor gene p16 or CDKN2A. In addition, somatic mutations in p16, p53, BRAF, and cKIT are present in MM. Genome-wide scan analyses on MM indicate positive associations for genes involved in melanocytic naevi, but MM is likely caused by a variety of common low-penetrance genes. Molecular dermatopathology is expanding, and its use in the assessment of melanocytic neoplasms appears to be promising in the fields of research and diagnosis. Molecular dermatopathology will probably make its way to an increased number of diagnostic laboratories. The expected benefit should improve the patient management. This evolution points to a need for evolution in the training requirements and role of dermatopathologists.

Toxic epidermal necrolysis and antifolate drugs in cancer chemotherapy.

Folates are one-carbon donors essential for synthesizing purines, pyrimidines, serine, and methionine. They correspond to anionic hydrophilic molecules essential for DNA synthesis in mammalian cells. The latter cells lack the capacity to synthesize folates. In some patients, high dosages of antifolate drugs (eg: methotrexate, pemetrexed) used in cancer chemotherapy alter the keratinocytes, endothelial cells and Factor XIIIa+ dermal dendrocytes in a range of various severities. Such conditions clinically designed under the heading antifolate cytotoxic skin reaction (ACSR) occasionally resemble the toxic epidermal necrolysis (TEN) / Stevens-Johnson syndrome (SJS) spectrum. Whether or not the TEN/SJS presentation of ACSR is a regular condition similar to that induced by other drugs or a variant condition supported by a unique pathomechanism is unsettled.

Bioimpact of EGFR antagonists on the pilosebaceous follicles.

Cancer patients under targeted chemotherapy to the epidermal growth factor receptor (EGFR) frequently suffer from unusual skin adverse events. In the past, these changes were globally qualified as a rash. Our aim was to assess objectively by non invasive bioinstrumentation some early structural and functional skin changes associated with EGFR inhibitor treatment. A series of 27 cancer patients aged 58-66 years were assessed using two ultraviolet light emitting CCD cameras, Visioscan(®) and Visiopor(®). Assessments were performed on the foreheads at inclusion and therefore at weekly intervals for 2 months at most. No topical treatment was applied during the assessment period. The Visioscan(®) camera revealed specular light reflectance at the site of follicular plugging. The interfollicular stratum corneum showed occasional focal hyperkeratosis. These features increased in severity with the EGFR inhibitor treatment, indicating follicular involvement as an early adverse event of the therapy. The follicular fluorescence revealed by the Visiopor(®) camera remained unchanged over the treatment period. The present findings suggest an EGFR inhibitor-induced kerosis (follicular hyperkeratosis) possibly responsible for acneiform reactions.