Alon Scope

Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents

Background: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. Methods: These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. Results: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk. Conclusions: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

Randomized Double-Blind Trial of Prophylactic Oral Minocycline and Topical Tazarotene for Cetuximab-Associated Acne-Like Eruption

PURPOSE To evaluate the ability of either oral minocycline, topical tazarotene or both, to reduce or prevent cetuximab-related acneiform rash when administered starting on day 1 of cetuximab therapy. PATIENTS AND METHODS Metastatic colorectal cancer patients preparing to initiate cetuximab were randomly assigned to receive daily oral minocycline or placebo, and to receive topical tazarotene application to either left or right side of the face. Both therapies were administered for 8 weeks. RESULTS Forty-eight eligible patients were randomly assigned to minocycline (n = 24) or placebo (n = 24). Total facial lesion counts were significantly lower in patients receiving minocycline at weeks 1 through 4. At week 4, a lower proportion of patients in the minocycline arm reported moderate to severe itch than in the placebo arm (20% v 50%, P = .05). Facial photographs, obtained at week 4, were reviewed for rash global severity. Patients in the minocycline arm trended toward lower frequency of moderate to severe rash than patients receiving placebo (20% v 42%, P = .13). The differences in total facial lesion counts and subjectively assessed itch were diminished by week 8. Cetuximab treatment was interrupted because of grade 3 skin rash in four patients in the placebo arm, and none in the minocycline arm. There was no observed clinical benefit to tazarotene application. Tazarotene treatment was associated with significant irritation, causing its discontinuation in one third of patients. CONCLUSION Prophylaxis with oral minocycline may be useful in decreasing the severity of the acneiform rash during the first month of cetuximab treatment. Topical tazarotene is not recommended for management of cetuximab-related rash.

Reflectance Confocal Microscopy Criteria for Squamous Cell Carcinomas and Actinic Keratoses

OBJECTIVE To identify criteria for the diagnosis of squamous cell carcinoma (SCC) and actinic keratosis (AK) by in vivo reflectance confocal microscopy (RCM). DESIGN Prospective RCM imaging of lesions suspected clinically and/or dermoscopically to be SCC or AK, followed by RCM assessment of the biopsy-proven SCCs and AKs. SETTING Private skin cancer clinic, Plantation, Florida. Patients A total of 38 lesions in 24 patients were assessed, including 7 AKs, 25 SCCs in situ, 3 invasive SCCs, and 3 keratoacanthomas. Interventions Prior to undergoing biopsy, all lesions were assessed by RCM. RESULTS Mosaic RCM images at the stratum corneum level revealed scale in 29 SCCs (95%) and in all 7 AKs. Polygonal nucleated cells at the stratum corneum were seen in 3 SCCs (10%) and 1 AK (14%). All 38 cases displayed an atypical honeycomb and/or a disarranged pattern of the spinous-granular layer of the epidermis; round nucleated cells were seen in the spinous-granular layer in 20 SCCs (65%) and 1 AK (14%). Round blood vessels in the superficial dermis were seen in 28 SCCs (90%) and 5 AKs (72%). CONCLUSIONS An increasing frequency of abnormal RCM features can be observed across the spectrum of keratinocytic neoplasias. The presence of an atypical honeycomb or a disarranged pattern of the spinous-granular layer, round nucleated cells at the spinous-granular layer, and round blood vessels traversing through the dermal papilla are the key RCM features of SCC.

Observation of Chrysalis Structures With Polarized Dermoscopy

C OLLAGEN BUNDLES HAVE BIREFRINGENT properties that cause a rapid randomization of polarized light, explaining why collagen is more conspicuous under polarized dermoscopy. Skin lesions with an increased amount of collagen will often reveal shiny, bright white, orthogonal linear streaks, which we have termed “chrysalis structures.” These structures are not apparent to the unaided eye nor are they visible with nonpolarized dermoscopy. The most obvious examples of lesions that display chrysalis structures are dermatofibromas (Figure 1) and scars. In basal cell carcinoma, chrysalis structures are often observed, probably owing to the associated fibroplasia (Figure 2). In addition,

New recommendations for the categorization of cutaneous features of congenital melanocytic nevi

BACKGROUND The diameter of congenital melanocytic nevi (CMN) has served as the lone criterion for determining risks of adverse outcomes such as melanoma. A standardized description of additional morphologic features is needed. OBJECTIVE We sought to develop a consensus-based standardized categorization of cutaneous features of CMN and to test agreement among experts on the proposed scheme. METHODS An interdisciplinary group of experts in the field of CMN was surveyed using a detailed questionnaire. Applicability of the expert consensus-based scheme was tested for interobserver agreement. RESULTS The principal variable of the consensus-based categorization is CMN size, based on maximal diameter the CMN is projected to attain by adulthood. CMN size categories include: small (<1.5 cm); medium (M1: 1.5-10 cm, M2: >10-20 cm); large (L1: >20-30 cm, L2: >30-40 cm); and giant (G1: >40-60 cm, G2: >60 cm). In addition, number of satellite nevi in the first year of life is categorized into none, 1 to 20, more than 20 to 50, and more than 50 satellites. Additional descriptors of CMN include anatomic localization, color heterogeneity, surface rugousity and presence of hypertrichosis (described as none, moderate, marked), and presence of dermal or subcutaneous nodules (none, scattered, extensive). Assessment of consistency among 3 experts showed moderate to excellent interobserver agreement for categorization of the clinical descriptors (kappa values 0.54-0.93). LIMITATIONS Applicability of the proposed scheme was tested in a virtual setting and only among experts. CONCLUSION The proposed categorization scheme for CMN was agreed upon by experts and showed good interobserver agreement. Such standardized reporting of patients with CMN facilitates the development of an international clinical database for the study of large and giant CMN.

Preliminary evaluation of in vivo reflectance confocal microscopy features of discoid lupus erythematosus

Background  Discoid lupus erythematosus (DLE) can simulate other inflammatory diseases both clinically and histologically. In vivo reflectance confocal microscopy (RCM) is a noninvasive, reproducible imaging technique already reported to be useful in the evaluation of several inflammatory skin conditions such as contact dermatitis, psoriasis and Darier disease.

New insights into nevogenesis: In vivo characterization and follow-up of melanocytic nevi by reflectance confocal microscopy

BACKGROUND Development of melanocytic nevi is a complex process. OBJECTIVE The aim of the study was to characterize the in vivo confocal microscopy patterns and histopathologic correlates of melanocytic nevi. In addition, for the first time, confocal follow-up of characteristic nevi was performed documenting histologic changes in nevi. METHODS For the correlation study, 33 melanocytic nevi showing characteristic dermatoscopic patterns were studied by confocal microscopy. For the follow-up study 20 nevi were monitored for 12 to 18 months. RESULTS Reticular nevi showed two different confocal patterns, ringed and meshwork, mostly corresponding to lentiginous and nested junctional patterns, respectively. Globular nevi presented large junctional clusters, whereas cobblestone nevi were constituted by dermal dense melanocytic clusters. Homogeneous nevi did not show distinctive confocal and histopathologic findings. Nevi with a rim of globules presented a meshwork pattern with junctional clusters at the periphery. At the confocal follow-up study all lesions showed limited dynamic changes resulting in stable dermatoscopic and confocal patterns, but 3 globular nevi with junctional nests at baseline evolved into reticular-meshwork pattern nevi with peripheral rim of globules-junctional nests. LIMITATIONS Longer confocal follow-up of more melanocytic nevi is required to confirm this theory and to validate our preliminary findings. CONCLUSIONS A model explaining the nevus classification and patterns of evolution of nevi observed in the study was proposed.

Frequency of Dermoscopic Nevus Subtypes by Age and Body Site: A Cross-sectional Study

OBJECTIVE To subclassify acquired nevi by dermoscopic pattern. DESIGN Cross-sectional study with consecutive enrollment. SETTING Pigmented lesion clinics in referral academic medical centers. PARTICIPANTS Individuals older than 2 years undergoing total skin examination were consecutively recruited between October 1, 2008, and May 31, 2009, and, based on their age, assigned to 1 of 8 groups. For each patient, the location and dermoscopic pattern of all nevi on the torso were recorded. Nevi were dermoscopically subclassified as globular, reticular, mixed (reticular-globular) pattern with peripheral or central globules, or unspecified pattern. MAIN OUTCOME MEASURE Frequency of dermoscopic nevus subtypes stratified by patient age and location of the nevi. RESULTS A total of 5481 nevi in 480 individuals were evaluated. The number of all nevus subgroups, except for unspecified pattern nevi, significantly increased before and decreased after the fourth decade of life. Globular nevi were most prevalent on the upper trunk in children and adolescents; the number decreased consistently after the second decade of life. The reticular pattern was the most common nevus pattern after the second decade of life and the most common nevus subgroup on the upper and middle back. Although uncommon, central globular nevi also showed an age-dependent trend, similar to that of reticular nevi. Nevi with the peripheral globular pattern declined rapidly after the third decade of life and were no longer observed after the sixth decade. The number of unspecified pattern nevi was stable across all age groups. CONCLUSION Age, dermoscopic pattern, and location of nevi should be jointly considered when evaluating melanocytic lesions.

The significance of reflectance confocal microscopy in the assessment of solitary pink skin lesions

BACKGROUND Solitary pink lesions often manifest nondescript clinical and dermatoscopic primary morphologic features. The differential diagnosis for pink lesions tends, therefore, to be broad, ranging from inflammatory processes to malignancy. In vivo reflectance confocal microscopy (RCM) may help in the evaluation of pink lesions. OBJECTIVE We sought to demonstrate the use of RCM as an adjunct to the bedside diagnosis of pink lesions. METHODS We describe a series of patients with clinically and dermatoscopically equivocal pink lesions for which RCM examination allowed for a rapid and accurate diagnosis. All lesions were excised for histopathologic evaluation. Integrating the findings in the case series with a literature review, we present RCM diagnostic criteria for pink lesions. RESULTS Lesions included basal cell carcinoma, squamous cell carcinoma, amelanotic melanoma, and inflamed seborrheic keratosis. RCM shows distinctive findings for each diagnostic entity when stratified by anatomic level into suprabasal epidermis, dermoepidermal junction, and papillary dermis. In the cases presented RCM allowed for a rapid and accurate noninvasive diagnosis. LIMITATIONS The study is descriptive and does not test accuracy of RCM criteria in a prospective series of pink lesions. CONCLUSION RCM may add useful diagnostic features to the clinical evaluation of solitary pink lesions.

Reflectance confocal microscopy and features of melanocytic lesions: An internet-based study of the reproducibility of terminology

OBJECTIVE To test the interobserver and intraobserver reproducibility of the standard terminology for description and diagnosis of melanocytic lesions in in vivo confocal microscopy. DESIGN A dedicated Web platform was developed to train the participants and to allow independent distant evaluations of confocal images via the Internet. SETTING Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy. PARTICIPANTS The study population was composed of 15 melanomas, 30 nevi, and 5 Spitz/Reed nevi. Six expert centers were invited to participate at the study. Intervention Evaluation of 36 features in 345 confocal microscopic images from melanocytic lesions. MAIN OUTCOME MEASURE Interobserved and intraobserved agreement, by calculating the Cohen kappa statistics measure for each descriptor. RESULTS High overall levels of reproducibility were shown for most of the evaluated features. In both the training and test sets there was a parallel trend of decreasing kappa values as deeper anatomic skin levels were evaluated. All of the features, except 1, used for melanoma diagnosis, including roundish pagetoid cells, nonedged papillae, atypical cells in basal layer, cerebriform clusters, and nucleated cells infiltrating dermal papillae, showed high overall levels of reproducibility. However, less-than-ideal reproducibility was obtained for some descriptors, such as grainy appearance of the epidermis, junctional thickening, mild atypia in basal layer, plump bright cells, small bright cells, and reticulated fibers in the dermis. Conclusion The standard consensus confocal terminology useful for the evaluation of melanocytic lesions was reproducibly recognized by independent observers.