Histopathologic correlation of high-risk MelaFindTM lesions: a 3-year experience from a high-risk pigmented lesion clinic.

BACKGROUND: A significant number of pigmented lesions are biopsied to rule out melanoma, but most will be benign. MelaFindTM is a highly sensitive, noninvasive computer-assisted system to aid in clinical diagnosis of melanoma. METHODS: A total of 140 high-risk patients were followed by one expert dermatologist. Biopsies were blindly and independently evaluated by two dermatopathologists and given histologic severity scores (HSS, 0-12) based on the histologic features of melanoma/dysplastic nevi and compared to pathologic diagnoses and MelaFindTM scores. RESULTS: MelaFindTM reduced the biopsy number of clinically ambiguous lesions (923 scanned to 253 biopsied, 73% reduction). Biopsied cases were usually benign (135/253, 53.4%, HSS = 2.8-3.2). Dysplastic nevi with varying degrees of atypia were observed next most commonly (80/253, 31.6%, HSS = 4.7-5.2 for mild dysplasia and 7-7.6 for moderate to severe dysplasia). Melanomas comprised 11/253 (4.3%) of biopsies (HSS = 9.3-10.7). Twenty-four cases were given miscellaneous diagnoses not within the dysplastic nevus-melanoma spectrum (9.5%, HSS = 1.3). Dermal fibrosis was the most commonly identified worrisome histologic feature (177/253, 70%), closely followed by other known atypical features. Nonthreatening histologic features in benign lesions with high MelaFindTM disorganization scores were common. The HSS differed significantly depending on pathologic diagnosis severity, while the MelaFindTM score did not (benign = 2.2; mildly atypical = 4.8; moderately to severely atypical = 2.3; in-situ or invasive melanoma = 3.1). CONCLUSIONS: MelaFindTM unequivocally reduced the number of biopsies, but banal lesions had histologic attributes resulting in high-risk MelaFindTM scores, and MelaFindTM does not correlate with degree of cytologic atypia. Knowledge of these limitations should increase bidirectional confidence when making clinicopathologic correlations in high-risk patients.

Mixed Versus Pure Variants of Desmoplastic Melanoma: The Cleveland Clinic Experience.

BACKGROUND: Desmoplastic melanoma (DM) is a subvariant of spindle cell melanoma, accounting for less than 4% of all cutaneous melanomas. It occurs later in life and is associated with chronic sun exposure. Desmoplastic melanoma prognosis is considered more favorable than other variants, with lower rates of metastasis and higher survival. Recently, DM has been further subclassified into pure and mixed, calling into question surgical management and patient outcomes as well as viability of current nationwide databases without this distinction. METHODS: We identified all patients with a histopathologic diagnosis of DM from the Cleveland Clinic electronic melanoma database (n = 58) from 1997 to 2013. Clinical and histopathologic data were collected. Comparison in clinical variables was performed between patients who had pure (n = 15) and mixed (n = 43) variants of DM. RESULTS: There were no differences in age, sex, location of lesion, Breslow depth, ulceration, or regression. Patients with mixed DM were more likely to have lymphovascular invasion (P = 0.03) compared with pure DM. There was no difference in performance of sentinel lymph node biopsy (P = 0.25) or sentinel lymph node positivity (P = 0.31) between the 2 groups. Recurrence was present in 13.3% of pure and 30.2% of mixed patients. Overall, Kaplan-Meier 3-year survival was 75% for pure and 80% for mixed DM (P = 0.53). CONCLUSIONS: Pure and mixed DMs seem to have similar clinical characteristics and outcomes. This indicates that analysis of national datasets without this subclassification remains viable.

Comparison between melanoma gene expression score and fluorescence in situ hybridization for the classification of melanocytic lesions.

Melanoma accounts for most skin cancer-related deaths and has an increasing incidence. Accurate diagnosis and distinction from atypical nevi can be at times difficult using light microscopy alone. Fluorescence in situ hybridization (FISH) and melanoma gene expression score (myPath, Myriad Genetics) have emerged as ancillary tools to further aid in this differential diagnosis. Our aim in this study was to correlate FISH results, gene expression score, consensus histopathologic impression and clinical outcome on a series of 117 challenging melanocytic lesions collected from three separate institutions. The lesions were separated into two groups: 39 histopathologically unequivocal lesions (15 malignant, 24 benign) and 78 challenging lesions interpreted by expert consensus (27 favor malignant, 30 favor benign, and 21 ambiguous). Melanoma-FISH was performed using probes for 6p25, 11q13, 8q24, and 9p21/CEP9 and scored according to established criteria. Analysis by myPath gene expression score was performed and interpreted by the manufacturer as 'benign', 'indeterminate,' or 'malignant'. In the unequivocal group, melanoma-FISH and myPath score showed 97 and 83% agreement with the histopathologic diagnosis, respectively, with 93 and 62% sensitivity, 100 and 95% specificity, and 80% inter-test agreement. In the challenging group, FISH and the myPath score showed 70 and 64% agreement with the histopathologic interpretation, respectively, with 70% inter-test agreement and similar sensitivities and specificities. The inter-test agreement was 73% overall, excluding indeterminate results. Discordant test results occurred in 27/117 cases from both unequivocal and challenging groups. Melanoma-FISH and gene expression score are valuable ancillary tools, though both have limitations and return discordant results in a subset of cases. Follow-up studies with more extensive clinical outcome data are warranted to establish the accuracy of these tests for the classification of melanocytic lesions.

The Genetic Evolution of Melanoma from Precursor Lesions.

BACKGROUND: The pathogenic mutations in melanoma have been largely catalogued; however, the order of their occurrence is not known. METHODS: We sequenced 293 cancer-relevant genes in 150 areas of 37 primary melanomas and their adjacent precursor lesions. The histopathological spectrum of these areas included unequivocally benign lesions, intermediate lesions, and intraepidermal or invasive melanomas. RESULTS: Precursor lesions were initiated by mutations of genes that are known to activate the mitogen-activated protein kinase pathway. Unequivocally benign lesions harbored BRAF V600E mutations exclusively, whereas those categorized as intermediate were enriched for NRAS mutations and additional driver mutations. A total of 77% of areas of intermediate lesions and melanomas in situ harbored TERT promoter mutations, a finding that indicates that these mutations are selected at an unexpectedly early stage of the neoplastic progression. Biallelic inactivation of CDKN2A emerged exclusively in invasive melanomas. PTEN and TP53 mutations were found only in advanced primary melanomas. The point-mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of the effects of ultraviolet radiation detectable at all evolutionary stages. Copy-number alterations became prevalent only in invasive melanomas. Tumor heterogeneity became apparent in the form of genetically distinct subpopulations as melanomas progressed. CONCLUSIONS: Our study defined the succession of genetic alterations during melanoma progression, showing distinct evolutionary trajectories for different melanoma subtypes. It identified an intermediate category of melanocytic neoplasia, characterized by the presence of more than one pathogenic genetic alteration and distinctive histopathological features. Finally, our study implicated ultraviolet radiation as a major factor in both the initiation and progression of melanoma. (Funded by the National Institutes of Health and others.).

Accuracy in melanoma detection: a 10-year multicenter survey.

BACKGROUND: Early excision is the only strategy to reduce melanoma mortality, but unnecessary excision of benign lesions increases morbidity and healthcare costs. OBJECTIVE: To assess accuracy in melanoma detection based on number-needed-to-excise (NNE) values over a 10-year period. METHODS: Information was retrieved on all histopathologically confirmed cutaneous melanomas or melanocytic nevi that were excised between 1998 and 2007 at participating clinics. NNE values were calculated by dividing the total number of excised lesions by the number of melanomas. Analyses included changes in NNE over time, differences in NNE between specialized clinical settings (SCS) versus non-specialized clinical settings (NSCS), and patient factors influencing NNE. RESULTS: The participating clinics contributed a total of 300,215 cases, including 17,172 melanomas and 283,043 melanocytic nevi. The overall NNE values achieved in SCS and NSCS in the 10-year period were 8.7 and 29.4, respectively. The NNE improved over time in SCS (from 12.8 to 6.8), but appeared unchanged in NSCS. Most of the effect on NNE in SCS was due to a greater number of excised melanomas. Higher NNE values were observed in patients younger than 40 years and for lesions located on the trunk. LIMITATIONS: No data concerning the use of dermatoscopy and digital monitoring procedures were collected from the participating centers. CONCLUSION: Over the 10-year study period, accuracy in melanoma detection improved only in specialized clinics maybe because of a larger use of new diagnostic techniques such as dermatoscopy.

Langerhans cells and melanocytes share similar morphologic features under in vivo reflectance confocal microscopy: a challenge for melanoma diagnosis.

BACKGROUND: Intraepidermal Langerhans cells (ILC) are difficult to differentiate from melanocytes under reflectance confocal microscopy (RCM) and their presence may simulate pagetoid spread of melanocytes on RCM images. OBJECTIVE: We sought to correlate bright round and dendritic cells in a pagetoid pattern identified on RCM with findings of conventional histopathology and immunohistochemistry for lesions that were falsely diagnosed as melanoma by RCM. METHODS: This retrospective study included histopathologically proven nevi, imaged by RCM, which displayed bright cells in a pagetoid pattern (BCPP) under RCM, resulting in the incorrect RCM diagnosis of melanoma. Morphological comparisons were made between RCM images of nevi showing BCPP, histopathologically proven melanomas displaying BCPP, and biopsy-proven nevi without BCPP. RESULTS: We identified 24 nevi that were falsely diagnosed as melanoma by RCM because of the presence of BCPP. These pagetoid cells on RCM corresponded on histopathology to ILC with a high density in 23 of the 24 nevi (95%) and to melanocytes in 7 of the 24 nevi (29%). Among 6 melanomas displaying BCPP on RCM, ILC with high density were observed histopathologically in 5 of the 6 cases (83%) and pagetoid melanocytes were seen in all 6 cases (100%). LIMITATIONS: The results cannot be generalized to clinically banal-appearing nevi. CONCLUSIONS: Although the finding of BCPP is a useful RCM feature for the diagnosis of melanoma, it does not always imply the presence of pagetoid melanocytes but may at times represent ILC.

The impact of physician screening on melanoma detection.

OBJECTIVE: To compare melanoma characteristics and detection patterns in new vs established patients in a pigmented lesion clinic at Memorial Sloan-Kettering Cancer Center (MSKCC) during a 10-year period. DESIGN: Single-center historical cohort study. SETTING: Academic practice of 2 dermatologists with expertise in the management of pigmented skin lesions. PATIENTS: The study included 394 patients diagnosed with cutaneous melanoma at MSKCC between 1998 and 2008. For the purposes of this study, we separated patients into 2 groups: established patients, defined as patients who have received professional services in a pigmented lesion clinic at MSKCC for at least 3 months, vs new patients, defined as patients new to our practice. MAIN OUTCOME MEASURES: Melanoma histologic characteristics and patterns of melanoma detection in established vs new patients. RESULTS: Established patients had more in situ disease (70% vs 57%; P < .001) and thinner invasive melanomas (0.45 mm vs 0.82 mm; P = .002) and were less likely to present with negative prognostic attributes such as ulceration and dermal mitoses compared with new patients. In new patients, 63% of melanomas were physician detected vs 82% in established patients; 18% of all melanomas were patient detected. Dermatologist-detected melanomas were thinner compared with self-detected melanomas. The majority of self-detected melanomas were noted by patients because of change (64%). The overall benign to malignant biopsy ratio over the 10-year period was 5.4:1. CONCLUSION: Physician-based screening leads to higher rates of physician-detected melanoma and detection of thinner melanoma.

Skin cancer prevention educational resources: just a click away?

BACKGROUND: The general public and health professionals are increasingly choosing the Internet to access skin cancer prevention information. OBJECTIVES: To identify the optimal mechanism for finding skin cancer educational resources through the Internet and to characterize the resources currently available on-line. METHODS: A survey of experts involved in skin cancer prevention, followed by standardized searches through popular general Internet search engines using a list of 10 terms relevant to skin cancer prevention resources. RESULTS: Internet search was the preferred modality for identifying skin cancer educational resources of all survey participants. The five most-trusted Internet sites identified by the survey participants ranked within the top 10 most findable web sites using general search engines. Ninety-six of 1,000 web pages retrieved using general web-search engines provided information regarding specific skin cancer prevention resources. Seven databases were identified that catalogued educational resources from multiple sources. Peer-reviewed analysis of the outcomes associated with the educational resources was available for only four of 489 resources identified (2.7%). CONCLUSIONS: Information on skin cancer educational resources available on the Internet is abundant but redundant, and direct access to these resources remains difficult. No sites were identified that comprehensively catalogued and characterized the resources available from the leading providers.

Sigma 1 receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding.

sigma Ligands modulate opioid actions in vivo, with agonists diminishing morphine analgesia and antagonists enhancing the response. Using human BE(2)-C neuroblastoma cells that natively express opioid receptors and human embryonic kidney (HEK) cells transfected with a cloned mu opioid receptor, we now demonstrate a similar modulation of opioid function, as assessed by guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTP gamma S) binding, by sigma(1) receptors. sigma Ligands do not compete opioid receptor binding. Administered alone, neither sigma agonists nor antagonists significantly stimulated [(35)S]GTP gamma S binding. Yet sigma receptor selective antagonists, but not agonists, shifted the EC(50) of opioid-induced stimulation of [(35)S]GTP gamma S binding by 3- to 10-fold to the left. This enhanced potency was seen without a change in the efficacy of the opioid, as assessed by the maximal stimulation of [(35)S]GTP gamma S binding. sigma(1) Receptors physically associate with mu opioid receptors, as shown by coimmunoprecipitation studies in transfected HEK cells, implying a direct interaction between the proteins. Thus, sigma receptors modulate opioid transduction without influencing opioid receptor binding. RNA interference knockdown of sigma(1) in BE(2)-C cells also potentiated mu opioid-induced stimulation of [(35)S]GTP gamma S binding. These modulatory actions are not limited to mu and delta opioid receptors. In mouse brain membrane preparations, sigma(1)-selective antagonists also potentiated both opioid receptor and muscarinic acetylcholine receptor-mediated stimulation of [(35)S]GTP gamma S binding, suggesting a broader role for sigma receptors in modulating G-protein-coupled receptor signaling.

Congenital melanocytic naevi.

Congenital melanocytic naevi, consisting of clusters of naevo-melanocytes, develop in utero. Although many congenital naevi are visible at birth, some may not become evident until later in life. The timing of naevo-melanocyte proliferation, senescence and melanogenesis may all contribute towards determining when a naevus will become clinically manifest on the skin. Besides the fact that congenital melanocytic naevi may be aesthetically displeasing, resulting in a multitude of psychosocial issues, they also increase the risk for developing cutaneous melanoma, leptomeningeal melanoma, neurocutaneous melanocytosis, malformations of the brain and, rarely, other tumours such as rhabdomyosarcoma and liposarcoma. Whereas the risk of developing malignancy in association with congenital naevi is dependent, to some extent, on the size of the naevus, the risk of developing neurocutaneous melanocytosis correlates best with the number of satellite naevi. Management of patients with congenital melanocytic naevi requires individualization, taking into account the naevus size and location, and the risk of developing cutaneous melanoma or neurocutaneous melanocytosis. When contemplating treatment options, it is important to set realistic expectations and to address the possible aesthetic and functional outcomes, while at the same time addressing the risk for developing cutaneous and/or extracutaneous melanoma.

Selective potentiation of opioid analgesia by nonsteroidal anti-inflammatory drugs.

Opioids are often used in conjunction with nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of moderate to severe pain. In this study we have examined interactions between these two classes of drugs. NSAIDs are inactive in the radiant heat tail-flick test, an assay of moderate to severe pain in which opioids are effective. In this assay, ibuprofen potentiated the analgesic actions of hydrocodone and oxycodone, shifting their ED(50) values by 2.5-fold and 4.6-fold despite its inactivity when given alone. These opioid/NSAID interactions were dependent upon both the opioid and the NSAID. Neither aspirin nor ketorolac influenced hydrocodone actions in this model and ibuprofen did not potentiate fentanyl or morphine analgesia. Together, these studies demonstrate potent interactions between selected combinations of opioids and NSAIDS and may help explain the clinical utility of combinations. However, the findings also illustrate differences between the drugs within each class.