Avaliação morfológica dos glóbulos periféricos nos nevos melanocíticos e no melanoma através da dermatoscopia / Melanoma and melanocytic nevi with peripheral globules: Clinical and dermoscopic features

Introdução: A morfologia e biologia do nevo melanocítico (NM) com glóbulos periféricos (GP) é descrita como parte do processo natural de evolução do nevo melanocítico sendo caracterizada como fase de crescimento. Por outro lado, os melanomas cutâneos (MC) com glóbulos periféricos ainda permanecem indefinidos. Objetivos: avaliar e descrever as características dos melanomas com glóbulos periféricos à dermatoscopia e, com isso, criar um algoritmo de conduta para facilitar o manejo das lesões melanocíticas em crescimento. Como objetivo secundário, foi realizado análise prospectiva de lesões melanocíticas com glóbulos periféricos à dermatoscopia através da utilização do algoritmo proposto previamente buscando comprovar sua aplicabilidade clínica. Materiais e métodos: Fase 1, estudo retrospectivo, foram avaliadas lesões melanocíticas com GP de 2006 a 2020. As imagens dermatoscópicas destas lesões foram avaliadas por dermatoscopista experiente, através da análise estatística foi possível desenvolver um algoritmo de conduta. Fase 2, na amostra inicial foram incluídas lesões melanocíticas com GP entre 2020 e 2023. Com esta nova amostra, foi realizada a validação do algoritmo de conduta através da aplicação estatística de um modelo preditivo. Em um segundo momento, 04 observadores avaliaram as imagens dermatoscópicas através do algoritmo proposto sendo possível estimar seu desempenho. Resultados: Fase 1, das 401 lesões, 179 foram excisadas sendo 41 melanomas. Os melanomas foram mais comuns quando localizados nos membros inferiores (p<0,1) e se apresentavam com padrão dermatoscópico desorganizado. Enquanto os nevos melanocíticos foram mais comuns no tronco e com padrão organizado. Além disso, a presença de uma das seguintes estruturas: pontos e glóbulos atípicos, estruturas vasculares atípicas ou área de borrão apresentaram associação com melanoma. Fase 2, as 55 lesões coletadas foram excisadas e adicionadas ao banco de dados final (n= 456), a partir dos valores preditos deste banco de dados, foi possível estabelecer uma curva ROC cuja área sob a curva foi de 0,834 e acurácia de 71,21%. A análise dermatoscópica de quatro observadores demonstrou área sob a curva ROC de 0,627 a 0,765. Conclusão: Lesões melanocíticas com glóbulos periféricos apresentam maior risco para melanoma quando em indivíduos acima de 30 anos de idade, se localizadas nos membros inferior e com a presença de uma ou mais das seguintes estruturas: pontos e glóbulos atípicos e/ou estruturas vasculares atípicas e/ou área de borrão. Estas características encontradas foram validadas por modelo preditivo demonstrando um bom desempenho através da análise da curva ROC e índice de acurácia dentro do esperado

Introduction: The morphology and biology of melanocytic nevus (MN) with peripheral globules (PG) is described as part of the natural process of evolution of melanocytic nevus and is characterized as a growth phase. On the other hand, cutaneous melanomas (CM) with peripheral globules remain unclear. Objectives: To evaluate and describe in detail the characteristics of melanocytic lesions with peripheral globules at dermoscopy, therefore, create an algorithm of management of growing melanocytic lesions. As a secondary objective, a prospective analysis of melanocytic lesions with peripheral globules was carried out using the previously proposed algorithm, seeking to prove its clinical applicability. Materials and methods: Phase 1, retrospective study, melanocytic lesions with PG were evaluated from 2006 to 2020. The dermoscopic images of these lesions were evaluated by an experienced dermatoscopist, through statistical analysis it was possible to develop a management algorithm. Phase 2, melanocytic lesions with peripheral globules were included between 2020 and 2023. In this phase, a predictive model was fitted to the dataset to evaluate the algorithm accuracy and ROC curve. In a second moment, 04 observers evaluated the dermoscopic images using the proposed algorithm, making it possible to estimate its performance. Results: Phase 1, of the 401 lesions, 179 were excised, 41 of which were melanomas. Melanomas were more common when located on the lower limbs (p<0.1) and presented a disorganized dermoscopic pattern. While melanocytic nevi were more common on the trunk and with an organized pattern. In addition, the presence of one of the following structures: atypical dots and globules, atypical vessels or blotch was associated with melanoma. Phase 2, the 55 lesions collected were excised and added to the final database (n= 456), based on the predicted values from this database, it was possible to establish a ROC curve whose area under the curve was 0.834 and accuracy was 71 .21%. Dermoscopic analysis by four observers demonstrated an area under the ROC curve of 0.627 to 0.765. Conclusion: Melanocytic lesions with peripheral globules are the greatest risk of melanoma in individuals older than 30 years if located on the lower limbs and if lesions reveal one or more of the following structures: atypical dots and globules, atypical vessels, or blotch. These characteristics found were validated by a predictive model demonstrating an excellent performance index through ROC curve analysis and an accuracy index within expectations

Dynamic markers based on blood perfusion fluctuations for selecting skin melanocytic lesions for biopsy.

Skin malignant melanoma is a highly angiogenic cancer, necessitating early diagnosis for positive prognosis. The current diagnostic standard of biopsy and histological examination inevitably leads to many unnecessary invasive excisions. Here, we propose a non-invasive method of identification of melanoma based on blood flow dynamics. We consider a wide frequency range from 0.005-2 Hz associated with both local vascular regulation and effects of cardiac pulsation. Combining uniquely the power of oscillations associated with individual physiological processes we obtain a marker which distinguishes between melanoma and atypical nevi with sensitivity of 100% and specificity of 90.9%. The method reveals valuable functional information about the melanoma microenvironment. It also provides the means for simple, accurate, in vivo distinction between malignant melanoma and atypical nevi, and may lead to a substantial reduction in the number of biopsies currently undertaken.

Growth and hormone profiling in children with congenital melanocytic naevi.

BACKGROUND: Multiple congenital melanocytic naevi (CMN) is a rare mosaic RASopathy, caused by postzygotic activating mutations in NRAS. Growth and hormonal disturbances are described in germline RASopathies, but growth and hormone status have not previously been investigated in individuals with CMN. OBJECTIVES: To explore premature thelarche, undescended testes, and a clinically abnormal fat distribution with CMN through prospective endocrinological assessment of a cohort of subjects with CMN, and a retrospective review of longitudinal growth of a larger group of patients with CMN from outpatient clinics (which included all subjects in the endocrinological assessment group). PATIENTS AND METHODS: Longitudinal growth in a cohort of 202 patients with single or multiple CMN was compared with the U.K. National Child Measurement Programme 2010. Forty-seven children had hormonal profiling including measurement of circulating luteinizing hormone, follicle-stimulating hormone, thyroid stimulating hormone, adrenocorticotrophic hormone, growth hormone, prolactin, pro-opiomelanocortin, estradiol, testosterone, cortisol, thyroxine, insulin-like growth factor-1 and leptin; 10 had oral glucose tolerance testing 25 had dual-energy X-ray absorptiometry scans for body composition. RESULTS: Body mass index increased markedly with age (coefficient 0·119, SE 0·016 standard deviation scores per year), at twice the rate of the U.K. population, due to increased adiposity. Three per cent of girls had premature thelarche variant and 6% of boys had persistent undescended testes. Both fat and muscle mass were reduced in areas underlying large naevi, resulting in limb asymmetry and abnormal truncal fat distribution. Anterior pituitary hormone profiling revealed subtle and variable abnormalities. Oral glucose tolerance tests revealed moderate-severe insulin insensitivity in five of 10, and impaired glucose tolerance in one. CONCLUSIONS: Interpersonal variation may reflect the mosaic nature of this disease and patients should be considered individually. Postnatal weight gain is potentially related to the underlying genetic defect; however, environmental reasons cannot be excluded. Naevus-related reduction of fat and muscle mass suggests local hormonal or metabolic effects on development or growth of adjacent tissues, or mosaic involvement of these tissues at the genetic level. Premature thelarche and undescended testes should be looked for, and investigated, as for any child.

Mole modifications following controlled ovarian stimulation for assisted reproduction technologies.

BACKGROUND: The role of estrogens on moles biology remains undefined although estrogenic receptors have been found on melanocytes. It has been postulated that supraphysiological estrogen levels could promote the progression of moles to melanoma. Women undergoing controlled ovarian stimulation (COS) for assisted reproductive technologies (ART) are exposed to high levels of estrogens, produced by the ovary in response to exogenous gonadotropin administration. The aim of this study is to assess whether COS for ART may have an impact on mole structure and/or characteristics. METHODS: Women undergoing to ART for various infertility conditions were included in the study. Personal and clinical data were collected. Dermatoscopic features and scores (total dermoscopy score--TDS) were statistically compared before COS and after a 6-month follow-up period. Statistical correlation was performed between estradiol, FSH blood levels and relative variation in moles dimensions. RESULTS: A total of 46 patients were included in the study. One hundred and seventy-five melanocytic lesions from 31 patients were evaluated at both time points. Although statistically significant differences were found in mole dimension and TDS between the two time points, these differences had no relevance in the clinical setting not suggesting the need for mole excision. Moreover, the only statistically significant correlation with estradiol blood concentration on hCG administration day was found with one-axis dimensional variation. CONCLUSIONS: To our knowledge this is the first work to evaluate the effect of COS on moles. The obtained results do not support a causal relation between the supraphysiological hormone levels stimulation and worsening of clinical and dermoscopical features of moles. Further study is needed to clarify whether estrogens plays a role in melanoma.

Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.

Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.

Serum DJ-1/PARK 7 is a potential biomarker of choroidal nevi transformation.

PURPOSE: There is substantial evidence that intraocular melanomas arise from benign nevi in the uveal tract. Previous studies performed by the authors revealed that uveal melanoma cells secrete the oncoprotein DJ-1/PARK7 into the extracellular environment and circulation. The aim of this study was to determine whether circulating DJ-1 serum levels correlate with known clinical risk factors of nevi growth. METHODS: Standardized ultrasonography, optical coherence tomography, and eye fundus examinations were used to evaluate the clinical risk factors of nevi growth. These clinical risk factors (including nevi size, distance of margins to the optic disc, detection of acoustic hollowness, presence of ocular symptoms, orange pigment, subretinal fluid, and absence of drusen) were examined in 53 consecutive patients from January 2009 to February 2011. Serum levels of DJ-1/PARK7 in these patients and in healthy age- and sex-matched controls (n = 32) were analyzed using ELISA. RESULTS: Within the choroidal nevi group, DJ-1 serum levels were higher in those with symptoms (P < 0.033), with a nevus thickness greater than 1.5 mm (P < 0.001), a large basal diameter greater than 8 mm (P < 0.001), and the presence of acoustic hollowness (P < 0.001), compared to those patients without these risk factors. Similar significant differences were found when these at risk nevi subgroups were compared to healthy persons. CONCLUSIONS: Elevated serum levels of DJ-1 are associated with choroidal nevi transformation risk factors. Therefore, DJ-1 appears to be a promising factor for predicting the growth of choroidal nevi and may be a potential biomarker of malignancy.

A novel biomarker harvesting nanotechnology identifies Bak as a candidate melanoma biomarker in serum.

BACKGROUND: Melanoma represents only 4% of all skin cancers, but nearly 80% of skin cancer deaths. This manuscript applies several new measurement technologies with the purpose of elucidating molecular signatures of melanoma aggressiveness. PURPOSE: We sought to determine whether low-abundant serum proteins related to apoptotic pathways could be measured and correlated with defined melanoma subtypes. Hydrogel core shell nanoparticles, a new technology capable of selectively entrapping low molecular weight proteins and protecting them from enzymatic degradation, were used to capture candidate serum biomarkers. Biomarker levels were correlated with confocal microscopy, thereby representing a combination of new technologies for in vivo histologic documentation. RESULTS: Among a panel of analyzed serum proteins, Bak was differentially expressed between nevi and melanomas. Melanomas with higher Bak serum levels exhibited more pronounced junctional activity on confocal imaging, whereas lesions with 'sparse' dermal nests had weak Bak expression. CONCLUSIONS: Our study links serum proteome analysis with confocal microscopic clinical in vivo histologic classification of melanomas. Bak has not been previously measured in serum. Bak differential expression among melanoma subtypes confirms the importance of the apoptotic pathway as a contributor to melanoma aggressiveness.

Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome.

We report on an adolescent who experienced the onset of linear nevus sebaceous syndrome (LNSS) prior to 1 year of age. At 7 years of age he was diagnosed to have hypophosphatemic rickets. He was suboptimally controlled with phosphate and calcitriol treatment and sustained numerous insufficiency fractures ipsilateral to the linear sebaceous nevus. Fibroblast growth factor-23 (FGF-23), the phosphaturic peptide, was elevated in the plasma. Treamtent with the somatostatin agonist, octreotide, and excision of the nevus were followed by normalization of FGF-23 and clinical improvement. The patient also had hyperimmunoglobulinemia E, which responded to octreotide and surgery. We speculate that in some patients with LNSS there may be more than one mediator of hypophosphatemia and that FGF-23 is the mediator of hyperphosphaturia in this and other hypophosphatemic syndromes.

Presence of activated lymphocytes in the peripheral blood of patients with halo nevi.

BACKGROUND: The involution of the central pigmented lesion in halo nevus (HN) seems to be mediated by an immune response against self antigens expressed by melanocytes. OBJECTIVE: We assessed the presence of activated lymphocytes in the peripheral blood lymphocytes from patients with HN. METHODS: Peripheral blood was obtained from patients with HN associated with benign pigmented lesions (5) or melanoma (2) as well as from patients with melanoma without HN (5) and healthy subjects (10). Activated lymphocytes were detected by flow cytometry analysis using monoclonal antibodies (mAb) against CD69, CD71, CD98, HLA-DR, and activated beta(1) integrins (HUTS-21 mAb). RESULTS: The peripheral blood lymphocytes from patients with HN, associated with either benign or malignant lesions, exhibited a significantly higher expression of all activation markers studied compared with patients with melanoma without HN or compared with healthy subjects. Therefore the peripheral blood of HN patients contained a significant fraction of lymphocytes with an activated (CD69(+), HLA-DR(+), CD98(bright)), cell proliferating (CD71( bright)), and high adhesive (HUTS-21(bright)) phenotype. These activated cells disappeared from peripheral blood after the surgical resection of the skin lesion. CONCLUSION: Our findings further support the involvement of immune activation in HN phenomenon.

Hypercalcemia in a patient with malignant melanoma arising in congenital giant pigmented nevus. A case of increased serum level of parathyroid hormone-related protein.

We describe a 43-year-old Japanese female who developed hypercalcemia associated with malignant melanoma. The patient underwent three resections of tumors on her groin and buttock secondary to a bathing trunk congenital nevus, and the histopathological findings showed benign congenital nevi. At the age of 42 years, she developed a malignant melanoma under the giant pigmented nevus in her groin. Fourteen months after the diagnosis of melanoma, she developed metastases to the lung, para-aortic lymph nodes and bones accompanied by hypercalcemia resulting from a remarkable increase in the serum level of parathyroid hormone-related protein (PTHrP). The patient died from acute renal and respiratory failure. In addition, we analyzed serum levels of calcium and PTHrP in 19 patients with advanced malignant melanoma. Seven patients had hypercalcemia, and 3 had increased serum levels of PTHrP.

Serum concentration of 5-S-cysteinyldopa in pediatric patients with giant pigmented nevi.

The serum concentrations of 5-S-cysteinyldopa (5-S-CD) in pediatric patients with giant pigmented nevi (GPN) were investigated and compared with those of pediatric patients with small- or medium-sized congenital nevi (CN), or non-melanocytic benign skin tumor (control group). Serum 5-S-CD levels in the GPN group (N = 21), particularly in patients less than 5 years old, were significantly higher (highest concentration 38.4, mean +/- S.D. 16.6 +/- 9.4 nmol/L) than those in the CN (N = 22) or control groups (N = 26). Serum 5-S-CD levels in the CN group were not significantly different from those in the control group. There was a significant correlation between the serum 5-S-CD level and size (surface area) of the GNP. There was a significant inverse correlation between the serum 5-S-CD level and age in the CN and control groups, but not in the GPN group. Serum 5-S-CD levels were transiently elevated immediately after treatment of patients with GPN with a combination of skin abrasion and cryotherapy with solid carbon dioxide. These results suggest that serum 5-S-CD levels in the GPN group reflected the 5-S-CD derived from GPN, particularly in patients less than 5 years old. This indicates that melanogenesis may be accelerated in infant patients in the GPN group.