Ultra-high-frequency ultrasound monitoring of melanomas arising in congenital melanocytic nevi: a case series.

The aims of our study were to evaluate with ultra-high-frequency ultrasound (UHFUS) the ultrasound features of congenital melanocytic nevi (CMNs) and malignant melanomas (MMs) arising in CMNs and the correlation between ultrasonographic thickness and histological thickness in MMs. We evaluated 10 patients with small-medium CMNs and 10 patients with MMs arising in small-medium CMNs. We collected patient's data, clinical and dermoscopic features. The UHFUS was performed using a 70 MHz frequency probe to study the ecostructure, shape and vascularization. Breslow thickness was compared with ultrasonographic thickness. In the MMs group the following dermoscopic features were described: hyperpigmentation (n = 9), regression area (n = 6), whitish-blue veil (n = 5), thickened network (n = 5), irregular globules (n = 3), inverse network (n = 2) and striae (n = 1). Hyperpigmentation (n = n = 9), thickened network (n = 7), irregular globules (n = 5), regression area (n = 5), striae (n = 1) and whitish-blue veil (n = 1) were found in the CMNs group. The multicomponent pattern was present in both MMs (n = 4) and in CMNs (n = 5). Moreover, the parameters indicative of suspected malignancy were variously combined in the two groups, without showing significant differences in the statistical analysis; with the exception of the blue veil that correlated with the diagnosis of MM. Ultrasonoghaphic vascularization was an ever-present parameter in MMs (100%), with high intensity of intratumoral signal, as opposed to CMNs. We also found a statistically significant correlation between ultrasound thickness and Breslow thickness. In the future, this technique could implement the diagnostic preoperative phase of MMs arising in CMNs in combination with standard clinical-dermatoscopic evaluation.

Clinical and dermoscopic characteristics of congenital and noncongenital nevus-associated melanomas.

BACKGROUND: No specific features of nevus-associated melanoma (NAM) are currently defined. OBJECTIVE: To identify clinical/dermoscopic features of NAM. METHODS: Retrospective evaluation of histopathologically diagnosed NAM. RESULTS: Eighty of 165 NAMs had a clinically recognizable nevus component, often raised or nodular, most frequently characterized by different morphologic clones and/or colors. In 111 of 165 NAMs, dermoscopy showed a nevus component, prevalently characterized by regular dots/clods and structureless brown areas. Clinically, the melanoma component was eccentric/peripheral in 45 of 80 cases and central in 35 of 80; dermoscopically, the figures were 59 of 111 and 52 of 111, respectively. Melanomas associated with congenital nevi (C-NAMs) occur at a younger age and have a thicker Breslow depth than melanomas associated with acquired nevi (NC-NAMs). Dermoscopically, regular dots/globules characterize C-NAMs, and hypopigmented structureless areas characterize NC-NAMs. LIMITATIONS: Retrospective analysis. CONCLUSION: C-NAMs are more often central to a congenital nevus, with a clod/globular or structureless brown pattern, typical of young patients. NC-NAMs are frequently hypopigmented nodules/plaques, eccentric/peripheral, with hypopigmented structureless areas, typical of older patients.

Imaging of pediatric cutaneous melanoma.

Melanoma accounts for 7% of all cancers in adolescents ages 15-19 years but is an unexpected malignancy in younger children. The prevalence of malignant melanoma is very rare in children ages 1-4 years, but certain non-modifiable risk factors such as xeroderma pigmentosum, congenital melanocytic nevus syndrome and other inherited traits increase the risk for its development in these young children. Recent genomic studies have identified characteristics of pediatric melanoma that differ from conventional melanoma seen in adults. In this review the authors inform on the types of melanoma seen in children and adolescents, discuss similarities and differences in melanoma between children and adults, and discuss the role of imaging in the care of these children.

Mass Spectrometry Imaging Can Distinguish on a Proteomic Level Between Proliferative Nodules Within a Benign Congenital Nevus and Malignant Melanoma.

Histopathological interpretation of proliferative nodules occurring in association with congenital melanocytic nevi can be very challenging due to their similarities with congenital malignant melanoma and malignant melanoma arising in association with congenital nevi. We hereby report a diagnostically challenging case of congenital melanocytic nevus with proliferative nodules and ulcerations, which was originally misdiagnosed as congenital malignant melanoma. Subsequent histopathological examination in consultation by one of the authors (R.L.) and mass spectrometry imaging analysis rendered a diagnosis of congenital melanocytic nevus with proliferative nodules. In this case, mass spectrometry imaging, a novel method capable of distinguishing benign from malignant melanocytic lesions on a proteomic level, was instrumental in making the diagnosis of a benign nevus. We emphasize the importance of this method as an ancillary tool in the diagnosis of difficult melanocytic lesions.

Congenital cutaneous melanoma in a dog.

BACKGROUND: Melanocytic tumours are derived from melanocytes and are common in older dogs with dark pigmented skin. Primary congenital cutaneous melanoma has been described in domestic mammals although there are no reports in the dog. HYPOTHESIS/OBJECTIVE: We describe a case of canine congenital cutaneous melanoma with rapid progression to metastasis and death. ANIMAL: A male, mixed breed dog was born with a circular ulcerated lesion near the left ear. By 12 days of age the lesion had grown significantly, with multiple soft, round nodules located at the outer base of the ear. METHODS AND RESULTS: Histopathological examination showed the proliferation of round and elongated neoplastic cells with eosinophilic cytoplasm that occasionally contained granules of melanin. Immunohistochemical analysis was positive for melan A, S-100 protein, neuron-specific enolase (NSE) and vimentin, confirming the diagnosis of melanoma. The tumour progressed rapidly and at six months the dog died suddenly. Postmortem examination revealed pulmonary, cardiac and lymph node metastases. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first report of a primary congenital melanoma in the dog. The neoplastic condition showed malignant behaviour and high metastatic potential.

Bone marrow metastasis of malignant melanoma in childhood arising within a congenital melanocytic nevus.

BACKGROUND: Malignant melanoma in childhood is infrequent and can arise within congenital melanocytic nevi. Spread of malignant melanoma to the bone marrow, especially in children, is extremely rare. METHODS AND RESULTS: Reported is a case of a 5-year-old boy with a congenital large melanocytic nevus of the head and neck who presented with a short history of low back and leg pain, fever and cervical lymphadenopathy. Despite regular follow-up by a dermatologist and plastic surgeon and repeatedly negative histology of previous partial excisions, diffuse bone marrow infiltration with malignant melanoma was diagnosed. The primary site was identified in the post-excision area. The disease progressed rapidly on ipilimumab immunotherapy and led to death at four months from the diagnosis. CONCLUSION: Surveillance is indispensable in children with a predisposition to melanoma and nonspecific symptoms such as bone pain, gait impairment or cytopenia, should always be taken into account.

Pigment Loss in Patients with Large Congenital Melanocytic Nevi: Various Clinical Presentations Documented in a Large Series.

BACKGROUND/OBJECTIVES: The association between vitiligo and congenital melanocytic nevi remains incompletely understood. The objective of this study was to investigate the frequency of depigmentation, including vitiligo, in patients with a large congenital melanocytic nevus (LCMN), which is a rare melanocytic tumor variant. METHODS: We retrospectively reviewed the files of 92 patients with an LCMN, including photographic documentation regarding the presence of pigment loss on the nevus mass, around the nevus, around the satellites, and elsewhere on the body. RESULTS: Depigmentation was observed in 8 (8.7%) of 92 patients with an LCMN. Depigmented areas within the main nevus mass were observed in six patients, and adjacent or remote vitiligo was observed in four patients. One patient also demonstrated halo depigmentation around some satellite nevi. CONCLUSION: The coexistence of an LCMN with vitiligo does not appear to be rare and may occur with a spectrum of clinical presentations.

Melanocytes Affect Nodal Expression and Signaling in Melanoma Cells: A Lesson from Pediatric Large Congenital Melanocytic Nevi.

Expression of Nodal, a Transforming Growth Factor-beta (TGF-ß) related growth factor, is associated with aggressive melanoma. Nodal expression in adult dysplastic nevi may predict the development of aggressive melanoma in some patients. A subset of pediatric patients diagnosed with giant or large congenital melanocytic nevi (LCMN) has shown increased risk for development of melanoma. Here, we investigate whether Nodal expression can help identify the rare cases of LCMN that develop melanoma and shed light on why the majority of these patients do not. Immunohistochemistry (IHC) staining results show varying degree of Nodal expression in pediatric dysplastic nevi and LCMN. Moreover, median scores from Nodal IHC expression analysis were not significantly different between these two groups. Additionally, none of the LCMN patients in this study developed melanoma, regardless of Nodal IHC levels. Co-culture experiments revealed reduced tumor growth and lower levels of Nodal and its signaling molecules P-SMAD2 and P-ERK1/2 when melanoma cells were grown in vivo or in vitro with normal melanocytes. The same was observed in melanoma cells cultured with melanocyte conditioned media containing pigmented melanocyte derived melanosomes (MDM). Since MDM contain molecules capable of inactivating radical oxygen species, to investigate potential anti-oxidant effect of MDM on Nodal expression and signaling in melanoma, melanoma cells were treated with either N-acetyl-l-cysteine (NAC), a component of the anti-oxidant glutathione or synthetic melanin, which in addition to providing pigmentation can also exert free radical scavenging activity. Melanoma cells treated with NAC or synthetic melanin showed reduced levels of Nodal, P-SMAD2 and P-ERK1/2 compared to untreated melanoma cells. Thus, the potential role for Nodal in melanoma development in LCMN is less evident than in adult dysplastic nevi possibly due to melanocyte cross-talk in LCMN capable of offsetting or delaying the pro-melanoma effects of Nodal via anti-oxidant effects of MDM.

Congenital uveal melanoma?

A 3-month-old infant with a white mother and Asian father presented with discoloration and prominence of the left eye since birth. Examination revealed a normal right eye. The left eye had hyperchromic heterochromia and an enlarged cornea (diameter, 13.0 mm) with intraocular pressure of 26 mm Hg. There were multiple areas of subconjunctival nodular pigmentation that extended posteriorly into the superior fornix. Fundus examination showed a large ciliochoroidal pigmented mass extending from 10:30 to 3:00 o'clock position involving the superior half of the choroid and adjacent ciliary body. The eye was enucleated, confirming the diagnosis of diffuse uveal melanoma with extraocular extension. Systemic surveillance (hepatic panel and ultrasonography of the liver) performed every 6 months for 5 years was has been negative for metastases. The tumor was investigated intensively for the panel of genes (BAP1, BRAF, NRAS12, NRAS61, GNAQ, Kit 9,11,13,17,18) implicated in pathogenesis of blue nevus, cutaneous melanoma, and mucosal melanomas with negative results. Moreover, germline BAP1 mutation could not be identified. This case possibly represents as yet unidentified uveal melanocytic proliferation rather than a true variant of uveal melanoma.

Amplification of mutated NRAS leading to congenital melanoma in neurocutaneous melanocytosis.

The mechanisms behind malignant progression in patients with giant nevi are largely unknown. Here, we aim to describe novel genetic findings and explain possible mechanisms resulting in the most severe form of neurocutaneous melanocytosis. Detailed histological (biopsy and post-mortem) studies, tissue culture, and high-resolution cytogenetic analysis, including chromosome and array comparative genomic hybridization, Ion AmpliSeq Cancer Panel, and Sanger sequencing, were performed on tissues from a white male who succumbed at 17 months of age to congenital melanoma associated with a bathing-trunk nevus. We also used quantitative PCR to quantitatively assess the expression of NRAS among normal cells, including fibroblast and melanocytes, as well as melanoma cells from our patient. Full autopsy documented tumors in the brain, spinal cord, lung, liver, testis, bone marrow, and, retrospectively, in the placenta. Next-generation sequencing and chromosome microarray in our patient revealed novel findings, including duplication of a mutated NRAS gene, leading to an aggressive clinical course and disseminated disease. Quantitative PCR showed a five-fold increase in NRAS expression in the melanoma cell line when compared with normal melanocytes. Finally, three amino acid-changing germline variants were detected: homozygous TP53 p.P72R, heterozygous KIT p.M541L, and homozygous KDR (VEGFR2) p.Q472H. These genes are involved in malignancy and other potentially relevant pathways, such as mast cell and melanocytic signaling, as well as angiogenesis. These findings provide novel insights into the biology of congenital melanocytic proliferations, showing that amplification of mutated NRAS seems to represent a new genetic mechanism leading to melanoma in the context of neurocutaneous melanocytosis.

Congenital nevi versus metastatic melanoma in a newborn to a mother with malignant melanoma - diagnosis supported by sex chromosome analysis and Imaging Mass Spectrometry.

A 37-year-old pregnant woman presented with a 2-cm irregular reddish nodule on her left upper arm during pregnancy. A biopsy from the lesion showed a 2.2-mm thick malignant melanoma with intravascular invasion, 25 mitosis/mm(2) and no ulceration. Following induction of labor, the patient underwent re-excision with sentinel lymph node biopsy. This showed no residual melanoma and no lymph node metastasis. The newborn boy had multiple pigmented lesions on the trunk, some of which were large and irregular. Two were biopsied and histologic examination showed dense dermal proliferation of medium sized melanocytes with multiple mitotic figures and no maturation with their descent into the dermis, raising suspicion of transplacental metastases. Examination of the placenta failed to show metastatic lesions. Multiplex polymerase chain reaction (PCR)-based genotyping, including testing for amelogenin locus for sex chromosome determination, demonstrated the presence of Y chromosome material in the melanocytes of the newborn's lesions excluding maternal origin. A diagnosis of congenital nevi was rendered. Subsequently, Imaging Mass Spectrometric analysis of the mother's lesion showed proteomic signature expression indicative of malignant melanoma, whereas the two lesions in the newborn showed changes indicative of nevi. This case demonstrates the utility of genotyping and Mass Spectrometry analysis in this challenging clinical scenario.

De novo congenital melanoma: analysis of 2 cases with array comparative genomic hybridization.

Congenital melanoma is extraordinarily rare, and 3 types have been described: transplacental metastases from the mother, de novo congenital melanoma, and melanoma occurring in association with a congenital melanocytic nevus. We describe 2 reports of array comparative genomic hybridization analysis of de novo congenital melanoma. The first patient was male, and the second was female; both had a scalp lesion present at birth, which grew quickly. The scalp mass from patient 1 showed a heterogeneous, anaplastic melanocytic neoplasm with large size and depth, high mitotic rate, ulceration, and necrosis. The scalp mass from patient 2 showed a broad melanocytic neoplasm with single cell and junctional nested proliferation at the dermal-epidermal junction and cellular, confluent aggregates of highly atypical melanocytes in the dermis with high mitotic rate. Patient 1 had lung and liver metastases detected by radiologic imaging and was treated with cisplatin, vinblastine, and dacarbazine but expired at the age of 5 months. Patient 2 developed a metastasis to the right neck with similar histologic features, and pulmonary metastases were also detected by imaging. Patient 2 is currently alive at the age of 4 years. Array comparative genomic hybridization analysis of the first case revealed loss of chromosomes 3p26.3-p21.31, 5p15.33-q23.1, 11q15.5-q13.2, 14 (complete deletion), and 15q11.1-q22.31. The second case displayed gains in chromosomes 1q21.1-q44, 2p25.3-p11.1, 2q11.1-q37.3, 6p25.3-p11.1, 7p22.3-p11.2, 7q11.1-q36.3, 8p23.3-p11.1, 8q11.1-q24.3, 9p24.3-p11.2, 9q12-q34.3, 11q13.2-q13.4, 13q11-q34, 18p11.32-p11.21, 19p13.3-p11, 19q11-q13.43, 20p13-p11.1, and 20q11.21-q13.33. In both cases, the presence of multiple chromosomal aberrations corroborated the diagnosis of melanoma.

Congenital malignant melanoma of the scalp in a 25-day-old neonate.

We present a case of congenital malignant melanoma of the scalp in a neonate. The child was born through caesarean section with a swelling, the size of a tennis ball, on the posterior scalp. At presentation to the clinic at 25 days after birth, the swelling had significantly increased in size and ulcerated. An excision was carried out but, because of extensive haemorrhage and haemodynamic instability, the procedure was limited to subtotal resection. Later on, completion of the excision and flap coverage of the wound were performed. After an initial stable course of a few months, the child came back with local recurrence. A re-excision was planned but the child developed pneumonia resulting in sepsis leading to the demise of the child. The report adds to the literature by describing a rare entity and challenges of managing large vascular scalp lesions with complete excision and defect coverage.

Congenital uveal malignant melanoma.

We report the clinical and pathological findings of a rare case of congenital uveal melanoma. A 7-week-old girl presented with history of a black area at the inner corner of her left eye since birth. Examination revealed an enlarged globe with an area of visible uveal pigment nasal to the cornea, an iris mass, and shallow anterior chamber in the left eye. Magnetic resonance imaging revealed an intraocular mass. Enucleation was performed when the girl was 2 months of age. Pathologic examination confirmed a malignant melanoma epithelioid cell type with extraocular extension. She was treated with chemotherapy and subtotal exenteration.

Giant congenital melanocytic nevus / Nevo melanocitico congenito gigante

Giant congenital melanocytic nevus is usually defined as a melanocytic lesion present at birth that will reach a diameter ≥ 20 cm in adulthood. Its incidence is estimated in <1:20,000 newborns. Despite its rarity, this lesion is important because it may associate with severe complications such as malignant melanoma, affect the central nervous system (neurocutaneous melanosis), and have major psychosocial impact on the patient and his family due to its unsightly appearance. Giant congenital melanocytic nevus generally presents as a brown lesion, with flat or mammilated surface, well-demarcated borders and hypertrichosis. Congenital melanocytic nevus is primarily a clinical diagnosis. However, congenital nevi are histologically distinguished from acquired nevi mainly by their larger size, the spread of the nevus cells to the deep layers of the skin and by their more varied architecture and morphology. Although giant congenital melanocytic nevus is recognized as a risk factor for the development of melanoma, the precise magnitude of this risk is still controversial. The estimated lifetime risk of developing melanoma varies from 5 to 10%. On account of these uncertainties and the size of the lesions, the management of giant congenital melanocytic nevus needs individualization. Treatment may include surgical and non-surgical procedures, psychological intervention and/or clinical follow-up, with special attention to changes in color, texture or on the surface of the lesion. The only absolute indication for surgery in giant congenital melanocytic nevus is the development of a malignant neoplasm on the lesion.

O nevo melanocítico congênito gigante é, geralmente, definido como lesão melanocítica presente ao nascimento e que atinge, no mínimo, 20 cm de diâmetro na vida adulta. Sua incidência é estimada em menos de 1:20.000 recém-nascidos. Contudo, apesar de sua raridade, possui importância tanto por estar associado a complicações graves, como o melanoma maligno e o acometimento do sistema nervoso central (melanose neurocutânea), quanto pelo grande impacto psicossocial que ocasiona no paciente e nos familiares, devido a seu aspecto comumente inestético. O nevo congênito gigante, geralmente, apresenta-se como lesão acastanhada, plana ou elevada, de bordas bem definidas e com hipertricose, e seu diagnóstico é eminentemente clínico. Do ponto de vista histológico, porém, os nevos melanocíticos congênitos são diferenciados dos nevos adquiridos, principalmente pelo seu tamanho maior, pela disseminação das células névicas para as camadas mais profundas da pele e pela sua arquitetura e morfologia mais variadas. O nevo congênito gigante é considerado fator de risco para o desenvolvimento do melanoma. Todavia, a real incidência de malignização ainda é controversa. Estima-se que o risco de melanoma ao longo da vida esteja entre 5 e 10%. Diante dessas incertezas e do tamanho das lesões, a abordagem do nevo gigante representa um desafio e deve ser individualizada. O tratamento pode incluir procedimentos cirúrgicos ou não cirúrgicos, intervenções psicológicas e/ou acompanhamento clínico, com atenção a mudanças de coloração, superfície ou textura do nevo. Considera-se que a única indicação absoluta para a intervenção cirúrgica é o surgimento de uma neoplasia maligna sobre a lesão.