RESUMO
BACKGROUND AND AIMS: PKC-fused blue naevi are a recently described group of melanocytic tumours that have distinctive morphological features, including a pigmented epithelioid melanocytoma-like junctional component or a dermal biphasic architecture associating with naevocytoid nests surrounded by dendritic and spindled pigmented melanocytes (so-called 'combined common and blue naevus'). There have been reports of smooth muscle hyperplasia in a hamartoma-like pattern in cases of combined blue naevi without genetic exploration. MATERIALS AND METHODS: Herein, we describe 12 cases of protein kinase C (PKC)-fused blue tumours associated with a co-existing smooth muscle hyperplasia, identified from a total of 98 PKC-fused melanocytic tumours. Archived slides of PKC-fused blue naevi with haematoxylin, eosin and phloxin staining, immunohistochemistry and molecular confirmation of a PKC-fusion by fluorescence in-situ hybridisation (FISH) or RNAseq were re-evaluated for identification of notable smooth muscle hyperplasia. Fifty-one of these slides had already been studied in a previous publication from our group. RESULTS: The hyperplasia ranged from hypertrophic arrector pili muscles to extensive horizontal bundles of disorganised fibres constantly associated and limited within a biphasic dermal melanocytic component. At least one arrector pili muscle was always visible within the tumour, with occasionally direct extension of the hyperplastic fibres from the main muscle body. These muscle fibres were devoid of a PKC-fusion signal by FISH. PKC molecules are involved in the regulation of smooth muscle function, offering an explanatory framework. CONCLUSIONS: These data suggest incorporating smooth muscle hyperplasia as a diagnostic morphological feature of PKC-fused blue melanocytic tumours.
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Hiperplasia , Músculo Liso , Nevo Azul , Proteína Quinase C , Neoplasias Cutâneas , Humanos , Hiperplasia/patologia , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Feminino , Masculino , Adulto , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genética , Nevo Azul/patologia , Nevo Azul/genética , Nevo Azul/diagnóstico , Músculo Liso/patologia , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Criança , IdosoAssuntos
Neoplasias Gastrointestinais , Nevo Azul , Neoplasias Cutâneas , Humanos , Proteínas Adaptadoras de Transdução de Sinal , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/complicações , Nevo Azul/diagnóstico , Nevo Azul/genética , Nevo Azul/complicações , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/complicaçõesRESUMO
Fusion genes involving homologs of protein kinase C (PKC) have been identified in a variety of tumors. We report the clinical and histologic presentation of 51 cutaneous melanocytic neoplasms with a PKC fusion gene (involving PRKCA in 35 cases, PRKCB in 15 cases, and PRKCG in a single case). Most tumors were in young adults (median age, 29.5 years; range, 1-73 years) but some presented in newborns. Histologically, 42 tumors were classified as benign, presenting predominantly as biphasic dermal proliferation (88%) with nests of small melanocytes surrounded by fibrosis with haphazardly arranged spindled and dendritic melanocytes, resembling those reported as "combined blue nevi." Most tumors (60%) were heavily pigmented and in 15%, hyperpigmented epithelioid melanocytes were present at the dermoepidermal junction. Two lesions were paucicellular and showed marked sclerosis. Three tumors, including 2 proliferating nodules, were considered intermediate grade. Six tumors had sheets of atypical melanocytes infiltrating the dermis and were classified as melanomas. Two of the melanomas displayed loss of BAP1 nuclear expression. The median follow-up time was 12 months, with 1 patient alive with metastatic disease and 1 dying of their melanoma. These results suggest that melanocytic tumors with PKC fusion genes have characteristic histopathologic features, which are more similar to blue nevi than to pigmented epithelioid melanocytomas. As is the case with GNA-mutated blue nevi, they can progress to melanomas via BAP1 inactivation and metastasize.
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Melanoma , Nevo Azul , Neoplasias Cutâneas , Recém-Nascido , Adulto Jovem , Humanos , Adulto , Nevo Azul/genética , Biomarcadores Tumorais/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Proteína Quinase C/genéticaRESUMO
Melanoma arising in blue nevus, also known as melanoma ex blue nevus, is a specific form of melanoma whose genetic profile is different to that of other cutaneous melanomas and surprisingly similar to that of uveal melanoma. Although melanoma ex blue nevus can appear de novo, it usually arises in a preexisting blue nevus or dermal melanocytosis. Not all nodular lesions arising in association with blue nevus or dermal melanocytosis are melanomas, however, and because clinical and histologic findings may be insufficient for a definitive diagnosis, additional studies such as comparative genomic hybridization are important. Detection of chromosomal aberrations supports a diagnosis of malignancy. Studies of the BAP1 gene are particularly useful in this setting because loss of expression is indicative of melanoma. We present 3 cases on the spectrum of blue nevus to melanoma ex blue nevus that were studied using molecular biology techniques.
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Melanoma , Nevo Azul , Neoplasias Cutâneas , Humanos , Nevo Azul/diagnóstico , Nevo Azul/genética , Nevo Azul/patologia , Prognóstico , Hibridização Genômica Comparativa , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genéticaRESUMO
Blue naevi (BN) form a wide group of benign dermal melanocytic proliferations. They are genetically distinct from common and Spitz naevi with frequent hotspot mutations occurring in Gαq genes. Clinically, BN display a female predominance, elective sites of emergence and a great variety of subtypes related to specific regions of the skin linked to early embryological genetic events. Histologically, most BN are located in the dermis with small, bland, spindled and dendritic pigmented melanocytes within a fibrous background. Variation in tumour volume, fibrosis, and melanin pigment load can be broad. A growth in size and cellularity can occur within a subset of tumours as they acquire the morphological features of cellular blue naevi, with a biphasic architecture associating a dendritic blue naevus morphology near the surface, and deep vertical cellular expansions of medium-sized, bland melanocytes often reaching the subcutis. Sclerosing and myxoid variants can be observed either as individual or combined modifications that can add complexity to an otherwise straightforward diagnosis. Malignant progression of a cellular blue naevus is exceptional with an intermediate stage named atypical cellular blue naevus. Malignant blue melanomas are fast growing, large, pigmented tumours with most often obvious features of malignancy. However, they are difficult to separate from other malignant dermal melanocytic proliferations. Herein, we will extensively detail and illustrate the clinical, histological and genetic features of the vast spectrum of blue naevi and related entities in the skin.
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Melanoma , Nevo Azul , Neoplasias Cutâneas , Feminino , Humanos , Masculino , Diagnóstico Diferencial , Melanócitos/patologia , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patologia , Nevo Azul/diagnóstico , Nevo Azul/genética , Nevo Azul/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologiaRESUMO
Blue Rubber Bleb Nevus Syndrome is a congenital rarity that manifests as vascular malformations throughout the body, including the gastrointestinal tract. With fewer than 300 cases reported, the etiology and clinical course is poorly understood; however, the literature suggests TEK mutations on chromosome 9 result in unregulated angiogenesis. We present the case of a young female treated for anemia of unknown etiology who presented in hemorrhagic shock due to gastrointestinal hemorrhage necessitating small bowel resection, with cutaneous, intestinal, hepatic, and lingual vascular malformations associated with a single somatic pathologic TEK mutation. Although uncommon, this case suggests that Blue Rubber Bleb Nevus Syndrome should be considered in the differential of a patient with persistent anemia and cutaneous lesions, carrying the potential for multiple gastrointestinal vascular malformations progressing to hemorrhage necessitating operative management. Additionally, a severe phenotype can occur without a double-hit TEK mutation.
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Neoplasias Gastrointestinais , Nevo Azul , Neoplasias Cutâneas , Malformações Vasculares , Feminino , Humanos , Nevo Azul/complicações , Nevo Azul/diagnóstico , Nevo Azul/genética , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/cirurgia , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/cirurgia , Malformações Vasculares/complicações , Malformações Vasculares/diagnóstico , Malformações Vasculares/cirurgia , Hemorragia Gastrointestinal/cirurgia , Hemorragia Gastrointestinal/complicaçõesRESUMO
Pigmented epithelioid melanocytomas (PEM) are intermediate-grade melanocytic lesions with frequent lymph node involvement and rare metastases that tend to follow an indolent course with a favorable outcome. We report two unique cases of congenital PEM with PRKCA fusion transcripts: a multifocal PEM with an aggressive incompletely resectable scalp tumor and a solitary palmar PEM with newly reported ITGB5-PRKCA fusion. Through these case reports and a summary of previously reported cases, we outline the spectrum of disease of PEM and highlight the key clinical and histopathologic features associated with PEM with PRKCA fusion transcripts. We also discuss the treatment options and suggest that surgical excision without further adjuvant systemic treatment is reasonable first-line therapy given the favorable prognosis.
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Nevo Azul , Neoplasias Cutâneas , Humanos , Nevo Azul/diagnóstico , Nevo Azul/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Melanócitos/patologiaRESUMO
AIMS: Blue naevi are benign melanocytic lesions that typically occur in the dermis. Melanoma arising in blue naevus is rare, and shows a molecular profile distinct from conventional forms of cutaneous melanoma and more similar to uveal melanoma and central nervous system (CNS) melanocytomas. In contrast to conventional cutaneous melanoma, these tumour types typically show activating driver mutations in GNAQ or GNA11, a low mutational burden without evidence of a UV signature and a reproducible pattern of chromosomal copy number changes. Blue naevi can also occur at extracutaneous sites. Here we report two cases of melanoma arising in extracutaneous blue naevus and compare their molecular features to cohorts of melanoma arising in cutaneous blue naevus (five patients) and uveal melanoma (six patients). METHODS AND RESULTS: We describe the clinical, histomorphological, immunohistochemical and molecular findings in these two cases of melanoma arising in extracutaneous blue naevus. We compare their molecular profiles to melanomas arising in cutaneous blue naevus and uveal melanoma using a targeted next-generation DNA sequencing platform and find striking similarities between all three groups. CONCLUSIONS: The close relationship between blue naevus-associated melanomas, regardless of their anatomical site, supports and validates the concept of melanoma arising in extracutaneous blue naevus and suggests that the two groups share common pathogenic mechanisms. The similarity of both groups to uveal melanoma in turn supports the close relationship between blue naevus-associated melanoma, uveal melanoma and CNS melanocytoma, and their distinction from conventional UV-associated melanoma. These findings have important implications for prognosis and therapy.
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Melanoma , Nevo Azul , Neoplasias Cutâneas , Neoplasias Uveais , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Humanos , Melanoma/patologia , Mutação , Nevo Azul/genética , Nevo Azul/patologia , Neoplasias Cutâneas/patologia , Neoplasias Uveais/genética , Melanoma Maligno CutâneoRESUMO
INTRODUCTION: Loss-of-function mutations in EED and SUZ12, core components of the polycomb repressive complex 2 (PRC2), occur in >90% of sporadic and radiation-associated malignant peripheral nerve sheath tumors (MPNST) and in roughly 70% of NF1-related tumors. PRC2 inactivation results in loss of H3K27me3 expression and aberrant downstream transcription. H3K27me3 expression is lost in 40-90% of spindle cell MPNST but is not specific. A single study has suggested that dimethylated H3K27 (H3K27me2) is a more specific marker of MPNST. METHODS: We compared the expression of H3K27me3 and H3K27me2 by immunohistochemistry in a series of MPNST (n = 26), neurofibroma (n = 11), conventional dermatofibrosarcoma protuberans (n = 8), fibrosarcomatous dermatofibrosarcoma protuberans (n = 7), spindle cell rhabdomyosarcoma (n = 6), high-risk solitary fibrous tumor (n = 9), dedifferentiated chondrosarcoma (n = 7), synovial sarcoma (n = 9), diffuse midline glioma, H3K27-altered (n = 13), conventional diffuse astrocytoma (n = 2), conventional cutaneous melanoma (n = 8), uveal melanoma (n = 8), cellular blue nevus (n = 17) and melanoma arising in blue nevus (n = 6). RESULTS: H3K27me3 and H3K27me2 expression patterns were concordant in 115/137 (84%) with 85 cases (62%) expressing both markers and 30 cases (22%) showing loss of both. Discordant results were seen in 22 cases (H3K27me3 loss with retained H3K27me2, 10 cases (7%); H3K27me3 expression with H3K27me2 loss, 12 cases (9%)). H3K27me2 loss was not specific for MPNST and was also seen in certain other tumors, in particular those in the "blue nevus family". CONCLUSION: We conclude that H3K27me2 loss is not specific for MPNST, and like H3K27me3, should be used in the appropriate clinicopathologic, immunohistochemical and molecular genetic context. Loss of H3K27me2 with retained H3K27me3 is a common feature of "blue nevus family" melanocytic tumors known to harbor GNAQ/GNA11 mutations.
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Melanoma , Neoplasias de Bainha Neural , Neurilemoma , Neurofibrossarcoma , Nevo Azul , Neoplasias Cutâneas , Biomarcadores Tumorais/metabolismo , Metilação de DNA , Histonas/metabolismo , Humanos , Melanoma/diagnóstico , Melanoma/genética , Neoplasias de Bainha Neural/metabolismo , Neurilemoma/diagnóstico , Neurofibrossarcoma/genética , Nevo Azul/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genéticaRESUMO
Blue nevi are benign, melanocytic neoplasms that show a range of clinical and morphologic patterns and include common/dendritic, cellular, and atypical cellular subtypes. Like other nevi, they most commonly occur in skin but can occasionally involve lymph nodes where they may be misinterpreted as representing metastatic melanoma. Moreover, whether benign blue nevi can metastasize to lymph nodes and their natural history and prognostic significance has been the subject of great controversy. To date, few cases of nodal blue nevi have been reported in the literature, and those reports have had limited clinical follow-up and supporting molecular data. This study sought to determine the clinical, pathologic, and molecular features of blue nevi involving lymph nodes, clarify their clinical significance, provide evidence for understanding their pathogenesis, and highlight potential pitfalls in the interpretation of lymph nodes with an ultimate aim of improving patient care. Thirteen cases of blue nevi involving lymph nodes were identified in the archives of Royal Prince Alfred Hospital, Sydney, Australia (1984-2018). A detailed assessment of the clinical and pathologic features of each case was performed, including an evaluation of all available immunohistochemical stains. Extended clinical follow-up was available for 9 patients. Droplet digital polymerase chain reaction for GNAQ Q209L, Q209P and GNA11 Q209L mutations was performed on 7 cases of blue nevi within lymph nodes together with matching cutaneous (presumed primary) blue nevi in 2 cases. All cases showed typical histologic features of blue nevi. BAP1 was retained in all cases (n=7). There were no recurrence or metastasis of blue nevus in any case on long-term clinical follow-up (n=9, median follow-up, 12 y). The majority of cases (n=5 of 7 evaluated) had GNAQ and GNA11 driver mutations. The 2 patients with a matched primary cutaneous blue nevus and regionally associated nodal blue nevus had the same GNAQ Q209L mutation in both sites in each patient. We conclude that blue nevi can involve lymph nodes and are associated with benign clinical behavior, and probably represent so-called "benign" metastasis. Awareness of these lesions is important when evaluating lymph nodes to avoid misdiagnosis as metastatic melanoma.
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Melanoma , Nevo Azul , Nevo , Neoplasias Cutâneas , Seguimentos , Humanos , Melanoma/patologia , Nevo/patologia , Nevo Azul/genética , Nevo Azul/patologia , Neoplasias Cutâneas/patologiaRESUMO
Melanocytic lesions in the nail apparatus are often challenging. Both subungual melanomas (SUM) and blue naevus of the nail are very rare. Occasionally, melanomas may mimic blue naevus histologically. Benign and malignant blue melanocytic lesions are commonly associated with G protein mutations, a distinct abnormality not associated with conventional subungual melanomas. We describe the clinical, histological and immunohistochemical features of nine cases of SUM with blue naevus-like morphological features. Mutations in exon 4 and 5 of GNAQ and GNA11 were investigated in two cases, which showed no mutations. RNA-seq of one case revealed unknown mutations along with mutations in ATM, METK and ARID1A. Our study delineates a variant of SUM that mimics blue naevus. Awareness of this pitfall is important when evaluating heavily pigmented lesions around the nail in order to avoid misdiagnosis. Appropriate sampling of subungual lesions and clinicopathological correlation are paramount to reach the correct diagnosis.
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Melanoma , Doenças da Unha , Nevo Azul , Neoplasias Cutâneas , Diagnóstico Diferencial , Humanos , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patologia , Doenças da Unha/diagnóstico , Doenças da Unha/patologia , Nevo Azul/diagnóstico , Nevo Azul/genética , Estudos Retrospectivos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologiaRESUMO
Pigmented epithelioid melanocytoma is a rare cutaneous melanocytic proliferation considered high-grade melanocytoma in the 2018 WHO Classification of Skin Tumors. Little has been reported about the associated genetic drivers in addition to BRAF and MAP2K1 mutations or PRKCA gene fusions. Here, we present a series of 21 cases of PRKAR1A -inactivated melanocytic tumors in which we could assess the associated genetic background. We identified 9 different driver genes related to the common, Spitz, blue nevi, and PRKC -fused groups. Nine cases were associated with a canonical BRAF p.V600E mutation, a hallmark of the common nevus group. They occurred mainly in young adults. All were combined (biphenotypic) cases with a variable proportion of compound nevus. The pigmented epithelioid melanocytoma component was made of thin fascicules or isolated epithelioid cells covered by a dense hyperpigmented melanophage background and was predominantly located in the upper dermis. One such case was malignant. Six cases were associated with Spitz-related genetic anomalies ranging from HRAS or MAP2K1 mutations to gene fusions involving MAP3K8 , MAP3K3 , and RET . They occurred mainly in children and young adults. Morphologically, they showed large confluent junctional nests in a hyperplastic epidermis and a fascicular dermal component of spindled and epithelioid melanocytes with a frequent wedged silhouette. Intravascular invasion was observed in 4/6 cases. Five cases were associated with canonical mutations of the blue nevus group with 4 CYSLTR2 p.L129Q and 1 GNAQ p.Q209L mutations. They were removed mainly in adults and showed a frequent junctional component with epidermal hyperplasia. The dermal component showed dense fascicules of spindled and epithelioid melanocytes predominating over melanophages. One case occurred in a PRKCA -fused tumor in an adolescent with classic morphologic features. These results could potentially shift the concept of PRKAR1A -inactivated melanocytoma, changing from a rather unified model to a more complex one, including genetic subgroup variations with clinical and morphologic specificities. The genetic background of PRKAR1A -inactivated melanocytic tumors should be systematically explored to better understand the extent and clinical behavior of these complex lesions.
Assuntos
Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico , Nevo Azul , Nevo de Células Epitelioides e Fusiformes , Nevo , Neoplasias Cutâneas , Adolescente , Criança , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Patrimônio Genético , Humanos , Nevo Azul/genética , Nevo Azul/patologia , Nevo de Células Epitelioides e Fusiformes/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Adulto JovemRESUMO
BACKGROUND: Uveal melanoma (UM) and conjunctival melanoma (CM) are distinct entities with different etiologies and genetic background. We present a case of an atypical subconjunctival melanoma arising from a blue nevus. PATIENTS AND METHODS: A 61-year-old female presented with a partially melanocytic epibulbar mass with surrounding episcleral pigmented spots. The lesion was detached from the overlying conjunctiva without an intraocular component. Excisional biopsy revealed a predominantly epithelioid melanoma, that was suggested to be metastasic, although there was no evidence of a primary melanoma elsewhere. RESULTS: Molecular analysis identified GNAQ and BAP1 pathogenic variants, which strongly suggested the diagnosis as a primary epibulbar melanoma arising from episcleral blue nevus. CONCLUSION: This case demonstrates the value of tumor molecular analysis using Next Generation Sequencing (NGS) for differentiating the origin of an unusually located ocular melanoma.
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Melanoma , Nevo Azul , Neoplasias Cutâneas , Neoplasias Uveais , Feminino , Genômica , Humanos , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Nevo Azul/genética , Nevo Azul/patologia , Neoplasias Cutâneas/genética , Neoplasias Uveais/diagnóstico , Neoplasias Uveais/genética , Neoplasias Uveais/patologiaRESUMO
Pigmented epithelioid melanocytoma (PEM) is an intermediate-grade melanocytic tumor with considerable histologic overlap with other melanocytic neoplasms such as epithelioid blue nevus (EBN), which is associated with the neoplastic syndrome Carney complex (CC). Next-generation sequencing is a valuable tool for identifying the primary drivers of melanocytic neoplasms and differentiating them from one another. While germline variants in the protein kinase cAMP-dependent regulatory type 1 alpha (PRKAR1A) gene have been associated with EBN and CC, fusions in protein kinase C-alpha (PRKCA) have been shown as sporadic drivers of PEM. Herein, we report the diagnosis and workup of a case of pigmented epithelioid melanocytoma with a novel protein kinase C-beta (PRKCB) fusion.
Assuntos
Nevo Azul , Neoplasias Cutâneas , Humanos , Nevo Azul/diagnóstico , Nevo Azul/genética , Nevo Azul/patologia , Proteína Quinase C beta , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/cirurgia , Tetraspanina 30RESUMO
ABSTRACT: Plaque-type blue nevus is a rare variant of blue nevi that was first described in 1954. This article presents clinical, macroscopic, histopathological, and genetic findings for a case of large plaque-type blue nevus expanding into the mammary gland tissue as well as the skin of the right breast. A 63-year-old woman presented with a congenital, large, blue-colored macule limited to the hypochondriac area of the right breast. A nodule 8 mm in diameter was also present in the mammary gland tissue. Magnetic resonance imaging was unable to detect diffuse melanin deposition in the mammary gland tissue, but pigmentation in the whole mammary parenchyma was observed in the cut surfaces of the mastectomy specimen. Histopathology revealed a sparse distribution of dendritic melanocytes in whole sections of the mammary fibrous tissue and partial sections of the dermis. The histopathological criteria for atypical cellular blue nevus were fulfilled for the mammary tumor. Nodal blue nevus was diagnosed in the sentinel lymph node. Sanger sequencing confirmed the GNAQ Q209P mutation, which was also identified in all 4 literature cases of plaque-type blue nevus, but rarely in conventional blue nevi and uveal melanoma. It should be noted that plaque-type blue nevus can expand into the mammary gland tissue, even if the pigmented lesion does not exist on the overlying breast skin. The mammary condition can be the origin of primary mammary melanocytic tumors. Mosaicism of the GNAQ Q209P mutation can be a characteristic genetic alteration to extensive blue nevi, including plaque-type blue nevus.
Assuntos
Neoplasias da Mama/patologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Nevo Azul/patologia , Neoplasias Cutâneas/patologia , Neoplasias da Mama/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Nevo Azul/genética , Neoplasias Cutâneas/genéticaRESUMO
AIMS: Blue naevi are uncommon dermal melanocytic neoplasms characterised by GNAQ/GNA11 mutations, which very rarely progress to melanoma. Such melanomas also often have BAP1 mutations, and lack genetic events associated with conventional melanoma. Exceptionally, blue naevi arise in extracutaneous locations; one melanoma arising in this setting has been reported. We report the clinicopathological, immunohistochemical and molecular genetic features of two cases of melanoma arising in extracutaneous blue naevus. METHODS AND RESULTS: Both arose in males, aged 25 and 63 years, with no history of other melanocytic lesions, and presented as large, painful intra-abdominal masses. The tumours were dark-brown/black, multilobulated, involved small intestinal mesentery and consisted of a predominantly fascicular and spindled, but occasionally nested and epithelioid, proliferation of variably pigmented, relatively monotonous cells with pale cytoplasm and ovoid nuclei with mild to moderate atypia. Mitotic activity was variable but generally low. Both cases showed areas of conventional and cellular blue naevus. Recurrent tumour in one case showed predominantly epithelioid morphology and greater cytological atypia and mitotic activity. One case expressed Melan-A, SOX10 and CD117, with absent expression of S100 protein and DOG1; the other expressed Melan-A, HMB45 and S100 protein. Next-generation sequencing identified GNAQ and BAP1 mutations in one case and GNA11 mutation in the other. Both patients developed widespread metastatic disease. CONCLUSION: Exceptionally rare, aggressive melanomas arising in extracutaneous blue naevi should be distinguished from metastatic melanoma, gastrointestinal stromal tumour and malignant melanotic nerve sheath tumour, especially given the significant therapeutic and prognostic differences between these different entities.
Assuntos
Neoplasias Gastrointestinais , Melanoma , Nevo Azul , Adulto , Biomarcadores Tumorais/genética , Diagnóstico Diferencial , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/etiologia , Neoplasias Gastrointestinais/patologia , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Antígeno MART-1/genética , Masculino , Melanócitos/patologia , Melanoma/diagnóstico , Melanoma/etiologia , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Nevo Azul/complicações , Nevo Azul/genética , Nevo Azul/patologia , Nevo Pigmentado/complicações , Nevo Pigmentado/patologia , Oncogenes/genética , Prognóstico , Proteínas S100/genética , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologia , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genéticaRESUMO
Cutaneous melanomas may demonstrate a variety of histopathological features and genetic abnormalities. Melanomas that arise in the setting of blue nevi, also known as "malignant blue nevus" or melanoma ex blue nevus (MBN), share a similar histopathological and mutational profile with uveal melanoma. Most uveal melanomas show characteristic GNA11 or GNAQ mutations; additional BAP1 mutation or loss is associated with the highest risk of metastasis and worst prognosis. However, the significance of BAP1 loss in melanomas ex blue nevus remains unclear. We present a case of MBN arising from the scalp of a 21-year-old woman. The diagnosis was established on histopathological findings demonstrating a markedly atypical melanocytic proliferation with increased mitotic activity, necrosis, and a focus of angiolymphatic invasion. Immunohistochemical analysis demonstrated the absence of BAP1 nuclear expression within tumor cells. Next generation sequencing detected GNA11 Q209L mutation and BAP1 loss (chromosome 3p region loss), supporting the diagnosis. We reviewed another 21 MBN cases with reported BAP1 status from the literature. MBN with BAP1 loss presented at a younger average age (41 vs. 61 years), demonstrated larger average lesion thickness (9.0 vs. 7.3 mm), and had a higher rate of metastasis (50% vs. 33%) compared with BAP1-retained MBN. BAP1 expression studies may assist in the diagnosis and management of MBN, but further research is needed.
Assuntos
Subunidades alfa de Proteínas de Ligação ao GTP/genética , Melanoma/genética , Nevo Azul/patologia , Neoplasias Cutâneas/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Feminino , Humanos , Melanoma/patologia , Nevo Azul/genética , Couro Cabeludo/patologia , Neoplasias Cutâneas/patologia , Adulto JovemRESUMO
This study piloted a pan-solid-tumor next generation sequence (NGS)-based laboratory developed test as a diagnostic aid in melanocytic tumors. 31 cases (4 "epithelioid" nevi, 5 blue nevi variants, 7 Spitz tumors [3 benign and 4 malignant] and 15 melanomas) were evaluated. All tumors [median diameter 7 mm (range 4-15 mm); median thickness 2.25 mm (range 0.25-12 mm)] yielded satisfactory results. The number of small nucleotide variants/tumor was significantly different between melanoma (median 18/tumor, range 4-71) and all other lesions (median 8/tumor, range 3-17) (P < 0.004) and malignant (median 16/tumor, range 4-71) vs benign lesions (median 7/tumor, range 3-14) (P = 0.01). BRAF, MET, NTRK1, and ROS fusions only occurred in benign Spitz tumors; EML4 fusion, BRAF, MAP2K1 and TERT mutations occurred in malignant Spitz tumors and/or melanoma. Amplifications and NRAS and NF1 mutations only occurred in melanoma. Most melanomas contained >1 pathogenic alteration. Developed NGS-based criteria correctly classified all malignant lesions in this series. 10/12 cases showed concordance with FISH; consensus diagnosis agreed with NGS classification in FISH-non-concordant cases. This pilot study suggests that NGS may be an effective diagnostic adjunct comparable to FISH, but further studies with larger numbers of cases are needed.