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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.

Blue rubber bleb nevus syndrome (BRBNS) commonly presents with anemia from bleeding gastrointestinal (GI) vascular malformations. Management is highly variable, as no consensus guidelines for medical treatment currently exist. Sirolimus has been used in BRBNS to decrease GI bleeding and seems well tolerated, though questions remain regarding dosing, duration of therapy, and adverse effects. Here, we report our single-center experience of four pediatric patients with BRBNS who were successfully treated with sirolimus and review the existing literature regarding sirolimus for treatment of GI bleeding in BRBNS. Further prospective studies are needed to establish optimal dosage, drug monitoring, and duration.

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).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.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.

An accurate diagnosis of melanocytic lesions requires a thorough histopathological evaluation accompanied by appropriate correlation with clinical examination findings. Although most melanocytic lesions can readily be classified as one of the defined diagnostic entities according to well-established diagnostic criteria, a subset of melanocytic lesions, particularly those with blue naevus-like (pigmented dendritic) morphology, have notoriously constituted an enduring challenge for pathologists. These lesions are rare and often show histological ambiguities, with features of both benignity and malignancy, thereby making accurate risk assessment and prediction of their biological behaviours difficult on histological grounds alone. Herein, we outline a practical and systematic approach for the diagnosis of melanocytic lesions with dendritic morphology, with a particular focus on histological and immunophenotypic features that help to distinguish one entity from another. In this review, we provide the most current knowledge on these melanocytic lesions in the literature and our experience with these rare entities, and we discuss the utility of molecular techniques as an ancillary tool, especially in histologically ambiguous and/or borderline lesions.

Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder that is characterized by multiple dome-shaped cutaneous venous malformations on the skin and visceral organs. Typical extra-cutaneous lesions have the appearance of blueish nipple-shaped nodules that can easily compress and refill. We described a rare case of a 23-year-old female with BRBNS and tuberous sclerosis complex (TSC) that presented with central nervous system (CNS) involvement including unprovoked focal impaired awareness seizure. Her BRBNS presents with hemangiomas involving multiple organs in the body including the brain, gastrointestinal (GI) system, and skin. This case highlights the importance of studying and understanding the association between BRBNS and TSC as it may lead to improved understanding

Blue nevi are a heterogeneous group of lesions that can display a variety of different clinicopathological characteristics. Although attempts are made to classify each lesion into defined subtypes, there can be overlap between the subtypes. The clinical , dermoscopic and histolopathologic features of a case of proliferative nodule arising within blue nevus is discussed. Running title: Blue nevi are an heterogeneous group of melanocytic lesions blue tinctorial properties. Proliferative nodules are rare benign lesions often present at birth as a component of a large congenital melanocytic nevi, congenital or acquired nevi. We first report a case of proliferative nodule arising within blue nevus.

Histologic distinction between melanoma ex-blue nevus and cellular blue nevus (CBN) can often be difficult, but features supporting melanoma include infiltrative growth pattern, frequent mitoses, cytologic atypia and pleomorphism, cell crowding, and tumor necrosis. Unfortunately, these features are not constantly dependable and frequently borderline lesions exist, so-called atypical CBN, which lack explicit malignant features. Furthermore, some CBN and atypical CBN show an assortment of features, which may lead to their misdiagnosis as melanoma, but to date necrosis is generally absent. We present an unusual case of an atypical cellular blue nevus with extensive necrosis mimicking melanoma ex-blue nevus.

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.

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 contained1 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.

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 similar histopathological and mutational profile with uveal melanoma. The majority of uveal melanomas show characteristic GNA11 or GNAQ mutations; additional BAP1 mutation or loss is associated with the highest risk for metastasis and worst prognosis. However, the significance of BAP1 loss in melanomas ex blue nevus remains unclear. We present a case of melanoma ex blue nevus arising from the scalp of a twenty-one-year-old female. 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 twenty-one MBN cases with reported BAP1 status from the literature. MBN with BAP1 loss presented at a younger average age (41 years versus 61 years), demonstrated larger average lesion thickness (9.0 mm versus 7.3 mm), and had a higher rate of metastasis (50% versus 33%) compared with BAP1-retained MBN. BAP1 expression studies may assist in the diagnosis and management of MBN, but further research is needed.

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.

Loss-of-function mutations in EED and SUZ12, core components of the polycomb repressive complex 2 (PRC2), occur in90% 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.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).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".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.

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.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.Molecular analysis identified GNAQ and BAP1 pathogenic variants, which strongly suggested the diagnosis as a primary epibulbar melanoma arising from episcleral blue nevus.This case demonstrates the value of tumor molecular analysis using Next Generation Sequencing (NGS) for differentiating the origin of an unusually located ocular melanoma.

Blue rubber bleb nevus syndrome (BRBNS) is a rare syndrome characterized by venous malformations in the skin and gastrointestinal tract, especially in the small intestine. Patients with BRBNS have increased risks of gastrointestinal hemorrhage and anemia. This is the first report in the English literature on BRBNS with hemangiomas in the small intestine that were treated successfully by endoscopic clipping using double-balloon endoscopy. A 25-year-old Japanese man presented to a local clinic with dyspnea, fatigue, and a hemoglobin level 5 g/dL. The diagnosis was iron deficiency anemia. Since childhood, he had had a hemangioma in the shoulder joint and hemangiomas in the skin on the left arm. However, neither upper nor lower gastrointestinal endoscopy showed any lesions and he was referred to us for further evaluation and treatment of the anemia. Small bowel capsule endoscopy (SBCE) revealed hemangiomas in the small intestine, one of which was bleeding. Transanal DBE revealed a 10-mm bluish-purple hemangioma with erosion on the surface, which became smaller after application of five clips. Follow-up SBCE on day 50 showed that the hemangioma had completely disappeared. Clipping may be a safe and effective treatment for small bowel hemangioma in BRBNS.

Carney complex (CNC) is a rare familial multi-neoplastic syndrome predisposing to endocrine and non-endocrine tumors due to inactivating mutations of PRKAR1A leading to perturbations of the cAMP protein kinase A (PKA) signaling pathway. Skin lesions are the most common manifestation of CNC, including lentigines, blue nevi and cutaneous myxomas, in unusual locations such as oral and genital mucosa. Unlike endocrine disorders, the pathogenesis of skin lesions remains unexplained. Here, we show that embryonic invalidation of the Prkar1a gene in Steroidogenic Factor-1-expressing cells, leads to the development of familial skin pigmentation alterations reminiscent of those in patients. Immunohistological and molecular analyses coupled with genetic monitoring of recombinant cell lineages in mouse skin, suggest that familial lentiginosis and myxomas occurs in skin areas specifically enriched in dermal melanocytes. In lentigines and blue nevi-prone areas from mutant mice and patients, Prkar1a/PRKAR1A invalidation occurs in a subset of dermal fibroblasts capable of inducing, under the influence of PKA signaling, the production of pro-melanogenic EDN3 and HGF signals. Our model strongly suggests that the origin of the typical CNC cutaneous lesions is the result of non-cell-autonomous pro-melanogenic activity of a dermal fibroblast population sharing a community of origin with SF-1 lineage.

Bean syndrome or blue rubber bleb nevus syndrome (BRBNS) is a rare disease characterized by venous malformations (VM) of the skin, soft tissues and visceral organs, most frequently affecting the gastrointestinal (GI) tract. BRBNS is mainly sporadic but can be inherited in an autosomal pattern. The most common symptoms are GI bleeding and secondary iron deficiency anemia. Treatment is largely symptomatic.

Preferentially expressed antigen in melanoma (PRAME) is an immunohistochemical biomarker that is diffusely expressed in most cutaneous melanomas and is negative in most benign nevi. Histologically challenging dermal melanocytic neoplasms, such as cellular blue nevi (CBN) and deep penetrating nevi (DPN), and soft tissue tumors with melanocytic differentiation, such as clear cell sarcoma and perivascular epithelioid cell tumor, may resemble primary or metastatic melanoma. PRAME immunohistochemistry (IHC) was applied to archived formalin-fixed, paraffin-embedded specimens of various dermal melanocytic neoplasms and soft tissue neoplasms with melanocytic differentiation. Staining was graded based on the percentage of melanocytes labeled (0-4+ as previously reported). The gold standard was final pathologic diagnosis using histologic, immunophenotypic, and in some cases molecular findings. Fifty-four cases were evaluated. 62.5% (5/8) of blue nevus-like melanomas and 50% (1/2) of DPN-like melanomas were PRAME positive (4+). Of the other tumors, 100% (20/20) of CBN (including 1 atypical CBN with borderline features); 100% (12/12) of DPN, combined DPN, or borderline DPN; 88.9% (8/9) of perivascular epithelioid cell tumors; and 100% (3/3) of clear cell sarcoma were PRAME negative (0-2+). Within the borderline categories specifically, all 8 tumors (1 borderline CBN and 7 borderline DPN) showed low (0-2+) PRAME expression. Overall, the sensitivity for melanoma in this context was 60%, with a specificity of 97.7%. Although our sample size is limited, the results suggest that IHC staining for PRAME may be useful in supporting a diagnosis of melanoma in the setting of challenging dermal melanocytic neoplasms and other epithelioid neoplasms with melanocytic differentiation. However, PRAME IHC lacks sensitivity in this context.

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.

BackgroundPrimary orbital melanoma is a rare disease and can occasionally develop from a pre-existing neoplasm of the blue naevus family of melanocytic lesions.Case presentationHerein we report a rare case of primary orbital melanoma arising from an unusual atypical diffuse (plaque-like) blue naevus/melanocytosis. A 27 year old man presented with mild pain and swelling of the left eye. Magnetic Resonance Imaging revealed a left lateral episcleral orbital mass and an incisional biopsy confirmed the diagnosis of malignant melanoma. Skin-sparing total left orbital exenteration was performed. Histopathological examination of the exenteration specimen revealed a primary orbital melanoma arising in a pre-existing blue naevus like melanocytosis.We demonstrate the evidence for histological progression, characterise the molecular profile of this tumour and discuss the related literature.ConclusionsThis case emphasises the importance of a meticulous clinicopathological correlation in recognising such a tumour as a primary orbital melanoma rather than a metastasis, which is managed differently.

Blue rubber bleb nevus syndrome (BRBNS) is a rare systemic syndrome characterized by venous malformations usually found in the skin and visceral organs. To date, 11 case reports describing BRBNS during pregnancy have been published. To our knowledge, this is the first report describing intracranial, airway, epidural, and birth canal involvement of venous malformations in the same parturient. Key lessons learned include clinical presentation, workup, team management, and care of obstetric patients with this disorder.

Recurrent activating Gαq mutations in the spectrum of blue nevi have been well studied. However, the clinicopathologic characteristics of the recently described CYSLTR2-mutant and PLCB4-mutant blue nevi remain limited, owing to their rarity. Herein, we present 7 CYSLTR2-mutant melanocytic neoplasms, including 1 cellular blue nevus, 4 atypical cellular blue nevi, and 2 blue nevus-like melanomas. They occurred on the scalp, breast, flank, forearm, thigh, leg, and ankle of 3 male patients and 4 female patients, with a median age of 43 (25 to 81) years at diagnosis. Five exhibited an exophytic growth, and 6 were heavily pigmented. A fascicular arrangement of medium to large spindle melanocytes was seen in 6 cases, but epithelioid cytology was present in only 2 cases, one of them being focal. A junctional component was present in 3 cases. Immunoreactivity for HMB45 was diffusely present, except in 1 cellular blue nevus. BAP1 nuclear immunoexpression was lost in 1 melanoma case. A canonical CYSLTR2 L129Q hotspot mutation was present in all cases. Altogether, these histopathologic findings suggest that CYSLTR2-mutant melanocytic blue neoplasms frequently exhibit a heavily pigmented exophytic tumor with a silhouette resembling "pigmented epithelioid melanocytoma" rather than usual cellular blue nevus. Moreover, most of these tumors were not clinically recognized as blue nevi and not located in the classic topography of cellular blue nevus aside from the scalp. However, a fascicular arrangement of medium to large-sized spindled melanocytes, as well as a lack of epithelioid or nevoid melanocytes, could be potential diagnostic clues to morphologically distinguish CYSLTR2-mutant tumors from "pigmented epithelioid melanocytoma."

Gradations in skin color are a consequence of differing amounts of melanin and their varying distribution. Although many darkly pigmented skin lesions are melanocytic and can be attributed to melanin content, the color of a black lesion can also be due to blood, necrotic tissue, or exogenous pigment. The source, pattern, and distribution of the color in black lesions usually offer important insight into its etiology. This contribution reviews conditions that can take on a black color, discussing the cause of the hue and any additional impact sun exposure may have.

Pigmented epithelioid melanocytoma (PEM) is considered an intermediate grade melanocytic lesion that is histologically indistinguishable from epithelioid blue nevi associated with Carney complex. PEM are characterized by an intradermal population of heavily pigmented epithelioid-shaped melanocytes along with some spindled and dendritic melanocytes with frequent melanophages. These melanocytic tumors occasionally involve regional lymph nodes but only rarely result in distant metastases. Recent studies have demonstrated a variable but limited number of specific genomic aberrations including protein kinase A regulatory subunit alpha (PRKAR1A), BRAF, GNAQ, and MAP2K1 mutations as well as protein kinase C alpha isoform (PRKCA) fusions. We performed an 8-year retrospective review of our database and identified 16 cases of PEM. Using targeted DNA sequencing and RNA-seq to assess 1714 cancer-related genes, we detected gene fusions involving PRKCA in 31% of cases (5/16) with 5' partners SCARB1(12q24) in 2 cases, CD63 (12q13) in 1 case, ATP2B4 (1q32) in 1 case, and MAP3K3 (17q23) in 1 case. Additional fusions were identified in TPR-NTRK1 (1/16), ALK (1/16), and MYO5A-NTRK3 (1/16). PRKCA fusion lesions tended to occur in younger-aged patients and histologic examination demonstrated sheets of monomorphic epithelioid-shaped melanocytes, moderate to high-grade nuclear atypia, and higher mitotic activity (P=0.037). Our gene panel also identified previously described mutations in PRKAR1A, GNAQ, MAP2K1, BRAF, NF1. To our knowledge, this is the largest and most comprehensive study of PEM integrating molecular data with histologic features that can be utilized in future studies for improved subclassification and prognostication of heavily pigmented melanocytic neoplasms.

Dermal melanocytoses (DMs) comprise a heterogeneous group of benign lesions, located on skin and mucous membranes, characterized by dendritic melanocytes in the dermis. Although they share common histopathological features, some variants may present only as bluish or grey patches, some only as papules/nodules/plaques and others may show combination of all of these lesions. Despite the fact that blue naevus (BN) is typically characterized with papulonodular lesions, its variants may show all of the aforementioned presentations. Mongolian spot, naevus of Ota and naevus of Ito are patchy DMs distinguished by their specific localizations. Apart from these classical forms, many atypical variants without unique clinicopathological characteristics have been described in the literature making the nomenclature of DMs more complicated. However, congenital dermal melanocytosis and acquired dermal melanocytosis seem to be crucial umbrella terms that encompass all patchy DMs in atypical locations. Papules or subcutaneous nodules on patchy lesions and association of epidermal pigmentation presenting as brownish patches may be encountered as rare features of DMs. On the other hand, delayed-onset subcutaneous nodules may be typical presentations of melanoma in patchy DMs; therefore, they deserve special attention. Large plaque-type BN with subcutaneous cellular nodules is a newly described entity, harbouring clinical features of various DMs together and has a high risk of melanoma. The whole spectrum of dermal dendritic melanocytic proliferations is discussed including novelties and controversial issues.

Distinguishing cellular blue nevi (CBNs) and atypical CBNs from blue nevus-like melanoma (BNLM) can be diagnostically challenging. Immunohistochemistry may inform the diagnosis in a subset of cases but is not always diagnostic. Further, ancillary molecular testing is expensive and often requires significant tissue to complete. Primary cilia are cell-surface organelles with roles in signal transduction pathways and have been shown to be preserved in conventional melanocytic nevi but lost in melanoma. Immunofluorescence staining of primary cilia can be performed using a single standard-thickness formalin-fixed paraffin-embedded tissue section and has a turnaround time similar to immunohistochemistry. The percentage of tumoral melanocytes retaining a primary cilium is quantified and reported as the ciliation index. In the current study, we explored the utility of the ciliation index in a series of 31 blue nevus-like lesions, including CBNs (12), atypical CBNs (15), and BNLM (4). The average ciliation index for the CBNs was 59±18%, with a median of 60 (range: 28 to 87). The average ciliation index for atypical CBNs was 59±23, with a median of 59 (range: 20 to 93). The average ciliation index for BNLM was 4±3, with a median of 3 (range: 1 to 8). There was no significant difference in ciliation index between the CBN and atypical CBN categories. There was a significant difference between CBN and BNLM and between atypical CBNs and BNLM (P

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.

Background Digital clubbing is a well-known clinical sign characterized by thickening of the distal phalanges of the fingers and toes. Unilateral clubbing occurs less frequently. A previous report showed for the first time two cases of unilateral clubbing as a clinical manifestation of lower limb venous malformation. The objective of the present study is to describe a series of 13 patients with a low-flow vascular malformation where a clubbing-like unilateral digital thickening is also observed. Methods All patients were retrospectively included after reviewing clinical photographs from a vascular malformations database. Results A total of 13 patients with low-flow vascular malformations were included in this study. The mean age at diagnosis was 11 years (range 5-26 years) with a female predominance (nine patients). The most frequent vascular malformation collected was a blue rubber bleb nevus syndrome in four patients, followed by common venous malformations in three patients. All patients characteristically exhibited a clubbing-like digital thickening. Seven patients had foot involvement and six patients hand involvement. Conclusions Although the number of cases is limited, our study is the first series of cases where a clubbing-like digital thickening is described in patients with a low-flow vascular malformation. The unilateral presence of clubbing or pseudoclubbing should lead to the suspicion of an underlying vascular malformation.

Objectives: Cerebriform intradermal nevus and giant congenital blue nevi are rarely reported melanocytic nevi with clinical and histopathologic similarities. Both are known to produce cutis verticis gyrata. We report a significantly large occipital scalp congenital blue nevus with secondary cutis verticis gyrata. The aim of this report is to increase clinical awareness of this entity, highlight histopathologic and mutational features of cerebriform intradermal nevi and giant congenital blue nevi, and stress the importance of clinicopathologic correlation for diagnosis. Methods: Case report and review of the literature. Results: A 20-year-old Asian male presented with a long-standing, large (20 cm × 30 cm), exophytic tumor at the occipital scalp and posterior neck. The skin overlying the lesion was arranged in thick folds resembling the surface of the brain, devoid of hair follicles, and discolored by salt-and-pepper pattern hyperpigmentation. After correlating the clinical and histopathologic findings, we diagnosed giant congenital blue nevus with secondary cutis verticis gyrata. Staged surgical excision was performed with subsequent treatment for hypertrophic scarring and occipital alopecia. Conclusions: Cerebriform intradermal nevus and giant congenital blue nevus have overlapping histologic and clinical features. Head and neck surgeons should be aware that nomenclature of these tumors is subjective and often imprecise. Diagnosis requires correlation of clinical findings, patient history, and histopathology. Surgical excision is advised due to rare malignant transformation potential.

Pigmented epithelioid melanocytoma is a rare, newly described melanocytic tumor that encompasses lesions previously classified as animal type melanomas and epithelioid blue nevus of the Carney complex. Pigmented epithelioid melanocytoma is a specific clinicopathological entity with particular clinical presentation and histological features. We present the case of a 5 year old female patient with a heavily pigmented papule on her right thigh that showed histological findings compatible with pigmented epithelioid melanocytoma and discuss the relevance /clinical significance of sentinel lymph node biopsy as a staging procedure in this particular neoplasm.

Abstract: Pigmented epithelioid melanocytoma is a rare, newly described melanocytic tumor that encompasses lesions previously classified as animal type melanomas and epithelioid blue nevus of the Carney complex. Pigmented epithelioid melanocytoma is a specific clinicopathological entity with particular clinical presentation and histological features. We present the case of a 5 year old female patient with a heavily pigmented papule on her right thigh that showed histological findings compatible with pigmented epithelioid melanocytoma and discuss the relevance /clinical significance of sentinel lymph node biopsy as a staging procedure in this particular neoplasm.