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Blue nevus is a benign melanocytic lesion, typically asymptomatic and of unknown etiology. Many histological subtypes are recognized, the most commons being: common blue nevus, cellular blue nevus, and combined blue nevus. New rare variants have been described in the literature, with emphasis on eruptive blue nevus, plaque, agminate, linear, with satellitosis, disseminated, familial and targetoid. The diagnosis of blue nevus usually presents no difficulties, however, the presence of structures such as irregular edges or satellitosis, are highly suggestive of malignancy, and the differential diagnosis with malignant blue nevus and melanoma with peripheral spread should be considered. We report a case of blue nevus with satellitosis in a 15-year-old female patient.

Cellular blue nevomelanocytic lesions (CBNLs) frequently pose diagnostic problems to pathologists, and their biological potential may be difficult to establish. In this study, the authors have analyzed the clinical, histological, and outcome data of 37 cellular blue nevomelanocytic lesions and the molecular characteristics of 4 lesions. The cohort of cases comprised 8 cellular blue nevi (CBNs), 17 atypical cellular blue nevi (ACBNs), and 12 blue-nevus-like melanomas (BNLMs) with a mean follow-up of 5 years. The average age at diagnosis was 25.9 years for patients with ACBN, versus 30.4 years for CBN, and 44.6 years for BNLM. Both CBN and ACBN occurred most frequently on the trunk or extremities, whereas BNLM primarily involved the scalp. Histologically, CBN and ACBN were characterized by a mean diameter of

Melanomas arising in association with a common or cellular blue nevus (MABN) comprise a relatively rare and heterogeneous group of lethal melanomas. Although GNAQ is known to be frequently mutated in common blue nevus, cellular blue nevus (CBN) and MABN and these malignant lesions present gross chromosome alterations harboring BAP1 mutations, little is known about other mutations that contribute to the development and progression of these neoplasms. Thus, the genetic profile of these tumors is important to increase the number of intervention and treatment modalities. Here, we characterized and genetically profiled two different sections of a rare MABN and two CBNs from three different patients. All of the samples harbored a GNAQ mutation, exhibited RAS pathway activation, and harbored additional mutations in genes associated with genomic instability and epigenetic regulation (KMT2C, FANCD2, ATR, ATRX, NBN, ERCC2, SETD2, and WHSC1). In addition, all neoplasms harbored mutations that directly or indirectly affected either the regulation or activation of the PI3K pathway (PIK3CA, NF1, INPP5B and GSK3B). Our results not only help understand the genetic complexity of these blue melanocytic lesions but provide a rationale to use the combination of PI3K/MTOR and MEK1/2 inhibitors against these types of tumors.

Blue nevi may display significant atypia or undergo malignant transformation. Morphologic diagnosis of this spectrum of lesions is notoriously difficult, and molecular tools are increasingly used to improve diagnostic accuracy. We studied copy number aberrations in a cohort of cellular blue nevi, atypical cellular blue nevi, and melanomas ex blue nevi using Affymetrix's OncoScan platform. Cases with sufficient DNA were analyzed for GNAQ, GNA11, and HRAS mutations. Copy number aberrations were detected in 0 of 5 (0%) cellular blue nevi, 3 of 12 (25%) atypical cellular blue nevi, and 6 of 9 (67%) melanomas ex blue nevi. None of the atypical cellular blue nevi displayed more than one aberration, whereas complex aberrations involving four or more regions were seen exclusively in melanomas ex blue nevi. Gains and losses of entire chromosomal arms were identified in four of five melanomas ex blue nevi with copy number aberrations. In particular, gains of 1q, 4p, 6p, and 8q, and losses of 1p and 4q were each found in at least two melanomas. Whole chromosome aberrations were also common, and represented the sole finding in one atypical cellular blue nevus. When seen in melanomas, however, whole chromosome aberrations were invariably accompanied by partial aberrations of other chromosomes. Three melanomas ex blue nevi harbored aberrations, which were absent or negligible in their precursor components, suggesting progression in tumor biology. Gene mutations involving GNAQ and GNA11 were each detected in two of eight melanomas ex blue nevi. In conclusion, copy number aberrations are more common and often complex in melanomas ex blue nevi compared with cellular and atypical cellular blue nevi. Identification of recurrent gains and losses of entire chromosomal arms in melanomas ex blue nevi suggests that development of new probes targeting these regions may improve detection and risk stratification of these lesions.

Blue rubber bleb nevus syndrome, a syndrome of multifocal venous malformations, has been reported rarely during pregnancy. This syndrome has been associated with airway lesions in some patients and neuraxial abnormalities in other patients. We report the anesthetic and obstetric management of a patient with an extensive distribution of both airway and neuraxial lesions.

Recently, sirolimus was demonstrated to be effective in treating vascular lesions and lessening the frequency of bleeding and secondary iron deficiency anemia. We present a child with blue rubber bleb nevus syndrome who had prolonged history of iron deficiency anemia secondary to unrecognized gastrointestinal bleeding. Treatment with propranolol, omeprazole and iron had failed. After 2.5 months of sirolimus therapy (trough levels 1 to 5 ng/mL), his hemoglobin concentration improved into the normal range and remained stable. Vascular malformations on both the patient's tongue and in the fundus of his stomach shrank within 5 months of the initiation of sirolimus. In gastrointestinal involvement of blue rubber bleb nevus syndrome sirolimus was found to be effective even in the tongue's vascular lesions.

Visceral vascular anomalies are common in patients with vascular malformations in other parts of the body and can include lymphatic, venous, and arteriovenous malformations. Depending on the organ or organs involved they may present differently and pose different treatment challenges. Defining the malformation and understanding its extent is paramount in devising management regimens. Medical, interventional, and surgical therapies are often required in combination to treat these complex lesions. There are new and promising advances in the development of therapeutic agents targeting the PI3K/AKT/mTOR pathway. Due to the complex nature of these lesions a coordinated, multi-disciplinary approach is necessary to manage and mitigate symptoms and complications of this diverse group of vascular malformations.

Described for centuries in the equines, especially gray horses, under the terminology of ‘equine melanotic disease’ and, subsequently recognized in non-equine animal models and in humans, particularly on non UV-exposed skin, animal-type melanoma, also known as pigmented epithelioid melanocytoma (PEM), is characterized by nodules and fascicles of epithelioid transformed melanocytes with pleomorphic nuclei and striking pigmentation, dendritic cells, numerous melanophages and, sometimes, lymphocytic infiltrate. Up today, only small series have been reported in humans and, therefore, its biological behavior remains unclear. Recently, some authors have supported that the tumor follows an indolent clinical course, with very low risk of spread beyond regional lymph nodes. Given the complexity of the matter, Elder and Murphy proposed a histological categorization of PEM and PEM-like lesions in: epithelioid blue nevus resembling PEM, strongly associated with the Carney complex; PEM, not associated with the Carney complex; tumoral melanosis mimicking PEM. A proper diagnostic framing is crucial in these controversial cases and a good histology in the hands of an expert dermatopathologist remains the most reliable diagnostic starting point. Moreover, a loss of expression of cAMP-dependent protein kinase type I-alpha regulatory subunit, an enzyme encoded by the tumor-suppressor gene PRKAR1A, has been found in PEM, but not in common melanoma or other melanocytic lesions. Therefore, it appears to have a great diagnostic value in helping to distinguish PEM from PEM-like lesions, which mimic the former histologically.

A young man presented with blue nodules on the trunk, face, and extremities that gradually increased in number and size. His mother had similar lesions. Initially, blue rubber bleb nevus syndrome was suspected, but histological findings confirmed the diagnosis of hereditary glomuvenous malformations. Making the correct diagnosis spares the patient unnecessary evaluation for the arteriovenous malformations of the gastrointestinal tract associated with the former diagnosis.

Background Bean syndrome (BS) is a rare congenital low-flow angiomatosis affecting multiple organ systems. About 200 cases with heterogeneous clinical presentation have been reported worldwide. The exact etiopathology is still not known. Most reported cases have occurred sporadically, although autosomal dominant inheritance has been suggested. BS predominantly presents with characteristic multifocal mucocutaneous lesions and often leads to refractory anemia caused by occult blood loss from the alimentary tract. Apart from the mucocutaneous and gastrointestinal tract involvement, this syndrome may rarely affect the central nervous system in the form of multiple venous anomalies. Patients often approach a dermatologist or gastroenterologist for treatment and this entity is usually less known among neurosurgeons. To the best of our knowledge, only 3 cases of sinus pericranii and 12 cases with orbital hemangioma as a presenting feature in BS have been reported. Case description Keeping neurosurgical management of this rare entity in mind, we discuss a case of a young female who presented with congenital naso-orbital swelling with a history of multiple-stage embolization and surgical excision of the orbital mass in her childhood. Now, she presented with recurrent swelling involving the right side of the forehead for cosmetic concerns and was subsequently diagnosed to have BS at 23 years of age. Conclusions Blue rubber bleb nevus syndrome is a lesser known entity among neurosurgeons that requires a high index of clinical suspicion for diagnosis. Red herrings, such as in our case, must prompt a search for characteristic mucocutaneous lesions and other associated lesions of blue rubber bleb nevus syndrome. A timely diagnosis may improve the quality of life and help avoid life-threatening complications.

The aim of this study is to review sirolimus as a treatment for blue rubber bleb naevus syndrome (BRBNS). A literature search of Medline, Embase, CINAHL, SCOPUS and Google Scholar was conducted for publications reporting treatment of patients with BRBNS with sirolimus. Of 46 articles identified, 17 studies reporting 23 patients met inclusion criteria. Sirolimus was well tolerated in all but one patient who required treatment cessation; 17/18 patients noted an improvement in gastrointestinal disease where this was reported; 21/22 patients noted an improvement in cutaneous disease where this was reported. Based on these results, sirolimus may be considered a first-line treatment of BRBNS depending on patient morbidity.

Osteonevus of Nanta is a rare histopathologic variant of melanocytic nevus that results from ossification of the dermis between dermal nests of melanocytes. Most cases described in the literature have been associated with long-standing intradermal nevi and were often located in the upper part of the body. We report a lesion on the shoulder of an elderly man showing the association of a common blue nevus and osteoma cutis, an exceptional feature which has been previously reported in 2 instances. We also describe for the first time the dermoscopic appearance of this "blue osteonevus."

Agminated blue nevi are dermal melanocytic proliferations that classically present as dark blue macules or papules in a grouped, linear, or blaschkoid distribution. In their more common sporadic form, blue nevi manifest in young adulthood as solitary blue papules or macules on the scalp, face, hands, or feet. By contrast, agminated blue nevi tend to manifest earlier in life, and are distributed more evenly across anatomic sites. Recent studies have identified mutations in sporadic blue nevi in the genes encoding G Protein subunit alpha Q and G protein subunit alpha 11 (GNAQ and GNA11). It is unknown whether agminated blue nevi share the same genetic changes. In the present paper, we present a case of agminated blue nevus on the wrist, and identify an activating mutation (c.626A > T, p.Glu209Leu) in GNAQ. We hypothesize that GNAQ/GNA11 activating mutations arising earlier during development may trigger agminated blue nevi, explaining the broader field of involvement in these cutaneous lesions.

Rationale: Blue rubber bleb nevus syndrome (BRBNS) is a rare vascular disorder consisting of multifocal venous malformations. Delayed diagnosis or misdiagnosis frequently occurs in patients without typical cutaneous lesions or gastrointestinal bleeding symptoms. This article reports a 10-year case of delayed diagnosis of BRBNS detected by capsule endoscopy. Patient concerns and diagnosis: A 15-year-old girl presented with refractory iron-deficiency anemia (IDA) for 10 years, without any hemorrhagic signs or noticeable cutaneous lesions, which led to her obvious physical growth retardation. Capsule endoscopic examination revealed dozens of vascular blebs distributed from the jejunum to the ileum and a site of active bleeding. Hence, she was diagnosed with BRBNS. Interventions: Laparotomy was performed with resection of the small bowel lesions, and iron supplementation was prescribed for 3 months. Postoperatively, the patient had an uncomplicated course. Outcomes: On follow-up after 3 years, IDA in this patient was cured and she did not require further blood transfusion and showed excellent vigor. Lessons: A high index of suspicion for BRBNS and adequate endoscopy examination will help to identify the origin of refractory IDA in older children, particularly in patients with vascular lesions of the skin.

PURPOSE: Blue nevus is a melanocytic tumor that has been commonly described in the skin. Extracutaneous presentations including the ocular surface are rare. As such, the purpose of this study was to characterize the clinical features and clinical course of the congenital melanocytic tumor (blue nevus) of the conjunctiva. DESIGN: Retrospective noncomparative case series PARTICIPANTS: 21 patients with 23 blue nevi of the ocular surface that were surgically excised between 2000–2016. METHODS: A chart review of patients identified from a database search of the Florida Lions Ocular Pathology Laboratory records. Pathological diagnoses were confirmed by two pathologists (SRD and GE). All specimens were bleached and tissue permitting, stained using SOX10 (MilliporeSigma, Darmstadt, Germany) and CD68 (Leica Biosystems, Nussloch, Germany). MAIN OUTCOME MEASURES: Clinical characteristics, pathological features, and clinical course. RESULTS: Mean age of the population was 55±15; 71.4% (n=15) were white and 57.1% (n=12) male. One patient had 3 lesions for a total of 23 lesions examined. Clinically, 13 lesions were on the bulbar conjunctiva, 3 on the tarsal conjunctiva, 3 in the fornix, 2 caruncular, 1 episcleral and 1 at the limbus. Pre-excision, 8 patients were thought to have primary acquired melanosis (PAM), 4 with concern for primary conjunctival melanoma, and 1 thought to have metastatic disease from a plantar melanoma. Five lesions were thought to be benign, and in 8 patients the lesions were identified incidentally after other ocular surgeries, with no pre-excision diagnosis of the lesions. Pathological features were consistent with simple blue nevi in 21 lesions and cellular blue nevus in 2 lesions. No malignant transformations were noted in any patient over the mean 20.2 months follow up period (range 2 weeks to 103 months). CONCLUSION: Blue nevus is a rare deeply pigmented congenital melanocytic lesion with a benign clinical course that can appear clinically similar to PAM or melanoma.

The blue rubber bleb nevus syndrome or Bean syndrome is a rare disorder characterised by the presence of haemangiomas in the skin and gastrointestinal tract. These lesions are usually accompanied by chronic hypochromic anaemia resulting from gastrointestinal bleeding. The cause of this syndrome is unknown. It mostly occurs as sporadic, but autosomal dominant inheritance has also been described. The diagnosis is based on endoscopy, magnetic resonance imaging and computer tomography. Treatment is usually symptomatic.

Rationale: Blue rubber bleb nevus syndrome (BRBNS) is a rare disease characterized by multiple venous malformations. The gastrointestinal bleeding and secondary iron deficiency anemia are the most common complications. There are currently no effective treatments for BRBNS. Here, we report a case of successful treatment with a small dose of sirolimus of a BRBN patient with a de novo gene mutation. Patient concerns: A 12-year-old female was admitted to our hospital with multiple hemangiomas for 12 years. The patient often displayed melena; she recently received transfusion of 2 units of red blood cells once every 2 weeks. Multiple fist-sized hemangiomas were piled up on both sides and back of the neck, and were also noted on the arms, legs, chest, back, and on the tip of the tongue. The laboratory findings demonstrated severe anemia. Blood sample sequencing detected a heterozygous de novo mutation c.2545C > Tin the TEK gene. Diagnoses: Based on these findings, final diagnosis of Blue rubber bleb nevus syndrome (BRBNS) was made. Interventions: After the diagnosis, low-dose sirolimus was orally administered. Outcomes: The patient's hemoglobin was increased after treatment with sirolimus for 1 month. Since the initial treatment with sirolimus, she had not received any blood transfusions. The skin and mucosal hemangioma decreased significantly, and new digestive tract hemorrhage, muscle hematoma, or adverse drug reactions were not observed. Lessons: we report a case of a mutation in exon 15 of the TEK gene leading to BRBN. It was successfully treated with a small dose of sirolimus as an alternative to blood transfusion in order to save the of BRBN patient's life.

Blue rubber bleb nevus syndrome (BRBNS) is a rare congenital vascular disease associated with important morbidity and non-insignificant risk of mortality in cases of severe gastrointestinal or neurological involvement. Early diagnosis in the neonatal period can be difficult as very often skin lesions appear progressively during childhood having no correlation with gastrointestinal lesion development. The appearance of one large venous malformation (VM) in the neonatal period has suggested a characteristic finding of this syndrome. The objective of the study was to identify a specific clinical sign in the congenital venous malformations (VMs) of the BRBNS to distinguish them from the conventional VMs. Clinical histories of all patients diagnosed with BRBNS were reviewed, including those who presented a large VM at birth. Clinical characteristics of congenital VM associated with BRBNS were recorded. Five patients with BRBNS were found to have a large VM since birth. All of them presented a fern-shaped patch over the surface of the VM.The finding of this macroscopic sign in the evaluation of the newborn with a VM could be considered as a guiding syndromic herald which should raise suspicion for BRBNS and allow for more accurate evaluation and surveillance for complications. What is Known: • BRBNS is a rare vascular disease associated with important morbidity and non-insignificant risk of mortality in cases of severe gastrointestinal or neurological involvement. • Early diagnosis in the neonatal period can be difficult as very often skin lesions appear progressively during childhood having no correlation with gastrointestinal lesion development. What is New: • Recognition of a fern-shaped patch in neonates with a VM should raise suspicion for BRBNS and allow for more accurate evaluation and surveillance for complications.

A 14-year-old female with a history of blue rubber bleb nevus syndrome (BRBNS) with gastrointestinal (GI) manifestations requiring previous endoscopy and bowel resection (Figure 1a,b) presented wit...

Blue naevi may present rarely as multiple lesions grouped in a circumscribed area, described as agminated blue naevi. This clinical presentation may mimic metastatic malignant melanoma. We present two cases of agminated cellular blue naevi of the penis, with dermoscopy, reflectance confocal microscopy and histopathological correlation. Dermoscopy of the area showed multiple grouped lesions of homogeneous dark-brown to blue colour. Using reflectance confocal microscopy, focusing on the bluish areas, predominantly bright dendritic cells were visible at the dermoepidermal junction and papillary dermis, while in the brownish areas the presence of dendritic and bright cells predominated in the basal layer. Our patients are of special interest as they are the first cases, to our knowledge, reported of agminated blue naevi on the penis, studied by both dermoscopy and confocal microscopy, confirming the diagnosis with histopathological correlation. Moreover, one case represented a divided or 'kissing' blue naevus of the penis.

Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.

Facial skin lesions are common; patients may present with a nodule, crack, ulcer or abnormal discoloration of the skin that is not normally present. Ideally, dentists should include face examination in their routine clinical examination. Any suspicious lesion should be referred to a dermatologist as an early diagnosis and treatment could be life-saving. This article will discuss the diagnosis and treatment of common lesions of the face. Clinical Relevance: Dentists should recognize facial lesions, understand the differential diagnosis and refer suspicious lesions for treatment.

A 57-year-old woman with cutaneous manifestations of (BRBNS) presented with acute left proptosis and venous congestion secondary to thrombosis within a superior ophthalmic vein varix. Multiple phleboliths were noted in the contralateral right orbit, and an incidental right middle cerebral artery aneurysm. Her symptoms spontaneously resolved within a few days. An English literature review found 7 reported cases of orbital vascular lesions in association with BRBNS from 1950 to 2012. All lesions showed contrast enhancement on CT or MRI: 4 had small orbital calcifications and 3 were distensible with raised venous pressure. The occurrence of a thrombosed orbital varix or cerebral artery aneurysm in BRBNS, to the best of the authors' knowledge, has not been previously reported. Although orbital vascular lesions in BRBNS have been described as hemangiomas, the biologic behavior and histology of most of the reported orbital lesions are most compatible with venous malformations.

Several types of maculopapular melanocytic naevi can occur in a multiple form, and be arranged in a nonrandom fashion on the skin. The most frequently reported segmentally grouped naevi are lentigines. Two types of segmentally arranged lentigines probably exist. The first is associated with neurofibromatosis (NF)1 or NF1 signs, features scattered light-brown lesions and can be considered a type of mosaic NF1. By contrast, non-NF1 associated lesions are characterized by densely packed, dark lesions, and can be defined as 'non-NF1 checkerboard-arranged lentigines'. Blue naevi, Spitz naevi and common acquired melanocytic naevi can occur, clustered in an agminated (or cannonball) shape. However, if large enough, they always follow a checkerboard pattern. Hence, such mosaic conditions should be termed 'checkerboard-arranged blue naevi', 'checkerboard-arranged Spitz naevi' and 'checkerboard-arranged common acquired melanocytic naevi'. Segmentally arranged dysplastic melanocytic naevi probably represent a mosaic form of dysplastic naevus syndrome. Dysplastic melanocytic naevi confined to a cutaneous segment could be defined as 'isolated segmental dysplastic naevus syndrome', while segmentally arranged dysplastic melanocytic naevi co-occurring with widespread, nonsegmental dysplastic melanocytic naevi might configure a 'superimposed segmental dysplastic naevus syndrome'. Small congenital melanocytic naevi are always grouped along Blaschko lines. The only other instances following Blaschko lines are the so-called 'linear lentiginous naevus' and a unique case of multiple deep penetrating naevi.

Blue rubber bleb nevus syndrome is a rare clinical entity. A 13-year-old Indian boy presented with characteristic cutaneous lesions, gastrointestinal malformations, skeletal involvement and pulmonary stenosis. Diagnosis was confirmed on skin biopsy, radiographic evaluation, colonoscopy and echocardiography. Echocardiography revealed pulmonary stenosis, an association hitherto undescribed. Detailed evaluation in a patient of blue rubber bleb nerves syndrome is mandatory.

Purpose: In the central nervous system, distinguishing primary leptomeningeal melanocytic tumors from melanoma metastases and predicting their biological behavior solely using histopathologic criteria may be challenging. We aimed to assess the diagnostic and prognostic value of integrated molecular analysis. Experimental Design: Targeted next-generation sequencing, array-based genome-wide methylation analysis, and BAP1 IHC were performed on the largest cohort of central nervous system melanocytic tumors analyzed to date, including 47 primary tumors of the central nervous system, 16 uveal melanomas, 13 cutaneous melanoma metastases, and 2 blue nevus–like melanomas. Gene mutation, DNA-methylation, and copy-number profiles were correlated with clinicopathologic features. Results: Combining mutation, copy-number, and DNA-methylation profiles clearly distinguished cutaneous melanoma metastases from other melanocytic tumors. Primary leptomeningeal melanocytic tumors, uveal melanomas, and blue nevus–like melanoma showed common DNA-methylation, copy-number alteration, and gene mutation signatures. Notably, tumors demonstrating chromosome 3 monosomy and BAP1 alterations formed a homogeneous subset within this group. Conclusions: Integrated molecular profiling aids in distinguishing primary from metastatic melanocytic tumors of the central nervous system. Primary leptomeningeal melanocytic tumors, uveal melanoma, and blue nevus–like melanoma share molecular similarity with chromosome 3 and BAP1 alterations, markers of poor prognosis. Clin Cancer Res; 24(18); 4494–504. ©2018 AACR.