Advertisement
MELANOCYTIC TUMOUR PATHOLOGY| Volume 55, ISSUE 2, P187-195, March 2023

Download started.

Ok

Blue naevi and the blue tumour spectrum

  • Arnaud de la Fouchardiere
    Correspondence
    Address for correspondence: Arnaud de la Fouchardière, MD, PhD, Department of Biopathology, Center Léon Bérard, 28, rue Laennec, Lyon, 69008. France.
    Affiliations
    Department of Biopathology, Center Léon Bérard, Lyon, France

    Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue Contre le Cancer, Lyon, France
    Search for articles by this author
Published:January 12, 2023DOI:https://doi.org/10.1016/j.pathol.2022.12.342

      Summary

      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.

      Key words

      Introduction

      Max Tièche, a pupil of Joseph Jadassohn, made the initial description of blue naevus at the beginning of the 20th century. The terminology ‘blue’ naevus originates from the clinical hue of the lesions induced by the Tyndall optical effect when an amount of melanin pigment is present only in the deep dermis. Blue naevi represent a wide subgroup of cutaneous pigmented proliferations with important variations in both their clinical and histological presentations. Many clinical variants are linked to specific topographies, related to an underlying neural distribution. Similarly to congenital naevi, lesions from the blue group are for the most part linked to an accidental genetic event in the neural crest during embryogenesis with a migration towards the skin of melanoblasts bearing specific genetic anomalies. The clinical localisations in which most blue naevi are found are the distal dead-end zone of the migration path of the melanoblasts. These predominant areas are the distal part of extremities, especially the back of the hand or foot, parieto-temporal cephalic area and the gluteal area (related to the vestigial tail). This review will only cover blue tumours located in the skin. Table 1 links all the terminologies used in this review with the matching histological grade.
      Table 1Grading of melanocytic tumours of the blue group
      BenignCongenital dermal melanocytosis
      Naevus of Ota
      Naevus of Ito
      Naevus of Hori
      Dendritic blue naevus
      Plaque type dendritic blue naevus
      Blue naevus with hypercellularity
      Sclerosing blue naevus
      Compound blue naevus
      Low grade melanocytoma WHO 2018Cellular blue naevus
      Cellular plaque-type blue naevus
      Myxoid/cystic cellular blue naevus
      Combined blue naevus
      High grade melanocytoma WHO 2018Atypical blue tumour
      Blue naevus with loss of PRKAR1A expression
      MelanomaMalignant blue melanoma
      WHO, World Health Organization.

      Genetic features

      Blue naevi have distinctive genetic anomalies compared to common and Spitz naevi. These anomalies are identical to those found in uveal and leptomeningeal melanocytic proliferations as they share a common neural crest precursor (melanoblast). The most frequent mutations are exon 4 and exon 5 mutations in GNAQ and GNA11, whilst mutations in CYSLTR2 and PLCB4 are much less common.
      • Van Raamsdonk C.D.
      • Bezrookove V.
      • Green G.
      • et al.
      Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi.
      • Onken M.D.
      • Worley L.A.
      • Long M.D.
      • et al.
      Oncogenic mutations in GNAQ occur early in uveal melanoma.
      • Griewank K.G.
      • Müller H.
      • Jackett L.A.
      • et al.
      SF3B1 and BAP1 mutations in blue nevus-like melanoma.
      • Möller I.
      • Murali R.
      • Müller H.
      • et al.
      Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi.
      • Van Raamsdonk C.D.
      • Griewank K.G.
      • Crosby M.B.
      • et al.
      Mutations in GNA11 in uveal melanoma.
      • Goto K.
      • Pissaloux D.
      • Paindavoine S.
      • et al.
      CYSLTR2-mutant cutaneous melanocytic neoplasms frequently simulate “pigmented epithelioid melanocytoma,” expanding the morphologic spectrum of blue tumors: a clinicopathologic study of 7 cases.
      • Johansson P.
      • Aoude L.G.
      • Wadt K.
      • et al.
      Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4.
      • Moore A.R.
      • Ceraudo E.
      • Sher J.J.
      • et al.
      Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma.
      All these alterations are recurrent hotspot mutations. These mutations are also found in several vascular malformations (such as congenital haemangiomas, Sturge–Weber syndrome or the Klippel–Trenaunay syndrome) with eventual association of both vascular and pigmented lesions as described in phakomatosis pigmentovascularis.
      • Lian C.G.
      • Sholl L.M.
      • Zakka L.R.
      • et al.
      Novel genetic mutations in a sporadic port-wine stain.
      • Nakashima M.
      • Miyajima M.
      • Sugano H.
      • et al.
      The somatic GNAQ mutation c.548G>A (p.R183Q) is consistently found in Sturge-Weber syndrome.
      • Lee C.-W.
      • Choi D.-Y.
      • Oh Y.-G.
      • et al.
      An infantile case of Sturge-Weber syndrome in association with Klippel-Trenaunay-Weber syndrome and phakomatosis pigmentovascularis.
      • Chhajed M.
      • Pandit S.
      • Dhawan N.
      • et al.
      Klippel-Trenaunay and Sturge-Weber overlap syndrome with phakomatosis pigmentovascularis.
      These mutations are mutually exclusive with each other and with the other mutations found in common naevi and melanomas derived from them (BRAF and NRAS mutations) as well as the genetic anomalies found in the group of Spitz naevi (HRAS mutations and activation gene fusions involving receptor tyrosine kinases ALK, ROS1, NTRK1/3 or serine threonine kinases BRAF and MAP3K8).
      • Broekaert S.M.C.
      • Roy R.
      • Okamoto I.
      • et al.
      Genetic and morphologic features for melanoma classification.
      • Bastian B.C.
      • LeBoit P.E.
      • Pinkel D.
      Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features.
      • Wiesner T.
      • He J.
      • Yelensky R.
      • et al.
      Kinase fusions are frequent in Spitz tumours and spitzoid melanomas.
      • Botton T.
      • Yeh I.
      • Nelson T.
      • et al.
      Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy.
      • Yeh I.
      • Busam K.J.
      • McCalmont T.H.
      • et al.
      Filigree-like rete ridges, lobulated nests, rosette-like structures, and exaggerated maturation characterize Spitz tumors with NTRK1 fusion.
      • Yeh I.
      • Botton T.
      • Talevich E.
      • et al.
      Activating MET kinase rearrangements in melanoma and Spitz tumours.
      • Newman S.
      • Fan L.
      • Pribnow A.
      • et al.
      Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas.
      All the mutated proteins involved in this group are tightly related to a cascade that activates the MAPKinase pathway. The CYSLTR2 (cysteinyl leukotriene receptor 2) transmembrane receptor (which binds leukotriene ligands) is a G protein-coupled receptor. The Gαq subunits (GNAQ and GNA11) have the ability to activate downstream PLCB4 (beta 4 phospholipase C). This induces a hydrolysation of PIP2 (phosphatidylinositol 4,5-biphosphate) into diacyl glycerol (DAG) and inositol triphosphate (IP3) which releases stored calcium (via IP3) and in turn activates protein kinase C (via DAG).
      The passenger anomalies found in the progression of blue naevi towards malignancy are also similar to those found in uveal and leptomeningeal melanomas and frequently involve BAP1, SF3B1 and EI1FAX.
      • Griewank K.G.
      • Müller H.
      • Jackett L.A.
      • et al.
      SF3B1 and BAP1 mutations in blue nevus-like melanoma.
      ,
      • Harbour J.W.
      • Onken M.D.
      • Roberson E.D.O.
      • et al.
      Frequent mutation of BAP1 in metastasizing uveal melanomas.
      ,
      • Küsters-Vandevelde H.V.N.
      • Creytens D.
      • van Engen-van Grunsven A.C.H.
      • et al.
      SF3B1 and EIF1AX mutations occur in primary leptomeningeal melanocytic neoplasms; yet another similarity to uveal melanomas.
      Recently, inactivating mutations in PRKAR1A, the genetic hallmark of pigmented epithelioid melanocytomas, have also been described in the blue setting.
      • Cohen J.N.
      • Joseph N.M.
      • North J.P.
      • et al.
      Genomic analysis of pigmented epithelioid melanocytomas reveals recurrent alterations in PRKAR1A, and PRKCA genes.
      • Cohen J.N.
      • Yeh I.
      • Mully T.W.
      • et al.
      Genomic and clinicopathologic characteristics of PRKAR1A-inactivated melanomas: toward genetic distinctions of animal-type melanoma/pigment synthesizing melanoma.
      • de la Fouchardiere A.
      • Tirode F.
      • Castillo C.
      • et al.
      Attempting to solve the pigmented epithelioid melanocytoma (PEM) conundrum: PRKAR1A inactivation can occur in different genetic backgrounds (common, blue, and Spitz subgroups) with variation in their clinicopathologic characteristics.

      Clinical variants

      There are numerous clinical variants of blue naevi. They are most often linked to a specific neural distribution. These pigmented lesions are usually present at birth or revealed shortly after. A female predominance is found throughout the whole spectrum.

      Congenital dermal melanocytosis (CDM)

      CDMs appear as a more or less extensive pigmented patch visible at birth without any modification of the skin surface. The former terminology, ‘mongelenfleck’ or ‘Mongolian spot’ was given at the end of the 19th century by Erwin Baelz, is currently not recommended.
      • Yale S.
      • Tekiner H.
      • Yale E.S.
      Reimagining the terms Mongolian spot and sign.
      These lesions have been universally observed with a low frequency (less than 10% of newborns) in fair skin tones and a gradual increase in frequency in darker skin tones, especially when dark hair is also present, that can reach over 90% of newborns. This suggests a similar frequency in all newborns, but a variable visibility related to pigment synthesis capacities in maturing melanocytes.
      • Cordova A.
      The Mongolian spot: a study of ethnic differences and a literature review.
      They are located in the gluteal, shoulder and temporo-parietal areas by decreasing frequency. Colouration varies from blue-green, blue-grey to brown. A spontaneous and progressive disappearance of the pigmentation is most frequently observed in these lesions after a few years, usually before adolescence. Lesions progressively shifting into a common or cellular blue naevus in the gluteal region have been reported as well as reminiscence during pregnancy.
      • Upshaw B.Y.
      • Ghormley R.K.
      • Montgomery H.
      Extensive blue nevus of Jadassohn-Tièche; report of a case.
      Morphologically they display scattered dendritic melanocytes throughout the dermis without associated fibrosis (Fig. 1). Melan-A, SOX10 and HMB45 stains can highlight melanocytes that are otherwise difficult to visualise.
      Fig. 1
      Fig. 1Congenital dermal melanocytosis. (A) Low power: barely visible fascicules in the mid-dermis. (B) High power: spindled and dendritic pigmented melanocytes with loose fasciculation centred around vascular structures.
      It is not exceptional to find small areas of dispersed dendritic melanocytes in the upper dermis in samples removed for other purposes, especially when melanocytic immunohistochemistry is performed for an adjacent collisional naevus.

      Naevus of Ota (naevus fuscoceruleus ophthalmomaxillaris or oculodermal melanocytosis)

      Described in 1939, the naevus of Ota is the most frequent of the systemised clinical variants.
      • Ota M.
      Naevus fusco-caeruleus ophthalmo-maxillaris.
      It is localised in the territory of the first or second branch of the trigeminal nerve as an ill-defined blue-grey pigmented patch with often a splashing border, centred in the malar or supra-ocular region. The extension is variable with some cases strictly limited to the ocular region while others extend widely on the hemi-face. Exceptional bilateral cases have been reported.
      • Sharan S.
      • Grigg J.R.
      • Billson F.A.
      Bilateral naevus of Ota with choroidal melanoma and diffuse retinal pigmentation in a dark skinned person.
      Pigmentation can also eventually be visible on the palate or the tympanic region.
      • Shetty S.R.
      • Subhas B.G.
      • Rao K.A.
      • et al.
      Nevus of Ota with buccal mucosal pigmentation: a rare case.
      These lesions do not disappear spontaneously compared to congenital dermal melanocytosis. The histological picture is similar in naevus of Ota, Ito and Hori, with isolated small dendritic melanocytes dispersed throughout the whole dermis. The density is higher than in dermal melanocytosis and there are frequent images of angiotropism with small, spindled melanocytes surrounding blood vessels or lymphatics (Fig. 2).
      Fig. 2
      Fig. 2Naevus of Ota. (A) Low power: extensive pigmented cellular areas throughout the whole dermis. (B,C) Fascicles of small spindled pigmented melanocytes in a fibrous background with adnexial and vascular tropism. (D) Pigmented fascicles without hypercellularity dissecting the deep facial muscular layer.

      Naevus of Ito (naevus acromioclavicularis)

      This less common variant is clinically similar to the naevus of Ota but is located on the acromioclavicular area in the territories of lateral brachial nerves of the shoulder and posterior supraclavicular nerves.
      • Ito M.
      Studies on melanin XXII. Naevus fusco-caeruleus acromio-deltoideus.
      A late onset has sometimes been described.
      • Resende C.
      • Araújo C.
      • Vieira A.P.
      • et al.
      Late onset Ito’s nevus.
      ,
      • Mataix J.
      • López N.
      • Haro R.
      • et al.
      Late-onset Ito’s nevus: an uncommon acquired dermal melanocytosis.
      A simultaneous occurrence of both Ota and Ito naevi has also been reported.
      • Mishima Y.
      • Mevorah B.
      Nevus ota and nevus Ito in American negroes.

      Naevus of Hori/Sun (naevus fusco-caeruleus)

      This rare clinical variant displays small, pigmented, scattered spots located in the facial area mainly the zygomatic region. They can be bilateral/symmetrical. Similar lesions can also potentially be found on the forehead, eyelids, temples, malar area, alae or root of the nose. These lesions are usually acquired during the third decade of life, sometimes in an eruptive manner. A familial history of Hori naevus was found between one-fifth to one-third of cases in some large series.
      • Zhong Y.
      • Huang L.
      • Yan T.
      • et al.
      Both age and disease duration are associated with clinical phenotype of Hori’s nevus in Chinese: a retrospective analysis of 497 cases.
      • Sun C.C.
      • Lü Y.C.
      • Lee E.F.
      • et al.
      Naevus fusco-caeruleus zygomaticus.
      • Hori Y.
      • Kawashima M.
      • Oohara K.
      • et al.
      Acquired, bilateral nevus of Ota-like macules.
      • Ee H.L.
      • Wong H.C.
      • Goh C.L.
      • et al.
      Characteristics of Hori naevus: a prospective analysis.

      Other acquired dermal melanocytosis

      These rare cases appear as often eruptive lesions described on the hand and/or facial areas.
      • Hidano A.
      • Kaneko K.
      Acquired dermal melanocytosis of the face and extremities.
      ,
      • Jun J.-Y.
      • Byun H.J.
      • Oh S.J.
      • et al.
      Acquired dermal melanocytosis confined to the hand.

      Plaque type blue naevus

      Localised, usually large patches of cellular blue naevus can occur in any topography and most often seem to follow a neural distribution.
      • Satake K.
      • Sudo T.
      • Sugino T.
      • et al.
      Large plaque-type blue nevus with GNAQ Q209P mutation, involving mammary gland tissue: under-recognized mammary condition as an origin of primary mammary melanocytic tumors.
      • Lee M.Y.
      • Jin S.
      • Lee K.-H.
      • et al.
      A cellular blue nevus with pigmented epithelioid melanocytoma-like pattern on the ipsilateral upper arm associated with a congenital plaque-type blue nevus on the hand.
      • Spring P.
      • Perrier P.
      • Erba P.
      • et al.
      Large agminated cellular “plaque-type” blue nevus surrounding the ear: a case and review.
      An exceptional case of linear plaque-type blue naevus in which the lesion followed an intercostal perineural distribution extending from the thoracic spine to the anterior midline has been reported.
      • Habougit C.
      • Michiels-Marzais D.
      • Wang Q.
      Linear variant of large plaque-type blue naevus with subcutaneous cellular nodules.
      Only the superficial (intradermal) lesions are clinically visible while the deepest ones can be restricted to the subcutis and remain silent unless they grow into a palpable deep nodule.
      • Busam K.J.
      • Woodruff J.M.
      • Erlandson R.A.
      • et al.
      Large plaque-type blue nevus with subcutaneous cellular nodules.
      • Zattra E.
      • Salmaso R.
      • Montesco M.C.
      • et al.
      Large plaque type blue nevus with subcutaneous cellular nodules.
      • Baraldi C.
      • Corti B.
      • Lambertini M.
      • et al.
      Large plaque-type blue naevus with cellular nodules: a rare unrecognized melanocytic tumour.
      For all these lesions, there is a low lifetime risk of progression towards melanoma (see below). Any clinical modification, especially in volume, should prompt performance of a diagnostic biopsy to rule out a melanoma ex-blue naevus.

      Histological variants of blue naevi

      Dendritic blue naevus/common blue naevus

      This is the most frequent clinical presentation of the blue group of tumours. They are most often found on the back of the hands and feet although they can be present elsewhere. They appear as clinically stable, small, bluish, dome-shaped papules. Most cases are isolated, although agminated or diffuse cases have been reported.
      • Eichenfield D.Z.
      • Cotter D.
      • Thorson J.
      • et al.
      Agminated blue nevus with a GNAQ mutation: a case report and review of the literature.
      ,
      • Maredia H.
      • Eseonu A.
      • Rozati S.
      Disseminated eruptive blue nevi in a young adult patient.
      Histologically they are formed of loose intradermal fascicules of spindled and dendritic melanocytes in a fibrous background that tend to regroup around vascular and adnexal structures, especially eccrine gland tubes. The melanin pigment, often abundant, is mostly found in the cytoplasm of melanocytes with only a few intermingled melanophages. There is no cytological or nuclear atypia nor mitotic activity (Fig. 3).
      Fig. 3
      Fig. 3Common/dendritic blue naevus. (A) Low power: ill-defined dermal, fasciculated, pigmented proliferation with fibrosis. (B) Significant tropism for adnexial strutures (eccrine sweat gland duct, pilar arrector muscle) with higher cell density. (C) Fascicles of small melanocytes with a pigmented cytoplasm and a spindled or undulated nucleus without atypia.
      The main differential diagnosis is widespread regressive metastasis of melanomas which only contain melanophages.
      • Busam K.J.
      Metastatic melanoma to the skin simulating blue nevus.
      Macrophage-targeting antibodies such as CD68 or CD163 can help discriminate both populations in difficult cases. A potential pitfall is the partial or weak positivity in melanophages with antibodies targeting melanosomes such as HMB45 (anti-GP100) or Melan-A.

      Blue naevus with hypercellularity

      Common/dendritic blue naevus and cellular blue naevus (CBN) form a spectrum of lesions with larger and more cellular areas at the CBN end of the spectrum. The terminology ‘blue naevus with foci of hypercellularity’ has been suggested for lesions that are denser than a common/dendritic blue naevus but in which no cellular nests are visible.
      • Busam K.
      • Gerami P.
      • Scolyer R.A.
      Pathology of Melanocytic Tumors.
      The dendritic cells are often arranged in cellular sheets, especially in the deep part surrounding the adnexal structures (Fig. 4). Thus, it is an ‘in between’ filler to describe larger lesions. They display a very bland cytology without cellular atypia nor mitotic activity.
      Fig. 4
      Fig. 4Blue naevus with hypercellularity. (A) Low power: intradermal, mildly pigmented, dense proliferation raising the epidermis without ulceration or obvious junctional component. (B) Superficial dermis with dense fascicles and small nests made of small to mid-sized spindled and dendritic melanocytes with a few admixed melanophages. (C) Deep part of lesion: loose fascicles in a dense fibrotic dermis.

      Cellular blue naevus

      CBN clinically presents as a slowly growing large indurated pigmented nodule with a size often less than 1 cm.
      • Hung T.
      • Argenyi Z.
      • Erickson L.
      • et al.
      Cellular blue nevomelanocytic lesions: analysis of clinical, histological, and outcome data in 37 cases.
      The most common location is the gluteal area. Histologically, there is a biphasic dermal pattern with, in the upper dermis, ill-defined patches reminiscent of dendritic blue naevus and deeper, large cellular nests forming vertical expansions into the subcutis (dumbbell structures). These cellular nests are often well demarcated, more or less pigmented, and made of mid-sized melanocytes with regular, oval-shaped nuclei (bland cytology). Mitotic activity is limited. Multinucleated melanocytes are a banal feature in the cellular areas and should not be seen as a worrisome finding. Similarly, the dendritic component can have focal areas made of foamy/clear cell melanocytes without nuclear atypia. There should be no areas of tumoural necrosis nor clonal variations (such as intensity of pigmentation) between the cellular areas (Fig. 5).
      Fig. 5
      Fig. 5Cellular blue naevus. (A) Low power: intradermal biphasic proliferation with a limited loose superficial component reminiscent of dendritic blue naevus and deeper nest coalescing into vertical dumbbell structures expanding into the subcutis. (B) Close-up view of the vertical transition from a fascicular into a small nest architecture. (C) Close-up view of the deep cellular nests with a bland cytology.
      Melan-A is diffusely positive in all areas. HMB45 is usually positive in the dendritic areas with variation in the intensity of the staining. Cellular nests often have less or no expression of HMB45. The S100 protein staining is negative or weakly positive in the cellular areas, especially regarding their nuclei. This staining pattern is present throughout all tumours of the blue naevus spectrum and is quite specific. S100 protein expression loss can be useful to discriminate CBNs from other dermal hyperpigmented lesions such as deep penetrating naevi.
      • Dei Tos A.P.
      • Khurana J.S.
      • Kurtin P.J.
      • et al.
      Absence of S-100 Protein immunoreactivity in cellular blue nevus: a potential diagnostic pitfall.

      Plaque-type blue naevus

      The histology of plaque-type blue naevus displays all the cytological features of dendritic or cellular blue naevus but more arranged sheet-like pattern in the deep dermis and/or the subcutis. The vertical expansions are absent with rather a more horizontal disposition, mixing cellular nests of bland cytology surrounded by pigmented dendritic melanocytes in a fibrous background. The presence of abnormal blood vessels with a dilated lumen (angiomatous aspect) are not exceptional (Fig. 6).
      Fig. 6
      Fig. 6Plaque type sclerosing blue naevus. (A) Low power: wide superficial intradermal pigmented proliferation on the scalp. The hair shaft density is lower in the central area. (B) Close-up view on deep vertical expansions with extensive areas of fibrosis destroying the subcutis. High power: bland small spindled and dendritic melanocytes encased in a fibrotic background with variable cytoplasmic pigment.

      Myxoid/cystic variant of cellular blue naevus

      This is a purely histological variant only seen in CBN and not in dendritic blue naevi.
      • Michal M.
      • Baumruk L.
      • Skálová A.
      Myxoid change within cellular blue naevi: a diagnostic pitfall.
      ,
      • Biernat W.
      • Kordek R.
      • Woźniak L.
      Cellular blue nevi with myxoid change--diagnostic difficulties and the review of the literature.
      The round nests of the cellular component of CBN appear surrounded by a massive oedema-like stromal reaction and seem to be floating in a myxoid/cystic liquid. This occurs predominantly in the deep/central part of the CBN where these nests are located and is frequently a very limited modification. HMB45 shows a concentric staining with the strongest positivity on the rim of the nests. The cystic spaces are negative.
      As CBNs are often clinically perceived as a cutaneous cyst (and they are mainly located on the buttocks where pilonidal cysts are frequent), it is not rare that a partial curettage is performed. If the curettage material contains only areas of myxoid/cystic architecture, the diagnosis of CBN can be challenging, especially as these areas are less pigmented.

      Sclerosing blue naevus

      These clinically indurated lesions frequently arise on the scalp, presenting as a hairless papule or a small nodule with more or less pigmentation. Histologically, they appear as an extensive dermal sclerosis, destroying the encased follicular structures. The dense fibrous tissue can extend vertically into the subcutis. Melanocytes are either dispersed, difficult to identify from fibroblasts or regrouped in small cellular areas sometimes in the deepest part of the lesion. They display a small, spindled nuclei without atypia. Schematically, they are dendritic blue naevi in which the background fibrosis is the main histological feature. The main differential diagnosis is a dermal scar or fibroma. Again, HMB45 antibody will help highlight dendritic melanocytes in the least cellular cases if needed. Exceptionally, CBNs can similarly display a massive sclerosis surrounding both the dendritic and cellular areas. Such variants are called ‘sclerosing cellular blue naevus’.

      Pigmentation-related variants

      Most blue naevi are more or less pigmented and the full spectrum can extend from amelanotic or hypomelanotic blue tumours to hypermelanotic cases.
      • Ferrara G.
      • Soyer H.P.
      • Malvehy J.
      • et al.
      The many faces of blue nevus: a clinicopathologic study.
      • Emley A.
      • Nguyen L.P.
      • Yang S.
      • et al.
      Somatic mutations in GNAQ in amelanotic/hypomelanotic blue nevi.
      • Ma C.
      • Chambers C.J.
      • Kiuru M.
      • et al.
      Amelanotic blue nevus.
      There is currently no known explanation for this phenomenon, but a hypothesis could be that, similarly to congenital dermal melanocytosis, pigment load may be related to an individual's aptitude to synthetise coarse melanin pigment.

      Compound blue naevus

      Most textbooks describe tumours of the blue spectrum as purely dermal. Historically, Kamino and Tam have described in rare occurrences a lentiginous junctional component of dendritic melanocytes.
      • Kamino H.
      • Tam S.T.
      Compound blue nevus: a variant of blue nevus with an additional junctional dendritic component. A clinical, histopathologic, and immunohistochemical study of six cases.
      The latter are better visualised by HMB45 immunohistochemistry. The underlying blue naevus, which can be of dendritic, cellular or ‘hypercellular’ subtype, is always located in the superficial dermis. Similarly, the junctional component is located in the central part of the lesion in a rather symmetrical manner. Recently, a description of central junctional nests has completed the original description.
      • Jaquemus J.
      • Perron E.
      • Buisson A.
      • et al.
      Compound blue nevus: a reappraisal of the concept in the genomic era.
      The melanocytes in these nests are often of small common/bland cytology and can have a faint HMB45 staining (Fig. 7). These nests are present in wide lesions, especially those located on the back of the foot. A classic, dendritic, lentiginous component expands laterally on both sides of the central nested area. This junctional component can modify the hue with black and brown streaks mixed with blueish areas.
      • Baklouti M.
      • Sellami K.
      • Elleuch N.
      • et al.
      Compound blue nevus: a misleading pigmented melanocytic tumor.
      ,
      • Ferrara G.
      • Argenziano G.
      • Zgavec B.
      • et al.
      Compound blue nevus”: a reappraisal of “superficial blue nevus with prominent intraepidermal dendritic melanocytes” with emphasis on dermoscopic and histopathologic features.
      Fig. 7
      Fig. 7Compound and combined blue naevus. (A) Low power: superficial compound melanocytic proliferation with low pigmentation and variable density within a fibrotic background. (B) High power: close-up view on large junctional nests of bland melanocytes. In the superficial dermis, nests of small melanocytes with round nuclei are surrounded by fascicles of spindled and dendritic cells.
      In addition, blue naevi with loss of PRKAR1A expression or those harbouring a CYSLTR2 mutation can have large junctional nests of spindled pigmented melanocytes (see specific sections below).

      Blue naevus with loss of PRKAR1A expression or ‘blue-PEM’

      This recently described variant is one of the subclasses following the breaking down of PRKAR1A-inactivated pigmented epithelioid melanocytomas according to their genetic background.
      • de la Fouchardiere A.
      • Tirode F.
      • Castillo C.
      • et al.
      Attempting to solve the pigmented epithelioid melanocytoma (PEM) conundrum: PRKAR1A inactivation can occur in different genetic backgrounds (common, blue, and Spitz subgroups) with variation in their clinicopathologic characteristics.
      Thus, these lesions are defined by a mutation of the blue group, especially CYSLTR2, but also GNAQ or GNA11, and an inactivation of the PRKAR1A protein. The latter is often assessed by immunohistochemistry with loss of cytoplasmic expression, and additional sequencing studies can identify inactivating mutations in PRKAR1A. These lesions are often found in adults.
      Histologically, most display a compound architecture with large hyperpigmented nests intricated with a verrucous, hyperplasic epidermis. There is no pagetoid ascent of cells. Numerous lentiginous dendritic melanocytes can be visualised by HMB45 immunohistochemistry especially in areas of epidermal hyperplasia. The dermal component is made of large bundles of spindled and epithelioid hyperpigmented melanocytes, similar to those found in the junction, intricated with patches of melanophages. There is no deep maturation from either an architectural or a cytological point of view. The fibrous background of the blue naevus group is present but difficult to visualise. Atypia is mild as well as mitotic activity. The nuclei harbour typical ‘fried egg’ morphology with a wide, unique, central nucleolus and thickening of the nuclear membrane. Inconstant features include deep dumbbell-like expansions similar to those found in CBN or a low melanin pigment load contrasting with the usual hyperpigmented PEM archetype (Fig. 8).
      Fig. 8
      Fig. 8Atypical blue naevus. (A) Low power: deep dense intradermal nodule with partial scarring from previous biopsy. (B) Medium power: the tumoural infiltration forms cellular sheet of confluent fascicles destroying the surrounding hair shafts and extending into the subcutis. (C) High power: moderate atypia with cellular density and nuclear hyperchromatism.

      Combined blue naevus

      This terminology relates to lesions presenting a mixture of histological features with some melanocytes displaying cytological aspects of either common or Spitz naevi intermingled with areas more consistent with blue naevus. As previously explicated, the blue group of lesions has a unique genetic background and Spitz or common naevi each have alternative types of anomalies. Unfortunately, most reports of such lesions are devoid of molecular studies and we can only speculate on the genetic background in these cases. Some could be a collision between two separate entities; others could represent undescribed variants of blue naevi or other naevi types with specific genetics features.
      • Scolyer R.A.
      • Zhuang L.
      • Palmer A.A.
      • et al.
      Combined naevus: a benign lesion frequently misdiagnosed both clinically and pathologically as melanoma.

      Atypical blue tumour (melanocytoma)

      This rare condition illustrates the intermediate stage in the progression from a blue naevus to a malignant blue melanoma. Usually, the clinician reports the presence of a pre-existing pigmented lesion described as growing in size and volume, or that has become ulcerated or with clinical asymmetry. Under the microscope, there appears to be more atypia than usually accepted in a cellular blue naevus but less than needed to make a diagnosis of malignant blue melanoma.
      • Tran T.A.
      • Carlson J.A.
      • Basaca P.C.
      • et al.
      Cellular blue nevus with atypia (atypical cellular blue nevus): a clinicopathologic study of nine cases.
      ,
      • Barnhill R.L.
      • Argenyi Z.
      • Berwick M.
      • et al.
      Atypical cellular blue nevi (cellular blue nevi with atypical features): lack of consensus for diagnosis and distinction from cellular blue nevi and malignant melanoma (“malignant blue nevus”).
      Most often the cellular areas are arranged in wide sheets rather than small nests and mitotic activity is mildly elevated. The reduction in size of the cytoplasm leads to a higher cellular density, with more obvious nuclear irregularities. This atypical blue naevus can appear as a deep clonal area within a CBN (Fig. 9). Melan-A and HMB45 can be more heterogeneously expressed, Ki-67 will often be in the 5–10% range. BAP1 nuclear expression is retained. Extensive molecular analysis is usually performed to rule out a malignant blue melanoma, especially array-comparative genomic hybridisation (CGH) which only displays whole chromosomal gains and losses and none of the malignant specific copy number variation patterns (see below). The prognosis of these lesions has not yet been thoroughly studied, mainly due to their rarity. European guidelines recommend a full excision with 5–10 mm clinical margins and follow-up.
      • de la Fouchardiere A.
      • Blokx W.
      • van Kempen L.C.
      • et al.
      ESP, EORTC, and EURACAN Expert Opinion: practical recommendations for the pathological diagnosis and clinical management of intermediate melanocytic tumors and rare related melanoma variants.
      Fig. 9
      Fig. 9Blue pigmented epithelioid melanocytoma. (A) Low power: small symmetrical hyperpigmented dermal nodule elevating the overlying epidermis. (B) High power: dense fascicules of spindled pigmented cell with mild atypia. (C) PRKAR1A IHC: complete loss of cytoplasmic staining throughout the whole tumour.

      Atypical blue tumours with CYSLTR2 mutations (melanocytoma)

      Common/dendritic blue naevi with a CYSLTR2 p. L129Q mutation do not show any morphological variations compared with those harbouring a GNAQ or GNA11 mutation.
      • Möller I.
      • Murali R.
      • Müller H.
      • et al.
      Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi.
      However, in larger, more cellular cases the morphology becomes unusual and does not match the typical cellular blue naevus architecture. These lesions become more reminiscent of those described with a PRKAR1A inactivation. Indeed, they frequently include a nested junctional component intricated with a warty, hyperplastic epidermis and a dense dermal component made of large bundles of spindled and epithelioid melanocytes in a fibrous background. Mitotic activity is low but present. Melan-A and HMB45 immunohistochemistry underscores the compound distribution and Ki-67 will often be in the 5–10% bracket. PRKAR1A should be performed to rule out a ‘blue-PEM’ variant.
      • Goto K.
      • Pissaloux D.
      • Paindavoine S.
      • et al.
      CYSLTR2-mutant cutaneous melanocytic neoplasms frequently simulate “pigmented epithelioid melanocytoma,” expanding the morphologic spectrum of blue tumors: a clinicopathologic study of 7 cases.

      Malignant blue melanoma (MBM)

      MBM (or blue-like melanoma; melanoma ex-blue naevus) is an exceedingly rare type of skin melanoma. They arise most often on the scalp, especially in the parieto-temporal area in adults, from a pre-existing pigmented patch known since childhood. These melanomas are fast growing and often bulky blue-black tumours. They can exceptionally occur in a pre-existing dermal melanosis including naevus of Ota variants or within a cellular blue naevus or even deeply in a plaque-type blue naevus.
      • Patel B.C.
      • Egan C.A.
      • Lucius R.W.
      • et al.
      Cutaneous malignant melanoma and oculodermal melanocytosis (nevus of Ota): report of a case and review of the literature.
      • Díaz Pérez J.L.
      • Burgos Bretones J.J.
      • Rivera Pomar J.M.
      [Malignant melanoma of the dermal component of Ota’s nevus].
      • Kopf A.W.
      • Bart R.S.
      Malignant blue (Ota’s?) nevus.
      • Dompmartin A.
      • Leroy D.
      • Labbé D.
      • et al.
      Dermal malignant melanoma developing from a nevus of Ota.
      • Gerami P.
      • Pouryazdanparast P.
      • Vemula S.
      • et al.
      Molecular analysis of a case of nevus of ota showing progressive evolution to melanoma with intermediate stages resembling cellular blue nevus.
      • Buntinx-Krieg T.
      • Ouyang J.
      • Cartwright M.
      An orbital malignant melanoma arising in cellular blue nevus in a patient with nevus of Ota.
      • Yeh I.
      • Fang Y.
      • Busam K.J.
      Melanoma arising in a large plaque-type blue nevus with subcutaneous cellular nodules.
      • Loghavi S.
      • Curry J.L.
      • Torres-Cabala C.A.
      • et al.
      Melanoma arising in association with blue nevus: a clinical and pathologic study of 24 cases and comprehensive review of the literature.
      • Yan L.
      • Tognetti L.
      • Nami N.
      • et al.
      Melanoma arising from a plaque-type blue naevus with subcutaneous cellular nodules of the scalp.
      Histologically, malignant features are generally obvious at low power and the main difficulty here is to correctly classify it as part of the blue spectrum. They usually form a dense dermal nodule without a junctional component. One or more areas of tumour necrosis can be present and are highly suggestive of malignancy. There can be a clonal distribution of the intracytoplasmic melanin pigment load with some hyperpigmented areas contrasting with low or even unpigmented deep nodules. At high power magnification, sheets and wide nests of large atypical, spindled or epithelioid melanocytes are visible. Identification in the vicinity of the nodule of areas of common/dendritic blue naevus is a major element to confirm this subtype. Similarly, areas of atypical blue naevus can also be present as expected in the multistep progression model (Fig. 10). Melan-A and HMB45 may be expressed in a diffusively positive pattern or may be heterogeneous and patchy. Ki-67 expression can vary according to clones and subclones. High expressing areas (hotspots) can help assess more precisely the mitotic activity. BAP1 nuclear expression can be lost in the malignant clones and be retained in the benign common/dendritic naevus. This is a factor of worse outcome similar to that extensively described in uveal melanomas (UM). Array-CGH will also re-iterate the class I and II profiles of UM where monosomy 3 (linked to BAP1 inactivation) is an indicator of bad prognosis.
      • Chan M.P.
      • Andea A.A.
      • Harms P.W.
      • et al.
      Genomic copy number analysis of a spectrum of blue nevi identifies recurrent aberrations of entire chromosomal arms in melanoma ex blue nevus.
      ,
      • Costa S.
      • Byrne M.
      • Pissaloux D.
      • et al.
      Melanomas associated with blue nevi or mimicking cellular blue nevi: clinical, pathologic, and molecular study of 11 cases displaying a high frequency of GNA11 mutations, BAP1 expression loss, and a predilection for the scalp.
      These array-CGH profiles are very different from the ones found in common/low-chronic sun damage (CSD) melanomas with BRAF or NRAS mutations. In the latter, chromosome 9 anomalies (where the CDKN2A gene is located) are almost constant, whereas in blue melanomas chromosome 9 is usually unaltered. Array-CGH profiles in MBM rather harbour an 8q gain, similar again to UM. An isochromosome 6p is however found in both types of melanomas. Sequencing techniques allow the identification of the blue driver genes, mainly GNAQ and GNA11, but also the recurrent passenger mutations.
      • Chang L.-W.
      • Kazlouskaya V.
      • Kazi R.
      • et al.
      Melanoma ex blue nevus with GNA11 mutation and BAP1 loss: case report and review of the literature.
      These prognostic anomalies, also derived from genetic studies in UM, schematically classify the melanomas into bad outcome (BAP1 mutation), intermediate outcome (EIF1AX mutation without BAP1 mutation) and favourable outcome (SF3B1 without BAP1 mutation).
      • Griewank K.G.
      • Müller H.
      • Jackett L.A.
      • et al.
      SF3B1 and BAP1 mutations in blue nevus-like melanoma.
      ,
      • Costa S.
      • Byrne M.
      • Pissaloux D.
      • et al.
      Melanomas associated with blue nevi or mimicking cellular blue nevi: clinical, pathologic, and molecular study of 11 cases displaying a high frequency of GNA11 mutations, BAP1 expression loss, and a predilection for the scalp.
      ,
      • Dai J.
      • Tetzlaff M.T.
      • Schuchter L.M.
      • et al.
      Histopathologic and mutational analysis of a case of blue nevus-like melanoma.
      • Martin M.
      • Maßhöfer L.
      • Temming P.
      • et al.
      Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3.
      • Yavuzyigitoglu S.
      • Koopmans A.E.
      • Verdijk R.M.
      • et al.
      Uveal melanomas with SF3B1 mutations: a distinct subclass associated with late-onset metastases.
      Fig. 10
      Fig. 10Malignant blue naevus. (A) Low power: vertical progression from dendritic blue naevus to malignant blue melanoma with visible intermediate stages. (B) Superficial dendritic blue naevus. (C) Upper dermis cellular blue naevus area. (D) Lower dermis atypical blue naevus with higher density and nuclear atypia. (E) Melanoma with obvious atypia and criteria for malignancy.
      Sequencing techniques with panels including their specific mutated genes should allow a better identification of MBM. This is important as they represent a completely different subtype (i.e., a different disease) and do not share the prognostic factors of low-CSD/SSM types of melanomas; their response to treatment regimens can also greatly vary. UM are known to not be good responders to immunotherapy. Specific regimens are currently tested in this setting and could also be applied to their skin counterpart.
      • Nathan P.
      • Hassel J.C.
      • Rutkowski P.
      • et al.
      Overall survival benefit with tebentafusp in metastatic uveal melanoma.
      The rarity of these lesions currently prevent large-scale studies.

      Conclusion

      Blue tumours form a large spectrum of tumours linked by a specific genetic background. There are a wide number of clinical, architectural and cytological variants each with multiple differential diagnoses. Most lesions are predominantly dermal and hyperpigmented. They can very rarely evolve into malignant blue melanomas, which behave differently compared to most common types of melanomas and thus should be considered as a separate type of disease. Specific antibodies do not exist, but immunohistochemistry is still of great help in the screening of these entities. Atypical and malignant lesions often require advanced genomic testing to be thoroughly assessed.

      Conflicts of interest and sources of funding

      The author states that there are no conflicts of interest to disclose. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

      References

        • Van Raamsdonk C.D.
        • Bezrookove V.
        • Green G.
        • et al.
        Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi.
        Nature. 2009; 457: 599-602
        • Onken M.D.
        • Worley L.A.
        • Long M.D.
        • et al.
        Oncogenic mutations in GNAQ occur early in uveal melanoma.
        Invest Ophthalmol Vis Sci. 2008; 49: 5230-5234
        • Griewank K.G.
        • Müller H.
        • Jackett L.A.
        • et al.
        SF3B1 and BAP1 mutations in blue nevus-like melanoma.
        Mod Pathol. 2017; 30: 928-939
        • Möller I.
        • Murali R.
        • Müller H.
        • et al.
        Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi.
        Mod Pathol. 2017; 30: 350-356
        • Van Raamsdonk C.D.
        • Griewank K.G.
        • Crosby M.B.
        • et al.
        Mutations in GNA11 in uveal melanoma.
        N Engl J Med. 2010; 363: 2191-2199
        • Goto K.
        • Pissaloux D.
        • Paindavoine S.
        • et al.
        CYSLTR2-mutant cutaneous melanocytic neoplasms frequently simulate “pigmented epithelioid melanocytoma,” expanding the morphologic spectrum of blue tumors: a clinicopathologic study of 7 cases.
        Am J Surg Pathol. 2019; 43: 1368-1376
        • Johansson P.
        • Aoude L.G.
        • Wadt K.
        • et al.
        Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4.
        Oncotarget. 2016; 7: 4624-4631
        • Moore A.R.
        • Ceraudo E.
        • Sher J.J.
        • et al.
        Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma.
        Nat Genet. 2016; 48: 675-680
        • Lian C.G.
        • Sholl L.M.
        • Zakka L.R.
        • et al.
        Novel genetic mutations in a sporadic port-wine stain.
        JAMA Dermatol. 2014; 150: 1336-1340
        • Nakashima M.
        • Miyajima M.
        • Sugano H.
        • et al.
        The somatic GNAQ mutation c.548G>A (p.R183Q) is consistently found in Sturge-Weber syndrome.
        J Hum Genet. 2014; 59: 691-693
        • Lee C.-W.
        • Choi D.-Y.
        • Oh Y.-G.
        • et al.
        An infantile case of Sturge-Weber syndrome in association with Klippel-Trenaunay-Weber syndrome and phakomatosis pigmentovascularis.
        J Korean Med Sci. 2005; 20: 1082-1084
        • Chhajed M.
        • Pandit S.
        • Dhawan N.
        • et al.
        Klippel-Trenaunay and Sturge-Weber overlap syndrome with phakomatosis pigmentovascularis.
        J Pediatr Neurosci. 2010; 5: 138-140
        • Broekaert S.M.C.
        • Roy R.
        • Okamoto I.
        • et al.
        Genetic and morphologic features for melanoma classification.
        Pigment Cell Melanoma Res. 2010; 23: 763-770
        • Bastian B.C.
        • LeBoit P.E.
        • Pinkel D.
        Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features.
        Am J Pathol. 2000; 157: 967-972
        • Wiesner T.
        • He J.
        • Yelensky R.
        • et al.
        Kinase fusions are frequent in Spitz tumours and spitzoid melanomas.
        Nat Commun. 2014; 5: 3116
        • Botton T.
        • Yeh I.
        • Nelson T.
        • et al.
        Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy.
        Pigment Cell Melanoma Res. 2013; 26: 845-851
        • Yeh I.
        • Busam K.J.
        • McCalmont T.H.
        • et al.
        Filigree-like rete ridges, lobulated nests, rosette-like structures, and exaggerated maturation characterize Spitz tumors with NTRK1 fusion.
        Am J Surg Pathol. 2019; 43: 737-746
        • Yeh I.
        • Botton T.
        • Talevich E.
        • et al.
        Activating MET kinase rearrangements in melanoma and Spitz tumours.
        Nat Commun. 2015; 6: 7174
        • Newman S.
        • Fan L.
        • Pribnow A.
        • et al.
        Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas.
        Nat Med. 2019; 25: 597-602
        • Harbour J.W.
        • Onken M.D.
        • Roberson E.D.O.
        • et al.
        Frequent mutation of BAP1 in metastasizing uveal melanomas.
        Science. 2010; 330: 1410-1413
        • Küsters-Vandevelde H.V.N.
        • Creytens D.
        • van Engen-van Grunsven A.C.H.
        • et al.
        SF3B1 and EIF1AX mutations occur in primary leptomeningeal melanocytic neoplasms; yet another similarity to uveal melanomas.
        Acta Neuropathol Commun. 2016; 4: 5
        • Cohen J.N.
        • Joseph N.M.
        • North J.P.
        • et al.
        Genomic analysis of pigmented epithelioid melanocytomas reveals recurrent alterations in PRKAR1A, and PRKCA genes.
        Am J Surg Pathol. 2017; 41: 1333-1346
        • Cohen J.N.
        • Yeh I.
        • Mully T.W.
        • et al.
        Genomic and clinicopathologic characteristics of PRKAR1A-inactivated melanomas: toward genetic distinctions of animal-type melanoma/pigment synthesizing melanoma.
        Am J Surg Pathol. 2020; 44: 805-816
        • de la Fouchardiere A.
        • Tirode F.
        • Castillo C.
        • et al.
        Attempting to solve the pigmented epithelioid melanocytoma (PEM) conundrum: PRKAR1A inactivation can occur in different genetic backgrounds (common, blue, and Spitz subgroups) with variation in their clinicopathologic characteristics.
        Am J Surg Pathol. 2022; 46: 1106-1115
        • Yale S.
        • Tekiner H.
        • Yale E.S.
        Reimagining the terms Mongolian spot and sign.
        Cureus. 2021; 13e20396
        • Cordova A.
        The Mongolian spot: a study of ethnic differences and a literature review.
        Clin Pediatr (Phila). 1981; 20: 714-719
        • Upshaw B.Y.
        • Ghormley R.K.
        • Montgomery H.
        Extensive blue nevus of Jadassohn-Tièche; report of a case.
        Surgery. 1947; 22: 761-765
        • Ota M.
        Naevus fusco-caeruleus ophthalmo-maxillaris.
        Jpn J Dermatol. 1939; 46: 369
        • Sharan S.
        • Grigg J.R.
        • Billson F.A.
        Bilateral naevus of Ota with choroidal melanoma and diffuse retinal pigmentation in a dark skinned person.
        Br J Ophthalmol. 2005; 89: 1529
        • Shetty S.R.
        • Subhas B.G.
        • Rao K.A.
        • et al.
        Nevus of Ota with buccal mucosal pigmentation: a rare case.
        Dent Res J. 2011; 8: 52-55
        • Ito M.
        Studies on melanin XXII. Naevus fusco-caeruleus acromio-deltoideus.
        Tohoku J Exp Med. 1954; 60: 10
        • Resende C.
        • Araújo C.
        • Vieira A.P.
        • et al.
        Late onset Ito’s nevus.
        BMJ Case Rep. 2013; 2013bcr2013009746
        • Mataix J.
        • López N.
        • Haro R.
        • et al.
        Late-onset Ito’s nevus: an uncommon acquired dermal melanocytosis.
        J Cutan Pathol. 2007; 34: 640-643
        • Mishima Y.
        • Mevorah B.
        Nevus ota and nevus Ito in American negroes.
        J Invest Dermatol. 1961; 36: 133-154
        • Zhong Y.
        • Huang L.
        • Yan T.
        • et al.
        Both age and disease duration are associated with clinical phenotype of Hori’s nevus in Chinese: a retrospective analysis of 497 cases.
        Clin Cosmet Investig Dermatol. 2021; 14: 65-71
        • Sun C.C.
        • Lü Y.C.
        • Lee E.F.
        • et al.
        Naevus fusco-caeruleus zygomaticus.
        Br J Dermatol. 1987; 117: 545-553
        • Hori Y.
        • Kawashima M.
        • Oohara K.
        • et al.
        Acquired, bilateral nevus of Ota-like macules.
        J Am Acad Dermatol. 1984; 10: 961-964
        • Ee H.L.
        • Wong H.C.
        • Goh C.L.
        • et al.
        Characteristics of Hori naevus: a prospective analysis.
        Br J Dermatol. 2006; 154: 50-53
        • Hidano A.
        • Kaneko K.
        Acquired dermal melanocytosis of the face and extremities.
        Br J Dermatol. 1991; 124: 96-99
        • Jun J.-Y.
        • Byun H.J.
        • Oh S.J.
        • et al.
        Acquired dermal melanocytosis confined to the hand.
        Ann Dermatol. 2018; 30: 380-381
        • Satake K.
        • Sudo T.
        • Sugino T.
        • et al.
        Large plaque-type blue nevus with GNAQ Q209P mutation, involving mammary gland tissue: under-recognized mammary condition as an origin of primary mammary melanocytic tumors.
        Am J Dermatopathol. 2021; 43: e248-e253
        • Lee M.Y.
        • Jin S.
        • Lee K.-H.
        • et al.
        A cellular blue nevus with pigmented epithelioid melanocytoma-like pattern on the ipsilateral upper arm associated with a congenital plaque-type blue nevus on the hand.
        J Cutan Pathol. 2019; 46: 383-388
        • Spring P.
        • Perrier P.
        • Erba P.
        • et al.
        Large agminated cellular “plaque-type” blue nevus surrounding the ear: a case and review.
        Dermatol Basel Switz. 2013; 227: 221-225
        • Habougit C.
        • Michiels-Marzais D.
        • Wang Q.
        Linear variant of large plaque-type blue naevus with subcutaneous cellular nodules.
        Pathology (Phila). 2017; 49: 542-544
        • Busam K.J.
        • Woodruff J.M.
        • Erlandson R.A.
        • et al.
        Large plaque-type blue nevus with subcutaneous cellular nodules.
        Am J Surg Pathol. 2000; 24: 92-99
        • Zattra E.
        • Salmaso R.
        • Montesco M.C.
        • et al.
        Large plaque type blue nevus with subcutaneous cellular nodules.
        Eur J Dermatol. 2009; 19: 287-288
        • Baraldi C.
        • Corti B.
        • Lambertini M.
        • et al.
        Large plaque-type blue naevus with cellular nodules: a rare unrecognized melanocytic tumour.
        J Eur Acad Dermatol Venereol. 2018; 32: e132-e133
        • Eichenfield D.Z.
        • Cotter D.
        • Thorson J.
        • et al.
        Agminated blue nevus with a GNAQ mutation: a case report and review of the literature.
        J Cutan Pathol. 2019; 46: 130-133
        • Maredia H.
        • Eseonu A.
        • Rozati S.
        Disseminated eruptive blue nevi in a young adult patient.
        Cureus. 2020; 12e11298
        • Busam K.J.
        Metastatic melanoma to the skin simulating blue nevus.
        Am J Surg Pathol. 1999; 23: 276-282
        • Busam K.
        • Gerami P.
        • Scolyer R.A.
        Pathology of Melanocytic Tumors.
        Elsevier. 2019; (Blue nevi and dermal melanocytosis)
        • Hung T.
        • Argenyi Z.
        • Erickson L.
        • et al.
        Cellular blue nevomelanocytic lesions: analysis of clinical, histological, and outcome data in 37 cases.
        Am J Dermatopathol. 2016; 38: 499-503
        • Dei Tos A.P.
        • Khurana J.S.
        • Kurtin P.J.
        • et al.
        Absence of S-100 Protein immunoreactivity in cellular blue nevus: a potential diagnostic pitfall.
        Appl Immunohistochem Mol Morphol. 1999; 7: 255
        • Michal M.
        • Baumruk L.
        • Skálová A.
        Myxoid change within cellular blue naevi: a diagnostic pitfall.
        Histopathology. 1992; 20: 527-530
        • Biernat W.
        • Kordek R.
        • Woźniak L.
        Cellular blue nevi with myxoid change--diagnostic difficulties and the review of the literature.
        Pol J Pathol. 1995; 46: 83-86
        • Ferrara G.
        • Soyer H.P.
        • Malvehy J.
        • et al.
        The many faces of blue nevus: a clinicopathologic study.
        J Cutan Pathol. 2007; 34: 543-551
        • Emley A.
        • Nguyen L.P.
        • Yang S.
        • et al.
        Somatic mutations in GNAQ in amelanotic/hypomelanotic blue nevi.
        Hum Pathol. 2011; 42: 136-140
        • Ma C.
        • Chambers C.J.
        • Kiuru M.
        • et al.
        Amelanotic blue nevus.
        JAAD Case Rep. 2017; 3: 93-94
        • Kamino H.
        • Tam S.T.
        Compound blue nevus: a variant of blue nevus with an additional junctional dendritic component. A clinical, histopathologic, and immunohistochemical study of six cases.
        Arch Dermatol. 1990; 126: 1330-1333
        • Jaquemus J.
        • Perron E.
        • Buisson A.
        • et al.
        Compound blue nevus: a reappraisal of the concept in the genomic era.
        Virchows Arch Int J Pathol. 2020; 476: 439-443
        • Baklouti M.
        • Sellami K.
        • Elleuch N.
        • et al.
        Compound blue nevus: a misleading pigmented melanocytic tumor.
        Clin Case Rep. 2022; 10e05311
        • Ferrara G.
        • Argenziano G.
        • Zgavec B.
        • et al.
        Compound blue nevus”: a reappraisal of “superficial blue nevus with prominent intraepidermal dendritic melanocytes” with emphasis on dermoscopic and histopathologic features.
        J Am Acad Dermatol. 2002; 46: 85-89
        • Scolyer R.A.
        • Zhuang L.
        • Palmer A.A.
        • et al.
        Combined naevus: a benign lesion frequently misdiagnosed both clinically and pathologically as melanoma.
        Pathology (Phila). 2004; 36: 419-427
        • Tran T.A.
        • Carlson J.A.
        • Basaca P.C.
        • et al.
        Cellular blue nevus with atypia (atypical cellular blue nevus): a clinicopathologic study of nine cases.
        J Cutan Pathol. 1998; 25: 252-258
        • Barnhill R.L.
        • Argenyi Z.
        • Berwick M.
        • et al.
        Atypical cellular blue nevi (cellular blue nevi with atypical features): lack of consensus for diagnosis and distinction from cellular blue nevi and malignant melanoma (“malignant blue nevus”).
        Am J Surg Pathol. 2008; 32: 36-44
        • de la Fouchardiere A.
        • Blokx W.
        • van Kempen L.C.
        • et al.
        ESP, EORTC, and EURACAN Expert Opinion: practical recommendations for the pathological diagnosis and clinical management of intermediate melanocytic tumors and rare related melanoma variants.
        Virchows Arch Int J Pathol. 2021; 479: 3-11
        • Patel B.C.
        • Egan C.A.
        • Lucius R.W.
        • et al.
        Cutaneous malignant melanoma and oculodermal melanocytosis (nevus of Ota): report of a case and review of the literature.
        J Am Acad Dermatol. 1998; 38: 862-865
        • Díaz Pérez J.L.
        • Burgos Bretones J.J.
        • Rivera Pomar J.M.
        [Malignant melanoma of the dermal component of Ota’s nevus].
        Actas Dermosifiliogr. 1980; 71: 219-224
        • Kopf A.W.
        • Bart R.S.
        Malignant blue (Ota’s?) nevus.
        J Dermatol Surg Oncol. 1982; 8: 442-445
        • Dompmartin A.
        • Leroy D.
        • Labbé D.
        • et al.
        Dermal malignant melanoma developing from a nevus of Ota.
        Int J Dermatol. 1989; 28: 535-536
        • Gerami P.
        • Pouryazdanparast P.
        • Vemula S.
        • et al.
        Molecular analysis of a case of nevus of ota showing progressive evolution to melanoma with intermediate stages resembling cellular blue nevus.
        Am J Dermatopathol. 2010; 32: 301-305
        • Buntinx-Krieg T.
        • Ouyang J.
        • Cartwright M.
        An orbital malignant melanoma arising in cellular blue nevus in a patient with nevus of Ota.
        Cureus. 2016; 8: e698
        • Yeh I.
        • Fang Y.
        • Busam K.J.
        Melanoma arising in a large plaque-type blue nevus with subcutaneous cellular nodules.
        Am J Surg Pathol. 2012; 36: 1258-1263
        • Loghavi S.
        • Curry J.L.
        • Torres-Cabala C.A.
        • et al.
        Melanoma arising in association with blue nevus: a clinical and pathologic study of 24 cases and comprehensive review of the literature.
        Mod Pathol. 2014; 27: 1468-1478
        • Yan L.
        • Tognetti L.
        • Nami N.
        • et al.
        Melanoma arising from a plaque-type blue naevus with subcutaneous cellular nodules of the scalp.
        Clin Exp Dermatol. 2018; 43: 164-167
        • Chan M.P.
        • Andea A.A.
        • Harms P.W.
        • et al.
        Genomic copy number analysis of a spectrum of blue nevi identifies recurrent aberrations of entire chromosomal arms in melanoma ex blue nevus.
        Mod Pathol. 2016; 29: 227-239
        • Costa S.
        • Byrne M.
        • Pissaloux D.
        • et al.
        Melanomas associated with blue nevi or mimicking cellular blue nevi: clinical, pathologic, and molecular study of 11 cases displaying a high frequency of GNA11 mutations, BAP1 expression loss, and a predilection for the scalp.
        Am J Surg Pathol. 2016; 40: 368-377
        • Chang L.-W.
        • Kazlouskaya V.
        • Kazi R.
        • et al.
        Melanoma ex blue nevus with GNA11 mutation and BAP1 loss: case report and review of the literature.
        Am J Dermatopathol. 2020; 42: 854-857
        • Dai J.
        • Tetzlaff M.T.
        • Schuchter L.M.
        • et al.
        Histopathologic and mutational analysis of a case of blue nevus-like melanoma.
        J Cutan Pathol. 2016; 43: 776-780
        • Martin M.
        • Maßhöfer L.
        • Temming P.
        • et al.
        Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3.
        Nat Genet. 2013; 45: 933-936
        • Yavuzyigitoglu S.
        • Koopmans A.E.
        • Verdijk R.M.
        • et al.
        Uveal melanomas with SF3B1 mutations: a distinct subclass associated with late-onset metastases.
        Ophthalmology. 2016; 123: 1118-1128
        • Nathan P.
        • Hassel J.C.
        • Rutkowski P.
        • et al.
        Overall survival benefit with tebentafusp in metastatic uveal melanoma.
        N Engl J Med. 2021; 385: 1196-1206