CYSLTR2-mutant Cutaneous Melanocytic Neoplasms Frequently Simulate "Pigmented Epithelioid Melanocytoma," Expanding the Morphologic Spectrum of Blue Tumors: A Clinicopathologic Study of 7 Cases.

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

Integrated Genomic Classification of Melanocytic Tumors of the Central Nervous System Using Mutation Analysis, Copy Number Alterations, and DNA Methylation Profiling.

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.

Blue Nevi and Related Tumors.

The major entities related to blue nevus are common blue nevus, cellular blue nevus, atypical blue nevus, and malignant blue nevus. These lesions share presence of dermal pigmented dendritic melanocytes derived from embryonal precursors to melanocytes, Schwann cells, and glial cells migrating to the skin from the ventral neural crest. Genetically, blue nevi harbor mutations in G-protein-coupled receptor subunits GNAQ and GNA11. Progression to malignant blue nevus is associated with additional mutations and partial gains and losses of chromosomal material. This article discusses recent advances in pathology of blue nevi with emphasis on differential diagnosis and molecular pathology.

Sinonasal small round blue cell tumors: An approach to diagnosis.

The differential diagnosis for small round cell tumors in the sinonasal tract is diverse and as the body of literature documenting not only uncommon presentations but also availability of ancillary studies grows, so does the need for a reminder to take a conservative and thorough approach before rendering a diagnosis. Small tissue samples are particularly problematic, with limitations that include volume of tumor cells available for studies, lack of architectural context and a non-specific gross description. Incorporation of patient history and presentation, radiologic findings, clinical impression and concurrent studies often guide the course of studies performed by the pathologist. If these are non-specific, the pathologist may need to perform ancillary studies, including a broad panel of immunohistochemical stains and molecular studies. If tissue is limited, a precise classification may not be achievable. Although the expectation to render a definitive diagnosis is high, the pathologist should never feel compelled to go further with a diagnosis than the tissue itself supports.

Melanocytic tumors of uncertain malignant potential: results of a tutorial held at the XXIX Symposium of the International Society of Dermatopathology in Graz, October 2008.

Several reports demonstrated the difficulties and lack of agreement in the histopathologic diagnosis of particular melanocytic tumors (atypical Spitz tumors, atypical blue nevi, deep penetrating nevi). These lesions are often referred to as "melanocytic tumors of uncertain malignant potential" (MELTUMP). We studied a large number of such tumors to find out whether repeatable histopathologic criteria for distinction of benign from malignant cases exist. Fifty-seven cases of MELTUMP were classified within 3 groups according to behavior as follows: (a) favorable (no evidence of metastatic disease after a follow-up of > or = 5 y), (b) unfavorable (tumor-related death and/or large metastatic deposits in the lymph nodes and/or visceral metastases), (c) borderline (small nodal deposits of tumor cells < or = 0.2 mm). There were no significant differences in tumor thickness and presence or absence of ulceration between the different groups. The only 3 histopathologic criteria that were statistically different between the groups of favorable and unfavorable cases were presence of mitoses, mitoses near the base, and an inflammatory reaction, all of them found more frequently in cases with unfavorable behavior. The major outcome of this study of a series of "MELTUMPs" suggests as a preliminary observation that these lesions as a group exist and that they may be biologically different from conventional melanoma and benign melanocytic nevi. The terminology remains highly controversial, reflecting the uncertainty in classification and interpretation of these atypical melanocytic tumors.

Equine skin tumours in 20 horses resembling three variants of human melanocytic naevi.

Melanocytic tumours are important in horses, especially grey horses. Intradermal common melanocytic naevi, cellular blue naevi and combined cellular blue naevi are subgroups of human melanocytic tumours, which have not been reported in horses. In this study, we describe 20 horses with skin tumours similar to these naevi of humans. These tumours represented individual skin masses in male and female horses of different breeds. Tumours resembling human intradermal common melanocytic naevi were noted in 12 horses aged between 2 and 17 years. Seven horses aged between 4 and 15 years developed cutaneous lesions similar to human cellular blue naevi. A combined cellular blue naevus-like tumour was diagnosed in a 20-year-old horse. All tumour types formed expansile, well-demarcated, non-encapsulated, symmetrical masses. Tumours similar to intradermal common melanocytic naevi were composed of nests of round and spindeloid neoplastic cells, often embedded in myxomatous stroma. Lesions resembling cellular blue naevi were formed by intradermal bundles of ovoid to elongated cells separated by collagen fibres. The combined cellular blue naevus-like tumour resembled human cellular blue naevus with in addition, an overlying junctional common melanocytic naevus. Neoplastic cells in all groups contained varying amounts of melanin pigment and were immunopositive for S100. These equine skin tumours differ from the commonly recognized equine melanocytic tumours by their cytomorphological features, random location and the absence of an increased tumour frequency in grey horses. The resemblance of these tumours to three distinct subgroups of human naevi expands the complexity of equine proliferative cutaneous melanocytic lesions.

Loss of expression of protein kinase a regulatory subunit 1alpha in pigmented epithelioid melanocytoma but not in melanoma or other melanocytic lesions.

Pigmented epithelioid melanocytoma (PEM) is a recently described entity comprising most cases previously described as "animal-type melanoma" and epithelioid blue nevus (EBN) occurring in patients with the multiple neoplasia syndrome Carney complex (CNC). Mutations of the protein kinase A regulatory subunit type 1alpha (R1alpha) (coded by the PRKAR1A gene) are found in more than half of CNC patients. In this study, we investigated whether PEM and EBN are related at the molecular level, and whether changes in the PRKAR1A gene status and the expression of the R1alpha protein may be involved in the pathogenesis of PEM and other melanocytic lesions. Histologic analysis of hematoxylin and eosin-stained sections and immunohistochemistry (IHC) with R1alpha antibody were performed on 34 sporadic PEMs, 8 CNC-associated PEMs from patients with known PRKAR1A mutations, 297 benign and malignant melanocytic tumors (127 conventional sections of 10 compound nevi, 10 Spitz nevi, 5 deep-penetrating nevi, 5 blue nevi, 6 cellular blue nevi, 2 malignant blue nevi, 3 lentigo maligna, and 86 melanomas of various types); in addition, 170 tissue microarray sections consisting of 35 benign nevi, 60 primary melanomas, and 75 metastatic melanomas, and 5 equine dermal melanomas, were examined. Histologic diagnoses were based on preexisting pathologic reports and were confirmed for this study. DNA studies [loss of heterozygosity (LOH) for the 17q22-24 locus and the PRKAR1A gene sequencing] were performed on 60 melanomas and 7 PEMs. IHC showed that R1alpha was expressed in all but one core from tissue microarrays (169/170), and in all 127 melanocytic lesions evaluated in conventional sections. By contrast, R1alpha was not expressed in the 8 EBN from patients with CNC and PRKAR1A mutations. Expression of R1alpha was lost in 28 of 34 PEMs (82%). R1alpha was expressed in the 5 equine melanomas studied. DNA studies correlated with IHC findings: there were no PRKAR1A mutations in any of the melanomas studied and the rate of LOH for 17q22-24 was less than 7%; 5 of the 7 PEMs showed extensive 17q22-24 LOH but no PRKAR1A mutations. The results support the concept that PEM is a distinct melanocytic tumor occurring in a sporadic setting and in the context of CNC. They also suggest that PEM differs from melanomas in equine melanotic disease, further arguing that the term animal-type melanoma may be a misnomer for this group of lesions. Loss of expression of R1alpha offers a useful diagnostic test that helps to distinguish PEM from lesions that mimic it histologically.

The many faces of blue nevus: a clinicopathologic study.

BACKGROUND: In recent years, several histopathologic variants of blue nevus have been identified, whose clinical and dermoscopic correlates need further clarification. METHODS: A comparative evaluation of histopathologic and dermoscopic features was carried out on 52 melanocytic proliferations belonging to the morphologic spectrum of blue nevus. RESULTS: On dermoscopy, all lesions showed a homogeneous, structureless pigment pattern, with a curious variety of colors (blue, white-blue, black, brown, and polychromatic). Histopathologically, the majority of blue lesions were common blue nevi (11/19); the majority of white-blue lesions were 'hypochromic' (sclerotic, hypomelanotic, and amelanotic) blue nevi (17/22); all the black lesions were 'compound' blue nevi (2/2); the majority of brown lesions were combined blue nevi (3/4); the unusual polychromatic dermoscopic appearance was often associated with a histopathologic diagnosis of deep penetrating nevus (2/5). CONCLUSION: A dermoscopic-pathologic approach now allows us to identify 'blue' (common) blue nevi, 'white' (hypochromic) blue nevi, 'black' (compound) blue nevi, 'brown' (combined) blue nevi, and 'polychromatic' (deep penetrating) blue nevi. A better recognition of the many dermoscopic faces of blue nevi is expected to give a morphologic guideline for the clinical management of these lesions.

Proposal of a new classification system for melanocytic naevi.

The lack of consensus among clinicians and pathologists due to the mixture of clinical and histopathological features used to define the various melanocytic naevi underscores the need of a better classification system for these benign lesions. We describe a dermoscopic classification system for melanocytic naevi that is directed to clinicians dealing with the early diagnosis of melanoma, as well to pathologists, in order to promote better communication between these different specialists.

Blue nevi of internal organs are more similar to the so-called dermal melanocytosis than to cutaneous blue nevi.

In this report, we examine several morphologic aspects of blue nevi of internal organs, and compare them to similar conditions of the skin. From a morphologic point of view, blue nevi of internal organs are more similar to the so-called dermal melanocytoses. Nevertheless, since melanocytoses and blue-nevi seem to have the same benign prognosis, and since blue nevus is a historically consolidated term to refer to pigmented spindle cell lesions of internal organs, a most appropriate term, to refer to the latter, will not be easily accepted in literature.

Genomic analysis of blue nevi and related dermal melanocytic proliferations.

Blue nevi are benign dermal melanocytic proliferations that can sometimes share overlapping microscopic features with melanoma. We used comparative genomic hybridization to analyze three groups of dermal melanocytic proliferations. Group 1 consisted of 10 cellular blue nevi and 1 deep penetrating nevus, none of which showed chromosomal aberrations. Group 2 consisted of 11 lesions that were histopathologically ambiguous. Three of these lesions demonstrated chromosomal aberrations (three or fewer per lesion). Group 3 consisted of seven histopathologically malignant lesions, each showing three or more chromosomal aberrations. Moderate to severe cytologic atypia and a mitotic rate of three or more mitoses per 10 high power fields were present in six of eight (75%) lesions that had at least three chromosomal aberrations but were absent in 15 of 20 (75%) lesions without chromosomal aberrations. Necrosis was present in four of the 29 (13%) lesions, with every lesion with necrosis demonstrating three or more genomic abnormalities. In conclusion, histopathologically unequivocally benign or malignant dermal melanocytic proliferations show nonoverlapping patterns of chromosomal aberrations. Ambiguous lesions can be separated into lesions with and without chromosomal aberrations. Future studies with clinical follow-up are necessary to determine which aberrations are most informative for classification of these lesions.

"Atypical" blue nevus, "malignant" blue nevus, and "metastasizing" blue nevus: a critique in historical perspective of three concepts flawed fatally.

The same errors that spawned, sustained, and continue to spur the notions of "atypical" Spitz's nevus, "malignant" Spitz's nevus, and "metastasizing" Spitz's nevus are animating of 3 other concepts flawed equally, namely, those of "atypical blue nevus," "malignant blue nevus," and "metastasizing blue nevus." Our intention here is to compel to the conclusion, by way of critique in historical perspective, that all neoplasms claimed to be "malignant blue nevus" and "metastasizing blue nevus;" in fact, are melanomas, that all "atypical blue nevi" are either a nevus or a melanoma, and that the trio of curious designations that serve as title of this work are mere evasions transparently from a diagnosis, straightforwardly, of 1 of only 3 possibilities, to wit, "blue nevus," melanoma, or melanoma in association with a "blue nevus." Rather than admit uncertainty forthrightly, those who employ circumlocutions that we deplore, such as those under scrutiny here, resort to linguistic maneuvers that, at first blush, seem to have the cachet of scholarship (the jargon used being in keeping with a slew of other well-accepted, but equally bogus diagnoses in [dermato]pathology, among those being "minimal deviation melanoma," "borderline melanoma," "nevoid melanoma," "potentially low-grade melanocytic neoplasm," and "melanocytic proliferation of uncertain biologic potential"). All those terms and phrases are constructed in a manner designed to make them appear to convey unbridled confidence on the part of a histopathologist, rather than what they are in actuality, that is, a cover abjectly for tentativeness. Scrutiny of the lingo, in very abbreviated form, just catalogued reveals it to be devoid of content utterly. For example, "malignant blue nevus" and "metastasizing blue nevus" not only are contradictions in terms, but they are outrageous violations of principles fundamental to classic Virchowian pathology. We seek here to debunk that claptrap in the same manner we did "atypical Spitz's nevus," "malignant Spitz's nevus," and "metastasizing Spitz's nevus." It is our hope that readers will consider our arguments worthy because they are logical, will find them convincing because they are irrefutable, and will incorporate the lessons communicated through them so that their own professional life, pathology as a discipline, and, ultimately, patients, are the beneficiaries.

Epiluminescence microscopy features of cutaneous malignant melanoma metastases.

Especially small and/or initial cutaneous malignant melanoma metastases (CMMMs) are tumours with inconspicuous clinical and sometimes histological features which may be difficult to differentiate from benign melanocytic lesions or angiomas. Thus it would be very valuable to have additional criteria for the differential diagnosis of such lesions. Thirty histologically verified CMMMs were examined using epiluminescence microscopy (ELM) in order to visualize a large number of morphological features permitting the recognition of malignancy. One hundred primary cutaneous malignant melanomas (PCMMs), 50 dysplastic naevi, 50 common naevi, 30 blue naevi and 20 haemangiomas served as the control group; these were randomly selected from a large data base and were all reviewed for histological diagnosis. Four of the 24 features studied were shown to differ significantly between CMMMs and the control group. Two features of the malignant tumour group (CMMM and PCMM) differed significantly from the benign tumour group. A polymorphic angiectatic base pattern and/or vascular aneurysms, peripheral erythema, brown-grey coloration as a negative criterion (i.e. its absence is indicative of CMMM) and a light brown halo had a specificity of 86.7-96.0% for CMMM. Areas of polymorphic and/or horizontally dilated capillaries and a saccular pattern had a specificity of 97.3-99.2% for the malignant group (CMMM and PCMM). Three features - peripheral greyish patches, lesions surrounded by grey streaks (melanoma cell infarcts of the vessels) and microscopic ovoid blood lakes (spontaneous microhaemorrhages)--were absent in the benign group. The prevalence of distinct ELM criteria in CMMM represents a useful enhancement for the diagnosis of malignancy in melanocytic skin lesions.

Nevo azul combinado gigante: relato de caso / Combined ble nevus: a case report

Relato de caso de nevo azul do tipo combinado em paciente de 47 anos de idade, do sexo feminino, que apresentava grande massa tumoral localizada na regiäo occipital. A designaçäo nevo azul combinado reporta-se a raros casos que apresentam superposiçäo de aspectos microscópicos de nevo azul e nevo melanocítico