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

Cutaneous melanomas may demonstrate a variety of histopathological features and genetic abnormalities. Melanomas that arise in the setting of blue nevi, also known as “malignant blue nevus” or melanoma ex blue nevus (MBN), share similar histopathological and mutational profile with uveal melanoma. The majority of uveal melanomas show characteristic GNA11 or GNAQ mutations; additional BAP1 mutation or loss is associated with the highest risk for metastasis and worst prognosis. However, the significance of BAP1 loss in melanomas ex blue nevus remains unclear. We present a case of melanoma ex blue nevus arising from the scalp of a twenty-one-year-old female. The diagnosis was established on histopathological findings demonstrating a markedly atypical melanocytic proliferation with increased mitotic activity, necrosis, and a focus of angiolymphatic invasion. Immunohistochemical analysis demonstrated the absence of BAP1 nuclear expression within tumor cells. Next Generation Sequencing detected GNA11 Q209L mutation and BAP1 loss (chromosome 3p region loss), supporting the diagnosis. We reviewed another twenty-one MBN cases with reported BAP1 status from the literature. MBN with BAP1 loss presented at a younger average age (41 years versus 61 years), demonstrated larger average lesion thickness (9.0 mm versus 7.3 mm), and had a higher rate of metastasis (50% versus 33%) compared with BAP1-retained MBN. BAP1 expression studies may assist in the diagnosis and management of MBN, but further research is needed.

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

Plaque-type blue nevus is a rare variant of blue nevi that was first described in 1954. This article presents clinical, macroscopic, histopathological, and genetic findings for a case of large plaque-type blue nevus expanding into the mammary gland tissue as well as the skin of the right breast. A 63-year-old woman presented with a congenital, large, blue-colored macule limited to the hypochondriac area of the right breast. A nodule 8 mm in diameter was also present in the mammary gland tissue. Magnetic resonance imaging was unable to detect diffuse melanin deposition in the mammary gland tissue, but pigmentation in the whole mammary parenchyma was observed in the cut surfaces of the mastectomy specimen. Histopathology revealed a sparse distribution of dendritic melanocytes in whole sections of the mammary fibrous tissue and partial sections of the dermis. The histopathological criteria for atypical cellular blue nevus were fulfilled for the mammary tumor. Nodal blue nevus was diagnosed in the sentinel lymph node. Sanger sequencing confirmed the GNAQ Q209P mutation, which was also identified in all 4 literature cases of plaque-type blue nevus, but rarely in conventional blue nevi and uveal melanoma. It should be noted that plaque-type blue nevus can expand into the mammary gland tissue, even if the pigmented lesion does not exist on the overlying breast skin. The mammary condition can be the origin of primary mammary melanocytic tumors. Mosaicism of the GNAQ Q209P mutation can be a characteristic genetic alteration to extensive blue nevi, including plaque-type blue nevus.

The family of blue nevi includes the common blue nevus (BN), cellular blue nevus (CBN), and atypical BN, while melanomas with BN-like morphology can either arise in association with a blue nevus (MABN) or in the de novo setting mimicking cellular blue nevus (MMCBN). Recent molecular and immunohistochemical studies have demonstrated loss of BAP-1 in MABN/MMCBN but not in BN/CBN, suggesting that loss of BAP-1 correlates with a malignant phenotype in these lesions. In this study, we applied anti-BAP-1 antibodies to a series of CBN/BN (n = 11) and MABN/MMCBN (n = 4). Nuclear BAP-1 expression was detected in the majority of CBN/BN (n = 10/11) but was lost in 1 case. Most cases of MABN/MMCBN showed loss of nuclear BAP-1 expression (n = 3/4), with one case of MMCBN showing preserved BAP-1 expression. Demonstration of BAP-1 loss in a single case of CBN and preservation of BAP-1 expression in 1 case of MMCBN may indicate that detection of alterations in BAP-1 protein expression by immunohistochemistry may not be a completely reliable biomarker for the distinction of BN/CBN from MABN/MMCBN. Further investigation of the significance of BAP-1 loss/preservation in BN-like tumors is warranted.

Recent studies have identified kinase fusions in Spitzoid melanocytic neoplasms, and approximately 10% of Spitzoid neoplasms harbor anaplastic lymphoma kinase (ALK) rearrangements and corresponding ALK immunoreactivity. Deep penetrating nevi (DPN), a subset of melanocytic neoplasms, have histologic and immunohistochemical overlap that have historically supported classification of DPN with blue/cellular blue nevi (CBN). However, HRAS mutations have rarely been detected in DPN, thereby also linking them to Spitz nevi. The purpose of this study was to see if DPN or CBN possess ALK rearrangements, thereby providing more evidence that these melanocytic lesions may be pathogenetically related to Spitzoid neoplasms. Using ALK immunohistochemistry as a surrogate for ALK rearrangement, the authors examined 26 DPN, 30 CBN, and 4 conventional blue nevi. ALK immunoreactive cases underwent fluorescent in situ hybridization to investigate for the presence of ALK gene rearrangement. Patchy and focal ALK immunostaining was found in only 1 case of DPN (1/26, 3.8%). Seven cases of CBN (7/30; 23%) showed ALK immunostaining (6 focal/patchy, 1 strong and diffuse). Fluorescent in situ hybridization using ALK break-apart probes showed various degrees of gain of 2p23 and rare ALK break-apart signals. Four CBN showed ALK rearrangement in 2%-4% of cells. Two cases of CBN showed gain of 2p23 in 10%-20% of cells. In our study, ALK rearrangements are uncommon in both CBN and DPN, making ALK an unlikely driver in tumorigenesis and classification of these melanocytic variants. However, our study did identify ALK molecular changes and immunohistochemical staining patterns that have not been previously described in CBN or DPN.

In this study, we present a rare case of a 35-year-old man with a long-standing blue-black lesion on his left hand with subsequent infraclavicular and axillary lymph node tumor deposits. The hand lesion and lymph nodes were excised revealing histological, immunohistochemical, and molecular findings consistent with cellular blue nevus. Despite nonregional lymph node involvement, there has been no progression at 12-months follow-up. This is an index case of a cellular blue nevus with metastasis to both regional and nonregional lymph nodes. The lack of atypical/malignant features in this lesion makes the metastatic behavior extraordinary, and hence the prognosis of lesions of this type is indeterminate.

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

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."

A blue nevus-like melanoma is a rare melanoma variant arising from or histologically similar to a blue nevus. It can be challenging to distinguish a cellular blue nevus from a blue nevus-like melanoma, particularly in cases of blue nevus-like melanoma lacking a transition from a clearly benign component. We present a case of a 78-year-old man who refused treatment for a previously existing melanoma and subsequently developed a gray nodule near the site of the previous melanoma. After fluorescence in situ hybridization revealed copy number gains in RREB1, this was diagnosed as a blue nevus-like metastatic melanoma. Blue nevus-like metastatic melanoma is most commonly seen near the site of the primary cutaneous melanoma. This entity should be considered in a patient with a history of melanoma and a new blue nevus-like lesion.

Ancient melanocytic nevi are benign melanocytic neoplasms that show degenerative and atypical changes, sometimes leading to a misdiagnosis of melanoma. We describe 6 patients (M:F ratio 4:2; age range, 15-84 years; median, 50 years) who presented with cellular blue nevi showing stromal changes resembling those of ancient melanocytic nevi. The lesions were located on the buttocks (4 patients) and on the trunk (2 patients) and clinically consisted of heavily pigmented nodules. Histology revealed the architectural pattern of cellular blue nevi. However, the architecture was strikingly altered by stromal changes like those seen in ancient melanocytic nevi, including increased number of large, dilated vessels with pseudoangiomatous features in 4 cases, hyaline angiopathy in 4 cases, myxoid changes, sclerosis or hyalinization of the stroma in all cases, and variable amounts of edema in 4 cases. In 2 cases, a large edematous area was present in the center of the lesion, and nests of ovoidal melanocytes and single dendritic melanocytes appeared to "float" in the stroma. Pleomorphic melanocytes were observed in all cases. Ancient blue nevi represent a morphologic variation of cellular blue nevi-Masson neuronevi with degenerative stromal changes. Recognition of these lesions can help prevent overdiagnosis of melanoma.

Melanoma or melanoma metastases can rarely mimic blue nevi clinically and/or histologically, presenting a diagnostic pitfall for both the clinician and the dermatopathologist. We report a case of an invasive lentigo maligna melanoma with subsequent development of multiple, cutaneous blue nevus-like localized metastases followed by a distant metastasis, heralding widespread systemic metastases.

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.

Rosette formation is a feature that has not been described as occurring in melanocytic neoplasms. We present such a unique case. A 59-year-old man presented with an asymptomatic, soft, hairy 3.0 x 2.0-cm pigmented lesion that had been present for many years in the right external ear, extending from the conchal bowl onto the antitragus area. Examination of histologic sections showed a proliferation of nonatypical and heavily pigmented melanocytes in the superficial dermis and around deep adnexal structures, characteristic of a congenital nevus. In other areas, pigmented spindled and dendritic cells infiltrated thickened collagen bundles in a pattern of a blue nevus. A nodular proliferation of epithelioid melanocytes was seen within the deep dermis and subcutaneous tissue. The periphery of the nodule merged with the surrounding nevus cells. Neoplastic cells with nuclear atypia, melanin pigment, pseudonuclear inclusions, and balloon cell change were present. In addition, there was rosette formation by the tumor cells, with a central aggregate of coarse cell processes. Neuroid cords were also noted. No prominent mitotic figures, necrosis, or significant inflammatory infiltrate were noted. The neoplastic cells were positive for S-100 protein, Mart-1, tyrosinase, neuron-specific enolase, and vimentin. HMB-45 and Ki-67 (MIB-1) labeled only rare neoplastic cells within the proliferative nodule. The tumor cells were negative for synaptophysin, protein gene product 9.5, CD57, epithelial membrane antigen, CD31, and CD34. The central cell processes of the rosettes were negative for trichome, type IV collagen, neurofilament protein, glial fibrillary acidic protein, and tyrosine hydroxylase. We also retrospectively examined 78 congenital nevi of 65 pediatric patients at our institution. Rosette formation was not seen in any of these cases.

Malignant blue nevus is a rare melanocytic tumor that is described by some authors as a variant of malignant melanoma, whereas others regard it as a distinct entity. To our knowledge no molecular studies of this tumor have been performed, although the molecular pathogenesis of conventional melanomas has been extensively described. We present a case of malignant blue nevus that developed in a 15-cm congenital blue nevus on the back of a 41-year-old man. Subsequent regional lymph node and lung metastases developed within 1 and 29 months, respectively. We performed a molecular analysis for loss of heterozygosity on microdissected samples from the spectrum of benign to malignant blue nevus, using a panel of eight genes (MTS1, MXI1, CMM1, p53, NF1, L-myc hOGG1, and MCC), many of which are commonly associated with conventional melanomas. No loss of heterozygosity was detected, despite informativeness in seven genes. We suggest that malignant blue nevus may represent a distinct entity with a different molecular pathway to tumorigenesis than that of conventional melanomas.

Cutaneous neurocristic hamartoma (NCH) is a rare, pigmented lesion consisting of cells that aberrantly develop from the neurocrest. In addition to a dermal melanocytic component, NCH can also harbor neurosustentacular and neuromesenchymal components. NCH has many features in common with other dermal melanocytic neoplasm, such as blue nevi. Recognition of NCH is important not only because of the potential for misinterpretation as melanoma, but also because melanoma arise within these lesions over an unpredictable time frame and remain undetected because of the deep location and already pigmented background. We report a case of a 17-year-old man with a large NCH resected from the posterior scalp showing involvement of the bone marrow.

The epithelioid blue nevus has recently been associated with the Carney complex, which is characterized by myxomas, spotty skin pigmentation, endocrine overactivity, and schwannomas. Using the general criteria proposed by Carney and Ferreiro, similar lesions were identified in 33 patients with no evidence of the Carney complex. Those lesions presented on the face, trunk and extremities of 15 males and 18 females. The mean age was 35 years, much older than those in the Carney complex (mean 16.3 years). Clinical diagnoses included malignant blue nevus, atypical nevus, melanoma, congenital nevus, and dermatofibroma. The lesions were symmetric, predominantly dermal melanocytic proliferations arranged as short fascicles, small nests, and single cells. Large polygonal and epithelioid melanocytes with moderate pleomorphism, and occasional nuclear pseudoinclusions were admixed with heavily pigmented dendritic and spindled melanocytes and melanophages. Rare mitotic figures were seen in some cases. The neoplasms showed a morphologic spectrum that encompassed a group of combined blue nevi with epithelioid melanocytes and other Spitz's nevus characteristics. These epithelioid combined nevi (ECN) fell into three phenotypes with morphologies that most closely paralleled those pictured by Carney and Ferreiro in the Carney complex: the classic or Carney complex pattern (ECN-CC), those that showed overlap with deep penetrating nevus (ECN-DPN), and those that have many dermal Spitz's nevus features, [BLue + SpITZ's nevus; (ECN-BLITZ)I. In six cases, there was such an admixture of features that it was difficult to ascribe them to one of the groups. Nine lesions had associated banal congenital nevus. Follow-up that averaged over 2.5 years (31 months) (range 6-162 months) showed no evidence of malignancy or recurrent disease after excision. Epithelioid combined nevus is a type of combined nevus with blue nevus and Spitz's nevus features, which may or may not be associated with the Carney complex. It shows morphologic overlap with the epithelioid blue nevus described by Carney (ECN-CC), deep penetrating nevus (ECN-DPN), and blue nevus with intradermal Spitz's (desmoplastic) nevus (ECN-BLITZ). Epithelioid combined nevus is thought to be a fitting nosologic designation for all of these lesions.

Nevus sebaceus of Jadassohn is a hamartoma that combines epidermal, follicular, sebaceous, and apocrine gland abnormalities. Classically, several types of cutaneous neoplasms have been associated with this hamartoma, with basal cell carcinoma being the most frequently described malignancy. We studied a series of 155 examples of nevus sebaceus of Jadassohn with clinicopathologic correlation. Several histopathologic changes related to the age of the patients were found. In our series, we could not identify any cases of authentic basal cell carcinoma. In contrast, several examples of primitive follicular induction and of trichoblastomas were seen. Other cutaneous hamartomas, hyperplasias, and neoplasms found in our series of nevus sebaceus of Jadassohn included syringocystadenoma papilliferum, sebomatricoma, apocrine gland cyst, poroma, different histopathologic variants of warts (classic warts, tricholemmoma, and desmoplastic tricholemmoma), primitive follicular induction, and ductal induction. In our series, no examples of malignant neoplasms were identified. On the basis of these findings, the classically recommended treatment for this hamartoma, which consists of early excision to prevent the development of malignancy, seems to be inappropriate.

Blue nevi are typically heavily melanized. We report a variant of blue nevus that is minimally pigmented. Of the 1,358 blue nevi seen in our laboratory during the last 6 years, 38 (2.7%) were selected that had scant or absent melanin. We refer to these blue nevi as the amelanotic type. Approximately half of the cases in clinical diagnosis were nevus of some type, whereas other differential diagnoses were basal cell carcinoma, dermatofibroma, and lesion. Histologically all specimens were characterized by the spindle-shaped cells seen in blue nevi, but with very little or no obvious melanin. Some lesions were markedly cellular, resembling the features of cellular blue nevus. No hemosiderin was identified on Perls' stain, whereas Fontana-Masson stain was variably positive. Usually there was fibrous stroma. In most cases, the histologic differential diagnosis was dermatofibroma. Other histologic differential diagnoses included amelanotic and/or spindle cell melanoma, dermal Spitz nevus, neurofibroma, and scar. There was no pleomorphism or increased mitotic activity. Evidence of epidermal melanocytic hyperplasia was seen in two cases. Furthermore, the lesions had been present for many years without evidence of recent change. Immunohistochemistry showed all cases to be strongly positive with anti Mel-5 antibody, but only weakly positive or negative with anti S-100 and HMB-45 antibodies. We would like dermatologists and pathologists to be aware of this unusual and uncommon entity.

Angiogenesis and vascularity are researched in melanocytic tumors for their importance in carcinogenesis. For the first time, to the best of our knowledge, the authors compared the microvascular characteristics between small/medium congenital nevocellular nevi (CN), common blue nevi (BN), common and dysplastic acquired melanocytic nevi (AMN), and melanomas. The authors collected 31 BN, 48 CN (≤5 cm), 35 AMN (14 common, 21 dysplastic), and 26 melanomas. Vessels were stained with factor VIII. Microvascular density (MVD) and total vascular area (TVA), where evaluated in high capillary density areas. Student t and Mann-Whitney tests were used. MVD (mean ± SD) was low in BN (3.52 ± 1.21) and significantly higher in CN (7.56 ± 2.47) (P0.001). TVA was low in BN and significantly higher in CN (Mann-Whitney U = 141, n1 = 48, n2 = 31, P0.001, 2-tailed). MVD was not significantly different between common and dysplastic AMN (20.64 ± 7.87 and 20.38 ± 9.54, respectively) (P0.05). TVA was not significantly different between common and dysplastic AMN (Mann-Whitney U = 164, n1 = 14, n2 = 21, P0.05, 2-tailed). MVD was significantly lower in CN (7.56 ± 2.47) compared with AMN (20.49 ± 8.79) (P0.001). TVA was significantly lower in CN compared with AMN (Mann-Whitney U = 1486, n1 = 48, n2 = 35, P0.001, 2-tailed). MVD was significantly lower in AMN (20.49 ± 8.79) compared with melanomas (33.77 ± 14.32) (P0.001). TVA (mean ± SD) was significantly smaller in AMN (18473.94 ± 7050.61) compared with melanomas (29308.50 ± 11307.22) (P0.001). Vascularity increased from BN to CN to AMN with melanomas being the most vascular. Common and dysplastic AMN had comparable vascularity. The implications of our results regarding melanoma transformation risk are considered.

We report 2 cases of patients who presented with blue macules clinically suspicious for blue nevi. One patient had no documented history of trauma or silver exposure, and the other reported exposure to silver over 30 years ago. Microscopic examination revealed a dermal population of brown-black globules predominantly adhering to collagen fibers. In both cases, no melanocytic proliferation was identified by immunohistochemistry. Analysis of the skin biopsies with scanning electron microscopy and energy dispersive x-ray spectroscopy demonstrated the presence of silver and selenium. These findings were diagnostic of localized cutaneous argyria. Our case reports highlight the importance of including localized cutaneous argyria in the differential diagnosis of pigmented lesions.

We describe five cases of cellular blue nevus (CBN) accompanied by an abundant desmoplastic reaction. The cells within the desmoplastic regions reacted strongly immunohistochemically with antibodies to S-100 protein and HMB-45 and were negative to antibodies to smooth muscle actin and desmin, providing evidence that the abundant collagen deposits were the product of the nevus cells. The microscopic picture of desmoplastic CBN can differ considerably from that of common CBN, and differential diagnosis is discussed.

We report a case of a 20-year-old Chinese man with an alopecic congenital combined compound and blue melanocytic nevus of the scalp, associated with alopecia areata. The diagnosis of a combined melanocytic nevus was confirmed by histopathological examination and immunohistochemical stains, with exclusion of neurocristic hamartoma, which can have a similar clinical and histopathological appearance but different prognosis. In addition, we explore the association of this large melanocytic lesion with alopecia areata.

Intracranial invasion of cellular blue nevus is extremely rare, and its malignant transformation is even less common. The differential diagnosis includes neurocutaneous melanosis and neurocristic cutaneous hamartoma. A 50-year-old female presented with intracranial melanoma in contiguity with a congenital blue nevus on the scalp. The patient showed a wide pigmented lesion on the scalp that had grown in the last few years over the congenital blue nevus. Magnetic resonance imaging revealed an intracranial tumor lying contiguous to the nevus. Despite aggressive surgery, the tumor relapsed and the patient developed systemic metastases. We report a rare case of cellular blue nevus showing an unexpected aggressive behavior with extensive extra- and intracranial expansion and distant metastases.

Desmoplastic (sclerotic) nevus is an infrequently reported poorly characterized benign melanocytic proliferation, with only 4 case series published to date. To better define this nevus, we examined the clinical and histologic features of 25 lesions. Desmoplastic nevus is seen in both children and adults and can be located on the face, trunk, or extremities. There is a female predominance. Clinically, it can resemble intradermal nevus, atypical nevus, melanoma, and pigmented basal cell carcinoma. These are generally small, symmetric, and well-circumscribed lesions, averaging 3.5 mm in diameter. The most distinctive features include predominantly compound growth, a zonal configuration with greater cellularity in the superficial portion of the lesion, and a mixture of melanocytic phenotypes including type A, B, and C nevus cells, ovoid and dendritic melanocytes, and Spitzoid melanocytes. A distinctive eosinophilic stroma which either resembles that of a dermatofibroma or neurofibroma is always present. Variable amounts of melanin pigment are found in both tumor cells and macrophages, but this is not a prominent feature. Mitotic activity is exceedingly rare (1 case), and pleomorphism is minimal. These lesions are distinct from typical compound nevus, Spitz nevus, epithelioid blue nevus, and desmoplastic melanoma, to which they are often compared. Strict application of these histologic features allows definitive diagnosis of desmoplastic nevus as a distinct form of a benign melanocytic nevus.

Nevus of Ota is a variant of congenital nevus, which is morphologically paucicellular and resembles a common blue nevus. Although nevus of Ota is a risk factor for uveal melanoma in white people, the development of cutaneous melanoma within nevus of Ota is a very rare occurrence with only a few reported cases. We present a case of a long-standing nevus of Ota, with radiologic imaging demonstrating a large retro-orbital mass and a biopsy showing melanoma. The histopathology of the eye exenteration specimen illustrated various stages of melanocytic progression including areas resembling a nevus of Ota, blue nevus, cellular blue nevus, and melanoma. There was heterogeneity in the overtly malignant sections with some areas displaying expansile nodules of blander appearing spindled cells, whereas other areas were composed of epithelioid cells with higher mitotic counts and zones of necrosis. The extensive lesion also infiltrated the soft tissue and bone. We performed gene mutation analysis for GNAQ, BRAF, NRAS, and KIT and fluorescence in situ hybridization (FISH) targeting commonly altered chromosomal loci in melanoma and comparative genomic hybridization (CGH). Copy number changes typical of melanoma were identified by both FISH and CGH in the morphologically malignant areas illustrating the relationship of tumor progression and the progressive acquisition of genetic aberrations.

A striking feature of cellular blue nevus consists in the presence, in its histologic picture, of numerous hypertrophic nerves and nerve-like figures, positive for histochemical and immunohistochemical methods for nerve fibers and myelin sheaths. These findings, first described in Masson's original article and repeatedly highlighted in the past for their possible histogenetic significance, are currently considered as merely coincidental. However, the thin conventional histologic sections, catching only short tracts of the nerves, preclude a correct observation of their route and do not allow us to verify if there is an architectural relationship between them and the nevus as a whole. With this aim, we observed a few specimens of cellular blue nevus on digitally overlapped images of contiguous 25-microm-thick sections, processed with Winkelmann's technique of silver impregnation for nerve fibers, which supplied an overall, 3-dimensional view of the lesions and the nerves running through them. In these images, the lobular form of the nevus could be seen gathering around a branching hypertrophic nerve, whose stem stretched vertically from the depth to the most superficial tract of the lesion. The nevus cell aggregates invested the stem and the limbs individually, and these followed the curvilinear contour of the nevus lobules. Our images represent evidence of a preferential perineural aggregation of cellular blue nevus, at least in its lobular form. This indicates that the numerous nerves and the neuroid figures, observed in detail-but within a limited perspective- in the conventional sections, are not merely coincidental and they could indeed be a sign of neural differentiation and/or a clue to the possible neural origin of the nevus.

We report a 55-year-old Japanese patient with a malignant blue nevus (MBN) on the scalp. The patient had regional lymph nodes metastases at his first visit, and a distant cutaneous metastatic papule appeared on the back 1 year later despite therapeutic intervention. Histology of the primary tumor lacked a junctional component and showed a typically biphasic pattern in the degree of pigmentation similar to a cellular blue nevus (BN). One pattern showed nests of less-pigmented, oval-shaped cells with a fairly uniform appearance, and the other pattern showed an aggregation of spindle-shaped cells containing a large amount of melanin pigment intermingled with heavily pigmented melanophages. Histology of metastatic regional lymph nodes also showed a biphasic proliferative pattern of oval-shaped, pale cells and spindle-shaped, richly pigmented cells. A distant cutaneous metastatic papule on the back showed massive proliferation of atypically large, pale, and oval-shaped melanoma cells with heavily pigmented melanophages just beneath the uninvolved epidermis. These histologic features were different from those of metastatic tumor proliferation from conventional melanoma. It seems probable that MBN might maintain a different biological and histopathologic character from conventional melanoma when it grows in metastatic sites.

Peripheral nerve sheath differentiation was studied in 120 specimens of blue nevi (112 specimens of "common" blue nevi and 8 specimens of "cellular" blue nevi). In 10 of 112 common blue nevi, fascicles of pigmented dendritic melanocytes or less pigmented spindle-shaped melanocytes with S-shaped nuclei were associated with wavy delicate collagen bundles. In 4 of these 10 specimens, the melanocytes showed a perifollicular arrangement. These nerve fascicle-like structures were seen in some cellular blue nevi (5 of 8 specimens). Structures closely resembling authentic nerve fascicles were not observed in common or cellular blue nevi. The fascicles with S-shaped nuclei and fibrillary collagenous tissue observed in blue nevi (which were well detected in the cellular type but rarely found in the common type) may be peripheral nerve sheath features and perhaps evidence that dermal dendritic melanocytes in the reticular dermis may have arisen within a peripheral nerve sheath milieu from primitive fibroblast-like precursors. Some of the examples presented here may be identical to those reported for "pilar neurocristic hamartoma" or "neurocristic hamartoma." I also speculate on the pathogenesis of blue nevi based on the observations made in this study.

We report two pediatric patients who had biopsies of solitary lesions diagnosed as epithelioid blue nevi. Histologically these lesions had wedge-shaped, heavily pigmented infiltrates extending to the subcutaneous fat. The infiltrate was composed of spindled and polyhedral cells that were nevomelanocytic cells with nuclear pleomorphism. Also noted were pigmented globular cells interpreted as melanophages. These lesions have the same characteristics as those blue nevi occurring in patients with Carney complex. More recently, adult patients have been identified with similar nevi, but without evidence of Carney complex. To our knowledge, pediatric patients with epithelioid blue nevi, but no evidence of Carney complex have not been described previously.

Balloon cells are altered melanocytes with clear vacuolated cytoplasm caused by a defect in the process of melanogenesis. Although rare, balloon cell change has been observed in a variety of melanocytic proliferations, particularly intradermal melanocytic nevi and melanoma. When present, such features may lead to difficulties in diagnosis, particularly with other clear cell neoplasms. We report an unusual case of the development of balloon cell change in a cellular blue nevus, a phenomenon that has not been extensively addressed in the literature. The importance of recognizing this change in cellular blue nevus to avoid misinterpreting the lesion as malignant is discussed.

We report a case of malignant blue nevus (MBN) of the vulva which led to an ovarian metastasis 15 years after the initial diagnosis. To our knowledge, this is the first report of MBN of the vulva. The patient was a 28-year-old woman with a nodule of the labia majora. The patient noted the lesion when she was 12 and stated it did not change at that time. The lesion had the histopathologic features of MBN and was characterized by a low mitotic rate but substantial cytologic atypia. No abnormality was noticed over a 15 year period of follow-up. Fifteen years after the initial diagnosis, vaginal examination and ultrasonography imaging showed a 6.5 cm solid ovarian tumor. Hysterectomy and bilateral salpingo-oophorectomy was performed. Histologic evidence of metastasis was identified in the ovary. Malignant blue nevus can lead to late metastasis and needs long-term follow-up, as do other types of melanoma. Despite low mitotic activity in a melanocytic lesion resembling cellular blue nevus, a careful assessment of cytologic atypia is necessary before ruling out malignancy.

Comparison of argyrophilic nucleolar organizer region (AgNOR) counts has been found to yield statistically significant differences between benign and malignant conditions albeit with considerable overlap. In this study we compared the size of AgNORs and the nuclear areas, as well as the AgNOR count in 23 benign melanocytic lesions and 9 melanomas. Of these parameters, the ratio AgNOR area/nuclear area was found to be the main discriminating factor between melanoma and all the other benign groups studied, with p values of < 0.01 and no overlap. Next to it was the nuclear area, which in our study gave significant differences between the groups evaluated. The total AgNOR area and the largest AgNOR gave results comparable to the simple AgNOR counting in all groups studied, except in Spitz nevus, in which the AgNOR counts were less significant than the other parameters (p = 0.0420). We conclude that the ratio AgNOR area/nuclear area discriminates benign from malignant melanocytic lesions better than AgNOR counts or other parameters studied.

Persistence of common melanocytic nevi has been fairly well characterized, clinically and histologically. In contrast, persistence of blue nevi has been reported infrequently. To define this entity better, nine cases of biologically persistent and clinically recurrent blue nevi are described. The persistent lesions in four cases were spindle-fascicular blue nevi; one showed senescent or "ancient" change and one had additional deep penetrating/epithelioid blue nevus features with atypical changes worrisome for malignancy. These changes included increased cellularity, cellular pleomorphism, mitotic figures, and a lymphocytic infiltrate. Three were biphasic dendritic-sclerotic/spindle-fascicular blue nevi, one of which had atypical changes. One case was a dendritic-sclerotic ("common") blue nevus. The original histology in one case was unavailable, but the recurrence was a combined blue nevus. The interval from initial biopsy to biopsy of the recurrent lesion was often longer (mean 2.7 years) for recurrent blue nevi than for recurrent common compound or intradermal melanocytic nevi. In addition, in contrast to recurrent common melanocytic nevi, the recurrence, in at least one case, extended beyond the scar of the original excision. These cases demonstrated that blue nevi of all histiotypes and combinations are capable of persistence with clinical recurrence. The persistence usually was histologically similar to the original, but in some cases was more "cellular" because, for the most part, the excisions of the persistent lesion revealed a deeper spindle-fascicular ("cellular") component not evident in the original superficial biopsy. In two cases, the original blue nevus appeared completely banal, but the persistent/recurrent lesions were histologically distinct and demonstrated atypical histologic features. Yet, follow-up (average 3.7 years) supports benign biology. Clinical recurrence is often associated with malignant transformation in blue nevus, but this series demonstrates that malignant tumor progression is not necessarily the case. In the absence of necrosis en mass, marked cytologic atypia, and frequent mitotic figures, the described atypical morphologic parameters in previously biopsied small blue nevi are probably reactive and "pseudomalignant." Awareness of this potential change may avoid diagnostic and prognostic errors.