The morphologic spectrum of germline‐mutated BAP1‐inactivated melanocytic tumors includes lesions with conventional nevic melanocytes: A case report and review of literature

Germline mutations in BRCA1‐associated protein 1 (BAP1) are associated with several neoplasms, including BAP1‐inactivated melanocytic tumors (BIMTs). BIMTs are classically described as biphenotypic melanocytic proliferations with BAP1‐deficient large epithelioid and rhabdoid melanocytes showing various degrees of cytologic atypia. This morphology has been traditionally classified as “spitzoid” despite the various differences between these lesions and the more classic Spitz nevi. Herein, we report a case of an otherwise healthy 11‐year‐old female patient with a family history of several malignancies who presented with multiple pink to brown papules. Histologic and immunohistochemical evaluation identified three lesions with loss of nuclear BAP1 staining. The histologic spectrum of these lesions included junctional spitzoid cells within a triphenotypic proliferation and a separate lesion composed entirely of dermal small to medium‐sized epithelioid melanocytes with maturation. BAP1 gene sequencing revealed a germline frameshift pathogenic BAP1 mutation, denoted c.1717delC. This case provides further evidence that not all BIMTs conform to classic morphological criteria and that the morphologic spectrum includes lesions resembling conventional nevi. As BIMTs can serve as an early marker of the BAP1 hereditary tumor predisposition syndrome, we believe a need exists for a more comprehensive combined clinical and pathological approach for BIMT identification.     

Installation of a network for patients with congenital melanocytic nevi in German‐speaking countries

In 2005, an Internet‐based network for the support of patients with congenital melanocytic nevi in German‐speaking countries was started ( http://www.naevus‐netzwerk.de ). Along with detailed information for patients and parents, the home‐page includes a nevus registry which is based on an electronic questionnaire and which aims at providing data on the long‐term course of nevi estimated to reach > 10 cm in largest diameter. In the past, congenital melanocytic nevi have been subject to various mythological interpretations (“Tierfellnävus”, lit.”animal coat nevus”;”Muttermal”). Today an increasing body of reliable scientific data allows a differentiated reflection of the risk of malignant transformation and has led to progress in the diagnostic and therapeutic management. Recent findings from the literature and considerations from scientific meetings are reviewed.     

Histological features and outcome of inverted type‐A melanocytic nevi

The presence of enlarged epithelioid/spindled nests located deep in the reticular dermis of a biphasic melanocytic neoplasm can mimic melanoma arising in a pre‐existing nevus, causing over‐interpretation of malignancy. We aimed to define the clinicopathologic significance of epithelioid/spindled nests in melanocytic nevi. Retrospectively using clinical and histologic information, we characterized 121 patients with a single lesion showing epithelioid/spindled melanocytes in the reticular dermis or subcutaneous fat, surrounded by melanophages, sometimes blending in with the adnexa. The majority of nevi occurred in women in the ages of 10 to 39 years, where the most frequent presentation was a changing mole. While 78% of the lesions displayed an anatomic (Clark’s) level of IV‐V, there was no ulceration, significant regression or inflammation. Up to 2 mitoses were found in only 12% of the cases, not correlating with the severity of cytological atypia. No recurrence or metastasis occurred during 45.5 months (mean) of clinical follow up in 26 patients. Notwithstanding the deep dermal extension, these findings suggest a benign histopathology and clinical outcome. Having compared the overlapping histopathology and clinical features between deep penetrating/clonal nevus and combined nevus, we posit that “inverted type‐A nevus” might be considered a variant of the two.     

Cutaneous epithelioid melanocytic neurofibroma arising in a patient with neurofibromatosis‐1

Tumors expressing both melanocytic and neural features can pose a diagnostic challenge to the dermatopathologist and provoke questions regarding their lineage. We report a case of a tumor arising on the right cheek of a 9‐year‐old boy with neurofibromatosis type 1 (NF‐1). This neoplasm featured nests of non‐pigmented epithelioid cells arising within a neurofibroma. The entire tumor stained strongly with S100, whereas the epithelioid population stained with MART‐1, HMB‐45 and MiTF. The neoplasm shows only scattered Ki‐67 positivity. This tumor represents a neurofibroma with portions that have undergone melanocytic differentiation (melanocytic neurofibroma). This exceedingly rare tumor represents a distinct entity from neurotized melanocytic nevi, combined melanocytic nevi or pigmented neurofibromas and provides further evidence that melanocytes arise indirectly from ventromedial neural crest‐derived Schwann cell precursors.     

Aggressive melanoma in an infant with congenital melanocytic nevus syndrome and multiple,NRAS and BRAF mutation‐negative nodules

We report the case of a newborn boy with multinodular NRAS and BRAF mutation‐negative congenital melanocytic nevi and cerebral lesions compatible with congenital intraparenchymal melanosis. Histopathology from skin lesions showed atypical nodular melanocytic proliferation with marked melanocytic atypia and a large number of mitoses and apoptosis, indicating aggressive proliferation. The child developed several new subcutaneous tumors and multiple internal lesions, which were confirmed to be metastases, and died at 5 months of age. This case may represent an infantile melanoma developing from a giant congenital melanocytic nevus or a congenital melanoma.     

巨大先天性黑素细胞痣恶变并淋巴结转移1例

报告1例巨人先天性黑素细胞痣恶变淋巴结转移，患儿男，14个月，出生后即发现腰骶部有巨人黑素细胞痔，14个月时皮损组织病理检查示，黑素细胞痣恶变并有右侧腹股沟淋巴结转移。     

Distant metastasis due to heavily pigmented epithelioid melanoma with underlying BRAF V600E,NOTCH1, ERBB3, and PTEN mutations

Pigment‐synthesizing melanoma (PSM) describes a morphologically and genetically diverse group of melanomas. In contrast, pigmented epithelioid melanocytoma (PEM) encompasses a spectrum of indolent tumors now classified as borderline/intermediate melanocytic tumors. Herein, we report a case of widely metastatic heavily pigmented epithelioid melanoma with fatal outcome in a 36‐year‐old woman. Next‐generation sequencing identified somatic (tumoral) mutations in BRAF V600E, PTEN, NOTCH1, and ERBB3. By contrast, GNAQ and GNA11 were wild type. Prkar1α and p16 expression were maintained. Identification of mutations in NOTCH1 and ERBB3 may support the diagnosis of heavily pigmented epithelioid melanoma. In contrast, PRKCA fusion genes and PRKAR1A mutations support the diagnosis of PEM. Given the heterogeneity, potential overlap (loss of Prkar1α expression), and evolving genetic profiles of these two distinct groups of tumors, careful appraisal of molecular profiles in the light of histomorphology and clinical history is necessary for distinction between PEM and PSMs including heavily pigmented epithelioid melanomas, with significant potential impact on prognosis and therapy.     

Immunohistochemical distinction of epithelioid histiocytic proliferations from epithelioid melanocytic nevi

Histiocytic tumors can be confused with melanocytic nevi and malignant melanoma and vice versa. To explore the use of immunohistochemistry for this diagnostic problem, we examined the expression of S-100 protein, gp100 (the antigen recognized by HMB-45), tyrosinase (T311), Melan-A (A103), Factor XIIIa (FXIIIa), and CD68 in 10 juvenile xanthogranulomas (JXGs), five epithelioid histiocytomas (EHs), and 15 melanocytic nevi composed of large epithelioid cells. All epithelioid melanocytic nevi were immunoreactive for Melan-A, tyrosinase, and S-100 protein in most melanocytes. Four nevi were completely negative with HMB-45. Nine nevi had only a minor HMB-45-positive component in the superficial dermis. Two nevi were diffusely HMB-45-positive. Melanocytes in all nevi were completely negative for FXIIIa. Thirteen nevi were completely negative for CD68. Two nevi contained rare cells with weak staining for CD68. All 15 histiocytic proliferations were completely negative for Melan-A, tyrosinase, and gp100. They lacked expression of S-100 protein or had at most 10% immunopositive cells. In JXGs, most cells were strongly reactive for CD68, although only a few were positive for FXIIIa. In EHs, 40% to 60% of cells were immunoreactive for FXIIIa, and only 20% to 30% were positive for CD68. Our results demonstrate that Melan-A and tyrosinase are sensitive and specific markers to distinguish epithelioid melanocytic nevi from epithelioid histiocytic tumors.     

Spitz Nevi and Other Spitzoid Neoplasms in Children: Overview of Incidence Data and Diagnostic Criteria

Spitz nevi are benign melanocytic neoplasms characterized by epithelioid or spindle melanocytes or both. In some rare cases their presentation overlaps with the clinical and histopathologic features of malignant melanoma, so a differential diagnosis can be difficult to make. Intermediate forms between Spitz nevi and malignant melanoma, with unpredictable behavior, have been called atypical Spitz tumors. A literature search was performed to review the clinical, dermoscopic, genetic, and histopathologic aspects of spitzoid tumors. Spitz nevi mainly occur in children, with no predilection for sex, and in young women. Common sites are the head and lower arms, where Spitz nevi present as pink nodules or hyperpigmented plaques. Spitzoid lesions may have diverse dermoscopic patterns: vascular, starburst, globular, atypical, reticular, negative homogeneous, or targetoid. The management of spitzoid lesions can be invasive or conservative; surgical excision is usually reserved for those with doubtful features, whereas clinical and dermoscopic follow‐up is preferred for typical pediatric Spitz nevi. The role of sentinel lymph node biopsy in atypical Spitz tumors is debated. Immunohistochemistry and new molecular techniques such as comparative genomic hybridization, polymerase chain reaction, and fluorescence in situ hybridization offer new diagnostic perspectives, investigating genetic alterations that are specific for malignant melanoma or for Spitz nevi.     

Distinguishing melanocytic nevi from melanoma by DNA copy number changes: comparative genomic hybridization as a research and diagnostic tool

Cancer typically results in loosened control over genomic integrity, resulting in alterations of the genome of cancer cells. Comparative genomic hybridization (CGH) is a method that can be used on DNA extracted from routinely fixed tissue to assess the entire genome for the presence of changes in DNA copy number. CGH analysis has revealed that melanoma differs from melanocytic nevi by the presence of frequent chromosomal aberrations. In contrast, melanocytic nevi typically show no chromosomal aberrations, or have a restricted set of alterations with basically no overlap to melanoma. These marked differences between aberration patterns in melanomas and melanocytic nevi can be exploited diagnostically to classify melanocytic tumors that are ambiguous based on histopathologic assessment. In addition to potential diagnostic applications, detailed analyses of recurrent aberrations can lead to the identification of genes relevant in melanocytic neoplasia.     

Spitz nevi and other Spitzoid lesions part I. Background and diagnoses

Spitz nevi are melanocytic proliferations that are characterized by spindled and/or epithelioid nevomelanocytes. First interpreted as juvenile melanoma, these lesions were later characterized as benign and were observed to affect all age groups. Today, contrasting opinions persist regarding the fundamental benignancy versus malignancy within the spectrum of Spitz tumors. Beyond clinical outcome, this controversy has also been fueled by complex and sometimes convoluted classification schemes based on pathologic characteristics. More recently, immunophenotypic and molecular analyses have begun to clarify the etiologic nature of these tumors. Recent evidence suggests that histopathologic features that suggest more aggressiveness in Spitz tumors relate to mitoses and inflammation.     

Congenital melanocytic nevus with features of hybrid schwannoma/perineurioma

Neural differentiation by melanocytic nevi represents a well‐recognized phenomenon, and melanocytic nevi with perineurial differentiation have been reported recently. We reported a case of a congenital melanocytic nevus with histopathologic features of hybrid schwannoma/perineurioma. The patient was a 36‐year‐old male who presented with a black tumor on his arm since birth. Histopathology showed a congenital melanocytic nevus in the superficial dermis, but more strikingly, in continuity with the melanocytic nevus, there was a well‐circumscribed but unencapsulated nodule in the deep dermis. The nodule was composed of cellular and myxoid areas with storiform, laminated or whorled growth patterns. The cellular area was mainly composed of proliferation of plump spindle, oval or epithelioid cells. The myxoid area was mainly composed of proliferation of slender spindle cells with mucin deposition. Immunohistochemical stains showed that the cellular area was positive for S100 and CD34, weakly positive for EMA, negative for Glut‐1 and collagen IV, the myxoid area was positive for S100, negative for CD34, strongly positive for EMA and focally positive for Glut‐1 and collagen IV. Our results show that congenital melanocytic nevi may show neural differentiation with histopathologic features of hybrid schwannoma/perineurioma.     

Two cases of discrete adenoid pseudogland formation within benign intradermal melanocytic nevi

We report 2 cases of benign intradermal melanocytic nevi with discrete glandular elements and mucin deposition engendering a diagnostic dilemma. The preliminary differential included entrapment of adnexal structures, collision with an adnexal neoplasm such as adenoid cystic carcinoma or metastatic adenocarcinoma. A colloidal iron special stain confirmed the deposition of mucin; however, a pankeratin AE1/AE3 immunohistochemical cocktail was surprisingly negative. Closer cytological examination of the discrete “glands” combined with nearby pseudoangiomatous (almost kaposiform) change hinted at melanocytic origin, which was confirmed with a positive melanoma antigen recognized by T‐cells 1 immunohistochemical stain. Histopathological variations in melanocytic morphology include balloon cell formation, pseudoangiomatous change, lipomatous change, nevus of Nanta (osteonevus) with osseous metaplasia, neurotization, cartilaginous nevus, calcification, increased elastic tissue, psamomma body formation, amyloid deposition, eczematous changes (Meyerson nevus), granular cell change and ancient change/atypia. Mucin deposition, tubule and pseudoacini formation, and now discrete adenoid cystic‐like “glands” may also be seen, all of which are important to recognize to avoid misdiagnosis.     

Animal‐type melanoma – tumor cell invasion of dermal lymphatics and molecular identification of lymph node metastasis

Animal‐type melanoma (ATM) represents a rare subtype within the wide spectrum of melanocytic tumors. Clinically, ATM lesions appear as sharply demarcated, brown, black and dark blue pigmented nodules, which show grey‐white surface elements on dermatoscopy. The tumor is restricted to the dermis and arranged in irregular fascicles, which are composed of spindle‐shaped and epithelioid melanocytes. Moderate tumor cell pleomorphism, mitoses and apoptotic cells all suggest a malignant process. Abundant, finely dispersed melanin pigment within tumor cells as well as numerous melanophages are strongly suggestive of ATM. Even though locoregional lymph node metastases are frequently found at diagnosis, the course of ATM is generally benign. Specific molecular changes may be detected in melanocytes from lesions and lymph nodes on fluorescence in situ hybridization (FISH). Such findings strongly indicate the malignant potential of ATM. The peculiar biology of ATM, as a moderately malignant tumor, is reflected in a new histopathological classification within the spectrum of dermal borderline melanocytic tumors (BMT).     

BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumors

Although discussed using variable terminology, cutaneous BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumor (BIMT) has been considered a discrete diagnostic entity since 2011. Here, we review the initial genomic studies that identified these distinct melanocytic tumors and the clinical and histopathological features that define these tumors. These epithelioid, predominantly dermal, and melanocytic tumors present as erythematous nodules and histopathologically have features that may overlap with Spitz nevi and nevoid melanoma. There is no sex predilection, and cutaneous BIMTs can appear at any age; however, in most familial (germline mutant) cases patients have multiple cutaneous tumors with a first diagnosis in the second or third decade of life; ocular melanoma and other tumors are increasingly identified in these kindreds with germline BAP1 mutation. These tumors have been described with a myriad of terms including: Wiesner nevus, nevoid melanoma‐like melanocytic proliferation (NEMMP), BAP1 mutant Spitz nevus, BAP1 mutant nevoid melanoma, cutaneous BAPoma, and most recently cutaneous BIMT.     

Melanocytic nevi clinically simulating melanoma

Melanoma and other benign or malignant pigmented skin tumors can significantly overlap in their clinical and dermoscopical presentations. Thus, pigmented skin lesions may be misdiagnosed in a large number of cases. An extensive review of the published work provides numerous examples of benign lesions mimicking melanoma. Although a number of melanocytic nevi may have been identified as melanomas, information about their clinical appearance is limited. In this report, we present the clinical appearances of two melanocytic nevi on the vulva and the upper extremity that were difficult to diagnose clinically. Detecting melanoma at an early stage is of the utmost importance. However, more attention should be given to the diagnostic accuracy of benign pigmented skin lesions, which otherwise may be diagnosed and treated as melanoma.     

SCALP syndrome with a germline heterozygous DOCK6 mutation and somatic mosaic NRAS Q61R mutation

We present a case of SCALP syndrome, which was diagnosed in a male infant with the characteristic findings of sebaceous nevi, central nervous system malformations, aplasia cutis congenita, limbal dermoid, and giant congenital melanocytic nevi, or pigmented nevi. We identified a germline compound heterozygous DOCK6 mutation and a somatic mosaic NRAS Q61R mutation in the giant congenital melanocytic nevus. This report will increase clinician awareness of SCALP syndrome and augment the literature in characterizing this rare syndrome, including its genetic background.     

Melanoma and melanocytic nevi in decorative tattoos: three case reports

Background: In response to the demands of style and fashion, the number of decorative tattoos has been increasing worldwide. This has been paralleled by a rising incidence of melanocytic proliferations, including melanoma. The coincidence of various dermatological diseases and skin tumors with tattoos has been documented with some frequency, but reports of melanoma associated with tattoos are exceedingly rare. To date, only 13 cases have been documented in the English language literature. The possibility of an association between melanocytic proliferations and tattoos remains an area for further study. Observations: This report presents two cases of melanocytic nevi and one of melanoma occurring in association with a decorative tattoos. Conclusions: At present, the pathogenesis of melanoma developing in a tattoo is unknown. Mere coincidence cannot be ruled out. However, trauma, ultraviolet light exposure, a photoallergic effect, or an inflammatory reaction may promote malignant transformation. Clinicians and histopathologists should be aware of the clinical and pathological features if they are to make a correct diagnosis. Varga E, Korom I, Varga J, Kohán J, Kemény L, Oláh J. Melanoma and melanocytic nevi in decorative tattoos: three case reports.