Deep-penetrating-nevus-like melanoma arising in patients with familial adenomatous polyposis syndrome.

Deep penetrating nevi (DPN) are uncommon but distinctive melanocytic neoplasms that show an epithelioid to spindle cell morphology, prominent pigmentation with melanophages, and a plexiform growth pattern. Molecularly, most DPN are thought to be characterized by dual activation of the mitogen-activated protein kinase and the wingless-related integration site (Wnt) pathways, the latter being most commonly driven by activating ß-catenin mutations. DPN-like melanomas are very rare but can be recognized through their overlapping morphologic and architectural features with DPN. Familial adenomatous polyposis (FAP) is a hereditary cancer predisposition syndrome associated with multiple tumor types including colorectal carcinoma and desmoid fibromatosis. Like DPN, FAP is also driven by activation of the Wnt pathway, most commonly through loss of function mutations in APC, which is a major negative regulator of ß-catenin. Here we report two cases of DPN-like melanoma arising in FAP patients. While the small number of cases precludes definitive establishment of an etiologic link between these entities, the shared molecular pathogenesis of DPN-like lesions and FAP suggests that FAP patients may be at increased risk for this rare subtype of melanoma.

Molecular analysis of atypical deep penetrating nevus progressing to melanoma.

Deep penetrating nevi (DPN) are dermal-based, heavily pigmented melanocytic proliferations primarily resulting from mutations in B-catenin and BRAF or, less commonly, NRAS. DPNs are considered to be intermediate grade tumors which are stable with low risk of malignant transformation. The precise risk for transformation is unknown. Only rare cases of DPN progressing to melanoma have been described. We present a case of a 53-year-old female with a blue-black thigh lesion, on histopathology illustrating a melanocytic proliferation with morphology most consistent with a DPN progressing to melanoma. Targeted next generation sequencing performed on both the atypical melanocytic proliferation and melanoma components showed NRAS and CTNNB1 mutations but no evidence of TERT promoter mutation or chromosomal copy number aberrations. The melanoma had additional mutations including a hotspot TERT promoter mutation as well as unbalanced chromosomal copy number aberrations. This report details the progression of DPN to melanoma through a prominent ultraviolet signature and acquisition of genetic aberrations. While the vast majority of DPNs are benign stable nevi, there are rare examples, which may progress to melanoma. This report documents a case and shows the molecular evolution by which the tumor transformed to melanoma.

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.

The deep penetrating nevus.

The deep penetrating nevus (DPN), also known as the plexiform spindle cell nevus, is a pigmented lesion that commonly arises on the head and neck in the first few decades of life. Histopathologically, the DPN is wedge-shaped and contains melanocytes that exhibit deep infiltration into the dermis. Given these features, DPN may clinically and histopathologically mimic malignant melanoma, sparking confusion about the appropriate evaluation and management of these lesions. The goal of this review is to summarize the clinical and histopathological features of DPN and to discuss diagnostic and treatment strategies for dermatologists.

Unusual conjunctival melanocytic proliferations. Report of five cases and review of the literature.

Indeterminate melanocytic proliferations of the conjunctiva have both benign and malignant features that previously made these lesions nearly impossible to categorize in existing classification schemes. With the evolution of immunohistochemistry and molecular genetics, however, subclassifications have emerged that allow for a more tailored diagnosis and management. These conjunctival melanocytic proliferations include deep penetrating nevus, granular cell nevus, and nevoid melanoma. There remains a small subset of conjunctival melanocytic proliferations that defy precise characterization as nevi, primary acquired melanosis, or melanomas despite currently available ancillary diagnostic modalities and remain indeterminate. We highlight these unusual types of nevi and melanomas, with an update on their morphologic, immunohistochemical, and molecular genetic characteristics.

Pediatric Atypical Melanocytic Proliferations: Single-Site Retrospective Cohort Assessment of Treatment and Long-Term Follow-Up.

Atypical and malignant cutaneous tumors are understudied in the pediatric population, with limited data on long-term follow-up. This study examines pediatric (0-18 years) atypical melanocytic proliferations over a twenty-year period (January 2002-December2022) using the EPIC SlicerDicer at our institution. Over a twenty-year period, there were 55 cases of pediatric melanoma (53 patients). The median follow-up time was 8 years, 11 months. A proportion of 96% were treated with wide local excision (WLE), and 47% had a sentinel lymph node biopsy (SLNB) (35% positive rate). There were 101 atypical Spitz tumor cases (85% atypical Spitz tumors, 15% Spitz melanoma), with a median follow-up duration of 9 years. A proportion of 77% were treated with WLE (with one patient dying of metastatic disease). There were 10 cases of atypical melanocytic proliferations not otherwise specified, including 5 pigmented epithelioid melanocytomas (PEM), 4 deep-penetrating nevi, and 1 atypical cellular blue nevus. This study adds to the growing body of knowledge on pediatric atypical cutaneous melanocytic proliferations, aligning with many described characteristics such as disease location and overall survival rates, with distinct exceptions (higher melanoma positive SLNB rate, lower atypical Spitz tumor WLE rate, and a case of fatal metastatic atypical Spitz tumor).

Conventional and Atypical Deep Penetrating Nevus, Deep Penetrating Nevus-like Melanoma, and Related Variants.

Deep penetrating nevus (DPN) is an uncommon acquired melanocytic lesion with a distinct histopathological appearance that typically behaves in an indolent manner. The lesion is characterized by a symmetrical proliferation of epithelioid to spindled melanocytes associated with abundant melanophages and wedge-shaped extension to the deep reticular dermis and subcutis. Pronounced cytologic atypia and mitotic figures are usually absent, which helps distinguish DPN from melanoma with a deep penetrating growth pattern. Recently, the concept of atypical DPN has been proposed for lesions that demonstrate borderline histomorphologic features and may be associated with lymph node deposits but lack the copy number aberrations typical of melanoma by either fluorescence in situ hybridization or comparative genomic hybridization. While most of these lesions have a favorable clinical course, rare lesions may progress to melanoma. In this review, we summarize the current literature on atypical DPNs with uncertain behavior/metastatic potential and outline the characteristics that distinguish these lesions from conventional DPN and melanoma with DPN-like features.

Molecular characterization of biphenotypic epithelioid and plexiform melanoma with deep penetrating nevus-like features.

Tumor heterogeneity is a relevant hallmark of melanoma due to the high mutation burden and immunogenicity commonly encountered. Heterogeneity at the histologic level frequently corresponds to heterogeneity at the molecular level. A better understanding of this feature of malignancy can help refine the development of predictive biomarkers and to define more effective targeted therapies. Here, we describe a case of melanoma displaying a dual phenotype: a DPN-like/plexiform portion in conjunction with a conventional epithelioid morphology. Molecular studies revealed shared BRAF and PTEN mutations in both components but a CTNNB1 mutation was exclusively found in the DPN-like area of the tumor, consistent with the distinct morphology observed. There was considerable heterogeneity in sequence variants identified in the two regions. Gene expression analysis highlighted differentially regulated genes between the two histologies, including a relevant cluster of genes in the receptor tyrosine kinase (RTK) family and related signaling pathways upregulated in the DPN-like/plexiform area.

Genetic and Methylation Analysis of CTNNB1 in Benign and Malignant Melanocytic Lesions.

Melanocytic neoplasms have been genetically characterized in detail during the last decade. Recurrent CTNNB1 exon 3 mutations have been recognized in the distinct group of melanocytic tumors showing deep penetrating nevus-like morphology. In addition, they have been identified in 1-2% of advanced melanoma. Performing a detailed genetic analysis of difficult-to-classify nevi and melanomas with CTNNB1 mutations, we found that benign tumors (nevi) show characteristic morphological, genetic and epigenetic traits, which distinguish them from other nevi and melanoma. Malignant CTNNB1-mutant tumors (melanomas) demonstrated a different genetic profile, instead grouping clearly with other non-CTNNB1 melanomas in methylation assays. To further evaluate the role of CTNNB1 mutations in melanoma, we assessed a large cohort of clinically sequenced melanomas, identifying 38 tumors with CTNNB1 exon 3 mutations, including recurrent S45 (n = 13, 34%), G34 (n = 5, 13%), and S27 (n = 5, 13%) mutations. Locations and histological subtype of CTNNB1-mutated melanoma varied; none were reported as showing deep penetrating nevus-like morphology. The most frequent concurrent activating mutations were BRAF V600 (n = 21, 55%) and NRAS Q61 (n = 13, 34%). In our cohort, four of seven (58%) and one of nine (11%) patients treated with targeted therapy (BRAF and MEK Inhibitors) or immune-checkpoint therapy, respectively, showed disease control (partial response or stable disease). In summary, CTNNB1 mutations are associated with a unique melanocytic tumor type in benign tumors (nevi), which can be applied in a diagnostic setting. In advanced disease, no clear characteristics distinguishing CTNNB1-mutant from other melanomas were observed; however, studies of larger, optimally prospective, cohorts are warranted.

Clinicopathologic and molecular characterization of melanomas mutated for CTNNB1 and MAPK.

Wnt/ß-catenin signaling plays crucial roles in melanocyte biology and may be implicated in melanoma progression. In this study, we retrospectively examined a real-life cohort of melanomas mutated for ß-catenin (CTNNB1), in association or not with a MAPK mutation (of BRAF or NRAS), and analyzed their clinical, histopathological, and molecular characteristics. Our results indicate that, regardless of the presence of a concurrent MAPK mutation, CTNNB1mut cutaneous primary melanomas display more proliferative hallmarks (increased Breslow thickness, mitotic index, and ulceration) than their CTNNB1 wild-type counterparts. Accordingly, they often progress to the metastatic stage. Furthermore, concurrent CTNNB1 and MAPK mutations do not necessarily confer a deep penetrating nevi phenotype. Altogether, this study provides evidence that CTNNB1 mutations in melanomas are associated with specific clinical and pathological features.

Recognizing Histopathological Simulators of Melanoma to Avoid Misdiagnosis.

Melanocytic lesions have a wide morphological spectrum, ranging from benign nevi to malignant melanoma. In contrast to a diagnosis of a benign nevus, a diagnosis of melanoma could mean intensive treatment, lifetime monitoring, and a worse prognosis. Therefore, melanocytic tumors are notoriously challenging and associated with a high risk of litigation in surgical pathology. After describing the basic features of nevi and melanoma, this article describes the detailed clinical and histological features of those lesions that share many similar features with melanoma. The entities included are Spitz nevi and atypical Spitz tumors (AST), Reed nevus, dysplastic nevus, cellular blue nevus (CBN), deep penetrating nevus, combined nevus, recurrent nevus, irritated nevus, congenital pattern nevus, acral nevus, and nevi of special sites. Knowledge of these imitators can help pathologists distinguish between benign and malignant cases and avoid misdiagnosis.

NGS-Based Analysis of Atypical Deep Penetrating Nevi.

Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or epithelioid melanocytes with a distinctive wedge-shaped configuration showing activation of the WNT pathway, with unusual cyto-architectural features. It is unclear whether they show a distinct genomic profile associated with a diverse metastatic potential. We describe herein a cohort of 21 atypical DPNs analyzed by next-generation sequencing using the Ion AmpliSeq™ Comprehensive Cancer Panel. We found that ß-catenin exon 3 was mutated in 95% and MAP kinase pathway genes in 71% of the cases. Less frequent mutations were observed in HRAS (19%) and MAP2K1 (24%). Isocitrate dehydrogenases 1 (IDH1) mutations, including R132C, V178I, and S278L, were identified in 38% of cases and co-existed with BRAF/HRAS mutations. The only case with progressive nodal disease carried alterations in the ß-catenin pathway and mutations in IDH1 and NRAS (codon 61). By a comprehensive mutation analysis, we found low genetic heterogeneity and a lack of significant associations between specific gene mutations and histopathological features, despite atypical features. Whether the acquisition of an NRAS or IDH1 mutation in an atypical DPN may represent a molecular evolution implying a pathway to melanoma progression should be confirmed in a larger series.

ESP, EORTC, and EURACAN Expert Opinion: practical recommendations for the pathological diagnosis and clinical management of intermediate melanocytic tumors and rare related melanoma variants.

The recent WHO classification of skin tumors has underscored the importance of acknowledging intermediate grade melanocytic proliferations. A multistep acquisition of oncogenic events drives the progressive transformation of nevi into melanomas. The various pathways described are modulated by the initial oncogenic drivers that define the common, blue, and Spitz nevi groups. Intermediate lesions are most often the result of a clonal evolution within such nevi. Based on this established classification, we have suggested for each pathway a practical diagnostic approach, benefiting from the recently developed molecular tools, both in the setting of general pathology labs and expert centers. Moreover, recommendations regarding the re-excision and clinical follow-up are given to support decision-making in multidisciplinary tumor boards.

Deep Penetrating Nevus and Borderline-Deep Penetrating Nevus: A Literature Review.

Deep penetrating nevi (DPN) are rare melanocytic nevi, which can exhibit atypical histological features hampering the differentiation from malignant melanoma. DPN are considered benign melanocytic lesions, but rare spread to lymph nodes and unfavorable clinical outcomes associated with borderline/atypical DPN (B-DPN) has been reported. Since no guidelines are available for DPN and B-DPN, we aimed to review the literature on DPN and B-DPN to assess the management and prognosis. We screened 3,513 references from EMBASE, Scopus and Medline databases, and included 15 studies with a total of 355 DPN patients and 48 B-DPN patients. Therapeutic interventions ranged from simple excision to wide excisions and sentinel lymph node biopsy (SLNB), with block lymph node dissection in some positive SLNB cases. Follow-up periods ranged from 3 months to 23 years during which a total of five recurrences, two in DPN and three in B-DPN group, and three metastases, in B-DPN group, were reported. While some of the included studies comprised clinical and histopathological correlation, few included genetic assessment. The present review highlights the need for prospective cohort studies applying composite measures to identify effective regimens of diagnostic workup and treatment in DPN and B-DPN.

Histopathological and Molecular Features of a Conjunctival Caruncular Deep Penetrating Nevus.

We describe the first presentation of a deep penetrating nevus (DPN) on the lacrimal caruncle. This lesion was seen in an 18-year-old woman presenting with hemorrhage of a long-standing pigmented mass on the caruncle. Histology showed a combined melanocytic neoplasm that consisted of two different melanocytic components. The differential diagnosis, based on histological examination, was a conventional melanocytic nevus, a Spitz nevus, or a combined melanocytic nevus. On the molecular level, one of the components revealed a mutation in the CTNNB1 gene encoding the ß-catenin protein, while both components harbored a BRAF V600E mutation, without molecular features of a malignant melanocytic lesion. This presentation of a DPN of the lacrimal caruncle emphasizes the similarities of the caruncle with the skin.

Combined deep penetrating nevi of the conjunctiva are relatively common lesions characterised by BRAFV600E mutation and activation of the beta catenin pathway: a clinicopathological analysis of 34 lesions.

BACKGROUND: Deep penetrating nevus (DPN) is not a widely recognised lesion on the conjunctiva and only a few cases consistent with combined DPN have been reported. METHODS: A review of all excised and histopathologically diagnosed conjunctival melanocytic lesions between 2003 and 2018 was performed in order to identify melanocytic nevi morphologically consistent with DPN. RESULTS: Thirty-four DPN were identified among 361 histopathologically examined conjunctival nevi (9.4%), including 33 (97%) combined with a common nevus and 1 (3%) pure DPN. The patients' age ranged from 7 to 51 years (median, 22 years). Clinically, 21 of 29 (72%) lesions with available data were darkly pigmented, and an increase in size and/or pigmentation was noted in 13 of 18 (72%) lesions with known history. All 24 lesions in which an immunohistochemical analysis was possible were diffusely positive for BRAFV600E (in DPN and common nevus components) and showed a diffuse nuclear positivity for beta catenin and cyclin D1 in the DPN component. None of the 21 lesions with available follow-up data recurred during a follow-up period from 0.3 to 16.3 years (median, 7.5 years). CONCLUSIONS: DPN of the conjunctiva is a relatively common lesion and usually presents as a combined nevus. Genetically, DPN of the conjunctiva are characterised by a combination of BRAFV600E mutation and activation of the beta catenin pathway. Recognition of DPN of the conjunctiva is important in order not to overdiagnose it as a melanoma, and to explain its potential atypical clinical features. DPN of the conjunctiva seems to be a benign lesion.

Histologic mimics of malignant melanoma.

Although spongiotic (eczematous), psoriatic and cutaneous skin infections are among the most common in dermatology consultations, melanocytic lesions - including the different types of nevi and melanomas - are among those that cause a great deal of concern and stress to patients and their clinicians. A diagnosis of benign melanocytic nevus carries a very good prognosis. However, a diagnosis of melanoma might indicate more aggressive treatment, lifelong surveillance and a worse prognosis. Differentiating between these conditions is not always a straightforward process for clinicians and pathologists. Therefore, knowledge of melanoma mimickers is very important for clinicians in general, and dermatologists and pathologists in particular. In this review, we called attention to some of the more frequent benign but unusual melanocytic lesions that are of diagnostic concern for clinicians evaluating these cutaneous proliferations.

The plexiform spindle cell nevus nevi and atypical variants: report of 128 cases.

The plexiform spindle cell nevus (PLXSCN) is a distinct melanocytic lesion that often provokes concern for melanoma. We describe the features of 119 typical PLXSCNs and 9 atypical/high-grade lesions. Histologically, all cases had a fascicular plexiform architecture and were composed of predominately spindled cells. The 6 atypical plexiform spindle cell tumors (PLXSCTs) exhibited features such as greater mitotic activity, increased cellularity/nodular confluence, and more concerning cytological atypia. Three high-grade tumors (perhaps evolving plexiform spindle cell melanomas) had additional alarming clinical or histologic characteristics, such as patient age greater than 40 years, greater degree of cellularity, higher degree of cytological atypia, mitotic rate greater than 3/mm(2), regional lymph node metastases, and greater than 1 positive sentinel lymph node. Follow-up data were available for 18 typical PLXSCNs: all patients were without tumor recurrence or death in a mean follow-up period of 3.9 years (range, 1 month to 10 years). One atypical PLXSCT and 3 high-grade lesions had follow-up information: the atypical PLXSCT had sentinel lymph node involvement, and the patient was alive without recurrent disease at 1-year follow-up; 2 of the 3 high-grade lesions were positive for lymph node involvement, and all 3 patients were alive with 2-, 4-, and 0.8-year follow-up periods. All PLXSCTs should be completely excised with clear margins, and high-grade or potentially malignant lesions may require management as melanoma.

Deep penetrating nevus-like borderline tumors: A unique subset of ambiguous melanocytic tumors with malignant potential and normal cytogenetics.

BACKGROUND: Deep penetrating nevi (DPN) are a relatively uncommon subtype of melanocytic nevi. A small subset of these lesions exhibit atypical features (cytologic and architectural atypia, mitotic activity) seen in melanoma. These lesions we term the deep penetrating nevus-like borderline tumor. Unequivocal melanomas can show overlapping morphologic features of DPN, which have been termed plexiform melanomas. PATIENTS AND METHODS: 40 cases of DPN-like borderline tumor were identified along with 6 cases of plexiform melanoma. Clinical follow up was obtained, along with cytogenetic analysis in the form of fluorescent in situ hybridization (FISH) and/or comparative genomic hybridization (CGH). RESULTS: The DPN-like borderline tumor cases included 24 females and 16 males. Of sentinel lymph node biopsies performed, 1/3 of cases showed lymph node involvement. All patients where an aggressive clinical approach was adopted remain free of disease. All 6 DPN-like borderline tumor cases tested by CGH showed normal cytogenetics, as did 7 of 9 cases tested by FISH. Of the plexiform melanomas, 4/6 patients died of disease. In 3 cases there was morphologic progression from a DPN-like borderline tumor to overt melanoma. In one case of progression, cytogenetics was normal in the DPN-like borderline tumor and then abnormal in the progressed melanoma. CONCLUSION: DPN-like borderline tumors are melanocytic tumors associated with a high incidence of regional lymph node disease and exhibiting the potential for melanoma progression despite a normal cytogenetic profile. Patients with these lesions should be aggressively managed, with at least complete re-excision and consideration of sentinel node biopsy, regardless of cytogenetic data.