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3.
Am J Dermatopathol ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33298708

RESUMO

In vulvar biopsies, we have observed histopathologic abnormalities of elastic fibers identical to solar elastosis, with thick, curled, and irregular pale grey fibers in the dermis. In severe cases, changes resemble nodular solar elastosis. We retrospectively evaluated 238 vulvar biopsies with the goal of defining and characterizing changes of vulvar elastosis. Of 238 vulvar biopsies reviewed, 107 (45%) exhibited vulvar elastosis. Patients with vulvar elastosis were older (mean = 65 years old) compared to those without (mean = 44 years old). Sixty-six (62%) were graded as mild, 27 (25%) moderate, and 14 (13%) severe. Vulvar elastosis was significantly more common in women ≥45 years old (P-value < 0.001). There was moderate correlation between age and severity (correlation coefficient = 0.55, P-value < 0.001). Vulvar elastosis was observed in a variety of inflammatory and non-inflammatory pathologies. In 5 cases, the sole pathology was vulvar elastosis presenting clinically as either a pruritic or painful white to white-yellow papule or plaque, or vulvar pain or burning without a clinical lesion. Vulvar elastosis is a novel diagnostic entity occurring in a sun-protected site and its pathogenesis may be a degenerative phenomenon possibly related to advancing age and/or hormonal changes.

4.
Am J Dermatopathol ; 42(12): 923-931, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33289976

RESUMO

With the advent of better molecular characterization of Spitz melanocytic neoplasms, there has been increasing effort to better understand and describe the relationships between specific driver fusion and/or mutations with the clinical and histomorphological characteristics of the lesions. Structural rearrangements in mitogen activated protein kinase genes have recently been noted to be important in Spitz neoplasms. Only very few reports, however, have described in detail melanocytic tumors with in frame deletions in MAP2K1. Cases in the literature with this aberration have been described as having a diagnosis of Spitz, deep penetrating nevi, or pigmented epithelioid melanocytoma. In this study, we describe a cohort of 6 cases with MAP2K1 activating in frame deletions. The morphologic spectrum of the cases was broad. Common features of these cases include Spitzoid cytomorphology (5/6) cases, prominent melanin pigmentation (4/6) cases, and deep penetrating nevi-like plexiform architecture (3/6) cases. The diagnoses at the time of clinical care of these cases included nevus of Reed (1/6), desmoplastic Spitz tumor (1/6), BAPoma (1/6), deep penetrating melanocytic nevus (2/6), and melanoma (1/6). Clinical follow-up was available in 3 of the 6 cases. None of the patients had a tumor recurrence. This builds on the growing literature to help expand the spectrum of changes associated with Spitzoid melanocytic neoplasms.

5.
Am J Dermatopathol ; 42(12): 916-922, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32732692

RESUMO

Desmoplastic melanoma can be difficult to diagnose and on average have a significantly higher T stage at the time of diagnosis compared with conventional melanomas. Histologically, these tumors typically consist of spindle cells in a fibrous matrix. The spindle cells may display fibroblast and/or Schwann cell-like features. In this study, we describe the features of 12 cases of desmoplastic melanoma closely simulating neurofibroma. Although the spindle cells in these tumors may be indistinguishable from those of neurofibroma, features such as prominent fibroplasia (12/12), poor lateral circumscription (8/9), diffuse infiltration of subcutaneous tissue (7/9), and lymphoid aggregates (10/12) may be helpful clues to the diagnosis. No immunohistochemical markers were reliable in distinguishing neurofibroma-like desmoplastic melanomas from neurofibroma. Clinical follow-up was available in 8 cases, of which 4 were initially misdiagnosed as benign neoplasms and given no further re-excision. All 4 of these cases recurred; 2 of which showed transformation to a more aggressive phenotype.

6.
Mod Pathol ; 2020 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-32862201

RESUMO

The presence of a characteristic chimeric fusion as the initiating genomic event is one defining feature of Spitz neoplasms. Characterization of specific subtypes of Spitz neoplasms allows for better recognition facilitating diagnosis. Data on clinical outcomes of the specific tumor types may help in predicting behavior. In this study we present the largest series to date on ROS1 fusion Spitz neoplasms. We present the clinical, morphologic, and genomic features of 17 cases. We compared the morphologic features of these 17 cases to a cohort of 99 other non-ROS1 Spitz neoplasms to assess for features that may have high specificity for ROS1 fusions. These tumors consisted of ten Spitz nevi and seven Spitz tumors. None of the cases met criteria for a diagnosis of Spitz melanoma. Morphologically, the ROS1 fusion tumors of this series were characterized by a plaque-like or nodular silhouette, often densely cellular intraepidermal melanocyte proliferation, frequent pagetosis, tendency toward spindle cell cytomorphology, low grade nuclear atypia, and floating nests with occasional transepidermal elimination. However, there was a significant range in microscopic appearances, including two cases with morphologic features of a desmoplastic Spitz nevus. Different binding partners to ROS1 were identified with PWWP2A and TPM3 being the most common. No case had a recurrence or metastasis. Our findings document that most ROS1 fusion Spitz neoplasms have some typical characteristic microscopic features, while a small proportion will have features overlapping with other genomic subtypes of Spitz neoplasms. Preliminary evidence suggests that they tend to be indolent or low grade neoplasms.

7.
J Cutan Pathol ; 47(12): 1132-1142, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32776349

RESUMO

BACKGROUND: Fusions involving the BRAF gene are responsible for 5% of Spitz neoplasms. To better characterize them, we report the clinical, morphological, and genomic findings of six BRAF fusion Spitz tumors. METHODS: The morphological, clinical, and molecular findings of six BRAF fusion Spitz neoplasms assessed by next generation sequencing (NGS) were compared to a control set of Spitz without BRAF fusions. RESULTS: BRAF fusion Spitz tumors had frequent predominance of epithelioid morphology (4/6 cases), frequent high-grade nuclear atypia and pleomorphism (5/6 cases), and a frequent desmoplastic base (3/6 cases). Five of six cases were diagnosed as atypical Spitz tumor and one as Spitz nevus. All cases had uneventful clinical follow-up. There were five different fusion partners, with CLIP2 being the most frequent. Secondary pathogenic mutations were frequent and chromosomal copy number changes were seen in three of six cases by an NGS platform. CONCLUSIONS: BRAF fusions Spitz usually have epithelioid morphology, high-grade nuclear atypia, and desmoplasia. Chromosomal copy number changes are not infrequent. While our cases had uneventful follow-up, a meta-analysis of the literature suggests that among the fusion subtypes associated with Spitz tumors, they are among the subgroups more likely to develop distant metastasis.

8.
Arch Dermatol Res ; 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770258

RESUMO

Dermatofibrosarcoma protuberans (DFSP) is a cutaneous sarcoma that has remained a challenge for oncologic and reconstructive surgeons due to a high rate of local recurrence. The objective of this study is to investigate the oncologic and reconstructive benefits of employing a multidisciplinary two-step approach to the treatment of DFSP. A retrospective review was conducted using a prospectively collected database of all patients who underwent resection and reconstruction of large DFSPs by a multidisciplinary team, including a Mohs micrographic surgeon, surgical oncologist, dermatopathologist, and plastic and reconstructive surgeon, at one academic institution from 1998-2018. Each patient underwent Mohs micrographic surgery for peripheral margin clearance (Step 1) followed by wide local excision (WLE) of the deep margin by surgical oncology and immediate reconstruction by plastic surgery (Step 2). 57 patients met inclusion criteria. Average defect size after WLE (Step 2): 87.3 cm2 (range 8.5-1073.5 cm2). Mean follow-up time was 37 months (range 0-138 months). There were no cases of recurrence. A two-step multidisciplinary surgical treatment approach for DFSP minimizes risk of recurrence, decreases patient discomfort, and allows immediate reconstruction after deep margin clearance.

9.
J Am Acad Dermatol ; 83(5): 1538-1539, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32682892
11.
J Cutan Pathol ; 47(12): 1150-1154, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32526042

RESUMO

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.

12.
J Am Acad Dermatol ; 83(4): 1028-1034, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32446823

RESUMO

BACKGROUND: Atypical network encompasses several patterns. Few studies assess the sensitivity, specificity, and positive and negative predictive values of network subtypes. OBJECTIVE: We assessed the diagnostic value of atypical network subtypes and their histopathologic correlates in cutaneous melanocytic lesions. METHODS: A retrospective search (2014-2018) from a high-risk melanoma clinic for cases scored for atypical network with accompanying dermoscopic photographs yielded 120 lesions (15 melanoma; 30 severely, 38 moderately, and 32 mildly atypical nevi; 4 compound nevi; and 1 junctional nevus). A dermatopathologist blinded to diagnosis assessed dermoscopic and histologic features. Network abnormality correlates with histopathology and clinical diagnoses were assessed with sensitivity, specificity, positive and negative predictive values, and odds ratios. RESULTS: A multivariable model with shiny white streaks (odds ratio 3.02) and inverse network (OR 4.46) was most predictive of melanoma or severe atypia. Positive predictive value for melanoma or severe atypia in decreasing order was inverse network (73.9%), shiny white streaks (71.4%), loss of network (46%), branched streaks (29.4%), and thick brown lines (28.4%). LIMITATIONS: Cases were retrospectively found from a pigmented lesion clinic and evaluated by a single dermatopathologist. CONCLUSION: Shiny white streaks and inverse network are most predictive of melanoma or severe atypia and warrant biopsy if found on dermoscopy.

13.
Arch Dermatol Res ; 2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32338293

RESUMO

Histopathologic assessment of melanocytic neoplasms is the current gold standard of diagnosis. However, there are well recognized limitations including inter-observer diagnostic discordance. This study aimed to determine if integrating dermoscopy with histopathology of melanocytic neoplasms impacts diagnosis and improves inter-observer agreement. We conducted a prospective cohort study in a pigmented lesion clinic. Consecutive melanocytic lesions were identified for biopsy based on atypical gross or dermoscopic features. Standardized immunohistochemistry and levels were ordered on each specimen. The cases were randomized. Three dermatopathologists blinded to the clinical impression assessed each lesion. The cases were then re-randomized and re-assessed with addition of gross clinical and dermoscopic images. Inter-rater reliability (IRR) using Fleiss' kappa statistic revealed an increase from 0.447 without to 0.496 with dermoscopy amongst all dermatopathologists. The kappa increased from 0.495 before to 0.511 with dermoscopy in separating high-grade atypia or melanoma from moderate atypia or less. In 16 of 136 cases, at least 2 of 3 dermatopathologists favored a diagnosis of melanoma only after dermoscopy. In total, the consensus grade of atypia changed in 24.3% (33/ 136) of cases thereby representing changes to excisional margins and patient follow up. This study is limited by the cohort size. Dermoscopy significantly impacts diagnosis and improves identification of early melanomas in high risk populations and improves inter-observer agreement.

14.
J Invest Dermatol ; 140(8): 1599-1608, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32004563

RESUMO

The newest World Health Organization classification of skin tumors suggests the elimination of cases with BRAF and NRAS mutations from the categories of Spitz tumors (ST) and Spitz melanoma (SM). The objective of this study is to better characterize the genomics of Spitz neoplasms and assess whether the integration of genomic data with morphologic diagnosis improves classification and prognostication. We performed DNA and RNA sequencing on 80 STs, 26 SMs, and 22 melanomas with Spitzoid features (MSF). Next-generation sequencing data were used to reclassify tumors by moving BRAF and/or NRAS mutated cases to MSF. In total, 81% of STs harbored kinase fusions and/or truncations. Of SMs, 77% had fusions and/or truncations with eight involving MAP3K8. Previously unreported fusions identified were MYO5A-FGFR1, MYO5A-ERBB4, and PRKDC-CTNNB1. The majority of MSFs (84%) had BRAF, NRAS, or NF1 mutations, and 62% had TERT promoter mutations. Only after reclassification, the following was observed: (i) mRNA expression showed distinct clustering of MSF, (ii) six of seven cases with recurrence and all distant metastases were of MSFs, (iii) recurrence-free survival was worse in MSF than in the ST and SM groups (P = 0.0073); and (iv) classification incorporating genomic data was highly predictive of recurrence (OR 13.20, P = 0.0197). The majority of STs and SMs have kinase fusions as primary initiating genomic events. The elimination of BRAF and/or NRAS mutated neoplasms from these categories results in the improved classification and prognostication of melanocytic neoplasms with Spitzoid cytomorphology.

15.
Am J Dermatopathol ; 42(9): 641-647, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32000215

RESUMO

BACKGROUND: Some melanomas closely resemble pigmented spindle cell nevi (PSCN) of Reed histologically. The distinction of these entities is important for clinical management. A recent study showed most PSCN (78%) are fusion-driven, commonly involving NTRK3 (57%). Conversely, BRAF V600E mutations are not characteristic of PSCN but are frequent in melanoma. OBJECTIVE: In this study, we assessed clinical, histologic and genomic differences between PSCN of Reed and Reed-like melanomas (RLMs). METHODS: We performed BRAF V600E immunohistochemistry (IHC) for 18 PSCN and 20 RLM cases. All 23 benign PSCN cases previously underwent whole transcriptome and targeted DNA sequencing with a 1711 gene panel. RESULTS: We previously demonstrated the majority of PSCN (18 of 23) has chimeric fusions. Among PSCN without a chimeric fusion, BRAF mutations were common. Noncanonical BRAF mutations were identified in 2 of 5 nonfusion cases, and 1 case had a canonical BRAF mutation. Alternatively, 70% of RLM demonstrated a BRAF V600E mutation. RLM also occurred more frequently in older patients. LIMITATIONS: The overall sample size was small. CONCLUSIONS: In diagnostically challenging cases, ancillary IHC studies can assist in distinguishing PSCN from RLM. Our study suggests positive staining by IHC for BRAF V600E and older age strongly favors a diagnosis of RLM.

16.
Pigment Cell Melanoma Res ; 33(2): 305-317, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31563153

RESUMO

The epidermis is the first line of defense against ultraviolet (UV) light from the sun. Keratinocytes and melanocytes respond to UV exposure by eliciting a tanning response dependent in part on paracrine signaling, but how keratinocyte:melanocyte communication is regulated during this response remains understudied. Here, we uncover a surprising new function for the keratinocyte-specific cell-cell adhesion molecule desmoglein 1 (Dsg1) in regulating keratinocyte:melanocyte paracrine signaling to promote the tanning response in the absence of UV exposure. Melanocytes within Dsg1-silenced human skin equivalents exhibited increased pigmentation and altered dendrite morphology, phenotypes which were confirmed in 2D culture using conditioned media from Dsg1-silenced keratinocytes. Dsg1-silenced keratinocytes increased melanocyte-stimulating hormone precursor (Pomc) and cytokine mRNA. Melanocytes cultured in media conditioned by Dsg1-silenced keratinocytes increased Mitf and Tyrp1 mRNA, TYRP1 protein, and melanin production and secretion. Melanocytes in Dsg1-silenced skin equivalents mislocalized suprabasally, reminiscent of early melanoma pagetoid behavior. Together with our previous report that UV reduces Dsg1 expression, these data support a role for Dsg1 in controlling keratinocyte:melanocyte paracrine communication and raise the possibility that a Dsg1-deficient niche contributes to pagetoid behavior, such as occurs in early melanoma development.

17.
Am J Dermatopathol ; 41(12): 871-878, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31764231

RESUMO

BACKGROUND: Eccrine duct dilation (EDD) was recently described to occur more frequently in cicatricial alopecias than noncicatricial alopecias. Because single EDD can be useful in the evaluation of alopecias, we aimed to determine whether dilation of multiple eccrine duct units, or "multiple eccrine duct dilation (MEDD)," could more specifically discriminate between cicatricial and noncicatricial alopecias. METHODS: We retrospectively evaluated 611 scalp biopsies (342 cicatricial alopecias and 269 noncicatricial alopecias). RESULTS: Among cicatricial alopecias, MEDD was found in 21% (25/118) of central centrifugal cicatricial alopecia, 26% (29/109) of lichen planopilaris, 13% (10/73) of discoid lupus erythematosus, 31% (5/16) of acne keloidalis nuchae, and 26% (7/26) of folliculitis decalvans. In noncicatricial alopecias, MEDD was found in 1% (1/102) of androgenetic alopecia, 0.7% (1/150) of alopecia areata, and 0% (0/17) of telogen effluvium. In cicatricial alopecias, MEDD occurred in a significantly higher frequency (22%; 76/342) compared with noncicatricial alopecias (0.7%; 2/269) (P-value <0.0001). The presence of MEDD correlated with a diagnosis of cicatricial alopecia with 22% sensitivity and 99% specificity. MEDD also occurred more frequently in cases with moderate to severe inflammation and fibroplasia, suggesting that EDD is a reactive change secondary to the scarring processes. CONCLUSION: The presence of MEDD on scalp biopsies may be a highly specific marker of cicatricial alopecia and can aid in rendering a more accurate diagnosis. MEDD without other definitive histopathologic features of cicatricial alopecia may compel pathologists to pursue additional workup and/or raise the possibility that a cicatricial alopecia cannot be entirely excluded.


Assuntos
Alopecia/patologia , Cicatriz/patologia , Glândulas Écrinas/patologia , Dermatoses do Couro Cabeludo/patologia , Couro Cabeludo/patologia , Alopecia/etiologia , Biópsia , Cicatriz/complicações , Bases de Dados Factuais , Diagnóstico Diferencial , Dilatação Patológica , Humanos , Valor Preditivo dos Testes , Estudos Retrospectivos , Dermatoses do Couro Cabeludo/complicações
18.
J Am Acad Dermatol ; 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31306728

RESUMO

BACKGROUND: Compared to sun-exposed melanomas, less is known regarding the pathogenesis of sun-protected melanomas. Sun-protected melanomas share many epidemiologic factors but their genetic heterogeneity is not well studied. OBJECTIVE: We investigated the genomic profile of acral, mucosal and vulvovaginal melanomas. We hypothesize that mucosal melanomas, recognized for their uniquely aggressive clinical behavior, have distinct genomic features. METHODS: We performed whole transcriptome mRNA and DNA (1711 genes) sequencing, mRNA expression profiling, TMB, UV signature and CNV analysis on 29 volar/digital acral, 7 mucosal and 6 vulvovaginal melanomas. RESULTS: There was significant genetic heterogeneity, particularly in acral melanomas with 36% having BRAF alterations while other melanomas had none (p = 0.0159). Nonzero UV signatures were more frequent in acral melanomas, suggesting greater UV involvement. Mucosal melanomas formed a distinct group with increased expression of cell cycle and proliferation genes. Various targetable aberrations were identified such as AURKA and ERBB2 in mucosal and acral melanomas, respectively. LIMITATIONS: There was a small sample size. CONCLUSION: There is significant genetic heterogeneity among sun-protected melanomas. Mucosal melanomas have upregulation in cell cycle and proliferation genes, which may explain their aggressive behavior. Ultraviolet radiation plays some role in a subset of acral but not other melanomas.

19.
J Cutan Pathol ; 46(11): 878-887, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31152596

RESUMO

Recent advances in next generation sequencing (NGS) have allowed for efficient whole transcriptome sequencing, leading to the identification of important kinase fusions as the primary driver in some melanocytic neoplasms. These fusions typically occur mutually exclusively of one another and other well-known initiating mutations such as BRAF, NRAS, NF1, KIT, and GNAQ. Fusions are found in over 50% of Spitz neoplasms, including ALK, BRAF, NTRK1, NTRK3, ROS1, MET, MAP3K8, and RET. Familiarity with the typical morphologic features of certain fusion-driven melanocytic neoplasms can help with classification, diagnosis, and identification of targeted molecular therapies in malignant cases. Spitz tumors with ALK, NTRK1, and NTRK3 fusions have characteristic morphologic features. BRAF and MAP3K8 fusions, in particular, tend to be epithelioid, high grade, and more frequent in Spitz melanoma than other fusion subtypes. Sporadic cases of pigmented epithelioid melanocytoma may have PRKCA fusions and sheets of monomorphic epithelioid melanocytes. Fusion events are also enriched among melanomas without the key mutations BRAF, NRAS, or NF1. Although NGS is the most reliable method to detect fusions, immunohistochemistry and fluorescence in situ hybridization are cost-effective alternatives in some cases. We describe recent discoveries regarding the role of kinase fusions in melanocytic neoplasms and their associated morphologies.


Assuntos
Fusão Gênica , Melanoma , Mutação , Nevo de Células Epitelioides e Fusiformes , Proteínas de Fusão Oncogênica , Neoplasias Cutâneas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Nevo de Células Epitelioides e Fusiformes/genética , Nevo de Células Epitelioides e Fusiformes/metabolismo , Nevo de Células Epitelioides e Fusiformes/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
20.
Lancet Child Adolesc Health ; 3(9): 646-654, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31204309

RESUMO

Paediatric melanoma is rare and challenging to diagnose. The three subtypes are Spitzoid melanoma, melanoma arising in a congenital melanocytic nevus, and conventional (also known as adult-type) melanoma. Spitzoid melanomas have characteristic histopathological and genomic aberrations. Despite frequent involvement of the sentinel lymph nodes, most cases have an uneventful clinical course. Among congenital nevi, the risk of melanoma varies by projected size in adulthood, with the greatest risk in large or giant nevi. The clinical course is generally aggressive and accounts for most melanoma-related deaths in childhood. In conventional melanoma, superficial spreading and nodular melanoma account for most cases, with risk factors and presentation largely similar to adult disease. In this Review, we discuss advances in histological diagnosis using adjunctive molecular assays, and summarise the genetic basis of paediatric melanoma.


Assuntos
Melanoma/diagnóstico , Melanoma/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Criança , Humanos , Melanoma/classificação , Melanoma/patologia , Nevo Pigmentado/congênito , Nevo Pigmentado/patologia , Prognóstico , Neoplasias Cutâneas/classificação , Neoplasias Cutâneas/patologia
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