Genomic Analysis Aids in the Management of Dermoscopically Atypical Pigmented Lesions.

BACKGROUND: Numerous melanoma-specific dermoscopic features have been described in invasive melanomas, while fewer features are found in melanoma in situ (MIS) and atypical nevi (ATN). Consensus regarding which features are critical for the differentiation of MIS from ATN has not been reached. PURPOSE: Determine 1) whether there are dermoscopic features that differentiate early MIS from ATN, and 2) whether non-invasive assessment of genomic biomarkers (LINC00518 and PRAME) can aid in patient management. METHODS: From 2018 to 2023, 56 melanomas were evaluated for 5 clinical and 13 dermoscopic features and melanoma-associated genomic biomarkers. Two groups of ATN with positive and negative genomic biomarkers were randomly selected for comparison. RESULTS: All melanomas in this study expressed one or both melanoma-associated genomic markers. MIS had an average of 3.90 (range, 2-7) of the 13 dermoscopic features, while invasive melanomas had an average of 4.44 (range, 3-6). Sixteen of 40 (40%) MIS and 3 of 16 (18.8%) invasive melanomas had 3 or fewer dermoscopic features. These findings were comparable to those observed in both ATN groups. The most common dermoscopic features were absent or diminished pigment network, regression structures, and granularity. This combination of features was most helpful in identifying lesions for genomic testing. CONCLUSIONS: Clinical and dermoscopic features alone could not differentiate MIS from ATN. Non-invasive genomic testing helped differentiate lower from higher-risk lesions and aid in clinical management decisions. Genomic testing was particularly helpful in patients with large numbers of lesions with several being considered for biopsy based on clinical and dermoscopic examination. J Drugs Dermatol. 2024;23(9):717-723. doi:10.36849/JDD.8454.

Skin Cancer Risk Is Increased by Somatic Mutations Detected Noninvasively in Healthy-Appearing Sun-Exposed Skin.

Skin cancer risk is increased by exposure to ultraviolet radiation (UVR). Because UVR exposure accumulates over time and lighter skin is more susceptible to UVR, age and skin tone are risk factors for skin cancer. However, measurements of somatic mutations in healthy-appearing skin have not been used to calculate skin cancer risk. In this study, we developed a noninvasive test that quantifies somatic mutations in healthy-appearing sun-exposed skin and applied it to a 1038-subject cohort. Somatic mutations were combined with other known skin cancer risk factors to train a model to calculate risk. The final model (DNA-Skin Cancer Assessment of Risk) was trained to predict personal history of skin cancer from age, family history, skin tone, and mutation count. The addition of mutation count significantly improved model performance (OR = 1.3, 95% confidence interval = 1.14-1.48; P = 5.3 × 10-6) and made a more significant contribution than skin tone. Calculations of skin cancer risk matched the known United States population prevalence, indicating that DNA-Skin Cancer Assessment of Risk was well-calibrated. In conclusion, somatic mutations in healthy-appearing sun-exposed skin increase skin cancer risk, and mutations capture risk information that is not accounted for by other risk factors. Clinical utility is supported by the noninvasive nature of skin sample collection through adhesive patches.

Clinical Use of a Diagnostic Gene Expression Signature for Melanocytic Neoplasms.

A gene expression signature has been validated as an adjunct to traditional methods of differentiating malignant and benign melanocytic neoplasms, and its use in clinical practice warrants further study. This study followed patients whose melanocytic neoplasms were managed according to a benign result from the gene expression signature (N=25). Eligible patients whose tested lesions were classified as benign by the gene expression signature and were subsequently treated as benign by their dermatology providers were observed for a mean follow-up period of 38.5 months. Results suggest that many patients with melanocytic neoplasms classified as benign by the gene expression signature may safely forego additional surgical excision.

A standardized approach to classifying melanocytic neoplasms? Comments on the MPATH-Dx system.

The potential benefits and limitations of the MPATH-Dx classification system for melanocytic neoplasms are presented and discussed.

Clinical validity of a gene expression signature in diagnostically uncertain neoplasms.

Aim: Evaluate the accuracy of a 23-gene expression signature in differentiating benign nevi from melanoma by comparing test results with clinical outcomes. Materials & methods: Seven dermatopathologists blinded to gene expression test results and clinical outcomes examined 181 lesions to identify diagnostically uncertain cases. Participants independently recorded diagnoses and responses to questions quantifying diagnostic certainty. Test accuracy was determined through comparison with clinical outcomes (sensitivity and percent negative agreement). Results: Overall, 125 cases fulfilled criteria for diagnostic uncertainty (69.1%; 95% CI: 61.8-75.7%). Test sensitivity and percent negative agreement in these cases were 90.4% (95% CI: 79.0-96.8%) and 95.5% (95% CI: 87.3-99.1%), respectively. Conclusion: The 23-gene expression signature has high diagnostic accuracy in diagnostically uncertain cases when evaluated against clinical outcomes.

Proliferative nodule resembling angiomatoid Spitz tumor with degenerative atypia arising within a giant congenital nevus.

Proliferative nodules arising within congenital melanocytic nevi often present a diagnostic challenge given a close resemblance to melanoma. Several morphologic variants have been characterized. In difficult cases, ancillary molecular tests can be used to better exclude the possibility of malignant degeneration. Herein, we report a case of an unusual proliferative nodule with overlapping features of angiomatoid Spitz tumor and ancient melanocytic nevus, which demonstrated normal findings on both chromosomal microarray and a gene expression profiling assay.

Correlation of melanoma gene expression score with clinical outcomes on a series of melanocytic lesions.

A 23-gene expression signature was recently developed as an adjunct to histopathology to differentiate melanocytic nevi from melanoma. The current study correlated the gene expression signature scores to actual clinical outcomes in cases from the first validation study. RNA was extracted from 127 archival formalin-fixed paraffin-embedded tissue sections of melanocytic lesions. Gene expression was measured using quantitative reverse-transcription polymerase chain reaction, and a weighting algorithm was used to generate a numeric score. Gene expression test results were compared to histopathological diagnoses and development of local recurrence, sentinel lymph node metastases, and distant metastases. Sixty-five lesions were diagnosed histopathologically as melanoma. Fourteen developed metastases. Gene expression test results were malignant in 61 of 65 (93.8%) lesions (including all lesions that metastasized), indeterminate in 2 of 65 (3.1%) lesions, and benign in 2 of 65 (3.1%) lesions. The remaining 62 lesions were diagnosed as benign by histopathology. Gene expression test results were benign in 48 of 62 (77.4%), indeterminate in 7 of 62 (11.3%), and malignant in 7 of 62 (11.3%). There was a strong correlation between the gene expression signature test results and clinical outcomes. All lesions that metastasized were correctly identified by the test as malignant melanoma.

Gene expression signature as an ancillary method in the diagnosis of desmoplastic melanoma.

Desmoplastic melanoma (DM) is a rare fibrosing variant of melanoma that can be difficult to diagnose. One of the diagnostic challenges is its distinction from a melanocytic nevus with desmoplasia. Here we investigate the use of a 23-gene signature, which has previously been shown to distinguish benign from malignant melanocytic neoplasms. We assessed 50 cases with a differential diagnostic consideration of DM that underwent gene expression testing. Hematoxylin and eosin-stained sections were reviewed, and the final cohort included 20 DMs, 5 nondesmoplastic melanomas, and 27 desmoplastic melanocytic nevi. Of the 20 DMs, the gene expression score was positive ("likely malignant") in 15 tumors, indeterminate in 1, and negative ("likely benign") in 4. None of the desmoplastic melanocytic nevi were positive. The gene expression score was negative in 24 of the melanocytic nevi and indeterminate in the remaining 3. Nine DMs were also analyzed cytogenetically by single-nucleotide polymorphism (SNP) array. The SNP array revealed chromosomal copy number aberrations consistent with melanoma in 7 DMs and failed to show any aberrations in 2. The results of SNP array analysis and gene expression testing were discordant in 4 cases. Our results document limitations in the sensitivity of both the gene expression signature and SNP array for the detection of DM. Nonetheless, our findings suggest a potential role of the gene expression signature as ancillary supportive evidence for the distinction of DM from desmoplastic nevus because positive scores were only seen in melanomas.

The influence of a gene-expression signature on the treatment of diagnostically challenging melanocytic lesions.

AIM: The effect of a gene-expression-based test on treatment of melanocytic neoplasms by dermatologists was evaluated. PATIENTS & METHODS: Pathologists submitted diagnostically challenging melanocytic neoplasms to a clinical laboratory for testing accompanied by pretest surveys documenting the intended treatment recommendations. The actual treatment rendered by dermatologists was then documented after testing. Changes between the pretest recommendations and actual treatment were analyzed. RESULTS: In 71.4% (55/77) of cases, there was a change from pretest recommendations to actual treatment. The majority of changes were consistent with the test result. There was an 80.5% (33/41) reduction in the number of biopsy site re-excisions performed for cases with a benign test result. CONCLUSION: The actual treatment of diagnostically challenging melanocytic neoplasms is influenced by the test.

Diagnostic Distinction of Malignant Melanoma and Benign Nevi by a Gene Expression Signature and Correlation to Clinical Outcomes.

Background: Histopathologic examination alone can be inadequate for diagnosis of certain melanocytic neoplasms. Recently, a 23-gene expression signature was clinically validated as an ancillary diagnostic test to differentiate benign nevi from melanoma. The current study assessed the performance of this test in an independent cohort of melanocytic lesions against clinically proven outcomes.Methods: Archival tissue from primary cutaneous melanomas and melanocytic nevi was obtained from four independent institutions and tested with the gene signature. Cases were selected according to pre-defined clinical outcome measures. Malignant lesions were defined as stage I-III primary cutaneous melanomas that produced distant metastases (metastatic to sites other than proximal sentinel lymph node(s)) following diagnosis of the primary lesion. Melanomas that were metastatic at the time of diagnosis, all re-excisions, and lesions with <10% tumor volume were excluded. Benign lesions were defined as cutaneous melanocytic lesions with no adverse long-term events reported.Results: Of 239 submitted samples, 182 met inclusion criteria and produced a valid gene expression result. This included 99 primary cutaneous melanomas with proven distant metastases and 83 melanocytic nevi. Median time to melanoma metastasis was 18 months. Median follow-up time for nevi was 74.9 months. The gene expression score differentiated melanoma from nevi with a sensitivity of 93.8% and a specificity of 96.2%.Conclusions: The results of gene expression testing closely correlate with long-term clinical outcomes of patients with melanocytic neoplasms.Impact: Collectively, this provides strong evidence that the gene signature adds valuable adjunctive information to aid in the accurate diagnosis of melanoma. Cancer Epidemiol Biomarkers Prev; 26(7); 1107-13. ©2017 AACR.

An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi.

BACKGROUND: Recently, a 23-gene signature was developed to produce a melanoma diagnostic score capable of differentiating malignant and benign melanocytic lesions. The primary objective of this study was to independently assess the ability of the gene signature to differentiate melanoma from benign nevi in clinically relevant lesions. METHODS: A set of 1400 melanocytic lesions was selected from samples prospectively submitted for gene expression testing at a clinical laboratory. Each sample was tested and subjected to an independent histopathologic evaluation by 3 experienced dermatopathologists. A primary diagnosis (benign or malignant) was assigned to each sample, and diagnostic concordance among the 3 dermatopathologists was required for inclusion in analyses. The sensitivity and specificity of the score in differentiating benign and malignant melanocytic lesions were calculated to assess the association between the score and the pathologic diagnosis. RESULTS: The gene expression signature differentiated benign nevi from malignant melanoma with a sensitivity of 91.5% and a specificity of 92.5%. CONCLUSIONS: These results reflect the performance of the gene signature in a diverse array of samples encountered in routine clinical practice. Cancer 2017;123:617-628. © 2016 American Cancer Society.

The influence of a gene expression signature on the diagnosis and recommended treatment of melanocytic tumors by dermatopathologists.

It is well documented that histopathologic examination is sometimes inadequate for accurate and reproducible diagnosis of certain melanocytic neoplasms. Recently, a 23-gene expression signature has been clinically validated as an adjunctive diagnostic test to differentiate benign nevi from malignant melanomas. This study aimed to quantify the impact of this test on diagnosis and treatment recommendations made by dermatopathologists.Diagnostically challenging melanocytic lesions encountered during routine dermatopathology practice were submitted for gene expression testing and received a melanoma diagnostic score (MDS). Submitting dermatopathologists completed a survey documenting pre-test diagnosis, level of diagnostic confidence, and recommendations for treatment. The survey was repeated after receiving the MDS. Changes between the pre- and post-test surveys were analyzed retrospectively.When the MDS was available as part of a comprehensive case evaluation in diagnostically challenging cases, definitive diagnoses were increased by 56.6% for cases that were initially indeterminate and changes in treatment recommendations occurred in 49.1% of cases. Treatment recommendations were changed to align with the test result in 76.6% of diagnostically challenging cases.The MDS impacts diagnosis and treatment recommendations by dermatopathologists confronted with diagnostically challenging melanocytic lesions. Increased data are needed in order to completely understand how use of the MDS will translate from dermatopathology to clinical practice.

Cutaneous involvement in multiple myeloma (MM): A case series with clinicopathologic correlation.

BACKGROUND: Disease-specific skin lesions are rare in patients with multiple myeloma (MM). OBJECTIVE: We sought to further characterize the clinical and pathologic features of patients with cutaneous involvement with MM. METHODS: We identified 13 patients with cutaneous lesions of MM. RESULTS: Cutaneous lesions consisted of pink, red, and violaceous papules, nodules, and/or plaques that varied in size. Histopathology revealed atypical plasma cells with occasional plasmablastic features. MM had aggressive biologic features and was at an advanced stage in the majority of patients. Despite aggressive management, including chemotherapy and stem-cell transplantation, most patients died of progressive disease within a few months after the development of cutaneous lesions. LIMITATIONS: The study group was relatively small. CONCLUSIONS: Cutaneous involvement with MM is associated with aggressive biologic behavior and short survival.

Gamma-delta T-cell lymphoma arising in a long-standing cutaneous plaque.

The precise classification and characterization of primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) has been hindered by clinical and morphologic features that overlap with other lymphomas, especially subcutaneous panniculitis-like T cell lymphoma (SPTCL). The recent World Health Organization/European Organization for Research and Treatment of Cancer (WHO/EORTC) classification distinguishes the more aggressive PCGD-TCL from the usually indolent SPTCL, however. We report a 30-year-old woman with an indurated violaceous plaque on the left cheek that had been present for several years. Biopsies showed a dense lymphocytic infiltrate involving the subcutis and dermis that consisted mostly of small and medium-sized lymphocytes, some with irregular nuclear contours and dense chromatin. These cells were positive for TIA-1, TCR-gamma and CD8, but negative for beta-F1 and granzyme-B. Staging with positron emission tomography-computed tomography (PET/CT), CBC and bone marrow with flow cytometry identified lymphadenopathy as well as blood and marrow involvement by an abnormal TCRgd-positive T-cell proliferation (Ann Arbor Stage IV). The patient's history of a long-standing lesion in this case is unusual, in that gamma-delta T-cell lymphomas are typically rapidly progressive neoplasms. As such, it raises the possibility of 'transformation' of a long-standing inflammatory process into an overt lymphoma.

Clinical validation of a gene expression signature that differentiates benign nevi from malignant melanoma.

BACKGROUND: Histopathologic examination is sometimes inadequate for accurate and reproducible diagnosis of certain melanocytic neoplasms. As a result, more sophisticated and objective methods have been sought. The goal of this study was to identify a gene expression signature that reliably differentiated benign and malignant melanocytic lesions and evaluate its potential clinical applicability. Herein, we describe the development of a gene expression signature and its clinical validation using multiple independent cohorts of melanocytic lesions representing a broad spectrum of histopathologic subtypes. METHODS: Using quantitative reverse-transcription polymerase chain reaction (PCR) on a selected set of 23 differentially expressed genes, and by applying a threshold value and weighting algorithm, we developed a gene expression signature that produced a score that differentiated benign nevi from malignant melanomas. RESULTS: The gene expression signature classified melanocytic lesions as benign or malignant with a sensitivity of 89% and a specificity of 93% in a training cohort of 464 samples. The signature was validated in an independent clinical cohort of 437 samples, with a sensitivity of 90% and specificity of 91%. CONCLUSIONS: The performance, objectivity, reliability and minimal tissue requirements of this test suggest that it could have clinical application as an adjunct to histopathology in the diagnosis of melanocytic neoplasms.

Epithelioid sarcoma resembling benign fibrous histiocytoma.

Epithelioid sarcoma (ES) is a rare malignancy notorious for its tendency to histologically mimic granuloma annulare and other palisading granulomatous processes. We report a case of ES on the right hand of a 23-year-old man that histopathologically resembled a benign fibrous histiocytoma. Superficial portions of the tumor were well differentiated, exhibiting spindled and ovoid cells with scant cytoplasm that surrounded sclerotic collagen bundles. More obvious atypia including greater cellularity, nuclear pleomorphism, and mitotic activity were mostly confined to the deep-seated regions of the tumor. In addition to palisading granulomatous processes, ES can mimic benign fibrous histiocytoma, and the superficial portions of ES may appear deceptively benign.

Soft-tissue myxomatous lesions: review of salient imaging features with pathologic comparison.

Myxoid soft-tissue lesions are a heterogeneous group of benign and malignant mesenchymal tumors with an abundance of extracellular mucoid material. These lesions may mimic cysts on radiologic evaluation because of the high water content, and histopathologic features also overlap. Benign myxoid lesions include intramuscular myxoma, synovial cyst, bursa, ganglion, and benign peripheral nerve sheath tumor, including neurofibroma and schwannoma. Malignant entities include myxoid liposarcoma, myxoid leiomyosarcoma, myxoid chondrosarcoma, ossifying fibromyxoid tumor, and myxofibrosarcoma. Some syndromes are associated with myxoid soft-tissue lesions, such as Mazabraud syndrome in patients with soft-tissue myxomas and fibrous dysplasia. Certain discriminating features, such as intralesional fat in a myxoid liposarcoma, perilesional edema and a rim of fat in soft-tissue myxoma, and the swirled T2-weighted signal intensity and enhancement pattern of aggressive angiomyxoma, assist the radiologist in differentiating these lesions. The presence of an internal chondroid matrix or incomplete peripheral ossification may suggest myxoid chondrosarcoma or ossifying fibromyxoid tumor, respectively. The entering-and-exiting-nerve sign is suggestive of a peripheral nerve sheath tumor. Communication with a joint or tendon sheath and peripheral enhancement may indicate a ganglion or synovial cyst. This article (a) reviews the magnetic resonance, computed tomographic, and ultrasonographic imaging characteristics of soft-tissue myxomatous lesions, emphasizing imaging findings that can help differentiate benign and malignant lesions; (b) presents differential diagnoses; and (c) provides pathologic correlation.

Mucocutaneous granulomatous disease in a patient with Hermansky-Pudlak syndrome.

IMPORTANCE: Hermansky-Pudlak syndrome (HPS) is a rare genodermatosis characterized by oculocutaneous albinism, platelet dysfunction, and in some patients, pulmonary fibrosis and granulomatous colitis. The granulomatous inflammation in the bowel of patients with HPS can be indistinguishable clinically and histologically from that of Crohn disease (CD); however, mucocutaneous granulomatous lesions have not been considered among the typical skin findings of HPS. OBSERVATIONS: We report a case of an albino woman in her 40s with a history of CD and pulmonary fibrosis who presented with ulcers, plaques, and nodules in the vulva, perineum, inguinal creases, and left axilla. These cutaneous findings had the typical clinical and histologic findings of metastatic cutaneous CD. However, she also had a genetically confirmed diagnosis of HPS. CONCLUSIONS AND RELEVANCE: It is unclear whether our patient's cutaneous findings were due to CD or secondary to HPS. This report reviews the features of HPS and CD, 2 entities characterized by a granulomatous inflammatory reaction pattern but with unique genetic and clinical features, and discusses the possible overlap between the 2 diagnoses.