A Droplet Digital Polymerase Chain Reaction-Based Tool to Aid in Melanoma Diagnosis.

CONTEXT.­: Detecting copy number variations (CNVs) at certain loci can aid in the diagnosis of histologically ambiguous melanocytic neoplasms. Droplet digital polymerase chain reaction (ddPCR) is a rapid, automated, and inexpensive method for CNV detection in other cancers, but not yet melanoma. OBJECTIVE.­: To evaluate the performance of a 4-gene ddPCR panel that simultaneously tests for ras responsive binding element protein 1 (RREB1) gain; cyclin-dependent kinase inhibitor 2A (CDKN2A) loss; MYC proto-oncogene, bHLH transcription factor (MYC) gain; and MYB proto-oncogene, transcription factor (MYB) loss in melanocytic neoplasms. DESIGN.­: One hundred sixty-four formalin-fixed, paraffin-embedded skin samples were used to develop the assay, of which 65 were used to evaluate its performance. Chromosomal microarray analysis (CMA) data were used as the gold standard. RESULTS.­: ddPCR demonstrated high concordance with CMA in detecting RREB1 gain (sensitivity, 86.7%; specificity, 88.9%), CDKN2A loss (sensitivity, 80%; specificity, 100%), MYC gain (sensitivity, 70%; specificity, 100%), and MYB loss (sensitivity, 71.4%; specificity, 100%). When one CNV was required to designate the test as positive, the 4-gene ddPCR panel distinguished nevi from melanomas with a sensitivity of 78.4% and a specificity of 71.4%. For reference, CMA had a sensitivity of 86.2% and a specificity of 78.6%. Our data also revealed interesting relationships with histology, namely (1) a positive correlation between RREB1 ddPCR copy number and degree of tumor progression; (2) a statistically significant correlation between MYC gain and nodular growth; and (3) a statistically significant correlation between MYB loss and a sheetlike pattern of growth. CONCLUSIONS.­: With further validation, ddPCR may aid both in our understanding of melanomagenesis and in the diagnosis of challenging melanocytic neoplasms.

Subungual melanoma with cartilaginous differentiation: Molecular insights.

Melanoma's rare capacity to undergo heterologous differentiation can create significant diagnostic challenges. The molecular mechanisms underlying this phenomenon are not well understood. We present an unusual case of subungual melanoma exhibiting extensive cartilaginous differentiation and provide insights into its molecular and cytogenomic features. Histopathologically, the tumor was predominantly composed of nodules of malignant cartilage in association with a smaller population of nested epithelioid to rhabdoid cells. Immunohistochemically, the tumor cells in both components were positive for S100, SOX10, and PRAME, and were negative for Melan-A and HMB-45. Molecular analysis by whole exome DNA sequence did not detect any pathogenic variants in genes commonly implicated in melanoma. Additional analysis by SNP chromosomal microarray revealed a complex genome characterized by numerous chromosomal losses and gains, including a homozygous deletion of the CDKN2A locus and a heterozygous deletion of the locus containing EXT2, a tumor suppressor implicated in hereditary multiple osteochondromas and secondary chondrosarcomas. This case underscores the importance of recognizing cartilaginous differentiation as a rare manifestation of melanoma, particularly at subungual sites, and suggests that at least some of these melanomas may be driven by non-canonical molecular pathways.

A novel method to assess copy number variations in melanocytic neoplasms: Droplet digital PCR for precise quantitation of MYC and MYB genes.

INTRODUCTION: While most melanocytic neoplasms can be classified as either benign or malignant by histopathology alone, ancillary molecular diagnostic tests can be necessary to establish the correct diagnosis in challenging cases. Currently, the detection of copy number variations (CNVs) by fluorescence in situ hybridization and chromosomal microarray (CMA) are the most popular methods, but remain expensive and inaccessible. We aim to develop a relatively inexpensive, fast, and accessible molecular assay to detect CNVs relevant to melanoma using droplet digital polymerase chain reaction (ddPCR) technology. METHODS: In this proof-of-concept study, we evaluated CNVs in MYC and MYB genes from 73 cases of benign nevi, borderline melanocytic lesions, and primary and metastatic melanoma at our institution from 2015 to 2022. A multiplexed ddPCR assay and CMA were performed on each sample, and the results were compared. RESULTS: Concordance analysis of ddPCR with CMA for quantification of MYC and MYB CNVs revealed a sensitivity and specificity of 89% and 86% for MYC and 83% and 74% for MYB, respectively. CONCLUSION: We demonstrate the first use of a multiplexed ddPCR assay to identify CNVs in melanocytic neoplasms. With further improvement and validation, ddPCR may represent a low-cost and rapid tool to aid in the diagnosis of histopathologically ambiguous melanocytic tumors.

Anti-PL-7, anti-Ro/SSA, anti-Mi-2, and anti-TIF1-γ correlate with specific patterns of histopathologic features in dermatomyositis: An analysis of 39 skin biopsy specimens from 25 patients.

BACKGROUND: In dermatomyositis (DM), myositis-specific and myositis-associated antibodies have been correlated with clinical features. It is unknown if histopathologic findings in lesional skin biopsies correlate with serologic subtypes of DM. METHODS: A retrospective chart review of patients with DM was performed. Patients with myositis antibodies and DM lesional skin biopsies were included in the study. Skin biopsies were reviewed by blinded dermatopathologists for 20 histopathologic features. RESULTS: There was a statistically significant (p < 0.05) association between anti-PL-7 serology and decreased degree of vacuolar degeneration, necrotic keratinocytes, and thickening of the epidermal basement membrane. Anti-aminoacyl tRNA synthetase (anti-ARS) antibodies had the same significant negative association with degree of vacuolar degeneration, necrotic keratinocytes, and thickening of the epidermal basement membrane. A similar pattern was seen with an anti-cytoplasmic serology; where there was a significant association with an increased degree of vacuolar degeneration and necrotic keratinocytes, and a nonsignificant trend of minimally thickened epidermal basement membrane. There was a statistically significant association between anti-Ro/SSA serology and increased degree of vacuolar degeneration. Anti-TIF1-γ serology was significantly associated with the increased presence of necrotic keratinocytes and pigment incontinence, and displayed a pattern of increased neutrophils. There was a significant association between anti-Mi-2 antibodies and pigment incontinence, as well as between myositis-specific antibodies and pigment incontinence. A statistically significant positive association was found between nuclear antibodies and degree of vacuolar degeneration, thickened epidermal basement membrane, pigment incontinence, and epidermal atrophy. CONCLUSION: In patients with DM, some specific serotypes, including anti-PL-7, anti-Ro/SSA, anti-Mi-2, and anti-TIF1-γ, may have characteristic histopathologic features.

Mohs Micrographic Surgery Versus Wide Local Excision in the Treatment of Merkel Cell Carcinoma: A Systematic Review.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive neoplasm with high rates of recurrences. Current guidelines recommend wide local excision (WLE) with 1 to 2 cm margins. However, Mohs micrographic surgery (MMS) offers a potential advantage over WLE because of its ability of sparing healthy tissue and assessing 100% of margins. OBJECTIVE: To systematically evaluate the surgical modalities for the treatment of MCC. MATERIALS AND METHODS: Eligible articles were identified using MEDLINE, Scopus, EMBASE, and Cochrane Library. All available studies investigating surgical treatment of MCC with WLE or MMS were considered. RESULTS: Forty studies met the inclusion criteria. Thirty-one studies described patients treated with WLE, 3 with MMS, and 6 with either WLE or MMS. Subgroup analysis of Stage I MCC showed recurrence rates similar in both surgical modalities with local recurrence rate of 6.8% for WLE versus 8.5% for MMS (p = .64) and a regional recurrence rate of 15.2% for WLE versus 15.3% for MMS (p = .99). CONCLUSION: Overall WLE cases were at a higher stage at presentation. Subgroup analysis showed that MMS is not inferior to WLE excision for the treatment of Stage I MCC and is a reasonable option for anatomic locations where tissue sparing is important.

Systemic Lupus Erythematosus and Angioedema: A Cross-Sectional Study From the National Inpatient Sample.

Objectives: This cross-sectional study aims to investigate the odds of developing angioedema (AE) in systemic lupus erythematosus (SLE) populations compared to non-SLE populations in hospital settings in the United States using a nationwide database. Materials and methods: We used the data from the National Inpatient Sample for the years 2012 to 2014. We constructed two models for multivariate logistic regression analysis. Model 1 was designed to adjust demographic information, while model 2 included each factor in model 1 and additionally accounted for AE-related comorbidities. Results: A total of 90,485 hospitalizations with an AE diagnosis were identified for the years 2012 to 2014, among which 1,505 hospitalizations had both SLE and AE. Compared to those without SLE, AE patients with SLE were younger and included more females. In AE hospitalizations, SLE was associated with higher odds of AE-related comorbidities including atopic disorder, leukocytoclastic vasculitis, eosinophilia, and infections. SLE was associated with higher odds of AE both as all inpatient diagnosis and as principal diagnosis (unadjusted odds ratio [OR] 3.24, 95% confidence interval [CI] 2.87-3.63, p<0.001, model 1 adjusted OR 2.54, 95% CI 2.26-2.86, p<0.001, model 2 adjusted OR 1.71, 95% CI 1.51-1.93, p<0.001). Conclusion: Our study demonstrates that SLE is associated with higher odds of having AE, including severe AE as the principal reason for inpatient admission. SLE is possibly an independent risk factor for AE.

A strategic evidence-based framework for international medical graduates (IMGs) applying to dermatology residence in the United States: a literature review.

Dermatology is one of the least diverse medical fields, partly owing to the low number of international medical graduates that apply and match to dermatology residency programs in the United States each year. Our objective was to determine and outline the factors that can increase competitiveness of international applicants interested in applying to dermatology residency in the U.S. Higher match rates for IMGs were associated with several applicant-dependent characteristics, including higher USMLE scores, higher research participation and numbers of publications, strong recommendation letters, and dermatology rotations. Although states with a greater number of dermatology residency positions (New York, Massachusetts, and California) had more IMGs matched from 2013 to 2018, certain states with a smaller number of residency positions, namely Colorado and Georgia, had the highest dermatology match rates for IMGs when adjusted for the total number of matched applicants. Evidenced-based application guidance for international applicants, as outlined in this literature review, may improve the competitiveness of IMGs and increase diversity within the field of dermatology. Rotating and applying to dermatology residency programs in states that have historically accepted a higher number of IMGs may further improve the applicants' chances of matching into a dermatology residency.

Chemotherapy-induced skin toxicity and capillary leak syndrome.

BACKGROUND: The occurrence of chemotherapy-related adverse cutaneous reactions in the setting of capillary leak syndrome (CLS) is quite rare. Our objective was to identify the type of skin reactions associated with CLS. METHODS: Leukemia or hematopoietic stem cell transplant patients between January 2010 and December 2017 were identified, and medical records were reviewed for a dermatology consultation occurring concomitantly with CLS. RESULTS: Five patients were identified, two with a diagnosis of toxic erythema of chemotherapy (TEC) and three others with a skin diagnosis of toxic epidermal necrolysis (TEN). Pathology of all patients was available for clinical-pathologic confirmation. CONCLUSIONS: Although TEC is generally self-limited, both TEC and TEN can present with severe adverse skin manifestations during CLS secondary to toxicity from chemotherapy.

Impact of gender on in-hospital outcomes in patients with Takotsubo syndrome: A nationwide analysis from 2006 to 2014.

BACKGROUND: Takotsubo syndrome (TTS) is characterized by acute, transient systolic dysfunction of the left ventricle not attributed to coronary artery disease (CAD). HYPOTHESIS: There are differences in hospital outcomes in patients admitted with TTS based on their gender. METHODS: The National Inpatient Sample database was searched for patients admitted with a principal diagnosis of TTS from 2006 to 2014 using the ICD9-CM code 429.83. Using Pearson's χ2 and Student's t test analyses, the P-value was calculated for differences among baseline characteristics of patients. Multivariate regression models were then created to adjust for potential confounders. RESULTS: A total of 39 662 admissions with TTS were identified, 91.7% female and 8.3% male with mean age of 66.5 and 61.6 years, respectively. The incidence of TTS increased progressively from 2006 to 2014. Female patients were more likely to have hypertension, hypothyroidism, or depression. Males were more likely to use tobacco, or have known CAD. Males had almost 4-fold higher probability of in-hospital mortality compared to females (3.7% vs 1.1%; P<0.001). Certain complications including cardiogenic shock, ventricular fibrillation/tachycardia, and acute kidney injury were more common in males. CONCLUSIONS: There are distinct gender differences in clinical characteristics of patients admitted with TTS. Although TTS is more common in females, it is associated with higher morbidity and mortality in males.

Clinical and histopathological spectrum of toxic erythema of chemotherapy in patients who have undergone allogeneic hematopoietic cell transplantation.

OBJECTIVE/BACKGROUND: Toxic erythema of chemotherapy (TEC) is a well-recognized adverse cutaneous reaction to chemotherapy. Similar to many skin diseases, the clinical presentations may vary. Our objective is to expand on the typical and atypical clinical and histopathological presentations of TEC. METHODS: Forty patients with a diagnosis of TEC were included from 500 patients who had undergone an allogeneic hematopoietic stem cell transplant. Relevant information and demonstrative photos and pathology were selected. RESULTS: Classic clinical presentations included hand and foot erythema and dysesthesias; atypical presentations included facial involvement, hyperpigmentation, dermatomyositis-like, and erythroderma associated with capillary leak syndrome. CONCLUSION: The diagnosis of TEC should be considered after a correlation of clinical and histological findings in conjunction with a timeline of chemotherapy administration. Suggested criteria for the diagnosis of TEC may be helpful to dermatologists and clinicians when caring for these patients.

Incidence of squamous cell carcinoma in oral lichen planus: a 25-year population-based study.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory condition of the oral mucosa. Multiple studies have shown that approximately 1% of patients with OLP will develop oral squamous cell carcinoma (OSCC), however, no study has taken a population-based multicenter approach to demonstrate this association. Our main objective was to determine the incidence of OSCC in OLP in a specific population and secondarily to assist physicians regarding appropriate long-term monitoring of patients with OLP. METHODS: We conducted a population-based retrospective cohort study. Patients with OLP from 1986 through 2010 were identified using the Rochester Epidemiology Project (REP) for Olmsted County, Minnesota. For each OLP case (n = 303), we randomly selected two age- and gender-matched referents (n = 606). OLP diagnosis was established based on the World Health Organization (WHO) criteria. Medical records were reviewed for development of OSCCafter the OLP diagnosis (index date). The association between OLP and development of OSCC was assessed. RESULTS: In total, 303 patients with incident OLP were identified; the overall incidence of OLP per 100,000 person-years was 11.4 (95% CI, 10.1-12.7). Among the OLP cohort, 7 had OSCC (incidence of OSCC, 3.1%; 95% CI, 0.6-6.4%) at 20 years after OLP diagnosis. Three OSCC cases were identified among the referents. Patients with OLP were 4.8 times more likely to have OSCC than the matched referents. The median time to OSCC development was 14.7 years earlier for the OLP cohort. CONCLUSIONS: Patients with OLP, particularly the erosive type, have an increased incidence of OSCC development and should be monitored closely.

The in-hospital burden of hidradenitis suppurativa in patients with inflammatory bowel disease: a decade nationwide analysis from 2004 to 2014.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease that significantly affects the patient's quality of life. Multiple studies have shown a strong association between HS and inflammatory bowel disease (IBD). Our primary goal was to explore the in-hospital burden of HS on patients with IBD. Our secondary goal was to establish unique baseline characteristics and comorbidities of IBD patients with HS. METHODS: This was a retrospective cohort study using the National Inpatient Sample (NIS) database for the years 2004 through 2014. All patients with ICD-9 CM codes for any diagnosis of IBD and HS were included. The primary outcome was the medical and financial burden of HS on patients with IBD. Medical burden was measured by in-hospital morbidity and mortality, and financial burden was measured by resource utilization. RESULTS: A total of 3,079,332 admissions with IBD were recorded, of which 4369 had a concomitant diagnosis of HS. IBD-HS patients were significantly younger and mostly African-American females; they were more likely to be smokers, obese, and have diabetes mellitus, depression, and anemia. There was no mortality difference between the IBD-HS and IBD-only groups; nevertheless, there was a higher likelihood of developing sepsis in the IBD-HS cohort (4.9% vs. 2.6%; P < 0.001). Patients with IBD-HS had an increased hospital length of stay (5 vs. 4 days; P < 0.001) and higher total hospitalization costs ($13,272 vs. $12,237; P = 0.013). CONCLUSIONS: This large-scale study strengthens the evidence that these two inflammatory conditions are truly associated and establishes their joint effect on overall morbidity, mortality, and resource utilization.

The Successful Treatment of a Case of Linear Psoriasis with Ixekizumab.

Linear psoriasis is an unusual clinical variation of psoriasis that manifests segmentally along the lines of Blaschko. A major differential diagnosis is inflammatory linear verrucous epidermal nevus (ILVEN). The treatment of linear psoriasis is often challenging, with inadequate response to biological agents reported in the literature. We report a case of a 25-year-old African-American female who presented with asymptomatic hyperkeratotic papules along the lines of Blaschko and was subsequently diagnosed with linear psoriasis. After failing conventional treatment regimens, the patient received a trial of ixekizumab with complete resolution of cutaneous lesions reported after 4 months and only 8 doses of the anti-IL-17 biologic agent.