PRAME Immunohistochemical Expression and TERT Promoter Mutational Analysis as Ancillary Diagnostic Tools for Differentiating Proliferative Nodules From Melanoma Arising in Congenital Nevi.

ABSTRACT: Proliferative nodules (PNs) are benign melanocytic proliferations that typically develop within congenital melanocytic nevi. These tumors have overlapping histological features with melanoma. Ancillary immunohistochemistry and genomic sequencing are often used in diagnostically challenging cases. To assess the utility of preferentially expressed antigen in melanoma (PRAME) immunoreactivity and telomerase reverse transcriptase (TERT) promoter mutation analysis in distinguishing PNs from melanoma arising in congenital nevi cases. Twenty-one PNs and 2 melanomas arising in congenital nevi were immunohistochemically stained with PRAME. Cases with adequate tissue were also assessed for TERT promoter mutations through sequencing studies. The positivity rates in the PN cases were compared with those of the melanomas. Two of 21 PN cases were diffusely positive for PRAME (≥75% of the tumor cells positive). Two of 2 melanomas arising in congenital nevus cases were also diffusely PRAME positive. The difference was statistically significant using a Fisher exact test. None of the tumors harbored TERT promoter mutations. PRAME immunohistochemical marker may have diagnostic value in distinguishing diagnostically challenging PNs from melanoma, but diffuse expression is not specific for melanoma.

Next-generation sequencing improves agreement and accuracy in the diagnosis of Spitz and spitzoid melanocytic lesions.

BACKGROUND: Spitzoid melanocytic neoplasms can be challenging to diagnose on histopathology alone. Next-generation sequencing (NGS) offers promise as a valuable aid in the diagnosis. Recently, one study reported increased inter-rater agreement in the diagnosis of spitzoid melanocytic neoplasms among 20 expert melanoma pathologists after incorporating NGS data. We hypothesized that NGS would carry a similar utility in a broader group of dermatopathologists and general pathologists. METHODS: Sixty-three participants of a live online (www.Dermpedia.org) CME course rendered a diagnosis on 70 cases composed of melanocytic neoplasms with spitzoid features. In Survey 1, cases included H&E slides and demographic information only, while Survey 2 included NGS data. RESULTS: With NGS information, inter-rater agreement significantly improved from "fair" to "almost perfect" and from "fair" to "substantial" for categorizing lesions as Spitz versus non-Spitz and conventional melanoma versus not, respectively. There was also an increase in diagnostic accuracy, evidenced by improved recognition of three metastatic tumors as being conventional melanomas. CONCLUSION: The study supports the adoption of NGS as a valuable diagnostic adjunct for both expert and broader dermatopathologists in their assessments of spitzoid neoplasms.

Next-Generation Sequencing Reveals a New Class of Melanocytic Neoplasms With Hybrid Genomic Features of PEM Including Protein Kinase R 1 Alpha Gene Inactivation and Spitz Tumor-Defining Protein Kinase Fusions.

BACKGROUND: Pigmented epithelioid melanocytoma (PEM) is a subtype of melanocytic tumor with frequent involvement of the sentinel lymph node but rare distant metastasis. Rendering a diagnosis and prognosis based on histology can be challenging. Recent genomic studies identified 2 molecular variants of PEM. One variant is characterized by the activation of the mitogen-activated protein kinase pathway and inactivation of the PRKAR1a gene. The other is associated with genomic fusions involving the protein kinase C ( PRKC ) gene family. OBJECTIVE: We investigated the molecular and clinicopathologic features of previously unreported PEM cases to improve tumor classification and report new classes of PEM. METHODS: Next-generation sequencing and histomorphologic assessment was performed on 13 PEM cases. RESULTS: We identified 2 novel PEM classes. Three cases harbored PRKAR1a inactivation and genomic fusions ( ALK , NTRK , and MAP3K8 ). These tumors had overlapping histologic features with pigmented Spitz neoplasms. Three cases had genomic fusions involving PRKCB . These cases had overlapping features with PRKCA fusions but, in 2 cases, had a notable spindle cell component. LIMITATIONS: The overall sample size and amount of clinical follow-up is limited, leaving some uncertainty regarding the expected clinical course of these novel cases. CONCLUSIONS: PRKAR1a-inactivated/Spitz fusion-associated PEMs and PRKCB fusion-associated PEMs represent 2 new molecular classes of PEM.

PRAME Expression Correlates With Genomic Aberration and Malignant Diagnosis of Spitzoid Melanocytic Neoplasms.

ABSTRACT: Spitzoid melanocytic neoplasms are a diagnostically challenging class of lesions in dermatopathology. Recently, molecular assays and immunohistochemical markers have been explored as ancillary methods to assist in the diagnostic workup. Specifically, preferentially expressed antigen in melanoma (PRAME) immunohistochemistry is a nuclear stain commonly positive in melanomas, but not in nevi. This study investigates PRAME immunoreactivity (≥75% positive nuclear staining in tumor cells) in a set of 59 spitzoid melanocytic neoplasms with known clinical outcomes. We compared PRAME status with (1) the clinical outcomes, (2) the morphologic diagnoses, and (3) the status of TERT promoter mutation. Regarding clinical outcomes, 3 cases developed metastatic disease, of which 2 expressed diffusely positive PRAME staining. Of the 56 cases that did not show evidence of metastasis, 6 expressed diffusely positive PRAME staining. Morphologically, diffusely positive PRAME staining was seen in 7 of 21 cases (33.3%) diagnosed as melanoma and only 1 benign tumor 1 of 38 (2.6%). There were 4 of 8 cases with a TERT promoter mutation which were diffusely PRAME-positive compared with 4 of 51 cases without TERT promoter mutation ( P = 0.001). Our results show a statistically significant correlation between PRAME expression and the diagnosis, outcome, and TERT promoter mutation status of atypical spitzoid melanocytic neoplasms, suggesting immunohistochemistry for PRAME can help support a suspected diagnosis. However, because of occasional false-positive and negative test results, correlation with the clinical and histologic findings as well as results from other tests is needed for the interpretation of diagnostically challenging spitzoid melanocytic neoplasms.

Gender Disparities in Outpatient Management of Postlaminectomy Syndrome.

INTRODUCTION: Postlaminectomy syndrome (PLS), also known as failed back surgery syndrome, is the persistence of radicular pain in the face of surgical intervention. Despite its prevalence in 10 to 40% of spine surgery patients, outpatient pharmacologic and interventional management remains poorly characterized. METHODS: The 2007 to 2016 National Ambulatory Medical Care Survey (NAMCS) was utilized to include all outpatients diagnosed with PLS. For each visit, documented pain medications (opioids, nonsteroidal anti-inflammatory drugs [NSAIDs], neuropathic agents, etc) as well as patient demographics and comorbidities (sex, age, race, insurance coverage, and medical history) were recorded. The association between medication class and rate of prescription relative to sex was assessed in the population-weighted cohort, using propensity score matching to control for potential confounders. RESULTS: A total of 70,343 PLS patients were identified, including 36,313 (51.6%) women. After accounting for baseline demographics and comorbidity differences between male and female patients, men were 2 to 3 times more likely to be prescribed opioids (OR: 2.38; 95%CI: 2.30-2.46) and procedural interventions for PLS compared to the female cohort, while women utilized neuropathic agents (OR: 0.53; 95%CI: 0.51-0.55) and NSAIDs (OR: 0.68; 95%CI: 0.65-0.70) more frequently. CONCLUSION: Pain management in outpatients presenting with PLS-related pain consisted of higher opioid utilization for men and higher neuropathic agents and NSAIDs utilization for the female patients. CLINICAL RELEVANCE: This article is the first to shed light on disparities in pain management among patients with post-laminectomy syndrome.

Risk factors for the development of Spitz neoplasms.

BACKGROUND/OBJECTIVES: The principal environmental risk factor for conventional nevi and melanomas is ultraviolet exposure. However, little is known about genetic or environmental risk factors for developing Spitz tumors. This study investigates risk factors associated with Spitz neoplasms. METHODS: Patients with Spitz tumors seen at Northwestern Memorial Hospital and Lurie Children's Hospital were surveyed with a 16-item questionnaire about environmental and inherited factors. Spitz tumor patients were compared to a pediatric control cohort from a similar clinical setting. This was supplemented with a meta-analysis of genetic and environmental causes of Spitz neoplasms. RESULTS: One hundred and six Spitz and 58 control surveys were obtained and no statistically significant differences in genetic or environmental risk factors were found between Spitz and control groups. CONCLUSION: Our data and meta-analysis suggest that typical risk factors associated with melanoma are not significantly associated with Spitz tumors. Identification of relevant genetic or environmental risk factors will likely require larger and population-based studies.

Off-Label studies on anakinra in dermatology: a review.

PURPOSE: Anakinra (Kineret®) is an interleukin-1 receptor antagonist (IL-1Ra) FDA approved for use in rheumatoid arthritis and in neonatal-onset multisystem inflammatory disease (NOMID). It has been used off-label for a variety of dermatologic conditions. A review of the available studies and cases of these off-label uses would be valuable to the dermatologist considering alternative treatments for these oftentimes poorly studied conditions. MATERIALS AND METHODS: The PubMed/MEDLINE, EMBASE, Scopus, and ClinicalTrials.gov databases were searched with the term 'anakinra.' Results were manually screened to identify published data on off-label uses of anakinra in dermatologic conditions and systemic conditions with prominent dermatologic manifestations. RESULTS: Anakinra appears to show efficacy for numerous dermatologic conditions, with the strongest evidence for hidradenitis suppurativa, Bechet's disease, Muckle-Wells syndrome, and SAPHO syndrome. Case reports and case series data are available for numerous other dermatologic conditions. CONCLUSION: Anakinra is a potential option for patients with certain difficult-to-treat dermatologic diseases, given its relatively benign adverse effect profile and its effectiveness in a wide array of conditions. Overall, anakinra appears to be a promising option in the treatment of numerous dermatologic inflammatory conditions refractory to first line therapies, but further and higher-quality data is needed to clarify its therapeutic role.

Parakeratosis and pagetoid melanocytosis in the evaluation of dysplastic nevi and melanoma.

BACKGROUND: It is our experience that parakeratosis with pagetosis is common in early melanoma when there is no history of trauma in the anatomical site. In lesions where the differential diagnosis includes dysplastic nevus (DN) and melanoma, we hypothesize that parakeratosis may be a marker for cases in which immunohistochemistry (IHC) may identify occult pagetosis. METHODS: We performed a retrospective case-control study on cases with a histologic differential diagnosis of DN versus melanoma, including 423 cases with parakeratosis and 125 cases without parakeratosis. IHC staining (Mart-1 and/or Sox-10) was performed in all cases. The frequency of pagetosis and diagnostic upgrades in the cases versus the controls was calculated. RESULTS: The presence of parakeratosis was significantly associated with pagetosis (p < 0.0001). Diagnostic upgrades were more frequent in the cases with parakeratosis versus controls without parakeratosis (p = 0.0029). In the favored moderate DN group, 56% of cases were upgraded compared to 30% of the controls (p = 0.0017). In the favored mild DN and severe DN groups, there were more case upgrades compared to the controls (p = 0.1386, p = 0.2738). CONCLUSIONS: Parakeratosis may be a useful marker to identify lesions with occult pagetosis for which IHC would be appropriate and may result in a diagnostic upgrade.

Benign and Intermediate-grade Melanocytic Tumors With BRAF Mutations and Spitzoid Morphology: A Subset of Melanocytic Neoplasms Distinct From Melanoma.

The current classification of Spitz neoplasms in the World Health Organization (WHO), Fourth Edition defines Spitz neoplasms as melanocytic proliferations with characteristic Spitz morphology and a Spitz-associated genomic fusion or HRAS mutation. In contrast, melanocytic neoplasms with BRAF mutations are considered typical of common acquired nevi, dysplastic nevi, and melanomas from intermittent sun-damaged skin. However, increased utilization of ancillary testing methods such as BRAFV600E immunohistochemistry and sequencing studies have made apparent a subgroup of benign-grade and intermediate-grade melanocytic neoplasms with Spitzoid morphology that harbor BRAFV600E mutations. We refer to these cases as BRAF mutated and morphologically Spitzoid (BAMS) nevi and tumors. Two experienced dermatopathologists reviewed a series of 36 BAMS nevi/tumors. Cases in which a diagnosis of melanoma was favored were excluded. The histomorphologic, clinical, and molecular findings were assessed by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing using validated gene panels. Characteristics of BAMS nevi/tumors were compared with a control set of Spitz tumors with previously reported fusion proteins. BAMS nevi/tumors had a decreased proportion of Kamino bodies (P=0.03) and a higher proportion of cytoplasmic pigmentation (P<0.00001). There were no differences in other morphologic features such as the silhouette, epidermal hyperplasia, pagetosis, and cytologic atypia compared with fusion-induced Spitz tumors. In 6/17 cases where next-generation sequencing studies were available, recurrent mutations in the KMT gene family were seen. This was higher than the proportion of such mutations seen in fusion Spitz tumors and lower than the frequency in cutaneous melanoma.

Impact of Next-generation Sequencing on Interobserver Agreement and Diagnosis of Spitzoid Neoplasms.

Atypical Spitzoid melanocytic tumors are diagnostically challenging. Many studies have suggested various genomic markers to improve classification and prognostication. We aimed to assess whether next-generation sequencing studies using the Tempus xO assay assessing mutations in 1711 cancer-related genes and performing whole transcriptome mRNA sequencing for structural alterations could improve diagnostic agreement and accuracy in assessing neoplasms with Spitzoid histologic features. Twenty expert pathologists were asked to review 70 consultation level cases with Spitzoid features, once with limited clinical information and again with additional genomic information. There was an improvement in overall agreement with additional genomic information. Most significantly, there was increase in agreement of the diagnosis of conventional melanoma from moderate (κ=0.470, SE=0.0105) to substantial (κ=0.645, SE=0.0143) as measured by an average Cohen κ. Clinical follow-up was available in all 70 cases which substantiated that the improved agreement was clinically significant. Among 3 patients with distant metastatic disease, there was a highly significant increase in diagnostic recognition of the cases as conventional melanoma with genomics (P<0.005). In one case, none of 20 pathologists recognized a tumor with BRAF and TERT promoter mutations associated with fatal outcome as a conventional melanoma when only limited clinical information was provided, whereas 60% of pathologists correctly diagnosed this case when genomic information was also available. There was also a significant improvement in agreement of which lesions should be classified in the Spitz category/WHO Pathway from an average Cohen κ of 0.360 (SE=0.00921) to 0.607 (SE=0.0232) with genomics.

Novel insights into the pathogenesis and treatment of NRAS mutant melanoma.

INTRODUCTION: NRAS was the first mutated oncogene identified in melanoma and is currently the second most common driver mutation in this malignancy. For patients with NRASmutant advanced stage melanoma refractory to immunotherapy or with contraindications to immune-based regimens, there are few therapeutic options including low-efficacy chemotherapy regimens and binimetinib monotherapy. Here, we review recent advances in preclinical studies of molecular targets for NRAS mutant melanoma as well as the failures and successes of early-phase clinical trials. While there are no targeted therapies for NRAS-driven melanoma, there is great promise in approaches combining MEK inhibition with inhibitors of the focal adhesion kinase (FAK), inhibitors of autophagy pathways, and pan-RAF inhibitors. AREAS COVERED: This review surveys new developments in all aspects of disease pathogenesis and potential treatment - including those that have failed, stalled, or progressed through various phases of preclinical and clinical development. EXPERT OPINION: There are no currently approved targeted therapies for BRAF wild-type melanoma patients harboring NRAS driver mutations though an array of agents are in early phase clinical trials. The diverse strategies taken exploit combined MAP kinase signaling blockade with inhibition of cell cycle mediators, inhibition of the autophagy pathway, and alteration of kinases involved in actin cytoskeleton signaling. Future advances of developmental therapeutics into late stage trials may yield new options beyond immunotherapy for patients with advanced stage disease and NRAS mutation status.

Pigmented Epithelioid Melanocytoma: Morphology and Molecular Drivers.

Pigmented epithelioid melanocytoma (PEM) was originally described based on keen morphologic analysis identifying a group of melanocytic tumors sharing heavily pigmented epithelioid melanocytes. It is defined as heavily pigmented epithelioid, spindled, and dendritic melanocytes with characteristic vesicular nuclei, prominent nucleoli, and melanophages. PEM often involves regional lymph nodes. Recent advances in molecular analysis have allowed for subclassification of PEM into more specific subsets of melanocytic tumors. The most common subsets include PRKCA fusions, which result in pure PEMs with sheets of monomorphic epithelioid melanocytes, and PEMs with combined pattern and mutations in both PRKAR1A and BRAF.

Off-label Studies on the Use of Ruxolitinib in Dermatology.

PURPOSE: Ruxolitinib (Jakafi) is a Janus kinase 1 and 2 small molecule inhibitor that the Food and Drug Administration approved for myelofibrosis and polycythemia vera. It has been expanded to off-label treatment for a variety of dermatologic conditions, with several clinical trials ongoing. A review of available studies and cases of off-label uses was performed to guide clinicians seeking evidence on the efficacy of this Janus kinase inhibitor for dermatologic disorders. MATERIALS AND METHODS: PubMed/MEDLINE, EMBASE, Scopus, and ClinicalTrials.gov databases were searched with the term "ruxolitinib," and results were manually reviewed to identify published data on off-label uses of ruxolitinib. Studies included are structured by quality of evidence available. RESULTS: Ruxolitinib may have utility in the treatment of atopic dermatitis, psoriasis, and vitiligo, with data from open-label and randomized trials supporting efficacy of topical formulations. Evidence of utility for alopecia areata is mixed and differs depending on topical versus oral form. Evidence for numerous other conditions is available through case reports and case series. CONCLUSIONS: There is growing evidence supporting potential off-label use of oral and topical ruxolitinib for a wide range of skin conditions. There are several ongoing investigations of ruxolitinib use in dermatology that will undoubtedly better define its efficacy and appropriate use in dermatology.

Readability of online patient education materials for juvenile dermatomyositis.

In this study, we sought to analyze the readability of online patient education materials (PEMs) related to juvenile dermatomyositis (JDM). We analyzed the top 100 Google results and using six different readability scores, found 53 PEMs which had an average grade reading level of 17.4 (graduate level). PEMs by health care providers were written at higher grade levels than those by non-health care providers. Our findings demonstrate a clear need for online JDM PEMs that are written at an appropriate reading level and can be comprehended by patients and families of all levels of health literacy.

Off-label studies on tofacitinib in dermatology: a review.

PURPOSE: Tofacitinib citrate is an oral Janus kinase 1/3 inhibitor approved for rheumatoid arthritis, ulcerative colitis, and active psoriatic arthritis. Tofacitinib is being increasingly used off-label for dermatological conditions, with varying efficacy across recent studies. A review of these studies will be a helpful resource for dermatologists considering the use of tofacitinib for conditions refractory to first-line therapies. MATERIALS AND METHODS: MEDLINE, Embase, CINAHL Plus, Cochrane Library, Scopus, Web of Science, Clinicaltrials.gov, and the WHO International Clinical Trials Registry Platform were all searched for articles and trials mentioning the term 'tofacitinib', then manually reviewed to identify published data on off-label uses of tofacitinib. The article was structured according to the quality of the evidence available. RESULTS: Tofacitinib appears to show strong efficacy for numerous dermatologic conditions. Randomized controlled trial data is available for atopic dermatitis, alopecia areata, and plaque psoriasis. Case report and case series data is available for numerous other dermatologic conditions. CONCLUSION: While tofacitinib has a wide array of immunoregulatory properties, making it a possible candidate for treating many dermatologic conditions refractory to other treatments, further testing is needed to better characterize its efficacy and utility moving forward, as well as its safety and adverse effect profile.

US Prescription trends of antihistamines for atopic dermatitis, 2011-2016.

Antihistamine use for primary treatment of atopic dermatitis (AD) is not recommended, but current guidelines state that sedating antihistamines are favored over non-sedating antihistamines for relief of burdensome pruritus. We analyzed the National Ambulatory Medical Care Survey data to compare use of antihistamines between dermatologists and non-dermatologists. Overall, dermatologists are more likely to prescribe sedating than non-sedating antihistamines when compared to non-dermatologists (P < .001, δabs  = 0.45). Patients under 21 years old (P = .03, δabs  = 0.10) and Black patients (P < .001, δabs  = 0.19) were also more likely to receive sedating antihistamines than non-sedating antihistamines. These findings highlight the differential prescribing practices for atopic dermatitis among physicians.

Lung Cancer Survival in Patients With Autoimmune Disease.

Importance: Patients with autoimmune disease and lung cancer pose a multidisciplinary treatment challenge, particularly with the advent of immunotherapy. However, the association between autoimmune disease and lung cancer survival is largely unknown. Objective: To determine the association between autoimmune disease and lung cancer survival. Design, Setting, and Participants: Retrospective cohort study between 2003 and 2019 at a single academic medical center (Northwestern University). A query of the Northwestern Medicine Enterprise Data Warehouse identified 349 patients with lung cancer and several autoimmune diseases. Types of lung cancers included small cell, adenocarcinoma, squamous cell carcinoma, non-small cell not otherwise specified, and large cell carcinoma. Autoimmune diseases included rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, myositis, and Sjögren syndrome. Inclusion criteria were biopsy-confirmed lung cancer, autoimmune diagnosis confirmed by a rheumatologist, and death or an encounter listed in the electronic medical record within 2 years of study end. A control group of patients with biopsy-proven lung cancer but without autoimmune disease was identified. Data analysis was conducted from March to July 2020. Exposure: Presence of autoimmune disease. Main Outcomes and Measures: Overall survival and progression-free survival in patients with autoimmune disease. The hypothesis was that patients with autoimmune disease would have worse progression-free survival and overall survival compared with patients in the control group. Results: Of the original 349 patients, 177 met inclusion criteria. Mean (SD) age at lung cancer diagnosis was 67.0 (10.0) years and 136 (76.8%) were women. Most common autoimmune diseases were rheumatoid arthritis (97 [54.8%]), systemic sclerosis (43 [24.3%]), and systemic lupus erythematous (15 [8.5%]). Most common lung cancers were adenocarcinoma (99 [55.9%]), squamous cell carcinoma (29 [16.4%]), and small cell lung cancer (17 [9.6%]). A total of 219 patients (mean [SD] age at diagnosis, 65.9 [4.1] years; 173 [79.0%]) were identified as having lung cancer without autoimmune disease and included in the control cohort. Compared with patients in the control group, patients with autoimmune disease experienced no difference in overall survival (log-rank P = .69). A total of 126 patients (69.5%) with autoimmune disease received standard of care vs 213 patients (97.3%) in the control group (P < .001). No individual autoimmune disease was associated with worse prognosis, even among patients with underlying interstitial lung disease. Conclusions and Relevance: Compared with institutional controls, patients with autoimmune disease experienced no difference in survival despite the fact that fewer patients in this group received standard-of-care treatment. No individual autoimmune disease was associated with worse prognosis. Future multicenter prospective trials are needed to further evaluate autoimmune disease and lung cancer survival.

Wireless, skin-interfaced sensors for compression therapy.

Therapeutic compression garments (TCGs) are key tools for the management of a wide range of vascular lower extremity conditions. Proper use of TCGs involves application of a minimum and consistent pressure across the lower extremities for extended periods of time. Slight changes in the characteristics of the fabric and the mechanical properties of the tissues lead to requirements for frequent measurements and corresponding adjustments of the applied pressure. Existing sensors are not sufficiently small, thin, or flexible for practical use in this context, and they also demand cumbersome, hard-wired interfaces for data acquisition. Here, we introduce a flexible, wireless monitoring system for tracking both temperature and pressure at the interface between the skin and the TCGs. Detailed studies of the materials and engineering aspects of these devices, together with clinical pilot trials on a range of patients with different pathologies, establish the technical foundations and measurement capabilities.