Identification of a Robust Methylation Classifier for Cutaneous Melanoma Diagnosis.

Early diagnosis improves melanoma survival, yet the histopathological diagnosis of cutaneous primary melanoma can be challenging, even for expert dermatopathologists. Analysis of epigenetic alterations, such as DNA methylation, that occur in melanoma can aid in its early diagnosis. Using a genome-wide methylation screening, we assessed CpG methylation in a diverse set of 89 primary invasive melanomas, 73 nevi, and 41 melanocytic proliferations of uncertain malignant potential, classified based on interobserver review by dermatopathologists. Melanomas and nevi were split into training and validation sets. Predictive modeling in the training set using ElasticNet identified a 40-CpG classifier distinguishing 60 melanomas from 48 nevi. High diagnostic accuracy (area under the receiver operator characteristic curve = 0.996, sensitivity = 96.6%, and specificity = 100.0%) was independently confirmed in the validation set (29 melanomas, 25 nevi) and other published sample sets. The 40-CpG melanoma classifier included homeobox transcription factors and genes with roles in stem cell pluripotency or the nervous system. Application of the 40-CpG melanoma classifier to the diagnostically uncertain samples assigned melanoma or nevus status, potentially offering a diagnostic tool to assist dermatopathologists. In summary, the robust, accurate 40-CpG melanoma classifier offers a promising assay for improving primary melanoma diagnosis.

Utility of TERT Promoter Mutations for Cutaneous Primary Melanoma Diagnosis.

Telomerase reverse transcriptase (TERT) promoter mutations are commonly found in malignant melanomas but rare in melanocytic nevi. To assess its potential diagnostic utility for the distinction of melanoma from nevus, we determined the TERT promoter mutation status of 86 primary melanomas, 72 melanocytic nevi, and 40 diagnostically problematic melanocytic proliferations. Of the 86 melanomas, 67 (77.9%) were TERT-positive, defined as harboring a hotspot TERT promoter mutation at positions -124C>T, -124_125CC>TT, -138_139CC>TT, or -146C>T. Of the 72 nevi, only 1 (1.4%) was TERT-positive. Of the 40 diagnostically uncertain melanocytic proliferations, 2 (5.0%) were TERT-positive. TERT positivity as a test for melanoma versus nevus had an accuracy of 87.3% [95% confidence interval (CI), 81.1-92.1], a sensitivity of 77.9% (95% CI, 68.9-85.4), a specificity of 98.6% (95% CI, 95.8-100), a positive predictive value of 98.5% (95% CI, 95.6-100), and a negative predictive value of 78.9% (95% CI, 72.6-85.4). Our results indicate that hotspot TERT promoter mutation status may be a useful ancillary parameter for the diagnosis of melanoma. In particular, the high specificity of these mutations for melanoma indicates the presence of a TERT promoter mutation in a melanocytic neoplasm associated with diagnostic controversy, or uncertainty should increase concern for a melanoma.

The performance of telescoping fat pad biopsies for detecting systemic amyloidosis: a four and a half year retrospective analysis and brief review of the fine needle aspiration literature.

Systemic amyloidosis has historically been diagnosed by organ biopsy and Congo red staining, with reported sensitivities that exceed 90%. The abdominal fat pad fine needle aspiration (FNA), introduced in the 1970's, carries sensitivity estimates largely derived from studies with deficiencies. Patient follow-up is often unclear and proportionally low numbers of patients are verified as true negatives. Issues in other studies include only testing verified systemic amyloidosis cases. The telescoping fat pad biopsy (TFPB) is used as an alternative to FNA and is similarly carried out quickly with low morbidity. Although the two methods would seem to be comparable intuitively, this has not been established because sensitivity data for the TFPB method is scarce to non-existent. The charts of 58 consecutive patients who underwent TFPB screening for amyloidosis in a single hospital from August of 2010 to January 2015 were examined. All six TFPB positive patients were determined to be true positives. Eight TFPB negative patients were concurrently determined to have systemic amyloidosis by other methods - organ biopsy (7) and mass spectrometry (1) resulting in a 43% sensitivity. The remaining patients were categorized into 25 true negatives and 18 that were indeterminate based on clinical course and other biopsy results.

Hair Follicle Nevus Located on the Chin of an Infant: Case Report and Review of Literature.

Hair follicle nevi are rare, benign, congenital hamartomas that usually occur in the distribution of the first brachial arch. Histopathologically, the distinction between hair follicle nevus, trichofolliculoma, and accessory tragus has recently come into question, and it may be that they are all on a spectrum of the same condition. We report the case of a 7-day-old boy who presented with a "tag"-like lesion on his midline chin that had been present since birth. Biopsy of the lesion proved it to be a hair follicle nevus.

Incidental finding of cutaneous meningeal heterotopia in aplasia cutis congenita.

Aplasia cutis congenita and cutaneous meningeal heterotopia are both rare congenital conditions that most commonly occur on the scalp and may appear clinically and histologically similar. A subtype of aplasia cutis congenita, membranous aplasia cutis congenita, and cutaneous meningeal heterotopia are both proposed to result from neural tube closure errors. However, neither non-membranous nor membranous aplasia cutis congenita are known to occur together with cutaneous meningeal heterotopia in the same lesion. We report the incidental finding of cutaneous meningeal heterotopia within a lesion of aplasia cutis congenita.

Imiquimod-induced subacute cutaneous lupus erythematosus-like changes.

Imiquimod is a topical immunomodulator used to treat genital warts and cutaneous malignancies that exerts its effects via induction of proinflammatory cytokines through activation of toll-like receptor (TLR) 7. Although subacute cutaneous lupus erythematosus (SCLE) has been reported in association with multiple systemic medications, SCLE in patients treated with topical agents has not been widely reported. We report the case of a 50-year-old woman with local induction of lesions that clinically and histologically resembled SCLE following treatment with topical imiquimod.

Mucosal pemphigus vulgaris anti-Dsg3 IgG is pathogenic to the oral mucosa of humanized Dsg3 mice.

There are two major clinical subsets of pemphigus vulgaris (PV)-mucosal PV (mPV) and mucocutaneous PV (mcPV). The mPV subset exhibits anti-human desmoglein (Dsg) 3 autoantibodies that fail to recognize murine Dsg3 (mDsg3); thus, passive transfer experiments of mPV IgG into wild-type (WT) mice have been unsuccessful at inducing disease. We therefore generated a fully humanized Dsg3 (hDSG3) murine model utilizing a hDsg3 transgenic animal crossed to the mDsg3 knockout line. Expression of hDsg3 in the mucosa rescues the mDsg3 knockout phenotype. Well-characterized mPV sera bind mucosal epithelia from the hDsg3 mice, but not mucosal tissues from WT mice, as detected by indirect immunofluorescence (IF). The majority of mPV sera preferentially recognize hDsg3 compared with mDsg3 by immunoprecipitation as well. Passive transfer of mPV IgG into adult hDsg3 mice, but not WT mice, induces suprabasilar acantholysis in mucosal tissues, thus confirming the pathogenicity of mPV anti-hDsg3 IgG in vivo. Human anti-hDsg3 antibodies are detected in perilesional mucosa as well as in sera of recipient mice by IF. These findings suggest that the Dsg3 epitopes targeted by pathogenic mPV IgG are human specific. This hDsg3 mouse model will be invaluable in studying the clinical transition from mPV to mcPV.

Dermatomyositis as a presentation of neuromyelitis optica spectrum disorder.

IMPORTANCE: This is the first report of neuromyelitis optica spectrum disorder (NMOSD) associated with dermatomyositis (DM). REPORT: A 40year-old Caucasian female presented with 6months of worsening fatigue, rash, acute weakness worse in her lower extremities, and urinary retention. She was found to have both NMOSD and anti-melanoma differentiation-associated gene (MDA)5 positive DM with interstitial lung disease (ILD). She was treated aggressively and she regained her ability to ambulate. CONCLUSION: We recommend considering NMOSD in the differential diagnosis of patients with DM and other autoimmune disorders that also present with clinical signs of myelopathy.

Metastatic spiradenocarcinoma occurring in an 8-year-old boy.

We recently saw the case of an 8-year-old boy with histologic findings of spiradenocarcinoma. Malignant adnexal tumors in children are exceedingly rare, and cases of spiradenocarcinoma in children are absent in the literature. We report the case of an 8-year-old boy with metastatic spiradenocarcinoma. A biopsy 2 years before his presentation at our institution was interpreted as a benign lesion, but when the lesion regrew, a repeat biopsy was performed that demonstrated ominous findings, prompting a reexcision. This reexcision demonstrated an area with significant necrosis, many mitoses, and cellular pleomorphism apparently arising out of a sharply demarcated, adjacent, lower-grade area. The histologic features of this patient's biopsies were those of spiradenocarcinoma, potentially arising out of a preexisting spiradenoma, a finding that has not been documented previously in this age group. Staging studies demonstrated multiple bilateral pulmonary nodules, which were confirmed using thoracoscopic biopsy to be metastatic disease. His chemotherapy regimen has included several cycles of cisplatin and 5-flourouracil, with ongoing disease progression of pulmonary disease. It has been 16 months since he presented to our institution (>3 years since the appearance of his initial lesion). Imaging studies demonstrate a slowly increasing size and number of pulmonary lesions. The long-term prognosis is guarded.

9 tips to help prevent derm biopsy mistakes.

The authors--with expertise in dermatology and pathology--provide pointers that can help you improve your approach to skin biopsy.

Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma.

UNLABELLED: NRAS mutation at codons 12, 13, or 61 is associated with transformation; yet, in melanoma, such alterations are nearly exclusive to codon 61. Here, we compared the melanoma susceptibility of an NrasQ61R knock-in allele to similarly designed KrasG12D and NrasG12D alleles. With concomitant p16INK4a inactivation, KrasG12D or NrasQ61R expression efficiently promoted melanoma in vivo, whereas NrasG12D did not. In addition, NrasQ61R mutation potently cooperated with Lkb1/Stk11 loss to induce highly metastatic disease. Functional comparisons of NrasQ61R and NrasG12D revealed little difference in the ability of these proteins to engage PI3K or RAF. Instead, NrasQ61R showed enhanced nucleotide binding, decreased intrinsic GTPase activity, and increased stability when compared with NrasG12D. This work identifies a faithful model of human NRAS-mutant melanoma, and suggests that the increased melanomagenecity of NrasQ61R over NrasG12D is due to heightened abundance of the active, GTP-bound form rather than differences in the engagement of downstream effector pathways. SIGNIFICANCE: This work explains the curious predominance in human melanoma of mutations of codon 61 of NRAS over other oncogenic NRAS mutations. Using conditional "knock-in" mouse models, we show that physiologic expression of NRASQ61R, but not NRASG12D, drives melanoma formation.

Validation of the VE1 immunostain for the BRAF V600E mutation in melanoma.

BACKGROUND: BRAF mutation status, and therefore eligibility for BRAF inhibitors, is currently determined by sequencing methods. We assessed the validity of VE1, a monoclonal antibody against the BRAF V600E mutant protein, in the detection of mutant BRAF V600E melanomas as classified by DNA pyrosequencing. METHODS: The cases were 76 metastatic melanoma patients with only one known primary melanoma who had had BRAF codon 600 pyrosequencing of either their primary (n = 19), metastatic (n = 57) melanoma, or both (n = 17). All melanomas (n = 93) were immunostained with the BRAF VE1 antibody using a red detection system. The staining intensity of these specimens was scored from 0 to 3+ by a dermatopathologist. Scores of 0 and 1+ were considered as negative staining while scores of 2+ and 3+ were considered positive. RESULTS: The VE1 antibody showed a sensitivity of 85% and a specificity of 100% as compared to DNA pyrosequencing results. There was 100% concordance between VE1 immunostaining of primary and metastatic melanomas from the same patient. V600K, V600Q, and V600R BRAF melanomas did not positively stain with VE1. CONCLUSIONS: This hospital-based study finds high sensitivity and specificity for the BRAF VE1 immunostain in comparison to pyrosequencing in detection of BRAF V600E in melanomas.

Case report of drug rash with eosinophilia and systemic symptoms demonstrating human herpesvirus-6 reactivation.

Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe drug-induced hypersensitivity syndrome that presents with diffuse cutaneous eruptions, fever, and multiorgan involvement. Here we present a pediatric case of DRESS complicated by human herpesvirus (HHV)-6 reactivation. After 1 week of sulfasalazine, our patient developed a diffuse morbilliform eruption. Sulfasalazine was discontinued. The patient presented to the emergency department soon thereafter with worsening eruption, fever, rigors, facial edema, and lymphadenopathy. Methylprednisolone was initiated. Peripheral smear did not demonstrate eosinophilia but showed toxic granulation with atypical lymphocytes. Transaminase levels and white blood cell count quickly became elevated, with increased eosinophils, suggesting DRESS. During the methylprednisolone taper, our patient experienced symptom exacerbation, acute hepatitis, and HHV-6 seroconversion, indicating HHV-6 reactivation as the cause. As demonstrated by our patient, a decelerated methylprednisone taper is important because of potential symptom flaring during taper. Additionally, in the care of individuals with DRESS, HHV-6 is often tested for upon admission and not repeated. Delay in the rise of titers necessitates repeat testing.

Squamous cell carcinoma of the lip associated with adalimumab therapy for ankylosing spondylitis: a case report and review of TNF-α inhibitors and cutaneous carcinoma risk.

Adalimumab is an anti-tumor necrosis factor α (TNF-α) agent approved for the treatment of ankylosing spondylitis (AS); psoriatic arthritis; and moderate to severe cases of rheumatoid arthritis (RA), plaque psoriasis, Crohn disease, ulcerative colitis, and polyarticular juvenile idiopathic arthritis. Evidence suggests that anti-TNF-α agents may increase a patient's risk for some types of cancers, including cutaneous squamous cell carcinoma (SCC). Cutaneous nonmelanoma skin cancers (NMSCs) have occurred during treatment with etanercept, infliximab, and adalimumab in the setting of RA and psoriasis, but data related to AS are less clear. We report the case of a 29-year-old woman with AS treated with adalimumab for 2 years who developed invasive SCC of the lower lip. We advocate increased NMSC surveillance in patients undergoing treatment with anti-TNF-α agents.

Superimposed methicillin-resistant Staphylococcus aureus infection of vulvar eczematous dermatitis: a case report.

BACKGROUND: Vulvar eczematous dermatitis predisposes patients to superimposed infections, which may result in late diagnosis and architectural destruction. Methicillin-resistant Staphylococcus aureus (MRSA) infection is on the rise in genitalia and lower extremities. CASE: A 44-year-old woman presented with recurrent vulvar lesions and pain. A diagnosis of MRSA in the setting of eczema was achieved with concomitant use of photography and dermatopathologic review. Antibiotics were tailored to the resistant infection and preventative moisturization therapy was utilized. CONCLUSION: Awareness of dermatologic conditions affecting the vulva is principal in routine gynecologic care. Barrier protection of eczematous vulvar skin may prevent superficial infections. The regular use of photographic documentation and dermatopathology may decrease time to diagnosis with infrequent or rare conditions.

Granuloma annulare arising in association with pulmonary coccidioidomycosis.

Granuloma annulare (GA) is a reactive process in the dermis, related to degeneration of collagen. It may occur as an idiopathic phenomenon or in conjunction with a myriad of systemic conditions, including infectious disease. We report an interesting case of GA precipitated by pulmonary coccidioidomycosis.

Cutaneous meningioma.

Cutaneous meningioma is a rare tumor that most commonly occurs on the scalp and occurs in both congenital and acquired forms. It invokes a wide clinical differential diagnosis, but diagnosis is based on characteristic histologic and cytologic findings. Congenital lesions can often present years after birth and even in adult patients. Acquired lesions occur in adulthood. We review histologic, cytologic, and electron microscopic findings and explore how these are used to separate this entity from other entities in the differential diagnosis. While ultrastructural and cytologic findings are similar to those of more common intracranial meningiomas, these tumors exhibit a range of histologic differences. A lack of awareness of this entity precludes correct diagnosis.