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We present a 3-year-old boy with Langerhans cell histiocytosis who developed granulomatous dermatitis while taking vemurafenib. Vemurafenib currently has Food and Drug Administration approval for the treatment of BRAF V600E+ metastatic melanoma in adults, but recent discoveries of BRAF V600E in more than half of tested Langerhans cell histiocytosis lesions have prompted clinical trials of vemurafenib therapy for children with refractory, multisystem Langerhans cell histiocytosis. This report contributes to the knowledge of its potential side effects when used in children., (© 2018 Wiley Periodicals, Inc.)

Idiopathic pulmonary arterial hypertension (IPAH) is a devastating pulmonary vascular disease in which autoimmune and inflammatory phenomena are implicated. B cells and autoantibodies have been associated with IPAH and identified as potential therapeutic targets. However, the specific populations of B cells involved and their roles in disease pathogenesis are not clearly defined. We aimed to assess the levels of activated B cells (plasmablasts) in IPAH, and to characterize recombinant antibodies derived from these plasmablasts. Blood plasmablasts are elevated in IPAH, remain elevated over time, and produce IgA autoantibodies. Single-cell sequencing of plasmablasts in IPAH revealed repertoires of affinity-matured antibodies with small clonal expansions, consistent with an ongoing autoimmune response. Recombinant antibodies representative of these clonal lineages bound known autoantigen targets and displayed an unexpectedly high degree of polyreactivity. Representative IPAH plasmablast recombinant antibodies stimulated human umbilical vein endothelial cells to produce cytokines and overexpress the adhesion molecule ICAM-1. Together, our results demonstrate an ongoing adaptive autoimmune response involving IgA plasmablasts that produce anti-endothelial cell autoantibodies in IPAH. These antibodies stimulate endothelial cell production of cytokines and adhesion molecules, which may contribute to disease pathogenesis. These findings suggest a role for mucosally-driven autoimmunity and autoimmune injury in the pathogenesis of IPAH., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Inflammatory dermatoses encompass a variety of histologic patterns that affect different portions of the skin. In spongiotic, psoriasiform, lichenoid, pityriasiform, and blistering disorders, there are predominately epidermal and junctional activities with variable superficial dermal inflammation. Hypersensitivity reactions can show either epidermal or mostly dermal changes depending on whether the exposure of the exogenous allergen occurs through an external or internal route, respectively. Exceptions include erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis, where the etiology is often due to infection or ingested medications, but the histologic features are almost exclusively confined to the epidermis and dermoepidermal junction. Autoimmune disorders are unique in that lesions typically incorporate a mixture of epidermal and dermal inflammatory patterns with periadnexal inflammation, while the vast majority of vasculitis/vasculopathy and alopecia have changes limited to only the vessels and hair follicles, respectively. It is critical to recognize that a relatively limited number of histologic patterns are seen in a large array of clinical entities. Therefore, clinicopathologic correlation and careful examination of histologic details are of the utmost importance when evaluating skin biopsies for inflammatory disorders.

Despite recent insights into prostate cancer (PCa)-associated genetic changes, full understanding of prostate tumorigenesis remains elusive owing to complexity of interactions among various cell types and soluble factors present in prostate tissue. We found the upregulation of nuclear factor of activated T cells c1 (NFATc1) in human PCa and cultured PCa cells, but not in normal prostates and non-tumorigenic prostate cells. To understand the role of NFATc1 in prostate tumorigenesis in situ, we temporally and spatially controlled the activation of NFATc1 in mouse prostate and showed that such activation resulted in prostatic adenocarcinoma with features similar to those seen in human PCa. Our results indicate that the activation of a single transcription factor, NFATc1 in prostatic luminal epithelium to PCa can affect expression of diverse factors in both cells harboring the genetic changes and in neighboring cells through microenvironmental alterations. In addition to the activation of oncogenes c-MYC and STAT3 in tumor cells, a number of cytokines and growth factors, such as IL1β, IL6 and SPP1 (osteopontin, a key biomarker for PCa), were upregulated in NFATc1-induced PCa, establishing a tumorigenic microenvironment involving both NFATc1 positive and negative cells for prostate tumorigenesis. To further characterize interactions between genes involved in prostate tumorigenesis, we generated mice with both NFATc1 activation and Pten inactivation in prostate. We showed that NFATc1 activation led to acceleration of Pten null-driven prostate tumorigenesis by overcoming the PTEN loss-induced cellular senescence through inhibition of p21 activation. This study provides direct in vivo evidence of an oncogenic role of NFATc1 in prostate tumorigenesis and reveals multiple functions of NFATc1 in activating oncogenes, in inducing proinflammatory cytokines, in oncogene addiction, and in overcoming cellular senescence, which suggests calcineurin-NFAT signaling as a potential target in preventing PCa., Competing Interests: The authors declare no conflict of interest.

Background: Mantle cell lymphoma (MCL) is associated with the worst prognosis among low-grade B-cell lymphomas. While cutaneous involvement by nodal or systemic MCL is uncommon, its differentiation from primary cutaneous B-cell lymphoma (CBCL) or cutaneous involvement by other extra-cutaneous BCL is challenging as neither histomorphology nor immunophenotype can be absolutely specific. We analyzed the diagnostic utility of SOX11 immunohistochemistry in differentiating secondary cutaneous MCL from other low-grade CBCL., Methods: Immunohistochemical staining with anti-SOX11 antibody was performed on 8 cases of secondary cutaneous MCL, 16 secondary cutaneous CLL, 20 primary cutaneous MZL, 12 cutaneous FCL (6 primary, 6 secondary), 7 primary cutaneous DLBCL, leg type, 5 systemic DLBCL and 3 B-ALL. SOX11 and cyclin D1 staining were compared in secondary cutaneous MCL., Results: Nuclear SOX11 staining was seen in seven of eight cases (88%) of secondary cutaneous MCL, including a case with minimal cyclin D1 expression. All other CBCL lacked detectable nuclear SOX11 expression. The sensitivity and specificity for SOX11 in MCL were 87.5 and 100%, respectively. Both the sensitivity and specificity for combined SOX11 and cyclin D1 immunohistochemistry were 100%., Conclusion: SOX11 immunohistochemistry could be a useful adjunct in distinguishing secondary cutaneous MCL from other CBCL., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The GATA family of transcription factors is an essential regulator of cellular proliferation and differentiation. In the skin, GATA-3 is critical for epidermal stratification and maintenance of barrier function. A role for GATA-3 in the development of human cutaneous squamous cell carcinoma (SCC) is not known. Here, we investigated GATA-3 immunohistochemical staining in premalignant and invasive cutaneous SCC from sun-exposed and sun-protected skin., Methods: GATA-3 immunohistochemistry was performed on actinic keratoses (AK) (n = 19), in situ squamous cell carcinomas with actinic [SCCIS (A)] (n = 9) or bowenoid features [SCCIS (B)] (n = 17), well-, moderately and poorly differentiated SCC (n = 36), Bowenoid papulosis of the perineum (n = 15) and penile SCC (pSCC) (n = 10)., Results: We found that GATA-3 immunohistochemical staining is progressively lost in sun-exposed skin as neoplasia progresses from pre-cancerous AK to SCCIS (A), and ultimately, to SCC, which shows near absent GATA-3 staining. This reduction in GATA-3 staining is independent of histological grade in SCC. Only slight down-regulation of GATA-3 was seen in all cases of SCCIS (B) and Bowenoid papulosis, while near absent GATA-3 expression was seen in pSCC., Conclusion: We propose that decreased GATA-3 immunohistochemical staining is associated with cutaneous SCC progression on both sun-exposed and sun-protected sites., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: A novel coaxial biopsy system powered by a handheld drill has recently been introduced for percutaneous bone biopsy. This technical note describes our initial experience performing fluoroscopy-guided vertebral body biopsies with this system, compares the yield of drill-assisted biopsy specimens with those obtained using a manual technique, and assesses the histologic adequacy of specimens obtained with drill assistance., Methods: Medical records of all single-level, fluoroscopy-guided vertebral body biopsies were reviewed. Procedural complications were documented according to the Society of Interventional Radiology classification. The total length of bone core obtained from drill-assisted biopsies was compared with that of matched manual biopsies. Pathology reports were reviewed to determine the histologic adequacy of specimens obtained with drill assistance., Results: Twenty eight drill-assisted percutaneous vertebral body biopsies met study inclusion criteria. No acute complications were reported. Of the 86 % (24/28) of patients with clinical follow-up, no delayed complications were reported (median follow-up, 28 weeks; range 5-115 weeks). The median total length of bone core obtained from drill-assisted biopsies was 28 mm (range 8-120 mm). This was longer than that obtained from manual biopsies (median, 20 mm; range 5-45 mm; P = 0.03). Crush artifact was present in 11 % (3/28) of drill-assisted biopsy specimens, which in one case (3.6 %; 1/28) precluded definitive diagnosis., Conclusions: A drill-assisted, coaxial biopsy system can be used to safely obtain vertebral body core specimens under fluoroscopic guidance. The higher bone core yield obtained with drill assistance may be offset by the presence of crush artifact.

Stereotactic radiosurgery and percutaneous radiofrequency ablation are emerging therapies for pain palliation and local control of spinal metastases. However, the post-treatment imaging findings are not well characterized and the risk of long-term complications is unknown. We present the case of a 46-year-old woman with delayed vertebral body collapse after stereotactic radiosurgery and radiofrequency ablation of a painful lumbar metastasis. Histopathologic-MRI correlation confirmed osteonecrosis as the underlying etiology and demonstrated that treatment-induced vascular fibrosis and tumor progression can have identical imaging appearances., (© The Author(s) 2015.)

The OnControl coaxial biopsy system (Vidacare Corporation, Shavano Park, TX) includes an inner diamond-tipped access needle and hollow biopsy needle that engage with a battery-powered hand drill. Herein, we report the use of this novel device to perform two CT-guided percutaneous skull biopsies. Both procedures were performed without complication and facilitated a pathologic diagnosis., (© The Author(s) 2015.)

Background: Mycosis fungoides (MF) is a neoplasm of skin-homing CD4(+) helper T (TH) lymphocytes with dysregulation of TH1 and TH2 immunity. Diagnosis of MF is challenging, as there is significant morphologic overlap with other dermatologic entities., Objective: We investigated diagnostic utility of TH1- and TH2-specific markers, T-bet, and GATA-3, respectively, in MF and its reactive and neoplastic mimics., Methods: Immunohistochemical staining for CD3/T-bet and CD3/GATA-3 was performed on inflammatory dermatoses (n = 56), MF (n = 37), Sezary syndrome (SS; n = 8), and cutaneous anaplastic large cell lymphoma (C-ALCL; n = 14)., Results: Inflammatory dermatoses showed epidermal T cells predominantly expressing GATA-3, except psoriasis, which exhibited a mixed GATA-3/T-bet staining. In contrast, neoplastic T cells in patch stage MF showed markedly increased T-bet positivity with minimal GATA-3 expression. Plaque stage MF had a mixed T-bet/GATA-3 phenotype, whereas tumor stage MF and SS exhibited diffuse GATA-3 expression. C-ALCL lacked significant staining for both markers., Limitations: Sample size was relatively small., Conclusions: A predominance of T-bet(+) T cells in the epidermis support patch stage MF over dermatitis. A predominance of GATA-3(+) T cells in the dermis support CD30(+) MF with large cell transformation over C-ALCL. These stains do not allow distinction between dermatitis and cutaneous infiltrates of SS., (Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive mature T-cell leukemia with frequent cutaneous presentation, which has not been well characterized. Among the 25 T-PLLs diagnosed between 1990 and 2013 at our institution, 32% (8/25) showed cutaneous manifestations, presenting as rash, purpura, papules, and ulcers. The skin biopsies showed leukemia cutis with perivascular and periadnexal irregular, small to medium-sized lymphoid infiltrates without epidermotropism. The lymphoid infiltrates were composed of mature CD4+ T cells expressing other T-cell antigens, and a subset (48%) showed dual CD4+/CD8+ coexpression. Higher median absolute peripheral blood lymphocyte count (43.0 vs. 13.0 k/mm; P=0.031) and elevated lactate dehydrogenase levels (P=0.00018) at the time of diagnosis were significantly associated with T-PLLs with skin involvement compared with those without. The extent of bone marrow involvement (P=0.849) and overall survival (P=0.144) was similar in the 2 groups. Fluorescence in situ hybridization or karyotype revealed frequent gains of MYC (67%; n=9), loss of ATM (64%; n=11), and TCL1A rearrangement or inversion 14q (75%; n=12). Gains of TCL1A was also seen (78%; n=9), including in some cases that had concurrent TCL1A rearrangement, whereas TP53 loss was less common (30%; n=10). No correlation was seen between the immunophenotype and morphology versus the presence or absence of skin involvement. These data suggest that cutaneous involvement by T-PLL is relatively common and often associated with significant peripheral blood involvement. The frequent MYC, ATM, and TCL1A alterations identified support that these genes are integral to the pathogenesis of T-PLL.

Human T-cell lymphotropic virus type 1 is associated with adult T-cell leukemia/lymphoma (ATLL). Published series of ATLLs seen at a United States medical institution are rare. We present the features of 4 ATLLs diagnosed at our North American tertiary care medical center from 1990 to 2012. Despite the absence of a history of origin from an endemic region, all our ATLLs demonstrated evidence of human T-cell lymphotropic virus type 1 infection. Central nervous system (CNS) involvement by ATLL was uncommon in our series, and represented only 1.6% (1/64) of all CNS B-cell or T-cell lymphomas diagnosed over a 20+ year period at our institution. Review of the medical literature reveals that the majority of CNS-involved ATLLs present with the lymphoma or acute subtype, and complete remission is difficult to achieve in these cases. CNS involvement frequently occurs with a systemic disease, which carries an aggressive clinical course with poor prognosis. In addition, CNS involvement by ATLL can be the initial presentation or seen with relapsed disease, can be the only site or be associated with other tissue sites of involvement, and may manifest with variable clinical signs/symptoms. Our retrospective study reveals that ATLLs are rare mature T-cell lymphomas in a native North American population, but the clinical and histopathologic features of ATLLs from this nonendemic region are similar to those seen from other endemic regions. Early recognition of these rare ATLLs involving uncommon sites, such as the CNS, will help optimize treatment for these infrequent mature T-cell lymphomas.

Purpose: Evidence shows acanthosis nigricans is often associated with hyperinsulinemia and may indicate increased risk of type 2 diabetes mellitus. The purpose of this study was to determine the association of acanthosis nigricans with type 2 diabetes risk factors and disease in young persons., Methods: We conducted a cross-sectional study in the Research in Outpatient Settings Network, a practice-based research network in southwestern US communities. Participating clinicians (N = 96) collected data on children and young adults aged 7 to 39 years seen during a 2-week sampling period. The main outcomes were the prevalence of acanthosis nigricans, type 2 diabetes risk factors (ethnicity, family history of type 2 diabetes, hypertension, overweight/obesity), type 2 diabetes, and the relationships among these., Results: Among 1,133 patients sampled, risk factors for type 2 diabetes were common: 69% had a family history of the disease; 3% of children (aged 7 to 19 years) and 12% of adults had hypertension; 43% of children and 73% of adults were overweight or obese; and 80% were members of ethnic minorities. Acanthosis nigricans was found in 17% of children and 21% of adults. Among children and adults alike, the more type 2 diabetes risk factors that were present, the higher the prevalence of acanthosis nigricans (P <.001). The prevalence ratio for type 2 diabetes in patients with acanthosis nigricans was 1.97 (95% confidence interval, 1.18-3.27; P = .01) after controlling for age, body mass index, and the number of type 2 diabetes risk factors. Clinicians reported that the identification of acanthosis nigricans frequently led to discussions about lifestyle modification for decreasing the risk of type 2 diabetes., Conclusions: Patients with acanthosis nigricans are likely to have multiple risk factors for type 2 diabetes. Acanthosis nigricans may be an independent risk factor for this disease. Detection of acanthosis nigricans may help clinicians more rapidly identify high-risk individuals for diabetes counseling.

The newborn daughter of a diabetic mother developed neonatal gangrene of an upper extremity with massive muscle necrosis of the forearm, and required early dorsal and volar fasciotomies with subsequent debridements to salvage the limb. Decreased perfusion and local ischemia resulting in neonatal gangrene may result from the greater propensity for intravascular thrombosis in infants whose mothers have diabetes mellitus. While previous investigators have suggested that surgical intervention should be avoided in neonatal gangrene, in more severe cases early fasciotomy may be required to salvage a limb and avoid life-threatening complications.