Sensitization of osteosarcoma to irradiation by targeting nuclear FGFR1.

Over the past 25 years, chemotherapy regimens for osteosarcoma have failed to improve the 65-70% long-term survival rate. Radiation therapy is generally ineffective except for palliative care. We here investigated whether osteosarcoma can be sensitized to radiation therapy targeting specific molecules in osteosarcoma. Large-scale RNA sequencing analysis in osteosarcoma tissues and cell lines revealed that FGFR1 is the most frequently expressed receptor tyrosine kinase in osteosarcoma. Nuclear FGFR1 (nFGFR1) was observed by subcellular localization assays. The functional studies using a FGFR1IIIb antibody or small molecule FGFR1 inhibitors showed that nFGFR1, but not membrane-bound FGFR1, induces G2 cell-cycle checkpoint adaptation, cell survival and polyploidy following irradiation in osteosarcoma cells. Further, the activation of nFGFR1 induces Histone H3 phosphorylation at Ser 10 and c-jun/c-fos expression to contribute cell survival rendering radiation resistance. Furthermore, an in vivo mouse study revealed that radiation resistance can be reversed by the inhibition of nFGFR1. Our findings provide insights into the potential role of nFGFR1 to radiation resistance. Thus, we propose nFGFR1 could be a potential therapeutic target or a biomarker to determine which patients might benefit from radiation therapy.

Improving the robustness of a catalyzed hairpin assembly with a three-arm nanostructure for nonenzymatic signal amplification.

Kinetically trapped hairpin DNA has great potential to dynamically build nanostructures, which can be initiated by sequence-specific nucleic acids. The branched junction, which has a multi-arm structure, is a representative nanostructure of DNA. In this study, we report a nonenzymatic and isothermal signal amplification accompanied by building a 3-arm structure based on a catalyzed hairpin DNA assembly (3-CHA). We improved the signal-to-background ratio of the 3-CHA by suppressing the leakage pathway of 3-CHA, thus eliminating unfavorable reaction sites exposed in the single-stranded region of hairpin DNAs. Background and amplified signals were analyzed with gel electrophoresis and real-time fluorescence monitoring. The limit of detection of the developed 3-CHA was estimated to be 29.3 pM for catalyst DNA at room temperature. Supported by the reduced leakage signal, the implemented 3-CHA showed great potential for detecting low concentrations of target DNA.

Appropriate use criteria for ancillary diagnostic testing in dermatopathology: New recommendations for 11 tests and 220 clinical scenarios from the American Society of Dermatopathology Appropriate Use Criteria Committee.

BACKGROUND: Appropriate use criteria (AUC) provide patient-centered physician guidance in test selection. An initial set of AUC was reported by the American Society of Dermatopathology (ASDP) in 2018. AUC reflect evidence collected at single timepoints and may be affected by evolving evidence and experience. The objective of this study was to update and expand AUC for selected tests. METHODS: RAND/UCLA (RAND Corporation [Santa Monica, CA]/University of California Los Angeles) methodology used includes the following: (a) literature review; (b) review of previously rated tests and previously employed clinical scenarios; (c) selection of previously rated tests for new ratings; (d) development of new clinical scenarios; (e) selection of additional tests; (f) three rating rounds with feedback and group discussion after rounds 1 and 2. RESULTS: For 220 clinical scenarios comprising lymphoproliferative (light chain clonality), melanocytic (comparative genomic hybridization, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, telomerase reverse transcriptase promoter), vascular disorders (MYC), and inflammatory dermatoses (periodic acid-Schiff, Gömöri methenamine silver), consensus by panel raters was reached in 172 of 220 (78%) scenarios, with 103 of 148 (70%) rated "usually appropriate" or "rarely appropriate" and 45 of 148 (30%), "appropriateness uncertain." LIMITATIONS: The study design only measures appropriateness. Cost, availability, test comparison, and additional clinical considerations are not measured. The possibility that the findings of this study may be influenced by the inherent biases of the dermatopathologists involved in the study cannot be excluded. CONCLUSIONS: AUC are reported for selected diagnostic tests in clinical scenarios that occur in dermatopathology practice. Adhering to AUC may reduce inappropriate test utilization and improve healthcare delivery.

Adult restoration of Shank3 expression rescues selective autistic-like phenotypes.

Because autism spectrum disorders are neurodevelopmental disorders and patients typically display symptoms before the age of three, one of the key questions in autism research is whether the pathology is reversible in adults. Here we investigate the developmental requirement of Shank3 in mice, a prominent monogenic autism gene that is estimated to contribute to approximately 1% of all autism spectrum disorder cases. SHANK3 is a postsynaptic scaffold protein that regulates synaptic development, function and plasticity by orchestrating the assembly of postsynaptic density macromolecular signalling complex. Disruptions of the Shank3 gene in mouse models have resulted in synaptic defects and autistic-like behaviours including anxiety, social interaction deficits, and repetitive behaviour. We generated a novel Shank3 conditional knock-in mouse model, and show that re-expression of the Shank3 gene in adult mice led to improvements in synaptic protein composition, spine density and neural function in the striatum. We also provide behavioural evidence that certain behavioural abnormalities including social interaction deficit and repetitive grooming behaviour could be rescued, while anxiety and motor coordination deficit could not be recovered in adulthood. Together, these results reveal the profound effect of post-developmental activation of Shank3 expression on neural function, and demonstrate a certain degree of continued plasticity in the adult diseased brain.

Risk factors for developing post-thymectomy myasthenia gravis in patients with thymoma.

BACKGROUND: Thymectomy is required for the treatment of thymoma-associated myasthenia gravis (MG). However, MG may develop only after thymectomy, a condition known as post-thymectomy MG. This study aimed to investigate the risk factors for post-thymectomy MG in patients with thymoma. METHODS: We retrospectively identified 235 patients with thymoma who underwent thymectomy at a single hospital from January 2008 to December 2017: 44 with preoperatively diagnosed MG were excluded, leaving 191 patients in the final analysis. Univariable survival analyses using Cox proportional hazards regression model and Kaplan-Meier estimate were conducted to identify risk factors for post-thymectomy MG. RESULTS: Post-thymectomy MG developed in 4.2% (8/191) of the patients with thymoma between 18 days and 108 mo after surgery. Hazard ratios (HRs) of pre- and postoperative anti-acetylcholine receptor antibody (AChR-Ab) titers were 2.267 (P = .002) and 1.506 (P < .001), respectively. Patients with extended thymectomy had a low chance of post-thymectomy MG (HR 0.035, P = .007). Larger thymoma (HR, 1.359; P = .005) and type A or AB thymoma according to World Health Organization histological classification (HR, 11.92; P = .021) were associated with higher chances of post-thymectomy MG. Within the subgroup of preoperatively AChR-Ab seropositive patients, post-thymectomy MG developed in 22.2% (6/27). CONCLUSIONS: Pre- and postoperative AChR-Ab levels should be measured in patients with thymoma. A large thymoma and partial thymectomy appear to be associated with a higher probability of post-thymectomy MG.

Chronic stress has lasting effects on improved cued discrimination early in extinction.

Chronic stress typically leads to deficits in fear extinction when tested soon after chronic stress ends. Given the importance of extinction in updating fear memories, the current study examined whether fear extinction was impaired in rats that were chronically stressed and then given a break from the end of chronic stress to the start of fear conditioning and extinction. Male rats were chronically stressed by restraint (6 h/d/21 d) and tested soon (termed immediate, STR-IMM), or 3 or 6 wk after a rest period from restraint (termed rest or "R," STR-R3, STR-R6). In Experiment 1, STR-R3 and STR-R6 discriminated between the cue and nonshock context better than STR-IMM or control. Interestingly, STR-IMM showed high freezing to the nonshock context. Consequently, Experiment 2 investigated whether STR-IMM generalized across contexts, which was not supported. Experiment 3 determined whether STR-IMM were susceptible to second-order conditioning to a novel context, but showed that the level of second-order conditioning was similar for all groups. These findings reveal that rats exposed to chronic stress and then given a rest period of 3 or 6 wk, express unique fear extinction profiles compared to control and STR-IMM. Specifically, STR-R demonstrated excellent cue and context discrimination during extinction, and perhaps showed a stress inoculation effect. For STR-IMM, the heightened freezing under these extensive acclimation parameters was not attributed to generalization nor to second-order fear conditioning to "safe" contexts and, instead, may reflect hypervigilance.

TERT and TERT promoter in melanocytic neoplasms: Current concepts in pathogenesis, diagnosis, and prognosis.

BACKGROUND AND OBJECTIVE: Located on chromosome locus 5p15.33, telomerase reverse transcriptase (TERT or hTERT) encodes the catalytic subunit of telomerase which permits lengthening and preservation of telomeres following mitosis. Mutations in TERT promoter (TERT-p) upregulate expression of TERT, allowing survival of malignant cells and tumor progression in wide variety of malignancies including melanoma. The objective of this review is to examine the roles of TERT and TERT-p in the pathogenesis, diagnosis, and prognostication of cutaneous melanoma. METHODS: All studies of TERT or TERT-p in cutaneous melanocytic neoplasms with the following inclusion criteria were reviewed: publication date between 2010 and 2019, English language, and series of ≥3 cases were reviewed for evidence supporting the role of TERT in pathogenesis, diagnosis, and prognosis. Studies with <3 cases or focused primarily on mucosal or uveal melanocytic tumors were excluded. RESULTS AND CONCLUSION: TERT-p mutations are frequent in chronic and non-chronic sun damage melanoma and correlate with adverse prognosis, inform pathogenesis, and may provide diagnostic support. While TERT-p mutations are uncommon in acral melanoma, TERT copy number gains and gene amplification predict reduced survival. Among atypical spitzoid neoplasms, TERT-p mutations identify biologically aggressive tumors and support the diagnosis of spitzoid melanoma. TERT-p methylation may have prognostic value in pediatric conventional melanoma and drive tumorigenesis in melanoma arising within congenital nevi. Finally, TERT-p mutations may aid in the differentiation of recurrent nevi from recurrent melanoma.

Use of the Ciliation Index to Distinguish Invasive Melanoma From Associated Conventional Melanocytic Nevi.

Our understanding of melanoma precursors and progression to melanoma has developed as a result of advances in the field of molecular diagnostics. We now better understand the potential for genetic heterogeneity within a single lesion. Combined tumors can pose a diagnostic challenge when deciding the line between benign and malignant, which in turn has direct implications for patient management. Primary cilia (PC) are ubiquitous sensory organelles that have essential functions in cellular proliferation, differentiation, and development. The ciliation index (percentage of ciliated melanocytes) has been shown to reliably differentiate melanoma, which fail to ciliate, from melanocytic nevi, which retain PC. We therefore analyzed the potential for using the ciliation index to differentiate benign and malignant components in combined melanocytic lesions. We collected patient samples (n = 10) of unequivocal combined lesions with both melanoma and associated nevus components. Melanocytes were highlighted with SOX10 and costained with gamma-Tubulin and acetylated alpha-Tubulin to highlight the basal body and cilium, respectively. The number of melanocytes retaining cilia under high-power microscopy was examined. The melanoma component had average of 4% ciliation (SD: 7%), whereas the associated nevus component was significantly higher with 59% ciliation (SD: 17%). These data show that PC may be a reliable means of distinguishing benign from malignant components within a single tumor. The ciliation index may be a helpful tool in distinguishing challenging cases of combined lesions of melanoma in situ with a dermal nevus component from invasive melanoma, thus promoting improved staging and clinical management.

Prevalence, Antibiotic-Resistance, and Virulence Characteristics of Vibrio parahaemolyticus in Restaurant Fish Tanks in Seoul, South Korea.

Vibrio parahaemolyticus is a marine bacterium that causes foodborne diarrhea. Many seafood restaurants keep live fish and shellfish in fish tanks for use in raw seafood dishes; thus, the present study aimed to investigate the prevalence, antibiotic-resistance, and virulence characteristics exhibited by V. parahaemolyticus detected in restaurant fish-tank water samples collected in Seoul, South Korea. Fish-tank water samples were collected from 69 restaurants in Seoul, and screened for the presence of V. parahaemolyticus via both a commercial detection kit, and a real-time polymerase chain reaction (RT-PCR) to detect the toxR gene. Antibiotic susceptibility and virulence determinants of V. parahaemolyticus isolates were evaluated and identified using standard disk-diffusion and RT-PCR methods, respectively. Thirty-five (50.7%) of the 69 analyzed water samples were found to be contaminated with V. parahaemolyticus. Those isolates were most often resistant to ampicillin (51.4% of isolates), followed by amikacin and tetracycline (11.4%), and ceftazidime (8.6%). Thirty (85.7%) out of the 35 isolates carried all four cytotoxicity-inducing type III secretion system 1 (T3SS1) genes [specifically, 34 (97.1%), 33 (94.3%), 35 (100%), and 32 (91.4%) isolates carried genes encoding the VP1670, VP1686, VP1689, and VP1694 T3SS1 proteins, respectively]. The type VI secretion systems (T6SS1 and T6SS2) genes were also detected in 11 (31.4%) and 27 (77.1%) isolates, respectively. However, virulence determinants such as the hemolysin (tdh and trh), urease (ureC), T3SS2α, or T3SS2ß genes that are known to be associated with enterotoxicity were not detected in all isolates. Although some known major virulence genes were not detected in the V. parahaemolyticus isolates, the results of this study indicate that restaurant fish tanks are a potential source of antibiotic-resistant V. parahaemolyticus. The presented data support the need for strict guidelines to regulate the maintenance of restaurant fish tanks to prevent antibiotic-resistant foodborne vibriosis.

Effects of a 4-Week Short-Foot Exercise Program on Gait Characteristics in Patients With Stage II Posterior Tibial Tendon Dysfunction.

CONTEXT: Clinically, it has been suggested that increased activation of intrinsic foot muscles may alter the demand of extrinsic muscle activity surrounding the ankle joint in patients with stage II posterior tibial tendon dysfunction. However, there is limited empirical evidence supporting this notion. OBJECTIVE: The purpose of this study was to investigate the effects of a 4-week short-foot exercise (SFE) on biomechanical factors in patients with stage II posterior tibial tendon dysfunction. DESIGN: Single-group pretest-posttest. SETTING: University laboratory. PARTICIPANTS: Fifteen subjects (8 males and 7 females) with stage II posterior tibial tendon dysfunction who had pain in posterior tibial tendon, pronated foot deformity (foot posture index ≥+6), and flexible foot deformity (navicular drop ≥10 mm) were voluntarily recruited. INTERVENTION: All subjects completed a 4-week SFE program (15 repetitions × 5 sets/d and 3 d/wk) of 4 stages (standing with feedback, sitting, double-leg, and one-leg standing position). MAIN OUTCOME MEASURES: Ankle joint kinematics and kinetics and tibialis anterior and fibularis longus muscle activation (% maximum voluntary isometric contraction) during gait were measured before and after SFE program. Cohen d effect size (ES [95% confidence intervals]) was calculated. RESULTS: During the first rocker, tibialis anterior activation decreased at peak plantarflexion (ES = 0.75 [0.01 to 1.49]) and inversion (ES = 0.77 [0.03 to 1.51]) angle. During the second rocker, peak dorsiflexion angle (ES = 0.77 [0.03 to 1.51]) and tibialis anterior activation at peak eversion (ES = 1.57 [0.76 to 2.39]) reduced. During the third rocker, the peak abduction angle (ES = 0.80 [0.06 to 1.54]) and tibialis anterior and fibularis longus activation at peak plantarflexion (ES = 1.34 [0.54 to 2.13]; ES = 1.99 [1.11 to 2.86]) and abduction (ES = 1.29 [0.50 to 2.08]; ES = 1.67 [0.84 to 2.50]) decreased. CONCLUSIONS: Our 4-week SFE program may have positive effects on changing muscle activation patterns for tibialis anterior and fibularis longus muscles, although it could not influence their structural deformity and ankle joint moment. It could produce a potential benefit of decreased tibialis posterior activation.

Role of imaging in low-grade cutaneous B-cell lymphoma presenting in the skin.

BACKGROUND: Whole-body imaging is the current standard of care for staging all patients presenting with skin lesions of B-cell lymphomas (BCLs), regardless of skin disease extent; however, supporting data are lacking. OBJECTIVE: To determine the clinical utility of imaging in the detection of systemic involvement in low-grade cutaneous BCLs in the skin. METHODS: Retrospective cohort analysis of patients presenting with cutaneous lesions of BCLs at Memorial Sloan Kettering Cancer Center and Stanford University during 1997-2016. RESULTS: At initial staging, of the 522 patients, extracutaneous disease was noted in 3.6% and 8.8% of patients with marginal zone lymphoma (MZL, n = 306) and follicle center lymphoma (FCL, n = 216) histology, respectively. In patients with systemic involvement, imaging alone identified 81.8% (9/11) of MZL cases and 89.4% of follicular lymphoma cases. In primary cutaneous MZL, 1.7% of patients subsequently had extracutaneous involvement (median follow-up 45 months), and in primary cutaneous FCL. 3.0% subsequently had extracutaneous involvement (median follow-up 47 months). LIMITATIONS: This was a retrospective study. CONCLUSION: Imaging is effective at identifying patients with systemic involvement in indolent BCLs present in the skin; however, incidence is low. After negative initial staging, primary cutaneous MZL patients may be followed clinically without routine imaging.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy, and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience, and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate" and 52 (25%) "rarely appropriate" and 43 (20%) having "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision to order specific tests rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-the AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Depletion of primary cilium in acral melanoma.

BACKGROUND: A eukaryotic cell's primary cilium (PC) is critical for cell signaling, migration and homeostasis. Primary cilium dysfunction has been demonstrated in several malignancies, but whether primary cilia loss occurs in acral melanoma has remained unknown. To address this, we examined the ciliation index (% melanocytes containing a PC) of patient-derived, biopsy-proven acral melanoma and compared these to benign acral nevi. METHODS: We generated a pilot initiative study that included six acral melanomas and seven acral nevi derived from the foot. Using fluorescent immunohistochemistry, we calculated ciliation indexes of Sox10+ melanocytes. RESULTS: Average ciliation index for acral nevi was 74.0% (SE of the mean [SEM] 3.3%) vs 9.3% for acral melanoma (SEM 5.7%), finding a statistically significant difference between the groups (P-value <.001, two tailed t test). CONCLUSION: The data show a significant loss of primary cilia in malignant acral melanoma vs benign acral nevi, suggesting that cilia may play an important role during acral melanoma formation. Our data, which should be validated by a larger study with longer follow-up period, suggest that examining ciliation index may be a useful diagnostic test when distinguishing benign acral nevi from melanoma.

Utility of CD30, Ki-67, and p53 in assisting with the diagnosis of mycosis fungoides with large cell transformation.

INTRODUCTION: Mycosis fungoides (MF) with large cell transformation (LCT) is an advanced stage of cutaneous lymphoma with a poor prognosis. Identification of LCT is critical and especially challenging when the number of large abnormal lymphocytes is near but below 25%. We propose that Ki-67 and p53 may be useful in making this diagnosis. METHODS: We identified 17 patients with advanced stage (T3 or T4) MF without LCT and 38 patients with a biopsy-confirmed new diagnosis of MF with LCT treated at our institution's cutaneous lymphoma clinic from 2012 to 2016. Seventeen patients underwent 22 biopsies with advanced stage MF (control), and 38 patients with 46 biopsies of MF with LCT were included in this study. RESULTS: The MF cohort had an average CD30 expression of 4%, while the MF-LCT cohort had an average CD30 expression of 22% (P < 0.05). The MF cohort had an average Ki-67 staining of 13%, while the MF-LCT group had an average Ki-67 staining of 57% (P < 0.05). Forty-seven percent of the MF-LCT group was positive for p53; on the other hand, none of the MF control group showed increased p53 expression (P < 0.05). DISCUSSION: While CD30 shows some value in delineating large cell transformation, Ki-67 and p53 appear to be useful immunohistochemical markers in the diagnosis of LCT.

Expression of the transcription factor ZBTB46 distinguishes human histiocytic disorders of classical dendritic cell origin.

Distinguishing classical dendritic cells from other myeloid cell types is complicated by the shared expression of cell surface markers. ZBTB46 is a zinc finger and BTB domain-containing transcription factor, which is expressed by dendritic cells and committed dendritic cell precursors, but not by plasmacytoid dendritic cells, monocytes, macrophages, or other immune cell populations. In this study, we demonstrate that expression of ZBTB46 identifies human dendritic cell neoplasms. We examined ZBTB46 expression in a range of benign and malignant histiocytic disorders and found that ZBTB46 is able to clearly define the dendritic cell identity of many previously unclassified histiocytic disease subtypes. In particular, all examined cases of Langerhans cell histiocytosis and histiocytic sarcoma expressed ZBTB46, while all cases of blastic plasmacytoid dendritic cell neoplasm, chronic myelomonocytic leukemia, juvenile xanthogranuloma, Rosai-Dorfman disease, and Erdheim-Chester disease failed to demonstrate expression of ZBTB46. Moreover, ZBTB46 expression clarified the identity of diagnostically challenging neoplasms, such as cases of indeterminate cell histiocytosis, classifying a fraction of these entities as dendritic cell malignancies. These findings clarify the lineage origins of human histiocytic disorders and distinguish dendritic cell disorders from all other myeloid neoplasms.

Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: A retrospective case-control study.

BACKGROUND: Cutaneous adverse events are common with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors. However, the nature of the specific cutaneous adverse event of dermatitis has not been investigated across various PD-1/PD-L1 inhibitors. Oncologic outcomes potentially associated with dermatitis are not well characterized. OBJECTIVE: To assess the nature of dermatitis after exposure to a PD-1/PD-L1 inhibitor and oncologic outcomes associated with dermatitis. METHODS: Retrospective, matched, case-control study conducted at a single academic center. RESULTS: The most common histologic patterns were lichenoid dermatitis (50%) and spongiotic dermatitis (40%). The overall tumor response rate was 65.0% for the case patients and 17.0% for the controls (P = .0007) (odds ratio, 7.3; 95% confidence interval, 2.3-23.1). The progression-free survival and overall survival times were significantly longer for the case patients than for the controls by Kaplan-Meier analysis (P < .0001 and .0203, respectively). LIMITATIONS: The retrospective design and relatively small sample size precluded matching for all cancer types. CONCLUSIONS: Lichenoid and spongiotic dermatitis associated with PD-1/PD-L1 inhibitors could be a sign of robust immune response and improved oncologic outcomes. The value of PD-1/PD-L1-related dermatitis in predicting cancer outcomes awaits investigation through prospective multicenter studies for specific cancer types.

Evidence behind the use of molecular tests in melanocytic lesions and practice patterns of these tests by dermatopathologists.

BACKGROUND: The gold standard for the diagnosis of melanocytic lesions is histologic examination. However, as histologic examination can have its limitations, there are many clinical scenarios in which additional testing may be appropriate in an attempt to render a definitive diagnosis. METHODS: A literature review for three ancillary tests-comparative genomic hybridization (CGH)/single-nucleotide polymorphism (SNP) array, fluorescence in situ hybridization (FISH), and gene expression profiling by quantitative reverse transcription polymerase chain reaction (qRT-PCR)-was compiled and current use patterns were tabulated. Survey of the practice patterns of these tests by dermatopathologists was also accessed in the attendees of the American Society of Dermatopathology Annual Meeting (Chicago, 2016). RESULTS: Here we summarize the use of these molecular tests in melanocytic lesions. We found that 54.4% of the respondents surveyed utilize (or expect consultants to utilize) molecular testing of melanocytic lesions in their practice when appropriate. CONCLUSIONS: CGH/SNP arrays, FISH testing, and qRT-PCR applied to melanocytic lesions have allowed for more accurate classification. Just over half of those surveyed use molecular testing for melanocytic lesion with the majority sending their cases out for completion of the molecular test.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate," 52 (25%) "rarely appropriate" and 43 (20%) "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision of when to order specific test rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Indeterminate Dendritic Cell Tumor: A Report of Two New Cases Lacking the ETV3-NCOA2 Translocation and a Literature Review.

Indeterminate dendritic cell tumor (IDCT) is a cutaneous proliferation of histiocytes that share morphologic and immunophenotypic properties with Langerhans cells. IDCT was recently included in the updated WHO classification of tumors of hematopoietic and lymphoid tissues. Recent studies have shown that some cases of IDCT demonstrate an ETV3-NCOA2 translocation, supporting the idea that IDCT is a clonal neoplasm. We report 2 new cases of IDCT at our institution lacking the ETV3-NCOA2 translocation. We also present a comprehensive review of reported cases of IDCT in the medical literature. Eighty-five cases of IDCT were reported in the literature between 1985 and 2016. The median age at diagnosis was 45 years. In contrast to Langerhans cell histiocytosis, IDCT is limited to the skin in the majority of cases (88%) and generally follows an indolent clinical course. Most reported lesions are cured with complete excision. However, the histologic features of IDCT and langerhans cell histiocytosis are similar. Conjoint immunostaining for CD1a and langerin is necessary for optimal classification.

Histopathologic approach to epidermotropic lymphocytic infiltrates.

Mycosis fungoides is the most common and therefore quintessential cutaneous lymphoma and is typically characterized by an epidermotropic infiltrate of atypical monoclonal CD4+ lymphocytes. Classical histopathologic findings include epidermotropism, lymphocytes with convoluted nuclear contours and surrounding perinuclear "halos," and papillary dermal fibrosis. Atypical lymphocytes may occasionally form Pautrier's microabscesses with tagging of lymphocytes along the basal keratinocytes. Unfortunately, a variety of benign inflammatory infiltrates, as well as other cutaneous lymphomas, may demonstrate some similar histopathologic findings. Herein, we review the wide array of epidermotropic T-cell lymphomas and discuss distinguishing features between these entities. We also offer an algorithmic approach utilizing histopathologic, immunophenotypic, and molecular techniques that can be used for analyzing an epidermotropic T-cell infiltrate in order to render a specific diagnosis.