Ryanne Ashley Brown, MD, MBA

All Publications

• Histopathologic and Clinical Characterization of Brentuximab Vedotin-associated Rash. The American journal of surgical pathology Narala, S., Saleem, A., Brown, R. A., Novoa, R. A., Kim, Y. H., Rieger, K. E. 2024

  Abstract

  Rash is one of the commonly observed adverse events with brentuximab vedotin (BV), a CD30-targeted antibody-drug conjugate used to treat cutaneous T-cell lymphoma (CTCL). However, clinical and histopathologic characterization of BV-associated rash (BVAR) is limited. Distinguishing BVAR from a patient's underlying CTCL can be challenging and can lead to treatment interruptions or even premature drug discontinuation. We performed a thorough clinical and histopathologic retrospective characterization of BVAR from a single institution. Utilizing polymerase chain reaction (PCR) and T-cell receptor high-throughput sequencing (TCR-HTS), we were able to isolate skin biopsy specimens from rash clinically suggestive of BVAR that also lacked a dominant TCR clone. A retrospective evaluation was performed of 26 biopsy specimens from 14 patients. Clinical features of BVAR included predominantly morbilliform or maculopapular morphology, delayed onset, and the trend toward moderate to severe classification, often requiring oral steroids. Most histopathologic specimens (25/26) showed spongiotic dermatitis as the primary reaction pattern. Many cases showed subtle findings to support a background interface or lichenoid eruption. Langerhans cell microabscesses were seen in one-fourth of specimens, and eosinophils were present in over one-half of the specimens. There were focal features mimicking CTCL, but these were not prominent. In 17 specimens with immunohistochemistry, the CD4:CD8 ratio in intraepidermal lymphocytes was relatively normal (1-6:1) in 65% (11/17) and 1:1 in 35% (6/17), demonstrating a trend toward increased CD8-positive cells compared with baseline CTCL. We have identified features that can help distinguish BVAR from a patient's CTCL, which can, in turn, help guide appropriate clinical management.

  View details for DOI 10.1097/PAS.0000000000002268

  View details for PubMedID 38907612

• Assessment of Mammalian Target of Rapamycin Pathway Activation in Basal Cell Carcinoma as a New Therapeutic Approach. The American Journal of dermatopathology Chang, A. L., Brown, R., Li, S., Betancourt, N., Teng, J. 2024

  Abstract

  Targeting the mammalian target of rapamycin (mTOR) pathway represents a potentially novel approach to treat basal cell carcinoma (BCC), but activation of this pathway has not been well described in human BCCs. The purpose of this study was to assess whether mTOR pathway activation occurs in BCCs (both sporadic and syndromic) and report a case of a patient with Gorlin syndrome (GS) whose clinically suspicious BCCs responded to mTOR inhibition through topical sirolimus treatment. After Stanford Institutional Review Board Approval, archived BCCs from patients with GS (n = 25), sporadic BCCs (n = 35), and control tissues were subjected to immunohistochemical analysis for the activation of mTOR pathway, and immunohistochemical staining intensity was evaluated by a dermatopathologist. BCCs (compared with normal skin) had elevated levels of eIF4EBP1 (Padjusted = 0.0336), which is downstream of mTOR. a serine/threonine kinase Phospho-(AKT), which interacts with mTOR, was also significantly elevated (perinuclear: Padjusted < 0.0001; cytoplasmic: Padjusted = 0.0021). When off-label topical 1% sirolimus was used on a pediatric patient with GS, we noted reduction of new BCC development and decreased size of existing neoplasms clinically suspicious for BCCs. This treatment was well tolerated after 2 years of continuous use, with no other treatments needed during this period. Topical sirolimus is a promising therapeutic candidate against both sporadic and GS-associated BCC. Multicenter, prospective studies are needed to understand the efficacy and safety of topical mTOR inhibitors in BCC treatment, and ascertain whether the immunohistochemical markers downstream of mTOR could have predictive value in identifying BCCs most likely to respond to topical mTOR inhibitors, such as sirolimus.

  View details for DOI 10.1097/DAD.0000000000002718

  View details for PubMedID 38648034

• Multi-Omics Profiling of Skin Biopsies of Patients with Sclerodermatous Graft-vs-Host Disease Suggests Therapeutic Potential of Targeting Don't Eat Me Signals Wadsworth, P., De Souza, C., Cui, L., Yiu, C., Poyser, J., Rieger, K., Brown, R., Arai, S., Shizuru, J., Muller, A., Wernig, G. ELSEVIER SCIENCE INC. 2023: S1252-S1253

  View details for Web of Science ID 000990969802351

• Utility of Interleukin-36 Immunohistochemical Staining to Differentiate Guttate Psoriasis and Pityriasis Rosea Anderson, J., Wang, L., Brown, R. ELSEVIER SCIENCE INC. 2023: S391

  View details for Web of Science ID 000990969800411

• Mimickers of Classical Urticaria: Cryopyrin-Associated Autoinflammatory Syndrome Presenting as Isolated Urticaria in an Infant. The journal of allergy and clinical immunology. In practice Solomon, B. D., Skaljic, M., Liu, L. Y., Yan, D., Sheahon, K. M., Broderick, L., Hoffman, H. M., Beres, S. J., Brown, R. A., Teng, J. M., Gernez, Y. 2023

  View details for DOI 10.1016/j.jaip.2022.12.037

  View details for PubMedID 36720659

• Purpuric eruption of the breasts, abdomen, thighs,and buttocks. JAAD case reports Masehi-Lano, J. J., Leatham, H. W., Brown, R. A., Chen, J. K. 2022; 30: 140-142

  View details for DOI 10.1016/j.jdcr.2022.04.031

  View details for PubMedID 36582488

• Multi-Omics Profiling of Skin Biopsies of Patients with Sclerodermatous Graft-Vs-Host Disease Suggests Therapeutic Potential of Targeting Don't Eat Me Signals Cui, L., De Souza, C., Lerbs, T., Poyser, J., Yu, C., Rieger, K., Arai, S., Brown, R., Shizuru, J. A., Mueller, A., Wernig, G. AMER SOC HEMATOLOGY. 2022

  View details for DOI 10.1182/blood-2022-169789

  View details for Web of Science ID 000893223200111

• Nontender white papule of the areola in a middle-aged female. JAAD case reports Young, P. A., Narala, S., Brown, R. A., Saleem, A., Rieger, K. E., Bae, G. H. 2022; 27: 6-8

  View details for DOI 10.1016/j.jdcr.2022.05.047

  View details for PubMedID 35941842

• Injectable Nanoparticle-Based Hydrogels Enable the Safe and Effective Deployment of Immunostimulatory CD40 Agonist Antibodies. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Correa, S., Meany, E. L., Gale, E. C., Klich, J. H., Saouaf, O. M., Mayer, A. T., Xiao, Z., Liong, C. S., Brown, R. A., Maikawa, C. L., Grosskopf, A. K., Mann, J. L., Idoyaga, J., Appel, E. A. 2022: e2103677

  Abstract

  When properly deployed, the immune system can eliminate deadly pathogens, eradicate metastatic cancers, and provide long-lasting protection from diverse diseases. Unfortunately, realizing these remarkable capabilities is inherently risky as disruption to immune homeostasis can elicit dangerous complications or autoimmune disorders. While current research is continuously expanding the arsenal of potent immunotherapeutics, there is a technological gap when it comes to controlling when, where, and how long these drugs act on the body. Here, this study explored the ability of a slow-releasing injectable hydrogel depot to reduce dose-limiting toxicities of immunostimulatory CD40agonist (CD40a) while maintaining its potent anticancer efficacy. A previously described polymer-nanoparticle (PNP) hydrogel system is leveraged that exhibits shear-thinning and yield-stress properties that are hypothesized to improve locoregional delivery of CD40a immunotherapy. Using positron emission tomography, it is demonstrated that prolonged hydrogel-based delivery redistributes CD40a exposure to the tumor and the tumor draining lymph node (TdLN), thereby reducing weight loss, hepatotoxicity, and cytokine storm associated with standard treatment. Moreover, CD40a-loaded hydrogels mediate improved local cytokine induction in the TdLN and improve treatment efficacy in the B16F10melanoma model. PNP hydrogels, therefore, represent a facile, drug-agnostic method to ameliorate immune-related adverse effects and explore locoregional delivery of immunostimulatory drugs.

  View details for DOI 10.1002/advs.202103677

  View details for PubMedID 35975424

• Preferentially Expressed Antigen in Melanoma Immunohistochemistry Labeling in Uveal Melanomas OCULAR ONCOLOGY AND PATHOLOGY Ahmadian, S. S., Dryden, I. J., Naranjo, A., Toland, A., Cayrol, R. A., Born, D. E., Egbert, P. S., Brown, R. A., Mruthyunjaya, P., Lin, J. H. 2022; 8 (2): 133-140

  View details for DOI 10.1159/000524051

  View details for Web of Science ID 000812351000009

• Randomized controlled trial investigating use of submucosal injection of EverLift in rates of complete resection of non-pedunculated 4-9mm polyps. International journal of colorectal disease Wei, M. T., Louie, C. Y., Chen, Y., Pan, J. Y., Quan, S. Y., Wong, R., Brown, R., Clark, M., Jensen, K., Lau, H., Friedland, S. 2022

  Abstract

  INTRODUCTION: Currently, cold snare polypectomy (CSP) without submucosal injection is recommended for removing polyps<10mm. Use of viscous submucosal agents has not been previously evaluated in CSP. We investigate the potential role of EverLift (GI Supply, Pennsylvania) in CSP.METHODS: The study is a single-center prospective randomized non-inferiority clinical trial evaluating CSP of non-pedunculated 4-9mm polyps, with or without submucosal injection of EverLift. Patients 18-80years of age presenting for colonoscopy were recruited. Eligible polyps underwent block randomization to CSP with or without EverLift. Following CSP, two biopsies were performed at the CSP site margin. The primary non-inferiority outcome was complete resection rate, defined by absence of residual polyp in the margin biopsies (non-inferiority margin-10%).RESULTS: A total of 291 eligible polyps underwent CSP, with 142 removed using EverLift. There was similar polyp size and distribution of pathology between the two groups. Overall, there was a low rate of positive margins with (1.4%) or without submucosal injection (2.8%), with no significant difference in complete resection (difference 1.28%, 95% CI:-2.66 to 5.42%), demonstrating non-inferiority of EverLift injection. Use of EverLift significantly increased CSP time (109.8 vs 38.8s, p<0.0001) and frequency of use of hemostatic clips (13.4 vs 3.6%, p=0.002).CONCLUSION: Submucosal injection of EverLift was non-inferior to CSP of 4-9mm polyps without injection and increased time for resection as well as use of hemostatic clips to control acute bleeding. Our results suggest that polypectomy of 4-9mm polyps can be safely performed without submucosal injection of EverLift.

  View details for DOI 10.1007/s00384-022-04136-4

  View details for PubMedID 35507047

• RANDOMIZED CONTROLLED TRIAL INVESTIGATING COLD SNARE AND FORCEPS POLYPECTOMY AMONG SMALL POLYPS IN RATES OF COMPLETE RESECTION: THE TINYPOLYP TRIAL Wei, M., Louie, C., Chen, Y., Pan, J. Y., Quan, S., Wong, R., Brown, R., Clark, M., Jensen, K. C., Lau, H. D., Friedland, S. W B SAUNDERS CO-ELSEVIER INC. 2022: S142-S143

  View details for Web of Science ID 000826446200345

• Randomized controlled Trial Investigating cold snare aNd forceps polypectomY among small POLYPs in rates of complete resection: the TINYPOLYP Trial. The American journal of gastroenterology Wei, M. T., Louie, C. Y., Chen, Y., Pan, J. Y., Quan, S. Y., Wong, R., Brown, R., Clark, M., Jensen, K., Lau, H., Friedland, S. 2022

  Abstract

  BACKGROUND: Optimizing complete resection during colonoscopy is important as residual neoplastic tissue may play a role in interval cancers. The United States Multi-Society Task Force recommends diminutive (<5mm) and small (6-9mm) polyps be removed by cold snare polypectomy (CSP). However, evidence is less clear whether CSP retains significant advantage over cold forceps polypectomy (CFP) for polyps <3mm.METHODS: This study is a single-center prospective non-inferiority randomized clinical trial evaluating CFP and CSP for nonpedunculated polyps <3mm. Patients >18 years of age undergoing colonoscopy for any indication were recruited. During each colonoscopy, polyps underwent block randomization to removal with CFP or CSP. Following polypectomy, two biopsies were taken from the polypectomy margin. The primary non-inferiority outcome was complete resection rate, defined by absence of residual polyp in the margin biopsies.RESULTS: A total of 179 patients were included. Patients had similar distribution in age, sex, race/ethnicity, as well as indication of procedure. A total of 279 polyps <3mm were identified, with 138 in the CSP group and 141 in the CFP group. Mean polypectomy time was longer for CSP compared to CFP (42.3 vs 23.2 seconds, p<0.001), though a higher proportion of polyps removed by CFP were removed in more than one piece compared to CSP (15.6 vs 3.6%, p<0.001). There were positive margin biopsies in 2 cases per cohort, with complete resection rate of 98.3% in both groups. There was no significant difference in cohorts in complete resection rates (difference in complete resection rates was 0.057%, 95% CI: -4.30 to 4.53%), demonstrating non-inferiority of CFP compared to CSP.CONCLUSIONS: Use of CFP was non-inferior to CSP in the complete resection of nonpedunculated polyps <3mm. CSP required significantly more time to perform compared to CFP. CFP should be considered an acceptable alternative to CSP for removal of polyps <3mm.

  View details for DOI 10.14309/ajg.0000000000001799

  View details for PubMedID 35467557

• Preferentially Expressed Antigen in Melanoma Immunohistochemistry Labeling in Uveal Melanomas. Ocular oncology and pathology Ahmadian, S. S., Dryden, I. J., Naranjo, A., Toland, A., Cayrol, R. A., Born, D. E., Egbert, P. S., Brown, R. A., Mruthyunjaya, P., Lin, J. H. 2022; 8 (2): 133-140

  Abstract

  Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and despite treatment of the primary tumor, approximately 15%-50% of patients will develop metastatic disease. Based on gene expression profiling (GEPs), UM can be categorized as Class 1A (low metastatic risk), Class 1B (intermediate metastatic risk), or Class 2 (high metastatic risk). PReferentially expressed Antigen in MElanoma (PRAME) status is an independent prognostic UM biomarker and a potential target for immunotherapy in metastatic UM. PRAME expression status can be detected in tumors using reverse-transcription polymerase chain reaction (RT-PCR). More recently, immunohistochemistry (IHC) has been developed to detect PRAME protein expression. Here, we employed both techniques to evaluate PRAME expression in 18 UM enucleations.Tumor material from the 18 UM patients who underwent enucleation was collected by fine-needle aspiration before or during enucleation and sent for GEP and PRAME analysis by RT-PCR. Histologic sections from these patients were stained with an anti-PRAME monoclonal antibody. We collected patient demographics and tumor characteristics and included this with our analysis of GEP class, PRAME status by RT-PCR, and PRAME status by IHC. PRAME IHC and RT-PCR results were compared.Twelve males (12/18) and 6 females (6/18) with an average age of 60.6 years underwent enucleation for UM. TNM staging of the UM diagnosed Stage I in 2 patients (2/18), Stage II in 7 patients (7/18), Stage III in 8 patients (8/18), and Stage IV in 1 (1/18). GEP was Class 1A in 6 tumors (6/18), Class 1B in 6 tumors (6/18), and Class 2 in 6 tumors (6/18). PRAME IHC showed diffusely positive labeling of all UM cells in 2/18 enucleations; negative IHC labeling of UM cells in 9/18 enucleations; and IHC labeling of subsets of UM cells in 7/18 enucleations. Eleven of the 17 UMs tested for PRAME by both RT-PCR and IHC had consistent PRAME results. In the remaining 6/17 cases tested by both modalities, PRAME results were discordant between RT-PCR and IHC.We find that PRAME IHC distinguishes PRAME-positive and PRAME-negative UM tumor cells. Interestingly, IHC reveals focal PRAME expression in subsets of tumor cells consistent with tumor heterogeneity. PRAME RT-PCR and IHC provide concordant results in most of our cases. We suggest that discordance in PRAME results could arise from spatial or temporal variation in PRAME expression between tumor cells. Further studies are required to determine the prognostic implications of PRAME IHC in UM.

  View details for DOI 10.1159/000524051

  View details for PubMedID 35959159

  View details for PubMedCentralID PMC9218614

• Exploring Potential Innate Immune Targets to Treat Fibrosis and Chronic Inflammation in Chronic Graft-Versus-Host Disease Paulson, N., De Souza, C., Cui, L., Lerbs, T., Poyser, J., Kooshesh, M., Saleem, A., Rieger, K., Brown', R., Kwong, B., Fernandez-Po, S., Arai, S., Shizuru, J., Mueller, A., Wernig, G. SPRINGERNATURE. 2022: 557

  View details for Web of Science ID 000770361801147

• Utility of Aberrant p53 Expression in the Differentiation of Atypical Fibroxanthoma From Atypical Fibrous Histiocytoma Toumi, G., Cloutier, J., Charville, G., Brown, R. SPRINGERNATURE. 2022: 362

  View details for Web of Science ID 000770361800337

• Utility of Aberrant p53 Expression in the Differentiation of Atypical Fibroxanthoma From Atypical Fibrous Histiocytoma Toumi, G., Cloutier, J., Charville, G., Brown, R. SPRINGERNATURE. 2022: 362

  View details for Web of Science ID 000770360200336

• Immunohistochemical and molecular updates in cutaneous soft tissue neoplasms. Seminars in diagnostic pathology Chukwudebe, O., Brown, R. A. 2022

  Abstract

  Accurate classification of soft tissue neoplasms of the skin and subcutis can be challenging given the sometimes significant histomorphologic and immunohistochemical overlap between the entities that comprise this ever-expanding category of tumors. With the benefit of continually emerging adjuncts to histologic diagnosis, pathologists have a number of tools at their disposal for navigating this group of neoplasms. This article aims to review recent immunohistochemical and molecular updates in the diagnosis of cutaneous soft tissue neoplasms.

  View details for DOI 10.1053/j.semdp.2022.02.004

  View details for PubMedID 35305853

• Spitz nevus with EHBP1-ALK fusion and distinctive membranous localization of ALK. Journal of cutaneous pathology Bahrani, E., Kunder, C. A., Teng, J. M., Brown, R. A., Rieger, K. E., Novoa, R. A., Cloutier, J. M. 1800

  Abstract

  ALK rearrangements define a histopathologically distinctive but diverse subset of Spitz tumors characterized by fusiform to epithelioid melanocytes with frequent fascicular growth and ALK overexpression. Molecularly, these tumors are characterized by fusions between ALK and a variety of other genes, most commonly TPM3 and DCTN1. We describe an unusual case of a Spitz nevus occurring in a 13-year-old female that manifested ALK immunopositivity with cell membrane localization. The proliferation was polypoid and composed of elongated nests of epithelioid melanocytes with enlarged nuclei, prominent nucleoli, and abundant cytoplasm without significant atypia and lacking mitotic figures. The nevus exhibited strong and diffuse expression of p16. Targeted next-generation RNA sequencing revealed an in-frame EHBP1-ALK fusion, which has been reported only once in the literature. EHBP1 encodes an adaptor protein with plasma membrane targeting potential. Together, these findings suggest that the 5' ALK fusion partner in Spitz tumors may dictate the subcellular localization of the ALK chimeric oncoprotein. In summary, this case highlights a rare ALK fusion associated with a distinct immunohistochemical staining pattern and further expands the spectrum of ALK-rearranged melanocytic tumors. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/cup.14209

  View details for PubMedID 35113459

• Primary cytotoxic T cell lymphomas harbor recurrent targetable alterations in the JAK-STAT pathway Lee, K., Evans, M. G., Yang, L., Ng, S., Snowden, C., Khodadoust, M., Brown, R. A., Trum, N., Querfeld, C., Doan, L. T., Song, J., Zhang, H., Wood, G. S., Wada, D. A., Shanmugam, V., Haun, P. L., Duncan, L. M., Guitart, J., Weinstock, D. M., Nardi, V., Choi, J. ELSEVIER SCI LTD. 2021: S8-S9

  View details for Web of Science ID 000719152800017

• Evaluation of EverLift in the Performance of Cold Snare Polypectomy (CSP) for 4-9mm Polyps Wei, M. T., Louie, C., Chen, Y., Pan, J. Y., Quan, S. Y., Wong, R., Brown, R., Clark, M., Jensen, K., Lau, H., Friedland, S. LIPPINCOTT WILLIAMS & WILKINS. 2021: S130-S131

  View details for Web of Science ID 000717526100297

• Primary Cytotoxic T Cell Lymphomas Harbor Recurrent Targetable Alterations in the JAK-STAT Pathway. Blood Lee, K., Evans, M. G., Yang, L., Ng, S., Snowden, C., Khodadoust, M. S., Brown, R. A., Trum, N. A., Querfeld, C., Doan, L. T., Song, J., Zhang, H., Gru, A., Wood, G. S., Wada, D. A., Shanmugam, V., Haun, P. L., Aster, J. C., Duncan, L. M., Guitart, J., Weinstock, D. M., Nardi, V., Choi, J. 2021

  View details for DOI 10.1182/blood.2021012536

  View details for PubMedID 34432866

• Consistent tumorigenesis with self-assembled hydrogels enables high-powered murine cancer studies. Communications biology Grosskopf, A. K., Correa, S., Baillet, J., Maikawa, C. L., Gale, E. C., Brown, R. A., Appel, E. A. 2021; 4 (1): 985

  Abstract

  Preclinical cancer research is heavily dependent on allograft and xenograft models, but current approaches to tumor inoculation yield inconsistent tumor formation and growth, ultimately wasting valuable resources (e.g., animals, time, and money) and limiting experimental progress. Here we demonstrate a method for tumor inoculation using self-assembled hydrogels to reliably generate tumors with low variance in growth. The observed reduction in model variance enables smaller animal cohorts, improved effect observation and higher powered studies.

  View details for DOI 10.1038/s42003-021-02500-8

  View details for PubMedID 34413455

• Comparison of PRAME antigen detection by Immunohistochemistry (IHC) and polymerase chain reaction (PCR) in Uveal Melanoma Naranjo, A., Ahmadian, S. S., Toland, A., Cayrol, R., Egbert, P. R., Born, D., Mruthyunjaya, P., Brown, R., Lin, J. H. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2021

  View details for Web of Science ID 000690761600101

• Cutaneous desmoid-type fibromatosis: a rare case with molecular profiling. Journal of cutaneous pathology Aghighi, M., Cloutier, J. M., Hoover, W. D., Roy, K., Lo, A. A., Brown, R. A. 2021

  Abstract

  Fibromatoses encompass a broad group of histopathologically similar fibroblastic/myofibroblastic proliferations with divergent clinical manifestations and behavior. Deep (desmoid-type) fibromatoses are typically large, rapidly growing, and locally aggressive tumors that occur in the abdominal wall, mesentery, and extraabdominal soft tissue, principally the musculature of the trunk and extremities. Most sporadic cases of desmoid fibromatosis harbor inactivating mutations in CTNNB1, the gene encoding beta-catenin. Tumors occurring in the context of familial adenomatous polyposis and Gardner syndrome bear inactivating mutations in APC. By contrast, mutations in CTNNB1 or APC have not been identified in cases of superficial fibromatosis. Cutaneous involvement by desmoid fibromatosis is exceedingly rare. Here we present a 78-year-old male with desmoid-type fibromatosis arising in the dermis of the right medial calf with a pathogenic mutation in CTNNB1 and a variant of unknown significance in APC. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/cup.14058

  View details for PubMedID 33978242

• Comparison of PRAME Immunohistochemistry (IHC) and PRAME RT-PCR in 14 Uveal Melanomas Ahmadian, S., Toland, A., Cayrol, R., Egbert, P., Born, D., Brown, R., Lin, J., Mruthyunjaya, P. SPRINGERNATURE. 2021: 1020

  View details for Web of Science ID 000629690900847

• Molecular Profiling of Cutaneous C-Group Non-Langerhans Cell Histiocytoses Wieland, R., Bencomo, T., Lee, C., Brown, R. SPRINGERNATURE. 2021: 319

  View details for Web of Science ID 000629694100270

• Cutaneous acral myofibroma with PDGFR-beta mutation in a patient with linear morphea - en coup de sabre. Journal of cutaneous pathology Pepper, M. A., Theparee, T., Messenger, E. A., Brown, R. A., Novoa, R. A. 2021

  View details for DOI 10.1111/cup.13971

  View details for PubMedID 33495995

• TTF-1 Expression in a Case of Cutaneous Sarcomatoid Squamous Cell Carcinoma. Journal of cutaneous pathology Nicholas, V., Say, B., Aasi, S., Rieger, K. E., Brown, R. A. 2021

  View details for DOI 10.1111/cup.13963

  View details for PubMedID 33458834

• High-resolution phenotyping of early acute rejection reveals a conserved alloimmune signature. Cell reports Harden, J. T., Wang, X. n., Toh, J. n., Sang, A. X., Brown, R. A., Esquivel, C. O., Martinez, O. M., Krams, S. M. 2021; 34 (9): 108806

  Abstract

  Alloimmune responses in acute rejection are complex, involving multiple interacting cell types and pathways. Deep profiling of these cell types has been limited by technology that lacks the capacity to resolve this high dimensionality. Single-cell mass cytometry is used to characterize the alloimmune response in early acute rejection, measuring 37 parameters simultaneously, across multiple time points in two models: a murine cardiac and vascularized composite allotransplant (VCA). Semi-supervised hierarchical clustering is used to group related cell types defined by combinatorial expression of surface and intracellular proteins, along with markers of effector function and activation. This expression profile is mapped to visualize changes in antigen composition across cell types, revealing phenotypic signatures in alloimmune T cells, natural killer (NK) cells, and myeloid subsets that are conserved and that firmly distinguish rejecting from non-rejecting grafts. These data provide a comprehensive, high-dimensional profile of cellular rejection after allograft transplantation.

  View details for DOI 10.1016/j.celrep.2021.108806

  View details for PubMedID 33657374

• Next generation sequencing confirms T-cell clonality in a subset of pediatric pityriasis lichenoides. Journal of cutaneous pathology Raghavan, S. S., Wang, J. Y., Gru, A. A., Marqueling, A. L., Teng, J. M., Brown, R. A., Novoa, R. A., Kim, Y., Zehnder, J., Zhang, B. M., Rieger, K. E. 2021

  Abstract

  Pityriasis lichenoides (PL) is a papulosquamous disease that affects both adults and children. Previous studies have shown a subset of this entity to have clonal T-cell populations via PCR based assays. In this study, we sought to implement next generation sequencing as a more sensitive and specific test to examine for T-cell clonality within the pediatric population.We identified 18 biopsy specimens from 12 pediatric patients with clinical and histopathologic findings compatible with PL. Patient demographics, clinical features, management, and histopathologic findings were reviewed. All specimens were analyzed for clonality with next generation sequencing of T-cell receptor beta (TRB) and gamma (TRG) genes.Of the 12 patients, 9 (75%) had complete resolution of lesions at the time of data collection (mean follow up 31 months). The remaining three patients significantly improved with methotrexate (with or without acitretin). Interestingly, 7 of 12 patients (58%) and 9 of 17 biopsy specimens (53%) showed evidence of T-cell clonality. Two patients showed matching TRB clones from different anatomic sites.T-cell clonality is a common finding in PL, likely representing a "reactive clonality" rather than a true lymphoproliferative disorder. Clonality alone cannot be used as a means to distinguish PL from lymphomatoid papulosis or cutaneous lymphoma. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/cup.14143

  View details for PubMedID 34614220

• Nodular fasciitis of the breast: clinicopathologic and molecular characterization with identification of novel USP6 fusion partners. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Cloutier, J. M., Kunder, C. A., Charville, G. W., Hosfield, E. M., García, J. J., Brown, R. A., Troxell, M. L., Allison, K. H., Bean, G. R. 2021

  Abstract

  Nodular fasciitis is a benign, self-limited, pseudosarcomatous neoplasm that can mimic malignancy due to its rapid growth, cellularity, and mitotic activity. Involvement of the breast is rare and diagnosis on biopsy can be challenging. In this largest series to date, we examined the clinicopathologic and molecular characteristics of 12 cases of nodular fasciitis involving the breast/axilla. All patients were female, with a median age of 32 years (range 15-61). The lesions were 0.4 to 5.8 cm in size (median 0.8). All cases presented as palpable masses, and two patients had overlying skin retraction. Microscopically, lesions were relatively well-circumscribed nodular masses of bland myofibroblastic spindle cells within a variably myxoid stroma. Infiltrative growth into adipose tissue or breast epithelium was frequent. Mitotic figures were present in all cases, ranging from 1 to 12 per 10 high-power fields (median 3). Immunohistochemically, all cases expressed smooth muscle actin and were negative for pan-cytokeratin, p63, desmin, CD34, and nuclear beta-catenin. Targeted RNA sequencing performed on 11 cases identified USP6 gene fusions in eight; one additional case was positive by break-apart fluorescence in situ hybridization. The common MYH9-USP6 rearrangement was detected in four cases; another case had a rare alternative fusion with CTNNB1. Three cases harbored novel USP6 gene fusions involving NACA, SLFN11, or LDHA. All fusions juxtaposed the promoter region of the 5' partner gene with the full-length coding sequence of USP6. Outcome data were available for eight patients; none developed recurrence or metastasis. Five patients elected for observation without immediate excision, and self-resolution of the lesions was reported in three cases. Albeit uncommon, nodular fasciitis should be considered in the differential diagnosis of breast spindle cell lesions. A broad immunohistochemical panel to exclude histologic mimics, including metaplastic carcinoma, is important. Confirmatory detection of USP6 rearrangements can aid in classification, with potential therapeutic implications.

  View details for DOI 10.1038/s41379-021-00844-4

  View details for PubMedID 34099872

• Immunohistochemical ALK Expression in Granular Cell Atypical Fibroxanthoma: A Diagnostic Pitfall for ALK-Rearranged Non-neural Granular Cell Tumor. The American Journal of dermatopathology Brown, R. A., Cloutier, J. M., Bahrani, E. n., Liman, A. n., Tasso, D. n., Palmer, A. n., Manning, M. A., Galperin, I. n., Rieger, K. E., Novoa, R. A., Lau, H. n., Louie, C. Y. 2021

  Abstract

  Atypical fibroxanthoma (AFX) is a neoplasm that most commonly occurs on sun-damaged skin of the head and neck in elderly patients and that usually exhibits indolent clinical behavior with complete excision. The granular cell variant of AFX demonstrates overlapping histopathologic features with dermal non-neural granular cell tumor (NNGCT), which typically arises on the extremities of young to middle aged adults with rare reports of regional metastasis. A subset of NNGCT harbors ALK rearrangements and expresses ALK by immunohistochemistry. Here, we present 2 cases of granular cell AFX occurring on the scalp of males aged 73 and 87 with ALK expression by immunohistochemistry and no evidence of an ALK rearrangement on fluorescence in situ hybridization, representing a diagnostic pitfall for NNGCT.

  View details for DOI 10.1097/DAD.0000000000001931

  View details for PubMedID 33767072

• Jun Activation in Dermal Fibroblasts Promotes Fibrosis and Inflammation in Sclerodermatous Graft-vs-host Disease in Mice and Humans Mueller, A., Cui, L., Lerbs, T., King, M., Muscat, C., Shibata, T., Lee, J., Brown, R., Fernandez-Pol, S., Arai, S., Shizuru, J., Wernig, G. SPRINGERNATURE. 2020: 13–14

  View details for Web of Science ID 000600556200003

• Disseminated non-Langerhans cell histiocytosis with an IRF2BP2-NTRK1 gene fusion identified by next-generation sequencing. JAAD case reports Chan, W. H., Shah, A., Bae, G., Hambro, C., Martin, B. A., Brown, R., Novoa, R., Kwong, B. Y. 2020; 6 (11): 1156–58

  View details for DOI 10.1016/j.jdcr.2020.05.032

  View details for PubMedID 33134460

• ALK-positive compound Spitz nevus with extensive perineural and intraneural neurotropism. Journal of cutaneous pathology Brown, R. A., Wang, J. Y., Raghavan, S. S., Zhang, J., Wan, D. C., Born, D., Koo, M., Hazard, F. K., Novoa, R. A., Rieger, K. E. 2020

  View details for DOI 10.1111/cup.13890

  View details for PubMedID 33034114

• Cutaneous T-cell lymphomas with pathogenic somatic mutations and absence of detectable clonal T-cell receptor gene rearrangement: two case reports. Diagnostic pathology Rojansky, R., Fernandez-Pol, S., Wang, E., Rieger, K. E., Novoa, R. A., Zehnder, J. L., Kunder, C. A., Kim, Y. H., Khodadoust, M. S., Brown, R. A. 2020; 15 (1): 122

  Abstract

  BACKGROUND: Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of extranodal non-Hodgkin lymphomas for which diagnosis can be challenging given the potential for overlap with inflammatory dermatoses. Current diagnostic criteria for CTCL incorporate clinical and histopathologic findings as well as results of T-cell receptor (TCR) gene sequencing. Molecular interrogation of TCR genes, TRG and TRB, has provento be a critical tool for confirming diagnoses of CTCL and for disease tracking after initiation of therapy or after stem cell transplant. Methods for confirming a diagnosis of lymphoma in the absence of TCR gene clonality are lacking. We present two patients with CTCL with pathogenic somatic mutations in the absence of TRG and TRB clonality.CASE PRESENTATIONS: Case 1: A 38-year-old male had a 19-year history of a diffuse skin rash with papulosquamous, granulomatous, and verrucous features and progressive ulcerated plaques and tumors demonstrating an atypical CD4+ T-cell infiltrate with expression of cytotoxic markers CD56, TIA-1, granzyme, and perforin on histopathology. No definitive evidence for T-cell clonality was detected by conventional PCR of 6 biopsies or by next-generation sequencing (NGS) of 14 biopsies. Somatic mutational profiling of a skin biopsy revealed pathogenic mutations in PIKC3D and TERT promoter hotspots, confirming the presence of a clonal process. Case 2: A 69-year-old male with a 13-year history of progressive, diffuse hypertrophic and eroded plaques showed an atypical CD4+ T-cell infiltrate with subset expression of TIA-1 and granzyme on histopathology. No TCR clonality was detected by TCR-NGS of 6 biopsies. Somatic mutational profiling of a skin biopsy detected a pathogenic mutation in TP53, confirming the presence of a clonal process.CONCLUSIONS: These cases highlight how detection of pathogenic somatic mutations can confirma diagnosis of lymphoma in a clinically and histopathologically suspicious cutaneous lymphoid proliferation without detectable TCR clonality.

  View details for DOI 10.1186/s13000-020-01022-x

  View details for PubMedID 32988392

• CD47 prevents the elimination of diseased fibroblasts in scleroderma. JCI insight Lerbs, T., Cui, L., King, M. E., Chai, T., Muscat, C., Chung, L., Brown, R., Rieger, K., Shibata, T., Wernig, G. 2020; 5 (16)

  Abstract

  Scleroderma is a devastating fibrotic autoimmune disease. Current treatments are partly effective in preventing disease progression but do not remove fibrotic tissue. Here, we evaluated whether scleroderma fibroblasts take advantage of the "don't-eat-me-signal" CD47 and whether blocking CD47 enables the body's immune system to get rid of diseased fibroblasts. To test this approach, we used a Jun-inducible scleroderma model. We first demonstrated in patient samples that scleroderma upregulated transcription factor JUN and increased promoter accessibilities of both JUN and CD47. Next, we established our scleroderma model, demonstrating that Jun mediated skin fibrosis through the hedgehog-dependent expansion of CD26+Sca1- fibroblasts in mice. In a niche-independent adaptive transfer model, JUN steered graft survival and conferred increased self-renewal to fibroblasts. In vivo, JUN enhanced the expression of CD47, and inhibiting CD47 eliminated an ectopic fibroblast graft and increased in vitro phagocytosis. In the syngeneic mouse, depleting macrophages ameliorated skin fibrosis. Therapeutically, combined CD47 and IL-6 blockade reversed skin fibrosis in mice and led to the rapid elimination of ectopically transplanted scleroderma cells. Altogether, our study demonstrates the efficiency of combining different immunotherapies in treating scleroderma and provides a rationale for combining CD47 and IL-6 inhibition in clinical trials.

  View details for DOI 10.1172/jci.insight.140458

  View details for PubMedID 32814713

• PRAME expression in melanocytic proliferations with intermediate histopathologic or spitzoid features. Journal of cutaneous pathology Raghavan, S. S., Wang, J. Y., Kwok, S., Rieger, K. E., Novoa, R. A., Brown, R. A. 2020

  Abstract

  BACKGROUND: PRAME (PReferentially expressed Antigen in MElanoma) has shown utility in distinguishing melanoma from benign melanocytic lesions, but knowledge of its expression pattern in intermediate melanocytic and spitzoid proliferations is limited.METHODS: Immunohistochemical expression of PRAME was examined in 112 melanocytic proliferations with intermediate histopathologic or spitzoid features.RESULTS: Any intensity of PRAME staining in at least 60% of lesional melanocytes was determined as the best threshold for diffuse staining in this cohort. Nearly all non-spitzoid melanomas (23/24; 95.8%) demonstrated diffuse PRAME expression. PRAME was completely negative in 95.6% (43/45) of mitotically-active nevi, traumatized nevi, nevi with persistent/recurrent features, and dysplastic nevi. Most Spitz nevi (15/20) and atypical Spitz tumors (10/13) entirely lacked PRAME expression. One Spitz nevus, one atypical Spitz tumor, and one case of spitzoid melanoma (1/2) demonstrated diffuse PRAME expression.CONCLUSIONS: Although diffuse PRAME expression is generally limited to malignant melanoma, benign Spitz nevi and atypical Spitz tumors can infrequently express diffuse PRAME. PRAME immunohistochemistry can be useful in the evaluation of atypical melanocytic proliferations with intermediate histopathologic features but should be interpreted with caution in the setting of spitzoid neoplasms. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/cup.13818

  View details for PubMedID 32700786

• Diagnostic Utility of LEF1 Immunohistochemistry in Differentiating Deep Penetrating Nevi From Histologic Mimics. The American journal of surgical pathology Raghavan, S. S., Saleem, A., Wang, J. Y., Rieger, K. E., Brown, R. A., Novoa, R. A. 2020

  Abstract

  Deep penetrating nevi (DPNs) are intermediate grade lesions which have the capacity to recur, metastasize, or progress to melanoma. Differentiating DPN from other melanocytic lesions including blue and cellular blue nevi can be diagnostically challenging, and markers to distinguish these entities can be useful. Mutations of the beta-catenin and mitogen-activated protein kinase pathways have recently been elucidated as distinctive of DPN. This pathway can subsequently activate lymphoid enhancer-binding factor 1 (LEF1), a transcription factor shown to facilitate the epithelial-mesenchymal transition to propagate tumorigenesis. Seventy-two cases in total were examined on hematoxylin and eosin sections and with beta-catenin and LEF1 immunohistochemistry. This included: DPN (14), cellular blue nevi (19), blue nevi (15), congenital melanocytic nevi (12), and melanoma (12). Nuclear expression of LEF1, present throughout the entire depth of the lesion, was noted in 13/14 (93%) of DPN, 0/19 (0%) of cellular blue nevi, 0/15 (0%) of blue nevi, 1/12 (8%) of congenital melanocytic nevi, and 9/12 (75%) of melanoma cases. Nuclear expression of beta-catenin, present throughout the entire depth of the lesion, was noted in 14/14 (100%) of DPN, 0/18 (0%) of cellular blue nevi, 0/15 (0%) of blue nevi, 1/12 (8%) of congenital melanocytic nevi, and 1/12 (8%) of melanoma cases. A majority of congenital melanocytic nevi demonstrated a gradient of LEF1 and beta-catenin expression with more intense staining superficially and loss of staining with increasing depth. Deep, uniform nuclear LEF1 combined with beta-catenin immunohistochemical staining can be useful in distinguishing DPN from histologic mimics.

  View details for DOI 10.1097/PAS.0000000000001513

  View details for PubMedID 32520758

• Molecular profiling of a primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid. Journal of cutaneous pathology Raghavan, S., Clark, M., Louie, C., Jensen, K. C., Dietrich, B., Beadle, B. M., El-Sawy, T., Baik, F., Kunder, C. A., Brown, R. A. 2020

  Abstract

  Primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid is a rare and aggressive neoplasm. Fewer than 50 cases have been reported in the literature, and the genetic driving mutations are unknown. Herein, we present a case of this rare disease along with the results of molecular profiling via targeted next generation sequencing. The patient is an 85-year-old man who presented with left eyelid swelling initially thought to be a chalazion. After no response to incision and drainage and antibiotics, an incisional biopsy was performed. Histologic sections revealed a proliferation of cells with signet-ring and histiocytoid morphology arranged singly and in cords infiltrating the dermis, subcutaneous tissue, and muscle. The lesional cells strongly expressed cytoplasmic cytokeratin 7 and nuclear androgen receptor. Next generation sequencing revealed a CDH1 mutation, which is known to confer signet-ring morphology in other carcinomas. Pathogenic mutations in NTRK3, CDKN1B and PIK3CA were also detected. To our knowledge, this is the first documented genetic analysis of this rare disease with findings that offer insights into disease pathogenesis and potential therapeutic targets. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/cup.13733

  View details for PubMedID 32358805

• Cutaneous Pleomorphic Fibromas Arising in Patients with Germline TP53 Mutations. Journal of cutaneous pathology Cloutier, J. M., Shalin, S. C., Lindberg, M., Gardner, J. M., Fernandez-Pol, S., Zaba, L., Novoa, R., Brown, R. A. 2020

  Abstract

  Pleomorphic fibromas are rare benign cutaneous neoplasms associated with deletion/loss of chromosomes 13q and 17p, where RB1 and TP53 are located, respectively. Herein, we report five cases of pleomorphic fibroma arising in patients with germline TP53 mutations, suggesting a potential link with Li-Fraumeni syndrome. All three patients were female and young (mean age 27) with a strong personal and/or family oncologic history and confirmed pathogenic germline TP53 mutations. In two patients, multiple pleomorphic fibromas were diagnosed. Clinically, the lesions arose at various cutaneous sites and were small (≤2cm) and raised (4/5). Histologically, the tumors were paucicellular, comprised of atypical spindled to stellate cells with hyperchromatic and variably pleomorphic nuclei. Mitotic activity was exceedingly low, although rare atypical mitotic figures were seen in one case. Immunohistochemically, the tumor cells were diffusely positive for p16 (3/3) and showed loss of Rb expression (5/5). All cases showed aberrant p53 expression (overexpression in 4, complete loss in 1). The tumors have followed a benign clinical course with no evidence of progression or recurrence. In conclusion, the development of multiple pleomorphic fibromas in a young patient may be a clue to an underlying genetic cancer syndrome involving TP53. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/cup.13686

  View details for PubMedID 32187703

• Disseminated Tuberculosis Presenting as Medium-Vessel Vasculitis in an Immunocompromised Host. Journal of cutaneous pathology Wang, J. Y., Brown, R. A., Pugliese, S., Kwong, B. Y., Novoa, R. A. 2020

  Abstract

  Cutaneous tuberculosis is an uncommon entity with several clinical forms recognized. Histopathologically, most cases are characterized by granulomatous inflammation and caseating necrosis, though less common findings, including vasculitis, have also been described. We report a 55-year-old male with a history of recently diagnosed dermatomyositis receiving immunosuppression with mycophenolate mofetil and prednisone, who developed multifocal soft tissue abscesses and an indurated erythematous plaque on the back. Skin biopsy of the back revealed a necrotizing medium-vessel vasculitis. M. tuberculosis was detected in the skin via acid-fast bacilli stain and confirmed by tissue culture and polymerase chain reaction. Cutaneous findings improved rapidly with anti-tuberculosis therapy. This case illustrates an uncommon clinical and histopathologic presentation of disseminated tuberculosis. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/cup.13678

  View details for PubMedID 32133689

• Histopathologic Characterization of Mogamulizumab-associated Rash. The American journal of surgical pathology Wang, J. Y., Hirotsu, K. E., Neal, T. M., Raghavan, S. S., Kwong, B. Y., Khodadoust, M. S., Brown, R. A., Novoa, R. A., Kim, Y. H., Rieger, K. E. 2020

  Abstract

  Rash is one of the most common adverse events observed with mogamulizumab, an anti-C-C chemokine receptor 4 monoclonal antibody approved for previously treated mycosis fungoides (MF) and Sezary syndrome (SS). Given the nonspecific clinical presentations of this rash, histopathologic distinction from MF/SS is critical for informing clinical management. We performed a comprehensive characterization of the histopathologic findings in mogamulizumab-associated rash (MAR) with the integration of high-throughput sequencing of T-cell receptor (TCR) genes. Fifty-two biopsy specimens from 19 patients were evaluated retrospectively. Three major histologic reaction patterns were identified: spongiotic/psoriasiform dermatitis (33/52), interface dermatitis (11/52), and granulomatous dermatitis (8/52). Almost half of the specimens (21/52) showed at least 2 of these reaction patterns concurrently. Dermal eosinophils were not a consistent feature, being present in only half (27/52) of specimens and prominent in only 3. Features mimicking MF/SS, including lymphocyte exocytosis, lamellar fibroplasia, and adnexal involvement, were commonly seen but tended to be focal and mild. In 38/43 specimens with available immunohistochemistry, intraepidermal lymphocytes demonstrated a CD4:CD8 ratio ≤1 : 1. Low background levels of the patient's previously identified MF/SS-associated TCR sequence(s) were demonstrated in 20/46 specimens analyzed by high-throughput sequencing of TCR. We conclude that MAR may demonstrate diverse histologic features. Findings that may distinguish MAR from MF/SS include the inverted or normalized CD4:CD8 ratio within intraepidermal lymphocytes and demonstration of absent or nondominant levels of disease-associated TCR sequences. Correlation with the clinical findings and immunohistochemical and molecular characterization of the patient's MF/SS before mogamulizumab, when possible, may facilitate recognition of MAR.

  View details for DOI 10.1097/PAS.0000000000001587

  View details for PubMedID 32976123

• Impact of a deep learning assistant on the histopathologic classification of liver cancer. NPJ digital medicine Kiani, A. n., Uyumazturk, B. n., Rajpurkar, P. n., Wang, A. n., Gao, R. n., Jones, E. n., Yu, Y. n., Langlotz, C. P., Ball, R. L., Montine, T. J., Martin, B. A., Berry, G. J., Ozawa, M. G., Hazard, F. K., Brown, R. A., Chen, S. B., Wood, M. n., Allard, L. S., Ylagan, L. n., Ng, A. Y., Shen, J. n. 2020; 3: 23

  Abstract

  Artificial intelligence (AI) algorithms continue to rival human performance on a variety of clinical tasks, while their actual impact on human diagnosticians, when incorporated into clinical workflows, remains relatively unexplored. In this study, we developed a deep learning-based assistant to help pathologists differentiate between two subtypes of primary liver cancer, hepatocellular carcinoma and cholangiocarcinoma, on hematoxylin and eosin-stained whole-slide images (WSI), and evaluated its effect on the diagnostic performance of 11 pathologists with varying levels of expertise. Our model achieved accuracies of 0.885 on a validation set of 26 WSI, and 0.842 on an independent test set of 80 WSI. Although use of the assistant did not change the mean accuracy of the 11 pathologists (p = 0.184, OR = 1.281), it significantly improved the accuracy (p = 0.045, OR = 1.499) of a subset of nine pathologists who fell within well-defined experience levels (GI subspecialists, non-GI subspecialists, and trainees). In the assisted state, model accuracy significantly impacted the diagnostic decisions of all 11 pathologists. As expected, when the model's prediction was correct, assistance significantly improved accuracy (p = 0.000, OR = 4.289), whereas when the model's prediction was incorrect, assistance significantly decreased accuracy (p = 0.000, OR = 0.253), with both effects holding across all pathologist experience levels and case difficulty levels. Our results highlight the challenges of translating AI models into the clinical setting, and emphasize the importance of taking into account potential unintended negative consequences of model assistance when designing and testing medical AI-assistance tools.

  View details for DOI 10.1038/s41746-020-0232-8

  View details for PubMedID 32140566

  View details for PubMedCentralID PMC7044422

• Reticulohistiocytoma (solitary epithelioid histiocytoma) with mutations in RAF1 and TSC2. Journal of cutaneous pathology Bahrani, E. n., Fernandez-Pol, S. n., Wang, J. Y., Aasi, S. Z., Brown, R. A., Novoa, R. A. 2020

  View details for DOI 10.1111/cup.13727

  View details for PubMedID 32342514

• Diffuse PRAME expression is highly specific for malignant melanoma in the distinction from clear cell sarcoma. Journal of cutaneous pathology Raghavan, S. S., Wang, J. Y., Toland, A. n., Bangs, C. D., Rieger, K. E., Novoa, R. A., Charville, G. W., Brown, R. A. 2020

  View details for DOI 10.1111/cup.13812

  View details for PubMedID 32681554

• Impact of a deep learning assistant on the histopathologic classification of liver cancer. NPJ digital medicine Kiani, A. n., Uyumazturk, B. n., Rajpurkar, P. n., Wang, A. n., Gao, R. n., Jones, E. n., Yu, Y. n., Langlotz, C. P., Ball, R. L., Montine, T. J., Martin, B. A., Berry, G. J., Ozawa, M. G., Hazard, F. K., Brown, R. A., Chen, S. B., Wood, M. n., Allard, L. S., Ylagan, L. n., Ng, A. Y., Shen, J. n. 2020; 3 (1): 23

  Abstract

  Artificial intelligence (AI) algorithms continue to rival human performance on a variety of clinical tasks, while their actual impact on human diagnosticians, when incorporated into clinical workflows, remains relatively unexplored. In this study, we developed a deep learning-based assistant to help pathologists differentiate between two subtypes of primary liver cancer, hepatocellular carcinoma and cholangiocarcinoma, on hematoxylin and eosin-stained whole-slide images (WSI), and evaluated its effect on the diagnostic performance of 11 pathologists with varying levels of expertise. Our model achieved accuracies of 0.885 on a validation set of 26 WSI, and 0.842 on an independent test set of 80 WSI. Although use of the assistant did not change the mean accuracy of the 11 pathologists (p = 0.184, OR = 1.281), it significantly improved the accuracy (p = 0.045, OR = 1.499) of a subset of nine pathologists who fell within well-defined experience levels (GI subspecialists, non-GI subspecialists, and trainees). In the assisted state, model accuracy significantly impacted the diagnostic decisions of all 11 pathologists. As expected, when the model's prediction was correct, assistance significantly improved accuracy (p = 0.000, OR = 4.289), whereas when the model's prediction was incorrect, assistance significantly decreased accuracy (p = 0.000, OR = 0.253), with both effects holding across all pathologist experience levels and case difficulty levels. Our results highlight the challenges of translating AI models into the clinical setting, and emphasize the importance of taking into account potential unintended negative consequences of model assistance when designing and testing medical AI-assistance tools.

  View details for DOI 10.1038/s41746-020-0232-8

  View details for PubMedID 33594170

• Painful Panniculitis and Polyarthritis in Pancreatic Adenocarcinoma: A Case Report. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases Ku, S. n., Balijepally, R. n., Horomanski, A. n., Fairchild, R. n., Brown, R. A., Liao, C. E. 2020

  View details for DOI 10.1097/RHU.0000000000001408

  View details for PubMedID 32496359

• An unusual presentation of recurrent T cell lymphoma: angiocentric pattern of cutaneous uptake on [18F]FDG PET/CT. European journal of nuclear medicine and molecular imaging Guja, K. E., Brown, R. n., Girod, B. n., Song, H. n., Harrison, C. n., Franc, B. L., Moradi, F. n., Davidzon, G. n., Iagaru, A. n., Aparici, C. M. 2020

  View details for DOI 10.1007/s00259-020-05026-z

  View details for PubMedID 32918110

• Inflammatory alopecia in patients on dupilumab: a retrospective cohort study at an academic institution. Journal of the European Academy of Dermatology and Venereology : JEADV Zhu, G. A., Kang, K. J., Chen, J. K., Novoa, R. A., Brown, R. A., Chiou, A. S., Ko, J. M., Honari, G. 2019

  Abstract

  Dupilumab targets IL-4Ralpha and is used for moderate-to-severe atopic dermatitis (AD). Prior reports have described new alopecia areata (AA),1 flaring of prior AA,2 as well as improvement or resolution of AA3 in patients treated with dupilumab. We conducted a retrospective cohort study to describe the natural history of prior or new inflammatory alopecia in patients on dupilumab.

  View details for DOI 10.1111/jdv.16094

  View details for PubMedID 31737955

• The PROCLIPI international registry of early-stage mycosis fungoides identifies substantial diagnostic delay in most patients. The British journal of dermatology Scarisbrick, J. J., Quaglino, P., Prince, H. M., Papadavid, E., Hodak, E., Bagot, M., Servitje, O., Berti, E., Ortiz-Romero, P., Stadler, R., Patsatsi, A., Knobler, R., Guenova, E., Child, F., Whittaker, S., Nikolaou, V., Tomasini, C., Amitay, I., Prag Naveh, H., Ram-Wolff, C., Battistella, M., Alberti-Violetti, S., Stranzenbach, R., Gargallo, V., Muniesa, C., Koletsa, T., Jonak, C., Porkert, S., Mitteldorf, C., Estrach, T., Combalia, A., Marschalko, M., Csomor, J., Szepesi, A., Cozzio, A., Dummer, R., Pimpinelli, N., Grandi, V., Beylot-Barry, M., Pham-Ledard, A., Wobser, M., Geissinger, E., Wehkamp, U., Weichenthal, M., Cowan, R., Parry, E., Harris, J., Wachsmuth, R., Turner, D., Bates, A., Healy, E., Trautinger, F., Latzka, J., Yoo, J., Vydianath, B., Amel-Kashipaz, R., Marinos, L., Oikonomidi, A., Stratigos, A., Vignon-Pennamen, M. D., Battistella, M., Climent, F., Gonzalez-Barca, E., Georgiou, E., Senetta, R., Zinzani, P., Vakeva, L., Ranki, A., Busschots, A. M., Hauben, E., Bervoets, A., Woei-A-Jin, F. J., Matin, R., Collins, G., Weatherhead, S., Frew, J., Bayne, M., Dunnill, G., McKay, P., Arumainathan, A., Azurdia, R., Benstead, K., Twigger, R., Rieger, K., Brown, R., Sanches, J. A., Miyashiro, D., Akilov, O., McCann, S., Sahi, H., Damasco, F. M., Querfeld, C., Folkes, A., Bur, C., Klemke, C. D., Enz, P., Pujol, R., Quint, K., Geskin, L., Hong, E., Evison, F., Vermeer, M., Cerroni, L., Kempf, W., Kim, Y., Willemze, R. 2019; 181 (2): 350-357

  Abstract

  Survival in mycosis fungoides (MF) is varied and may be poor. The PROCLIPI (PROspective Cutaneous Lymphoma International Prognostic Index) study is a web-based data collection system for early-stage MF with legal data-sharing agreements permitting international collaboration in a rare cancer with complex pathology. Clinicopathological data must be 100% complete and in-built intelligence in the database system ensures accurate staging.To develop a prognostic index for MF.Predefined datasets for clinical, haematological, radiological, immunohistochemical, genotypic, treatment and quality of life are collected at first diagnosis of MF and annually to test against survival. Biobanked tissue samples are recorded within a Federated Biobank for translational studies.In total, 430 patients were enrolled from 29 centres in 15 countries spanning five continents. Altogether, 348 were confirmed as having early-stage MF at central review. The majority had classical MF (81·6%) with a CD4 phenotype (88·2%). Folliculotropic MF was diagnosed in 17·8%. Most presented with stage I (IA: 49·4%; IB: 42·8%), but 7·8% presented with enlarged lymph nodes (stage IIA). A diagnostic delay between first symptom development and initial diagnosis was frequent [85·6%; median delay 36 months (interquartile range 12-90)]. This highlights the difficulties in accurate diagnosis, which includes lack of a singular diagnostic test for MF.This confirmed early-stage MF cohort is being followed-up to identify prognostic factors, which may allow better management and improve survival by identifying patients at risk of disease progression. This study design is a useful model for collaboration in other rare diseases, especially where pathological diagnosis can be complex.

  View details for DOI 10.1111/bjd.17258

  View details for PubMedID 30267549

• Clonal replacement of tumor-specific T cells following PD-1 blockade. Nature medicine Yost, K. E., Satpathy, A. T., Wells, D. K., Qi, Y. n., Wang, C. n., Kageyama, R. n., McNamara, K. L., Granja, J. M., Sarin, K. Y., Brown, R. A., Gupta, R. K., Curtis, C. n., Bucktrout, S. L., Davis, M. M., Chang, A. L., Chang, H. Y. 2019

  Abstract

  Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear2-4. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.

  View details for DOI 10.1038/s41591-019-0522-3

  View details for PubMedID 31359002

• A Case Report of Pediatric Clear Cell Carcinoma of the Urinary Bladder Associated With Polyomavirus AJSP-REVIEWS AND REPORTS Saleem, A., Brown, R. A., Higgins, J. T., Troxell, M. L., Kunder, C. A., Pinsky, B. A., Zambrano, E., Kao, C. 2018; 23 (6): 291–95

  View details for DOI 10.1097/PCR.0000000000000284

  View details for Web of Science ID 000457629000012

• Orbital and chorioretinal manifestations of Erdheim-Chester disease treated with vemurafenib. American journal of ophthalmology case reports Huang, L. C., Topping, K. L., Gratzinger, D., Brown, R. A., Martin, B. A., Silva, R. A., Kossler, A. L. 2018; 11: 158–63

  Abstract

  Purpose: We report a patient with severe multi-organ dysfunction of unknown origin who presented with bilateral orbital and chorioretinal manifestations that led to the diagnosis of Erdheim-Chester Disease (ECD).Observations: ECD is a rare, histiocytic, proliferative disorder characterized by multi-systemic organ involvement that has historically lacked effective therapy. Our patient underwent genetic testing that was positive for the BRAF V600E mutation; therefore, the patient was treated with vemurafenib.Conclusions and importance: This case demonstrates the rare orbital and intraocular manifestations of ECD and the unfortunate impact of a delayed diagnosis, the importance of early gene therapy testing for management decisions, and the utilization of targeted directed therapy to improve visual outcomes and quality of life.

  View details for PubMedID 30094395

• Loss of PERP as a Diagnostic Biomarker for Differentiated Vulvar Intraepithelial Neoplasia (dVIN) Devereaux, K., Brown, R., Barry-Holson, K., Yang, E., Kong, C. NATURE PUBLISHING GROUP. 2018: 416–17

  View details for Web of Science ID 000429308603037

• Expression of the transcription factor ZBTB46 distinguishes human histiocytic disorders of classical dendritic cell origin. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Satpathy, A. T., Brown, R. A., Gomulia, E. n., Briseño, C. G., Mumbach, M. R., Pan, Z. n., Murphy, K. M., Natkunam, Y. n., Chang, H. Y., Kim, J. n. 2018

  Abstract

  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.

  View details for PubMedID 29743654

• Primary cutaneous anaplastic large cell lymphoma. Journal of cutaneous pathology Brown, R. A., Fernandez-Pol, S., Kim, J. 2017; 44 (6): 570-577

  Abstract

  Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) is a CD30+ lymphoproliferative disorder (LPD) of the skin with a relatively good prognosis in the absence of high-stage disease. CD30+ LPDs comprise approximately 25%-30% of primary cutaneous lymphomas and as a group represent the second most common clonal T-cell neoplasm of the skin behind mycosis fungoides. Diagnosis of PC-ALCL relies strongly on clinicopathologic correlation given the potential morphologic, clinical and molecular overlap with the other cutaneous CD30+ LPD, lymphomatoid papulosis, and more aggressive hematolymphoid neoplasms.

  View details for DOI 10.1111/cup.12937

  View details for PubMedID 28342276

• ETV3-NCOA2 in indeterminate cell histiocytosis: clonal translocation supports sui generis. Blood Brown, R. A., Kwong, B. Y., McCalmont, T. H., Ragsdale, B. n., Ma, L. n., Cheung, C. n., Rieger, K. E., Arber, D. A., Kim, J. n. 2015

  View details for PubMedID 26438513