Publications by authors named "Ryanne A Brown"

27 Publications

  • Page 1 of 1

Next generation sequencing confirms T-cell clonality in a subset of pediatric pityriasis lichenoides.

J Cutan Pathol 2021 Oct 6. Epub 2021 Oct 6.

Departments of Dermatology, Stanford University Medical Center, Stanford, CA.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1111/cup.14143DOI Listing
October 2021

Consistent tumorigenesis with self-assembled hydrogels enables high-powered murine cancer studies.

Commun Biol 2021 08 19;4(1):985. Epub 2021 Aug 19.

Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA.

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.
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http://dx.doi.org/10.1038/s42003-021-02500-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376877PMC
August 2021

Nodular fasciitis of the breast: clinicopathologic and molecular characterization with identification of novel USP6 fusion partners.

Mod Pathol 2021 Oct 7;34(10):1865-1875. Epub 2021 Jun 7.

Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

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.
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http://dx.doi.org/10.1038/s41379-021-00844-4DOI Listing
October 2021

Cutaneous desmoid-type fibromatosis: A rare case with molecular profiling.

J Cutan Pathol 2021 Sep 30;48(9):1185-1188. Epub 2021 Jun 30.

Department of Pathology, Stanford Medicine, Stanford, California, USA.

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 extra-abdominal 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.
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http://dx.doi.org/10.1111/cup.14058DOI Listing
September 2021

Immunohistochemical ALK Expression in Granular Cell Atypical Fibroxanthoma: A Diagnostic Pitfall for ALK-Rearranged Non-neural Granular Cell Tumor.

Am J Dermatopathol 2021 Nov;43(11):831-834

Department of Pathology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA.

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.
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http://dx.doi.org/10.1097/DAD.0000000000001931DOI Listing
November 2021

High-resolution phenotyping of early acute rejection reveals a conserved alloimmune signature.

Cell Rep 2021 03;34(9):108806

Department of Surgery, Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA, USA; Stanford Immunology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.celrep.2021.108806DOI Listing
March 2021

Cutaneous acral myofibroma with PDGFRB mutation in a patient with linear morphea en coup de sabre.

J Cutan Pathol 2021 Aug 11;48(8):1097-1100. Epub 2021 Feb 11.

Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.

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http://dx.doi.org/10.1111/cup.13971DOI Listing
August 2021

TTF-1 expression in a case of cutaneous sarcomatoid squamous cell carcinoma.

J Cutan Pathol 2021 Jun 2;48(6):821-823. Epub 2021 Feb 2.

Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.

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http://dx.doi.org/10.1111/cup.13963DOI Listing
June 2021

ALK-positive compound Spitz nevus with extensive perineural and intraneural neurotropism.

J Cutan Pathol 2021 Jan 8;48(1):154-159. Epub 2020 Nov 8.

Department of Pathology, Stanford Medicine, Stanford, California, USA.

Historically recognized by their characteristic histopathologic features, Spitz neoplasms are now known to be molecularly defined by mutually exclusive recurrent abnormalities that cause activation of the MAPK pathway. Spitz neoplasms with ALK rearrangements frequently demonstrate polypoid growth with a plexiform arrangement of nested, fusiform melanocytes in intersecting fascicles. Although neurotropism has been described in indolent Spitz neoplasms, this feature is not frequently mentioned in publications on histopathologic assessment of this group of melanocytic tumors. Here, we present an unusual case of a 3-year-old female with an ALK-positive compound Spitz nevus with extensive perineural and intraneural neurotropism occurring on the vermilion border of the lower lip.
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http://dx.doi.org/10.1111/cup.13890DOI Listing
January 2021

Cutaneous T-cell lymphomas with pathogenic somatic mutations and absence of detectable clonal T-cell receptor gene rearrangement: two case reports.

Diagn Pathol 2020 Sep 28;15(1):122. Epub 2020 Sep 28.

Department of Pathology, Stanford Medicine, Stanford, CA, 94305, USA.

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 proven to 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 confirm a diagnosis of lymphoma in a clinically and histopathologically suspicious cutaneous lymphoid proliferation without detectable TCR clonality.
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http://dx.doi.org/10.1186/s13000-020-01022-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523289PMC
September 2020

Histopathologic Characterization of Mogamulizumab-associated Rash.

Am J Surg Pathol 2020 12;44(12):1666-1676

Department of Dermatology, Stanford University School of Medicine, Redwood City.

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.
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http://dx.doi.org/10.1097/PAS.0000000000001587DOI Listing
December 2020

PRAME expression in melanocytic proliferations with intermediate histopathologic or spitzoid features.

J Cutan Pathol 2020 Dec 10;47(12):1123-1131. Epub 2020 Sep 10.

Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.

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 nuclear 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 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.
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http://dx.doi.org/10.1111/cup.13818DOI Listing
December 2020

Diffuse PRAME expression is highly specific for malignant melanoma in the distinction from clear cell sarcoma.

J Cutan Pathol 2020 Dec 10;47(12):1226-1228. Epub 2020 Sep 10.

Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.

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http://dx.doi.org/10.1111/cup.13812DOI Listing
December 2020

Diagnostic Utility of LEF1 Immunohistochemistry in Differentiating Deep Penetrating Nevi From Histologic Mimics.

Am J Surg Pathol 2020 10;44(10):1413-1418

Departments of Pathology.

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 β-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 β-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 β-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 β-catenin expression with more intense staining superficially and loss of staining with increasing depth. Deep, uniform nuclear LEF1 combined with β-catenin immunohistochemical staining can be useful in distinguishing DPN from histologic mimics.
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http://dx.doi.org/10.1097/PAS.0000000000001513DOI Listing
October 2020

Molecular profiling of a primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid.

J Cutan Pathol 2020 Sep 15;47(9):860-864. Epub 2020 Jun 15.

Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.

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. Histopathologic 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.
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http://dx.doi.org/10.1111/cup.13733DOI Listing
September 2020

Reticulohistiocytoma (solitary epithelioid histiocytoma) with mutations in RAF1 and TSC2.

J Cutan Pathol 2020 Oct 20;47(10):985-987. Epub 2020 Jul 20.

Department of Pathology, Stanford University Medical Center, Stanford, California, USA.

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http://dx.doi.org/10.1111/cup.13727DOI Listing
October 2020

Cutaneous pleomorphic fibromas arising in patients with germline TP53 mutations.

J Cutan Pathol 2020 Aug 6;47(8):734-741. Epub 2020 Apr 6.

Department of Pathology, Stanford University School of Medicine, Stanford, California.

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 (≤2 cm) and raised (4/5). Histopathologically, the tumors were paucicellular, composed 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.
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http://dx.doi.org/10.1111/cup.13686DOI Listing
August 2020

Impact of a deep learning assistant on the histopathologic classification of liver cancer.

NPJ Digit Med 2020 26;3:23. Epub 2020 Feb 26.

3Center for Artificial Intelligence in Medicine & Imaging, Stanford University, Stanford, CA USA.

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 ( = 0.184, OR = 1.281), it significantly improved the accuracy ( = 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 ( = 0.000, OR = 4.289), whereas when the model's prediction was incorrect, assistance significantly decreased accuracy ( = 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.
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http://dx.doi.org/10.1038/s41746-020-0232-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044422PMC
February 2020

Disseminated tuberculosis presenting as medium-vessel vasculitis in an immunocompromised host.

J Cutan Pathol 2020 Aug 19;47(8):725-728. Epub 2020 Mar 19.

Department of Dermatology, Stanford University Medical Center, Stanford, California, USA.

Cutaneous tuberculosis is an uncommon entity with several clinical forms recognized. Histopathologically, most cases are characterized by granulomatous inflammation and caseating necrosis, although 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. Mycobacterium 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 antituberculosis therapy. This case illustrates an uncommon clinical and histopathologic presentation of disseminated tuberculosis.
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http://dx.doi.org/10.1111/cup.13678DOI Listing
August 2020

Clonal replacement of tumor-specific T cells following PD-1 blockade.

Nat Med 2019 08 29;25(8):1251-1259. Epub 2019 Jul 29.

Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.

Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer. 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 unclear. 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 CD8CD39 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.
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http://dx.doi.org/10.1038/s41591-019-0522-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689255PMC
August 2019

Orbital and chorioretinal manifestations of Erdheim-Chester disease treated with vemurafenib.

Am J Ophthalmol Case Rep 2018 Sep 25;11:158-163. Epub 2018 Jul 25.

Byers Eye Institute, Department of Ophthalmology, Stanford University, 2452 Watson Court, Palo Alto, CA, United States.

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 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.
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http://dx.doi.org/10.1016/j.ajoc.2018.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076364PMC
September 2018

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

Mod Pathol 2018 09 9;31(9):1479-1486. Epub 2018 May 9.

Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.

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.
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http://dx.doi.org/10.1038/s41379-018-0052-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138663PMC
September 2018

Primary cutaneous anaplastic large cell lymphoma.

J Cutan Pathol 2017 Jun 25;44(6):570-577. Epub 2017 Apr 25.

Department of Pathology, Stanford University School of Medicine, Stanford, California.

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.
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http://dx.doi.org/10.1111/cup.12937DOI Listing
June 2017

ETV3-NCOA2 in indeterminate cell histiocytosis: clonal translocation supports sui generis.

Blood 2015 Nov 5;126(20):2344-5. Epub 2015 Oct 5.

Departments of Pathology and Dermatology, Stanford University School of Medicine, Stanford, CA.

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http://dx.doi.org/10.1182/blood-2015-07-655530DOI Listing
November 2015

Diagnostic utility of the spatial versus individual planar QRS-T angles in cardiac disease detection.

J Electrocardiol 2011 Jul-Aug;44(4):404-9. Epub 2011 Feb 24.

Baylor College of Medicine, Houston, TX, USA.

Introduction: We compared the diagnostic utility of various planar QRS-T angles to that of the spatial QRS-T angle in detecting various cardiac diseases.

Materials And Methods: Electrocardiographic (ECG) and derived vectorcardiographic (VCG) data were analyzed from 370 patients with imaging-proven cardiac disease (coronary artery disease, hypertrophic cardiomyopathy, or left ventricular systolic dysfunction) and 210 apparently healthy controls. The areas under the curve (AUC) of the Receiver Operating Characteristic (ROC) for distinguishing cardiac health from disease for each disease condition were statistically compared for the spatial mean QRS-T angle versus the ECG-derived frontal and VCG-derived frontal, left sagittal and horizontal planar QRS-T angles.

Results: The AUC ROC of the spatial mean QRS-T angle, which ranged from 0.801 ± 0.035 to 0.987 ± 0.007 depending on the specific comparison, was always significantly greater than that of the ECG frontal planar QRS-T angle (range from 0.680 ± 0.043 to 0.796 ± 0.045) and usually significantly greater than that of all other QRS-T angles for the diseases studied.

Discussion: The spatial mean QRS-T angle is statistically significantly more diagnostically powerful than the ECG-derived frontal planar QRS-T angle and also generally more diagnostically powerful than all VCG-derived planar QRS-T angles in detecting cardiac disease. The ECG frontal planar QRS-T angle should not be considered an adequate diagnostic substitute for the spatial QRS-T angle.
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http://dx.doi.org/10.1016/j.jelectrocard.2011.01.001DOI Listing
November 2011
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