Publications by authors named "Roberto A Novoa"

44 Publications

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

Am J Dermatopathol 2021 Mar 9. Epub 2021 Mar 9.

Department of Pathology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA; Department of Pathology, Stanford University School of Medicine, Stanford, CA; Department of Dermatology, Stanford University School of Medicine, Stanford, CA; Department of Pathology, Veterans Affairs Central California Health Care System, Fresno, CA; and Cytogenetics Laboratory, Department of Pathology, Stanford Health Care, 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
March 2021

TrueImage: A Machine Learning Algorithm to Improve the Quality of Telehealth Photos.

Pac Symp Biocomput 2021 ;26:220-231

Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA† Correspondence authors*These authors contributed equally,

Telehealth is an increasingly critical component of the health care ecosystem, especially due to the COVID-19 pandemic. Rapid adoption of telehealth has exposed limitations in the existing infrastructure. In this paper, we study and highlight photo quality as a major challenge in the telehealth workflow. We focus on teledermatology, where photo quality is particularly important; the framework proposed here can be generalized to other health domains. For telemedicine, dermatologists request that patients submit images of their lesions for assessment. However, these images are often of insufficient quality to make a clinical diagnosis since patients do not have experience taking clinical photos. A clinician has to manually triage poor quality images and request new images to be submitted, leading to wasted time for both the clinician and the patient. We propose an automated image assessment machine learning pipeline, TrueImage, to detect poor quality dermatology photos and to guide patients in taking better photos. Our experiments indicate that TrueImage can reject ~50% of the sub-par quality images, while retaining ~80% of good quality images patients send in, despite heterogeneity and limitations in the training data. These promising results suggest that our solution is feasible and can improve the quality of teledermatology care.
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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

Concurrent Trypanosoma cruzi and Cytomegalovirus Reactivation in an Immunosuppressed Patient With Limited Cutaneous Systemic Sclerosis.

Am J Dermatopathol 2020 Nov 16. Epub 2020 Nov 16.

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

Chagas disease, a multisystem infection caused by the protozoan Trypanosoma cruzi, is primarily found in Latin America. In recent years, prevalence has increased in the United States, where reactivation is the most common clinical scenario. Here, we describe cutaneous reactivation of T. cruzi in a patient with limited cutaneous systemic sclerosis on immunosuppression therapy who simultaneously presented with cytomegalovirus reactivation. Histopathology showed parasitized histiocytes in the superficial and deep dermis. Occasional epidermal keratinocytes were also parasitized, and rare organisms were also seen in the walls of blood vessels. Also noted were viral cytopathic changes within the vascular endothelium, and immunostaining confirmed cytomegalovirus. In this report, we describe the difference in cutaneous findings between reactivated and acute Chagas disease, and we also review the histopathologic features that help distinguish T.cruzi from other intracellular organisms.
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http://dx.doi.org/10.1097/DAD.0000000000001842DOI Listing
November 2020

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

Differentiation syndrome during ivosidenib treatment with immunohistochemistry showing isocitrate dehydrogenase R132H mutation.

J Cutan Pathol 2020 Nov 28;47(11):1042-1045. Epub 2020 Aug 28.

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

We report a case of differentiation syndrome in a patient receiving the IDH1 inhibitor ivosidenib, with skin biopsy showing isocitrate dehydrogenase (IDH) R132H-mutated leukemia cutis. A 72-year-old man with IDH1-mutated acute myeloid leukemia (AML), status-post allogeneic cell transplantation, on ivosidenib for 6 months, was admitted for culture-negative neutropenic fever, pink and purpuric plaques and patches on the legs, abdomen and back, edema, hypotension, and shortness of breath. Skin biopsy revealed an infiltrate of atypical, immature, myeloperoxidase-positive mononuclear cells compatible with leukemia cutis or Sweet syndrome. Although dermal edema and interstitial neutrophilic infiltrate with karyorrhexis characteristic of Sweet syndrome were not seen, the atypical cells lacked expression of CD117 and CD34, which were expressed in the original leukemia. Additional immunohistochemical staining of suspected blasts was strongly positive for IDH1 R132H, suggesting a diagnosis of leukemia cutis. As the immunophenotype of blasts in skin infiltrates can significantly differ from the immunophenotype seen in blood and bone marrow, this case shows that mutation-specific antibodies such as anti-IDH1 R132H may be useful to help distinguish malignant from non-malignant infiltrates in the skin. Furthermore, differentiation syndrome may show histopathologic features of leukemia cutis on skin biopsy.
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http://dx.doi.org/10.1111/cup.13780DOI Listing
November 2020

Simultaneous coccidioidomycosis and phaeohyphomycosis in a kidney transplant recipient: A case report and literature review.

Transpl Infect Dis 2020 Dec 25;22(6):e13365. Epub 2020 Jun 25.

Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Advances in solid organ transplantation have improved the survival of end-stage organ disease at the expense of an increased risk for opportunistic infections. Unusual clinical presentations and the possibility of concurrent infections make diagnosing invasive fungal infection (IFI) more difficult. Here, we present a case of simultaneous vertebral infection caused by Coccidioides immitis-posadasii and subcutaneous phaeohyphomycosis due to Nigrograna mackinnonii in a kidney transplant recipient. The diagnosis of both infections required invasive procedures to obtain tissue and a high index of suspicion that more than one IFI could be present. A multidisciplinary team approach for the management of immunocompromised patients with suspected or diagnosed IFI is warranted.
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http://dx.doi.org/10.1111/tid.13365DOI 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

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

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

J Cutan Pathol 2020 Aug 3;47(8):710-719. Epub 2020 Apr 3.

Laboratorio Recavarren Emanuel, Clínica Ricardo Palma, Lima, Peru.

Background And Objective: Located on chromosome locus 5p15.33, telomerase reverse transcriptase (TERT or hTERT) encodes the catalytic subunit of telomerase which permits lengthening and preservation of telomeres following mitosis. Mutations in TERT promoter (TERT-p) upregulate expression of TERT, allowing survival of malignant cells and tumor progression in wide variety of malignancies including melanoma. The objective of this review is to examine the roles of TERT and TERT-p in the pathogenesis, diagnosis, and prognostication of cutaneous melanoma.

Methods: All studies of TERT or TERT-p in cutaneous melanocytic neoplasms with the following inclusion criteria were reviewed: publication date between 2010 and 2019, English language, and series of ≥3 cases were reviewed for evidence supporting the role of TERT in pathogenesis, diagnosis, and prognosis. Studies with <3 cases or focused primarily on mucosal or uveal melanocytic tumors were excluded.

Results And Conclusion: TERT-p mutations are frequent in chronic and non-chronic sun damage melanoma and correlate with adverse prognosis, inform pathogenesis, and may provide diagnostic support. While TERT-p mutations are uncommon in acral melanoma, TERT copy number gains and gene amplification predict reduced survival. Among atypical spitzoid neoplasms, TERT-p mutations identify biologically aggressive tumors and support the diagnosis of spitzoid melanoma. TERT-p methylation may have prognostic value in pediatric conventional melanoma and drive tumorigenesis in melanoma arising within congenital nevi. Finally, TERT-p mutations may aid in the differentiation of recurrent nevi from recurrent melanoma.
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http://dx.doi.org/10.1111/cup.13691DOI Listing
August 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

Marking the Path Toward Artificial Intelligence-Based Image Classification in Dermatology.

JAMA Dermatol 2019 Oct;155(10):1105-1106

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

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http://dx.doi.org/10.1001/jamadermatol.2019.1633DOI Listing
October 2019

Artificial intelligence and dermatology: opportunities, challenges, and future directions.

Semin Cutan Med Surg 2019 Mar 1;38(1):E31-37. Epub 2019 Mar 1.

Department of Dermatology, Stanford University, Stanford, California.

The application of artificial intelligence (AI) to medicine has considerable potential within dermatology, where the majority of diagnoses are based on visual pattern recognition. Opportunities for AI in dermatology include the potential to automate repetitive tasks; optimize time-consuming tasks; extend limited medical resources; improve interobserver reliability issues; and expand the diagnostic toolbox of dermatologists. To achieve the full potential of AI, however, developers must aim to create algorithms representing diverse patient populations; ensure algorithm output is ultimately interpretable; validate algorithm performance prospectively; preserve human-patient interaction when necessary; and demonstrate validity in the eyes of regulatory bodies.
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http://dx.doi.org/10.12788/j.sder.2019.DOI Listing
March 2019

Biomarker discovery analysis: Alterations in p14, p16, p53, and BAP1 expression in nevi, cutaneous melanoma, and metastatic melanoma.

Pigment Cell Melanoma Res 2019 05 10;32(3):474-478. Epub 2019 Feb 10.

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

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http://dx.doi.org/10.1111/pcmr.12768DOI Listing
May 2019

Paraneoplastic granulomatous dermatitis in a patient with Hodgkin's disease: a diagnostic pitfall.

BMJ Case Rep 2018 Aug 11;2018. Epub 2018 Aug 11.

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

The association of malignant lymphomas with non-necrotic epithelioid granulomas has been reported rarely since 1977. Hodgkin's disease-associated widespread cutaneous granuloma annulare (GA) has been reported in only eight patients. We report the second case of subcutaneous GA associated with Hodgkin's disease. A 73-year-old man with Epstein-Barr virus-associated Hodgkin's lymphoma and paraneoplastic subcutaneous GA, presented 3 months after the diagnosis of malignancy. Examination revealed a large, broad erythematous, indurated, subcutaneous plaque spanning the majority of the left lower back and flank with no associated symptoms. Initial biopsy was suggestive of morphea. Prompted by positron emission tomography (PET) findings of increased fluorodeoxyglucose (FDG) uptake, a second, deeper biopsy was performed, revealing subcutaneous palisaded granulomatous dermatitis. After complete workup, the diagnosis most strongly suggested subcutaneous GA. This case highlights the importance of deep incisional biopsies, the fluorodeoxyglucose - positron emission tomography (FDG-PET) findings in GA and the rare association of GA with Hodgkin's disease which may signal the presence of malignancy.
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http://dx.doi.org/10.1136/bcr-2018-224961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088301PMC
August 2018

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

J Cutan Pathol 2018 Nov 22;45(11):839-846. Epub 2018 Aug 22.

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

Background: The gold standard for the diagnosis of melanocytic lesions is histologic examination. However, as histologic examination can have its limitations, there are many clinical scenarios in which additional testing may be appropriate in an attempt to render a definitive diagnosis.

Methods: A literature review for three ancillary tests-comparative genomic hybridization (CGH)/single-nucleotide polymorphism (SNP) array, fluorescence in situ hybridization (FISH), and gene expression profiling by quantitative reverse transcription polymerase chain reaction (qRT-PCR)-was compiled and current use patterns were tabulated. Survey of the practice patterns of these tests by dermatopathologists was also accessed in the attendees of the American Society of Dermatopathology Annual Meeting (Chicago, 2016).

Results: Here we summarize the use of these molecular tests in melanocytic lesions. We found that 54.4% of the respondents surveyed utilize (or expect consultants to utilize) molecular testing of melanocytic lesions in their practice when appropriate.

Conclusions: CGH/SNP arrays, FISH testing, and qRT-PCR applied to melanocytic lesions have allowed for more accurate classification. Just over half of those surveyed use molecular testing for melanocytic lesion with the majority sending their cases out for completion of the molecular test.
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http://dx.doi.org/10.1111/cup.13327DOI Listing
November 2018

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

J Am Acad Dermatol 2019 Jan 22;80(1):189-207.e11. Epub 2018 Apr 22.

Departments of Pathology, Dermatology, and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy, and physician decision-making.

Objectives: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology.

Methods: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience, and expert judgment, was used to develop AUC in dermatopathology.

Results: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate" and 52 (25%) "rarely appropriate" and 43 (20%) having "uncertain appropriateness."

Limitations: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost.

Conclusions: The ultimate decision to order specific tests rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-the AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.
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http://dx.doi.org/10.1016/j.jaad.2018.04.033DOI Listing
January 2019

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

J Cutan Pathol 2018 Aug 7;45(8):563-580. Epub 2018 Jun 7.

Bey Dermatology and Cosmetic Surgery, Spring Hill, Florida.

Background: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy and physician decision-making.

Objectives: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology.

Methods: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience and expert judgment, was used to develop AUC in dermatopathology.

Results: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate," 52 (25%) "rarely appropriate" and 43 (20%) "uncertain appropriateness."

Limitations: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost.

Conclusions: The ultimate decision of when to order specific test rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.
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http://dx.doi.org/10.1111/cup.13142DOI Listing
August 2018

Variability in the Expression of Immunohistochemical Markers: Implications for Biomarker Interpretation in Cutaneous T-Cell Lymphoma.

J Invest Dermatol 2018 05 14;138(5):1204-1206. Epub 2017 Dec 14.

Department of Dermatology, Stanford University School of Medicine, Palo Alto, California, USA; Stanford Cancer Institute, Stanford University School of Medicine, Palo Alto, California, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2017.11.035DOI Listing
May 2018

Development of RET mutant cutaneous angiosarcoma during BRAF inhibitor therapy.

J Cutan Pathol 2017 Dec 13;44(12):1053-1056. Epub 2017 Sep 13.

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

Treatment with BRAF inhibitors may lead to paradoxical mitogen-activated protein kinase (MAPK) pathway activation and accelerated tumorigenesis in cells with preexisting oncogenic hits. This phenomenon manifests clinically in the development of squamous cell carcinomas (SCCs) and keratoacanthomas (KAs) in patients treated with BRAF inhibitors. Cases of extracutaneous malignancies associated with BRAF inhibitors have also been reported. We present a case of a patient who developed a cutaneous angiosarcoma 6 months after initiation of vemurafenib therapy. Next-generation sequencing (NGS) revealed a mutation in RET, which lies upstream of the MAPK pathway. This case highlights that treatment with BRAF inhibitors may promote the accelerated growth of secondary malignancies. Physician awareness of the spectrum of secondary malignancies associated with BRAF inhibitor treatment will support their early detection and treatment.
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http://dx.doi.org/10.1111/cup.13024DOI Listing
December 2017

Dermatologist-level classification of skin cancer with deep neural networks.

Nature 2017 02 25;542(7639):115-118. Epub 2017 Jan 25.

Department of Computer Science, Stanford University, Stanford, California, USA.

Skin cancer, the most common human malignancy, is primarily diagnosed visually, beginning with an initial clinical screening and followed potentially by dermoscopic analysis, a biopsy and histopathological examination. Automated classification of skin lesions using images is a challenging task owing to the fine-grained variability in the appearance of skin lesions. Deep convolutional neural networks (CNNs) show potential for general and highly variable tasks across many fine-grained object categories. Here we demonstrate classification of skin lesions using a single CNN, trained end-to-end from images directly, using only pixels and disease labels as inputs. We train a CNN using a dataset of 129,450 clinical images-two orders of magnitude larger than previous datasets-consisting of 2,032 different diseases. We test its performance against 21 board-certified dermatologists on biopsy-proven clinical images with two critical binary classification use cases: keratinocyte carcinomas versus benign seborrheic keratoses; and malignant melanomas versus benign nevi. The first case represents the identification of the most common cancers, the second represents the identification of the deadliest skin cancer. The CNN achieves performance on par with all tested experts across both tasks, demonstrating an artificial intelligence capable of classifying skin cancer with a level of competence comparable to dermatologists. Outfitted with deep neural networks, mobile devices can potentially extend the reach of dermatologists outside of the clinic. It is projected that 6.3 billion smartphone subscriptions will exist by the year 2021 (ref. 13) and can therefore potentially provide low-cost universal access to vital diagnostic care.
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http://dx.doi.org/10.1038/nature21056DOI Listing
February 2017

Sarcoidosis and squamous cell carcinoma: a connection documented in a case series of 3 patients.

Cutis 2016 Dec;98(6):377-380

Department of Dermatology, University of Pennsylvania, Philadelphia, USA.

Sarcoidosis is a chronic multisystem disease characterized by the formation of noncaseating granulomas in multiple organs, including the skin. An association between multisystem sarcoidosis and an increased risk for malignancy has been established. Dermatologists should be aware of the increased risk for nonmelanoma skin cancers in patients with sarcoidosis. We report a series of 3 patients with primarily cutaneous sarcoidosis who presented with new-onset cutaneous squamous cell carcinoma (SCC). Two patients were black women and 1 patient presented with lesions of cutaneous sarcoidosis arising concurrently with SCCs in the same location, distinguishable only by biopsy. These cases highlight the association between sarcoidosis and an increased risk for SCC. Because dermatologists may be the primary clinicians caring for these patients, it is important that they remain aware of the increased risk for cutaneous malignancies and that they have a low threshold for biopsy of new and unusual skin lesions. Furthermore, 2 patients were black women, a population not commonly affected by skin cancer, which further exemplifies the need for comprehensive skin examinations in black patients. Although the precise mechanism for an increased risk for malignancy in these patients requires further investigation, chronic inflammation and immune dysregulation may play a role.
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December 2016

Gain of CD26 expression on the malignant T-cells in relapsed erythrodermic leukemic mycosis fungoides.

J Cutan Pathol 2017 May 10;44(5):462-466. Epub 2017 Feb 10.

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Loss of CD26 surface expression on the circulating malignant T-cell is the most widely accepted diagnostic marker in patients with leukemic cutaneous T-cell lymphoma (CTCL). CTCL cases with reemergence of CD7 and/or CD26 surface expression are unusual and of uncertain prognosis. We report the case of an erythrodermic leukemic mycosis fungoides patient who had achieved temporary remission after several months on multimodality immunotherapy and extracorporeal photopheresis, but who relapsed with aggressive disease phenotypically characterized by CD4+ T-cells with high CD26 expression. Polymerase chain reaction studies and high-throughput sequencing analyses from peripheral blood mononuclear cells at presentation and relapse consistently showed an identical clonal T-cell receptor suggesting evolution of her original malignant clone which lacked CD26 expression. Interestingly, quantitative expression of the sialomucin, CD164, mirrored her clinical picture, thus favoring its reliability as a novel biomarker in CTCL.
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http://dx.doi.org/10.1111/cup.12899DOI Listing
May 2017

Low-dose radiotherapy for primary cutaneous anaplastic large-cell lymphoma while on low-dose methotrexate.

Cutis 2016 Oct;98(4):253-256

Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.

Primary cutaneous anaplastic large-cell lymphoma (pcALCL) is part of a spectrum of CD30+ primary cutaneous lymphoproliferative disorders (pcLPDs) that also includes lymphomatoid papulosis (LyP). Localized radiotherapy at doses of 34 to 44 Gy is first-line treatment of pcALCL, but the use of low-dose radiotherapy for pcALCL has not been reported. We present the case of a patient with a history of pcALCL/LyP who was treated with low-dose radiotherapy while on oral low-dose methotrexate (MTX) once weekly. This report suggests that low-dose radiotherapy can be an effective palliative treatment of pcALCL. Low-dose radiotherapy may offer certain advantages over traditional radiotherapy, such as a more economical and efficient treatment for patients, potentially fewer short-term and long-term side effects, and the potential for concomitant use with low-dose MTX.
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October 2016
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