Publications by authors named "Alejandro A Gru"

140 Publications

Secondary Skin Involvement in Classic Hodgkin Lymphoma: Results of an International Collaborative Cutaneous Lymphoma Working Group Study of 25 Patients.

J Cutan Pathol 2021 Jun 4. Epub 2021 Jun 4.

Pathology Department, Université de Paris, Hôpital Saint-Louis, Paris, France.

Aims: Cutaneous involvement by classic Hodgkin lymphoma (CHL) is an extraordinarily rare phenomenon in the current era. To date, no single large case series of cutaneous involvement by Hodgkin lymphoma has ever been reported in the literature.

Methods And Results: A total of 25 cases of classic Hodgkin lymphoma were found. All cases represented examples of systemic CHL with secondary skin dissemination. A single lesion, usually a tumor, nodule or infiltrative plaque was observed in 56% of cases and multiple lesions were present in 28% of cases. Most patients (86% - 12/14) had a diagnosis of stage IV disease at first diagnosis. The interval between the clinical (first) diagnosis of HL and development of skin lesions ranged between 6-108 months (average 33.75 months). Comprehensive histopathologic evaluation of these cases (at the initial diagnosis) revealed a diagnosis of classic HL not otherwise specified (NOS) in 60% of cases (15/25), nodular sclerosis type in 24% (6/25), mixed cellularity in 12% (3/25), and lymphocyte depleted in 4% (1/25).

Conclusions: We provide documentation of a large series of classic Hodgkin lymphoma with secondary skin involvement in association with CHL with additional clinical, morphologic and immunophenotypic features. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/cup.14077DOI Listing
June 2021

PD-1 and PD-L1 Immunohistochemistry as a Diagnostic Tool for Classic Hodgkin Lymphoma in Small-volume Biopsies.

Am J Surg Pathol 2021 Jun 3. Epub 2021 Jun 3.

Department of Pathology, Stanford Medicine, Stanford, CA Department of Pathology, University of Virginia, Charlottesville, VA.

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http://dx.doi.org/10.1097/PAS.0000000000001743DOI Listing
June 2021

Primary Cutaneous CD4-Positive Small/Medium T-Cell Lymphoproliferative Disorder Mimicking Jessner Lymphocytic Infiltrate and Tumid Lupus-A Report of Two Cases.

Am J Dermatopathol 2021 May 17. Epub 2021 May 17.

Department of Dermatology, University of Virginia School of Medicine, Charlottesville, VA; and Department of Pathology and Dermatology, University of Virginia Health System, Charlottesville, VA.

Abstract: Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder is a benign lymphoproliferative disorder composed of small-sized to medium-sized pleomorphic cells expressing a follicular helper T-cell phenotype. Jessner lymphocytic infiltrate and tumid lupus are cutaneous conditions characterized by the presence of rich dermal lymphocytic infiltrates with a superficial, deep, perivascular and periadnexal distribution that include copious amounts of dermal mucin deposition. We report 2 cases of primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder presenting with markedly increased dermal mucin, mimicking both Jessner lymphocytic infiltrate and tumid lupus and provide a review of the differential diagnosis and highlight key distinguishing features.
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http://dx.doi.org/10.1097/DAD.0000000000001982DOI Listing
May 2021

Rare EBV-associated B cell neoplasms of the gastrointestinal tract.

Semin Diagn Pathol 2021 Jul 29;38(4):38-45. Epub 2021 Apr 29.

Department of Pathology, University of Virginia, Charlottesville, VA, United States. Electronic address:

EBV-driven B cell neoplasms can rarely present as an extranodal mass in the gastrointestinal tract and can be missed, even by experienced pathologists, because of this uncommon presentation. A selection of these neoplasms, namely EBV-positive diffuse large B cell lymphoma, not otherwise specified (DLBCL NOS), EBV-positive mucocutaneous ulcer (EBV MCU), extracavitary primary effusion lymphoma (EPEL), and EBV-positive Burkitt lymphoma, will be discussed in the present review. Besides the common thread of EBV positivity, these lymphoproliferative disorders arise in unique clinical settings that are often associated with immunodeficiency, immunosuppression or immunosenescence and can present as solitary masses albeit rarely, within the gastrointestinal tract.
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http://dx.doi.org/10.1053/j.semdp.2021.04.004DOI Listing
July 2021

Primary Cutaneous Monomorphic Post-transplant Lymphoproliferative Disorder Mimicking Squamous Cell Carcinoma In Situ.

Am J Dermatopathol 2021 Apr 21. Epub 2021 Apr 21.

Departments of Pathology, and Dermatology, University of Virginia, Charlottesville, VA.

Abstract: Post-transplant lymphoproliferative disorder (PTLD) is a term used to describe a range of lymphoproliferative disorders that occur after solid organ transplant. Although the clinical presentation is variable, primary cutaneous PTLD typically presents as isolated nodules that appear as dermal-based proliferations. We present a case of a 70-year-old woman with a history of a kidney transplant who presented with a 2-month history of an asymptomatic, erythematous plaque on the right shin, clinically suspected to be squamous cell carcinoma in situ. Histomorphology demonstrated a dermal proliferation of atypical plasma cells with dense chromatin, variable nucleoli, and irregular nuclear borders. The atypical plasma cells were positive for Epstein-Barr virus by in situ hybridization and markedly kappa-restricted by RNAscope in situ hybridization. A diagnosis of cutaneous monomorphic PTLD, plasma cell neoplasm variant, was rendered, a rare diagnosis in the skin. Treatment for PTLD typically involves reduction of immunosuppression, although our patient progressed and developed new lesions despite this intervention. In this study, we present an atypical presentation of cutaneous PTLD, plasma cell neoplasm variant, presenting as squamous cell carcinoma in situ.
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http://dx.doi.org/10.1097/DAD.0000000000001950DOI Listing
April 2021

Solitary irregular hyperkeratotic and eroded plaque on the shoulder of a child.

Pediatr Dermatol 2021 03;38(2):490-491

Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

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http://dx.doi.org/10.1111/pde.14491DOI Listing
March 2021

Response to brentuximab vedotin versus physician's choice by CD30 expression and large cell transformation status in patients with mycosis fungoides: An ALCANZA sub-analysis.

Eur J Cancer 2021 May 29;148:411-421. Epub 2021 Mar 29.

Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, 40 Landsdowne Street, 02139, Cambridge, MA, USA. Electronic address:

Introduction: Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, can lead to disfiguring lesions, debilitating pruritus and frequent skin infections. This study assessed response to brentuximab vedotin in patients with MF in the phase III ALCANZA study.

Methods: Baseline CD30 levels and large-cell transformation (LCT) status were centrally reviewed in patients with previously-treated CD30-positive MF using ≥2 skin biopsies obtained at screening; eligible patients required ≥1 biopsy with ≥10% CD30 expression. Patients were categorised as CD30 < 10% (≥1 biopsy with <10% CD30 expression), or CD30 ≥ 10% (all biopsies with ≥10% CD30 expression) and baseline LCT present or absent. Efficacy analyses were the proportion of patients with objective response lasting ≥4 months (ORR4) and progression-free survival (PFS).

Results: Clinical activity with brentuximab vedotin was observed across all CD30 expression levels in patients with ≥1 biopsy showing ≥10% CD30 expression. Superior ORR4 was observed with brentuximab vedotin versus physician's choice in patients: with CD30 < 10% (40.9% versus 9.5%), with CD30 ≥ 10% (57.1% versus 10.3%), with LCT (64.7% versus 17.6%) and without LCT (38.7% versus 6.5%). Brentuximab vedotin improved median PFS versus physician's choice in patients: with CD30 < 10% (16.7 versus 2.3 months), with CD30 ≥ 10% (15.5 versus 3.9 months), with LCT (15.5 versus 2.8 months) and without LCT (16.1 versus 3.5 months). Safety profiles were generally comparable across subgroups.

Conclusion: These exploratory analyses demonstrated that brentuximab vedotin improved rates of ORR4 and PFS versus physician's choice in patients with CD30-positive MF and ≥1 biopsy showing ≥10% CD30 expression, regardless of LCT status.

Clinical Trial Registration: Clinicaltrials.gov, NCT01578499.
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http://dx.doi.org/10.1016/j.ejca.2021.01.054DOI Listing
May 2021

Iron control of erythroid microtubule cytoskeleton as a potential target in treatment of iron-restricted anemia.

Nat Commun 2021 03 12;12(1):1645. Epub 2021 Mar 12.

Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Anemias of chronic disease and inflammation (ACDI) result from restricted iron delivery to erythroid progenitors. The current studies reveal an organellar response in erythroid iron restriction consisting of disassembly of the microtubule cytoskeleton and associated Golgi disruption. Isocitrate supplementation, known to abrogate the erythroid iron restriction response, induces reassembly of microtubules and Golgi in iron deprived progenitors. Ferritin, based on proteomic profiles, regulation by iron and isocitrate, and putative interaction with microtubules, is assessed as a candidate mediator. Knockdown of ferritin heavy chain (FTH1) in iron replete progenitors induces microtubule collapse and erythropoietic blockade; conversely, enforced ferritin expression rescues erythroid differentiation under conditions of iron restriction. Fumarate, a known ferritin inducer, synergizes with isocitrate in reversing molecular and cellular defects of iron restriction and in oral remediation of murine anemia. These findings identify a cytoskeletal component of erythroid iron restriction and demonstrate potential for its therapeutic targeting in ACDI.
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http://dx.doi.org/10.1038/s41467-021-21938-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955080PMC
March 2021

Cross-reactivity of NRASQ61R antibody in a subset of Spitz nevi with 11p gain: a potential confounding factor in the era of pathway-based diagnostic approach.

Hum Pathol 2021 Jun 24;112:35-47. Epub 2021 Feb 24.

Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, 03766, USA; Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA. Electronic address:

The most recent World Health Organization classification for skin tumors (2018) categorizes melanomas and their precursor lesions, benign or intermediate, into nine pathways based not only on their clinical and histomorphologic characteristics but also on their molecular profile and genetic fingerprint. In an index case of a partially sampled atypical spitzoid lesion, which proved to be an 11p-amplified Spitz nevus with HRASQ61R mutation, we observed cross-reactivity with the NRASQ61R antibody (clone SP174). Overall, we assessed the status of HRAS and NRAS genes and their immunoreaction to NRASQ61R antibody in 16 cases of 11p-amplified Spitz nevi/atypical Spitz tumors. We also assessed the immunoexpression of NRASQ61R antibody in various malignancies with proven BRAFV600E, NRASQ61R, L or K, KRASQ61R and HRASQ61R, and HRASQ61R mutations and ALK+ Spitz lesions. Finally, we assessed the expression of PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry in our 11p Spitz cohort. Three of 16 cases (3/16) harbored the HRASQ61R mutation and exhibited diffuse immunoreaction with the NRASQ61R antibody. All the cases in our cohort were negative for the NRASQ61R mutation. All NRASQ61R-, KRASQ61R-, and HRASQ61R-mutated neoplasms were positive for the antibody, further supporting the cross-reactivity between the RAS proteins. All the cases of our cohort were essentially negative for PRAME immunohistochemistry. In the era of pathway-based approach in the diagnosis of melanocytic neoplasms, the cross-reactivity between the NRASQ61R- and HRASQ61R-mutated proteins can lead to a diagnostic pitfall in the assessment of lesions with spitzoid characteristics.
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http://dx.doi.org/10.1016/j.humpath.2021.02.001DOI Listing
June 2021

Pemphigus erythematosus: A case series from a tertiary academic center and literature review.

J Cutan Pathol 2021 Feb 20. Epub 2021 Feb 20.

Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Background: Pemphigus erythematosus (PE) is a rare autoimmune skin condition with clinical, histopathological, and serological features that show overlap between lupus erythematosus and pemphigus foliaceus. It typically presents with erythematous, scaly plaques and has a female predominance.

Methods: After Institutional Review Board (IRB) approval, we searched the internal pathology database for "pemphigus erythematosus" in the diagnostic line between 1 January 2000 and 30 July 2020. A comprehensive chart review was performed to collect patient demographics, clinical presentation, and treatment course. We performed a review of the literature and clinical, histopathological, and serological features were collected for comparison to our case series.

Results: Five patients in the case series and 87 patients in the literature were diagnosed with PE. Clinical, histopathological, and serological features were consistent with what has been reported in the literature, although our cohort demonstrated a younger age at presentation, along with a higher proportion (80%) of Black patients. Of the 25 patients in the literature whose race was reported, only five patients (20%) were reported to be Black.

Conclusion: This is the first case series of PE that has shown an increased prevalence among middle-aged Black patients. No specific trend in regards to race was seen in the review of the literature.
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http://dx.doi.org/10.1111/cup.13992DOI Listing
February 2021

Immunophenotypic Spectrum and Genomic Landscape of Refractory Celiac Disease Type II.

Am J Surg Pathol 2021 Jul;45(7):905-916

Department of Pathology and Cell Biology, Columbia University Irving Medical Center.

Refractory celiac disease type II (RCD II), also referred to as "cryptic" enteropathy-associated T-cell lymphoma (EATL) or "intraepithelial T-cell lymphoma," is a rare clonal lymphoproliferative disorder that arises from innate intraepithelial lymphocytes. RCD II has a poor prognosis and frequently evolves to EATL. The pathogenesis of RCD II is not well understood and data regarding the immunophenotypic spectrum of this disease and underlying genetic alterations are limited. To gain further biological insights, we performed comprehensive immunophenotypic, targeted next-generation sequencing, and chromosome microarray analyses of 11 RCD II cases: CD4-/CD8- (n=6), CD8+ (n=4), and CD4+ (n=1), and 2 of 3 ensuing EATLs. Genetic alterations were identified in 9/11 (82%) of the RCD II cases. All 9 displayed mutations in members of the JAK-STAT signaling pathway, including frequent, recurrent STAT3 (7/9, 78%) and JAK1 (4/9, 44%) mutations, and 9/10 evaluable cases expressed phospho-STAT3. The mutated cases also harbored recurrent alterations in epigenetic regulators (TET2, n=5 and KMT2D, n=5), nuclear factor-κB (TNFAIP3, n=4), DNA damage repair (POT1, n=3), and immune evasion (CD58, n=2) pathway genes. The CD4-/CD8- and other immunophenotypic subtypes of RCD II exhibited similar molecular features. Longitudinal genetic analyses of 4 RCD II cases revealed stable mutation profiles, however, additional mutations were detected in the EATLs, which occurred at extraintestinal sites and were clonally related to antecedent RCD II. Chromosome microarray analysis demonstrated copy number changes in 3/6 RCD II cases, and 1 transformed EATL with sufficient neoplastic burden for informative analysis. Our findings provide novel information about the immunophenotypic and genomic characteristics of RCD II, elucidate early genetic events in EATL pathogenesis, and reveal potential therapeutic targets.
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http://dx.doi.org/10.1097/PAS.0000000000001658DOI Listing
July 2021

Histomorphological and immunophenotypical spectrum of cutaneous myoepitheliomas: A series of 35 cases.

J Cutan Pathol 2021 Jul 7;48(7):847-855. Epub 2021 Jan 7.

The University of Virginia, Virginia, USA.

Myoepithelial tumors comprise a group of mesenchymal lesions that show heterogeneous histomorphological features, including dual epithelial, neural, and myoid differentiation. Cutaneous myoepithelioma is a rare neoplasm that is composed primarily of myoepithelial cells and represents one end of a histopathological spectrum of cutaneous myoepithelial neoplasms including chondroid syringoma and myoepithelial carcinoma. These tumors display a wide histopathological spectrum and immunophenotypical profile often showing epithelial and myoepithelial differentiation. In this series, we studied 35 cases of cutaneous myoepitheliomas. Our cases highlighted the broad histopathological range where most cases showed a non-infiltrative and non-encapsulated tumor exclusively located in the dermis and with no subcutaneous involvement. The majority of our cases had a solid growth pattern (syncytial pattern) and the remainder of cases had a multinodular growth pattern. The tumor cells were epithelioid in 23 cases, spindled in eight cases and there was a mixture of epithelioid and spindled cells in four cases. Mitotic figures ranged from 0 to 5 per 10 HPF. By immunohistochemistry epithelial membrane antigen (EMA) was expressed in 59% of cases S100 was positive in 88% of cases, CAM 5.2 was positive in 16% of cases, AE1/AE3 was positive in 44% of cases, p63 was positive in 17% of cases, smooth muscle actin was positive in 38% of cases, desmin was positive in 6% of cases, calponin was positive in 22% of cases, and glial fibrillary acidic protein was positive in 36% of cases. In addition, there were five cases without EMA, keratin, or p63 expression that only showed S100 expression. We describe a large series of cutaneous myoepitheliomas delineating their histomorphological spectrum and immunophenotypical profile. Awareness of some of the unusual histopathological features and the heterogeneous immunohistochemical may pose difficulties for the diagnosis.
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http://dx.doi.org/10.1111/cup.13942DOI Listing
July 2021

Primary cutaneous follicle center lymphoma in a 16-year-old girl.

J Cutan Pathol 2021 May 13;48(5):663-668. Epub 2021 Jan 13.

Department of Pathology, University of Virginia, Charlottesville, Virginia, USA.

In the pediatric and adolescent age group, primary cutaneous lymphomas are rare, especially cutaneous B-cell lymphomas. According to the World Health Organization, the three main subtypes of primary cutaneous B-cell lymphomas are primary cutaneous marginal zone B-cell lymphoma (PCMZL), primary cutaneous follicle center lymphoma (PCFCL), and primary cutaneous diffuse large B-cell lymphoma, leg type. We present an extraordinary case of PCFCL arising in a 16-year-old female, only the sixth case of PCFCL to be reported in the literature in a patient less than 20 years old. Although PCMZL was considered in this case, the finding of lambda light chain restriction in the BCL-6 and CD10 positive population of lymphocytes established the diagnosis of primary cutaneous follicle center lymphoma. Not many data currently exist on the prognosis of PCFCL in young individuals, but adult PCFCL has a good prognosis with an indolent course and 5-year survival rates over 95%. Because of its uncommon manifestation in young patients, the diagnosis of PCFCL is often delayed or missed. This case is presented to raise awareness of PCFCL in the pediatric/ adolescent population and to contribute to the ongoing research of this condition.
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http://dx.doi.org/10.1111/cup.13939DOI Listing
May 2021

Histopathology of primary cutaneous adenoid cystic carcinoma of the scrotum presenting with predominantly solid growth.

J Cutan Pathol 2020 Dec 14. Epub 2020 Dec 14.

Department of Pathology, University of Virginia, Charlottesville, Virginia.

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http://dx.doi.org/10.1111/cup.13928DOI Listing
December 2020

PRAME immunohistochemistry as an adjunct for diagnosis and histological margin assessment in lentigo maligna.

Histopathology 2021 Jun 2;78(7):1000-1008. Epub 2021 Apr 2.

Department of Pathology, University of Virginia, Charlottesville, VA, USA.

Aims: Lentigo maligna (LM), the most common type of melanoma in situ, is a diagnostically challenging lesion for pathologists due to abundant background melanocytic hyperplasia in sun-damaged skin. Currently, no laboratory methods reliably distinguish benign from malignant melanocytes. However, preferentially expressed antigen in melanoma (PRAME) has shown promise in this regard, and could potentially be applied to diagnosis and margin assessment in difficult cases of LM.

Methods And Results: Ninety-six cases with a diagnosis of LM (n = 77) or no residual LM (n = 19) following initial biopsy were identified and stained with an antibody directed towards PRAME. Immunohistochemistry (IHC) was scored as positive or negative, and measurement of histological margins by PRAME was performed and compared to the measurement of histological margins using conventional methods [haematoxylin and eosin (H&E) and/or sex-determining region Y-box 10 (SOX10) and/or Melan-A]. Of cases with LM, 93.5% (72 of 77) were PRAME and 94.7% (18 of 19) of cases with no residual LM were PRAME . Of the 35 cases with no margin involvement by PRAME or conventional assessment, 14 cases (40.0%) had no difference in measurement, 17 (48.6%) had a difference of 1 mm or less and four (11.4%) differed by between 1 and 3.5 mm. There was a high correlation between margin assessment methods (r = 0.97, P < 0.0001).

Conclusions: PRAME IHC is a sensitive (93.5%) and specific (94.7%) method for diagnosing LM on biopsy and excision, and measurement of histological margins by PRAME shows a high correlation with conventional methods for margin assessment. Furthermore, the nuclear expression of PRAME makes it a good target for use in dual-colour IHC stains.
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http://dx.doi.org/10.1111/his.14312DOI Listing
June 2021

Spindle-cell (Sarcomatoid) Variant of Cutaneous Anaplastic Large-cell Lymphoma (C-ALCL): An Unusual Mimicker of Cutaneous Malignant Mesenchymal Tumors-A Series of 11 Cases.

Am J Surg Pathol 2021 Jun;45(6):796-802

Department of Pathology & Dermatology, The Ohio State University Wexner Medical Center, Columbus, OH.

Cutaneous anaplastic large-cell lymphoma (C-ALCL) represents one of the entities within the group of CD30-positive lymphoproliferative disorders of the skin. Most cases are ALK-negative, though isolated cases of ALK-positive C-ALCL have also been reported. By definition, the diagnosis of C-ALCL requires the expression of CD30 in >75% of the cells. Histopathologically, C-ALCL shows a dermal-based nodular and circumscribed proliferation of large pleomorphic cells with vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasm, including hallmark cells. Since 1990, isolated case reports of a so-called "sarcomatoid" variant have been published in the literature. Herein, we present a series of 11 cases of spindle (sarcomatoid) C-ALCL, with comprehensive histopathologic, immunophenotypic, and molecular data. Spindle C-ALCL represents a potential mimicker of malignant mesenchymal or hematopoietic tumors in the skin and should always be considered in the differential diagnosis when assessing cutaneous pleomorphic spindle cell neoplasms.
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http://dx.doi.org/10.1097/PAS.0000000000001623DOI Listing
June 2021

Case and review: Cutaneous involvement by chronic neutrophilic leukemia vs Sweet syndrome- A diagnostic dilemma.

J Cutan Pathol 2021 May 9;48(5):644-649. Epub 2020 Dec 9.

Department of Dermatology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Chronic neutrophilic leukemia (CNL) is a rare leukemia with approximately 150 total cases reported. Cutaneous neutrophilic infiltrates, including Sweet syndrome (SS) and leukemia cutis (LC), have been reported in six patients with CNL. In the setting of CNL, these two conditions are difficult to differentiate due to clinical and histopathological similarities, but it is important to do so because LC is associated with a worse prognosis. In general, SS is distinguished by its tenderness, fever, and improvement with steroids (vs chemotherapy for LC). Biopsy of LC reveals immature leukocytes, whereas SS shows almost exclusively mature leukocytes, but morphology alone may not be sufficient in some cases. Here, we report a case of a 72-year-old male with CNL and a cutaneous eruption with clinical and pathological features which made the distinction between the two diseases difficult.
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http://dx.doi.org/10.1111/cup.13925DOI Listing
May 2021

IDO1 Expression in Melanoma Metastases Is Low and Associated With Improved Overall Survival.

Am J Surg Pathol 2021 Jun;45(6):787-795

Departments of Surgery.

Indoleamine 2-3 dioxygenase 1 (IDO1) expression may contribute to immunologic escape by melanoma metastases. However, a recent clinical trial failed to identify any clinical benefits of IDO1 inhibition in patients with unresectable metastatic melanoma, and prior characterizations of IDO1 expression have predominately studied primary lesions and local metastases, generating uncertainty regarding IDO1 expression in distant metastases. We hypothesized that IDO1 expression in such lesions would be low and correlated with decreased overall survival (OS). Metastases from patients (n=96) with stage IIIb to IV melanoma underwent tissue microarray construction and immunohistochemical staining for IDO1. Th1-related gene expression was determined quantitatively. Associations between OS and IDO1 expression were assessed with multivariate models. Of 96 metastatic lesions, 28% were IDOpos, and 85% exhibited IDO1 expression in <10% of tumor cells. IDOpos lesions were associated with improved OS (28.9 vs. 10.5 mo, P=0.02) and expression of Th1-related genes. OS was not associated with IDO1 expression in a multivariate analysis of all patients; however, IDO1 expression (hazard ratio=0.25, P=0.01) and intratumoral CD8+ T-cell density (hazard ratio=0.99, P<0.01) were correlated with OS in patients who underwent metastasectomy with curative-intent. IDOpos metastases were less likely to recur after metastasectomy (54% vs. 16%, P=0.01). IDO1 expression was low in melanoma metastases and correlated with OS after metastasectomy with curative-intent. Intratumoral CD8+ T cells and Th1-related genes were correlated with IDO1 expression, as was tumor recurrence. These suggest that IDO1 expression may be a marker of immunologic tumor control, and may inform participant selection in future trials of IDO1 inhibitors.
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http://dx.doi.org/10.1097/PAS.0000000000001622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102301PMC
June 2021

Persistent Plaque on the Scalp With Cutis Verticis Gyrata-Like Features: Answer.

Am J Dermatopathol 2020 Oct;42(10):793-794

Dermatology, University of Virginia, Charlottesville, VA.

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http://dx.doi.org/10.1097/DAD.0000000000001541DOI Listing
October 2020

PRAME expression in 155 cases of metastatic melanoma.

J Cutan Pathol 2021 Apr 8;48(4):479-485. Epub 2020 Nov 8.

Department of Pathology, University of Virginia, Charlottesville, Virginia, USA.

Background: PRAME (preferentially expressed antigen in melanoma) is a promising immunohistochemical marker in distinguishing benign from malignant primary cutaneous melanocytic lesions and lymph node deposits. We hypothesize that PRAME may also reliably identify melanoma metastases that are clinically detected in skin, lymph nodes, or small intestine.

Methods: A total of 155 cases of metastatic melanoma to lymph node (N = 54) and non-lymph node (N = 101) sites were stained with an antibody against PRAME. Nuclear expression was scored in tumor cells as negative, 1% to 25% (1+), 26% to 50% (2+), 51% to 75% (3+), or 76% to 100% (4+).

Results: PRAME expression was seen in 151/155 (97.4%) cases, with 4+ expression in 64 cases (41.3%), 3+ expression in 46 cases (29.7%), 2+ expression in 18 cases (11.6%), and 1+ expression in 23 cases (14.8%). Lymph node metastases were more likely to show lower expression as compared to metastases to other anatomic sites (P = 0.003).

Conclusions: A high level of PRAME immunoreactivity was identified in this cohort of metastatic melanoma. Lymph node metastases showed more focal or absent PRAME expression as compared to metastases to other sites. Overall, PRAME is a useful tool for confirming the diagnosis of melanoma in a metastatic setting, in both nodal and visceral deposits.
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http://dx.doi.org/10.1111/cup.13876DOI Listing
April 2021

A 40-Year-Old Woman With Hypopigmented Patches and a New Papular Rash: Challenge.

Am J Dermatopathol 2020 Sep;42(9):e126-e127

Pathology and Dermatology, University of Virginia, Charlottesville, VA.

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http://dx.doi.org/10.1097/DAD.0000000000001575DOI Listing
September 2020

A 40-Year-Old Woman With Hypopigmented Patches and a New Papular Rash: Answer.

Am J Dermatopathol 2020 Sep;42(9):712-713

Pathology and Dermatology, University of Virginia, Charlottesville, VA.

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http://dx.doi.org/10.1097/DAD.0000000000001574DOI Listing
September 2020

Tissue microRNA expression profiling in hepatic and pulmonary metastatic melanoma.

Melanoma Res 2020 10;30(5):455-464

The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute.

Malignant melanoma has a propensity for the development of hepatic and pulmonary metastases. MicroRNAs (miRs) are small, noncoding RNA molecules containing about 22 nucleotides that mediate protein expression and can contribute to cancer progression. We aim to identify clinically useful differences in miR expression in metastatic melanoma tissue. RNA was extracted from formalin-fixed, paraffin-embedded samples of hepatic and pulmonary metastatic melanoma, benign, nevi, and primary cutaneous melanoma. Assessment of miR expression was performed on purified RNA using the NanoString nCounter miRNA assay. miRs with greater than twofold change in expression when compared to other tumor sites (P value ≤ 0.05, modified t-test) were identified as dysregulated. Common gene targets were then identified among dysregulated miRs unique to each metastatic site. Melanoma metastatic to the liver had differential expression of 26 miRs compared to benign nevi and 16 miRs compared to primary melanoma (P < 0.048). Melanoma metastatic to the lung had differential expression of 19 miRs compared to benign nevi and 10 miRs compared to primary melanoma (P < 0.024). Compared to lung metastases, liver metastases had greater than twofold upregulation of four miRs, and 4.2-fold downregulation of miR-200c-3p (P < 0.0081). These findings indicate that sites of metastatic melanoma have unique miR profiles that may contribute to their development and localization. Further investigation of the utility of these miRs as diagnostic and prognostic biomarkers and their impact on the development of metastatic melanoma is warranted.
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http://dx.doi.org/10.1097/CMR.0000000000000692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484309PMC
October 2020

Inflammatory lobular hemangioma: A vascular proliferation with a prominent lymphoid component. Review of a series of 19 cases.

J Cutan Pathol 2021 Feb 30;48(2):229-236. Epub 2020 Sep 30.

Department of Pathology, University of Virginia, Charlottesville, Virginia, USA.

In the last 30 years, there has been a strong interest in vascular proliferations. Pyogenic granuloma was not only renamed lobular capillary hemangioma, but also the conceptual interpretation was also changed from an overgrowth of granulation tissue to a genuine hemangioma (or benign vascular neoplasm). We describe 19 cases of patients who presented clinically with a vascular lesion, characteristically a pyogenic granuloma or lobular hemangioma, where the histopathological findings led to the pathologic concern for a lymphoma of the skin. These benign lesions with a dense lymphoid infiltrate were further defined on the basis of different vascular and lymphoid immunohistochemical markers as inflammatory lobular hemangiomas. We propose that given the considerable histopathological overlap between acral pseudolymphomatous angiokeratoma, T-cell rich angiomatoid polypoid pseudolymphoma of the skin, and other designations of some of these vascular proliferations with a rich and dense lymphoid infiltrate, they might constitute a spectrum of vascular lesions with varying clinical presentations.
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http://dx.doi.org/10.1111/cup.13844DOI Listing
February 2021

Quality assurance in dermatopathology: A review of report amendments.

J Cutan Pathol 2021 Jan 14;48(1):34-40. Epub 2020 Sep 14.

Department of Pathology, University of Virginia, Charlottesville, Virginia, USA.

Background: Systematic review of amended reports in surgical pathology has been recommended as a valuable exercise in promoting quality assurance and improvement. Examination of report amendments can identify defects in the surgical pathology process and inspire new approaches to decreasing error rates and improving overall patient care.

Methods: We performed a retrospective review of all amended dermatopathology reports over a 1.5-year period at a large academic institution.

Results: During the study period, 86 amended reports out of a total 7950 skin-specific reports were issued (1.08%). Of these amended reports, about 59% (51/86) were because of non-interpretative errors (eg, wrong site, chin vs shin, etc.) while 41% (35/86) were diagnostic misinterpretations. Of these 35, 24 were considered major diagnostic changes while six were minor. Five amendments provided additional diagnostic information. Of those amended reports with diagnostic misinterpretations, 14/35 involved melanocytic lesions, 8/35 involved non-melanoma skin cancers or keratinocyte atypia, 10/35 were inflammatory lesions and 3/35 involved other tumors.

Conclusion: Our review points to several quality improvement areas that can be targeted to potentially avoid diagnostic errors in dermatopathology, including standardizing certain anatomic sites to prevent misidentification and seeking out clinicopathologic correlation in challenging melanocytic cases.
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http://dx.doi.org/10.1111/cup.13827DOI Listing
January 2021

T-Cell Lymphoblastic Lymphoma/Leukemia Presenting as a Diffuse Viral Exanthem-like Reaction: A Clinical and Histopathological Challenge.

Am J Dermatopathol 2020 Dec;42(12):986-988

Pathology and Dermatology, University of Virginia, Charlottesville VA.

Cutaneous involvement by leukemia, or leukemia cutis, is a rare manifestation of leukemic disorders, most frequently occurring in children. The skin findings, which usually include multiple violaceous or erythematous nodules on the face, most often follow the classic presenting signs and symptoms of leukemia and occur in patients with an established primary diagnosis. Patients with T-cell acute lymphoblastic leukemia and associated leukemia cutis typically present with a solitary firm red to bluish nodule, often with an accompanying mediastinal mass, that can produce respiratory symptoms. In this article, we report a case of a patient with primary T-cell acute lymphoblastic leukemia/lymphoma presenting with a diffuse exanthem mimicking a viral illness with an associated SET-NUP214 translocation.
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http://dx.doi.org/10.1097/DAD.0000000000001766DOI Listing
December 2020

Shapiro xanthogranuloma: An essential diagnosis for dermatologists and dermatopathologists to recognize to avoid misdiagnosis of a hematopoietic malignancy in infants and neonates.

J Cutan Pathol 2021 Apr 10;48(4):558-562. Epub 2020 Sep 10.

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

The Shapiro xanthogranuloma is a histopathologic form of xanthogranuloma that shows closely packed monomorphous cells, which can extend into the subcutaneous fat; it usually lacks routine diagnostic features of xanthogranuloma. Herein we describe two cases of Shapiro xanthogranuloma occurring in a neonate and in an infant, which were initially thought to be hematologic malignancies. One patient's presentation as a "blueberry muffin baby" added to the diagnostic confusion. Pediatric dermatologists, dermatologists, and dermatopathologists need to be aware of the Shapiro xanthogranuloma and its clinicopathologic features to avoid misdiagnosis of a hematopoietic malignancy in neonates and infants.
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http://dx.doi.org/10.1111/cup.13823DOI Listing
April 2021

Epidermotropic Epstein-Barr virus-Positive Diffuse Large B-Cell Lymphoma: A Series of 3 Cases of a Very Unusual High-Grade Lymphoma.

Am J Dermatopathol 2021 Jan;43(1):51-56

Department of Pathology, University of Virginia, Charlottesville, VA; and.

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http://dx.doi.org/10.1097/DAD.0000000000001718DOI Listing
January 2021