Publications by authors named "Jonathan L Curry"

146 Publications

A pearly nodule on an indurated plaque.

Dermatol Online J 2021 Dec 15;27(12). Epub 2021 Dec 15.

Center for Clinical Studies, Webster, Texas, USA.

We present an 81-year-old man who presented for evaluation of an indurated plaque with an exophytic, pearly, skin-red-brown colored nodule with central ulceration on his chest that evolved over the course of several months and was initially suspected to be basal cell carcinoma. Biopsy demonstrated histological features of dermal spindle cell proliferation in a storiform fashion with CD34 positivity confirming a diagnosis of dermatofibrosarcoma protuberans (DFSP). Dermatofibrosarcoma protuberans are rare, slowly progressive soft tissue sarcomas. The rate of DFSP is greatest among African Americans (8.3/1,000,000), occurring nearly twice as frequently when compared to Caucasians. Aside from race/ethnicity, age, and skin trauma, no specific risk factors are associated with DFSP. Complete excision is curative. Given its pearly skin colored appearance, papular/nodular/atrophic morphology variants, and tendency to form indurated plaques, DFSP may be mistaken for nodular and morpheaform basal cell carcinoma subtypes, as well as a variety of other conditions. This case highlights the importance of maintaining DFSP on the differential diagnosis of slowly progressive nodules and indurated plaques, especially in African Americans.
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http://dx.doi.org/10.5070/D3271256715DOI Listing
December 2021

Eosinophilic homogeneous intracytoplasmic inclusion bodies: Unique viral cytopathic changes associated with epidermodysplasia verruciformis and human papillomavirus type 49.

J Cutan Pathol 2022 Mar 8. Epub 2022 Mar 8.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Epidermodysplasia verruciformis (EDV) is a rare genodermatosis that predisposes affected individuals to persistent infection with certain types of human papillomavirus (HPV), particularly those that belong to the genus beta-HPV, including HPV-5 and HPV-8, which carry high oncogenic potential. There are three main HPV-related viral cytopathic changes in cutaneous verrucae in terms of intracytoplasmic inclusion bodies (ICBs), namely, granular, filamentous, and homogeneous type ICBs. To date, only HPV-4, HPV-60, and HPV-65 have been found in association with homogeneous ICBs. We report a unique case of HPV-49-associated EDV in a 41-year-old woman with common variable immunodeficiency, mycosis fungoides, and multiple cutaneous malignancies, including squamous cell carcinoma and Merkel cell carcinoma who presented with multiple pink papules and hyperpigmented macules on the left upper extremity. One of the skin lesions histopathologically revealed keratinocytic nuclear enlargement with abundant blue-gray cytoplasm, accompanied by hypergranulosis, characteristic of EDV, along with peculiar bright eosinophilic and homogeneous ICBs. To the best of our knowledge, this is the first reported case of EDV with detection of HPV-49 by genotyping, which features eosinophilic homogeneous ICBs, like those seen in the setting of HPV-4, HPV-60, or HPV-65 infection.
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http://dx.doi.org/10.1111/cup.14221DOI Listing
March 2022

Programmed cell death ligand 1 expression in aggressive pediatric non-Hodgkin lymphomas: frequency, genetic mechanisms, and clinical significance.

Haematologica 2022 Jan 27. Epub 2022 Jan 27.

Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology, Texas Children's Hospital, Houston, Texas.

Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are immunomodulatory molecules overexpressed in lymphomas and are promising immunotherapy targets for hematologic malignancies. However, studies of PD-1/PD-L1 overexpression and their clinical significance in aggressive pediatric non-Hodgkin lymphomas (NHLs) are limited. We assessed PD-1/PD-L1 overexpression using immunohistochemistry in 68 aggressive pediatric NHLs: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL, n=8), Burkitt lymphoma (BL, n=27), and large B-cell lymphoma (LBCL) [de novo LBCL (n=22) and diffuse LBCL arising as monomorphic post-transplant lymphoproliferative disorder (PTLD-DLBCL, n=11)]. In LBCL, correlations between PD-L1 overexpression and Epstein-Barr virus (EBV) status, cell of origin, stage, nodal status, overall survival (OS), and event-free survival (EFS) were examined. The genetic mechanisms of PD-L1 overexpression were investigated using targeted nextgeneration sequencing (NGS) and cytogenetic data. All ALK+ ALCL samples, 50.0% of de novo LBCLs (11/22), 72.7% of PTLD-DLBCLs (8/11), and no BLs overexpressed PD-L1. Overexpressed PD-L1 correlated with EBV-positivity (p=0.033) in LBCLs and lower EFS in de novo LBCL (p=0.017). NGS of select LBCLs revealed distinct somatic mutations and an ultrahypermutated PTLD-DLBCL. Most cases with 9p24.1 copy gains overexpressed PD-L1 although some cases had no discernible genetic drivers of PD-L1 overexpression. Overexpressed PD-L1 is common in pediatric LBCL, associated with EBV-positivity and 9p24.1 gains, and may have prognostic significance in de novo LBCL. Furthermore, diverse molecular mechanisms for PD-L1 overexpression in aggressive pediatric NHL can occur. Thus, additional studies exploring the therapeutic and prognostic significance and molecular mechanisms of PD-L1 overexpression in aggressive pediatric NHLs are warranted.
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http://dx.doi.org/10.3324/haematol.2021.280342DOI Listing
January 2022

Cutaneous Lymphoid Hyperplasia With T-Cell Clonality and Monotypic Plasma Cells Secondary to a Tick Bite: A Hidden Critter and the Power of Deeper Levels.

Am J Dermatopathol 2022 Mar;44(3):226-229

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; and.

Abstract: Cutaneous lymphoid hyperplasia (CLH) is a benign reactive process with T-cell or B-cell lymphocytic infiltration in the skin, which can simulate cutaneous lymphomas both clinically and histologically. Various antigenic stimuli have been implicated in the development of CLH, including tick bites. Finding histologic evidence of such triggering factors, however, is often difficult. Moreover, the presence of clonality in CLH can potentially be interpreted as a neoplastic process, posing a further diagnostic challenge to dermatopathologists, if one is not aware of such peculiar phenomena. Herein, we describe a case of CLH secondary to a tick bite, featuring both T-cell clonality and monotypic plasma cells with lambda light chain restriction; the diagnostic clue being tick parts, which became evident on assessment of deeper levels. To the best of our knowledge, this is the first reported case of a tick-associated clonal CLH with simultaneous detection of monoclonal T cells and monotypic lambda light chain restriction, mimicking primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder and Borrelia-associated primary cutaneous marginal zone B-cell lymphoma, respectively.
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http://dx.doi.org/10.1097/DAD.0000000000002067DOI Listing
March 2022

Severe de novo pustular psoriasiform immune-related adverse event associated with nivolumab treatment for metastatic esophageal adenocarcinoma.

J Cutan Pathol 2022 May 22;49(5):472-481. Epub 2021 Dec 22.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Breakthrough targeted therapies have produced significant improvements in survival for cancer patients, but have a propensity to cause cutaneous immune-related adverse events (irAEs). Psoriasiform irAEs, representing about 4% of dermatologic toxicities associated with immune checkpoint inhibitor (ICI) therapy, are usually mild, occur in older patients and present as an exacerbation of existing psoriasis after several doses of ICI therapy. We report a case of a 58-year-old woman with metastatic esophageal adenocarcinoma and no prior history of psoriasis who developed a pustular psoriasiform irAE, beginning 3 days after initiation of nivolumab and progressing to confluent erythroderma with pustules over 2 weeks despite topical steroid use. She had concurrent acrodermatitis enteropathica, clinically diagnosed and confirmed with a low serum zinc level, that improved with supplementation. Her psoriasiform irAE was refractory to systemic steroids and acitretin, prompting discontinuation of nivolumab and treatment with ustekinumab and concomitant slow taper of acitretin and prednisone. Pustular psoriasiform irAE is a rare but severe dermatologic toxicity resulting from ICI therapy. Given the diverse morphologic types of cutaneous irAEs that can occur during ICI therapy, a clinical and histopathologic examination of dermatologic toxicities is critical to identify patients who may benefit from biologic therapy.
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http://dx.doi.org/10.1111/cup.14185DOI Listing
May 2022

Ibrutinib skin toxicities: Report of two cases.

J Cutan Pathol 2022 Apr 17;49(4):363-368. Epub 2021 Nov 17.

Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.

Ibrutinib is a Bruton tyrosine kinase inhibitor used to treat many hematologic conditions, most commonly B-cell lymphomas and leukemias. Reportedly, skin rash is an adverse event in up to 27% of treated patients. Histopathologic description of these lesions is limited. We present two cases of ibrutinib-associated skin toxicities showing diverse histopathologic features. Case 1: A 72-year-old man was started on ibrutinib for chronic lymphocytic leukemia. Two months later, he developed multiple erythematous crusted papules on the chest, abdomen, and extremities. Biopsies revealed varied histopathology including poorly formed granulomatous dermatitis, epidermal necrosis, ulceration, and panniculitis. Ibrutinib was discontinued and his skin lesions resolved within 1 month. Case 2: A 48-year-old man received ibrutinib after failing standard therapy for primary central nervous system EBV positive diffuse large B-cell lymphoma. Two months after initiation of ibrutinib, he developed multiple firm, red, non-tender nodules on the forehead, buttock, and thigh. Biopsies revealed "pseudolymphoma"-like reaction with dense pandermal lymphohistiocytic inflammation and granulomas. His skin toxicity resolved without cessation of therapy. Awareness of the spectrum of histopathologic features that may be encountered in skin lesions of patients treated with ibrutinib, as illustrated by these two cases, will be critical for optimal patient management.
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http://dx.doi.org/10.1111/cup.14160DOI Listing
April 2022

Diverse landscape of dermatologic toxicities from small-molecule inhibitor cancer therapy.

J Cutan Pathol 2022 Jan 21;49(1):61-81. Epub 2021 Oct 21.

Department of Pathology, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Advances in molecular biology and genetics have contributed to breakthrough treatments directed at specific pathways associated with the development of cancer. Small-molecule inhibitors (Nibs) aimed at a variety of cellular pathways have been efficacious; however, they are associated with significant dermatologic toxicities.

Methods: We conducted a comprehensive review of dermatologic toxicities associated with Nibs categorized into the following five groups: (a) mitogen-activated protein kinase; (b) growth factor/multi-tyrosine kinase; (c) cell division/DNA repair; (d) signaling associated with myeloproliferative neoplasms; and (e) other signaling pathways. Prospective phase I, II, or III clinical trials, retrospective literature reviews, systematic reviews/meta-analyses, and case reviews/reports were included for analysis.

Results: Dermatologic toxicities reviewed were associated with every class of Nibs and ranged from mild to severe or life-threatening adverse skin reactions. Inflammatory reactions manifesting as maculopapular, papulopustular/acneiform, and eczematous lesions were frequent types of dermatologic toxicities seen with Nibs. Squamous cell carcinoma with keratoacanthoma-like features was associated with a subset of Nibs. Substantial overlap in dermatologic toxicities was found between Nibs.

Conclusions: Dermatologic toxicities from Nibs are diverse and may overlap between classes of Nibs. Recognition of the various types of toxicities from Nibs is critical for patient care in the era of "oncodermatology/dermatopathology."
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http://dx.doi.org/10.1111/cup.14145DOI Listing
January 2022

The utility of digital pathology in improving the diagnostic skills of pathology trainees in commonly encountered pigmented cutaneous lesions during the COVID-19 pandemic: A single academic institution experience.

Ann Diagn Pathol 2021 Oct 16;54:151807. Epub 2021 Aug 16.

Department of Pathology, University of Texas, MD Anderson Cancer Center, United States of America. Electronic address:

Digital pathology has become an integral part of pathology education in recent years, particularly during the COVID-19 pandemic, for its potential utility as a teaching tool that augments the traditional 1-to-1 sign-out experience. Herein, we evaluate the utility of whole slide imaging (WSI) in reducing diagnostic errors in pigmented cutaneous lesions by pathology fellows without subspecialty training in dermatopathology. Ten cases of 4 pigmented cutaneous lesions commonly encountered by general pathologists were selected. Corresponding whole slide images were distributed to our fellows, along with two sets of online surveys, each composed of 10 multiple-choice questions with 4 answers. Identical cases were used for both surveys to minimize variability in trainees' scores depending on the perceived level of difficulty, with the second set being distributed after random shuffling. Brief image-based teaching slides as self-assessment tool were provided to trainees between each survey. Pre- and post-self-assessment scores were analyzed. 61% (17/28) and 39% (11/28) of fellows completed the first and second surveys, respectively. The mean score in the first survey was 5.2/10. The mean score in the second survey following self-assessment increased to 7.2/10. 64% (7/11) of trainees showed an improvement in their scores, with 1 trainee improving his/her score by 8 points. No fellow scored less post-self-assessment than on the initial assessment. The difference in individual scores between two surveys was statistically significant (p = 0.003). Our study demonstrates the utility of WSI-based self-assessment learning as a source of improving diagnostic skills of pathology trainees in a short period of time.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450757PMC
October 2021

Localized cutaneous argyria: Review of a rare clinical mimicker of melanocytic lesions.

Ann Diagn Pathol 2021 Oct 26;54:151776. Epub 2021 Jun 26.

Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA; Department of Dermatology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. Electronic address:

Localized cutaneous argyria is a rare cutaneous disorder that has been associated with occupational exposure, dental procedures, topical agents, acupuncture, earrings, and nasal piercings. In this paper, we review the current literature on localized cutaneous argyria, highlight its clinical and histologic diagnostic features, and then discuss the clinical and histological differential diagnoses for blue-gray skin and black dermal pigment, respectively. We also discuss the utility of ancillary techniques, such as deeper histologic levels, special stains, darkfield microscopy, and advanced micro-analytical techniques in helping diagnose localized cutaneous argyria. Furthermore, we emphasize that a thorough clinical history and astute clinico-pathologic correlation can be the most important diagnostic techniques in correctly diagnosing this rare disorder. Our review aims serve as a reminder to clinicians and pathologists of the importance of including localized cutaneous argyria in the clinical and histological differential diagnosis of pigmented lesions.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151776DOI Listing
October 2021

PARP and CDK4/6 Inhibitor Combination Therapy Induces Apoptosis and Suppresses Neuroendocrine Differentiation in Prostate Cancer.

Mol Cancer Ther 2021 09 22;20(9):1680-1691. Epub 2021 Jun 22.

Genitourinary Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, Texas.

We analyzed the efficacy and mechanistic interactions of PARP inhibition (PARPi; olaparib) and CDK4/6 inhibition (CDK4/6i; palbociclib or abemaciclib) combination therapy in castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) models. We demonstrated that combined olaparib and palbociblib or abemaciclib treatment resulted in synergistic suppression of the p-Rb1-E2F1 signaling axis at the transcriptional and posttranslational levels, leading to disruption of cell-cycle progression and inhibition of E2F1 gene targets, including genes involved in DDR signaling/damage repair, antiapoptotic family members ( and ), , and neuroendocrine differentiation (NED) markers and In addition, olaparib + palbociclib or olaparib + abemaciclib combination treatment resulted in significantly greater growth inhibition and apoptosis than either single agent alone. We further showed that PARPi and CDK4/6i combination treatment-induced CDK1 inhibition suppressed p-S70-BCL-2 and increased caspase cleavage, while CDK1 overexpression effectively prevented the downregulation of p-S70-BCL-2 and largely rescued the combination treatment-induced cytotoxicity. Our study defines a novel combination treatment strategy for CRPC and NEPC and demonstrates that combination PARPi and CDK4/6i synergistically promotes suppression of the p-Rb1-E2F1 axis and E2F1 target genes, including and NED proteins, leading to growth inhibition and increased apoptosis and Taken together, our results provide a molecular rationale for PARPi and CDK4/6i combination therapy and reveal mechanism-based clinical trial opportunities for men with NEPC.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456452PMC
September 2021

Cutaneous Toxicities in the Setting of Immune Checkpoint Blockade:: The Era of Oncodermatopathology.

Surg Pathol Clin 2021 Jun 28;14(2):209-224. Epub 2021 Apr 28.

Department of Dermatology, The University of Pennsylvania, Philadelphia, PA 19104, USA.

Advancements in cancer therapy with monoclonal immune checkpoint antibody blockade have impacted the practice of all medical specialties. Cutaneous immune-related adverse events (irAEs) are a frequent, unintended, off-target consequence of immune checkpoint inhibitor (ICI) therapy that have ushered in the era of oncodermatopathology. Knowledge of the diverse morphologic types of cutaneous irAEs from ICI therapy allows further classification of cutaneous irAEs according to major histopathologic reaction patterns. Early studies suggest that immune mechanisms of lichenoid dermatitis irAE, psoriasiform dermatitis irAE, and bullous pemphigoid irAE show some similarities and differences from their histopathologic counterparts not associated with ICI therapy.
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http://dx.doi.org/10.1016/j.path.2021.01.002DOI Listing
June 2021

Case Report: Enfortumab Vedotin for Metastatic Urothelial Carcinoma: A Case Series on the Clinical and Histopathologic Spectrum of Adverse Cutaneous Reactions From Fatal Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis to Dermal Hypersensitivity Reaction.

Front Oncol 2021 4;11:621591. Epub 2021 Mar 4.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Enfortumab vedotin is a Nectin-4 directed antibody-drug conjugate approved in metastatic urothelial carcinoma following progression on a platinum-containing chemotherapy and immune checkpoint blockade. On-target dermatologic toxicity may occur from Nectin-4 expression in the skin. We highlight a case of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis following enfortumab infusions that was ultimately fatal. The second case describes an erythema multiforme-like rash with interface dermatitis related to enfortumab. Dermatologic findings, immunohistochemistry studies, and immune profiling are detailed. These cases demonstrate the potentially catastrophic outcomes in some patients treated with enfortumab. Patients must be monitored for cutaneous toxicities with early involvement of dermatology and dermatopathology.
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http://dx.doi.org/10.3389/fonc.2021.621591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970171PMC
March 2021

Is immunohistochemical expression of GATA3 helpful in the differential diagnosis of transformed mycosis fungoides and primary cutaneous CD30-positive T cell lymphoproliferative disorders?

Virchows Arch 2021 Aug 18;479(2):377-383. Epub 2021 Feb 18.

Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Mycosis fungoides with large cell transformation (MFLCT) can be difficult to distinguish from primary cutaneous CD30+ T cell lymphoproliferative disorders (PC CD30+ LPD), especially primary cutaneous anaplastic large cell lymphoma (PC-ALCL). This diagnostic distinction is critical for appropriate patient management. GATA3 has been proposed to be useful in the discrimination between these two entities. We identified 25 cases of MFLCT and 24 cases of PC CD30+ LPDs (including lymphomatoid papulosis (n=14), PC-ALCL (n=6), and CD30+ LPD, not otherwise specified (n=4)) diagnosed at our institution from 2002 to 2019. Sections from archived specimens were stained to evaluate for GATA3 expression by immunohistochemistry and compared among cutaneous CD30+ T cell LPDs. The majority of the MFLCT cohort had strong, diffuse expression of GATA3 ranging from 0 to 100% of dermal T cells (mean 53.20%) with 15/25 cases (60%) showing GATA3 expression greater than 50%, while the PC CD30+ LPD group showed variable, moderate GATA3 labeling ranging from 0 to 60% of dermal T cells (mean 23.26%), with 5/6 cases (83%) showing GATA3 expression less than 40% (p =0.003). The calculated sensitivity and specificity were 56% and 74%, while positive and negative predictive values were 70% and 61%, respectively. Based on the percent staining of positive cells, using 50% as a cutoff value for expression, GATA3 might be a useful immunohistochemical marker to discriminate MFLCT from PC CD30+ LPDs, including PC-ALCL.
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http://dx.doi.org/10.1007/s00428-021-03056-yDOI Listing
August 2021

Discordance in Diagnosis of Melanocytic Lesions and Its Impact on Clinical Management.

Arch Pathol Lab Med 2021 12;145(12):1505-1515

From the Departments of Pathology (Ronen, Al-Rohil, Keiser, Jour, Nagarajan, Tetzlaff, Curry, Ivan, Middleton, Torres-Cabala, Aung, Prieto).

Context.—: Accurate diagnosis of melanocytic lesions is fundamental for appropriate clinical management.

Objective.—: To evaluate the degree of discordance, if any, between histopathologic diagnoses of melanocytic lesions at referring institutions and at a tertiary referral cancer center and the potential impact of such discordance on clinical management.

Design.—: We retrospectively identified all patients referred to our comprehensive cancer center for evaluation of a melanocytic lesion from January 2010 to January 2011. For each patient, the histopathologic diagnosis from the referring institution was compared with the histopathologic diagnosis from a dermatopathologist at our center. Discordances were classified as major if they resulted in a change in clinical management and minor if they did not.

Results.—: A total of 1521 cases were included. The concordance rates were 72.2% (52 of 72) for dysplastic nevus, 75.0% (15 of 20) for all other types of nevi, 91.1% (143 of 157) for melanoma in situ, 96.1% (758 of 789) for invasive melanoma, and 99.6% (478 of 480) for metastatic melanoma. Major discordances were found in 20.2% of cases (307 of 1521), and minor discordances were found in 48.8% of cases (742 of 1521). Compared with the guideline-based treatment recommendation based on the referring-institution diagnosis, the guideline-based treatment recommendation based on the cancer center diagnosis was more extensive in 5.9% (89 of 1521) of patients and less extensive in 5.0% (76 of 1521) of patients.

Conclusions.—: Our findings underscore the importance of secondary histopathologic review of melanocytic lesions by expert dermatopathologists because significant changes in the diagnosis, tumor classification, and/or staging may be identified, thus, resulting in critical changes in recommendations for clinical management.
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http://dx.doi.org/10.5858/arpa.2020-0620-OADOI Listing
December 2021

Tertiary lymphoid structures with overlapping histopathologic features of cutaneous marginal zone lymphoma during neoadjuvant cemiplimab therapy are associated with antitumor response.

J Cutan Pathol 2021 May 13;48(5):674-679. Epub 2021 Jan 13.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

The development of immune checkpoint inhibitor (ICI) therapy with anti-CTLA-4 and anti-PD-1/L1 monoclonal antibodies has led to a paradigm shift in cancer therapy. ICI neoadjuvant therapy followed by surgery has become the standard of care for several advanced-stage cancers. The pathology associated with ICI therapy is vast and includes neoadjuvant-associated tissue reactions and activation of tertiary lymphoid structures (TLSs) at the site of the tumor bed and off-target immune-related adverse events. TLSs are thought to recapitulate lymph node function and may act as localized immune machinery to mount an antitumor response. B-cell activation in TLSs during neoadjuvant ICI therapy has been correlated with antitumor response. We report a patient with a history of sarcomatoid squamous cell carcinoma treated with neoadjuvant ICI cemiplimab who developed clonal expansion of B-cells in the TLSs of the tumor bed. The TLSs morphologically mimicked a cutaneous marginal zone lymphoma with plasmacytic differentiation. Awareness of clonal expansion of B-cells in TLSs during neoadjuvant ICI therapy is critical to recognize a response to ICI therapy and to avoiding an incorrect diagnosis of low-grade B-cell lymphoma.
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http://dx.doi.org/10.1111/cup.13953DOI Listing
May 2021

Prognostic Significance of Subungual Anatomic Site in Acral Lentiginous Melanoma.

Arch Pathol Lab Med 2021 08;145(8):943-952

From the Department of Pathology (Mejbel, Torres-Cabala, Ivan, Nagarajan, Curry, Prieto, Aung), The University of Texas MD Anderson Cancer Center, Houston.

Context.—: Acral lentiginous melanoma is a rare and aggressive type of cutaneous melanoma that arises on the acral skin and the nail unit. The prognostic significance of subungual anatomic site in acral lentiginous melanoma is not established.

Objective.—: To assess the impact of subungual anatomic site on overall survival and disease-specific survival in acral lentiginous melanoma.

Design.—: Retrospective cohort analysis. Clinicopathologic characteristics of 627 primary acral lentiginous melanomas (45 [7%] subungual and 582 [93%] nonsubungual) were summarized, and the impact of these characteristics on overall survival and disease-specific survival was determined using univariate and multivariable analyses.

Results.—: No significant differences in clinicopathologic features were identified between the subungual and nonsubungual acral lentiginous melanomas. The 1-, 5-, and 10-year overall survival rates were 81%, 40%, and 28%, respectively, for subungual acral lentiginous melanoma and 94%, 59%, and 38%, respectively, for nonsubungual acral lentiginous melanoma (P = .04); risk of death was significantly higher for subungual tumors (hazard ratio [95% confidence interval] = 1.59 [1.02-2.50]; P = .04). The 1-, 5-, and 10-year disease-specific survival rates were 94%, 56%, and 48%, respectively, for subungual acral lentiginous melanoma versus 96%, 69%, and 55%, respectively, for nonsubungual acral lentiginous melanoma (P = .18). By multivariable analysis, independent poor prognostic factors included older age and ulceration for overall survival and greater Breslow thickness and sentinel lymph node positivity for overall survival and disease-specific survival. Subungual anatomic site was not an independent prognostic factor for overall or disease-specific survival.

Conclusions.—: Subungual anatomic site is not an independent prognostic factor for acral lentiginous melanoma.
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http://dx.doi.org/10.5858/arpa.2020-0308-OADOI Listing
August 2021

Telomerase Reverse Transcriptase Protein Expression Is More Frequent in Acral Lentiginous Melanoma Than in Other Types of Cutaneous Melanoma.

Arch Pathol Lab Med 2021 07;145(7):842-850

From the Departments of Pathology (Cho, Wang, Nagarajan, Curry, Ivan, Lazar, Prieto, Torres-Cabala, Aung), The University of Texas MD Anderson Cancer Center, Houston.

Context.—: Molecularly distinct from cutaneous melanomas arising from sun-exposed sites, acral lentiginous melanomas (ALMs) typically lack ultraviolet-signature mutations, such as telomerase reverse transcriptase (TERT) promoter mutations. Instead, ALMs show a high degree of copy number alterations, often with multiple amplifications of TERT, which are associated with adverse prognosis. The prognostic value of TERT protein expression in acral melanomas, however, is not established.

Objective.—: To evaluate the frequency and pattern of TERT immunoreactivity and assess the potential utility of TERT expression as a prognostic indicator in ALMs.

Design.—: TERT expression by immunohistochemistry was analyzed in a series of 57 acral and nonacral melanocytic lesions, including 24 primary and 6 metastatic ALMs. Clinical outcome in patients with ALMs by TERT expression was assessed.

Results.—: TERT expression was more frequent in ALMs than in nonlentiginous acral melanomas and nonacral cutaneous melanomas, and was absent in acral nevi (P = .01). When present, TERT expression in ALMs was cytoplasmic and more intense than TERT expression in other melanocytic lesions (P = .05) with a higher H-score (P = .01). There was a trend toward decreased overall survival in patients with ALMs with TERT immunoreactivity, but it did not reach statistical significance. Furthermore, no correlation was found between TERT expression and disease-specific survival in patients with ALMs.

Conclusions.—: Although TERT protein expression was frequently detected in both primary and metastatic ALMs, TERT immunoreactivity in ALMs did not correlate with survival in our study. Further studies with larger cohorts are needed to elucidate the prognostic value of TERT expression in ALMs.
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http://dx.doi.org/10.5858/arpa.2020-0330-OADOI Listing
July 2021

Bullous Pemphigoid-like Eruption Triggered by Targeted Therapy for Metastatic Melanoma.

Acta Derm Venereol 2020 Nov 26;100(18):adv00334. Epub 2020 Nov 26.

Oncology-Pathology and Department of Oncology/Skin Cancer Center, Theme Cancer, Karolinska Institutet, Karolinska University Hospital Solna, SE-176 76 Stockholm, Sweden. E-mail:

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http://dx.doi.org/10.2340/00015555-3648DOI Listing
November 2020

Prognostic significance of acral lentiginous histologic type in T1 melanoma.

Mod Pathol 2021 03 5;34(3):572-583. Epub 2020 Aug 5.

Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Acral lentiginous melanoma (ALM) is a rare type of cutaneous melanoma with a poor prognosis. It is unclear whether the poor outcome of ALM is due to its inherent disease characteristics or advanced stage at initial diagnosis. To address this question, we retrospectively analyzed the clinicopathologic factors of 828 thin (T1; Breslow thickness ≤1.0 mm) melanomas [129 (15.6%) ALMs and 699 (84.4%) non-ALMs] and their nodal and distance metastases and local recurrence rates and determined their relationship with the disease-specific (DSS), overall (OS), and recurrence-free survivals (RFS) at the pathologic stages T1, T1a, and T1b with a median follow-up time of 84.5 months. With the exception of OS at T1b stage, ALM patients showed significantly lower 5- and 10-year DSS, OS, and RFS rates at every pathologic stage when compared with non-ALM. In multivariable analysis, ALM histologic type, SLN positivity, age, and the use of systemic therapy were detected as independent poor prognostic factors associated with significantly lower survival rates. ALM histologic type was associated with lower DSS and OS rates at T1 and T1a stages and lower RFS rates at T1b stage. SLN positivity was associated with lower DSS, OS, and RFS rates at T1, T1a, and T1b stages. Age was associated with lower OS rates at T1 and T1b stages. Whereas the use of systemic therapy was associated with lower DSS rates at T1a stage and RFS rates at T1b stage. In addition, the ALM group showed significantly older median age patients and higher rates of female sex, Hispanic ethnicity, nevoid cytology, non-brisk tumor-infiltrating lymphocytes, nodal metastasis, and local recurrence at every pathologic stage of thin melanoma. Our findings suggest that ALM is inherently more aggressive than other types of cutaneous melanoma. This information may be useful for prognostic stratification of patients with thin melanomas, especially to help guide the clinical decision-making for SLN biopsy and patients entering clinical trials.
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http://dx.doi.org/10.1038/s41379-020-0641-xDOI Listing
March 2021

Langerhans cell sarcoma involving skin and showing epidermotropism: A comprehensive review.

J Cutan Pathol 2021 Apr 7;48(4):547-557. Epub 2020 Sep 7.

Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Langerhans cell sarcoma (LCS) is rare and aggressive; patients have an overall survival rate of less than 50%. We present a 62-year-old man with a history of superficial spreading melanoma of the upper back with sentinel lymph node metastasis, Langerhans cell histiocytosis, and LCS. The patient presented with erythematous papules and scaly areas on his face, neck, arms, chest, abdomen, and legs. A skin biopsy revealed a proliferation of large neoplastic cells involving the dermis and with epidermotropism. These cells had atypical bean-shaped nuclei, with ample cytoplasm and abundant mitotic figures including atypical forms. Immunohistochemical studies showed the tumor to be diffusely positive for CD1a, S100 protein, and langerin (CD207) and negative for melanocytic markers. Some tumor cells were positive for cyclin D1. A diagnosis of LCS involving the skin was established. The present study is a very unusual case of LCS showing epidermotropism. The patient's history of metastatic melanoma posed additional challenges for diagnosis, underlying the need of immunophenotyping in these cases. Consensus for optimal standard therapy has not been established in LCS, and thus, early recognition is important since these neoplasms tend to recur and metastasize. LCS in skin is discussed and published cases are comprehensively reviewed.
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http://dx.doi.org/10.1111/cup.13803DOI Listing
April 2021

Cutaneous adnexal carcinosarcoma: Immunohistochemical and molecular evidence of epithelial mesenchymal transition.

J Cutan Pathol 2021 Apr 14;48(4):526-534. Epub 2020 Sep 14.

Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Cutaneous carcinosarcomas are rare biphenotypic tumors that simultaneously show epithelial and mesenchymal differentiation. The most common carcinomatous components in skin carcinosarcomas are basal cell carcinoma and squamous cell carcinoma; adnexal carcinomas are rarely encountered. We report a case of an adnexal carcinoma with ductal and squamous differentiation and spindle cell component, which is interpreted as carcinosarcoma. Loss of immunohistochemical expression of E-cadherin and β-catenin detected in the sarcomatous component suggested epithelial mesenchymal transition (EMT). RNA sequencing analysis identified several gene mutations and alterations such as translocations and upregulations/downregulations, either shared by the two components of the tumor or differentially present in the carcinoma or the sarcoma parts. Thus, mutations in genes, such as TP53, were found in both components of the tumor while mutations in PDGFRA and RB1 (a pathogenic missense mutation) were exclusively present in the sarcomatous areas, further supporting EMT. EMT is a dynamic process by which tumors acquire mesenchymal phenotype while simultaneously losing epithelial properties. Although the pathways involved in EMT have been extensively studied, this phenomenon still needs to be investigated in cutaneous tumors of adnexal origin for a better understanding of their pathogenesis. These molecular changes may represent promising targets for personalized therapies.
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http://dx.doi.org/10.1111/cup.13782DOI Listing
April 2021

TERT amplification but not activation of canonical Wnt/β-catenin pathway is involved in acral lentiginous melanoma progression to metastasis.

Mod Pathol 2020 10 13;33(10):2067-2074. Epub 2020 May 13.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Acral lentiginous melanoma (ALM) is a rare tumor that occurs on non-sun exposed skin areas of the hands and feet. Reports suggest that ALM exhibits poor prognosis, although mechanisms driving this remain poorly understood. Alterations in TERT and the Wnt/β-catenin (Wnt) pathway have been suggested to correlate with prognosis of ALM. Thus, immunohistochemical expression of β-catenin and LEF1 along with TERT amplification by FISH was investigated in 34 primary ALMs, 20 metastatic ALMs, 10 primary non-ALMs, and 15 acral nevi. Foot/toe was the most common primary tumor location (85%) for ALM. TERT amplification was detected in 6 of 28 (21.4%) primary ALM, 2 of 8 (25%) primary non-ALM, and 8 of 18 (44.4%) metastatic ALM, the latter showing significantly higher frequency compared with primary melanomas (P = 0.043). Most metastatic ALMs positive for TERT amplification lacked BRAF V600E (87.5%). Cytoplasmic and nonnuclear expression of β-catenin was variably detected in all cases. Metastatic ALM revealed lower expression of β-catenin compared with primary ALM (P = 0.017). No differences in LEF1 expression were detected among the groups; however, acral nevi showed decreased labeling with dermal descent, in contrast to melanoma. No molecular-genetic alteration correlated with prognosis. TERT amplification by FISH is a frequent finding in primary ALM and appears to increase in metastatic tumors, suggesting a role in tumor progression to metastasis. Although TERT amplification has been reported to be infrequent in primary non-ALM, it showed comparable frequency with ALM in our series. Our immunohistochemical findings are not fully supportive of activation of either canonical or noncanonical Wnt cascades in ALM. TERT amplification by FISH and LEF1 immunohistochemistry may help in the differential diagnosis between primary ALM and acral nevus. TERT amplification appears to be a promising target for therapy in patients with metastatic ALM.
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http://dx.doi.org/10.1038/s41379-020-0565-5DOI Listing
October 2020

Hypertrophic lichenoid dermatitis immune-related adverse event during combined immune checkpoint and exportin inhibitor therapy: A diagnostic pitfall for superficially invasive squamous cell carcinoma.

J Cutan Pathol 2020 Oct 10;47(10):954-959. Epub 2020 Jun 10.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Immune checkpoint inhibitors (ICIs) for cancer treatment have revolutionized the field of medicine. However, an unintended but frequent consequence of ICI therapy is the development of cutaneous immune-related adverse events (irAEs), such as lichenoid dermatitis irAEs (LD-irAEs). The hypertrophic variant of LD-irAE may be a diagnostic challenge since it can mimic superficially invasive squamous cell carcinoma (SCC). A 79-year-old woman with metastatic melanoma who began treatment with an ICI-pembrolizumab-plus exportin-1 (XPO1) inhibitor presented after 1 month of therapy with symmetrical violaceous papules coalescing into plaques and with two nodules of the bilateral dorsal hands. Biopsy of the nodules revealed an actinic keratosis and atypical epidermal proliferation concerning for SCC. However, in the ensuing 3 weeks, the patient developed multiple new erythematous, violaceous, and scaly macules and papules, some coalescing into plaques on the extremities. Biopsies of these lesions revealed exuberant irregular epidermal hyperplasia with hypermaturation and lichenoid infiltrate concentrated at the base of the elongated, broadened rete ridges, consistent with hypertrophic LD-irAE. Treatment included topical fluocinonide ointment, intralesional triamcinolone injections and oral acitretin. Distinguishing hypertrophic LD-irAE and SCC can be challenging since both entities share histopathologic features; thus, correlation with clinical presentation is essential for diagnosis and optimal patient management.
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http://dx.doi.org/10.1111/cup.13739DOI Listing
October 2020

BAP-1 Expression Status by Immunohistochemistry in Cellular Blue Nevus and Blue Nevus-like Melanoma.

Am J Dermatopathol 2020 May;42(5):313-321

Associate Professor, Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.

The family of blue nevi includes the common blue nevus (BN), cellular blue nevus (CBN), and atypical BN, while melanomas with BN-like morphology can either arise in association with a blue nevus (MABN) or in the de novo setting mimicking cellular blue nevus (MMCBN). Recent molecular and immunohistochemical studies have demonstrated loss of BAP-1 in MABN/MMCBN but not in BN/CBN, suggesting that loss of BAP-1 correlates with a malignant phenotype in these lesions. In this study, we applied anti-BAP-1 antibodies to a series of CBN/BN (n = 11) and MABN/MMCBN (n = 4). Nuclear BAP-1 expression was detected in the majority of CBN/BN (n = 10/11) but was lost in 1 case. Most cases of MABN/MMCBN showed loss of nuclear BAP-1 expression (n = 3/4), with one case of MMCBN showing preserved BAP-1 expression. Demonstration of BAP-1 loss in a single case of CBN and preservation of BAP-1 expression in 1 case of MMCBN may indicate that detection of alterations in BAP-1 protein expression by immunohistochemistry may not be a completely reliable biomarker for the distinction of BN/CBN from MABN/MMCBN. Further investigation of the significance of BAP-1 loss/preservation in BN-like tumors is warranted.
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http://dx.doi.org/10.1097/DAD.0000000000001551DOI Listing
May 2020

T-Cell Repertoire in Combination with T-Cell Density Predicts Clinical Outcomes in Patients with Merkel Cell Carcinoma.

J Invest Dermatol 2020 11 15;140(11):2146-2156.e4. Epub 2020 Apr 15.

Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address:

The integrity of the immune system represents a pivotal risk factor and prognostic biomarker for Merkel cell carcinoma. A higher density of tumor-associated T cells correlates with improved Merkel cell carcinoma-specific survival, but the prognostic importance of the T-cell infiltrate reactivity is unknown. We evaluated the T-cell receptor repertoire associated with 72 primary Merkel cell carcinomas and correlated metrics of the T-cell receptor repertoire with clinicopathologic characteristics and patient outcomes. We showed that a high Simpson's Dominance index (SDom) was significantly associated with fewer metastases (P = 0.01), lower stage at presentation (P = 0.02), lower final stage at last follow-up (P = 0.05), and longer time to first lymph node metastasis (P = 0.04). These correlations were mostly preserved in the Merkel cell polyomavirus-negative subgroup. Combining SDom with CD3 or CD8 T-cell density revealed three distinct prognostic groups with respect to disease-specific survival. Patients with both high SDom and high CD3 or CD8 T-cell density had markedly improved disease-specific survival compared with patients with low SDom and low CD3 or CD8 T-cell density (P = 0.002 and P = 0.03, respectively). Patients with either high SDom or high CD3 or CD8 had intermediate disease-specific survival. Our findings demonstrate that the quality of the tumor-associated T-cell infiltrate informs patient prognosis in primary Merkel cell carcinoma beyond the T-cell density.
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http://dx.doi.org/10.1016/j.jid.2020.02.031DOI Listing
November 2020

Lichen planus related to transforming growth factor beta inhibitor in a patient with metastatic chondrosarcoma: a case report.

J Cutan Pathol 2020 May 27;47(5):490-493. Epub 2020 Jan 27.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Transforming growth factor-beta1 (TGF-β1) is expressed in normal epidermis. TGF-β1 potently inhibits keratinocyte proliferation and immunomodulatory properties, mainly by suppressing immune responses to self-antigens. Lichen planus (LP) is a form of dermatitis caused by cell-mediated immune dysfunction, but the exact pathogenic pathways are unknown, which poses therapeutic challenges. We report on a 68-year-old man who developed multiple pruritic, discrete, and well-demarcated, flat-topped red-purple papules and macules on the back and upper arms following 4 cycles of treatment with TGF-β receptor I (TGFBR-I) inhibitor, ly3200882, for metastatic chondrosarcoma. The biopsy showed hyperkeratosis, wedge-shaped hypergranulosis, elongation of the rete ridges, and a dense band-like lymphohistiocytic infiltrate admixed with colloid bodies and pigment incontinence, consistent with LP. Temporal correlation suggested that the TGFBR-I inhibitor might be a trigger. Treatment with topical clobetasol and oral metronidazole led to partial resolution of the lesions with postinflammatory hyperpigmentation. We believe this is the first reported case of LP related to TGFBR-I inhibitor therapy. This report expands the list of cutaneous adverse events associated with this novel class of targeted therapy. More importantly, this report supports emerging evidence that failure of TGF-β1 activation/signal transduction is an important mechanism in the pathogenesis of LP and suggests the TGF-β1 pathway as a potential therapeutic target in this disease.
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http://dx.doi.org/10.1111/cup.13645DOI Listing
May 2020
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