Publications by authors named "Paul W Harms"

103 Publications

Genomic evidence suggests that cutaneous neuroendocrine carcinomas can arise from squamous dysplastic precursors.

Mod Pathol 2021 Sep 30. Epub 2021 Sep 30.

Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma without a known dysplastic precursor. In some cases, MCC is associated with SCCIS in the overlying epidermis; however, the MCC and SCCIS populations display strikingly different morphologies, and thus far a relationship between these components has not been demonstrated. To better understand the relationship between these distinct tumor cell populations, we evaluated 7 pairs of MCC-SCCIS for overlapping genomic alterations by cancer profiling panel. A subset was further characterized by transcriptional profiling and immunohistochemistry. In 6 of 7 MCC-SCCIS pairs there was highly significant mutational overlap including shared TP53 and/or RB1 mutations. In some cases, oncogenic events previously implicated in MCC (MYCL gain, MDM4 gain, HRAS mutation) were detected in both components. Although FBXW7 mutations were enriched in MCC, no gene mutation was unique to the MCC component across all cases. Transcriptome analysis identified 2736 differentially expressed genes between MCC and SCCIS. Genes upregulated in the MCC component included Polycomb repressive complex targets; downregulated transcripts included epidermal markers, and immune genes such as HLA-A. Immunohistochemical studies revealed increased expression of SOX2 in the MCC component, with diminished H3K27Me3, Rb, and HLA-A expression. In summary, MCC-SCCIS pairs demonstrate clonal relatedness. The shift to neuroendocrine phenotype is associated with loss of Rb protein expression, decrease in global H3K27Me3, and increased expression of Merkel cell genes such as SOX2. Our findings suggest an epidermal origin of MCC in this setting, and to our knowledge provide the first molecular evidence that intraepithelial squamous dysplasia may represent a direct precursor for small cell carcinoma.
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http://dx.doi.org/10.1038/s41379-021-00928-1DOI Listing
September 2021

Phospholipase A2 enzymes represent a shared pathogenic pathway in psoriasis and pityriasis rubra pilaris.

JCI Insight 2021 Oct 22;6(20). Epub 2021 Oct 22.

Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.

Altered epidermal differentiation along with increased keratinocyte proliferation is a characteristic feature of psoriasis and pityriasis rubra pilaris (PRP). However, despite this large degree of overlapping clinical and histologic features, the molecular signatures these skin disorders share are unknown. Using global transcriptomic profiling, we demonstrate that plaque psoriasis and PRP skin lesions have high overlap, with all differentially expressed genes in PRP relative to normal skin having complete overlap with those in psoriasis. The major common pathway shared between psoriasis and PRP involves the phospholipases PLA2G2F, PLA2G4D, and PLA2G4E, which were found to be primarily expressed in the epidermis. Gene silencing each of the 3 PLA2s led to reduction in immune responses and epidermal thickness both in vitro and in vivo in a mouse model of psoriasis, establishing their proinflammatory roles. Lipidomic analyses demonstrated that PLA2s affect mobilization of a phospholipid-eicosanoid pool, which is altered in psoriatic lesions and functions to promote immune responses in keratinocytes. Taken together, our results highlight the important role of PLA2s as regulators of epidermal barrier homeostasis and inflammation, identify PLA2s as a shared pathogenic mechanism between PRP and psoriasis, and as potential therapeutic targets for both diseases.
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http://dx.doi.org/10.1172/jci.insight.151911DOI Listing
October 2021

Viral Status Predicts the Patterns of Genome Methylation and Decitabine Response in Merkel Cell Carcinoma.

J Invest Dermatol 2021 Aug 30. Epub 2021 Aug 30.

Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA; Department of Urology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA. Electronic address:

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that is classified as Merkel cell polyomavirus-positive (virus positive [VP]) or Merkel cell polyomavirus-negative (virus negative [VN]). Epigenetic changes, such as DNA methylation, can alter gene expression and influence cancer progression. However, patterns of DNA methylation and the therapeutic efficacy of hypomethylating agents have not been fully explored in MCC. We characterized genome-wide DNA methylation in 16 MCC cell lines from both molecular subclasses in comparison with other cancer types and found that the overall profile of MCC is similar to that of small-cell lung carcinoma. Comparison of VP MCC with VN MCC revealed 2,260 differentially methylated positions. The hypomethylating agent decitabine upregulated the expression of antigen-presenting machinery in MCC cell lines and stimulated membrane expression of HLA-A in VP and VN MCC xenograft tumors. Decitabine also induced prominent caspase- and large T antigen‒independent cell death in VP MCC, whereas VN MCC cell lines displayed decreased proliferation without increased cell death. In mouse xenografts, decitabine significantly decreased the size of VP tumors but not that of VN tumors. Our findings indicate that viral status predicts genomic methylation patterns in MCC and that decitabine may be therapeutically effective against MCC through antiproliferative effects, cell death, and increased immune recognition.
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http://dx.doi.org/10.1016/j.jid.2021.07.173DOI Listing
August 2021

Molecular pathology of skin adnexal tumors.

Histopathology 2021 Jul 1. Epub 2021 Jul 1.

Department of Pathology, University of Michigan, Ann Arbor, 48109, MI, USA.

Aims: Tumors of the cutaneous adnexa arise from, or differentiate toward, structures in normal skin such as hair follicles, sweat ducts/glands, sebaceous glands, or a combination of these elements. This class of neoplasms includes benign tumors and highly aggressive carcinomas. Adnexal tumors often present as solitary sporadic lesions, but can herald the presence of an inherited tumor syndrome such as Muir-Torre Syndrome, Cowden Syndrome, or CYLD Cutaneous Syndrome. In contrast to squamous cell carcinoma and basal cell carcinoma, molecular changes in adnexal neoplasia have been poorly characterized, and there are few published reviews on the current state of knowledge.

Methods And Results: We reviewed findings in peer-reviewed literature on molecular investigations of cutaneous adnexal tumors published through June 2021.

Conclusions: Recent discoveries have revealed diverse oncogenic drivers and tumor suppressor alterations in this class of tumors, implicating pathways including Ras/MAPK, PI3K, YAP/TAZ, beta-catenin, and NF-kappaB. These observations have identified novel markers, such as NUT for poroma and porocarcinoma, and PLAG1 for mixed tumors. Here, we provide a comprehensive overview and update of the molecular findings associated with adnexal tumors of the skin.
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http://dx.doi.org/10.1111/his.14441DOI Listing
July 2021

Constitutive Hedgehog/GLI2 signaling drives extracutaneous basaloid squamous cell carcinoma development and bone remodeling.

Carcinogenesis 2021 Aug;42(8):1100-1109

Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.

Uncontrolled activation of the Hedgehog (Hh) signaling pathway, operating through GLI transcription factors, plays a central role in the pathogenesis of cutaneous basal cell carcinoma and contributes to the development of several malignancies arising in extracutaneous sites. We now report that K5-tTA;tetO-Gli2 bitransgenic mice develop distinctive epithelial tumors within their jaws. These tumors consist of large masses of highly proliferative, monomorphous, basaloid cells with scattered foci of keratinization and central necrosis, mimicking human basaloid squamous cell carcinoma (BSCC), an aggressive upper aerodigestive tract tumor. Like human BSCC, these tumors express epidermal basal keratins and differentiation-specific keratins within squamous foci. Mouse BSCCs express high levels of Gli2 and Hh target genes, including Gli1 and Ptch1, which we show are also upregulated in a subset of human BSCCs. Mouse BSCCs appear to arise from distinct epithelial sites, including the gingival junctional epithelium and epithelial rests of Malassez, a proposed stem cell compartment. Although Gli2 transgene expression is restricted to epithelial cells, we also detect striking alterations in bone adjacent to BSCCs, with activated osteoblasts, osteoclasts and osteal macrophages, indicative of active bone remodeling. Gli2 transgene inactivation resulted in rapid BSCC regression and reversal of the bone remodeling phenotype. This first-reported mouse model of BSCC supports the concept that uncontrolled Hh signaling plays a central role in the pathogenesis of a subset of human BSCCs, points to Hh/GLI2 signaling as a potential therapeutic target and provides a powerful new tool for probing the mechanistic underpinnings of tumor-associated bone remodeling.
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http://dx.doi.org/10.1093/carcin/bgab050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374060PMC
August 2021

Update on Molecular Genetic Alterations of Cutaneous Adnexal Neoplasms.

Surg Pathol Clin 2021 Jun;14(2):251-272

Department of Dermatology, University of Michigan, 1910 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5314, USA; Department of Pathology, University of Michigan, 2800 Plymouth Road, Building 35, Ann Arbor, MI 48109 - 2800, USA. Electronic address:

Cutaneous adnexal tumors recapitulate follicular, sweat gland, and/or sebaceous epithelia, and range from benign tumors to aggressive carcinomas. Adnexal tumors can be hallmarks for inherited tumor syndromes. Oncogenic drivers of adnexal neoplasms modulate intracellular pathways including mitogen-activated protein kinase, phosphoinositide-3-kinase, Wnt/β-catenin, Hedgehog, nuclear factor κB, and Hippo intracellular signaling pathways, representing potential therapeutic targets. Malignant progression can be associated with tumor suppressor loss, especially TP53. Molecular alterations drive expression of specific diagnostic markers, such as CDX2 and LEF1 in pilomatricomas/pilomatrical carcinomas, and NUT in poromas/porocarcinomas. In these ways, improved understanding of molecular alterations promises to advance diagnostic, prognostic, and therapeutic possibilities for adnexal tumors.
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http://dx.doi.org/10.1016/j.path.2021.03.004DOI Listing
June 2021

Immunohistochemical expression of PAX8, PAX2, and cytokeratin in melanomas.

J Cutan Pathol 2021 Oct 13;48(10):1246-1251. Epub 2021 May 13.

Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.

Background: Deviations from the classic melanocytic immunophenotype in melanoma can present a diagnostic challenge. PAX8 and PAX2 are common markers for renal or Müllerian differentiation. While most PAX8+ or PAX2+ carcinomas are seldom confused with melanoma, some cases may show a more ambiguous immunophenotype, especially when MiTF family altered renal cell carcinoma (MiTF-RCC) is in the differential diagnosis. Neither PAX8 nor PAX2 expression has been reported in melanoma to date. We aimed to better characterize PAX8, PAX2, and cytokeratin immunoreactivity in a large series of melanomas.

Methods: Tissue microarrays consisting of 263 melanomas were immunostained for PAX8, PAX2, and cytokeratin and graded by an h-score.

Results: PAX8 expression was seen in 7.9% of melanomas and was significantly associated with spindle cytomorphology. PAX2 was positive in one (0.4%) melanoma. Cytokeratin positivity was seen in three (1.2%) cases and was associated with metastases.

Conclusions: PAX8 is expressed in a subset of melanomas and may be strong/extensive. As PAX8 positivity does not exclude a diagnosis of melanoma, it should be used in conjunction with other immunohistochemical markers, such as cytokeratin and PAX2, when melanoma, MiTF-RCC, and other PAX8+ tumors are in the differential diagnosis.
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http://dx.doi.org/10.1111/cup.14041DOI Listing
October 2021

IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses.

J Invest Dermatol 2021 Oct 15;141(10):2436-2448. Epub 2021 Apr 15.

Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. Electronic address:

Many inflammatory skin diseases are characterized by altered epidermal differentiation. Whether this altered differentiation promotes inflammatory responses has been unknown. Here, we show that IRAK2, a member of the signaling complex downstream of IL-1 and IL-36, correlates positively with disease severity in both atopic dermatitis and psoriasis. Inhibition of epidermal IRAK2 normalizes differentiation and inflammation in two mouse models of psoriasis- and atopic dermatitis-like inflammation. Specifically, we demonstrate that IRAK2 ties together proinflammatory and differentiation-dependent responses and show that this function of IRAK2 is specific to keratinocytes and acts through the differentiation-associated transcription factor ZNF750. Taken together, our findings suggest that IRAK2 has a critical role in promoting feed-forward amplification of inflammatory responses in skin through modulation of differentiation pathways and inflammatory responses.
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http://dx.doi.org/10.1016/j.jid.2021.03.019DOI Listing
October 2021

Immunophenotypic switch in cutaneous T-cell lymphoma: A series of three cases and review of the literature.

J Cutan Pathol 2021 Jul 26;48(7):986-994. Epub 2021 Apr 26.

Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.

Primary cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of neoplasms with variable clinical behavior. Immunophenotypic switch (IS) is a phenomenon that occurs during lymphoma progression and is defined by an alteration in the immunophenotypic expression of a tumor with retention of its genotypic signature. This has been well-recognized in hematopoietic neoplasms; however, it has been rarely reported in CTCL and its clinical implications are not well understood. We present the clinical, histopathologic, immunophenotypic, and genetic findings of three cases of CTCL that demonstrated IS post treatment with variable outcomes. We add our cases to the small number previously reported to increase awareness of this phenomenon and its diagnostic challenge.
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http://dx.doi.org/10.1111/cup.14026DOI Listing
July 2021

Virus-positive Merkel Cell Carcinoma Is an Independent Prognostic Group with Distinct Predictive Biomarkers.

Clin Cancer Res 2021 May 5;27(9):2494-2504. Epub 2021 Feb 5.

Department of Dermatology, University of Michigan, Ann Arbor, Michigan.

Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can be divided into two classes: virus-positive (VP) MCC, associated with oncogenic Merkel cell polyomavirus (MCPyV); and virus-negative (VN) MCC, associated with photodamage.

Experimental Design: We classified 346 MCC tumors from 300 patients for MCPyV using a combination of IHC, ISH, and qPCR assays. In a subset of tumors, we profiled mutation status and expression of cancer-relevant genes. MCPyV and molecular profiling results were correlated with disease-specific outcomes. Potential prognostic biomarkers were further validated by IHC.

Results: A total of 177 tumors were classified as VP-MCC, 151 tumors were VN-MCC, and 17 tumors were indeterminate. MCPyV positivity in primary tumors was associated with longer disease-specific and recurrence-free survival in univariate analysis, and in multivariate analysis incorporating age, sex, immune status, and stage at presentation. Prioritized oncogene or tumor suppressor mutations were frequent in VN-MCC but rare in VP-MCC. mutation developed with recurrence in one VP-MCC case. Importantly, for the first time we find that VP-MCC and VN-MCC display distinct sets of prognostic molecular biomarkers. For VP-MCC, shorter survival was associated with decreased expression of immune markers including granzyme and IDO1. For VN-MCC, shorter survival correlated with high expression of several genes including .

Conclusions: MCPyV status is an independent prognostic factor for MCC. Features of the tumor genome, transcriptome, and microenvironment may modify prognosis in a manner specific to viral status. MCPyV status has clinicopathologic significance and allows for identification of additional prognostic subgroups.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0864DOI Listing
May 2021

Unknown primary Merkel cell carcinoma in the immunosuppressed patient: Case series.

JAAD Case Rep 2021 Feb 1;8:19-22. Epub 2020 Dec 1.

Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan.

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http://dx.doi.org/10.1016/j.jdcr.2020.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806541PMC
February 2021

Histologic progression of acne inversa/hidradenitis suppurativa: Implications for future investigations and therapeutic intervention.

Exp Dermatol 2021 Jun 20;30(6):820-830. Epub 2021 Jan 20.

AbbVie Inc, North Chicago, IL, USA.

Since first recognized in 1839, the pathogenesis of acne inversa (AI) has undergone repeated revisions. Although there is agreement that AI involves occlusion of hair follicles with subsequent inflammation and the formation of tracts, the histologic progression of this disease still requires refinement. The objective of this study was to examine the histologic progression of AI based on the examination of a large cohort of punch biopsies and excisional samples that were examined first by hematoxylin and eosin staining. The most informative of these samples were step-sectioned and stained by immunohistochemistry for epithelial and inflammatory markers. Based on this examination, the following observations were made: 1) AI arises from the epithelium of the infundibulum of terminal and vellus hairs; 2) These form cysts and epithelial tendrils that extend into soft tissue; 3) Immunohistochemical staining demonstrates the epithelium of AI is disordered with infundibular and isthmic differentiation and de novo expression of stem cell markers; 4) The inflammatory response in AI is heterogeneous and largely due to cyst rupture. The conclusions of this investigation were that AI is an epithelial-driven disease caused by infiltrative, cyst forming tendrils and most of the inflammation is due to cyst rupture and release of cornified debris and bacteria. Cyst rupture often occurs below the depths of punch biopsy samples indicating their use for analysis may give an incomplete picture of the disease. Finally, our data suggest that unless therapies inhibit tendril development, it is unlikely they will cause prolonged treatment-induced remission in AI.
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http://dx.doi.org/10.1111/exd.14273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247901PMC
June 2021

Prognostic value of intratumoral lymphocyte-to-monocyte ratio and M0 macrophage enrichment in tumor immune microenvironment of melanoma.

Melanoma Manag 2020 Nov 2;7(4):MMT51. Epub 2020 Nov 2.

Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.

Skin cutaneous melanoma is characterized by significant heterogeneity in its molecular, genomic and immunologic features. Whole transcriptome RNA sequencing data from The Cancer Genome Atlas of skin cutaneous melanoma (n = 328) was utilized. CIBERSORT was used to identify immune cell type composition, on which unsupervised hierarchical clustering was performed. Analysis of overall survival was performed using Kaplan-Meier estimates and multivariate Cox regression analyses. Membership in the lymphocyte:monocyte, monocyte  and M0 cluster was an independently poor prognostic factor for survival (HR: 3.03; 95% CI: 1.12-8.20; p = 0.029) and correlated with decreased predicted response to immune checkpoint blockade. In conclusion, an M0-macrophage-enriched, lymphocyte-to-monocyte-ratio-low phenotype in the primary melanoma tumor site independently characterizes an aggressive phenotype that may differentially respond to treatment.
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http://dx.doi.org/10.2217/mmt-2020-0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727784PMC
November 2020

Cutaneous follicle center lymphomas with plasmacytic differentiation.

J Cutan Pathol 2021 May 29;48(5):632-636. Epub 2020 Nov 29.

Department of Pathology, Michigan Medicine, Ann Arbor, Michigan, USA.

Follicle center lymphomas, including primary cutaneous follicle center lymphoma (PCFCL), may rarely show plasmacytic differentiation. Such cases can pose a diagnostic challenge and can be mistaken for other lymphomas that more commonly include plasma cells. Here, we report four cases of PCFCL and one case of systemic follicular lymphoma involving the skin with associated monotypic plasma cells, including the clinical, morphologic and immunophenotypic features.
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http://dx.doi.org/10.1111/cup.13917DOI Listing
May 2021

Cytokinocytes: the diverse contribution of keratinocytes to immune responses in skin.

JCI Insight 2020 10 15;5(20). Epub 2020 Oct 15.

Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.

The skin serves as the primary interface between our body and the external environment and acts as a barrier against entry of physical agents, chemicals, and microbes. Keratinocytes make up the main cellular constitute of the outermost layer of the skin, contributing to the formation of the epidermis, and they are crucial for maintaining the integrity of this barrier. Beyond serving as a physical barrier component, keratinocytes actively participate in maintaining tissue homeostasis, shaping, amplifying, and regulating immune responses in skin. Keratinocytes act as sentinels, continuously monitoring changes in the environment, and, through microbial sensing, stretch, or other physical stimuli, can initiate a broad range of inflammatory responses via secretion of various cytokines, chemokines, and growth factors. This diverse function of keratinocytes contributes to the highly variable clinical manifestation of skin immune responses. In this Review, we highlight the highly diverse functions of epidermal keratinocytes and their contribution to various immune-mediated skin diseases.
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http://dx.doi.org/10.1172/jci.insight.142067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605526PMC
October 2020

Eccrine Porocarcinoma: Avoiding Diagnostic Delay.

Foot Ankle Spec 2020 Oct 17;13(5):415-419. Epub 2020 Aug 17.

Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Health System, Ann Arbor, Michigan.

Skin cancer is the most common cancer within the United States. Reports estimate that 1 in 5 Americans will develop some form of skin cancer. Eccrine porocarcinoma is a rare type of skin cancer of sweat gland origin. Eccrine porocarcinoma is most commonly found on the lower extremities. Clinically it may appear similar to benign skin lesions and it has significant metastatic potential. The authors present a case report with 22 months' follow-up. It describes a multiyear delay in diagnosis involving 3 specialties, including primary care, dermatology, and wound physical therapy. Information is given on techniques when high-risk cutaneous cancers are suspected or encountered. A multispecialty treatment plan is discussed. Level V.
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http://dx.doi.org/10.1177/1938640020946190DOI Listing
October 2020

Merkel Cell Polyomavirus in Merkel Cell Carcinoma: Integration Sites and Involvement of the KMT2D Tumor Suppressor Gene.

Viruses 2020 08 31;12(9). Epub 2020 Aug 31.

Medical Oncology Molecular Laboratory, Medical Oncology Department, Tata Memorial Hospital, Mumbai 400012, India.

Merkel cell carcinoma (MCC) is an uncommon, lethal cancer of the skin caused by either Merkel cell polyomavirus (MCPyV) or UV-linked mutations. MCPyV is found integrated into MCC tumor genomes, accompanied by truncation mutations that render the MCPyV large T antigen replication incompetent. We used the open access HPV Detector/Cancer-virus Detector tool to determine MCPyV integration sites in whole-exome sequencing data from five MCC cases, thereby adding to the limited published MCPyV integration site junction data. We also systematically reviewed published data on integration for MCPyV in the human genome, presenting a collation of 123 MCC cases and their linked chromosomal sites. We confirmed that there were no highly recurrent specific sites of integration. We found that chromosome 5 was most frequently involved in MCPyV integration and that integration sites were significantly enriched for genes with binding sites for oncogenic transcription factors such as LEF1 and ZEB1, suggesting the possibility of increased open chromatin in these gene sets. Additionally, in one case we found, for the first time, integration involving the tumor suppressor gene , adding to previous reports of rare MCPyV integration into host tumor suppressor genes in MCC.
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http://dx.doi.org/10.3390/v12090966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552051PMC
August 2020

Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.

JCI Insight 2020 10 2;5(19). Epub 2020 Oct 2.

Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton's tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS.
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http://dx.doi.org/10.1172/jci.insight.139930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566715PMC
October 2020

"Autoinflammatory psoriasis"-genetics and biology of pustular psoriasis.

Cell Mol Immunol 2021 02 19;18(2):307-317. Epub 2020 Aug 19.

Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.

Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical presentations. Plaque psoriasis, which is the most common manifestation of psoriasis, is located on one end of the spectrum, dominated by adaptive immune responses, whereas the rarer pustular psoriasis lies on the opposite end, dominated by innate and autoinflammatory immune responses. In recent years, genetic studies have identified six genetic variants that predispose to pustular psoriasis, and these have highlighted the role of IL-36 cytokines as central to pustular psoriasis pathogenesis. In this review, we discuss the presentation and clinical subtypes of pustular psoriasis, contribution of genetic predisposing variants, critical role of the IL-36 family of cytokines in disease pathophysiology, and treatment perspectives for pustular psoriasis. We further outline the application of appropriate mouse models for the study of pustular psoriasis and address the outstanding questions and issues related to our understanding of the mechanisms involved in pustular psoriasis.
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http://dx.doi.org/10.1038/s41423-020-0519-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027616PMC
February 2021

Expression of p16 in Merkel cell carcinoma.

J Cutan Pathol 2021 Mar 9;48(3):455-457. Epub 2020 Sep 9.

Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

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http://dx.doi.org/10.1111/cup.13790DOI Listing
March 2021

A genomic survey of sarcomas on sun-exposed skin reveals distinctive candidate drivers and potentially targetable mutations.

Hum Pathol 2020 08 12;102:60-69. Epub 2020 Jun 12.

Department of Pathology, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA; Department of Dermatology, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA; Rogel Cancer Center, University of Michigan, 1500 E. Medical Center Drive Ann Arbor, MI, 48109, USA. Electronic address:

Sarcomas on photodamaged skin vary in prognosis and management, but can display overlapping microscopic and immunophenotypic features. Improved understanding of molecular alterations in these tumors may provide diagnostic and therapeutic insights. We characterized 111 cutaneous sarcomatoid malignancies and their counterparts, including primary cutaneous angiosarcoma (n = 7), atypical fibroxanthoma (AFX) (n = 21), pleomorphic dermal sarcoma (PDS) (n = 17), extracutaneous undifferentiated pleomorphic sarcoma (n = 8), cutaneous leiomyosarcoma (LMS) (n = 5), extracutaneous LMS (n = 9), sarcomatoid squamous cell carcinoma (spindle cell squamous cell carcinoma) (S-SCC) (n = 24), and conventional cutaneous squamous cell carcinoma (SCC) (n = 20), by next-generation sequencing (NGS) using the StrataNGS panel for copy number variations, mutations, and/or fusions in more than 60 cancer-related genes. TP53 mutations were highly recurrent in most groups. Angiosarcoma displayed previously reported MYC amplifications, as well as CCND1 gains. RB1 mutations were relatively restricted to cutaneous LMS. As previously reported, PIK3CA mutations occurred in AFX, whereas RAS activation was more frequent in PDS. CDKN2A mutations were recurrent in AFX and S-SCC, whereas PDS displayed frequent CDKN2A deletion. S-SCC displayed mutational similarity to conventional SCC. BRCA1/2 mutations were specific to tumors with disease progression. In a subset, we detected potential driver events novel to these tumor types: activating mutations in IDH2 (PDS), MAP2K1 (angiosarcoma, PDS), and JAK1 (S-SCC) and copy gains in FGFR1 (angiosarcoma, S-SCC), KIT (AFX), MET (PDS), and PDGFRA (PDS). Our findings confirm and expand the spectrum of known genomic aberrations, including potential targetable drivers, in cutaneous sarcomatoid malignancies. In addition, certain events are relatively specific to particular tumors within this differential diagnosis and hence might be diagnostically informative.
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http://dx.doi.org/10.1016/j.humpath.2020.06.003DOI Listing
August 2020

Invasive squamous cell carcinomas and precursor lesions on UV-exposed epithelia demonstrate concordant genomic complexity in driver genes.

Mod Pathol 2020 11 27;33(11):2280-2294. Epub 2020 May 27.

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.

Although squamous cell carcinomas (SCC) are the most frequent human solid tumor at many anatomic sites, the driving molecular alterations underlying their progression from precursor lesions are poorly understood, especially in the context of photodamage. Therefore, we used high-depth, targeted next-generation sequencing (NGS) of RNA and DNA from routine tissue samples to characterize the progression of both well- (cutaneous) and poorly (ocular) studied SCCs. We assessed 56 formalin-fixed paraffin-embedded (FFPE) cutaneous lesions (n = 8 actinic keratosis, n = 30 carcinoma in situ [CIS], n = 18 invasive) and 43 FFPE ocular surface lesions (n = 2 conjunctival/corneal intraepithelial neoplasia, n = 20 CIS, n = 21 invasive), from institutions in the US and Brazil. An additional seven cases of advanced cutaneous SCC were profiled by hybrid capture-based NGS of >1500 genes. The cutaneous and ocular squamous neoplasms displayed a predominance of UV-signature mutations. Precursor lesions had highly similar somatic genomic landscapes to SCCs, including chromosomal gains of 3q involving SOX2, and highly recurrent mutations and/or loss of heterozygosity events affecting tumor suppressors TP53 and CDKN2A. Additionally, we identify a novel molecular subclass of CIS with RB1 mutations. Among TP53 wild-type tumors, human papillomavirus transcript was detected in one matched pair of cutaneous CIS and SCC. Amplicon-based whole-transcriptome sequencing of select 20 cutaneous lesions demonstrated significant upregulation of pro-invasion genes in cutaneous SCCs relative to precursors, including MMP1, MMP3, MMP9, LAMC2, LGALS1, and TNFRSF12A. Together, ocular and cutaneous squamous neoplasms demonstrate similar alterations, supporting a common model for neoplasia in UV-exposed epithelia. Treatment modalities useful for cutaneous SCC may also be effective in ocular SCC given the genetic similarity between these tumor types. Importantly, in both systems, precursor lesions possess the full complement of major genetic changes seen in SCC, supporting non-genetic drivers of invasiveness.
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http://dx.doi.org/10.1038/s41379-020-0571-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934000PMC
November 2020

DNA copy number changes correlate with clinical behavior in melanocytic neoplasms: proposal of an algorithmic approach.

Mod Pathol 2020 07 17;33(7):1307-1317. Epub 2020 Feb 17.

Department of Pathology, Michigan Medicine, 2800 Plymouth Rd, Ann Arbor, MI, 48109, USA.

Increasingly, molecular methods are being utilized in the workup of melanocytic neoplasms. To this end, we sought to correlate data from a single nucleotide polymorphism (SNP) array platform based on molecular inversion probes with clinical data. Copy number variation (CNV) data were obtained on 95 melanocytic tumors (6 ordinary nevi, 15 atypical nevi, 34 ambiguous neoplasms, and 40 melanomas) from 92 patients. The average number of significant CNVs was 0 for nevi, 0.6 for atypical nevi (range 0-3), 2.8 for ambiguous neoplasms (range 0-17), and 18.1 for melanomas (range 0-69). Clinical follow-up data were available in 57 of 95 lesions (56 of 92 patients). Tumors from patients with adverse events demonstrated an average number of CNVs of 24.5 (range 6-69) as compared with 7.9 (range 0-35) among tumors without an associated adverse event (p ≤ 0.001). No adverse events were observed in nevi including atypical nevi. Adverse events were found in 2 of 19 ambiguous neoplasms and 10 of 32 melanomas with follow up. In these two latter groups of neoplasms, the correlation between adverse events and the average number of CNVs remained statistically significant even when controlled for Breslow depth (21.5 versus 8.7, p value = 0.036). No neoplasm with adverse events had ≤3 CNVs. These results provide further evidence that SNP array testing for CNVs may be helpful in the classification and prognostication of ambiguous neoplasms. Based on these results, an algorithmic approach to challenging melanocytic neoplasms using CNV data is suggested, using as cutoff of >3 CNVs with some caveats, as the threshold for a positive result. Future clinical validation, using a larger cohort of relevant tumors, will be necessary.
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http://dx.doi.org/10.1038/s41379-020-0499-yDOI Listing
July 2020

Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses.

J Allergy Clin Immunol 2020 05 28;145(5):1406-1415. Epub 2019 Dec 28.

Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Background: Although multiple studies have assessed molecular changes in chronic atopic dermatitis (AD) lesions, little is known about the transition from acute to chronic disease stages, and the factors and mechanisms that shape chronic inflammatory activity.

Objectives: We sought to assess the global transcriptome changes that characterize the progression from acute to chronic stages of AD.

Methods: We analyzed transcriptome changes in paired nonlesional skin, acute and chronic AD lesions from 11 patients and 38 healthy controls by RNA-sequencing, and conducted in vivo and histological assays to evaluate findings.

Results: Our data demonstrate that approximately 74% of the genes dysregulated in acute lesions remain or are further dysregulated in chronic lesions, whereas only 34% of the genes dysregulated in chronic lesions are altered already in the acute stage. Nonlesional AD skin exhibited enrichment of TNF, T1, T2, and T17 response genes. Acute lesions showed marked dendritic-cell signatures and a prominent enrichment of T1, T2, and T17 responses, along with increased IL-36 and thymic stromal lymphopoietin expression, which were further heightened in chronic lesions. In addition, genes involved in skin barrier repair, keratinocyte proliferation, wound healing, and negative regulation of T-cell activation showed a significant dysregulation in the chronic versus acute comparison. Furthermore, our data show progressive changes in vasculature and maturation of dendritic-cell subsets with chronicity, with FOXK1 acting as immune regulator.

Conclusions: Our results show that the changes accompanying the transition from nonlesional to acute to chronic inflammation in AD are quantitative rather than qualitative, with chronic AD having heightened T2, T1, T17, and IL36 responses and skin barrier repair mechanisms. These findings provide novel insights and highlight underappreciated pathways in AD pathogenesis that may be amenable to therapeutic targeting.
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http://dx.doi.org/10.1016/j.jaci.2019.11.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214216PMC
May 2020

Expanding the differential of superficial tumors with round-cell morphology: Report of three cases of CIC-rearranged sarcoma, a potentially under-recognized entity.

J Cutan Pathol 2020 Jun 10;47(6):535-540. Epub 2020 Jan 10.

Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, One Medical Center Drive, New Hampshire, Lebanon.

Among sarcomas with a round-cell morphology that lack rearrangement of the EWSR1 gene, rearrangements involving the CIC gene are the most common. In comparison with Ewing Sarcoma, CIC-rearranged sarcomas present at an older average age, arise almost exclusively in soft tissues, are clinically more aggressive, and are more likely to be resistant to the chemotherapy regimens used for Ewing sarcoma. CIC-rearranged sarcomas present more commonly in a deep location, and we suspect that superficial presentations may be under-recognized. In this case series, we report three of such cases. Overall, the morphology is similar to CIC-rearranged sarcomas of deeper locations. We hope to raise awareness among the dermatopathology community by expanding the differential of superficial tumors with round cell morphology.
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http://dx.doi.org/10.1111/cup.13639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353993PMC
June 2020

Next-generation sequencing implicates oncogenic roles for p53 and JAK/STAT signaling in microcystic adnexal carcinomas.

Mod Pathol 2020 06 19;33(6):1092-1103. Epub 2019 Dec 19.

Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.

Microcystic adnexal carcinoma is a locally aggressive sweat gland carcinoma characterized by its infiltrative growth and histopathologic overlap with benign adnexal tumors, often posing challenges to both diagnosis and management. Understanding the molecular underpinnings of microcystic adnexal carcinoma may allow for more accurate diagnosis and identify potential targetable oncogenic drivers. We characterized 18 microcystic adnexal carcinomas by targeted, multiplexed PCR-based DNA next-generation sequencing of the coding sequence of over 400 cancer-relevant genes. The majority of cases had relatively few (<8) prioritized somatic mutations, and lacked an ultraviolet (UV) signature. The most recurrent mutation was TP53 inactivation in four (22%) tumors. Frame-preserving insertions affecting the kinase domain of JAK1 were detected in three (17%) cases, and were nonoverlapping with TP53 mutations. Seven (39%) cases demonstrated copy number gain of at least one oncogene. By immunohistochemistry, p53 expression was significantly higher in microcystic adnexal carcinomas with TP53 mutations compared with those without such mutations and syringomas. Similarly, phospho-STAT3 expression was significantly higher in microcystic adnexal carcinomas harboring JAK1 kinase insertions compared with those with wild-type JAK1 and syringomas. In conclusion, microcystic adnexal carcinomas are molecularly heterogeneous tumors, with inactivated p53 or activated JAK/STAT signaling in a subset. Unlike most other nonmelanoma skin cancers involving sun-exposed areas, most microcystic adnexal carcinomas lack evidence of UV damage, and hence likely originate from a relatively photo-protected progenitor population in the dermis. These findings have implications for the biology, diagnosis, and treatment of microcystic adnexal carcinomas, including potential for therapeutic targeting of p53 or the JAK/STAT pathway in advanced tumors.
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http://dx.doi.org/10.1038/s41379-019-0424-4DOI Listing
June 2020

Danger is only skin deep: aggressive epidermal carcinomas. An overview of the diagnosis, demographics, molecular-genetics, staging, prognostic biomarkers, and therapeutic advances in Merkel cell carcinoma.

Mod Pathol 2020 01 1;33(Suppl 1):42-55. Epub 2019 Nov 1.

Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

Merkel cell carcinoma (MCC) is a high grade primary cutaneous neuroendocrine carcinoma and is among the most aggressive cutaneous malignancies. The rising incidence of MCC, together with its often rapidly aggressive course, underscore a critical need to recognize the histopathologic and the immunohistochemical features that inform its accurate diagnosis. In the current review, we summarize the current state of knowledge regarding the accurate diagnosis of MCC and the exclusion of other entities in the differential diagnosis. We provide a comprehensive review of genomic studies that identified the molecular-genetic drivers of MCC as well as a summary of studies identifying prognostic biomarkers that can facilitate risk stratification. Importantly, Merkel cell polyomavirus (MCPyV) appears to be causative in most cases of MCC and represents both a diagnostic and prognostic marker. Finally, as staging of MCC has undergone critical refinements with the introduction of the 8th Edition of the American Joint Committee on Cancer staging system, we provide an update on MCC staging. In particular, the prognostic significance of the sentinel lymph node (SLN) in MCC necessitates a systematic approach to its evaluation and diagnosis to ensure accurate and consistent risk stratification for patients, and we therefore provide a comprehensive overview of SLN evaluation in MCC. Finally, the intimate relationship between MCC and the integrity of the host immune system has led to paradigm-shifting therapeutic advances with the successful application of immune checkpoint blockade to treat patients with advanced disease, and we therefore summarize those studies and the correlative studies in which predictive biomarkers have been identified.
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http://dx.doi.org/10.1038/s41379-019-0394-6DOI Listing
January 2020

A pediatric case of pigmented epithelioid melanocytoma with chromosomal copy number alterations in 15q and 17q and a novel NTRK3-SCAPER gene fusion.

J Cutan Pathol 2020 Jan 11;47(1):70-75. Epub 2019 Sep 11.

Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan.

Pigmented epithelioid melanocytoma (PEM) represents a group of rare, heavily pigmented melanocytic tumors encompassing lesions previously designated as "animal-type melanomas" and "epithelioid blue nevi." Despite the association of multiple such tumors in the setting of Carney complex, most cases of PEM occur spontaneously as solitary neoplasms in otherwise healthy patients. PEM may arise in both children and adults, and has a known propensity to spread to the regional lymph nodes. Despite this latter finding, recurrence at the biopsy site or spread beyond the lymph node basin is exceptionally uncommon. Although the molecular basis for PEM continues to be characterized, findings to date suggest that this category of melanocytic neoplasia has genetic alterations distinct from those seen in common nevi, dysplastic nevi, Spitz nevi, and melanoma. Herein, we present an in-depth clinical, histopathologic, and molecular analysis of a case of PEM occurring on the scalp of a young African American girl found to have a novel NTRK3-SCAPER gene fusion.
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http://dx.doi.org/10.1111/cup.13566DOI Listing
January 2020

A Case of Adjacent, Clonally Distinct Borderline Melanocytic Tumors on the Arm.

Am J Dermatopathol 2020 Jan;42(1):e7-e10

Departments of Pathology; and.

Atypical Spitz tumor (AST) is a melanocytic proliferation that shares histopathologic features of Spitz nevus and spitzoid melanoma. Distinction of AST from spitzoid melanoma is critical because the majority of ASTs will follow an indolent course. Array-based comparative genomic hybridization (aCGH) has been suggested as a potential tool for evaluating malignant potential in spitzoid tumors. We present a case of a 52-year-old woman with an AST in which aCGH was crucial in guiding correct diagnosis and management. The patient first presented with a flesh-colored papule on her arm that was changing color. Biopsy revealed a dermal nevoid melanocytic tumor of indeterminate histopathology, favored to be a severely atypical nevus. The tumor was excised. One year later, another flesh-colored papule proximal to the excision site of the first tumor was biopsied and showed a predominantly dermal atypical spitzoid melanocytic proliferation with a differential diagnosis of AST versus spitzoid melanoma. Recurrent or metastatic melanoma was also a concern given proximity to the previous excision site. Molecular analysis of both lesions by aCGH revealed distinct molecular signatures, supporting the 2 tumors to be clonally unrelated. Furthermore, the new tumor displayed limited evidence of genomic instability, supporting classification as an AST with predicted indolent behavior. This case highlights the utility of aCGH in evaluating borderline melanocytic lesions, including assessment of malignant potential in ASTs, and clonality analysis to assist in exclusion of metastatic disease.
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http://dx.doi.org/10.1097/DAD.0000000000001472DOI Listing
January 2020

Clinicopathologic Features and Calcium Deposition Patterns in Calciphylaxis: Comparison With Gangrene, Peripheral Artery Disease, Chronic Stasis, and Thrombotic Vasculopathy.

Am J Surg Pathol 2019 09;43(9):1273-1281

Departments of Pathology.

Diagnosis of calciphylaxis is crucial, yet its distinction from other vascular diseases can be challenging. Although vascular calcification and thrombosis are hallmarks of calciphylaxis, the incidence and patterns of these features in other vascular diseases have not been well characterized. The specificity of fine calcium deposits in vessel walls (identifiable on von Kossa [VK] stain only) and other extravascular calcifications is not entirely clear. We retrospectively examined the clinicopathologic features in calciphylaxis (n=27), gangrene and viable skin at amputation margin (n=20 each), chronic stasis (n=22), and thrombotic vasculopathy (n=19) to identify useful discriminators. Calcification of subcutaneous small vessels appreciable on hematoxylin and eosin stain was relatively specific for calciphylaxis, although sensitivity was low (56%). VK detected fine calcium deposits in vessel walls not appreciable on hematoxylin and eosin, however, specificity was limited by frequent finding of similar deposits in peripheral artery disease. Combining calcium deposits detected by VK and thrombosis of subcutaneous small vessels resulted in optimal sensitivity (85%) and specificity (88%) for calciphylaxis. Similar observations applied to medium-sized vessel calcification. Calcification of eccrine gland basement membranes, elastic fibers, and perineurium did not effectively distinguish calciphylaxis from other groups. Diffuse dermal angiomatosis was exclusively found in calciphylaxis in this study. In conclusion, VK is useful in enhancing the detection of vascular calcification and avoiding the false-negative diagnosis, but this finding requires concomitant subcutaneous small vessel thrombosis to support a diagnosis of calciphylaxis. Diffuse dermal angiomatosis should increase suspicion for underlying calciphylaxis and prompt deeper sampling in the appropriate clinical setting.
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http://dx.doi.org/10.1097/PAS.0000000000001302DOI Listing
September 2019
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