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Objectives To describe consecutive vulvar biopsy cases and to create an educational template for pathology trainees and practicing pathologists. Methods We reviewed 189 consecutive biopsies from the female genital area skin and mucosa. We classified them based on etiologies and examined limited clinical information. Results We classified diagnoses as squamous intraepithelial neoplasia (21.5%), melanocytic neoplasia (17.9%), lichenoid dermatoses (15.9%), nonlichenoid dermatoses (11.3%), infectious (6.2%), reparative (4.6%), or miscellaneous (22.6%). The miscellaneous diagnoses included common entities (polyps and cysts) and rarer entities (calcinosis cutis, adnexal neoplasms, or basal cell carcinoma) and nonspecific descriptive diagnoses. Clinicians most often included the actual diagnosis in their differential for melanocytic lesions (83%) and least often for inflammatory lesions (32%). However, some cases included a clinical description without a differential diagnosis (14%) or no helpful clinical information (4%). The distribution of whether correct diagnoses were included in the clinical differential was similar between submitting physicians and midlevel providers. Conclusions Understanding squamous and melanocytic pathology and the various lichenoid and other inflammatory diagnoses is critical for signing out female genital tract skin pathology. The cases examined in this report can serve as an educational template for trainees and practicing pathologists.

Melanomas that have histopathologic features that overlap with those of Spitz nevus are referred to as spitzoid melanomas. However, the diagnostic concept is used inconsistently and genomic analyses suggest it is a heterogeneous category. Spitz tumors, the spectrum of melanocytic neoplasms extending from Spitz nevi to their malignant counterpart Spitz melanoma, are defined in the 2018 WHO classification of skin tumors by the presence of specific genetic alterations, such as kinase fusions or HRAS mutations. It is unclear what fraction of “spitzoid melanomas” defined solely by their histopathologic features belong to the category of Spitz melanoma or to other melanoma subtypes. We assembled a cohort of 25 spitzoid melanomas diagnosed at a single institution over an 8-year period and performed high-coverage DNA sequencing of 480 cancer related genes. Transcriptome wide RNA sequencing was performed for select cases. Only nine cases (36%) had genetic alterations characteristic of Spitz melanoma, including HRAS mutation or fusion involving BRAF, ALK, NTRK1, or MAP3K8. The remaining cases were divided into those with an MAPK activating mutation and those without an MAPK activating mutation. Both Spitz melanoma and spitzoid melanomas in which an MAPK-activating mutation could not be identified tended to occur in younger patients on skin with little solar elastosis, infrequently harbored TERT promoter mutations, and had a lower burden of pathogenic mutations than spitzoid melanomas with non-Spitz MAPK-activating mutations. The MAPK-activating mutations identified affected non- V600 residues of BRAF as well as NRAS, MAP2K1/2, NF1, and KIT, while BRAF V600 mutations, the most common mutations in melanomas of the WHO low-CSD category, were entirely absent. While the “spitzoid melanomas” comprising our cohort were enriched for bona fide Spitz melanomas, the majority of melanomas fell outside of the genetically defined category of Spitz melanomas, indicating that histomorphology is an unreliable predictor of Spitz lineage.

Melanocytic tumors with inactivation of protein kinase A regulatory subunit-α (PRKAR1A) have large oval nuclei and intense pigmentation. Historically, these tumors have been categorized under various names, including epithelioid blue nevus, pigmented epithelioid melanocytoma (PEM) and animal-type melanoma. Although a subset of PEM harbor BRAF activating mutations and biallelic inactivation of PRKAR1A, there are only a few reports of melanomas, or of tumors with genomic alterations beyond those of PEMs. Herein, we describe the clinicopathologic and genetic features of 8 melanomas and tumors that lack PRKAR1α expression by immunohistochemistry but do not fit with conventional PRKAR1A-inactivated melanocytomas. These tumors tended to affect younger patients than conventional melanomas (median age=38 y) and presented as dark brown/black papules and nodules. Histopathologically, they demonstrated nodularity, sometimes in a background of conventional melanoma, and large vesicular nuclei with prominent nucleoli. With the exception of 1 case, the mitotic index was not significantly elevated. Immunohistochemically, all cases showed loss of PRKAR1α and of p16 expression. Seven tumors underwent massively parallel short read (next-generation) sequencing of a panel of 480 cancer-associated genes. Five tumors demonstrated truncating mutations of PRKAR1A and the 2 in which such mutations were not identified demonstrated loss of heterozygosity of the PRKAR1A locus. Four of the tumors harbored BRAF V600E mutations, and 1 harbored a FAM39B-BRAF gene fusion. Another harbored a GNA11 activating mutation. A MAP kinase activating mutation was not identified in the remaining case. Four tumors displayed TERT promoter mutations and chromosomal copy number changes supporting the diagnosis of melanoma. Two cases without these alterations and were classified as "high-grade PRKAR1A-inactivated melanocytomas". The 1 case with widespread metastases demonstrated mutations in TP53 and RB1. Overall, we provide the first genetic characterization of PRKAR1A-inactivated melanomas, discuss the differential diagnosis of heavily pigmented epithelioid melanocytic neoplasms, and propose a new nomenclature for such tumors.

Summary: Perturbations in the transcriptional programs specifying epidermal differentiation cause diverse skin pathologies ranging from impaired barrier function to inflammatory skin disease. However, the global scope and organization of this complex cellular program remain undefined. Here we report single-cell RNA sequencing profiles of 92,889 human epidermal cells from 9 normal and 3 inflamed skin samples. Transcriptomics-derived keratinocyte subpopulations reflect classic epidermal strata but also sharply compartmentalize epithelial functions such as cell-cell communication, inflammation, and WNT pathway modulation. In keratinocytes, ∼12% of assessed transcript expression varies in coordinate patterns, revealing undescribed gene expression programs governing epidermal homeostasis. We also identify molecular fingerprints of inflammatory skin states, including S100 activation in the interfollicular epidermis of normal scalp, enrichment of a CD1C+CD301A+ myeloid dendritic cell population in psoriatic epidermis, and IL1βhiCCL3hiCD14+ monocyte-derived macrophages enriched in foreskin. This compendium of RNA profiles provides a critical step toward elucidating epidermal diseases of development, differentiation, and inflammation. : Cheng et al. report single-cell RNA sequencing of normal and inflamed human epidermis, revealing a discrete set of specialized keratinocytes that exhibit a distinct composition at different anatomic sites. Myeloid dendritic cells and macrophages also vary sharply with epidermal anatomic site and inflammation, indicating dynamic programming of antigen-presenting cells. Keywords: epidermis, single-cell RNA-seq, keratinocyte, skin

Genetic variation in the NF-κB inhibitors, ABIN1 and A20, increase risk for psoriasis. While critical for hematopoietic immune cell function, these genes are believed to additionally inhibit psoriasis by dampening inflammatory signaling in keratinocytes. We dissected ABIN1 and A20's regulatory role in human keratinocyte inflammation using an RNA sequencing-based comparative genomic approach. Here we show subsets of the IL-17 and tumor necrosis factor-α signaling pathways are robustly restricted by A20 overexpression. In contrast, ABIN1 overexpression inhibits these genes more modestly for IL-17, and weakly for tumor necrosis factor-α. Our genome-scale analysis also indicates that inflammatory program suppression appears to be the major transcriptional influence of A20/ABIN1 overexpression, without obvious influence on keratinocyte viability genes. Our findings thus enable dissection of the differing anti-inflammatory mechanisms of two distinct psoriasis modifiers, which may be directly exploited for therapeutic purposes. Importantly, we report that IL-17-induced targets of A20 show similar aberrant epidermal layer-specific transcriptional upregulation in keratinocytes from diseases as diverse as psoriasis, atopic dermatitis, and erythrokeratodermia variabilis, suggesting a contributory role for epidermal inflammation in a broad spectrum of rashes.

Activating kinase fusions have recently been described as early oncogenic events that are mutually exclusive with HRAS and BRAF mutations in Spitz tumors. Here, we report a series of 32 Spitz tumors with ALK fusions (6 Spitz nevi, 22 atypical Spitz tumors, and 4 spitzoid melanomas) in patients ranging from 5 months to 64 years (median=12 y) of age. The tumors typically presented as exophytic papules on the extremities and were occasionally darkly pigmented. In addition to ALK fusions previously described in other tumor types (NPM1-ALK, TPR-ALK), we identified 2 novel ALK fusions (CLIP1-ALK and GTF3C2-ALK) in our cohort of Spitz tumors. Array comparative genomic hybridization of 19 of these tumors demonstrated a high frequency of chromosome 2 aberrations (where ALK resides, 63%) and chromosome 1p loss in 37% of the cases. Spitz tumors with ALK fusions demonstrated unique histopathologic features. Clefts and small vesicle-like spaces were arrayed between plump spindled melanocytes with fibrillar cytoplasm and enlarged nuclei. These melanocytes were typically arrayed in elongated and fusiform nests with radial orientation. The tumors often had extension into the dermis or subcutis with a wedge-shaped or bulbous lower border (45% and 17%, respectively). An infiltrative growth pattern was often present at the periphery of the tumor and was highlighted by ALK immunohistochemistry. In conclusion, Spitz tumors with ALK rearrangement show distinct histopathologic features that should aid in improving classification of these diagnostically challenging tumors.

We report the unprecedented case of reactive eccrine syringofibroadenoma (ESFA) secondary to primary cutaneous amyloidosis. A 62-year-old woman of Asian ethnicity presented with a pruritic rash on the back of long-standing duration. Physical examination revealed diffuse hyperpigmentation localized to the interscapular region; there were a multitude of hyperpigmented macules merged in a rippled pattern intermixed with scattered papules and cobblestone-like areas. A punch biopsy from a papule was taken. Histopathological examination revealed a network of epithelial strands and cords hanging from the epidermis and harboring foci of ductal differentiation. Eosinophilic collections of amorphous material were found between the epithelial strands, obscuring the superficial dermis. The microscopic picture was consistent with primary cutaneous amyloidosis associated with reactive ESFA. Results of histochemical and immunohistochemical staining confirmed the diagnosis. We speculate that pathogenetic mechanisms intrinsic to primary cutaneous amyloidosis, in addition to unknown genetic factors, resulted in clinical changes of lichen amyloidosus associated with an abnormal hyperplastic epithelial response with histopathological features of ESFA rather than the common epidermal change of acanthosis and hyperkeratosis.

A 29-year-old woman with hepatitis C presented 2 years after an orthotopic liver transplant with several weeks of fevers, abdominal pain, nausea, and a painful ulcerated nodular eruption on her abdomen and lower extremities. The patient was evaluated, and her case is presented and the differential discussed.

Background The term "diffuse neonatal hemangiomatosis" has been used historically to describe multifocal vascular lesions affecting the skin and viscera in infants. Objective We hypothesized that many cases reported as diffuse neonatal hemangiomatosis did not have infantile hemangiomas (IH), but represented more recently described neonatal vascular diseases. Methods A literature search was performed using PubMed database (1950-2009) with the terms "neonatal hemangiomatosis," "benign hemangiomatosis," and "diffuse hemangiomatosis." A total of 180 articles were identified. Exclusion criteria included disease onset later than 3 years of age and absence of multifocal skin involvement. In all, 73 cases were selected and categorized into 3 groups: IH/probable IH; multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT)/probable MLT; and multifocal vascular lesions, not otherwise specified. Results Of the 73 cases, 43 had IH/probable IH, 17 had MLT/probable MLT, and 13 had multifocal vascular lesions, not otherwise specified. The clinical outcomes of these groups differed in that two of 43 (5%) patients with IH died whereas 11 of 17 (65%) patients with MLT died (odds ratio 37.6, confidence interval 5.6-387.6, P value Limitations This was a literature-based meta-analysis, which inherently has limitations of incomplete and inconsistently presented information. Conclusions Many cases reported in the literature as diffuse neonatal hemangiomatosis represent newly described multifocal vascular anomalies such as MLT, which has a strikingly higher mortality than IH. We propose the term "multifocal infantile hemangioma–with or without extracutaneous disease" instead of "diffuse neonatal hemangiomatosis" for multiple cutaneous IH. Accurate diagnosis of multifocal neonatal vascular lesions is imperative to facilitate appropriate evaluation, treatment, and prognosis.

We observed that basal cell carcinoma (BCC) on the ear demonstrates a more aggressive phenotype compared with other body sites.We sought to determine if it is statistically significant that BCC on the ear is more aggressive.We queried our 2009 database for all BCCs biopsied from the ear. Multiple data points, including tumor subtype and risk level, were analyzed for 100 BCCs on the ear and 100 BCCs on the cheek.BCC on the ear was diagnosed 471 times. Of the first 100 occurrences of BCC on the ear, 57% were high risk compared with 38% on the cheek (odds ratio 2.16, 95% confidence interval 1.23-3.81, P = .01). Men were more likely to have BCC on the ear: 79% male on the ear and 53% male on the cheek (P.001). However, BCC on the ear in women is also more likely to be aggressive (57%, 12 of 21).The data were retrieved from a single year at our institution, and there could potentially be regional bias given that the population of data is from a single institution. Many of the specimens we evaluate are reviewed in consultation and may thus represent a selection bias.BCC on the ear presents as an aggressive phenotype in the majority of cases for both men and women, and it occurs much more frequently in men. Knowledge of this information can help guide physicians and ensure that these tumors are adequately biopsied and treated.

Hair re-pigmentation in adults is a rare phenomenon. We describe a 58-year-old woman who developed hair re-pigmentation on her vertex scalp as a marker of underlying melanoma. Histopathology revealed a nodular melanoma that was surrounding but not invading follicular epithelium. To our knowledge, there have only been 4 other previously published cases describing hair re-pigmentation in the setting of scalp melanoma. Focal hair re-pigmentation in adults should prompt a thorough evaluation for an underlying melanoma.

Atypical fibroxanthoma (AFX), is a rare type of skin cancer affecting older individuals with sun damaged skin. Since there is limited genomic information about AFX, our study seeks to improve the understanding of AFX through whole-exome and RNA sequencing of 8 matched tumor-normal samples. AFX is a highly mutated malignancy with recurrent mutations in a number of genes, including COL11A1, ERBB4, CSMD3, and FAT1. The majority of mutations identified were UV signature (C>T in dipyrimidines). We observed deletion of chromosomal segments on chr9p and chr13q, including tumor suppressor genes such as KANK1 and CDKN2A, but no gene fusions were found. Gene expression profiling revealed several biological pathways that are upregulated in AFX, including tumor associated macrophage response, GPCR signaling, and epithelial to mesenchymal transition (EMT). To further investigate the presence of EMT in AFX, we conducted a gene expression meta-analysis that incorporated RNA-seq data from dermal fibroblasts and keratinocytes. Ours is the first study to employ high throughput sequencing for molecular profiling of AFX. These data provide valuable insights to inform models of carcinogenesis and additional research towards tumor-directed therapy.

Background Graft-vs-host disease (GVHD) is a rare and often fatal complication of orthotopic liver transplantation (OLT). The skin is frequently involved early in disease progression, but clinical and histopathological features may be nonspecific, presenting a diagnostic challenge. While the detection of peripheral blood chimerism has been proposed as a diagnostic criterion for post-OLT GVHD, it is not known whether peripheral blood chimerism is an absolute requirement for the diagnosis. Materials and methods We report a case of a 57-year-old man who developed post-OLT GVHD with cutaneous, enteric, and bone marrow involvement. We also review the epidemiology, pathogenesis, clinical presentation, histopathology, molecular diagnostic techniques, and treatment of GVHD following liver transplantation. Results In our patient, analysis of the peripheral blood by short-tandem repeat polymerase chain reaction did not detect circulating donor lymphocytes. Donor lymphocytes were detected in the buccal mucosa, however, confirming the diagnosis. A review of chimerism patterns in 63 previously published cases of post-OLT GVHD reveals that this is the first reported case in which chimerism was absent in the peripheral blood but present in another site. Conclusions Peripheral blood chimerism may be absent in cases of post-OLT GVHD. A combination of clinical, histopathological, and molecular features is therefore required to make this challenging diagnosis.

Germline loss of function mutations in BAP1 are associated with the development of cutaneous melanocytic tumors with some histopathologic characteristics seen in Spitz nevi. Similar melanocytic tumors occurring in a sporadic setting have been demonstrated to have biallelic loss of BAP1. In some of these sporadic tumors, loss of BAP1 occurs through mutation of one allele and genomic loss of the other. We screened our database of comparative genomic hybridization profiles of ambiguous melanocytic tumors to identify cases with a single genomic event involving loss of the BAP1 locus. The prevalence of tumors with a single genomic event involving loss of BAP1 was 6.7% in our study population. We further characterized the BAP1 status in 17 of these tumors with available additional material, confirming loss of BAP1 in all cases. We describe BAP1 loss in a blue nevus like melanoma and further expand the histopathologic spectrum of spitzoid melanocytic neoplasms with BAP1 loss.

OBJECTIVE AND IMPORTANCE: The goal of this report was to describe the successful percutaneous endovascular use of a Gianturco-Roubin-2 coronary stent in the treatment of an acute atherothrombotic occlusion of the basilar artery. To our knowledge, the percutaneous endovascular deployment of an intra-arterial stent for the treatment of an acute atherothrombotic occlusion of the basilar artery and the percutaneous endovascular placement of a Gianturco-Roubin-2 stent in the basilar artery have not been previously reported. CLINICAL PRESENTATION: An 83-year-old man presented with a recurrent, transient, locked-in syndrome resulting from a lower basilar artery occlusion caused by vertebrobasilar thrombosis superimposed on severe proximal basilar artery atheromatous stenosis. INTERVENTION: After successful superselective intra-arterial thrombolysis of the vertebrobasilar clot, balloon angioplasty of the underlying basilar artery stenosis was performed, without significant angiographic improvement. Percutaneous endovascular deployment of a Gianturco-Roubin-2 coronary stent of 4-mm diameter was subsequently performed, with excellent angiographic results. CONCLUSION: The patient made a very good neurological recovery but unfortunately died as a result of cardiogenic shock and sepsis. Detailed neuropathological follow-up results are presented; stent patency was revealed in the postmortem examination. The anatomic and pathophysiological considerations of basilar artery stent placement for the treatment of acute basilar artery occlusion related to atherosclerotic stenosis are discussed.

Background Cutaneous squamous cell carcinoma (cSCC) is the most common malignancy after solid organ transplantation, with an increased risk of recurrence and metastasis over the general population. The newly updated 7th edition American Joint Committee on Cancer (AJCC) staging system for cSCC is based on consensus expert opinion and requires validation in large cohort studies and in specific patient subpopulations. Objective Our objective was to evaluate the risk of cSCC recurrence in a high-risk population of heart and lung transplant recipients, based on the 7th edition AJCC staging system. Methods We performed a 10-year retrospective cohort study of all primary cSCC diagnosed in heart and lung transplant recipients at a tertiary care academic dermatology center. Results The cumulative incidence of local recurrence was 4% for cSCC in situ and 19% for stage I cSCC at 5 years, and 54% for stage II cSCC at 3 years. Stage II tumors had a 10-fold greater risk of recurrence than stage I, and a 43-fold greater risk of recurrence than in situ tumors. Limitations This study is limited to a specific patient subgroup at a tertiary care center, and may not be generalizable to all populations. Conclusions Heart and lung transplant recipients are at high risk for local recurrence of cSCC. These data substantiate the prognostic accuracy of the newly updated 7th edition AJCC staging system for stage 0, I, and II cSCC in this population and demonstrate the aggressive behavior of this cancer in immunosuppressed patients.

Despite its modest potential benefit, alpha-interferon is one of the most frequently employed therapies for melanoma. With the increasing incidence of melanoma, a parallel increase in interferon use and the associated adverse reactions that accompany interferon therapy should be expected. We present a case of an interferon-induced sarcoidosis-like reaction in a melanoma patient that was initially misinterpreted clinically and radiographically as metastatic melanoma. The etiology of sarcoidosis remains a mystery, but appears to involve Th-1 cytokines such as interferon and interleukin-2. Observance of a sarcoidosis-like reaction induced by interferon therapy lends additional support to the importance of this cytokine in the pathogenesis of sarcoidosis. It is important for pathologists to be aware of this entity when interpreting biopsies from melanoma patients treated with interferon. North J, Mully T. Alpha-interferon induced sarcoidosis mimicking metastatic melanoma.

We investigated effects of plant density on floral phenology and potential mating in artificial populations of the outcrossing ornamental Nicotiana alata planted at three densities. Path analysis revealed that increasing plant density yielded significantly earlier peak flowering dates, significantly earlier last flowering dates, and significantly lower plant biomass. Direct effects of density on final flower number were not significant. Variation among replicate plots for first date of flowering was larger than variation among densities, indicating that factors other than density influence floral initiation.We did not record actual mating, but determined from phenological data the number and identity of potential mates. Increased density had several effects on potential mating patterns and on potential N

Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumours with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumours lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K) and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist.

Clear cell acanthoma is a benign epidermal lesion with a variable clinical appearance and distinct histopathology features. Although, it is considered an entirely benign entity, few case reports describe unusual or atypical variants of clear cell acanthoma. We observed a case of a large clear cell acanthoma that also has features of a keratoacanthoma.

Clear cell acanthoma is a benign epidermal lesion with a variable clinical appearance and distinct histopathology features. Although, it is considered an entirely benign entity, few case reports describe unusual or atypical variants of clear cell acanthoma. We observed a case of a large clear cell acanthoma that also has features of a keratoacanthoma.