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Context.— Myriad forces are changing teaching and learning strategies throughout all stages and types of pathology education. Pathology educators and learners face the challenge of adapting to and adopting new methods and tools. The digital pathology transformation and the associated educational ecosystem are major factors in this setting of change. Objective.— To identify and collect resources, tools, and examples of educational innovations involving digital pathology that are valuable to pathology learners and teachers at each phase of professional development. Data Sources.— Sources were a literature review and the personal experience of authors and educators. Conclusions.— High-quality digital pathology tools and resources have permeated all the major niches within anatomic pathology and are increasingly well applied to clinical pathology for learners at all levels. Coupled with other virtual tools, the training landscape in pathology is highly enriched and much more accessible than in the past. Digital pathology is well suited to the demands of peer-to-peer education, such as in the introduction of new testing, grading, or other standardized practices. We found that digital pathology was well adapted to apply our current understanding of optimal teaching strategies and was effective at the undergraduate, graduate, postgraduate, and peer-to-peer levels. We curated and tabulated many existing resources within some segments of pathology. We identified several best practices for each training or educational stage based on current materials and proposed high-priority areas for potential future development.

The Human Reference Atlas (HRA) aims to map all of the cells of the human body to advance biomedical research and clinical practice. This Perspective presents collaborative work by members of 16 international consortia on two essential and interlinked parts of the HRA: (1) three-dimensional representations of anatomy that are linked to (2) tables that name and interlink major anatomical structures, cell types, plus biomarkers (ASCT+B). We discuss four examples that demonstrate the practical utility of the HRA.

The cytokine interleukin-23 (IL-23) is critical for development and maintenance of autoimmune inflammation in nonlymphoid tissues; however, the mechanism through which IL-23 supports tissue-specific immunity remains unclear. In mice, we found that circulating memory T cells were dispensable for anamnestic protection from Candida albicans skin infection, and tissue-resident memory (T RM ) cell–mediated protection from C. albicans reinfection required IL-23. Administration of anti–IL-23 receptor antibody to mice after resolution of primary C. albicans infection resulted in loss of CD69 + CD103 + tissue-resident memory T helper 17 (T RM17 ) cells from skin, and clinical anti–IL-23 therapy depleted T RM17 cells from skin of patients with psoriasis. IL-23 receptor blockade impaired T RM17 cell proliferation but did not affect apoptosis susceptibility or tissue egress. IL-23 produced by CD301b + myeloid cells was required for T RM17 maintenance in skin after C. albicans infection, and CD301b + cells were necessary for T RM17 expansion during the development of imiquimod dermatitis. This study demonstrates that locally produced IL-23 promotes in situ proliferation of cutaneous T RM17 cells to support their longevity and function and provides mechanistic insight into the durable efficacy of IL-23 blockade in the treatment of psoriasis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome, characterized by aberrant activation of T lymphocytes and macrophages leading to hypercytokinemia. HLH can be familial or a result of various secondary etiologies. We present a case of a 46-year-old woman with a past medical history of multiple sclerosis on rituximab who presented as a transfer from an outside hospital with numerous clinical abnormalities including recurrent episodes of fever of unknown origin for 3 weeks, persistent leukocytosis, hypertriglyceridemia, and steatohepatitis. Given the uncertain nature of her illness, she underwent a random skin biopsy from the abdominal region to exclude hematolymphoid malignancy. Histopathology revealed a brisk histiocytic rich dermal infiltrate accompanied by perivascular lymphocytic infiltrate. The histiocytes were enlarged and positive for muraminadase and CD68 stains exhibiting hemophagocytosis focally. As per the HLH-2004 protocol, our patient met the diagnostic criteria of HLH. Concurrent bone marrow biopsy revealed similar rare hemophagocytosis. Cytogenetics and molecular studies were negative, supporting secondary HLH.

Becker nevus (BN) is a benign cutaneous smooth muscle hamartoma that presents with a hyperpigmented patch or plaque with or without hypertrichosis.1 BN may be associated with ipsilateral breast hypoplasia or other musculoskeletal abnormalities, an association which has been termed Becker nevus syndrome (BNS).

Mapping the human body at single cell resolution in three-dimensions (3D) is an important step toward a “digital twin” model that captures important structure and dynamics of cell-cell interactions. Current 3D imaging methods suffer from low resolution and are limited in their ability to distinguish cell types and their spatial relationships. We present a novel 3D workflow: MATRICS-A (Multiplexed Image Three-D Reconstruction and Integrated Cell Spatial - Analysis) that generates a 3D map of cells from multiplexed images and calculates cell type distance from endothelial cells and other features of interest. We applied this workflow to multiplexed data from sequential skin sections from younger and older donors (n=10; 33-72 years) with biopsies from ten anatomical regions with different sun exposure effects (mild, moderate-marked). Up to 26 sequential sections from each sample underwent multiplexed imaging with 18 biomarkers covering 12 cell types (keratinocytes (granular, spinous, basal), epithelial and myoepithelial cells, fibroblasts, macrophages, T helpers, T killers, T regs, neurons and endothelial cells, markers of DNA damage and repair (p53, DDB2) and cell proliferation (Ki67). Following cell classification, the tissue and classified cells were reconstructed into 3D volumes. A significant inverse correlation between DDB2 positive cells and age was found (corr= -0.78, adj. p=0.047). This suggests reduced capacity for repair in non-cancer older sun-exposed individuals. While absolute immune cell count did not differ by age or sun exposure, the ratio of T Helper/T Killer cells was positively correlated with age (corr=0.82, adj. p=0.048) This is the first such 3D study in skin and paves the way for cataloging more cell types and spatial relationships in aging and disease in skin and other organs.

Cutaneous melanomas may demonstrate a variety of histopathological features and genetic abnormalities. Melanomas that arise in the setting of blue nevi, also known as “malignant blue nevus” or melanoma ex blue nevus (MBN), share similar histopathological and mutational profile with uveal melanoma. The majority of uveal melanomas show characteristic GNA11 or GNAQ mutations; additional BAP1 mutation or loss is associated with the highest risk for metastasis and worst prognosis. However, the significance of BAP1 loss in melanomas ex blue nevus remains unclear. We present a case of melanoma ex blue nevus arising from the scalp of a twenty-one-year-old female. The diagnosis was established on histopathological findings demonstrating a markedly atypical melanocytic proliferation with increased mitotic activity, necrosis, and a focus of angiolymphatic invasion. Immunohistochemical analysis demonstrated the absence of BAP1 nuclear expression within tumor cells. Next Generation Sequencing detected GNA11 Q209L mutation and BAP1 loss (chromosome 3p region loss), supporting the diagnosis. We reviewed another twenty-one MBN cases with reported BAP1 status from the literature. MBN with BAP1 loss presented at a younger average age (41 years versus 61 years), demonstrated larger average lesion thickness (9.0 mm versus 7.3 mm), and had a higher rate of metastasis (50% versus 33%) compared with BAP1-retained MBN. BAP1 expression studies may assist in the diagnosis and management of MBN, but further research is needed.

Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal B-cell lymphoma, which has traditionally been associated with poor outcomes. Despite increasing recognition, IVLBCL requires a high degree of clinical suspicion on the part of the clinician for its diagnosis. Case Series: We present four patient cases: A 69-year-old female with constitutional symptoms and cognitive decline; a 78-year-old female with kidney injury and constitutional symptoms whose disease rapidly progressed to multiorgan failure and death; a 70-year-old asymptomatic female with an incidentally found, enlarged thyroid; and a 63-year-old male with cytopenia and constitutional symptoms. Retrospective chart analysis was performed on these four patients diagnosed with IVLBCL at our Institute to identify the pathognomonic features of the disease and compare these to the published evidence. IVLBCL has a heterogeneous presentation, as seen in our four patients. The disease is characterized by the exclusive presence of malignant cells inside the blood vessels and lack of organ infiltration. Traditional preliminary diagnostic modalities such as imaging are usually inconclusive, given the paucity of lymphomatous aggregates. A bone marrow biopsy, random skin biopsies, or a focal organ biopsy in appropriate cases is required for diagnosis. Immunosuppression might play a role in the pathogenesis. Timely initiation of aggressive cancer-directed therapy was associated with improved outcomes. Monitoring for disease response and relapse continues to be a challenge. Conclusion: Our mini-series highlights the significance of timely diagnosis and intervention in IVLBCL and emphasizes the importance of further research to determine its association with immunosuppression.

Basaloid follicular hamartoma (BFH) is a rare, benign follicular neoplasm which typically presents as brown to skin-colored papules on the face, scalp, and trunk. Histologically, BFH consists of cords and strands of basaloid cells forming cystic structures with scant stroma and should be distinguished from infundibulocystic basal cell carcinoma to avoid overly aggressive treatment. Although BFH has been found to be associated with distinct syndromes, including alopecia, myasthenia gravis, and cystic fibrosis, there is often clinical, histopathologic, and genetic overlap with nevoid basal cell carcinoma syndrome (NBCCS). In this article, we describe a case of a 13-year-old patient with NBCCS who presented with multiple BFHs and propose that it its inclusion into the diagnostic criteria for NBCCS be considered.

This cross-sectional study examines the costs of skin cancer detection and screening via total body skin examination.

Sarcoidosis is a granulomatous condition with diverse clinical presentations, including neurological findings. It was previously hypothesized that perineural sarcoidal granulomas in the skin may be an explanation of small-fiber neuropathy. Herein, we present a case of a 55 year old female with anesthetic cutaneous lesions mimicking leprosy clinically and histopathologically and discuss the importance of this differential diagnosis.

CD8 marker is not unique to primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (pc CD8+ AECTCL). Moreover, it occurs in seven other entities presented in the following table. There is a certain clinical and morphological overlap of γδ-positive and CD8-positive cases. Due to various aberrant expression of CD56, TCRγ, and CD8 markers, it was suggested that the term “primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma” without specification may be better suited for those lymphomas. There is a range of CD8+ pseudolymphomas and CD8+ non-lymphomatous proliferations should be kept on a list of differential diagnosis such as actinic reticuloid, CD8+ drug-associated eruptions, and HIV-associated CD8+ LPD.

The unusual MF symmetricity of primary morphological elements is a striking feature of PTCL. PTCL also tends to present with monomorphic granulomatous confluent papulonodules on the upper back, around elbows and knees, which is also quite uncommon for MF. The disproportion of the severity of lymph node involvement (fully effaced) in a patient with “MF IA” disease should render a re-evaluation of “MF as a diagnosis in favor of PTCL.” While histological features may significantly overlay with MF, there are several diagnostic features of PTCL, such as high Ki67 (>50%) and an absence of epidermotropism.

Primary cutaneous γδ T-cell lymphoma (PCGD-TCL) is characterized by the expression of cytotoxic markers and shares clinical features with extranodal NK/T-cell lymphoma and primary cutaneous CD8+ aggressive epidermotropic T-cell lymphoma. γδ-Positive cases with panniculitis-like presentation should be called as PCGD-TCL with panniculitis-like presentation and not as subcutaneous panniculitis-like T-cell lymphoma with γδ expression. Those cases were shown to originate almost exceptionally from TCR-Vδ2 γδ T cells comprising the separate category. PCGD-TCL has a predilection for extremities and frequently ulcerates. Frequently, in clinical practice, the absence of β-F1 expression is considered to be an equivalent of γδ positivity. However, there is a small cohort of “TCR silent” cases with a lack of both markers. Therefore, TCRγ staining is still necessary. The absence of cytotoxic markers characterizes cases of MF with γδ expression. In the recent study, CCR4 expression was found to be useful in differential diagnosis of MF which are CCR4 positive from PCGD-TCL which are CCR4 negative. Clinically and prognostically, γδ-positive MF has no difference with classic counterparts. The cases with EBV+ CD56+ TCRγ+ presents a matter of active debate is that an extranodal NK/T-cell lymphoma with aberrant TCRγ expression or is that a case of EBV+ CD56+ primary cutaneous γδ T-cell lymphoma.

The xanthomatous changes are uncommon in lymphocytes but may be present in old persistent tumors. Akilov and colleagues present a case of tumor stage mycosis fungoides, where atypical cells contained lipid inclusions in a tumor neglected by the patient for 2 years.

The number of reactive CD30+ infiltrates is disproportionally higher than cases of CD30+ lymphomas in the practice of dermatologists and oncologists. It should be a rule to exclude all benign conditions first in case of CD30+ cells’ presence on biopsy since CD30 is not a marker of malignancy. Anaplastic large cell lymphoma is not a pediatric lymphoma. Paraphrasing a popular expression, the children’s skin is not an adult skin in a small format. The cells appear to be more active and with ease acquire activation marker CD30 in cases of various arthropod assaults; the proliferative index is always high. Those morphologies without contest always look worrisome. Clinicopathologic correlation is crucial to avoid devastating treatments like in one of the cases below.

Akilov and colleagues present a case of very unusual cutaneous T-cell lymphoma with granulomatous features that disseminated rapidly all over the skin. The pontine lesion manifested by dysarthria. While multiple chemotherapeutic regimens failed to provide the improvement, whole-body skin irradiation resolved in long-lasting complete response.

Akilov and colleagues present a case of folliculotropic mycosis fungoides whose hyperkeratotic plaques were misdiagnosed as hypertrophic actinic keratosis. Unusual presentation signifies the importance of adequate biopsies in confusing circumstances.

Mycosis fungoides (MF) patients have an increased risk of cutaneous infections by multiple mechanisms including extracutaneous lymphoma involvement and consequent immunosuppression, iatrogenic immunosuppression, and disruption of the skin barrier due to bullous subtypes of disease, scratching, or iatrogenic ulcers. Additionally, patients with greater body surface area affected by MF and those with long-standing MF have a higher likelihood of infection In this case report, the author present disseminated infection of the skin in MF patient by poxvirus.

Akilov and colleagues present a case of aberrant expression of CD20 in CD4+ mycosis fungoides with the response to anti-CD20 antibody treatment.

While exfoliative or waxy erythroderma is a part of a triad for Sezary syndrome, it is not always present. Sezary syndrome in most of the case does not present diagnostic problems relying on the presence of more than 1000 clonal cells/mm3 in the peripheral blood. The difficulties arise with the choice of therapeutics in advanced leukemic cases when the cell number reaches more than 100,000 cells/mm3. The aberrant expression of CD30, CD26, and CD25 de novo is an indicator of poor prognosis.

Parakeratosis variegata (in old books, “parapsoriasis variegate”) represents a unique type of poikilodermatous MF where the lichenoid infiltrate contributes to mottled discoloration of the skin. In this book, we present three similar cases. Interestingly, both of those cases had CD8+ phenotype of MF.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy primarily in elderly males. Almost all patients present with cutaneous tumors characterized by purpuric hue secondary to thrombocytopenia. Lymphadenopathy and pancytopenia are noted to have varying degrees, and CNS involvement is seen in up to 30% of cases. BPDCN arises from plasmacytoid dendritic cells. Those are large cells typically positive for CD4, CD56, BDCA-2, CD123, and TCL1 and negative for markers of myeloid, T-lymphoid, B-lymphoid, or monocyte lineage. Up to 10–20% of patients with BPDCN have a concurrent history of hematologic malignancy, including myelodysplastic syndrome, chronic myelomonocytic leukemia, and acute myeloid leukemia. BPDCN often undergoes a leukemic transformation with a median survival of less than 1 year. A new subset of skin-limited BPDCN with an excellent prognosis was recently defined; however, it is not clear which patient will remain to have a skin-limited disease since cases of metastatic spread after a presentation with an isolated cutaneous nodule were also described.

Akilov and colleagues presented a case of CD30+ lymphoproliferative disorder that initially manifested as a patch and plaque stage of mycosis fungoides. Fungating tumors later in the course and CD30+ epidermotropic atypical cells in the early biopsy signify the importance of close monitoring of those patients.

Akilov and colleagues discuss the importance of differential diagnostics in mycosis funogides.

This document outlines the required criteria for donor inclusion of skin specimens in the Human BioMolecular Atlas Program (HuBMAP). The study intends to be as inclusive as possible of race and ethnicity, dependent only on the consent for donor tissue for research. Disease known at the time of donation or later identified during the research will not necessarily exclude the sample from the research program.

Background Epithelioid fibrous histiocytoma (EFH) is an uncommon dermal neoplasm expressing anaplastic lymphoma kinase (ALK) protein. Rarely a histopathological variant of this entity exhibits exclusively spindle cells. We report three cases of EFH that do not completely fulfill phenotypic criteria featuring spindle cell morphology and expressing ALK protein. We also analyze the fusion partner genes rearranged with ALK in these cases. Methods ALK expression and rearrangement status were evaluated by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next generation sequencing based gene fusion analysis. Results Three cases, all from females between 25 and 55 years old, have been biopsied from back, left arm, and thumb. All three cases showed tumor with exclusively spindle cell morphology without any epithelioid cells. The tumor cells exhibited strong ALK expression by IHC and FISH study confirmed ALK gene rearrangement in all three cases. DCTN1-ALK fusion was identified in two cases. Conclusion EFH is not always purely epithelioid and its spindled cell variant, spindle cell histiocytoma, should be included in the differential diagnosis of superficial dermal spindled cell neoplasms. ALK immunostain is a useful diagnostic marker for this entity and further studies may be useful to investigate whether DCTN1-ALK fusion mutations are specific to EFH with spindled cell features.

Hypopigmented mycosis fungoides (HMF) is the most common variant of mycosis fungoides (MF) in children. Large-cell transformation in HMF has never been reported. Herein we report a case of HMF in an 8-year-old boy who presented with a 6-year history of hypopigmented patches on the bilateral arms, lower back, buttocks, posterior thighs, and lower legs. Biopsy revealed an abnormal CD8+ epidermotropic T-cell infiltrate consistent with the diagnosis of MF. The T-cell clonality study was positive. The patient was started on narrowband ultraviolet B (NBUVB) phototherapy and topical steroids. He had a 50% reduction in his patches after 10 months of treatment, after which he developed a single annular plaque on his left thigh. The biopsy specimen demonstrated large cells that were diffusely CD8+ and CD30−. Clobetasol propionate ointment was prescribed, which led to complete resolution of the plaque within 2 weeks. NBUVB phototherapy was continued and the patient had a complete response within the following 5 months. The case is an example of exceptionally rare large-cell transformation in pediatric MF and stresses the importance of regular follow-up of these patients.

Background Dysplastic nevi with severe atypia (severely dysplastic nevi [SDN]) are frequently re-excised because of the concern that these lesions may in fact represent early melanoma. Data on long-term follow-up of these patients are limited. Objective We sought to determine the rate of subsequent melanoma development in patients with SDN who underwent re-excision versus those who did not and to determine factors associated with decision to re-excise. Methods A retrospective single institutional study was conducted with 451 adult patients (mean age 41.3 years) with SDN biopsied between November 1994 and November 2004, with clinical follow-up of at least 5 years. Results In 451 patients with SDN, re-excision was performed on 36.6%. Two melanomas were diagnosed in the re-excision specimens. Subsequent metastatic melanoma developed in 7 patients, all of whom had a history of melanoma. Margin comments influenced decision to re-excise. Limitations This was a retrospective study at a single institution. Conclusion Re-excision of all SDN may not be necessary.