Discoid lupus erythematosus (DLE) is the most common type of cutaneous lupus and is clinically characterized by alopecia, depigmentation, and scars on sun‐exposed skin. Squamous cell carcinoma is a ...potential long‐term complication. The most important risk factor for squamous cell carcinoma development in people with dark skin is chronic scarring and inflammation, such as those seen in long‐standing discoid plaques. African Americans who develop squamous cell carcinoma in the setting of chronic scarring and inflammation have a greater risk of metastasis and recurrence compared to sun‐induced squamous cell carcinoma seen in whites. Despite this, the pathogenesis of squamous cell carcinoma development in chronic DLE is not fully understood. Herein, we describe a case of an African American patient who developed squamous cell carcinoma on a long‐standing discoid plaque. Analysis of the lesion revealed a null type pattern of p53 protein expression and abundant CD123+ plasmacytoid dendritic cells, as potential drivers of oncogenesis and inflammation, respectively. Dermatologists should be aware of the increased risk of squamous cell carcinoma development within long‐standing discoid plaques for a prompt early diagnosis and active long‐term surveillance.
Rhabdomyosarcoma (RMS) encompasses a heterogeneous group of tumors with striated muscle differentiation. RMSs are classified as alveolar, embryonal, spindle cell/sclerosing, and pleomorphic types and ...molecular analysis of these tumors has identified aberrations that are useful in their further subclassification. Spindle cell rhabdomyosarcoma (SpRMS) is uncommon and has been described with VGLL2 fusions, EWSR1/FUS‐TFCP2 rearrangements, and myoD1 mutations—the mutations are associated with significantly different prognoses. In addition, the NCOA2‐MEIS1 fusion gene was recently described in two primary intraosseous RMS that contained spindle cell components. Herein, we report three cases of SpRMS harboring different novel fusion genes, one possessing EP300‐VGLL3, a second with NCOA2‐MEIS1 and CAV1‐MET, and the third case had HMGA2‐NEGR1 and multiple amplified genes.
The classification of bone neoplasms composed of small round cells is experiencing a transformation after the discovery of various gene fusion rearrangements that determine diagnosis, behavior, and ...response to therapy. We present herein 4 new cases of small round cell tumor of the bone that harbor NFATc2 rearrangements involving either EWSR1 or FUS genes. We studied the clinical presentation, pathologic features, genetics (FISH, targeted RNA sequencing) and outcome in these 4 patients. We also reviewed the literature describing similar cases. All our patients were male. The median age at diagnosis was 33.5 years. All tumors presented in long bones of the extremities as a large destructive mass with a mean size of 12.5 cm. All cases were hypercellular with prominent collagenous stroma and consisted of small to medium size round cells arranged in cords, thin trabeculae, and pseudoacinar structures. Most cases showed focal or diffuse membrane staining for CD99; whereas S100, synaptophysin and chromogranin were negative. EMA showed cytoplasmic staining in one case. Genetic studies identified EWSR1-NFATc2 fusion in 3 cases, and FUS-NFATc2 fusion in one case. Two patients were treated with neoadjuvant chemotherapy using Ewing sarcoma regimens, and surgical excision was performed on 3 patients; necrosis was minimal. Follow-up is limited; after a median follow-up of 8.7 months, one patient developed local recurrence and metastases to the lungs. Poorly differentiated round cell sarcoma with EWSR1/FUS-NFATc2 fusions are uncommon. The tumors have consistent clinical findings, morphology, and immunoprofile that in combination are distinctive and differ from that of Ewing sarcoma. Importantly, these tumors do not respond to Ewing sarcoma chemotherapy regimens.
•The classification of bone neoplasms composed of small round cells is experiencing a transformation after the discovery of various gene-fusion rearrangements that determine diagnosis, behavior, and response to therapy.•Poorly differentiated round cell sarcoma with EWSR1/FUS-NFATc2 fusions are uncommon.•EWSR1/FUS-NFATc2 tumors have consistent clinical findings, morphology, and immunoprofile that in combination are distinctive and differ from that of Ewing sarcoma.•EWSR1/FUS-NFATc2 tumors do not respond to Ewing sarcoma chemotherapy regimens.
Gene of the month: DDIT3 Diaz-Perez, Julio A; Kerr, Darcy A
Journal of clinical pathology,
04/2024, Letnik:
77, Številka:
4
Journal Article
Recenzirano
DNA damage-inducible transcript 3 (DDIT3) gene, mapped to the human chromosome 12q13.3, encodes a protein that belongs to the CCAAT/enhancer-binding protein family of transcription factors. DDIT3 is ...involved in the proliferative control that responds to endoplasmic reticulum stress in normal conditions, dimerising other transcription factors with basic leucine zipper (bZIP) structural motifs. DDIT3 plays a significant role during cell differentiation, especially adipogenesis, arresting the maturation of adipoblasts. In disease, FUS/EWSR1::DDIT3 fusion is the pathogenic event that drives the development of myxoid liposarcoma. The amplification of DDIT3 in other adipocytic neoplasms mediates the presence of adipoblast-like elements. Another fusion, GLI1::DDIT3, has rarely been documented in other tumours. This paper reviews the structure and function of DDIT3, its role in disease—particularly cancer—and its use and pitfalls in diagnostic testing, including immunohistochemistry as a tissue-based marker.
Aims
Simple bone cysts are benign intramedullary tumours primarily involving the long bones in skeletally immature individuals. Several mechanisms have been proposed for their pathogenesis. Although ...the diagnosis is typically straightforward, the interpretation can be problematic, because of superimposed fracture causing them to resemble aneurysmal bone cysts and other tumours. EWSR1–NFATC2 or FUS–NFATC2 fusions, which are characteristic of a subset of aggressive round cell sarcomas, have been recently detected in simple bone cysts. The aim of this study was to examine the clinicopathological and molecular features in a series of simple bone cysts.
Methods and results
Using RNA‐based next‐generation sequencing and/or fluorescence in‐situ hybridisation, we investigated the presence of EWSR1 or FUS rearrangements in nine simple bone cysts. The patients were five females and four males, aged 3–23 years (median, 14 years); the tumours ranged from 19 mm to 160 mm (median, 46 mm) in size, and involved the femur (n = 3), humerus (n = 2), fibula (n = 2), tibia (n = 1), and iliac wing (n =1). We identified three cases with EWSR1–NFATC2 fusion (showing identical breakpoints to those in EWSR1–NFATC2 sarcomas) and one additional case with FUS rearrangement. Unlike in EWSR1–NFATC2 sarcomas, immunohistochemical expression of NKX3.1 and NKX2.2 was absent in two simple bone cysts tested.
Conclusions
More than 40% of simple bone cysts harbour genetic alterations confirming that they are neoplastic, investigation of EWSR1 and/or FUS rearrangement may help to distinguish simple bone cysts from mimics, and NFATC2 rearrangement is not pathognomonic of malignancy.
EWSR1‐NFATC2 fusion in simple bone cyst.
We performed a retrospective analysis of angiosarcoma (AS) genomic biomarkers and their associations with the site of origin in a cohort of 143 cases. Primary sites were head and neck (31%), breast ...(22%), extremity (11%), viscera (20%), skin at other locations (8%), and unknown (9%). All cases had Next Generation Sequencing (NGS) data with a 592 gene panel, and 53 cases had Whole Exome Sequencing (WES) data, which we used to study the microenvironment phenotype. The immunotherapy (IO) response biomarkers Tumor Mutation Burden (TMB), Microsatellite Instability (MSI), and PD-L1 status were the most frequently encountered alteration, present in 36.4% of the cohort and 65% of head and neck AS (H/N-AS) (p < 0.0001). In H/N-AS, TMB-High was seen in 63.4% of cases (p < 0.0001) and PDL-1 positivity in 33% of cases. The most common genetic alterations were TP53 (29%), MYC amplification (23%), ARID1A (17%), POT1 (16%), and ATRX (13%). H/N-AS cases had predominantly mutations in TP53 (50.0%, p = 0.0004), POT1 (40.5%, p < 0.0001), and ARID1A (33.3%, p = 0.5875). In breast AS, leading alterations were MYC amplification (63.3%, p < 0.0001), HRAS (16.1%, p = 0.0377), and PIK3CA (16.1%, p = 0.2352). At other sites, conclusions are difficult to generate due to the small number of cases. A microenvironment with a high immune signature, previously associated with IO response, was evenly distributed in 13% of the cases at different primary sites. Our findings can facilitate the design and optimization of therapeutic strategies for AS.
Nivolumab is a fully human IgG4 monoclonal antibody directed against programmed cell death protein 1 (PD‐1). PD‐1 inhibition allows T‐cell activation and recruitment to destroy cancer cells. ...Checkpoint inhibitors have shown significant survival advantage and relatively low side‐effects in comparison with conventional chemotherapy in several types of advanced cancer. Granulomatous cutaneous reactions have been reported showing sarcoidal and panniculitic morphology. Here we present a case of drug‐induced lichenoid and granulomatous dermatitis after checkpoint inhibitor therapy observed in a 63‐year‐old male treated with nivolumab for advanced glioblastoma. This morphology has not been previously reported. We documented a high number of CD8+ T‐cells within the lesions. Additionally, we review the side‐effects observed with the use of checkpoint inhibitors, with special focus on cutaneous manifestations.
Vascular tumors are the most common mesenchymal neoplasms of the skin and subcutis, and they encompass a heterogeneous group with diverse clinical, histological, and molecular features, as well as ...biological behavior. Over the past two decades, molecular studies have enabled the identification of pathogenic recurrent genetic alterations that can be used as additional data points to support the correct classification of these lesions. The purpose of this review is to summarize the available data related to superficially located benign and low-grade vascular neoplasms and to highlight recent molecular advances with the role of surrogate immunohistochemistry to target pathogenic proteins as diagnostic biomarkers.
Radiation therapy (RT) can induce upregulation of programmed death ligand 1 (PD-L1) on tumor cells or myeloid cells, which may affect response to PD-1-based immunotherapy. PD-L1 upregulation during ...RT is a dynamic process that has been difficult to monitor during treatment. The aim of this study was to evaluate the RT-induced PD-L1 upregulation in the tumor and its microenvironment using immunoPET/CT imaging of two syngeneic murine tumor models (HPV+ head and neck squamous cell carcinoma (HNSCC) or B16F10 melanoma). Tumors were established in two locations per mouse (neck and flank), and fractionated RT (2 Gy × 4 or 2 Gy × 10) was delivered only to the neck tumor, alone or during anti-PD-1 mAb immunotherapy. PD-L1 expression was measured by PET/CT imaging using Zr-89 labeled anti-mouse PD-L1 mAb, and results were validated by flow cytometry. PET/CT imaging demonstrated significantly increased tracer uptake in irradiated neck tumors compared with non-irradiated flank tumors. Ex vivo analysis by biodistribution and flow cytometry validated PD-L1 upregulation specifically in irradiated tumors. In the HNSCC model, RT-induced PD-L1 upregulation was only observed after 2 Gy × 10 fractionated RT, while in the B16F10 model upregulation of PD-L1 occurred after 2 Gy × 4 fractionated RT. Fractionated RT, but not anti-PD-1 therapy, upregulated PD-L1 expression on tumor and infiltrating inflammatory cells in murine models, which could be non-invasively monitored by immunoPET/CT imaging using Zr-89 labeled anti-mouse PD-L1 mAb, and differentially identified anti-PD-1 responsive as well as selectively irradiated tumors in vivo.
Mechanistic target of rapamycin (mTOR) complex (mTORC)1 and mTORC2 regulate the differentiation and function of immune cells. While inhibition of mTORC1 antagonizes dendritic cell (DC) ...differentiation and suppresses graft rejection, the role of mTORC2 in DCs in determining host responses to transplanted tissue remains undefined. Using a mouse model in which mTORC2 was deleted specifically in CD11c+ DCs (TORC2DC−/−), we show that the transplant of minor histocompatibility Ag (HY)‐mismatched skin grafts from TORC2DC−/− donors into wild‐type recipients results in accelerated rejection characterized by enhanced CD8+ T cell responses in the graft and regional lymphoid tissue Correction added on January 9, 2019, after first online publication: in the previous sentence, major was changed to minor. Similar enhancement of CD8+ effector T cell responses was observed in MHC‐mismatched recipients of TORC2DC−/− grafts. Augmented CD8+ T cell responses were also observed in a delayed‐type hypersensitivity model in which mTORC2 was absent in cutaneous DCs. These elevated responses could be ascribed to an increased T cell stimulatory phenotype of TORC2DC−/− and not to enhanced lymph node homing of the cells. In contrast, rejection of ovalbumin transgenic skin grafts in TORC2DC−/− recipients was unaffected. These findings suggest that mTORC2 in skin DCs restrains effector CD8+ T cell responses and have implications for understanding of the influence of mTOR inhibitors that target mTORC2 in transplant.
Transplantation of minor histocompatibility antigen–mismatched skin grafts lacking mechanistic target of rapamycin complex 2 in dendritic cells into wild‐type recipients results in accelerated rejection characterized by enhanced CD8+ effector T cell responses with similar enhancement of the CD8+ T cell response observed when the complex is absent in dendritic cells of major histocompatibility complex–mismatched donors.
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