Epithelioid hemangioendothelioma-its history, clinical features, molecular biology and current therapy.

Epithelioid hemangioendothelioma (EHE) is a remarkably rare tumor arising from endothelial cells that is classified as a vascular tumor in the WHO classification. The tumor is predominantly characterized by the presence of fusion genes, such as WWTR1-CAMTA1 or YAP1-TFE3, with a minority of cases exhibiting other rare fusion genes. EHE exhibits a broad age of onset, typically presenting at ~50 years, but it is not uncommon in pediatric populations. It manifests in a variety of organs, including the liver, lung, soft tissue and bone. Initial multiple-organ involvement is also observed. The tumor's biological behavior and prognosis vary substantially based on the primary site of manifestation. From a therapeutic perspective, initial active surveillance might be considered in selected cases, although surgical intervention remains the mainstay of treatment, especially for localized single-organ involvement. Chemotherapy is administered to patients with progressive unresectable tumors. Recent advances in the biological analysis of EHE fusion genes have elucidated their diverse functions. Additionally, next-generation sequencing has facilitated the identification of other mutations beyond the fusion genes. These continuous efforts to understand the biology of the fusion genes themselves and/or the dysregulated signaling by fusion genes are expected to lead to the development of novel therapeutic strategies for EHE. This article aims to provide a comprehensive review of EHE, encompassing its historical context, clinical manifestations, molecular biology and the current state of treatment.

Vascular tumors of intermediate malignancy: An update.

The term "hemangioendothelioma" is used for endothelial neoplasms of intermediate malignancy and describes a group of rare neoplasms having biologic behavior falling in between that of the benign hemangiomas and fully malignant angiosarcomas. The hemangioendotheliomas fall into several specific, clinicopathologically and genetically distinct entities, specifically epithelioid hemangioendothelioma, kaposiform hemangioendothelioma, papillary intralymphatic angioendothelioma and retiform hemangioendothelioma (hobnailed hemangioendothelioma), pseudomyogenic hemangioendothelioma, composite hemangioendothelioma, and YAP1::TFE3-fused hemangioendothelioma. The clinical, morphologic, immunohistochemical, and genetic features, and the differential diagnosis of each of these rare entities are discussed in this review.

Clear cell stromal tumor of the lung with multinucleated giant cells: a report of a case with YAP1-TFE3 fusion.

BACKGROUND: Clear cell (hemangioblastoma-like) stromal tumor of the lung (CCSTL) is a rare pulmonary neoplasm. Recently, 9 cases of CCSTL harboring the YAP1-TFE3 gene fusion have been described, and it has been suggested that this aberration could be a characteristic feature of this tumor. CASE PRESENTATION: We here report another case of CCSTL in a 57-year-old male, which presented as a solitary lung nodule 45 mm in the greatest dimension. Microscopically, the tumor consisted of epithelioid to spindled cells with mild-to-moderate nuclear atypia, finely granular or vesicular chromatin, and small nucleoli. Nuclear indentations were a common finding. There were up to 3 mitoses per 10 HPF. The cytoplasm was slightly eosinophilic or clear. Scattered non-tumor large multinucleated cells were present. Immunohistochemically, the tumor cells showed diffuse positivity for TFE3, CD10, vimentin, and IFITM1. Other markers examined were negative, and the expression of lineage-specific markers was not found. NGS analysis revealed a fusion transcript of the YAP1 and TFE3 genes, and a pathogenic variant of the MUTYH gene. CONCLUSION: Our finding supports the recent data suggesting that CCSTL represents a distinct entity characterized by the recurrent YAP1-TFE3 fusion.

Clear cell stromal tumour of the lung with YAP1::TFE3 fusion: four cases including a case with highly aggressive clinical course.

AIMS: Clear cell stromal tumour of the lung (CCST-L) is a rare, recently recognised neoplasm which has been found to express TFE3 and harbour YAP1::TFE3 fusions. Initial data suggested a benign process; however, a single reported case gave rise to distant metastases. We sought to describe the clinicopathological and molecular features of additional cases of CCST-L. METHODS AND RESULTS: Pathology and molecular archives were searched for cases of CCST-L or tumours with YAP1::TFE3 fusions. Clinical features were noted. Available slides, including immunohistochemical studies, were re-reviewed for diagnosis confirmation and assessment of pathological features. Results of molecular studies were also recorded. Four tumours were identified, all occurring in women (median age = 61 years, range = 24-69). Median tumour size was 4.4 cm (range = 1-9.5 cm); three tumours were unifocal and one was multifocal. Tumours were composed of epithelioid to spindled cells with eosinophilic to clear cytoplasm and grew in sheets, vague nests and short fascicles. Nuclear atypia was predominately mild; however, two cases showed scattered atypical cells. Mitotic activity was generally low, although one case showed a mitotic count of 6/2 mm2 . All tumours expressed TFE3 and harboured YAP1::TFE3 fusions. One case was unresectable and was treated with chemotherapy, and two underwent complete resection. One patient died of disease 7 months following diagnosis, while a second patient was alive with no evidence of disease after 43 months. Follow-up was not available for two cases. CONCLUSION: CCST-L expresses TFE3, harbours YAP1::TFE3 fusions and at least rare cases behave in an aggressive manner.

A YAP1::TFE3 cutaneous low-grade fibromyxoid neoplasm: A novel entity!

Cutaneous fibromyxoid neoplasms (CFMN) comprise a vast category of benign and malignant tumors that include, but are not limited to, low-grade fibromyxoid sarcoma, myxofibrosarcoma, myxoid dermatofibrosarcoma protuberans, myxoid solitary fibrous tumor, and myxoid neurofibroma with differing implications for treatment and prognosis. Herein, a case of CFMN arising as a painless, slow-growing, flesh-colored forearm mass in a 53-year-old female is presented. The neoplasm comprised of copious myxoid material with banal spindle cells, exhibiting mild hyperchromasia, dissecting the dermal collagen table. Focal perivascular accentuation of spindle cells was identified in the absence of vasoformative features. Immunohistochemically, lesional cells were strongly and diffusely positive for CD34 and multifocally for Factor XIIIa and epithelial membrane antigen while negative for CD31, ERG, FLI-1, D2-40, smooth muscle actin, Desmin, S100, HMB-45, STAT6, MUC4, and keratins. RNA- and DNA-sequencing identified a YAP1::TFE3 fusion transcript that were subsequently corroborated by fluorescence in situ hybridization and immunohistochemistry for TFE3 (Xp11.23) locus rearrangement and strong, diffuse TFE3 immunoreactivity, respectively. To date, the YAP1::TFE3 fusion has only been identified in a subset of epithelioid hemangioendotheliomas and clear cell stromal tumors of the lung. This is the first report of a CFMN featuring a YAP1::TFE3 fusion (YAP1 Exon 1 and TFE3 Exon 4). The morphologic findings are unlike those previously described for epithelioid hemangioendothelioma and suggest that this neoplasm may represent a yet unclassified or novel CFMN entity. Although the patient is 1-year status postsurgical excision with no evidence of clinical recurrence, the clinical behavior of this novel entity remains to be fully characterized.

Cytologic features of hepatic YAP1-TFE3 rearranged epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor of intermediate malignancy, often with indolent behavior. Though most cases have a characteristic WWTR1-CAMTA1 gene fusion, a subtype of EHE with YAP1-TFE3 fusions and a distinct morphology has recently been described histologically, but no cases of YAP1-TFE3 EHE have been described in the cytology literature. We herein report on a case of YAP1-TFE3 fusion associated EHE diagnosed on fine-needle aspiration and core biopsy of a liver mass in an 18-year-old male patient who presented with synchronous lung and liver involvement. We also discuss the differential diagnosis of EHE on cytology specimens.

Multicentric visceral epithelioid hemangioendothelioma, with extremity dermal deposits, unusual late recurrence on the nasal bridge, and TFE3 gene rearrangement.

Epithelioid hemangioendothelioma (EHE) is a malignant neoplasm with vascular differentiation that most frequently occurs within soft tissues, bone, lung, and liver. It is histologically typified by epithelioid or spindle cells present singly or in cords or clusters, many with cytoplasmic vacuoles that can contain intraluminal erythrocytes (in keeping with primitive vascular differentiation), within myxohyaline or sclerotic matrix. Up to 50% present with synchronous lesions as multifocal disease. The WWTR1-CAMTA1 fusion has been demonstrated in EHEs at a variety of sites and is considered to represent its genetic hallmark. We describe a case of EHE in a patient who initially presented with multiple liver and pulmonary deposits, was found to have a soft tissue lesion in the foot, and then presented with further lesions on the nasal bridge and the arm approximately 6 years after initial presentation. Interestingly, the case showed diffuse CAMTA1 expression but negative TFE3 immunohistochemically, but in contrast showed TFE3 gene rearrangement with fluorescence in situ hybridization but no evidence of WWTR1-CAMTA1 translocation. The clinical behavior of EHE is unpredictable, and this case highlights unusual anatomic, immunohistochemical, and molecular cytogenetic findings. Characterization of the genetics of EHE is important because targeted therapies toward products of the specific WWTR1-CAMTA1 gene fusion may have an impact in the near future.