Clinicopathological Study Of Epithelioid Hemangioendothelioma

【Objective】Epithelioid hemangioendothelioma(EHE)is a rare vascular tumor.Classically,it is composed of epithelioid endothelial cells arranged strips,small nests or scattered pattern within a distinctive myxohyaline stroma;a small subset of tumors show distinct morphology,with well-formed vessels lined by epithelioid endothelial cells with abundant eosinophilic cytoplasm.Their biological behaviors are also quite different.Some EHEs are relatively indolent,while others are aggressive with high recurrent and metastatic rate.Combined with the collected cases and literature reports,this paper will discuss the clinical features,pathological features,immunophenotype,molecular profile,diagnosis and differential diagnosis of EHEs,in order to improve the understanding of EHEs and help the diagnosis and differential diagnosis of this tumor.【Materials and methods】35 cases of EHEs were diagnosed by the Department of Pathology of the first Affiliated Hospital of Nanjing Medical University(Jiangsu Provincial Hospital)between 2010 to 2021.En Vision method and fluorescence in situ hybridization(FISH)were used to detect immunophenotype,WWTR1-CAMTA1 fusion and TFE3 gene rearrangement,respectively,and one case was tested by the next generation gene sequencing to detect novel fusions.【Results】Among the 35 cases of EHEs,there were 15 males and 20 females,ranging from17 to 74 years(median 49 years).The tumors located in lung(n=10),liver(n=9),liver and lung(n=7),soft tissue(n=6),bone(n=1),bone and soft tissue(n=1),both lungs and mediastinum(n=1).Among them,multiple nodules were found in pulmonary(n=4),liver(n=4),lung and liver(n=7).Multiple nodules accounted for57.7%(15/26)EHEs presenting in liver or lung.Some patients had respiratory and digestive tract symptoms,some patients were asymptomatic,and multiple low-density nodules are found in radiological examination.Histophologically,24 cases showed classic EHEs morphology,the tumor cells were arranged in the form of single scattered cells,short strands,and small nests in a distinctive myxohyaline stroma,with mild nuclear atypia;2 cases showed epithelioid endothelial cells with amount of abundant eosinophilic cytoplasm arranged in solid or pseudoalveolar pattern with nuclear reactivity for TFE3;9 cases had atypical morphological manifestations:mitotic number>1/2mm~2,solid growth pattern,spindle cells,necrosis and nerve invasion.Dabska-like areas could be seen in 8 cases.Immunohistochemically,tumor cells expressed vascular endothelial markers:CD31(33/33,100%),CD34(30/32,94%),ERG(23/23,100%),FLI-1(17/17,100%).In some cases,tumor cells expressed epithelial markers:CK-pan(9/21,42.8%),CK7(4/19,21%).25 cases were detected by CAMTA1,21 cases were positive,35 cases were detected by TFE3,2cases showed strong nuclear positive staining and turned out to be TFE3-rearranged EHEs,3 cases of classic EHEs showed weak nuclear positive staining.FISH examination was performed in 9 cases and WWTR1-CAMTA1 fusion signals were seen in 7 cases.TFE3 gene breakage was found in 2 cases,and fusion transcript of YAP1-TFE3 and PTPRM-CCDC120 was found in 1 case by NGS test.Follow-up data was avaliable in 25 cases and the intervals range from 2 to 108 months(average32 months).Univariate analysis showed that atypical morphology was associated with poor prognosis(P=0.01).Large tumor size(diameter>3cm)had a certain correlation with poor prognosis,but the correlation did not arrive significant statistical difference(P=0.071).The overall survival rates of the low-risk group,intermediate-risk group and high-risk group were 100%,100%and 50%,respectively,The difference among the survival rates of the three groups was statistically significant(P=0.005).The metastases rates of the low-risk group,intermediate-risk group and high-risk group were 8.3%(1/12),42.9%(3/7),and 83.3%(5/6),respectively.Chi-square test showed the difference among the metastases rates of the three groups was statistically significant(P=0.004).【Conclusion】1.EHEs occur in patients with a wide range of ages,with a slightly predonimance in middle-aged women,especially in visceral EHEs.Most of soft tissue EHEs are solitary,while liver and lung lesions are often multiple-lesioned.2.The classical EHEs were somposed of tumor cells with mild nuclear atypia,arranged in short strands,small nests,or scattered within a background of myxohyaline stroma,Immunohistochemically tumor cells expressed CAMTA1 and molecular test can detect WWTR1-CAMTA1 fusion...3.The morphology of TFE3-rearranged EHEs are as follows:large epithelioid cells,well-formed vascular channels,and solid,nested or pseudoalveolar pattern arrangement;a few cases showed biphasic differentiation,presenting with both TFE3-rearranged EHEs and classical EHEs morphology.Immunohistochemically,tumor cells strongly and diffusely expressed TFE3 and molecular test can detect TFE3rearrangement.4.Atypical EHEs morphology manifested as:increased mitosis(>1/2mm~2),solid growth pattern,spindle cell region,necrosis,and nerve invasion.Histophathologically,there is a partial overlap between atypical EHEs and angiosarcoma.Biologically,atypical EHEs present with a higher rate of metastasis and mortality.Immunohistochemical detection of CAMTA1,TFE3 and molecular test for WWTR1-CAMTA1 and YAP1-TFE3 fusion gene are helpful for differential diagnosis.5.Large tumor size(>3cm)and histologic atypia can be used as criteria for evaluating poor prognosis.Patients assigned in high-risk group have high possibility of poor prognosis.