The Expression Of Epithelial Markers In Thymoma And Thymic Carcinoma And Its Correlation With Histological Classification, Staging, And Prognosis

Background and objectiveThymic epithelial tumors（TETs）are rare tumors,including thymoma,thymic carcinoma,and thymic neuroendocrine tumor,thymoma is one of the most common TETs.The morphologic appearance of thymoma is extremely heterogeneous and complicated.The classification of thymoma is mostly based on the morphology of proliferating tumor epithelial cells and the type and number of lymphocytes.Most thymomas can be classified according to the morphology of the tumor epithelium and the type and number of lymphocytes.However,due to the morphological overlap between different histological subtypes of thymoma,there is a problem of poor reproducibility of classification during the diagnosis,especially the diagnosis of type B thymoma（TBT）and type AB thymoma（TABT）and the differential diagnosis of type B3thymoma（TB3T）and thymic squamous cell carcinoma（TSCC）.The role of immunohistochemical staining in the diagnosis and classification of thymoma has been demonstrated,for example,CD3,CD5,CD20,CD1 a and Td T can mark lymphocytes in thymoma and help to evaluate the number and type of lymphocytes.The commonly used epithelial cell markers CK,p40,p63 and CK5/6 are expressed to various degrees in each histological subtype of thymoma and help to identify epithelial cells.Also,several new markers have been explored by investigators,but none have been widely used in clinical work.The application of thymic cortical epithelial markers（β5t,PRSS16,and cathepsin V）and thymic medullary epithelial markers（claudin-4,CD40,and AIRE）in the diagnosis and differentiation of thymoma and TSCC has been less studied.In the present study,we investigated the relationship between the expression of thymic cortical/medullary epithelial markers in thymoma and thymic TSCC and their histological classification,staging and prognosis,as well as to investigate whether thymic cortical/medullary epithelial markers can be used as immunological markers for the diagnosis and differentiation of thymoma and TSCC,or whether thymic cortical/medullary epithelial markers can be potential factors for determining the staging and prognosis of thymoma and TSCC.Materials and methodsIn total,53 cases of thymoma and TSCC were collected in the Department of Pathology,The Second Hospital of Jilin University from December 2011 to May 2021.Diagnosis and classification were performed according to the World Health Organization（WHO）thoracic tumor classification of the 5th edition of 2021,and staging was performed based on the Masaoka-Koga staging system.The clinicopathological characteristics were collected and analyzed.The expression of cortical/medullary epithelial markers was detected by immunohistochemical staining,and thymic cortical/medullary epithelial immunophenotypes was scored in all cases.The relationship between the expression of cortical/medullary epithelial markers and the histological type,stage and prognosis of patients was analyzed by statistical methods.Results1.The expression of cortical epithelial markers in each type of thymoma and TSCC was as follows: β5t,PRSS16,and Cathepsin V were expressed in most of TBT and TABT with a positive rate higher than 60%,and to a limited degree in Type A thymoma（TAT）and TSCC.Micronodular thymoma with lymphoid stroma（MNT）does not express cortical epithelial markers.In the seven groups with difficult histological typing,there was a significant difference in the rate of β5t,PRSS16,and cathepsin V positivity between TABT and MNT（P<0.05）.There was a significant difference in the rate of β5t and PRSS16 positivity between TABT and TAT（P<0.05）.2.The expression of medullary epithelial markers in all types of thymoma and TSCC was as follows: CD40,claudin-4 and AIRE were expressed in all types of thymoma and TSCC,with all cases of MNT expressing only the medullary epithelial markers and most cases of TAT and TSCC expressing the medullary epithelial markers.The positive rate of medullary epithelial markers in TBT was lower than that of cortical epithelial markers.Among the seven subtypes with difficulties in histological typing,there were significant differences in AIRE positivity rates between TB3 T and TABT and between TB3 T and TAT（P<0.05）.Also,there was no significant difference in the rate of CD40 and claudin-4 positivity in the 7 groups of cases with histological typing difficulties（P>0.05）.3.In each type of thymoma and TSCC,the cortical/medullary epithelial immunophenotype was evaluated as follows: TAT and MNT preferred a medullary epithelial immunophenotype,TSCC,TBT and TABT could show both cortical and medullary epithelial immunophenotypes or only one of the cortical or medullary epithelial immunophenotypes,with most cases of TSCC preferring to show the medullary epithelial phenotype,while TBT tended to show the cortical epithelial phenotype and TABT showed comparable proportions of cortical or medullary epithelial immunophenotypes.In TBT,there was no significant difference in the cortical/medullary epithelial immunophenotype between TB1 T,TB2T and TB3T（P>0.05）.4.Among 52 thymomas and TSCC with Masaoka-Koga staging information,there was a significant difference in β5t positivity rate between Masaoka-Koga stage I and Masaoka-Koga stages II,III,and IV（P<0.05）.5.In 34 follow-up cases,cathepsin V expression was associated with prolonged progression-free survival（PFS）（P<0.05）and there was no correlation with overall survival（OS）（P>0.05）.Conclusions1.The expression of thymic cortical epithelial markers differed between histological subtypes of thymoma.The positivity of thymic cortical epithelial markers β5t,cathepsin V and PRSS16 was higher in TABT compared to MNT.β5t,cathepsin V and PRSS16 help identify TABT and MNT.The positivity of thymic cortical epithelial markers β5 and PRSS16 was higher in TABT compared to TAT.β5t and cathepsin V help identify TABT and TAT.2.The expression of thymic medullary epithelial markers differed between histological subtypes of thymoma.The positivity rate for AIRE was higher for TAT and TABT than TB3 T.AIRE helps to differentiate TB3 T from TABT and TAT.3.The different histological subtypes of thymoma and TSCC show various cortical/medullary epithelial immunophenotypes,except for some cases that lack a cortical/medullary epithelial immunophenotype,TAT and MNT show only a medullary epithelial immunophenotype.TSCC tends to show a medullary epithelial immunophenotype,TBT tends to show a cortical epithelial immunophenotype,and TABT shows a comparable proportion of cortical or medullary epithelial immunophenotypes.4.There was a difference between thymic cortical/medullary epithelial marker expression and Masaoka-Koga stage,with a higher rate of Masaoka-Koga stage I in patients positive for thymic cortical epithelial marker β5t and thymic medullary epithelial marker CD40 compared to negative patients.5.Expression of the thymic cortical epithelial marker cathepsin V correlated with the prognosis of thymoma and TSCC.The expression of cathepsin V was associated with prolonged PFS and there was no correlation between it and OS.