Pattern‐based interpretation of SOX2 expression in ovarian teratomas: avoiding diagnostic pitfalls in the distinction between immature and mature neuroectodermal elements

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Abstract
Aims: The distinction between ovarian immature teratoma (IT) and mature teratoma (MT) relies on the identification of immature neuroectodermal tissue in the former, a task that may be challenging in some tumours and carries significant prognostic and therapeutic implications. SRY‐box transcription factor 2 (SOX2) has been proposed as a marker of immature neuroepithelium, although its expression in mature components of ovarian teratomas has not been systematically investigated. We aimed to assess the diagnostic value and limitations of SOX2, in comparison with SALL4, in differentiating immature from mature neuroectodermal elements. Methods and results: We retrospectively analysed a multicentric cohort of 61 ovarian teratomas (52 MTs and 9 ITs). SOX2 and SALL4 immunohistochemical expression was evaluated across all tissue components with correlation to detailed morphological assessment. SOX2 showed diffuse expression in both immature neuroepithelium and mature neuroectodermal tissues, including glia and ependymal structures, as well as a characteristic layer‐restricted pattern in retinal tissue, while cerebellar tissue was consistently negative; some non‐neural mature epithelial tissues were also positive. SALL4 expression was variably positive in immature neuroectodermal components (specifically in neuroectodermal rosettes) and was absent in all mature components. Notably, heterogeneous SOX2 expression in rosette‐like structures prompted systematic morphological reassessment, leading to reclassification of 5/9 (55.6%) cases initially diagnosed as IT into MT. These findings highlight that SOX2 expression alone may represent a significant diagnostic pitfall, particularly in distinguishing immature neuroepithelium from mature ependymal rosettes. Conclusions: SOX2 is a sensitive marker of neuroectodermal lineage but does not discriminate between immature and mature elements. Its interpretation requires integration with morphology and SALL4 expression to avoid overdiagnosis and inappropriate tumour classification and grading of ITs. A pattern‐based approach to SOX2 staining may improve diagnostic accuracy in ovarian teratomas.
Funding Information
  • Fondazione AIRC per la ricerca sul cancro ETS (MFAG 2021 – ID 26319)

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