The Prognostic Impact of the Tumor Immune Microenvironment in Synovial Sarcoma: An Immunohistochemical Analysis Using Digital Pathology and Conventional Interpretation.

Abstract

Background and objectives: Innate and adaptive immune responses serve a crucial role in neoplasms. The interaction of immune cells with the neoplastic tissue influences tumor behavior, resulting in either pro-tumorigenic or anti-tumorigenic effects. However, the prognostic significance of the tumor immune microenvironment (TIME) in synovial sarcoma (SS) remains poorly studied. This study aimed to analyze the TIME of SS to determine its impact on the prognosis by examining the intratumoral lymphocytic and macrophagic infiltrate and its potential correlation with survival and recurrence.

Methods: We conducted a retrospective observational study of 49 fusion-confirmed SS cases collected from two different institutions. We obtained clinical and follow-up data, and SSs were histologically classified according to WHO criteria. Immunohistochemical analysis, including of CD163, CD68, CD3, CD8, and CD20, was conducted in tissue microarrays using an analog scale. We examined the whole-slide tissue for the 23 cases with sufficient material available and then assessed the positive area by scanning the slides and analyzing the images using QuPath (0.4.4, Belfast, Northern Ireland) to calculate the positive area in an immune hotspot. We correlated the expression of these markers with clinical outcomes. A log-rank test and Kaplan-Meyer curves were used as appropriate (significance: p ≤ 0.05).

Results: The most frequent morphological subtype was monophasic (59.6%), followed by biphasic (26.9%) and undifferentiated (7%). The mean disease specific survival (DSS) was 55.3 months, with a median of 33 months. The median overall survival (OS) was 50 months (range: 2-336 months). Both evaluation methods showed a good correlation for all antibodies, with Chi-square values of p < 0.05. All cases showed variable amounts of CD163-positive macrophages. The cases that showed a higher density of CD163-positive macrophages in whole-slide images subjected to digital analysis demonstrated an improved OS and DSS on Kaplan-Meier curves. Cases with lower CD8 and CD3 positivity showed a tendency toward faster progression and a slightly worse prognosis.

Conclusions: The tumor immune microenvironment in sarcomas is a complex system that requires further investigation to fully understand its impact on tumorigenesis and patient clinical outcomes. Our results demonstrate that a higher amount of intratumoral CD163-positive macrophage infiltrate is associated with an increased OS and DSS. Our findings show that digital pathology is more precise than subjective quantitative analysis.