Extrauterine mesonephric-like carcinoma: a tumor with a cold lymphocytic immune microenvironment

Extrauterine mesonephric-like carcinoma (ExUMLC) is a rare female genital tract tumor associated with advanced stage disease and distant recurrences. Although there is a histologic and mutational overlap with extrauterine low grade endometrioid carcinoma (ExULGEC), the distribution of the main components of the tumor microenvironment (TME) in these two neoplasms is not known. In this study we evaluated the clinicopathologic characteristics and the main lymphocyte populations in different compartments of the TME in cases of ExUMLC (18) and ExULGEC (17) - diagnosed at a single institution. A multiplex immunofluorescence panel including CD3, CD4, CD8, CD20, CD56, pancytokeratin, Foxp3, and Ki-67 was applied in all cases. The median age of ExUMLC was 60.5 years (range: 37-69 years), while in ExULGEC was 53 years (range: 22-83 years). The tumor compartment and total area analyzed of ExUMLC were significantly enriched in CK + Ki-67 + cells [(tumor: median 478 vs. 37.4 cells/mm², p = 0.029) and (total: median 304.5 vs. 33.2 cells/mm², p = 0.044)], CD3 + CD4+ T-cells [(tumor: median 0.6 vs. 0 cells/mm², p = 0.01) and (total: median 2.6 vs. 0.3 cells/mm², p = 0.022)], and CD3 + CD4+Foxp3 + T-cells [(tumor: median 0 vs. 0 cells/ mm², p = 0.035) and (total: median 0.8 vs. 0 cells/mm², p = 0.007)]. Importantly, distances from CK + to CD3 + CD4+ cells were also significantly lower in the ExUMLC group compared to ExULGEC. ExUMLC has a unique lymphoid microenvironment characterized by an overall low concentration of lymphocytes with a higher concentration of CD4 + T-cells and classic Tregs when compared to ExULGEC. This "cold" and immunosuppressive TME may be implicated in the more aggressive biology, and potentially pose a challenge for targeted treatment options in patients with ExUMLC.