Heterogeneity of Cervical Cancer-Associated Tertiary Lymphoid Structures (TLSs) and Their Specific Interrelation With Clinicopathological Parameters.

OBJECTIVE: The study investigates morphological variants of tertiary lymphoid structures (TLSs) in relation to cervical cancer development, from intraepithelial neoplastic lesions to invasive carcinomas with locoregional lymph node metastases.

MATERIALS AND METHODS: This retrospective analysis comprised 100 cervical cancer cases who had had total hysterectomy with lymphadenectomy in the Obstetrics and Gynecology Clinic of the Municipal Emergency Clinical Hospital of Timisoara, Romania, from 2020 to 2023. Bilateral ilio obturator lymphadenectomy and total hysterectomy were used to acquire biopsy samples. The presence of germinal centers, other stromal structures, TLS density, topography relative to the tumor lesion, and malignant cell islets are used to evaluate and classify TLS.

RESULTS: We first globally evaluated the total number of TLSs (TLS.T). We observed topographically two places in the cervical stroma: TLS immediately peritumorally positioned and TLS away from tumor lesions. Invasive carcinomas have bigger superficial TLSs with a well-defined germinal center. As they approached the tumor, TLSs increased in size and density. We also detected a special type of TLS associated with nerve fibers, which we named tertiary lymphoid structures associated with nerves (TLS.N). The total number of TLSs did not correlate with age, but 85.71% of patients presenting TLS.N were aged between 59 and 72 years old. Our findings showed a strong correlation between age (postmenopausal, p = 0.005) and TLS-N presence. Similarly, TLS parameters evolved with tumor differentiation. Only in the TLS.N group did the tumoral grading (G) 3 correlate with TLS (p = 0.041), while TLS.T did not correlate with G. All TLS.N. patients, except one, had lymphovascular invasion and massive histiocytosis. On the first point, TLS.N correlated with lymphovascular invasion (p = 0.032).

CONCLUSION: Tertiary lymphoid structures associated with nerves have not been previously reported in cervical cancer, and their effects on prognosis and aggression are unknown. There was a substantial association between TLSs.N presence and age over 60, suggesting it is exclusive to menopausal women. They were also substantially connected with lymphovascular invasion and G3, suggesting they may be a poor cervical cancer prognostic factor.