Recurrent Detection of TERT Promoter Mutation in HPV-independent Cervical Squamous Cell Carcinoma: A Letter Regarding Horn et al.

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To the Editor: We read with great interest the recent article by Horn et al. (2024) in the International Journal of Gynecological Pathology, which provided valuable insights into the morphologic and molecular characteristics of HPV-independent cervical squamous cell carcinoma (HPVI SCC)1. Here, we present an additional HPV-independent SCC case with a TERT promoter mutation, further supporting the potential relevance of telomerase-related pathways in the pathogenesis of this rare tumor subtype. A 69-yr-old woman presented with abnormal uterine bleeding. Gynecologic examination revealed a 2 cm cervical mass. A cervical punch biopsy was performed. Histopathologic evaluation demonstrated pronounced keratinization, extensive necrosis, and large tumor cells with abundant eosinophilic cytoplasm. No precursor lesion was observed. Severe lymphocytic host response was noted. Immunohistochemically, CK5/6 and p63 showed diffuse positivity, p16 was negative, and p53 exhibited a wild-type expression pattern. HER2 staining was negative (score 0). PD-L1 expression was observed in 0.2% of tumor cells and 6% of tumor-associated immune cells, with a combined positive score (CPS) of 6.2. High-risk HPV was not detected using the Aptima assay, confirming the HPV-independent nature of the tumor. Next-generation sequencing (NGS) identified a G to A substitution at position chr5:1295228 in the TERT promoter region (allele fraction: 24%). Further staging with PET-CT revealed pelvic lymph node metastasis. To our knowledge, TERT promoter mutations in HPV-independent cervical SCC have been reported only once before2. While TERT promoter mutations have been described in HPV-independent squamous carcinomas of the vulva and penis3,4, they remain rare in the cervix. The recurrence of this finding in our cases suggests a potential pathogenic role of telomerase activation in a subset of HPV-independent cervical SCCs, independent of TP53 and PIK3CA alterations. Given the aggressive nature and poor prognosis associated with HPV-independent SCC5, recognition of recurrent molecular alterations such as TERT promoter mutations may provide insight into tumor biology and guide future therapeutic approaches. Further studies involving larger cohorts are necessary to determine the prevalence and clinical implications of TERT alterations in cervical cancer.

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