A 40-year-old woman was diagnosed with FIGO 2018 stage IVB cervical large-cell neuroendocrine carcinoma (LCNEC) positive for HPV18. The disease was advanced at presentation with both nodal and skeletal metastases identified on baseline imaging. The clinical course was aggressive and the patient experienced rapid progression despite multimodality therapy that included immune checkpoint inhibition.
Histopathology of the cervical biopsy demonstrated large tumor cells with prominent nuclei, coarse chromatin, and moderate to abundant cytoplasm. Immunohistochemistry confirmed neuroendocrine differentiation with diffuse positivity for chromogranin A and synaptophysin. The tumor showed strong and diffuse p16 overexpression and a high proliferative fraction, with Ki-67 labeling approximately 80% in hotspot regions. Staining for somatostatin receptor 2 (SSTR2) was negative. PD-L1 immunohistochemistry (22C3 assay) demonstrated weak membranous staining in about 1% of tumor cells.
Magnetic resonance imaging revealed an irregular, hyperintense cervical mass with suspected parametrial invasion on T2-weighted sequences. FDG-PET/CT showed uptake in pelvic bones, including the pubic bone and right acetabulum, and demonstrated extensive lymph node and skeletal metastases on whole-body maximum intensity projection images. These findings established metastatic (stage IVB) disease at baseline.
Initial systemic therapy combined paclitaxel and carboplatin with bevacizumab plus the anti–PD-1 antibody pembrolizumab. Despite this regimen, followed by concurrent chemoradiotherapy and subsequent cytotoxic regimens, imaging documented progressive disease with new pulmonary metastases and an increased overall disease burden. Tumor markers (neuronal specific enolase [NSE] and squamous cell carcinoma antigen [SCC]) showed transient decreases after initial treatment but did not correlate with durable radiologic response. The clinical timeline culminated in continued progression and disease-related death as summarized in the case timeline.
Comprehensive genomic and immunogenomic assessment of the tumor revealed multiple features consistent with a poorly immunogenic phenotype: very low tumor mutational burden (TMB 1.21 mutations/Mb), microsatellite stability (MSS), no evidence of homologous recombination deficiency (HRD negative), and minimal PD-L1 expression (~1%). Together, these parameters indicate limited neoantigen load and minimal adaptive immune engagement within the tumor microenvironment (TME).
The combination of low TMB, MSS, absent HRD, and minimal PD-L1 expression suggests a TME that is unlikely to mount an effective anti-tumor immune response to PD-1 blockade. Although the tumor was HPV18-positive and diffusely p16-positive—markers that can be associated with virus-driven oncogenesis—these viral markers alone did not translate into clinical benefit from pembrolizumab in this LCNEC case. The neuroendocrine histology and its associated biology likely contributed to primary resistance to immune checkpoint inhibition despite combined chemotherapy and antiangiogenic therapy.
This case highlights several practical considerations for clinicians treating rare, high-grade neuroendocrine carcinomas of the cervix:
Histologic subtype and functional immunogenomic features should be incorporated into therapeutic decision-making rather than relying solely on HPV or p16 positivity.
Comprehensive profiling (including TMB, microsatellite status, HRD assessment, and PD-L1) can identify tumors with poorly immunogenic TMEs that may not benefit from standard immune checkpoint inhibitor (ICI) strategies.
For advanced cervical LCNEC with an immunogenomic profile similar to this case, alternative approaches or enrollment in investigational trials should be considered, given the likelihood of limited ICI efficacy.
Conventional tumor markers and transient biochemical responses may not reflect durable clinical benefit; radiologic and systemic disease assessments remain essential.
This report describes an HPV18-positive cervical LCNEC that progressed rapidly despite combined chemotherapy, bevacizumab, and pembrolizumab. Comprehensive immunogenomic testing demonstrated very low TMB, microsatellite stability, absent homologous recombination deficiency, and minimal PD-L1 expression—features consistent with a poorly immunogenic tumor microenvironment and plausible explanations for the lack of response to PD-1 blockade. The case emphasizes that viral or p16 positivity alone does not guarantee sensitivity to ICIs in high-grade neuroendocrine cervical cancers and supports the use of detailed biological assessment to guide treatment selection and consideration of alternative or investigational therapies for this aggressive histology.