---
title: "HPV18-Positive Cervical Large-Cell Neuroendocrine Carcinoma: Rapid Progression Despite Pembrolizum"
id: "pubmed-42521492"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42521492"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42521492/"
doi: "10.1111/jog.70426"
published_at: "2026-08-01T00:00:00.000Z"
evidence_level: "Case Reports"
license: "CC-BY-NC-4.0 / Informational Use"
---
# HPV18-Positive Cervical Large-Cell Neuroendocrine Carcinoma: Rapid Progression Despite Pembrolizum
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42521492
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42521492/)
- **DOI:** [10.1111/jog.70426](https://doi.org/10.1111%2Fjog.70426)
- **Published At:** 2026-08-01T00:00:00.000Z
- **Evidence Rating:** Case Reports
## Executive GIST (TL;DR)
- A 40-year-old woman presented with FIGO 2018 stage IVB **large-cell neuroendocrine carcinoma (LCNEC)** of the cervix that was positive for **HPV18**. - Initial biopsy showed neuroendocrine morphology with large nuclei, coarse chromatin, and abundant cytoplasm; immunohistochemistry was diffusely positive for **chromogranin A** and **synaptophysin**. - Tumor cells had strong diffuse **p16** expression and a high proliferative index (Ki-67 ~80% in hot spots). - Baseline imaging (MRI and FDG-PET/CT) demonstrated an irregular cervical mass with suspected parametrial invasion and extensive lymph node and skeletal metastases. - The patient received first-line therapy comprising paclitaxel, carboplatin, bevacizumab plus **pembrolizumab**, followed by concurrent chemoradiotherapy and later cytotoxic regimens. - Despite combination therapy that included immune checkpoint inhibition, the disease progressed rapidly with new pulmonary metastases and increasing overall tumor burden; tumor markers (NSE and SCC) transiently decreased but did not predict durable response. - Comprehensive molecular profiling showed very low **tumor mutational burden (TMB 1.21/Mb)**, microsatellite stability, absence of homologous recombination deficiency, and minimal **PD-L1** expression (~1% by 22C3), indicating a poorly immunogenic **tumor microenvironment (TME)**. - The authors conclude that **HPV** or p16 positivity alone did not predict benefit from pembrolizumab in this advanced cervical LCNEC, and that biological profiling should inform treatment selection and consideration of alternative or investigational strategies for this aggressive histology. - The report provides practical clinical observations and immunogenomic data to guide clinicians managing rare, high-grade neuroendocrine cervical tumors.
## Clinical Analysis & Structured Key Points
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Affiliations Expand ### Affiliation * 1 Department of Obstetrics and Gynecology, Saiseikai Noe Hospital, Osaka, Japan. * PMID: **42521492** * PMCID: [ PMC13413610 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC13413610/) * DOI: [ 10.1111/jog.70426 ](https://doi.org/10.1111/jog.70426) Item in Clipboard Case Reports # HPV18-Positive Cervical Large Cell Neuroendocrine Carcinoma With Rapid Progression Despite Pembrolizumab Combined With Chemotherapy: A Case Report With Immunogenomic Insights Jumpei Ogura et al. J Obstet Gynaecol Res. 2026 Aug. Show details Display options Display options Format Abstract PubMed PMID J Obstet Gynaecol Res Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22J+Obstet+Gynaecol+Res%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22J+Obstet+Gynaecol+Res%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42521492/) . 2026 Aug;52(8):e70426. doi: 10.1111/jog.70426. ### Authors [Jumpei Ogura](https://pubmed.ncbi.nlm.nih.gov/?term=Ogura+J&cauthor_id=42521492)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42521492/#short-view-affiliation-1 "Department of Obstetrics and Gynecology, Saiseikai Noe Hospital, Osaka, Japan."), [Shimpei Sato](https://pubmed.ncbi.nlm.nih.gov/?term=Sato+S&cauthor_id=42521492)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42521492/#short-view-affiliation-1 "Department of Obstetrics and Gynecology, Saiseikai Noe Hospital, Osaka, Japan."), [Yuichiro Koshida](https://pubmed.ncbi.nlm.nih.gov/?term=Koshida+Y&cauthor_id=42521492)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42521492/#short-view-affiliation-1 "Department of Obstetrics and Gynecology, Saiseikai Noe Hospital, Osaka, Japan."), [Maya Kasuga](https://pubmed.ncbi.nlm.nih.gov/?term=Kasuga+M&cauthor_id=42521492)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42521492/#short-view-affiliation-1 "Department of Obstetrics and Gynecology, Saiseikai Noe Hospital, Osaka, Japan."), [Takuya Yokoe](https://pubmed.ncbi.nlm.nih.gov/?term=Yokoe+T&cauthor_id=42521492)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42521492/#short-view-affiliation-1 "Department of Obstetrics and Gynecology, Saiseikai Noe Hospital, Osaka, Japan."), [Naokazu Kanamoto](https://pubmed.ncbi.nlm.nih.gov/?term=Kanamoto+N&cauthor_id=42521492)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42521492/#short-view-affiliation-1 "Department of Obstetrics and Gynecology, Saiseikai Noe Hospital, Osaka, Japan.") ### Affiliation * 1 Department of Obstetrics and Gynecology, Saiseikai Noe Hospital, Osaka, Japan. * PMID: **42521492** * PMCID: [ PMC13413610 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC13413610/) * DOI: [ 10.1111/jog.70426 ](https://doi.org/10.1111/jog.70426) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract HPV18-positive cervical large cell neuroendocrine carcinoma (LCNEC) is exceptionally rare. We report a 40-years-old woman with FIGO 2018 stage IVB LCNEC who progressed rapidly despite paclitaxel-carboplatin-bevacizumab plus pembrolizumab, followed by concurrent chemoradiotherapy and later cytotoxic regimens. Biopsy showed chromogranin A and synaptophysin positivity, diffuse p16, and Ki-67%~80%. Comprehensive profiling revealed very low tumor mutational burden (TMB, 1.21/Mb), microsatellite stability, no homologous recombination deficiency, and minimal PD-L1 (~1%), consistent with a poorly immunogenic tumor microenvironment (TME). This profile may explain the limited effect of immune checkpoint inhibition in this histology. The case suggests that HPV or p16 positivity alone did not predict clinical benefit from pembrolizumab-based therapy in advanced cervical LCNEC, and supports careful biological assessment before treatment selection. These observations provide practical guidance for clinicians and support evaluation of alternative or investigational strategies for this aggressive tumor. **Keywords:** biopsy; cervical cancer; chromogranin A; immune checkpoint; large‐cell neuroendocrine cancer; neuroendocrine cervical carcinoma; oncology; pembrolizumab; synaptophysin; tumor microenvironment. © 2026 Japan Society of Obstetrics and Gynecology. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement An earlier version of this article was presented at The 67th Annual Meeting of Japan Society of Gynecologic Oncology, which was held in Tokyo, Japan, on 17–19 July 2025. The authors declare no conflicts of interest. ## Figures [ ![FIGURE 1](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3b69/13413610/553f777296dc/JOG-52-0-g003.gif) ](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3b69/13413610/44e31c2a0a89/JOG-52-0-g003.jpg) ** FIGURE 1 ** Baseline imaging findings of the… ** FIGURE 1 ** Baseline imaging findings of the cervical tumor and bone metastases. (a) Sagittal T2‐weighted… **FIGURE 1** Baseline imaging findings of the cervical tumor and bone metastases. (a) Sagittal T2‐weighted MRI showing an irregular cervical mass (arrowheads). (b) Axial T2‐weighted MRI depicting a hyperintense cervical tumor with suspected parametrial invasion (arrowheads). (c) Axial PET‐CT image showing FDG uptake in the pubic bone. (d) Axial PET‐CT revealing uptake in the right acetabulum. (e, f) Whole‐body PET maximum intensity projection images in frontal (e) and lateral (f) views showing extensive lymph nodes and skeletal metastases of the pelvic bones. [ ![FIGURE 2](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3b69/13413610/9ec4716f9a0a/JOG-52-0-g002.gif) ](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3b69/13413610/0709c6877c5b/JOG-52-0-g002.jpg) ** FIGURE 2 ** Histopathological and immunohistochemical findings of… ** FIGURE 2 ** Histopathological and immunohistochemical findings of cervical biopsy. (a, b) Hematoxylin and eosin (HE)… **FIGURE 2** Histopathological and immunohistochemical findings of cervical biopsy. (a, b) Hematoxylin and eosin (HE) staining shows tumor cells with large nuclei, coarse chromatin, and moderate to abundant cytoplasm at low and high magnification. (c, d) Immunohistochemistry shows diffuse positivity for synaptophysin and chromogranin A. (e) Strong nuclear and cytoplasmic p16 overexpression was observed. (f) Ki‐67 labeling index was approximately 80% in hot spot regions. (g) Immunostaining for somatostatin receptor 2 (SSTR2) was negative in tumor cells. (h) PD‐L1 immunohistochemistry (22C3) showed weak membranous staining in approximately 1% of tumor cells. All black scale bars indicate 100 μm. [ ![FIGURE 3](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3b69/13413610/c80025da1ac7/JOG-52-0-g001.gif) ](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3b69/13413610/9e205494820c/JOG-52-0-g001.jpg) ** FIGURE 3 ** Clinical course and imaging‐based evaluation… ** FIGURE 3 ** Clinical course and imaging‐based evaluation of treatment response. A visual timeline summarizes the… **FIGURE 3** Clinical course and imaging‐based evaluation of treatment response. A visual timeline summarizes the clinical course, including treatment regimens, radiological assessments, and disease progression. CT and MRI images demonstrate the primary cervical tumor and subsequent pulmonary metastases. The tumor marker (NSE and SCC) levels are plotted alongside imaging findings. Although NSE and SCC transiently decreased after initial treatment, imaging showed progressive disease, with new pulmonary metastases and an increased overall disease burden. Abbreviations: DOD: Died of disease; FDG, fluorodeoxyglucose; PD, progressive disease. [See this image and copyright information in PMC](https://pubmed.ncbi.nlm.nih.gov/42521492/) ## Similar articles * [ An immunohistochemical study of cervical neuroendocrine carcinomas: Neoplasms that are commonly TTF1 positive and which may express CK20 and P63. ](https://pubmed.ncbi.nlm.nih.gov/20182342/) McCluggage WG, Kennedy K, Busam KJ.McCluggage WG, et al.Am J Surg Pathol. 2010 Apr;34(4):525-32. doi: 10.1097/PAS.0b013e3181d1d457.Am J Surg Pathol. 2010.PMID: 20182342 * [ Pembrolizumab plus GX-188E therapeutic DNA vaccine in patients with HPV-16-positive or HPV-18-positive advanced cervical cancer: interim results of a single-arm, phase 2 trial. ](https://pubmed.ncbi.nlm.nih.gov/33271094/) Youn JW, Hur SY, Woo JW, Kim YM, Lim MC, Park SY, Seo SS, No JH, Kim BG, Lee JK, Shin SJ, Kim K, Chaney MF, Choi YJ, Suh YS, Park JS, Sung YC.Youn JW, et al.Lancet Oncol. 2020 Dec;21(12):1653-1660. doi: 10.1016/S1470-2045(20)30486-1.Lancet Oncol. 2020.PMID: 33271094Clinical Trial. * [ Human papillomavirus type and clinical manifestation in seven cases of large-cell neuroendocrine cervical carcinoma. ](https://pubmed.ncbi.nlm.nih.gov/19443298/) Wang KL, Wang TY, Huang YC, Lai JC, Chang TC, Yen MS.Wang KL, et al.J Formos Med Assoc. 2009 May;108(5):428-32. doi: 10.1016/S0929-6646(09)60088-7.J Formos Med Assoc. 2009.PMID: 19443298 * [ Adjuvant chemotherapy combined with pembrolizumab immunotherapy for primary triple-negative neuroendocrine carcinoma of the breast: a case report and literature review. ](https://pubmed.ncbi.nlm.nih.gov/42327776/) Shen X, Yang J, Du Y, Fu D.Shen X, et al.Front Immunol. 2026 Jun 4;17:1848635. doi: 10.3389/fimmu.2026.1848635. eCollection 2026.Front Immunol. 2026.PMID: 42327776Free PMC article.Review. * [ Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer. ](https://pubmed.ncbi.nlm.nih.gov/33316104/) Ferrara R, Imbimbo M, Malouf R, Paget-Bailly S, Calais F, Marchal C, Westeel V.Ferrara R, et al.Cochrane Database Syst Rev. 2020 Dec 14;12(12):CD013257. doi: 10.1002/14651858.CD013257.pub2.Cochrane Database Syst Rev. 2020.Update in: [Cochrane Database Syst Rev. 2021 Apr 30;4:CD013257. doi: 10.1002/14651858.CD013257.pub3.](https://pubmed.ncbi.nlm.nih.gov/33930176/)PMID: 33316104Free PMC article.Updated. [ See all similar articles ](https://pubmed.ncbi.nlm.nih.gov/?linkname=pubmed_pubmed&from_uid=42521492) ## References 1. 1. Wang K. L., Wang T. Y., Huang Y. C., Lai J. C., Chang T. C., and Yen M. S., “Human Papillomavirus Type and Clinical Manifestation in Seven Cases of Large‐Cell Neuroendocrine Cervical Carcinoma,” Journal of the Formosan Medical Association 108, no. 5 (2009): 428–432. - [PubMed](https://pubmed.ncbi.nlm.nih.gov/19443298/) 2. 1. Li C., Wu M., Zhang W., et al., “Large Cell Neuroendocrine Carcinoma of the Cervix: A Case Report,” Frontiers in Oncology 14 (2024): 1419710. - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC11303192/) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/39114303/) 3. 1. Lorusso D., Colombo N., Dubot C., et al., “Pembrolizumab Plus Chemotherapy for Advanced and Recurrent Cervical Cancer: Final Analysis According to Bevacizumab Use in the Randomized KEYNOTE‐826 Study,” Annals of Oncology 36, no. 1 (2025): 65–75. - [PubMed](https://pubmed.ncbi.nlm.nih.gov/39393777/) 4. 1. Embry J. R., Kelly M. G., Post M. D., and Spillman M. A., “Large Cell Neuroendocrine Carcinoma of the Cervix: Prognostic Factors and Survival Advantage With Platinum Chemotherapy,” Gynecologic Oncology 120, no. 3 (2011): 444–448. - [PubMed](https://pubmed.ncbi.nlm.nih.gov/21138780/) 5. 1. Tempfer C. B., Tischoff I., Dogan A., et al., “Neuroendocrine Carcinoma of the Cervix: A Systematic Review of the Literature,” BMC Cancer 18, no. 1 (2018):
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