Persistent nodal disease with squamous differentiation and spatial immune heterogeneity after chemoimmunotherapy in biliary tract cancer: a high-resolution pathological analysis
- 1Division of Gastroenterological, General and Transplant Surgery, Department of Surgery, Jichi Medical University
- 2Department of Clinical Oncology, Jichi Medical University Hospital
- 3Department of Diagnostic Pathology, Jichi Medical University Hospital
Abstract
Background: Heterogeneous responses across disease sites may occur after systemic therapy for biliary tract cancer (BTC), but their pathological and immune features remain poorly characterized. We report a case with pathological complete response (pCR) at the primary and pulmonary metastatic sites but persistent nodal disease after sequential chemotherapy and immunotherapy.
Case presentation: A man in his 50s with metastatic perihilar cholangiocarcinoma received gemcitabine plus cisplatin. Cisplatin was discontinued because of an allergic reaction without radiographic progression, followed by gemcitabine plus durvalumab, gemcitabine alone, and durvalumab maintenance. Resection demonstrated pCR in the primary biliary lesion and a pulmonary metastasis, whereas viable carcinoma persisted in 3 of 22 regional lymph nodes. All three metastatic lymph nodes showed prominent keratinizing squamous differentiation with p40 expression and loss of CK7 expression. Spatial analysis of one lymph node showed higher CD8-positive cell abundance at the tumor margin than in the core by both positive-cell proportion and cell density. FoxP3-positive cells also showed a margin-predominant distribution, whereas LAG-3 expression and PD-L1 H-score were higher in the core and TIM-3 was broadly distributed. Another lymph node showed a different CD8 distribution, indicating inter-nodal heterogeneity.
Conclusion: This case shows site-specific pathological heterogeneity after chemoimmunotherapy for BTC, with persistent nodal disease despite pCR at the primary and pulmonary metastatic sites. Residual nodal metastases showed keratinizing squamous differentiation and inter-nodal heterogeneity in immune-cell distribution. Because paired pretreatment nodal tissue, molecular or clonality analyses, cell type-specific checkpoint assessment, and spatial immune profiling were unavailable, the biological basis and generalizability remain unresolved.
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BibTeX
@article{sasanuma2026persistent,
title = {{Persistent nodal disease with squamous differentiation and spatial immune heterogeneity after chemoimmunotherapy in biliary tract cancer: a high-resolution pathological analysis}},
author = {Hideki Sasanuma and Keita Suto and Yuki Kimura and Yuichi Aoki and Masanobu Taguchi and Naoya Kasahara and Kazue Morishima and Hideyuki Ohzawa and Naoki Sano and Noriyoshi Fukushima and Hironori Yamaguchi and Naohiro Sata},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1855354},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1855354/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Persistent nodal disease with squamous differentiation and spatial immune heterogeneity after chemoimmunotherapy in biliary tract cancer: a high-resolution pathological analysis
AU - Hideki Sasanuma
AU - Keita Suto
AU - Yuki Kimura
AU - Yuichi Aoki
AU - Masanobu Taguchi
AU - Naoya Kasahara
AU - Kazue Morishima
AU - Hideyuki Ohzawa
AU - Naoki Sano
AU - Noriyoshi Fukushima
AU - Hironori Yamaguchi
AU - Naohiro Sata
PY - 2026
DA - 2026/10/23
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1855354
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1855354/full
AB - Background: Heterogeneous responses across disease sites may occur after systemic therapy for biliary tract cancer (BTC), but their pathological and immune features remain poorly characterized. We report a case with pathological complete response (pCR) at the primary and pulmonary metastatic sites but persistent nodal disease after sequential chemotherapy and immunotherapy. Case presentation: A man in his 50s with metastatic perihilar cholangiocarcinoma received gemcitabine plus cisplatin. Cisplatin was discontinued because of an allergic reaction without radiographic progression, followed by gemcitabine plus durvalumab, gemcitabine alone, and durvalumab maintenance. Resection demonstrated pCR in the primary biliary lesion and a pulmonary metastasis, whereas viable carcinoma persisted in 3 of 22 regional lymph nodes. All three metastatic lymph nodes showed prominent keratinizing squamous differentiation with p40 expression and loss of CK7 expression. Spatial analysis of one lymph node showed higher CD8-positive cell abundance at the tumor margin than in the core by both positive-cell proportion and cell density. FoxP3-positive cells also showed a margin-predominant distribution, whereas LAG-3 expression and PD-L1 H-score were higher in the core and TIM-3 was broadly distributed. Another lymph node showed a different CD8 distribution, indicating inter-nodal heterogeneity. Conclusion: This case shows site-specific pathological heterogeneity after chemoimmunotherapy for BTC, with persistent nodal disease despite pCR at the primary and pulmonary metastatic sites. Residual nodal metastases showed keratinizing squamous differentiation and inter-nodal heterogeneity in immune-cell distribution. Because paired pretreatment nodal tissue, molecular or clonality analyses, cell type-specific checkpoint assessment, and spatial immune profiling were unavailable, the biological basis and generalizability remain unresolved.
SN - 1664-3224
ER -