Complete pathological response after neoadjuvant chemoimmunotherapy in PD-L1-negative unresectable primary hepatic small cell carcinoma: a case report and tumor microenvironment analysis.

BACKGROUND: Primary hepatic small cell carcinoma (PHSCC) is an extraordinarily rare and aggressive malignancy with a dismal prognosis. No standard treatment exists, and the role of immunotherapy in this tumor type, especially in programmed cell death ligand 1 (PD-L1) negative cases, remains unexplored. CASE PRESENTATION: A 55-year-old woman presented with a large, unresectable liver mass. Biopsy confirmed a neuroendocrine carcinoma, small cell type, with a PD-L1 Combined Positive Score (CPS) of 0. She received neoadjuvant therapy with cisplatin/carboplatin, etoposide, and serplulimab; after the first cycle, cisplatin was switched to carboplatin due to renal impairment. After 4 cycles, imaging showed a partial response, allowing for successful surgical resection. Pathological examination of the resected specimen revealed a complete pathological response (pCR) with no viable tumor cells. Multiplex immunofluorescence (mIF) analysis of the tumor microenvironment post-resection revealed an immune-rich stroma, characterized by a high density of CD38+ cells (800 cells/mm2) and PD-L1+ macrophages, alongside a prominent intratumoral CD8+ T-cell infiltrate. CONCLUSION: This case demonstrates that neoadjuvant chemoimmunotherapy can achieve pCR and facilitate surgical resection in initially unresectable PHSCC, even with a negative PD-L1 status. The response may be mediated by a chemotherapy-synergized, PD-1 inhibitor-driven immune activation within a receptive tumor microenvironment, particularly the stromal compartment. The presence of an immune-rich stroma may serve as a critical determinant for immunotherapy efficacy, highlighting the limitations of relying solely on tumor cell PD-L1 expression as a biomarker in this rare malignancy.