Prognostic and therapeutic implications of Ki-67, BCL-2, HER2, and PD-L1 in signet ring cell carcinoma: A narrative review

Anar  Tulyayeva; Marzhan  Aitmagambetova; Nurgul  Kereyeva; Arip  Koishybaev; Saule Akhmetova; Nurgul  Ablakimova

doi:10.23750/abm.2026.18427

Prognostic and therapeutic implications of Ki-67, BCL-2, HER2, and PD-L1 in signet ring cell carcinoma: A narrative review

Authors

Anar Tulyayeva Department of Oncology, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
Marzhan Aitmagambetova Department of Oncology, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
Nurgul Kereyeva Department of Oncology, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
Arip Koishybaev Department of Oncology, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
Saule Akhmetova Department of Pathological Anatomy and Forensic Medicine, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
Nurgul Ablakimova Department of Pharmacology, Clinical Pharmacology, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan; Department of Hospital Pharmacy, Regional Perinatal Center, Aktobe, Kazakhstan

Keywords:

Carcinoma, Signet Ring Cell, Ki-67 Antigen, Proto-Oncogene Proteins c-bcl-2, Receptor, ErbB-2, Programmed Cell Death 1 Ligand 1 Protein

Abstract

Background and aim: Signet ring cell carcinoma (SRCC) is a biologically aggressive subtype of adenocarcinoma characterized by diffuse growth, early dissemination, and limited response to conventional therapies. Despite its clinical relevance, SRCC remains underrepresented in biomarker-focused research. This narrative review summarizes and critically appraises current evidence on the expression and clinical significance of key molecular biomarkers in SRCC across different anatomical sites.

Methods: A comprehensive narrative literature review was conducted using major biomedical databases, including Scopus and Web of Science. Studies evaluating the prognostic and therapeutic implications of Ki-67 antigen (Ki-67), B-cell lymphoma 2 (BCL-2), human epidermal growth factor receptor 2 (HER2), and programmed death-ligand 1 (PD-L1) in SRCC of gastric, colorectal, breast, and other origins were identified, screened, and qualitatively synthesized.

Results: Available evidence indicates that elevated Ki-67 expression is generally associated with aggressive tumor behavior and poorer outcomes, although pronounced intratumoral heterogeneity limits the use of uniform cut-off values. BCL-2 expression demonstrates marked site- and context-dependent variability and is frequently absent in gastric SRCC, reducing its value as an isolated prognostic marker. HER2 amplification is rare in SRCC, restricting the applicability of HER2-targeted therapies to molecularly confirmed exceptional cases. In contrast, PD-L1 expression, particularly when integrated with immune microenvironment features or circulating biomarkers such as exosomal PD-L1, may identify subsets of patients with potential sensitivity to immune checkpoint inhibition.

Conclusions: Individual biomarkers in SRCC should not be interpreted in isolation. An integrated, context-aware evaluation of proliferative, apoptotic, oncogenic, and immune markers more accurately reflects SRCC biology and may improve prognostic stratification and therapeutic decision-making.

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