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Opinion|Videos|December 22, 2025

NSCLC Cast Study 2: Deciphering Mixed Histology and Negative Biomarkers in NSCLC

Author(s)Martin Dietrich, MD, PhD, Mark A. Socinski, MD

Experts discuss how to manage a complex non-small cell lung cancer (NSCLC) case with ambiguous neuroendocrine markers and initially negative biomarker testing. They note that mixed biphenotypic tumors are not uncommon but present a diagnostic challenge.

Episodes in this series

2 experts are featured in this series

EP. 1 My Treatment Approach: NSCLC Testing and Management of Complex Cases

2 experts are featured in this series

EP. 2 Tissue is Critical: Best Practices for NSCLC Biomarker Testing

2 experts are featured in this series

EP. 3 NSCLC Case Study 1: Staging & Diagnostic Workup for a Lung Nodule

2 experts are featured in this series

EP. 4 NSCLC Case Study 1: Essential Molecular Testing for New Lung Cancer Diagnosis

2 experts are featured in this series

EP. 5 NSCLC Case Study 1: PD-L1 30% and No Mutations

2 experts are featured in this series

EP. 6 Managing Recurrent NSCLC After Immunotherapy & Surgery

2 experts are featured in this series

EP. 7 The Role of DNA & RNA in Comprehensive Genomic Profiling

2 experts are featured in this series

EP. 8 NSCLC Case Study 2: A Never-Smoker with Neuroendocrine Markers

2 experts are featured in this series

EP. 9 NSCLC Cast Study 2: Deciphering Mixed Histology and Negative Biomarkers in NSCLC

2 experts are featured in this series

EP. 10 NSCLC Case Study 2: Navigating Treatment After a RET Fusion Discovery

2 experts are featured in this series

EP. 11 The Diagnostic Challenge of Rare NSCLC Subtypes and Fusions

2 experts are featured in this series

EP. 12 The Critical Role of Multidisciplinary Teams in NSCLC

2 experts are featured in this series

EP. 13 Lymph Node Status & Tumor Size in Lung Cancer Adjuvant Therapy

2 experts are featured in this series

EP. 14 The Future of Lung Cancer: Screening, Treatment & Unmet Needs

Experts discuss how to manage a complex non-small cell lung cancer (NSCLC) case with ambiguous neuroendocrine markers and initially negative biomarker testing. They note that mixed biphenotypic tumors are not uncommon but present a diagnostic challenge.

The panel highlights the critical role of a multidisciplinary team, specifically emphasizing deep collaboration with pathology. They recommend reviewing the specific tumor component used for initial NGS testing to ensure it was representative. For treatment, a cisplatin/pemetrexed regimen is favored for adjuvant therapy.

To resolve the diagnostic uncertainty, the experts strongly advise a repeat biopsy to obtain more tissue for a comprehensive DNA and RNA-based NGS test. While they suggest a liquid biopsy (plasma-based testing) could be used to maximize the chance of finding an actionable marker, they caution that its sensitivity may be low due to the patient's small tumor volume. The definitive next step remains a tissue-based re-biopsy.

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