Rare but clinically complex tumor combinations. Approximately 5% of EGFR mutation-positive non-small cell lung cancers transform into small-cell lung cancer over the course of treatment, and combined tumors containing both adenocarcinoma and small-cell carcinoma components have been observed in resected specimens. These mixed histological tumors present exceptional diagnostic and therapeutic challenges because standard treatment protocols for NSCLC and SCLC are well established separately, but guidelines for managing combined subtypes are lacking.
Conventional biopsy techniques including transbronchial lung biopsy and CT-guided biopsy are inherently limited by sampling error -- they can only analyze a small portion of a tumor and may miss genetically distinct subclones present in other lesions or tumor regions. In histologically heterogeneous tumors, a biopsy that captures only one component may entirely miss key genetic alterations present in the other component, leading to incomplete or misleading molecular characterization.
Liquid biopsy, which analyzes circulating tumor DNA (ctDNA) shed from all tumor sites into the bloodstream, has emerged as a complementary approach that can capture genomic information from multiple tumor sites simultaneously and non-invasively. This makes it particularly valuable in patients with mixed histology tumors where traditional tissue sampling may fail to provide a complete genomic picture.
Metastatic disease with multiple elevated tumor markers. A 73-year-old woman with a smoking history presented with right iliac pain. CT imaging revealed a right upper lobe lung mass and multiple metastatic lesions throughout the body. Her performance status was 1, and blood tests showed markedly elevated tumor markers including CYFRA (29.1 ng/ml), CEA (816.2 ng/ml), CA15-3 (176.8 U/ml), and CA19-9 (259.3 U/ml), while pro-gastrin-releasing peptide (Pro-GRP), a neuroendocrine marker elevated in SCLC, was within normal range at 49.2 pg/ml.
CT-guided biopsy of the iliac lesion identified metastatic lung adenocarcinoma with immunohistochemical confirmation of pulmonary origin. Initial genetic testing showed EGFR wild-type status, negative ALK and ROS1, and PD-L1 tumor proportion score of 5%, yielding a diagnosis of stage IVB EGFR wild-type adenocarcinoma. The normal Pro-GRP level was consistent with adenocarcinoma rather than small-cell histology at this stage.
The patient was started on first-line ipilimumab plus nivolumab dual immunotherapy, which produced partial symptom relief and regression of the iliac metastasis. However, after four months CT imaging showed progression of lung lesions while lymph nodes remained stable, prompting repeat biopsy of lung tissue via transbronchial lung biopsy.
Revised diagnosis reveals mixed small-cell and adenocarcinoma histology. Repeat transbronchial lung biopsy of lung tissue after immunotherapy progression revealed small-cell carcinoma with neuroendocrine marker negativity. The diagnosis was revised to combined small-cell carcinoma and adenocarcinoma, reflecting that the patient's tumor had heterogeneous histological components distributed across different sites -- adenocarcinoma predominantly in the iliac metastasis and small-cell carcinoma in the lung.
Second-line therapy with carboplatin, etoposide, and durvalumab (a regimen designed for SCLC) maintained disease control for eight months. Third-line carboplatin plus paclitaxel lasted six months. When neuron-specific enolase (NSE), a neuroendocrine tumor marker, became elevated, amrubicin was introduced as fourth-line therapy and stabilized disease for four months.
At this point, with the patient having progressed through four lines of therapy and the tumor's inter-tumoral histologic diversity making additional tissue biopsies impractical, multiplex liquid genomic profiling using FoundationOne Liquid CDx was performed to comprehensively survey the genomic landscape of the patient's tumor across all sites.
The liquid biopsy identified an EGFR exon 19 deletion -- specifically the T751_A755del variant -- that had not been detected in any prior tissue biopsy. This finding was clinically actionable because EGFR exon 19 deletions are established predictors of response to EGFR tyrosine kinase inhibitors including osimertinib.
Osimertinib achieves 6.5 months of disease control. Based on the EGFR exon 19 deletion identified by FoundationOne Liquid CDx, osimertinib was initiated as fifth-line treatment. This was the first targeted therapy the patient received despite the original diagnosis of EGFR wild-type adenocarcinoma. Osimertinib temporarily reduced tumor markers including CEA and achieved disease stability for 6.5 months.
After progression on osimertinib, sixth-line therapy with carboplatin, paclitaxel, bevacizumab, and atezolizumab was administered for five months, after which the patient transitioned to palliative care. The liquid biopsy-guided osimertinib course represented one of the longer disease control periods in this patient's treatment history, underscoring the clinical impact of identifying the actionable mutation.
The sequence of tumor markers CEA (predominantly reflecting adenocarcinoma activity) and NSE (reflecting neuroendocrine or small-cell activity) showed fluctuating patterns throughout treatment, consistent with varying contributions of the two tumor components to disease burden at different time points. These biomarker trends illustrated the dynamic temporal heterogeneity of the combined tumor throughout its clinical course.
Two dimensions of heterogeneity operating simultaneously. This case illustrates both spatial and temporal tumor heterogeneity. Spatial heterogeneity was evident from the beginning: the iliac biopsy showed adenocarcinoma while the lung tumor contained small-cell carcinoma components, reflecting site-dependent histological variation that could not be captured by a single biopsy from one location.
Temporal heterogeneity manifested over the course of treatment, with evolving NSE levels suggesting fluctuating dominance of the SCLC component at different time points and variable PD-L1 and neuroendocrine marker expression across biopsies. The EGFR exon 19 deletion may have been present in a clonal subpopulation from the beginning but was not represented in the tissue samples obtained -- a sampling bias that liquid biopsy was able to overcome.
Whether this case represents a single truly mixed tumor arising from one cell of origin or two synchronous independent malignancies that happened to coexist cannot be definitively established. However, the clinical management implications are the same regardless: comprehensive genomic profiling of both components is necessary to identify all potentially actionable targets.
Multiplex liquid biopsy proved superior to single-plex genetic testing in this context, consistent with previous reports showing that multiplex analysis identifies mutations missed by single-gene tests. The comprehensive nature of FoundationOne Liquid CDx, which simultaneously analyzes hundreds of cancer-relevant genes, was essential for identifying the rare EGFR T751_A755del deletion that single-gene EGFR testing might have missed or inadequately covered.
Non-invasive profiling enables personalized therapy where tissue fails. This case illustrates that liquid biopsy can succeed where tissue biopsy fails -- specifically in detecting actionable mutations in histologically heterogeneous tumors where repeated invasive sampling is impractical, anatomically risky, or yielding insufficient tumor material for comprehensive profiling.
The clinical scenario described here -- a patient with mixed adenocarcinoma and SCLC histology, multiple prior lines of therapy, and no remaining detected actionable targets by tissue testing -- represents a situation where liquid biopsy provided the only path to a genomically guided treatment decision. The 6.5 months of disease control achieved with osimertinib validated the clinical utility of the approach.
This case also highlights that initial EGFR wild-type classification from tissue biopsy is not necessarily definitive in tumors with spatial heterogeneity. A mutation present in one component or tumor site may be undetected when sampling captures only a different site or histological subclone. Liquid biopsy, by sampling ctDNA shed from all tumor sites, can capture this broader genomic landscape.
Future clinical practice in patients with mixed histological lung cancers or complex metastatic presentations may benefit from earlier and more routine integration of liquid biopsy alongside tissue-based testing, rather than reserving it as a last resort after multiple lines of failed therapy. Earlier identification of actionable mutations could enable targeted therapy to be introduced at a more favorable disease stage.