Journal of clinical pathology
September 3, 2026 · via Europe PMC
Anaplastic lymphoma kinase immunohistochemical positivity in high-grade pulmonary neuroendocrine carcinoma: an actionable signal or merely a shadow?
Batra U, Choudhary S, Choudhury R, +5 more, Venkataraman P.
AI summary — for doctors, generated from the abstract only
In a study of 8 South Asian patients with high-grade lung neuroendocrine carcinoma showing ALK positivity by immunohistochemistry, true, clinically actionable ALK gene rearrangements were confirmed in only 2 cases (both only detectable by RNA sequencing), while ALK IHC-positive but genetically negative cases did not benefit from ALK-targeted drugs.
What was studied
A retrospective analysis of 8 South Asian (Indian and Nepali) patients with de novo high-grade pulmonary neuroendocrine carcinoma and diffuse ALK immunohistochemical positivity (identified from 319 cases diagnosed 2019-2025), using DNA- and RNA-based next-generation sequencing and ALK FISH to determine the true rate of ALK gene rearrangements and clinical response to ALK-targeted tyrosine kinase inhibitors.
Key findings
- ALK IHC positivity was found in 8 of 100 selectively tested cases among 319 high-grade pulmonary neuroendocrine carcinomas; the cohort included 7 small cell lung cancers (one combined with adenocarcinoma) and 1 large-cell neuroendocrine carcinoma, with median age 51, 75% female, and 87.5% never-smokers.
- Among 5 comprehensively molecularly profiled cases, true ALK rearrangements were confirmed in only 2 (one large-cell neuroendocrine carcinoma, one small cell lung cancer), and both were detectable only by RNA sequencing, not by DNA sequencing alone.
- Durable benefit (over 16 months) from ALK-targeted tyrosine kinase inhibitor therapy was seen only in the molecularly confirmed large-cell neuroendocrine carcinoma case, while ALK IHC-positive but NGS-negative cases progressed rapidly on such therapy.
Clinical relevance
The findings suggest that ALK immunohistochemistry positivity alone is an unreliable predictor of benefit from ALK-targeted therapy in high-grade pulmonary neuroendocrine carcinoma, and that comprehensive molecular confirmation, with RNA sequencing as the preferred method for detecting fusions, should be performed before starting ALK-targeted treatment.
Who should care
Limitations
This is a very small, retrospective study (8 patients, only 5 with comprehensive molecular profiling) from a single center, limiting how broadly these findings can be generalized.
ALK positivity by immunohistochemistry in high-grade lung neuroendocrine carcinoma often does not reflect a true, actionable ALK gene rearrangement, so RNA sequencing confirmation is essential before considering ALK-targeted therapy.
This is an AI-generated summary of the published abstract, not a clinical recommendation. It may not reflect the full text or subsequent updates — verify against the original source before acting on it.
Abstract
Aims
Anaplastic lymphoma kinase (ALK) rearrangements are actionable drivers in non-small cell lung carcinoma (NSCLC), but the biological significance of ALK-immunohistochemistry (IHC) positivity in high-grade pulmonary neuroendocrine carcinoma (NEC) remains unclear. This study evaluated the diagnostic and therapeutic implications of discordant ALK IHC and genomic findings and the role of multimodal molecular testing in resolving them.
Methods
We retrospectively analysed eight South Asian patients (Indian and Nepali) with de novo high-grade pulmonary NEC and diffuse ALK immunoreactivity treated at a tertiary cancer centre in India. Comprehensive molecular profiling using DNA- and RNA-based next-generation sequencing (NGS) and ALK fluorescence in situ hybridisation (where tissue was adequate) was performed. Clinical outcomes and responses to ALK-targeted tyrosine kinase inhibitors (TKIs) were assessed.
Results
ALK IHC positivity was observed in 8 of 100 selectively tested cases among 319 high-grade pulmonary NECs diagnosed between 2019 and 2025. The cohort included seven SCLCs (one combined adenocarcinoma-SCLC) and one large-cell neuroendocrine carcinoma (LCNEC). Median age was 51 years; 75% were female and 87.5% never-smokers. Among five comprehensively profiled cases, true ALK rearrangements were confirmed in two (one LCNEC and one SCLC), both detectable only by RNA sequencing. Durable benefit from ALK-TKI therapy was seen only in the molecularly confirmed LCNEC case (>16 months), whereas ALK IHC-positive but NGS-negative cases progressed rapidly.
Conclusions
True ALK rearrangements in high-grade pulmonary NEC are rare but highly actionable. ALK IHC alone is an unreliable predictor of therapeutic benefit. RNA-based sequencing is essential for fusion detection. Comprehensive molecular confirmation, with RNA sequencing as the preferred modality, should precede any initiation of ALK-targeted therapy in high-grade pulmonary NEC.
DOI
10.1136/jcp-2026-210789
PMID
42692813
Research metadata (titles, abstracts, authors, publication dates) is sourced from Europe PMC, which aggregates content from PubMed/MEDLINE, PubMed Central, and other providers under the U.S. National Library of Medicine (NLM/NCBI). NLM does not claim copyright on abstracts; the original journal publishers or authors may hold rights to the full articles. AI-generated summaries are derived only from the abstract, never the full text, and are always labeled as AI-generated.
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