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Histological transformation into SCLC: An important resistance mechanism of NSCLC upon immunotherapy
Jiao Zeng1,2, Xinjing Ding3, Jianghua Ding1
1Department of Hematology & Oncology, Jiujiang University Affiliated Hospital, Jiujiang, Jiangxi, China.
Abstract:
The phenomenon of histological transformation has been widely reported in advanced non-small cell lung cancer (NSCLC) with EGFR mutations following the failure of EGFR-TKI treatment. Recent evidence suggests that similar histological changes can also occur in advanced NSCLC without driver gene mutations after developing resistance to immunotherapy. In this review, it was found that 66.7% of cases with immunotherapy-induced histological transformation were classified as lung squamous cell carcinoma (LSCC), while histological conversion into lung adenocarcinoma (LUAD) without EGFR or ALK gene mutations has rarely been reported. There have been sporadic reports on the occurrence of mutual transformation between LUAD and LSCC. The histological conversion from NSCLC into small cell lung cancer (SCLC) appears to be significantly underestimated, likely due to the infrequency of re-biopsy following the development of immunotherapy resistance. Several studies have reported a close association between the transformation and mutations at TP53 and the RB1 splice site, as well as the loss of an FBXW7 mutation. However, the exact mechanisms underlying this conversion remain unclear. Currently, there is a lack of guidelines for the management of transformed SCLC from NSCLC following immunotherapy, with chemotherapy being the most commonly employed treatment approach.
Insights
Histological transformation in advanced non-small cell lung cancer (NSCLC) after immunotherapy resistance is underrecognized, particularly the conversion to small cell lung cancer (SCLC). Management strategies for this transformation are currently lacking.
Area of Science:
- Oncology
- Cancer Biology
- Genetics
Background:
- Histological transformation is a known phenomenon in advanced non-small cell lung cancer (NSCLC) with EGFR mutations after EGFR-TKI treatment failure.
- Emerging evidence indicates similar histological changes can occur in advanced NSCLC lacking driver gene mutations following immunotherapy resistance.
Purpose of the Study:
- To review the phenomenon of histological transformation in advanced NSCLC, particularly after immunotherapy resistance.
- To highlight the underestimation of NSCLC transformation into small cell lung cancer (SCLC) and discuss potential underlying mechanisms and management challenges.
Main Methods:
- Literature review of studies reporting histological transformation in advanced NSCLC.
- Analysis of reported cases of immunotherapy-induced histological transformation, focusing on specific subtypes and genetic mutations.
Main Results:
- A significant proportion (66.7%) of immunotherapy-induced histological transformations were lung squamous cell carcinoma (LSCC).
- Histological conversion to lung adenocarcinoma (LUAD) without EGFR/ALK mutations and mutual LUAD-LSCC transformation are rare.
- Conversion of NSCLC to small cell lung cancer (SCLC) post-immunotherapy is likely underestimated, with associations noted with TP53, RB1 splice site, and FBXW7 mutations.
Conclusions:
- Histological transformation in NSCLC post-immunotherapy is a complex event, with SCLC transformation being particularly underrecognized.
- The precise mechanisms driving these transformations remain elusive.
- There is a critical need for established management guidelines for SCLC transformed from NSCLC after immunotherapy, with chemotherapy currently being the primary approach.
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