# Histologic transformation

Source: https://onco.cc/terms/histologic-transformation/  
OnCo record `histologic-transformation` (Term). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

When a lung adenocarcinoma escapes targeted therapy by turning into a different cell type, usually small-cell.

## Summary

Histologic transformation is the escape of a lung adenocarcinoma from targeted therapy by changing cell type, most often into small-cell lung cancer and sometimes into squamous carcinoma. It accounts for a minority of resistance to EGFR tyrosine kinase inhibitors, is more likely when RB1 and TP53 are lost at baseline, and is also seen after ALK and KRAS inhibitors. It is not detectable by ctDNA genotyping, so it requires a repeat tissue biopsy, after which treatment switches to platinum-etoposide. The term connects to the resistance bottleneck, the resistance-routes map, the lineage plasticity pathway and the hallmark of unlocking phenotypic plasticity. Transformation is also described in follicular lymphoma, peripheral T-cell lymphoma and Waldenström macroglobulinaemia.

## Fields

- Kind: Term
- Last checked: 2026-09-06

## Notes

- Lung cancer: transformation from EGFR-mutant adenocarcinoma to small-cell carcinoma occurs in 3 to 14% of rebiopsies at resistance (Sequist 2011, Yu 2013) and is predictable before it happens. It requires both RB1 and TP53 to be inactivated: that combination was present in 82% of transformed against 3% of non-transformed cases (odds ratio 131, 43-fold risk) (Lee 2017), and the EGFR, RB1 and TP53 triple-mutant group is 5% of EGFR-mutant lung cancers but supplies 18% of transformations, with a time to inhibitor discontinuation of 9.5 against 36.6 months (Offin 2019). After transformation the median time from diagnosis is 17.8 months, platinum and etoposide work, immunotherapy does not (no responses in 17 patients), and median survival is 10.9 months (Marcoux 2019).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Transdifferentiation
- Sequist et al., Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors (Science Translational Medicine 2011): https://doi.org/10.1126/scitranslmed.3002003

## Connected records

- terms: [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Hallmark (2022): unlocking phenotypic plasticity](https://onco.cc/terms/unlocking-phenotypic-plasticity/), [Neuroendocrine differentiation in prostate cancer](https://onco.cc/terms/neuroendocrine-differentiation/)
- cancers: [EGFR-mutated non-small-cell lung cancer](https://onco.cc/cancers/egfr-mutant-nsclc/), [Extrapulmonary neuroendocrine carcinoma](https://onco.cc/cancers/extrapulmonary-nec/), [Follicular lymphoma](https://onco.cc/cancers/follicular-lymphoma/), [Limited-stage small-cell lung cancer](https://onco.cc/cancers/limited-stage-sclc/), [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Neuroendocrine and small-cell prostate cancer](https://onco.cc/cancers/prostate-nepc/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma)](https://onco.cc/cancers/peripheral-t-cell-lymphoma/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Small-cell lung cancer](https://onco.cc/cancers/sclc/), [Waldenström macroglobulinaemia](https://onco.cc/cancers/waldenstrom/)
- targets: [ALK](https://onco.cc/targets/alk/), [EGFR](https://onco.cc/targets/egfr/), [RB1](https://onco.cc/targets/rb1/), [TP53](https://onco.cc/targets/tp53/)
- key papers: [Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers](https://onco.cc/key-papers/paper-yu-acquired-resistance-rebiopsy-egfr-ccr-2013/), [Androgen receptor pathway-independent prostate cancer is sustained through FGF signalling](https://onco.cc/key-papers/paper-bluemn-double-negative-prostate-fgf-mapk-cancer-cell-2017/), [Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas](https://onco.cc/key-papers/paper-lee-clonal-history-small-cell-transformation-jco-2017/), [Combined tumour suppressor defects characterise clinically defined aggressive variant prostate cancers](https://onco.cc/key-papers/paper-aparicio-aggressive-variant-prostate-tumour-suppressors-ccr-2016/), [Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes](https://onco.cc/key-papers/paper-offin-rb1-tp53-transformation-risk-jto-2019/), [Detecting neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis](https://onco.cc/key-papers/paper-berchuck-cfdna-methylation-nepc-detection-ccr-2022/), [Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer](https://onco.cc/key-papers/paper-beltran-nepc-divergent-evolution-nat-med-2016/), [EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes](https://onco.cc/key-papers/paper-marcoux-egfr-small-cell-transformation-outcomes-jco-2019/), [Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors](https://onco.cc/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/), [Molecular characterisation of neuroendocrine prostate cancer and identification of new drug targets](https://onco.cc/key-papers/paper-beltran-nepc-aurka-mycn-cancer-discov-2011/), [Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer](https://onco.cc/key-papers/paper-labrecque-mcrpc-phenotypes-jci-2019/), [Proposed morphologic classification of prostate cancer with neuroendocrine differentiation](https://onco.cc/key-papers/paper-epstein-neuroendocrine-prostate-morphologic-classification-ajsp-2014/), [Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance](https://onco.cc/key-papers/paper-ku-rb1-trp53-lineage-plasticity-science-2017/), [SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer](https://onco.cc/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/)
- biomarkers: [Treatment-emergent neuroendocrine transformation (recognising it)](https://onco.cc/biomarkers/nepc-transformation/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/)
- pathways: [Cancer stem cells & phenotypic plasticity](https://onco.cc/pathways/cancer-stem-cells-plasticity/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/)

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