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Histological sarcomatoid transformation in a lung adenocarcinoma patient following immune checkpoint blockade
Xiuju Liang1, Yaping Guan2,3,4, Baocheng Wang1
1Department of Oncology, 960th Hospital of the People's Liberation Army, Jinan, China.
Abstract:
Histological transformation is a phenomenon that is well described as one of the causes of tyrosine kinase inhibitor resistance in oncogene-driven non-small-cell lung cancer (NSCLC). The use of immune checkpoint inhibitors (ICIs) as a potential mechanism of acquired resistance to immunotherapy in NSCLC to small-cell lung cancer was also recently found. Here, we report the histological transformation of sarcomatoid carcinoma and metastasis in a lung adenocarcinoma patient without targetable genetic alterations who experienced long-term disease remission after nivolumab therapy. The patient subsequently developed rapid progression in the mediastinal and retroperitoneal lymph nodes, bones, and small intestine. Surgical resection of the small intestine lesion due to acute small intestine bleeding revealed the transformation of NSCLC to sarcomatoid carcinoma. The patient died 3 months after sarcomatoid carcinoma transformation and extensive disease progression, although he was rechallenged with immunotherapy. Genomic and immunohistochemical analyses revealed a comparable abundance of gene mutations and a limited number of immune cells in the tumor microenvironment, with low infiltration of CD8+ T cells, CD4+ T cells, regulatory T cells, and PD-L1+ macrophages in metastatic tumors, revealing a noninflamed immune microenvironment for ICI-resistant tumors.
Insights
Histological transformation to sarcomatoid carcinoma can cause resistance to immunotherapy in non-small-cell lung cancer (NSCLC). This case study highlights a patient with an inflamed tumor microenvironment who developed resistance after initial response to nivolumab therapy.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Histological transformation is a known cause of resistance to tyrosine kinase inhibitors in non-small-cell lung cancer (NSCLC).
- Acquired resistance to immune checkpoint inhibitors (ICIs) in NSCLC, potentially involving transformation to small-cell lung cancer, is an emerging concern.
Observation:
- A patient with lung adenocarcinoma and no targetable mutations achieved long-term remission with nivolumab but later experienced rapid disease progression.
- Surgical resection of a small intestine metastasis revealed a histological transformation to sarcomatoid carcinoma.
- The patient's condition worsened despite re-challenge with immunotherapy.
Findings:
- Genomic analysis showed similar gene mutation abundance between primary and metastatic tumors.
- Immunohistochemical analysis revealed a noninflamed tumor microenvironment in metastatic lesions, characterized by low infiltration of CD8+ T cells, CD4+ T cells, regulatory T cells, and PD-L1+ macrophages.
- This suggests a lack of immune cell activity contributing to immunotherapy resistance.
Implications:
- Histological transformation to sarcomatoid carcinoma represents a mechanism of acquired resistance to ICIs in NSCLC.
- A noninflamed immune microenvironment may predict poor response to ICI therapy in transformed NSCLC.
- Further research is needed to understand and overcome ICI resistance in NSCLC with sarcomatoid transformation.
