Histological sarcomatoid transformation in a lung adenocarcinoma patient following immune checkpoint blockade

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.

Keywords: acquired resistance; histological transformation; immune checkpoint inhibitor; non-small-cell lung cancer; programmed cell death protein-1; sarcomatoid carcinoma.

Figure 1.

Timeline of anticancer treatment and radiographical evaluations. (a) The timeline of diagnosis and anticancer treatment. (b) PR after first-line treatment with pemetrexed and carboplatin. (c) PR to second-line treatment with nivolumab monotherapy. (d) Mediastinal lymph node metastasis after the discontinuation of immunotherapy due to immune-related pneumonia and gastritis. (e) PR to third-line treatment with anlotinib. (f) Progressed lesions in the left supraclavicular lymph nodes with biopsy-confirmed infiltrating adenocarcinoma. (g) Extensive tumor metastasis in the small intestine and retroperitoneal lymph nodes. (h) Enteroscopy shows jejunum stenosis and severe bleeding in the patient’s intestinal tract. The white arrow indicates the specific masses. irAEs, immune-related adverse effects; LN, lymph node; PC, pemetrexed and carboplatin; PD, progressive disease; PR, partial response.

Figure 2.

Histopathological analysis and next-generation sequencing results for tumors before and after nivolumab treatment. (a) Representative images of primary pulmonary and ICI-resistant metastatic intestinal tumor tissues stained with hematoxylin plus eosin (H&E), NSCLC markers, including cytokeratin (CK), CK5/6, and thyroid transcription factor-1 (TTF-1); the cell proliferation marker ki67; and the sarcomatoid carcinoma marker vimentin. (b) Representative images of p63 expression in primary pulmonary tumor tissues and p40 expression in resistant intestinal tumor tissues. (c) Comparison of the abundance of gene mutations between primary pulmonary and ICI-resistant metastatic intestinal tumor tissues. The mutation abundance was calculated from alternating allelic observations divided by the read depth at each position. The figure shows the clustering analysis of the data obtained from the exonic regions of the genome using the ‘Euclidean’ distance metric and the ‘complete’ clustering method for rows. The color scheme used in the figure is based on the ‘maf’ of the data. ICI, immune checkpoint inhibitors; maf, minor allele frequency; NSCLC, non-small-cell lung cancer.

Figure 3.

Immune-related microenvironment analysis of primary pulmonary and ICI-resistant metastatic intestinal tumor tissues. (a) PD-L1 expression and CD8⁺ cell infiltration were determined by immunohistochemical staining in primary pulmonary and ICI-resistant metastatic intestinal tumor tissues. (b) Quantitative analysis of PD-L1⁺ and CD8⁺ cells. (c) Multiplex immunofluorescence staining showing the infiltration of PD-L1⁺ cells, Tregs, CD8⁺ T cells, CD4⁺ T cells, and PD-L1⁺ macrophages in ICI-resistant metastatic intestinal tumor tissues. The staining intensity of the samples was analyzed via a tissue cytometry analysis system. For each group, three regions of interest were chosen for analysis, and the number of targeted cells was calculated. The significance of the difference in the means between two groups of compared cells was analyzed by a two-tailed Student’s t-test. The white arrow indicates positive cells with specific markers. ***p < 0.001. ICI, immune checkpoint inhibitor; PD-L1, programmed cell death ligand-1; Tregs, regulatory T cells.