case_images: PMC10919128_01
case_images: 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.
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case_images: PMC10919128_01_10.1177_17588359241236450-fig1.jpg
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case_images: The patient was partially responsive to pemetrexed and carboplatin [Figure 1(b)]. The patient responded well to immunotherapy but developed immune-related pneumonia and gastritis after 18 cycles of nivolumab [Figure 1(c)]. Immunotherapy was discontinued, and anlotinib was started when the disease progressed with mediastinal lymph node metastasis [Figure 1(d) and (e)]. In July 2020, the patient had new progressive lesions in the left supraclavicular lymph nodes and received chemotherapy with nab-paclitaxel and local radiotherapy [Figure 1(f)]. A CT scan indicated extensive tumor metastasis in the mediastinal lymph nodes, retroperitoneal lymph nodes, bones, and small intestine [Figure 1(g)]. Enteroscopy revealed jejunum stenosis and severe bleeding in the intestinal tract [Figure 1(h)].
case_images: 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.
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case_images: Pulmonary biopsy revealed a diagnosis of typical infiltrating adenocarcinoma in the lower lobe of the left lung [Figure 2(a) and (b)]. The patient underwent surgical resection of the small intestine lesion, the bleeding was relieved, and pathology confirmed sarcomatoid carcinoma [Figure 2(a)] considering the following histologic features: more undifferentiated, giant cells, loose cellular cohesion, and strong and diffuse vimentin expression. Ki-67, a tumor cell proliferation and growth marker, increased from 30% to 75% after transformation [Figure 2(a)]. The gene profiling results revealed that a total of 16 genes were mutated in primary and ICI-resistant tumors [Figure 2(c)].
case_images: 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.
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case_images: Furthermore, immunohistochemical staining revealed that the proportion of CD8+ T cells, but not PD-L1+ cells, was greater in the primary tumor than in the metastatic tumor [Figure 3(a) and (b)]. Multiplex immunofluorescence staining also revealed that a limited number of immune cells were present in the tumor microenvironment, with low infiltration of CD8+ T cells, CD4+ T cells, and PD-L1+ macrophages, and absence of regulatory T cells (Tregs) in metastatic tumors, revealing a noninflamed immune microenvironment for ICI-resistant tumors [Figure 3(c)].