A 54-year-old female farmer presented to the Affiliated Hospital of Qinghai University (Xining, China) in January 2025 with the symptoms of chest tightness, dyspnea and chest pain that had persisted for 1 month, with exacerbation over the past 5 days.

The patient developed a persistent stabbing pain in the right thoracic and back region without apparent cause at the end of January 2025, with a numerical pain rating scale (NRS) score of 6 (7). Symptoms markedly worsened after physical exertion, accompanied by progressively worsening dyspnea and nocturnal paroxysmal dyspnea requiring orthopnea, as well as a dry cough, palpitations and hyperhidrosis. In mid-January 2025, a chest computed tomography (CT) scan performed at an external hospital revealed a mediastinal mass with multiple right lung metastases, massive right pleural effusion, interstitial lung disease with inflammation in both lungs and localized bilateral pleural thickening.

The patient had no smoking history or drug allergy history, with a declared allergy to seafood.

The patient's body temperature was 36.1°C, pulse rate was 78 beats/min, respiration rate was 16 breaths/min, blood pressure was 124/82 mmHg and body surface area was 1.5 m². The Eastern Cooperative Oncology Group performance status (ECOG PS) score was 2 (8). A physical examination of the chest revealed reduced right thoracic expansion compared with that on the contralateral side, with absent breath sounds in the right lung.

To establish a definitive diagnosis, the patient underwent a series of examinations.

Chest CT performed on day 22 after the initial presentation (Fig. 1) revealed the following: i) An irregular soft-tissue mass was observed in the dorsal segment of the right lower lobe, suggestive of central lung cancer (cT4 stage), accompanied by adjacent obstructive pneumonia; ii) multiple nodules of varying sizes were present in both lungs, indicating intrapulmonary metastasis (M1a) according to the eighth edition of the TNM staging system (9); and iii) multiple enlarged lymph nodes were detected in the mediastinum and right hilar region, suggesting lymph node metastasis (N2) (9).

No definitive metastatic signs were observed on cranial magnetic resonance imaging with contrast enhancement, pelvic CT, or whole-body bone scintigraphy. Abdominal CT revealed a small cyst in the S4 segment of the liver and bilateral renal cysts.

Percutaneous lung biopsy guided by CT revealed a poorly differentiated non-small cell carcinoma.

The biopsy specimen was fixed in 10% neutral-buffered formalin at room temperature (~25°C) for 12–24 h, processed through graded alcohols, cleared in xylene and embedded in paraffin wax. Serial sections were cut at a thickness of 4 µm and mounted on poly-L-lysine-coated glass slides. For immunohistochemical staining, sections were deparaffinized in xylene and rehydrated through graded ethanol. Antigen retrieval was performed using citrate buffer (pH 6.0) at 95°C for 20 min in a water bath. Endogenous peroxidase activity was blocked by incubation with 3% hydrogen peroxide in methanol at room temperature for 10 min. Non-specific binding was blocked by incubation with 5% normal goat serum (cat. no. ab7481; Abcam) at room temperature for 30 min. The sections were then incubated with primary antibodies at 4°C overnight in a humidified chamber. The primary antibodies used were as follows: Pan-CK (clone AE1/AE3; cat. no. ab27976; 1:200; Abcam), CK7 (clone OV-TL 12/30; cat. no. ab9021; 1:100; Abcam), thyroid transcription factor-1 (clone 8G7G3/1; cat. no. M3575; 1:100; Dako; Agilent Technologies, Inc.), napsin A (clone IP64; cat. no. MCA2119; 1:200; Bio-Rad Laboratories, Inc.), p40 (clone BC28; cat. no. ab202493; 1:200; Abcam), p63 (clone D2K8X; cat. no. 13540; 1:200; Cell Signaling Technology, Inc.), SMARCA4/BRG1 (clone EPNCIR111A; cat. no. ab110641; 1:100; Abcam), synaptophysin (clone DAK-SYNAP; cat. no. M0776; 1:100; Dako; Agilent Technologies, Inc.) and Ki-67 (clone MIB-1; cat. no. M7240; 1:100; Dako; Agilent Technologies, Inc.). After washing with phosphate-buffered saline, the sections were incubated with horseradish peroxidase-conjugated goat anti-rabbit or anti-mouse secondary antibody (cat. nos. ab205718 and ab205719; 1:200; Abcam) at room temperature for 30 min. Immunoreactivity was visualized using 3,3′-diaminobenzidine chromogen (cat. no. ab64238; Abcam) for 2–5 min at room temperature, followed by counterstaining with Mayer's hematoxylin for 1 min. The sections were then dehydrated, cleared and coverslipped with mounting medium. All stained sections were examined under a light microscope, and images were captured at ×400 magnification.

Next-generation sequencing (NGS) was conducted on formalin-fixed paraffin-embedded (FFPE) tumor tissue obtained from the CT-guided percutaneous lung biopsy. DNA was extracted using a laboratory-developed solid tumor gene panel FFPE extraction kit, and libraries were prepared using a laboratory-developed test (LDT) solid tumor gene panel library preparation kit. Sequencing was performed on an Illumina NovaSeq 6000 platform with 150-bp paired-end reads.

Raw reads were preprocessed using Fastp (version 0.21.0; OpenGene; URL: http://github.com/OpenGene/fastp) to remove adapter sequences and low-quality bases, with quality control assessed using FastQC (version 0.11.9; Babraham Bioinformatics; http://www.bioinformatics.babraham.ac.uk/projects/fastqc/). Clean reads were aligned to the GRCh37/hg19 reference genome using BWA-MEM (version 0.7.17; Li H; URL: http://bio-bwa.sourceforge.net). PCR duplicates were removed using Samblaster (version 0.1.24; Gregory Faust; http://github.com/GregoryFaust/samblaster). Variant calling was performed using a custom in-house algorithm integrating Pisces (version 5.3.0.0; Illumina; http://github.com/Illumina/Pisces) and GATK (version 4.0.4.0; Broad Institute; http://github.com/broadinstitute/gatk/releases). Variant filtering criteria included a variant allele frequency (VAF) >1.3%, a mean sequencing depth >500×, and specific SNP/InDel depth >50×. Functional annotation was performed using a custom pipeline integrating Annovar (version 2022-01-13; Wang K; http://annovar.openbioinformatics.org), VEP (version 111.0; Ensembl; http://useast.ensembl.org/info/docs/tools/vep/index.html) and SnpEff (version 5.3; Cingolani P; http://github.com/snpEff/snpEff).

PD-L1 expression was evaluated as the TPS, defined as the percentage of tumor cells showing partial or complete membranous staining at any intensity. A TP53 missense mutation was identified, and no driver gene mutations were detected for EGFR, ALK or ROS1.

The final diagnosis was adenocarcinoma of the middle and lower lobes of the right lung (cT4N2bM1a, stage IVa), according to the eighth edition of the TNM staging system (9). with pulmonary metastasis, multiple lymph node metastases in the mediastinum and hilar region, and malignant pleural effusion.

The patient's treatment plan was developed through multidisciplinary team discussions. The timeline of diagnosis and treatment is summarized in Table I.

The patient was admitted to the Affiliated Hospital of Qinghai University with concurrent pulmonary infection and massive right-sided pleural effusion. Empirical anti-infective therapy with levofloxacin (500 mg once daily for 7 days) was administered, followed by closed thoracic drainage, resulting in symptom relief. To control the pleural effusion, three intrapleural perfusion treatments of 60 mg cisplatin + 200 mg bevacizumab were performed on days 1, 6 and 9 of the intrapleural perfusion regimen. Post-treatment, the pleural effusion was well controlled.

Based on the patient's high PD-L1 expression status, ivonescimab (AK112) was initiated as monotherapy on day 6 of the intrapleural perfusion regimen (concurrent with the second intrapleural perfusion), at a dose of 900 mg administered intravenously every 3 weeks. The treatment course proceeded smoothly.

Baseline imaging performed on day 22 after initial presentation is shown in Fig. 1. Chest enhanced CT re-examination was performed after two cycles of treatment (April 2025) (Fig. 2) and four cycles of treatment (June 2025) (Fig. 3). Percutaneous lung biopsy guided by CT revealed a poorly differentiated non-small cell carcinoma (Fig. 4A and B). Immunohistochemical staining results were as follows: Thyroid transcription factor-1 (+) (Fig. 4C), napsin A (+) (Fig. 4D), tumor protein p40 (−) (Fig. 4E), tumor protein p63 (−) (Fig. 4F), pan-cytokeratin (pan-CK) (+) (Fig. 4G), CK7 (+) (Fig. 4H), SMARCA4/BRG1 (−) (Fig. 4I), synaptophysin (−) (Fig. 4J) and a Ki-67 proliferation index ~70% (Fig. 4K). These findings supported a diagnosis of pulmonary adenocarcinoma. According to the Response Evaluation Criteria in Solid Tumors 1.1, both assessments demonstrated a partial response (PR). Specifically, the sum of the longest diameters of the target lesions decreased by 33 and 47%, respectively, compared with baseline. The dynamic changes in serum tumor markers are shown in Table II, with marked reductions in carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), cytokeratin 19 fragment (CYFRA21-1) and neuron-specific enolase (NSE) levels compared with pre-treatment levels. Notably, SCC remained within the normal range throughout the treatment course.

Based on achieving a good response to systemic therapy, sequential chest radiotherapy was initiated in June 2025 to consolidate local lesion control. Intensity-modulated radiotherapy was employed, with the following target volumes defined: Gross tumor volume 1 (GTV1) was the imaging-confirmed primary lesion in the right lung, with a prescription dose of 1,000 cGy/5 fractions; and GTV2 included the right lung metastatic lymph nodes and high-risk lymphatic drainage prophylaxis areas, with a prescription dose of 5,000 cGy/25 fractions. The radiotherapy plan was successfully completed.

Approximately 20 days after radiotherapy (end of July 2025), a follow-up CT scan revealed stable primary lesions but new ground-glass opacities and linear opacities in the lungs, suggestive of radiation pneumonitis. Pulmonary function tests revealed mild reductions in small airway function, with maximal mid-expiratory flow at 62% of predicted and maximal expiratory flow at 25% recorded at 65% of predicted, while forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) remained within normal limits (FEV1 89% of predicted, FVC 92% of predicted). After comprehensive evaluation, the diagnosis was Grade I (10) radiation pneumonitis (Fig. 5). Treatment included intravenous dexamethasone (5 mg on days 1–3), followed by sequential oral methylprednisolone starting at 20 mg/day, tapered by 4 mg every 3 days to a maintenance dose of 4 mg/day, then reduced by 2 mg every 3 days to discontinuation over a total of 4 weeks. Both imaging abnormalities and symptoms resolved within a short period. As of the last follow-up in August 2025, the patient had achieved 8 months of progression-free survival, with the ECOG PS score improving from a baseline of 2 points to 0 points, and a notable improvement in the quality of life.