Seven years ago, a 50-year-old Chinese male with cough and expectoration (black phlegm) for about 2 weeks, sometimes accompanied with bloody sputum and breathlessness, was admitted to our hospital. These symptoms developed without apparent cause and in the absence of problems such as chest pain and/or distress, fever, nausea, or vomiting. A computed tomography (CT) scan of his chest showed a rough-edged shadow measuring nearly 32x22x10 mm in the right upper lobe of his lung, as shown in Figure 1 (A: before surgery; B: after surgery). The patient acknowledged several chronic disorders, including a 10-year history of bronchitis and emphysema, and was a smoker with a 30-pack-year history. The patient had no family history of lung cancer. There was no obvious abnormality noted in his system review. The results of a peripheral blood count, baseline serum chemistry screening, and urinalysis were normal on admission, and tumor biomarker tests and a purified protein derivative test for tuberculosis were also negative. A rough-edged shadow of his right upper lobe was once again seen on an enhanced CT scan of his chest, although a CT scan of his abdomen, magnetic resonance imaging of his brain, and a bone scan were all normal. His right bronchial tree also appeared normal on bronchoscopic examination, with no indication of malignancy in the biopsy and washings procured.
A right-sided upper lobectomy and systematic mediastinal lymphadenectomy were performed. A tumor of his right upper lobe, roughly 3 cm in diameter, was evident at surgery, without puckering of visceral pleura. Microscopic sections showed the following findings: there were many large, multi-core, and bizarre giant cells, without special arrangement; cytoplasm was moderate to abundant, dense, and eosinophilic; nucleus was pleomorphic and phylloid; and the tumor cells appeared to have lost adhesion, and to be separated and embedded in a fibrous myxoid stroma. Histopathologic examination revealed the tumor cells were positively reactive to cytokeratin (CK) and vimentin, while immunostaining for chromogranin A (CgA) and synaptophysin (Syn) was negative, as shown in Figure 2. Diagnostically, vimentin is the major cytoskeletal component of mesenchymal cells and is often used as a marker of mesenchymally derived cells or cells undergoing an epithelial-to-mesenchymal transition during metastatic progression. Here, it was used as a sarcoma tumor marker to identify mesenchyme. Syn is often combined with CgA as a specific marker to identify tumors arising from neural and neuroendocrine tissues, such as neuroblastoma, carcinoid, and small-cell carcinoma. Therefore, the above findings supported the diagnosis of a GCCL. The detection of bronchial stump and mediastinal lymph nodes was negative, and it indicated that there was no lymph node metastasis in this patient.
Since 2 months after surgery, the patient was treated with combined chemotherapy using gemcitabine (1,000 mg/m2 on days 1 and 8) and cisplatin (75 mg/m2 on day 1) every 3 weeks for four cycles, and then whole-body radiography examinations were carried out every year in a local hospital. He was still alive 7 years after surgery, free from disease progression. Written informed consent was obtained from the patient for the publication of this case report and the accompanying images.
Until now, the therapeutic result of this case is satisfactory. With the development of high-throughput sequencing technology, more and more genomes have been successfully sequenced. Recently, in order to explore the molecular structure of this tumor, mutations of 295 tumor-related driver genes were detected by a high-throughput sequencing test (Burning Rock Biotechnology Inc., Guangzhou, People's Republic of China). All the 295 genes are listed in Table S1. We analyzed normal and tumor tissues of this patient, after ruling out genetic variations; nine tumor-related somatic mutations were confirmed, of which six were missense variants and three were synonymous variants. The high-throughput screening results of the patient are shown in Table S2. The six missense mutations included KRAS, KMT2D, TP53, SETD2, TET2, and MAP3K. As a hotspot mutation, KRAS gene mutation on chromosome 12, exon 2 p.G12D, with a mutant abundance of about 26.7%, indicated the tumor may be sensitive to MEK inhibitor and CDK 4/6 inhibitor like trametinib and abemaciclib. TP53 gene mutation on chromosome 17, exon 7 p.R249K, with a mutant abundance of about 8.30%, indicated the tumor cell may be sensitive to some novel compound that can reverse the TP53 mutation like APR-246. For the other four somatic mutations, including KMT2D, SETD2, TET2, and MAP3K, there was no sufficient evidence to show their correlation with target drugs known so far in clinical use.