Global cancer statistics revealed that lung cancer is the leading cause of cancer-related mortality worldwide (1). Non-small cell lung cancer (NSCLC) accounts for the majority (approximately 85%) of lung cancer cases. Compared with well differentiated ones, poorly differentiated NSCLC had an increased mortality by 83% and a 2.1-fold increase of recurrence due to its rapid growth rate and high metastasis propensity (2). More than 60% poorly differentiated NSCLC patients suffer from distant metastasis (3), including lymph nodes, liver, adrenal glands, bone, and brain. The occurrence of gastrointestinal tract metastasis is relatively uncommon, with only 1.77% reported, but it severely impacts the survival of lung cancer patients (4). A retrospective analysis of 366 lung cancer patients with gastrointestinal metastasis revealed that over half of them passed away within 3 months from diagnosis, with a median overall survival of 2.8 months (5). Among them, small intestine metastasis was further rare, reported in 11.9% of gastrointestinal cases, but substantially shortened the survival of lung cancer patients (6).

With technological development, next generation sequencing (NGS) is increasingly applied to detect genetic alterations and guide personalized treatments for patients in clinic. It has been demonstrated that mutations in driver genes such as EGFR, ALK, and KRAS are associated with metastases in various sites in NSCLC, including the brain, bone, liver, and lungs (7), but not the intestine. Reports and studies on lung cancer with small intestine metastasis remain relatively limited. Early detection or prediction is critical and necessary to improve efficacy and patient survival.

In this report, we presented 2 cases of poorly differentiated NSCLC with small intestine metastasis. By juxtaposing their NGS results, we unearthed the most correlated genes, including but not limited to, TP53, LRP1B, and FGFR2. Investigating genetic profiles in NSCLC with small intestine metastasis is crucial for early detection and prevention, and may provide insights to the underlying molecular mechanisms and potential therapeutic targets.

Our analysis of reported cases small intestine metastasis from NSCLC over the past 5 years indicated that most patients were over 60 years old ( Figure 3A ), the primary pathological type was mostly adenocarcinoma ( Figure 3B ), and that the initial symptoms of metastatic disease typically manifested as abdominal pain and anemia, with a poor prognosis that often resulted in death within 6 months ( Figure 3C , Table 1 ).

We discovered that the mutations in these two patients were predominantly missense mutations. TP53 is the most commonly mutated gene in human cancer, and 70% of its mutations are missense in the DNA-binding domain (29). These mutations increase the incidence of distant metastasis, and are associated with reduced survival rates. TP53 serves as the major prognostic factor for early and advanced NSCLC, with an OS of 27 vs. 19 months (p < 0.001) (30). The co-occurring mutations with other genes such as EGFR, STK11, or KRAS have been shown to be independent biomarkers for immune checkpoint inhibitors. LRP1B was reported to reduce NSCLC cell proliferation and migration as a putative tumor suppressor, and its loss-of-function mutations might lead to oncogenesis (31). Compared with the NGS results before small intestine metastasis in patient 2, a newly emerging mutation of FGFR2 was found in the metastatic tumors. A retrospective analysis of 5,557 Chinese solid tumor patients showed that the frequency of FGFR2 alterations in lung cancer was 1%, and FGFR2 was highly expressed in NSCLC tissues, which was correlated with tumor metastasis and poor prognosis (32). Targeted therapy against FGFR2 has become a hot topic in lung cancer treatment, and the role of FGFR inhibitors including ponatinib, regorafenib, pazopanib, lenvatinib, and nintedanib in NSCLC is being intensively studied.

Between patients, there existed some distinct genetic subregions. The heterogeneity of either patient’s tumor might serve as one contributing factor, whereby diverse subclonal populations or mutational patterns might even coexist within a single patient’s sample. Tumor heterogeneity engenders high genetic, epigenetic, and phenotypic diversity among tumor cells, thus constituting a significant constraint on targeted therapies (33). In addition, tumor progression and evolution epitomize a dynamic process, wherein the course may vary among different patients, owing to disparities such as the tumor microenvironment. One aspect we can ascertain is that investigating shared mutated genes holds promise as a future avenue of researches.

Furthermore, the gene mutations in the primary lung tumors were essentially the same as those in the metastatic tumors. However, the mutation frequency decreased after the small intestine metastasis, leading us to speculate that the metastasis might cause selective pressure on the NSCLC cells, resulting in the survival and expansion of a specific subset of cells with lower mutation frequency. Only 20% of detected mutations were demonstrated to exhibit significant alterations following conventional therapy, including a tendency towards a decrease in mutation frequency.

NGS was not conducted on the small intestine metastasis in Patient 1 due to the inherently limited quantity of the endoscopically obtained tissue sample. The sample was utilized not only to ascertain the origin of the small intestine mass whether primary or metastatic, but also underwent additional immunohistochemical analyses. Subsequently, PD-L1 testing was performed to further establish immunotherapy indications. Determining the nature of the tumor and guiding immunotherapy decisions stand as paramount considerations for clinical practitioners. Furthermore, the incomparability of the patient’s blood sample results led us to abandon the notion of utilizing blood samples.

The treatment of intestine metastasis of lung cancer is not standardized in clinical practice. For patients with multiple metastases of lung cancer, RT and chemotherapy are preferred, and surgery can be an effective palliative treatment for severe complications such as bleeding, obstruction, and perforation. RT can reduce the risk of distant metastasis in early-stage NSCLC patients. In NSCLC cases with small intestine metastasis, RT can further control the growth of metastatic lesions and alleviate abdominal pain and digestive dysfunction. The efficacy of RT is influenced by genomic molecular variations that determine the radiosensitivity of cancer cells. Moreover, RT can enhance the efficacy of systemic treatments through its abscopal effects. In cases of metastatic lung cancer, concurrent local RT and metastatic targeting therapy can strengthen the sustained control of local metastases (34). Further research is needed to determine the optimal combination and sequence of RT and other treatments, such as chemotherapy or targeted therapy.

More molecular studies are required to elucidate the underlying mechanisms driving NSCLC migration to the small intestine. The mutated genes TP53 and LRP1B, shared by the 2 patients, along with the newly mutated gene FGFR2 that has emerged after small bowel metastasis, need to be further verified as the driving force behind the spread of lung cancer to the small intestine. Targeting the mutated genes or their downstream signaling pathways represents a breakthrough for exploring novel therapeutic strategies.

Metastasis is a complex multi-step process that involves various factors such as tumor microenvironment, genetic instability, and immune response. It is essential to perform molecular marker detection in NSCLC patients and clarify the correlation between the pattern of small intestine metastasis and driver gene mutations. This not only enables the identification of tumor progression, but also serves as a biological predictor of radiation sensitivity and an identifying factor for potential therapeutic targets, thereby guiding personalized treatment plans.

The emergence of small bowel metastasis signified disease progression for the patient. The patient exhibited high compliance during further examinations and treatments, and demonstrated an understanding of the importance of NGS testing. In the absence of therapeutic targets, the patient received immunotherapy. The efficacy assessments after every two cycles showed stable disease, with an improvement in the patient’s quality of life.

The patient in this case report had given consent for anonymous publication.

The datasets presented in this article are not readily available because of ethical/privacy restrictions. Requests to access the datasets should be directed to the corresponding authors.

The studies involving humans were approved by Zhongnan Hospital of Wuhan University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

YG: Project administration, Supervision, Writing – review & editing. MW: Visualization, Writing – original draft. GC: Data curation, Writing – original draft. JL: Investigation, Writing – original draft. ZF: Investigation, Writing – original draft. YL: Investigation, Writing – original draft. CX: Project administration, Supervision, Writing – review & editing.