Durable response to immunotherapy in NSCLC with duodenal metastasis

Abstract

Lung cancer is the leading cause of tumor-related death in the world. Duodenal metastasis from lung adenocarcinoma is an exceptionally rare occurrence and is often asymptomatic. Currently, there are no FDA-approved, well-defined treatment guidelines for this patient subgroup, and clinical studies in this area are scarce, limited to several case reports. Further investigation is needed to identify suitable treatments for this group. Here, we present a case of lung adenocarcinoma with duodenal metastases in a patient who exhibited a notable clinical response to immunotherapy over 39 months. Due to the limited data available on duodenal metastases from lung adenocarcinoma, this case highlights the challenges faced by clinicians in managing such cases and provides new ideas for future management of the disease.

Introduction

Lung cancer is the most commonly diagnosed cancer globally, with approximately 2.5 million new cases reported annually [1]. It is generally classified into two main subtypes: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with NSCLC accounting for the majority of cases. Within NSCLC, adenocarcinoma is the most common histopathology. Metastasis from lung cancer is commonly observed in the brain, adrenal glands, bones and liver with reported rates of 39%, 34%, 20%, and 8%, respectively [2, 3]. However, metastasis to the small intestine is extremely rare, with a probability of less than 2% [4]. Among small intestine metastases, the jejunum is the most frequently affected site, followed by the ileum and duodenum. Primary lung cancer metastasis to the duodenum accounts for only 15.8% of small intestine metastases [5]. For localized lung adenocarcinoma, some patients can be cured through surgery or radiotherapy, while others may benefit from targeted therapy after chemotherapy failure. Immunotherapy has also shown promise in some cases [6]. For advanced lung cancer, a combination of chemotherapy, radiotherapy, immunotherapy, and targeted therapy is recommended as the first-line treatment approach. In this report, we present a case of lung adenocarcinoma with duodenum metastasis, which achieved long-lasting efficacy through immunotherapy. By the time of this report, the patient had a durable response to immunotherapy over 39 months. To our knowledge, this is the first report of long-term survival achieved through immunotherapy.

Case report

A 54-year-old male presented in December 2021 with pain in the left shoulder and back without an apparent trigger. Later, in January 2022, the pain worsened, particularly when coughing. In March 2022, the patient underwent a computed tomography (CT) scan, which revealed a nodule in the posterior segment of the upper lobe of the right lung, along with multiple lymph node metastases in the mediastinum and right hilar region. Additionally, retroperitoneal, abdominal, and hepatic hilar lymph nodes, bilateral adrenal glands, and bone metastases were observed (Fig. 1). The gastric wall was slightly thickened. A CT-guided biopsy in the right lung confirmed invasive adenocarcinoma, with immunohistochemistry showing PCK (+) and TTF-1 (a small amount +), P40(-),C-MET(2+) (Fig. 2A). And the PD-L1 TPS score is 75%. Further evaluation with whole-body PET-CT revealed hypermetabolic nodules in the right upper lobe, irregular thickening of the gastric wall, and multiple hypermetabolic lymph nodes in the mediastinum and abdominal regions. Increased glucose uptake was also seen in the bone, with some areas of bone destruction. Gastroscopy showed a large bleeding ulcer in the duodenal bulb, and pathology indicated that the cancerous tissue shows a poorly differentiated solid growth pattern, and there is no definite dysplasia in the surrounding intestinal mucosal glands, which suggests a higher possibility of metastasis(Fig. 2B). Immunohistochemistry results for the duodenal lesion were PCK (+), CK7 (+), CK20 (-), Villin (-), CDX2 (-), TTF-1 (-), NapsinA (+), P40(-) ,GATA-3(-),PAX8(-),PSA(-). And PD-L1 TPS score ≥ 60% (Fig. 2C). The immunohistochemical results of the primary pulmonary lesion showed PCK (+) and TTF-1 (a small amount +). The immunohistochemical results of the metastatic lesion showed the tumour was positive for NapsinA, CK7, and negative for CK20, Villin, CDX2. Combined with the clinical imaging findings and needle biopsy results, a pulmonary origin is considered highly likely.

Fig. 1.

CT findings of primary lung adenocarcinoma and adrenal metastases. SD stable disease, PR partial remission, PD progressive disease

Fig. 2.

A Pathological findings of primary lung adenocarcinoma. B Pathological findings of duodenal metastases. C PD-L1 staining of duodenal metastases

The final diagnosis was stage IV lung adenocarcinoma (cT2N2M1), with metastases to abdominal lymph nodes, adrenal glands, bones, and the duodenum (according to AJCC staging). The patient was treated with PC (pemetrexed + carboplatinum) chemotherapy since March 12, 2022. For 3 weeks of chemotherapy, the disease was evaluated as SD. The re-examination of CT showed that the right lung lesion was slightly smaller than before, the lymph node metastasis and bilateral adrenal metastasis were larger than before, and the patient was treated with 1 cycle of albumin paclitaxel and nedaplatinum regimen on April 3, and the chemotherapy was suspended due to diarrhea. On April 27, the patient initiated a cycle of treatment with tegafur and anlotinib but experienced poor tolerance. On May 16, the disease was reassessed as PD, the CT showed that the right lung lesion was not significantly changed, bilateral adrenal metastases were significantly enlarged, and some metastatic lymph nodes were larger. Therefore, since May 18 2022, he was treated with keytruda regularly. No evidence of disease recurrence or progression was observed during the follow-up period. The assessment of the lesions on August 23 was partial remission (PR). Follow-up CT showed smaller right lung lesion and bilateral adrenal metastases compared to the previous one. To June 20, 2025, the patient’s treatment response has consistently remained stable disease (SD).

Discussion

To our knowledge, we present the first case of a patient with lung adenocarcinoma and duodenal metastasis who maintained a durable response to immunotherapy for over three years. Given the rarity of this metastatic pattern, we further performed a literature search focusing on gastrointestinal metastases arising from lung adenocarcinoma, as well as their associated clinical characteristics and therapeutic regimens.And we have summarized the relevant previous literature, and the specific content is shown in Table 1.

Table 1.

Summary of relevant literature

Year	Author	Age	Symptom	IHC	Other metastasis	Stage	Treatment	PFS (months)
2015	Eyad Fawzi AlSaeed [7]	52	melena	CK7(+),TTF-1(+),CK20(-),Villin(-), CDX2(-)	Ipsilateral hilar and contra-lateral para-tracheal, peri-carinal, sub-carinal and hilar lymph nodes	T4N3M1	Cisplatinum + Bevacizumab, Erlotinib	>3+
2020	Minjie Zhu [8]	62	Hematochezia	CK7(+),TTF-1(+),Napsin-A(+)	Brain, bone and hepatic	T4N2M1	Chemotherapy + anlotinib	>2+
2020	Robert Sean O’Neill [9]	56	Jaundiced	CK7(+),TTF-1(+)	Brain, left adrenal, mediastinal, supraclavicular, and peri-portal lymph nodes	T3N3M1	Keytruda (PD after use)	>9+
2022	Sai Karthik Kommineni [10]	63	Abdominal pain, fever, chills, loss of appetite.	CK7(+),TTF-1(+),CDX2 (-),DOG1(-)	Mesentery	T1NxM1	Medical and surgical oncology follow-up	NA

The gastrointestinal tract is considered a rare site for metastasis of primary lung cancer. According to clinical statistics, the incidence of such metastasis is less than 2% [5].Additionally, studies have shown that among all cases of gastrointestinal metastasis from primary lung cancer, more than half occur in the small intestine, with the lowest probability of involvement in the duodenum [7].Duodenal metastases rarely present with clinical symptoms; however, duodenal metastases from lung cancer can cause symptoms such as abdominal pain, upper gastrointestinal (GI) bleeding, malabsorption, intussusception, and obstruction [8].Gastrointestinal metastasis from lung cancer is an indicator of poor prognosis. Studies have reported that gastrointestinal metastases usually extensively involve the submucosa and surrounding lymph nodes, with a median survival time of no more than 15 months for patients with such metastases [4, 5, 9, 10].

The diagnosis of duodenal metastasis from lung adenocarcinoma requires a multi-modal approach, incorporating laboratory tests and imaging. Around 93% of lung cancer patients with gastrointestinal metastases exhibit positive findings on CT scans, such as wall thickening, intracavitary masses, or protruding lesions. PET/CT can also aid in the detection of gastrointestinal metastases [4]. For a definitive diagnosis, histopathology and immunohistochemistry are crucial. Positive TTF-1 and NapsinA immunohistochemical markers are indicative of lung adenocarcinoma. However, emerging studies have demonstrated that a subset of lung-derived metastatic adenocarcinomas may exhibit TTF-1 negativity. Notably, Napsin-A demonstrates greater sensitivity than TTF-1 when distinguishing primary lung carcinoma from other adenocarcinomas [11–14].Moreover, CK7+/CK20- staining will help us distinguish metastatic lung adenocarcinoma from primary lung adenocarcinoma.The combination of TTF-1 (+), CK7 (+), and CK20 (-) is highly significantly associated with primary lung adenocarcinoma, whereas CK7-/CK20 + suggests gastrointestinal origin [15, 16]. In our case, the patient’s immunohistochemical results showed CK7 (+), CK20 (-), TTF-1 (-), and NapsinA (+), pulmonary origin is highly suspected. Furthermore, CDX2 and Villin is a highly sensitive and specific marker for gastrointestinal malignant tumors [17, 18]. In our patient, CDX2 and Villin were both negative, which helped us rule out primary gastrointestinal tumors.

In this case, CT, pathology, and immunohistochemistry confirmed the primary lesion as lung adenocarcinoma. The duodenal lesion was asymptomatic and not clearly visible on CT, but was identified incidentally during a PET-CT scan. Gastroscopy revealed a neoplasm in the duodenal bulb, which was biopsied. Immunohistochemistry showed CK7 (+), CK20 (-), Villin (-), CDX2 (-), TTF-1 (-), NapsinA (+), confirming the lesion as a metastatic deposit from the lung adenocarcinoma.

For prior cases of duodenal metastasis from lung cancer, the main treatment modalities usually include surgical intervention, palliative chemotherapy, targeted therapy, immunotherapy, and/or supportive care [19–22]. In our case, chemotherapy and targeted therapy were initially administered, but no significant improvement was observed, and the disease continued to progress. Considering both of the primary lung adenocarcinoma and the duodenal metastasis exhibited high PD-L1 expression (75% and ≥ 60%, respectively), we switched to immunotherapy for subsequent treatment. Following immunotherapy, the lesions significantly regressed, and the patient demonstrated good tolerance to the treatment.Currently, the patient remains under regular follow-up and is in a state of stable disease.

Treating duodenal metastasis from lung adenocarcinoma poses significant challenges, depending on the location and size of the lesion. For stage IV lung cancer without driver mutations, the median survival with palliative chemotherapy is approximately 10 to 12 months [23]. Targeted therapy in patients with driver mutations improves median survival to around 25 months [6]. Surgical options, such as duodenectomy or pancreaticoduodenectomy, are often necessary for symptom relief [24–28]. Endoscopic resection is considered a safe and effective option for smaller duodenal metastases (≤ 1 cm) when complete removal is feasible. The role of radiotherapy in treating duodenal metastasis is not well-established, with only limited case reports documenting its use. Overall, the prognosis for lung cancer patients with duodenal metastasis remains poor, with survival ranging from 3 months to 1 year. Only a few cases survived for more than 12 months after surgical resection of duodenal metastases, and only one patient survived for 46 months [19–22]. The use of immunotherapy further improves the overall survival rate. However, a few patients have survived over 12 months post-surgical resection, with one case reporting survival for 46 months. Immunotherapy has the potential to further extend survival, especially in patients with high PD-L1 expression, where five-year survival rates exceed 25%. In addition, tumors with high PD-L1 scores exhibit a good response to immunotherapy [29]. This case also highlighted the spatial heterogeneity of PD-L1 expression, a phenomenon supported by prior studies. The high PD-L1 expression in both the primary and metastatic lesions justified the use of immune checkpoint inhibitors (ICIs), which elicited a positive therapeutic response in this case. Previous research has shown that PD-L1 expression in both primary lung tumors and distant metastases can serve as a predictive marker for ICI treatment (Conclusion). However, when PD-L1 expression is high in the primary tumor (> 1%) but low in distant metastases (< 1%), or vice versa, the choice between chemotherapy alone or a combination of ICIs and chemotherapy remains an area of ongoing investigation.

Duodenal metastasis from lung adenocarcinoma is clinically rare. In this case, the patient with high PD-L1 expression (primary lesion TPS 75%, duodenal metastatic lesion TPS ≥ 60%) achieved disease stability for more than 39 months after immunotherapy. This is the first confirmation that immunotherapy can serve as an effective treatment option for such rare metastatic cases, providing a reference treatment paradigm for lung cancer patients with rare metastases, no driver gene mutations, and high PD-L1 expression in clinical practice, and preventing such patients from missing the benefits of immunotherapy due to lack of evidence-based support.Additionally, for lung cancer patients with rare metastases who have failed conventional treatment, biomarker testing (e.g., PD-L1, TMB, etc.) should be completed as early as possible. We recommend that in clinical practice, for atypical metastatic lesions of lung cancer (such as duodenal metastases), priority should be given to obtaining tissue from the metastatic lesions for PD-L1 testing. Compared with relying solely on the testing results of primary lesions, the biomarker status of metastatic lesions can better reflect the immune microenvironment of the current lesion, which can reduce the deviation in immunotherapy decision-making caused by heterogeneity.Given the specificity of duodenal metastasis from lung cancer, future research can further explore directions such as the synergistic effect of immunotherapy combined with local therapy and salvage regimens for immunotherapy resistance. In addition, the consistent PD-L1 expression between the metastatic lesion and the primary lesion in this case suggests that there may be “homology” in their immune microenvironments. However, it remains unclear whether the immune microenvironment of the duodenal mucosa affects the efficacy of immunotherapy, which is also a direction that requires attention in the future.

In summary, this case contributes novel insights to the existing literature in multiple respects. Firstly, it illustrates that immune checkpoint blockade can elicit a durable clinical response exceeding 39 months in lung adenocarcinoma with a rare duodenal metastasis—a clinical context typically associated with poor prognosis and in which previous case reports have seldom documented survival beyond one year. This observation thereby broadens the evidence supporting the efficacy of immunotherapy in a rare and understudied metastatic site. Secondly, both the primary pulmonary lesion and the duodenal metastatic site exhibited high PD-L1 expression levels (75% and ≥ 60%, respectively). This finding not only reinforces the utility of PD-L1 as a predictive biomarker but also suggests that, in certain instances, metastatic lesions may preserve the immune phenotype of the primary tumor, thereby supporting the rationale for biopsy and biomarker assessment of atypical metastatic sites. Thirdly, the survival duration observed in this case surpasses the median survival of approximately 10 to 12 months typically reported with palliative chemotherapy and aligns with the long-term benefits documented in the KEYNOTE clinical trials among patients exhibiting high PD-L1 expression. Finally, an analysis of key determinants associated with prolonged survival indicates that the favorable outcome in this patient may be attributable to the interplay of several factors, including elevated PD-L1 expression, absence of oncogenic driver mutations, and an early tumor response to PD-1 inhibition. Future investigations should incorporate additional biomarkers, such as tumor mutational burden, tumor-infiltrating lymphocytes and systemic inflammatory markers to enhance patient stratification and elucidate the mechanisms underlying exceptional responses in individuals with atypical metastatic presentations. Collectively, these findings underscore the uniqueness of this case and its valuable contribution to the expanding body of evidence regarding long-term responders to immunotherapy in non-small cell lung cancer.

Conclusion

Clinicians should remain vigilant for the possibility of duodenal metastasis in patients with primary lung adenocarcinoma. Additional immunohistochemical staining with markers such as NapsinA, TTF-1, CK7, and CK20 can assist in distinguishing the tumor origin, whether pulmonary or gastrointestinal. Treatment options, including palliative chemotherapy, surgery, immunotherapy, and radiotherapy, should be tailored to the patient’s clinical condition. Immunotherapy, in particular, has been shown to significantly enhance survival rates, with PD-L1 expression serving as a predictive marker for response to immune-based therapies. In this case, both primary lung adenocarcinoma and metastatic duodenal lesions exhibited high PD-L1 scores and responded well to immunotherapy. This may be one of the reasons that enabled the patient to achieve long-term survival after receiving immunotherapy, and this report will provide valuable insights into the treatment of duodenal metastases from lung adenocarcinoma.

Abbreviations

CDX2

Caudal Type Homeobox 2

CK7

Cytokeratin 7

CK20

Cytokeratin 20

CT

Computed tomography

FDA

Food and drug administration

GI

Gastrointestinal

ICI

Immune checkpoint inhibitor

IHC

Immunohistochemistry

MMP

Matrix metalloproteinase

NSCLC

Non-small cell lung cancer

PAX8

Paired box gene 8

PC

Pemetrexed + Carboplatin

PD

Progressive disease

PD-1

Programmed cell death protein 1

PD-L1

Programmed Death-ligand 1

PET-CT

Positron emission tomography–computed tomography

PFS

Progression-free survival

PR

Partial remission

PSA

Prostate-specific antigen

SCLC

Small cell lung cancer

SD

Stable disease

TMB

Tumor mutational burden

TPS

Tumor proportion score

TTF-1

Thyroid transcription factor-1

Author contributions

Rui Meng and Shaoxian Cheng conceived the study, Yufei Li and Leichong Chen collected the literature and drafted the manuscript, Yijin Li and Qiang Luo participated in collecting data and revised the manuscript. Shuang You, Qianwen Li and Yan Zong prepared the figures and participated in writing. All authors read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82373228), Natural Science Foundation of Hubei Province of China(No.2024AFD440), Natural Science Foundation of Hubei Province of China (No. 2022CFB070), Guangdong Association of Clinical Trials (GACT) /Chinese Thoracic Oncology Group (CTONG) and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer(Grant No. CTONG-YC20220118), Beijing Xisike Clinical Oncology Research Foundation (No. Y-zai2022/ms-0190 and Y-2024AZ(EGFR)MS-0041).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

The study was conducted in accordance with the principles of the Declaration of Helsinki principles. The Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology gave a approval for this study. The research was carried out following the guidelines of the ethics committee listed in the ethics statement.

Consent for publication

For any potentially identifiable images, data, or personal information of participants included in this article, written informed consent to publish has been obtained from all relevant individuals.

Informed consent

Participants involved in this study provided written informed consent to participate after being fully informed of the study’s purpose, procedures, potential risks, and benefits.

Competing interests

The authors declare no competing interests.