Gastric metastasis from PD-L1-positive lung squamous cell carcinoma combined with multiple primary malignant tumors: a case description

Introduction

According to estimates from Global Cancer Statistics 2020, lung cancer is the leading cause of cancer-related death, causing an estimated 1.8 million deaths (18%) (1). In the United States, lung cancer incidence declined annually from 2009 to 2018 by almost 3% in males and 1% in females (2). In contrast, lung cancer incidence increased significantly from 2000 to 2015 in China (3). Although advanced non-small-cell lung cancer (NSCLC) has a poor prognosis (4), the treatment of NSCLC has changed from traditional cytotoxic therapy to personalized treatment based on molecular heterogeneity (5). For the treatment of cases of advanced NSCLC without driver mutations, single-agent immunotherapy and immunotherapy plus chemotherapy are currently available. Immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) monoclonal antibodies, have dramatically changed the therapeutic landscape of NSCLC (6). With the recognition of the tumor immune microenvironment (TIME) and the development of next-generation sequencing (NGS) and other detection methods, multiple indicators can be combined to identify reliable markers for use with PD-1/PD-L1 inhibitors. The dynamic changes in PD-L1 expression that occur during immunotherapy may predict disease response (7).

Distant metastases are usually found in the adrenal glands, bone, liver, brain, and kidney for squamous NSCLC (8). The gastrointestinal tract is a rare distant metastatic site of squamous NSCLC, so endoscopic examination of patients with squamous NSCLC is not often routinely performed during clinical follow-up. Therefore, it is difficult to detect metastasis of squamous NSCLC in the gastrointestinal tract. The majority of diagnosed gastrointestinal metastasis cases have certain clinical characteristics (e.g., perforation, obstruction, hemorrhage, and intussusception) (9). In the past, the presence of multiple primary malignant tumors (MPMTs) was regarded as rare, and MPMTs are defined as the presence of two or more primary cancers of different organs in the same patient (10). However, as diagnostic techniques improve, the incidence of MPMTs is increasing.

Herein, we present the case of a patient with gastric metastasis from PD-L1-positive primary squamous NSCLC who developed a second primary colonic internal mucosal adenocarcinoma. This patient had a good response to toripalimab plus chemotherapy but developed gastric metastasis and a second primary intracolonic adenocarcinoma. Early diagnosis and treatment of these rare cases are critical to improving prognosis.

Case presentation

An elderly patient with physical discomfort (cough and chest distress for 3 weeks) presented to his local hospital on May 4, 2019. A chest-enhanced computed tomography (CT) scan showed a mass of 5.43 cm × 5.22 cm in the left upper lung lobe that invaded the left hilar structure and hilum of the left lung along with mediastinal lymph node enlargement on May 9, 2019 (Figure 1A). Subsequently, the patient underwent bronchoscopy and biopsy, with pathology indicated NSCLC. And thus, central lung cancer was considered. Subsequently, the patient was admitted to our hospital for left upper lung lobe resection and mediastinal lymph node dissection. The pathological characteristics of the mass indicated that it was lung squamous cell carcinoma. Immunohistochemical staining revealed CK5/6 (−), P63 (+), P40 (+), CK7 (−), and TTF-1 (−). The patient was diagnosed with stage IIIA squamous cell lung carcinoma (T2aN2M0) after a series of clinical evaluations.

Figure 1 Chest CT scans showing that the patient’s lung continued to change between initial diagnosis and after treatment. (A) Chest CT scans showing pulmonary lesions (5.43 cm × 5.22 cm) and mediastinal lymph nodes at initial diagnosis as a baseline. (B) After left upper lung lobe resection, PD was found on chest CT scans, showing pulmonary nodules in the right lung and no significant changes in lymph nodes. (C) Following treatment with gemcitabine and cisplatin chemotherapy for three cycles, PD was noted on chest CT scans, with enlargement of the pulmonary nodules and no significant changes in the lymph nodes. (D) Following treatment with toripalimab plus paclitaxel for four cycles, PR was noted on chest CT scans with a significant reduction in the size of the pulmonary nodules and lymph nodes. (E) Following treatment with toripalimab plus paclitaxel for six cycles and toripalimab for seven cycles, PR was noted on chest CT scans by a further reduction in the size of the pulmonary nodules and lymph nodes. (F) Following treatment with toripalimab plus anlotinib for eight cycles, chest CT scans confirmed persistence of PR. The red arrows in images indicate the lesion area. PD, progressive disease; PR, partial response; CT, computed tomography.

A review of the chest CT image obtained prior to postoperative adjuvant chemotherapy revealed multiple nodules in the right lung on July 4, 2019 (Figure 1B). Systemic evaluation revealed multiple lung nodule metastases, the tumor-node-metastasis (TNM) stage was determined to be T2aN2M1a, and the stage was IVA. Further postoperative chemotherapy with gemcitabine (1.4 g on days 1 and 8) and cisplatin (30 mg on days 2–5) was administered.

Chest CT review was performed after three cycles of chemotherapy and showed postoperative changes in the left lung, multiple metastases in both lungs, left pleural effusion, and pleural thickening. Imaging was conducted to evaluate progressive disease (PD) (Figure 1C). With the consent of the patient, PD-L1 expression, TIME characteristics, and tumor mutation burden (TMB) (Burning Rock Biotech, Guangzhou, China) were analyzed, and the assay results revealed positive PD-L1 expression [tumor positive score (TPS) ≥1%]. Treatment with anti-PD-1 monoclonal antibody is recommended for patients with stage IVA NSCLC according to the guidelines of the National Comprehensive Cancer Network (NCCN) (11) and Chinese Society of Clinical Oncology (CSCO) (12). Therefore, the patient received six cycles of toripalimab (240 mg on day 1; Junshi Biosciences Co., Ltd., Shanghai, China) combined with paclitaxel (240 mg on day 2) and 7 cycles of toripalimab (240 mg on day 1) maintenance therapy. Multiple repeated chest CT examinations were subsequently performed to evaluate the patient’s condition to maintain partial response (PR) (Figure 1D-1F).

The patient reported that he experienced weakness in the right limb and occasional dizziness for 2 weeks. Considering that the case of pulmonary mass resection in the patient suggested squamous cell carcinoma of the lung (Figure 2A), the possibility of imaginary metastasis was suspected, and the patient was immediately arranged to undergo cranial CT examination. Cranial CT performed on September 21, 2020, showed a mass of 2.93 cm × 2.22 cm in the left occipital lobe, which was considered brain metastasis from the lung cancer (Figure 2B). After careful multidisciplinary discussion and receipt of patient consent, video-assisted left occipital lobe lesion resection was performed. The pathologic results revealed metastatic carcinoma, consistent with squamous cell carcinoma (Figure 2C). Then, the patient received 8 cycles of toripalimab (240 mg on day 1) combined with anti-angiogenic therapy (anlotinib 12 mg daily, administered days 1–14 every 3 weeks; Tai-Tianqing Pharmaceutical Co., Ltd., Nanjing, China). Multiple cranial magnetic resonance imaging (MRI) examinations indicated no recurrence during treatment (Figure 2D).

Figure 2 Histopathological images of the lesions and imaging scans with head CT findings. (A) H&E staining demonstrating squamous NSCLC in primary lung lesions (×100). (B) Head CT scans showing metastatic brain lesions (2.93 cm × 2.22 cm) with encephaledema. (C) H&E staining demonstrating squamous cell carcinoma in metastatic brain lesions (×100). (D) After left occipital lobe lesion resection and subsequent treatment with toripalimab plus anlotinib for eight cycles, head MRI scans showed that the left occipital lobe had softened, and no recurrence was noted. (E) Images of gastric slices showing squamous cell carcinoma by H&E staining (×100). (F) Images of colonic slices showing internal mucosal adenocarcinoma by H&E staining (×100). CT, computed tomography; T1WI, T1-weighted imaging; T2WI, T2-weighted imaging; H&E, hematoxylin and eosin; NSCLC, non-small cell lung cancer; MRI, magnetic resonance imaging.

Unfortunately, the patient had persistent black stool without obvious inducement on September 2, 2021. The fecal occult blood (OB) test (gold standard method) was positive. With the consent of the patient, electronic gastroscopy and colonoscopy were performed. Pathological examination after electronic gastroscopy indicated that the invasive carcinoma at the rear wall of the stomach was likely squamous cell carcinoma (Figure 2E). Immunohistochemical staining revealed P63 (3+), P40 (3+), CAM5.2 (−), CK7 (−), CK20 (−), CEA (−), and Ki-67 (3+, 50%). Pathological examination after electronic colonoscopy showed a colonic internal mucosal tumor 25 cm from the anal edge (internal mucosal cancer) (Figure 2F) that had invaded the mucosal muscle layer. Immunohistochemical staining revealed colonic internal mucosal adenocarcinoma with CEA (2+), CAM5.2 (+), CK5/6 (−), P63 (−), P40 (−), CK7 (−), CK20 (−), and Ki-67 (3+, 60%).

Positron emission tomography (PET)-CT revealed that fluorodeoxyglucose (FDG) metabolism was increased throughout the body on October 18, 2021 (Figure 3A). In particular, (I) FDG metabolism was increased in the gastric greater curvature (Figure 3B); (II) FDG metabolism was increased in the colonic spleen region (Figure 3C); (III) left adrenal thickening was noted with the nodular increase in FDG metabolism (Figure 3D); and (IV) lymph node shadows with high FDG metabolism were observed in the bilateral neck, mesenteric lymph nodes in the abdominal cavity and anterior abdominal aorta in the retroperitoneum. Thus, lymph node metastasis was considered (Figure 3E). After multidisciplinary consultation among the Gastroenterology Department, Gastroenterology Surgery and Radiotherapy Department, Imaging Department, and Pathology Department, the patient was considered to have multiple metastases with no indications for surgery or endoscopic treatment, and a comprehensive medical treatment plan was developed. The patient received 3 cycles of albumin-bound paclitaxel (300 mg on day 1) combined with nedaplatin (100 mg on day 2). Best supportive care (BSC) was given because the patient could not tolerate chemotherapy. Finally, patient died on April 18, 2022. A schematic of the whole treatment process and survival time for the patient is shown in Figure 3F.

Figure 3 PET-CT scans revealed that FDG metabolism was increased throughout the body. (A) FDG metabolism was increased in multiple sites throughout the body. (B) FDG metabolism was increased in the gastric greater curvature. (C) FDG metabolism was increased in the colonic spleen region. (D) Left adrenal thickening was noted with an increase in nodular FDG metabolism. (E) Lymph node shadows with high FDG metabolism were observed and considered lymph node metastases (representative image: left neck lymph node). (F) Schematic of the timeline of the treatment course. PET, positron emission tomography; CT, computed tomography; PD, progressive disease; PR, partial response; FDG, fluorodeoxyglucose.

During the progression of the patient’s disease, TIME characteristics, PD-L1 expression, and TMB were assessed in the primary lung lesions, metastatic brain lesions, and gastric metastases. The TIME signature of the patient’s squamous cell carcinomatous lesions was examined by multiplex immunohistochemistry (mIHC) (Figure 4A). The results of these analyses showed that CD8⁺ T cells, CD3⁺ T cells, PD-1⁺ cells, and PD-L1⁺ cells had infiltrated the tumor and stroma. In the tumor regions, CD8⁺ and PD-L1⁺ cell infiltration was greatest in the primary lung lesions, while CD3⁺ and PD-1⁺ cell infiltration was the greatest in the metastatic brain lesions. In the stromal regions, the infiltration of these four cell types was highest in the metastatic brain lesions. In all regions, infiltration of these four cell types was similarly high (Figure 4B).

Figure 4 Comprehensive evaluation of TIME characteristics, PD-L1 expression, and TMB in squamous cell carcinomatous lesions. (A) mIHC staining for CD3, CD8, PD-1, and PD-L1 in primary lung lesions, metastatic brain lesions, and gastric metastases (×200). With this staining technique, visible cells include CD8⁺ T cells (green), CD68⁺ macrophages (cyan), CD57⁺ cells (red), PD-1⁺ cells (magenta), and PD-L1⁺ cells (orange). (B) The percentages of positively stained cells in the tumor and stroma and of total nucleated cells were determined. (C) Immunohistochemistry staining showed low positive PD-L1 expression according to the TPS and CPS in primary lung lesions, metastatic brain lesions, and gastric metastases (×400). (D) TPS and CPS of PD-L1-positive cells in all nucleated cells in squamous cell carcinomatous lesions by mIHC assay. (E) Quantitative analysis of TMB in primary lung lesions, metastatic brain lesions, and gastric metastases. mIHC, multiplex immunohistochemistry; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; DAPI, 4',6-diamidino-2-phenylindole; TPS, tumor positive score; CPS, combined positive score; TMB, tumor mutation burden; TIME, tumor immune microenvironment.

Subsequently, a TPS of 15% and a combined positive score (CPS) of 10% in the lung primary tumor specimens were found. Similarly, a TPS of 20% and a CPS of 30% were found in the brain metastases. A TPS of 3% and a CPS of 10% were found in the gastric metastases (Figure 4C,4D). These results indicated that PD-L1 positivity and PD-L1 expression were relatively high in brain metastases compared to the two other specimen types. Next, we calculated TMBs of 14.96, 12.96, and 15.95 mut/Mb in the lung, brain, and gastric tumor biopsy specimens, respectively (Figure 4E). All the values were greater than 10 mut/Mb, indicating that an anti-PD-1 monoclonal antibody would have relatively good efficacy.

The tumor lesions were further analyzed through NGS targeting 520 cancer-associated genes (all exons or hotspots). NGS revealed a TP53 (c.376-1G>T) mutation and a CCNE1 (19q12) amplification in 3 tumor biopsy tissue samples. In addition, a PIK3CA (c.1633G>A) mutation was detected in lung and brain lesions, and a MET (7q31.2) amplification and a KEAP1 (c.959G>A) mutation were detected in gastric lesions (Table 1). Microsatellite instability (MSI) in the lesions was also assessed, and all lesions were microsatellite stable (MSS). Regrettably, there are no effective drugs targeting TP53 and KEAP1 mutations. After comprehensive consideration, the patient was treated primarily with toripalimab and exhibited a good response. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

We present the case of an elderly man with lung squamous cell carcinoma that progressed after the resection of lung lesions and chemotherapy. The patient was then treated with anti-PD-1 antibody therapy combined with chemotherapy, and the patient’s condition partially improved according to a series of imaging observations. Unfortunately, the patient developed brain metastases and underwent subsequent surgery to remove the lesions. He then received anti-PD-1 antibody therapy combined with a molecular targeted agent, and no recurrence of the brain tumors was observed. Ultimately, due to hematochezia, gastric metastatic carcinoma and primary intracolonic adenocarcinoma were detected on endoscopy. PET-CT examination revealed that the patient had rare distant gastric metastasis and MPMTs. After multidisciplinary team consultation, he was treated with chemotherapy.

In recent years, anti-PD-1 monoclonal antibody and anti-PD-1 monoclonal antibody immunotherapy have become the standard first-line treatment for stage V lung squamous cell carcinoma. Based on the results of the KEYNOTE 024 (13) (n=305) and KEYNOTE 042 (14) clinical trials (n=1,274), pembrolizumab monotherapy has been approved by the Food and Drug Administration (FDA) and National Medical Products Administration (NMPA) as first-line therapy for patients with locally advanced or metastatic NSCLC and positive PD-L1 expression (TPS ≥1%) without EGFR or ALK gene mutations.

For NSCLC patients with varied PD-L1 expression, chemotherapy combined with immunotherapy has been recommended as the most effective treatment. The KEYNOTE 407 trial (15) showed that the objective response of patients with first-treated metastatic squamous NSCLC was noticeably improved in the pembrolizumab plus chemotherapy group compared with the chemotherapy alone group. Toripalimab is the first domestic anti-PD-1 monoclonal antibody in China with completely independent intellectual property rights. The CHOICE-01 study enrolled 465 patients with advanced or metastatic NSCLC who lacked sensitizing EGFR or ALK mutations. The patients were randomly assigned 2:1 to receive toripalimab or placebo combined with standard first-line chemotherapy. The median progression-free survival (PFS) with toripalimab was 8.4 months, compared with 5.6 months in the control arm. In subgroup analyses, a high TMB was associated with improved PFS among patients given toripalimab, and regardless of PD-L1 expression, the 1-year PFS rate in the treatment group was twice as high as that in the control group (16). These clinical results suggest that different PD-L1 expression subgroups could benefit from anti-PD-1 monoclonal antibody combined with chemotherapy.

Many types of immune cells play various roles in tumor progression. Moreover, tumor-infiltrating lymphocytes (TILs) are an important class of lymphocytes that infiltrate tumor tissue, immune infiltration can be highly heterogeneous, even between different patients with the same cancer type or within one patient. They are an effective immune defense against various malignant tumors (17). Increased levels of CD3⁺ and CD8⁺ TILs were associated with a better outcome in a large case series of NSCLC (18). ICIs induce sustained responses in different cancer types, particularly NSCLC (19). Therefore, the paradigm of chemotherapy as the traditional approach has shifted to include a chemotherapy combined with immunotherapy approach for advanced NSCLC patients without driver mutations. In addition, a study showed that the total density of CD3⁺ and CD8⁺ TILs was higher in early thymic carcinoma stages. In advanced thymic carcinoma stages, the density of CD3⁺ and CD8⁺ TILs was lower than that in early thymic carcinoma stages. We boldly hypothesized that CD3⁺/CD8⁺ cell density was lower in the advanced stage of lung squamous cell carcinoma than in the early stages (20). Therefore, the detection of predictive biomarkers such as PD-L1 expression, CD3⁺/CD8⁺ TILs, TMB, and TIME characteristics may be helpful in predicting patient prognosis and formulating individualized treatment plans for patients.

In this case report, a sufficient diagnosis and treatment plan were made according to the NCCN guidelines and based on the patient’s TIME characteristics, PD-L1 expression, and TMB. These findings were conducive to providing an individualized treatment scheme of anti-PD-1 monoclonal antibody plus chemotherapy, which achieved certain therapeutic effects over a period of time. Although the patient did not have a specific genetic mutation that could be targeted by treatment, he responded well to anti-PD-1 antibody therapy, which allowed for the control of disease progression in the primary organ. Moreover, to the greatest extent possible and within the economic scope of patient health care costs, surveillance for metastatic lesions by regular PET-CT examination should be performed as often as possible to evaluate the general situation and to enable timely adjustment of the treatment scheme. For cases of rare distant metastasis and MPMTs, there remains no definitive treatment plan, and such strategies remain to be developed in the future.

Acknowledgments

The authors wish to gratefully acknowledge the patient and his family for allowing us to publish his clinical case.

Funding: This study supported by the Natural Science Research Project of Anhui Educational Committee (grant No. KJ2021A0714), the College Teaching Quality Engineering Project of Anhui Educational Committee (grant No. 2021jyxm0954), and the 512 Talent Cultivation Plan of Bengbu Medical College (grant No. by51201319).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-186/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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