Gastric amphicrine carcinoma with leptomeningeal metastases: A case report

Abstract

BACKGROUND

Amphicrine carcinoma (AC) is a rare tumor characterized by the coexistence of exocrine and neuroendocrine differentiation within the same cell. Leptomeningeal metastasis (LM) is likewise an uncommon occurrence in gastric cancer. We report the first documented case of advanced gastric AC with LM.

CASE SUMMARY

The patient was a 66-year-old man who presented with progressively worsening abdominal pain, along with acid reflux, belching, nausea, and melena. Imaging studies revealed a malignant mass in the gastric antrum with multiple lymph node and hepatic metastases. Gastroscopy demonstrated a large ulcerative lesion in the gastric antrum. Biopsies were sequentially obtained from the primary gastric tumor and the liver metastasis. Pathological evaluation consistently revealed a single population of tumor cells co-expressing adenocarcinoma (mucin 1 [MUC-1], MUC-2, D-PAS) and neuroendocrine markers (chromogranin A, synaptophysin [Syn], insulinoma-associated protein 1), supporting the diagnosis of AC. Treatment was administered according to standard gastric adenocarcinoma protocols. The treatment outcomes demonstrated that progression-free survival ranged only from approximately 1.6 months to 5 months in the following three lines of treatments, with an overall survival of 10 months. One week prior to the patient’s death, cerebrospinal fluid (CSF) biopsy was performed following an episode of generalized (grand mal) epilepsy. The detection of carcinoma cells in the CSF confirmed the presence of LM.

CONCLUSION

Accurate diagnosis of gastric AC is challenging, as it requires concurrent immunohistochemical staining for both epithelial mucin markers and neuroendocrine-associated markers. Currently, no standard treatment protocol has been established. Both gastric AC and the development of LM are associated with a poor prognosis.

Key Words: Gastric carcinoma; Neuroendocrine neoplasm; Amphicrine carcinoma; Hepatic metastasis; Leptomeningeal metastasis; Case report

Core Tip: Based on histopathological findings from both the primary tumor and metastatic site, this case was diagnosed as advanced gastric amphicrine carcinoma. The patient underwent multiple lines of therapy, along with serial imaging and endoscopic evaluations. Nevertheless, the tumor did not respond well to treatment regimens typically used for conventional adenocarcinoma. In the end, the patient died from a rare leptomeningeal metastasis, indicating an unfavorable prognosis.

INTRODUCTION

Amphicrine carcinoma (AC) is a rare malignancy characterized by the concurrent presence of neuroendocrine and exocrine glandular differentiation within a single tumor cell[1]. AC is characterized by marked heterogeneity and poor differentiation. Due to these unusual pathological features, it is clearly different from conventional adenocarcinoma and neuroendocrine tumors, which complicates accurate diagnosis. Furthermore, research on its biological behavior, optimal treatment strategies, and prognosis is still limited, especially in advanced stages.

AC is an uncommon malignant neoplasm defined by the fact that the same tumor cell has both exocrine and neuroendocrine differentiation, with the gastrointestinal tract being the most common primary site[2]. The concept of dual differentiation was first reported in 1938[3], and the term “amphicrine carcinoma” was later introduced in 1977 to define this entity[4]. Previously regarded as a subtype of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), AC was formally recognized as a distinct tumor entity in the 2022 World Health Organization classification of neuroendocrine neoplasms[5].

Leptomeningeal metastasis (LM) reportedly occurs in approximately 5%-15% of patients with advanced cancer[6]. In gastric cancer, its occurrence is exceedingly rare; a study published in 1999 found only 5 cases of LM among 8080 patients with advanced gastric carcinoma, representing an incidence of 0.06%[7]. The cerebrospinal fluid (CSF) cytology is the gold standard of LM diagnosis. Although the common treatment includes radiotherapy and intrathecal chemotherapy, the prognosis remains poor, with an average survival of approximately 2 months[8].

This report describes a patient with advanced gastric AC and outlines the complete clinical course, spanning from initial diagnosis to therapeutic intervention. It highlights the pathological characteristics, treatment decision-making, and disease outcome, including the development of LM. In addition, a review of relevant literature is provided to enhance clinicians’ and pathologists’ understanding of the features of AC.

CASE PRESENTATION

Chief complaints

The patient presented with a 2-year history of intermittent upper abdominal pain.

History of present illness

In February, 2024, a man developed upper abdominal pain of unclear origin, which was initially relieved with analgesics. Over the following year, the pain progressively worsened and was accompanied by symptoms of acid reflux, belching, and nausea. Until April 2025, due to the increasing severity of these symptoms, he was admitted to our hospital for further evaluation and management.

History of past illness

The patient was diagnosed with hypertension in 2019, which has been well controlled at approximately 130/80 mmHg with sustained-release nifedipine. In March 2025, he received a 400-mL blood transfusion for anemia.

Personal and family history

The patient had a 30-year history of alcohol consumption, averaging about 55 mL of samshu daily, but had abstained from alcohol for the past 6 years. Meanwhile, the patient had smoked for 40 years, with an average of 25 cigarettes per day, and had quit smoking for 10 years. His father had gastric cancer, while his mother had diabetes.

Physical examination

The examination of the lungs showed no abnormalities. The abdomen was flat and soft, with localized tenderness but no rebound tenderness or varicose veins. No evidence was found for hepatosplenomegaly, lump, shifting dullness, or Murphy's sign. Bowel sounds were also normal.

Laboratory examinations

Routine blood examination was basically normal, except for the level of hemoglobin, which was decreased to 116 g/L (reference range: 130-175 g/L). The indicators of heart, liver, and kidney function were all unremarkable. Levels of neuron-specific enolase and pro-gastrin-releasing peptide were elevated, measuring 19.21 ng/mL (reference range: < 16.30 ng/mL) and 126.12 pg/mL (reference range: ≤ 67.42 pg/mL), respectively. Other main tumor markers were within normal range, including carcinoembryonic antigen, carbohydrate antigen 19-9, and carbohydrate antigen 72-4. The changes in tumor marker levels are shown in Figure 1. Anti-parietal cell antibody and anti-intrinsic factor antibody tests were negative. The level of pepsinogen I was decreased at 62.4 ng/mL (reference range: 67-200 ng/mL), while gastrin-17 and pepsinogen II remained within normal limits.

Figure 1 Variation curve of tumor markers throughout the course of treatment. CA724: Carbohydrate antigen 72-4; CA199: Carbohydrate antigen 19-9; CEA: Carcinoembryonic antigen; NSE: Neuron-specific enolase; Pro-GRP: Pro-gastrin-releasing peptide.

Imaging examinations

Contrast-enhanced computed tomography (CT) revealed irregular thickening of the gastric wall at the antrum with heterogeneous enhancement. Multiple hypovascular nodules and masses were identified in the liver, the largest of which measured approximately 73 mm × 66 mm. Additionally, enlarged lymph nodes were observed along the lesser curvature, in the porta hepatis, and around the gastric antrum, as illustrated in Figure 2A and B.

Figure 2 Computed tomography manifestations during the first-line treatment. A and B: Before first-line treatment; C and D: After two cycles of first-line treatment; E and F: After four cycles of first-line treatment; G and H: After six cycles of first-line treatment.

Gastroscopy revealed a nearly circumferential mass in the gastric antrum, with surface ulceration and a coating of necrotic debris. The lesion extended to involve the pylorus, which was mildly narrowed but remained traversable with the endoscope, as illustrated in Figure 3A and B.

Figure 3 Gastroscopy examination. A and B: Before first-line treatment; C and D: After three cycles of second-line treatment.

Contrast-enhanced magnetic resonance imaging (MRI) of the liver findings were consistent with CT findings, and no tumor-related lesions were detected on brain MRI.

Fluorodeoxyglucose-labeled positron emission tomography-CT revealed irregular thickening of the gastric wall at the antrum, accompanied by increased radiotracer uptake (maximum standardized uptake value [SUVmax] 8.1). Multiple lymph nodes of varying sizes were identified around the lesion, along the portal vein, and on the lesser curvature of the stomach, with an SUVmax of 6.6. In the liver, several low-density lesions were observed, the largest measuring approximately 6.8 cm × 6.3 cm in the left lobe, with an SUVmax of 15.0. These findings are suggestive of a malignant gastric lesion with multiple metastases, as illustrated in Figure 4.

Figure 4 Positron emission tomography-computed tomography examination. A-C: Hypermetabolic lesions in the gastric wall of the antrum (A and B), the liver (B and C), and lymph nodes around the portal vein and along the lesser curvature of the stomach (B and C).

The imaging findings suggested a lesion in the gastric antrum, with multiple metastatic lesions in the liver and lymph nodes.

MULTIDISCIPLINARY EXPERT CONSULTATION

The histopathological examination of gastroscopy biopsy revealed infiltration by a poorly differentiated carcinoma in the gastric antral mucosa. The morphological characteristics are illustrated in Figure 5.

Figure 5 Pathology of the gastric antrum lesion. A: Tumor cells arranged in clusters with a micropapillary pattern (hematoxylin and eosin [H&E], 200 ×); B: Tumor cells exhibiting cord-like or linear arrangements (H&E, 200 ×); C: In certain regions, tumor cells appeared in cord-like or linear patterns, with scattered signet ring cells present within a mucinous background (H&E, 100 ×); D: The majority of tumor cells were moderately large, displaying fine chromatin, inconspicuous nucleoli, and readily identifiable mitotic figures; Some nuclei were eccentrically displaced (H&E, 400 ×); E: Signet ring cells within the mucinous background showed marked atypia, with visible nucleoli (H&E, 400 ×).

Immunohistochemical analysis of the gastric antrum lesion showed the following results: Chromogranin A (CgA) (diluted +), cluster of differentiation 56 (majority +), synaptophysin (Syn) (diluted strong +), insulinoma-associated protein 1 (INSM1) (diluted +), cytokeratin 7 (CK7) (majority +), somatostatin receptor 2 (SSTR2) (3+, with 50% strong positivity), mouse double minute 2 homolog (MGMT) (+), mucin 1 (MUC-1) (focally +), MUC-2 (diluted +), p53 (nonsense mutation), retinoblastoma (Rb) (negative, with loss of expression), Ki-67 (MIB-1; approximately 80%+), Alcian Blue-Periodic Acid Schiff (AB-PAS) (+), and Diastase-PAS (D-PAS) (+).

Immunohistochemical staining demonstrated that the same tumor cells co-expressed adenocarcinoma markers (positive mucin staining) and neuroendocrine differentiation, consistent with a diagnosis of AC, as shown in Figure 6.

Figure 6 Immunohistochemistry of the gastric antrum lesion. A: Chromogranin A (CgA) expression was diffusely positive (EnVision, 200 ×); B: Synaptophysin (Syn) showed diffuse positive expression (EnVision, 200 ×); C: Insulinoma-associated protein 1 (INSM1) demonstrated diffuse positivity (EnVision, 200 ×); D and E: Mucin 1 (MUC1) and MUC2 expression were both positive (EnVision, 200 ×); F: Diastase-Periodic Acid-Schiff (D-PAS) staining revealed intracellular mucin within the cytoplasm of tumor cells (Special stain, 400 ×); G: Cytokeratin 7 (CK7) expression was diffusely positive (EnVision, 200 ×); H: Ki-67 proliferation index (EnVision, 200 ×); I: Dual staining showing combined positivity of D-PAS special staining and INSM1 immunohistochemistry (400 ×).

FINAL DIAGNOSIS

The patient was diagnosed with AC of the gastric antrum (adenocarcinoma and neuroendocrine neoplasm), accompanied by hepatic metastases and involvement of abdominal lymph nodes. Assessment of potential therapeutic targets showed that human epidermal growth factor receptor 2 (HER2) was negative, and claudin 18.2 was positive. Regarding immunotherapy-related biomarkers, programmed death-ligand 1 (PD-L1) expression was low (tumor proportion score 2%, combined positive score [CPS] 3), tumor mutation burden was low, and microsatellite status indicated stability.

TREATMENT

Currently, there is no standardized consensus regarding the treatment of AC, particularly in advanced cases, and clinical experience remains limited. In this case, following multidisciplinary team discussion, based on the dual expression characteristics of biphasic adenocarcinoma and neuroendocrine tumor in gastric AC, treatment strategies were extrapolated from those used for gastric adenocarcinoma. According to the National Comprehensive Cancer Network (NCCN) guidelines for gastric cancer, for patients with HER2-negative gastric cancer with PD-L1 CPS ≥ 1, combination therapy with oxaliplatin, fluoropyrimidine-based chemotherapy, and immunotherapy is a recommended first-line treatment option. If the PD-L1 CPS is ≥ 5, this regimen is recommended with category 1 evidence. Given the patient's PD-L1 CPS score of 3, and next-generation sequencing findings demonstrating tumor protein p53 and ataxia-telangiectasia mutated mutations, which may suggest an enhanced responsiveness to PD-1/PD-L1 inhibitors, the SOX plus tislelizumab regimen was ultimately selected as first-line treatment. Another potential therapeutic target was somatostatin receptor 2 (SSTR2) expression. Somatostatin analogs, such as octreotide or lanreotide, are generally indicated for patients with slow-growing gastroenteropancreatic neuroendocrine tumors with Ki-67 ≤ 10% and positive SSTR2 expression, and have limited tumor-shrinking effects. This patient, who had a high tumor burden and elevated Ki-67 index, was not considered an appropriate candidate for this approach. In addition, peptide receptor radionuclide therapy remains in the clinical trial stage in China and has not yet been approved for clinical use.

Following diagnosis, the patient underwent three sequential lines of therapy. A summary of the treatment regimens is provided in Table 1.

Table 1 Whole course of the therapeutic regimens.

Initiation of therapy to disease progression	Therapeutic stage	Therapeutic regimen	Medication usage	PFS (month)
April 17, 2025 to September 26, 2025	First-line therapy	SOX + tislelizumab	Oxaliplatin 120 mg, ivggt, d1; S1: 40 mg, po, bid, d1-14; tislelizumab 200 mg, ivggt, d1; a 21-day cycle	5
September 28, 2025 to November 27, 2025	Second-line therapy	FOLFIRI + tislelizumab	Irinotecan 200 mg, ivggt, d1; calcium folinate 300 mg, ivggt, d1; 5-fluorouracil 500 mg, bolus, d1; 5-fluorouracil 3000 mg, CIV, 46 hours; a 14-day cycle; tislelizumab 200 mg, ivggt, d1; a 21-day cycle	2
December 5, 2025 to January 22, 2026	Third-line therapy	Abraxane + zotuximab	Abraxane 200 mg, ivggt, d1; zotuximab 1000 mg as initial dose, 600 mg as maintenance dose, ivggt, d1; a 21-day cycle	1.6

CIV: Continuous intravenous infusion; ivggt: Intravenous guttae; PFS: Progression-free survival; S1: Tegafur gimeracil oteracil potassium capsule.

OUTCOME AND FOLLOW-UP

Following four cycles of first-line therapy, there was a reduction in the size of multiple hepatic metastases and previously noted small lymph nodes. The largest liver lesion measured approximately 56 mm × 66 mm at that time. However, after two additional cycles of the same treatment, the hepatic tumors increased in size and showed evident calcification, as illustrated in Figure 2.

During the treatment course, the patient underwent two liver biopsies (August 1, 2025, and December 5, 2025).

Histopathological evaluation revealed poorly differentiated carcinoma. Based on the combined findings of morphology, immunohistochemistry, and clinical history, the results were consistent with hepatic metastasis originating from gastric AC (Figure 7).

Figure 7 Pathological findings of the liver lesion and cerebrospinal fluid. A: Tumor cells exhibited marked atypia with nuclear displacement and a morphology resembling signet ring cells (hematoxylin and eosin [H&E], 400 ×); B and C: Insulinoma-associated protein 1 (INSM1) showed diffuse positive expression (EnVision, 200 ×); D and E: Diastase-Periodic Acid-Schiff (D-PAS) staining demonstrated the presence of mucin within the cytoplasm of tumor cells (Special stain, 400 ×); F: Tumor cells were relatively uniform in size, with inconspicuous nucleoli and eccentrically located nuclei, resembling signet ring cells; occasional tumor giant cells were noted (H&E, 400 ×); G: Tumor cells displayed features similar to those in panel D, with identifiable mitotic figures (H&E, 400 ×). CSF: Cerebrospinal fluid.

Immunohistochemical analysis of the liver biopsy demonstrated the following profile: INSM1 (+), CgA (minor +), Syn (+), p53 (nonsense mutation), Rb (-, loss of expression), MUC1 (+), MUC2 (+), Ki-67 (MIB-1) proliferation index of 90%, AB-PAS (+), and D-PAS (+).

However, despite three cycles of second-line treatment followed by two cycles of third-line treatment, the hepatic lesions continued to progress, as illustrated in Figure 8. Repeat gastroscopy demonstrated progression of the submucosal tumors, although the ulcerative component had improved, as shown in Figure 3C and D.

Figure 8 Computed tomography manifestations during the second-line and third-line treatment. A: Before the second-line treatment; B: After three cycles of second-line treatment; C: After two cycles of third-line treatment.

The progression-free survival (PFS) of three lines of treatments were 5 months, 2 months, and 1.6 months, respectively. Following these anti-tumor therapies, the patient's general condition markedly declined. Active oncologic treatment was discontinued, and best supportive and palliative care were initiated. Approximately 1 month later, the patient developed a generalized tonic-clonic seizure, presenting with persistent upper limb tremor, dysarthria, loss of consciousness, and reduced strength in the left lower limb. Although brain MRI revealed no space-occupying lesions, the detection of malignant cells in the CSF (Figure 8G) confirmed LM. The patient passed away 1 week later (February 14, 2026). From the confirmed diagnosis on April 15, 2025, the total survival time was 10 months.

The overall clinical course of diagnosis and treatment is summarized in Figure 9.

Figure 9 Process of diagnosis and treatment. PD: Progressive disease; PFS: Progression-free survival.

DISCUSSION

AC is frequently misinterpreted as carcinoma with neuroendocrine expression, carcinoma with neuroendocrine differentiation, or MiNEN. As illustrated in the schematic diagram in Figure 10, AC is characterized by the simultaneous presence of exocrine and neuroendocrine expression within the same tumor cell. Tumor cells typically show diffuse, strong positivity for neuroendocrine markers, along with concurrent positivity on D-PAS staining in immunohistochemical analysis[9]. By contrast, MiNEN consists of two clearly different cell populations, which can be distinguished by their morphologically and immunohistochemical appearance. These include neuroendocrine neoplasm and non-neuroendocrine neoplasm, each comprising more than 30% of the tumor[10]. When the neuroendocrine component makes up less than 30% and the tumor is mainly conventional carcinoma, it is classified as carcinoma with neuroendocrine differentiation. Another type, called carcinoma with neuroendocrine expression, refers to a conventional carcinoma that does not have the typical neuroendocrine tumor appearance but still demonstrates immunohistochemical positivity for neuroendocrine markers, usually in a patchy or isolated pattern[11].

Figure 10  Schematic diagram of four types of mixed carcinomas. MiNEN: Mixed neuroendocrine–non-neuroendocrine neoplasms.

Therefore, the diagnosis of AC rests largely on its characteristic morphology, aided by immunohistochemical profiling and special staining techniques. The combined use of neuroendocrine markers and histochemical stains is thus essential for an accurate diagnosis.

The cellular origin of AC remains poorly understood; it remains unknown whether it arises from multipotent tumor stem cells or reflects divergent differentiation of adenocarcinoma cells. A study reported that CD44v9, a functional cancer stem cell marker, was expressed immunohistochemically in the cells of AC[12]. During evaluation after the first two cycles of initial chemotherapy, some hepatic metastatic lesions had shrunk significantly, almost disappearing entirely, suggesting responsiveness to chemotherapy typically effective against adenocarcinoma. By contrast, other liver metastases showed minimal response, indicating possible intratumoral heterogeneity. Subsequently, as the hepatic lesions advanced, biopsy specimens taken from two separate metastatic sites each showed biphasic carcinoma. Based on these observations, we hypothesize that AC may occur together with other differentiated tumor components. At the start of therapy, chemotherapy may selectively eliminate those tumor components that are sensitive to conventional regimens, while sparing the AC cells, which are more resistant. These surviving cells may contribute to rapid disease progression, which may lead to serious complications such as LM. This finding offers indirect support for the hypothesis that AC may originate from multipotent tumor stem cells. However, this hypothesis is based on a single-case observation, with no defined mechanism, thereby remaining speculative and subject to significant limitations. Further studies are required to validate this proposed mechanism.

Furthermore, a study using whole-exome sequencing to compare the molecular profiles of gastric AC and gastric MiNEN found no clear mutation patterns that reliably distinguish the two entities[13]. These findings indicate that while AC and MiNEN are considered separate tumor types, they may share a common genetic origin. That said, the above hypothesis and observations are constrained by small sample sizes, and further validation using larger case series will be necessary.

Although AC has been described in sporadic pathological reports, most documented cases were identified at non-advanced stages and were amenable to surgical resection[14-19], as summarized in Table 2. Most patients with AC are older men, and the predilection sites are the cardia and gastric antrum. For non-advanced stages, the standard treatment strategy consists of surgery combined with chemotherapy. Based on the imaging characteristics, the present case represents a newly diagnosed advanced AC. However, data on disease progression characteristics and treatment response evaluation currently remain limited, hindering a comprehensive clinical understanding and optimal management of AC.

Table 2 Clinical characteristics and follow-up outcomes of patients with gastric amphicrine carcinoma.

Ref.	Case	Sex	Age (year)	Lesion location	Size (cm)	TNM staging	Stage	Treatment	Outcomes (month)
Li et al[14], 2026	1	Male	52	Gastric body	4.5	T4aN2M0	IIIA	Surgery + chemotherapy	AWD, 15
	2	Male	69	Gastric antrum	4.3	T3N3aM0	IIIB	Surgery + chemotherapy	DOD, 6
	3	Male	53	Gastric antrum	4.0	T4aN3aM0	IIIB	Surgery + chemotherapy	NED, 18
	4	Male	72	Gastric cardia	4.0	T3N1M0	IIB	Surgery + chemotherapy	NED, 17
Chen et al[15], 2025	5	Male	64	Gastric cardia	4.0	T3N1M0	IIB	Surgery + chemotherapy	NED, 8
	6	Male	70	Gastric cardia	3.0	T3N2M0	IIIA	Surgery + chemotherapy	NED, 49
	7	Male	62	Gastric antrum	3.0	T3N3M0	IIIB	Surgery + chemotherapy	NED, 27
Qian and Feng[16], 2022	8	Male	69	Gastric body/antrum	8.5	TxN3bM0	IIIC	Surgery + chemotherapy	NED, 6
Sciarra et al[17], 2023	9	Male	63	Gastric cardia	1.2	T1b(sm)NxM0	IA	Surgery	NED, 18
Huang et al[18], 2019	10	Male	61	Gastric body	5.5	T4N1M0	IIIA	Surgery + chemotherapy	NED, 63
	11	Male	58	Gastric antrum	NA	T2N0M0	IB	Surgery	NED, 10
	12	Male	63	Gastric antrum	3.0	T1N0M0	IA	Surgery	NED, 10
	13	Male	56	Gastric body	2.5	T4N2M0	IIIA	Surgery	DOD, 42
	14	Male	68	Gastric antrum	4.5	T4N3bM0	IIIC	Surgery + chemotherapy	NED, 12
	15	Male	60	Gastric cardia	2.0	T4N1M0	IIIA	Surgery	DOD, 11
	16	Male	67	Gastric cardia	3.5	T3N0M0	IIA	Surgery + chemotherapy	NED, 6
Gao et al[19], 2025	17	Male	59	Gastric body	1.5	T1b (sm)N0M0	IA	ESD only	NED, 6
Current case	18	Male	66	Gastric antrum	3.0	T4N1M1	IV	Immunotherapy + chemotherapy	DOD, 10

Stage is according to the AJCC 8^th edition gastric cancer staging system. AWD: Alive with disease; DOD: Dead of disease; ESD: Endoscopic submucosal dissection; NED: No evidence of disease; TNM: Tumor-node-metastasis.

In the present case, we provide extensive clinical data to help address this gap. Furthermore, integrated Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated enrichment of the estrogen signaling pathway in AC[13], which may partly explain the higher incidence observed in male patients.

However, the outcomes were notably poorer compared to conventional gastric adenocarcinoma, particularly during later-line treatments following disease progression. In the RATIONALE-305 study, the median PFS for patients receiving tislelizumab in combination with chemotherapy as a first-line treatment for gastric adenocarcinoma was 5.9 months[20]. For later-line management of advanced disease, the median PFS was reportedly approximately 4 months with FOLFIRI and 3.6 months with paclitaxel monotherapy, respectively[21,22]. By contrast, the patient in this case did not achieve comparable therapeutic outcomes, even with the addition of immunotherapy or targeted treatment.

Accordingly, advanced AC demonstrates a poor response to standard therapeutic approaches and is associated with an unfavorable prognosis. The observation implies that the biological behavior of AC is not merely a mixture of two tumor components, but rather may constitute a distinct and more aggressive neoplasm, which matches its updated pathological classification.

Additionally, in the late stage of disease, the patient progressed to LM, a rare complication in gastrointestinal malignancies. LM occurs in approximately 1%-8% of patients with cancer[23], and most commonly arises in late-stage cancers of the breast, lung and melanoma being the most common primary cancers[24]. There are multiple routes of LM. Malignant tumor cells can reach the subarachnoid space via hematogenous, lymphatic, perineural, or perivascular mechanisms, and may also disseminate by direct extension from brain, cranial, or spine metastases[25]. Following the diagnosis of leptomeningeal involvement, the average survival for gastric cancer patients is approximately 8 weeks[8], reflecting an extremely poor prognosis. In this case, even though brain MRI showed no obvious metastatic lesions, the neurological symptoms and seizures raised significant concern for leptomeningeal spread. Definitive confirmation relies on cytopathological examinations of the CSF. That said, CSF analysis may yield false-negative results, frequently requiring repeat lumbar punctures to collect adequate samples[26]. Cytology following the initial lumbar puncture has a diagnostic yield of approximately 50%-60%, whereas repeating the procedure can increase sensitivity and specificity to about 75%-80%[27]. In addition, contrast-enhanced MRI is still the most sensitive imaging technique for detecting LM, it usually shows abnormal leptomeningeal enhancement together with tiny nodular spots in the subarachnoid space. Therefore, quickly recognizing neurological symptoms and relevant imaging findings is essential for early diagnosis and timely management.

One limitation of this case report was the absence of an effective treatment regimen. Despite receiving sequential standard treatment modalities, including chemotherapy, immunotherapy, and targeted therapy, the patient’s overall survival from diagnosis was limited to 10 months. This outcome underscores the pressing need for further investigation of novel therapeutic approaches, supported by additional clinical evidence, to extend patient survival. With ongoing advances in our understanding of AC, more effective and individualized treatment strategies are likely to emerge.

CONCLUSION

Advanced gastric AC constitutes a highly aggressive malignancy that does not respond well to conventional therapies used for typical adenocarcinoma. As such, it should be considered as a distinct entity among mixed tumor types. Accurate diagnosis requires dual immunohistochemical staining for both glandular epithelial mucin and neuroendocrine markers. Furthermore, the development of LM carries an unfavorable prognosis; therefore, early detection through recognition of neurological symptoms, contrast-enhanced brain MRI, and CSF analysis is important to enable timely diagnosis.

ACKNOWLEDGEMENTS

We would like to thank this patient and his families for their understanding and support of this manuscript.