¹⁸F-AlF-NOTA-FAPI-04 PET/CT as a complementary tool for detecting occult signet-ring cell gastric adenocarcinoma when FDG imaging is inconclusive: a case report

Abstract

Background

Accurate identification of the primary site in metastatic cancer remains a significant challenge when conventional imaging, such as fluorine-18 fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT), yields inconclusive results. This issue is particularly evident in stroma-rich tumors, such as signet-ring cell carcinoma, which exhibit low glycolytic activity and are characterized by an abundance of cancer-associated fibroblasts (CAFs). ¹⁸F-AlF-NOTA-FAPI-04 PET/CT, which targets fibroblast activation protein (FAP), offers a promising alternative by providing detailed imaging of the tumor microenvironment (TME).

Case Description

A 34-year-old male presented with altered bowel habits and right inguinal lymphadenopathy. Histology of the lymph node revealed metastatic poorly differentiated carcinoma, suggesting gastrointestinal origin. However, abdominal CT and ¹⁸F-FDG PET/CT failed to identify the primary lesion, showing only mild gastric wall thickening with weak FDG uptake. One week later, fluorine-18 fibroblast activator protein inhibitor (¹⁸F-FAPI) PET/CT revealed significantly increased uptake in the gastric fundus and body, and a hypermetabolic lesion in the right iliopsoas muscle. Guided by these findings, targeted biopsies confirmed poorly differentiated gastric adenocarcinoma with signet-ring cell features. After eight cycles of capecitabine plus oxaliplatin (XELOX) chemotherapy over a 6-month period, follow-up ¹⁸F-FAPI PET/CT showed marked tumor regression.

Conclusions

¹⁸F-FAPI PET/CT can provide complementary biological and diagnostic information when ¹⁸F-FDG imaging is inconclusive, particularly in stroma‑rich gastric cancers with signet‑ring cell features. In this patient, FAPI PET/CT enabled targeted biopsy and demonstrated treatment response, suggesting its potential value in clinical management. Larger prospective studies are warranted to further define the role of ¹⁸F-FAPI PET/CT in the diagnostic algorithm of occult primary tumors.

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Key findings

• ¹⁸F-FAPI PET/CT can provide complementary biological and diagnostic information when ¹⁸F-FDG imaging is inconclusive, especially in stroma-rich gastric cancers with signet-ring cell features.

What is known and what is new?

• ¹⁸F-FDG PET/CT has limited sensitivity in signet-ring cell and diffuse-type gastric cancers because of low glycolytic activity and abundant desmoplastic stroma. Fibroblast activation protein (FAP) is highly expressed on cancer-associated fibroblasts (CAFs) in many epithelial tumours, including gastric cancer. By imaging the tumor microenvironment, ¹⁸F-FAPI PET/CT addresses the limitations of ¹⁸F-FDG PET/CT in low-FDG-avidity tumors. It may be a powerful complementary tool and, for signet-ring cell carcinoma with equivocal or negative FDG imaging, a preferred diagnostic alternative. Our ¹⁸F-AlF-NOTA-FAPI-04 tracer offers a logistical advantage over 68Ga-FAPI: the longer ¹⁸F half-life permits larger production batches and wider availability in high-volume centres.

What is the implication, and what should change now?

• ¹⁸F-FAPI PET/CT can complement ¹⁸F-FDG PET/CT when the latter is inconclusive, especially in stroma-rich gastric cancers with signet-ring cell features. It can help localize occult primary tumours, guide targeted biopsies, and monitor treatment response. The longer half-life and larger production capacity of ¹⁸F-labelled FAPI tracers may facilitate wider clinical adoption than ⁶⁸Ga-based agents. Clinicians should consider ¹⁸F-FAPI PET/CT in suspected gastric cancer with negative or inconclusive endoscopy and non-diagnostic ¹⁸F-FDG PET/CT. Because FAPI uptake is not entirely tumour-specific and may occur in inflammation or fibrosis, histopathological confirmation of FAPI-avid lesions remains essential whenever feasible.

Introduction

Accurately identifying the primary tumor in metastatic cancer remains a key challenge, especially when routine imaging examinations and fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) results are unclear. While ¹⁸F-FDG PET/CT is effective for detecting hypermetabolic tumors, its sensitivity is markedly reduced in stroma-rich gastrointestinal cancers, due to the tumor microenvironment (TME) of such tumors being mainly dominated by cancer-associated fibroblasts (CAFs) (1,2). In the histological subtype of signet ring cell carcinoma, which has typical low glycolytic activity, this limitation is further exacerbated. Therefore, we introduce a novel application of ¹⁸F-labelled fibroblast activator protein inhibitor (FAPI) PET/CT with paradigm shift significance in detecting occult gastric adenocarcinoma with atypical metastasis, demonstrating its superiority over traditional metabolic imaging techniques in matrix rich malignant tumors (3). We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0158/rc).

Case presentation

A 34-year-old male with no prior medical history presented to the outpatient clinic with a four-month history of altered bowel habits, including tenesmus and frequent defecation (6–8 times daily), in the absence of bleeding or discharge. Initial endoscopic evaluation revealed proctitis and internal hemorrhoids; biopsy specimens showed no evidence of malignancy. Subsequent gastroscopy identified a gastric ulcer at the angulus (suspected malignant), a gastric polyp, and chronic non-atrophic gastritis. Immunohistochemical staining was negative for Cam5.2 and CK8/18. During follow-up, the patient developed abdominal lymphadenopathy, prompting surgical lymph node dissection. The lymph nodes on the right side of the groin appear to be isolated and represent distant lymph nodes, as no other suspicious lymph node enlargement was found during the examination. Postoperative pathological examination confirmed metastatic poorly differentiated carcinoma. The immunohistochemistry (IHC) results—positive for CK7, Villin, and MUC1; negative for CK20, SATB-2, NKX3.1, PSA, and Pax-8—the findings were most consistent with a carcinoma of gastric origin. Despite this clue, both a subsequent abdominal CT and an ¹⁸F-FDG PET/CT scan proved non-diagnostic. The maximum intensity projection (MIP) of baseline ¹⁸F-FDG PET/CT showed physiological distribution without clear highlighting of the tumor lesions (Figure 1A). The PET/CT revealed only mild thickening of the gastric fundus and body with minimally elevated FDG uptake (Figure 1B), and no definitive primary gastric tumor was identified. Additionally, mildly increased FDG uptake was noted in the iliopsoas muscle (Figure 1C).

Figure 1.

18F-FDG PET/CT imaging. (A) MIP of baseline 18F-FDG PET/CT showing physiological distribution without clear highlighting of the tumor lesions. (B) Axial fused PET/CT image at the gastric level, displaying physiological hepatic and splenic distribution, with no obvious abnormal hypermetabolic focus. (C) Axial fused PET/CT image at the level of the iliopsoas muscle, demonstrating mildly increased focal uptake in the left iliopsoas muscle. 18F-FDG, fluorine-18 fluorodeoxyglucose; MIP, maximum intensity projection; PET/CT, positron emission tomography/computed tomography.

Considering the limitations of ¹⁸F-FDG PET/CT in the application of gastrointestinal tumors, one week later, ¹⁸F-FAPI whole-body PET/CT scan was conducted, revealing the MIP image (Figure 2A) revealed extensive and intense FAPI accumulation in the abdominal and pelvic cavities, predominantly involving the stomach and multiple intra-abdominal lesions suggestive of widespread metastasis. Significantly increased tracer uptake in the fundus and body of the stomach (Figure 2B), which suggested a high probability of a primary gastric tumor with metastasis. Additionally, a density with increased metabolic activity was observed in the right iliopsoas muscle (Figure 2C), indicating potential metastasis. The involvement of skeletal muscle is a rare event in gastric cancer, in stark contrast to its typical metastatic pattern to sites such as the liver, lymph nodes, or peritoneum. This unusual presentation significantly heightened the diagnostic difficulty, while also underscoring the capability of ¹⁸F-FAPI PET/CT to reveal otherwise occult disease. Following the ¹⁸F-FAPI PET/CT image guidance, multiple-point targeted biopsies were performed on the suspicious areas by gastroscopy. Pathological analysis ultimately confirmed the presence of poorly differentiated adenocarcinoma, including components of signet-ring cell carcinoma. Genetic testing results indicated the absence of target mutations and the IHC results: HER-2 staining was negative. Consequently, the patient underwent eight cycles of capecitabine plus oxaliplatin (XELOX) chemotherapy over a 6-month period. After chemotherapy, the patient was re-evaluated with ¹⁸F-FAPI PET/CT. The patient’s primary tumor and metastatic lesions demonstrated a significant regression (Figure 3A-3C), indicating that the current treatment regimen was significant treatment response. Therefore, the patient will undergo continuous maintenance therapy to achieve optimal therapeutic efficacy.

Figure 2.

18F-FAPI PET/CT imaging. (A) Whole-body MIP demonstrating extensive and diffuse abnormal radiotracer accumulation distributed throughout the abdominopelvic cavity, with multiple prominent foci. (B) Axial fused PET/CT image at the gastric level showing intense focal FAPI uptake corresponding to a gastric lesion. (C) Axial fused PET/CT image at the pelvic level revealing focal increased tracer accumulation involving the right iliopsoas muscle region. 18F-FAPI, fluorine-18 fibroblast activation protein inhibitor; MIP, maximum intensity projection; PET/CT, positron emission tomography/computed tomography.

Figure 3.

18F-FAPI PET/CT imaging after eight cycles of chemotherapy. (A) MIP image showing the overall systemic biodistribution of the tracer with no prominent abnormal accumulation in the abdominopelvic cavity. (B) Axial fused PET/CT image at the level of the stomach, demonstrating substantial regression of the primary gastric lesion with markedly reduced FAPI uptake compared to the baseline scan. (C) Axial fused PET/CT image at the level of the iliopsoas muscles, revealing significant shrinkage and nearly complete resolution of the previous hypermetabolic activity in the right iliopsoas lesion. 18F-FAPI, fluorine-18 fibroblast activation protein inhibitor; MIP, maximum intensity projection; PET/CT, positron emission tomography/computed tomography.

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 Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This case demonstrates the clinical utility of ¹⁸F-FAPI PET/CT in a diagnostically challenging patient with metastatic poorly differentiated gastric adenocarcinoma with signet-ring cell features. Several aspects of this case are particularly instructive: the failure of initial endoscopic biopsy to establish the diagnosis, the inconclusive findings on conventional imaging and ¹⁸F-FDG PET/CT, the successful localization of the primary tumor by ¹⁸F-FAPI PET/CT, and the subsequent targeted biopsy that confirmed the diagnosis. This indicates that FAPI PET/CT can serve as a supplementary method for diagnosing gastrointestinal tumors using FDG (4).

The limited sensitivity of ¹⁸F-FDG PET/CT in gastric cancer, particularly in signet-ring cell and diffuse-type carcinomas, is well documented (5). Several studies have demonstrated that FAPI PET/CT significantly outperforms ¹⁸F-FDG PET/CT in detecting primary gastric tumors and metastatic lesions (1,6). Our case aligns with these findings, showing a striking disparity between weak FDG uptake and intense FAPI uptakein the same gastric lesion. Beyond detection, this case uniquely demonstrates how FAPI imaging directly guides clinical procedures: from guiding gastroscopy biopsies to monitoring patient prognosis, this practical aspect is often overlooked in large-scale case series.

The right inguinal lymph node presentation in this case is unusual for gastric cancer, which typically metastasizes to perigastric, celiac, or supraclavicular nodes, liver, or peritoneum. This atypical metastatic pattern, coupled with the initial symptoms of tenesmus, initially suggested a lower gastrointestinal primary. However, the immunohistochemical profile (CK7+, CK20−, SATB2−) and negative colonoscopy ultimately supported a gastric origin. The identification of a suspected iliopsoas lesion on FAPI PET/CT further highlights the ability of this modality to reveal otherwise occult disease; but FAPI uptake is not entirely tumor-specific and can occur in inflammatory, fibrotic, degenerative, or traumatic processes (7). Subsequently, through imaging examinations, we confirmed that the right iliac psoas muscle injury was a metastatic lesion. Therefore, clinicians are advised to interpret FAPI-avid lesions with due caution and to seek additional confirmatory evaluation whenever clinically indicated.

The biological rationale for FAPI PET/CT lies in its targeting of fibroblast activation protein (FAP), a transmembrane serine protease that is highly expressed on CAFs in over 90% of epithelial-derived tumors, including gastric cancer (8). In contrast to ¹⁸F-FDG, which reflects glycolytic metabolism of tumor cells, FAPI uptake reflects the stromal response—a complementary biological dimension. This distinction is critical: FAPI PET/CT does not measure tumor “metabolic activity” in the same sense as FDG, but rather provides a molecular readout of the tumor microenvironment (9). In stroma-rich tumors such as signet-ring cell carcinoma, where tumor cells are dispersed within a prominent desmoplastic stroma, FAP expression on CAFs can be substantially higher than the glycolytic activity of the sparse tumor cells themselves, potentially explaining the superior lesion conspicuity observed with FAPI imaging (1).

¹⁸F-FAPI is a radioactive tracer targeting FAP, with a structure that binds to FAP’s active site for PET/CT imaging. Unlike ¹⁸F-FDG PET/CT, which has limitations due to its reliance on tumor glycolysis, ¹⁸F-FAPI PET/CT scan precisely image the TME by reflecting CAF activation. It demonstrates higher sensitivity in the diagnosis of gastric cancer (10). It also has lower background uptake in tissues like the heart and brain, reducing false positives. Additionally, ¹⁸F-FAPI PET/CT contributes to distinguish different cancer types (11).

Following eight cycles of XELOX chemotherapy, follow-up ¹⁸F-FAPI PET/CT demonstrated a significant reduction in both primary tumor and suspected metastatic (Figure 3A-3C). This suggests that FAPI PET/CT may have utility in monitoring treatment response, although this observation from a single case is preliminary and requires validation in larger prospective studies.

This case has several limitations that should be acknowledged. IT’s a single case report, and findings cannot be generalized. We did not perform FAP IHC or CAF quantification on the biopsy specimens, so the mechanistic link between FAPI avidity and tumor stromal composition remains speculative for this particular patient. The follow-up period after chemotherapy is relatively short, and long-term outcomes remain unknown. Despite these limitations, this case provides a compelling real-world example of how ¹⁸F-FAPI PET/CT can complement conventional imaging in diagnostically challenging cases, with direct implications for patient management.

Conclusions

This case illustrates that ¹⁸F-FAPI PET/CT can provide complementary biological and diagnostic information when ¹⁸F-FDG imaging is inconclusive, particularly in stroma-rich gastric cancers with signet-ring cell features. By enabling targeted biopsy and demonstrating treatment response, ¹⁸F-FAPI PET/CT proved valuable in the clinical management of this patient. We need to conduct larger-scale prospective studies to further clarify the role of ¹⁸F-FAPI PET/CT in the diagnostic process of occult primary tumors, and to establish its practicality as a biomarker for treatment monitoring.

Supplementary

The article’s supplementary files as

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 Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.