IgG4-related disease (RD) is an autoimmune-mediated disorder that involves different organs. A large amount of immune cell infiltration of the IgG4-related disease induced a focal mass that mimics a malignancy tumor in imaging examination (1). Especially in the pancreas, autoimmune pancreatitis has sometimes been misdiagnosed as pancreatic cancer (2). It is of great importance to distinguish IgG4-RD from tumors. Previous studies have validated the utility of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT in the differential diagnosis (3). Fibroblast activation protein is not only present in tumor stroma but also in some benign lesions with prominent fibroblast proliferation. ⁶⁸Ga-labeled fibroblast activation protein inhibitor (⁶⁸Ga-FAPI) is a novel PET agent. Some researchers have highlighted that ⁶⁸Ga-FAPI PET/CT would contribute to diagnosing IgG4-related disease (RD) (4), but few studies to date have compared the role of ¹⁸F-FDG PET/CT and ⁶⁸Ga-FAPI PET/CT in the follow-up of IgG4-RD. Here, we reported a case comparing the pre- vs. post- and ¹⁸F-FDG vs. ⁶⁸Ga-FAPI-04 images of an IgG4-RD patient who underwent the prednisone treatment.

A 57-year-old man with jaundice for 4 months, abdominal pain and diarrhea for 2 months was presented to the emergency department. He was diagnosed with suspected cholangiocarcinoma because of the thickening of the bile duct wall observed on contrast-enhanced CT. The ¹⁸F-FDG PET/CT and ⁶⁸Ga-FAPI-04 PET/CT were executed for the differential diagnosis and possible tumor staging (Figure 1 Maximum intensity projection images of ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 PET/CT). The pre-treatment ¹⁸F-FDG PET/CT pictures (Figures 2A–E) showed elevated uptake of the following lesions: cervical (SUVmax 4.7) and mediastinal lymph nodes (SUVmax 2.7), intrahepatic bile ducts (SUVmax 3.3), pancreas (SUVmax 3.0), and prostate (SUVmax 2.3). ⁶⁸Ga-FAPI-04 PET/CT was also performed, and higher uptake in most lesions mentioned above was observed except for the cervical and mediastinal lymph nodes, Besides that, submandibular glands were also involved (Figures 3A–E). The patient's total bilirubin was elevated to 94.7 µmol/L. The tumor marker CA19-9 was 204.63 U/ml. The amylase was 228 U/L, and the IgG4 was 26.2 g/L (reference range: 0.03–2.1 g/L). A loco-regional lymphadenectomy and biopsy were performed. According to the biopsy result of the cervical lymph nodes, the final diagnosis was classified as an IgG4-RD. Subsequently, treatment with oral prednisone was initiated. The initial dose was 40 mg/d which lasted for 2 weeks. Then reduced by 5 mg every week, until the final dose of 5 mg/d which was used for 6 months. One month after treatment with prednisolone, the value of IgG4 was decreased to 13.6 g/L, CA19-9 to 36.94 U/ml, and the total bilirubin was reduced to 29.8 µmol/L. The symptoms of jaundice were relieved remarkably. During the same period of time, a slight FDG-avid lesion was detected only in the right cervical lymph node (SUVmax 1.7) (Figures 2F–J), but the raised uptake of ⁶⁸Ga-FAPI-04 could still be observed in the pancreas (SUVmax 5.6) and submandibular glands (SUVmax 2.3) (Figures 3F–J).

The FDG accumulation is the reflection of glucose metabolism in the tumor or inflammation lesion. Considerable evidence has demonstrated the ability of ¹⁸F-FDG PET to assess IgG4-RD both at initial evaluation and after therapy (2, 3). ⁶⁸Ga-FAPI is thought to be the potential broad-spectrum tumor PET agent targeting FAP (5). Fibroblasts were activated in some benign diseases (6), such as IgG4-RD, and it can also be FAPI-positive.

In IgG4-RD, large quantities of fibroblasts lead to fibrosis in the extracellular matrix (7, 8). Some case reports and articles have also explored the utility of ⁶⁸Ga-FAPI PET/CT to assess IgG4-RD (8, 9). One study of 26 IgG4-RD patients revealed that ⁶⁸Ga-FAPI PET/CT detected more involved organs in 13 (50.0%) patients and significantly higher SUV than that of ¹⁸F-FDG PET/CT (4). However, FDG-avid lymph node did not accumulate ⁶⁸Ga-FAPI (4, 10). The two results were both validated in this case report. The mismatch of ⁶⁸Ga-FAPI and ¹⁸F-FDG revealed that the lesion was probably in different stages; the FDG-avid lesion was inflammatory-proliferative, while the ⁶⁸Ga-FAPI positive lesion was likely in a fibrotic phase. Another possible pathological reason is that fibrosis is rare in most lymphadenopathy patterns of IgG4-RD (11). Our previous study about pancreatic cancer found that ⁶⁸Ga-FAPI-04 PET/CT detected more positive lymph nodes whose activity was over background than ¹⁸F-FDG PET/CT (12). The critical parameters of ¹⁸F-FDG PET/CT for diagnosing malignant metastatic lymph nodes have been highly explored such as the SUVmax cut-off point, groups of lymph nodes, and the SUV value of tumor (13). But the utility of ⁶⁸Ga-FAPI in detecting malignant metastatic lymph nodes is still in the stage of development and in comparison with ¹⁸F-FDG (14).

After the prednisone treatment, slight uptake in cervical lymph node was only observed in ¹⁸F-FDG PET/CT, whereas uptake in pancreas and submandibular glands were more noticeable in the ⁶⁸Ga-FAPI-04 PET/CT. The laboratory test result of IgG4 of 13.6 g/L, which was also above the reference range, partly confirmed the involvement of IgG4-RD. In another cross-sectional clinical study with inflammatory, fibrotic and overlapping manifestations of IgG4-related disease, the responsiveness to immunosuppressive therapy was more sensitive in inflammatory lesions than in fibrotic lesions (15). This reason might explain the difference in ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG imaging after treatment with prednisone.

Notwithstanding its limitation, our case report found that ⁶⁸Ga-FAPI-04 could provide additional insights into IgG4-RD beyond the inflammation process that demonstrated by ¹⁸F-FDG. The combination of ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 may demonstrate even greater potency in the efficacy assessment of IgG4-RD in the future.