FAPI PET/CT Imaging-An Updated Review

Abstract

Despite revolutionizing the field of oncological imaging, Positron Emission Tomography (PET) with [¹⁸F]Fluorodeoxyglucose (FDG) as its workhorse is limited by a lack of specificity and low sensitivity in certain tumor subtypes. Fibroblast activation protein (FAP), a type II transmembrane glycoprotein, is expressed by cancer-associated fibroblasts (CAFs) that form a major component of the tumor stroma. FAP holds the promise to be a pan-cancer target, owing to its selective over-expression in a vast majority of neoplasms, particularly epithelial cancers. Several radiolabeled FAP inhibitors (FAPI) have been developed for molecular imaging and potential theranostic applications. Preliminary data on FAPI PET/CT remains encouraging, with extensive multi-disciplinary clinical research currently underway. This review summarizes the existing literature on FAPI PET/CT imaging with an emphasis on diagnostic applications, comparison with FDG, pitfalls, and future directions.

Keywords: FAPI; PET/CT; diagnostic; fibroblast activation protein (FAP); imaging; theranostics.

Figure 1

Maximum intensity projection PET images demonstrating the physiological distribution of [⁶⁸Ga]Ga-FAPI-04 in two representative cases. Low-grade uterine uptake (green arrow) noted in a 55-year-old post-menopausal woman (A) is in stark contrast to the intense uterine uptake (red arrow) noted in a 42-year-old premenopausal woman (B).

Figure 2

[⁶⁸Ga]Ga-FAPI-04 and FDG PET/CT images in a 59-year-old woman with biopsy-proven metastatic left lung adenocarcinoma. [⁶⁸Ga]Ga-FAPI-04 PET/CT images revealed intensely tracer avid left hilar mass lesion ((B)—green arrow), multiple enlarged mediastinal ((A,C)—green arrows) lymph nodes, and bilateral adrenal metastases ((A,D)—green arrows depicting left adrenal lesion). Additionally, moderate left-sided pleural effusion with associated left lung lower lobe collapse was noted. Overall, FAPI PET/CT demonstrated higher tracer avidity and TBRs than FDG PET/CT ((E–H)—red arrows).

Figure 3

FDG and [⁶⁸Ga]Ga-FAPI-04 PET/CT images in a 42-year-old woman with biopsy-proven gastric adenocarcinoma. The primary lesion in the stomach showed no abnormal FDG uptake ((A,C)—red arrows) with intense [⁶⁸Ga]Ga-FAPI-04 tracer avidity ((B,D)—green arrows). FAPI PET/CT revealed a tracer avid hypodense lesion in segment V of the liver ((B,F)—green arrows), which was not picked up on FDG PET/CT ((E)—red arrow), leading to upstaging of disease. Additionally, the uterus showed no abnormal FDG uptake ((G)—red arrow) but had diffuse intense FAPI uptake ((H)—green arrow), which was interpreted as physiologic/benign uptake.

Figure 4

Incremental role of [⁶⁸Ga]Ga-FAPI-04 PET/CT over FDG PET/CT in a 42-year-old woman with metastatic gastric adenocarcinoma for post-chemotherapy response assessment. Baseline (A) and follow-up (C) FDG PET/CT scans did not reveal significant abnormal tracer uptake in the primary and metastatic lesions. Baseline [⁶⁸Ga]Ga-FAPI-04 PET/CT (B) showed tracer avid gastric primary (green arrow), abdominal lymph nodes (orange arrow), and solitary liver metastasis (red arrow). Post-chemotherapy [⁶⁸Ga]Ga-FAPI-04 PET/CT (D) demonstrated minimal tracer avidity in the gastric primary (green arrow) with resolution of tracer avidity in the abdominal lymph nodes (orange arrow) and liver lesion (red arrow), suggesting a favorable response to treatment.

Figure 5

FDG and [⁶⁸Ga]Ga-FAPI-04 PET/CT in a 33-year-old man with histopathologically proven mucinous adenocarcinoma of appendix post cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, and platin-based adjuvant chemotherapy. FDG PET/CT (A) did not reveal significant abnormal tracer uptake. However, FAPI PET/CT (B) performed two days later revealed multiple tracer avid paracolic gutter, omental, peritoneal, and liver metastases (green arrows). Palliative chemotherapy with capecitabine and oxaliplatin was started. Subsequent response assessment was performed after 3 cycles of this second-line chemotherapy. FDG PET/CT (C) underestimated disease burden when compared with FAPI PET/CT (D), which showed few new peritoneal deposits (red arrows) in addition to pre-existing lesions (green arrows), suggestive of disease progression. This impacted management as the patient was started on third-line agents, irinotecan and panitumumab.

Figure 6

[⁶⁸Ga]Ga-FAPI-04 performed better than FDG PET/CT for initial staging in a 51-year-old woman with histopathologically proven triple receptor-negative invasive breast cancer. FDG PET/CT (A) revealed mildly tracer avid right breast primary ((C)—red arrow) with few faintly FDG avid right axillary lymph nodes ((A)—red arrow). FAPI PET/CT (B) demonstrated intensely tracer avid right breast primary ((D)—green arrow), multiple right axillary lymph nodes ((B)—green arrows), and few lytic skeletal lesions such as one involving the left transverse process of C2 vertebra ((F)—green arrow), which showed no abnormal FDG uptake ((E)—red arrow).

Figure 7

Forty-four-year-old woman, a known case of epithelial ovarian carcinoma post hysterectomy and bilateral salpingo-oophorectomy, underwent FDG and [⁶⁸Ga]Ga-FAPI-04 PET/CT for restaging. FAPI tracer avid ((C,D)—green arrows) and non-FDG avid ((A,B)—red arrows) ill-defined soft tissue density nodule (~1 × 0.8 cm) was noted in the upper outer quadrant of the left breast, which was corroborated on the fused PET-MR mammogram images ((E,F)—green arrows). Subsequently, an ultrasound-guided left breast biopsy was performed which showed invasive lobular carcinoma with ER/PR positive and HER2 negative receptor status.

Figure 8

Forty-seven-year-old woman, a known case of ovarian carcinoma (clear cell type) post-surgery and adjuvant platin-based chemotherapy had rising serum CA-125 levels. She underwent [⁶⁸Ga]Ga-FAPI-04 and FDG PET/CT for restaging, which revealed a heterogeneously enhancing lesion (~5.1 × 3.5 cm) in segment VII of the liver ((C,F)—green arrows) with intense FAPI uptake ((A,B,E)—green arrows) and no significant FDG uptake ((D,G,H)—red arrows) suggestive of liver metastasis.