Abnormal adnexal uptake in 68Ga-FAPI PET/CT: from physiological variants to malignant characterization

Figure 1 presents the study flowchart. A total of 121 female patients (mean age: 53.8 ± 12.2 years; range: 18–80 years) were included. We identified 184 adnexal lesions with abnormal 68 Ga-FAPI uptake. Bilateral uptake was observed in 63 patients, and unilateral uptake in 58 patients (31 left, 27 right). Based on the reference standard, 100 patients (82.6%) were confirmed as having malignant, including 84 with primary malignancies and 16 with metastases. Additionally, we identified 2 borderline tumors, 7 benign lesions, and 12 cases attributed to physiological uptake. Detailed patient demographics are summarized in Table  1 . Fig. 1 Study flowchart. FAPI = fibroblast activation protein inhibitor Study flowchart. FAPI = fibroblast activation protein inhibitor Table 1 Patient demographics ( n  = 121) Age, mean ± SD (range) 53.8 ± 12.2 (18–80 years) Lesion location  Bilateral 63  Unilateral 58   left-sided 31   right-sided 27 Biochemistry of tumor markers  CEA (> 5 ng/ml) 28 (22.3%)  CA125 (> 38 U/ml) 106 (97.5%)  CA153 (> 19 U/ml) 79 (69.4%)  CA199 (> 34U/ml) 53 (47.1%) Histopathological parameters  Ki-67 expression    30% 69  p53 expression 75 Final Diagnosis  High-grade serous carcinoma 69 (57.0%)  Metastatic 16 (13.2%)  Physiological uptake 12 (9.92%)  Clear cell carcinoma 5 (4.13%)  Endometrioid carcinoma 4 (3.30%)  Teratoma 3 (2.48%)  Low-grade serous carcinoma 2 (1.66%)  Mucinous adenocarcinoma 2 (1.66%)  Borderline tumor 2 (1.66%)  Abscess 2 (1.66%)  Small cell carcinoma 1 (0.83%)  Yolk sac tumor 1 (0.83%)  Serous Cystadenofibroma 1 (0.83%)  Luteal cyst 1 (0.83%) Patient demographics ( n  = 121) The characteristics of the adnexal lesions are detailed in Table  2 . Among the malignancies, high-grade serous ovarian carcinoma was the most prevalent subtype, accounting for 57.0% of cases. Malignancies (primary and metastatic) exhibited predominantly solid or cystic-solid morphology (Fig.  2 ), with mean SUVmax values of 12.52 ± 5.41 and 9.78 ± 3.39, and mean diameters of 7.59 ± 3.96 cm and 5.43 ± 3.42 cm, respectively. In contrast, uptake of non-malignancy uptake (including physiological variations, cysts, abscesses, borderline tumors, mature teratomas, and serous cystadenofibroma) was predominantly cystic (Fig.  3 ), with a significantly lower mean SUVmax of 5.52 ± 4.17 and a mean diameter of 5.31 ± 5.94 cm. A statistically significant difference in SUVmax was observed among the three groups (Welch’s F (2, 38.01) = 20.69, p  < 0.001). Specifically, SUVmax was significantly higher for primary malignancies than for both non-malignancy ( p  < 0.001) and metastases ( p  = 0.032). Furthermore, metastatic lesions demonstrated significantly higher SUVmax than non-malignancy ( p  = 0.004). No significant difference in mean lesion diameter was observed among the three groups ( p  > 0.05) (Fig. 4 ). Table 2 Characteristics of abnormal adnexal uptake Diagnosis N Density Diameter (cm) SUVmax TBR Primary malignancy 84 solid/cystic-solid 7.59 ± 3.96 12.52 ± 5.41 15.50 ± 6.13 Metastasis 16 solid/cystic-solid 5.43 ± 3.42 9.78 ± 3.39 12.38 ± 4.05 Non-malignancy 21 cystic/cystic-solid 5.31 ± 5.94 5.52 ± 4.17 6.79 ± 4.62 SUVmax Standardized Uptake Value Maximum, TBR Target to Liver Ratio, Non-malignancy including physiological variations, benign and borderline lesions Characteristics of abnormal adnexal uptake SUVmax Standardized Uptake Value Maximum, TBR Target to Liver Ratio, Non-malignancy including physiological variations, benign and borderline lesions Fig. 2 Adnexal uptake of malignancy on 68 Ga-FAPI PET/CT (Dashed arrow, adnexal lesions; Arrow, uterine uptake). OYST, yolk sac tumor; OEC, Endometrioid Carcinoma; OCCC, Clear Cell Carcinoma; LGSC, Low-grade Serous Carcinoma; HGSC, High-grade Serous Carcinoma; MOC, Mucinous Adenocarcinoma Adnexal uptake of malignancy on 68 Ga-FAPI PET/CT (Dashed arrow, adnexal lesions; Arrow, uterine uptake). OYST, yolk sac tumor; OEC, Endometrioid Carcinoma; OCCC, Clear Cell Carcinoma; LGSC, Low-grade Serous Carcinoma; HGSC, High-grade Serous Carcinoma; MOC, Mucinous Adenocarcinoma Fig. 3 Adnexal uptake of non-malignancy on 68 Ga-FAPI PET/CT (Dashed arrow, adnexal lesions; Arrow, uterine uptake) Adnexal uptake of non-malignancy on 68 Ga-FAPI PET/CT (Dashed arrow, adnexal lesions; Arrow, uterine uptake) Fig. 4 Comparative 68 Ga-FAPI PET/CT imaging and pathological sections ( A ); Quantitative comparisons of SUVmax ( B ) and TBR ( C ) across the Primary Malignancy, Metastatic Malignancy, and Non-malignancy Comparative 68 Ga-FAPI PET/CT imaging and pathological sections ( A ); Quantitative comparisons of SUVmax ( B ) and TBR ( C ) across the Primary Malignancy, Metastatic Malignancy, and Non-malignancy The positive predictive value of abnormal adnexal 68 Ga-FAPI uptake for malignancy was 83.5%. ROC curve analysis demonstrated that SUVmax alone yielded an AUC of 0.85 for diagnosing malignancy. Diagnostic performance improved when SUVmax was combined with serum tumor markers, achieving an AUC of 0.89 (Fig.  5 ). Fig. 5 ROC curves for tumor markers, SUVmax, and their combination ROC curves for tumor markers, SUVmax, and their combination Tumor marker levels measured within one week prior to PET/CT were analyzed. Elevated levels were observed in a subset of patients (CEA: 28, CA125: 106, CA15-3: 79, CA19-9: 53), with the majority occurring in the malignant group (CEA: 23, CA125: 91, CA15-3: 66, CA19-9: 44). No significant correlation was found between the degree of elevation (stratified into  10-fold) of any tumor marker and the PET parameters SUVmax or TBR ( p  > 0.05 for all). Immunohistochemistry data were available for 86 lesions (from biopsy or surgical specimens). Among 75 lesions with available data, the mean p53 expression rate was 64% ± 25%. Excluding tumor types with fewer than 3 cases, the mean Ki-67 proliferation index was approximately 57% for high-grade serous carcinoma, 42% for clear cell carcinoma, and 38% for endometrioid carcinoma. Spearman’s rank correlation analysis revealed a statistically significant positive correlation between SUVmax and both Ki-67 ( r  = 0.361, p  < 0.001) and p53 expression rate ( r  = 0.419, p   20% (a commonly used clinical threshold) demonstrated a significantly higher mean SUVmax than those with Ki-67 ≤ 20% ( p  < 0.001). Table 3 Correlation between 68 Ga-FAPI PET/CT parameters and Ki-67, p53 parameters Ki-67 P53 r p r p SUVmax 0.361 ** < 0.001 0.419 ** < 0.001 TBR 0.372 ** < 0.001 0.431 ** < 0.001 **. Correlation is significant at the 0.01 level; r . correlation coefficient Correlation between 68 Ga-FAPI PET/CT parameters and Ki-67, p53 **. Correlation is significant at the 0.01 level; r . correlation coefficient

This retrospective study analyzed all female patients who underwent 68 Ga-FAPI PET/CT at the Department of Nuclear Medicine of our hospital from November 2021 to June 2024 for oncological evaluation (e.g., staging, restaging, or detection of unknown primary tumors based on clinical suspicion). From this cohort, clinical data were systematically reviewed using a standardized case report form. The recorded data included patient demographics, clinical symptoms, levels of serum tumor markers (CA125, CA19-9, CA15-3, CEA) measured within one week prior to the PET/CT scan, and detailed histopathological reports when available. Inclusion criteria were as follows: (1) female patients aged 18–80 years; (2) presence of newly discovered abnormal uptake in the adnexal region on PET/CT, with the nature of the lesion undetermined at the time of imaging. Exclusion criteria were: (1) history of reproductive system tumors; (2) history of prior surgery or specific treatment (e.g., chemotherapy, radiotherapy) targeting the adnexal region in question; (3) lack of definitive pathological confirmation or sufficient follow-up data (≥ 6 months) to determine the final nature of the adnexal lesion. Histopathological analysis (from biopsy or surgical specimens) served as the gold standard for diagnosis whenever possible. For lesions with pathological confirmation, immunohistochemical markers relevant to tumor grading and prognosis, specifically p53 expression status and the Ki-67 proliferation index, were documented from pathology reports. For patients without pathological verification, a composite clinical-imaging reference standard was used. Follow-up assessments consisted primarily of ultrasound, contrast-enhanced CT or pelvic MRI, combined with clinical evaluation and serum tumor marker tests. The first follow-up was typically conducted within 3 months after the PET/CT scan, with subsequent evaluations every 3 to 6 months thereafter. A minimum follow-up of 6 months was required for inclusion in the final analysis to ensure reliable determination of the lesion’s biological behavior. Adnexal lesions were considered malignant based on the following criteria: (a) typical malignant characteristics confirmed by imaging and laboratory tests; (b) clear evidence of significant disease progression on serial imaging studies during follow-up; or (c) substantial remission of the lesion following institution of anti-cancer therapies (e.g., chemotherapy, radiotherapy, targeted therapy, immunotherapy). Benign lesions were defined as those showing stability or regression without specific anti-tumor treatment over the follow-up period. This study was approved by the hospital ethics committee, and written informed consent was obtained from all patients. Two experienced nuclear medicine physicians conducted a consensus evaluation of the 68 Ga-FAPI PET/CT images. Any adnexal uptake exceeding background blood pool activity was included in the study. For patients with bilateral lesions, the lesion with the highest SUVmax was selected as the representative lesion for that patient. The maximum diameter of each lesion was measured, and a fixed circular region of interest (ROI, 1.5 cm in diameter) was delineated in the area of highest uptake. Tracer uptake was quantified using the maximum standardized uptake value (SUVmax). To obtain background activity, the mean standardized uptake value (SUVmean) was measured by placing a 3-cm spherical volume of interest (VOI) within the right lobe of the liver, carefully avoiding major blood vessels and biliary structures. The tumor-to-background ratio (TBR) was calculated as SUVmax (tumor) / SUVmean (liver). The diagnostic efficacy of 68 Ga-FAPI PET/CT for adnexal malignancy was assessed by comparison with final pathology results and/or follow-up findings. Statistical analyses were performed using GraphPad Prism 7.0 and IBM SPSS Statistics 23.0. A p -value < 0.05 was considered statistically significant. Continuous variables were assessed for normality using the Shapiro-Wilk test and for homogeneity of variances using Levene’s test. Normally distributed data are presented as mean ± SD, and non-normally distributed data as median (interquartile range). Categorical variables are expressed as frequencies and percentages. ROC curve analysis with area under the curve (AUC) was used to evaluate the diagnostic accuracy of PET parameters. For two-group comparisons, the independent-samples t-test (normal distribution) or Mann-Whitney U test (non-normal) was used. For multiple group comparisons: one-way ANOVA with Tukey’s post hoc test when normality and homogeneity of variances were satisfied; Welch’s ANOVA with Games-Howell post hoc test when variances were unequal; and Kruskal-Wallis H test with Dunn’s post hoc test for non-normally distributed data. Correlations between PET parameters and tumor markers or immunohistochemical indices were assessed using Pearson (normal distribution) or Spearman (non-normal) correlation coefficients.

In conclusion, 68 Ga-FAPI PET/CT is a molecular imaging technique with high diagnostic efficacy for adnexal lesions. Its quantitative parameters, SUVmax and TBR, can not only effectively differentiate benign from malignant lesions, but also serve as non-invasive biomarkers reflecting stromal activation associated with tumor proliferative activity and p53 status, providing a new dimension for preoperative risk assessment. Combining these parameters with serum tumor markers can further optimize diagnostic accuracy. The results of this study provide strong evidence supporting the application of 68 Ga-FAPI PET/CT in the precise diagnosis and individualized management of adnexal lesions, particularly in challenging cases.

This study systematically evaluated the diagnostic value of 68 Ga-FAPI PET/CT for focal abnormal uptake in the female adnexal region with a relatively large sample size, and further explored the association between its quantitative parameters and tumor biomarkers. The results indicate that 68 Ga-FAPI PET/CT has high diagnostic efficacy for malignant adnexal tumors. Its semi-quantitative parameters, SUVmax and TBR, not only effectively differentiate benign from malignant lesions but also show a modest but statistically significant positive correlation with key immunohistochemical markers reflecting tumor proliferative activity (Ki-67) and malignant transformation (p53). The modest strength of these correlations suggests that while 68 Ga-FAPI uptake is associated with proliferative activity and p53 status, it is not a direct surrogate for these markers. Although 18 F-FDG PET/CT has been widely used for malignant tumors, its specificity in the female adnexal region is limited [ 20 ]. Physiological uptake (such as menstrual cycle-related ovarian changes) and benign inflammatory lesions often lead to false positives. 68 Ga-FAPI targets activated cancer-associated fibroblasts (CAFs) in the tumor microenvironment, which are expressed at extremely low levels in normal ovarian tissue [ 21 , 22 ]. CAFs play a significant role in tumor proliferation, invasion, and metastasis by secreting various growth factors and cytokines and degrading extracellular matrix proteins [ 23 ]. Lactate and ketone bodies produced by CAFs are transported to adjacent tumor cells to fuel glycolysis, further promoting tumor proliferation and metastasis [ 17 , 24 ]. For patients with adnexal masses but atypical features on conventional imaging, 68 Ga-FAPI PET/CT can provide crucial molecular-level information to assist in characterization. Semi-quantitative parameter thresholds can serve as decision-support tools, helping to avoid unnecessary invasive procedures. This study confirmed that the SUVmax of malignancies was significantly higher than that of benign lesions, providing a reliable quantitative basis for differential diagnosis. Cihan et al. evaluated FAPI uptake in healthy tissues of cancer patients, reporting that normal ovaries had an average FAPI uptake of 1.7 (SUVmax 0.3–5.87), while glandular cells in the fallopian tubes showed moderate FAP expression with no significant differences between premenopausal and postmenopausal women [ 21 ]. Notably, while the literature suggests that baseline expression of FAP in normal ovarian tissue is not affected by the menstrual cycle [ 25 ], the physiological uptake observed in this study (e.g., in the corpus luteum) indicates that cycle-related physiological structures or benign lesions themselves may become sources of FAPI uptake due to local repair, angiogenesis, and other processes accompanied by fibroblast activation [ 26 , 27 ]. Therefore, the key to interpreting abnormal adnexal FAPI uptake lies in differentiating “pathological” from “non-malignancy”activation, rather than simply identifying malignancy. The SUVmax differences and TBR values established in this study provide an objective reference for this purpose. Another important finding of this study is the positive correlation between SUVmax and both the Ki-67 index and p53 expression. This finding is not coincidental but is rooted in the biological function of FAP. CAFs are core regulators of the tumor microenvironment, directly promoting tumor proliferation, invasion, and metastasis by secreting growth factors, cytokines, and remodeling the extracellular matrix. A high Ki-67 index indicates active tumor cell proliferation [ 28 , 29 ], and this state is often accompanied by a more activated stromal environment. Similarly, p53 mutation or loss leads to genomic instability and malignant progression [ 30 ], and such highly malignant tumor clones typically recruit more CAFs to support their growth. Therefore, the high uptake of 68 Ga-FAPI, which reflects CAFs activity, is associated with Ki-67 and p53. This association reveals the synergistic co-evolution between activated stroma and tumor invasiveness during disease progression. This result suggests that imaging information from 68 Ga-FAPI PET/CT may non-invasively reflect the intrinsic invasiveness potential of the tumor. In this study, there was no significant correlation between serum tumor marker levels and SUVmax. Although CA125 was elevated in 90% of malignant cases, its well-documented rise in various benign conditions (such as endometriosis and pelvic inflammatory disease) limits its diagnostic specificity [ 31 , 32 ]. This lack of correlation underscores that these biomarkers and FAPI uptake reflect fundamentally distinct biological processes. For example, serum CA125 is a glycoprotein secreted into the systemic circulation, indicative of tumor burden and secretory activity, whereas SUVmax on 68 Ga-FAPI PET/CT quantifies the localized density of activated cancer-associated fibroblasts within the tumor microenvironment. Consequently, they provide complementary rather than overlapping information. Their combination offers complementary diagnostic value, as supported by our data showing that combining SUVmax with markers such as CA125 increased the diagnostic AUC from 0.85 (SUVmax alone) to 0.89. Several limitations should be acknowledged. First, the retrospective design may introduce selection bias; all patients underwent PET/CT due to suspected malignancy, which may overestimate the performance of FAPI in truly incidental lesions. Second, the lack of a direct head-to-head comparison with ¹⁸F-FDG PET/CT prevents a quantitative assertion within this dataset that 68 Ga-FAPI is superior to 18 F-FDG, although theoretical advantages exist. Third, the number of cases with benign and borderline tumors is relatively small. Larger samples are needed in the future to further refine the uptake characteristics of various lesions. Finally, whether FAPI uptake can independently predict treatment response and prognosis requires verification through prospective follow-up studies.

Statistics show that up to 35% of premenopausal women and 17% of postmenopausal women carry adnexal lesions, with a trend toward onset at a younger age [ 1 ]. These lesions encompass a spectrum of changes from benign to malignant. When evaluating adnexal lesions, the primary considerations are whether emergency surgical intervention is necessary and the potential impact on fertility. Secondary considerations include differentiation between benign and malignant lesions, as well as staging. Ovarian malignancies, given their subtle onset, are often diagnosed at advanced stages. They have the highest mortality rate among gynecological cancers, posing a severe threat to women’s health and survival [ 2 , 3 ]. Tumor markers play a crucial role in disease prevention, diagnosis, treatment, and prognosis. Serum CA125 is the most widely used indicator for assessing ovarian lesions, with abnormal elevation in approximately 80% of patients with epithelial ovarian cancer (EOC) or fallopian tube cancer, particularly in postmenopausal women [ 4 – 6 ]. A meta-analysis revealed that CA125 has a sensitivity of 69–87% and a specificity of 81–93% for detecting cancer in postmenopausal women. However, up to 20% of patients still exhibit normal CA125 levels, and the marker is not expressed in pure mucinous carcinoma [ 7 ]. Other markers, such as CEA, CA153, and CA199, also provide some indication of adnexal lesions, but their specificity is relatively low. Therefore, accurate diagnosis requires comprehensive evaluation combining these markers with other clinical information [ 8 ]. Compared with conventional imaging, molecular imaging techniques—particularly positron emission tomography/computed tomography (PET/CT)—can provide deeper insights into disease heterogeneity and biological characteristics. PET/CT has been incorporated into routine protocols for preoperative evaluation and postoperative follow-up of ovarian cancer. 18 F-FDG remains currently the most widely used PET tracer. However, its specificity is relatively low, especially in the female reproductive system [ 9 – 12 ]. Certain physiological changes, such as follicular cysts and hemorrhagic corpus luteum, can result in false-positive 18 F-FDG uptake. This not only leads to potential misdiagnosis but may also obscure underlying pathological changes [ 9 , 13 , 14 ]. Bacanovic et al. reported a case where a hemorrhagic follicle mimicked a malignant tumor on 18 F-FDG imaging [ 15 ]. In a study by Minamimoto et al., 80 women underwent 18 F-FDG PET/CT screening for suspected ovarian cancer, with 19 cases were subsequently confirmed as benign [ 16 ]. These findings underscore the limitations of 18 F-FDG PET/CT in accurately detecting lesions within the female reproductive system. In recent years, 68 Ga-FAPI has been widely used in PET imaging and has demonstrated exceptional performance in early tumor detection, treatment planning, and postoperative assessment [ 17 ]. Fibroblast activation protein (FAP), a type II transmembrane serine protease, is absent or minimally expressed in normal adult tissues but is highly expressed in cancer-associated fibroblasts in over 90% of epithelial tumors. Its presence correlates with tumor invasiveness and poor prognosis. Previous research has shown that 68 Ga-FAPI PET/CT exhibits a favorable target-to-background ratio in the female reproductive system, characterized by high tumor uptake and low background activity. The maximum standardized uptake value (SUVmax) for ovarian cancer has been reported to range from 6 to 10, although with significant interindividual variability [ 17 ]. However, studies directly evaluating adnexal tumors and non-neoplastic conditions using 68 Ga-FAPI remain limited. Distinguishing the nature of abnormal uptake in the adnexal region, whether physiological, inflammatory, or tumor-related, remains an urgent challenge for clinicians and nuclear medicine specialists. Previous studies have established correlations between p53 and Ki-67 expression and radiotracer uptake on 18 F-FDG PET/CT [ 18 , 19 ]. However, the relationship between 68 Ga-FAPI uptake and immunohistochemical findings remains inconclusive. This study retrospectively analyzes 68 Ga-FAPI PET/CT images to determine the clinical significance of increased abnormal uptake in the adnexal region. It further explores the diagnostic efficacy of 68 Ga-FAPI PET/CT in conjunction with common tumor markers and immunohistochemical indicators, aiming to provide valuable reference information for the future diagnosis and treatment of adnexal diseases.