Sarcomas are a heterogeneous group of malignant tumors arising from mesenchymal cells. According to the World Health Organization (WHO), they now comprise over 50 histologic subtypes. Soft Tissue Sarcomas, or STS, constitutes an extremely rare and heterogeneous group of tumors; thus, the prognosis in metastatic disease is abysmal, with median OS at 8-12 months only. Metastasis usually occurs in the lungs, bones, and lymph nodes.
Because sarcomas are so heterogeneous and complex, high-resolution imaging has been critical to aid in their diagnosis, staging, and designing treatment protocols. The standard techniques currently employed that have proven robust include CT, MRI, and more recently, the 18F-FDG PET/CT scan. FAPI PET CT scan with its latest upgrades holds great potential and eliminates the issues with a few previous investigations.
Imaging in the Treatment of Sarcoma
18F-FDG PET/CT: 18F-fluorodeoxyglucose 18F-FDG PET/CT is used in the treatment of sarcoma for the following:
- Detection of local recurrence and metastasis.
- Follow-up assessment for response to treatment.
- Prognostic assessment.
Though the mentioned advantages are achieved, 18F-FDG PET/CT also has its limitations:
- False Positives: Physiologic uptake and inflammatory response lead to frequent false positives
- False Negatives: Hyperglycemia acts as an interfering agent in its sensitivity.
- Subtype Sensitivity: 18F-FDG cannot detect all the subtypes of sarcomas, especially low-grade.
Fibroblast Activation Protein (FAP) in Sarcomas
Fibroblast activation protein or FAP is a type II transmembrane serine protease, and it is largely overexpressed in more than 90% of sarcomas. The localization of FAP mainly takes place in cancer-associated fibroblasts or CAFs that are a part of the tumor microenvironment, and it acts as a supportive factor in tumorigenesis and growth.

In contrast most normal tissues, where FAP expression is minimal, the abundance of this protein in sarcomas will make it an excellent target for imaging and therapeutic interventions. This distinction has led to the development of FAPI-based imaging modalities such as 68Ga-FAPI PET/CT that have superior diagnostic accuracy.
Advantages of 68Ga-FAPI PET/CT on Sarcoma Imaging
1. High Sensitivity and Specificity
68Ga-FAPI PET/CT is highly sensitive with the PPV being higher compared to 18F-FDG PET/CT. Such a high degree of accuracy in detection is very crucial for the identification of recurrences.
2. Higher Tumor-to-Background Ratio
68Ga-FAPI PET/CT is diagnosed with higher contrast in tumor background with superior imaging for sharp detail. TBR is also high and superior compared to 18F-FDG to reduce physiologic uptake artifacts.
3. Better Performance Regardless of Tumor Grades
Low-Grade Sarcomas: Has greater uptake than 18F-FDG, so it will be exempted from one of the main drawbacks of conventional imaging.
High-Grade Sarcomas: Due to a similar or higher uptake than 18F-FDG, so will be suitable for evaluation.
4. Shorter Scan Time and Ease
68Ga-FAPI PET/CT does not need fasting and extensive preparation. The scan time is much shorter than that in 18F-FDG PET/CT.
Application of 68Ga-FAPI PET/CT in Clinics of Sarcomas
Primary lesions and Recurrent lesions
68Ga-FAPI PET/CT is superior in the detection of both primary and recurrent sarcomas. It is superior to:
- Liposarcoma
- Malignant solitary fibrous tumor (MSFT)
- Interdigitating dendritic cell sarcoma (IDCS)
Others include undifferentiated pleomorphic sarcoma (UPS) and rhabdomyosarcoma (RMS), and 18F-FDG has a slight advantage in diagnosis.

Whole-Body Scan
The sensitivity for metastasis detection, especially at challenging sites, is higher with FAPI PET/CT, particularly for lung metastases, equivalent to 18F-FDG with fewer false positives.
- Bone Metastases: Excellent sensitivity with better lesion contrast.
- Brain Metastases: Low background activity in normal brain tissue enhances the contrast of cerebral lesions and leptomeningeal metastases.
- Visceral Metastases: Better visualization of peritoneal carcinomatosis and omental lesions, independent of intestinal activity or anti-diabetic drugs.
Limitations and False Positives
Even though 68Ga-FAPI PET/CT has high sensitivity and specificity, it is not free from pitfalls.
Physiological Activity: An increased uptake at the site of wound healing, arthritis, and periodontitis makes it mimic tumor activity
Hormonal Effect: Activity may vary during hormonal activity and hence needs careful observation in pre or post-menopausal patients.
Potential Therapeutic for FAPI with Sarcomas
FAP-Targeted Radioligand Therapy: The use of FAPIs with beta-emitting isotopes such as Lutetium-177 (177Lu) offers a targeted radiotherapy modality. The approach is more promising for recurrent soft tissue sarcomas since the tumor microenvironment has high fibroblastic activity, thus making FAP an ideal target for therapy. This precision therapy has the advantage of minimizing damage to normal tissues with metastatic disease.
Conclusion
Although chemotherapy, immunotherapy, and targeted therapies have advanced significantly in metastatic soft-tissue sarcoma, the disease still is often unmanageable. In this respect, FAPI-based theranostic applications such as PET CT scan for patients with incurable, recurrent sarcoma can become a ground for hope.
Recently, 68Ga-FAPI PET/CT has emerged as a new diagnostic and management tool for sarcomas. It is capable of identifying low-grade and high-grade tumors with accuracy. Moreover, it is highly sensitive to recurrent lesions and metastases, making it extremely useful in treatment planning.
Beyond imaging, theranostic agents with FAPI promise to lead the way into targeted therapy that would meet this significant unmet need in the management of metastatic and recurrent sarcoma. In the future, these advances in research will make PET scan a keystone of the changing landscape in oncology and raise hopes for outcomes that would have been considered unthinkable for what has always been considered a deadly disease a century ago.