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Pictorial Essay
41 (
2
); 258-268
doi:
10.25259/IJNM_147_25

[18F]-FDG and [68Ga]Ga-FAPI-04 PET/CT in Radioiodine-refractory Differentiated Thyroid Cancer: A Comparative Pictorial Review along with Insights into Potential for Theranostics and Nonspecific Uptake Patterns on [68Ga]Ga-FAPI-04 PET-CT

, ,
1Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Centre Annexe, Jerbai Wadia Road, Parel, Mumbai, Maharashtra, India
2Homi Bhabha National Institute, Mumbai, Maharashtra, India

*Corresponding author: Dr. Sandip Basu, Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Centre Annexe, Jerbai Wadia Road, Parel, Mumbai, Maharashtra, 400012, India. drsanb@yahoo.com

Received: , Accepted: ,
© 2026 Published by Scientific Scholar on behalf of Indian Journal of Nuclear Medicine
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This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Mali MR, Verma P, Basu S. [18F]-FDG and [68Ga]Ga-FAPI-04 PET/CT in Radioiodine-refractory Differentiated Thyroid Cancer: A Comparative Pictorial Review along with Insights into Potential for Theranostics and Nonspecific Uptake Patterns on [68Ga] Ga-FAPI-04 PET-CT. Indian J Nucl Med 2026;41:258-68. doi: 10.25259/IJNM_147_25

Abstract

Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) poses challenges to oncologists and nuclear medicine physicians owing to its poor disease-specific survival rates and limited therapeutic options. In this present pictorial review, we present qualitative visual representation coupled with semiquantitative standardised uptake value findings in patients of RAIR-DTC, evaluated with dual-tracer positron emission tomography–computed tomography (PET/CT), namely [18F]-FDG-PET/CT and [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 PET/CT. Whole-body PET/CT imaging was performed using standard protocols after intravenous injection of 185–259 MBq of [18F]-FDG and 74–111 MBq of [68Ga]Ga-FAPI-04 on two separate days within a time period of 2 weeks. A relatively small fraction of patients in the current series portrayed good fibroblast activation protein (FAP) expression, which offers a potential therapeutic avenue to FAP-targeted radioligand therapy. In addition, a few nonspecific uptake patterns encountered on [68Ga]Ga-FAPI-04 PET-CT studies are also highlighted, which will enable the readers’ insight into false-positive uptakes of FAPI. At the end of this review, we discuss the feasibility of FAPI theranostics in the examined patient population based upon our findings and portray a clinical context on FAPI’s role in the RAIR-DTC scenario.

Keywords

[18F]-FDG positron emission tomography–computed tomography
[68Ga]Ga- fibroblast activation protein inhibitor-04 positron emission tomography–computed tomography
Cancer-associated fibroblasts
Fibroblast activation protein
Fibroblast activation protein-targeted radioligand therapy
Nonspecific uptake patterns
Radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC)

INTRODUCTION

In this pictorial review, a brief discussion on Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) and fibroblast activation protein inhibitor (FAPI), followed by clinical case vignettes with their dual-tracer positron emission tomography–computed tomography (PET/CT) imaging findings vis-à-vis radioiodine scintigraphy, is presented, coupled with illustrations.

Radioiodine-refractory differentiated thyroid cancer: A therapeutic challenge

Radioiodine-refractory differentiated thyroid cancer (RAIRDTC) coherently means thyroid cancer that does not respond to radioiodine therapy. This unresponsiveness is attributed to loss of iodine concentration or an aggressive transformation of the disease that progresses despite considerable iodine concentration. The American Thyroid Association (ATA) formally defines RAI refractoriness based on four fundamental scenarios. However, with evolving insights into disease pathogenesis and molecular pathways, the definition of RAI refractoriness keeps on evolving, and diagnosis should be made on a case-by-case basis rather than by strict defining criteria.[1] Incidence of RAIR-DTC is estimated to be about 4–5 new cases per year per million people.[2] As described earlier, RAIR-DTC is a spectrum encompassing differentiated thyroid cancers concentrating but not responding to RAI at one end to non-Radioactive iodine (RAI) concentrating disease at the other, with an intermediate mixed pattern in between. [18F]-FDG PET/CT has an established role in imaging of RAJ-DTC for diagnosis and management guidance, prognostication, to assess dedifferentiation and aggressiveness (flip-flop phenomenon), and monitoring treatment response. The ATA recommends it in cases with elevated Tg >10 ng/mL and negative RAI imaging.[1,3,4] The major therapeutic hurdle lies in extensive, metastatic, and unresectable RAIR-DTC, where tyrosine kinase inhibitors (TKIs) constitute the only approved systemic therapy to date.[3,5] Although empirical RAI therapy is still advocated by the ATA and National Comprehensive Cancer Network (NCCN) guidelines in progressive disease, which had previously demonstrated response to RAI, it is falling out of favour due to limited therapeutic value in non-RAI-avid RAIRDTC.[1,6] TKIs, while effective, are not universally applicable due to potential adverse effects and patient-specific contraindications. Given the paucity of effective therapies, there remains a significant unmet need for the advancement of new therapeutic approaches.

Fibroblast activation protein inhibitor positron emission tomography-computed tomography: a novel theranostic avenue?

Fibroblast activation protein (FAP) is a transmembrane type II glycoprotein belonging to the dipeptidyl peptidaseIV family that is highly expressed on cancer-associated fibroblasts (CAFs), playing a pivotal role in angiogenesis, epithelial to mesenchymal transition, tumour progression, and stromal remodelling.[7] FAP has been shown to be expressed in multiple cancers and also carries a poor prognosis.[8] It has also been shown that CAFs are positively associated with dedifferentiation and aggressive behaviour in thyroid carcinoma.[9] Advances in understanding the functions of CAFs and their role in tumour progression have paved the way for strategies that target these functions, positioning CAFs as promising therapeutic targets.[10] FAPI is a small-molecule enzyme inhibitor of FAP that has been polished out and advanced to enhance its diagnostic and therapeutic efficacy. In oncology, it has shown promising results in comparison studies with [18F]-FDG by demonstrating higher sensitivity for detecting malignant lesions owing to its lower background and higher target-to-background ratios.[11] Preliminary studies suggest that FAPI may have potential in improving diagnostic evaluation and contributing to therapeutic applications in RAIR-DTC.[12-14]

While FAPI demonstrates high tumour-to-background contrast, its expression in benign infective, inflammatory, and fibrotic lesions highlights the importance of correlating imaging findings with clinical and pathological context.[15]

Evaluation of [68Ga]Ga-fibroblast activation protein inhibitor-04 positron emission tomography–computed tomography versus [18F]-FDG positron emission tomography–computed tomography: A duel in RAIR-DTC

For better comprehension, we will be presenting cases of RAIR-DTC where FAP-directed therapy would be feasible or not feasible based on the uptake patterns, along with a few false-positive uptake patterns on [68Ga]Ga-FAPI-04 imaging.

The feasibility of FAP-targeted therapy has been assessed, taking into account the factors as follows:

  1. Patients with good FAP expression at all FDG-avid metastatic sites.

  2. No to minimal discordant lesions on FDG.

  3. No intralesional heterogeneity in FAP expression compared to FDG concentration.

  4. Non-FDG-concentrating stable disease – The absence of FDG uptake likely reflects low metabolic activity of the disease, which biologically corresponds to a less aggressive tumour phenotype and clinically translates to a more favourable prognosis, and observation is preferred in these cases.[3]

Building on this background, we now proceed to the comparative pictorial depiction of [68Ga]Ga-FAPI-04 and [18F]-FDG-PET/CT in RAIR-DTC. Uptake values at each site are represented by the maximum standardised uptake value (SUVmax) comparing [18F]-FDG and [68Ga]Ga-FAPI-04 uptake in each individual case vignette.

Feasible for fibroblast activation protein-targeted radioligand therapy

Case 1

A 60-year-old male patient of recurrent papillary thyroid carcinoma with negative iodine scintigraphy and elevated Tg of >300 ng/mL (TENIS) for disease staging and therapy guidance.

The metastatic disease in cervical nodes and mediastinal nodes (SUVmax: 9.91 vs. 13.44), bilateral lungs (SUVmax: 7.14 vs. 7.95), sternum and right acetabular lesions (SUVmax: 10.5 vs. 8.6) are comparable on both [18F]-FDG and [68Ga] Ga-FAPI-04 PET/CT [Fig 1]. There is notably good FAP expression in all the lesions, with minimal discordant lesions, making this case amenable to FAP-directed treatment.

Comparative evaluation of [18F]-FDG and [68Ga]Ga-fibroblast activation protein inhibitor [FAPI]-04 positron emission tomography -computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing intense FDG-concentrating lesions in bilateral neck (nodes), mediastinum (sternal lesion and mediastinal nodes), bilateral lungs (solid lung nodules), and right pelvic region (right acetabulum). (B) Axial fused [18F]-FDG PET/CT showing intense FDG concentration in bilateral lung nodules, sternal lytic lesion (green arrow), and right acetabular metastasis (yellow arrow) (top to bottom). (C) Representative CT images showing bilateral solid lung nodules, an expansile lytic lesion involving the sternal bone, and non-NCCT delineated lesion in the right acetabulum (top to bottom). (D) Axial fused [68Ga]Ga-FAPI-04 PET/CT showing good FAP expression in the lung, sternal (green arrow), and right acetabular lesions (yellow arrow) (top to bottom). [E] [68Ga]Ga-FAPI-04 PET/CT MIP showing fibroblast activation protein (FAP) expression similar to that of FDG.
Fig 1: Comparative evaluation of [18F]-FDG and [68Ga]Ga-fibroblast activation protein inhibitor [FAPI]-04 positron emission tomography -computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing intense FDG-concentrating lesions in bilateral neck (nodes), mediastinum (sternal lesion and mediastinal nodes), bilateral lungs (solid lung nodules), and right pelvic region (right acetabulum). (B) Axial fused [18F]-FDG PET/CT showing intense FDG concentration in bilateral lung nodules, sternal lytic lesion (green arrow), and right acetabular metastasis (yellow arrow) (top to bottom). (C) Representative CT images showing bilateral solid lung nodules, an expansile lytic lesion involving the sternal bone, and non-NCCT delineated lesion in the right acetabulum (top to bottom). (D) Axial fused [68Ga]Ga-FAPI-04 PET/CT showing good FAP expression in the lung, sternal (green arrow), and right acetabular lesions (yellow arrow) (top to bottom). [E] [68Ga]Ga-FAPI-04 PET/CT MIP showing fibroblast activation protein (FAP) expression similar to that of FDG.

Case 2

A 60-year-old male patient of metastatic papillary thyroid cancer with no concentration of iodine in the metastatic disease and elevated Tg levels of >300 ng/mL (TENIS). Evaluated for disease extent evaluation and prognostication.

Note the mediastinal nodes (SUVmax: 6.49 vs 10.86), bilateral lower zone predominant florid lung metastasis (SUVmax: 12.04 vs 13.25), and solitary skeletal metastasis involving T2 vertebra (SUVmax: 8.09 vs 9.14) show no significant difference between the two scans [Fig 2].

Comparative evaluation of [18F]-FDG and [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography– computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing intense FDG concentration in bilateral basal lung regions and mid-thorax region (mediastinal nodes and lytic lesion in T2 (red arrow). (B) Coronal-fused [18F]- FDG PET/CT showing FDG concentration in bilateral lower zone predominant lung nodules. (C)
Fig 2: Comparative evaluation of [18F]-FDG and [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography– computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing intense FDG concentration in bilateral basal lung regions and mid-thorax region (mediastinal nodes and lytic lesion in T2 (red arrow). (B) Coronal-fused [18F]- FDG PET/CT showing FDG concentration in bilateral lower zone predominant lung nodules. (C)

(C) Representative coronal lung window CT image showing bilateral lower zone predominant lung nodules. (D) Coronal fused [68Ga]GaFAPI-04 PET/CT showing good FAP expression in bilateral basal predominant florid lung nodules. (E) [68Ga]Ga-FAPI-04 PET/CT MIPshowing good fibroblast activation protein (FAP) expression in bi-basal lungs and mid-thorax (T2 lesion - red arrow). PET/CT: Positron emission tomography -computed tomography, CT: Computed tomography, FAPI: Fibroblast activation protein inhibitor

Case 3

A 54-year-old female patient of metastatic papillary thyroid carcinoma post 30 GBq RAI therapy eventually became refractory to RAI with negative iodine scintigraphy and elevated Tg levels of 260 ng/mL (TENIS). Referred for staging and prognostication.

The lung metastasis (SUVmax: 12.2 vs. 11.6) is well-correlated on both imaging studies [Fig 3].

Learning points: The abovementioned cases (1, 2, and 3) demonstrate good FAP expression in almost all lesions with nil to minimal discordance on FDG-PET/CT, rendering them feasible candidates for FAP-targeted radioligand therapy.

Comparative evaluation of [18F]-FDG and [68Ga]Gafibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing intense foci of FDG concentration in bilateral lungs. (B) [68Ga]Ga-FAPI-04 PET/CT MIP showing foci of good fibroblast activation protein (FAP) expression comparable to the one on FDG. (C) Axial fused [18F]-FDG PET/CT showing FDG-concentrating bilateral lung nodules. (D) Representative axial lung window CT image demonstrating bilateral well-defined solid lung nodules. (E) Axial fused [68Ga]Ga-FAPI-04 PET/CT showing good FAP expressing bilateral lung nodules. PET/CT: Positron emission tomography–computed tomography, CT: Computed tomography, FAPI: Fibroblast activation protein inhibitor
Fig 3: Comparative evaluation of [18F]-FDG and [68Ga]Gafibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing intense foci of FDG concentration in bilateral lungs. (B) [68Ga]Ga-FAPI-04 PET/CT MIP showing foci of good fibroblast activation protein (FAP) expression comparable to the one on FDG. (C) Axial fused [18F]-FDG PET/CT showing FDG-concentrating bilateral lung nodules. (D) Representative axial lung window CT image demonstrating bilateral well-defined solid lung nodules. (E) Axial fused [68Ga]Ga-FAPI-04 PET/CT showing good FAP expressing bilateral lung nodules. PET/CT: Positron emission tomography–computed tomography, CT: Computed tomography, FAPI: Fibroblast activation protein inhibitor

Patients not feasible for fibroblast activation protein-targeted therapy

Case 4

A 54-year-old male patient of recurrent papillary thyroid carcinoma with negative iodine scintigraphy and elevated Tg of 156 ng/mL (TENIS) was referred for disease staging, therapy guidance, and prognostication.

Note the metastatic disease in cervical nodes (SUVmax: 39 vs. non-FAP expressing), mediastinal nodes (SUVmax: 37.3 vs. 18.67), and bilateral lungs (SUVmax: 40.23 vs. 11.03) are more vividly demonstrated on FDG as compared to [68Ga] Ga-FAPI-04 PET/CT, with most of the lesions not showing FAP expression [Fig 4].

Comparative evaluation of [18F]-FDG and [68Ga]Gafibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT). (A) [18F]-FDG PET/CT maximum intensity projection, MIP showing intense FDG concentration in bilateral neck (cervical nodes), mid-thorax (mediastinal nodes), and bilateral thoracic regions (bilateral lung metastasis). (B) Axial fused [18F]-FDG PET/CT showing intense FDG concentration in the upper left paratracheal node (yellow arrow) and bilateral solid well-defined lung nodules (top to bottom). (C) Representative CT images showing a well-defined left upper paratracheal node (yellow arrow) and bilateral solid well-defined lung nodules (red arrow heads) (top to bottom). (D) Axial fused images of [68Ga]Ga-FAPI-04 PET/CT showing heterogeneous FAP expressing left upper paratracheal lymph node (yellow arrow) and no to minimal FAP expressing lung lesions (top to bottom). (E) [68Ga]Ga-FAPI-04 PET/CT MIP showing a few areas of heterogeneous fibroblast activation protein (FAP) expression in the mid-thorax (mediastinal node) and bilateral thorax regions (lung metastasis). PET/CT: Positron emission tomography–computed tomography, CT: Computed tomography, FAPI: Fibroblast activation protein inhibitor
Fig 4: Comparative evaluation of [18F]-FDG and [68Ga]Gafibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT). (A) [18F]-FDG PET/CT maximum intensity projection, MIP showing intense FDG concentration in bilateral neck (cervical nodes), mid-thorax (mediastinal nodes), and bilateral thoracic regions (bilateral lung metastasis). (B) Axial fused [18F]-FDG PET/CT showing intense FDG concentration in the upper left paratracheal node (yellow arrow) and bilateral solid well-defined lung nodules (top to bottom). (C) Representative CT images showing a well-defined left upper paratracheal node (yellow arrow) and bilateral solid well-defined lung nodules (red arrow heads) (top to bottom). (D) Axial fused images of [68Ga]Ga-FAPI-04 PET/CT showing heterogeneous FAP expressing left upper paratracheal lymph node (yellow arrow) and no to minimal FAP expressing lung lesions (top to bottom). (E) [68Ga]Ga-FAPI-04 PET/CT MIP showing a few areas of heterogeneous fibroblast activation protein (FAP) expression in the mid-thorax (mediastinal node) and bilateral thorax regions (lung metastasis). PET/CT: Positron emission tomography–computed tomography, CT: Computed tomography, FAPI: Fibroblast activation protein inhibitor

Case 5

A 59-year-old female patient of metastatic papillary thyroid carcinoma postthyroidectomy and RAI therapy with a cumulative dose of 14.9 GBq eventually became iodine refractory. Low-dose iodine scan showed no RAI concentration with elevated Tg levels of 253 ng/mL and positive antithyroglobulin antibody (TENIS).

Note the metastatic disease in the large mediastinal node (SUVmax: 33.6 vs. 9.34), lung nodules (SUVmax: 14.2 vs. 9.22), and skeletal metastasis (sternum and right femur) (SUVmax: 33.3 vs. 11.09) are more accurately demonstrated on [18F]-FDG PET/CT compared to [68Ga]Ga-FAPI-04 PET/CT [Fig 5]. An important observation that is made is that even though there is FAP expression, it is heterogeneous and concentrated peripherally. This case does not qualify for FAP-targeted treatment.

Comparative evaluation of [18F]-FDG and [68Ga]Gafibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET-CT). (A) [18F]-FDG PET/CT MIP showing intense FDG concentration in bilateral thorax regions (lung nodules) and left hilar node, mid-thorax (sternum), and two foci in right lower limb region (proximal and distal femur lytic lesions). (B) Axial fused [18F]-FDG PET/CT showing intense FDG-concentrating large mediastinal node (blue arrow) and proximal right femur (yellow arrow) and distal right femur (green arrow) skeletal metastases (top to bottom). (C) Representative CT images showing a large soft-tissue density nodal mass in the left hilar region (blue arrow) and lytic lesions in the right proximal (yellow arrow) and distal (green arrow) femur (top to bottom). (D) Axial fused [68Ga]Ga-FAPI-04 PET/CT showing peripheral and heterogeneous FAP expressing mediastinal node (blue arrow) and right femoral proximal (yellow arrow) and distal (green arrow) lesions (top to bottom). There was absent FAP expression in the sternal and a few lung metastases, which were FDG concentrating. (E) [68Ga] Ga-FAPI-04 PET/CT MIP showing heterogeneous fibroblast activation protein (FAP) expression in the left thorax (hilar node), right thorax (lung lesion) and two foci in the right lower limb. PET/CT: Positron emission tomography–computed tomography, CT: Computed tomography, FAPI: Fibroblast activation protein inhibitor
Fig 5: Comparative evaluation of [18F]-FDG and [68Ga]Gafibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET-CT). (A) [18F]-FDG PET/CT MIP showing intense FDG concentration in bilateral thorax regions (lung nodules) and left hilar node, mid-thorax (sternum), and two foci in right lower limb region (proximal and distal femur lytic lesions). (B) Axial fused [18F]-FDG PET/CT showing intense FDG-concentrating large mediastinal node (blue arrow) and proximal right femur (yellow arrow) and distal right femur (green arrow) skeletal metastases (top to bottom). (C) Representative CT images showing a large soft-tissue density nodal mass in the left hilar region (blue arrow) and lytic lesions in the right proximal (yellow arrow) and distal (green arrow) femur (top to bottom). (D) Axial fused [68Ga]Ga-FAPI-04 PET/CT showing peripheral and heterogeneous FAP expressing mediastinal node (blue arrow) and right femoral proximal (yellow arrow) and distal (green arrow) lesions (top to bottom). There was absent FAP expression in the sternal and a few lung metastases, which were FDG concentrating. (E) [68Ga] Ga-FAPI-04 PET/CT MIP showing heterogeneous fibroblast activation protein (FAP) expression in the left thorax (hilar node), right thorax (lung lesion) and two foci in the right lower limb. PET/CT: Positron emission tomography–computed tomography, CT: Computed tomography, FAPI: Fibroblast activation protein inhibitor

Case 6

A 70-year-old male patient of recurrent poorly differentiated thyroid cancer with negative iodine scintigraphy and elevated Tg of 303 ng/mL (TENIS). Evaluated for the extent of disease and therapy guidance.

Note the metastatic disease presenting as cervical and mediastinal nodes (SUVmax: 22.58 vs. non-FAP expressing) and a large left lung mass (SUVmax: 33.04 vs. 7.9), which are evident on [18F]-FDG PET/CT and not readily detectable on [68Ga]Ga-FAPI-04 PET/CT [Fig 6].

Comparative evaluation of [18F]-FDG and [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography– computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing foci of FDG concentration in bilateral neck (cervical nodes -green arrow), mid-thorax (subcarinal node - yellow arrow), and left thorax region (lung mass - red arrow). (B) Axial fused [18F]-FDG PET/CT showing intense metabolism in the subcarinal node (yellow arrow) and mass in the left lung lower lobe (red arrow) (top to bottom). (C) Representative CT images showing a large subcarinal node (yellow arrow) and a left lung mass (red arrow) (top to bottom). (D) Axial fused [68Ga]Ga-FAPI-04 PET/CT showing absent FAP expression in the subcarinal node (yellow arrow) and nil to very minimal heterogeneous FAP expression in the lung mass (red arrow) (top to bottom). (E) [68Ga] Ga-FAPI-04 PET/CT MIP showing no significant abnormal fibroblast activation protein (FAP) expression.
Fig 6: Comparative evaluation of [18F]-FDG and [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography– computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing foci of FDG concentration in bilateral neck (cervical nodes -green arrow), mid-thorax (subcarinal node - yellow arrow), and left thorax region (lung mass - red arrow). (B) Axial fused [18F]-FDG PET/CT showing intense metabolism in the subcarinal node (yellow arrow) and mass in the left lung lower lobe (red arrow) (top to bottom). (C) Representative CT images showing a large subcarinal node (yellow arrow) and a left lung mass (red arrow) (top to bottom). (D) Axial fused [68Ga]Ga-FAPI-04 PET/CT showing absent FAP expression in the subcarinal node (yellow arrow) and nil to very minimal heterogeneous FAP expression in the lung mass (red arrow) (top to bottom). (E) [68Ga] Ga-FAPI-04 PET/CT MIP showing no significant abnormal fibroblast activation protein (FAP) expression.

Case 7

A 70-year-old male patient of recurrent papillary thyroid cancer with negative iodine scintigraphy and elevated Tg levels of >300 ng/mL (TENIS) for disease extent evaluation.

Note the primary recurrence (SUVmax: 66.12 vs. non-FAP expressing), right cervical nodes and mediastinal nodes (SUVmax: 16.5 vs. non-FAP expressing), and lung nodules (SUVmax: 17.5 vs. non-FAP expressing) are only demonstrated on FDG and show no FAP expression on [68Ga]Ga-FAPI-04 PET/CT [Fig 7], rendering this case not suitable for FAP targeted radioligand therapy.

Comparative evaluation of [18F]-FDG and [68Ga]Gafibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT) in the same patient.
Fig 7: Comparative evaluation of [18F]-FDG and [68Ga]Gafibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT) in the same patient.

(A) [18F]-FDG PET/CT MIP showing intense FDG concentration in the neck (primary site recurrence – blue arrow), cervical nodes (green arrow), mediastinum (lymph nodes – yellow arrow), and a few bilateral lung nodules (red arrows). (B) [68Ga]Ga-FAPI-04 PET/CT MIP showing no abnormal fibroblast activation protein expression in the whole-body survey. PET/CT: Positron emission tomography–computed tomography, FAPI: Fibroblast activation protein inhibitor

Case 8

A 30-year-old male patient of papillary thyroid carcinoma with negative iodine scintigraphy and elevated Tg levels of 223 ng/mL (TENIS) was evaluated with high-resolution computed tomography of the lungs, which showed multiple tiny nodules in the bilateral lungs. Referred for prognostication.

Note that both [18F]-FDG and [68Ga]Ga-FAPI-04 tracers are not concentrated in the lung metastasis [Fig 8]. Lack of FDG avidity indicates a good clinical prognosis in this patient. FAP-targeted radioligand therapy is not justified given the clinical and imaging profile.

Comparative evaluation of [18F]-FDG and [68Ga]Ga-FAPI-04 positron emission tomography-computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing no abnormal FDG concentration in the whole-body survey. (B) Axial fused [18F]-FDG PET/CT showing a few well-defined bilateral lung nodules (black arrows), which do not concentrate FDG. (C) Axial fused [68Ga]Ga-FAPI-04 PET/CT showing no FAP expression in bilateral lung nodules (black arrows). (D) [68Ga]Ga-FAPI-04 PET/CT MIP showing no abnormal fibroblast activation protein (FAP) expression in the whole-body survey. PET/CT: Positron emission tomography– computed tomography, FAPI: Fibroblast activation protein inhibitor
Fig 8: Comparative evaluation of [18F]-FDG and [68Ga]Ga-FAPI-04 positron emission tomography-computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing no abnormal FDG concentration in the whole-body survey. (B) Axial fused [18F]-FDG PET/CT showing a few well-defined bilateral lung nodules (black arrows), which do not concentrate FDG. (C) Axial fused [68Ga]Ga-FAPI-04 PET/CT showing no FAP expression in bilateral lung nodules (black arrows). (D) [68Ga]Ga-FAPI-04 PET/CT MIP showing no abnormal fibroblast activation protein (FAP) expression in the whole-body survey. PET/CT: Positron emission tomography– computed tomography, FAPI: Fibroblast activation protein inhibitor

Case 9

A 70-year-old male patient of follicular variant of papillary thyroid carcinoma with nodal and lung metastasis, postcumulative dose of 40 GBq of RAI, progressed within 1 year of last RAI therapy to have an increase in the number of lung metastasis and a new onset of solitary skeletal metastasis in the right iliac bone, from which a biopsy came out to be follicular thyroid carcinoma.

Note the metastatic sites at the last iodine posttherapy scan were RAI concentrating [Fig 9(I)]. The mediastinal nodal (SUVmax:8.58 vs 8.8), lung (SUVmax: 5.5 vs 8.6), and iliac metastasis (SUVmax: 11.5 vs 14.93) are more precisely visualised and better delineated in [18F]-FDG PET compared to [68Ga]Ga-FAPI-04 PET/CT [Fig 9(II)]. [68Ga]Ga-FAPI-04 PET/CT missed most of the lung lesions and also demonstrates nonuniform mottled uptake in the periphery of lesions. FAP-targeted radionuclide therapeutic intervention is not indicated in this case.

(I) Anterior and posterior projections (left to right) of [131I]-NaI posttherapy scintigraphy showing RAI concentration in the bilateral upper thorax region corresponding to lung metastasis (black arrows). (II) Comparative evaluation of [18F]-FDG and [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT) in the same patient. (A) [18F]-FDG PET/CT MIP showing intense FDG concentration in mediastinum (nodes - blue arrow), bilateral lungs (lung nodules - red arrows), and right-sided pelvis (iliac bone lytic lesion - yellow arrow). (B) Axial fused [18F]-FDG PET/CT showing intense FDG concentration in the upper mediastinal node (blue arrow) and peripheral intense FDG concentration in the right iliac lytic lesion with large soft-tissue component (yellow arrow) (top to bottom). (C) Representative axial CT images demonstrating a large inhomogeneously enhancing mediastinal lymph node (blue arrow) and a lytic right iliac lesion with peripherally enhancing soft-tissue component (yellow arrow) (top to bottom). (D) Axial fused [68Ga]
Fig 9: (I) Anterior and posterior projections (left to right) of [131I]-NaI posttherapy scintigraphy showing RAI concentration in the bilateral upper thorax region corresponding to lung metastasis (black arrows). (II) Comparative evaluation of [18F]-FDG and [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT) in the same patient. (A) [18F]-FDG PET/CT MIP showing intense FDG concentration in mediastinum (nodes - blue arrow), bilateral lungs (lung nodules - red arrows), and right-sided pelvis (iliac bone lytic lesion - yellow arrow). (B) Axial fused [18F]-FDG PET/CT showing intense FDG concentration in the upper mediastinal node (blue arrow) and peripheral intense FDG concentration in the right iliac lytic lesion with large soft-tissue component (yellow arrow) (top to bottom). (C) Representative axial CT images demonstrating a large inhomogeneously enhancing mediastinal lymph node (blue arrow) and a lytic right iliac lesion with peripherally enhancing soft-tissue component (yellow arrow) (top to bottom). (D) Axial fused [68Ga]

Ga-FAPI-04 PET/CT showing heterogeneous and peripheral FAP expression in mediastinal node (blue arrow) and iliac lytic lesion (yellow arrow) (top to bottom). (E) [68Ga]Ga-FAPI-04 PET/CT MIP showing minimal and heterogeneous fibroblast activation protein (FAP) expression in mediastinum (blue arrow), focal uptake in left thorax (red arrow), and right pelvic region (yellow arrow). PET/CT: Positron emission tomography–computed tomography, CT: Computed tomography, FAPI: Fibroblast activation protein inhibitor

Case 10

A 66-year-old female patient of minimally invasive follicular thyroid carcinoma with skeletal metastasis received a total of 40.7 GBq of RAI. Post last cycle of RAI patient progressed biochemically within a year from a Tg of 183 ng/mL to 264 ng/mL, and the disease was persistent.

Note the skeletal metastatic sites were all RAI-avid at the last post-RAI therapy scan [Fig 10(I)]. The skeletal metastatic sites involving the skull and spine were all non-FDG concentrating and non-FAP expressing [Fig 10(II)]. Prognosis is deemed favourable given the lack of FDG accumulation. The patient is not a candidate for FAP-directed radioligand therapy.

(I) Anterior and posterior projections (left to right) of [131I]-NaI posttherapy scintigraphy showing RAI concentration in the skull (black arrows) and vertebral metastasis (green arrows). (II) Comparative evaluation of [18F]-FDG and [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing no abnormal FDG uptake anywhere in the body. (B) Axial and sagittal fused [18F]-FDG PET/CT showing non-FDG-concentrating lytic lesions in the frontal bone (red arrow), L3 and L4 vertebrae (yellow arrow) (top to bottom). (C) Axial and sagittal fused [68Ga] Ga-FAPI-04 PET/CT showing no FAP expression in the frontal (red arrow) and L3, L4 vertebral lytic lesions (yellow arrow) (top to bottom). (D) [68Ga]Ga-FAPI-04 PET/CT MIP showing no abnormal fibroblast activation protein (FAP) expression in the whole-body survey. PET/CT: Positron emission tomography–computed tomography, FAPI: Fibroblast activation protein inhibitor
Fig 10: (I) Anterior and posterior projections (left to right) of [131I]-NaI posttherapy scintigraphy showing RAI concentration in the skull (black arrows) and vertebral metastasis (green arrows). (II) Comparative evaluation of [18F]-FDG and [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing no abnormal FDG uptake anywhere in the body. (B) Axial and sagittal fused [18F]-FDG PET/CT showing non-FDG-concentrating lytic lesions in the frontal bone (red arrow), L3 and L4 vertebrae (yellow arrow) (top to bottom). (C) Axial and sagittal fused [68Ga] Ga-FAPI-04 PET/CT showing no FAP expression in the frontal (red arrow) and L3, L4 vertebral lytic lesions (yellow arrow) (top to bottom). (D) [68Ga]Ga-FAPI-04 PET/CT MIP showing no abnormal fibroblast activation protein (FAP) expression in the whole-body survey. PET/CT: Positron emission tomography–computed tomography, FAPI: Fibroblast activation protein inhibitor

Case 11

A 74-year-old female patient of follicular variant of papillary thyroid carcinoma with high-grade features, with a solitary skeletal metastasis to the right humerus, showed no response clinically, biochemically, and radiologically after 35 GBq of cumulative RAI dose. Evaluated for prognostication [Fig 11].

Note the solitary skeletal metastasis of the right humerus is intensely RAI concentrating on post-RAI therapy scan [Fig 11(I)]. The right humerus lesion demonstrates heterogeneous FDG concentration and FAP expression (SUVmax: 13.08 vs. 7.59) [Fig 11(II)]. Uptake of [68Ga]Ga-FAPI-04 was even more heterogeneous than that of [18F]-FDG, and the imaging features preclude the patient from being considered for FAP-targeted radioligand therapy.

(I) Anterior and posterior projections (left to right) of [131I]-NaI posttherapy scintigraphy showing intense RAI concentration in a solitary right humerus metastasis (red arrows). (II) Comparative evaluation of [18F]-FDG and [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP and (B) coronal fused PET/CT showing heterogeneous FDG-concentrating lytic lesion in right mid- and distal humerus (red arrow) and an intense FDG concentration in the right renal fossa (blue arrow) corresponding to the hydronephrotic right kidney. (C) Representative coronal bone window CT showing a large expansile lytic lesion involving the right mid- and distal humerus. (D) Coronal fused [68Ga]Ga-FAPI-04 PET/CT and (E) [68Ga] Ga-FAPI-04 PET/CT MIP showing moderate heterogeneous fibroblast activation protein expression in the right humerus lesion (red arrow). PET/CT: Positron emission tomography–computed tomography, CT: Computed tomography, FAPI: Fibroblast activation protein inhibitor
Fig 11: (I) Anterior and posterior projections (left to right) of [131I]-NaI posttherapy scintigraphy showing intense RAI concentration in a solitary right humerus metastasis (red arrows). (II) Comparative evaluation of [18F]-FDG and [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP and (B) coronal fused PET/CT showing heterogeneous FDG-concentrating lytic lesion in right mid- and distal humerus (red arrow) and an intense FDG concentration in the right renal fossa (blue arrow) corresponding to the hydronephrotic right kidney. (C) Representative coronal bone window CT showing a large expansile lytic lesion involving the right mid- and distal humerus. (D) Coronal fused [68Ga]Ga-FAPI-04 PET/CT and (E) [68Ga] Ga-FAPI-04 PET/CT MIP showing moderate heterogeneous fibroblast activation protein expression in the right humerus lesion (red arrow). PET/CT: Positron emission tomography–computed tomography, CT: Computed tomography, FAPI: Fibroblast activation protein inhibitor

Learning points: The patients depicted in cases 4–11 are not suitable candidates for FAP-targeted radioligand therapy.

Cases 4, 6, 7, and 9 are not feasible candidates for FAP therapy owing to the complete absence of FAP expression in all or most of the FDG-concentrating lesions.

Cases 8 and 10 show neither FDG concentration nor FAP expression at the disease sites, precluding them from FAP-targeted therapy. In limited disease scenarios, FDG can stratify patients either for observation or treatment. The role of FAPI in the prognostication of RAIR-DTC is lacking, and long-term follow-up studies are essential for establishing the correlation.

In cases 5 and 11, although most of the lesions are FAP-expressing, the uptake pattern is quite heterogeneous and incongruent compared to FDG, and mostly limited to the periphery of lesions. For this reason, the patients may not benefit from FAP-targeted therapy.

Nonspecific/false-positive uptake patterns of [68Ga]Gafibroblast activation protein inhibitor-04

While this section focuses primarily on nonspecific [68Ga]Ga-FAPI-04 uptakes in the examined patients, we also address the disease findings and their therapeutic implications. We have encountered infectious changes in the lungs, nonossifying fibroma in the bone, periportal uptake, adenomyosis, and granulomatous inflammation.

Infectious etiology

Case 12

A 57-year-old male patient of papillary thyroid carcinoma with lung metastasis, post 6.9 GBq of RAI for follow-up evaluation, showed negative iodine scintigraphy and elevated Tg levels of 76.58 ng/ml (TENIS). Referred for disease extent evaluation and prognostication.

Note the uptake of [18F]-FDG and [68Ga]Ga-FAPI-04 in the pleural-based consolidatory lesion (SUVmax: 5.32 vs. 8.03), which has shown a considerable increase in extent in just a span of 6 days (interval between the scans). Both the morphology and the kinetics of lesion growth indicated an infective aetiology of the lesion [Fig 12].

Comparative evaluation of [18F]-FDG and [68Ga]Gafibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing low-grade focal FDG concentrations in the upper mediastinum (nodes - blue arrow), left lung (lung nodule -red arrow), and irregular moderate FDG concentration in the right lower thorax region (green arrow). (B) Axial CT and axial fused [18F]- FDG PET/CT showing moderate grade FDG concentration in irregularly shaped pleural-based consolidation in the basal segment of the right lung lower lobe (green arrows) (top to bottom). (C) Axial CT and fused [68Ga]Ga- FAPI-04 PET/CT showing interval increase in size of pleural-based consolidation with good FAP expression representing infective aetiology (green arrows) (top to bottom). (D) [68Ga] Ga-FAPI-04 PET/CT scan done with an interval of 6 days, MIP showing good foci of good fibroblast activation protein (FAP) expression in the mediastinal nodes (blue arrows), left lung nodule (red arrow), and irregularly shaped good FAP expression in the right thorax region (green arrow). PET/CT: Positron emission tomography–computed tomography, FAPI: Fibroblast activation protein inhibitor
Fig 12: Comparative evaluation of [18F]-FDG and [68Ga]Gafibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing low-grade focal FDG concentrations in the upper mediastinum (nodes - blue arrow), left lung (lung nodule -red arrow), and irregular moderate FDG concentration in the right lower thorax region (green arrow). (B) Axial CT and axial fused [18F]- FDG PET/CT showing moderate grade FDG concentration in irregularly shaped pleural-based consolidation in the basal segment of the right lung lower lobe (green arrows) (top to bottom). (C) Axial CT and fused [68Ga]Ga- FAPI-04 PET/CT showing interval increase in size of pleural-based consolidation with good FAP expression representing infective aetiology (green arrows) (top to bottom). (D) [68Ga] Ga-FAPI-04 PET/CT scan done with an interval of 6 days, MIP showing good foci of good fibroblast activation protein (FAP) expression in the mediastinal nodes (blue arrows), left lung nodule (red arrow), and irregularly shaped good FAP expression in the right thorax region (green arrow). PET/CT: Positron emission tomography–computed tomography, FAPI: Fibroblast activation protein inhibitor

Note the metastatic disease in mediastinal nodes (SUVmax: 3.92 vs 8.7) and lungs (SUVmax: 3.05 vs 4.2) is more vividly visible on [68Ga]Ga-FAPI-04 PET/CT compared to that of [18F]-FDG PET/CT. Patient is a suitable candidate for FAP targeted therapy.

Non-ossifying fibroma (Benign bone lesion)

Non-ossifying fibromas are self-limiting osteoclastic and giant cell-rich benign bone lesions usually found in the metaphysis of long bones, and the diagnosis is mainly based on characteristic radiographic features.[16] No literature has yet been reported regarding the uptake of FAPI in nonossifying fibroma.

Case 13

A 35-year-old male patient of papillary thyroid carcinoma post 5.3 GBq of RAI for follow-up evaluation showed negative iodine scintigraphy with elevated Tg levels of 339 ng/mL (TENIS). Evaluated for disease extent.

Note the lytic lesion in the left femur, which showed moderate FAP expression with no/minimal FDG uptake (SUVmax: non-FDG concentrating vs. 5.16) [Fig 13(I)]. Magnetic resonance imaging (MRI) of the pelvis showed an irregularly shaped lytic lesion with sclerotic margins in the subtrochanteric region of the left femur with features in favour of a non-ossifying fibroma [Fig 13(II)]. Note that the cervical nodes are well-demarcated on [68Ga]Ga-FAPI-04 PET/CT compared to [18F]-FDG (SUVmax: 6.08 vs. 9.4). Although the patient meets the criteria for therapeutic eligibility, FAP-targeted therapy is generally deferred in this case in favour of more established first-line surgical treatment for localised neck disease.

(I) Comparative evaluation of [18F]-FDG and [68Ga]Gafibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing low-grade focal FDG concentration in the right lower neck (red arrow) along with uptake in the bilateral supraclavicular fossa (SCF) (brown fat uptake - yellow arrow). (B) Axial fused [18F]-FDG PET/CT showing FDG concentration in right paratracheal node (red arrow), bilateral SCF (yellow arrow), and non-FDG-concentrating lytic lesion in the neck of the left femur (green arrow) (top to bottom). (C) Representative CT sections showing paratracheal nodes (red arrow) and lytic lesion in the left femur neck (green arrow) (top to bottom). (D) Axial fused [68Ga] Ga-FAPI-04 PET/CT showing focal FAP expressing right-sided paratracheal nodes (red arrows) and focal FAP expressing lytic lesion in the neck of the femur (green arrow) (top to bottom). (E) [68Ga]Ga-FAPI-04 PET/CT MIP showing focal areas of fibroblast activation protein (FAP) expression in the bilateral neck (red arrows) and left upper thigh region (green arrow). (II) Magnetic resonance imaging (MRI): MRI pelvis of the same patient. (A) Axial T1, (B) coronal T1, (C) axial T2, and (D) axial T2* weighted images of the pelvis showing a hyperintense, irregularly shaped lytic lesion with sclerotic margins in the subtrochanteric region of the left femur in an eccentric location with cortical breach and calcifications. (E) Axial T1-weighted STIR and (F) coronal T1-weighted STIR images showing inhomogeneous suppression. These features of the lesion are likely suggestive of non-ossifying fibroma (yellow arrows in A-F). PET/CT: Positron emission tomography–computed tomography, CT: Computed tomography, FAPI: Fibroblast activation protein inhibitor , STIR: Short tau inversion recovery.
Fig 13: (I) Comparative evaluation of [18F]-FDG and [68Ga]Gafibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT). (A) [18F]-FDG PET/CT MIP showing low-grade focal FDG concentration in the right lower neck (red arrow) along with uptake in the bilateral supraclavicular fossa (SCF) (brown fat uptake - yellow arrow). (B) Axial fused [18F]-FDG PET/CT showing FDG concentration in right paratracheal node (red arrow), bilateral SCF (yellow arrow), and non-FDG-concentrating lytic lesion in the neck of the left femur (green arrow) (top to bottom). (C) Representative CT sections showing paratracheal nodes (red arrow) and lytic lesion in the left femur neck (green arrow) (top to bottom). (D) Axial fused [68Ga] Ga-FAPI-04 PET/CT showing focal FAP expressing right-sided paratracheal nodes (red arrows) and focal FAP expressing lytic lesion in the neck of the femur (green arrow) (top to bottom). (E) [68Ga]Ga-FAPI-04 PET/CT MIP showing focal areas of fibroblast activation protein (FAP) expression in the bilateral neck (red arrows) and left upper thigh region (green arrow). (II) Magnetic resonance imaging (MRI): MRI pelvis of the same patient. (A) Axial T1, (B) coronal T1, (C) axial T2, and (D) axial T2* weighted images of the pelvis showing a hyperintense, irregularly shaped lytic lesion with sclerotic margins in the subtrochanteric region of the left femur in an eccentric location with cortical breach and calcifications. (E) Axial T1-weighted STIR and (F) coronal T1-weighted STIR images showing inhomogeneous suppression. These features of the lesion are likely suggestive of non-ossifying fibroma (yellow arrows in A-F). PET/CT: Positron emission tomography–computed tomography, CT: Computed tomography, FAPI: Fibroblast activation protein inhibitor , STIR: Short tau inversion recovery.

[68Ga]Ga fibroblast activation protein inhibitor 04 uptake in periportal area and adenomyosis

Case 14

A 50-year-old female patient of papillary thyroid carcinoma with lung metastasis, with elevated Tg (106.19 ng/mL) and negative iodine scintigraphy (TENIS) for disease evaluation. NGS showed a positive BRAF mutation.

Disease (lung nodules) was non-FDG concentrating. [68Ga] Ga-FAPI-04 PET also showed no FAP expression in the lung nodules. However, abnormal nonspecific FAP expression was seen at the porta hepatis and origin of the left branch of the main portal vein (SUVmax: 6.5) with no CT discernible lesions. MRI was advised, but the patient refused to follow up. Diffuse FAP expression is also noted in this known case of adenomyosis (SUVmax: 17.25) with a uniformly enlarged uterus [Fig 14].

[68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT) MIP of the same patient (A) showing irregular fibroblast activation protein (FAP) expression in the right hypochondriac region (green arrow) and mid-pelvic region (red arrow) above the bladder. (B) Axial PET, (C) axial CT, and (D) axial [68Ga]Ga-FAPI-04 fused PET/CT (top to bottom) showing FAP expression at the porta hepatis and along the origin of the left branch of the portal vein. Axial PET (E) axial CT (F) and axial fused PET/CT (G) (top to bottom) showing intense heterogeneous FAP expression in a uniformly enlarged and bulky uterus (known case of adenomyosis). PET/CT: Positron emission tomography–computed tomography, FAPI: Fibroblast activation protein inhibitor
Fig 14: [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography–computed tomography (PET/CT) MIP of the same patient (A) showing irregular fibroblast activation protein (FAP) expression in the right hypochondriac region (green arrow) and mid-pelvic region (red arrow) above the bladder. (B) Axial PET, (C) axial CT, and (D) axial [68Ga]Ga-FAPI-04 fused PET/CT (top to bottom) showing FAP expression at the porta hepatis and along the origin of the left branch of the portal vein. Axial PET (E) axial CT (F) and axial fused PET/CT (G) (top to bottom) showing intense heterogeneous FAP expression in a uniformly enlarged and bulky uterus (known case of adenomyosis). PET/CT: Positron emission tomography–computed tomography, FAPI: Fibroblast activation protein inhibitor

Inflammation (Granuloma)

Case 15

A 25-year-old female patient of papillary thyroid carcinoma, classical type, with nodal and lung metastasis, with RAI scan showing no concentration in the lung nodules and elevated Tg > 300 ng/mL (TENIS).

Note the linear uptake of RAI in the midline of the neck, which on SPECT/CT is seen corresponding to the tracheostomy tube. Both the [18F]-FDG and [68Ga]GaFAPI-04 demonstrated uptake in the pretracheal node (SUVmax: 4.4 vs 4.5) and soft-tissue growth in the lumen of trachea (SUVmax: 5.68 vs 6.64) [Fig 15]. Biopsy from the intratracheal growth was negative for dysplasia and malignancy and favoured granuloma. The findings in this case illustrate nonspecific tracer accumulation of RAI, FDG, and FAPI in inflammatory settings.

(A) Anterior and (B) posterior projections of a low-dose iodine scan showing linear RAI uptake in the mid-neck region (black arrows in A and B). (C) SPECT/CT of the neck and thorax localising the RAI uptake to tracheostomy tube lining (non-specific). [18F]-FDG positron emission tomography–computed tomography (PET/CT) MIP (D) showing bifocal FDG concentration in the central neck (corresponding to pretracheal node (upper – red arrow) and intratracheal soft-tissue growth (lower – yellow arrow) with no concentration in bilateral lung nodules. [68Ga]Ga-fibroblast activation protein inhibitor-04 PET/CT MIP (E) of the same patient demonstrates the same uptake pattern as FDG with fibroblast activation protein expression in the pretracheal node (red arrow) and intratracheal lesion (yellow arrow). PET/CT: Positron emission tomography–computed tomography, FAPI: Fibroblast activation protein inhibitor
Fig 15: (A) Anterior and (B) posterior projections of a low-dose iodine scan showing linear RAI uptake in the mid-neck region (black arrows in A and B). (C) SPECT/CT of the neck and thorax localising the RAI uptake to tracheostomy tube lining (non-specific). [18F]-FDG positron emission tomography–computed tomography (PET/CT) MIP (D) showing bifocal FDG concentration in the central neck (corresponding to pretracheal node (upper – red arrow) and intratracheal soft-tissue growth (lower – yellow arrow) with no concentration in bilateral lung nodules. [68Ga]Ga-fibroblast activation protein inhibitor-04 PET/CT MIP (E) of the same patient demonstrates the same uptake pattern as FDG with fibroblast activation protein expression in the pretracheal node (red arrow) and intratracheal lesion (yellow arrow). PET/CT: Positron emission tomography–computed tomography, FAPI: Fibroblast activation protein inhibitor

In view of no FAP and FDG expression in the lung nodules, FAP-targeted therapy is not appropriate in this context.

Learning points: Cases 12–15 highlight that although [68Ga] Ga-FAPI-04 uptake is commonly associated with malignancy, it may also be observed in a variety of non-specific and benign conditions, as illustrated above. Therefore, comprehensive clinicoradiological correlation is essential to ensure accurate interpretation of imaging findings and to avoid inappropriate selection of patients for FAP-targeted radioligand therapy.

CLINICAL SIGNIFICANCE

This pictorial review illustrates cases of radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC) evaluated with FAPI-04 and FDG PET/CT imaging modalities. Among the illustrated patients, cases 1, 2, and 3 appear feasible candidates for FAP-targeted therapies. In contrast, cases 4–11 are not considered feasible owing to absent tracer uptake, discordant findings on FDG imaging, or marked heterogeneity. A few false-positive uptake patterns on FAPI-04 imaging, namely infection, inflammation, benign bone tumours (non-ossifying fibroma), and adenomyosis, are also highlighted.

FDG is the imaging modality of choice for staging, risk stratification, and prognostication. Despite this, FAPI PET/CT holds potential value in selected clinical scenarios where it may serve as an adjunct tool, thereby helping to stratify patients who may benefit from FAP-targeted therapies.

False-positive uptakes remain a recognised limitation of FAPI imaging, necessitating further knowledge development of nonspecific uptake patterns and their cautious interpretation.

Author contributions:

MRM, PV and SB: Concept, drafting, analysis of the data, reviewing and revising the manuscript.

Ethical approval:

The study/research was approved by the Institutional Review Board.

Declaration of patient consent:

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given consent for their images and other clinical information to be reported in the journal. The patient understand that the patient’s names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Financial support and sponsorship: Nil

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