Mapping Aggressive Fibromatosis: Targeting Fibroblast Activated Protein (FAP) Using Radiolabelled Inhibitors (⁶⁸Ga - FAPI) PET/CT

INTRODUCTION

Aggressive fibromatosis (AF) is a rare form of musculoskeletal fibromatosis, a benign pathology with potential to infiltrate into adjacent tissue and recur but not metastasise.^[1,2]

These desmoid tumours, as they are often referred to, can further be categorised based on clinical pathological parameters and location – intra-abdominal, extra-abdominal (most common), and abdominal wall.^[3]

The patients are usually evaluated either with computed tomography (CT) or magnetic resonance imaging (MRI). Non-contrast CT usually shows the lesion to have similar or mildly higher attenuation than the skeletal muscle, with a mild to moderate enhancement on contrast CT.^[4,5] The common pattern on MRI is heterogeneity, with iso to hyper-intense signal to muscle on T2 and iso- intense on T1-weighted images.^[6] A large number of lesions show contrast enhancement on gadolinium-enhanced MRI.^[7]

Surgery with clear margins was considered a good option for curative intent, with a meta-analysis identifying a recurrence rate of 30% when treated with surgery along with RT.^[8] However, due to the infiltrative nature of the disease, getting a clear margin is often difficult, and it often leads to the sacrifice of important tissues and function if extensive surgery is done to obtain an R0 resection.

Since this is a rare disease, with no prospective studies or large retrospective data available regarding the optimum management, a consensus committee was formed to look into the literature to decide on the same. The joint global consensus-based guideline on the management of desmoid tumours in adult and paediatric patients was recently published; it suggests active surveillance as the first line of treatment, with surgical intervention (for abdominal sites) or local ablative therapies (non-abdominal sites ) when there is a progression or for symptomatic relief (second line). Other tumour shrinking or stabilising options of chemotherapy, and receptor-directed inhibitors or hormones are offered with the goal of pain alleviation and minimal morbidity.^[9]

Patients frequently present with a large inoperable lesion, also not amenable to radiotherapy, and are offered an option of targeted medical therapy. The high cost of these targeted medicines makes it non affordable, especially in developing countries. In such situations, amputation of the limb is often considered as an option.

Recently, FAPI PETCT has gained momentum as a modality for localising disease in various malignancies, especially those where FDG shows low to absent uptakes. The other advantage of exploring FAPI PETCT is the possibility of using this as a theranostic agent for localised radiotherapy.

CASE SERIES

With an intention to look into the feasibility of offering local ablative therapy for recurrent or refractory AF using ⁶⁸Ga/¹⁷⁷ Lu labelled FAPI theranostic, the paediatric solid tumour multimodality working group (PSTMWG) at our tertiary cancer institute, with permission from the IEC on humanitarian grounds, permitted a pilot diagnostic evaluation of ⁶⁸Ga FAPI PET/CT in 4 patients.

These children had failed all lines of therapy and were either planned for best supportive care or limb amputation. The scans were carried out after informed consent from the parents of the children.

4 children with extra-abdominal recurrent refractory fibromatosis, not amenable to surgery (one planned for amputation of limb), were considered for a whole-body ⁶⁸Ga FAPI - 04 PETCT scan. The history and indication of each case are as follows.

Case 1

An 8-year-old child with recurrent left gluteal region AF underwent excision due to the inability to sit or lie down comfortably. The child was initiated on chemotherapy with a tyrosine kinase inhibitor (TKI) for a recurrent lesion and underwent imaging as she presented with a slow increase in size of the lesion and restriction of hip movements. This patient had failed all lines of treatment, and a FAPI scan was advised to evaluate the expression of FAP [Fig 1].

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Fig 1 An 8-year-old child with recurrent left gluteal region AF underwent excision due to the inability to sit or lie down comfortably. The child was initiated on chemotherapy with a tyrosine kinase inhibitor (TKI) for a recurrent lesion and underwent imaging as she presented with a slow increase in size of the lesion and restriction of hip movements. (A) The MIP image of ⁶⁸Ga FAPI scan shows a large area of intense FAPI uptake in the left pelvic region (arrow); (B) Corresponding to the irregular soft tissue mass in the gluteal region (arrow) extending superiorly to posterior aspect of the left hip and inferiorly to the medial thigh as seen in the coronal CT images (arrow heads); well appreciated in the (C) Fused PETCT coronal image (arrowheads). MIP: Maximum intensity projection; ⁶⁸Ga: ⁶⁸Gallium; FAPI: Fibroblast activation protein inhibitor; MRI: Magnetic resonance image; PET/CT: Positron emission tomography/computed tomography

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Case 2

AF involving the left calf in a 12-yr old male child was kept under observation for 2 years. Subsequently, chemotherapy was initiated due to severe pain; however, within a year of medical therapy, there was an increase in the size of the lesion associated with restricted knee joint movements. Surgical excision of the large lesion was not feasible, and hence, it was treated with local radiotherapy. The patient returned after 6 months with increasing immobility. The patient was planned for a morbid surgery - hip amputation [Fig 2].

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Fig 2: Agressive fibromatosis involving the left calf in a 12 yr old male child was kept under observation for 2 years. Subsequently chemotherapy was initiated due to severe pain, however within a year of medical therapy there was an increase in size of the lesion associated with restricted knee joint movements. Surgical excision of the large lesion was not feasible and hence treated with local radiotherapy. The patient returned after 6 months with increasing immobility. (A) The MIP image of the ⁶⁸Ga FAPI 04 scan showed intense uptake in the clinically appreciated large irregular mass in the left lower limb, involving the calf region, extending into the knee joint and further superiorly into lower thigh (arrow) also noted were uptake in the upper thigh and the gluteal region (arrowhead); (B) The enlarged coronal PET images of the lower limb show scattered foci of uptake in the thigh and the gluteal region more clearly (arrowhead) along with the clinical lesion in the calf (arrow); (C) The coronal CT images show correlative hypodense lesions in the primary site in the calf (arrow) with extension along the intermuscular fascia into the gluteal region (arrowhead); (D) The fused coronal PET/CT image depicts the uptakes in large primary at the calf site (arrow) and the extension along intramuscular fascia upto the gluteal region (arrowhead). The patient was planned for a below hip amputation, however the extension into the gluteal region altered the surgical decision to a hip disarticulation. MIP: Maximum intensity projection; ⁶⁸Ga: ⁶⁸Gallium; FAPI: Fibroblast activation protein inhibitor; MRI: Magnetic resonance image; CT: Computed tomography; PET/CT: Positron emission tomography/computed tomography

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Case 3

A case of AF involving the left thigh in a 4-year-old body who had been managed conservatively for 3.5 years, followed by chemotherapy, and presenting with clinical progression of the disease. The clinically discernible large lesion did not allow the child to sit, and he had difficulty walking, too. He had to be carried by the caretakers and had to always be lying prone [Fig 3].

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Fig 3: Left thigh AF in a 4 yr old boy managed conservatively for 3.5 years and on oral chemotherapy was seen in the outpatient with progression of lesion. The clinically appreciated large left thigh mass extending into the gluteal region (A) MIP image of ⁶⁸Ga FAPI 04 shows intense uptake in primary mass lesion in thigh (arrowhead), while 2 other small areas of diffuse uptake were seen in the lower limb (arrows); (B) The corresponding coronal CT images show the primary soft tissue in the left tibial region and another lesion in the ankle region (arrowheads); (C) Fused coronal PET/CT images also depict the additional ankle lesions with intense FDG uptake (arrowheads). The FAPI PET/CT scan revealed synchronous sites of disease involvement suggesting a multifocal disease. AF: Aggressive fibromatosis; MIP: Maximum intensity projection; ⁶⁸Ga: ⁶⁸Gallium; FAPI: Fibroblast activation protein inhibitor; MRI: Magnetic resonance image; CT: Computed tomography; PET/CT: Positron emission tomography/computed tomography; FDG: Fluorodeoxyglucose

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Case 4

A 14-year-old girl operated for AF involving the left ankle region; she subsequently received chemotherapy and local radiotherapy for recurrence. Presented with a recurrent nodule at the local site. The patient has exhausted all treatment options and was planned for possible amputation [Fig 4].

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Fig 4: A 14-year-old girl child operated for aggressive fibromatosis involving the left ankle region after progression on chemotherapy & local radiotherapy, was evaluated for a recurrent nodule at the local site. (A) The MIP images of ⁶⁸Ga FAPI 04 scan show focal tracer concentration in 2 nodules in the left ankle (arrow); (B) Sagittal CT images of the lower limb show well demarcated nodules (arrow); (C) Fused sagittal PET/CT image with arrow identify these nodular lesions in ankle; (D) Fused coronal PET/CT of the thigh region locates an intense fusiform uptake in the left thigh region (seen as arrowhead in A) which corresponds to a soft tissue lesion in the intermuscular plane of the thigh (arrow in D); (E) A MRI of the thigh showed a hyperintense lesion on T2 weighted images with areas of hypodense fibrotic content within (arrow), confirming another site of aggressive fibromatosis; again highlighting the role of whole body scan in identifying multifocal disease. MIP: Maximum intensity projection; FAPI: Fibroblast activation protein inhibitor; CT: Computed tomography; PET/CT: Positron emission tomography/computed tomography; MRI: Magnetic resonance imaging

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DISCUSSION

Theranostic has been incorporated into the treatment guidelines of GEP neuroendocrine tumours^[10] and has been proven to be beneficial in the management of castrate resistant metastatic prostate cancer,^[11] using Gallium 68/Lutetium 177 (⁶⁸Ga/¹⁷⁷ Lu) pairs labelled to somatostatin receptor analogues (SSTR) and prostate-specific membrane antigen (PSMA), respectively.

Cancer-associated fibroblast (CAF), abundant in the tumour microenvironment, secretes a protein (FAP) which causes angiogenesis and is responsible for therapy resistance.^[12]Inhibitors targeting this protein (FAPI) are being considered as a mode of immunotherapy. FAPI has been labelled with⁶⁸Ga and has shown a good uptake at metastatic sites along with primary tumours in various malignancies.^[13]

Overexpression of fibroblasts is documented in tissues where remodelling is in process, e.g., inflammation and fibrosis, leading to increased FAPI uptake in non-malignant disease,^[14] also confirmed in the recent systematic review.^[15,16]

Due to the predominance of myofibroblasts and fibroblasts, which also express a variant of the FAP (alpha) protein, FAP is also seen in AF.^[17] Our case series confirms the presence of a variant of FAP expression in non-malignant tumours, AF.

A case report by Wei J et al. demonstrates the presence of FAPI uptake in an incidentally detected mesenteric AF,^[18]part of a trial evaluating the uptake of ⁶⁸Ga-FAPI in various malignancies.

An interesting, unpublished data presented as an abstract evaluated intra-abdominal desmoid fibromatosis with both FDG and FAPI; this data suggests a higher uptake of FAPI in the intra-abdominal desmoid fibromatosis than FDG^[19] and also suggests its usefulness in distinguishing AF from metastases of GIST.

Both the above studies, though assessing intra-abdominal AF, confirm the expression of FAP in this non-malignant yet aggressive pathology.

To our knowledge, there is no data on utilising ⁶⁸Ga FAPI in evaluating paediatric extra-abdominal fibromatosis in the literature.

This disease is often a crippling pathology in paediatric patients due to multiple recurrences caused by its infiltrative nature, as is seen in all the 4 cases seen in this series.

Multifocal AF is a rare entity, usually sporadic, but could be associated with genetic predispositions.^[20] The FAPI PETCT,by virtue of its whole-body evaluation, helped locate the sites of recurrence with its extent and also delineated multifocality in 2 of our 4 patients.

The case series provides the following teaching points about FAPI scans in AF :

1. It illustrates the presence of the target FAP in aggressive fibromatosis, though a benign disease.

2. Useful in mapping the disease - delineates the extent of primary disease and also can unearth multifocal disease, which can alter management.

3. Portray the potential use of FAPI as a carrier for theranostic, offering a tumour-specific conformal ablative treatment for the intrusive, debilitating pathology, especially when surgery is not feasible.

CONCLUSION

To conclude, radiolabelled FAPI theranostic can be considered in the management of AF and fit into the algorithm provided by the consensus guidelines when considering a non-surgical treatment option. Its systemic therapeutic option will be especially useful in multifocal disease.