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European Journal of Nuclear Medicine and Molecular Imaging

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Open Access 01-11-2021 | Metastasis | Original Article

Targeting fibroblast activation protein in newly diagnosed squamous cell carcinoma of the oral cavity – initial experience and comparison to [¹⁸F]FDG PET/CT and MRI

Authors: Christian Linz, Roman C. Brands, Olivia Kertels, Alexander Dierks, Joachim Brumberg, Elena Gerhard-Hartmann, Stefan Hartmann, Andreas Schirbel, Sebastian Serfling, Yingjun Zhi, Andreas K. Buck, Alexander Kübler, Julian Hohm, Constantin Lapa, Malte Kircher

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 12/2021

Abstract

Purpose

While [¹⁸F]-fluorodeoxyglucose ([¹⁸F]FDG) is the standard for positron emission tomography/computed tomography (PET/CT) imaging of oral squamous cell carcinoma (OSCC), diagnostic specificity is hampered by uptake in inflammatory cells such as neutrophils or macrophages. Recently, molecular imaging probes targeting fibroblast activation protein α (FAP), which is overexpressed in a variety of cancer-associated fibroblasts, have become available and might constitute a feasible alternative to FDG PET/CT.

Methods

Ten consecutive, treatment-naïve patients (8 males, 2 females; mean age, 62 ± 9 years) with biopsy-proven OSCC underwent both whole-body [¹⁸F]FDG and [⁶⁸Ga]FAPI-04 (FAP-directed) PET/CT for primary staging prior to tumor resection and cervical lymph node dissection. Detection of the primary tumor, as well as the presence and number of lymph node and distant metastases was analysed. Intensity of tracer accumulation was assessed by means of maximum (SUV_max) and peak (SUV_peak) standardized uptake values. Histological work-up including immunohistochemical staining for FAP served as standard of reference.

Results

[¹⁸F]FDG and FAP-directed PET/CT detected all primary tumors with a SUV_max of 25.5 ± 13.2 (FDG) and 20.5 ± 6.4 (FAP-directed) and a SUV_peak of 16.1 ± 10.3 ([¹⁸F]FDG) and 13.8 ± 3.9 (FAP-directed), respectively. Regarding cervical lymph node metastases, FAP-directed PET/CT demonstrated comparable sensitivity (81.3% vs. 87.5%; P = 0.32) and specificity (93.3% vs. 81.3%; P = 0.16) to [¹⁸F]FDG PET/CT. FAP expression on the cell surface of cancer-associated fibroblasts in both primary lesions as well as lymph nodes metastases was confirmed in all samples.

Conclusion

FAP-directed PET/CT in OSCC seems feasible. Future research to investigate its potential to improve patient staging is highly warranted.

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Hernandez-Guerrero JC, Jacinto-Aleman LF, Jimenez-Farfan MD, Macario-Hernandez A, Hernandez-Flores F, Alcantara-Vazquez A. Prevalence trends of oral squamous cell carcinoma. Mexico City’s General Hospital experience. Med Oral Patol Oral Cir Bucal. 2013;18:e306-11.CrossRef

Sadick M, Schoenberg SO, Hoermann K, Sadick H. Current oncologic concepts and emerging techniques for imaging of head and neck squamous cell cancer. GMS Curr Topics Otorhinolaryngol Head Neck Surg. 2012;11:Doc08. https://doi.org/10.3205/cto000090.CrossRef

Bagan J, Sarrion G, Jimenez Y. Oral cancer: clinical features. Oral Oncol. 2010;46:414–7. https://doi.org/10.1016/j.oraloncology.2010.03.009.CrossRefPubMed

Tandon P, Dadhich A, Saluja H, Bawane S, Sachdeva S. The prevalence of squamous cell carcinoma in different sites of oral cavity at our Rural Health Care Centre in Loni, Maharashtra - a retrospective 10-year study. Contemp Oncol (Pozn). 2017;21:178–83. https://doi.org/10.5114/wo.2017.68628.CrossRef

DiTroia JF. Nodal metastases and prognosis in carcinoma of the oral cavity. Otolaryngol Clin North Am. 1972;5:333–42.CrossRef

Kumar T, Patel MD. Pattern of lymphatic metastasis in relation to the depth of tumor in oral tongue cancers: a clinico pathological correlation. Indian J Otolaryngol Head Neck Surg. 2013;65:59–63. https://doi.org/10.1007/s12070-012-0504-y.CrossRefPubMed

Sparano A, Weinstein G, Chalian A, Yodul M, Weber R. Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg. 2004;131:472–6. https://doi.org/10.1016/j.otohns.2004.04.008.CrossRefPubMed

Teichgraeber JF, Clairmont AA. The incidence of occult metastases for cancer of the oral tongue and floor of the mouth: treatment rationale. Head Neck Surg. 1984;7:15–21.CrossRef

Haigentz M Jr, Hartl DM, Silver CE, Langendijk JA, Strojan P, Paleri V, et al. Distant metastases from head and neck squamous cell carcinoma Part III. Treat Oral Oncol. 2012;48:787–93. https://doi.org/10.1016/j.oraloncology.2012.03.019.CrossRefPubMed

10.

de Bree R, Castelijns JA, Hoekstra OS, Leemans CR. Advances in imaging in the work-up of head and neck cancer patients. Oral Oncol. 2009;45:930–5. https://doi.org/10.1016/j.oraloncology.2009.07.011.CrossRefPubMed

11.

Edge SB, Compton CC. The American joint committee on cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–4. https://doi.org/10.1245/s10434-010-0985-4.CrossRefPubMed

12.

Huang SH, O’Sullivan B. Overview of the 8th Edition TNM classification for head and neck cancer. Curr Treat Options Oncol. 2017;18:40. https://doi.org/10.1007/s11864-017-0484-y.CrossRefPubMed

13.

Cho JK, Ow TJ, Lee AY, Smith RV, Schlecht NF, Schiff BA, et al. Preoperative (18)F-FDG-PET/CT vs contrast-enhanced CT to identify regional nodal metastasis among patients with head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg. 2017;157:439–47. https://doi.org/10.1177/0194599817703927.CrossRefPubMedPubMedCentral

14.

Dammann F, Horger M, Mueller-Berg M, Schlemmer H, Claussen CD, Hoffman J, et al. Rational diagnosis of squamous cell carcinoma of the head and neck region: comparative evaluation of CT, MRI, and 18FDG PET. AJR Am J Roentgenol. 2005;184:1326–31. https://doi.org/10.2214/ajr.184.4.01841326.CrossRefPubMed

15.

Hirshoren N, Olayos E, Herschtal A, Ravi Kumar AS, Gyorki DE. Preoperative positron emission tomography for node-positive head and neck cutaneous squamous cell carcinoma. Otolaryngol Head Neck Surg. 2018;158:122–6. https://doi.org/10.1177/0194599817731735.CrossRefPubMed

16.

Krabbe CA, Balink H, Roodenburg JL, Dol J, de Visscher JG. Performance of 18F-FDG PET/contrast-enhanced CT in the staging of squamous cell carcinoma of the oral cavity and oropharynx. Int J Oral Maxillofac Surg. 2011;40:1263–70. https://doi.org/10.1016/j.ijom.2011.06.023.CrossRefPubMed

17.

Subramaniam RM, Agarwal A, Colucci A, Ferraro R, Paidpally V, Mercier G. Impact of concurrent diagnostic level CT with PET/CT on the utilization of stand-alone CT and MRI in the management of head and neck cancer patients. Clin Nucl Med. 2013;38:790–4. https://doi.org/10.1097/RLU.0b013e31829f8ca5.CrossRefPubMed

18.

Wallowy P, Diener J, Grunwald F, Kovacs AF. 18F-FDG PET for detecting metastases and synchronous primary malignancies in patients with oral and oropharyngeal cancer. Nuklearmedizin. 2009;48:192-9; quiz N42. https://doi.org/10.3413/nukmed-0242.

19.

Kircher M, Lapa C. Infection and inflammation imaging: beyond FDG. PET Clin. 2020;15:215–29. https://doi.org/10.1016/j.cpet.2019.11.004.CrossRefPubMed

20.

Plaxton NA, Brandon DC, Corey AS, Harrison CE, KaragulleKendi AT, Halkar RK, et al. Characteristics and limitations of FDG PET/CT for imaging of squamous cell carcinoma of the head and neck: a comprehensive review of anatomy, metastatic pathways, and image findings. AJR Am J Roentgenol. 2015;205:W519–31. https://doi.org/10.2214/AJR.14.12828.CrossRefPubMed

21.

Bae JY, Kim EK, Yang DH, Zhang X, Park YJ, Lee DY, et al. Reciprocal interaction between carcinoma-associated fibroblasts and squamous carcinoma cells through interleukin-1alpha induces cancer progression. Neoplasia. 2014;16:928–38. https://doi.org/10.1016/j.neo.2014.09.003.CrossRefPubMedPubMedCentral

22.

Wang H, Wu Q, Liu Z, Luo X, Fan Y, Liu Y, et al. Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma. Cell Death Dis. 2014;5:e1155. https://doi.org/10.1038/cddis.2014.122.CrossRefPubMedPubMedCentral

23.

Scanlan MJ, Raj BK, Calvo B, Garin-Chesa P, Sanz-Moncasi MP, Healey JH, et al. Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci U S A. 1994;91:5657–61. https://doi.org/10.1073/pnas.91.12.5657.CrossRefPubMedPubMedCentral

24.

Garin-Chesa P, Old LJ, Rettig WJ. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci U S A. 1990;87:7235–9. https://doi.org/10.1073/pnas.87.18.7235.CrossRefPubMedPubMedCentral

25.

Brennen WN, Isaacs JT, Denmeade SR. Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol Cancer Ther. 2012;11:257–66. https://doi.org/10.1158/1535-7163.MCT-11-0340.CrossRefPubMedPubMedCentral

26.

Liu F, Qi L, Liu B, Liu J, Zhang H, Che D, et al. Fibroblast activation protein overexpression and clinical implications in solid tumors: a meta-analysis. PLoS ONE. 2015;10:e0116683. https://doi.org/10.1371/journal.pone.0116683.CrossRefPubMedPubMedCentral

27.

Niedermeyer J, Garin-Chesa P, Kriz M, Hilberg F, Mueller E, Bamberger U, et al. Expression of the fibroblast activation protein during mouse embryo development. Int J Dev Biol. 2001;45:445–7.PubMed

28.

Lindner T, Loktev A, Altmann A, Giesel F, Kratochwil C, Debus J, et al. Development of quinoline-based theranostic ligands for the targeting of fibroblast activation protein. J Nucl Med. 2018;59:1415–22. https://doi.org/10.2967/jnumed.118.210443.CrossRefPubMed

29.

Luo Y, Pan Q, Zhang W. IgG4-related disease revealed by (68)Ga-FAPI and (18)F-FDG PET/CT. Eur J Nucl Med Mol Imaging. 2019;46:2625–6. https://doi.org/10.1007/s00259-019-04478-2.CrossRefPubMed

30.

Luo Y, Pan Q, Zhang W, Li F. Intense FAPI uptake in inflammation may mask the tumor activity of pancreatic cancer in 68Ga-FAPI PET/CT. Clin Nucl Med. 2020;45:310–1. https://doi.org/10.1097/rlu.0000000000002914.CrossRefPubMed

31.

Pan Q, Luo Y, Zhang W. Recurrent immunoglobulin G4-related disease shown on 18F-FDG and 68Ga-FAPI PET/CT. Clin Nucl Med. 2020;45:312–3. https://doi.org/10.1097/rlu.0000000000002919.CrossRefPubMed

32.

Schmidkonz C, Rauber S, Atzinger A, Agarwal R, Götz TI, Soare A, et al. Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging. Ann Rheum Dis. 2020;79:1485–91. https://doi.org/10.1136/annrheumdis-2020-217408.CrossRefPubMed

33.

Hao B, Wu X, Pang Y, Sun L, Wu H, Huang W, et al. [(18)F]FDG and ([68)Ga]Ga-DOTA-FAPI-04 PET/CT in the evaluation of tuberculous lesions. Eur J Nucl Med Mol Imaging. 2021;48:651–2. https://doi.org/10.1007/s00259-020-04941-5.CrossRefPubMed

34.

Robbins KT, Clayman G, Levine PA, Medina J, Sessions R, Shaha A, et al. Neck dissection classification update: revisions proposed by the American head and neck society and the American academy of otolaryngology-head and neck surgery. Arch Otolaryngol Head Neck Surg. 2002;128:751–8.CrossRef

35.

Campbell RS, Baker E, Chippindale AJ, Wilson G, McLean N, Soames JV, et al. MRI T staging of squamous cell carcinoma of the oral cavity: radiological-pathological correlation. Clin Radiol. 1995;50:533–40. https://doi.org/10.1016/s0009-9260(05)83187-3.CrossRefPubMed

36.

Trotta BM, Pease CS, Rasamny JJ, Raghavan P, Mukherjee S. Oral cavity and oropharyngeal squamous cell cancer: key imaging findings for staging and treatment planning. Radiographics Rev Publ Radiol Soc North Am Inc. 2011;31:339–354. https://doi.org/10.1148/rg.312105107.

37.

Forghani R, Yu E, Levental M, Som PM, Curtin HD. Imaging evaluation of lymphadenopathy and patterns of lymph node spread in head and neck cancer. Expert Rev Anticancer Ther. 2015;15:207–24. https://doi.org/10.1586/14737140.2015.978862.CrossRefPubMed

38.

Som PM, Curtin HD, Mancuso AA. Imaging-based nodal classification for evaluation of neck metastatic adenopathy. AJR Am J Roentgenol. 2000;174:837–44. https://doi.org/10.2214/ajr.174.3.1740837.CrossRefPubMed

39.

Henry LR, Lee HO, Lee JS, Klein-Szanto A, Watts P, Ross EA, et al. Clinical implications of fibroblast activation protein in patients with colon cancer. Clin Cancer Res. 2007;13:1736–41. https://doi.org/10.1158/1078-0432.CCR-06-1746.CrossRefPubMed

40.

Serfling S, Zhi Y, Schirbel A, Lindner T, Meyer T, Gerhard-Hartmann E, et al. Improved cancer detection in Waldeyer’s tonsillar ring by (68)Ga-FAPI PET/CT imaging. Eur J Nucl Med Mol Imaging. 2020. https://doi.org/10.1007/s00259-020-05055-8.CrossRefPubMedPubMedCentral

41.

Pentenero M, Cistaro A, Brusa M, Ferraris MM, Pezzuto C, Carnino R, et al. Accuracy of 18F-FDG-PET/CT for staging of oral squamous cell carcinoma. Head Neck. 2008;30:1488–96. https://doi.org/10.1002/hed.20906.CrossRefPubMed

42.

Lowe VJ, Duan F, Subramaniam RM, Sicks JD, Romanoff J, Bartel T, et al. Multicenter Trial of [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography staging of head and neck cancer and negative predictive value and surgical impact in the N0 neck: results from ACRIN 6685. J Clin Oncol Off J Am Soc Clin Oncol. 2019;37:1704–12. https://doi.org/10.1200/jco.18.01182.CrossRef

43.

Yongkui L, Jian L, Wanghan, Jingui L. 18FDG-PET/CT for the detection of regional nodal metastasis in patients with primary head and neck cancer before treatment: a meta-analysis. Surg Oncol. 2013;22:e11-6. https://doi.org/10.1016/j.suronc.2013.02.002.CrossRefPubMed

44.

Syed M, Flechsig P, Liermann J, Windisch P, Staudinger F, Akbaba S, et al. Fibroblast activation protein inhibitor (FAPI) PET for diagnostics and advanced targeted radiotherapy in head and neck cancers. Eur J Nucl Med Mol Imaging. 2020;47:2836–45. https://doi.org/10.1007/s00259-020-04859-y.CrossRefPubMedPubMedCentral

45.

Giesel FL, Kratochwil C, Lindner T, Marschalek MM, Loktev A, Lehnert W, et al. (68)Ga-FAPI PET/CT: biodistribution and preliminary dosimetry estimate of 2 DOTA-containing FAP-targeting agents in patients with various cancers. J Nucl Med. 2019;60:386–92. https://doi.org/10.2967/jnumed.118.215913.CrossRefPubMedPubMedCentral

46.

Luo Y, Pan Q, Yang H, Peng L, Zhang W, Li F. Fibroblast activation protein-targeted PET/CT with (68)Ga-FAPI for imaging IgG4-related disease: comparison to (18)F-FDG PET/CT. J Nucl Med. 2021;62:266–71. https://doi.org/10.2967/jnumed.120.244723.CrossRefPubMed

47.

Pure E, Blomberg R. Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics. Oncogene. 2018;37:4343–57. https://doi.org/10.1038/s41388-018-0275-3.CrossRefPubMedPubMedCentral

Title: Targeting fibroblast activation protein in newly diagnosed squamous cell carcinoma of the oral cavity – initial experience and comparison to [18F]FDG PET/CT and MRI
Authors: Christian Linz
Roman C. Brands
Olivia Kertels
Alexander Dierks
Joachim Brumberg
Elena Gerhard-Hartmann
Stefan Hartmann
Andreas Schirbel
Sebastian Serfling
Yingjun Zhi
Andreas K. Buck
Alexander Kübler
Julian Hohm
Constantin Lapa
Malte Kircher
Publication date: 01-11-2021
Publisher: Springer Berlin Heidelberg
Keywords: Metastasis
Molecular Imaging
Magnetic Resonance Imaging
Magnetic Resonance Imaging
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 12/2021
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-021-05422-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Targeting fibroblast activation protein in newly diagnosed squamous cell carcinoma of the oral cavity – initial experience and comparison to [¹⁸F]FDG PET/CT and MRI

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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