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Tenosynovial giant cell tumor: case report of a patient effectively treated with pexidartinib (PLX3397) and review of the literature

Tenosynovial giant cell tumor: case report of a patient effectively treated with pexidartinib... Background: Tenosynovial giant cell tumors ( TGCTs) or giant cell tumors of tendon sheath are neoplasms that arise in the synovium. They can be categorized as nodular (localized) or diffuse type (D-TGCT ). Historically, surgery has been the mainstay of therapy, but diffuse type disease recurs at a high rate and treatment often requires increasingly mor - bid procedures. Elucidation of the importance of the colony-stimulating factor (CSF1)/CSF1 receptor (CSF1R) pathway in the pathogenesis of this disease has created significant interest in targeting this pathway as a novel TGCT treatment approach. Pexidartinib, a selective tyrosine kinase inhibitor against CSF1R, showed an 83% disease control rate (52% with partial response and 31% with stable disease) in a recent phase 1 study of patients with TGCT. Case presentation: We present an illustrative example of a TGCT patient who would have required a morbid opera- tion who derived considerable clinical benefit from pexidartinib treatment. Her tumor volume decreased by 48% after 4 months of treatment, and 55 months after starting treatment the patient exhibits continued disease stability with minimal clinical symptoms, and significant improvement in functional status. Conclusions: This case illustrates the effectiveness of systemic therapy in controlling a disease associated with high surgical morbidity. This approach may be especially useful in the treatment of extra-articular disease which often invades neurovascular bundles; as the effectiveness in metastatic disease is still unknown. In the future, systemic treatment for TGCT may be appropriate for the neoadjuvant setting to decrease disease burden prior to surgery with the aim of decreasing recurrence rates. However, properly designed prospective studies will need to be carried out to answer these questions. Keywords: Tenosynovial giant cell tumor, TGCT , Giant cell tumor of tendon sheath, GCT-TS, Pigmented villonodular synovitis, PVNS, Pexidartinib, PLX3397, Case report, CSF1 Background biological features of these neoplasms affect treatment Tenosynovial giant cell tumor (TGCT), is a neoplasm [1]. derived from the synovium that causes recruitment of Localized TGCT is characterized by a discrete nodule, immune cells, specifically macrophages, leading to for - with a predilection for the radial three digits [2]. Diffuse mation of a mass. These tumors are often classified TGCT (D-TGCT), formerly known as pigmented villo- by their growth pattern (localized or diffuse) and site nodular synovitis (PVNS), is characterized by a diffuse (intra- or extra-articular). These pathological distinc - proliferation in the synovium most commonly occurring tions are important because variability in the clinical and in and around the knee (~ 75% of tumors) [3]. While local and diffuse disease occur intra-articularly throughout the body, D-TGCT can also be extra-articular, and, in rare *Correspondence: asingh@mednet.ucla.edu circumstances, can metastasize to adjacent lymph nodes Division of Hematology and Oncology, University of California Los and the lungs. Angeles (UCLA), 2825 Santa Monica Blvd. Suite 200, Santa Monica, CA 90404, USA Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Giustini et al. Clin Sarcoma Res (2018) 8:14 Page 2 of 5 Both localized and diffuse TGCT occur primarily in can be used to effectively reduce the disease burden in a the 3rd–4th decades of life with a female:male predomi- patient with D-TGCT [12]. nance of 1.6–2.1:1 in the localized type and no sex pre- dilection in the diffuse type. The annual incidence in the Case presentation United States is approximately 11 per million; of that, 9.2 RM is a 47-year-old woman who initially presented when being localized and 1.8 diffuse types. In a more recent she was 40 years old with 3 months of right knee pain in epidemiological study from the Netherlands, the world- December 2010. At that time, a radiograph of the knee wide incidence rate of TGCT (including both localized showed two lesions: a 3-cm circumscribed lytic lesion and diffuse) was estimated to be 43 per million [4]. of the posterolateral distal femur thought possibly to be Clinical presentation of TGCT is variable. The first sign a nonossifying fibroma, as well as a 2-cm circumscribed for patients with pathology in the hand is often a pain- lytic lesion with sclerotic margins involving the proximal less, slow-growing, firm nontender mass, which may tibial epiphysis. An MRI 1  month later showed lesions eventually become painful and edematous as it impinges suspicious for TGCT; an orthopedic oncologist recom- on anatomic structures [2]. When presenting in the knee, mended a diagnostic arthroscopy with possible conver- intermittent swelling without antecedent trauma is a sion to open anterior and posterior synovectomy. The common symptom [5]. patient declined and underwent a trial of oral prednisone In 2006, the landmark article by West et  al. shed light with some symptomatic relief until October 2012 when on the pathogenesis of TGCT. Chromosomes 1 and 2 she re-presented with worsening pain, edema, and a limp. undergo a translocation at 1p13, which fuses to 2q35, At that time, she underwent biopsy, which was read as a leading to the fusion of CSF1 to COL6A3 and the over- likely inflammatory process. One week later the patient production of CSF1. However, in collected samples, ele- underwent an incisional biopsy. vated CSF1 expression was found in only 2–16% of the Histology of the neoplasm showed a hypercellular cells comprising the tumor. This may be in keeping with lesion consistent with D-TGCT. Immunohistochemistry the fact that only a small fraction of the TGCT mass is revealed negative pankeratins, negative desmin, negative considered the malignant clone. As CSF1R is present on CD1a, positive CD68 in a patchy distribution, and a Ki-67 immune cells, specifically macrophages, it has been pos - of 10%. A repeat MRI at the time of diagnosis showed tulated that overexpression of CSF1 from the malignant a marked increase in the size of the synovial soft mass component of the tumor causes a tremendous immune extending into the suprapatellar compartment, as well as infiltrate, which comprises the bulk of the tumor [6, 7]. anterior and posterior infrapatellar compartments. The Historically, TGCT has been treated using surgery with suprapatellar aspect measured 20  cm × 9.9  cm × 13  cm the consideration for adjuvant radiation. Surgical options (CC × AP × TV). A PET-CT scan indicated no metastatic for TGCT are partial or total synovectomy using arthro- disease and an SUV of 21.7 in the lesions (Fig. 1). Con- max scopic or open techniques. While localized disease is sidering the extent of disease, nonsurgical management readily curable with arthroscopic or open surgery, diffuse was indicated as surgical resection would likely result in disease has shown high recurrence rates with arthros- significant morbidity. In February 2013, 1 week after the copy (40%) and open surgery (14%). Open surgery also PET-CT, the patient consented to oral therapy with pex- leads to increased morbidity in the form of stiffness and idartinib (PLX3397) at 600 mg qAM and 400 mg qHS for pain [8]. a cumulative 1000-mg daily dose. At this time, the patient Newer systemic treatments are being used for TGCT had an ECOG of 1, was on disability and could no longer ranging from less selective tyrosine kinase inhibitors, work as a nurse given her requirement for a walker, and such as imatinib and nilotinib, to CSF1R inhibitors such was managing her pain with naproxen, morphine, and as emactuzumab and cabiralizumab (monoclonal anti- acetaminophen–hydrocodone. body) and pexidartinib (a selective tyrosine kinase inhibi- At the 2-week follow-up, the patient reported an tor) with encouraging results [9]. In the only published improvement of pain and an increased range of motion. phase 2 study of a drug for TGCT, nilotinib led to a dis- Three weeks after initiation, a repeat PET-CT showed ease stabilization rate in 90% of patients at 6  months, disease response with an SUV of 6.3. By 1 month after max but only 6% of patients had a RECIST 1.1 objective initiation, the patient reported she was transitioning to response [10]. In a phase 1 study of emactuzumab, partial crutches and using fewer opioids. By the 4-month MRI, responses were seen in 24/28 patients and 2 patients had there was a reduction in her tumor burden by 48% via complete responses [11]. In particular, the CSF1R inhibi- RECIST 1.1 (14.3 × 7.0 × 12.6  cm to 8.1 × 1.7 × 6.0  cm, tors are being evaluated in patients with cases with high 5.6 × 2.9 × 8.3  cm to 1.8 × 1.5 × 3.5  cm, and operative morbidity. The case presented exemplifies the 9.0 × 2.4 × 9.1  cm to 5.0 × 0.8 × 3.5  cm CC × AP × T V ). situation in which CSF1R inhibitors, namely pexidartinib, At this time, her ECOG was changed to 0 as she was Giustini et al. Clin Sarcoma Res (2018) 8:14 Page 3 of 5 Discussion In 1941, Jaffe et  al. [13] initially created the category of pigmented villonodular synovitis, bursitis, and teno- synovitis, forming a classification for a seemingly diffuse group of entities. Much later, Rao and Vigorita [14] sug- gested that PVNS is a true neoplastic, rather than inflam - matory, process involving fibroblastic or histiocytic mesenchymal cells. Subsequent research identified chro - mosome translocations present in TGCT cases which induce overexpression of CSF-1 in neoplastic synovial cells, in turn causing recruitment of macrophages and other immune cells form the bulk of the tumor mass [6]. Some TGCT cases do not appear to harbor such trans- locations, though notably they still show elevated lev- els CSF1 protein or RNA, suggesting there are alternate mechanisms of CSF1 overproduction [15]. Pexidartinib, or PLX3397, is a selective CSF1R inhibi- tor which targets the CSF1/CSF1R pathway implicated in TGCT pathogenesis. Pexidartinib was designed to simu- late the autoinhibited state of the CSF1R by interacting with the CSF1R juxtamembrane region which is respon- sible for folding and inactivation of the kinase domain and prevents binding of CSF1 and ATP [16]. Based on an initial phase I dose escalation study evaluating the safety and tolerability of pexidartinib in patients with solid tumors, the maximum tolerated dose of 1000  mg/day was chosen for an extension study to evaluate efficacy in TGCT. This multicenter, single cohort extension study enrolled 23 patients with advanced TGCT. Eligibility requirements included a histologically confirmed diagnosis of TGCT that had shown progres - sion within the previous year and was deemed surgi- cally challenging (recurrent vs. inoperable vs. requiring extensive surgery for attempted resection). The mean age of patients was 46  years old with 18 patients having Fig. 1 MRI scan of suprapatellar aspect in January 2013 (a) and May undergone previous surgery, four patients having pre- 2017 (b) viously been treated with either imatinib or nilotinib, and one patient with metastatic disease. Mean duration of treatment was 254  days with 61% of patients requir- ambulating without assistance and returned to work; ing dose reduction and 30% requiring a temporary drug she had also reduced her pain medications to occasional withdrawal, most commonly for fatigue. A common labo- naproxen and had weaned herself off opioids. During the ratory abnormality was elevated aminotransferase levels course of treatment, the dose was adjusted to 400  mg in approximately 50% of patients (only 13% were grade qAM and qHS for 2  months and then to 400  mg qAM 3 and all resolved to grade 1 with temporary drug cessa- and 600  mg qHS, in an effort to manage nausea. Other tion), thought secondary to CSF1 inhibition on Kupffer side effects included fatigue, dysgeusia, and peri-orbital cell functioning [16]. edema. After 55  months of therapy, the patient had sta- In an intention-to-treat analysis of response using ble disease following the initial response with no pro- RECIST 1.1, a total of 83% of patients exhibited disease gression at any time during the treatment course. The control with 52% showing partial response and 31% most recent MRI imaging on 9/8/2017 showed only two showing stable disease. Due to the complex shape of aspects of the lesion, measuring 0.4 × 4.9  cm (AP × T V many TGCTs, conventional tumor response assessment with inability to visualize CC view) and 1.2 × 1.5 × 2.9 cm methodologies are not ideal for discerning response (CC × AP × T V ). in this disease. Tumor volume score, an unvalidated Giustini et al. Clin Sarcoma Res (2018) 8:14 Page 4 of 5 Abbreviations calculation of the tumor volume as a percentage of the TGCT : tenosynovial giant cell tumor; D-TGCT : diffuse tenosynovial giant cell total synovium, similar to a scoring system in use for tumor; CSF1: colony-stimulating factor-1; CSF1R: colony-stimulating factor-1 rheumatoid arthritis, was used to evaluate 14 patients. receptor; PVNS: pigmented villonodular synovitis; qAM: each morning; qHS: each evening. Of these, 11 had a partial response and three had stable disease with a mean decrease in volume of 61%. Com- Authors’ contributions parison of pre- and post-treatment biopsies obtained AS, NG, and NB were major contributors in writing the manuscript. All authors contributed to data collection and interpretation. All authors read and from one patient showed marked decreases in mac- approved the final manuscript. rophages and general cellularity in the tissues. The patient with metastatic disease was the only patient Author details Division of Hematology and Oncology, University of California Los Angeles who showed disease progression using RECIST 1.1, (UCLA), 2825 Santa Monica Blvd. Suite 200, Santa Monica, CA 90404, USA. which occurred after 8  months of stable disease on Division of Orthopedic Oncology, University of California Los Angeles (UCLA), therapy [16]. 1250 16th Street, Suite 2100, Santa Monica, CA 90404, USA. Our patient, RM, who presented with extensive local Acknowledgements disease of the knee, was deemed to not be a candidate The authors would like to thank all the patients with TGCT who have given us for surgery, with or without adjuvant radiation, because an immense education about this disease. it would likely lead to significant unacceptable morbid - Competing interests ity due to the extent of disease, her young age, and her Arun Singh: Advisory board participation: Eli Lilly, Eisai, Roche. Speaker’s profession. Given these factors, as well as the promis- bureau participation: Eli Lilly, Novartis. Nick Giustini, Susan Bukata: None. Nick Bernthal: Consultant: Onkos/Zimmer Biomet. ing results in the study evaluating pexidartinib as treat- ment for TGCT, she was enrolled to start therapy with Availability of data and materials pexidartinib. Not applicable. Consent for publication Written informed consent was obtained from the patient for publication of Conclusions this Case Report and the clinical images. Tenosynovial giant cell tumor is a tumor driven by CSF1 Ethics approval and consent to participate overexpression in neoplastic synovial cells. Before uncov- The study was approved by the ethics committee/institutional review board ering the pathogenesis of this disease, treatment was of the University of California—Los Angeles. primarily surgical. Now systemic therapies, such as the Funding tyrosine kinase inhibitor pexidartinib and the monoclo- Daiichi Sanyo provided funding for editorial support and publication costs. nal antibody emactuzumab, are able to take advantage of the known molecular mechanism of TGCT pathogen- Publisher’s Note esis by targeting the CSF1R. Several other CSF1R inhibi- Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. tors are being evaluated clinically and a comprehensive review of this class of drugs can be found elsewhere [9]. Received: 6 March 2018 Accepted: 19 May 2018 As evidenced in our case report and in a clinical study, pexidartinib has the potential to decrease or stabilize the size of TGCT masses, reduce pain and improve mobility [16, 17]. Bibliography As the use of systemic therapies such as pexidartinib 1. de Saint Aubain Somerhausen NS, van de Rijn M. Tenosynovial giant cell tumor: localized type, diffuse type. In: Fletcher C, Bridge J, Hogendoorn P, become more established as treatments for TGCT, future Martens F, editors. World Health Organization classification of tumours of avenues of study abound. To date, complete response soft tissue and bone. Lyon: IARC Press; 2013. p. 100–3. with pexidartinib has not been established as the neo- 2. Monaghan H, Salter DM, Al-Nafussi A. Giant cell tumour of tendon sheath (localised nodular tenosynovitis): clinicopathological features of 71 cases. plastic cells are only suppressed, not removed. It has been J Clin Pathol. 2001;54:404–7. noted that TGCT patients coming off of pexidartinib do 3. Ottaviani S, et al. Pigmented villonodular synovitis: a retrospective single- show disease relapse (author’s unpublished observation). center study of 122 cases and review of the literature. Semin Arthritis Rheum. 2011;40:539–46. As such, consideration for neoadjuvant pexidartinib 4. Mastboom MJL, et al. Higher incidence rates than previously known in to allow less morbid surgical resection may be a viable tenosynovial giant cell tumors. Acta Orthop. 2017;88:688–94. option. In addition, post-surgical pexidartinib in these 5. Ravi V, Wang WL, Lewis VO. Treatment of tenosynovial giant cell tumor and pigmented villonodular synovitis. Curr Opin Oncol. 2011;23:361–6. cases or in patients with known previous recurrence 6. West RB, et al. A landscape effect in tenosynovial giant-cell tumor from may be effective in delaying repeat recurrence. However, activation of CSF1 expression by a translocation in a minority of tumor answers to these questions will require further validation cells. Proc Natl Acad Sci USA. 2006;103:690–5. 7. Nilsson M, et al. Molecular cytogenetic mapping of recurrent chromo- studies of this effective targeted therapy. somal breakpoints in tenosynovial giant cell tumors. Virchows Arch. 2002;441:475–80. Giustini et al. Clin Sarcoma Res (2018) 8:14 Page 5 of 5 8. Staals EL, et al. Diffuse-type tenosynovial giant cell tumour: current treat - 13. Jaffe HL, Lichtenstein L, Sturo CJ. Pigmented villonodular synovitis, bursi- ment concepts and future perspectives. Eur J Cancer. 2016;63:34–40. tis and tenosynovitis. Arch Pathol. 1941;21:731–65. 9. Brahmi M, Vinceneux A, Cassier PA. Current systemic treatment options 14. Rao AS, Vigorita VJ. Pigmented villonodular synovitis (giant-cell tumor for tenosynovial giant cell tumor/pigmented villonodular synovitis: of the tendon sheath and synovial membrane). A review of eighty-one targeting the CSF1/CSF1R Axis. Curr Treat Options Oncol. 2016;17:10. cases. J Bone Joint Surg Am. 1984;66:76–94. 10. Gelderblom H, et al. Nilotinib in locally advanced pigmented villonodu- 15. Cupp JS, et al. Translocation and expression of CSF1 in pigmented villo- lar synovitis: a multicentre, open-label, single-arm, phase 2 trial. Lancet nodular synovitis, tenosynovial giant cell tumor, rheumatoid arthritis and Oncol. 2018;19:639–48. other reactive synovitides. Am J Surg Pathol. 2007;31:970–6. 11. Cassier PA, et al. CSF1R inhibition with emactuzumab in locally advanced 16. Tap WD, et al. Structure-guided blockade of CSF1R kinase in tenosynovial diffuse-type tenosynovial giant cell tumours of the soft tissue: a giant-cell tumor. N Engl J Med. 2015;373:428–37. dose-escalation and dose-expansion phase 1 study. Lancet Oncol. 17. Gelhorn HL, et al. Patient-reported symptoms of tenosynovial giant cell 2015;16(8):949–56. tumors. Clin Ther. 2016;38:778–93. 12. Cannarile MA, et al. Colony-stimulating factor 1 receptor (CSF1R) inhibi- tors in cancer therapy. J Immunother Cancer. 2017;5:53. Ready to submit your research ? 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Tenosynovial giant cell tumor: case report of a patient effectively treated with pexidartinib (PLX3397) and review of the literature

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Abstract

Background: Tenosynovial giant cell tumors ( TGCTs) or giant cell tumors of tendon sheath are neoplasms that arise in the synovium. They can be categorized as nodular (localized) or diffuse type (D-TGCT ). Historically, surgery has been the mainstay of therapy, but diffuse type disease recurs at a high rate and treatment often requires increasingly mor - bid procedures. Elucidation of the importance of the colony-stimulating factor (CSF1)/CSF1 receptor (CSF1R) pathway in the pathogenesis of this disease has created significant interest in targeting this pathway as a novel TGCT treatment approach. Pexidartinib, a selective tyrosine kinase inhibitor against CSF1R, showed an 83% disease control rate (52% with partial response and 31% with stable disease) in a recent phase 1 study of patients with TGCT. Case presentation: We present an illustrative example of a TGCT patient who would have required a morbid opera- tion who derived considerable clinical benefit from pexidartinib treatment. Her tumor volume decreased by 48% after 4 months of treatment, and 55 months after starting treatment the patient exhibits continued disease stability with minimal clinical symptoms, and significant improvement in functional status. Conclusions: This case illustrates the effectiveness of systemic therapy in controlling a disease associated with high surgical morbidity. This approach may be especially useful in the treatment of extra-articular disease which often invades neurovascular bundles; as the effectiveness in metastatic disease is still unknown. In the future, systemic treatment for TGCT may be appropriate for the neoadjuvant setting to decrease disease burden prior to surgery with the aim of decreasing recurrence rates. However, properly designed prospective studies will need to be carried out to answer these questions. Keywords: Tenosynovial giant cell tumor, TGCT , Giant cell tumor of tendon sheath, GCT-TS, Pigmented villonodular synovitis, PVNS, Pexidartinib, PLX3397, Case report, CSF1 Background biological features of these neoplasms affect treatment Tenosynovial giant cell tumor (TGCT), is a neoplasm [1]. derived from the synovium that causes recruitment of Localized TGCT is characterized by a discrete nodule, immune cells, specifically macrophages, leading to for - with a predilection for the radial three digits [2]. Diffuse mation of a mass. These tumors are often classified TGCT (D-TGCT), formerly known as pigmented villo- by their growth pattern (localized or diffuse) and site nodular synovitis (PVNS), is characterized by a diffuse (intra- or extra-articular). These pathological distinc - proliferation in the synovium most commonly occurring tions are important because variability in the clinical and in and around the knee (~ 75% of tumors) [3]. While local and diffuse disease occur intra-articularly throughout the body, D-TGCT can also be extra-articular, and, in rare *Correspondence: asingh@mednet.ucla.edu circumstances, can metastasize to adjacent lymph nodes Division of Hematology and Oncology, University of California Los and the lungs. Angeles (UCLA), 2825 Santa Monica Blvd. Suite 200, Santa Monica, CA 90404, USA Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Giustini et al. Clin Sarcoma Res (2018) 8:14 Page 2 of 5 Both localized and diffuse TGCT occur primarily in can be used to effectively reduce the disease burden in a the 3rd–4th decades of life with a female:male predomi- patient with D-TGCT [12]. nance of 1.6–2.1:1 in the localized type and no sex pre- dilection in the diffuse type. The annual incidence in the Case presentation United States is approximately 11 per million; of that, 9.2 RM is a 47-year-old woman who initially presented when being localized and 1.8 diffuse types. In a more recent she was 40 years old with 3 months of right knee pain in epidemiological study from the Netherlands, the world- December 2010. At that time, a radiograph of the knee wide incidence rate of TGCT (including both localized showed two lesions: a 3-cm circumscribed lytic lesion and diffuse) was estimated to be 43 per million [4]. of the posterolateral distal femur thought possibly to be Clinical presentation of TGCT is variable. The first sign a nonossifying fibroma, as well as a 2-cm circumscribed for patients with pathology in the hand is often a pain- lytic lesion with sclerotic margins involving the proximal less, slow-growing, firm nontender mass, which may tibial epiphysis. An MRI 1  month later showed lesions eventually become painful and edematous as it impinges suspicious for TGCT; an orthopedic oncologist recom- on anatomic structures [2]. When presenting in the knee, mended a diagnostic arthroscopy with possible conver- intermittent swelling without antecedent trauma is a sion to open anterior and posterior synovectomy. The common symptom [5]. patient declined and underwent a trial of oral prednisone In 2006, the landmark article by West et  al. shed light with some symptomatic relief until October 2012 when on the pathogenesis of TGCT. Chromosomes 1 and 2 she re-presented with worsening pain, edema, and a limp. undergo a translocation at 1p13, which fuses to 2q35, At that time, she underwent biopsy, which was read as a leading to the fusion of CSF1 to COL6A3 and the over- likely inflammatory process. One week later the patient production of CSF1. However, in collected samples, ele- underwent an incisional biopsy. vated CSF1 expression was found in only 2–16% of the Histology of the neoplasm showed a hypercellular cells comprising the tumor. This may be in keeping with lesion consistent with D-TGCT. Immunohistochemistry the fact that only a small fraction of the TGCT mass is revealed negative pankeratins, negative desmin, negative considered the malignant clone. As CSF1R is present on CD1a, positive CD68 in a patchy distribution, and a Ki-67 immune cells, specifically macrophages, it has been pos - of 10%. A repeat MRI at the time of diagnosis showed tulated that overexpression of CSF1 from the malignant a marked increase in the size of the synovial soft mass component of the tumor causes a tremendous immune extending into the suprapatellar compartment, as well as infiltrate, which comprises the bulk of the tumor [6, 7]. anterior and posterior infrapatellar compartments. The Historically, TGCT has been treated using surgery with suprapatellar aspect measured 20  cm × 9.9  cm × 13  cm the consideration for adjuvant radiation. Surgical options (CC × AP × TV). A PET-CT scan indicated no metastatic for TGCT are partial or total synovectomy using arthro- disease and an SUV of 21.7 in the lesions (Fig. 1). Con- max scopic or open techniques. While localized disease is sidering the extent of disease, nonsurgical management readily curable with arthroscopic or open surgery, diffuse was indicated as surgical resection would likely result in disease has shown high recurrence rates with arthros- significant morbidity. In February 2013, 1 week after the copy (40%) and open surgery (14%). Open surgery also PET-CT, the patient consented to oral therapy with pex- leads to increased morbidity in the form of stiffness and idartinib (PLX3397) at 600 mg qAM and 400 mg qHS for pain [8]. a cumulative 1000-mg daily dose. At this time, the patient Newer systemic treatments are being used for TGCT had an ECOG of 1, was on disability and could no longer ranging from less selective tyrosine kinase inhibitors, work as a nurse given her requirement for a walker, and such as imatinib and nilotinib, to CSF1R inhibitors such was managing her pain with naproxen, morphine, and as emactuzumab and cabiralizumab (monoclonal anti- acetaminophen–hydrocodone. body) and pexidartinib (a selective tyrosine kinase inhibi- At the 2-week follow-up, the patient reported an tor) with encouraging results [9]. In the only published improvement of pain and an increased range of motion. phase 2 study of a drug for TGCT, nilotinib led to a dis- Three weeks after initiation, a repeat PET-CT showed ease stabilization rate in 90% of patients at 6  months, disease response with an SUV of 6.3. By 1 month after max but only 6% of patients had a RECIST 1.1 objective initiation, the patient reported she was transitioning to response [10]. In a phase 1 study of emactuzumab, partial crutches and using fewer opioids. By the 4-month MRI, responses were seen in 24/28 patients and 2 patients had there was a reduction in her tumor burden by 48% via complete responses [11]. In particular, the CSF1R inhibi- RECIST 1.1 (14.3 × 7.0 × 12.6  cm to 8.1 × 1.7 × 6.0  cm, tors are being evaluated in patients with cases with high 5.6 × 2.9 × 8.3  cm to 1.8 × 1.5 × 3.5  cm, and operative morbidity. The case presented exemplifies the 9.0 × 2.4 × 9.1  cm to 5.0 × 0.8 × 3.5  cm CC × AP × T V ). situation in which CSF1R inhibitors, namely pexidartinib, At this time, her ECOG was changed to 0 as she was Giustini et al. Clin Sarcoma Res (2018) 8:14 Page 3 of 5 Discussion In 1941, Jaffe et  al. [13] initially created the category of pigmented villonodular synovitis, bursitis, and teno- synovitis, forming a classification for a seemingly diffuse group of entities. Much later, Rao and Vigorita [14] sug- gested that PVNS is a true neoplastic, rather than inflam - matory, process involving fibroblastic or histiocytic mesenchymal cells. Subsequent research identified chro - mosome translocations present in TGCT cases which induce overexpression of CSF-1 in neoplastic synovial cells, in turn causing recruitment of macrophages and other immune cells form the bulk of the tumor mass [6]. Some TGCT cases do not appear to harbor such trans- locations, though notably they still show elevated lev- els CSF1 protein or RNA, suggesting there are alternate mechanisms of CSF1 overproduction [15]. Pexidartinib, or PLX3397, is a selective CSF1R inhibi- tor which targets the CSF1/CSF1R pathway implicated in TGCT pathogenesis. Pexidartinib was designed to simu- late the autoinhibited state of the CSF1R by interacting with the CSF1R juxtamembrane region which is respon- sible for folding and inactivation of the kinase domain and prevents binding of CSF1 and ATP [16]. Based on an initial phase I dose escalation study evaluating the safety and tolerability of pexidartinib in patients with solid tumors, the maximum tolerated dose of 1000  mg/day was chosen for an extension study to evaluate efficacy in TGCT. This multicenter, single cohort extension study enrolled 23 patients with advanced TGCT. Eligibility requirements included a histologically confirmed diagnosis of TGCT that had shown progres - sion within the previous year and was deemed surgi- cally challenging (recurrent vs. inoperable vs. requiring extensive surgery for attempted resection). The mean age of patients was 46  years old with 18 patients having Fig. 1 MRI scan of suprapatellar aspect in January 2013 (a) and May undergone previous surgery, four patients having pre- 2017 (b) viously been treated with either imatinib or nilotinib, and one patient with metastatic disease. Mean duration of treatment was 254  days with 61% of patients requir- ambulating without assistance and returned to work; ing dose reduction and 30% requiring a temporary drug she had also reduced her pain medications to occasional withdrawal, most commonly for fatigue. A common labo- naproxen and had weaned herself off opioids. During the ratory abnormality was elevated aminotransferase levels course of treatment, the dose was adjusted to 400  mg in approximately 50% of patients (only 13% were grade qAM and qHS for 2  months and then to 400  mg qAM 3 and all resolved to grade 1 with temporary drug cessa- and 600  mg qHS, in an effort to manage nausea. Other tion), thought secondary to CSF1 inhibition on Kupffer side effects included fatigue, dysgeusia, and peri-orbital cell functioning [16]. edema. After 55  months of therapy, the patient had sta- In an intention-to-treat analysis of response using ble disease following the initial response with no pro- RECIST 1.1, a total of 83% of patients exhibited disease gression at any time during the treatment course. The control with 52% showing partial response and 31% most recent MRI imaging on 9/8/2017 showed only two showing stable disease. Due to the complex shape of aspects of the lesion, measuring 0.4 × 4.9  cm (AP × T V many TGCTs, conventional tumor response assessment with inability to visualize CC view) and 1.2 × 1.5 × 2.9 cm methodologies are not ideal for discerning response (CC × AP × T V ). in this disease. Tumor volume score, an unvalidated Giustini et al. Clin Sarcoma Res (2018) 8:14 Page 4 of 5 Abbreviations calculation of the tumor volume as a percentage of the TGCT : tenosynovial giant cell tumor; D-TGCT : diffuse tenosynovial giant cell total synovium, similar to a scoring system in use for tumor; CSF1: colony-stimulating factor-1; CSF1R: colony-stimulating factor-1 rheumatoid arthritis, was used to evaluate 14 patients. receptor; PVNS: pigmented villonodular synovitis; qAM: each morning; qHS: each evening. Of these, 11 had a partial response and three had stable disease with a mean decrease in volume of 61%. Com- Authors’ contributions parison of pre- and post-treatment biopsies obtained AS, NG, and NB were major contributors in writing the manuscript. All authors contributed to data collection and interpretation. All authors read and from one patient showed marked decreases in mac- approved the final manuscript. rophages and general cellularity in the tissues. The patient with metastatic disease was the only patient Author details Division of Hematology and Oncology, University of California Los Angeles who showed disease progression using RECIST 1.1, (UCLA), 2825 Santa Monica Blvd. Suite 200, Santa Monica, CA 90404, USA. which occurred after 8  months of stable disease on Division of Orthopedic Oncology, University of California Los Angeles (UCLA), therapy [16]. 1250 16th Street, Suite 2100, Santa Monica, CA 90404, USA. Our patient, RM, who presented with extensive local Acknowledgements disease of the knee, was deemed to not be a candidate The authors would like to thank all the patients with TGCT who have given us for surgery, with or without adjuvant radiation, because an immense education about this disease. it would likely lead to significant unacceptable morbid - Competing interests ity due to the extent of disease, her young age, and her Arun Singh: Advisory board participation: Eli Lilly, Eisai, Roche. Speaker’s profession. Given these factors, as well as the promis- bureau participation: Eli Lilly, Novartis. Nick Giustini, Susan Bukata: None. Nick Bernthal: Consultant: Onkos/Zimmer Biomet. ing results in the study evaluating pexidartinib as treat- ment for TGCT, she was enrolled to start therapy with Availability of data and materials pexidartinib. Not applicable. Consent for publication Written informed consent was obtained from the patient for publication of Conclusions this Case Report and the clinical images. Tenosynovial giant cell tumor is a tumor driven by CSF1 Ethics approval and consent to participate overexpression in neoplastic synovial cells. Before uncov- The study was approved by the ethics committee/institutional review board ering the pathogenesis of this disease, treatment was of the University of California—Los Angeles. primarily surgical. Now systemic therapies, such as the Funding tyrosine kinase inhibitor pexidartinib and the monoclo- Daiichi Sanyo provided funding for editorial support and publication costs. nal antibody emactuzumab, are able to take advantage of the known molecular mechanism of TGCT pathogen- Publisher’s Note esis by targeting the CSF1R. Several other CSF1R inhibi- Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. tors are being evaluated clinically and a comprehensive review of this class of drugs can be found elsewhere [9]. Received: 6 March 2018 Accepted: 19 May 2018 As evidenced in our case report and in a clinical study, pexidartinib has the potential to decrease or stabilize the size of TGCT masses, reduce pain and improve mobility [16, 17]. Bibliography As the use of systemic therapies such as pexidartinib 1. de Saint Aubain Somerhausen NS, van de Rijn M. Tenosynovial giant cell tumor: localized type, diffuse type. In: Fletcher C, Bridge J, Hogendoorn P, become more established as treatments for TGCT, future Martens F, editors. World Health Organization classification of tumours of avenues of study abound. To date, complete response soft tissue and bone. Lyon: IARC Press; 2013. p. 100–3. with pexidartinib has not been established as the neo- 2. Monaghan H, Salter DM, Al-Nafussi A. Giant cell tumour of tendon sheath (localised nodular tenosynovitis): clinicopathological features of 71 cases. plastic cells are only suppressed, not removed. It has been J Clin Pathol. 2001;54:404–7. noted that TGCT patients coming off of pexidartinib do 3. Ottaviani S, et al. Pigmented villonodular synovitis: a retrospective single- show disease relapse (author’s unpublished observation). center study of 122 cases and review of the literature. Semin Arthritis Rheum. 2011;40:539–46. As such, consideration for neoadjuvant pexidartinib 4. Mastboom MJL, et al. Higher incidence rates than previously known in to allow less morbid surgical resection may be a viable tenosynovial giant cell tumors. Acta Orthop. 2017;88:688–94. option. In addition, post-surgical pexidartinib in these 5. Ravi V, Wang WL, Lewis VO. Treatment of tenosynovial giant cell tumor and pigmented villonodular synovitis. Curr Opin Oncol. 2011;23:361–6. cases or in patients with known previous recurrence 6. West RB, et al. A landscape effect in tenosynovial giant-cell tumor from may be effective in delaying repeat recurrence. However, activation of CSF1 expression by a translocation in a minority of tumor answers to these questions will require further validation cells. Proc Natl Acad Sci USA. 2006;103:690–5. 7. Nilsson M, et al. Molecular cytogenetic mapping of recurrent chromo- studies of this effective targeted therapy. somal breakpoints in tenosynovial giant cell tumors. Virchows Arch. 2002;441:475–80. Giustini et al. Clin Sarcoma Res (2018) 8:14 Page 5 of 5 8. 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Lancet nodular synovitis, tenosynovial giant cell tumor, rheumatoid arthritis and Oncol. 2018;19:639–48. other reactive synovitides. Am J Surg Pathol. 2007;31:970–6. 11. Cassier PA, et al. CSF1R inhibition with emactuzumab in locally advanced 16. Tap WD, et al. Structure-guided blockade of CSF1R kinase in tenosynovial diffuse-type tenosynovial giant cell tumours of the soft tissue: a giant-cell tumor. N Engl J Med. 2015;373:428–37. dose-escalation and dose-expansion phase 1 study. Lancet Oncol. 17. Gelhorn HL, et al. Patient-reported symptoms of tenosynovial giant cell 2015;16(8):949–56. tumors. Clin Ther. 2016;38:778–93. 12. Cannarile MA, et al. Colony-stimulating factor 1 receptor (CSF1R) inhibi- tors in cancer therapy. J Immunother Cancer. 2017;5:53. Ready to submit your research ? 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Journal

Clinical Sarcoma ResearchSpringer Journals

Published: Dec 1, 2018

Keywords: cancer research; oncology; surgical oncology

References